(Alan R. Katritzky, Otto Meth-Cohn, and Charles W.

Comprehensive Organic Functional
Group Transformations
Volume 1
Synthesis: Carbon with No Attached Heteroatoms
Part I: Tetracoordinated Carbon with No Attached Heteroatoms

1.01 One or More CH Bond(s) Formed by Substitution: Reduction of C---Halogen
and C---Chalcogen Bonds, Pages 1-26, Alan G. Sutherland
1.02 One or More CH Bond(s) Formed by Substitution: Reduction of Carbon–
Nitrogen, –Phosphorus, –Arsenic, –Antimony, –Bismuth, –Carbon, –Silicon, –
Germanium, –Boron, and –Metal Bonds, Pages 27-70, Joshua Howarth
1.03 Two or More CH Bond(s) Formed by Addition to CC Multiple Bonds, Pages
71-103, Keith Jones
1.04 One or More CC Bond(s) Formed by Substitution: Substitution of Halogen,
Pages 105-169, Gavin L. Edwards
1.05 One or More CC Bond(s) Formed by Substitution: Substitution of Chalcogen,
Pages 171-247, Timothy N. Birkinshaw
1.06 One or More CC Bond(s) Formed by Substitution: Substitution of Carbon–
Nitrogen, –Phosphorus, –Arsenic, –Antimony, –Boron, –Silicon, –Germanium
and –Metal Functions, Pages 249-292, Philip C. Bulman Page, Heather L.
McFarland and Andrea P. Millar
1.08 One or More CC Bond(s) Formed by Addition: Addition of Carbon Radicals and
Electrocyclic Additions to CC Multiple Bonds, Pages 319-375, Andrew J. Clark
and Paul C. Taylor
1.09 One or More CH and/or CC Bond(s) Formed by Rearrangement, Pages 377-423,
Iain Coldham
Part II: Tricoordinated Carbon with No Attached Heteroatoms
1.10 One or More =CH Bond(s) Formed by Substitution or Addition, Pages 425-460,
Martin A. Hayes
1.11 One or More =CC Bond(s) Formed by Substitution or Addition, Pages 461-500,
Patrick G. Steel by kmno4
1.12 One or More C=C Bond(s) Formed by Addition, Pages 501-551, Andrew C. Regan
1.13 One or More C=C Bond(s) by Elimination of Hydrogen, Carbon, Halogen or

Oxygen Functions, Pages 553-587, Jonathan M. Percy
1.14 One or More C=C Bond(s) by Elimination of S, Se, Te, N, P, As, Sb, Bi, Si, Ge, B
or Metal Functions, Pages 589-671, Anita R. Maguire
1.15 One or More C=C Bond(s) Formed by Condensation: Condensation of
Nonheteroatom Linked Functions, Halides, Chalcogen or Nitrogen Functions,
Pages 673-717, Christopher M. Rayner
1.16 One or More C=C Bond(s) Formed by Condensation: Condensation of P, As, Sb,
Bi, Si or Metal Functions, Pages 719-770, Ian Gosney and Douglas Lloyd
1.17 One or More C=C Bond(s) by Pericyclic Processes, Pages 771-791, Hamish
McNab
1.18 One or More =CH, =CC, and/or C=C Bonds Formed by Rearrangement, Pages
793-842, Patrick J. Murphy
1.19 Tricoordinate Anions, Cations, and Radicals, Pages 843-951, Julian O. Williams
and Michael J. Kelly
Part III: Dicoordinate and Monocoordinate Carbon with No Attached

Heteroatoms
1.20 Allenes and Cumulenes, Pages 953-995, Christian Bruneau and Pierre H. Dixneuf
1.21 Alkynes, Pages 997-1085, Mark Furber
1.22 Ions, Radicals, Carbenes and Other Monocoordinated Systems, Pages 1087-
1145, Julia M. Dickinson
1.23 References to Volume 1, Pages 1147-1316
by kmno4
Comprehensive
Organic
Functional Group
Transformations
Editors-in-Chief
Alan R. Katritzky, FRS
University of Florida, Gainesville, FL, USA
Otto Meth-Cohn
University of Sunderland, UK
Charles W. Rees, FRS
Imperial College of Science, Technology and Medicine, London, UK
Volume Editors
Volume 1. Synthesis: Carbon with No Attached Heteroatoms

Stanley M. Roberts, University of Exeter, UK
Volume 2. Synthesis: Carbon with One Heteroatom Attached by a Single Bond

Steven V. Ley, FRS, University of Cambridge, UK
Volume 3. Synthesis: Carbon with One Heteroatom Attached by a Multiple Bond

Gerald Pattenden, FRS, The University of Nottingham, UK
Volume 4. Synthesis: Carbon with Two Heteroatoms, Each Attached by a Single Bond
Gordon W. Kirby, University of Glasgow, UK
Volume 5. Synthesis: Carbon with Two Attached Heteroatoms with at Least One
Carbon-to-Heteroatom Multiple Link
Christopher J. Moody, Loughborough University of Technology, UK
Volume 6. Synthesis: Carbon with Three or Four Attached Heteroatoms

Thomas L. Gilchrist, University of Liverpool, UK
Preface
Some years ago the three of us met in a London club reviewing an ongoing publishing venture in
Organic Synthesis. The conversation drifted to a consideration of volumes on the synthesis of key
functional groups. No doubt the good wine helped since we actually broached the idea of a work
on the synthesis of all functional groups. Would it be useful? Definitely. Would it be feasible? How
would it be organized? Where do you start? We recognized that functionality was based on the
coordination and heteroatom attachment of a carbon atom. But putting together a complete
framework seemed particularly daunting. Two of us became very interested in the fascinating
bouquet of the Muscat de Beaumes de Venise.
At our next dinner together Alan announced that he had solved the problems posed last time—
problems that Charles and I hoped he had forgotten! He brought out a remarkable matrix analysis
of all functional groups, analysed rigorously and logically. Even unknown functions were covered.
Although we were all very impressed, the practicalities of the idea still seemed daunting. Those who
know Alan's terrier instincts will appreciate that he would not give up such a challenge so easily.
Our twice yearly club get-togethers, occasionally with friends from Pergamon, refined our thinking.
Alan's cosmic vision was tempered by Charles's intuitive realism and fully supported by the
publishers.
Another major problem remained: how to reduce our thinking into a practical handbook for
authors—a dismaying task for three busy chemists. We settled on a seven-volume work and the
indomitable ARK produced a rough breakdown to fit such a format. Putting flesh on these bones
became feasible during a fortuitous three-month break between jobs by myself, and the largest
handbook ever assembled by Pergamon (120 pages) was written and page allocations agreed—even
for little or unknown functional groups. Sample chapters were commissioned and finally proved
very encouraging, despite our first chosen topic uncovering virtually no known examples!
Contracts were defined and agreed, volume editors approached, and potential authors considered
during a pleasant preconference stay in Grasmere. Following the sale of Pergamon to Elsevier
Science Ltd there was a lull in the project but soon Comprehensive Organic Functional Group
Transformations was back on track, and everyone adhered to a very businesslike timetable.
OTTO METH-COHN CHARLES W. REES

Sunderland London
ALAN R. KATRITZKY
Florida
Introduction
OBJECTIVES, SCOPE, AND COVERAGE
Comprehensive Organic Functional Group Transformations (COFGT) aims to present the vast
subject of organic synthesis in terms of the introduction and interconversion of functional groups.
All organic structures can be considered as skeletal frameworks of carbon atoms to which functional
groups are attached3; it is the latter which are mainly responsible for chemical reactivity and which
are highlighted in COFGT. All known functional groups fit a logical and comprehensive pattern
and this forms the basis for the detailed list of contents. The format of the present work was designed
with the intention to cover systematically all the possible arrangements of atoms around a carbon,
including those which are quite unfamiliar. The work also considers the possibility of as yet unknown
functional groups which may be constructed in the future and prove to be important; thus COFGT
also indicates what is not known and so points the way to new research areas.
The philosophy of the present work has been to rationalize this enormous subject within as logical
and formal a framework as possible, in a scholarly and critical fashion. COFGT is designed to
provide the first point of entry to the literature for synthetic organic chemists, together with an
unrivalled source for anyone interested in less common, obscure, or unknown functional groups.
All functional groups are viewed as being carbon based (even if the group contains no carbon).
Thus, a nitro compound is considered from the standpoint of the immediately attached carbon
atom, whether di- (sp), tri- (sp2), or tetracoordinated(.s/?3). The work is organized on the basis of
formation or rupture of bonds to a carbon atom and it is the nature of the carbon atom left after
the transformation that determines the classification of the overall sequence. Several key criteria
have been used to organize the work and to minimize overlap. These are, in order of priority:
1. the number of attached heteroatoms;
2. the coordination of the carbon atom involved in the functional group;
3. the nature of the immediately attached heteroatom(s); and
4. the Latest Placement Principle.
These four key principles have been used to determine the content of each volume, and to develop
the detailed chapter breakdown within each volume.
Thus, according to the number of attached heteroatoms:
Volume 1 deals with synthetic reactions which result in the alteration of bonding at carbon atoms
which are left with no attached heteroatoms.
Volume 2 deals with syntheses which result in carbon atoms attached to one heteroatom by a
single bond.
Volume 3 deals with syntheses which result in carbon atoms attached to one heteroatom by a
double or by a triple bond.
Volume 4 deals with syntheses which result in carbon atoms attached to two heteroatoms, each
by a single bond.
Volume 5 deals with syntheses which result in carbon atoms attached to two heteroatoms by one
single and one double bond, or by two double bonds, or by one single and one triple bond.
Volume 6 deals with syntheses which result in carbon atoms attached to three or four heteroatoms.
Volume 7 comprises the author and subject indexes.
Certain key principles apply to all the volumes because all functional groups are viewed as carbon
based (e.g. a nitro group is either alkyl-, vinyl-, aryl-, or alkynyl-); these are:
(a) Volumes are subdivided according to the coordination of the carbon atom which is the product
of the reaction, i.e., tetra- coming before tri- before di- before monocoordinated carbon functions.
"The major exception to this lies in heterocyclic compounds, where the cyclic heteroatoms are more logically considered
as part of the framework. The subject of heterocycles has been treated elsewhere in the companion work Comprehensive
Heterocyclic Chemistry published in 1984 with a second edition to be published in 1996.
Introduction
In Volumes 1 and 6, reactions producing four-coordinated carbon are considered first, followed by
three- and then two-coordinated carbon. The other volumes contain a more limited range of
coordination types (Volumes 2 and 4 only four-coordinated, Volumes 3 and 5 only two- or three-
coordinated). Each type of coordination is allocated a separate section in each volume.
(b) Attached heteroatoms are discussed in the following order of priority:
Halogens—F, Cl, Br, I
Chalcogens—O, S, Se, Te
Nitrogen—N
Other group 15 elements—P, As, Sb, Bi
Metalloids—B, Si, Ge
Main group metals—Sn, Pb, Al, Ga, In, Tl, Be, Mg, Ca, Sr, Ba, Li, Na, K, Rb, Cs
Transition metals—Cu, Ag, Au, Zn, Cd, Hg, Ti, Zr, Hf, Cr, Mo, W, Mn, Fe, Co, Ni, Pd,
Pt, and others.
Higher coordination of heteroatoms is treated after lower. Thus, in sections dealing with iodo
compounds, monocoordinate (e.g. iodides) are discussed before dicoordinate (e.g. iodoxyls) and
tricoordinate functions.
(c) The Latest Placement Principle (or Last Position Principle) is used to avoid undue overlap in
the work. Thus, the carbon attached to the heteroatom is discussed at the last possible position in
the above prioritizing of heteroatoms. Examples of its application are noted later. On this basis, for
example, when both C—C and C—H bonds are formed the reaction will appear in the latest chapter
(i.e. Chapters 1.04—1.10 rather than in the earlier Chapters 1.01-1.03), and when both C—C and
C = C bonds are formed, this will be found in the later Chapter 1.17. The Latest Placement Principle
is particularly important in determining where to find electrocyclic reactions in Volume 1. If C—H,
= C — C , and C = C bonds are all formed in a reaction, then the latest appropriate chapter will deal
with the reaction. Only if a change in heterofunction occurs is the reaction left to a later volume.
Exceptions to the above principles are rare. However the reactions of heteroarenes are mentioned
along with those of arenes. If on reduction no change in the heterofunction occurs (e.g. in going
from thiophene to tetrahydrothiophene or from pyridine to 2,3,4,5-tetrahydropyridine) the reaction
is found in Volume 1. However, when the function changes (e.g. pyridine to piperidine), the
conversion is considered in Volume 2. Conversion of methyl phenyl sulfone into methyl cyclohexyl
sulfone appears in Volume 2, whereas the formation of cyclohexyl methyl ketone is treated in
Volume 1, since the coordination of the carbon atom to the heteroatoms is changed in the first but
not in the second hydrogenation.
Some further exceptions to the rigorous ordering of the work have been made for the purpose of
easy reference. Thus, in Volume 1, a special chapter on ions, radicals, and carbenes is added: this
chapter is limited to the treatment of species capable of more than a transitory existence. Throughout
the work aspects of the Latest Placement Principle are occasionally ignored for reasons of clarity.
Thus metal ligands that are incidental to the chemistry under discussion are not considered when
prioritizing. Also, references to aromatic substituents, some of which involve a heteroatom (e.g.
pyridyl, thienyl, etc.) but are incidental to the chemistry being described, are not viewed as changing
the priority.
Within each section, we have endeavored to explain the influence of important secondary effects
such as inclusion in a ring, degree of strain, degree of substitution, various types of activation,
influence of stereochemistry, and so on, on the transformation under consideration. General syn-
thetic methods are treated before specific methods.
Transient intermediates, as such, do not fall within the scope of this work. Although there is
clearly no sharp division, we have attempted to restrict coverage of radicals, etc., to more stable,
longer lived species. It is the aim of this work to consider all organic functional groups provided
that the molecules which incorporate them, though they may be unstable, can have a finite lifetime
and chemistry. The whole work deals with the generation and transformation of functional groups,
not of molecules such as CO 2 , COS, CS 2 , CICN, etc. Such simple carbon derivatives are not treated
unless a further carbon is attached (e.g. R N = C = O ) .
VOLUME 1 SYNTHESIS: CARBON WITH NO ATTACHED HETEROATOMS

Volume 1 deals solely with the formation of nonheteroatom functional groups and as such is
different in style to the remaining volumes.
Introduction
In addition to the general principles, Volume 1 is further organized as follows:
1. By the type of bond formed (i.e. C—H before C—C).
2. By the type of reaction involved (i.e. substitution, then addition, then rearrangement). With
C = C bond formation the order is addition, elimination, condensation, then electrocyclic and other
methods. One rearrangement chapter only is devoted to each of the Parts I and II.
3. In Parts II and III the treatment of formation of ions, radicals, and carbenes is added at the
end of the section dealing solely with those species with a significant rather than a transient lifetime.
In Volume 1, the heteroatom sequence is a secondary feature since only remote heteroatom
functions are involved in the products: but the standard order pertains in reactants that contain
heteroatoms (see, e.g. Chapters 1.01 and 1.02).
All the major structural influences that are treated throughout this work apply equally (or
perhaps more importantly) in Volume 1. Thus the effects of conjugation, remote substituents, rings,
stereochemistry, strain, kinetic or thermodynamic factors, solvation, primary, secondary and tertiary
nature, etc., are mentioned whenever relevant.
VOLUME 2 SYNTHESIS: CARBON WITH ONE HETEROATOM ATTACHED BY A

SINGLE BOND
Volume 2 is arranged in three parts: I, II and III, dealing respectively with sp3, sp2, and sp carbon
linked to the heteroatom. In each chapter we have endeavored to explain important effects due to
such features as the primary, secondary, tertiary nature, ring effects, strain activation, effect of beta,
gamma, and more remote functionality, stereochemical effects, and so on. Methods that are common
to a larger group are dealt with at their first appearance and suitably cross-referenced.
Volumes 2-6 all deal with the synthesis of functions involving at least one heteroatom. To avoid
major overlap we have applied the Latest Placement Principle; that is, the chemistry is discussed at
the last possible position based on the prioritization of the carbon attached to the heteroatom. Thus
the compound CH 3 ONH 2 is treated under "Alkyl Chalcogenides" in the subsection "Functions
Based on the RON-Unit" (i.e. 2.02.6). However, CH 3 ONHCH 3 appears under "Alkyl Nitrogen
Compounds" (2.06.2.3) since the Latest Placement Principle prevails. Also, dialkyl ethers appear in
Part I of Volume 2 (Functions Linked by a Single Bond to an sp2" Carbon Atom), while alkyl aryl
ethers appear in Part II of Volume 2 (Functions Linked by a Single Bond to an sp2 Carbon Atom).
Exceptions to the rule are:
(a) When a fully unsaturated heterocyclic substituent (e.g. thienyl, pyridyl, etc.) is used as an
example Of an aryl group, the ring heteroatom(s) is (are) not taken into account (e.g. 2-methoxy-
pyridine should strictly appear in Volume 6, but is covered in Volume 2 along with 3- and
4-methoxypyridine).
(b) Carbon-based metal ligands that are incidental to the synthesis under discussion (e.g.
carbonyls, cyclopentadienyls, etc.) are not taken into consideration.
VOLUME 3 SYNTHESIS: CARBON WITH ONE HETEROATOM ATTACHED BY A

MULTIPLE BOND
Volume 3 follows the logical development indicated in Volume 2. Thus, according to the Last
Placement Principle, the imines, RCH=N—R, appear in Volume 3 rather than in Volume 2 (where
functions singly bonded to carbon are treated). Furthermore, acetophenone, PhCOCH 3 , is treated
under cc,/J-unsaturated ketones (3.05) rather than saturated ketones (3.04). Chloronitroacrylonitriles
would appear under the section "a,/?-Vinylic Nitriles with Nitrogen-based Substituents" (3.19.2.7),
not under the related earlier section dealing with halo-substituents (3.19.2.3).
VOLUME 4 SYNTHESIS: CARBON WITH TWO HETEROATOMS, EACH ATTACHED

BY A SINGLE BOND
Volume 4 is in three parts. Part I deals with tetracoordinated carbon bearing two heteroatoms,
Part II with tricoordinated carbon bearing two heteroatoms, and Part III (a brief chapter) with
stabilized radicals, ions, and the like bearing two heteroatoms. The material is arranged according
Introduction
to the Latest Placement Principle: thus, the synthesis of CHBr 2 CHI 2 would appear in the section
dealing with diiodo, not dibromo functions (i.e. in 4.01.5, not 4.01.4), and the synthesis of CF 3 CH-
BrCl is discussed in Volume 6 (carbons bearing three heteroatoms), rather than in Volume 4.
VOLUME 5 SYNTHESIS: CARBON WITH TWO ATTACHED HETEROATOMS WITH AT

LEAST ONE CARBON-TO-HETEROATOM MULTIPLE BOND
Volume 5 is in three parts. Part I deals with functions with one doubly bonded and one singly
bonded heteroatom, Part II with functions containing two doubly bonded heteroatoms and Part
III with one triply bonded and one singly bonded heteroatom. Part I constitutes the bulk of Volume 5.
The arrangement of the chemistry in each part follows the same logical sequence. The multiply
bonded heteroatom is focused on first and then the other heteroatom in a secondary classification,
both following the priority rules already described. Each section excludes the coverage of the
previous sections. Thus, all carbonyl derivatives will appear in Chapters 5.01-5.10 but not in
Chapters 5.11, et seq.
According to the Latest Placement Principle structure RC(O)OC(S)R is discussed in the chapter
dealing with carbons bearing a doubly bonded sulfur and singly bonded oxygen (5.12.3), not in that
dealing with doubly and singly bonded oxygen (5.04.1). Another effect of the Latest Placement
Principle is that the amides RCONMePh are discussed under Af-arylalkanoamides (5.06.2.4), rather
than 7V-alkylalkanoamides (5.06.2.2). Again, exceptions are made to the latest placement rules for:
(a) hetaryl rings used as examples of aryl substituents which are not viewed as functional groups.
Thus, 2-methylimidazole is not considered as an example of an amidine function and 2-methoxy-
pyridine is not an example of a doubly bonded nitrogen, singly bonded oxygen function; (b) metal
ligands that are incidental to the organic chemistry under discussion are not viewed as functions in
priority considerations.
VOLUME 6 SYNTHESIS: CARBON WITH THREE OR FOUR ATTACHED

HETEROATOMS
Volume 6 is in four parts. Part I deals with tetracoordinate carbons bearing three heteroatoms.
Part II covers tetracoordinate compounds bearing four heteroatoms, i.e. substituted methanes, and
Part III deals with tricoordinate systems bearing three heteroatoms, i.e. where one heteroatom is
attached by a double bond. Part IV is brief and deals with stabilized radicals and ions. Not
surprisingly, the coverage of Volume 6 is very large—and also shows that many gaps in the
development of organic chemistry still exist.
The organization within the three sections not only follows the same broad logic developed in
the previous volumes, but also has a structure unique to the multiheteroatom volume. According
to the Latest Placement Principle CF 3 C(NR 2 ) 3 appears in the section dealing with carbons bearing
three nitrogens (6.05.1.1), not that dealing with carbons bearing three halogens (6.01.2), while
(CF 3 CH 2 O) 2 CO appears in Part III, not in Part I.
In the chapter dealing with iminocarbonyl functions in Part III, the substituents on nitrogen are
discussed in each appropriate subsection in the order outlined above. Thus, the R N = group would
be first considered with R = H, then alkyl, alkenyl, aryl and hetaryl, alkynyl and then heteroatom
substituents in the usual order.
In each relevant section, we have endeavored to explain the influence of important secondary
effects on the synthesis such as structure (primary, secondary, etc.), ring effects, strain, activation,
stereochemistry, remote substituent effects, etc.
The arrangement of the chemistry in each of Parts I—III follows a similar pattern. Thus, each
section commences with functions containing at least one halogen. This section deals with all
combinations of halogen with other heteroatoms in the described order. The next section deals with
functions containing at least one chalcogen in combination with any other heteroatoms except
halogens. Subsequent sections each exclude the previous title heteroatom functions.
VOLUME 7 INDEXES
Subject Indexes are included in each of Volumes 1-6 and Cumulative Subject and Author Indexes
appear in Volume 7. Most entries in the Subject Index consist of two or three lines: the first line is
the entry itself (e.g. Lactones) and the second line is descriptive of that entry (e.g. reduction); in
many cases more detail is given (e.g. with 9-BBN).
Introduction
REFERENCES
The references are handled by the system previously used successfully in Comprehensive Hetero-
cyclic Chemistry. In this system reference numbers appear neither in the text, nor as footnotes, nor
at the end of chapters. Instead, each time a reference is cited in the text there appears (in parentheses)
a two-letter code assigned to the journal being cited, which is preceded by the year (tens and units
only for twentieth-century references) and followed by the page number. For example: "It was
shown <8OTL1327> that . . .". In this phrase, "80" refers to 1980, "TL" to Tetrahedron Letters, and
"1327" to the page number. For those journals which are published in parts, or which have more
than one volume number per year, the appropriate part of the volume is indicated, e.g. as in
<73JCS(P2)1594> or <78JOM(l62)6ll>, where the first example refers to / . Chem. Soc, Perkin Trans 2,
1973, page 1594, and the second to J. Organomet. Chem., 1978, volume 162, page 611.
This reference system is adopted because it is far more useful to the reader than the conventional
"superscript number" system. It enables readers to go directly to the literature reference cited,
without first having to consult the bibliography at the end of each chapter.
References to the last century quote the year in full. Books have a prefix "B-" and if they are
commonly quoted (e.g. Organic Reactions) they will have a code. Otherwise, as with uncommon
journals, they are given a miscellaneous code (MI) and numbered arbitrarily abbl, abb2, etc., where
abb refers to the volume and chapter number and 1, 2, etc., are assigned sequentially. Patents are
assigned appropriate three-letter codes.
The references are given in full at the end of each volume. They include Chemical Abstract
references when these are likely to help; in particular, they are given for all patents, and for less
accessible sources such as journals in languages other than English, French, or German, company
reports, obscure books, and theses.
Notes on the Reference Style within
this Work
The original print version of Comprehensive Organic Functional Group Transformations gathered references
for each volume into a section at the end of that volume. In this online version, references cited in the text of
each chapter may be found in the ‘‘References’’ section at the end of the Chapter HTML, but are not featured
in the PDF files since they were not part of the original printed chapters. The entire reference section for each
volume may be accessed in both HTML and PDF format via the ‘‘Table of Contents’’ tab and at the end of
each volume.
1.01
One or More CH Bond(s) Formed
by Substitution: Reduction of
C0Halogen and C0Chalcogen
Bonds
ALAN G. SUTHERLAND
University of North London, UK
0[90[0 REDUCTION OF C0HALOGEN BONDS TO CH 0
0[90[0[0 General Methods 0
0[90[0[1 Reduction of Fluoroalkanes 5
0[90[0[2 Reduction of Chloroalkanes 5
0[90[0[3 Reduction of Bromoalkanes 7
0[90[0[4 Reduction of Iodoalkanes 09
0[90[0[5 Reduction of Hypervalent Haloalkanes 00
0[90[1 REDUCTION OF C0OXYGEN BONDS TO CH 00
0[90[1[1 Reduction of C0OX Bonds 01
0[90[1[1[0 Reduction of C0OH bonds 01
0[90[1[1[1 Reduction of C0O0C bonds 02
0[90[1[1[2 Reduction of C0O0heteroatom bonds 06
0[90[1[2 Reduction of C1O Bonds to CH1 07
0[90[1[2[0 Reduction of aldehydes 07
0[90[1[2[1 Reduction of ketones 07
0[90[1[3 Reduction of "C1O#X to CH2 19
0[90[1[4 Reduction of C"OX#n Systems 10
0[90[2 REDUCTION OF C0SULFUR\ C0SELENIUM AND C0TELLURIUM BONDS TO CH 10
0[90[2[1 Reduction of C0SX Bonds 10
0[90[2[2 Reduction of C1S to CH1 13
0[90[2[3 Reduction of C"1S#X to CH2 13
0[90[2[4 Reduction of C"SX#n Systems 13
0[90[2[5 Reduction of C0Se Systems 14
0[90[2[6 Reduction of C0Te Systems 14
0[90[0 REDUCTION OF C0HALOGEN BONDS TO CH
0[90[0[0 General Methods

A large majority of the methods available for the reduction of alkyl halides to the corresponding
alkanes\ often referred to as the process of hydrogenolysis in earlier works\ can be loosely grouped
0
1 Reduction of C0Haloèn and C0Chalcoèn Bonds
into four categories] catalytic hydrogenation\ low!valent metal reduction\ metal hydride nucleophilic
displacement and radical substitution[
Generally\ the observed reactivity is in the order I×Br×Cl××F for all four categories\
matching the order of bond strengths "C0I 42 kcal mol−0\ C0Br 56 kcal mol−0\ C0Cl 70 kcal
mol−0\ C0F 098 kcal mol−0#[ Benzylic and\ to a lesser extent\ allylic halides also tend to be more
reactive than similar alkyl halides[ The order of reactivity between primary\ secondary and tertiary
alkyl halides tends to be dependent on the reagent in use[ a!Halo carbonyl compounds are par!
ticularly prone to reduction by these methods\ especially in the case of low!valent metal reductions
ð72OR052Ł\ although competing carbonyl group reductions may occur with some procedures[
Until the late!0869s the _rst three categories appeared more commonly\ as re~ected in a con!
temporary review ð79S314Ł\ but radical reduction procedures have dominated since[
Catalytic hydrogenation methods have been reviewed ðB!74MI 090!90Ł[ Practical di.culties can be
encountered in utilising these procedures\ owing to catalyst poisoning by the hydrogen halide
evolved\ particularly in the reduction of alkyl ~uorides ð79S314Ł[
Palladium!on!carbon is employed most regularly as the catalyst in these reductions[ Early reports
ð35JA150Ł suggested that only activated systems such as ethyl bromoacetate or benzyl chloride could
be reduced while\ for example\ primary alkyl bromides were inert\ even under high hydrogen
pressure[ However\ many examples have been reported since which demonstrate a wider reactivity\
concomitant with high chemoselectivity "Scheme 0# ð68T774\ 73CAR"029#014Ł[ Isolated examples of
reductions of benzylic ~uorides ð52JA0598Ł and even a secondary alkyl ~uoride "Scheme 0#
ð60LA"637#012Ł have been reported[
Br
AcO H2
AcO
O O
Pd–C
AcO OCH2Ph EtOAc AcO OCH2Ph
Br 90%
O O
H2
AcO Pd–C AcO

EtOH
53%
F
F
HO H2
HO
O O
Ra–Ni
HO OMe MeOH HO OMe
OH ∆ OH
Scheme 1
a!Haloketones are readily dehalogenated with no competing carbonyl reduction ð47JOC0827\

67JA0675Ł\ while the possibility of utilising transfer hydrogenation has also been highlighted
ð74JOC2397Ł[
Raney!nickel has been shown to catalyse the reduction of a series of alkyl bromides and iodides
in addition to tertiary and benzylic chlorides ð48CB0699Ł\ while the range can be extended to primary
alkyl ~uorides under more forcing conditions "Scheme 0# ð59JCS187Ł[ Platinum oxide has been
reported to catalyse the reduction of a benzylic ~uoride under relatively mild conditions ð54CJC0578Ł[
As indicated above\ low!valent metal!based procedures appear to be the method of choice for the
reduction of a!halocarbonyl compounds ð72OR052Ł[ The metal employed most commonly in this
context is zinc\ although the use of iron pentacarbonyl ð68JOC530Ł and of samarium"II# iodide
ð75JOC0024Ł has been exempli_ed[
The zinc reductions are generally performed in the presence of a proton source\ typically acetic
acid ð61JOC1252Ł or ammonium chloride ð67BCJ1634\ 67JA0654Ł\ and give high yields for chloro!
ð68JA3992\ 74JOC2846Ł\ bromo! ð67JA0675Ł and iodocompounds "Scheme 1# ð54LA"570#085Ł[ The
C0Haloèn Bonds to CH 2
chemoselectivity of these processes is high\ notably alkenes which are reduced preferentially or
competitively in catalytic hydrogenation procedures remain intact ð67JA0675Ł[
Cl Cl
H H
O Zn O
MeO2C MeO2C
AcOH
81%
H H H H
O O
MeO N MeO N
Zn(Cu)
Br
MeOH
NH4Cl
Br 100%
O O
R1 R1
I R2 Zn R2
AcOH
O 71% O
Scheme 2
Alkyl halides which are not adjacent to a carbonyl group can also be reduced by low!valent
metals[ Here\ lithium or sodium are generally used in conjunction with an alcohol acting as proton
source[ This procedure is often used to reduce polycyclic alkyl halides "Scheme 2# ð75JA0154\ 76JA6129\
89S538Ł[
O O O O
Na, ButOH
Cl
THF, ∆
75%
OMe OMe
MeO MeO
Cl
Cl Li, NH3, EtOH
Cl Et2O, –78 °C
Cl 82%
NH2 NH2
OH OH
Scheme 3
Alkyl ~uorides are not reduced by the above procedures[ However\ potassium has been reported
to e}ect a high yielding reduction of a range of ~uorinated steroids in the presence of an excess of
crown ether ð70TL1472Ł[
Despite the obvious analogy of generating a Grignard reagent from an alkyl halide\ followed by
reacting with a proton source\ there has been little use of magnesium in the context of a direct
reduction ð52PCS108Ł[ Samarium"II# iodide causes the reduction of primary iodides and bromides\
but primary chlorides are unreactive\ and both benzylic and allylic systems undergo Wurtz coupling
ð79JA1582Ł[
The utility of a wide range of metal hydrides in the reduction of carbonÐhalogen bonds has been
compared ð79JOC738Ł[ Lithium aluminium hydride has long been known to reduce primary or
secondary alkyl iodides and bromides and also benzylic chlorides ð38JA0564Ł[ Benzylic ~uorides
have also been shown to be prone to reduction ð52JA0598Ł\ particularly in the presence of an ortho
or para electron!donating group ð60CC354Ł\ while primary ~uorides may be reduced after the
addition of aluminium chloride ð53CJC461\ 53JOC1769Ł[ More recently\ the simple expedient of
employing a clear solution of lithium aluminium hydride in THF\ rather than the more typical
slurry\ has been shown to markedly improve the reduction process such that secondary alkyl
chlorides are reduced readily at room temperature ð71JOC165Ł[ Alternatively\ DIGLYME has been
shown to be an excellent solvent for these reactions ð79JOC1449Ł[ The reduction can also be promoted
by the addition of nickel"II# chloride or cobalt"II# chloride ð67JOC0152Ł[ The main drawback to the
use of lithium aluminium hydride in this context is the poor chemoselectivity obtained\ particularly
through the competing reduction of carbonyl groups "Scheme 3# ð38JA0564\ 53CJC461\ 60CC354\
60LA"637#012\ 76TL2772Ł[
O
O F LiAlH4, AlCl3 O
N N
Et2O
O F O
40%
Br O
LiAlH4
Ph OEt THF
Ph OH
Br 59%
NaBH4
Cl
S
O2
120 °C, 84%
OMe OMe
NaBH4
DMSO
20 °C, 91%
Cl
Br
Zn(BH4)2
Br Br
Ph Et2O Ph
81%
Scheme 4
Sodium borohydride has been shown to reduce alkyl chlorides\ bromides and iodides but not
~uorides[ Initially\ two!phase solvent systems were utilised ð55JA0362Ł\ but polar aprotic solvents
such as DMSO ð58JOC2812Ł\ sulfolane ð60JOC0457Ł and hexamethylphosphoramide "HMPA#
ð67JOC1148Ł are now used almost exclusively\ although the use of phase transfer catalysis has
been recommended ð70JOC2898Ł[ There is evidence to suggest that these reactions proceed via an
eliminationÐalkene hydroboration mechanism ð69CC227Ł[ Tertiary alkyl chlorides\ which often
prove resistant to reduction by other methods\ are converted cleanly\ although elevated temperatures
are required ð60JOC0457Ł[ More activated systems are converted at room temperature "Scheme 3#
ð75JOC2491Ł[
Sodium borohydride shows greater chemoselectivity than lithium aluminium hydride in that
esters remain intact ð67JOC1148Ł[ Under similar conditions\ sodium cyanoborohydride has been
shown to reduce alkyl bromides in the presence of ketones\ aldehydes and benzylic epoxides
ð66JOC71Ł[
Zinc borohydride o}ers unusual reactivity\ reducing only tertiary and benzylic halides "Scheme
3# ð72AG"E#451Ł[
Lithium triethylborohydride reduces primary alkyl ~uorides ð72ACS"B#030Ł and both primary and
secondary alkyl iodides\ bromides and chlorides[ Tertiary bromides undergo elimination
ð72JOC2974Ł[
Radical reduction processes have been dominated by the use of organostannanes\ principally
tributyltin hydride ð76S554Ł\ although organosilanes have attracted more recent attention
ð81ACR077Ł[ Primary\ secondary and tertiary alkyl chlorides\ bromides and iodides are all reduced^
however\ alkyl ~uorides do not react[
The popularity of the tributyltin hydride!mediated reduction arises from the high chemoselectivity
of the reaction[ Thus\ acetals ð65CB2487Ł\ benzyl ethers\ esters ð73CAR"029#014Ł\ lactones ð81TL5562Ł\
lactams ð68TL3520\ 80JCS"P0#545Ł\ carbamates ð73CAR"029#092Ł\ ketones ð72AJC1132Ł\ a!acyloxy!
carbonyls ð72LA694Ł\ nucleosides ð72S293Ł\ epoxides ð71JOC4930Ł and some alkenes ð66CB0712Ł
represent some of the functional groups which are not reduced under the same conditions "Scheme
4#[ Azides\ converted to amines\ are a notable exception here ð70LA0104Ł[ Alkenyl halides\ which
contain a carbonÐcarbon multiple bond removed by _ve atoms from the halogen\ undergo radical
dehalogenation\ but with concomitant _ve!membered ring formation ð76S554Ł[
HO Br H HO H H
S Bu3SnH S
N C6H6, ∆ N
O 95% O
CO2CH2Ph CO2CH2Ph
Br
OH Bu3SnH OH
O O
O AIBN O
PhMe, ∆
O 72% O
Cl Cl
Cl
Bu3SnH
Cl
AIBN
O O C6H6, ∆ O O
59%
AcO AcO
O O
OH OH
F F
Bu3SnH
AIBN
Br THF, ∆ H
59%
O O
Cl Cl
Scheme 5
The marked di}erence in rates of radical formation between di}erent halogens and between the
same halogen in di}erent environments ðB!72MI 090!90Ł can also be readily exploited in highly
selective dehalogenations "Scheme 4# ð68JOC040\ 73S838Ł[
The di.culties which can be encountered in removing the organotin residues from the product
have led to the development of carbonÐhalogen bond reduction procedures which are catalytic in
tin ð64JOC1443\ 76JOC362Ł but\ in common with the use of a water!soluble tin hydride reagent
ð89TL1846Ł\ these have yet to be exploited widely[
Tris"trimethylsilyl# hydride reduces a similar range of alkyl halides as tributyltin hydride with
similar e.ciency ð77JOC2530\ 80JOC567Ł[ Attempts to use this relatively esoteric reagent in a catalytic
process were partially successful ð78TL1622Ł\ but simpler silanes may also prove equally useful in
stoichiometric processes ð81JOC1316\ 81JOC2394Ł[ The readily available triethylsilane also exhibits
utility in this context when used in conjunction with a thiol {polarity reversal catalyst| ð80JCS"P0#092Ł[
a!Halocarbonyl compounds undergo a further general reaction unique to their class[ Treatment
with a nucleophile\ typically iodide\ in the presence of a Bronsted ð79TL2084Ł or Lewis acid ð60TL026\
68S48\ 79JOC2420\ 72JOC2556\ 75S469Ł results in formation of a halogenÐhalogen bond with cleavage of
the halogenÐcarbon bond and consequent reduction of the substrate "Scheme 5#[
O NaI, H2SO4 O
Ph Br Ph
THF, H2O
88%
O O
i, LiI, BF3•Et2O, THF

Br
ii, H2O
98%
OMe OMe
Scheme 6
0[90[0[1 Reduction of Fluoroalkanes
Fluoroalkanes are the most di.cult class of alkyl halides to reduce by any given procedure[
Indeed\ no examples of successful radical substitution!based methods have been reported[ A recur!
rent problem encountered is that other groups tend to be reduced preferentially ðB!65MI 090!90Ł[
Catalytic hydrogenation procedures tend to su}er from the catalyst poisoning e}ect of the ~uoride
ion that is liberated in the reaction ð79S314Ł[ Nonetheless these reactions can be performed under
su.ciently forcing conditions[ Experiments in the mid 0849s using simple ~uoroalkanes at elevated
temperatures in the gas phase indicated that secondary ~uorides are reduced more readily than
primary under palladium!on!carbon catalysis ð45JPC0343Ł[ The same catalyst has been shown to
reduce more complex secondary ~uorides "Scheme 0# ð60LA"637#012Ł and benzylic ~uorides
ð52JA0598Ł under less forcing conditions\ while an example exists of the reduction of a primary
~uoride at ambient temperature and elevated pressure "Equation "0## ð81JA630Ł[
H H
OH N N
O H2
F F
N3 + (1)
Pd–C
MeOH HO HO
HO
OH OH
52% 11%
Raney!nickel has been employed to reduce a primary ~uoride "Scheme 0# ð59JCS187Ł\ while
platinum oxide catalysed the reduction of a benzylic ~uoride under mild conditions ð54CJC0578Ł[
Low!valent metal!mediated reductions have seen little use[ Benzylic ~uorides have been shown
to be resistant to both zinc and sodium amalgam ð52JA0598Ł\ while elimination reactions compete
when magnesium is employed ð52PCS108Ł[ The most successful of these methods is the use of
potassium in the presence of 07!crown!5 which was shown to reduce a range of primary\ secondary
and tertiary ~uorides in high yield ð70TL1472Ł[
Lithium aluminium hydride can sometimes be used to reduce alkyl ~uorides\ particularly when
used in conjunction with aluminium chloride\ but high yields from such reactions are rare ð53CJC461\
53JOC1769\ 60LA"637#012Ł[ Many benzylic systems are either inert or reduced in low yield ð38JA0656\
52JA0598Ł but the presence of an amino! or hydroxy! functional group in the ortho or para position
causes high yielding conversions to occur\ possibly via an eliminationÐaddition mechanism
ð60CC354Ł[
Sodium borohydride ð70JOC2898Ł and sodium cyanoborohydride ð66JOC71Ł are apparently not
powerful enough reducing agents to cleave C0F bonds\ but lithium triethylborohydride does
reduce primary ~uorides\ although the reduction of secondary or hindered primary systems is slow
ð72ACS"B#030Ł[
Electrochemical techniques have been used to reduce a!~uorocarbonyl ð46JA0435\ 57CC823Ł and
benzylic systems ð69CC627Ł[
0[90[0[2 Reduction of Chloroalkanes

Reports of the catalytic hydrogenation of chloroalkanes are relatively rare[ Palladium!on!carbon
catalyses the reduction of benzyl chlorides using either a hydrogen atmosphere ð35JA150Ł or transfer
hydrogenation ð74JOC2397Ł[ Primary and secondary chloroalkanes do not undergo hydrogenation
in the presence of Raney!nickel\ but this catalyst does mediate the reduction of tertiary and benzylic
systems\ as well as geminal and vicinal dichloroalkanes ð48CB0699Ł[
Primary\ secondary and tertiary chloroalkanes can be reduced by a variety of low!valent metals\
typically in the presence of an alcohol proton source[ Examples include lithium with ethanol
ð89S538Ł or t!butanol ð59CI"L#394\ 76JOC3673Ł\ sodium with t!butanol ð57JA6160\ 75JA0154Ł\ potassium
ð70TL1472Ł\ magnesium with isopropanol ð52PCS108Ł and samarium"II# iodide ð79JA1582Ł[ Wurtz
coupling can occur with these procedures in the reduction of benzylic and allylic systems ð79JA1582Ł[
a!Chlorocarbonyl compounds are dechlorinated cleanly by zinc in acetic acid[ These reaction
conditions are employed most commonly in the reduction of cyclic ketone systems\ for example\
with four! ð61JOC1252\ 72JA1324Ł and _ve!membered rings "Scheme 1# ð68JA3992\ 74JOC2846Ł\ but are
also compatible with lactone ð72JOC759Ł\ lactam and carboxylic acid moieties "Scheme 6# ð76TL4228Ł[
The combination of samarium"II# iodide and methanol has been shown to be of use in this context
ð75JOC0024Ł[
Zn
NCH2Ph NCH2Ph
AcOH
Cl O 69% H O
HO2C Cl HO2C
Cl Cl
NaBH4
Cl DMSO
85%
Cl Cl
Bu3SnH
AIBN, THF
Cl O 84% O
Cl
(TMS)3SiH
AIBN
PhMe, ∆
93%
O i, LiI, BF3•OEt2, THF O

ii, H2O
Cl
Ph ~100%
Ph
O O Saccharomyces OH O
cerevisiae
Ph OEt 100% conversion
Ph OEt
Cl
Scheme 7
Early reports ð38JA0564Ł\ which indicated that lithium aluminium hydride reduced only activated
chloroalkanes\ have been countered more recently ð71JOC165Ł by demonstrations that relatively
unreactive systems\ such as secondary chloroalkanes\ can be reduced cleanly at ambient temperature
by homogenous solutions of the reagent in THF[ The use of cobalt"II# and nickel"II# chloride has
also been shown to promote these reductions ð67JOC0152Ł\ and even a tertiary neopentyl chloride
has been reduced ð76TL2772Ł[
Sodium borohydride also reduces chloroalkanes ð55JA0362Ł[ Generally\ these reactions are per!
formed in polar aprotic solvents such as DMSO ð58JOC2812\ 75JOC2491Ł\ sulfolane ð60JOC0457Ł or
HMPA ð67JOC1148Ł\ and often at elevated temperatures\ but still tend to o}er greater chemo!
selectivity than lithium aluminium hydride "Scheme 6# ð70JOC2898\ 67JOC1148Ł[ Other borohydride
systems of use in this context include zinc borohydride "tertiary systems# ð72AG"E#451Ł\ sodium
cyanoborohydride ð66JOC71Ł and lithium triethylborohydride ð71JOC1489\ 72JOC2974Ł[
Primary\ secondary ð65CB2487\ 70LA0104\ 73S838Ł and tertiary ð79TL176Ł chloroalkanes are all
reduced in high yield by tributyltin hydride by a radical mechanism[ The power of this approach is
illustrated by an example where low!valent metal procedures failed and ionic metal hydrides would
o}er no chemoselectivity "Scheme 6# ð76JOC296Ł[
A similar range of substrates undergo radical reduction using silyl hydrides[ Tris"trimethyl!
silyl#silane has seen most use\ with the reaction being initiated by the use of light\ peroxides
ð77JOC2530Ł or azobisisobutyronitrile "AIBN# "Scheme 6# ð80JOC567Ł[ The use of bis"trimethyl!
silyl#methylsilane ð81JOC2394Ł\ triethylsilane in the presence of a thiol catalyst ð80JCS"P0#092Ł and\
although with lower e.ciency\ tris"alkylthio#silanes ð81JOC1316Ł have also been demonstrated in
this reduction[
a!Chlorocarbonyl compounds can be reduced by iodide ion in the presence of a Lewis acid[ The
reaction generally proceeds in high yields with both ketones and esters ð75S469Ł\ utilising a range
of Lewis acids ð68S48\ 79JOC2420\ 75S469Ł\ unless the system is particularly hindered "Scheme 6#
ð60TL026Ł[
A biological reductive dechlorination has also been reported ð81TL6226Ł[ Treatment of ethyl a!
chlorobenzoylacetate with bakers| yeast at low concentrations "0 g l−0# results in reduction of both
the carbonyl group and the C0Cl bond "Scheme 6#[ At higher concentrations\ the carbonyl group
is reduced but the chloro moiety remains intact\ suggesting that the dechlorination is an enzyme!
catalysed process and not the result of a fortuitous noncatalysed chlorination of a constituent of
the microorganism[
0[90[0[3 Reduction of Bromoalkanes

Although it was suggested initially that only activated "e[g[\ benzylic and a!carbonyl# bromoalkane
systems were reduced by hydrogenation over palladium!on!carbon ð35JA150Ł\ it has now been
demonstrated that a full range of these compounds can be reduced by this procedure "Scheme 0#
ð47JOC0827\ 68TL774\ 73CAR"029#014Ł[ This approach can fail if other functional groups\ that are prone
to hydrogenation\ are present ð67JA0675\ 73CAR"029#014Ł[ Allylic bromides may be reduced by such
procedures\ but concomitant alkene migration can occur ð44JA4859Ł[
Catalytic hydrogenation can also be performed over Raney!nickel ð48CB0699Ł or using a homo!
genous palladium"9# catalyst in conjunction with transfer hydrogenation techniques ð75JOC623Ł[
There are remarkably few examples of the reduction of simple bromoalkanes using a low!valent
metal\ and the procedure appears low yielding ð76JA6129Ł[ Samarium"II# iodide does reduce primary
alkyl bromides in high yield\ but allylic and benzylic substrates undergo Wurtz coupling ð79JA1582Ł[
In common with the chloroalkane analogues described above\ zinc cleanly reduces a!bromo!
carbonyl compounds "Scheme 1# ð67BCJ1634\ 67JA0675Ł and the diastereoselectivity of the protonation
step in this reaction has been investigated ð48JA2523\ 48JA2533Ł[ These substrates can also be reduced
with samarium"II# iodide in high yield "Scheme 7# ð75JOC0024Ł and\ in moderate yield\ with iron
pentacarbonyl ð68JOC530Ł[
O O
2 SmI2
OEt THF, MeOH, –78 °C OEt
Br 98%
LiAlH4
Br OTs OTs
DIGLYME
78%
NH2 NH2
N N
N Bu3SnH N
AcO N N AIBN AcO N N

O O
PhMe, ∆
Br
76%
OAc OAc
(TMS)3SiH
( )14 Br ( )14
AIBN
PhMe, ∆
96%
Scheme 8
Lithium aluminium hydride reduces most bromoalkanes ð38JA0564Ł[ Benzylic and primary systems
are the most reactive\ but secondary and tertiary systems can also be reduced\ particularly in the
presence of nickel"II# or cobalt"II# chloride ð67JOC0152Ł or when a homogenous solution of lithium
aluminium hydride in THF is used ð71JOC165Ł[ The carbonÐbromine bond can be reduced by lithium
aluminium hydride in the presence of other reactive centres when DIGLYME is used as the solvent
"Scheme 7# ð79JOC1449Ł[
Sodium borohydride reduces primary and secondary bromoalkanes in high yield and with good
chemoselectivity[ These reactions are usually carried out in polar aprotic solvents\ typically DMSO
ð58JOC2812Ł\ sulfolane or HMPA ð67JOC1148Ł\ although two!phase systems involving an aqueous
layer have been used successfully in conjunction with phase transfer catalysis ð70JOC2898Ł[ Zinc
borohydride shows complementary activity\ reducing only tertiary and benzylic bromoalkanes\ even
in the presence of primary alkyl bromides "Scheme 3# ð72AG"E#451Ł[
Sodium cyanoborohydride in HMPA o}ers very high chemoselectivity[ BromineÐcarbon bonds
can be reduced by this system in the presence of a variety of functional groups\ including carboxylic
acids and esters\ ketones\ nitriles and epoxides ð66JOC71Ł[
Other metal hydride systems have also been used to reduce bromoalkanes\ for example\ lithium
triethylborohydride ð72JOC2974Ł and potassium hydride ð76JOC3188Ł\ but these reagents have yet to
see widespread use[
The most popular method for the reduction of bromoalkanes is the use of tributyltin hydride in
a radical substitution procedure[ Essentially\ all classes of bromoalkane can be reduced\ usually in
high yield\ with excellent chemoselectivity\ thus sul_des\ b!lactams and benzyl ethers ð68TL3520Ł\ g!
lactams ð80JCS"P0#545Ł\ epoxides and lactones "Scheme 4# ð71JOC4930Ł\ alkyl ~uorides\ alkyl chlor!
ides\ ketones and enones "Scheme 4# ð68JOC040Ł\ ethers ð61S372Ł\ a!acyloxyketones ð72LA694Ł\
alkenes ð66CB0712Ł\ strained ð72TL0036Ł and rigid cycloalkanes ð72AJC1132Ł\ carbohydrates
ð73CAR"029#014\ 81JA09027Ł and nucleosides ð72S293Ł are all una}ected by typical reaction conditions
"Scheme 7#[
The main di.culty encountered with these procedures is the removal of tin residues from the
product ð76S554Ł[ Attempts to circumvent this by developing methodology which is catalytic in tin
"and stoichiometric in sodium borohydride# have achieved some success ð64JOC1443\ 76JOC362Ł but
see little contemporary use[
Silyl hydrides have again been shown to be of use in place of tributyltin hydride[ Tris"trimethyl!
silyl#silane has seen the most investigation "Scheme 7# ð77JOC2530\ 80JOC567Ł\ including its use in
catalytic amounts ð78TL1622Ł\ but other silanes have also been shown to work well ð80JCS"P0#092\
81JOC1316\ 81JOC2394Ł[
The carbonÐbromine bond of a!bromoketones can be reduced by treatment with iodide ion in
the presence of an acid[ Although sulphuric acid has been used in this context "Scheme 5# ð79TL2084Ł\
the reaction is usually driven by a Lewis acid "Scheme 5# ð60TL026\ 68S48Ł[ When trimethylsilyl
chloride is employed\ the silyl enol ether intermediate is usually not isolated\ and is hydrolysed in
situ "Scheme 8# ð79JOC2420\ 72JOC2556Ł[
i, NaI, TMS-Cl, MeCN

O O
ii, H2O
89%
Br
O O
i, NaI, TMS-Cl, MeCN
Br
Ph Ph
ii, H2O
Ph 92% Ph
Me
N
Ph
N
O Me O
(1)
Ph O Ph O
THF or dioxane
Br 94%
Me
N
Ph
N
O Me O
(1)
Ph Ph
THF or dioxane
Br 89%
Scheme 9
The dihydrobenzimidazole "0# has been shown to e}ect an unusual\ but high yielding\ reduction
of a!bromocarbonyl compounds ð75JOC4399Ł[ The process\ which presumably involves hydride
transfer assisted by the nitrogen lone pairs\ is highly chemoselective "Scheme 8#[
0[90[0[4 Reduction of Iodoalkanes

Iodoalkanes undergo facile reduction by all the general methods available[ Perhaps as a conse!
quence of this\ with there being little need to develop new methods or re_ne old ones\ there are
relatively few investigations of these reductions reported in the literature[
As would therefore be expected from the precedents described above\ iodoalkanes can be reduced
by catalytic hydrogenation over palladium ð79S314Ł or Raney!nickel ð48CB0699Ł[
Samarium"II# iodide is a particularly e.cient low!valent metal reducing agent for simple alkyl
iodides ð79JA1582Ł\ while the {classic| combination of zinc in acetic acid cleanly reduces a!iodoketones
"Scheme 1# ð54LA"570#085Ł[
Again\ as might be predicted\ lithium aluminium hydride reduces iodoalkanes readily ð38JA0564\
71JOC165Ł[ The rate of the reaction can be promoted by the use of solvents such as GLYME or
DIGLYME ð79JOC1449Ł or the addition of nickel"II# or cobalt"II# salts ð67JOC0152Ł\ but yields are
generally high regardless of the method used[
Similarly\ other metal hydride reagents "such as sodium borohydride ð58JOC2812\ 70JOC2898Ł\
sodium cyanoborohydride ð66JOC71Ł and lithium triethylborohydride ð72JOC2974Ł# capable of
reducing bromoalkanes also work well with iodoalkanes\ while o}ering the possibility of greater
chemoselectivity than that available with lithium aluminium hydride[
Chemoselectivity is also the strength of the radical substitution of iodoalkanes using tributyltin
hydride\ where high yielding reductions can be performed in the presence of a wide range of other
sensitive functional groups "Scheme 09# ð71JFC"19#202\ 73CAR"029#092\ 80JOC5195\ 81TL5562\ 81TL6318Ł[
Methodology for performing these reductions in the presence of catalytic amounts of the reducing
agent\ together with an inexpensive coreductant\ is recorded ð64JOC1443Ł[
Bu3SnH
n-C4F9 OAc n-C4F9 OAc
AIBN, 25 °C
I 93%
OH Bu3SnH OH
PhCH2O AIBN PhCH2O
I
PhMe, 70 °C
OH 78% OH
O O
NaI, 5% H2SO4 (aq.)
Ph THF, 20 °C Ph
I 70%
O O
PhSH, K2CO3
I
Ph EtOH, 20 °C Ph
95%
Scheme 10
As with chloro! and bromoalkanes\ such radical!based reductions can also be performed with a
range of silanes in place of tributyltin hydride with no loss in yield or e.ciency ð77JOC2530\ 78TL1622\
80JCS"P0#092\ 80JOC567\ 81JOC1316\ 81JOC2394Ł[
a!Iodoketones can be reduced by a range of procedures distinct from those described above
"Scheme 09#[ Thus treatment of aryl a!iodoketones with iodide in the presence of a Lewis ð60TL026Ł
or Bronsted ð79TL2084Ł acid has been shown to provide a clean reduction[ A closely related process
is the reaction with benzene thiolate or benzene selenolate ion\ which gives high yields for the
reduction of both aryl and alkyl ketones ð70JOC1485Ł[ Curiously\ this reaction fails for the cor!
responding a!bromoketones\ when thioester formation occurs[ An isolated example of the reduction
of an a!iodoketone in the presence of an a!bromoketone moiety using sodium bisul_te has also been
reported ð49JA251Ł[
C0Oxyèn Bonds to CH 00
0[90[0[5 Reduction of Hypervalent Haloalkanes
There have been few reports of the reduction of a hypervalent haloalkane to the corresponding
alkane[ The esoteric nature of this reaction is highlighted by the fact that the only alkanes that have
been formed by these processes are all b!dicarbonyl compounds[
When an ethanolic solution of phenyldimedonyliodone is re~uxed\ decomposition occurs to give
dimedone as a minor component in a complex mixture of products "Equation "1## ð69BCJ1495Ł[
Cleaner reductions of the same substrate have been performed with either aryl thiols ð67JOC1565Ł
or sodium bisul_te ð66JOU0922Ł as the reducing agent "Equation "1##\ and the latter method has
been shown to be applicable to a wider range of substrates[
i or ii or iii
(2)
O O– O O
I+
Ph
i, EtOH, reflux, 10%
ii, 4-ClC6H4SH, CH2Cl2, 86%
iii, NaHSO3, H2O, 90%
0[90[1 REDUCTION OF C0OXYGEN BONDS TO CH

It is di.cult to identify general methods for the reduction of carbonÐoxygen single bond systems\
particularly due to the dramatic variation in reactivity of the di}erent structures which come into
this class[
While benzylic systems can be reduced by catalytic hydrogenation "Scheme 00# ð42OR"6#152\
71SC872\ 82T7322Ł\ most alcohols "and simple derivatives thereof# are largely inert to direct reduction[
These species are transformed to alkanes by conversion to a more reactive substrate\ usually one of
the range of thionoethers or a sulfonate\ then reduction of this intermediate by a radical substitution
or nucleophilic displacement procedure\ respectively "Scheme 01# ð64JCS"P0#0463\ 66JOC71Ł[
OH
CO2H H2 or HCO2H CO2H
Pd–C
hexane
OAc
AcO AcO
H2
AcO Pd–C AcO

EtOAc, HClO4
94%
OAc
Scheme 11
Most aldehydes and ketones can be reduced to methyl and methylene compounds\ respectively\
by treatment with hydrazine and base\ the Wol}ÐKischner reduction ð37OR"3#267Ł[ The HuangÐ
Minlon modi_cation of this procedure is usually employed ð35JA1376Ł\ and high yields are often
obtained "Scheme 02# ð38JA2290\ 76JOC2194Ł[
Benzylic aldehydes and ketones can also be reduced\ via the benzylic alcohol intermediate\ to the
corresponding alkane by catalytic hydrogenation[ Again\ high yields can be obtained\ and the
procedure is tolerant of many other functional groups "Scheme 03# ð79TL1526\ 71JOC3293Ł[
Aldehydes and ketones can also be deoxygenated by conversion to a dithioacetal derivative\ then
treatment with Raney!nickel[ This approach is discussed in Section 0[90[2[4[
O O
O O Bu3SnH O O
MeS O PhMe, ∆
O O
80–90%
S O O
OMs
NaBH3CN
Ph CO2Me HMPA Ph CO2Me
72%
Scheme 12
O
MeO MeO
H2NNH2•H2O
KOH
MeO O MeO
HO OH
77%
O
H2NNH2•H2O
KOH
O
HO OH
76%
Scheme 13
Ra-Ni
EtOH, H2O
HO2C HO2C
89%
OMe OMe
CO2Et CO2Et
H2, Pd–C
CO2Et CO2Et
EtOH, HCl
~100%
OMe O OMe
Scheme 14
0[90[1[1 Reduction of C0OX Bonds
0[90[1[1[0 Reduction of C0OH bonds

As indicated above\ the C0O bond of alcohols is not particularly prone to reduction\ and only
systems activated through a neighbouring group can be transformed readily[
Catalytic hydrogenation over palladium!on!carbon is an e}ective method for the reduction of
benzylic alcohols ð35JA150\ 42OR"6#152Ł\ and it has been demonstrated that transfer hydrogenation is
as least as e}ective as the use of a hydrogen atmosphere "Schemes 00 and 04# ð82T7322Ł[ Tertiary
alcohols can be hydrogenated under platinum"IV# oxide catalysis in tri~uoroacetic acid "when the
intermediacy of an alkene is probable# ð53JOC1214Ł or in the presence of Raney!nickel ð77JOC321Ł[
Selective reduction of the alcohol in the presence of a primary bromoalkane functional group has
been achieved by the latter method[ Allylic alcohols can be converted to alkenes by hydrogenation
in the presence of the hydridopentacyanocobaltate anion\ although double bond migration can
occur and tertiary allylic alcohols are reported not to react ð89TL3090Ł[
OH
H2 or HCO2H
CO2H CO2H
Pd–C
Cl hexane Cl
i, TMS-Cl, NaI, MeCN

OH
ii, Zn, AcOH
80%
OH NaBH4 Ph
Ph Ph
Ph F3CCO2H
70%
Scheme 15
By analogy with a!halocarbonyl compounds\ it might be expected that the alcohol moiety of the
corresponding a!hydroxycarbonyl series should be reduced by the action of low!valent metals[
While this is the case\ it would seem that here the combination of zinc in acetic acid ð43JCS2934Ł is
less popular than samarium"II# iodide ð75JOC0024\ 76JA3313Ł[
The use of lithium in ammoniacal THF containing ammonium chloride has been shown to reduce
benzylic alcohols without concomitant Birch reduction ð64JOC2040Ł\ while zinc has been employed
in the latter stage of a two!stage\ one!pot process to reduce primary\ secondary and benzylic alcohols
through the intermediacy of the corresponding iodoalkane "Scheme 04# ð70S21Ł[
The combination of an acid and a hydride source\ often termed ionic hydrogenation ð63S522Ł\
reduces alcohols where the intermediate carbonium ion is relatively stable "i[e[\ tertiary and benzylic
alcohols#[ Initially\ triethylsilane was used as the hydride donor in the presence of tri~uoroacetic
acid ð58JOC3\ 60JOC647Ł\ but it has since been demonstrated that the use of sodium borohydride with
the same acid is highly e}ective "Scheme 04# ð66S061Ł[ The use of zinc iodide\ rather than a
protic acid\ together with sodium cyanoborohydride\ also reduces tertiary and benzylic alcohols
ð75JOC2927Ł\ while the combination of diisobutylaluminium hydride "dibal!H# with aluminium
bromide reduces benzylic alcohols in high yield\ and has been shown to provide a rare method for
a direct\ if low!yielding\ reduction of a secondary alcohol ð81JOC1032Ł[
0[90[1[1[1 Reduction of C0O0C bonds
"i# Reduction of oxiranes

There are\ not unexpectedly\ few examples of the reduction of both carbonÐoxygen bonds of an
oxirane "epoxide#[ The use of titanocene has met with some success\ although yields are variable\
being poor for highly substituted epoxides ð63JA4189Ł[ Triethylsilane\ in combination with boron
tri~uoride\ also performs this reduction "Scheme 05# ð68TL738Ł\ but rearrangement of the inter!
mediate carbonium ion can also occur[
titanocene
O C6H6
68–81%
O
Et3SiH, BF3
CH2Cl2, 0 °C
~100%
Scheme 16
Procedures involving the reduction of only one carbonÐoxygen bond of an oxirane are relatively
common\ and usually involve the use of metal hydride reagents[ Here\ the question of the regio!
selectivity of the reduction of unsymmetrically substituted epoxides is important[
In aliphatic substituted systems where one oxirane carbon atom has fewer substituents "i[e[\ 1!
alkyl\ 1\1!dialkyl or 1\1\2!trialkyloxiranes#\ reduction with highly nucleophilic metal hydride
reagents "such as lithium aluminium hydride ð81JOC0507\ 81T8316Ł\ lithium triethylborohydride
ð79JOC0Ł and dibal!H ð81JOC0507Ł# occurs at the less substituted position "Scheme 06#[ In contrast\
reducing agents with Lewis acid character ð81JOC0507Ł\ or used in the presence of an acid ð70JOC4103\
81JCS"P0#0770Ł tend to deliver hydride to the more substituted carbon centre "Scheme 06#[
O OH
LiAlH4
O O Et2O O O
92%
O OH
LiEt3BH
THF, 0 °C
~100%
(Bui)2AlH
O n-C7H16
95% OH
Bui3Al
OH
O THF
93%
O LiEt3BH
Ph
Ph THF OH
sole product
O LiEt3BH OH
Ph THF Ph
sole product
Scheme 17
When the more substituted carbon of the oxirane is also benzylic\ selective delivery of hydride to
that centre can be achieved by a range of reagents including either borane ð57CC0438Ł or sodium
cyanoborohydride ð70JOC4103Ł in combination with boron tri~uoride\ and also triisobutylaluminium
ð81JOC0507Ł[ Reduction of these compounds at the less substituted carbon atom can still be per!
formed using reagents such as lithium aluminium hydride\ but the regioselectivity of this process is
not always as clear cut as with the nonbenzylic systems ð81JOC0507\ 57JA1816Ł[
Reductions of 1\2!disubstituted oxiranes tend to give mixtures of products\ even when one
substituent is aromatic\ and the geometry of the oxirane can have a dramatic e}ect on the outcome
of the reaction "Scheme 06# ð72JOC2980Ł[
Reduction takes place at the allylic carbonÐoxygen bond when oxiranes with vinyl substituents
are treated with reagents such as lithium aluminium hydride ð74JA6867\ 76JOC3787Ł or dibal!H
ð71CC0181Ł[
The popularity of the Sharpless asymmetric epoxidation procedure has led to the study of the
reduction of glycidols "hydroxymethyloxiranes# as an approach to 0\1! and 0\2!dihydroxylated
systems[ When the glycidol alcohol moiety is primary\ selective reductions to give 0\2!diols can be
performed using sodium bis"methoxyethoxy#aluminium dihydride "Red!Al# "Scheme 07# ð71CC0181\
71JOC0267Ł[ Reductions to the 0\1!dihydroxy system are more di.cult\ unless the site of reduction
is benzylic ð71TL2486Ł[ The most e}ective systems are dibal!H ð71TL1608\ 71TL2486Ł and lithium
borohydride:titanium tetraisopropoxide "Scheme 07# ð75TL3232Ł[ Glycidols with a secondary alcohol
and terminal oxirane can be reduced to the vicinal diol using lithium aluminium hydride
ð74JOC4567Ł[
Oxiranes with a carbonÐoxygen bond a to an aromatic ring or carbonyl group can be reduced
selectively using low!valent metal techniques[ Samarium"II# iodide ð75JOC1485\ 76TL3326Ł\ lithium
and potassium ð75AG"E#542Ł have all been used with success[
Catalytic hydrogenation methodology can be employed to reduce certain oxiranes\ for example\
those with vinyl ð78JA5179Ł or carbonyl ð80CC424Ł substituents[
OH
O
Red–Al
O OH O OH
O THF, 22 °C O
<1% 1,2-diol
OH
OH (Bui)2AlH OH OH
+
O CH2Cl2, 0 °C
OH
5:1
OH
OH LiBH4, Ti(OPri)4 OH OH
+
O C6H6, 10 °C
OH
13 : 1
Scheme 18
"ii# Reduction of other ethers

Ethers share a resistance to reductive cleavage similar to the corresponding alcohols[
Although benzyl ethers are frequently used as alcohol protecting groups in synthesis and are
subsequently cleaved by catalytic hydrogenation\ the alkane product\ toluene\ is of no synthetic
interest[ Hydrogenation of cyclic benzylic ethers\ where both alcohol and alkane are part of the
required product\ have been reported and work well ð37JA0389Ł[
Allylic ethers can be reduced to the corresponding alkenes by the combination of a homogenous
palladium"9# catalyst and lithium triethylborohydride in high yields with little or no double bond
migration ð71JOC3279Ł while g!alkoxy!a\b!unsaturated esters can be reduced to the corresponding
fully saturated ester by the action of magnesium in methanol "Equation "2## ð82JCS"P0#8Ł[ Alkyl
methyl ethers can also be reduced by low valent metal methods after in situ conversion to the
corresponding alkyl iodide ð70S21Ł\ while a!alkoxyketones are reduced cleanly by samarium"II#
iodide ð75JOC0024Ł[
Mg, MeOH OH
O O (3)
Ph O CO2Me
Ph O 83%
CO2Me
"iii# Reduction of esters

The reduction of the alkyl carbonÐoxygen bond of esters can be performed in preference to the
reduction at the carbonyl carbon atom in some speci_c situations[
In common with benzyl ethers\ benzyl esters are often used as protecting groups in organic
synthesis\ and are subsequently removed by catalytic hydrogenation[ There are\ however\ examples
of this reaction with more complex aromatic systems\ where the alkane formed is the required
product of the reaction "Schemes 00 and 08# ð72JCS"P0#76\ 71SC872Ł[
CO2Me CO2Me
H2, Pd–C
O O
CO2H
AcOH, HClO4
98%
O O O O
H2, PtO2
AcO AcO
EtOAc, Et3N
AcO OAc 75% OAc
Scheme 19
The b!acetoxy group of a\b!diacetoxybutanolides can be reduced by catalytic hydrogenation over
Raney!nickel in the presence of base "Scheme 08# ð82OS"61#37Ł\ via an alkene[ If platinum"IV# oxide
or palladium!on!carbon is used as catalyst then reduction of the a!acetoxy group also occurs
ð80TL3852Ł[
a!Acetoxyketones can be reduced using zinc in acetic acid ð44JA3256\ 46JA4439Ł or samarium"II#
iodide ð75JOC0024Ł[ The latter procedure is particularly selective\ notably the reduction can be
performed in the presence of a primary iodide[ A vinylogous example of this type of reduction has
been performed with magnesium in methanol as the reducing system\ although alkene reduction
also occurred under these conditions ð82JCS"P0#8Ł[
Sterically hindered esters are reduced by the action of lithium in ethylamine[ Less hindered
systems undergo oxygenÐcarbonyl bond cleavage under these conditions\ but this selectivity can be
exploited bene_cially ð70JCS"P0#0490Ł[ The similar conditions of lithium in ammoniacal THF have
been employed to reduce benzylic esters selectively in the presence of alkenes ð76JOC3767Ł[
"iv# Reduction of thionoethers

One of the most important methods for the deoxygenation of alcohols is the radical chain
reduction of a thionoether derivative\ typically using tributyltin hydride as the reducing agent[ This
process\ often termed the BartonÐMcCombie reaction ð64JCS"P0#0463Ł\ has been the subject of
extensive reviews ð72T1598\ 76S554\ B!78MI 090!90Ł[
A range of thionoethers has been used in this procedure[ While thioesters were utilised in the
original paper in this area ð64JCS"P0#0463Ł\ these intermediates now see little use and S!methyl
dithiocarbonate "xanthate# ð64JCS"P0#0463\ 82TL1622Ł\ phenylthiocarbonate ð76JOC2695\ 89SL694Ł and
imidazoylthiocarbonyl ð70JOC3732\ 82TA514Ł derivatives are employed now[
These reductions are used most commonly in the deoxygenation of secondary\ often cyclic\
alcohols and are high yielding\ notably in the presence of acid or base sensitive functionality
"Schemes 01 and 19# ð64JCS"P0#0463\ 76JOC2695\ 82TA514Ł[ The procedure is used only rarely for
primary alcohols\ and can be low yielding ð70JOC3732\ 80JCS"P0#092Ł\ although the use of high boiling
solvents can be bene_cial ð70S632Ł[ Tertiary alcohols can be deoxygenated cleanly if elimination of
the thionoether can be avoided\ and a revised methodology for the synthesis of these intermediates
has been reported ð82TL1622Ł[
S
O O
PhO O
H Bu3SnH H
N AIBN N
C6H6, ∆
MeO2C O 98% MeO2C O
H H
N
S N
Bu3SnH
O OSiPh2But
AIBN N
OSiPh2But PhMe, ∆ Boc
N 50%
Boc
O O
Ph2SiH2
S Et3B/O2
F
C6H6, 25 °C
96%
F
S Ph2SiH2
n-C18H38
Et3B/O2
( )16 O O C6H6, 80 °C
87%
Scheme 20
The practical di.culty of removing unwanted tin!containing residues from the reaction product
can be avoided by the use of polystyrene!supported tin hydrides ð81SL790Ł[
More recently\ the use of organosilanes to reduce thionoethers to alkanes has seen a rise in
popularity matching the analogous usage in the reduction of haloalkanes ð81ACR077Ł[ The most
useful of these reagents seem to be tris"trimethylsilyl#silane ð89SL694\ 80JOC567Ł and diphenylsilane
ð89TL3570Ł[ The combination of the latter reagent with the triethylborane:oxygen initiator system
and p!~uorophenyl thiocarbonyl substrates seems particularly e}ective "Scheme 19# ð89TL3570Ł[
A number of other silanes have been reported to perform these reductions in high yields but have
yet to see widespread use ð81JOC1316\ 81JOC2394Ł[ The least esoteric of these\ triethylsilane\ can be
used in the presence of a thiol catalyst ð80JCS"P0#092Ł or in excess with relatively large amounts of
initiator in what has been shown not to be a conventional chain reaction process ð80TL6076\ 82JOC138Ł[
0[90[1[1[2 Reduction of C0O0heteroatom bonds

The reduction of alcohols is often achieved by conversion to a group more prone to nucleophilic
displacement\ usually a "p!toluene or benzene# sulfonate\ then treatment with a suitable metal
hydride reagent[
Thus highly nucleophilic reagents such as lithium aluminium hydride ð67JOC0152Ł and lithium
triethylborohydride ð72JOC2974Ł have been used to e}ect e.cient reductions of such esters[ The
chemoselectivity of such reactions can be poor ð71AJC0784Ł\ but choice of solvent can be important
LiAlH4
Br OTs Br
Et2O
83%
NaBH4
OTs
DMSO
85%
NaBH3CN
OTs
HMPA
78%
OH
i, Py•SO3, THF
ii, LiAlH4
87%
O2
S i, NaBH4, DMA OH
O O
CO2Me
ii, H3O+ C15H31
C15H31 CO2Me 90%
Scheme 21
The use of less reactive reagents such as sodium borohydride ð58JOC2812\ 67JOC1148Ł or sodium
cyanoborohydride ð66JOC71Ł still allows the reduction of sulfonates\ but with a consequent increase
in chemoselectivity "Scheme 10#[
Sulfonates can also be reduced electrochemically ð68TL1046Ł or\ in the case of primary ð79JA1582Ł
or a!carbonyl ð75JOC0024Ł systems\ by reaction with samarium"II# iodide in the presence of a proton
source[
Sulfates can also be reduced via nucleophilic displacement by a metal hydride reagent\ but only
benzylic\ allylic or a!carbonyl systems seem to have su.cient reactivity "Scheme 10# ð58JOC2556\
75TL3702\ 77JA6427Ł[
Phosphates and phosphoramidates can be reduced by lithium in the presence of ethylamine and
t!butanol in a procedure that appears to be e.cient for primary\ secondary and tertiary systems but
has few proponents ð61JA4987\ 75JA2724Ł[
The reduction of the carbonÐoxygen bond of relatively activated silyl ethers "allylic\ benzylic and
a!carbonyl systems# has been reported in a few speci_c instances ð70S21\ 71JOC3279\ 75JOC0024Ł[ These
procedures may be of value in particular circumstances\ but would not be one of the _rst methods
of choice if starting from the corresponding alcohol[
0[90[1[2 Reduction of C1O Bonds to CH1
0[90[1[2[0 Reduction of aldehydes

There is a surprisingly small number of reports of the direct reduction of aldehydes to methyl groups
compared to those devoted to the analogous conversion of ketones to methylene moieties\ which
may be more a re~ection of the relative synthetic utilities of the procedures than of ease of reaction[
The Clemmensen reduction\ using zinc in the presence of an acid\ illustrates this point[ While the
original paper on this procedure reported the reductions of heptanal and benzaldehyde in moderate
yield ð02CB0726Ł\ very few aldehyde reductions have appeared subsequently ð31OR"0#044\ 48AG615Ł\
and the reaction is now used almost exclusively for the deoxygenation of ketones ð64OR"11#390Ł[
The Wol}ÐKischner reduction\ in which the carbonyl compound is treated with hydrazine and a
base ð37OR"3#267Ł\ has seen rather more use in the reduction of aldehydes than the Clemmensen
procedure[ The HuangÐMinlon modi_cation of the reaction\ where "tri! or# diethylene glycol is used
as solvent\ and volatile by!products are removed by distillation as the reaction temperature is raised
from 079>C to 199>C ð35JA1376Ł\ is now employed generally\ and aryl and aliphatic aldehydes which
are tolerant of base and these elevated temperatures can be reduced in high yields "Schemes 02 and
11# ð38JA2290\ 73JA5691Ł[
O
H2NNH2•H2O
KOH
O
HO OH
88%
O
H2NNH2•H2O
K2CO3
MeO O MeO
HO OH
72%
O
Ra-Ni
EtOH, H2O Me2N

Me2N 95%
Scheme 22
The variant of the Wol}ÐKischner reduction in which the tosylhydrazone of the aldehyde is
formed\ then converted to the methyl compound by treatment with a metal hydride reagent also
works well[ Lithium aluminium hydride is used in the conversion of aromatic aldehydes ð52T0016Ł
but tends to give alkenic by!products with aliphatic systems when sodium borohydride becomes the
reagent of choice ð53CI"L#042Ł[ Carbohydrate aldehydes have also been reduced by this approach\
using potassium borohydride\ in moderate yields ð53CI"L#0578Ł[
Benzylic aldehydes can be reduced directly to the corresponding toluene derivative by catalytic
hydrogenation ð42OR"6#152Ł[ Systems with electron!donating substituents on the ring tend to react
more quickly\ particularly when transfer hydrogenation techniques are used ð77TL2630Ł\ but high
yields can be obtained in many cases\ especially when Raney!nickel is employed "Schemes 03 and
11# ð79TL1526Ł[
An aldehyde unit attached to an electron!rich aromatic system can be reduced directly to the
methyl group using Red!Al ð58TL0628Ł or sodium cyanoborohydride in the presence of zinc iodide
ð75JOC2927Ł[ An aliphatic aldehyde has been reduced quantitatively by the combination of tri!
ethylsilane and boron tri~uoride ð68TL738Ł\ while titanocene has been reported to reduce aliphatic\
but not aromatic\ aldehydes ð63JA4189Ł[
0[90[1[2[1 Reduction of ketones

The Clemmensen reduction\ in which the substrate is reduced by the action of zinc in the presence
of an acid\ is one of the longest established methods for ketone deoxygenation ð64OR390Ł[ The
reaction does not work well for diketones owing to pinacol coupling\ a process which can also be a
signi_cant side reaction\ in an intramolecular sense\ for monoketones ð35JA1376Ł\ and the alkene
unit of a\b!unsaturated ketones is reduced in tandem with the carbonyl group ð61BCJ153Ł[ Nonethe!
less\ high yields of alkanes can be obtained for this procedure\ particularly when the reaction is
carried out under anhydrous conditions "Scheme 12# ð61BCJ153Ł[ A variation in the procedure\ using
base rather than acid\ has also shown promise ð76JOC2194Ł[
R1 R1
R2 R2
Zn
Et2O, HCl
O 89%
H H
O
Zn
Et2O, HCl
42%
Scheme 23
The Wol}ÐKischner reduction\ in which the ketone is treated with hydrazine and a base\ is as
well established a procedure as the Clemmensen reduction ð37OR"3#267Ł[ It has been demonstrated
that\ if the intermediate hydrazone is isolated _rst\ the reaction can be carried out in DMSO at
room temperature ð51JA0623Ł[ However\ most practitioners use the procedure at elevated tem!
perature "079Ð199>C# with in situ hydrazone formation "termed the HuangÐMinlon modi_cation
ð35JA1376Ł#\ and are generally rewarded with high yields "Schemes 02 and 13# ð35JA1376\ 71JOC1489\
73JA5589\ 76JOC2194Ł[
O H2NNH2•H2O
Ph
Ph KOH
O
HO OH
82%
H2NNH2•H2O
K2CO3
O
O
H HO OH H
72%
Scheme 24
Hindered ketones are not reduced by these procedures ð38JA2290Ł and\ sometimes\ pyrazoline
formation can compete with the reduction of a\b!unsaturated ketones ð76JOC2194Ł[
A useful variation of the Wol}ÐKischner procedure involves forming the tosylhydrazone\ and
treating this intermediate with a reducing agent such as sodium borohydride ð53CI"L#042\ 76TL3648Ł\
sodium cyanoborohydride ð74JOC1596Ł or catecholborane ð64JOC0723\ 74JA4621Ł[ These reactions are
performed at much lower temperatures than the HuangÐMinlon type procedures and give com!
parable yields "Scheme 14# ð64JOC0723\ 76TL3648Ł[
Aromatic ketones can be reduced\ via the benzyl alcohol\ to arylalkanes ð42OR"6#152Ł[ Both
Raney!nickel and palladium!on!carbon are e}ective catalysts for this procedure\ and the reactions
can be carried out under a hydrogen atmosphere or using transfer hydrogenation techniques
ð77TL2630Ł[ These reactions are generally high yielding\ although some functional groups "e[g[\
chloro! or nitroarenes# are reduced preferentially "Schemes 03 and 15# ð47JOC022\ 79TL1526\ 71JOC3293\
71S839\ 72CJC1304Ł[ Aliphatic ketones are normally reduced to the corresponding alcohol by catalytic
hydrogenation but it has been reported that\ under strongly acidic conditions and platinum"IV#
oxide catalysis\ conversion to the alkane "without the intermediacy of the alcohol# can occur
ð56TL1218Ł[
The combination of sodium borohydride and tri~uoroacetic acid has been shown to reduce a
range of diaryl ð67S652Ł and aryl alkyl ketones "Scheme 16# ð74JOC4340Ł in high yield\ unless a
strong electron withdrawing group is present ð67S652Ł[ This range of ketones can also be reduced
e.ciently by the action of hydride reagents in conjunction with Lewis acids\ for example\ lithium
i, TsNHNH2
O O
ii, BH
O
CHCl3
iii, NaOAc
41%
O
i, TsNHNH2
HO HO
ii, NaBH4, MeOH
OH OH OH OH
80%
Scheme 25
H2, Pd–C
EtOAc, ∆
~100%
O CO2H CO2H
OH O OH
O2N Cl– H3 N+
H2, Pd–C
H2O, HCl
85%
Cl O
Ra-Ni
EtOH, H2O
91%
Scheme 26
aluminum hydride ð47JA1785\ 76TL1826Ł or sodium borohydride "Scheme 16# ð76S625Ł with aluminum
chloride\ dibal!H with aluminum bromide ð81JOC1032Ł\ sodium cyanoborohydride with zinc iodide
ð75JOC2927Ł\ and triethylsilane with boron tri~uoride ð70OS"59#097Ł have all been used to good e}ect[
This last combination has also been shown to reduce a\b!unsaturated ketones without alkene
reduction ð76JOC0873Ł[
NaBH4, CF3CO2H
N 96% N
SO2Ph SO2Ph
NaBH4, AlCl3
THF Br
Br 94%
Scheme 27
0[90[1[3 Reduction of "C1O#X to CH2

The sole example of the direct hydrogenation of a carboxylic acid derivative to a methyl group
by catalytic hydrogenation is the quantitative transformation of benzoic acid to toluene under
C0Sulfur\ C0Selenium and C0Tellurium Bonds to CH 10
rhenium"II# oxide catalysis ð52JOC1236Ł[ Aliphatic acids are converted to alcohols under the same
conditions[
A series of benzoic acids and esters "with electron!donating substituents on the ring# has been
converted to the corresponding toluene derivatives by reduction with Red!Al in re~uxing xylene
ð58TL0628Ł[
Aliphatic esters and lactones undergo this type of reduction upon treatment with titanocene\ but
the reduction stops at the benzylic alcohol stage with aromatic systems ð63JA4189Ł[
The most clearly delineated method for the full reduction of benzoic acids involves the sequential\
one!pot treatment with excess trichlorosilane\ then a tertiary amine\ then hydroxide in aqueous
methanol ð69JA2121Ł[ The _rst step is thought to cause anhydride formation[ In the presence of an
amine\ the excess silane converts the anhydride to two moles of benzyl silane\ which is cleaved to
give the toluene derivative and a silanol[ The reaction is highly chemoselective\ aryl bromides\ and
even ester groups remain intact "Scheme 17# ð69JA2121\ 62JOC2559Ł[ The procedure can be extended
to the reduction of aryl esters by preliminary treatment with trimethylsilyl iodide and iodine\ forming
the trimethylsilyl ester\ followed by the reduction sequence ð68JOC1074Ł[
CO2H i, SiHCl3, MeCN

ii, Pri3N
iii, KOH, (aq.) MeOH

Br Br
94%
CO2H
i, SiHCl3, MeCN
ii, Prn3N
iii, KOH, (aq.) MeOH

41%
MeO2C MeO2C
Scheme 28
0[90[1[4 Reduction of C"OX#n Systems

Many methods are available for the reduction of ortho!esters to acetals\ or of acetals to ethers
ðB!73MI 090!90\ B!78MI 090!90Ł[ However\ complete reduction to the alkane oxidation state is rare[
Some simple benzylic acetals have been reduced to the corresponding toluene derivative by
catalytic hydrogenation ð42OR"6#152Ł[ Very occasionally this methodology is used to deprotect
benzylidene derivatives of carbohydrates ð17CB0649\ 52JOC0284Ł[
0[90[2 REDUCTION OF C0SULFUR\ C0SELENIUM AND C0TELLURIUM BONDS TO

CH

The most general method for reduction to alkanes in this area is by treatment with Raney!nickel
ð51CRV236\ 51OR"01#245Ł[ Thiols ð49JCS2999Ł\ sul_des ð81TL4456Ł\ sulfoxides ð75CC0577Ł\ dithioacetals
ð49JA3185Ł and selenium systems ð65TL1532Ł are all reduced cleanly and chemoselectively by this
procedure "Scheme 18#[
Radical chain reactions using stannanes are e.cient for the reduction of selenium and tellurium
systems "Scheme 29# ð79JA3327Ł but generally do not work well for the complete reduction of sulfur
analogues[
0[90[2[1 Reduction of C0SX Bonds

Historically\ the most important method for the reduction of alkyl thiols is Raney!nickel ð51CR236\
51OR245Ł\ which provides excellent chemoselectivity with consequent high yields "Schemes 18 and
20# ð49JCS2999\ 40JCS445Ł[
SH
OH OH
HO i, Ra-Ni, H2O HO
HO ii, Ac2O HO
OH 67% OH
SH
OH O
OH O
Ra-Ni, MeOH, ∆
51%
S
MeO
MeO
NMe Ra-Ni, (aq.) EtOH
MeO
NMe
Tol 51% MeO
+
S
O–
MeS SMe
Ra-Ni, EtOH
CO2Et
CO2Et
78%
SePh Ra-Ni, EtOH

C11H23
C11H23 65%
Scheme 29
SePh Ph3SnH, PhMe, ∆

N N
88%
CO2Et CO2Et
OH OH
Ph3SnH, PhMe, ∆
95%
TePh
Scheme 30
OH OH
O O
H H
MeO2C N Ph Ra-Ni, MeOH, ∆ MeO2C N Ph
N N
H 81% H
O O
SH
Mo(CO)6, AcOH
SH
83%
SH Mo(CO)6, THF
HO2C HO2C
67%
Scheme 31
More recently the use of homogenous transition metal reagents\ such as molybdenum hexa!
carbonyl "Scheme 20# ð79CC058\ 74JOC4302Ł\ and catalysts ð78JOC3363Ł have become popular ð89S78Ł
while stannane!mediated radical reductions have also proved successful ð71JA1935Ł[
In common with thiols\ the desulfurisation of dialkyl or aryl alkyl sul_des is often performed by
treatment with Raney!nickel ð51CRV236\ 51OR"01#245Ł[ The mild conditions a}orded by this procedure
are particularly useful when the stereochemical integrity of labile chiral centres elsewhere in the
molecule is important "Scheme 21# ð81TL4456\ 81TL5256Ł[
O
O
Ra-Ni, EtOH
Ph
Ph
70%
S
O O
PhS Zn, NH4Cl, THF
95%
Scheme 32
Homogenous transition metal catalysts and reagents have also been used in this context ð89S78Ł\
but seem to have a less general reactivity\ with most reported reductions being of relatively activated
"i[e[\ benzylic and a!carbonyl# sul_des ð74JOC4302\ 78JOC3363Ł[
Sul_des that are in the a!position of a carbonyl group can be reduced by a range of methods
which includes the use of Raney!nickel ð74JOC1478Ł\ but also low!valent metals\ such as samarium"II#
iodide and zinc\ in the presence of a proton source "Scheme 21# ð75JOC0024\ 76JOC1206Ł[ Allylic sul_des
are also prone to reduction by low!valent metals ð79JOC3986Ł\ or by lithium triethylborohydride in
the presence of a palladium"9# catalyst ð71JOC3279Ł[
There are relatively few examples of the desulfurisation of alkyl sulfoxides\ but here again Raney!
nickel appears to be the reagent of choice "Schemes 18 and 22# ð40JA0417\ 51OR"01#245\ 75CC0577Ł[
Sulfoxides a to a carbonyl group are reduced conveniently by low!valent metal systems such as
aluminium amalgam "Scheme 23# ð70JA1775Ł\ samarium"II# iodide ð75JOC0024Ł and zinc ð76JOC1206Ł[
Benzylic sulfoxides have been reduced by lithium aluminium hydride in the presence of a homo!
genous nickel catalyst ð78JOC3363Ł[
O O
O– Ra-Ni, Me2CO
S+
75%
R1 Ph R1
R2 R2
O– O O
S+ Al(Hg), THF, H2O
77%
Scheme 33
Na(Hg), MeOH
OH
95% OH
SO2Ph
SO2Ph
Na(Hg), MeOH
K2HPO4 H2N CN
O2N CN 84%
OAc SO2Ph OH
Mg, HgCl2 (cat.)
Ph Ph
EtOH
98%
Scheme 34
The reduction of sulfones to alkanes has been reviewed ðB!82MI 090!90Ł[ Most of these reactions
have been performed with low!valent metal reducing reagents\ most commonly sodium amalgam
"Scheme 23# ð65BSF402\ 65BSF414\ 70S44Ł "sodium in liquid ammonia has also been employed
ð75JOC747Ł#[ More recently\ other low!valent metal reagents\ such as lithium in ethylamine
ð81JOC3487Ł\ aluminium amalgam ð73JOC0135Ł and samarium"II# iodide ð75JOC0024\ 80TL0838Ł\ have
been employed and\ of these\ the use of magnesium in ethanol with a catalytic amount of mercury"II#
chloride seems particularly e}ective "Scheme 23# ð82TL3430Ł[
Potassium\ dispersed ultrasonically in toluene\ has been used to reduce only one carbonÐsulfur
bond of cyclic alkyl sulfones in high yields ð74TL3384\ 80TL2440Ł[ Unsymmetrical systems are reduced
at the more substituted position[
Benzylic sulfones can be reduced by dibal!H ð73RTC119Ł or by lithium aluminium hydride under
nickel catalysis ð78JOC3363Ł\ while allylic sulfones have been reduced by lithium triethylborohydride
in the presence of a palladium catalyst ð71JOC3279Ł[
Sulfoximines have been reduced by Raney!nickel ð71JOC0082Ł[
0[90[2[2 Reduction of C1S to CH1

There is little evidence to suggest that Raney!nickel is an e}ective agent for the desulfurisation of
thioaldehydes or thioketones ð51CRV236Ł[
Biarylthioketones have been reduced by zinc in aqueous acid ð55CB0282Ł\ diphosphorus tetraiodide
then sodium bisul_te ð74BCJ1310Ł\ a nicotinamide derivative in the presence of a dimercurated
benzene derivative "Scheme 24# ð74JA5010Ł and the tetrahydridocarbonylferrate anion "Scheme
24# ð64JOC1583Ł[ The last of these methods is the only one shown to be applicable to aliphatic
thioketones[
S HgO2CCF3
HgO2CCF3
CONH2
O O
N MeCN
Ph
73%
HFe(CO)4–
OMe
Me2N NMe2 MeO Me2N NMe2
77%
Scheme 35
0[90[2[3 Reduction of C"1S#X to CH2

Toluenes are formed in the reduction of methyl dithiobenzoates by zinc\ but only as minor
components of a complex mixture of products in which the corresponding methyl benzyl sul_de
predominates "Equation "3## ð55CB0282Ł[
S
Zn(Hg), HCl, H2O
Ph SMe + PhMe (4)
Ph SMe
58% trace
0[90[2[4 Reduction of C"SX#n Systems

One of the most important methods of deoxygenation of a ketone is by conversion to a dithioacetal
derivative\ which is then desulfurised by treatment with Raney!nickel "Schemes 18 and 25# ð38JA1769\
49JA3185\ 74JOC1596Ł[
EtS SEt
NHAc NHAc
HO
Ra-Ni, (aq.), EtOH HO
OH 56% OH
OH OH
OH OH
SMe Ra-Ni, EtOH

MeS CO2Et
CO2Et Ph
Ph 77%
S S
Ra-Ni, EtOH H
H
66%
Scheme 36
Although the method involves two separate reactions\ certain advantages are presented in com!
parison to protocols such as the Wol}ÐKischner and Clemmensen reductions[ Thus enone systems
are cleanly reduced without alkene reduction "Scheme 25# ð76JA2914\ 76JOC2235Ł\ and dicarbonyl
compounds can be reduced to a monocarbonyl derivative if selective dithioacetal formation can be
obtained "e[g[\ an aldehyde can be reduced in the presence of a ketone ð75CC340Ł#[
Dithioacetals in which both sulfur atoms are in the sulfone oxidation state can be reduced to the
alkane by treatment with magnesium in methanol "Scheme 26# ð77JOC0712\ 77T5744Ł[
O Ph O Ph
PhSO2 Mg, MeOH
PhSO2 77%
O Ph O Ph
O2
S Mg, MeOH
Ph
S 72%
O2 Ph
Scheme 37
0[90[2[5 Reduction of C0Se Systems

Although Raney!nickel can be used to reduce selenides and diselenoacetals "Schemes 18 and 27#
ð65TL1532\ 70T3986Ł\ these compounds are more commonly reduced "in higher yields# by radical
reduction procedures using stannanes "Schemes 18 and 27# ð79JA3327\ 70TL0512\ 70T3986Ł or silanes
ð81JOC1316\ 81JOC2394Ł[
Selenides have also been reduced by lithium in ethylamine ð65TL1532Ł and nickel boride
ð73CC0306Ł[ Allylic systems can be reduced by lithium triethylborohydride under palladium"9#
catalysis ð71JOC3279Ł[
0[90[2[6 Reduction of C0Te Systems

Tellurides can be reduced in a radical chain process by triphenylstannane "Schemes 29 and 28#
ð79JA3327Ł[ Telluride dichlorides are also reduced under these conditions at faster rates despite the
reduction proceeding via the corresponding telluride "Scheme 28# ð79JA3327Ł[
SeMe
Ra-Ni, EtOH, ∆
C13H28
C11H23 65%
C10H21 SeMe Ra-Ni, EtOH, ∆

C21H44
C10H21 SeMe 80%
SePh Ph3SnH, PhMe, ∆

C10H21 C11H24
SePh 84%
O
O
O
Bu3SnH, AIBN O
PhMe, ∆
PhSe 97%
O O
Bu3SnH, AIBN
SePh PhMe, ∆
87%
SePh
Scheme 38
TePh
Ph3SnH, PhMe, ∆
C12H26
C10H21 77%
TeCl2Ph
Ph3SnH, PhMe, ∆
C12H26
C10H21 92%
OAc
Ph3SnH, PhMe, ∆ OAc
C8H17
71% C8H17
TePh
Scheme 39
Copyright # 1995, Elsevier Ltd. All R ights Reserved Comprehensive Organic Functional Group Transformations
1.02
One or More CH Bond(s)
Formed by Substitution:
Reduction of Carbon–Nitrogen,
–Phosphorus, –Arsenic,
–Antimony, –Bismuth, –Carbon,
–Silicon, –Germanium, –Boron,
and –Metal Bonds
JOSHUA HOWARTH
Dublin City University, Republic of Ireland
0[91[0 THE REDUCTION OF CARBONÐNITROGEN BONDS TO CARBONÐHYDROGEN BONDS 17
0[91[0[0 Reduction of CarbonÐNitroèn Sin`le Bonds 17
0[91[0[0[0 Loss of sulfonamide anion 17
0[91[0[0[1 Loss of succinimide 18
0[91[0[0[2 Loss of pyridine derivatives 29
0[91[0[0[3 Loss of amines 21
0[91[0[0[4 Loss of nitroèn às 24
0[91[0[0[5 Loss of nitro `roups 25
0[91[0[0[6 Loss of cyanide 27
0[91[0[1 Reduction of CarbonÐNitroèn Double Bonds to Methylene and Methyl Groups 27
0[91[0[1[0 Reduction of C1N0NR0R1 systems where R0 is an aryl sulfonyl `roup 28
0[91[0[1[1 Reduction of C1N0NR0R1 systems where R0 or R1 is alkyl\ acyl\ aryl or hydroèn 30
0[91[0[1[2 Reduction of diazo systems 33
0[91[0[1[3 Reduction of N!alkylimine type systems 34
0[91[0[2 Reduction of CarbonÐNitroèn Triple Bonds to the Methyl Group 35
0[91[0[2[0 Reduction usin` palladium catalysts 36
0[91[0[2[1 Reduction usin` oxide supported catalysts 37
0[91[0[2[2 Reduction usin` hydride reaènts 37
0[91[1 REDUCTION OF CARBONÐPHOSPHORUS\ ÐANTIMONY AND ÐBISMUTH BONDS

TO CARBONÐHYDROGEN BONDS 38
0[91[1[0 Reduction of CarbonÐPhosphorus Bonds 38
0[91[1[0[0 CarbonÐphosphorus bond cleavaè to ìve a desired product not containin` phosphorus 38
0[91[1[0[1 CarbonÐphosphorus bond cleavaè to ìve a desired product containin` phosphorus 41
0[91[1[1 Reduction of CarbonÐArsenic Bonds 42
0[91[1[2 Reduction of CarbonÐAntimony Bonds 43
0[91[1[3 Reduction of CarbonÐBismuth Bonds 43
16
17 Reduction of CarbonÐNitroèn\ ÐPhosphorus\ etc[ Bonds
0[91[2 REDUCTIVE SCISSION OF A CARBONÐCARBON BOND TO TWO
CARBONÐHYDROGEN BONDS 44
0[91[2[0 Reductive Cleavaè when one Carbon is Part of a Nitrile Group 44
0[91[2[0[0 Use of hydride reaènts 44
0[91[2[0[1 Use of alkali metals in liquid ammonia 44
0[91[2[1 Cleavaè of CarbonÐCarbon Bonds where both Products are Hydrocarbons 45
0[91[2[1[0 Cleavaè usin` aluminum or aluminum:metal catalysts 45
0[91[3 REDUCTION OF CARBONÐBORON\ ÐSILICON AND ÐGERMANIUM BONDS

TO CARBONÐHYDROGEN BONDS 46
0[91[3[0 Reduction of CarbonÐBoron Bonds to Hydrocarbons 46
0[91[3[0[0 Cleavaè of carbonÐboron bonds under acidic conditions 47
0[91[3[0[1 Cleavaè of the carbonÐboron bond under neutral conditions 48
0[91[3[0[2 Cleavaè of the carbonÐboron bond with base 59
0[91[3[1 Reduction of CarbonÐSilicon Bonds 59
0[91[3[1[0 Cleavaè by acid 50
0[91[3[1[1 Cleavaè by base 51
0[91[3[1[2 Metal mediated desilylations 52
0[91[3[1[3 Desilylation by thermal decomposition and miscellaneous methods 52
0[91[3[2 Cleavaè of CarbonÐGermanium Bonds to CarbonÐHydroèn Bonds 53
0[91[4 REDUCTION OF CARBONÐMETAL BONDS TO CARBONÐHYDROGEN BONDS 54

0[91[4[0 Reduction of CarbonÐMercury Bonds 54
0[91[4[0[0 Protonolysis 54
0[91[4[0[1 Metal hydride demercuration 55
0[91[4[0[2 Miscellaneous methods 57
0[91[4[1 Cleavaè of Other Metals from Carbon to ìve a CarbonÐHydroèn Bond 58
0[91[4[1[0 Protonolysis 58
0[91[0 THE REDUCTION OF CARBONÐNITROGEN BONDS TO CARBONÐHYDROGEN

BONDS
0[91[0[0 Reduction of CarbonÐNitrogen Single Bonds

Reductive deaminations have been the subject of many reviews\ the last of which appeared in
0871 ðB!71MI 091!90Ł[ There have been several other earlier reviews on reductive deamination
ðB!45MI 091!90\ 55JCE0910\ B!57MI 091!90Ł[ The following sections are categorized with respect to the
type of nitrogen moiety lost in the deamination[
0[91[0[0[0 Loss of sulfonamide anion

The mechanism for such a reduction is essentially a nucleophilic displacement of a good leaving
group by a nucleophilic hydride "Equation "0##[ Sodium borohydride in polar aprotic solvents
"hexamethylphosphoramide "HMPA#\ DMSO# furnishes a convenient and e}ective source of nucle!
ophilic hydride which may be used for the reductive displacement of disulfonimides[ The incor!
poration of two powerfully electron!withdrawing groups\ principally sulfonyl ð67JOC1148Ł\ or
carbonyl ð62JOC0237Ł moieties\ on the nitrogen atom\ can be su.cient to stabilize the departing
anion[ Since non!basic anions are produced when sulfonimide is used as the stabilizer of the anion\
several synthetic applications have been developed using this method ð67JOC1148Ł[ An excellent
procedure exists for the production of disulfonimides from readily obtainable sulfonamides
ð63JOC2414Ł[ This procedure is\ however\ only applicable for unhindered primary amines[ To date\
no high!yielding method of producing disulfonimides from hindered amines has been found[ It
appears that sulfonamides resist addition of a second sulfonyl moiety in even moderately hindered
environments[ Research has suggested that the steric requirement of the disulfonimide surpasses
that of the trimethylammonium ion ð55LA"580#04\ 64JA5762Ł[ The range of compounds investigated
in this type of reduction spans several substituted aniline and straight chain primary amine deriva!
tives as well as a number of cyclic amines "Scheme 0#[
CarbonÐNitroèn Bonds 18
BH4–
R1N(SO2R2)2 R1 H + –N(SO R2)
2 2 (1)
HMPA
N(Tos)2 NaBH4
HMPA
78%
MeO MeO
N(Tos)2
MeO MeO
32%
Cl Cl
N(Tos)2
Cl Cl
22%
N(Tos)2
Et
77%
N(Tos)2
( )9 91% ( )8
N(Bros)2
( )9 73% ( )8
N(Tf)2
( )9 36% ( )8
( ) N(Bros)2 ( )
6 66% 6
Bros = p-bromobenzene sulfonyl
Scheme 1
0[91[0[0[1 Loss of succinimide

The development of a monomethylation procedure for aromatic amines ð62JOC0237Ł seren!
dipitously led to a method where certain succinimides derived from Mannich bases may be
reductively deaminated using sodium borohydride "Equation "1##[ Fortunately\ functionalities such
as ester\ nitrile\ or amide do not interfere with the reaction[ There is circumstantial evidence to
suggest that the reaction proceeds via a stabilized nitrogen anion\ similar to the case of the sul!
fonimide reductions "Scheme 1#[
O O
NaBH4 –
N ArNHMe + :N (2)
ArHN
O O
O O
Ar H
base NaBH4
+ – :N
N N CH2 Ar N
ArHN Me
O O
Scheme 2
0[91[0[0[2 Loss of pyridine derivatives
This method of reduction has been thoroughly investigated ð68CC299\ 68JCS"P0#331\ 79JCS"P0#1443\
79T568\ 73AG"E#319\ 73JCS"P0#0560Ł[ Highly substituted pyrilium salts are used for a two!step conversion
of the amino group in amines into numerous other functionalities[ The _rst step involves the
conversion of the pyrilium salt and the amine into a N!substituted pyridinium salt[ This salt is then
reacted with a nucleophile[ In the case of reduction this nucleophile is a hydride donor "Scheme 2#[
The amines used can be categorized into three di}erent groups\ depending on the substituted
pyrilium salt needed to perform the conversion[
Ph Ph Ph Ph
R NH2 NaBH4 heat

RMe +
+
Ph O Ph Ph N Ph Ph N Ph Ph N Ph
+
R R
(1)
Scheme 3
The _rst group consists of N!allyl\ N!benzyl\ and N!heteroarylmethyl amines[ The N!substituted
1\3\5!triphenylpyridinium salts "0# are reduced by sodium borohydride in good yields to the 0\1!
dihydro derivatives[ For these substituents the dihydropyridines decompose smoothly at around
199>C to give 1\3\5!triphenylpyridine and the product in which the amino group in the original
compound has been replaced by a hydrogen atom "Table 0#[
Table 0 Yields of deaminated products
RCH2 from the thermolysis of 0!"CH1R#!
1\3\5!triphenyl!0\1!dihydropyridines[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
R Yield
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
CH11CH 70
Ph 71
1!Furyl 71
1!Pyridyl 64
3!Pyridyl 66
*
NMR studies have suggested that this type of reaction could possibly involve a radical mechanism
"Scheme 3# ð68CC299Ł\ although unpublished work has suggested that the N!allyl type substituent
may undergo deamination via an electrocyclic course "Scheme 4#[
Ph Ph
D
Ph Ph
Ph N Ph N +
D • D
•
H2C
Scheme 4
Ph
D
D
Ph D
Ph N +
D
Scheme 5
The second group consists of primary alkylamines[ These amines react readily with 1\2\4\5!
tetraphenylpyrilium cations "1# to yield the corresponding pyridinium salts[ Steric hindrance directs
attack by the sodium borohydride to the para position and hence 0\3!dihydropyridines are produced
"Scheme 5#[ These decompose at 079Ð199>C to give the corresponding alkane "Table 1#[
Ph Ph Ph Ph Ph Ph
RNH2 NaBH4 heat
RH
+
Ph O Ph Ph N Ph Ph N Ph
+
R R
(2)
Scheme 6
Table 1 Yields of deaminated products

RH from the thermolysis of 0!substi!
tuted ! 1\2\4\5 ! tetraphenyl ! 0\3 ! dihydro!
pyridines[
R Yield
")#
*
n!C5H02 47
n!C7H06 77
Ph 43
PHCH1 33
Ph"CH1#1 53
p!ClC5H3CH1 51
*
Primary arylamines make up the third and _nal group[ The method described above for alkyl!
amines can be applied to arylamines for their conversion to the corresponding hydrocarbons\ but
the temperature required for decomposition is high\ 299>C\ and the yields using this method vary
considerably[ If N!aryl!1\3!diphenyl!4\5!dihydrobenzoðhŁquinolinium ~uorides "2# are formed and
heated to 059>C the corresponding arenes are produced in yields of around 59) "Table 2# "Equation
"2##[ The mechanism has not been resolved\ but is thought to be of the radical type similar to that
shown in Scheme 3 ð79T568Ł[
Ph Ph
heat
+ ArH + HF (3)
+
N Ph N Ph
Ar
F–
(3)
Table 2 Reduction deamination of

primary arylamines via N!"Ar#!1\3!di!
phenyl ! 4\5 ! dihydrobenzoðhŁquinolin!
ium ~uorides[
N!Substituent "Ar# Yield
")#
*
C5H4 59
p!Cl0C5H4 46
p!Br0C5H4 51
*
0[91[0[0[3 Loss of amines
Many examples are found where the leaving group involved in the reduction of an amine is also
an amine[ Amine salts of alkyl or aryl systems can be reduced to the corresponding alkyl or aryl
moiety in a number of ways\ including catalytic hydrogenation\ metal reductions\ and various
hydrides[ All these methods have been extensively reviewed ðB!45MI 091!90\ 55JCE287\ B!57MI 091!90\
62S633\ B!74MI 091!90Ł[ In addition electrolytic reductions are known and have also been reviewed
ðB!57MI 091!90Ł[
Catalytic hydrogenation using palladium on carbon and formic acid ð79JOC3815Ł has been found
to reduce amines attached to molecules containing carbonÐcarbon double bonds and hydroxyl
functionality[ Essentially the corresponding alkene is formed with little rearrangement of the carbonÐ
carbon double bond "Table 3#[
Table 3 Catalytic hydrogenation using palladium on carbon and formic acid[

Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Amine Major product Yield
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
E!MCH"CH2#CH1CHCH1CH"OCH2#1 Z!2! and 3!hexenal dimethyl acetal 50
E!"Pip#CH"CH2#CH1CHCH1CH"OCH2#1 Z!2! and 3!hexenal dimethyl acetal 56
E!"CH2Pip#CH"CH2#CH1CHCH1CH"OCH2#1 I Z!2! and 3!hexenal dimethyl acetal 52
E!"Pip#CH1C"CH2#1CHCH1C"CH2#1OH "CH1#1C1CHCH1C"CH2#1OH 48
E!"Pip#CH1C"CH2#1CHCH1Ph "CH1#1C1CHCH1Ph 59
E!"Pip#C"CH2#1CH1CHCH1CH"OCH2#1 "CH2#1CHCH1CHCH1CH"OCH2#1 20
"CH2#1C1CH"CH1#CH"OCH2#1 20
*
M morpholino\ Pip piperidino[
Reduction of non!allylic systems appears not to have been attempted using this method[ However\
reduction of a range of amines using a platinum halide on silica has been investigated ð73JOC1764Ł[
This method can reduce amines to the alkanes or arenes and ammonia "Table 4#[ In some cases the
temperature needed for the reduction to occur is as high as 114>C[ The reaction system will also
reduce nitrogen heterocycles to arenes or alkanes and ammonia "Scheme 6#[
Table 4 Reduction of amines using platinum halides on silica[

Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Amine Product Yield
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
n!Hexylamine n!Hexane 88
Cyclohexylamine Cyclohexane 88
0!Adamantane amine No reaction 88
0!"Methylamino#adamantane 0!Methylladamantane 88
Piperidine n!Pentane 88
Quinuclidine 2!Ethylpentane 77
Aniline Cyclohexane 88
Diphenylamine Cyclohexane 88
*
Pt, H2
+
N
Pt, H2
+
N
H
Scheme 7
In all\ this is a good method for defunctionalizing simple amines to their corresponding hydro!
carbons[ The problem of reduction of other functionality in more complex systems has not been
fully investigated[
The use of other hydrides such as tri!n!butyltin hydride ð77SC0196Ł\ aluminum hydrides ð70T1686Ł\
and borohydrides ð67CC0978Ł in the reduction of amines has also been researched in some detail[
Tri!n!butyltin hydride was used to reduce a series of similar compounds as shown in Scheme 7
ð77SC0196Ł[ This appears to be the only examination of this reagent as an amine reductant[ Tem!
peratures of 199>C were required to e}ect the reaction^ the method can also be used to reduce
oxides and salts of the amine "Scheme 8#[
OH OH
Me
N
Me 85%
OH OH
N
90%
Me
N
Me
OH OH
89%
OH OH
Me
N 65%
N Me N
O O
Me
N
Me 67%
Scheme 8
OH OH
+ Me
N I–
Me
Me 82%
OH OH
+ Bun
N
Bun
O– 81%
Scheme 9
The mild and selective reagent\ sodium cyanoborohydride\ has been used very successfully in the
high!yield reduction of quaternary ammonium salts "Scheme 09# ð67CC0978Ł[ The reduction occurs
in the presence of halogen\ ester\ nitrile and nitro functionality[ Several benzenoid derivatives have
been reduced to the parent benzenoid compound "Table 5#[ However\ the drawback with this
method is the simultaneous use of two highly toxic compounds "HMPA and dimethylsulphate# in
the reaction[
Me2SO4 + NaBH3CN
Ar NMe2 Ar NMe3 + MeSO4– ArMe
THF HMPA
Scheme 10
Table 5 The reduction of benzenoid tertiary amine derivatives using Me1SO3 followed by NaBH2CN[
OH NMe2
NMe2
NMe2
Amine OH
N
R H
Yield of R=H Cl CO2Et CH2CN NO2

methyl
product (%) 71 83 91 72 90 74 77
In general amides can be reduced to the corresponding aldehyde[ To obtain the aldehyde by
cleavage of the amide it is necessary to maintain the amide in excess[ The reagent commonly used
for this process is an aluminum hydride\ usually lithium aluminum hydride\ but variations have
been used ðB!74MI 091!90Ł[
A nice demonstration of the selectivity of hydride reagents is clearly shown by the use of lithium
aluminum hydride ð70T1686Ł on an amide containing an epoxide "3#[ The amide was reduced to the
corresponding aldehyde without any unwanted reduction of the epoxide unit "Scheme 00#[
CO2Me O
i, LiAlH4
N
O O Ph
ii, H2O
O Ph
(4)
Scheme 11
Early methods of reducing amines to the corresponding alkane commonly revolved around the
use of metal reductions such as zinc and acetic acid at re~ux temperature ð47JA0543\ 64BCJ0781Ł or
Raney nickel hydrogenolysis at 59Ð099 atm and at 79>C "Scheme 01# ð42JA0017Ł[ Some methods
used sodium methoxide at 079>C ð40JA1607Ł[ These are all harsh conditions\ and since more subtle
and selective methods for functional group interconversions have been developed\ the tendency to
use these harsher methods has become minimal\ although tin chloride has been used recently
"Scheme 02# ð72SC566Ł[ One of the methods that is useful in the reduction of amines is the cleavage
of tetraalkyl ammonium halides using sodium in liquid ammonia[ This method has been carried out
on a large number of substrates and results in good yields in almost every case "Equation "3##
ð48JA3749Ł[ This is a mild way of reducing amines\ useful as long as there is no other functionality
in the molecule which dissolving metal reductions can a}ect[
Na/NH3, 78 °C
Bun4N+ Br– BunH + Bun3N + NaBr + NaNH2 (4)
79%
An example of an electrolytic reduction is shown in Equation "4#[ This involves the reduction of
a!amino acid esters to the corresponding b!keto esters in good yields ð62JOC1620Ł[
O O
R1 2e– + 2H+ R1
R3 R3 + NH4Cl (5)
CO2R2
+
NH3 – CO2R2
I
O O
OH OH
O Zn/MeCO2H
N 51%
I–
Cl +NMe Cl
OH 3 OH
OH OH
Zn/MeCO2H
CONH2 73% CONH2

OH OH
OH O OH O OH O OH O
NaOMe, 180 °C
N 49%
OH OH
Scheme 12
MeO CHO MeO CHO

i, Ac2O/reflux
HO ii, conc HCl HO

iii, SnCl2•2H2O
HCl/dioxane/reflux
NMe2
Scheme 13
0[91[0[0[4 Loss of nitrogen gas

Amine reductions which result in the formation of a nitrogen molecule are\ in most cases\ believed
to proceed via a diimide intermediate[
An example of this strategy is the reaction of primary amines with di~uoroamine "Scheme 03#[
This conversion and its mechanism have been previously reviewed ð52JOC0097\ 55JCE287\ B!57MI
091!90\ 69MI 091!90\ 60ACR082\ B!61MI 091!90Ł[
R
RNH2 + HNF2 RH + N2
N NH
Scheme 14
The _rst reported procedure for reductive deamination of amines to form alkanes via the diimide\
involved the reaction of hydroxylamine!O!sulfonic acid "Scheme 04# or chloramine with aryl!
sulphonamides[ Similar reductions are observed when alkylhydrazines are oxidized to alkyldiimides
ð52JA0097Ł[ A similar reaction of primary amines with hydroxylamine!O!sulfonic acid has been
reported "Equation "5## ð67JA230\ B!71MI 091!90Ł[ This is a direct\ general and selective method of
deamination "Table 6#[
ArSO2Cl OH–
RNH2 RNHSO2Ar RH + ArSO3H + N2
NH2X
X = OSO3H or Cl
Scheme 15
NH2OSO3H
RNH2 RH + SO42– + N2 (6)
HO–, 0 °C
Table 6 Reduction of primary amines using hydroxylamine!O!sulfonic acid[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Substrate Product Yield
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
1!Aminobenzoic acid Benzoic acid 61
1!Amino!2!methylbenzoic acid 2!Methylbenzoic acid 15
Benzylamine Toluene 54
2!Aminopropionic acid Propionic acid 49
Alanine Propionic acid 49
L!Alanyl!L!phenylalanine N!Propionyl!L!phenylalanine 40
*
As can be seen from Table 6\ several amines can be reduced by this method in yields of 15Ð61)[
Carbonyl and amide groups seem not to seriously interfere with the reduction of 1!aminobenzoic
acid to benzoic acid or 1!amino!2!methylbenzoic acid to 2!methyl!benzoic acid[ Diazoketones may
be reduced to methyl ketones by hydrogen iodide "Equation "6## ð57AJC0264Ł[ Since it is possible to
obtain diazoketones from the corresponding amine\ this is a useful type of deamination[
RCOCHN2 + 2 HI RCOMe + N2 + I2 (7)
Aromatic deaminations may be accomplished in either two!step or by one!step reactions[ In the

latter case the diazonium ion is produced _rst[ This is then followed by reductive dediazonisation[
Hypophosphorus acid tends to be the most common reducing agent used "Equation "7##\ although
a number of others have been reported ð33OR"1#151\ 41JA2963\ 52RCR48\ 66JOC1320\ B!74MI 091!90Ł[
i, HNO2
ArNH2 ArH + N2 (8)
ii, H3PO2
Using the one!step procedure\ the arylamines are treated with alkyl nitrites in solvents such as
ethers or DMF ð62JCS"P0#430\ 66JOC1320Ł[ Variations of this method ð66JOC1320Ł have resulted in
good yields for deamination[ Evidence exists for a free radical mechanism for this reaction "Scheme
05# ð66JOC1320Ł[ The alkyl nitrite method of deamination has been applied to the conversion of the
adenine derivative "4# to the corresponding purine "5# "Equation "8## ð68TL0070Ł[
Ar
ArNH2 + RONO + H2O
N NOR
Ar
ArN2• + RO•
N NOR
ArN2• Ar• + N2
Solvent + Ar• ArH + Solvent•
Scheme 16
NH2
N N
N Me(CH2)4ONO N
+ N2 (9)
N THF N
N N
Et Et
(5) (6)
0[91[0[0[5 Loss of nitro groups

Much research has been carried out on the reduction of nitroalkanes to the corresponding alkane[
The dominant method for achieving this conversion involves the use of trialkyltin hydrides\ in
particular tri!n!butyltin hydride ð70TL0694\ 71JOC0936\ 72CC764\ 72JA3906\ 72TL2366\ 73HCA150\ 74JOC2581\
74S158\ 74T3902\ 75JOC1721\ 76JOC4942\ 76S710Ł[ The reaction is extremely versatile and only presents
problems if other groups are present in the molecule which are susceptible to radical attack[ The
examples shown in Scheme 06 illustrate the versatility of this procedure[
O O
Bu3SnH, AIBN
Bun Bun
80 °C, 2 h,
NO2 87%
NO2
O O
85%
O O
EtO EtO
NO2
P(OEt)2
90%
P(OEt)2 O
O
O O
82%
NO2
Scheme 17
Other hydrides such as sodium hydrogentelluride have been used to remove the nitro group[ It is
claimed ð74BCJ0956Ł that this reagent overcomes some of the drawbacks associated with other
methods\ such as high temperatures\ chromatographic separation problems and long reaction times[
The reagent is successful for a range of substrates and gives high yields "Scheme 07#[
COMe NaHTe, EtOH

COMe
NO2
CO2Et 100% CO2Et
MeOC MeOC
NO2
98%
EtO2C EtO2C
MeO NO2 MeO

85%
Scheme 18
Lithium aluminum hydride has also been used as a reductant "Equation "09## ð72S026Ł[ It is
interesting to note that although lithium aluminum hydride can be used to reduce carbonÐnitrogen
double bonds "see Section 0[91[0[1[0# this does not occur in the reaction illustrated in Equation
"09#[
NO2
Tos N LiAlH4, THF Tos N
N N (10)
89%
H Prn H Prn
Other methods for reduction of the nitro group to the corresponding alkane include using the
sodium salt of methanethiol in dipolar aprotic solvents ð74BCJ0956Ł\ potassium hydroxide in ethylene
glycol ð57JOC0310Ł\ and N!benzyl!0\3!dihydronicotinamide ð73TL3306Ł[
0[91[0[0[6 Loss of cyanide
There are two common methods currently found in the literature for deamination via the isonitrile[
One of the procedures uses tri!n!butyltin hydride as the reductant ð57JA3071\ 68CC234\ 68TL1180\ 79S57Ł[
This radical!induced deamination of isonitriles gives high yields and the reaction is tolerant of a
large number of functional groups[ An example of this tolerance is given below "Equation "00##[
The mechanism is thought to be that shown in Scheme 08[
O O
O Bun3SnH O
(11)
89%
CN
R13SnH R13Sn•
R2 R2
R13Sn• + •
N CH2 N CSnR13
R2 β-scission
• R2• + R13SnCN
N CSnR13
R2• + R13SnH R13Sn• + R2H
Scheme 19
The second method utilizes a dissolving metal reduction\ the mechanism of which "Scheme 19#
and a typical reaction "Equation "01## are shown[
e–
R:– + CN–
e– "H•"
RNC [RNC]•– RH
–CN–
R•
e–
R:–
Scheme 20
Ph DME, Na Ph
(12)
Ph NC naphthalene, –10 °C Ph
Several isonitriles have been reduced in this way using alkali or alkali earth metals in liquid
ammonia "Equation "02## ð50CB0046\ 55HCA0034\ 67JOC1285Ł[ The yields are extremely good and
examples are listed in Table 7[
RNC + 2M + NH3 RH + MCN + MNH2 (13)
0[91[0[1 Reduction of CarbonÐNitrogen Double Bonds to Methylene and Methyl Groups

This section considers the reduction of systems "C1N#X to methylene or methyl groups\ where
X is carbon\ hydrogen or a heteroatom[ The reduction of carbonÐnitrogen double bonds can be
divided into three distinct groups of substrates[ Firstly there are the arylhydrazones derived from
an aldehyde or ketone\ with the general formula C1N0NR0R1\ where R0 is an arylsulfonyl moiety[
Table 7 Reduction of isonitriles "RNC# with M:NH2[
R Metal (M) Yield

(%)
But Na 93
C6H11 Li 96
n-C12H25 Na 88
PhCH2 Na 58
Na 57
The next group consists of those hydrazones\ C1N0NR0R1 where R0 or R1 are anything but
arylsulfonyl groups[ The last group contains the molecules with the imino group C1NR0R1 where
R0 or R1 can be alkyl\ aryl\ acyl or arylsulfonyl[
0[91[0[1[0 Reduction of C1N0NR0R1 systems where R0 is an aryl sulfonyl group

The conversion of alkyl!arylsulphonyl compounds to alkyl compounds was investigated in a very
deliberate fashion[ It was known that alkyl!p!toluenesulfonyl hydrazides could undergo thermal
decomposition\ in protic or aprotic solvents\ with or without basic catalysis\ to nitrogen\ p!toluene!
sul_nic acid and alkanes ð52JA0097Ł[ The intermediate was thought to be an alkyl!diimide "Scheme
10# ð25JCS473\ 52JA0097Ł[
H
N R N R TosH + N2 + RH
Tos N Tos N
2H
H
Scheme 21
Alkyl!p!toluenesulphonyl hydrazones\ on the other hand\ decompose with basic reagents to give
alkenes ð41JCS3624\ 54JA824\ 55T376Ł\ but via a common intermediate\ diimide[ So it was reasoned\ if
the carbonÐnitrogen double bond of a p!toluenesulfonyl hydrazone could be reduced to a carbonÐ
nitrogen single bond\ then the decomposition of the substituted p!toluenesulfonyl hydrazide so
formed should lead to the formation of a methylene or methyl group "Scheme 11#[ A whole series
of p!toluenesulfonyl hydrazones was subjected to reaction with lithium aluminum hydride or sodium
borohydride ð52T0016\ 55T376Ł[ These included p!toluenesulfonyl hydrazones derived from both
ketones and aldehydes\ the former giving a methylene group on reduction and the latter a methyl
group "Table 8# ð52T0016Ł[
H R1 H R1 R1
N N N TosH + N2 + R1 R2
Tos N R2 Tos N R2 Tos N R2
H
Scheme 22
The reaction using lithium aluminum hydride as the reducing agent has since been used suc!
cessfully in some natural product syntheses[ A particular example is the synthesis of "Z#!8!tricosene
"6#\ the sex pheromone of the domestic house~y ð89JOC4048Ł[ A typical reaction is given in Scheme
12 and further examples are given in Table 09[
Other reducing agents have been used to e}ect this reaction[ One such reductant is a zinc modi_ed
cyanoborohydride reagent which has been put to use in the deoxygenation of aldehydes and ketones\
using the p!toluenesulfonyl hydrazone in methanol and a 1 ] 0 ratio of cyanoborohydride to zinc
chloride ð74JOC0816Ł[ The yields are in excess of 74) "Table 00#[ The same method was used
to produce disubstituted cyclohexanes for research into aliphatic liquid crystals "Equation "03##
ð77CB0928Ł[
Table 8 Reduction of some p!toluenesulfonyl hydrazones with lithium
aluminum hydride or sodium borohydride[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
p!Toluenesulfonyl hydrazone of Product Yield
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
4a!Cholestan!2!one Cholestane 69
Coprostan!2!one Coprostane 54
2b!Acetoxy!4a!cholestan!6!one 2b!Hydroxy!4a!cholestane 54
Hecogenin Tigogenin 49
Indol!2!aldehyde Skatole 49
a!Naphthaldehyde a!Methylnaphthalene 69
*
H
O
TosNHNH2
N LiAlH4
R2 Tos N R2
R1 R2 R1
MeOH THF, 60 °C
NO2 R1
NO2
R1 = Me(CH2)6 (CH2)6CH2 (7)
R2 =
Scheme 23
Table 09 Reduction of more complex p!toluenesulfonyl hydrazones[
p-Toluenesulfonyl hydrazone of R Yield of alkane

(%)
O
Me 70
R
Ph n-C8H17 61
NO2
O
Ph 67
NO2
O
Me 65
R
( )10
n-C8H17 68
NO2
Table 00 Reduction of hydrazones using cyanoborohydride and

zinc chloride[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
p!Toluenesulfonyl Product Yield
hydrazone of ")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
1!Undecanone Undecane 67
3!t!Butylcyclohexanone 3!t!Butylcyclohexane 74
Cholestan!2!one Cholestane 83
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Tos
H N
N NaBH3CN
Ph Ph (14)
ZnCl2/MeOH
85%
Catechol borane has also been used as a reducing agent for p!toluenesulfonyl hydrazone systems
ð64JOC0723\ 65JOC463\ 66S013\ 68SC164Ł[ The metalborohydride\ bis"triphenylphosphine#copper"I#
tetrahydroborate can facilitate the reduction of a wide range of ketone and aldehyde hydrazones
although yields for the latter are not particularly high "Table 01# ð79TL3920Ł[
Table 01 Reduction of hydrazones using bis"triphenylphosphine#
copper"I# tetrahydroborate[
p!Toluenesulfonyl Product Yield
hydrazone of ")#
*
Cholestanone Cholestane 69
Adamantone Adamantane 73
3!t!Butylcyclohexanone 3!t!Butylcyclohexane 63
Nonan!4!one Nonane 69
Cyclohexanone Cyclohexane 57
Cyclopentanone Cyclopentane 46
N!Methylpiperid!3!one N!Methylpiperidine 06
Nonanal Nonane 45
Palmitaldehyde Hexadecane 37
3!Methoxybenzaldehyde 3!Methylanisole 19
3!Nitrobenzaldehyde 3!Nitrotoluene 09
*
Using the p!toluenesulfonyl hydrazone "7# of a ketone adjacent to a sul_de a reaction involving
the 0\1!transposition of a carbonyl group has been carried out[ This reaction involves a conversion
of a carbonÐnitrogen double bond to a methylene unit via a vinyl sulphide\ formed by the action of
n!butyllithium on the hydrazone "Scheme 13# ð67CC303Ł[
H
N
N Tos
SMe SMe O
MeLi HgCl2
Et2O MeCN/H2O
(8)
Scheme 24
0[91[0[1[1 Reduction of C1N0NR0R1 systems where R0 or R1 is alkyl\ acyl\ aryl or hydrogen

This second type of reduction of carbonÐnitrogen double bonds is dominated by the Wol}Ð
Kishner reaction "Scheme 14# which was originally discovered in 0801 ð37OR"3#267Ł[ A ketone is
reacted with hydrazine and a strong base[ A hydrazone is formed in situ\ and reacts with the strong
base to form an alkane and nitrogen ð37OR"3#267Ł[ The original reaction has almost entirely been
replaced by the HuangÐMinlon modi_cation ð35JA1376\ 38JA2290Ł in which the reaction is carried
out in diethylene glycol at re~ux[ The method is not suitable for a\b!unsaturated aldehydes or
ketones\ which give pyrazolines under these conditions[ Sterically hindered ketones are resistant to
reduction but can be reduced by vigorous treatment with anhydrous hydrazine ð44JCS1933Ł[ The
reaction has been used successfully on a more complex molecule "8# "Equation "04## ð41JCS1016Ł[
R –OH
R –OH
R
NH2 NH N– + H2O
R N R N R N
R –N2 – H2O
N– R R R R
+ OH–
R N
Scheme 25
N NH2
25% KOH(aq.), reflux
O O (15)
S 84% S
(9)
Several N!unsubstituted hydrazones of aldehydes have been subjected to treatment with potassium
hydroxide[ The product of the reaction is the methyl analogue of the original aldehyde ð32CB0141Ł[
The yields ranged from 67) to 75) "Table 02#[
Table 02 Reduction of hydrazones using potassium hydroxide[

Hydrazone of Product Yield
")#
*
Benzaldehyde Toluene 68
1!Chlorobenzaldehyde 1!Chlorotoluene 71
1\5!Dichlorobenzaldehyde 1\5!Dichlorotoluene 79
1!Aminobenzaldehyde 1!Aminotoluene 55
1!Hydroxybenzaldehyde 1!Hydroxytoluene 75
Anthracenealdehyde!"8# 8!Methylanthracene 67
Pyrenealdehyde!"2# 2!Methylpyrene 73
*
The same general conditions can be applied to acylhydrazones or semicarbazones as in the

conversion sequence shown in Equation "05# ð72JOC2755Ł[ In this case the reaction conditions for
reduction of the acylhydrazone "09# were 1!methoxymethanol and sodium hydroxide at re~ux
temperature for 29 minutes[ The conditions are claimed to be milder than usual[
NaOH
(16)
MeO
N OH
50%
MeO N O O
H
O
(10)
Several heterocyclic molecules\ pyrrole\ furan\ and thiophene have been transformed from their 1!
formyl derivatives to the corresponding methyl analogue by initial conversion to the semicarbazone
followed by reduction using a strong base "Scheme 15# ð40JA3922\ 45JOC807\ 65T718Ł[ The yields of
the methyl derivatives were substantially higher than in previous methods and the reactions more
straightforward[ Another semicarbazone which has been reduced to the corresponding alkane is the
cyclic compound "00# "Equation "06## ð48CB805Ł[
N O
N
S S
H
H2N
KOH(aq.)
N O
N
N 75% N
H
H H
Scheme 26
H
N N KOH
HO
O O (17)
88%
(11)
A further modi_cation of this procedure\ involving the slow addition of hydrazones of aldehydes
and ketones to a solution of sublimed potassium t!butoxide in anhydrous DMSO at 14>C\ a}ords
a mild method of reduction "Equation "07## ð51JA0623Ł[
NH2
N
ButOK, DMSO
(18)
72%
There are two other distinct methods of reducing a hydrazone[ In at least two instances ð60JOC626\
76JCS"P0#1260Łpalladium on carbon with hydrogen has been used as the reductant "Equation "08##[
As Table 03 shows\ the reaction is extremely e}ective\ and it can be applicable even when there is a
range of other functionalities in the molecule ð76JCS"P0#1260Ł[
Y
Pd–C, H2
(19)
R R MeCO2H R R
Table 03 Reduction of hydrazones to methylene using palladium on carbon and hydrogen[
Yield (%) of alkane when Y =

NNHC6H3(NO2)2 NNHCONH2 NNHC6H5
92 93 96
81 97 94
But
84 85
Y
Y
71
95
An alternative method of reduction is with lithium aluminum hydride "Equation "19##[ Unlike
most other hydrazone reductions\ the reaction proceeds at room temperature under non!acidic
conditions\ thus furnishing a mild pathway to the methylene group ð80TL0580Ł[ Several substrates
have been examined "Table 04# and the reaction gives moderate "33)# to good "70)# yields[ The
reaction utilizes an N!aminoaziridine to form the requisite hydrazone[ This method has also been
used to reduce arylhydrazones derived from aldehydes to the corresponding methyl compound
ð47CB1272Ł^ alkyl substituted benzylamines were produced "Equation "10##[
Ph
N LiAlH4
N Ph (20)
R R
R R
Table 04 Reduction using lithium aluminum hydride[
Hydrazone of Yield
(%)
But O 81
59
O
O 48
O
Ph
N O 44
O R C6H5(NO2)2 R
Pd–C, H2
N (21)
Ph O N N H toluene H2N
H
R = Ph or p-MeOC6H5
0[91[0[1[2 Reduction of diazo systems

Diazocompounds can be reduced to the corresponding methylene compounds using 4) palladium
on charcoal and hydrogen in an autoclave at room temperature for one hour "Equation "11##
ð74JCS"P0#382Ł[ A better reducing system "in terms of yields#\ developed by the same research team\
involves the use of Rh1"OAc#3 "Equation "12##[ However this reagent also catalyses a rearrangement
which converts the neighbouring hydroxyl group to a carbonyl group ð68CC848Ł[
OH O 5% Pd–C OH O
MeOH
(22 )
R OEt 63–75%
R OEt
N2
HO
R = Me, Pri, n-C7H15, Ph, or
AcO OAc
H
OH O O O
Rh2(OAc)4
(23)
R OEt DME
R OEt
N2 92–100%
R = Pri, Prn, Ph2CH, CH2=CH, PhCH=CH or Ph

Several diazoketones have been reduced to the corresponding methyl ketone ð43JCS2506\ 70CPB2378\
89SL354Ł[ Many of the conversions are carried out by means of the standard Wol} method as shown
in Scheme 16 ð32JA0405Ł[ The reduction of diazoketones has been used to produce variants on
antimalarial drugs ð35JA0702Ł[
N2
O O
OAc OAc
HI, H2O
OAc OAc
OAc OAc
OAc OAc
OAc OAc
MeCO2CH2CHN2 MeCO2CH2Me
NaOH
PhCOCHN2 PhCOCH NNH2 PhCOMe
Scheme 27
0[91[0[1[3 Reduction of N!alkylimine type systems

Several methods for the deamination of the N!alkylimine type of system are found[ The _rst is
just an extension of the HaungÐMinlon adaptation of the Wol}ÐKishner reduction mentioned in
Section 0[91[0[1[1 ð35JA1376Ł\ an example of which is shown in Equation "13# ð55JCS"C#314Ł[
N diethylene glycol NH2

(24)
KOH, N2H4•xH2O
N 92% N
H H
The second is by use of hydrides[ Several amidines have been reduced using hydride reagents\
such as lithium aluminum hydride "Table 05# ð76S608Ł and lithium borohydride "Equation "14##
ð69KGS384Ł[
Table 05 Reduction using lithium alum!

inum hydride with variation of substituent
R for Equation "14#[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
R Yield
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Ph 49
3!MeOC5H4 61
Cyclopentyl 49
Cyclohexyl 55
Et 03
CH2CH"C1H4# 45
Cyclopropyl 34
Cycloheptyl 33
*
Tos
N
LiAlH4, THF
R N R N (25)
O O
Sodium borohydride in ethanol has also been used in the reduction of diarylimines to the
corresponding diarylmethanes "Equation "15##[ It is the o!hydroxydiarylimines\ such as "01#\ that
produce the diarylmethanes and a mechanism has been proposed ð74IJC"B#48Ł[
OH OH
NaBH4, EtOH
(26)
Ph 74%
N
MeO OH MeO OH
(12)
It has been shown that arylimines can be used to produce methyl substituted resorcinols
ð32HCA799Ł using a palladium catalyst[ However the conditions employed\ 019>C for _ve hours and
with the hydrogen pressure at 19 atm\ are rather severe "Equation "16##[
HO OH HO OH
Pd–C, H2
N (27)
Ph 20 atm
62%
One isolated case of an imine being reduced to the corresponding methylene compound by the
action of hydrogen sul_de in DMF at 19Ð54>C has been reported "Equation "17## ð58M613Ł[
Bun
N H H
H2S, DMF
N N (28)
Ph Bun 20 °C to 65 °C Ph Bun
S S
A decalin derivative was produced as shown in Scheme 17 ð64JOC2575Ł[ The imine was produced
from hydrazine and potasium hydroxide in triethyleneglycol[ The reaction was left for one hour at
59>C and then for nine hours at 109>C "whereby a distillate was collected# then a further 01 hours
at 109>C[ This procedure yielded the desired product[
N2
HCl, 0 °C benzene, Dean and Stark
O O
79%
O O O
N
H
85%
Scheme 28
The simple methylimine of benzaldehyde shown in Equation "18# was reduced to the p!methoxy!
toluene using sodium telluride ð77TL1460Ł[ Some amine was also produced[
Me Me
N N
H
NaTeH
EtOH, 24 h + (29)
OMe OMe OMe
25% 75%
0[91[0[2 Reduction of CarbonÐNitrogen Triple Bonds to the Methyl Group

Three ways of reducing the nitrile group to a methyl group are known[ Reduction using a source
of hydrogen and a catalyst\ which may either consist of palladium or Raney!nickel\ can be used[
Associated with this method are the procedures which use metal catalysts supported by oxides such
as silica[ Finally the reduction can be achieved using a hydride reagent[
0[91[0[2[0 Reduction using palladium catalysts

The _rst example in this category was the result of an accidental discovery[ The real aim of the
experiment ð76T2706Ł was to debenzylate the 2!indolecarbonitrile using palladium on carbon and
hydrogen "Equation "29##[ The reaction was left for one week^ the only product formed was the 4\5!
dimethoxy!1\2!dimethyl!0!"phenylmethyl#!0H!indole "74)#[
CN
MeO MeO
5% Pd–C, H2
(30)
N 85% N
MeO MeO
Bn Bn
An earlier investigation ð55CB116Ł examined the use of terpene hydrogen donors with palladium
on carbon catalysts "Equation "20##[ It was observed that aromatic nitriles were readily reduced to
the corresponding methyl compounds[ With the exception of three examples\ all of the 10 nitriles
tested could be reduced to the methyl analogue in under two hours\ with half the reactions giving
yields between 74) and 89)\ the others giving yields in the range 69) to 74)[ Temperatures
needed for the reaction varied from 89Ð204>C[
Pri Pri
PhCN PhMe (31)

10% Pd–C
Ammonium formate has also been used as the source of hydrogen\ using palladium on carbon as
the catalyst "Equation "21## ð71S0925Ł[
CN
10% Pd–C
+
(32)
HCO2– NH4, MeOH
20 h, RT
OMe OMe
The reduction of several nitriles using Raney!nickel has been achieved by two separate methods[
The _rst uses Raney!nickel in ethanol ð76S735Ł[ Here the nitrile\ ethanol and Raney!nickel are
simply mixed and heated to re~ux temperature for a period of _ve hours "Equation "22##[ Yields of
around 69) were achieved[
CN
HO HO
Raney Ni, EtOH
SMe SMe (33)
N reflux, 5 h N
79–92%
R R
R = Ph, 4-ClC6H5, 4-MeOC6H5, C6H5CH2
The second uses Raney!nickel and hydrogen as the reductant[ The 1!cyano!3!methylamino!5!
hydroxy!s!triazine "02# with a catalytic amount of Raney!nickel and sodium acetate in acetic
anhydride\ was hydrogenated at 1[5 atm and 49>C for one hour ð51JA2633Ł "Equation "23##[ The
product\ 1!methyl!3!methylamino!5!hydroxy!s!triazine "03# was obtained in 55) yield[
CN
Raney Ni, H2, 50 °C
N N N N (34)
66%
Me2N N OH Me2N N OH
(13) (14)
0[91[0[2[1 Reduction using oxide supported catalysts

In one of the _rst investigations into the use of metals and oxides to reduce nitriles to the
corresponding methyl analogue ð48BCJ750Ł p!amino benzonitrile "04# was heated under nitrogen to
229>C in the presence of NiO on a CuÐSiO1 support\ to produce p!aminotoluene "05#[ Another
example\ using the same catalyst\ involved the reduction of cinnamonitrile "06# to b!methylstyrene
"07# "Scheme 18#[ Some years later several nitriles were reduced over a platinum!on!silica catalyst
ð73JOC1764Ł[ Although the yields for this method were\ in most cases\ greater than 83) "Table 06#\
there are two major drawbacks to its use[ First\ it requires a special ~ow apparatus\ which for a
one!o} experiment would be prohibitive\ and second the catalyst requires a high percentage of
platinum\ thus making the method costly[ Another ~ow method was used to reduce cyano!
adamantane "Equation "24## ð68AG"E#828Ł[ In this case the support was aluminum oxide and the
metal was nickel[ As in the previous example the yield was high "88)#[
CN
H2, NiO, CuO–SiO2
3 h, 330 °C
H2N H2N
(15) (16)
CN
H2, NiO, CuO–SiO2
3 h, 330 °C
(17) (18)
Scheme 29
Table 06 Reduction of nitriles over platinum on silica catalysts with

hydrogen[
Nitrile Product Yield
")#
*
Decanenitrile Decane 87
Cyclohexane!carbonitrile Methylcyclohexane 88
0!Cyanoadamantane 0!Methyladamantane 88
0!Adamantane acetonitrile 0!Ethyladamatane 83
Benzonitrile Methylcyclohexane 64
*
30% Ni–Al2O3
(35)
CN 180 °C, H2
99%
0[91[0[2[2 Reduction using hydride reagents

The use of hydrides for the reduction of nitriles to the methyl analogue seems to have been
scarcely investigated to any degree[ Sodium borohydride in acetonitrile was used to reduce p!
cyanotoluene to the corresponding xylene "Equation "25## ð67JCS"P0#0022Ł[
CarbonÐPhosphorus\ etc[ Bonds 38
CN
NaBH4, MeCN
(36)
Sodium bis"1!methoxyethoxy#aluminum hydride was used to reduce the nitrile "08# to its methyl
analogue in 71) yield "Equation "26##[ The reaction seems to have been performed purely to obtain
NMR data ð75T1318Ł[ In an elegant synthesis of the natural product laurenene "19# "Equation "27##
ð77JOC366Ł\ a nitrile was reduced to a methyl group in 54) yield using diisobutylaluminum hydride
"dibal!H# in dry benzene over a period of one hour[
[(MeOCH2CH2O)2AlH2]Na
(37)
82%
NC O O
OEt OEt
(19)
O-TMS OH
i, dibal-H
CN
ii, N2H4, K2CO3
(38)
triethyleneglycol
(20)
0[91[1 REDUCTION OF CARBONÐPHOSPHORUS\ ÐANTIMONY AND ÐBISMUTH

BONDS TO CARBONÐHYDROGEN BONDS
0[91[1[0 Reduction of CarbonÐPhosphorus Bonds

The reduction of carbonÐphosphorus bonds to carbonÐhydrogen single bonds or a methylene
group can be segregated into two separate approaches[ The _rst involves the use of a phosphorus
moiety as an incidental unit in the overall reaction scheme[ In other words the cleavage of the
carbonÐphosphorus bond leaves a molecule that contains no phosphorus and which is either the
desired product or a substrate to be used further in the reaction pathway[ The second and more
common case is where the resultant molecule containing phosphorus\ after carbonÐphosphorus
bond cleavage\ is the desired product[
0[91[1[0[0 CarbonÐphosphorus bond cleavage to give a desired product not containing phosphorus
"i# Cleavaè by stron` bases

One of the earliest methods for converting phosphorus containing compounds to the cor!
responding hydrocarbon moiety involved the use of hydroxides or alkoxides[ It had been reported
that quaternary phosphonium halides were decomposed by hydroxide to hydrocarbon and phos!
phine oxide with cleavage of the most electronegative group ð18JCS1231Ł[ A further investigation
into this reaction involved the phosphonium bromide "10# "Equation "28## ð69JA1028Ł[ Cleavage of
the allylphosphonium bromide with hydroxide or t!butoxide resulted in a 2 ] 0 mixture of the two
isomers "11# and "12# "Equation "28##[ There was however signi_cant competition between allyl and
phenyl as the leaving group[
+ (39)
+
PPh3 Br–
3 : 1
(21) (22) (23)
Alkaline induced cleavages of benzylð1!"N\N!dimethylamino#phenylŁdiphenylphosphonium bro!

mide "13# and benzylð3!"N\N!dimethylamino#phenylŁdiphenylphosphonium bromide "14# have been
studied "Scheme 29#[ The former undergoes decomposition to give N\N!dimethylaniline 85[4) and
benzene 2[4)\ while the latter gives toluene "099) yield# in a reaction that is approximately 0999
times slower ð76JOC3718Ł[
NMe2
NMe2
+ KOH
P +
Br–
96.5% 3.5%
(24)
Me2N
+ KOH
P
100%
Br–
(25)
Scheme 30
An equally interesting divergence was seen between benzylbisð1!"N\N!dimethylamino#phenylŁ

phenylphenylphosphonium bromide and benzylbisð3!"N\N!dimethylamino#phenylŁphenylphos!
phonium bromide^ the _rst compound gives PhNMe1 in 83[1) yield and benzene in 0[1) yield\
with no toluene being detected\ while the second reaction yields only toluene in quantitative yield[
An attempt at rationalizing the di}erences has been made\ but no concrete conclusions were drawn[
Investigations have been carried out into the reaction of vinyl phosphonium salts ð68TL238Ł[
Conditions for preferential benzene or alkene elimination were studied in detail[ As shown in
Scheme 20\ sodium hydroxide in a water:ethanol solvent gives the alkene\ whilst the same hydroxide
in a water:benzene mixture produces benzene[
The mechanisms for simple alkaline decomposition of acyclic quaternary phosphonium salts is
OMe
NaOH, H2O + Ph3PO
EtOH
OMe
+
Ph3P OMe
NaOH, PhH Ph2P + PhH

O
Scheme 31
well understood and documented ðB!62MI 091!90\ 67CJC0822\ 67JA6201\ 72JCS"P1#0812\ 75TL0198Ł[ The
basic mechanism is detailed in Scheme 21[
+ HO– HO–
P Ph HO P Ph –O P Ph
–
H2O
O P Ph P O + Ph– PhH + HO– + P O
Scheme 32
Other bases can be used to cleave carbonÐphosphorus bonds[ The tetraphosphine allene "15# in
Scheme 22 can have a phosphine unit cleaved o} using n!butyllithium as the base[ This results
in the lithium allene anion adduct being formed\ which can then react with electrophiles[ The
tetraphosphine allene is simply dissolved in THF at −69>C and n!butyllithium is added[ The
electrophile is then introduced to this reaction mixture "Scheme 22# ð76CB0392Ł[ A similar cleavage
has been observed using a lithium:amine mixture ð44JA2129Ł[
Ph2P PPh2 Ph2P PPh2 Ph2P PPh2
MeLi H+
• • •
Ph2P PPh2 Ph2P Li Ph2P
(26)
Scheme 33
"ii# Cleavaè by hydrides

Lithium aluminum hydride has also been used for carbonÐphosphorus bond cleavage ð46JA2456\
69JA1028Ł[ When lithium aluminum hydride was used for the reduction of the phosphonium bromide
"10# "Equation "28## only "12# was produced[ Lithium aluminum hydride has also been used in
another reaction which is formally a reduction of a phosphorus compound\ as illustrated in Equation
"39# ð46JA2456Ł[
Ph
Ph LiAlH4 Me Ph
P P (40)
MeBr
Me
Ph
"iii# Cleavaè by metal!based reductants

Acyl ylides have been reduced successfully using aluminum amalgams ð53JA0528\ 71JOC3852Ł[ Of
several compounds tested\ all gave greater than 70) yields[ The reductions were conducted typically
at room temperature\ with an excess of the aluminum amalgam and with a periodic addition of acid
"Scheme 23#[ This is an excellent method for the preparation of b!keto esters[
O O O O
Al–Hg
O O
81%
PPh2
O O O O
O Al–Hg O
PPh2 94%
Scheme 34
Other metal based reductions of phosphoranes are found[ One such reduction uses a zinc!acid
mix as the reagent ð44JA2129\ B!68MI 091!90Ł[ An important industrial process which relies on the
cleavage of carbonÐphosphorus bonds ð73OM"2#812Ł is the rhodium!promoted hydroformylation
process which produces benzaldehydes and phenols[ Scheme 24 outlines the general procedure[
PPh2
2CO
RhH(CO)(Ph3P)3
RhH2(CO)2PPh2
Ph
Ph
P
RhH2(CO)2
CORhH(CO)2PPh2
O
H2, C3H7
CHO + 1/2 [Rh(CO)2PPh2]2 CHO +

RhH(CO)2(Ph3P)(Ph2PC3H7)
Scheme 35
0[91[1[0[1 CarbonÐphosphorus bond cleavage to give a desired product containing phosphorus

Essentially this section can be sub!divided into two parts[ In the _rst part loss of a group attached
to a tertiary phosphine forms a phosphorus nucleophile or reagent[ The second group is where units
are lost from the phosphorus atom to form another more unusual phosphorus species[
"i# Formation of phosphorus nucleophiles and reaènts

There are many methods for the formation of tertiary phosphines\ Ph1PR\ where R is alkyl or
aryl ð65MI 091!90Ł[ Most of these methods cannot be utilized conveniently because they have di.cult
working procedures or the yields from the reactions are poor[ One method exists ð65MI 091!90Ł\
however\ that is undoubtedly the most convenient\ both in terms of the availability of starting
materials and of the simplicity of the practical procedure[ It is the reaction of lithium diphenyl!
phosphide with an alkyl or aryl halide[ This method is generally applicable to a wide range of
phosphines as is shown in Scheme 25[ It o}ers high yields\ especially when the phenyllithium
produced on cleavage of triphenylphosphine by lithium metal is selectively destroyed by means of
t!butyl chloride[
PPh3 + 2 Li PPh2Li + PhLi
PhLi + BuCl PhH + LiCl +
Ph2PLi + BuCl Ph2P–Bu + LiCl
Scheme 36
Diphosphines of the class RPhP"CH1#nPPhR "n1Ð5#\ have been prepared from Ph1P"CH1#nPPh1
with alkali metals followed by alkylation "Scheme 26#[ It was stressed that ultrasound irradiation
should be carried out at the reductive cleavage stage\ so as to assure the purity of the _nal products
and give good yields\ in excess of 79) in most cases ð74JOC3218Ł[
MePhP PPhMe
i, Li, ultrasound
Ph2P PPh2
ii, ButCl
iii, MeI Ph2PMe
Scheme 37
However not only triphenylphosphine carbonÐphosphorus bonds can be cleaved using alkali
metals[ There has been signi_cant work on 0\0?!diphosphometallocene chemistry "Equation "30##
which is involved in producing 0H!phosphol!0!yl anions[ In doing so\ it is often a carbonÐphos!
phorus bond which is broken to give an anion and hydrocarbon ð79JA883Ł[ Various procedures for
the creation of this type of anion have been reported[ These include using lithium in THF at room
temperature ð60JA5194\ 60T4412Ł\ potassium in boiling THF\ dioxane or toluene and sodium in
boiling THF ð63MI 091!90Ł[ An example of a typical reaction ð79JA883Ł is given in Equation "31#[
[M(CO)2]2
M (41)
150 °C
P P
Ph
M = Mn(CO)3, Fe(C5H5)
Li, THF, RT
Ph Ph Ph Ph + PhLi (42)
P P
Ph Li
"ii# Reduction of carbonÐphosphorus bonds in order to study properties of the reaction rates and
chirality about phosphorus
It was mentioned in Section 0[91[1[0[0["i# that the mechanisms for simple alkaline decomposition
of acyclic quaternary phosphonium salts is well understood and documented and references to this
literature were given in that section[ The discussion of chirality about phosphorus in cleavage
reactions has also been extensively documented ð64CB792\ 80COS"7#747Ł[
If the rate of reaction is being studied\ then both those products containing phosphorus\ and
more importantly for this discussion\ those not containing phosphorus are of interest[ However\
these studies rarely produce reactions that are of synthetic value\ and as such they will not be dealt
with here[
0[91[1[1 Reduction of CarbonÐArsenic Bonds

When compared with phosphorus\ the reduction of carbonÐarsenic bonds to carbonÐhydrogen
bonds has been severely neglected[ There are very few examples of this type of reaction in the
literature[
As with certain phosphorus compounds "Section 0[91[1[0[0["i##\ it has been shown that an alkyl
group on arsenic can be removed by addition of butyllithium ð77JA3235Ł[ The example given in
Scheme 27 was carried out in an attempt to produce optically active arsenic containing macrocycles[
OH i, BuLi ONa H+ OH
ii, Na/NH2 93%
AsMe2 AsMeNa AsMeH
Scheme 38
A further example of reduction of a carbonÐarsenic bond is where arsonium ylides of the type
shown in Scheme 28 are treated with hydrogen chloride in dichloromethane at room temperature
to form b!keto esters or b!keto ketones ð75MI 091!90Ł[
O O HCl, CH2Cl2 O
+ +
Ph3As + PhCOCl Ph3As
OEt OEt RT OEt
–
Cl–
Ph O Ph O
Scheme 39
0[91[1[2 Reduction of CarbonÐAntimony Bonds

It is also possible to form ylides containing antimony[ These are formed on reaction of a diazo
compound with triphenylantimony[ The resulting ylides are called stilbonium ylides[ Until 0875
only one of these ylides existed "16# "Equation "32## ð56CI"L#676Ł[
Ph Ph
Ph Ph
150 °C +
N2 – SbPh3 (43)
Ph Ph
Ph Ph
(27)
Further work using copper catalysts has resulted in the isolation of several more species ð75T2776Ł[
In protic solvents these ylides are slowly cleaved to give triphenylantimony oxide and the cor!
responding methylene compound "Equation "33##[
PhO2S PhO2S
+
– SbPh3 + Sb(O)Ph3 (44)
PhO2S PhO2S
Antimony compounds containing the Sb"CF2#1 group can loose this moiety on photolysis over
099 h ð77ZAAC"459#030Ł[ As shown in Equation "34#\ two compounds are formed resulting from the
simple replacement of Sb"CF2#1 by hydrogen and transformation of the CF2 group into a C2F6 unit[
Sb(CF3)2
hν, 100 h
+ (45)
CF3 CF3 C3F7
0[91[1[3 Reduction of CarbonÐBismuth Bonds

There appears to be only one reaction described where there is cleavage of a carbonÐbismuth
bond to give the corresponding hydrocarbon[ Bis"diphenylbismutino#methane was synthesized in
0874 ð74CB0928Ł[ It is possible to remove one of the diphenylbismuto groups using phenyllithium[
This leaves an anion as shown in Scheme 39 which can\ on addition of methanol\ give the methyl!
diphenylbismutine[
PhLi + BiPh3
Ph2Bi BiPh2 Ph2Bi Li
MeOH
Ph2BiMe
Scheme 40
Scission of CarbonÐCarbon Bonds 44
0[91[2 REDUCTIVE SCISSION OF A CARBONÐCARBON BOND TO TWO CARBONÐ
HYDROGEN BONDS
There are two types of reaction which dominate this section[ The _rst is the reductive cleavage
where one carbon atom is that of a nitrile group[ Here a carbonÐnitrile bond is cleaved to furnish a
carbon!hydrogen bond[ The second reaction is the direct scission of an alkyl or aryl carbonÐcarbon
bond to give two new hydrocarbons[
0[91[2[0 Reductive Cleavage when one Carbon is Part of a Nitrile Group

There are two methods of cleaving a nitrile to give the corresponding hydrocarbon and\ formally\
hydrogen cyanide\ namely hydride reagents\ or alkali metals in liquid ammonia[
0[91[2[0[0 Use of hydride reagents

The conversion can be accomplished using either lithium aluminum hydride or sodium borohy!
dride[ The 1!cyano!0\1!dimethylpiperidine "17# was transformed into the corresponding dimethyl!
piperidine using lithium aluminum hydride "Equation "35## ð46JA4168Ł[ Previous reports ð43MI 091!90\
43MI 091!91\ 52BSF0317Ł on the reduction of carbonÐnitrile bonds using lithium aluminum hydride
only gave satisfactory results in special cases[
LiAlH4
CN (46)
N 60% N
Me Me
(28)
In studies relating to the synthesis of isoquinoline! and indole!alkaloids\ the removal of nitrile
groups using sodium borohydride was investigated because both reduction of the nitrile group to
an amine unit and cleavage to the hydrocarbon was observed when lithium aluminum hydride was
used\ and a milder cleavage reagent was sought[ The authors succeeded in removing the nitrile unit
from various types of a!amino acids "Scheme 30# ð58TL2094Ł[
CN NaBH4, DIGLYME
Ph Ph
NHCOMe 85% NHCOMe
CN NaBH4, EtOH
Ph Ph
N 93% N
Me Me Me Me
CN
NaBH4, EtOH
N 92% N
Me Me
Scheme 41
0[91[2[0[1 Use of alkali metals in liquid ammonia

Sodium in liquid ammonia was investigated as a reducing reagent for the cleavage of nitriles in
connection with the synthesis of "¦#!maritidine "18# "Equation "36## ð65TL46Ł[ The nitrile was
stirred for 04 minutes in THF at −67>C with sodium in liquid ammonia and a modest yield of "18#
"47)# was obtained[ As a prelude to this reaction several model studies were carried out ð65TL50Ł[
Applying the same conditions to some simpler model systems gave higher yields "Scheme 31#[
OH OH
MeO Na, NH3 MeO

(47)
CN –78 °C, 15 min
N 58% N
MeO MeO
(29)
CN
Na, THF/NH3, –78 °C
N 85% N
Me Me
CN
N 97% N
Ac Ac
CN
N 95% N
Me Me Me Ac
CN
N 94% N
H Ac H Ac
Scheme 42
0[91[2[1 Cleavage of CarbonÐCarbon Bonds where both Products are Hydrocarbons

In the majority of cases these cleavage reactions result in the formation of at least one new aryl
derivative[ On the whole\ the reaction conditions are harsh and the molecules involved are simple[
0[91[2[1[0 Cleavage using aluminum or aluminum:metal catalysts

It is possible to dealkylate alkylbenzenes over alumina:metal catalysts[ The metals that have been
used are rhodium and nickel[ At 329>C the dealkylation of toluene to methane and benzene is
extremely e}ective[ The dealkylation of xylene with a steam covered rhodium:aluminum oxide
catalyst gives toluene in 82) yield and is much faster than the dealkylation of toluene itself "Scheme
32# ð60MI 091!90Ł[
Rh/Al2O3
PhMe PhH + MeH
Rh/Al2O3
93%
Scheme 43
In a rather harsh reaction "Equation "37##\ toluene was converted into benzene in 84) yield using
a cobalt:molybdate:alumina catalyst in the presence of sodium hydroxide and steam at 459Ð599>C
and 69 atm ð47IEC0566Ł[ A similar catalytic system using nickel rather than rhodium has been
studied[ Various isomers of picoline\ cresol and xylene were demethylated in the presence of water
vapour and a nickel:aluminum oxide catalyst at temperatures between 399>C and 339>C[ The results
showed that the greater the deviation an isomer had from aromaticity the higher reactivity it
possessed in the catalytic reaction ð54MI 091!90Ł[
CarbonÐBoron\ etc[ Bonds 46
Co/Mo/Al2O3
PhMe PhH + MeH (48)
70 atm, 560 °C
95%
Lewis acids have been used in cleavage reactions[ In particular aluminum chloride has been used
to cleave the molecule shown in Equation "38#[ Aluminum chloride in benzene was shaken for _ve
hours with the tetrachloride whereupon\ 1\4!dichlorophenol was produced in 75) yield along with
propane ð64OPP078Ł[
OH
Cl Cl Cl Cl
AlCl3, PhH
(49)
50 °C, 2 h
HO OH 85%
Cl Cl
In an attempt to perform an intramolecular FriedelÐCrafts reaction using compound "29#\ with

aluminum chloride as the catalyst\ an isopropyl group was cleaved "Equation "49##[ The reaction is
dependent on the nature\ position and branching of substituents ð33BSF238Ł[
O AlCl3
(50)
Cl
(30) O
Lithium aluminum hydride has been used successfully to reduce the nitro compound featured in
Equation "40# to give the corresponding benzylamine "89)# and nitro ester ð44LA066Ł[ Dinitro
compounds can also be cleaved using Raney nickel ð46CB0663Ł[ A similar reaction was observed
when the dinitro compound shown in Equation "41# was reacted with concentrated hydrochloric
acid in ethanol[ This reaction is claimed to have given a 099) yield ð47CB649Ł[ The biphenyl "20#
can be reduced to give toluene "Equation "42## ð36CB191Ł[
Et Et
NH O NH O
OEt LiAlH4 OEt

+ (51)
NO2 ether NO2
Cl Cl
NO2
NO2
EtOH, HCl, 2 h
+ (52)
100%
OAc O2N
O2N
OAc
(53)
(31)
0[91[3 REDUCTION OF CARBONÐBORON\ ÐSILICON AND ÐGERMANIUM BONDS TO

CARBONÐHYDROGEN BONDS
0[91[3[0 Reduction of CarbonÐBoron Bonds to Hydrocarbons

The cleavage of carbonÐboron bonds can be e}ected under acid\ neutral or basic conditions[ The
common factor in all the conditions employed is that the cleaving reagent contains an oxygen atom[
0[91[3[0[0 Cleavage of carbonÐboron bonds under acidic conditions
Trialkyl boranes are relatively stable towards hydrolysis by water ð46CB1622Ł and strong mineral
acids ð75T4386Ł although they can also be cleaved by anhydrous hydrogen ~uoride "Equation "43##
ð61JA6748Ł[ Compared to hydrogen ~uoride\ hydrogen bromide reacts slowly and removes only one
alkyl group "Equation "44## ð27JA004Ł[
RT
R3B + 3 HF 3 RH + BF3 (54)
R = Me, Et, Pri
55–60 °C
Bun3B + HBr BunH + Bun2BBr (55)
It has been known for several decades that one alkyl group is rapidly removed using acetic acid
ð25JPR140\ 44AG609Ł[ A second alkyl group is cleaved at a much slower rate "Equation "45##
ð50JOC520Ł[ This type of reaction has since been studied in some depth[ A long chain fatty acid has
been used to cleave a variety of boranes to the corresponding hydrocarbons[ The results and yields
of two of these reactions are detailed in Scheme 33 ð73JOM"159#06\ 73JOM"169#8Ł[
(n-C6H13)3B + 2 MeCO2H 2 n-C6H14 + n-C6H13B(O2CMe)2 (56)
CO2H
( )16
B 75%
R
R = Me, Et
CO2H
( )16
MeO B 71%
Scheme 44
The use of acids in carbonÐboron bond cleavage was systematically studied in 0875\ ð72JOM"144#024\
75T4386Ł when ten di}erent acids were used to investigate the cleavage of tri!n!hexylborane "Table
07 and Equation "46##[ In the same publication several organoboranes were treated with acetic acid
to yield the alkane according to the general reaction given in Equation "47#[ The full results are
listed in Table 08[ Further investigations involved changing the acid and using polyethers to aid the
reaction "Equation "48# and Table 19#[ The last two entries in Table 19 are the results when
isomerisation takes place before protonolysis[
Table 07 Reaction of tri!n!hexylborane with various acids[

Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Acid Yield of hexane
")#
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Acetic 59
Acetic ¦ acetic anhydride 73
Propionic 79
Isobutyric 70
Butyric 79
Glycolic 44
Methanesulfonic 30
Hydrochloric 25
Phosphoric 01
*
B B
O O
(57)
H H
O O
R
R R i, BH3
R (58)
R
R R ii, MeCO2H
R
Table 08 Reaction of ethanoic acid with organoboranes derived from alkenes[

Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Alkene Yield of alkane
")#
*
0!Pentene 49
0!Hexene 35
1!Methyl!0!butene 00
2!Methyl!0!butene 33
2\2!Dimethyl!0!butene 25
1!Methyl!1!butene 9[3
Styrene 49
a!Methylstyrene 21
trans!b!Methylstyrene 2
cis!1!Pentane 2
Cyclopentene 35
Cyclohexene 20
Norbornene 16
*
R
R R i, BH3
R (59)
R
R R ii, acid in polyether
R
Table 19 The use of polyethers in cleavage reactions[

Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Alkene Yield of alkane ")#
Proprionic acid Caprylic acid
in DIGLYME in TRIGLYME
*
0!Hexene 89 80
0!Octene 84 89
1!Hexene 49
Cyclohexene 65 73
1\3\3!Trimethyl!0!pentene 71
Styrene 77 73
1!Heptene 40 68
1\3\3!Trimethyl!1!pentene 4
1!Heptene 74 89
1\3\3!Trimethyl!1!pentene 66 74
*
The conclusions drawn from this study on protonolysis were that the steric requirements of the
alkyl groups attached to the boron play an important role in the rates of hydrolysis[ Secondary
alkyl groups protonolyze less readily than primary alkyl groups and more hindered alkyl groups
are even more resistant[ The stereochemistry of the protonolysis was established via deuterioboration
of norbornene and dueterolysis of the product[ The protonolysis was seen to proceed by retention
of con_guration at the migrating carbon atom[
0[91[3[0[1 Cleavage of the carbonÐboron bond under neutral conditions

It is possible to cleave the carbonÐboron bond in molecules such as "21# under neutral conditions
using ethers such as THF and polyethers such as DIGLYME or TRIGLYME "Scheme 34# ð75T4386Ł[
O
or DIGLYME
B(C6H13)3 C6H14
B TRIGLYME
(32)
Scheme 45
Several organoboranes have been cleaved by alcohols[ An interesting example of this is the use
of the cyclic polyol octahydroxycyclobutane ð72CB0225Ł[ A suspension of the polyol in mesitylene
is reacted with triethylborane "activated with diethylboryl pivalate# to release eight equivalents of
ethane and form the product "22# "Equation "59##[
Et Et
B B
HO OH O O
4 BEt3 O O
HO OH + 8 EtH (60)
OH HO O O
HO OH B
O O
Et
B
Et
(33)
In a reaction of _ve!membered ring enamines with boranedimethyl sulphide with subsequent

heating in methanol at 54>C\ some protonolyzed product was formed "Equation "50##[ Other cases
gave only the borate dimethyl ester ð76JOC3903Ł[
O O O
N i, BH3•SMe2 N N OMe
+ (61)
ii, MeOH, 65 °C B
OMe
18% 40%
0[91[3[0[2 Cleavage of the carbonÐboron bond with base

It has been reported that certain organoboranes can be cleaved using potassium hydroxide^ an
example is given below "Equation "51## ð71JOM"115#004Ł[
KOH
O B (62)
75%
0[91[3[1 Reduction of CarbonÐSilicon Bonds

There is a plethora of methods for the cleavage of carbonÐsilicon bonds to give carbonÐhydrogen
bonds\ ranging from the use of acid or base to thermolysis[
0[91[3[1[0 Cleavage by acid
Acids have been used on several occasions to desilylate compounds and produce the corresponding
hydrocarbon[ Cleavage of an alkylÐsilicon bond using concentrated sulphuric acid was _rst reported
in about 0809 ð79JPR492Ł and has since been used as a route to functionalize the silicon centre of
organosilicon compounds "Equation "52##[ In the case of TMS!R "where R is any of the alkyl groups
shown in Equation "53## one mole of methane is evolved per mole of tetraorganosilane reacted
ð79JPR492Ł[
Et
Si
H2SO4 Prn
O + MeH (63)
Si Et Prn
H2O
Me Prn Si
Et
H2SO4
TMS-R Me2Si(HSO4)R + MeH (64)
R = –CH2NMe2, –CH2CH2NH2, –CH2CH2CO2H, –CH2CCOMe
The use of the mineral acids\ such as sulfuric acid\ has been exploited in conjunction with
ammonium ~uoride to produce coumarins containing the SiMe1F group[ The trimethyl silyl com!
pound "23# was prepared and reacted with the mineral acid[ This results in the cleavage of one
methyl group from the silicon atom\ to produce methane "Equation "54##[ With only the acid present
the methyl group was replaced by a hydroxyl group\ whereas when ammonium ~uoride was present\
it was replaced by a ~uorine atom ð79JPR492Ł[ Not only can the siliconÐmethyl bond be cleaved\
but cleavage of the coumarinÐsilicon bond can also occur "Equation "55##[
TMS SiFMe2
H2SO4
+ MeH (65)
NH4F
HO O O HO O O
(34)
TMS
H2SO4
+ (Me2Si)2O (66)
NH4F
HO O O HO O O
Tri~uoroacetic acid has also been used to cleave carbonÐsilicon bonds[ With the 0\3!bis"trimethyl!
silyl# compound shown in Equation "56#\ the acid cleaves the alkylÐsilicon bond in preference to the
vinylÐsilicon bond\ but the yield is very poor ð70ZOB319Ł[
CF3CO2H
Si Si Si (67)
14%
The cleavage of the carbonÐsilicon bond by electrophilic reagents such as Lewis acids is well
established in organosilicon chemistry[ In some cases the Lewis acid is used in conjunction with a
hydrogen halide as in Equation "57# ð79JPR492Ł[ However in others\ such as the reaction of tri!
ethylsilane with aluminum tribromide\ it is the only reagent used "Equation "58## ð72ZOB795Ł[
AlCl3
Me4Si + HCl TMS-Cl + MeH (68)
AlBr3
Et3SiH EtH (69)
Simple b!trimethylsilyl ketones like "24# can be desilylated in ethanol to give the corresponding
ketone "Scheme 35# ð69MI 091!91Ł[ The ester analogue "25# requires hydrogen chloride for cleavage
to produce the simple ester "Scheme 35#[
TMS EtOH
+ TMS-OEt
O O
(35)
OEt HCl OEt
TMS + TMS-Cl
O O
(36)
Scheme 46
0[91[3[1[1 Cleavage by base

There have been several reports that show the cleavage of a carbonÐsilicon bond to give a carbonÐ
hydrogen bond using a base[ One of the earliest of these reports showed that tetramethylsilane
could be cleaved by potassium t!butoxide in DMSO "Equation "69## ð56JOC3015Ł[ This reaction was
later modi_ed to cleave a series of trimethylsilyl!compounds to the corresponding hydrocarbons[
The new conditions employed were a 4) solution of potassium t!butoxide in 08 ] 0 DMSO:water
mixture at room temperature for 05 hours "Equation "60##[ Some compounds needed 37 hours to
desilylate completely ð71JA5798Ł[
HO TMS ButOK
HO
+ (70)
DMSO R
R R
TMS
OH OH
ButOK
(71)
DMSO/H2O
30%
This cleavage is part of a reaction sequence resulting in stereospeci_c reductive methylation via a
radical cyclizationÐdesilylation mechanism ð75JA5715Ł[ In the reaction sequence shown in Equation
"61#\ it is possible to convert the tricyclic compound "26# to the methyl analogue "27# using _ve
equivalents of potassium t!butoxide in DMSO at room temperature[ The same research group has
applied the reaction to steroids and to the production of acyclic systems "Equation "62##[
OBut OBut
ButOK
(72)
DMSO
O HO
H H
Si
(37) (38)
OH
O Si
(73)
Ph
Ph
If ~uoride ions in DMSO are used to desilylate vinyl silanes\ then the resulting product is the
parent alkene "Equation "63## ð63TL2368Ł[
R1 TMS i, F–, DMSO R1

R2 R2 (74)
ii, H2O
HO HO
Potassium hydride was used to form alkenes of type "28# shown in Equation "64#[ The methyl
substituted compound "39# was formed as a side product of the reaction ð76CB0938Ł[ The use of
potassium butoxide or caesium ~uoride gave the same result[
HO TMS-O
TMS
KH, THF
N N + N (75)
But But But
N N N N N N
(39) (40)
0[91[3[1[2 Metal mediated desilylations

Several transition metal!mediated reactions of vinylsilanes have been described[ The reaction of
"E#!vinyl!0\1!dimethyl!0!trimethylsilane with the dinuclear platinum complex yields "Z#!1!butene
as shown in Scheme 36[ Reaction of the "Z#!vinyl!0\1!dimethyl!0!trimethyl silane yields primarily
the "E#!1!butene ð65JOM"009#028Ł[
TMS
Pt2Cl4(CH2=CH2)2
(Z):(E) 89:11 (E):(Z) 87:13
Pt2Cl4(CH2=CH2)2
TMS
(E):(Z) 95:5 (Z):(E) 95:5
Scheme 47
In a side reaction of cyclopalladation as shown in Equation "65#\ the palladium complex "30# is
broken down to give the butan!1!oxime complex[ The authors suggest that this decomposition could
be attributable to hydrogen chloride\ formed by reaction of the N!hydroxyl moiety with the
trimethylchlorosilane that is produced slowly in the process ð74OM0800Ł[
Ph
N NOH
Si 50%
Cl Pd Cl + Cl Pd Cl (76)
N NOH NOH
Ph
(41)
A combination of copper sulfate and methanol can cleave a cyclopentadiene ring from a silafulvene
"Equation "66## ð74OM473Ł[
Ph Ph
Ph Ph
i, ButOH
SiMe2 (77)
ii, CuSO4, MeOH
Ph Ph
Ph Ph
0[91[3[1[3 Desilylation by thermal decomposition and miscellaneous methods

The four!membered heterocycle shown in Equation "67# can be decomposed to ethane and
diethylsul_de upon heating ð70JOM"103#034Ł[
Si heat
S + EtH (78)
S
Aromatic ipso!desilylation "Equation "68## is well documented in the literature ð63JCS"P1#485Ł[ If

there is a source of protons available then the substitution results in the formation of carbonÐ
hydrogen bonds[ The reaction has been used in the synthesis of oestrone "Equation "79## ð79JA4142Ł[
E+
TMS E (79)
1 1
O O
H CF3CO2H, –20 °C H
TMS (80)
Pb(OCOCF3)4
H H H H
80%
TMS HO
The desilylations so far have all concentrated on the desilylated products[ A method for the
preparation of trimethylsilyl esters of strong acids focuses attention on the silicon containing
fragment "Equation "70## ð66AG"E#288Ł[ The method produces hydrocarbons as side products[
HX
Ar TMS TMS X + ArH (81)
X = C3F5SO3, C3F5CO2, F2P(O)O
0[91[3[2 Cleavage of CarbonÐGermanium Bonds to CarbonÐHydrogen Bonds

There are very few examples of the reduction of carbonÐgermanium bonds to carbonÐhydrogen
bonds[ However there is a report in which a germanium bridged cyclohexadiene "31# was heated to
give the corresponding benzene derivative and a germanium!containing species which polymerized
"Equation "71## ð62JA2967Ł[
Et
Et
Ge CF3
450 °C
CF3 + Et2Ge CH2 (82)
Cl CF3
Cl
CF3
(42)
There have also been cleavages of carbonÐgermanium bonds to carbonÐhydrogen bonds through
photochemical means[ For instance\ the triethylaryl germanes shown in Equation "72# lost the aryl
group on exposure to light of wavelength 149 nm ð75BCJ1796Ł to furnish the hydrocarbon[ The
cleavage is thought to proceed by a radical mechanism "Scheme 37# ð75BCJ1796Ł[
250 nm
Et3GeAr Et3GeR + (Et3Ge)2 + ArH + C12H26 (83)
hexane
Ar = Ph or p-toluene
R = n-C6H13, CH(Me)Bu, CH(Et)Pr
CarbonÐMetal Bonds 54
Et3GeAr Et3Ge• + Ar•
RH + Ar• R• + ArH
Et3Ge• + R• Et3GeR
2 Et3Ge• (Et3Ge)2
RH = hexane
Scheme 48
Some work has been carried out to investigate the addition reactions of organo!metal alkoxides
to carbon suboxide ð77G466Ł[ When germanium alkoxides are exposed to carbon suboxide a
malonate diester bonded to germanium is formed[ This breaks down on addition of water to form
dimethyl malonate "Scheme 38#[
C3O2 + 2 Bun3GeOMe (Bun3Ge)2C(CO2Me)2
(Bun3Ge)2C(CO2Me)2 + 2 H2O H2C(CO2Me)2 + 2 BunGeOH
Scheme 49
0[91[4 REDUCTION OF CARBONÐMETAL BONDS TO CARBONÐHYDROGEN BONDS

The largest contributor to this section is\ without question\ the reduction of carbonÐmercury
bonds[ Apart from this group\ barring a few miscellaneous reactions\ protonolysis reactions are
involved\ in general\ removing unreacted organometallic reagent or producing deuteriated molecules[
In these reactions\ a carbonÐmetal bond "where the metal is an alkali or alkali earth metal# is
reduced to a carbonÐhydrogen bond by reaction with a proton donor\ such as water or acid[
0[91[4[0 Reduction of CarbonÐMercury Bonds

The reduction of carbonÐmercury bonds falls mainly into two categories\ protonolysis and
metal hydride demercuration[ In addition there are a few miscellaneous reactions which will be
discussed[
0[91[4[0[0 Protonolysis
There has been a great deal of attention focused on the protonolysis of organomercurials[ It is
possible to prepare organomercurials in high purity^ in addition there are few problems with
manipulation and they are monomeric in solution[ These properties make them ideal candidates for
mechanistic studies on the protonolysis of carbonÐmetal s bonds[ Several reviews ð57PAC68\ 58MI
091!90\ 58PAC0\ B!61MI 091!91\ 67T1716\ 80COS"7#749Ł and a book ð73JA2692Ł have been written dealing
with these studies[
As would be expected there are several mechanisms for the protonolysis reaction[ The cleavage
of diphenylmercury in acetic acid containing perchloric acid and the reaction of dialkylmercury
with mercury nitrate exhibit only an SE1 mechanism ð57PAC68Ł[ Other protonolysis reactions\ such
as the reaction of an alkylmercury halide with hydrochloric acid\ proceed through a four!centre
transition state according to Scheme 49[
R Hg X R Hg X R Hg X
RHgX + HCl +
H Cl H Cl H Cl
Scheme 50
The intramolecular nucleophilic participation of the chloride conjugate base is arguable[ There
is evidence\ based on studies of protonolysis of unsymmetrical alkylmercurials\ that suggests there
is a three!centre transition state ð58JCS"B#0960Ł[ Whatever the transition state\ further reaction occurs
by front side attack on the carbon centre\ forming a transition state containing a pentacoordinate
carbon atom ð73JA2692Ł[ There are some reports of unimolecular SE0 reactions ð57PAC68\
58JCS"B#0960Ł[
The carbonÐmercury bonds are generally stable to water and alcohols\ thus the protonolysis of
these bonds requires stronger acids such as hydrochloric acid or sulfuric acid[ Carboxylic acids are
much less e}ective[ In general the acid cleavage of dialkylmercurials is much more facile than that
of alkylmercuric salts[ The arylÐmercury bonds are cleaved more readily than alkylÐmercury bonds
ðB!79MI 091!90Ł[
The protonolysis of solvomercurated products derived from the alkene leads back to the alkene
ð66JOM"024#0Ł and so other than the introduction of deuterium or tritium\ this process has little
synthetic utility[ However the protonolysis of those alkenylmercurials derived from the sol!
vomercuration of alkynes allows the preparation of stereoisomerically pure alkenes[ Thus a 2 ] 0
mixture of the vinylmercury compounds featured in Equation "73# were re~uxed for two hours in
acetic acid[ Protonolysis occurred almost quantitatively\ to give a 2 ] 0 mixture of the corresponding
esters ð79JCS"P0#0987Ł[
Ph HgCl Ph OAc AcOH Ph Ph OAc

+ + (84)
ClHg reflux, 2 h
AcO AcO
The alkenylmercury acetate in Scheme 40 undergoes protonolysis to give a product alkene with
entirely inverted stereochemistry ð71JOC2696Ł[ A mercurinium ion intermediate has been proposed
and the steric interaction of the two phenyl groups forces the inversion of stereochemistry[
Protonolysis as the second step of intramolecular C!vinylation induced by mercury"II# salts has
been described ð73JA3107\ 74JA0615Ł and some examples are given in Scheme 41[
Ph H
Ph Ph Ph H Ph
+ AcO + Ph +HgCl
Ph +
Hg
AcO HgOAc AcO HgCl AcO Ph
Cl
Scheme 51
TMS-O
O D
i, HgCl2, CH2Cl2, HMDS
ii, DCl, NaI
H
NH2 N
i, Hg(OAc)2, HOAc
Prn
ii, NaCl
Prn
HMDS = hexamethyldisilazide
Scheme 52
0[91[4[0[1 Metal hydride demercuration

Both sodium borohydride and aluminum hydrides have been used to reduce organomercurials
to produce the corresponding hydrocarbon[ The mechanism through which sodium borohydride
reduces the organomercurials is believed to be a free radical mechanism as shown in Scheme 42
ð65JA4862\ 73TL4128\ B!74MI 091!91Ł[
RHgX RHgH + NaBH3X
R• + RHgH RH + RHg•
RHg• R• + Hg
Scheme 53
There is a disadvantage with using sodium borohydride in the reduction of organomercurials\ in

that rearrangements of the initially formed radical can occur as illustrated by Equation "74# ð63JA769\
65JA4862Ł[
HgBr
NaBH4
+ (85)
Reduction of exo! and endo!norbornylmercury"II# bromide with sodium borodeuteride provides

exo!ð1!1H0Łnorbornane as the major product "Equation "75## ð69JA5500Ł[ Other examples of this
phenomenon can be found in the literature ð70JOC452Ł[
NaBD4
+ (86)
D
HgBr D
endo or exo 10 : 90
The stereoselectivities observed on cleavage of the carbonÐmercury bond with sodium borohy!
dride depend upon the nature of the radical intermediates and the reaction conditions[ Attempts to
_nd optimal conditions for this stereoselective cleavage have been made ð72JA6396Ł[ The dia!
stereoselectivity in metal hydride demercuration of a!mercury"II# carbonyl compounds is dependent
on the nature of the solvent\ the amount of hydride used\ the mode of addition\ the nature of the
hydride source and the ligand on mercury\ so any rationalization of these factors will be di.cult
ð75JOC1913Ł[ Reductive elimination appears to be the major problem[ This is often minimized by
the use of alkaline borohydride "Equation "76## ð73T1206Ł[
O O
O
O NaBH4, MeOH O
+ (87)
NaOH, –78 °C HO
HgOAc
H
90%
However\ alkaline sodium borohydride must be avoided in the demercuration of organomercurials

obtained by alkoxymercuration of vinyl ethers bearing conjugated electron!withdrawing groups\
because of the danger of substantial reductive elimination[ For simple vinyl ethers "Equation "77##
however\ no problems are encountered ð72TL3812Ł[
HgOAc
NaBH4, THF/H2O
(88)
O OBu NaOH O OBu
85%
The products obtained from the oxymercuration!demercuration of alkenylacetates under stan!

dard conditions "sodium borohydride with 2 M sodium hydroxide# are diols[ With methoxy! and
hydroxyalkenes the yields are much lower because of competing deoxymercuration ð70JOC420Ł[
Increasing the concentration of base increases the yield of hydrated products[ Phase transfer reagents
are sometimes used to avoid deoxymercuration and other side reactions "Scheme 43# ð68S780\ 72T1752\
72TL2886\ 73JOC1727\ 75CC744Ł[
R
N NaBH4
phase transfer
standard conditions R1 R1
Hg N conditions N
)2 R R
ClHg R2 R2
R1 R2
Scheme 54
There have been numerous publications on the use of sodium borohydride to cleave carbonÐ
mercury bonds and\ although there are other methods available\ this is the method of choice
ð80COS"7#749Ł[
A number of demercurations of RHgX or R0HgOR1 species use n!tributyltin hydride ð72JA5771\
73T1206Ł\ or triphenyltin hydride ð73JA7202Ł\ but complete removal of tin residues can prove di.cult[
As with sodium borohydride\ there is also a problem with competitive deoxymercuration when
using tin hydrides ð73T1206Ł[ The presence of sodium acetate prevents this problem if triphenyltin
hydride is used ð73JA7202Ł[ The use of tri!n!butyltin hydride instead of alkaline sodium borohydride
in the demercuration of peroxymercurials has led to improved yields of peroxides "Table 10#
ð71JCS"P0#0686Ł[
Table 10 Comparison of yields for formation of peroxymercurials using Bun2SnH and NaBH3[
X X
Peroxymercurial OOBut OOBut
(X = HgBr)
OOBut OOBut X X
Yield of peroxide (%)

(X = H)
Bun3SnH 63 24 59 61
NaBH4/NaOH 0 0 2 13
Lithium aluminum hydride has been little used as the reducing agent in demercuration ð72JA5771\
75JA1983Ł[ However the reduction of organomercury"II# halides with lithium aluminum hydride has
been investigated and the _ndings suggest an electron transfer mechanism\ involving attack of the
alkyl radical on the metal hydride "Scheme 44# ð72TL0300Ł[
R• + AlH4– RH + AlH3•
AlH3•– + RHgX R• + AlH3 + Hg + X
Scheme 55
0[91[4[0[2 Miscellaneous methods

Although sodium borohydride is most often used for the reduction of carbonÐmercury bonds\
there has been a signi_cant increase in the number of other reagents tried and utilized\ for example
thiols and sodium amalgam "vide intra#[ Reduction with hydrogen sul_de ð73JCS"P0#0578Ł\ sodium
dithionite ð68JOC117Ł\ metals ð79JA226\ 73AG"E#113Ł\ alcohols ð77S033Ł\ alkaline aqueous bases\
ð73CC751Ł\ aromatic amines ð79JCS"P0#0319Ł\ Wilkinson|s catalyst ð79JA226Ł and electrochemical
reductions ð74JOC562Ł have also all been used[
Organomercurials react with thiols by a free radical substitution mechanism "Scheme 45#[ The
reaction between the hexenylmercury chloride and benzene thiol is initiated by light or 1\1?!
azobisisobutyronitrile "AIBN#[ A mixture of 0!hexene and methylcyclopentane is produced
ð72JA0287Ł[ A limitation in the use of certain thiol reagents is\ as for most reagents used for
demercuration\ their ability to undergo elimination with reversion to the starting material
ð80COS"7#749Ł[
•
PhS• + RHgCl RHg(PhS)Cl
•
RHg(PhS)Cl R• + PhSHgCl
R• + PhSH PhS• + RH
Scheme 56
The sodium amalgam cleavage of alkylmercurials involves an ionic mechanism ð61JOC3230Ł[ The
reaction is also stereospeci_c with retention of con_guration at the carbon centre[ No rearrangement
was observed in the rearrangement!prone nortricyclyl!norbornenyl system shown in Equation "78#
ð70JOC452Ł[ Sodium amalgam has also been used for reducing the amidomercurial derived from
methyl undecalene ð74BSF64Ł[
AcO Na–Hg AcO

HgCl D (89)
D2O, NaOD
The replacement of mercury by hydrogen can be achieved using trans!metallation followed by

hydrolysis "Scheme 46# ð71JOC2696\ 73AG"E#113Ł[
HgBun Li Li
H2O
HgBun or BunLi
Li
Scheme 57
The latest addition to the numerous reagents for reduction of organomercurials is N!benzyl!
0\3!dihydronicotinamide^ it is thought to reduce the C0Hg bond via an electron transfer chain
substitution mechanism ð70TL3384Ł[
0[91[4[1 Cleavage of Other Metals from Carbon to give a CarbonÐHydrogen Bond
0[91[4[1[0 Protonolysis
There are many carbonÐmetal bonds which can be reduced on addition of a proton donor to the
reaction[ The carbonÐaluminum bond can be readily cleaved on addition of HX "where X is a
hydroxyl or alkoxyl group\ etc# to give the corresponding hydrocarbon as given by Equation "89#
ðB!61MI 091!92Ł[
H2O or ROH
R Al RH (90)
In general\ all organometallic compounds of the type RM "where M is lithium\ sodium or

potassium# and of the type RMgX "where X is a halogen# will undergo protonolysis readily\ if not
violently\ when they come into contact with a proton donor "Scheme 47# ðB!79MI 091!90Ł[
H2O
RM RH + MOH
H2O
RMgX RH + Mg(OH)2 + HX
M = Li, Na, K
X = Cl, Br, I
Scheme 58
The carbonÐtin bond is very susceptible to attack by electrophiles[ Water and aliphatic alcohols
are generally inert\ but phenols\ mercaptans and carboxylic acids readily cleave the carbonÐtin bond
to give a carbonÐhydrogen bond "Equation "80## ðB!79MI 091!90Ł[ The tin moiety can also undergo
transmetallation to form alkyllithiums and so\ indirectly\ can be replaced by hydrogen "Scheme 48#
ð65JOM"096#028Ł[
HX
R1 SnR23 R1H + XSnR23 (91)
SnBu3 BuLi Li H2O
Scheme 59
The reaction shown in Equation "81# is one of the very few examples of reduction of transition
metalÐcarbon bonds which has any synthetic utility ð67AG"E#589Ł[
Bz Bz
MeCO2H, hν
(92)
Fe(CO)3
1.03
Two or More CH Bond(s)
Formed by Addition to CC
Multiple Bonds
KEITH JONES
King’s College London, UK
0[92[0 REDUCTION OF ALKENES 60
0[92[0[0 General Methods for Alkene Reduction 60
0[92[0[1 Reduction of Alkyl!substituted Alkenes 67
0[92[0[2 Reduction of Alkenyl!\ Aryl!\ Heteroaryl! and Alkynyl!substituted Alkenes 68
0[92[0[3 Reduction of Heteroalkyl!substituted Alkenes 70
0[92[0[4 Reduction of Remotely Substituted Alkenes 73
0[92[1 REDUCTION OF ARENES AND HETEROARENES 76

0[92[1[0 Types of Reaction 76
0[92[1[1 Heteroèneous Hydroènation 76
0[92[1[2 Homoèneous Hydroènation of Arenes 82
0[92[1[3 Dissolvin` Metal Reductions 84
0[92[1[4 Hydride Reductions 091
0[92[1[5 Electrochemical Reductions 092
0[92[0 REDUCTION OF ALKENES
0[92[0[0 General Methods for Alkene Reduction

The most common and e}ective method for the reduction of carbonÐcarbon double bonds is
catalytic hydrogenation using molecular hydrogen over a heterogeneous catalyst[ The heterogeneous
nature of the catalyst allows for simple removal at the end of the reaction by _ltration[ The reduction
of ethene was _rst reported in 0763 ð0763CB241Ł but it was Sabatier and his group ð0786MI 092!90Ł
who explored this reaction extensively[ Heterogeneous hydrogenation using a number of
di}erent metals as catalyst has been reviewed ðB!54MI 092!90\ B!56MI 092!90\ B!67MI 092!90\ 68MI 092!90\
B!74MI 092!90Ł[ The mechanism of the reaction is extremely complicated and not well understood[
However\ the mechanism suggested in 0823 by Polanyi explains many of the features of importance
to the organic chemist ð23MI 092!90Ł "Scheme 0#[ Hydrogen is dissociatively adsorbed onto two
catalytic sites on the metal surface while the alkene is adsorbed on two adjacent sites[ A hydrogen
atom is transfered to one carbon giving a monoadsorbed alkyl species which undergoes an irre!
versible transfer of the second hydrogen to give an alkane which is desorbed from the metal[
Isomerisation and double bond migration can be understood in this mechanism as involving the
monoadsorbed species undergoing a con_gurational change or returning to a doubly!adsorbed
species which is di}erent to the original[ This mechanism also suggests that both these processes
will be retarded at high hydrogen concentration[ The type of catalyst used is the major factor
60
61 Two or More CH Bonds Formed by Addition
in~uencing the pathway of the reaction "i[e[\ reduction versus isomerisation or double bond
migration#[ The classic example of this is shown in Scheme 1\ involving the hydrogenation of car!
2!ene ð55JCS"C#30Ł[ Hydrogenation over platinum yields cis!carane in high yield but the same
reaction using palladium gives a mixture of products of which trimethylcycloheptane is the major
one[ This is caused by the propensity for palladium to give double bond migration followed by
hydrogenolysis of the allylic cyclopropane and _nally reduction of the C1C double bond[ This is
a property of the metal and is not a}ected much by the support[ A decreasing order of activity in
double bond migration is Pd×NiŁRhŁRu¼Os×Ir¼Pt ðB!74MI 092!90Ł[ For isomerisation\ the
following order of decreasing activity has been suggested\ PdŁRhRuPt×Os×Ir[ Another
side reaction is the hydrogenolysis of allylic\ benzylic and vinylic C0heteroatom bonds[ The order
of decreasing activity in hydrogenolysis of allylic and benzylic functions is Pd×PtŁRhRu
ðB!74MI 092!90Ł whereas the order of decreasing activity in hydrogenolysis of vinylic functions is
PtŁIr×Rh×OsŁRuPd ð60BCJ055Ł[ The nature of the catalyst support can play a role in the
reaction[ In general if the initial product can be further hydrogenated a support such as calcium
carbonate or barium sulfate is best as these seem to adsorb the intermediates less strongly than
catalysts supported on carbon or alumina[ Recently\ a rhodium catalyst has been prepared by
heating rhodium carbonyl with titanium dioxide[ The resulting catalyst displays a strong metal!
support interaction and is about twice as active as rhodium on alumina ð89RTC76Ł[ The extent of
double bond migration can be a}ected by the solvent[ For example benzene has been found to
inhibit migrations when used as a cosolvent ðB!74MI 092!90Ł[
H H
2* + H2
* *
H
*
2* + * H H H
* *
* represents a catalytic site on the surface of the metal
Scheme 1
Pd, H2 Pt, H2
+ +
Scheme 2
Transition metal boride and aluminide reagents can be prepared by reaction of sodium borohy!
dride and lithium aluminum hydride respectively with various transition metal salts[ Their use as
heterogeneous catalysts in the reduction of a variety of functional groups including alkenes has
been reviewed ð75CRV652Ł[
The stereochemistry of hydrogenation of alkenes generally involves cis addition of hydrogen to
the least hindered face of the alkene ð55MI 092!90Ł[ The problem comes about in deciding which is
the least hindered face of an alkene and avoiding isomerisation ð64JOC2962Ł[ Norbornenes usually
undergo hydrogenation from the exo!face unless the bridging carbon carries a large group
ð61JOC0071Ł although many factors such as reaction conditions and alkene purity can a}ect the
outcome[ A further complication arises when the alkene carries groups capable of binding to
the surface of the catalyst and presenting the alkene in a particular orientation ð62JA5268Ł[ This
phenomenon is called haptophilicity[ An example of this is shown in Equation "0# ð79JOC794Ł[
CO2R CO2R CO2R
10% Pd/C
+ (1)
30 psi H2
O O O
H H
R=K 100% 0%
R = Me 75% 25%
Reduction of Alkenes 62
Although heterogeneous catalysts o}er an excellent method for the reduction of alkenes\ the use
of transition metal complexes which are soluble in the reaction medium "homogeneous catalysts# is
a viable and useful alternative[ The pioneering work of Wilkinson and co!workers on rhodium
tristriphenylphosphine monochloride ð54CC020\ 54CI"L#459Ł demonstrated the utility of such systems
and this area has been reviewed ð65OR"13#0Ł[ Homogeneous catalysts have advantages in that they
are usually more selective than heterogeneous catalysts] they are not as susceptible to poisoning^
they lead to cleaner labelling owing to negligible scrambling and they have been shown to be useful
in asymmetric hydrogenations[ A number of homogeneous catalysts have been used to reduce
alkenes[ In addition to Vaska|s catalyst\ Ir"CO#"PPh2#1Cl ð51JA568Ł the reactivity of which resembles
Wilkinson|s catalyst\ there is the rhodium monohydride\ RhH"CO#"PPh2#2 ð57JCS"A#1554Ł and
pentacyanocobalt"III# which is particularly useful for the reduction of electron!poor alkenes
ð61BCJ1612Ł[ A soluble catalyst can also be prepared by treatment of rhodium trichloride trihydrate
with sodium borohydride in DMF ð60CC739Ł[ The crystalline complex formed can be used for the
reduction of alkenes[
Wilkinson|s catalyst is selective for the reduction of mono! and disubstituted double bonds[ In
particular\ terminal double bonds are very readily reduced ð56JCS"A#0463Ł[ As can be seen from
Table 0\ simple cyclic alkenes and terminal alkenes are very rapidly reduced while as soon as steric
hindrance is introduced either near the double bond or actually on the double bond\ the rate of
reduction slows dramatically[ In addition\ trans double bonds are less reactive than cis double
bonds[ The stereoselectivity of reduction is sensitive to both temperature and solvent as illustrated
by the reaction in Equation "1#[ In benzene at 9>C the product shown with an axial methyl is formed
selectively but the use of ethanol as solvent or an increase in temperature gives a mixture of axial
and equatorial methyl[ Although speci_c deuteriation can be achieved by reduction of alkenes using
Wilkinson|s catalyst\ the solvent can a}ect the course of this reaction "Scheme 2#[ Reaction of
styrene with Wilkinson|s catalyst and deuterium in benzene leads to clean addition of deuterium to
give 0\1!dideuteriophenylethane but in chlorinated solvents or with ethanol:benzene a mixture of
partially deuterated products is formed ð69CC384\ 69CC386\ 69CC460Ł[ Most other functional groups
are tolerated by Wilkinson|s catalyst with the exception of aldehydes[ Decarbonylation can be a
serious problem but can be suppressed using high catalyst and hydrogen concentrations ð55TL0594Ł[
Vaska|s catalyst has been prepared by an improved route ð57IS090Ł and reduces alkenes with similar
steric preferences to Wilkinson|s catalyst[ However\ it shows a greater propensity for not only
cis:trans isomerisation but also regioisomerism of the double bond ð61JOM"31#052Ł[
Table 0 Relative rates of reduction of alkenes with Wilkinson|s

catalyst ð56JCS"A#0463Ł[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Alkene Relative rate
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Cyclohexene 20[5
Cyclopentene 23[2
0!Methylcyclohexene 9[5
0!Hexene 18[0
1!Methylpent!0!ene 15[5
cis!1!Pentene 12[1
cis!3!Methylpent!1!ene 8[8
trans!3!Methylpent!1!ene 0[7
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
O Ph O Ph
O O
(Ph3P)3RhCl, H2
(2)
OMe OMe
Rh(PPh3)3Cl, D2 Rh(PPh3)3Cl, D2, PhH Ph D

Mixture of D0, D1, D2 ethylbenzenes Ph
CHCl3 or CDCl3 100% D
or PhH/EtOH
Scheme 3
RhH"CO#"PPh2#2 is a very selective catalyst\ reducing 0!hexene to hexane while not reducing
cyclohexene ð57JCS"A#1554Ł[ Most other functional groups are tolerated and there is little or no
isomerisation[ The pentacyanocobalt"III# ion reacts with hydrogen to give a cobalt hydride species
which is valuable for the reduction of conjugated dienes\ styrenes and electron!poor alkenes
ð61BCJ1612Ł[ a\b!Unsaturated carboxylic acids are reduced in high yield "Equation "2##[ However\
this catalyst also promotes hydrogenolysis of allylic functions such as alcohols\ acetates and halides[
The catalyst formed from rhodium trichloride and sodium borohydride readily catalyses the
reduction of simple alkenes ð60CC739Ł but also reduces C1N\ N1N and nitro groups
ð62JCS"P0#1498Ł[
Ph CO2H Co(CN)52–, H2 Ph CO2H

(3)
100%
The reduction of alkenes using catalytic transfer hydrogenation involves the use of a hydrogen
donor rather than molecular hydrogen[ This approach has been reviewed ð74CRV018Ł[ Both homo!
geneous catalysts and heterogeneous catalysts have been used in conjunction with a wide range of
hydrogen donors to achieve the successful reduction of alkenes[ The most common donors are
trialkylammonium formates\ cyclohexene\ indoline and sodium phosphinate[ The rate of reduction
and indeed the regiospeci_city of reduction can vary with di}erent hydrogen donors ð72JOC0527Ł[
Thus\ along the series cyclohexene\ 0!methylcyclohexene\ 0!methyl!3!isopropylcyclohexene and
0!methyl!3!t!butylcyclohexene the rate of reduction increases by a factor of ten ð72JOC0527Ł[ Among
the heterogeneous catalysts\ the most commonly used is palladium ð74CRV018Ł whilst homogeneous
catalysts based on palladium\ platinum\ ruthenium\ rhodium\ iridium\ iron and nickel have been
reported ð74CRV018Ł[ The reaction presumably proceeds in a similar manner to the reaction using
the same catalyst with molecular hydrogen except that the hydrogen donor is oxidised\ for example
in the case of cyclohexene to benzene[ Benzylic hydrogenolysis can occur^ indeed transfer hydro!
genation has been reported to provide the best method for removal of the carbobenzyloxy group
ð81TL1188Ł[ Partial hydrogenolysis of the C0S bond in benzylic systems has been reported
ð68JOC2331Ł[ Carbon0halogen bonds can be cleaved by various catalytic transfer conditions
although the C0F bond is stable[ The order of ease of cleavage of C0X bonds is as expected\
namely C0I×C0Br×C0Cl[ The C0Cl bond can be cleaved using sodium phosphinate as the
hydrogen donor ð66JCS"P0#332Ł[ The advantages of this method are that special equipment such as
hydrogenators and pressure equipment are not required as the source of hydrogen is usually a
simple solid or liquid[
Reduction of alkenes using diimide was _rst reported in 0894 and has been reviewed ð80OR"39#80Ł[
In all reductions using diimide\ the diimide is generated in situ[ There are a large number of methods
for achieving this ð80OR"39#80Ł but the most common are] "0# acid!promoted decomposition of
sodium or potassium azodicarboxylate ð51CI"L#373Ł\ "1# thermal or base!catalysed decomposition
of arenesulfonyl hydrazines\ for example 1\3\5!triisopropylbenzene sulfonyl hydrazine ð65T1046Ł
and "2# the reaction of hydrazine with an oxidising agent\ for example hydrogen peroxide and
copper"II# ð50TL242Ł\ iodosobenzenediacetate ð76SC692Ł or nickel salts ð73JCS"D#0366Ł[ The reaction
has been shown to involve a stereospeci_c syn addition of hydrogen "or deuterium# to one face
"usually the least hindered# of the alkene ð62JA3235Ł "Equation "3## and has been suggested to involve
a concerted type of mechanism ð50JA1846Ł[ A comparison of the rate of reaction in di}erent solvents
has been carried out and acetonitrile has been shown to lead to the highest rates of reduction ð58MI
092!90Ł[ A wide variety of alkenes are reduced by diimide although the rate of reaction varies with
a number of factors[ Table 1 shows the relative rates of reduction of some representative alkenes[
The higher strain in cyclopentene leads to a faster reaction than with cyclohexene while increasing
substitution slows the reaction down considerably[ Conjugated dienes are more reactive than simple
alkenes ð64JOC2488Ł and conjugation with a carboxylic acid also speeds up the reaction[ There is
evidence that\ usually\ trans!alkenes are reduced more rapidly[ The considerable rate di}erences
between di}erently substituted alkenes makes this method one of the best for achieving selective
reductions "Equation "4## ð67T1870Ł[ In addition to this selective reduction\ a large number of
functional groups survive diimide reduction[ Alkynes are reduced more readily than alkenes but
allylic and benzylic C0heteroatom bonds survive[ Thus\ allylic halides\ esters\ alcohols\ amines and
disul_des are reduced without reduction of the allylic function[ Vinyl halides and vinyl ethers are
reduced slowly again without reduction of the halide or ether function while alkenes conjugated to
carbonyl groups undergo ready reduction without reaction at the carbonyl group[ However\ the
reduction of the aldehyde group in aromatic aldehydes has been reported ð56JCS"C#0019Ł[ Bonds
which are usually very easily cleaved reductively such as N0N\ N0O and O0O survive diimide
reduction[ The advantages of diimide reduction over catalytic hydrogenation include practical
simplicity "no special equipment is required# and high selectivity[
O H O H
O KO2CN=NCO2K, AcOD O
(4)
MeOD, RT D
92%
H D H
Table 1 Relative rates of reduction of alkenes with diimide[

Alkene Relative rate Reference
*
Cyclohexene 0 54JA1821
Cyclopentene 04[4 54JA1821
0!Pentene 19[1 54JA1821
trans!1!Pentene 1[48 54JA1821
cis!1!Pentene 1[54 54JA1821
1!Methylbut!1!ene 9[17 54JA1821
Fumaric acid 099 51AG"E#102
Maleic acid 09 51AG"E#102
*
NH2NH2, CuII, H2O2

(5)
87%
A two!stage procedure for the reduction of carbonÐcarbon double bonds involves the hydro!
boration of the alkene using borane to give an alkylborane followed by protonolysis to give an
alkane ð48JA3097Ł[ The area of borane reagents has been reviewed ðB!77MI 092!90Ł[ Hydroboration
of alkenes occurs readily on reacting borane with a wide variety of alkenes although the number of
hydrogens of the borane replaced by alkyl groups depends strongly on the steric hindrance of the
alkene[ Thus unhindered alkenes react to give trialkylboranes while tetrasubstituted alkenes react
to give monoalkylboranes[ Addition to the double bond occurs in an anti!Markovnikov manner
"the boron atom becomes attached to the least substituted carbon of the alkene# and the boron and
hydrogen add in a cis!manner "Equation "5##[ Although the resulting trialkylboranes are stable to
water\ they are cleaved by heating in carboxylic acids such as propionic\ isobutyric and pivalic
acids ð48JA3097Ł[ Higher carboxylic acids can be used if higher temperatures are needed[ Primary
alkylboranes react most readily followed closely by secondary alkylboranes[ Tertiary alkylboranes
are far less reactive towards carboxylic acids ð60JINC0046Ł[ The protonolysis reaction occurs with
retention of con_guration at the alkyl group ð57JCS"C#0363Ł[
BH3•THF
H
B (6)
H
Although the methods described above constitute the most usual alkene reductions\ a wide
variety of other reagents have been reported to reduce carbonÐcarbon double bonds\ particularly
in a\b!unsaturated systems "see Section 0[92[0[4#[
The use of sodium borohydride with cobalt"II# chloride or nickel"II# chloride for the direct
reduction of alkenes has been reported ð68JOC0903Ł[ Reduction of limonene using this system led to
selective reduction of the less!substituted double bond "Equation "6##[ It has been suggested that
this reaction actually involves the formation of molecular hydrogen and a cobalt boride catalyst
ð75CRV652Ł[ Similar reductions using lithium aluminum hydride along with catalytic amounts of
cobalt\ nickel or titanium chlorides have been studied ð67JOC1456Ł[
NaBH4, CoCl2, EtOH

(7)
79%
Some simple alkenes can be reduced using triethylsilane and excess tri~uoroacetic acid ð56T1124Ł[
Methylcyclohexene is reduced to methylcyclohexane "Equation "7## although under the same con!
ditions 0!pentene is not reduced[
Et3SiH, CF3CO2H (excess)

(8)
72%
The enantioselective formation of alkanes by reduction of alkenes has become an extremely

valuable process in organic chemistry[ This will be treated in this section\ although the substrates
are inevitably heavily substituted alkenes\ in order to make the presentation coherent[ Undoubtedly
the most impressive results have been obtained using homogeneous catalysts but the earliest results
were achieved using heterogeneous catalysts[ In 0845\ Akabori et al[ reported the reduction of
alkenes using a catalyst consisting of palladium and silk _broin\ the water insoluble part of the silk
protein from wild silkworms ð45MI 092!90Ł[ Reduction of an oxazolone with this system was claimed
to give amino acids in 29Ð69) enantiomeric excess "Equation "8##[ It has been reported that this
result is di.cult to reproduce ð80TA732Ł\ perhaps not surprisingly given the nature of the catalyst[
More success has been achieved in reducing N!acetylcinnamic acid derivatives using a polymer!
bound cationic rhodium catalyst ð73AG"E#324Ł[ In this way\ N!acetylphenylalanine has been prepared
in high chemical and stereochemical yield "Equation "09##[
O
Ph i, H2, Pd/silk fibroin CO2H
O Ph (9)
N ii, aqueous acid NHEt
30–70% ee
CO2H H2 (4 atms) CO2H

Ph Ph (10)
NHAc catalyst* NHAc
100%, 95% ee
Ph
Ph
catalyst = P
N +Rh(cod)
P
Ph
Ph
Homogeneous catalysts have provided a much more fruitful area for asymmetric reduction of
alkenes[ The _rst examples involved the modi_cation of Wilkinson|s catalyst by the addition of chiral
tertiary phosphines[ Reduction of simple alkenes proceeded in 2Ð04) ee ð57AG"E#831\ 57CC0334Ł[ The
advent and use of chelating C1!chiral bisphosphines as ligands has revolutionised this area par!
ticularly with the N!acetylcinnamic acid substrates[ For example\ the preparation of N!acetylphenyl!
alanine can be achieved in high chemical and stereochemical yield using the DIPAMP ligand
"Equation "00## ð66JA4835Ł[ This system is used industrially for the synthesis of "S#!DOPA ""S#!2!
"2\3!dihydroxyphenyl#alanine# which is used in the treatment of Parkinson|s disease ð77BSF735Ł[ A
cationic rhodium complex with a chiral bisphosphinamide ligand is used for the synthesis of
"S#!phenylalanine which is used in the nonnutritive sweetner aspartame ð78T5890Ł[ Axially!chiral
ligands such as BINAP have also been used with considerable success in such reductions ð73T0134Ł[
The stereochemical results of these hydrogenations are sensitive to the initial hydrogen pressure and
the optical yields obtained fall o} dramatically at high initial hydrogen pressures[ The mechanism
of this hydrogenation has been the subject of extensive studies by Halpern ð76JA0635Ł and Brown
ð79JA2939Ł and shown to involve reaction through the minor\ less stable alkene:metal complex[
Unfortunately\ these rhodium!catalysed hydrogenations are successful with only a limited range of
substrates[ Although the carboxyl group of the N!acylcinnamic acids can be replaced with other
electron!withdrawing groups and the phenyl group can be replaced with other aryl groups\ alkyl
groups or hydrogen\ the amide function and the b!hydrogen seem to be essential requirements[ In
the light of this limitation\ Noyori and Takaya have developed the use of ruthenium"II#!BINAP
complexes for the hydrogenation of a wide range of prochiral alkenes ð89ACR234Ł[ This catalyst is
particularly useful for the reduction of unsaturated carboxylic acids ð76JOC2063Ł\ for example in the
synthesis of naproxen "Equation "01## although high pressure is required[ The double bond reduced
does not have to be conjugated\ although it does have to be near to the carboxyl group which
complexes to the ruthenium "Equation "02##[ Other functionalities capable of complexing with the
ruthenium can also be reduced with good stereocontrol[ Enamides can be reduced to give 0!
benzylisoquinolines such as tetrahydropapaverine "Equation "03## with excellent enantiocontrol
ð75JA6006Ł[ Allylic alcohols are also good substrates for the ruthenium"II#!catalysed hydrogenations
ð76JA0485\ 76JA3018Ł[ Thus geraniol is reduced both chemo! and stereoselectively to "R#!citronellol
using ruthenium"II#!"S#!BINAP "Equation "04##[
CO2H H2 Rh(R,R)-DIPAMP CO2H

Ph Ph (11)
NHAc 100%, 96% ee NHAc
Ar
P
DIPAMP = Ph Ar = 2-methoxyphenyl
Ph
P
Ar
CO2H H2 (135 atms) CO2H

(12)
RuII-(S)-BINAP
MeO 100%, 97% ee MeO
H2 (101 atms)
(13)
CO2H RuII-(R)-BINAP CO2H
81% ee
MeO MeO
N H2 (4 atms) N
MeO COPh MeO COPh (14)
OMe RuII-(S)-BINAP OMe
100%, 96% ee
OMe OMe
H2 (30 atms)
(15)
OH RuII-(S)-BINAP OH
100%, 96% ee
The use of baker|s yeast for the enantioselective reduction of alkenes has also been reviewed
ð89S0Ł[ The most common substrates for this biotransformation are systems in which the double
bond is conjugated with an electron!withdrawing group such as a carbonyl group[ Allylic alcohols
can be reduced with good enantioselectivity ð77T0188Ł[ For example a phenylthio!substituted alkene
has been reduced with high ee although the yield is moderate and the reaction time long "Equation
"05##[ Trisubstituted allylic alcohols can also be reduced with excellent stereocontrol as demonstrated
by the reduction of geraniol to optically!pure citronellol ð76T3370Ł[ Unsaturated esters can be
reduced in moderate to good yields and with excellent enantioselectivity "Equation "06##
ð65HCA0721Ł[ The reduction of the masked aldehyde in this reaction is a common feature of the
baker|s yeast reduction of unsaturated aldehydes[ Cinnamaldehyde derivatives are readily reduced
to optically!active alcohols[ Thus a furylacrolein has been reduced using baker|s yeast to the
saturated alcohol "Equation "07## in high chemical yield and with complete control of the stereo!
chemistry ð77JCS"P0#2950Ł[
,
baker s yeast
OH OH (16)
PhS 96% ee PhS
,
OMe baker s yeast
(17)
49%, 97% ee EtO2C OH
EtO2C OMe
,
baker s yeast
OH
(18)
CHO 72%, 100% ee
O O
0[92[0[1 Reduction of Alkyl!substituted Alkenes

Alkyl!substituted alkenes are reduced by a wide range of heterogeneous catalyst systems although
the reduction becomes more di.cult as the number of alkyl groups on the double bond increases
presumably due to the di.culty of adsorption of the alkene[ An example illustrating this is the
selective reduction of limonene "Equation "08## which can be achieved to cleanly reduce the least!
substituted double bond providing hydrogen uptake is stopped after one equivalent has been used
ð72JOC2051Ł[ However\ care needs to be exercised in determining the most hindered double bond as
shown by the examples in Equations "19# and "10#[ Reduction of the octalin "Equation "19## proceeds
readily at room temperature and atmospheric pressure to give a mixture of cis! and trans!decalins
ð26JCS0025Ł whereas addition of an extra ring means that drastic conditions are required "Equation
"10## ð67T0150Ł[ Strain also increases the susceptibility of a double bond to reduction "Equation
"11##[ The reaction can be readily halted after reduction of the strained cyclobutane double bond
ð41JA3756Ł[ Simple cyclic alkenes are readily hydrogenated "Equation "12##[ This reduction can be
achieved using platinum oxide "in which case a prereduction of the catalyst is required# or palladium
on carbon ð52OSC"3#293Ł[
W-4 Raney Ni, H2

(19)
96%
PtO2, EtOH, H2 (1 atm)

(20)
Raney Ni, 250 °C

(21)
H2 (200 atms)
CO2K CO2K
10% Pd/C, H2O
(22)
H2 (1 atm)
CO2K CO2K
CO2Et CO2Et
PtO2 (or Pd/C), EtOH
(23)
CO2Et H2 (1 atm) CO2Et
96%
The reduction of simple alkyl substituted terminal alkenes "Equation "13## has been studied
extensively using Wilkinson|s catalyst often as kinetic experiments ð56JCS"A#0463Ł[ As can be seen
from Table 0\ the reduction of terminal double bonds is kinetically favoured[ Although double
bonds conjugated to carbonyl groups can be reduced using Wilkinson|s catalyst "see below#\ the
selective reduction of the terminal double bond in carvone "Equation "14## is well known ð65OR"13#0Ł[
RhCl(PPh3)3, H2
(24)
R R
PhH
R = n-alkyl
O O
RhCl(PPh3)3, H2
(25)
PhMe
95%
Simple alkenes have been reduced using palladium on carbon and cyclohexene ð64S337Ł or
triethylammonium formate "Equation "15## ð67JOC2874Ł[ Cyclic alkenes are also readily reduced\
for example cyclohexene "Equation "16## using indoline as the hydrogen donor ð64S337Ł[
Et3NHHCO2, Pd/C, 7 h
(26)
81%
indoline, 5% Pd/C, 1 h
(27)
43%
0[92[0[2 Reduction of Alkenyl!\ Aryl!\ Heteroaryl! and Alkynyl!substituted Alkenes

Conjugated dienes can undergo three types of reduction] selective 0\1!reduction of one of the
double bonds\ 0\3!reduction or complete reduction[ An example of the latter two reactions is shown
in Scheme 3 ð45ZOB0064Ł[ A similar e}ect of the catalyst chosen is found in the reduction of mevinolin
"Scheme 4#[ Palladium leads to 0\3!reduction whereas platinum leads to complete hydrogenation
ð72JOC0880Ł[ Conjugated dienes such as 0\2!pentadiene are reduced slowly by Wilkinson|s catalyst
although a simple rhodium hydride has been used to successfully reduce 0\2!butadiene "Equation
"17## to 0!butene although a higher temperature and pressure was required ð63JOM"69#78Ł[ Reduction
of 0\2!butadiene with pentacyanocobalt"III# occurs under milder conditions but gives a mixture of
products "Equation "18## ð61BCJ1612Ł[ Dienes are also reduced under catalytic transfer conditions
but the reaction is slower than with simple alkenes and can lead to a mixture of products "Equation
"29## ð67JOC2874Ł[
O O O
PtO2, H2 Raney Ni, H2
Pd/CaCO3, H2
Scheme 4
HO O HO O HO O
O O O
O O O
Pd/CaCO3 PtO2
EtOH EtOAc
3:1 trans:cis
Scheme 5
RhH(PPh3)4, C6H12
(28)
50 °C, 15 atms H2
Co(CN)52–, H2
+ + (29)
ROH
Et3NHHCO2, Pd/C
+ (30)
21 h
51% 28%
Allenes are generally reduced in a stepwise manner to alkenes and then alkanes with palladium
being more selective than platinum ð53MI 092!90Ł[ Allenes with a terminal double bond are selectively
reduced at the terminal double bond[ This is illustrated by the reduction 1\2!butadienoic acid over
palladium to give crotonic acid "Equation "20## ð43JCS2086Ł[ A similar reaction for a phosphorus!
substituted allene has been reported "Equation "21## ð69JOC2409Ł but yielding the opposite stereo!
chemistry in the product[
• Pd/CaCO3, EtOH
(31)
CO2H H2 (1 atm) CO2H
•
Pd/C, H2 (1 atm)
P(OBut)2 P(OBut)2 (32)
O O
There are many examples of the reduction of aryl!substituted double bonds mostly of cinnamic
acid derivatives using heterogeneous catalysts "Equation "22## ð52OSC"3#025Ł[ Phenylalanine is readily
prepared from acetamidocinnamic acid by reduction using platinum under a slight pressure of
hydrogen "Equation "23## ð32OSC"1#380Ł[ As discussed above "see Section 0[92[0[0#\ ace!
tamidocinnamic acids are good substrates for homogeneous catalytic reduction "Equation "24##
ð58CC0254Ł[ Styrenes can be reduced by many of the homogeneous catalysts including pentacyano!
cobalt"III# ð61BCJ1612Ł[ Wilkinson|s catalyst reduces styrene itself smoothly at room temperature
ð56JCS"A#0463Ł while Vaska|s catalyst requires a higher temperature "Scheme 5# ð61RTC0946Ł[ Con!
jugation of the alkene with an aromatic ring is no hinderance to reduction using catalytic transfer
hydrogenation "Equation "25## ð64S337Ł although the reduction of stilbene "Equation "26## is slow
and requires a modi_ed palladium catalyst ð67S4286Ł[ There are two rather more unusual methods
that have been reported to reduce the double bond in styrene systems[ The reaction of 0\0!diar!
ylethenes with lithium aluminum hydride leads to the alkane in good yield "Equation "27##[ Electron!
donating substituents on the aryl rings slow down the reaction and the solvent is important for a
clean reaction ð65JOC2571Ł[ A phase!transfer reduction of 0\0!diarylethenes and related systems has
been reported using a low oxidation state cobalt catalyst and tetra~uoroboric acid ð72CC254Ł[ Such
activated double bonds are reduced in high yield "Equation "28##[
CO2H CO2H
Raney Ni, 95 °C
(33)
95%
CO2H CO2H
NHAc Pt, HOAc, H2 (3 atms) NHAc
Ph Ph (34)
CO2H 80% CO2H
NHAc RhCl(PPh3)3, H2, PhH NHAc

Ph Ph (35)
CO2H >95% CO2H
IrCl(CO)(PPh3)2 RhCl(PPh3)3, H2
Ph Ph Ph
H2, PhH, 50 °C PhH, 25 °C
Scheme 6
indoline
5% Pd/C, 1 h, 90 °C
(36)
Ph Ph
97%
cyclohexene
10% Pd/C/AlCl3, 46 h
Ph Ph (37)
Ph 96% Ph
Ph LiAlH4, THF, 65 °C
Ph
(38)
Ph 80% Ph
Ph Co2(CO)6(PBu3)2, HBF4
Ph
(39)
Ph H2O/PhH, C12H25C6H4SO3Na, 4 h Ph
97%
Heteroaryl!substituted double bonds are similarly straightforward to reduce[ A wide variety of

heteroaryl!substituted acrylic acids have been studied ð49JA2428Ł and found to undergo clean
reduction to the substituted propionic acid using Raney nickel\ even if the heteroaromatic system
is easily reduced "Equation "39##[ Palladium on calcium carbonate has also been successfully used
for the reduction of the quinoxaline!substituted system "Equation "30## but the use of Raney nickel
in this case has been reported to lead to a lactam by!product resulting from reduction of the
heteroaromatic ring "Equation "31## ð54JA0873Ł[
Raney Ni
Heteroaryl Heteroaryl (40)
CO2H 75–93% CO2H
N N
Pd/CaCO3, NaOH, H2O
(41)
N CO2H H2 N CO2H
H
N N N
Raney Ni
+ (42)
N CO2H N CO2H N
0[92[0[3 Reduction of Heteroalkyl!substituted Alkenes

Heteroalkyl!substituted alkenes can present problems for catalytic hydrogenation as a major side
reaction is the hydrogenolysis of the C0heteroatom bond[ However\ vinyl halides are reduced to
alkyl halides albeit rather poorly using diimide "Equation "32## ð56JOC782Ł[ A thorough study on
the hydrogenation of an enol ether using a variety of metal catalysts has been carried out ð60BCJ055Ł[
Some results of this study are shown in Equation "33#[ Palladium leads to the cleanest reduction
while platinum gives the largest amount of hydrogenolysis[ Oxygen!substituted alkenes such as vinyl
acetate can be reduced using Wilkinson|s catalyst "Equation "34## ð57MI 092!90Ł\ although it should
be noted that it may be possible to reduce other double bonds in the presence of an enol ether
"Equation "35## ð60AJC402Ł[ In this case\ it is possible the major in~uence on the selectivity of the
reaction is the steric hindrance of the enol ether double bond compared to the other double bond[
Enol ethers are also somewhat resistant to diimide reduction\ for example dihydropyran does not
undergo reduction ð56JCS"C#0019Ł[ However\ a bisvinyl ether has been reported to undergo reduction
"Equation "36## ð64JOC2488Ł[ Enol ethers are hydroborated to give exclusively 1!alkoxyalkylboranes
regardless of the substitution pattern on the double bond[ However\ these organoboranes are
susceptible to elimination ð57IJ580Ł[
NH2NH2, O2, CuII

(43)
H
48 h, RT
Cl 22% Cl
OEt OEt OH
M, EtOH
(44)
H2 (1 atm), 25 °C
M = Ru 78%
M = Rh 55% 30%
M = Pd 98%
M = Pt 45% 40%
RhCl(PPh3)3, H2
OAc OAc (45)
PhH, 22 °C
OMe OMe
RhCl(PPh3)3, H2
(46)
PhH, 22 °C
O O
KO2CN=NCO2K, RCO2H
(47)
MeOH
O O
Enamines can be reduced using platinum oxide as the catalyst "Equation "37## ð25CB1095Ł although
they are more usually reduced in other ways[ Thus sodium borohydride in acetic acid reduces
enamines to amines ð52BSF687Ł[ For example the enamine derived from cholestenone undergoes
reduction to give the homoallylic amine "Equation "38## ð52JOC310Ł[ Enamines also undergo
reduction on heating with formic acid "Equation "49## ð74ACS"B#076Ł[ This reaction also works with
enamines derived from morpholine "Equation "40##[ An elegant deuterium labelling experiment has
been carried out to shed light on the mechanism of this reaction and prepare speci_cally labelled
amines "Scheme 6# ð46JA5109Ł[ Nitrogen!substituted alkenes with the nitrogen in a variety of
oxidation states are reduced to alkanes using Wilkinson|s catalyst[ Thus b!nitrostyrene is reduced
to a nitroalkane ð55JCS"C#0783Ł with no reduction of the nitro group "Equation "41##[ The reduction
of acetamidocinnamic acid derivatives has already been discussed[ In common with simple vinyl
ethers\ simple enamines undergo no reduction of the double bond with diimide ð54CC60Ł[
N PtO2, H2, EtOH N

(48)
NaBH4, HOAc, THF

(49)
44%
N N
HCO2H, 100 °C
N N (50)
52%
Ph Ph
O O
N HCO2H, 100 °C N
(51)
D
D D
DCO2D DCO2H
N N N
Scheme 7
RhCl(PPh3)3, H2, PhH

Ph Ph (52)
NO2 NO2
Vinylic sul_des are a particular problem since sulfur is an excellent catalyst poison and high
catalyst ratios are required with long reaction times[ Under such conditions hydrogenolysis of the
C0S bonds is the most common reaction "Equation "42##[ However\ reduction of the same com!
pound using a sulfur!treated palladium catalyst gave clean reduction of the double bond although
the reaction was slow "Equation "43## ð79JA0054Ł[ Although there are no reports on the reduction
of vinylsilanes using diimide\ the clean reduction of the double bond in a vinylstannane "Equation
"44## has been reported by Kuivila and co!workers ð62JOM"50#056Ł[
CO2Me CO2Me
S
Pd/C, H2
(53)
N N
H H
CO2Me CO2Me
S S
PdS/C
(54)
EtOH, 5 atms
N N
H H
NH2NH2, H2O2, CuII

(55)
0 °C, EtOH
74%
SnMe3 SnMe3
0[92[0[4 Reduction of Remotely Substituted Alkenes
Allylic substituents can also undergo hydrogenolysis although the activity of catalysts towards
hydrogenolysis is rather di}erent to that observed for vinylic systems[ Palladium causes most
hydrogenolysis followed by platinum and rhodium[ Allylic chlorides "Equation "45## are reduced in
high yield by diimide ð65BCJ0326Ł as are allylic bromides "Equation "46## ð56JCS"C#0019Ł[ Hydro!
boration of alkenes containing a range of functional groups is possible although for functionalities
on or near the double bond some e}ect on the regioselectivity of addition is found[ Allylic halides
direct the boron unit to the proximal carbon of the double bond "Equation "47##[ However\ the
resulting 1!haloboranes are unstable with respect to elimination to the alkene under either acid or
base catalysis and hence such substrates cannot be used in the protonolysis reaction to give alkanes
ð57MI 092!90Ł[
Cl Cl
NH2NH2, O2, CuII

(56)
MeOH, reflux, 1 h
92%
Cl Cl
KO2CN=NCO2K, AcOH
Br Br (57)
MeOH, 25 °C
Cl Cl Me
BMe3 B
(58)
Me
Rhodium on carbon gives clean reduction of an allylic acetate "Equation "48## whereas both
platinum oxide and palladium lead to extensive cleavage of allylic acetates ð68TL0530Ł[ Allylic
oxygen functions survive reduction of the double bond using diimide and cause no di.culties[ For
example\ an allylic ozonide has been reported to undergo smooth reduction of the double bond
"Equation "59## ð76JMC0494Ł[ The reduction of the double bond in allylic alcohols using lithium
aluminum hydride has been reported and the mechanism of the reaction studied by NMR
ð76BSF351Ł[ Homogeneous catalysts have been used to control the facial selectivity of double bond
reduction[ Although the reduction of alkenes can occur with some diastereoselectivity\ it is very
hard to predict the result[ Initially\ Stork and Kahne ð72JA0961Ł and subsequently Evans and
Morrissey ð73JA2755Ł realised that soluble catalysts combined with directing groups in the substrate
could overcome this problem[ Stork showed that cyclic allylic and homoallylic alcohols undergo
diastereoselective reduction using a cationic iridium complex but perhaps the most striking example
is the reduction of a hydroxyindenone "Equation "50##[ Evans used both a cationic iridium complex
and a cationic rhodium complex with a range of cycloalkenols but also demonstrated that acyclic
systems undergo diastereoselective reduction using the rhodium catalyst and a higher pressure of
hydrogen "Equation "51##[
OAc OAc
O O
Rh/C, H2, EtOAc
(59)
O 95% O
OGlu(Ac)4 OGlu(Ac)4
OAc OAc
OH KO2CN=NCO2K, AcOH OH
O O (60)
O CH2Cl2, 36 h O
O 99% O
OH OH
Ir(cod)py(PR3)PF6
(61)
O CH2Cl2, H2 (1 atm) O
H
96% trans-indanone
OH O OH O
Ph Rh(NBD)(DIPHOS)BF4 Ph
N N
(62)
O CH2Cl2, H2 (40 atms) O
O O
86% de
Sulfur functionalities are not a}ected by diimide reduction "Equation "52## ð63JOC2084Ł[ One
particularly useful alkene reduction which is often best achieved via hydroboration is the reduction
of allylsul_des to sul_des[ Thus allylmethylsul_de is reduced to methylpropylsul_de without causing
problems of catalyst poisoning or hydrogenolysis "Equation "53## ð48JA3097Ł[
D
N2D2, CDCl3
D (63)
CO2Me CO2Me
SO2Ph SO2Ph
i, BH3
(64)
MeS ii, AcOH, heat MeS
Using cyclohexanol as the source of hydrogen\ catalytic transfer reduction of the double bond in
a tetrahydropyridine has been reported to take place in high yield "Equation "54## ð68MIP04043Ł[
Me Me
N N
Raney Ni, cyclohexanol

(65)
160 °C, 1 h
95%
N N
H H
A particularly useful alkene reduction is the selective reduction of the carbon1carbon double
bond of a\b!unsaturated carbonyl compounds[ A wide variety of reagents have been reported to
achieve this transformation[ Palladium is probably the most suitable heterogeneous catalyst for
this as reduction of the carbonyl group is rare "Equation "55## ð72JOC2269Ł[ In the reduction of
eremorphilone using palladium\ the conjugated double bond is reduced in preference to the rather
unhindered double bond in the isopropenyl group "Equation "56## ð56JOC1902Ł[ The presence of a
carbonyl group conjugated to the double bond can cause problems with homogeneous catalysts
particularly where the carbonyl group is an aldehyde\ when decarbonylation can be a side reaction[
Reduction of acrolein using Wilkinson|s catalyst gives propanal in yields varying between 50) and
71) depending on the concentration of catalyst and hydrogen pressure "Equation "57##
ð56JCS"C#169Ł[ The reduction of the conjugated double bond in juglone has been reported "Equation
"58## ð56TL2346Ł[ Reduction of a\b!unsaturated carbonyl compounds\ nitriles\ etc[\ proceeds
smoothly using catalytic transfer technology and there are many examples ð63CRV456Ł[ The
reduction of crotonaldehyde has been reported in 70) yield "Equation "69## ð67JOC2874Ł[
O
O
AcO Pd/BaSO4, H2
(66)
100%
OAc
TBDMS-O
Pd, H2
(67)
O O
RhCl(PPh3)3, H2
CHO CHO (68)
PhH, 25 °C
O O
RhCl(PPh3)3, H2
(69)
PhH, 25 °C
OH O OH O
Et3NHHCO2, 10% Pd/C, 8 h

CHO CHO (70)
81%
The reaction of tributyltin hydride with catalytic palladium"9# reduces cinnamaldehydes unless
they have an electron!donating group in the para position[ Some hints concerning the mechanism
can be gleaned from the reactions shown in Scheme 7[ Lipshutz et al[ have reported the reduction
of unsaturated ketones to saturated ketones using tributyltin hydride:copper"I# iodide ð78SL53Ł
which is suggested as involving hydridocuprates[ The copper hydride reagent of Stryker and co!
workers achieves these reactions cleanly ð77JA180Ł[ Even cyclic ketones substituted at the b!position
are reduced in high yield "Equation 60# along with the double bond in unsaturated esters[ Isolated
double bonds do not react[
D
Bu3SnH, Pd0 Bu3SnD, Pd0
CHO CHO CHO
Ph Ph Ph
D2O workup H2O workup
D 99% 99%
Scheme 8
O O
[(Ph3P)CuH]6, PhH, H2O
(71)
96%
Cyclohexenones have also been reduced to cyclohexanones using methylcopper and diiso!
butylaluminum hydride "dibal!H# in hexamethylphosphoramide "HMPA#\ a system that reduces
unsaturated esters to saturated esters ð75JOC426Ł[ Silanes in the presence of a transition metal catalyst
will reduce the carbon1carbon double bond of enones[ Phenylsilane and catalytic molybdenum
hexacarbonyl e}ect reduction of benzylidene acetone "Equation "61## ð76JOC1465Ł although the
reaction with cyclohexenone gives cyclohexanone in poor yield[ Rhodium"I# also catalyses the
reaction of silanes and enones ð78JA5146Ł[ The reaction presumably proceeds via hydrosilylation to
give the silylenol ether followed by hydrolysis during workup "Scheme 8#[ Potassium triphenyl!
borohydride has been reported to be a useful reagent for the conjugate reduction of both cyclic and
acyclic enones "Equation "62## ð77SC78Ł although if an aromatic ring is also conjugated to the double
bond\ preferential 0\1!reduction occurs[ An unusual system consisting of carbon monoxide\ water
and selenium reduces enones to ketones in the presence of a strong base such as 0\4!
diazabicycloð4\3\9Łundec!4!ene "dbu# "Equation "63## ð78BCJ0571Ł[ Unsaturated esters\ acids and
amides also react but need higher temperatures while enals undergo reduction at the aldehyde[
Magnesium in methanol will reduce unsaturated esters to saturated esters ð75TL1398Ł[ Isolated
double bonds and epoxides are unreactive and the use of deuteriated methanol leads to the overall
addition of D1 across the double bond "Equation "64## ð76TL4176Ł[
Reduction of Arenes 76
O PhSiH3, Mo(CO)6, THF
O
(72)
Ph 65 °C, 1.5 h Ph
100%
O OSiPr3 O
Pr3SiH, RhI
THF, 60 °C
Scheme 9
KPh3BH, 0 °C, 6 h
(73)
94%
O O
O CO, H2O, Se, dbu, 50 °C

O
(74)
Ph 82% Ph
dbu = 1,5-diazabicyclo[5.4.0]undec-5-ene
D
Mg, CD3OD
CO2Et CO2CD3 (75)
95%
D
0[92[1 REDUCTION OF ARENES AND HETEROARENES
0[92[1[0 Types of Reaction

The reduction of arenes and heteroarenes can be accomplished by a variety of methods[ Hetero!
geneous hydrogenation using a number of di}erent metals as the catalyst has been reviewed
ðB!54MI 092!90\ B!56MI 092!90\ B!67MI 092!90\ 68MI 092!90\ B!74MI 092!90Ł[ This approach generally requires
moderate temperatures and pressures to achieve the reduction of arenes\ while some heteroarenes
can be reduced under milder conditions[ Such reductions are commonly used in industrial processes[
More recently\ homogeneous hydrogenation of arenes has been explored and reviewed ð68ACR213Ł[
Dissolving metal reduction of arenes leads to partially reduced aromatic systems ð81OR"31#0Ł and
has found considerable use in synthesis ð75NPR24Ł[ Reduction of arenes by hydride reducing agents
is generally very di.cult but the corresponding reaction of electron!de_cient heteroarenes such as
pyridine is much easier ð75AHC"28#0Ł[ Electrochemical reduction particularly of polycyclic arenes
ðB!61MI 092!90Ł and heteroarenes ð73AHC"26#056Ł has also found some applications[ The following
sections will consider each of these methods separately[
0[92[1[1 Heterogeneous Hydrogenation

The _rst reported reductions of aromatic rings involved the reduction of phenol and aniline
ð93BSF090Ł and benzene ð03BSF117Ł using a nickel metal catalyst[ Rhodium\ ruthenium\ iridium\
palladium and platinum on a solid support will catalyse the reduction of benzene to cyclohexane
under pressures of about 5[8 MPa of hydrogen and at temperatures of about 099>C[ However\
rhodium and ruthenium are the best catalysts with rates approaching 099 times those of the other
metals "Table 2#[ Generally\ the metal is supported on either carbon or alumina[ The choice of
support is not usually important although the reduction of acetophenone to cyclohexylethanol using
rhodium occurs in higher yield when alumina is used as the catalyst support ð68MI 092!90Ł[ In
common with many catalytic reactions\ trace impurities in the substrate can dramatically a}ect the
rate of reduction[ Metal ions such as sodium can inhibit reduction in platinum oxide catalysed
reactions[ The traditional poisons for noble metal catalysts such as lead and mercury do not seem
to have much e}ect on the rate of reduction ðB!56MI 092!90Ł[ Acids can act as either inhibitors or
promotors^ HCl inhibits the reduction of toluene or benzoic acid over 4) rhodium on carbon or
alumina ð50JOC0724Ł whereas reduction over rhodium on alumina is promoted by acetic acid[
ð44JA3151Ł[
Table 2 Relative rates of reduction of
benzene[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Catalyst Relative rate
*
Ir 0
Pd 0
Pt 0
Rh 66
Ru 099
*
Rhodium on alumina is probably the catalyst of choice for the hydrogenation of aromatic rings
under the mildest conditions without benzylic hydrogenolysis[ For example mandelic acid is reduced
to hexahydromandelic acid using 4) rhodium on alumina without racemisation "Equation "65##
ð51JOC1177Ł[ Hydrogenation of arenes using ruthenium catalysts is generally performed at 099>C
and 5[8 MPa[ Under these conditions\ benzylic hydrogenation can occur as shown in Equation "66#
ð47JA4169Ł[ However\ the hydrogenation of ephidrene "Equation "67## using ruthenium has been
reported to occur without racemisation ð47JA4169Ł[ Platinum oxide in the presence of a trace of
acetic acid can be used to hydrogenate benzyl alcohol without hydrogenolysis but as the amount of
acetic acid is increased so does the amount of benzylic hydrogenolysis ðB!56MI 092!90Ł[ Palladium is
the preferred catalyst for the hydrogenolysis of benzylic functionalities and hence is least widely
used for reduction of arenes[
OMe OMe
CO2H 5%Rh/alumina/H2 CO2H

(76)
RuO2, H2
(77)
6.9MPa, 100 °C
OH OH
RuO2, H2
(78)
NHMe 8.3MPa, 90 °C, 90 min NHMe
Although the e}ect of the support is usually small for alumina and carbon\ a strong metal!support
interaction has been described for Group 8 metals with transition metal oxides such as titanium
dioxide ð76ACR278Ł[ This has led to the development of a highly active rhodium catalyst formed by
deposition of rhodium on titanium dioxide via decarbonylation of Rh3"CO#01 followed by activation
by exposure to air ð89RTC76Ł[ In the reduction of toluene at 0 atmosphere of hydrogen and 49>C\
this catalyst was found to be about twice as active as the commercial rhodium:alumina[
Partial hydrogenation of arenes using heterogeneous catalysis is di.cult to achieve as the inter!
mediates are reduced faster than the arene and low selectivity is observed ðB!56MI 092!90Ł[ The fusion
of a less easily reduced aromatic ring can also allow partial reduction as shown in Equation "68#
ð50JA2059Ł[ The use of a modi_ed ruthenium surface has been reported to enable the partial reduction
of benzene ð52MI 092!90Ł[
NO2 NO2
30% Pd/C, H2
CO2Et CO2Et (79)
N HOAc N
H H
Alkyl!substituted benzenes can be reduced to alkyl!substituted cyclohexanes using a variety of
catalysts although the reaction becomes slower with increasing number of substituents[ With xylenes
the product is predominantly the cis isomer indicating addition of hydrogen from one face
ð46CRV784Ł although this varies with catalyst and isomer "Table 3# ðB!56MI 092!90Ł[
Table 3 Reduction of dimethylbenzenes[

Isomer Catalyst Ratio "cis ] trans#
*
0\1 Rh 78 ] 00
0\1 Ru 82 ] 6
0\2 Rh 63 ] 15
0\2 Ru 74 ] 04
0\2 PtO1 70 ] 08
0\3 Rh 53 ] 25
0\3 Ru 69 ] 29
*
Halogen!substituted aromatics su}er ready loss of the halogen[ Generally\ the C0F bond is
stable ð44JA3151Ł while the C0Cl and the C0Br bonds are cleaved with increasing ease ð42CB056Ł
and the C0I bond is cleaved rapidly[ The use of nonpolar solvents has been reported to retard
halogen loss ð38JA3043Ł[
Phenols can undergo ring reduction with three possible outcomes\ namely reductive cleavage of
the C0O bond\ formation of a cyclohexanone or formation of a cyclohexanol[ Reduction with
cleavage of the C0O bond is prevalent with platinum and iridium catalysts ðB!56MI 092!90Ł[ For!
mation of cyclohexanones is relatively rare but has been observed with palladium catalysts "Equation
"79## ð53JA007Ł[ Formation of the cyclohexanol product is favoured using rhodium and ruthenium
catalysts[ The reduction of 0!naphthol to decanol proceeds in high yield "Equation "70## using a
rhodium catalyst ð60OS"40#092Ł[ Ruthenium requires higher pressure but is equally successful in
reducing phenols to cyclohexanols "Equation "71## ð52JOC5Ł[
OH O
Pd/C, H2
(80)
OH OH
5%Rh/alumina, EtOH
(81)
380–410 kPa H2, 12 h
94–97%
cis, cis is major isomer
in 55% yield
OH RuO2, 50 °C, 8 h OH
(82)
10.3 MPa H2
95%
Anilines can be reduced to cyclohexylamines but su}er from the concommitant formation of
dicyclohexylamines by reductive coupling ðB!56MI 092!90Ł[ Again rhodium and ruthenium are the
most active catalysts[ Nitrobenzenes are more readily reduced at the nitro!group using catalysts
such as platinum or palladium at low pressures and temperatures[
Heteroaromatic systems vary in their susceptibility to hydrogenation and with the nitrogen!
containing rings\ the presence of acid is often helpful to cause protonation and prevent poisoning
of the catalyst by the more basic reduced product ðB!60MI 092!90Ł[ Pyridine has been reduced to
piperidine using a variety of catalysts with rhodium being the most active under mild conditions\
platinum having been widely used\ palladium and ruthenium being used industrially and Raney
nickel requiring higher temperatures and pressures ðB!74MI 092!90Ł[ Under acid conditions\ the
pyridinium salt is formed which is reduced more readily than the free base and quaternary pyridinium
salts are reduced even more readily probably because the products are poorer catalyst poisons[ In
quinoline\ selectivity of reduction is possible[ Thus reduction using platinum in TFA causes reduction
of the carbocyclic ring while use of nickel catalyst at high temperature causes reduction of the
pyridine ring[ Using nickel and high temperature and pressure\ leads to the decahydroquinoline as
a mixture of cis and trans isomers "Scheme 09# ðB!60MI 092!90Ł[ Isoquinoline also undergoes selective
reduction depending on the conditions "Scheme 00#[ In methanol with a platinum catalyst\ reduction
of the pyridine ring occurs whereas in strong acid\ the carbocyclic ring is reduced ð64JOC0080Ł[
Pyrimidine is reduced to the tetrahydropyrimidine using palladium or platinum catalysts under
acidic conditions "Equation "72## ð51CHE329Ł[ Pyrrole is less readily reduced than benzene but can
nonetheless be reduced to pyrrolidine using platinum or rhodium as the catalyst[ Ruthenium at
099Ð199>C and 09[23 MPa has been successful ðB!60MI 092!90Ł[ The solvent can play an important
role as shown in Scheme 01[ In ether only the alkene double bond is reduced while in ethanol the
pyrrole ring is reduced to give the pyrrolizidine ð55JOC769Ł[ Indole resembles pyrrole in being
di.cult to reduce and the most successful catalysts are Raney nickel\ ruthenium and copper chromite
ð30JA0452Ł[ Thus hydrogenation of indole over ruthenium at 099>C and 74 atmospheres pressure
gave octahydroindole whereas treatment with Raney nickel in ethanol at the same temperature and
pressure gave indoline in 71) yield "Scheme 02#[
PtO2/H2 Ni/H2, 210 °C
TFA
N N N
H
Ni/H2, 480/kPa
210 °C
N
H
Scheme 10
Pt/H2, HCl Pt/H2, MeOH
N N NH
Scheme 11
N Pd or Pt/H2, acid NH
(83)
N N
5%Rh/C, H2 5%Rh/C, H2
N ether N ethanol N
81% high yield
Scheme 12
Ru, 85 atms, H2 Raney Ni, 85 atms, H2
N 100 °C N EtOH, 100 °C N

H H 82% H
Scheme 13
Furans can undergo simple reduction to tetrahydrofurans particularly using palladium\ ruthenium
or rhodium catalysts[ Furan has been reduced quantitatively to tetrahydrofuran using palladium
and hydrogen at 589 kPa "Equation "73## ð32OSC"1#455Ł[ Under harsher conditions or with platinum
catalyst\ hydrogenolysis takes place ð56T104Ł[ Benzofurans have been hydrogenated in the furan
ring to give 1\2!dihydrobenzofurans using palladium at 099>C and moderate pressure "Equation
"74## ð65CB1517Ł[ There are very few reports concerning the hydrogenation of thiophenes although
reduction over palladium to a tetrahydrothiophene is the key step in a biotin synthesis "Equation
"75## ð66JOC024Ł[
Pd, 690 kPa H2, 15 h

(84)
100%
O O
Pd/C, 100 °C, H2

(85)
O O
MeO2CHN NHCO2Et MeO2CHN NHCO2Et

Pd/C, AcOH, 50 °C
(86)
CO2H CO2H
( )4 10.3 MPa H2 ( )4
S 95% S
Hydrogenation of hydroxypyridines "pyridones# can result in hydrogenolysis in addition to

reduction[ 2!Hydroxypyridine is susceptible to reduction of the carbon0oxygen bond and gives a
mixture of piperidine and 2!hydroxypiperidine "Equation "76## whereas the 1! and 3!pyridones
retain the oxygen\ although in the case of 3!pyridone the product is 3!hydroxypiperidine "Equations
"77# and "78## ð46JA4168Ł and ð47JA5301Ł[ Amino!substituted pyridines also undergo hydrogenolysis
to give piperidine "Equation "89## ð50JOC707Ł[ Carboxy!substituted pyridines can undergo decar!
boxylation on catalytic hydrogenation ð51JOC3935Ł[ Nicotinic acid "Equation "80## gives a mixture
of piperidine!2!carboxylic acid and piperidine when reduced over rhodium\ ruthenium or platinum
although it has been reported that the use of rhodium on alumina in aqueous ammonia only gives
reduction with no decarboxylation ð51JOC0395Ł[ The presence of a carbonyl!substituent at the
2!position has also been reported to allow the isolation of the tetrahydro product[ Thus the reduction
of 2!acetylpyridine over palladium leads to the isolation of a tetrahydropyridine ð57JOC636Ł[ Pyri!
dines carrying substituents with remote functional groups generally present no complications in
terms of reduction of the pyridine ring unless the functional group is particularly susceptible to
reduction[ Hydrogenation of the pyridine!2!acetic acid as the pyridinium salt was achieved over a
mixed catalyst in 59Ð69) yield "Equation "81## ð68CJC0866Ł[ Benzylic hydrogenolysis is less of a
problem in pyridines as shown by the reduction of the ketal of 1!acetylpyridine over platinum to
give the piperidine ketal in high yield "Equation "82## without hydrogenolysis of the benzylic
carbon0oxygen bonds ð70T2504Ł[
OH OH
catalyst/H2
+ (87)
N N N
H H
PtO2/3 atms H2
(88)
HOAc
N O N O
H H
O OH
RuO2/3 atms H2
(89)
N HOAc N
H 74% H
catalyst/H2
+ NH3 (90)
N NH2 N
H
CO2H CO2H
M/H2
+ + CO2 (91)
N N N
H H
M = Ru, Rh, PtO2
CO2H PtO2 or 5%Rh/alumina CO2H

(92)
+ +
N 2.5 atms H2 N
H 60–70% H2
PtO2, 410 kPa H2, MeOH

(93)
NH4Cl
N N
OMe >90% H OMe
OMe OMe
The introduction of electron!withdrawing substituents into pyrrole seems to increase the rate of
hydrogenation[ Thus N!phenylpyrrole is reduced with di.culty using Raney nickel at high tem!
perature and pressure "Equation "83## ð30JA0452Ł[ However\ the introduction of electron!with!
drawing substituents on the nitrogen enable the smooth reduction of the pyrrole ring ð73JOC3192Ł[
For example N!"t!butoxycarbonyl#pyrroles are reduced to the corresponding pyrrolidines using
platinum on carbon at room temperature and atmospheric pressure "Equation "84##[ The large
amount of the trans isomer obtained in the reduction of the 1\4!disubstituted pyrrole is unusual
"Equation "85##[ The reduction of 1!substituted pyrroles carrying a carboxylic acid group in the side
chain has been achieved using 4) rhodium on alumina to yield the amino acid after ester hydrolysis
"Equation "86## ð68CJC0866Ł[ Given the di.culty of hydrogenation of indoles\ there are few reports
of such reactions of substituted indoles[ Electron!withdrawing substituents on nitrogen "e[g[\ acetyl#
lead to more selective reduction of the nitrogen!containing ring compared to unsubstituted indoles
while N!alkyl indoles are more di.cult to reduce ðB!74MI 092!90Ł[ The reduction of 1!phenylindole
to 1!phenylindoline using copper chromite at high temperature has been reported "Equation "87##
ð30JA0452Ł[
N Raney Ni, 165 °C N N

+ (94)
250 atms H2
15% 27%
5%Pt/C, 25 °C
(95)
N 1 atm H2, 2 h
N
t-BOC O 85% t-BOC O
5%Pt/C, 25 °C
+ (96)
N 1 atm H2, 1.5 h
N N
t-BOC t-BOC t-BOC
24% 72%
CO2Et i, HCl, 5%Rh/alumina, H2, 20 h CO2H

+ (97)
N ii, 37% HCl, reflux N
45% H2 Cl–
H
CuCr2O4, H2, 155 °C

(98)
N 43% N
Ph Ph
0[92[1[2 Homogeneous Hydrogenation of Arenes
Homogeneous hydrogenation of arenes can be achieved with a number of complexes[ In 0863\
Muetterties and Hirsekorn reported that p!allylCoL2 complexes where Lphosphine or phosphite
would reduce benzene to cyclohexane ð63JA3952Ł[ No cyclohexenes are detected and the reaction is
accomplished at 19>C and 0 atmosphere pressure of hydrogen with 9[90 molar equivalents of the
cobalt complex ð65IC1268Ł[ Hydrogenations using this catalyst are stereospeci_c giving the products
of cis reduction[ Thus\ naphthalene gave cis!decalin as the sole product "Equation "88## ð67JA1394Ł
and reduction of benzene with deuterium gave ×84) of the all cis isomer of hexa!
deuteriocyclohexane ð64JA126Ł[ Alkyl!substituents slow the reaction down as do electron!with!
drawing substituents such as F or NO1[ Substituents which are capable of protonating the catalyst
"OH and CO1H# also inhibit the reaction[ The mechanism of the reaction has been extensively
studied ð68ACR213Ł and the rate of reaction with alkenes has been shown to be broadly the same as
the rate of reaction with arenes ð64JA126Ł[ The allyl!rhodium complex\ p!allylRhðP"OR#2Ł1 has been
reported to reduce benzene under conditions of room temperature and atmospheric pressure of
hydrogen ð68ACR213Ł[ This catalyst does not display the stereospeci_city of the cobalt complex and
reduces alkenes some 094 times faster than arenes[ A bis"rhodium# complex\ ðRh"C4Me4#Cl1Ł1\ has
been reported by Maitlis and co!workers ð66CC316Ł for the reduction of benzene[ The presence of a
base and a mildly coordinating solvent is required ð67JCS"D#506Ł[ Reduction of electron!rich benzenes
such as methoxybenzene is problematic "Equation "099##[ Nitro!substituents are reduced "Equation
"090## but other electron!withdrawing substituents such as acetyl survive "Equation "091##[ A
ruthenium!based catalyst\ "C5Me5#1Ru has been reported to reduce 0\3!dimethylbenzene to a mixture
of cyclohexane and cyclohexene derivatives under elevated temperature and pressure "Equation
"092## ð67JA6314Ł[
H
C3H5Co[P(OMe)3]2
(99)
1 atm H2, 20 °C, 24 h
>95% H
OMe OMe OMe
[Rh(C5Me5)Cl2]2, 15–50 atms H2

+ (100)
Et3N, PriOH, 50 °C
6% 19%
NO2 NH2

(101)
Et3N, PriOH, 50 °C
96%
O O

(102)
Et3N, PriOH, 50 °C
100%
(C6Me6)2Ru, 1–3 atms H2, 80 °C

+ (103)
50% 50%
Several groups have explored the use of immobilised rhodium complexes as hydrogenation
catalysts for arenes[ The advantage of these systems lies in the ease of separation of the product[
The _rst such system to be reported involved the reaction of RhCl2 = 2H1O with an anthranilic acid
polymer to give the catalyst ð68JOC128Ł[ Reduction of benzene to cyclohexane was achieved at room
temperature in excellent yield "Equation "093## but substituted benzenes are poor substrates for this
system[ For example nitrobenzene is reduced quantitatively to aniline[ Stille and Sekiya reported
the preparation of both rhodium! and cobalt!carbonylcyclopentadienyl complexes anchored to
polystyrene via the cyclopentadienyl group ð70JA4985Ł[ The rhodium complex acted as a hydro!
genation catalyst reducing benzene at elevated temperature and pressure "099>C and 3[4 MPa#[ This
catalyst will reduce methoxybenzene "Equation "094##[ In 0870\ Schwartz and Ward reported the
synthesis of a silica!bound allylrhodium hydride complex ð70JMOC286Ł[ Reduction of benzene to
cyclohexane was achieved at moderate pressures of hydrogen but naphthalene "Equation "095##
gave a mixture of tetralin and decalin consisting mainly of tetralin ð70JA4142Ł[ This catalyst reduces
methoxybenzene and aniline to the corresponding cyclohexanes in good yield although the reactions
are a factor of 1 and 39 times slower respectively[ A phosphinated polyacetylene polymer has been
used to immobilise a bis"rhodiumnorbornadiene#chloride complex ð71CL592Ł[ After activation of
the catalyst and support by stirring in heptane under nitrogen\ the quantitative reduction of benzene
to cyclohexane occurred at 29>C and 79 atmospheres pressure of hydrogen in 0 hour[ Although
methoxybenzene is reduced to methoxycyclohexane under these conditions\ nitrobenzene is simply
reduced to aniline while chlorobenzene and acetophenone are poor substrates[
RhCl3 on polymer, 340 kPa H2

(104)
25 °C, 18 h
99%
OMe OMe
Rh(CO)2C5H4-polymer
(105)
4.5 MPa H2, 100 °C, 38 h
100%
silica-ORh(allyl)H
+ (106)
3.4 MPa H2, 22 °C
80%
15 : 1
The partial reduction of arenes to cyclohexenes can be achieved using homogeneous transition
metal complexes[ Complexation of benzene to hexamethylbenzene ruthenium\ cyclopentamethyl
rhodium or cyclopentamethyliridium followed by hydride reduction gave the corresponding cyclo!
pentadienyl complex "Scheme 03# which could be further reduced under more forcing conditions to
the cyclohexadiene complex[ Reaction of this with acid liberated cyclohexene in high yield and
complete selectivity[ The reaction has been made catalytic by the use of tetra~uoroboric acid
ð73JCS"D#0636Ł[ In a similar way\ hydrogenation of a benzeneÐosmium complex using Pd:C as
catalyst gave the cyclohexene complex in quantitative yield from which cyclohexene could be
liberated with a mild oxidant ð77JA6895Ł[ An attempt to make the process catalytic using the
ruthenium complex failed[
NaBH4 NaAlH2(OR)2 BF3, H2O

L-Ru2+ + Ru-L Ru-L L-Ru2+ +
+
H2O 60%
Scheme 14
A variation on the theme of homogeneous catalysis involves the use of phase!transfer systems[ A
system consisting of bisðrhodium!"0\4!hexadiene#chlorideŁ with a hydrocarbon solvent\ an aqueous
bu}er solution and a quaternary ammonium salt quantitatively reduced benzene to cyclohexane at
room temperature and atmospheric pressure of hydrogen ð72OM0944Ł[ Naphthalene is reduced to a
mixture of cis!decalin and tetralin "Equation "096##[ Methoxybenzenes are reduced to the cor!
responding cyclohexanes while phenols can give either cyclohexanones or cyclohexanols depending
on the conditions[ Acetophenone gives a mixture of products[ Simple pyridines and furans are
reduced in moderate yields[ Equally mild conditions for the reduction of benzene have been reported
for the two!phase system involving aqueous RhCl2 and Aliquat 225 "methyltrioctylammonium
chloride# with 0\1!dichloroethane as the organic phase ð72TL3028Ł[ After 4 hours under 0 atmosphere
pressure of hydrogen at 29>C\ a 40) conversion of benzene to cyclohexane was obtained with
no other products[ Further work on the mechanism of this reagent mixture has been reported
ð76JOC1793Ł[
H
[Cl(1,5-hexadiene)Rh]2
+ (107)
hexane/water, CTAB
25 °C, 1 atms H2 H
80% 20%
0[92[1[3 Dissolving Metal Reductions

This type of reduction has proven extremely useful in synthesis as the products are generally
partially!reduced arenes which are ripe for further synthetic transformations[ The _rst report of the
dissolving metal reduction of an arene was in 0826 when toluene was reduced by sodium in ammonia
ð26JA485Ł[ However\ the partial reduction of aromatic systems using an alkali metal in liquid
ammonia was pioneered by Birch ð33JCS329Ł and the reaction now bears his name ð77MI 092!91Ł[
The reaction proceeds via a complicated mechanism involving radicals\ radical anions and anions
ð78T0468Ł and the exact pathway followed depends on the substituents on the aromatic ring[ This
means that di}erent types of aromatic molecule react in subtly di}erent ways[ Thus benzene and
benzene rings substituted with electron!donating groups "alkyl\ amino\ alkoxy# need an alcohol to
be present in the reaction mixture as ammonia is not a strong enough acid to protonate the
intermediates[ In addition\ it is not possible to reductively alkylate such aromatics to give substituted
cyclohexadienes[ Activated benzenes\ carrying for example carbonyl substituents\ biphenyls and
smaller polycyclic aromatics\ do not require the presence of an alcohol for reduction and can be
reductively alkylated[ Finally\ there are some larger polycyclic aromatics in which the _nal inter!
mediate dianion is resistant to protonation owing to its stability[ These systems are di.cult to
reduce[ The metals generally employed are lithium\ sodium and "occasionally# potassium\ with
lithium being the most reactive and potassium the least[ The proton source in the reaction is also
critical and the best yields are obtained for the less acidic proton donors "ButOH×EtOH×water#
ð48JA2547Ł[
Although the reduction of benzene to 0\3!cyclohexadiene is often quoted as the archetypical Birch
reduction\ it was not until 0889 that a reliable method for this reaction "Equation "097## was
published ð89SC1054Ł[ The di}ering results previously reported apparently arose from iron impurities
present in liquid ammonia[ The stereochemistry of the reduction has been studied using hexa!
deuteriobenzene and shown to give equal amounts of the cis and trans isomers ð57JA2489Ł[ Poly!
nuclear aromatics are more reactive than monocyclic systems ð69S050Ł[ For example the reduction
of naphthalene has been carried out under a variety of conditions and di}erent products are isolated
excess Li, liquid NH3

(108)
ButOH, 1 h
>90%
Na, –78 °C, NH3

+ +
rapid quench NH4Cl
96% 2% 2%
Na, –78 °C, NH3

+
quench NH4Cl
80% 20%
Scheme 15
The reduction of substituted benzenes is generally governed by whether the substituent is electron!
donating or electron!withdrawing "Scheme 05#[ This feature has been extensively discussed by Birch
et al[ ð79JA2269\ 79JA3963\ 79JA5329\ 70JA173Ł and later by Zimmerman and Wang ð82JA1194Ł[ Alkyl!
substituted aromatics are reduced much as expected with the alkyl group"s# attached to alkenic
carbons in the 0\3!cyclohexadiene product[ Toluene is reduced in 77) yield to give 0!methyl!0\3!
cyclohexadiene "Equation "098## ð71AG"E#719Ł[ The xylenes are reduced in a similar manner as
shown in Equations "009#Ð"001# ð48JA2547\ 62OSC"4#356Ł[ The reduction of alkyl!substituted naph!
thalenes gave di}erent results depending on the site of substitution[ Thus 0!methylnaphthalene gave
exclusively reduction in the unsubstituted ring on treatment with lithium in ammonia and ether
followed by an aqueous quench "Equation "002## while 1!methylnaphthalene gave a mixture of
products with predominant reduction in the substituted ring "Equation "003## ð61RTC0958\
70JOC0482Ł[ However\ it should be noted that the conditions for these two reactions are rather
di}erent[
G G G
M/NH3 M/NH3
G = electron-withdrawing G = electron-donating
Scheme 16
Li/NH3, ether, PriOH

(109)
88%
Na/NH3, ether, EtOH, 5 h

(110)
H2O quench
77–92%
Li/NH3, ether, EtOH quench

(111)
92%
Li/NH3, ether, EtOH quench

(112)
96%
Li/NH3, ether, 3 h
(113)
H2O quench
96%
Li/NH3, THF, –78 °C, 30 min

+ (114)
NH4Cl quench
3 : 1
Carbonyl!substituted aromatic rings can be successfully reduced using Birch reduction conditions^
indeed the presence of the electron!withdrawing group increases the rate of the reaction[ However\
preferential reduction of the carbonyl group can occur particularly with ketones[ Reduction of
acetophenone "Equation "004## using potassium gave ethylbenzene in 67) yield ð43JCS002Ł[
However\ reduction of 0!acetylnaphthalene using sodium gave a dihydronaphthalene\ with retention
of the carbonyl group\ in 70) yield "Equation "005## ð71JCS"P0#764Ł although the quenching agent
used is important ð60JOC1477Ł[ Reduction of indanone with lithium in the presence of a catalytic
amount of cobalt metal gave clean reduction of the ketone with no ring reduction[ Probably the
most important substituent after the methoxy group in the Birch reduction is the carboxy group^
this survives the reduction intact and there are many examples[ Benzoic acid is reduced by sodium
in ammonia in 78Ð84) yield ð62OSC"4#399Ł to give the unconjugated isomer "Equation "006##[
Similarly\ the naphthalene!0!carboxylic acid is reduced quantitatively to the nonconjugated isomer
"Equation "007## with no reduction in the unsubstituted ring ð79SC516Ł[ Esters and amides generally
survive the Birch reduction conditions to give the expected products "Equations "008# and "019##
although benzaldehydes can be formed ð67JOC0996\ 73JOC0433Ł[
O
Et
K/NH3, ButOH
(115)
78%
O O
Na/NH3, THF, 1 h
(116)
EtOH/H2O quench
81%
CO2H CO2H
Na/NH3, EtOH
(117)
NH4Cl quench
89–95%
CO2H CO2H
Na/NH3, ether, –78 °C, 10 min

(118)
NH4Cl quench
100%
CO2Et CO2Et
Na/NH3, THF, H2O (1.5 equiv.), –78 °C, 25 min

(119)
NH4Cl quench
64%
CONH2 CONH2
Na/NH3, ButOH
(120)
NH4Cl quench
82%
Reduction of halobenzenes is problematical as the carbon0halogen bond is usually cleaved

rapidly[ Reduction of a chloroalkane with lithium gave rise to a mixture consisting mainly of
propylbenzene "Equation "010## with a small amount of the dihydropropylbenzene ð67JCS"P0#0368Ł[
The chloroindanone "Equation "011## underwent reduction of both the carbonyl group and the
chlorine atom on treatment with lithium in ammonia ð60JOC1477Ł[
Pr Pr
Cl Li/NH3, ether, –78 °C, 2 h
+ (121)
EtOH quench
9 : 1
O
Li/NH3, THF, Al, 2 h
(122)
NH4Cl quench
Cl 90%
Aromatic ethers\ in particular the methoxy!substituted benzenes\ probably represent the most
useful class of substrates for this reduction[ The cyclohexadiene products have been widely used in
organometallic chemistry ðB!74MI 092!91Ł and in synthesis ð80JOC630Ł[ Thus\ the reduction of anisole
using lithium in ammonia gave exclusively the 0!methoxy isomer "Equation "012## in 64) yield
ð77OSC"5#825Ł[ This product can be rearranged to a variety of products by treatment with acids or
base[ This ability to use a methoxy!substituted benzene as a masked version of a cyclohexenone has
been widely used in synthesis ð71JCS"P0#0270Ł[ Alkyl!substituted aromatic ethers undergo reduction
although the conditions required may vary[ For example 0!methoxytetralin required the use of
lithium for its reduction "Equation "013## while the 1!methoxytetralin was reduced by sodium
"Equation "014## ð33JCS329Ł[ However\ there can be problems with the reduction of aryl ethers
involving the cleavage of the alkoxy group[ This is particularly likely to happen if the alkoxy group
is situated para to an activating group as in the reduction of 3!methoxyacetophenone "Equation
"015##[ A study of this process using a variety of metals and conditions has been reported[ The
methoxynaphthalenes present a more complicated picture[ 0!Methoxynaphthalene has been reduced
to a mixture of naphthalene and 0\3!dihydronaphthalene "Equation "016## on treatment with sodium
in ammonia in the absence of an alcohol ð45CB1094Ł[ This appears to be caused by the benzylic
nature of the methoxy group since 1!methoxynaphthalene is reduced under the same conditions
"Equation "017## to give mainly the dihydronaphthalene "retaining the methoxy group# ð45CB1094Ł[
On the other hand\ in the presence of a proton source "ethanol# and with a water quench\ the same
compound gave the tetrahydronaphthalene "retaining the methoxy group# in 70) yield "Equation
"018## ð40JCS0834Ł[
OMe OMe
Li/NH3, THF, ButOH, 1 h

(123)
OMe O
i, Li/NH3, EtOH
(124)
ii, HCl
MeO O
Na/NH3
(125)
MeOH
O O
i, K/NH3, THF, ButOH

(126)
ii, MeI
30%
OMe
OMe
Na/NH3, ether
+ (127)
NH4Cl quench
2 : 1
OMe OMe
Na/NH3, ether
+ (128)
NH4Cl quench
57% 7%
OMe OMe
Na/NH3, EtOH
(129)
H2O quench
81%
Phenols are generally rather poor substrates for Birch reduction owing to the formation of
the radical dianion[ This feature has been utilised to enable selective reduction[ Reduction of a
phenanthrene derivative using lithium in ammonia in the presence of t!butanol gave a product in
which the phenolic ring was untouched "and the benzylic ketone reduced# while the methoxy!
substituted ring was reduced "Equation "029## ð56TL746Ł[ Under forcing conditions involving a high
concentration of lithium\ Fried and co!workers reported the reduction of hydroxytetralin to the
hydroxyoctalin "Equation "020## in 65) yield ð56JA0933Ł[
O OH
HO HO
i, Li/NH3, ButOH
(130)
ii, H3O+
MeO O
Li/NH3, THF, EtOH

(131)
76%
HO HO
A study on the reduction of aromatic amines has been reported ð45JA3593Ł[ The reduction of a
range of 1!alkyl!substituted anilines to 1!substituted cyclohexenones was achieved although
signi_cant amounts of saturated ketones were isolated "Equation "021##[
NH2 O O
Li/NH3, ButOH, 1 h
+ (132)
H2O quench, then HCl
50% 18%
The reduction of arylsilanes using lithium in ammonia has been reported ð64JCS"P0#369Ł[ The
product of the reduction of a 3!methyl!substituted arylsilane was the isomer with the trimethylsilyl
group and the methyl group attached to the tetrahedral carbons in the 0\3!cyclohexadiene product
"Equation "022##[ The removal of the trimethylsilyl group enables overall control of the regio!
chemistry of reduction to give isomers which are otherwise di.cult to obtain[
TMS TMS
Li/NH3, EtOH, –70 °C

(133)
58%
As might be expected\ it is possible to reduce heteroaromatic systems under Birch!type conditions[

The reduction of pyridine and simple 3!alkylpyridines proceeds to give 0\3!dihydropyridines "Equa!
tion "023## in good yield ð64CC379Ł[ 1!Substituted pyridines have been reduced and the products
treated with acid and:or base to give ring opening followed by aldol cyclisation and dehydration
ð64JA279Ł[ Thus 1!methylpyridine was reduced with sodium in ammonia and\ after an aqueous
quench\ the reaction mixture was subjected to treatment with sulfuric acid at 099>C ð36JCS0169Ł[
The product was cyclohexenone in 01) yield "Equation "024##[ 1!Vinylpyridine after reduction with
lithium in ammonia followed by acid treatment gave 1!methylcyclohexenone in 52) yield "Equation
"025## ð64JOC2595Ł[ Quinoline and isoquinoline also undergo reduction in high yield[ Quinoline was
reduced "Equation "026## to 0\3!dihydroquinoline using lithium in ammonia ð63TL1284Ł whereas
isoquinoline was reduced "Equation "027## to 0\1\2\3!tetrahydroisoquinoline using sodium in
ammonia in the presence of ethanol ð48T037Ł[
R R
Li/NH3, EtOH
(134)
NH4Cl quench
N N
H
R = H, 90%
R = Me, 80%
O
Na/NH3, EtOH
(135)
H2O quench
N
then H2SO4, 100 °C
12%
Li/NH3, ether, EtOH

(136)
quench EtOH, NaOH
N
then acid
63%
Li/NH3, quench NH4Cl

(137)
N 100% N
H
Na/NH3, EtOH, quench H2O

(138)
N NH
The p!excessive heterocycles are not so easily reduced and there are fewer examples of such
reactions in the literature[ Pyrrole is resistant to reduction as shown by the reaction of N!phenyl!
substituted pyrrole with sodium in ammonia which resulted in reduction of the phenyl ring
ð58AJC0210Ł[ Furans carrying activating groups will undergo reduction[ Furan!1!carboxylic acid is
reduced to give the 1\4!dihydro product "Equation "028## in 79) yield ð52MI 092!91Ł[ Interestingly\
the 2!isomer is reduced by lithium in ammonia in the presence of propan!1!ol to give the expected
1\2!dihydro product "Equation "039## but in the presence of methanol or ethanol\ the alcohol is
incorporated and the ester is formed ð64BCJ0754Ł[ In a similar fashion to furan\ thiophene is only
usefully reduced when carrying an activating group[ The reduction of thiophene has been reported
to give a complex mixture ð40JCS1445Ł whereas thiophene!1!carboxylic acid can be reduced by
lithium in ammonia followed by diazomethane treatment "Equation "030## to give the 1\2!dihy!
drothiophene as its methyl ester ð68TL3874Ł[ The benzannelated systems\ as expected\ usually
undergo reduction in the benzene ring[ Indole is reduced by lithium in the presence of methanol to
the 3\6!dihydroindole "Equation "031## in 40) yield ð60JOC168Ł[ The N!methyl derivative behaves
in the same manner but the N!phenyl derivative is reduced in the heterocyclic ring "Equation "032##
using sodium in the absence of alcohol to give the 1\2!dihydroindole ð58CI"L#0484Ł[ In the oxygen
series\ benzofuran is reduced to the 3\6!dihydrobenzofuran "Equation "033## even with the electron!
donating methoxy group ð56JOC1683Ł[
Li/NH3, –78 °C, 3 min
(139)
O CO2H NH4Cl quench O CO2H
80%
CO2H CO2H
Na/NH3, PriOH
(140)
O NH4Cl quench O
85%
i, Li/NH3, 5 min then NH4Cl quench

(141)
S CO2H ii, CH2N2 S CO2Me
Li/NH3, –78 °C, MeOH

(142)
N 51% N
H H
Na/NH3, THF
(143)
N NH4Cl quench N
87%
Ph Ph
MeO MeO
Li/NH3, EtOH
(144)
O NH4Cl quench O
88%
The use of alkali metals in other solvents has been explored and can be of some synthetic use[
Reductions of aromatic rings utilising alkali metals in THF:HMPA have been reported
ð76AG"E#193Ł[ Reactions follow a similar pathway to the Birch reduction but are slower and o}er
no advantage for the reduction process\ but are useful for reductive alkylation as there is no proton
source[ Crown ethers in THF have been used for reductions with alkali metals ð68AG"E#476Ł and the
reduction of benzoic acid by this methodology has been achieved[ The well!known BouveaultÐBlanc
reduction conditions involving sodium in alcohol are not only applicable to carbonyl reduction and
have been applied to the reduction of aromatic systems ð62OSC"4#287Ł[ The reduction of a pyridine
to a piperidine in the presence of a furan "Equation "034## has been reported[
Na, EtOH, xylene

N NH (145)
reflux
27%
O O
Probably the most widely explored alternative solvents for dissolving metal reductions are simple
aliphatic amines[ Under such conditions\ the reduction generally proceeds further than the Birch
reduction and gives fully!reduced products ð61S280Ł[ Benkeser and co!workers were the _rst to
report the reduction of benzene using lithium in ethylene diamine ð44JA2129Ł[ This led to a mixture
of cyclohexene and cyclohexane with no cyclohexadiene products formed "Equation "035##[ The
exact nature of the solvent is crucial to the course of these reactions as illustrated by the reduction
of naphthalene "Scheme 06#[ Using ethylene diamine as solvent\ the sole product is the fully!reduced
decalin ð44JA2129Ł whereas using a mixture of methylamine and ethylamine as solvent led to the
formation of a mixture of isomeric octalins ð77OSC"5#741Ł[ Replacement of lithium with the less
reactive calcium "Equation "036## enabled the reduction of aromatic rings to monoene products
ð68JOC2626\ 72JOC1685Ł[ In synthetic terms the most useful conditions were found by using calcium
in an amine containing an alcohol "Equation "037## and this useful alternative to the Birch reduction
has become known as the Benkeser reduction ð73TL1978Ł[ These conditions o}er signi_cant advan!
tages over the Birch conditions on larger scales[ Reduction of anthracene using calcium in ethylene
diamine "with butylamine added to prevent freezing# and t!butanol gave 65) of the hexahydro!
anthracene product along with a small amount of overreduction product "Equation "038##[ Alkyl!
substituted benzenes behave in a similar manner[ Thus 0\1\3\4!tetramethylbenzene was reduced to
a cyclohexa!0\3!diene "Equation "049## using calcium in a mixture of methylamine and ethylene
diamine ð72SC0092Ł[
Li
+ (146)
ethylene diamine
Li
ethylene diamine
Li
+
MeNH2/EtNH2
80% 20%
Scheme 17
Ca
+ (147)
MeNH2/EtNH2
92%
77% 23%
OMe OMe
Ca, EtNH2, ButOH

(148)
86%
Ca, ButOH, BuNH2

+ (149)
ethylene diamine
76% 6%
Ca, MeNH2, ethylene diamine

(150)
0[92[1[4 Hydride Reductions

Pyridine itself is not reduced by sodium borohydride but on treatment with lithium aluminum
hydride a complex containing a mixture of 0\1! and 0\3!dihydropyridines is obtained ð52JA1125Ł[
Although this mixture can act as a reducing agent\ no dihydropyridines can be isolated from it[
Pyridines bearing electron!withdrawing substituents and pyridinium salts can be reduced by sodium
borohydride[ Thus reduction of 2!cyanopyridine with sodium borohydride can be controlled to give
either dihydro or tetrahydro product "Scheme 07# ð58TL2090Ł[ The reduction of an N!methyl!
pyridinium derivative leads to a mixture of products "Equation "040## ð65JCS"P0#34Ł[ The reduction
of pyridine by sodium borohydride in the presence of chloroformates can be controlled to give 0\1!
dihydropyridines with high selectivity "Equation "041## ð61JOC0210Ł[ Although pyrrole is inert to
hydride reducing agents\ indoles are reduced to indolines by tetrabutylammonium borohydride
ð79H"03#0330Ł and sodium cyanoborohydride "Equation "042## under acidic conditions ð66S748Ł[
CN
NaBH4
pyridine, 8 h N
CN H
52%
CN
N NaBH4, EtOH
N
H
main product
Scheme 18
CN CN CN CN
NaBH4, MeOH
+ + (151)
+
N N N N
Me Me Me Me
NaBH4, EtOH, –78 °C

(152)
PhCO2Cl
N N
CO2Ph
NaCNBH3, AcOH
(153)
N 15 °C N
H 90% H
trans:cis 3:1
0[92[1[5 Electrochemical Reductions

Although electrochemical methods have been widely explored by industry\ synthetic organic
chemists have been reluctant to utilise this approach[ The reduction of benzene to 0\3!cyclohexadiene
has been reported ð70MI 092!90Ł and Monsanto has also explored this process extensively[ Polycyclic
aromatics are easier to reduce ð31JA1254Ł and naphthalene has been reduced to the 0\3!dihydro
product on a preparative scale ð57BCJ1810Ł[ This trend has been quanti_ed by measurement of the
redox potential of aromatic hydrocarbons ð78JA1214Ł[
Substituted benzenes are more amenable to reduction electrochemically[ Phthalic acid has been
reduced to a cyclohexene biscarboxylic acid "Equation "043## in alkali at a mercury cathode
ð38HCA0303Ł[ Aromatic rings carrying electron!donating substituents can also be reduced[ For
example 1!methoxynaphthalene has been reduced to the dihydronaphthalene "Equation "044## in
85) yield ð41JA3015Ł[ The e}ect of substituents on the redox potentials of aromatic compounds has
been reported ð80ZOR0026Ł[
CO2H CO2H
Hg cathode, NaOH
(154)
78%
CO2H CO2H
OMe OMe
Hg cathode
(155)
96%
The reduction of heteroaromatics by electrochemical means has been explored ð54MI 092!91Ł[ For
example the reduction of pyridine to piperidine was reported in 0784 ð0784MI 092!90Ł and the
reduction of the quaternary pyridinium derivative of nicotinamide to the 0\3!dihydro derivative in
quantitative yield has been reported ð54JOC0043Ł[ This area has been reviewed ð66CJC2281Ł and
electron!withdrawing substituents make reduction easier[ The reduction of thiophene!1!carboxylic
acid "Equation "045## to the dihydrothiophene in 69) yield has been reported ð64IZV777Ł[
Hg cathode, 2M LiOH
(156)
S CO2H 70% S CO2H
1.04
One or More CC Bond(s) Formed
by Substitution: Substitution
of Halogen
GAVIN L. EDWARDS
The University of New South Wales, Sydney, NSW, Australia
0[93[0 INTRODUCTION AND SCOPE 094
0[93[0[0 General Comments and Methods 094
0[93[0[1 The Leavin` Group*Comparison of F\ Cl\ Br\ and I Derivatives 096
0[93[0[2 Hi`her Valent Haloèn Derivatives 097
0[93[1 CARBANIONS WITH NO STABILIZING GROUP 098
0[93[1[0 General Comments 098
0[93[1[1 Group I Metals 009
0[93[1[2 Group II Metals 003
0[93[1[3 Orànocopper Derivatives and Copper!Catalyzed Couplin`s 005
0[93[1[4 Orànoboron Compounds 014
0[93[1[5 Miscellaneous Species with No Stabilizin` Group 015
0[93[2 CARBANIONS WITH ONE STABILIZING GROUP 018
0[93[2[0 General Comments 018
0[93[2[1 Enolates and Related Carbanions 018
0[93[2[2 Oxyèn Stabilized Carbanions 024
0[93[2[3 Sulfur Stabilized Carbanions 028
0[93[2[4 Nitroèn Stabilized Carbanions 036
0[93[2[5 Phosphorus Stabilized Carbanions 046
0[93[2[6 Silicon Stabilized Carbanions 048
0[93[2[7 Boron Stabilized Carbanions 051
0[93[2[8 Miscellaneous Stabilizin` Groups 053
0[93[3 CARBANIONS WITH TWO AND THREE STABILIZING GROUPS 054
0[93[4 POLYHALOALKANES 057
0[93[5 ACKNOWLEDGMENTS 058
0[93[0 INTRODUCTION AND SCOPE
0[93[0[0 General Comments and Methods

If carbonÐcarbon bond formation is central to synthetic organic chemistry\ then transformations
involving the carbonÐhalogen bond must surely be the most important[ The commercial availability
of a wide range of halocarbons\ as well as the ready accessibility of these compounds by simple
functional group interconversions\ helps consolidate their position as the most valuable functions
in organic chemistry[ This usefulness is still apparent despite the alternate strategy\ much used
in contemporary synthesis\ of activation of alcohols via sulfonate ester formation[ Numerous
094
095 One "or More# C0C Bond"s# formed by Substitution of Haloèn
fundamentally di}erent reactions have an overall outcome of replacement or substitution of a
halogen function by a carbon group^ representative examples are depicted in Scheme 0[
Nucleophilic substitution
i, LDA, THF
ii, PhCH2CH2Br O
N
N iii, O3, CH2Cl2 Ph (1)
65%, 93% ee
OMe
"Umpolung" by conversion to an organocuprate
TMS
CN
i, ButLi 2–
O
Cu OPMB OMe
I OPMB
ii,
S Cu(CN)Li S 2Li+
PMB = MeO CH2 TMS OPMB (2)
OMe OH
overall yield 88%
Free radical approach

I CO2Me
CO2Me
CO2Me Bu3SnH CO2Me
(3)
Electrophilic (Friedel–Crafts) approach

EtO2C CO2Et i, SbF5, SO2 EtO2C CO2Et
ii, toluene
Br (4)
52%
MeO MeO
Organometallic-based syntheses
O CO2Me
H
Cl Ni(CO)4, MeOH, RT
+ CO2Me (5)
72%
MeO2C H
Scheme 1
Perhaps the most important class of reactions involves the use of halogen as a leaving group in
nucleophilic substitution "Equation "0## ð82CC313Ł\ either directly or in a single electron transfer
process[ Alternatively\ the carbonÐhalogen bond can serve as a precursor to an organometallic
reagent which can itself act as a nucleophile\ thus reversing the polarity of the original carbonÐ
halogen bond "Equation "1## ð82CC506Ł[ Abstraction of the halogen atom "or homolysis of the C0X
bond# can provide a carbon!centered radical which\ following addition to a multiple bond\ can give
a product where a halogen atom has been replaced "in a formal sense# by carbon "Equation "2##
ð82PAC0042Ł[ Activation of an alkyl halide by reaction with a Lewis acid can give electrophilic
species which can result in carbonÐcarbon bond formation "Equation "3## ð75TL3742Ł] the FriedelÐ
Crafts alkylation is perhaps the best known reaction of this type although other electrophilic
substitutions are possible[ Conversion of an allyl halide into\ for example\ a p!allyl species can
precede additions to multiple bonds or carbonylations where the _nal product has the original
halogen atom apparently replaced by a carbon!based group "Equation "4## ð82JOM"340#0Ł[
Introduction 096
Coverage of all these areas is beyond the scope of this chapter\ and discussion will be limited to
displacement of halogens from alkyl halides by carbon nucleophiles\ usually as carbanionic or
organometallic species[ The extent of the subject and the great variation possible in the carbon
nucleophiles\ means that the discussion will be structured according to the nature of the carbon
nucleophile rather than the particular alkyl halide[ Following some brief comments on a comparison
of the di}erent halogens\ the _rst class to be mentioned will be carbanions with no stabilizing group\
i[e[ {{simple|| organolithium\ !magnesium\ !copper\ etc[\ nucleophiles[ Allyl and benzyl groups will
be treated as normal carbon substituents\ with special mention of enhanced or di}ering reactivity
and ambident behavior being made where appropriate[ "A separate review on allyl and benzyl
carbanions is given in Orànic Reactions ð71OR"16#0Ł[# This review will then consider carbanions
based on a single stabilizing group\ concluding with a brief section on the e}ects of combining two
or three stabilizing groups[ Some speci_c comments on reactions of polyhaloalkanes\ as opposed to
monohaloalkanes\ will be made where appropriate[ Many topics within this chapter have already
been reviewed extensively\ and relevant references will be given under individual section headings[
Comparisons of metal ions in the organometallic component\ as well as questions of diastereo! and
enantioselectivity\ will also be covered where relevant[ Other aspects of carbanion and organ!
ometallic chemistry are covered throughout this work[
0[93[0[1 The Leaving Group*Comparison of F\ Cl\ Br\ and I Derivatives

The e}ects of substrate structure and variation of reaction conditions on substitution reactions
have been studied thoroughly^ extensive discussions can usually be found in most good textbooks
ðB!76MI 093!90\ B!81MI 093!90Ł\ and details will not be repeated here[ However\ one aspect which
deserves some comment is the e}ect of changes of halogen upon reaction rate[ "Astatine\ having no
isotopes with half!lives beyond a few hours\ will not be considered in this review[# Both electro!
negativities and carbonÐhalogen bond strengths "Table 0# increase in the order I³Br³Cl³F^ in
fact\ ~uorine forms the strongest single bond to carbon of any of the elements ð81JA8465Ł\ and
conventional wisdom states that iodide and bromide are the best leaving groups\ alkyl chlorides
react at much slower rates and alkyl ~uorides are very poor substrates indeed[
Table 0 Bond dissociation energies for methyl halides

D"Me!X# "kcal mol−0#[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Experimental Theoretical
X value value "MP2# a
*
F 097[0 094[0
Cl 72[4 68[3
Br 69[9 57[8
I 45[2 47[3
*
a
llerÐPlesset perturbation calculations ð81JA8465Ł[
MP2Third order Mo
Some of the factors that could possibly a}ect the rate of halide displacement have been discussed
ð68COC"0#382Ł[ Many studies have reported on the reactivity of alkyl halides with "usually noncarbon#
nucleophiles ð15MI 093!90\ 26JCS0066\ 26JCS0072\ 42JA135Ł\ and the general trend is that reactivity
increases in the order F³Cl³Br³I[ Measurements in the gas phase have shown that\ in the
reaction of MeX "XF\ Cl\ Br# with various carbon and noncarbon nucleophiles\ the leaving group
ability follows the established order with F− being the poorest\ and Br− the best leaving group
ð63JA3916\ 65CJC0532Ł^ displacement of ~uoride occurs at least 099 times slower than displacement
of chloride[ A more reactive substrate can be prepared by the Finkelstein reaction giving the alkyl
iodide ð09CB0417Ł\ or alternatively a catalytic amount of lithium iodide can be added to the reaction
mixture if one of the lower halides "Cl\ Br# is used[ It is believed that this procedure interposes a
Finkelstein!like step into the reaction sequence\ where the more reactive alkyl iodide is prepared in
situ\ thus increasing the overall rate of substitution ð89JA2443Ł[ If a polyhalo substrate is treated
with a carbon nucleophile\ then selectivity towards cleavage of the more labile C0X bond will be
observed ð45JA2373\ 46JA1200Ł[ Displacement of ~uoride has been reported "although the yield is not
given in the text# in a double alkylation of ethyl acetoacetate with 0!chloro!1!~uoroethane "0#
"Equation "5##\ although there can be little doubt that the _rst step would involve displacement of
Cl− and kinetic factors would then favor the second carbonÐcarbon bond formation ðB!81MI 093!91Ł[
O O
O O NaOEt, EtOH
+ F (6)
Cl OEt
OEt
(1)
Although C0F bonds are generally considered to be inert towards nucleophiles\ substitutions at
saturated carbon atoms can occur ð52AFC52Ł and several examples of C0C bond formation have
been reported] as these reactions are relatively rare\ and as ~uorocarbons would not otherwise
feature largely in this chapter\ several reactions will be considered here[ Benzylic organolithium
reagents will couple with benzyl ~uorides to a}ord phenyl!substituted ethanes in high yields\
typically ×89) ð65JA1479Ł[ Displacement of ~uoride by Grignard reagents has been observed for
a!~uoroketones ð43JA3026\ 50JCS2341Ł and for a!~uorophenylacetic esters ð69BSF880Ł[ In the latter
case substitution occurs\ presumably via the intermediacy of a magnesium alkoxide which then
undergoes a 0\1!shift with concomitant magnesium!induced loss of ~uoride "Scheme 1#[ "Similar
reactions of other a!halocarbonyl compounds\ where rearranged ketones are isolated in addition to
simple 0\1!addition products\ are known ð48JOC732\ 63TL0340\ 75CPB2488Ł[# These reactions do not
appear to be generally applicable\ as addition of Grignard reagents to a!~uoro aliphatic esters give
normal products of 0\1!addition to the carbonyl group ð69BSF880Ł[
Br
F F Mg
R2MgBr, –60 °C
OEt O
R1 R1 = Ph
O R2 OEt
R2MgBr
–60 °C
R2 R2
F F OEt R2
R2 R2 +
R1 + R1 O O
R2
O OH R2 = Ph 10% 45%
40–55% <10% Bun 0% 50%
R1 = alkyl
R2 = Ph, Bun, cyclohexyl
Scheme 2
0[93[0[2 Higher Valent Halogen Derivatives

The existence of hypervalent halogen compounds "where the halogen atom has more than one
ligand# opens up\ at least in theory\ new possibilities for carbonÐcarbon bond formation[ This class
of compounds has been reviewed extensively ðB!72MI 093!90Ł\ and the most commonly investigated
species are trivalent iodine compounds[ Although the chemistry of aryl\ alkynyl\ and alkenyl
hypervalent iodine compounds is now well established ð81AG"E#163Ł\ the preparations and reactions
of alkyl derivatives are relatively rare[ Simple alkyl iodinanes do not appear to be stable^ while the
electron!withdrawing nature of the iodine"III# center makes the attached carbon more prone to
nucleophilic attack\ it renders the compound liable to elimination and rearrangement in addition
to the desired displacement of iodine by nucleophiles[ When optically active 1!iodooctane "1# is
treated with Cl1 or Br1\ nonracemic 1!octyl chloride or bromide is isolated "Scheme 2#[ Oxidation
of the iodine substituent to an unstable iodonium species is believed to precede displacement of IX1^
although the substitution occurs with predominant inversion of con_guration\ some racemization
is observed ð43JA5939\ 44JA4422Ł[ Similar results are obtained when alkyl iodides are treated with
peracids] primary iodides give displacement products\ whereas secondary iodides give mixtures
resulting from either displacement\ elimination\ or oxidation of the halogen!bearing carbon atom
ð58JOC2863\ 58JOC2867\ 67JA3777\ 79JA6659\ 71JOC0893Ł[ Useful yields of products can sometimes be
obtained\ as in the case of oxidation of a norbornyl iodide with peracetic acid ð66CC210Ł[
Electronegative ~uorocarbon ligands are capable of stabilizing hypervalent iodine species\ and
poly~uorinated derivatives "RfCH1I"OTf#¦\ where Rf per~uoroalkyl# can be isolated^ treatment
with noncarbon nucleophiles results in cleavage of the CH10I bond ð76BCJ2296\ 80BCJ1997Ł[ Dis!
placement of the iodine!based unit by a carbon nucleophile is achieved if the iodonium tri~ate is
treated with a trimethylsilyl ether in the presence of KF "Equation "6##\ although the yields are
Carbanions With No Stabilizin` Group 098
Cl Cl
I Cl2, CHCl3:pet. ether (1:1) I Cl
–78 °C to 0 °C
70.6%
(2)
mcpba
MeOH
LiCl
O
I OMe Cl
+
45% net inversion 82% net inversion

44% 16%
Scheme 3
variable ð76BCJ2712Ł[ Substitutions in similar hypervalent iodine species are often accompanied by
other reactions] Yagupol|skii and co!workers showed that the ~uoroborate salts\ on reaction with
N\N!dimethylaniline\ gave mainly the product of N!alkylation "69)# accompanied by some para!
substituted dimethylaniline "08)# "Equation "7## ð77JOU429Ł[ Aniline gave only N!alkylated
products[
OTf O-TMS O
Rf I
KF, CH2Cl2, reflux
+ Rf (7)
32–87%
Rf = CF3, C2F5, i-C3F7, n-C7H15
F NMe2 NMe2
F F F F F
Me
+ +
I F
Me N F
F FF F + F FF F (8)
F F F
BF4 –
F
F FF F
19% 70%
The decomposition of iodonium ylides\ usually in the presence of copper"I# salts\ gives compounds
which formally have new carbonÐcarbon bonds in place of iodine\ and which appear to arise from
an initial loss of iodobenzene and the formation of a carbene or copper carbenoid ð69BCJ1495Ł[
Reactions are often complicated by the formation of sideproducts[ Work by Moriarty et al[\ where
intramolecular {{displacement|| of iodobenzene by an alkene leads to cyclopropane formation\ casts
doubt on the carbene proposal ð78JA5332\ 89JA0186Ł[ An alternative mechanism\ involving initial
addition of the alkene to the electrophilic iodine\ transannular cyclization\ and _nal reductive
elimination of PhI to give the cyclic product\ is suggested "Scheme 3#[ Moriarty et al[ have used this
intramolecular cyclopropanation reaction in an approach towards the 2\4!cyclovitamin D ring A
synthon ð82TL3018Ł[ Although enantiomerically pure b!keto esters were used for preparation of the
iodonium ylides\ diastereoselectivity in the ring closure step was poor[
0[93[1 CARBANIONS WITH NO STABILIZING GROUP
0[93[1[0 General Comments

The formation of a carbonÐcarbon bond with no heteroatom attached to either carbon atom can
be accomplished readily by the reaction of a suitable organometallic reagent with a haloalkane\
with acceptable yields being obtained with methyl\ primary\ and secondary haloalkanes[ In most
H
H +
O
CuCl, CH2Cl2, 0 °C
– OMe O O
+
I I – I
Ph O Ph CO2Me Ph CO2Me
90%
CO2Me
Scheme 4
cases\ tertiary haloalkanes give poor yields as elimination tends to become the major pathway[ The
selection of the correct organometallic partner is vital for the success of the coupling*injudicious
choice will allow a range of side reactions to compete or even to dominate[ In general\ organocopper
reagents provide the most reliable route although acceptable yields can sometimes be obtained with
other metals[ The methods for preparation of the organometallic species will occasionally be
considered\ as both the metal itself as well as other attendant ions can markedly a}ect a reaction|s
outcome[ If one "or both# of the carbon centers in the new carbonÐcarbon bond is chiral\ then
problems arise in that a degree of racemization can accompany coupling[ Often\ alternative routes
need to be sought if complete stereocontrol is essential[
0[93[1[1 Group I Metals

Although organometallic compounds of Group I metals are usually represented simply as RM\
it is now well known that these compounds are generally oligomeric both in solution and in the
solid state[ The x!ray crystal structures of organolithium compounds ð74AOC"13#242Ł\ and also of
organic derivatives of sodium\ potassium\ caesium\ and rubidium ð76AOC"16#058Ł have been reviewed
extensively[ Conceptually\ the reaction of Group I organometallic compounds with alkyl halides is
one of the simplest procedures for carbonÐcarbon bond formation^ however\ it is little used in
synthesis[ While stabilized carbanions with Li\ Na\ or K as counterions frequently can be alkylated
smoothly and in high yield\ the analogous reactions of alkyl halides with nonstabilized carbanions
can be plagued by a range of competing reactions[ These include metalÐhalogen exchange\
a!metallation "giving a carbenoid#\ a! or b!elimination "giving a carbene or alkene\ respectively#\
Wurtz!like processes "leading to mixtures of coupled products#\ and radical reactions arising from
electron transfer processes in the course of the reaction ðB!63MI 093!90\ 71JOC2410\ B!76MI 093!91Ł[ For
example\ in an extreme case where steric factors are likely to interfere with {{normal|| substitution
reactions\ the reaction of a!phenyl neopentyl chloride "2# with diphenylmethyllithium "3# gave a
mixture of products "Equation "8##[
H H H
Cl Ph
Ph THF, 25 °C
Ph Ph Ph But Ph But
H H Ph
+ Li + H + H + H (9)
Ph
But Ph But
Ph Ph Ph Ph But But Ph
(3) (4) 50.5% 18.2% 10.4% 7.2%
In a more straightforward example\ a simple cycloalkyllithium "4# reacted with iodomethane to

give\ as the predominant product\ an iodo compound resulting from lithiumÐiodine exchange
"Scheme 4#[ Reaction of the cycloalkyllithium "4# with 0\1!dibromoethane resulted in bromination
of the alkyllithium\ with ethene being liberated as the by!product ð58JOC530Ł[ Halogen transfer to
the alkyllithium occurred with retention of con_guration in both cases[ These metalÐhalogen
exchange reactions can also lead to mixtures of products ð33JA0404Ł\ for example\ the attempted
alkylation of benzyl chloride with n!butyllithium gave n!pentylbenzene "10)# in addition to 0\1!
diphenylethane "20)# and n!octane "a small quantity#^ the unpredictable nature of these reactions
was demonstrated by the fact that no 0\1!diphenylethane was isolated from the reaction of benzyl
chloride with 0!naphthyllithium[ Where couplings are successful\ the substrates of choice are usually
bromo! or iodoalkanes\ as the reactions of analogous chlorides will lead predominantly to dehy!
drohalogenation and other side reactions[
Br MeI
Br
Br Li I
But 42% But But
60%
97% retention of (5) 90% retention of
configuration configuration
Scheme 5
Although organolithium reagents are well!known as strong bases\ the simple alkyl derivatives are
relatively weak nucleophiles and a high degree of aggregation in hydrocarbon solvents further
inhibits their reactivity[ Use of coordinating solvents\ or the addition of ligands such as TMEDA\
can reduce the degree of aggregation and enhance the reactivity of the organolithium species[
Addition of even a small amount of ether will break up aggregates and enhance the rate of coupling
markedly ð52JA1060Ł[ Nevertheless the reactions are often unpredictable and better alternatives
exist[ In contrast to simple alkyllithiums\ haloalkanes will readily alkylate vinyl\ allyl\ benzyl\ aryl\
allenyl\ and alkynyl lithium reagents ðB!76MI 093!91Ł[ Several examples of these reactions are dis!
cussed below[
The acidity of terminal alkynes and their ready conversion to lithium alkynides on reaction with
n!butyllithium provides\ following their subsequent alkylation with haloalkanes\ a convenient and
adaptable route to substituted alkynes ð80COS"2#160Ł[ Although the basic nature of the lithium
alkynide can lead to some dehydrohalogenation "especially with secondary and tertiary haloalkanes#\
substitutions are usually successful if primary haloalkanes are employed[ This method has found
widespread use and has been exploited as a stereoselective route to alkenes\ for example\ by Corey
and Cheng in their prostaglandin and leukotriene syntheses "Equation "09## "ðB!78MI 093!90Ł and
references therein#[ Double deprotonation of a diyne "5# and treatment with a\v!diiodoalkanes "6#
"Equation "00## has been developed by Semmelhack and Gallagher as an entry to enediyne structures
ð82TL3010Ł[ The reaction of vinylic lithium compounds with primary haloalkanes in THF at room
temperature gives high yields of substituted alkenes "Equation "01##^ elimination is the main reaction
with secondary haloalkanes[ The geometry of the double bond is retained during the alkylation
reaction^ as expected\ the reactivity of the halides decreases in the order I×Br×Cl ð63TL2798Ł[ The
ready availability of con_gurationally pure vinylic lithium reagents makes this reaction a useful
method for stereocontrolled alkene synthesis "ð65TL3728Ł and references therein#[ Deprotonation of
allenes by n!butyllithium "or metalÐhalogen exchange with a bromoallene# gives a lithioallene that
can be alkylated smoothly and in high yield with haloalkanes to give the substituted allene with
only minimal contamination by the isomeric substituted alkyne "Equation "02##^ an advantage of
this procedure is that further lithiation and substitution can be carried out with the allene always
being the major product ð64CC450Ł[ However\ choice of base\ reaction conditions\ and alkylating
agent are important] Creary has shown that use of lithium diisopropylamide "LDA# to generate the
allenyl anion and alkylation with benzyl chlorides leads to predominant formation of substituted
alkynes with isolation of methylenecyclopropanes as by!products "Equation "03## ð66JA6521Ł[ Sub!
stituted allenes are formed in negligible amounts[ The cyclopropanes presumably arise by proton
transfer from the benzyl chloride to the allenyl lithium "giving a benzyl carbene or carbenoid#\
followed by addition of the carbene to the allene[ Use of the more reactive benzyl bromides e}ectively
suppresses the formation of carbene[ Alternatively\ addition of base to a mixture of benzyl halide
and allene results in almost exclusive formation of methylenecyclopropanes[
i, BunLi, THF
ii, Cl Br
(10)
O O THF, 70–75 °C O O
80% Cl
i, 2BunLi, THF, –78 °C to 0 °C

O O
ii, HMPA, I ( )n I (7), 0 °C to 23 °C
( )n (11)
O n = 2, 40%; n = 3, 53% O
(6)
n-C8H17I
Li, ether THF, 25 °C
(12)
Cl Li 100% C8H17
i, BunLi, ether, –70 °C

ii, n-C8H17I
• • (13)
Br 91% C8H17
LDA, Et2O, RT p-RC6H4CH2Cl, 0 °C R

• • + (14)
Li
R
R = OMe, 94% R = OMe, 6%
R = H, 64% R = H, 36%
Resonance!stabilized organolithium species\ such as allyllithium and benzyllithium reagents\ are

weaker bases and stronger nucleophiles compared with non!stabilized organolithium compounds\
and will therefore react readily with alkyl halides to give coupled products[ In a study of substitutions
of cyclohexyl and 1!"phenyl#ethyl halides\ yields were superior for bromo! and iodo! compared
with chloro!substrates ð63JOC0057Ł[ Where unsymmetrical allylic lithium reagents were used\ a ] g
selectivity was usually modest^ however\ alkylation was controlled by steric factors and pre!
dominated at the less!substituted "a# end "Equation "04##[ Alkene geometry in the products was not
reported^ however\ under these conditions the isolation of a mixture of E and Z isomers might be
expected[ The temperature dependency of alkene geometry vs[ metal counterion in allylmetal systems
has been studied ð80JA4782Ł[
R
R
R Br
ether, RT
+ + (15)
Li
R = Me, 75%, α:γ = 85 : 15

R = H, 70%, α:γ = 68 : 32
Another problem with the substitution of halogen by organolithium reagents concerns the stereo!
chemistry of coupling[ While the substitution reactions often follow second!order rate laws and
exhibit halogen e}ects characteristic of an SN1 process ð68JA1196Ł\ simple alkyllithium reagents react
with optically active secondary alkyl halides to give low yields of coupled product\ with signi_cant
racemization of the stereocenter ð42JA2864Ł] in the reaction between n!butyllithium and "¦#!1!
bromobutane in hydrocarbon solvent\ a 26) yield of "−#!2!methylheptane was recovered along
with butene and butane\ and the coupled product was almost completely racemized "87)#[ A study
of benzyl\ benzhydryl\ and allyllithium species with optically active secondary alkyl halides revealed
that the stereochemistry of the coupling process "in diethyl ether as solvent# is predominantly by
inversion\ although signi_cant racemization is observed with optically active phenethyl chloride
ð69JOC11Ł[ However\ the yields are still variable\ and are often disappointing "39Ð59)#[
The organic derivatives of heavier alkali metals display increased reactivity when compared with
organolithium compounds[ However\ they su}er from similar synthetic drawbacks including a
liability to thermal decomposition\ poor solubility in hydrocarbon solvents\ and a tendency to react
with solvents "such as THF# used to enhance their solubilities[ Although couplings occur with some
net inversion\ signi_cant racemization is frequently observed[ The substitutions often give mixtures
of products\ for example\ the reaction of ethylsodium with "¦#!1!chlorooctane gave octene "26)\
isomer not speci_ed#\ octane "7[4)#\ "¦#!2!methylheptane "5[3)\ approximately 19) race!
mization#\ and "¦#!6\7!dimethyltetradecane "2[6)#^ extensive racemization is observed if the more
reactive bromooctane is used ð49JA4016Ł[ Allylsodium reacts with optically active 1!bromooctane in
hexane to give 3!methyl!0!decene "resulting from inversion# in 72) yield with approximately 19)
racemization ð49JA738Ł[
The major exception is the use of sodium alkynides for the preparation of substituted alkynes^
couplings occur smoothly and in good yields "Equation "05##[ Some relatively clean substitutions
have been observed with simple organosodium "Equations "06# and "07## and organopotassium
compounds ð53AG"E#251Ł^ however\ these couplings in general only proceed satisfactorily with the
more reactive halides "methyl\ allyl\ benzyl# and therefore the method has found little use
ð53AG"E#176Ł[ Side reactions can interfere or dominate even when a more reactive halide is employed^
treatment of camphene "7# with a mixture of n!pentylsodium and potassium t!butoxide led to a
vinylic metal species "believed to be a vinylsodium compound# which gave\ upon reaction with
iodomethane\ a 0 ] 0 mixture of the desired methylated compound "8# and the iodoalkene "09#
resulting from metalÐhalogen exchange "Equation "08## ð65HCA342Ł[
i, CH3CH2CH2I, NH3
ii, NaNH2
iii, Cl(CH2)3Br
H C C: Na+ ClCH2CH2CH2 CH2CH2CH3 (16)
64%
Na
+ Br (17)
74%
Na
+ Br (18)
44%
Na I
CH2 n-C5H11Na MeI
+ (19)
t-BuOK 68%
(8) (9) (10)
One signi_cant area where positive results have been achieved involves the alkylation of allyl!
potassium species which can be generated by treatment of alkenes with one of Schlosser|s {{super!
bases||[ The preparation and con_gurations of allyl organometallic species "MLi\ Na\ K\ Cs\
MgX# have been reviewed by Schlosser et al[ ð82T09064Ł[ Allylpotassium reagents have been alkylated
successfully with haloalkanes and the couplings have been applied to the introduction of unsaturated
sidechains into several natural products[ Djerassi and co!workers have shown that a range of
steroids with unsaturated sidechains can be prepared in good yields "up to 84)# by this method if
symmetrical allylpotassium reagents are used ð78JOC1006Ł^ although steric bulk in substituents gave
decreased yields\ in general they are still acceptable "Scheme 5#[ Unsymmetrical allylpotassium units
"such as prenylpotassium "00## gave mixtures of substitution products\ where the major product
arose from attack at the least substituted terminus of the allyl group[ In contrast\ reaction of the
allyl reagent derived from 1\2!dimethyl!1!butene gave a complex mixture of 02 products dominated
by Wurtz coupling\ and reaction of the steroidal iodide with metallated THF[ Substitution with the
allylpotassium reagent in this case was a minor pathway[ Schlosser and Zhong have used the
allylpotassium route to develop a short synthesis of a!santalol ð82TL4330Ł^ interestingly the pre!
nylpotassium reagent "00# reacted with the hindered bromoalkane "01# to give a!santalene "02# in
53) yield "Equation "19##[ Nevertheless\ despite the success of alkynide and allylmetal reagents\ in
general the heavier metals provide little bene_t in carbonÐcarbon bond formation when compared
with organolithium reagents\ and more predictable results are obtained when the organometallic
reagent is coupled with the alkyl halide under the in~uence of copper"I#\ either catalytically or in
stoichiometric quantities[
I
K R
K R
(11)
87%
A
+
OMe R = CHMe2, 98%

R = C(Me)Et2, 72%
B
A:B = 77:23
K
O
2
+ + +
46% 21% 2.8% 6.2%

+ nine other products
Scheme 6
Br
K
(11)
(20)
64%
(12) (13)
0[93[1[2 Group II Metals

Although the reaction of a Grignard reagent*which is generally the most readily formed reactive
organometallic species*with an alkyl halide may conceptually seem to provide the simplest route
to new carbonÐcarbon bonds\ in practice it has little overall synthetic usefulness[ The reactions of
Grignard reagents with a variety of haloalkanes\ and limitations of the process\ have been discussed
ðB!43MI 093!90\ B!56MI 093!90\ B!76MI 093!92Ł[ This procedure has been used for the preparation of
hindered alkanes] treatment of 1\2\2!trimethyl!1!chlorobutane with methylmagnesium chloride in
ether at 19>C gave a 27) yield of 1\1\2\2!tetramethylbutane ð33JA0278Ł[ However\ organo!
magnesium halides are normally insu.ciently nucleophilic towards haloalkanes for couplings to
occur at an acceptable rate\ and similar side reactions as befall Group I organometallic!based
substitutions can compete[ Typical side reactions include a! and b!deprotonation leading to carbenes
and alkenes respectively\ metalÐhalogen exchanges\ and single electron transfer processes providing
free!radical derived products[ In a similar manner to Group I organometallic species\ the ster!
eochemistry of reaction of optically active haloalkanes with organomagnesium reagents occurs with
inversion\ although the degree of racemization can be unpredictable[ For example\ pyrrylmagnesium
bromide reacts with 1!bromooctane to give a mixture of 1! and 2!substituted pyrroles where
displacement of bromide has occurred with complete inversion ð51JA3559Ł\ and coupling between
allylmagnesium bromide and 1!bromooctane gives 3!methyl!0!decene in 67) yield and with
only 19) racemization ð49JA738Ł[ In contrast to this\ benzylmagnesium bromide reacts with
1!bromobutane to give 1!methyl!0!phenylbutane in only 06) yield\ and substitution takes place
with 80) racemization[
Benzyl Grignard reagents are capable of acting as ambident nucleophiles^ while benzylmagnesium
chloride reacts with iodomethane to give ethylbenzene "38)# as the sole product ð57JOC1192Ł\
reaction with t!butyl halides gives some ortho! and para!t!butyltoluene in addition to neopentyl
benzene ð69T1572Ł[ Use of nonpolar solvents such as n!heptane\ in which the Grignard reagent is
insoluble\ increased the proportion of ring!substituted products[ In a similar manner to reactions
of a!~uorocarbonyl compounds "as already discussed in Section 0[93[0[1#\ addition of RMgX to
other a!haloketones can result in displacement of the halogen by addition to the carbonyl and
subsequent Lewis!acid "Mg# induced rearrangement ð63TL0340\ B!72MI 093!91\ 75CPB2488Ł[ Where two
possible pathways for rearrangement exist "i[e[ where two di}erent alkyl groups in the intermediate
alkoxide could migrate#\ then both products could be formed[ That the pinacol!type rearrangement
is initiated by an electrophilic interaction between Mg and the a!halogen was demonstrated by
addition of alkyllithium reagents to a!halo ketones^ only alcohols were isolated\ which could be
induced to rearrange by transmetallation with magnesium"II# ð61JOC3989Ł[ The rearrangements
appear to be under stereoelectronic control\ as demonstrated in reactions of rigid decalone precursors
"Scheme 6# ð61JOC3989Ł[ The most successful substitutions with Grignard reagents involve the more
reactive haloalkanes such as allylic and benzylic halides^ however\ even in these cases the yields are
often only moderate[ The reaction of Grignard reagents with a 0\2!dibromo!0!propene "03# o}ers
some selectivity in substitution reactions ð82SL078Ł\ whereas an organocopper reagent will replace
both halogens\ the analogous organomagnesium reagent will only substitute the more reactive
"allylic# center "Scheme 7#[
O HO Br O
Cl Cl Mg
PriMgBr
i, Cl
O
MeLi ii, PhH, heat
H H H H
58% overall yield
OH
Cl H
BrMg
O
O Cl
Cl H
H i, PriMgBr
MeLi ii, PhH, heat
+ +
HO H
H
Cl O
Cl 50% overall yield
BrMg O
H
Scheme 7
Bu2CuLi2(CN)
TMS Bu (2 equiv.) TMS Br BuMgI, THF TMS Bu
73% 70%
Bu Br Br
(14)
Scheme 8
The chemistry of organocalcium derivatives has produced erratic results[ The outcome of reactions
depended on the nature of the calcium used\ as commercially available samples could contain
various impurities such as sodium or magnesium that were believed to a}ect the preparation and
reactivity of the organometallic species ð52JCS466Ł[ While primary "and\ to some extent\ secondary#
organocalcium reagents could be prepared by the direct reaction of alkyl iodides or bromides with
calcium metal\ preparation of the tertiary derivatives was often plagued by disproportionation
reactions giving appreciable yields of alkene and alkane ð62JOC3157\ 62T0958Ł[ Preparation of the
benzylcalcium compounds was complicated by signi_cant Wurtz!type coupling ð62T0958Ł[ Direct
access to organocalcium reagents has been facilitated by the development of a highly reactive
form of calcium by Rieke and co!workers ð89JOC4934Ł[ Reduction of calcium halides by lithium
biphenylide in THF at room temperature gave a colored\ soluble calcium species which reacted with
organic halides at temperatures as low as −67>C for primary\ secondary\ and tertiary haloalkanes
"including 0!bromoadamantane# or −19>C for aryl halides[ Fluorobenzene was converted to the
organocalcium reagent at room temperature[ The formation of Wurtz!coupled sideproducts was
not reported\ with the exception of rapid homocoupling of allylcalcium species with starting allyl
halides[ A novel carbocyclic ring synthesis using organocalcium reagents emerged from this work
"Scheme 8#[ Reaction of highly active calcium with 0\2!dienes gave intermediate metallocycles "04#
which reacted with a\v!dihaloalkanes to give carbocycles in a highly regio! and stereospeci_c
manner[ In most cases the 0\1!addition products were observed\ with the exception of reaction
with 0\1!dihaloalkanes where 0\3!addition products dominated[ 0\1!Elimination from the ethylene
dihalides\ giving ethene as a sideproduct\ apparently did not compete[ This procedure is an improve!
ment on the magnesium!mediated method described earlier by Xiong and Rieke ð78JOC2136Ł\ as the
organocalcium metallocycles regularly gave dialkylation products "carbocycles# in higher yields
while in some cases the magnesium metallocycle gave the monoalkylated product\ requiring higher
temperatures to e}ect cyclization[ The regiochemistry "0\1!addition# was the same for both Ca and
Mg species with the exception of addition to 0\1!dihaloethanes*only calcium gave an addition
product\ producing the 0\3!regioisomer[
"Ca" CH2Cl2
Ph Ph Ph Ph
Ca Ph
Ph
(15) 47%
Br
(+ 43% starting material)
(CH2Cl)2 ( )n
Br
Ph ( )n
Ph Ph
Ph
80% n = 1, 91%
7% for (CH2Br)2 n = 2, 53%
Scheme 9
Organobarium compounds have found relatively little application in organic synthesis^ however\
Yamamoto and co!workers have recently developed a straightforward method for the preparation
of allylbarium reagents ð80JA7844Ł[ Reaction of barium"II# iodide with lithium biphenylide in THF
"the {{Rieke method|| used for preparation of active calcium and other metals# gave highly reactive
barium which readily converted allylic chlorides to allylbarium reagents at −67>C[ Although the
structure of these allylbarium compounds is uncertain\ Corey and Shieh have suggested that they
may have h2\ p!complex structures which do not rapidly interconvert with isomeric s!allylbarium
forms ð81TL5324Ł[ The remarkable a!selectivity in their reaction with carbonyl groups\ as well as the
excellent retention of double bond geometry compared with other allylmetal species "magnesium
and calcium lead predominantly to g!substitution\ while lithium and cerium are less selective
ð80JA7844Ł#\ led Corey and co!workers to investigate the alkylation of allylbariums with allyl halides
ð81TL5324\ 82TL4884Ł[ Alkylations proceeded in good yields "44Ð55)# under mild conditions "−67>C
to room temperature#\ with complete a!selectivity and retention of double bond geometries in both
allyl units[ In cases where displacement of either bromide or chloride could have occurred\ selective
alkylation by displacement of bromide was observed[ This remarkable selectivity of organobarium
reagents has led to the development of a remarkably short\ enantioselective synthesis of 1\2"S#!
oxidosqualene "Scheme 09# ð82TL4884Ł[
0[93[1[3 Organocopper Derivatives and Copper!Catalyzed Couplings

Whereas carbonÐcarbon bond formation by substitution of a halogen with an organometallic
reagent of a Group I or Group II metal often gives poor results with a range of competing
reactions intervening\ the use of copper to mediate the process*either in stoichiometric amounts
or catalytically*has proven a great success and now forms one of the cornerstones of modern
organic synthesis[ The volume of literature on the topic is immense\ and the various aspects of
organocopper chemistry have been reviewed ð63AOC104\ 64OR"11#142\ 67PAC698\ 73T530\ 76S214\
80COS"2#196\ 81OR"30#024Ł[ Improvements and variations since the original work by Gilman et al[
BaX
Cl "Ba", THF
Cl –78°C
Br THF, –78 °C
55%
BaX O
Br
O
THF, –78°C
66%
Scheme 10
ð41JOC0529Ł have meant that organocopper!mediated bond formation provides one of the most
reliable reactions in synthesis[
One of the disappointments of early organometallic approaches to organic synthesis was that\
although Grignard reagents were readily formed from a wide variety of substrates and many
organolithium compounds were also accessible\ coupling reactions with haloalkanes were generally
unreliable[ The early history of the e}ectiveness of transition metal salts as additives was not
encouraging^ for instance\ Kharasch and Fields demonstrated that arylmagnesium bromides\ in the
presence of cobalt"II# chloride or silver"I# bromide\ gave only biaryls on reaction with haloalkanes
such as bromoethane ð30JA1205Ł[ While a silver catalyst was shown by Tamura and Kochi to be
e}ective for couplings where both alkyl groups were the same "e[g[ BunMgBr and BunBr gave
n!octane in 68) yield# ð60S292Ł\ reaction of Grignard reagents with haloalkanes where the organic
residues di}ered led to a mixture of all three possible coupling products "e[g[ BunMgBr and
n!C5H02Br gave n!octane\ n!decane\ and n!dodecane\ in the ratio 0[8 ] 0[3 ] 0[9#[ Free radicals were
implicated in the process ð60JA0372Ł[ Ferric chloride has been used to catalyze the reaction between
a bromocyclobutane "05# and vinylmagnesium bromide "Equation "10## ð72CB771Ł[
O O
MgBr FeCl3, THF
O + O (21)
61%
Br
(16)
The e}ect of copper on the substitution reactions has had a chequered history] an early report by
Turner is of interest*he reported that\ following addition of ethyl a!bromobutyrate "06# to mag!
nesium in ether {{as soon as a vigorous reaction had set in\ 19 grams of cupric chloride were
added|| ð19MI 093!90Ł[ Although this reaction produced the homocoupled product "07# in 29) yield
"Equation "11##\ the possibility of organocopper intermediates was not contemplated[ Initial studies
by Linn and Noller on the reaction between ethylmagnesium bromide and ethyl bromide in the
presence of CuCl showed that {{no butane could be detected|| ð25JA705Ł; "However\ a later re!
investigation by Parker and Noller did detect the production of butane in the reaction ð53JA0001Ł[#
O
O i, Mg, ether
ii, CuCl2 OEt
OEt (22)
30% OEt
Br
O
(17) (18)
The early work on organocopper chemistry by Gilman et al[ ð41JOC0529Ł was followed by
several other groups\ including Corey and Posner ð56JA2800\ 57JA4504Ł who showed that lithium
dialkylcuprates were excellent reagents for the displacement of bromide or iodide from haloalkanes
by an alkyl ligand from copper[ Although side reactions "reductions\ eliminations\ and homo!
couplings# were sometimes noted\ yields were usually good to excellent[ Reaction of 0!bromo!3!t!
butylcyclohexane "08# with lithium dimethylcuprate "Equation "12## occurred largely "but not
exclusively# by inversion^ some elimination and reduction products were also detected ð56JA2800\
64OR"11#142Ł[ The reaction also proved useful for the displacement of both halogen atoms in a
geminal dibromo substrate "19#\ although the reduction pathway was a signi_cant contributor
"Equation "13## ð57JA4504Ł[ The mechanisms involved are obviously complex^ one of the more
popular proposals involves initial\ rate!determining oxidative addition of the haloalkane to the
cuprate with inversion of con_guration at the carbon atom of the haloalkane component\ followed
by reductive elimination ð80COS"2#196Ł[ However\ Bertz et al[ have recently described the reactions
of Bu1CuLi=LiX with iodocyclohexane "for example\ Equation "14## and explained the product
distribution as resulting from electron transfer from the cuprate to the alkyl iodide and subsequent
cyclohexyl radical formation ð80JA520Ł[ Yields of butylcyclohexane depended on the counterion X
in the cuprate complex\ decreasing in the order Bu1CuLi=LiCN "69Ð79)#×Bu1CuLi=LiBr "36Ð
42)#¼Bu1CuLi=LiOTf "33Ð49)#×Bu1CuLi=LiI "18Ð21)#[ Formation of the radical intermediate
apparently depends upon the reduction potential of the haloalkane^ if the potentials are not
su.ciently positive "as is likely for primary haloalkanes and secondary bromoalkanes# then trans!
metallations can account for side reactions[
Br
Me2CuLi (5 equiv.),
ether, 0 °C
+ + + (23)
But But But But But

(19) 45% 10% 35% 5%
Br Et2CuLi Et
+ Et (24)
Br Et
(20) 60% 20%
I
–78 °C, 1 h
THF
+ Bu2CuLi•LiI + + +
32% 28% 18% 15%

+ n-octane (25)
33%
Whitesides et al[ have investigated the reaction of diorganocuprates with a variety of alkyl halides\
and high yields of coupled products were obtained ð58JA3760Ł[ Branching in the cuprate was
tolerated in that primary\ secondary\ and tertiary alkyl cuprates all coupled with primary alkyl
halides in good to excellent yields "with yields being highest for alkyl iodides and bromides\ and
lower for the corresponding alkyl chlorides#[ Use of THF as solvent led to increased reactivity\ even
for the usually sluggish alkyl chlorides\ and acceptable yields were then obtained[ Couplings are
most successful with primary alkyl halides^ alkyl cuprate couplings with secondary and tertiary
alkyl halides generally give poorer yields or fail completely[ "It is noted that coupling between
Ph1CuLi and a secondary alkyl halide can be achieved in good overall yield[# A brief study on the
relative e}ectiveness of catalytic versus stoichiometric copper showed that yields are somewhat
lower in the catalytic case "e[g[ n!iodooctane couples with Me1CuLi in ether to give n!nonane in
86) yield\ whereas MeLi in the presence of 4 mol[) CuI gives n!nonane in 53) yield# ð58JA3760Ł^
nevertheless the couplings are still signi_cantly more successful than in the absence of copper[
Lipshutz et al[ have investigated couplings between secondary haloalkanes and the higher order
cuprates derived from CuCN\ which can be formulated as Li1ðR1Cu"CN#Ł ð70JA6561Ł[ In general\
the couplings proceed in excellent yields with both bromides and iodides[ Substitution of halogen
in a secondary haloalkane introduces the question of stereoselectivity[ Whitesides et al[ demonstrated
that lithium diphenylcuprate reacted with a secondary alkyl bromide "10# with predominant "73Ð
81)# inversion "Equation "15## ð58JA3760Ł\ and in a more extensive study by Lipshutz and Wilhelm\
it was shown that secondary iodoalkanes gave essentially racemic mixtures on coupling with
organocuprates whereas the corresponding bromides reacted with almost complete inversion
ð71JA3585Ł[ Given the mechanistic discussion of Bertz et al[\ it is likely that radical intermediates
intervene in the case of the iodides while the bromides undergo an SN1!like displacement ð80JA520Ł[
The reaction of organometallic reagents with unsymmetrical allyl halides opens up the possibility
of regiocontrol by either SN1 or SN1? displacement of the halogen by the carbanionic alkyl group[
In an extensive study\ Yamamoto et al[ have shown that the regioselectivity can be controlled with
judicious choice of reagent ð79JA1207Ł[ While Grignard reagents gave products of a!substitution
"the SN1 alternative#\ organocopper reagents favored g!regioselectivity "SN1? attack#[ The greatest
control was observed when Lewis acid modi_ed alkylcopper reagents were used in THF\ with the
best results being obtained consistently with RCu=BF2[ Phenylcopper reagents were less selective[
Use of lithium dialkylcuprates\ or organocopper species derived from Grignard reagents "whether
complexed with Lewis acids or not# gave poorer results[
Ph2CuLi
ether-THF
H H (26)
Br Et
Et Ph
(21)
Whereas stoichiometric organocopper reactions usually proceed best when the cuprates are
derived from organolithium reagents\ catalytic reactions normally involve Grignard reagents "which
also have the added bene_t of being easier to prepare#[ A major contribution to the area of
organocuprate chemistry was made by Tamura and Kochi with the introduction of the THF!soluble
cupric salt Li1CuCl3^ here\ the copper"II# species is reduced to an active copper"I# catalyst in situ
ð60S292\ 61JOM"31#194Ł[ The catalyst has been shown to be superior to cuprous iodide for these cross!
coupling reactions in a number of ways ð72JOC0801Ł] its use allows for lower reaction temperatures
and provides higher yields of more easily puri_ed products[ Catalyst ratios as low as 0 mol[) still
give excellent yields of product[ A typical halogen dependency is observed with reactivity decreasing
in the order I×BrŁCl[ In contrast with the Ag!catalyzed couplings ð60S292Ł\ copper!catalyzed
reactions give predominantly the desired coupling products with only negligible amounts of
unwanted homocouplings[ A useful synthesis of v!functionalized aldehydes has been developed by
Volkmann et al[ ð72JOC0656Ł[ The Grignard reagent derived from 1!"1!bromoethyl#!0\2!dioxolane
was treated with a variety of functionalized haloalkanes in THF containing Li1CuCl3 "4 mol[)# to
give\ following hydrolysis\ v!functionalized aldehydes in good to excellent yields "typically 69Ð
74)#[ Functional groups in the haloalkane\ such as methoxy\ chloroalkyl\ cyano\ and ester\ did not
interfere with the magnesio!cuprate addition[ The catalyst has proven useful for homologation
reactions where copper!catalyzed coupling of a Grignard reagent with an a\v!dibromoalkane\ using
as little as 0 mol[) catalyst\ could be controlled to give a monosubstituted product in 59Ð85)
yields "Equation "16## ð63JA6090Ł[ However\ two!carbon homologations using this procedure
"RMgX:Li1CuCl3 ¦BrCH1CH1Br# fail and metalÐhalogen exchange occurs giving ethene and a
new bromoalkane R0X which undergoes coupling with remaining Grignard reagent to produce
moderate yields of dimeric alkanes[ Conversion of a vicinal dibromo compound to the corresponding
alkene also occurs with preformed organocuprates ð62SC170Ł[
Li2CuCl4
(1 mol. %)
THF, 5-10 °C
But MgCl + Br Br But Br (27)
76%
A disadvantage of stoichiometric lithium dialkylcuprate substitutions is that one of the alkyl

ligands on copper is essentially {{lost|| and\ while this may be of little concern if the precursor is
readily available\ loss of alkyl ligands that are expensive or not readily prepared can be distressing[
Thus\ the use of {{dummy|| ligands which are not transferred is a preferable procedure[ Mandeville
and Whitesides have studied a variety of ligands and conclude that ligands that produce relatively
stable organocopper compounds\ such as alkynyl and alkoxy ligands\ are most successful "Equation
"17## ð63JOC399Ł[ Corey et al[ developed an alkynyl ligand derived from 2!methoxy!2!methyl!0!
butyne which provides cuprates with appreciable solubility in THF\ as well as acting as a {{dummy||
ligand that is not readily transferred ð67JOC2307Ł[ Another useful higher order cuprate appears to
be the mixed complex incorporating both 1!thienyl and cyano ligands as non!transferable groups^
good yields of coupled products are obtained "Equation "18## ð76S214Ł[ It is assumed that dp
backbonding from the Cu"I# to the alkynyl or cyano ligands accounts for their limited transfer rates
from cuprate reagents ð77JA1530Ł[ Johnson and Dhanoa have reported that the dimsyl anion
MeS"O#CH− 1 acts as a nontransferable ligand ð76JOC0774Ł^ the cuprates were prepared by treatment
of DMSO with BunLi followed by CuI and then 0 equivalent of the desired alkyllithium[ Couplings
with primary iodoalkanes proceed in high yields and the DMSO produced on hydrolysis of the
reaction mixture is easily separated from the product[ The alkylation reactions succeed where the
transferable organic residue is derived from either an organolithium or a Grignard reagent ð75T1762Ł[
THF
– –78 °C to RT
Prn Cu But + Br
Li+
Prn
+ (28)
But
83% <1%
–78 °C to 0 °C,
2– 1 h, THF CN
+ CN (29)
S Cu Br
+ 82%
CN 2Li
Another nontransferable group that has shown considerable success is the thiophenoxide ligand\
which can be readily incorporated by treatment of an alkyllithium with CuSPh ð62JA6677Ł[ The
reactions of organobis"cuprates# based on this {{dummy|| ligand have been described by Wender and
White ð77JA1107Ł^ the addition of these novel reagents "11# to 2!halocycloalk!1!enones "12# provides
a convenient method for the generation of spirocyclic compounds "Scheme 00#[ The observed halogen
dependency is the reverse of that usually encountered\ i[e[ yields are similar for bromo! and chlo!
roalkenones "typically 69Ð85)#\ and poorer for the iodo analogues "49)#[ Use of the thiophenoxide
gave the highest yields\ and preparation of the dicuprate from a Grignard\ instead of organolithium\
reagent also led to signi_cantly reduced yields[ It is interesting to note that the second addition
resulting in quaternization only occurs readily in these intramolecular cases^ addition of ordinary
cuprates RCu"SPh#Li to the alkenones "12# only gave products of single addition unless much higher
reagent concentrations were used "and yields were only modest even at saturation#[
Cu(SPh)Li
( )n O
Li(PhS)Cu Cu(SPh)Li O
O
(22)
THF –15 °C Li(PhS)Cu
n = 1, 85% THF –20 °C

( )n n = 2, 74% Cl 39%
(23)
Scheme 11
One of the main bonuses of cuprate!based reactions is that a wide range of functional groups can
be incorporated into the haloalkane component without the need for protection^ alkene\ ester\ amide\
ketone\ nitrile\ sulfonamide\ as well as most popular protecting groups\ are all tolerated remarkably
well[ While high yields are the norm\ and can generally be relied upon in these reactions\ very
occasionally "and inexplicably# a single cuprate will fail to react with a haloalkane where others
succeed[ In a series of papers directed towards novelb!amino acids and naturally occurring alkaloids\
Je}ord et al[ demonstrated that primary iodoalkanes "13# underwent nucleophilic substitution when
treated with a range of lithium dialkylcuprates "Equation "29## ð82TL0000\ 82TL1800\ 82TL6446Ł[ Various
primary\ secondary\ and tertiary alkyl groups were introduced in yields ranging from 31 to 85)\ with
most conversions occurring in over 69) yield[ However\ attempted introduction of a phenyl group
by reaction with lithium diphenylcuprate was unsuccessful\ with the reaction leading to either recovery
of starting material or b!elimination ð82TL0000Ł[ This result is intriguing as a similarb!"N!tosyl#amino
alkyl iodide "14# underwent smooth substitution with Ph1CuLi "Scheme 01# ð82TL4016Ł[
NHTs NHTs
Z I THF –30 °C, 6 h Z R
+ R2CuLi (30)
42–96%
O OEt O OEt
Z = H, OH
(24)
NHTs NHTs NHTs

i, Bu4NF, THF iv, Ph2CuLi, THF
HO OSiButPh2 HO I HO Ph
ii, TsCl, py 55%
CN iii, NaI, acetone CN (over steps i–iv) CN
(25)
Scheme 12
Je}ery et al[ have developed a novel synthesis of skipped enynes and diynes which avoids the
necessity for preparation of carbanionic intermediates prior to formation of cuprates "Equation
"20##[ Coupling can be achieved in excellent yields by the reaction of a terminal alkyne with an allyl
ð78TL1114Ł or propargyl ð81TL4646Ł halide in the presence of a catalytic amount of a copper"I# salt[
The catalyst system containing CuI:Bun3NCl "catalytic quantity of each#:Na1CO2 or K1CO2 in DMF
gives 0\3!enynes or diynes in "typically# better than 69) yield[ The reactions are highly chemo! and
regioselective\ giving products of exclusive a!attack in all cases except the reaction of 2!chlorobut!
0!ene where substitution on the terminal "g# carbon dominates "¼09 ] 0#[ A variety of functional
groups "alcohol\ ester\ chloroalkyl\ trimethylsilyl# are tolerated without the need for protection[
CuI, DMF
Na2CO3, Bun4NCl, OH
Br OH
–20 °C to RT, 16h TMS
TMS + (31)
(CH2)4Me
(CH2)4Me 75%
While organocopper reagents can tolerate a wide range of functionalities in the haloalkane com!
ponent with which they couple\ one aspect that has limited their usefulness is their preparation from
organolithium or magnesium reagents that will react with these functional groups*any synthetic
design must avoid leaving these functionalities in the cuprate[ Therefore two strategies have usually
been adopted] protection of sensitive functional groups\ or strategic bond disconnection to place
problematic functionalities in the haloalkane component[ Work byRieke et al[ has gone some way
towards solving this problem in that they have demonstrated that certain organocopper compounds
"of uncertain overall composition# can be prepared directly by reaction between a halide substrate
and {{zerovalent copper||\ an active species usually produced by reduction of copper"I# complexes
such as Cu"I#I=PR2 by lithium naphthalenide ð82JOC1372Ł[ A range of functional groups such as ester\
nitrile\ less reactive halides "Cl\ F#\ epoxides\ and ketones are tolerated ð76JOC4945Ł[ In an extensive
series of papers "see ð82JOC1381Ł for leading references#\ Rieke has shown that these organocopper
derivatives undergo many of the reactions typical of other\ more classical\ copper!based reagents\
including couplings with haloalkanes[ Arylcopper reagents coupled with alkyl halides in variable
yields "Equation "21##\ however reactions were occasionally plagued with homocouplings of the alkyl
residues of both the organocopper and the alkyl halide components\ and the yields were sometimes
disappointing[ Alkylcopper reagents prepared by reaction of the zerovalent copper with primary
haloalkanes couple with other haloalkanes to give unsymmetrically coupled products in moderate
yields at best "Equation "22##^ rapid homocoupling of the organic residues in the organocopper reagent
competes and often dominates ð73JOC4179\ 77JOC3371Ł[ However\ more promising results are outlined
in another report ð81JA4009Ł[ Reduction of CuCN=nLiCl "n0\1# at −099>C by lithium naphthalenide
in THF produced an active copper"9# species which underwent oxidative addition on treatment with
allyl chlorides to give allylcopper reagents^ at this low temperature homocoupling was negligible[ The
allylcopper reagents contained a wide range of extra functional groups "ketone\ enone\ epoxide\ nitrile\
ester\ alkyl chloride\ and carbamate# which were not a}ected[ Treatment of the allylcopper reagent
with allyl bromide gave a mixture of 0\4!dienes in excellent yield\ indicating that coupling had occurred
at both a and g ends of the copper reagent^ the major products corresponded to g!attack[ A new
approach to thienyl!based organocopper reagents has been reported by Rieke et al[ ð82JOC1381Ł\
providing a route to stable alkylcopper reagents where homocouplings or eliminations do not compete[
However\ their reactions with haloalkanes were unsatisfactory^ for example\ addition of the n!
octylcopper reagent to iodomethane gavenonane in only 21) yield\ and reaction with benzyl bromide
gave only bibenzyl "37)# and toluene "19)#[
Br
i, "active Cu"
ii, BunI, THF, 25 °C
(32)
58%
O OEt O OEt
I "active Cu", THF, 0 °C

+ Br
45%
+ homocoupled products (33)
An alternative method for the preparation of organocopper reagents involves transmetallation

of other organometallic species such as zinc! and titanium!based compounds "see Section 0[93[1[4
for the copper!catalyzed transfer of ligands from boron#[ Organozinc reagents are generally much
less reactive than organomagnesium and organolithium compounds ð63AOC72Ł\ and they do not
generally react with alkyl halides unless the alkyl halide is in some way made more reactive "as in
the case of an a!alkoxy haloalkane# or transition metal catalysis is employed[ The copper"I#!
catalyzed allylation of organozinc reagents proceeds in good to excellent yields ð76JOC3307Ł^ the
highly reactive nature of allyl halides means that chlorides and bromides show similar reactivity[
Unsymmetrical allylating reagents gave mixtures of products\ although g!alkylation predominated[
Excellent g or SN1? selectivity was observed by Nakamura et al[ when a Gilman reagent R1CuLi was
treated with anhydrous ZnCl1 "0 equiv[# prior to addition of the allyl halide^ almost complete
diastereofacial selectivity was also noted when chiral substrates were used ð78JA2980Ł[ Virtually
identical results were obtained when a dialkylzinc reagent was treated with catalytic CuBr=SMe1
"Equation "23##[ A model involving interaction between a copper d!orbital and the antisymmetric
p!orbital of the alkene has been proposed by Nakamura to account for the observed 0\1!asymmetric
induction ð80SL428Ł[ Nakamura et al[ have developed a route to zinc homoenolates "15# using
anhydrous zinc chloride to regioselectively cleave one carbonÐcarbon bond in a cyclopropanone
ketal "16# ð76JA7945\ 76TL226Ł[ Transmetallation with CuBr gave a zincÐcopper reagent which\ in the
presence of hexamethylphosphoramide "HMPA#\ reacted with various carbon electrophiles includ!
ing allyl bromides "Equation "24##[
Zn(CH2CH2CO2Pri)2
O Ph CuBr•SMe2 (catalytic) O Ph
THF, RT
Cl (34)
73%
α:γ = 0:100 CO2Pri
de = 100%
i, CuBr•SMe2, HMPA O
ii,
ZnCl2, ether O
Br
OMe RT OMe
ClZn OMe (35)
H O-TMS 59%
96% ee
(27) (26) (after hydrogenation)
In the preparation of organozinc species from oxidative addition reactions between haloalkanes
and zinc metal\ commercial samples usually display limited reactivity and require activation[ A
method used by Knochel and co!workers in an extensive series of reports on organozinc chemistry
involves treatment of zinc dust in THF successively with 0\1!dibromoethane and then chloro!
trimethylsilane[ This activated zinc will then readily insert into carbonÐhalogen bonds[ For example\
2!iodopropionitrile reacts with activated zinc to produce 1!cyanoethylzinc iodide which\ following
transmetallation with the soluble copper salt CuCN=1LiCl gave a new copper organometallic
species that reacted regiospeci_cally with allyl halides giving g!alkylated products in 72Ð88) yields
ð77TL1284Ł[ Alternatively\ the a!substituted product could be obtained by treating the organozinc
reagent with the allyl halide in the presence of 0 mol[) of Pd"PPh2#3 "Scheme 02#[ This procedure
even allows the preparation and alkylation of zincÐcopper organometallics containing acidic hydro!
gen atoms^ amines "including indoles#\ amides\ terminal alkynes\ and "to some extent# alcohols were
tolerated ð80JOC4863Ł[ For example\ 2!"1!iodoethyl#indole "17# could be converted to the zinc
reagent\ transmetallated with CuCN=1LiCl\ and alkylated with an allyl bromide "limiting reagent#
in 84) yield "Equation "25##[
Ph CN
Ph Br
Pd(PPh3)4
68%
I Zn, THF IZn CuCN•2LiCl

CN IZn(CN)Cu
CN CN
Ph Br
92%
CN
Scheme 13 Ph
I Cu(CN)ZnI
i, Zn, THF
ii, CuCN•2LiCl
N N
H H
(28)
CO2Et
Br
(0.62 equiv.)
95%
CO2Et
(36)
N
H
In an elegant extension of this work\ Rao and Knochel combined carbocupration of alkynes
using highly functionalized zincÐcopper organometallics\ with alkylation "or reaction with other
electrophiles# as a new\ stereospeci_c synthesis of polyfunctional alkenes ð80JA4624Ł[ Addition of
the cuprate Me1Cu"CN#Li1 to a functionalized organozinc allowed formation of the organocuprate[
These reagents added e.ciently and stereospeci_cally to alkynes "terminal or 0!methylthioalkynes
in intermolecular reactions# giving vinylcuprates which could then be alkylated with allyl halides to
give 0\3!dienes[ An intramolecular variant "Scheme 03# allowed rapid construction of densely
functionalized carbocycles[ These intramolecular carbometallations proceeded more readily than
similar reactions using lithium or magnesium copper reagents^ yields ranged from 46 to 65)[
Rieke and co!workers have developed a procedure for the preparation of active zinc by reduction
of zinc halides with lithium naphthalenide ð80JOC0334Ł^ alkyl bromides containing a range of
functional groups can be added to this zinc species to produce organozinc reagents which\ following
transmetallation with CuCN=1LiBr\ gave organocuprates ðRCu"CN#ZnXŁ[ Reaction with a variety
of allyl halides gave alkylation products where the g!regioselectivity was\ in general\ superior to that
obtained by Yoshida and co!workers ð76JOC3307Ł[ Even relatively hindered allyl halides such as
dimethylallyl bromide gave at least 84) g!regioselectivity "Scheme 04#[ One interesting observation
was that the regioselectivity showed little temperature dependence^ reactions run at −67>C and
allowed to warm gradually to room temperature gave almost the same results as reactions carried
out at 9>C[
I Cu(CN)Li•ZnMe2
i, activated Zn, THF
Bu ii, Me2Cu(CN)Li2 Bu
–70 °C to –20 °C
O O O O
CO2Et
Br Cu(CN)Li•ZnMe2
O O CO2Et 60% overall O O

Bu Bu
Scheme 14
i, active Zn
O ii,CuCN•2LiBr CN O
Br (ZnX)Cu
OEt OEt
Br
88%
γ:α = 98:2
O O
+
OEt OEt
γ-alkylation α-alkylation
Scheme 15
While organotitanium reagents will add to carbonyl groups\ they show little reactivity towards
haloalkanes\ including activated systems such as allyl halides ð81T4698Ł[ However\ addition of a
catalytic amount of a copper"I# salt "5Ð6[4 mol[)# allows allylation of the organometallic reagent\
giving a substitution product with excellent SN1? regioselectivity^ the selectivity is very high with
allyl chlorides "usually better than 88 ] 0#\ but poor with the corresponding bromide[ It appears as
though both copper and titanium are required to obtain high selectivity as the titanium reagent
R0Ti"OR1#2 is inert to allyl chlorides\ and simple Gilman reagents R1CuLi give more modest results[
Superior SN1? selectivity is obtained for {{long chain|| alkyltitanates "butyl\ hexyl\ etc[#\ but methyl!\
benzyl!\ allyl!\ and phenyltitanium reagents were observed to give only moderate selectivity[ The
titanium reagents R0n¦0Ti"OR1#2Lin\ "n9\0#\ show both excellent chemoselectivity "Equation "26##
towards allylation rather than conjugate addition\ and diastereoselectivity in addition to allyl
chlorides "e[g[ Structure "18## bearing a chiral center "Equation "27##[ High yields and SN1? regio!
selectivity were also reported for a reagent derived from Bu1Zn and CuI=1LiCl ð81T4698Ł[
O CuI•2LiCl O
THF, –70 °C
+ Bun2Ti(OPri)3Li (37)
96%
Cl Bun
O Ph
O Ph CuI•2LiCl
Cl THF, –70 °C
+ Bun2Ti(OPri)3Li (38)
92% Bun
99% SN2'
(29) de 100%
Organomanganese"II# chloride reagents ordinarily will not react with haloalkanes\ and lithium
trialkylmanganates such as LiMnMe2 give only moderate yields of cross!coupled products\ even
with primary haloalkanes\ whereas manganates with larger alkyl ligands give very poor yields and
side reactions "including reduction\ elimination\ and homocouplings# intervene ð69TL204Ł[ However\
the addition of a catalytic quantity of Li1CuCl3 "2 mol[)# and also a polar solvent "N!methyl!
pyrrolidone is superior to DMSO and DMF# to THF solutions of RMnCl gives a reagent that will
e}ectively alkylate haloalkanes "Br\ I# in very good to excellent yields "Scheme 05#^ both the copper
catalyst and the polar solvent are essential for e.cient alkylation[ Primary\ secondary\ tertiary\
vinyl\ and aryl manganese chlorides give high yields\ but allylmanganese chloride gives only a 11)
yield of 0!tetradecene when treated with 0!bromoundecane[ Phenylmanganese chloride reacted
better in the absence of the polar solvent[ Alkylations are only successful with primary haloalkanes\
with little or no reaction occurring with secondary and tertiary substrates[ The additions are highly
chemoselective\ and a wide variety of functional groups is tolerated in the bromoalkane\ including
chloroalkyl\ sulfonate ester\ carboxylate ester\ carbonate\ ketone\ alcohol\ and carboxylic acid
"1 mol[ equiv[ RMnCl required for ROH and RCO1H#[ Leaving groups on the b!carbon atom are
also tolerated remarkably well[ Yields were shown to be 09Ð04) higher for catalyzed RMnCl
substitutions when compared with catalyzed Grignard substitutions ð82SL34Ł[
O
Br O
OEt
C4H9MnCl + Li2CuCl4 (3 mol. %) C4H9
92% OEt
O
OSO2Ph
Br Br
O OEt
74%
87%
O
OSO2Ph
C4H9 C4H9
O OEt
Scheme 16
0[93[1[4 Organoboron Compounds

While organoboron compounds are less frequently used for carbonÐcarbon bond formation by
reaction with haloalkanes\ nevertheless there are some cases where transfer of an alkyl group from
boron "usually as a four!coordinate boron!ate complex# will occur[ Lithium methyl"trialkyl#borates
will selectively transfer an alkyl group to an allyl or propargyl halide in good to excellent yields
"typically 42Ð85)# in the presence of a catalytic quantity of a copper"I# salt^ in most cases the
methyl group is not transferred[ Substitution of allyl halides gives substituted alkenes "in the case
of cinnamyl chloride\ the product of g!substitution predominates#\ whereas propargyl substrates
give allenes "Scheme 06# ð66BCJ1088Ł[
i, CuBr
ii, Cl
) –
3 BMe
87%
i, CuBr
ii, Br
53%
Scheme 17
Anions derived from a!halo esters ð57JA707Ł\ ketones ð58JA1036Ł\ and nitriles ð58JA5743Ł "prepared
using hindered bases# react with trialkylboranes to give alkylated products via an interesting
rearrangement[ Initial attack of the stabilized carbanion on the electrophilic boron center gives a
boron!ate complex which then rearranges to a new trialkylborane where an alkyl group on boron
has displaced a halogen atom[ Synthesis of the precursor organoborane via a hydroboration reaction
allows control of the stereochemistry of the _nal product "Scheme 07# ð58JA1049Ł[ Where the borane
is symmetrical\ only one alkyl group will migrate and the other two groups are {{wasted||\ however
introduction of the 8!BBN ligand "which is not transferred# overcomes this problem[ In the case of
a!halo esters and ketones\ Matteson has proposed that the intermediate borane "29# is unstable and
rearranges to the boron enolate^ the alkylated product is then liberated from boron by reaction with
a proton source in the reaction mixture ðB!76MI 093!93Ł[ Reactions in THF containing some ButOH
generally give very good to excellent yields of alkylated products[ Complexation of the anion derived
from dichloroacetonitrile provides a route to e}ect a double alkylation on carbon by sequential
displacement of both halogen atoms ð69JA4689Ł[
BrCH2CO2Et –
9-BBN-H B ButOK B
Br
EtO2C
B
ButOH
B
O
CO2Et CO2Et
EtO
60% overall yield (30)
≥98% trans
Scheme 18
Pelter et al[ have reported a novel method "Scheme 08# for the synthesis of substituted ketones
ð62CC433Ł and 0\3!dicarbonyl compounds ð62TL3380Ł using alkynylborates[ Alkylation with reactive
haloalkanes gives intermediate vinylboranes^ both primary and secondary alkyl groups "R0# will
readily migrate from boron to carbon and the alkylation appears to be regiospeci_c\ with the ligand
from boron "R0# migrating to the a carbon atom and the alkyl group "R2# from the haloalkane being
introduced to the b carbon center of the alkynyl residue[ Yields of ketones "following oxidation#
are excellent "67Ð77)#[ Protonation of the intermediate vinylboranes also can provide alkenes in
good yields although the E:Z selectivity is relatively poor^ use of the sterically demanding thexyl
ligand on boron leads to greater selectivity ð64TL0522Ł[
0 °C, R3Br, R12B R2

DIGLYME –78 °C to RT
R13B + Li R2 R13B R2
R1 R3
R1 = n-alkyl, cyclopentyl H2O2

R2 = n-alkyl NaOH
R3 = allyl, PhCH2 78–88%
O
R3
R1
R2
Scheme 19
0[93[1[5 Miscellaneous Species with No Stabilizing Group

A profusion of other organometallic reagents will react with haloalkanes to give coupled products\
often in quite good yields[ However\ the applications of these alkylations are generally quite limited
as similar or better results can usually be obtained using methodologies outlined in preceding
sections[ Nevertheless the chemistry is often interesting and some representative examples are given
below[
p!Allylnickel reagents can be used to allylate haloalkanes^ they are weakly basic and can tolerate
other functionalities such as ketones\ esters\ and chloroalkyl groups ð61OR"08#004Ł\ and yields range
from good to excellent[ Corey and Semmelhack used the coupling in a brief synthesis of a!santalene
"02# ð56JA1644Ł^ coupling occurred at the less hindered end of the allyl unit "Equation "28##[ A
cycloplatinated complex has been reported to react with iodomethane giving an adduct reminiscent
of Wheland intermediates ð71JA5598Ł^ this complex can be isolated as the ~uoroborate salt\ or
decomposed on addition of cyanide "Scheme 19# to give the methylated arene ð71OM0255Ł[ While
cyclometallation reactions provide an e}ective method for regiospeci_c functionalization of organic
substrates\ the requirement for stoichiometric quantities of expensive transition metal precursors
restricts their usefulness to cases where chelation!directed lithiation reactions are inappropriate[
I DMF
Br
+ (39)
Ni
88%
2
(13)
OH2 BF4– I
+ Me2N NMe2
Me2N Pt NMe2 MeI
Me2N Pt NMe2
CN–
87%
+
"only organic
product"
Scheme 20
Zinc alkyl reagents are generally inert to haloalkanes^ in an early investigation Noller showed
that dialkylzinc compounds would not react with primary\ secondary\ or allyl haloalkanes ð18JA483Ł[
Tertiary halides gave coupling products\ but in moderate yields[ For example\ diethylzinc reacted
with t!butyl chloride in xylene to give 1\1!dimethylbutane in 34) yield[ More recently\ Reetz et al[
have developed this reaction into a useful synthesis of compounds containing quaternary carbon
centers where the presence of zinc chloride facilitates substitution of the halogen atom by an alkyl
group ð79CC0191Ł[ Although the reaction may have some carbocationic nature\ the mild Lewis
acidity of the zinc reagent is believed to reduce the tendency to rearrangement "Equation "39##[ In
contrast to saturated zinc alkyls\ allylzinc halides are reactive and couple readily with allyl halides
to give 0\4!dienes in good yields[ Excellent regioselectivity is often achieved\ where allylzinc bromide
reagents couple g to the zinc substituent\ and attack the allyl halide to give products of SN1!type
reactions ð53BSF1374\ 57CR"C#0503Ł[ However\ reactions with cinnamyl bromide and allylzinc\ or with
cinnamylzinc bromide and allyl halides\ give mixtures of a! and g!substituted products[
Cl
But Pri
ZnMe2, –78 °C
+ (40)
81%
ratio 96.2 : 3.8
Organocadmium reagents are generally insu.ciently nucleophilic to react with primary and
secondary haloalkanes by displacement ð46JOC0215\ 62JOC2078Ł\ and reaction with tertiary halides
leads to elimination of HX ð25RTC407\ 46JOC0215Ł[ However\ Kollonitsch has contended that the
reaction with tertiary haloalkanes results from the presence of magnesium salts in organocadmium
reagents that are prepared by transmetallation of organomagnesium compounds and then used in
situ ð55JCS"A#342Ł[ For example\ distilled diethylcadmium reacted with t!butyl chloride to the extent
of only 3)\ whereas addition of magnesium halides increased the conversion to 34)[ Jones and
Costanzo have reported that activated haloalkanes "allyl\ benzyl# react with organocadmium
reagents to give alkylated materials in variable yields ð62JOC2078Ł^ this is in contrast to Cason and
Fessenden who were unable to obtain any signi_cant yields of coupled product with allyl bromide
ð46JOC0215Ł[ Alkylation of a!bromoketones and esters has been reported to proceed in modest to
poor yield ð57JOC0564\ 62JOC2078Ł^ however\ attempted alkylation of a!chloroesters with alkyl!
cadmium chlorides failed and side reactions intervened[ Where the a!bromoester is tertiary\ con!
densation reactions dominate "Equation "30##\ and racemization occurs in reactions involving
secondary substrates "Equation "31##[
Br
OEt OEt
BuCdX + (41)
72%
O O O
Br ether Ph
PhCdCl + (42)
H CO2Me 60% CO2Me
racemic
product
Organomercury compounds are usually quite inert to haloalkanes\ with reactions only taking
place under forcing conditions ðB!56MI 093!91\ 67AG"E#16\ 71T0602Ł[ In an extensive study\ Whitmore
and Thurman showed that a range of haloalkanes gave no reaction with bis"p!tolyl#mercury on
heating in toluene for over 299 h ð18JA0380Ł^ reactions of both activated "allyl# and non!activated
halides were generally unsuccessful with numerous side reactions intervening[ A rare success was
obtained with bromodiphenylmethane\ where a 89) yield of triphenylmethane was recorded when
the electrophilic bromoalkane was reacted in toluene with diphenylmercury for 069 h[ A similar
reaction with dibutylmercury gave much poorer conversion[ Alkylations have been reported to
occur at lower temperatures "although in modest yield# when Lewis acids such as aluminum bromide
are employed as a catalyst ð71T0602Ł[ Activated compounds such as a!mercuriocarbonyl reagents
are reported to react readily and in the absence of a catalyst "Equation "32## ðB!56MI 093!91Ł\ however\
Curtin and Hurwitz have shown that while trityl chloride reacts with these organomercurials
readily\ catalysis with stannic chloride is required for reaction with benzhydryl chloride ð41JA4270Ł[
Carbocation intermediates are implicated[ Organomercury compounds will react with allyl halides
to give substitution products in the presence of palladium "II# catalysts^ however\ it is likely that the
reaction proceeds by initial transmetallation of the aryl ð57JA4420Ł or vinyl ð67JOM"045#34Ł mercurial
to give an organopalladium species which adds to the double bond of the allyl chloride[ Elimination
of PdCl1−3 from the alkylpalladium intermediate leads to a product of formal SN1? substitution[ The
reactions are catalytic in palladium[
O benzene, RT O
ClHg + Ph3CCl Ph3C (43)
H 65% H
The reactions of alkylaluminum reagents with haloalkanes have been reported ð55JOC897Ł^
whereas triethylaluminum reacted with benzyl halides and 1!phenylethylhalides to give coupled
products in acceptable yields accompanied by some reduced material\ reactions with primary\
secondary\ and tertiary haloalkanes were generally unreliable with reduction\ elimination\ and
rearrangement products contributing to the total yield[ Kennedy has reported that alkylation of
tertiary chloroalkanes occurred in excellent yields in chloromethane as a solvent^ substitution of
cyclopentane as a solvent led to much slower reactions ð69JOC421Ł[ Nevertheless\ the carbocationic
nature of the reaction suggests that its applications to synthesis are limited[ One successful and
useful procedure involving organoaluminum reagents centers on the hydroalumination of alkynes[
Stereospeci_c syn addition of an aluminum hydride reagent gives a vinylalane^ treatment with MeLi
gives the ate complex which will alkylate reactive haloalkanes ð65JOC1103Ł[ The reaction proved
most successful with symmetrical and terminal alkynes^ for example\ hydroalumination of 0!octyne
and subsequent allylation gave isomerically pure 0\3"E#!undecadiene in 57) yield[ Allyltin reagents
will react with haloalkanes to give substitution products^ however\ the reactions usually involve
radical intermediates\ or they are catalyzed by Lewis acids or transition metals ðB!76MI 093!94Ł[ For
example\ in the reaction of bromoalkanes\ homolysis of the carbonÐbromine bond occurs
either thermally or under irradiation to give an alkyl radical which adds to the allyl stannane[
Subsequent cleavage of the carbonÐtin bond gives products of SH1? substitution "Equation "33##
ð64JOM"85#114Ł[
Carbanions With One Stabilizin` Group 018
Br
150 °C OMe
+ OMe (44)
Bu3Sn
30%
O O
0[93[2 CARBANIONS WITH ONE STABILIZING GROUP
0[93[2[0 General Comments

The introduction of a substituent into an alkyl chain has the potential to lower the pKa values of
a!hydrogen atoms by providing stabilization of a!carbanions and therefore\ at least in theory\ a
route to direct metallation[ Electronegative elements such as oxygen can stabilize negative charges
by induction\ whereas boron with its vacant p orbital\ and unsaturated functionalities such as
carbonyl groups\ can act as p!acceptors[ However\ the degree of in~uence varies] ethers and
alkylamines have limited e}ects\ and a!protons are removed only with strong bases "and then\ only
with some di.culty and with little practical value#\ while the nitro group has such a dramatic e}ect
that hydroxide will readily convert many nitroalkanes to their corresponding nitronate salts[ One
advantage of this increased acidity lies in the reduced basicity of the conjugate bases^ side reactions
such as deprotonation of the haloalkane substrates by the carbanions are reported less frequently[
In general\ the nucleophilicities of the anions are enhanced and the choice of cation causes less
trouble\ with Group I metals proving quite acceptable in most cases[ The proliferation of lithium
amide bases has provided virtually limitless opportunities for the generation of lithium carbanions\
and their alkylations proceed\ in general\ in good to excellent yields[ None the less\ there are no
universal guidelines for this class of reactions^ whereas many reactions proceed in high yield\ others
such as nitronates react in poor yields or give unchanged starting material[ Two new factors are
introduced for consideration with this group of carbanions[ Asymmetric syntheses become possible
by either the use of con_gurationally stable carbanions or by the addition of chiral auxiliaries to
the molecule[ The stabilizing group can provide a useful synthetic handle for further manipulation[
0[93[2[1 Enolates and Related Carbanions

Carbonyl groups and their reactions are fundamental to modern organic synthesis\ and the
development of reliable methods for a!alkylations has been one of the most keenly researched areas
throughout the history of organic chemistry[ At _rst sight\ the process appears straightforward] the
reaction of the neutral molecule with a base generates an anion a to the carbonyl group[ The
negative charge is readily stabilized\ as the carbonÐoxygen double bond has a relatively low!lying
vacant p orbital capable of delocalizing the electron density ð70JOC0582Ł[ Subsequent addition of
a haloalkane to the reaction mixture should give the product of nucleophilic substitution[ However\
the reaction is not always that simple\ and several complicating factors need to be considered[ An
injudicious choice of base could result in competing nucleophilic addition to the carbonyl group[
Unsymmetrical ketones can su}er competing a! and a?!deprotonation\ giving regioisomeric enolates[
While the geometry of the enolate is of little importance in achiral systems or where the ster!
eochemistry of the product is of no consequence\ in asymmetric synthesis the selective formation of
either the "E#! or "Z#!enolate is vital[ The enolate can act as an ambident nucleophile and therefore
alkylation on oxygen and carbon can compete[ In the alkylation of enolates that contain asymmetric
elements the p!faces of the enolate are diastereotopic and therefore diastereomeric products can
result[ Simple ester enolates may not be stable with respect to ketene formation[ Finally\ if the rate
of alkylation is slow relative to intermolecular proton transfer\ then the residual enolate can act as
a base and deprotonate alkylated material giving a new enolate^ the ultimate outcome of this process
would be a mixture of starting material and mono! and polyalkylated products[
In this section\ the alkylation of enolates derived from ketones and aldehydes\ as well as carboxylic
acids and their derivatives\ will be considered[ "Various nitrogen!based enolate equivalents\ such as
oximes and hydrazones\ are discussed brie~y in Section 0[93[2[4[# However\ the alkylations of
enolates and related species have been reviewed extensively and frequently\ and fuller discussions
of regiospeci_c enolate generation ð65T1868Ł\ the structure and reactivity of alkali metal enolates
ð66T1626Ł\ enamines ð71T0864Ł\ stereoselective alkylations ðB!73MI 093!90Ł\ tandem conjugate
additionÐalkylation procedures ð74S253Ł and stereoelectronic in~uences ð78T3802Ł can be found in
these articles[ Reviews by Caine ð80COS"2#0Ł and Heathcock ðB!81MI 093!92Ł provide detailed and
excellent coverage[
Many solutions to the above mentioned problems have been provided\ and nucleophilic attack
by a base can be readily avoided by selection of strong\ nonnucleophilic bases "such as the hindered
alkali metal dialkylamides#[ In most cases organolithium or Grignard reagents can be considered
inappropriate[ Alternative methods for enolate generation that also avoid this problem include
conjugate reduction of a\b!unsaturated compounds using metal:ammonia techniques ð54JA164\
64PAC442Ł\ 0\3!addition of cuprates to enones and similar substrates ð74S253Ł\ and preparation
of enolates via enol acetates ð54JOC1491Ł and silyl enol ethers ð57JA3351\ 57JA3353\ 79C154\ 72TL0234Ł[
Likewise the potentially serious problem of ester enolate instability _nds an easy and acceptable
solution with the application of lithium amide bases] whereas sodium ester enolates are readily
unstable ð69JA2111Ł\ the stronger lithiumÐoxygen interaction allows the preparation and even iso!
lation of lithium ester enolates ð62JA2949\ 62JOM"49#8Ł[
The prospect of competing O! and C!alkylation is a dilemma that deserves closer scrutiny[
Theoretical studies on the alkylation of acetaldehyde enolate with methyl ~uoride have indicated
that\ while the C!alkylated product is favored thermodynamically\ the path to enol ether formation
has a lower energy of activation and the O!alkylated compound is therefore kinetically favored
ð75JA1548\ 76JCPB654Ł[ However\ methyl ~uoride is a {{relatively {hard| and unreactive electrophile||
ð75JA1548Ł\ and both studies examined {{naked|| enolates without consideration of cations\ solvents\
aggregation e}ects\ and other factors[ In reality O!alkylation does not pose a major problem
especially when lithium enolates are employed^ reactions in moderately polar solvents such as diethyl
ether and THF also favor C!alkylation while highly polar solvents such as DMSO\ which solvate
cations strongly\ lead to increased proportions of O!alkylated material "Equation "34## ð57JOC1111\
60JOC0001\ 66T1626Ł[ The haloalkane approaches the enolate at an angle of 095> ð75JA1548Ł\ and this
stereoelectronic constraint dictates the outcome of intramolecular alkylations ð66CC122\ 67JOC699Ł[
If the v!halo enolate will lead to a _ve!membered ring\ O!alkylation dominates and the exo!
methylene ether is formed "Scheme 10#[ In contrast\ exclusive C!alkylation occurs for six!membered
ring formation[ These trends have been borne out in a recent theoretical study where it was shown
that\ while cycloalkanone formation is generally favored\ cyclization to give an enol ether dominates
for _ve!membered ring synthesis ð80JPO338Ł[
O– Na+ O O
PrnBr*
+ (45)
Ph *PrnCl Ph Ph
for alkylation
in DMSO
Solvent O:C ratio
ether 0.00
DME 0.25
DIGLYME 0.27
DMSO 1.34
O O
i, LDA, –60 °C to 0 °C
ii, HMPA, 0 °C to 20 °C
( )n n=2
55 to 68%
Br
i, LDA, –60 °C to 0 °C
ii, HMPA, 0 °C to 20 °C
n=1
41%
O
+ condensation products
Scheme 21
Development of the hindered alkali metal amide bases has introduced a new and important
control element into enolate chemistry[ In addition to their ease of preparation and good solubility
in organic solvents\ the lithium amides allow regioselective enolate formation to be e}ected in
unsymmetrical ketones[ Where the two a!sites of a ketone impose di}erent steric constraints on an
approaching base\ then the hindered amides will preferentially abstract a proton from the less
substituted or less hindered a!position[ At low temperatures and in the absence of acids "such
as neutral ketones#\ these {{kinetic|| enolates can be formed with moderate to good selectivities[
Alternatively\ formation of an enolate under equilibrating conditions "in the presence of acids such as
alcohol or an excess of the ketone# results in the formation of the most substituted "thermodynamic#
enolate[ These two extremes are illustrated in the intramolecular alkylation of an acetyl cyclopentane
"20# "Scheme 11# ð67JOC1042Ł and an a!phenyl ketone "21# "Scheme 12#[
O O
O i, LDA, THF, –72 °C H
ii, reflux
+
Br
H
(31) 77 – 84% 2%
ButOK, ButOH
reflux
86 – 94%
H
Scheme 22
O i, LDA, 2 – 4°C O
O ButOK, ButOH
reflux Ph ii, HMPA, 2 °C Ph
+
Ph 51–67%
Ph
O Br
82–95% 1% (32)
Scheme 23
Various hindered dialkylamides have been developed and employed for enolate formation and
an excellent discussion of their relative merits can be found in Heathcock|s review ðB!81MI 093!92Ł[
A recently introduced\ extremely hindered base is lithium bis"1!adamantyl#amide "LBAA# which
has been developed by Collum and co!workers and may _nd future applications as a result of its
simple synthesis] the parent amine can be prepared by reductive amination of adamantanone with
NH3Cl ð82TL4102Ł[ The amide is monomeric under all conditions\ and it readily forms mixed
aggregates with alkyllithium reagents and lithium enolates\ but not apparently with lithium halides[
Enolization of 2!pentanone was studied under a variety of conditions\ and LBAA frequently gave
"E# ] "Z# ratios of at least 49 ] 0 "when the enolate was trapped as the silyl ether\ in situ#[ Nevertheless\
LDA remains one of the most widely used sterically encumbered bases as it gives\ generally\
satisfactory "E# ] "Z# selectivity[ Either isomer can be prepared selectively depending on the solvent
employed\ and a model developed by Ireland et al[ ð65JA1757Ł provides an explanation for the
di}ering behavior] deprotonation in THF occurs via a closed\ chair!like transition state giving the
"E#!enolate\ whereas the addition of a strongly coordinating solvent such as HMPA allows for a
more open transition state leading to the "Z#!enolate ðB!81MI 093!92Ł[ However\ recent studies by
Collum and co!workers have indicated that the process is signi_cantly more complex\ with added
factors such as enolate aggregation and salt e}ects playing important roles ð80JA4640\ 80JA8460\
82TL4102Ł[
Despite the potential pitfalls that could plague the formation of stereo! and regiode_ned enolates\
and the possibility of ambident reactivity\ alkylations with activated and primary haloalkanes
generally proceed satisfactorily although results with less reactive alkyl halides are somewhat more
modest[ One problem that occasionally complicates product puri_cation arises when the rate of
substitution is slow and proton transfer competes\ resulting in enolate scrambling and poly!
alkylation[ Classical solutions to these problems often involve several steps\ such as the preparation
of b!ketoesters\ alkylation of the derived monoanion\ and hydrolysis and decarboxylation to remove
the activating ester group[ More direct approaches center upon transmetallation of enolates giving
species that can be selectively monoalkylated[ Several groups have reported the usefulness of tin
"IV# enolates "which can be mixtures of enolates and a!stannylated carbonyl compounds#^ Pereyre
and co!workers ð56CR"C#0193\ 58TL494\ 69CR"C#099\ 62JOM"44#162Ł and Tardella ð58TL0006Ł showed that
reactive alkyl halides will alkylate tin enolates either in the presence of HMPA or in the absence of
solvent[ The reactions generally gave monoalkylated products with little or no polyalkylation being
recorded[ Jung and Blum demonstrated that\ while the lithium enolate of acetaldehyde gives
polymeric material on treatment with haloalkanes\ transmetallation and subsequent alkylation of
the tributyltin derivative leads to a!monoalkylated products in moderate "39Ð57)# yields "Scheme
13# ð66TL2680Ł[
H O
BunLi OLi Bu3SnCl OSnBu3
+
O Bu3Sn
R Yield(%) RX,
HMPA
Me 61
Et 40
H O
PhCH2 68
allyl 41
R
Scheme 24
Transmetallation with tin "IV# reagents provides an e}ective solution for the regioselective
a!alkylation of cyclopentanone enolates derived from conjugate addition^ in general\ enolate equi!
libration would be expected to provide isomeric and polyalkylated by!products especially if unac!
tivated haloalkanes are employed[ However\ sequential conjugate addition\ formation of the tin "IV#
enolate\ and addition of HMPA prior to alkylation\ suppresses the equilibration and regiospeci_c
alkylation is e}ected ð73TL112\ 73TL1376Ł^ this approach has been used by Noyori and co!workers in
a highly successful three!component coupling as a key step in a prostaglandin synthesis "Scheme
14# ð74JA2237\ 77JA3607Ł[ It is likely that the reactive species is actually a penta! or a hexacoordinate
stannate rather than a neutral four!coordinate tin enolate[ The Noyori reaction requires a large
excess of the alkylating agent for acceptable yields to be obtained^ when the enolate and allyl iodide
are present in equimolar quantities the desired product is isolated in 44) yield "reduced from 70)#
along with 24) of non!alkylated 0\3!adduct[ The separation of the alkylated material from tin
residues can be tedious\ and therefore Noyori and co!workers have developed a zinc!based technique
to overcome this shortcoming ð78JOC0674Ł[ Addition of HMPA and dimethylzinc to the lithium
enolates prior to alkylation suppresses proton exchange\ enolate equilibration\ and polyalkylation
to less than 0)[ However\ a large excess of the alkylating agent is still required for optimum
yields[
One solution to the problem of polyalkylation and enolate scrambling has been provided by
O
– i, ether, THF, –78 °C
(Bun)3P•ICu C5H11 ii, HMPA, Ph3SnCl, –78 °C
Li+ +
O-TBDMS
TBDMS-O
CO2Me
OSnPh3
CO2Me O
I
(5 equiv.)
78%
TBDMS-O (+3% of C-2 epimer)
C5H11 TBDMS-O
C5H11
TBDMS-O
TBDMS-O
Scheme 25
Negishi et al[\ via the use of triethyl boron!ate complexes of potassium enolates "Scheme 15#
ð68TL734Ł[ The reaction routinely gave high yields of monoalkylated products\ whereas omission of
BEt2 gave the expected mixture of products[ Use of BEt2 and correct choice of metal cation "K# is
critical] more hindered trialkylboranes do not allow complete complexation to the enolate oxygen
atom and mixtures of products inevitably result[ Similarly\ use of lithium enolates also gives
mixtures\ as the stronger Li0O interaction apparently inhibits reaction of the enolate with the
boron electrophile[ The method is versatile because the choice of base can determine whether kinetic
"using KN"SiMe2#1# or thermodynamic "using KH# enolates are generated and then trapped with
BEt2\ as r74) regioisomerically pure species ð72TL0230Ł[ The boron enolate methodology has
been incorporated by Motherwell and co!workers into a conceptually unique approach to enolate
chemistry ð80CC0288\ 81TL5076Ł[ The strategy centers on transition metal!mediated isomerization of
allylic alkoxides and their derivatives as a direct route to stable enolates[ "Although simple enols
can be produced by a similar procedure\ reaction of the enols with reactive halides was not reported
ð80JA847Ł[# The lithium alkoxide or triethylboron!ate complex of an allylic alcohol was isomerized
using Rh"I# catalysts\ and the resultant enolate was monoalkylated cleanly with reactive alkyl halides
"Equation "35##[ Yields were variable "29Ð79)#\ depending on substrate structure[ Where further
isomerization of the enolate is possible\ use of a Rh"I# catalyst gave an undesirable mixture of
a! and a?!alkylated ketones[ Using "Cy2P#1NiCl1 e}ectively suppressed the second isomerization
ð81TL5076Ł[
i, KH i, KHMDS
O ii, BEt3 O ii, BEt3 O
iii, MeI iii, MeI
79% 86%
90% 2,2-diMe 93% 2,6-diMe
KHMDS = potassium hexamethyldisilazide

Scheme 26
OH i, BunLi O O
ii, catalyst
iii, allyl Br
+ (46)
α-alkylation α'-alkylation
Catalyst Yield (%) α : α'

[Rh(dppe)]ClO4 79 1 : 1.2
(Cy3P)NiCl2 78 15 : 1
Manganese "II# enolates have been used by Reetz and Haning to e}ect a!methylation of ketones
in excellent yields ð82TL6284Ł[ Regioselectivity is high\ and polymethylated products are generally
less than 2) of the total yield[ The base of choice is LiN"SiMe2#1^ substitution of LDA gives lower
yields and signi_cantly more polyalkylation[ In addition\ the reaction cannot be extended readily
to other primary alkyl iodides^ alkylations with BunI {{do not work as well||[
Alkylation of silyl enol ethers can be readily e}ected by a number of methods[ Addition of a
mixture of enol ether and benzyltrimethylammonium ~uoride in THF gives monoalkylated products
in moderate to good yields\ although some nonalkylated material often accompanies the desired
product ð71JA0914\ 74ACR070Ł[ Yields are modest with nonactivated haloalkanes\ and cyclopentanone
silyl enol ether gave signi_cant quantities of dialkylated material[ However\ silyl enol ethers can
provide routes to materials that are not otherwise readily available[ While enolates generally react
with t!alkyl halides by an E0 mechanism\ silyl enol ethers readily alkylate these substrates in the
presence of a Lewis acid such as TiCl3 or ZnBr1 ð68TL0408\ 71AG"E#85Ł[ This method also _nds uses
for alkylation of otherwise unreactive bridgehead halides^ however\ simple primary haloalkanes
have failed to react until recently ð68BCJ0130\ 68TL0408Ł[ Benzylation of silyl enol ethers can be
e}ected with silver "I# catalysis ð68BCJ0130Ł\ and Je}ord et al[ have recently shown that primary
iodoalkanes can be induced to react with the enol ethers in the presence of silver tri~uoroacetate in
yields that range from 16 to 72) but generally exceed 49) "Equation "36## ð81TL0744Ł[ Alkyl
bromides and secondary iodoalkanes fail to react[
O-TMS RI, AgO2CCF3 O
CH2Cl2 R
(47)
R = Me, 83%
R = Bun, 56%
Most alkylations considered thus far in this section have centered on reactions that lead to racemic
material[ However\ introducing a chiral element into an enolate renders the p!faces diastereotopic\
and therefore facial discrimination in the alkylation step becomes crucial to avoid the formation of
diastereomeric products[ Other substituents already present in the enolate can a}ect the facial
selectivity\ as demonstrated in Noyori|s prostaglandin synthesis which results in the 1\2!trans isomer
as the dominant product "Scheme 14#[ Achiral carbonyl compounds can be modi_ed by covalent
inclusion of a chiral auxiliary to direct subsequent alkylation^ this is one of the most intensely
studied _elds in carbonyl chemistry and a comprehensive coverage of all aspects is beyond the scope
of this chapter[ Nevertheless\ several examples of asymmetric alkylations are presented in Equations
"37#Ð"44#[ Most auxiliaries can be readily identi_ed as being derived from the chiral pool^ popular
sources are terpenes\ monosaccharides\ and amino acids[ For example\ camphor!derived auxiliaries
"Equations "37# and "38## ð72TL2102\ 76T0858Ł and oxazolinones originating from amino acids such
as valine ð71JA0626Ł often provide products in high enantiomeric excess[ An interesting double
alkylation of a dianion has recently been reported which uses Evans| oxazolinone auxiliary to
control the alkylation "Equation "49## ð82T3036Ł[ Each alkylation appears to be controlled locally
with no long!range e}ects being detected[ Another useful amino acid!derived auxiliary is the bicyclic
lactam pioneered by Romo and Meyers ð80T8492Ł\ which has found a variety of applications
including the synthesis of chiral\ nonracemic quaternary centers "Equation "40## ð82JOC6496\
82TL6690Ł[ While the source of all chirality must ultimately be natural\ there are many auxiliaries
that are prepared in nonracemic form by resolution and their relationship to natural products is
not obvious[ For example\ highly stereoselective a!alkylations can be achieved using acyl iron
reagents ð74CC198\ 74TL2964\ 75CC384Ł[ While an acetyl group can be alkylated twice\ the resulting
a\a?!disubstituted acyl iron reagents are not enolizable[ Therefore a conjugate additionÐalkylation
sequence is required "Equation "41## ð75CC384Ł[ Products are generally formed as single dias!
tereoisomers[ 1\1?!Binaphthol has been used as an auxiliary for the asymmetric alkylation of the
derived crotonic ester ð80TL6170Ł[ Deprotonation with LDA and alkylation gives the a!substituted
esters exclusively in yields ranging from 21 to 72)\ de r79) "Equation "42##[ A new polycyclic
oxazolinone has been employed for asymmetric alkylations of amide derivatives ð83TL610Ł[ Yields
are generally excellent and products are consistently isolated with diastereomeric ratios ×039 ] 0^ in
some cases only a single diastereoisomer is detectable "Equation "43##[
i, LICA, THF, –80 °C

ii, PhCH2Br, HMPA, THF, –63 °C
N N (48)
O2S 89% O2S Ph
O O
Ph de 94% Ph
O O
LICA = lithium isopropyl cyclohexyl amide
i, LICA, THF, HMPA, –80 °C

ii, PhCH2Br, –63 °C
N N (49)
O 2S O 94% O2S O Ph
Ph de 90% Ph
O O
O O O O O O
O O
i, NaHMDS, THF, –78 °C
( ) ii, MeI, –78 °C ( )
N n N N n N
O O O O (50)
n = 4, 48% (dr ≥ 20 : 1)
n = 5, 68% (dr = 9.8 : 1)
Ph Ph Ph Ph
H H
O i, LDA, R1X O R1
ii, LDA, R2X
N N (51)
88–99%
R2
O de 52–88% O
CO CO
Ph2 i, BunLi, THF, –78 °C Ph2 Et
P ii, EtI, –78 °C P
Fe Fe Bun (52)
82%
O O
i, LDA, THF-HMPA, –78 °C

OH ii, PriI, –78 °C to –45 °C OH
(53)
O 64% O
de 80%
O O
O O
N i, LDA N R
O ii , RX O
O O (54)
100%
de > 99.6%
RX = Ph Br , allylBr
Ph
O i, LiBr, toluene O
N ii, PhCH2Br
+ N (55)
Ph
Li O 89%
MeO ee 92%
Alternatively\ asymmetry can be introduced in a!alkylations with the chiral auxiliary present but
bonded in a noncovalent fashion^ however\ results thus far have been variable[ Chiral lithium amide
bases can be used to e}ect enantioselective deprotonations and subsequent alkylations ð80TA0\
82TA0846Ł^ for instance\ Koga and co!workers have used a phenylglycine!derived lithium amide to
give enolates that can be alkylated in up to 81) enantiomeric excess with reactive haloalkanes
"Equation "44## ð89CC0546Ł[ Lithium bromide is essential for high optical yields\ and the enanti!
oselectivity is due to an enolate ] LiBr ] chiral amine complex[ Asymmeteric a!alkylations have also
been mediated by secondary ð82TL0852Ł and tertiary amines ð78CPB0019Ł\ and by ammonium salts
under phase transfer conditions ð76JOC3634Ł^ however\ in most cases the optical yields vary over a
wide range[
0[93[2[2 Oxygen Stabilized Carbanions

The chemistry described in this section is concerned solely with a!oxygenated carbanions\ with a
fuller discussion of enolates being found in Section 0[93[2[1[ While oxygen is a p!donor and might
be expected to destabilize a negative charge on atoms directly bonded to it\ its relatively high
electronegativity means that oxygen substituents can act to stabilize carbanions by inductive or s!
e}ects[ Theoretical studies by Schleyer et al[ suggest that bridged geometries may contribute to the
stabilizing in~uence ð73JA5356Ł[ The methods for preparation of carbanions with a!oxy substituents
have been reviewed by Cheshire ð80COS"2#082Ł[ Direct deprotonation may seem the most attractive
method\ and reaction of tetrahydrofuran with BunLi as a route to acetaldehyde enolate is well
known to all organic chemists ð66TL2680Ł[ However\ a!metallated ethers and acetals generally cannot
be prepared by deprotonation at low temperature unless further activation "such as aryl\ alkenyl\
or alkynyl substituents# is provided[ An exception was demonstrated by Corey and Eckrich\ where
t!butyl methyl ether "used as solvent in the reaction# was treated with Schlosser|s base BusLi:ButOK
at −67>C giving the lithio species which was alkylated with benzyl bromide in 72) yield "Equation
"45## ð72TL2054Ł[ Facile removal of the t!butyl group results in the ether acting as an overall
hydroxymethyl anion equivalent[
BusLi, ButOK PhCH2Br

ButOMe ButO (56)
ButO Li Ph
–78 °C 83%
Both the groups of Evans ð63JA4459Ł and Still ð63JA4450Ł have examined the deprotonation and
subsequent alkylation reactions of allyl ethers[ Treatment of alkyl or silyl allyl ether with BusLi at
low temperature "below −54>C# gave resonance!stabilized carbanions which could be quenched
with haloalkanes to give a mixture of a! and g!alkylated ethers^ in almost all cases\ the g!regioisomer
dominated[ Evans et al[ found that the proportion of g!alkylation "Equation "46## depended on the
nature of the alkyl moiety of the ether "a ] g ratios varied from ¼0 ] 0 to ¼09 ] 0#\ but that other
factors such as solvent or temperature had little e}ect[ Still and MacDonald showed that allyl silyl
ethers gave excellent yields of alkylated material where g!alkylation again dominated in most cases\
although the proportion depended on the structure of the haloalkane "Equation "47## ð63JA4450Ł[
The proportion of a!substituted allyl ether was lowest for small primary alkyl halides and sig!
ni_cantly greater for secondary haloalkanes^ when cyclohexyl iodide was used as alkylating agent\
the a!regioisomer was the major product[ Substitutions displayed the usual halogen dependency\
the highest yields being obtained for iodides and bromides "with yields typically ×84)#\ with
chlorides giving poor conversions[
i, BusLi
ii, n-C6H13I RO
RO + RO C6H13 (57)
75–95% C6H13
α-substituition γ-substituition
R THP Et But
α:γ 46 : 54 25 : 75 11 : 89
i, BusLi, –78 °C, THF

ii, RI, HMPA Et3SiO R
Et3SiO + (58)
>70% R OSiEt3
α-substituition γ-substituition
R Me Pri cyclohexyl
α:γ 3 : 97 40 : 60 61 : 39
The introduction of extra stabilization as two aryl groups allows formation and alkylation of
C\O!dilithiated compounds[ Yus and co!workers have shown that benzophenones may undergo
two successive single electron transfer "SET# reduction steps on treatment with Li:naphthalene for
09 min at −29>C to give dilithio species which can be alkylated selectively on carbon\ generally in
good to excellent yields "Equation "48## ð82T0216Ł[ However\ the reaction occasionally proved to be
unpredictable^ whereas methylation of the dianion derived from benzophenone proceeded smoothly
giving methyl diphenyl carbinol in 81) yield\ similar treatment of ortho!tolyl phenyl ketone gave
only 21) of the desired material along with 40) of a ring!methylated\ deoxygenated compound
"Equation "59##[ The temperature and timing of the reaction are vital for successful alkylation^ Fry
and co!workers showed that benzophenone and other diaryl ketones\ on sonication with Li:3\3?!
di!t!butylbiphenyl at room temperature for 13 h\ and subsequent alkylation\ gave C!alkylated\
deoxygenated products exclusively ð89TL5044Ł[ Substitution on carbon most likely precedes deoxy!
genation\ and treatment of the original C\O!dilithio species with two di}erent electrophiles provides
a novel method for dialkylation "Scheme 16#[
i, Li, C10H8, THF, –30 °C
O ii, EtBr Et OH
(59)
Ph Ph 96% Ph Ph
O i, Li, C10H8, THF, –30 °C OH

ii, MeI
+ (60)
32% 51%
Li, But )2
THF,
O Li OLi
i, MeI
ii, EtI
96% overall yield
OLi
Li Et
Scheme 27
While nucleophilic alkyllithium reagents might ordinarily be expected to react with esters
"especially benzoates\ where a!deprotonation is precluded# by addition to the carbonyl group\ the
introduction of steric hindrance can serve to block the approach of the organometallic component
and therefore other pathways become important[ Beak and Carter ð70JOC1252Ł and Seebach and
co!workers ð67HCA401Ł have shown that benzoates with bulky groups "such as isopropyl and
t!butyl# in the 1! and 5!positions are not attacked at the carbonyl group by bases such as BusLi^
instead\ interaction with the ester carbonyl oxygen atom serves to direct lithiation to the a!position
providing a!oxygenated carbanions which could be alkylated in moderate to good yields "Equation
"50##[ The reactions were successful with a number of haloalkanes^ however\ use of benzyl halides
provided an exception since the isolated products were dimers of the organolithium reagent
ð70JOC1252Ł[ The degree of steric shielding at the carbonyl group is illustrated by the resistance of
these esters to simple hydrolysis^ cleavage could only be achieved by reductive methods "LiAlH3#[
O O Li
BusLi, TMEDA,
OMe –78 °C, THF O
BuI
50%
(79% crude)
O
(61)
Hoppe et al[ have demonstrated that the principle of deprotonation can be extended to a range
of carbamates ð89AG"E#0313Ł[ The carbamate derived from nonracemic "ee 86)# 0!phenylethanol
was deprotonated with s!butyllithium and TMEDA at −67>C to give a benzyl carbanion^ at this
low temperature\ the organolithium species is essentially con_gurationally stable[ Addition of an
electrophile "n!propyl bromide# gave a tertiary carbamate in good optical and chemical yield
"Equation "51##[ Chiral a!oxygenated organolithium reagents are also accessible by means of a novel
asymmetric deprotonation ð81AG"E#0348Ł[ Treatment of carbamates with s!butyllithium in ether at
−67>C in the presence of the chiral diamine "−#!sparteine gave the chiral a!oxy carbanion in high
diastereomeric excess ð81TL4212Ł[ Addition of iodomethane gave the secondary carbamate in 70)
yield\ ee 85) ð89AG"E#0311Ł[ Asymmetry is introduced at the deprotonation stage\ where the
s!butyllithium="−#!sparteine complex discriminates between the enantiotopic a!protons in the car!
bamate "Equation "52##[ In a related example\ Schwerdtfeger and Hoppe have demonstrated that a
neighboring chiral center can in~uence the course of metallation and subsequent alkylation steps]
deprotonation of a carbamate derived from proline gave a lithio species that was methylated in
61) yield with a diastereomeric ratio of ×84 ] 4 "Equation "53## ð81AG"E#0494Ł[ Replacement of
TMEDA by "−#!sparteine gave a lower yield of product "45)# with similar diastereoselectivity[
N(Pri)2
BusLi, TMEDA, O
O N(Pri)2 hexane, –78 °C PrnBr O N(Pri)2
O (62)
Ph Li 77% Ph
Ph O Prn O
Me2N NMe2 ee 85%
BusLi, (–)-sparteine, N
O ether, 5 h, –78 °C N
O Li
O N O C6H13 H
O N O C6H13
MeI
81%
ee 96%
O
(63)
O N O C6H13
i, BusLi, TMEDA,
ether, 3 h, –78 °C
ii, MeI
O N O O N O (64)
N 72% N
H H
O dr > 95 : <5 O
Ph Ph
a!Alkoxystannanes are versatile reagents that provide another route to a!alkoxy carbanions\ and
can be prepared by a number of methods including addition of R2Sn− to aldehydes and subsequent
alkylation of the a!stannyl alcohol ð67JA0370Ł[ These compounds can also be obtained in high
enantiomeric purity by asymmetric reduction of acyl stannanes with binaphthol!modi_ed LiAlH3
ð77JOC4473Ł or from enantiomerically pure boronic esters ð78JA3288Ł[ The carbanion can be gen!
erated by tinÐlithium exchange or reaction of the a!alkoxystannane with alkyllithium reagents[ This
method provides a mild and regiospeci_c procedure for generation of these important carbanionic
intermediates^ lithio species which are not otherwise accessible by direct deprotonation can be
prepared and alkylated in high yields "Scheme 17# ð67JA0370Ł[ The tinÐlithium exchanges are reported
by McGarvey and co!workers to proceed most satisfactorily in dimethoxyethane as a solvent
ð73JA2265Ł[ An important feature of the a!alkoxyorganolithium species is their con_gurational
stability at low temperatures^ the additional chelation which is available in acetal groups further
increases the barrier to inversion "and hence racemization# of the organolithium species ð79JA0190Ł[
The a!alkoxystannane is converted to the lithio reagent with retention of con_guration\ and sub!
sequent reaction with haloalkane electrophiles also occurs with retention of con_guration
ð73JA2265Ł[ However\ while simple a!alkoxylithio reagents "especially where added benzylic sub!
stitution is present# undergo e.cient carbonÐcarbon bond formations when treated with iodoalkanes
"Equation "54##\ the reaction of the epimeric 3!t!butylcyclohexyl analogues gave very di}erent
results[ Attempted alkylation with haloalkanes "I\ Br\ Cl# gave mixtures of products corresponding
to protonation of an intermediate RLi with both retention and inversion of con_guration\ and also
a signi_cant proportion of enol ether "Equation "55##[ In general\ no alkylated material was
recovered[ No trends were apparent\ although the intervention of radical intermediates was possible
ð73JA2265\ 77JA731Ł[
O i, BusLi, THF
O
ii, MeI
O O O O
i, Bu3SnLi
ii, Cl
O O
O
O O O
95%
H Bu3Sn
i, BuLi
ii,
Cl
69%
O O
Scheme 28
i, BunLi, DME
O OMe O OMe
ii, BunI
(65)
SnMe3 92%
Ph Ph
O OMe
Li
Ph
i, BunLi
O OMe ii, BunI
But SnBu3
O OMe H O OMe
+ + (66)
But H But O OMe But
35% 30% 35%
0[93[2[3 Sulfur Stabilized Carbanions

An assortment of di}erent sulfur!containing functional groups can be employed to stabilize
carbanions\ and allow subsequent alkylations\ with varying degrees of success[ Several aspects of
the alkylations of a!metallated sulfur!containing compounds will be described in this section^ an
excellent review by Krief of the alkylation of many classes of sulfur!stabilized carbanions has
appeared ð80COS"2#74Ł\ and more particularly the chemistry of sulfones ð66T1908\ B!77MI 093!90\
B!82MI 093!90Ł and sulfoxides ð63ACR036\ 70S074\ B!77MI 093!90\ 81TA850Ł has also been reviewed on
several occasions[ The structural features of lithio derivatives of various sulfur!containing car!
banions "such as sulfones\ sulfoxides\ and sulfoximes# have been reviewed by Boche ð78AG"E#166Ł[
Sulfur is highly nucleophilic and therefore competing alkylations on sulfur can occur[ Anions
derived from b!oxo dithioic acids are alkylated exclusively on sulfur to give the corresponding
ketenedithioacetals ð75T2918Ł[ Likewise\ a!carbalkoxyenethiols\ which can be regarded as tautomers
of a!thioketoesters "thiopyruvates#\ can be deprotonated with sodium hydride and alkylated on
sulfur "Scheme 18# ð74JOC2565Ł[ Deprotonation of thiols with 0 equiv[ of base leads to the cor!
responding thiolate^ additional stabilization provided by allyl or benzyl substituents allows a second
deprotonation to take place a to the sulfur atom when allyl or benzyl thiolates are treated with
a second equivalent of a strong base such as BunLi=TMEDA[ The C\S!dianion derived from
phenylmethanethiol "benzyl mercaptan# can be dialkylated with either an excess of a haloalkane\
or with 0\2!dibromopropane giving 1!phenyltetrahydrothiophen "Equation "56## ð63AG"E#191Ł[
1!Propenethiol can likewise be deprotonated twice under similar conditions "BunLi\ TMEDA\
9>C# and the resulting dianion can be alkylated successively with two electrophiles[ The reactivity
of the two anions di}ers su.ciently to permit speci_c alkylation on carbon to occur _rst\ although
the allyl anion is alkylated with modest g!regioselectivity ranging from 1 ] 0 to 3 ] 0 ð63AG"E#368Ł[
The g!alkylation is stereoselective\ giving the "Z#!alkene with ×84) control "Equation "57##[ While
addition of HMPA can reverse the regioselectivity of alkylation on carbon\ product ratios are
generally no better than 3 ] 0 ð66CB0722Ł[
O
OTHP OTHP NHCO2CH2Ph OTHP
Ph2CHO
NaH/DMSO I CO2CHPh2
SH S– Na+ 66%
S
NHCO2CH2Ph
CO2Me CO2Me CO2Me
Scheme 29
SH i, BunLi, TMEDA,
THF-pentane, –5 °C S
ii, Br(CH2)3Br
(67)
67%
i, BunLi, TMEDA
ii, PriCl
iii, PhCH2Br
SH + (68)
S Ph S Ph
54% 26%
While a range of di}erent types of reactions can be considered for formation of a!thio organ!
ometallic compounds from thioethers "dialkyl sul_des#\ the simplest and most direct approach uses
the acidifying e}ect of the sulfur substituent to facilitate deprotonation[ Simple thioethers can be
deprotonated a to sulfur using strong bases such as BunLi\ either alone or in the presence of
complexing reagents such as TMEDA\ 0\3!diazabicycloð1[1[1Łoctane\ "dabco# and HMPA[ Anions
derived from simple dialkyl sul_des are quite basic\ and alkylation reactions are often plagued by
competing elimination ð56JOC0606Ł[ Peterson has shown that dimethyl sul_de can be deprotonated
and monoalkylated with 0!bromodecane in 21) yield^ however\ metallation of higher alkyl sul_des
led to decomposition\ presumably via b!elimination "Equation "58##[ Reasonable yields of alkylated
materials can be obtained using anions derived from alkyl phenyl sul_des\ for example\ Corey and
Seebach have shown that thioanisole can be metallated at 9>C by BunLi in the presence of dabco\
and the resulting phenylthiomethyllithium reagent can be alkylated with 1!iodopropane to give
substituted material in 44) yield ð55JOC3986Ł[ Dolak and Bryson have similarly reported successful
alkylations^ however\ attempted benzylation gave only stilbene "67)# and unchanged sul_de "Equa!
tion "69## ð66TL0850Ł[
BunLi, TMEDA
SMe (69)
42%
i, BunLi, THF-HMPA, –78 °C

ii, RX, –78 °C to RT PhS (70)
PhS
R
R Yield(%)
Et 79
Allyl 82
PhCH2 78 (stilbene)
Coordination!directed metallation of an SMe group has been used by Block and Aslam in an
e.cient approach to a synthetic equivalent for the methanethiol carbanion HSCH− 1 ð74JA5618Ł[
Protection of the sulfur with the 1!"tetrahydropyranyl# and 1!"tetrahydrofuranyl# groups provides
a reagent that is cleanly metallated on the S!methyl group^ there was no evidence of deprotonation
at the tertiary position between oxygen and sulfur[ This result is in contrast to the exclusive
metallation of 0\2!oxathianes on C!1 ð74JOC546Ł^ Block and Aslam have attributed the facile
deprotonation of the S!methyl group to a favorable oxygenÐlithium interaction directing the base\
as well as steric hindrance and decreased acidity of the tertiary hydrogen ð74JA5618Ł[ The stabilized
carbanion can be alkylated with bromo! and iodoalkanes in 38Ð87) yields "Equation "60##[
i, ButLi, THF-HMPA, –90 °C

ii, Br(CH2)6Br
(71)
O SMe 98% O S S O
( )6
Alkyl vinyl sul_des are deprotonated selectively on the sp1 carbon atom giving a vinyllithium
species which can be alkylated in good to excellent yields "41Ð89)# and which\ ultimately\ can be
viewed as an acyl anion equivalent[ Yamamoto and co!workers extended the procedure to the
dialkylation of a\v!dihaloalkanes giving\ ultimately\ diketones in good yield ð62JA1583Ł[ However\
while 0\3!dibromobutane gave a 59) yield of 1\6!octanedione\ a similar reaction with 0\2!dibromo!
propane gave the aldol product 2!methylcyclohex!1!enone "Scheme 29#[ Allyl and propargyl sul_des
are metallated a to sulfur in the unsaturated group giving resonance!stabilized carbanions where
subsequent alkylations generally occur selectively a to sulfur[ An intramolecular variant has been
used by Vedejs et al[ to prepare 1!vinyltetrahydrothiophen "Equation "61## ð67JOC0074Ł[ Depro!
tonation of 1H!thiopyran using alkali metal amides leads to a resonance!stabilized anion which can
be alkylated with t!butyl bromide in up to 43) yield exclusively a to sulfur "Equation "62##
ð67CC485Ł^ this reaction illustrated one of the few successful alkylations with a tertiary haloalkane[
Alkylation of the stabilized carbanion with bromocyclohexane gives a mixture of 1! and 3!substituted
products in an 74 ] 04 ratio[ The lithiation and alkylation of allyl vinyl sul_de occurs exclusively on
the allyl moiety^ however\ the regioselectivity of the alkylation depends upon the metallation
conditions[ While alkylations of carbanions derived from metallation with BunLi=dabco proceed
with modest a ] g selectivity "¼6 ] 2#\ deprotonations using BusLi in the absence of added complexing
agents leads to an allyl anion that can be alkylated with ×84) a!selectivity ð62JA1582Ł[ "This
regiocontrol is in contrast with results obtained with 1!propenethiol dianions ð63AG"E#368Ł[# As
expected\ the highest yields are obtained with bromides and iodides\ and chloroalkanes are con!
siderably less reactive[ Yamamoto and co!workers have demonstrated that the alkylated products
will undergo a thio!Claisen rearrangement and subsequent hydrolysis when treated with CaCO2 in
hot aqueous DME\ providing a convenient synthesis of g\d!unsaturated aldehydes "Scheme 20#
ð62JA1582Ł[ The rearrangement gives the "E#!alkene selectively\ contaminated with less than 0) of
the "Z#!isomer[ Negishi et al[ have studied the alkylation of 2!"phenylthio#prop!0!yne^ 1 equiv[ n!
butyllithium generate an a\g!dianion which is selectively alkylated by allyl bromides a to the
sulfur substituent in excellent yields "Equation "63## ð70JOC4930Ł[ The corresponding sulfoxides and
sulfones do not give coupled products in signi_cant yields under similar conditions[
SEt BusLi, THF–HMPA, –78 °C Li SEt
i, Br(CH2)3Br i, Br(CH2)4Br
ii, HgCl2, MeCN-H2O ii, HgCl2, MeCN-H2O
52% 60%
O O
O
Scheme 30
Br LDA, THF, –70 °C

(72)
85% S
S
i, KNH2, –65 °C
ii, ButBr
(73)
S S But
C8H17 C8H17
i, BusLi, THF, –78 °C CaCO3, DME, H2O 57%
S ii, n-C8H17Br S reflux S (over 3 steps)
C8H17
Scheme 31
i, BunLi (2 equiv.)
ii,
Br
(74)
SPh 83% SPh
The e}ect of varying the oxidation state of sulfur on the acidity of neighboring hydrogen atoms
can be judged by considering the pKa values as determined by Bordwell and co!workers] methyl
phenyl sulfone "18[9# and dimethyl sulfone "20[0# are more acidic than dimethyl sulfoxide "24[0#\
and methyl phenyl sul_de "thioanisole^ extrapolated value ¼39# ð64JA6995\ 67JOC2090Ł[ Thus\ it is
apparent that the higher valence sulfur!containing functional groups have more marked acidifying
e}ects and will lead to more stabilized carbanions[
The anion derived by deprotonation of dimethyl sulfoxide with strong bases such as sodium
hydride\ which is often referred to as the dimsyl anion\ can be alkylated with primary alkyl bromides
to give coupled products in good yields ð54CC18Ł[ However\ attempted benzylation fails ð54JA0234Ł^
the highly basic nature of the carbanion leads to the formation of trans!stilbene "31)# plus {{an oily
mixture of sulfoxides[|| A similar reaction between the dimsyl anion and benzhydryl chloride gives
tetraphenylethene in 87) yield[ In general\ sulfoxides can be deprotonated with lithium amides or
methyllithium at low temperatures^ use of n! or t!butyllithium promotes carbonÐsulfur bond cleavage
in addition to a!metallation ð63CJC650Ł\ and t!butyllithium also racemizes aryl t!butyl sulfoxides
within minutes at −67>C[ Trost and Bridges have demonstrated that aryl benzyl sulfoxides are
readily deprotonated by lithium N!isopropylcyclohexylamide and the resulting anions are alkylated
with allyl bromides or primary alkyl iodides ð64JOC1903Ł^ thermolysis of the substituted products
gives alkenes in 30Ð76) yields "Scheme 21#[ Allyl sulfoxides can likewise be deprotonated\ and
alkylations proceed with predominant a!regiocontrol ð63ACR036Ł[
Li O
N
i, S Ph
O Ph
DME, reflux Ph
S Ph O O
Ph ii, 57%
O O O
I
O
Scheme 32
Unsymmetrical sulfoxides are chiral at sulfur and therefore a!sul_nyl carbanions are diastereo!
meric and the possibility of diastereoselective alkylation exists[ Durst et al[ have shown that
unsymmetrical alkyl benzyl sulfoxides can be deprotonated selectively at the activated "benzylic#
position\ and the resulting a!lithiosulfoxides can be methylated to provide substituted sulfoxides
with varying diastereoselectivity ð60JA2966Ł] methylation of benzyl phenyl sulfoxide gave a 67)
yield of monomethylated product as a 0[4 ] 0 mixture of isomers\ whereas benzyl t!butyl sulfoxide
gave a 84) yield as a single diastereoisomer "Equation "64##[ The intermediate a!lithio sulfoxide is
deuteriated or carboxylated with retention of con_guration^ methylation occurs with inversion[ The
con_guration of the sulfoxide is una}ected throughout the reaction[ The mechanism of the reaction
has been discussed extensively ð60JA2966\ 75BCJ1790\ 76JOC0303\ 80COS"2#74Ł[
O But
i, ii, iii SO2
: S (75)
But H
95%
Ph Ph
i, MeLi, THF, –60 °C; ii, MeI (product as a single diastereoisomer); iii, mcpba
Diastereoselective alkylations using sulfoxide!stabilized carbanions have been reviewed

ð81TA850Ł^ an example is the use of the sulfoxide to direct alkylation in the synthesis of biotin
and biotin analogues ð67JA0447Ł[ Deprotonation was best e}ected with methyllithium^ use of n!
butyllithium gave 19Ð14) carbonÐsulfur bond cleavage in addition to low yields of the desired
product[ In all cases the alkylation product was accompanied by some recovered starting material\
which arose from reprotonation of the anion "presumably by enolization of the ester# as carbanion
formation was essentially complete[ Addition of HMPA led to higher yields of alkylated material[
A second alkylation could be carried out to give a\a?!disubstituted products with the two alkyl
substituents in a cis!relationship "Scheme 22#[ Bravo et al[ have shown that alkyl p!tolyl sulfoxides
can be deprotonated with LDA or lithium tetramethylpiperidide "LITMP# at −64>C in THF and
alkylated with lithium a!bromomethyl acrylate to give diastereomeric products in 44Ð77) yields
with variable diastereoselectivities "de 11Ð89)# "Equation "65## ð74TL1802Ł[ Marginally better
selectivities\ but slightly lower yields\ were obtained using a more hindered base "LITMP#[
O O O
Bn Bn i, MeLi, DIGLYME Bn Bn i, MeLi, DIGLY ME Bn Bn

N N N N N N
ii, MeI ii, I(CH2)4CO2But
H H H H H H
84% 57% ButO2C
S S ( )4 S
O O O
Scheme 33
i, LITMP
ii, CO2Li CO2H
Br
p-Tol p-Tol (76)
S 75% S
O de 68% O
:
:
Cyclic sulfoxides*especially those with bulky substituents that can act as conformational
{{anchors||*are alkylated with high diastereoselectivities[ Simpkins and co!workers have studied
the alkylations of a 3!silyloxy thiopyranyl derivative\ where deprotonation with LDA and alkylation
with reactive haloalkanes gives excellent yields of products as single diastereoisomers[ In a similar
manner to the biotin synthesis described above\ a second alkylation can be e}ected in the a?!position
with excellent diastereoselectivity^ the 1\5!cis product is formed\ contaminated by only minor
amounts of the 1\5!trans isomer ð81SL086Ł[ Attempted asymmetric deprotonation with an enanti!
omerically pure lithium amide base gave\ following subsequent methylation\ the 1!methyl derivative
in excellent yield and diastereoselectivity\ but with only modest enantioselectivity "Equation "66##
ð82JCS"P0#2988Ł[
Li
OSiPh2But i, OSiPh2But
N
Ph
ii, MeI
(77)
81%
S ee 55–60% S
O O
a!Sulfonyl carbanions have become the most widely used of the sulfur!stabilized carbanions as a
result of their synthetic versatility and\ ultimately\ their facile removal[ A sulfonyl group will act as a
temporary activating substituent to direct alkylation\ and desulfonylation is possible under reductive
conditions ðB!77MI 093!91\ 80TL0838Ł^ substitution of the sulfonyl moiety using organometallic
reagents is possible with vinyl ð89T5840Ł and allyl ð72T2172Ł sulfones^ sulfones are increasingly useful
in alkene synthesis\ especially utilizing the Ramberg!Backlund ð57ACR198\ 66OR"14#0Ł and the Julia
ð62TL3722\ 74PS"13#86Ł reactions[ The required a!sulfonyl carbanions can be prepared by various
routes including conjugate nucleophilic addition to vinyl sulfones ð67JA235Ł^ however\ the simplest
and most widely used process simply involves deprotonation with strong bases such as alkali
metal amides "including the dialkylamides such as LDA#\ sodium hydride\ alkyllithiums\ and even
potassium alkoxides[ Dimethyl sulfone can be deprotonated with 1 equiv[ sodium amide and
alkylated with 0!bromobutane giving di"n!pentyl# sulfone in 44) yield ð62JOM"48#42Ł[ The greater
acidity of a!protons "compared with sulfoxides# means that bases such as n!butyllithium can be used
without competing carbonÐsulfur bond cleavage intervening^ alkylations with primary haloalkanes
can be e}ected in excellent yields "Equation "67## "for example\ ð64TL0996Ł#[ In contrast\ while
organomagnesium compounds are also e}ective bases for a!deprotonation\ the resulting a!sulfonyl
Grignard reagents give only modest yields of coupled products on treatment with haloalkanes
ð48JA1461Ł[ However\ Eisch and Galle have demonstrated that an a!sulfonyl Grignard reagent\
prepared by conjugate addition of certain organomagnesium halides to 2!bromo!0!"phenylsulfonyl#
propene\ can undergo an intramolecular alkylation giving cyclopropanes in 39Ð65) yields as single
stereoisomers "Scheme 23# ð68JOC2166Ł[
i, BunLi, THF, –75 °C
ii,
PhO2S O SO2Ph
I
(78)
O 86%
O
SO2Ph R MgX H SO2Ph

RMgX
Br R H
Br SO2Ph
R = allyl, 76%; propargyl, 50%; Ph, 40%; PhCH2, 54%; Me, 0%, Et, 0%; But, 0%
Scheme 34
In general\ the alkylation of sulfones proceeds with good mono]dialkylation control[ However\
Pine et al[ have shown that deprotonation and subsequent alkylation of methyl phenyl sulfone
at 9>C gives signi_cant levels of dialkylated material\ with the ratio being relatively una}ected
by reversing the order of addition ð89JOC1123Ł[ Primary haloalkanes give products with a
mono ]dialkylation ratio of ¼2[5 ] 0\ and reactive "allyl\ benzyl# haloalkanes give signi_cantly more
dialkylated material[ Dialkylation is a stepwise process^ despite the lower acidity of the a!protons
in the monoalkylated material compared with the starting sulfone\ proton transfer occurs to give a
low concentration of a more reactive\ substituted a!sulfonyl carbanion which is then alkylated at a
signi_cantly faster rate ð89JOC1123Ł[ Addition of TMEDA leads to only a marginal increase in the
proportion of monoalkylated material\ however\ changing the counterion to potassium\ which will
reduce ion pairing\ gives a much higher mono ] dialkylation ratio "Scheme 24#[
i, KH, 0 °C, THF i, BunLi, 0 °C, THF Bun

ii, BunBr, 0 °C ii, BunBr, 0 °C PhO2S Bun +
mono:dialkylation ratio = 21 PhSO2Me PhO2S
Bun
mono:dialkylation ratio = 3.5
(4.2 in the presence of TMEDA)
Scheme 35
Sulfonyl alkenes are readily metallated by strong bases\ giving a!sulfonyl vinyllithium reagents
which can be alkylated in good to excellent yields ð68JOC2168\ 76TL878\ 78JOC0380Ł[ The metallating
reagent must be chosen carefully as conjugate addition of the base can compete^ for instance\ while
s! and t!butyllithium satisfactorily deprotonate a g!morpholino vinyl sulfone\ n!butyllithium gives
a 0 ] 0 mixture of a!vinyllithio and b!butyl a!lithioalkyl species "Scheme 25# ð82TL1992Ł[ However\
the problem is apparently substrate dependent\ as others have reported no problems with n!butyl
ð76TL878Ł and methyllithium ð68JOC2168\ 78JOC0380Ł[ Eisch and Galle have developed an alternative
route to circumvent this problem] conjugate addition of dimethyl amine gives the b!amino sulfone
which can then be deprotonated with n!butyllithium and alkylated with iodoalkanes a to the sulfone
ð79JOC3423Ł[ Quaternization of the nitrogen and elimination with NaOH generates the a!substituted
vinyl sulfone[ Allyl sulfones are readily deprotonated to give resonance!stabilized carbanions which
can be selectively alkylated a to sulfur ð80COS"2#74Ł[ An intramolecular variant leading to meth!
ylenecyclopropanes has been studied by Je}ery and Stirling ð82JCS"P1#0506\ 82JCS"P1#1052Ł[ 1\4!Dihy!
drothiophen!S\S!dioxides "ð81T7852Ł and references therein# and 1\6!dihydrothiepin!S\S!dioxides
ð82SL718Ł can be alkylated selectively a to the sulfonyl group in satisfactory yields and therefore
provide synthetic routes to substituted butadienes and hexatrienes respectively[ Deprotonation and
alkylation of the thiophen dioxide can be carried out satisfactorily at −67>C\ whereas the thiepin
is somewhat more sensitive and reactions must be e}ected below −099>C "Equation "68##[
p-TolSO2
O BusLi, –78 °C
Li N
p-TolSO2 N
O
BunLi
MeI
90%
Bu
p-TolSO2
p-TolSO2 O
Li N + p-TolSO2 N
Li N
O
O
Scheme 36
O2 O2
S i, BunLi, THF-HMPA, –105 °C S
ii, MeI
(79)
57%
Treatment of alkyl sulfones with an excess of strong base can lead to the formation of dimetallated
species ð45JA81\ 66T1908\ 78AG"E#166Ł[ Where a!protons are available on both alkyl residues\ a\a?!
dimetallated intermediates are formed which lead to a\a?!dialkylated products on reaction with
haloalkanes "Equation "79## ð66OS"46#42Ł^ where only one a!site is available for deprotonation\ then
a\a!dianions can be formed and dialkylated[ Eisch et al[ have shown that the dianion of methyl
phenyl sulfone reacts with a\v!dihalides to give cyclic products ð74JOC2563Ł[ Studies by Gais and
Vollhardt ð77TL0418Ł suggest that\ with alkyl phenyl sulfones\ the o\a!dilithio species is formed
initially which subsequently rearranges at higher temperatures to the a\a!dilithio compound
ð80COS"2#74Ł[
H H
i, BunLi (2 equiv.), –78 °C
ii, MeI, –78 °C to RT
SO2 SO2 (80)
87%
H H
A _nal point of interest concerns the con_gurational stability of the a!sulfonyl carbanions[ While
the intermediate carbanions are chiral "ðB!82MI 093!90Ł and references therein#\ in general they are
not con_gurationally stable and racemization is fast even at low temperatures[ Exceptions are
tri~uoromethyl ð78AG"E#0914Ł and t!butyl sulfones ð81JA3328Ł\ where chiral nonracemic a!lithio
species can be generated "CF2SO1C"Li#"Me#CH1Ph has an extrapolated half!life of 29 days at
−67>C\ whereas the t!butyl analogue has t0:1 2 h at −094>C# and subsequently alkylated with
good enantioselectivity[ However\ racemic "or substantially racemized# products can usually be
expected] Williams et al[ have studied the deprotonation and alkylation of epimeric 4!"phe!
nylsulfonyl#bicycloð1[1[1Łoct!1!enes and reported that while the alkylations are stereoselective\ they
never give just one product^ the stereoselectivity results from other structural features in the molecule\
not from the geometry of the parent sulfones "Equations "70# and "71## ð89JOC2739Ł[
i, BunLi, HMPA-THF, –78 °C

+ (81)
93% SO2Ph
SO2Ph SO2Ph
3.3:1
i, BunLi, HMPA-THF, –78 °C

+ (82)
SO2Ph 88% SO2Ph
SO2Ph
4.8:1
The sulfoximine is a sulfur!containing functional group at the same oxidation level as a sulfone
which possesses the additional bene_t of chirality at sulfur\ and therefore diastereoselective
alkylations become possible[ However\ reports thus far have been sporadic and results less than
encouraging "ð75AG"E#824Ł\ for example#[ S!Allyl sulfoximines are deprotonated readily with
n!butyllithium\ and the resulting anions can be alkylated in 43Ð70) yield with primary haloalkanes
ð80TL5386Ł[ While the alkylations occur with complete regioselectivity a to sulfur\ the dias!
tereoselectivity is poor "0 ] 0 to 1 ] 0# "Equation "72##[ More positive results have been reported
recently by Trost and Matsuoka using N!nitrosulfoximines ð81SL16Ł[ It was anticipated that the
strongly electron!withdrawing N!nitro group would increase the acidity of the a!hydrogens and also
improve the con_gurational stability of the carbanion through a shortening of the a carbonÐsulfur
bond[ Deprotonation of the S!methyl group could be e}ected with sodium hydride "preferred for
the _rst alkylation# or lithium hexamethyldisilazide "LiHMDS#[ The latter reagent is preferred for
the second step as the stronger ion!pairing between Li¦ and the sulfoximinyl carbanion leads to
greater diastereoselectivity compared with Na¦ or K¦[ An attempted metallation with n!butyl!
lithium led to decomposition of the N!nitrosulfoximine[ The _rst alkylation of the S!methyl group
was carried out in 37Ð58) yield\ and the a\a!dialkylated material was then obtained in 49Ð85)
yield "Scheme 26#[ When the second alkylation is carried out at −67>C\ diastereomeric ratios
approaching 09 ] 0 are attainable[
Ph Ph
N N
p-Tol S ii, RX p-Tol S
O O (83)
R
RX Yield(%) d.r.
MeI 69 1:1
EtI 81 1:1
PrnBr 54 1.3:1
i, NaH
ii,
O O O O i, LiHMDS O
Ph S Ph I O O Ph ii, MeI O O Ph
S S
Me N 69% Ph N 88% Ph N
NO2 d.r. 8:1
NO2 NO2
Scheme 37
Sulfonamides can likewise be expected to activate a!hydrogen atoms towards direct deprotonation
by strong bases\ and simple sulfonamides can be double deprotonated by treatment with strong
bases such as LDA to give a\N!sulfonamide dianions[ However\ addition of iodomethane to the
species generated from methanesulfonamide gave\ in addition to unchanged starting material\
N\N!dimethylmethanesulfonamide as the major product with only a trace of C!alkylated material
ð73JOC0699Ł[ Davis et al[ have similarly reported a failure to alkylate the dianion derived from
benzylsulfonamide ð89TL0542Ł[ Introduction of a bulky group on nitrogen hindered alkylation at
that site and Ca!alkylated material was isolated in good yields "Equation "73##^ N!alkylation was
e}ectively suppressed ð73JOC0699Ł[
H i, 2 LDA H
ii, Ph Br
N Ph N (84)
MeO2S But 82% S But
O2
Davis et al[ have developed an e.cient route to nonracemic a!substituted sulfonamides using
camphor!based chiral auxiliaries[ Deprotonation of a camphor N!sulfonylimine with 0 equiv[ LDA
gives an azaenolate which is alkylated exclusively on nitrogen ð78TL0502Ł[ A second equiv[ of a
strong base allows generation of a dianion where the second site of metallation is a to sulfur[
Benzylation occurs exclusively a to sulfur in excellent yields^ however\ the products are isolated as
a ¼0 ] 0 mixture of diastereoisomers ð78TL0502\ 80T062Ł[ In general\ camphor N!sulfonylimines give
dianions on treatment with either 1 equiv[ n!butyllithium or 2 equiv[ LDA^ while better results are
obtained with LDA\ the enantiomeric purities of the a!substituted sulfonamides "which can be
liberated from the auxiliary by treatment with ethanolic HCl# are unacceptable[ Signi_cantly\
alkylation a to sulfur can only be e}ected on the dianion] deprotonation of the fenchone
N!sulfonylimine "which is incapable of forming an azaenolate# gives a sulfur!stabilized carbanion
which cannot be alkylated ð89TL0542Ł[ Improved diastereoselectivities are obtained on alkylation of
dianions derived from the N!sulfonylimines of camphorsulfonamides "Scheme 27#^ in these cases
a!alkylated benzylsulfonamides are obtained with enantiomeric excesses in the range 55Ð84)\ with
lower optical yields resulting from the alkylation of ethanesulfonamides ð82JOC3789Ł[
0[93[2[4 Nitrogen Stabilized Carbanions

Although the lone pair on nitrogen in an amine would be expected to destabilize a carbanion on
a neighboring carbon atom by p!donation\ the higher electronegativity of nitrogen relative to carbon
means that\ in a similar manner to a!oxygenated species\ a nitrogen substituent is able to stabilize
a negative charge by an inductive mechanism[ Consequently hydrogen atoms on a!carbon atoms in
R
i, 3 LDA, –78 °C HCl, EtOH R
Ph ii, RX Ph reflux
N S N S H2N
SO2 O2 SO2 O2 S Ph
O2
N N
RX Yield(%) ee(%)
MeI 82 75
PhCH2Br 79 93
Me2CHI 58 90
Scheme 38
amines are rendered slightly acidic\ and tertiary amines such as triethylamine can be metallated by
n!butyllithium[ The resulting s!stabilized carbanions can be alkylated in low "03Ð14)# yields with
n!iodobutane ð55JOC1950Ł[ N!Methylpiperidine and other N!methyldialkylamines can be selectively
deprotonated on the N!methyl carbon atom using one of Schlosser|s mixed base systems\ BusLi:
ButOK\ at 9>C^ the resultant anions can be alkylated in good yields ð73TL0242Ł[ However\ the
metallation of alkyl groups attached to nitrogen using this method is by no means universal\ for
example\ N\N!dimethylaniline is only metallated in the phenyl ring\ predominantly in the ortho
position ð55JOC1936Ł[ In addition\ deprotonation of unmodi_ed secondary and primary amines on
a!carbon atoms is not feasible owing to the higher acidity of the amino hydrogen atoms[ None the
less\ these classes of amines and other nitrogen!containing molecules can be deprotonated and
e.ciently alkylated via a wide variety of derivatives] conjugating groups can be employed to
delocalize the negative charge and stabilize the anion "as in benzylamines and N!allylamines#\
electron!withdrawing substituents on nitrogen can establish dipoles "as in N!nitrosoamines#\ and
heteroatom!containing groups can be used to direct deprotonation and stabilize the resulting
organometallic reagent by chelation "such as amides#[ An extensive and systematic review of a!
metalloamine synthetic equivalents has been published ð73CRV360Ł[ Nitrogen substituents can also
participate in the stabilization of negative charges\ usually by conjugation\ in a number of classes
of compounds including oximes\ nitriles\ and hydrazones[ Many examples in this latter group of
stabilized carbanions have been developed as solutions to the problem of ketone alkylation[
One e}ective route to activation of a!hydrogen atoms involves the preparation and use of
N!nitrosoamines ð64AG"E#04Ł[ Deprotonation a to nitrogen is e}ected using bases such as BunLi or
LDA\ and the resulting dipole!stabilized anions can be alkylated with a range of primary and other
activated haloalkanes in typically 59Ð84) yields[ However\ the potential risks associated with this
class of compounds would suggest that\ except in rare cases where other methods fail\ alternative
approaches are preferable[ One such approach\ similar to the coordination!directed deprotonation
of sterically encumbered benzoate esters\ centers on deprotonation of amides[ If no hydrogen atoms
are available on the carbon atom a to the carbonyl group\ and if nucleophilic addition to the
carbonyl group is blocked\ then coordination of the organolithium base to the amide oxygen
atom directs deprotonation a to nitrogen ð72JA1979\ 77JA7034Ł[ However\ while the organometallic
intermediate can usually be alkylated in acceptable yields\ regeneration of the free amine is often
di.cult and can require forcing conditions[ Beak and Lee have studied the reactions of a?!lithio!
allylamides^ lithiation could be readily e}ected with ButLi at −67>C and subsequent alkylations
were usually g?!selective\ although some exceptions were noted ð78JOC347Ł[ The use of a\v!dihaloal!
kanes and an excess of base allowed for the formation of spirocyclic compounds with the quaternary
center a to nitrogen\ although the yields were modest "Equation "74##[
BunLi (2 equiv.)
Cl(CH2)4Cl, THF
–78 °C to RT
N N (85)
31%
O O
Vastly superior results have been obtained by employing either the formamidine "developed largely
by Meyers et al[ since the early 0879s# or the t!butoxycarbonyl functions to direct deprotonation and
subsequently stabilize the organometallic intermediate[ The formation of a 0 ] 0 adduct prior to
metallation of formamidines has been demonstrated by Meyers et al[ using IR measurements
ð72JA1971Ł[ The resulting a!lithioformamidines can be alkylated in good to excellent yields^ the
reaction occasionally gives oxidation products "enamines# which are characteristic results of electron
transfer processes "Scheme 28#^ however\ these can be suppressed either by addition of HMPA
"which presumably increases the rate of substitution reaction# or by transmetallation with
0!pentynylcopper[ a\a?!Dialkylation of saturated heterocycles can be e}ected^ however\ there is little
or no diastereoselectivity evident in the second alkylation ð73JA2169Ł[ Removal of the formamidine\
providing the free amine\ can be accomplished using KOH\ N1H3\ or LiAlH3[ One advantage of the
Meyers technology is that chiral auxiliaries can be attached directly to the imino nitrogen atom of
the formamidine\ allowing for the asymmetric alkylation of a!amino carbanions[ Correct choice of
the chiral auxiliary is vital] deprotonation and subsequent alkylation of tetrahydroisoquinolines via
an "R#!phenethylamine!derived formamidine proceeded in excellent yields but with poor to moderate
enantioselectivity\ whereas the "bis#silyl ether "22# gave excellent "S#!selectivity "Scheme 39#
ð72JA006Ł[ The presence of an additional oxygen atom in the auxiliary\ either as an alkyl or silyl
ether\ is essential for high enantioselectivity\ presumably acting as an extra donor to chelate the
lithium atom ð73T0250Ł[ While the low basicity of silyl ethers would normally suggest that chelation
would be less important for these auxiliaries ð89JA586Ł\ it is likely that an oxygenÐlithium interaction
is still involved[
ButLi MeI
"major product"
N N Li N
N
N N
But
But But
Prn Cu
i, MeI
ii, KOH
Prn
N – N
Cu 71%
H
N Li+ trans:cis 1:1
But
Scheme 39
O-TMS O-TMS N2H4

N i, LDA, –78 °C N 70.3%
ii, Br(CH2)3Cl, –100 °C ee 90.3%
H Ph H Ph N
N H N H
O-TMS Cl O-TMS
(33)
Scheme 40
More recently\ formamidines derived from O!t!butyl valinol have been used to good e}ect in the
synthesis of a range of natural products^ some examples from the Meyers group include salsolidine
ð76T4984\ 78OS"56#59Ł\ emetine "a formal total synthesis\ ð80JOC5762Ł#\ corynantheine alkaloids
ð80JOC1980Ł\ homolaudanosine ð76T4984Ł\ reticuline ð78H"17#184Ł\ deplancheine ð75JOC2097Ł\ yohim!
bone ð77JA3667Ł\ and cryptaustoline ð81JA7372Ł[ Several isoquinoline alkaloids\ which can be pre!
pared from similar starting materials using the formamidine directing group\ are depicted in
Scheme 30[ The formamidine!based procedure has been extended recently to the asymmetric syn!
thesis of alkylated tetrahydrobenzazepines ð82T0796Ł^ while the optical yields are not always as high
as for the corresponding isoquinolinyl compounds\ enantiomeric excesses between 73 and 85) are
generally observed[ However\ this method is not directly applicable to the a!alkylation of pyr!
rolidines or piperidines as the fully saturated heterocycles are only metallated as the achiral N!t!
butyl formamidines^ introduction of oxygenated chiral auxiliaries prevents deprotonation from
taking place[ As a solution to this problem Meyers et al[ discovered that the introduction of b\g!
unsaturation into the heterocycles allows deprotonation to occur at −099>C\ and alkylation occurs
to give the 1!substituted products in good yields with ×89) enantiomeric excess ð74JA6863Ł[ While
some 1\2!enamine is formed as a result of g!alkylation "7Ð29)# it is of little concern as the
hydrazinolysis step decomposes the unwanted regioisomer "Scheme 31#[
N
MeO O Me
NH
MeO
MeO
(–)-Salsolidine
OMe
RO (+)-Ocoteine
N
R1O
N
O O
ButO
MeO
+ Me
N
HO
HO
OMe
N
OMe MeO Me
(+)-Cryptaustoline (–)-Reframoline
Scheme 41
(CH2)3Br
Ph
N i, BunLi, –100 °C
N N
ii, Ph(CH2)3Br
N N + N
α : γ = 92 : 8
ButO ButO ButO
N2H4
76% N2H4
(three steps)
H2, Rh/C
Ph Ph decomposition
N 81% N
H ee 95% H
Scheme 42
Modi_cation of the chiral auxiliary by replacement of the O!t!butyl group with the smaller O!
methyl substituent allows metallation and alkylation to be carried out at a tertiary carbon atom in
tetrahydroisoquinolines ð80TL4490Ł^ the second alkyl group is introduced in good chemical and
optical yields "Equation "75##\ although the stereochemical outcomes are less satisfactory than for
alkylation of the corresponding unsubstituted heterocycles[ The facial selectivity for the second
alkylation is the opposite of the _rst] excellent b!face selectivity is observed in the _rst alkylation
leading to the tertiary center\ whereas the second alkylation occurs with more moderate "ee 63Ð
75)# a!face selectivity giving a quaternary carbon atom[ The con_gurational stability of the
intermediate lithio formamidine ð80TL4494Ł\ and factors in~uencing this remarkable switch in facial
selectivity ð80TL4498\ 81JOC2708Ł\ have been analyzed[
MeO MeO
i–v
(86)
N N
MeO MeO
N
ee 74%
MeO
i, BusLi; ii, I(CH2)3OTBDMS; iii, F–; iv, PBr3; v, N2H4
The t!butoxycarbonyl "t!BOC# group provides another versatile approach to a!aminocarbanions[

Acyclic amines such as dimethylamine can be alkylated in good yields "Equation "76## ð78TL0086Ł\
and the t!BOC auxiliary can be removed under mild conditions[ Oxazines can be alkylated using
the t!BOC directing group\ providing a useful 0!lithio!2!hydroxy!0!propylamine synthetic equivalent
"Equation "77## ð82JOC712Ł[ While alkylation gives the oxazines as mixtures of diastereoisomers\
this is of little consequence as liberation of the g!hydroxyamine by treatment with acid removes the
chiral center at C!1[ Beak and Lee have shown that t!BOC protected\ saturated nitrogen heterocycles
can be alkylated on a!carbon atoms in yields that are variable\ but generally greater than 59)
ð82JOC0098Ł[ The products can be lithiated a second time on the a?!carbon atom\ and subsequent
alkylation in piperidines and perhydroazepines occurs trans to the _rst alkyl group "Scheme 32#
ð89JOC1467\ 82JOC0098Ł[
Me Me i, BusLi Me Prn
N N
ii, EtI
(87)
ButO O 81% ButO O
O i, BusLi, TMEDA, –78 °C O

ii, RX
N N R (88)
ButO O ButO O
R Me PhCH2 Bun
Yield (%) 80 55 52
Ph Ph Ph
i, ii i, ii
N N N
ButO 83% ButO 83% ButO
O O O
i, BusLi, TMEDA, –78 to –20 °C; ii, MeI
Scheme 43
Meyers and Milot have demonstrated that the formamidine and t!BOC directing groups can
provide complementary outcomes and are therefore equally valuable in the armoury of the synthetic
chemist[ Indolines and 0\1\2\3!tetrahydroquinolines can be deprotonated at C!1 a to nitrogen using
the formamidine auxiliary to direct the alkyllithium base\ whereas the t!BOC group directs the
metallating reagent to the ortho site on the aromatic ring "Equations "78# and "89## ð82JOC5427Ł[
Application of this chemistry to decahydroquinolines likewise produces di}erent*and equally
valuable*results[ While both groups direct the alkyllithium to e}ect deprotonation at C!1 in the
trans!isomer "deprotonation at C!7a\ giving a tertiary organolithium intermediate\ is not observed#\
methylation of the formamidine!based anion leads to the equatorial product predominantly "in
contrast\ transmetallation with 0!pentynylcopper leads to reversal in stereoselectivity# whereas the
t!BOC stabilized anion gives largely axial alkylation[ The cis!perhydroquinoline gives essentially
pure equatorial alkylation regardless of the auxiliary "in this case\ transmetallation with the alkynyl!
copper reagent results in loss of stereocontrol#[ Unfortunately\ alkylation with n!iodopropane failed
and electron transfer processes intervened giving the 1\2!enamine^ {{nucleophilic displacement on
alkyl groups larger than methyl "except allylic or benzylic# appeared to be futile|| ð82JA5541Ł[
Introduction of the n!propyl sidechain was e}ected instead by allylation and subsequent catalytic
reduction[
i, BusLi, TMEDA
ii, Br Cl
(89)
N 60% N
O OBut Cl O OBut
i, ButLi, –20 °C
ii, BunI, Pri Cu
(90)
91%
N N
NBut NBut
Dipole!stabilized carbanions can also be prepared by metallation of 1!"0!piperidinyl#oxazolines

ð78JOC064Ł[ Deprotonation is e}ected smoothly at −12>C with BusLi in the presence of TMEDA^
however\ the alkylations are disappointing[ Methylation occurs in only 29) yield "giving a single
diastereoisomer#\ and coupling either does not occur with other haloalkanes or occurs in negligible
yields and with virtually no stereoselectivity[ Transmetallation of the intermediate lithio species
with cuprous cyanide gives a better yield of methylated material "42)#\ however\ the previously
observed stereoselectivity is lost[ The mechanism of coupling with nonmethyl substrates almost
certainly involves single electron transfer processes\ as alkylation with a radical probe "4!hexenyl
bromide# gives a mixture of hexenyl and cyclopentylmethyl!substituted compounds as well as
disproportionation products "Scheme 33#[
N O N O
BusLi, TMEDA, –23 °C Br
N Li N
N O N O N O N O
+ + +
N N N N
dr 1:1 dr 1:1
Scheme 44
Nitrogen substituents can participate in the stabilization of negative charges not only by inductive
mechanisms as outlined above\ but also by delocalization of the electron density into unsaturated
functional groups such as imines\ hydrazones\ oximes\ and nitroalkanes[ Formation of monoanions
or dianions provides a number of procedures for alkylation either a or b to the nitrogen substituent[
Perhaps the simplest example involves deprotonation of N!alkyl imines\ which is readily achieved
using bases such as LDA[ Subsequent alkylations occur in high yields giving masked ketones or
aldehydes\ as exploited by De Kimpe et al[ in a synthesis of cyclic imines "Scheme 34# ð82TL3582Ł[
Chiral auxiliaries can be readily incorporated into the N!alkyl moiety\ leading to facial dis!
crimination in the alkylation of the intermediate imine anion[ A number of groups\ including Meyers
et al[\ have shown that these imines give chiral\ nonracemic lithioenamines on deprotonation which
can be alkylated in high chemical and optical yields "see ð70JA2970Ł for leading references#[ For
example\ Meyers et al[ demonstrated that cyclohexanone and cycloheptanone imines could be
alkylated in 51Ð76) yield and with 79Ð88) enantiomeric excess ð70JA2970Ł[ Unfortunately\ cyclo!
octanone and indanone imines racemized extensively on hydrolysis\ and larger rings "Equation "80##
and acyclic imines gave variable results "ee 07Ð86)# ð70JA2977Ł[
N i, LDA, THF, 0 °C N N ( )n
ii, BrCH2(CH2)nNStb NStb K2CO3, MeOH
( )n
N N N
Me n = 1, 56%
Me n = 2, 88%
Si
—NStb = N
Si
Me
Me
Scheme 45
Ph
N O
i, LDA, –20 °C, THF
OMe ii, MeI, –78 °C
(91)
( )n iii, hydrolysis ( )n
n = 1, 65% ee 87%
n = 2, 90% ee 85%
n = 5, 71% ee 31%
n = 10, 75% ee 37%
In a similar manner to oximes N\N!dialkylhydrazones act as carbonyl equivalents and provide

an e}ective route for a!monoalkylation[ Deprotonation can be e}ected with strong bases such as
LDA\ and alkylation of conformationally rigid hydrazone monoanions occurs with excellent axial
selectivity "Equations "81# and "82## ð74JA1967Ł[ This result is in dramatic contrast with the alkylation
of analogous ketone enolates where only modest selectivity is observed "see ð74JA1967Ł for leading
references#[ The improved selectivity with hydrazone anions is believed to be due to a combination of
stereoelectronic e}ects and stereoselectivity in lithium coordination^ aggregation of the intermediate
organolithium species is not believed to play a major role in the outcome of the reaction[ Metallation
of unsymmetrical hydrazones usually occurs on the least substituted carbon atom\ unless additional
stabilization of the incipient negative charge is present^ for example\ the hydrazone of phenylacetone
is metallated on the benzylic carbon atom ð65TL2Ł[
N
i, LDA, THF NMe2
N
NMe2 ii, EtI, –78 °C But
But (92)
ax:eq = 14:1
i, LDA, 0 °C
N N
NMe2 ii, MeI, 0 °C NMe2
(93)
95%
trans:cis = 97:3
The development of hydrazones into useful chiral auxiliaries has been pioneered largely by
Enders et al[ ðB!73MI 093!91\ 73T0234Ł[ Ready access to both "S#! and "R#!enantiomers of 0!amino!1!
methoxymethylpyrrolidine "SAMP and RAMP# from "S#!proline and "R#!glutamic acid respectively
has provided a simple and successful route to either epimer of a range of chiral compounds[
Deprotonation of the hydrazones can generally be e}ected in high yield with LDA\ and alkylations
at low temperature give the a!substituted hydrazones in excellent yields and diastereoselectivity[
Cleavage of the hydrazones\ usually by ozonolysis\ regenerated the optically active substituted
ketone or aldehyde "Equation "0#\ for example#[
In contrast to N\N!dialkylhydrazones\ Baldwin and co!workers have shown that N!monoalkyl!
hydrazones are deprotonated readily on treatment with butyllithium\ giving resonance!stabilized
anions that can be alkylated selectively "but not exclusively# on the sp1 hybridized carbon atom[
Aldehyde t!butylhydrazones act as acyl anion equivalents\ giving ketones in variable yields "04Ð
72)# on hydrolysis "Equation "83## ð72CC0939Ł[ Alkylation of the anion with iodomethane gives
predominantly N!alkylated material^ however\ use of bulkier haloalkanes results in C!substituted
products[ Ketone hydrazones have been developed as a!amino carbanion equivalents ð75CC065Ł^
alkylation of the intermediate lithio species gives a stable azo compound which can be reduced
homolytically to give a tertiary alkane "Scheme 35#[ Alternatively\ treatment of the azo compound
with TFA results in loss of isobutene and formation of a benzophenone hydrazone which can either
be hydrolyzed to give a hydrazine or hydrogenolyzed to provide a substituted amine[
H i, BunLi, THF, 0 °C H
N ii, n-C7H15I, –78 °C N
N But iii, TFA N But H+, H2O O
(94)
Ph H Ph C7H15 83% Ph C7H15
(four steps)
H
N But N But
N i, BunLi,
N C7H15
Ph C7H15 Ph
Ph ii, n-C7H15I Ph PhSH, PhH, ∆
88% 64%
i, BunLi
ii, PhCH2Br
100%
N But N Ph H2, Pd/C

EtOH/HCl Ph NH2•HCl
N HN
Ph TFA 50 °C, 1 atm.
Ph Ph Ph Ph
71%
Scheme 46
While the hydroxyl proton is the most acidic hydrogen in simple oximes and addition of bases
will readily give the oxy anion\ this does not preclude a second deprotonation a to the sp1 hybridized
carbon atom on reaction with strong bases such as BunLi ð58JA565\ 65JOC328Ł[ Anion formation with
1 moles of an organolithium base gives a C\O!dilithio species^ the site of the second deprotonation
"and hence the subsequent alkylation# is dependent upon the con_guration of the starting oxime\
occurring syn to the oxime oxygen indicating that the metallation is directed by chelation[ These
dianions can be alkylated on carbon with primary and secondary haloalkanes ð65JOC328\ 65TL0328Ł
in good to excellent yields[ An important and useful aspect is that the intermediate dilithio species
are con_gurationally stable\ and therefore a second metallation and alkylation can be carried out
leading to a geminally dialkylated product "Equation "84##[ However\ this procedure cannot be
extended to the alkylation of a tertiary center\ as the lithiation step fails[ Where the hydroxyl group
is syn to a tertiary carbon atom\ the anti position is metallated slowly in preference and the resulting
anion can be alkylated in poor yields ð65TL0328Ł[ Aldehydes can also be alkylated smoothly via the
oxime dianions ð73TL152Łâcetaldehyde oxime dianions can be alkylated in excellent yields[ Metallation
is e}ected at −67>C and the dianion can be alkylated e.ciently[ In a similar manner to the ketone
oximes\ repetition of the procedure results ina\a!dialkylated aldehyde oximes "Scheme 36#[
i, ii, iii, iv (67%) OH

or N
OH
N i, iv, iii, ii (64%)
(95)
Ph
i, BunLi (2 equiv.); ii, MeI; iii, BunLi (1 equiv.); iv, PhCH2Cl
Both cyano and isocyano groups are capable of stabilizing a negative charge^ whereas the
cyanomethyl anion is essentially planar indicating substantial delocalization with much of the
negative charge on nitrogen ð76JA4885Ł\ the isocyanomethyl anion has a pyramidal carbon with the
i, BunLi i, BunLi HO
HO HO N
N ii, PrnI N ii, PrnI
Prn
96% Prn 85%
Prn
Scheme 47
charge localized on the CH1 group ð76JA5993Ł[ The various reactions of a!metallated isocyanides
have been reviewed by Schollkopf ð66AG"E#228Ł[ Methyl isocyanide is deprotonated with n!butyl!
lithium and alkylated in variable "16Ð69)# yields^ however\ the introduction of added stabilization
for the carbanion in\ for example\ benzyl isocyanide\ allows deprotonation with potassium
t!butoxide and subsequent alkylations to occur in consistently higher yields ð66LA39Ł[ Optically
pure cyclopropyl isocyanides can be deprotonated at low temperature "LDA\ −67>C# and alkylated
with iodomethane in high chemical and optical yields "Equation "85## ð63JA2600Ł[ While the anion
appears to be con_gurationally stable below −49>C\ epimerization is observed at higher tempera!
tures[ Signi_cantly\ the con_gurational stability is independent of alkali metal "Li\ Na\ K# and is
una}ected by added complexing agents such as crown ethers\ TMEDA or HMPA[ However\ this
behavior is not extended to acyclic isocyanides which are racemized to a large extent at temperatures
where the cyclopropyl anion is resistant to epimerization ð66JA1520Ł[ Nevertheless\ the high barrier
to inversion observed for the isocyanocyclopropyl anion is remarkable] analogous cyanocyclopropyl
carbanions are racemized completely at −67>C in aprotic solvents ð44JA5915Ł[
Ph H i, LDA, THF, –72 °C Ph

ii, MeI
Ph N C: Ph N C: (96)
96%
ee 99%
The cyano group has a modest acidifying e}ect on a!hydrogen atoms "the pKa of acetonitrile has
been measured as 20[2 in DMSO ð64JA6995Ł# and therefore relatively strong bases are required to
e}ect deprotonation unless additional stabilization is available "for example\ cyano~uorene is
considerably more acidic\ with a measured pKa of 7[2 in DMSO ð64JA6995Ł#[ Methods for the
preparation of nitrile!stabilized carbanions\ and their subsequent reactions\ have been reviewed
extensively ð73OR"20#0Ł\ and many examples of alkylations can be found in the tables accompanying
that review[ Strong bases such as LDA or organolithium reagents are frequently employed for anion
generation\ although there are occasional reports of the use of Grignard reagents[ For example\
Fauvarque et al[ showed that the monoanions prepared with Grignard reagents can be mono!
alkylated in good yields\ although some dialkylated material "³19)# was also recovered
ð57CR"C#0051Ł[ However\ nucleophilic attack by the organolithium\ or magnesium\ reagent on the
nitrile group is an alternative reaction that often takes place ð89S390Ł[ In general\ it is desirable
to generate the carbanion rapidly and with high conversion to avoid side reactions such as con!
densations with neutral nitrile molecules[ Addition of a second equiv[ of strong base such as BunLi
or ButLi can provide a dianion\ often described as a {geminal| dilithio species but more correctly
represented as a C\N!dilithiated ketenimine[ While dialkylation via this species is possible "Equation
"86## ð62JOM"36#306Ł\ an alternative pathway involves formation and alkylation of a monoanion\
deprotonation of the monoalkylated product and _nal alkylation of this second monoanion[ This
pathway can be especially relevant if the reaction between the base and the haloalkane is relatively
slow ð63TL0266\ 73OR"20#0Ł[
R
i, BunLi (2 equiv.), ether, RT R
CN ii, RX CN
Fe Fe (97)
R MeI BuBr PhCH2Cl (CH2Cl)2
Yield (%) 60 56 70 53 (cyclopropyl)
The nitro group has a remarkable acidifying e}ect on a!hydrogen atoms "for example\ compare the
value for CH2NO1\ pKa 00\ with acetone\ pKa 19\ ð42JA1328\ 67JOC2984Ł#\ and the corresponding
nitronates can be prepared quantitatively using relatively weak bases[ These anions are important
synthetic intermediates as the nitro group can be readily reduced to the amine ð77TL4622Ł or
hydrolyzed to a carbonyl function using either Nef or McMurry conditions ð62JOC3256Ł\ and
therefore the alkylation of nitronates would prove to be an important synthetic method[ However\
while some alkylations proceed in acceptable yields ð43JA2861Ł\ the anions can act as ambident
nucleophiles and reactions with haloalkanes are frequently dominated by O!alkylated products[
Allyl halides react with sodium or potassium nitronates by this route giving carbonyl compounds
following decomposition of the _rst!formed aci!nitro structures ð46HCA0149\ B!58MI 093!90\ 74SC0012Ł[
Palladium "9# catalysis allows this reaction to become a useful procedure for oxidation of allyl
chlorides to the corresponding a\b!unsaturated carbonyl compounds "Equation "87## as C!alkylated
products are produced in less than 09) yield ð74SC0012Ł[ Successful C!alkylations were obtained
by Kitajima and co!workers in a synthesis of polysubstituted 0!indanones ð82T426Ł^ however\ the
desired carbocycles were isolated only with relatively hindered substrates where the aromatic nucleus
was fully substituted[ Substrates that were unsubstituted ortho to the nitromethyl group gave seven!
membered heterocycles exclusively\ resulting from O!alkylation "Scheme 37#[
OMe
OMe NO2 OMe
Me2C=NO2– K+
Bun O + (98)
ButOH, Pd(PPh3)4 Bun Bun
Cl
78% 8%
E:Z = 84:16
O O O
NEt3, PhH dbu, C6H6
R=H R = Me
O
59% Br 88%
N
R NO2 NO2
O
dbu = 1,5-diazabicyclo [5.4.0] undec-5-ene
Scheme 48
Relatively hindered nitrobenzyl halides are known to react with the 1!nitropropane anion to give
C!alkylated products^ however\ the reactions do not proceed via conventional SN0 or SN1 mech!
anisms[ Instead\ a single electron transfer process intervenes where an intermediate benzyl halide
radical anion loses a halide ion giving a benzyl radical which couples with the nitronate ð55JA4552Ł[
A range of substrates have since been shown to give C!alkylated material by this process "Equation
"88##\ although the yields and product distributions are sensitive to reaction conditions "for example\
see ð80TL3014Ł#[ Dickens and Luche have shown that sonication can a}ect the course of SET
reactions ð80TL3698Ł^ while O!alkylation can predominate in the absence of irradiation\ sonication
can increase the proportion of C!alkylated material dramatically[
O O
Me2C=NO2– Li+
DMSO, hν
(99)
83% NO2
O Cl O
The nitro group is so e}ective at stabilizing negative charges that dianions can be formed readily
on treatment with a second equiv[ of a strong base such as BunLi or ButLi[ 1!Aryl!0!nitroethanes
can be deprotonated at the a! and b!positions "relative to the nitro group# giving a dianion that can
be considered as a {{super enamine[|| Alkylation occurs in good yields "45Ð65)# b to the nitro
substituent ð65HCA1102\ 68CB123Ł[ Open chain and cyclic nitroalkanes can likewise be doubly depro!
tonated using one equivalent each of BunLi and ButLi in THF:HMPA or DMPU "N\N?!dime!
thylpropyleneurea#^ unsymmetrical nitroalkanes are deprotonated exclusively on the less substituted
b!carbon atom "a kinetic {{enolate||#[ However\ the reactivity of these dianions with haloalkanes is
limited] benzyl and cinnamyl bromide are alkylated in only 29Ð39) yields "Equation "099## and
allyl bromide and n!hexyl iodide failed to react ð66TL0050\ 75CB464Ł[
NO2 i, ii, iii
NO2
(100)
40% Ph
i, BunLi; ii, ButLi; iii, PhCH2Br
"Phenylthio#nitromethane can be doubly deprotonated on the a!carbon atom and alkylated with
haloalkanes in good yields ð65AG"E#494Ł^ however\ the poor nucleophilicity of the corresponding
monoanion is demonstrated by the reaction with 0\4!dibromopentane "Scheme 38#\ where no cyclic
material is isolated ð66TL0050Ł[
i, BunLi (2 equiv.) PhS NO2 PhS NO2 PhS NO2
PhS NO2 ii, Br(CH2)5Br
+
Br
40% 30%
Scheme 49
0[93[2[5 Phosphorus Stabilized Carbanions

Phosphorus in both its tri! and pentavalent states should be capable of stabilizing a negative
charge on an a carbon atom\ and carbanions with a variety of di}erent phosphorus!containing
substituents are known and their alkylation reactions have been reported[ Although the over!
whelming majority of publications detailing these carbanions are in the area of Wittig and related
alkene syntheses\ organophosphorus reagents can be alkylated\ and this is a legitimate route to
higher alkyl phosphines and related species[ For instance\ in an early report Wittig and Rieber
demonstrated that a tetramethylphosphonium salt could be deprotonated with phenyllithium to
give an ylide which could then be alkylated with iodomethane "the yield was not reported#
ð38LA"451#066Ł[ A number of intramolecular examples have been described by Bestmann and Hab!
erlein ð51ZN"B#676Ł and by Markl ð52AG"E#042\ 52ZN"B#73Ł "Schemes 49 and 40#[ An e.cient synthesis
of 0\4!dienes using phosphorane reagents has been devised by van Tamelen and co!workers
ð69JA1028Ł[ Deprotonation of the allylphosphonium salt "23# gave a resonance!stabilized phos!
phorane "24# which reacted cleanly with an allyl bromide to give the alkylated phosphonium salt[
Only a!substitution was observed and the alkene geometry was retained in both components "Scheme
41#[
+ PPh3
Br PPh3 Br– Ph
NaOEt (2 equiv.) PhCHO
65% overall
Scheme 50
PhLi/toluene
or
Br ButOK/DMF base
R R
+ +
P R P P
Ph2 Ph2 Ph2
R = H, Ph
Scheme 51
Direct deprotonation of the a carbon in a phosphine using alkylithium bases does not appear to
be a useful procedure\ as yields of the corresponding carbanions are variable ð54JOC0828\ 55JOC1262Ł^
indeed\ the displacement of alkyl substituents such as benzyl from phosphorus has been reported
ð65JA3794Ł[ An exception is the use of BunLi:TMEDA which is reported to deprotonate methyl!
diphenyl phosphine satisfactorily ð74IC2579Ł[ However\ complexation of borane to the phosphorus
atom provides an excellent method for activating a hydrogen atoms in a variety of phosphines\ and
also for protection of the phosphorus against oxidation and alkylation[ Although phosphineÐ
boranes can be prepared by the reaction of a phosphine with borane\ a more convenient procedure
Br
+
+
PBun3 Br– PBun Br– PBun3
3
PhLi, THF, –76 °C

85%
(34) (35)
Scheme 52
has been developed by Imamoto et al[] secondary and tertiary phosphine oxides undergo deoxy!
genation and in situ conversion to the phosphineÐborane adducts on treatment with a mixture of
LiAlH3\ NaBH3\ and CeCl2 "approximate ratio 0[1 ] 2 ] 2 with respect to phosphine oxide#\ with
yields generally falling in the range 51Ð85) ð74JA4290\ 89JA4133Ł[ The cerium chloride plays a dual
role of activating the phosphine oxides towards reduction by LiAlH3\ and activating the NaBH3 for
formation of the phosphineÐborane adduct ð74JA4290Ł[ This method has the advantage of employing
relatively stable phosphine oxides as starting materials\ and allowing their direct conversion to the
adduct without requiring isolation of "relatively# air!sensitive phosphines[ While Schmidbaur et al[
originally demonstrated that diphosphinomethane compounds\ on complexation to 1 mol[ BH2\
could be deprotonated and alkylated ð68AG"E#671Ł\ Imamoto et al[ have extended this early work
to provide a general method for alkylation a to phosphorus[ Deprotonation of Ph1P"BH2#Me was
readily e}ected using alkyllithium reagents or LDA\ and addition of haloalkanes "allyl bromide\
n!butyl bromide# gave alkylated products in good yields "¼59Ð69)#[ Alternatively\ addition of
CuCl1 gave a dimeric product as a result of oxidative coupling "Scheme 42#[ The borane protecting
group could be removed by addition of diethylamine or morpholine^ the phosphine is regenerated
with complete retention of con_guration at phosphorus[ The analogous reactions did not work with
secondary phosphineÐborane complexes\ as the borane activated the P0H proton and it was
abstracted with relatively weak bases such as KOH "Equation "090## ð89JA4133Ł[ Le Corre and co!
workers have used this method for the preparation of phosphineÐborane complexes with more
substituted carbon centers attached to phosphorus "Scheme 43# ð82TL0900Ł[ Yields were in the range
46Ð79)[
LiAlH4, NaBH4 BH3
O BH3
CeCl3, THF BuSLi, –78 °C, 2 h
Ph2P Me Ph2P
96% Ph2P Me
Li
BunBr
CuCl2
66%
81%
BH3 BH3
Ph2P Ph2P
PPh2
BH3
Scheme 53
BH3 KOH, MeOH, BunBr

BH3
(101)
Ph2P H 86% Ph2P
Phosphine oxides and phosphonates also exert an acidifying e}ect on neighboring hydrogen
atoms[ Phosphine oxides can be deprotonated on an a carbon using LDA ð76JOC1069Ł\ and the
methyl substituent on ethyl methyl phenyl phosphine oxide "25# was deprotonated selectively by
n!butyllithium at −69>C^ quenching with benzyl bromide gave a single alkylated product ð78TL366Ł[
However\ introduction of a dimethylamino group into the ethyl side chain directs deprotonation
"and therefore subsequent alkylation# into the C!1 group[ Unfortunately\ benzylation gave the
monoalkylated phosphine oxide as a mixture of diastereoisomers "45)^ 0[1 ] 0#^ apparently the
chiral phosphorus atom exerted little in~uence on the course of the alkylation step[ In this case\ the
product was contaminated with some dialkylated material "13)# "Scheme 44#[
Ph Ph
R2
i, ii, iii iv, v
Ph3P BH3 Ph2P R1 Ph2P R1
BH3 BH3
i, Li; ii, Me3CCl; iii, PhCH(R1)X; iv, BunLi, 0 °C, THF; v, R2X, –78 °C
R1 R2 Yield (%)
H Me 74
H Bun 80
CH2Ph Me 76
Scheme 54
i, BunLi, –70 °C, 2 h

Ph O
ii, PhCH2Br P
(X = H, 89%) Ph
Ph O
P
Me
i, BunLi, –70 °C, 2 h Ph O Ph O
X P P
ii, PhCH2Br Ph Me Ph Ph
+
(X = NMe2)
Me2N Me2N
56% 24%
dr 1.2:1
Scheme 55
Deprotonation of allyl phosphonates can be e}ected with n!butyllithium at −59>C\ and the
resulting resonance!stabilized carbanions can be alkylated with a range of bromoalkanes^ typically
products are isolated in better than 64) yield ð63AG"E#396Ł[ Coupling occurs exclusively on the a
carbon atom[ A novel approach to phosphorus!stabilized carbanions involves conjugate addition
of organocopper reagents to vinylphosphorus compounds ð73JOC0411Ł[ Reaction of lithium dibutyl!
cuprate with the phospholene system "26# gave the carbanionic species "presumably a cuprate# which
was alkylated cleanly with allyl bromide to give the disubstituted heterocycle "27# as a single
diastereoisomer "Equation "091##^ the chiral phosphorus controlled both the conjugate addition and
the alkylation step[ However\ conjugate addition to\ and alkylation of\ the vinylphosphine oxide
"28# gave the substituted phosphine oxide "39# as a 6 ] 4 mixture of diastereoisomers "Equation
"092##\ implying limited stereocontrol in the alkylation of a!phosphinoyl anions in acyclic systems
ð73JOC0411Ł[
i, Bu2CuLi, ether
ii, allyl bromide
P P (102)
EtO O EtO O
(37) (38)
single diastereoisomer
Ph O Ph O
i, Bu2CuLi, ether
P P
ii, allyl bromide Me
Me (103)
53%
dr 7:5
(39) (40)
0[93[2[6 Silicon Stabilized Carbanions

Silicon is considerably less electronegative than carbon\ and its highly polarizable nature means
that a silyl substituent is capable of stabilizing a negative charge on an a carbon atom ð73JA5356Ł[
The predominant use of a!silyl carbanions features the addition to carbonyl compounds as the _rst
step in the Peterson alkenation ð73S273\ 89OR"27#0Ł[ The review by Ager includes an extensive
discussion of methods for the preparation of a!silyl carbanions\ of which direct deprotonation with
alkyllithium bases is the most direct but least successful approach\ at least for simple alkyl silanes
ð89OR"27#0Ł[ Other methods include metalÐhalogen exchange "for example\ Grignard reagent for!
mation#\ transmetallation "such as SnÐLi interchange#\ single desilylation of geminal disilyl alkanes\
and conjugate additions to alkenyl and alkynyl silanes[ While direct deprotonation of alkylsilanes
is an unreliable method for generation of carbanions\ deprotonation and subsequent alkylation can
be achieved in good yields in oxygenated systems where chelation to an oxygen substituent directs
the base to an activated hydrogen atom "Equation "093##[ The resulting a!silyl carbanion can be
alkylated with iodomethane or with benzyl bromide in 63) and 59) yield\ respectively ð81TL432Ł[
i, ButLi, –78 °C to –10 °C

O ii, MeI O
(104)
O Me 74% O Et
Si dr 7:3 Si
Me Me
But But
A range of silyl reagents of general constitution Z2SiCH1MgX has been developed as e.cient
alkylating and hydroxymethylating agents^ the latter application is especially useful as treatment of
the resulting alkylated silane with an oxidant "usually H1O1 or mcpba# in the presence of ~uoride
causes replacement of the silyl substituent with a hydroxyl with retention of con_guration at the
carbon center[ Trialkoxysilylmethyl chlorides can be converted to the corresponding Grignard
reagents and alkylated in good yields "51Ð69)# ð82JOM"340#C0\ 82TL1000Ł^ although the tris"ethoxy#
derivatives slowly undergo self!condensation at room temperature\ they are stable at −19>C for
extended periods and can even be manipulated successfully at 9>C[ The diisopropoxy"methyl#
silylmethyl Grignard reagent was developed by Tamao et al[ as a nucleophilic hydroxymethylation
agent ð72JOC1019Ł[ Coupling with n!alkyl and allyl halides occurred in excellent yields "×89)# in
the presence of 09 mol[) of CuI catalyst in THF\ and the subsequent oxidative desilylation was
carried out with H1O1:KF in DMF[ This process was extended to a!silyl carbanions derived from
conjugate additions to vinyl silanes ð73TL0894\ 73TL0898\ 73TL0802Ł[ A range of ligands on silicon was
examined\ with various amino and alkoxy groups being tested for their stability to organolithium
and Grignard reagents ð73TL0894Ł[ Yields of alkylated materials were generally good "59Ð69)#
ð73TL0898Ł[ The ability to introduce di}erent ligands on silicon resulted in the development of an
asymmetric variant on the reaction^ however\ the levels of optical induction obtained using eph!
edrine!derived systems were variable "ee 1Ð59)# and never outstanding "Scheme 45# ð73TL0802Ł[
Me
Li Ph Me Me i, BunLi, ether, 0 °C
Me N
Cl Me OMe Si Ph ii, MgBr2
Si N
Cl –78 °C to 0 °C
Me OMe
2
Me Me i, allyl bromide, CuI, THF, RT

ii, HCl
BrMg Si Ph iii, 90% H2O2, KHF2, DMF OH
N
51%
Me OMe over six steps
2 ee 60%
Scheme 56
The addition of Grignard reagents to 0!trialkylsilyl!0!alkynes is a regio! and stereoselective

reaction which results in an a!silylalkenyl Grignard reagent which can be alkylated[ Alkylcopper
compounds\ generated from Grignard reagents and CuBr\ add in a conjugate manner to ethynyl!
silanes in the presence of triethyl phosphite^ the resulting a!silyl alkenylcopper species can be
alkylated with n!iodoalkanes in moderate to good yields "28Ð60)#[ The isomeric purity of the
products is excellent "×88)#\ with resultant syn addition of the alkyl groups ð66TL0794Ł[ Utimoto
and co!workers have reported an intramolecular version of the reaction\ which proceeds in excellent
yields for the synthesis of _ve! and six!membered rings "Scheme 46# ð73TL0888Ł[ Allylation of the
vinyl Grignard reagent proceeded without need for copper catalysis[ Attempted extension of the
method to smaller ring sizes was less successful^ the exo!alkylidenecyclobutane was isolated in only
8) yield\ accompanied by alkylated open chain product "61)#[
Br Mg, RT MgBr
THF reflux
TMS TMS
TMS MgBr TMS

allyl bromide
97%
Scheme 57
In addition to the carbometallation of vinylsilanes\ the analogous hydrometallation reactions are

equally regio! and stereoselective[ Hydromagnesiation of 0!trimethylsilyl!0!alkynes occurs on
treatment with isobutylmagnesium bromide in the presence of a catalytic amount of Cp1TiCl1
"4 mol[)# in ether ð72TL0930Ł[ Hydride is added regiospeci_cally b to the silicon center resulting in
an a!silyl Grignard reagent which can be alkylated directly with reactive "methyl\ allyl# halides\ or
with n!alkyl iodides under copper"I# catalysis giving substituted vinylsilanes with excellent E:Z
selectivity "Equation "094##[ Alternatively\ hydroboration of alkynylsilanes with dicyclohexylborane
gives vinylboranes which can be converted to the alkenyl borates by treatment with MeLi
ð65JOC1830Ł[ These borates can be alkylated directly in better than 69) yield with reactive halides\
or in variable yield with n!alkyl halides following transmetallation with CuI "Equation "095##[ In
most cases excellent syn additions are observed[ Hydroalumination reactions follow a similar course
ð65JOC1103\ 65JOC1104Ł[ For example\ a stereoselective synthesis of Z!0\1!dialkylalkenylsilanes may
be achieved in good overall yields "61Ð73)# by the following sequence] hydroalumination with
diisobutylaluminum hydride "dibal0H#\ formation of the ate complex on addition of MeLi\ trans!
metallation with CuI=P"OEt#2\ and _nally addition of the alkyl bromide or iodide "methyl\ ethyl\
butyl# ð73TL020Ł[ In all cases\ the Z!stereoselectivity was r83) "i[e[ syn addition of H and alkyl#
"Equation "096##[
i, BuiMgBr, Cp2TiCl2 n-C5H11 TMS

ii, 4-iodo-1-butene, CuI
n-C5H11 TMS (105)
86%
TMS i–v
(106)
85% Et
O O O O
(Z):(E) = 85:15
TMS
i, (c-C6H11)2BH; ii, MeLi; iii, CuI; iv, P(OEt)3, HMPA; v, EtI
i–iv
(107)
82% Bun
TMS
TMS
i, Dibal-H, ether; ii, MeLi; iii, CuI•P(OEt)3, THF; iv, BunI
Direct deprotonation a to silicon\ and alkylation in high yields\ can be achieved for allyl and
benzyl groups attached to silicon[ Bases such as Schlosser|s base "BunLi:KOBut#\ s!butyllithium\
and LDA give delocalized carbanions which can be alkylated regioselectively depending on the
nature of the groups attached to silicon and on the size of the haloalkane employed[ Mixtures of
products usually resulted\ however\ smaller groups on silicon and those with metal!complexing
capabilities often gave higher proportions of a!alkylated products while bulkier silicon ligands
favored g!substituted products ð78JOC206\ 80TL1768Ł[ By replacing one of the groups on silicon with
a chiral chelating ligand\ highly enantioselective syntheses of benzyl ð78JA7626Ł\ allyl ð78JOC206Ł\
and propargyl ð82TL0338Ł alcohols can be realized "Scheme 47#[ The introduction of a chelating
ligand also heavily favored a!substitution[
OMe OMe
i, BusLi, ether H2O2, KF, NaHCO3
ii, I RT, 15 h
N N
82% 90% HO Ph
Me Si de>95% Me Si ee >99.5%
Me Ph Me Ph
Scheme 58
0[93[2[7 Boron Stabilized Carbanions

Although the main uses of boron reagents in organic synthesis focus on reduction\ hydroboration\
and boron enolate chemistry\ the formation and reaction of anions a to a boron atom have also
played an important role[ An ab initio study by Pross et al[ has shown that the strong p!accepting
nature of the boron leads to stabilization of a negative charge on an adjacent carbon center by
overlap of the _lled p!orbital on carbon with the vacant p!orbital on boron ð70JOC0582Ł[ While the
inherent stability of a!boryl carbanions suggests that deprotonation may provide a suitable route
to these species\ in practice a serious drawback is the reaction of the base at boron to give an ate
complex rather than a carbanion[ One solution to this problem that works well is the use of sterically
hindered\ nonnucleophilic bases which cannot form stable complexes with the organoborane[ Thus
Rathke and Kow have shown that amide bases such as LITMP will e}ectively deprotonate a
to boron] B!methyl!8!borabicyclononane "B!methyl!8!BBN!H# can be alkylated on carbon by
deprotonation and subsequent treatment with 0!bromobutane ð61JA5743Ł[ Oxidation with alkaline
H1O1 gave 0!pentanol in 31) yield "Scheme 48#[ One reason for the moderate yield is that incomplete
deprotonation occurred^ 1 mol[ equiv[ of base and 13 h exposure gave only 64) anion formation
"as indicated by deuteriation#[ Other B!alkyl!8!BBN substrates could be deprotonated by LITMP\
although the yields of carbanions were much lower ð61JA5743Ł[ In a subsequent report\ Kow and
Rathke reported that vinylboranes could be deprotonated to give allyl anions which could be
quenched with a variety of electrophiles^ the products were examined following oxidation with
alkaline H1O1 ð62JA1604Ł[ The regioselectivity of substitution depends on the nature of the elec!
trophile^ carbanions reacted with silyl and carbonyl reagents g to boron\ however\ protonation and
alkylation "with MeI# occurred predominantly a to boron "Scheme 59#[
Li
Me
B N B B
Li BunBr H2O2, OH–
OH
benzene 42%
Scheme 59
(CH2)4Me
(CH2)5Me • – i, MeI
N
B Li B ii, NaOH, H2O2
Li+
THF
O
+
OH
70% 6%
Scheme 60
An alternative approach\ investigated initially by Wilson ð79JOM"075#186Ł and subsequently by
Pelter et al[ ð72TL512\ 72TL516\ 72TL520Ł\ uses sterically hindered ligands on boron to inhibit ate
complex formation on reaction with moderately hindered bases^ an added bene_t is a decrease in the
rate of aerial oxidation of the trialkylborane substrates[ Dimesityl methyl borane "mesityl1\3\5!
trimethylphenyl# and benzyl dimesityl borane could be readily deprotonated using hindered bases
such as lithium dicyclohexylamide or mesityllithium^ bases such as n!butyllithium and NaH gave
ate complexes ð72TL512Ł[ The boron!stabilized carbanions could be alkylated smoothly with primary
haloalkanes^ bromides and iodides gave the most satisfactory results "with yields being typically
×74)#\ and chlorides were somewhat less reactive[ The basic nature of the carbanion led to
elimination rather than substitution when secondary haloalkanes were employed[ The resultant
alkylated boranes could either be oxidized to give primary alcohols "providing an e.cient homolo!
gation procedure#\ or deprotonated again and alkylated to give dialkylated material ð72TL516Ł[
Oxidation provided secondary alcohols in good to excellent yields "55Ð85)# "Scheme 50#[ In the
analogous reaction with allyl dimesityl borane\ deprotonation and subsequent alkylation gave the
g!alkylated product in a regio! and stereospeci_c manner for all haloalkanes except for iodomethane
where some a!substitution was observed ð72TL520Ł[ Oxidation converted the E!vinylboranes to
aldehydes in excellent yields\ and this procedure provides a useful three!carbon homologation
sequence "Scheme 51#[ The g!selectivity is in marked contrast to the earlier work of Kow and
Rathke\ where exclusive a!alkylation of the less sterically hindered B!allyl!8!BBN was reported
ð62JA1604Ł[
i, MesLi, THF
ii, n-C6H13I
MesLi, THF MeI iii, H2O2, NaOH
Mes2BMe Mes2B Li Mes2BEt
92% 68% OH
} = Mes
Scheme 61
i, MesLi, THF Mes

ii, n-C7H15I H2O2, NaOH
Mes2B B
Mes
90% overall
O
Scheme 62
Instead of blocking formation of ate complexes with bulky groups\ a di}erent approach to the
problem uses heteroatom ligands "such as alkoxy# on boron that are capable of p!back donation\
thus discouraging complexation of bases at boron[ A simple and synthetically accessible example is
the boronic ester\ alkyl B"OR#1[ Unfortunately\ carbanions stabilized by a single boronic ester
cannot be prepared by deprotonation\ a result in contrast to the facile deprotonation of diboronic
esters by hindered bases such as LITMP ð66JA2085\ 71OM19Ł[ Similarly\ while abstraction of a boryl
group from geminal tri! and tetraborate esters leads to anionic species which are readily alkylated
"for example\ see ð69JOM"13#152\ 65JOM"003#0Ł#\ attempts to cleave carbonÐboron bonds in diboronic
esters have been unsuccessful ð74OM0589Ł[ However\ destannylation of an a!trimethylstannyl boronic
ester by treatment with MeLi at −099>C gave the a!lithio species^ similarly treatment of an a!
iodoboronic ester with ButLi at −099>C also gave the organometallic reagent[ Unfortunately\ it
failed to react with iodomethane ð74OM0589Ł[ The successful alkylation of these a!boryl organ!
ometallic reagents has been reported by Knochel ð89JA6320Ł[ Reaction of an a!haloboronic ester
with zinc and subsequent transmetallation with CuCN=1LiCl gave a zincÐcopper compound which
reacted readily with a range of electrophiles including allyl bromides^ yields were typically better
than 79) "Scheme 52#[
While geminal diboronic esters are unsatisfactory starting materials for the generation of stabilized
carbanions\ Zweifel et al[ have developed a procedure using geminal diboranes as stable precursors
to a!boryl anions ð62S26Ł[ Dihydroboration of terminal alkynes provides a convenient and reliable
O i, Zn, THF, 25 °C O Br
ii, CuCN•2LiCl, 0 °C CO2But
B O B O
EtO2C EtO2C 83% overall
Br Cu(CN)ZnBr
O
B O
EtO2C
CO2But
Scheme 63
entry to the sequence\ and addition of 0 mole of methyllithium gives an ate complex which
decomposes to yield a trialkylborane and intermediate a!borylcarbanion[ Addition of a range of
haloalkanes leads to alkylated products which can be oxidized under standard conditions to give
secondary alcohols in 58Ð73) yields "Scheme 53#[
R2BH
(2 equiv.) BR2 MeLi BR2
BR2 – BR2
Me
69–84%
–MeBR2
OH H2O2, OH– BR2 R1X BR2
R1 R1 Li
R2BH =
B
H
Scheme 64
0[93[2[8 Miscellaneous Stabilizing Groups

While functional groups based on other elements can be used to either facilitate the formation
of\ or stabilize the negative charge in\ carbanions\ most of the alternatives do not enjoy widespread
use[ a!Halocarbanions are frequently referred to as carbenoids ð61AG"E#362Ł^ these highly reactive
species must be prepared at low temperatures to prevent their decomposition[ Geminal dihaloor!
ganolithium reagents can be prepared in almost quantitative yields by deprotonation of the cor!
responding 0\0!dihaloalkane at −89>C using BunLi=TMEDA^ alkylations proceed in 57Ð77) yields
with primary haloalkanes ð66BSF654Ł[ HalogenÐmetal exchange can occur in a\a!dihalo compounds
on treatment with alkyllithium reagents when deprotonation is not possible^ 0\0!dihalo!
cyclopropanes give relatively stable carbenoids which can be alkylated in good yields ð66BCJ2177Ł[
Selenium!stabilized carbanions can be readily prepared\ generally by seleniumÐlithium exchange
between selenoacetals and alkyllithium reagents\ and the lithio species that result can generally be
alkylated in good yields^ these reagents have been reviewed in detail by Krief ð80COS"2#74Ł[
One of the most fascinating classes of activating:stabilizing groups involves the use of transition
metals to stabilize the negative charge[ a!Stannylcuprates can be prepared by transmetallation of
an a!iodoalkyltin compound^ the resulting reagent reacts with allyl halides\ however the regio!
and diastereoselectivities are generally poor ð81SL780Ł[ Astruc and co!workers have shown that
hexamethylbenzene can be hexaalkylated via the sandwich compound ðFeCp"C5Me5#Ł¦PF5−
ð78CC503\ 81SL46Ł^ while ButOK is a satisfactory base for deprotonation and alkylation with methyl\
Carbanions With Two and Three Stabilizin` Groups 054
allyl\ and benzyl halides ð71JA6438Ł\ its use with {normal| primary alkyl halides is precluded as
dehydrohalogenation occurs at a faster rate than deprotonation:alkylation of the methyl groups\
and the parent organometallic compound is recovered unchanged[ Remarkably\ KOH in DME
proves to be su.ciently basic to allow the reaction to proceed^ yields greater than 44) are reported
"Equation "097##[ Chromium carbenes can also be metallated a to the chromium"9# substituent\
which renders the hydrogen atoms on a neighboring methyl group highly acidic ð63JA0129Ł[ Depro!
tonation of chromium carbenes "bearing an additional oxygen or nitrogen stabilizing group# gives
a stabilized anion that can be alkylated in good yields "Equation "098## "ð89JA1153\ 82JA76Ł\ and
references therein#[
R R
R R
MeO(CH2)6I, KOH(excess), DME
R R (108)
Fe Fe
60%
R = (CH2)7OMe
i, BunLi, THF
O CO2Me
ii,ButO2CCH2Br ButO2C
iii, hν, MeOH
N N (109)
Ph
52%
(CO)5Cr Ph de 93% O
0[93[3 CARBANIONS WITH TWO AND THREE STABILIZING GROUPS

The union of the stabilizing in~uences of any two or three substituents described in the previous
section provides a wealth of new chemistry centered upon an abundance of useful reagents\ however\
the range of possibilities makes the _eld so expansive that a truly comprehensive survey becomes
impossible within the space limitations of this chapter[ Nevertheless\ some general comments can
be made and speci_c examples provided[ Introduction of a second or even a third stabilizing group
will both increase the acidity of an a!hydrogen atom and also enhance the stabilization of the
resulting carbanionic or organometallic species[ Several important advantages of these multiply
stabilized anions are apparent] deprotonation becomes the favored preparative route and it can
generally be e}ected under milder conditions "compare the following pKa values measured in DMSO]
MeNO1 "06[19#\ PhSCH1NO1 "00[82#\ EtO1CCH1NO1 "8[14#\ PhSO1CH1NO1 "6[19# ð67JOC2090Ł#[
The selective enhancement of acidity at a single site can improve the regioselectivity of deprotonation
and subsequent alkylation "for example\ the use of b!ketoesters as directing agents#\ and the di! and
trifunctional reagents can often be readily transformed into a variety of functional groups[ This last
point is borne out in the frequent use of these species as synthetic equivalents for other unstable\ or
frequently unattainable\ synthons[ Alternatively\ they are used for the procurement of certain
products that are not readily available in high yields or purities by more direct methods[ For
example\ b!ketoesters are well known synthetic equivalents that have been used classically for
enolate monoalkylation] another possibility involves the addition of a second equiv[ of a "strong#
base to the b!ketoester enolate generating a dianion in the a?!position "for a recent review of dianion
chemistry\ see ð80T3112Ł#[ Alkylation will occur selectively at the more nucleophilic "basic# site^ both
concepts have been combined by Mori and Watanabe in a synthesis of the spiroketal pheromone
isolated from Andrena wilkella\ where the dianion of ethyl acetoacetate is alkylated _rst to introduce
one chiral element\ and then in a second step the monoanion is generated with K1CO2 for the
addition of the second asymmetric center "Scheme 54# ð75T184Ł[
A fertile area for investigation has centered upon the development of new reagents that act as
acyl anion equivalents^ whereas nitroalkanes and hydrazones can be used in this manner "see Section
0[93[2[4#\ many other species also enjoy widespread use[ Perhaps the most widely used of these are
the reagents based upon dithianes ð78T6532Ł\ an example of which can be found in the stepwise
alkylation of a benzodithiepin used as a central part of Mori|s syntheses of spiroketal pheromones
"Scheme 55# ð74T1640\ 74T2552Ł[ Another approach uses cyanohydrin derivatives and a!dialkyl!
aminonitriles ð72T2196Ł\ as applied by Larcheve¼que and Lalande to the synthesis of exo!brevicomin
"Scheme 56# ð74CC72Ł[ Several other examples of acyl anion equivalents are depicted in Scheme 57
ð68TL2264\ 72JCS"PI#0020\ 83SL010Ł\ and many more examples are referred to in Wardell|s review
ðB!76MI 093!91Ł[
O– O
O – O O O
OMe
O O
I 63% OMe
OTHP
I
K2CO3
acetone, DMF
100%
i, KOH, MeOH-H2O
ii, p-TsOH, MeOH O O OTHP
O O
42%
O OH (four steps)
CO2Me
Scheme 65
S THF, –35 °C to 0 °C S O O
Li + O O
I 60%
S
S
(41)

ii, (41), 010 °C to 0 °C
55%
CuCl2•H2O, CuO S S
O acetone-H2O O O O O
heat
HO
O
28.7%
HO (from (41))
Scheme 66
Et Et i, SiO2, H2O
I Et2NCH(Me)CN ii, 0.5 M H2SO4 O
LDA CN
O O O O Et2N 75% O
over three steps
Scheme 67
A simple approach to "racemic# a!amino acids has been reported by Luche and co!workers where
the trianion of N!t!BOC!protected glycine is generated by treatment with 2 equiv[ LDA and then
subsequently alkylated with a variety of primary and secondary haloalkanes in good to excellent
yields "Equation "009## "39Ð79)# ð81TL5350Ł[ No dialkylation is reported[ Some starting material
is recovered^ the basic nature of the trianion is believed to cause partial dehydrohalogenation of the
haloalkane[ Alternatively\ masked glycine equivalents can be employed "Equation "000## ð82TL0806Ł[
Of greater importance\ however\ is the development of new methods for the synthesis of optically
active amino acids which can be extended to the preparation of a range of structures of non!
proteinogenic nature[ One recent example is shown in Scheme 58 ð82TL52Ł[ Many other synthetic
approaches have been reviewed by Williams ðB!78MI 093!91Ł and more recently by Duthaler
ð83T0428Ł[
Carbanions With Two and Three Stabilizin` Groups 056
i, BunLi, TMEDA C5H11 i, mcpba O
ii, n-C5H11I ii, heat
PhS TMS 86%
PhS TMS C5H11 H
68%
i, BunLi
O ii, n-C6H13I O heat O
C6H13
S 86% S 97% C6H13 H
O2 O2
i, p-TsOH, MeOH
O O THPO(CH2)4I, K2CO3, acetone O O ii, NaOH(1%)
ButO 90% ButO 55% (two steps)

CN OTHP
CN
O O
OH
O OBut
O
Scheme 68
i, LDA (3 equiv.), THF, 0 °C R

Boc ii, RX, 20 °C
N CO2H Boc (110)
H N CO2H
H
RX Yield(%)
MeI 80
BunBr 47
Me2CHCH2I 48
PriI 41
i, BunLi
ii,
O2N
Br
N CPh2 iii, HCl, H2O O2N NH2•HCl
(111)
CO2But 58%
CO2H
O O
i, NaOH, EtOH
NH2 ii, ButCHO, pentane, heat R
R N
iii, H2C=CHCH2OC(O)Cl But
H H
CO2 H 60 to 82% O
O
iv, KHMDS, –78 °C
R = CH2Ph v,
CH2CHMe2
CHMe2 Br
71 to 96%
vi, NaOH, MeOH, heat O O

v, MeI, K2CO3, DMF
CO2Me vi, Pd(PPh3)4, dimedone N But
NH2 66 to 77% R
R O
O
de > 95%
Scheme 69
An interesting example of a carbanion stabilized by boron is the o!carborane system\ where
deprotonation can be e}ected using n!butyllithium[ While monolithiation would\ in theory\ provide
a route to monoalkylated carboranes\ facile proton transfer leads to the isolation of di!C!substituted
products ð52IC0000\ 81CRV198Ł[ Development of an e.cient alkylation procedure is becoming more
important with the search for new neutron capture agents[ Use of the t!butyldimethylsilyl "TBDMS#
group to protect one carbon allows the monoalkylation to be carried out in good yields "69Ð75)#^
the silicon group can be removed almost quantitatively with tetra!n!butylammonium ~uoride "tbaf#
"Scheme 69# ð80JA4804\ 81JOC0273Ł[ Kabalka et al[ have shown that C!methyl o!carborane can be
lithiated with n!butyllithium and alkylated with bromoalkanes in high yields "65Ð85)# to give 0\1!
di!C!alkylated!o!carboranes^ catalytic lithium iodide assists the alkylation "Scheme 60# ð81TL6576Ł[
However\ a 3!bromo!0!butyne failed to alkylate in the presence of catalytic LiI^ the lithiocarborane
is relatively basic and elimination is the major pathway unless an excess of LiI is added[ In contrast\
Gomez and Hawthorne have shown that the silyl!protected carborane alkylates 3!bromo!0!butene
in 70) yield ð81JOC0273Ł[
i, BunLi
H H ii, TBDMS-Cl H TBDMS
99%
B10H10 B10H10
iii, BunLi
iv, BunBr
80%
Bun H tbaf, –76 °C to 0 °C Bun TBDMS
B10H10 90% B10H10
Scheme 70
Me
Me Si
i, BunLi, THF, 0 °C
Me H Me
ii, RBr, –20 °C, LiI (1.5 equiv.)
B10H10 96% B10H10
i, BunLi, THF, 0 °C
ii, RBr, –20 °C, LiI (0.2 equiv.)
Me Br
RBr = Si
Me
Me
Si
Me
Scheme 71
0[93[4 POLYHALOALKANES
The reactions of dihaloalkanes as electrophiles have already been embraced within this chapter\
and in general the reactions follow the basic guidelines set down in Section 0[93[0[1[ Where two
di}erent halogens are present in an a\v!dihaloalkane\ then the reactivity generally follows the order
I×Br×Cl×F and selective replacement can often be e}ected "Equations "5# and "09#^ Scheme 09#^
2!bromo!0!chloropropane is a commercially available\ useful reagent for the introduction of the
2!chloropropyl side chain "Equation "78#^ Scheme 39#[ Substrates such as 0\2!dibromopropane or
butane frequently will give mixtures of mono! and disubstituted material as well as unchanged
starting dihalide "Equations "00#\ "60# and "74#^ Schemes 8\ 29 and 38#\ although clean mono!
alkylation is sometimes attainable "Equation "16##[ While disubstitutions of 0\1!dihalo compounds
Acknowled`ments 058
are known "Schemes 8 and 86#\ problems can arise with 0\1!dihaloalkanes\ where some nucleophiles
react at halogen leading to elimination and generation of the alkene "Scheme 4#[ Disubstitutions of
0\0!dihalo substrates are also achievable "Schemes 8 and 13#[
0[93[5 ACKNOWLEDGMENTS
I would like to thank Professor David Black for reading sections of this chapter\ and especially
my wife Alison for her patient assistance in the preparation and checking of this manuscript[
1.05
by Substitution: Substitution
of Chalcogen
TIMOTHY N. BIRKINSHAW
Astra Charnwood, Loughborough, UK
0[94[0 SUBSTITUTION OF OXYGEN FUNCTIONS 061
0[94[0[0 Radical Reactions 061
0[94[0[0[0 Intermolecular reactions 061
0[94[0[0[1 Intramolecular reactions 063
0[94[0[1 Displacement of Alcohol Derivatives 066
0[94[0[1[0 Alkyl alcohol derivatives 066
0[94[0[1[1 Allylic alcohol derivatives 075
0[94[0[1[2 Propar`ylic alcohol derivatives 086
0[94[0[1[3 Benzylic alcohol derivatives 199
0[94[0[2 Openin` of Epoxides 193
0[94[0[2[0 Simple epoxides 193
0[94[0[2[1 Glycidic epoxides 119
0[94[0[2[2 Vinyloòus epoxides 114
0[94[0[2[3 Oxetanes and b!lactones 118
0[94[1 SUBSTITUTION OF SULFUR FUNCTIONS 129
0[94[1[0 Radical Reactions 129
0[94[1[1 Thermal and Photochemical Reactions 120
0[94[1[2 Rin` Contractions and Rearranèments 122
0[94[1[2[0 ð0\1Ł!Shifts 122
0[94[1[2[1 ð1\2Ł!Witti` rearranèments 123
0[94[1[2[2 Other rearranèments 124
0[94[1[3 Metal Exchanè Reactions 125
0[94[1[4 Sulfur Leavin` Groups 126
0[94[1[4[0 Allylic and benzylic sulfur systems 126
0[94[1[4[1 Intramolecular reactions 139
0[94[1[4[2 Sulfonium salts 130
0[94[1[4[3 Miscellaneous reactions 130
0[94[1[5 Openin` of Thiiranes 131
0[94[2 SUBSTITUTION OF SELENIUM AND TELLURIUM 132
0[94[2[0 Thermal and Radical Reactions 132
0[94[2[1 MetalÐExchanè Reactions 134
0[94[2[2 a!Carbanion Formation 135
0[94[2[3 Mi`rations of Selenides and Tellurides 135
0[94[2[4 Miscellaneous Reactions 135
060
061 One or More CC Bond"s# Formed by Substitution of Chalcoèn
0[94[0 SUBSTITUTION OF OXYGEN FUNCTIONS
Radical replacements of oxygen functionality stand alone as a separate area[ Epoxides are also
treated separately due to their distinctive reactivity[
0[94[0[0 Radical Reactions

The use of radicals in organic synthesis has been reviewed by Giese ðB!75MI 094!90Ł\ Neumann
ð76S554Ł and Curran ð77S306\ 77S378Ł and includes the addition to carbon multiple bonds of radicals
generated from alcohol derivatives[ These reactions will be covered in broader terms in Chapters
0[96 and 0[97[ Many of these reactions can also be carried out with radicals generated from halogens
"Chapter 0[93#\ which in turn are often prepared from oxygen compounds and so represent a formal
C0O to C0C transformation[
0[94[0[0[0 Intermolecular reactions

Barton and Crich ð74TL646Ł substituted tertiary alcohols\ including adamantanol via thermolysis
of a mixed oxalate e[g[ "0# in the presence of alkenes "Equation "0##[ The scope is limited by the need
to use very reactive alkenes and by the side reaction which gives the thio ether "1#[
O CN CN
80 °C
OH + + (1)
O S N 32% S N
O NC Na+ O– CN
(1)
S N
(2)
Moderate to good yields could be obtained from radical addition to a variety of electron de_cient
alkenes using Bu2SnH "generated in situ from the chloride and NaBH3# and 1\1?!azo!
bisisobutyronitrile"AIBN# ð73AG"E#58Ł "Scheme 0#[ This method can be extended to more complex
systems such as the galactofuranose "Equation "1## where competing hydrogen abstraction from the
reagent gives a 09) yield of deoxygenated compound "3# along with 24) of the required alkylated
product "2# as a single stereoisomer\ with approach of the alkene from the less hindered face[ A
mixture of isomers is obtained when the steric demands are not quite so clear cut[
CN CN
CN CN
63% 45%
O S
Me
S
CO2Me
CN
CO2Me Bu3SnCl (cat.), NaBH4 CN
AIBN, PhMe, 110 °C
50% 40%
45 : 55
Scheme 1
Substitution of Oxyèn 062
CN
O O O
Bu3SnCl (cat.), NaBH4
O AIBN, PhMe, 110 °C
O O
O O O + O (2)
O 45% O
O O O O
S
MeS NC
(3) 75 : 25 (4)
Keck et al[ ð74JOC3206Ł used a radical allylation as the key step in the synthesis of pseudomonic
acid C from L!lyxose "Equation "2##[ Thermolytic generation of a radical from the thiocarbonate
"4# gave the product "5# derived from the approach of allyl tin to the less sterically congested face
of the sugar[ The reaction is analogous to the radical reduction method using Bu2SnH^ the most
reactive group is abstracted\ generating Bu2Sn radical which continues the chain[ Initiation with
AIBN proved less satisfactory as did the use of xanthate "6# or imidazole thiocarbonate "7# as
radical precursors ð71JA4718Ł[ Radical attack on allyltributyltin generates tributyltin radicals which
then attack the sulfur and continue the radical chain[ The reaction is limited to allyl and methallyl
stannane^ with crotylstannane "8# the alkane is too unreactive and allylic H!abstraction occurs to
give butadiene ð74T3968Ł[ Mori and Takechi ð89H"20#0078Ł used similar conditions to e}ect radical
allylation in their synthesis of a prostacyclin analogue "Equation "3##[ Allyl attack was again from
the less hindered face[
O O
O O Ph 2 equiv. O O Ph
S + SnBu3 (3)
O 20 °C, toluene O
X O 80–93%
(5) X = OPh (6)

(7) X = SMe
(8) X = Imidazole
SnBu3
(9)
MeO MeO
SnBu3 (3 equiv.), hν, PhH, 10 h

O O (4)
O 75% O
MOM-O OCOSPh MOM-O
The isomeric hexoses "09#Ð"02# were allylated to give the axially substituted compounds "03# and
"04# ð80CC589Ł[ The latter readily isomerized to the equatorial isomer "05#\ showing that the a!keto
radical reacts under kinetic control "Scheme 1#[ Roberts and co!workers have e}ected radical
allylation in a monocyclic system "Equation "4## ð89JCS"P0#1241Ł[ Here the facial discrimination of
the radical intermediate was not quite so great and an 76 ] 02 "eq ] ax# mixture of isomers was
obtained[
O O O
CN SnBu3 CN CN
+ (5)
OCSOPh PhH, hν, 20 °C
95%
ButMe2SiO ButMe2SiO ButMe2SiO
87 : 13
Allylic and benzylic alcohols can be reductively coupled by low!valent titanium\ a reaction which
proceeds via a radical intermediate[ McMurray et al[ ð67JOC2138Ł have investigated the reaction\
O X SnBu3 , AIBN O
Ph O Ph O
O O
PhH, 80 °C
Y ~100%
O OMe O OMe
(10) X = OBz, Y = H (14)
(11) X = H, Y = OBz
O SnBu3 , AIBN O SiO2 O

Ph O Ph O Ph O
O O O
X PhH, 80 °C
O OMe 87% O OMe O OMe
Y
(12) X = OBz, Y = H (15) (16)

(13) X = H, Y = OBz
Scheme 2
_rst discovered by van Tamelen and Schwartz ð54JA2166Ł\ using TiCl2:LiAlH3 to generate tin"II#
in situ and found that the reaction works well "57Ð84)# with benzylic and simple allylic systems
"Equations "5# and "6## but gives mixtures of products with unsymmetrical alcohols and does not
work at all with nonallylic alcohols[ Attempts to couple allylic diols intramolecularly gave only
reduction products[
TiCl3, LiAlH4, DME
Ph (6)
Ph OH Ph
78%
TiCl3, LiAlH4, DME

OH (7)
87%
0[94[0[0[1 Intramolecular reactions

Intramolecular reactions have allowed a greater variety of functional groups to be used as radical
traps as the problem of hydrogen abstraction is reduced by a more favourable entropy factor[ Much
work has been done in this area on both oxygen and bromine derived radicals ð74JOC435\ 75JA2091\
80ACR028Ł[ Sharma et al[ ð89TL3820\ 80T408Ł have used intramolecular radical reactions in the
synthesis of fungal metabolites from sugars "Equations "7# and "8##[ In both cases only one stereo!
isomer was formed[
C8H17 O OMe C8H17 O OMe

Bu3SnH, AIBN (cat.), PhH
S (8)
O O 80 °C, 6 h O
MeS 80%
Bu O OMe Bu O OMe
Bu3SnH, AIBN (cat.), PhH
(9)
O O 80 °C, 6 h O
84%
MeS
S
Clive et al[ have investigated the intramolecular cyclisation of radicals generated from thio!
carbonylimidazolides onto triple bonds ð73JOC0202Ł using slow addition of Ph2SnH and AIBN in
re~uxing benzene[ The addition to terminal alkyne was low yielding "Equation "09## but those to
substituted alkynes proceeded in good yield "Equation "00##[ Of the additions to nitriles "Equations
"01#\ "02# and "03## only that forming the ð4\4Ł ring system gave an unsatisfactory yield "Equation
"01##[ Competing reduction of the oxygen function occurred in low yield in some cases[
S Im
H
O Ph3SnH, AIBN, slow addition
(10)
PhH, 80 °C, 15 h
24%
Im = N N
S Im R
R
H
(11)
PhH, 80 °C, 15 h
R = Ph, 79%
R = C5H11, 81%
S Im
O
CN + CN (12)
PhH, 80 °C, 15 h
then hydrolysis
34% 44 : 56
S Im
H O
O
CN Ph3SnH, AIBN, slow addition CN
+ (13)
PhH, 80 °C, 15 h
then hydrolysis
78% 86 : 14
S Im
H O
O
CN Ph3SnH, AIBN, slow addition CN
+ (14)
PhH, 80 °C, 15 h
then hydrolysis
74% 97 : 3
A cyclopentane ring can be constructed in good yield by intramolecular cyclisation of the

tetrahydrofuran xanthate "06# "Equation "04## ð81TL4150\ 82JOC1783Ł[ A small amount of the thio
compound "07#\ derived from a competing radical chain propagation reaction\ was also isolated[
This can be converted to the required compound by radical desulfurisation[ Bartlett et al[ have
shown that oxime ethers\ in contrast to carbonyl groups\ act as e}ective radical traps in intra!
molecular cyclisations to give cyclopentanes and cyclohexanes "Equation "05## ð77JA0522Ł[ Com!
peting reduction is a problem in some cases and mixtures of cis and trans isomers are formed[
O O O
O O O
H H H
O Bu3SnH, AIBN O O
MeO2C + MeO2C (15)
MeO2C PhMe, 110 °C H H
O SMe
S
S SMe
Bu3SnH, AIBN
O
(17) PhMe, 110 °C, 71% (18)
74% 10%
OCH2Ph
N OCH2Ph OCH2Ph
HN HN
OCH2Ph
PhOCSO OCH2Ph OCH2Ph
Bu3SnH, AIBN
PhCH2O + PhCH2O (16)
OCH2Ph PhH, 110 °C
PhCH2O OCH2Ph 93% PhCH2O OCH2Ph PhCH2O OCH2Ph
62 : 38
Ziegler et al[ ð82JA1470Ł have used the selectivity of a thiocarbonate derived radical ð89JOC0305Ł
cyclising "in a 4!exo!dig fashion# onto an alkyne to prepare a substituted cyclopentene "Equation
"06##[ The starting material is a 0[5 ] 0 mixture of diastereoisomers but the isomer ratio of the product
is not quoted[ RajanBabu has used an enol ether as the radical trap in a synthesis of a Corey lactone
"Equation "07## ð77JOC3411Ł[ The unusual 0\4 trans stereochemistry is rationalized by postulating a
boat!like transition state "08# which removes the unfavourable steric interaction between the ben!
zyloxy group and the cyclic acetal that would be found in the more usual chair transition state "19#
which would give rise to the cis stereochemistry[ With the opposite chirality at the benzyloxy centre
the expected 0\4!cis stereochemistry is obtained\ while the desoxy compound gives a 66 ] 12 mixture
of cis ] trans isomers[
O-TBDMS O-TBDMS
O-TBDMS
Bu3SnH, AIBN (cat.)
• (17)
O PhMe, reflux
60% Bu3SnS O
O HO
S
O
62 :38
Im S
OMe
O
O OMe Bu3SnH, AIBN O
OCH2Ph (18)
PhMe, 110 °C
O OCH2Ph O
Ph O Ph O
O • OMe O •
OMe
PhCH2O
PhCH2O H
(19) (20)
The tricyclic skeleton of the sesquiterpene silphinene was prepared by radical cyclisation of
the thiocarbonate "10# "Equation "08## creating the quaternary carbon centre and the correct
stereochemistry at the adjacent stereogenic centre ð77TL096Ł[
O
O
S
Bu3SnH, AIBN
O O (19)
PhMe, 80 °C
70%
(21)
A limitation of radical cyclisations can be seen in Snider and Kulkarni|s syntheses of tricyclic
sesquiterpenes "Scheme 2# ð74TL4564Ł[ The two required compounds "14# and "15# were each isolated
in only 7) yield from the radical cyclisation of compound "11#^ the major products "12# and "13#
being derived from tributyltin cleavage of the thiocarbonylimidazole[ The reduction product "16#\
derived from competing hydride abstraction from tributyltin hydride\ was not observed[
(23) R = H, 25%
(24) R = CH2SH, 40% OR
Bu3SnH, PhMe, 3 h
8%
O Im
S (25)
(22)
8%
(26)
(27)
Scheme 3
0[94[0[1 Displacement of Alcohol Derivatives

Alcohol derivatives which are good leaving groups can be displaced by nucleophiles under neutral
or basic conditions[ The hybridization of the carbon atom b to the alcohol carbon atom has a
substantial e}ect on the reactivity at the a carbon atom and so this section is divided according to
the nature of the adjacent group[ Some reactions are speci_c to that section while others are more
general in their scope[
0[94[0[1[0 Alkyl alcohol derivatives
"i# Sulfates\ sulfonates and phosphorus derivatives

Alkyl sulfonates and sulfates react readily with nucleophiles[ A systematic study of comparative
leaving group abilities of the di}erent sulfonate "and other# leaving groups does not appear to have
been done "and would be nucleophile dependent# but the relative ease of displacement parallels the
acid strengths of the leaving groups and their rate of solvolysis and is shown in Figure 0 ð71S74Ł[
For most purposes tosylates su.ce "mesylates can be deprotonated from the methyl group# but the
more reactive tri~ates as well as dialkyl sulfates and halides also react in a similar fashion "see
Chapter 0[93#[ Cuprates and copper!catalysed reagents are the best carriers for simple alkenyl and
alkyl nucleophiles "Equations "19# and "10## ð76H"15#0180\ 78JOC4720Ł[ In some cases halides may be
preferable ð72JOC2223Ł[ Displacement occurs with inversion of con_guration via an SN1 mechanism
ð78JOC4720Ł[ It is possible to displace two di}erent sulfonate groups sequentially "Equation "11##
ð78TL2888\ 89JOC3306Ł^ since dialkylcuprates are more reactive than the copper!catalysed Grignard
reagents\ in that they tend to displace both sulfonates\ the latter reagents are preferred for the _rst
step[ It is claimed that secondary and tertiary tosylates give low yields or do not react at all ð63AG49Ł
but this is contradicted for secondary tosylates by the example given above[ Recently\ displacement
of a bridgehead mesylate in a gibberellin has been reported ð82CC0000Ł[ A hetero!atom b to the
nucleofuge usually causes rate retardation ð81JCS"P0#84Ł but rate enhancement can also occur
ð78JOC4720Ł[ The displacing nucleophile can come from an aromatic Grignard reagent ð75BCJ2986Ł
or from an anion generated reductively "Equation "12## ð75JOM"209#024Ł[
C4F9SO3 > CF3SO3 > FSO3 > O2N SO3 > Br SO3 > PhSO3 > TolSO3 > MeSO3
nonaflate nosylate brosylate
Figure 1
MeO MeO
NHBOC CuI, THF NHBOC
+ MgBr (20)
OTs 63%
MeO MeO
OTs Bu2CuLi, ether, –20 °C

TBDPS-O O SMe TBDPS-O O SMe (21)
72%
O O i, CuBr, 0 °C, 4 h O O
OTf ii, Me2CuLi, 20 °C, 10 h
+ (22)
OTs MgBr O O
O 63% O
OMe i, Li di-t-butylbiphenyl, THF, –78 °C OMe

ii, add triflate, –78 °C
+ MeOTf (23)
SPh 79%
Sulfonates and sulfates alkylate stabilized anions such as alkynes ð81JCS"P0#84Ł "Equation "13##
ð52HCA0681Ł\ cyanide "Equation "14## "in this case under mild phase!transfer conditions# ð77HCA36Ł\
phosphonate anion ð82JOC5063Ł\ sulfur!based anions ð55AJC410\ 79CJC605Ł\ boron!stabilized anions
ð76JOC4373Ł and those derived from carbonyl compounds including dianions of b!ketoesters
ð75H"13#2038Ł "Equation "15##[ Sulfates give better yields than bromides and iodides\ with little
O!alkylation or di!alkylation occurring "Equation "16## ð89SC014Ł[ Regio! and diastereoselective
alkylations are possible ð63LA258\ 77BCJ460Ł[ The abilities of several alkylating agents to alkylate
ketone enolates have been compared ð82JOC3358Ł[ Cyclohexanone and tri~ates ð66CRV58Ł gave by
far the best results with no dialkyl products formed and the highest yields obtained "Equation "17##
ð82JOC3358Ł[ Signi_cant amounts of dialkylation occurs with methyl iodide and benzyl bromide
under similar reaction conditions[ Tri~ates are more di.cult to work with as they cause poly!
merisation of THF^ exchange of alkyl groups can occur when using diethyl ether as the solvent[
Hexane is a better solvent[
BuLi, THF, 20 °C
+ O-THP (24)
C5H11 80% C5H11
O O
OTf
O-THP
O-TBDMS Bu4N+ CN–, CH2Cl2, 20 °C O-TBDMS

(25)
MeO2C 92% MeO2C
OTs CN
NTs i, NaH, BuLi, THF NTs

MeO2C ii, add tosylate, 0 °C MeO2C
+ OTs (26)
O 86% O
O NaOEt, Al2O3, 20 °C, 5 d O

CO2Et + (EtO)2SO2 CO2Et (27)
76%
O O O O
KH, ether
+ + (28)
MeI, ether 0 °C to 25 °C 70% 15% + 15% SM

MeOTf, hexane –30 °C to 25 °C 91% 0% + 9% SM
Alcohols can be displaced by cyanoacetate anion under Mitsunobu conditions "Equation "18##
ð61TL0168\ 65TL1344\ 70S0Ł\ whereas 0\2!dicarbonyl compounds give largely O!alkylation[ Bissulfones
react in high yield ð82JOC4781Ł under Mitsunobu conditions and cyanide has also been used as the
nucleophile ð65HCA1099\ 74SC552Ł[
CO2Et
OH dead, Ph3P, THF, –20 °C to 20 °C
NC CO2Et + CO2Et (29)
45% NC
CO2Et
dead = diethyl azodicarboxylate
Replacement of hydroxyl by cyanide is achievable under a wide range of conditions[ Tri~uoro!

acetate esters can be replaced by cyanide in re~uxing THFÐhexamethylphosphoramide "HMPA#
ð77SC334Ł[ This is only useful for primary alcohols and can be used to chemoselectively replace one
hydroxyl group of a diol[ Trimethylsilyl chloride and sodium cyanide convert a range of primary\
secondary\ tertiary "including adamantanol# and benzylic alcohols ð70JOC1874Ł "Equation "29##[ The
presence of a catalytic amount of sodium iodide is necessary[
OH CN
2 TMS-Cl, NaCN, NaI
(30)
C6H13 DMF–DMSO, 60 °C C6H13
75%
Tri~ates a to an ester group can be displaced with cuprates "Equation "20## ð89TL1038Ł or
b!ketoesters "Equation "21## ð82TL1940Ł in high optical purity "−83) ee#[ The choices of cuprate
and solvent appear to be critical to the success of the reaction\ reduction of the tri~ate being the
main side reaction[ The corresponding tosylates readily eliminate tosic acid under similar conditions[
Displacement of a benzoate group a to a carbonyl moiety has been accomplished using samarium
diiodide ð81H"23#1136Ł[ The reaction proceeds via reductive generation of an enolate and subsequent
aldol reaction "Equation "22##[
OTf
Me2CuLi, ether–pentane, –70 °C
(31)
Bu CO2Et 73% Bu CO2Et
i, NaH, THF
ii, add triflate
O iii, LiOH, THF (aq.), reflux O
CO2Et + (32)
TfO CO2Me 64% CO2H
94% ee
O O O O
SmI2, THF–HMPA
OBz SmIII OBz
OBz OBz 72% OBz
O O
HO
OBz
O O + (33)
HO OBz
OBz
OBz
74 : 14
Chiral alkylations have been performed with sulfonates[ Alkylation of the {Enders hydrazone|
"17# with methyl tosylate gives better enantiomeric excesses "ees# than with methyl iodide "Equation
"23## ð76CC247Ł[ Tri~ates also react with the chiral amino acid synthon "18# in much higher yields than
the corresponding iodides "Equation "24## ð75TL2392Ł[ One possibility for sulfates and sulfonates not
open to halides is to have a chiral leaving group[ Duhamel et al[ have studied a number of chiral
sulfate and sulfonate methylating agents with glycinate anions and obtained ees up to 50)\ although
most ees were in the range 9Ð19) "Equation "25## ð77T4384Ł[
N
N i, LDA, THF O
ii, MeOTs, –95 °C
OMe (34)
iii, MeI
iv, 2M HCl
(28) 100% ee
O-MOM O-MOM
O i, LDA, THF–toluene O
N ii, triflate, –78 °C N
+ (35)
N OTf N
68%
MeS MeS
SMe O-MOM SMe Pri O-MOM
(29)
O
i, LDA, THF
ii, sulfate, HMPA, –70 °C
Ph N CO2Me O OSO3Me iii, 6M HCl H2N CO2Me
+ O (36)
Ph O 75%
O 69 : 31 (S) : (R)
"ii# Friedel!Crafts reactions

Friedel!Crafts alkylations have been reviewed by Olah et al[ ð80COS"2#182Ł "which includes a
section on alkylation with oxygen functions# and in a monograph ðB!73MI 094!90Ł[
The relative ease of alkylation of alcohols decreases in the order benzylic¼allylic¼
tertiary×secondary×primary×methyl\ so the Friedel!Crafts reaction of alcohols is most useful for
benzylic and allylic alcohols[ A wide variety of catalysts can be used including SnCl3\ TiCl3\ ZnCl1\
BF2 = Et1O\ AlCl2ÐMeNO1\ P1O4\ H1SO3\ TeCl3 "but not SeCl3# ð75BCJ2506Ł\ various sulfonic and
carboxylic acids "including polymer!bound super acids such as Na_on!H# as well as the more usual
AlCl2[ K09!Montmorillonite has been used as a catalyst for alkylation with primary and secondary
alcohols^ the former gave substantial amounts of rearrangement products but good yields were
obtained with the latter ð82TL0086Ł[
Shen et al[ have achieved a Friedel!Crafts alkylation of the normally unreactive nitrobenzene
"Equation "26## ð89JOC2850Ł[ AlCl2 coordinates the nitro group and further deactivates the benzene
ring[ Sulfuric acid does not do this and so the reaction proceeds in moderate yield[ The ortho ]
meta ] para ratio is 08 ] 69 ] 00[ The selectivity of this Friedel!Crafts alkylation is poorer than that of
nitration reactions suggesting that the former procedes via an early transition state[
O2N O2N
H2SO4, EtOH, 110 °C, 6 h
+ OH (37)
42% + 52% recovered SM
Phosphorus acid derivatives are also substrates for Friedel!Crafts alkylations "Equation "27##
ð60S192\ 61S031Ł[ "MeO#1POCl\ "PriO#2P and "PriO#2O are also substrates[
Pri But
O AlCl3, PhH, 8 °C, 2 h
PriO + (38)
P
PriO OBut 45%
85 : 15
Lactones undergo Friedel!Crafts alkylation to give\ initially\ arylalkanoic acids which can be
further cyclized[ Co!ordination of Lewis acid "LA# to the carbonyl group weakens the C0O bond
with attack of the aromatic nucleus occurring at the carbon atom "Scheme 3#[ The lactone "29#
reacts readily with benzene at low temperature to give the acid "20# "Equation "28## ð77T0456Ł[
Friedel!Crafts acylation of the acid requires much more forcing conditions "polyphosphoric acid
"ppa# at 019>C#[ The lactone "21# alkylates and then acylates dimethyl catechol in one step under
more forcing conditions "Equation "39## ð64CPB0806Ł[ Lactone "22# reacts selectively at the ester
oxygen atom and not the a!hydroxyl group "Equation "30## ð51BSF0771Ł[ Esters are also substrates
"Equations "31# and "32## ð52JCS3411\ 58AG385Ł[ In the latter the more reactive benzylic ester reacts
preferentially[
LA
O O O LA
O
O δ+ O
Ar
ArH
Scheme 4
EtO2C
Ph
O CO2Et
AlCl3, PhH, 5 °C
O (39)
48% CO2H
(30) (31)
O
O
MeO MeO
ppa, 95 °C, 1 h
+ (40)
O 59%
MeO MeO
(32)
O
O PhMe, AlCl3, 110 °C
O (41)
OH 45%
OH
(33)
O O O O O O
PhMe, AlCl3, 20 °C, 40 min
(42)
O2CMe 83%
O O O O
O PhMe, H2SO4 (conc.), 60 °C, 1–3 h

But (43)
O 96% But
Piccolo and co!workers have investigated the reaction of a number of optically active 1!sul!
fonyloxypropanoates and 2!sulfonyloxybutanoates with aromatic systems\ catalysed by AlCl2
ð74JOC2834\ 80JOC072Ł[ These reactions proceed in good yield and high stereospeci_city with inversion
of con_guration[ The ees of the products need to be treated with a certain amount of caution as
most were calculated from comparison of ðaŁD
values[ Mesylates are preferred over tosylates\ tri~ates
and chlorosulfonates as they give the best ees and yields and are the easiest to prepare from the
corresponding alcohols[ Representative examples are shown in Scheme 4 and Equations "33# and
"34#[ The reaction is thought to proceed via a cyclic transition state "23#\ as proposed by Suga and
co!workers ð68BCJ1266Ł[ The aluminum coordinates the sulfonate group and the arene approaches
from the opposite side to give inversion of stereochemistry[ When no arene is present chloride ion
forms the nucleophile and 1!chloropropanoate and 2!chlorobutanoate are the products obtained in
high yields and optical purities[ The sulfonates also react with other aromatic systems apart from
benzene\ including toluene\ chlorobenzene and naphthalene[ Optical yields\ where determined\ are
lower than with benzene and poor regioselectivities were observed[
CO2Me PhH, AlCl3, 80 °C, 6 h CO2Me PhH, AlCl3, 25 °C, 2 h CO2Me
OSO2Me 80%, 97% ee Ph 40%, 86% ee OSO2CF3
Scheme 5
CO2Et
CO2Et PhMe, AlCl3, 30 °C, 4 h

(44)
84%, ee not determined
OSO2Me 35 : 33 : 32 isomer ratio
Me
OSO2Me Ph
PhH, AlCl3, 0 °C, 2 h
CO2Me CO2Me (45)
63%, 88% ee
ArH
* OR
XO O
LA
(34)
E}enberger and Weber ð76AG"E#031\ 77CB310Ł found that the stereochemical outcome of Friedel!
Crafts alkylation using threonine tri~ates depended on the relative stereochemistries of the two
chiral centres "Scheme 5#[ The di}erent behaviours of "RR# and "RS# diastereomers is explained in
terms of the di}erent conformations of intermediate carbonium ions[ The yields are low as elim!
ination to the a\b and b\g enones "24# and "25# occurs in 14Ð29) and 24Ð39) yields\ respectively[
NPhth CF3SO3H, PhH NPhth NPhth
80 °C, 10 h
CO2Me CO2Me + CO2Me
24%
CF3SO2O Ph Ph
97 : 3
O
Phth =
O
NPhth CF3SO3H, PhH NPhth NPhth
80 °C, 10 h
CO2Me CO2Me + CO2Me
23%
CF3SO2O Ph Ph
40 : 60
NPhth NPhth
CO2Me CO2Me
(35) (36)
Scheme 6
"iii# Cyclisations
Intramolecular displacements of oxygen functionalities are well documented in the literature\
especially for the formation of three!\ _ve! and six!membered rings\ both carbo! and heterocyclic[
Lithium diisopropylamide "LDA# treatment of the sulfonate "26# gives the cyclopentane "27# in
moderate yield with good diastereoselectivity "Equation "35## ð77CC659Ł[ Potassium hexa!
methyldisilazide "KHMDS# as base gave a lower de "77 ] 01#[ Six!membered rings ð75TL832Ł and
heterocyclic systems can also be prepared "Equation "36## ð89CL482\ 81BCJ2376Ł[ In the absence of
HMPA a 10) yield "70 ] 08 isomer mix# was obtained[ The corresponding iodide gave eliminated
product[ Cyclopropanes may also be prepared "Equation "37## ð75AG"E#643\ 82TL0806Ł[ Intra!
molecular Mitsunobu coupling of hydroxy!bis!sulfones and hydroxy!nitrosulfones proceeds in high
yield to give cyclized products with ring sizes of three to seven "Equation "38## ð81JOC2646\ 81TL5612\
82JOC4781Ł[ Annulation reactions with diols are also high yielding "Equation "49##[ This is in marked
contrast to the Mistsunobu reactions mentioned earlier[
CO2Et
LDA, THF, –78 °C, 1 h
CO2Et
(46)
TsO 45%
(37) (38)
92 : 8
TsO
LDA, THF–HMPA, –20 °C to 20 °C, 17 h
(47)
O CO2But 54% O
CO2But
i, ButOK, THF, –78 °C

ii, –20 °C, pH 7
iii, HCl, 5 °C
MsO CO2But iv, heat, 2 h CO2But
(48)
NC 62% NH2
PhO2S SO2Ph
OH H
SO2Ph dead, Ph3P, PhH, 20 °C
(49)
SO2Ph 84%
H
OH SO2Ph dead, Ph3P, PhH, 20 °C SO2Ph

+ (50)
OH SO2Ph 86% SO2Ph
Polycyclic molecules may also be prepared by intramolecular displacement of oxygen leaving

groups\ including the ð0[0[9Łbicyclobutane "28# "Equation "40## ð71JOC1453Ł and spirocycle "39#
"Equation "41## ð76JCS"P1#0110Ł[ Cyclisation of the anion of the sulfone "30# requires more forcing
conditions "009>C# "Equation "42## ð77S743Ł[ Dialkyl phosphate can be used as the leaving group
"Equation "43## ð77H0464Ł^ "in this case the anion is generated by reductive cleavage of an amino!
nitrile#[ Annulation can be e}ected when a bissulfonate is reacted with a molecule with two
nucleophilic centres such as a diester "Equation "44## ð79S278Ł[ This can be used to prepare _ve! and
six!membered rings in 23Ð60) yields[ Moderate to good diastereoisomeric excesses can be obtained
using dimenthyl succinate as the diester with dihalides and bistosylates "Equation "45## ð74JA2232Ł[
Five! and six!membered rings can be obtained from tosylates giving ratios of isomers ×84 ] ³4
trans ] cis[ The chirality is dependent on the enolate geometry[
PhSO2 SO2Ph
BuLi, THF, –15 °C
Pri (51)
91%
Pri H
OTs
(39)
TsO
KOBut, THF, 20 °C
(52)
N 77% N
H
(40)
PhSO2
O OTs O
NaH, toluene, 110 °C
SO2Ph (53)
O 53% O
(41)
Bu OPO(OEt)2 Bu Bu
Pr N CN K, 18-crown-6, THF, 20 °C Pr N Pr N
+ (54)
70% H H
90 : 10
CO2Me
CO2Me PhSO3 2LDA, THF–HMPA, 22 °C
+ (55)
PhSO3 71%
CO2Me
CO2Me
RO2C RO2C
TsO 2LITMP, THF, –78 °C
+ (56)
TsO 61%
RO2C RO2C
R = menthyl 87 : 13 (SS) : (RR)
Intramolecular Friedel!Crafts alkylations are possible "Equations "46# and "47## ð78HCA0426\
89JOC0227Ł[ In the former case\ rearrangement of the secondary carbonium ion to tertiary ion occurs[
H H
P2O5, MeSO3H, 40 °C
+ (57)
73%
HO But
H H
79 : 21
HO
HSO3F, CH2Cl2, –78 °C
(58)
40%
"iv# Cyclic sulfates

Cyclic sulfates "see review ð81S0924Ł\ popularized by Gao and Sharpless ð77JA6427Ł\ are a special
case as they behave very much like epoxides "vide infra#^ they are more reactive "the much better
leaving group more than compensates for the lower ring!strain# and in some cases both oxygen
functions can be displaced[ Copper!catalysed Grignard reagents ð77JA6427Ł "Equation "48## and
dithiane "with the cyclic sulfate of a 0\3 diol# "Equation "59## ð80S236Ł have been used as nucleophiles
and annulation occurs with malonate "Equation "50## ð82JOC2656Ł[
Ph
O2S O
O BnMgCl, Li2CuCl4 (1%), THF, –78 °C PriO2C
CO2Pri CO2Pri (59)
73%
CO2 Pri OH
S
i, BuLi, THF–HMPA, –40 °C to 20 °C
BnO O ii, H2SO4 (aq.), 50 °C BnO S
S
SO2 + CO2Et (60)
60%
BnO O S CO2Et BnO OH
OBn OBn
ButO2C
O2S O NaH, DME, reflux CO2But
OBn + ButO2C CO2But (61)
O
76%
OBn
"v# Miscellaneous reactions

Hydroxyl groups can be displaced by cyanide ions under conditions which generate the chloride
in situ ð56JOC744\ 79S0996Ł[ DMSO is by far the best solvent\ giving yields in the range 34Ð69) for
primary and secondary alcohols[
Phenoxide is the leaving group in the reaction of the phenoxy acetic acid dianion with the
8!borabicycloð2[2[0Łnonyl "8!BBN# derivative "Equation "51## ð89JOC5245Ł[ The reaction goes via an
{ate| complex\ with simultaneous migration of a group from boron and elimination of phenoxide[
Yields are in the range 31Ð89)[ Three! to seven!membered ring ethers can be opened with carbon
monoxide and trialkylsilane under cobalt catalysis to give one!carbon chain!extended diols "Equa!
tion "52## ð78JA6827Ł but the reaction has only been thoroughly investigated for oxiranes[
i, LDA, THF–hexane, 0 °C
ii, add borane, 0 °C
B iii, 66 °C, 6 h
iv, NaOH, H2O2, 0 °C CO2H
PhO CO2H + (62)
60%
Co2(CO)8 (20 mol %)

toluene, 80 °C, 3 d OSiMeEt2
+ CO + Et2MeSiH Et2MeSiO (63)
56%
O
Tetrahydrofuran is ring!opened by "R#! and "S#!"−#!0!amino!1!methoxymethylpyrollidine hydra!

zones in the presence of a silyl tri~ate in high de "Equation "53## ð82S0981Ł[ The silane acts as a
Lewis acid\ activating the cyclic ether[ b!Quaternary acids and esters can be prepared from tertiary
alcohols and 0\0!dichloroethene in concentrated sulfuric acid in moderate to good yield "Equation
"54## ð54AG856\ 74S382Ł[
N
i, LDA, THF, 0 °C
N ii, TBDMS-OTf, –78 °C N
OMe
OMe + O-TBDMS (64)
Ph O 95% Ph
Ph Ph
TBDMS = t-butyldimethylsilyl OTf = triflate >95% de
i, H2SO4, 5 °C, 2.5 h

Cl ii, EtOH, 40 °C, 2 h
OH + CO2Et (65)
Cl 50%
Simple tertiary alcohols can be methylated to give quaternary compounds using Me1TiCl1
ð70CC126Ł or Me2Al at 049>C ð61CC484Ł[
0[94[0[1[1 Allylic alcohol derivatives

Allylic alcohols and their derivatives have proved to be highly versatile molecules due to their
high reactivity and utility[ The adjacent double bond has a great e}ect on the hydroxyl group\
stabilising a positive charge at the allylic position and complexing to transition metals "especially
palladium#[ Attack of a nucleophile can be at the oxygen centre "SN1# or at the distal carbon atom
"SN1?# "with either syn or anti attack# with movement of the double bond "Scheme 6#[ Alternatively
the stabilisation of the positive charge over the allyl system makes an SN0 mechanism possible\
especially under acidic conditions[ The stereochemistry of the reaction greatly depends on the
reagent used as well as on the substrate itself[ Allylic substitution has been reviewed ð79T0890Ł as
have intramolecular reactions ð81T6272Ł[
SN2' SN 2
OX Nu
Nu
Nu
Scheme 7
"i# Main `roup metals and copper
A great range of leaving groups is available on derivatisation of allylic alcohols[ As well as
sulfonate esters\ carboxylic esters\ carbonates\ phosphates and ethers have been used[ Allylic tos!
ylates readily alkylate enolates ð73JA0968Ł\ zinc reagents "Equation "55## ð76JOC3307Ł and 0\2!
dicarbonyl compounds "Scheme 7# ð77CB0350Ł[ In the last case attack occurs at the less hindered
end of the allylic system[ Under copper catalysis organometallic reagents readily displace acetate
and similar leaving groups[ The regiochemistry of attack at allylic acetates has been studied by a
number of groups including Backvall et al[ "Scheme 8# ð89JA5504Ł "and references cited there#[ They
found that the regiochemistry of copper!catalysed Grignard additions to primary allylic acetates
was dependent on a number of factors[ a!Addition was favoured by rapid addition of the Grignard
reagent\ THF and lower temperatures[ g!Attack is favoured by slow addition of Grignard reagent\
higher concentrations of catalyst\ higher temperatures and ether as solvent[ Heterosubstituents at
the d!position also had a g!directing e}ect\ as did addition of BF2 = OEt1[ The solvent e}ect is most
marked when CuCN is used as catalyst[ The remarkable change is believed to be due to competition
between two di}erent catalytic cycles involving di}erent copper species[ Other groups have found
high g!selectivity using CuCN catalyst with allylic pivalates "copper halides tend to give mixtures of
a and g substitution products# ð75JOC1773Ł and solvent e}ects ð67CC0974Ł[ However each system
appears to have its own idiosyncrasies of selectivity "Equation "56## ð72S793Ł[
In cyclic systems the nucleophile often attacks anti to the leaving group\ that is\ the nucleophile
and leaving group are on opposite sides of the allylic moiety[ syn Attack occurs under some
conditions for example allylic carbonates and carbamates where the nucleophile is delivered to the
g!carbon atom from the same face as the leaving group "Equations "57# and "58## ð76JOC786\ 77TL4550\
78JOC2128Ł[ Allyloxybenzthiazoles show a similar e}ect "g\ syn# in 5!membered rings in reactions
involving copper nucleophiles ð89JOC1183Ł[ Denmark and Marble have made use of an asymmetric
SN1? reaction where the leaving group blocks one face of the allyl system and directs the nucleophilic
attack "Equation "69## ð89JOC0873Ł[ In this system ees of up to 84) were obtained[ Displacement
of the dialkyl phosphate unit in compound "31# occurs in high ee with inversion of con_guration
"anti attack at the g!carbon atom# "Equation "60## ð80SL140Ł[ In this case phosphate proved superior
to other leaving groups in respect of both chirality transfer and regioselectivity[ Ethylidene!0\2!
dithiane attacks from the g!position to displace phosphate ð68JOC2317Ł[
THF–dimethyl acetamide
CuCN, 60 °C
+ IZn
Ph OTs CO2Et 80%
Ph
+ (66)
CO2Et Ph CO2Et
87 : 13
Me2CuLi, ether, –10 °C
80% Pri
ClMg CO2Me
+
CO2Me Pri OTs CO2Me
THF, 20 °C
77%
CO2Me
Pri
Scheme 8
R R
CuBr, THF, 0 °C
+ BrMg (67)
OAc O Ph 75% O Ph
R=
Bu
BuMgBr
PhO PhO + PhO
OAc Bu
Solvent Addition time Temp. (° C) cat. (%)

THF 1.5 min –30 Li2CuCl4 2 96 : 4
THF 2.5 h 0 Li2CuCl4 5 14 : 86
THF 2 min –78 CuCN 10 100 : 0
ether 3 min 20 CuCN 10 8: 92
Bu
BuMgBr
Pr OAc Pr Bu + Pr
Solvent Addition time Temp. (° C) cat. (%)

THF 4 min –70 Li2CuCl4 2 99 : 1
THF 30 h 0 Li2CuCl4 10 15 : 85
THF 25 min 0 CuCN 10 99 : 1
ether 3.5 h 0 CuCN 10 0 : 100
Scheme 9
OCOBut
Me2CuLi
(68)
88%
H H
96 : 4 cis : trans 80 : 20 trans : cis
OCONHPh
Me2CuLi
(69)
88%
H H
O R
OMe i, MeLi, ether
O N ii, MeCu, 23 °C
H (70)
66%
R = naphthyl 91% ee
i, CuCN, LiCl, THF, 0 °C

MgCl ii, add phosphate, –78 °C Ph
Ph + (71)
OPO(OPri)2 81%
(42)
The reaction of copper reagents with g!mesyloxy!a\b!enoates has been extensively studied\
especially systems with a chiral centre at the d!position ð81SL658Ł[ Unlike many allylic compounds\
the acetate group in g!acetoxy!a\b!enoates is not displaced by organocopper reagents\ reduction
being the main reaction ð74CC0341\ 77CC338Ł[ Mesylate is displaced in an anti SN1? fashion to give an
a!alkylated g\d!enoate ð78JA3753Ł[ Alkyl or dialkylcyanocuprateÐboron tri~uoride complex is the
best reagent\ giving ×88) a!alkylation in 67Ð87) yield[ The chirality of the new chiral centre is
determined by both mesylate chirality and double bond geometry^ the new double bond is always
"E#[ It is thus possible to prepare all four isomers "i[e[ two enantiomeric pairs# of a\d dichiral
compounds in two ways "Scheme 09# ð78JA3753Ł[ Alkyl groups at the a!C are tolerated "Equation
"61## ð78JOC3944Ł as are protected d!amino groups "Equation "62## ð89AG"E#790\ 80JOC3269Ł[ Zinc
cuprates obviate the need for a Lewis acid in the reaction\ so reducing problems with acid!sensitive
groups ð81JOC0913Ł[ Reduction of the mesyloxy group occurs with vinyl copper reagents but use of
vinyl zinc cuprates overcomes this problem ð82T8368Ł[ In a few cases a syn!SN1? reaction is observed
ð82JOC0196Ł[ For some syn!mesylates\ for example those with a protected ring nitrogen atom
attached at the d!carbon centre\ syn!SN1? is the predominant mode of reaction "Equation "63##[ Only
with bulky groups on copper "e[g[\ But\Pri# are signi_cant amounts of syn!SN1? products seen with
other substrates[
O-TBDMS O-TBDMS O-TBDMS
CO2Me R2CuCNLi2•BF3, THF, –78 °C CO2Me
or
OMs OMs CO2Me R
O-TBDMS O-TBDMS O-TBDMS

CO2Me R2CuCNLi2•BF3, THF, –78 °C CO2Me
or
OMs OMs CO2Me R
R = Me, Et, Pr, Bu
Scheme 10
CuCN, BuLi, THF–hexane

BF3•OEt2, 0 °C
CO2Me CO2Me (72)
TBDMS-O TBDMS-O
97%
OMs Bu
>99 : 1
NH-t-BOC CuCN, MeLi, THF–ether NH-t-BOC

BF3•OEt2, –78 °C
CO2Me CO2Me (73)
93%
OMs
de >93%
RCuCNMgCl•BF3
N-t-BOC THF, –78 °C N-t-BOC N-t-BOC
O O + O (74)
CO2Me CO2Me CO2Me
OMs R R
R Yield (%)
Et 96 36 : 64
Bui 98 25 : 75
But 83 2 : 98
Lewis acid catalysed reactions involving silyl enol ethers give good yields of the g\d unsaturated
ketones "Equation "64## ð73CB211Ł[ An adjacent thioether acts as a directing group in the TMS
tri~ate catalysed reaction of the unsymmetrical acetate "32# "Equation "65## ð80TL3200\ 82BCJ737Ł[
Isomer ratios were in the range 78 ] 00 to 099 ] 9[ The reaction probably proceeds via an episulfonium
ion[ Mukaiyama et al[\ found that the trityl cation catalyses the reaction of allyl ethers "secondary
and tertiary# with silyl enol ethers "Equations "66# and "67## ð68S650\ 75CL0998Ł[ Tertiary ethers react
at the g position while secondary ones give poor a\g selectivity[
OCOMe But
O-TMS ZnCl2, CH2Cl2, 0 °C
+ (75)
But 81%
TMS-OTf, CH2Cl2
SPh –78 °C to 20 °C
+
OAc 82%
O-TMS
(43)
SPh
Pri
Pri + SPh (76)
O
O
89 : 11
Ph3CClO4, CH2Cl2
OMe O-TMS –78 °C, 1 h Ph O O
+ + (77)
Ph But 83% But Ph But
92 : 8
Ph3CClO4, CH2Cl2
OMe O-TMS –78 °C, 4 h Ph O O
+ + (78)
Ph Ph 93% But Ph Ph
48 : 52
Allyl vinyl ethers usually undergo a ð2\2Ł sigmatropic rearrangement "the Claisen rearrangement#
"Chapter 0[06#[ However\ on treatment with 2 M LiClO3 in Et1O\ allyl vinyl ethers rearrange in a
ð0\2Ł sigmatropic fashion to give g\d enones "Equations "68#Ð"70## ð80JA4377Ł[ The reaction is not
concerted\ as shown by the di}erent stereochemical features of the reactions displayed in Equations
"79# and "70# "the former gives largely retention^ the latter exclusively inversion# and by a crossover
experiment with the two ethers "33# and "34# which gives all four possible products[ Pearson|s and
Grieco|s groups have independently discovered that\ under the same conditions\ allylic acetates and
alcohols react with silyl enol ethers and other nucleophiles to give g\d enones ð81JOC1875\ 81TL3624\
82CC409Ł[ Representative examples are shown in Equations "71# and "72# and Scheme 00[ The
concentration of LiClO3 is critical^ concentrations lower than 2 M give substantial amounts of by!
products[ The products obtained are those with the most highly substituted double bond[
O
O
3 M LiClO4, Et2O
(79)
94%
O H O H O H
3 M LiClO4, Et2O
O O O + O (80)
83%
O O
16 : 84
3 M LiClO4, Et2O
(81)
94%
O O
O O
(44) (45)
3 M LiClO4, Et2O, 20 °C, 1 h

+ TMS (82)
82%
Bu OAc Bu
OH CO2Me
O-TBDMS 3 M LiClO4, Et2O, 20 °C, 15 min
+ (83)
86%
OMe
EtO O-TBDMS
3 M LiClO4, Et2O, 0 °C, 1 h

CO2Et
92% Ar
Indole
3 M LiClO4, Et2O, 0 °C, 3 h
Ar
85%
Ar OAc
N
H
TMS
3 M LiClO4, Et2O, 0 °C, 1.5 h
67% •
O Ar
Ar =
O
Scheme 11
b\g!Unsaturated nitriles are the products obtained on treating allylic methoxymethyl "MOM#
ethers with TMS cyanide "Equation "73## ð76CL0056Ł[ The corresponding a\b unsaturated nitriles
are not detected[ For the cyclic systems "4! and 5!membered rings# shown in Equation "74# ð76TL4410Ł
the mechanism of the reaction is probably via Michael attack followed by elimination of acetate "or
silyl ether# rather than by a simple SN1 or SN1? pathway[ Similar reactions on a 1!nitroallyl
acetate system have been carried out ð73HCA150Ł[ Ethers may also be displaced ð73CL0494Ł[ The
displacement reaction for the cyclic ether "35# and similar compounds is solvent dependent[ No
reaction occurs in ether\ elimination to a diene occurs in DME ð82TL3480Ł while in TMEDA SN1?
ring opening takes place "Equation "75## ð81TL1506Ł[
TMS-CN, TrClO4, CH2Cl2, –45 °C

(84)
Ph O-MOM 53% Ph CN
CO2Et CO2Et
BuMgCl, CuI (2.5 mol %), THF, –60 °C
(85)
OAc 78% Bu
OH
O
MeLi, TMEDA–ether, 0 °C
(86)
72% OH
OH
(46)
"ii# p!Allylic intermediates

Loss of the leaving group from an allylic system leaves an allyl cation which can readily co!
ordinate to certain transition metals\ especially palladium and nickel but also iron\ molybdenum
and tungsten[ These allyl transition metal complexes can then react with a variety of nucleophiles
including carbon!based systems[
"a# Palladium and nickel[ Allylic substrates with a good leaving group "e[g[\ halide\ ester\ car!
bonate# readily react with palladium"9# species "usually in the presence of a phosphine ligand# to
give a p!allylpalladium complex "36#"Scheme 01#[ Nucleophiles can then attack at either of the
terminal carbon atoms\ in most cases from the opposite face to the palladium "i[e[\ the reaction
proceeds with overall retention of con_guration#[ However some {hard| nucleophiles react with
inversion[ "Z# Double bonds are often at least partly isomerized "via pÐsÐp complexes# to the more
stable "E#!con_guration[ Nucleophilic attack is usually directed at the less substituted end of the
allylic system[ The regioselectivity of malonate attack on dienyl acetates has been studied but there
is disagreement concerning the details of the selectivity and mechanism ð82JA5598\ 82TL6402Ł[ The
area has been extensively reviewed ð79ACR274\ B!79MI 094!90\ 71COMC!I"7#688\ 71PAC086\ B!74MI 094!90\
75T3250\ 76JOM"223#132\ 81TA0978Ł[ The simplest nucleophile is carbon monoxide\ which can readily
act as a ligand for many transition metals including palladium[ Carbonylation of allyl phosphates
and acetates can be accomplished in the presence of a hindered base to give b\g enolates "Equations
"76# and "77## ð82JOC0427Ł[ The reactions proceed best under pressure but acceptable yields can be
obtained at atmospheric pressure[ The carbonylation of allylic acetates requires the presence of
sodium bromide to displace acetate from the coordination sphere of palladium\ otherwise acetate
rejoins to the allyl unit[ Carbonylation occurs at the least substituted end of the system\ with
isomerisation to the "E#!alkene taking place in the disubstituted examples[ The reaction proceeds
with inversion of con_guration "Equation "78## as CO migrates intramolecularly from palladium to
the allyl unit\ rather than attacking from the opposite face[ Other examples involving carbamates
ð81SL212Ł and cyclic carbonates ð76TL2386Ł have been reported[
Pd0 Nu
R1 R2 R1 R2 R1 R2
OX PdLnn Nu
Nu
(47)
R2 Pd0 R2 R1 R2
R1 OX PdLnn
Nu
R1
Scheme 12
Pr CO (30 atm), 0.5 mol% Pd2(dba)3•CHCl3

Ph3P, Pri2NEt, EtOH, 50 °C
or (87)
Pr OPO(OEt)2 OPO(OEt)2 Pr CO2Et
74–88%
84 : 16 (E) : (Z)
OAc CO (60 atm), 2 mol% Pd2(dba)3•CHCl3 CO2Et

Ph3P, NaBr, Pri2NEt, MeOH, 50 °C
(88)
59%
95 : 5 (E) : (Z)
CO2Me CO2Me
CO (60 atm), Pd2(dba)3•CHCl3
Ph3P, Pri2NEt, MeOH, 50 °C
(89)
68%
OPO(OEt)2 CO2Me
100% cis 4 : 96 cis : trans
Cyanation of allylic acetates and carbonates can be carried out using TMS!CN ð82JOC05Ł "Equa!
tion "89##[ Alkene isomerisation was observed^ the "E# ] "Z# ratios depend on the bulk of the
substituents[
TMS-CN, (Ph3P)4Pd, THF, 67 °C

or
OCO2Me 80–89%
OCO2Me
+ (90)
CN
CN
71 : 29 (E):(Z)
Compounds with an acidic hydrogen atom attached to a carbon centre will act as nucleophiles in
the palladium!catalysed allylation reaction[ Malonate anion displaces phosphate\ acetate and other
leaving groups "Equations "80# and "81## ð71TL4438\ 78JOC1648Ł[ The overall stereochemistry of
replacement of the leaving group is retention of con_guration\ with isomerisation of acyclic "Z#
double bonds[ When carbonates are used as leaving groups\ alkoxide is generate in situ and so it
is not necessary to provide a base to deprotonate the nucleophile "Equation "82## ð74JOC0412Ł[
Isocyanocarboxylates also react in good yields ð76TL3738Ł[ Reactions can be carried out intra!
molecularly "Equation "83## ð73TL4810\ 78TL506Ł[ In the last case there is a very high degree of
chirality transfer[ Most compounds with two electron withdrawing groups attached to a carbon
centre "i[e[ 0CH"EWG#1# will act as nucleophiles[ Less stabilized nucleophiles such as nitro com!
pounds\ nitriles\ sulfones and ketones can be allylated using diallyl carbonate ð74JOC0412Ł[ Allenyl
phosphates also react with stabilized nucleophiles "Equation "84## ð77S872Ł[
i, NaH, THF
ii, add acetate, (Ph3P)4Pd MeO2C OAc
CO2Me
THF, 25 °C
(EtO)2OPO OAc
+ (91)
72% CO2Me
CO2Me
i, NaH, THF
CO2Me
ii, add acetate, (Ph3P)4Pd
CO2Me
HO OAc THF, 20 °C HO
+ CO2Me (92)
CO2Me 86%
O Pd2(dba)3•CHCl3, Ph3P CO2Me

THF, 30 °C
Ph OCO2Me + CO2Me Ph (93)
90%
O
O O
CO2Me Pd2(dba)3•CHCl3, L CO2Me
O OCO2Me NaH, DMSO–THF, 40 °C O
(94)
53–88%
C5H11 C5H11
P
O O
L= O
Et
Ph Li Pd(dba)2, Ph3P
THF, –78 °C to 20 °C • N Ph
• + CO2Me
(95)
OPO(OEt)2 Ph N
51%
MeO2C Ph
When the allylic unit contains an allylic silyl or stannyl group a palladium!coordinated trimethyl!
enemethane "TMM# synthon is formed which can be used to annelate a _ve!membered ring onto
activated alkenes "Equation "85## ð75AG"E#0\ 78JA6376Ł[ Spirosystems can be prepared with moderate
diastereoselectivity ð78TL0384Ł[ Trost et al[ have obtained some diastereoselectivity in the reaction
using a cyclic chiral auxiliary "Equation "86## ð78JA5371Ł[ This type of reaction also encompasses
additions to vinyl sulfoxides ð78TL0792Ł\ imines ð75CC0190Ł\ aldehydes ð89JA397Ł and dienes
ð76JA2372Ł "generating cycloheptenes#[ A related reaction is the palladium!catalysed addition of
1!bromozincmethyl allylic ethers to ketones and imines ð77TL2468\ 82TL2298Ł[
TBDMS-O OAc TBDMS-O
H
Pd(OAc)2, (PriO)3P
PhMe, 80 °C
+ (96)
SO2Ph TMS 87%
SO2Ph
TMM =
Pd
Me OAc Me
O O O
N Pd(OAc)2, (PriO)3P N
PhMe–dioxan, 110 °C
+ (97)
Pri O Ph TMS 84%
O Ph CO2Me
O Pri O Pri CO2Me
A number of groups have investigated enantioselective allylic substitutions using chiral ligands
to coordinate the palladium with varying success "reviews]! ð80COS"3#474\ 81TA0978\ 82AG"E#436Ł[ Most
of the systems have symmetrically substituted allyl units with termini rendered enantiotopic by the
chiral ligands on palladium[ Most ligands used only give high ees in a few cases[ Representative
examples are shown in Scheme 02 ð77PAC6\ 80HCA121\ 82AG"E#455\ 82TL0658\ 82TL2038Ł[ Asymmetric
ð2¦1Ł cycloadditions "up to 62) ee# ð78TL264Ł\ enolate alkylations "46) ee# ð75TL3462Ł and
alkylation with chiral enolate "and achiral ligands# "39Ð71) ee# ð80CC261Ł have been reported[
CO2Me MeO2C CO2Me
OAc chiral ligand, Pd0, base
+
Ph Ph CO2Me Ph Ph
OH
N O O
OH O
ligand = PPh2 H Ph Ph
Fe N N
PPh2 N
Pri HO OH
PPh2
Scheme 13
Vinyl tin ethers have been used as nucleophiles and give clean monoalkylation of the resultant
ketones ð79TL1480\ 76CL0126Ł "Equation "87##[ The overall stereochemistry is retention of con!
_guration^ the tin does not co!ordinate to the palladium before adding\ but approaches from the
opposite face[ Examples of additions of Grignard reagents are rare due to competing reactions^
advantages are gained on using copper!based chemistry\ and zinc and tin reagents have been used
ð72JOC4291\ 78JA3870Ł[ Sato and co!workers have reacted a Grignard reagent with chiral silylallyl
phosphates with high regio! and stereo!selectivities "Equation "88## ð82CC0484Ł[ Palladium gave a
much better regiocontrol than nickel and copper and better enantiopurities than iron "³82) ee#[
The silyl unit is only partially responsible for the stereocontrol as the t!butylallyl compound gave
poor regiocontrol[
CO2Me
OSnBu3 CO2Me O
(Ph3P)4Pd, THF, 20 °C
+ (98)
85%
AcO
MeMgBr, PdCl2, dppf
TMS C5H11 THF–ether, –20 °C TMS C5H11
(99)
OPO(OEt)2 69%
>99% ee 97 : 3 α : γ, 98%ee
Allylic acetates and carbonates will react intramolecularly with alkenes and alkynes under pal!
ladium "or nickel# catalysis in a formal {metallo!ene| type reaction ð89PAC0830Ł[ The reaction
proceeds via a p!allyl palladium species with the ole_n inserting into the palladiumÐallyl bond with
overall inversion of con_guration "Scheme 03# ð77TL3694Ł except in a few bicyclic systems where
stereochemical constraints do not allow the formation of trans ring junctions ð76HCA0366Ł[ The
reaction can be combined with carbonylation ð78TL4772\ 83T304Ł[ Stereochemical features have been
investigated ð77TL3698\ 89TL0154Ł and a very high degree of chirality transfer can be obtained with
optically!active allylic alcohols "Scheme 03# ð89TL5884Ł[ The "Z#!allylic acetate isomerizes in situ to
the "E#!alkene of opposite chirality\ probably via a pÐsÐp palladium complex "vide supra#[ A similar
phenomenon has been reported with malonate attack on allyl systems ð78JOC358Ł[ No chirality
transfer is seen with the terminally non!substituted allylic acetates[ The chirality transfer is catalyst
and substrate concentration dependent[
MeO2C CO2Me MeO2C CO2Me MeO2C CO2Me

H H H
(Ph3P)4Pd, AcOH, 70 °C
60%
AcO
H
Pd
t-BOC t-BOC t-BOC t-BOC

N N N N
(Ph3P)4Pd, AcOH, 70 °C (Ph3P)4Pd, AcOH, 70 °C
OAc 60% OAc 70%
98.6% ee >96% ee 98.6% ee >96% ee

(E) : (Z) = 99.6 : 0.4 (E) : (Z) = 1.3 : 98.7
Scheme 14
The reactivity of allylic acetates and alcohols can be reversed in the presence of palladium catalyst
and certain reducing metals[ Allylic acetates and two equivalents of samarium"II# iodide ð75TL0084Ł
or one equivalent of tin"II# chloride ð77CC33Ł in the presence of a palladium complex add to ketones
and aldehydes "Equation "099##[ Allyl alcohols also react ð77JA3362Ł[ The reaction gives an allyl
metal species which then adds to the carbonyl group[ Regio! and stereo!selectivities with these
samarium mediated reactions are not very high[ Diethylzinc may also be used as the reducing agent
ð82TL6508Ł[
SmI2, (Ph3P)4Pd, THF, 0 °C C6H13
Ph OAc + OHCC6H13 Ph (100)
63%
OH
Nickel salts ð71COMC!I"7#602\ 71COMC!I"7#662Ł have also been used in reactions involving allylic
alcohol derivatives and they catalyse a similar variety of reactions ð75JOM"206#272\ 77JOM"228#088Ł
including Grignard additions ð72S690\ 76TL3436Ł[ Some of these reactions utilize chiral phosphine
ligands and generate ees of 1Ð89) "Equation "090## ð74TL2148\ 75T1932Ł[ These reactions\ which do
not work with palladium based reagents\ are very substrate dependent[ Intramolecular insertions
into alkenes have been performed ð77TL5322Ł[ These reactions proceed with a high degree of
chirality transfer "T[ N[ Birkinshaw and W[ Oppolzer\ unpublished results# and high stereoselectivity
ð89TL0154Ł[
MgBr (S,S)-Chiraphos, NiCl2, ether, 20 °C Ph
PhO + (101)
Ph 87%
90% ee
"b# Iron[ Iron carbonyl complexes ð71COMC!I"3#266\ 71COMC!I"7#828Ł of allylic ethers and car!
bonates can be prepared from diiron nonacarbonyl or Bu3NðFe"CO#2NOŁ ð76JOC863Ł[ Iron\ which
can form h2\ h3 as well as h4 complexes\ tends to react with nucleophiles at the site at which the
leaving group was attached^ being con_gurationally more stable than the corresponding palladium
complexes "Scheme 04# ð74JOM"174#C02Ł[ Regioselectivities range from 53 ] 25 to 099 ] 9[ Chirality
transfer is high "Equation "091## ð77JOC3308Ł[ The stoichiometric iron complexes of g!alkoxyenoates
react with silylenol ethers in the presence of a Lewis acid "Equation "092## ð82TL3386Ł[ "Z# Double
bond geometry is retained if ZrCl3 is used as Lewis acid[ The intermediate iron complexes can be
prepared from vinylic epoxides and cyclic sulfonates ð89SL113Ł[ The iron complexes also allylate
electron!rich aromatic systems ð76TL4304Ł[
OCO2Et
100 : 0
Bu4N+ Fe(CO)3NO 76%
CO2Me (25 mol%) CO2Me
or + Na+ – + CO2Me
CO (1 atm) CO2Me
CO2Me
THF, 67 °C
OCO2Et 7 : 93 CO2Me
78%
Scheme 15
Bu Bu4N+ Fe(CO)3NO (25 mol %) Bu

CO2Me CO (1 atm), THF, 67 °C
+ Na+ – (102)
OCO2Me 80%
CO2Me MeO2C CO2Me
>95% ee >95% ee
O-TMS i, Fe2(CO)9, ether O

ii, BF3•OEt2, silyl, CH2Cl2
BnO iii, Me3NO
+ (103)
O 81% O
"c# Other metals[ A number of other metals catalyse the reaction of allylic alcohol derivatives
with nucleophiles[ Molybdenum catalyses the reaction of allyl acetates ð76T3706Ł and carbonates
ð76BCJ0414Ł with a di}erent regiochemistry to that displayed in the corresponding palladium cat!
alysed reactions^ attack at a secondary centre is preferred over attack at a primary site with
some anions but requires much higher temperatures "½099>C#[ Tungsten also gives a di}erent
regiochemistry\ tending to react at the more substituted end regardless of the nature of the nucleo!
phile ð73JA5726\ 76JA1065Ł[ Ruthenium complexes catalyse allylation of aldehydes ð78JOM"258#C40Ł
while rhodium has been used for allylation under neutral conditions ð73TL4046Ł as well as for
carbonylations ð74CL0366Ł[ A number of di}erent metals has been used and these results have been
surveyed ð74JOM"185#158Ł#[
"iii# Rearranèments
Rearrangements such as the ð1\2Ł!Wittig rearrangement will be covered elsewhere "see reviews
ð69AG"E#652\ 75CRV774\ 80COS"2#864\ 82TL7936Ł#[
"iv# Miscellaneous reactions

Carbenes\ generated from diazo!compounds\ insert into the C0O bond of allylic ethers under
rhodium or copper catalysis "Scheme 05# ð75JA5959\ 82TL3274Ł[ In this case rhodium gives mostly the
product from C0H insertion[ Reduced zirconocene "{Cp1Zr|# inserts into allyl ethers to give
allylzirconium species which can react with electrophiles such as aldehydes "Equation "093##
ð81TL0184Ł[ Propargylic ethers give mostly acetylenic compounds with some allenic by!products
ð81TL2658Ł[ C0C Bonds may be formed intramolecularly "Equation "094## ð82JA7724Ł[ Stereo!
selectivities range from 64 ] 14 up to 099 ] 9 for the formation of four! and _ve!membered rings[
Zirconocene catalyses selective g!displacement of alkyl ethers\ probably via a zirconocycle inter!
mediate ð82JA7374Ł[
O Cu(hexafluoro-acac)2 O
CH2Cl2, 40 °C Rh2(OAc)4, THF, 67 °C O
83% N2 58% + 12% (48)

O O O
(48)
Scheme 16
i, Cp2ZrCl2, BuLi OH
hexane, –78 °C
ZrCp2 ZrCp2 (104)
OBn ii, add alkene, THF Ph
OBn OBn
–78 °C to 0 °C
iii, PhCHO, 0 °C 64 : 36
i, Cp2ZrCl2, BuLi, hexane, –78 °C

O
ii, add alkene, THF, –78 °C to 0 °C
BnO OMe iii, BF3•OEt2, –20 °C BnO OH
(105)
65%
BnO OBn BnO OBn
0[94[0[1[2 Propargylic alcohol derivatives

Propargylic alcohol functions "and halides# are readily isomerized to allene derivatives when
treated with nucleophiles[ The reaction of the former compounds with copper!based reagents has
been studied by Macdonald et al[ "Scheme 06# ð79JOC3639Ł[ Their results suggest that the extent of
direct displacement of the leaving group "acetate\ methyl carbonate or tosylate# is dependent on the
nature of the copper species and steric bulk on the alkyne\ but much less so on solvent\ temperature
and leaving group "Equation "095##[ Bulkier groups on copper give no allenic products ð67CC765Ł[
Cleavage of the leaving group can be a problem with some reagents[ Badouy and Gore ð70JCR"S#167Ł
have shown that the steric bulk of the cuprate reagent "in their case mixed ones# favours alkyne
over allene formation "Equation "096##[ Direct displacement of a silyloxy group with Grignard
reagent has been reported "Equation "097## ð65JCS"P0#0273Ł[
R 'RCu' X 'RCu' R
•
Scheme 17
0 °C
+ + (106)
87–95%
OAc OH
•
C5H11 C5H11 C5H11
C5H11
Me2CuLi ether 26 : 21 : 53
MeCu•MgBrI THF 72 : 17 : 11
MeCu•LiBr•MgBrI THF 0 : 100 : 0
O O O O
Cu– THF, (Me2N)3P, –78 °C
C5H7 + TsO (107)
80%
C5H11 C5H11
Li+
OMe O-TMS i, 2 EtMgBr, THF, reflux OMe Et

ii, CO2
iii, CH2N2
(108)
67% CO2Me
MeO OEt MeO OEt
Displacement of the mesylate derived from the alcohol "38# appears to be direct but actually
proceeds through the intermediacy of a chiral allenic bromide\ which can be isolated "Scheme 07#
ð77G746Ł[ Terminal propargylic mesylates can be displaced by reaction with zincates\ giving allenyl!
zinc species\ which can subsequently react with electrophiles ð82JOC5055Ł[ Both regio! and stereo!
selectivities are good "Equations "098# and "009##[
i, BuLi, MsCl
OH THF, –70 °C BuMgCl, CuBr Bu
ii, LiCu2Br3, –70 °C LiBr, –70 °C
•
60%
Br
(49)
Scheme 18
O
OMs i, Bu3ZnLi, THF, –85 to 0 °C
ii, MeCOCl, –85 °C O
+ (109)
Ph 80%
Ph Ph •
Bu
Bu
89 : 11
OH
OMs i, Bu3ZnLi, THF, –85 °C to 0 °C
ii, ZnCl2
iii, EtCHO, –85 °C
(110)
89%
97 : 3 isomer ratio
The anions of a!phenoxy alkynes react with boranes in a similar fashion to a!phenoxy acid
derivatives "see Section 0[94[0[1[0"v## "Equation "000## ð68SC798\ 71ACR067Ł[ In the absence of HMPA
allenes are produced[
i, BuLi, TMEDA, –78 °C

ii, add borane, –78 °C
OPh iii, AcOH–HMPA, –40 °C to 0 °C Bu
+ Bu3B (111)
TMS 51%
TMS
The Nicholas reaction ð76ACR196Ł occurs between the dicobalt hexacarbonyl complexes of pro!
pargylic alcohols or ethers and nucleophiles and it is a simple way of avoiding the problems of
isomerisation to allenes[ Alkynes readily react with dicobalt octacarbonyl to give dicobalt hexa!
carbonyl complexes[ Treatment of these compounds with either protic acid "usually HBF3# or Lewis
acid gives the stabilized carbonium ion "49# which can then react with a variety of nucleophiles
"Scheme 08#[ The carbonium ion will also undergo Friedel!Crafts type alkylations[ Addition of
aluminum alkyne to the cobalt complex of the propargylic ester "40# with subsequent oxidative
removal of the cobalt gives the skipped diyne "41# "Equation "001## ð72TL1128Ł[ 0\2!Dicarbonyl
compounds can be used as the nucleophile ð67TL3238Ł[ Reaction of Evans!type boron enolates with
cobalt alkynes gives good yields and selectivities "Equation "002## ð76JA4638\ 82TL1470Ł[ Intra!
molecular aldol condensations have been reported in a ten!membered ring "calichemycin*espera!
mycin ring system# ð78TL740Ł or with the alkyne unit as an exocyclic feature ð82SL658Ł[ Allylsilanes
also react inter! ð79TL0484Ł and intramolecularly "Equation "003## ð75JA2017Ł[ Six! to eight!mem!
bered rings were prepared with the intermediate cobalt complexes being further reacted[ Radical
dimerisations of the cobalt complex have been reported ð83TL252Ł[
R2
R1 OR4 R4 = H or Me
R3
Co2(CO)8
O-TMS O
R2 OR4 R2 i, R7 or R7 R2
HBF4 or R6 R6 R3 O
R1 R3 Lewis acid R1 + ii, [O] R1
R3
(CO)3Co Co(CO)3 Co2(CO)6 R6
R7
(50)
i, R53Al i, TMS
ii, [O]
ii, [O]
R2 R2
R1 R5 R1 R3
R 3
Scheme 19
i, Co2(CO)8, CH2Cl2
ii, add alane, 0 °C
iii, can, Me2CO, –78 °C
+ (Bu )3Al (112)
OAc 63%
Bu
(51) (52)
O OBBu2 OMe O O
i, Bu2BOTf, CH2Cl2, –78 °C
TMS ii, can
O N O N
+ (113)
(CO)3Co Co(CO)3 85–98%
Pri Pri TMS
syn : anti = 98 : 2
TMS BF3•OEt2, CH2Cl2, –78 °C

(114)
OMe 67%
(CO)3Co Co(CO)3 (CO)3Co Co(CO)3

The intermediate carbonium ions are\ in principle\ chiral but undergo rapid epimerisation at the
carbonium centre ð76JA4638Ł so that\ although they will react with high de with optically active
substrates only racemic products are obtained from reaction with optically inactive nucleophiles[
Ca}yn and Nicholas have prepared the complex "42# with a phosphine ligand which is stable enough
for the two diastereomers to be separated ð82JA5327Ł "the alkyneÐcobalt complex is a chiral centre#
"Equation "004##[ These compounds reacted with silylenol ethers with modest to good dias!
tereoselectivity "0[0 ] 0Ð09[4 ] 0#[
i, Co2(CO)8
OH ii, phosphite, 50 °C
HO Ph HO Ph
Ph + (115)
50–75%
H H
H
L(CO)2Co Co(CO)3 (CO)3Co Co(CO)2L
phosphite, L = [(CF3)2CHO]3P (53) 57 : 43
0[94[0[1[3 Benzylic alcohol derivatives

The increased reactivity of benzylic compounds compared to the corresponding alkyl derivatives
means that a greater choice of leaving groups is available^ reactions proceed under mild conditions[
Halides "often chlorides# "see Chapter 0[93# are used but many oxygen functions can be readily
displaced due to the stabilising e}ect of the adjacent aromatic ring[ Hydroxyl groups can be displaced
by a cyanide ion\ using trialkylphosphine:carbon tetrachloride to generate the chloride in situ
"Equation "005## ð56JOC744\ 79S0996Ł[ Benzyl alcohol reacts with o!nitroarylacetonitrile "43# under
Mitsunobu conditions "Equation "006## ð80TL6084\ 82H"24#238Ł[ Both of these methods work for
allylic and primary alcohols\ while the latter procedure has been used on secondary alcohols[
Tri~ates may be displaced by alkynes\ even in the absence of base "Equation "007## ð71JOC3466Ł[
The reaction probably proceeds via an SN0 mechanism[ Benzylic hydroxyl groups may be substituted
by in situ preparation of the acetate followed by displacement with cyanide or alkyne under slightly
acidic conditions "Scheme 19# ð75S578Ł[ This largely gets round the problem of a competitive
elimination process observed with some secondary benzylic compounds[ Similar conditions allow
the alkylation of silylenol ethers with benzylic compounds "Equations "008# and "019## ð73CB211\
75AJC1984\ 89H"20#0248Ł[ Stereochemical details are not given for most examples cited in the literature[
Benzylic alcohols can be allylated with allyltrimethylsilane:BF2 in variable yield "Equation "010##
ð71JOC1014Ł[ The reaction is limited to bisbenzylic and tertiary benzylic alcohols^ other alcohols give
low yields[ Neighbouring groups may e}ect the course of a reaction[ The o!methoxy group is
necessary for displacement of the carbonate of the alcohol "44#\ for in its absence only the dimethyl!
amino group is displaced "Equation "011## ð89SC2236Ł[ Some p!nitro!t!benzylic esters and ethers
can be displaced by carbon nucleophiles via an electron!transfer mechanism "Equation "012##
ð77JOC0364Ł[
KCN, Bu3P, CCl4
OH 18-crown-6, MeCN, 20 °C CN
(116)
82%
i, Ph3P, dead, THF, 0 °C CN

MeO
CN OH ii, add alcohol MeO
+ (117)
70%
NO2
NO2
(54)
Ph CH2Cl2, 40 °C
Ph
OTf + Ph Ph (118)
Ph 73% Ph
CO2Et
O HO2C
O i, ZnCl2, CH2Cl2, 0 °C to 20 °C
OMe OEt ii, KHSO4 (aq.)
+ (119)
O-TMS 86%
OMe
60 : 40
i, Ac2O, pyridine
ii, Et2AlCN, THF, 0 °C CN
89%
MeO
OH
MeO
i, Ac2O, pyridine
ii, alkyne, ether, 0 °C
89%
Ph
alkyne = Et2Al Ph MeO
Scheme 20
O O
O
O-TMS ZnX2, CH2Cl2, 22 °C
+ (120)
X = Cl, 66%
X = I, 91%
OH
BF3, CH2Cl2, 0 °C
+ TMS (121)
100%
OH CN
MeO i, EtO2CCl, NaHCO3, PhH, 20 °C MeO

NMe2 ii, KCN, DMF, 20 °C CN
(122)
73%
(55)
NO2
O2CPh HMPA, 20 °C, 2 h
+ LiMe2CNO2 (123)
O2N 70% O2N
1!t!Butylphenol is alkylated in moderate yield to give only one isomer "Equation "013## ð70S014Ł^
similarly the anthraquinone featured in Equation "014# is alkylated at its most reactive position
ð64BCJ1828Ł[
Ph
Ph AlCl3 (0.5 equiv.), Et2O, 30 °C Ph

OH + (124)
62%
Ph HO HO
But But
OH
O
HO H2N HO
O O SnCl4, dioxan, 101 °C O

+ (125)
81% NH2 O
O O O
The per~uorinated sulfonic acid resin Na_on!H has been used to catalyse benzylation of benzene
and substituted benzenes ð80JOC1978Ł[ The advantages of this catalyst are the relatively mild con!
ditions employed and the ease of work!up "_ltration#[ Small amounts of the bisbenzyl ethers are
found "Equation "015## but yields are generally quite good^ ortho:para selectivities are similar to those
obtained with more conventional systems "Equation "016##[ Bisbenzylation is possible[ Bisbenzyl
compounds can also be prepared from the Friedel!Crafts alkylation of chromium tricarbonyl
complexes of benzyl alcohols "see below# ð82SL212Ł[
OH Nafion-H, PhH O
+ (126)
reflux R R
R R
R Yield (%) Yield (%)

H 54 16
4-Me 81 3
4-But 85 2
4-NO2 52 19
OH Nafion-H, PhMe, 90 °C
+ (127)
70%
Me
o : m : p 42 : 3 : 55
Simple benzyl alcohols are carbonylated by carbon monoxide in the presence of dicobalt octa!
carbonyl catalyst\ often at high temperature and pressure ðB!79MI 094!91Ł[ Chain extended esters
and amides can be prepared in variable yields "19Ð71)# under much milder conditions ð71BCJ532\
77JOC2295Ł "Equations "017# and "018##[ Reductive carbonylation can be performed under similarly
mild conditions "14>C\ 0 atm# using trimethylsilane as the reducing agent "Equation "029##
ð89JOC4812Ł[ The one!carbon extended silyl ethers are the products[
CO (1 atm), Pri2NH, Co2(CO)8 (5 mol%)

OH NaI, ethyl polyphosphate, 20 °C CONPri2
(128)
MeO 47% MeO
CO (1 atm), MeOH, Co2(CO)8 (5 mol%)

OH NaI, ethyl polyphosphate, 20 °C CO2Me
(129)
77%
CO, TMS-H, Co2(CO)8

PhH, 1 atm, 25 °C
OAc (130)
O-TMS
S 59% S
Arene chromium tricarbonyl complexes are readily prepared from the corresponding arenes[ They
can display quite di}erent chemical properties from the parent arenes ðB!80MI 094!90\ 82SL212Ł\ for
example they have the ability to stabilize a carbonium ion at a benzylic position[ The metal can be
readily removed under mild oxidative conditions such as atmospheric oxygen and sunlight[ In some
respects arene chromium tricarbonyl complexes are the aromatic equivalents of the cobalt complexes
of alkynes but unlike such cobalt complexes the chromium complexes are con_gurationally stable\
with implications for the synthesis of chiral materials[ The area has recently been reviewed
ð82SL212Ł[
The chromium complexes of benzyl alcohols "45# readily form the carbonium ions "46# which
react with Grignard reagents or undergo an intramolecular reaction "Scheme 10 and Equation
"020## ð76JOM"225#032\ 78TL2470Ł[ The latter case demonstrates the stereochemical course of the
reaction which involves a double inversion at the benzylic centre[ Benzylic acetates react with silyl
enol ethers ð72TL1726Ł and trimethylaluminum "Equations "021# and "022## ð75JOC1748\ 75TL856\
75TL1368Ł and the corresponding alcohols react with allyl silanes and b!dicarbonyl compounds
ð75JOM"188#008Ł[ Bicyclic "5\4 and 5\5# systems have also been used[ In these cases inversion of
con_guration at the benzylic centre occurs "Equation "023## ð74TL656\ 75S275\ 89JOM"271#010Ł[
R2
+
R1
Cr(CO)3
OH BuMgBr, ether, –40 °C Bu

HBF4 or HPF6
R2 R2
1 20–55% 1
R R
Cr(CO)3 R2 Cr(CO)3
(56)
R1
Cr+(CO) 3
(57)
Scheme 21
(CO)3Cr
HBF4
MeO HO Cr(CO)3 (131)
MeO
76%
N Me
N
MeO Me MeO
>98% ee
O
OAc O-TMS ZnCl2, CH2Cl2, 22 °C
+ (132)
84%
Cr(CO)3 Cr(CO)3
i, Ac2O
ii, Me3Al
(133)
OH 68%
Cr(CO)3 Cr(CO)3
( )n ( )n
Me3Al
(134)
OAc
Cr(CO)3 n =1, 2 Cr(CO)3
ortho Substituents can a}ect the stereochemical course of a reaction as the syn conformer is much
less stable than the anti conformer "Equation "024##^ loss of stereochemical integrity has been seen
in some systems ð82SL212Ł[ However the two diastereomerically pure acetates "47# and "48# give the
corresponding products stereospeci_cally "Scheme 11# ð75JOC1748Ł[
R
+
+
R
(135)
X X
(CO)3Cr (CO)3Cr
anti syn
OAc
Me3Al, CH2Cl2, –78 °C to 0 °C
(CO)3Cr Pri 74% (CO)3Cr Pri

OMe OMe
(58)
OAc
Me3Al, CH2Cl2, –78 °C to 0 °C
H H
Pri 53% Pri
(CO)3Cr (CO)3Cr
OMe OMe
(59)
Scheme 22
0[94[0[2 Opening of Epoxides

Epoxides "oxiranes# are special cases of oxygen!functionalised groups in that two adjacent carbon
atoms are involved[ Displacement of oxygen at one centre still leaves the other C0O bond in place\
and so the process constitutes a synthesis of alcohols[ Although this topic will be covered in Chapter
1[91[0 "for related rearrangements see Chapter 0[02[3# the following text gives an overview of the
area from the point of view of carbon nucleophiles displacing oxygen leaving groups to give a
carbon atom with no attached heteroatoms[ Vinyl epoxides "ethenyloxirane derivatives# which can
react via SN1 or SN1? fashions\ glycidic epoxides and oxetane derivatives are also discussed[
Synthetically useful reactions of epoxides have been reviewed ð73S518Ł and sections 1[2 and 1[3
of that review "which deal with the opening of epoxides with carbon nucleophiles and intramolecular
reactions# are particularly relevant to this discussion[
0[94[0[2[0 Simple epoxides

CarbonÐcarbon bond formation by the opening of epoxides with carbon nucleophiles\ both
stabilized and non!stabilized\ is very well documented in the literature and has been widely used in
synthesis[ A good overview of the area is provided in the review ð73S518Ł[
"i# Unstabilized nucleophiles

The carbonÐoxygen bonds of epoxides are strained[ However\ since alkoxides are normally poor
leaving groups\ coordination of the epoxide oxygen atom "to metal or Lewis acid# greatly facilitates
displacement of the oxygen atom[ Organolithium\ organomagnesium\ organoaluminum and organo!
copper are the most common reagents used in this process and each has its own advantages^ in
particular alkyl\ alkenyl and aryl copper reagents have found widespread use as\ in general\ they
have proved superior to lithium and magnesium reagents[
The reaction of styrene oxide "59# with carbon nucleophiles illustrates the e}ect of di}erent
metals[ Three di}erent products can result depending on the reagent used[ Methyl Grignard gives
a 49 ] 49 mixture of the rearrangement product "52# "common for this type of reagent due to the
Lewis acidity of magnesium halides# and the product "50#\ the less Lewis acidic dialkyl magnesium
gives only the product "50# formed by attack at the more substituted carbon atom while normal
cuprates and higher order cuprates give a reversal of selectivity "Scheme 12# ð66TL2396\ 67TL1288\
71JA1294Ł[ Halohydrin formation can also be observed[
Simple lithium and magnesium reagents are now little used to open epoxides due to the superiority
of cuprates and other reagents[ Very polar solvents such as HMPA and DMSO do allow acceptable
yields to be obtained with alkenyl and alkynyl lithium reagents "Equations "025#\ "026# and "027##
ð64TL40\ 67S15\ 70S389\ 70S764Ł[ Several groups have reported that BF2 = Et1O catalyses the addition of
lithium reagents to epoxides in good yields ð71TL4118\ 72JA4835\ 72TL4010Ł[ The method is especially
useful for alkyne nucleophiles where copper reagents are not useful "Equation "028## ð72TL280Ł[
Ganem and co!workers have studied the mechanism and synthetic utility of this process "Equation
"039## ð73JA2582Ł[ Alkylboron ~uorides are not involved and the reaction is believed to go via
BF2 = Et1O coordination to the oxygen atom followed by nucleophilic attack[ In a few cases traces
R
OH Yield (%)
Ph
(61) Reagent (61) (62)
Me(CN)CuLi 81 18
OH Bu(CN)CuLi 74 21
O
Bu2Cu(CN)Li2 8 85
R
Ph Ph
(60) (62)
O R
Ph Ph
OH
(63)
Scheme 23
of product arising from attack on the THF solvent were observed[ Nonetheless this is now the
method of choice for opening epoxides with alkynes[
OH
DMSO, 25 °C, 24 h
O + Li (136)
92%
i, BuLi, HMPA
O ii, add epoxide, THF, –78 °C
+ (137)
• 83% • OH
OH
HMPA, NH3, –40 °C
O + Li (138)
60%
OH
BF3•OEt2, THF, –78 °C
O + Ph Li (139)
100%
Ph
Ph
BuLi (3 equiv.), BF3•OEt2
O THF, –78 °C, 10 min Ph OH
+ (140)
Ph 100%
OH
64 : 36
The dianion of the allylic alcohol "53# "deprotonated with Schlosser|s base# opens cyclohexene
oxide to give\ after oxidation\ the lactone "54# "Equation "030## ð72SC126Ł[
i, BuLi, ButOK, hexane, 20 °C H

ii, HCl O O
iii, MnO2
O + OH (141)
40%
H
(64) (65)
Lithium reagents have been converted into samarium and other lanthanide reagents in order to
open epoxides in high yield "Equation "031## ð75AG"E#659Ł[ Similarly gallium reagents "prepared
with a catalytic amount of trimethylgallium# can be used "Equation "032## ð73TL4312Ł[
i, MeLi, Sm[N(TMS)2]3, ether, 1 h, –78 °C OH
ii, 20 °C, 1 h
O (142)
100%
Me3Ga (16 mol %), THF

hexane, 0 °C to 20 °C, 1 h HO
O (143)
+ Li C6H13
92% C6H13
Organocuprates have proved to be very useful reagents for opening epoxides and have found
wide application in organic synthesis "see reviews ð76S214\ 89SL008\ 81OR"30#024\ 64OR"11#142Ł#[ Copper
reagents can be generated from Grignard reagents and a catalytic amount of copper salt\ "usually
copper iodide# and they react with epoxides "Equations 033Ð035# ð67CL662\ 71TL0156\ 75TL4680Ł[ In
the last case "Equation "035## the hydroxyl group must be protected before Grignard addition[ In
the _rst case "Equation "033## absence of catalyst gives a mixture of bromohydrin and rearrangement
product[ Yields are in the range 30Ð66)[ In Equation "036# attack from the g!position of the allylic
Grignard reagent "4# occurs in the absence of catalyst while\ with 09) CuI present\ attack occurs
from the a!position ð67TL3958Ł[ Preformed {lower!order| organocuprates "Gilman reagents# add
to epoxides "Equation "037## ð63JA4143Ł\ "Equation "038## ð79TL3254Ł but unlike mixed cuprates
"Equation "049## ð66TL2396Ł\ su}er from the disadvantage that only one of the alkyl groups is used[
OH
TMS MgBr CuI (5 mol %), THF, –30 °C
O + (144)
77% TMS
Et Bu MgBr Bu
CuI (0.1 equiv.), THF, 0 °C
+ TMS (145)
TMS Et
O 93% OH
O i, TMS-Cl OH
ii, Grignard, CuI, –78 °C
BnO iii, K2CO3, MeOH
BnO
MgCl
+ (146)
70%
OH OH
OH
O MgBr
+ + (147)
OH
(5)
No CuI 9 91
10% CuI 99 1
OH OH
Bu2CuLi, ether, –26 °C
(148)
Bu O 82% Bu Bu
OH
O
O O
O furyllithium (3 equiv.), ether, –20 °C
+ (149)
Cu But
But 75%
Li
OH
O BuCuCNLi, ether, –78 °C OH

(150)
92% Bu
{Higher!order| cuprates have been developed which readily open epoxides in good yield[ "Equa!
tions "040# and "041## ð71JA1294\ 73JOC0036Ł[ Higher order cuprates which have dummy or non!
transferable ligands such as thiophene and cyanide also open epoxides "Equation "042##
ð74JOM"174#326\ 77TL782Ł[ The greater di.culty of preparation of these latter reagents must be
balanced against the value of half of the ligand being discarded in a reaction involving a simple
dialkylcuprate[ Allyl groups can be used to open epoxides by preparing the cuprates from allyltin
reagents ð89JA3952Ł or by using highly activated copper prepared by the reduction of copper salts
ð82TL2952Ł "Scheme 13#[ In the latter case a methyl group is used as a dummy ligand[ Both of these
methods avoid Wurtz coupling of the allyl moieties[
O Bu2CuCNLi2, THF, –20 °C, 2 h OH
Ph Ph (151)
96%
Bu
O THF, –30 °C OH
BnO + Cu2– CN (152)
86%
BnO
2Li+
O S THF, –78 °C to 0 °C OH
Ph + Cu2– CN Ph (153)
81%
Li+, Na+
Me2CuCNLi2 THF, 0 °C, 1 h

SnBu3 CuCNLi2 + O
90%
2 OH
THF, –78 °C to –20 °C

i, Li naphthalenide + CuCN, LiCl 2h
ii, methylallyl chloride
CuCNLi2
+ O
iii, MeLi, –90 °C 98%
2.5 equiv.
Scheme 24
Lewis acid catalysis\ speci_cally BF2 = OEt1 catalysis\ has proved bene_cial to some cuprate
additions to epoxides ð73TL4848Ł "Equation "043##[ Other Lewis acids gave low yields[
OH
CN ether, –78 °C, 2 h
O + (154)
S Cu2– BF3•Et2O (1 equiv.), 86%
no BF3•Et2O, 0%
Bun
2Li+
Organoaluminum reagents open epoxides readily but have found greatest utility for the transfer
of alkenyl and alkynyl groups[ Alkenylaluminum reagents are readily prepared from alkynes via
carbo!alumination ð73OR"21#264\ 76ACR54\ 80COS"3#754Ł "see also Chapter 1[08# and give products of
well!de_ned stereochemistry "Equations "044# and "045## ð74JCS"P0#0478\ 82AG"E#0957Ł[ The former
example uses an aluminate species while the latter uses a simple alane[ Boron reagents have also
been used to open epoxides ð63T2926\ 66T0834Ł[ Alkenyl or alkynyl boronates open epoxides by
transfer of the alkenyl or alkynyl group to give the boronate complexes "55# and "56# which can be
further manipulated\ especially by oxidative cleavage of boron "Schemes 14 and 15#[
i, Me2Al, Cp2ZrCl2, 1,2-dichloroethane, 20 °C
OBn ii, BuLi, THF, –78 °C to –30 °C OBn
iii, oxirane, –30 °C, 4 h
OH (155)
62%
i, Me2Al, Cp2ZrCl2, CH2Cl2, H2O, -23 °C OH
O ii, methyloxirane, –23 °C
Bu + Bu (156)
80%
Bu OH
O ether, 20 °C, 18 h 3 M NaOH, 30% H2O2, ether Bu
+ Bu3 B– Bu2B
93%
Li+ O OH
(66)
Scheme 25
3 M NaOH C5H11 OH
30% H2O2, THF
Bu
O Bu C5H11 70%
THF, 67 °C, 5 h
+ Bu2B
O i, AcOH
Bu3Bu C5H11 67 °C, 10 h
C5H11 OH
ii, 6 M NaOH Bu
Li+
(67)
75%
O
Scheme 26
Epoxides can be opened under high pressure "4 kbar# by a manganese pentacarbonyl species with
subsequent migration of carbon monoxide and attack of the acyl complex on a Michael acceptor
"Equation "046## ð77JOC3781Ł[ Yields are in the range 39Ð88)[
i, Mn(CO)5, 5 kbar, ether
ii, methyl acrylate, 2–4 d TMS-O O R
O
BnO (157)
BnO 48% CO2Me
R = Mn(CO)4
32%
R=H
"ii# Stabilized nucleophiles

The simplest carbon nucleophile is cyanide which in its various guises will open epoxides[ Pot!
assium cyanide in aqueous DMF can be used "Equation "047## ð75BCJ0252Ł[ Silylcyanides react in
the presence of acidic catalysts such as aluminum!based compounds ð75S0921\ 76JOC0902Ł\ lanthanides
ð76TL4402\ 89TL5198Ł\ calcium and other metal oxides "Equations "048# and "059## ð89CL370Ł "the
high regioselectivity in the latter case is believed to derive from the formation of a calcium chelate#
and basic catalysts such as potassium cyanide "Equation "050## ð89JOC1905Ł and aluminum cyanides
"Equations "051# and "052## "note the trans diaxial opening in the former case# ð69JCS1254\ 77S832Ł[
TBDMS-O H TBDMS-O H CN
KCN, DMF–H2O (3 : 1), 20 °C
O OH (158)
N 77% N
O H O H
CaO, heptane, 20 °C
+ TMS-CN NC (159)
O O-TMS
84%
94 : 6 regiochemistry
O
O
Pr O
Pr CaO, heptane, 20 °C
O + TMS-CN (160)
O 86% NC OH
F
KCN, 18-crown-6, 75 min
F + TMS-CN (161)
O 74% NC
O-TMS
OH OH
Et3Al, HCN, THF, 20 °C NC

(162)
O H H 66% H H
HO
H H
NH2 NH2
N N
N N
HO Et2AlCN, toluene–THF, 80 °C
N HO N N (163)
N HO
O 62% O
O
CN
Epoxides can be opened by a variety of enolate anions including dialkyl malonate anions and the
anion of acetate esters[ The dianions of carboxylic acids are particularly useful as the products can
be readily lactonized "Equation "053## ð72JOC0344Ł[ In the latter reaction the absence of HMPA
causes the yield to fall to 44)[ Anions of tertiary amides "Equation "054## ð70JOC1720Ł and dianions
of secondary amides "Equation "055## also react ð77SC0048Ł[ The former reaction is moderately
stereoselective in ether when the substituents on nitrogen are large[ The presence of a Lewis acid in
the latter reaction improves yields and reduces reaction times[ Dianions of acetoacetates react at
the terminal carbon atom as normal ð67JOC677Ł[ The aluminum enolates of t!butyl esters open
epoxides in poor to moderate yields "01Ð60)# and with syn ] anti selectivities of 51 ] 27 to 84 ] 4
ð82JOC6293Ł[ A variety of a!substituted acetate anions open epoxides and the incorporated sub!
stituent allows further functionalisation of the molecule[ Representative examples are shown in
Equations "056# ð63CL274Ł\ "057# ð76TL0770Ł\ "058# ð64CC426Ł and "069# ð75AG"E#643Ł[ Anions a to
nitriles also open epoxides in good yield ð67S110Ł[ The product obtained depends on the work up
conditions employed "Equations "060# and "061## ð79SC38Ł[ When a!silyl acetonitriles are used\ silyl
transfer accompanies carbonÐcarbon bond formation ð68JCS"P0#15Ł[ The intermediate anion can
react further with epoxides or other nucleophiles ð68BCJ1278Ł[ Epoxides can also be opened by
isocyanide anions in good yield to give oxazines or isocyanoalcohols depending on work!up con!
ditions "Scheme 16# ð62AG"E#212Ł[
MeO O MeO O
2 BuLi, THF, HMPA, 50 °C O
+ CO2H (164)
OMe 85% OMe
O O i, LDA, ether O O
ii, epoxide, 0 °C, 5 h
+ + (165)
(Pri)2N 40% (Pri)2N (Pri)2N
OH OH
84 : 16
i, 2 BuLi, THF, HMPA, –72 °C O
O O ii, epoxide, BF3•OEt2, 0 °C
+ PhHN (166)
PhHN 80%
OH
SPh
i, 2LDA, 0 °C
ii, epoxide, –60 °C
O iii, 89 °C
O
+ PhS CO2H O (167)
90%
i, 2LDA, THF, 0 °C EtO

ii, epoxide, 20 °C. 3 h O
O iii, AcOH, reflux, 6 h
EtO
+ PhSe CO2H O (168)
56%
SePh
i, 2LDA, THF, –78 °C TMS

O ii, TsOH, PhH, reflux
+ TMS CO2H (169)
100%
O O
i, BuLi, THF, –78 °C

ii, epoxide, BF3•OEt2, 10 min
O iii, MsCl, CH2Cl2, –10 °C, 30 min MeSO3 CO2But
+ CN CO2But (170)
77% NC
NH
i, LDA, ether–hexane, –78 °C
O ii, EtOH O
+ (171)
CN 92%
i, LDA, ether–hexane, –78 °C

ii, NH4Cl
O iii, 2M HCl CN
+ (172)
CN 72%
i, BuLi, pentane
ii, epoxide, THF, –70 °C
iii, MeOH O N
82%
OMe
O
+ CN OMe
i, BuLi, pentane
ii, epoxide, THF, –70 °C
NC
iii, AcOH
82% HO OMe
Scheme 27
Sulfur!stabilized anions can be used to open epoxides "Equation "062## ð71TL1268Ł[ Allylic sulfur!
stabilized anions can attack from the a!carbon atom "Equation "063## ð77CL534Ł or predominantly
from the g!carbon atom "Equation "064## ð64TL3916Ł[ The regioselectivity of the reaction is ascribed
to the intramolecular chelation of lithium[ Dithianes are also good nucleophiles "Equation "065##
ð54AG"E#0964\ 66AG"E#153\ 82JOC1070Ł[ Other sulfur!stabilized anions that can be used to open epoxides
include those derived from sulphoxides ð61TL3594Ł\ b!keto sulfoxides "dianions# "Equation "066##
ð63JOC621Ł\ tris"methylthio#methane ð82SC700Ł "which is a high!yielding carboxylate anion synthon#
and sulfones "Equations "067#Ð"079## ð82TA288\ 77TL1948\ 74TL3636Ł[ Ylides generated from sulf!
oxonium salts give oxetanes from epoxides "Equation "070## ð72JOC4022Ł[
O PhS Li THF, –78 °C to 20 °C SPh

+ (173)
86% HO
SPh OH
TMS-O TMS-O R
SPh
O
BuLi, TMEDA, 0 °C MOM-O
O R O
R + R (174)
63%
MOM-O
O-MOM O-MOM
R=
S i, LDA, THF, –78 °C

O ii, add epoxide, –65 °C
MeO +
S NMe2 78%
C6H13
OH
OH S C6H13 S
+ (175)
MeO
C6H13 S NMe2 S NMe2
OMe
81 : 19
S O
i, BuLi (2 equiv.), TMEDA, DMPU, 0 °C, 3 h
MeO + ii, add epoxide
S
TBDPS-O 92%
HO
OH
S S
MeO (176)
TBDPS-O
HO
DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone
i, NaH, THF
ii, BuLi + Ph
+ Ph iii, epoxide, 20 °C S
O + S (177)
85% O O–
O O– OH
i, BuLi, THF–hexane, –78 °C to 0 °C

R ii, NaH, reflux O-TBDPS
O-TBDPS iii, PPTS, MeOH
+ TMS (178)
O SO2Ph R = H, 74%
R OH
R = Me, 87%
SO2Ph
O i-v
+ (179)
OPh OPh
74%
O O
MeO OMe
OMe
i, BuLi, THF, HMPA; ii, epoxide, 20 °C; iii, H3O+; iv, TsOH; v, Et3N or dbu
SO2Ph
i, BuLi, TMEDA, THF, HMPA, –78 °C SO2Ph
O O ii, epoxide, –78 °C, 30 min then 25 °C, 2 h HO
+ (180)
68% O
HN
Ph HN Ph
Me
O ButOK, ButOH, 50 °C, 5 d O
+ Me S+ O (181)
Ph Me 94%
I– Ph
Other species that have been used to open epoxides include anions derived from methyl oxazoles
"Equation "071## ð70JOC0309Ł\ imines ð64S145Ł\ ketones ð79JA5052Ł\ hydrazones ð65TL00Ł as well
as Wittig and phosphonate reagents ð56JA4749\ 82TL2428Ł[ Pelter et al[ have recently published a
study of the opening of epoxides with dimesitylboron stabilized anions which\ on oxidative work!
up\ gave 0\2 diols ð82T2996Ł[ Transition metals catalyse epoxide opening with carbon monoxide
ð71COMC!I"7#688\ 73JA5982\ B!80MI 094!91Ł but often require excess epoxide in order to reduce further
reaction of the carbonyl compounds that are produced[ A recent method using rhodium catalysis
appears to have overcome this problem "Equation "072## ð82JOC3076Ł[
HO
O O
O BuLi, THF, 0 °C, 3 h
+ (182)
N Ph N
Ph 72%
PhMe2SiH, [RhCl(CO)2]2
1-methylpyrazole (40 mol %)
O CH2Cl2, CO, 50 atm, 25 °C, 20 h CHO OSiMe2Ph
+ (183)
60% OSiMe2Ph CHO
77 : 23
"iii# Friedel!Crafts and acid!catalysis

Epoxides and other cyclic ethers can be used in Friedel!Crafts alkylations ð37BSF707\ 37BSF711\
37BSF714\ 37BSF716Ł^ reactivity decreases with increasing ring size 2×3×4×5 and with less sub!
stitution tertiary×secondary×primary ð59MI 094!90Ł[ Friedel!Crafts alkylations have been
reviewed by Olah et al[ ð80COS"2#182Ł "this review includes a section on alkylation with oxygen
functions# and in a monograph ðB!73MI 094!90Ł[
Isomerisation of epoxides to aldehydes can compete with alkylation^ the extent of isomerization
is dependent on the Lewis acid employed[ With mild acid catalysts such as BF2 = Et1O\ ZnCl1 and
magnesium halides isomerisation is faster than alkylation and the products isolated are aldehydes
or aldehyde!derived products "Scheme 17# ð67BCJ063Ł[ Strong Lewis acid catalysts such as AlCl2 or
SnCl3 give the expected oxirane ring!opened products "Equation "073## ð57JHC226\ 64BCJ859Ł[ The
ring!opening proceeds to give the more stable carbonium ion\ although this intermediate must be
strongly coordinated by the catalyst as Suga and co!workers have shown that almost complete
stereochemical integrity can be retained in this reaction ð64BCJ859Ł "Equation "074##[
PhH, AlCl3, 20 °C, 1 h Ph

O
OH via +
OAlCl2 (184)
O PhH, AlCl3 Ph
R OH
Et (185)
H
Et
H
Epoxides can also react with nonbenzenoid aromatic systems as exempli_ed by the reaction of
oxirane with substituted azulenes "Equation "075## ð61JOC1846Ł\ and reaction of the epoxide "57#
with indole "Equation "076## ð72LA115Ł[ Vinylepoxides also undergo stereoselective Friedel!Crafts
reactions ð82CPB44Ł[
LA
R O R OLA R Ar
strong high temperature
Lewis acid
Ar Ar
ArH
R O
weak
Lewis acid LA
R O R R Ar
reactive substrate
O Ar
H
Scheme 28
AlCl3, CH2Cl2 OH
O 0 °C, 10 min
MeO + MeO (186)
48% (93% on recovered SM)
OH
CO2Me
O SnCl4, –5 °C
+ (187)
N 52% N
H CO2Me H
(68)
Allylsilanes and stannanes will alkylate oxiranes ð68S335Ł under Lewis acid catalysis "Equation
"077##[ This method is particularly useful in some intramolecular reactions "see below#[
OH
O TiCl4, CH2Cl2, –78 °C
+ (188)
TMS 87%
"iv# Intramolecular reactions

Intramolecular cyclisations of anions onto epoxides rely\ for a large part\ on the rapid generation
of the nucleophile and a slow rate for the intermolecular attack[
Direct ortho lithiation of the phenyl ether "58# at −099>C followed by warming gave the cor!
responding bicyclic compound in 53) yield "Equation "078## ð67JOC2799Ł[ The observed stereo!
chemical outcome follows from Baldwin|s Rules "4!exo tet versus 5!endo tet# ð65CC623Ł[ Trans!
metallation can also be used to generate the nucleophile "Scheme 18# ð79JOC811Ł[ The presence of
magnesium bromide alters the regiochemistry\ giving the product of epoxide opening at the terminal
carbon atom[ Formation of an intermediate bromohydrin by attack of Br− on the terminal carbon
atom\ with subsequent ring formation is the rationale for this di}erence in behaviour[
O
O BuLi, hexane–THF
–100 °C to 25 °C O
(189)
64%
(69) OH
O
O BuLi, MgBr2 O BuLi, hexane–THF
THF–ether–hexane –100 °C to 25 °C O
–78 °C to 20 °C
OH Br
OH
Scheme 29
The e}ect of ring size on the intramolecular attack of epoxides has been studied by a number of
groups[ Cooke and Houpis have studied the cyclisations of a series of v!iodoepoxides "Scheme 29#
ð74TL2532Ł[ The course of the reaction is in~uenced by the substitution pattern and the presence of
Lewis acids[ Copper bromide reverses the selectivity of cyclisation of 3!iodobutyloxirane[ These
results suggest that the observed selectivity is a _ne balance between several factors[ Similar reactions
can be used to prepare strained tricyclic systems ð55JA1146\ 71JOC2100Ł[
O
ButLi (2.2 equiv.), ether–pentane, –78 °C
OH
I
Additive Yield (%)
none 77
MgBr2 77
R1
O R1 OH
R2
R2 ButLi (2.2 equiv.), ether–pentane, –78 °C R2
+ R1
R2 OH
I R2
R2
Additive Yield (%)
R 1 = R2 = H none 82 88 : 12
R1 = Me, R2 = H none 45 5 : 95
R1 = H, R2 = Me none 66 95 : 5
R1 = R2 = H MgBr2 60 15 : 85
R1 = Me, R2 = H MgBr2 0
R1 = H, R2 = Me MgBr2 49 25 : 75
R1 = R2 = H CuBr•Me2S 30 <1 : >99
O
OH
ButLi (2.2 equiv.), ether–pentane, –78 °C
OH +
I
Additive Yield (%)
none 78 91 : 9
MeMgBr 56 94 : 6
BF3•OEt2 40 >99 : <1
CuBr•Me2S 59 19 : 81
O
ButLi (2.2 equiv.), ether–pentane, –78 °C OH
I 15%
Scheme 30
Stork et al[ have studied the intramolecular reactions of a!cyanocarbanions and epoxides
ð63JA4157\ 63JA4169Ł[ They found that with equal substitution of the two ends of the epoxide
cyclisation occurs to give the smaller possible ring[ Attack at the distal end occurs only when it is
the less substituted^ cyclobutane ring systems are not easily made by this method "Scheme 20#[ The
e}ect of epoxide geometry on the outcome of the reaction has been studied ð64TL474Ł[ Sulfone
anions also react to give products of various ring sizes ð65JOC2537\ 70CJC0304Ł but the outcomes are
dependent on the base used[ LDA deprotonation gives cyclopropanes from g!epoxysulfones but
fails to give cyclobutanes from d!epoxysulfones[ Deprotonation with methylmagnesium iodide gives
cyclobutanes from g!epoxysulfones and cyclopentanes from d!epoxysulfones via the formation of
iodohydrins and subsequent displacement of the distal iodine atom "Scheme 21#[ The same e}ect
is seen with nitrile substrates[ Further substitution around the epoxide unit can also alter the
regiochemistry[ Vinyl sulfones "Equation "089## ð74TL5290Ł and other stabilized anions are also
suitable nucleophiles\ particularly for the formation of small rings "Equations "080# and "081##
ð70TL0640\ 71JOC1453\ 71TL0232Ł[ The cyclisation of the epoxyamide "69# sets up the correct trans
b!lactam stereochemistry for the synthesis of thienamycin!type antibiotics "Equation "082##
ð77TL704Ł[ Macrocyclisations have also been accomplished "Equation "083## ð73TL4670Ł[
H CN
R CN
R=H R = Me
O OH
75% 80%
OH CN
HO
OH O
CN CN
CN
Scheme 31
OH
HO
LDA E 2MeMgI
O
E E
E = CN E
E = PhSO2 I
O–
HO LDA
2MeMgI HO SO2Ph
SO2Ph
O
SO2Ph
Scheme 32
H HO
LDA, THF, 0 °C
O O O (190)
60%
SO2Ph
SO2Ph
Me2NOC
O
LDA, THF, –78 °C H
CONMe2 (191)
72%
HO
O
H
LDA, THF, –78 °C HO CO2But
(192)
90%
CO2 But
HO H CO2But
TBDPS-O O CO2But
N LiN(TMS)2, THF, –25 °C
TBDPS-O N
O (193)
O 50%
OMe OMe
(70)
BuLi, dabco, 0 °C
(194)
60%
O H
PhS PhS HO
dabco = 1,4-diazabicyclo[2.2.2]octane
The intramolecular Friedel!Crafts cyclisation "Equation "084## ð72JOC1388Ł gives mainly the
expected seven!membered ring compound as well as the six!membered ring isomer^ the reaction
also works with heteroaromatics such as the furan "60# "Equation "085## ð72JOC3461Ł[ A combined
intramolecular epoxide opening followed by a Friedel!Crafts alkylation was discovered ser!
endipitously in the process described in Equation "086#[ The epoxides "61# and "62# undergo Lewis
acid catalysed intramolecular epoxide opening with subsequent lactonisation to give the same 59 ] 39
mixture of cyclopropanes "Scheme 22# ð82JA1869Ł[ The SnCl3ÐMeNO1 combination is the same as
that used by van Tamelen and Anderson in their work on the cyclisation of squalene oxide
ð61JA7114Ł[ Similar cationic cyclisations can give pentacyclic structures ð82TL6738Ł[ Cyclisations of
allylsilanes and stannanes take place readily with good regio! and stereo!selectivity "Equations "087#
and "088## ð78JOC2003\ 76TL1642Ł[ In the latter case six!membered ring formation is prefered[ A
number of groups have carried out related work ðB!70MI 094!90\ 72CJC103\ 73CC474\ 73CC0162\ 75CJC473\
78TL3734\ 89JCS"P0#0115Ł concerning the regio! and stereoselectivities of such cyclisations[
SnCl2, CH2Cl2, reflux, 4 h

RT, 19 h
+ (195)
64%
O OH
OH
77 : 23
ZnI2, CH2Cl2, 25 °C
O OH (196)
O 71% O
(71)
SnCl4, PhMe, 0 °C, 1.5 h

H + H (197)
64%
O H H
OH OH
75 : 25
i, TiCl4, CH2Cl2, 0 °C O
O O ii, K2CO3
HO
(198)
TMS 75%
TMS OH
TBDMS-O
EtO2C OH
OH BF3•OEt2, CH2Cl2, 0 °C
O (199)
TBDMS-O 80%
CO2Et
"v# Stereo! and reìochemistry

With unsymmetrically substituted epoxides there is the possibility of attack at either end of the
epoxide unit[ In the majority of cases attack occurs at the least substituted end of the epoxide with
SnCl4, MeNO2
O 0 °C, 1.5 h
CO2H
44% OH H OH H
H H
OH O O O O
(72)
+
SnCl4, MeNO2 OH H OH H
O 0 °C, 1.5 h
CO2H
60 : 40
54%
OH
(73)
Scheme 33
inversion of con_guration "SN1# "e[g[\ Equation "199## ð73JOC2817Ł[ There are exceptions to this
generalization\ mostly involving aromatic epoxides "Equation "190## ð89H"20#0886Ł "similar reactions
occur with MeLi and MeMgI#\ "Equation "191## ð75TL1904Ł which are attacked at the more reactive
benzylic position\ "see also Scheme 12#[ Alkylaluminum reagents can open aromatic epoxides with
reversed regiochemistry and retention of con_guration "Scheme 23# ð80TL0948Ł "and see ð78H"18#138Ł
in Section 0[94[0[2[1#[ MO calculations provide an explanation for this phenomenon in that they
suggest that there is considerable carbonium ion character at the carbon atom next to the phenyl
group^ migration of the methyl group takes place from the aluminum species co!ordinated to the
oxygen atom[ Silyl epoxides are also exceptions to the normal rule[ In this case selectivity is
determined by the bulk of the silyl group and the presence or absence of Lewis acid "BF2 = Et1O#
"Scheme 24# ð82TL2584Ł[ Lewis acid and bulky silyl groups favour {conventional| regioselectivity[
The reactions of symmetrically substituted epoxides "i[e[ both ends of the epoxide are mono! or
disubstituted# are much harder to predict but electronic\ steric and coordination factors come into
play[ Attack on silyloxyepoxides is probably a}ected by the steric bulk of the silyl group "Equation
"192## ð78TL5852Ł[ Several groups have studied the regioselectivities of cuprate and alane addition
to epoxyacids ð70JOC4131\ 74TL3572Ł and epoxyesters ð62JOC3152\ 62JOC3235Ł[ The regioselectivities of
additions to glycidic systems are covered in the following section[ A theoretical study of the addition
of nucleophiles to oxiranes conjugated with unsaturated groups such as alkenes "see next section#\
ketones and aldehydes\ esters and enol ethers has been undertaken ð77JOC028Ł[ With ketones and
aldehydes the prefered site of attack for both hard and soft nucleophiles is the carbonyl group while
for esters it is the epoxide carbon atom which lies next to the carbonyl group[
Pr2CuCNLi2, THF, –78 °C, 1 h

O (200)
OH
86%
MeCuCNLi, ether, 0 °C
OH (201)
O 90% O
O
Ph
O i, EtONa, EtOH, reflux OBn
Ph OBn ii, NaOH, H2O, reflux
+ MeO2C CO2Me
HO2C
O (202)
80%
O
S
DMPU, THF, 0 °C TBDPS-O
TBDPS-O + (203)
S S OH S
O 76%
(74) Li
O Me3Al, hexane, 0 °C
OH + OH
60–98% R R
R
inversion retention
R
hexyl 98 : 2
decyl 97 : 3
phenyl 15 : 85
pentafluorphenyl 35 : 65
Scheme 34
A; Me2CuLi, THF or OH
O B; Me2CuLi•BF3, ether
OH +
80–90% R13Si R13Si
R13Si
(74a) (74b)
(74a) : (74b)
R13Si A B
PriMe2Si 100: 0 94 : 6
ButMe2Si 98: 2 34 : 66
Pri3Si 62:38 0 : 100
Scheme 35
Attack on epoxide units appended to six!membered rings "and other conformationally restricted
systems# usually occurs to give the trans!diaxial product[ Scheme 25 shows sequential trans diaxial
openings in an anhydrosugar ð74TL3000Ł[ Equations "193# and "194# ð77SC040\ 89S174Ł contrast the
reaction pro_les of b and a epoxysugars[ Equatorial attack can occur if steric factors or neighbouring
groups exert directing e}ects[ Attack of nucleophiles on the epoxycyclohexanols "64# "65# and silyl
ethers "66# "67# appears to be controlled by these factors "Scheme 26# ð66JOC283Ł^ "see also ð76JOC23\
78TL574Ł#[
CN
Ph O TMS-CN, AlCl3, CH2Cl2, reflux, 18 h Ph O
O O O O (204)
47%
O OBn OH OBn
TMS-O TMS-O
O OH
hexane, 50 °C, 4 h
O + Me3Al– TMS O (205)
84%
OBn OBn
TMS
In other bicyclic ring systems the regiochemistry of attack is largely determined by stereochemical
considerations[ For 5!oxabicycloð2[0[9Łhexanes the factors governing the regiochemistry of nucleo!
philic attack are not always very clear^ steric hindrance and coordination of the nucleophile to other
groups in the vicinity of the oxirane can play a role[ The regioselectivities observed for the nucleo!
philic opening of the epoxides "68# and "79# are di}erent^ the selectivity can be reversed by using an
alanate nucleophile instead of an alane "Scheme 27# ð74JOC2812Ł[ Cuprate and dithiane attack the
epoxide "70# at di}erent sites[ The cuprate is probably directed to the more hindered site by the
methoxymethyl group "Scheme 28# ð72JA0877Ł[ Selectivity is seen in the opening of the nucleoside
epoxide "71# "Equation "195## ð74TL86Ł[ This is the usual site of attack in this type of structure[
Opening of the epoxide "72# in a prostaglandin synthesis was less successful^ only 29) of the
required isomer was obtained "Equation 196# ð69TL200Ł[
O O O
O O O PhS Li
MeMgCl, CuBr (cat.) MeONa
74% 78% 74%

OTs OTs
O O
OH
O O
O HO
O
=
OH SPh SPh
Scheme 36
OR OH OH
i, LiCH2CO2Li, DME, 55 °C
ii, TsOH, PhH
O O + O
O O
(75) R = H 66% 75 : 25
(76) R = TMS 24 : 76
O
OR O OH
i, LiCH2CO2Li, DME, 55 °C
ii, TsOH, PhH
O + O
OH O
(77) R = H 61% 76 : 24
(78) R = TMS 50% 18 : 82
Scheme 37
OH OH OH
HO HO HO
+
R OH
O
OH R
(79)
Me2AlR 77 : 23
Me2AlR2Li 19 : 81
C5H11
R=
OBut
O O O
O O O
+
R OH
O
(80) OH R
Me2AlR 41 : 59
Me2AlR2Li 77 : 23
Scheme 38
HO
O-MOM
Me2CuLi, ether TBDMS-O
O O
50%
O-MOM
TBDMS-O
O i, BuLi, THF, S S
ii, Raney nickel, EtOH OH
(81)
38% O-MOM
TBDMS-O
O
Scheme 39
O O
NH ethylene diamine, DMSO NH

+ Li (206)
68% TrO N O
TrO N O
O O
O
OH
(82) Tr = trityl
OMe OMe OMe

O SMe O O
THF, –78 °C
+ + (207)
70%
Li
O OH HO
SMe MeS SMe
SMe MeS
(83)
57 : 43
Selective opening of one epoxide in the presence of a second can be achieved if there is su.cient
di}erence in the reactivities of the two epoxides^ in the case of the example shown in Equation "197#
nucleophile attack occurs on the terminal epoxide ð82CC503Ł[
TBDMS-O O TBDMS-O O
i, CuI, THF, –25 °C
ii, PCC, CH2Cl2 ( )2
O + MgCl O (208)
89%
TBDMS-O TBDMS-O
0[94[0[2[1 Glycidic epoxides

Glycidols "epoxyalcohols# and their derivatives ð80CRV326Ł provide interesting examples to illus!
trate the subtleties of epoxide ring!openings as the neighbouring group often in~uences the course
of the reaction[ This is especially true when the neighbouring group is another leaving group[ The
adjacent oxygen functionality can have a directing e}ect on the regiochemistry of attack on the
epoxide ring[ Pfaltz and Mattenberger have studied the regioselectivity of attack of a number of
di}erent carbon nucleophiles on benzyl protected allylic and homoallylic epoxyalcohols "Schemes
39 and 30# ð71AG"E#60\ 71AG"S#050Ł[ Trimethylaluminum in the presence of a catalytic amount of
butyllithium opens these epoxides to give 0\1 diols "C!2 attack#[ In contrast cuprate\ lithium and
Grignard reagents gave mixtures of 0\1 and 0\2 diols "C!1 attack#[ A similar dichotomy is seen in
cyclic systems ð72JOC398Ł[ The related homoallylic cases show the same regiochemistry\ giving 0\2
diols with aluminum or mixtures of 0\2! and 0\3!diols with other metals "Scheme 31#[ Roush et al[
ð72TL0266Ł and Oshima and co!workers ð71TL2486Ł found similar high selectivities for attack at C!
2 of the epoxyalcohols with aluminum species giving 0\1!diols "Equations "198#Ð"100##[ More
reactive substrates and longer reaction times by!pass the need for the formation of the ate complex[
The selectivity is greatly reduced when the C!2 substituent is oxygenated[ This may be due to
inductive deactivation of C!2\ or it may be due to the incorporation of an alternative site for
aluminum coordination[ Copper"I#!catalysed Grignard addition to similar substrates ð72JOC3020Ł
gives the expected 0\2!diols "addition at C!1# with regioselectivities of 58 ] 20 to 76 ] 02 "Equations
"101# and "102##[ Selectivities were not improved when the benzyloxy group was one carbon atom
further away from the reactive unit[ See ð66JOC283\ 76JOC23\ 78TL574Ł for examples in cyclic systems
"Section 0[94[0[2[0"iv##[
OH
O O
1 OBn or OBn OBn + OBn
3
(Z) (E) OH
Yield (%) ratio

(Z) MeLi, ether, 20 °C, 22 h 82 59 : 41
(Z) Me2CuLi, ether, –20 °C, 30 min 43 47 : 53
(Z) Me3Al, BuLi (0.3 equiv.), toluene, –20 °C, 3 h 76 >99 : 1
(E) Me2CuLi, ether, –40 °C, 1 h 83 78 : 22

(E) Me3Al, BuLi (0.3 equiv.), toluene, –20 °C, 1 h 76 >99 : 1
Scheme 40
OH
O O
or +
OBn OBn OBn OBn
(Z) (E) OH
Yield (%) ratio

(Z) Me2CuLi, ether, –20 °C, 2 h 83 59 : 41
(Z) Me3Al, MeOLi (0.3 equiv.), toluene, 0 °C, 6 h 87 95 : 5
(E) Me2CuLi, ether, –40 °C, 15 min 90 68 : 32

(E) Me3Al, MeOLi (0.3 equiv.), toluene, 0 °C, 3 h 85 99 : 1
Scheme 41
i, Me3Al, petrol, 0 °C, 1 h

O ii, NaIO4
iii, LiAlH4
OH
OH
(209)
65–69%
i, Me3Al, CH2Cl2, 23 °C
OH ii, NaIO4, THF, H2O CHO OH
BnO BnO + BnO (210)
O 82–87%
OH
95% ee 95% ee 84 : 16
i, Me3Al, petrol
0 °C to 23 °C, 15 h
OH
BnO OH ii, NaIO4
iii, LiAlH4 OH
BnO + BnO (211)
O 61%
OH
82% ee 82% ee 88 : 12
OH
OH MeMgI, 10% CuI, ether, –40 °C OH OH
BnO BnO + BnO (212)
O 87%
OH
83 : 17
Ph Ph Ph Ph
+ +
OH OH OH OH
OH OH Ph OH Ph OH
94.5% 3.5% >99% <1%
Ph
Me2CuCNLi2, ether, –45 °C
78% BuLi, BF3•OEt2, THF, –78 °C
90%
O
OH
Ph MgCl
R3Al, CH2Cl2, –70 °C to –40 °C (84) THF, –20 °C
96%
R = Me, 87%
R = Et, 73%
Ph Ph Ph Ph
+ +
R OH R OH OH OH
OH OH OH OH
3% 97% >99% <1%
50% 50%
Scheme 42
OH
BnO OH MeMgI, 10% CuI, ether, –40 °C OH OH
BnO + BnO (213)
84%
O OH
86 : 14
Epoxide opening of the aromatic substrate "73# ð78H"18#138Ł occurs at the benzylic position "C!2#
"with inversion of con_guration# with Grignard and cuprate nucleophiles "Scheme 31#^ retention of
con_guration is observed when trimethylaluminum is the nucleophile[ Triethylaluminum gives much
poorer stereocontrol[ Aluminum reagents generally give much poorer selectivities suggesting that
an SN0 pathway is competing with the normal SN1 route when an adjacent group is capable of
stabilizing a carbocation^ in contrast to the result obtained for the aliphatic glycidol "74# "Equation
"103## ð73LA0054Ł[
O
+ Pr AlEt2 OH (214)
OH 38%
Pr OH
(85)
Treatment of the epoxyalcohol "75# with lithium acetylide "76# and BF2 = Et1O gave mixtures of
the alcohols "77# and "78# "Scheme 32# ð73CC191\ 76T1690Ł[ The latter compound arises from direct
attack on the epoxide\ formation of the former compound involves a Payne rearrangement
ð51JOC2708Ł[ "The rearrangement does not occur if the BF2 = OEt1 is added to the alkyne before the
epoxide ð78H"18#138Ł#[ Under the same conditions the isomeric epoxyalcohol "89# gave only the
expected product "Equation "104## arising from attack at the less hindered carbon atom[
O BF3•OEt2, –78 °C
Ph O OH + Li n-C5H11
75%
(86) (87)
OH OH n-C5H11
Ph O Ph O
+
OH n-C5H11
OH
(88) 33 : 67 (89)
Scheme 43
OH OH
BF3•OEt2, –78 °C
Ph O + Li n-C5H11 Ph O (215)
75%
O OH n-C5H11
(90)
Sharpless and co!workers found that higher order cuprates open the epoxide "80# selectively\ in
moderate yield\ with complete retention of chirality "Equation "105## ð78JOC0184Ł[ Opening of
glycidyl tosylate "80# with simple Grignard and lithium reagents gave unsatisfactory results[ The
bisaddition product "81# is formed as a by!product in varying amounts[ Copper!catalysed Grignard
addition to the antipode gave the hydroxytosylate "82#\ again with complete retention of chirality
and only a small amount of epoxide "Equation "106##[ The optical rotation of this epoxide indicates
that it is derived from ring closure of the major product and not from direct displacement of tosylate[
A major side reaction is epoxide opening by the halide ion associated with the Grignard reagent[
Halohydrin formation is signi_cantly reduced\ but not eliminated\ when Li1CuCl3 is used as the
catalyst[ Phenylithium!boron tri~uoride etherate also a}ords the hydroxytosylate in modest yield
"55)#\ with no sign of products resulting from tosyl displacement[ Starting material "27)# was also
recovered[ A similar result was obtained by Rotstein and Walker who opened both enantiomers of
glycidal tosylate "83# with Grignard reagent "84# under copper catalysis to give the corresponding
optically active tosylate "85# in ×88[4) ee after crystallisation "Equation "107## ð82TA0410Ł[ Selec!
tive epoxide opening of glycidal tosylate using diethylaluminum cyanide is also possible "Equation
"108## ð78JOC0184Ł[ Attack of the anion of the thionitrile "86# on the homoallylic epoxide!mesylate
gives epoxide opening then displacement of the mesylate group by the reformed anion to give the
cyclopentane "87# "Equation "119## ð74TL2010Ł[
O Ph2Cu(CN)Li2 O OH
+ (216)
OTs Ph Ph Ph
THF, –78 °C
64%
(91) 88% ee 88% ee (92)
O PhMgBr, 5% Li2CuCl4, THF OH O

+ (217)
OTs Ph OTs Ph
(93) 94% ee 79%, 94% ee 5%, 88% ee

O Li2CuCl4 (cat.), THF, –35 °C OH

+ Ar MgCl (218)
OTs OTs
68–77% Ar
(94) (95) (96)
O Et2AlCN, toluene, 20 °C OH
NC OTs (219)
OTs
96%
MsO PhS CN
NaN(TMS)2, DMF, 0 °C
+ PhS CN (220)
O 70%
BnO
BnO OH
(97) (98)
In contrast French workers ð76T1690Ł found that the glycidyl tosylate "88# is attacked by both
alkyl copper!catalysed Grignard reagents and cuprate reagents with displacement of the tosyl group
"Equation "110##[ Alkenyl and alkynyl reagents did not react^ starting material was recovered
unchanged[ The corresponding tosylate "099# is inert to both ring opening and tosyl group dis!
placement[ This suggests that there is a _ne balance between attack at epoxide and displacement of
the sulfonate group[
O Bun2CuLi, Et2O, –10 °C O

Ph O OTs Ph O Bun (221)
or BuMgBr, CuI, THF, RT
(99)
OTs
Ph O
O
(100)
Aitken and co!workers have studied the stereochemical course of the reaction of various glycidol
derivatives using the anion of the aminonitrile "090# "Scheme 33# ð82SL488Ł[ The reaction can take
two routes\ either via direct displacement of the leaving group or via epoxide opening and subsequent
closing to give product of opposite chirality[ It was found that with tri~ate as the leaving group the
reaction proceeded via route A^ with bromide\ chloride and benzenesulfonate route B was more
prominent[ The corresponding tosylate\ mesylate and nosylate did not react[ The regioselectivity of
the benzenesulfonate is unexpectedly poor considering that sulfonates are generally considered to
be better leaving groups that bromides ð71S74Ł[ The lack of reactivity of the mesylate is also
surprising[
Reaction of optically pure epichlorohydrin with the aluminate "091# gave only the product from
epoxide opening "Equation "111## ð89T3492Ł[ Similar selectivity is seen in the reaction of dimethyl
malonate with epichlorohydrin "Equation "112## ð78HCA0290Ł^ initial attack occurs at the epoxide
unit with formation of the chlorohydrin as an intermediate[
– AlMe2Bu OH
Cl pentane–hexane, –30 °C to 0 °C
+ (222)
O 75%
Cl
OBn OBn
(102)
NBn2 NC NBn2
X NC NBn2 LDA, HMPA, THF, –78 °C LDA, HMPA, THF, –78 °C
+ NC
O –
A O OH
(101)
B
NBn2
NBn2 NC NBn2
CN LDA, HMPA, THF, –78 °C
NC
O OH
O–
X X = Cl, Br, PhSO3 or TfO
Scheme 44
O O
O MeONa, MeOH, 20 °C
+ MeO2C CO2Me (223)
Cl
36% CO2Me
0[94[0[2[2 Vinylogous epoxides

Vinylepoxides "monoepoxydienes or ethenyloxiranes# can be opened by nucleophiles at any of
three positions^ namely either end of the epoxide "one of which is vinylic# or in an SN1? fashion by
attack at the distal end of the alkene[ The modi_ed neglect of diatomic overlap "MNDO# study of
oxiranes by Font and co!workers mentioned above ð77JOC028Ł suggested that hard nucleophiles
should attack the epoxide "the two ends being of roughly equal reactivity# and soft nucleophiles
should target the alkene "Figure 1#[ The same is true where the alkene is oxygenated at C!2 "an enol
ether#[ These theoretical results are largely borne out in practice\ where copper reagents are {soft|
and most other metals are {hard|\ except that attack at the unsubstituted end\ C!0\ is fairly rare^
there appears to be little study or rationale of the C!0:C!1 selectivity[ In contrast propargyl epoxides
are attacked at C!0 by cyanide and cuprate reagents ð61JOU1429\ 80TA832\ 82TL7152Ł[
C-1 O
O O O
C-2 C-4
Hard nucleophiles
Soft nucleophiles
Figure 2
Sulfone anion "092# opens epoxide "093# at C!0\ with subsequent lactonisation\ in moderate yield
ð77TL1948Ł "Equation 113# "see also ð70SC612Ł#[ The proportion of HMPA was critical in the reaction
of allene anion with vinylepoxide\ concentrating the attack of the anion at C!0 "Scheme 34# ð68S497Ł[
In the absence of HMPA a mixture of products is seen[ A Wittig reagent and cobalt octacarbonyl
also react through attack at C!0 "Scheme 35# ð77TL0652\ 78JA6827\ 89JOC213Ł[
i, THF–HMPA, –20 °C to 20 °C
O
ii, H2SO4
O Li OMe iii, TsOH, CH2Cl2 O
+ OMe (224)
C5H11 PhSO2 OMe 57% PhSO2 C5H11
(103) (104)
BuLi, THF–HMPA, –70 °C OH
THF : HMPA 1 : 1
O 78%
+ •
BuLi, THF–HMPA, –70 °C OH
THF : HMPA 20 : 1 •
77%
Scheme 45
Ph
i, BuLi, THF, 0 °C to 20 °C Ph Ph
O ii, NaH, THF, 67 °C, 5 h
P
+
+ Ph3PMe Br– O
89%
Co2(CO)8, KOH, MeI, H2O, PhH

O phase transfer catalysis, 20 °C OH CO2H
CO2H + OH
49%
85 : 15
Scheme 46
Opening of vinylepoxides by attack at C!1 is favoured by Grignard\ dialkylmagnesium and

lithium reagents ð69JA3867\ 69JA3868\ 60JA2936\ 62JOC3152\ 70JOC4268Ł[ Aluminum reagents open
vinyl epoxides by direct displacement at C!1 "Equation "114## ð72S173Ł[ An intramolecular reaction
gives a six!membered ring product from C!1 opening "Equation "115## ð89JA0550Ł[ Iron carbonyl
inserts into the C!1 position of cyclohexadiene monoepoxide "Equation "116## ð70JCS"P0#169Ł[ Vinyl
epoxides react with allylsilanes in the presence of BF2 = OEt1 "Equation "117## ð76CL852Ł[
0\1!Addition occurs unless the vinyl epoxide has a phenyl group at C!3 or is dialkylated at C!3\
whereupon the addition goes 0\3[
CO2Me
i, (TMS)2NLi, THF, –10 °C, 10 min
ii, 20 °C, 2.5 h O
(225)
60%
O
O
THF, –55 °C CO2But

O + Et2Al CO2But (226)
94%
OH
i, Fe(CO)5, hν, PhH, 20 °C O

ii, can, EtOH, –5 °C
O (227)
86% O
OH
O
BF3•OEt2, CH2Cl2, –78 °C
+ TMS (228)
91%
Copper reagents tend to favour C!3 attack "SN1? or 0\3 addition# but not exclusively so[ The
regio! and stereo!chemistry of these reactions in both cyclic ð76JOC3787Ł and acyclic systems
ð77JOC3163\ 78T280Ł have been studied and reviewed ð78CRV0492Ł[ In acyclic cases the highest
SN1? ] SN1 ratio is obtained with mixed cuprates "RCuCNLi1# in ether^ THF and the {harder|
dialkylcopper reagents give poorer SN1? ] SN1 ratios ð77JOC3163\ 78T280Ł[ Ratios of anti ] syn attack
are generally ×8 ] 0[ Scheme 36 shows typical results indicating that the product ratios are dependent
on both reagent type and substrate stereochemistry[ The "Z# analogue of the benzyloxy substrate in
Scheme 36 gives "E# ] "Z# ratios of ½04 ] 74[ In cyclic systems addition of cuprates is largely\ if not
exclusively anti and 0\3 "SN1?#\ especially with cyanocuprates ð76JOC3787Ł[ Signi_cant amounts of
products of 0\1 addition are only observed with alkenyl and phenyl cuprates[ Sequential 0\3 additions
can be performed "Scheme 37#[ The e}ect of solvent can be signi_cant^ in THF\ cuprate reagents
add 0\1 to the vinylepoxide while in ether 0\3 addition occurs "Scheme 38# ð71CC0220Ł[ Organozinc
reagents also add in a 0\3 fashion ð82SL166\ 82SL168Ł[
Me2CuLi, THF–ether (4 : 1), 0 °C

OH OH
OH
+
O 81% OH OH
84 : 16
Me2CuLi, THF–ether (4 : 1), 0 °C

OH OH
+
O 75% OH OH
OH
3 : 97
THF–ether (4 : 1) OH
BnO –20 °C to 0 °C BnO BnO
OH OH
+
O
Reagent Yield (%) anti : syn (E):(Z)

Me2CuLi 89 99 : 1 55 : 45
MeCuCNLi 76 91 : 9 75 : 25
Scheme 47
i, CrO3
R1CuCNLi
HO R1 ButO2H, VO(acac)2 HO R1
ii, LDA, (EtO)2POCl
O
O
R2
(EtO)2OPO R1 (EtO)2OPO R1
R2CuCNLi
O OH
Scheme 48
O-TMS O-TMS O-TMS
MeCuCNLi, ether MeCuCNLi, THF

O
77% 62%
OH OH
Scheme 49
The special case of the g\d!epoxides of a\b\g\d!dienoates has been studied with both copper and
aluminum nucleophiles[ {Harder| copper reagents such as methyl copper and dimethyl cuprate
favour SN1 attack while {softer| cyanocuprates favour SN1? reactions^ the presence of BF2 does not
alter the ratios greatly\ but does increase the proportion of syn product "Scheme 49# ð78T324\
81SL658Ł[ Alanes and aluminates react in an SN1 anti!mode[ In the presence of traces of water
trimethylaluminum adds only to the epoxide unit\ with predominant anti attack at the d position
and only a small amount of product resulting from attack at the g position "Equation "118##
ð80JOC5372Ł[ When the epoxide is oxygenated at o "epsilon#\ z "zeta# or h "eta# positions\ only the
product of g anti attack is seen "Equation "129##[
OH OH
CO2Me CO2Me anti
δ O β
CO2Me +
γ α OH OH
CO2Me CO2Me syn
OH Reagent Yield (%) anti : syn SN2' : SN2 anti : syn

MeCu 65 87 : 13 25 : 75 97 : 3
CO2Me
MeCuCNLi 59 + 12% (105) 99 : 1 68 : 32 97 : 3
Me2CuCNLi2•5BF3 84 30 : 70 79 : 21 54 : 46
(105) Me3Al 47 45 : 55 11 : 89 83 : 17
Scheme 50
Me3Al, H2O
δ O β CH2ClCH2Cl, –30 °C
CO2Me
γ α 85%
OH
CO2Me + CO2Me + CO2Me (229)
OH OH
80 : 18 : 2
Me3Al, H2O OH
ζ O CH2ClCH2Cl, –30 °C
ε CO2Et CO2Et (230)
BnO BnO
90%
Vinyl epoxides are readily opened by transition metal catalysts to give p!allyl species which readily
react with nucleophiles in a similar fashion to the p!allyl species prepared from allyl acetates etc[
ð71COMC!I"7#090Ł[ The regiochemistry of attack of the incoming nucleophile "which approaches from
the same face as the alkoxide group# is in~uenced by stereochemical factors[ For example\ the
presence of a bulky silyl group determines the position of attack on the vinyl epoxides "095# and
"096# "Scheme 40# ð77TL232Ł[ Aryl and alkenyl tin reagents can act as carbon nucleophiles ð78T868Ł^
the products are mostly those resulting from 0\3 attack "Equation "120##[ Palladium!catalysed
carbonylations are also possible\ albeit in low yield ð82TL1024Ł[ Nickel catalyses the addition of
vinyl boron species "Equation "121## ð71JOM"122#02Ł[ Vinyl epoxides can be used as allylating
agents\ again via a p!allyl species\ in high yield and selectivity using chromium"II# "Equation "122##
ð89JOC0694Ł[
CO2Me
Pd2(dba)3•CHCl3
Bu3P, THF, 20 °C TMS
R = TMS, 76% O
O O OH
+
CO2Me
R Pd2(dba)3•CHCl3 CO2Me
Bu3P, THF, 20 °C
(106) R = H
(107) R = TMS R = H, 72% OH
O
Scheme 51
O Pd(MeCN)2Cl2, DMF, 23 °C
+ Me3Sn OH + (231)
77%
(E) : (Z) 91 : 9 OH
87 : 13
O Bu
O (Ph3P)2Ni, THF, 25 °C
+ B (232)
Bu O 55%
OH
i, CrCl2, LiI, THF, 0 °C Ph Ph

O ii, aldehyde, 0 °C
+ OHC Ph + (233)
97% OH OH
OH OH
96 : 4
0[94[0[2[3 Oxetanes and b!lactones
"i# Oxetanes
Oxetanes can be opened by carbon nucleophiles in a similar fashion to epoxides\ but not quite so
readily[ Grignard reagents ð65CB2264Ł\ cuprates ð68TL0492Ł\ lithium reagents ð76CB0584Ł and sta!
bilized nucleophiles ð64JOC1852\ 73TL0048Ł have all been used as nucleophiles "Equations "123#Ð"126##[
With trialkylsilane and cobalt carbonyl catalysis oxetane gives a chain extended diol ð78JA6827Ł[
Intramolecular cyclisations can be e}ected in a similar fashion to epoxides "Equation "127##
ð73TL3438Ł[ Cyclisation to cyclohexanes and cyclopropanes are also possible[
MgBr ether, 34 °C
+ OH (234)
O 37%
CuI, ether, –30 °C

+ Bu MgCl OH (235)
O 75%
i, EtMgBr, THF, 65 °C
N ii, oxetane, 0 °C O
iii, AcOH
+ (236)
O 80% OH
i, LDA, THF, –78 °C

ii, BF3•OEt2, –95 °C to –40 °C
+ Me CO2But CO2But (237)
O HO
90%
O LDA, HMPA, ether, 20 °C

+ (238)
65% Ph Ph
Ph OH OH
87 : 13
Allylsilanes and stannanes will also alkylate oxetanes under Lewis acid catalysis "Equation "128##
ð74JOC1671Ł[ 1!Phenyloxetane undergoes Friedel!Crafts alkylation\ in this case with opening at the
more reactive benzylic position "Equation "139## ð62ACS2833Ł[
O TiCl4, CH2Cl2, –100 °C

+ OH (239)
TMS 83%
Ph
Ph i, AlCl3, 5–10 °C, 90 min
O ii, 20 °C, 12 h OH
+ (240)
90%
Vinyl oxetanes are opened in a 0\2 fashion "SN1?# by a variety of nucleophiles to give homoallylic
alcohols in yields ranging from 11Ð73) "Equation "130## ð89SL230Ł[ Palladium catalysis can be
applied to poorer nucleophiles such as organomercurials and 0\2!dicarbonyl anions ð77TL4958\
78TL2376Ł "Equations "131# and "132##[
vinylmagnesium bromide, 5% CuI, ether, –15 °C

(241)
O
68% OH
(E ) : (Z) 65 : 35
10% Li2PdCl4, THF, NH4Cl (aq.)

0 °C, 2 h then 25 °C, 8 h
+ Ph HgCl (242)
O Ph OH
49%
O HO
O O O 2% Pd(PPh3)4, THF, 40 °C
+ (243)
82%
OH O OH
"ii# b!Lactones
b!Lactones "1!oxetanones# unlike most other lactones and esters\ can be opened through attack
by soft nucleophiles at the alkyl group bonded to the ring oxygen atom[ Hard nucleophiles "e[g[\
alkyllithiums# attack at the carbonyl carbon atom ð76HCA0215Ł[ Copper!catalysed Grignards and
alkyllithiums add to give products of 2!carbon extension "Equation "133## ð79TL824\ 79TL1070Ł[
With the oxetanone "097# inversion of con_guration at the stereogenic centre occurs as expected
ð71TL2476Ł[ Mixed cuprates have also been used as nucleophiles ð76JA3538Ł[
i, butyl lithium, CuBr•Me2S, ether, –70 °C
O ii, add oxetane, –70 °C to 20 °C
(244)
CO2H
87%
O
0[94[1 SUBSTITUTION OF SULFUR FUNCTIONS

A useful review of sulfone chemistry has been published ðB!82MI 094!90Ł[
0[94[1[0 Radical Reactions

Reactions of radicals have been reviewed by Giese ðB!75MI 094!90Ł\ Neumann ð76S554Ł and Curran
ð77S306\ 77S378Ł and include the addition to carbon multiple bonds of radicals generated from sulfur
O
(108)
derivatives[ Radicals from sulfur compounds are not as readily formed as those from selenides[
Allylic sulfur compounds can act as radical traps "SH1?#[
Substitution of Sulfur 120
Radicals can be generated from xanthates with visible light "and an acylxanthate as a {trigger|#
or with UV light "Equation "134## ð78H"17#060Ł[ Alkyl radical generation from acid chloride and
thiopyridyl salt in the presence of an allylic sul_de gives the substituted enones via radical addition
to the alkene and loss of a sulfur radical\ which continues the radical chain process "Equation "135##
ð75JCS"P0#0502Ł[ Keto!esters can be allylated by generation of the manganese radicals and trapping
with an allylic sul_de ð89TL246Ł[ Poor yields and bisallylated products are obtained with some
substrates[ Cyclisations in 5!exo!trig ð89TL712Ł and 5!endo!trig ð80TL732Ł fashions have been carried
out "Equation "136##[ Radicals generated thermally or photochemically from hydroxamate esters
can cyclize\ with loss of sulfur\ to produce cyclopropanes ð89TL5974Ł^ the intervention of activated
alkenes generates cyclopentanes "Equations "137# and "138## ð89TL3192Ł[ The phenylsul_nyl radical
"generated in situ from allylic sulfones# can act as the propagator ð74CC786Ł[ In the example shown
in Equation "149#\ the phenylsul_nyl radical is trapped by the intermediate primary radical[
O O
PhCOSCSOEt, visible light MeO S
S PhMe, 110 °C
Bn + N Me
S
N Me (245)
S OMe 78%
Bn
O O
ButS
chlorobenzene, 133 °C
+ + C15H31COCl
N S 69%
CO2Et
ONa
ButS
• (246)
C15H31 C15H31
CO2Et CO2Et
MeO MeO
(Bu3Sn)2, hν, PhH, 10 °C
Br (247)
55%
SPh 52 : 48
Ph
S
O PhH, 110 °C
N SPh (248)
S 32% Ph
O
S CN
hν, PhH, 20 °C
O
N SPh + CN (249)
70%
O
SO2Ph
PhSO2
(PhCO2)2, CCl4, reflux
(250)
75% O
O
0[94[1[1 Thermal and Photochemical Reactions

Synthetically useful extrusion reactions of sulfur compounds that result in the formation of a
C0C bond have been reviewed ð77T5130Ł[
Photochemical desulfurization of bisbenzylsul_des in the presence of phosphite has been much
used to prepare ð1[1Ł!cyclophanes "Equations "140# and "141## ð64S796\ 78BCJ053Ł[ Yields are very
variable and seem to depend on the degree of strain in the system formed ð78CB236\ 78CB0002Ł[ The
reaction\ which also works for alkyl and allyl sul_des ð58JOC0122\ 62JA0436Ł\ proceeds via a radical
mechanism[ Extrusions can be selective for one sulfur atom ð62C297Ł "Equation "142##[ Note that
benzylic sul_des are normally moderately thermally stable[
(EtO)3P, hν, 20 °C
S S (251)
85%
S S
(EtO)3P, PhH, hν, 20 °C
(252)
93%
S S
sublimation, 0.3 torr

(EtO)3P, hν, 25 °C 65 °C, Et3P
S S S (253)
23% 15%
N N N
Sulfur dioxide can be extruded from cyclic sul_tes both thermally and photochemically in high
yield "Equations "143# and "144## ð67CJC401\ 72CJC646Ł[ In the photochemical reactions a phenyl
group is needed to act as a chromophore[ Sulfur dioxide is also extruded from cyclic sulfones under
similar conditions[ This has been used to prepare cyclophanes ð64AG"E#448\ 67SC174\ 80JHC178Ł[
Bridges of four to eight carbon atoms can be built in this way[ In some cases "e[g[\ sulfolenes# SO1
can be extruded via an electrocyclic reaction to give a diene\ which can then recyclize to form a
cyclobutene[ Extrusion of SO1 from the benzoðcŁthiophenedioxide "098# involves a disrotatory
process and this is followed by a conrotatory ring closure "Equation "145## ð61CC430Ł[ The driving
force for cyclisation is rearomatisation[ The photochemical reaction has reversed topicity "N[B[ the
WoodwardÐHo}mann rules#[ Hydride abstraction can be a competing process as shown by the
di}erent outcomes of the thermal and photochemical reactions in Equation "146# ð70JCS"P0#0735Ł[
Photochemical extrusion of SO1 from four!membered rings gives cyclopropanes in high yields
"Equation "147## ð67S468Ł[ Thermal reactions often give signi_cant amounts of alkenes\ especially
at higher temperatures ð60JA565Ł[ b!Lactams can be prepared via photochemical extrusion of SO1
but not in very high yield or stereochemical purity "Equation "148## ð72JOC383Ł[
O
O S
quartz tube, 700 °C, 0.01mm Hg

(254)
90%
O
S hν, PhH–acetone, 20 °C
O (255)
98%
Ph
Ph
D
D
10–6 mmHg, 500 °C
SO2 (256)
95%
D
D
(109)
hν 450–600 °C
SO2 (257)
55%
hν, CH2Cl2, 20 °C Ph
Ph (258)
SO2 95%
O2 Ph
S Ph hν, ButOH, MeCN
+ 28% SM (259)
N 39% N
O Me
O Me
cis : trans 80 : 20
0[94[1[2 Ring Contractions and Rearrangements
0[94[1[2[0 ð0\1Ł!Shifts
ð0\1Ł!Shifts of sulfur compounds are of two types\ for example Wittig rearrangements ðB!64MI 094!90\
80COS"2#864Ł of a anions and Stevens rearrangements ð80COS"2#802Ł of ylides[ Both reactions are
{forbidden| and proceed via radical pair intermediates ð69AG"E#652Ł[ The two methods are commonly
used to prepare cyclophanes[ For example\ the ylide of a bipyridyl "Equation "159##\ prepared in
situ\ spontaneously rearranges to the carbocyclic compound ð70JOC0636Ł[ Treatment of thietane
with diazomalonate gives the ring expanded product resulting from rearrangement of the inter!
mediate ylide "Equation "150## ð61JOC0610Ł[ An example of intramolecular ylide formation gives
cyclic products "Equation "151## ð77TL5994Ł[ The reaction is limited to migrating groups without a
b!hydrogen atom which otherwise eliminates in competition to the migration process[ The Wittig!
type rearrangement generally gives better yields and is easier to perform than the Stevens rearrange!
ment "Equation "152## ð64TL108Ł and has been much used in cyclophane chemistry ð71JA1459\
74CB0129\ 77JOC3361Ł[
i, Me3O+ PF6–, CH2Cl2, 20 °C

N ii, NaH, THF N + N
S S Me (260)
N 35% N N
– SMe
CO2Me CO2Me
CuSO4, PhMe, 110 °C
+ N2 (261)
S 26% CO2Me
CO2Me S
O O O
Rh2(OAc)4, PhH, 80 °C xylene, 135 °C
CO2Et (262)
+ 55%
S N2 CO2Et S CO2Et S
Ph
Ph Ph
i, BuLi or LDA, hexane–THF, 0 °C

ii, MeI
S S (263)
94%
Deprotonation of the cyclic sul_de "009# gives a cyclopentane derivative[ The reaction does not
go through a ð0\1Ł!shift but probably involves elimination of malonate followed by intramolecular
addition of that to the intermediate moiety thioaldehyde unit "Equation "153## ð77JA4821Ł[
CO2Et i, LDA, HMPA, –78 °C
ii, MeI CO2Et
CO2Et (264)
S 76% CO2Et
(110) SMe
Sulfur!containing four!membered ring compounds undergo an anionic ð0\1Ł!shift that results in

ring contraction[ Thus thietanonium salts\ when treated with butyl lithium\ give cyclopropanes
stereoselectively via a sulfur"IV# intermediate "Equation "154## ð60JA565Ł[ The stereochemistry of
the rearrangement of cyclic sulfoxides has been studied ð71CC478Ł and shown to be stereospeci_c in
most cases "Scheme 41#\ with retention of con_guration at the migrating carbon atom and inversion
at the migration terminus[ Although the stereochemistry can be accounted for by a concerted
mechanism it is believed that the reaction involves a biradical intermediate[ Cyclic sulfones also
rearrange in a similar manner ð52CI"L#0192Ł[
Ph Ph
BF4 –
(265)
S+ 25% S Bu
Ph Ph
Ph Me Ph Me
cis : trans
cis 10 : 90
trans 87 : 13
C6H13 i, LICA, THF, –20 °C C6H13

ii, MeI
+S
63%
–O SOMe
C6H13 i, LICA, THF, –20 °C C6H13 C6H13

ii, MeI MeSO
+S
+
98%
–O SOMe
97 : 3
Scheme 52
0[94[1[2[1 ð1\2Ł!Wittig rearrangements

Allylic sulfur compounds readily form ylides which rearrange via a ð1\2Ł!Wittig reaction forming
a new C0C bond "Equation "155## "see review ð73ACR247Ł#[ Treatment of the appropriate allylic
sul_de with an alkylating agent and then a strong base generates the ylide "000# which rearranges
to a ring expanded product "Equation "156## ð67JOC0074Ł[ Selectivity between two allylic groups can
be achieved "Equation "157## ð67TL408Ł and ring sizes of up to 06 atoms have been prepared
ð66HCA0250Ł[ Another way of generating ylides which then undergo rearrangement is by rhodium!
catalysed insertion of a carbene "generated from a diazo compound# ð75CRV808Ł[ The intermediate
ylides\ many of which are stable\ rearrange on heating "Equation "158## ð76CL0458Ł[ Copper com!
pounds and BF2 = OEt1 can also be used to catalyse the reaction\ with the copper system giving fewer
by!products "Equation "169## ð79TL284Ł[ Intramolecular insertions give six!and seven!ring sulfur
compounds although the yields for some of the seven!ring compounds are poor due to competing
b!elimination "Equation "160## ð77TL5994Ł[ SimmonÐSmith conditions generate sulfur ylides which
rearrange in situ to give rearranged products incorporating one extra carbon atom "Equation "161##
ð71JOC3994\ 71TL2908Ł[ Chiral ð1\2Ł!rearrangement of an ylide with a chiral auxiliary gave low yields
and ees "5Ð36) and 3Ð45) respectively# ð71CL0760Ł[ Anions of allyl sul_des "i[e[\ non!ylides# also
rearrange via a ð1\2Ł reaction\ but at much lower temperatures "Equation "162## ð70CL204\ 71CL240Ł[
CH2– (266)
+
S S
Me
Me
i, TfOCH2CO2Et CO2Et
ii, ButOK
+ – (267)
S 80% S S
CO2Et
(111)
ButOK
(268)
S+ 72% S
CO2Et
CO2Et Rh2(OAc)4, PhMe, 110 °C CO2Et
+ N2 SPh (269)
SPh 84%
CO2Et
N2 H
S Cu(acac)2, CH2Cl2, 20 °C S
SPh PhS
+ (270)
N 65% N
O O
CO2CH2CCl3 CO2CH2CCl3
O O O
Rh2(OAc)4, PhH, 80 °C – CO2Et (271)
S N2 CO2Et S+ CO2Et S
78%
Ph
Ph Ph
SPh
CH2I2, Et2Zn, PhH, 55 °C

(272)
78% SPh
i, 2LDA, THF, 0 °C SMe

ii, MeI
(273)
S CO2H CO2H
82%
0[94[1[2[2 Other rearrangements

Allylic sul_des add to activated alkynes under Lewis acid catalysis "Equation "163## ð73JOC0874Ł[
The stereochemical outcome depends on the Lewis acid employed "AlCl2 gives largely "E#!alkene
while ZnCl1 gives mostly "Z#!alkene#[ Suitably substituted allyl groups show that the reaction
proceeds with allylic rearrangement via a sulfonium species[ Sulfur compounds can also undergo a
thio!Claisen rearrangement[
Lewis acid, CH2Cl2, 25 °C CO2Me

CO2Me + PhS + PhS (274)
PhS
CO2Me
AlCl3 71% 72 : 28
ZnCl2 92% 3 : 97
0[94[1[3 Metal Exchange Reactions

Sulfur can be readily exchanged for lithium and then alkylated to form a new C0C bond
ð78ACR041Ł[ Reductive lithiation can be achieved with a number of reagents including lithium in
ammonia ð63TL2844Ł\ lithium naphthalenide ð78CB692Ł\ lithium 3\3?!di!t!butylbiphenylide "LDBB#
ð82JA2744Ł and lithium 0!"dimethylamino#naphthalenide "LDMAN# ð75T1792Ł[ In all these cases the
sp2C0S bond is cleaved selectively[ These sulfur!derived anions undergo reaction with electrophiles
such as CO1 and aldehydes "Equations "164# and "165## ð73TL3238\ 82JA2744Ł[ At low temperatures a
"Z#!alkene is formed exclusively from an allyl sulphide "Equation "166## ð76JA3609Ł[ Attack is at the
least substituted end of the system\ in contrast to the similar reaction in the presence of titanium
isopropoxide ð75T1792Ł[ Stabilized anions can be generated by metal exchange using a tin reagent
on thiocyanohydrins "Equation "167## ð74CL0038Ł[
i, LDBB, THF, –78 °C
OMe OMe
ii, CO2, –78 °C
(275)
SPh 80% CO2H
i, LDBB, THF, –78 °C HO

SPh ii, aldehyde, –78 °C
+ (276)
OHC 82%
i, LDBB, THF, –78 °C

ii, CeCl3, THF
PhS iii, aldehyde, –78 °C OH
+ OHC (277)
72%
i, Bu3SnLi, THF–HMPA, –78 °C

SEt ii, MeI, –78 °C to 25 °C
(278)
Ph CN 89% Ph CN
Dialkylcuprate cleaves an a!ketosulfoxide to generate an enolate which can then be alkylated

"Equation "168## ð70JA1775Ł[ The mechanism is not known[ a!Sulfonylketones are reductively cleaved
to give enolates which\ once again\ can be alkylated "Equation "179## ð74JOC2735Ł[
O O– O
S+ i, Me2CuLi (3 equiv.), ether–THF, 0 °C
Tol ii, bromide, HMPA, 25 °C CO2Me
+ Br (279)
CO2Me
89%
OMe OMe
O i, Li, NH3, THF, –33 °C O

O-THP ii, Bu3SnCl
SO2Tol iii, bromide, HMPA, –78 °C
+ (280)
Br 83%
O-THP
0[94[1[4 Sulfur Leaving Groups
There are many reactions which involve alkylation a to a sulfur group with subsequent reductive
cleavage of the C0S bond giving overall\ a formal C0S to C0C conversion[ This section covers
only those reactions where sulfur is displaced directly[ Direct displacements of sulfur groups at alkyl
carbon atoms are rare^ mostly allylic and benzylic sulfur systems are involved except for some
intramolecular reactions[
0[94[1[4[0 Allylic and benzylic sulfur systems

Allylic and benzylic sulfur leaving groups\ especially sulfones\ are readily displaced by nucleophiles
in a similar fashion to oxygen!based leaving groups[ However sulfones require more forcing reaction
conditions than\ for example\ the corresponding acetates "see Section 0[94[0[1[1#[
"i# Main `roup metals and copper

Copper!based nucleophiles displace sulphone as sul_nate in both SN1 and SN1? fashion "Equations
"170# and "171## ð72T2172Ł[ Attack is usually at the less substituted end of the allylic system but a
number of factors including solvent\ the attendant halogen atom and alkene geometry a}ect the
outcome[ As with oxygen leaving groups using ether as solvent favours g attack[ Displacement is in
the anti mode "Equation "172## ð76JA5285\ 77JA4105Ł[ Sulfoxide groups can also be displaced with
similar yields and selectivities "Equation "173## ð74JCS"P0#0060Ł[ Copper catalysis may not always be
necessary ð78TL2726Ł[ Aluminum alkenes and alkynes displace allylic sulfones under Lewis acid
catalysis at the less substituted carbon centre "Equations "174# and "175## ð75JA0987Ł[
C6H13MgBr, THF
Cu(acac)2, 20 °C
+ (281)
PhSO2 C6H13 C6H13
40%
(E) : ( Z) 3 : 97 (E) : (Z) 11 : 89 74 : 26
C6H13MgX, solvent
Cu(acac)2, 20 °C
+ C6H13 (282)
PhSO2 C6H13
THF 65% 16 : 84 (E) : (Z) 40 : 60
ether 51% 6 : 94 (E) : (Z) 61 : 39
Me2CuLi, ether, –40 °C to 0 °C

(283)
SO2Ph 54%
>95% cis
Me2CuLi, ether, –20 °C to 15 °C

O O O O (284)
PhS(O)n α: γ (E) : (Z)

n=1 69% 91 : 9 79 : 21
n=2 74% 95 : 5 97 : 3
C6H13 AlCl3, ether–hexane, reflux C5H11

+ Et2Al C5H11 (285)
77–87% C6H13
SO2Ph
α : γ 83 :17
AlCl3, hexane, –78 °C

+ Bui2Al (286)
C5H11
46%
SO2Ph C5H11
cis : trans 90 : 10
A number of other sulfur leaving groups have been used including the simple phenylthio!moiety
ð66JOM"031#0\ 79JA0953Ł[ Thiobenzothiazoles are readily displaced by copper!catalysed Grignard
reagents in either SN1 and SN1? fashion depending on the solvent "Scheme 42# ð72JCS"P0#1842Ł[
Dialkylcopper reagents are less selective[ Isothiouronium salts are displaced under very mild\
non!basic conditions using copper catalysis in aqueous solution "Equation "176## ð73JOC0359Ł[
Sulfonamidsul_nyl ð73TL1024Ł and 0!phenyltetrazoyl!4!thio ð77TL3094Ł have also been used as
leaving groups[
Ph
BuMgBr, CuI, ether–THF (1 : 1) BuMgBr, CuI, ether Bu
–30 °C to 25 °C N –30 °C to 25 °C
Bu Ph S
Ph
79% S 81%
Scheme 53
NH2 CO2Me
CO2Me
+ Cu(OAc)2, NaOAc MeO2C
S NH2 EtOH–H2O, 20 °C
+ MeO2C OAc (287)
54%
O
O
MeO MeO
Electron!de_cient tertiary benzylic sulfones can be displaced by nucleophiles such as malonate

and nitroalkanes under conditions that favour electron transfer processes ð77JOC0364Ł[
"ii# Transition metal catalysis

Palladium and other transition metals catalyse the replacement of sulfur by carbon nucleophiles[
Transition!metal mediated C0S bond cleavage reactions have been reviewed ð89S78Ł[ Under stan!
dard conditions sulfone is displaced by malonates and other stabilized anions to give\ for
a\b!unsaturated sulfones\ mixtures of regioisomers "Equation "177## ð79JA4868Ł[ The regioselectivity
depends on the substitution pattern and the steric bulk of the nucleophile and proceeds with net
retention of con_guration "i[e[\ a double inversion# "Equation "178## ð76JA5285Ł[ Nickel
ð75JOM"206#272Ł and molybdenum complexes ð78BCJ1802\ 89JOC0016Ł also catalyse this type of reaction
but with di}erent regiochemical consequences "Equation "189##[ Molybdenum is selective for alkyl!
ation at the more substituted end of the allylic system\ but the reaction products indicate a _ne
balance between steric and electronic factors^ in some cases selectivities up to 099 ] 9 have been
achieved ð78BCJ1802Ł[ Other leaving groups have been used with palladium catalysis including
phenyltetrazoylthio "001# ð77TL3094Ł and thiophosphonate "002# ð72JOC0182Ł[ Molybdenum hexa!
carbonyl catalysed the displacement of phenylthio but the reaction is slower than that for the
sulfones ð78BCJ1802Ł[ Molybdenum also catalyses benzocyclobutane formation from acylsilanes
"Equation "180## ð89TL1602Ł[ Chromium\ tungsten and palladium can also be used as catalysts[
Nickel is the best catalyst for cross!coupling of allyl sul_des with Grignard reagents ð68TL2314\
73CL0494Ł[ Modest "up to 46) ee# enantioselection has been obtained using chiral ligands ð75T1932Ł[
Ph
(Ph3P)4Pd, THF, 20 °C Ph X
Bu + X CO2Me
Bu (288)
57–82% CO2Me
SO2Ph
α:γ
X = CO2Me 87 : 13
X = SO2Ph 93 : 7
NMe2 (Ph3P)4Pd, dppe NMe2 NMe2

CO2Me THF, 67 °C
+ – + (289)
64% CO2Me MeO2C
SO2Ph CO2Me
Na+ CO2Me MeO2C
65 : 35
CO2Me
CO2Me MeO2C
+ – + (290)
SO2Ph
Na+ CO2Me CO2Me CO2Me
Mo(CO)6, PhMe 61% 90 : 10
(Ph3P)4Pd, THF 67% 68 : 32
Ni(dppe)2, THF 92% 39 : 61
SPh
Bu
Bu Mo(CO)6, PhMe, 110 °C
(291)
TMS 74%
O
O
Ph
S OEt
N N P
Ph
N O
S N
(112) (113)
Benzylthiols can be carbonylated under high pressure "59 atm# using a cobalt catalyst "Equation
"181## ð74JOC036Ł[ Dibenzyldisulphides can be carbonylated to give thioesters ð74TL1598Ł[
SH Co2(CO)8, CO, MeOH, 190 °C CO2Me

(292)
83%
"iii# Lewis acid catalysed reactions

Silylenol ethers and allylstannanes "but not allylsilanes# can be alkylated with allylic and benzylic
sulfur compounds in the presence of Lewis acids "Equations "182# and "183## ð76CL0580\ 76CL0584Ł[
A silver salt is used to activate the thiotetrazole leaving group in this alkylation reaction "Equation
"184## ð89TL154Ł[ Yields are in the range 49Ð87) for allylic and benzylic substrates[ Aluminum
trichloride catalyses Friedel!Crafts alkylation of allylic and benzylic sulfones "Equations "185# and
"186## ð73JA6159\ 89IJC"B#289Ł[
Ph3CBF4, CH2Cl2
SEt S Ph –78 °C to 20 °C O S
+ (293)
S O-TMS 85% Ph S
SEt S Ph3CSbF6, CH2Cl2, 20 °C S

+ Ph Sn (294)
3
S 69% S
N N O-TMS MeO
N AgOTf, CH2Cl2, 20 °C
S N + (295)
OMe 92%
Ph CO2Me
MeO
AlCl3, ether, 35 °C
N (296)
Me 40% N
SO2Ph Me
CO2Me CO2Me
PhH, AlCl3, 20 °C
SO2Tol Ph (297)
56%
0[94[1[4[1 Intramolecular reactions

When symmetrical 0\2!diphenylthiopropane derivatives are deprotonated a to the sulfur atom
they readily cyclize with loss of thiophenol to give cyclopropanes exhibiting trans ring geometry
"Equation "187## ð71BCJ1854\ 76CL798Ł[ Moderate diastereoselectivities\ which depend on the bulk of
the silyl unit\ are obtained when a chiral auxiliary is attached "Equation "188## ð77JA6074Ł[ Other
internal nucleophiles will displace sulfur "providing it is not possible to deprotonate a to sulfur#
"Equation "299## ð71T582Ł if the nucleophile is of higher or comparable acidity to the sulfur leaving
group "Equations "290# and "291## ð55CC646\ 74TL5004Ł[ A sulfur group may also be displaced by an
internal nucleophile generated from an addition process such as a Michael reaction "Equations
"292# and "293## ð76JOC107\ 70JOC4916Ł[
BuLi, HMPA, –78 °C

(298)
PhS SPh 88% SPh
SPh
H SPh
O O
ii, BuN4F, 20 °C
NH SPh NH (299)
OSiPri3 84% OH
83% de
SPh
BuLi, TMEDA–hexane, 20 °C
(300)
87%
dimsyl Na, DMSO, 70 °C

MeS(O) Ph (301)
97% But Ph
But
KH, DMSO, 80 °C
MeO2C SO2Ph CO2Me (302)
97%
MeO2C CO2Me
PhSO2 CN NC
O NaOEt, EtOH, 20 °C
+ NC SO2Ph (303)
59%
O
O–
i, BusLi, TMEDA PriNHCO PriNHCO

PriNHCO ii, CuBr•Me2S, –100 °C
SPh + + (304)
CONHPh 39%
CONHPh CONHPh
75 : 25
0[94[1[4[2 Sulfonium salts
Sulfonium salts can act as alkylating agents with dialkylsul_de acting as the leaving group[ When
the groups on sulfur are not the same problems of chemoselectivity can arise[ The important factors
are that the nucleophile must be insu.ciently basic to generate an ylide from the sulfonium salt and
that the counterion must be nonnucleophilic[ The soft leaving group favours carbon vs[ oxygen
alkylation of 0\2!dicarbonyl compounds ð79TL3700\ 72JOC0251Ł[ Five!membered ring thioethers are
ring!cleaved while six!membered ring thioethers react at the exocyclic carbon atom except when the
sulfur centre is allylic "Scheme 43#[ This endocyclic vs[ exocyclic attack has been studied with other
nucleophiles ð65JOC0941Ł[ A thallium salt of a b!ketoester opens a tricyclic compound selectively
"Equation "294## ð60TL2680Ł[ Intramolecular alkylation is possible "Equation "295## ð57AG"E#345Ł as
is Friedel!Crafts alkylation ð67AG"E#163Ł[ Sulfonium salts with three di}erent substituents are
optically active and have been used in asymmetric alkylations ð78JOC1263Ł[ Unfortunately the
reaction is neither chemo! nor enantioselective "Equation "296##[
O i, NaH, THF O
ii, add salt, 67 °C CO2Me
+ SEt
CO2Me + Et S
88%
BF4–
O O
i, NaH, THF
CO2Me
CO2Me + ii, add salt, 67 °C
+ Et S O
62%
BF4–
O O
i, NaH, THF CO2Me
CO2Me + ii, add salt, 67 °C
+ Et S SEt
98%
BF4–
Scheme 54
O O
HN
O
NH DMF, 20 °C HN NH
Br– + – CO2Et CO2Et (305)
100%
S+
Tl+ S O
O O
Ph NaOEt, EtOH, 20 °C Ph
Ph Ph (306)
+ 76%
SMe2
Et
O
:
S+
K2CO3, CH2Cl2, 20 °C
Me + CO2Et
74%
Cl
O O
CO2Et
+ (307)
CO2Et
10% ee 59 : 41 10% ee
0[94[1[4[3 Miscellaneous reactions

Acylation of the oxathianedioxide "003# "two equivalents# and then in situ hydrolysis gives
g!hydroxyketones in 42Ð78) yield "Equation "297## ð76CC338Ł[
i, LDA, THF, –78 °C
O ii, silica, CH2Cl2
+ (308)
80%
CO2Me S OH
O2
O
(114)
0[94[1[5 Opening of Thiiranes

Like epoxides thiiranes "thioepoxides# ð73CHEC"6#020Ł are readily ring!opened by a similar range
of nucleophiles[ Grignard reagents attack\ via an SN1 process\ at the less hindered carbon centre
"Equation "298## ð67M598Ł[ The allyl lithium "004# attacks from the g!position and the resultant thio
anion displaces chloride ion to give a thietane "Equation "209## ð74S0958Ł[ Cyanide opens the ring
under Lewis acid catalysis\ again at the less hindered position "Equation "200## ð72TL1200Ł[ Malonate
derivatives open thiiranes and the resultant thiol anion cyclizes onto esters and nitriles to give
thiolactones and thioimidates "Equations "201# and "202## ð75BCJ1210Ł[ Phenyl thiirane is an excep!
tion to the norm\ giving a 69 ] 29 selectivity of attack at the more substituted carbon centre[
SH
ether, reflux
+ (309)
S ClMg 83%
THF, –90 °C S
+ Li Cl (310)
S 73%
(115)
S-TMS
AlCl3, CH2Cl2, 40 °C
+ TMS-CN CN (311)
S 42%
CO2Et EtONa, EtOH, reflux

+ S (312)
S CO2Et 65%
EtO2C O
CN EtONa, EtOH, reflux

+ S (313)
S CN 62%
NC NH2
Anions a to isocyanide open thiiranes to give\ after cyclisation\ the six!membered ring heterocycles
"Equation "203## ð68LA340Ł[ Cobalt!catalyzed carbonylation gives b!thiol acids "Equation "204##
ð76OM0514Ł[ The thiirane is opened at the more substituted position[ A similar reaction can be
performed on thietanes ð78JOC19Ł[ Under Lewis acid catalysis methylenethiiranes "005# add to
enones to give tetrahydrothiophenes in variable yields "6Ð75)# "Equation "205## ð73TL3900Ł[ Intra!
molecular cyclisation onto an alkene has also been reported ð78JOC3559Ł[
S i, BuLi, pentane, –20 °C S N

ii, CuI, PhH, 80 °C
EtO + CN EtO (314)
Ph Ph
56%
OEt EtO
Co2(CO)8, MeI, PEG-400

S KOH, PhH–H2O, 20 °C CO2H
(315)
SH
Ph 78% Ph
PEG = polyethylene glycol

Substitution of Selenium and Tellurium 132
Ph
S O
BF3•OEt2, ether, 25 °C
+ O (316)
Ph Ph 23% S
Ph
(116)
0[94[2 SUBSTITUTION OF SELENIUM AND TELLURIUM

The chemistries of selenium ðB!75MI 094!91Ł and tellurium ð80S682\ 80S786Ł have been reviewed[
0[94[2[0 Thermal and Radical Reactions

Vacuum pyrolysis of selenides and tellurides results in extrusion of the free element and formation
of a C0C bond "see review of extrusion reactions ð77T5130Ł#^ intramolecular reactions have been
reported for tellurium "Equation "206## ð64TL0782Ł and both inter! and intramolecular reactions for
selenium "Equation "207## ð79SC484\ 70CL516\ 71BCJ071Ł^ the last ploy has been used to prepare
paracyclophanes[ The method is limited to benzylic compounds[ ð1\1Ł!Paracyclophanes can also be
prepared photochemically in good yield ð76BCJ3916Ł[ Detelluration can be achieved with bisallylic
substrates in those cases where deselenation fails ð71JOC0530Ł[
0.4–0.5 mmHg, 500 °C

Te (317)
74%
600 °C
(318)
Se
87%
Cleavage of carbon0selenium and carbon0tellurium bonds takes place homolytically to form

carbon!centred radicals which will add to the normal range of radical acceptors ðB!75MI 094!90Ł[
Phenyl selenium compounds have several advantages over other radical precursors "of which a
pleasant odour is not one# including ease of synthesis from a variety of sources "see Chapter 1[03#[
Radicals derived from selenium and tellurium add to acrylates in moderate to good yields ð71JOC2237\
78TL0198Ł "Equations "208# and "219##[ Phenylselenium was much better than either iodide or
mercury acetate as a radical precursor[ Reduced compounds are the main by!products and
stereochemical integrity is only retained in the ð4\4Ł bicyclic system[ Selenium!derived radicals a to
carbonyls also add to alkenes in 24Ð78) yields "Equation "210## ð89TL116\ 89TL4586Ł[ In the absence
of a hydride source the intermediate radical is trapped by a phenylselenyl moiety[ Mixtures of
isomers are obtained with some of the nucleoside radical acceptors ð89TL116Ł[ Tin compounds are
useful radical traps^ reacting with selenium derived radicals to give 0\3!dicarbonyl compounds
"Equation "211## ð89TL5558Ł and g\d!enoates "Equation "212## ð77JA3704\ 80SL301Ł and alkenes
ð72TL0246Ł[
MeO2C
H SePh H
methyl acrylate, Ph3SnH
O AIBN, PhMe, 110 °C O
O O (319)
70%
H H
MeO
TeCl2 i, NaBH4 MeO2C

ii, methyl acrylate, Bu3SnH
O toluene, 100 °C, 10 h
O O
O O + O (320)
64%
CO2Me i, hν, PhH, Ar MeO2C SePh
+ ii, 80 °C, 16 h
OBn OBn (321)
MeO2C SePh 88%
MeO2C
O O
SePh Bu3Sn hν, PhH, 20 °C

+ (322)
O 83%
O
O O
SePh ( )
5 CO2Me
hν, PhH, 20 °C
+ Bu3Sn CO2Me (323)
TMS-O ( )5 76% TMS-O
C5H11 C5H11
TMS-O TMS-O
Radicals derived from selenium compounds have been much used in intramolecular C0C bond
formation[ The a!cyano!compounds "006# cyclize in 64Ð80) yields as mixtures of isomers "Equation
"213## ð76JOC3832Ł[ The photochemically initiated cyclisations shown in Equation "214# ð80CC243Ł
give the trans compounds with selenium transfer[ Annellations are sensitive to substitution and
stereochemistry[ The nucleoside analogue "007# gives a single isomer at the new chiral centre
"Equation "215## while its C!2 epimer gives a mixture of compounds ð80T1126Ł[ Cyclisation of the
compound "008# gives a 49 ] 49 mixture of products\ while its analogue "019# gives a single isomer
"Equation "216## ð74TL5320Ł[ This method does not work for compounds involved in the formation
of six!membered rings[ Bicyclic systems can be produced by similar cyclisation of reactions "Equation
217# ð89JOC0675Ł^ spiro\ heterospiro and bridged systems are also available^ mixtures of isomers are
obtained in some cases ð77TL0204\ 78TL2754Ł[ Selenium compounds can be cyclized onto aldehydes
at ambient temperature "Equation "218## ð82CC318Ł[
Ph
Ph
OH
Ph3SnH, AIBN, PhH, 80 °C
OH SePh CN (324)
91%
CN
(117)
O O
PhSe hν, PhH, 20 °C PhSe
(325)
47%
O O O O
H H
O N O O N O
O N O N
TrO Bu3SnH, AIBN, PhH, 80 °C TrO
(326)
95% H H
O SePh O
(118)
O OH O
H H OH
Bu3SnH, AIBN, PhMe, 110 °C
(327)
95%
SePh H
Pri
(119) 50 : 50
CO2Me CO2Me
Ph3SnH, AIBN, PhH, 80 °C H
(328)
PhSe CO2Me 80% CO2Me
H
CO2Me CO2Me
Ph3SnH, Et3B, air, hexane, 20 °C
(329)
CHO 73%
O
H
SePh
O OH
H
SePh
(120)
Free radical ring expansion takes place regioselectively in 0\2!dicarbonyl systems to give six! and
seven!membered 0\3!dicarbonyl products "Scheme 44# ð77JA1454\ 78TL5018Ł[ Inter! and intra!
molecular hydride extraction are competing processes especially with N!benzyl piperidones\ giving
rise to reduced products[
O O O
CO2Et CO2Et
SePh
Bu3SnH, AIBN, PhH, 80 °C CO2Et
+
N N N
X X X
X = Bn 41% 37 : 63
X = Tr 74% 89 : 11
Scheme 55
0[94[2[1 MetalÐExchange Reactions

Organoselenium and organotellurium compounds are readily transmetallated with reagents such
as butyllithium[ Alkyl lithiums have a high a.nity for selenium and attack the selenium centre
preferentially\ in contrast to sulfur!based systems where a!deprotonation is the normal mode of
attack[ That bond is cleaved which gives the most stable lithium species[ Thus benzylic and allylic
selenides form the benzyl and allyl lithium species\ "Equations "229# and "220## ð74TL0982\ 75CC346\
70TL3230Ł which readily couple with primary halides or add to carbonyl compounds and enones "up
to 099) 0\3 addition#[ In some cases potassium diisopropylamide was found to be a better reagent
than LDA or butyl lithium "Equation "221## ð75TL0612Ł[ A few examples of displacement of tellurium
by carbon via telluriumÐlithium exchange are known but these are probably of limited synthetic
value except for allyl and benzyl tellurides where the corresponding lithium "and magnesium# species
are di.cult to obtain "Scheme 45# ð76AG"E#0076\ 78TL6242Ł[
O O
SeMe BuLi, THF–HMPA, –78 °C

+ (330)
Ph 65% Ph
SeMe i, BuLi, THF, –78 °C C9H19

ii, nonyl bromide
(331)
75%
i, KN(Pri)2, THF, –78 °C

SeMe ii, add bromide
+ Br (332)
Ph 78%
Ph
OH
BuLi PhCHO
+ Bun O
2Te
O Te O Li 66%
Bun
OH
PhTeLi PhLi PhCHO
Ph
Br Te –Ph2Te Li
96%
Scheme 56
The benzyl lithiums derived from selenides will add to unactivated double bonds to form _ve!
membered rings\ regenerating alkyl lithiums ð76CC0103\ 80TL306Ł[
0[94[2[2 a!Carbanion Formation

Treatment of the selenoester "010# with an alkoxide results in the extrusion of metallic selenium\
giving 0\2!dicarbonyl compounds in 35Ð75) yields "Equation "222## ð67CL0996Ł[
O –O O O O
, t-pentanol, 20 °C Se
Tol KO
Ph Se Ph Tol Ph Tol (333)
86%
O
(121)
0[94[2[3 Migrations of Selenides and Tellurides

a!Oxygen substituted selenides and tellurides undergo oxidative or base!catalysed rearrangement
of the pinacol type which leads to migration of an alkyl group and loss of selenium or tellurium
ð74JOC4199\ 75JCS"P0#0872Ł[ These reactions will be covered elsewhere[ Under some conditions\ for
example using thallium hydroxide and a haloform to generate carbenes\ replacement of the selenium
and hydroxyl moieties by C"hal#1 is observed yielding cyclopropanes ð76TL0438Ł[
0[94[2[4 Miscellaneous Reactions

Copper!catalysed Grignard reagents displace phenylselenyl groups\ with SN1 inversion "Equation
"223## ð80TL4698Ł[ Selenophenoxide can be used as a leaving group\ in a similar fashion to thio!
phenoxide\ in the molybdenum!catalysed allylation "Equation "224## ð78BCJ1802Ł[ Yields and sel!
ectivities are little di}erent from the sulfur analogues[ Selenium can also be used in place of sulfur
in the copper!catalysed insertion of diazo compounds into carbon0chalcogen bonds ð79TL284Ł[
SePh
H H
CuI, THF, –35 °C
+ BrMg (334)
N 83% N
O O
CO2Me CO2Me
Mo(CO)6, dioxan, 101 °C CO2Me
+ – + (335)
36% CO2Me
SePh CO2Me MeO2C
Na+
58 : 42
Tellurium is eliminated from tellurides in high yield when treated with palladium and a base
ð77TL2422Ł "Equation "225##[ The reaction is intramolecular as no scrambling occurs when unsym!
metrical tellurides are demetallated "Equation "226##[ It is postulated that the reaction procedes via
a telluriumÐpalladium complex "011# which undergoes a double alkyl migration\ elimination of
tellurium and coupling of the alkyl "or alkyl and aryl groups# "Scheme 46#[ The reaction is stoi!
chiometric in palladium[
Pd(OAc)2, Et3N, MeCN

(336)
10 h, 65 °C
Te 85%
Pd(OAc)2, Et3N, MeCN

Te (337)
10 h, 65 °C
81%
R1 R1 R1 R1
Te Pd0 Te PdII Te Pd Pd
R2 R2 R2 R2
(122)
Scheme 57
Tetraalkyltellurium reagents add to alkynes in 05Ð87) yields "GC^ based on tellurium# to give
cis alkenes\ with dialkyltellurium as by!product "Equation "227## ð82OM362Ł[ The reaction is believed
to proceed via a radical mechanism[
ether, 20 °C
Ph + Bu4Te + Bu2Te (338)
60%
Ph Bu
(E) : (Z) 8 : 92
Trimethylselenium and trimethyltellurium ions in super acid media "HSbF5# methylate toluene
ð77JOM"237#088Ł[ While the selenium reagent gives an ortho ] meta ratio of ca[ 1 ] 0 "similar to the
sulfur and oxygen analogues# tellerium gives a ratio ortho\ meta\ para of 82 ] 5 ] 0[
1.06
by Substitution: Substitution of
Carbon-Nitrogen, -Phosphorus,
-Arsenic, -Antimony, -Boron,
-Silicon, -Germanium and
-Metal Functions
PHILIP C. BULMAN PAGE, HEATHER L. McFARLAND and
ANDREA P. MILLAR
University of Liverpool, UK
0[95[0 SUBSTITUTION OF NITROGEN FUNCTIONS 149
0[95[0[0 Nitro Compounds 149
0[95[0[1 Quaternary Ammonium Salts 141
0[95[0[2 Tertiary Amines 144
0[95[0[3 Secondary Amines 147
0[95[0[4 Diazotization of Primary Amines 147
0[95[0[5 Functionalized Benzotriazoles 159
0[95[0[6 Azides 152
0[95[0[7 Rin` Openin` of Aziridines 152
0[95[0[8 Radical Mediated Processes 154
0[95[0[09 Rearranèments 155
0[95[0[00 Electrophilic Substitution 156
0[95[1 SUBSTITUTION OF PHOSPHORUS\ ARSENIC AND ANTIMONY FUNCTIONS 157
0[95[1[0 Substitution of Phosphorus Functions 157
0[95[1[1 Substitution of Arsenic Functions 157
0[95[1[2 Substitution of Antimony Functions 160
0[95[2 SUBSTITUTION OF BORON\ SILICON AND GERMANIUM FUNCTIONS 161
0[95[2[0 Substitution of Boron Functions 161
0[95[2[0[0 Conjuàte addition to a\b!unsaturated ketones and aldehydes 162
0[95[2[0[1 Conjuàte addition to a\b!unsaturated carboxylic acid derivatives 165
0[95[2[0[2 Conjuàte addition to vinyl and alkynyl epoxides 166
0[95[2[0[3 Aromatic and alkenic substitution 167
0[95[2[0[4 Aliphatic substitution 179
0[95[2[1 Substitution of Silicon Functions 170
0[95[2[1[0 Alkylation 170
0[95[2[1[1 Hydroxylation:aldol reactions 172
0[95[2[1[2 Acylation 173
0[95[2[1[3 0\2!Dipole formation 174
138
149 One or More CC Bond"s# formed by Substitution Carbon!Nitroèn\ etc[
0[95[2[1[4 Free radical mediated reactions 178
0[95[2[2 Substitution of Germanium Functions 189
0[95[3 SUBSTITUTION OF METAL FUNCTIONS 180
0[95[0 SUBSTITUTION OF NITROGEN FUNCTIONS
0[95[0[0 Nitro Compounds

Aliphatic nitro compounds are versatile synthetic intermediates[ The highly electron!withdrawing
nitro group facilitates a!carbanion formation "and subsequent carbonÐcarbon bond forming pro!
cesses# and is easily converted into other functional groups ð80S312Ł[
Kornblum discovered that substitution reactions of the nitro group in various types of tertiary
nitro compounds can be induced by relatively soft nucleophiles through single electron transfer
chain processes "SRN0# "Scheme 0# ð64AG"E#623Ł[ These reactions proceed by a chain sequence in
which radical anions and free radicals are intermediates[ They occur readily under mild conditions
and in excellent yields[ In contrast to SN1 displacements they are rather insensitive to steric hindrance
and are useful for the synthesis of highly branched structures that are otherwise di.cult to prepare[
NO2 Nu
Nu–, DMSO, 25 °C
94–96%
NO2 NO2
Nu = PhS, N3, CH(CO2Me)2, CMe2NO2
Scheme 1
A more general substitution was discovered in the early 0879s whereby primary\ secondary and
tertiary allylic nitro compounds undergo displacement of the nitro group by various nucleophiles
with the aid of metal catalysts such as palladium phosphine complexes ð71CC710\ 71JA2616Ł and
Lewis acids ð75CC0174Ł[ For example\ the reaction of 0!"nitromethyl#!2\3!dihydronaphthalene with
sodio!1!carboethoxycyclopentanone in DMF at 19>C using 0Ð4 mol) of both tetrakis!
"triphenylphosphine# palladium"9# and 0\1!bis"diphenylphosphino#ethane "dppe# gave the nucleo!
philic displacement product in 53) yield "Equation "0## ð75JOC3264Ł[
O
EtO O
NO2
ONa O
Pd(PPh3)4, dppe, DMF, 20 °C
+ (1)
OEt 64%
Acyclic allylic nitro compounds also serve as reactive substrates for tetra!
kis"triphenylphosphine#palladium"9#!catalysed substitution reactions "Scheme 1# ð75JCS"P0#0328Ł[
The regiochemistry of such substitution of tertiary allylic nitro compounds is governed primarily
by the steric factors of the nucleophiles[ Generally\ bulky nucleophiles attack selectively at the less
hindered terminus "Scheme 1\ entry 0#\ whereas less bulky groups tend to give direct substitution
"entry 1#[ The regiochemistry is also controlled by the steric and electronic e}ects of the a!sub!
stituents[ Again\ bulky alkyl groups assist substitution at the less hindered carbon atom "entry 2#\
while less bulky groups result in direct substitution "entry 3#[ Groups which are electron withdrawing\
such as esters\ cause selective attack at the terminal carbon atom with allylic displacement
"entry 4#[
Substitution of Nitroèn 140
NO2 Nu–, Pd(PPh3)4 Nu R
+ Nu
R R
A B
Entry R Nu– Yield (%) Ratio
A:B
1 Me p-MeC6H4SO2C–(Me)CO2Et 90 0:100
2 Me –CH(CN)CO Me 75 99:1
2
3 n-C6H13 –CH(CO Me) 78 42:58
2 2
4 Me –CH(CO Me) 60 73:27
2 2
5 CO2Et –CH(CO Me) 75 0:100
2 2
Scheme 2
In contrast to the palladium!catalysed substitution of allylic nitro groups by various nucleophiles\

a novel uncatalysed reaction\ speci_c for cyclic a!nitroalkyl enones\ was reported in 0878 ð78TL1302Ł[
For example\ the reaction of 1!"nitromethyl#cyclohexenone with ethyl sodio!1!cyanobutanoate in
DMF at room temperature gave the nucleophilic displacement product in 61) yield "Equation "1##
ð78TL1302Ł[ Mechanistic studies concluded that the formation of the SN1 product occurs by a
double additionÐelimination sequence to give the thermodynamically more stable product[ The high
reactivity of cyclic 1!"nitroalkyl#enones is however due to the leaving ability of the NO1 group[ The
b!functionalized cyclic enone products were used for further synthetic manipulation[
O CO2Et O
–
CN
NO2 (2)
DMF, RT
72%
NC CO2Et
Lewis acid!catalysed nucleophilic substitution reactions of tertiary\ benzylic and allylic nitro!
alkanes normally proceed through an SN0 mechanism involving a carbocation intermediate[ Inter!
and intramolecular FriedelÐCrafts reactions of these compounds can best be achieved by using two
equivalents of tin tetrachloride "Scheme 2#[ Other Lewis acids such as aluminum trichloride\ titanium
tetrachloride and zinc chloride are less e}ective ð75CC0174Ł[
OMe
OMe
SnCl4, CH2Cl2, RT, 1 h
But NO2 +
74%
But
SnCl4, CH2Cl2, RT, 2 h

NO2
74%
Ph Ph
Scheme 3
Benzylic and tertiary allylic nitro compounds react with allytrimethylsilane rapidly at −09>C in
the presence of one equivalent of tin tetrachloride "Equation "2## ð75CC0174Ł[
SnCl4, CH2Cl2, –10 °C, 30 min

+ TMS (3)
Ph NO2 40% Ph
Secondary and tertiary allylic nitro compounds can undergo Lewis acid!catalysed substitution by
silyl enol ethers[ For example\ 0!trimethylsilyloxycyclohexene reacts at ca[ −19>C in the presence
of one equivalent of tin tetrachloride to produce allylated products "Equation "3## ð75CC0174Ł[
O-TMS SnCl4, CH2Cl2 O

–20 °C, 30 min
O
NO2 + + (4)
62%
35 : 65
Secondary and tertiary allylic nitro compounds also react with cyanotrimethylsilane in the pres!
ence of 9[1 equivalents of tin tetrachloride to give b\g!unsaturated nitriles as a mixture of isomers
"Equation "4## ð75TL2914Ł[ Titanium tetrachloride is also an e}ective catalyst for these trans!
formations\ but zinc chloride\ aluminum chloride and boron tri~uoride etherate mediate slow\ poor!
yielding reactions[ Ester and nitrile functional groups were tolerated in the substrate when tertiary
allylic nitro groups were replaced by nitrile at room temperature[ In general\ secondary allylic nitro
compounds were poorer substrates than tertiary species[
NO2 TMS-CN, SnCl4 CN

CH2Cl2, RT, 30 min
CO2Me CO2Me + CO2Me (5)
75%
CN
30 : 70
Lewis acids are also required for the displacement of the nitro groups in primary\ secondary\
tertiary and benzylic b!nitro sul_des ð76JOC3022Ł[ These sul_des can be prepared in a one!pot
procedure by reaction of aldehydes or ketones with nitro compounds and thiols in the presence of
amines[ Their treatment with cyanotrimethylsilane or allyl trimethylsilane in the presence of a Lewis
acid "AlCl2\ SnCl3 or TiCl3# gave the substitution products as shown "Scheme 3#[ Similar treatment
of 1!nitrobutane gave no substitution reaction\ showing the importance of the b!phenylthio function[
The reactions are thought to proceed via episulfonium ions\ and the ratio of products depends on
the electron donating or withdrawing nature of the substituents[ The predominant product is formed
by attack of the nucleophile at the incipiently more electropositive terminus of the episulfonium ion
intermediate[ A 0\1!migration of the thiophenyl group occurs when the nitro group is primary and
the thiophenyl group is located on a tertiary or benzylic position "Scheme 3\ entry 0# ð78JOC3887Ł[
R3 R3 R1 R2
TMS
PhS PhS PhS
NO2
+
Lewis acid, CH2Cl2
R1 R1
R2 R2 R3
A B
Entry R1 R2 R3 Lewis acid Yield (%) Ratio
A:B
1 Me Me H AlCl3 72 7 : 93
2 Et H Me TiCl4 55 75 : 25
Scheme 4
Stereoselectivity in the formation of carbonÐcarbon bonds by nitro displacement using pure anti
and pure syn b!nitrosul_des was examined[ In each case the anti isomer reacted more rapidly with
nucleophiles than the corresponding syn isomer[ Cyclic compounds could also be formed through
this process by intramolecular nitro group displacement in b!nitrosul_des with retention of con!
_guration "Equation "5##[
SnCl4, RT, 6 h
SPh (6)
O2N 76% SPh
H
0[95[0[1 Quaternary Ammonium Salts

Many examples of carbonÐcarbon bond formation with cleavage of carbonÐnitrogen bonds in
quaternary ammonium salts can be found in the literature[ A representative selection is described
below[
Reactions of various quaternary ammonium salts with enolate anions derived from activated
methylene compounds provide a synthetic route for 1!aryl!prop!0!ene systems "Scheme 4#
ð78SC1304Ł[ Sodium hydride as base and acetonitrile as solvent were found to give the best results[
The enolates derived from ethyl malonate\ ethyl acetoacetate and ethyl cyanoacetate were treated
with quaternary ammonium salts derived from 1!aryl!2!"N\N!dimethylamino#!prop!0!enes[ The
reactions were generally clean and e.cient\ giving 1!arylalk!0!ene systems in high yields[
Ar X CO2Et Ar X
+
NMe3 I– NaH, MeCN, ∆ CO2Et
Ar = MeO
X Yield (%)
CO2Et 93
MeCO 69
CN 24
Scheme 5
2!Substituted isoprenylsilanes are useful\ not only as nucleophilic reagents for the introduction of
a 0\2!diene skeleton\ but also as highly reactive 0\2!dienes[ They can be prepared by the displacement
reaction between an ammonium halide salt of 1!ð"dimethylamino#methylŁ!2!ð"trimethylsilyl#methylŁ!
0\2!butadiene and a Grignard reagent in the presence of dilithium tetrachlorocuprate as a catalyst
"Scheme 5# ð76JOC1836Ł[ Oddly\ the use of other catalysts such as cuprous chloride\ cuprous bromide
and cuprous iodide did not give satisfactory results[ Furthermore\ e.cient reaction often required
a large excess of Grignard reagent[
TMS BuMgX, Li2CuCl4, THF TMS

+ Bu
RMe2N
X–
R X Yield (%)
Me I 88
Bu I 52
PhCH2 Cl 92
Scheme 6
"E#\"Z#!Diene!containing pheromones can be prepared by nucleophilic substitution of an "E#\"Z#!

dienyl ammonium salt\ as illustrated by the synthesis of 6"E#\8"Z#!dodecadien!0!yl acetate\ the sex
pheromone of Lobesia botrana\ a major pest of vineyards "Scheme 6# ð79TL56Ł[ For these reactions\
use of lithium diorganocuprate reagents as nucleophiles was found to give better yields of the
"E#\"Z#!dienes with greater selectivity than did use of copper!catalysed Grignard reagents[
+
I– Me3N RM
O-THP
O-THP
RM Yield (%) Ratio

(E),(Z) : (E),(E)
MeMgBr/Li2CuCl4 53 90 : 10
Me2CuLi 68 92 : 8
Scheme 7
The transformation of 1!"0!"dimethylamino#ethyl#!2!"1!hydroxyethyl#!0H!indole into the cor!

responding nitriloalcohol has been used in alkaloid synthesis[ The reaction involves conversion of
an amine into a quaternary ammonium iodide followed by displacement with KCN:07!crown!5 in
acetonitrile to give the desired nitriloalcohol in 71) yield "Equation "6## ð70JOC2182Ł[
OH OH
i, MeI, EtOAc
ii, KCN, MeCN, 18-crown-6
(7)
82%
N NMe2 N CN
H H
Another example of displacement of an ammonium salt\ involving formation of a new carbonÐ

carbon bond\ is used in a novel route to 5!t!butyl!1!arylpyridines "Scheme 7# ð81SC240Ł[ The starting
material\ 3\3!dimethyl!0!piperidino!pentan!2!one\ was quaternised with methyl iodide[ Reaction
with various aryl b!ketoesters in the presence of base provided the crude substituted products which
were hydrolysed and decarboxylated to give the 0\4!diketones in fair yields[ Cyclization provided
the 5!t!butyl!1!arylpyridines[
O O O
H
i, MeI, K2CO3 hydrolysis and
But + N But Ar
ii, ArCOCH2CO2R, K2CO3 decarboxylation
Cl– CO2R
O O NH3
But Ar cyclization
But N Ar
Scheme 8
Benzyl! and allyltriethylammonium halides can undergo catalytic carbonylation to give the
corresponding acids in the presence of dicobalt octacarbonyl ð72JOC0808Ł[ These reactions were
carried out at 54>C under a slow stream of carbon monoxide[ Irradiation using a sunlamp was
necessary "Scheme 8#[
+ CO (1 atm), Co2(CO)8, 5M NaOH
R NEt3 X– R CO2H
hν, 12 h, 65 °C
R X Yield (%)
C6H5 Br 85
2-MeC6H4 Cl 85
Scheme 9
An allylic quaternary ammonium salt can be prepared from diisopropylethylamine by addition

to methallyl phenyl sulfoxide and trimethylsilyl tri~ate in dry dichloromethane at 9>C[ This salt has
been shown to alkylate sodium dimethyl malonate regioselectively in THF at room temperature\
using tetrakis"triphenylphosphine# palladium"9# as a catalyst to give the product in 59) yield
"Scheme 09# ð77TL1146Ł[
i, Pd(PPh3)4, THF, RT
O– i, Pri2NEt, CH2Cl2, 0 °C ii, Na+ –CH(CO2Me)2
+
S+ Pri2EtN SPh TfO–
Ph ii, TMS-OTf 60%
MeO2C
SPh
MeO2C
(E):(Z) 6:1
Scheme 10
1!Azanorbornene!1!spiro!0?!aziridinium tri~ate can be used for the aminoethylation or N!methyl!

aminoethylation of carbonyl compounds[ This spiroaziridinium salt can be prepared by an aqueous
DielsÐAlder reaction between cyclopentadiene and the immonium ion derived from formaldehyde
and 1!bromoethylamine hydrobromide^ subsequent treatment with silver tri~ate provides the spiro!
aziridinium tri~ate which is extremely stable at ambient temperature in the absence of moisture
ð81TL3390Ł[ The ability of 1!azonianorbornene!1!spiro!0?!aziridinium tri~ate to function as an
alkylating agent is well illustrated by its reaction with the enolate derived from a bicyclic lactone[
This reaction provided the alkylated lactone in 63) yield "Scheme 00#[ This spiroaziridinium tri~ate
has been used to alkylate a variety of enolates in good yields[
OBn
H
O– N
O
OBn
AgOTf H H
N + –OTf 74%
N
O
Br
O
H
Scheme 11
0\1!bis!"Cyanomethyl#arenes are useful synthetic building blocks for a variety of benzazepine and
indene derivatives which have important biological activities[ They can also be used in the prep!
aration of benzobiphenylenes and cyclo!octatetraenes[ The preparation of 2!methoxy!0\1!
bis!"cyanomethyl#benzene from 2!methoxy!0!"dimethylaminomethyl#benzene involves a cyanide
displacement of the dimethylamino unit of 2!methoxy!1!hydroxymethyl!0!"dimethylamino!
methyl#benzene\ via the benzyl chloride\ itself produced in situ by displacement of a quaternary
ammonium salt "Scheme 01# ð89SC2236Ł[ Concurrent displacement of both the dimethylamino and
hydroxy groups occurred when a hydroxymethyl substituent was sited ortho to the alkoxy group[
i, NaHCO3 (1 equiv.),
OMe OMe ClCO2Et (2 equiv.)
OMe
i, BuLi, Et2O, –78 °C ii, KCN
OH CN
ii, CH2O 78%
NMe2 NMe2 CN
Scheme 12
The condensation of a quaternary ammonium salt derived from 1!thiolo!2!diethylamino!

methylimidazole with 03C!labelled ethyl acetamido cyanoacetate in the presence of sodium ethoxide
was used to produce labelled 1!methylthiohistidine after hydrolysis and decarboxylation in 72)
yield ð47JA3394Ł[ Greater yields were obtained by the use of ion!exchange resins for puri_cation
rather than by isolation via the mercury complex as had previously been carried out[ Cleavage with
sodium in liquid ammonia provided labelled 1!thiolohistidine\ a key intermediate for the synthesis
of ergothionene "Equation "7##[
+ CO2H
NMeEt2 *
CO2Et i, NaOEt
+ AcHN NH2 (8)
N NH *
ii, hydrolysis, N NH
CN
decarboxylation
SH SMe
0[95[0[2 Tertiary Amines

Classically\ Mannich reactions of enolisable carbonyl compounds to yield b!aminoketones have
involved treatment of an acidic mixture of formaldehyde and a simple secondary amine such as
dimethylamine with the ketone in ethanol under re~ux for several days[ Alternatively\ the reaction
of enolates or silyl enol ethers with iminium ions such as N\N!dimethylmethyleneiminium ions may
be used[ b!Aminoketones have also been synthesized from aminals^ for example\ reactions between
boron enolates and N\N\N?\N?!tetramethyldiaminomethane "TMDM# are often used for the gen!
eration of N\N!dimethylmethyleneiminium ions "Equation "8## ð89CC0421Ł[ The mechanism involves
a Mannich process\ in which the boron atom activates the aminal by functioning as a Lewis acid[
The reactions do not proceed with the less Lewis acidic lithium enolate[ Reduced yields were
however obtained for dimethylaminomethylation at sterically hindered positions of ketones using
this method[
OBBu2 O NMe2
Me2N NMe2
(9)
CH2Cl2
57%
OBn OBn
Tertiary amines have been used in a number of alkylation reactions[ For example\ a b!amino!
ketone formed by reaction of an aryl methyl ketone with paraformaldehyde and dimethylamine
hydrochloride was used to alkylate potassium cyanide with displacement of dimethylamine to give
a b!aroylpropionitrile "Scheme 02# ð47JOC0170Ł[ Only amines possessing an aryl group adjacent to
the carbonyl group undergo this displacement[ The reaction has been used to prepare pyrrolidines
which are potential antihypertensive agents ð36JCS0089Ł[
R
O (CH2O)n O KCN, H2O, ∆ O [steps]
Ar N
Ar Me2NH•HCl Ar NMe2 30 min Ar CN
Scheme 13
A further example is the alkylation of indole with diethylaminoacetonitrile\ which provides a

convenient method for the preparation of indole!2!acetonitrile on a small scale "Equation "09##
ð42JA2478Ł[ Diminished yields were obtained upon attempted scale up[ The authors suggest that this
is due to the great sensitivity of the cyanomethylation reaction to temperature ~uctuations[
CN
Et2NCH2CN, N2, 170 °C, 6 h
(10)
N up to 44%
H N
H
N!Unsubstituted a!alkylated pyrrole!a!acetonitriles are a di.cult class of compounds to prepare\

but are potentially useful in indole synthesis[ One viable route involves treatment of a!branched
pyrrole tertiary amines with p!toluenesulfonic acid in the presence of excess sodium cyanide in
acetonitrileÐwater solution at re~ux "Scheme 03#[ These nitriles are thought to arise through an
eliminationÐaddition mechanism\ via the azafulvenes[ The a!branched tertiary amines were pro!
duced by reaction of 5!dimethylamino!0!azafulvene with an excess of various alkyl lithium reagents
ð76SC752Ł[
NMe2 TsOH, NaCN, ∆ CN

R
N N
H N H
R R
R Yield (%)
But 78
Bus 96
H 70
Scheme 14
An unusual example of alkylation involving tertiary amines is that of 2!"dimethyl!

aminomethyl#indole "gramine# with triethoxycarbonylmethane\ again through an eliminationÐ
addition process "Scheme 04# ð38JA552Ł[ Further treatment of gramine with boiling 84) aqueous
ethanolic sodium cyanide for eighty hours gave indole!2!acetamide\ which could be smoothly
converted into indole!2!acetic acid in high yield by hydrolysis with sodium hydroxide "Scheme 04#
ð37JA2669Ł[
CO2Et
NMe2 CO2H
HC(CO2Et)3, KOH, H2O i, NaCN, H2O, EtOH
EtOH, 8 h, ∆ CO2Et ii, NaOH
67% 88%
N N
H N H
H
Scheme 15
Similar base catalysed alkylation of a Reissert compound with gramine in the presence of sodium
occurs to give 0!cyano!0!skatyl!1!benzoyl!0\1!dihydroisoquinoline in 35) yield ð49JA1023Ł[ Further
basic hydrolysis provides 0!substituted isoquinolines in quantitative yields "Equation "00##[
HN
NMe2
Na, p-xylene, 3 h, ∆
+ N Ph O NC (11)
46%
N CN O
H Ph N
2!Substituted 1!exo!methylene!cycloalkanones can be prepared from 1!"nitro!methyl#

cyclohexenones by conjugate addition of organocuprates followed by elimination of the nitro group[
This methodology has been extended to asymmetric synthesis using chiral amines in place of the
nitro group[ The required "S#!1!"1!"methoxymethyl#!0!"pyrrolidinyl#methyl#!1!cyclohexen!0!one
can be prepared in 78Ð83) yield from 1!"nitromethyl#!1!cyclohexen!0!one and "S#!1!"methoxymethyl#!
pyrrolidine[ Optically active 2!substituted 1!exo!methylene!cyclohexanones were obtained in 89)
enantiomeric excess by zinc bromide assisted asymmetric conjugate addition of lithium diorgano!
cuprates\ followed by elimination of the pyrrolidine in aqueous work!up "20Ð61) yields# "Scheme
05#[ The absence of zinc bromide did not a}ect the ee but was found greatly to decrease the yields
ð89JOC397Ł[
O OMe O OMe i, Bu2CuLi, ZnBr2

MeCN, 25 °C, 1 h ii, H2O
NO2 + N
HN 89%
O O
Ph2CuLi
Ph
72%
Bu Bu
Scheme 16
Tri~ates have also been used to convert primary amines into reactive leaving groups for nucleo!
philic substitution[ Lithium dimethyl and diphenyl cuprates have been found to react with N\N!
bistri~uoromethanesulfonimides of benzylic or allylic primary amines to give the substitution prod!
ucts "Scheme 06# ð67TL3616Ł[ The reactions are speci_c for benzylic and allylic bistri~uoro!
methanesulfonimide groups and are carried out with _ve equivalents of cuprate in ether or ether:
THF as solvent[ Investigation into the mechanism of these substitution reactions concluded that
direct displacement at the allylic position seemed more probable than displacement at the terminus
followed by rearrangement of the double bond[
NTf2
Me2CuLi
60–70%
Ph2CuLi
NTf2
73%
Scheme 17
0[95[0[3 Secondary Amines

Investigation into the alkylating properties of the secondary amines N!"a!"2!indolyl#ethyl#!N!
isopropylamine\ N!"a!"2!indolyl#methyl#!N!t!butylamine\ and N!"a!"2!indolyl#ethyl#!N!t!butyl!
amine with dialkyl and diaryl acetamidomalonates showed most rapid alkylation using N!"a!"2!
indolyl#ethyl#!N!t!butylamine "Equation "01## ð46JA1106Ł[ The reactions could be followed semi!
quantitatively by titration of the volatile amines evolved[ All three indoles gave excellent yields and
required lower temperatures or shorter reaction times than those reported for gramine\ perhaps
because of the bulky groups attached to the acyclic nitrogen atom[
CO2Bn
NHPri CO2Bn
CO2Bn NaOMe, toluene, 85–95% NHAc
+ AcHN (12)
CO2Bn 97%
N
H N
H
In a di}erent type of reaction\ the secondary amine N\N!diphenyl trimethylenediamine breaks

down smoothly at 129Ð149>C\ in the presence of hydrobromic acid\ to give aniline and 0\1\2\3!
tetrahydroquinoline ð59JOC352Ł[ Decomposition of the monohydrobromide was found to be fastest
using 9[0 M hydrobromic acid[ The proposed mechanism involves intramolecular nucleophilic
displacement of the ammonium salt "Scheme 07#[
H
N H H
N + N
HBr
50%
NHPh
Scheme 18
0[95[0[4 Diazotization of Primary Amines

Diazotization with formation of a new carbonÐcarbon bond involves the generation of a diaz!
onium ion\ commonly from a primary amine by the action of nitrous acid followed by nucleophilic
displacement[ The diazonium ion intermediate can decompose with loss of nitrogen^ the incipient
carbocation may be trapped by reaction with an external nucleophile\ the classical reaction for
aromatic amines\ or may rearrange or decompose\ a common fate for aliphatic amines ð65AG"E#140\
76CL0052Ł[ The rate!determining step in the case of aliphatic primary amines is thought to be the
formation of a nitrosamine which isomerises to a diazonium salt in the presence of acid[ This salt
then rapidly loses nitrogen with attack by an external nucleophile to form the carbocation[ The
process has been thoroughly reviewed ðB!57MI 095!90\ B!67MI 095!90\ B!75MI 095!90Ł[
A representative diazotization followed by attack by an external nucleophile is provided by the
reaction of the hydrochloride salt of a protected 1!aminomethyl pyrrole with nitrous acid and a
porphobilinogen lactam ester "Scheme 08# ð60JA1627Ł[
MeO2C
MeO2C MeO2C
NaNO2, AcOH O
CO2Me
CO2Me 90 °C, 1 h
+ O NH
+ 73% MeO2C N
NH3 Cl– H
MeO2C NH NH
N N
H H
CO2Me
Scheme 19
An unusual and interesting example with intramolecular carbonÐcarbon bond formation is seen
in the diazotization of 8!aminomethyl!0\3!dimethyltriptycene\ carried out by treatment of the
hydrochloride salt with ten equivalents of sodium nitrite in acetic acid at room temperature for
_fteen hours[ The production of the carbocation at the a!position of the bridgehead and the presence
of the methyl group at one of the peri!positions of the triptycene skeleton are found to favour
intramolecular insertion as opposed to skeletal rearrangement[ The transformation is shown in
Equation "02# ð76CL0052Ł[ In this case the intermediate carbocation inserts into a C0H bond of the
0!methyl group as opposed to su}ering attack by a nucleophile[ The reaction is thought to take
place via a pentacoordinated species which undergoes proton loss\ favoured by the close proximity
of the participating carbon atoms[
NaNO2, HOAc
(13)
NH2
A further intramolecular example thought to involve a WagnerÐMeerwein rearrangement is

observed when 07!amino!4a!pregnane!2b\19!diol is treated with nitrous acid in acetic acid to give
03b\07!cyclo!4a!pregnene!2b\19!diol "Scheme 19# ð53T0148Ł[ WagnerÐMeerwein rearrangement to
give the tertiary carbenium ion is followed by attack on the carbocation by the other bridgehead
carbon atom with loss of a proton[
H 2N OH OH
+
H HONO H
HOAc
H H H H
HO HO
H H
OH
H
HO
H
Scheme 20
0[95[0[5 Functionalized Benzotriazoles
Functionalized benzotriazole moieties are well known as versatile synthons for the introduction
of heteroalkyl groups in reactions with carbon nucleophiles "Equation "03##\ and there are therefore
many examples of carbonÐcarbon bond formation through carbonÐnitrogen bond cleavage with
displacement of benzotriazole units ð80JOC3328Ł[ The methodology\ developed by Katritzky\ has
proved popular\ no doubt partly due to the ease of preparation of the substituted benzotriazole
reagents from readily available starting materials[ Reactions with carbon nucleophiles generally
proceed under mild conditions\ and the benzotriazole unit may be recovered at the end of the
reaction ð78JCS"P0#114Ł[ Amines ð76JCS"P0#794Ł\ hydrazines ð78JCS"P0#1186Ł\ aminoesters ð78S212\
78S636Ł\ aminoketones ð89T876Ł\ ethers ð78JOC5911Ł\ sul_des ð80HCA0813Ł\ amides and thioamides
ð77JOC4743Ł have all been prepared using this chemistry[
N
N R N
Nu–
N + N (14)
Nu X N –
X
R
In the simplest cases\ aromatic secondary amines may be prepared from 0!"0!"arylamino#
alkyl#benzotriazoles using Grignard reagents "Scheme 10# ð76JCS"P0#794Ł[
N
N N
R2MgX R2
N
N +
N
NHAr R1 NHAr MgX
R1
R1 R2MgX Yield (%)

Pri MeMgI 80
Me MgBr 62
H BnMgCl 78
Scheme 21
This methodology utilising Grignard reagents has been extended to the syntheses of many types
of compound\ including 0\0!disubstituted hydrazines\ 1!acyl!0\0!disubstituted hydrazines
ð78JCS"P0#1186Ł\ amides and thioamides ð77JOC4743Ł[ Similarly\ symmetrical secondary amines can
be prepared by reaction of bis"benzotriazol!0!ylmethyl#amine with Grignard reagents at room
temperature "Equation "04## ð78JCS"P0#114Ł[
H Ph MgCl H
Bzt N Bzt N (15)
Ph Ph
Bzt = 1-benzotriazolyl
A similar reaction takes place between bis"benzotriazol!0!ylmethyl#hydroxylamine and Grignard

reagents or lithium phenylacetylide\ giving N\N!disubstituted hydroxylamines in high yields "Scheme
11#[ It is thought that a nitrone is the intermediate species[
OH RMgX OH
Bzt N Bzt R N R
RMgX Yield (%)

PhMgBr 94
Ph Li 87
Scheme 22
N\N!Dialkyl!1!alkynamines are of considerable pharmaceutical interest and may be prepared by
reaction of 0!"dialkylaminoalkyl#benzotriazoles with alkynyl lithiums at 19>C "Scheme 12# ð78S20Ł[
i, Ph Li
Bzt ii, H3O+ R1
Ph
R1 NR22 33–97% NR22
R1 R2 Yield (%)
H Me 79
Pri Bn 95
Scheme 23
Nucleophilic displacement of dialkylamino "0!benzotriazolyl# acetic esters by a carbanion such

as an organozinc derivative gives 1!dialkylaminoalkanoic esters in good yield "Equation "05##
ð78S212Ł[ In this case\ Grignard reagents give poor results\ perhaps due to deprotonation and:or
reaction of the Grignard reagent at the ester group[ However\ organozinc reagents react smoothly
at 19Ð14>C to give the amino esters in good yields[ A general method for the preparation of
b!aminoesters has also been reported using zinc powder and chloromethylsilane[ Reaction with
a!0!dialkylamino!0!"0!benzotriazolyl#alkanes and bromoesters gives the desired products in good
yields ð78S636Ł[
Bzt PhZnX, THF, 0 °C CO2Et

(16)
EtO2C NEt2 75% Ph NEt2
N!Substituted 0!"benzotriazolyl#!1\1!diethoxyethylamines react with Grignard reagents to give

the corresponding 1!aminoalkanol diethyl acetals[ Hydrolysis provides the corresponding a!amino!
aldehydes "Scheme 13# ð89S0062Ł[
Bzt R3
R3MgX, THF, RT
EtO EtO
NR1R2 NR1R2
OEt OEt
R1 R2 R3 Yield (%)
Ph H Ph 71
Bn Bn Et 96
Ph Me Et 91
Scheme 24
Symmetrical vicinal tertiary and secondary diamines are important in polyazamacrocycle syn!
thesis and in metal chelation\ and are useful intermediates for the construction of nitrogen heter!
ocycles[ A simple two step procedure for their preparation using benzotriazole chemistry has been
reported ð89JOC2198Ł[ Double condensation of an amine with glyoxal and benzotriazole provides
the bis"benzotriazolyl# products in high yields[ Treatment with two equivalents of Grignard reagent
induces displacement of both benzotriazole units\ giving the vicinal diamines "Scheme 14#[
Grignard or organolithium reagents can be used in the synthesis of primary amines by reaction
N R1R2N Bzt R1R2N R3

EtOH R3MgX, THF
N + OHC CHO + R1R2NH
N RT 51–83%
H Bzt NR1R2 R3 NR1R2
R1R2NH R3MgX Yield (%)

BnNH PhMgBr 81
BnNH MeMgBr 83
O NH BunMgCl 68
Scheme 25
with N!triphenylphosphorylidene!0!"benzotriazol!0!yl# methylamine "Scheme 15#\ which can be
prepared from the readily available 0!azidomethylbenzotriazole by Staudinger phosphorylation
ð78TL2292Ł[ The resulting phosphazenes can be hydrolysed during basic workup to give primary
amines\ which may be converted into hydrochlorides for isolation or subjected in situ to various
phosphazene transformations[ Alkyl\ cycloalkyl\ aralkyl\ aryl and heteroaryl Grignard reagents and
lithium phenylacetylide give equally good yields[
PPh3 Bzt N RMgBr or RLi R N
Bzt N3 R NH2
PPh3 PPh3 65–93%
Organometallic Yield (%)

n-C12H25MgBr 87
Ph Li 86
c-C6H11MgBr 77
Scheme 26
Symmetrical and unsymmetrical bis!heterocyclic alkanes\ which are important in the food indus!
try\ in dyestu} chemistry and as intermediates in the synthesis of various heterocyclic macro!
molecules\ have been prepared using benzotriazole chemistry[ These compounds have proved
di.cult to synthesize\ but the use of benzotriazole intermediates has provided a general and
convenient method for their preparation ð82JOC3265Ł[ Symmetrical bis"heteroaryl#alkanes can be
prepared in excellent yields by reaction of methyl N!"a!benzotriazol!0!ylalkyl# carbamates with an
excess of 1!methylthiophene or 1!methylfuran in dichloromethane at room temperature using ZnCl1
as the Lewis acid catalyst "Scheme 16#[ Unsymmetrical bis!heterocycles can be formed by isolation
of the monosubstituted intermediate and further reaction with a di}erent heterocyclic molecule[
This methodology provides a route to a wide range of bis"heteroaryl#alkanes in excellent yields
"Scheme 17#[
Bzt ZnCl2, CH2Cl2, RT

+ X X
R NHCO2Me X
R
X R Yield (%)
O Pri 88
O Ph 90
S Pri 90
S Ph 94
Scheme 27
Bzt
ZnCl2, CH2Cl2, RT
S +
Pri S O
O 92%
Pri
Bzt
ZnCl2, CH2Cl2, RT
Pri +
X X = O, 84% N
X Me
N X = S, 90%
Pri
Me
Scheme 28
Grignard reagents can also displace the benzotriazole group of various a!benzotriazoyl methyl
ethers to give the corresponding methyl ethers "Scheme 18# ð80JCS"P0#2184Ł[ It has been found that
a!"N!benzotriazolyl# undecyl\ benzyl and octyl methyl ethers react smoothly with butylmagnesium
iodide to give the expected products in 46Ð57) yield[ Octylmagnesium iodide was found to react
in a similar way with a!"N!benzotriazoyl# butyl methyl ether[ Ethers with the general formula
R0R1CHOMe can thus be formed by nucleophilic attack onto the carbocations formed on loss of
the benzotriazole group[ The heteroatom\ which is separated from the leaving group by one carbon
atom\ assists in the departure of the benzotriazole anion[
Bzt R2MgX OMe
R1 OMe R1 R2
R1 R2MgX Yield (%)

Bn BuMgI 68
Bu n-C8H17MgI 60
C10H21 BnMgBr 50
Scheme 29
Other examples in which the benzotriazole group is displaced include the preparation of
t!alkyl sul_des by reaction of a!0!benzotriazolylsul_des with Grignard reagents "Equation "06##
ð80HCA0813Ł[
Ph
Bzt SPh BnMgX
SPh (17)
Pri Bu 75%
Pri Bu
0[95[0[6 Azides
CarbonÐcarbon bond forming reactions via azides seem to be relatively uncommon[ b!Azido
substitution can be achieved in cyclic enol ethers in excellent yields by treatment of several tips enol
ethers with trimethylsilyl azide and iodosobenzene in dichloromethane solution at −04 to −07>C[
The products were isolated in place of the expected a!azidocyclohexanone and are thought to arise
via enonium ions ð81JA2882Ł[ The b!azido enol ether reacts with carbon nucleophiles in the presence
of Lewis acids with azide displacement to form the nucleophilic substitution products without loss
of the enol ether moiety\ again via the enonium ions "Scheme 29#[
0[95[0[7 Ring Opening of Aziridines

Aziridines have been used on a number of occasions as electrophiles in reactions with carbon
nucleophiles[ It has been shown that boron tri~uoride etherate promotes nucleophilic ring opening
of N!substituted aziridines by diorganocopper lithium reagents\ providing a route to primary and
secondary amines "Scheme 20# ð74TL0042Ł[
A cuprate reagent has also been used in the absence of Lewis acid for such a carbonÐcarbon bond
formation\ in a stereocontrolled synthesis of "2#!perhydrohistrionicotoxin[ The key step involved
reaction of an acylaziridine with lithium dibutylcopper to a}ord the lactam "Equation "07##
ð64JOC1998Ł[
Bu2CuLi, THF, RT
N O N O (18)
H
Bu
OPri OPri
Aziridines are activated towards cleavage by nucleophiles by the presence of an electron!with!

drawing group "such as tosyl or t!butoxycarbonyl# bonded to the nitrogen atom[ For example\
reaction of t!butyl 1"S#!N!tosylaziridine carboxylate with copper catalysed Grignard reagents gave
the ring opened products in greater yields than those observed for the corresponding unactivated
aziridines[ A reduction product\ perhaps arising through hydride transfer\ was also observed as a
by!product in most reactions with the activated substrates[ The C20N cleavage was favoured over
the C10N cleavage for the bulky butyl\ ethyl and isopropyl reagents\ while the reverse proved true
+
OSiPri3 OSiPri3
X N3
OSiPri3 Ph I
N3
+
OSiPri3 Pri3SiO N3
X = N3, O-TMS N3 N3
OSiPri3
OSiPri3
N
H
Me3Al, CH2Cl2, –70 °C
82%
N3
N
H
OSiPri3
OSiPri3
MeO NMe2
Me2AlCl, hexane, 25 °C
79%
N3
MeO NMe2
OSiPri 3 OSiPri3
Et2AlCN, THF, ∆
60%
N3 CN
Scheme 30
R1 R22CuLi, BF3•OEt2
R2
N NHR1
R1 R2 Yield (%)
Bn Me 80
Me Bu 94
DMB Ph 80
DMB = 4,4'-dimethoxybenzhydryl
Scheme 31
for the methyl cuprate reagent[ The C20N cleavage products were converted into the parent amino
acids in high optical yields "×84) ee# "Scheme 21# ð78CC0741Ł[
Highly selective nucleophilic opening of oxiranes by cyanotrimethylsilane under lanthanide cata!
lysis has been reported[ The reaction was also applied to aziridines derived from easily accessible
a!amino acids[ Optically pure 1!substituted aziridines react with cyanotrimethylsilane in the presence
of ytterbium trinitrile to give b!amino nitriles in optically pure form by selective attack of cyanide
at the less substituted carbon atom of the ring "Scheme 22# ð89TL5268Ł[ The authors suggest that
this reaction provides a new route for the synthesis of optically active b!lactams\ which could be
formed from the b!amino acids derived\ in turn\ from the optically active b!amino nitriles[
Almost quantitative cleavage of N!tosylaziridine rings can be achieved with dianions of glyoxylic
Ts
RMgCl, CuBr•Me2S, CO2But NHTs R
N +
R TsHN
75–85% CO2But CO2But
CO2But
R Ratio
A:B
Pri 47:28
Me 30:55
Scheme 32
Ts
TMS-CN, Yb(CN)3 NHTs
N
Ph CN
Ph 84%
Ts
TsHN CN
N TMS-CN, Yb(CN)3
98%
Scheme 33
acid derivatives\ such as bis"ethylthio#acetic acid\ using potassium as the counterion "Equation
"08## ð79CJC605Ł[ The 1\1!bis"ethylthio#carboxylic acids so formed were easily converted into the
corresponding a!ketoacids using N!bromosuccinimide[
Ts O
KN(TMS)2 (2 equiv.), THF TsHN SEt
N + SEt SEt (19)
HO Ph
Ph 93% CO2H
SEt
0[95[0[8 Radical Mediated Processes

Radical mediated cleavage of carbonÐnitrogen bonds with formation of carbonÐcarbon bonds is
unusual[
One example involves the use of 1!cyanopropyl radicals to introduce a tertiary carbon atom
bearing an electronegative group into the C8 position of an anthracene derivative[ 8!t!Alkyl anthra!
cenes are usually prepared by the Grignard reaction of t!alkyl!magnesium halides with anthrone
followed by dehydration[ Cyano! and alkoxycarbonyl groups are however too reactive to be
introduced by this process[ Oki and co!workers have found that the action of 1!cyanopropyl radicals
upon anthrone\ especially under basic conditions\ provides the substitution product in 77) yield[
The 1!cyanopropyl radicals were generated by thermal decomposition of azobisisobutyronitrile
"AIBN# "Scheme 23# ð66TL1330Ł[ Reduction with sodium borohydride a}ords a mixture of geo!
metrical isomers of the alcohol^ reaction with phosphorus pentoxide then yields the desired
8!substituted anthracene as the major product[
CN CN
AIBN, ∆, 6 h, 90 °C i, NaBH4
ii, P2O5
OH O
Scheme 34
In an alternative reaction\ treatment of anthrone with dimethyl azobisisobutyrate using the
conditions described above was used to produce the substitution product "0# in 51) yield "Equation
"19##[
CO2Me
CO2Me
N
N
MeO2C
(20)
62%
OH O
(1)
Kinetic studies into the isonitrile!nitrile rearrangement by ~ash!pyrolysis using inhibitors has led
to the proposal of a free radical chain mechanism ð73TL2330Ł[ Flash!pyrolysis gives almost quan!
titative yields of nitriles with complete retention of stereochemistry "Scheme 24#[
540 °C
97%
NC CN
+ •
R= .... R• + R N C– R N C R
•
R N C R R• + N R
Scheme 35
0[95[0[09 Rearrangements
The following reactions illustrate rearrangements in which new carbonÐcarbon bonds are formed
by substitution of carbonÐnitrogen bonds[
Iodide ion!mediated rearrangement of N!vinylaziridines possessing a carbonyl group at the
b!position occurs to give pyrrolines "Scheme 25# ð56JA2599Ł[ The mechanism of this reaction is
presumably similar to that proposed by Heine for iodide ion catalysed rearrangement of N!acyl!
aziridines ð52JA1632Ł\ involving initial nucleophilic attack by halide ion at an aziridine carbon atom
with ring cleavage[ Internal alkylation of the resulting negative charge with expulsion of iodide then
occurs[
I
O
–N N
I–
R R
N R
O O
Scheme 36
The key step in a total synthesis of the alkaloid "2#!crinine involves just such a rearrangement
of a highly functionalised N!vinylaziridine\ induced by treatment with anhydrous sodium iodide in
diethylene glycol dimethyl ether at 034>C "Equation "10## ð56JA2599Ł[
O O
O
O O
NaI, 145 °C, 2.5 h O
(21)
55%
N
N
Phosphorus!substituted heterocycles can be obtained by rearrangement of phosphonium sub!

stituted vinyl aziridines\ prepared by addition of aziridines to prop!1!ynyl triphenylphosphonium
bromide or 1!phenylethynyl triphenylphosphonium bromide in methylene chloride "Scheme 26#
ð67JOC3196Ł[ Heating these activated aziridines under re~ux in acetonitrile induces rearrangement
to give the phosphonium substituted 1!pyrrolines in good yields\ in a similar process to the iodide!
mediated rearrangement discussed above[ "1!Methyl!1!pyrrolin!2!yl# triphenylphosphonium bro!
mide has been found to undergo both N!alkylation and Wittig reaction with aldehydes in the normal
manner ð67JOC3196Ł[
+ +
PPh3 Br– PPh3 Br–
H + MeCN, ∆
N PPh3 Br–
N 65%
N
H
+
+ Ph PPh3 Br–
H Ph PPh3 Br– + MeCN, ∆
N PPh3 Br–
N 86%
N Ph
H
Scheme 37
0[95[0[00 Electrophilic Substitution

As discussed above\ there are many examples of nucleophilic substitution of nitrogen containing
groups with attack of a carbon nucleophile\ thus introducing a new carbonÐcarbon bond[ Elec!
trophilic substitution involving loss of electrofugal nitrogen is however much less common[ In one
rare example\ methyl dialkylcyanoazocarboxylates can lose nitrogen to form mixtures of cyano
esters and methylated nitriles upon treatment with lithium methoxide and methyl iodide\ the
chemoselectivity depending upon the reaction conditions "Scheme 27# ð60JA3207Ł[ The formation of
methylated nitriles required at least stoicheiometric quantities of base[ The in situ methylation of
cyclohexyl azocarboxylates provided predominantly the products of equatorial methylation[
R2 R2 R2
CN LiOMe, MeI, DME
CN + CN
R1 R1 R1
88–93%
N N CO2Me
CO2Me
A B
R1 R2 Ratio
A:B
H H 77:13
H Me 63:25
But H 70:23
Scheme 38
0[95[1 SUBSTITUTION OF PHOSPHORUS\ ARSENIC AND ANTIMONY FUNCTIONS
0[95[1[0 Substitution of Phosphorus Functions

Reactions involving simultaneous sp2 carbonÐphosphorus bond cleavage and sp2 carbonÐcarbon
bond formation are very rare in the literature[ The vast majority of carbonÐphosphorus bond
cleavage reactions where carbonÐcarbon bonds are formed involve Wittig or related alkenation
processes\ and all involve phosphonium ylides[
The use of phosphorus ylide reactions to prepare cyclopropane compounds involves carbonÐ
carbon single bond formation\ either through conjugate addition of the ylide carbanion to activated
double bonds with subsequent expulsion of the tertiary phosphine "Scheme 28# ð47JA3275\
51AG"E#005Ł\ or through epoxide cleavage by nucleophilic attack of the ylide carbanion\ followed by
thermal decomposition of the oxaphospholane formed "Scheme 39# ð48JA5229\ 51JA565\ 51JA566\
51JA2833\ 53T0584Ł[ The suggested mechanism involves cleavage of the oxaphospholane carbonÐ
phosphorus bond to produce a carbanion which cyclises with concurrent expulsion of phosphine
oxide ð53QR0853Ł[ Good yields of products are only achieved when the oxaphospholane intermediate
bears a carbanion stabilising group in an appropriate position[
+
–
Ph3P
R
R R R
R Yield (%)
C3H7 50
H 23
Scheme 39
+
Ph3P – + +
O R O– PPh3 O PPh3 PPh3
O
R –
R
R
R
+ Ph3PO
R Yield (%)
Ph 21
C6H13 26
Scheme 40
In a similar process\ cyclopropylketones may be prepared by treatment of esters of

2!hydroxypropylphosphonium salts with potassium t!butoxide in re~uxing t!butanol ð60JOC1268Ł[
The corresponding cyclopropylketones were produced in 31Ð48) yields "Scheme 30#[
0[95[1[1 Substitution of Arsenic Functions

All the reactions in which the breaking of an sp2 carbonÐarsenic bond and the formation of a new
2
sp carbonÐcarbon bond take place involve an arsonium ylide as the reactive intermediate[ In a
typical example\ treatment of triphenylarsine with 1!bromomethylnaphthalene at elevated tem!
peratures a}orded "1!naphthyl#methyl triphenyl arsonium bromide in good yield ð65JOM"097#064Ł[
Deprotonation using sodium hydride generated 1!naphthylmethylene triphenylarsenane[ The reac!
tions of this ylide with a range of substituted benzaldehydes at room temperature were explored[
The corresponding trans epoxides were produced in good yields in a process mechanistically similar
to the more well known sulfur!based epoxide formation "Scheme 31#[
An example by Still involves the stereoselective synthesis of trans epoxides from aliphatic
Substitution of Phosphorus\ etc[ 158
O
O R3 R1 O R1
R2 R2
– + R3
R1 O PPh3 + R3
–O PPh3 PPh3
R2 O
O O
R1
R3 –
R1
+
R2 O PPh3 R3 R2
R1 R2 R3 Yield (%)
Ph H H 59
Me Ph PhCO 54
Scheme 41
+
Br Ph3As AsPh3 Br– NaH
∆ PhH
– O
+ Ar
AsPh3 ArCHO
Ar Yield (%)
Ph 90
4-ClC6H4 92
Scheme 42
aldehydes ð70JA0172Ł[ The route again proceeds in a highly stereoselective manner[ For example\
the reaction of triphenylarsonium ethylide with octanal to produce largely "E#!dec!1!ene oxide
proceeds in 65) yield "Equation "11##[ Interestingly\ optimum selection for the trans product is
observed under the same salt!free conditions used to give cis stereochemistry in the Wittig reaction[
The orange ylide was prepared by deprotonation of ethyltriphenylarsonium ~uoroborate with
potassium hexamethyldisilazide "KHMDS# in 09) HMPAÐTHF at −39>C[ The solution is then
chilled to −67>C before addition of the aldehyde[
– +
AsPh3 O
CHO (22)
76%
98% (E)
In a further example by Mioskowski\ vinylic epoxides were synthesized in high yields from allylic
arsonium ylides and carbonyl compounds in very high yields "44Ð84)# "Scheme 32# ð72TL3308Ł[
This is a particularly useful reaction\ since vinylic epoxides cannot easily be prepared from allylic
dimethylsulfonium ylides\ which undergo ð1\2Ł!sigmatropic rearrangements\ nor from allylic
diphenylsulfonium ylides\ which are di.cult to prepare[ Since triphenylarsine is more nucleophilic
than diphenylsul_de\ it reacts well with allylic bromides to produce the corresponding allylic
arsonium salts\ and hence the corresponding allylic arsonium ylides[
An unusual variation involves the reaction of aromatic aldehydes with b!hydroxyethyltriphenyl!
arsonium bromide in the presence of solid potassium hydroxide at room temperature[ These
reactions produce 1\2!epoxy!2!aryl!propanols in good yields under solidÐliquid phase transfer
conditions "Scheme 33# ð77TL4184Ł[ It is of note that bases such as triethylamine\ piperidine and
potassium carbonate do not induce this reaction at room temperature\ and furthermore\ standard
conditions such as treating the arsonium salt with strong bases at −67>C followed by addition of
O
+ +
R1 Br Ph3As R1 AsPh3 Br– LDA R1 AsPh3 R3 R4
–
R2 MeCN THF
R2 R2
R3
R1
R4
O
R2
R1 R2 Aldehyde/ketone Yield (%)

Ph H PhCHO 83
H H CHO 65
H H But O 70
O
Ph H 81
Ph H CHO 75
Scheme 43
the aldehydes did not produce the derived alcohols in reasonable yields[ Only by using a solidÐ
liquid phase transfer process could the desired products be obtained in good yields "39Ð73)#[
+
AsPh3 Br– KOH (s), THF/H2O, RT
+ ArCHO HO Ar
HO O
Ar Yield (%)
Ph 83
py 77
Scheme 44
A vinylogous version of this reaction is also known\ where 4!aryl!3\4!trans!epoxypent!1!en!0!ols

were conveniently synthesized in a one!step reaction of aldehydes with "E#!3!hydroxybut!1!enyl
triphenyl arsonium salts under the above conditions ð80TL2888Ł[ During the reaction of the "Z#!salt\
the original double bond is partially isomerized "Scheme 34#[ When potassium ~uorideÐalumina\
which is less basic than potassium hydroxide\ was used as the base and acetonitrile used as the
solvent instead of THF\ the yield increased\ but the ratio of isomers did not change[ Use of the "E#!
3!hydroxybut!1!enyl triphenyl arsonium salt produced the 4!aryl!3\4!trans!epoxy!"E#!pent!1!en!0!
ols in good yields "42Ð67)# with no isomerization of the double bond[
+
KOH (s), THF/H2O, RT
O Ph
HO AsPh3 + PhCHO HO + HO Ph
O
+ KOH (s), THF/H2O, RT

AsPh3 + PhCHO HO Ph
HO 58%
O
Scheme 45
A further interesting variation of this type of reaction is found in the synthesis of "trimethyl!
silylethynyl# cyclopropanes via an arsonium ylide ð77S210Ł[ This involves the reaction of 2!"trimethyl!
silyl#!1!propynylidenetriphenylarsorane\ generated in situ from the corresponding arsonium salt and
Substitution of Phosphorus\ etc[ 160
butyllithium\ with a\b!unsaturated ketones to produce cyclopropanes in 85Ð099) yield with high
stereoselectivity "Equation "12##[
O
TMS i, BuLi, THF, –78 °C
+ Ph (23)
AsPh3 Br– ii Ar O TMS
Ph Ar
0[95[1[2 Substitution of Antimony Functions

Although several reports have appeared dealing with organoantimony chemistry ð77JOM"14#240Ł\
few have dealt with the use of organoantimony reagents in sp2 carbonÐcarbon bond forming
reactions[ One example by Henry et al[ in 0859 involves the reaction of triphenylmethylstibonium
salts with benzophenone "Scheme 35# ð59JA452Ł[ Triphenylmethylstibonium iodide can be prepared
by _rst treating triphenylstibine with trimethyloxonium tetra~uoroborate to produce the quaternary
boron tetra~uoride salt of triphenylstibine\ which is easily converted to the corresponding iodide[
+ O– Ph3Sb
PhLi + Ph2CO
Ph3Sb+Me I– Ph3Sb CH2– Ph3Sb O Ph
Ph
Ph Ph
O
Ph Ph
O Ph
Ph3Sb + Ph3SbO +
Ph Ph
Ph
(trace)
>90%
Scheme 46
The authors envisaged two possible pathways for the subsequent reaction with benzophenone\
leading either to diphenylethylene or to the corresponding epoxide "Scheme 35#[ The latter pathway
is supported by the isolation in almost quantitative yield of diphenylacetaldehyde\ a rearrangement
product of the unstable epoxide\ with only a trace of diphenylethylene observed[
Another reaction using organoantimony reagents for the formation of sp2 carbonÐcarbon bonds
is found in the use of bis"diphenylstibinyl#methane as a precursor to the reactive species diphenyl!
stibinylmethyllithium\ which reacts with ketones\ haloalkanes and other organometallic reagents
"Scheme 36# ð72CB362Ł[ bis"Diphenylstibinyl#methane is treated with phenyllithium to give diphenyl!
stibinylmethyllithium\ with cleavage of one carbonÐantimony bond and generation of triphenyl!
stibine[
i, R1 R2 OH
Ph2Sb SbPh2 PhLi Ph2Sb Li Ph2Sb
R1
ii, H3O+ R2
Aldehyde or ketone Yield (%)
CHO 66
PhCHO 39
O
82
Scheme 47
A paper in 0889 by the same author also concentrates on the reactions of carbonyl compounds
with organoantimony reagents mediated by a range of strong bases ð89CC74Ł[ While treatment of
quaternary stibonium salts with weakly nucleophilic strong bases such as lithium diisopropylamide
"LDA# or potassium t!butoxide a}ords stibonium ylides\ strong nucleophiles such as organolithiums
or Grignard reagents produce pentaorganostiboranes[ The quaternary stibonium salt used in this
case was benzyltributylstibonium bromide which\ upon treatment with alkyl! or phenyllithiums\
gave pentaorganostiboranes which reacted with aromatic aldehydes with transfer of the benzyl
group to produce alcohols "Scheme 37#[ Benzyltrialkylstibonium bromides are easily prepared by
mixing a trialkylstibine with benzylbromide at room temperature[
O
+ BuLi or BuMgBr i, R
OH
Bu3Sb Ph Bu4Sb Ph Ph
Br– THF, –78 °C ii, H3O+ R
Aldehyde Yield (%)
PhCHO 92
Cl CHO 94
MeO CHO 74
Scheme 48
The reactions of pentaorganostiboranes with ketones and acyl chlorides have also been examined
"Scheme 38#[ In the absence of any additional catalyst\ benzyltetrabutylstiborane reacts with acyl
chlorides to give the corresponding benzyl ketones in good yields "69Ð89)#[ No butyl ketones\
resulting from transfer of a butyl group from antimony\ were observed[ Alkyl groups may however
be transferred selectively from pentaalkylstiboranes^ for example\ a methyl group is transferred from
tributyldimethylstiborane[ Both ethyl and butyl groups are transferred from tributyldiethylstiborane
ð81JOC663Ł[
O
PhCOCl
Bu3Sb+R2
Ph R
R Yield (%)
Bu 92
Et 62
Me 79
O
PhCOCl
Bu4Sb Ph
Ph
Ph
O
PhCOCl
PhBu3Sb Ph
44%
Scheme 49
0[95[2 SUBSTITUTION OF BORON\ SILICON AND GERMANIUM FUNCTIONS
0[95[2[0 Substitution of Boron Functions

Trialkylboranes are important reagents for the formation of sp2 carbonÐcarbon bonds\ and are
readily available through hydroboration processes[ They may be used in various types of addition
reactions\ particularly conjugate additions induced by oxygen radicals\ bases and electrochemical
Substitution of Boron\ etc[ 162
processes "Scheme 49#[ Another important area of these carbonÐcarbon bond forming reactions
involves substitution by alkyl groups at sp1 centres in various alkenes and aromatic heterocycles in
a FriedelÐCrafts type alkylation[
R1
Li
Ar—Li R2 R1
EWG
Ar R1 R1 3B
EWG
or Ar—Hal R2
Hal
R2 CO2R3
R1
R2 CO2R3
Scheme 50
0[95[2[0[0 Conjugate addition to a\b!unsaturated ketones and aldehydes

One of the _rst examples of conjugate addition reactions with trialkylboranes\ published by
Hawthorne in 0854\ is a reductive alkylation of quinones with trialkylboranes in the preparation of
alkylhydroquinones "Scheme 40# ð54JA3474Ł[ This reaction nicely illustrated the potential use of
trialkylboranes in organic synthesis[ The reactions proceed in nearly quantitative yield\ and the only
limitation on the reaction is the availability of the trialkylborane being used[ Previously\ preparation
of alkylhydroquinones had involved much less e.cient\ often multistep\ processes\ such as electro!
philic alkylation of hydroquinones or acylation by FriedelÐCrafts reactions followed by reduction[
O R2BO R OBR2
R
R3B R3B
O O OH
R Yield (%)
C6H13 99
Bu 86
Bus 94
Bn 90
Scheme 51
Much of the work involving organoboranes as reagents for the formation of new sp2 carbonÐ
carbon bonds was carried out by Suzuki and Brown in the 0869s[ Results of a collaboration between
the two groups on the reactions of organoboranes as a means of synthesizing aldehydes was
published in 0856 and describes the conjugate addition reactions of trialkylboranes to acrolein
ð56JA4698Ł[ The reaction _rst produces an intermediate enolborinate which undergoes hydrolysis to
yield the corresponding aldehyde "Scheme 41#[ This reaction is particularly convenient since it can
be carried out in one pot\ by adding water to a THF solution of the organoborane\ and then
introducing acrolein into the reaction mixture[ This procedure results in concomitant conjugate
addition and hydrolysis to produce the aldehyde[ The reaction takes place over about one hour at
room temperature "in some cases it is complete within ca[ _ve minutes# and is very general[
A similar reaction of organoboranes with methyl vinyl ketone was also examined by Suzuki and
Brown ð56JA4697Ł\ giving the corresponding methyl ketones in almost quantitative yields[ Again\
both the addition and hydrolysis may occur within a few minutes at 14>C[ Since methyl ketones
can be readily converted into the corresponding acids using the haloform reaction ð56JA4609Ł\ this
O R3B H2O
R OBR2 R O
R Yield (%)
Bu 55
Bus 96
c-C6H11 77
Scheme 52
process could also provide a simple synthesis of carboxylic acids[ Several illustrative examples are
shown in Scheme 42[
O i, R3B R O
ii, H2O
R Yield (%)
Me2CHCH2 70
80
Bu 86
Scheme 53
The corresponding addition to b!substituted a\b!unsaturated ketones and a\b!alkynyl ketones

does not occur spontaneously\ requiring some form of radical initiator[ Suitable radical initiators
include ultraviolet light and:or traces of oxygen^ for example\ acetylethyne readily undergoes
conjugate addition in the presence of a catalytic amount of oxygen "Scheme 43# ð69JA2492Ł[ The
initially formed allenic intermediates undergo hydrolysis to produce the corresponding a\b!unsatu!
rated methyl ketones in good yield[ This reaction illustrates the versatility of conjugate addition
reactions with organoboranes\ even with unreactive substrates[ In situ hydrolysis in this case mini!
mizes the attack of the allenic intermediate by the free!radicals[
O R3B, O2 (cat.)
OBR2 O
H2O
•
THF, 25 °C R R
R Yield (%)
Et 77
c-C6H11 65
Scheme 54
The principal disadvantage of all of these reactions is that only one of the three substituent groups
on the boron atom can normally participate under the mild conditions used\ but the simplicity and
rapidity of the reactions perhaps provides adequate compensation[ The methodology can be
extended to allow conjugate addition to many a\b!unsaturated carbonyl compounds including
a!methylacrolein ð57JA3054Ł\ a!bromoacrolein ð57JA3054Ł and a!methylenecycloalkanones "Scheme
44# ð57JA3055Ł[ b!Substituted a\b!unsaturated carbonyl compounds do not however react spon!
taneously with organoboranes\ but require an initiator[
Conjugate addition of trialkylboranes to crotonaldehydes or other a\b!unsaturated carbonyl
compounds may proceed spontaneously as discussed above\ under irradiation or in the presence of
radical initiators ð60JA0495\ 60JA0497Ł[ A further method of inducing a reaction between tri!
alkylboranes and crotonaldehyde has been developed using excess pyridine to promote reaction at
room temperature over eight days "Equation "13## ð62TL676Ł[ Use of only equimolar quantities of
pyridine "three equivalents# results in much lower yields of the aldehydic product[ Tertiary amines
do not\ in general\ promote the reaction to such an extent\ although 3!picoline a}orded a yield of
i, R13B
ii, H2O
R1
CHO 92–97% CHO
i, R23B
Br ii, H2O
Br
R2
CHO 65–85% CHO
O i, R33B O
ii, H2O
R3
54–90%
R1 Yield (%) R2 Yield (%) R3 Yield (%)

Bu 95 Bu 85 c-C5H9 85
c-C6H11 92 c-C6H11 65
Scheme 55
85) after eight days[ The most e}ective solvent for the reaction was toluene\ and the best yield
"ca[ 88)# was obtained using tricyclopentylborane as the substrate[ It has been suggested that the
promotion of the reaction by pyridine involves a radical intermediate[
B O
O 3
(24)
pyridine, RT, 8 d
A particularly interesting variation is the reaction with 0!acyl!1!vinylcyclopropanes\ where the

products after hydrolysis are the corresponding g\d!unsaturated ketones\ isolated in good yields\
predominantly with the "E#!con_guration "Scheme 45#[ The authors suggest a mechanism involving
electron transfer\ as shown in Scheme 45\ for the reaction of cuprous methyltrialkylboranes with
0!benzoyl!1!vinylcyclopropane ð61JA4384Ł[
O
BR3•MeCu•LiX O– (R3BMe)CuII +
Ph
• Ph
O– H3O+ O
R R
Ph Ph
R Yield (%)
Pr 84
Bu 81
Scheme 56
An example of such substitution in quinone systems using organoboranes is the preparation of

1!alkyl!0\3!naphthaquinones from 0\3!naphthaquinones[ Although the preparation of 1!alkyl!
quinones may be carried out in up to quantitative yields by the reaction of quinones with alkyl
radicals produced by treatment of trialkyl boranes with catalytic amounts of oxygen "Scheme 46#\
quinones other than p!benzoquinone are usually relatively unreactive ð60JOM"22#14Ł[ A modi_cation
developed in 0881\ in which trialkylborane is added to the quinone and water in the presence of
oxygen\ followed by oxidation with silver oxide\ a}ords 1!alkyl!0\3!naphthaquinones in good yields
"Scheme 47# ð81S350Ł[ 1\2!Dialkyl!0\3!naphthaquinones are produced in the presence of magnesium
bromide[
O OBR2 OH
R3B, O2 (cat.) H2O
R R
O O OH
R Yield (%)
Et 95
Bu 85
Scheme 57
O O
i, (C6H13)3B, MgBr2, THF, H2O, O2, ∆, 1 h C6H13
ii, Ag2O, MeOH, RT, 15 min
75% C6H13
O O
O O
R
i, R3B, THF, H2O, O2, ∆, 1 h
ii, Ag2O, MeOH, RT, 15 min
O O
R Yield (%)
c-C5H9 94
(CH2)3Ph 79
Scheme 58
0[95[2[0[1 Conjugate addition to a\b!unsaturated carboxylic acid derivatives

Simple carboxylate derivatives such as acrylonitrile and ethyl acrylate do not undergo addition
of organoboranes through any of the processes described above\ perhaps because of ready poly!
merisation or because the unstable intermediates undergo other reactions[ These di.culties are
overcome when cuprous methyltrialkylborates\ which are readily obtained from trialkylboranes by
addition of alkyllithium followed by a copper"I# salt\ are used as reagents ð65TL144Ł[ For example\
alkyl nitriles are produced in good yields from the reaction with acrylonitriles in 08Ð82) yields
"Scheme 48#[ The choice of cuprous halides used in the generation of the cuprous methyl!
trialkylborate is crucial] in the preparation of hexanenitrile\ use of cuprous iodide gave only a
08) yield\ while cuprous bromide gave an 73) yield[ While many other methods for producing
alkylnitriles may be available\ including electrochemical methods ð64CL412Ł\ this reaction does
provide a novel and general synthetic procedure[ A similar reaction with ethyl acrylate proceeds
readily under the same conditions "Equation "14##[
i, [Pr3BMe]Cu
ii, H2O
CO2Et CO2Et (25)
44%
Organoboranes also undergo clean electrochemically mediated reactions with acrylates in good
yields "40Ð83)#\ providing a convenient preparative method for substituted carboxylic esters "Equa!
tion "15## ð67BCJ228Ł[ The electrolyte of choice for the reaction was tetrabutylammonium iodide[
The suggested mechanism for the reaction involves independent reactions at the anode and cathode[
R23B, Bu4NI, MeCN

R1 electrolysis R1
R2 (26)
CO2Et 51–94% CO2Et
R1 = H, Me
MeLi CuX
R3B [R3BMe]Li [R3BMe]Cu•LiX
i, [R3BMe]Cu•LiX
R
CN CN
ii, H2O
R X Yield (%)
Pr I 19
Pr Br 84
Pr Cl 65
Bu Br 88
Scheme 59
0[95[2[0[2 Conjugate addition to vinyl and alkynyl epoxides

Suzuki and Brown have also examined conjugate addition reactions of organoboranes to various
a\b!unsaturated epoxides[ Like b!substituted a\b!unsaturated ketones\ these species fail to react
with organoboranes spontaneously\ requiring some form of radical initiator[ Again\ suitable radical
initiators include ultraviolet light and:or traces of oxygen[
In the presence of catalytic oxygen or other free radical initiators\ 0\2!butadiene monoepoxide
undergoes conjugate addition with trialkylborane\ providing the corresponding 3!alkylbut!1!en!0!
ols in high stereochemical purity and reasonable yields "33Ð64)# "Scheme 59# ð60JA1681Ł[ One
interesting aspect of this particular reaction is that THF\ although it is the normal solvent for such
reactions\ could not be used\ as considerable quantitatives of 3!"1!tetrahydrofuryl#but!1!en!0!ol
were formed in the reaction mixture\ presumably resulting from free radical mediated conjugate
addition of THF to the epoxide as a competing side reaction "Equation "16##[ This di.culty was
circumvented by using benzene as the solvent[
Et3B, O2 (cat.), PhH H2O

OBEt2 OH
O 89%
Scheme 60
Et3B, O2 (cat.)
(27)
O THF, H2O O OH
The analogous reaction with 2\3!epoxy!0!butyne is also known ð62S294Ł[ Conjugate addition
produces allenic derivatives which were hydrolysed to give the corresponding allenic carbinols
"Scheme 50#[ The reaction was successful using both triethyl and tricyclopentylborane^ the reactions
were carried out in both benzene and tetrahydrofuran\ benzene producing the higher yields in most
cases[ 2\3!Epoxy!2!methyl!0!butyne was also used as a substrate\ although reduced yields were
obtained[
i, R23B, PhH, O2 (cat.) R2 •

O OH
ii, H2O
R1 R1
R1 R2 Yield (%)
H Et 53
Me Et 47
Scheme 61
0[95[2[0[3 Aromatic and alkenic substitution
Most of the organoboron reactions discussed so far involve some kind of conjugate addition[ A
di}erent type of reaction is found in the substitution of proton or halide substituents in aromatic
rings or alkenes in a reaction mimicking electrophilic substitution[ The reactions are successful with
aliphatic trialkyl boranes[
In 0856 Zweifel devised an elegant synthesis of both "Z#! and "E#!0\1!disubstituted alkenes
involving boron chemistry ð56JA2541\ 57JA5132\ 60JA5298\ 61JA5459Ł[ "E#!Vinylboranes\ prepared by
addition of dialkylboranes to alkynes\ were shown to undergo transfer of one ligand from boron to
the alkenic carbon atom followed by a highly stereoselective elimination process upon treatment
with electrophiles[ It is interesting that\ although in the absence of base a thermal syn elimination
takes place to give the "E#!alkenes\ an anti elimination occurs in the presence of base to give the
"Z#!alkenes "Scheme 51#[ The process was later modi_ed by Evans through the use of boronic esters
to prevent competition between ligands in the transfer of the alkyl group ð65JOC2836Ł[
BrCN I2/HO– R1
R2 BR22
R1 R1 R2
Scheme 62
Subsequently\ a modi_cation allowing the stereoselective preparation of trisubstituted alkenes

was reported by Levy[ For example\ reaction of ethylmagnesium bromide with 0!octyne in the
presence of cuprous bromide dimethyl sul_de complex leads\ after treatment with iodine\ to a 52)
yield of the "E#!1!ethyl!0!iodo!0!octene[ Subsequent sequential treatment of this vinyl iodide with
butyllithium\ triethylborane and elemental iodine at low temperature leads to a 64) yield of
"E#!3!ethyl!2!decene "Equation "17## ð67JOC0168Ł[
I i, BuLi, –65 °C
ii, Et3B, –78 °C
(28)
C6H13 iii, I2 C6H13
75%
Treatment of the vinyl iodide intermediate with butyllithium leads to halogenÐmetal exchange[
Subsequent transfer of the alkyl group from boron occurs with retention of con_guration at the
vinyl carbon atom[ The mechanism of the subsequent rearrangement is similar to the halogenation
reactions of vinylboranes[ Reaction of the vinyllithium with the trialkylborane gives an {ate| complex[
Addition of iodine leads to migration of an alkyl group from boron to carbon^ syn elimination of
dialkyliodoborane then gives the product alkene "Scheme 52#[
– R3
–
R1 Li R3 R1 BR33 Li+ R1 BR32
3B I2
R2 H
R2 R2 + I
R3
BR32 –R32BI R1 R3
R1
H
R2 syn elimination
R2
I
Scheme 63
Furans and pyrroles respond poorly to normal methods of aromatic substitution such as the
FriedelÐCrafts reaction[ Ring destruction and polymerization are commonly observed rather than
substitution[ However\ organoboranes can be used to introduce alkyl groups using metallated
species generated via halides or by deprotonation of furans and pyrroles\ usually at the C1 position
"Scheme 53# ð67JOC3573\ 68BCJ0754\ 68TL1202Ł[
The 1!alkylated heterocycles are produced in variable yields[ The mechanism for the reaction is
similar to that of trisubstituted alkene preparation "Equation "17##\ and is thought to proceed in
three stages] "i# reaction of the trialkylborane with the carbanion derived from the heterocyclic
–
Li R3B BR3 Li+ I2 R
N N N
Me Me Me
R Yield (%)
Et 79
c-C5H9 79
Cl
R3B NCS
– R
O Li O BR3 R
O O
BR2
R Yield (%)
C6H13 82
c-C5H9 73
i, R3B
N Li N R
ii, NCS or I2
Me Me
R Yield (%)
Pr 92
C6H13 70
Scheme 64
compound to give a borate species^ "ii# electrophilic attack by iodine at the 4!position in the
heterocycle\ with migration of an alkyl group from boron to the C1!position and "iii# collapse to
the product with loss of dialkylhaloborane and halide "Scheme 53# ð62JA2979Ł[
Coupling of vinyl boranes and vinyl boronates with aryl and vinyl halides is a well known and
reliable reaction "Scheme 54# ð70TL016\ 76CL14\ 76S262\ 80COS"2#130Ł[ Direct substitution\ in which
transition metal!catalysed cross coupling of trialkylboranes with aryl and 0!alkenyl halides takes
place with formation of a carbonÐcarbon single bond\ is also a mild and straightforward reaction
ð79PAC558Ł[ Use of a palladium catalyst containing bis"diphenylphosphine#ferrocene "dppf# ligand
enables the coupling of 0!alkenyl and aryl halides with trialkylboranes such as 8!alkyl!8!borabicyclo!
ð2[2[0Ł nonanes to take place in the presence of bases ð75TL5258Ł "Scheme 55#[ Use of the dppf ligand
helps to suppress competing b!hydride elimination in the transferred alkyl groups ð73JA047Ł[ The
base used is commonly sodium methoxide\ and yields are good to excellent "59Ð88) in most
cases#[ An unusual application of this reaction is seen in the synthesis of functionalized organotin
compounds using 8!"v!stannylalkyl#!8!BBN as the organoboron reagent ð80SL576Ł[ Use of
"PdCl1"dppf## or Pd"PPh2#3 as the palladium catalyst and potassium phosphate as the base in dioxane
solution was essential for successful coupling\ in the case shown presumably through an additionÐ
elimination process[ The products may be cyclodestannylated in the presence of acid catalysts to
provide carbocyclization products "Scheme 56#[
I BR22 R1
R1
Pd0
BR32
R1 R2 R1
Br R2
Pd0
Scheme 65
I (C8H17)3B, NaOMe
Pd(dppf)Cl2
98%
9-octyl-9-BBN, NaOH
Pd(dppf)Cl2
Br 85%
Scheme 66
SnMe3
B
O O O
i, TiCl4
K3PO4, dioxane, Pd(PPh3)4 ii, H2O
88%
Br SnMe3
Scheme 67
0[95[2[0[4 Aliphatic substitution

A useful example of substitution of a halide by an alkyl group from an organoborane at an sp2
carbon atom involves a!haloesters as substrates\ providing a simple synthesis of esters "Scheme 57#
ð57JA707\ 57JA0800Ł[ The reaction may also be carried out using dihaloesters to provide either the
mono! or disubstituted products in yields of 36Ð87)[
Br CO2Et R3B R CO2Et
Et KOBut, ButOH Et
R Yield (%)
Et 87
C6H13 63
Scheme 68
In another carbonÐcarbon bond forming reaction using organoboranes\ a ligand is transferred

from a trialkylborane to displace the acetoxy group in a!imino!a!acetoxy carboxylates\ producing
the corresponding a!substituted a!iminocarboxylates\ which may be hydrolysed to give a!amino
acids in good yields "Scheme 58# ð74CC0057Ł[
Ph N CO2Et R3B Ph N CO2Et HCl/H2O
R CO2H
Ph OAc THF, 0 °C Ph R NH2
R Yield (%)
c-C6H11 90
But 59
Ph 57
C8H17 92
Scheme 69
A rather unusual and interesting reaction reported by Hunter involves an acetal as the substrate\
the leaving group being one of the alkoxy moities "Equation "18## ð78TL1902Ł[ The methodology
may be extended to the ring opening of cyclic acetals[ Products were isolated in 53Ð64) yield[ The
lithium butyltriallylborate used in this case was produced by treating triallylborane with one
equivalent of butyllithium in THF at 9>C[
OMe – OMe
BBu•Li+
3
OMe (29)
KOH, H2O2, TMS-OTf, THF
MeOH, –78 °C
94%
Allylboranes can undergo a typical organometallic addition to the carbonyl group of a wide range
of aldehydes and ketones in dichloromethane solution "Scheme 69# ð80TL5638Ł[
O (PhO)2B
OH
Br
Br
THF, H2O, 12h
89%
O Br
HO
80%
Scheme 70
In contrast to the reactivity of allylboranes\ allylboronates normally react with ketones with
transfer of one alkyl group from boron only under high pressure conditions[ Allylboronates will
however react with a!ketocarboxylic acids in the presence of triethylamine to give a!hydroxy!
carboxylic acids "Scheme 60# ð80TL3508Ł[ The reaction may proceed through a bicyclic transition
state[
O HO R
(PriO)2B OH
OH
R Et3N, CH2Cl2
O O
R Yield (%)
Ph 94
Me 86
Et 90
Scheme 71
0[95[2[1 Substitution of Silicon Functions
0[95[2[1[0 Alkylation
Simple substitution reactions of sp2 carbonÐsilicon bonds which form new sp2 carbonÐcarbon
bonds are not common[ The vast majority of such reactions involve desilylation\ e}ected by any
one of a number of ~uoride ion reagents such as caesium ~uoride or t!butylammonium ~uoride
"tbaf#\ followed by attack of the anionic desilylated species\ or other intermediate\ at a carbon
electrophile such as an alkyl halide\ aldehyde\ ketone\ a\b!unsaturated ketone or carbon dioxide
ð64JA2146Ł[
Silanes in tri~uoroacetic acid have been used to e}ect the ionic hydrogenation of alkenes by
protonation followed by hydride transfer from the silanes ð63S522Ł[ Although tetrasubstituted
silanes do not react with alkenes in the absence of catalyst\ in the presence of tri~uoroacetic acid
and Lewis acids a methyl group may be transferred from tetramethylsilane to an alkene double
bond "Scheme 61#[ The reaction is believed to take place through initial protonation\ and is successful
with tri! and tetra!substituted ethylenes which can form tertiary carbenium ions upon protonation\
to produce saturated hydrocarbons containing quaternary carbon atoms ð79CC637Ł[ One interesting
aspect of this reaction is that\ although the reaction proceeds with other tetramethyl group 03
derivatives including those of tin and germanium\ it does not proceed with TMS!Br\ TMS!Cl or
TMS!O!TMS[ Even so\ these reactions are useful for the synthesis of hydrocarbons with quaternary
carbon atoms[
Me4Si, TFA, AlBr3
Me4Si, TFA, AlBr3
Scheme 72
In an interesting application of the ~uoride induced nucleophilic addition process\ a!halosilanes

can be converted by treatment with ~uoride ion into reactive species\ formally the a!halocarbanions\
which can be used in the synthesis of stilbenes\ epoxides\ cyclopropanes\ benzazepines and phthal!
idylisoquinolines "Scheme 62# ð80JOC2897Ł[ For example\ a!halosilanes are desilylated using caesium
~uoride in DMF in the presence of a\b!unsaturated ketones to give cyclopropanes through a
conjugate addition:halide displacement process[
X –
CsF, DMF Ph
Ph
X
TMS O
RCHO R
O
O
R
Ph R
Ph
R Yield (%) R Yield (%)
Ph 87 Me 50
4-MeOC6H4 58 OMe 59
Scheme 73
Alkylation is achieved in moderate yield upon cleavage of the silyl group of 2!trimethylsilyloxetan!
1!ones\ readily available by ð1¦1Ł!cycloaddition reactions\ in the presence of methyl iodide[ The
reaction presumably proceeds via an enolate intermediate\ generated upon addition of the 1¦1
adduct to a rapidly stirred suspension of tris""dimethylamino#sulphur trimethylsilyl#di~uoride
"TASF# and methyl iodide "_ve molar equivalents# in tetrahydrofuran at 9>C "Equation "29##[ Other
~uoride sources\ including caesium ~uoride and tetrabutylammonium ~uoride\ were examined\ but
with little success ð78TL5718Ł[
O O
O TASF, MeI, THF, 0 °C O
(30)
Ph O 40–65% Ph O
TMS
85:15 trans:cis
The ready loss of the trimethylsilyl unit from 1!trimethylsilyl!0\2!dithiane has been used in a
tandem bisalkylation with epoxides ð83SL400Ł[ 1!Lithio!1!trimethylsilyl!0\2!dithiane is alkylated
with epoxides in the presence of crown ethers to give the alkoxide\ which undergoes rapid migration
of the silyl moiety from carbon to oxygen\ generating a new 1!lithio!0\2!dithiane species which
reacts with a second molecule of epoxide[ The process was used in a synthesis of enantiomerically
pure C1!symmetric 0\4!diols "Scheme 63#[
O
ii, , 12-crown-4, –20 °C
O– S O-TMS
S S S S
TMS S –
TMS
i, H3O+
ii, NaF, THF/H2O steps OH OH
O– O-TMS OH OH
S S S S
89%
Scheme 74
0[95[2[1[1 Hydroxylation:aldol reactions

A simple example of a hydroxyalkylation reaction involving carbonÐsilicon bond cleavage\
reported by Kuwajima\ involves the treatment of a!trimethylsilyl esters with a carbonyl compound
in the presence of a catalytic amount of tbaf in an aprotic solvent such as THF ð65TL0588Ł[ b!
Silyloxyesters are produced by migration of the silyl group\ and can subsequently be hydrolysed
using acetic acid and water to produce the b!hydroxy esters "Scheme 64#[ Only small amounts of
isolable by!products were detected except where aliphatic aldehydes were used^ these tended to
undergo self!condensation\ with only small amounts of the crossed aldol adduct being produced[
O– O-TMS OH
Bu4NF R1 R1 AcOH R1
TMS CO2R CO2R CO2R CO2R
O R2 R2 R2
–
R1 R2 TMS
Aldehyde/ketone Yield (%)

CHO 81
Ph
CHO 82
PhCHO 76
O
88
Ph Ph
Scheme 75
In a related reaction\ N\N!dimethyl!1!trimethylsilylacetamide may be deprotonated by LDA to

form the lithium enolate\ which has been shown to add to epoxides with ring cleavage and similar
silyl group migration "Scheme 65# ð67JOC0836Ł[
Acyl silanes undergo a rearrangement induced by ~uoride ion in which alkyl group migration from
i, LDA, THF, 0 °C
O O O–
O ii,
H3O+
TMS NMe2 NMe2
NMe2 75%
O– TMS O-TMS
NMe2
OH
Scheme 76
silicon to carbon occurs\ followed by Brook!type rearrangement\ ultimately producing secondary
alcohols "Scheme 66# ð76TL3344Ł[
O
O Bu4NF O– H3O+ OSiR22F OH
– R2
R1 SiR23
R1 SiR23 R1 SiR22F R1 R2 R1 R2
F
R1 R2 Yield (%)
Me(CH2)5 Me 68
Ph Ph 54
Scheme 77
An interesting example by Paquette involves the reaction of cyclopropyl anions with carbonyl
species ð73JA5331Ł[ Attempts to deprotonate the cyclopropanes led only to the formation of self!
condensation products[ Although protons attached to three!membered rings exhibit greater acidity
than normal\ those cyclopropanes carrying carbonyl\ nitro and sulfonyl groups are markedly less
acidic than their acyclic counterparts[ This has been explained by the formation of an exocyclic p!
bond upon proton abstraction\ maximising charge delocalization and increasing p!character[ As a
result\ ring strain and chemical reactivity are enhanced[ Cyclopropanes bearing electron!with!
drawing substituents which also contain an a!trimethylsilyl group can however be e.ciently de!
silylated in the presence of carbonyl group electrophiles to form the alkylated products "Scheme
67#[ The electron!withdrawing substituent may be a nitro\ cyano or carboxyl group[ Use of caesium
~uoride produced substantial amounts of the silyl enol ether derivatives along with the expected
aldol products[ The best catalyst for desilylation in this case was tbaf in THF as a solvent[
O O OH
Bu4NF, THF, 0 °C
TMS
OMe RCHO MeO R
R Yield (%)
Me 90
But 51
Scheme 78
0[95[2[1[2 Acylation
Desilylation of a silylcyclopropane derivative has also been carried out using carbon dioxide as
the electrophilic species in an e.cient conversion into the corresponding cyclopropyl carboxylic
acid after aqueous workup "Equation "20## ð80SL808Ł[ Interestingly\ the reaction proceeds in a very
facile manner using one atmosphere of carbon dioxide[ In this case the most successful ~uoride ion
reagent was caesium ~uoride\ used in ten!fold excess[ In THF poor solubility proved a problem and
silylcyclopropane was recovered[ In solvents such as DMF and pyridine\ however\ the reactions
proceed smoothly in quantitative yields[
i, CsF, CO2, 0 °C, THF O

TMS CN
ii, H3O+ CN
HO (31)
97%
Ph
Ph
DesilylationÐacylation of cyclopropylsilanes mediated by Lewis acid is also known[ Lewis acid

mediated synthesis of cyclopropyl ketones from cyclopropyltrimethylsilane and simple acid chlorides
in the presence of aluminum trichloride was reported by Calas "Scheme 68# ð65S626Ł[ Previously\
cyclopropyl ketones had generally been prepared from acyclic carbonyl compounds\ cyclization
being the last step[
O
TMS AlCl3, RCOCl, CH2Cl2
R
R Yield (%)
Me 60
Ph 50
Scheme 79
Under the Calas reaction conditions\ only very small amounts "³0)# of ring cleaved products
were observed[ This is remarkable\ since the action of acyl chlorides on cyclopropane or methyl!
cyclopropane normally results exclusively in the formation of chloroketones by ring cleavage\
suggesting either a change in reaction mechanism or modi_cation of the reactivity of the cyclopropyl
ring by the trimethylsilyl group[ a\b!Unsaturated acyl chlorides react similarly\ giving rise to a\b!
unsaturated cyclopropylketones in good yields[
0[95[2[1[3 0\2!Dipole formation

A further type of reaction which leads formally to the generation of sp2 carbonÐcarbon bonds
from sp2 carbonÐsilicon bonds is found in 0\2!dipolar cycloaddition reactions[ A silicon!containing
0\2!dipole precursor is treated with either ~uoride ion or Lewis acid to generate the 0\2!dipole by
desilylation[ Cycloaddition to a dipolarophile leads to the formation of cyclic systems with the
formation of a new carbonÐcarbon bond[
"i# Azomethine ylides

The 0\2!dipolar cycloaddition of an azomethine ylide with an alkene leads to a simple synthesis
of a pyrrolidine ð81TL5596Ł[ Desilylation of appropriately substituted N!"silylmethyl#amines has
proved a very useful method for preparing nonstabilized azomethine ylides\ which readily react
with electron!de_cient alkene dipolarophiles including a\b!unsaturated esters\ ketones\ nitriles and
amides "Scheme 79#\ and is usually achieved by treatment with Lewis acid or ~uoride ion[ The
reactions all proceed in good to excellent yields and can be carried out in one pot[ The reactivity of
the alkene depends upon the nature of the alkenic substituent\ which in all the cases studied was an
aromatic ring[
Ar
Ph Ph
F– Ar
+ + HX
TMS N X N
H+ N
–
Bn
X = CN, OMe
Ar Yield (%)
3-nitrophenyl 85
4-cyanophenyl 76
4-methoxyphenyl 20
2-pyridyl 79
Scheme 80
In one rather unusual example\ the azomethine ylide is generated using photo!induced electron
transfer "PET# to initiate desilylation\ instead of ~uoride ion ð81CC0202Ł[ The ylide precursor\
bis"trimethylsilylmethyl#benzylamine\ is easily prepared and the two trimethylsilyl groups act as
activating groups[ The irradiation process is carried out using a 349!W Hanovia medium pressure
lamp with a pyrex _lter of ×179 nm\ in the presence of 8\09!dicyanoanthracene "DCN#[ Irradiation
is carried out in a methanolÐwater solution "8 ] 0#[ The process results in the formation of an amine
cation radical which easily loses an electron and silyl cation to form the trimethylsilylallyliminium
salt which undergoes further desilylation to generate the nonstabilized azomethine ylide capable of
reaction with dipolarophiles including benzophenone\ methyl cinnamate and phenylvinylsulfones
Ph A B
Ph
hν, DCN A B
+ N
TMS N TMS MeOH/H2O N
– Bn
A=B Yield (%)

O
80
Ph Ph
O O
S 75
Ph
O
78
Ph OMe
Scheme 81
"ii# Thiocarbonyl ylides

Treatment of alkoxymethylthiomethyl silanes with ~uoride ion leads formally to the generation
of thiocarbonyl ylides capable of 0\2!dipolar cycloaddition to aldehydes to form 0\2!oxathiolanes
"Scheme 71# ð81CL0962Ł[ The reaction is said to take place stepwise\ by initial nucleophilic addition
followed by ring closure under acidic conditions[
R2
TMS OMe i, R2CHO, F–
O
R1 S ii, H3O+
R1 S
R1 R2 Yield (%)
H Ph 84
H But 87
Ph 4-MeOC6H4 82
Scheme 82
Alternatively\ treatment of the alkoxymethylthiomethylsilanes with a silyl enol ether in the

presence of Lewis acid leads to the formation of 2!hydroxythiolanes\ again purportedly through a
two!step process\ in this case involving the alkoxymethylthiomethylsilane as the electrophile attack!
ing the silyl enol ether[ The product then undergoes desilylation\ using a ~uoride ion\ leading to
ring closure "Equation "21##[
O-TMS i, Lewis acid HO

TMS OMe ii, F–
+ (32)
Ph S 92% Ph S
In both types of reaction\ yields were good to excellent[ t!Butylammonium ~uoride\ used in
catalytic quantity\ was found to be the best source of ~uoride[
"iii# Trimethylenemethane
Of all the 0\2!dipoles generated through carbonÐsilicon bond cleavage\ the best known is certainly
the trimethylenemethane "TMM# system invented by Trost[ In this system\ reaction of 1!
acetoxymethyl!2!allyltrimethylsilane with dipolarophiles under conditions of palladium"9# catalysis
leads to e.cient annelation to give _ve!membered carbocycles or heterocycles bearing an exo!
methylene unit through a formal 0\2!dipolar cycloaddition process[ The reactive intermediate may
be formulated as a delocalized trimethylenemethane species "Scheme 72# ð68JA5318Ł[ The reagent is
prepared as shown in Scheme 73 by silylation of a!methylallyl alcohol followed by acetylation[
TMS –OAc
" "
TMS
Pd(L)
≡
+
+ + –
OAc Pd
Pd(L)
Scheme 83
i, BuLi, TMEDA
ii, TMS-Cl AcX
OH TMS OH TMS OAc
O+
iii, H3
65%
Scheme 84
Palladium!catalysed 0\2!dipolar addition of TMM systems to a range of dipolarophiles has been

thoroughly reviewed\ including the chemoselectivity\ regioselectivity and diastereoselectivity of the
process\ in both intermolecular and intramolecular reactions ð75AG"E#0Ł[ Palladium catalysts which
may be used typically include tetrakis"triphenylphosphine# palladium"9# and palladium
acetate:triisopropylphosphite\ which Trost has shown to increase the e.ciency of the reaction
ð75TL0334Ł[ Scheme 74 illustrates a range of intermolecular reactions with dipolarophiles containing
electron withdrawing groups including ester\ nitrile and sulfone ð68JA5318Ł[ Many similar examples
are known ð77JA0591\ 78AG104\ 89T0748\ 80JA8996Ł[
TMS Pd(OAc)2, (PriO)3P

CO2Me
+
63%
OAc CO2Me CO2Me
CO2Me
Pd(PPh3)4
+ CN
35%
CN
Pd(PPh3)4
+
SO2Ph 58%
SO2Ph
TMS
Pd(OAc)2
+ MeO2C CO2Me
OAc
MeO2C CO2Me
Scheme 85
TMM dipolar addition reactions are known to be diastereoselective[ For example\ dipolar
addition to bicycloð1[1[0Łnon!0!ene 0\1!dicarboxylates are highly exo selective ð75TL0334Ł\ a reaction
used in an approach to "2#!albene ð71JA5557Ł "Schemes 74 and 75#\ and high diastereoselectivity is
seen in the addition to simple a\b!unsaturated esters ð77JA2576Ł and other derivatives "Equation
"22## ð75JA5940\ 78JA5371Ł[
Pd(OAc)2, (PriO)3P
TMS THF, ∆ CO2Me
CO2Me
+ + CO2Me
OAc 84% CO2Me
CO2Me
CO2Me
3.4:1
Scheme 86
TMS O Pd(PPh3)4
+ Ph
OAc O toluene
O O
Ph Ph
O + O (33)
90% 5%
An optically pure vinyl sulfoxide has also been shown to undergo highly diastereoselective dipolar
addition with TMM "Equation "23## ð78TL0792Ł\ as have cyclic g!alkoxy vinyl sulfones "Equation
"24## ð78JA6376\ 78TL0384Ł[
O–
O– Ar
TMS H
Pd(OAc)2, (PriO)3P, THF, ∆ S+
S+
+ Ph (34)
OAc 80%
80% de
SO2Ph
SO2Ph
TMS toluene, ∆, Pd(IOPri3P)4
+ 4 (35)
OAc 93%
H
O-MOM
O-MOM
4β:4α 9:1
TMM dipolar cycloaddition reactions are successful even with tropone "a ð5¦2Ł!cyclization#
ð76JA504Ł and some dienoate systems "Scheme 76# ð76JA2372Ł[
O
OMe
TMS O
Pd0, THF, ∆, 8.5 h
+
OMe 76%
OAc
H R
R TMS
Pd0, toluene
+ O O
62%
OAc
Scheme 87
Carbon!heteroatom double bonds can also be successful dipolarophiles[ The carbonyl groups of
a\b!unsaturated and a\b!acetylenic ketones\ in cases where the double bond is sterically hindered\
provide an interesting illustration of functionalized tetrahydrofuran synthesis using this procedure
ð78JA4891\ 78JA5371\ 89JA397\ 82TL6072\ 82TL6892Ł[ In the example illustrated\ indium tris"acetylacetate#
is used as cocatalyst "Equation "25##[
O Pd(OAc)2, DIBAL, PPh3, CHCl3

TMS In(acac)3, ∆ O
+ Ph (36)
OAc 81% Ph
Imines also undergo dipolar addition to give the corresponding substituted pyrrolidines
ð75CC0190Ł[ Equation "26# shows such a case in which\ unusually\ a nickel catalyst is used[
TMS Ni(POEt3)4, toluene, ∆, 12 h

+ N Ph (37)
Ph Ph
OSO2Me 77% N
Ph
A number of instances of TMM cyclizations in intramolecular situations have appeared in the

literature\ with the formation of bicyclic "Scheme 77# or even tricyclic "Equation "27## carbocyclic
products ð71JA2622\ 71JA5768\ 71TL0156\ 80JA6249\ 80JA6252\ 81JOC575Ł\ as well as heterocycle formation
by addition to aldehydes\ seen in an approach to the phyllanthocin ring system "Equation "28##
ð78H"17#210Ł[
O TMS
TMS
steps Pd(PPh3)4, dppe, THF, ∆
+ O O RO
51%
MgBr
MeO MeO
MeO2C H
Scheme 88
O
O H
MeO O
O Pd0 O
+ isomers (38)
43%
H SO2Ph
O H
TMS
SO2Ph
O
H H
MeO O (PriO)3P, Pd2(dba)3
TMS + (39)
Bu3Sn, 40 min O O
CHO H H
0[95[2[1[4 Free radical mediated reactions

Titanium dioxide has been used as a catalyst for photochemical oxidation\ in the presence of
silver sulphate\ for the generation of free radical species from a range of benzyltrimethylsilanes\
leading to the formation of diarylethanes in good yields with loss of the silyl moieties "Scheme 78#
ð81CC48Ł[ The reaction is said to take place by initial cation radical formation followed by a very
fast carbonÐsilicon bond cleavage\ leading to the formation of benzyl radicals[
hν, TiO2, Ag2SO4 Ar

Ar TMS
Ar
MeCN
Ar Yield (%)
Ph 74
4-MeC6H4 71
3-CF3C6H4 50
Scheme 89
Silver sulfate is used as the reducible species in this case and the whole process is carried out using
a 499 W high!pressure mercury lamp in acetonitrile as solvent[ Under these conditions the reactions
proceed e.ciently "49Ð63) yield#[ The rate of the reaction is highly dependent upon the nature of
any ring substituent^ it is depressed in the presence of electron!withdrawing substituents and
increased by electron!donating substituents[ For example\ the irradiation time for the reaction when
the substrate contained an electron!donating methyl group was two hours\ while\ when an electron!
withdrawing tri~uoromethyl group was present\ the irradiation time increased to twenty hours[
Some allylic and benzylic silanes undergo similar oxidative coupling induced by oxovanadium
species ð82TL4590Ł[ Treatment of cinnamyltrimethylsilane with VO"OEt#Cl1 in dichloromethane
leads to regioselective oxidative coupling to form the 0\4!hexadiene "Scheme 89#[ The reaction
does not occur with less reactive silanes such as allyltrimethylsilane or methallyltrimethylsilane[
Interestingly\ however\ cross coupling of each of these species with the more reactive
cinnamyltrimethylsilane is successful in producing the corresponding unsymmetrical dienes in
moderate yields "39Ð49)# together with a small amount of the self!coupling product of
cinnamyltrimethylsilane "5Ð01)#[
R2 R1 R1
VO(OEt)Cl2
Ph TMS + TMS Ph +
CH2Cl2, RT, 8 h
R1 R2 Ph R2
A B
R1 R2 Yield (%) Ratio

A:B
H H 40 2.5 : 1
H Me 51 1.5 : 1
Me H 56 2.0 : 1
Scheme 90
0[95[2[2 Substitution of Germanium Functions

There are very few reactions of alkyl organogermanium species in which a new carbonÐcarbon
bond is formed at the expense of the sp2 carbonÐgermanium bond ð75S665Ł[ Reactions of species
containing sp1 carbon!germanium bonds are much more common ð77JOM"14#237\ 77OM628Ł[
One example of such a reaction of an alkyl organogermanium species involves the preparation
of the germanium reagent\ triphenylgermylacetyl triphenylgermane\ which can act as an acetate
equivalent in a Lewis acid!mediated reaction with aldehydes to form the corresponding aldol
products "Scheme 80# ð76CL384Ł[ The germanium reagent was prepared using known methodology
for the synthesis of acyl germanes ð74CL0718Ł by reacting the corresponding ester with three
equivalents of triphenylgermyllithium at room temperature for ten minutes[
The reagent also reacts with a\b!unsaturated aldehydes to produce the corresponding aldol
products\ and\ perhaps surprisingly\ does not undergo any conjugate addition "Equation "39##[ The
Substitution of Metal 180
O Ph3GeLi O HO O
RCHO
Br Ph3Ge
OEt GePh3 R GePh3
R Yield (%)
Ph 81
PrCHO 75
Scheme 91
yields of the reaction range from 57Ð70) and no by!products are produced[ The reagent does not
react with ketones or acetals under similar conditions[
O CHO OH O
Ph3Ge (40)
GePh3 68% GePh3
Ethyl "trimethylgermyl#acetate reacts with carboxylic acid derivatives such as acyl chlorides\ acyl
imidazoles\ thioesters and esters via its lithium enolate ð89OM0214Ł[ The authors| studies of the
reaction suggest that the most likely of the possible reaction pathways is that which involves initial
formation of the2!oxoalkanoic ester enolate through the loss of chlorotrimethylgermane "Scheme 81#[
X O
–O
O LDA O– RCOX –Me3GeX
Me3Ge Me3Ge R OEt
OEt OEt
GeMe3
O– O H3O+ O O
R OEt 35–92% R OEt
R = Me, Pr, Ph; X = Cl, imidazolide, CN, OEt, SCH2Ph
Scheme 92
A rather more unusual reaction\ investigated by Seyferth ð58JOM"05#492Ł\ involved the ring expan!
sion of 0\0!diethyl!0!germacyclobutane by dichlorocarbene insertion into a germaniumÐcarbon
bond[ When 0\0!diethyl!0!germacyclobutane is allowed to react with phenyl"bromodichloromethyl#
mercury "in slight excess# in benzene solution at re~ux\ the major product obtained\ in 24) yield\
was shown to be 0\0!diethyl!1\1!dichloro!0!germacyclopentane "Equation "30##[ Ring expansion has
therefore occurred\ in the _rst case of carbene insertion into a carbonÐgermanium bond[
PhHgCCl2Br, PhH, ∆ Et2Ge

Et2Ge (41)
35% Cl
Cl
0[95[3 SUBSTITUTION OF METAL FUNCTIONS

In the literature\ reactions are very rare in which two organometallic species containing di}erent
metals\ each having the metal atom bonded to an sp2 carbon atom\ undergo exchange to give the
product of coupling of the alkyl groups together with a new bimetallic species[
In one such reaction\ conjugated dienes can be activated towards nucleophilic attack by com!
plexation with tricarbonyliron followed by treatment with ~uoroboric acid under an atmosphere of
carbon monoxide[ The resulting cationic salts are known to undergo nucleophilic addition by a
wide variety of soft nucleophiles[ These include triphenylphosphine\ pyridine\ malonates\ secondary
amines\ electron!rich aromatic compounds and organocadmium reagents ð81CC02Ł[ For example\
dialkylcadmium reagents were shown to react with an acyclic allyliron complex to provide mainly
"Z#!alkenes in reasonable yields[ The reactions proceed regioselectively and with retention of alkene
con_guration "Equation "31## ð64TL2506Ł[
R2Cd, THF, 0 °C R R
+ + (42)
Fe(CO)4 BF4 –
50–60%
Highly functionalized copper zinc reagents can be prepared by transmetallation from the cor!
responding functionalized zinc compounds with cuprous cyanide in THF solution[ These react
e}ectively with the above cationic salts to give a variety of polyfunctionalized isoprenyl derivatives
including isoprenyl compounds and b\g!unsaturated ketones "Scheme 82#[
EtO2C(CH2)3Cu(CN)ZnI, THF
+ CO2Et
53%
Fe(CO)4 BF4–
PhCH2Cu(CN)ZnI, THF
+ Ph
Fe(CO)4 BF4 – 58%
Scheme 93
The cations undergo preferential nucleophilic attack at the less substituted allyl terminus with
complete regioselectivity\ yielding principally alkenic products with a trace of ketones "Scheme 83#[
Ketones are thought to arise by initial addition to a coordinated carbon monoxide ligand\ producing
a metalÐacyl intermediate[ This is followed by migration of the acyl group to the less substituted
terminus of the allyl unit and detachment of the iron carbonyl moiety[ One example shows approxi!
mately equal amounts of alkene and ketone products\ possibly due to steric factors at the allyl
terminus of the cation[ However\ this is not re~ected upon reaction with benzylic copper reagents[
R1
R1 R1
pathway b –Fe(CO)3 R3
R2
R2 R3Cu(CN)ZnI (CO)3Fe
+ R3
Fe(CO)4 R2 O
O
pathway a
R3Cu(CN)ZnI R1, R2 = H, Me
R1
R3
R2
Scheme 94
1.08
by Addition: Addition of Carbon
Radicals and Electrocyclic
Additions to CC Multiple Bonds
ANDREW J. CLARK and PAUL C. TAYLOR
University of Warwick, Coventry, UK
0[97[0 ADDITION OF CARBON RADICALS TO CARBONÐCARBON MULTIPLE BONDS
TO GIVE TETRACOORDINATE PRODUCTS 219
0[97[0[0 Introduction 219
0[97[0[1 Basic Principles 219
0[97[0[1[0 Synthetic advantaès of carbon!centred radical reactions 219
0[97[0[1[1 Stability and structure of alkyl and vinyl radicals 210
0[97[0[2 Intermolecular Radical Additions 211
0[97[0[2[0 Introduction 211
0[97[0[2[1 Electronic nature of radicals 212
0[97[0[2[2 Stereoselectivity 214
0[97[0[2[3 Methods for conductin` radical reactions 218
0[97[0[3 Intramolecular Radical Additions 225
0[97[0[3[0 Introduction 225
0[97[0[3[1 The 4!hexenyl radical] reìoselectivity 225
0[97[0[3[2 Stereoselectivity in substituted 4!hexenyl radical cyclisations 226
0[97[0[3[3 Allyl\ vinyl and aryl cyclisations 227
0[97[0[3[4 Formation of six!membered rin`s 228
0[97[0[3[5 Formation of other rin` sizes 239
0[97[0[3[6 Methods for facilitatin` radical cyclisation reactions 230
0[97[0[4 Tandem Processes 236
0[97[0[4[0 Intramolecular:intramolecular sequences 236
0[97[0[4[1 Intramolecular:intermolecular processes 237
0[97[0[4[2 Intermolecular:intramolecular additions 237
0[97[0[4[3 Intermolecular:intermolecular additions 237
0[97[1 ELECTROCYCLIC ADDITIONS TO CARBONÐCARBON MULTIPLE BONDS TO

GIVE TETRACOORDINATE PRODUCTS 238
0[97[1[0 Introduction 238
0[97[1[0[0 Scope 238
0[97[1[0[1 General mechanistic aspects 238
0[97[1[0[2 General reìochemical aspects 249
0[97[1[0[3 General stereochemical aspects 240
0[97[1[1 Formation of Three!membered Rin`s 241
0[97[1[1[0 Additions of free carbenes 241
0[97[1[1[1 Additions of metal carbenoids 241
0[97[1[2 Formation of Four!membered Rin`s 243
0[97[1[2[0 Thermal ð1¦1Ł additions 243
0[97[1[2[1 Photochemical ð1¦1Ł additions 244
0[97[1[2[2 Metal!catalysed ð1¦1Ł additions 246
208
219 Addition of Carbon Radicals and Electrocyclic Additions
0[97[1[3 Formation of Five!membered Rin`s 247
0[97[1[3[0 ð2¦1Ł Additions of three!carbon fra`ments 247
0[97[1[3[1 ð2¦1Ł Additions of CXC fra`ments 254
0[97[1[4 Formation of Six!membered Rin`s 261
0[97[1[4[0 ð3¦1Ł DielsÐAlder additions of dienes 262
0[97[1[4[1 ð3¦1Ł DielsÐAlder additions of heterodienes 264
0[97[0 ADDITION OF CARBON RADICALS TO CARBONÐCARBON MULTIPLE BONDS

TO GIVE TETRACOORDINATE PRODUCTS
0[97[0[0 Introduction
The ability to form carbonÐcarbon bonds is one of the primary tasks in the construction of
organic molecules[ In the 0879s and 0889s this has been increasingly achieved by the addition of
carbon!centred radicals to carbonÐcarbon multiple bonds[ This review will focus on the reactivity\
chemoselectivity\ regioselectivity and stereoselectivity of carbon radical additions[ Other reviews on
intermolecular and intramolecular radical addition reactions have been published by Curran ð77S306\
77S378\ 80COS"3#604\ 80COS"3#668\ 80CRV0126Ł[ These contain examples of carbon\ oxygen\ nitrogen and
other heteroatom!centred radical additions and cyclisations and are recommended reading[ Curran
himself recommends as {the bible of radical chemistry\ new testament| a review by Giese
ð78HOU"E08a#Ł[ The reader is also directed to two books which cover the important concepts and
principles ðB!75MI 097!90\ B!81MI 097!90Ł[ Acyclic diastereofacial selection in intermolecular radical
reactions covering the literature up to October 0882 has been reviewed ð83SL0Ł[ Other reviews on
the stereochemical outcome of intermolecular additions ð78AG"E#858\ 80ACR185Ł and intramolecular
additions ð80ACR028Ł have also appeared[ Retrosynthetic planning ð80SL52Ł and computer!assisted
retrosynthetic analysis ð89JCI347\ 89JOC8Ł have also been reviewed[ In addition there are a number
of earlier reviews which cover the basic principles ð72AG"E#642\ 73SCI772\ 74AG"E#442\ 76T2430\ 77CSR250Ł[
A review of transition metal mediated radical reactions has been published ð83CRV408Ł[
This chapter is organised according to the classi_cation of the reaction "e[g[\ intermolecular\
intramolecular or tandem radical additions# and the type of method by which it is conducted[ For
a more detailed account of the preparation of carbon!centred radicals from radical precursors see
Chapters 0[08 and 0[10[
0[97[0[1 Basic Principles
0[97[0[1[0 Synthetic advantages of carbon!centred radical reactions

Carbon!centred radicals are highly reactive intermediates which often show great chemo!
selectivities\ regioselectivities and stereoselectivities upon addition to carbonÐcarbon multiple bonds[
They can be prepared under essentially neutral conditions "see Chapters 0[08 and 0[11#\ and thus
many of the undesired side reactions that are often associated with basic anionic reagents "such as
epimerisation# are generally avoided[ Neutral carbon!centred radicals are less sensitive to solvent
e}ects than ionic reagents because they do not have associated with them a degree of aggregation
or ion pairing[ Consequently\ they are particularly suited for the synthesis of crowded bonds
"such as quaternary centres# and for carrying out transformations in highly hindered frameworks
ð71JA1210Ł[ There are some limiting factors however\ when choosing a solvent for a given radical
reaction[ Mainly these concern the rate of radical:solvent reactions "which are particularly important
when dealing with relatively long!lived radicals# and the solubility of reagents[ There are two further
di}erences between ionic and radical reactions that should be mentioned[ First\ carbon!centred
radicals can only attack functional groups if the bimolecular rate constant k exceeds 091 mol−0 s−0
"see Section 0[97[0[3[0#[ This means that carbon!centred radicals are generally inert to such
functionalities as OH\ NH1 or CO1H groups "unlike basic carbanions\ or electrophilic carbocations#
ðB!75MI 097!90Ł[ This is primarily due to the endothermic nature of homolysis of the strong O0H\
or N0H bonds[ Consequently\ it is not necessary to protect such functionalities\ and this can cut
down on the number of steps in a synthesis[ An example is the cyclisation of "0# via the vinyl radical
"1#^ the facile formation of the quaternary centre should also be noted "Scheme 0# ð71JA1210Ł[ The
Addition of Carbon Radicals 210
other consequence is that radical reactions do not need to be conducted under strictly anhydrous
conditions[ On the other hand\ most radicals will react with triplet oxygen and so reactions should
generally be carried out under an inert atmosphere[ Another major di}erence between ionic and
radical reactions is that carbon radicals do not normally undergo facile b!elimination of OR or NR1
groups^ this is because a less stable p C0C bond would be formed at the expense of the stronger
s C0O or s C0N bond[ Weaker bonds such as b C0Br ð57QR438Ł\ C0SR ð65JA840Ł\ C0SnR2
ð74T3968Ł and C0Co ð72ACR232Ł do undergo b!elimination of Br\ SR\ SnR2 and Co radicals\
respectively\ fast enough to be problematic or\ conversely\ synthetically useful "Scheme 1#[
•
Br •
Bu3Sn• Bu3SnH
HO 70%
HO CN OH CN
CN OH CN
(2)
(1)
Scheme 1
RO RO
facile nonfacile
– + RO– • + RO•
X
facile
• + X•
X = Br, SR, CoIII, SeR, R3Sn
Scheme 2
0[97[0[1[1 Stability and structure of alkyl and vinyl radicals

The relative stability of substituted carbon!centred radicals can be approximated by comparing
the C0H bond dissociation energies D"C0H# in a number of compounds ð75TCC0Ł[ The lower the
D"C0H# the more stable the radical "Table 0#[
Table 0 C0H bond dissociation energies[
•
• •
• < < < • < Et• < Me• < • <
Allyl Benzyl 3° 2° 1° Me Vinyl Aryl
D298(R–H) (kcal mol–1)a (kJ mol–1 in parentheses)
86 (360) 88 (368) 95.8b (401) 96 (402) 100 (418) 105 (439) 105 (439) 111 (464)
a Except where noted, these values are from 〈B-88MI 108-01〉. b From 〈90ACR375〉.
Carbon!centred radicals can adopt either a planar or pyramidal structure "Figure 0# ðB!62MI 097!90Ł[
Conjugating substituents favour the planar structure while alkyl and heteroatom substituents
can cause pyramidalisation ð63JA1190Ł[ The barrier to inversion in the pyramidal structures is very
low and as a consequence stereochemical information at the proradical centre is lost ð72HCA1109Ł[
Vinyl radicals also have a low barrier to inversion ð53JCP"39#102Ł which enables either stereoisomeric
precursor to be used[ Hence\ both the "E# and "Z# isomers "2# are converted to the carbocycle "3#
via the interconverting "E#! and "Z#!vinyl radicals "Scheme 2# ð71JA1210Ł[ Vinyl radicals can either
exist in the bent form or the linear form "Figure 1#[ The latter is preferred with conjugating
substituents ð64JA3158Ł[
• •
•
Planar Pyramidal and inverting
Alkyl radicals
Figure 1 Structure of carbon-centred radicals.

only (E)
Bu3SnH isomer
Br AIBN • can cyclize
75%
•
(3) (Z) (E)
MeO2C CO2Me
(4)
AIBN = 2,2'-azobisisobutyronitrile
Scheme 3
R • •
R
• R
Bent and inverting Linear
Vinyl radicals
Figure 2 Structure of vinyl radicals.
0[97[0[2 Intermolecular Radical Additions
0[97[0[2[0 Introduction
Carbon!centred radicals can undergo intermolecular addition reactions with carbonÐcarbon
double and triple bonds[ The formation of a new s C0C bond "77 kcal mol−0\ 257 kJ mol−0# is at
the expense of a p C1C bond "43Ð48 kcal mol−0\ 115Ð136 kJ mol−0# and is a highly favourable
exothermic process "Equation "0##[ This process is normally not reversible unless the starting radical
is particularly stable relative to the product radical\ or the s C0C bond is weak or the p C1C
bond is strong[ Theoretical studies for radical additions to alkenes indicate that the transition state
is early and that the angle of attack of the radical on to the alkene is tetrahedral[ All the carbons
are slightly pyramidalised and there is little charge separation "Figure 2# ð75JOC1763Ł[
addition R1 R2
R13C• + R2 • (1)
R1
R1
•
C 109°
Figure 3 Radical attack on an alkene.
0[97[0[2[1 Electronic nature of radicals

All carbon!centred radicals can be classi_ed as nucleophilic\ electrophilic or ambiphilic depending
upon the substituents attached to the carbon radical[ The character of the radical will determine
the types of addition reactions that it can undergo[
"i# Nucleophilic radicals

Simple alkyl radicals can be considered nucleophilic and react preferentially with electron!poor
alkenes in high yields ðB!75MI 097!90Ł[ The early transition state for radical additions to alkenes
allows reactions to be rationalised using frontier molecular orbital "FMO# theory ðB!65MI 097!90Ł[
The SOMO of a nucleophilic radical will combine with the LUMO of an alkene "Figure 3#[ Electron!
withdrawing substituents attached to the alkene lower the LUMO and hence increase the rate of
reaction[ This can be illustrated by the following examples of cyclohexyl radical additions "Table 1#[
The addition to acrolein is some 7499 times faster than to hex!0!ene ð72AG"E#642Ł[
R•
LUMO
SOMO
Figure 4 Orbital interaction for nucleophilic radicals.
Generally\ intermolecular addition of nucleophilic radicals to unactivated alkenes are too slow
as to render them synthetically useful[ Addition of alkyl substituents at the radical centre often gives
rise to a small acceleration in the rate of addition to alkenes despite an increased steric demand
ð72TL692Ł[ This is because the addition of electron!donating substituents serves to raise the energy
of the SOMO causing a corresponding rate acceleration[ Consequently\ tertiary radicals are more
reactive than secondary radicals\ which in turn are more reactive than primary radicals ð72TL692Ł[
The most synthetically useful reaction of nucleophilic radicals is addition to the b position of
activated alkenes and alkynes[ Substitution of a further electron!withdrawing group at the a position
of the alkene can increase the rate of addition even further\ while substitution at the b position
generally retards the rate of addition due to steric e}ects "Tables 2 and 3#[ Substitution at the b
position also a}ects the regioselectivity of the addition[ As the b group becomes larger\ the tendency
for attack at the a position increases "Figure 4# ð72AG"E#642Ł[ For a more complete treatment of
Table 1 Relative rates of addition of cyclohexyl radicals to alkenes[
krel •
C6H11• + R C6H11
R
krel is the relative rate compared to that of addition to styrene (ka ~4 x 104 M–1 s–1)
R krel R krel
CHO 34 COMe 13
CN 24 CO2Et 6.7
Cl 0.12 OAc 0.016
O
Bu 0.004 N 4.5a
O O
N 28a N 200a
O O
Except where noted, these values are from 〈83AG(E)753〉. a From 〈93TL4489〉.
radical additions by FMO theory and more information on the rate of addition of carbon!centred
radicals to alkenes\ see ð72AG"E#642Ł[ Nucleophilic radicals can also add to internal alkenes and to
alkynes[
Table 2 In~uence of the substituents Z on the rate

of addition of C5H00 = to acrylates at 19>C[
Z
CO2Me
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Z krel Z krel
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
CN 209 CO1Me 049
Cl 01 C5H4 5[3
H 0 Me 9[64
*
Table 3 In~uence of the substituents Y on the rate

of addition of C5H00 = to acrylates at 19>C[
Y
CO2Me
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Y krel Y krel
*
CN 5[9 CO1Me 4[9
Cl 9[56 C5H4 9[998
H 0 Me 9[900
*
Values from ð72AG"E#642Ł[
0.2%
12% 80%
Et But
CO2Me
CO2Me CO2Me
99.8%
88% 20%
Figure 5 Regioselectivity of addition of cyclohexyl radicals to substituted acrylates

"ii# Electrophilic radicals
Carbon!centred radicals that contain two electron!withdrawing groups such as esters or nitriles
have relatively low!lying SOMOs and react preferentially with electron!rich alkenes that contain
high energy HOMOs[ These are called electrophilic radicals and they have been far less studied than
their nucleophilic counterparts "Table 4#[ For more information\ see ð75CB333\ 75JOC4996\ 76JOC194\
77CB1952Ł[
Table 4 Relative rates for the addition of the malonyl radical to styrenes
at 009>C[
EtO2C Ph EtO2C Ph
krel
• + •
EtO2C Z EtO2C Z
Z krel Z krel
*
N"Et#1 5[0 OMe 1[0
Me 0[9 C5H4 0[1
CO1Et 9[16 COC5H4 9[07
*
Values from ð77CB1952Ł[
"iii# Ambiphilic radicals

There are another class of carbon!centred radicals called ambiphilic radicals that have SOMO
energies intermediate between that of nucleophilic and electrophilic radicals[ These in theory can
combine with either electron!rich or electron!de_cient alkenes with close!lying HOMOs and
LUMOs\ respectively[ Accurate rate studies for the addition of such radicals have been carried out
and show that the rate can be accelerated by addition to both electron!withdrawing alkenes and
electron!rich alkenes ð77CB1952\ B!78MI 097!90Ł[
0[97[0[2[2 Stereoselectivity
"i# Cyclic radical additions

Cyclic radicals that contain b substituents can exhibit a high degree of diastereoselection in
the addition to activated alkenes ð78AG"E#858Ł[ In a series of cycloalkene radicals\ high trans
diastereoselectivities were achieved "Table 5#[ When ROEt stereoselectivities were found to
increase upon changing the solvent from hexane to acetonitrile[ This was explained by the increase
in solvation of the ether oxygen atom and hence its greater steric bulk as a directing group[ The
e}ect of substituents on the alkene has also been investigated and found to have an in~uence on the
selectivity ð72TL4232\ 73CB1021Ł[ Thus\ styrene gave a higher diastereoselectivity than chloro!
acrylonitrile\ and the selectivity was found to increase as the rate of addition to the alkene decreased
ð74CB0234Ł[ If more than one directing group is attached to the ring then the direction of addition
is determined by the overall geometry of the ring ð73AG"E#58\ 74JA3221Ł[
Table 5 Stereoselectivity of addition of cyclic radicals to activated alkenes at 19>C[

R R R
Y
Y Y
+ +
• • •
( )n Z ( )n Z ( )n Z
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
n Y Z R Solvent anti:syn n Y Z R Solvent anti:syn
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
0 H CN OEt hexane 57 ] 21 0 H CN OEt CH1Cl1 66 ] 12
0 H CN OEt CH2CN 70 ] 08 0 H CN Me CH1Cl1 81 ] 7
0 H Ph OEt CH1Cl1 89 ] 09 0 Cl CN OEt CH1Cl1 61 ] 17
1 H CN OMe CH1Cl1 54 ] 24 1 H NHAc OMe CH1Cl1 ×84 ] ³4
*
Values from ð78AG"E#858Ł[
In six!membered rings\ b substituents also direct addition via anti attack\ although the stereo!
selectivity is generally not as high as in the analogous _ve!membered ring case "Table 5#[ Both axial
and equatorial substituents direct anti\ leading to high selectivity ð72TL4232\ 73CB1021Ł[ The anti
selectivity can be increased if the alkene component has a substituent at the reacting radical addition
site[ Further substituents on the cyclic radical can either increase or decrease the selectivity depending
upon the overall geometry of the molecule^ however\ with two axial or equatorial substituents
adjacent to the radical centre\ stereoselectivity is increased ð73TL1632Ł[
"ii# Acyclic radical additions

In the 0889s stereocontrol in acyclic radical addition reactions has attained prominence[ High
stereoselectivities can now be achieved by either chiral auxiliary or substrate control[ For a thorough
treatment of this _eld the reader is directed to two reviews ð80ACR185\ 83SL0Ł[ Most studies have
involved proton\ deuteron or halogen abstraction by chiral radicals and so do not come under the
remit of this chapter[ However\ as all radical addition reactions to alkenes eventually lead to other
radicals which are then trapped by various reagents\ speci_c examples of 0\1!induction will be found
in the text where they illustrate a method[
Radical additions to various alkenes containing chiral auxiliaries lead to good diastereoselection[
0\3!Asymmetric induction has been achieved with a number of auxiliaries "compounds "4#Ð"5##
ð80ACR185\ 83SL0Ł[ Porter and co!workers have shown that good stereoselectivity "79:0# can be
accomplished in the addition of t!butyl radicals to the acrylamide "4# ð78JA7200\ 80JA0680Ł[ Addition
of cyclohexyl radicals to the related trisubstituted acrylamide "5# is regioselective "a position# and
highly diastereoselective "014:0# ð89TL0568\ 80TL696Ł[ The main drawback with this method is the
di.culty of removing the auxiliary[ The oxazolidine auxiliary does not su}er from this problem as
it can be removed with acid hydrolysis without loss of chirality[ Addition of the cyclohexyl radical
to oxazolidine "6# gave an 79:0 mixture of stereoisomers ð80JA6677\ 81JA6553Ł[ Giese has shown that
high diastereoselectivities can be achieved in radical additions to methylacrylamides "7# followed by
trapping of the resultant radical "Scheme 3# ð82TL1334Ł[ This high 0\3!induction was rationalised
via attack opposite from the shielding pyrrolidine group in the conformation shown in Figure 5[ As
expected this model accurately predicts that the 0\3!induction will increase with the increasing size
of the initial radical "R = #[ Radical addition to activated alkenes containing other chiral auxiliaries
such as the imide "8# ð80JA4807\ 81JA6996Ł\ the camphor sultam "09#\ ð89JA5627\ 81JA6553Ł and the
bis"methoxymethyl#pyrrolidine "00# ð82TL1334Ł have also been explored[
MeO2C O MeO2C O
O
N MeO2C N MeO2C N
N O
O
But
(5) (6) (7)
O RHgCl, NaBH4, 20 °C O O
or
RBr, Bu3SnH, hν, 20 °C
N R N + R N
30–75%
(8) R = But 90 : 10
R = Me 67 : 33
Scheme 4
Attack
N • O
CH2R
Figure 6 Radical attack on methylacrylamides.

O OMe
O CO2Et O
N S O N
O N
N
O O
OMe
(9) (10) (11)
The vast majority of substrate!controlled 0\1!asymmetric inductions that have been studied
involve reactions of conformationally restricted conjugated radicals ð80ACR185\ 83SL0Ł[ Addition of
t!butyl radicals to diethyl citraconate "01# followed by reduction of the intermediate radical by
ButHgH furnishes essentially one diastereoisomer "threo:erythro ratio\ 39:0#[ This is in marked
contrast to the similar reaction with the cyclic alkene citraconic anhydride "02# which furnishes the
opposite diastereoisomer "07:0# after transesteri_cation "Scheme 4# ð80SL312Ł[ The 0\1!induction for
"01# has been explained by postulating that the conformation which leads to the lowest energy
transition state is that where A0\2 strain is minimised "Figure 6# ð80SL314Ł[ Attack of the radical
trapping agent from the less hindered face then leads to the observed product[ This explanation has
been used to rationalise the preferential formation of syn isomers from trapping of conformationally
restricted a!ester\ a!amide and a!benzyl radicals ð83SL0Ł[
CO2Et i i, ii
40:1
But CO2Et But CO2Et 1:18
+
EtO2C 80% EtO2C EtO2C 81% O O
O
(12) threo erythro (13)
i, ButHgCl, NaBH4, H2O, CH2Cl2; ii, EtOH, reflux, evaporation, K2CO3, EtI, acetone, reflux
Scheme 5
Attack
EtO2C OEt
•
O
H
But
Figure 7 Radical attack on diethyl citraconate.
The e}ect of the groups X "alkyl\ aryl\ OR\ OH\ F\ CO1Et#\ R0 "alkyl\ aryl# and R1 "alkyl\ H# on
the diastereoselectivity of additions to alkenes and other radical traps has been extensively inves!
tigated "Table 6# by\ for example\ Hart ð80SL301\ 81JOC3346Ł\ Guindon ð80JA8690\ 81JA3801\ 82TL4774Ł\
Giese ð81JOC2883\ 81SL331\ 81TL1562\ 82HCA330\ 82JA7474\ 82TL1334\ 82TL4774Ł\ Curran ð80TL5296\ 81JA3325\
81JA6996\ 82JA7474\ 82T3710\ 82T3730Ł and Porter ð80JA6991\ 80JA6677\ 80TL696\ 81JA6553Ł[ This has allowed
an assessment of the steric and stereoelectronic factors which a}ect the diastereoselectivity to be
probed ð80ACR185\ 83SL0Ł[ In general syn selectivity has been observed in the addition of chiral
secondary a!ester and chiral a!amide radicals to allyltributylstannane whereas anti selectivity has
been observed for reactions of conformationally restricted b!hydroxylated a!esters and amides[ This
anti selectivity has been shown to be solvent dependent "Table 6# ð81JOC3346Ł[ Asymmetric induction
in diester substrates can be increased by the addition of lanthanides such as Eu"fod#2 ð83CC876Ł[
The preference for syn products has been rationalised by considering that most radical reactions
have early transition states and so ground state conformations should be taken into account[ ESR
and theoretical models have indicated that the lowest energy conformation of ester!substituted
radicals is that which minimises allylic A0\2 strain "Figure 6# ð82TL4774Ł[ Attack then occurs at the
least hindered side of the molecule to produce syn products preferentially[ Work by Curran on the
addition to secondary and tertiary a!amide radicals has highlighted that models based upon ground
state conformations may be inadequate ð82T3710\ 82T3730Ł[ He emphasises the need to take into
account the steric energy cost to approaching reagents\ and that such factors could outweigh ground
state energy!based requirements[
Table 6 Relative 0\1!asymmetric inductions in allylation of conformationally restricted radicals[

X O X O
X O
SnBu3 R1 R3 R1 R3
• +
R1 R3
R2 R2
R2
syn anti
R0 R1 R2 X Solvent Yield Temperature syn:anti Ref[
")# ">C#
*
Me H OEt OMe THF 64 −67 3[8:0 81JOC3346
Me H OEt OH PhMe 64 −67 0:0[4 81JOC3346
Me H OEt OH THF 64 −67 2[2:0 81JOC3346
But H NMePh OAc PhH 53 14 8:0 80JOC3224
But H NMePh OH THF 53 14 0:02 80JOC3224
*
Asymmetric 0\3!induction in the addition of chiral radicals to alkenes has also been observed
ð80ACR185\ 83SL0Ł[ The reactions of conformationally restricted a!ester and a!amide radicals con!
taining chiral auxiliaries such as the "−#!7!phenylmenthol "03# ð82T5308Ł\ 1\4!dimethylpyrrolidine
"04# ð89JA5639Ł\ 1\4!dimethoxymethylpyrrolidine "05# ð81JA6996Ł\ camphor sultam "06# ð89JA5627Ł
and imide "07# ð81JA6996Ł have been investigated[ Addition of the imide radical "07# to allyl stannane
followed by hydrolysis gave the acid "08# as essentially one diastereomer "85:3# "Equation "1##
ð81JA6996Ł[ Similar selectivities were obtained for the other auxiliaries ð80ACR185\ 83SL0Ł[ Radical
allylation of the camphor sultam radical derivative "06# at −19>C was more selective than allylation
of the corresponding lithium enolate[
R
O NHBOC O O
Ph •
• N
O • N O
N • N
Et O S
O
R O O
(14) (15) R = H (17) (18)
(16) R = OMe
O I
O
N i, ii CH2
O (2)
OH
N
O
(S)-(+)-(19)
i, (0.35 M) allyltributylstannane (2.0 equiv.), AIBN, 5 mol%, C6H6, 80 °C, 4 h, 38%;

ii, LiOH•H2O, 30% H2O2, THF, 18 h, RT, 55%
Addition of the chiral radical "04# to ethyl acrylate furnished the desired product "19# in 73) de
"Equation "2##[ The diastereoselectivity could be increased if the radical was allowed to react with
the chiral acrylamide also derived from the same auxiliary\ to give the product "10# "Equation "3##
ð89JA5639\ 80JA6991Ł[ Presumably the increased selectivity is due to a {matched| double asymmetric
induction[
CO2Et
• CO2Et
N N (3)
Et 84% de Et
O O
(15) (20)
O
N
•
N (4)
Et 92% de
N O
O Et
O
(15) (21)
0[97[0[2[3 Methods for conducting radical reactions
"i# Introduction
For a given radical addition to an alkene to be successful certain reactivity and selectivity
requirements have to be met ðB!75MI 097!90Ł[ First\ the rate of addition ka of the radical "11# to the
alkene "12# must be faster than any destructive reactions of the radical such as radicalÐradical
recombination or disproportionation "Scheme 5#[ These latter unwanted reactions normally take
place at rates approximating to the di}usion!controlled limit\ and for additions to be synthetically
useful\ chain reactions are normally required[ In chain reactions the concentration of the reacting
radical is maintained at a lower concentration "normally 09−6Ð09−7 M# than that of the alkene or
alkyne partner "the concentration of the latter is variable but is typically of the order of 0 M#
ðB!62MI 097!91Ł[ This concentration di}erence enables radical additions to carbonÐcarbon multiple
bonds to be synthetically useful providing the rate of addition ka exceeds 091 mol−0 s−0[ Further
addition of this newly formed radical "13# to another molecule of alkene or alkyne "polymerisation#
is normally avoided by trapping the radical[ Trapping may be achieved with hydrogen donors
"Equation "4##\ heteroatom donors "Equation "5## or electron donors "Equation "6## "see Scheme 6#\
or intramolecular homolytic bond cleavage of a suitably substituted b leaving group "Equation "7##
"see Section 0[97[0[1[0#[ The rate of trapping must be faster than that for polymerisation but less
than that for trapping of the original radical "11# otherwise no addition of this radical will take
place[ Despite these limiting factors\ a number of successful chain reaction methods can be used[
For further discussion see ðB!75MI 097!90\ 80COS"3#604Ł[
Y Y Y
(23) • (23) •
R• R
ka Y kp
R
(22) (24) Y
Polymerization
Scheme 6
X–H
RH + X• (5)
• X–Y
R RY + X• (6)
Y
e–
(24) R– (7)
Scheme 7
X R • X –X• R
R• + (8)
"ii# Initiation of chain reactions
Radical chain reactions are normally initiated by either photolytic or thermal homolytic cleavage
of a chemical initiator such as a peroxide ð68COC"0#898Ł or an azo compound ð79CRV88Ł[ The most
common initiator is 1\1?!azobisisobutyronitrile "AIBN#\ which decomposes on heating "59Ð019>C#
or photolysis to two isobutyronitrile radicals[ The amount of initiator required in any given reaction
depends upon the e.ciency of the chain transfer step[ Chains with a slow chain transfer step will
require more initiator than faster ones[ For more information see ð80COS"3#604\ B!81MI 097!90Ł[
Triethylborane has also been used as an initiator to form Bu2Sn = from Bu2SnH ð78BCJ032Ł[
"iii# Chain reactions

"a# Tin hydrides[ This is one of the most common methods for facilitating radical reactions
ð76S554Ł[ Typically trialkyl! or triaryltin hydrides are reacted with alkyl iodides in the presence of
an activated alkene and AIBN ð74AG"E#442Ł[ The chain carrier is the Bu2Sn = "14# radical which
reacts with the alkyl iodide to form the desired nucleophilic alkyl radical "11#[ This radical then
adds to the activated alkene partner "12# to form the new electrophilic radical "13#\ which is trapped
by Bu2SnH to form the desired product "15# and regenerate the chain transfer reagent Bu2Sn = "14#
"Scheme 7#[ A full treatment of the factors which e}ect the outcome of tin!mediated cyclisations
has been published by Giese ðB!75MI 097!90Ł and Curran ð80COS"3#604Ł[
Y
(23)
R•
(22)
R X
Y
Bu3Sn• R •
(25) (24)
Y
R
(26) Bu3SnH
Scheme 8
Accurate kinetic rate measurements for the reactions of a number of radicals with alkenes and
hydrogen and halogen abstraction reactions are known[ For example\ competitive trapping of the
cyclohexyl radical "16# by Bu2SnH "kH2×094 M−0 s−0# "instead of addition to methyl acrylate
"1×095 M−0 s−0## is generally avoided by employing a low concentration of the hydride donor with
respect to the alkene "Scheme 8# ð80COS"3#604Ł[ Either a huge excess of the alkene can be used\ or a
slow dropwise addition of the reducing agent can be employed via a syringe pump[ Alternatively\ a
low concentration of Bu2SnH can be generated by the reduction of a catalytic amount of Bu2SnCl
by NaBH3 or NaCNBH2 in situ ð52JOC1054\ 75JA292\ 75JOC2615Ł[ For the success of the next step the
reverse is required\ that is\ radical "17# must be trapped before competitive addition of another
molecule of methyl acrylate can occur[ This can be accomplished because the electronic pairing
between the electrophilic:ambiphilic radical "17# and methyl acrylate is now mismatched "see Sec!
tions 0[97[0[2[1[1 and 0[97[0[2[1[2# thus slowing the rate of the polymerisation reaction[ The yields of
intermolecular addition reactions of nucleophilic radicals to electron!poor alkenes can be increased if
the alkene becomes more activated[ This is because the rate of addition ka is increased while the rate
of polymerisation kp is decreased[
Other radical precursors such as bromides ð77JOC0321Ł\ selenides ð78T824Ł\ xanthates ð73AG"E#58Ł
and tertiary nitroalkanes ð74T3902Ł can be used^ however\ chlorides are not generally applicable as
precursors because abstraction by the Bu2Sn = radical is slow enough for competitive hydro!
stannylation of the partner alkene or alkyne to be observed[ Iodides are the precursors of choice
since abstraction by Bu2Sn = radicals occurs at rates approaching the di}usion!controlled limit
ð73JA232Ł[ Primary\ secondary and tertiary alkyl\ vinyl\ allyl\ allenyl and aryl radicals have all been
CO2Me CO2Me
• •
Bu3SnH CO2Me Bu3SnH
ka = 2 x 106 M–1 s–1 kH = 3 x 105 M–1 s–1
(28) (27)
Scheme 9
prepared using this method ð74AG"E#442\ B!75MI 097!90\ 80COS"3#604Ł[ The tin method has been used
widely in the formation of carbonÐcarbon bonds ð74AG"E#442Ł\ as in the synthesis of natural products
ð80CRV0126Ł and sugar derivatives ð78AG"E#858Ł[ The reaction of electrophilic radicals with electron!
rich alkenes can also be accomplished by the tin method ð75CB333Ł[
"b# Germanium hydrides[ Like tin hydrides\ germanium hydrides can mediate chain reactions
between radicals prepared from alkyl iodides and bromides with alkenes[ Whereas tri!
alkylgermanium radicals are as reactive as trialkyltin radicals in halogen abstractions the cor!
responding hydride is a much poorer hydrogen donor ð74JA3483\ 76JOC2498\ 77T5184Ł[ This
characteristic can be useful for minimising the amount of reduction product obtained in radical
addition reactions ð80COS"3#604Ł[
"c# Silicon hydrides[ Organotin hydrides are extremely toxic ðB!74MI 097!90Ł and often di.cult to
remove from the reaction products ð89S337Ł[ Silicon hydrides would be a preferable alternative^
however\ the Si0H bond is much stronger than the Ge0H or Sn0H bond\ and hydrogen donation
from simple alkyl silanes is too slow to maintain chains ð75JA3021Ł[ Tris"trimethylsilyl#silane
"TTMSS# has a relatively weak Si0H bond "68 kcal mol−0\ 229 kJ mol−0#\ and this enables it to
take part in radical chain reactions as a hydrogen donor ð76JA4156\ 77JOC2530\ 78TL570Ł[ Despite the
relative weakness of the Si0H bond in TTMSS\ it is still stronger than in germanium or tin hydrides\
and consequently it is a poorer hydrogen atom donor ð81ACR077Ł[ This often enables increased
yields of addition products to be formed at the expense of the undesired reduction products[
Addition of the cyclohexyl radical "16# to methyl acylate in the presence of TTMSS gave the desired
product "18# in 74) yield "Equation "8## ð78TL570Ł[ Roberts has shown that simple trialkylsilanes
"Si0H bond energy 89 kcal mol−0\ 266 kJ mol−0# can be used as hydrogen donors in radical chain
reactions\ providing a suitable polarity reversal catalyst is present "Scheme 09# ð78CC0276\ 89TL4982\
80JCS"P0#092Ł[ Other silicon hydrides have been used with varying success ð81ACR077Ł[
CO2Me
•
(TMS)3SiH, (TTMSS)
(9)
CO2Me
(27) (29)
R• + XSH RH + XS•
XS• + R3SiH XSH + R3Si•
Scheme 10
"d# Carbon hydrides[ The C0H bond strength is even greater than the Si0H bond strength\ and
so only activated C0H bonds such as those adjacent to carbonyl groups are capable of sustaining
a radical chain process[ Unlike the examples already mentioned\ an excess of donor reagent does
not cause problems of premature reduction of the initial radical prior to the addition to the alkene[
This is because reduction of the initial radical regenerates the trapping agent and another starting
radical[ Only suitably activated C0H bonds can be used in synthetically useful procedures[ Hence\
the electrophilic radical "29# undergoes addition to the electron!rich alkene "20# in the presence
of di!t!butylbenzoyl peroxide "DTBP# as a radical initiator "Equation "09## ð50IZV0988Ł[ Other
electrophilic radicals adjacent to esters and lactones have also been employed ðB!75MI 097!90Ł[
O O C8H17 O
DTBP (31)
C10H21 (10)
•
71%
(30)
"e# Mercury hydrides[ The use of mercury hydrides as donor reagents was pioneered by Giese
and co!workers\ who have shown their wide applicability in intermolecular radical addition reactions
ð74AG"E#442\ B!75MI 097!90\ 77CRV376Ł[ The Hg0H bond is weaker than the corresponding Sn0H
bond\ and mercury hydrides are therefore better hydrogen atom donors ð73CB2059Ł[ Consequently\
the rate of reduction kH of the initial radical "11# is often faster than the rate of addition ka to the
desired alkene "12#[ Radical additions using this method are therefore limited to very reactive
alkenes only "Scheme 00#[ However\ there are a number of advantages to using the mercury method[
First\ the reagents are prepared in situ\ and reactions can be accomplished under mild conditions[
Second\ no thermal or photochemical initiation is necessary[ This is due to the spontaneous
decomposition of the reactive mercury hydrides[ Third\ mercury hydrides act as both the radical
precursor and the radical trap^ _nally\ reactions carried out using this method are easier to work
up and purify than those utilising the corresponding tin or germanium hydrides ð80COS"3#604Ł[
Y
NaBH4 (23) • RHgH
RHgX [RHgH] R• R R + R• + Hg0
Y Y
(22) ka
(24) (26)
kH RHgH
RH + R• + Hg0
X = halide or acetate
Scheme 11
The mercury hydride reagents are normally generated in situ by the reduction of alkyl mercury
halides or alkyl mercury acetates[ Alternatively\ alkyl mercury hydrides can be prepared by hydro!
boration of alkenes\ followed by transmetallation of the resulting alkyl boranes with mercuric
acetate followed by reduction[ This enables alkenes to couple with other alkenes ð70AG"E#854Ł[ Use
can be made of the regioselectivity and stereoselectivity of the hydroboration reactions of alkenes
to couple the terminal alkene unit in "21# to methyl vinyl ketone "MVK# selectively "Equation "00##
ð70AG"E#854Ł[ For a comprehensive account of this methodology see ð77CRV376Ł[
i, (C6H11)2BH
ii, Hg(OAc)2 O
iii, NaBH4
+ (11)
O 50%
(32)
"f# The Barton method[ One disadvantage with the hydrogen atom donor reagents is that the
radical chain is terminated by reduction[ Trapping with a heteroatom enables a functional handle
to be introduced into the _nal product[ The best known method for conducting this type of group
transfer reaction was introduced by Barton and his co!workers ð76MI 097!90\ B!81MI 097!90Ł[ Homolysis
of thiohydroxamate esters "22# either photolytically with a tungsten lamp or thermally generates
carboxy radicals which undergo loss of CO1 to form nucleophilic radicals "11# ð74TL4832Ł[ Addition
to activated alkenes or alkynes followed by trapping of the new radical as the pyridyl sul_de "23#
furnishes the functionalised products "Scheme 01#[ Primary\ secondary and tertiary radicals can be
prepared in high yield using this method ð76MI 097!90Ł[ With unreactive alkenes trapping of the
initial radical "11# before addition can become competitive[ To maximise formation of the addition
products an excess of alkene is normally required[ Good yields are only obtained for activated
alkenes\ alkynes and doubly activated internal alkenes ð75JCS"P0#28Ł[ Other classes of thio!
hydroxamate esters have been evaluated for their e.ciency in carrying out these transformations\
with varying success ð75JCS"P0#28\ 81T6980Ł[ The thiohydroxamate esters can be prepared from the
corresponding carboxylic acids by a number of methods] a procedure utilising dipyridyl disul_de
and tributylphosphine has been recommended ð81T6972Ł[ The resulting pyridyl sul_des are useful
synthetic precursors for a number of functional groups[ Barton has developed a two!carbon "Equa!
tion "01## ð82TL5494Ł and a three!carbon "Equation "02## ð81TL4906Ł homologation procedure giving
rise to acids\ amides\ esters\ aldehydes and ketones[
O
N
R O
Y S
O
heat or hν (23) • (33)
N R• R
R O Y N S
–CO2 (22) ka
(24) R
S Y
(33) (34)
Scheme 12
CN
CF3
i, hν, 0 °C O
O
O ii, LiAlH4
iii, NaIO4, CHCl3
N Ph CHO (12)
Ph O 78%
S
CO2Et
CF3
i, hν, 0 °C O
O O O
ii, K2CO3, Me2CO, H2O, RT
MeO N HO (13)
O OH
83%
O S O O
"`# The borane method[ Alkyl radicals "11# can be generated from trialkyl boranes "24# by
reaction with oxygen ð61AG"E#581Ł[ The adduct radicals are trapped as boron enolates "25# and can
undergo further reactions such as aldol reactions "Scheme 02# ð62JA856Ł[ Addition products "e[g[\
26# are limited to those from reactions with activated alkenes such as a\b!unsaturated aldehydes
and ketones[ Polymerisation is observed for additions with nitrile! and ester!activated alkenes\
presumably because the adduct radicals polymerise far quicker than they add to the borane
ð61AG"E#581Ł[ A disadvantage of this method is that only one alkyl group is transferred from boron^
however\ modi_cation of the ligands on boron can circumvent this problem ð60JA2666Ł[ Atom
transfer additions have also been initiated by triethylborane either in the presence of Ph2SnH or in
its absence[ Hence\ addition of three equivalents of t!butyl iodide to MVK in the presence of
triethylborane gave the desired adduct "27# and the by!product "28# arising from addition of an
ethyl radical to the alkene after quenching with methanol "Equation "03## ð77TL0930Ł[ In 0878\
Nozaki extended this methodology to additions of alkyl radicals on to alkynes ð78TL2044Ł[ The
radicals are generated from iodides and undergo smooth atom transfer additions to give iodoalkenes
in good yield "Equation "04##[ This method has also been used to initiate the addition of t!butyl
radicals to chiral unsaturated keto!sulfoxides in an asymmetric radical addition ð82JA353Ł[
Et3B, MeOH But Et

ButI + + (14)
O O O
(38) (39)
79% 5%
EtI, Et3B, hexane

TMS Et
TMS (15)
84% I
R2CHO
R1 O
aldol R1 OBR12
HO R2 (36) O
R1•
(22)
R1 OBR13 R1 O•
(37)
R13B
(35)
Scheme 13
"h# The fra`mentation method[ As already mentioned in Section 0[97[0[1[0\ relatively weak
bonds such as C0Br\ C0SnR2 and C0SR\ can fragment if they are located b to a radical[ This
unimolecular process is generally fast and liberates a radical as a leaving group which can propagate
the chain[ This method for conducting radical chain reactions has the advantage over the metallic
hydride donors in that the problem of reduction of the initial radical "11# no longer exists and that
the process is not reductive[ Consequently\ this method is useful for conducting radical additions
to unactivated alkenes and for retaining a functionality handle in the molecule after addition
ð77S378Ł[ The use of allyl and vinyl stannanes has become popular for generating the Bu2Sn = as the
chain carrier "Equation "05## ð71JA4718Ł[ Although the procedure is very versatile\ crotyl stannanes
are not normally tolerated ð74T3968Ł[ Johnson has shown the applicability of allyl cobalt complexes
for carrying out similar reactions\ and demonstrated that methyl substitution at the allylic sites is
tolerated "Equation "06## ð72ACR232Ł[
SnBu3
O O
OBn AIBN catalyst, toluene, 80 °C OBn
(16)
Br 76%
MeO O MeO O
EtO2C Co(dmgH)2py EtO2C

•
R + EtO2C (17)
EtO2C R
dmgH = dimethylglyoximate
"i# The atom transfer method[ Photolysis of the alkyl iodide "39# in the presence of the alkene
"30# and a catalytic amount of "Bu2Sn#1 furnishes the radical addition product "31#\ where the
product radical has been trapped by iodine atom transfer from another molecule of the starting
material "Equation "07## ð78JA5154\ 80COS"3#604Ł[ The initial radical is formed either by direct photo!
lytic cleavage of the iodide or from abstraction by the Bu2Sn = [ This method is particularly suited
for the formation of adducts where the rate of addition of the radical to the alkene is slow
ð78JOC2039Ł[ This is because\ unlike the metal hydride or Barton methods\ atom transfer from the
starting iodide to the initial radical reproduces both entities\ that is\ the initial radical is not trapped
before addition[ The limiting factor is the rate of atom transfer ð78JOC0715Ł[ If this is too slow then
polymerisation can occur[ One way to facilitate fast atom transfer steps is to use reactive iodides as
radical precursors and to ensure that the adduct radical is less stable than the initial radical "i[e[\
the initial radical is stabilised#[ These criteria generally restrict this type of reaction to the addition
of electrophilic radicals to electron!rich alkenes[
I
CO2Me CO2Me
10% (Bu3Sn)2, PhH, hν
+ CO2Me (18)
I CO2Me 68%
(40) (41) (42)
"iv# Nonchain reactions

"a# Orànocobalt `roup transfer[ Photolysis or thermolysis of the relatively weak CoIII0C bond
"07Ð14 kcal mol−0\ 64Ð094 kJ mol−0# in RCo"salen#\ RCo"salophen# or RCo"dmgH#1py complexes
"salen "N\N?!bis"salicyclidene#ethylenediamino#^ salophen "N\N?!bis"salicyclidene#o!phenylenedi!
amino#^ dmgH "dimethylglyoximato#^ py "pyridine## occurs homolytically to generate an alkyl
radical "11# and a CoII complex ð77CSR250Ł[ Addition of this radical "11# to an alkene "12# fol!
lowed by retrapping with the CoII complex furnishes a new alkyl CoIII complex "32# that can
undergo elimination of CoIIIH to form alkenes "33# "Scheme 03#[ The precursor alkyl cobalt com!
plexes can be prepared by reaction of alkyl halides or tosylates with supernucleophilic CoI complexes
prepared in situ ð65AG"E#306Ł[ Branchaud and co!workers have used this method to produce the
sugar derivative "34# from the organocobaloxime "35# "Equation "08## ð77TL056Ł[ In this case the
unsaturated product is formed by b!elimination of HCoIII"dmgH#1py by {dehydrocobaltation|\ from
the intermediate cobaloxime[ The more activated the radical alkene acceptor\ the more facile is this
elimination process[ The sp1Ðsp1 coupling of two alkenes via a {hydrocobaltationÐdehydro!
cobaltation| procedure has been demonstrated by Pattenden and co!workers "Scheme 04#
ð89JCS"P0#1698Ł[ The cobaloxime radical precursor "36# is formed by the addition of cobalt and
hydrogen across the activated alkene "37# ð77CC0009Ł[ Photolysis in the presence of styrene followed
by dehydrocobaltation gave the addition product[
Y
(23) • CoIII
IIICo
hν R CoII –CoIIIH R
R R• + CoII R Y
Y
Y
(22) (24) (43) (44)
Scheme 14
Co(dmgH)2py Ph
Co(dmgH)2py
Ph
O hν, 95%, EtOH
O O (19)
AcO OBn Ph
85%
AcO OBn AcO OBn
AcO OAc
AcO OAc AcO OAc
(46) (45)
Co(dmgH)2•2H2O heat (sunlamp)

py(dmgH)2Co CN
CN CN Ph
H2, MeOH, NaOH (aq.) Ph
(48) (47)
Scheme 15
Reductive cobalt!mediated additions have been achieved with a catalytic amount of reduced
vitamin B01 in the presence of an electrochemical or chemical reductant "such as zinc# ð72JA6199Ł[
As in the oxidative cases the radical precursors are normally alkyl halides\ and the initial radicals
are formed by homolytic cleavage of CoIII alkyl complexes[ Radical addition followed by reduction
and reformation of the CoI complex completes the cycle[
"b# Electron transfer processes[ Nucleophilic alkyl radicals can be oxidised to cations by a number
of metallic species[ For a review on the use of titanium\ vanadium\ chromium\ niobium\ manganese\
iron\ cobalt\ copper and ruthenium complexes in oxidative and reductive radical reactions\ see
ð83CRV408Ł[ The most widely studied metal!mediated method for conducting radical additions to
alkenes involves the use of two equivalents of MnIII"OAc#2 in conjunction with the desired alkene\
and an activated radical precursor "Equation "19## ð63JA6866\ 63JOC2345Ł[ The radical precursor
"normally an enol derivative of a b!keto ester\ b!keto acid\ b!diketone\ ester\ ketone or an aldehyde#
is oxidised to the enol radical\ which can undergo addition to an electron!rich alkene ð77JOC1026Ł[
Further oxidation of this newly formed nucleophilic radical by a second equivalent of MnIII"OAc#2
yields the corresponding carbocation\ which can undergo reaction with a nucleophile to furnish the
lactone "38# ð76TL064Ł[ Alternatively\ if no suitable nucleophile is present then elimination of a
proton may result ð72JOC0262Ł[ MnIII"OAc#2 is slow to promote the oxidation of 1> or 0> nucleophilic
radicals to carbocations and so CuII"OAc#1 is often added to perform this transformation[
CN CN NC
NC
Mn(OAc)3 Mn(OAc)3
HO2C HO2C (20)
HO2C O
• + O
(49)
0[97[0[3 Intramolecular Radical Additions
0[97[0[3[0 Introduction
This section is organised similarly to that on intermolecular additions[ The reader is strongly
recommended to read the previous section for a more detailed account of the mechanisms and
principles involved in carrying out radical reactions and also to consult the reviews by Curran
ð77S306\ 77S378\ 80COS"3#604\ 80COS"3#668\ 80CRV0126Ł\ Giese ðB75!MI 097!90Ł and Ramaiah ð76T2430Ł[
Radical cyclisation reactions are normally easier to carry out than intermolecular radical additions[
This is because most cyclisations proceed at a much quicker rate "kc 4!hexenyl cyclisation\ 1×095 s−0#
ð76JOC2498Ł than in intermolecular additions[ Like intermolecular reactions\ the rate of cyclisation
of the initial radical and the rate of trapping of the _nal radical must be greater than termination
of the chain by unwanted side reactions[ One requirement is that the initial radical must not be
trapped before cyclisation has occurred[ This is not normally a problem even though the initial
radical and the cyclised radical often have the same nucleophilicity[ In practice\ low concentrations
of trapping agent can be employed but are not normally required unless the cyclisation is particularly
slow[
0[97[0[3[1 The 4!hexenyl radical] regioselectivity

The factors which e}ect radical cyclisation reactions are best illustrated by ring closure of the
4!hexenyl radical "49# "Equation "10##[ The 4!hexenyl radical cyclises at 14>C to furnish both the
4!exo tri` product "40# and the 5!endo tri` product "41# in a ratio of 87 ] 1[ The rate of cyclisation has
been measured and found to be of the order of 1×095 s−0 for the 4!exo cyclisation and 3×094 s−0
for the 5!endo cyclisation ð76JOC2498Ł[ The reaction itself is highly exothermic\ irreversible and
under kinetic control[ In contrast to the intermolecular additions already described\ the radical
acceptor does not need to be activated\ although cyclisation is faster for activated alkenes[ The
factors which determine the regioselectivity of the cyclisation have been the focus of considerable
theoretical attention[ The reader is directed to reviews of Beckwith ð74T2814Ł and Houk ð76JOC848Ł
or the synopsis by Curran ð80COS"3#668Ł[ In brief\ MM1 and STO!2G calculations seem to indicate
that the less strained transition state is that which leads to the smaller ring\ and that cyclisation
occurs via a strain!free\ chair!like transition state "Figure 7#[ The same conclusion has been reached
by Baldwin using a vector analysis approach ð65CC623Ł[
• •
•
+ (21)
(50) (51) (52)

98 : 2
Figure 8 The chair-like 1,5-transition state.
The e}ects of substituents on the outcome of cyclisation of the 4!hexenyl radical have been
thoroughly investigated[ A methyl group at the reacting alkene centre will reduce the rate of
cyclisation on to that carbon atom primarily due to steric e}ects ð74T2814Ł[ Consequently\ sub!
stitution at the 4 position furnishes mainly the 5!endo product "Equation "11##[ Substitution at the
1\ 2 and 3 positions increases the rate of 4!exo cyclisation\ probably by raising the energy of the
ground state relative to the transition state[ Substitution of alkyl groups at the reacting radical
centre has little e}ect on the outcome of the cyclisation "Equation "12##[ The incorporation of
heteroatoms "such as oxygen or nitrogen# in the 2 position of the chain causes a marked increase in
the rate of cyclisation\ with the 4!exo product predominating "Equation "13##[ This e}ect is due to
better overlapping of the radical with the alkene partner in the 4!exo transition state primarily due
to the smaller bond angles and bond lengths associated with the carbonÐheteroatom bonds than
with the carbonÐcarbon bonds ð74T2814Ł[ Conversely\ incorporation of a silicon atom into the chain
favours the 5!endo product "Equation "14## ð74T2868Ł[
•
• •
+ (22)
33 : 66
•
• •
+ (23)
99 : 1
•
•
(24)
O
O
• •
(25)
Si Si
Me Me Me Me
Electrophilic radicals with two radical stabilising groups often undergo reversible cyclisations to
furnish 5!endo products preferentially ð60ACR275Ł[ 5!endo Products have also been observed to form
preferentially in radical cyclisations of keto!substituted radicals ð78JOC2039Ł[
0[97[0[3[2 Stereoselectivity in substituted 4!hexenyl radical cyclisations

The stereochemical outcome of the cyclisation of 0!\ 1!\ 2! and 3!substituted 4!hexenyl radicals
has been studied and has been rationalised by the model proposed by Beckwith ð72AJC434Ł[ The
cyclisation occurs via a chair!like transition state with the substituents occupying pseudoequatorial
positions "Figure 7#[ Hence\ cyclisation of 1! and 3!substituted 4!hexenyl radicals gives trans products
while cyclisation of 2!substituted 4!hexenyl radicals gives cis products predominantly "Equation
"15## ð74T2814Ł[ Small alkyl substituents at C!0 generally give cis products while larger alkyl groups
and ether substituents at C!0 predominantly give trans products[ Other studies indicate that the
minor diastereomeric products are produced from less stable chair and boat transition states
ð78JA0648Ł[ Rajanabubu and co!workers have shown that the directing e}ect of a substituent at the
3 position is important in determining the stereochemical outcome of cyclisations which lead to
fused rings ð78JA0648Ł[ Cyclisation of the radical "42# gives the trans!0\1 product "43#\ presumably
via a low!energy boat conformation "Equation "16##[
• •
•
+ (26)
R1 R1 R1
R2
R2 R2
R1 = H, R2
= Me 75 : 25
R1 = Me, R2 = H 17 : 83
•
O • H
O
OBn (27)
Ph O OBn
H Ph O
OBn H OBn
(53) (54)
0[97[0[3[3 Allyl\ vinyl and aryl cyclisations

The cyclisation of aryl and vinyl radicals is much more rapid than the corresponding alkyl radicals
"kc ¼2×097 s−0# and consequently higher yields are often obtained in simple 4!exo cyclisations
ð74T2814Ł[ A vinyl radical cyclisation is a useful transformation because the product contains a
double bond that can be further functionalised if needed "Equation "17## ð77S306Ł[ Vinyl radicals
can be prepared from vinyl halides but are harder to form than alkyl radicals due to the increase in
strength of the sp1 carbonÐhalogen bond[ Bromo! and iodo!substituted alkenes give the best results\
with less reactive precursors giving lower yields ð72TL0760Ł[ The geometry of the initial vinyl halide
precursors is irrelevant as the barrier to inversion of the vinyl radical is low "Scheme 2# ð81TL2432Ł[
The exo ] endo ratio is normally dependent upon the concentration of any added radical trap[ For
example\ cyclisation of "44# with a 9[91 M concentration of Bu2SnH gave "45# and "46# in a ratio of
64 ] 14\ while cyclisation with a higher concentration "0[6 M# gave the 4!exo product exclusively
ð75TL3418Ł[ This is because at low Bu2SnH concentrations the cyclised radical "47# can undergo a
rearrangement to give the ring!expanded product "48# "Scheme 05#[
Br
Bu3SnH
+ (28)

(55) (56) (57)
•
• •
3-exo

(58) (59)
Scheme 16
Allyl radicals can undergo radical cyclisations\ although they are not as reactive as their vinyl
radical counterparts "delocalisation energy 03[9Ð03[4 kcal mol−0\ 47[5Ð59[6 kJ mol−0# ð77JA5800Ł[
Allenyl radicals have been used in carbocyclisations to form vinylidene!substituted cyclopentanes
ð82TL4140Ł[
Aryl radical cyclisation has become a popular method for the formation of benzo fused _ve! and
six!membered rings "Equation "18## ð80COS"3#668Ł[ Aryl radical cyclisations can been directed
5!endo by steric crowding on the 4!exo carbon ð89TL1204Ł or by cyclisation on to suitably activated
alkenes[ Hence\ Glover and co!workers have shown that 5!endo cyclisation of "59# is faster
"kc 3[5×097 s−0# than 4!exo cyclisation "kc 0[4×097 s−0# at 79>C ð82JOC1004Ł[ The ratio of
products was found to be dependent upon the nitrogen substituent[ Radical cyclisation of precursors
that contain suitably activated rings can undergo a ring expansion in a process related to that
observed with vinyl radicals[ This process is similarly dependent upon the concentration of the
radical trapping agent employed "Equation "29## ð75TL1722Ł[
OMe OMe •
• (29)
O O
•
N
Bu
(60)
CHO CHO CHO

Br
Bu3SnH, AIBN
+ (30)
OMe OMe OMe

0.15M 91 : 9
0.02M 43 : 57
0[97[0[3[4 Formation of six!membered rings

Cyclisation of the 5!heptenyl radical "50# is possible although it is less regioselective than cyclis!
ation of the 4!hexenyl radical "Equation "20##[ The rates for 5!exo cyclisation at 14>C "kc 4×092
s−0# and 6!endo cyclisation "kc 6×091 s−0# are much slower than for the corresponding 4!exo and
5!endo cyclisations ð63CC361Ł[ Cyclisations can be accomplished if low concentrations of trapping
agents are used or atom transfer cyclisations are utilised[ One competing reaction is often reduction
of the initial radical by intramolecular 0\4!hydrogen transfer to form the allyl radical "Equation
"21## ð77JA4899Ł[ This problem can be addressed if suitable substituents are located on the chain to
block the hydrogen transfer reaction or if the alkene component is activated[ Aryl and vinyl radical
0\4!hydrogen transfer processes are more exothermic than for simple alkyl radicals\ and Curran and
his co!workers have developed this facile rearrangement for the preparation and cyclisation of many
heterosubstituted radicals ð77JA4899\ 82JA5940Ł[
• • •
+ (31)
(61) 85 : 15
•
•
(32)
0[97[0[3[5 Formation of other ring sizes
6!exo and 7!exo Alkyl radical cyclisations are disfavoured processes and are not normally syn!
thetically useful[ The best method for the formation of medium!sized rings utilising a radical strategy
is via ring expansion of smaller rings by a process analogous to that observed in vinyl radical
cyclisations "see Section 0[97[0[3[3#[ For a description of these procedures the reader is directed to
the excellent review by Dowd ð82CRV1980Ł[ 6!endo and 7!endo Aryl radical cyclisations have been
reported using Mn"OAc#2 to form the cycloheptane "51a# and the cyclooctane "51b# "Equation "22##
ð80T7552Ł[ Larger rings can be prepared by a radical macrocyclisation approach[ This has been
shown to be successful for 00Ð05!membered rings\ although an activated radical acceptor is required
ð75JA1676Ł[ An endo attack is the natural mode for macrocyclisation\ and a number of natural
products have been successfully synthesised utilising this approach "Equation "23## ð81JCS"P0#0202Ł[
Cyclisation on to both activated alkenes and alkynes is possible ð81T2302Ł[ Electrophilic radicals
prepared from iodomalononitriles have been used in macrocyclisations on to unactivated alkenes
using atom transfer conditions ð89JA8390Ł[ Chiral induction in a radical macrocyclisation process
has been reported ð78JA7298Ł[
O Cl O
Cl
Mn(OAc)3 (2 equiv.)
n( ) CO2Et n( ) CO2Et (33)
Cu(OAc)2 (1 equiv.), AcOH
(62) a; n = 1, 58%
b; n = 2, 47%
O O
Bu3SnH
(34)
40%
I
(E):(Z) = 4:1
Cyclisation of 2!butenyl and 3!pentenyl radicals to produce cyclopropanes and cyclobutanes\

respectively\ is possible in theory\ although both these reactions are reversible with the equilibrium
generally favouring the open!chain radicals "Scheme 06# ð80COS"3#668Ł[ Cyclisation and trapping of
2!exo and 3!exo cyclisation products is possible if the cyclised radical is particularly stable with
respect to the starting open!chain radical[ Cyclisation and trapping with Bu2SnH to form cyclo!
propanes is possible when the cyclised radical is stabilised by virtue of it being allylic ð83JOC607Ł\
benzylic ð81JOC3173Ł or a to a keto group ð81TL6296Ł[ Vinyl cyclopropanes have been formed by
2!exo cyclisation followed by fragmentation of a PhS = "Equation "24## ð83TL3420Ł[ Cyclopropane
formation has also been reported in alkenes having intrinsically large amounts of ring strain
with favourable geometric alignment of the homoallylic radical and the alkene "Equation "25##
ð82TL1980Ł[
• •
•
•
Scheme 17
PhS
0.02 M (Bu3Sn)2, AIBN, hν

(35)
54%
N
N Ts
Ts
0.03 M (Bu3Sn)2, AIBN, hν

Br (36)
100%
0[97[0[3[6 Methods for facilitating radical cyclisation reactions
"i# Introduction
The following sections indicate the di}erent methods available to facilitate radical cyclisation
reactions[ The reader is strongly advised to _rst read Sections 0[97[0[3[0 and 0[97[0[3[1 to become
familiar with the factors which a}ect the success of radical chain reactions[
"ii# Radical chain methods

"a# Tin hydrides and èrmanium hydrides[ The most commonly employed method to facilitate
radical cyclisation reactions is the tributyltin hydride method ðB!75MI 097!90\ 76S554\ 80COS"3#668\
80CRV0126Ł[ The mechanism for the chain reaction has already been mentioned "see Section
0[97[0[2[3"ii#"a##[ Typically\ trialkyl! or triaryltin hydrides and AIBN are reacted with alkyl\ vinyl
or aryl halides that contain a suitably positioned radical acceptor "Scheme 07#[ The chain carrier is
the Bu2Sn= radical which reacts with alkyl\ vinyl or aryl halides "52# to form carbon!centred radicals
"53# ð74AG"E#442Ł[ Due to the increased rate of radical addition in intramolecular reactions compared
to intermolecular addition\ cyclisation of nucleophilic and electrophilic radicals can be achieved
without the need to activate the radical acceptor[ Trapping of the initial radical "53# with Bu2SnH
before cyclisation can be avoided if low concentrations of the reagent are employed "typically
9[91 M concentrations are required for e.cient cyclisation of alkyl radicals#[ For particularly slow
cyclisations very low concentrations of Bu2SnH are often required ð75JA1676Ł[ These conditions can
be accomplished by utilising either a syringe pump addition of Bu2SnH or by using one of the
catalytic procedures ð52JOC1054\ 75JA292\ 75JOC2615Ł[
•
X
Bu3SnH, AIBN kc Bu3SnH
•
(63) (64)
Bu3SnH
Scheme 18
The rate of 4!exo or 5!exo cyclisation of vinyl and aryl radicals is much faster than the cor!
responding alkyl radicals\ and these cyclisations can be accomplished in high yields with the
minimum of reduction products ð77S306Ł[ Allenyl radicals have also been generated and cyclised
successfully using this method ð82TL4140Ł[ Various radical precursor groups can be employed\
with the order of abstraction by Bu2Sn = being I×Br×SePh¼OC"S#Me×Cl×SPh ð80CRV0126Ł[
Iodides are the precursors of choice since abstraction by Bu2Sn= radicals occurs at rates approaching
the di}usion!controlled limit ð73JA232Ł[ Thiophenyl precursors have been used where halo pre!
cursors were inconvenient and di.cult to prepare or were unstable[ For example\ acylamino radicals
have been generated in this manner ð73JA7198Ł[ The mild and neutral nature of radical cyclisations
mediated by Bu2SnH is particularly suited for transformation of sugars and sugar derivatives[
Various _ve! and six!membered ring functionalised carbocycles have been prepared by 4!exo or 5!
exo radical cyclisation of sugar derivatives "Equation "26## ð75JA2091Ł[ This is a particularly powerful
strategy for the formation of highly functionalised frameworks ð82CRV1668Ł[ The tin method has
been used frequently to prepare heterocyclic units ð80COS"3#668\ 80CRV0126Ł[ g!Lactones are easily
prepared by the reductive cyclisation of unsaturated bromoacetals followed by Jones oxidation
"Equation "27## ð72JA2630Ł[ The increased rate of 4!exo cyclisation observed for heteroatom!sub!
stituted chains leads to particularly high regioselectivity[ This accelerating e}ect can even overcome
factors that might otherwise lead to competitive 5!endo cyclisation "Equation "28## ð74JOC4519Ł[
Cyclisation of chains with oxygen in the 0\ 1\ 2 and 3 positions have all been reported[ Numerous
cyclisations to form _ve! and six!membered nitrogen heterocycles have also been achieved ðB!75MI
097!90\ 80COS"3#668\ 80CRV0126\ B!81MI 097!90Ł[ Stannylation of alkynes can be used to generate vinyl
radicals that may undergo cyclisation on to suitably positioned acceptors "Equation "39## ð78TL114Ł[
Hydrostannylation normally occurs at the less hindered terminal end of alkynes[ Vinyl radicals can
also be generated from vinyl halides utilising the tin method[ Yields were shown to increase when
moving from chloro\ via bromo\ to iodo precursor groups ð72TL0760Ł[ Aryl radical cyclisations have
also been successfully carried out using the Bu2SnH method\ as have radical macrocyclisations and
radical transannular reactions ð80COS"3#668Ł[
OBn MeO2C OBn

OH OH
BnO OBn Bu3SnH (5 equiv.), AIBN, C6H6, 85 °C
(37)
MeO2C
85% OBn
Br OBn
H
O OEt i, 0.02 M Bu3SnH, AIBN, 80 °C
ii, Jones oxidation
O
O (38)
81%
Br
H
Br
Bu3SnH, 80 °C, C6H6, AIBN
(39)
N 85% N
Ts Ts
MeO2C MeO2C
Bu3SnH, 80 °C, C6H6, AIBN
(40)
75%
OH OH
SnBu3
Trialkylgermanium hydrides have been less widely employed in radical cyclisation reactions[ The
mechanism of the radical chain reaction is identical to that of cyclisation with Bu2SnH\ the major
di}erence being that Bu2GeH is a far less reactive hydrogen atom donor ð76JOC2498Ł[ This reagent
is useful for mediating relatively slow cyclisations[
"b# Silicon hydrides[ Trialkyltin hydrides react with many functional groups via a radical chain
mechanism and play an important role in synthesis[ However\ among the disadvantages su}ered by
organotin hydrides are] "i# they are extremely toxic ðB!74MI 097!90Ł\ "ii# they are often di.cult to
remove from the reaction products ð89S337Ł and "iii# they are expensive[ Organosilicon hydrides are
a desirable alternative^ however\ the Si0H bond is much stronger than the Sn0H bond and
hydrogen donation from simple alkyl silanes is too slow to maintain chain reactions ð75JA3021Ł[
Tristrimethylsilylsilane "TTMSS# can be used in radical chain reactions because its Si0H bond
energy is low enough to sustain the chain ð81ACR077Ł[ Despite the relative weakness of the Si0H
bond it is still stronger than in germanium hydrides or tin hydrides and so it is a poorer hydrogen
atom donor[ Giese and co!workers have demonstrated that intramolecular cyclisation reactions can
be mediated by the use of TTMSS "Equation "30## ð78TL570Ł[ Cyclisation of 5!bromohexene "54#
with TTMSS led to a 13 ] 0 ratio of cyclised products to uncyclised products\ while with Bu2SnH
the ratio was 5 ] 0 under the same conditions[ This observation suggests that the TTMSS reagent
may be useful for mediating slow cyclisations[ TTMSS has been used to mediate radical macro!
cyclisation of the precursor "55# to give the 03!endo!tri` product "56#\ which was a key intermediate
in the sythesis of "−#!zearalenone "Equation "31##[ Use of the silane led to the same products and
yields as the Bu2SnH!mediated reaction but was easier to work up ð89TL2530Ł[ The TTMSS radical
can be successfully added to alkynes to form a vinyl silane radical which can undergo a reductive
vinyl radical cyclisation ð82TL5676Ł[
Br
+ + (41)
(65) (TMS)3SiH 93 : 2 : 4.1

Bu3SnH 83 : 1.2 : 15
OMe O
OMe O
(TMS)3SiH, AIBN, 80 °C
MeO (42)
55% MeO
O
O
Br
(66) (67)
"c# Mercury hydrides[ Most reductive radical cyclisation reactions are carried out using the tin
method^ however\ mercury hydrides can also be used to generate radicals suitable for cyclisation
ð74AG"E#442\ 77CRV376Ł[ The Hg0H bond is much weaker than the Sn0H bond and consequently
mercury hydrides are better hydrogen donors[ This limits the methodology to particularly rapid
cyclisations[ Precursors can be prepared by oxymercuration of alkenes to give alkylmercury salts\
which can be reduced to the mercury hydrides in situ "Equation "32##[ The procedure is simple to
carry out and puri_cation is less problematic than with the tin method ð71JOC1120Ł[
i, Hg(OAc)2
ii, NaBH(OMe)3
(43)
70% O
O H
"d# Hydroèn atom transfer reactions[ Pioneering work in the area of hydrogen atom transfer
cyclisations was carried out by Julia ð60ACR278\ 63PAC442Ł[ He showed that stabilised radicals "57#
prepared from benzoyl peroxide and cyanomalonates "58# cyclised to give mixtures of exo and endo
products\ and that the reaction was reversible due to the stability of the initial radical "57# "Scheme
08# ð56BSF1530\ 58BSF1316Ł[ In fact this method is probably the most useful for carrying out reversible
cyclisations to give thermodynamic mixtures of products[ Cyclisation of "58# at high temperatures
gave the 5!endo product predominantly while at lower temperatures the 4!exo product predominated[
Hydrogen abstraction from C0H bonds is very slow relative to abstraction from metal hydrides\
consequently ring opening to give back the stable electrophilic radical "57# is favoured over hydrogen
atom abstraction[ This method is generally limited to simple molecules[
•
CN
Bz2O2 CN
CO2Et CO2Et + • CO2Et
heat • CO2Et
CN CN
(69) (68)
(69) (69)
CN
CN
+ CO2Et
CO2Et
Scheme 19
"e# The Barton method[ The Barton method "see Section 0[97[0[2[3"iii#"f## has been used to
facilitate radical cyclisation reactions[ Homolysis of thiohydroxamate esters initially gives radicals
which rearrange to cyclised radicals and are trapped as the pyridyl sul_de to furnish functionalised
products "Equation "33## ð76MI 097!90\ 80COS"3#668\ B!81MI 097!90Ł[ Although not as commonly
employed as the tin method it has the advantage of being nonreductive in nature[ The radical
precursors are prepared from acids via the acid chlorides and the initial radicals are formed by
decarboxylation[ This is often a good method for forming radicals where other carbonÐheteroatom
bond precursors are di.cult or impossible to prepare ð76TL0302Ł[ Minimisation of the thiohydrox!
amate concentration in theory should allow relatively slow cyclisations to be conducted[
Ac H Ac H Ac
N CO2But N N
hν, THF CO2But CO2But
O + (44)
N 64%
H H
O pyS pyS
S
"f# The fra`mentation method[ As already mentioned in Section 0[97[0[2[3"iii#"h#\ relatively weak
bonds such as C0Br\ C0SnR2 and C0SR can fragment if they are substituted b to a radical[ This
unimolecular process is generally fast and liberates a radical as a leaving group[ This radical may
then react with a radical precursor to propagate the chain[ Radical cyclisation reactions carried out
utilising this method have the advantage over the metallic hydride donors in that the problem of
reduction of the initial radical no longer exists and that the process is not reductive[ Consequently\
this method should be useful for conducting particularly slow radical cyclisations and for introducing
functionality into the molecule after addition "Equation "34## ð74TL2200Ł[ The use of allyl and
vinyl stannanes ð89JA4590Ł have become very popular methods of generating the chain carrier
ð80CRV0126Ł[
SnMe3
Bu3SnH catalyst, AIBN
(45)
90%
MeO2C CO2Me
Br
"`# Atom transfer reactions[ Atom transfer cyclisations "see Section 0[97[0[2[3"iii#"i## o}er ver!
satile alternatives to metal hydride mediated radical cyclisation reactions ð77S378\ 80COS"3#668\
80CRV0126Ł[ Both heteroatoms "e[g[\ halogens# and hydrogen atoms "see Section 0[97[0[3[6"ii#"d##
can undergo atom transfer reactions although the halo atom transfer cyclisations are the more
versatile because the products contain a functionality handle "i[e[\ a halogen#[ Atom transfer
cyclisations are particularly suited for mediating slow cyclisation reactions[ Irradiation of "69# with
a catalytic amount of "Bu2Sn#1 formed the bicyclic iodide "60#\ whereas normal reductive radical
cyclisation with Bu2SnH furnished only the reductive product "61# even with low concentrations
"9[91 M# of Bu2SnH "Scheme 19# ð78JOC2039Ł[ The Bu2SnH!mediated cyclisation fails because the
initial radical is reduced prior to cyclisation\ while the atom transfer method succeeds because the
initial radical has su.cient lifetime to undergo cyclisation[ One way to facilitate fast atom transfer
steps is to use the reactive iodides as radical precursors and to ensure that the _nal radical is less
stable than the initial radical ð78JOC2039Ł[ Consequently\ a!iodo esters\ and nitriles\ are excellent
precursors for atom transfer reactions[ Even relatively unstable unconjugated alkyl radicals can
undergo e.cient atom transfer cyclisation as long as the adduct radical is even less stable "Equation
"35## ð78JA5154Ł[ Thermoneutral iodide atom transfer reactions can also be employed^ however\ the
rate of transfer is relatively low 0×094 M−0 s−0\ and other side reactions can occur ð75TL4710Ł[ Due
to the absence of hydrogen atom donors in atom transfer cyclisations these reactions are particularly
suited for forming six! and seven!membered rings and for facilitating tandem processes where the
cyclisations are particularly slow ð78JA5154Ł[
(Bu3Sn)2, hν
I (46)
65%
O O O
I O
O 0.02 M Bu3SnH O (Bu3Sn)2, hν H
55%
H
I
(72) (70) (71)
Scheme 20
"iii# Nonchain reactions

"a# Orànocobalt `roup transfer[ Photolysis or thermolysis of the relatively weak CoIII0C bond
"07Ð14 kcal mol−0\ 64Ð094 kJ mol−0# in RCo"salen#\ RCo"salophen# or RCo"dmgH#1py complexes
occurs homolytically to generate a carbon!centred radical and a CoII complex "see Section
0[97[0[2[3"iv#"a## ð77CSR250\ 83CRV408Ł[ These initial radicals can undergo cyclisation followed by
trapping in situ by CoII to generate a new RCoIII complex "Scheme 10#[ These RCoIII complexes can
then undergo a variety of reactions such as elimination or oxidation to furnish functionalised
products via a formal oxidative radical cyclisation "Scheme 11# ð73TL3206Ł[ The most common
organocobalt complexes used are those with Schi}!base ligands such as dimethylglyoximato
""dmgH#1#\ salen or salophen ð77CSR250\ 83CRV408Ł[ The initial RCoIII complexes can be formed by
reacting supernucleophilic CoI complexes with a variety of substrates including alkyl and aryl halides
and tosylates ð65AG"E#306Ł[ Hence\ the vinyl ether bromoacetal halide "62# reacts with CoI"dmgH#1
to form the bicyclic cobaloxime "63# via a 4!exo alkyl radical cyclisation followed by trapping with
CoII"dmgH#1[ Elimination of HCoIII"dmgH#1 by photolysis or insertion of oxygen followed by
reduction leads to the functionalised products "64# and "65#\ respectively "Scheme 11# ð89JCS"P0#1580Ł[
This oxidative method has been used in approaches towards kainic acid ð76CC055Ł and the alkaloid
physovenine ð81T5764Ł[ Radical cyclisations have also been initiated by the addition of CoI"dmgH#1
to oxiranes ð80TL132Ł[
CoIII
•
CoIII
hν or heat kc CoII
•
Scheme 21
OH
H
OEt
i, hν, O2
ii, NaBH4 O
Br CoIII(dmgH)2py H
CoI(dmgH) 2py (76)
OEt hν
O OEt
O 70% H
(73) (74)
OEt
O
H
(75)
Scheme 22
Sche}old has used the reduced form of vitamin B01 in catalytic amounts to mediate the cyclisation
of the alkyl halide "66# "Equation "36##[ The reduced vitamin B01 can be produced electrochemically
or by reduction with zinc metal ð79JA2531Ł[ A novel reductive procedure utilising a catalytic amount
of CoIICl1 and two equivalents of a Grignard reagent has been used to produce and cyclise aryl
radicals ð83CC30Ł[ This o}ers a high!yielding\ catalytic\ cheap\ {industrial friendly| alternative to the
utilisation of toxic trialkyltin hydrides in mediating reductive aryl radical cyclisation reactions[
O
O Br
vitamin B12 catalyst, e–
(47)
85%
(77)
Cyclisation of aryl radicals can be accomplished by the addition of CoIsalen to aryl iodides "67#
"Equation "37## ð75TL1292Ł[ Cyclisation followed by trapping with CoIIsalen furnishes RCoIIIsalen
complexes "68#\ which can be further functionalised to halides\ sul_des\ selenides\ nitriles\ alcohols\
amines and sulfonic acids ð89JCS"P0#1698Ł[ Minor amounts of chiral induction in cobalt!mediated
aryl radical cyclisations has been observed ð78TL4374Ł[
CoIIIsalen
I
CoIsalen, THF
(48)
O
O
(78) (79)
"b# Manànese!mediated cyclisations[ MnIII"OAc#2 has been used to oxidise b!ketoesters\

b!diketones and b!diesters to radicals which can undergo oxidative radical cyclisations ð83CRV408Ł
"see also Section 0[97[0[2[3"iv#"b## The reactions are terminated by oxidation of the _nal radical to
a carbocation with either another equivalent of MnIII"OAc#2 "for 2> radicals# or by an equivalent of
CuII"OAc#1 "for 0> or 1> radicals# "Scheme 12#[ Elimination of a proton ð72JOC0262Ł\ or reaction of
the carbocation with an appropriately positioned nucleophile then terminates the reaction ð76TL064Ł[
The slow step in the overall transformation is normally the formation of the MnIII!enolate which
then rapidly loses MnIII to give the free radical ð77JOC1026Ł[ This method has been used to mediate
4!exo\ 5!exo\ 5!endo\ 6!endo and 7!endo radical cyclisations ð77TL4198Ł[
•
CO2H Mn(OAc)3, AcOH
CO2H
O O
H
H H
Mn(OAc)3 O
O O
H H H
• +
H CO2H H CO2H O
O
Scheme 23
Overoxidation is sometimes a problem with products that contain an enolisable hydrogen atom[
This problem can be overcome by blocking the oxidation site with a chlorine atom ð77JOC1026Ł[
The solvent of choice for MnIII"OAc#2!mediated cyclisations is normally AcOH^ however\ EtOH
and DMSO have been used for acid!sensitive substrates ð82JOC5106Ł[ Snider has investigated the
e}ect of the ligand on the outcome of the cyclisation ð82JOC5106Ł[ Asymmetric induction in an
MnIII"OAc#2 cyclisation has also been reported "12Ð81) de# ð82JOC6539Ł[
"c# Other metal!mediated radical cyclisation reactions[ For a review on metal!mediated radical
cyclisation reactions which include reactions mediated by manganese\ iron\ ruthenium\ copper\
chromium and cobalt\ see ð83CRV408Ł[ Many of these metals mediate the chlorine atom transfer
cyclisation of perchlorocarbonyl compounds and so do not fall into the remit of this chapter[
However\ the use of two equivalents of CrII"OAc#1 has been shown to mediate the cyclisation of a!
bromoesters "Equation "38## ð81SL632Ł[ The second equivalent reduces the _nal radical to an
organochromium compound that can undergo b!elimination of a suitably orientated leaving group
"OH# or addition to aldehydes and ketones "Equation "38##[
HO Br CO2Et CO2Et CO2Et

Cr(OAc)2 (3 equiv.), THF
+ (49)
78%
O OEt OEt OEt
O O
3.9:1
Samarium diiodide is becoming a popular reagent for conducting radical cyclisations\ particularly
of aryl and vinyl radicals ð81SL832Ł[ Both aryl and vinyl radicals can be prepared from their
corresponding bromides or iodides by reaction with SmI1 in hexamethylphosphoramide "HMPA#[
Alkyl radicals can also be generated by reduction of alkyl halides with SmI1^ however\ further
reduction to the alkyl samarium prior to cyclisation is possible[ Curran has measured the rate
constants for reduction of alkyl radicals to alkyl samariums by SmI1 in HMPA ð82TL0606Ł[ Whereas
0> and 1> radicals are reduced easily by SmI1 in HMPA "0×095 M−0 s−0#\ 2> alkyl\ vinyl and aryl
radicals do not undergo this reaction[ Consequently\ cyclisation of aryl or vinyl radicals followed
by reduction of the newly formed alkyl radical to the alkyl samarium is a facile process[ Trapping
of the intermediate alkyl samarium by an electrophile then gives functionalised products "Equation
"49## ð81JA5949Ł[ The e}ects of additives upon the reduction reaction with SmI1 has been investigated
ð89SL662Ł[
SmI2 E
I
SmI2, THF, HMPA E+
(50)
O
O O
0[97[0[4 Tandem Processes
0[97[0[4[0 Intramolecular:intramolecular sequences

The process of two or more sequential radical addition reactions is known as a tandem or {cascade|
process[ These transformations often enable complex structural frameworks to be produced from
relatively simple radical precursors[ For reviews on tandem radical reactions\ see ð80COS"3#668\
B!81MI 097!91Ł[ The most common variety of tandem processes involve two or more sequential radical
cyclisation reactions "normally of the 4!hexenyl type#[ For example\ Curran and co!workers have
synthesised the linear triquinane natural product hirsutene via a Bu2SnH!mediated cyclisation
"Equation "40## ð74JA0337Ł[ During such reactions the same general rules governing the regio!
selectivity and stereoselectivity of normal radical cyclisation reactions apply[ Care must be taken
when designing a tandem process to ensure that the rate of addition of all the intermediate radicals
is faster than any termination step "such as reduction with tributyltin hydride#[ Consequently\ if
using a reductive method it is important to keep the concentration of the hydrogen donor low\ or
use a catalytic sequence[ The most common variants of these reactions involve the initial Bu2SnH!
mediated cyclisation of an alkyl radical on to an alkene or alkyne ð80COS"3#668Ł[ Other tandem
processes have been conducted utilising the fragmentation method ð89CC0432Ł\ the halogen transfer
method ð78JA5154Ł\ the organocobalt method ð81TL1740Ł and the manganese"III# method ð89JA1648Ł[
An approach towards complex\ fused skeletons is the tandem macrocyclisation:transannular cyclis!
ation method pioneered by Pattenden and co!workers[ Hence\ the taxane skeleton was formed via
a novel 03!endo macrocyclisation followed by a 5!exo transannular cyclisation "Equation "41##
ð81TL3732Ł[ Other studies have shown that 5\5!fused\ 4\6!fused\ 4\5!fused and 4\6\4!ring!fused cyclic
systems can be prepared by this methodology ð83TL1302\ 83TL1306Ł[
I H H
0.02 M Bu3SnH, 80 °C, AIBN
(51)
65%
H H
Hirsutene
O O
H
Bu3SnH, 80 °C, AIBN
(52)
25%
I H
H O H O
0[97[0[4[1 Intramolecular:intermolecular processes

The combination of an intramolecular cyclisation followed by an intermolecular addition is only
possible if the rate of the cyclisation reaction is much faster than that of addition[ Slow cyclisations
can be utilised if the initial radical and the acceptor are electronically unmatched[ This type of
sequence has been conducted by most of the general radical methods ð80COS"3#668\ 80CRV0126Ł^ an
example utilising the fragmentation method ð76JOC1847Ł is shown in Equation "42#[
OEt OEt
I O
O O
AIBN
+ Bu (53)
Bu
Bu3Sn
O-TBDMS O-TBDMS O
0[97[0[4[2 Intermolecular:intramolecular additions

This type of tandem process is much less common than those already described[ One major
problem is that the initial radical and the _nal radical are often similar electronically and that a
further unwanted intermolecular addition can take place[ This is often observed for the tin hydride
ð75TL4782Ł or the Barton method ð77CC174Ł[ An elegant solution to this problem is to use the
fragmentation method to terminate the sequence at the desired point "Equation "43## ð78TL1490Ł[
Alternatively\ Curran and co!workers have shown that the atom transfer method can be employed
by careful planning of a sequence in which the _nal radical is the least resonance stabilised and so
abstracts iodine from the initial precursor before further addition can take place ð76JA5447Ł[
TBDMS TBDMS
CO2Et 10% (Bu3Sn)2, hν
SnMe3 + CO2Et (54)
56%
I
(E):(Z) = 98:2
0[97[0[4[3 Intermolecular:intermolecular additions

Sequential intermolecular:intermolecular additions are particularly di.cult to perform without
polymerisation occurring[ A solution to this problem involves the suitable electronic pairing of the
initial nucleophilic radical derived from "79# with the activated alkene "70# ð77JA0177Ł[ Upon addition
the new electrophilic radical produced adds to the allyl stannane "71# at a greater rate than the
electronically mismatched alkene "70# "Equation "44##[ Elimination of the stannane radical ter!
minates the sequence and acts as a chain carrier[
SnBu3 NC CN
O I CN (82) O
O + (55)
Ph O
Ph CN
Ph
(80) (81)
Electrocyclic Additions 238
0[97[1 ELECTROCYCLIC ADDITIONS TO CARBONÐCARBON MULTIPLE BONDS TO
GIVE TETRACOORDINATE PRODUCTS
0[97[1[0 Introduction
0[97[1[0[0 Scope
The term {electrocyclic addition| usually applies to reactions which proceed with a concerted
cyclic movement of electrons[ As it is often di.cult to establish that a particular addition is
truly concerted this criterion has been interpreted somewhat loosely[ The result is that stepwise
cycloaddition processes have been included if the intermediates appear to be short!lived species[
The remaining restrictions are as follows[ Only reactions of C1C bonds are considered[ Fur!
thermore\ in the cyclic products the two carbon atoms derived from the C1C bond must each be
bonded to four carbon atoms[ Most of these reactions are summarised by Equation "45#[ The one
class of reaction not covered by Equation "45#\ but within the scope of the chapter\ is the addition
of carbenes "Equation "46##[
+ X X (56)
R R
+ : (57)
R R
Finally\ it should be remarked that\ if an electrocyclisation produces a new C1C bond as well as
a new C0C bond "e[g[\ the conventional DielsÐAlder reaction#\ it most properly belongs in Chapter
0[06[ However\ a very brief account of the DielsÐAlder reaction is included for the sake of
completion[
0[97[1[0[1 General mechanistic aspects

Since the universally acclaimed work of Woodward and Ho}mann ð58AG"E#670Ł\ chemists have
been able to bene_t from a deep understanding of the mechanisms of cycloaddition reactions[ It is
not intended to discuss these ideas at length here\ but a reminder of some of the points pertinent to
this chapter is not out of place[ All the reactions described herein involve an alkene\ which has two
p electrons\ as one partner[ The full range of reactions to be discussed can be categorised as either
1p¦1p or 1p¦3p[ The 1p components covered are alkenes\ carbenes and allyl cations[ The 3p
components are dienes "the DielsÐAlder reaction# and heterodienes^ carbonyl\ thiocarbonyl and
azomethine ylides^ allyl and azaallyl anions and trimethylene methane[
The _rst point to consider is that for small p systems such as these\ the antarafacial mode of
cycloaddition is geometrically very unlikely and suprafacial addition is therefore the norm\ as
illustrated for the DielsÐAlder reaction in Figure 8[ Suprafacial 1p¦1p reactions are photo!
chemically allowed and thermally forbidden by the WoodwardÐHo}mann rules^ suprafacial 1p¦3p
additions are\ conversely\ thermally allowed and photochemically forbidden[
However\ there are many cycloaddition reactions which break these rules[ This is because not all
Suprafacial Antarafacial
Figure 9 Suprafacial and antarafacial addition for small π systems.

cycloadditions proceed by a truly concerted pathway[ The extreme opposite of the concerted reaction
is the two!step reaction "Scheme 13#[ In practice many reactions fall somewhere between these two
limits[ Knowledge of which type of mechanism applies in a particular reaction is not merely of
academic importance[ The regiochemical and stereochemical outcomes of reactions may be pro!
foundly a}ected by the preferred pathway\ as discussed in the subsequent sections[
+
–
stepwise
concerted
+
stepwise
–
+
Scheme 24
The FMO approach to cycloadditions allows the outcome to be predicted by considering the
overlap of either the HOMO of the 1p or 3p component with the LUMO of the alkene\ or the
LUMO of the 1p or 3p component with the HOMO of the alkene[ Clearly it is important to know
which case applies[ This is done by estimation of the two HOMOÐLUMO energy gaps[ The smaller
gap represents the more important contribution\ and it is this one which should be considered[ In
practice\ this means that if the alkene bears electron!withdrawing substituents its LUMO will be
important and its interaction with the HOMO of the 3p component should be considered[ In the
case of an electron!rich alkene the alkene HOMO 3p component LUMO should be considered[
Similar arguments apply to 1p¦1p additions[
These fundamental observations are necessary for the discussions of regiochemical and stereo!
chemical considerations which follow[
0[97[1[0[2 General regiochemical aspects

If both partners in a cycloaddition are unsymmetrically substituted there are two possible regio!
isomeric products[ If one regioisomer predominates the reaction is said to be regioselective[ Clearly
it is desirable for the reaction to be highly regioselective\ leading to only one isomer[ In addition\ it
is important to be able to predict which of the regioisomers will be preferred[
For truly concerted cycloadditions the origins of any regioselectivity lie in the polarisation of the
HOMO and LUMO by their substituents[ As mentioned in Section 0[97[1[0[1\ it is important to
know which HOMOÐLUMO interaction is important[ Once this has been decided\ the e}ect of the
substituents on the coe.cients of the termini of the reacting p systems should be estimated[ Both
these factors can be easily assessed by reference to standard texts ðB!65MI 097!90Ł[ The preferred
regioisomer can then be predicted by matching the large coe.cient terminus of one partner with
the large coe.cient terminus of the other[
The e}ect of substituents on the polarisation of the p system is often relatively small[ For this
reason\ the regioselectivity of concerted cycloadditions is often unspectacular[ The use of\ in particu!
lar\ Lewis acid catalysts to enhance the polarisation\ and hence regioselectivity\ of DielsÐAlder
cycloadditions is widespread and is discussed later[ However\ this principle has not been widely
applied to other categories of cycloadditions[
Cycloadditions which proceed by {more stepwise| pathways often have higher regioselectivities[
The origin of such regioselectivity may result from minimisation of steric interactions but\ more
often than not\ it is due to the ability of a substituent to stabilise developing charge in the
intermediate[ For instance\ the reaction of azaallyl anion "72# with styrene proceeds via the inter!
mediate in which the developing negative charge is stabilised by a phenyl group to yield the more
sterically congested regioisomer "73# "Equation "47## "see Section 0[97[1[3[1#[ A basic understanding
of the mechanism of a particular cycloaddition is very important in prediction of its regiochemical
outcome[
Ph Ph
Ph Ph
–
– Ph Ph (58)
Ph N N
Ph N Ph H
(83) (84)
0[97[1[0[3 General stereochemical aspects

If all four reacting carbon centres in a cycloaddition are prochiral\ a total of 05 stereoisomers can
be formed\ corresponding to eight enantiomeric pairs[ The immense power of cycloaddition chem!
istry in synthesis is due to the fact that a great deal of selectivity is observed\ and the goal of
producing just one of these 05 isomers in a wide range of cycloaddition reactions now appears
possible[
In a perfectly concerted cycloaddition reaction there will be absolute correspondence between
both the stereochemistry of the starting materials and the stereochemistry of the product[ In the
case of a thermal 1p¦3p addition\ retention of the stereochemistry of both components is predicted
from FMO considerations[ Similarly\ the outcome of other classes of cycloadditions can be predicted[
Partial loss of stereochemistry of the starting materials in a cycloaddition is strongly indicative of a
nonconcerted mechanism[ However\ complete conservation of stereochemistry should not be taken
as proof of a concerted mechanism as many stepwise cycloadditions proceed via strongly coordinated
intermediates in which the stereointegrity is retained "e[g[ see azaallyl anion addition in Section
0[97[1[3[1#[
If it is accepted that antarafacial addition will not occur\ a concerted "1p¦3p# cycloaddition has
only four possibilities left for isomerism[ For example\ the cycloaddition in Equation "48# can give
a mixture of the four isomers "74#Ð"77#[ Product "74# and its enantiomer "76# result from so!called
endo addition whereas "75# and "77# result from exo addition[ In fact\ the endo product is usually
favoured\ perhaps due to secondary orbital e}ects "overlap of p orbitals of substituents# ðB!65MI
097!90Ł\ but this e}ect is not universal[ In practice\ endo:exo product mixtures usually result[ One of
the major challenges in cycloaddition chemistry is to achieve the highest possible endo:exo selectivity[
endo exo
OAc OAc
O O
O O
O O
OAc
OAc OAc
O
(85) (86)
+ O (59)
O
OAc OAc
OAc
O O
O O
O O
OAc OAc
(87) (88)
The _nal stereochemical hurdle is that of facial selectivity[ In the example in Equation "48# the
two possible enantiomeric endo products result from the addition of the 3p component to both
prochiral faces of the alkene[ If\ due to a chiral environment\ addition to one of these prochiral
faces is favoured\ the reaction will be enantioselective[ In practice\ this task is made easier by
attaching the chiral environment to one of the reacting partners in the form of a chiral auxiliary[ In
this case the products are diastereomers\ not enantiomers\ and the success of the reaction will be
judged by its diastereoselectivity\ not enantioselectivity[
Three stereochemical features will be highlighted in the subsequent discussion] degree of retention
of stereochemistry of starting materials\ endo:exo selectivity and enantioselectivity "or diastereofacial
selectivity if a chiral auxiliary is involved#[
0[97[1[1 Formation of Three!membered Rings
0[97[1[1[0 Additions of free carbenes

The addition of carbenes to alkenes to produce cyclopropanes is a very important process
"Equation "59##[ Free carbenes are in general much too reactive to be useful "with some exceptions
ðB!81MI 097!92Ł# due to competing reactions\ in particular C0H bond insertion[ However\ there are
other methods of {carbene transfer| which achieve the same result in a more controlled fashion
ðB!81MI 097!92Ł[ Of these\ alkylidene ylides "e[g[\ sulfonium ylides# are prominent[ However\ the
mechanism of the {carbene transfer| from these ylides is clearly stepwise and excludes them from
the scope of this chapter[
R R
+ : (60)
R R
0[97[1[1[1 Additions of metal carbenoids

Two main classes of {carbene transfer| remain to be discussed[ March provides an excellent
introduction to the _rst protocol\ the SimmonsÐSmith procedure ðB!81MI 097!92Ł[ This involves an
organozinc reagent derived from a diiodoalkane and zinc "usually activated as a copper couple#[
Bond formation proceeds as if concerted\ with retention of stereochemistry of the alkene and some
diastereofacial selectivity "e[g[\ Equation "50## ð71JOC0504Ł[
I
I
+ (61)
Zn-CuCl
OH OH OH
76 : 24
Another development in the SimmonsÐSmith methodology is the discovery of an enantioselective

version ð81CL50Ł[ In this case the substrates are allylic alcohols\ the organozinc reagent is diethylzinc
and the asymmetric induction is due to a chiral diol "Equation "51##[ Although ee values are modest\
these initial results are most promising and invite further investigation[
i, Et2Zn
HO OH
ii,
EtO2C CO2Et
Ph OH (62)
iii, Et2Zn, CH2I2 Ph OH
54%, 71% ee
Some signi_cant developments in carbene chemistry have involved metal!stabilised keto!

carbenoids "78# "the term {carbenoid| is usually employed when free carbenes are not involved#[ The
most usual precursors of "78# are diazo compounds "89#\ but dibromides\ sulfur ylides and iodonium
ylides have also been used ð75ACR237\ 75CRV808\ 76TCC64\ 80COS"3#0920Ł[ The two prevalent metals
are copper"I# and rhodium"II#\ but palladium"II# has also proved useful[
R R
MLn N2
O O
R R
(89) (90)
It is worth noting that\ although the metal carbenoid species are much more selective than the
corresponding free carbene systems\ mixtures will usually result if more than one alkene is present
in a molecule ð80COS"3#0920Ł[ Carbene cycloadditions proceed with retention of stereochemistry of
the alkene "Equation "52## ð73OM33Ł[
CO2Et CO2Et
CO2Et Rh2(OAc)4
+ + (63)
R1 R2 N2
R1 R2 R1 R2
(91) (92)
The reaction illustrated in Equation "52# also highlights the need to consider diastereofacial
selectivity[ Unfortunately\ this selectivity is often rather poor[ It is possible to increase the proportion
of the trans isomer "80# signi_cantly ð71TL1150Ł\ but the cis isomer "81# remains largely inaccessible[
The asymmetric cyclopropanation of alkenes by ketocarbenoids is a topic of interest[ Both copper
and rhodium catalysts have been modi_ed with chiral ligands for this purpose and the results have
been most impressive ð80RTC294Ł[ The early leaders in the _eld were the salicylaldehyde!derived
imines "82# developed by Aratani as ligands for copper ð74PAC0728Ł[ A typical example is the
preparation of a chrysanthemic acid precursor "83# "Equation "53##[ The ee values were found to be
useful\ but the problem of cis:trans mixtures again proved to be a problem[
C8H17O
R
N R=
R
OH
OH
But
(93)
CO2But Cu-(S)-(93)
+ + cis isomer (64)
N2 75% ee CO2But
(94)
Semicorrin and bisoxazoline ligands with the general structures "84# and "85# have been shown
to be excellent chiral ligands for copper catalysts ð80HCA121\ 80JA615\ 80RTC294\ 80TL6262Ł[ One
example where the enantioselectivity is outstanding and the cis:trans ratio is very good is given in
Equation "54# ð80JA615Ł[ However\ catalysts with ligands of the type "84# and "85# have not been
shown to be e}ective with more substituted alkenes^ in such cases the Aratani catalysts "utilizing
ligand "82## remain the most useful ð83T3408Ł[
R1 R1 R1
O O
R3 R3
N N N N
H
R2 R2 R2 R2
(95) (96)
Ph RO2C CuOSO2CF3 Ph
+ (65)
N2 O O CO2R
N N
But But
85%, 89% de, 99% ee
R = 2,6-di-t-butyl-4-methylphenol
Chiral ligands have also been used to modify rhodium catalysts[ The most e}ective ligands
have been of the 4S!MEPY type "86#\ the rhodium complexes of which catalyse the asymmetric
cyclopropanation of mono! and disubstituted alkenes with respectable ee values but poor cis:trans
ratios ð80RTC294Ł[
O N CO2Me
H
(97)
As so often with cycloaddition reactions\ the problems of stereoisomerism can be avoided by way
of intramolecular reactions[ Indeed\ the intramolecular cyclopropanation of alkenes by carbenes
has proved a useful reaction ð80COS"3#0920Ł[ Bicyclic skeletons with cyclopropane rings fused with
cyclobutanes and cyclopentanes are accessible by this route[ The reactions shown in Scheme 14 are
typical and highlight the stereochemical control possible in these processes ð66TL098Ł[
H
CuSO4
N2
58%
CO2Me CO2Me
O
O
H
N2 CuSO4
60%
CO2Me CO2Me
O
O
Scheme 25
In view of the promising results obtained from intramolecular cyclopropanation reactions\ it is

surprising that little progress has been made with the asymmetric version[ However\ the rhodium!
4S!MEPY complexes mentioned above hold promise ð83T3408Ł[ The example shown in Equation
"55# illustrates the potential of these reactions[
But
N Rh2(97)4 Et
N (66)
Et N2 94%, 90% ee But
O
O
(Absolute stereochemistry uncertain)
0[97[1[2 Formation of Four!membered Rings

The addition of one alkene to another is an obvious route to cyclobutanes[ This kind of reaction
can be achieved in three ways\ as described below] "i# thermally\ "ii# photochemically or "iii# by
metal catalysis[
0[97[1[2[0 Thermal ð1¦1Ł additions

The thermal 1p¦1p addition of alkenes is forbidden by the WoodwardÐHo}mann rules[
However\ such additions do occur and have been reviewed ð80COS"4#52Ł[ The mechanism is therefore
expected to be stepwise\ and experimental evidence supports this postulate[ For the purpose of
understanding the results of thermal ð1¦1Ł additions\ a mechanism via a diradical intermediate is
su.cient and will be used here[
The thermal dimerisation of acrylonitrile "87# is illustrative "Equation "56##[ The reaction is highly
regioselective\ giving the so!called head!to!head product[ However\ the stereoselectivity is very poor\
a mixture of cis and trans isomers being observed[ These phenomena are readily explained by the
intermediacy of diradical "88#[ This is the most thermodynamically favourable diradical\ as both
radical centres are stabilised by substituents[ The possibility for free rotation around carbonÐcarbon
bonds in "88# is evident[ Little stereoselectivity would therefore be expected[ Similar results are
observed with other alkene dimerisations ð80COS"4#52Ł[
CN CN CN
CN •
• + (67)
CN CN CN
(98) (99)
Alkenes bearing electron!withdrawing substituents are found to react readily with electron!rich
alkenes[ Tetracyanoethylene has been widely used as a substrate ð80COS"4#52Ł[ The example in
Equation "57# is typical[ In this case both the regioselectivity and stereoselectivity are good
ð53JOC839Ł[ The latter selectivity is probably due to formation of the thermodynamically favoured
product "099#\ in which steric interactions are minimised[
OMe
CN OMe
OMe
+ (68)
CN
Ph CN OMe
Ph CN
(100)
Diastereoselectivity in thermal ð1¦1Ł additions can be good[ For example\ reaction of tetra!
cyanoethylene with a chirally substituted alkene was found to proceed with very high de values\
giving essentially one product "090# in 83) yield "Equation "58##[
H CN
O
NC CN O
But CN
+ But (69)
N 94% CN
N
MeO2C NC CN
MeO2C H CN
(101)
Intramolecular thermal alkene cycloadditions have also been investigated[ This can be a useful
method of producing polycyclic skeletons[ The reaction in Equation "69# provides a simple example\
apparently proceeding with good stereoselectivity ð66JA3306Ł[ A more exotic variation is the con!
struction of the hydrocarbon "091# "Equation "60## ð73JOC0242Ł[
Ph
Ph
(70)
Ph
Ph
Ph
Ph
Ph
(71)
Ph
(102)
The high regioselectivity and diastereofacial selectivity observed in thermal ð1¦1Ł additions\
coupled with the fact that the stereoselectivity can also be high in favourable cases\ makes these
reactions potentially very useful synthetically[
0[97[1[2[1 Photochemical ð1¦1Ł additions

In contrast to the thermal ð1¦1Ł additions discussed above\ the photochemical addition of one
alkene to another is allowed by WoodwardÐHo}mann theory[ However\ such cycloadditions are
considered not to be truly concerted processes\ but stepwise\ proceeding via a diradical intermediate
ð80COS"4#012Ł[
The regiochemistry of photochemical alkene cycloadditions is rather unpredictable[ For example\
replacement of H by CH2 in the enone "092# has a huge e}ect on the regiochemical outcome
"Equation "61##[ The regiochemistry varies under the in~uence of a number of factors[ The polarity
of the alkenes\ steric interactions and relative stabilities of intermediate diradicals have all been used
to attempt to rationalise the direction of regioselectivity[ However\ rationalisation remains di.cult[
The most important point is that regioselectivity can be very good[
O O O
OAc
hν
+ + (72)
OAc ~80%
R R OAc R
(103) R=H 100 : 0
R = Me 20 : 80
The reaction medium can also have a profound e}ect on regioselectivity[ The reaction in Equation
"62# illustrates the result of changing solvent polarity ð57CC871Ł[ The preorganisation of the sub!
strates is also signi_cant[ Addition of potassium dodecyl sulfate to a cyclohexane solution of "093#
and "094# reverses the selectivity ð71CJC314Ł "Equation "63##[ Variation of regiochemistry with
temperature has also been noted ð67TL1946Ł[
O
O O O O
hν
+ + (73)
O O
OAc AcO O O
AcO
Cyclohexane 2 : 98
Methanol 55 : 45
O O O
AcO OAc C5H11
hν
+ + (74)
C5H11
Bun Bun C5H11 Bun OAc
(104) (105)
Without potassium dodecyl sulfate 0 : 100
With potassium dodecyl sulfate 70 : 30
The stereoselectivity of photochemical cyclobutane formation is rather easier to predict[ If it is

geometrically feasible for the stereochemistry of the alkene to be lost\ it will be[ This point is
demonstrated by the reaction of a cyclopentene and a cyclohexene "Equation "64## ð71CJC314Ł[ The
six!membered ring is ~exible enough for cis:trans isomerism to occur\ whereas the stereochemistry
of the geometrically constrained _ve!membered ring is retained[ Loss of stereochemistry is almost
always observed with acyclic alkenes[
O H H
O
hν
+ (75)
The second point to note is that\ if stereochemistry is retained\ the anti arrangement around the
new carbonÐcarbon bonds will nearly always result\ as illustrated in Equation "65#[
O O
H H
hν O
+ O (76)
O O
H H
Diastereofacial selectivity is often rather poor in photochemical alkene cycloadditions[ However\
highly diastereofacial addition of a chirally substituted alkene to cyclopentenone did permit a
synthesis of bourbonene\ but unfortunately there was no regioselectivity in the photochemical
reaction "Scheme 15# ð57JA5060Ł[
O H H O H H H H
hν
+ +
O H H H
50 : 50 Bourbonene
Scheme 26
The attachment of a chiral auxiliary to one of the alkenes is an obvious strategy for preparation
of optically pure cyclobutane derivatives ð81CRV630Ł[ For example\ Meyers|s group successfully used
the substituted alkene "095# to prepare "−#!grandisol "Scheme 16# ð75JA295Ł[ The diastereofacial
selectivity in the crucial ð1¦1Ł addition step was good "×89) de#[
O O H H
H
hν
N + N O
MeO2C
O O HO
(106) Grandisol
Scheme 27
It would be appropriate here to correct a misconception arising from original literature ð71JA0631\
74TL3696\ 74TL5052\ 76TL1722\ 77TL1502Ł\ and persisting in review articles ð80COS"4#012\ 81CRV630Ł\
regarding the e}ects of chiral ester groups on ð1¦1Ł additions[ The _gures which should have been
highlighted from these papers were the de values\ which are generally low "3Ð73)#[ The ee values
quoted\ after removal of the chiral auxiliary\ simply re~ect the extent to which the authors were
successful in separating\ or otherwise\ the diastereomeric products[ The use of chiral ester groups
as auxiliaries for these reactions should not\ therefore\ be considered particularly successful[
Circularly polarised light has been used to promote asymmetric photochemical additions of
alkenes ð81CRV630Ł\ but so far ee values have been mainly in single _gures[
As pointed out by Crimmins ð80COS"4#012Ł\ the main problem with intermolecular ð1¦1Ł photo!
chemical cycloadditions as synthetic tools is that the regio! and stereoselectivities\ though sometimes
very good\ are rather unpredictable[ It is no surprise\ therefore\ that intramolecular versions of these
reactions have become more popular[ Many such reactions have been reported\ often using a chiral
building block to produce optically pure products ð80COS"4#012Ł[
The most important generalisations regarding these intramolecular reactions are that regio!
selectivity is usually very high\ that the stereoselectivity is not so good "alkene stereochemistry can
still be lost# and that diastereofacial selectivity can be extremely high[ Two examples "Scheme 17#
have been chosen to illustrate the utility of ring!fused cyclobutanes as precursors to larger rings
ð79CC0084\ 79HCA0087Ł[
0[97[1[2[2 Metal!catalysed ð1¦1Ł additions

In their review\ Kricka and Ledwith complained of a paucity of examples of metal!catalysed
cycloadditions of alkenes ð63S428Ł[ In fact\ although only dimerisation reactions had been studied\
quite a number of metals had been used[ However\ there has been little further development of this
area[ Work has concentrated on copper tri~ate catalysts "e[g[\ ð79TL1366\ 72T374Ł# and titanium
catalysts "e[g[\ ð61JA5756Ł#\ as illustrated in Equation "66#[
Ph O O
OCO2CH2Ph
O hν
92%
H O
O
Longifolene
O O
O H
hν
98%
O Ph O Ph H H
O
Epiprecapnelladiene
Scheme 28
H H
OH hν, CuOSO2CF3
+ (77)
91% H H
H
HO H
OH
75 : 25
A breakthrough in ð1¦1Ł cycloaddition methodology was the discovery that a chiral titanium
complex catalysed the reaction of a ketene dithioacetal "096# with an electron!de_cient alkene "097#[
The cyclobutane derivative "098# was produced in 85) yield and 87) ee "Equation "67## ð81JA7758Ł[
In this case the titanium centre is presumably acting as a Lewis acid[
O
O
O O
SMe MeO2C
TiL4 N O
+ MeO2C N (78)
SMe O 96%, 98% ee
SMe
SMe
(107) (108) (109)
0[97[1[3 Formation of Five!membered Rings
0[97[1[3[0 ð2¦1Ł Additions of three!carbon fragments

"i# Additions of trimethylenemethane
Trimethylenemethane "TMM# "009# is an intriguing molecule^ whether it is a dipole or a diradical
"and\ if the latter\ whether it is in the singlet or triplet state# has been the subject of numerous studies
ð67ACR335Ł[ Whatever its structure\ TMM and its derivatives represent an accessible and versatile
class of 3p three!carbon fragments which\ on addition to alkenes\ yield cyclopentanes[ Free TMM
"009# is too reactive to be synthetically useful ð75AG"E#0Ł but the successful use of derivatives is
described below[
• • +
or or or
• • –
(110)
"a# 1!Alkylidenecyclopentane!0\2!diyls[ One of the reactions of TMM which must be avoided\
if trapping is to be successful\ is ring closure to the corresponding cyclopropane "Equation "68##
ðB!89MI 097!90Ł[ For cyclic derivatives such as "000# the product of ring closure would be highly
strained\ and these 1!alkylidenecyclopentane!0\2!diyls "henceforth called {diyls|# therefore have a
signi_cant lifetime ð67ACR335Ł[
•
(79)
•
•
(111)
Little has described how functionalised bicyclic diazenes "001# can be used to generate useful diyl
species ð75CRV764\ 80COS"4#128Ł\ either photochemically or thermally[ The diyl typically equilibrates
before cycloaddition "Scheme 18#[ Intermolecular reaction with an electron!de_cient alkene\ though
successful in terms of trapping of the diyl\ led to a mixture of regio! and stereoisomers[ This poor
selectivity\ which was presumably due to the highly reactive nature of the diyls\ indicated the need
for further steric constraints[
•
•
N •
N •
(112)
Scheme 29
Two examples serve to demonstrate the excellent selectivities which can be attained in intra!
molecular diyl cycloadditions[ The _rst shows how the stereochemistry of the alkene component is
conserved "H0 relative to CO1Me#\ how the cis ring junction "H0 relative to H1# is always preferred
and how the anti con_guration "H0 relative to H2# is preferred to the syn "Equation "79## ð70JA1633Ł[
H2 CO2Me CO2Me
CO2Me H3 H1 H3 H1
reflux
H1 + (80)
MeCN
N
N H2 H2
87 : 13
The second example illustrates the e}ect of introducing a chiral centre into the tether[ The
conformational preference of the substituent "OSiR2 in this case# should lead to a marked preference
for one of the possible cyclic transition states[ Indeed\ the tricyclic product "002# was isolated almost
pure "Equation "70## ð74JA1384Ł[ The close analogy between structure "002# and a range of natural
products has been noted ð80COS"4#128Ł[
OSiR3
H2 CO2Me CO2Me
CO2Me H3 H1 H3 H1
hν
H1 + (81)
MeCN
N
N H2 H2
OSiR3 OSiR3
(113)
98 : 2
Little has remarked that the intermolecular version of the reaction may return to prominence in the
long term due to the more ready availability of the starting materials ð75CRV764Ł[ The intermolecular
reaction also appears to hold promise for asymmetric induction[
"b# Trimethylenemethane acetals[ The presence of an acetal substituent on TMM appears to aid
stability[ Nakamura and co!workers showed that the intermediate "003# was generated by the
thermolysis of a methylenecyclopropanone acetal and could be trapped with electron!de_cient
alkenes "Scheme 29# ð78JA6174\ 89JOC4442Ł[ The reaction was found to be stereospeci_c\ the stereo!
chemistry of the alkene being retained[
EWG
O EWG
R1 R2
O O O O R2
O
R1
• •
(114)
Scheme 30
Further investigation by the same group established that substituted TMM acetals react highly
stereoselectively with alkenes\ the preferred stereoisomer resulting from the endo transition state
"e[g[\ Scheme 20\ Equation "71## ð81JA7696Ł[ However\ the regioselectivities of the cyclisations were
rather poor\ except when a trans!alkene and a hindered TMM were used "Scheme 20\ Equation "72##[
CO2Me
O CO2Me O CO2Me
O O CO2Me
+ (82)
O CO2Me O CO2Me
•
•
95 : 5
CO2Me
O O O O CO2Me
+ (83)
• O CO2Me O
•
96 : 4
Scheme 31
The simplicity of the cycloadditions of TMM acetals\ which can be prepared in a few steps\ makes
this method of cyclopentane synthesis potentially very important\ especially in view of the possible
use of catalysis to improve the regioselectivity and to induce asymmetry[
"c# Transition metalÐtrimethylenemethane complexes[ A number of synthetic equivalents of
dipolar TMM have been proposed\ including the isobutene derivative "004# ð75JA3572\ 77PAC096\
82JOC5605Ł^ however\ cyclisations using most of these reagents proceed in two distinct steps and are
thus beyond the scope of this chapter[ In contrast\ certain metal complexes of TMM react with
alkenes in what can appear a {concerted| fashion\ as no intermediates have been observed[ Although
the mechanism is almost certainly stepwise ð75AG"E#0Ł\ these reactions are usually classi_ed as
cycloadditions and are therefore discussed here[
PhO2S Br
(115)
As Trost remarked\ palladium"9# complexes of TMM "005# are ideal TMM equivalents as they
bind TMM with su.cient strength to stabilise it\ but not so tightly that it becomes unreactive
ð75AG"E#0Ł[ In addition\ the ability of palladium"9# compounds to ionise bonds from carbon to
poor leaving groups permits a straightforward preparation of the complexes from the readily
available TMM synthetic equivalent "006#[ Derivatives of "006# are also accessible by a range of
methods ð75AG"E#0Ł[
–
TMS OAc
+
PdLn
(116) (117)
Unsubstituted TMM complexes "005# were used to determine the fundamental characteristics of
the intermolecular cycloadditions of these compounds to alkenes[ The two typical examples in
Scheme 21 demonstrate "i# a marked preference for reaction with electron de_cient alkenes\ on the
less hindered face and "ii# that the stereochemistry of a trans!alkene is retained[ However\ the
stereochemistry of cis!alkenes can be partly lost[ The latter observation is just one indication of the
fact that the reactions of TMM complexes are not truly concerted[
(116)
O O
(116)
CO2Me
CO2Me
Scheme 32
Reactions of substituted TMMs introduce two new stereochemical problems "Equation "73##
ð75AG"E#0Ł[ Cycloadditions of monosubstituted TMMs are most unusual in having three possible
regiochemical outcomes[ The two possible relative stereochemistries "between R and Z# for each
regioisomer mean that there are six possible products[ However\ the reactions are highly regio!
selective\ which means that four of the possibilities are not observed ð81S040Ł[ Unfortunately the
diastereoselectivity is generally poor\ resulting in mixtures of cis and trans products[ Trost and co!
workers have shown that the stereochemical problems can be recti_ed by epimerisation ð75AG"E#0Ł\
or circumvented by incorporation of a phenylthio group ð80JA8996Ł[ The reactions of symmetrically
disubstituted TMMs follow the same rules\ yielding only one regioisomer of a possible three "rather
than six if the substituents were di}erent#\ but all four possible diastereoisomers are obtained
"Equation "74## ð81S040Ł[
Z R Z
TMS OAc Pd Z
+ + + (84)
Z
R R
R
CO2Me
MeO2C CO2Me
Pd CO2Me
TMS OAc + (85)
Ph Ph
One other important aspect of the regiochemistry of cycloadditions of TMMs is that it is

independent of the TMM precursor[ Hence\ for example\ "007# and "008# both lead to the same
product mixture[
TMS OAc TMS OAc
(118) (119)
Intramolecular cycloadditions of palladiumÐTMM complexes have also been investigated
ð80JA6249\ 81JOC575Ł[ The cyclisations are highly regioselective and usually proceed with retention
of the con_guration of the trans!alkene and\ although most examples do give rise to mixtures of
diastereoisomers\ one product usually predominates[ For example\ the products "019# and "010#
"RMe#\ which bear a bridgehead alkyl substituent\ were formed in a ratio of 1[3 ] 0[ Furthermore\
the stereochemical problem is obviated by the facile isomerisation of the products "019# and "010#[
O O
H SO2Ph H SO2Ph
(120) (121)
The synthetic application of palladiumÐTMM complexes has largely been restricted to unsub!
stituted TMM[ The _rst two examples show how palladiumÐTMM can be instrumental in con!
structing cyclopentane building blocks "Schemes 22 and 23# ð89CC0325\ 89T0748Ł[ The excellent
tolerance of palladiumÐTMM for remote functional groups are illustrated by Equation "75# and
Scheme 24 ð81JA6264\ 82JOC3187Ł[
Ar NO2
NO2 Pd
Ar + TMS OAc Cephalotaxine
(117)
Scheme 33
H O
O
Pd
+ (117) Hirsutene
H
Scheme 34
TMS
TMS
CO2Me
Pd
+ (117) (86)
CO2Me
TMS
TMS
Tetracyclic diterpenes
(117)
MeO2C Hydroxykempenones
Pd
MeO2C
O O
H H
Scheme 35
The related nickel"9#! and palladium"9#! catalysed additions of methylenecyclopropanes to elec!

tron!poor alkenes provide another synthetic route to methylenecyclopentanes ð75AG"E#0Ł[
Two signi_cant developments in methylenecyclopropane addition chemistry illustrate the poten!
tial of the process[ The _rst example shows how a trimethylsilyl derivative "011# can be used as a
synthetic equivalent of methylenecyclopropane "Scheme 25# ð76CB0822Ł[ Its use avoids the di.cult
reaction conditions required by methylenecyclopropane itself[ Equation "76# highlights the excellent
stereoselectivity observed when a chiral auxiliary is employed ð78LA628Ł[
TMS
Pd CF3CO2H
+
EWG
TMS
EWG
(122) EWG
Scheme 36
Ni
+ (87)
CO2R* up to 98% de
CO2R*
R* = chiral auxiliary
"ii# Additions of allyl anions

The addition of an allyl anion\ as a 3p component\ to a 1p alkene is a potentially useful method
for synthesis of cyclopentanes[ An early example of such a reaction was published by the group of
Kau}mann ð63AG"E#357Ł[ A carbamoyl!stabilised lithium allyl compound "012# was found to react
with its parent alkene "013# to produce the cyclopentane "014# "Equation "77##[
CONR2
CONR2
+ (88)
CONR2 26%
– CONR2
(123) (124) (125)
The chemistry described in this paper was later developed into a useful synthetic process by Beak
et al[ ð75JOC3516Ł[ Addition of a similar anion to a variety of carbamoyl!substituted alkenes gave
reasonable yields of the cyclopentanes "015# "Equation "78##[ The regioselectivity and stereo!
selectivity were found to be good\ with the exception of the con_guration at C!3^ two epimers were
often observed[ The stereochemical outcome is consistent with a stepwise mechanism proceeding
via anion "016#[ The apparent need for carbamoyl substituents is presumably a re~ection of the
ability of the nitrogen atom to coordinate to lithium in the intermediates[
CONR2 E CONR2
CONR2 R R
– E+
+ (89)
–
R CONR2 R CONR2 R CONR2
R R R R
(127) (126)
"iii# Additions of allyl cations

Allyl cations are 1p fragments which are expected to react thermally with 3p partners\ that is\
they should rightly be categorised as dienophiles[ Indeed\ this strategy has been used in synthesis of
seven!membered rings ð75T3500Ł[ Noyori argued that allyl cations could be induced to react\ in a
symmetry!forbidden manner\ with alkenes if a nonconcerted mechanism was encouraged ð67JA0680Ł[
He postulated that this could be achieved by stabilising the cationic intermediate with an electron!
releasing group as discussed below[
When a\a?!dibromoketones "017# were reacted with Fe1"CO#8 "018#\ intermediates "029# were
formed which added successfully to a range of aryl!substituted alkenes with excellent yields in some
cases "Scheme 26# ð67JA0680Ł[ Despite the stepwise nature of the reactions\ they proceeded with
retention of alkene stereochemistry and are therefore synthetically useful[
R2 R3 O
O LnFe
Fe2(CO)9 O Ar R1 R1
R1 R1
R1 R1
Ar
Br Br +
R2 R3
(128) (129) (130)
Scheme 37
The main disadvantage of the methodology is the limited range of a\a?!dibromoketones which
can be used ð75T3500Ł\ the most severe limitation being the failure of the simplest example\ a\a?!
dibromoacetone\ to react[ This means that the products will inevitably bear alkyl substituents\ which
may be unwanted[ Unfortunately this problem was not resolved by the introduction of a mixed
lanthanumÐtin chloride reagent ð78BCJ1237Ł[
An alternative approach to the generation of allyl cations has been developed by the group of
Ho}mann ð77T2788Ł\ who investigated the use of alkoxy and trialkylsilyloxy groups for the stabil!
isation of the cationic intermediates[ These variations permitted the introduction of allylic alcohols
as starting materials[ The allylic alcohols "020# react with Lewis acids such as titanium tetrachloride
to form the allyl cations "021# "Equation "89##[ Despite the observation of one ð2¦1Ł adduct in a
reaction with a diene\ the reactions of these cations with simple alkenes do not appear to have been
studied ð77T2788Ł[
OR2 OR2
TiCl4
R1 R1 R1 R1 (90)
+
OH
R1 R1 R1 R1
(131) (132)
R2 = alkyl, R3Si
"iv# Meta photocycloaddition of arenes

The photocycloaddition of arenes to alkenes has been intensely studied from a theoretical and
mechanistic point of view ð82CRV504Ł[ The simplest example\ the reaction of benzene with ethene\
is shown in Equation "80#[ Variation by substitution both on the benzene nucleus and on the alkene
is possible ð82CRV504Ł[ The intramolecular version of the meta photocycloaddition is illustrated by
the reaction of phenylpentene "022# "Equation "81##[ It is clear that such reactions are uniquely
powerful for the rapid construction of polycyclic skeletons[ The production of cyclopentane units
is of particular interest[
hν
+ (91)
hν
(92)
(133)
The intermolecular meta photocycloaddition reaction has not found much synthetic application
ð82CRV504Ł[ However\ Wender and co!workers have shown that the intramolecular version is a
valuable synthetic tool ð89PAC0486Ł[ For example\ their synthesis of silphinene "023# is remarkably
short "Scheme 27#[ The production of two isomers in the _rst step is typical of these cycloadditions\
but\ if the number of possible isomers is considered\ this selectivity is excellent[ The reviews by
Cornelisse ð82CRV504Ł and Wender ð89PAC0486Ł are recommended for further reading[
hν
+
Li-MeNH2
(134) (±)-Silphinene
Scheme 38
The enantiomerically pure arylpentene "024# can be rapidly converted to "−#!retigeranic acid
"025# "Scheme 28#[ The development of a catalytic asymmetric version of the process remains a
signi_cant challenge[
hν H
HO2C
(135) (136) (–)-Retigeranic acid
Scheme 39
0[97[1[3[1 ð2¦1Ł Additions of CXC fragments
"i# Additions of carbonyl ylides

Disconnection of a tetrahydrofuran gives\ among other possibilities\ an alkene and a carbonyl
ylide "Scheme 39#[ Some simple methods of preparing carbonyl ylides and representative examples
of their cycloaddition reactions are discussed below[ The problems posed by carbonyl ylides are
largely due to their highly reactive and transient nature[
+
O O
–
Scheme 40
The earliest approaches to carbonyl ylides involved thermolysis or photolysis of certain epoxides
"Scheme 30# ðB!65MI 097!91Ł[ A logical extension of this chemistry was to facilitate the thermolysis
by incorporating a group which would undergo extrusion\ nitrogen from oxadiazolines "026# or
carbon dioxide from dioxolanones "027# being appropriate ð80COS"3#0958Ł[ The simple cycloaddition
chemistry of these compounds is summarised in Padwa|s review ðB!73MI 097!90Ł[ The regiochemistry
of the reactions is predictable from FMO theory if one uses the carbonyl ylide HOMO in reactions
with electron!poor alkenes and the ylide LUMO in reactions with electron!rich alkenes
ð80COS"3#0958Ł[
O
N N
(137)
O
O
–N2
O
O
(138)
–CO2
+
O
–
Scheme 41
FMO theory is also useful for prediction of the stereochemical outcome of the reaction[ Hence\
for example\ the epoxide "028# opens in a symmetry!allowed fashion on thermolysis\ that is\ with
conrotation\ to produce the carbonyl ylide "039#\ which\ in turn\ reacts with the alkene trap with
retention of alkene stereochemistry\ as expected "Scheme 31#[ The endo:exo selectivity cannot\ of
course\ be predicted from FMO theory[ In fact\ mixtures of stereoisomers usually result[
MeO2C
Ph Ph Ph Ph
O + O O
Ph heat Ph O Ph CO2Me
–
H CN + H CN
Ph
CN CN MeO2C CO2Me MeO2C CO2Me
(139) (140)
Scheme 42
The thermal and photochemical ring!opening reactions described above do have synthetic limi!
tations as these conditions can accelerate other\ unwanted reactions[ A method which avoids use of
these more forcing conditions is the reaction of a carbene or carbenoid with a carbonyl compound
"Equation "82##[ This chemistry has been extensively studied by the group of Padwa\ and reported\
along with leading references to related work\ in a review ð80ACR11Ł^ the combination is particularly
e}ective when the carbeneÐcarbonyl reaction is intramolecular\ as in Scheme 32[
+
N2 O transition metal O
+ –
(93)
O
OMe OMe Ph
O N O MeO NPh
O Cu O +
O
– O
N2
O O
O
Scheme 43
Padwa|s group have also investigated intramolecular trapping of carbonyl ylides ð80ACR11Ł[ The
example shown in Scheme 33 is typical and demonstrates how this {tandem cyclisation| procedure
can quickly assemble a polycyclic skeleton[ The regiochemistry and relative stereochemistry become
excellent when the alkene and ylide are tethered in this manner[
The major disadvantage of the rhodium carbenoid approach is that an a!keto group is a prerequi!
site[ Alternative methodology\ based on halosilane elimination\ o}ers an answer to this problem
ð82TL4832Ł\ although only arylcarbonyl ylides have been prepared in this way[ The reaction of "030#
O O
O
O Rh O + O
–
N2
O O O
Scheme 44
with caesium ~uoride promotes the elimination of the elements of trimethylsilylchloride to generate
the carbonyl ylides "031# "Equation "83##[ Intermolecular trapping of these ylides proceeds with
retention of stereochemistry of the alkene[ Regiochemistries and relative stereochemistries are not
outstanding\ however[
Ar –
CsF
Ar O (94)
TMS O Cl +
(141) (142)
The rhodium carbenoid and halosilane elimination routes to carbonyl ylides are complementary[
The use of these routes in intramolecular cycloadditions to alkenes provides a powerful method for
the construction of tetrahydrofuran!based polycyclic compounds[
"ii# Additions of thiocarbonyl ylides

The methods of generation of the sulfur compounds "032# are similar in many respects to those
used for their oxygen counterparts[ Hence\ extrusion of nitrogen from heterocyclic compounds
"033# ð65T1054Ł\ addition of carbenes to thiocarbonyl groups ð72TL3070\ 73BSB400\ 74TL2900Ł and
elimination from silyl precursors "034# ð75TL3928Ł all provide access to the reactive intermediates
"032# "Scheme 34#[
S :
+ O
S
TMS S TMS
N N
(144)
–N2 –(TMS)2O (145)
+
S
–
(143)
Scheme 45
The cycloadditions of thiocarbonyl ylides to some\ mainly electron!de_cient\ alkenes have been
studied "e[g[\ Scheme 35#[ Prediction of the regiochemistry of the reaction appears di.cult ð65T1054Ł
but\ as expected\ the reactions proceed with retention of stereochemistry of the alkene and with
rather good endo:exo selectivity[
S Ph
O O N O
+ Ph
TMS S TMS S Ph
– O O
Ph N
Ph
Scheme 46
There have been few synthetic applications of thiocarbonyl ylides ð80COS"3#0958Ł[ Only a handful
of intramolecular examples are known ð80COS"3#0000Ł and there appears to have been no report of
an asymmetric version of the reaction[ This may be due to the tendency of the thiocarbonyl ylides
"032# to isomerise to the corresponding thiirane\ which as an intramolecular reaction can compete
favourably with an intermolecular cycloaddition[
"iii# Additions of azomethine ylides

The nitrogen analogues of carbonyl and thiocarbonyl ylides are called azomethine ylides\ and
these ylides have become widely used in organic synthesis[ The methods of generation of
these reactive intermediates are similar to those described above for carbonyl and thiocarbonyl
ylides\ and the reactivity of the ylides towards alkenes is also comparable[ As there are already a
number of reviews dealing with generation and trapping of stabilised azomethine ylides ð77H"16#870\
B!77MI 097!91\ 78AHC"34#120\ B!89MI 097!90\ 80COS"3#0958\ 80COS"3#0000Ł\ this chemistry will be brie~y
summarised[ In this review a more detailed discussion focuses on work involving nonstabilised
azomethine ylides and asymmetric azomethine ylide cycloadditions[
The principal routes to stabilised azomethine ylides "035# are from aziridines such as "036#\ by
thermolysis or photolysis\ from readily accessible oxazolidines such as "037#\ and from imines such
as "038#\ by thermal isomerisation "which can be acid!catalysed#[ These three methods are illustrated
in Scheme 36[ The intermolecular cycloaddition of a stabilised azomethine ylide to an alkene is
e.cient when the alkene possesses electron!withdrawing groups[ In this case the regioselectivity can
be predicted by considering the dipole HOMO and the alkene LUMO[ The 1\3!disubstituted
pyrrolidine product thus predominates if the alkene is monosubstituted "e[g[\ Equation "84##[
R R
– +
RO2C N R
R
(146)
MeO2C – +
MeO2C N
N
Ar
Ar
(147)
Me Me Me
+ +
PhSiH3, CsF N –
N N
Ph OEt
Ph O OEt Ph O OEt
O
(148)
CO2Me CO2Me
+
Ph N Ph N –
H
(149)
Scheme 47
CO2Bu
– +
MeO2C N + CO2Bu (95)
MeO2C N
Ar
Ar
The stereoselectivity of azomethine ylide cycloadditions is also typical of a concerted reaction[

Hence\ the stereochemistry of the alkene is retained[ Although stereoisomers are usually observed\
endo:exo selectivity can be very high[ The synthesis of allo!kainic acid "049# illustrates all these
points "Scheme 37#[ The electron!withdrawing groups are found in the 1 and 3 positions in the
cycloadduct[ The trans!alkene stereochemistry is observed as an anti relationship in the product\
and the endo:exo selectivity is excellent[
O OR O OR
CO2Me
O heat
N + +
OR 70%
N CO2Me N CO2Me
Ph
Ph Ph
98 : 2
CO2H
N CO2H
H
(150) allo-kainic acid
Scheme 48
The attempted parallel synthesis of kainic acid from the cis!enone "040# "Scheme 38# highlights
one of the main problems of the aziridine\ or any other thermal\ approach to azomethine ylides\
that is\ the relatively high temperatures required for the thermolysis[ Under these conditions the
thermal isomerisation of the enone from cis to trans is fast enough to pose a problem[ Another
potential pitfall is that\ although the aziridine thermolysis is stereospeci_c\ the stereochemistry of
the product ylide can be lost under the reaction conditions[
CO2H
O OR
N CO2H
(151) H
kainic acid
OR
Scheme 49
Although electron!de_cient alkenes are required for intermolecular cycloaddition to stabilised

azomethine ylides\ intramolecular reactions with unactivated alkenes can proceed smoothly
ð74T2436Ł[ This type of reaction was recognised as appropriate for the construction of the skeleton
of the marine alkaloid sarain A "Equation "85## ð80JOC2109\ 81JOC6945Ł[ The latter paper also
described a general strategy for the preparation of diazabicycloalkanes "041# using intramolecular
azomethine ylide cycloadditions[
O O Ph
H
Ph N N Ph N
heat Ph N
(96)
H OBn
OBn
O CO2Et
NR
RN
( )n
H
(152) n = 1–3
All of the reactions outlined so far have involved stabilised azomethine ylides\ which are more
accessible than their nonstabilised counterparts[ Silyl precursors to carbonyl and thiocarbonyl ylides
have already been described\ and this methodology has also been applied to the formation of
nonstabilised azomethine ylides[
The disadvantages of the earlier desilylation routes to azomethine ylides are highlighted in a
paper which describes an apparently superior method ð82TL3750Ł[ Bis"trimethylsilyl# derivatives of
certain trialkylamines were reacted with silver ~uoride[ The azomethine ylide intermediates were
trapped by alkenes "and other dipolarophiles# in quantitative yield to produce pyrrolidines[ The
utility of the process was illustrated by the synthesis of pyrrolizidine and indolizidine skeletons
"Scheme 49#[ Although the regioselectivity and stereoselectivity are modest\ the combined yield of
87) is very good for the trapping of a reactive intermediate[
TMS CO2Et H CO2Et H

AgF
N
+ +
N ( )n 98% CO2Et
( )n TMS – ( )n N ( )n N
n = 1–2 85%, 40% de 15%
Scheme 50
Azomethine ylide cycloaddition to alkenes is one of the few categories of _ve!membered ring
formation where signi_cant asymmetric induction has been realised^ this has been achieved through
the use of chiral auxiliaries[ In principle\ the auxiliary could be placed on either the ylide or the
alkene partner in the cycloaddition[ Indeed\ successful applications of both these strategies have
been reported ð83AG"E#572\ 83JOC3Ł\ and high levels of stereoselection are observed with the use of
well!known\ recoverable auxiliaries[
The attachment of Oppolzer|s chiral sultam to either an aziridine or imine precursor has been
demonstrated to lead to azomethine ylides which react with alkenes with\ in some cases\ high endo
selectivity and with excellent diastereofacial selectivity "Scheme 40# ð83JOC3Ł[ Interestingly\ the
stereochemistry of the product depends on which method is used to generate the ylide[ This can be
explained by assuming that the aziridine!derived ylide is cis whereas a trans!ylide results from the
imine tautomerisation[
Ar
Ar Ar MeO2C CO2Me
heat +
N COX*
N N
–
82%
COX* COX*
MeO2C CO2Me
80% de
Ar
Ar MeO2C CO2Me N
PhCHO Ph COX*
H2N COX* Ph N + COX*
TsOH 82%
–
X* = Oppolzer's sultam MeO2C CO2Me
85% de
Scheme 51
The most impressive stereoselectivities have been observed\ however\ under the in~uence of
alkene!bound auxiliaries[ For example\ the reaction of the proline!derived acrylamide "042# with
various imine!derived azomethine ylides proceeded\ in several cases\ with essentially complete
control of stereochemistry to yield only one isomer "Scheme 41# ð83AG"E#572Ł[ It was also dem!
onstrated that the auxiliary could be removed by acid hydrolysis[
CO2Bn
O CO2Bn
N O
Li
R2 N CO2Me R3N, LiBr + (153) N
R2 N – CO2Me
R1 R1
R1 R2 N CO Me
H 2
98% de
Scheme 52
"iv# Additions of azaallyl anions

1!Azaallyl anions "043# are the nitrogen analogues of allyl anions "see Section 0[97[1[3[0#^ cyclo!
addition of these entities to alkenes\ when followed by protonation\ is equivalent to the addition of
the corresponding azomethine ylide "see Section 0[97[1[3[1[iii#[ Indeed\ the azaallyl addition is
complementary to the azomethine ylide addition\ since the latter species generally require electron!
poor alkenes ð83TL1530Ł[
–
N
(154)
The early work on the cycloaddition reactions of azaallyl anions was carried out by the group of
Kau}mann ð63AG"E#516Ł[ Two methods of preparing the anions were described\ the lithiation of an
imine "044# by a dialkylamide and the ring!opening reaction of a lithiated aziridine "045#[ The
reactions with alkenes are typi_ed by high regioselectivity\ for example as in Scheme 42[ Although
this was\ perhaps\ indicative of a stepwise mechanism\ the stereochemistry of the reaction suggested
otherwise\ the alkene stereochemistry being retained[ A stepwise mechanism via a strongly lithium!
bound intermediate\ as proposed by Kau}mann\ would explain both these phenomena\ and appears
most plausible[
R1 R2 R2NLi R1 R2
–
Ph N Ph N
(155)
Ph Ph
Ph
N –
Ph N
Li
(156)
Ph
Ph Ph
–
Ph
Ph N N
Ph H
?
Ph
Li
Ph
N
Ph
Scheme 53
Both the methods described by Kau}mann for the preparation of azaallyl anions are restricted
to cases where the anions are stabilised enough for their formation to be thermodynamically possible
but not so much that they do not react ðB!89MI 097!90Ł[ These restrictions are perhaps responsible
for the fact that Carruthers|s 0889 review of the area revealed few developments[
Although a desilylation strategy was successful in producing azaallyl anions\ this route was limited
to the production of stabilised anions ð76JOC1412Ł[ Nonstabilised azaallyl anions became more
readily accessible when the reaction of trialkylstannylmethanimines "046# with alkyllithiums was
investigated ð81JA0218Ł[ Precursors "046# were prepared by an aza!Wittig reaction "Equation "86##[
Reaction with either methyl! or butyllithium and an alkene trap produced pyrrolidine products in
high yields[ Although the stereochemistry of the alkene was found to be retained\ mixtures of
regioisomers and diastereoisomers were usually observed "Scheme 43#[ The preference for the
more sterically crowded regioisomer is consistent with the results from the Kau}mann group
ð63AG"E#516Ł[
PPh3, R2R3CO R3
N3 SnR13 (97)
R2 N SnR13
(157)
Ph Ph
Ph
RLi – i,
But N SnR3 But N +
ii, MeI N But N But
Me Me
Scheme 54
One of the remaining problems with the azaallyl anion methodology was the need for the
activating "usually aryl# group on the alkene\ which might well be an unwanted substituent[ This
restriction can be removed by use of vinyl sul_des\ selenides and silanes[ The heterosubstituent on
the product pyrrolidine can thus be removed readily after it has ful_lled its function as an activator
ð81JA0218Ł[
As expected\ the intramolecular addition of azaallyl anions to alkenes has proved less prob!
lematical than the intermolecular reaction[ Hence\ stabilised anions have been shown to add
successfully to unactivated alkenes with a reasonable degree of stereoselectivity "Equation "87##
ð75JA1658Ł[ Nonstabilised azaallyl anions have also been shown to take part in intramolecular
cycloadditions ð81JA0218Ł[
H H
LDA
Ph + Ph (98)
63% N N
N Ph
H H H H
85% 15%
0[97[1[4 Formation of Six!membered Rings

The reaction of a diene\ or a heterodiene\ with a dienophile is usually known as the DielsÐAlder
reaction[ This process has won recognition as one of the most powerful synthetic methods[ As a
new C1C bond is formed in the reaction\ it is classi_ed in Chapter 0[06[ However\ to permit
comparison with the related cycloadditions in this chapter a very brief account is provided here[
The other restrictions on scope have been applied[ Thus\ DielsÐAlder reactions of alkenes with
dienes\ or heterodienes with two carbon termini\ qualify[
0[97[1[4[0 ð3¦1Ł DielsÐAlder additions of dienes
"i# Intermolecular additions

Intermolecular DielsÐAlder reactions ð80COS"4#204Ł generally proceed with retention of both
alkene and diene stereochemistries\ but the regiochemistry and endo:exo selectivity is often poor[
The reaction in Equation "88# is typical[ Without doubt the most signi_cant advance in DielsÐAlder
chemistry was the discovery that Lewis acids catalyse the process[ Thus\ aluminum trichloride
controls the reaction in Equation "88#\ making it highly regioselective and endo selective while
reducing the optimum temperature from 019>C to 19>C ð56JOC758Ł[
CO2Me
CO2Me CO2Me
+ + + + (99)
CO2Me CO2Me
No catalyst 45 : 39 : 11 : 5
0.15 equiv. AlCl3 93 : 5 : 2 : 0
In 0872\ other methods of improving on the reactivity and selectivity of DielsÐAlder reactions
were investigated[ The reduction in reaction time\ increase in yield and improved selectivity observed
when using the sodium carboxylate "048# in water\ rather than the traditional ester "047# in benzene\
are most impressive results "Equation "099## ð72TL0786Ł[ High pressure and ultrasound have been
used to promote DielsÐAlder reactions "e[g[\ Equation "090##[ Although less attractive than Lewis
acids they may prove useful in reactions where the dienophile lacks a group which is able to
coordinate to a Lewis acid ð80COS"4#204Ł[
MeO MeO MeO

CO2R CO2R CO2R
CHO
(158) or (159)
CHO + CHO (100)
O O O
H H H
(158) R = Et, benzene, 288 h, 52% 46 : 54
(159) R = H, water, 5 h, 100% 75 : 25
O-MOM O O-MOM
CO2Me
OMe
+ (101)
0.001 kbar, 0%
15 kbar, 70%
CO2Me CO2Me
High diastereofacial selectivity has also been achieved in the intermolecular DielsÐAlder reaction[
The chiral auxiliary approach has proved extremely e}ective ð80COS"4#204Ł[ The auxiliary can be
attached to either the alkene "Equation "091## or\ less commonly\ the diene "Equation "092##[ Once
again\ the use of Lewis acid catalysts is central to the success of the reactions[
O TiCl4, –10 °C
+ O + (102)
81%
O CO2R*
O CO2R*
97 : 3
O O O
Ph
O CHO BF3 O R* O R*
OMe
+ CHO + CHO (103)
97 : 3
Chiral Lewis acids have been used to catalytically control the absolute stereochemistry of DielsÐ
Alder reactions ð81CRV0996Ł[ Impressive results have been obtained in this area\ with chiral boron\
aluminum and titanium Lewis acids being particularly e}ective "e[g[\ Scheme 44# ð78JA4382\ 80JA6683\
80TA532Ł[
CO2Me [B]*
+
97%
CO2Me
97% ee
BnO
O O
OBn [Al]*
+ N
O N
O
95% ee
O O
[Ti]*
+ N
O
O N
O
O
94% ee
Ph
Ph Ph
O-TMS
[B]* = BCl2 [Al]* = F3CO2SN NSO2CF3 [Ti]* = TiCl4 +
Al O-TMS
R
Ph
Scheme 55
"ii# Intramolecular additions

The intramolecular DielsÐAlder reaction has also found widespread use in synthesis ð80COS"4#402Ł[
The steric constraints of the tether will usually obviate the problem of regiochemistry[ However\
mixtures of stereoisomers do result[ The example in Equation "093# is typical[ As there is a pre!
existing chiral centre\ endo:exo and diastereofacial selection are both involved[ The importance of
Lewis acid catalysis is demonstrated once again[ With dimethylaluminum chloride the reaction
proceeds at room temperature and with much higher stereoselectivity ð73JOC4166Ł[
CHO
R3SiO
CHO CHO CHO CHO
+ + + (104)
OSiR3 OSiR3 OSiR3 OSiR3

Thermal 27 : 27 : 33 : 13
EtAlCl2 15 : 75 : 10 : 0
Asymmetry has been induced in intramolecular DielsÐAlder reactions by chiral auxiliaries

ð80COS"4#402Ł\ in a similar manner to the intermolecular counterparts\ and also by the use of
chiral Lewis acid catalysts ð81CRV0996Ł[ The intramolecular DielsÐAlder reaction in Equation "094#
illustrates how two new rings and four contiguous new chiral centres can be formed in one reaction
with almost complete control of stereochemistry ð80TA0294Ł[
O
O
O O O N
[Ti]* H
N (105)
O
70%
S
S S
S H
>95% ee
0[97[1[4[1 ð3¦1Ł DielsÐAlder additions of heterodienes

DielsÐAlder reactions of alkenes and heterodienes with two carbon termini "059# are not common
ð80COS"4#340Ł[ 1!Azabutadienes have been employed in this connection] Scheme 45 illustrates an
elegant method for the preparation of the heterodiene by desilylation of an imide[ Addition to
maleic anhydride proceeded with high endo selectivity to give one major product ð71JA0317Ł[
X X
(160)
H O
O TBDMS-O O O O O
TBDMS-OTf, Et3N
N N O
H H 92% HN
O O-TBDMS H O
TBDMS-O
Scheme 56
1.09
One or More CH and/or
CC Bond(s) Formed by
Rearrangement
IAIN COLDHAM
University of Exeter, UK
0[98[0 TYPES OF REACTION 266
0[98[0[0 Substituent Mi`rates as a Cation 267
0[98[0[0[0 0\1!Electrophilic mi`ration 267
0[98[0[0[1 TruceÐSmiles rearranèment 268
0[98[0[1 Substituent Mi`rates as an Anion 268
0[98[0[1[0 Wa`nerÐMeerwein rearranèment 279
0[98[0[1[1 Pinacol rearranèment 273
0[98[0[1[2 Rearranèment of epoxides 275
0[98[0[1[3 Semipinacol rearranèment 277
0[98[0[1[4 Favorskii rearranèment 280
0[98[0[1[5 Wolff rearranèment 282
0[98[0[2 Substituent Mi`rates as a Radical 284
0[98[0[2[0 0\1!Witti` rearranèment 285
0[98[0[2[1 0\1!Stevens rearranèment 287
0[98[0[3 Si`matropic Rearranèments 399
0[98[0[3[0 0\2!Si`matropic rearranèments 399
0[98[0[4 Electrocyclic Reactions 306
0[98[0[4[0 Cyclobutene formation 307
0[98[0[4[1 Cyclohexadiene formation 308
0[98[0[4[2 Nazarov cyclisation 310
0[98[0 TYPES OF REACTION

This chapter will address the preparation of saturated carbon atoms with no attached heteroatoms
by rearrangement reactions[ Reviews in this area have normally focused on a speci_c rearrangement
reaction\ although a number of more general reviews are available ðB!52MI 098!90\ B!62MI 098!90\
B!81MI 098!90Ł[ The following sections are arranged according to the type of migrating group[ In
most cases it is easy to distinguish which is the migrating group and which the backbone and this
review will use the conventional terminology in which both the breaking and forming bonds are to
the same migrating carbon or hydrogen atom[ When the group migrates without its bonding
electrons the rearrangement is said to involve the migration of the substituent as a cation^ with its
bonding electrons the substituent migrates as an anion and with a single bonding electron as a
radical[ The use of sigmatropic rearrangements and electrocyclic reactions will also be discussed for
the preparation of new C0C or C0H bonds[
266
267 CH and:or CC Bonds Formed by Rearranèment
0[98[0[0 Substituent Migrates as a Cation
The migration of a substituent as a cation "electrophilic rearrangement# is possible by a stepwise
mechanism\ normally involving initial anion formation\ interaction of the anion with the migrating
group R and rearrangement to give a new anion "Scheme 0#[ This type of rearrangement is\ however\
rare in comparison with the migration of a substituent as an anion[ The migrating group R must
be one which is able to support an additional pair of electrons such as an aromatic ring[
R R
– –
Scheme 1
If the migrating group R is a saturated carbon atom then a concerted mechanism would necessitate
inversion at the carbon!centred R group[ The forming C0C and breaking C0C bonds would then
have to become colinear in the three!membered ring transition state and this situation would clearly
not be favoured[ As a result\ there are no known examples of such a concerted 0\1!electrophilic
rearrangement[ The related 0\1!Wittig and 0\1!Stevens rearrangements have been found to involve
radical pair intermediates and these rearrangements are discussed under migration of a substituent
as a radical in Section 0[98[0[2 and in Chapter 0[07[
0[98[0[0[0 0\1!Electrophilic migration

A new C0C bond can be formed on metallation of 0\0!diaryl!1!haloalkanes or 0\0\0!triaryl!1!
haloalkanes\ by migration of an aromatic ring[ The best method appears to be the use of sodium
metal to form the carbanion "0# at the migration terminus ð46JA3874\ 46JA4344Ł[ An aromatic group
then migrates to give the more stable carbanion "1# in which the negative charge is delocalised
around the remaining aromatic substituents "Scheme 1#[ If the reaction is quenched with an alcohol
then a new C0C bond "by rearrangement# and a new C0H bond "by quenching# are formed[
Quenching with CO1 is also possible and this sets up two new C0C bonds[
Ph 2 Na, dioxane
Ph Ph Ph
Ph ROH
Cl Ph CH2– – Ph Ph
Ph Ph Ph Ph
(1) (2)
CO2
Ph
Ph
Ph
–O C
2
Scheme 2
In addition to the sodium salt it has been shown that this rearrangement can be e}ected with the
lithium or potassium salt of "0#[ The potassium derivative can be prepared from the chloride with
potassium metal in DME ð50JA301Ł[ Rearrangement of the potassium salt of "0# occurs at −49>C
whereas the corresponding lithium salt must be warmed to 9>C or higher for any rearrangement to
occur[ These facts suggest that the reaction is indeed anionic rather than radical as the propensity
for rearrangement increases with the increasing ionic character of the carbonÐmetal bond[ Further
con_rmation of the anionic nature of the rearrangement has been obtained from the chloride
"2# "Scheme 2#[ The potassium salt rearranges instantaneously and can be prepared from the
dialkylmercury derivative\ which in turn can be prepared from the magnesium Grignard of the
starting halide "2# ð50JA0085Ł[ Neither the magnesium nor the mercury derivatives undergo
rearrangement and the lithium derivative "3# must be heated before rearrangement occurs[ The new
C0C bond forms to the phenyl group rather than the methyl group as the phenyl group is
better able to stabilise the negative charge during migration[ Rearrangement of 1!phenyl!1!"p!
tolyl#propyllithium occurs with preferential migration of the phenyl group which lends further
support to the carbanion rather than free radical mechanism[
Types of Reaction 268
Ph Mg, THF Ph HgCl2 Ph
Ph Ph Ph
Cl MgCl Hg
(3) 2
i, K, THF, –50 °C
Li, Et2O, 0 °C ii, CO2
Ph 40 °C Li CO2 Ph
Ph Ph
Li Ph Ph
HO2C
(4)
Scheme 3
0[98[0[0[1 TruceÐSmiles rearrangement

The Smiles and related rearrangements have been reviewed ð69OR"07#88Ł[ Like the 0\1!electrophilic
migrations discussed in Section 0[98[0[0[0\ the TruceÐSmiles rearrangement allows the formation of
a new C0C bond to an aromatic ring ð47JA2514Ł[ Yields are best with 1\5!disubstituted aryl sulfones
such as "4# ð48JA370Ł[ Deprotonation with BunLi in ether has been used most commonly and gives
a red anion which\ after rearrangement is quenched to give the o!benzylarenesul_nic acid "Scheme 3#[
BunLi, Et2O 98%

SO2Ph SO2Ph SO2H
Li Ph
(5)
Scheme 4
The migration of a p!tolyl group maintains the p!tolyl con_guration in the product\ so dem!
onstrating that attack of the carbanion takes place on the aromatic ring at the carbon atom which
is bonded to sulfur[ However\ the migration of a 0!naphthyl group gives the 1!naphthyl derivative
ð69JOC0717Ł[ Migration of a tertiary alkyl group can be e}ected under similar conditions ð75JA2355Ł
although in this case the mechanism involves radical intermediates[
0[98[0[1 Substituent Migrates as an Anion

Rearrangement reactions which involve formation of a new C0C or C0H bond by migration
of a substituent as an anion are relatively common in organic chemistry "nucleophilic rearrange!
ments# ðB!59MI 098!90Ł[ They can be represented as shown in Scheme 4 with initial cation formation
by loss of X−\ followed by migration of the R group with its bonding electrons to give a new cation
"5# at the migration origin[ The extent to which the R group migrates before complete ionisation at
the migration terminus depends on a number of factors\ not least the leaving group ability of X and
the stability of the initial cation[ Inversion of con_guration at the migration terminus is often
observed "when this centre is chiral#\ suggesting some interaction of the R group with the developing
cation rather than complete ionisation[ When the R group contains a chiral centre at the migrating
carbon\ then the con_guration at this centre is retained completely[ Nucleophilic rearrangements
give rise to a new C0C or C0H bond at the migration terminus\ leaving the more stable\ usually
more substituted cation "5#\ with the positive charge at the migration origin[ This cation can then
react with a nucleophile or lose a proton "or other positively!charged species# to give the _nal
rearranged product[ If one of the substituents which remains at the migration origin is an alcohol
or alkoxide then the new carbocation will be quenched to give a carbonyl group[ This is the most
common type of substrate for nucleophilic rearrangements and sets up a new C0H or C0C bond
a to a carbonyl group[
R R R
+ +
X
(6)
Scheme 5
A discussion of which group migrates in the rearrangement and further stereochemical impli!
cations are outlined in the following sections and in Chapter 0[07[ A discussion of WagnerÐMeerwein
rearrangements\ pinacol rearrangements\ rearrangements of epoxides\ semipinacol rearrangements\
Favorskii rearrangements and Wol} rearrangements are given\ as these illustrate the types of
functional group transformations which are possible by nucleophilic rearrangement[
0[98[0[1[0 WagnerÐMeerwein rearrangement

In this section attention will focus on the new C0C bond formed and the type of bicyclic ring
system generated by a WagnerÐMeerwein rearrangement[ There are a number of general reviews in
this area ðB!59MI 098!90\ B!52MI 098!90\ 74MI 098!90\ 80COS"2#694Ł[ This section will also cover formation
of a new C0H or C0C bond when the migrating bond is not part of a ring system[
The WagnerÐMeerwein rearrangement is a nucleophilic rearrangement involving 0\1!migration
of a ring carbon atom in a bicyclic or polycyclic molecule[ As such it gives rise to a new bicyclic or
polycyclic ring system\ and so can be a powerful technique for the generation of complicated
structures\ with C0C bonds in positions di.cult to access by conventional chemistry[ Original
work by Wagner and Brickner centred on the rearrangement of a!pinene "6# to bornyl chloride "7#
"Equation "0## ð0788CB1296Ł and Meerwein and Van Emster proposed the involvement of cationic
intermediates ð11CB1499Ł[ There have been a number of mechanistic studies "see general reviews and
references therein#\ the most widely accepted involving a two electron\ three!centre bond\ termed a
carbonium ion or non!classical carbonium ion[
HCl
(1)
Cl
(7) (8)
WagnerÐMeerwein rearrangements are best known in terpenoid systems where the presence of
branched bicyclic rings promote cationic rearrangements[ The initially formed carbocation is nor!
mally generated by\ either loss of a good leaving group or\ protonation of an alkene[ Rearrangement
then generates a new C0C bond with retention of absolute con_guration at the migrating carbon
and a new\ usually more stable\ bicyclic carbocation[ This tends to limit the new C0C bond to be
part of a _ve! or six!membered ring[ In concerted rearrangements the best alignment would occur
when the leaving and migrating groups are antiperiplanar[ Such an arrangement is rarely the case
in constrained bicyclic systems\ however this stereochemical preference allows the prediction that
the best aligned bond will be the one that migrates[ For example\ the exo!brosylate "8# rearranges
exclusively to the endo!brosylate "09#\ whereas the endo!brosylate "00# rearranges quantitatively to
the brosylate "01# "Scheme 5# ð53JA1611Ł[ In both cases the four!membered ring is opened\ with
exclusive migration of the carbon atom of the four!membered ring which is anti to the brosylate
leaving group[ Of the six s!bonds adjacent to the carbocation "02#\ only two are roughly coplanar
with the empty p!orbital[ WagnerÐMeerwein rearrangement gives the bicyclic system "03#\ "Equation
"1## whereas methyl group migration "Nametkin rearrangement# gives the carbocation "04# "Equa!
tion "2##[ Both these pathways generate a new C0C bond and a new carbocation which can undergo
further rearrangement or be quenched by attack of a nucleophile or by proton loss[
Wagner–Meerwein
+ (2)
+
(13) (14)
Nametkin
+ + (3)
(13) (15)
OBs +
OBs
(9) (10)
OBs OBs
(11) (12)
Scheme 6
The possibility of a number of competing rearrangement pathways may limit the synthetic
usefulness of a strategy based on the WagnerÐMeerwein rearrangement[ Protonation of fenchyl
alcohol "05# gives rise to a number of rearranged products of which the alkene "06# "the product of
a WagnerÐMeerwein rearrangement# and the alkene "07# "the product of a Nametkin rearrangement#
predominate "Equation "3## ð65ACR146Ł[ In addition\ racemisation of optically!pure starting material
is possible\ particularly if a symmetrical carbonium ion is formed[ Treatment of optically!pure
norbornyl brosylate "08# with acetic acid gives racemic norbornyl acetate "Equation "4## ð41JA0043\
38JA1842Ł[ Racemisation can sometimes be avoided by incorporation of an appropriate substituent
ð65JCS"P0#248Ł[
OH
+ (4)
(16) (17) (18)
AcOH
+ (5)
OBs OAc AcO
(19)
By careful consideration of the possible rearrangement pathways\ the WagnerÐMeerwein

rearrangement can be used successfully in syntheses involving the construction of new C0C bonds
and complex bicyclic structures[ So far in this section\ only rearrangements which give the bornane
skeleton "a bicycloð1[1[0Łheptane ring system# have been outlined[ WagnerÐMeerwein rearrange!
ments have been used for the synthesis of other ring systems such as the bicyclooctanes based on
the ð2[1[0Ł\ ð1[1[1Ł and ð2[2[9Ł arrangements[ Examples of each of these structural classes will be
described[
The bicycloð1[1[0Łheptane ring system has received the most study and has been the subject of
mechanistic work[ This ring system can be prepared by rearrangement of the bicycloð2[0[0Ł\ ð1[1[0Ł
or ð2[1[9Ł carbocations as outlined in Scheme 6[ New C0C bond formation by rearrangement of
the bicycloð2[0[0Ł carbocation has been discussed[ The bicycloð1[1[0Ł skeleton can also form a useful
approach to the bornane system by WagnerÐMeerwein rearrangement[ For example\ rearrangement
of the secondary carbocation\ generated by tosylation of the alcohol "19#\ takes place to give the
more stable tertiary carbocation which loses a proton to give "−#!b!santalene "10# "Equation "5##
ð63JCS"P0#0827Ł[ Formation of a new C0C bond in the bicycloð1[1[0Łheptane system by rearrange!
ment of a bicycloð2[1[9Ł carbocation is less common ð54JOC3129Ł[
; ;
+ +
+
[2.2.1]
Scheme 7
TsCl, pyridine
OH (6)
(20) (21)
The bicycloð2[1[0Łoctane ring system has been prepared from a number of di}erent bicyclic rings
as illustrated in Scheme 7[ Common to many examples of WagnerÐMeerwein rearrangements is the
presence of a bridgehead methyl or hydroxyl group to stabilise the new carbocation[ For example\
rearrangement of the bicyclooctane "11# with BF2 = OEt1 generates the carbocation "12#\ which is
stabilised by the methyl substituent ð56T682Ł[ Suitably activated bicycloð3[1[9Łoctane rings "often
conveniently accessed by ð1¦1Ł cycloaddition# can be used to prepare the bicycloð2[1[0Łoctane ring
system[ This approach has been used towards the synthesis of a!caryophyllene\ as illustrated in
Scheme 8 ð53JA0541Ł and towards the trichothecenes ð70JOC2265Ł[ New C0C bond formation by
rearrangement of the bicycloð1[1[1Ł carbocation has also provided a useful route to the
bicycloð2[1[0Łoctanes ðB!52MI 098!90\ 71HCA260Ł[ Conversely\ the bicycloð2[1[0Ł carbocation may be
used for the construction of the bicycloð1[1[1Łoctane\ although this is much rarer ð61JCS"P0#0163Ł[
; ;
+ + +
[3.2.1]
;
+
+
Scheme 8
BF3•OEt2 +
O OH
H OH H
H
AcO AcO
H H
(22) (23)
OH H
H H
H2SO4
OH
H H
Scheme 9
The formation of a new C0C bond as part of a bicycloð2[2[9Łoctane ring can be accomplished
from the bicycloð2[1[0Łoctane or bicycloð3[1[9Łoctane ring systems "Scheme 09#[ From a
bicycloð2[1[0Łoctane\ ring contraction must take place ð70TL3202\ 73JOC1826Ł\ whereas a combined
ring expansionÐcontraction of a bicycloð3[1[9Łoctane gives rise to the ð2[2[9Ł ring system[ This type
of WagnerÐMeerwein rearrangement of the ð3[1[9Ł ring system has been used in the synthesis of
isocomene "13# "Equation "6## ð70JA71Ł and quadrone ð73JOC3983Ł[
;
+
[3.3.0]
Scheme 10
TsOH, benzene
(7)
(24)
Other bicyclic ring systems may undergo WagnerÐMeerwein rearrangement\ as may systems in
which the carbocation is not part of the bicyclic framework[ These latter cases are best described as
simple ring expansions\ exempli_ed by the Demjanov rearrangement shown in Equation "7#[ Like the
WagnerÐMeerwein rearrangement\ the ring expansion of the cyclopropylmethyl cation is believed to
involve nonclassical carbonium ions ð48JA3289Ł[ Its usefulness in terms of setting up a new C0C
bond by rearrangement is limited by the mixture of products normally formed and because scram!
bling of the carbon atoms occurs[ In the related four! to _ve!membered ring expansion reactions
there is no evidence for nonclassical ions ð96CB3848Ł[
NH2 NaNO2, HClO4 (aq.) OH

+ + OH (8)
60% OH
47 : 48 : 5
Related to the WagnerÐMeerwein rearrangement is the 0\1!alkyl shift known as the Nametkin
rearrangement[ This is most commonly observed in ring systems where the original carbocation is
generated adjacent to a geminal dialkylated or other tetrasubstituted carbon atom[ For example\
the alkene "07# is formed by dehydration of the alcohol "05# "vide supra#[ A combination of Nametkin
and hydride shifts occur in steroidal systems\ in which an axially!oriented methyl group or hydrogen
atom can undergo 0\1!migration to an adjacent carbocation[ This can generate a number of new
C0C and C0H bonds\ exempli_ed by the rearrangement in acid of the alkene "14# to the alkene
"15# "Equation "8## ð45JCS1308Ł[
H
H+
H H H (9)
H H
H
(25) (26)
Finally\ in acyclic systems 0\1!migration of an alkyl group to an adjacent carbocation allows a

new C0C bond to be formed[ The absolute con_guration of the migrating group is retained in the
rearrangement[ This is illustrated in the conversion of the amine "16# to the alcohol "17# "Equation
"09## ð62CB0265Ł[ These rearrangements are normally restricted to neopentylic systems[ A mixture
of products is often generated\ because the new tertiary carbocation can be quenched by reaction
with a nucleophile or by loss of a proton[ These drawbacks can be avoided by using the related
pinacol rearrangement\ a more controlled and reliable method for C0C bond formation in acyclic
systems[
NH2 HNO2 (aq.) HO

H (10)
H
(27) (28)
0[98[0[1[1 Pinacol rearrangement
The pinacol rearrangement of vicinal diols involves a 0\1!shift with formation of a new C0H or
C0C bond a to a carbonyl group[ Original work by Fittig ð0759LA"003#43Ł used tetramethylethylene
glycol "pinacol# which rearranges in sulfuric acid to methyl t!butyl ketone "pinacolone# "Equation
"00##[ The pinacol rearrangement is not restricted to tetrasubstituted diols\ but may also occur in a
variety of substituted 0\1!dioxygenated systems[ A number of reviews are available ð59QR246\ B!55MI
098!90\ 80COS"2#610Ł[ Sulfuric acid has been most commonly employed as the catalyst although many
other acids "e[g[\ perchloric acid\ phosphoric acid\ tri~uoroacetic acid\ tosic acid# and Lewis acids
"e[g[\ BF2 = OEt1\ TMSOTf "trimethylsilyl tri~ate## can e}ect the rearrangement[ The use of cold
H1SO3 is often desirable as this minimises dehydration[
H2SO4
(11)
HO OH O
When the pinacol rearrangement is performed on vicinal diols in which all four substituents are
identical there is no ambiguity as to the identity of the migrating group[ This type of substrate is
therefore particularly popular and often used in model studies[ Vicinal diols with two di}erent
substituents may give a mixture of two isomeric products on 0\1!migration[ Similarly\ with three
di}erent substituents up to three carbonyl compounds may result and four di}erent substituents
may allow up to four new products each with a new C0C or C0H bond a to the carbonyl group[
Clearly this mixture of isomeric products may limit the synthetic value of the pinacol rearrangement\
unless there is a clear preference for one regioisomeric product[ In such cases\ when there is more
than one type of functional group which may migrate\ an understanding of the di}erent migratory
aptitudes is important in determining which new C0C or C0H bond is formed[ This\ however\ is
not the only factor which must be borne in mind\ as the relative stabilities of the two possible
carbocations from an unsymmetrical diol may dictate from which carbon centre migration occurs[
Indeed this is normally of paramount importance in determining the regiochemistry as ð07OŁH1O
studies have demonstrated the likelihood of a carbocation intermediate in the pinacolÐpinacolone
rearrangement ð47JCS392Ł[
Rearrangement of tetrasubstituted vicinal diols provides a useful route to a!trisubstituted and
spirocyclic ketones[ For example\ the diol "18# prepared by reductive coupling of cyclopentanone\
rearranges in sulfuric acid to the spirolð3[4Łdecane ring system "29# "Equation "01## ð43JA1642Ł[ The
tetrasubstituted vicinal diol "20# with two di}erent substituents also gives rise to only one carbocation
intermediate regardless of which hydroxyl group is lost[ This type of diol can rearrange to two
isomeric ketones "21# and "22# and therefore acts as a direct comparison between the migratory
aptitudes of the two substituents R0 and R1 "Equation "02##[ In general\ the group which migrates
to form the new C0C or C0H bond is the one which is better able to stabilise a positive charge[
Hence aryl groups normally migrate more readily than alkyl groups and at a similar rate to the
migration of a hydrogen atom ð48JA3622Ł[ The presence of electron!donating substituents on the
aromatic ring or increased substitution on the alkyl group will enhance the propensity for migration\
although conformational and neighbouring group e}ects may also play a role in determining which
group migrates[ For example\ the ethyl group migrates in preference to the methyl group in the
rearrangement of the diol "23#\ although the selectivity is not high "Equation "03## ð11CB0859Ł[ In
contrast\ rearrangement of the diol "24# proceeds with exclusive phenyl group migration to give the
ketone "25#\ because the phenyl group is better able to support a positive charge via a bridged
phenonium ion "Equation "04## ð52JA0437Ł[
H2SO4
(12)
HO OH O
(29) (30)
R2 R2 R2 R2 R1 R2
H+
R1 R1 R1 + R2 (13)
HO OH O R1 O R1
(31) (32) (33)
H2SO4
+ (14)
HO OH O O
(34) 4 : 1
Ph Ph Ph
TsOH
Ph (15)
HO OH O
(35) (36)
Although a comparison of migratory aptitudes can be used to predict which of two groups
migrate in a symmetrical vicinal diol\ in an unsymmetrical diol a consideration of the stabilities of
the two intermediate carbocations must also be taken into account[ Hence the diol "26# rearranges
under kinetic conditions "cold H1SO3# with methyl group migration as this proceeds through the
more stable intermediate carbocation[ Under thermodynamic conditions "acetic acid\ cat[ H1SO3#
the product of phenyl group migration "27# is formed "Scheme 00#[
H2SO4 Ph AcOH, cat. H2SO4 Ph Ph
Ph Ph
Ph O HO OH O
(36) (37) (38)
Scheme 11
Rearrangement of trisubstituted diols provides a route to a!trisubstituted aldehydes or to ketones[

It may be possible to control\ to some extent\ the outcome of such rearrangements by use of
appropriate conditions[ Under kinetic control with mild\ dilute acid the aldehyde may be preferred\
whereas harsher conditions often favour the ketone[ For example\ rearrangement of the diol "28#
with aqueous oxalic acid gives a signi_cant amount of the aldehyde "39#\ whereas cold\ concentrated
H1SO3 allows essentially exclusive formation of the ketone "30# "Scheme 01# ð44JA4406Ł[
Ph Ph Ph Ph Ph
Ph Ph CHO +
HO OH Ph Ph O
(39) (40) (41)
oxalic acid 30 : 70
conc. H2SO4 0 : 100
Scheme 12
The combination of a more stable tertiary carbocation intermediate and the greater preference
for hydrogen atom migration over alkyl group migration often leads to a new C0H bond a to a
ketone as the major product[ Conformational e}ects may also play a role in determining the
outcome of the rearrangement as illustrated in Scheme 02 ð48JA0386Ł[ Both the cis! and trans!diols
rearrange via the more stable tertiary carbocation but give di}erent ratios of hydrogen atom or
carbon atom migration[ In addition to the regiochemical control required to e}ect a successful and
useful pinacol rearrangement\ the stereochemistry at the migration terminus may also need to be
controlled[ If the rearrangement proceeds via a planar carbocation then a mixture of products is
possible\ particularly in acyclic systems[ This may further limit the synthetic usefulness of the
rearrangement in setting up a new C0C or C0H bond[
Ph
OH Ph
BF3•OEt2
+ But
Ph But CHO
But OH
O
cis-diol 93 : 7
OH
BF3•OEt2 Ph
Ph Ph + But
But But CHO
OH O
trans-diol 61 : 39
Scheme 13
Rearrangement of vicinal diols in which one centre is a primary alcohol normally gives rise to
aldehydic products[ This is to be expected based on the formation of the more stable secondary or
tertiary carbocation followed by hydrogen atom migration[ The product aldehydes may\ however\
be unstable under the acidic reaction conditions[ Conversion of the primary or secondary hydroxyl
group of a vicinal diol to a leaving group "e[g[\ with MsCl or TsCl# allows migration from the more
substituted carbon centre[ This reversal of regiochemistry "based on carbocation stability# is often
a very controlled and useful modi_cation of the pinacol rearrangement and is discussed in Section
0[98[0[1[3 under the semipinacol rearrangement[
0[98[0[1[2 Rearrangement of epoxides

An epoxide may rearrange when activated by protonation or Lewis acid complexation of the
oxygen atom of the epoxide group[ Ring opening of the epoxide can generate the same carbocation
intermediate as that proposed for the pinacol rearrangement "Section 0[98[0[1[1#[ This carbocation
may undergo a 0\1!shift to give a new C0H or C0C bond a to the new carbonyl group[ Alter!
natively\ the epoxide may open to give a vicinal disubstituted compound "e[g[\ a vicinal diol or
halohydrin# which may itself rearrange under the reaction conditions[ The type of reaction which
occurs depends chie~y on the acid used but may also be a}ected by the substitution pattern\ the
solvent and the temperature[ As in the pinacol rearrangement\ the regiochemical and stereochemical
outcome must be controlled for successful use in a synthesis[ As would be expected\ the more
stable carbocation will be preferred and the substituent with the higher migratory aptitude will
preferentially form the new C0H or C0C bond[ The rearrangement of epoxides has been com!
prehensively reviewed by Rickborn ð80COS"2#622Ł[ The factors that a}ect carbocation formation or
ring opening to "normally# a vicinal halohydrin and aspects of control in the rearrangement are
discussed in this section[
The choice of protic or Lewis acid for the rearrangement of a given epoxide may be crucial in
controlling the regiochemical outcome and hence which new C0H or C0C bond is formed[ The
use of a proton as the acid source may not promote rearrangement at all\ as the conjugate base is
often nucleophilic enough to allow direct epoxide ring!opening and the formation of a vicinal
disubstituted compound[ Although this does not preclude the use of an acid catalyst such as H1SO3
or TFA\ the rearrangement is normally better promoted by a Lewis acid[ The choice of Lewis acid
is important as the presence of bromide or iodide counterions allow initial halohydrin formation
before rearrangement[ Lithium perchlorate "LiClO3# or the more commonly used boron tri~uoride
"BF2# are both thought to allow initial carbocation formation followed by rearrangement[ These
reactions are normally carried out by heating in nonpolar solvents[
Like the pinacol rearrangement the regiochemistry is determined by which C0O bond breaks
and which substituent "one of four# migrates[ This can be predicted on the basis of carbocation
stability and migratory aptitude[ For example\ the epoxide "31#\ when treated with LiClO3\ gives
the aldehyde "32# in which a new C0H bond has been formed by migration of a hydrogen atom to
the tertiary carbocation "Equation "05## ð60JA0582Ł[ Anhydrous LiClO3 should be used in order to
aid solubility[ The presence of only small amounts of catalyst and a weakly nucleophilic counterion
provide relatively mild conditions[
O LiClO4 Et
Et CHO (16)
PhH, 80 °C
Et Et
(42) (43)
The importance of the choice of Lewis acid is illustrated in Scheme 03 which depicts the rearrange!
ment of 0!methylcyclohexene oxide[ With LiClO3 the tertiary carbocation intermediate is formed
and hydride migration then takes preference over alkyl migration[ With LiBr "which requires the
solubiliser hexamethylphosphoramide "HMPA## 1!methylcyclohexanone is not produced\ therefore
precluding carbocation intermediates[ In this case the trans!bromohydrins are formed\ which can
only rearrange by alkyl migration to give the ring contracted products[ Hence lithium halide catalysis
may reverse the regiochemical outcome\ although in acyclic epoxides a mixture of regioisomers
is often obtained[ Lithium halide catalysis has been shown to promote the rearrangement of
spirocyclic epoxides[ This is most useful as a route to cyclopentanones as outlined in Equation
"06# ð64CR"C#680Ł[ In substituted cyclobutanes the new C0C bond is formed to the more substituted
centre[
PhH, 80 °C
O + +
O CHO O
LiClO4 80 : 20 : 0
LiBr, HMPA 0 : 95 : 5
Scheme 14
O LiI
O (17)
The relative migratory aptitudes of the two substituents determines which group migrates in the
rearrangement[ The stereochemistry may also in~uence the outcome of the rearrangement[ The two
diastereoisomeric epoxides of 1!butene rearrange to give a di}erent ratio of products[ In each case
1!butanone is the major product as expected on the basis of the higher migratory aptitude of a
hydrogen atom over a methyl group[ However\ some isobutyraldehyde\ the product of methyl group
migration\ is observed from the trans!isomer "Scheme 04# ð58T3334Ł[ This can be rationalised by
invoking rapid migration to the carbocation intermediate from the _rst!formed conformer which is
correctly set up for 0\1!migration[ Rotation of the OBF2− group away from the bulkier substituent
on the adjacent carbocation allows the prediction of which new C0H or C0C bond will be formed[
From the example in Scheme 04\ the OBF2− group will prefer to rotate away from the methyl group
on the adjacent carbocation\ so setting up hydrogen atom migration from the cis!epoxide but methyl
group migration from the trans!epoxide[ Due to the lower migratory aptitude of a methyl group\
further rotation must compete with methyl group migration[
O BF3 OBF3– OBF3– O

+ H +
O BF3 OBF3– OBF3– O

+ +
H CHO +
H
1 : 3
Scheme 15
In cases where epoxide opening is relatively slow and migration is fast\ then inversion at the
migration terminus would be expected[ In practice a mixture of products is often observed with some
preference for inversion\ suggesting the intermediacy of a carbocation but with some stereochemical
memory[ Rearrangement of isomeric 0\0!disubstituted epoxides "derived from exo!methylene
steroids with BF2 = OEt1 in benzene# results in similar product ratios of both epimeric aldehydes
ð58T0368Ł[ However\ work with bulky aluminum catalysts has allowed the synthesis of aldehydes
with nearly complete inversion at the migration terminus ð81T2638Ł[ For example\ the epoxide "33#
rearranged to the aldehyde "34# with excellent diastereoselectivity "Equation "07##[ The choice of
triphenylsilyl as the protecting group for the adjacent alcohol gave the highest diastereomeric excess[
Inversion at the migration terminus has also been observed in the rearrangement of acyl epoxides[
Acyl group migration in the rearrangement of epoxides "35# and "36# gave the 0\2!dicarbonyl
compounds "37# "Equation "08## and "38# "Equation "19## respectively ð67JA0594Ł[
Ph3SiO Ph3SiO
(ArO)2AlMe
CHO (18)
Bu CH2Cl2, –40 °C Bu
O 73%
(44) (45) 95% de
Ar = 4-bromo-2,6-di-t-butylphenyl
Ph
O
BF3•OEt2
Ph (19)
COPh CHO
Ph
O
(46) (48)
O Ph
BF3•OEt2
Ph Ph (20)
COPh CHO
O
(47) (49)
Rearrangement of acyl epoxides derived from cyclohexenones provides a convenient access to

cyclopentanones by ring contraction "Equation "10## ð74TL874Ł[ This can be compared with the ring
expansion outlined in Equation "06#[
O O
BF3•OEt2 CHO
(21)
O CH2Cl2, RT
Lewis acid treatment of an epoxide containing an adjacent quaternary carbon may allow new
C0C bond formation by a 0\1!shift from the quaternary centre[ This gives rise to a homoallylic
alcohol after loss of a proton from the new tertiary carbocation[ Epoxide rearrangement promoted
by a Grignard reagent usually results in the formation of alcohol products[ This occurs via ring
opening of the epoxide with the halide\ to give the magnesium salt of the halohydrin which then
rearranges on heating in a nonpolar solvent[ The product aldehyde and:or ketone is then captured
by the Grignard reagent to give a secondary and:or tertiary alcohol[ For example\ rearrangement
of cyclohexene oxide with MeMgBr gives the alcohol "49# as the major product "Equation "11##
ð58CR"C#456Ł[ With MeMgI a mixture of the alcohol "49# together with substantial amounts of the
product derived from hydrogen atom migration is obtained[ A very similar ratio of C0C ] C0H
formation is observed on rearrangement with MgBr1 or MgI1[ The presence of such mixtures in this
and other epoxide rearrangements and the absence of a standard set of conditions to promote
rearrangement to a single\ predictable regio! and stereoisomer often detracts from what is a useful
method for the formation of a new C0H or C0C bond a to a carbonyl group[
MeMgBr OH
O (22)
PhH, 80 °C, 1 h
54%
(50)
0[98[0[1[3 Semipinacol rearrangement

The semipinacol rearrangement has many similarities to the pinacol and epoxide rearrangements
and\ like these\ provides a route to carbonyl compounds with a new C0H or C0C bond a to
the carbonyl group ð80COS"2#666Ł[ The semipinacol rearrangement has come to represent all 0\1!
migrations of 1!heterosubstituted alcohols related to the pinacol rearrangement[ The conditions for
the rearrangement vary with the heteroatom "X in Equation "12##[ Most commonly the semipinacol
rearrangement refers to the case when X is a nitrogen atom\ although many such rearrangements
with X being an oxygen\ sulfur\ selenium or halogen atom are known[ The transformation has
advantages over the related pinacol and epoxide rearrangements in that it is generally more con!
trolled and proceeds under milder conditions[ The regiochemical outcome is more de_ned because
migration normally occurs from the carbon atom bearing the hydroxyl group[ The criteria for which
of the two groups on this carbon atom migrate can be judged on the basis of their relative migratory
aptitudes "see Section 0[98[0[1[1# ð48JA3622\ 70TL3958Ł\ although this is commonly overriden by
stereochemical e}ects or the relief of ring strain[ Inversion of con_guration at the migration terminus
is normally observed and this has obvious value in chiral synthesis[ The reaction works best when
migration occurs from a tertiary origin to generate a ketone "or ester#[ Competing epoxide formation
can be minimised by avoiding basic conditions or certain leaving groups "e[g[\ XSR1#[
R2 R3 R1 R2
R1 (23)
HO X O R3
The semipinacol rearrangement of a 1!amino alcohol with HNO1 is known as the Ti}eneauÐ
Demjanov rearrangement ð59OR"00#046Ł[ The preferred rearrangement conditions involve dissolving
the amino alcohol in dilute aqueous acid and adding aqueous sodium nitrite at 9>C\ maintaining a
pH 3Ð5[ This generates HNO1 which reacts with the amine to give an intermediate diazo compound
which then loses nitrogen on rearrangement[ Addition of acid and nitrite is continued until gas
evolution ceases[ The reaction is quite e}ective for ring expansion\ as shown in Scheme 05[ The
diazo intermediate may alternatively be generated by the reaction of a ketone with a diazoalkane[
In such cases the rearrangement works best with cyclic ketones and with ether as the solvent\ because
polar aprotic solvents promote epoxide formation[ Ethyl diazoacetate with Lewis acid catalysis may
also be employed and provides the homologated b!keto ester[
HNO2
NH2 N2+
75%
OH OH O
Scheme 16
The more substituted group normally migrates to form the new C0C bond\ although con!
formational e}ects may take precedence\ particularly in cyclic systems where the group which is
antiperiplanar to the leaving group becomes involved[ This is clearly illustrated in Scheme 06 in
which the isomeric 1!amino alcohols give di}erent products on treatment with HClO3"aq#:NaNO1"aq#
ð54JCS1402Ł[ The equatorially!oriented amino group allows ring contraction "Equations "13# and
"14## whereas the axially!oriented amino group forces hydrogen atom migration "Equation "15## or
epoxide formation "Equation "16##\ depending upon which group is antiperiplanar to the breaking
C0N bond[ In each case inversion at the migration terminus has occurred\ so discounting car!
bocation intermediates[
OH
HNO2
OH (24)
But N2+ 90% But CHO
But NH2
OH
OH
HNO2
But N2+
(25)
98% But CHO
But NH2
OH O
HNO2
OH
But (26)
76%
But NH2 + But
N2
OH
OH
HNO2 O
But (27)
77% But
But NH2 +
N2
Scheme 17
A convenient and important modi_cation of the pinacol rearrangement "XOH\ Equation "12##
"see Section 0[98[0[1[1 for a discussion of the pinacol rearrangement# involves the conversion of one
of the alcohol groups to\ normally\ a mesylate "XOSO1Me# or tosylate "XOSO1Tol#[ This
provides access\ on rearrangement\ to complimentary regioisomeric products in which migration
takes place from the tertiary to the secondary or primary centre[ In the pinacol rearrangement
migration takes place to the tertiary centre[ A Lewis acid is used to promote the reaction\ typically
Et2Al or Et1AlCl in cold CH1Cl1\ or LiClO3 in THF[ In the latter case the conditions are particularly
mild\ especially if CaCO2 is added to neutralise the acid formed in the reaction[ An example of the
use of this transformation by Corey et al[ is shown in Equation "17# as part of an approach to the
sesquiterpene longifolene ð53JA367Ł[ The complete inversion of con_guration at the migration
terminus ð72TL3886Ł has been made use of in a number of syntheses\ for example to "S#!naproxen
"Scheme 07#\ which uses Et2Al in the rearrangement step ð81TA0440Ł[
O O O O
LiClO4
TsO (28)
THF, CaCO3 O
50 °C, 60 h
HO 41–48%
Ar Et3Al
(S)-naproxen
CH2Cl2, –78 °C O Ar
HO OMs
Ar =
MeO
Scheme 18
1!Hydroxy sul_des "XSR\ Equation "12## and selenides "XSeR# are known to undergo
semipinacol rearrangement\ the outcome being determined\ at least in part\ by the reaction
conditions[ Protic acids such as TsOH or HBF3 favour loss of the hydroxyl group as water and
migration from the carbon atom bearing the sulfur "or selenium# group[ Hydrolysis then gives the
ketone with the opposite regiochemistry from the normal semipinacol rearrangement[ The potential
for episulfonium ion formation and hence products derived from it\ restrict C0C bond formation
to the expansion of small rings\ particularly cyclopropanes\ as developed by Trost et al[ ð62JA2957Ł[
For example\ the ring expansion of the 1!hydroxy sul_de "40# occurs with aqueous HBF3 in ether
at room temperature to give the cyclobutanone "41# "Equation "18##[
HBF4(aq.), Et2O
(29)
HO SPh RT, 25 min O
89%
(51) (52)
The use of Lewis acid conditions instead of protic acids favours loss of the sulfur or selenium group\
followed by rearrangement[ The preferred conditions make use of silver"I# or copper"I# as their BF3−
or tri~ate salts\ or the use of dichlorocarbene generated in situ from TlOEt in CHCl2 ð73TL1602Ł[
Substituents "but not small rings# at the migration terminus "the carbon bearing the sulfur or selenium
group# promote rearrangement[ Semipinacol rearrangement with 1!hydroxy sulfones can also be
promoted by Lewis acids\ in particular Et1AlCl[ This is exempli_ed in Equation "29# ð81JA4321Ł[
H H
Et2AlCl
(30)
CH2Cl2, 0 °C
SO2Ph 86%
OH O
Semipinacol rearrangement of halohydrins provides another route to a!substituted carbonyl

compounds[ The hydroxyl proton can be removed with a strong base such as BunLi or RMgX\ then
rearrangement occurs on heating\ normally in nonpolar solvents such as benzene at 79>C[ Epoxides
may be formed and this has been implicated in a number of such rearrangements[ The halohydrin
"42# undergoes hydrogen atom migration "as expected# to give a new C0H bond a to the ketone
"43#[ The minor product "44# presumably arises from the epoxide "Equation "20## ð44JA4972Ł[
Halohydrins may be prepared from epoxides using a lithium halide as discussed in Section 0[98[0[1[2[
Br O
i, EtMgBr, PhH
+ (31)
ii, 80 °C
OH O
80 : 20
(53) (54) (55)
Rearrangements of halohydrins with a second halogen atom at the migration terminus are known\
as are those with a second oxygen!bound substituent at the migration origin[ The latter "1!halo
acetals# provide access to a!substituted esters under particularly mild conditions\ especially when
the migrating group is electron!rich[ Acetals such as "45# rearrange on heating in alcohol solvent
"e[g[\ 0\1!ethanediol# containing a mild base "e[g[\ sodium acetate# to avoid acetal hydrolysis "Equa!
tion "21## ð74S494Ł[ Silver tetra~uoroborate in methanol or other Lewis acids may be used to
promote the rearrangement ð73AG"E#302Ł[
Ar HO Ar
OH
MeO MeO2C (32)
NaOAc, 125 °C
MeO Br
(56)
The presence of a good leaving group vicinal to an alcohol is implicated in the semipinacol
rearrangement[ Inversion at the migration terminus normally occurs unless a carbocation inter!
mediate is formed in which rotation is faster than migration[ A carbocation may be formed from
an alkene\ as in the cyclisation onto an acetal "Scheme 08# ð78JA0403Ł[ Cyclisation occurs on
treatment with a Lewis acid\ particularly SnCl3 in CH1Cl1\ to give the carbocation which rearranges
to the ketone[
OMe
OMe H
H
OMe SnCl4, CH2Cl2
OMe
–78 °C to –23 °C + 82%
TMS-O TMS-O O
Scheme 19
0[98[0[1[4 Favorskii rearrangement

The Favorskii rearrangement is related to the rearrangements described in this section as the
overall transformation involves the migration of a substituent as an anion to give a new C0C bond
a to a carbonyl group[ In the Favorskii rearrangement the starting material is an a!halo ketone
which is transformed\ via carbanion intermediates\ into a carboxylic acid or its derivative[ A
simpli_ed representation of the reaction is outlined in Equation "22#\ although the situation is more
complicated than depicted as up to two regioisomers of the product may result[ The scope and
limitations of the rearrangement\ named after early work by Favorskii ð0783MI 098!90Ł\ are described
in this section and in a number of reviews ð49BSF24\ 59OR"00#150\ 69RCR621\ 80COS"2#728Ł[
R1 R2 base R4O R1
R3 R2 (33)
e.g. NaOR4
O X O R3
X = Br, Cl
The Favorskii rearrangement is most useful for the preparation of branched!chain aliphatic
carboxylic acids and their derivatives and for ring contraction of cyclic ketones[ In acyclic systems
the reaction works best when the carbon atom bearing the halide is substituted[ The conditions for
the rearrangement may vary depending on the structure of the a!halo ketone[ Most commonly
sodium methoxide in methanol or in diethyl ether is used[ Other bases such as hydroxides or
carbonates of Group 0 metals may be used\ although this may lead to hydroxy ketone formation[
There are examples however where these bases are particularly appropriate\ such as the rearrange!
ment of 1!chlorocycloheptanone to cyclohexanecarboxylic acid which occurs in 58) yield with hot
aqueous K1CO2\ or the rearrangement of some 06!bromo!19!ketosteroids[ The use of ammonia or
other amines has been reported but is of limited scope[ The choice of alkoxide may a}ect the yield
and the use of NaOEt or NaOPri "or NaOBn# may have some bene_ts over NaOMe "Equation "23##
ð39JA1489Ł[
NaOR RO
(34)
O Br Et2O
O
R = Me, 39%
R = Et, 61%
R = Pri, 64%
Usually the a!halo ketone is added to a fairly concentrated solution or suspension of the alkoxide
at 9>C or room temperature in an alcohol or ethereal solvent[ Heterogeneous reactions "e[g[\ NaOMe
in Et1O# require longer reaction times and may be accelerated by heating[ Excess alkoxide may
improve the yield of the rearranged product[ a!Bromo ketones are more prone to reduction or
disproportionation in the presence of strong bases than a!chloro ketones\ but both have been used
extensively for Favorskii rearrangements[
The two isomeric a!chloro ketones "46# and "47# rearrange to the same ester on treatment with
NaOMe in Et1O "Scheme 19# ð40JA2899Ł[ Such examples\ together with the work of Loft_eld using
03
C labelled a!chloro ketones ð40JA3696Ł demonstrate the involvement of a common intermediate\
generally accepted to be the cyclopropanone[
O O
NaOMe CO2Me NaOMe
Et2O Et2O
Cl 65% 77% Cl
(57) (58)
Scheme 20
Enolate formation is thought to be followed by cleavage of the carbonÐhalogen bond to give

either the oxy!allyl cation\ or directly the cyclopropanone "Scheme 10#[ The three!membered ring
breaks down to give the more stable carbanion "primary×secondary×tertiary# and this determines
the regiochemical outcome[
O O– O–
RO–
R1 X R1 X R1 R4
+
R4 R4
R2 R3 R2 R3 R2 R3
O O OR5
RO– R1 OR5 O R4
R1 R4 +
R4 R1
R2 R3 R2 R3 R2 R3
Scheme 21
The stereochemical outcome at the new carbon centre a to the carbonyl group must also be taken
into account[ If the rearrangement proceeds via the oxy!allyl cation then a mixture of stereoisomers
should result[ If direct displacement of the halogen occurs then inversion at this centre should be
observed[ The pathway taken seems to be a}ected by the structure of the a!halo ketone and by the
solvent[ The diastereomeric a!chloro ketones "48# and "59# rearrange stereospeci_cally in Et1O to
the esters "50# "Equation "24## and "51# "Equation "25## respectively ð59JA3296Ł[ However\ in meth!
anol the reaction is nonstereospeci_c\ suggesting that the more polar\ protic solvent favours the
intermediate oxy!allyl cation[ Steric factors may also a}ect the stereochemistry if direct ring closure
to the cyclopropanone is hindered\ thereby favouring oxy!allyl cation formation[
Cl O CO2CH2Ph
PhCH2O–Na+
(35)
Et2O
(59) (61)
O
PhCH2O–Na+
CO2CH2Ph (36)
Cl Et2O
(60) (62)
The sensitivity of a!halo ketones makes them prone to the formation of a number of side products[
These may include a!alkoxy ketones\ unsaturated ketones and epoxyethers "especially from aryl
substituted a!halo ketones# and products derived from them[ Epoxyether formation is the main
pathway in the attempted rearrangement of a!bromo ketone "52#\ although the corresponding
chloride "53# can be induced to rearrange on careful exclusion of water ð43JA24Ł[ The isomeric a!
bromo ketone "54# rearranges easily and ether is the preferred solvent "Scheme 11# ð49JA1773Ł[
Br
O
(63)
NaOMe NaOMe
Cl MeOH Et2O O
O 38% CO2Me 79% Br
(64) (65)
Scheme 22
The application of the Favorskii rearrangement to ring contraction has been particularly suc!
cessful for the preparation of threeÐ or _veÐten!membered rings[ The preparation of four!membered
rings from 1!halocyclopentanones usually fails except in certain constrained systems such as those
leading to the cubanes[ Ring contraction of 1!chlorocyclohexanone can be accomplished by heating
with NaOMe in Et1O as outlined in Equation "26# ð48OS"28#26Ł[ The preparation of cyclo!
propanecarboxylic acids and their derivatives can be achieved from 1!halocyclobutanones using
NaOH\ KOH or NH2\ and proceeds with inversion at the carbon bearing the halogen atom[ This is
believed to occur via a semipinacol!type "or semibenzilic# pathway rather than via enolate and
cyclopropanone formation[ This mechanism is also thought to occur in the rearrangement of a!halo
ketones which have no a?!hydrogen atom[
O
Cl NaOMe CO2Me
(37)
Et2O
61%
While a!halo ketones can be transformed into a!substituted carboxylic acids\ esters or amides\
dihalo or polyhalo ketones normally give\ on rearrangement and elimination\ unsaturated carboxylic
acids and their derivatives[
0[98[0[1[5 Wolff rearrangement

Like the Favorskii rearrangement\ the Wol} rearrangement leads to the formation of a new C0C
bond a to a carboxylic acid or its derivative[ The starting material for the rearrangement is an a!
diazo ketone and the discovery of its transformation into carboxylic acids and derivatives was made
by Wol} ð01LA"283#12Ł[ Many a!diazo ketones have been shown to undergo the rearrangement
and several reviews are available ð31OR"0#27\ 59AG424\ 56RCR159\ 64AG"E#21\ 80COS"2#776Ł[ The overall
process is outlined in Scheme 12[ In most cases R0 is a hydrogen atom and the a!diazo ketone can
be prepared by the reaction of an acid chloride "RCOCl# with diazomethane[ Other methods for
the preparation of a!diazo ketones\ such as the transfer of a diazo group from tosyl azide to an
enolate\ are given in Chapter 2[98
O
R1
HO
H2 O
R2
O O
R3OH
N2 R1
R2 R3O
R1 R2
(66) O
R32NH R1
R32N
R2
Scheme 23
When the rearrangement occurs with the a!diazo ketone "55^ R0 H#\ the reaction allows the
one!carbon homologation of the carboxylic acid "RCO1H# in a three!step process called the ArndtÐ
Eistert synthesis ð24CB199Ł[ This involves the conversion of the carboxylic acid "RCO1H# to its acid
chloride "see Chapter 4[90#\ which in turn is converted to its a!diazomethyl ketone using diazo!
methane[ Rearrangement then gives the homologated acid "RCH1CO1H# or its derivative[ The
conditions for the rearrangement normally involve heating the diazo ketone in an appropriate
solvent "depending upon which acid derivative is required#\ often in the presence of a transition
metal catalyst\ the most e}ective and popular being silver oxide or occasionally silver benzoate or
silver nitrate[ Photolysis of the a!diazo ketone using a medium!pressure mercury arc is an alternative
and e}ective method\ permitting the use of lower reaction temperatures to promote rearrangement[
The mechanism of the Wol} rearrangement may depend on the substrate and the conditions of
the reaction[ Carbene intermediates have been postulated although these will no doubt be associated
with any metal present in the reaction medium[ Migration of the R group in the a!diazo ketone "55#
is followed by ketene formation[ The ketene is trapped by water\ an alcohol\ a thiol or an amine to
give the product carboxylic acid\ ester\ thioester or amide[ The R group is known to migrate with
retention of con_guration\ as illustrated in Equation "27# ð30JA0563Ł[ Note however that racem!
isation may occur at high temperatures or in the presence of a catalyst\ if the chiral centre contains
an enolisable hydrogen atom[ Racemisation can be avoided by using photochemical conditions
ð72JCS"P0#1276Ł[ Aqueous dioxane is commonly employed as the solvent when a carboxylic acid is
required[ A mild base such as sodium carbonate\ sodium thiosulfate or a tertiary amine is often
used in silver catalysed rearrangements[ If the yield of the carboxylic acid is only mediocre then this
may be improved by resorting to ester or amide formation[
O
Ag2O
N2 CO2H (38)
H2O–dioxane Ph
Ph Na2S2O3, 70 °C
For the preparation of esters\ the a!diazo ketone may be heated with silver oxide in an alcoholic
solvent such as methanol[ Alternatively\ photochemical activation in an alcoholic solvent is a useful
method for rearrangement to the ester[ The use of metal catalysis is not always necessary and indeed
detrimental for a!substituted diazo ketones[ For example\ the diazo ketone "56# did not rearrange
with silver oxide in methanol[ However\ excellent yields of rearranged product "57# can be obtained
by heating in benzyl alcohol "Equation "28##[ High temperatures "069Ð089>C# and the presence of
a tertiary amine such as isoquinoline gave the highest yields ð37JOC652Ł[
O PhCH2OH
N2 isoquinoline
CO2CH2Ph (39)
170 °C, 2 min
86% Cl
Cl
(67) (68)
The formation of a new C0C bond at a saturated carbon atom a to a carboxylic amide may be
accomplished by Wol} rearrangement in the presence of ammonia or an amine[ As with the
formation of carboxylic acids or esters\ one of three general methods may be employed[ Addition
of aqueous ammonia or an amine and aqueous silver nitrate to the diazo ketone in dioxane followed
by heating gives the amide[ Without silver catalysis higher temperatures are needed[ In these cases
rearrangement may be e}ected by using the amine "e[g[\ aniline# as the solvent[ Alternatively\
photolysis of the a!diazo ketone in the presence of the amine in ether or benzene leads to the
carboxylic amide[ For example\ the simple a!diazo ketones "58# rearrange on photochemical acti!
vation to give the amides "69# "Equation "39## ð48CB417Ł[
O
O hυ
Ph R (40)
N2 N
R PhNHMe, PhH
Me
(69) (70)
R = Me, 45%
R = Ph, 77%
R = CH2Ph, 80%
Ring contraction of cyclic a!diazo ketones is possible\ particularly under photochemical activation
ð44CB823Ł[ Most examples involve the formation of cyclobutane or cyclopentane carboxylic acids
or their derivatives[ Contraction of larger rings is possible although side!products may predominate\
depending upon the conditions used[ The cyclic a!diazo ketones "60^ n0Ð5# rearrange smoothly
under photochemical conditions "Equation "30## ð58CB2766Ł[ Using silver oxide catalysis\ the major
product is the unrearranged a\b!unsaturated ketone formed by 0\1!shift of a hydrogen atom[
O O
THF, H2O
(CH2)n HO2C (CH2)n + (41)
(CH2)n
N2
(71) –
hυ (n = 1–6) 62–95%
Ag2O (n = 3–6) 2–15% 54–70%
The reactivity of a!diazo ketones makes them prone to competing reaction pathways[ These may
include 0\2!dipolar cycloaddition\ diazo!coupling\ cyclopropanation\ hydrogen atom abstraction
"giving products of insertion# or reaction with a soft nucleophile "giving ylide formation#[ Careful
choice of reaction conditions may avoid these side products and provide a useful method for C0C
bond formation by the Wol} rearrangement[
0[98[0[2 Substituent Migrates as a Radical

The formation of a new C0C or C0H bond by rearrangement with the migration of a neutral
species is less common than when the substituent migrates as an anion[ Migration of a substituent
as an anion normally occurs from a carbocation or other electron!de_cient species\ while a sub!
stituent may migrate as a radical from a carbanion or a radical species[ When carbanions are
involved\ such as the 0\1!Wittig and 0\1!Stevens "including sulfur ylide# rearrangements "see Sections
0[98[0[2[0 and 0[98[0[2[1#\ dissociation into the radical and radical anion takes place "Scheme 13#[
Rapid migration of the radical and recombination with the radical anion gives the rearranged
product[
R3 R1 •R3 R3
–
R1 –
–
X X • X R1
R2 R2 R2
Scheme 24
Alternatively\ the formation of a free radical may allow the migration of a substituent as a radical[
Such rearrangements can be represented by the 0\1!shift of the R2 group of the radical "61# "Equation
"31## ðB!52MI 098!90\ B!54MI 098!90Ł[ Free radicals are rapidly destroyed by bimolecular reactions
leading to either coupling or disproportionation[ The 0\1!shift generates a new radical which is in
turn capable of further reaction[ Free radicals can be generated in a number of ways but show little
tendency to rearrange\ except when a vicinal aromatic group is present which may undergo a 0\1!
shift as illustrated in Scheme 14 ð36JA1805\ 41JA4270Ł[ Dilution to a 0 M solution in chlorobenzene
generally gives improved yields of the rearranged product[ By comparison\ no rearrangement of
Me2CCH1CHO in t!butyl hydroperoxide "tbhp# occurs and in general 0\1!shifts of an alkyl group
or a hydrogen atom do not occur[ This has made possible the controlled chemistry of carbon
radicals for C0C and C0H bond formation as described in this volume\ "e[g[\ chapter 0[97[0#[
R1 R1
• • (42)
R2 CH2
R3 R2 R3
(72)
Ph TBHP, 120 °C Ph Ph
• •
CHO CH2
70%
Ph
Ph 50 : 50
Scheme 25
0[98[0[2[0 0\1!Wittig rearrangement

The migration of a substituent as a radical and the formation of a new C0C bond by rearrange!
ment of a!alkoxy carbanions was developed by Wittig ð31LA"449#159\ 36LA"446#194Ł after early work
by Schorigin ð13CB0523\ 14CB1917Ł[ The transformation is outlined in Scheme 15 and involves the
formation of a carbanion\ normally by direct deprotonation with strong base\ a to the oxygen atom
of the ether[ Rearrangement gives the alcohol product ð69AG"E#652\ 80COS"2#864Ł[
M R3
R1 base
OR3 R1 OR3 R1 OH
R2 R2 R2
Scheme 26
Initial studies on benzyl ethers "62# used either phenyllithium in THF ð31LA"449#159Ł or potassium
amide in diethyl ether ð40JA0326Ł to e}ect deprotonation "Equation "32##[ The rate of rearrangement
depends on the metal counterion and generally follows the order Li×Na×K\ with no reaction
being observed with zinc or magnesium compounds[ As illustrated in Table 0 the relative migratory
aptitudes of the R group are in the order benzyl¼allyl×alkyl×aryl[ When the alkyl group R
contains a b!hydrogen atom\ elimination to benzyl alcohol is possible and yields are often poor\
particularly with straight!chain alkyl groups[ Benzyl alcohol\ the alkene and other minor by!
products such as benzaldehyde may often be observed[ When the migrating group R is allylic the
rearrangement proceeds through a 1\2!shift "see Section 0[98[0[3[3# with some competing 0\1!shift
depending upon the substitution pattern ð69CC3Ł[
The new C0C bond is formed by rearrangement of the R group as a radical ð55JA67\ 57TL1798Ł
although a substantial degree of retention at the migrating carbon is normally observed[ This is
ascribed to a rapid recombination of the radical and radical anion which are held in a solvent cage[
The optically!active benzyl ethers "63^ RH\ Ph# rearrange in THF on addition of BuLi with
partial inversion of the migrating group "Equation "33## ð50LA"531#0\ 52LA"552#11Ł[
Table 0 Rearrangement of benzyl ethers[
R
base
(43)
Ph OR Ph OH
(73)
R Conditions Yield Ref.

(%)
Ph Excess Na, 100 °C, 20 h 30–35 a

2 KNH2, Et2O, reflux, 18 h 0 b
Me PhLi, Et2O, RT, 40 h 35 c
1.1 ButLi, THF, TMEDA, –60 °C, 1 h 52 d
Et 2 KNH2, Et2O, reflux, 19 h 0 (40% PhCH2OH) b
PhLi, Et2O, RT, 40 h 0 (44% PhCH2OH) c
1.1 ButLi, THF, TMEDA, –60 °C, 10 min 34 (33% PhCH2OH) d
Bus 2 KNH2, Et2O, reflux, 140 h 27 b
Pri 1.1 ButLi, THF, TMEDA, –60 °C, 10 min 62 d
But 1.1 ButLi, THF, TMEDA, –74 °C, 30 min 45 d

5 MeLi, THF, RT, 48 h 51 e
1-Adamantyl 2 MeLi, THF, RT, 48 h 54 e
2 KNH2, Et2O, reflux, 15 h 65 b

CH2Ph 2 KNH2, Et2O, reflux, 15 h 61–67 b
PhLi, Et2O, RT, 40 h 30 c
5 MeLi, THF, RT, 48 h 65 e
a 〈24CB1634〉. b 〈51JA1437〉. c 〈42LA(550)260〉. d 〈68TL2809〉. e 〈62JOC1933, 66JA78〉.
R
R BuLi
* (44)
Ph O * THF, –60 °C
(74) Ph OH
R Retention at C* (%)
H 60
Ph 90
The use of allyl rather than benzyl ethers gives a mixture of the 0\1! and 0\3!rearrangement
products "Equation "34## ð58TL710\ 66TL2374\ 78T1538Ł[ In such cases BunLi has been used to depro!
tonate a to the oxygen atom and yields of the 0\1!product are normally in the range 19Ð29)[ With
b!alkoxyalkyl allyl ethers in which chelation to the alkoxy group can occur\ the 0\1!products are
formed with high diastereoselectivity ð76TL0932Ł[
BuLi R
+ CHO (45)
OR R
THF, –20 °C OH
The problem of controlling the regioselectivity in the deprotonation has been addressed using
anion!stabilising groups such as ketones or nitriles ð43JA383\ 59JCS2410Ł in which KOH in EtOH or
NaOBun in BunOH were used as bases\ although the range of migrating groups appears to be
limited[ More recent work has focused on methods which allow complete regioselectivity in the
anion formation using exchange reactions[ For example\ a benzyl group migrates on heating a benzyl
stannylmethyl ether after tinÐlithium and lithiumÐzirconium exchange ð78OM0482Ł[ Treatment of
an acetal with lithium metal in THF exchanges one of the alkoxy groups for lithium to give the
required a!alkoxy lithium which can undergo rearrangement by a 0\1!shift "Scheme 16\ Table 1#
ð89JOC4421Ł[ As with direct deprotonation methods\ substantial amounts of benzyl alcohol are
formed when the migrating group is a primary alkyl group[
Table 1 Rearrangement from acetals[
Ph OR1 Li
Li R1
Ph OR1 Ph OH
R2 OR1 THF, RT R2 R2
Scheme 27
R1 R2 Yield
(%)
Me H 70
Et H 41 (33% PhCH2OH)
Bun H 42 (29% PhCH2OH)a
Me Me 73
Me Bun 75
aK, THF, RT.
Carbanion formation with sulfur to lithium ð81JA264Ł and selenium to lithium ð81CB0846\ 82TL186Ł
exchange have allowed an investigation into the stereocontrol at the carbanion centre[ Either
diastereoisomer of the selenide "64# gives rise to the organolithium "65# via the radical intermediate[
The 0\1!Wittig rearrangement of the organolithium "65# creates the new C0C bond which gives the
alcohol "66#\ in which complete inversion of con_guration has occurred at the migration terminus
"Scheme 17#[ The 0\1!Wittig rearrangement\ although lower!yielding and less frequently used than
the 1\2!Wittig rearrangement "see Section 0[98[0[3[3 and Chapter 0[07#\ can set up a new C0C bond
with a high degree of stereocontrol[
SePh Li Li OH
60% Ph
OCH2Ph naphthalene OCH2Ph
But But But
THF, –78 °C
20 min
(75) (76) (77)
Scheme 28
0[98[0[2[1 0\1!Stevens rearrangement

This section will cover the formation of a new C0C bond by 0\1!rearrangement of ylides
ð80COS"2#802Ł[ An alkyl group "especially benzyl# of an ammonium ylide can migrate from the
quaternary nitrogen atom to the carbanion a to the nitrogen atom "Stevens rearrangement#
ð69OR"07#392\ B!65MI 098!90Ł[ Similarly\ an alkyl group of a sulfonium ylide can migrate from the
sulfur atom to the carbanion a to the sulfur atom ðB!64MI 098!90Ł[ Initial studies\ performed by
Stevens et al[\ were conducted with acyl!stabilised ammonium ylides "Equation "35##[ Aqueous
NaOH "or sodium alkoxide in alcohol# can be used to e}ect deprotonation and rearrangement
of the ammonium salt ð17JCS2082\ 29JCS1096Ł[ The new C0C bond is formed with retention of
stereochemistry at the migrating carbon centre ð36JCS82\ 41JA4068\ 51AG"E#044\ 52JCS2286\ 58TL2304Ł as
studied for an a!methylbenzyl migrating group "Equation "36##\ particularly if the reaction is kept
at 9>C ð72JCS"P0#0998Ł[ In this case both the stereoselectivity "88) retention at the migrating carbon#
and intramolecularity "88[8)# are very high[ The use of NaOMe or a higher temperature reduces
the stereoselectivity\ as may the presence of substituents on the migrating carbon centre or around
the aromatic ring of the migrating a!methylbenzyl group[ Electron!withdrawing substituents on the
aromatic ring of the migrating benzyl group increase slightly the rate of rearrangement whereas
electron!donating substituents tend to decrease the rate ð21JCS44\ 21JCS0815Ł[
O
O Me Br–
Me 10% NaOH NMe2
+
N Ph Ph (46)
Ph H2O, 1 h
90%
Ph
O
O Me Br– NaOH (aq)
Me NMe2
+
N Ph Ph (47)
Ph 0 °C
84%
Ph
99% retention
As with the 0\1!Wittig rearrangement\ the alkyl group is thought to migrate as a radical in a
solvent cage ð58TL2304\ 69JA0658\ 72JCS"P0#0998Ł[ Small amounts of radical coupled products can
sometimes be isolated[ The corresponding acyl!stabilised sulfonium ylide "67# has been described as
undergoing an analogous rearrangement ð21JCS58Ł although it has been shown that the choice of
solvent is crucial ð57JOC69\ 57TL4270\ 58TL1508\ 69LA"626#047Ł[ With polar\ protic solvents such as
MeOH a mixture of the enol ether "68# and the SommeletÐHauser product "see Section 0[98[0[3[3#
"79# is formed[ With aprotic solvents such as THF\ CHCl2 or benzene the 0\1 product "70# is
preferred "Scheme 18#[ Studies on the 0\1!rearrangement of sulfonium ylides also suggest the
intermediacy of radicals ð58TL1508\ 58JA0126\ 69CC465Ł[
O
O
O Me Br– SMe
a, b, c Ph SMe
S+ Ph Ph O + + Ph
Ph
MeS Ph Ph
(78) (79) (80) (81)

a, 5% Na, MeOH, 60 °C, 2 h 78% 3% –
b, 15% Na, MeOH, 60 °C, 2 h trace 69% –
c, i, NaOMe, MeOH 0 °C; ii, THF, 43 h – – 73%
Scheme 29
Although NaOH and NaOMe can be e}ective bases for acyl!stabilised ylide formation\ stronger
bases such as NaNH1 or BunLi are generally required[ Dibenzyldimethylammonium bromide
rearranges on treatment with BunLi in Et1O ð56JOC0044Ł or KNH1 in re~uxing toluene ð44JOC0008Ł
"Equation "37##[ The choice of solvent and temperature are important as the more polar KNH1 in
liquid ammonia at lower temperature gives almost exclusive SommeletÐHauser product[ The necess!
ity of using strong bases may promote side reactions such as direct displacement[ This can sometimes
be minimised using lower temperatures although this can favour the SommeletÐHauser rather than
the 0\1!Stevens product[ Methyl group migration is less favoured than migration of a benzyl group
and benzyltrimethylammonium iodide "71# gives predominantly the SommeletÐHauser product with
NaNH1 in liquid ammonia ð52OSC"3#474Ł[ The use of PhLi ð37LA"459#005Ł or BunLi ð54JOC2777\
56JOC0044Ł in Et1O\ however\ allows competing 0\1!Stevens rearrangement to the amine "72# "Equa!
tion "38##[
Br– Ph NMe2
Me +
Me KNH2
Ph N Ph (48)
PhMe, reflux
59% Ph
+
BunLi Ph NMe2
Ph NMe3 I– + Sommelet-Hauser product (49)
Et2O, 24 h
(82) (83)
Conditions Yield (%)
RT 25
68 °C 32
Aryl groups do not normally migrate and the presence of a b!hydrogen atom often allows
Hofmann elimination[ As a result of the lack of regioselectivity in the deprotonation\ a mixture of
products may be formed ð68JOC1237Ł[ A solution to this may lie in regiospeci_c anion formation by
desilylation "or other exchange reactions#[ With allyl!substituted quaternary amines 0\1!\ 0\3! and
1\2!rearrangement pathways are possible and may occur concurrently[ These facts tend to limit the
scope and usefulness of the rearrangement[
When the heteroatom forms part of a ring 0\1!rearrangement may give rise to ring contracted or
ring expanded products\ particularly for four! or _ve!membered rings[ For example\ the trans!
formation of the dihydropyrrole "73# into the tetrahydropyridine "74# can be accomplished by
re~uxing the ylide in benzene "Equation "49## ð70JCS"P0#0842Ł[
Br–
O i, NaOH (aq.) 0 °C (84%)
+ Ph (50)
N ii, PhH, 80 °C (90%) N
Me Ph
Me O
(84) (85)
An alternative method for ylide formation which has been receiving more recent attention is the
reaction of the heteroatom with a carbene ð66ACR068\ 75ACR237\ 80CRV152Ł[ Sul_des in particular
ð61CC759\ 61JOC0610\ 73JOC0806\ 89T5490Ł\ but also amines ð82JA0066Ł\ ethers ð75JA5951\ 81JOC2368Ł and
halides ð70JOC4983Ł\ react to give an ylide which may undergo 0\1!rearrangement[ Intramolecular
capture of a carbene\ normally with Cu"II# or Rh"II# catalysis leads to cyclic products\ as represented
by the examples in Scheme 29[ As expected\ a benzyl or allyl group migrates in preference to an
alkyl group[ SommeletÐHauser "from benzyl!substituted ylides# and 1\2!sigmatropic rearrangements
"from allyl!substituted ylides# which often compete with the 0\1!rearrangement will be discussed in
Section 0[98[0[3[3[
O
O
O CuSO4 –
+
N2 S 51%
Ph S dioxane, heat S
Ph
Ph
O O
1 mol% O
O Rh2(OAc)4
– +
N2 PhH, RT
+
55%
MeO O OMe OMe
Me
82 : 18
Scheme 30
0[98[0[3 Sigmatropic Rearrangements

This section deals with the transformation of an unsaturated to a saturated carbon centre with
the formation of a new C0C or C0H bond at this centre by a sigmatropic rearrangement[ As the
s!bond shifts across one or more p!systems the double bonds become reorganised in the process[
Such transformations have been rationalised by Woodward and Ho}mann in terms of the appli!
cation of orbital symmetry concepts ð54JA1400\ 58AG"E#670Ł[ This section will cover migrations across
p!systems involving 0\2!\ 0\4!\ 0\6!\ 1\2! and 2\2!sigmatropic rearrangements which lead to the
formation of a new C0C or C0H bond at a saturated carbon centre[ The related 0\1!sigmatropic
rearrangements have been covered in the previous sections[
0[98[0[3[0 0\2!Sigmatropic rearrangements

The migration of a carbon atom by a 0\2!sigmatropic rearrangement occurs suprafacially across
the p!system and many examples are known ð57ACR041\ 57QR227\ 65CRV076\ 80COS"4#888\ 82OR82Ł[
High temperatures are commonly required unless use is made of anion!assisted systems[ Thermal
0\2!sigmatropic rearrangements\ in accord with the WoodwardÐHo}mann rules have been shown
to proceed stereospeci_cally with inversion of con_guration at the migrating carbon atom ð56JA4492\
58TL1596\ 58JA3211Ł[ For example\ both the bicycloð2[1[9Łheptene "75# and the bicycloð1[0[0Łhexene
"76# rearrange on heating\ with inversion at the migrating carbon centre "Equations "40# and "41#
respectively#[
decalin, 300 °C
(51)
D OAc
AcO D
(86)
Me H
102 °C
H H (52)
(87)
Rearrangements with retention of con_guration at the migrating carbon centre are known\
particularly for charge!accelerated rearrangements ð70JA6550Ł[ The presence of an alkoxy group
increases the rate of rearrangement allowing the use of lower temperatures[ Magnesium and zinc
salts can be used although lithium and especially potassium alkoxides react most rapidly\ often at
room temperature[ The allylic or homoallylic alcohol is normally treated with BunLi or KH in a
polar solvent such as THF\ DIGLYME or HMPA[ Complexing agents such as 07!crown!5 can
accelerate the rearrangement[ Representative 0\2!sigmatropic rearrangements of acyclic homoallylic
alcohols are shown in Equation "42# and Table 2[ The rearrangement works best when the homo!
allylic alcohol is substituted with bulky or aromatic groups to give predominantly the cis!alkene
product[ Some fragmentation to the ketone is often observed as a by!product[ Homoallylic amines
are also known to undergo 0\2!sigmatropic rearrangement on heating ð79JCS"P0#0347Ł[
Table 2 Rearrangement of homoallylic alkoxides[

R1 R1
R2 R3 (53)
R2
R3 OM OM
R4 R4
M R1 R2 R3 R4 Solvent Temp Time Yield (E) : (Z) Ref.

(°C) (h) (%)
Li H Me Et Et DIGLYME 162 168 7 28 : 72 a
Li H Pri Et Et DIGLYME 162 48 27 30 : 70 a
Li H Ph Et Et THF 65 6 76 25 : 75 a
Li H Me Et Ph DIGLYME 162 144 77 b a
K Me Me H Ph HMPA 75 12 85 b c
Li H Me Pri But THF 25 12 98 19 : 81 a
MgBr H Me Pri But THF 25 96 84 29 : 71 d
Li H Me But But THF 25 1.2 91 14 : 86 a
Li H Pri Pri Pri THF 65 48 86 50 : 50 a
Li H Me C6H11 But THF 25 12 81 19 : 81 a
Li H Ph Pri Pri THF 25 0.7 78 b a
K CH2=CH2 Me H C6H13 THF –7 0.1 60–80 100 : 0 e
a〈78JA2134〉. b(E) : (Z) ratio undetermined. c〈79TL2779〉. d〈69JA5162〉. e〈77TL2559〉.
Treatment of an allylic alcohol with base\ such as KH in HMPA\ allows 0\2!sigmatropic

rearrangement by migration of an allyl\ benzyl or other anion!stabilising group[ This has allowed
the transformation of 0!substituted cycloalkenols to 2!substituted cycloalkanones "Equation "43##
ð70JA6550\ 82OR82Ł or a two!carbon ring expansion ð65CC735\ 67JOC0949\ 71JOC687Ł[
O
R OH
KH
(54)
HMPA, RT ( )n
( )n
R
0\2!Sigmatropic rearrangements when one of the atoms of the breaking s!bond is a heteroatom
are known[ Allyl vinyl ethers rearrange with migration of the allyl group using LiClO3 activation
ð80JA4377\ 81TL3624Ł[ This allows the conversion of a C0O bond to a C0C bond as exempli_ed in
Equation "44#[ The 2\2!sigmatropic rearrangement may compete with the 0\2 process when the
migrating group is allylic[
CHO
O
3.0 M LiClO4
(55)
Et2O, 1 h
86%
The ring expansion of vinylcyclopropanes "Equation "45## and vinylcyclobutanes can be classed as
a 0\2!sigmatropic rearrangement ð74OR"22#136\ 80COS"4#788Ł[ These rearrangements can be promoted
thermally or photochemically and are accelerated when the ring is substituted by an alkoxy group[
(56)

The migration of both a hydrogen atom and a carbon!centred group by a 0\4!sigmatropic shift
is known and has been reviewed ð57QR227\ 58CRV092\ B!60MI 098!90\ 65CRV076Ł[ The rearrangement is
promoted thermally and is characteristic of cis!0\2!pentadienes and cis!0!alkyl!1!vinylcyclopropanes
"Scheme 20#[
(R)H H(R)
H(R)
(R)H
Scheme 31
The suprafacial\ concerted nature of the 0\4!sigmatropic rearrangement has been demonstrated
by Roth et al[ who heated the diene "77# to 149>C to e}ect the 0\4!hydrogen shift ð69CB315Ł[ A
mixture of the dienes "78# and "89# was produced\ both of which arise by a suprafacial migration of
the hydrogen atom "Equation "46##[
H
250 °C Et D
H + (57)
2h
Et D 73%
Et D H
(88) (89) 40 : 60 (90)
The 0\4!sigmatropic rearrangement\ which takes place by a suprafacial pathway\ is a thermally!

allowed process and so can occur in cyclic systems ð55C118Ł[ These rearrangements occur at lower
temperatures than in the acyclic series and many such examples have been reported[ 0\2!Cyclohep!
tadienes and cycloheptatrienes rearrange at 59Ð039>C ð58RTC155Ł\ whereas cyclopentadienes
rearrange at room temperature ð54T1218Ł[ Further acceleration of rearrangement occurs with anion!
assisted systems[ As with other sigmatropic rearrangements\ potassium alkoxides are particularly
e}ective[ The potassium salt of the alcohol "80# rearranges by a 0\4!hydrogen shift 094 times faster
than the alcohol itself "Equation "47## ð79JA2861Ł[
OH O
KH
(58)
THF, RT
(91)
The formation of a new C0C bond by a 0\4!sigmatropic shift of an alkyl group is considerably
slower than the migration of a hydrogen atom[ The rearrangement is known in cyclic systems and
follows a suprafacial pathway with retention of con_guration at the migrating group ð69CC0057Ł[
The 0\4!alkyl shift is normally followed by more rapid 0\4!hydrogen shifts leading to the most stable
diene[ Representative is the rearrangement of the cyclopentadiene "81# which requires heating to
219>C and leads to the cyclopentadiene "82# "Scheme 21# ð57RTC187Ł[
320 °C
30 min
(92) (93)
Scheme 32
0\4!Sigmatropic rearrangements in substituted indenes have allowed a comparison of the relative

migratory aptitudes of a number of substituents ð60JA549\ 79JCS"P0#603\ 82JCS"P0#570Ł[ The rate of
migration has been found to follow the order CHO×COMe×H×vinyl×CO1Me×CN¼
C2CH×aryl×alkyl[ Such rearrangements commonly employ diphenyl ether as the solvent and
temperatures in the region of 199Ð299>C[ Accelerated migrations of alkyl\ vinyl\ aryl and cyclopropyl
groups in cyclopentadiene derivatives have been observed when activated by an alkoxy substituent
ð73CC889Ł[

Thermal 0\6!shifts are thought to proceed by an antarafacial process and therefore require open!
chain systems\ namely 0\2\4!heptatrienes ð57QR227\ 65CRV076Ł[ In cyclic trienes the 0\4!sigmatropic
shift is preferred as this may proceed thermally through a symmetry!allowed suprafacial pathway[
For an antarafacial 0\6!hydrogen shift a helical!like transition state has been postulated[ This is
only possible if the central double bond of the triene and at least one of the other two double bonds
is cisoid[ If this is not the case\ then a 0\4 shift\ an electrocyclic ring closure or a 3¦1 cycloaddition
usually takes place[ For example\ the "Z\Z#!0\2\4!undecatriene "83# undergoes a thermal 0\6!hydro!
gen shift above room temperature to give the triene "84# "Equation "48##\ whereas even above 099>C
the corresponding "Z\E#!\ "E\Z#! and "E\E#!isomers do not undergo 0\6!hydrogen shifts but follow
alternative reaction pathways ð64HCA0905Ł[
>25 °C
(59)
H
(94) (95)
An early and well!known example of a 0\6!sigmatropic rearrangement is the interconversion of

vitamin D and precalciferol "Equation "59## ð38BSF490\ 46RTC578\ 53RTC0062Ł[ The 0\6!hydrogen shift
has been shown to be reversible ð69HCA062\ 76JA7940Ł and the position of equilibrium depends on
the substitution pattern of the triene[
C9H17 C9H17
(60)
H H
HO HO
Photochemically!induced 0\6!sigmatropic rearrangements proceed by a suprafacial pathway and
have been observed in cycloheptatrienes[ A 0\6!hydrogen shift ð52AG"E#577\ 54RTC130Ł or a 0\6!alkyl
shift ð51JOC1180\ 56JA0779Ł occurs on irradiation of the cycloheptatriene in\ for example\ benzene\
ether or methanol with a high!pressure mercury lamp[ The rearrangement competes with formation
of the bicycloð2[1[9Łheptadiene[

The 1\2!sigmatropic rearrangement reaction is a well!known and widely!used method for C0C
bond formation[ The reaction occurs by an irreversible\ suprafacial process which is symmetry!
allowed\ involving carbanion formation a to a heteroatom and rearrangement through a _ve!
membered ring envelope!shaped transition state[ Most commonly an allylic framework is used\ as
generalised in Equation "50#\ although examples with benzylic\ propargylic and allenylic substrates
are known[ The stereoselectivity at the new double bond and at the two new chiral centres must be
high for a useful transformation[ These factors\ together with general synthetic methods\ will be
discussed in the following two subsections which are classi_ed according to the type of heteroatom
"X in Equation "50##[
R X (61)
R X M
M
X = heteroatom
M = metal
"i# 1\2!Rearranèment of ethers

The 1\2!rearrangement of ethers "XO# is known as the 1\2!Wittig rearrangement and has been
the subject of a number of reviews ð68AG"E#452\ 75CRV774\ 80COS"2#864\ 80COS"5#762\ 80S483Ł[ The
carbanion is normally generated by direct deprotonation a to the oxygen atom using BunLi or lithium
diisopropylamide "LDA#[ This deprotonation must be regioselective except when symmetrical ethers
are employed\ such as in the early work by Hauser and Kantor using diallyl ether and KNH1\ Et1O
ð40JA0326Ł[ The regioselectivity will be dependent on the substituent R "Equation "50## which can
be classi_ed into one of three categories] hydrocarbon groups "vinyl\ alkynyl or aryl#\ acyl groups
and unstabilised systems in which RH\ alkyl[ This last category requires regiospeci_c anion
formation\ for example\ by tinÐlithium exchange or reductive lithiation of O\S!acetals[ The con!
ditions used to e}ect the rearrangement and the selectivities achieved tend to depend upon which
category of R group is present and so each substrate will be discussed in turn[
To generate a carbanion stabilised by a vinyl\ alkynyl or aryl group BunLi in THF is normally
used[ The BunLi is best added at low temperature "often −67>C# to minimise side reactions such as
the 0\1!Wittig rearrangement[ When bisallylic ethers are employed as substrates\ deprotonation
takes place a to the oxygen atom on the less substituted allylic group as this generates the more
stable carbanion ð70JA5381\ 72JOC168Ł[ In most cases rearrangement gives very good stereoselection
in favour of the "E#!isomer of the C1C bond[ The stereoselection across the new C0C bond\
pertinent to the review in this section "see Chapter 0[07 for C1C formation#\ is normally high in
favour of the syn diastereoisomer from the "Z#!alkene "Equation "51#\ Table 3#[ This dias!
tereoselectivity is often ×89 ] 09 and therefore provides a useful route to homoallylic alcohols of
de_ned stereochemistry[ As would be expected\ the use of a g!substituted allylic ether with "E#
geometry favours the alternative anti diastereoisomer "Table 3# although in these cases the degree
of stereoselection is often lower[
With an electron!withdrawing R group "Equation "50## such as an acyl group the carbanion is
normally generated using LDA[ Representative examples of Equation "52# are shown in Table 4[
With a carboxylic acid\ two equivalents of LDA are required and low temperatures are normally
employed ð70TL58Ł[ The use of ester enolates has been documented "Table 4# and selectivities can
be high in favour of the syn diastereoisomer\ especially in the presence of Cp1ZrCl1 or Cp1TiCl1
ð75TL3470\ 77TL3652\ 81BCJ0730Ł[ Lewis acids such as trimethylsilyl tri~ate "TMSOTf# or Bun1BOTf
with a tertiary amine such as Et2N or Pri1NEt in CH1Cl1 provide alternative reaction conditions to
promote the 1\2!Wittig rearrangement ð75TL3400\ 80TL3536Ł[
Table 3 1\2!Wittig rearrangement with hydrocarbon stabilising groups[
OH
R1 O R3 BunLi R2
R3 (62)
R2 R1
R1 (E or Z) R2 R3 Conditions Yield (E) : (Z) syn : anti Ref.

(%)
Me (Z) H Ph Et2O–hexane, TMEDA, –80 °C 100 : 0 a
Me (Z) Pri Ph THF 89 100 : 0 93 : 7 b
Me (Z) H CH=CH2 THF, –85 °C 88 92 : 8 c
Me (Z) H CMe=CH2 THF, –85 °C 71 95 : 5 c
Me (Z) Pri CH=CH2 THF 84 100 : 0 92 : 8 b
Me (Z) H C≡CH THF, –85 °C 56 90 : 10 d
Me (Z) H C≡CMe THF, –85 °C 55 100 : 0 d
Me (Z) H C≡CTMS THF, –85 °C 74 100 : 0 d
Re (Z) H C≡CTMS THF, –78 °C 77 98 : 2 f
Me (Z) Pri C≡CH THF 89 100 : 0 91 : 9 b
Me (Z) Pri C≡CTMS THF 62 100 : 0 >98 : 2 b
Me (Z) Me C≡CTMS THF, –85 °C 64 >99: 1 >99 : 1 g
Bun (Z) Me C≡CTMS THF, –85 °C 96 100 : 0 99 : 1 h
Et (Z) Me C≡CMe THF, –78 °C 75 100 : 0 >99 : 1 i
Me (E) H Ph Et2O–hexane, TMEDA, –80 °C 50 : 50 a
Me (E) Pri Ph THF 95 82 : 18 24 : 76 b
Me (E) Me Ph THF, 0 °C 83 : 17 j
Me (E) H CH=CH2 THF, –85 °C 81 16 : 84 c
Me (E) H CMe=CH2 THF, –85 °C 70 28 : 72 c
Me (E) Pri CH=CH2 THF 75 100 : 0 40 : 60 b
Me (E) H C≡CH THF, –85 °C 72 1 : 99 d
Me (E) H C≡CMe THF, –85 °C 65 1 : 99 d
Me (E) H C≡CTMS THF, –85 °C 72 73 : 27 d
Re (E) H C≡CTMS THF, –78 °C 93 60 : 40 f
Me (E) Pri C≡CH THF 63 92 : 8 11 : 89 b
Me (E) Me C≡CH THF, –85 °C 62 100 : 0 9 : 91 d
a〈70CC4〉. b〈84JOC1842〉. c〈81JA6492, 83JOC279〉. d〈84T2303〉, Re = (S)-CH(Me)O-TBDMS. f〈88TL4587〉. g〈84TL565〉. h〈85CL1723〉.
i〈91JOC5973〉. j〈71JA3556〉.
High yields and syn diastereoselectivities have been achieved in the 1\2!sigmatropic rearrangement
of a!allyloxyacetamides using LDA or lithium hexamethyldisilazide "LHMDS# in THF at −67 to
−74>C ð74CL0618Ł[ Rearrangement when the carbanion is stabilised by an oxazoline or dihy!
drooxazine is also known to occur in THF at −67>C\ deprotonation being e}ected with LDA or
BunLi ð72TL402Ł[
Regioselective carbanion formation a to the oxygen atom by tinÐlithium exchange\ followed by
1\2!Wittig rearrangement\ was introduced by Still and Mitra ð67JA0816Ł[ The trialkyltin group can
be exchanged for lithium using BunLi in THF at −67>C[ This generates a relatively unstabilised
carbanion which undergoes rearrangement at low temperature to give the homoallylic alcohol
"Equation "53#\ Table 5#[ The alternative sulfur to lithium exchange has been e}ected using lithium
naphthalenide in THF ð78JA1870Ł[
The use of exchange reactions with an alkyl group at the carbanion centre has allowed the
discovery that rearrangement proceeds with inversion of stereochemistry at this centre ð81AG"E#536\
81JA264\ 81TL4684Ł[ For example\ transmetallation of the stannane "85# with BunLi gives the homo!
allylic alcohol "86# with essentially complete anti diastereoselectivity and with essentially no loss of
enantiomeric purity through an inversion pathway "Equation "54##[
Table 4 1\2!Wittig rearrangement with acyl stabilising groups[
O OH
R1 O BunLi R2 R3 (63)
R3
R2 R1 O
R1 (E or Z) R2 R3 Conditions Yield (E) : (Z) syn : anti Ref.

(%)
H Me OH 2 LDA, THF, –78 °C 87a >95 : 5 b
H C7H15 OH 2 LDA, THF, –78 °C 74 >95 : 5 b
Me (Z) H OH 2 LDA, THF, –78 °C 73a 75 : 25 b
Me (E) H OH 2 LDA, THF, –78 °C 60a 35 : 65 b
Me (Z) H OPri LDA, THF, –100 to –20 °C 20 67 : 33 c
Me (E) H OPri LDA, THF, –100 to –20 °C 14 82 : 18 c
Me (E) Me OPri LDA, THF, –100 to –20 °C 72 60 : 40 80 : 20 c
Me (Z) H OPri LDA, THF, Cp2ZrCl2, –100 to –20 °C 15 88 : 12 c
Me (E) H OPri LDA, THF, Cp2ZrCl2, –100 to –20 °C 47 98 : 2 c
Me (E) Me OPri LDA, THF, Cp2ZrCl2, –100 to –20 °C 91 0 : 100 99 : 1 c
Me (E) C8H17 OPri LDA, THF, Cp2ZrCl2, –100 to –20 °C 70 0 : 100 99 : 1 c
Me (E) CH2OBn OPri LDA, THF, Cp2ZrCl2, –100 to –20 °C 72 60 : 40 100 : 0 d
Me (E) CH2OBn OPri LDA, THF, Cp2TiCl2, –100 to –20 °C 53 98 : 2 98 : 2 d
Me (Z) H OMe TMSOTf, Et3N, CH2Cl2 86 53 : 47 e
Me (E) H OMe TMSOTf, Et3N, CH2Cl2 83 92 : 8 e
Me (Z) H OMe Bu2BOTf, Pri2NEt, CH2Cl2, –78 °C to RT 54 30 : 70 f
Me (E) H OMe Bu2BOTf, Pri2NEt, CH2Cl2, –78 °C to RT 55 92 : 8 f
aQuench with TsCl. b〈81TL69〉. c〈86TL4581〉. d〈88TL4763, 92BCJ1841〉. e〈86TL4511〉. f〈91TL4647〉.
Table 5 1\2!WittigÐStill rearrangement[

R2 R2
R1 O SnBu3 BunLi R3
OH (64)
R3 R1
R1 (E or Z) R2 R3 Conditions Yield (E) : (Z) Ref.

(%)
H Me Bun THF, –78 °C, 30 min 95 3 : 97 a
H H C7H15n THF, –78 °C, 30 min 95 40 : 60 a
Me (Z) H C7H15n THF, –78 °C, 30 min 91 100 : 0 a
Me (Z) H Pri THF, –78 to 0 °C 72 100 : 0 b
Me (E) H C7H15n THF, –78 °C, 30 min 96 35 : 65 a
Me (E) H Pri THF, –78 to 0 °C 72 53 : 47 b
Me (E) H CH2NHTr hexane, –110 °C 80 60 : 40 c
a〈78JA1927〉. b〈85TL5013〉. c〈92T6425〉.
O SnBu3 OH
1.5 BunLi
(65)
THF, –78 °C
95%
(96) 88% ee (97) >99% de, 87% ee
The related 1\2!thia!WittigÐStill rearrangement in which the ether oxygen atom has been replaced
by a sulfur atom proceeds e.ciently using transmetallation with BunLi ð81TL6212\ 82CB0116Ł\
although rearrangement of N!allyl aminomethylstannanes to the homoallylic amine has been shown
to occur by a 0\1!rearrangement ð82JCS"P0#0164Ł[ Sulfur and nitrogen ylides rearrange by a 1\2!
sigmatropic process as discussed below[
Many examples of asymmetric induction in the 1\2!Wittig rearrangement have been investigated
using the three general methods for the rearrangement described in this section[ As the rearrangement
is suprafacial\ transfer of chirality across the allyl system is observed[ Examples of diastereoselection
using a chiral auxiliary "especially on the acyl group# or with an adjacent allylic chiral centre\ or
using a chiral base on cyclic allylic ethers are known and have been discussed in the given reviews\
for example ð80S483Ł[
"ii# 1\2!Rearranèment of ylides

A number of reviews ðB!60MI 098!91\ 68AG"E#452\ 80COS"2#802\ 80COS"5#762Ł cover the 1\2!sigmatropic
rearrangement of allyl!substituted ylides "XNR1\ SR\ OR\ halogen\ Equation "50## often referred
to as the 1\2!Stevens rearrangement after early work by Stevens ð21JCS0821Ł[ Ylides can be generated
by deprotonation "or desilylation# of ammonium or sulfonium salts "prepared by alkylation of
amines or sul_des# or by direct reaction of the amine\ sul_de\ selenide\ ether or halide with a carbene[
The ylide so formed rearranges "often at room temperature# through a _ve!membered ring transition
state with the formation of a new C0C bond in an acyclic or a cyclic substrate\ the latter potentially
providing a useful ring expansion or contraction method[ Each of these aspects will be dealt with
in turn[
Deprotonation of an ammonium or sulfonium salt is a common method for ylide formation and
can be e}ected with a variety of bases[ Mild conditions such as K1CO2 in EtOH or H1O can be used
for generation of sulfonium ylides[ Slightly harsher conditions such as NaOH\ NaOMe or NaNH1
are normally needed for ammonium ylide formation[ Table 6 gives a number of examples of the
1\2!Stevens rearrangement when the carbanion is stabilised by a hydrocarbon "aryl\ alkenyl or
alkynyl# group "Equation "55##[ If one of the substituents on the heteroatom is a benzyl group then
deprotonation and rearrangement may give rise to accompanying SommeletÐHauser rearrangement[
The SommeletÐHauser rearrangement has been reviewed ð69OR"07#392\ 80COS"2#802Ł and may be
favoured with protic solvents[
Table 6 1\2!Ylidic rearrangement with hydrocarbon stabilising grops[

R3 XR3
+
R1 X R4 (66)
R4
R2 R1 R2
R1 R2 XR3 R4 Conditions Yield syn : anti Ref.

(%)
H H SEt Ph NaOEt a b
Me Me SEt Ph NaOEt a b
Ph H SEt Ph K2CO3 a 60 : 40 b
Ph H SEt CH=CHPh K2CO3, EtOH 100 c d
Me Me NMe2 Ph NaNH2, NH3, –33 °C 44e f
Me Me NMe2 CH=CMe2 NaNH2, NH3, –33 °C 65 f
H H NMe2 CH=CH2 NaOMe, DMSO, RT 50 d
Ph H NMe2 CH=CHPh NaOMe, DMSO, RT 65g 91 : 9 d
H H NMe2 C≡CPh NaOMe, DMSO, RT 85 d
Ph H NMe2 C≡CPh NaOMe, DMSO, RT 91 86 : 14 d
H Ph NMe2 C≡CPh NaOMe, DMSO, RT 85 10 : 90 d
Ph H NMe2 C≡CH NaOMe, DMSO, RT 99 100 : 0 d
aHigh yield. b〈69CC293〉. cRatio not determined. d〈80JCS(P1)1436〉. e Together with 42% Sommelet–Hauser product. f〈72HCA2233〉.
gTogether with 28% 1,2-product.
Deprotonation adjacent to an acyl group in a sulfonium or ammonium salt followed by rearrange!

ment allows transformation to a homoallylic sul_de or amine "Equation "56#\ Table 7#[ In these
examples and those in Table 6 "and with the 1\2!Wittig rearrangement#\ the diastereoselectivity is
dependent upon whether the substituent is located preferentially exo or endo to the _ve!membered
ring transition state[ A mixture of diastereoisomers is normally observed\ especially from acyclic
ylides\ although selectivities can be good[ The double bond stereoselection is normally in favour of
the E isomer ð75T1868\ 81JOC317Ł[
Table 7 1\2!Ylidic rearrangement with acyl stabilising groups[

R3 O XR3
+
R1 X R4 (67)
R4
R2 R1 R2 O
R1 R2 XR3 R4 Conditions Yield syn : anti Ref.

(%)
H H SMe Ph 2M K2CO3 (aq.) 69 a
H H SMe Me 2M K2CO3 (aq.) 63 a
Me H SMe Ph 2M K2CO3 (aq.) 94 b a
Me Me SMe Ph 2M K2CO3 (aq.) 96 a
Me Me SMe Me 2M K2CO3 (aq.) 90 a
Me Me SMe OEt 2M K2CO3 (aq.) 91 a
H H SEt Ph NaOEt c d
Me Me SEt Ph NaOEt c d
Ph H SEt Ph K2CO3 c b d
Me Me NMe2 Ph 2M NaOH (aq.), RT, 1 h 98 e
Me Me NMe2 Me 10M NaOH (aq.), RT, 1 h 60 e
Me Me NMe2 OMe NaOMe, DMSO, RT 93 e
Ph H NMe2 Ph 2M NaOH (aq.), 60 °C 98 27 : 73 e
Ph H NMe2 Ph NaOH (aq.), CHCl3, 0 °C 17 : 83 f
H Ph NMe2 Ph NaOH (aq.), CHCl3, 0 °C 67 : 33 f
Ph H NMe2 But NaOH (aq.), Et2O, RT 10 : 90 f
a〈80JA2125〉. b〈Ratio not determined〉. cHigh yield. d〈69CC293〉. e〈80JCS(P1)1450〉. f〈81JCS(P1)1953〉.
Analogous to the 1\2!WittigÐStill rearrangement is the rearrangement of relatively unstabilised

ylides\ normally generated by desilylation using CsF in diglyme or MeCN ð68JA5341\ 74JOC1854Ł or
in hexamethylphosphoramide "HMPA# ð89JA0888Ł[ For example\ the ammonium salt "87# can be
desilylated with CsF in HMPA and the resulting ylide rearranges to give the "E#!homoallylic amine
"88# "Equation "57##[ Quite remarkable is the complete "Z# selectivity in the rearrangement of the
ylide generated from the ammonium salt "099# "Equation "58## ð89JA0888Ł[ This rearrangement is
thought to proceed by initial deprotonation to give the allyl anion[ Proton transfer then sets up the
required ylide for 1\2!sigmatropic rearrangement to the "Z#!homoallylic amine "090#[
Me2 CsF, HMPA

RT, 1 h
N TMS (68)
+ NMe2
–OTf 68%
(98) (99)
+ NaNH2, NH3 (1)

NMe3 (69)
NMe2
I– –33 °C, 30 min
72%
(100) (101)
The above methods for ylide generation require the prior formation of a sulfonium or ammonium
salt\ followed by deprotonation "or desilylation# of the salt[ An alternative method\ which also
encompasses oxonium and halonium ylide formation\ involves the use of a carbene[ The carbene
can be generated from a diiodoalkane and Et1Zn ð71TL2908Ł or more commonly from a diazoalkane
and copper"II#\ rhodium"II# or light ð61JA2769\ 70JOC4983Ł[ Table 8 gives examples of the conversion
of an allylic sul_de "or selenide# into a homoallylic sul_de "or selenide# "Equation "69## and Table
09 gives further acyclic examples from allylic amines\ ethers and halides "Equation "60##[ Slow
addition of the diazoacetate or diazomalonate to a catalytic amount of anhydrous CuSO3 or
Rh1"OAc#3 and the allylic substrate generally gives the best results[ In most cases the 1\2!sigmatropic
rearrangement occurs with very little or no competing cyclopropanation or 0\1!Stevens rearrange!
ment[
Table 8 1\2!Sulfonium and selenonium ylide rearrangement from carbenes[

R5
R3 : R3 XR7
R1 XR7 R6 R6
R4 (70)
R5
R2 R4 R1 R2
XR7 R1 R2 R3 R4 R5 R6 Conditions Yield (E) : (Z) Ref.
(%)
SPh H H H H H H Et2Zn, CH2I2, PhH, 55 °C 55 a
SPh Me Me H H H H Et2Zn, CH2I2, PhH, 55 °C 80 a
SePh Me Me H H H H Et2Zn, CH2I2, PhH, 55 °C 75 a
SPh Me Me H Me H H Et2Zn, CH2I2, PhH, 55 °C 75 100 : 0 a
SPh Me Me H H Me H Et2Zn, MeCHI2, PhH, 55 °C 70 a
SPh H H H H CO2Me CO2Me N2C(CO2Me)2, hν 32 b
SPh H H H H CO2Me CO2Me N2C(CO2Me)2, CuSO4, 100 °C 90 b
SBun H H H H CO2Me CO2Me N2C(CO2Me)2, CuSO4, 100 °C 93 b
SPh Me H H H CO2Me CO2Me N2C(CO2Me)2, CuSO4, 100 °C 92 b
SPh H H Me Bun CO2Me CO2Me N2C(CO2Me)2, CuSO4, 100 °C 70 90 : 10 c
SMe H H H H CO2Et H N2CHCO2Et, Rh2(OAc)4, 60 °C 91 d
SEt H H H H Ph H N2CHPh, CuSO4, 110 °C 49 e
SEt H H H H Ph Ph N2CPh2, CuSO4, 110 °C 38 e
a〈82TL3019〉. b〈72JA3870〉. c〈73JOC2572〉. d〈81JOC5094〉. e〈72JOC3791〉.
Table 09 1\2!Ammonium\ oxonium and halonium ylide rearrangement from carbenes[

R2
XR4
N2
R3 R3
R1 XR4 (71)
R2
R1
XR4 R1 R2 R3 Conditions Yield syn : anti Ref.
(%)
NEt2 H CO2Me CO2Me CuSO4, 100 °C 40 a
NEt2 Me CO2Me CO2Me CuSO4, 100 °C 27 a
NMe2 H CO2Et H Rh2(OAc)4, 60 °C 60 b
NMe2 Me CO2Et H Rh2(OAc)4, 60 °C 79 75 : 25 b
NMe2 Ph CO2Et H Rh6(CO)16, 60 °C 78 72 : 28 b
OMe H CO2Me CO2Me CuSO4, 100 °C 60 a
OMe Me CO2Me CO2Me CuSO4, 100 °C 75 a
OEt Me CO2Me CO2Me CuSO4, 100 °C 15 a
Cl H CO2Me CO2Me hν 53 a
Cl H CO2Me CO2Me CuCl, 110 °C 32 a
Cl H CO2Et H Rh2(OAc)4 5c b
Br H CO2Me CO2Me hν 38 a
Br H CO2Et H Rh2(OAc)4 21d b
Br H CO2Et CO2Me Rh2(OAc)4 86 b
I H CO2Et H Rh2(OAc)4 98 b
a〈72JA3870〉. b〈81JOC5094〉. cTogether with 90% cyclopropanation. d Together with 55% cyclopropanation.
Other copper salts have been shown to be e}ective catalysts for the reaction[ For example\ the
carbene generated from the compound "091# with Cu"acac#1 reacts with allyl phenyl sul_de or allyl
methyl sul_de to give a mixture of the diastereoisomeric b!lactams "092# ð71JCS"P0#1646Ł[ A related
ammonium ylide gave the 1\2!rearranged product in 64) yield as a single diastereoisomer
ð60JA1231Ł[ Ylides have been formed through intramolecular addition of an ether or amine to a
carbene\ followed by a 1\2!sigmatropic rearrangement "Scheme 22# ð75JA5959\ 75JA5951\ 81TL5082\
82TL3274Ł[ This gives rise to 1!allyl!2!ketotetrahydrofurans and other saturated heterocycles with
both good yields and good diastereoselectivities[
N2
S
Cu(acac)2 S
SR + RS
N
O CH2Cl2, RT N
CO2CH2CCl3 O
CO2CH2CCl3
(102) R = Me, 60% (80:20) (103)
R = Ph, 65% (87:13)
O O
i or ii
N2
R O R O
i, Rh2(OAc)4, CH2Cl2, R = H, 70%; R = Me, 65% (93 : 7)

ii, Cu(acac)2, THF, reflux, R = Pri or Prn, 83% (>97 : 3)
Scheme 33
When the 1\2!sigmatropic rearrangement forms a new C0C bond within a ring then a useful ring
expansion or contraction is possible[ In ring expansions ð73ACR247Ł which give eight!membered
rings the "Z#!alkene is preferred "Equation "61## ð64JA5767Ł\ whereas for nine!membered or larger
rings the "E#!alkene is favoured "Equation "62## ð67JOC3720Ł "except when the carbanion is axially!
oriented ð67TL412Ł#[ Rearrangement with ring contraction "Scheme 23# may be slower than in the
acyclic series[ The sulfonium ylide "093# can be isolated and requires heating to 079>C to e}ect
rearrangement ð61JA2769Ł[ However\ the ylides formed by deprotonation of the salts "094# and
"095# rearrange at 9>C or room temperature to give the cis!disubstituted _ve!membered rings
ð70JCS"P0#0842Ł[
dbu
+S (72)
ClO4– PhMe, 90 °C COPh
74% S
COPh
(Z):(E) 10 : 1
dbu
+S
(73)
TfO– MeCN, 0 °C S
CO2Et 96%
CO2Et

A great many examples of the 2\2!sigmatropic rearrangement have been documented and the
reaction has found particular use for the stereocontrolled preparation of C0C bonds[ This is
because the reaction proceeds through a symmetry!allowed\ highly!ordered six!membered ring
transition state\ which "unless constrained conformationally# prefers the chair!shape and therefore
allows a prediction of the stereochemical outcome across the new C0C bond and at the new
C1C bond"s#[ The basic framework of the reaction is shown in Equation "63# and involves the
interconversion of 0\4!dienes[ With the all!carbon system the reaction is known as the Cope
rearrangement\ whereas when X is a heteroatom the reaction is termed a Claisen rearrangement[
CO2Me
N2
CO2Me 180 °C
+ CO2Me
hυ S 30 min
S S CO2Me
– 83%
MeO2C CO2Me
(104)
NaOH (aq.)
+
Br– S
CH2Cl2, 0 °C, 1 h COPh
86% S
COPh
(105) cis : trans 25 : 1
R
NaOH (aq.)
Br– + RT COPh
N N
86–89%
Me COPh Me
(106) R = H, Et, But
Scheme 34
As the general synthetic methods for each classi_cation "and within each classi_cation# di}er to
some extent\ the reaction will be discussed in the following two subsections[
(74)
X X
X = CH2 : Cope
X = O : Claisen
"i# Cope rearranèment

The Cope rearrangement is so named after work in the early 0839s by Cope ð39JA330\ 30JA0732\
30JA0741Ł[ The rearrangement has found many synthetic applications\ particularly when modi_ed
as the oxy!Cope and anionic oxy!Cope variants[ As a result\ many accounts of the Cope rearrange!
ment have been published and readers should refer to the following reviews and references therein
ð52AG"E#004\ 64OR"11#0\ 73CRV194\ 80COS"4#674Ł[ The parent Cope rearrangement is often carried out
by heating the 0\4!diene neat or in a high!boiling solvent such as xylene or decalin[ The choice of
solvent is taken on the basis of the boiling!point required to e}ect the rearrangement as the polarity
seems to have little in~uence on the rate of the reaction[ For volatile dienes gas!phase reactions in
static or ~ow systems may be used ð64OR"11#0Ł[
The 2\2!sigmatropic rearrangement of 0\4!hexadienes is a reversible process and the position of
equilibrium depends on the substitution pattern and:or strain of the dienes[ It is well known that
the thermodynamic stability of an alkene increases with increasing substitution and it is therefore
not surprising that the equilibrium lies in favour of the more substituted product[ On heating
2!methyl!0\4!hexadiene "Equation "64## a mixture of the two isomeric dienes results\ with the
equilibrium lying in favour of the isomer 0\4!heptadiene ð54JPC0167Ł[ Using less vigorous conditions\
more complete conversion than with alkyl substituted dienes may be observed when the diene is
substituted by a group capable of p!orbital overlap with the newly formed C1C bond[ Some of the
early work by Cope used dienes such as those in Scheme 24 in which a phenyl group "Equation
"65## ð33JA0573Ł or an acyl group "Equation "66## ð30JA0732\ 30JA0741Ł comes into conjugation with
one of the C1C bonds on rearrangement[ This type of 2\2!sigmatropic rearrangement can\ in
general\ be e}ected at temperatures in the range 049Ð199>C[ As mentioned above\ the di}erence in
strain between the two 0\4!dienes can in~uence the position of equilibrium[ Some cis!0\1!divi!
nylcyclopropanes such as the parent diene "096# are only stable at low temperature "e[g[\ −19>C#
and rearrange rapidly at room temperature ð62CC208Ł\ while others are stable enough to be isolable
and require heating to promote the Cope rearrangement[ The rearrangement of divinyl!
cyclopropanes gives rise to a new C0C bond in a cycloheptadiene ring\ for example "097# in
Equation "67#[ Rearrangement of cis!0\1!divinylcyclobutanes normally requires heat and gives
access to the cyclooctadiene ring[
220–300 °C
(75)
15 : 85
trans : cis 2 : 1
Ph 165–185 °C Ph
(76)
65 h
72%
EtO2C EtO2C
200 °C, 8 h
EtO2C (77)
90% EtO2C
Scheme 35
H
t1/2 7.5 min, 20.4 °C
(78)
H
(107) (108)
When there are one or more substituents at C!2 and:or C!3 of the 0\4!diene\ rearrangement can
give a mixture of "E#! and "Z#!isomers of the product diene[ The "E# ] "Z# ratio depends on the
orientation of the substituent in the transition state[ As this is normally chair!shaped\ the substituent
generally prefers the less!hindered equatorial position and this leads to the "E#!isomer of the product
ð51T56Ł[ The degree of stereocontrol across the new C0C bond is also very high and the preferred
diastereoisomer can be related to the alkene geometry of the starting 0\4!diene[ This is a result of
the chair!shaped transition state which imparts stereospeci_city to the rearrangement such that the
"E\E#! and "Z\Z#!isomers of the starting diene give predominantly the syn!diastereoisomer of the
product\ whereas the "E\Z#!isomers give the anti!diastereoisomer ð76JOC4087Ł[ In addition\ as a
consequence of the ordered transition state\ chirality transfer across the allylic system is possible
ð73MI 098!90Ł[
When the 0\4!diene is substituted by a hydroxy or alkoxy group at C!2 and:or C!3\ the 2\2!
sigmatropic shift is known as the oxy!Cope rearrangement[ This gives rise\ initially\ to an enol
or enol ether which is converted to the corresponding carbonyl compound[ Early work on this
rearrangement ð53JA4906\ 53JA4908\ 54JA0049\ 55TL5004Ł demonstrated that the reaction provided a
convenient method for the preparation of d\o!unsaturated carbonyl compounds\ although tem!
peratures in excess of 199>C are normally required[ Despite this the oxy!Cope rearrangement has
found a number of applications as its irreversibility has allowed the synthesis of large rings which
are disfavoured by the parent Cope rearrangement[ For example\ the diene "098# rearranges on
heating to the ten!membered ring "009# "Equation "68## ð69TL498Ł\ whereas the equilibrium for the
Cope rearrangement lies in favour of the six!membered ring[
O
OH
220 °C, 3 h
(79)
90%
H
(109) (110)
The simple diene "000# undergoes an oxy!Cope rearrangement to give the unsaturated aldehyde
"001# "Equation "79## when distilled at 279>C ð54JA0049Ł and the e}ect of substitution on each of
the six carbon atoms has been investigated ð56JA2351Ł[ A major side!reaction in the oxy!Cope
rearrangement is a fragmentation by a competing retro!ene process[ This was found to reduce the
yield of the Cope rearrangement product particularly when the 2!hydroxy!0\4!diene is substituted
at C!0\ C!4 and:or C!5[ Competing fragmentation in the oxy!Cope rearrangement may be minimised
by the use of an alkoxy or acyloxy group in place of the hydroxy group\ or by the use of N!methyl!
1!pyrrolidinone as the solvent ð67CC861Ł[
HO 380 °C
O
(80)
57%
(111) (112)
In addition to the thermal activation of the Cope and oxy!Cope rearrangements\ it is known that
these rearrangements can be promoted by the addition of an acid or metal catalyst ð73AG"E#468\
73CRV194Ł[ A few examples of acceleration of the Cope rearrangement with acids such as H1SO3 or
HCl\ or with Lewis acids such as AlCl2\ BF2 = OEt1 or Al1O2 have been reported ð73CRV194Ł[ More
examples have been documented with the use of a metal catalyst\ especially a palladium"II# complex\
but also nickel"9# and mercury"II# salts ð73CRV194\ 73AG"E#468\ 89JA2834Ł[ The preferred complex
seems to be PdCl1"PhCN#1 which is used normally in benzene or THF at room temperature[ Some
examples are given in Scheme 25 illustrating the relative ease of these processes "the diene "002#
requires heating to a temperature of 049>C for 4 h to e}ect the thermal rearrangement# ð55JOM"5#301\
62JOM"38#366Ł[ The rearrangement of acyclic dienes can be promoted using palladium"II# catalysis
and this can be e}ective with less than one equivalent of PdCl1 ð79JA754Ł[ The oxy!Cope rearrange!
ment of tertiary alcohols\ for example the diene "003#\ proceeds at room temperature in the presence
of 09 mol) PdCl1"PhCN#1 ð72TL0046Ł[ A major drawback\ however of these metal!catalysed 2\2!
sigmatropic rearrangements in acyclic dienes is the necessity for the diene to be substituted at either
C!1 or C!4[
i, PdCl2(PhCN)2
PhH, RT, 3 h 82%

ii, KCN
(113)
Ph 6 mol % PdCl2(PhCN)2 Ph
PhH, RT, 1 h
87%
(E):(Z) 93:7
O
HO
10 mol % PdCl2(PhCN)2
THF, RT, 3 h
100%
(114) Scheme 36
An alternative and now common method for catalysing the oxy!Cope rearrangement is the
addition of a base to deprotonate the alcohol[ This was popularised by Evans and Golob ð64JA3654Ł
who showed that enormous rate enhancements are possible[ The anionic oxy!Cope rearrangement
"Scheme 26# is often best accelerated as the potassium salt "using KH or potassium hexa!
methyldisilazide "KHMDS# as the base\ normally in THF#\ although sodium alkoxides may work
well "deprotonation with NaH#[ Whereas the oxy!Cope rearrangement requires high temperatures\
deprotonation of the alcohol at room temperature may be followed directly by rearrangement[ In
cases which are reluctant to proceed at re~ux in THF\ the use of DIGLYME as the solvent or the
addition of 07!crown!5 or TMEDA may promote the reaction[ An improvement in the yield of the
rearranged product "the d\o!unsaturated carbonyl compound# may result from cleaning the KH
with iodine ð75JOC0013Ł[
The 0\2!sigmatropic rearrangement may compete with the anionic oxy!Cope rearrangement\
HO M + –O O
base
Scheme 37
although the 2\2!sigmatropic process is usually favoured ð66TL1448Ł[ Like the parent Cope rearrange!
ment the anionic oxy!Cope rearrangement has been demonstrated to prefer the chair!shaped tran!
sition state[ This is illustrated in the conversion of the potassium salt of the 2!hydroxy!diene "004#
into the ketone "005# on heating "Equation "70## ð79JA663Ł[ The diastereoselectivity across the new
C0C bond of the ketone "005# re~ects the chair!like transition state with the alkoxy group in the
pseudoequatorial position[ In acyclic systems the preference for the pseudoequatorial alkoxy group
is diminished\ resulting in poor chirality transfer from the carbon bearing the hydroxy group across
the allylic system ð81JA4907Ł[ However\ the rearrangement of dienes in which one of the C1C bonds
is constrained to a ring often proceeds with a high degree of stereocontrol and is a powerful
technique for the construction of complex bicyclic and polycyclic ring systems[
OMe
KH, DIGLYME H
MeO O (81)
HO 110 °C, 38 h
H
77%
(115) (116) trans:cis 96:4
"ii# Claisen rearranèment

Since the _rst report by Claisen ð01CB2046Ł\ the rearrangement of allyl vinyl ethers and modi!
_cations of this 2\2!sigmatropic process have been the subject of a great many mechanistic and
stereochemical studies\ and have formed the key step in many synthetic strategies ð64OR"11#0\ 79T2\
73CRV194\ 77CRV0312\ 78S60\ 80COS"4#716\ 82MI 096!90Ł[ The rearrangement proceeds with the formation
of a new C0C bond at the expense of a C0O "or other CÐheteroatom# bond through a highly
ordered six!membered ring transition state[ As a result\ the rearrangement shows a high degree of
stereospeci_city with the stereochemical outcome at the new C0C bond determined by the geometry
of the double bonds in the starting material[
The Claisen rearrangement has been successful with a wide variety of substrates including allyl
aryl ethers\ allyl vinyl ethers "in open!chain or cyclic systems# and substrates in which the allyl group
has been replaced by a propargyl or an allenyl group[ In addition\ aza!Claisen\ thia!Claisen and
metalla!Claisen rearrangements have been investigated[ A number of methods for the preparation
of allyl vinyl ethers are known ð80COS"4#716Ł[ These commonly involve the reaction of an allylic
alcohol with a simple alkyl vinyl ether using a catalytic amount of a protic or Lewis acid "particularly
Hg"OAc#1# ð46JA1717Ł[ The various modi_cations of the Claisen rearrangement\ especially those of
Eschenmoser ð53HCA1314Ł\ Johnson ð69JA630Ł and Ireland ð61JA4786Ł provide simpler methods for
accessing the required allyl vinyl ether arrangement and each will be discussed in turn "see Chapter
0[07#[
Aromatic Claisen rearrangements involve the rearrangement of allyl aryl ethers with migration
of the allyl group through an allylic transposition to the ortho position of the aromatic ring "Scheme
27# ðB!52MI 098!90Ł[ Further 2\2!sigmatropic rearrangements to the para position may take place to
give a mixture of the ortho and para substituted products[ The rearrangement can be promoted by
heating the allyl aryl ether neat or in an appropriate solvent "e[g[\ dimethyl aniline# in the temperature
range 049Ð199>C ð64OR0Ł[ A lower temperature may be employed when the reaction is conducted
in the presence of a Lewis acid catalyst such as BF2\ BCl2\ Et1AlCl or a transition metal derivative
ð73CRV194Ł[
O O HO
Scheme 38
Aliphatic Claisen rearrangements of allyl vinyl ethers give rise to g\d!unsaturated carbonyl com!
pounds[ The rearrangement is normally e}ected by heating the substrate neat or in a solvent such
as decalin and generally requires temperatures in the range 099Ð199>C[ Allyl vinyl ether itself
rearranges to 3!pentenal at 144>C "Equation "71## ð27JA0894Ł although lower temperatures can be
used at the expense of longer reaction times and reduced yields ð49BSF010Ł[
255 °C
(82)
O O
The presence of a substituent a to the oxygen atom in the allyl unit of the allyl vinyl ether gives
rise\ on rearrangement\ to predominantly\ if not entirely\ the "E#!alkene product ð59JA3570Ł[ This
arises from the preferential orientation of the substituent in the less!hindered pseudo!equatorial
position of the chair!shaped transition state[ The preference for the chair form in the rearrangement
of acyclic allyl vinyl ethers is of the order of 84Ð85) ð63T0848Ł and this accounts for the high degree
of stereocontrol in the Claisen rearrangement[ Ab initio quantum mechanical calculations also
support the chair!shaped transition structure ð77JA1203Ł[ As a result\ the stereochemical outcome
at the new C0C bond can be predicted on the basis of the geometry of the C1C bonds in the allyl
vinyl ether[ This is illustrated in Scheme 28 in which the "E\E#! and "Z\Z#!isomers give predominantly
"84)# the threo diastereoisomer whereas the "E\Z#! isomers give predominantly "84)# the
alternative erythro diastereoisomer ð57HCA0346\ 64HCA0182Ł[ When the allyl unit of the allyl vinyl
ether forms part of a ring system then conformational constraints may favour the boat!shaped
transition structure with the consequence that a reduced or even reversed stereoselection may result[
143–160 °C 160–190 °C
O O O
145–170 °C 145–165 °C
O O
O
Scheme 39
A reduction in the temperature required to e}ect the Claisen rearrangement may be made in the
presence of a catalyst ð73CRV194Ł[ Most successful have been the use of alkylaluminium or palladium
based catalysts\ rearrangement taking place often at room temperature[ Of note is the use of
Et1AlSPh in 0\1!dichloroethane which allowed the rearrangement of the allyl vinyl ether "006# to the
g\d!unsaturated aldehyde "007# at room temperature "Equation "72## ð70TL2874Ł[ The corresponding
thermal rearrangement required heating the allyl vinyl ether "006# in a sealed tube to 079>C\ but
gave a high stereoselection at the new C1C bond "×84) "E##[ The catalysis of the Claisen
rearrangement with bulky aluminium reagents has been successful ð77JA6811\ 89JA205Ł[ A reduction
or reversal of the stereoselection normally observed in the thermal Claisen rearrangement is also
observed with palladium catalysts[ A catalytic amount of the palladium"II# salt PdCl1"MeCN#1 in
THF or benzene is e}ective in promoting the Claisen rearrangement of allyl vinyl ethers at room
temperature ð75TL5156\ 76TL4768\ 78SC1098Ł[ Competing cleavage of the allyl vinyl ether is\ however\
observed especially if the vinyl group is unsubstituted[
Et2AlSPh
(83)
O ClCH2CH2Cl, RT O
84%
(117) (118) (E) : (Z) 39 : 61
In 0850 Meerwein et al[ reported the use of the Claisen rearrangement for the preparation of g\d!
unsaturated carboxylic amides "Scheme 39\ conditions a# ð50LA"530#0Ł[ This discovery was later
developed by Eschenmoser and co!workers ð53HCA1314\ 58HCA0929Ł[ This method obviated the need
for the prior formation of an allyl vinyl ether using an acid catalyst[ The general procedure involves
heating a dialkyl acetal of an N\N!dialkylamide with an allylic alcohol in the temperature range
099Ð079>C[ Alternatively\ treatment of the lithium salt of the allylic alcohol with the methylated
amide gives the Claisen product at room temperature ð74JOC4898Ł "Scheme 39\ conditions b#[
As expected\ the MeerweinÐEschenmoser modi_cation of the Claisen rearrangement occurs
through a chair!shaped transition state and this allows control over the stereochemistry at the new
C0C bond\ as depicted in Scheme 30 ð60CB2568Ł[ The use of the dimethyl acetal of a propionamide
"or higher amide# results in the preferential formation of the "Z# geometry of the ketene N\O!acetal[
Therefore\ the choice of "E#! or "Z#!allylic alcohol determines the stereochemical outcome of the
rearrangement^ the "E#!allylic alcohol giving the erythro product\ the "Z#!allylic alcohol giving the
a or b O
OH O
NMe2 NMe2
a: MeC(OEt)2NMe2, 130 °C, b: i, BunLi, THF; ii, MeCONR2, MeSO2CF3, THF, RT

Scheme 40
threo product[ With a substituent in the a position of the allyl unit the "E# geometry of the g\d!
unsaturated amide predominates\ although competitive elimination to a diene may be observed
ð55TL5314Ł[
OH EtC(OMe)2NMe2
O
xylene 138 °C, 15 h O 76%
NMe2
Me2N 95 : 5
OH EtC(OMe)2NMe2
O
xylene 138 °C, 7 h O 65%
NMe2
Me2N 97 : 3
Scheme 41
Related to the MeerweinÐEschenmoser method is that of Johnson et al[ ð69JA630Ł in which the
allylic alcohol is reacted with an ortho!ester in the presence of a catalytic amount of a weak acid[
Like the MeerweinÐEschenmoser method\ a temperature in the range 099Ð079>C over a period of
0Ð37 h is generally required for ketene acetal formation and rearrangement\ although microwave
irradiation is known to accelerate this process ð81JCS"P0#200Ł[ The Johnson modi_cation of the
Claisen rearrangement gives access to g\d!unsaturated esters in one step from allylic alcohols[ For
example\ heating the allylic alcohol "008# with excess triethyl orthoacetate and a catalytic amount
of propionic acid gives the g\d!unsaturated ester "019#[ The corresponding allyl vinyl ether rearrange!
ment via ether "010# requires a two!step operation giving the g\d!unsaturated aldehyde "011# in
lower overall yield and with a lower stereoselectivity "Scheme 31#[
excess MeC(OEt)3
92%
6 mol% EtCO2H
OH 138 °C, 1 h O
EtO2C
(119) OEt (120) (E):(Z) 98:2
OEt
HgOAc2
60%
83–98 °C, 61 h
O 98%
OHC
(121) (122) (E):(Z) 86:14
Scheme 42
A more controlled and now popular method for e}ecting the Claisen rearrangement was developed
by Ireland et al[ ð61JA4786\ 64TL2864\ 65JA1757Ł who used acylated allylic alcohols "Scheme 32#[ The
method requires only one equivalent of an acylating agent and lithium dialkylamide to deprotonate
to the corresponding enolate[ Control over the enolate geometry is possible\ unlike earlier related
methods using a b!keto ester "Carroll modi_cation# ð39JCS693\ 39JCS0155\ 30JCS496\ 32JA0881Ł or using
other bases ð38JA0049\ 38JA1328\ 59JOC0704\ 61SC16Ł[ The IrelandÐClaisen rearrangement proceeds at
low temperatures to give g\d!unsaturated carboxylic acids ð82MI 098!90Ł[ The problem of aldol side
products is avoided by formation of the silyl ketene acetal from the enolate prior to rearrangement[
This is accomplished normally by the addition of trimethylsilyl chloride or t!butyldimethylsilyl
chloride "TBDMS!Cl# "which gives less C!silylation# to the enolate in THF at −67>C\ or by an in
situ quench with the silyl chloride[ On warming these silyl ketene acetals the 2\2!sigmatropic
rearrangement takes place[ This generates the silyl ester of the rearranged product which can be
hydrolysed in acid or base to the corresponding carboxylic acid[
R2NLi, THF, –78 °C

O O O
O OLi OH
Scheme 43
As the acyclic IrelandÐClaisen rearrangement proceeds through a chair!shaped transition state\

the control over the enolate geometry allows a control over the diastereoselectivity at the new C0C
bond[ Enolisation at −67>C in THF followed by trapping with the silyl chloride favours the "E#!
silyl ketene acetal\ whereas THF:12) hexamethylphosphoramide "HMPA# as the solvent favours
the "Z#!silyl ketene acetal "Scheme 33# ð64TL2864Ł[ The use of THF:DMPU "N!N?!dimethyl!
propyleneurea# may improve the selectivity further ð80JOC549Ł[ On warming\ the "E#!isomer "with
the "E#!allylic alcohol# rearranges to predominantly the erythro diastereoisomer and the "Z#!isomer
to the threo diastereoisomer "Scheme 33#[ The diastereoselectivity is reversed from the "Z#!allylic
alcohol[ When the allylic group is constrained to a ring then the boat!shaped transition state may
be favoured ð80JOC2461Ł[
i, LDA, THF, –78 °C 65 °C, 1 h

O O
ii, TBDMS-Cl, –78 °C then 2% HCl, HO2C
O THF (aq.)
OSiMe2But
79% 87 : 13
i, LDA, –78 °C
THF/23% HMPA 65 °C, 1 h
O O
ii, TBDMS-Cl, –78 °C then 2% HCl, HO2C
O THF (aq.)
OSiMe2But
73% 81 : 19
Scheme 44
The preference for a de_ned transition state in the Claisen rearrangement makes possible the
transfer of chirality across the allyl unit[ In addition\ a chiral centre at a position other than a to
the oxygen atom in the allyl unit may in~uence the stereochemical outcome of the rearrangement[
Noteworthy in the IrelandÐClaisen rearrangement is the use of a chiral boron reagent to generate a
boron enolate which rearranges with high diastereoselectivity and enantioselectivity ð80JA3915Ł[
Future developments and applications of the Claisen rearrangement will enhance further the status
of this useful method for the stereocontrolled formation of C0C bonds[
0[98[0[4 Electrocyclic Reactions

This section of the chapter will give a brief outline of electrocyclic processes that create a new
C0C s bond[ This new s bond is formed between the terminal ends of a polyene\ with concomitant
reorganisation of the p system[ The C0C bond becomes part of a ring "containing one less p bond
than the polyene# and the rearrangement occurs with almost total stereospeci_city[ A description
of the orbital symmetry involved in electrocyclic reactions has been discussed by Woodward and
Ho}mann ð54JA284\ 58AG"E#670\ B!69MI 098!90Ł and by Fukui ð60ACR46Ł[ The most important of these
electrocyclisations for C0C s bond formation are the 0\2!diene!cyclobutene interconversion\ the
0\2\4!triene!cyclohexadiene interconversion and the Nazarov cyclisation[ A general review of these
and other electrocyclisations can be found in the monograph by Marvell ðB!79MI 098!90Ł[ A discussion
of aspects of electrocyclisations with particular reference to the formation of the new C1C bond"s#
is given in Chapter 0[06[
0[98[0[4[0 Cyclobutene formation

The interconversion of a cyclobutene and a butadiene can be promoted thermally or pho!
tochemically ðB!79MI 098!90\ 80COS"4#564Ł[ As cyclobutenes have a high degree of ring strain they are\
in general\ thermodynamically less stable than butadienes[ Four electron electrocyclisations have
therefore been used most widely for the controlled preparation of a diene\ rather than for cyclobutene
formation[ Particularly noteworthy in this regard is the formation of o!quinodimethanes from
benzocyclobutenes and their subsequent use for the preparation of bicyclic and polycyclic ring
systems[ Benzocyclobutenes are actually thermodynamically more stable than their open!chain
dienes\ although the diene can be trapped\ normally by a dienophile in a DielsÐAlder reaction[ For
example\ the o!quinodimethane "012#\ formed by extrusion of SO1 at 009>C can be trapped by a
dienophile "Scheme 34#[ In the absence of a dienophile\ the benzocyclobutene "013# can be isolated
in good yield ð75CJC682Ł[ Similarly\ the parent benzocyclobutene can be isolated by heating the
corresponding sulfone neat at 179Ð299>C "or in the vapour phase at 359>C# ð48JA3155Ł[ Other
cyclobutenes which tend to be more stable than their ring!opened dienes include di~uorinated\
poly~uorinated or other polysubstituted cyclobutenes[ In addition\ bicyclic butenes may be more
stable than their monocyclic dienes if considerable ring strain is present in the diene[ This is the case
with medium ring dienes containing a double bond of "E# geometry[ On warming "E\Z#!0\2!
cyclooctadiene "014# to 79>C\ bicycloð3[1[9Łoctene "015# is formed essentially quantitatively "Equa!
tion "73## ð54JA2885Ł[ In contrast\ the reduced ring strain in "E\Z#!0\2!cyclodecadiene\ the two!
carbon homologue of "014#\ favours the diene over the bicycloð5[1[9Łdecene ð56TL3890Ł[
OAc OAc CO2Me OAc

CO2Me
PhMe, reflux MeO2C
SO2
90%
CO2Me
Ph Ph Ph
(123)
76%
OAc
Ph
(124)
Scheme 45
80 °C
(84)
(125) (126)
Despite the lower thermodynamic stability of simple cyclobutenes\ they can be prepared from
0\2!dienes under photochemical conditions ð51JA3030\ 51PCS223\ 54T0990\ 67AG"E#049Ł[ Irradiation of
butadiene itself gives rise to cyclobutene in moderate yield\ together with side products which
include bicyclobutane ð52JA3934Ł[ Electrocyclisation takes place from the excited singlet state of the
0\2!diene[ Normal conditions involve irradiation of a solution of the 0\2!diene in Et1O with a
medium!pressure mercury lamp[ The stereochemical outcome at the new C0C bond can be inter!
preted on the basis of the WoodwardÐHo}mann rules ð54JA284\ 58AG"E#670Ł\ which state that a four
electron electrocyclisation occurs by a thermal conrotatory or photochemical disrotatory pathway[
Irradiation of 1\3!hexadiene causes rapid "E#Ð"Z# isomerisation to give a mixture of the "E\E#!
"24[6)#\ "Z\E#! "29[4)# and "Z\Z#! "22[6)# isomers "Scheme 35#[ Further irradiation leads to
cis!2\3!dimethylcyclobutene "016# which\ from rate studies\ was shown to arise from the "E\E# diene
by a disrotatory process ð57JA3387Ł[
hυ hυ hυ, Et2O
33%
(127)
Scheme 46
Photochemical electrocyclisation of cyclic 0\2!dienes gives rise to bicycloðn[1[9Łalkenes by a dis!

rotatory process ð51JA3030\ 51JOC0809\ 55JA0962Ł[ "Z\Z#!0\2!Cyclooctadiene "017# can be transformed
into bicycloð3[1[9Łoctene "015# using a mercury arc lamp[ Addition of a sensitiser "e[g[\ acetophenone#
causes prior isomerisation to the "Z\E#!isomer\ which undergoes electrocyclisation on warming to
79>C by a conrotatory closure "Scheme 36# ð56JA001Ł[
H
hυ
Et2O, 200 h
36–41%
H
(128) (126)
hυ, PhH 80 °C, 12 h
PhCOMe 85%
(125)
Scheme 47
0[98[0[4[1 Cyclohexadiene formation

Unlike most butadiene!cyclobutene electrocyclisations\ the thermal hexatriene!cyclohexadiene
electrocyclisation lies in favour of the ring!closed product[ The parent 0\2\4!hexatriene "Equation
"74## in which the central C1C bond has "Z# geometry can be converted into 0\2!cyclohexadiene
on heating to 009>C ð53JCS2979Ł[ The rearrangement of hexatrienes is normally performed by
heating the triene in a hydrocarbon solvent such as pentane\ hexane\ cyclohexane or xylene[
Although photochemical conditions have also been documented to e}ect this electrocyclisation\
these conditions are used mostly for the reverse process\ ring!opening of cyclohexadienes[ The
electrocyclisation of hexatrienes has been the subject of a number of reviews ð52AG"E#0\ B!79MI 098!90\
B!70MI 098!90\ 72RCR50\ 80COS"4#588Ł[
110 °C
(85)
hυ
An important and early example of the six!electron electrocyclisation came from studies on the
rearrangement of precalciferol "previtamin D# to pyrocalciferol and isopyrocalciferol ð44BSF0230\
50T035Ł[ In this system thermal and photochemical induced cyclisations give complementary ster!
eochemical results[ This led to the development of the WoodwardÐHo}mann rules for electrocyclic
reactions ð54JA284\ 58AG"E#670Ł[ A consideration of orbital symmetry allows the prediction that
a thermal six!electron electrocyclisation should occur by a disrotatory mechanism\ whereas the
photochemical reaction would prefer the conrotatory pathway[ This has been veri_ed in the
rearrangement of both acyclic and cyclic trienes[ The electrocyclisation of "E\Z\E#!1\3\5!octatriene
"018# in pentane at 021>C "in a sealed tube# gives the cis isomer of dimethylcyclohexadiene "029# by
a disrotatory closure "Equation "75## ð54TL274\ 54TL280\ 62T2670Ł[ The cyclisation is stereospeci_c\
giving the cis product with a diastereoisomeric purity of ×88[4)[ The corresponding "E\Z\Z#!
triene "020# interconverts readily with the "Z\Z\Z#!isomer at 009>C via consecutive 0\6!hydrogen
shifts[ On further heating to 067>C in hexane this mixture cyclises to give the trans!di!
methylcyclohexadiene "021# and the cyclohexadiene "022# derived from the diene "021# by a 0\4!
hydrogen shift "Equation "76## ð54TL274\ 62T2670Ł[
pentane
(86)
132 °C, 5.5 h
(129) (130)
hexane
+ (87)
178 °C, 5 h
(131) (132) (133)
The 0\6!hydrogen shift requires that the central C1C bond and at least one of the other C1C
bonds of the triene are of "Z# geometry[ In these cases\ the 0\6!hydrogen shift competes favourably
with the electrocyclisation process[ This gives rise to a new triene which may undergo elec!
trocyclisation\ or a further 0\6!hydrogen shift to give a di}erent geometrical isomer of the original
triene[ On further heating\ the same diastereoisomer of the cyclohexadiene may\ therefore\ result
from both the "Z\Z\Z#! and "E\Z\Z#!trienes[ Applications of the electrocyclisation reaction for C0C
s bond formation in cyclohexadienes are\ therefore\ limited by competing 0\4! and 0\6!hydrogen
shifts ð64TL2444\ 67T1672\ 68JCS"P1#709\ 76JA7940Ł\ and by the di.culty of preparing the required triene
geometrically pure[
The photochemical electrocyclisation of trienes should occur by a conrotatory pathway and
indeed\ irradiation of "E\Z\E#!1\3\5!octatriene "018# in ether with a high pressure mercury arc lamp\
gives some trans!dimethylcyclohexadiene "021# ð51TL438Ł[ However\ a considerable amount of
starting material is reisolated together with polymeric products[ Substitution at C!1 of the acyclic
triene improves the yield and increases the rate of formation of the cyclohexadiene to some extent
ð57BSF2390\ 58BSF2554\ 62T0282\ 64TL2630Ł[ Irradiation of trienes is known to cause "E#Ð"Z# iso!
merisation ð57JOC2568\ 60JA0421Ł and the formation of bicyclic alkenes ð62PAC086\ 67AG"E#049\ B!79MI
098!91\ 76RTC502Ł[ The mixture and complexity of products that arise from the photochemical
electrocyclisation tend to limit this method to the reverse ring!opening process[
Ring!fused trienes give rise\ on electrocyclisation\ to bicyclic dienes[ When the central C1C bond
of the triene is part of a ring then this double bond is locked in the "Z# con_guration and the
reaction is facilitated[ For example\ the triene "023# rearranges on heating at 014>C to give the
bicyclic diene "024# "Equation "77## ð62T2686\ 72JOC3161Ł[ Electrocyclisation may occur at low tem!
peratures when cyclisation leads to the formation of an aromatic ring ð61CC0923Ł[ The triene "025#\
formed by photochemical ring!opening of trans!0\1!dimethyl!0\1!dihydronaphthalene\ undergoes
thermal disrotatory electrocyclisation at room temperature "Equation "78## ð61HCA2994Ł[
cyclohexane
(88)
125 °C, 18 h
sealed tube
(134) (135)
hexane, RT
(89)
(136)
The formation of a new C0C bond across the ring junction of a bicyclic diene is possible by
electrocyclisation of a medium ring triene[ The general transformation "for the "Z\Z\Z#!triene# is
outlined in Equation "89##[ The proximity of the terminal ends of the triene in such cyclic systems
can cause large rate e}ects[ Electrocyclisation of cycloheptatrienes to norcaradienes "n0\ Equation
"89## occurs at low temperatures\ although the equilibrium lies in favour of the triene in the
unsubstituted case ð56AG"E#391\ B!79MI 098!90Ł[ Electron!withdrawing groups\ especially at C!6 "or
suitably bridged or ring!fused derivatives#\ stabilise the bicyclic form[ Likewise\ cyclooctatriene is
favoured over bicycloð3[1[9Łoctadiene "n1\ Equation "89## unless substituted at C!6 and:or C!7
ð41JA3756\ 57TL4104Ł[
( )n ( )n (90)
Larger ring trienes "n2\3\ Equation "89## can be converted cleanly to the bicyclic form on
heating[ The stereochemical outcome across the new C0C bond depends on the geometry of the
triene\ the rearrangement following a thermal disrotatory pathway ð70JOC576Ł[ For example\
"Z\Z\Z#!cyclononatriene "026# cyclises to the cis!fused bicycloð3[2[9Łnonadiene "027# on heating at
099>C in cyclohexane "Equation "80## ð54TL266Ł\ whereas "E\Z\Z#!cyclononatriene "028#\ which
rearranges at a slightly faster rate than the all!"Z# isomer "026#\ gives the trans!fused diene "039# on
electrocyclisation "Equation "81## ð54TL280Ł[ However\ attempted photochemical electrocyclisation
gave none of the diene product ð62PAC086\ 70T2152Ł[ Using cyclodecatrienes it has been shown that
increased substitution at C!0 and C!5 "the terminal ends of the triene# slows the rate of elec!
trocyclisation ð52JA3922\ 62JA2821\ 71JA5763Ł[
H
cyclohexane
(91)
100 °C
H
(137) (138)
H
RT
(92)
H
(139) (140)
0[98[0[4[2 Nazarov cyclisation

The formation of a new C0C bond by electrocyclisation of a divinyl ketone is named after
studies by Nazarov ð31IZV281\ 32IZV278\ 33IZV54Ł[ A series of papers by Nazarov "see ð46JGU582\
59JGU654Ł and references therein# triggered the development of this reaction for the synthesis
of cyclopentenones[ Reviews of the cyclisation have been fairly comprehensive ð72S318\ 73S418\
80COS"4#640Ł[ The original work involved the hydrolysis of a dienyne to an allyl vinyl ketone[ This
allyl vinyl ketone isomerises to a divinyl ketone and it is this species which\ on acid catalysis\
undergoes an electrocyclisation to the cyclopentenone[ Both protic and Lewis acid conditions e}ect
the cyclisation\ the most commonly used acids being H2PO3\ H1SO3\ HCl\ BF2 = OEt1\ AlCl2\ SnCl3
or FeCl2[ The reaction normally proceeds at reasonable rates at room temperature or on slight
warming[ Protonation or Lewis acid complexation of the oxygen atom of the carbonyl group of a
divinyl ketone generates a pentadienyl cation "Scheme 37#[ This cation undergoes a four!electron
electrocyclisation to generate a new C0C bond in a _ve!membered ring containing an allyl cation[
Substituents capable of stabilising the intermediate cation "e[g[\ aromatic groups a to the carbonyl
group# increase the rate and yield of the reaction[ The intermediate allyl cation may be trapped by
a nucleophile "e[g[\ the acid counteranion or the solvent# ð61JCS"P0#1160Ł or lose a proton[ Loss of a
proton and enol!keto tautomerism leads to the cyclopentenone product"s# "Scheme 37#[
Divinyl ketones are\ in general\ unstable compounds and the Nazarov cyclisation is therefore
often e}ected from a precursor which can be transformed into the divinyl ketone[ Subsequent
electrocyclisation of the divinyl ketone to the cyclopentenone then takes place under the reaction
conditions used for its formation[ Common methods for the hydrationÐelectrocyclisation of dienynes
employ phosphoric acid or concentrated HCl at 49Ð89>C[ For example\ the dienyne "030#\ on
warming with concentrated HCl\ is transformed into the divinyl ketone "031#\ which cyclises to the
cyclopentenone "032# "Scheme 38# ð32IZV278Ł[ With unsymmetrical dienynes there exists the problem
of regioselectivity during the hydration of the alkyne[ This generates up to two divinyl ketones[
O OH OH OH
R1 R3 H+ R1 + R3 R1 R3 R1 R3 –H+
+ +
R2 R4 R2 R4 R2 R4 R2 R4
O O
R1 R3 R1 R3
+
R2 R4 R2 R4
Scheme 48
Unsymmetrical divinyl ketones will cyclise to the cyclopentenone with the most highly substituted
C1C bond[
O O
conc. HCl
60–70 °C, 4 h 71%
(141) (142) (143)

Scheme 49
The dienyne may be prepared by dehydration of an acetylenic alcohol[ If the acidic conditions
for this step promote hydration of the alkyne then the cyclopentenone may be formed directly[ In
fact\ the acid!catalysed transformation of acetylenic diols to cyclopentenones is well documented[
The acid H1SO3 in methanol is often used for this multistep transformation ð65JCS"P0#309\ 65TL2474\
68JA0488\ 70BCJ1636Ł[
A number of allyl vinyl ketones and divinyl ketones can be prepared and have been shown to
undergo Nazarov cyclisation[ Common conditions for the cyclisation use phosphoric acid in formic
or acetic acid at 49Ð89>C to give the cyclopentenone in 49Ð79) yield ð33IZV54\ 35IZV522\ 36IZV194\
41JCS0329Ł[ Other methods for the formation and electrocyclisation of a divinyl ketone include the
acylation of an alkene with a carboxylic acid "using polyphosphoric acid at 44Ð099>C# ð46JIC058\
57T434\ 57TL1090\ 69BSF1870Ł or with an acid halide "using a Lewis acid such as AlCl2 in CH1Cl1#
ð42JCS013\ 48JCS3906\ 68TL3442\ 73JOC2769Ł[ Alternatively\ the acylation of a vinyl silane with an acid
halide "using a Lewis acid such as AlCl2 and:or SnCl3 in CH1Cl1# ð68TL0884\ 68TL0888\ 79JOC0935\
79JOC2906Ł or "less commonly# the acylation of a vinyl cuprate with an acid halide ð77HCA057Ł give
access to the required divinyl ketone[ Elimination of a b? heteroatom from an a\b!unsaturated
ketone ð42JCS1136\ 45BSF0542\ 48JCS3906\ 74CL0026Ł or oxidation of a 0\0!divinyl carbinol ð41JCS0329Ł
provide further alternative methods for the preparation of a divinyl ketone[
The Nazarov cyclisation of a divinyl ketone generates the thermodynamically most stable cyclo!
pentenone with the C1C bond in the most substituted state[ Control over the position of the C1C
bond is possible with a suitably positioned trialkylsilyl group ð71JA1531\ 72HCA1266\ 72HCA1286\
75T1710\ 77HCA057Ł[ Desilylation is generally preferred over deprotonation\ and the known b!cation
stabilising e}ect of a silyl group helps to reduce side reactions resulting from the intermediate
carbocations[ For example\ the divinyl ketone "033# undergoes electrocyclisation via the allyl cation
"034# on treatment with FeCl2 in CH1Cl1[ Loss of the silyl group directs the position of the C1C
bond to the less substituted side of the cyclopentenone "035# "Scheme 49# ð71JA1531\ 72HCA1266Ł[
The stereochemical outcome a to the carbonyl group is dependent upon which side the enolate is
protonated[ From acyclic divinyl ketones this commonly results in a mixture of diastereoisomers[
In cyclic systems\ such as the divinyl ketone "033#\ the diastereoselectivity can be high[ If the whole
of the divinyl ketone is incorporated into a ring\ then the Nazarov cyclisation will lead to a bicyclic
product ð57TL2524\ 64JA817\ 79BCJ058\ B!79MI 098!92Ł[
The stereochemical outcome across the new C0C bond is often obscured by the loss of a proton
at one of these centres during the cyclopentenone formation[ Observation of the expected thermal
conrotatory nature of this electrocyclisation ð54JA284\ 58AG"E#670Ł is possible if the intermediate allyl
cation is quenched by a nucleophile or if the proton lost is exo to the _ve!membered ring[ The latter
situation has been described by Woodward ðB!69MI 098!90Ł for the electrocyclisation of the divinyl
ketone "036# "Equation "82##[ The resultant tricyclic ketone "037# has trans stereochemistry\ as
_
O OFeCl3 O
FeCl3
+
CH2Cl2, 0 °C, 4 h 84%

TMS
TMS
(144) (145) (146)
Scheme 50
expected for a conrotatory electrocyclisation[ The cis stereoisomer of the same ketone was reported
to be produced by a disrotatory photochemically activated electrocyclisation[
O O O
H3PO4
+ (93)
AcOH
H H
(147) (148)
The Nazarov cyclisation\ being an electrocyclic ring closure of a pentadienyl cation\ is not
restricted to the cyclisation of divinyl ketones[ Divinyl chlorides\ vinyl allene oxides and other
suitably substituted unsaturated systems may be converted to the required pentadienyl cation
necessary for a four!electron electrocyclisation[ Methods for pentadienyl cation formation and
electrocyclisation have been reviewed by Denmark ð80COS"4#640Ł[
1.10
One or More 1CH Bond(s)
Formed by Substitution or
Addition
MARTIN A. HAYES
Xenova Group, Slough, UK
0[09[0 ONE OR MORE 1CH BOND"S# BY SUBSTITUTION 314
0[09[0[0 Reduction of 1CÐHaloèn Bonds 314
0[09[0[0[0 Reduction of aryl halides 314
0[09[0[0[1 Reduction of vinyl halides 318
0[09[0[1 Reduction of 1C0O Bonds 321
0[09[0[1[0 Reduction of phenols and derivatives 321
0[09[0[1[1 Reduction of enol ethers and derivatives 323
0[09[0[2 Reduction of 1CÐSulfur\ Selenium and Tellurium Bonds 324
0[09[0[2[0 Reduction of aryl sul_des\ selenides and tellurides 324
0[09[0[2[1 Reduction of vinyl sul_des\ selenides and tellurides 327
0[09[0[3 Reduction of 1C0N Bonds 330
0[09[0[3[0 Reduction of arylcarbonÐnitroèn bonds 330
0[09[0[3[1 Reduction of vinylcarbonÐnitroèn bonds 332
0[09[0[4 Reduction of 1C0P\ 1C0As\ 1C0Sb\ 1C0Bi Bonds 333
0[09[0[4[0 Reduction of arylcarbonÐphosphorus\ Ðarsenic\ Ðantimony and Ðbismuth bonds 333
0[09[0[4[1 Reduction of vinylcarbonÐphosphorus bonds 335
0[09[0[5 Reduction of 1C0B\ 1C0Si\ 1C0Ge Bonds 336
0[09[0[5[0 Reduction of aryl boranes\ silanes and èrmanes 336
0[09[0[5[1 Reduction of vinyl boranes\ silanes and èrmanes 338
0[09[0[6 Reduction of 1C0Metal Bonds 341
0[09[0[6[0 Reduction of arylcarbonÐmetal bonds 341
0[09[0[6[1 Reduction of vinylcarbonÐmetal bonds 342
0[09[1 ONE OR MORE 1C0H BONDS BY ADDITION 344
0[09[1[0 Addition to Alkynes 344
0[09[1[0[0 Addition of hydroèn to alkynes 344
0[09[1[0[1 Addition of C0H to alkynes 347
0[09[1[1 Addition to Allenes 347
0[09[1[1[0 Addition of hydroèn to allenes 347
0[09[1[1[1 Addition of C0H to allenes 359
0[09[0 ONE OR MORE 1CH BOND"S# BY SUBSTITUTION
0[09[0[0 Reduction of 1CÐHalogen Bonds
0[09[0[0[0 Reduction of aryl halides

The reduction of aryl halides has been reviewed ð79S314\ B!73MI 009!92\ 80COS"7#784Ł[ A wide variety
of synthetic methods have been used to achieve this transformation[ These methods include catalytic
314
315 1CH Bond"s# by Substitution or Addition
hydrogenation and reduction by] "i# tin hydrides\ "ii# complex hydrides\ "iii# metals\ and "iv# elec!
trochemical means[ The ease of hydrogenolysis of an aryl halide bond is observed to follow
the order I×Br×Cl×F^ this di}erence in cleavage rate allows the selective reduction of mixed
halogenoarenes[
"i# Reduction of aryl ~uorides

The chemistry of aryl ~uorides is featured in review articles ð57FCR204\ B!65MI 009!90Ł[ Generally
rather severe conditions are required to hydrogenolyse the aryl C0F bond[ The majority of
successful syntheses fall into three categories] "a# reduction with LAH in combination with other
reagents\ "b# hydrogenolysis via catalytic hydrogenation\ and "c# miscellaneous methods[ Beckwith
and Goh ð72CC896Ł found that a mixture of LAH and di!t!butylperoxide under irradiation e}ectively
reduced a range of ~uorinated aromatics in good yield "Equation "0##[ Imamoto et al[ reported that
LAH in combination with CeCl2 in DME or THF to be e}ective for the reduction of aryl halides\
including ~uoronaphthalene "Equation "1## ð74CL0380Ł[ Alsop et al[ noted that the LAH reduction
of per~uorotoluene proceeded regioselectively yielding 35[8) of the product de~uorinated para to
the ~uoromethane group "Equation "2## ð51JCS0790Ł[ LAH in re~uxing Et1O was reported to reduce
penta~uorobenzene to 0\1\3\4!tetra~uorobenzene mainly ð51JCS2142Ł[
LAH, (ButO)2, hν
(1)
THF
R R
R = Me, 90%
R = MeO, 93%
LAH, CeCl3
(2)
DME
94%
F
F F F F
LAH, Et2O
(3)
46.9%
F F F F
CF3 CF3
The reduction of p!~uorobenzoic acid under catalytic hydrogenation conditions has been
described ð19MI 009!90Ł[ In 0852 Oelschlager and Schmersahl ð52AP"185#213Ł reported the reduction
of ~uoroaniline[ Only a poor yield "19)# of aniline was obtained[
Many miscellaneous reductions of aryl ~uorides are reported in the literature[ These include
reduction with Raney nickel or copper alloys ð76OPP331Ł[ This method gives excellent yields of
de~uorinated arene but lacks selectivity as noted by the simultaneous reduction of the C0F bond
and the methyl ketone moiety on reaction of p!~uoroacetophenone[ Respess and Tamborski reported
that Grignard reagents in combination with CoCl1 reduced hexa~uorobenzene to penta~uoro!
benzene in 80) yield "Equation "3## ð58JOM"07#152Ł[ The reduction of a!~uoronaphthalene to
naphthalene with EtSHÐAlCl2 has been achieved "Equation "4## ð71TL578Ł[ The regioselective
de~uorination of per~uoroaryl diazonium salts on treatment with base has been reported "Equation
"5## ð53JOC2931Ł[
F
F F F F
EtMgBr, CoCl2
(4)
THF
F F 91% F F
F F
By Substitution 316
F
EtSH, AlCl3
CH2Cl2
(5)
87%
F
F F F F
NaOH
(6)
F F 90% F F
N+
N
"ii# Reduction of aryl chlorides

The replacement of chloride by hydrogen in an aryl chloride is signi_cantly easier than the
reduction of the C0F bond in aryl ~uorides[ The synthetic methods of choice are catalytic hydro!
genation and reduction with Raney nickel[
Catalytic hydrogenation has been extensively studied as a method of dechlorinating aryl halides
ð80COS"7#784Ł[ Many catalysts are known to be e}ective\ including Adam|s catalyst "PtO1#\ Pd:C
ð35JA150Ł and Pd:Si ð72ZN"B#0586Ł[ Hydrogenolyses using the above catalysts exhibit a degree of
chemoselectivity\ the reaction tolerating functionality such as phenols and aromatic nitro groups[
A paper by Grushin and Alper ð80OM0519Ł has extended the scope of this reaction[ Using a rhodium
complex of the type L1Rh"H#Cl1 "where L1"Cyp#2P or "Pri2P#1# under phase transfer conditions\
chloroarenes were reduced to the corresponding arene in excellent yields[ Carboxylic acid\ amine
ether and ketone functionality were tolerated as was a tri~uoromethyl group "Equation "6##[ Cata!
lytic hydrogen transfer reactions with hydrogen donors such as formate have been used successfully
"Equation "7## ð74TL0270Ł[ Reduction of chloroarenes with complex hydrides such as LAH and
NaBH3 are notoriously di.cult ð80JOC3607Ł[ Complex hydrides in combination with Lewis acids
reduce chloroarenes to arenes\ a good example being the reduction of chloronaphthalene with a
mixture of LAH and TiCl3 ð62CL180Ł[ NaBH1"OCH1CH1OMe#1 with NiCl1 in THF is an extremely
potent dechlorinating system ð82TL2152Ł^ pentachlorophenol was completely dechlorinated to
phenol "and a little cyclohexanol# with the above reagent in two hours at 57>C "Equation "8##[ A
combination of LAH and CeCl2 has also been described as a good reagent for the dechlorination
of aryl chlorides ð74CL0380Ł[ Aromatic halides have been dehalogenated by electrochemical means
in a highly e.cient manner ðB!72MI 009!90Ł[ A development in this methodology ð80SC1266Ł has
been to e}ect the electrochemical reduction in the presence of a catalytic amount of SmCl2[ Under
the reaction conditions ether\ nitrite and ester functionalities remained untouched "Equation "09##[
CF3 CF3
H2/[Cy3P)2Rh(H)Cl2
(7)
PhCH2N(C2H5)3Cl, PhMe
87%
Cl
OH OH
Cl Cl
Pd(C), NH4CO2H
(8)
MeOH
100%
Cl
OH OH
Cl Cl
NaBH2(OCH2CH2OMe)2/NiCl2
(9)
MeOCH2CH2OH/THF
Cl Cl
Cl
CO2Me CO2Me
Cl
(e–), SmCl3, Bun4NBF4
(10)
DMF
98%
Reduction of aryl chlorides with Raney nickel and related alloys has been widely used but the
method su}ers from a lack of chemoselectivity ð76OPP331Ł although both catalytic hydrogenation
ð54JCS4934Ł and LAH reductions ð58JOC2807Ł have been carried out to selectively reduce out
chlorine in mixed chloro~uoro systems[ Miscellaneous methods of reduction include the use of a
combination of zinc\ NiCl1\ PPh2 and NaI\ which reduces p!chloroanisole almost quantitatively
ð71JOC1511Ł and the reduction of chlorobenzene with triethyl silane in the presence of Pd:C and
light ð58JOC527Ł[
"iii# Reduction of aryl bromides

The conversion of aryl bromides to their corresponding arenes is probably the most widely studied
of all the aromatic halide to arene reductions[ The synthetic methods which have been utilised to
carry out this reduction include catalytic hydrogenation ð62OSC"4#235Ł and reduction with complex
hydrides ð58JOC2807Ł and tin hydrides ð76S554Ł[
Palladium and platinum based catalysts have been extensively used for catalytic hydrogenation
of aromatic bromides[ The use of hydrogen donors "e[g[\ HCO1H# rather than molecular hydrogen
is a development that avoids the hazards of using hydrogen gas "Equation "00## ð71S765Ł[ Reduction
with LAH and other complex hydrides is a general method for reduction of bromoaromatics\ in
contrast to chloro! and ~uoroaromatics[ LAH reduction frequently occurs at\ or just above\ room
temperature ð58JOC2807Ł[ LAH combined with TiCl3 is a powerful reagent for the reduction of
aromatic bromides ð62CL180Ł[
Narisada et al[ have reported the selective reduction of aryl halides "speci_cally bromides and
iodides# with NaBH3ÐCu1Cl1 in MeOH[ This system reduced aryl bromides to the corresponding
arenes\ working particularly well for a!methoxy! and a!carbomethoxy!bromobenzenes "Equation
"01## ð78JOC4297Ł[ It has been shown that both triphenyl ð59JOC1192Ł and tributyltin hydrides
ð76S554Ł reduce bromoarenes with high yield and selectivity[
Br
Pd(C), HCO2H
(11)
DMF
85–90%
NaBH4–CuCl2
(12)
MeOH
R R
X = Br, I
R = Me, MeO
Electrochemical reductions provide an elegant way to obtain unusually substituted thiophene

derivatives[ Dapperheld et al[ found that simply by varying the metal salts and counter ions
in solution it was possible to change the substitution pattern of the product on reduction of
tetrabromothiophene and a range of derivatives ð89S392Ł[ 1\2\4!Tribromothiophene is reduced by
zinc in AcOH to 2!bromothiophene ð62OSC"4#038Ł[ p!Bromo~uorobenzene was reduced to ~uoro!
benzene in quantitative yield by electrochemical reduction in DMF in the presence of SmCl2
ð80SC1266Ł[
Other important methods for reduction of bromarenes are Caubere|s complex reducing reagents\
i[e[ mixtures of NiCl1\ NaH and t!pentyl alcohol ð72AG"E#488Ł\ and also the combination of EtSH
and AlCl2 ð73JOC2530Ł[
By Substitution 318
"iv# Reduction of aryl iodides
Aryl iodides are reduced to arenes on reaction with hydrides such as NaBH3 ð58JOC2812Ł and by
hydrides in combination with metal salts "e[g[\ NaBH3ÐCeCl2ÐMeOH ð78JOC4297Ł#[ In the latter
example all iodo derivatives investigated were smoothly converted to the corresponding arene
in quantitative yield at 9>C[ NaBH3 in combination with Cp1TiCl1 ð70JOM"193#234Ł reduced p!
bromoiodobenzene to bromobenzene\ though a small amount "ca[ 01)# of debrominated product
was also observed "Equation "02##[ Catalytic hydrogenation and Raney nickel have been much
used for the reduction of iodobenzenes and the methodology is amply covered in review articles
ð80COS"7#784Ł and ð79S314Ł[
Br Br
NaBH4, Cp2TiCl2
+ (13)
DMF
85%
I 12%
0[09[0[0[1 Reduction of vinyl halides

The reduction of a vinyl halide to the corresponding alkene has been successfully achieved in
many ways ð80COS"7#784Ł[ These include] "i# dissolving metal reductions\ "ii# reductions with complex
hydrides or tin hydrides\ "iii# electrochemical reductions\ and "iv# hydrogenolysis via catalytic
hydrogen ðB!73MI 009!92\ 79S314Ł[
"i# Reduction of vinyl ~uorides

The ease of reaction generally follows the order of bond strengths for the carbonÐhalogen bond\
C0F being the most di.cult bond to cleave[ Reduction of a vinyl ~uoride to the corresponding
alkene can be achieved by reaction with either LAH or NaBH3[ Normant and co!workers found
that treatment of some tri~uorinated allylic alcohols with LAH in re~uxing diethyl ether led to the
replacement of one terminal ~uorine atom "Equation "03## ð67S017Ł[ The product was obtained as
a 2 ] 0 mixture of "E#! and "Z#!isomers in 71) yield[ Dmowski reported stereo! and regiospeci_c
reduction of "E#! and "Z#!0!phenyl~uoropropenes ð74JFC"18#162Ł[ The substrates were treated with
LAH in GLYME at either −04>C to 09>C or between 9Ð29>C[ The higher temperature reaction
led to replacement of two vinyl ~uorine atoms\ whereas the lower temperature reaction gave a
monoreduced product\ the ~uorine in the benzylic position being replaced[ Snieckus and co!workers
reduced di~uoroalkenes to mono~uoroalkenes in excellent yield and stereoselectivity using LiBEt2:
THF "Equation "04## ð82TL304Ł[ Elegant syntheses of "E#! and "Z#!0\1\2\2\2!penta~uoropropene
have been reported ð78JFC"33#0526Ł[ The "E#!isomer was formed by reduction of hexa~uoropropene
with Bu2P\ followed by hydrolysis "Scheme 0#[ Isomerisation of the "E#!product with SbF4 yielded
the corresponding "Z#!isomer "Equation "05##[ A stereoselective reduction of 1\1!di~uorovinyl!
phosphine oxides to mono~uorovinylphosphine oxides with LiAlH"OBut#2 has been published
ð81SL722Ł[Fluorovinylsilanes were reduced with LAH to vinyl silanes ð77T3024Ł[ Burton and Johnston
published a vinyl ~uoride reduction that featured an interesting reversal in the chemoselectivity[
Treatment of 0!chloroper~uorocyclopentene with NaBH3 in DIGLYME unexpectedly led to a
replacement of a ~uorine atom ð53JA4250Ł[
F F
LAH, Et2O
F (14)
82%
OH F OH F
OCONEt2 OCONEt2
LiBEt3H, THF
F (15)
TMS TMS
87%
F F
F
SbF5
F3C F 3C (16)
F
96%
F F
F F F
Bu3P H2O
F3C F3C F 3C
F PBu3
Et2O DIGLYME
F F F F
Scheme 1
The catalytic hydrogenation of vinyl ~uorides generally leads to mixtures of products via com!
peting hydrogenolysis and saturation reactions ð58BSF731Ł^ a straightforward method for C0F
bond cleavage without concomitant double bond saturation has not yet been reported ð80COS"7#784Ł[
"ii# Reduction of vinyl chlorides

Vinyl chlorides are reduced by complex hydrides without concomitant double bond reduction
while\ in contrast\ reduction under catalytic hydrogenation conditions is plagued by problems of
overreduction and hydrogenolysis leads to complex mixtures of products[ The combination of LAH
with TiCl3 proved to be an excellent system for reducing vinyl chlorides to alkenes ð62CL180Ł[
Complex reducing agents "CRAs# are a variation of this hydride based reduction methodology
ð70JOC0169Ł[ 0!Chlorocyclohexene and also 3!methyl!0!chlorocyclohexene were reduced by a mix!
ture of NaH:Ni"OAc#1:t!C4H00OH in high yield "−89)# "Equation "06##[ Only small quantities of
saturated products were observed[
Dissolving metal reductions are also an important route to alkenes from the corresponding
vinyl chlorides[ Gassman and Marshall published an e.cient procedure for the synthesis of 6\6!
dimethoxybicycloð1[1[0Łheptene from 6\6!dimethoxy!0\1\2\3!tetrachlorobicycloð1[1[0Łhept!1!ene
ð57OS"37#57Ł by reduction of the former compound with Na in t!butyl alcohol^ both vinylic and
allylic chlorine atoms were removed "Equation "07##[ Zinc in AcOH is a highly chemoselective
reducing system\ reduction of a vinyl chlorosulfone proceeding in excellent yield "75)# with selective
loss of the chlorine atom "Equation "08## ð74S565Ł[ Iron pentacarbonyl has also been used with some
success for the reduction of vinyl chlorides ð62TL336Ł[
Cl
NaH, Ni(OAc)2
(17)
t-C5H11OH, DME
R R
R = H, 90%
R = Me, 97%
OMe OMe
MeO Cl MeO
Cl Na, ButOH
(18)
THF
Cl 62.8%
Cl
SO2Ph SO2Ph
Zn, AcOH
(19)
Cl 86%
Ph Ph
"iii# Reduction of vinyl bromides

The reduction of vinyl bromides to the corresponding alkenes is more straightforward than the
reduction of vinyl ~uorides and chlorides[ Indeed additional synthetic methods\ such as catalytic
hydrogenation\ are suitable for the reduction of vinyl bromides[
By Substitution 320
The LAH reduction of vinyl bromides is a much used procedure for alkene synthesis ð79JOC2402Ł\
the reaction proceeding in some cases via a free radical mechanism[ Sodium hydride\ together with
Ni"OAc#1\ also exhibits good selectivity for vinyl bromide reduction over saturation of the double
bond[ 0!Bromocyclooctene was reduced to cyclooctene at room temperature\ with only 4) of the
fully saturated product being formed ð70JOC0169Ł[
MetalÐhalogen exchange with subsequent hydrolysis of the intermediate vinylmetal species has
been used to e}ect\ overall\ a reduction ð81JOC4794\ 82JOC3786Ł[ Thus 0\0!dibromo and 0!bromo!
0!chloroalkenes were treated with lithium trialkyl zincates or BuLi at low temperatures to give
the corresponding 0!bromo! and 0!chloro!alkenes respectively\ after hydrolysis of the vinylmetal
intermediate[ Yields and selectivities depend on the reactivity of the substrate and on the method
by which the vinylmetal intermediate is generated[ An illustrative example is the reaction of chloro!
bromoalkene "0# with "Bu#2ZnLi\ which gave\ on hydrolysis\ a 81) yield of the "E#!alkene "Equation
"19##[ It was suggested that a chelating e}ect involving the alkoxy group led to the high selectivity
observed[ A chelation e}ect was also proposed by Grandjean and Pale ð82TL0044Ł to explain the
high stereoselectivity observed when dibromoalkene epoxide "1# was treated with MeLiÐTHF at
−094>C[ No "Z#!isomer was observed "Equation "10##[
Ph Cl i, BunZnLi
Ph Cl
(20)
MeO Br ii, H+ MeO
92%
(1)
Br Br
OSiButPh2 i, MeLi, THF OSiButPh2
Br (21)
ii, H+
O 96% O
(2)
Vinyl bromides were studied as substrates for a model NAD"P#¦ÐNAD"P#H reduction system
ð74JOC2172Ł[ Reduction of "Z#! and "E#!ethyl 1!bromocinnamates with N!benzyl!0\3!dihydro!
nicotinamide in the presence of catalytic ClRh"Ph2#2 was achieved with good yield[ Interestingly\
the "E#!vinyl bromide was reduced with concomitant interconversion to the "E#!alkene\ indicating
the intermediacy of a vinyl radical "Equation "11##[
CONH2
N
Ph Br Ph
Ph
(22)
RhCl(PPh3)3
CO2Et 90% CO2Et
Catalytic hydrogenation is a popular route to alkenes from vinyl bromides[ Kupchan and Afonso
prepared ethyl 1!methylcrotonate from ethyl 1!methyl!2!bromocrotonate in 60) yield via catalytic
hydrogenation over Pd:BaSO3 ð59JOC1106Ł[
"iv# Reduction of vinyl iodides

It is well documented that the ease of reduction of vinyl halides follows the strength of the C0X
bond and therefore one would assume that the C0I bond is the easiest to cleave\ however this is a
reaction that is little studied[ Reduction with complex hydrides\ for example NaBH3 ð60JFC"0#010Ł
or NaAlH3 ð71JFC"19#046Ł works well\ as does reduction by Zn:HCl ð42JCS811Ł[ 2!Iodocyclohexenone
was reduced by N!benzyl!0\3!dihydronicotinamide "BNAH# in the presence of ClRh"Ph2#2
ð74JOC2172Ł[ Ochiai and co!workers have advocated the use of vinyl iodonium tetra~uoroborates
as vinyl cation equivalents ð77T3984Ł[ These vinyl iodonium salts were shown to react with a wide
variety of nucleophiles\ a representative example being the reaction with diphenylcopperlithium\
"Ph#1CuLi "Equation "12##[ Vinyl iodium tetra~uoroborates\ on treatment with base\ yield carbene
intermediates\ which undergo insertion reactions ð77JA5454Ł to form cyclopentenes\ and:or
rearrangement to form alkynes "Equation "13##[ It would appear reasonable to assume that cleavage
of the sp1!C0I bond might be achieved readily with hydride reagents such as NaBH3 or LAH[
PhI+ BF4– Ph
Ph2CuLi
(23)
THF
90%
But But
H
Et3N, THF
or
(24)
ButOK, THF
80–84% H
I+PhBF4–
0[09[0[1 Reduction of 1C0O Bonds
0[09[0[1[0 Reduction of phenols and derivatives

Deoxygenation of phenol has been carried out by heating phenol in the presence of dry LAH at
249>C[ The harsh conditions of this reaction obviously makes this transformation unrealistic for
most synthetic chemists[ This type of direct displacement is considerably more successful when
applied to polycyclic aromatic hydrocarbons containing phenolic groups[ Treatment of 0!hydroxy!
napthalene with AlCl2 in EtSH at re~ux for _ve hours yields the corresponding hydrocarbon in
65) yield "Equation "14## ð71TL578Ł[ Hydroiodic acid in acetic acid at re~ux has also been used for
similar transformations ð68JOC3702Ł[ Phenolic ethers\ particularly methyl ethers are similarly
reduced using the aforementioned reagents[
OH
AlCl3, EtSH
(25)
CH2Cl2
76%
Phenolic ethers have been displaced by re~uxing with sodium in EtOH ð00CB1023Ł[ Regiospeci_c
reductive demethoxylation of 0\1\2!trimethoxybenzene was reported by Azzenza et al[ ð78S17Ł^ the
electron!transfer type reduction was carried out using _nely divided alkali metal in THF[ The
intermediate anions were found to react with a range of electrophiles "Equation "15## ð89JOC4275Ł[
OMe
MeO OMe Na MeO OMe
(26)
THF
85%
R R
R = H, Me, n-C5H11
Phenols\ when converted to the corresponding phosphate ester by reaction with diethylchloro!
phosphidate and base\ are reduced to hydrocarbons by dissolving metal reduction[ Treatment of the
phosphate ester with either Li:NH2"l# or Na:NH2"l# provides good yields of aromatic hydrocarbons
ð44JCS411Ł[ The reaction has also been carried out using activated titanium metal in THF
ð67JOC3686Ł[ Shono and co!workers reduced phenolic phosphate esters electrochemically
ð68JOC3497Ł] this methodology has been used for a synthesis of the polyketide olivetol "2#
"Scheme 1#[
A number of related phenolic derivatives have been found to be susceptible to hydrogenolysis\
the overall reaction being deoxygenation[ Most common are the phenolic ethers formed by reaction
of phenol with 1!chlorobenzoxazole ð55JA3160Ł or 0!phenyl!4!chlorotetrazole "Equation "16##
ð73JMC0464Ł[ Both ethers are hydrogenolysed under standard conditions "H1\ 4) Pd:C# giving
reasonable yields of hydrocarbon[
By Substitution 322
OPO(OEt)2
MeO OMe + e– MeO OMe HO OH
DMF, H2O
67%
(3)
Scheme 2
Me
N
OMe
Pd(C), H2
(27)
AcOH
O 55%
Ph
N N
N N
A methodology developed in the 0879s and 0889s has begun to dominate phenolic deoxygenation[
Conversion of phenol to the corresponding tri~uoroalkanesulfonate ester\ with subsequent dis!
placement by either radical or catalytic means\ has led to a deoxygenation reaction that is high
yielding and chemoselective[ The preparation of per~uoroalkanesulfonic esters has been reviewed
ð71S74Ł as have the synthetic transformations of both aryl and vinyl tri~ates ð82S624Ł[
One of the earliest examples of the displacement of an aryl tri~uoroalkanesulfonate by hydrogen
was reported by Subramanian ð73S370Ł[ A range of aryl nona~ates were prepared by reaction with
n!C3F8SO1F and base[ These intermediates were then subjected to palladium!catalysed hydro!
genolysis leading to good yields "73Ð099)# of reduced products "Scheme 2#[ The main problem
encountered was a lack of chemoselectivity\ that is the alkenic double bonds and C0halogen bonds
were reduced^ quinoline derived nona~ates were overreduced[ Reduction of phenol tri~ates by
homogenous palladium"9# catalysis has overcome this problem[ Reduction with trialkylammonium
formate as hydrogen donor\ combined with either PPh2 or dppf as a chelating ligand\ gave good
yields "59Ð87)# of deoxygenated products and tolerated ketone\ alkene\ nitro\ a\b!unsaturated ester
and amide functionalities "Equation "17## ð75TL4430Ł[ Aryl tri~ates have also been reduced by a
nickel"9# based catalyst using MeOH as the hydrogen donor ð80CL1906Ł[ A binary ligand system
based on nickel combining both PPh2 and 0\0?!bis"diphenylphosphino#nitrate "dppn# was found to
be most successful "Equation "18##[ This reduction was also found to be tolerant of a range of
functionalities and gave good yields[ Use of MeOD as a deuterium source yielded a route to
regiospeci_cally labelled arenes[ Chen and He reported a one!pot reduction of arylper~uoro!
alkenesulfonates which was closely related to Cacchi|s original procedure ð77S785Ł[ Good yields
were reported for this highly chemoselective methodology[ The selectivity of this method was further
exempli_ed during a synthesis of "¦#!3!demethoxydaunomycinone ð89JCS"P0#317Ł[ The 3!OH phenol
was tri~ated selectively\ due to the greater acidity of the 3!OH over the 5! and 00!OH groups[
Palladium!catalysed reduction with HCO1H and dppf as the coordinating ligand led to an 71)
yield of the desired product[ Deprotection with TFA yielded "¦#!3!demethoxydaunomycinone "3#
"Scheme 3#[ Similar results were reported by Chen and co!workers using Pd "PPh2#1Cl1 or Pd"PPh2#3
in combination with per~uoroalkanesulfonates of the type ArSO1"CF1#1O"CF1#1H ð75CC0341Ł[
Highly hindered\ electron!rich phenols were deoxygenated via the corresponding tri~ates under both
homogenous and heterogenous conditions ð89JOC880Ł[ Trioxygenated aromatics were e.ciently
deoxygenated via the corresponding tri~ate to give moderate to good yields of resorcinol dimethyl
ether "4# "Equation "29##[ Mechanistic studies indicated a number of hydrogen donors were present
in the reaction medium ð75TL4430Ł[
CO2Me CO2Me
Pd(OAc)2, DPPF
(28)
Et3N, HCO2H
81%
OTf
OH OSO2C4F9
C4F9nSO2F, Et3N Pd(C), H2
Et2O MeOH
R 80–93% R R
R = H, o, p-Me, MeO, Cl
Scheme 3
O O
O OH O OH
O O
Pd(OAc)2, dppf TFA
OH OH
HCO2H, Et3N, DMF
82%
OTf O OH OH O OH OH
O OH O
OH
O OH OH
(4)
Scheme 4
OTf
Ni0, dppn/PPh3, Zn
(29)
MeOH
R 70–97% R
R = Me, MeO, CN, MeCONH, MeCO
OTf
MeO OMe MeO OMe
PdCl2, PPh3, dppf
(30)
HCO2H, Bun3N, DMF
89%
(5)
0[09[0[1[1 Reduction of enol ethers and derivatives

The reduction of an enol derivative to the corresponding alkene is a di.cult transformation and
has been tackled by a variety of strategies[ Enol ethers have been reduced to alkenes by dibal!H
ð55JOC210Ł and also by sodium in a Birch!type reduction ð69AJC0530Ł[ Treatment of silyl enol ethers
with borane followed by subsequent acid!induced elimination give good yields of alkene ð64TL3994Ł[
The reduction of the enol phosphate moiety is generally carried out by dissolving metal reduction
using lithium metal in ButOH together with ammonia or amines "RNH1"RH\ Me\ Et##[ The
method was originally described by Ireland ð58TL1034Ł as a way of transforming ketones to alkenes[
Many natural products have been synthesised utilising this methodology including a quassinoid
ð73JA2242Ł\ "¦:−#!seychellene ð74JOC1557Ł and the potent antitumor antibiotic "−#!ptilocaulin
"Equation "20## ð73JA610Ł[ Ishihara and co!workers described a chemoselective reduction of an
enolphosphate in the presence of both phosphonate and halide functionality with lithium dibu!
tylcuprate in TMEDA:THF ð76JOC299Ł[ The closely related enol phosphoramidate is also reduced
by lithium in amines ð61JA4987Ł[ An important ole_n unit was introduced into the indacene subunit
of ikarugamycin using this reduction method "Equation "21## ð76TL20Ł[
By Substitution 324
OP(OEt)2
Li, EtNH2
(31)
HO ButOH, THF HO
95%
OMe O
H OMe H
O
i, LDA, (Me2N)POCl
(32)
ii, Li, EtNH2
H iii, H+ H
Vinyl tri~ates are reduced to alkenes by palladium catalysis with either tin hydrides\ silicon
hydrides ð75JA2922Ł or formate ð73TL3710Ł acting as the hydrogen source[ Vinyl tri~ates were
e.ciently reduced to alkenes in high yield by trialkylammonium formate under palladium"9#
catalysis ð73TL3710Ł[ A range of steroidal dienoyl tri~ates were reduced to dienes in a highly
chemoselective manner\ the reaction tolerating a range of functionality "Equation "22## ð89OS"57#027Ł[
Donnelly has used this methodology to synthesise a series of rare neo~avonoids "Equation "23##
ð89JCS"P0#1740Ł[ Similarly Ortar and co!workers prepared a series of 5\6!didehydrooestrogens using
this methodology ð89SC0182Ł[
O O
OH Pd(OAc)2(PPh3)2 OH
(33)
HCO2H, Bun 3N, DMF
93%
TfO
OMe OMe
O O
Pd(OAc)2, PPh3
OTf (34)
HCO2H, Et3N, DMF
OMe 69% OMe
MeO MeO
Elegant mechanistic studies were carried out by Scott and Stille on the reduction of 3!t!butylcyclo!
hexenyl tri~ate ð75JA2922Ł[ A wide range of reducing agents were investigated and it was found that
both Bu2SnH and Et2SiH e}ectively reduced vinyl tri~ates in the presence of Pd"Ph2#3 and LiCl
"Equation "24##[ Other more nucleophilic reducing agents were not e}ective giving rise to problems
of S0O cleavage and catalyst decomposition[ Interestingly\ an attempted reduction with tributyl!
ammonium formate yielded no alkene[
OTf
BunSnH or Et3SiH
Pd(PPh3)4, LiCl
(35)
>95%
But But
0[09[0[2 Reduction of 1CÐSulfur\ Selenium and Tellurium Bonds
0[09[0[2[0 Reduction of aryl sul_des\ selenides and tellurides

"i# Reduction of aryl sul_des
An enormous number of aryl thiols and sul_des have been desulfurised by reaction with Raney
nickel ð51CRV236\ 51OR"01#245Ł and this method remains a powerful tool for the reduction of aryl
sul_des "for an example see ð72JOC3308Ł#[ The extensive use of this reagent has also highlighted its
drawbacks[ The reagent is pyrophoric\ it is di.cult to weigh out accurately\ it loses activity on
storage and displays such high chemical reactivity that over!reduction of substrates is a common
occurrence[
Nickel boride\ formed from the in situ reduction of nickel"II# salts with NaBH3 displays a number
of advantages over Raney nickel[ The reagent is more chemoselective and the amount of reagent
used can be accurately determined[ A number of benzothiophene derivatives have been desulfurised
with nickel boride in high yield with short reaction times "04Ð59 min# ð89CC708Ł[ Ethyl\ methyl and
phenyl thioethers were also reduced in moderate to excellent yields with nickel boride "Equation
"25## ð75SC668Ł[
S R
NiCl2•H2O, NaBH4
R (36)
MeOH, THF
R=H R = Et, 73%

R = Me R = Prn, 62%
Dissolving metal reductions\ particularly Li:NH2"l#\ are known to e}ect rapid desulfurisation of
aromatic thiols and thioethers[ This reaction has been reviewed ð66T1908\ 67CRV252Ł[ The role of
alkali metals as desulfurising agents has also been extensively studied[ The reduction is known to
proceed via a single electron transfer mechanism and this limits the practical use of this method to
simple thiol and sul_des due to the over!reduction of neighbouring functional groups[
Advances in transition metal!mediated C0S bond cleavage have been reviewed ð89S78Ł[ Hom!
ogenous nickel"9# species have been shown to be e.cient desulfurising reagents\ especially when
used in combination with a complex hydride "Equation "26## ð75JA6652Ł[ A novel nickel complex\
LiAlH1"THF#n = "C09H7N1#Ni "formed by reaction of LiAlH3 with 1\1?!bipy!"0\4!cyclooctadiene#
nickel# desulfurised phenoxathiin to diphenyl ether[ Without the presence of hydride the complex
remains a desulfurisation reagent but yields di}erent products[ Both reactions are thought to
proceed via single electron transfer mechanisms\ the di}ering products being rationalised in terms
of the greater anionic character of nickel in the NiÐLiAlH1 complex[ A similar organonickel complex\
which has been used for the reduction of aromatic thiols and thioethers\ is nickeloceneÐLiAlH3
"Equation "27## ð74CC0509Ł[ 1!Napthalene thiol was reduced to napthalene and the reaction was
found to work for a number of aromatic thiols[ The reagent was highly chemoselective\ tolerating
esters and alkenic double bonds\ though reduction of aromatic nitro groups was observed[ Further
study on this reagent has revealed the facile desulfurisation of thiols including dibenzothiophene
ð77JOC3355Ł[ The same research group has employed NiBr1 = DME = PPh2 and LiAlH3 in a similar
series of reductions ð78JOC3363Ł[
O O
(2,2'-bipy)(cod)Ni
(37)
LAH, THF
S 95%
SH
nickelocene
(38)
LAH, THF
An older but no less e}ective desulfurisation method was described by Wenkert and Ferreira
ð71CC739Ł[ The reaction of secondary Grignard reagents with alkylthioarenes\ in the presence of a
0 ] 0 mixture of NiCl1 and PPh2\ led to the substitution of thioalkyl groups by hydrogen "Equation
"28##[ It was observed that manipulation of the ligands on nickel led to alkylation rather than
substitution[ In a related study an indole thioether was reduced to the indole in 49) yield
ð74JOC0014Ł[
SMe
NiCl2, PPh3
(39)
PriMgBr, 70%
or CyxMgBr, 74%
PhH, Et2O
But But
By Substitution 326
Metal carbonyls such as Co1"CO#7\ ð72TL4218Ł\ Mo"CO#5 and Mn1"CO#09 ð63JOM"62#248Ł have
also come to the fore as e}ective desulfurisation reagents[ The most studied complex in this group
is Mo"CO#5 ð79CC058Ł[ The actual species carrying out the reduction is probably a molybdenum"II#
species\ tetrakis"acetodimolybdenum#\ generated in situ from reaction of Mo"CO#5 and HOAc[
Good yields of hydrocarbon were obtained at ca[ 019>C "Equation "39##[ It was observed that if the
Mo reagent was preadsorbed onto silica the same reductions could be accomplished at room
temperature[ Desulfurisations with Mo"CO#5 occur via a free radical mechanism and with good
chemoselectivity compared with other metal carbonyl reagents ð74JOC4302Ł[ Nickel complex reduc!
ing agents "NiCRAs#\ mixtures of NaH\ Ni"OAc#1 and t!C4H00OH\ with or without a coordinating
ligand are known to reduce aryl thiols and thioethers ð77TL1852Ł[ Aryl sulfoxides and sulfones are
also reduced to hydrocarbons with this reagent system "Equation "30## ð89JOC5083Ł[
SH
Cl Cl
Mo(CO)6
(40)
AcOH
Cl 71% Cl
Ni(OAc)2, NaH
(41)
DME
S
n = 1, 75%
(O)n n = 2, 81%
"ii# Reduction of aryl selenides

The reduction of the carbonÐselenium bond has been the focus of much study due to the extensive
use of organoselenium reagents in synthetic organic chemistry[ The majority of methods published
up to 0884 concentrate on the cleavage of alkyl!C0Se bonds rather than aryl!C0Se bonds[
Wiseman and Gould reduced dibenzoselenophenoxide to biphenyl with Raney nickel "Equation
"31## ð43JA0695Ł[ Phenyl alkyl selenides undergo cleavage of the alkyl C0Se bond on exposure to
Ph2SnH ð80COS"7#724Ł[ Clive and co!workers also described the use of Ph2SnH at elevated tem!
peratures "ca[ 019>C# for reducing the R0SePh bond "Equation "32## ð79JA3327Ł[ The reduction
proceeded equally successfully with diselenoacetals[
Raney Nickel
(42)
+ PhH, EtOH
Se 72%
O–
Ph3SnH
R–SePh R–H (43)
Kreif and co!workers utilised Raney nickel for the reduction of alkylphenyl selenide ð65TL1532Ł[
Dissolving metal reductions with Li:NH2"l# proceed in a similar fashion ð80COS"7#724Ł[
"iii# Reduction of aryl tellurides

Despite considerable interest in organotellurium chemistry ð81PS"56#072Ł\ little work has been
done on the selective reduction of the carbonÐtellurium bond ð78TL0198Ł[ Transmetallation of alkyl
and aryl telluriums with BuLi was described by Sonoda and co!workers ð76AG"E#0076Ł[ Reaction of
the aryl!Li species with electrophiles\ "e[g[\ H1O or PhCHO# yielded substituted arenes "Scheme 4#[
Phenyl tellurol "PhTeH# is formed by the reaction of diphenylditelluride with NaBH3 in EtOH
ð71TL0070Ł[ Diaryl telluride "Ar1Te#\ when treated with Grignard reagents "RMgX# under nickel"II#
or cobalt"II# catalysis yielded cross! and homo!coupled products of the type Ar0R\ Ar0Ar and
R0R[ A similar reaction has been achieved using Li in THF ð64JOM"77#064Ł[ Reductions with nickel
or copper powder have been attempted\ but lack chemoselectivity ð81PS"56#072Ł[ Reduction of the
aryl!C0Te bond in R!TePh with Ph2SnH was reported by Clive and co!workers ð79JA3327Ł[
PhCHO OH
BunLi
Ph–TePh PhLi
77% Ph Ph
Scheme 5
0[09[0[2[1 Reduction of vinyl sul_des\ selenides and tellurides
"i# Reduction of vinyl sul_des\ sulfoxides and sulfones

The use of Raney nickel for the transformation of vinyl sul_des to alkenes is well documented
ð51CRV236\ 55OR"01#245Ł[ The problems arising from the use of this reagent are well known\ in the
case of vinyl sul_de concomitant reduction of the ole_nic double bond is most troublesome[
Nonetheless\ Corey and Schmidt utilised a vinyl sul_de reduction with deactivated Raney nickel in
a synthesis of the C!04ÐC!19 segment of rifamycin "Equation "33## ð68TL1206Ł[ Nickel boride has
also been used to reduce vinyl sul_des to alkenes ð62JCS"P0#543Ł[
SMe
Raney Nickel
(44)
O O Me2CO O O
95%
TBDMS-O TBDMS-O
Trost and Ornstein developed an elegant desulfurisation procedure using a combination of

secondary Grignard reagents and "PPh2#1NiCl1 in Et1O:THF ð70TL2352Ł[ Moderate to good yields
of alkene were realised with high stereospeci_city and no overreduction observed "Equation "34##[
The methodology was used in a synthesis of the douglas _r tussock moth pheromone "5#[ In a
related procedure bisthioalkenes were desulfurised to vinyl sul_des by treatment with PriÐMgBr and
NiCl1PPh2 ð71CC739Ł[ Again manipulation of the ligands on nickel led to alkylation rather than
reduction[ Treatment of dithioacetal with the higher order cuprate\ Me1CuCNLi1 also led to vinyl
sul_de formation "Equation "35## ð89CC0173Ł[ Caubere|s nickel complex reducing agent\ NiC!
RA"bipy# was found to reduce vinyl sul_des in good yield with moderate to excellent stereoselectivity
ð89JOC5083Ł[ Ketene dithioacetals were stereospeci_cally reduced to vinyl sul_des by SmI1 "Equation
"36## ð82JOC5430Ł[
PhS PriMgBr
NiCl2(PPh3)2
(45)
R1 THF, Et2O R1
R2 50–76% R2
O Bu
C10H21
(6)
Et CO2Me Et CO2Me
Me2Cu(CN)Li
(46)
MeS SMe Et2O MeS
CO2Et CO2Et
SmI2
(47)
THF, HMPA
MeS SMe 95%
MeS
By Substitution 328
The direct conversion of a vinyl sulfoxide to an alkene is a rare transformation but the nickel
complex reducing agents reported in 0889 are known to e}ect this reaction ð89JOC5083Ł[ Sodium
hydride poor NiCRAs gave the corresponding alkene with modest stereoselectivity[ Trost et al[
reported an interesting reaction of a vinyl sulfoxide\ which\ upon re~uxing in ethanolic NaOEt\
rearranges and loses sulfenate giving an allylic alcohol "Equation "37## ð72JA4964Ł[ Theobald and
Okamura reported a stereospeci_c reduction of vinyl sulfoxides using ButLi and MeOH as the
proton source "Equation "38## ð76TL5454Ł[ The use of MeOD provided a route to stereospeci_cally
labelled alkenes[
O O
CO2Et SOPh NaOEt CO2Et
(48)
EtOH OH
SOPh
ButLi
(49)
MeOH
72%
An excellent review by Simpkins highlights the importance of vinyl sulfones in organic synthesis
ð89T5840Ł[ Many di}erent methodologies have been used for the reduction of vinyl sulfones to
alkenes[ An early paper by Umani!Ronchi described the use of Al!"Hg# amalgam for the stereo!
speci_c reduction of a\b!unsaturated sulfones ð62CC240Ł "see also ð71JOC3602Ł#[ A modi_cation of
this methodology using Na!"Hg# amalgam in phosphate bu}er as solvent was used by Djerassi and
co!workers in a synthesis of the marine sterol xestosterol "Equation "49## ð75TL1076Ł[ A synthesis of
vinyl ~uorides also features an amalgam based reduction of a vinyl sulfone ð89TL4338Ł[ Potassium
graphite\ C7K\ is another reagent that has been studied in this connection[ High yields of desul!
fonated products were observed but extensive "E#Ð"Z#!isomerisation occurred ð66JCS"P0#012Ł[ Nickel
complex reducing agents "NiCRAs# have also been examined and\ although they do cleave the C0S
bond\ a considerable amount of sulfone is recovered and again "E#Ð"Z#!isomerisation is evident
ð89JOC5083Ł[
ArSO2
2% Na/Hg
(50)
NaHPO4, THF, MeOH
67%
OMe
Julia and co!workers described a stereospeci_c reduction of vinyl sulfones using Grignard reagents
"e[g[\ BunMgCl# in the presence of the transition metal catalysts Pd"acac#1 or Ni"acac#1 ð72TL3200\
76T748Ł[ Palladium catalysis gave greatest stereoselectivity "×87[4)# depending on the choice of
ligand "Equation "40##[ Desulfonation using sodium dithionite has been described by the same group
ð71TL2154Ł^ sulfones treated with dithionite and bicarbonate in aqueous DMF are reduced in a
highly stereospeci_c manner "up to 099)# to the corresponding alkenes "Equation "41##[ The
reduction involves a Michael!type addition of HSO1−\ followed by loss of SO1 and expulsion of
sul_nate in an anti fashion ð75T1364Ł[ Pak and co!workers reported an e.cient desulfonylation of
a vinyl sulfone using Mg in EtOH\ catalysed by HgCl1 ð82TL3430Ł[ Unsaturated cyclic sulfones are
ring opened at the sp1C0S bond by ultrasonically dispersed potassium metal ð76JOC1113Ł[ Sodium
hydrogen telluride was used to desulfonate a!methylthiosulfones to give vinyl sul_des as mixtures
of "E#! and "Z#!isomers "Equation "42## ð78S31Ł[
BunMgCl
Ni(acac)2, Pd(acac)2
(51)
PhSO2 C9H19 THF C9H19
70%
NaS2O4
DMF, H2O, NaHCO3
(52)
PhSO2 Bu 80% Bu
Ar NaTeH Ar
EtOH
(53)
67–82%
PhSO2 SMe SMe
A useful synthesis of vinyl ~uorides ð80JA6328Ł relies on the stereospeci_c displacement of a vinyl
sulfone by Bu2SnH[ The resulting vinyl stannanes were stereospeci_cally destannylated by treatment
with methanolic NH2 "Scheme 5# ð82OS"61#105Ł[ The method was also used for the stereospeci_c
introduction of deuterium label simply by destannylating in MeOD containing NaOMe[
PhSO2 F Bu3Sn F F
Ph Ph Ph
Bu3SnH NaOMe
AIBN MeOH
74–87% 97–100%
Scheme 6
Vinyl sulfones have been desulfonated by an addition:elimination mechanism on treatment with

Bu2SnLi ð72CC508Ł[ Addition of Bu2SnLi to an unsaturated sulfone yields a tributylstannyl sulfone
which undergoes b!elimination on contact with silica gel to form the corresponding alkene "Scheme
6#[ It was observed that this b!elimination also took place on heating the intermediate in xylene[ In
a related study vinyl silanes were prepared by trapping the intermediate anionic species formed on
the addition of Bu2SnLi to an unsaturated sulfone with TMS!Cl[ The b!elimination of this silyl!
stannyl sulfone was studied and found to be stereoselective ð72CL0346Ł[
R2 Bun3SnLi R2 SnBu3 R2
CHCl3 SiO2
PhSO2 R1 78–98% PhSO2 R1 R1
Scheme 7
"ii# Reduction of vinyl selenides

The chemistry of vinyl selenides has been reviewed ð72JOM"142#020Ł\ as has the reduction of
seleniumÐcarbon bonds ð80COS"7#724Ł[ There exist few general methods for the reduction of a vinyl
selenide to an alkene[
It is possible to reduce the sp1C0Se bond in a vinyl selenide with nickel boride ð73CC0306\
77JOC2704Ł[ A variety of selenosulfones were reduced in up to 84) yield\ though considerable "E#Ð
"Z#!isomerisation was noted "Equation "43##[ The in situ derived reagent spared isolated double
bonds\ ketones and aromatic nitro groups[ It was also observed that hydrogen was incorporated
from MeOH "and not THF#\ suggesting that the reaction does not proceed via a radical mechanism[
Deselenisations of vinyl selenides to alkenes tend not to be carried out with Raney nickel\ probably
due to overreduction of alkene double bonds by this reagent[ Selenium is more sensitive to nucleo!
philic attack than sulfur and as such reacts with strong bases:nucleophiles[ In the case of vinylic
selenides\ reaction with BunLi followed by protonolysis leads to alkene formation[ Krief has shown
that a 0\0!bis"methyl#selenoalkene\ upon treatment with BunLi in THF\ forms the corresponding 0!
lithio!0!selenoalkene ð71TL2300Ł[ Upon electrophilic quench with D1O:H1O the 0!selenoalkene is
formed in a ca[ 39 ] 59 mixture of "E#! and "Z#!stereoisomers "Equation "44##[ Deselenisation of vinyl
selenides via hydride radicals is an e.cient method of synthesising alkenes ð71TL2300Ł[ Treatment
of vinylic selenide with Bu2SnHÐAIBN at 89>C leads to the formation of alkene "no stereochemical
details were reported#[ Allylic alcohols were also reduced under similar conditions forming alkenes[
The authors also reported the use of P1I3 as an e.cient reagent for deselenisation[ Allenes were
By Substitution 330
formed by reaction of b!hydroxyselenides with P1I3[ The oxidation of vinyl selenides with mcpba
leads to allene formation ð81PS"56#192Ł[
Bu SO2C6H4-p-Me Bu SO2C6H4-p-Me
NiCl2•6H2O, NaBH4
(54)
THF, MeOH
PhSe Bu 95%
Bu
SeMe i, BunLi
SeMe
(55)
R SeMe ii, H+ R
95%
"iii# Reduction of vinyl tellurides

The chemistry of vinyl tellurides has been reviewed ð80SR0Ł[ An important method for breaking
the sp1!C0Te bond is via transmetallation:hydrolysis[ The exchange reaction with lithium is well
established ð64CB203Ł as exempli_ed by Brandsma and co!workers ð81JOM"330#0Ł[ They found that
thiatellurin\ when treated with two equivalents of BuLi\ yielded a dilithiated adduct which was
stable at −094>C[ This compound was subsequently treated with a variety of electrophiles\ including
H1O which led to the formation of divinyl sul_de "Equation "45##[
S S
i, BunLi
(56)
ii, H+
R Te R 60% R R
R = H, Me, But
Similarly a vinyllithium was formed from the reaction of vinyl telluride and BuLi ð78TL6242Ł[ The
vinyllithium was quenched with electrophiles including PhCHO and C7H06Br "though not H2O¦#
with strict retention of double bond geometry "Equation "46##[ Similarly vinyl tellurides have been
transformed into cuprates\ which also react with electrophiles "e[g[ a\b!unsaturated ketones# again
with retention of double bond geometry ð89SC0570Ł[
TeR i, BunLi
E
(57)
ii, E+ R
70–85%
Raney nickel acts as a catalyst for the reduction of vinyl tellurides ð81PS"56#072Ł[ The problems
with using Raney nickel for chemoselective reactions have been emphasised previously[
0[09[0[3 Reduction of 1C0N Bonds
0[09[0[3[0 Reduction of arylcarbonÐnitrogen bonds

Occasionally aromatic nitro groups have been directly displaced from arenes by reaction with
NaBH3 ð57HCA260\ 72JA3906Ł "Equation "47##[ The reaction is by no means general and cleavage of
the aryl!C0N bond is more usually carried out via the corresponding aryl amine[
Cl Cl
NaBH4
(58)
DMF
80–83%
NO2 Cl Cl
Many synthetic methodologies exist for the reduction of an aryl nitro group to aryl amines[
These include reduction by "i# metals:H¦\ "ii# catalytic hydrogenation ðB!65MI 009!90Ł "iii# catalytic
hydrogen transfer with HCO1H:Pd ð66JCS"P0#332Ł\ and "iv# complex hydride:transition metal catalyst
combinations such as NaBH3:NiCl1"PPh2#1 ð68JCS"P0#1398Ł[ A detailed examination of this reaction
is beyond the scope of this chapter[
The reductive removal of a primary aromatic amine is commonly carried out by reduction of the
corresponding diazonium salt ðB!67MI 009!90Ł[ The diazonium salt is formed by reaction of arylamine
with sodium or potassium nitrite at low temperature\ most diazonium salts being unstable above
4>C[ Tetra~uoroborate ð75JCS"P0#762Ł and hexa~uorophosphate salts ð52JOC457Ł are notable excep!
tions[ The diazonium salt can then be reduced with a variety of reagents including hypophosphorous
acid\ H2PO1 ð38JA1026Ł\ EtOH ð31JCS637Ł\ formaldehyde ð28JA1307Ł and by metals such as zinc
ð39JCS196Ł[ Sn:HCl ð76JCS"P0#0840Ł\ NaBH3 ð50JA0140Ł\ Bun2SnH and Et2SiH ð69T3598Ł have also
been utilised[
Hypophosphorous acid remains the most selective reducing agent for this transformation
ð38JA1026Ł[ It exhibits a high degree of selectivity for the protonolysis of diazonium salts over a
range of functionalities present on the arene ring[ Indeed even aliphatic amine groups remain inert
to diazotisation:reduction with H2PO1 "Equation "48##[
NH2
i, 50% H3PO2, NaNO2, 5 °C

(59)
ii, RT
m-, 87%
NH2CH2 p-, 84%
NH2
Sodium borohydride in MeOH or DMF is an e}ective reagent:solvent combination for the

reduction of diazonium salts "Equation "59## ð50JA0140Ł[ Treatment with t!butyl nitrite in DMF
also has been described as a useful method ð66JOC2383\ 75JCS"P0#762Ł[ Cadogan and Molina reported
a simple {one!pot| deamination procedure using pentyl nitrite in re~uxing THF "Equation "50##
ð62JCS"P0#430Ł[ Other examples include the use of Bun2SnH in polar solvents for the reduction of
diazonium tetra~uoroborate salts\ although this reagent lacks chemoselectivity\ reducing aromatic
nitro groups also[ Triethylsilane exhibits improved chemoselectivity compared with Bun2SnH "Equa!
tion "51## ð69T3598Ł[
N2+ BF4–
NaBH4
(60)
MeOH
68%
CO2H CO2H
NH2
Br Br pentyl nitrite
Br Br
(61)
THF
87%
N2+ BF4–
Et3SiH
(62)
MeCN
90%
OMe OMe
The mechanism of the reduction depends on the reaction conditions\ the type of reducing agent
and the nature of the diazonium salt[ Diazonium salts decompose to yield aryl cations and N1 in
polar solvents[ Subsequently arenes are formed by hydrogen transfer from either the solvent or the
reducing agent[ A free radical mechanism has been proposed for this type of reduction ð32JCS75Ł[
The reduction of diazonium salts with Bun2SnH proceeds via two pathways\ one involving hydrogen
atom abstraction from Bun2SnH\ the other involving reaction of an arene radical with solvent
ð69T3598Ł[ Evidence that the reduction of diazonium salts with formamide proceeds intramolecularly
has come from labelling studies ð66JOC2383Ł[
Hydrazines of the type ArNH0NH1 are oxidised by a variety of reagents including HgO and
By Substitution 332
K2Fe"CN#5 to give azo compounds ArN1NH ð66S228Ł[ These species readily decompose to ArH
and N1 ð62TL2386Ł[
0[09[0[3[1 Reduction of vinylcarbonÐnitrogen bonds

Lewis and co!workers reported the unusual replacement of an amine for hydrogen during studies
on the reaction of AlH1Cl with enamines ð52PCS08Ł[ Later studies found that enamines were
e.ciently cleaved to alkenes with either chloroalane or alane "AlH2# itself "Equation "52## ð57T3378Ł[
Mechanistically the process is an addition:elimination\ for example the addition of alane to the
double bond followed by elimination yielding alkene and an amine[ The methodology was applied
to a series of pyrrolidine!derived enamines[ The same group reported enamine cleavage was also
observed on treatment with diborane\ B1H5 "Scheme 7# ð53TL1928Ł[ A report by Singaram and
Brown et al[ extended this boron based reduction methodology ð78JA273\ 80JOC0432Ł] a series of
aldehyde and ketone derived enamines were subjected to reduction by 8!BBN forming high yields
of the corresponding alkenes "Scheme 8#[ Terminal alkenes and dienes\ cycloalkenes\ heterocyclic
and acyclic "Z#! and "E#!alkenes were synthesised using this methodology[ Interestingly\ the hyd!
roborating reagent and workup conditions were found to play a major role in determining the
stereochemistry of the alkene formed from reaction of enamines derived from acyclic ketones[
For example\ hydroboration of "E#!"0#!morpholino!0!phenylprop!0!ene by 8!BBN followed by
methanolysis gave the "Z#!alkene in isomerically pure form in 79) yield[ On the other hand
hydroboration of the same substrate by boraneÐdimethyl sul_de complex "BMS#\ followed by
methanolysis and oxidation with H1O1 yielded "E#!0!phenylprop!0!ene as the pure geometric isomer[
i or ii or iii
N (63)
Et2O
i, AlHCl2, 75%; ii, AlH2Cl, 75%; iii, AlH3, 80%
B2H6 AcOH
N N
94%
H2B
Scheme 8
N
BMS 9-BBN
MeOH, [O] MeOH

81% 75%
Scheme 9
The mechanistic rationale given for these transformations is as follows] hydroboration by boraneÐ
dimethyl sul_de\ followed by methanolysis and oxidation proceeds via an intermediate dimethyl!
boronate ester\ which on oxidation forms the N!oxide[ This species is thought to undergo a
syn elimination forming the "E#!alkene "Scheme 09#[ Hydroboration with 8!BBN\ followed by
methanolysis involves the coordination of MeOH to the boron atom followed by an anti elimination
"Scheme 00#[
Barton and co!workers published an elegant alkene synthesis based on the radical induced
elimination of a nitro group from a nitroalkene ð82TL7940Ł[ Nitroalkenes were reacted with ethyl
trithiocarbonate to yield b!nitrotrithiocarbonates "Scheme 01#[ Adducts of this kind underwent a
radical!induced elimination on exposure to a combination of Barton esters\ visible light and heat to
form alkenes as mixtures of "E#! and "Z#!stereoisomers[ Ono and co!workers have investigated the
use of tin hydride!based methodologies to e}ect the transformation of nitroalkenes to alkenes
ð74T3902Ł[
O O
+
N H N O– H H
syn elimination
H B(OR)2 H B(OR)2 B(OR)2
O N
Scheme 10
O O
MeOH
N H N H
H BR2 H BR2
anti elimination
Scheme 11
S
EtS O
NO2 S NO2 N R2
O R3
S PhH, ∆, hν
R1 R2 R1 R2 79–83% R1
Scheme 12
0[09[0[4 Reduction of 1C0P\ 1C0As\ 1C0Sb\ 1C0Bi Bonds
0[09[0[4[0 Reduction of arylcarbonÐphosphorus\ Ðarsenic\ Ðantimony and Ðbismuth bonds

"i# The reduction of arylcarbonÐphosphorus bonds
A variety of methods exist for reducing aryl!C0PIII bonds\ the commonest being the reduction
with alkali metals[ The reduction yields the corresponding phosphide anion\ which can be quenched
with water or alcohols yielding secondary phosphines ðB!61MI 009!90Ł[ The alkali metal reduction of
tertiary phosphines has been enhanced by ultrasound ð74JCR"S#07Ł[ It has been reported that
metalÐPPh2 complexes undergo C0P bond cleavage under speci_c conditions ð74CRV060Ł[ Almost
quantitative amounts of benzene were formed when complexes of the type RuH1"PPh2#3 were heated
in pyrrolidine ð79JOM"082#26Ł[
Two general methods exist for the cleavage of aryl phosphonium salts\ these being hydrolysis or
reduction with LAH ð72PS"04#248Ł[ Generally the alkaline hydrolysis of a phosphonium salt is used
to prepare the corresponding phosphine oxide either with or without fracture of the aryl!C0P bond
ð80COS"7#724Ł[
Posner and Lu described the hydrolysis of a phosphonium bromide with KOH "Equation "53##
ð74JA0313Ł[ Similarly Minami et al[ hydrolysed cyclobutene phosphonium perchlorate to cyclo!
butenephosphine oxide and benzene "Equation "54## ð72JOC1458Ł[
O
+
PPh3 Br– PPh2
KOH
(64)
By Substitution 334
O
+
PPh3 ClO4– NaOH PPh2
(65)
THF, H2O
70%
Extensive studies were carried out on the hydrolysis of s!chlorophenyltriphenylphosphonium

iodide ð56JOC1690Ł with methoxide[ Sodium naphthelenide has been used for the selective cleavage
of one aryl!C0P bond in tertiary diphosphines ð75JOM"201#42Ł[ Bickelhaupt and co!workers reduced
0!phenylphosphoniumadamantane bromide with elemental sodium to yield 0!phosphadamantane
"Equation "55## ð72T3114Ł[
Ph
+ I–
P Na P
(66)
PhMe
64%
There are few general methods available for the reduction or hydrolysis of aryl!C0PV bonds
ð80COS"7#724Ł[ Hydrolysis of aryl phosphonates and phosphates generally occurs at the P1O bond
rather than at the P0C bond[ Methods which have given P0C bond cleavage include heating
with solid KOH[ In certain cases reduction with hydride has produced P0C bond cleavage[
Dibenzophosphepin was treated with NaH to yield\ initially\ the ring opened product "Equation
"56## ð79PS"7#132Ł[
NaH
(67)
P 69% H
O Ph P
Ph
O
"ii# Reduction of arylcarbonÐarsenic\ Ðantimony and Ðbismuth bonds

The chemistry of organic arsenic\ antimony and bismuth compounds has been reviewed ðB!83MI
009!90Ł[Triorganoarsenic compounds\ diarsines and diorganoarsenic halides are reduced by alkali
metals to a}ord the corresponding diorganoarsenic species "Scheme 02# ð56JOC1516Ł[ Selectivity in
the reduction of unsymmetrical tertiary arsines is thermodynamically controlled[ In the case of
diphenyl ethyl arsine this leads to formation of phenyl ethyl arsine anion ð63S217Ł[ Arsenide anions
react with protic acids "e[g[\ H1O# to give hydrides ð54JCS3019Ł[ Protonolysis of triorganoarsenic"III#
compounds with HI leads to formation of organoarsenic"III# diiodides "Equation "57##
ð75JCS"D#886Ł[ Triphenylarsine was reduced electrochemically to Ph1AsH ð63JA4921Ł[ Triorgano!
arsenic"IV# dihalides\ under thermolytic conditions\ form diorganoarsenic"III# halides ð46ZAAC237Ł[
Wittig and Hellwinkel reported that pentaorganoarsenic"V# compounds when treated with electro!
philes such as EtOD formed triorganoarsenic"III# compounds "Scheme 03# ð53CB658Ł[
Na H2O
Ph3As Ph2As– Na+ Ph2AsH
NH3 (l) 79%
Scheme 13
OEt D
EtOD D
As As As
Et Et
Scheme 14
HI
Ph2As AsPh2 I2As AsI2 (68)
The cleavage of the aryl!C0As bond has also been achieved using sodium hydrogen sul_te
ð17JCS2935Ł and by aqueous alkali at elevated temperatures ð39CA"23#5396Ł[ Arsenous acids react
with HgO breaking the As0C bond ð23CB206Ł[ Organoantimony"III# and bismuth"III# hydrides
are thermally unstable[ Antimony hydrides can be formed by hydride reduction of organoantimony
halides at low temperatures ð64ZAAC"307#047Ł[ Only MeBiH1 and Me1BiH are known ð50CB0336Ł[
Protonolysis of triorganoantimony and !bismuth compounds with mineral acids gives diorgano!
antimony and diorganobismuth"III# halides ð74JOM"145#C0Ł and ð55ZAAC"232#085Ł[ Reaction of Ph2Bi
with benzoic acid leads to the formation of PhBi"OCOPh#1 ð40JA1779Ł[
Pentaorganoantimony and !bismuth compounds react with electrophiles such as HF\ HCl and Br1
leading to the formation of tetraorganoantimony and !bismuth halides ð41LA"466#15\ 41LA"467#025Ł[
Pentaphenyl antimony "Ph4Sb# disproportionates to Ph2Sb and Ph0Ph at 059Ð199>C\ as does
Ph4As ðB!83MI 009!91Ł[ Treatment of pentaphenyl antimony with Cl1 led to the formation of Ph3SbCl
"Equation "58##[ Quaternary halides "Ph3SbBr2# thermolise at 079>C to give Ph2SbBr1 and PhBr[
Quaternary bismuth halides "e[g[\ Ph3BiCl# are unstable at room temperature and disproportionate
to give Ph2Bi "Scheme 04# ð41LA"467#025Ł[
Cl2
Ph5Sb Ph4SbCl (69)
76%
HCl
Ph5Bi Ph4BiCl Ph3Bi
54%
Scheme 15
0[09[0[4[1 Reduction of vinylcarbonÐphosphorus bonds

An e.cient route to substituted alkenes and allenes from vinyl phosphines occurs with metallation
of an intermediate phosphine with MeLi\ followed by hydrolysis of the resultant vinyllithium[ This
approach was taken by Schmidbaur and co!workers during the synthesis of 0!"diphenylphosphino#!
0\2!diphenylallene "Equation "69## ð76CB0392\ 78CB148Ł[ Vinyl phosphonium salts are generally
hydrolysed with either base or acid to give the corresponding alkenes[
Ph Ph i, MeLi
Ph Ph
• • (70)
Ph2P PPh2 ii, H2O PPh2
Larpent and Meigian hydrolysed a series of water!soluble vinyl phosphonium salts stereo!
speci_cally with NaOH ð82TL3220Ł[ The same group reported the preparation of regiospeci_cally
labelled fumaric and cinnamic acids from D1O:HCl hydrolysis of a sulfonated vinyl phosphonium
salt ð77TL3466Ł[ Fluorinated vinyl phosphonium salts were hydrolysed with NaOH ð72JA549\
74JA1700Ł] the ~uoroalkenes were formed in good yields with complete retention of alkene geometry
"Equation "60##[ Enol ethers ð89TL1890Ł and ketenethioacetals ð68CB17Ł have also been synthesised
via hydrolysis of the corresponding vinyl phosphonium salts[
+
Bu3P R NaOH
R
X– (71)
F 76% F
(E):(Z) 13:87 R = Ph (E):(Z) 87:13

By Substitution 336
0[09[0[5 Reduction of 1C0B\ 1C0Si\ 1C0Ge Bonds
0[09[0[5[0 Reduction of aryl boranes\ silanes and germanes

"i# Reduction of aryl boranes
The aryl!C0B bond appears to have similar reactivity to alkenylcarbonÐboron bonds\ though
little data exist which allow direct comparison[ The reduction of aryl boranes is treated brie~y in a
review ðB!76MI 009!90Ł and a book ðB!50MI 009!90Ł on organoboron chemistry[ Aryl boronic acids
undergo protodeboronation on treatment with a carboxylic acid\ for example HCO1H ð50JA1048Ł[
The reaction proceeds via the formation of a six!membered cyclic transition state "Scheme 05#[
OH
B(OH)2
HO B
O
HCO2H
H + (HO)2BO2CH
O
Scheme 16
The cleavage of the arylcarbonÐboron bond was studied in the early 0829s[ Hydrolytic cleavage
was e}ected by heating PhB"OH#1 with water\ acid or base ð29JCS1060Ł[ Dimethylamino! and 3!
methoxy!a!napthyl!boronic acids were readily deboronated under mild conditions ð37JA121Ł[ The
presence of metal salts "e[g[ CuCl1# has also been found to promote aryl!C0B bond cleavage
ð29JCS1060Ł[ Ammonical AgNO2 proved e.cient at deboronating phenyl boronic acid ð27JA010Ł
Dearylation of borinic acids is known\ and has been e}ected by prolonged exposure to heat[
Treatment with aqueous ethanolic dimethylaminoethanol has also proved e}ective ð47JCS0340Ł[ Tri
a!napthyl boron gave napthalene and trimethyl borate on treatment with excess methanol ð44JOC8Ł[
"ii# Reduction of aryl silanes

The chemistry of aryl silanes has been extensively covered in a large number of books and review
articles\ for example ðB!70MI 009!90\ B!78MI 009!90\ 82SL060Ł[
The ipso substitution of silicon for hydrogen in an aryl silane is a well!studied reaction[ Eaborn
reported in 0864 that the C0Si cleavage occurred via a mechanism analogous to electrophilic
aromatic substitution via a Wheland!type intermediate ð64JOM"099#32Ł[ This ipso substitution of
silicon is favoured over replacement of hydrogen due to the stabilisation of the incipient carbocation
b to silicon in one of the canonical forms which can be drawn for the intermediate[ The b!e}ect has
also been the subject of intensive study and is now thought to arise due to a combination of four
e}ects\ namely inductive\ _eld\ "pÐd#p bonding and hyperconjugation ð82SL060Ł[
The competing electrophilic substitution of hydrogen over silicon is known to occur but\ to date\
appears to be limited to reaction with nitrating agents "e[g[\ NO1¦# ð61JCS"P1#061Ł though\ even with
nitrating agents\ ipso substitution for silicon has been observed ð46JCS387Ł[
A number of factors need to be taken into account when discussing the protodesilylation
reaction[ The type of substitution on silicon can have a profound e}ect on the rates of C0Si bond
cleavage[ Silicon with electron!rich groups attached "e[g[\ SiR2 where RMeOC5H3# has a greatly
increased C0Si cleavage rate\ this e}ect being due to the greater stabilisation of the b!carbocation
ðB!78MI 009!90Ł[
It should also be noted that both steric and electronic factors play signi_cant roles in determining
aryl silane reactivity[ Silanes of the type ArSiCl2 are cleaved more slowly than Ar!TMS\ re~ecting
the weak electron!withdrawing e}ect of halogen\ whereas those of the type ArSiPh2 are also cleaved
more slowly than Ar!TMS\ this e}ect being a combination of steric bulk and electron donation[
Ring substituents\ especially those exerting powerful directing e}ects "e[g[ R1N ð50CA"44#03239Ł and
OMe ð59JCS068Ł# are known to promote reactions that dominate over the ipso substitution of silicon
and therefore ring substitution occurs without loss of Si[ The nature of the electrophile may also
exert some in~uence on the mode of substitution in aryl silanes[ With two SiR2 groups present on
an aryl nucleus it is known that the _rst C0Si bond cleaves some 39 times faster than the second\
thereby allowing for substitution of silicon by di}erent nucleophiles ð73AG"E#428Ł[
Most commonly\ the method of cleavage used synthetically is treatment of the aryl silane with
either mineral acid "e[g[\ HCl ð59JCS0455Ł# or carboxylic acid "e[g[\ CF2CO1H ð66JA4372Ł#[
An e.cient regioselective desilylation of a disilylated steroid was achieved with TFA\ subsequent
oxidation of the remaining C0Si bond leading to a concise synthesis of "¦:−#oestrone "Equation
"61## ð73AG"E#428Ł[ E}enberger also described the use of a number of carboxylic and sulfonic acids
as e.cient desilylating reagents ð67S644Ł[ Cleavage of C0Si bonds in aryl and other aromatic
systems initiated by nucleophilic attack at silicon is a less favourable process than C0Si cleavage
initiated by electrophilic attack at carbon[ However\ in recent years this type of desilylation has
come to the fore from a synthetic standpoint[
H i, CF3CO2H
TMS (72)
ii, Pb(O2CCF3)4
H H HO
80%
TMS
The most commonly used reagents for desilylation via nucleophilic catalysis are butoxide and
F−[ Butoxide was used by Vollhardt et al[ in a synthesis of terphenylene ð72CC491Ł[ An interesting
one!pot protodesilylation and carbodesilylation was described by Dunogues et al[ ð89TL5068Ł] a bis!
silylated ~uoroarene was treated under FriedelÐCrafts conditions with acetyl chloride in the presence
of KF[ A 68) yield of the desilylated ~uorobenzophenone was isolated "Equation "62##[ Caesium
~uoride in DMF:H1O has also proved a popular method for desilylating aryl silanes "Equation
"63## ð78CPB25\ 78JOC3261Ł[ Interestingly a tris!silylated arene was desilylated to the bissilylated
product simply on standing in CH1Cl1 ð74JA0268Ł[ The reason for this reaction occurring spon!
taneously is probably the relief of the massive steric congestion built into the starting material[
Selective protodesilylations of bis!silylated arenes with t!butyl ammonium ~uoride "tbaf# have been
reported ð76AG"E#0924Ł[ The bis!silylated cobalt complex shown in Equation "64# was treated with
tbaf at room temperature for two hours to a}ord 80) of the monosilylated product[
O
TMS
O
F F
Cl
(73)
AlCl3, DMF, KF
79%
TMS
SH O SH O
NEt2 CsF NEt2

(74)
TMS DMF, H2O
78%
OMe OMe
TMS TMS
H H
N TMS N
tbaf
N N (75)
H THF H
91%
O Co O Co
"iii# Reduction of aryl èrmanes

Aryl germanes have a lower carbonÐmetal bond energy than aryl silanes and therefore are
expected to be more susceptible to reaction with electrophiles[ ArGeMe2 was readily degermylated
with HCl in aqueous dioxane ð53JCS3793Ł[ The reaction was observed to be signi_cantly slower
By Substitution 338
when D1O was used in place of H1O\ indicating that the attachment of a proton to the aryl ring was
the rate determining step in the protiodegermylation[ Methanolic perchloric acid has also been
utilised for the cleavage of ArGeEt2 ð59JCS0455Ł[ Tri~uoroacetic acid in CFCl2 was used to deger!
mylate mixtures of trimethylgermyl~uoroarenes "Equation "65## ð76JFC"25#52Ł[ The C0Ge bond in
an aryl germane is also broken by methanolic sodium methoxide ð65JCS"P1#814Ł[ Tetraphenylgermane
formed triphenylgermane on treatment with Br1 ð49JA4455Ł[ Kobayashi et al[ investigated the
photochemical behaviour of several aryl alkyl germanes ð75BCJ1796Ł[ It was found that the aryl!
C0Ge bond cleaved readily under photolytic conditions\ generating germyl radicals[ Aryl radicals
reacted with solvent forming benzene or its derivatives[ The Et2Ge = species subsequently reacted
with solvent derived radicals to form Et = GeR or dimerised to form Et2GeGeEt2 "Equation "66##[
Aryl dialkyl digermanes of the type "ArMe1Ge#1 undergo Ge0Ge bond cleavage on photolysis
ð77OM0758Ł[
CF3CO2H
(76)
CFCl3
18F 18F
GeMe3
hν, 250 nm
Et3GeAr Et3GeR + (Et3Ge)2 + ArH + C12H26 (77)
hexanes
The halogenodegermylation of aryltrimethylgermanes has been used in the synthesis of 66Br and
020
I radiolabelled arenes ð76JOC553Ł[ The short reaction times "ca[ one minute for completion# makes
this an ideal synthetic route to radiolabelled compounds containing radionuclei with short half lives
"Equation "67##[
R R
Br2 or Cl2
(78)
AcOH
GeMe3 80–99%
X
0[09[0[5[1 Reduction of vinyl boranes\ silanes and germanes
"i# Reduction of vinyl boranes

The hydroboration of alkynes is an important synthetic transformation which has been featured
in many reviews ðB!64MI 009!90\ B!77MI 009!90Ł[ Depending on the conditions of the subsequent
cleavage of the intermediate vinylboron species a range of functionality can be introduced[ In this
section the replacement of boron by hydrogen "most commonly carried out by protonolysis# is of
prime importance[ Protonolysis can be carried out under such mild conditions that many functional
groups remain unreactive[
All three alkenyl groups are cleaved from a trialkenyl borane on treatment with carboxylic acid
at 9>C ð48JA0401Ł[ The protonolysis is known to proceed with retention of con_guration thus leading
to a stereospeci_c synthesis of "Z#!alkenes ð60JA2284Ł[ Acetic acid has been used to cleave the sp1!
C0B bond of an allenylborane ð63JA4519Ł[ Brown has reported a synthesis of "Z#!0!haloalk!0!enes\
via hydroboration with "cyclohexyl#1BH or 8!BBN\ the intermediate organoboranes being cleaved
with AcOH "Equation "68## ð78JOC5953Ł[ This method has also been used for a "Z#!enyne synthesis
ð78TL5376Ł and also for the synthesis of "Z#!vinyl silanes "Equation "79## ð89TL4002Ł[ Alkenyl dialkyl
boranes are preferentially cleaved "e[g[ by methanolysis# at the alkeneÐboron bond\ ð75JOC3401Ł[ A
variety of 8!BBN derivatives were treated under such conditions giving high yields "×75)# of the
corresponding alkene "Equation "70##[ Acid catalysis "pivalic acid# was found to be required for
sterically hindered derivatives[ Treatment with HCl leads to protonolysis ð63S228\ 64JOC1734Ł[
R X R X
AcOH
(79)
BChx2 CCl4 or THF
quantitative
R TMS R TMS
AcOH
(80)
B(cyclohexyl)2 quantitative
( )5 MeOH ( )5
(81)
R2B 96%
R2 = 9-BBN
Negishi described an elegant method for cleaving the boronÐcarbon bond in alkenyltrialkylborates
ð65JOC2373Ł[ Representative alkenyldialkylboranes were treated with BunLi[ The borate intermediate
so formed was subsequently hydrolysed stereospeci_cally with NaOH forming the "Z#!alkene
"Scheme 06#[ Corey and Ravindranathan utilised Ag"NH2#1NO1 to break a vinylÐboron bond in the
presence of an acetal group "Equation "71## ð61JA3902Ł[ Catalytic cleavage of a vinyl borane by
Pd"OAc#1 under essentially neutral conditions was observed by Yamamato et al[ "Equation "72##
ð67CC691Ł[
R32BH
R1 R2 NaOH R1 R2
R1 R2 Li+
BunLi R32B – 86–95%
Bu
Scheme 17
Ag(NH)3)2NO3
(82)
C5H11 65%, 4 steps
(thexyl)B
OMe O-THP C5H11
O-THP
R1 R2 Pd(OAc)2 R1 R2
(83)
THF
B(siamyl)2
30–95%
R1 = Bun, Hexn, Ph, Octn

R2 = Bun, Et, Ph, H, (CH2)7CO2Me
"ii# Reduction of vinyl silanes

The chemistry of vinyl silanes has been extensively reviewed ð68S650\ B!70MI 009!90\ B!78MI 009!90\
78OR"26#46Ł[ Sommer and co!workers reported that b!trimethylsilylstyrene was cleaved by mineral
acid to yield styrene ð43JA0502Ł[ The stereospeci_city of the reaction was subsequently investigated
ð62JA2305Ł\ Koenig and Weber _nding that trimethylsilylstyrene on treatment of DCl was converted
to b!deuteriostyrene with complete retention of alkene geometry[ The mechanistic details of this
substitution have been investigated and are described in detail in a review ð78OR"26#46Ł[ This
substitution of silicon for hydrogen with preservation of the double bond and retention of con!
_guration appears to be general and a number of e.cient reagentÐsolvent combinations have been
reported to carry out this transformation[ Thus a variety of acids have been utilised[ These include
hydroiodic acid "HI# ð65JOC1104Ł or iodine in H1O:benzene "Equation "73## ð72TL0930Ł\ HF ð72T824Ł\
HBr ð60JOM"22#210Ł\ AcOH ð71JOC3602Ł and particularly HCl in either MeOH ð74JCS"P0#1288Ł or
acetone ð75JA2405Ł "used in a synthesis of protomycinolide"IV##\ or diethyl ether ð70JOM"106#32Ł[
Fluoroboric acid is also an e.cient desilylating agent for vinyl silanes ð73JA2557Ł[ Isomerisation of
the product alkene can be a problem[ A mild reagent for this transformation is p!toluene sul_nic
acid "TsH#\ a much quoted example of its use being the cleavage of the acid sensitive sesquiterpene
"6# "Equation "74## ð66TL3294Ł[ Desilylations with TsH are known to lack stereospeci_city compared
with mineral acid based transformations[ Sensitive systems have been successfully desilylated with
By Substitution 340
TsOH in mixed aqueous!organic solvent systems "Equation "75## ð73TL0888Ł[ This methodology has
been extended to the synthesis of stereospeci_cally deuteriated alkenes[ Useful reagent combinations
are I1ÐD1O ð64TL1714Ł\ DCl!organic solvent ð62JA2305Ł\ or AcODÐD1O ð68JOC044Ł[ Vollhardt and
co!workers used CF2CO1D to probe the di}ering reactivities between C!0 and C!1 bissilylated
alkenes on protodesilylation ð75JA0248Ł[
Bun HI Bun
(84)
H2O, PhH
TMS ( )6 O-THP ( )6 O-THP
82%
TsH
(85)
ACN, H2O
O O
TMS
(7)
TMS
TsOH
(86)
MeCN, THF, H2O
73%
Vinyl silanes are known to be desilylated under conditions of nucleophilic catalysis ð78OR"26#46Ł
speci_cally where good nucleophiles for silicon "i[e[\ F−\ or alkoxide# are employed[ Conditions
tend to be harsh or prolonged for e.cient desilylation "e[g[\ ð64JA4592Ł# unless other factors come
into play\ for example the stabilisation of the putative vinyl anion intermediate[ E}ective stabilising
groups include hydroxy ð63TL2368Ł\ halogen ð70S888Ł and cyano ð71CC45Ł moieties[ Proto!
desilylation then occurs under considerably milder conditions[ t!Butyl ammonium ~uoride "tbaf#
has been used by many groups for e.cient desilylation of {stabilised| vinyl silanes "Equation "76##
ð68JA3319\ 72JOC2650Ł[
OH OH
O O tbaf O O
(87)
THF
TMS 73%
HO HO
Examples of alkoxide catalysis include those of Tamao et al[ ð64JA4592Ł who used NaOEt in
DMSO at 029>C to cleave bis!silylated alkenes[ The vigorous conditions led to loss of stereointegrity
of the product alkene "Equation "77##[ Kusakabe and Sato showed that a vinyl silane containing an
acid sensitive acetonide could be smoothly converted to the corresponding alkene using NaH in
HMPA "Equation "78## ð75CL0362Ł[
Bun TMS NaOEt Bun

(88)
TMS Bun DMSO Bun
(E) (E), 90%; (Z), 6%
TMS O NaH O
O O (89)
HMPA
OH OH
"iii# Reduction of vinyl èrmanes

Vinyl germanes\ have not been exploited extensively in synthetic chemistry[ For example\ very
few reports exist which describe their reaction with electrophiles[
Oda and co!workers described a straightforward synthesis of vinyl germanes from the platinum!
catalysed hydrogermylation of terminal alkynes ð73TL2110Ł[ The regiochemical and stereochemical
outcomes were dependent on the catalyst used[ The vinyl germanes were treated with bromine or
iodine to form vinyl halides in good yield\ with excellent stereoselectivity in the case of iodine[ Cyclic
alkenyl germanes give excellent yields of vinyl iodides when treated with iodine ð74CL42Ł[
Piers has extended this methodology in an elegant synthesis of the tetraquinane diterpenoid "¦#!
crinipellin B ð82JOC00Ł[ Ikenaga et al[ exploited the reactivity of vinyl germanes "PhCH1CHGeMe2#
with arene diazonium tetra~uoroborates "ArN1BF3# under palladium catalysis to yield products of
the type PhCH1CHAr ð89CL074Ł[
0[09[0[6 Reduction of 1C0Metal Bonds
0[09[0[6[0 Reduction of arylcarbonÐmetal bonds

The substitution of a metal for a proton in an arylmetal species is most commonly carried out by
simple protonation by electrophiles such as H1O or mineral acids[ Less commonly\ reduction by
complex hydrides is used ðB!76MI 009!91Ł[
PhLi reacts with a variety of proton donors including H1O\ ROH and RCO1H to yield arenes
ðB!76MI 009!91Ł[ The protonolysis of an aryl!Li intermediate was reported by Parham and co!workers
"Equation "89## ð65JOC0073Ł[
ROH
PhLi PhH (90)
quantitative
Aryl Grignard reagents\ ArMgX\ are readily hydrolysed to arenes with H1O or dilute mineral
acid "Equation "80## ðB!76MI 009!92Ł[ The organometallic chemistry of calcium\ strontium and
barium has been less thoroughly investigated[ Organo calcium\ strontium and barium {Grignard|
reagents have been prepared at low temperature and appear to show similar reactivity towards
electrophiles ð62T0958\ 67JCS"D#546Ł[ Diaryl beryllium reagents\ such as Ph1Be\ are readily synthesised
but their chemistry remains poorly investigated ð71COMC!I"0#010Ł[ The tantalum moiety of aryl
tantalum"III# compounds undergoes ipso substitution with a variety of atoms or groups including
F\ CN\ SeCN and NO1 ðB!76MI 009!93Ł[ Reduction with NaBD3 in EtOD is an e.cient method for
the deuteriodethallation of aryl tantalum"III# species "Equation "81## ð62TL0264Ł[
H2O or H+
ArMgX ArH (91)
quantitative
NaBH4, EtOD
ArTaIIIZ2 ArD (92)
or NaBD4, EtOH
Aryl stannanes\ on protonolysis with carboxylic and mineral acids\ yield arenes ð76MI 009!94Ł[
Eaborn et al[ prepared a variety of deuteriobenzenes from the corresponding aryltin derivatives
ð62JCS"P0#026Ł[ Aryl trimethylstannanes on treatment with AcOD\ containing 09) D1O\ yielded
labelled arenes in good yield and high "×87)# isotopic purity "Equation "82##[ Seitz and co!workers
reported a related method for the synthesis of 2H!tamoxifen ð70SC170Ł[ s!Stannylated tamoxifen
was tritiodestannylated on treatment with excess "CF2CO1#1O and T1O[ The destannylation pro!
cedure was equally applicable to other starting materials "Equation "83##[
SnMe3 D
AcOD
(93)
D 2O
X 60% X
X = o-Me, m-Me, p-Me, m-Cl, p-Cl, m-OMe, m-CF3, p-F
By Substitution 342
NMe2 NMe2
O O
SnBu3 3H
(CF3CO2)O, 3H2O
(94)
THF
93%
Aryl mercurials are cleaved by AcOH:perchloric acid giving\ in the case of diphenylmercury\
benzene and mercury"II# salts[ The bond!breaking process is known to be a simple SE1!type
electrophilic substitution[
0[09[0[6[1 Reduction of vinylcarbonÐmetal bonds

Organoalkali metal compounds react with a range of proton sources including H1O\ ROH\
RCO1H\ RNH1 and mineral acids[ Alkenyllithiums react with H1O or H¦ to form alkenes with
retention of con_guration "Equation "84## ð66JA7245\ B!76MI 009!91Ł[ Vinyl Grignard reagents are
also readily hydrolysed in H1O forming alkenes "Equation "85##[ Carbomagnesiation of alkynes via
Normant reagents RCu = MgX1 leads to the formation of intermediate vinyl cuprates which also
break down on protonolysis to form alkenes "Equation "86## ð67PAC698Ł[ Vinyl derivatives of the
remaining Group 1 metals "calcium\ strontium\ barium and beryllium# are less well known though
the similar reactivities of Ca\ Sr\ and Ba {Grignard| reagents has been reported ðB!76MI 009!92Ł[
But Li But D
D2O
N N (95)
quantitative
O O
R1 R2 H2O R1 R2
(96)
quantitative
MgX R3 R3
R2 H+
R2
(97)
R1 CuMgX2 quantitative R1
Vinylaluminum species are commonly formed by the hydro! or carboalumination of alkynes[ The
hydroalumination reaction has been reviewed ð73OR"21#0\ B!76MI 009!91Ł[ Vinyl alanes are generally
cleaved by reaction with proton donors such as MeOH or H1O "Equation "87## ð52JOC0143\ 54CB713Ł[
The scope of the carboalumination reaction has been greatly broadened by the observation that
catalysis with zirconium leads to a 099) cis carbometalation ð70JA3874\ 70PAC1222Ł[
n-C6H13
i, dibal n-C6H13 ( )5 Cl
(98)
ii, H2O
( )5
Cl
Lipshultz and co!workers used a in situ generated Schwartz reagent\ Cp1Zr"H#Cl\ for the hydro!
zirconation of alkynes ð89TL6146Ł[ Reaction of the intermediate vinyl!Zr species with electrophiles
such as H1O\ D1O and N!bromosuccinimide "NBS# led to the formation of alkenes in good yield
and without loss of acid!sensitive functionality "Scheme 07#[
Vinyl!Ni complexes of the type Ni"acac#"PPh2#"C"Ph#1C"R1#CH2# are cleaved with both elec!
trophilic and nucleophilic reagents "e[g[\ H1O\ TsOH\ LAH# to form alkenes in good to excellent
yields ð70JA2991Ł[ The protiodethallation of monovinylthallium"III# compounds proceeds with
Cp2ZrCl2 E+
R R Cl R
Zr E
LiEt3BH Cp 80–93%
THF Cp
E+ = H2O, D2O, I2, NBS
E = H, D, I, Br
Scheme 18
retention of con_guration of the alkene upon heating in AcOH ð63BCJ1552Ł or by reduction with
NaBH3 in protic solvents "Equation "88## ð70JCS"P0#880Ł[
Vinyl mercurials are cleaved to the corresponding alkene by either protonolysis or reduction\
both methods being dealt with in extensive reviews ð67T1716\ B!74MI 009!91\ 80COS"7#724Ł[ The ace!
toxymercuration of alkynes\ with subsequent hydrolysis of the intermediate vinyl mercurial\ is an
important route to stereochemically pure alkenes ð79JCS"P0#0987Ł[ Protodemercuration of a range of
alkylphenyl alkynes with AcOH takes place with strict retention of con_guration at the site of
substitution[ A combination of HCl:NaI has been used for the demercuration of vinyl mercurials
"Scheme 08# ð74JA0615Ł[
OAc
Ph Tl OAc NaBH4
Ph D
(99)
AcO Tl Ph THF, D2O AcO D
OAc
O-TMS O O D
HgCl2 HgCl DCl, NaI
CH2Cl2, HMDS 83%
HMDS = hexamethyldisilazide (Z) >95%
Scheme 19
A non!cage free radical mechanism is thought to operate during the NaBH3 mediated reduction
of organomercurials ðB!74MI 009!90Ł[ Interestingly LAH appears to have been little used to e}ect
reductions of this type[ The main problem encountered on reduction of organomercurials is reverse
deoxymercuration^ this di.culty is usually overcome by using a basic homogenous reaction medium[
Use has been made of NaBH3 in NaOH for e}ectively cleaving vinylmercurials ð73JOC2300Ł[
The use of phase transfer catalysis is a powerful methodology for cleavage of vinyl mercurials
where competing side reactions have proved troublesome[ The reduction of vinyl mercurial with
NaBH3 in CH1Cl1 has been carried out with benzyltriethylammonium chloride as the phase transfer
catalyst "Equation "099## ð68S780\ 72TL2886Ł[
R1 R1
NaBH4, Et3N+BzCl
R2 R2 (100)
N CH2Cl2 N
>35%
R3 HgCl2 R3
The mercury atom in a vinyl mercurial is susceptible to HgÐmetal exchange[ This exchange
process\ followed by protonolysis\ leads to e.cient alkene formation[ Bis"halogenomercurio#methyl!
enecyclohexanes were transmetallated with either lithium metal or ButLi[ After one hour the reaction
was quenched with D1O leading to the formation of exocyclic methylene compounds in ca[ 49)
yield ð73AG"E#113Ł[ Zinc dust in AcOH was utilised to reduce vinyl mercurials where the more
standard NaBH3:NaOH conditions gave divinyl mercurials ð71JOC2696Ł[ Miscellaneous methods
for reducing organomercurials include NaÐHg amalgam ð71JOC2696Ł and reaction with thiols
ð72JA0287Ł[
Eaborn and co!workers studied the destannylation of a variety of b!trimethylstannylstyrenes
under both acidic "AcOHÐMeOH# and basic "NaOHÐMeOH# conditions[ A number of signi_cant
factors including double bond geometry\ substituents and reaction conditions were observed to play
By Addition 344
a major role in determining the rate of sp1!C0Sn bond cleavage ð79JOM"190#122Ł[ Kinetic data are
available for the protonolysis of vinyl trialkylstannanes on treatment with HClÐMeOH ð71OM475Ł[
Stereoselective syntheses of three insect sex pheromones including "5"E#\ 00"Z##!hexadeca!5\00!
dien!0!yl acetate "from the wild silkworm Antheraea polyphemus# have been reported ð73JOC4064Ł[
In the _nal step of the synthesis the "E#!double bond was generated by stereospeci_c protonolysis
of both vinyl stannane and vinyl borane moieties with AcOH "Equation "090##[ Comins and
co!workers reported a synthesis of dihydrocannivonine\ the intermediate vinyl stannane being
destannylated using oxalic acid ð73TL3756Ł[ A series of a!methylene!g!valerolactones was synthesised
using an intramolecular radical cyclisation of acetylenic ketones onto propiolates ð89TL4928Ł[ The
resultant vinyl stannanes were protonolysed by treatment with HCl in diethyl ether[
9-BBN SnBu3
AcOH
(101)
( )5 ( )5
AcO AcO
Casson and Kocienski transmetallated a series of a!alkoxyvinyl stannanes with BuLi leading to
formation of the corresponding a!alkoxyvinyllithiums[ Protonolysis with D1OÐH1O led to formation
of enol ethers "Scheme 19# ð82SL0022Ł[ The cleavage of poly~uorovinylstannanes has been inves!
tigated ð50JOC1823Ł[ The ~uorostannyl alkenes were treated with reagents such as iodine\ HBr\
AcOH and EtONa[ It was found that 1C0Sn bond cleavage took place a great deal more readily
in the per~uorovinylstannyl series than with the corresponding protiovinylstannanes[
SnBu3 Li D
BunLi D2O
Bun O THF Bun O Bun O

quantitative
Bn Bn Bn
Scheme 20
0[09[1 ONE OR MORE 1C0H BONDS BY ADDITION
0[09[1[0 Addition to Alkynes
0[09[1[0[0 Addition of hydrogen to alkynes

A vast array of synthetic methodologies exist for reducing an alkyne to an alkene[ These include]
"i# hydrogenation under the in~uence of both heterogenous and homogenous catalysis\ "ii# dissolving
metal reductions\ "iii# transition metal:complex hydride reductions\ "iv# hydrometallations\ with
subsequent hydrolysis\ and "v# catalytic hydrogen transfer under both heterogenous and hom!
ogenous catalysis[ Each method will be described in more detail later in the article with comment
on the stereospeci_city\ mechanism and e.ciency where appropriate[
"i# Addition of hydroèn to alkynes by heteroèneous catalysts

The hydrogenation of alkynes under heterogenous catalysis is featured in many reviews
ðB!73MI 009!90\ 74CRV018\ B!74MI 009!90\ 80COS"7#306Ł[ Generally palladium!\ platinum! and nickel!
based catalysts are used\ the metals being dispersed on inert supports such as carbon or silica[
Polymer bound PdCl1!based catalysts have been introduced more recently with some success
ð68MI 009!90Ł[ Reactions are generally carried out under an H1 atmosphere\ typically 0Ð29 atm[
Hydrogenations of this kind must be carefully monitored to ensure semihydrogenation occurs\
signi_cant yields of over!reduced products being widely reported ð80COS"7#306Ł[ Addition of amines\
particularly pyridine and quinoline\ are used to halt the hydrogenation at the alkene level[ The most
frequently used heterogenous catalyst is the Lindlar catalyst\ PdÐCaCO2\ Pd"OAc#1 poisoned with
quinoline ð62OS779Ł[ Alkynes reduced with this catalyst generally give "Z#!alkenes\ the reaction
being most selective at low temperature ð66T346Ł[
The vast majority of palladium! and nickel!based heterogenous hydrogenation catalysts give
higher yields of the less thermodynamically stable "Z#!isomer\ though the actual mechanism is not
well understood ð80COS"7#306Ł[ Analogies have been made with the syn!addition of hydrogen
observed by mononuclear homogenous hydrogenation catalysts as studied by Muetterties et al[
ð70ICA0Ł[
Good chemoselectivity is observed with catalysts of this type[ Chemoselective reduction of triple
bonds in the presence of conjugated and non!conjugated double bonds is known ð62S346Ł[ The
reduction of diynes leads to the formation of ""Z#\"Z##!alkenes ð66T0734Ł[
Developments in heterogenous hydrogenation catalysis include the use of _nely divided palladium
metal dispersed in a siloxane polymer matrix ð89JOC2341Ł[ The catalyst is reported to be highly
stereoselective\ reducing dec!4!yne to dec!4!ene in a 19 ] 0 ratio of ""E# ] "Z## stereoisomers\ in
quantitative yield "Equation "091##[ Kuno and co!workers reported the use of a Pd!zeolite catalyst\
modi_ed with diphenyldiethoxysilane\ for the stereospeci_c reduction of alkynes to alkenes
ð81CL0614Ł[
Pd(OAc)2, (EtO)3Si
Bun Bun Bun Bun
(102)
THF, H2O
100%
"ii# Addition of hydroèn to alkynes by homoèneous catalysis

The reduction of alkynes by hydrogenation under homogenous catalysis is the subject of many
reviews ð65OR"13#0\ 71COMC!I"0#010\ 80COS"7#332Ł[ Alkynes were reduced to alkenes using Wilkinson|s
catalyst ðRhCl"PPh2#2Ł ð70MI 009!90Ł in benzene containing either phenol or 1\1\1!tri~uoroethanol
ð57MI 009!90Ł[ Similarly hydrogenations using D1 and ðRh"COD#"PPh2#"Py#ŁPF5 as the catalyst
converted phenylacetylene into "Z#!PhD1CHD ð66JOM"030#002Ł[ In the presence of ðRhH"PMe1
Ph#4ŁPF4 internal and terminal alkynes are reduced to alkenes ð74JMOC102Ł[ Dinuclear rhodium
and iridium complexes of the type Rh1"m!X#"CO#1"Ph1ECH1EPh1#1¦ and ðIr1Cl"CO#2Ph1PCH1PPh1#1Ł
were reported to be potent alkyne hydrogenation catalysts ð71CJC0252Ł[
Novel areneÐCr"CO#2 complexes are known to catalyse a variety of synthetic transformations
ð82S532Ł[ Catalysts of the form MBz = Cr"CO#2 and NP = Cr"CO#2\ "MBzmethyl benzoate and
NPnapthalene# are known to reduce disubstituted alkynes with high stereospeci_city and yield
"76Ð099)# to form the "Z#!alkenes "Equations "092# and "093## ð74JOC0036Ł[
MBz•Cr(CO)3•H2
(103)
OH
Me2CO
95%
OH
NP•Cr(CO)3•H2
(104)
THF
92%
This methodology is reinforced by many other organometallic catalysts which have exhibited
good stereoselectivity for the synthesis of "Z#!alkenes[ These include Ti"Cp#1"CO#1 ð55BCJ0067Ł\
Ti"Cp#1Cl1 ð75CC0206Ł\ and the iron cluster m4!C4H4Fe!m2!"CO#3 ð68JOM"067#32Ł[
The formation of "E#!double bonds by catalytic hydrogenation via homogenous catalysis is
an uncommon transformation[ Acetylene dicarboxylic acid dimethylester is reduced to dimethyl
fumarate by hydrogen in the presence of RhH1"h1!O1COH#"P0Pri2#1[ The rhodium complex was
reported to catalyse the isomerisation of "Z#! to "E#!alkene bonds "Equation "094## ð72JA5162Ł[
[RhH2(O(CO)OH)(PPri3)2]
MeO2C
MeO2C CO2Me (105)
H2
CO2Me
"iii# Addition of hydroèn to alkynes by other methods

"a# Dissolvin` metal reductions[ The discovery that alkynes were stereospeci_cally reduced to
"E#!alkenes by Na:NH2"l# was a major breakthrough in organic synthesis ð30JA105Ł[ This method
By Addition 346
then complemented the known methods for synthesising "Z#!alkenes and it remains powerful
methodology[ Variations on this theme include reductions with Li:RNH1 ð44JA2267Ł\ Na:HMPA
ð63JOC636Ł and Yb:NH2 ð67JOC3444Ł[ Calcium:RNH1 mixed solvent systems has also been used to
perform alkyne reductions but problems are encountered with extensive double bond migration
ð73JOC0551Ł[ Alkyne reduction has also been carried out with zinc either in combination with
BrCH1CH1Br or as a ZnÐCu couple "Equation "095## ð79TL0958Ł This reduction tends to give "Z#!
products[ Little work appears to have been done to determine the mechanism of reduction with
zinc[
Zn/Cu
R R (106)
MeOH R R
95%
R = Ph, CH2OH
Dissolving metal reductions exhibit reasonable chemoselectivity\ tolerating many functionalities

including acetals\ ethers and acetates[ The reduction of enynes leads to preferential reduction of the
triple bond ð73CC624Ł[
"b# Catalytic transfer hydroènation[ The catalytic transfer hydrogenation of alkynes to alkenes
has been reviewed ð74CRV018\ 63CRV456Ł[ The reaction can be carried out under both heterogenous
ð79JOC3815Ł and homogenous ð78TL3546Ł palladium catalysis\ though both methods have been
plagued by over!reduction and the formation of ""E# ] "Z##!isomer mixtures[ A report highlights the
use of homogeneous palladium"9# catalysis for the preparation of "Z#!alkenes in high stereochemical
purity ð82CC275Ł[ Disubstituted alkynes were reduced in 66Ð85) yield using Pd1"dba#2ÐPBu2 as
catalyst and HCO1HÐNEt2 as the hydrogen source "Equation "096##[ A high degree of stereo!
selectivity "×87)# was observed[
[Pd2(dba)3]–PBu3
R1 R2 (107)
HCO2H, Et3N R1 R2
71–98%
R1 = n-C8H17, Ph, Et, n-C5H11

R2 = H, Me, CO2Me, CH2OH
Catalytic transfer hydrogenation reactions exhibit a number of favourable characteristics over

classical hydrogenation reactions\ in that no special apparatus is required\ the reactions are more
economical and considerably less hazard is involved[ Potentially these characteristics will lead to
this type of reaction being exploited more fully[
"c# Low valent metal reductions[ The reduction of alkynes by low valent chromium"II# species
has been reported ð53JA3247Ł[ A number of alkynes were reduced stereospeci_cally to "E#!alkenes
in excellent yield by reaction with CrSO3 in DMF:H1O[ The mechanism leading to the observed
stereochemistry was rationalised in terms of a bis!metallated alkyne intermediate\ with subsequent
hydrogen transfer "Equation "097##[
CrSO4 R1
R1 R2 (108)
DMF, H2O
R2
84–94%
R1 = H, CO2H, Ph, Me, CH2OH

R2 = CH2OH, Ph, CO2H
A stereospeci_c reduction of both terminal and disubstituted alkynes with low valent niobium
and tantalum species has been described ð89TL254Ł[ Dodec!0!yne was reduced with NbCl4 and zinc
in DME:C5H5[ The reaction was quenched with NaOD:D1O to a}ord dideuteriated 0\1!ð1H1Ł!dodec!
0!enes[ Similarly\ low valent tantalum\ formed from the reaction of TaCl4 and Zn gave good yields
of "Z#!alkenes at considerably faster rates than those observed for the low valent niobium reductions
"d# Transition metal hydride reductions[ A wide range of transition metal salts in combination
with LAH\ NaBH3 and other hydride reducing agents are known to e}ect the reduction of alkynes
to alkenes[ Dialkylalkynes are cleanly reduced to "Z#!alkenes by LAH at low temperature in the
presence of NiCl1 ð67JOC1456Ł[ A similar reaction is observed using LAH and stoichiometric quan!
tities of FeCl1 ð67JOC1456Ł[ Sodium borohydride in the presence of cobalt"II# is also an e}ective
NbCl5, Zn NaOH
R1 R2 R1 R2
HMPA, THF, PhH
62–86%
R1 = n-C10H21, Ph, n-C5H11, But, TMS

R2 = n-C10H21, n-C5H11, n-C6H13, n-C7H15
Scheme 21
combination ð68JOC0903Ł[ Related reagent mixtures include MgH1ÐCuI ð67JOC646Ł and NaHÐ
Ni"OAc#1 ð66TL0958Ł[ Synthetically this reaction is restricted to compounds lacking functionality
sensitive to hydride reducing agents[
Alkynes have also been reduced with transition metal salts such as CoCl1 = 3PPh2 and SmI1\ with
ROH as the proton source] "Z#!alkenes were formed in good yield "Equation "098## ð80TL4448Ł[
Interestingly\ addition of HMPA led to a reversal of stereoselectivity[ The use of the copper"I#
hydride reagent ð"Ph2P#CuHŁ5 for selectively reducing terminal alkynes to alkenes and disubstituted
alkynes to "Z#!alkenes has been documented "Equation "009##[ The reaction is highly chemoselective
tolerating propargylic alcohols and acetates[ Related copper"I# hydride {ate| complexes also gave
the corresponding alkene ð89TL1286Ł[
OH CoCl2•4PPh3
Bu Bu C6H13 (109)
AcOH
C6H13 80%
HO
OH [(Ph3P)CuH]6 HO
Ph Ph C6H13 (110)
H2O. PhH
C6H13 76%
"e# Reduction with diimide[ The reduction of alkynes with diimide has been reviewed
ð80COS"7#360Ł[ This reduction has been known for many years and remains a most simple and
elegant way of reducing a triple bond to a "Z#!alkene with high stereospeci_city and chemoselectivity[
The reduction with diimide is extremely chemoselective tolerating ester\ amide\ and allylic halide
functionality[ Iodinated alkenes have been prepared by diimide reduction of 0!iodoalkynes
ð61JA8145Ł[ The main drawback is that dialkylalkenes are as reactive as the starting alkynes\ which
can lead to the production of fully saturated compounds ð80COS"7#360Ł[
The reagent can be generated in many ways\ the most popular method being the oxidation of
hydrazine with molecular O1 or H1O1 in the presence of copper"II# and:or a carboxylic acid
ð50TL236Ł[ The transfer of hydrogen occurs in a syn fashion and generally the reaction proceeds in
high yield\ as in the reduction of diphenylacetylene to "Z#!stilbene ð50TL236Ł[ The high degree of
stereoselectivity was fully exploited during Cornforth|s synthesis of chiral acetate ð58NAT0101Ł[
"f# Hydrometallation of alkynes to alkenes[ The hydrometallation of alkynes with boron\ alumi!
num\ zirconium and other metals with subsequent hydrolysis of the metalÐalkene bond is covered
in other sections of this article[
0[09[1[0[1 Addition of C0H to alkynes

The addition of C0H to alkynes is reviewed in Chapter 0[01[
0[09[1[1 Addition to Allenes
0[09[1[1[0 Addition of hydrogen to allenes

Allenes are important synthetic intermediates due to their ability to react with nucleophiles\
electrophiles and radical species and their chemistry has been extensively reviewed ðB!79MI 009!90\
B!71MI 009!90\ B!73MI 009!91\ 82S054Ł[ The semihydrogenation of allenes to alkenes has been successfully
achieved by hydrogenation under both heterogeneous and homogeneous catalysis[ Allenes have
By Addition 348
also been reduced to alkenes by] "i# dissolving metal reductions\ "ii# diimide and "iii# by complex
hydrides[
Heterogeneous catalytic hydrogenation over both palladium and platinum have been described[
On addition of D1 to buta!0\1!diene using palladium on alumina as catalyst three products were
formed\ "Z#!but!1!ene\ "E#!but!1!ene and but!0!ene in the ratio 39 ] 42 ] 6 respectively ð52JA1770Ł[
Reduction of allenes over platinum catalysts tends to lead to complete saturation of both allene
double bonds ðB!73MI 009!91Ł[
Wilkinson|s catalyst\ RhCl"PPh2#2\ was investigated for the reduction of allenes to alkenes
ð61TL0280Ł[ The reduction proved to be regiospeci_c and highly stereoselective for acyclic allenes
such nona!0\1!diene and 2!ethylpenta!0\1!diene "Equation "000##[ However\ a low rate of conversion
was observed with nona!0\1\5!triene[ It was thought that this may be due to the ability of the triene
and the product dienes to coordinate to Rh[
• H2, RhCl(PPh3)3
(111)
( )5 ( )5
66%
The diisobutylaluminum hydride "dibal!H# reduction of allenes has been investigated ð79TL40Ł[
Addition of dibal!H at room temperature or at 59>C led to the formation of an intermediate
vinylalane\ which\ on protonolysis\ yielded an alkene[ It was found that the more substituted double
bond of an allene was selectively reduced\ leading to the formation of an alkene product with
the opposite regioselectivity observed for reduction by catalytic hydrogenation "Equation "001##[
Reduction of an allenyl silane with dibal!H gave a mixture of two products in the ratio 68 ] 10[ The
products were identi_ed as the vinyl silane and 0!trimethylsilyldecane "Equation "002##[
n-C7H15 dibal
n-C8H19 + n-C10H22 (112)
• 83%
96% 4%
n-C7H15 TMS dibal n-C8H19

• + n-C10H21-TMS (113)
74%
TMS
79% 21%
Diimide preferentially reduces allenes to "Z#!alkenes[ The reagent reduces the less substituted end
of the allene and does so via approach from the less hindered face[ Reductions of this type can be
complicated by overreduction to alkanes because allenes and alkenes have similar reactivities
towards diimide[ However\ nona!0\1!diene is reduced to "E#!nona!1!ene in 21) yield^ only a small
amount "ca[ 0)# of the "Z#!isomer was observed ð79JOC0593Ł[ Cyclic allenes for example cyclonona!
0\1!diene and cyclonona!0\1\5!triene were e.ciently converted to "Z#!cyclononene and ""Z#\"Z##!
cyclonona!0\4!diene\ respectively ð69TL3132Ł[ Cyclopropylallene was regio! and stereospeci_cally
reduced to the corresponding vinylcyclopropane[ "Equation "003## ð62TL1406Ł[ Dissolving metal
reductions\ particularly NaÐNH2"l# have been used extensively for reducing allenes to alkenes[
Acyclic alkyl allenes "e[g[\ octa!0\1!diene and nona!0\1!diene# give excellent yields of the cor!
responding 1!"E#!alkenes when treated with NaÐNH2"l# ð69JOC236Ł[ Interestingly\ nona!1\2!diene
yielded an equimolar mixture of "E#!non!1!ene and "E#!non!2!ene in 74) yield[ The dissolving!
metal reduction of phenyl substituted allenes gave primarily alkyl benzenes[
Ph Ph
N2H2
• (114)
The reduction of a series of 0\1!cyclic allenes "from cyclonona!0\1!diene to cyclotetradeca!0\1!

diene# with NaÐNH2"l# was investigated in the presence and absence of a proton source "EtOH#
"Scheme 11#[ Profound di}erences in product ratios were observed ð60TL1964Ł[ More "E#!alkene
was formed in the presence of a proton donor and it was suggested that this re~ected the intermediacy
of a more stable "E#!allylic radical species[ ""Z#\"Z##!Cyclonona!0\4!diene ð56JOC3032Ł and ""Z#\"Z##!
cyclodeca!0\5!diene ð57CJC73Ł were prepared by dissolving!metal reduction of cyclonona!0\1\5!
triene and cyclodeca!0\1\5!triene respectively "Scheme 11#[ Reduction of trisubstituted cyclic allenes
under these conditions is both regiospeci_c and stereoselective ð64S083Ł[ 0!Methylcyclonona!0\1!
diene gave predominately "Z#!0!methylcyclonon!0!ene[ Cyclopropyl allenes on reduction with NaÐ
NH2"l# led to 0 ] 0 mixtures of "E# ] "Z#!vinylcyclopropanes in ca[ 69) yield "Equation "004##
ð67TL2372Ł[
Na, NH3 (l)

•
80%
Na, NH3 (l)
76%
Scheme 22
Et Na, NH3 (l)

• Et (115)
70%
(E):(Z) 50:50
0[09[1[1[1 Addition of C0H to allenes

The addition of C0H to allenes is reviewed in Chapter 0[01[
1.11
One or More 1CC Bond(s)
Formed by Substitution or
Addition
PATRICK G. STEEL
University of Durham, UK
0[00[0 INTRODUCTION 350
0[00[1 BY SUBSTITUTION 351
0[00[1[0 Substitution of Haloèn 351
0[00[1[0[0 Substitution of alkyl halide 351
0[00[1[0[1 Substitution involvin` vinyl halides 355
0[00[1[0[2 Substitution of aryl halides 369
0[00[1[1 Substitution of Oxyèn 364
0[00[1[1[0 Substitution of alkylÐoxyèn leavin` `roups 364
0[00[1[1[1 Substitution of alkenylÐoxyèn leavin` `roups 368
0[00[1[1[2 Displacement of arylÐoxyèn leavin` `roups 371
0[00[1[2 Substitution of Other Chalcoèns 372
0[00[1[2[0 Substitution of alkylÐchalcoèn leavin` `roups 372
0[00[1[2[1 Substitution of alkenyl! or aryl!chalcoèn leavin` `roups 373
0[00[1[3 Substitution of Nitroèn 375
0[00[1[4 Substitution of Boron 376
0[00[1[5 Substitution of Silicon and Germanium 378
0[00[1[6 Substitution of a Metal 389
0[00[1[7 Substitution of Hydroèn 381
0[00[1[7[0 FriedelsÐCraft alkylations usin` alkenes and alkanes 381
0[00[1[7[1 Orànopalladium!mediated substitution of alkenes 382
0[00[1[7[2 Miscellaneous methods 384
0[00[2 BY ADDITION 384
0[00[2[0 Nucleophilic Addition to Allenes 384
0[00[2[1 Free Radical Additions to Allenes 386
0[00[2[2 Cycloaddition Reactions Involvin` Allenes 386
0[00[2[3 Carbene Additions to Allenes 388
0[00[0 INTRODUCTION
Although this chapter is concerned with the formation of C0C1 bonds by substitution or
addition\ a liberal view has been taken of the mechanistic interpretation of these classi_cations[
Consequently\ many processes that are only formally substitution processes have been included\ for
example\ addition:elimination and cross!coupling reactions[ In this respect a signi_cant number of
these procedures can be considered as substitutions in either direction[ However\ in order to minimise
repetition most have only been listed once and the interested reader is advised to consider both
possibilities[
350
351 1C0C Bonds by Substitution or Addition
0[00[1 BY SUBSTITUTION
0[00[1[0 Substitution of Halogen
0[00[1[0[0 Substitution of alkyl halide
"i# FriedelÐCrafts alkylation

Alkylation of aromatic and unsaturated aliphatic hydrocarbons with alkyl halides is dominated
by the FriedelÐCrafts reaction ð0773AC"P#338Ł[ This particular method has been the subject of a
number of reviews and monographs ð80COS"2#182Ł[ Although both classes of hydrocarbons undergo
the reaction under similar conditions\ the synthetic utility of alkene alkylation is limited since it
tends to produce complex product mixtures through competing alkene oligomerisation ð71MI 000!
90Ł[ Although much of the work on this reaction has been carried out using alkyl halides these are
not the only species to undergo the reaction^ alkanes\ alkenes\ alkynes\ alcohols\ ethers\ epoxides
and certain carboxylic acid derivatives are also viable electrophiles[ The use of these species will be
discussed where appropriate elsewhere in this chapter[
The reactivity of the alkyl halides decreases down the group F×Cl×Br×I[ Although the use
of alkyl ~uorides can lead to selective reactions "Equation "0## ð53JOC1206Ł\ the low cost and ready
availability of alkyl chlorides and bromides make these compounds the most commonly used
reagents[ The use of alkyl iodides is limited owing to problems of side reactions and:or decompo!
sition[ A similar trend in reactivity is found in the nature of the alkyl moiety\ with benzyl and
tertiary halides being the most reactive^ followed\ in order\ by secondary\ primary and methyl
halides[ However\ steric factors can a}ect this order "see below#[
Cl
BF3, –10 °C, 30 min
+ Cl F (1)
91%
The general class of catalysts and co!catalysts is large and includes acidic halides and chalco!
genides\ metal alkyls\ acidic cationÐexchange resins\ protic acids\ and Bro nstedÐLewis superacid
combinations[ There have been a number of attempts to order these\ particularly the Lewis acids\
according to their reactivity ð61JA6337\ 74MI 000!90Ł[ With the exception of the solid supported
reagents most of these species are moisture sensitive and cannot be recycled[ However\ lanthanide
trihalide compounds are e.cient catalysts for the alkylation of a wide range of aromatic substrates
and can be recovered\ after aqueous workup of the reaction mixture\ and reused with no signi_cant
loss of catalytic activity ð75CL246Ł[
Alkylation of arenes with primary alkylhalides frequently a}ords products derived from iso!
merisation of the initially formed carbocation[ For example\ alkylation of toluene with n!propyl!
chloride a}ords only a mixture of isopropyltoluenes ð68NJC158Ł[ Similar side reactions including
isomerisation and hydride transfer products are also observed with higher halides "Scheme 0#
ð47JA4756\ 68CL0992Ł[ In the latter example\ alkylation by the tertiary pentyl carbocation is retarded
due to unfavourable steric factors\ thus permitting the contrathermodynamic carbocation rearrange!
ment to the corresponding sec!pentyl species[ A similar result was obtained commencing with
methylbutene[ This tendency for isomerisation to precede alkylation can be suppressed by the
incorporation of electron!accepting groups such as 0CO1H\ 0CO1Me and 0CN into the alkyl
chain "Equation "1## ð76BAU216Ł[ An alternative pathway for the alkylation of arenes\ which avoids
the problems of isomerisation\ is via the reduction of the corresponding aryl ketone prepared by a
FriedelÐCrafts acylation reaction[
AlCl3 R R
+ Cl R + (2)
R= Me 76% 24%
R= CO2H 2% 98%
R= COMe 0% 100%
R= CO2Me 0% 100%
By Substitution 352
O O
O O O
O
RCl
+ + + +
HF-SbCl5
–20 °C, 5 min
Bu
R= Bu 15% 3% 55% 7% 20%
R= 17% trace 57% 7% 19%
R= 21% 9% 67% 3% 0%
AlCl3 or FeCl3 or
Cl +
AlCl3•MeNO2
Scheme 1
Asymmetric induction may be observed in the FriedelÐCrafts reaction[ For example\ both "−#!
1!chloro!0!phenylpropane "0# and "¦#!0!chloro!1!phenylpropane "1# react with benzene in the
presence of aluminum trichloride to a}ord "−#!0\1!diphenylpropane "3# ð72BCJ0978Ł[ To account
for the retention of con_guration\ this reaction is postulated to proceed via a double inversion
mechanism involving the phenonium intermediate "4# "Scheme 1#[ Similar intermediates are sug!
gested to occur in the reaction of 0\1!dihaloethanes ð49JGU349Ł and reactions commencing with
optically active 0\n!dihaloalkanes proceed with moderate stereoselectivity ð79CC75Ł[ However\ in
many of these reactions with polyhaloalkanes\ complex product mixtures result due to competing
isomerisation\ polysubstitution and dehydrogenation pathways ð52CA"48#1621\ 55JOC2484Ł[ Other
examples of asymmetric arene alkylation exist[ However\ many of these are heteroatom assisted
ð76AG"E#572Ł and\ as such\ are beyond the scope of this chapter[
AlCl3, 0 °C AlCl3, 0 °C
C6H6
Ph C6H6 Ph
Ph Ph Cl
Et +
Cl 62% Ph Ph 60%
(1) (3) (4) (2)
From (1) 24% 76%
From (2) 25% 75%
+ AlCl4–
(5)
Scheme 2
"ii# Substitution by orànometallic sp1 carbanions

CarbonÐcarbon bond!forming reactions between vinylic organometallic species and a range of
electrophiles has been comprehensively reviewed ð80COS"2#130Ł[ The range of alkylating agents
involved is large and varied and includes alkyl halides\ alkyl tosylates\ epoxides\ esters and related
derivatives[ Each of these will be considered where relevant in this chapter[
Nominally\ the most direct method for the formation of this unit is the WurtzÐFittig reaction in
which an alkylated aromatic is generated through the sodium metal mediated coupling of an aryl
bromide and an alkyl iodide ð58T4660Ł[ However\ the yields are not good and the same result is best
achieved in two discrete steps[ In this respect the SN1 alkylation of a vinyl! or aryl Grignard or
lithium species with an alkyl halide provides the simplest entry to this structural class ð64S323Ł[
Vinyllithiums combine e.ciently with primary alkyl bromides and iodides\ but alkyl chlorides a}ord
much lower yields[ The reaction is not e.cient in solvents other than THF\ nor does it proceed
with secondary alkyl halides[ Similar coupling reactions of organomagnesium reagents in THF or
hexamethylphosphoramide "HMPA# have also been reported ð55BSF0777Ł[ Trisubstituted alkenes
can be prepared in this fashion\ indicating that steric bulk in the vinyl anion moiety is not a
problem[ Since alkene isomerisation is not normally observed\ then\ provided clean generation of
the vinyllithium is possible\ either cis or trans alkenes can be prepared[ Under certain conditions
some chemoselectivity can be observed[ For example\ in the presence of TMEDA vinyllithiums
undergo selective monoalkylations with a\v!dibromoalkanes ð63JA6090Ł "however\ see ð89SC1238Ł#[
Cycloalkylation is also possible\ although apart from lithium\ the use of other "v!haloalkenyl#
organometallics "Al\ Zn\ Zr\ Si# requires the presence of an additional silyl or second metal group
on the metal bearing carbon ð77JA4272Ł[
This chemistry can easily be extended to allenyllithiums which are readily generated by either
direct deprotonation or lithiumÐhalogen exchange[ These couple e.ciently and rapidly with primary
alkyl bromides or iodides to produce substituted allenes ð64CC450Ł[ Competing formation of the
corresponding alkyne can be suppressed by careful control of the reaction conditions and the
presence of additives such as HMPA ð68TL826Ł[
Due to transmetallation and other competing pathways many vinylic and aryllithium species do
not combine e.ciently with allylic halides[ In these cases the use of the corresponding Grignard
reagent\ either prepared directly or via transmetallation with magnesium bromide\ can circumvent
this problem ð73JOC626Ł with the reaction proceeding in ethereal solvents at ambient temperatures[
The use of other transition metals such as zinc and copper as transmetallating agents also proves
satisfactory "see below#[ However\ even with these modi_cations the use of nonpolar solvents or
less reactive alkyl halides requires elevated temperatures for the e.cient coupling with aryl and
vinyl Grignard reagents[ a!Haloketones combine with aryl Grignard reagents in a two!step process\
involving initial carbonyl attack followed by a "0\1# aryl migration of the intermediate magnesio!
halohydrin "Scheme 2# ð48JOC732Ł[ Vinyl Grignard reagents behave similarly ð62CL556\ 70TL1132Ł
and in this respect it has been noted that\ although both a!chloro and a!bromo ketones are substrates\
the former are more e.cient[ Tertiary chlorides also undergo this rearrangement and this provides
an e.cient entry into quaternary vinyl!substituted carbon centres "Equation "2##[ The conceptually
similar reaction of a!haloketones with phenylcopper reagents fails due to competing reduction[
However\ a!arylketones may be obtained from the reaction of a!bromoketones with arylboranes
ð58JA5741Ł\ or the coupling of phenylcopper reagents with in situ generated a!bromoenamines
ð76JOC2586Ł or a!halotosylhydrazones ð64JA6261Ł[
O BrMgO Ar O
Cl ArMgBr Cl –BrMgCl Ar
Et2O-PhH, ∆
Ar = Ph, 68%
Ar = p-tolyl, 68%
Ar = m-anisyl, 52%
Ar = α-naphthyl, 50%
Scheme 3
O OH
i, MgBr , THF, 0 °C, 2 h
Cl (3)
ii, MgBr , reflux, 3 h
60%
By Substitution 354
The scope of these reactions between aryl and vinyl Grignard and lithium reagents can be greatly
extended through the use of copper salts[ Primary iodides and tosylates "see below# react in the
presence of copper"I# iodide under much milder conditions than those required for direct alkylation
ð81OR024Ł[ In this respect a common strategy is to generate the lithium divinyl! or diarylcuprate\
R1CuLi[ These react e.ciently with both primary alkyl iodides and bromides\ and activated sec!
ondary halides[ In many cases additional additives\ for example\ phosphines\ sul_des\ etc[ are
required\ whilst the choice of solvent can also prove to be crucial ð65OS"44#092Ł[ One problem with
the use of this methodology is the loss of 0 equiv[ of a potentially valuable aryl or alkenyl unit[ In
certain cases\ such as those involving reactive alkylating agents "e[g[\ allylic halides# the use of
HMPA can promote e.cient transfer of both vinyl groups[ With less reactive electrophiles the
addition of 2 equiv[ of triethylphosphite has been shown to promote the second alkylation ð68S715Ł[
This problem is avoided through the use of either heterocuprates containing nontransferable ligands
ð76JOC0774Ł or higher order cuprates ð76S214Ł[ These latter species frequently provide for greater
reactivity when compared with their homocuprate analogues[ For example\ the higher order vinyl!
cuprate "8# reacts smoothly with the secondary alkyl iodide "5# whereas the corresponding homo!
cuprate "7# does not "Equation "3## ð70JA6561Ł[ In contrast\ whilst the analogous aryl species\
Ph1Cu"CN#Li1\ reacts with primary chlorides but does not couple with secondary iodides\ the
corresponding homocuprate\ Ph1CuLi\ combines e.ciently with both primary and secondary bro!
mides[ These reactions are predominantly SN1 processes as evidenced by the almost complete
inversion of stereochemistry observed with enantiomerically pure substrates[ In all of these trans!
formations there is almost complete retention of alkene geometry ð60HCA0828Ł[
)2 M
I
(4)
THF, 0 °C, 6 h
(8) M = CuLi, 23%
(6) (9) M = Cu(CN)Li2, 90% (7)
With Grignard reagents a substoichiometric amount of the copper species can be used[ As with
the organolithium!derived reagents these species show considerable di}erences in reactivity when
compared with the parent species[ For example\ the direct coupling with haloacetates and halo!
alcohols is possible ð66TL2152Ł[ A further degree of chemoselectivity is observed with copper!
catalysed organomanganese chloride reagents which\ in the presence of N!methylpyrrolidine "NMP#\
selectively and e.ciently alkylate primary bromides in the presence of chlorides\ sulfonates\ acids
and esters ð82SL34Ł[ A CuXÐTMEDA catalyst system has been demonstrated to be a useful com!
bination for the alkylation of aryl Grignard reagents with primary iodides and benzylic halides
ð61BCJ1471Ł[ However\ as with the stoichiometric reactions these catalytic methods tend to give
much lower yields with less reactive electrophiles[ Some improvements in reactivity can be realised
through the use of dilithium tetrachlorocuprate ð60S292Ł although in some cases excess Grignard
reagent is required for good yields to be obtained[ Iodides ð60S292Ł and tosylates ð63AG"E#71Ł "see
below# provide the best substrates[
Similar catalysis of vinyl carbanion alkylation can be achieved through the use of other transition
metal catalysts[ Besides organolithium and Grignard reagents a variety of other carbanionic species
have been used including those based on B\ Al\ Sn\ Zr\ Cd and Hg ð80COS"2#324Ł[ In this respect
complexes of nickel and palladium are particularly prominent[ In addition to allylic halides these
catalysts have found applications to alkylations with a variety of other allylic electrophiles with a
particular emphasis on those containing oxygenated leaving groups "see below#[ The use of unac!
tivated C sp2 electrophiles is limited by competing reduction and b!hydride elimination[ The latter
problem can be overcome through the use of B!alkyl!8!BBN "8!BBN8 borabicycloð2[2[0[Łnonyl#
derivatives ð80PAC308Ł "below#\ whilst the use of diorganozincs derived from arylmagnesium chlor!
ides "not bromides# permits e.cient coupling with relatively unreactive neopentyl iodides
ð82JOC3755Ł[ Of the other vinylmetallic species employed\ those containing aluminum and zirconium
are of particular importance since they can readily be accessed through the hydrometallation of the
corresponding alkyne[ Although simple alkylation is only e.ciently observed with reactive alkyl
halides\ for example\ MOM!Cl "MOMmethoxymethyl# ð65S514Ł\ enhanced reactivity is realised
through the formation of the corresponding {ate| complex ð73OR"21#264Ł[ Alternatively\ productive
alkylation of these and other related vinyl organometallics is possible in the presence of an additional
transition metal catalyst "above#[
a!Aryl carbonyl compounds can be obtained through the nickel phosphine catalysed coupling of
arylzinc reagents with a!haloesters ð72OM487Ł and a!halonitriles ð76S39Ł[ The corresponding cad!
mium reagents can be alkylated with primary and secondary a!bromoesters and secondary allylic
bromides but fail to combine e.ciently with simple alkyl bromides and a variety of related electro!
philes ð62JOC2078Ł[ These latter reactions proceed via free radical intermediates\ as evidenced by
ESR spectroscopy and the complete loss of optical activity when R!"¦#!bromopropionate was used
as the electrophile[
0[00[1[0[1 Substitution involving vinyl halides
"i# Alkyl nucleophiles

Although the direct reaction of C sp2 organometallic reagents with sp1 halides is known\ most of
these couplings proceed by initial metalÐhalogen exchange followed by nucleophilic substitution in
the reverse direction ð82JOC4865Ł "for alkenyl organometallics and alkyl halides\ see Section
0[00[1[0[0"i##[ However\ with some ~uoroalkenes a SNV "nucleophilic vinylic substitution# process is
observed with both organolithium and Grignard reagents "Scheme 3#[ However\ the initial product
can readily undergo further reaction to form the corresponding acetylide ð77BCJ0514Ł[
F Cl F Cl
excess RM
PhM + Ph M
F Cl Ph Cl
M = Li, 60%
M = Mg, 85%
Scheme 4
Alkyliron\ !cobalt and !copper reagents may be employed for the substitution of both alkenyl
and aryl bromides\ chlorides and ~uorides in good yields[ The use of Me3FeLi1 provides useful
levels of discrimination between di}erent halogens[ The coupling may also be achieved using a
substoichiometric quantity of FeCl1 together with the appropriate Grignard reagent ð82CB0336\
57JA4504Ł[ In general\ the use of a transition metal catalyst is necessary for the e.cient substitution
of alkenyl halide[ These processes are of much synthetic use since they proceed with retention of
alkene stereochemistry\ providing good routes to di!\ tri! and tetrasubstituted alkenes[ Alkenyl
halides may be coupled with alkyl!\ vinyl! or aryllithiums in palladium\ ruthenium or rhodium
catalysed processes ð68JOC1397Ł[ However\ the use of organolithium reagents in these reactions is
not normally as e.cient as that of the corresponding Grignard or organozinc species[ The range of
catalysts used is large\ with those based on nickel being the most widely used[ A great variety of
nucleophiles "alkyl\ aryl and alkenyl Grignard# and alkenyl halides "iodide\ bromide\ chloride and
even ~uorides ð62JOM"49#C01Ł# can be coupled with this reagent combination ð65BCJ0847\ 67OS"47#016Ł[
The reactions are strongly exothermic and care must be taken to add the Grignard reagent slowly
to the catalyst and alkenyl halide[ Alkenyl Grignards are somewhat less reactive and\ whilst
cyclohexyl Grignards couple smoothly under nickel catalysis\ the use of other secondary Grignard
reagents\ with either nickel or palladium catalysts\ frequently results in alkene isomerisation[ This
isomerisation is varied and the extent depends considerably on the nature of all three reaction
partners ð62JOM"49#C01\ 73JA047\ 75JOM"201#232Ł[ In this respect alkenyl bromides tend to be the halides
of choice\ since depending on the particular catalyst\ both the presence of b!hydrogen atoms and
also some degree of branching are acceptable within the Grignard component[ Chiral alkenyl
ð73TL4658Ł and allenyl bromides ð80JOM"306#178Ł can be coupled e.ciently with a variety of organo!
metallic reagents under transition metal catalysis with little deterioration of optical integrity[
However\ the stereochemical outcome can depend dramatically on the speci_c conditions[ Whereas
alkylation of the more reactive allenyl iodides occurs with retention of con_guration\ chloro! and
bromoallenes react predominantly by an invertive pathway ð74JOC2931Ł[ This can lead to the fully
substituted\ enantiomerically pure\ allene products of opposite con_guration to the starting halide
ð80JOM"306#178Ł[ The nature of the cuprate species is also critical^ homocuprates giving substituted
allenes with inversion of con_guration whilst the use of heterocuprates "cyano! and bromo!# favour
retention[ The steric bulk of the organocopper species is also signi_cant\ tertiary groups leading to
allenic products whereas straight!chain primary groups frequently result in the production of alkynyl
by!products[ Alkenyl! and allenyliodides may be directly displaced by Grignard reagents in the
presence of the soluble copper catalyst\ dilithium tetrachlorocuprate ð66JOM"017#0Ł and with these
substrates even tertiary alkyl Grignards react with little isomerisation[
Dihaloalkenes are also acceptable substrates[ 0\0!Dichloroalkenes undergo a double displacement
By Substitution 356
reaction on treatment with an alkyl Grignard:nickel catalyst combination[ Using an alkylzinc
chloride as the nucleophile and palladium catalysis the trans chlorine atom can be replaced more
rapidly and\ consequently\ it is possible to achieve a stepwise dialkylation with di}erent alkyl groups
ð76JA0146Ł[ There is a similar di}erence in reactivity between "Z# and "E# bromoalkenes although
the extent and nature of this di}erence is very dependent on the catalyst used[ For example\ "E#!
bromoalkenes are found to be more reactive in palladium!catalysed coupling processes ð75TL1418Ł
whilst the reverse is true for the combination of a primary alkyl Grignard reagent "not MeMgX#
and an iron catalyst\ Fe"DBM#2 "DBMdibenzoylmethido!#[ However\ with this iron catalyst and
the more sterically demanding secondary and tertiary alkyl Grignard reagents\ preferential reactions
with "E#!bromoalkenes occur with no complications due to rearrangement of the Grignard reagent
being observed ð65JOC491Ł[
Selective monoalkylation of 0\1!dichloroalkenes with Grignard reagents can be realised through
the use of excess alkene and a nickel catalyst ð70TL204Ł[ Unsymmetrical 0\1!dihaloalkenes may be
selectively monoalkylated depending on the lability of the leaving group ð65CL0126Ł[ Leaving ability
is found to decrease in the order Br×Cl×SR×OR[ Within this series it is possible to achieve two
sequential alkylations with di}erent Grignard reagents ð74JCS"P0#0004Ł[
There are several alternatives to the use of alkyl Grignard reagents[ Foremost amongst these are
the organozinc reagents which couple smoothly under both nickel and palladium!based catalysis
ð81T8466Ł[ Both primary and secondary alkyl zincs are normally satisfactory although in certain
cases alkyl isomerisation can occur with the latter species ð79JA2187Ł[ In contrast to the cor!
responding Grignard reagents\ a wide variety of functionality can be tolerated in both components
ð80JOC0334\ 82CRV1006Ł[ For example\ Grignard!labile functionality\ such as unmasked carbonyl
groups\ can be present in the vinyl halide moiety as evidenced by the use of both a! and b!
halocarbonyl compounds ð80TL3342Ł[ The latter provide an entry to b!alkylated!a\b!unsaturated
carbonyl compounds "see below# "Scheme 4# while b\g!unsaturated esters may be accessed through
the use of Reformatsky!type reagents ð70JOM"198#098Ł[ Although with these latter reagents\ "E#!
alkenyl bromides react with predominant retention of stereochemistry\ signi_cant scrambling of
alkene geometry has been observed with the corresponding "Z# isomers "Equation "4##[
TBS-O ZnX Pd(PPh3)4, THF, RT, 6 h TBS-O

+ I O-TBS O-TBS
82%
Pd(PPh3)4, THF
+ C4F9ZnI
Br 67% C 4 F9
CO2Me Pd(PPh3)4, THF CO2Me

Br + ZnCl
62%
(>98% E) (>97% E)
Scheme 5
Ph R1 Ph
Pd(PPh3)4, EtO2CCH2ZnCl Ph CO2Et
+ (5)
R2 CO2Et
R1 = H, R2 = Br 34% 0:100
R1 = Br, R2 = H 44% 44:54
The analogous lithium enolates may also be coupled with alkenyl bromides[ These reactions
require the use of a stoichiometric amount of a nickel promoter ð66JA3722Ł[ In a number of cases
the same product can be obtained from the equivalent stannylated ester albeit with moderate yields[
"ii# Alkenyl nucleophiles

The direct coupling "or dimerisation# of alkenyl halides can simply be achieved by heating the
reactants in the presence of an activated copper species[ Since the temperature requirement fre!
quently precludes the use of many sensitive substrates\ milder conditions have been sought[ These
have included the development of more active copper catalysts\ for example the species obtained
through treatment of Cu"OTf# with aqueous ammonia in acetone ð64JOC2538Ł[ The nature of these
catalytic species remains ill!de_ned and more recent progress has been obtained through the use of
speci_c transition metal complexes[ A variety of metal centres have been exploited for this purpose\
notably those involving nickel ð70JA5359\ 82BCJ1335Ł and palladium ð74CC860Ł[
The use of such transition metal complexes provides the principal methods for the synthesis of
dienes through the coupling of dissimilar alkenyl halides[ In general\ provided that functionality
can be tolerated\ it is better to use the more sterically hindered Grignard reagent[ In cases in which
there is little di}erence between the two alkenyl halides\ the direction of the addition can signi_cantly
a}ect the yield of the reaction "Scheme 5# ð75TL1770Ł[
Br MgBr NiCl2(dppp) TMS NiCl2(dppp) MgBr Br

+ +
TMS NMe2 NMe2 TMS NMe2
75% 56%
Scheme 6
Nickel and palladium catalysts are generally employed with the latter providing the greatest
selectivity and e.ciency[ Vinyl iodides are the most reactive halides and o}er advantages over the
corresponding acyclic tri~ates in that they can readily be obtained stereochemically pure with either
the "Z# or "E# geometry ð76JA702Ł[ A large variety of alkenyl organometallic species may be employed
including those based on Li\ Mg\ Cu\ Cd\ Hg\ B "see below#\ Si\ Ti\ Ce and more importantly Sn
ð75AG"E#497\ 81S792Ł\ Al\ Zr and Zn ð76JA1282Ł[ The reactions proceed rapidly under mild conditions
with retention of con_guration in both components ð67TL080Ł whilst substitution in either com!
ponent does not adversely a}ect the rate or stereochemical outcome ð72BSF221Ł[ The reaction can
also be extended to include the use of a variety of alkynylorganometallic reagents ð76JA1027Ł[
The use of lithiodivinylcuprates require the addition of ZnCl1 as a co!catalyst ð70TL848Ł[ These
not only accelerate the reaction but\ in the case of divinylmagnesiocuprates\ permit the transfer of
both vinyl ligands[ This is believed to occur through the dissociation of the cuprate into an
alkenylzinc and a mixed alkenylzinc cuprate ð73T1630Ł[ In general\ the direct use of alkenylzinc
reagents\ which can be easily accessed from the corresponding organolithium by transmetallation\
provides both higher yields and greater stereocontrol ð80TL5572Ł[ When prepared using activated
zinc\ a wide range of functionality can be incorporated into the organometallic unit ð82T18Ł[ These
reactions are most e.ciently catalysed by a palladium"9# species\ usually Pd"PPh2#3 ð71ACR239Ł[
This methodology is also amenable for the alkylation of both aryl and allenyl halides "see
below#[ Although the use of zinc!based reagents a}ords signi_cant advantages over the other
organometallic species\ these reactions frequently require an excess of the nucleophile to achieve
complete substitution of the vinyl halide[ Polyhaloalkenes are also acceptable substrates[ With
both 0\0! and 0\1!dichloroethylenes\ selective monosubstitution has been reported ð73TL5990\
76JA0146\ 76TL0538Ł[
Similar palladium or nickel!catalysed couplings can be achieved using vinyl alanes ð77OS"55#59Ł[
The presence of a co!catalyst\ either ZnCl1 or CdCl1\ is found to be essential for e.cient coupling
ð67JA1143Ł[ With the exception of some vinyl iodides the reactions are usually stereospeci_c\ pro!
ceeding with retention of con_guration[ In this respect\ being somewhat more selective\ palladium
phosphine complexes are generally preferred as catalysts to those based on nickel ð65JA5618Ł[ The
vinyl alanes can be readily prepared by hydroalumination of alkynes which results in the formation
of the "E#!alkenyl alane[ This is in contrast to\ and complementary with\ alkyne carbocupration
which a}ords "Z#!alkenyl cuprates[ Consequently di! and trisubstituted alkenes of either geometry
can be easily obtained from the same alkyne[ Good yields are normally observed\ with a range of
functionality being tolerated in the vinyl halide component ð66JA2057Ł\ although the presence of
excessive steric hindrance in the alane moiety can hinder the coupling ð65JA5618Ł[ Zirconium reagents
formed in a similar fashion may be used as alternatives to alkenyl alanes with a similar degree of
success with the added advantage that hydrozirconation is more tolerant of a wider range of
functionality than is hydroalumination ð67JA1141\ 67TL0916Ł[ In general\ the e.ciency of the cross!
coupling is enhanced by transmetallation of either alane or zirconane to the corresponding al!
kenylzinc "rel[ rate Al ] Zr ] Zn1 ] 2 ] 1999# ð76JA1282Ł[ Similar palladium catalysis can be employed
in the synthesis of enyne and allenynes[ Milder\ nonbasic conditions are found in the presence of
By Substitution 358
copper salts ð72S21Ł or in aqueous conditions ð81SL604Ł[ Copper salts may be avoided through the
use of the corresponding aryl or vinyl tri~ate in an amine base solvent system "see below# ð82TL5392Ł^
whilst neutral coupling conditions\ that are relatively insensitive to oxygen\ moisture or other
catalyst poisons\ can be achieved without palladium through the use of stoichiometric copper"I#
salts[ However\ this method does require relatively high reaction temperatures and the use of HMPA
as the solvent ð78SC1088Ł[
"iii# Aryl nucleophiles

In an analogous fashion\ vinyl halides may be coupled with a variety of aryl nucleophiles[ Many
of the features of this process are similar to the coupling of an alkenyl organometallic and an alkenyl
halide "see Section 0[00[1[0[1"ii## and will not be repeated here[ Although this coupling can be
achieved in either sense\ the union of an aryl Grignard and vinyl halide is generally found to the
more e.cient strategy[ The principal exception to this is found when there are problems of steric
crowding in the halo component[
Although arylzinc reagents and nickel or palladium catalysts are the favoured combination\ other
transition metals have found use as the catalyst centre\ for example\ Fe"III# ð75BCJ0545Ł[ Similarly\
other organometallic components can be used\ notably RLi "see above#[ Alternatively\ with aryl
nucleophiles it is possible to avoid the requirement for the catalyst through the use of a diarylcuprate
ð58JA3760Ł or arylmanganese!ate complexes[ However\ both methods have limitations^ only one
aryl ligand is transferred from the cuprates whilst the manganese reagents are restricted to alkenyl
iodides and result in scrambling of the alkene geometry ð78IZV1512Ł[
"iv# AdditionÐelimination displacements of vinyl halides

Substitution of the chlorine atom in b!chloroenones with carbon nucleophiles can readily be
achieved through their reaction with a variety of active methylene compounds ð55CRV050Ł[ However\
acceptable yields of the b!alkylated vinyl ketone are only obtained with those compounds possessing
a single acidic hydrogen atom[ Reagents with two acidic hydrogen atoms undergo a very rapid
further reaction\ leading to aromatic side!products[ Hindered b!haloenones\ such as chloro!
methylene camphor ð05CB14Ł undergo facile displacement of the halide on treatment with Grignard
reagents\ while most b!haloenones undergo preferential 0\1 addition[ However\ the resultant car!
binols undergo rapid rearrangement on mild acid hydrolysis to a}ord alkylated a\b!unsaturated
ketones ð40BSFC02Ł[ Direct substitution of b!chloroenones can be achieved using diethyl or dialkenyl
cadmium reagents\ but the yields are poor ð48AC"P#430Ł[
Direct displacement of halogen occurs readily on treatment of b!haloketones with a variety of
copper!based reagents[ With simple dialkyl cuprates\ cyclic b!haloenones produce the products of
halogen substitution in good yield\ but acyclic or exocyclic b!haloenones frequently a}ord the
saturated ketone product "Equation "5## ð65JOC525Ł[ These problems of conjugate addition can be
circumvented by the use of lithium"phenylthio#alkylcuprates ð71CJC0145Ł[ In general\ the bromides
are the substrate of choice since\ although the reactivity of the haloenone increases in the order
Cl³Br³I\ iodoenones are considerably less easy to handle[
O Cl Cl O O O
Me2CuLi (2 equiv.), Et2O But
+ + (6)
2:1 2:1
b!Haloenoates are also suitable substrates in these substitution reactions[ For example\ ethyl b!
bromoacrylate undergoes e.cient alkylation on treatment with the methyl triethylborate copper
complex "ðEt2BMeŁCu#[ As with many of these additionÐelimination reactions this is a stereospeci_c
reaction with retention being the favoured pathway ð66TL2258Ł[ The stereoselectivity is\ however\
substrate:reagent dependent[ "Z#!1!b!Chlorocinnamates react with Grignard reagents in the pres!
ence of a copper"I# catalyst with retention of con_guration whereas reaction of the corresponding
"E#!isomer shows no stereochemical preference ð72ACS"B#062Ł[
A number of other carbanion reagents may also be employed[ For example simple ketone enolates
combine e.ciently with b!chloroacrylate ð67CJC308Ł\ and allyl phosphorus ylides react with b!
chloroenones to provide a general polyene synthesis "Scheme 6# ð64TL0248Ł[ Radical!based strategies
are also possible although the stereochemical outcome is somewhat variable ð82TL2930Ł[
Cl +
Ph3P + Ph3P CO2Me Cl–
CO2Me
Ph3P CO2Me RCHO CO2Me

R
R = Ph, 85% (100% EEE)
R = Bui, 67% (1:1.5 EEE:EEZ)
Scheme 7
Alternative coupling partners exist\ notably b!halovinylsulphones[ These are particularly good
substrates for displacement of either ~uorine\ chlorine or bromine with lithium dialkylcuprates[
Good selectivity is observed\ although only at low temperatures with chlorides and bromides[
Iodides similarly can be displaced\ with high stereoselectivity\ on treatment with n!butyl copper!
bis"diisopropylsulphide# complex[ The corresponding dialkyl cuprate is not stereospeci_c "Equation
"6## ð63JOC2063Ł[ Substitution of halides from sulphone!activated systems may also be achieved with
active methylene compounds ð81JOC0050Ł[ Reactions using the analogous sulphoxides are also
possible ð81JOC0607Ł[
SO2Et SO2Et Bu SO2Et

Bu[M]
+ (7)
I Bu
Bu2CuLi 80:20
BuCu(SPri2)2 100:0
0[00[1[0[2 Substitution of aryl halides
"i# Alkyl nucleophiles

These coupling reactions bear considerable resemblance to those involving alkenyl halides[ Pri!
mary Grignard reagents are the most reactive species\ whilst secondary and tertiary Grignard
reagents frequently undergo isomerisation prior to reaction[ Reactivity can also be controlled by
the nature of the catalyst[ In general\ with primary Grignard reagents and nickel catalysts\ the
reactivity of the halides decrease as the group is ascended "ArI×ArBr×ArClŁArF# while for
the same reagents and palladium catalysts both aryl chlorides and ~uorides are relatively inert
"ArI×ArBrŁArCl\ ArF#[ Thus\ with nickel catalysis the use of aryl chlorides often a}ords the
best balance between rate and product selectivity[ However\ under more forcing conditions all the
aryl halides may be substituted in this fashion[ Likewise with palladium catalysis the use of bromo!
arenes is favoured[ With the exception of alkoxy substituents which accelerate the reaction\ aryl
ring substituents in~uence the reaction in much the same way as they do for nucleophilic aromatic
substitution "see Section 0[00[1[0[2"iv##[ However\ these reactions are subject to some steric demands
with hindered\ notably ortho!substituted\ aryl halides failing to react with Grignard reagents bearing
b!hydrogen atoms[ In these cases reductive elimination of the corresponding alkene occurs pref!
erentially ð65BCJ0847Ł[ These competing pathways can\ to a certain extent\ be regulated by the
choice of catalyst[ For example\ with NiCl1"dppp# isopropylmagnesium chloride couples with
chlorobenzene to a}ord isopropylbenzene in 85) yield^ while using NiCl1"PEt2#1\ reduction is the
principal pathway[ In general\ for most coupling reactions\ switching from a monodentate to a
bidentate phosphine ligand favours coupling with respect to reduction[ Similarly\ the chiral pentyl
Grignard reagent couples with chlorobenzene\ in the presence of NiCl1"dppp#\ with little degradation
By Substitution 360
of optical purity whilst with NiCl1"dmpe# signi_cant stereochemical scrambling is observed "Equa!
tion "7## ð61JA8157Ł[
NiCl2L, PhCl
MgCl Ph (8)
Et2O, reflux, 20 h
96% ee L = dppp 95% ee

L = dmpe 86% ee
Further enhancements can be achieved through the use of the equivalent zinc and tin reagents[
Both are more tolerant of a wider range of functionality than the corresponding Grignard reagent[
Coupling reactions of tetraorganostannanes require the presence of HMPA as a co!solvent to ensure
e.cient ligand transfer[ The use of such additives ð68JA3881\ 73CL0114Ł\ or the presence of internal
coordination sites on the tin ligand ð81JA5445Ł is frequently essential for e.cient alkyl transfer from
tin reagents[ These palladium!catalysed couplings of alkyl stannanes usually proceed most smoothly
with the aryl iodide[ However\ with allyltributyltin higher reactivity is observed with the aryl
bromide "ArI³ArBr×ArCl# ð66CL290Ł[ Although most aryl chlorides are unreactive to these
conditions\ alkylations with tetrabutyltin can be achieved on arene activation through complexation
with chromium hexacarbonyl ð76CC0644Ł[
Reformatsky reagents can also be used to provide an entry into a variety of a!arylated carbonyl
compounds[ The catalysts of choice are either Pd"PPh2#3 or Ni"PPh2#3[ The latter compound provides
greater versatility\ allowing coupling with iodides\ bromides and chlorides\ whilst the palladium
catalyst is only suitable for use with aryl iodides[ E.cient reaction is only achieved in the presence
of a strongly coordinating co!solvent such as DMF\ HMPA or NMP ð68JOM"066#162Ł[
Under palladium catalysis and in the presence of tributyltin ~uoride\ aryl bromides are alkylated
by silylenol ethers ð71JA5720Ł or silylketene acetals ð80JOC150Ł and it is hypothesised that the active
nucleophile is the corresponding a!stannylketone[
Difunctional reagents have also been reported for both reaction partners[ bis Grignard reagents
produce the dicoupled product in low yield ð64JA3394Ł[ Although complete substitution is normally
observed with di! and polyhaloarenes\ selectivity can be achieved either through the use of excess
electrophile\ or through the application of di}erent leaving groups ð80CL1962Ł[ A number of sub!
stituent groups\ including methyl\ methoxy and oxazolinyl\ demonstrate useful directing e}ects
ð71JOC3208\ 73OM529Ł[ This is also true of heteroaryl halides[
"ii# Alkenyl nucleophiles

The more e.cient way of achieving this connection is normally the reverse process\ namely a
coupling reaction between an aryl organometallic and alkenyl halide "see Section 0[00[1[0[1"iii##[
However\ in cases in which there is severe steric hindrance in the arene moiety the use of vinyl
nucleophiles and aryl halides can o}er some advantages[ In these cases the use of a copper salts
allows the inclusion of a variety of functional groups into the arene unit ð72JOC0801Ł[ The most
e.cient coupling reaction is observed with aryl iodides[ In certain cases\ in which di.culties arise
in the direct formation of the cuprate\ the corresponding zinc species "accessible either through
transmetallation ð70TL2740Ł or directly via reaction with activated zinc ð82T18Ł# together with a
palladium catalyst can provide a convenient alternative strategy[ As with the copper!catalysed
displacements\ aryl iodides are usually the substrates of choice^ the reactivity re~ects the ease of
oxidative addition of the aryl halide to palladium"9# ð66ACR323Ł\ that is PhI×p!ClC5H3Br
×PhBr×o!MeC5H3Br×o!MeOC5H3Br[ Vinyl stannanes can similarly be combined with aryl
halides in the presence of palladium catalysis[ With the exception of a free amino group a broad
spectrum of functional groups are compatible with the reaction conditions\ although electron!
withdrawing groups result in lower reactivity ð76JOC311Ł[
Alkenyl alanes or the corresponding zirconium species\ readily accessible by hydrometallation of
an alkyne\ also undergo nickel or palladium!catalysed coupling with aryl halide "Scheme 7# ð65CC485\
67JA1143Ł[ This strategy can provide access to tetrasubstituted arylalkenes ð76S705Ł although the
geometry of the alane component is restricted to the "E# isomer[ With sterically demanding substrates
the addition of ZnCl1 can aid the conversion ð67JA1143Ł although in extreme cases it is frequently
better to convert the alkenyl alane into the corresponding iodide and then couple with an aryl
Grignard reagent[
Ph Ph
Ph Ph
Et3Al ArBr, Pd(PPh3)4 Et
Ph Ph
PhMe, 90 °C, 24 h Et AlEt2 THF, reflux, 24 h
35% NMe2
O
Scheme 8
This connection can also be attained through the use of vinyl boranes ð68CC755Ł and vinyl
boronates[ The latter have been found to be more e}ective with 1!alkenyl boron reagents[ Both
classes of reagent require the involvement of a palladium"9# catalyst and also the presence of a base[
The strength of this base can\ particularly with vinyl boronates\ control the regiochemistry of the
processes[ Stronger bases such as ethoxide favour a head!to!head coupling whilst triethylamine and
other weaker bases a}ord the products of a head!to!tail union "Equation "8## ð70JOM"102#C42Ł[
O PhI, Pd black (cat.)

Bu Bu
B + (9)
Bu O base Ph Ph
Base = NaOEt, 78% 39:61
Base = Et3N, 94% 96:4
Aryl alkynes are obtained from aryl halides on treatment with a cuprous acetylide ð61OS"41#017Ł[
This\ the StephensÐCastro coupling reaction can be carried out more simply using palladium
catalysis ð64TL3356Ł[ A milder\ more e.cient\ variant is obtained under phase transfer conditions
ð71T520Ł[ Similar methodology has been applied to the synthesis of enynes and allenynes ð72S21Ł[
"iii# Aryl nucleophiles

The recent developments in the synthesis of biaryls has been reviewed ð89AG"E#866Ł[ Symmetrical
biaryls may be accessed through the dimerisation of aryl halides on heating in the presence of a
copper salt[ This\ the Ullmann reaction\ works for all but aryl ~uorides with reactivity increasing
as the following series is descended "ArCl³ArBr³ArI#[ The reaction requires both a highly polar
solvent "pyridine\ quinoline\ DMF and tetramethylurea are common choices# and high temperatures
"¾159>C#[ In general\ provided it is compatible with the temperature requirement\ a broad spectrum
of functionality is tolerated[ Alkyl\ alkoxy and ortho!alkoxycarbonyl groups accelerate the reaction
whilst free protic groups\ OH\ NH1\ CO1H\ etc[\ inhibit the reaction[ The Ullmann reaction is
sensitive to steric e}ects and for particularly crowded aryl halides it is advisable to form the
corresponding aryl organometallic and couple using transition metal catalysis "see below#[ In order
to circumvent the high temperatures\ a variety of more activated copper species can be prepared^ for
example by potassium naphthalenide reduction of cuprous iodide ð68JOC2334Ł\ or by combination of
Cu"OTf# and aqueous ammonia in acetone ð71JCS"P0#1188Ł[ The latter combination allows the
reaction to proceed e.ciently at room temperature[
Nickel salts can also be used to replace the copper species in the Ullmann reaction ð70JA5359\
78JOC3739Ł[ Although similar to the classical Ullmann reaction in terms of substituent e}ects\ this
modi_cation is somewhat more sensitive to the steric demands of the reaction partners[ Likewise\
protic functional groups tend to a}ord products of simple reduction whilst the presence of a nitro
group completely inhibits the coupling reaction[ Although less reactive than the corresponding
nickel!catalysed coupling of aryl Grignard and lithium reagents\ this process is more compatible
with sensitive functional groups[ A further attraction of this modi_cation is that by using zinc
together with triphenylphosphine as a stoichiometric reducing agent\ the coupling process can be
rendered catalytic in nickel ð66TL3978\ 75JOC1516Ł[ With this system it is most pro_table to use the
aryl chloride\ which a}ords a greater ratio of coupling to reduction\ than the corresponding bromide
and iodide[
The Ullmann reaction can be used for coupling of di}erent aryl halides provided there is su.cient
di}erence in reactivity[ Apart from the halide itself\ the electronic e}ects of the other arene sub!
stituents are important[ In general\ the best results are achieved through the coupling of the iodide
By Substitution 362
of the electron!rich arene\ which undergoes rapid oxidative addition to form the corresponding aryl
copper species\ and the bromide of an electron!de_cient arene[ Alternatively\ some success can be
achieved through the use of a large excess of the active copper species and running the reaction at
a temperature below that required for dimerisation of the less reactive component ð66TL1904Ł[
Greater speci_city in heterocoupling\ together with a much reduced temperature requirement\ are
obtained using preformed arylcopper species[ Simple diarylcuprates couple with unfunctionalised
iodoarenes[ However\ for e.cient transfer\ the presence of various additives\ for example\ lithium
bromide or triphenyl phosphine together with the {correct| solvent is necessary ð58JA3760Ł[ One
attractive option which allows the coupling to be achieved at ambient temperatures is to use a
preformed arylcopper reagent which contains a ligating ortho substituent "Equation "09## ð79JA689Ł[
Steric hindrance is not normally a problem with this reaction and the only restriction with its use is
the requirement for the activating ortho groups in both components[ An alternative and more
versatile strategy involves the coupling of two arene units through the low temperature oxidative
coupling of higher order mixed diarylcuprates ð82JA8165Ł[
i, BuLi
ii, CuI•P(OEt)3
O Br
O O O CHO
iii, NC6H11
O O
Br
(10)
iv, H3O+ O
NC6H11 58%
CHO O
The best alternative to these high temperature processes are the nickel or palladium!catalysed
coupling of aryl halides and aryl Grignard reagents ð67OS"47#016Ł[ Aryllithium reagents generally
produce much poorer yields[ As with alkenyl coupling reactions it is more e.cient to use the
Grignard reagent derived from the more hindered arene[ In general\ there is no apparent restriction
on the degree of substitution provided that not more than two ortho substituents are present\
preferably both on the Grignard component ð75T1000Ł[ A wide range of catalytic species have been
employed using both nickel and palladium complexes[ Whilst the palladium!catalysed reaction
shows greater chemoselectivity\ tending to be restricted to activated aryl bromides ð75T1000Ł\ nickel
catalysts are more tolerant of sterically hindered aryl halides including a broad range of aryl
bromides and iodides[ Asymmetry may be incorporated into this process through the use of chiral
ferrocenyl phosphine nickel complexes ð77JA7042Ł[ Finally\ selective mono! or polyarylation is
possible with certain nickel catalysts ð79TL734\ 71JOC3208Ł[ In most of these reactions the use of
ultrasound is found to signi_cantly accelerate the reaction ð75BCJ1933Ł[
Arylzinc reagents also couple e.ciently under similar conditions[ These reagents are additionally
attractive being not only more tolerant of functionality in the electrophilic component\ but are also
readily accessible through transmetallation of the corresponding aryllithium ð77OS"55#56Ł[ Similarly\
arylstannanes have been employed with the transfer of a single aryl unit from tetraphenyltin being
possible ð68JA3881Ł[
Another good source of aryl nucleophiles are the corresponding boronic acids\ although these do
not couple with aryl chlorides ð80PAC308Ł[ Arylboranes have also been employed in this regard and
both tolerate a wide spectrum of functionality[ Steric e}ects appear to be relatively unimportant
and e.cient ligand transfer can be realised with very small amounts of catalyst ð70SC402Ł[ Again\
many of these species are readily available through transmetallation of the corresponding aryllithium
ð76TL4982Ł[ This sequence may be used in an iterative fashion for the regiospeci_c construction of
polyphenols "Scheme 8# ð76TL4986Ł[
"iv# Nucleophilic aromatic substitution

SNAr displacement of aryl halogen requires the presence of an appropriately sited activating
group or heteroatom[ For a given compound the ease of halide displacement is in the order
F×Cl½Br½I[ Displacement by alkyllithium reagents normally fails due to competing lithiumÐ
halogen exchange reactions[ However aryllithium and Grignard reagents will displace the halogen
from 1!~uoro! and 1!bromo!1!aryloxazolines ð74T726Ł\ and 1!aryloxazoles ð76CL08Ł[ Chiral biaryls
can be prepared using this strategy\ either through the use of chiral auxiliaries ð82S149Ł or chiral
catalysts ð81JA7621Ł[
O-MOM MOM-O i, BuLi, ClB(OMe)2
Ph B(OH)2 Pd(0), NaHCO3 ii, Pd(0), NaHCO3
Ph
OR
Br Br
OR OR
72% 63%
MOM-O OR
Ph
OR
MOM = methoxymethyl
R = CONEt2
Scheme 9
Active methylene compounds are also suitable nucleophiles with diarylation rarely being a
signi_cant problem ð05CB1111\ 40CRV162Ł[ These stabilised nucleophiles also provide for a very
e.cient substitution process on reaction with haloarene transition metal complexes[ The use of
more basic\ reactive carbanions tend to a}ord products of hydrogen as opposed to halogen sub!
stitution "Scheme 09# ð70T2846\ 89BSF390Ł[
i, LiC(Me)2CN, 3 h, 0 °C i, LiC(Me)2CN, 20 h, 25 °C
ii, I2 Cl ii, H2O
CN CN
56% Cr(CO)3 iii, I2
Cl 85%
Scheme 10
Displacement of aryl halogen may also take place via the SRN0 pathway and in this case the order
of reactivity is found to be I×Br×ClŁF[ Aryl ~uorides are su.ciently inert such that exclusive
monosubstitution of halo~uorobenzenes is observed[ Both hydrocarbon and heteroaromatic halides
are acceptable substrates[ Although unsubstituted arylhalides do react\ in many cases the sub!
stitution fails without the presence of an activating group "see below#[ With the exception of the
nitro group and protic functionality\ most substituents are tolerated provided that they do not react
with the nucleophile or create excessive steric hindrance[ In the latter case reduction can be a
competing process ð64CPB1519Ł[
The SRN0 reaction provides an e.cient route to a!arylketones through the reactions of ketone
enolates ð80COS"3#340Ł[ Whilst nitrile!stabilised carbanions behave similarly\ the use of ester enolates
is not nearly so e}ective[ b!Dicarbonyl nucleophiles can be used although the success of the
reaction is very dependent upon the particular reagent:substrate combination[ In a related process
unsymmetrical biaryls can be prepared using phenoxide anions through an electrochemical!mediated
reaction "Equation "00## ð77CC192Ł[ In this reaction synthetically useful yields are only observed in
the presence of speci_c substituents ð77TL0178Ł[ A similar coupling can be achieved using arylamide
anions ð76TL3542Ł[
CN
But
CN
e–, NH3
+ But (11)
68%
But
Cl HO
O–
But
Most unstablised hydrocarbon nucleophiles tend to be too basic for the solvents used in these
reactions although some limited success can be obtained with conjugated hydrocarbons[ However\ in
many cases these processes are complicated by competing reduction of the nucleophile ð62JOC2919Ł[
By Substitution 364
0[00[1[1 Substitution of Oxygen
0[00[1[1[0 Substitution of alkylÐoxygen leaving groups

"i# FriedelÐCrafts alkylations
As with alkyl halides the reactivity of alcohols to FriedelÐCrafts substitution decreases along the
series benzyl\ allyl\ tertiary×secondary×primary×methanol[ Whilst reactions with secondary
and the more reactive alcohols proceed smoothly\ primary alcohols require an excess of the Lewis
acid and invariably a}ord products resulting from rearrangement of the initial formed carbocation[
Enhanced reactivity is observed with the corresponding mesylates and tosylates[ A highly stereo!
selective alkylation of benzene occurs on reaction with sulfonate esters of lactic acid and related
analogues[ The reaction proceeds with almost complete inversion of con_guration at the reacting
centre re~ecting the SN1 nature of this pathway ð80JOC072Ł[ The reaction is postulated to proceed
by way of the chelated intermediate "09# "Scheme 00#[ If the acid catalyst employed cannot form
this complex\ for example CF2SO2H\ then complete racemisation is observed ð76AG"E#031Ł[ In
an unusual process tri~uoroacetic acid reacts with unhindered arenes in the presence of sodium
borohydride to produce 0\0!diaryltri~uoroethane ð74S645Ł[ The reaction presumably proceeds by
way of the corresponding tri~uoroacetaldehyde since more hindered arenes yield the corresponding
0!aryltri~uoroethanol and similar conversions have been reported for chloral and other reactive
aldehydes ð53MI 000!90Ł[
AlCl3
MsO O
Ph O
MsO H O PhH, AlCl3
OMe
OMe (10) 80% OMe
(100% ee) (97% ee)
Scheme 11
Whilst acyclic ethers are generally unreactive\ alkylations can be achieved with their cyclic
analogues[ The reactivity of these compounds is proportional to ring strain and consequently
decreases with increasing ring size "Scheme 01# ð37BSF700Ł[ Similarly\ alkyl substitution in the
a!position enhances reactivity consistent with the cationic nature of the reaction "Scheme 02#
ð59DOK"020#16Ł[ With higher homologues reaction is frequently accompanied by competing side
reactions including rearrangements\ condensations\ intramolecular reactions\ etc[ ð47DOK20Ł[
Epoxides undergo regioselective ring opening at either carbon atom depending upon the nature of
the Lewis acid used[ Mild species\ such as MgBr1 and ZnBr1\ lead to diarylmethane products via
ring opening to the aldehyde whilst stronger Lewis acids promote direct SN1 ring opening to a}ord
b!hydroxyarylalkanes which can react further to produce diarylalkanes ð67BCJ063Ł[ Epoxides are
opened with almost complete stereocontrol to produce\ initially\ the product with inverted con!
_guration at the reacting centre ð64BCJ859Ł[ Exceptional selectivity is observed in the FriedelÐCrafts
reaction of 4\5!epoxycyclodecene "00# "Equation "01##\ which on treatment with an arene and SnCl3
a}ords the decalinol "01# as a single isomer ð70JOC1698Ł[ The invertive pathway is also observed
with oxetane substrates\ although again the nature of the Lewis acid can critically a}ect the optical
purity of the product "Scheme 03# ð71BCJ056Ł[ Preferential reaction occurs at the most substituted
carbon atom indicating the involvement of considerable carbocationic character in the transition
state[ As the ring size is increased the selectivity decreases\ although inversion through an SN1 type
process is still the favoured pathway[
Ar
H
SnCl4, ArH
(12)
O
H
OH
(11) (12)
O > > >

O O O
Scheme 12
> >
O O O
Scheme 13
Ph OH
PhH H
H AlCl3
O
O Cl AlCl2 AlCl3 H
AlCl3
H PhH Ph OH
Scheme 14
Similar cyclic ion pair intermediates "02# are postulated to account for the high degree of
asymmetric induction observed in alkylations using lactones as substrates "Scheme 04# ð56JA4310Ł[
These reactions are often complicated by the propensity of the _rst formed arylalkanoic acids to
cyclise a}ording the corresponding tetralone[ As with ethers\ simple acyclic esters are not su.ciently
reactive to be e}ective substrates[
δ–
O O AlCl3 δ+ O PhH H
OAlCl3
H Ph CO2H
H
(100% ee) (13) (40% ee)
Scheme 15
"ii# Substitution by orànometallic sp1 carbanions

The most direct method for achieving this coupling is through the reaction of an alkyl tosylate
with a vinyl! or arylcuprate or copper!modi_ed Grignard reagent ð81OR024Ł[ This reaction is very
similar to the corresponding process using alkyl halide electrophiles[ However\ both primary and
secondary tosylates react more e.ciently and readily than do the analogous halides ð62JA6666Ł[
Other alcohol activating groups can be used with equal e.cacy\ notably allylic acetates and b!
lactones[ The latter substrates provide a useful three!carbon homologation sequence "Equation "02##
ð79TL824Ł[ v!Ethenyl lactones undergo an SN1? displacement and this can provide easy access to
dienoic acids ð70CL0296\ 71TL2472Ł[ This last method is also applicable to larger lactones in which there
is no competing strain!assisted direct displacement "Equation "03##[ These last SN1? displacements are
examples of the transition metal!catalysed alkylation of Grignard reagents that can be achieved
with a variety of allylic electrophiles[ Alcohols\ esters\ sulfonates\ phosphates and ethers have all
been employed with some success[ The nature of the leaving group can a}ect the rate of substitution[
For example\ for the palladium!catalysed reactions of vinyl alanes the order has been found to
increase along the series OSiR2 ³OPO"OEt#1 ³OAlMe1 ³OAc "¼Cl# and within this series some
selectivity may be observed "Equation "04## ð70TL2626Ł[ Although allyl alcohols may be coupled
directly ð65JOC155Ł "see below# it is frequently more e.cient to carry out the reaction in two discrete
steps\ that is activation and substitution[ In one particularly attractive strategy\ allyl alcohols are
coupled e.ciently via the in situ conversion to the corresponding iminium salt "03# "Scheme 05#
ð72TL4634Ł[ Phenyl and vinyl Grignard reagents react regioselectively at the a!carbon atom whilst
the addition of CuX:HMPA favours the formation of products of allylic substitution[
By Substitution 366
O Et2O, –10 °C to RT CO2H

Bu Cu(C6H9)Li + O (13)
65% Bu
R
MgX ( )n CO2H
( )n (14)
O CuI R
O
n = 0, 1, 2; R = H, Me
Pd(PPh3)4
AlMe2 + +
Bu OAc
O-TBDMS
+ (15)
Bu
O-TBDMS
82% 100%
TBDMS = t-butyldimethylsilyl
Cl R2 R4
R2 R4 R1MgX, THF
N R3 R1
R2 R4 R3 O
+
R3 OH N
R1MgX, THF R2
CuI, HMPA
R1
(14) R3 R4
R2 = R3 = R4 = H, alkyl; R1 = Ph, vinyl
Scheme 16
In general\ as with the corresponding displacement of allylic halides\ the regiochemistry of this
reaction is very dependent upon the nature of the nucleophile\ electrophile and catalyst and it is
di.cult to make any general predictions ð80COS"2#357Ł[ For example\ copper!catalysed addition of
vinyl Grignards to allylic phosphates a}ords products of direct SN1 displacement ð66JCR"M#1090Ł
whereas aryl Grignards react with with allylic acetates in the presence of a nickel catalyst in an SN1?
fashion[ Similarly\ in the treatment of allylsilyl ethers with aryl Grignard reagents\ Pd catalysis
a}ords predominantly the disubstituted alkene and nickel"II# catalysis generates the terminal alkene
"Equation "05## ð70CC202Ł[ In these transition metal!catalysed processes\ the harder nickel centre
tends to favour attack at the more substituted carbon atom\ re~ecting the greater degree of carbo!
cation character in the h2allyl ligand\ whilst the softer palladium forms an essentially symmetrically
bound h2allylpalladium species which is attacked at the position of least steric hindrance[ In an
exception to this\ allylic alcohols are substrates in nickel"II#!catalysed displacement reactions\ albeit
requiring a large excess of the Grignard reagent\ in which exclusive terminal substitution is observed
ð66JOM"016#260Ł[ When these transition metal catalysts contain chiral ligands then signi_cant asym!
metric induction can be observed "Equation "06## ð74TL2148Ł[
PhMgBr, catalyst Ph
OSiEt3 Ph + (16)
Et2O, RT, 4 h
catalyst NiCl2(dppf) 75% 12 88

PdCl2(dppf) 85% 96 4
Ph2
P
Cl2Ni
P
R2 R3 Ph2 R2
ArMgBr + (17)
16–65%
OR1 Ar R3
60–89% ee
R1 = Me, CO2R, COR; R2, R3 = H, Me
The other major class of oxygen!based electrophiles are those containing epoxides[ Although
most organometallic epoxide opening reactions require the use of copper!based reagents to obtain
good yields\ the direct coupling of heteroaromatic and allenyllithium reagents with unhindered
epoxides occurs e.ciently[ With the latter reagents\ the rate and e.ciency of the coupling can be
signi_cantly enhanced through the use of HMPA as a co!solvent[ With 0\1!disubstituted epoxides
regioselectivity can be problematical and the results obtained are very substrate:nucleophile depen!
dent[ In certain cases selective alkylation of unsymmetrical epoxides can be obtained\ for example\
predominant attack is observed at C!1 of b\g!epoxyalcohols ð72JOC3020Ł[ The e.ciency of these
direct couplings can be enhanced by the addition of Lewis acids\ notably BF2 = OEt1\ to the epoxide
ð73JA2582Ł[ This modi_cation is su.ciently active to permit the ring!opening alkylation of oxetanes
whilst the reduction in ring strain renders THF su.ciently inert to be used as the solvent for this
reaction "Equation "07##[ The direct intramolecular alkylation of epoxides with organolithiums is
also possible ð67JOC2799Ł[ Again\ these reactions can be enhanced through the addition of an
appropriate Lewis acid\ although the nature of this latter species can be critical[ In both these cases
the use of such catalysts may alter the regioselectivity of the process[ For example\ the presence of
magnesium bromide can promote a variety of side reactions through the formation of halohydrin
and aldehydic intermediates "Scheme 06# ð79JOC811Ł[
O PhLi, BF3•OEt2 OH
(18)
Ph THF, –78 °C, 5 min Ph Ph
98%
O i, BuLi, –100 °C
O
O
ii, 25 °C, 3 h O MgBr2, BuLi
64% –78 °C to RT
OH
OH Br
Scheme 17
With unhindered epoxides\ aryl and vinyl Grignard reagents a}ord comparable yields with or
without copper catalysis\ whilst with more hindered substrates the requirement for copper!based
reagents\ in either stoichiometric or catalytic quantities\ becomes essential ð67TL3958\ 68TL0492Ł[ In
this respect both copper"I# halides and cyanides are suitable sources of copper[ Lower order
lithiocuprates regiospeci_cally open terminal epoxides in good yield\ whilst more hindered tri!
substituted epoxides are best cleaved using higher order cuprates ð73JOC2817Ł[ As above\ 0\1!
disubstituted epoxides often give mixtures of regioisomers with the major product being controlled
by steric factors within the substrate ð68TL3232Ł\ although electronic factors can in~uence the
outcome ð74TL3572Ł[ As with other displacements using vinylic cuprates the major problem is the lack
of e.cient transfer of the second vinyl ligand[ The use of mixed lower order cuprates\ RCu"CN#Li
ð66TL2396Ł or RTRsCuLi ð79T0850Ł o}ers an economical route to homoallylic alcohols[ The latter
species can be formed by the in situ addition of lithium acetylide to the vinyl copper species
formed after transfer of the _rst vinyl unit thus permitting e.cient use of both vinyl groups of a
divinylcuprate[ In this respect\ unlike their aliphatic analogues\ many heteroaryl copper species are
essentially inert\ frequently _nding a role as a nontransferable ligand in mixed and higher order
cuprates[ One particularly attractive method that circumvents this problem is to use an active
elemental form of copper generated in situ by lithium naphthalide reduction of a CuIÐPBu2 complex[
In addition to providing increased reactivity the resulting reagent\ which can be generated from
either vinyl or aryl halides\ provides access to functionalised species not available through standard
organolithium or Grignard technology ð76JOC4946Ł[ Alternatively\ the activity of the copper species
towards epoxides can be enhanced by the addition of Lewis acids ð75AG"E#836Ł[ Under these
conditions those cuprates which generate lithium halide salts in their preparation frequently produce
By Substitution 368
halohydrin by!products[ This is not observed with the lower! or higher!order cyanocuprates[ The
latter\ in combination with Lewis acids\ a}ord an extremely powerful nucleophile with respect to
epoxides "Equation "08## ð75T4596Ł[ In addition to epoxides a number of other functional groups
including allylic ethers and acetals also undergo substitution ð73TL2964Ł[
OH
Et2O•BF3
–78 °C to –50 °C, 1 h
O + )2 Cu(CN)Li2 (19)
87%
(±)
Magnesiocuprates obtained from the addition of Grignard reagents to alkynes combine e.ciently
with terminal epoxides but only sluggishly with more substituted species[ Higher yields may be
obtained through the formation of the corresponding {ate| complex by addition of lithium acetylide
ð67TL1354Ł[ Similar behaviour is observed with the alkenylaluminate obtained from the addition of
butyllithium to an alkenyl alane ð65CC06Ł[ The corresponding lithiodialkenylcuprate prepared from
acetylene can be prepared stereospeci_cally as the "Z# isomer and as such provides a convenient
entry to "Z# homoallylic alcohols ð79T0850Ł[ In common with most copper reagents these compounds
do not react with esters[ Consequently\ this functionality may be located in either reaction partner
"Scheme 07# ð76TL0670Ł[ However\ in some cases in which the ester is contained on the cuprate
moiety products of alkene isomerisation have been recorded ð72JOC3510Ł[
O Et2O, –20 °C
CO2Et
+ CuLi CO2Et
81%
OH
CO2Et
O
OH
Et2O, –20 °C
MeCu(C6H9)Li
CO2Et 40%
CO2Et
Cu(C6H9)Li O
CO2Et
C6H11 OH
Et2O, RT
61%
C6H11
Scheme 18
Vinylic epoxides are ambident electrophiles and as such can alkylate carbanions to produce up
to three isomeric products[ Grignard reagents tend to provide a mixture of products favouring 0\1
addition\ with the eventual outcome dependent on the nature of the reacting partners ð69JA3867Ł[
Copper!based reagents favour 0\3 addition through an SN1? pathway ð67S417\ 67TL1916Ł as does the
use of aryl and vinyl stannanes in conjunction with a palladium catalyst ð78T868Ł[ Similar selectivity
is observed in the reactions of cyclic vinyl epoxides[ Vinyl epoxides derived from a\b!epoxyketone
derivatives "enolates\ enolethers and enol phosphates# can undergo selective allylic displacement to
provide a convenient route to functionalised a!aryl! and a!vinylketones[ However the regiochemistry
does depend on the substitution pattern "Scheme 08# ð71JA2054Ł[
0[00[1[1[1 Substitution of alkenylÐoxygen leaving groups
"i# Substitution by orànometallic carbanions

Enol phosphates may be simply converted to the corresponding alkenes on treatment with
reactive cuprates such as lithium dibutylcuprate[ However\ less reactive reagents such as lithium
dimethylcuprate give poor yields whilst more hindered enol phosphates are unreactive ð65TL3394Ł[
Enol phosphates may also be displaced by a variety of Grignard reagents using nickel catalysis
ð70S0990Ł[ The only palladium species to be e}ective in this coupling is tetrakis"triphenyl!
O-TMS O
PhCu(CN)MgBr Ph
O 70%
OH
O O-TMS O
Cu(CN)Li Cu(CN)Li
R = H, 80% O R = Me, 80% OH
OH R
Scheme 19
phosphine#palladium although\ in this case\ much longer reaction times are required[ The presence
of b!hydrogen atoms in the Grignard component can be problematical although the use of bidentate
phosphine ligands\ for example\ NiCl1"dppp#\ can circumvent this di.culty ð72TL4026Ł[ Although
palladium"9# catalysis is not suitable for coupling of enol phosphates with either organolithium or
Grignard reagents\ the less nucleophilic organoaluminum compounds are e}ective\ providing the
desired alkene in good to excellent yield ð73BCJ097Ł[ These reactions are highly stereospeci_c and a
range of organoaluminum compounds can be used with alkenyl! and alkynylaluminum ligands
showing greater migratory aptitude than alkyl groups[ With triethylaluminum it is more e}ective
to use diphenylphosphates\ although diethylphosphate can be e.ciently displaced in re~uxing 0\1!
dichloroethane[ Unlike the corresponding nickel!catalysed Grignard displacements\ a variety of
other vinyl leaving groups are stable\ notably vinyl sulphides\ and this can lead to the stereocontrolled
synthesis of tri! and tetrasubstituted alkenes[ Palladium catalysis is also required for the displacement
of enol phosphates with trialkylmanganates\ R2MnM "MLi\ MgBr#\ prepared in situ from
Li1MnCl3 and the organometallic species ð76CL1192Ł[ Reagents derived from organolithiums are
superior to those from the corresponding Grignard reagent whilst higher alkyl reagents tend to give
side!products from reduction and vinyl coupling[ These manganese reagents can also e.ciently
displace the tri~ate group from an enol tri~ate without the need for a co!catalyst[ With phenyl\
benzyl and alkylmagnesiumbromide the amount of Li1MnCl3 can be reduced to a catalytic quantity[
Enol "or vinyl# tri~ates are\ in general\ more reactive than the corresponding enol phosphate and
can readily be replaced by a variety of organometallic reagents and are a particularly attractive
source of cycloalkyl electrophiles\ being readily and stereospeci_cally obtained from the cor!
responding cyclic ketone ð77ACR36Ł[ Aryl!\ vinyl! and alkylcuprates\ including Me1CuLi\ a}ord the
corresponding alkene in high yield and with complete stereospeci_city ð79TL3202Ł[ The reaction is
relatively independent of the steric environment in either parameter with the only restriction being
that acyclic vinyl tri~ates can be di.cult to prepare regiospeci_cally[ The parent organolithium
reagents are not suitable for these reactions since they lead to S0O bond cleavage[ The major
C0C bond!forming use of vinyl tri~ates is in the palladium!catalysed coupling reactions
with organostannanes ð89OS"57#005Ł or organoboron compounds ð82JOC1190Ł[ In the presence of
¾1 mol) of tetrakis"triphenylphosphine#palladium and at least one equivalent of LiCl\ a variety
of organostannanes "alkyl\ vinyl\ acetylenic and aryl# couple e.ciently ð82S624Ł[ The presence of
the lithium salt is essential and aryl groups may be coupled if the equivalent arylzinc chloride is
employed[ In this and the corresponding displacement of aryl or vinyl halides other additives may
be equally e}ective\ including copper iodide ð89JOC4248Ł and copper oxide ð82JOM"359#016Ł[ Vinyl
groups are transferred more readily than alkyl groups whilst for the latter group b!hydrogen atom
elimination is not a problem[ In general\ both trimethyl and tributyl stannanes can be used\ both
o}ering di}erent advantages[ The former provides water soluble by!products and shorter reaction
times\ but is considerably more toxic and expensive\ and can be less easy to handle[ The reaction
proceeds in most polar solvents\ for example\ DMF\ DMSO\ HMPA and N\N?!dimethyl!
propyleneurea "DMPU#\ which not only solubilise LiCl but also act as ligands for the intermediate
complexes in the catalytic cycle ð75JA2922Ł[
Various vinyl ethers may also be converted to substituted alkenes on treatment with Grignard
reagents in the presence of nickel catalysts[ Both alkyl enol ethers ð73JOC3783Ł\ and silyl enol ethers
ð79TL2804Ł undergo the reaction with aryl and alkyl Grignard reagents[ The coupling is most facile
using nickel acetylacetonate as the catalyst when it proceeds in re~uxing ether[ However\ under
these conditions there is scrambling of alkene geometry[ Greater selectivity can be achieved through
the use of NiCl1"dppp# or related chelating phosphines[ With higher alkyl Grignard reagents\
By Substitution 370
competing reduction through b!hydrogen elimination can be suppressed through the use of the
ferrocenyl ligand "dppf#[ Cyclic vinyl ethers\ dihydrofuran "DHF# and dihydropyran "DHP# are
also substrates producing di! and trisubstituted homo! and bishomoallylic alcohols respectively in
good yield\ with predominant retention of alkene stereochemistry "see below#[ Although vinyl Grignard
reagents are not suitable\ a range of other alkyl and aryl Grignards are e}ective and provided the
reaction is quenched e.ciently almost complete stereoselectivity can be observed ð81JCS"P0#2308Ł[
Grignard reagents possessing b!hydrogen atoms are considerably less reactive\ giving product mixtures
containing reduction and isomerised by!products[ In general\ pyran substrates are less reactive requiring
higher catalyst loadings\ longer reaction times and give more modest yields "49Ð59)#\ failing completely
with Grignard reagents possessing b!hydrogen atoms ð81JCS"P0#2320Ł[
The opposite alkene stereochemistry can be obtained from the corresponding lithiated vinyl ether
through ring!opening reactions with alkyllithiums in the presence of CuCN "Scheme 19#[ The
intermediate cyanocuprate can be trapped with a range of electrophiles to provide the desired
substituted homoallylic alcohol of high isomeric purity ð78JA1252Ł[ The identical transformation
has also been reported to occur without the addition of CuCN ð80TL4892Ł[
R1X, pentane, THF

R1
R2MgX
O Li reflux, 2 h O R1 (Ph3P)2NiCl2 R2
69–96% 62–96% HO
>94% isomeric purity
BuLi, CuCN
Br HO
LiO
Cu(CN)Li 78%
>97% (Z)
R1 = alkyl, R2 = Me, PhCH2, TMS-CH2, Ph
Scheme 20
Treatment of the vinyl etherÐiron complex "04# with lithium enolates followed by subsequent
acid!promoted elimination a}ords the a!alkenylketone "05# ð77OS"55#84Ł[ Similarly\ treatment of the
"0\1!dialkoxyethylene# iron complexes "06# with cuprates\ Grignard reagents or enolates a}ords
moderate yields of either the cis or trans alkenes "Scheme 10# ð73JA6153Ł[ Finally diketene combines
with primary alkyl Grignard reagents in the presence of cobalt ð71BCJ2444Ł or nickel catalysts
ð66CL092\ 72CPB3235Ł to a}ord 2!methylene carboxylic acid in good yields[
OLi
i, , –78 °C
OEt O
ii, HBF4•OEt2, –78 °C
Fp+ iii, NaI, 25 °C
(15) (16)
O i, Me2CuLi O
EtO OEt
i, Me2CuLi ii, RT, 30 min
ii, OLi iii, OLi , –78 °C

Fp+
(17)
iii, NaI, 25 °C
37% iv, NaI, 25 °C
38%
Fp = η5-C5H5Fe(CO)2
Scheme 21
"ii# Displacement of vinylÐoxyèn by additionÐelimination

Regiospeci_c displacement of a vinyl alkoxy group from b!alkoxy enones is not possible with
either organolithium or Grignard reagents since preferential 0\1 attack occurs[ However\ on acidic
workup\ hydrolysis of the vinyl ether occurs with concomitant elimination of water to a}ord the
isomeric b!alkylated enone "Equation "19## ð62JOC0664\ 78S366Ł[ Similar transformations are also
possible commencing with the corresponding silylenol ether ð71SC684Ł[ The acidic workup step can
be avoided through the use of cerium!catalysed Grignard reagents ð81SC0842Ł[
C8H17
C8H17
O
Et2O, –78 °C, 5 min
then RT, 1 h
+ • (20)
93%
•
OBui
Li
O
ipso Substitution via additionÐelimination of an oxygen!centred leaving group is possible through

the use of lithium dialkylcuprates or related reagents[ There is considerable variety in the nature of
the leaving group^ b!alkoxy ð62CC896\ 77SC232Ł\ b!acetoxy! ð63TL814Ł and b!phosphoryloxy!ab!
unsaturated carbonyl compounds ð73OS"51#03Ł all a}ord good yields of the b!alkylated enone
"enoate#[ The corresponding sulphonates can also be used ð89ACS731Ł\ although elimination and a
second conjugate addition to a}ord the activated carbonyl compound can compete ð70JOC086Ł[
As with the analogous displacement of b!haloenones the reactions proceed with predominant
retention of stereochemistry[ With acyclic b!acetoxy substrates the use of phosphine!stabilised
cuprates and very low temperatures "½−009>C# are required for good stereoselectivity[ Similar
temperature requirements for high selectivity are also found for the readily accessible enol phos!
phates of b!ketoesters[ For these substrates the process is further limited to primary dialkylcuprates[
With the more reactive b!phosphoryloxy ketones even lithium di"t!butyl#cuprate reacts e.ciently
and can provide an e.cient entry to tetrasubstituted alkenes\ "Equation "10## ð68CJC0320Ł[ Higher
order cyanocuprates are required for e.cient substitution of a pivolate from b!pivaloyloxy
sulphones[ The stereochemical outcome\ although good\ is found to vary according to the bulk of
the transferred alkylcuprate ð76CC196Ł[
O i, NaH, (EtO)2P(O)Cl But O

CO2Me ii, (But)2CuLi (4 equiv.)
But (21)
80%
0[00[1[1[2 Displacement of arylÐoxygen leaving groups
"i# Substitution by orànometallic carbanions

As with enol ethers\ aryl methyl ethers can undergo displacement by Grignard reagents under
conditions of nickel catalysis[ However\ the reaction requires relatively vigorous conditions and is
limited to aryl Grignard reagents ð68JA1135Ł[ Much better yields are obtained using aryl phosphates
although a large excess of the Grignard reagent is required ð70TL3338Ł[ Similarly\ good yields
are obtained much more rapidly under mild conditions using the corresponding tetrazolyl ether
ð77TL4442Ł[ Aryl tri~ates\ being less reactive than their alkenyl counterparts\ are not displaced by
Gilman type cuprates\ undergoing competing S0O bond scission instead[ However\ clean coupling
is obtained on reaction with higher order cyanocuprates and with these latter reagents a wide range
of functionality is compatible ð72TL1612Ł[ Aryl tri~ates are also excellent substrates for palladium!
mediated coupling with a wide range of organostannanes ð76JA4367Ł\ organoboranes ð82JOC1190Ł
and trialkylaluminums ð78JCS"P0#1402Ł[
Arylstannanes are particularly suitable coupling partners for electron!rich aryl tri~ates providing
a convenient route to unsymmetrical biaryls ð81JOC567Ł[ Enhanced yields in this process may be
obtained through the use of the equivalent arylzinc species[ Symmetrical biaryls are obtained when
the aryl tri~ate is treated with only 9[4 equivalents of hexamethyldistannane[ These products
By Substitution 372
may also be accessed through modi_ed Ullmann reactions involving either ultrasound activation
ð75CL396Ł or transition metal catalysis ð82SL457Ł[
Aryl tri~ates may also be substituted\ in a palladium!catalysed process\ by silylketene acetals
ð80JOC150Ł or siloxycyclopropanes ð77JA2185Ł to a}ord\ in moderate to good yields\ a! or b!arylated
carbonyl compounds respectively "Scheme 11#[ In this reaction the presence of halide salts are
deleterious to the process[ Similar products may also be obtained in the palladium!catalysed reaction
of zinc Reformatsky reagents with phenyl ~uoroalkylsulphonates[ The analogous alkynyl and benzyl
zinc reagents also react e.ciently ð76TL1276Ł[ The resultant phenylalkynes can also be accessed
directly from the parent alkyne through a palladium!mediated Heck reaction ð75TL0060Ł\ "see also
Section 0[00[0[7[1#[
TMS-O OTf [(allyl)PdCl]2, PPh3 O

PhH, 100 °C, 3 h
+
84%
(methallyl)Pd(OAc)2, dppf
OMe TfO LiOAc, 65 °C, 6 h
+ MeO2C
O-TMS 70%
Tf = trifyl (trifluoromethanesulfonyl)
Scheme 22
"ii# Nucleophilic aromatic substitution

Oxygen!based leaving groups may be displaced from activated arenes through an SNAr process[
In this respect the displacement of methoxy groups from 0!methoxy!1!oxazolinyl arenes provides
an attractive route into enantiomerically pure biaryls ð74JA571Ł[ Other activating groups may be
employed provided that they are inert to the reaction conditions[ In this respect certain highly
hindered arylketones and nitriles have proved successful ð40CRV162Ł[ An alternative possibility to
achieve arene activation is via complexation with a transition metal[ However\ in this case the
process is normally one of non ipso substitution with the alkoxide being lost on protonation[
Suitably substituted heterocycles also undergo ipso substitution through an additionÐelimination
pathway ð75H"13#2226Ł[ For example\ sulphonates may be selectively displaced from the 1!position
of pyridines on treatment with a range of Grignard reagents[
SRN0 processes are possible with oxygen nucleofuges[ However\ only aryldialkoxy!phosphates
show any synthetic potential ð63JA001Ł[
0[00[1[2 Substitution of Other Chalcogens
0[00[1[2[0 Substitution of alkylÐchalcogen leaving groups

Displacement of alkyl sulfur leaving groups with vinyl organometallic nucleophiles is relatively
rare and is restricted to allylic substrates[ As with many allylic displacements regioisomeric products
frequently result[ Allylic sulfur ylides ð66JOM"031#0Ł\ sulfones ð72T2172Ł and sulfoximines ð80JA0331Ł
may be displaced by Grignard reagents in the presence of copper salts[ Other cuprates are less
e}ective[ Tertiary allylic sulfones\ which cannot be deprotonated\ undergo direct displacement
without the need for a transition metal catalyst ð76BSF376Ł[ Nickel catalysts are required for the
displacement of allylic seleno! ð79TL76Ł and thioethers ð68TL2314Ł whilst alkyl sulfones combine
with vinyl alanes in the presence of palladium catalysts ð75JA0987Ł[ Tertiary alkylsulfones have also
found a role in FriedelÐCrafts alkylation reactions "Equation "11## ð73JA6159Ł[
AlCl3 (2 equiv.)
SO2Ph
CH2Cl2, –78 °C to 0 °C, 1 h
(22)
70–80%
0[00[1[2[1 Substitution of alkenyl! or aryl!chalcogen leaving groups

Although b!styrylmethylthioether can be e.ciently combined with lithium di!n!butylcuprate all
other cuprate:substrate combinations are ine}ective in this addition ð62JOC1636Ł[ This is probably
not a direct displacement but rather follows an addition elimination pathway "see below#[
Grignard reagents\ but not the corresponding organolithiums\ may be utilised in the presence of
a nickel catalyst ð68CC526\ 68TL32Ł[ In general\ alkenyl thioethers are more labile than aryl thioethers\
whilst all these sulfur containing compounds are more reactive than the corresponding oxygen
species and this trend continues as the group is descended[ In most of these reactions\ there is
predominant retention of alkene stereochemistry although in some cases this is found to depend on
the exact nature of the catalytic species[ A similar observation can be made for the corresponding
selenides[ Displacement of vinyl sul_de can provide access to dienes and through the use of
dienylsul_des\ trienes and polyconjugated aromatic species ð77PAC68\ 78TL132Ł[ Cyclic vinyl thio!
ethers are cleaved by primary alkyl Grignard reagents although an excess of the Grignard reagent
is required if high yields are to be obtained ð74JOC2717Ł[ Thiophene\ selenophene and tellurophene
undergo a double substitution reaction to give "Z\Z# dienes stereospeci_cally with the exception
that phenyl magnesium bromide a}ords exclusively the "E\E# isomer "Equation "12##[ The yields are
normally good\ although the less reactive aliphatic Grignard reagents result in signi_cant "½09)#
amounts of arylated dienes formed by transfer from the phosphine ligands of the nickel catalyst
ð73CC506Ł[ Benzothiophene undergoes the analogous reaction and in this case\ consistent with the
reactivity order alkenyl×aryl\ the alkenylÐsulfur bond is cleaved _rst[ The di}erence is not large
and in many cases the cleavage of both bonds is competitive[ However\ selectivity can be observed
on the basis of steric size "Scheme 12# ð72T1178Ł[ Aryl thiols\ thioethers\ sulfoxides and sulfones are
all cleaved under similar conditions ð68CC526\ 82CC0571Ł[ Aryl selenides behave similarly with methyl
Grignards and are generally found to be more reactive "ArSeMeŁArCl×ArSMe#[ Within this
series\ some selectivity can be observed ð79TL76\ 80G48Ł[ The coupling is less e.cient with Grignard
reagents possessing b hydrogen atoms[ Selectivity is also observed with ketene dithioacetals which
can undergo stepwise substitution\ with the trans alkylthio group being replaced more rapidly\ to
a}ord trisubstituted alkenes in a stereospeci_c fashion "Scheme 13# ð71CC739Ł[
R2
R2MgX, NiCl2(PPh3)2
R1 (23)
R1 E R1 R1
R2
E = S, Se, Te; R1 = alkyl not aryl
SMe R1 R1
R1MgX R2MgX
NiCl2(PPh3)2 NiCl2(PPh3)2
SPri SPri R2
Scheme 23
SEt EtMgBr (1 equiv.) SEt MeMgBr
Ph SEt NiCl2(dppp) Ph NiCl2(dppp) Ph

85% 66%
Scheme 24
Diarylselenides are converted to biaryls on treatment with Raney nickel in the absence of solvent
ð57ACS0772Ł[ Diaryl sul_des and sulfones behave similarly on a variety of solid supports ð54JOC2786Ł[
By Substitution 374
Vinyl sulfones are good substrates for transition metal!catalysed displacement by Grignard
reagents ð74BSF651Ł[ The coupling is highly dependent on the Grignard:catalyst combination[ Aryl
Grignard reagents couple under either nickel or iron catalysis whereas the use of methyl magnesium
bromide is only possible with nickel catalysts[ In the latter case\ the geometrical purity of the product
alkene is found to decrease in the order Cl×Br×I ð71TL1358Ł[ Higher alkyl Grignard reagents\
notably secondary and tertiary species which with other catalysts a}ord signi_cant amounts of
competing reduction and isomerisation\ couple more e.ciently using Fe"acac#2 catalysis ð74BSF661\
77T000Ł[
Provided there are not propargylic hydrogen atoms present\ alkynyl sulfones are displaced by
phenyllithium or phenylmagnesium bromide\ in a single electron transfer process\ to a}ord the
corresponding phenylalkyne ð68JOC2333Ł[ Similar displacements are also possible from vinyl and
aryl sulfones ð73TL3740Ł[ Vinyl selenones undergo direct substitution on treatment with dimethyl!
copperlithium ð73JOC0129Ł[ "E#!alkenes are produced on treatment of vinyl sulfones with tri!
alkylboranes ð63BCJ492Ł[ Symmetrical diaryl sulfones are cleaved on reaction with 1 equiv[ of lithium
triethylborohydride to produce one equivalent of the alkylated arene[ This transformation is much
less e}ective with arylethyl sulfones ð72OM668Ł[
Vinyl sulfoximines are displaced\ with complete retention of stereochemical integrity\ on treatment
with an organozinc reagent in the presence of a nickel catalyst and a magnesium\ lithium or zinc
salt as a co!catalyst ð81TL350Ł[ The use of the analogous Grignard or organolithium reagent
produces the a!metallated sulfoximine and\ although substitution does occur on addition of a second
equivalent of the Grignard reagent\ the alkene is produced nonselectively[ Styryl sulfonylchlorides
may be coupled with alkenes in a ruthenium"II# mediated reaction to a}ord either "E\E#!0\3!diaryl!
0\2!butadienes or the haloalkylated alkene depending on the nature of the alkene substituent
"Equation "13## ð74JOC4934\ 77BCJ0120Ł[
[RuCl2(PPh3)3]
HCl, PhH, 150 °C, 43 h R
SO2Cl + R or Ar (24)
Ar R Ar
Cl
R = aryl, 74–97% R = alkyl, 46–53%
b!Thioalkyl!a\b!unsubstituted carbonyl compounds undergo ready substitution on treatment

with a range of copper!based reagents[ With the less reactive esters the reaction occurs with retention
of con_guration ð62CL0986Ł[ At low temperatures ketones are also suitable substrates although
more reactive cuprates can lead to double conjugate addition ð62CC896Ł[ With moderately reactive\
unhindered "E#!vinylogous thioesters "b!alkylthioenones# high selectivity with inversion is found in
Et1O\ whilst in THF\ retention occurs[ With one exception\ the equivalent "Z#!vinylogous thioesters
uniformly a}ord products with retention of alkene stereochemistry "Equation "14## ð75JOC3576Ł[
These vinylogous thioesters can be accessed by the addition of organometallic reagents to a!
oxoketenedithioacetals ð75T2918Ł[ The two alkylthio groups may be sequentially substituted to
a}ord tri! and tetra!substituted enones with high stereoselectivity[ Invariably\ the initial substitution
results in alkylation cis to the ketone "Equation "15## ð74JA3568Ł[ The corresponding b!alkyl!
thioenoates do not undergo substitution but are instead reduced to the parent enoate[ b!Methyl!
a\b!unsaturated esters are obtained following rearrangement on hydrolysis of the initial 0\1 adduct
formed by addition of methylmagnesium bromide[ More sterically demanding Grignard reagents
result in initial 0\3 displacement of an alkylthio group "Scheme 14# ð74JCS"P0#0178Ł[
O R2 Bu2CuLi O O Bu
+ (25)
R1 Bu
R1 = SMe, R2 = Me THF•Me2S, –78 °C, 93% 97:3
R1 = SMe, R2 = Me Et2O, –65 °C, 95% 5:95
R1 = Me, R2 = SMe Et2O, –78 °C, 61% 4:96
R1 = Me, R2 = SMe THF, –78 °C, 64% 8:92
O SR1 Me2CuLi O
THF, –78 °C, 5 min
(26)
SR2 R1 = Et, R2 = Me, 45% SR2
R1 = Me, R2 = Et, 67%
i, MeMgBr, reflux i, PhMgBr (3 equiv.), reflux

O ii, BF3•OEt2, MeOH O SMe ii, BF3•OEt2, MeOH Ph O
Ph OMe 56% Ph SMe 63% Ph Ph
Scheme 25
Aryl sulfones may be similarly displaced from a variety of activated alkenes ð78TL062\ 89JOC4335Ł[
Similarly\ ketone enolates may be used to displace a b!sulfonyl or b!sul_nyl group from a\b!
unsaturated carbonyl compounds ð89AJC0264Ł[ The phenylseleno group of b!selenosulfones can be
replaced by a range of active methylene compounds and alkylselenocuprates[ The use of a seleno!
cuprate is necessary to eliminate problems of double conjugate addition and transfer of the other
copper ligands[ Complete retention of stereochemistry is observed and consequently trisubstituted
sulfones may be formed stereospeci_cally[ The corresponding Cu"SePh#!catalysed Grignard addition
may be used with unhindered substrates albeit o}ering a less predictable stereochemical outcome
ð76JOC3147Ł[
0[00[1[3 Substitution of Nitrogen

The displacement of amino nitrogen from an sp2 carbon atom by a vinyl or aryl organometallic
reagent normally requires some additional activation such as the release of strain in the ring opening
of N!tosylaziridines ð78JOC4213Ł[ As with epoxide opening reactions\ cuprates are the most e}ective
reagents\ with coupling normally proceeding with enhanced e.ciency in the presence of Lewis acids[
On quaternisation\ allylic amines may be displaced by vinylcuprates ð74JA5026Ł and aryl Grignard
reagents in the presence of Li1CuCl3 ð76JOC1836Ł[ The use of butyl and benzylammonium salts
a}ords higher yields\ presumably due to enhanced solubility[
Cuprates may be employed for the displacement of allylic nitro groups ð73CC163Ł whilst tertiary
and benzylic nitro compounds may be employed in the FriedelÐCrafts alkylation of activated
arenes ð75CC0174Ł[ Alkylated arenes are also accessible through the reaction of a!diazoacetates
with phenyllithium although the same coupling can be achieved far more e.ciently using the
corresponding aryl ð62JOC1463Ł[ In a similar fashion b!g!unsaturated esters are obtained from the
related coupling of a!diazoacetates with vinyl chloroboranes ð80SL573Ł[
b!Vinyl nitrogen groups may be displaced from a variety of activated alkenes in an additionÐ
elimination process[ Enaminones undergo substitution on reaction with both Grignard ð20CB1432\
82TL3556Ł and organolithium reagents ð67JOC3137Ł\ although the former frequently required doubly
activated enaminones for e.cient coupling[ Similar substitution reactions have been reported
for noncarbonyl activated substrates\ for example\ nitroenamines ð58CB1855Ł[ Other nucleophiles\
notably ketone and ester enolates\ may be employed with some degree of success ð76CL0664Ł[
Arylnitro groups are readily displaced in a variety of SNAr reactions ð67T1946Ł whilst aryl diazonium
salts can be e.ciently replaced in an SRN0 process ð82T124Ł[
Early work on the copper!catalysed coupling of an aryl diazonium salts with activated alkenes\
the Meerwein arylation\ has been comprehensively reviewed ð65OR114Ł[ The reaction has been
re_ned such that the requirement for preparation and isolation of the diazonium salt can be
circumvented through in situ diazotisation by treatment of the free amine with an alkyl nitrite
ð66JOC1320Ł[ Further simpli_cation can be achieved on replacing the copper salt with a low valent
palladium complex[ This modi_cation extends the process to include alkenes substituted with both
electron!donating and !withdrawing groups[ Only acrylonitrile and enamines are not e.ciently
arylated[ Problems are observed with hindered alkenes whilst 0\1 disubstituted alkenes undergo a
competitive isomerisation ð70T20Ł[ In situ generation of the diazonium salt is also possible in
this palladium!catalysed reaction\ although only in strongly acidic conditions ð70JOC3774Ł[ Since
diazonium salts are amongst the most reactive of leaving groups some selectivity can be observed
with a wide variety of other substituents "Equation "16##[ Similar products may be obtained under
neutral conditions in the {Stille| cross coupling of vinylstannanes with arylazo compounds
ð72JOC0222Ł[ Recent developments have enabled these and the related arene alkylations with tri!
alkylstannanes to be carried out in aqueous media ð89IZV1554\ 82JCS"P0#0832Ł[ Finally\ aryl and allyl
trialkylammonium iodides may be substituted by a range of Grignard reagents in a nickel phosphine!
By Substitution 376
catalysed reaction[ As with many of these coupling reactions alkyl Grignard reagents possessing b!
sp2 hydrogen atoms are not suitable\ functioning instead as reducing agents ð77CC864Ł[
NH2 PhCH=CH2, ButONO, Pd(dba)2 (5 mol%) Ph

AcOH-ClCH2CO2H, 50 °C, 30 min
(27)
X = 2-Cl, 58%
X X = 4-Cl, 84% X
X = 4-I, 46%
X = 4-NO2, 78%
X = 2-CO2H, 46%
0[00[1[4 Substitution of Boron

Dialkylalkenylboranes\ readily accessible via hydroboration of alkynes\ can be converted into a
range of substituted alkenes "Scheme 15# ð60JA5298Ł[ Enantiomerically pure "×88)# alkenes of
de_ned geometry are readily accessible through the use of homochiral hydroborating agents pre!
pared from monoisopinocamphenylorganoboranes ð80TA166Ł[ Treatment of 0\0!""Z#!0!bromo!
alkenyl#dialkylboranes "08# with base\ followed by protonolysis of the resulting alkylated
alkenylborane a}ords\ the disubstituted "E#!alkene "19# ð56JA4975Ł[ The isomeric "Z#!alkenes "11#
are obtained on treatment of "E#!alkenyldialkylboranes "10# with sodium hydroxide and iodine
ð56JA2541Ł[ Trisubstituted alkenes "13# can also be prepared in a similar fashion commencing from
disubstituted alkynes ð64S265\ 77JOC5998Ł[ Despite the high stereoselectivity of these conversions\ all
su}er from the need to generate the starting alkenylborane through hydroboration of an alkene
with the dialkylborane[ In order to obtain chemoselectivity in this process it is necessary to use
large\ sterically demanding alkyl groups which obviously restricts the possible alkenes that can be
prepared[ Furthermore\ synthetic e.ciency is low as only one of the alkyl groups may be transferred[
i, NaOMe
ii, MeCO2H
+ Br Bu )2B
)2BH 64%
Br Bu Bu
(19) (20)
I2, NaOH Bu
+ Bu )2B
)2BH 70%
Bu
(21) (22)
I2, NaOH
+ But )2B
)2BH 68%
But But
(23) (24)
Scheme 26
Most of these di.culties can be circumvented through the use of alkyldihaloboranes followed by
controlled reduction "{hydridation|# "Scheme 16# ð77JOC128Ł[ However\ the formation of "Z#!alkenes
via transfer of a primary alkyl group su}ers from competing "E#!vinyl iodide formation although
this can be minimised by carrying out the reaction at low temperatures[ Similar side products
complicate the synthesis of trisubstituted alkenes through the addition of vinyllithiums to B!alkyl!
8!BBN derivatives ð79S834Ł[ Alternatively\ hydrolysis of the alkenyldibromoborane followed by
treatment of the resultant boronic acid derivative "14a# with a stereode_ned vinyllithium yields the
{ate| complex "15# which\ on reaction with iodine and base\ then a}ords the substituted alkene of
inverted geometry "Scheme 17# ð65JOC2836Ł[ The order of addition to the boron centre may be
reversed[ This variation\ the combination of a vinyldialkoxyborane "14b# with an organolithium or
Grignard reagent ð77JOC128\ 77JOC5998Ł\ allows for the incorporation of groups not accessible by
hydroboration notably aryl and heteroaryl\ whilst the addition of a!halocarbanions can provide an
entry to a!alkenylketones and related species ð75JOC2287Ł[ Both "Z# and "E# isomers can be formed
selectively although the reaction leading to trisubstituted b\g!unsaturated carbonyl compounds is
nonselective[ For these targets\ high selectivity and moderate overall yields can be obtained through
the use of "1!"tributyltin#alkenyl#boranes ð82JOC0838Ł[
Br H
R1 LiAlH4 R2
HBBr2•SMe2 B B
R1 Br (0.25 equiv.) R1 Br
Br
R1 R2 + R2
B
R1 R2
I
59–79% <16%
Scheme 27
R2 OMe
B + R1Li
OMe OMe
MeO I2, NaOH R1 R2
(25a)
B–
R1 R2
OMe
R1 B + Li (26)
R2
OMe
(25b)
Scheme 28
In a similar fashion selective diene and enyne synthesis is possible "Scheme 18# ð75MI 000!90Ł[
Symmetrical "Z\E#!dienes can be prepared from the corresponding dialkenylborane although good
yields are only obtained with boranes containing a nonmigrating group ð62JOC0506\ 65JOC0674Ł[ The
use of alkyldialkenylboranes\ including those derived from thexylborane\ is not satisfactory as
competitive alkyl group migration can occur^ this problem can be circumvented by prior oxidation
with trimethylamine!N!oxide\ to yield the corresponding dialkenylborinate ð57JA5132Ł[ Unsym!
metrical dienes can also be prepared using similar strategies to those illustrated for simple alkenes[
"Z\E# Dienes are synthesised through the addition of lithium acetylide to dialkylalkenylboranes
followed by treatment with boron tri~uoride and in situ protonolysis ð67JOM"045#048Ł and "E\E#
dienes from "0!haloalk!0!enyl#alkenylboranes ð80T232Ł[ The equivalent symmetrical "E\E# and "Z\Z#
dienes can be e.ciently obtained from the appropriate alkenylborane in a copper bromideÐmethyl!
sulphide catalysed procedure ð79JOC438Ł[ This is postulated to proceed via the dimerisation of the
corresponding alkenylcopper compound\ as are the related processes involving treatment of either
alkenyldibromoboranes ð79JOC278Ł or dialkenylchloroboranes ð66JA4541Ł with three equivalents of
methyl copper[
R1 R2
R1 R2 I2, NaOH
R1
85–90%
3 B
R2
i, NaOMe R2
B R1 ii, CuBr•SMe2 R1
2
79–99% R1
R2 R2
R1 = H, R2 = alkyl or R1 = alkyl, R2 = H
Scheme 29
Many of these methods\ particularly those directed towards conjugated "E\E# dienes\ have been
superseded by developments in the palladium!catalysed coupling of organoborane derivatives with
By Substitution 378
a wide variety of haloalkenes\ !alkynes and !arenes as well as the corresponding tri~ates[ The
reactivity varies in the order I×Br×OTfŁCl ð80PAC308\ 82JOC1190Ł[ Chlorides may be employed\
albeit with some di.culty\ their successful replacement requiring the use of bidentate phosphine
ligands ð81T7006Ł[ The reaction proceeds with complete retention of alkene stereochemistry in both
components[ Both boranes and boronates may be employed with the latter providing greater
e.ciency ð82ACS110Ł\ particularly when a "Z#!alkenyl boron group is to be coupled ð75TL2634Ł[
The reactions require the presence of a base "alkoxide\ acetate\ hydroxide# to facilitate the
transmetallation between the organopalladium intermediate and organoborane[ However\ as
noticed previously "see Section 0[00[1[0[2"ii## the nature of the base can alter the regiochemistry of
the addition ð70JOM"102#C42Ł[ Although both Heck! and Suzuki!type couplings can occur with the
same substrate\ reasonable selectivity for either pathway can be achieved although the precise
outcome can depend upon the reaction conditions "Equation "17## ð82TL2488Ł[
CO2Me
I CO2Me CO2Me O
O B
B
O
O + (28)
58%
Pd(OAc)2 (5 mol%), phenanthroline, ButOK, MeCN, 45 °C, 66 h 100% 0%

Pd(OAc)2, Ph3P, Bu3N, PhMe, 120 °C, 18 h 13% 87%
The organoboron component may be alkenyl ð89OS"57#029Ł\ aryl ð70SC402\ 81SL196Ł or alkyl
ð78JA203Ł[ In alkylation reactions the nature of the phosphine ligand can be crucial since com!
plications due to phosphine quaternisation or competitive phenyl transfer from the phosphine can
occur[ These problems can be minimised through the use of substituted phosphine ligands\ for
example\ tris"1!methoxyphenyl#phosphine[ Further improvements can be achieved through the
addition of excess phosphine although this results in a slower reaction ð81TL5568Ł[ Both alkyl borane
and boronic acid derivatives may be employed[ The latter couple more e.ciently as the free acid
ð89TL5498Ł whilst further enhancements of both the rate and the yield are obtained through the
use of thallium hydroxide as the base "rel[ rate KOH0\ TlOEt4\ Ag1O29\ TlOH0999#
ð76JA3645Ł[ Methyl\ primary and secondary alkyl groups may be employed[ Although secondary
alkyl groups only couple slowly\ b!hydrogen elimination is not normally a problem[
Aryl boronates also o}er advantages over the corresponding boranes in that they are more
accessible\ air stable reagents "being prepared by transmetallation from the corresponding aryl!
lithium reagent#\ that only require weak bases to facilitate the cross!coupling reaction[ The use of
tetraaryl borates "NaAr3B# with vinyl and aryl tri~ates can eliminate the need for a base altogether\
although an equimolar quantity of the borate is required ð81TL3704Ł[
Polysubstituted alkenylboranes may be employed with halide groups undergoing preferential
substitution\ and as a result\ selective synthesis of trisubstituted alkenes ð75CL0218\ 82CL0318Ł and
unsymmetrical polyenes is possible ð77CL798Ł[ Multiple functionalisation is also tolerated in the
{acceptor| component and this can provide an alternative entry to a!vinyl! and arylketones\ etc[
ð81BCJ1752Ł[ Finally\ alkenylation and alkylation may be achieved in both an inter! and intra!
molecular fashion providing a convenient synthesis of cycloalkenones "Equation "18##[
O O O O
i, 9-BBN, THF, RT
(29)
ii, PdCl2, NaOH
71%
9-BBN = 9-borabicyclo[3.3.1]nonyl
0[00[1[5 Substitution of Silicon and Germanium

Although aryl and vinyl silanes undergo a vast number of electrophilic ipso substitution reactions\
relatively few lead to simple alkene:arene coupling:alkylation[ Biaryls may be prepared from aryl
silanes whilst vinyl silanes may be dimerised\ although geometrical mixtures of isomers result[
Stereospeci_c alkene synthesis is possible from vinyl silanes in a indirect fashion via epoxidation\
cuprate opening and Peterson elimination ð78JOC757Ł[ Arenes may be e.ciently allylated on reaction
with either allyl silanes or allyl germanes in the presence of thallium tri~uoroacetate ð70TL3380Ł[
The reaction probably proceeds via the corresponding organothallium salt as does the analogous
thallium"III# promoted arylation with aryl silanes ð63TL2280Ł[ Although the C0Si "and C0Ge#
bond is less polar than the corresponding C0B bond and consequently activation by transition
metal catalysts more di.cult\ vinyl and styryl silanes may be employed in the Heck reaction
ð60TL3690Ł[ Vinyl silanes combine with aryl halides under palladium catalysis to a}ord styrene
derivatives[ These arise through re!addition of the initially formed palladium hydride and subsequent
antielimination of the trimethylsilyl and palladium moieties[ Addition of silver salts suppress the
re!addition and styryl silanes are isolated ð75JOC4175Ł[ Similar results have been observed in the
coupling of aryl diazonium salts with vinyl silanes under palladium catalysis[ Although a!substituted
alkenyl silanes react with high selectivity ð77CL762Ł\ substitution of the b!isomers proceeds with loss
of regio! and stereochemical integrity "Scheme 29# ð75JCS"P0#0848Ł[ Similar observations have been
recorded for the analogous germyl derivatives ð89CL074Ł[
Ph R1 ArN2BF4
Ph D Ph Ph D
+ +
R2 Pd(dba)2(cat.), MeCN Ar Ar D Ar
R1 = D, R2 = TMS 86%, 89% 11% 0%
R1 = TMS, R2 = D 91%, 83% 0% 17%
Ph ArN2BF4 Ph Ph
+
Pd(dba)2(cat.), MeCN
Et3Si Ar Ar
>99 <1
Scheme 30
E.cient substitution of silicon frequently requires the formation of a pentacoordinate silicon

species[ Commonly generated by addition of ~uoride\ these organo~uorosilicates are e}ective
alkenyl and aryl transfer reagents a}ording\ in the presence of palladium salts\ routes to 0\2! and
0\3!dienes as well as substituted arenes ð71OM431\ 80SL734\ 82CRV0260Ł[ In the presence of various
late transition metal salts\ homocoupling to produce symmetrical "E\E# dienes is possible ð69JPR049\
68TL0026\ 68TL0030Ł[
Vinyl\ alkynyl and allyl silanes couple with aryl\ alkenyl and allyl iodides and bromides in
the presence of "trisdiethylamino#sulfoniumdi~uoro trimethylsilicate "TASF# and allylpalladium
chloride dimer[ The coupling is stereoselective\ clean\ high yielding and tolerant of a wider range of
functionality "including unprotected alcohol and carbonyl groups# than most related transition
metal coupling processes ð77JOC807Ł[ However\ under these conditions the reactions of aryl halides
is limited to the iodides and even these require the presence of HMPA as a co!solvent[ Likewise\ the
addition of methylphosphite is bene_cial for couplings with alkenyl halides[ Similarly the nature of
the silyl groups can signi_cantly a}ect the e.ciency of the coupling ð78JOC157Ł[
TASF can also act as an arene methylating reagent ð77TL86Ł and consequently alternative sources
of ~uoride\ such as tetra!n!butylammonium ~uoride "tbaf#\ can prove advantageous with aryl
halides[ Similarly\ competitive transfer of the methyl group from aryl methyl di~uorosilanes can
occur[ In this case the use of the ethyl analogue suppresses this pathway and allows for the e.cient
synthesis of biaryls in the presence of either tbaf or potassium ~uoride ð78CL0600Ł[ Alkoxy!
dialkylsilylalkenes behave analogously and have advantages over halosilanes in that they are stable
and can be easily regiospeci_cally prepared through intramolecular hydrosilylation "Scheme 20#
ð78TL5940Ł[
Finally\ vinyl tri~ates couple e.ciently with alkenyl\ aryl\ alkynyl and alkyl organo~uorosilicates[
Although migration of an alkyl group is slow\ those containing b!hydrogen atoms prove to be
acceptable substrates ð89TL1608Ł[
0[00[1[6 Substitution of a Metal

Direct substitution of a metal by a carbon nucleophile is relatively rare[ Soft nucleophiles "b!
dicarbonyl compounds\ etc[# displace lead from aryl! ð79TL854Ł and vinylleadtriacetates
ð77JCS"P0#1736Ł[ Otherwise\ formation of carbonÐcarbon bonds through substitution of a metal
occurs principally in the dimerisation of organometallic units[ In order not to repeat material
By Substitution 380
Me
i, (HMe2Si)2NH Me
C6H11 C6H11 Si
OH ii, H2PtCl6•6H2O O
Br
Ph PhI
[allylPdCl]2, tbaf
P(OEt)3, THF, 50 °C
Ph Ph
C6H11 C6H11
OH OH
42% (overall), >99% (E, E) 67% overall, >99% (E)
tbaf = tetra-n-butylammonium fluoride
Scheme 31
covered elsewhere\ this section will not refer to those methods involving transiently generated
organometallic species[
The simplest method to obtain symmetrical dienes through this connection is the thermal dimer!
isation of a vinylcopper or silver salt[ The reaction proceeds in good to excellent yields with almost
complete retention of monomer stereochemistry ð60JA0268Ł[ The same conversion may be achieved
on addition of a variety of transition metal salts\ or\ more e.ciently\ by bubbling oxygen through
a cooled solution of the vinylcopper or cuprate ð63JOM"66#158\ 65JA2621Ł[ Other oxidising species
may also be employed[ In this respect various nitrogen!containing oxidising agents\ for example\
NO1\ MeNO2 and LiNO2\ are particularly e}ective for the silver!promoted coupling of vinyl and
aryl Grignard reagents ð61BCJ0019Ł[ The latter can frequently be coupled more e.ciently on com!
bination of the aryl Grignard reagent with a thallium salt ð65OS"44#37Ł[ A wide range of aryl and
vinyl Grignard and lithium reagents may be dimerised on treatment with a variety of transition
metal complexes including Li1CuCl3 ð75T0288Ł\ Pd"PPh2#1Cl1 ð76JOM"223#070Ł and Cr\ CoII and MnII
salts ð65JOM"002#88Ł[
Other organometallic species also couple on addition "transmetallation# with copper salts\ notably
alkenyl alanes ð69JA5567Ł\ zirconanes ð66TL0292Ł and stannanes ð76JOC3185Ł[ Alkenyl! and aryl!
stannanes are also dimerised on treatment with palladium chloride in HMPA ð78S522Ł[ A similar
dimerisation is obtained on reaction with palladium acetate and tert!butylhydroperoxide and with
this catalyst combination selective cross!coupling with allylstannanes occurs "Equation "29##
ð76CL4Ł[
SnBu3
Ph + Ph (30)
SnEt3 Ph Ph
Pd(OAc)2, ButOOH
PhH, RT
72%, 100% (E) 0%
Provided that the toxicity is not considered a problem\ symmetrical biaryls can be e.ciently
prepared from the corresponding arylthallium bis"tri~uoroacetate# on treatment with a catalytic
amount of Li1PdCl3[ Given that aryl thallation is relatively simple to control\ a variety of di}erently
substituted products can be easily accessed by this method ð72JOC0813Ł[
Vinylmercury compounds provide an attractive entry to symmetrical dienes ð75MI 000!91Ł[ Vinyl
and aryl mercuric halides dimerise in high yield on treatment with LiPd1Cl3 ð65JOC1130Ł[ A wide
range of functionality may be present whilst steric hindrance presents no problems[ However\ the
reaction does require stoichiometric palladium chloride and the use of HMPA as a solvent[ These
problems may\ in part\ be circumvented through the use of either divinylmercury reagents which
dimerise on treatment with catalytic quantities of palladium"9# phosphine complexes ð63TL2196Ł[
However such divinyl mercurials are considerably more di.cult to handle than the corresponding
halide salts and more importantly the reactions proceed with a small but signi_cant "³04)#
loss of stereochemical integrity[ Similar loss of stereochemical information occurs on addition of
stoichiometric cuprous chloride to recycle the palladium catalyst[ Interestingly\ in this case inversion
of alkene geometry is the favoured pathway "Equation "20## ð63CB0543Ł[ The use of the rhodium
carbonyl complex ðRh1"CO#3Cl1Ł[LiCl avoids these di.culties and cleanly and e.ciently provides the
head!to!head coupled dimer ð66JOC0579Ł[ Replacing LiCl by the more soluble tetraalkylammonium
halides can provide for a faster reaction ð73IZV1479Ł[ The head!to!tail diene is obtained selectively
using palladium catalysis and switching to a non!polar solvent\ for example\ benzene\ in the absence
of lithium chloride "Equation "21##[ The addition of a base\ for example\ triethylamine\ to neutralise
the HCl generated a}ords enhanced yields\ whilst the process can be rendered catalytic in palladium
on addition of 1 equiv[ of cuprous chloride ð67JOC0357Ł[
Ph CO2H Ph CO2H CO2H

Ph HgCl
Li2PdCl4, CuCl2 Ph Ph
+ + (31)
92%
Ph
CO2H
HO2C Ph HO2C HO2C
86% 14% 0%
cat.
(32)
HgCl
cat.
PdCl2 (10 mol%), 2 CuCl, 2 Et3N, PhH, RT 0% 98%
[ClRh(CO)2]2 (1 mol%), 2 LiCl, HMPA, RT 90% 0%
Finally\ the dimerisation of aryl mercurials can provide a particularly useful\ and complementary\
modi_cation to the classical Ullmann reaction[ Aryl mercurials containing an amino group\ which
completely inhibits the normal copper!catalysed reaction\ are converted to biaryls on treatment
with the palladium dichloride:copper"I# chloride catalyst system ð65JOC1550Ł[
0[00[1[7 Substitution of Hydrogen
0[00[1[7[0 FriedelsÐCraft alkylations using alkenes and alkanes

The intermediate carbocation in the FriedelÐCraft alkylation of arenes can also be generated
from the corresponding alkene and this strategy is of considerable industrial importance\ notably
in the manufacture of ethyl! and isopropylbenzene[ Through careful choice of catalyst and reaction
conditions it is possible to observe some degree of control over product formation[ For example
ortho!alkylation of phenol can be realised on treatment with 0!hexene in the presence of aluminum
phenolate "Equation "22## ð75UKZ0989Ł[ Similarly\ provided the catalyst and:or the conditions are
mild\ then alkylation without rearrangement may be observed ð61ZOR0373Ł[ Control in this class of
FriedelÐCrafts alkylation may also be achieved through the use of functionalised alkenes ð80JA0253Ł[
For example\ the use of protonated nitroalkenes as the electrophilic component provides an e.cient
entry to a!arylated ketones which can be di.cult to prepare through classical FriedelÐCrafts
alkylation "Equation "23## ð78JOC622Ł[
OH OH
200 °C, 8 h
+ + (PhO)3Al (cat.) (33)
molar ratio [ 3 : 1 : 0.3 ]
i, CF3SO3H, –40 °C, CH2Cl2, RT R2

NO2 ii, MeOH, –78 °C to RT
+ R2 O (34)
R1 37–87%
R1
R1 = alkyl, phenyl; R2 = H, alkyl, phenyl

By Substitution 382
Alkylation of arenes with alkanes can also be achieved[ However\ this process is accompanied by
competing isomerisation and disproportionation reactions and is consequently not of great synthetic
viability[
0[00[1[7[1 Organopalladium!mediated substitution of alkenes

Organopalladium derivatives lacking b hydrogen atoms combine with unhindered alkenes in a
process that results in e}ective substitution of vinylhydrogen[ This\ the Heck reaction\ proceeds via
a syn!additionÐsyn!elimination pathway and\ where possible\ leads preferentially to the "E# alkene
isomer ð80COS"3#722Ł[ The initial organopalladium species is normally generated in situ by either
transmetallation of a palladium"II# salt with an organometallic reagent\ direct palladation "of
arenes#\ or by oxidative addition of an alkyl\ alkenyl or aryl halide\ tri~ate\ diazonium salt\ etc[ to
a low!valent palladium complex ð74MI 000!91Ł[ The reaction may be rendered both catalytic in
palladium and enantioselective "see below#[ Ruthenium complexes may also be employed and in
some cases show considerably greater activity than the corresponding palladium species
ð81JOM"312#394Ł[
Electrophilic aromatic substitution with palladium acetate occurs readily although\ as with many
aromatic substitution reactions\ mixtures of isomeric products arise[ However\ some selectivity can
be observed in cases in which the arene contains a good ligating group "Scheme 21# ð70T062Ł[ A
second drawback to this approach is the requirement for a stoichiometric quantity of the initial
palladium salt although a number of catalytic modi_cations have been reported ð73T1588Ł[
O
Cl O
)2
Li2PdCl4 Pd Et3N
NMe2 NMe2 98%
MeO NMe2
MeO MeO
Scheme 32
Transmetallation of hard organometallic species is complicated by competing redox processes[

Although good synthetic yields can be realised with the appropriate choice of palladium ligands\
particularly with stabilised anions\ the fact that the process cannot be rendered catalytic limits its
use ð73T1304Ł[ As a result\ generation of organopalladium species by a transmetallation process is
only viable using soft organometallic species such as organoboranes ð64JOC0972Ł\ organomercurials\
organosilanes ð63JOM"61#052Ł and organothallium reagents ð64JOM"88#C7\ 79BCJ442Ł[
Transmetallation of alkyl\ aryl and alkenyl mercurials "RHgX and R1Hg#\ is fast and selective
although the use of alkyl groups is restricted to those lacking a b hydrogen atom[ The preparation
of the corresponding arylmercurials is relatively facile and tolerant of a wide range of functionality[
The coupling reactions are normally highly regioselective\ favouring substitution at the least hin!
dered terminus of the alkene and at the b!position of Michael acceptors ð57JA4407Ł[ "E:Z# alkene
isomerisation can be problematical although in some cases use of the corresponding thallium salt
can be advantageous ð73JA4163Ł[ Diene synthesis is possible although the yields are frequently low
due to readdition of the palladium hydride species to a}ord p!allyl palladium complexes[ The
addition of tertiary amine bases alleviates this problem and synthetically useful yields of 0\2!and
0\3!dienes may be realised ð70TL4120Ł[ Although such an approach can be rendered catalytic in
palladium through the addition of an oxidant\ for example\ CuCl1 ð58JA5696Ł\ it is normally more
e.cient to generate the organopalladium species via oxidative addition of RX to a palladium"II#
salt[ These are all catalytic with the only requirements being the presence of a base\ to neutralise
the acid formed in the reaction\ and in most cases a triarylphosphine to solubilise the various
catalytic intermediates[ In this respect temperature control is critical to achieve a balance between
reaction rate and palladium solubility "the latter decreases at higher temperatures#[ A variety of
electrophiles may be employed with the reactivity decreasing down the series] 0N1¦ ×0OTf
×0I×0Br×0Cl×0SO1Cl×0COCl[
Whilst intermolecular alkene alkylation is limited to benzylic halides ð63JA0022Ł\ intramolecular
processes are known for a range of substrates including those containing b!sp2 hydrogen atoms[
However\ it should be noted that many of these processes a}ord halide products ð74TL0408Ł\
presumably via a competing\ radical!mediated atom transfer pathway[ Multiple C0C bond!forming
processes are possible in situations in which the intermediate alkylpalladium hydride can be inter!
cepted by a second alkene prior to elimination "Scheme 22# ð82JA8310\ 83T248Ł[
OMe
OMe
Pd2(dba)3•CHCl3 (2.5 mol%)
PhO2S Ph3Sb (10 mol%), AcOH, PhH, 65 °C
PhO2S 84% PhO2S

3 PhO2S
CHO
Pd(OAc)2, Ph3P, KOAc CHO

N anisole, 130 °C, 24 h N
I
91%
N N
SO2Ph SO2Ph
Scheme 33
Alkene arylation is most e}ectively achieved with aryl iodides and in many cases these couplings
occur at ambient temperatures in the absence of any phosphine ð68JOC3967Ł[ In contrast\ aryl
bromides require excess phosphine ligands to maintain catalyst solubility and to minimise the e}ect
of competing phosphine quaternisation[ This\ and problems associated with competing phenyl
transfer from the phosphine\ can be alleviated by the use of more bulky substituted phosphines\ for
example\ tri!ortho tolylphosphine ð67JOC1830Ł[ However\ even relatively unreactive aryl chlorides
may be utilised in the presence of a NaIÐNiBr1 mixture which probably results in the in situ
generation of the corresponding iodide ð77JA1544Ł[ A number of other aryl groups may similarly be
employed including stannanes ð76JOC4953Ł\ acid chlorides ð71JOM"122#156\ 73JOM"154#212Ł\ sulfonyl
chlorides ð89JCS"P0#1196Ł\ sul_nates ð69JOC2162Ł and sulfonates ð75TL0060Ł and diazonium salts "see
above#[ A wide range of other substituents is tolerated including\ when diazonium salts are employed\
the ortho!carboxy group[ In general\ electron!withdrawing groups accelerate and electron!donating
groups retard the reaction[ Consequently\ coupling is frequently complicated by competitive
reduction for these less reactive electron!rich arenes[ Dienes behave similarly although synthetically
useful yields are only obtained with dienes additionally conjugated to an electron!withdrawing
group ð67JOC4907Ł[ As with simple alkenes\ preferential attack occurs at the least substituted diene
terminus[ Butadiene combines with reactive arenes to a}ord products of double arylation[ With
unsymmetrical alkenes some regioselectivity can be obtained by varying the nature of the phosphine
ligands[ Using aryl tri~ates\ bidentate phosphines favour a!arylation whilst b!aryl alkenes are
produced with monodentate ligands[ However\ bidentate palladium phosphine complexes are only
suitable for the coupling of aryl halides in the presence of a halide!sequestering agent ð81JOC2447Ł[
The Heck reaction between vinyl iodides and activated alkenes provides a very e.cient route
to conjugated dienes ð67JOC2787Ł[ Similar results are obtained through the use of vinyl tri~ates
ð74JOC1291Ł[ The coupling reaction is sensitive to steric restrictions\ in either component[ As with
alkene arylation\ acceptable yields of dienes are only obtained when the acceptor alkene is activated
by an electron!withdrawing group[ In these cases predominant formation of the "E\E# isomer results
due to isomerisation through reversible additionÐelimination of the palladiumÐhydride species
generated in the reaction[ In situations in which there are di}erent hydrogen atoms available for
elimination this isomerisation can result in the formation of alkene regioisomers[ This complication
can be suppressed through the use of milder reaction conditions accessible through a combination
of DMF as the solvent and the presence of an alkali metal acetate as a co!promoter ð77TL894Ł[
Various other additives including silver ð76JOC3029Ł and thallium salts ð80TL576Ł have also been
utilised successfully[ Recent developments using phase transfer catalysis ð73CC0176Ł\ high pressures
ð83SL078Ł or aqueous conditions ð81SL604Ł have enabled the reaction to be carried out at much
lower temperatures[
By Addition 384
Finally through the use of chiral phosphines the Heck reaction may be rendered enantioselective[
The highest enantioselectivities are obtained with vinyl tri~ates ð81TL1478Ł although similarly good
results may also be obtained from vinyl iodides\ provided a silver salt is present "Equation "24##
ð83T260Ł[
O-TBDMS O-TBDMS
X Cl2Pd[(R)-binap]
(35)
H
X = I, NMP, Ag3PO4, 60 °C, 84 h, 67% 80% ee
X = OTf, PhMe, K2CO3, 60 °C, 55 h, 35% 92% ee
0[00[1[7[2 Miscellaneous methods

Through cobalt!mediated radical coupling procedures it is possible to e}ectively substitute a
vinylic hydrogen atom ð80TL5162Ł[ This is e}ectively an alkyl equivalent of the Heck reaction\ a
process that is normally severely restricted due to b!H elimination[ This {substitution| process may
be combined with a series of radical cyclisations enabling the incorporation of structurally complex
alkyl groups "Equation "25## ð89JCS"P0#1698Ł[ The reverse connection\ e}ective substitution of alkyl
hydrogen by an alkene unit\ can be achieved through the use of in situ!generated alkylidene carbenes
"Equation "26## ð72JOC4140Ł[ Similar ketocarbene insertion reactions can provide access to alkyl
substituted arenes and related cyclic polyenes ð80COS"3#0920Ł[ Finally\ in the presence of an oxidising
agent\ direct substitution of electron de_cient arenes is possible with a variety of organolithium and
Grignard reagents ð67HCA338Ł[
I i, CoII(salophen), 1% Na/Hg CO2Et

THF, 25 °C, dark
(36)
ii, CO2Et , hν
O O
65%
O (RO)2P(O)CHN2, THF
(37)
KOBut, –78 °C, 2 h
Bu
51%
0[00[2 BY ADDITION
0[00[2[0 Nucleophilic Addition to Allenes

Direct addition of organometallic units "carbometallation# to unactivated allenes is possible\
although limited to the more reactive species such as organolithium and Grignard reagents
ð61JOM"23#0Ł[ Intermolecular reactions are possible and tend to occur at the central carbon atom
ð60TL2674Ł[ However\ low reactivity is a common problem\ for example\ organocuprates do not add
ð78T302Ł\ and in general the addition is more facile in an intramolecular fashion ð58TL1202Ł[ In these
cases the length of the tether controls the regiochemistry of the resultant cycloalkene "Equation
"27## ð81TL4200Ł[ In many cases these reactions probably proceed by a radical pathway since the
product ratios are similar to those obtained under free radical conditions ð67JCR"S#305\ 71BSF158Ł[
Softer nucleophiles\ such as active methylene compounds\ may be employed in the presence of a
palladium catalyst to a}ord moderate yields of unsymmetrical 1\2!dialkyl!0\2!butadienes "Equation
"28## ð62JOC0372Ł[
•
E
i, –100 °C to T °C (see below) E noncyclized
( )n + + (38)
ii, E+ (H+ or PhCHO)
material
M
n=1 M = MgBr RT 0% 100% 0%

n=1 M = Li –78 °C 100% 100*% 0% 0%
n=2 M = Li –78 °C 86% 3% 50% 47%
n=2 M = Cu(CN)Li 0 °C 86% 0% 80% 20%
(* 7:3 mixture of exo / endocyclic alkene isomers)
(Ph3P)2•C4H2O3, THF, 100 °C R2

• + R1 R2 (39)
28–86%
R1
R1, R2 = MeCO-, CO2Et, CN
Simpler\ more e.cient addition is obtained with allenes containing an activating group\ either
alkoxy! or electron!withdrawing\ and with these substrates the use of copper!based reagents is
particularly e}ective[ 0!Alkoxyallenes combine with both lithiumorganocopper and cuprates to
produce the "Z# and "E# alkenic products\ respectively "Scheme 23#[ Exclusive addition occurs at
C!2 with high stereoselectivity being observed in both cases ð73IJ002\ 81BSF060Ł[ The corresponding
magnesio species are not selective ð65TL836Ł[ In contrast\ allylmetal reagents "Zn\ Cu# preferentially
attack at C!0[ Allenes bearing large substituents undergo elimination of zinc alkoxide leading to
e}ective substitution of the alkoxy group[ Similar products are obtained if the alkoxyallene is
metallated prior to addition of the allylzinc reagent[ A variety of carbonyl groups may be employed\
in which case the reaction is essentially a Michael addition[ The use of vinyl nucleophiles provides
an easy entry to 1!substituted butadienes ð81TL6918\ 81TL2452Ł[ These products can also be obtained
through SN1? displacement of an allylic leaving group ð80CB1964Ł[
OMe
•
+
OMe Oct OMe
Oct
C7H15Cu, LiCl, THF, –30 °C 92% 3% 97%
(C7H15)2CuLi, Et2O, –40 °C 92% 91% 3%
i, BuLi
ZnBr
• ii, Bu
Bu OEt •
iii, MeOD
75% D
Scheme 34
Enynes are obtained through the palladium!catalysed coupling of terminal alkynes with allenes[
The presence of a strong electron!withdrawing group on the allene is essential for high yields and
regioselectivity\ although these are still very catalyst:substrate dependent ð89JA1705Ł[ On treatment
with a polymer supported bimetallic nickelÐchromium catalyst\ a\v!alkenylallenes undergo cyclis!
ation to form cyclic 0\3!pentadiene compounds "Equation "39## ð77JA4120Ł[ A similar coupling can
be achieved in an intermolecular fashion on treatment with Wilkinson|s catalyst\ although with
somewhat variable allene regioselectivity ð75JOM"206#262Ł[ Allenes may also participate in Heck!type
reactions with haloalkenes and arenes[ The intermediate palladium p!allyl species can be trapped
by an appropriate nucleophile to produce functionalised butadienes of well de_ned stereochemistry[
The "E# isomer is generally favoured with substituted alkenyl halides and through the use of hindered
phosphines\ polar aprotic solvents and good nucleophiles[ With vinyl bromide lower selectivity is
observed\ although the use of bulky less nucleophilic anions provides for preferential formation of
corresponding "Z# isomer "Scheme 24# ð89PAC0756\ 81BSF162Ł[
By Addition 386
TBS-O TBS-O
• PS––PPh2NiCl2•CrCl2
(40)
THF-EtOH, RT
78%
>99% de
NaCH(CO2Et)2, Pd(dba)2 CO2Et EtO2C

• Br dppe, THF, 140 °C, 45 h
C7H15
+ +
CO2Et EtO2C
84%
C7H15 C7H15
94%, (100% (E)) 6%
Ph
Ph
LiCH(N=CPh2)CO2Et
• Br Pd(dba)2, PPh3, THF N Ph
C7H15
+ N Ph +
43%
C7H15 CO2Et
CO2Et
C7H15
83% 17%
Scheme 35
0[00[2[1 Free Radical Additions to Allenes

The addition of simple methyl radicals "CH2=\ CX2=# to allenes occurs preferentially at a terminal
carbon atom ð61JOC2770Ł[ However\ this appears to be an anomalous result and most other radical
species attack at the central carbon atom to produce an allylic radical intermediate[ Incorporation
of an acceptor group onto the allene greatly facilitates the addition and can enhance the selectivity
ð80TL2548Ł[ As with alkene substrates\ intramolecular radical cyclisations involving allenes generally
follow an exo!mode of ring closure ð81SL610\ 82TL596Ł[ However\ reduction of the allyl radical is
frequently nonselective producing mixtures of the endo! and exo!cyclic alkene ð73JOC1014\ 77T6926Ł\
although in certain cases the nature of the tether can provide some degree of control ð74T3990Ł[
Finally\ alleneÐenynes may be employed in Bergmann!cycloaromatisation sequences which proceeds
via radical intermediates "Scheme 25# ð82JOC0540Ł[
•
PhH, reflux
•
50%
•
Scheme 36
0[00[2[2 Cycloaddition Reactions Involving Allenes

Allenes undergo a range of cycloaddition processes including ð1¦1Ł\ ð3¦1Ł and ð0\2Ł dipolar
cycloadditions[ The _rst group can occur with alkenes\ alkynes and other allenes and can be carried
out under both thermal and photochemical initiation[
Thermal allene dimerisation leads to 0\1!diethylenecyclobutane derivatives but is frequently
accompanied by the formation of higher oligomers[ Only when the temperature and conditions are
carefully regulated are synthetically useful yields obtained[ The combination of two di}erent allenic
species requires the use of a large excess of the less reactive allene to prevent interference from
homodimerisation ð61JOC849Ł[ As with most allene cycloadditions the regiochemistry of these
dimerisations is very substrate dependent[
Ketenes react with allenes to produce methylenecyclobutanones[ Good yields may be obtained
but the reaction generally shows relatively poor stereoselectivity ð74T1648Ł although in certain
cases\ notably small cyclic allenes\ very high selectivity can be observed together with a degree of
asymmetric induction ð61TL0078Ł[ The initial adducts frequently undergo thermal rearrangement to
form bicyclo!ð3[n[9Ł!alkenones in moderate yields ð79JCR"S#87Ł[
Provided that the alkene is activated by suitable electron!donating substituents alleneÐalkene
cycloadditions can similarly provide synthetically viable yields[ Simple terminal alkenes and cyclo!
hexene do not react^ neither do sterically encumbered alkenes ð64AG"E#698Ł[ The use of unsubstituted
allenes requires the use of excess acceptor alkenes\ otherwise further reaction occurs to produce
octahydronaphthalene products ð47JA640\ 48JA1612Ł[ In general\ the reactivity of the allene com!
ponent is enhanced by substitution[ However\ in these cases problems of regioselectivity can arise
although the reaction preferentially occurs at the less substituted allene double bond[ Although not
normally the case\ the reaction can be exceptionally stereoselective ð57JA3076Ł[ In this respect\ the
stereochemistry of the alkene is usually maintained ð71JA2565Ł and some degree of asymmetric
induction from a chiral allene can be observed ð58CC0114\ 81JOC0035Ł[ Both the regio! and stereo!
selectivity of the thermal alleneÐalkene cycloaddition can be a}ected by a number of external
variables[ For example\ carrying out the reaction under elevated pressure results in a faster reaction
with greater conservation of allene and alkene geometry\ albeit with a corresponding decrease in
the regioselectivity "Equation "30## ð89JOC600Ł[
F F
F F
F
F F F
• + + F + + (41)
Ph D
F
Ph D Ph D
Ph D Ph D
∆, 70 °C 83% (59:41) 17% (79:21)
13 kbar, RT 70% (86:14) 30% (95:5)
A highly stereoselective ð1¦1Ł cycloaddition between alkenes and allenic esters is obtained on
catalysis by Lewis acids ð75JOC2532Ł[ The reaction is limited to those activated allenes which can
easily form a vinyl cation intermediate^ simple alkyl allenes do not react[ Re~ecting the formation
of this intermediate\ very high regioselectivity is observed\ with addition only occurring at the
remote allene double bond "Equation "31##[ Lewis acid catalysed ð1¦1Ł cycloaddition is also possible
in the opposite electronic sense with 0!heterosubstituted allenes "notably alkylthio ð81JA7758Ł#
combining with electron!de_cient alkenes to form good yields of the methylene cyclobutene[ In this
particular case the use of chiral Lewis acids has been shown to impart high asymmetric induction
to the cycloaddition[ Alkyl allenes do react with alkynes to produce alkylidene cyclobutenes
ð77JOC3796Ł although in certain cases ene!type processes are found to compete\ a}ording cross!
conjugated trienes ð63JCS"P0#0198Ł[
MeO2C MeO2C
MeO2C CO2Me
EtAlCl2
+ + + (42)
• CH2Cl2, 25 °C, 15 d
70% 3% 1%
In contrast to these thermal ð1¦1Ł cycloadditions which favour production of the head!to!tail
regioisomers\ the equivalent photochemical activated process leads predominantly to the head!to!
head coupled adduct ð53JA4469\ 53TL2584Ł[ Within these isomers a variety of stereochemical outcomes
are possible and the precise ratio is very dependent on the exact reaction conditions ð77ACS"B#148Ł[
Synthetic e.ciency is best achieved with electron!de_cient alkenes\ particularly enones\ and in this
respect the product stereochemistry may be predicted from a consideration of a set of empirical
rules ð79T608Ł[ The reaction may be carried out in both an inter! and intramolecular fashion[ In the
latter case the shape of the tether controls the regiochemistry of the addition although with larger
tethers both regioisomers can be formed ð71JOC2186Ł[ Similar variations in the regiochemistry have
also been observed on varying the nature of the enone component ð74TL878\ 74TL0318Ł[
Allenes also undergo a variety of DielsÐAlder cycloadditions participating as both diene and
dienophile components\ the former requiring the presence of additional conjugation[ These can
occur both intra! and intermolecularly and normally exhibit high stereoselectivity ð78JA2606Ł[ In the
By Addition 388
intramolecular case the nature of the tether can be crucial[ For example\ cyclisation of a vinyl allene
system to a}ord hydrindane is more facile than that of the homologous substrate leading to a
decalin ring system "Scheme 26# ð72JOC3269Ł[ However\ alkyl allenes and other unactivated allenes
show low dienophile activity requiring forcing conditions for e.cient coupling and only display
poor regio! and stereoselectivity[ Increased reactivity is observed in strained allenes ð89JA5305Ł or
by generation of an a!carbocation "Equation "32## ð80TL5362Ł[ Enhanced e.ciency is also observed
on incorporation of electron!withdrawing groups to the allene ð89TL3748Ł and this can be addition!
ally accentuated through the use of Lewis acid catalysis ð89JCS"P0#1074Ł[ Consequently\ providing
that the correct dieneÐallene combination is obtained\ a highly selective and e.cient cycloaddition
can be obtained[ Which allene double bond participates depends on the balance of electronic
properties of both components "Scheme 27#[ For example\ electron!poor allenes and electron!rich
dienes combine at the allene 0\1 double bond ð71JCR"S#299Ł\ as do electron!rich allenes with electron!
de_cient dienes ð79TL3676Ł[ Electron!rich allenes similarly add to electron!rich dienes at the more
electron!rich allene bond\ although this is not strictly a cycloaddition\ proceeding by an electron
transfer process ð82TL7320Ł[
• ( )n
• ( )n n = 2, PhMe, 140 °C, 2 h, 7% (two steps)
( )n H
O H
MeO2C n = 1, RT (in situ), 21%
CO2Me
Scheme 37
, BF3•OEt2
O O CH2Cl2, –78 °C, 0.5 h
O O
(43)
65%
O O
PhH, 160 °C Ph
• Ph Ph Ph
+
quantitative
Ph Ph Ph Ph
• ZnCl2, CH2Cl2, 42 °C, 2 h

+
70% O
O
•
But N But , 3 N+•
+
MeCN, 0 °C, 5 min
80%
Ar
MeO
Scheme 38
0[00[2[3 Carbene Additions to Allenes

Although allenes react readily with electrophilic carbenes the addition is not an e.cient method
for the synthesis of alkenic compounds\ as double addition to form spirocyclopentanes frequently
occurs[ Monoaddition is possible\ particularly in the reaction of substituted allenes with dihalo!
carbenes[ In this case preferential reaction occurs at the more substituted allene double bond
ð80ZOR377Ł[ Depending on the mode of carbene generation some regiocontrol may be obtained
since singlet carbenes add to the 0\1!bond of dimethylallene and triplet carbenes to the 1\2!bond
ð79JA0500Ł[ Similarly\ whilst generation of the carbene from diazoalkanes under either photolytic
or copper!catalysed initiation a}ords considerable amounts of spiropentane products\ the use of
palladium initiators allows the isolation of methylene cyclopropanes in good yields ð76ZOR1434Ł[
Both steric and electronic factors are signi_cant\ as demonstrated by the fact that terminal cyclo!
propanes are formed preferentially\ although aryl allenes react nonselectively[
Transition metal carbene complexes\ LnM1C"R#Ph "LnM"CO#3Fe\ "CO#4Cr\ "CO#4Mo and
"CO#4W^ ROEt# react with allenes to form the corresponding trimethylenemethane complexes[
These may subsequently be trapped by alkynes to produce 3!methylenecyclopentenes ð80CB1224Ł[
The carbene complex\ "CO#4W1"H#Ph\ behaves di}erently\ combining with 0! and 0\1!disubstituted
allenes to produce methylenecyclopropanes in a highly stereoselective fashion ð89CC747Ł[ Finally in
a related process\ photolysis of a monosubstituted allene in the presence of chromium hexacarbonyl
a}ords moderate yields of the cyclopentadienone "16# formed from 1 equiv[ of the allene and one
molecule of carbon monoxide "Equation "33## ð76AG"E#246Ł[
O
• CO, Cr(CO)6, hν
Ph (44)
Ph 77% Ph
(27)
1.12
One or More C1C Bond(s)
Formed by Addition
ANDREW C. REGAN
University of Manchester, UK
0[01[0 REDUCTION OF ALKYNES TO ALKENES 491
0[01[0[0 Heteroèneous Catalytic Hydroènation 491
0[01[0[0[0 Catalysts 491
0[01[0[0[1 Stereoselectivity 494
0[01[0[0[2 Catalytic hydroènation of functionalized alkynes 495
0[01[0[1 Homoèneous Catalytic Hydroènation 496
0[01[0[2 Dissolvin` Metal Reductions 497
0[01[0[3 Hydride Reducin` Aènts 498
0[01[0[3[0 Hydroboration 498
0[01[0[3[1 Hydroalumination 400
0[01[0[3[2 Other hydride reducin` aènts 403
0[01[0[4 Miscellaneous Reducin` Aènts 404
0[01[1 ELECTROCYCLIC ADDITIONS 405

0[01[1[0 ð1¦1Ł!Cycloaddition Reactions 405
0[01[1[1 DielsÐAlder Reactions 408
0[01[1[2 0\2!Dipolar Cycloaddition Reactions 412
0[01[1[3 Ene Reactions 413
0[01[1[3[0 Metallo!ene reactions 415
0[01[1[4 ð2¦1Ł!Cycloaddition Reactions 416
0[01[1[5 The PausonÐKhand Reaction 417
0[01[1[6 Cyclotrimerization and Cyclo!oliòmerization of Alkynes 429
0[01[2 IONIC ADDITIONS 420

0[01[2[0 Hydrometallation of Alkynes followed by C0C Bond Formation 420
0[01[2[0[0 Hydroboration followed by C0C bond formation 420
0[01[2[0[1 Hydroalumination followed by carbonÐcarbon bond formation 422
0[01[2[0[2 Hydrosilylation followed by carbonÐcarbon bond formation 424
0[01[2[0[3 Hydrostannylation followed by carbonÐcarbon bond formation 424
0[01[2[0[4 Hydrozirconation followed by carbonÐcarbon bond formation 425
0[01[2[1 Ionic Additions of Stabilized Carbanions to Activated Alkynes 426
0[01[2[2 Carbometallation of Alkynes 427
0[01[2[2[0 Additions of orànolithium and Gri`nard reaènts to alkynes 428
0[01[2[2[1 Addition of orànocopper reaènts to alkynes 428
0[01[2[2[2 Addition of orànoboron reaènts to alkynes 431
0[01[2[2[3 Addition of orànoaluminum reaènts to alkynes 431
0[01[2[2[4 Addition of orànozinc reaènts to alkynes 432
0[01[2[2[5 Other carbometallation reactions of alkynes 433
0[01[2[3 Addition of Sulfur\ Selenium\ and Tellurium Reaènts to Alkynes 434
0[01[2[4 Addition of Iron Reaènts to Alkynes 434
0[01[2[5 Palladium!catalyzed Additions to Alkynes 435
0[01[3 FREE RADICAL ADDITIONS 435

0[01[3[0 Intermolecular Free Radical Additions 435
0[01[3[1 Intramolecular Free Radical Additions 436
490
491 C1C Bond"s# by Addition
0[01[4 CARBENE AND OTHER ADDITIONS 438
0[01[4[0 Addition of Simple Carbenes and Carbenoids to Alkynes 438
0[01[4[1 Reaction of Fischer Carbene Complexes with Alkynes 440
0[01[0 REDUCTION OF ALKYNES TO ALKENES
0[01[0[0 Heterogeneous Catalytic Hydrogenation

The heterogeneous catalytic hydrogenation of alkynes to form alkenes has been reviewed in
several monographs\ usually as part of a more general review of hydrogenation ðB!54MI 001!90\
B!60MI 001!90\ B!67MI 001!90\ B!68MI 001!90\ B!74MI 001!90\ B!74MI 001!91Ł[ There have also been some
reviews speci_cally of this area ð62S346\ 66T0734Ł[ Both terminal and internal alkynes are readily
hydrogenated over metal catalysts\ with internal alkynes generally being reduced to give "Z#!alkenes\
often with high stereoselectivity "Equation "0##[ This is one of the most important methods for
stereoselective synthesis of "Z#!disubstituted alkenes[
H2, cat.
R1 R2 (1)
R1 R2
0[01[0[0[0 Catalysts
Alkynes are usually more strongly adsorbed to the catalyst than alkenes\ allowing partial hydro!
genation to the alkene to be achieved selectively[ The most common catalysts to be employed are
palladium and nickel[ Platinum is not usually selective\ with the product alkene being reduced at a
similar rate to the alkyne ð41QR090Ł\ but has been used successfully on some occasions "e[g[\
Equation "1## ð33HCA0186Ł[ The method of preparation of the catalyst\ the nature of the support\
solvent and any additives can all have important e}ects on the reaction[
H2, Pt
(2)
100%
OH OH
Palladium catalysts generally a}ord the greatest selectivity[ Although colloidal palladium was
used in early work\ this has now been replaced by supported catalysts for synthetic applications[
Pd0C is not always selective\ and often requires the reaction to be interrupted after uptake of one
equivalent of hydrogen "e[g[\ Equation "2## ð69HCA0602Ł[ The selectivity of Pd0C can be greatly
improved by addition of quinoline "e[g[\ Equation "3## ð36HCA0800Ł[
H2, Pd–C
Ph (3)
Ph
EtOAc
70% CHO
CHO
OH
H2, Pd–C
(4)
OH quinoline, MeOH HO
97%
OH
The most commonly used supports are calcium carbonate\ barium sulfate\ and barium carbonate[
Pd0CaCO2 has been used both without additives\ and with the addition of quinoline ð31CRV66Ł[
The best known modi_cation of Pd0CaCO2 is Lindlar|s catalyst ð55OS"35#78\ 62OSC"4#779Ł\ obtained
by treatment of Pd0CaCO2 with lead acetate\ which lowers its activity\ apparently by a}ecting the
morphology of the metal ð76JOC2015Ł[ This has been used many times\ both with and without
modi_ers\ to achieve partial reduction of alkynes[ Hydrogenations over Lindlar|s catalyst often
slow down or stop spontaneously after the uptake of one equivalent of hydrogen[ For example\ the
reduction of the alkynoic acid "0# stopped after 84) of the theoretical amount had been adsorbed
Reduction of Alkynes 492
"Equation "4## ð71JOC0110Ł[ However\ the structurally similar amide "1# did not stop or slow down
after the uptake of one equivalent of hydrogen "Equation "5##[
CO2H
H2, Lindlars cat.
(5)
quinoline, EtOAc
OH O
(1) O
CONH2
H2, Lindlars cat.
(6)
quinoline, EtOAc
O O CONH2
(2)
Lindlar recommended that quinoline should be used as a modi_er with his catalyst for high
selectivity ð55OS"35#78Ł\ and there are many examples of this strategy "e[g[\ ð79TL0628\ 72BCJ1428\
72JCS"P0#276Ł#[ However\ its use is often omitted\ and this may be responsible for the lower selectivities
sometimes reported[ Lindlar also suggested 1\1?!"ethylenedithio#diethanol as a more e}ective
additive than quinoline ð62OSC"4#779Ł[
Other modi_ers have also been used with Lindlar|s catalyst\ particularly other amines\ for example
pyridine\ piperidine\ aniline\ and diethylaniline ð40JA4962\ 43JA3335\ 54JOC0641\ 72JCS"P0#276\ 72JOC3329Ł[
Other types of modi_er include chlorobenzene\ hydroxides ð51JOC1287\ 51JOC3212Ł\ and sulfur com!
pounds[
Representative examples of hydrogenations using Lindlars catalyst are shown in Table 0[
Palladium on barium sulfate has also often been used\ and in some cases has been found to be
more selective than the Lindlar catalyst[ For example\ the former catalyst was successful for the
reduction shown in Equation "6#\ whereas Lindlar|s catalyst was not ð62JOC2541Ł[
OH OH OH
H2, Pd–BaSO4
OH (7)
quinoline, EtOAc
95%
OH OH
Again\ quinoline has often been used as an additive\ and this system has been claimed to be
more reproducible than the Lindlar procedure ð45JA1407Ł[ The use of neat pyridine as a solvent
ðB!56MI 001!90Ł has been claimed to be even better than quinoline {{for all cases examined\|| with
uptake of hydrogen stopping sharply at the alkene stage\ with no over!reduction ð71JOC3143Ł[ Some
examples of the use of Pd0BaSO3 are shown in Table 1[ This catalyst has also been used for the
formation of annulenes by partial reduction of cyclic alkynes ð69TL4028Ł[
Raney nickel has also been used as the hydrogenation catalyst\ although it has now generally
been replaced by Lindlar|s catalyst[ It may be useful in certain cases\ and its selectivity can be
achieved by interruption of the hydrogenation\ or by the use of piperidine or zinc additives ð41JA184\
42JCS2183Ł[ Freshly prepared Raney nickel is not selective\ but is improved by aging in ethanol
ð42JCS2045Ł[ Raney nickel has been found useful for hydrogenation of 1!alkyne!0\3!diols\ where
palladium catalysts are often unsuitable "Equation "7## ð40JA0955\ 42CR"125#0933Ł^ however\ palladium
on charcoal with small amounts of NaOH\ KOH\ or Et2N has since been found to be better for
these substrates ð51JOC1287Ł[ A later nickel catalyst is the P!1 form\ which is prepared from Ni"OAc#1
and NaBH3 in EtOH ð62JOC1115Ł\ and is particularly stereoselective when used with ethylenediamine
as an additive "Equation "8## ð64T0735\ 72JOC1155\ 72JOC1163Ł[
H2, Raney Nickel
(8)
HO OH 86% HO OH
( )10
H2, P-2 Ni HO ( )10
(9)
HO H2NCH2CH2NH2
EtOH
92%
(3) (4)
Table 0 Hydrogenations of alkynes over Lindlar|s catalyst[
Entry Substrate Conditions Yield (%) Ref.
1 Ph quinoline, hexane ~100 73OSC(5)880

(not isolated)
n-C5H11
2 PhH 99 90JOC1670
OCOR
n-C5H11 Cl
3 hexane 92 90TL5749
HO CO2Me
( )4
4 PhH, cyclohexane 96 84AG(E)847
n-C5H11
TBDMS-O O-THP
O
CO2Me
5 EtOH 89 88BCJ2859
n-C5H11
OH
6 S S EtOAc 98 88CB2239
7 OCOCH2OMe EtOAc 79 83JOC5221
8 OH Et3N, THF 90 83TL4883

O
The stereoselectivity of the reduction for a given catalyst may vary markedly with even small
changes in the structure of the substrate\ and similarly\ for a given substrate\ it may be necessary to
try several di}erent catalysts before satisfactory results are obtained[ For example\ the diyne alcohol
"2# is reduced to the "Z\Z#!dienol "3# with high stereoselectivity using P!1 nickel "Equation "8##
ð72JOC1155Ł\ whereas the triyne alcohol "4# gives a mixture of products both using P!1 nickel and
also with Pd0BaSO3 and Pd0CaCO2 with Et2N[ Lindlar|s catalyst with quinoline\ on the other
hand\ gave good stereoselectivity for the all!"Z#!trienol "5# "Equation "09## ð72JOC1169Ł[
10( )
( )10
H2, Lindlars cat.
HO HO (10)
quinoline, EtOH
(5) (6)
In order to obtain good selectivity\ the alkene product must be desorbed rapidly from the catalyst\
relative to further reduction or isomerization[ Usually the alkyne is more strongly bound than the
alkene\ and competes e}ectively for the catalytic sites\ blocking re!adsorption of the alkene\ or
displacing it[ The order of reactivity with a palladium catalyst is usually as follows] terminal
alkyne×internal alkyne×alkene "terminal or internal#\ and this is clearly seen in the sequence of
hydrogenations shown in Scheme 0 ð50T05Ł[ If both the triple bonds of a diyne are internal\ then
hydrogenation gives the diene[
Enynes can be selectively hydrogenated to dienes^ this is highly selective for nonconjugated
systems\ but less so for conjugated ones ð62S346\ 66T0734Ł[
Table 1 Hydrogenations of alkynes over Pd0BaSO3[
Entry Substrate Conditions Yield (%) Ref.
1 CO2Et quinoline, Et2O 93–98 90OSC(7)226

MeO2C CO2Me
2 quinoline, MeOH 97 56JA2518
OH
3 hexane 96 84CC534
Ph
TMS
O
Et
4 pyridine ~100 82JOC4254
CO2Me
R
5 CO2H quinoline, EtOH >70 80TL1739
HO
OH
6 pyridine 71 84JOC747
CO2Me
n-C5H11
7 OH pyridine 70 83TL409
OH
8 pyridine ~100 83JA5373
MOM-O
H2, Pd–C
Prn Prn
Prn Prn
Scheme 1
Towards the end of the reaction\ when the alkyne concentration becomes low\ the alkene may
start to react[ The function of amine additives appears to compete e}ectively with the alkene\ but
not with the alkyne\ for catalytic sites\ and to be una}ected by the reaction conditions\ and hence
remain at constant concentration throughout the reaction ð60RTC850Ł[
In some cases\ the alkene product may undergo double!bond migration or cisÐtrans isomerization
on the catalyst faster than further reduction\ and in such circumstances it may be bene_cial to stop
the reaction before one equivalent of hydrogen is absorbed ð72BCJ242\ 72JA1812Ł[
The e}ect of temperature on selectivity has been studied[ Lowering the temperature to −09>C to
−29>C has been found to improve the selectivity using Lindlar|s catalyst ð66T0734Ł[ With other
catalysts\ however\ the opposite e}ect has been observed ð53MI 001!90Ł[
0[01[0[0[1 Stereoselectivity
Catalytic hydrogenation of internal alkynes usually a}ords the "Z#!alkene often with high stereo!
selectivity[ However\ varying amounts of the "E#!alkene are also always formed\ which is generally
believed to result from isomerization of "Z#!alkene\ although some may also be formed as an initial
product ð62S346\ B!74MI 001!91Ł[
Palladium is the most stereoselective of the group 09 catalysts\ with platinum being less so[
Lindlar|s catalyst is generally the most stereoselective of the supported palladium catalysts\ being
relatively inactive towards alkene isomerization and hydrogenation[ The highest stereoselectivity is
achieved in nonpolar solvents "ranging from pentane and hexane to THF and ethyl acetate#\ and it
is often lower in alcohols ðB!74MI 001!91Ł[ The temperature may be an important factor in determining
stereoselectivity\ and subambient temperatures "9Ð19>C# are often better than room temperature[
Pd0BaSO3 has been widely used for formation of "Z#!alkenes\ and in some cases has been found
to be more satisfactory than the Lindlar catalyst[ Examples of stereoselective reductions using both
Lindlar and Pd0BaSO3 catalysts are shown in Tables 0 and 1[
0[01[0[0[2 Catalytic hydrogenation of functionalized alkynes

It is often possible to reduce an alkyne in the presence of other functional groups\ because of the
selective absorption of the alkyne on the catalyst[ However\ functional groups adjacent to the alkyne
may cause problems\ especially if hydrogenolysis of the product is possible ð46JCS0511Ł[
Propargylic alcohols can usually be hydrogenated to "Z#!alkenols[ Glycols are more sensitive
than alcohols to the catalysts and conditions^ they undergo hydrogenolysis more readily ð51JOC3212Ł
and may also cyclize to tetrahydrofurans in acid conditions ð51JOC1287Ł[ Palladium is usually the
preferred metal\ with both Lindlar|s catalyst and Pd0BaSO3 _nding widespread use[ Palladium
with small amounts of KOH also works well ð51JOC3212\ 56ANY"034#80Ł\ although large amounts of
alkali lead to cisÐtrans isomerization ð48JCS1891Ł[ Reduction of alkynols and glycols is often less
stereoselective than with unfunctionalized alkynes ð64JOC0477Ł[ Use of subambient temperatures
can be helpful in minimizing hydrogenolysis and isomerization "Equation "00## ð58JA4890\ 66T0734\
68T1928Ł[ Reduction of alkynols may sometimes be accompanied by isomerization to the ketone[
Alkyne epoxides are reduced readily to the epoxy alkene\ provided that the product is not an
allylic epoxide "Equation "01## ð71JCS"P0#434Ł[
OH
( )7
H2, Lindlars cat.
(11)
quinoline, pentane, –10 °C
OH
( )7 84%
O
O H2, Lindlars cat.
(12)
quinoline, petrol
94%
With amino alkynes\ hydrogenolysis may be important\ and this is sensitive to the structure of
the substrate ð50JOC0962Ł[ Hydrogenolysis has been reduced by using platinum rather than
palladium\ and by reducing the amine salt rather than the free amine ð38CR"117#0490\ 49BSF0294\
50JOC2661Ł[
Alkynyl aldehydes and ketones are reduced readily to the corresponding alkenes\ if the carbonyl
group is not conjugated with the alkyne[ Internal conjugated alkynes are often unsatisfactory
substrates "Equations "02# and "03## ð38JCS626\ 38JCS0716\ 38JCS1917\ 61JOC1878Ł and better results are
obtained with terminal alkynes "Equation "04## ð69HCA374\ 61JOC1878Ł[
O H2, Pd–C
(13)
quinoline, MeOH
20%
Ph H2, Pd–CaCO3 or Lindlars cat.

complex mixtures (14)
quinoline
EtOAc, MeOH or heptane
H2, Pd–C
(15)
CHO EtOAc–hexane CHO
60%
0[01[0[1 Homogeneous Catalytic Hydrogenation

Homogeneous catalysts have been rarely used for the hydrogenation of alkynes[ Palladium
chloride has been used for the reduction of diphenylethyne to cis!stilbene "Equation "05##\ and was
found to be more selective than 09) palladium on carbon ð72BCJ242Ł[
H2, PdCl2, polyethyleneglycol
Ph Ph (16)
CH2Cl2 Ph Ph
Wilkinsons catalyst "and also ðRh"OAc#"PPh2#2Ł# usually gives complete reduction of the triple
bond ð60JCS"A#2113Ł[ However\ in benzene with acidic cosolvents "e[g[\ CF2CO1H or PhOH# sel!
ectivity is possible with terminal alkynes\ because the reduction of the alkyne "but not the alkene#
is accelerated ð57MI 001!90Ł[ Another rhodium catalyst\ ðRh"COD#PPh2PyŁPF5 in the presence
of benzoate ion\ is also e}ective for the selective reduction of terminal alkynes "Equation "06##
ð66JOM"030#002Ł[
H2, [Rh(cod)(PPh3)(py)]PF6
(17)
OH C6H6, PhCO2H, Et3N OH
Chromium complexes of the type ð"arene#Cr"CO#2Ł catalyze hydrogenation of internal alkynes

to "Z#!alkenes with high selectivity "Equation "07## ð74JOC0036\ 74JOC2135Ł[ 0!Phenylpropyne and
tetradec!6!yne are reduced to "Z#!alkenes using these catalysts[
H2, 30 kg cm–2
OH (18)
arene–Cr(CO)3
OH THF or acetone, 45 °C, 3 h
95%
Opposite stereoselectivities with two di}erent rhodium catalysts have been observed for the
same substrate dimethyl acetylenedicarboxylate "DMAD#^ ð"m!H#1H1Rh1"triphos#1Ł1¦ gives dimethyl
maleate\ albeit very slowly "Equation "08## ð77IC3318Ł\ whereas ðRhH1"OC"1O#OH#"PPri2#1Ł gives
dimethyl fumarate "Equation "19## ð72JA5162Ł[ The latter catalyst also reduces diphenylethyne to
trans!stilbene\ in contrast to PdCl1 "see above#[ On the other hand\ with ðRhCl2"Py#2Ł and NaBH3
in DMF\ diphenylethyne is reduced to trans!stilbene\ but DMAD is reduced with "Z#!selectivity to
dimethyl maleate ð58CC0492Ł[
H2, [(µ-H)2H2Rh2(triphos)2]2+
MeO2C CO2Me (19)
MeO2C CO2Me
CO2Me
H2, [RhH2(OC(=O)OH)(PPri3)2]
MeO2C CO2Me (20)
MeO2C
Catalytic transfer hydrogenation is also possible using formic acid and Pd0C catalyst "Equation
"10## ð79JOC3815Ł\ or alternatively\ using a homogeneous palladium catalyst "Equation "11##
ð82CC275Ł[
H2, Pd–C
CHO (21)
HCO2H–Et3N, THF
58%
CHO
O-THP
H2, [Pd2(dba)3]–PBu3 O-THP
(22)
HCO2H–Et3N, THF
96%
cis:trans 97:3
0[01[0[2 Dissolving Metal Reductions

The _rst dissolving metal reductions of dialkyl alkynes to give trans!alkenes using sodium in
liquid ammonia were reported by Campbell and Eby ð30JA105Ł[ Before this\ the reduction of alkynes
to "Z#!alkenes by catalytic hydrogenation was well known^ however\ there was no satisfactory
method for a trans!selective reduction[
Shortly afterwards\ terminal alkynes were successfully reduced to 0!alkenes\ also using sodium in
liquid ammonia\ provided that an ammonium salt was added to the reaction mixture "Equation
"12## ð32JA1919Ł[ Without the ammonium salt\ substantial metallation of the acidic alkyne occurs[
Na, (NH4)2SO4
C7H15 (23)
C7H15
NH3(l)
90%
Other metalÐamine combinations include lithium or calcium and an alkylamine[ Lithium and
ethylamine reduce internal alkynes to trans!disubstituted alkenes at −67>C "Equation "13##\ but at
06>C over!reduction to the alkene also occurs\ especially if excess lithium is used ð44JA2267Ł[ Calcium
and an amine also gives this reaction in 69Ð77) yields\ but some migration of the p!bond occurs
"Equation "14## ð73JOC0551Ł[ Lithium in water reduces internal alkynes to trans!alkenes
ð75AG"E#056Ł[
Li, EtNH2, –78 °C

(24)
52%
Ca (1.25 equiv.) C6H13

C6H13 + + Bun (25)
C5H11
MeNH2, H2NCH2CH2NH2
80% : :
91 6 2
The combination of sodium in hexamethylphosphoramide "HMPA# gives di}erent results depend!

ing on the conditions ð63JOC636Ł[ In the presence of t!butanol as a proton donor trans!alkenes are
obtained in good yields[ However\ without the t!butanol present\ a mixture of cis! and trans!alkenes
is formed\ and some p!bond migration also occurs[
Ytterbium in liquid ammonia gives trans!alkenes in good yields^ however\ this reagent is very
expensive ð67JOC3444Ł[
Zinc has been used for the reduction of alkynes[ With a zincÐcopper couple in an alcohol solvent\
terminal alkynes are reduced to 0!alkenes in very good yield "Equation "15##\ and disubstituted
alkynes give the "Z#!alkenes "Equation "16##\ in contrast to the stereoselectivity of the other dissolving
metal reductions discussed above ð79TL0958\ 76TL4284Ł[ The combination of zinc and 0\1!dibromo!
ethane is also e}ective[ Conjugated diynes are reduced to "Z#!enynes by zinc and dibromoethane
"Equation "17## ð73CC624Ł[ In this case the triple bond closer to the heteroatom is reduced\ and the
carbonÐoxygen bond is not cleaved[ Conjugated enynes can be reduced to dienes without a}ecting
the alkene double bond "Equation "18##^ 0\3!diethoxybut!1!yne is reduced by zinc\ dibromoethane\
and LiCuBr1 without cleavage of the propargylic oxygen functionalities "Equation "29## ð73CC624Ł[
Zn–Cu, MeOH
Ph (26)
Ph
reflux
OH
Zn–AcOH, MeOH
MeO2S (27)
OH reflux
MeO2S
OEt
Zn–BrCH2CH2Br
EtO (28)
OEt EtOH, reflux, 5 min
>70% OEt
Zn–BrCH2CH2Br
(29)
EtOH, reflux, 5 min
>70%
Zn–BrCH2CH2Br–LiCuBr2
(30)
EtO OEt EtO OEt
EtOH, reflux, 1.5 h
0[01[0[3 Hydride Reducing Agents
0[01[0[3[0 Hydroboration
Alkynes can be reduced to alkenes by hydroboration followed by protonolysis of the resulting
alkenylborane\ and this results in overall cis!addition of H1 ðB!67MI 001!91\ B!77MI 001!90\ 80COS"7#692Ł[
BoraneÐTHF generally gives complex mixtures as a result of further reaction of the initially formed
alkenylborane\ especially with terminal alkynes\ whereas internal alkynes can give reasonable yields
of monoaddition products ð50JA2723\ 56JA180\ 60JA2284Ł[ However\ use of more sterically hindered
dialkylboranes gives selective monoaddition\ and disiamylborane is most generally used reagent\
readily reacting with both terminal and internal alkynes "Scheme 1# ð48JA0401\ 50JA2723\ 56JA180\
60JA2284\ 68JOC1217\ 71JOM"114#52Ł[ The resulting dialkylalkenylboranes undergo protonolysis pref!
erentially at the alkenylÐboron bond to give the corresponding alkenes after treatment with a
carboxylic acid at 9>C^ the stereoselectivity for the formation of "Z#!alkenes is generally high
ð48JA0401\ 50JA2723\ 70T1506Ł[
BSia2
Sia2BH R2CO2H, 0 °C
R1
THF R1
R1
Sia2BH
BSia2 R3CO2H, 0 °C
R1 R2 + regioisomer R1 R2
THF R1 R2
Scheme 2
Various reagents have been used for the hydroboration of alkynes[ With terminal alkynes the
boron atom becomes attached to the terminal carbon atom[ With unsymmetrical internal alkynes
the regioselectivity of the addition of the borane is determined by both steric and electronic factors\
depending upon the particular reagent used\ and representative examples are shown in Table 2
ð72TL0322Ł[ This regioselectivity is\ of course\ irrelevant if protonolysis is to follow\ but is important
for subsequent carbonÐcarbon bond!forming reactions "see Section 0[01[2[0[0#[
Dicyclohexylborane has also been used successfully\ and has been recommended as having
signi_cant advantages over disiamylborane\ especially in terms of storage of the reagent and thermal
stability of the alkenylborane products ðB!77MI 001!91Ł[ It may also show di}erent selectivity to
disiamylborane\ for example disiamylborane has been used to achieve monohydroboration of a
conjugated diyne\ whereas dicyclohexylborane reacts with both triple bonds "Scheme 2# ð69JA3957Ł[
Both reagents react selectively with the triple bond of an enyne ð69JA3957\ 60JA0297Ł\ whereas
8!borabicycloð2[2[0Łnonane "8!BBN!H# shows the opposite selectivity ð68JOC1217Ł[
Dicyclohexylborane has also been used to reduce a skipped triyne system to the all!"Z#!triene
Table 2 Regioselectivities of hydroboration of internal alkynes[
Prn Ph
BH3•THF 40 60 74 26
Sia2BH 39 61 19 81
Catecholborane 40 60 27 73
9-BBN-H 22 78 65 35
Br2BH•SMe2 25 75 64 36
Mes2BH 10 90 2 98
i, Chx2BH, THF i, Sia2BH, THF

ii, AcOH ii, AcOD D
Bun
Bun Bun Bun
Bun 79% 76%
Bun
Scheme 3
ð77AG"E#187Ł\ and to selectively reduce a propargylic ether in the presence of a conjugate diene
ð73TL0544Ł[
8!BBN0H is useful for the hydroboration of internal alkynes and the regioselectivity is a result
of both steric and electronic e}ects ð68JA85Ł[ With terminal alkynes\ diaddition is mostly obtained\
and disiamylborane is generally a better choice of reagent[ The alkenylboranes formed with either
8!BBN0H or dicyclohexylborane can also be hydrolyzed to the alkenes with methanol alone
"Scheme 3#\ whereas those formed from disiamylborane are more stable\ and require the addition
of a catalytic amount of a carboxylic acid ð75JOC3401Ł[
R4CO2H
MeOH
R32BH BR32
R1 R2 i, BunLi
THF R1 R2
R1 R2
ii, NaOH (aq.)
Pd(OAc)2 (cat.)
THF or acetone
Scheme 4
Where the substrate contains acid!sensitive functional groups\ the hydrolysis of the alkenylborane
may be performed under basic conditions by _rst converting it into the boronate with BunLi\
followed by treatment with aqueous NaOH "Scheme 3# ð65JOC2373Ł[ Alternatively\ both acidic and
basic conditions may be avoided by using a neutral procedure\ involving simply the addition of a
catalytic amount of Pd"OAc#1^ the required proton is derived from the solvent "Scheme 3# ð67CC691\
79BCJ0569Ł[
Dimesitylborane is a very hindered dialkylborane which reacts readily with terminal and internal
alkynes\ but very slowly with alkenes^ and it is also more regioselective than any other borane
reagent ð72TL0322Ł[
Catecholborane has also been used for hydroboration of alkynes^ however\ it is less reactive
than dialkylboranes\ and requires re~uxing in THF ð61JA3269\ 72JOC4979\ 74JA2515Ł[ The resulting
alkenylboranes may be useful for other synthetic transformations ð65T870Ł[
Other reagents which have been used for hydroboration of alkynes include the haloboranes ClBH1
ð62JOC0506Ł\ and Br1BH = SMe1 ð79JOC278Ł^ the latter reagent can be used in dichloromethane\ and
is selective for an internal alkyne over a terminal alkene\ unlike 8!BBN!H ð72JOC533Ł[
0[01[0[3[1 Hydroalumination
Hydroalumination of an alkyne\ followed by hydrolysis of the resulting alkenyl aluminum
compound\ results in overall reduction of the alkyne to an alkene ðB!67MI 001!91\ 73OR264\ 80COS"7#622Ł[
The reagent most often used for this process is diisobutylaluminum hydride "dibal!H# ð59LA"518#111\
67JOC1628Ł\ and this will reduce both terminal and internal alkynes[ The reagent is selective for
alkynes over alkenes "Equation "20## ð66TL2530Ł\ and terminal alkynes react faster than internal
alkynes[ The reduction is stereoselective\ and gives the "Z#!alkene from an internal alkyne
ð57JOM"00#P6Ł[ The stereoselectivity is usually very good\ for example 0!phenylpropyne gives only
the "Z#!alkene using dibal!H\ whereas hydroalumination over a nickel catalyst gives 5) of the
trans!isomer "Equation "21## ð57JOM"01#P22Ł[ A number of side reactions may interfere with the
hydroalumination[ Terminal alkynes undergo metallation of the terminal C0H to a small extent\
although this is less serious when the alkyl group attached to the triple bond is secondary or tertiary\
rather than primary ð73OR"21#264Ł[ With conjugated terminal alkynes\ metallation competes with
addition to a much greater extent\ for example phenylethyne gives 19) metallation "Equation "22##
ð73OR"21#264Ł[ Other side reactions include over!addition\ exchange of C0H and aluminum in the
product\ and dimerization of the intermediate alkenylaluminum compounds ð80COS"7#622Ł[ The
intermediate syn!alkenylaluminum compound may also isomerize to the anti!isomer\ via a second
addition of the aluminum reagent[
dibal-H
AlBui2 (31)
i, dibal-H
Ph + (32)
ii, H2O
Ph
Ph
uncatalysed 100 : 0
Ni catalysed 94 : 6
AlBui2
dibal-H
Ph + Ph AlBui2 (33)
Ph
80 : 20
For the reaction of dibal!H with terminal alkynes\ it is best to use a hydrocarbon solvent\ since
over!addition occurs in ether\ while metallation takes place in tertiary amine solvents[ Internal
alkynes give negligible over!addition\ especially in hydrocarbon solvents\ but do give a few percent
of dimerized product ð73OR"21#264Ł[ However\ the use of a twofold excess of dibal!H over alkyne
reduces the dimerization[ The complex Ni"acac#1 catalyzes the addition but the regio! and stereo!
selectivity are lower ð57JOM"01#P22Ł[
With conjugated enynes\ if the alkene is terminal "i[e[ an alk!0!en!2!yne# then mainly polymeric
products are obtained^ however\ if both unsaturated units are internal\ then the alkyne undergoes
hydroalumination preferentially "Equation "23## ð66JOC2870Ł[ A conjugated ynone has been reduced
with dibal!H in HMPA\ with the stereoselectivity being dependent upon the conditions "Equation
"24## ð76JOC0513Ł[ In the absence of MeCu the "E#!isomer is favoured\ whereas with MeCu present\
a 0[4 ] 0 ratio of "Z#! to "E#!isomers is formed[ Terminal alkynes can also be reduced with dibal!H:
MeCu to give terminal alkenes in good yield "Equation "25## ð71JOM"115#C44Ł[
AlBui2
dibal-H
(34)
50 °C, 5 h
O O
O
i, dibal-H, CuMe, HMPA
+ (35)
ii, HCl (aq.)
Bun Bun Bun
48% 32%
i, dibal-H, CuMe, HMPA
n-C6H13 (36)
ii, H+
n-C6H13
80%
The reduction of a tertiary propargyl amine with dibal!H gives the opposite stereoselectivity to
that normally observed\ with formation of the "E#!isomer ð68TL2034\ 75JMC001Ł[ Similarly\ a tertiary
aminodiyne has been reduced selectively to give the "E#!enyne in 35) yield\ accompanied by 08)
of the "Z\ E#!diene "Equation "26## ð73JMC0428Ł[
Propargyl silanes can be selectively reduced to the "Z#!allylsilanes "Equation "27## ð73S002Ł[
But
Me
N
i, dibal-H, PhMe, 40 °C, 18 h
ii, H+
Me But Me
N N
+ (37)
But
46% 19%
Bun i, dibal-H, hexane

(38)
TMS ii, H+
TMS Bun
85%
In an unusual reaction dibal!H reduced a long!chain skipped diyne to give the "E\E#!diene
"Equation "28## ð52JOC0143Ł[ One alkyne bond of a diynol "Equation "39## was selectively reduced
to give the "E#!enynol using a combination of dibal!H and BunLi in a procedure which is claimed
to be milder and more selective than the use of LAH ð73S629Ł[ The same combination of reagents
reduces a 0!silyldiyne to either the "E#!enyne or the "Z\ E#!diene\ depending upon the conditions
Bun
i, dibal-H Bun ( )8
Cl (39)
ii, H+
8( ) Cl 83–94%
n-C7H15 i, dibal-H, BunLi (22%), heptane n-C7H15 (40)

OH ii, HCl (aq.)
70% OH
96% (E)
i, dibal-H, BunLi, hexane–GLYME n-C6H13

n-C6H13 TMS (41)
ii, HCl (aq.) TMS
95%
Lithium aluminum hydride does not generally reduce alkynes\ except at elevated temperatures
"019Ð049>C:DIGLYME:THF# ð73OR"21#264Ł\ unless there is another functional group present\
particularly if this is an oxygen!containing group adjacent to the alkyne[ For example\ 0!phenyl!0!
propyne reacts regioselectively at a lower temperature "Equation "31##[
LAH, THF
Ph
Ph (42)
reflux, 13 h LiH3Al
Reduction of propargyl alcohols by LAH to "E#!allylic alcohols is a standard method "Equation
"32## ð72TL3788Ł[ The solvent is important for stereoselectivity\ for example trans!addition normally
occurs in THF\ but cis!addition may predominate in diisopropyl ether ð69JA3787\ 63JOC857Ł[ The
enynol "6# gives the dienol "7# "Equation "33## ð43JCS0743Ł\ and the aminodiol "8# is similarly reduced
to the alkene "09# "Equation "34## ð48HCA390Ł[ In the reduction of the alcohol "00# the chiral centre
adjacent to the alkyne is not a}ected "Equation "35## ð67CC510Ł[
n-C5H11 LAH, THF

n-C5H11 OH (43)
OH 75%
LAH, Et2O
OH (44)
OH 88%
(7) (8)
H2N OH H2N OH
LAH, THF n-C12H25
(45)
n-C12H25 70%
OH OH
(9) (10)
LAH, THF
(46)
O OH 85% O
EtO EtO OH
(11)
Where a compound contains several alkyne groups\ selective reduction may be possible\ for
example LAH reduces only the alkyne adjacent to the hydroxyl group in "01# "Equation "36##
ð72TL3772Ł[ When there is an ester or carboxylic acid group adjacent to an alkyne\ then both groups
are reduced to give an allylic alcohol[ For example the ester "02# gives the "E#!alkenol "03# "Equation
"37## ð43JCS2106Ł\ and ethyne dicarboxylic acid "04# gives "E#!butene!0\3!diol "05# "Equation "38##
ð40JA4333Ł[ An etherÐoxygen on the carbon adjacent to the alkyne may also facilitate reduction^ for
example the benzyl!protected C!glycoside "06# is reduced to the "E#!alkene "07#^ however\ an elevated
temperature "89>C# in GLYME is required "Equation "49## ð72TL3722Ł[
LAH, Et2O
(47)
91% OH
Et OH Et
(12)
CO2Et LAH, Et2O

(48)
94% OH
(13) (14)
LAH, Et2O
HO2C CO2H HO (49)
OH
84%
(15) (16)
OBn
BnO O LAH, GLYME BnO O OBn
(50)
90 °C, 12 h
BnO OBn 57% BnO OBn
OBn OBn
(17) (18)
It is not always necessary for the alcohol group to be adjacent to the alkyne in order for reduction
with LAH to be successful^ for example\ the alkynol "08#\ where the hydroxyl group is remote from
the alkene\ is reduced to the "E#!alkenol "Equation "40## ð66S450\ 70CB181\ 73TL0444Ł[
HO
LAH, DIGLYME
HO (51)
89%
(19)
Propargyl amines are reduced by LAH to the "E#!allylic amines ð76JOC4933Ł\ and 1!alkynenitriles
are reduced chemoselectively to the alkenenitriles ð68S329Ł[
Sodium bis"1!methoxyethoxy#aluminum hydride "Red!Al# also reduces propargyl alcohols to
allylic alcohols "Equation "41## ð65JOC2386\ 75OS"51#071Ł[
OH OH
NaAlH2(OCH2CH2OMe)2
(52)
Et2O R
R
84%
Unfunctionalized alkynes can be reduced by LiHAlMe"Bui#1 ð56JA4974Ł\ and this reagent also
reduces conjugated internal alkynes\ with no addition to the second triple bond "Equation "42##
ð66S41Ł[ With unsymmetrical conjugated alkynes there is no selectivity[
LiBui2MeAlH But
But But But (53)
DIGLYME, 25 °C, 8 h AlR2
Simple alkynes can be reduced by LAH in the presence of various transition metal salts[ The "Z#!
alkenes are usually obtained\ and the metal salt is generally a halide of one of the transition metals
from titanium to nickel ð67JOC1456Ł[ For example\ 1!hexyne is reduced by LAH in the presence of
NiCl1 to "Z#!hex!1!ene in excellent yield "Equation "43## ð66TL3370Ł\ and terminal alkynes are
also reduced successfully[ Other halides which have been used include TiCl3 ð65TL04Ł and NbCl4
ð71CL046Ł[
LAH–NiCl2
Prn (54)
THF, –40 °C Prn
91%
0[01[0[3[2 Other hydride reducing agents

NaBH3 has also been used to generate a hydrogenation catalyst from Ni"OAc#1 in order to reduce
an internal alkyne to give the "Z#!alkene selectively "Equation "44## ð73TL1068Ł[ Similarly\ the
alkyne "19# was reduced using aminoantipyrine as an additive "Equation "45## ð77CA12941Ł[ Alkynes
conjugated with amides can also be reduced by NaBH3\ in the presence of catalytic amounts of
FeCl1 and lipoamide\ to give a mixture of geometrical isomers\ with moderate selectivity for the
"E#!isomer "Equation "46## ð74CL0740Ł[ Alkyl! or phenyl!substituted alkynes give mostly "Z#!alkenes
under these conditions[
HO CO2Me NaBH4–Ni(OAc)2
( )4 CO2Me (55)
( )4
H2NCH2CH2NH2, EtOH, H2
HO
NaBH4–Ni(OAc)2 n-C6H13
Bun n-C6H13 + (56)
aminoantipyrine, H2
Bun n-C6H13
Bun
(20) 90% 6%
NaBH4, FeCl2 (cat.) CONHBn

Ph CONHBn + (57)
lipoamide (cat.) Ph CONHBn
Ph
38% 62%
Diphenylethyne is reduced by NaBH30PdCl10PEG199 to give "Z#!stilbene "Equation "47##

ð74T1276Ł^ in this and other examples the benzene ring and nitrile groups were una}ected[
NaBH4, PdCl2
Ph Ph (58)
PEG200, CH2Cl2
Ph Ph
91%
Only one alkyne in the sulfone diyne "10# is reduced by NaBH3 in the presence of Et2N\ to give
mostly the "Z#!enyne "11# "Equation "48## ð89SC2366Ł^ in the absence of the base no reduction occurs[
SO2-p-C6H4Cl NaBH4–Et3N
MeOH–THF
(21) 90%
SO2-p-C6H4Cl
SO2-p-C6H4Cl
+ (59)
(22) 85 : 15
NaBH3 has been used without any additives to reduce the propargylic alcohol "12#\ in which the
alkyne is also conjugated to an allene\ to the "E#!enol "Equation "59## ð63S462Ł[
n-C8H17 n-C8H17
• NaBH4, THF, 70 °C •
(60)
80%
OH
OH
(23)
Other metal hydrides which have been used in the presence of transition metal salts include
NaH:Ni"OAc#1 ð66TL0958Ł\ and MgH1 in the presence of CuI ð67JOC646Ł or Cp1TiCl1 ð67CC29Ł[ A
copper hydride "generated from CuBr and Redal# has been used to reduce conjugated alkynoic
esters\ giving a mixture of isomers with the "Z#!isomer predominating ð64JOC2508Ł[
Silanes have occasionally been employed in the presence of transition metals as hydride donors\
to reduce internal alkynes to the corresponding "Z#!alkenes[ The combination of "EtO#2SiH and a
catalytic amount of RhCl2 reduces an alkyne without a}ecting an ester group ð81JOC3675Ł[ Terminal
alkynes and propargyl alcohols are not suitable substrates\ however[ Trichlorosilane has also been
used in the presence of KF and CuF1 ð68TL0030Ł[
Hydrozirconation of alkynes\ followed by protonolysis of the resulting alkenylzirconium com!
plexes gives overall cis!reduction of the alkyne ð80COS"7#556Ł^ however\ because this procedure is
stoicheometric in reagent\ it is not usually the method of choice[
The pyrophoric intermetallic hydride LaNi4H5\ prepared by adsorption of hydrogen onto LaNI4
alloy\ reduces 1!butyne!0\3!diol to the "Z#!alkene\ but this method is not superior to hydrogenation
over Lindlar|s catalyst "Equation "50## ð76JOC4584Ł[
LaNi5H6
(61)
HO OH THF–MeOH HO OH
60%
0[01[0[4 Miscellaneous Reducing Agents

Chromium"II# salts\ for example\ CrSO3 in aqueous DMF\ have been used to reduce alkynes
to "E#!alkenes in excellent yields "Equation "51## ð53JA3247Ł[ Terminal alkynes are also reduced
successfully[ This reduction is selective for alkynes because simple alkenes do not undergo reduction
by chromium"II# ð55JA3853\ 75JOC142Ł[ Cr"ClO3#1 has also been employed for the reduction of
terminal alkynes "Equation "52##\ and in contrast to CrSO3\ reduces internal alkynes to "Z#!alkenes
ð68JOC2360Ł[ 1!Butyn!0!ol is reduced with complete stereoselectivity to "E#!1!buten!0!ol using
Cr"ClO3#1 in aqueous DMF\ whereas in DMF0Et2N the "Z#!isomer is formed preferentially\ albeit
with much lower stereoselectivity ð68JOC2360Ł[ Conjugated ynones are reduced to the "E#!enones
using either CrSO3 or CrCl1 ð75S073Ł[
CrSO4
R2
R1 R2 (62)
DMF/H2O R1
Cr(ClO4)2
Bun Bun
(63)
DMF, H2NCH2CH2NH2
96%
Internal alkynes are reduced stereoselectively to the "Z#!alkenes by the complex "CuHPPh2#5
"Equation "53## ð89TL1286Ł\ and also in very high yield and stereoselectivity with SmI1 in the presence
of catalytic "PPh2#3CoCl1 ð80TL4448Ł[ Butyl Grignard reagents in the presence of CuI are also
e}ective for the cis!reduction of alkynes ð65JOC3978Ł[
(CuHPPh3)6
Prn Prn Prn (64)
Prn
PhH/H2O/Et2O
reflux
96%
0[01[1 ELECTROCYCLIC ADDITIONS

This section includes formal cycloaddition reactions\ which may be nonconcerted and involving
radical or ionic processes\ as well as concerted electrocyclic reactions[ Cycloaddition reactions
involving alkynes have been reviewed ðB!67MI 001!92\ B!89MI 001!90Ł[ Many cycloaddition reactions
involving alkynes are catalyzed by transition metals\ and this area has also been reviewed
ð77CRV0970Ł[
0[01[1[0 ð1¦1Ł!Cycloaddition Reactions

ð1¦1Ł!Cycloaddition reactions between alkynes to alkenes may occur either photochemically or
thermally\ and result in the formation of cyclobutenes[
Photochemical cycloaddition gives products which may react further by photochemical electro!
cyclic ring opening or addition to a second molecule of alkene\ and this reaction has been
reviewed ðB!67MI 001!93Ł[ Thus diphenylethyne gives a good yield of the ð1¦1Ł adduct "Equation
"54## ð69JOC0126Ł[ With DMAD and ethene\ it is di.cult to isolate any cyclobutene\ because the
ring opening and double addition are fast ð60JA671Ł[
Ph
hν (254 nm)
Ph Ph + (65)
82% Ph
O O
0!Hexyne undergoes photochemical ð1¦1Ł!cycloaddition to cyclohexenone to give the regio!

isomeric cyclobutenes with a 8 ] 0 selectivity "Equation "55## ð68T66Ł[ In an intramolecular version
of this reaction the regioselectivity is complete because of the geometric constraints imposed by the
tether^ however\ the diastereoselectivity is poor "Equation "56## ð71JA4457\ 73JA1004Ł[
O O O
Bun
hν, –23 °C
+ Bun + (66)
Bun
10 : 90
H H
O O O
hν
H + H (67)
uranium glass
60% H H
1:2
Alkynes undergo ð1¦1Ł!photochemical cycloaddition to aromatic rings[ With hexa~uorobenzene

the cyclobutene can be isolated in high yield "Equation "57## ð66JA2493Ł[ With benzene the cyclo!
butene products usually undergo thermal electrocyclic ring opening to the cyclooctatetraene
ð64T1744Ł while with naphthalene and diphenylethyne the initially formed cyclobutene undergoes a
further intramolecular cycloaddition^ this second step can be reversed by heating\ allowing the
cyclobutene to be isolated "Equation "58## ð60AJC1214Ł[
F F
F Ph
F F F
hν
+ Ph But (68)
86%
F F F But
F
F F
Ph
Ph Ph
hν hν
+ Ph Ph Ph (69)
(pyrex) heat
Quinones undergo ð1¦1Ł!cycloaddition to the C1C bond "with diphenylalkyne# to give cyclo!
butenes if the lowest excited triplet state is "p\p# "e[g[\ Equation "69## ð58JOC419Ł\ whereas addition
to the C1O bond occurs if the "n\p# state is lower in energy ð56JCS"C#0514\ B!63MI 001!90Ł[
O O
OMe Ph
OMe
hν (>400 nm)
+ Ph Ph (70)
70%
Ph
O O
Cyclobutene formation from alkynes and alkenes can also be catalyzed by Lewis acids ð68JOC137\
68JOC142Ł[Transition metal catalysis is also possible ð77CRV0970Ł^ however\ this is limited to nor!
bornene and similar alkenes "Equation "60## ð53CB1340Ł\ and to certain alkynes "e[g[\ DMAD#[
Ph
Ni(CN)2(PPh3)2 (cat.)
+ Ph Ph (71)
heat, 5 h
59% Ph
Transition metal catalyzed cycloaddition of two molecules of an alkyne to give cyclobutadienes

is well studied^ Fe"CO# complexes are almost universally employed\ since the cyclobutadiene may
be readily liberated from the product complex ð72JOC0151Ł[ The chemistry of cyclobutadienes has
been reviewed ð66CRV580\ 79T232\ B!74MI 001!92Ł[
Cycloaddition of two molecules of an alkyne using a rhenium catalyst gives a 2!methylene
cyclobutene rather than a cyclobutadiene "Equation "61## ð73CB2058Ł[
+
(CO)5ReFBF3 NaI
2 Re(CO)5 (72)
CH2Cl2, 5 °C, 2 d 45–80%
The enamine of cyclohexanone "13# adds to DMAD to give the cyclobutene "14# "Equation
"62## ð75JOC1993Ł[ In similar reactions the cyclobutenes can often be isolated\ particularly at low
temperature\ but usually undergo electrocyclic ring expansion upon heating[
N CO2Me
N
+ MeO2C CO2Me (73)
CO2Me
(24) (25)
Two sequential ð1¦1Ł!cycloadditions to alkynes can be observed^ thus DMAD _rst adds to one
double bond of norbornadiene\ and then diphenylethyne adds to the other\ catalyzed by a ruthenium
complex ð83AG"E#479Ł[
Cycloadditions of alkynes have also been performed with ketenes ð72JOC2271\ 73TL4932\ 89OS"57#21Ł\
including cyanoketene ð62TL8Ł this is a good route to the formation of cyclobutenones[
Heterocycles have been used as the alkene component in ð1¦1Ł!cycloadditions to alkynes^ for
example dihydropyridines add to DMAD to give fused cyclobutenes "Equation "63## ð62JCS"P0#1707Ł\
and the enamine "15# gives cyclobutene "16# "Equation "64## ð61TL4158Ł[ The dihydropyran "17#
undergoes a similar addition to DMAD^ however\ the product then undergoes ring opening at the
aminoacetal\ followed by ring closure and electrocyclic ring expansion to give the highly substituted
cyclohexadiene derivative "18# "Scheme 4# ð64TL2040Ł[
R2 MeO2C R2
+ MeO2C CO2Me (74)
N MeO2C N
R1 R1
CO2Me
N N
CO2Me
+ MeO2C CO2Me (75)
O O
(26) (27)
NEt2
NEt2 CO Me R2O2C
R2O O NEt2 R2O O 2 CO2Me
+ MeO2C CO2Me R1
R1 R1 CO2Me CO2Me
(28) (29)
Scheme 5
For the combination of allenes and alkynes there are two competing reactions] the ð1¦1Ł!
cycloaddition and an {{ene|| reaction[ 0\0!Dimethylallene and bis"tri~uoromethyl#ethyne give a
mixture of the two cyclobutenes "Equation "65## ð60CC0033Ł\ whereas tetramethylallene gives only
the {{ene|| product ð63JCS"P0#0198Ł[ Both the ð1¦1Ł and the {{ene|| reactions appear to occur via the
same diradical intermediate ð63JCS"P0#0733Ł[ Allenes can undergo reaction at either double bond^ in
the example above with 0\0!dimethylallene\ reaction occurs mainly at the less!substituted double
bond^ however\ with "29# and the hexa~uorobutyne the more!substituted double bond reacts\
presumably because this results in a relief of bond!angle strain in the cyclopropane ring "Equation
"66## ð64JA3302Ł[
CF3 CF3
• + F3C CF3 + (76)
CF3 CF3
Ph CF3
Ph
• + F3C CF3 (77)
(30) CF3
ð1¦1Ł!Cycloadditions can be catalyzed by Lewis acids\ giving the cyclobutenes if the alkene
is 0\1!disubstituted "Equation "67## ð65JOC2950\ 71OM286Ł\ and the ene product if the alkene is
monosubstituted "see below#[
CO2Et
AlCl3
+ CO2Et (78)
0[01[1[1 DielsÐAlder Reactions

Simple isolated alkynes are not normally reactive as dienophiles in the DielsÐAlder reaction
ðB!89MI 001!90Ł[ For thermal cycloadditions between simple dienes and alkynes\ drastic conditions
are required ð72AG"E#667Ł[ However\ the DielsÐAlder reaction between butadiene and diphenylethyne
proceeds in good yield at 19>C in the presence of an iron catalyst "Equation "68## ð57JOC2837\
72AG"E#667Ł[ Some cyclic alkynes\ for example cyclooctyne\ react as dienophiles\ as a result of the
relief of ring strain ð78CB012Ł\ and arynes can similarly serve as reactive dienophiles ð51AG"E#304\
B!56MI 001!91Ł[ An ortho!quinone dimethide is a very reactive diene which can be generated in situ
"e[g[\ by a thermal electrocyclic ring opening of the benzcyclobutane "20## and it reacts with a simple
unactivated alkyne\ for example propyne\ to give the regioisomeric adducts in quantitative yield
"Equation "79## ð65TL770Ł[
Ph
FeCl3, PriMgCl
+ Ph Ph (79)
Et2O, 20 °C, 2 d
68% Ph
190 °C, 168 h

+ + (80)
100%
(31) (excess) 65 : 35
Addition of activating groups\ which can be removed later\ results in dienophiles which are
synthetic equivalents for ethyne\ and the use of these has been reviewed ð73T1474Ł[
Alkynes activated by electron!withdrawing groups react well as dienophiles\ for example ethyne
activated by a butanoyl group reacts thermally with butadiene "Equation "70##\ and benzoylethyne
reacts readily with cyclopentadiene "Equation "71## ð35JCS41Ł[ But!2!yn!1!one reacts with a steroid!
derived diene to give the DielsÐAlder adduct in 80) yield "Equation "72## ð75TL4722Ł[ The chiral
heterobicyclic diene "21# also reacts with high endo face!selectivity with the same dienophile "Equa!
tion "73## ð73JOC1409Ł[
O
O
120 °C, 3 h Bun
+ (81)
Bun 99%
O
O
20–30 °C
+ Ph (82)
Ph 99%
Ph Ph
O
O
H H
+ (83)
91%
H H
MeO MeO
O 2N
O S O
S
NO2
O
50 °C O
+ (84)
S PhH S
84%
NO2 NO2
(32)
A formyl!activating group has been used in the reaction of alkynal "22# with the symmetrical
bis"silyloxy#diene "23# at 004>C in benzene "Equation "74## ð73JOC0787Ł[
O-TBDMS O-TBDMS
115 °C, 96 h OAc

OAc + (85)
OHC PhH CHO
68%
O-TBDMS O-TBDMS
(33) (34)
Methyl propiolate has been widely used as a dienophile\ and reacts with cyclopentadiene at only
49>C in an uncatalyzed reaction "Equation "75## ð76CB420Ł[ With a protected 0!aminobutadiene the
same dienophile gives only a 09) yield of the DielsÐAlder adduct\ with the normal regioselectivity
ð73JA1332Ł^ with a 1!silyloxybutadiene a 62) yield and good regioselectivity is obtained ð73TL3246Ł[
However\ with 0!trimethylsilylpenta!0\2!diene a mixture of regioisomers is obtained "Equation "76##
ð70S642Ł[
50 °C, 12 h
CO2Me + (86)
70%
CO2Me
TMS TMS TMS

CO2Me
heat
CO2Me + + (87)
68%
CO2Me
3:1
There have been a few examples of reaction of chiral dienes with methyl propiolate[ The threonine!
derived diene "24# gives a 2 ] 0 ratio of diastereoisomers "25# and "26# when reacted in benzene at
009>C "Equation "77##^ this reverses to a 0 ] 0[6 ratio at 119>C\ which in turn improves to 0 ] 09 at high
pressure and room temperature ð76JA4056Ł[ An alkynic ortho!ester has been used as an equivalent for
ethyl propiolate in a low!temperature addition to cyclohexa!0\2!diene\ catalyzed by TMS!OTf
TBDMS-O
110 °C, 24 h
O-TBDMS + CO2Me
PhH
NHCO2Bn 85%
(35)
MeO2C MeO2C
TBDMS-O TBDMS-O
H + H (88)
O-TBDMS O-TBDMS
BnO2CHN BnO2CHN
(36) 3:1 (37)
OEt TMS-OTf, CH2Cl2

OEt + (89)
–78 °C to 15 °C, 1.6 h
OEt
78%
CO2Et
Among alkyne dienophiles with two activating groups\ dimethyl and diethyl ethyne dicarboxylate
have been extensively used with a wide range of dienes\ and some representative examples are shown
in Table 3[ As well as acyclic and carbocyclic dienes\ a variety of heterocyclic dienes have been
reacted successfully with these two dieneophiles[ Furans "including furan itself# react well "entry 4#[
N!protected pyrroles usually give poor yields in the thermal reaction^ however\ the addition of
several equivalents of AlCl2 gives good yields at lower temperatures "entry 5#[
Photochemical ð3¦1Ł!cycloadditions are also possible\ using pyrroles ð57AG"E#56Ł\ furan
ð57CC441Ł\ and thiophene ð62CB563Ł^ thermal ð3¦1Ł!cycloadditions have also been documented
ð55AG"E#0928Ł[
Alkenylketene acetals have been used as dienophiles with either DMAD or methyl propiolate^
this results in adducts which readily undergo aromatization via elimination to give oxygenated
benzoate esters "Scheme 5# ð67CL538\ 68JA6990Ł[
OMe MeO OMe OMe

CO2Me CO2Me
OMe
+ CO2Me
TMS-O TMS-O TMS-O
Scheme 6
Ethyne dicarboxylic acid itself has been used as a dienophile\ for example with the diene
"27# "Equation "89## ð44JA62Ł[ The diacid chloride has also been used in a cycloaddition with
cyclopentadiene ð71CB793Ł[ The reactions of butynedinitrile\ DMAD and diethyl ethyne dicar!
boxylate as dienophiles with furan!2\3!dinitrile have been compared ð51JOC2419Ł[
CO2H
PhH
+ HO2C CO2H (90)
reflux, 24 h
84% CO2H
(38)
Bis"tri~uoromethyl#ethyne is another symmetrical and very reactive dienophile which has been
quite often used "Equation "80## ð79TL2212Ł[ Its thermal reaction with N!benzoylpyrrole is unusual
in that it gives a quantitative yield of the DielsÐAlder adduct ð71JOC3668Ł\ and with the unprotected
Table 3 Examples of DielsÐAlder additions to dimethyl and diethyl ethynedicarboxylate[
Entry Substrate Product Conditions Yield (%) Ref.
CO2Et
1 40–45 °C, 134 h 98 83JOC273
CO2Et pressure bottle
H
O
MeO2C O PhH, reflux or H2O 91JCS(P1)1255
2 85
O O
H MeO2C
MeO OMe MeO OMe CO2Et

CO2Et
3 PhH, 160 °C, 72 h 83 89JA5948
sealed tube
MeO OMe MeO OMe
HO HO
CO2Me
4 THF, reflux 95 83TL1129
CO2Me
PhSO2 PhSO2
O
5 O CO2Me Et2O, reflux, 130 h 75 66AG1057
CO2Me
CO2Me
N
6 NCO2Me AlCl3, CH2Cl2, 40 °C, 1 h 90 69CJC2391
CO2Me
CO2Me
pyrrole itself cycloaddition still occurs\ with a second equivalent undergoing addition of the pyrrole
N0H atoms ð64TL252Ł[ It also reacts with silicon! and germanium!containing heterocyclic dienes
ð61JA5118\ 61JOM"31#C10\ 62JA2967Ł[
PhMe, hydroquinone
+ F3C CF3 (91)
NBz reflux, 23 h
NBz
F3C
62%
CF3
Dewar benzenes can be prepared from cyclobutadienes and alkynes^ in Scheme 6 DMAD adds
to a cyclobutadiene ð60S028\ 75CB133Ł and in another example a stabilized tricyclic diene undergoes
a purely thermal reaction with methyl phenylpropiolate ð70TL0564Ł[
CO2But
But But CO2But But CO2Me
But 80 °C DMAD
CO2But 4h But CO2Me
But But But
N2 But
Scheme 7
Alkynes have also been used as dienophiles with heterodienes^ for example electron!rich pyrim!
idines undergo addition to DMAD ð64LA0002Ł[ 0!Amino!substituted 1!azabutadienes react with
methyl propiolate at low temperature without a catalyst to give substituted pyridines "Equation
"81## ð64JA3398Ł[ Oxazoles can react as heterodienes with unactivated alkynes^ in the _rst example
shown in Scheme 7 the adduct loses benzonitrile to give the furan ð72TL1362Ł[ An intramolecular
version of this reaction is also shown in Scheme 7 ð70JOC1954Ł[
N CO2Me
N (92)
MeCN, –20 °C N
NMe2 CO2Me
72%
NMe2
OAc 180 °C N OAc OAc

N O O
+ O
–PhCN
Ph
Ph
N N
O
PhEt
O O
reflux –HCN
O O
O
Scheme 8
Intramolecular DielsÐAlder cycloadditions of alkynes are also possible ð73OR0Ł[ The link between
the alkyne and the diene generally has to have at least three atoms "e[g[\ ð70S642Ł#\ and two examples
are shown in Equations "82# ð74TL4282Ł and "83# ð73OR"21#0Ł[ Intramolecular DielsÐAlder reactions
with an ester linkage have been employed in the synthesis of a naphthalene derivative ð55JOC1265Ł
and in a stereoselective synthesis of the A and B rings of gibberellic acid ð62TL3366Ł[ Intramolecular
DielsÐAlder reactions of alkynes have also been catalyzed by\ for example\ compounds of nickel
ð78JA5321Ł\ aluminum ð78TL6046Ł\ and rhodium ð89JA3854Ł[
The 0\1!diazine "28# undergoes an intramolecular DielsÐAlder reaction\ with loss of nitrogen from
the adduct to give a dihydroindole "Equation "84## ð76JA1606Ł[
Bun3N
(93)
hydroquinone
78%
CO2Me
CO2Me
Pri Pri
110 °C
(94)
O O
O HO
TBDMS-O O-TBDMS
N N
230 °C
N (95)
MeO N
Ac
MeO COMe COMe Ac
(39)
0[01[1[2 0\2!Dipolar Cycloaddition Reactions

0\2!Dipolar cycloaddition reactions have been reviewed ðB!73MI 001!90Ł[ Within the scope of this
chapter\ the 0\2!dipole is limited in structure to those where atoms 0 and 2 are both carbon in order
to obtain a nonheterosubstituted alkene product[
Stabilized azomethine ylides add to DMAD\ and the ylide can be generated by a thermal
conrotatory ring opening of an aziridine[ The cycloaddition to DMAD then takes place under the
same conditions\ faster than isomerization of the ylide\ resulting in good stereoselectivity in the
formation of the cycloadduct "Scheme 8# ð56JA0642\ 58AG"E#593Ł[ Nonstabilized azomethine ylides
have also been prepared in situ\ by desilylation of silylmethyl imminium salts^ addition to DMAD
gives the pyrrolidine ð68JA5341\ 73JOC2203Ł[
Ar
Ar Ar MeO2C H
100 °C + MeO2C CO2Me N
N MeO2C N
– H CO2Me
conrot 100 °C
MeO2C CO2Me CO2Me
MeO2C CO2Me
Scheme 9
Intramolecular addition of azomethine ylides generated from aziridines has also been
accomplished with an ester linkage containing 2 or 3 atoms^ here\ terminal alkynes give better yields
than internal ones\ and oxidation of the adduct yields bicyclic pyrroles ð74JOC1298Ł[ The azomethine
ylides can also be generated from an oxazole precursor ð78TL1516Ł\ and the linkage can also
include an aryl ring ð74T2436Ł[ An intramolecular addition where the azomethine ylide is part of a
dihydroisoquinoline ring has been reported ð75JOC0048Ł[
Nitrile ylides have been used as 0\2!dipoles in cycloadditions to alkynes[ An intramolecular
example is shown in Equation "85# ð66JHC836Ł[
An intramolecular cycloaddition of a carbonyl ylide to a terminal alkyne gives the complex
tricyclic system shown in Scheme 09 ð72TL0564Ł[
H Ar
N
– +
N R
Ar (96)
R = H, 18%
O R = Ph, 6% O
R
O O OH
OH O O
80 °C – O
O
O O
O 42% +
O
N
N N Me
Me Me
Scheme 10
0[01[1[3 Ene Reactions

Ene reactions have been reviewed ð58AG"E#445\ 67AG"E#365\ 79ACR315\ 80COS"4#0Ł[ Ene reactions
between alkenes and alkynes result in the formation of 0\3!dienes[ Alkynes are more reactive
than alkenes as enophiles in both intermolecular and intramolecular ene reactions ð58AG"E#445\
67AG"E#365Ł[ Intermolecular ene reactions occur thermally between simple unactivated ene com!
ponents and electron!de_cient alkynes "e[g[\ DMAD\ alkyl propiolates\ dicyanoethyne# at tem!
peratures below 199>C "Scheme 00# ð51LA"540#030\ 58AG"E#445Ł[ Disubstituted alkenes give both
higher yields and regioselectivity than monosubstituted alkenes\ and limonene gives 69Ð79) of the
ene product with methyl propiolate ð68TL1514Ł[
Lewis acid catalysis allows ene reactions to occur at room temperature with activated alkynes[
For example\ methyl propiolate reacts with a variety of alkenes "0\0!di!\ tri! and tetrasubstituted#
in the presence of AlCl2 or EtAlCl1 "Equation "86## ð65JOC2950\ 68JA4172\ 68JOC1791Ł[ With 0\1!
disubstituted alkenes ð1¦1Ł!cycloaddition occurs\ and with monosubstituted alkenes a mixture of
CO2Me
CO2Me
200 °C
+ CO2Me +
30%
Bun
Bun Bun
4:1
CO2Me
CO2Me
200 °C
+ CO2Me +
50%
96 : 4
Scheme 11
ð1¦1Ł and ene products is formed[ For alkenes with nonbasic substituents\ one equivalent of Lewis
acid usually gives optimal yields^ however\ if basic functional groups are also present\ an extra
equivalent of catalyst should be added for each basic site ð68JA4172Ł[ Similar results are obtained
using DMAD ð68TL0852\ 70CJC177Ł[
With DMAD and trisubstituted alkenes\ the regioselectivity of transfer of the hydrogen has been
studied ð68JA0895\ 79JOC1662Ł\ as indicated in Equation "87#[
H(R) H(R) (R)H

AlCl3 or EtAlCl2 CO2Me
+ CO2Me (R)H (97)
25 °C
R R
transferred
H
R1
R1
AlCl3 or EtAlCl2
+ MeO2C CO2Me (98)
25 °C R2
R2
MeO2C CO2Me
H
not transferred
2!Butyn!1!one is also an e}ective enophile in Lewis acid!catalyzed reactions ð66TL1720Ł[

Intramolecular ene reactions result in the formation of a new ring[ Dehydrolinlool "39# cyclizes
in quantitative yield upon heating to 199>C "Equation "88## ð60LA"636#59\ 61TL1902Ł[ Similar results
have been obtained by heating in a microwave oven for 04 minutes ð75TL3834Ł[ Stork has used this
type of intramolecular ene reaction to construct the _ve!membered ring in a prostaglandin synthesis
ð65JA5636Ł[
OH OH
200 °C
(99)
100%
(40)
The e}ect of alkyne substitution upon reactivity in the formation of _ve!membered rings has been
investigated^ the order of reactivity is ester×terminal alkyne×internal alkyne\ and the temperatures
required vary between 024 and 114>C "Scheme 01# ð67JOC1050Ł[ Higher temperatures are required
for intramolecular ene reactions of alkynes which give the corresponding six!membered rings
"Scheme 02# ð67JOC1050Ł\ and there are few examples of this process[
Oxygen!containing heterocycles can be constructed using an ether linkage ð76CL1236Ł and the
same order of reactivity was found as above[
Intramolecular ene!type products can also be obtained using palladium catalysis\ with a reversed
regioselectivity for the transfer of the hydrogen atom compared with the thermal reaction "Scheme
03# ð74JA0670\ 74TL3776\ 76TL0500Ł[
Enols react as the ene component with alkynes in intramolecular ene reactions "the Conia
R R
200 °C
100%
R Conditions Yield
H 210 °C, 62 h >95%
CO2Me 135 °C, 24 h >95%
Me 225 °C, 48 h 15%
Scheme 12
R
200 °C
100%
R Conditions Yield
H 225 °C, 48 h 17%
CO2Me 225 °C, 60 h 85%
Scheme 13
MeO2C Pd(OAc)2 (5 mol %) MeO2C MeO2C

+
MeO2C 60–66 °C MeO2C MeO2C
R R R
80% 6 : 94
Thermal, 625 °C 83% 100 : 0
Scheme 14
reaction#\ either thermally ð64S0Ł\ or at much lower temperatures using zinc or tin halides "Equation
"099## ð70JCS"P0#0405Ł[
O O
E
E
280 °C
(100)
or, ZnI2, PhMe, reflux
or, SnCl4, CH2Cl2, 25 °C H
E = CO2Et
Use of alkynyl silylenol ethers and mercuric chloride allows milder conditions to be employed^
mercuration of the terminal alkyne occurs and allows introduction of electrophiles stereoselectively
"Scheme 04# ð74JA0615\ 76BSF0995\ 76BSF0904\ 76TL2812Ł[
0[01[1[3[0 Metallo!ene reactions

The metal used for metallo!ene reactions with alkynes is usually nickel "formed by reaction of
Ni"CO#3 with an allyl halide# and this strategy has been reviewed ð56AG"E#013Ł[
O-TMS HgCl E
HgCl2 O O
E+
HMDS
E = H, D, CO2Me, COMe
Scheme 15
Ethyne itself can participate as the enophile\ as in Scheme 05^ insertion of CO into the metallo!
ene product results in the unsaturated ester "30#[
R
Ni(CO)4
+
R NiLn
HC≡CH, CO 35–80% R O
Cl MeOH, 20 °C CO
OMe
(41)
Scheme 16
With unsubstituted allyl chloride\ the intermediate acyl nickel species undergoes cyclization
to give a cyclopentenone and this process has been used in the synthesis of methylenomycin B
ð74TL5286Ł[
An intramolecular version of this reaction gives a bicyclic cyclopentenone "Equation "090##
ð76TL3634Ł[
Ni(CO)4 (2 equiv.) H
Br (101)
MeOH–hexane H
15–40 °C
50% OMe
O
OMe
0[01[1[4 ð2¦1Ł!Cycloaddition Reactions

ð2¦1Ł!Cycloaddition reactions result in _ve!membered ring formation\ with the alkyne con!
tributing two of the atoms[ For example\ the silylallene "31# reacts with 2!butyn!1!one in a ð2¦1Ł!
reaction catalyzed by TiCl3 "Equation "091## ð72T824Ł[
Trimethylene methane additions to alkynes have been achieved using alkenylcyclopropane pre!
cursors^ in the diphenyl!substituted example shown in Equation "092# good regioselectivity is
obtained ð74AG"E#205\ 76TCC66Ł[
An intramolecular version of this reaction is shown in Equation "093#^ here a palladium catalyst
is used instead of nickel ð78TL6096Ł[
The same type of product can be obtained by cycloaddition of a diradical\ prepared by thermal
extrusion of nitrogen\ onto DMAD "Scheme 06# ð74JOC1399Ł^ in this case\ a bicyclic product is
obtained from an intermolecular addition[
O
O TMS TiCl4, CH2Cl2 TMS
+ • (102)
–78 °C, 1 h
53%
(42)
Ph Ph
Ph Ph
Ni(cod)2 Ph
+ + (103)
(ArO)3P, 80 °C Ph
6% 89%
Ph
Ph Ph
(dba)2Pd, Pri3P
Ph (104)
CO2Me PhMe, 110 °C, 42 h
79%
TMS-O
TMS-O CO2Me
dba = dibenzylideneacetone
heat • MeO2C CO2Me

CO2Me
N 76%
N •
CO2Me
Scheme 17
0[01[1[5 The PausonÐKhand Reaction

The PausonÐKhand reaction involves the formation of a cyclopentenone from an alkyne\ an
alkene\ and carbon monoxide\ in the presence of Co1"CO#7\ and is a formal ð1¦1¦0Ł!cycloaddition
"Equation "094##[ It was _rst reported by Khand and Pauson ð62JCS"P0#864\ 62JCS"P0#866Ł\ and has
been reviewed ð74T4744\ 80OR"39#0Ł[ The reagents are usually heated together in a hydrocarbon or
ethereal solvent and yields are typically in the range of 39Ð59)[ The mechanism involves formation
of the complex Co1"CO#5 = R0C2CR1 as the _rst step ð80OR"39#0Ł[ Ethyne and terminal alkynes
work best\ whereas internal alkynes give lower yields[ The alkene structure is more limited in scope[
O
R3 R5 R3
Co2(CO)8 R1
R1 R2 + (105)
R4
heat
R4 R6 R5
hydrocarbon or
ether solvent R2 R6
In the intermolecular reaction\ simple alkenes su}er from a lack of both reactivity and regio!
selectivity[ Ethene itself is an exception\ and reacts well with many alkynes\ for example with
terminal alkynes "Equation "095##[ There is usually high regioselectivity with respect to the alkyne\
with the alkyl group becoming incorporated at the 1!position of the cyclopentenone[ However\ with
terminal alkenes\ there is usually little regioselectivity with respect to the alkene\ although it remains
good for the alkyne "Equation "096## ð77TL888Ł[
O
H H Co2(CO)8 n-C5H11
n-C5H11 + (106)
PhMe, 85 °C
H H 55%
O O
n-C6H13 Co2(CO)8 Bun n-C6H13 Bun

Bun + + (107)
95–100 °C
42% n-C6H13
1:1
The reaction between internal alkynes and terminal alkenes gives reduced yields\ but high regio!
selectivity for incorporation of the alkene "Equation "097## ð77TL888Ł[ Allyl ethers and homoallyl
thioethers also give high regioselectivity as alkene components ð80OR"39#0Ł[
O O
n-C6H13 Co2(CO)8 n-C6H13

+ + (108)
95–100 °C
20% n-C6H13
19 : 1
Alkynes substituted with electron!withdrawing groups do not generally undergo the PausonÐ
Khand reaction\ although intramolecular reaction is possible ð78IZV384Ł[ With electron!withdrawing
groups on the alkene an anomalous reaction occurs\ giving dienes with high regioselectivity[
Styrenes are intermediate in reactivity between terminal alkenes and alkenes substituted with an
electron!withdrawing group\ and so give a mixture of cyclopentenones and 0\2!dienes\ often in good
overall yield "Equation "098## ð67JCR"M#3343Ł[ More!substituted acyclic alkenes are not useful
substrates\ unless a homoallylic heteroatom is present[
110 °C
Ph •Co2(CO)6 +
MeO PhMe, 7 h
Ph O
MeO
+ Ph (109)
MeO
42% 27%
Monocyclic alkenes react with terminal alkynes in 29Ð69) yields\ and the yield can sometimes
be substantially improved by the addition of a trialkylphosphine oxide "Equation "009##
ð77JOM"243#122Ł[ Cyclohexene gives poor yields\ whereas cycloheptene and cyclooctene give moderate
yields\ but even then only with phenylethyne\ and not terminal alkyl ethynes ð66JCR"M#057Ł[
Cyclohexa!0\2!diene reacts twice with phenylethyne\ _rst in a DielsÐAlder reaction\ and then in a
PausonÐKhand reaction "Equation "000## ð67JCR"M#3390Ł[
O
70 °C
n-C5H11 •Co2(CO)6 + n-C5H11 (110)
hexane, 24 h
41%, 70% with Bun3PO
60–80 °C Ph O
Ph •Co2(CO)6 + (111)
PhMe, 5–6 h Ph
65%
Ring!fused cyclobutenes give good yields "Equation "001## and the cyclopentenone is formed on
the exo!face with complete regioselectivity ð66JCR"M#042Ł[ The ring!fused cyclopentene in Scheme
07 undergoes isomerization before PausonÐKhand reaction with t!butyldimethylsilyl "TBDMS#!
protected propargyl alcohol giving an angular fused triquinane ð74T4884Ł[
OMe H OMe
60–80 °C
•Co2(CO)6 + (112)
PhMe, 4–6 h
H 65% H H
O
Norbornene reacts with internal alkynes in 19Ð39) yields\ and with terminal alkynes in 29) to
×89) yields "Equation "002##^ 099) exo selectivity is observed ð78TL3910Ł[ Dry!state absorption
onto silica instead of traditional liquid phase reaction improves the yield in this and many other
PausonÐKhand reactions[ Addition of "R#!"¦#!glyphos to the reaction in Equation "002# results in
TBDMS-O O
•Co2(CO)6 80 °C
+
TBDMS-O PhH, 24 h 18%
65%
Scheme 18
an asymmetric coupling in 099) ee ð77JOM"244#338Ł[ Norbornadiene reacts in moderate to low

yields with alkynes at one or both double bonds\ respectively[ Heterocyclic bridged alkenes have
also been used ð74JOC4104Ł[
O
55 °C
Ph •Co2(CO)6 + Ph (113)
SiO2, 2 h
86%
Intramolecular PausonÐKhand reactions are possible using enynes which result in _ve! or six!
membered rings "Equation "003## ð75JA2724Ł[ Reactions which would give four!membered rings
result in alkyne trimerization instead ð70JOC4325Ł[ Terminal and internal alkenes react well\ as do
trisubstituted alkenes with terminal alkynes[ Dry!state absorption conditions work best for "pro!
tected# hydroxyl!containing substrates ð75TL0130Ł[ Heteroatom!linked enynes have also been used
successfully ð78S361Ł[ Asymmetric intramolecular cyclizations are possible using chiral auxiliaries
attached to the enyne "Equation "004## ð89JA8277Ł[
Co2(CO)6
120 °C
O (114)
heptane, 3 d
58%
Ph R*O R*O
H H
O
Co2(CO)8
O + O (115)
isooctane, 95 °C, 1.5 h
7:1
0[01[1[6 Cyclotrimerization and Cyclo!oligomerization of Alkynes

The cyclotrimerization of alkynes to benzenes has been an intensively studied reaction\ and has
been reviewed ðB!74MI 001!92Ł[ Many catalysts are available\ and the preparation of highly substituted
benzenes is often made simple by this method[ Equation "005# shows the synthesis of symmetrical
hexaalkyl benzenes using a palladium catalyst which is particularly straightforward to prepare
ð76JOC0050Ł[ Reactions of this type between diynes and alkynes are possible "e[g[\ Equation "006##
using either cobalt or Wilkinson|s catalysts^ such reactions have been reviewed ð73AG"E#428Ł[
Cyclotetramerization of alkynes is also possible using nickel catalysts ð37LA"459#0Ł\ but cyclo!
trimerization may compete "Equation "007## ð50JA1833Ł[
Other multicomponent cycloadditions involving alkynes\ catalyzed by transition metals\ can be
found in the review by Schore ð77CRV0970Ł[
R
R R
Pd–C, TMS-Cl
R R (116)
THF, heat, 3–6 h
100% R R
R
R = Et, Bu, Ph
Ionic Additions 420
R1
CpCo(CO)2
( )n + R1 R2 ( )n (117)
R2
CO2Me
MeO2C CO2Me CO2Me
[Ni(PCl3)4]
CO2Me + (118)
MeO2C CO2Me
CO2Me
83 : 17
0[01[2 IONIC ADDITIONS
0[01[2[0 Hydrometallation of Alkynes followed by C0C Bond Formation

Hydrometallation of alkynes followed by replacement of the carbonÐmetal bond by a carbonÐ
carbon bond results in alkene formation by overall addition of hydrogen and carbon[ A wide range
of hydride!containing reagents may be used for this process\ and the hydrometallation steps are the
same as those discussed in Section 0[01[0[3[
0[01[2[0[0 Hydroboration followed by C0C bond formation

Hydroboration of alkynes by dialkylboranes\ as discussed above in Section 0[01[0[3[0 gives
alkenylboranes "see also Chapter 1[07[0#[ The C0B bond can be replaced by a C0C bond\ using a
variety of reagents\ resulting in overall addition of hydrogen and a carbon substituent to the alkyne[
With internal alkynes\ the regioselectivity of hydroboration becomes important\ and is generally
controlled by steric e}ects\ with the boron atom becoming attached to the less sterically hindered
carbon atom ðB!67MI 001!91Ł[
Hydroboration of a terminal alkyne with 8!BBN!H\ followed by reaction with aldehydes gives
allylic alcohols ð66JOC468Ł[ Hydroboration of terminal alkynes with catecholborane\ followed by
palladium!catalyzed carbonylation in methanol gives a\b!unsaturated methyl esters ð70CL768\
75CL0218Ł[ Alternatively\ the intermediate borane can be coupled with aryl or alkenyl halides
"Scheme 08# ð70JOM"102#C42Ł[
R1 O R2X, Pd (cat.) R1
catecholborane
R1 B
Et3N
O R2
R2 = aryl, alkenyl
Scheme 19
Treatment of alkenylboranes derived from terminal alkynes with iodine and NaOH or NaOMe
results in transfer of one of the alkyl groups on boron onto the alkene\ with inversion of the alkene
geometry\ giving a "Z#!alkene "Scheme 19# ð71JOC0681\ 71JOM"114#C0\ 71T1244Ł[ On the other hand\
treatment with either BrCN ð61JA5459\ 66CC741Ł or Pd"OAc#1:Et2N ð79BCJ0569Ł results in retention
of con_guration and gives the "E#!alkene[
A variation on this reaction is the use of a bromoalkylborane dimethylsul_de complex for the
hydroboration step^ reaction with NaOMe and I1 then gives the alkene "Scheme 10# ð71JOC060\
71JOC2795\ 71JOC4396Ł[ 0\2!Dienes can also be prepared by hydroboration of two equivalents of an
internal alkyne by thexylborane\ followed by oxidation and reaction with NaOMe and I1 as above
"Scheme 11# ð57JA5132Ł[ Chloroborane reacts with two equivalents of an alkyne to give the
dialkenylchloroborane^ reaction with either iodine or MeCu then gives coupled dienes of di}erent
stereochemistry ð62JOC0506\ 64JA4595Ł[ 0\2!Dienes are also obtained by successive reaction of thexyl
borane with a 0!haloalkyne followed by a terminal alkyne^ treatment of the intermediate borane
R1 R2
CO2Me R2
R1 R1
NaOH BrCN
I2 CH2Cl2
CO, MeOH
PdCl2, NaOAc
BR22 R1
R22BH CuBr, 0 °C
R1
R1 NaOMe, CuBr, 0 °C
R1
Br
Br
MeLi, CuI
Br NaOMe, CuBr
CuI –15 °C
R1 R1
R1
Scheme 20
with methoxide results in C0C bond formation by alkenyl migration^ protonolysis liberates the
diene ð62CC595Ł[
R3
R3BHBr•SMe2
BBr•SMe2 NaOMe R2
R1 R2
R1 R2 I2 R1 R3
Scheme 21
R1 R2
BH2 R1 R2
i, Me3NO R1
R1 R2 B
ii, NaOH, I2
R2
R1 R2
Scheme 22
The C0B bond in the alkenylborane can be replaced by an alkyl group from reactive alkylating
agents such as allyl\ propargyl\ or benzyl bromide under a variety of conditions\ often involving
copper or palladium reagents "Scheme 19#[ Allyl bromide reacts using\ for example\ NaO!
Me:CuBr = SMe1 ð79JOC449Ł\ MeCu ð79JOC0539Ł\ or CuI:MeLi ð79BCJ0360Ł^ these last conditions
can also be used for alkylation with propargyl bromide[ Catalytic Pd"OAc#1 is also successful for
allyl bromide ð79BCJ0569Ł\ and Pd"PPh2#3 has been used for allyl and benzyl bromides\ and also aryl
halides ð68CC755\ 79TL1754\ 71JOC1006Ł[ 0!Bromoalkynes can also be used as alkylating agents\
again using either a copper"I# salt ð73JA351Ł or catalytic palladium"9# ð68TL2326\ 70T1506\ 70TL016\
74JA861\ 74PAC0638Ł[ Alternatively\ the same products may be obtained using a 0!lithioalkyne in the
presence of I1 ð62CC763\ 75TL428Ł[
By using alkylthexylborane as the reagent for hydroboration of ethyl propiolate\ the
alkenylborane "32# is formed[ The alkyl group on boron rather than the thexyl group is selectively
transferred upon treatment with bromine and\ depending upon the conditions\ either the "E#! or
"Z#!isomer of the a\b!unsaturated ester may be obtained "Scheme 12# ð63JOC1210Ł[
Ionic Additions 422
CO2Et
heat R
R Br
Br2
B B Br
NaOEt
CO2Et R CO2Et
(43) R CO2Et
Scheme 23
0[01[2[0[1 Hydroalumination followed by carbonÐcarbon bond formation

Addition to alkynes of the aluminum hydride reagents described in Section 0[01[0[3[1 results in
alkenylalane intermediates "see also Chapter 1[08[4#[ With suitable reagents\ alkenes can be
produced\ with a new carbonÐcarbon bond being formed with retention of the stereochemistry of the
alkenylalane ð73OR"21#264Ł[ The alkenylalane intermediates react as alkenyl carbanion equivalents^
however\ their nucleophilicity is low because of the empty p!orbital on aluminum\ and reaction with
carbon electrophiles is often not very satisfactory[ However\ addition of an organolithium reagent
generates an intermediate alanate\ which then has a complete octet\ is negatively charged\ and is
much more reactive towards carbon electrophiles ð73OR"21#264Ł[
Addition of dibal!H to unfunctionalized terminal alkynes results in cis!addition of hydrogen and
aluminum to give the alkenylaluminum intermediate "33#\ which can then be alkylated with the
reactive choromethylmethyl ether to give the alkene "Scheme 13# ð65S705Ł[ While simple primary
alkyl halides do not react with "33#\ they can undergo aminomethylation ð79TL2652Ł[ Vinyl and aryl
halides react with "33# to give conjugated "E#!alkenes\ using either nickel"9# ð76JA1282Ł or pal!
ladium"9# ð65CC485\ 65JA5618\ 76JA1282\ 76TL0538\ 76TL3764Ł as catalysts "Scheme 13#[ This is a poor
reaction starting from internal alkynes^ however\ addition of ZnCl1 gives improved yields and
shorter reaction times "Equation "008## ð67JA1143Ł[ 0!Haloalkynes can also be used as electrophiles
with "33#\ giving conjugated trans!enynes from terminal alkynes "Scheme 13# ð67JA1143Ł[
R
Bun OMe
CO2Me
R
R Bun I
92%
Ni0 or Pd0 (cat.) (R = n-C5H11)
ZnCl2 MeOCH2Cl R
ClCO2Me Br
AlBui2
dibal-H
R
(Ph3)4Ni
R 73% (R = Bun)
(44)
CO2Me
PhCHO, Et2O
Ph 67% 50% (R = n-C13H27)
(R = Bun) CuCl
Ph
Ph CO2Me OH
R
R
R
R
Scheme 24
Et Et
i, dibal-H
Et Et (119)
ii, I
(PPh3)4, ZnCl2
88%
Addition of "33# to aldehydes results in a stereoselective synthesis of allylic alcohols ð56JA1643\

71TL1976\ 76TL4018Ł[ Ketones react similarly to give tertiary alcohols\ although if they are hindered
then competing reduction of the carbonyl group may occur ð73OR"21#264Ł[ Michael addition is
also possible with a\b!unsaturated ketones and esters "Scheme 13# ð61TL3972Ł\ and reaction with
chloroformates gives "E#!a\b!unsaturated esters ð67TL1246Ł[
Self!coupling of "33# with CuCl gives symmetrical\ geometrically pure "E\E#!dienes "Scheme 13#
ð69JA5567Ł and cross!coupling with allylic halides using CuCl is also possible\ to give 0\3!dienes
ð63S547Ł[
Reaction of dibal!H with two equivalents of an internal alkyne generates the dienylalane with
new C0C bond formation^ protonolysis then yields the symmetrical "E\E#!diene with high stereo!
selectivity "Equation "019## ð59LA"518#111Ł[
Et Et
i, dibal-H (0.5 equiv.)
Et Et (120)
ii, H3O+
Et Et
The intermediate aluminum enolate formed by addition of dibal!H to methyl propiolate can be
alkylated by bromocyclohexene "Equation "010## ð76JOC0513Ł[ Other allylic bromides react similarly[
CO2Me
i, dibal-H
CO2Me (121)
ii,
Br
Reaction of the intermediate "33# with methyllithium results in formation of an alanate\ which
reacts with a wider range of electrophiles\ as illustrated in Scheme 14[ Alkylation with simple alkyl
halides is possible ð65TL0816Ł[ Epoxides can also be used if not too hindered\ giving homoallylic
alcohols ð64S521\ 65CC06Ł[ Carboxylation with CO1 gives a\b!unsaturated carboxylic acids ð56JA1643Ł[
CN
(CN)2
R = Bun, 87%
R
OH
O
AlBui2MeLi R = n-C6H13, 81%

i, dibal-H R
R
ii, MeLi R MeI
R = C5H11, 65%
R
i, CO2
CO2H
ii, H3O+
R = Bun, 78%
R
Scheme 25
Disubstituted alkynes undergo trans!addition of LiBui1MeAlH\ and the resulting alanate is

thus the opposite geometrical isomer to that formed with dibal!H and MeLi^ the alanate can be
carboxylated\ or trapped by formaldehyde "Equation "011## ð56JA4974Ł[ Cyanogen reacts with both
the alanate and alane intermediates to give the alkenyl nitriles as geometrical isomers "Equations
"012# and "013## ð57JA6028Ł[
Ionic Additions 424
i, LiBui2MeAlH Et
Et Et (122)
ii, HCHO Et OH
68%
i, LiBui2MeAlH Et
Et Et (123)
ii, (CN)2 Et CN
65%
i, dibal-H CN
Et Et (124)
ii, MeLi Et Et
iii, (CN)2
76%
0[01[2[0[2 Hydrosilylation followed by carbonÐcarbon bond formation

Alkynes undergo platinum!catalyzed hydrosilylation to give isolable\ stable alkenyl silanes "see
Chapter 1[07[1#\ which can then undergo electrophilic substitution to give alkenes "Scheme 15#
ð66TL2206\ 68S650Ł "see also Chapter 0[00[0[5#[
R23SiH SiR23 E+ E
R1
H2PtCl6 R1 R1
Scheme 26
Alkynes also undergo hydrosilylation with HSiCl2^ reaction with KF then gives an alkenylsilicate
dianion intermediate which can be reacted with a variety of reagents catalyzed by palladium\
resulting in new carbonÐcarbon bond formation ð71OM431Ł[ Without additional reagents\ self!
coupling is catalyzed by PdCl1\ giving symmetrical "E\E#!0\2!dienes[
0[01[2[0[3 Hydrostannylation followed by carbonÐcarbon bond formation

Terminal alkynes undergo hydrostannylation by Bun2SnH regioselectively to give "E#!alk!
enylstannanes with cis!addition of the hydrogen and tin atoms "Scheme 16# "see Chapter 1[08[5#[
Treatment with BunLi then gives the corresponding alkenyllithium compound\ which can be reacted
with an appropriate electrophile\ for example to e}ect alkylation ð64JOC1154\ 66TL2736Ł^ alternatively\
cuprate formation allows Michael addition to an enone ð64JOC1154\ 65TL3694\ 67JOC2349Ł[
i, BunLi R2
ii, R2X
R1
Bun3SnH
SnBun3
R1
O
R1 i, BunLi
ii, PrnC≡CCu
iii,
O
R1
Scheme 27
Treatment of ethyne itself with Ph2SnCu or "Ph2Sn#1CuLi followed by an alkyl halide gives
"Z#!alkenylstannanes^ these species can be transmetallated with BunLi and then reacted with an
electrophile with retention of alkene geometry "Scheme 17# ð71TL1686Ł[
i, BunLi
i, Ph3SnCu ii, CO2
H H
ii, RX
R SnPh3
iii, MeOH R CO2Me
Scheme 28
0[01[2[0[4 Hydrozirconation followed by carbonÐcarbon bond formation

Both terminal and internal alkynes undergo hydrozirconation with Cp1ZrHCl\ giving "E#!alkenyl
zirconium compounds "34#\ resulting from cis!addition at the H and Zr atoms "Scheme 18#[ In the
case of terminal alkynes this process is also regioselective\ the zirconium atom becoming attached
to the terminal carbon atom[ The C0Zr bond can be transformed into a C0C bond with a variety
of reagents\ resulting in stereoselective formation of di! or trisubstituted alkenes ð74MI 001!93Ł[
CN
R2
R1
X
R1
ButNC, I2
R2
Pd0 (cat.)
R1
Cp2ZrHCl
ZrClCp2
CuCl
R1
R1
R1
(45)
(π-C3H5PdCl)2 (cat.)
COR2 Cl
Ni(acac)2 (cat.)
or CuOTf, LiI
R2 R1
O
R1
Scheme 29
Self!coupling occurs in the presence of CuCl1\ giving symmetrical conjugated dienes ð66TL0292Ł[
Unsymmetrical conjugated dienes can be obtained by coupling with alkenyl halides\ catalyzed by
palladium"9# ð67TL0916\ 71TL52\ 76JA1282\ 76TL3764\ 76TL3768Ł[ Allylation may be achieved using either
"p!C2H4PdCl#1 ð79JA6270\ 70TL3544Ł\ or allyl chloride with catalytic "p!C2H4PdCl#1 ð70TL1518Ł[
Michael addition to a\b!unsaturated ketones is possible in the presence of either CuOTf and LiI
ð66TL0292Ł\ or catalytic Ni"acac#1 ð66JA7934Ł[ Replacement of zirconium by CN may be achieved
using t!butyl! or trimethylsilylisonitrile and iodine\ giving a\b!unsaturated nitriles ð76TL184Ł[
Treatment of enynes with ZrCp1 results in bicyclic organozirconium compounds "35#^ protonation
then gives alkenyl cycloalkanes^ whereas treatment with carbon monoxide gives cyclopentenones
"Scheme 29# ð74JA1457\ 75JOC3979\ 75TL1718\ 76TL806Ł[
Ionic Additions 426
R
H3O+
R
R
ZrCp2
ZrCp2
R
(46) CO
O
Scheme 30
0[01[2[1 Ionic Additions of Stabilized Carbanions to Activated Alkynes

The conjugate addition of stabilized carbanions and organometallics to alkynes activated by
a conjugative electron!withdrawing group has been covered by several reviews ðB!58MI 001!90\
B!67MI 001!94\ 80COS"3#0\ B!81MI 001!91Ł[ Further reactions may ensue after the initial addition\ such as
cyclization\ or addition of a second molecule of the nucleophile[
The anion of diphenylacetonitrile adds to ethyl propiolate in 81) yield using a quaternary
ammonium hydroxide as the base "Equation "014## ð42HCA0798Ł[ Addition of an oxazolone to
0!phenylpropynone initially gives the "Z#!adduct^ however\ this can be isomerized to the "E#!isomer
upon heating "Scheme 20# ð60AG"E#542Ł[
Ph CN
BuMe3N+OH– Ph
CN + CO2Et (125)
92% Ph CO2Et
Ph
O
Pri Pri
N Pri O N N
Et3N Ph
Ph + Ph Ph Ph
O Ph 70–96% O O
O O O O
Scheme 31
The reaction of dimethyl malonate with DMAD results in two products "Equation "015##
ð54JCS3244\ 56JCS"C#0875Ł\ which are the result of sequential addition of the initial adduct to two
further molecules of DMAD\ followed by isomerization and Dieckmann cyclization ð53JOC312Ł[
Replacement of the malonate with ethyl cyanoacetate in this reaction gives cyclic products resulting
from one molecule of nucleophile and two molecules of DMAD "Equation "016##[
E E E E
E E E E
CO2Me py–AcOH
+ MeO2C CO2Me + (126)
CO2Me
E E E E
E = CO2Me 63% 4%
EtO2C O
CN py–AcOH CO2Et
+ MeO2C CO2Me NC (127)
68%
CO2Et
EtO2C CO2Et
Conversely\ the successive Michael additions of a ketone enolate to two molecules of ethyl
propiolate\ followed by ring closure\ gives the benzene derivative featured in Equation "017#
ð58JOC3023Ł[
CO2Et
Ph
O NaH
Ph + 2 CO2Et (128)
Ph MeOCH2CH2OMe
Ph CO2Et
Products of the Robinson annelation can be obtained by the addition of ketone enolates to
alkynyl ketones "Equation "018##\ however the yields are usually low because the initial Michael
adduct is formed preferentially as the "E#!isomer ð49JA383Ł\ and better yields are obtained using
alkoxy!substituted alkynes[
O
NaH, Et2O
+ (129)
O 10%
O
Intramolecular additions are also known\ for example the b!ketoester "36# adds to its alkynyl
ketone side chain in a 5!endo!dig process to give the bicyclic enone "37# "Equation "029## ð75TL4344Ł[
Corresponding _ve!membered ring compounds can also be synthesized^ however\ yields for the
seven! and eight!membered ring compounds are poor[ Intramolecular conjugate addition may also
be followed by trapping of the intermediate enolate\ for example by alkylation "Equation "020## to
give a tricyclic enone ð76TL2346Ł[
O O CO2Me
CO2Me
O CsCO3
(130)
THF–DMF, 25 °C
O
89% H
(47) (48)
O
CO2Me CO2Me
O CsCO3 O
(131)
DMF, 65 °C O
Br 80%
In the example shown in Equation "021# the second addition which forms the ring is not the
5!endo!dig Michael addition^ instead\ a 4!exo!dig cyclization occurs onto the second alkyne
ð57T3174Ł[ Another 4!exo!dig cyclization is shown in Equation "022#^ in this case a bridged bicyclic
system is formed ð68JA0173Ł[
O
O
O NaOMe/MeOH
+ CO2Et Ph (132)
0 °C, 2.5 h
Ph Ph 68% CO2Et
Ph
O
NC CN
CO2Me Et3N, PhMe
(133)
110 °C, 12 h
65–70% CO2Me
O
O
0[01[2[2 Carbometallation of Alkynes

Addition of an organometallic reagent to an alkyne generates an alkenylmetallic compound\
which is often not isolated\ but is reacted in situ with another electrophile[ Both protonation and
reaction with carbon!centred electrophiles give alkenes with no attached heteroatoms[ Carbo!
metallation of alkynes has been reviewed ð70S730\ 80COS"3#754Ł[
Ionic Additions 428
0[01[2[2[0 Additions of organolithium and Grignard reagents to alkynes
The addition of noncuprate organometallics to activated alkynes does not usually give good
results because multiple addition can easily occur ð61OR"08#0Ł[
The addition of organolithium reagents to simple alkynes is also not usually a synthetically useful
reaction ð80COS"3#761Ł[ Terminal alkynes are deprotonated\ as are disubstituted alkynes "at the
propargylic position#[ Grignard reagents also deprotonate terminal alkynes\ but addition to alkynes
occurs in moderate yields in the presence of certain transition metal complexes ð80COS"3#766Ł[
Intramolecular addition gives better results[ With disubstituted alkynes with no hydrogen atoms a
to the triple bond\ addition may occur\ as illustrated by the addition of ButLi to diphenylethyne
"Equation "023##^ however\ some metallation of the aromatic rings also occurs ð58JOC0825Ł[ Grignard
reagents also add to diphenylethyne in high yield ð64JOM"85#C36Ł[
i, ButLi, TMEDA, hexane

D Ph Ph Ph
Ph Ph + + Ph Ph (134)
ii, D2O Ph But D But (1.79D in ring)
74 : 12 : 14
Intramolecular addition of organolithium and Grignard reagents to alkynes is possible\ for

example in a simple 4!alkynyl Grignard reagent "Equation "024## ð57TL0346Ł[
i, Mg, THF, 100 °C, 6 d

(135)
Cl ii, H2O
90%
Biphenyl systems can also undergo intramolecular addition after activation as either the organo!
lithium or organomagnesium compound ð55JA2916Ł[
With propargyl alcohols yields of addition products may be high\ because the intermediate
alkenyllithium compound can be stabilized by coordination of the alkoxide oxygen atom\ and this
also results in overall trans!addition to the alkyne "Scheme 21# ð63TL1050Ł[ Trapping the intermediate
with CO1 gives the lactone[
O
Ph
CO2
O
Li O– 77%
OH BunLi, TMEDA Ph Bun
Ph Et2O
Li+ H2 O OH
Bun
90%
Ph Bun
Scheme 32
Addition of Grignard reagents to propargyl alcohols gives overall trans!addition as for organo!
lithium reagents ð66TL056Ł\ however\ if the hydroxyl group is moved one carbon atom further away\
then the regioselectivity is much reduced ð60TL2666Ł[
Benzynes show unusual reactivity towards nucleophilic addition\ and difunctionalization is also
possible by trapping the intermediate arylmetal species with an electrophile ð74T726\ 77JA6067\
77JCS"P0#728\ 77T016Ł[
0[01[2[2[1 Addition of organocopper reagents to alkynes

The addition of organocopper reagents to alkynes is the most useful carbometallation reaction\
and is included in several reviews ð67PAC698\ 70S730\ B!72MI 001!90\ 73T530\ 80COS"3#785Ł[
"i# Addition of orànocopper reaènts to activated alkynes
The conjugate addition of organocuprates to a\b!unsaturated carbonyl compounds\ including
alkynes\ has been reviewed ð61OR"08#0\ 64OR"11#142\ 80COS"3#058Ł[
The addition of the divinylcuprate to the ester "38# at −67>C occurs in a cis!fashion "Equation
"025## ð70S730Ł\ and this reaction seems to be general for other organocopper reagents ð62TL0500\
70S730Ł[ Addition of lithium dimethylcuprate to methyl phenylpropiolate at −79>C gives cis!
addition\ resulting in the "Z#!product "40# after protonation\ but warming the intermediate organo!
cuprate "49# to 14>C results in isomerization\ and the "E#!isomer "41# is then obtained "Scheme 22#
ð58JA0742\ 62JCS"P1#0860Ł[ Reaction of n!butylcopper = 8!BBN!H with DMAD also results in cis!
addition "Equation "026##^ however\ the use of other Lewis acid ligands on boron gives less selectivity\
except for BEt2 ð68JOC0633\ 75AG"E#836Ł[
CO2Me
THF, –78 °C CO2Me
+ n-C5H11 (136)
CuLi
2 90% n-C5H11 O-TMS
O-TMS
(49)
Ph CO2Me Ph CO2Me
–80 °C H3O+
Ph CO2Me + Me2CuLi
Cu
(50) (51)
25 °C
Ph Cu Ph
H3O+
CO2Me CO2Me
(52)
Scheme 33
MeO2C CO2Me
BunCu•9-BBN
MeO2C CO2Me (137)
Bun
Conjugate addition of organocuprates may be followed by trapping of the intermediate\ for

example using an acid chloride as in Equation "027# ð70JOC2585Ł[ Here again there is overall cis!
addition to the alkyne\ but with electrophiles which are less reactive than acid chlorides\ equilibration
of the intermediate enolate may occur[
O
CO2Et
i, Et2O, –78 °C
CO2Et + (MeCu Bun)Li (138)
ii, COCl
, –78 °C
92%
"ii# Additions of orànocuprate reaènts to unactivated alkynes

Organocuprates are the most important and useful of the organometallic reagents for addition
to unactivated alkynes[ Almost completely stereoselective cis!addition occurs\ and high regio!
selectivity is obtained with terminal alkynes ð70S730Ł[ A wide variety of types of organocuprate
reagent may be used\ for example RCu = MgX1\ R1CuMgX\ R1CuLi\ and RCu"X#Li "where
XOBut\ SPh\ CN\ etc[#[ The choice of reaction conditions "solvent\ cosolvent\ ligand# is critical
for each reagent and the alkyne involved ð63BSF0545Ł^ for example in the addition of MeCu to
phenylethyne coupling reactions compete ð60TL1472\ 63JOM"56#356Ł^ however\ BunCu adds to 0!hexyne
in 74) yield "Equation "028##\ in the presence of MgBr1[ With reagents of the type RCu = MgX1 and
terminal alkynes\ high yields of the coupled products are obtained ð64JOM"85#360Ł[ Me1S = MgX1
Ionic Additions 430
complexes of organocuprates have been found to give improved and more reproducible results
"Scheme 23# ð75OS"53#0Ł[ Grignard reagents modi_ed by the addition of copper"I# salts will similarly
add to terminal alkynes only in the presence of excess MgBr1 ð77TL3202Ł[
–35 °C to –15 °C Bun

Bun + BunCu•MgBr2 (139)
85%
Bun
MeCu[Me2S]•MgBr2
Cu[Me2S]•MgBr2
RLi
n-C6H13 OH
Et2O, Me2S, –25 °C, 120 h O
n-C6H13 n-C6H13
Scheme 34
Ethyne itself is the most reactive unfunctionalized alkyne towards the addition of organocuprates
"Equation "039## ð73OS"51#0Ł\ and the lithium diorganocuprates\ R1CuLi\ work best in this case[
However\ reagents of the type R1CuLi do not add to ethyne or other alkynes when RPh\
allyl\ vinyl\ or alkynyl[ Ethyne can also undergo oligomerization initiated by the addition of the
organocuprate\ and the intermediate can then be trapped by a suitable electrophile "Scheme 24#
ð70S730\ 71TL4040\ 74TL2174Ł[
Et2O, –50 °C to –20 °C

R2CuLi + H H R CuLi
(140)
80%
2
Bun Bun Bun

H H (2 equiv.) MeI
CuLi
Et2O, 20 °C 81%
Bun CuLi Bun Bun
2 2
Scheme 35
Secondary alkyl cuprates often add to terminal alkynes with low regioselectivity "Equation "030##
ð66TL1912Ł\ whereas additions of secondary and tertiary Grignard reagents using CuCl and excess
MgBr1 in THF are regioselective ð77TL3202Ł[
PriCuMgLi•LiBr Ph Ph
Ph + (141)
THF, –50 °C, 5 min Pri
Pri
95%
68 : 32
Organocuprates do not usually add to disubstituted alkynes which do not have extra functional
groups^ however\ intramolecular reactions of this type are possible "Equation "031## ð73JOC0463Ł[
But2CuLi, PBu3
Ph
Ph
(142)
Et2O–pentane
I 90%
The presence of functional groups on the alkyne can alter the regioselectivity of the addition
reaction\ particularly when a heteroatom is present at a propargylic or homopropargylic position\
which may give rise to products from chelation or steric control ð70S730Ł[
The intermediate alkenyl copper or cuprate species formed in the above reactions can be proton!
ated\ or alternatively trapped with a variety of carbon!centred electrophiles ð68JOC2777\ 70S730Ł\ and
a good summary of possible transformations can be found in the review by Knochel ð80COS"3#785Ł
and the compilation of methods by Larock ðB!78MI 001!90Ł[ Some selected examples are shown in
Scheme 25[ The dialkenyl cuprates are more reactive than the alkenyl copper reagents\ and are
required for reaction with certain electrophiles[ The reactivity of an alkenyl copper can be enhanced
by addition of HMPA\ or an alkynyllithium\ or magnesium salts "e[g[\ for reaction with epoxides
ð68JOC2777Ł#[ The intermediate cuprate can also be coupled with an alkynyl phenyl iodosyl salt\
giving a stereoselective synthesis of enynes ð76JA6450Ł[
R1
R1 R2
R2
R1
R2 OH R1
R4 R3
(using cuprate) O R2 Ar
10–20 °C or
R3 R4 O2, –20 °C
60–80% ArCH2X, HMPA
BF3•OEt2 80–98%
60–70%
R3
R1 I R1 R1
R3 X
R3 R3
ZnCl2, THF HMPA
R2 Pd(PPh3)4, –10 °C to 20 °C R2 CuLn R2
80–94%
O R3CH2X, HMPA
P(OEt)3, –20 °C
R3 R4 77–85%
65–95% ZnCl2, R3COCl
Pd(PPh3)4, 25 °C
R1 70–100%
R1
R2 R1
R3 R4 R2 R3
O R2 O
R3
Scheme 36
0[01[2[2[2 Addition of organoboron reagents to alkynes

Although trialkylboranes will react with alkynes\ this reaction is of limited synthetic utility\
because severe reaction conditions are required\ and further reaction is often possible ð80COS"3#775Ł[
Carboboration of terminal alkynes by BBr2 and an organozinc reagent followed by palladium!
catalyzed cross!coupling allows the synthesis of stereochemically de_ned trisubstituted alkenes
i, BBr3, CH2Cl2 Bun
ii, PdCl2(PPh3)2
n-C6H13 (143)
iii, BunZnCl n-C6H13
iv, LiOMe, CH2=CHCH2Br
56%
0[01[2[2[3 Addition of organoaluminum reagents to alkynes

Formation of alkenylaluminum compounds from alkynes and subsequent useful transformations
have been reviewed speci_cally ð73OR"21#264\ 80COS"3#777Ł\ and as part of a more general review on
carbometallation of alkynes ð70S730Ł[
Trialkylaluminum and chlorodialkylaluminum compounds add to terminal alkynes in the pres!
ence of Cp1ZrCl1\ giving alkenylalane intermediates "42# resulting from cis!addition\ which can then
react with a variety of reagents to give further C0H or C0C bond formation "Scheme 26#[ This
process has been reviewed ð70PAC1222\ 74MI 001!93Ł[ Various functional groups can be tolerated on
the alkyne\ including protected and free hydroxyl groups\ sul_de\ halogen and alkene moieties
ð70JOC3982Ł[
Protonation of the alkenyl alanes "42# results in formation of 0\0!disubstituted alkenes "Scheme 26#
ð59LA"518#111Ł[ The intermediate "42# can be coupled with organic halides\ catalyzed by palladium"9#\
nickel"9#\ or zinc"II# and this process has been reviewed ð71ACR239\ 76TL1110Ł[ The halides can be
aryl\ vinyl\ alkynyl\ allyl\ or benzyl[ Treatment with ethyl chloroformate results in stereoselective
formation of a\b!unsaturated esters ð67TL1246\ 70JOC3982\ 71TL16Ł[ Michael addition of "42# is also
possible with a\b!unsaturated ketones\ for example methyl vinyl ketone ð70PAC1222Ł[
Ionic Additions 432
CO2Et
R1
R1
ClCO2Et
H3O+
Me3Al, Cp2ZrCl2
AlMe2 R2X
R2
R1
R1 Pd0, Ni, 0, or ZnII R1
(53)
CO2H
CO2
BunLi R1
R1 = n-C5H11, 64%
OMe
AlMe2BunLi ClCH2OMe
R1 = n-C5H11, 79% R1
R1
(54) (CH2O)n
OH
R1 = n-C5H11, 82%
R1
Scheme 37
Treatment of the intermediate "42# with BunLi gives the more reactive alanate "43#\ which reacts
with\ for example\ formaldehyde\ ketones\ chloromethyl methyl ether\ CO1\ and epoxides "Scheme
26# ð67TL1246\ 79JOC4112\ 70JOC3982Ł[
Internal alkynes also add Me2Al in the presence of Cp1ZrCl1\ although the regioselectivity is
usually poor\ except in special cases\ for example 0!phenylpropyne ð73OR"21#264Ł[ Addition to
symmetrical internal alkynes followed by protonation gives "Z#!trisubstituted alkenes "Equation
"033## ð67JA1141Ł[ 2!Alkyn!0!ols undergo regioselective addition of trimethylaluminum in the pres!
ence of TiCl3\ resulting in stereoselective formation of trisubstituted homoallylic alcohols "Equation
"034## ð70JOC796\ 74JOC1013Ł[
i, Me3Al•Cp2ZrCl2
Bun Bun (144)
ii, H3O+ Bun Bun
89%
Et i, Me3Al, TiCl4
Et (145)
OH OH
ii, MeOH
Allyl and benzyl alanes also undergo zirconium!promoted addition to terminal and internal
alkynes\ although the regioselectivity is moderate ð73TL4752Ł[
0[01[2[2[4 Addition of organozinc reagents to alkynes

Organozinc reagents add to alkynes more readily than to alkenes ð80COS"3#768Ł^ for example allyl
zinc bromide readily adds to terminal alkynes\ and also to propargyl alcohol "Equation "035##
ð65TL2972Ł[
The zinc enolate of diethyl methylmalonate adds to terminal alkynes\ but often gives a mixture
of regioisomers "Equation "036## ð64CR"C#888Ł[
OH
20 °C, 3 h
+ ZnBr (146)
OH 74%
CO2Et THF, 42 °C, 4–24 h R CO2Et
BrZn CO2Et + R CO2Et (147)
20–60%
The same portfolio of regioisomeric products are formed in the addition of allyl zinc bromide to
the terminal and internal aminoalkynes "Equation "037##^ the internal alkynes add the allyl zinc
reagent to the carbon atom distal to the amino group with complete regioselectivity\ whereas with
the terminal alkynes the regioselectivity is reversed ð61JOM"33#58Ł[ Propargyl zinc bromides also add
to functionalized alkynes regioselectively to give enynes ð68JOM"055#0Ł[ Nonfunctionalized internal
alkynes do not react with allyl zinc reagents^ however\ intramolecular reaction is possible "Equation
"038##\ giving the syn!addition product ð67CR"C#154Ł[ Dialkylzinc reagents add to both terminal and
internal alkynes promoted by a zirconium complex ð77S0\ 72OM452Ł[ Addition of crotyl zinc bromide
to the bromoalkyne "44# results in an intermediate which cyclizes to a cyclobutene "Equation "049##
ð73JA5094Ł[
THF, RT, 23 h
ZnBr NEt2
+ (148)
NEt2 65%
Br
Zn, THF
(149)
65 °C, 24 h
50%
+ ZnBr (150)
Br
(55)
0[01[2[2[5 Other carbometallation reactions of alkynes

Organosilver reagents add to alkynylnitriles to give cis!addition of the alkyl group and hydrogen
"Equation "040## ð68TL2216\ 70JOM"195#146Ł[ Conjugated diynes also undergo addition of organosilver
reagents\ and the intermediates can be trapped to give further C0C bond formation\ for example
with allyl bromide or CO1 "Equation "041## ð70RTC226Ł[
i, R22AgMgX2•LiBr R1 CN
R1 CN (151)
ii, H2O R2
R1
i, R22AgMgX2•LiBr
R1 (152)
ii, CH2=CHCH2Br
R2
Intramolecular carbomercuration is possible with alkynyl silyl enol ethers\ giving _ve! or six!
membered rings ð72S790Ł^ acylation of the intermediate results in a second carbonÐcarbon bond
formation\ and overall cis!addition with high stereoselectivity "Scheme 27#[
O-TMS O
O
HgCl2, (TMS)2NH, CH2Cl2 O
HgCl MeCOX
30 °C, 0.5 h
Scheme 38
Ionic Additions 434
The nickel complex MeNi"acac#1PPh2 adds to alkynes\ and the C0Ni bond in the resulting
alkenyl nickel complexes can be replaced by either C0H using TsOH or LAH\ or by C0C using
Me2Al or MeLi "Equation "042## ð70JA2991Ł[ Reaction with CO and MeOH results in a\b!unsaturated
esters[
i, MeNi(acac)2PPh3 R1 R2
R1 R2 (153)
ii, MeLi
Carbon dioxide adds to alkynes in the presence of Ni"cod#1\ and the intermediate cyclic nickel
complex can undergo further carbonÐcarbon bond formation with CO\ alkyl halides\ or even
addition to another alkyne "Scheme 28# ð73JOM"155#192\ 73JOM"169#C04Ł[
R1 R1
Ni(cod)2, CO2, L i, R2X
R1 R1
R1 R1
40–89% L-Ni ii, H3O+
O O R2 CO2H
L = bidentate N or P ligand
Scheme 39
Hydrogen cyanide adds to internal alkynes\ in the presence of a nickel or palladium catalyst\ to
give a\b!unsaturated nitriles "Equation "043## ð71CC0120Ł[
R1 R2
HCN, Ni catalyst
R1 R2 (154)
CN
0[01[2[3 Addition of Sulfur\ Selenium\ and Tellurium Reagents to Alkynes

Terminal alkynes undergo regioselective addition of ArSO1SePh to give alkenylsulfones "Scheme
39#^ treatment with an organocuprate then results in conjugate additionÐelimination of the phenyl!
selenide\ and _nally Na"Hg# amalgam reduction yields terminal alkenes ð75TL1076\ 76JOC3147Ł[
R1 SO2Ar R1 SO2Ar R1
ArSO2SePh (R2CuSePh)Li Na(Hg)
R1
PhSe R2 R2
Scheme 40
Terminal alkynes also undergo trans!addition of PhTe0H to give "Z#!alkenyltellurides^ the

tellurium can then be replaced by a Grignard reagent ð71TL0070Ł\ or by carbonylation ð76JOC3748Ł\
both with retention of alkene geometry "Scheme 30#[
(PhTe)2 R1 TePh CO, PdCl2 (cat.), CuCl2 R1 CO2R2

R1
NaBH4 R2OH
Scheme 41
0[01[2[4 Addition of Iron Reagents to Alkynes

Internal alkynes can be converted into the alkynyl iron complex "45#[ The triple bond is then
activated towards the addition of nucleophiles\ including carbon!centred nucleophiles such as Me−\
Ph−\ and malonate anions[ Transfer of a CO ligand from the iron followed by reaction with alcohol
results in stereoselective formation of a\b!unsaturated esters "Scheme 31# ð75JA0839\ 77ACR118Ł[
+
CpFe(CO)P(OPh)3
EtO2C
BF4– i, EtO2C CO2Et R1 CO2Et
R1 R2 R1 R2
ii, R3OH, (NH4)2Ce(NO3)6
(56) R3O2C R2
Scheme 42
0[01[2[5 Palladium!catalyzed Additions to Alkynes

A reductive Heck!type coupling reaction between an alkyne and an aryl iodide yields aromatic
alkenes "46# "Equation "044## ð73TL2026Ł[ The reducing agent is formate\ and the Ar and H are
added stereoselectively cis to the triple bond[ Propargyl alcohols can also be used ð74T4010Ł[
(PPh3)2Pd(OAc)2 (cat.)
Ph Ph + (155)
Et3N, HCO2H
I 93%
Ph Ph
(57)
Terminal alkynes can be dimerized to give enynes in the presence of catalytic Pd"OAc#1 and PAr2
ð76JA2375Ł[ Unsymmetrical coupling is also possible between a terminal alkyne and an alkyne
bearing a carboxylate ester[ Enynes can be cyclized to methylenecyclopentanes in the presence of a
trialkylsilane\ acetic acid\ and a palladium catalyst "Equation "045## ð76JA2050Ł[ This process is also
possible without the reductive step\ giving 0\1!bis"alkylidene#cyclopentanes ð76JA2372Ł[ Cascade
cyclizations are also possible\ where an organopalladium intermediate undergoes intermolecular
addition to an alkyne\ and this is followed by intramolecular cyclization onto an alkene ð82TL042\
82TL046Ł[
R
AcOH, Et3SiH, Pd (cat.) R
(156)
Palladium!catalyzed carbonylation of alkynols gives a!methylene lactones with _ve! or six!mem!

bered rings^ fused bicyclic lactones can also be prepared in this way ð70JA6419Ł[
0[01[3 FREE RADICAL ADDITIONS

Free radical addition reactions have been the subject of many reviews\ and additions to alkynes
are included in several of these articles ðB!75MI 001!90\ 77S306\ 77S378\ 80COS"3#604\ 80COS"3#668\
B!81MI 001!90Ł[
0[01[3[0 Intermolecular Free Radical Additions

Alkynes have been relatively little used in intermolecular additions of carbon!centred free radicals^
alkenes are more reactive ð71AG"E#657Ł\ and much more often used[ The radical formed by hydrogen
abstraction from propan!1!ol adds to propiolic acid with subsequent lactonization\ in moderate
overall yield ð51CR"143#0706Ł and t!butyl radical adds to methyl propiolate to give mainly the "Z#!
product ð71AG"E#657Ł^ this stereoselectivity is rationalized by invoking steric hindrance of the t!butyl
group during the hydrogen abstraction by the intermediate radical addition product[ The radical
generated from 6!bromoheptan!1!one by catalytic vitamin B01\ with a chemical or electrochemical
reductant undergoes addition to ethyl propiolate\ with a 6 ] 0 "E# ] "Z# selectivity ð72JA6199\ 76PAC252Ł[
Free radicals generated from trialkylboranes react with conjugated ynones in an SH1 process\
yielding a\b!unsaturated ketones as a mixture of geometrical isomers ð69JA2492Ł[
Free Radical Additions 436
0[01[3[1 Intramolecular Free Radical Additions
The simplest example of this type of reaction is the 4!hexynyl radical\ which\ like the 4!hexenyl
system\ cyclizes in the 4!exo mode rather than the 5!endo mode\ to give methylenecyclopentane
ð68JCS"P1#0424\ 74T2814Ł[ Many examples of this type of process can be found in the reviews listed
above[ Heteroatom linkages have also been widely used\ for example the bromoacetal "47#\ which
after radical cyclization is oxidized to the a!methylene lactone "Equation "046## ð77TL5376Ł\ and
highly functionalized sugar!derived iodide "48# "Equation "047## ð78TL46Ł[ Aryl radicals have also
been cyclized in 4!exo mode "Equation "048## ð74TL5990Ł[
Br
i, Bun3SnH
O (157)
ii, [O] O
O OMe 70%
(58)
O O O O
AcO AcO
Bun3SnH
(158)
AcO I 85% AcO
OAc OAc Ph
Ph
(59) (E):(Z) 1:3
OMe OMe
I
Bun3SnH
(159)
52% O
O
This preference for 4!exo cyclization is not universal\ however\ and although the pyrrolidinone
"59# gives clean 4!exo cyclization "Equation "059##\ the compound lacking the TMS group cyclizes
to give a mixture of _ve! and six!membered ring products ð74T2848Ł[ Intermolecular radical addition
to an activated alkene can be followed by cyclization onto an alkyne\ as in Equation "050# ð74CC879Ł[
TMS
TMS
PhS
OAc OAc
Bun3SnH
N (160)
N
61%
O O
(60)
Br
Bun3SnH
+ CO2Me CO2Me (161)
44%
Ph Ph
The 5!heptynyl system also cyclizes in the exo mode "e[g[ Equation "051## ð73JOC3133Ł[ When the
chain linking the radical to the alkyne is part of a b!lactam\ then 6!endo cyclization is preferred
ð71TL1494Ł[ Again\ addition of a substituent to the alkyne terminus reverses the selectivity^ in this
case phenyl substitution results in 5!exo cyclization[ The cyclohexyl radical formed from "50#
similarly cyclizes in 5!exo mode onto the phenyl!substituted alkyne in good yield "Equation "052##
ð73JOC0202Ł[
Ph
Ph
Br
Cr(ClO4)2
(162)
H2NCH2CH2NH2, DMF
74%
N
O N Ph
H
O Bun3SnH
Ph (163)
hexane, heat
79%
(61)
When the radical is stabilized\ as in cyano ester "51#\ the 6!endo mode is preferred "Equation
"053## ð60ACR275Ł[ In contrast\ the same type of radical in a hexynyl system undergoes 4!exo
cyclization onto the alkyne\ whereas the corresponding alkene undergoes 5!endo cyclization
ð51CR"144#848Ł[ Nitro groups can serve as precursors to radicals\ and in Equation "054# cyclization
onto the alkynyl ether gives a methylene tetrahydrofuran ð74T3902Ł[
EtO2C CN
EtO2C CN
(BzO)2
(164)
PhH, heat
65%
(62)
CN CN
O 2N
Bun3SnH
(165)
79%
Ph O Ph O
Acyl radicals undergo cyclization onto alkynes^ in Equation "055# the radical is generated from a
selenocarbonate ð75TL530Ł[ Radical anions generated by reduction of carbonyl groups cyclize onto
alkynes\ resulting in unsaturated alcohols[ The radical anions can be generated using a variety of
reducing agents^ for example Na:THF or sodium naphthalenide "Equation "056## ð70JOC1511\
75TL1132Ł\ Na:NH2 ð68JA6096Ł\ Zn:TMS!Cl ð72TL1710Ł\ and cathodic reduction ð59JCS0934\
57CR"C#0723Ł[ Ultraviolet light can also be used to generate the ketyl radical ð76TL3436Ł[
Ph Ph
SePh Bun3SnH
O (166)
O O 90% O
OH
O
NaC10H8
(167)
52%
H
The cyclization onto the alkyne can be part of a tandem radical cyclization^ for example cycli!
zation onto an alkene "Equation "057## can be followed by cyclization of the intermediate radical
onto the terminal alkyne ð74TL3880Ł[ This approach has been used as a key step in the synthesis of
tricyclic sesquiterpenes[ A ketyl radical generated by reduction by SmI1 has also been used in a
tandem cyclization "Equation "058## ð77JA4953Ł[ The order of cyclizations can be reversed "Equation
"069## such that the initial radical cyclization is onto the alkyne\ and the resulting alkenyl radical
cyclizes onto a cyclohexene unit ð72JA2619Ł[ In Scheme 32 a di}erent type of sequence takes place\
with initial intermolecular addition of a stannyl radical to the alkyne\ followed by 5!exo cyclization
of the resulting alkenyl radical[ Protodestannylation then results in the loss of the tin group and
formation of the exo!methylene group ð76JA1718\ 77OS"55#64Ł[
Carbene and Other Additions 438
H H
Br Bun3SnH
(168)
61%
OH
O H
i, SmI2 O
O (169)
ii,H3O+
O 65%
H H
O O Cl
O O
Cl
Br Bun3SnH
(170)
47%
Bun3Sn
Bun3SnH H+
Scheme 43
0[01[4 CARBENE AND OTHER ADDITIONS
0[01[4[0 Addition of Simple Carbenes and Carbenoids to Alkynes

Addition of carbenes to alkynes is a good method for the preparation of cyclopropenes
ðB!58MI 001!91\ B!67MI 001!92Ł[ Carbenes substituted with a!carbonyl groups add to internal alkynes
ðB!76MI 001!90\ 76TCC"026#64\ 77TCC026Ł[ Copper catalysis was generally used\ and although this is
successful for internal alkynes\ terminal alkynes preferentially undergo C0H insertion[ This limi!
tation can be overcome by the use of bis"trimethylsilyl#ethyne followed by removal of the silyl
groups after carbene addition "Scheme 33#\ and is equivalent to the overall addition to ethyne itself
ð76JOC3764Ł[ Enynes react selectively at the alkene double bond\ giving alkynyl cyclopropanes[
Diazoalkanes can also undergo 0\2!dipolar cycloaddition to alkynes^ with alkynes substituted with
electron!withdrawing groups\ this is often faster than formation of the carbene[ Another side
reaction which can occur with phenylcarbenes is indene formation via a diradical intermediate^ this
is the major product in the reaction of diphenylcarbene with terminal alkynes\ but the minor one
with dimethylethyne ð62JA5175Ł[
TMS
CO2Me Cu(acac)2 CO2Me K2CO3 CO2Me
TMS TMS + N2
CO2Me 33% CO2Me THF–H2O CO2Me
TMS 85%
Scheme 44
Rhodium!catalyzed carbene formation from a!diazoesters is generally better than the use of
copper catalysts\ and addition of the carbene derived from ethyl diazoacetate to alkynes is the
method of choice for the synthesis of cyclopropene!2!carboxylic acid esters "Equation "060##
ð67TL0128Ł[ These cyclopropene carboxylic esters can also be made to undergo ring expansion to
give cyclobutenes ð60JA2717Ł[ Terminal alkynes usually react successfully^ however\ phenylethyne
fails because the alkyne polymerizes[ In some cases on using carbenes substituted with a!carbonyl
groups furans are formed instead of cyclopropenones^ which pathway is followed depends upon the
particular carbenoid and alkene used ð80COS"3#0920Ł[
R1
CO2Me Rh2(OAc)4
R1 R2 + CO2Me (171)
N2 38–86%
R2
0\0!Dihalocarbenes\ which are readily prepared\ react sluggishly with alkynes compared to alkenes
ð80COS"3#888Ł[ The resulting dihalocyclopropenes are unstable^ however\ hydrolysis results in a good
method for the preparation of cyclopropenones "Equation "061## ð66CB043Ł[ Again\ internal alkynes
add dihalocarbenes\ whereas terminal alkynes do not\ and enynes react preferentially at the alkene
double bond[ An alkylidene carbene can be generated by a!elimination of an enoltri~ate^ addition
to an alkyne then gives the alkylidene cyclopropene ð64JA2743Ł[
O
i, :CCl2
CO2Et (172)
ii, H2O
CO2Et
Intramolecular addition of carbenes to alkynes is also possible and\ although it is much less
studied than with alkenes\ the subject has been reviewed ð81T4274Ł[ The highly strained bicyclic
cyclopropene "52# is thought to be initially produced^ this species forms a vinyl carbene "53#\ which
gives various products\ often with only a single C0C bond derived from the alkyne "Scheme 34#
ð89JOC303Ł[
O O O
N2
Rh2(OAc)4
products
R
R R
LnRh
(63) (64)
Scheme 45
In Scheme 35 the vinyl carbene produced adds to a double bond of the diene^ ð2\2Ł!rearrangement
of the divinylcyclopropane "54# _nally yields the tetracyclic compound "55# ð80JOC1412Ł[ An unusual
example of a sequential double reaction with two alkynes is shown in Scheme 36[ The initial
intramolecular attack on the _rst alkyne gives a vinyl carbene as usual^ this is then trapped by a
second intermolecular addition of 1!butyne giving a cyclopropene ð80TL2644Ł[ An intramolecular
version of the second addition is known ð81T4274Ł[
O O
N2
Rh2(OAc)4
CH2Cl2, 0 °C
LnRh
O O
[3,3]
58%
(65) (66)
Scheme 46
Carbene and Other Additions 440
RhLn
Rh2(OAc)4 40%
N2
O O O
Scheme 47
0[01[4[1 Reaction of Fischer Carbene Complexes with Alkynes

Chromium carbene complexes react with alkynes to give cyclobutenones "Scheme 37#
ð76JOM"223#8Ł[ However\ the most useful reaction of Fischer carbene complexes with alkynes is that
of an arylalkoxy chromium carbene complex with carbon monoxide and an alkyne "Scheme 38#
ð70JA6566Ł[ This reaction has been reviewed ð77CRV0970Ł[ The chromium can be easily removed
from the product complex by CO to give a naphthol\ or oxidatively to give a quinone[ The reaction
is general for both terminal and internal alkynes\ and is highly regioselective with respect to the
alkyne\ being completely so for terminal alkynes[ The p!system attached to the carbene may be aryl\
heteroaryl\ or alkenyl[ Intramolecular reactions of this type are also recorded ð82JA09560Ł[
O OMe
i, Et2O–THF, –80 °C to RT
OMe i, Ph Ph Ph
PhLi + Cr2(CO)8 (CO)5Cr
ii, Me3O+ BF4– Ph ii, [O]
Ph Ph
51%
Scheme 48
O O
Prn
i, THF, 45 °C, 1 d
+ Prn +
OMe ii, (NH4)2Ce(NO3)6
HNO3 (aq.), 25 °C, 30 min Pr n
OMe Cr(CO)5 OMe O OMe O
47% 17%
Scheme 49
1.13
One or More C1C Bond(s) by
Elimination of Hydrogen,
Carbon, Halogen or Oxygen
Functions
JONATHAN M. PERCY
University of Birmingham, UK
0[02[0 BY ELIMINATION OF HYDROGEN 443
0[02[0[0 Dehydroènation of Hydrocarbons 443
0[02[0[1 Dehydroènation of Ketones 443
0[02[0[2 Dehydroènation of Silyl Enol Ethers 445
0[02[1 ELIMINATION OF CARBON FUNCTIONS 448

0[02[1[0 Elimination of Hydroèn Cyanide 448
0[02[1[1 Elimination of Carbon Oxides 459
0[02[1[1[0 Decarboxylation 459
0[02[1[1[1 Didecarboxylation 451
0[02[1[1[2 Decarboxylation:dehydration 454
0[02[1[1[3 Decarboxylation:dehaloènation 457
0[02[2 BY ELIMINATION OF HALOGEN "OR H!HAL# 457

0[02[2[0 Elimination of Dihalides 457
0[02[2[1 Elimination of Hydroèn Halides 469
0[02[2[1[0 Dehydro~uorination 469
0[02[2[1[1 Dehydrochlorination 460
0[02[2[1[2 Dehydrobromination 461
0[02[2[1[3 Dehydroiodination 463
0[02[3 BY ELIMINATION OF OXYGEN FUNCTIONS 464

0[02[3[0 Dehydration 464
0[02[3[0[0 Usin` Burèss| reaènt 464
0[02[3[0[1 Usin` Martin|s sulfurane reaènt 465
0[02[3[0[2 Dehydration by other methods 465
0[02[3[1 Elimination of Alcohols "H0OR# 468
0[02[3[2 Eliminative Rin` Openin` of Epoxides 479
0[02[3[3 Elimination of a Carboxylic Acid "H0OCOR# 471
0[02[3[4 Elimination of a Sulfonic Acid 472
0[02[3[5 Elimination of 0\1!Diols 474
0[02[3[6 Deoxyènation of Epoxides 476
442
443 C1C Bonds by Elimination of Hydroèn\ Carbon\ Haloèn or Oxyèn
0[02[0 BY ELIMINATION OF HYDROGEN
0[02[0[0 Dehydrogenation of Hydrocarbons

The most demanding dehydrogenation would involve the regioselective removal of two hydrogen
atoms from an unactivated alkane[ Active iridium and rhodium catalysts have been described
ð73TL0168\ 76JA7914Ł\ which achieve the transformation\ consuming an alkene oxidant during the
catalytic cycle[ Unsymmetrical alkanes have been oxidized with modest regio! and stereoselectivities
ð81JA8381Ł[ Though none of the current methods appear suitable for use in the synthesis of complex
molecules\ the area is developing rapidly and signi_cant progress is being made[
The best known examples of reactions in this class lie outside the scope of this chapter and involve
the aromatisation of polycyclic hydroaromatic compounds ð67CRV206Ł[ A number of reagents have
been employed to e}ect dehydrogenations\ via hydride abstraction from benzylic or allylic positions[
The reagent of choice 1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq#"0#\ is commercially avail!
able and chemically reactive\ although the cost of the reagent is relatively high[ Chloranil "1# is a
less expensive alternative[ Reactions are normally performed in inert\ high boiling solvents including
toluene\ chlorobenzene\ xylene and 0\3!dioxan[ The corresponding dihydroquinol is formed during
the reaction\ and can be removed by _ltration or chromatography on alumina[ Solvents must be
dry to prevent nucleophilic attack by water on the quinone leading to decomposition[ Nucleophilic
functional groups should be protected[
O O
NC Cl Cl Cl
NC Cl Cl Cl
O O
(1) (2)
When hydride abstraction generates a highly stabilised carbenium ion\ dehydrogenations occur
smoothly under mild conditions ð80TL2568Ł[ Oxidations of this type are unusual\ but appealing\
when further unwanted oxidation steps are impossible "Equation "0##[
MeO TBDMS-O MeO TBDMS-O

H
ddq
(1)
O 23 °C, 14 h O
88%
TBDMS = t-butyldimethylsilyl
0[02[0[1 Dehydrogenation of Ketones

The direct dehydrogenation of saturated ketones is a common and well!used reaction[ The
mechanism probably involves initial enolisation of the ketone\ followed by nucleophilic attack on
the quinone oxidant[ Elimination of the hydroquinol follows to form the a\b!double bond "Scheme 0#[
Bulky substituents at the b!carbon reduce the rate of oxidation\ presumably by impeding the
nucleophilic addition step ð76BCJ3357Ł[ A range of ketones have been oxidised in this way "Table 0\
entries 0Ð6#[
OH OH
X X O
X X
(1) or (2) O
+
O OH X X X
X
O OH
Scheme 1
A substituted cycloheptenone "entry 0# underwent e.cient dehydrogenation when re~uxed with

ddq in benzene ð70JOC0Ł[ Flavanone and chromanone substrates underwent smooth oxidation to
Of Hydroèn 444
Table 0 Dehydrogenations with ddq[
Entry Substrate Product Yield

(%)
O O
O O
CO2Me CO2Me
1 90
O OMe O OMe
O O
2 75
O O
HO O Ph HO O Ph
3 50
O O
MeO O Ph MeO O Ph
4 75
O O
O O
5 84
O O
O O
6 98
O O
7 MeO2C MeO2C 77
O O
H H
the corresponding ~avones and chromones "entries 1Ð3# ð72S209Ł[ The e}ect of the presence of a
nucleophilic functional group was a reduction in yield\ possibly through nucleophilic attack on the
oxidant[ The addition of an acid catalyst appeared to accelerate the reaction\ presumably by
increasing the rate of enolisation ð56JCS"C#0619Ł[ Oxidation was complete within 4 hours\ when
p!toluene sulfonic acid was added to the reaction mixture "entry 5#^ in the absence of the catalyst\ a
reaction time of 04 hours was required "entry 4#[ The regiochemical outcome of the reaction also
changed^ oxidation occurred in the B!ring when the catalyst was present[ The b!ketoester oxidation
"entry 6# is unusual\ but the observation is entirely consistent with the proposed mechanism via an
enol ð81JA6264Ł[
Attempts to oxidise "2# and "3# using a ddq procedure were unsuccessful[ The a!and b!faces of
the steroid A!ring in "2# are both sterically hindered around the b!carbon atom\ impairing attack
on the oxidant ð78T5398Ł[ In "3#\ enolisation of the b\g!unsaturated ketone may occur to generate a
sterically hindered enol ð81JA4848Ł[ Flavanone oxidation has been studied by a number of groups\
and alternative methods use thallium salts ð81JCS"P0#1454Ł[
O O
NCO2Me
H
OMe
O
O
H
O
(3) (4)
Ketone!to!enone conversions have been achieved by other methods[ Scheme 1 shows a fortuitous
procedure\ applied to the synthesis of prostanoid intermediates ð72TL444Ł[ The straightforward one!
step oxidation used commercial "88)# copper"II# bromide\ and o}ered signi_cant advantages over
more conventional multistep procedures ð79JOC3691Ł[ However\ the method does not appear to
have found other applications[
O O
CuBr2
CO2Me CO2Me
CHCl3, EtOAc
reflux, 0.7 h
66%
O O
CO2Me CuBr2 CO2Me
CHCl3, EtOAc
reflux, 0.7 h
CHO 38% CHO
Scheme 2
Cation radical oxidants achieved a regioselective oxidation of substituted cyclopentanones to

a}ord the more substituted cyclopentenone products in modest yield "Scheme 2# ð89T1260Ł[ The
salts could be preprepared or generated in situ[ An excess of oxidant was required\ and the reactions
were performed in aqueous acetonitrile in the presence of collidine[ Lead tetraacetate:copper"II#
acetate has been used to dehydrogenate b!ketoesters and b!ketoamides "Scheme 3#[ The amides
were easy to prepare and were oxidised in better yield than the corresponding esters[ The procedure
could be used on a multigramme scale ð82TL2910Ł[
O + • O
R3NSbCl6–
R R
collidine
H2O, MeCN
R = Me, 50% yield/65% conversion

R = But, 40% yield/65% conversion
Scheme 3
0[02[0[2 Dehydrogenation of Silyl Enol Ethers

The oxidation of a silyl enol ether is a valuable synthetic method\ allowing the conversion of
ketones to enones in a stepwise procedure[ The method combines well with the developments in
regiocontrolled silyl enol ether formation[ E}ective oxidants include ddq\ palladium"II# compounds
and tritylium salts[
Initial studies using ddq deployed a large excess of the oxidant to obtain enones in moderate
yields ð67TL2344Ł[ Tritylium salts\ generated in situ\ oxidised enol ethers to cyclic enones in moderate
yield[ The products were usually contaminated with ketone[ Acyclic silyl enol ethers were oxidised
in low yield\ and ddq failed to yield oxidation products ð66JOC2850Ł[ Both methods were re_ned by
Fleming and Paterson in an elegant study combining conjugate addition methods with silyl enol
ether oxidation ð68S625Ł[ Table 1\ entries 0Ð6 show the scope of the reaction[
The ease of oxidation varied with level of substitution at the carbon atom b! to the carbonyl
Of Hydroèn 446
O O
CO2Me Pb(OAc)4, Cu(OAc)2•2H2O CO2Me
PhH, RT
78%
O O O O
Pb(OAc)4, Cu(OAc)2•2H2O
NEt2 PhH, RT NEt2

72%
OMe OMe
O O O O
Pb(OAc)4, Cu(OAc)2•2H2O
N PhH, RT N
55%
Scheme 4
Table 1 Dehydrogenations of silyl enol ethers with ddq[

(%)
TMS-O O
1 74
TMS-O O
2 73
TMS-O O
3 52
TMS-O O
4 >80
CO2Me CO2Me
TMS-O O
5 H H >45
OMe OMe
H
H OMe H OMe
6 65
TMS-O O
TMS-O O
7 >57
SnMe3 SnMe3
group[ When the position was trisubstituted "entry 0#\ one equivalent of ddq a}orded high yields of
enone[ When the position was less substituted\ ddq was used in excess\ and collidine was required
to remove the dihydroquinol formed in the reaction "entries 1 and 2#[ Unless the oxidation was
rapid\ the dihydroquinol acted as a general acid catalyst and protonated the silyl enol ether\ leading
to the formation of the saturated ketone[ The oxidation has been applied in syntheses of complex
molecules ð81JA6264Ł and the conditions were compatible with the presence of a methyl ester
ð89TL768Ł\ an allylic ketal ð89JA8173Ł and a trialkylstannyl group ð80TL4108Ł[ A _nal example
described an oxidation of an O!silyl imidate with applications in the steroid _eld ð77JA2207Ł[
Equation "1# shows the reaction\ which tolerated the presence of a range of functional groups in the
D!ring of the steroid[ A four!fold excess of silylating agent was used\ so the nucleophilic functional
groups were probably protected in situ[
CO2H CO2H
O-TMS
F3C
N-TMS
(2)
1.0 ddq
1,4 dioxan
O N 20 °C, 4 h then O N
H H 110 °C, 18 h H H
85%
Oxidation with palladium acetate\ usually in acetonitrile\ has proved a general and valuable
method[ One equivalent of the oxidant was required\ though 9[4 equivalents could be used when
benzoquinone was present as a co!oxidant[ The stoichiometric method is expensive to perform but
valuable products have been obtained[ The reaction conditions are very mild^ high yields of enones
were obtained by stirring the enol ether and oxidant in acetonitrile^ workup was usually facile[ Small
amounts "generally ð09)# of saturated ketone were also formed[ Table 2 shows a range of examples
including several from recent natural product syntheses[ Acyclic silyl enol ethers were oxidised to
E!enones or enals ð67JOC0900Ł[ Exposed ð78LA1040Ł and protected ð82CC508Ł hydroxyl groups were
tolerated[ Other examples described steroid manipulations ð80TL2246Ł\ homochiral cyclohexenone
syntheses ð82TA10Ł and a building block for an asymmetric synthesis of "−#!D8"01#!capnellene
ð83T544Ł[ Catalytic versions of the reaction were developed in Tsuji|s laboratory ð72TL4524Ł[ Silyl
enol ethers\ enol acetates and enol carbamates underwent e.cient oxidation in the presence of
palladium acetate\ dppe and diallyl carbonate[ However\ relatively high temperatures were required
to initiate the catalytic cycle^ the reactions were performed in acetonitrile or benzonitrile at re~ux
"Equation "2##[ Enol acetates underwent the catalytic reaction in high yield "Equation "3##[ A range
of conditions were described ð75T1860Ł\ so a careful choice may be essential for optimum yields to
be obtained[ The tributyltin methoxide coreagent was required to convert the stable enol acetate to
the reactive tin enolate in situ[ Enol allyl carbamates underwent dehydrogenation in the presence of
catalytic amounts of palladium acetate and triphenylphosphine "Equation "4##[ The reactions were
performed on a 9[0 mol scale and a}orded high isolated yields ð76S881Ł[
O-TMS O
Pd(OAc)2/dppe
(3)
diallyl carbonate/MeCN
100%
OAc O
Pd(OAc)2/dppe/MeOSnBu3
(4)
OCO2Me
97%
O O CHO
Pd(OAc)2/Ph3P
O (5)
MeCN
reflux, 1.5 h
82%
Ketene acetals and aminals also underwent oxidation with catalytic palladium acetate in ace!
tonitrile or benzonitrile in the presence of two equivalents of allyl methyl carbamate "Equation "5##[
The reactions in benzonitrile were performed at _ve!fold higher concentration[
Of Carbon 448
Table 2 Dehydrogenations with palladium acetate[

(%)
O-TMS O
1 97
2 O-TMS O 92
OMe OMe
3 >88
O-TBDMS O-TBDMS
O-TMS O
O-TMS O
4 >74
TMS TMS
Ph Ph
5 high
O-TMS O
O-TMS O
6 84
MeO MeO
O O O O
O-TMS O
7 92
O O
O OH O OH
O-TMS O
Pd(OAc)2
O O (6)
diallyl carbonate/MeCN
70%
It is surprising that the catalytic chemistry developed by Tsuji has not found wider application in
target syntheses[ Despite the higher cost of the palladium reagents\ the most popular method appears
to be the stoichiometric oxidation[
0[02[1 ELIMINATION OF CARBON FUNCTIONS
0[02[1[0 Elimination of Hydrogen Cyanide

The range of examples in the literature is very limited\ re~ecting the modest nucleofugacity of the
cyanide anion[ Reaction mechanisms are most likely to be E0cb or E0cb!like[ Enamines were
prepared by elimination of hydrogen cyanide\ following alkylation of a!aminonitriles\ a useful early
class of acyl anion equivalent[ Equation "6# shows a typical result ð68S016Ł[
CN NMe2
NMe2 KOH
(7)
PhMe Ph
Ph reflux, 16 h
71%
The experimental procedure appears straightforward[ Shorter reaction times were possible when
potassium t!butoxide replaced potassium hydroxide in the role of base[ Other eliminations of
hydrogen cyanide are shown in Equations "7#Ð"00#[ Forcing conditions were used in most cases\ as
exempli_ed in Equation "7# ð81M828Ł[ In some cases\ cyanide loss occurred directly from the enolate\
though full experimental details were not reported ð66TL2076Ł[ Equation "09# shows a typical strong
base procedure ð45JA71Ł[ Equation "00# is interesting because of the high reactivity of TCNE
towards neutral aromatic nucleophiles[ The very mild conditions for the elimination re~ect the
high degree of carbanion stabilisation in the conjugate base ð51ACS"B#412Ł[ In other cases\ direct
elimination of hydrogen cyanide occurred in the reaction mixture ð48OS"28#57Ł[
N O N O
KOH
NC (8)
DMF/H2O
120 °C
80%
O O
NaNH2
(9)
CN
PhH
reflux
70%
CN KNH2 Ph
Ph Ph (10)
Ph
Ph NH3 Ph
94%
OH OH
ethanol/pyridine
(11)
100 °C, 0.5 h
NC CN 95% CN
NC
NC
CN CN
0[02[1[1 Elimination of Carbon Oxides
0[02[1[1[0 Decarboxylation
The decarboxylation of carboxylic acids to form alkenes has been achieved with lead tetraacetate[
The reagent is commercially available and inexpensive\ and its preparation is facile[ Polar solvents
"acetic acid\ acetonitrile\ DMF# were used in most cases[ The literature contains many examples of
successful decarboxylations using the reagent ð61OR"08#168Ł[
The ease of decarboxylation is related to the stability of the carbenium ion formed at the
carboxyl!bearing carbon atom[ Tertiary acids undergo decarboxylation at room temperature with
photochemical initiation at 249 nm[ Running the reaction at low temperature prevents oxidation of
the nucleophilic trisubstituted alkene products[ Side reactions have proved problematic in pro!
cedures using this reagent^ for example\ a\b!unsaturated ketones are oxidised at the a?!position
ð81S124Ł[ The decarboxylation of secondary and even primary acids has been achieved in the
Of Carbon 450
presence of a low concentration of copper"II# acetate monohydrate to promote the oxidation of the
_rst!formed alkyl radical to the corresponding carbenium ion[ Rearrangement and poor regio!
selectivity have attended the decarboxylation reaction\ in common with other carbenium ion!
dependent processes[ Some conversions are shown in Table 3\ entries 0Ð5[
Table 3 Decarboxylations with lead tetraacetate[

(%)
1 CO2H 87
CO2H
2 78
CO2H
3 84
HO2C
H H
4 90
H H
N OMe N OMe
O O
H H H
5 CO2Me CO2Me + CO2Me 56
CO2H
6
CO2H
+ 19 + 37
OAc
Entries 0 to 2 ð57T1104Ł and entry 3 ð80H"21#1978Ł represent typical results[ Entry 4 displayed a
low degree of regioselectivity ð50JA816Ł while\ in entry 5\ the dienic propellane was not the major
reaction product ð82S359Ł[ In the absence of copper acetate\ none of the desired alkene was obtained[
Ring opening and rearrangement product predominated^ considerable strain relief resulted upon
opening the propellane bond[
Non!Kolbe electrolysis of carboxylic acids has proceeded with decarboxylation to form alkenes[
Table 4 lists some examples[ Entries 0 ð79CPB171Ł\ 1 and 2 ð63JOC1375Ł are examples of e.cient
syntheses of a\b!unsaturated lactones[ Electrolyses were performed in aqueous pyridine solutions
containing triethylamine with graphite electrodes[ Entries 3 to 5 were performed in ace!
tonitrile:ethanol containing potassium hydroxide ð77CB0040Ł[ The non!Kolbe electrolysis proceeded
through a carbenium ion intermediate and was assisted by the well!known stabilising e}ect of the
b carbonÐsilicon bond[ The in~uence of reaction conditions on the selectivity of the non!Kolbe
process has been discussed\ though prescriptive guidelines are not yet available ð82CB0512Ł[
When a carbanion stabilising group is present\ mild catalytic decarboxylation methods become
feasible[ Allyl esters of a!cyano! and b!ketocarboxylic acids underwent decarboxylation to cyano!
alkenes ð76S881Ł and enones ð73S0998Ł\ respectively\ in the presence of palladium catalysts[ Some
examples are shown in Schemes 4 and 5[ Direct access to an a!~uoroenone "Equation "01# is
particularly appealing because the chemistry of such species is almost unexplored ð83T376Ł[
O O O
F
F
O Pd2(dba)3•CHCl3
(12)
Ph3P, MeCN
reflux, 2 h
74%
Table 4 Decarboxylation under non!Kolbe conditions[
Entry Substrate Method Product Yield

(%)
1 HO a HO 67
H CO2H H
O O
O O O O
2 a 85
HO2C
CO2H
3 O b O 95
O O
4 b 60
CO2H
TMS
TMS
5 b 82
CO2H
a Graphite electrode, aqueous pyridine, triethylamine. b Graphite electrode, ethanolic potassium hydroxide, acetonitrile.
NC CO2allyl Pd2(dba)3•CHCl3 CN
Ph3P, EtCN
reflux, 1 h
78% (E):(Z) 8 : 1
CN
Pd2(dba)3•CHCl3
O
CN
Ph3P, EtCN
O reflux, 1 h
(E):(Z) = 5 : 3
68%
O CN
NC Pd2(dba)3•CHCl3
O
Ph3P, EtCN
reflux, 1 h
81%
Scheme 5
0[02[1[1[1 Didecarboxylation
The strategic signi_cance of the didecarboxylation reaction has diminished with the introduction
of modern alkyne equivalents for cycloaddition chemistry[ De Lucci and Modena provided an
excellent survey of the area up to 0873 ð73T1474Ł[ The main methods include lead tetraacetate
oxidation\ anodic oxidation and a transition metal complex!mediated procedure[
Some reactions with lead tetraacetate are shown in Table 5\ entries 0Ð3[ Both diacids and cyclic
anhydrides underwent didecarboxylation with the lead reagent[
Cyclic anhydrides fused to four!membered rings were particularly reactive "entry 0# ð50JA0694Ł^
trans!0\1!dicarboxylic acids were more reactive than the cis!isomers "entries 1 and 2# ð68S006Ł[ The
Of Carbon 452
O O O
Pd(OAc)2
O MeCN, 80 °C
79%
O O O
Pd(OAc)2
O
dppe, MeCN
reflux, 4 h
72%
O O O O
CO2allyl Pd2(dba)3•CHCl3
Ph3P, MeCN
reflux, 2 h
79%
Scheme 6
Table 5 Didecarboxylations with lead tetraacetate[

(%)
O
O
O
1 O 56
O
O O
O
CO2H
CO2H
2 18
CO2H
HO2C
3 29
O O
4
O CO2H O
CO2H
O O
most common experimental procedure used the diacid and the presence of oxygen was advantageous^
yields were moderate at best[ A range of other functional groups survives the conversion "entry 3#
ð57JA002Ł[ Electrochemical didecarboxylations have been performed on cyclic anhydrides and
dicarboxylic acids[ Moderate to good yields have been obtained\ but scales were limited and special
equipment and forcing conditions were required[ Experimental details for these procedures are few
and far between\ though aqueous pyridine containing triethylamine appeared to be the usual reaction
medium[ Some examples are shown in Table 6\ entries 0Ð5[
A range of other functionalities including amide groups "entry 0# ð79AG"E#352Ł\ carbonÐcarbon
double bonds "entry 1# ð79JOC4267Ł\ and ketone carbonyl groups "entry 2# ð70JOC0763Ł was com!
patible with the electrochemical reaction conditions[ Entries 3 and 4 represent key steps in general
approaches to linear and angular triquinanes ð74AG"E#862Ł[ Entry 6 provided some experimental
details^ in this case\ the reaction was performed in re~uxing methanolic sodium methoxide with
Table 6 Didecarboxylations under electrochemical conditions[

(%)
O
O
Bz
N Bz
1 N 45
CO2H
CO2H
CO2H
2 47
CO2H
O
O O
3 57
O
O
O-MEM
O-MEM
4 45
O CO2H
O
CO2H
O-MEM
O-MEM
5 55
O CO2H
O
CO2H
Cl
Cl Cl Cl
Cl Cl Cl
6 Cl 54
CO2H
HO2C
MEM = methoxyethoxymethyl
platinum electrodes ð83JCS"P0#682Ł[ The alkene was obtained in moderate yield "43)#^ dehy!
drochlorination by elimination or reduction processes was not reported[
The complex bis"triphenylphosphine#nickel dicarbonyl "4# _rst described by Trost ð60TL1592Ł has
found application in the preparation of a range of bicyclic and polycyclic systems[ The reagent is
commercially available "though fairly expensive# and reacts with cyclic anhydrides in re~uxing
DIGLYME[ In many cases\ an excess of the reagent was required[ Workup was usually complicated
by the contamination of the product with two equivalents of triphenylphosphine which had to
removed by chromatography followed by repeated recrystallisation ð73JA5691Ł[ Monocyclic alkenes
were not formed cleanly^ reduction and aromatisation led to mixtures of products[ Table 7\ entries
0Ð4 show some successful and attempted conversions[ Other functional groups including ketone
"entry 3# ð75LA0467Ł and ester "entries 0 and 1# ð60TL1592\ 73JA5691Ł carbonyl groups withstood the
reaction conditions but some 0\3!reduction of an enone occurred "entry 2# ð80JOC886Ł[ The reagent
appeared to be highly sensitive to subtle changes in the molecular architecture of the substrate[
Entries 3 and 4 di}ered only in the absence or presence of a bridgehead methyl group\ yet this minor
alteration reduced the yield to zero in the latter case ð75LA0467\ 81M476Ł[ Despite the limitations and
variation in reaction yield\ the nickel!mediated procedure has remained a useful method for the
manipulation of architecturally complex polycyclic hydrocarbons ð76JA3515Ł[
Of Carbon 454
Table 7 Nickel complex!mediated didecarboxylations[
Ph3P CO
Ni
Ph3P CO
(5)
Entry Substrate Equivalents of (5) Product Yield

(%)
CO2Me
O
CO2Me
1 53
O
O
CO2Me
O CO2Me
2 1.5 50
MeO O
MeO
O
O
O
O
3 1.5 43
O
O
O
O
4 0.2 64
O
O
O
O
O
5 0
O
O
O
0[02[1[1[2 Decarboxylation:dehydration
Decarboxylation\ coupled with loss of a hydroxyl group\ has been achieved under mild conditions
making b!hydroxyacids useful alkene precursors[ Elimination can be performed directly\ or in a
stepwise procedure\ via a b!lactone ð82S330Ł^ both processes are stereospeci_c[ In the more direct
route\ the hydroxyacid was re~uxed with an excess "4 to 5 equivalents# of DMF dimethylacetal in
dry chloroform[ Reaction times ranged from 1 to 09 hours\ and good yields of alkenes were obtained[
In some cases\ DMF neopentyl acetal was used[ The cost of both reagents is fairly high\ but valuable
products have been obtained\ and workup was usually straightforward[ The reaction mechanism
involves activation of the hydroxyl group followed by decarboxylation via an antiperiplanar "E1!
like# transition state with signi_cant partial positive charge development at the hydroxyl!bearing
carbon atom[ Substituents capable of stabilising the developing charge accelerated the reaction[
Table 8\ entries 0Ð4 show a range of examples[ Highly substituted alkenes formed smoothly "entry 0#
ð64TL0434Ł[ Entry 1 described the preparation of a "Z#!alkene ð73T0158Ł In entry 2\ a pure
diastereoisomer was obtained via a silylcuprate conjugate addition to an unsaturated ester\ followed
by enolate trapping with an aldehyde ð81JCS"P0#2240Ł^ in the ensuing decarboxylation:dehydration
the allylsilane was obtained as the pure "E#!stereoisomer[ Similar methodology a}orded "E#! or
"Z#!disubstituted allylstannanes ð76JCS"P0#1148Ł[ Dienes have also been prepared using the dineo!
pentyl acetal reagent "entries 3 and 4# ð64HCA042\ 73JOC1968Ł[
Table 8 Dehydration:decarboxylations with amide acetals[
Entry Substrate Reagent Product Yield

(%)
CO2H
OH
1 a 70
OH
CO2H
2 a high
Ph
Ph
SiMe2Ph SiMe2Ph
CO2H
3 a 91
OH
CO2H
4 b 94
OH
O O-TBDMS
5 b O O-TBDMS 68
CO2H
OH
a DMF dimethyl acetal. b DMF dineopentyl acetal.
The reagent of choice for conversion of b!hydroxy acids to b!lactones appears to be benzene
sulfonyl chloride[ Dehydration usually occurred in dry pyridine with an excess of the halide[ The
rate of carbon dioxide elimination was strongly dependent on structure[ Trans!disubstituted
b!lactones were more reactive than the cis!isomers[ Bulky substituents retarded the reaction\ the e}ect
on the cis!isomers being more pronounced[ Substituents capable of stabilising a developing positive
charge at C!1 accelerated the pyrolysis[ Forcing conditions were required in some cases and sealed
tube procedures have been used ð70JOC2248Ł[ A particularly convenient procedure generated
b!lactones directly in good yield by trapping thioester enolates with aldehydes and ketones "Scheme
6# ð80JOC0065Ł[ Pyrolysis was performed by Kugelrohr distillation from 129Ð399 mesh silica gel for
more volatile alkenes\ or by re~uxing with silica gel in benzene or cyclohexane for the less volatile
species[ The silica gel catalysis was e}ective only in highly substituted cases[ Table 09 shows some
transformations achieved using this method[ Cost!e}ectiveness and ease of puri_cation were
combined in this appealing alternative to Wittig and related methods for alkene assembly[
a!Methylene!b!lactones underwent rapid DielsÐAlder cycloaddition with dienes "Scheme 7#[ Pyrolysis
revealed alkylidene norbornenes\ the formal products of cyclopentadiene:allene cycloaddition
ð82CB0370Ł[ Simple allenes are poor dienophiles\ so the equivalence is useful even if the requirement
for a pyrolysis procedure limited the scale to approximately 0 mmol[ b!Lactone pyrolyses have also
been performed in DMF ð73TL3770Ł and collidine at re~ux "Equation "02##[ The developing positive
charge receives some allylic stabilisation in this case[
Of Carbon 456
O R1 R3
R2 R4 R1 R3
R1
i, LDA ∆
SPh
ii, R3COR4 O
R2 R2 R4
O
Scheme 7
Table 09 Silica!mediated b!lactone pyrolyses[

(%)
O
O
1 88
O
O
2 95
O
O
3 CO2Et 97
CO2Et
O
O
4 93
TBDMS
TBDMS
O
O
5 OH 77
OH
O
O + O
50 °C, 24 h
94%
O O
7 : 3
400 °C
flash distillation
quartz tube
71%
Scheme 8
PhO O
DMF
(13)
O 100 °C, 2 h PhO
high yield
Alternatively\ catalytic chemistry has been developed ð81TL5672Ł allowing the direct conversion
of b!hydroxy acids to alkenes and enol ethers "Equation "03##[
CO2H
WOCl4/TMEDA
(14)
MeCN
OH 73%
(E):(Z) 10 : 1
0[02[1[1[3 Decarboxylation:dehalogenation
Useful examples of the reaction are very limited[ b!Bromoesters were converted to alkenes in
moderate to excellent yield upon heating in hexamethylphosphoramide "HMPA# at 039>C "Equation
"04##[ Synthesis of the bromoesters imposed the main limitation upon this methodology ð72TL0364Ł[
The reaction was also performed successfully in the noncarcinogenic 0\2!dimethyl!1!imidazoli!
dininone "5#[ A related procedure was used in a synthesis of "2#!acarenoic acid "Equation "05##[
Heating the bromoester in pentan!2!one with sodium iodide led to the formation of furanone in
excellent yield[ The reaction proceeded only in the ketone solvent\ and formed part of a versatile
furanone synthesis ð76BCJ1806Ł[
Ph Ph
140 °C
Br (15)
HMPA
CO2Me 95%
Me N N Me
(6)
CO2Et
CO2Et
Br NaI
CO2Me (16)
pentan-3-one ( )10 O
( )10 O reflux, 2 h O
O 93%
0[02[2 BY ELIMINATION OF HALOGEN "OR H!HAL#
0[02[2[0 Elimination of Dihalides

The elimination of a dihalide has only limited use in the synthetic chemist|s repertoire[ The most
convenient starting material for a 0\1!dihalide is usually an alkene ð61HOU"4:0b#079Ł[ As Kocienski
pointed out ð80COS"5#864Ł\ {Unless there are very pressing reasons\ one cannot advocate the synthesis
of alkenes from alkenes] to travel in circles is the domain of astronomers not chemists;| Alkenes
form 0\1!dibromides in high yield and under mild conditions[ A signi_cant limitation for alkene
protection by dibromide formation has been the severity of the conditions required for\ and the low
e.ciency of\ debromination[ Simple alkenes containing robust functional groups were obtained by
heating the corresponding dibromide in DMF at 044Ð059>C ð80S716Ł[ A sodium selenite:cysteine
reducing system was used to achieve debromination under mild aqueous conditions "Equation "06##[
Excellent yields of alkenes were obtained and functional groups such as the ketonic carbonyl group
were tolerated[ The reaction system was odourless and exhibited a distinctive range of colour
changes on progression to completion ð89CC629Ł[ An alternative procedure used a tellurium reagent
and tolerated some useful and delicate functional groups ð89TL5180Ł "Scheme 8#[
Of Haloèn "or H!Hal# 458
Br Br NH3+
HS
CO2–
(17)
NaSeO3, H2O
0 °C, 5 min
99% O
O
Br
(Ph3Sn)2Te
PhO2S PhO2S
CsF, MeCN
Br RT, 5 h
97%
Br O (Ph3Sn)2Te O
CsF, MeCN
Br O RT, 4 h O
100%
Scheme 9
Though the cost of reagents would be high\ chemistry of such subtlety may _nd applications in
total syntheses of complex molecules[ Debromination of 0\3!dibromides to form dienes is a useful
method\ particularly when ortho!quinodimethanes are formed[ A range of metals can be used to
achieve the transformation[ Trapping conditions are usually employed\ so that the reaction mixture
also contains a dienophile\ to allow bi! and polycyclic systems to be constructed in an e.cient
manner[ Cava and co!workers reported an example in which iodide anion was used to initiate
didebromination in a 0\3!sense\ forming an ortho!quinodimethane\ which was trapped in situ "Equa!
tion "07## ð71JOC398Ł[
O OMe O OMe O
Br MVK, NaI
(18)
Br DMA, 70 °C
75%
O OMe O OMe
MVK = methyl vinyl ketone
More forcing conditions are required for the elimination of chlorine[ However\ the reaction is
worthwhile because chloroalkenes undergo e.cient photochemical ð1¦1Ł additions to enones to
a}ord cyclobutane products[ Reductive dechlorination reveals the carbonÐcarbon double bond for
further transformation "Scheme 09# ð82S359Ł[ High yielding free radical dechlorinations have been
reported[ Equation "08# shows an application of the tin method in a simple cyclohexane derivative[
Cl
Cl i, ethane-1,2-diol, H2SO4, PhH, reflux, 5 d
ii, Na/NH3(l), diethyl ether, –78 °C, 3 h

iii, dilute HCl, diethyl ether, RT, 4 d
O O
Scheme 10
Cl
Bu3SnH, AIBN
(19)
xylene
Cl reflux
Dechlorination occurred upon exposure of a dichlorodi~uoroenone to zinc metal in an interesting

synthesis of g\g!di~uoro!b\g!enones "Equation "19## ð82JOC4052Ł[ A range of zinc!based reaction
conditions were investigated^ sonication was essential for the success of the elimination[
O
O Cl Zn, ZnCl2
F (20)
Ph
Ph CF2Cl ultrasound
MeOH F
25 °C, 6 h
67%
Despite the high strength of the carbonÐ~uorine bond\ mild de~uorinations have been described[
Pez and co!workers ð81JOC1745Ł have described conversions of per~uorocyclohexane and per~uoro!
decalin to per~uorobenzene and per~uoronaphthalene\ respectively\ with sodium:benzophenone
ketal in THF[ Chambers has described a mild de~uorination procedure using either a sodium:
mercury amalgam or tetrakis"dimethylamino#ethene "Equations "10# and "11## ð83JCS"P0#2004Ł[
Na/Hg
0.5% w/w amalgam
F F F F (21)
<RT, 66%
NMe2
NMe2
F3C CF3 Me2N F3C CF3
NMe2
F3C CF3 (22)
CH2Cl2
O 0 °C to RT F3C O CF3
F F
0[02[2[1 Elimination of Hydrogen Halides

The mechanistic aspects of these reactions were studied extensively during the halcyon days of
physical organic chemistry[ In simple unsymmetrical haloalkanes\ the elimination may be regio!
chemically ambiguous^ it is unlikely that any modern synthetic sequence would include such a step[
The issues a}ecting such reactions ð80COS"5#838Ł and detailed mechanistic aspects ðB!78MI 002!90Ł
have been reviewed[
0[02[2[1[0 Dehydro~uorination
Dehydro~uorination in simple unactivated systems required the use of strong bases[ One recent
systematic study revealed that lithium diisopropylamide "LDA# was required for clean dehydro!
~uorination "Equation "12## and inferred that the solvent of choice was ether or ether:hexane
ð77T1744Ł[ The elimination of the ~uoride anion received some electrophilic assistance from the
lithium cation^ the cation was only available for this role when weakly solvated in the less polar
solvents[
LDA
(23)
F diethyl ether
40 °C, 48 h (E):(Z) 94 : 6
76%
Poor yields of alkene were obtained when alkoxide bases were used in alcohol solvents[ Vigorous
conditions were required because ~uoride ion elimination involves a transition state with a high
degree of E0cb character[
Synthetically useful dehydro~uorinations have been performed on derivatives of tri~uoroethanol[
Strategically\ these methods transform the relatively inert tri~uoromethyl group into a manipulable
di~uorovinylic unit ð78TL0530\ 81CC0366Ł[ Dehydro~uorination occurred in good yield upon exposure
of a tri~uoromethyl dithioketal to methyllithium in ether "Equation "13## a}ording a useful building
block for the synthesis of tetrathiafulvene derivatives ð82JOC3574Ł[
S MeLi S F
CF3 (24)
S diethyl ether S F
–78 °C to RT
12 h
75%
0[02[2[1[1 Dehydrochlorination
As the nucleofugacity of the halide anion "X−# increases\ the character of the transition state for
HX elimination becomes more E1!like\ and progressively weaker bases and milder conditions can
be used[
A range of bases including sodium acetate and amines has been used to dehydrochlorinate
b!chloro carbonyl compounds[ Equations "14#Ð"16# show some examples which occurred in moderate
to good yields[ In Equation "14#\ the reaction required four days at room temperature with excess
triethylamine in ether ð80JOC6066Ł[ Sodium acetate was used to e}ect dehydrochlorination in a
useful enone synthesis "Equation "15## ð77OSC"5#216Ł[ A range of cyclic enones was prepared in high
yield by this route[ In a reactive system derived from a quinone\ dehydrochlorination proceeded
instantaneously with diethylamine in ether at room temperature "Equation "16## ð77OSC"5#109Ł[ The
dehydrochlorination of a cyclobutane dinitrile was also performed in good yield using triethylamine
"Equation "17## ð77OSC"5#316Ł[ A cyclopropene was prepared in good yield from the corresponding
chlorocyclopropane upon treatment with potassium t!butoxide in THF under mild conditions
"Equation "18## ð70OS"59#42Ł[
OH
Et3N OH
Cl (25)
CO2Et Cl
diethyl ether CO2Et
Cl RT, 4 d
43%
O O
NaOAc
(26)
MeOH
Cl reflux, 3 h
80%
O O
But
But
Et2NH
Cl (27)
diethyl ether
But Cl RT, seconds But Cl
O 99% O
Cl CN
CN Et3N
(28)
PhH
CN reflux, 2 h CN
Ph Ph Ph
Ph
ButOK
Cl (29)
THF
Ph –78 °C to RT, 16 h Ph
88%
Unactivated substrates required more strongly basic conditions[ The multiple dehydrochlorinations
performed by Stoddart and co!workers ð81JA5229Ł required a large "7[4!fold# excess of potassium
t!butoxide at low temperature "Equation "29##[ Lithium carbonate has also been used in dehydro!
chlorination reactions "Equation "20## ð79JOC1925Ł[ An alternative approach to dehydrochlorination
was used by Viehe and co!workers ð74T2220Ł[ Treatment of a\a!dichloroamides with aluminum
chloride in dichloromethane\ led to the isolation of chloroenamides in good yield "Equation "21##[
O O
ButOK
Cl (30)
Cl
THF
Cl Cl 0 °C, 14 h
89%
Cl
H Cl Cl
Li2CO3
O O (31)
DMF
85 °C, 30 min
H H
96%
Cl Cl Cl
n-C13H27 NMe2 AlCl3
n-C13H27 NMe2 (32)
CH2Cl2, ∆
O 78% O
The procedure was also applied successfully to cyclic cases[ Dehydrochlorination failed with bases
such as lutidine and collidine\ even at 067>C[ Bases such as 0\4!diazabicycloð4[3[9Ł undec!4!ene "dbu#
are of limited use for dehydrochlorination[ The sharp contrast between activated and unactivated
systems was emphasised by a paper which described a useful synthesis of vinyl sulfones ð67JOC0197Ł[
Attempts to dehydrochlorinate at the sul_de level required prolonged reaction times at high tem!
perature\ and led to mixtures of regioisomeric vinyl sul_des[ The b!chlorosulfones reacted rapidly
at low temperature to a}ord quantitative yields of regioisomerically pure vinyl sulfones "Scheme 00#[
PhS Cl PhS PhS

dbu
+
120 °C, 3 h
40% 40%
PhO2S Cl PhO2S
dbu
CH2Cl2
0 °C, 0.5 h
100 %
Scheme 11
0[02[2[1[2 Dehydrobromination
Bromides have proved slightly easier to eliminate than the corresponding chlorides[ Useful bases
for this purpose include alkoxides\ amidines and phosphazenes[ Potassium t!butoxide has proved
popular\ although the choice of solvent appears to be important[ The base has been used in
petroleum ether in the presence of a phase transfer catalyst "07!crown!5# at re~ux temperature[
Hindered secondary bromides underwent elimination in excellent yield "Equation "22##[ However\
less hindered bromoalkanes were converted to t!butyl ethers in a side reaction\ accounting for
09Ð19) of the product mixture ð68S261Ł[ The importance of the antiperiplanar conformation in the
E1 elimination was revealed by a study of spiroketals "Equation "23##[
ButOK, 18-crown-6
(33)
petrol
Br 120 °C, 6 h
92%
Br
Br ButOK
O O
+ O (34)
O DMSO O
O 100 °C, 8 h
79%
The axial bromide was consumed within 049 minutes in DMSO containing potassium t!butoxide
at 099>C[ The equatorial epimer required a four!fold longer reaction time for dehydrobromination
ð82JOC1490Ł[ The product alkene underwent double bond isomerisation upon prolonged heating[
When the reaction was performed in THF\ proton abstraction occurred at the a!carbon atom\
followed by spiroketal ring opening[ The use of amide bases produced the same result[ A simple
workup procedure involved saturating the DMSO solution with salt and extracting the volatile
spiroketal products into pentane[ The combination of dipolar aprotic solvent and hindered alkoxide
base appears to represent the procedure of choice ð81JA8308Ł[ A useful desymmetrisation procedure
used a potassium alkoxide base in THF[ A signi_cant degree of carbanion stabilisation was provided
by the ionised carboxylate group\ allowing the elimination to proceed at low temperature "Equation
"24## ð82CC005Ł[ A bromoalkane survived exposure to potassium t!butoxide in pentane at lower
temperature\ allowing a useful isomerisation to be achieved "Scheme 01#[ Dehydrobromination
required treatment with dbu at higher temperature ð82CC0927Ł[ This amidine base ð61S480Ł has
allowed valuable alkenes to be isolated in good yield[ Alkylation of the amidine is normally slow in
comparison with the elimination reaction[ In unreactive cases\ dbu has been used as the reaction
solvent "Equation "25## ð82TA768Ł[ More reactive bromides underwent dehydrobromination in
nonpolar solvents containing dbu "Scheme 02# ð81JA8562\ 81JOC4446Ł[ An application involving a
sensitive substrate was described by Ganem during the synthesis of senepoxide "Equation "26##
ð67JA5372Ł[ Dehydrobromination occurred in benzene at room temperature^ at higher temperature\
decarboxylation accompanied the elimination[
OK
But But
Ph
NMe2
(35)
THF, –90 °C
70% yield
Br CO2H 90% ee
HO2C
Br
dbu
110 °C, 3 h
O 70% O
Br Br
ButOK •
pentane
O RT, 12 h O
70%
Scheme 12
O O
O dbu O
(36)
Br 70–75 °C, 18 h
91%
Br CO2Me
dbu
CO2Me
CHCl3
100%
CO2Me CO2Me
TBDMS-O TBDMS-O
O O
Br
dbu
PhH
90%
H
AcO O AcO O
Scheme 13
O O
O OBz dbu O OBz

(37)
O PhH, RT
91% O
Br
In some applications\ even hindered amidine bases were alkylated[ Schwesinger and co!workers
have described extremely hindered and yet reactive phosphazene bases which may be useful in
such circumstances ð76AG"E#0056Ł[ A 85) yield of 0!octene was obtained upon treatment of
0!bromooctane with "6# after 5 hours at room temperature[ Only 2) of alkylation product was
obtained[ In contrast\ the phase transfer method of von Dehmlow a}orded a 64) yield of alkene
after 2 hours at 59>C accompanied by a signi_cant amount "07)# of t!butyl octyl ether[
P(NMe2)3
(Me2N)3P N
N P NBut
N
P(NMe2)3
(7)
The most reactive base for E1 elimination is phosphazenium ~uoride "7# ð80AG"E#0261Ł[ This
extraordinary {naked ~uoride| reagent is unstable but e}ected the dehydrobromination of a primary
substrate at −67>C; Fluoroalkane "09)# was also formed in the reaction[ The reagent found
use in a synthesis of the architecturally complex and thermally sensitive isopagodane skeleton
ð83AG"E#006Ł[
Me2N NMe2
+
Me2N P N P NMe2 F–
Me2N NMe2
(8)
Amidine bases failed to provide good yields of bromoalkenes from 0\1!dibromides[ Morpholine
and DMSO were required to achieve the dehydrobromination in good yield "Equation "27##
ð89S732Ł[
Br morpholine Br
(38)
DMSO
Br reflux, 2 h
70%
Bromoalkenes were obtained when a\v!dibromides were heated in HMPA at high temperature[
Amine and amidine bases were unsuccessful in this role ð73S774Ł[
0[02[2[1[3 Dehydroiodination
Examples of the elimination are relatively scarce[ An e.cient vinyl isocyanide synthesis was
achieved using an excess of potassium t!butoxide at low temperature "Equation "28## ð78TL2224Ł[
Fluoroalkenes have been prepared via dehydroiodination using dbu in dichloromethane "Equation
"39## ð80TL0104Ł[
O-TBDMS O-TBDMS
I ButOK, THF
(39)
–78 °C to RT
NC 3h NC
80%
I
dbu Ph
Ph (40)
CH2Cl2
F RT, 12 h F
93%
Of Oxyèn 464
0[02[3 BY ELIMINATION OF OXYGEN FUNCTIONS
0[02[3[0 Dehydration
0[02[3[0[0 Using Burgess| reagent

Burgess| reagent "ðN\N!diethyl!N!ð"methoxycarbonyl#aminoŁsulphonylŁ ethanaminium hydrox!
ide\ inner salt# "8# has been used to dehydrate a range of secondary and tertiary alcohols under mild
conditions ð62JOC15Ł[ The reagent is crystalline\ commercially available and readily prepared in
high yield on a 0[4 mol scale "Scheme 03# ð89JA7322Ł[
O MeOH
O Et3N
O
+ –
Cl S N • O Cl S NHCO2Me Et3N S NHCO2Me
PhH PhH
O 92% O 81% O
(9)
Scheme 14
Dehydration occurred smoothly in benzene or toluene at 49>C\ normally using a slight excess
"0[0 to 0[4 equivalents# of the reagent[ Workup is always simple\ often involving hydrolysis and
solvent extraction[ However\ when the product alkenes were volatile\ the reactions were performed
neat\ allowing the alkenes to distil from the reaction mixture[ Table 00\ entries 0Ð4 show a range of
alcohols dehydrated successfully using the reagent[ The products include highly acid!sensitive species
"entries 0 and 1# ð62JOC15Ł\ a densely functionalised quinocarcinol methyl ester precursor "entry 2#
ð74JA0310Ł and a sensitive propellane "entry 3# ð73JA0407Ł[ In entry 4\ dehydration a}orded only the
nonconjugated diene in good yield ð89JA8173Ł[
Table 00 Dehydrations with Burgess| reagents[
Entry Substrate Method Product Yield

(%)
OH
1 a 66
OH O
O
2 a 69
MeO O MeO O
N N
3 NMe b NMe 53
OH CO2Me CO2Me
O O
OH
4 b 92
OH
H
5 a 66
O O
H H
a Neat reagent. b Benzene solution, 50 °C.
A mechanism has been proposed for the reaction which involves a syn!elimination from an
intermediate sulphamate ester[ However\ the ester is a good leaving group\ and the products of E0
elimination have been observed where stabilised carbenium ions are accessible[ McCague used
Burgess| reagent to prepare a tamoxifen analogue\ producing the same 1[7 ] 0 mixture of "Z# and
"E#!alkenes from both diastereoisomeric alcohols "Scheme 04# ð76JCS"P0#0900Ł[ Mixtures of products
have been obtained where elimination could occur across a number of possible C0C bonds[ Thus
endo!1!methyl!1!norborneol was converted to endo! and exo!cyclic alkenes "0 ] 0# in 55) yield
"Scheme 05# ð89JA7322Ł\ while a mixture of unsaturated esters resulted upon dehydration of a
pyrethroid precursor "Scheme 06# ð76T742Ł[
Ph Ph Ph
Ph Ph
Ph Ph
HO HO Ph
(9)
or +
PhH
50 °C
OMe OMe OMe OMe

2.8 : 1
Scheme 15
(9)
+
MeCN
50 °C, 2.5 d
OH 66% 1:1
Scheme 16
CO2Me CO2Me CO2Me CO2Me
(9)
+ +
PhMe
HO MeO2C
CO2Me CO2Me CO2Me
26% 22% 2%
Scheme 17
0[02[3[0[1 Using Martin|s sulfurane reagent

Martin|s sulfurane "bis"a\a!bisðtri~uoromethylŁbenzyloxy#diphenyl sulfur# "09# is a moisture!
sensitive and expensive commercial reagent[ However\ the material has been prepared on a 149 g
scale\ and stored inde_nitely in the absence of moisture ð66OS"46#11Ł[ The mechanism of dehydration
has been investigated ð61JA4992Ł[ Like Burgess| reagent\ tertiary alcohols reacted via an E0!like
mechanism^ for secondary alcohols\ an E1!like pathway was inferred while primary alcohols formed
stable ethers[
The reagent appears to be particularly useful for the dehydration of alcohols prone to carbenium
ion rearrangement[ Even cyclopropyl alcohols underwent elimination[ Table 01\ entries 0Ð6 show
the scope of the dehydration[ Entry 3 underwent skeletal ð2\2Ł!rearrangement following dehydration
ð75JA2628Ł[ In the extreme case of entry 0\ the tricyclopropyl alcohol rearranged\ resulting in a low
"21)# yield of the dehydration product ð61JA4992Ł[ The development of angle strain in the alkene
retards the rate of elimination ð71TL0232\ 74JA3853Ł[ Entries 4 and 5 indicate that the more acidic
proton was removed when a choice was available ð75JOC2987\ 81JOC4197Ł[ A sensitive diene was
prepared in entry 6 ð77LA432Ł[
0[02[3[0[2 Dehydration by other methods

Treatment of alcohols with strong acids has been used to achieve dehydration[ The method is
most useful when highly stabilised carbenium ions are accessible\ and proton loss is unambiguous
Of Oxyèn 466
Table 01 Dehydrations with Martin|s sulfurane reagent "09#[
F3C CF3 Ph Ph CF3 CF3
S
Ph O O Ph
(10)
Entry Substrate Temperature Product Yield

(°C) (%)
OH
1 25 32
CONMe2 CONMe2
2 HO –78 92
OH
3 25 52
OH
OH
4 25 60
EtO2C EtO2C
OH
5 0 80
TBDMS-O O-TBDMS TBDMS-O O-TBDMS

CO2Et CO2Et
OH
6 25 93
O-TBDMS O-TBDMS
MeO O O MeO O O
7 25 >50
HO
or can be thermodynamically controlled[ An e.cient acid!catalysed dehydration will almost

invariably be more economical than any other method[ A recent example involved an acid!catalysed
dehydration of a tertiary benzylic alcohol[ The reaction was performed in benzene using DeanÐ
Stark apparatus and a catalytic quantity of p!toluene sulfonic acid to a}ord the more stable
endocyclic alkene in good yield "Equation "30## ð83JOC395Ł[
HO OMe OMe
TsOH
(41)
PhH, reflux
45 min
OMe 90% OMe
Supporting the acid catalyst on silica gel allowed the e.cient dehydration of secondary and
tertiary alcohols[ Re~uxing the alcohol with the supported reagent in benzene a}orded good yields
of D1! and D2!steroids "Equation "31## ð74S0048Ł[ A strong acid ion exchange resin was used to
dehydrate sterols[ Double bond migration accompanied dehydration when a sterol was re~uxed
with Na_on!H in chloroform "Scheme 07# ð76CC389Ł[ Other dehydrations were performed with a
sulfuric acid catalyst ð89OSC"6#252Ł and in tri~uoroacetic acid ð75TL0338Ł[
TsOH on silica gel

(42)
PhH
reflux, 8 h
97%
HO
H H
O O
Nafion-H
OH
CHCl3
reflux, 1 d
50%
O O
O O
H2SO4 (cat.)
DMF
O 95 °C, 3 h O
OH 70–76%
O OH O
H
TFA
4h
O O
H H
Scheme 18
A useful method involved generation of the expensive sulfonyl diimidazole reagent in situ[ Selective
reaction at a steroidal hydroxyl group was followed by elimination[ This is an attractive method
because the byproducts from the reaction are particularly easy to remove "Equation "32## ð77JPR298Ł[
OH
SOCl2, imidazole
(43)
THF
10 °C to 60 °C
1.5 h
O O
Synthetically useful nitroalkenes were generated by a dehydration reaction on alumina

ð81JOC1059Ł[ An unusual but general dehydration allowed the direct conversion of primary and
secondary alcohols to alkenes[ The reaction produced volatile byproducts and involved an easy
workup "Equation "33## ð77SC0684Ł[
Of Oxyèn 468
O
Cl3C CF3
(44)
OH TsOH, PhH
reflux, 6 h
0[02[3[1 Elimination of Alcohols "H0OR#

The low nucleofugacities of simple alkoxide anions means that elimination usually occurs under
E0cb conditions[ Some useful reactions have been reported and are shown in Scheme 08[ Potassium
t!butoxide ð81JOC0502Ł\ potassium hexamethyl disilazide "KHMDS# ð83JOC283Ł and dbu ð82T5606Ł
have all found applications[ Fragmentation of the leaving group to release acetone prevented the
back reaction[ In the _nal example\ the amidine proved superior to a range of hydride and amide
bases[
O O
O O ButOK O OH SEt
O
SEt
EtS SEt
OH
O
O CO2Me
CO2Me MeO2C
KHMDS
HN Ph
HN Ph THF
MeO2C
–78 °C, 1 h
97%
O O
O O
i, dbu, RT
OMe HO
O
ii, HCl, H2O
O 84% OMe
Ph
Scheme 19
Superbase!mediated eliminations from simple homoallyl ethers form a interesting class of reac!
tions[ A range of dienes and trienes were prepared by alkoxide elimination using LIDAKOR
"LDA:ButOK# in THF "Scheme 19# ð89T1300Ł[
LIDAKOR
OMe
THF, –50 °C
72%
LIDAKOR
O THF, –50 °C HO
55%
EtO LIDAKOR
EtO THF, –50 °C EtO

91%
Scheme 20
Pivalate esters underwent elimination at slightly higher rates[ Eliminations of alkoxy groups from
acetals and ketals have a}orded enol ethers[ ð71TL212\ 71TL520Ł[ A method of choice which uses
readily available reagents has been described ð77JOC4465Ł[ The eliminations were highly regio!
selective\ with removal of the least hindered proton[ A range of substituents was tolerated in the
ketal moiety "Equation "34##[ Under acidic conditions\ ethanol was eliminated from an acetal to
form an enol ether[ A signi_cant amount of hemiacetal was formed in the reaction "Equation "35##
ð83JOC200Ł[
O OH
TMS-OTf
O O (45)
DIPEA
CH2Cl2
–20 °C to RT
94%
DIPEA = Pri2NEt
O O
HCl2C HCl2C
O O
O O
2,6-lutidinium tosylate
HCl2C CO2Me HCl2C CO2Me (46)
PhMe, ∆
70%
O OEt O
H H
0[02[3[2 Eliminative Ring Opening of Epoxides

Epoxides open readily under Lewis acid or Bronsted base conditions ð73S518Ł[ Chiral amide bases
have been used in desymmetrisation procedures involving epoxide opening by elimination[ Equation
"36# shows an example ð82CC773Ł[
Ph
OBn OBn
OLi
LiNH
(47)
THF
–78 °C to 0 °C
O 91% yield OH
81% ee
The products were obtained in moderate enantiomeric excess^ changing the solvent from THF to
a benzeneÐTHF mixture allowed the other enantiomer to be isolated[ Magnesium amides appear to
combine basicity with Lewis acidity in a useful way\ allowing epoxides to be opened in high yield
ð75TL188Ł[ The amides were prepared in toluene by reacting the lithium amide with Grignard
reagent[ An excess "2Ð3 fold# of the amide was required\ reactions were run at 9>C\ and the choice
of solvent was critical[ Poor yields were obtained in THF\ with and without additives such as
HMPA[ Proton abstraction usually occurred from methyl groups rather than from methylene
positions[ Table 02\ entries 0Ð4 show some typical examples^ the amide reagents tolerated other
functional groups "entries 0Ð2# ð75TL188Ł[ In entry 2\ the less acidic proton was removed[ The
regioselectivity displayed in entry 4 was exceptional ð81T09154Ł and was reversed when the elim!
ination was performed in monoglyme[ The procedure was deployed in an asymmetric synthesis of
R!"¦#!perrillaldehyde from limonene ð77SC0894Ł[
Epoxide opening can also occur under E0cb conditions using weak bases[ A useful sequence used
arsonium ylide chemistry to prepare b\g!epoxy aldehydes^ treatment with triethylamine in ether led
to the formation of g!hydroxy!a\b!unsaturated aldehydes "Equation "37## ð78TL068Ł[
OH
O
CHO Et3N CHO
(48)
diethyl ether
79%
Of Oxyèn 470
Table 02 Epoxide opening with magnesium amide bases[
Entry Substrate Base Product Yield

(%)
O
OH
1 a 96
O-TMS OH
O OMe O OMe
TrO TrO
2 a 94
HO
O
CO2H CO2H
3 a 51
O OH
O HO
4 b 74
H H
OH
O
5 c 92
H H
a MeMg(PriNC6H11), PhMe, 0 °C, 1.5–7.5 h. b MeMg(PriNC6H11), DME, 0 °C. c MeMgBr, LDA, PhMe, –5 °C, 6 h.
The product described in Equation "37# corresponds to the addition to aldehydes of a b!acyl vinyl
anion equivalent[ Similar eliminations were used to prepare an enone intermediate during a total
synthesis of "2#!breynolide ð81JA8308Ł[ Using an amidine base at low temperature ensured that the
most acidic proton was removed "Equation "38##[ Epoxide opening was used to trigger an anionic
cyclisation during the total synthesis of an elfamycin natural product "Scheme 10# ð74JA0580Ł[ Useful
pyranone syntheses have also involved eliminative epoxide openings "Scheme 11# ð82TA0684Ł[
CO2Me CO2Me
dbu
O O (49)
MeOH, CH2Cl2 OH
O –78 °C to RT
79%
MeO2C O O O
MeO2C
dimsyl potassium OH
PhMe, DMSO O O
O O
–20 °C to RT
O
MeO2C
TBDMS-Cl O-TBDMS
imidazole O O
DMF
0 °C to RT
>90%
Scheme 21
OH
SPh BuLi SPh
BnO BnO
O
OH –78 °C OH OH
81% O O
BnO
Scheme 22
0[02[3[3 Elimination of a Carboxylic Acid "H0OCOR#

Acetate anion has been eliminated in high yield from activated and unactivated substrates[ An
alkylidene furanone synthesis combined a furan metallation procedure with a high!yielding acetate
elimination in acidic media "Equation "49## ð81BCJ1255Ł\ presumably via an E0!type mechanism[
H2SO4 (cat.)
(50)
O O AcOH, Ac2O O O
AcO
80 °C, 1–2 h
95%
Acetate anion was eliminated from an unactivated substrate upon treatment with a transition
metal catalyst "00# ð80T7044Ł[ The regiochemical outcome of the reaction was unexpected[ Depro!
tonation occurred from a methylene position in the ring rather than from the more accessible methyl
group[ Mild reaction conditions were employed to achieve this interesting transformation "Equation
"40##[ Tri~uoroacetylation of a tertiary alcohol in situ led to an elimination reaction "Equation "41##
ð82OSC"7#109Ł[ Conversion to the corresponding mesylate also led to a good yield of enone\ but
sulfur!containing byproducts were di.cult to remove from the product[ The preparation of a
particularly reactive tri~uoroacetylating agent was reported ð89OSC"6#495Ł[
Mo+ BF4–
(11)
(11)
OAc (51)
AcOH, 1,4-dioxan
H reflux, 3 h H
100%
O HO TFAA O
(52)
Ph E3N, dmap Ph
CH2Cl2
dmap = 4-dimethylaminopyridine; TFAA = trifluoro acetic anhydride
A wide range of E0cb eliminations has been described[ The elimination of a pivalate unit occurred
upon Kugelrohr distillation of the ester from anhydrous potassium carbonate^ this was used in a
synthesis of "R#!ionone on a gramme scale "Equation "42## ð81HCA0912Ł[ Other useful bases included
aqueous potassium hydroxide ð80TL2628Ł\ Hunig|s base ð78CPB1771Ł and dbu "Scheme 12# ð89CC73\
81JOC1169\ 83JOC170Ł[
OPiv O O
K2CO3
(53)
Kugelrohr
140 °C/10 mm Hg
Of Oxyèn 472
OAc
1N KOH
diethyl ether
100%
O O
MeO OMe
H OH
MeO DIPEA OMe
PhH CHO
80 °C
H good yield
AcO OMe CHO
O CN O
dbu CN
BzO BzO
CH2Cl2
BzO OBz 95% BzO
AcO
H
dbu
O-MOM CH2Cl2 O-MOM

O O 45 °C, 15 h O O
CO2Me CO2Me
CONH2 CONH2
BnO2C O O O BnO2C O O
U dbu O U
H H
AcO OAc PhH
OAc
MeO OPiv 28 °C, 0.5 h OPiv
OAc MeO
OAc
U = uridine; MOM = methoxymethyl
Scheme 23
0[02[3[4 Elimination of a Sulfonic Acid

A popular method of alkene formation involves formation of the methanesulfonate "mesylate#
ester followed by treatment with base ð89SC0352Ł[ In some cases\ isolation of the ester was unnecess!
ary[ Activated substrates underwent elimination directly in high yield upon treatment with methane!
sulfonyl chloride and an amine base "Scheme 13# ð81JOC2504\ 83JOC221Ł[ In hindered cases\
3!dimethylaminopyridine "dmap# was used to facilitate the esteri_cation ð83T0286Ł[ Other mesylate
O O
MsCl
ButO2C 0–RT, 2 h
ButO2C
93%
Ph OH Ph
(CO)3 (CO)3
HO Co Co
O H O
Co(CO)3 MsCl Co(CO)3
Et3N, dmap
54%
TBDMS-O O TBDMS-O O
HO O O
MsCl
But But
dmap, THF
reflux, 93%
Scheme 24
eliminations have been performed with alkoxide bases[ Table 03\ entries 0Ð4 provide a selection of
examples[
Table 03 Mesylate eliminations with alkoxide bases[
Entry Substrate Conditions Product Yield

(%)
MEM-O
NHPf MEM-O
NHPf
a 78
1
OMs
OMs
b 58
2
MsO OMs
O O b O O 84
3
OMs H H
H H
O b O OBn 70
OBn
4
O N H O N H
MsO H
5 c 76
O
O
H O HO H
HO O
a MeOCH2CH2ONa, DMF, 0 °C. b ButOK, DMSO. c MeCH2C(Me)2ONa, PhH, reflux. Ph

Pf =
In entry 0\ the 8!phenyl!8!~uorenyl "Pf# protecting group was used to prevent proton abstraction
a! to the amino group ð83JOC283Ł[ The regiochemical outcome was unambiguous in entries 1
ð81JA7707Ł and 2 ð81JA3017Ł[ In entry 3\ the major regioisomer is shown ð81JOC6174Ł[ In entry 4\ the
mesylate was locked in an equitorial environment on the trans!fused decalin system\ and the
antiperiplanar transition state required for the E1 elimination could not be reached[ Instead\ an
interesting elimination reaction involving simultaneous ring expansion occurred ð83JOC263Ł[ The
phosphazenium naked ~uoride base "7# converted a steroidal benzene sulfonate to the corresponding
diene in excellent yield under very mild conditions "Equation "43## ð80AG"E#0261Ł[ In comparison\
only a 64) yield of the alkene was obtained after 3 days in the presence of potassium t!butoxide in
DMSO at 79>C[ Amidine bases have also been used in a number of cases[ Equation "44# shows a
high yielding example ð81JA8308Ł[ In Equation "45#\ aromatisation followed elimination with 0\4
diazabicycloð3[2[9Łnon!4!ene "dbn# in benzene solution ð89JA8173Ł[ Palladium!catalysed mesylate
elimination in the absence of a base led to the formation of a range of interesting glycals "Scheme 14#
ð81JA0380Ł[
Of Oxyèn 474
(8)
(54)
THF
RT, 0.5 h
99%
BzO
MsO H H
dbu
(55)
+ S PhH + S CO2Me
CO2Me 94–100%
H O H
– O – O-MEM
O-MEM
OMs
H
dbn
(56)
50 °C, 8 h
O O
88%
H
O OH O
i, ii
BnO BnO
60%
BnO OBn BnO OBn
BnO BnO
O i, ii O
BnO OH BnO
87%
BnO OBn BnO OBn

O O
O O
O OH i, ii O
15%
O O O O
i, Ms2O, collidine, CH2Cl2, RT, 1 h

ii, Pd(PPh3)4, 50 °C, 12 h
Scheme 25
0[02[3[5 Elimination of 0\1!Diols

Vicinal eliminations involving two hydroxyl groups "or their derivatives# have formed the subject
of a review ð73OR"29#346Ł[ The reactions have found useful applications in the areas of carbohydrate\
nucleoside and enediyne chemistry[ The CoreyÐWinter reaction was developed to deoxygenate 0\1!
diols via thionocarbonate formation followed by treatment with a diaminophosphorane ð71TL0868Ł[
Scheme 15 shows examples from the enediyne ð82TL3010Ł and nucleoside ð78JOC1106Ł _elds[ The
mildness of the reaction conditions allowed a range of other functional groups to survive the
dideoxygenation procedure[ Organometallic procedures using bis"cyclooctadienyl#nickel a}orded
lower yields in the enediyne case\ and involves using hydrogen sul_de gas in the workup[
Table 04\ entries 0Ð4 highlight a range of vicinal eliminations performed under free radical
conditions[ Treatment of a ribonucleotide bis"xanthate#ester using the usual tin method conditions
a}orded a dideoxynucleoside in 82) yield "entry 0#\ o}ering a clear advantage over the CoreyÐ
Winter method which a}orded the dideoxynucleoside in only 40) yield ð78JOC1106Ł[ Halides also
served as e}ective leaving groups in free radical elimination[ Entries 1 ð89S300Ł and 2 ð89TL2718Ł
illustrate high yielding eliminations[
Me
N
PMe
O-TBS N O-TBS
O Me
S diethyl ether
0 °C, 4 h
O 84%
Me
N
O Ad PPh
TBDMS-O N
Me O Ad
O O 51% TBDMS-O
Scheme 26
Table 04 Eliminations via free radicals[
Entry Substrate Conditions Product Yield

(%)
TBDMS-O
O Ad TBDMS-O
a O Ad
1 S S 93
O O
MeS SMe
H
N N H
O
O NH2 N N
O O
AcO O NH2
2 a 58
N N O
AcO
Br O N
N
S
OPh
TrO O
O TrO O
N O
N N
3 S H b N 84
O H
O Cl O
PhO
TBDMS-O
O Ad TBDMS-O
O Ad
4 S S c 70
O O
MeS SMe
O OMe
O S
O OMe
Ph O O SMe O
5 c 76
O SMe Ph O
S
a Bu3SnH, AIBN, PhMe, reflux. b Bu3SnH, AIBN, PhMe, 60 °C. c Ph2SiH2, AIBN, PhMe, reflux.
Of Oxyèn 476
Barton has developed chemistry that avoids the use of toxic tin compounds^ instead\ a silane
serves as the chain carrier "entries 3 and 4# ð80TL1458Ł[ The method developed by Samuelsson et al[
"Equation "46## is particularly suitable for larger scale operations because all the byproducts from
the reaction are soluble in water ð89JOC3162Ł[ Treatment of dibenzoates with samarium diiodide
"Equation "47## a}orded elimination products in moderate to good yield ð81TL462Ł[ The method is
noteworthy because of the routine use of benzoate esters in carbohydrate chemistry[ Short reaction
times and facile workup also add to the appeal of the samarium!mediated reaction[
O OMe O OMe
O PhPCl2 O
(57)
Ph O OH imidazole, I2 Ph O
PhMe
OH 88%
O O SmI2 O O
BzO (58)
BzO
THF
BzO OBz 75 °C, 0.5 h
60%
0[02[3[6 Deoxygenation of Epoxides

One!pot sequences are available involving nucleophilic ring opening\ followed by elimination[ An
acid!sensitive glycal was prepared by a mild procedure "Equation "48## ð66CB1016Ł[ Epoxide opening
was e.cient\ but the elimination step proceeded in only moderate yield[ A simple and inexpensive
combination of reagents "chlorotrimethyl silane:sodium iodide in acetonitrile# converted a cis!
epoxide into a "Z#!alkene in good yield ð70TL2440Ł[ A range of metals has been used in deoxygenation
reactions\ including low!valent titanium ð67JOC2138Ł\ niobium ð71CL046Ł\ and samarium ð79JA1582Ł[
A procedure based on an organotungsten intermediate tolerates the presence of ester and ether
groups ð70OS"59#18Ł\ but the most sensitive method involves an organotitanium reagent "Equation
"59## ð89JA5397Ł[
O OMe O OMe
i, NaI, AcOH, 98%
(59)
ii, POCl3, pyridine, 45%
AcO AcO
O
OTr
O OTr
Cp2TiCl O
TrO OMe (60)
THF TrO OMe
O 66%
Attempts to deoxygenate the furanoid epoxide by other methods led exclusively to the formation
of the furan\ via elimination of the alkoxy group[
1.14
Elimination of S, Se, Te, N, P,
As, Sb, Bi, Si, Ge, B or Metal
Functions
ANITA R. MAGUIRE
University College Cork, Republic of Ireland
0[03[1 BY ELIMINATION OF SULFUR\ SELENIUM OR TELLURIUM FUNCTIONS 489

0[03[1[0 Elimination of Sul_de\ Selenide or Telluride Groups 489
0[03[1[0[0 Elimination of sul_de `roups 489
0[03[1[0[1 Elimination of selenide `roups 481
0[03[1[0[2 Elimination of telluride `roups 483
0[03[1[1 Elimination of Sulfoxide\ Selenoxide or Telluroxide Groups 484
0[03[1[1[0 Elimination of sulfoxide `roups 484
0[03[1[1[1 Elimination of selenoxide `roups 599
0[03[1[1[2 Elimination of telluroxide `roups 509
0[03[1[2 By Elimination of Sulfone\ Selenone or Tellurone Groups 501
0[03[1[2[0 Elimination of sulfone `roups 501
0[03[1[2[1 Elimination of selenone and tellurone `roups 519
0[03[1[3 Elimination of Sul_limine\ Selenimide\ Tellurium Imide\ Sul_namide\ Sulfoximine\
Sulfonamide and Sulfonate Groups 510
0[03[1[4 Elimination of Sulfonium\ Selenonium and Telluronium Salts and Ylides 511
0[03[2 BY ELIMINATION OF NITROGEN FUNCTIONS 512

0[03[2[0 Elimination of Amine Oxides*the Cope Reaction 512
0[03[2[1 Elimination of Quaternary Ammonium Salts 516
0[03[2[1[0 Hofmann elimination of quaternary ammonium hydroxides 516
0[03[2[1[1 Elimination of quaternary ammonium salts on treatment with base 517
0[03[2[2 Alkenes from Arenesulfonylhydrazones 529
0[03[2[2[0 The BamfordÐStevens and Shapiro reactions 529
0[03[2[2[1 Alkenes from hydrazones by alternative routes 524
0[03[2[3 Elimination of Amine Derivatives 524
0[03[2[4 Elimination of Nitro Groups 526
0[03[3 BY ELIMINATION OF PHOSPHORUS\ ARSENIC\ ANTIMONY OR BISMUTH FUNCTIONS 527

0[03[3[0 Elimination of Phosphorus Groups 527
0[03[3[0[0 Elimination of phosphine oxide*the Witti` reaction 528
0[03[3[0[1 Extension to phosphoryl derivatives*the HornerÐWadsworthÐEmmons modi_cations 528
0[03[3[0[2 Elimination of phosphonium `roups 539
0[03[3[0[3 Elimination of b!hydroxy phosphine oxides 530
0[03[3[0[4 Elimination of b!hydroxyphosphinothioic amides 532
0[03[3[0[5 Elimination of b!hydroxyphosphonic acid bisamides 532
0[03[3[0[6 Elimination of phosphonothioate esters 534
0[03[3[0[7 Elimination of triethyl phosphate 535
478
489 C1C Bond"s# by Elimination of Sulfur etc[\ Nitroèn etc[\ or Silicon etc[
0[03[3[1 Elimination of Arsenic\ Antimony and Bismuth Functions 535
0[03[3[1[0 Elimination of arsenic `roups 535
0[03[3[1[1 Elimination of antimony and bismuth `roups 536
0[03[4 BY ELIMINATION OF SILICON\ GERMANIUM OR BORON FUNCTIONS 537
0[03[4[0 Elimination of Silicon Groups 537
0[03[4[0[0 Elimination of b!hydroxysilanes 537
0[03[4[0[1 Elimination of b!halosilanes 541
0[03[4[0[2 Elimination of other b!substituted silanes 542
0[03[4[1 Elimination of Germanium Groups 545
0[03[4[2 Elimination of Boron Functions 546
0[03[4[2[0 Elimination of alkylboranes 546
0[03[4[2[1 Elimination of b!substituted alkylboranes 547
0[03[5 BY ELIMINATION OF METAL FUNCTIONS 552
0[03[5[0 Elimination of Groups 0 and 1 Metals*Li\ Na\ K\ M` 552
0[03[5[1 Elimination of Group 02 Metals*Aluminum 554
0[03[5[2 Elimination of Group 03 Metals*Tin and Lead 555
0[03[5[3 Elimination of Transition Metals 557
0[03[0 INTRODUCTION
Elimination reactions involving heteroatomic groups often provide very useful synthetic routes
to alkenes\ e[g[\ alkenes are formed e.ciently by elimination of sulfoxide or selenoxide groups[
Furthermore\ many alkene syntheses involve elimination of a heteroatomic moiety as a step in the
overall process\ e[g[\ the Wittig and the Peterson reactions[ In the following discussion of these
transformations\ particular emphasis is placed on the synthetic utility of the elimination reactions[
0[03[1 BY ELIMINATION OF SULFUR\ SELENIUM OR TELLURIUM FUNCTIONS
0[03[1[0 Elimination of Sul_de\ Selenide or Telluride Groups
0[03[1[0[0 Elimination of sul_de groups

Elimination of sul_des to form alkenes can be e}ected on treatment with base ð77JA1955\ 77JA4964Ł\
e[g[\ BuLi ð68JA2172Ł or KOH:HMPA ð54CI"L#0657Ł "Equation "0##[ Similarly on treatment with
potassium 2!aminopropylamide\ vinyl sul_des are transformed to terminal alkynes by elimination
followed by isomerization ð67JOC2972Ł^ vinyl ethers under the same conditions lead to diene forma!
tion[ Elimination of the elements of a thiol from thioacetals and thioketals to form vinyl sul_des
can be brought about by treatment with cuprous ions in the presence of an amine ð64JOC701\
65JOC2107\ 79OS"48#191Ł[ Extension of this methodology to the formation of dienes by elimination of
two equivalents of thiophenol is illustrated in Equation "1#[
S
Me BuLi, TMEDA
(1)
hexane
65%
SPh SPh Cu2(OTf)2

SPh (2)
SPh NR3
84%
Elimination of b!substituted sul_des to form alkenes has been investigated\ most commonly with
phenylthio derivatives\ but occasionally with alkylthio groups*thus b!hydroxy sul_des can be
transformed to alkenes on treatment with methyllithium and o!phenylene phosphorochloridite
ð61TL626Ł\ thionyl chloride\ phosphorus triiodide\ or diphosphorus tetraiodide ð68TL3000\ 70TL3998Ł\
N!ethyl!1!~uoropyridinium tetra~uoroborate\ triethylamine and lithium iodide ð67CL302\ 79JOC2438\
77TL548Ł\ electrochemically ð67TL1796Ł\ using titanium tetrachloride and zinc or lithium aluminum
hydride ð63CL0412\ 64CL760Ł\ by transformation to S!methylthiocarbonates followed by treatment
with tributyltin hydride ð66TL3112Ł\ or by transformation to the benzoate followed by reduction
Sulfur\ Selenium or Tellurium 480
with sodium naphthalenide ð75TL0232Ł or lithium in liquid ammonia ð61JA3647Ł[ Equation "2#\
showing an elimination used in the synthesis of "−#!periplanone!B ð75TL0232Ł\ illustrates the
synthetic utility of this transformation[ Application of this reductive elimination in the methyl!
enation of ketones is illustrated in Scheme 0 ð61JA3647Ł^ this method compares favourably with the
Wittig reaction giving e.cient reaction even with the highly hindered tricyclic ketone shown[
OR OH
i, PhCOCl, dmap, py
ii, Dowex 50W(H+), MeOH
(3)
iii, Na-C10H8, –78 °C
HO SPh 82% for elimination step
R = THP → H
dmap = 4-dimethylaminopyridine
PhCO2
O SPh
H H H
i, PhSCH2Li, THF Li/NH3
ii, BunLi, (PhCO)2O 64%

49%
Scheme 1
Elimination of b!hydroxy sul_des using N!ethyl!1!~uoropyridinium tetra~uoroborate\ tri!

ethylamine and lithium iodide ð67CL302\ 79JOC2438\ 77TL548Ł proceeds stereoselectively to form the
"Z#! and "E#!alkenes from syn and anti isomers of the b!hydroxy sul_des\ respectively[ This
elimination has been employed in a stereoselective synthesis of "Z#!a\b!disubstituted acrylates
"Equation "3## ð77TL548Ł[ Formation of appreciable amounts of the more stable "E#!isomer were
observed only when extended conjugation was present "RPhCH1CH#[
SPh R CO2Me
R OMe + + LiI (4)
+
N F
HO O
Me BF4–
R = Ph, Ph(CH2)2, n-C7H15
b!Oxygenated sul_des can be eliminated to form alkenes on treatment with sodium in liquid
ammonia ð68CC72Ł or TMS!Cl and NaI "Equation "4## ð70JOC120Ł[ b!Hydroxy thiols can be trans!
formed to the corresponding alkenes via the oxathiolanes on treatment with lithium diiso!
propylamide "LDA# "Scheme 1# ð63JCS"P0#322\ 77JCS"P0#702\ 77JCS"P0#706Ł[
H
TMS-Cl, NaI CO2H
O (5)
O
PhX H
X = S, 91%
X = Se, 84%
HO
PhCHO O LDA
SH Ph
p-TsOH S Et2O, 20 °C
92%
LDA = lithium diisopropylamide
Scheme 2
Similarly\ b!chloro or bromo sul_des can be reduced to alkenes using tributyltin hydride "Equation
"5## ð65JA840\ 66TL3112Ł\ or by use of metals such as Mg\ Zn or Na ð33JOC209Ł[ Allyl 1!pyridyl
sul_des\ on alkylation with tributylstannylmethyl iodide\ undergo elimination of the stannyl and
sul_de groups to form 0\2!dienes directly "Scheme 2# ð71TL1194Ł "see also Section 0[03[5[2#[ b!Nitro
sul_des eliminate stereoselectively on treatment with tributyltin hydride ð73TL4208\ 77CC0167Ł^ this
methodology has been employed in the synthesis of "E#!allyl alcohols "Equation "6## "see Section
0[03[2[4#[
Bu3SnH
Ph Cl Ph (6)
SPh
Bun3Sn
i, BuLi
ii, Bun3SnCH2I
S N S N
47%
Scheme 3
NO2
Bun3SnH, AIBN
Ph OH Ph OH (7)
toluene, 110 °C
SPh 80%
Pyrolysis of a!halo sul_des produces alkenes "Scheme 3# ð70AG"E#474Ł^ this transformation\ which
resembles the RambergÐBacklund reaction of a!halo sulfones\ may proceed via a thiirane which
then loses a sulfur atom to form the alkene[ Removal of sulfur from episul_des to produce alkenes
has been discussed ð79T446Ł[ On treatment with triethylphosphite episul_des undergo a highly
stereoselective removal of sulfur to form the alkene in a syn fashion "Equation "7## ð48JA467Ł
indicating that attack by phosphorus occurs at sulfur rather than at carbon\ in contrast to the
reactivity pattern observed with epoxides[ Other reagents which transform episul_des to alkenes
include phenyllithium ð48JA467Ł\ methyl iodide ð38JCS171\ 53JOC2147Ł\ diphosphorus tetraiodide\
tributyltin hydride or Raney nickel ð72TL0546Ł\ lithium aluminum hydride ð51CI"L#0125Ł\ 2!methyl!
1!selenoxobenzothiazole ð65S199Ł\ and ethyl diazoacetate and cupric salts ð64JA1442Ł[
S CO2Me S
Me ∆ CO2Me
Br CO2Me
Scheme 4
S P(OEt)3
H H + SP(OEt)3 (8)
0[03[1[0[1 Elimination of selenide groups

Reductive elimination of b!hydroxyselenides provides a useful route to alkenes ð67T0938\ 68ACR11Ł[
Once it was observed that the adducts derived from benzeneselenenyl tri~uoroacetate addition
to alkenes could revert to alkenes under certain conditions "Equation "8## ð63CC099\ 63JOC317Ł\
investigation of conditions which could be employed for the transformation of b!hydroxyselenides
to alkenes was undertaken[ Reich demonstrated that methanesulfonyl chloride and triethylamine
"both reagents being used in excess# resulted in good yields of the alkenes ð64CC689Ł[ The elimination
occurs in an anti fashion and is believed to be the reverse of the electrophilic addition of selenium
reagents to alkenes\ proceeding via an episelenonium ion "Scheme 4# ð68JA5527Ł[ Krief and co!
workers ð65TL0274\ 65TL2116\ 65TL2632\ 67TL1582\ 71CC453Ł subsequently demonstrated that this trans!
formation can also be achieved using toluenesulfonic acid in pentane\ perchloric acid in ether\
tri~uoroacetic acid anhydride and triethylamine\ thionyl chloride and triethylamine\ phos!
phochloridite and sodium hydride\ phosphorus oxychloride and triethylamine\ or phosphorus
triiodide and triethylamine^ both phenylseleno and methylseleno derivatives were investigated[ Anti
elimination was observed under these conditions also[ Application of this stereoselective elimination
to the synthesis of allyltrimethylsilanes is illustrated in Equation "09# ð76TL1950\ 89T0774Ł[ Clive
and Kale demonstrated that trimethylsilyl chloride and sodium iodide can similarly transform b!
hydroxyselenides into alkenes ð70JOC120Ł[
SePh
PhSeO2CCF3
(9)
silica
O2CCF3
Ph
PhSe PhSe Se+
OH OMs
Scheme 5
OH
MsCl, Et3N
TMS n-C7H15 TMS n-C7H15 (10)
80%
SePh
As b!hydroxyselenides can be derived by nucleophilic attack of selenide anions on an epoxide

ð65TL0274Ł\ or by reduction of a!seleno aldehydes or ketones ð65TL2116\ 68ACR11Ł\ or by attack
of an a!selenocarbanion on an aldehyde or ketone ð65TL0274\ 71CC453Ł\ or by reduction of b!
hydroxyselenoxides ð68JA5537Ł\ elimination of these compounds can be employed for the trans!
formation of epoxides to alkenes\ of aldehydes and ketones to alkenes\ or of a!seleno ketones to
alkenes "Scheme 5#[ The elimination of b!hydroxyselenides is e.cient\ even for the formation of
tetrasubstituted alkenes ð65TL2632\ 71CC453Ł and in some cases is preferable to the Wittig reaction
for the preparation of such hindered alkenes[ Equation "00# illustrates the use of the elimination in
the synthesis of highly substituted dienes ð76CC0439Ł[
O R1Se – R3 O
R2 R4 +
R2 R4 R5
R3 R5
R1Se R4 R2 R4
R2 R5
R3 OH R3 R5
R1Se R4 O– O–
O
R2 R1Se+ R4 Se+ R3
R3 O R2 R5 R1 –
+
R4 R5
R3 OH R2
Scheme 6
HO
R
R SePh SOCl2, Et3N
(11)
CH2Cl2
54–66%
R = Ph, (CH2)2Ph, (CH2)5Me

The elimination of b!hydroxyselenides can be applied to the formation of a\b!unsaturated esters\
lactones ð67TL1582Ł and lactams ð75JOC2097Ł^ use of this transformation was made in Meyers|
synthesis of "S#!"−#!deplancheine "Scheme 6# ð75JOC2097Ł[
O O
N i, LDA, (PhSe)2 N SOCl2
SePh
N ii, LDA, MeCHO N
H H
OH
MeO MeO
O
N
N
H
MeO
(E):(Z) 1.2:1
Scheme 7
Elimination of b!oxygenated selenides "in which the selenide bears an ether\ silyloxy or lactone
group# to form an alkene can be brought about using sodium in ammonia ð68CC72Ł or chloro!
trimethylsilane and sodium iodide "Equation "4## ð70JOC120Ł[ A similar transformation is possible
with b!oxygenated sul_des albeit at higher temperatures ð70JOC120Ł[
b!Haloselenides can be eliminated to form alkenes on treatment with phenylselenolate ð79TL0766Ł[
Destannylselenenylation ð81JOC2034Ł "analogous to known destannylsulfurization processes
ð74JOC2511Ł#\ to form alkenes can be brought about by ~uoride ion\ Lewis acid\ silica gel\ bases or
a variety of other conditions "Equation "01## "see Section 0[03[5[2#[
O O
SePh tbaf, Et2O
(12)
0 °C
86%
SnBu3
Treatment of a selenide\ containing an appropriately positioned cyclopropane ring\ with tri!

butyltin hydride or triphenyltin hydride results in formation of a cyclopropylmethyl radical which
undergoes ring opening to form an alkene "Scheme 7# ð78CC221Ł[
Bun3SnH
hν • 84%
PhSe
• CH2
Scheme 8
0[03[1[0[2 Elimination of telluride groups

Primary tellurides form alkenes in high yields on treatment with chloroamine!T^ the elimination
is believed to proceed via the adduct shown in Scheme 8 ð70CL336\ 78JOC3280Ł[
NSO2Tol
TePh + TolSO NClNa TePh + PhTeNHSO2Tol
R 2 R R
Scheme 9
Alkene inversion occurs on treatment of alkenes with tellurium"IV# chloride followed by sodium
sul_de^ this is believed to involve elimination via an epitelluride "Scheme 09# ð70TL0808\ 72JOC2807\
75S0Ł[ Further examples in which epitellurides are proposed as alkene precursors have been described
ð80S682\ 80S786Ł[
R1 H R2 H R2 Te
TeCl4 Na2S R1 R2
R1 H R1 H H H
R2 Cl TeCl3 Cl Te– R1 R2
Scheme 10
0[03[1[1 Elimination of Sulfoxide\ Selenoxide or Telluroxide Groups
0[03[1[1[0 Elimination of sulfoxide groups

Thermal elimination of alkyl aryl sulfoxides to form alkenes was _rst reported by Kingsbury and
Cram in 0859 ð59JA0709Ł^ since then this has become widely accepted as a useful synthetic route to
alkenes ð80COS"5#0900Ł[ Cram|s proposed mechanism involved a stereospeci_c cis elimination as
shown in Scheme 00[
–O
O Ph
S+ Ph H S
–PhSOH
Ph Ph Ph Ph Ph
Ph
Scheme 11
Subsequently it was demonstrated ð53JOC1588\ 54CC18Ł that pyrolysis of dialkyl sulfoxides to

form alkenes is also possible\ although higher temperatures are required than for aryl sulfoxides[
Eliminations involving pyridyl! ð67HCA887\ 76JCR"S#242\ 82JOC0468Ł and pyrazinylsulfoxides
ð77H"16#150Ł have also been reported[ In unsymmetrical dialkyl sulfoxides there is an enhanced
tendency towards thermolytic cleavage of the bond connecting sulfur to the more highly substituted
alkyl group ð56JOC091Ł[ The sulfenic acid produced in the pyrolysis of sulfoxides can be trapped
and identi_ed "see for example ð69CC0572\ 62IJS194\ 66JCS"P0#0463Ł#[
In the 0869s\ following Cram|s initial report\ considerable investigation of this reaction was
undertaken to determine more fully the conformational and electronic factors involved "ð65JA3776Ł
and references therein#[ For example\ the rate of elimination in benzenesul_nyl substituted cyclo!
alkanes is dependent on ring size "Equation "02##\ indicating energy di}erences in achieving the
conformation required for the cis elimination ð56JOC0520Ł[
O–
S+ 130 °C
Ph + PhSOH (13)
( )n ( )n
n = 1,2,3
Relative rates = 25:1:120
Jones et al[ ð65JCS"P0#348Ł demonstrated in a series of steroids that the stereochemistry at the
sulfoxide could control the regiospeci_city of the elimination process as shown in Equation "03#[ The
regioselectivity of sulfoxide elimination in 0\2!difunctional sulfoxides has been studied ð78JCR"S#29\
80JCR"S#51Ł^ elimination occurs selectively away from an alkoxy group and towards an alkylthio
group "Equation "04##[
110 °C
–O
+ (14)
+ toluene
S
H H H
R
R = 1-adamantyl
(R)-isomer 0% 73%
(S)-isomer 75% 0%
∆
Ph O SEt Ph O SEt (15)
41%
S
O Ph
There are many examples of the application of sulfoxide thermolyses to alkene synthesis\ e[g[\
Ley et al[ reported the preparation of a dihydrofuran acetal derivative via sulfoxide elimination
ð76TL110Ł\ while Takano et al[ employed the thermolysis of an aryl sulfoxide in the presence of
calcium carbonate to form "¦#!goniothalamin quantitatively as a single isomer having the "E#
con_guration "Equation "05## ð81TA742Ł\ illustrating the preference for formation of the ther!
modynamically more stable isomer whenever possible given the restraint that the elimination occurs
in a cis fashion[ Synthesis of novel avermectin derivatives containing terminal alkenyl groups was
possible by methyl sulfoxide pyrolysis\ again in the presence of calcium carbonate to neutralize the
sulfenic acid produced ð80SL762Ł[ In the last example\ only one of the two diastereoisomeric
sulfoxides eliminated to form the alkene in good yield^ the other failed to eliminate at temperatures
below which degradation of the molecule occurs[
Ph O
S CaCO3, toluene
(16)
Ph O O ∆, 1 h Ph O O
quantitative
(+)-Goniothalamin
The principal synthetic application of the thermal elimination of sulfoxides has been in the
transformation of esters\ ketones and related compounds into the corresponding a\b!unsaturated
compounds[ Trost has described this process in detail ð65JA3776\ 67ACR342\ 67CRV252Ł[ Introduction
of a sulfenyl group a to a carbonyl compound is a facile process^ subsequent oxidation with a wide
variety of oxidizing agents\ e[g[\ mcpba or NaIO3\ followed by thermolytic extrusion of a sulfenic
acid constitutes an exceptionally mild and general route to the a\b!unsaturated derivatives "Scheme
01#[ Frequently the elimination process may be conducted without puri_cation of the intermediate
sulfoxide[
O O O O O
S S
R1 R1 R3 R1 R3 ∆ R1
R2 R2 R2 R2
Scheme 12
The mildness of this method of introduction of unsaturation is evidenced by the wide variety
of functional groups which can tolerate this sequence ð65JA3776Ł[ For example\ the tricyclic
a!phenylsul_nyl ketone "0# eliminates readily to form the cyclopentenone "1# in over 89) yield
"Equation "06##[
O O
CCl4, ∆, 16 h
(17)
SOPh >90%
EtO2CO EtO2CO
(1) (2)
a\b!Unsaturated ketones\ esters\ lactones and lactams have been synthesized by this approach
ð65JA2911\ 65JA3776\ 67ACR342\ 75JA2274Ł^ some examples are shown in Table 0[ The stereochemical
preference in the elimination process is illustrated in entry 1*formation of the methyl ester of the
queen substance "3# with exclusively "E# stereochemistry resulted from pyrolysis of the methyl
sulfoxide "2# at 009>C ð67ACR342Ł[ Entries 4 and 5 illustrate that this methodology may also be
extended to the synthesis of a\b!unsaturated tosylhydrazones ð76JOC0107Ł and oxazolines ð76TL4498Ł[
Use of the pyrazinylsul_nyl group as a leaving group for sulfoxide elimination has been applied to
the synthesis of a\b!unsaturated nitriles "Equation "07## ð77H"16#150Ł[
Table 0 Sulfoxide elimination to form a\b!unsaturated ketones\ esters\ lactones\ lactams and related
compounds[
Entry Sulfoxide Alkene Yield Ref.

(%)
O O
1 84 76JA4887
SOMe
O
O
CO2Me
2 ( )5 CO2Me >86 78ACR453
( )5
SOMe
(4)
(3)
O O
MeSO O
3 O O 95 76JA4887
O
87 : 13
O O
N N
SOPh
4 N N 86 from sulfide 76JA3022
H H
EtO2C Et EtO2C Et
NNHTs NNHTs
5 SOPh 78 87JOC1218
PhSO O O
6 88 87TL5509
N N
N R N R Ph CN
i, NaH
(18)
R N S CN ii, PhCH2Br R N S CN Ph
O O
R = Et, Pri
The temperatures required for the elimination reactions are substantially lower for the compounds
with adjacent carbonyl groups than for simple alkyl sulfoxides ð65JA3776Ł\ and depend strongly on
the nature of the second substituent on the sulfoxide*aryl sulfoxides may be eliminated at tem!
peratures of 14Ð79>C\ whereas temperatures of 009Ð029>C are necessary with alkyl sulfoxides[ The
relative facility of elimination in the carbonyl containing compounds can be explained by the e}ect
of dipoleÐdipole interactions in the ground!state conformation of the sulfoxide and the conjugative
stabilization of the newly introduced double bond ð65JA3776Ł[ In cases where the higher temperature
associated with the alkyl sulfoxide elimination is damaging\ use of phenyl sulfoxide can overcome
the problem[ For example\ when the methyl sulfoxide "4a# was employed\ a retro!DielsÐAlder
reaction resulted in formation of ethyl benzoate\ but the phenyl sulfoxide "4b# eliminated smoothly
to form the a\b!unsaturated ester "5# "Scheme 02# ð62JA5739\ 65JA3776Ł[
O
R = Me R = Ph
S
R 84%
CO2Et
CO2Et CO2Et
(5) a; R = Me
(6)
b; R = Ph
Scheme 13
Trost and Parquette introduced the use of methyl 1!pyridinesul_nate as a reagent for the sul!
_nylationÐdesul_nylation of ketones and esters to form their a\b!unsaturated derivatives "Scheme
03# ð82JOC0468Ł[ Using potassium hydride as a base\ sul_nylation of ketones proceeds e.ciently at
room temperature^ thermolysis then leads directly to the enones[ Ketones are selectively targeted in
compounds containing both keto and ester groups[ Addition of metal salts or dihydropyran increases
the e.ciency of the elimination process[ This procedure clearly has the advantage of obviating the
necessity for an oxidation step[
O Ph O
KH 110 °C
+ S
Ph OMe O toluene Ph
N S
N
O
Scheme 14
In certain cases use of trapping agents "such as calcium carbonate\ trimethyl phosphite and 1!
thiolbenzothiazole# for the sulfenic acid produced in the thermolysis can be advantageous*either
in simplifying the puri_cation procedure or in improving the reaction e.ciency[ For example\ the
e.cient conversion of oestrone methyl ether to its unsaturated derivative required the use of
trimethyl phosphite as a sulfenic acid trap for e.cient reaction ð67CRV252Ł[
The regiochemical preference for sulfoxide elimination in acyclic systems is generally
C1CCH1 ½C2CCH1 ×ArCH1 ½CH2 ŁC0CH1 ×××C0H ð67CRV252Ł[ In the acyclic a!sul_nyl
ester "6# exclusive elimination towards the methyl group was observed following the expected order
of ease of H abstraction[ Closure to form the exo!methylene lactone indicates the synthetic utility
of this regiospeci_c elimination "Scheme 04# ð64TL3086Ł[
H SOPh H H
CO2Me P(OMe)3 CO2Me TsOH
O
70 °C PhH O
OH OH
H
(7)
Scheme 15
In cyclic systems\ provided the elimination occurs in a cisÐsyn fashion\ endo!cyclic alkene for!
mation is preferred[ Thus internal elimination was observed in the keto sulfoxide "7# to form carvone
"Equation "08## ð65JA4906\ 66JA7005Ł "see also entries 0 and 2 in Table 0#[ However due to geometric
constraints only exo cyclic elimination was observed for "8# "Equation "19## while its C"2# epimer
generated the endo!cyclic product exclusively ð63TL0986\ 67CRV252Ł[ Similarly\ exo elimination is
preferred in a cyclic b!keto sulphoxide "exo ] endo4 ] 0# while in the corresponding hydroxy!
sulfoxide\ endo elimination predominated ð81T22Ł[ Therefore both regiochemical and stereochemical
preferences are reversed on reducing the ketone to the corresponding alcohol\ indicating the in~uence
of conformational factors on the course of the thermolytic elimination process[ In large!ring cyclic
ketones\ elimination to form the "E# alkene is observed ð67CRV252\ 81TL6070Ł[
O O
(19)
PhSO
(8) Carvone
H SOPh H
O O (20)
O O
H H
(9)
As the presence of a sulfur substituent a to a carbonyl group enhances considerably the acidity
of the adjacent a!hydrogen atom\ regiospeci_c alkylation of a carbonyl compound followed by
sulfoxide elimination provides a useful route to alkylated a\b!unsaturated derivatives\ an approach
which has been employed widely ð63JA6054\ 67CRV252Ł\ and which complements the Wittig reaction
and related processes[ The preparation of an a\b!unsaturated ester "Equation "10## illustrates this
process[ This transformation has also been conducted under phase!transfer conditions ð76SC0728Ł[
O O i, PhSOCH2CO2Me, NaH O O
(21)
ii, 85 °C
I 80% CO2Me
Following this alkylationÐelimination procedure\ disubstituted alkenes are usually obtained with
the "E# con_guration\ while trisubstituted alkenes are formed as a mixture of "E# and "Z# isomers[
This overall sequence was employed in Oppolzer|s synthesis of acorenone "Equation "11##
ð66HCA1277Ł[ An extension of this alkylative elimination sequence to sulfoxides bearing activating
groups other than carbonyl groups\ e[g[\ aryl\ sulfenyl\ sul_nyl and nitrile groups\ was also reported
ð64JOC1903Ł[
O O
i, LDA, MeI
(22)
SPh ii, mcpba
iii, 70 °C, CCl4
Acorenone
Paterson and Fleming extended this route to a\b!unsaturated carbonyl compounds to include
elimination of b!sul_nyl substituted compounds as illustrated in Equation "12#[ Application of this
methodology to the synthesis of a!methylene lactones and esters ð68TL882Ł\ ketones ð68TL884Ł and
a!alkylidene ketones\ aldehydes\ esters and lactones ð68TL1068Ł was demonstrated[ Similarly Crich
and Lim have observed facile elimination in a b!pyridinesul_nyl ester ð76JCR"S#242Ł[ An example of
syn!elimination of a b!benzenesul_nyl group to form a spirocyclic butenolide "09# is illustrated in
Equation "13# ð81JCS"P0#1292Ł\ see also ð65SC246Ł[
SPh
H H
i, NaIO4
O O (23)
O ii, ∆ O
H H
O O
O i, NaBO3 O
PhS (24)
ii, 110 °C, DMSO
27%
N N
(10)
While sulfoxide elimination is usually brought about thermally\ the corresponding base!catalysed
process\ believed to occur via an E1 mechanism\ has been observed when aliphatic sulfoxides
ð53JA0450Ł were treated with potassium t!butoxide in DMSO[
Formation of alkenes from b!hydroxysulfoxides on treatment with NBS\ NCS\ SO1Cl1 ð62JA2319Ł
or o!phenylene phosphorochloridite ð61TL538Ł has also been reported[ Durst and co!workers sug!
gested that b!sultines are formed as intermediates in this process followed by facile loss of SO1
"Scheme 05# ð62JA2319Ł[ Stereoselective elimination of b!bromosulfoxides to form alkenes occurs
on treatment with tributyltin hydride ð67JA2763Ł[ Regiospeci_c alkene formation by silicon!directed
sulfoxide elimination has been achieved by thermal elimination of sulfenic acid from b!trimethylsilyl
sulfoxides followed by protodesilylation "Scheme 06# ð71CC170Ł "see Section 0[03[4[0[2#[
R1
O OH O OH
R2 SO2Cl2 R2 O R2
S S+ S+ Cl–
But R3 CH2Cl2 But R3 But
Cl O R1
R1 R1
R1
O R2 R2
–SO2
S
O R1 R1 R3
R1, R2, R3 = alkyl or aryl
Scheme 16
Ph O ∆ H+
S Bun
Prn TMS
Prn TMS 99%
(E):(Z) 57:1
Scheme 17
Thermolysis of allylic sulfoxides to form dienes has been reported "Equation "14## ð71JOC3790Ł[
However allylic rearrangement of the sulfoxides prior to elimination may occur leading to isomeric
dienes ð70TL3026Ł[ Formation of 0!nitro!0\3!cyclohexadienes "which are readily converted to aro!
matic nitro compounds# by sulfoxide elimination has been reported ð77JOC140Ł[ Sulfoxide elim!
ination to form allenes\ in good chemical yields but in low enantiomeric purities\ is illustrated in
Scheme 07 ð81TL3874Ł[ This is believed to proceed via a stable s!copper species[ Very little allene
formation is observed from the diastereomeric sulfoxide mesylate\ indicating the strict steric and:or
electronic requirements for this process[
Et3N, toluene
( )8 (25)
∆
PhOS OH 60% ( )7 OH
OMs O OMs O
S Me2CuLi-LiI Ph S
Ph p-Tol Bun Ph p-Tol
•
Bun Bun
Scheme 18
0[03[1[1[1 Elimination of selenoxide groups

Selenoxide syn!elimination is one of the most useful methods for introducing a C1C bond\
largely because of the extremely mild conditions required to e}ect elimination of selenenic acids
from selenoxides bearing a hydrogen atom at the b!position\ allowing preparation of sensitive
alkenes such as a!methylene derivatives of lactones\ even b!lactones ð67T0938\ 82JOC211Ł[ Following
the publication of isolated examples of the reaction "Equation "15## ð56MI 003!91\ 69CC75\ 60JOC1450Ł\
the enormous synthetic potential of this method was recognized only in 0862 when Sharpless et al[
ð62JA1586\ 62JA5026\ 62TL0868\ 64CS8Ł and Reich et al[ ð62JA4702Ł independently demonstrated its
utility in the synthesis of alkenes "Equation "16##[ Selenoxide eliminations have been widely used in
synthesis since this time and have been discussed in many reviews and books ð67T0938\ 68ACR11\ B!73MI
003!90\ B!75MI 003!90\ B!75MI 003!91\ B!75MI 003!92\ B!76MI 003!90\ B!76MI 003!91\ B!76MI 003!92\ 80COS"5#0900Ł[
C8H17 C8H17
H H
20 °C
(26)
95%
H H
Se
Ph O
H2O2
+ + (27)
~100%
PhSe
79% 7% 14%
While the selenoxide syn elimination is very similar mechanistically to the analogous sulfoxide
elimination process\ requiring all _ve participating centres to be coplanar as shown in Scheme 08
ð62TL0868Ł\ the rate of elimination from selenoxides is much faster than from sulfoxides^ in fact
these eliminations often occur below room temperature\ approximately 099>C lower than the
corresponding sulfoxide elimination process ð63JOC019\ 63TL0986\ 65JA3776\ 67JOC0586\ 67T0938Ł[
SeR O– +
oxidation H SeR
+ RSeOH
Scheme 19
Many aryl selenoxides containing a suitably positioned hydrogen atom are unstable and fragment
spontaneously at room temperature ð67T0938\ 68ACR11Ł[ Frequently the selenide is oxidized to the
selenoxide which is not isolated but eliminates directly in situ to form the alkene on warming to
room temperature or in some cases on addition to a re~uxing solvent such as carbon tetrachloride
or hexane ð65JOC0285\ 67JOC0586Ł at which temperature the elimination is essentially spontaneous[
The oxidation to the selenoxide can be achieved with a range of diverse reagents ð67T0938\ B!76MI
003!91Ł\ e[g[\ hydrogen peroxide ð62TL0868Ł\ ozone ð64JA4323Ł\ sodium periodate ð62CC584Ł\ mcpba
and other peracids ð64JA2149Ł\ t!butyl hydroperoxide ð67JOC0578Ł and sodium perborate
ð73JCS"P0#0482Ł[ Use of t!butyl hydroperoxide has been reported to minimize side reactions which
may occur in the elimination process ð67JOC0578Ł while the presence of alumina may be bene_cial
ð67TL0030Ł also[ Side reactions which may occur during the selenoxide elimination include epox!
idation of the double bond ð67JOC0586Ł\ addition of the selenenic acid or one of its dis!
proportionation products to the newly formed double bond ð65JOC1492\ 67JOC0578\ 67JOC0586Ł\
isomerization of double bonds already present in the compound ð70T152Ł and reduction of the
selenoxide to selenide by the selenium"II# by!products ð65JOC1492Ł[ It is recommended that the
elimination is conducted in the presence of an amine\ e[g[\ triethylamine ð65JOC1492\ 67JOC0586Ł as
this removes the selenenic acid as it is formed\ thereby reducing the possibility of side products[ Water
decreases the rate of the elimination process\ via hydrate formation^ therefore it is recommended that
anhydrous conditions are employed for e.cient reaction ð62TL0868Ł[
The synthesis of colnelic acid "Equation "17## ð76TL3806Ł by Corey et al[ employed elimination of
a methyl selenoxide\ formed by oxidation of the selenide with 1!benzenesulfonyl!2!phenyl!
oxaziridine\ to give an equimolar mixture of the "E# and "Z# isomers[ Alkyl selenoxides eliminate
more slowly than aryl selenoxides ð67TL0030Ł[ The presence of electron!withdrawing substituents
on the aryl ring further increases the rate of the reaction ð64JA0486\ 64JOC836\ 67JOC0586Ł^ o!
nitrophenylseleno groups have been found to be particularly useful[ The 1!pyridylseleno group has
been demonstrated to result in extremely e.cient elimination ð79TL4926\ 74JCS"P0#262\ 74T3236Ł[ While
the advantage of the phenylseleno group is the ready availability and ease of introduction of this
group\ in cases where the elimination proves di.cult use of the more reactive groups can be
advantageous "Scheme 19# ð64JA4323\ 73JOC2685Ł[
SeMe
CO2Me
O i, oxidation
ii, 40 °C, hexane

79%
CO2Me
O O
+ CO2Me (28)
(E):(Z) 1:1
O
O SeR O SeR O O SeR O O
R = Ph
+ +
14%
R = 2-pyridyl
>82% HO2C CO2H
O +
if H2O2 is employed as oxidant
Scheme 20
In general\ the same regiochemical preferences are observed as for sulfoxides\ i[e[
C1C0CH½C2C0CH×PhCH1 ½CH2 ×CH1 ×CH ð62JA4702\ 62TL0868\ 64JA2149Ł[ Therefore
when elimination in more than one direction is possible\ elimination towards the less!substituted
position is generally observed\ see for example Equation "16#\ i[e[\ b!alkyl substitution slows the
elimination process\ except when formation of a conjugated alkene is possible\ e[g[\ b!phenyl
substituents enhance the rate of the elimination ð67JOC0586Ł[ In cyclic systems elimination to form
an endo alkene is preferred over elimination to produce the exo product ð62JA4702\ 64JA4323\ 64JOC431Ł\
provided the transition state required for the syn elimination is conformationally accessible[ Thus
the selenoxide in Equation "18# eliminates in an endo fashion to form the butenolide even though
exo elimination would result in greater conjugation in the product[ However in the selenide "00a#
elimination occurs on oxidation to form selectively the more stable endo alkene while the epimeric
compound "00b# produces the exo product only ð63JOC019Ł^ presumably the transition state required
for endo elimination is not readily attained "Equations "29a# and "29b##[ Interestingly\ in a synthesis of
the cyclohexanediol fragment of nonaromatic b!milbemycins ð76CC779Ł\ "Equation "20##\ exocyclic
elimination was preferred in a cyclohexanol derivative\ while in the corresponding cyclohexanone\
endocyclic elimination predominated[
Ph
Ph
SePh H2O2, 0 °C
(29)
C6H13 O O 85% C6H13 O O
H H H
O H2O2
O O
O O + O (30a)
H SePh H
(11a) endo 9:1 exo
H H
O H2O2
O
O O (30b)
H SePh H
(11b) exo only
CO2Et CO2Et CO2Et

HO HO HO
H2O2
+ (31)
O O O
SePh X Y X Y
X Y
X, Y = O 85 : 15
X = H, Y = OH 10 : 90
When the selenoxide is substituted by a heteroatom at the b!position this may dramatically a}ect
the regiochemical preference for the elimination process ðB!76MI 003!91Ł[ In general hydroxy\ alkoxy
or acetoxy groups direct elimination away from the substituent "Equation "21## ð63JOC318Ł[ Nitrogen
substitution in the form of amino ð64JOC2202\ 74JA2780Ł\ amido ð70JOC3616Ł or azido ð68TL1586Ł
groups also directs elimination to the allylic position while by contrast\ isothiocyanate directs
elimination towards the formation of the vinylic product ð72JOC4135Ł "Equation "22##[ In contrast
to the behaviour with oxygen substituents elimination towards a b!thiobenzoyloxy group to form
the vinylthiobenzoate is favoured over formation of the allyl derivative "Equation "23##
ð77JCS"P0#464Ł[ The e}ect of halogen substituents is less predictable and often both regioisomers are
observed ð70JOC0735\ 70JOC2610Ł[ Groups which have an acidifying e}ect on an adjacent hydrogen
atom "e[g[\ carbonyl ð62TL0868Ł\ cyano ð71CC760Ł\ sulfone ð72JOC3875Ł\ sulfoxide ð70JA2375Ł\ nitro
ð71TL3622Ł# usually accelerate the rate of elimination towards the substituent\ frequently regio!
speci_cally[ Elimination in secondary selenoxides bearing a tributylstannyl group in the 2!position
has been investigated ð80JCS"P0#318Ł^ when elimination towards a methyl group is possible then
homoallylic stannanes are produced selectively\ otherwise a mixture of allylic and homoallylic
stannanes is formed "Equations "24a# and "24b##[ Thus the tributyltin substituent has little e}ect on
the regioselectivity of the selenoxide elimination[
SePh
H 2O 2
+ (32)
OR OR OR
R = H, Ac, alkyl >97 : <3
SePh
oxidation
+ (33)
X X X
X = NHAc 100 : 0
X = N3 60 : 40
X = NCS 17 : 83
mcpba
PhCOS ( )6 PhCOS ( )6 + PhCOS ( )6 (34)
98%
SePh
(E):(Z) 72:18 (E):(Z) 8:2
R mcpba
R R
+ (35a)
SnBu3 SeAr SnBu3 SnBu3
Ar = 2-nitrophenyl major minor
R = H, Me, Ph
mcpba
+ (35b)
SnBu3 SeAr SnBu3 SnBu3
40 : 60
The stereochemical outcome of the elimination process is again similar to that observed in
sulfoxide eliminations] in acyclic systems disubstituted alkenes are generally formed preferentially
with the "E# con_guration\ as for example\ in the Sharpless synthesis of the methyl ester of a
naturally occurring pheromone "Equation "25## ð62JA5026Ł\ while trisubstituted alkenes are formed
as a mixture of "E# and "Z# isomers ð62JA4702\ 64JA4323Ł[
SePh
CO2Me CO2Me
NaIO4, MeOH (aq.)
(36)
80%
Synthesis of terminal alkenes by selenoxide elimination has been widely employed in synthesis
ðB!73MI 003!90Ł\ for example in a preparation of vernolepin "Equation "26## ð65JA0501Ł[ Elimination
to form terminal alkenes is best achieved by using the o!NO1C5H3Se group ð64JOC836Ł or the 1!
pyridylseleno group ð71TL1094Ł which eliminate more readily than phenylseleno on oxidation to the
corresponding selenoxide ð64JA0486Ł[ Addition of the eliminated selenenic acid to terminal double
bonds can be a major side reaction leading to b!hydroxyselenides[ However use of an amine to trap
the selenenic acid as it is formed or an excess of the oxidizing agent to oxidize the Se"II# species to
seleninic acid can reduce the extent of this side reaction considerably "Equation "27## ð67JOC0586Ł[
The synthesis of selenides as precursors of terminal alkenes has been conducted by nucleophilic
displacement reactions using ArSeNa "Scheme 10# ð67CC407Ł[ Grieco developed a particularly
useful route for direct transformation of terminal alcohols to selenides by treatment of the former
compounds with o!nitrophenylselenocyanate in the presence of tributylphosphine ð79JOC2426Ł[ This
route has the added advantage that selective reaction at primary alcohols occurs under these
conditions^ Equation "28# illustrates the application of this selectivity in Grieco|s synthesis of
estradiol ð79JOC1136Ł[ Replacement of the o!nitrophenylselenocyanate in this sequence by N!phenyl!
selenophthalimide "N!PSP# is possible ð68JA2693Ł[
OMe OMe
OAc OAc
ArSe H 2O2
(37)
89%
MeO2C OAc CO2Me MeO2C OAc CO2Me
ArSe = o-NO2C6H4Se
O
OH
Se + PhSe (38)
Ph Ph Ph Ph
CDCl3 40 : 60
CDCl3 + Me2NH (1.5 equiv.) 100 : 0
O Br o-NO2C6H4SeNa O SeAr i, H2O2 O
N 64% N ii, ∆ N
O O 48% O
CO2Me CO2Me CO2Me
Scheme 21
OH OH
i, ArSeCN, Bu3P
(39)
MeO ii, NaIO4 MeO
89%
OH
Elimination of vinylic selenoxides to form alkynes or allenes has been studied by Reich and Willis
ð79JA4856Ł and Back and co!workers ð78JOC3035Ł[ As shown in Equation "39#\ when a cis!hydrogen
atom is present elimination to form the alkyne is preferred\ if not then elimination to form the allene
predominates[ Acetylenic ð70TL4000Ł and allenic ð72JOC3665\ 76TL0626Ł sulfones have been prepared
by this approach[
O
TolSe R1
•
Pri + (40)
Pri
R2
R1 = H, R2 = Pri 85% 15%
R1 = Pri, R2 = H <3% 81%
Formation of a\b!unsaturated carbonyl compounds by selenoxide elimination\ a powerful syn!

thetic method _rst developed by Sharpless et al[ ð62JA5026Ł and Reich et al[ ð62JA4702\ 64JA4323Ł\ is
now the most widely used application of organoselenium chemistry[ Scheme 11 illustrates this
general method*the enol or enolate of a carbonyl compound is treated with an electrophilic
selenium reagent to introduce the a!seleno substituent\ which is then oxidized to the selenoxide
which undergoes syn elimination[ This mild\ e.cient and regioselective method of introducing
a\b!unsaturation has been applied to aldehydes\ ketones\ esters\ lactones\ amides\ lactams and
b!dicarbonyl compounds[ Equations "30#Ð"32# display examples of these transformations[
O OR O O
SeAr
ArSeX oxidation
X = Br, Cl, SePh, etc.

R = H, metal, SiR3, Me
Scheme 22
O O
O3
(41)
80%
SePh
PhSe
O3
SePh (42)
O 60% O
H H
O O
O O
O O
i, NaH-PhSeCl
CO2Me CO2Me (43)
ii, O3
81%
With aldehydes and ketones introduction of the a!seleno group can be achieved simply by
treatment with phenylselenenyl chloride in ethyl acetate^ oxidation and elimination may then be
carried out directly to form the unsaturated products "Scheme 12# ð62JA5026Ł[ Reich developed an
alternative procedure ð64JA4323Ł in which the enolate is formed by deprotonation\ usually with
LDA\ to form the kinetic enolate followed by addition of PhSeCl or PhSeBr "Scheme 13#[ For
acyclic aldehydes and ketones elimination occurs to form the "E#!enones preferentially "Equation
"30## ð62JA5026\ 64JA4323Ł[ In cyclic systems\ the stereochemistry of the elimination is generally
controlled by ring size and by conformational e}ects ð62JA5026Ł[ Clearly the direction of the
selenenylation of unsymmetrical ketones is determined by the regiochemistry of the enolization^
therefore the alkene\ resulting from formation of the kinetic enolate\ is introduced on the less
substituted side of the ketone ð64JA4323Ł[ An application of this methodology in the synthesis of a
naturally occurring cyclopentenone is shown in Equation "33# ð81JCS"P0#1572Ł[
O O O
PhSeCl H2O2 or
R1 R2 EtOAc R1 R2 NaIO4 R1 R2
SePh
R1, R2 = H,alkyl, aryl
Scheme 23
O O O
i, LDA, –78 °C H2O2, O3
R1 R2 ii, PhSeCl or PhSeBr R1 R2 NaIO4 or mcpba R1 R2

SePh
R1, R2 = H,alkyl, aryl
Scheme 24
O O
i, LiHMDS, PhSeBr
(44)
CO2Et ii, H2O2, py CO2Et
59%
OH OH
If selenenylation of unsymmetrical ketones with the opposite regiochemistry to that obtained

from the kinetic enolate is required\ an alternative possibility is to react the enol acetates or silyl
enol ethers "which can be formed on the thermodynamically favoured side of the ketone# with
electrophilic selenium reagents such as PhSeCl or PhSeBr or PhSeOCOCF2 "Scheme 14 ð63JOC1022\
64JA4323Ł and Scheme 15 ð73CC0234Ł#[ The methodology involving silyl enol ethers was employed
in the synthesis of hydrindan derivatives ð81JOC2062Ł[
O OAc O O
Ph i, MeLi Ph Ph i, LDA Ph
ii, PhSeBr ii, PhSeCl
iii, H2O2 iii, H2O2
Scheme 25
Selenenylation of enones usually occurs at the a?!position producing a\b\a?\b?!unsaturated

dienones\ as shown in Equation "34# ð64JA4323Ł\ or if this position is blocked substitution occurs
at the g!position producing the a\b\g\d!unsaturated ketone following oxidation and elimination
O O-TMS O
TMS-I i, PhSeCl
O H HN(TMS)2 O H ii, H2O2 O H

OMe OMe OMe
O O O
Scheme 26
O O
SePh
H2O2
(45)
61%
O O
i, LDA
ii, PhSeBr
(46)
O iii, H2O2 O
50–60%
In some cases the yields of cyclic enones obtained may be low*presumably because the con!
formational preference of the cyclic ketone con~icts with the transition state required for the syn
elimination thereby allowing alternative reaction pathways to be followed[ For example when 1!
phenylselenocyclooctane is treated with hydrogen peroxide a mixture of products is formed "Scheme
19# ð64JA4323Ł[ In addition to the product of the syn elimination\ Pummerer!type reaction or
formation of vinyl selenides is observed[ In such cases\ the yield of the enone can be improved by
using the more reactive 1!pyridylseleno group in place of the phenylseleno group[
With esters and lactones generation of the enolate under basic conditions is required prior to
treatment with PhSeCl or PhSeBr or PhSeSePh followed by oxidation and elimination to form the
a\b!unsaturated ester or lactone ð62JA5026Ł[ Formation of the "E#!a\b!unsaturated ester is favoured
as illustrated in Equation "25#[ With lactones\ formation of the endocyclic alkene is usually preferred
as shown in Equation "18# ð64JOC431Ł\ as observed also with sulfoxides[ However Grieco has used
exo elimination of selenoxides to form a!methylene lactones extensively in synthesis by ensuring that
the seleno group and the b!hydrogen atom are trans oriented thereby directing the syn elimination to
occur in an exo fashion "Equations "29a# and "29b## ð63JOC019Ł[ Equation "31# demonstrates the
use of this methodology in the synthesis of tuberiferine\ where a double elimination is achieved to
introduce both the a\b!unsaturated cyclohexenone and the a!methylene lactone functionalities in a
single step ð65CC471Ł[
Relatively few examples of the formation of a\b!unsaturated amides and lactams are known[ In
the selenenylation of the lactam shown in Scheme 16 ð66JHC570Ł\ two equivalents of the base were
required to prevent formation of diselenated products[ Similarly for e.cient selenenylation of
nitriles two equivalents of base are required ð64JOC1054Ł[
O O O O
PhSe i, LDA (1 equiv.) i, LDA (2 equiv.) H2O2
Me Me PhSe Me Me
N N N N
PhSe ii, PhSeCl ii, PhSeCl 57%
55% 55%
Scheme 27
Selenenylation of numerous b!dicarbonyl compounds followed by transformation to their unsatu!

rated derivatives has been undertaken ðB!76MI 003!91Ł[ One example of the synthesis of an unsatu!
rated b!keto ester is shown in Equation "32# ð64JA4323Ł[ As the acidity of b!dicarbonyl compounds
is increased compared to the simpler carbonyl compounds\ use of milder bases for the introduction
of the seleno group is possible[ However sodium hydride is commonly employed for this trans!
formation[
Elimination of selenoxides derived from b!seleno ketones to form a\b!unsaturated ketones is also
possible "Equation "36## ð62TL0868\ 70TL0798Ł[ The observed regiospeci_city of the elimination may
be due to the formation of the conjugated alkene[ Similarly selenoxide elimination to form a\b\g\d!
unsaturated ketones is possible as shown in Scheme 17^ the b!seleno aldehyde is essentially acting
as a crotonaldehyde equivalent ð75TL1838Ł[
PhSe O O
H2O2
(47)
95%
R NaH
R H2O2 R
OHC P(OMe)2
+
SePh O O O SePh O
72–87%
Scheme 28
Selenoxide elimination has also been employed in the synthesis of a\b!unsaturated nitro com!
pounds ð70CC150Ł\ nitriles ð63TL1168\ 64JOC1054\ 66JA4109Ł\ sulfones ð79JOC0375Ł\ sulfoxides
ð64JA4323Ł\ phosphonates ð70TL2986Ł and phosphine oxides ð68CB244Ł "Equations "37# and "38##[
SePh H2O2
(48)
CN ~96% CN
(E):(Z) 54:46
O
Ph2P O
H2O2
Ph2P (49)
PhSe 85%
An interesting extension of the syn elimination process is in the functionalization of alkenes

via selenium reagents^ treatment of alkenes with electrophilic selenium reagents\ e[g[\ PhSeBr\
PhSeO1CCF2\ gives the trans!substituted selenide ð63CC099\ 63JOC317\ 63JOC318\ 67JOC0578Ł which may
then be oxidized and eliminated ð63JOC318Ł to form an allylic substituted product or a vinylic
substituted product depending on the nature of the substituent "Scheme 18^ see also Equations "21#
and "22##[ Ring opening of epoxides to give b!hydroxyselenides\ which usually proceeds with a high
degree of stereoselectivity of selenide attack at the less!substituted carbon atom\ followed by
oxidation and elimination\ furnishes allylic alcohols "Scheme 29# ð62JA1586Ł[ This protocol has been
widely applied in synthesis "Equation "49##[
SePh
PhSeX oxidation
+
X X X
X = e.g. OH, OR, OAc, Cl, Br, NHCOMe
Scheme 29
SePh
PhSeM oxidation
O
OH OH
Scheme 30
OR
(50)
R = H, Ac, alkyl
Allylic selenoxides rearrange readily to form allylic alcohols via a ð1\2Ł!sigmatropic rearrangement
ð61JA6043\ 62JA1586\ 62TL0868Ł[ Therefore\ while allylic sulfoxides eliminate to form 0\2!dienes
ð63ACR036\ 71JA6940Ł in the case of selenoxides the equilibrium lies much more towards the selenenate
ester which is hydrolysed to the allylic alcohol as illustrated in Scheme 20[ This has been exploited
by Reich for the preparation of allylic alcohols "Equation "40## ð64JOC1469Ł and by Clive et al[ for
the 0\2!transposition of primary allylic alcohols "Scheme 21# ð67CC669Ł[ Back has reported ð1\2Ł
sigmatropic rearrangement of a dienyl selenoxide to produce an allenic alcohol "Scheme 22#^ use of
an enol ether "in addition to an amine# as a scavenger for the selenenic acid formed was found to
be necessary ð81TL3614Ł[
R + O– RSe
Se O OH
very little diene

formed
R + O– RS
S O
good yields
Scheme 31
H2O2
Ph Ph (51)
80%
SePh OH
OH ArSeCN SeAr H2O2
Bun 3P 68%
OH
93%
Scheme 32
CO2Me mcpba CO2Me
SePh SePh
O
[2,3]
CO2Me CO2Me
HO O PhSeO
• Et3N •
H 47% H
Scheme 33
Asymmetric selenoxide elimination to form chiral allenes has been reported\ albeit with moderate
enantioselectivity "Scheme 23# ð81CC35Ł[
O
*
R SeAr R SeAr R
Ti(OPri)4
•
(+)-diethyl tartrate –ArSeOH
Ts Ts Ts
ButO2H
Ar = Ph, 2-nitrophenyl 1–21% ee
R = Prn, n-C7H15, Cl
Scheme 34
Direct introduction of a selenoxide group by use of benzeneseleninyl chloride was brie~y inves!
tigated as shown in Equation "41# ð64JA4323Ł but proved less convenient than the two!step "selenen!
ylation followed by oxidation# procedure[ A variation of the selenoxide elimination reaction using
PhSeCl2 for the introduction of the selenium substituent has been reported "Scheme 24# ð76CS404Ł[
Formation of a similar intermediate "bearing a PhSeCl1 group# by chlorination of b!chloro selenides
with sulfuryl chloride followed by hydrolysis and selenoxide elimination has been applied to the
synthesis of chloroalkenes ð76TL0352Ł[
O i, LDA O
ii, PhSeOCl
(52)
Ph iii, AcOH
Ph
80%
O O O
PhSeCl3 SePhCl2 NaHCO3
Scheme 35
Carbanions may be generated adjacent to selenoxides by treatment with a base such as LDA\
provided the selenoxide cannot undergo syn elimination\ e[g[\ methyl phenyl selenoxide\ or the
selenoxides are handled below 9>C to prevent the selenoxide fragmentation ð64JA2149Ł[ The resulting
carbanions react with alkyl halides\ aldehydes and ketones and may subsequently undergo elim!
ination to form an alkene[ Scheme 25 gives an illustrative example of this alkylative elimination
process[
O O
O3, –78 °C LDA Br
Se Ph Se Ph Se Ph
Ph Ph Ph
–78 °C –
O
Se
Ph
Ph
64% from selenide
Ph
Scheme 36
Selenoxide elimination has also been employed for the conversion of enones into b!alkyl enones
ð63JOC1022\ 64JA4323Ł^ the copper enolate resulting from a conjugate addition to an enone can be
trapped with PhSeBr or PhSeSePh "frequently a mixture of the two is employed# to form the selenide
which can subsequently be oxidized to e}ect elimination to form the b!substituted enone "Scheme
26#[
O Me2CuLi O PhSeBr and PhSeSePh O oxidation
Ph –40 °C Ph –40 °C Ph
– 83%
SePh
O
Ph
Scheme 37
0[03[1[1[2 Elimination of telluroxide groups

Syn elimination in telluroxides to form alkenes has also been observed ð64CS8Ł^ however this
process is much less useful than the corresponding selenoxide or sulfoxide elimination processes
and therefore has attracted much less attention[ Equation "42# shows that\ as for selenoxides and
sulfoxides\ elimination towards the less!substituted position is preferred\ with greater regioselectivity
observed for the telluroxide elimination than that observed with selenoxides and sulfoxides
ð72JA1637Ł[ Also when a b!oxygen! ð71TL0066\ 72JOM"149#192\ 72TL3236\ 74TL784Ł or amido!
ð78JCS"P0#0664Ł substituent is present\ elimination occurs away from the substituent to form the
allylic product as illustrated in Equation "43#[ Telluroxide elimination also exhibits the same
stereochemical preference as selenoxide elimination*formation of the "E# isomer of the alkene is
preferred^ however\ unlike selenoxides\ the stereoselection is sensitive to the amount of oxidant
present and when an excess of oxidant is employed formation of the "Z# isomer is also observed
ð74CC0926Ł[ Interestingly\ the cyclohexyl telluroxide derivative undergoes elimination only at elev!
ated temperatures "199Ð139>C#^ conformational factors may be responsible for decreasing the rate
of the elimination ð72JA1637Ł[ Similarly\ the telluroxide shown in Equation "44# eliminated only on
re~uxing in aqueous THF containing sodium hydroxide ð78JOC3280Ł[ Elimination to form terminal
alkenes has been achieved in good yields from 3!methoxyphenyltelluroxides ð70CC166Ł\ while good
yields of alkenes are obtained on treatment of secondary alkylphenyltellurides with mcpba ð75S0Ł[
Oxidative elimination of a b!phenyltelluro group to form an a\b!unsaturated ketone is also possible
ð78CL596Ł[
Ph O
Te
RT
+
57% 19%
OH O
+ + (53)
4% 10% 10%
R R
(54)
TePh
O
R = OH, OMe, NHAc
NaOH
(55)
O THF (aq.), ∆ O
Te Ph 53%
O
The telluroxides may be formed either by oxidation of the corresponding tellurides ð79JOC163Ł
with\ for example\ mcpba ð74TL784Ł or t!butyl hydroperoxide ð64CS8Ł\ or by treatment of the
appropriate tellurium dibromide with aqueous base ð70CC166\ 89CE150Ł[ In a related process\ tel!
lurides may be oxidized with chloroamine T ð70CL336\ 72S0995\ 78JOC3280Ł to form alkenes in good
yields[
In comparison with selenoxide elimination\ telluroxide fragmentation frequently requires much
higher temperatures "ca[ 199>C# ð72JA1637Ł making this a much less useful reaction synthetically[
Possible reasons which have been suggested for this decreased reactivity of telluroxides include the
longer bond lengths which may result in a greater distance between the oxygen atom and the b!
hydrogen atom and the fact that telluroxides form stable hydrates[ Furthermore\ control of the level
of oxidation of tellurium ð70CC166Ł is much more di.cult than for selenium*the tellurenic acid
produced by the elimination readily reduces the telluroxide to telluride\ lowering the reaction yield
considerably\ and also the telluroxides are easily overoxidized to tellurones\ thereby limiting the
oxidants which may be employed to form the telluroxide[ Adduct formation with excess oxidant\
e[g[\ mcpba\ has been proposed ð74TL784Ł[ Formation of alcohols via a 0\1!shift may compete with
the telluroxide elimination process ð64CS8Ł[
The formation of an allylic alcohol in the oxidation of an allylic telluride "Scheme 27# is believed
to indicate that a ð1\2Ł sigmatropic rearrangement\ similar to that observed in allylic selenoxides\
occurs also in allylic telluroxides ð74TL810\ 80S786Ł[
OTePh OH
H2O2 [2,3]
TePh TePh 94%
Scheme 38
0[03[1[2 By Elimination of Sulfone\ Selenone or Tellurone Groups
0[03[1[2[0 Elimination of sulfone groups

Alkene formation by sulfone elimination has been discussed in detail by Simpkins ðB!82MI 003!
90Ł[ Three di}erent elimination processes can be identi_ed*base!catalysed elimination\ elimination
of b!substituted sulfones "including the Julia reaction# and the RambergÐBacklund reaction[ Of
these\ the reactions of b!substituted sulfones are by far the most widely used in synthesis[
"i# Elimination of sulfones

Fenton and Ingold _rst reported elimination of sul_nic acids from sulfones on treatment with
sodium ethoxide ð29JCS694Ł^ later work in this area demonstrated that potassium t!butoxide in
DMSO is a particularly e.cient method of e}ecting sulfone elimination ð52JA1628\ 53JA0450\
60JOC0787Ł[ In simple sulfones\ regioselective Hofmann!type elimination occurs to produce the less!
substituted alkene "Equation "45##[ An E1 or ElcB mechanism is believed to operate "especially if the
hydrogen atom is being removed from an activated position# ð64CC839\ 76MI 003!90Ł[ Benzenesulfonyl
groups are widely employed but other groups have also been used\ for example the dichloro!
methylsulfonyl group ð78ZOR543Ł[
ButOK, py
+ (56)
SO2Ar 95 : 5
Eliminations of activated sulfones\ e[g[\ allylic and homoallylic sulfones\ have been employed in
synthesis[ For example\ Julia|s synthesis of retinoic acids utilizes ButOK in THF to produce the "E#!
alkene unit required in the heart of the polyene "Scheme 28# ð62BSF635Ł[ Sulfones stabilize a!
carbanions particularly e.ciently^ this enables facile alkylation of the sulfone prior to base!induced
elimination which allows considerable versatility in the alkene synthesis[ The elimination reaction
displays selectivity for the "E#!alkene^ thus when the "E#!isomer of the homoallylic sulfone shown
in Equation "46# was treated with base "E\E#!1\3!undecadiene was produced as the major product
ð75T3796Ł[
SO2Ph base
+ Br CO2R
SO2Ph
CO2R CO2R
base
Scheme 39
SO2Ph ButOK
(57)
n-C6H13 THF n-C6H13
65%
96% (E, E)
Elimination in b!sulfonyl carbonyl compounds to form a\b!unsaturated derivatives is relatively
facile "Equation "47## ð71CL054\ 77TL1948Ł and occurs under mild conditions\ for example with
0\4!diazabicycloð4[3[9Łundec!4!ene "dbu#\ basic alumina ð75TL2622\ 82JCS"P0#876Ł or with sodium
carbonate in DMF "Equation "48## ð66JOC0238Ł[ It is noteworthy that the sulfone in Equation "59#
eliminates under acidic conditions[ While elimination to form a\b\g\d!unsaturated derivatives is
frequently quite e.cient "Equation "50## ð75TL2226Ł\ in one example "Equation "51## Trost et al[
found that e.cient elimination occurred only in the presence of a palladium catalyst ð79JA4868Ł[
SO2Ph
dbu
(58)
O O R O O R
Na2CO3
(59)
Ph Ph
DMF
TolSO2 O 97% O
5% HCl O
O O
(60)
THF
90%
SO2Ph
Tol
O S O F F
F F
LDA
(61)
CO2Et CO2Et
dbu, (Ph3P)4Pd
SO2Ph (62)
71%
O O
An interesting example of sulfone elimination to form cyclopent!0!enecarboxamide derivatives is

illustrated in Scheme 39 ð78JOC0536Ł[ When the lithium derivative of a b?!sulfonyl acrylamide is
reacted with an activated alkene to form a cyclopentyl derivative as an anion\ elimination of the
benzenesulfonyl group occurs spontaneously to form the a\b!unsaturated amide[ In addition to
acting as a leaving group in this process\ the sulfone group stabilizes the anion and controls the
regioselectivity of the addition to the alkene[
Elimination of sulfones to form "nitroaryl#ethylene derivatives occurs under mild conditions
ð76S0031Ł[ Base!induced elimination of b!alkoxy or b!acetoxy!substituted sulfones produces dienes
or alkynes depending on the nature of the sulfone "Equations "52# and "53## ð73JA2569\ 75JOC2729\
75JOC2723\ 75JOC2785Ł[ The presence of a geminal heteroatom\ e[g[\ S\ O or N\ appears to facilitate
base!induced sulfone elimination "Equation "54## ð72TL3882Ł[ Cyclic sulfones can be transformed to
cycloalkenes on treatment with butyllithium followed by lithium aluminum hydride "Equation "55##
ð66OS"46#42\ 76JA2629Ł[
SO2Ph
ButOK (excess)
R R + (63)
OAc
major R
minor
R = C5H11
CONPri2 CONPri2 R CONPri2
LiTMP
PhSO2 PhSO2 + PhSO2
–
E
Li+ – R
CONPri2 CONPri2 E
– –PhSO2 –
PhSO2
22–89%
R R
E E
R = H, Me, THS
E = ester, ketone, amide or sulfone
Scheme 40
SO2Ph
Ph ButOK
Ph Ph Ph (64)
86%
OAc
OMe
ButOK
(65)
PhS SO2Ph 20 °C PhS OMe
H H
i, BuLi
SO2 (66)
ii, LiAlH4
H 19.5% H
"ii# Elimination of b!substituted sulfones

"a# Julia reaction[ Reductive elimination of sulfones with leaving groups at the b!position\
especially hydroxyl groups or derivatives thereof\ has been widely investigated[ b!Hydroxysulfones
are readily formed by reaction of a sulfonyl carbanion with an aldehyde or ketone^ reductive
elimination of these compounds directly\ or following derivatization of the hydroxyl group\ furnishes
a useful route to alkenes in a process which has been named the Julia reaction "Scheme 30#
ð62TL3722Ł[ Two reviews of this process are available ð70CI"L#437\ 74PS"13#366Ł[ An example of the
use of this alkenation procedure "Equation "56## is a step in Ley|s synthesis of a fragment of the
ionophore tetronasin ð89TL4414Ł[ Alternatively the b!hydroxysulfones may be obtained by reduction
of b!keto sulfones formed by acylation of the sulfonyl carbanion ð77JCS"P0#42\ 77TL5246Ł[
R1 i, base
PhO2S R3 PhO2S R3
PhO2S R1 R4 R1 R4
R2 ii, R3COR4 R2 O M+
– R2 OX
PhO2S R3 R1 R3
R1 R4
R2 OH R2 R4
X = COMe, COPh, SO2Me
Scheme 41
PhSO2 i, ButLi, –78 °C

ii, BzCl, –78 °C
+
O O CHO iii, Na(Hg), KH2PO4, MeOH, –40 °C
OMe 52%
O H
O H
(67)
O O O
H H
OMe
O
Sodium amalgam in methanol\ sometimes with the addition of a cosolvent as recommended by

Kocienski et al[ ð67JCS"P0#718Ł\ is frequently employed to e}ect the reductive elimination of b!
hydroxysulfones\ e[g[\ Equation "57# ð66JOC1925Ł[ Alternatively\ functionalization of the hydroxyl
group prior to treatment with sodium amalgam\ for example with MsCl ð62TL3722\ 71TL0852Ł or
SOCl1:pyridine ð75JA1665Ł\ or an acyl group ð76CC0231Ł\ or a silyl group "Equation "58##
ð68JCS"P0#0189Ł\ may lead to more e.cient alkene formation[ However\ radical reduction may also
be employed provided the hydroxyl group is _rst transformed into an appropriate group "Equation
"69## ð66TL3112\ 80TL1692Ł^ in the case of the diene illustrated in Equation "60#\ elimination of the b!
hydroxysulfone occurred directly on treatment with Bun2SnH without prior functionalization of the
hydroxyl group ð70TL1564Ł[ Similarly\ samarium iodide e}ects e.cient elimination of b!hydroxy
imidazolyl sulfones without prior functionalization of the hydroxyl group "Scheme 31# ð89TL6094Ł[
Electrochemical reductive elimination of b!hydroxysulfones can also be used especially for the
production of terminal alkenes ð67CL58\ 67MI 003!90Ł[
SO2Ph
OH
6% Na-Hg
(68)
MeOH
77%
OMe OMe
C9H19 C9H19
PhSO2 H Li(Hg) H
(69)
O-TMS MeOH, THF
BzO BzO
S
C7H15 O Bun3SnH
C7H15
Ph (70)
61% C6H13
PhSO2 C6H13
Bun3SnH, AIBN
OH (71)
C8H17 SO2Tol 92% C8H17
The stereochemical preference of the elimination for selective formation of "E#!alkenes is illus!
trated in Equation "61# ð67JCS"P0#718Ł[ Furthermore\ when conjugated double bonds are formed\
the stereochemistry of the pre!existing alkene unit is una}ected[ Mechanistically\ it is believed that
electron transfer to the sulfone group followed by expulsion of a benzene sul_nate anion or the
corresponding radical produces the carbanion which subsequently undergoes elimination in an anti!
Me Me
O2 O2
R1 S N R1 S N
i, NaHMDS SmI2
R2
N ii, R2CHO N R1
R2 OH
Scheme 42
periplanar fashion to produce the alkene[ Thus the stereoselectivity of the process can be explained
by rapid equilibration in the carbanionic intermediate so that the substituents are as far apart as
possible before the elimination occurs "Scheme 32# ð79JCS"P0#0934Ł[ As a consequence of the anti!
periplanar requirement of the process\ elimination is di.cult in cyclic systems in which the leaving
group cannot easily adopt an anti!periplanar arrangement to the carbanionic lone pair ð70CI"L#437Ł[
Interestingly\ while use of the silyloxy group\ or alternatively an acetoxy group\ produces the desired
triene in Equation "58#\ use of a benzoyloxy leaving group results in a mixture of stereoisomers
about the central double bond ð68JCS"P0#0189Ł[
Na(Hg)
AcO (72)
SO2Ph
MeOH, EtOAc
SO2Ph H
+ 2e– –
R2 R1 R2 R2
R1 –PhSO2– –OAc– R1
H OAc
OAc
Scheme 43
"b# Elimination of b!silyl\ nitro\ stannyl and sulfonyl sulfones[ Fluoride induced elimination of b!
silyl sulfones is a very mild route to unsaturated systems "see Section 0[03[4[0[2# ð68TL1538\
77JOC1577Ł[ Treatment with tetra!n!butylammonium ~uoride "tbaf# in re~uxing THF usually pro!
duces the alkene in high yields\ e[g[\ Equation "62#[ Extension of this strategy to the production of
vinylogous systems gives "E#!dienes in good yields "Equation "63## ð73TL0108Ł[
tbaf, THF
TMS (73)
C8H17 SO2Ph 56% C8H17
tbaf = tetra-n-butylammonium fluoride
i, BuLi, RX, HMPA

TMS (74)
SO2Ph ii, tbaf
R
R = alkyl, benzyl
b!Stannyl sulfones are even more labile towards elimination on treatment with ~uoride ion "see
Section 0[03[5[2# "Equation "64## ð71TL1194\ 72CC508\ 74JOC2511Ł and frequently are not isolated but
eliminate to form the alkene either directly or on contact with silica gel "Equation "65##\ thereby
furnishing a useful method for methylenation[ The more stable 1!pyridyl sulfone derivative can be
isolated prior to elimination[
SO2Ph
SnBun3 tbaf, THF
(75)
But 97% But
BuLi
(76)
Bu3SnCH2I
75%
SO2Ph
Elimination of b!nitrosulfones under reducing conditions to form alkenes has been investigated
"see Section 0[03[2[4# ð67TL652\ 70CL0028\ 76JOC4000Ł[ 0\3!Cyclohexadienes have been synthesized
using this reductive elimination as illustrated in Scheme 33 ð77JOC140Ł[ While Na1S and NaTeH
may be employed for this transformation\ Bun2SnH has the advantage of e}ecting a highly stereo!
speci_c anti!elimination "Equation "66##[ Only Bun2SnH gives satisfactory results in eliminations to
form alkenes which are not conjugated[
C7H15 C7H15 C7H15

NO2
NO2 110 °C Bu3SnH, AIBN
+ PhSO2
toluene 110 °C, toluene
SO2Ph
95% 79%
Scheme 44
OBz
BzO
SO2Ph
Bu3SnH, AIBN
H (77)
O2N Pri
Pri
(E):(Z) 93:7
Reductive desulfonylation of 0\1!disulfones is achieved using either sodium amalgam in bu}ered

methanol ð73JOC485Ł or magnesium in methanol ð74JOC0638Ł "Equation "67##[
Na(Hg), NaH2PO4, MeOH

(78)
SO2Ph 61%
SO2Ph
"iii# Ramber`ÐBacklund reaction

Base treatment of a sulfone bearing an a!halogen atom "or another leaving group# and an a?!
hydrogen atom results in elimination of SO1 and formation of an alkene "Equation "68##[ This
transformation was _rst reported in 0839 ð39MI 003!90Ł and has attracted considerable attention
both from a mechanistic point of view and due to its synthetic utility[ Many reviews of this
reaction have appeared ðB!56MI 003!90\ 57ACR198\ 57MI 003!93\ 69ACR170\ 66OR"14#0\ B!67MI 003!90\ 71T1746\
80COS"2#750\ B!82MI 003!90Ł[ Equation "79# illustrates application of this reaction to the synthesis of
conjugated enediynes ð77JA3755Ł[
R1 X R1 R3
R3 base
(79)
R2 S R4
R2 R4
O O
Cl
ButOK or MeLi
O2S ( )n ( )n (80)
20–80%
n = 2–8
The mechanism of the reaction is believed to be that shown in Scheme 34\ being established
predominantly through Bordwell|s research ð40JA4076Ł[ Intramolecular displacement of the leaving
group by the sulfonyl!stabilized carbanion produces an episulfone intermediate which is unstable^
loss of SO1 produces the alkene under the basic reaction conditions[ The leaving group is most
commonly chloride but other halides\ sul_nate ð79JOC0608\ 89JA7973Ł or tri~inate ð75JA1247Ł may
also be used[ Isolation of an episulfone "Equation "70## further established the intermediacy of this
species in the RambergÐBacklund reaction ð78TL2156Ł[
R2 R2 R1 R2
base – –X– –SO2 R1 R2
R1 S X R1 S X S
O2 O2 O2
Scheme 45
O O O O
Ph ButOK, < 0 °C
Ph (81)
I S
O2 S
O2
The bases employed for the reaction are generally NaOH\ NaOMe or KOBut in H1O\ MeOH\
ButOH\ THF or DMSO[ The use of phase!transfer conditions has also been reported ð71S493Ł[
Meyers developed an alternative method in which in situ chlorination and RambergÐBacklund
reaction take place on treatment of the sulfone with KOH\ ButOH and CCl3 "Equation "71##
ð58JA6409\ 63TL0094Ł[ These conditions e.ciently transform diallylic sulfones to trienes "Equation
"72## ð71TL4932Ł^ the new double bond is formed selectively with "E# geometry[ However\ these
conditions are not suitable for use with simple primary dialkyl sulfones as dichlorination occurs
more rapidly than episulfone formation resulting in formation of vinylsulphonic acid salts via a
thiirene dioxide intermediate "Scheme 35# ð62TL0732Ł[
KOH, ButOH Ph
Ph S Ph Ph (82)
O2 CCl4, H2O
100%
O2
S KOH, ButOH
(83)
CCl4, H2O
Bu Bu
SO3K KO3S
KOH, CCl4, ButOH, H2O
R1 S R2 +
O2
R1 R2 R1 R2
Cl O2 O2
Cl S S
R1
R1 S R2
O2 R2 R1 R2
Cl
Scheme 46
Application of the RambergÐBacklund reaction to the preparation of strained alkenes has proved
successful\ e[g[\ the anti!Bredt alkene shown in Equation "73# was obtained in this way ð72HCA0989Ł[
However\ in cyclic sulfones the RambergÐBacklund reaction is successful only when certain geo!
metric requirements are met ð58JA2769\ 72HCA0989Ł\ otherwise 0\1!elimination competes "Equations
"74a# and "74b##[ Thus if the H0C0S0C0X atoms are in a W!type arrangement\ the RambergÐ
Backlund reaction is most favourable ð72HCA0989Ł[ The reaction has also been applied to the
synthesis of medium!size rings\ e[g[\ in a synthesis of "¦#!eremantholide A ð80JA8571Ł[
ButOK
Br (84)
–78 °C
S
O2
(85a)
S Br
H O2
H H
(85b)
S Br S
H O2 H O2
Homologation of alkenes to dienes via the RambergÐBacklund reaction has been achieved
"Scheme 36# ð72JA5053\ 75JA3457\ 76OS"54#89Ł[ Free!radical halosulfonylation with bromomethane!
sulfonyl bromide followed by base!induced elimination "for example\ with 0\4!diazabicyclo!
ð3[2[9Łnon!4!ene "dbn## produces the bromomethyl alkenyl sulfone\ which can undergo a vinylogous
RambergÐBacklund reaction to give the diene\ formed preferentially with "Z# stereochemistry
ð77CL1998Ł[
i, BrCH2SO2Br, hν O2 ButOK
S Br
Bun ii, dbn Bun –20 °C Bun
(Z) : (E) 83 : 17
Scheme 47
Synthesis of a\b!unsaturated esters and acids can be accomplished "Equation "75## ð67JOC3773Ł[
The RambergÐBacklund approach has been employed in many cyclopentenone syntheses "for
example\ ð78T344Ł#[ The formation of the cyclopentenone derivatives shown in Equation "76#
illustrates a number of features ð74JOC1009Ł^ _rstly use of an additional sulphone group in place of
the halogen allows regioselective alkylation prior to the elimination process thus increasing the
versatility of this process^ secondly use of tri~one allows elimination to be conducted under relatively
mild conditions presumably due to the leaving group ability of tri~inate[
NaH, Cl3CCCl3
(86)
S DME
O2 75%
CO2Et CO2Et
R1 O2 R1 R2
S R2
K2CO3
Tf (87)
THF O
O
Michael addition of sul_nate to unsaturated sulfones bearing a suitably positioned leaving group
can result in a RambergÐBacklund reaction "Equation "77## ð70T306Ł[ As an alternative\ episulfones\
as a mixture of cis and trans isomers\ may be formed by reaction of primary sulfonyl chlorides with
triethylamine^ thermolysis produces the corresponding symmetrically substituted "E#! and "Z#!
alkenes through loss of SO1 "Scheme 37# ð78TL2020Ł[
Cl
RSO2M
(88)
S SO2R
O2
O2 R
Cl 3 Et3N ∆
S
2 R S
O O MeCN –SO2
R
R R
R = H, alkyl, aryl
Scheme 48
While episulfone intermediates in the RambergÐBacklund reaction are usually insu.ciently stable
to isolate\ the corresponding thiirene dioxides can be isolated and characterized "Scheme 38# ð60CC11\
60JA365Ł prior to loss of SO1[ Extrusion of SO1 from episulfones is believed to occur in a nonconcerted
fashion ð57JA318\ 57JA324\ 63TL2876Ł\ in contrast to the concerted chelotropic eliminations of SO1
from 1\4!dihydrothiophene!0\0!dioxide and 1\6!dihydrothiepin!0\0!dioxide "Equation "78##
ð55JA1746\ 58JA4571\ 77CC0933\ 78JCR"S#164Ł[ Extrusion reactions in sulfur\ selenium and tellurium
compounds which are synthetically useful\ including reactions which form alkenes\ have been
reviewed ð77T5130Ł[
Cl O2
Cl i, dabco, DMSO S ∆
Ar Ar
Ar S Ar ii, H2O
O2 Ar Ar
dabco = 1,4-diazabicyclo[2.2.2]octane
Ar = Ph, p-ClPh, p-MePh
Scheme 49
∆
(89)
S
O2
0[03[1[2[1 Elimination of selenone and tellurone groups

In contrast to elimination reactions of sulfones\ much less is known about selenone and tellurone
elimination[ One of the reasons for this is that selenones are not readily available^ furthermore\
both selenones and tellurones are very susceptible to nucleophilic displacement of seleninate and
tellurinate anions[ However\ selenones can be prepared by oxidation of selenoxides "for example\
with mcpba#\ and elimination to form an alkene has been reported "Equation "89## ðB!72MI 003!90Ł\
while Cava et al[ reported pyrolysis of an alkyl aryl tellurone\ formed by sodium periodate oxidation
of a telluroxide\ to form an alkene inter alia "Equation "80## ð70CC166\ 71CC053Ł[ Oxidation of
selenides or tellurides in MeOH with mcpba leads to the corresponding methyl ethers\ believed to
be formed by initial oxidation to the selenone or tellurone followed by nucleophilic displacement
by methanol ð72TL3236\ 74JCS"P0#360Ł[ The ability of the selenone moiety to act as a leaving group
has been demonstrated in a fragmentation sequence leading to an enol ether ð70JOC4135Ł[
O O
∆ Ph
Se Ph (90)
Ph 32%
OMe
NaIO4 110 °C
n-C10H21 n-C10H21 Ar
Te Te
O O O
n-C10H21 + n-C10H21 OH + n-C24H50 (91)
55% 15% trace

0[03[1[3 Elimination of Sul_limine\ Selenimide\ Tellurium Imide\ Sul_namide\ Sulfoximine\
Sulfonamide and Sulfonate Groups
As sulfoxide and selenoxide elimination provides an extremely useful route to alkenes\ inves!
tigation of the reactivity of the corresponding sul_limines and selenimides was undertaken[ Oae
ð60T3810\ 60T5090Ł reported that the sulfonimido analogues eliminate much more rapidly than the
sulfoxides in a concerted cis fashion "Equation "81##[ Sharpless reported that oxidation of a selenide
with chloroamine!T under phase!transfer conditions results in rapid formation of the alkene via a
selenimide as shown in Scheme 49 ð64CS8Ł^ the corresponding selenoxide elimination is much slower[
Similarly on treatment with chloroamine!T\ tellurides are transformed to the corresponding alkenes
presumably via a tellurium imide ð70CL336\ 72S0995\ 78JOC3280Ł[ The elimination of the telluride
shown in Equation "82# on oxidation with chloroamine!T resulted in a higher yield of the alkene
than the corresponding telluroxide elimination shown in Equation "44# ð78JOC3280Ł[ However\ as
formation of the imide derivatives of sul_des and selenides is less attractive than simple oxidation\
these eliminations o}er little advantage over the sulfoxide ð65JA3776Ł and selenoxide elimination
processes[
TsN– H 120–130 °C, 2 h

+ PhS–NHTs (92)
S+ 80%
Ph
Na+
N–
NTs
Ts Cl
SePh SePh
n-C10H21 PTC n-C10H21 n-C10H21
Scheme 50
chloroamine-T
(93)
82%
O Te Ph O
Corey and Durst have demonstrated that cis!elimination of b!hydroxy sul_namides to produce
alkenes\ believed to proceed as illustrated in Scheme 40\ may be brought about thermally ð55JA4545\
57JA4437\ 57JA4442Ł[ Scheme 41 illustrates how this elimination may be used to transform carbonyl
compounds to alkenes[ Fragmentation of unsaturated sul_namides to form terminal alkenes is
illustrated in Equation "83# ð77TL2144Ł[
OH
OH O O– OH
O S NR2
S S + + SO2 + HNR2
NR2 NR2
R = H, alkyl, aryl
Scheme 51
O OH O
O Ph PhH, ∆
Ph
Li S Ph S Ph
+ N Ph N
Ph Ph >98% Ph
Li H
Scheme 52
O
n-C8H17 S
N H2O, Et2O•BF3
n-C8H17 (94)
O dioxane, 0 °C
90%
Reductive elimination of b!hydroxy sulfoximines with aluminum amalgam furnishes alkenes
"Equation "84## ð62JA5351\ 68JA2591Ł[ Mixtures of cis and trans isomers are formed in this elimination
process[ Base!induced elimination of sulfoximines is also possible^ on treatment with potassium
dimsylate in DMSO\ benzothiazines "Equation "85## undergo an elimination of the sulfoximine
group to form an alkenyl sul_namide ð80T7744Ł^ this reaction is believed to occur via an Elcb
mechanism[ The stereoselectivity of the elimination is low[ Nucleophilic attack of lithium cyanide
or lithium dimethylphosphonate on vinylsulfoximines is followed by elimination of the sulfoxime
group to form a\b!unsaturated nitriles or phosphonates "Equation "86## ð80TL2008Ł[
MeN O OH Al-Hg, AcOH

S ( )4 (95)
Ph ( )4 100%
(E):(Z) 60:40
R2 R2
R1
R1
i, KDMSO
R3 (96)
S O ii, H+ R3
N 59–95% NH
Tol
SOTol
R1, R2, R3 = H, alkyl
TsN O LiCN, DMF, RT CN

(97)
S 63–81%
Ph R R
R = alkyl
Elimination of the sulfonamide shown in Equation "87# to form a naphthalene derivative occurs
readily ð81T1404Ł[ Formation of "nitroaryl#ethylene derivatives by elimination of sulfonamide or
sulfonate ester groups is illustrated in Scheme 42 ð76S0031Ł[
SO2 (98)
MeO N MeO
But
SO2X
K2CO3
+ CO2Et CO2Et
Ar SO2X Br CO2Et Ar 73–91% Ar
Ar = nitroaryl groups
X = NMe2, OPh, OCH2But
Scheme 53
Fragmentation of 0\1!dithietane!0\0!dioxides on treatment with lithium cyanide forms "Z#!alkenes

"Equation "88## ð82SL728Ł[
H
R SO2 LiCN, THF, 0 °C R R
H S + SO2 + LiSCN (99)
89–93%
R
0[03[1[4 Elimination of Sulfonium\ Selenonium and Telluronium Salts and Ylides

Sulfonium salts undergo elimination to form alkenes in a process which is similar to that observed
with ammonium salts^ thermal decomposition of sulfonium hydroxides and base!induced elim!
Nitroèn 512
ination of sulfonium salts are well established ðB!70MI 003!90Ł[ Considerable investigation of the
mechanistic aspects of this elimination has been undertaken ðB!70MI 003!90Ł^ see\ for example\
ð89JA5849Ł[ Elimination to form the less!substituted alkene is preferred ð77T1802Ł[ On treatment
with nucleophilic alkyllithiums such as methyl\ phenyl or n!butyllithium\ sulfonium n!alkylides lead
to signi_cant amounts of alkenes through b!elimination\ in addition to ylide formation "Equation
"099## ðB!67MI 003!91Ł[ An interesting example of this elimination process is illustrated in Equation
"090# whereby a polymeric sulfonium salt was thermolysed to e}ect elimination and produce a
highly conjugated polymer ð81JCS"P0#2114Ł[ Elimination of sulfonium salts in medium rings on
treatment with potassium t!butoxide has been observed "Equation "091## ð77CB1128Ł[
R R
R
base
S+ + S + S+ (100)
R R
R –
R = alkyl, aryl
S+R2Cl– 220–300 °C
(101)
vaccuum
n n
KOBut
(102)
82%
S+ SMe
CF3SO3–
Me
Sulfonium ylides bearing a b?!hydrogen can undergo an a\b?!elimination process on treatment
with base "Scheme 43# ð59CB1708\ 54TL1788\ B!67MI 003!92Ł[
MeCD2 + CD2Me
S D
Ph3C–
(MeCD2)3S+ + Ph3CD MeCD2 CDHMe +
S
– D D
Scheme 54
Krief and co!workers ð67TL076\ 68TL3122\ 79TL0886Ł have demonstrated that elimination of selenon!
ium salts to form alkenes can be employed as an alternative to selenoxide elimination^ alkylation of
the selenide with reagents such as dimethyl sulfate\ methyl ~uorosulfate or methyl iodide followed
by base!induced elimination "for example\ using potassium t!butoxide in DMSO# produces alkenes
in good yields "Equation "092##[
SeR i, MeOSO2F
n-C10H21 n-C10H21 + n-C10H21 (103)
ii, KOBut, DMSO
82–88%
65:35
R = Me, Ph
While sulfonium and selenonium ylides condense with aldehydes and ketones to produce epoxides\
the analogous telluronium salts and ylides react with aldehydes and ketones to produce alkenes
"Equation "093## ð72TL1488\ 76TL790\ 77JOC3751\ 80S786Ł[
∆
ArCHO + COPh (104)
Bu2Te+ COPh Ar
THF
Br– 88–97%
0[03[2 BY ELIMINATION OF NITROGEN FUNCTIONS
0[03[2[0 Elimination of Amine Oxides*the Cope Reaction

Although elimination of amine oxides to form alkenes and hydroxylamine derivatives had been
reported earlier ð0787CB0442Ł\ the synthetic utility of this transformation was _rst recognized by
Cope ð38JA2818Ł[ Reviews of the Cope reaction have appeared ð59CRV320\ 59OR"00#206\ B!57MI 003!90\
80COS"5#0900Ł[ Frequently the Cope reaction is carried out by oxidizing an amine with reagents such
as hydrogen peroxide ð52OSC"3#501Ł or mcpba ð75JA0928Ł^ without isolation of the amine oxide\
pyrolysis "usually at 099Ð049>C# e}ects elimination to provide the alkene[ Cram demonstrated that
Cope elimination occurs in dry DMSO or THF at room temperature ð51JA0623Ł[ The synthetic
utility of the Cope reaction is that\ due to the fact that it occurs under relatively mild conditions\
little isomerization of the alkene is observed "Equation "094## ð41JA1026\ 46JA859Ł compared with the
Hofmann elimination\ and there are few side reactions[ Occasionally rearrangement of a benzyl or
allyl group can occur to form an O!alkylated hydroxylamine ð38JA2818Ł[
O–
Me ∆
Ph
Ph +N (105)
+ Me2NOH
Me
The elimination of amine oxides follows an Ei!type mechanism via a _ve!membered planar cyclic
transition state as shown in Equation "095#^ thus the amine oxide derived from threo!1!amino!2!
phenylbutane produces the cis alkene\ while the erythro amine gives the trans isomer ð43JA4639Ł[
Furthermore\ cis! and trans!1!phenylcyclohexyldimethylamine oxides selectively form di}erent
alkenes as shown in Equations "096a# and "096b# ð46JA859Ł\ due to the stereochemical requirements
of the planar cyclic transition state[ Cyclooctyldimethylamine oxide produces only cis!cyclooctene
on pyrolysis ð42JA2101Ł^ originally this was believed to indicate that the elimination must occur in
a syn fashion[ However Bach et al[ later demonstrated that\ in an analogous ylide elimination of a
cyclooctyl ammonium derivative which proceeds via a similar cyclic mechanism\ formation of trans!
cyclooctene is possible ð60JA6007\ 61JA7597Ł[ Therefore the formation of only cis!cyclooctene in the
Cope reaction could not be taken as de_nitive proof of a syn elimination[ Instead Bach con_rmed
the syn nature of the amine oxide elimination using deuterium labelling studies as shown in Equation
"097# ð62JOC0631Ł[ Kwart et al[ have used kinetic isotope e}ects to probe the nature of the transition
state of the Cope reaction ð67JA2816\ 70JA3549Ł[
Ph H + Me2NOH (106)
H +N Me Ph
–O Me
threo cis
Ph Ph Ph
+ (107a)
+ 96%
NMe2
O– 85% 15%
Ph Ph Ph
+ (107b)
+ 72%
NMe2
O– 2% 98%
Me2
+
N
O– 110 °C
(108)
D D
99% deuterium retention
In contrast to the Hofmann elimination\ alkyl substitution has little e}ect on the direction of
elimination in the Cope reaction^ in acyclic amines it is governed almost entirely by the number of
hydrogen atoms at the b!position\ except in the case of a bulky t!butyl group or if a conjugated
alkene may be formed ð46JA3619Ł "Equations "098# and "009##[ Equation "098# also demonstrates
the preference for formation of the trans alkene if both cis and trans alkenes may be formed[
Nitroèn 514
–O +
NMe2
+ (109)
91%
33% 67%
64% trans
36% cis
–O +
NMe2
Ph + Ph (110)
Ph
92% 8%
In cyclic systems the direction of elimination is controlled by the requirement of a planar cyclic
transition state "Equations "096a# and "096b## ð46JA859Ł[ Similarly in the menthyl and neomenthyl
derived amine oxides "Equations "000a# and "000b## ð47JA244Ł\ a cis b!hydrogen atom is available
only in the 1!position in the neomenthyl derivative and therefore only 1!menthene is produced[ In
contrast\ the menthyl derived amine oxide has cis b!hydrogens at both the 1! and 3!positions and
therefore both menthene isomers are formed[ When elimination may occur in an endo or exo cyclic
fashion in cycloalkylamine oxides\ elimination to form the endo alkene is generally preferred
"Equation "001## for ring sizes of 4 and 6Ð09 ð59JA3552Ł[ However\ in cyclohexyl derivatives\
elimination is almost entirely exo cyclic ð46JA3618Ł[ It is believed that the planar cyclic transition
state which would be required for endo cyclic elimination in the cyclohexyl derivatives is not readily
accessible[ In medium!size rings "8 or 09# the Cope reaction forms the trans cycloalkenes ð44JA0517Ł
in a synthetically useful process[ Cope investigated eliminations of amine oxides to form 1!nor!
bornene and 1\4!norbornadiene ð48JA1688Ł^ the exo amine oxide derivatives gave higher yields than
the endo isomers[ Lower yields were obtained in these Cope eliminations than in the Hofmann
eliminations that form the same bicyclic alkenes[
Pri
+ (111a)
Me2N + 85%
O–
Dimethylmenthylamine oxide 64% 36%
+ O–
Me2N
Pri + (111b)
84%
Dimethylneomenthylamine oxide
100% 0%
+ + (112)
84%
NMe2
–O
15% 85%
Heterocyclic tertiary amines may be cleaved on oxidizing to the corresponding amine oxides
followed by elimination ð59JA3545Ł[ Cleavage of N!methylpiperidine oxide does not occur on heating
as the steric requirements of a cyclohexyl ring do not allow the preferred planar transition state to
be attained[ However\ on increasing the ring size to 6 and 7\ the cleavage to produce unsaturated
hydroxylamine derivatives becomes increasingly easy "Equation "002##[ N!Methyl!a!pipecoline oxide
undergoes elimination "Equation "003## ð59JA3545Ł to form the unsaturated hydroxylamine in
addition to the bicyclic side product believed to be formed by nitrone cycloaddition to the initially
formed alkene[ Only the trans isomer of the amine oxide underwent elimination[
( )n ( )n
(113)
+
N N
Me O– Me OH
n = 1, 2, 3 n = 1, 0%
n = 2, 53%
n = 3, 79%
H
+
NMe + O (114)
N N
O– HO Me H Me
While the Cope reaction can provide a useful synthetic route to alkenes\ it has also been used to
prepare dialkylhydroxylamines\ particularly unsymmetrical derivatives "Equation "004## ð44JCS658Ł[
O R1 O
R1 + N OH + (115)
N X X
R2
O– R2 (not isolated)
X = Ph, OAlkyl
Application of the Cope reaction in synthesis is illustrated by its use in the synthesis of Vitamin
B01 "Equation "005## ð75JA0928Ł\ and in the synthesis of norsecularines ð77H"16#1256Ł[ Elimination to
form a conjugated diene is illustrated in Equation "006# ð77MI 003!90Ł[ The reverse Cope elimination\
in which unsaturated hydroxylamines undergo cyclization\ is also possible^ an example of this\ in
which pyrrolidine and piperidine N!oxides are formed\ is illustrated in Scheme 44 ð89JOC2996Ł[ The
sila!Cope reaction ð71JA6555Ł\ where a b!silyl substituent is eliminated in place of the hydrogen
atom has been used in a pheromone synthesis "Equation "007## ð89TL0754Ł "see Section 0[03[4[0[2#[
CN CN
NC NC
i, mcpba
(116)
Me ii, DMSO, ∆
O N O
Me
O–
N+ ∆
(117)
Ph LiAlH4 Ph
O– OH Ph
Ph Ph 89%
N+ N +N O–
Ph
Me Me
Me
Scheme 55
O-TBDMS
Me + O– TBDMS Me N TBDMS
N
Me
MeCN
+ N (118)
40 °C HO
sila-Cope product Cope product

Nitroèn 516
0[03[2[1 Elimination of Quaternary Ammonium Salts
0[03[2[1[0 Hofmann elimination of quaternary ammonium hydroxides

Thermal decomposition of a quaternary ammonium hydroxide to form an alkene\ an amine and
water "the _nal step of the Hofmann degradation process# was _rst reported in 0740 ð0740LA"67#142Ł[
The Hofmann elimination has been the subject of a number of reviews ð59OR"00#206\ B!57MI 003!91\ B!
62MI 003!90Ł[ Hofmann degradation "Scheme 45# involves the treatment of an amine with su.cient
methyl iodide to convert it to the corresponding quaternary ammonium iodide\ treatment with
silver oxide to convert it to the hydroxide salt\ which is then thermally decomposed "099Ð199>C# by
distilling an aqueous or alcoholic solution of the hydroxide often at reduced pressure[ This process
has been used extensively for structural determination of amines\ especially alkaloids[ Nucleophilic
attack of hydroxide to produce the alcohol as a side product can occur under the conditions
employed for the Hofmann elimination ð59OR"00#206Ł[ Improved yields in the elimination step have
been reported by concentrating the reaction mixture and conducting the elimination under reduced
pressure ð60JCS"C#0216Ł^ lower temperatures are required to e}ect elimination under these conditions[
Use of an ion!exchange resin for the preparation of quaternary ammonium hydroxides is possible
ð65OS"44#2Ł[ An alternative procedure for the elimination involves heating the ammonium salt
with alkali hydroxides in polyethylene glycol monomethyl ether ð68LA0814Ł[ Hofmann elimination
proceeded on treatment of quaternary benzyltetrahydroisoquinoline related alkaloids with a large
excess of diazomethane ð77H"16#640Ł[
MeI Ag2O ∆
+ I– + OH– + H2O
N N N
N
Me Me Me Me Me
Me Me
MeI Ag2O ∆
I– OH– + H2O + Me3N
+ +
N N N
Me Me Me Me Me Me
Me Me
Scheme 56
Extensive investigation of the mechanism of the Hofmann elimination has been undertaken[ The
usual mechanism is E1 ð50JA2750Ł leading to the product of trans elimination ð45JA689Ł^ in the
Hofmann degradations of threo and erythro 0\1!diphenylpropylamines ð45JA689Ł the erythro isomer
produces the "Z#!alkene while the threo isomer produces the "E#!alkene "Equations "008a# and
"008b##[ However on changing the base to t!butoxide in t!butanol both threo and erythro isomers
produce the same "E#!alkene\ indicating a change in the mechanism of the reaction with the stronger
base[ In certain cases cis elimination is observed "Equation "019## ð56JA5690\ 56JCS"B#498Ł[ In the case
of some highly hindered ammonium salts an alternative Ei mechanism is involved ð52JA0838Ł[
Me +NMe Ph Ph
3
Ph (119a)
H Ph
erythro (Z)
Me +NMe Ph
3
Ph (119b)
H Ph Ph
threo (E)
D ∆
+ (120)
NMe3 OH–
The direction of elimination of ammonium salts has been summarized in the Hofmann Rule] the
b!hydrogen atom is removed most readily if it is located on a methyl group\ next on a methylene
group and least readily from a methine group[ Therefore\ elimination proceeds to give the least
substituted alkene[ This preference is illustrated in Equation "010#[ However\ for cyclic compounds
elimination within the ring is controlled largely by the requirement that the amino group and
hydrogen atom are trans to each other "Scheme 46# ð49AP"172#25\ 41JCS042\ 47JA244\ 59OR"00#206Ł[ When
both b!hydrogen atoms are trans to the ammonium group\ elimination from the more substituted
position occurs "pathway "a##\ i[e[\ contrary to the Hofmann rule giving instead the Saytze} product[
Whenever a conjugated alkene may be formed the direction of elimination is that which produces
the conjugated product^ see for example Equation "011# where elimination of the cis hydrogen atom
occurs to form the conjugated alkene ð59JA3581\ 51JOC182Ł[
(121)
+
N N
Me Me Me Me
R1 R2
R1 = Me R1 = H
R2 = H R2 = Me
N b N+ a N
Me Me Me
Scheme 57
Ph
Ph
(122)
+NMe
3
The stereochemistry of the alkene formed in the elimination process depends on the substituents^
aliphatic alkenes such as 1!pentene and cyclooctene are formed as mixtures of cis and trans isomers
ð46JA3619\ 57JA4450\ 62OSC"4#204Ł\ while stilbene is formed as the more stable trans isomer ð21JCS0821Ł[
The stereochemical course of the reaction can be controlled by the trans coplanar stereochemical
requirement for the elimination "Equations "008a# and "008b## ð45JA689Ł[
Hofmann elimination has been used in the synthesis of dienes and trienes "Equation "012##
ð62OSC"4#597\ 81JCR"S#298Ł[ Equation "013# illustrates the use of the Hofmann elimination in the
synthesis of 1!vinyltryptamines ð81S272Ł^ higher yields were obtained by use of sodium hydroxide
rather than with silver oxide[
+
Br– NMe2CH2Ph
NaOH (aq.)
(123)
CN CN
+NMe I– NaOH, ∆
3 (124)
MeOH (aq.)
N 92% N
H H
0[03[2[1[1 Elimination of quaternary ammonium salts on treatment with base

When quaternary ammonium halides are treated with a strong base\ e[g[\ potassium amide or
phenyllithium\ elimination of the amine occurs to form an alkene ð46LA"501#091Ł[ However this is
Nitroèn 518
mechanistically quite di}erent to the Hofmann elimination as it is an a?\b!elimination proceeding
via an ylide "Scheme 47# ð60JA6007\ 61JA7597\ 63CC708\ 63CC719\ 80JA3601Ł[ Products of syn elimination
are usually formed in this elimination process^ therefore the alkenes may be isomeric to those
obtained in the Hofmann elimination which generally proceeds in an anti fashion[ The mechanism
of the elimination is dependent on the conditions employed^ while treatment of cyclooctylammonium
iodide with dimsyl anion in DMSO results in elimination via an ylide intermediate\ use of potassium
t!butoxide in DMSO leads to E1 elimination ð68TL2704\ 80JA7710Ł[ The regiochemistry in the elim!
ination of trimethylammoniumalkyl ethers\ as their iodide salts\ on treatment with aqueous sodium
hydroxide has been studied ð76ZOR0559Ł[
Me Me
+ n + n
N Bu BuLi N Bu
Me I– CH2 + Me2NBun
–
pentane
H
Mixture of cis and trans isomers
Scheme 58
The aziridinium ion shown in Equation "014# underwent eliminative cleavage in addition to
substitution on treatment with base ð77JOC0622Ł^ in less!substituted aziridinium ions only sub!
stitution is observed[
Me + Me
N CD3O–
TfO– NMe2 + NMe2 (125)
CD3O
66.5% 33.5%
Elimination of pyridines from pyridinium cations to form alkenes has been investigated
ð80JA5849Ł\ for example in the synthesis of 1!vinylthiophene ð52OSC"3#879Ł[ Base!induced elimination
"dbu# of pyridine from a pyridinium salt has been used in a sequence for the a!alkoxyalkylation of
a\b!enones via pyridiniosilylation ð80TL1932Ł[ Base!induced elimination of related systems such as
isoquinilinium cations has also been investigated ð78JA1147Ł[ Katritzky et al[ developed a mild
alternative to the Hofmann elimination which involves conversion of primary amines\ bearing
primary or secondary alkyl groups\ to a pyridinium salt "Scheme 48# which subsequently undergoes
elimination to form the alkene ð70CC85Ł[ With primary alkyl groups\ elimination occurs on heating
to 049Ð079>C ð71JOC2495Ł\ but with secondary alkyl groups elimination occurs at 19>C via a
carbonium ion intermediate ð71JCS"P0#1236Ł[
Elimination of b!silyltetraalkylammonium salts can be brought about on treatment with caesium
Ph Ph
R2
+ X– + + X–
O NH2 N
R1
R1
Ph R2
R2
+
N
R1
X = BF4, OTf; R1 = H, alkyl; R2 = alkyl, aryl
Scheme 59
~uoride ð71JA6555Ł in a silyl equivalent of the Hofmann elimination "Equation "015## "see Section
0[03[4[0[2#[
Me + Me TBDMS
N
CsF
I– (126)
77% Me
N
Me
0[03[2[2 Alkenes from Arenesulfonylhydrazones
0[03[2[2[0 The BamfordÐStevens and Shapiro reactions

Decomposition of toluene!p!sulfonylhydrazones\ bearing a!hydrogen atoms\ with strong bases to
form alkenes was _rst reported by Bamford and Stevens ð41JCS3624Ł[ This important transformation
of an aldehyde or ketone to an alkene via its hydrazone derivative "Scheme 59# has been thoroughly
investigated and widely applied in alkene synthesis since that time[ Excellent reviews of this trans!
formation have appeared in the literature ð65OR"12#394\ 72ACR44\ 89OR"28#0Ł[ The original conditions
employed were sodium in ethylene glycol\ i[e[\ protic conditions^ an aprotic version of the BamfordÐ
Stevens reaction is also possible using solvents such as DIGLYME[ The most commonly employed
base is sodium alkoxide but sodium hydride ð55LA"580#30Ł\ lithium hydride ð56BSF564Ł\ sodium
amide ð55LA"580#30Ł and lithium aluminum hydride ð51TL0150\ 53G426\ 54CB2125\ 74JOC4359Ł have also
been used to decompose the hydrazones to form alkenes[ Decomposition of dihydrazones by alkali
has been reported ð56JCS"C#0853Ł[
O NNHTs
base
R1 R1 R1
R2 R2 R2
Scheme 60
Perhaps the most signi_cant development in terms of the synthetic utility of the transformation
was the discovery that alkyllithiums ð56JA4623\ 56JA4625Ł may be used to decompose the toluene!p!
sulfonylhydrazones to form vinyllithiums which give alkenes on protonation^ this modi_cation
became known as the Shapiro reaction[ The synthetic utility of the Shapiro reaction was enhanced
by extension to "1\3\5!triisopropylbenzene#sulfonylhydrazones "trisylhydrazones# which fragment
more rapidly to form alkenes than tosylhydrazones and obviate the necessity for excess base
ð67JOC036Ł[ In 0881\ use of N\N!diethylaminosulfonylhydrazones in the Shapiro reaction was
reported ð81MI 003!90Ł[ While the Shapiro reaction is in general extremely useful and successful\ if a
large excess of alkyllithium is employed\ substitution can compete with elimination ð58CC0284Ł[ This
side reaction can also occur with highly a!substituted derivatives ð89OR"28#0Ł[ With tosylhydrazones
derived from aldehydes\ addition of the alkyllithium to the azomethine bond occurs rather than
elimination to form the alkene as illustrated in Scheme 50 ð66TL024Ł\ representing a major limitation
of the Shapiro methodology[ Tosylhydrazones containing only tertiary a!hydrogen atoms do not
undergo elimination on treatment with alkyllithiums leading instead to substitution products
ð64TL0700\ 65OR"12#394Ł^ however by use of LDA in place of the alkyllithium\ trisubstituted alkenes
can be prepared "Equation "016## ð67JOC0393Ł[ LDA has also been employed in the synthesis of
disubstituted alkenes "Equation "017## ð76JOC2235Ł[
ButLi, THF, –22 °C

Ph NNHTs Ph But Ph But
61%
NLi
LiN
Ts
Scheme 61
Nitroèn 520
NNHTs
LDA, TMEDA
(127)
54%
O
O O
i, TsNHNH2, HCl
(128)
O H ii, LDA O H
77%
O-TBDMS O-TBDMS
O O
The products obtained from the BamfordÐStevens reaction frequently depend on the solvent
employed ð57JA420Ł\ the nature of the base ð56JA360\ 56JA0331Ł and the number of equivalents of
base present ð48T294\ 54JA548Ł[ The reaction is believed to proceed initially to form a diazo compound
then via either a carbene or carbocation intermediate ð61JA6970Ł with subsequent formation of
alkenes from these intermediates "Scheme 51# "discussed in detail in ð65OR"12#394Ł#[ The carbocation
mechanism is frequently found under protic conditions while the carbene mechanism is found in
aprotic conditions^ however\ there are exceptions to this generalization[ With simple unbranched
ketones "e[g[\ cyclohexanone# good yields of alkenes may be obtained "Equation "018## ð58T2096Ł\
but with branched ketones or strained cyclic ketones\ rearranged products or insertion products are
often present in the reaction mixtures thereby limiting the synthetic utility of the BamfordÐStevens
reaction ð41JCS3624Ł[ However\ the reactions of cyclopropanecarboxaldehyde tosylhydrazones under
aprotic conditions have proved useful in the synthesis of cyclobutene derivatives "Equation "029##
ð54CB3911Ł[ In contrast to the BamfordÐStevens reaction where rearranged products are commonly
obtained\ the Shapiro reaction generally leads cleanly to unrearranged alkenes ð56JA4623Ł\ even in
neopentyl and highly strained systems ð57JA799Ł\ and is therefore much more useful synthetically
"Equation "020## ð60JCS"C#2062Ł[
:
Carbene-derived
R1 R2 products
NHTs – NTs
N base N –Ts– N2
–N2
R1 R2 R1 R2 R1 R2
N2+ + Carbonium
R1 R2 ion-derived
R1 R2 products
Scheme 62
TsHNN R2 R2
NaOMe
(129)
DIGLYME
R1O R1O
H H
NNHTs
NaOMe
+ fragmentation products (130)
DIGLYME
H H
NNHTs
MeLi
(131)
The regiochemical outcome of the tosylhydrazone decomposition also depends on the reaction
conditions "Scheme 52#[ While the BamfordÐStevens reaction in general leads to the more!substituted
alkene ð59JA523\ 53JOC1677Ł\ under Shapiro conditions the less!substituted alkene is almost always
the exclusive product ð56JA4623Ł^ in the methyllithium!induced decomposition of the hydrazone
derived from phenylacetone\ the terminal alkene is produced rather than the conjugated product
ð65OR"12#394Ł[ The regioselection of the Shapiro reaction was important in Paquette|s synthesis of
precapnelladiene "Equation "021## ð74JA6241Ł[ The mechanism which is believed to operate for the
Shapiro reaction is shown in Scheme 53 ð63JOC1291\ 72ACR44Ł[ Thus the alkyllithium transforms the
tosylhydrazone to the dianion\ loss of tosylsul_nate and nitrogen produce the vinyllithium which
gives the alkene on protonation[ In ether or hydrocarbon solvents\ the dianion formed is almost
invariably the syn dianion ð64TL0700Ł "except for a\b!unsaturated ketones ð66JA2303Ł# which there!
fore controls the regiochemistry of the product "Scheme 54#^ however\ in strongly cation!coor!
dinating solvents such as TMEDA ð67JOC036Ł\ the directional in~uence of the nitrogen anion no
longer operates and the least substituted vinyl anion is produced instead[ However Trost and
Nanninga have observed the formation of a mixture of regioisomers on treatment of the tosyl!
hydrazone shown in Equation "022# with alkyllithiums ð74JA0182Ł^ the ratio of regioisomers
depended on the nature of the alkyllithium and the solvent[
NaOMe + + other products

N-methylpyrrolidone
∆
NNHTs 63% 27% 10%
MeLi, Et2O <2% >98% -

RT
Scheme 63
BunLi
NHTs + (132)
N DIGLYME
H H H
3:1
E+
N – N – N – Li
NTs –H+ NTs –Ts– N –N2
Li+ Li+ Li+ H2O
Li Li
Scheme 64
–
TsHN TsN
N N
R1 R2 R1 R2 R1 R2
–
–
NHTs NTs
N N
R1 R2 R1 R2 R1 R2
–
Scheme 65
Nitroèn 522
N NHTris Li Li
RLi
+ (133)
Tris = 2,4,6-triisopropylbenzenesulfonyl
The Shapiro reaction produces selectively the "E#!vinyllithium\ thereby leading to the cis alkene
ð57TL234Ł\ as illustrated in Equations "023# ð67JOC036Ł and "024# ð71OM0338Ł^ however\ if branching
is present at the a?!position\ the degree of stereoselection is reduced considerably[ Investigation of
the stereochemical preference in eliminations in medium!size rings "6Ð04 atoms# has demonstrated
that the ratio of cis!to!trans isomers depends on the ring size ð64T0924Ł[ In the LDA!induced
formation of trisubstituted alkenes there is also a stereochemical preference for the formation of
the cis isomer ð67JOC0393Ł[ A low trans!to!cis product ratio was reported in the BamfordÐStevens
reaction indicating a low degree of stereoselection in this process ð59JA523Ł[ Marshall et al[ dem!
onstrated that in large rings\ the BamfordÐStevens reaction also leads to a mixture of cis and trans
isomers ð73JA5995Ł[
Li
(134)
NNHTris Et
NNHTris Li
BunLi, TMEDA/hexane
(135)
When applied to a\b!unsaturated ketones the Shapiro reaction leads to diene formation ð57JA3651\
71TL2622Ł[ Applicationof this diene formation in a synthesis of compactin is illustrated in Equation
"025# ð76JOC2430Ł[
OH OH
OAc OH
H H
MeLi
(136)
NNHTs
Originally the Shapiro reaction was limited to the formation of simple alkenes by protonation
of the alkenyllithium ð56JA4623Ł[ Later it was discovered that trapping of the vinyllithium with
electrophiles other than a proton can be achieved if the vinyllithium is generated using an excess of
BunLi in TMEDA ð64TL0704\ 65TL1836Ł\ or alternatively by use of "1\3\5!triisopropyl!
benzenesulfonyl#hydrazones ð67JOC036Ł which fragment very rapidly "use of this derivative obviates
the necessity for excess base#[ The alkenyllithiums thus formed have been trapped by a very wide
range of electrophiles "e[g[\ alkyl halides\ DMF\ CO1\ aldehydes\ silyl chlorides\ etc[# ð89OR"28#0Ł
"Equation "026## ð65TL1176Ł[ The versatility of the Shapiro reaction is extended further by the ability
to alkylate the dianion prior to fragmentation by keeping the temperature of the reaction below
that required for the fragmentation "typically 9Ð19>C#^ subsequent addition of a further equivalent
of base brings about the elimination reaction "Scheme 55# ð67JOC0398\ 79JOM"075#044\ 70JCS"P0#1737\
70JOC0204Ł[ Shapiro and Lipton have demonstrated the application of this methodology in the
synthesis of homoallylic alcohols "Scheme 56# ð67JOC0398Ł[ Notably the elimination from the trianion
occurs preferentially in the direction away from the oxygen atom in the b!hydroxytosylhydrazones
ð67JOC0398Ł[
NNHTs i, BuLi CHO

ii, DMF
(137)
iii, H2O
60%
– –
NHTris NTris NTris
N 2BunLi N R1R2CO N BunLi
–78 °C –78 °C to –50 °C –78 °C

–
R1 O–
R2
–
NTris
N Li O
–78 °C to 0 °C i, CO2
–
O
ii, TFA
R1 O– R2
R1 O–
R2 R2 R1
33–66%
Scheme 66
–
NNHTs i, RLi, THF NNTs i, RLi
ii, MeCOMe ii, H+ OH
O–
Scheme 67
When applied to a!keto amides "Scheme 57# the Shapiro reaction generates the dianion which
protonates or alkylates at carbon\ thereby acting as a synthon for the propenoic acid anion ð70CC54\
70T2824Ł[ Baldwin and Bottaro used a Shapiro reaction on an amide derivative to produce an acyl
anion equivalent "Equation "027## ð70CC0010Ł[
–
NHTris NTris
N N O– E
– E+
NHR N • NHR
– R NR
–
O O O
E = H+, alkyl halide, aldehyde, ketone, etc.
Scheme 68
NNHTris Li
Ph ButLi Ph
N N (138)
THF
O O
The Shapiro reaction has been employed for the synthesis of polycyclic alkenes "Equation "028##
ð76JOC1533\ 76TL0874\ 76TL5048Ł\ while a triple Shapiro degradation was employed in the synthesis of
ð3[3[3Łpropellahexaene ð76JA2063Ł[ When the hydrazone bears a leaving group in the a!position\
elimination occurs at the monoanion stage to form a tosylazoalkene^ this may be employed for the
preparation of lithioalkadienes "Scheme 58# ð70JA4203Ł[ With the tri~uoromethyl derivative shown
in Equation "039# elimination occurred to form the di~uoroallene ð78JFC"33#050Ł[
H H H
MeLi, Et2O
+ (139)
0 °C
TsHNN
H H H
NNHTris F R
BuLi
R • (140)
F3C –78 °C to 0 °C F
45–80%
R = H, alkyl, Ph
Nitroèn 524
NTs
NNHTs N Li
Br Et3N MeLi
–78 °C
But But But
Scheme 69
0[03[2[2[1 Alkenes from hydrazones by alternative routes

Tosylhydrazones of a\b!unsaturated carbonyl compounds can be transformed to alkenes in which
the double bond has migrated towards the carbon centre which was originally the carbonyl carbon
atom\ on treatment with sodium cyanoborohydride in acidic conditions ð64JOC812\ 65JA1164\
67JOC1188\ 68OPP190\ 73JA2242\ 74JOC1687Ł\ or catecholborane ð65JOC463\ 79OS"48#31\ 75JA5165\ 75JA6575Ł[
The reaction is believed to proceed via a 0\4!sigmatropic rearrangement in an intermediate diazene
as illustrated in Scheme 69[ The migration occurs cleanly even if the double bond is moving out of
conjugation and proceeds stereoselectively to furnish the "E# isomer as the major product[ The
transformation can prove useful in preparing less!substituted alkenes\ in moving double bonds out
of conjugation "see\ for example\ Equation "030## ð64JOC812Ł and in moving an endocyclic double
bond to an exocyclic position[
NaBH3CN –TsH –N2

+
NHNHTs NHNHTs H
N N
Scheme 70
O
i, TsNHNH2
(141)
ii, NaBH3CN, HCl
DMF-sulfolane
65–70%
While 0\1!dihydrazones are converted to alkynes by treatment with reagents such as Ag1O\ HgO
or Cu"II#:O1:pyridine ð42JA1042\ 69TL650\ 72T2168Ł\ formation of a small amount of an alkene has
been observed ð69TL650Ł[
0[03[2[3 Elimination of Amine Derivatives

Elimination of amines under conditions other than those employed for the Hofmann and Cope
reactions is also possible[ Deamination in Mannich bases has been discussed in a review ð89T0680Ł[
This is a particularly facile process in b!amino ketones and other carbonyl derivatives^ for example\
Equation "031# illustrates the elimination of azetidine to form an a\b!unsaturated carboxylic acid
ð62OS"42#02Ł\ while Equation "032# illustrates the elimination of dimethylamine to form func!
tionalized decalin derivatives ð89HCA539Ł[ The stereochemistry of the elimination of the secondary
amine illustrated in Equation "033# is dependent on the conditions employed ð77BCJ2100Ł[
CO2Et
KOH CO2K
N N H + + EtOH (142)
R R R
R R R
–Me2NH
+ (143)
NMe2
R = CO2Me or CN
H Ph Ph CO2Me Ph COPh
–R2NH
MeO2C NR2 + (144)
PhCO H COPh CO2Me
MeCN, 20–60 °C 100% 0%

AcOH 51–62% 38–49%
R2 = –(CH2)4–, –(CH2)5–, –(CH2)6–
Secondary amines are readily transformed to a magnesium amide which decomposes on heating
to 049Ð149>C to form an alkene "Scheme 60# ð67JOC3649Ł[ The elimination follows syn stereo!
chemistry and is believed to proceed via a six!membered cyclic transition state as shown "Scheme
60#[ A similar reaction occurs with zinc and aluminum amides[ An amine bearing a b!chloro
substituent eliminates on treatment with magnesium ð52JOC767Ł[
NH N–MgMe NMg NH2
Me2Mg ∆ H2O
+ CH4 +
–CH4
2 2
N
Mg
Me
H
Scheme 71
Primary amines\ bearing secondary alkyl groups\ on transformation to N\N!disulfonimide deriva!

tives followed by pyrolysis "059Ð199>C# eliminate very cleanly to form alkenes with good stereo!
control "Scheme 61# ð70TL088Ł[
SO2Ar
NH2 N SO2Ar
p-NO2C6H4SO2Cl (2 equiv.)
SO2Ar ∆
+ H N
base SO2Ar
Scheme 72
Elimination of aziridines to form alkenes has been reviewed ð79T446Ł[ On nitrozation with a
variety of reagents\ such as n!butyl nitrite or nitrosyl chloride\ aziridines deaminate to form alkenes
with retention of the stereochemistry of the aziridine in the product "Equation "034## ð53JOC0205\
58TL3990Ł[ Treatment of aziridines with di~uoroamine leads to alkene formation with a similar
retention of stereochemistry ð56JA0650Ł[ Oxidation of N!aminoaziridines with manganese dioxide
again results in alkene formation^ the stereochemistry of the aziridine is not retained when phenyl
substituents are present ð69JA0673Ł[ N!Alkylaziridines can be deaminated by reaction with mcpba
"Equation "035## ð69AG"E#263Ł\ ferrous iodide ð63CL054Ł\ dichlorocarbene ð61TL2716Ł or the copper
carbenoid derived from ethyl diazoacetate ð61TL3548Ł[ The reaction with mcpba presumably pro!
ceeds via an N!oxide intermediate[ When conducted in benzene in the dark\ this reaction proceeds
stereospeci_cally and produces the alkene e.ciently^ in dichloromethane both the yield and stereo!
speci_city are much lower[
Nitroèn 526
H
N BunONO
(145)
58% Ph Ph
Ph Ph
Ph
N mcpba
(146)
85–90% PhOC COPh
PhOC COPh
Elimination of amides to form alkenes ð59CRV320\ 59OR"00#206Ł can occur on pyrolysis with
ð33JCS211\ 35JA491\ 38JCS0963Ł or without ð47JOC885Ł phosphorus pentoxide[ An example of this
elimination in a colchicine derivative is shown in Equation "036# ð33JCS211Ł[ In the reaction with
P1O4\ formation of a nitrile from the amido group is likely\ while in the absence of P1O4 the reaction
appears to be analogous to acetate pyrolysis\ proceeding with similar regiochemistry^ however\
higher temperatures are required for amide elimination ð47JA3477\ 48JA540Ł[ Acetamides in which
the nitrogen atom bears a tertiary alkyl group eliminate on re~uxing in 04) HCl ð37JA3934Ł[
MeO MeO
NHCOMe P2O5, xylene
(147)
MeO ∆
MeO
OMe OMe
OMe OMe
Deamination of amines with nitrous acid frequently results in the formation of alkenes "among
other products#\ via elimination in intermediate diazonium or carbonium ions ðB!57MI 003!92Ł^ an
example is shown in Equation "037# ð78JOC4313Ł[ However\ rearrangements are common ð78CB278Ł
and this process is rarely synthetically useful[ Elimination of nitrogen from diazoalkanes also leads
to alkenes ðB!75MI 003!93\ 76TCC64Ł^ for example the a!diazoester shown in Equation "038# leads to
the cis!enoate on catalytic decomposition with rhodium"II# acetate ð69CJC1009\ 70TL3052Ł[ Thermal
decomposition of N!nitrosoacetamides "readily prepared from amines# leads to diazoalkanes^ if this
thermolysis is conducted in the presence of rhodium"II# acetate the diazoalkane is intercepted
forming rhodium carbenoids^ a 0\1!hydrogen migration then leads to alkenes "Scheme 62#
ð89JA2606Ł[ Palladium!catalysed decomposition of 2\2!pentamethylenediazirine a}ords cyclohexene
"Equation "049## ð89JMOCL0Ł\ presumably via a carbene intermediate[
nitrous acid or
NH2 OH +
sodium nitroprusside
+ + (148)
OH trans:cis 4: 1
CO2Me Rh2(OAc)4 Pri CO2Me

(149)
N2 benzene
99%
N PdII
N (150)
80%
0[03[2[4 Elimination of Nitro Groups

Nitrous acid elimination may be e}ected thermally from quaternary nitroalkanes ð77TL1794\
78BSF398\ 89JOC4790Ł
or from an angular tertiary nitro group on contact with silica gel or neutral
alumina ð73JOC569Ł or by treatment with a base\ for example\ sodium methoxide ð60JA3205Ł[
Thermal elimination of nitrous acid from quaternary nitroalkanes proceeds selectively to give the
COMe
NH2 i, Ac2O/py N benzene N2 Rh2(OAc)4
ii, N2O4, CH2Cl2 NO ∆
RhLn
78%
Scheme 73
less!substituted alkene "Equation "040## ð77TL1794Ł[ Notably\ thermal nitrous acid elimination
produces b\g!unsaturated esters in good yields with no evidence of double!bond migration
ð89JOC4790Ł[
∆
NO2
But But + But (151)
–HNO2
20% 73%
Treatment of b!substituted nitro compounds with tributyltin hydride produces alkenes via a
radical elimination*this has been observed with b!nitrosul_des as illustrated in Equation "6#
ð73TL4208Ł\ b!nitrosulfones as shown in Scheme 33 and Equation "66# ð70CL0028\ 76JOC4000\ 77JOC140Ł
and b!dinitro compounds ð70CL0028Ł[ Formation of "E#!allyl alcohol derivatives in a stereoselective
fashion by elimination of b!nitrosul_des is shown in Equation "6# ð77CC0167Ł[ The elimination of
the nitro and sul_de:sulfone groups occurs stereospeci_cally in an anti conformation "see Sections
0[03[1[0[0 and 0[03[1[2[0# while the elimination of a dinitro compound is nonstereospeci_c as
illustrated in Equation "041# ð70CL0028Ł[ Elimination of b!dinitro compounds to form tetra!sub!
stituted alkenes can also be achieved by use of sodium sul_de ð60JA3205Ł or calcium amalgam
ð66JOC1833Ł[ Tin"II# chloride e}ects elimination in a\b!diaryl vicinal dinitro compounds but not in
the corresponding aliphatic compounds ð68BCJ0096Ł^ the reaction is believed to proceed via a radical
anion intermediate[ Only the trans alkene is produced irrespective of the stereochemistry of the
starting material[ Best results are obtained by use of an excess of tin"II# chloride in ethanol\ although
DMF may also be employed for this transformation[ In contrast to the eliminations under free!
radical conditions\ thermolysis of symmetrical dinitrotetraalkylethanes forms alkylated 0\2!buta!
dienes by elimination of nitrous acid ð77C095Ł[
O2N Et Et
Bu3SnH, AIBN
(152)
Ph NO2 Ph
(E):(Z) 1:1
0[03[3 BY ELIMINATION OF PHOSPHORUS\ ARSENIC\ ANTIMONY OR BISMUTH

FUNCTIONS
0[03[3[0 Elimination of Phosphorus Groups

Elimination of phosphorus groups almost always involves concurrent loss of b!oxygenated
groups^ the a.nity of phosphorus for oxygen is largely responsible for this reactivity[ The most
widely employed alkene formation involving elimination of phosphorus groups is the Wittig reaction
ð42LA"479#33Ł and modi_cations thereof[ As these transformations are discussed in detail in Chapter
0[05 only the elimination step in these processes will be described here[ Many reviews of these
extremely useful reactions have appeared "for example ð52QR395\ 54OR"03#169\ 63CRV76\ 66OR"14#62\ B!
68MI 003!90\ 78CRV752Ł#[
Phosphorus\ Arsenic\ Antimony or Bismuth 528
0[03[3[0[0 Elimination of phosphine oxide*the Wittig reaction
Elimination of a phosphine oxide from a phosphonium betaine\ formed by condensation of a
phosphonium ylide with an aldehyde or ketone\ is believed to proceed via an oxaphosphetane
intermediate "Scheme 63#[ The relative importance of betaine versus oxaphosphetanes as inter!
mediates has been studied in detail ð78CRV752Ł\ and it appears that oxaphosphetanes are more likely
as genuine intermediates even though some evidence for the existence of the betaine intermediate
has been obtained\ for example when benzaldehyde is treated with methylenetriphenylphosphorane
the zwitterion could be isolated as its hydrobromide[ Treatment with base regenerates the betaine
which decomposes on heating to 54>C to give triphenylphosphine oxide and styrene ð43CB0207Ł[ As
the elimination occurs in a syn fashion the stereochemistry of the resulting alkene is dependent on
the stereochemistry of the betaine[ Thus the erythro diastereomer of the betaine leads to the cis
alkene while the threo leads to the trans alkene "Scheme 64# ð57AG"E#549Ł[ Therefore the stereo!
chemical outcome of the Wittig reaction is dependent on the factors which control the stereo!
chemistry and reversibility of the formation of the zwitterion "see for example ð53AG"E#149Ł#[ While
"Z# isomers are preferred from reactions with {nonstabilized| ylides\ mixtures of "Z#! and "E#!isomers
are commonly obtained[
+ R1 R1
R1 O Ph3P R2 R2 R1
+ Ph3P R2 O
Ph3P – + +
O R3 PPh3
R2 R3 R4 –O R3 R3 R4
R4 R4
Scheme 74
O– R1
+PPh
3
H R2
H R1 R2
–
O erythro cis
+
Ph3P+ R1
R2
O– R1
+PPh
3
H R2
R1 H R2
threo trans
Scheme 75
0[03[3[0[1 Extension to phosphoryl derivatives*the HornerÐWadsworthÐEmmons modi_cations

Carbanions obtained by deprotonation of phosphine oxides\ R1P"O#CH1R\ phosphinates\
RP"OR#"O#CH1R\ or phosphonates\ "RO#1P"O#CH1R\ may be used in place of the phosphonium
ylide in the Wittig reaction resulting in elimination of phosphinate\ phosphonate or phosphate
anions\ respectively ð47CB50\ 48CB1388\ 63CRV76\ 66OR"14#62Ł[ The phosphinate modi_cation has
received little attention as the carbanions are more di.cult to prepare than either of the other two[
Use of phosphonates can o}er considerable advantage over the Wittig reaction ð50JA0622Ł\ for
example\ ease of workup\ availability of reagents and convenient reaction conditions[ Mech!
anistically these reactions are believed to be similar to the Wittig reaction again proceeding via a
four!membered cyclic transition state possessing some double!bond character "Scheme 65#
ð63CRV76Ł[ There is strong evidence for the existence of the intermediate oxyanion^ in some cases\ the
protonated forms\ b!hydroxyphosphonates\ are isolated from the reaction instead of the elimination
products "Scheme 66# ð55JA4543Ł[ E.cient elimination occurs only if the phosphonate bears an
electron!withdrawing group a to the phosphorus atom\ i[e\ R0 or R1\ to activate the intermediate
"Equation "042## ð57CC0588Ł[ The stereochemistry of the alkene resulting from the Horner or
WadsworthÐEmmons modi_cations is controlled by the stereochemistry in the intermediate oxy!
anion as the elimination occurs in a syn manner\ similar to the Wittig reaction[ However trans
alkene formation predominates in the phosphoryl reactions^ reversibility in the formation of the
oxyanion eventually results in the formation of the thermodynamically more stable isomer
ð66OR"14#62\ 73T4042Ł[ Use of barium hydroxide as the preferred base for a HornerÐWadsworthÐ
Emmons reaction with a base!sensitive aldehyde has been reported ð82SL663Ł[
O – 1
O R1 X O R
O P R2
P – R1 X Y P R2
X + Y
Y R3 R4 O R3
R2 –O R4
R3 R4
O R2 R1
P +
X O–
Y R3 R4
X, Y = alkyl, alkoxy
Scheme 76
O i, BunLi O OH
ii, Ph2CO Ph Ph
P P
MeO MeO Ph
MeO iii, H2O MeO Ph
Scheme 77
O
P CO2Et + R–CHO CO2Et (153)
EtO R
EtO –
0[03[3[0[2 Elimination of phosphonium groups

Unlike ammonium salts\ phosphonium salts decompose to give a hydrocarbon and phosphine
oxide rather than an alkene ð18JCS1231\ 59OR"00#206Ł[ However betaines\ like those formed as inter!
mediates in the Wittig reaction\ undergo elimination of phosphine oxide to form alkenes[ These
betaines may be formed from epoxides by treatment with triphenylphosphine ð44CB0543Ł or
diphenylphosphide followed by quaternization with methyl iodide ð60JA3969\ 62JA711Ł[ As the epox!
ide ring opening to form the betaine occurs with inversion of con_guration followed by syn
elimination of the phosphine oxide\ this results in an overall change of stereochemistry of the alkene
unit as illustrated in Scheme 67\ and therefore may be used for isomerization of alkenes ð79T446Ł[
"Alternatively the b!hydroxy phosphine derivatives formed by epoxide ring opening with diphenyl
phosphide can be oxidized to the corresponding phosphine oxide prior to elimination with sodium
hydride ð63CC031Ł as discussed below[# Both di! and trisubstituted alkenes can be formed under
these conditions^ trans!cyclooctene and cis\trans!0\4!cyclooctadiene are produced with ×88[4)
stereospeci_city from the corresponding cis epoxides ð60JA3969Ł[ However\ formation of trans!
cycloheptene was not possible ð60JA3969Ł^ whereas betaine decomposition usually occurs at 14>C\
the betaine derived from cycloheptene oxide is stable at this temperature[ On re~uxing in THF
elimination occurs to form the vinyl phosphonium salt "Scheme 68#[ If dbu is present\ then cis!
cycloheptene is also formed[ Clearly the four!membered cyclic transition state required for syn
elimination is not easily accessible in the seven!membered ring[ While the diphenylphosphide
reaction may be conducted with keto epoxides under carefully controlled conditions\ the presence
of an ester group is not compatible with the reaction conditions\ as the anion attacks the ester group
ð62JA711Ł[
An unusual elimination from a phosphonium ylide believed to proceed via an oxaphosphinane
has been reported ð78CC0353Ł[
+
–O H –O PPh2Me
O i, LiPPh2 25 °C
n-C5H11 ≡ n-C5H11
n-C5H11 ii, MeI H
+
H
PPh2Me H
n-C5H11 + P
Me Ph
77% Ph
Scheme 78
+
PPh3
I–
THF
O– ∆
O +
i, LiPPh2
PPh3
ii, MeI dbu, THF
+
∆ PPh3
+ I–
30–45% ~50%
Scheme 79
0[03[3[0[3 Elimination of b!hydroxy phosphine oxides

Syn elimination of b!hydroxy phosphine oxides on treatment with sodium hydride may be
employed for alkene isomerization as illustrated in Scheme 79 ð63CC031Ł[ This modi_cation of
Vedejs| method ð60JA3969\ 62JA711Ł has the advantage that the diphenylphosphinate salt produced
in the elimination is water soluble\ thereby facilitating workup[
O
R R H PPh2 R O
R R i, Ph2PLi NaH, DMF
R H + P
–O Ph
O ii, AcOH, H2O2 HO R R Ph
Scheme 80
Warren and co!workers have developed stereoselective syntheses of alkenes by elimination of

phosphinate anions from b!hydroxy phosphine oxides ð70CC099\ 72TL000\ 72TL4182\ 77JCS"P0#0688Ł[
Addition of the lithium derivatives of alkyl diphenylphosphine oxides to aldehydes forms the
phosphinoyl alcohols\ predominantly as the erythro diastereomer\ in good yields[ Isolation of the
alcohol as a single diastereomer is possible[ Syn elimination occurs on treatment with sodium
hydride in DMF at 49>C to form the "Z# alkene "Scheme 70# ð70CC099\ 73JCS"P0#132Ł[ When a
secondary alkyl phosphine oxide is employed\ a mixture of diastereomers is formed^ however\ these
may be separated and eliminated separately to produce both the "E#! and "Z#!trisubstituted alkenes
as single isomers ð72TL000Ł[ Alternatively\ trisubstituted alkenes can be formed by reaction of
primary alkyl phosphine oxides with ketones\ as in a synthesis of "Z#!a!bisabolene "Scheme 71#
ð72TL000Ł[ However\ this approach can lead to di.culties in some cases^ for example\ one hydroxy
phosphine oxide adduct reverted to starting materials on treatment with base while another decom!
posed rapidly even at −49>C preventing diastereomer separation and thereby producing alkene
mixtures[
An alternative approach to b!hydroxy phosphine oxides involves the reduction of b!keto phos!
phine oxides with sodium or lithium borohydride^ this produces the opposite stereoisomer to that
described above ð74JCS"P0#1296Ł[ b!Keto phosphine oxides "readily obtained by acylation of alkyl
phosphine oxides with esters or lactones# give the threo alcohols selectively^ these can be puri_ed to
a single diastereomer and eliminated to form the "E# alkene as shown in the synthesis of fenicullin
"Scheme 72# ð70CC099\ 72TL4182Ł[ With secondary alkyl phosphine oxides\ acylation with esters is
i, BunLi H H
Ph2P NaH, DMF R
R
O ii, RCHO
Ph2P OH
O
erythro
R = alkyl, aryl
Scheme 81
O
H
O Ph2P
i, BuLi NaH, DMF
Ph2P H
ii, O 91%
HO
53%
Scheme 82
ine.cient but on reacting the appropriate copper derivative with an acid chloride the keto derivatives
are readily obtained "Scheme 73# ð72TL000Ł[ Reduction of these ketones leads to a mixture of
diastereomers which are separable and therefore can be transformed to either the "E# or "Z# alkene[
Alternatively\ if a mixture of diastereomers of b!hydroxy phosphine oxides is formed by alkylation
with an aldehyde\ then oxidation to form the corresponding b!keto phosphine oxide followed by
stereoselective reduction can be employed to form the "E# alkene "Scheme 74# ð72TL4182Ł[
O
MeO2C Ph2P
O BuLi NaBH4
+
Ph2P 61% 74%
O O
O
O
H
Ph2P
NaH, DMF
HO
H 71%
O O
Scheme 83
Ph Ph
O O O O
i, BuLi, CuII NaBH4
Ph2P Ph Ph2P Ph Ph2P + Ph2P
ii, MeCOCl
64%
O HO H HO
H
Ph Ph
(Z) (E)
Scheme 84
Extension of this transformation to the synthesis of "Z# or "E# unsaturated carboxylic acids has
been undertaken via separation of intermediate diastereomeric lactones prior to elimination
O O
i, BuLi PDC, DMF
Ph2P Ph2P
ii, O 88%
HO
70%
O O
H
Ph2P Ph2P
NaBH4 H NaH
O 75% HO DMF
H 98%
Scheme 85
ð74TL494\ 75TL1154\ 77JCS"P0#0688\ 81JCS"P0#1044Ł[ Application of this methodology to the synthesis of

unsaturated alcohols ð73TL246\ 77JCS"P0#1860\ 81JCS"P0#2396Ł and dienols ð80JCS"P0#0374Ł has also been
reported[ Formation of an allyl sul_de ð72JCS"P0#0058Ł and conjugated dienes ð66JCS"P0#449\
66JCS"P0#0341Ł have also been observed[
The synthetic utility of this methodology is demonstrated in Wittman and Kallmerten|s synthesis
of oudemansins ð76JOC3292Ł whereby stereoselective formation of the desired alkene was achieved
by use of the lithium borohydride reduction "Scheme 75#^ use of the Wittig or WadsworthÐEmmons
reactions led to mixtures of alkene isomers[ Interestingly\ in this case the alkene formed directly on
reduction with lithium borohydride[
O O
Ph2P Ph2P OMe
R1 R1
i, BuLi LiBH4
ii, OMe O THF, 0 °C

R2 R2 ~30%
MeO2C
OMe
R1
R2
R1 = H, OMe; R2 = H, Cl
Scheme 86
0[03[3[0[4 Elimination of b!hydroxyphosphinothioic amides

Johnson and Elliott have demonstrated that b!hydroxyphosphinothioic amides\ on treatment
with methyl iodide in the presence of a base such as pyridine\ undergo syn elimination to form
alkenes ð71JA6930Ł[ This method has been employed for the methylenation of ketones and for the
preparation of di!\ tri! and tetrasubstituted alkenes[ As the diastereoisomeric b!hydroxyphos!
phinothioic amides can be separated prior to elimination\ the alkenes can be formed in isomerically
pure form "Scheme 76#[ Optical resolution in the alkene formation is possible by use of a homochiral
phosphinothioic amide ð71TL4994Ł[
0[03[3[0[5 Elimination of b!hydroxyphosphonic acid bisamides

This methodology has been developed by Corey and co!workers ð55JA4541\ 55JA4542\ 57JA5705\
58JOC2942Ł[
While b!hydroxyphosphonates\ or their anions\ do not eliminate to form alkenes unless
S S
Ph Ph
H P P
NMe2 NMe2
O
OH OH
S
+ P Li +
Ph
Me2N
86% 6%
(as mixtures of diastereomers at phosphorus)
MeI, py MeI, py
acetone acetone
78% 84%
Scheme 87
they bear an adjacent activating group "Scheme 66 and Equation "042## ð55JA4543\ 57CC0588Ł\ b!
hydroxyphosphonic acid bisamides decompose to form alkenes on heating via a syn elimination
ð55JA4541\ 55JA4542\ 57JA5705Ł[ This reaction can be used for the synthesis of mono!\ di!\ tri! and
tetrasubstituted alkenes^ the ease with which tetrasubstituted alkenes are formed is notable[ The b!
hydroxyphosphonamides can be prepared either by reaction of simple a!lithio phosphonamides
with aldehydes or ketones "the intermediate alkoxy anions do not eliminate# or by reduction of b!
ketophosphonamides^ as observed with the phosphine oxide derivatives opposite stereochemical
outcomes are obtained by these complementary methods leading to stereoselective synthesis of both
"E# and "Z# alkenes "Scheme 77#[ The phosphonamide route leads e.ciently to trans!0!t!butyl!0!
alkenes in contrast to the preference for formation of the cis isomer from the conventional Wittig
reaction[
O OH O
i, BunLi benzene Ph
P P
NMe2 ii, PhCHO Ph NMe2 ∆
NMe2 iii, H2O NMe2
98% 2.5:1 mixture of from the major diastereomer
diastereomers A and B
O O O OH O Ph
i, BunLi NaBH4 benzene
P P P
NMe2 ii, PhCO2Me Ph NMe2 80% Ph NMe2 ∆
NMe2 79% NMe2 NMe2
98% of diastereomer B
(above)
Scheme 88
Epoxide ring opening with the diamidophosphite anion also produces b!hydroxyphosphonamides
which can subsequently be transformed to alkenes by thermolysis ð58JOC2942Ł[ Evidence was
obtained that the elimination is syn\ proceeding via a betaine in a fashion similar to that observed
with b!hydroxy sul_namides "Scheme 78# ð57JA4442Ł^ thus opening of the epoxides derived from cis!
and trans!but!1!ene furnished the diastereoisomeric b!hydroxyphosphonamides which could be
eliminated to trans! and cis!but!1!ene\ respectively ð79T446Ł[
Application of the phosphonamide elimination to the synthesis of conjugated dienes has also
been demonstrated "Scheme 89# ð58JOC2942Ł[ Conditions had to be controlled to ensure a!alkylation
occurred as the adduct formed by g!alkylation did not eliminate[ The thermolysis was conducted in
mineral oil containing calcium carbonate to maintain neutrality in the reaction mixture[
Elimination of 0\1!diaryl!1!hydroxyethanephosphonamides under acidic conditions produced
styrene derivatives stereoselectively ð77PS"39#58Ł[
O O OH OH O–
P i, BuLi
(Me2N)2P ∆ (Me2N)2P +
Me2N H O R4 R4
Me2N ii, R1 R3 R3 R3
R2 R1 R2 R1
R2 R4
iii, H2O
OH O O
R2 R3
(Me2N)2P + P
R4 Me2N OH
R3 R1 R4 Me2N
R2 R1
a; R1 = H, R2 = Me, R3 = H, R4 = Me
b; R1 = H, R2 = Me, R3 = Me, R4 = H
Scheme 89
Me Me
ON O N
i, BunLi ∆
P P
N ii, R1R2CO N CaCO3
iii, H2O R1 R2
Me Me
R1 OH
R2
R1, R2 = H, alkyl, phenyl
Scheme 90
Chiral phosphonic diamides have been developed which exhibit high diastereoselectivity in their
reactions with substituted cyclohexanones "Equations "043a# and "043b## ð73JA4643Ł[
Me
N Et
P (154a)
O
N O
Me But
But
(R):(S) 95:5
Me
N Et
P (154b)
N O
Me But
(R):(S) 5:95
0[03[3[0[6 Elimination of phosphonothioate esters

While b!hydroxyphosphonates which do not bear an adjacent activating group\ or their anions\
do not eliminate to form alkenes ð55JA4543Ł as shown in Scheme 66\ the anions of b!hydroxyphos!
phonothioates eliminate under mild conditions "14>C is su.cient when conjugated alkenes are
formed# to form 0\0!disubstituted\ tri! or tetra!substituted alkenes "Scheme 80# ð55JA4543Ł[ The rate
of elimination is increased by silver"I# catalysis[ Only the anions of b!hydroxyphosphonothioates
derived from the reaction of aldehydes with dimethyl n!alkylphosphonothioates failed to eliminate[
Li+
S O– S Ph
i, BunLi Ph 6 h, 25 °C
P P
OMe ii, Ph2CO Ph OMe
OMe OMe Ph
93%
Scheme 91
0[03[3[0[7 Elimination of triethyl phosphate

Deoxygenation of epoxides can be e}ected with trialkyl phosphites ð46JOC0007Ł^ this trans!
formation is believed to proceed by epoxide ring opening with the phosphite followed by syn
elimination of "EtO#2P1O[ In contrast desulfurization of episul_des with trialkyl phosphite occurs
by attack of the phosphite on sulfur ð48JA467Ł[
0[03[3[1 Elimination of Arsenic\ Antimony and Bismuth Functions
0[03[3[1[0 Elimination of arsenic groups

Elimination of methyldiphenylarsine oxide from the trans!b!hydroxy arsonium salt on treatment
with sodium hydride leads to a mixture of alkene and epoxide "Equation "044## ð64CS8Ł[ Inves!
tigations of condensations of arsonium ylides with aldehydes have demonstrated that this behaviour
is typical of b!oxy arsonium compounds as discussed below[
OH
NaH
O + (155)
+ THF
AsPh2Me
1:2
Alkene formation by reaction of arsonium ylides ðB!69MI 003!90Ł with carbonyl compounds in a
Wittig!type reaction is well documented\ involving elimination of arsine oxide from a b!oxyarsonium
intermediate[ This area has been reviewed ð71AOC"19#004\ 76CSR34\ B!89MI 003!90Ł[ Alkenes and:or
epoxides are generated in reactions of arsonium ylides with carbonyl compounds*elimination of
arsine oxide is in competition with arsine displacement to form epoxides^ the product distribution
and the diastereoselectivity can be a}ected by the nature of the ylide\ the carbonyl compounds and
the reaction conditions[ Thus arsonium ylides display behaviour intermediate to that of sulfonium
ylides\ which lead to epoxides exclusively\ and phosphonium ylides\ which form alkenes only[
Arsonium ylides are more reactive than phosphonium ylides\ e[g[\ ~uorenylidenetriphenylarsorane
reacts with p!dimethylaminobenzaldehyde to give the alkene in excellent yield "Equation "045##\
whereas the corresponding phosphorus reagent failed to react with this aldehyde ð59JOC072Ł[ In the
arsonium ylide!mediated methylenation of benzophenone to form 0\0!diphenylethene\ diphenyl!
acetaldehyde is also obtained which may result from rearrangement of 0\0!diphenyloxirane
ð50JA306Ł[
CHO
+ (156)
97%
AsPh3 NMe2
Me2N
In general\ if the arsonium ylide is stabilized "with a carbonyl group for example#\ elimination of
arsine oxide to form alkenes is preferred^ nonstabilized ylides lead to epoxides instead ð61T232\
78CRV752Ł[ Formation of the "E#!alkene or trans epoxide usually predominates ð72TL3308\ 75TL3472\
76JOC2447\ 76TL1044\ 76TL1048Ł[ Semistabilized ylides may lead to products of either pathway] the
products may vary depending on the reaction conditions[ For example\ in the reaction shown in
Scheme 81\ epoxide formation predominated in the presence of a lithium salt while formation of
the "E#!alkene was preferred under salt!free conditions ð77BSB160Ł[
Ph O salt-free
+ Ph
Ph3As Ph
Ph
lithium salt
Ph Ph
cis:trans 17:1
Scheme 92
Huang et al[ ðB!89MI 003!90Ł have developed the synthesis of "E#!a\b!unsaturated aldehydes
ð74TL5336Ł\ ketones\ amides ð76TL1048\ 77TL2838Ł and polyenones ð76TL1044Ł by the reaction of
triphenylarsonium salts with aldehydes in the presence of a base[ Application to the synthesis of a
number of unsaturated natural products has been undertaken ð75TL3472\ 76JOC2447\ 77LA266\
77TL2838Ł^ Scheme 82 illustrates the use of this methodology in the synthesis of trichonine ð77LA266Ł[
Insect sex pheromones containing "Z\E#!conjugated dienes have been synthesized using a con!
densation with an arsonium salt to introduce the "Z# alkene followed by a Wittig reaction
ð76JOC2447Ł[ In addition\ a catalytic Wittig!type reaction catalysed by tri!n!butylarsine has been
developed which involves elimination of tributylarsine oxide in the catalytic cycle ð78JOC1916Ł[
+
+
Br– K2CO3, THF/Et2O Ph3As CON(CH2)4 Br–
CHO + CHO
( )14 Ph3As CHO n-C15H31 K2CO3, MeCN
trace H2O, 25 °C
90% trace H2O, 25 °C
97%
n-C15H31 N
Trichonine
Scheme 93
Alkene generation has also been observed on thermal decomposition of arsonium ylides^ the
mechanism is believed to involve elimination of an arsine fragment ð56ZOR487\ 76CSR34Ł[ Elimination
of triphenylarsine from 1\1\1!triphenyl!0\1!oxa!ars"V#olan on heating to form allyl alcohol has also
been reported ð56JCS"C#0988Ł[
0[03[3[1[1 Elimination of antimony and bismuth groups

Alkene formation involving elimination of antimony groups has also been investigated "reviewed
in ðB!69MI 003!91\ 76CSR34\ 81ACR071Ł#[ In 0859\ Henry and Wittig reported that only a trace of alkene
formation was observed in the reaction of a stibonium ylide with benzophenone ð59JA452Ł[ Later\
Lloyd demonstrated fulvene formation on reaction of triphenylstibonium tetraphenyl!
cyclopentadienylide with aryl aldehydes ð61T232Ł[ Reaction of tributylstibonium ylides with
aldehydes and ketones leads to alkene formation ð67TL3288Ł involving elimination of tri!
butylstibonium oxide "which readily forms a hydrate# from a b!oxy stibonium intermediate "Scheme
83# ð89JCR"S#277Ł[ Trialkylstibines mediate a condensation of a!bromocarboxylic acid derivatives\
a!bromonitriles or a!bromoketones with aldehydes and ketones to form a\b!unsaturated esters\
amides\ nitriles and enones via the intermediacy of a stibonium salt "Equation "046## ð75TL1892\
78JOM"255#76\ 78SC72\ 78SC490\ 81ACR071Ł[ Remarkably\ this reaction proceeds in the absence of base[
Br– Prn CO2Et

+
i, KOBut H2O
Bu3Sb CO2Et + Bu3Sb O Bu3Sb(OH)2
ii, PrnCOMe
84%
Scheme 94
Br
120 °C, 7 h
+ + Bu3Sb (157)
O CHO CO2Et 92% O CO2Et
(E):(Z) 60:40
Relatively few reports of bismuthonium ylides have appeared ð56CC0931\ 61T232\ 76CSR34\ 77S208\
78CC0638Ł[ Structural properties and relative reactivity of stibonium and bismuthonium ylides
bearing electron!withdrawing substituents have been discussed^ these ylides do not appear to par!
ticipate in alkene forming reactions ð77JCS"P1#0718Ł[
0[03[4 BY ELIMINATION OF SILICON\ GERMANIUM OR BORON FUNCTIONS
0[03[4[0 Elimination of Silicon Groups

Alkene formation by elimination from organosilanes with a leaving group at the b!position\
typically hydroxy or halo substituents\ is very useful synthetically and has been the subject of many
reviews "see for example ð67CSR04\ 68COC"2#430\ B!70MI 003!91\ B!72MI 003!91\ 73S273\ 74S606\ B!77MI 003!91\
B!77MI 003!92\ 78JOM"259#28\ 80COS"0#618\ 80COS"5#0999Ł#[ The Peterson alkenation involving elimination
from b!hydroxysilanes in a process similar to the Wittig reaction is probably the most frequently
employed example of an elimination reaction involving silicon ð80SL653Ł[
0[03[4[0[0 Elimination of b!hydroxysilanes

While earlier examples of elimination from b!hydroxysilanes had been reported ð36JA0440Ł the
synthetic utility of this transformation was recognized and demonstrated by Peterson in 0857
ð57JOC679Ł and subsequently developed by Peterson\ Hudrlik\ Chan and co!workers ð63JOC2153\
63TL060\ 64JOC1152\ 67TL1272Ł[ The trimethylsilyl group is commonly employed but phenyl!
dimethylsilyl has also been used ð78TL118Ł[ This silyl group has the advantage that the b!hyd!
roxysilane is su.ciently stable to purify by chromatography over silica prior to elimination[
Elimination can be e}ected under acidic "typically acetic acid\ sulfuric acid or boron tri~uoride
etherate# or basic "typically potassium t!butoxide or potassium hydride or sodium hydride# con!
ditions ð73S273Ł[ Johnson and Tait have successfully employed aqueous hydro~uoric acid to e}ect
elimination ð76JOC170Ł[ Alternatively\ the hydroxy group can be activated with thionyl chloride
ð63TL060Ł\ acetyl chloride ð63JOC2153\ 67TL1272Ł\ mesyl chloride ð63JOC2153\ 64JOC1152Ł or tri~uoro!
acetic anhydride ð63TL060Ł prior to elimination\ which is frequently e}ected by ~uoride ion "Equa!
tion "047## ð74BCJ1701Ł[ This process can be particularly advantageous in cases where isomerization
of alkenes is a problem or with terminal alkenes[ In a synthetic approach to mitomycins\ Danishefsky
used new conditions for the hydroxysilane elimination^ the intermediate in this case was stable
to the usual elimination conditions[ However\ on treatment with 1\2!dichloro!4!5!dicyano!0\3!
benzoquinone "ddq#\ quinone formation and hydroxysilane elimination proceeded in quantitative
yield "Equation "048## ð77JOC2280Ł[
OH
O TMS O
i, (CF3CO)2O
OH OH (158)
N N
O N MBn ii, Bun4NF, KF, MeOH O N MBn
81%
BnM O BnM O
Silicon\ Germanium or Boron Functions 538
Et3SiO O O
MeO OR MeO OR
i, LiCH2-TMS
(159)
N NMe ii, ddq, THF N NMe
OMe O
R = H, Me
ddq = 2,3-dichloro-5-6-dicyano-1,4-benzoquinone
The stereospeci_city of the elimination process is noteworthy] under acidic conditions elimination
occurs in an anti fashion while syn elimination is observed under basic conditions "Scheme 84#
ð64JA0353Ł[ Thus\ provided a single diastereomer of the b!hydroxysilane can be obtained\ this can
be converted into either isomer of the alkene[ Evidence for the anti!periplanar geometry of the acid!
induced elimination includes the fact that the b!hydroxysilane "01# is stable to acid ð65CC586Ł[
Through use of b!hydroxysilanes which are chiral at silicon\ Larson et al[ have demonstrated that
the acid!catalysed elimination process proceeds with inversion of con_guration at silicon while
retention at silicon occurs when the elimination is conducted with potassium hydride ð77T2670Ł[
Nu:
Prn TMS O– TMS H TMS H

KH H+ Prn Prn
H Prn H Prn H Prn
+
Prn Prn H Prn OH Prn OH2
Scheme 95
OH
TMS
OH
(12)
The b!hydroxysilanes used in the elimination reactions are frequently obtained by condensation
of an a!silylcarbanion with a carbonyl compound "Scheme 85# ð57JOC679Ł[ When magnesium is used
as the countercation\ the hydroxysilane can be isolated as elimination does not occur spontaneously^
however\ with alkali metals the alkene is frequently isolated directly from the reaction mixture
ð68COC"2#430Ł[ When lithium ions are involved and if the substituent X is capable of stabilizing an
anion\ then the elimination of the b!oxidosilane is usually rapid and the alkene is isolated directly^
however\ if X is not anion!stabilizing then the b!hydroxysilanes are generally isolable and eliminate
on treatment with acid or base[ While a four!centred Wittig!type intermediate can be envisaged for
the elimination from the b!oxidosilane\ it is also possible that transfer of the silyl group to the
oxygen atom can occur to form a carbanion which then loses the siloxy anion to form the alkene
ð62JOC1553Ł[ In competitive situations\ elimination of a silyl group occurs rather than a phosphorus
moiety ð51JOC2536\ 57JOC679Ł[ In the case of a b!gorgonene precursor "Equation "059## methylenation
could be achieved using trimethylsilylmethylmagnesium chloride but was not possible using the
corresponding Wittig reagent ð62TL2386Ł[ Furthermore the by!product of the Peterson alkenation\
hexamethyldisiloxane\ is much more easily removed from alkene products than triphenylphosphine
oxide due to its volatility ð57JOC679Ł[ An example of the Peterson methodology in synthesis\ in
which good selectivity is observed\ is illustrated in Equation "050# ð77T3228Ł[ The chemoselectivity
of the Peterson alkenation can be modi_ed by use of titanium or cerium reagents^ in the presence
of titanium tetrachloride ð70TL4920Ł\ aldehydes but not ketones are methylenated with trimethyl!
silylmethylmagnesium chloride^ use of cerium trichloride ð76JOC170Ł leads to better results with
base!sensitive aldehydes and ketones[
i, TMS-CH2MgCl
(160)
ii, NaOAc, AcOH
H H
O
–O
O – SiR3
+ SiR3
X X X
HO
SiR3
X
Scheme 96
i, ClMgCH2-TMS
O ii, H2SO4, THF O
O (161)
iii, HF, MeCN
TBDMS-O 88% TBDMS-O
O O
b!Hydroxysilanes can be formed by regiospeci_c ring opening of epoxysilanes "Scheme 86#

ð64JOC1152\ 65JOC1504Ł\ or from b!ketosilanes "Scheme 87# ð63TL0022\ 64SC04\ 65JOC1839Ł on treatment
with organometallic reagents or\ in the case of b!ketosilanes\ hydride reducing agents ð64JA0353Ł[
Ring opening of epoxysilanes with silicon tetra~uoride followed by elimination with potassium
hexamethyldisilazide has been used to synthesize ~uoroalkenes ð78TL856Ł[ Organosilyl anions attack
epoxides to form b!oxidosilanes which undergo spontaneous syn b!elimination to form alkenes
"Scheme 88# ð65JA0154\ 65S088Ł^ as this step proceeds stereospeci_cally\ it provides an excellent
method for isomerization of alkenes ð79T446Ł[ b!Hydroxysilane precursors for the elimination may
also be formed by BaeyerÐVilliger oxidation of b!silylketones and hydrolysis of the lactone thus
formed ð79JA5783Ł\ furnishing a useful route to unsaturated carboxylic acids[ Treatment of ethyl
trimethylsilylacetate with two equivalents of Grignard reagent followed by treatment with acid to
e}ect elimination of the intermediate b!oxidosilane produces 0\0!disubstituted ethylenes as illus!
trated in Equation "051# ð71TL0924Ł[
Prn Prn
KH
O H H
Prn2CuLi
TMS OH H+ Prn
TMS Prn Prn Prn
Prn
Scheme 97
KOBut C5H11
Pr
O 74%
TMS (E):(Z) 9:1
C5H11 MeLi
Pr Pr H
TMS LiO C5H11 Pr
NaOAc, AcOH
major C5H11
69%
(E):(Z) 1:9
Scheme 98
MO H
R1 O R33SiM R1 R2
R1 R2
R2 H SiR33
R33SiM = TMS-K, PhMe2SiLi
Scheme 99
i, PhMgBr (excess)
Ph
TMS CO2Et (162)
ii, H2SO4 Ph
Elimination of b!hydroxysilanes has been employed to prepare many unsaturated systems such
as allenes "Scheme 099# ð67JOC0415Ł\ a\b!unsaturated esters ð63BCJ1418\ 63JA0519Ł\ acids ð64CC426Ł\
amides ð64SC248\ 67JA0437Ł\ lactams "Equation "052## ð67S635\ 75JOC447Ł\ nitriles ð63TL3994Ł and
enynes "Equation "053## ð70JA4457\ 71TL608Ł[
OH
O Li i, SOCl2 •
+ n-C10H21 n-C10H21
n-C10H21 SiPh3 ii, Et4NF
SiPh3 44%
Scheme 100
R2
TMS R1
i, LDA
(163)
N ii, ketone, R1COR2 N
O Ph O Ph
TMS i, ButLi TMS

+ R–CHO (164)
TBDMS ii, MgBr2
R
(E):(Z) 1:30–50
Conjugated dienes may be synthesized by reaction of an a!silylanion with an a\b!unsaturated

aldehyde or ketone ð69TL0026Ł or by reaction of a silylallyl anion with a carbonyl compound
ð67TL1272\ 79JA4993Ł[ However\ the latter reaction can lead to side products due to attack at the g!
position thereby reducing the yield of the diene[ This problem has been overcome by use of boronic
esters to control the condensation "Scheme 090# ð70TL1640Ł[ Furthermore\ the b!hydroxysilane is
formed diastereoselectively^ therefore both "Z#! and "E#!dienes may be prepared by choosing the
appropriate elimination conditions[ An alternative which has been investigated is the use of 0\2!
bis"trimethylsilyl#propenyl anion with aldehydes or ketones to form 0!silyl!0\2!dienes stereo!
selectively "Scheme 091# ð71CC858\ 72CC810\ 73JOM"153#196\ 76TL100Ł[ Alexakis and Jachiet developed
a new approach to conjugated dienes\ used in pheromone synthesis\ by stereoselective ring opening
of epoxysilanes with "Z#!alkenyl cuprates in the presence of boron tri~uoride etherate\ followed by
elimination under basic or acidic conditions to form the "Z#! or "E#!conjugated dienes ð78T270Ł[
Thus stereoselective diene synthesis is possible with the Peterson reaction while the Wittig reaction
is not as e.cient ð60HCA0656Ł[
OH
O i, RCHO KH
B R R
O ii, N(CH2CH2OH)3
TMS
TMS
H2SO4
Scheme 101
The vinylogous Peterson elimination has been investigated ð73CC423\ 89CC0464Ł^ under basic
conditions the elimination occurs stereospeci_cally syn to form the conjugated diene[ When a cis
double bond is relocated it is transposed to the position which originally carried the hydroxy group
"Equations "054a# and "054b##[
OH
–
i, MgBr2 H+
TMS TMS
TMS TMS R R
ii, RCHO
Li+ TMS
KH
R
TMS
R = alkyl, phenyl
Scheme 102
PhMe2Si
OH
KH, THF
(165a)
PhMe2Si
OH
KH, THF
(165b)
Allylsilane synthesis by hydroxysilane elimination has been developed by Fuchs and Anderson
ð76SC510Ł as well as Narayanan and Bunnelle "Scheme 092# ð76TL5150Ł\ while Soderquist and
Santiago have employed elimination of b!hydroxysilanes in a method of conversion of vinylsilanes
to allylsilanes ð78TL4582Ł[
TMS
O TMS-CH2M silica gel
R TMS TMS
R X CeCl3 or R
HO TMS-Cl, Florisil
R = alkyl, aryl; X = Cl, O-alkyl; M = Li, MgCl
Scheme 103
b!Hydroxysilanes have been employed as alkene!protecting groups in pheromone synthesis\

thereby exploiting the ease with which they may be eliminated stereospeci_cally to a}ord either the
"E# or "Z# alkene ð82TL0482Ł[
0[03[4[0[1 Elimination of b!halosilanes

b!Halosilanes readily undergo b!elimination ð37JA1758Ł to form alkenes sometimes simply on
heating ð58JCS"B#541Ł but frequently on treatment with ~uoride ions[ The elimination usually
proceeds in an anti fashion ð58JCS"B#741\ 65JOM"02#C00\ 65JOM"010#182Ł\ except on thermolysis when a
four!centred intermediate appears to be involved ð58JCS"B#541Ł[ Chan and co!workers have used
this strategy to prepare reactive alkenes such as allenes\ allene oxides "Equation "055## ð63TL060\
63TL2400\ 64TL2272\ 67JOC1883\ 79T1158Ł and strained alkenes "Equation "056## ð66JA825Ł[ Thus
t!butylallene oxide could be isolated in this manner^ other allene oxides with less bulky substituents
which were too reactive to isolate could be generated by ~uoride!induced halosilane elimination
and trapped in situ[ Similarly the bridgehead alkene shown in Equation "056# was generated as an
intermediate and was subsequently trapped in a cycloaddition process[
O CsF O
But TMS But (166)
55%
Cl
TMS Br Br
PhCH2NMe3F
(167)
Br
b!Silylcarbonyl compounds do not readily eliminate to form a\b!unsaturated derivatives^ however\

on bromination the a!bromo!b!silyl derivatives undergo facile elimination of the 0\1!halosilane
either on treatment with ~uoride ion or thermally ð45ACS522Ł[ Fleming et al[ have developed this as
a method for protection of an enone as a b!silyl derivative "Scheme 093# ð67CC065\ 67CC066\ 67CC067\
79JCS"P0#0382Ł[ Notably the bromination usually occurs selectively on the same side of the ketone as
the silyl substituent[ However\ even if the other regioisomer is formed\ enolization or equilibration
can provide pathways for elimination to form the enone[ Conjugate additions of organosilyl lithiums
to enones form enolates which can be alkylated regiospeci_cally^ as the product contains a b!silyl
derivative\ bromination can be used to reintroduce the double bond "Scheme 094# ð67CC066Ł[
Fluoride ion!induced desilylchlorination has been employed in the synthesis of a!methyl!
enecyclobutanones and a!methylenecyclopentanones from the corresponding a!chloro!b!silyl
ketones "Equation "057## ð73JOC0206Ł[
O O O
Br
Br2/CCl4, 0 °C NaF, EtOH, ∆
65% 75%
TMS TMS
Scheme 104
O O O
i, PhMe2SiLi/CuI CuBr2
SiPhMe2
ii, MeI
Scheme 105
TMS
H Cl H
O O
tbaf, DMSO
O O (168)
( )n 20 °C ( )n
H H
n = 0, 30%
n = 1, 73%
Vinylsilanes can be transformed stereospeci_cally to vinylhalides by treatment with chlorine or

bromine followed by elimination of the halosilane "Scheme 095# ð63TL432Ł[ When iodine is employed
the cis!vinyliodide is isolated instead[ Reaction of ~uorovinylsilanes with bromine involves elim!
ination in the intermediate bromosilane to form bromo~uoroalkenes ð89JOM"283#26Ł[ Elimination
of halosilanes has been employed for the synthesis of vinyl sul_des ð78T2052Ł and vinyl sulfones
ð71TL2344Ł[
0[03[4[0[2 Elimination of other b!substituted silanes

Silanes bearing alkoxy\ acetoxy\ sulfonyl\ amino groups\ etc[\ at the b!position undergo elim!
ination to form alkenes\ frequently on treatment with ~uoride ions[ The stereochemistry of the
X
Bu TMS Cl2 or Br2 NaOMe Bu
TMS
Bu
X X
X = Cl or Br
Scheme 106
elimination is usually anti "Equations "058# and "069## ð72TL3040\ 72TL3042\ 73JOM"160#170Ł[ Fluoride
ion!induced elimination of a b!tri~uoroacetylsilane was used to synthesize "E#!0!iodohex!0!ene
ð63TL432Ł[ Thermolysis of b!methoxysilanes to form alkenes appears to proceed via a four!centre
intermediate while the acid!catalysed elimination of the same substrates proceeds in a trans!coplanar
fashion ð58JA403Ł[
O OH
tbaf
Ph Ph (169)
SiMe2Ph 91%
H
SiMe2Ph
OAc tbaf
(170)
The ease of fragmentation of b!silyl!substituted compounds has been exploited in the development
of new protecting groups ð74S706Ł[ 1!Trimethylsilylethyl esters eliminate on treatment with ~uoride
ion to form ethene\ trimethylsilyl~uoride and carboxylate "Equation "060## and are therefore a
useful method of protection of carboxylic acids ð66HCA1600\ 66HCA2928Ł\ employed for example in
the synthesis of a highly reactive carboxylate salt ð76CC095Ł[ This methodology has been extended
to provide a protecting group for alcohols^ b!trimethylsilylethoxymethyl "SEM# ethers are removed
as shown in Equation "061# ð79TL2232\ 73JOC2560Ł[ Amines can be protected in a similar fashion
ð67CC247\ 72CC529Ł[
O H H
tbaf
TMS RCO2– + + TMS-F (171)
R O
H H
OMe OMe
HO tbaf/THF HO
(172)
O R HO R
TMS
O
Fluoride ion!induced elimination of b!silyl sulfones "see Section 0[03[1[2[0[ii# provides a mild
route to alkenes ð68TL1538\ 77JOC1577Ł and\ in its vinylogous form\ to dienes ð73TL0108\ 77JOC1577Ł^
the synthetic utility is limited by the accessibility of b!silyl sulfones[ They are usually prepared by
alkylation of a sulfone anion with iodomethyltrimethylsilane\ thereby limiting the alkenes syn!
thesized to monosubstituted or 0\0!disubstituted alkenes[ Application of the methodology to the
introduction of the C!00 methylene unit of moenocinol is illustrated in Equation "062# ð67JCS"P0#718Ł[
An alternative route to a b!silyl sulfone\ employed in the synthesis of the antibiotic bicyclomycin\
involves a conjugate addition to an unsaturated b!silyl sulfone ð75CC519Ł^ elimination to form the
alkene was e}ected on treatment with tbaf as usual[ 0!Trimethylsilyl!1!benzenesulfonylethylene can
act as an alkyne equivalent in DielsÐAlder cycloadditions\ as elimination of the silyl!sulfone units
in the adducts forms alkenes "Scheme 096# ð72JOC3865Ł[ Furthermore alkylation of the sulfone prior
to elimination on treatment with ~uoride ion increases the versatility of this methodology[
OBn i, tbaf/THF OBn

(173)
ii, Na/NH3
R SO2Ph 40%
i, LDA R=H
ii, TMS-CH2I R = CH2-TMS
SO2Ph
SO2Ph
∆ TMS tbaf
+
98% 84%
TMS
Scheme 107
b!Silyl sulfoxides in which the sulfoxide moiety does not have a b!hydrogen atom undergo syn
elimination of silylsulfenate on heating "Equation "063## ð71JCS"P0#0452Ł[ Similarly sila versions of
the Ho}mann and Cope eliminations are possible in b!silyl derivatives of ammonium salts and
amine oxides respectively "see Sections 0[03[2[0 and 0[03[2[1[1# ð71JA6555Ł[ Thus ~uoride ion!
induced fragmentation of a silyl ammonium iodide produced the "Z\E#!diene via an anti elimination
"Equation "015## while the corresponding amine oxide decomposed spontaneously by a syn elim!
ination to form the "Z\Z#!diene "Scheme 097# "see also Equation "007##[ Related 0\3!fragmentation
processes e}ected by ~uoride ion have been employed in the generation of o!quinodimethanes
"Scheme 098# ð79JA5774\ 71JA6598\ 77JA5468Ł[
O O
90 °C
(174)
TMS
S+
–O Ph
Me SiPh2But Me O– SiPh2Bu
t
N mcpba
N+
Me
N
OSiPh2But
Scheme 108
O O O
TMS H
CsF/MeCN
H H H H
86%
MeO MeO MeO
+NMe I–
3
Scheme 109
Silyl!directed fragmentation reactions leading to alkenes have been extensively investigated^ for
example oxidative fragmentation of g!trimethylsilyl alcohols on treatment with ceric ammonium
nitrate to form keto alkenes is illustrated in Equation "064# ð76JOM"221#42Ł\ while Equation "065#
shows fragmentation of the silacyclohexane ring on treatment with trityl ~uoroborate ð63JOM"70#30Ł[
R OH O
can R
(175)
75–93%
TMS
R = Me or Ph
cis or trans
can = ceric ammonium nitrate
+ Ph3C+ BF4– + Ph3CH + BF3 (176)

Si Si F
Me Me Me Me
Silacyclopropanes undergo thermal cycloreversion on heating to form a silylene and an alkene as

illustrated in Equation "066# ð64JA6051Ł[
Me2
Si 60–80 °C
+ [Me2Si:] (177)
0[03[4[1 Elimination of Germanium Groups

Germanes bearing leaving groups at the b!position undergo elimination to form alkenes analogous
to the behaviour of silanes^ b!halogermanes decompose very readily forming ethene "Equation
"067## ð52MI 003!90\ B!56MI 003!92Ł[ The unstable heterocycles 1!oxa and 1!thia!germacyclobutanes
lead to alkenes and transient germanones or germathiones via b!elimination "Scheme 009#
ð72JOM"132#170\ 89CRV172\ 89JOM"399#010Ł[ A similar elimination to form a butadiene has been pro!
posed ð73OM0239Ł[ Carbonyl alkenation\ similar to the Wittig reaction\ is possible with germanium!
based reagents^ fragmentation of four!membered intermediates is proposed for these reactions
ð74TL3412\ 89CRV172\ 89JOM"399#010Ł[ Treatment of aldehydes\ but not ketones\ with the reagent
Me2GeCH1TiCl2\ leads to alkenes in good yields "Equation "068## ð70TL4920Ł\ presumably involving
elimination from a b!oxygenated germane intermediate[ Butadienes are formed during the gas!
phase pyrolysis of 0\1!digermacyclohex!3!enes "Equation "079## ð73JOM"156#82Ł[
H H
Me3Ge X + Me3GeX (178)
H H
Et2Ge X
X ∆
+ Et2Ge [Et2Ge X] + R
R R
X = O; R = H, Ph
X = S; R = H
Scheme 110
i, Et2O
O ii, H2O
+ Me3Ge TiCl3 C6H13 (179)
C6H13 88%
R1 R1
Et2Ge
R2 + [Et2Ge GeEt2] (180)
Et2Ge
R2
0[03[4[2 Elimination of Boron Functions
0[03[4[2[0 Elimination of alkylboranes

On heating alkylboranes\ in which the alkyl group bears at least one b!hydrogen atom\ elimination
may occur "retrohydroboration# reversibly to give an alkene ð44JA4905\ 57JCS"B#0933Ł^ this can be
driven to completion by using another "usually less volatile# alkene as a trap and by removing the
alkene by distillation as it is formed "Equation "070## ð56JA456\ 68BCJ1831Ł[ In the latter case\ after
7 h at 059>C\ 89) of the hexyl group was displaced by 0!decene\ with only 1) of the norbornyl
group undergoing displacement^ the alkene isolated was almost entirely 0!hexene containing only
minor amounts of 1!hexene and 2!hexene[ Thus selective displacement of alkenes from alkyldi!exo!
norbornylborane is possible under these conditions^ with other trialkylboranes bearing di}erent
alkyl groups mixtures of alkenes may be formed due to less!selective elimination[ Borane elimination
forms the more substituted alkene wherever possible "Equation "071## ð56JA456Ł[
1-decene (6 equiv.)
BR2 BR2 + (181)
( )5 160 °C ( )9
R = exo-norbornyl
Et Et
∆
(182)
Et –R2BH Et
BR2
Alternatively\ the B0H bond may be trapped irreversibly with alkynes\ thereby liberating the
alkenes and forming alkenylboranes in the process "Equation "072## ð54JCS5558Ł\ or with aldehydes
such as formaldehyde ð61JA5438Ł\ benzaldehyde ð67JOM"045#192Ł\ ketones ð67JOM"045#192Ł or azo
compounds ð61JCS"P1#792\ 62TL390Ł[ In some cases the elimination of alkenes occurs very rapidly
under mild conditions in reactions using these trapping agents as illustrated for example for the B!
alkyl!8!BBN derivatives in Equation "073# ð67JOM"045#192Ł^ it is possible that a cyclic transition state
ð57DOK"068#0233Ł involving the displacing group is involved in these reactions[ The rate of elimination
from the B!alkyl!8!BBN derivatives increases with increasing substitution at the b!carbon atom and
increasing ability of the alkyl group to adopt a syn!planar B0C0C0H conformation[ Brown and
Ford have illustrated the utility of this in the transformation of cycloalkenes to methylene!
cycloalkenes as illustrated in Scheme 000 ð70JOC536Ł[ The methylene derivative was formed
speci_cally via the displacement reaction^ in contrast methylenation of isopinocamphone would
result in signi_cant by!products due to epimerization or rearrangement[ Alkene displacements may
also be conducted with other unsaturated compounds ð68COC"2#680Ł such as allyl alcohols and
amines ð54MI 003!90Ł\ vinylsilanes ð59ZOB2504Ł\ dienes ð48AG419Ł and nitriles ð58JCS"A#322Ł[
B
5-decyne Bu
B + (183)
3 160–200 °C Bu
3
91%
H
O Ph
PhCHO
+ B (184)
B
B
= 9-BBN
H O Ph
steps B PhCHO B
+
Scheme 111
The major synthetic use of borane eliminations is for contrathermodynamic alkene isomerization
ð55JA0339\ 56JA456Ł[ On heating\ alkylboranes undergo isomerization to the most stable isomer which
is in fact the least sterically crowded isomer\ via elimination and re!addition to the alkene[ Therefore
if an internal alkene is hydroborated then heated to e}ect isomerization to the terminal alkylborane\
followed by displacement\ this results in isomerization of an internal alkene to its less stable
terminal isomer "Scheme 001#\ a transformation which is di.cult to achieve otherwise[ As di!exo!
norbornylborane is an excellent agent for selective displacement of alkyl groups as alkenes as
illustrated in Equation "070#\ this reagent is particularly well suited to the hydroborationÐiso!
merizationÐdisplacement sequence to e}ect isomerization of alkenes from internal to terminal
positions ð68BCJ1831Ł[
BR2
B
NaBH4, BF3 ∆ C8H17
B +
C8H17
3
Scheme 112
Organoboron compounds in which a halo or alkylthio group is attached to boron can eliminate
alkenes by using more forcing displacement conditions than those required with alkylboranes^
when dialkylamino or alkoxy groups are bonded to boron elimination of alkenes is not observed
ð57IZV437Ł[
0[03[4[2[1 Elimination of b!substituted alkylboranes

Alkylboranes bearing a heterosubstituent at the b!position can undergo elimination of R1BX
either in an uncatalysed syn elimination process or a catalysed "usually by acid or base# anti
elimination "Scheme 002# ð68COC"2#680Ł[ With b!chloroalkylboranes elimination to form the alkene
and the boron halide occurs readily especially in the case of acyclic alkenes ð53JA0790\ 55JOM"4#495\
57JA1895Ł^ the b!~uoro derivatives are also quite labile ð57IC0903Ł while the iodo analogues appear
to be more stable ð69BSF1494Ł[ As illustrated in Scheme 003\ elimination of b!chloroalkylboranes
occurs rapidly under normal hydroboration conditions\ at 9>C[ This illustrates a signi_cant feature
of the hydroborations of substituted alkenes^ if b!elimination occurs readily under the reaction
conditions\ then subsequent hydroboration of the newly formed alkene results in isolation of the
product of a second hydroboration[ The cyclic analogues are more stable than the acyclic b!
chloroalkylboranes ð55JOC1666\ 57JA3334Ł^ cis!1!chlorocyclohexylboranes are quite stable while the
trans isomer eliminates rapidly in THF at room temperature but is stable in diethyl ether\ indicating
that in THF the solvent acts as a nucleophile resulting in anti!elimination[ Alkenylboranes with b!
chloro ð69JA0316Ł or b!alkoxy groups ð63JA205Ł eliminate to form allenes "Scheme 004#[
Boranes bearing other leaving groups such as acetoxy\ benzyloxy and tosyloxy at the b!position
behave very similarly to the chloro compounds readily eliminating to form alkenes ð57JA1895Ł[ b!
Alkoxyorganoboranes undergo uncatalysed syn elimination "Scheme 005# ð55JOC1666Ł although
they have been reported to be more stable than the chloro derivatives ð51IZV0262Ł[ Catalysis with
nucleophiles such as THF ð53JA0790Ł or electrophiles such as BF2 ð53JA3232\ 62JOM"59#08Ł results in
anti elimination "Scheme 005# ð55JOC1666Ł[ In cyclic derivatives the trans isomers are su.ciently
stable to allow oxidation to occur ð57JA3328\ 57JA3334Ł[ Other oxygen substituents behave similarly\
BR2
+ R2BX
R2B X
X
Nu –
BR2
+ R2BNu + X–
Scheme 113
BH3, THF
Cl Cl + R2B–Cl
BR2
BH3, THF
BR2
Scheme 114
Cl R Cl R
Cy2BH NaOH
R •
BCy2
Scheme 115
e[g[\ phenoxy ð57JA1895Ł\ dialkylboryloxy ð57JA1895\ 57JA3328Ł\ lithium alkoxide ð55TL3204Ł and
trimethylsilyloxy groups ð64JOM"091#012Ł[ In contrast organoboranes bearing b!alkylthio or b!aryl!
thio groups do not undergo uncatalysed elimination but on treatment with butyllithium give alkenes
via anti elimination "Equation "074## ð55JOC1666Ł[
D
Prn2BD, 0 °C D
Prn2B H OEt 1 h, RT
Ph OEt
H Ph Ph
BuLi or BF3•Et2O
Ph D
Scheme 116
D
BuLi D
H S Ph (185)
Prn2B
or OH–
Ph
Ph H
Organoboranes with b!dialkylamino groups eliminate in an anti manner even in the absence of a
catalyst^ presumably self!catalysis occurs via an acidÐbase B0N interaction ð55JOC1666Ł[ Addition
of a carboxylic acid facilitates the elimination and on heating this produces the alkenes in good
yields "Equation "075## ð58JCS"B#752Ł[ As with oxygen substituents\ cyclic amino derivatives are
usually su.ciently stable to allow removal of the boron oxidatively without elimination occurring
ð60BSF2867Ł[ Elimination of a b!amidoborane on treatment with tetrahydroborate resulted in cleav!
age of the bicyclic system as shown in Equation "076# ð55JOC2387Ł[
N i, diborane
(186)
ii, AcOH, ∆
98%
CO2Me
Me
NCO2Me BH4– N
B NHCO2Me (187)
Me NCO2Me
The facility with which boranes eliminate when b!acetoxy or b!amino substituents are present
can be exploited in the transformation of ketones to alkenes via enol acetates or enamines as
illustrated in Scheme 006 ð53TL1928Ł[ Since the regiochemistry of enol acetate and enamine formation
are complementary either the more!substituted or less!substituted alkene\ respectively\ can be
obtained[
O OAc OAc
R2B
BH3•THF Ac2O
64%
NR2 NR2
BR2
BH3•THF EtCO2H
95%
Scheme 117
Elimination of boranes with an oxygen substituent in the b!position has been employed in a
boronÐWittig reaction ð72TL524\ 76CC186Ł[ The anion formed by condensation of dimesitylboryl!
stabilized carbanions with aromatic aldehydes eliminates to form selectively either "E# or "Z# alkenes
on treatment with TMS!Cl:HF or "CF2CO#1O\ respectively "Scheme 007#[ The "E# alkene results
from anti elimination while the "Z# alkene is formed by a syn elimination process[
TMS-Cl, –78 °C
HF, MeCN (aq.)
n-C7H15
– 84%
BMes2 Ar
Li O 100% (E)
+ p-MeOC6H4–CHO n-C7H15
H
Mes2B n-C7H15
Ar H (CF3CO)2O
Ar n-C7H15
76%
Ar = p-MeCOC6H4 (E):(Z) 9:91
Scheme 118
Fragmentation of d!substituted boranes with\ for example\ a sulfonyloxy group at the 3!position
may occur as illustrated in Scheme 008 ð69TL2750Ł[
Alkenylboronic esters undergo deboronobromination to form vinyl bromides with excellent
stereochemical control^ both the addition of bromine to the alkenylborane and the elimination on
treatment with base occur stereospeci_cally anti resulting in formation of the bromoalkene of
opposite stereochemistry to the starting alkenylborane "Scheme 019# ð54JA0415\ 62JA5345\ 77TL10\
78T0748Ł[ This methodology has been used in the stereospeci_c synthesis of both "E# and "Z# 0\1!
OSO2Me OSO2Me
i, BH3•THF NaOH
ii, H2O
B(OH)2 major product
Scheme 119
disubstituted vinyl bromides ð77TL10Ł[ The opposite stereochemical result is observed when "E#!
alkenylboronic acids are iodinated in the presence of base ð62JA4675Ł or with chloramine!T:sodium
iodide ð77MI 003!93Ł to form the "E#!iodoalkenes as shown in Equation "077#[ Thus alkynes can be
readily transformed to cis and trans vinyl bromides and trans vinyl iodides via hydroboration to the
trans borane derivatives followed by halogenation[
R2
O O
O B Br
B Br2 OH–
R1 O Br R2
R1 R2
H R1
Br
Scheme 120
OH I2
I (188)
B R
R1 OH NaOH
This deboronobromination may also be applied to certain alkenyldialkylboranes as illustrated in

Scheme 010 ð56JA3420Ł^ by e}ecting the elimination from the dibromo intermediate thermally the
product of syn elimination is obtained whereas the base!induced process results in the product
of anti elimination[ Furthermore\ phenylethenyl derivatives consistently result in the opposite
stereochemical outcome to those observed with alkenyl derivatives[
BSia2 Br
Sia2BH i, Br2
R +
ii, H2O or ∆ R Br
R R
R = alkyl
Thermal 88–100% 0–12%
Solvolysis 2–5% 95–98%
R = phenyl
Thermal 18% 82%
Solvolysis 96% 4%
Sia2BH = disiamylborane
Scheme 121
More frequently the reaction of alkenyldialkylboranes with bromine or iodine proceeds with
migration of one of the alkyl groups on boron[ This methodology\ which is useful for the stereo!
selective transformation of alkynes to alkenes\ has been extensively investigated and developed\
mainly by Brown et al[ Thus when alkynes are hydroborated to form "E#!alkenyldialkylboranes and
this is followed by treatment with iodine and base "typically hydroxide or methoxide#\ migration of
one of the alkyl groups from the boron occurs followed by anti elimination of the iodine and boron
group to form the "Z#!alkene "Scheme 011# ð56JA2541Ł[ The migration of the alkyl group occurs
with inversion at the migration terminus and retention of con_guration of the migrating group
ð60JA5298Ł[ This methodology can also be extended to the stereospeci_c synthesis of trisubstituted
alkenes ð71JOC060\ 71JOC643\ 71JOC4396Ł and also b!aminoalkenes ð71T1244Ł[
OH
R R H R
R 2B I2, NaOH B– OH–
R2BH R I
Bun B R Bun
H Bun
Bun OH H
+I
Bun 99% cis
75%
R = cyclohexyl
Scheme 122
In order to stereoselectively form "E#!alkenes from the "E#!alkenyldialkylboranes\ treatment with

bromocyanogen instead of iodine is employed^ the strongly electron!withdrawing group on the
boron enhances the tendency for syn elimination\ thereby producing the trans alkene "Scheme 012#
ð61JA5459Ł[ Bromination of thexylalkylalkenylboranes has been employed to synthesize either the
"Z# or "E# isomer of a\b!unsaturated esters with very high stereoselection ð63JOC1210Ł[ Thermal
elimination is employed to form the "E# isomer by syn elimination while use of sodium ethoxide to
e}ect the elimination produces the "Z# isomer by anti elimination[
CN
syn
R2 B RB Br R
BrCN elimination
H Bun
Bun R H Bun
R = cyclohexyl cis:trans 4:96
80%
Scheme 123
Only one of the alkyl groups on the boron is transferred in the halogenationÐelimination sequence
which can be wasteful unless the alkene from which they are derived is readily available[ However
considerable success has been achieved in using di}erent substituents on boron[ Negishi has applied
the iodinationÐbase catalysed elimination methodology with borates to the synthesis of trans!enynes
"Scheme 013# ð62CC763Ł[ A leukotriene synthesis involving similar trans!enyne formation has also
been reported ð75TL428Ł[ Negishi|s enynes are readily transformed to cis\trans!dienes as illustrated
by application to the synthesis of the pheromone bombykol[ Small amounts of migration of the
thexyl group are observed in this reaction "see also ð61JA3902Ł#[ However\ in other cases thexyl group
migration can compete e}ectively ð57JA5132Ł[ To overcome this problem\ Evans et al[ employed
the iodinationÐbase!catalysed elimination sequence with boronic ester derived ate complexes to
synthesize prostaglandin model systems as illustrated in Scheme 014 ð65JOC2836Ł[ Similarly
alkenylalkylbromoboranes and alkenylalkylmethoxyboranes ð71JOC643\ 71JOC4396Ł can be employed
thereby circumventing the migration problem as illustrated in the synthesis of the pheromone
muscalure "Equation "078## ð71JOC2795Ł[
Prn
Prn
R2B R2B –
Prn Li I2
NaOH
( )9 O-TMS ( )9 O-TMS ( )9 O-TMS
63%
Prn
( )9 OH
Bombykol
R = Me2CHCHMe2–
Scheme 124
Metal 552
Et Et
Et Li C5H11 –
B(OMe)2 I2, OH–
+
O-TBDMS TBDMS-O
B(OMe)2
C5H11
TBDMS-O C5H11
22%
Scheme 125
n-C13H27 C8H17 I2, MeONa n-C13H27 C8H17

B (189)
59%
Br
muscalure
Trans!alkenylborepanes undergo elimination on treatment with iodine and base to form "Z#!6!
alkenyl!0!boronate esters which on oxidation furnish "Z#!6!alkenyl!0!ols "Scheme 015# ð71JOC0681Ł[
Yamamoto et al[ have demonstrated that alkenyldialkylboranes are transformed stereoselectively
to "E# alkenes on treatment with palladium acetate and triethylamine via a cis b!elimination
ð66CC741\ 79BCJ0569Ł[ 0!Halo!0\1!dialkylalkenes may be synthesized stereoselectively from "0!halo!
0!alkenyl#dialkylboranes on treatment with lead"IV# acetate or "diacetoxyiodo#benzene ð79BCJ0541Ł[
OMe Bun
I2, MeONa B trans oxidation
H (MeO)2B
elimination
B H
I Bun
Bun
Bun
HO
78%
Scheme 126
0[03[5 BY ELIMINATION OF METAL FUNCTIONS

Frequently alkyl metal compounds in which there is a b!hydrogen atom are unstable and eliminate
readily to form alkenes ð65CRV108\ 65CRV132Ł[ However\ as highlighted in these reviews\ while this
decomposition pathway is important\ it may be overemphasized[
0[03[5[0 Elimination of Groups 0 and 1 Metals*Li\ Na\ K\ Mg

Organolithiums in which the alkyl group has a b!hydrogen atom decompose thermally to form
alkenes and lithium hydride usually via b!elimination ð49LA"456#068\ 54JOC0147\ B!63MI 003!90Ł^
occasionally the products of a!elimination and coupling are observed also[ With primary alkyl!
lithiums temperatures of over 099>C are usually required to e}ect elimination but the secondary
and tertiary derivatives are less stable and eliminate more easily[ If aromatization occurs as a result
of elimination then the decomposition occurs rapidly ð27JA1222Ł[ As illustrated in Equation "089#
s!butyllithium produces mainly the product of Zaitsev elimination^ furthermore formation of the
cis alkene is preferred over the trans!alkene ð54JOC0147Ł[ Elimination in alkyllithums is believed to
proceed via a four!centre cyclic transition state ð72OM443Ł^ therefore it is likely that the conformation
required for elimination to form the cis!alkene is favoured over that for the trans!isomer[ Elimination
occurs also in organosodium and organopotassium compounds^ the ease of elimination increases
on going from lithium to potassium ð51CI"L#784\ 52TL740Ł[
78 °C
+ + (190)
Li
34% 51% 15%
Organolithium derivatives bearing a leaving group in the b!position\ e[g[\ a silyloxy group\
may also undergo elimination to form alkenes ð77JOM"235#C0Ł[ Per~uoroalkyllithiums decompose
thermally via b!LiF elimination ð68JOC2320Ł[ Treatment of 0\1!diiodoadamantane with n!butyl!
lithium generates adamantene as a reactive intermediate via elimination of LiI "Equation "080##
ð65JCS"P0#123Ł[ Occasionally elimination of ethylene to form an alkyllithium can occur "Equation
"081## if the carbanion corresponding to the newly formed organolithium is highly stabilized
ð57C227Ł[
BunLi
I (191)
Li RLi + C2H4 (192)

R
Frequently ring opening may occur in eliminations of alkyllithium reagents\ for example the
cleavage of cyclic ethers as shown in Equation "082# ð67CI"L#123Ł and other heterocyclic compounds
"Equation "083## ð68JCR"S#43Ł[ Ring opening is also possible when the lithium is exo!cyclic\ for
example with furans "Equation "084## ð67JOC3124Ł\ azoles ð62JA2397Ł and the reversible opening of
lithiated dihydrooxazines illustrated in Equation "085# ð69TL3244Ł[ Similar fragmentation forming
alkynes is possible with a wide variety of heterocyclic systems ð60JCS"C#2336\ 65ACS"B29#374\ 71COMC!
I"6#74Ł[
O Li O
(193)
O OLi
Li
Cl Ph
Cl
Ph (194)
N
O N LiO
R2 R1 •
R1 (195)
O R3 OLi R2
Li R3
Ph
O OLi
(196)
Ph • R
N N
R
Li
On treatment with ethylene and nickel chloride organolithium and magnesium reagents undergo
elimination to form alkenes "Equation "086## ð79LA060Ł[ Under these conditions a slight preference
for formation of the less!substituted alkene is observed[ Similarly on treatment with hydride
acceptors such as triphenylmethyltetra~uoroborate or tricyclohexylborane\ organolithium and
organomagnesium compounds eliminate under mild conditions to produce selectively the alkene
formed by Hofmann elimination ð66AG"E#33aŁ[ This elimination has been employed in nucleophilic
substitution of vinylic hydrogen atoms on activated alkenes by carbanions "Scheme 016#
ð66AG"E#33bŁ[
Metal 554
CH2=CH2, NiCl2, 0 °C
+ (197)
62%
MgCl 44% 56%
(E):(Z) 3:1
Li Li
Ph Ph Ph Ph
Ph3B i,
Li
Ph Ph Ph ii, Ph3B Ph
Scheme 127
Pyrolysis of organomagnesium compounds results in elimination to form alkenes\ such as ethene

and 0!butene\ and magnesium hydride ð41CB482\ 54JOM"3#238\ 58JOM"05#6Ł[ In the pyrolysis of ethyl!
magnesium halides\ other hydrocarbons have also been identi_ed\ e[g[\ ethane and 0!butene
ð58JOM"05#6Ł[ Photolysis of Grignard reagents also results in alkenes via b!elimination ð64JOM"74#0Ł[
In reactions of Grignard reagents with carbonyl compounds\ b!elimination can compete if steric
hindrance by bulky alkyl groups slows the usual reaction pathway[ Occasionally reduction products
are observed in the product mixtures as a result of this elimination process "Equation "087## ð55MI
003!90\ B!79MI 003!91Ł[
R
+ OMgX (198)
H MgX R
R2C=O
Organomagnesium compounds bearing a leaving group in the b!position undergo facile elim!
ination\ e[g[\ 0\1!dibromoethane forms ethylene on reaction with magnesium via the b!bromo
Grignard reagent ðB!79MI 003!90Ł[ Similarly b!alkoxy groups can be eliminated ð76JCS"P0#364Ł[
0[03[5[1 Elimination of Group 02 Metals*Aluminum

Organoalanes eliminate reversibly to form alkenes and an aluminohydride even more easily than
organoboranes ð59LA"518#0\ 59LA"518#42\ 59LA"518#109Ł^ this has been used industrially in the synthesis
of long!chain alkenes mainly due to the pioneering work of Ziegler ð71COMC!I"6#254Ł[ Elimination
to form terminal alkenes is generally quite e.cient at 199Ð299>C^ the aluminohydride formed may
be trapped with ethene to form the ethylaluminum thereby displacing the alkene with ethene[ Thus
alkene polymerization can be conducted as illustrated in Scheme 017^ _rstly ethene inserts into
ethylaluminum to form chains with even numbers of carbon atoms\ then by using conditions
which favour displacement "typically 199Ð299>C# the alkene is displaced by ethene regenerating the
triethylaluminum[ Alternatively the displacement reaction can be catalysed by nickel ð59LA"518#061Ł[
As an extension of this research\ the development of ZieglerÐNatta catalysts "involving aluminum
and a transition metal such as titanium# for alkene polymerization was particularly signi_cant
ð44AG430\ B!68MI 003!91Ł[
H H
H H 200–300 °C
Et3Al [Et(CH2CH2)nCH2CH2]3–Al 3 Et(CH2CH2)nCH=CH2 + Et3Al
H H
H H
n = 0–3
Scheme 128
Elimination of b!branched alkylaluminums\ such as isobutylaluminum\ is particularly facile and

occurs quite rapidly at 099Ð049>C "Equation "088##[ When tripropylaluminum is treated with
propene at 039Ð199>C catalytic dimerization of the propene occurs as insertion of propene forms
a b!branched alkylaluminum which rapidly eliminates at this temperature "Scheme 018#[ Thus
monosubstituted alkenes may readily be dimerized[ Equilibria can be established between organo!
aluminum compounds derived from various alkenes*alkenes are generally displaced by less!sub!
stituted alkenes thereby forming the more stable organoaluminum compound ð59LA"518#03\
59LA"518#42Ł[
140 °C
Bui3Al Bui2AlH + (199)
60–70 °C
pressure
Prn3Al + Prn2Al –H +
Prn2Al Prn Prn
Prn3Al
Scheme 129
Elimination to form an alkylaluminum and an alkene is possible with trineopentylaluminum and

like compounds "Equation "199## but only under extreme conditions ð59LA"518#196Ł[
R2Al But R2Al –Me + (200)
When trialkylaluminum compounds are reacted with carbonyl compounds reduction products
are often observed as well as addition products[ The reduction is a result of b!elimination in the
organoaluminum compound "Scheme 029# ð62JOC0029\ 89OM2975Ł[ Triisobutylaluminum is par!
ticularly e}ective as a reducing agent[
R O R
O
+ R2Al H +
R2Al R2Al
R H R O R
H R
Scheme 130
0[03[5[2 Elimination of Group 03 Metals*Tin and Lead

On treatment with trityl cation\ tetraalkyltin and tetraalkyllead compounds "and also dialkyl!
mercuries# undergo elimination to form alkenes "Equation "190## ð60JA5167Ł[ Hydride abstraction
in these reactions is facilitated by stabilization of the carbonium ion intermediate by the metal[ b!
Trichlorostannyl aldehydes and ketones undergo dehydrostannation on heating in DMSO or on
treatment with bases such as pyridine\ triethylamine\ 0\3!diazabicycloð1[1[1Łoctane "dabco#\ or
TMEDA^ as these b!trichlorostannyl aldehydes and ketones are readily accessible by ring opening
of siloxycyclopropanes with stannic chloride\ this provides a useful route from siloxycyclopropanes
to a!methylene aldehydes and ketones "Scheme 020# ð75JOC1278\ 81JOC06Ł[ The elimination to form
unsaturated aldehydes is much more facile than that to form methylene ketones[
H H
Et4M + Ph3C+ BF4– Ph3CH + + Et3M+ BF4– (201)
H H
M = Sn or Pb
Metal 556
TBDMS-O O SnCl3 O
SnCl4 TMEDA
83% 90%
Scheme 131
Elimination of organotin and organolead units in compounds bearing a leaving group in the b!
position is also possible^ acid!catalysed elimination of b!hydroxyalkyl triphenylmetal compounds
has been reported "Equation "191## ð58JOM"07#P0\ 69JOC0292Ł[ Interestingly\ the corresponding
triphenylsilicon and triphenylgermanium compounds do not eliminate under these conditions[ Thus
the ease of elimination of the Group 03 elements is Pb×SnŁGe×Si[ The rate of elimination
increases with increasing substitution at the sites of elimination[ The stereochemistry of the elim!
ination has been established as trans by use of the threo 2!triphenylstannyl!1!butanol prepared from
cis!1\2!butene oxide "Scheme 021#[ Elimination of a hydroxy and a tributylstannyl group from b!
hydroxyvinylstannanes under acidic conditions has been applied to the synthesis of a!allenylsilanes
"Equation "192## ð76TL1640Ł[ As b!stannylalcohols can be formed by reaction of trialkyl or
triarylstannylmethyllithium with carbonyl compounds and subsequently eliminated under acidic
conditions or thermally this can prove a useful method for methylenation of ketones "Scheme 022#
ð66AG"E#751\ 67TL3288\ 73CL0786Ł[ Thus methylenation of cis!0!decalone proceeds in excellent yield
without any epimerization whereas the corresponding Wittig reaction proceeds to give a mixture of
cis and trans isomers in lower yield ð89S148Ł[ Vinyl oxiranes can be prepared in this fashion
employing silica gel to e}ect the elimination of the hydroxy and tin groups "Scheme 023# ð74TL1194\
89S148Ł[ Interestingly while Wittig reactions with a!chloro ketones can be complicated ð57JOC1864Ł\
reaction of a!chloro ketones with trimethylstannylmethyllithium leads to allyl alcohols in reasonable
yields ð73CL0786\ 89S148Ł*elimination from an intermediate epoxystannane is the proposed mech!
anism "Scheme 024#[ Similarly\ epoxystannanes have been proposed as intermediates in the mcpba
oxidation of allylstannanes to form allyl alcohols ð79S0900Ł[
R R R
R HClO4
OH Ph3MOH + (202)
Ph3M MeOH (aq.)
R R R
R
M = Sn, Pb
H
O Ph3SnNa H+
H H OH
SnPh3
H
Scheme 132
SnBu3 CF3SO3H
(203)
R • R
TMS TMS
OH
R = Ph, 92%
R = Pr, 72%
O HO SnR3
H H H
R3SnCH2Li
H H H
91%
Scheme 133
Elimination of stannyl halide has been postulated as a pathway in the transformation of a!

haloepoxides to allyl alcohols on treatment with trialkylstannates ð76CJC0710Ł[ Diene formation by
O HO
Me3SnCH2Li silica
O O O
Me3Sn
Scheme 134
O R1 O– O
Me3SnCH2Li
R2 Me3Sn R2 R2
R1 Me3Sn R1
Cl Cl R1 R2 OH
Scheme 135
elimination of b!stannyl and sul_de groups is illustrated in Scheme 2 ð71TL1194Ł "Section 0[03[1[0[0#[
Elimination of b!stannyl sulfones is quite facile as discussed in Section 0[03[1[2[0 ð71TL1194\
74JOC2511Ł\ occurring on silica gel or by heating to form alkenes "Scheme 025# ð72CC508Ł[ Stereo!
selectivity in this example was low[ Alkene formation by destannylselenylation of a b!stannyl
selenide is also possible as illustrated in Equation "01# in Section 0[03[1[0[1 ð81JOC2034Ł[
SnBu3
i, Bu3SnLi xylene
PhSO2 PhSO2
R R R
ii, MeI ∆
Scheme 136
The ability of the tributylstannyl group to participate in fragmentation has been employed to
direct BaeyerÐVilliger and Beckmann fragmentations ð89JA5618Ł[
0[03[5[3 Elimination of Transition Metals

Decomposition of alkyl transition metals bearing a b!hydrogen atom via b!elimination is very
frequently observed ð65CRV108\ 65CRV132\ B!67MI 003!93\ B!74MI 003!90\ B!76MI 003!93Ł^ however\ as
pointed out by Lappert and Schrock\ there is in fact a risk that its importance may be over!
emphasized[ The elimination is believed to proceed via a four!centre planar cyclic transition state
"Scheme 026#[ The elimination illustrated in Equation "193# of the deuterium!labelled alkyl copper
con_rms that the b!hydrogen atom is transferred to the metal ð69JA0315Ł[ Therefore\ the transition!
metal complex must be coordinatively unsaturated with vacant cis coordination sites to allow the
elimination to occur[ In the transition!metal series the alkene formed by the elimination may remain
within the coordination sphere of the metal "Scheme 027# ð61JA4147Ł[ Whitesides et al[ have studied
eliminations from dialkylplatinum complexes in detail "Scheme 027# ð62JA3340\ 65JA5410\ 75OM0362Ł[
This elimination\ which is _rst order\ is inhibited by addition of triphenylphosphine\ presumably by
slowing the dissociation of phosphine from the complex[ The reversibility of this elimination is
illustrated by scrambling of deuterium labels "see also ð57JCS"A#089Ł#[ Once the butene elimination
has occurred\ n!butane is produced also\ by reductive elimination from the resulting platinum
hydride[
+ M–H
M H M H
M
H
Scheme 137
Metal 558
D
Bu3PCuCH2CD2Et Bu3PCuD + (204)
Et
Et
Bun Bun Bun Bun H
Et +
Pt Ph3P Pt Pt Pt(PPh3)2 + butane
Ph3P PPh3 –PPh3 Bun Pt Ph3P PPh3
Ph3P H
Bun
Scheme 138
Elimination to form the less!substituted alkene is normally preferred\ e[g[\ terminal alkenes are
formed preferentially when the alkyliron complexes are treated with trityl ion followed by iodide to
liberate the alkene from the transition!metal complex "Scheme 028# ð67TL2296Ł[
Ph3CBF4 I– + CpFe(CO)2I
60%
FeCp(CO)2 +FeCp(CO)
2
Scheme 139
Metallacyclic complexes "02# are much more stable thermally than their acyclic analogues as the
planar four!centre transition state is not easily attained in the cyclic systems ð62JA3340\ 65JA5410\
75OM0362Ł[ Similarly use of bulky ligands can prevent the dihedral angle of the M0C0C0H bond
approaching 9> as seen for example in CrBu3t ð61JOM"31#C28Ł[ In the alkyliridium"I# complex "03#
the kinetic isotope e}ect for b!hydrogen elimination is kH:kD 1[1729[19 indicating that in the
transition state\ both C0Ir and H0Ir bond formation are important ð63JOM"70#C26Ł[ In this
complex elimination is rate determining and there are no complications of deuterium scrambling[
( )n PPh3 X
Pt IrCO(PPh3)2
PPh3 n-C6H13
n = 1, 2 X = H/D
(13) (14)
Isomerization of alkenes in the presence of transition metal complexes "e[g[\ Pd or Pt# to form an
equilibrium mixture of alkenes may also proceed via a reversible alkene additionÐelimination
sequence ð53JA0665\ 58CRV688Ł[ The isomerization of the alkyl group in the complex shown in
Equation "194# proceeds via elimination followed by alkene addition leading to the more stable
alkylmetal\ again illustrating the reversibility of the process ð63JA5039Ł[ Similarly alkylzirconium
complexes rearrange rapidly to place the zirconium at the least!hindered position on the alkyl chain
"Equation "195## ð63JA7004Ł[ In general secondary and tertiary alkyls are least stable^ thus on
treatment of Cp1ZrCl1 with t!butyl Grignard reagent the hydride complex Cp1ZrClH is formed\
presumably via elimination from an intermediate alkyl zirconium ð73TL2396Ł[ A further example of
b!elimination in the early transition metals is illustrated in Equation "196# ð60JA2682Ł[
AuMe2ButPPh3 AuMe2BuiPPh3 (205)
Cl
Cp2ZrClH + Cp2Zr (206)
–C2H4
Cp2NbEt(C2H4) Cp2NbH(C2H4) (207)
Fragmentation of metallacyclobutanes to form alkenes and carbene complexes has been inves!
tigated "Equation "197## ð75JA622\ 75OM610Ł[ Unlike most other metallacyclobutanes\ titanacyclo!
butanes are more stable than their fragmentation products and therefore their exchange reactions
with alkenes are readily studied[ In this case the alkene is displaced by the highly strained
cyclopropene[ Carbonyl methylenation using Cp1TiCl1:AlMe2 ð67JA2500Ł or TiCl3:Zn:CH1Br1
ð67TL1306Ł proceed via the reactive species ðCp1Ti1CH1Ł formed by fragmentation of aluminum
alkyl adducts or titanacyclobutanes ð75OM610\ 80JOM"394#0Ł[
0 °C Cp2Ti
Cp2Ti + + (208)
PhH
b!Elimination of alkyl transition!metal complexes frequently features as a step in catalytic cycles

of reactions involving transition metal complexes\ e[g[\ as a termination step in alkene polymerization
ðB!79MI 003!92Ł[ In the decarbonylation of acyl halides with RhCl"PPh2#2\ the stereospeci_c formation
of alkenes as illustrated in Scheme 039 and Equations "198a# and "198b# is consistent with syn b!
hydride elimination from an intermediate alkyl rhodium species ð63JA0407Ł[
Ph
Ph
H COCl RhCl(PPh3)3
Ph (209a)
Ph
H
erythro trans
Ph COCl Ph Ph
RhCl(PPh3)3
Ph (209b)
H
threo cis
O L
RhClL3 L OC Cl β-elimination
COCl Cl Rh
R –L
R Rh
R L Cl
L Cl
L
OC Cl
Rh + R RhCl(CO)L2
–HCl
H L Cl
Scheme 140
Elimination of ethene or propene from titanium"III# alkyls on treatment with carbon dioxide has
been reported "Equation "109## ð76CC738Ł[ Addition of alkyl radicals generated from alkyl cobalt
{salophen| reagents to activated alkenes followed by elimination of a cobalt hydride produces new
alkenes "Scheme 030# ð76CC760Ł[
R
(η5-C5Me5)2TiCH2CH2R + CO2 (η5-C5Me5)2TiO2CH + (210)
R = H, Me
[Co]
O O
Co(salophen)py
O hν –H-[Co]
+
O O O
50%
Scheme 141
Chiral allenes can be prepared by reaction of chiral propargylic ethers and acetates with organo!
copper reagents as shown in Scheme 031 ð89JA7931Ł[ This process involves an anti elimination of
Metal 560
the copper group and the methoxy group as shown[ Extension of this process to the use of a
Grignard reagent in the presence of a catalytic amount of a copper"I# salt has also been undertaken^
the stereochemistry of the elimination step is anti if the counterion present is iodide but syn with
chloride[
Bu Bu Cu
Bu
–40 °C H
H + BuCu•MgBr2•2P(OEt)3 •
Bu Bu
OMe
MeO H Chemical yield, 95%
Optical yield, 96%
Scheme 142
Alkylmercury compounds react with chlorocarbons thermally\ photochemically or by free!radical

initiation to form alkenes via radical intermediates as shown in Equation "100# ð66JOM"013#216\
66JOM"013#238\ 66JOM"013#260Ł[ Secondary and tertiary alkylmercurials are particularly unstable ther!
mally[ Elimination of alkenes from dialkylmercury compounds on treatment with trityl cation
proceeds rapidly via a hydride abstraction from the position b to the carbon0mercury bond
ð60JA5167Ł "see Section 0[03[5[2#[ Deoxymercuration under acidic conditions to form alkenes is
believed to proceed via a metal bridged ionic intermediate ð59JA628\ 54JOC0482Ł[ Nitroalkenes can
be prepared by base!induced elimination from b!nitro mercuric halides formed by nitromercuration
of alkenes "Scheme 032# ð67JA5183Ł[
But2Hg + CCl4 + ButCl + Hg + CHCl3 + C2Cl6 (211)
NO2 NO2
HgCl2, NaNO2 i, NaOH (aq.)
80% ii, HCl (aq.)

HgCl
>98%
Scheme 143
1.15
Formed by Condensation:
Condensation of Nonheteroatom
Linked Functions, Halides,
Chalcogen or Nitrogen Functions
CHRISTOPHER M. RAYNER
University of Leeds, UK
0[04[0 BY CONDENSATION FROM NONHETEROATOM LINKED FUNCTIONS 563
0[04[0[0 Oxidative Couplin` of Hydrocarbons 563
0[04[0[1 Alkene Metathesis 563
0[04[1 BY CONDENSATION OF HALIDES] METAL MEDIATED CONDENSATION OF èm!DIHALIDES

AND RELATED COMPOUNDS WITH CARBONYL GROUPS 565
0[04[1[0 Chromium!mediated Condensation 565
0[04[1[1 Zinc!mediated Condensation 567
0[04[1[2 Condensations Mediated by Other Metals 568
0[04[2 BY CONDENSATION OF OXYGEN FUNCTIONS 570

0[04[2[0 Synthesis of b!Lactones and Subsequent Decarboxylation 570
0[04[2[1 Conversion of Carbonyl Compounds to 0\2\3!Thia! and 0\2\3!Selenadiazolines and Extrusion of N1 and
S or Se and Related Reactions 573
0[04[2[2 McMurry Couplin` of Carbonyl Compounds 576
0[04[2[3 Addition of Orànometallic Reaènts to Carbonyl Compounds and In Situ Dehydration 581
0[04[3 BY CONDENSATION OF SULFUR\ SELENIUM OR TELLURIUM FUNCTIONS 582

0[04[3[0 Alkylation of Sulfur"II# Stabilised Carbanions and Elimination 582
0[04[3[1 Alkylation of Sulfur"IV# Stabilised Carbanions followed by Elimination 582
0[04[3[1[0 Alkylation of sulfoxides and elimination 582
0[04[3[1[1 Alkylation of sul_namides and elimination 584
0[04[3[2 Alkylation of Sulfur"VI# Stabilised Carbanions followed by Elimination 585
0[04[3[2[0 The Julia reaction and related transformations 585
0[04[3[2[1 The Ramber`ÐBacklund reaction 693
0[04[3[2[2 Alkylation of sulfoximine stabilised carbanions followed by eliminationÐthe Johnson
"N!methylphenylsulfonimidoyl#methyl lithium method 609
0[04[3[3 Alkylation of Selenium"II# and Selenium"IV# Stabilised Carbanions Followed By Elimination 601
0[04[3[4 Alkylation of Tellurium Stabilised Anions Followed By Elimination 605
0[04[4 BY CONDENSATION OF NITROGEN FUNCTIONS 606

0[04[4[0 Rhodium Catalysed Dimerisation of Diazo Compounds 606
562
563 C1C Bonds by Condensation of Halides\ Chalcoèn or Nitroèn
0[04[0 BY CONDENSATION FROM NONHETEROATOM LINKED FUNCTIONS
0[04[0[0 Oxidative Coupling of Hydrocarbons
The oxidative coupling of hydrocarbons to give alkenes is a reaction of relatively little use
synthetically\ as harsh reaction conditions are required and yields are low\ and so will be mentioned
only brie~y[ The coupling of methane to give ethylene using a manganese oxide:sodium chloride
catalyst at 649>C occurs in up to 29) yield ð76CC277Ł[ Other catalysts based on ytterbium"III#
oxide:calcium oxide are less e.cient\ particularly at lower temperatures ð89AC48Ł[
0[04[0[1 Alkene Metathesis

The metathesis of alkenes using transition metal catalysts was _rst reported in 0853 ð53IEC069Ł\
and has since been the subject of a number of extensive reviews ð71COMC!I"7#388\ 75JOM"299#138\ B!
75MI 004!90\ 80COS"4#0004Ł[ The metathesis reaction is basically a transition metal "e[g[\ Ti\ Ta\ W\
Mo\ Ru\ Re\ Os# ð75JOM"299#138Ł catalysed exchange of the carbon atoms "and their substituents#
which make up the double bond of an alkene "Equation "0##[ The reaction has been the subject of
considerable mechanistic investigation ð71COMC!I"7#388\ 74CC763\ 76JA788Ł^ however\ this is beyond
the scope of this chapter[
R catalyst
R R1
2 + (1)
R1 R R1
At present\ one of the major limitations of the reaction is the sensitivity of the catalyst to
functional groups ð65CL0908Ł which\ although better catalysts are being developed\ has limited the
synthetic applications of the standard metathesis reaction[ This is particularly the case for catalysts
based on early transition metals such as Ti\ Ta\ W and Mo[ More recently\ systems using the later
transition metals such as Re and Ru are potentially more useful as they are able to metathesise
alkenes containing basic functional groups ð80COS"4#0004Ł[ Catalysts have been developed which will
tolerate a number of functional groups including quaternary ammonium salts ð66CC491\ 66RTC"M#80Ł\
ethers ð63CC682\ 65CL0908\ 66CC087Ł\ nitriles ð63CC682\ 65CL0908\ 66CC087\ 70CC0970\ 74CC0705Ł\ esters
ð63CC682\ 65MAC0238\ 66TL330\ 79TL0604Ł and sulfonates ð71TL1886Ł[
The reaction is an equilibrium\ and often mixtures of products are obtained which can be di.cult
to separate[ The reaction is\ however\ very important industrially and is used for the production of
alkenes\ for example\ the Shell Higher Ole_n Process is used to make C01 to C05 alkenes which are
used in the manufacture of surfactants ð56HP121\ 68CT383\ 71COMC!I"7#388Ł[
Alkene metathesis has been used for the synthesis of a number of macrocyclic alkenes[ Cyclohep!
tene and cyclooctene undergo metathetic dimerisation using Re1O6:Al1O2[ The activity of the catalyst
is increased signi_cantly by the addition of SnMe3[ Good yields are obtained by displacing the
equilibria using a Soxhlet!type apparatus to promote metathesis of the more volatile components
of the reaction mixture "Scheme 0# ð76AG"E#691Ł[ In an approach to the synthesis of civetone "0#\ the
metathesis of unsaturated ester "1# gave the diester "2# which could be isolated by chromatography as
a 0[2 ] 0 mixture of cis "Z#! and trans "E#!isomers in good yield[ Conversion to the macrocycle by
Dieckman condensation\ hydrolysis and decarboxylation gave civetone as an inseparable mixture
of isomers "Scheme 1# ð79TL1844Ł[
The use of cyclic alkenes in metathesis reactions leads to the production of polymeric systems by
Re2O7/Al2O3
Me4Sn
68% isolated yield
Re2O7/Al2O3
Me4Sn
30% isolated yield

Scheme 1
Nonheteroatom Linked Functions 564
O
WOCl4
Me(CH2)7CH=CH(CH2)7CO2Et EtO2C(CH2)7CH=CH(CH2)7CO2Et
(2) Cp2TiMe2 (3)
87%
(1)
Scheme 2
a process known as ring opening metathesis polymerisation "ROMP#[ A full discussion of ROMP
is beyond the scope of this chapter^ however\ extensive reviews are available ð71COMC!I"7#388\
75JOM"299#138\ 78SCI896Ł[ Metathesis of alkenes such as norbornene derivatives\ using tungsten\
ruthenium or osmium catalysts\ gives rise to low polydispersity homopolymers "Equation "1##
ð76MM0058\ 76MM1539Ł[
ROMP
(2)
n
The ROMP of 6!oxabicycloð1[1[0Łhept!4!ene derivatives provides an interesting example of the

choice of catalyst "Equation "2##[ Highly Lewis acidic catalysts such as WCl5 or WOCl3 preferentially
coordinate to\ and cationically open\ the bridging ether[ However\ less Lewis acidic catalysts such
as RuCl2\ Ru"0\4!COD#Cl2\ and OsCl2 are much more successful[ The homogeneity and cis:trans
ratio of the polymer can be controlled depending on the catalyst used ð77JA859Ł[ A related reaction
has also been carried out under aqueous conditions using RuCl2 as a catalyst ð77JA6431Ł[ The poly"6!
oxanorbornene# products are believed to adopt a helical structure "3# with the tetrahydrofuranyl
oxygen atoms pointing inwards\ and thus have potential as ionophores and ion channels[ Recently
reported chiral molybdenum!based systems give all!cis highly tactic poly"1\2!"R#1norbornadiene#
"RCF2 or CO1Me# with superior selectivity to that previously observed ð82JA3302Ł[
O
O
R RuCl3
(3)
R
R R n
R = H, OH, OMe, CH2O-TMS
O O
O O
O O
O O
O
O
(4)
Metathesis of alkynes is also a known reaction ð74JA4876Ł^ however\ more relevant to this
chapter is work recently reported by Trost et al[ on enyne metathesis "Scheme 2# ð80JA0749\ 82S713Ł[
Catalysts based on the palladacycle 1\2\3\4!tetrakis"methoxycarbonyl#palladacyclopentadiene
"TCPC# "4^ RMe# ð77JA0525Ł provide good yields and a high degree of selectivity for the enyne
metathesis reaction\ which is exploited in an approach to the botrydianes[
RO2C CO2R
OBn catalyst (5 mol%) OBn
dimethyl acetylenedicarboxylate (1.1 equiv.)
RO2C CO2R
Pd
(5 mol%) (5)
P
O )3 Catalyst (5) Time Yield(%)
R = Me 60h 62
R = CH2C3F7 22h 66
Scheme 3 R = CH2CF3 1h 68
0[04[1 BY CONDENSATION OF HALIDES] METAL MEDIATED CONDENSATION OF

gem!DIHALIDES AND RELATED COMPOUNDS WITH CARBONYL GROUPS
This section describes methods for the formation of alkenes by metal mediated condensation of
èm!dihalides\ or equivalent species with carbonyl compounds[ The reactions are divided according
to the metal involved\ and approaches involving Cr\ Zn\ Mg\ Al\ Zr\ Ti\ Sm and Li are included[
This kind of reaction has found particular application in the synthesis of terminal alkenes\ although
in some cases more substituted systems can be prepared[ The main emphasis is on reactions where
the metal complex is generally not isolated but generated and used in situ^ reactions of more speci_c
isolated organometallic reagents will be covered elsewhere "see Section 0[05[2#[
0[04[1[0 Chromium!mediated Condensation

The condensation of a èm!dihalide\ usually the iodide or bromide\ with aldehydes and ketones
mediated by a chromium"II# species provides a method for direct formation of an alkene ð57JCS"A#23\
76JA840\ 80COS"0#796\ 81S137Ł[ Reduction of a dihalide by CrCl1 gives the èm!dichromium intermediate
"5# which reacts e.ciently with aldehydes with high "E# selectivity "Scheme 3#[ Lower "E#:"Z#
selectivity is observed using CrCl2:Zn as the source of chromium"II# species[ The reaction is most
successful with 0\0!diiodoethane and aldehydes in THF[ With other diiodides\ dramatic increases
in yields are observed in the presence of a donor such as DMF "0 equivalent#\ which greatly increases
the reduction power of the chromium"II# species ð76JA840Ł "Scheme 4#[ The reaction is also promoted
by ultrasound ð73BCJ1224\ 76JA840Ł[ Even so\ low yields are still obtained with èm!dibromides and
chlorides\ although the presence of a!trimethylsilyl or !phenylsulfenyl substituents allow use of
dibromides for the preparation of vinylsilanes and vinylsul_des\ respectively\ again with high "E#
selectivity[ CrCl2:LiAlH3 can also be used in place of CrCl1 as the source of chromium"II# species
for these reactions ð76TL0332Ł[ The reaction with ketones is only really successful using diiodoethane\
other diiodides giving low yields[ However\ the low basicity of the reagent system means that easily
enolisable ketones are converted e.ciently to alkenes\ subject to the above limitations "Equation
"3##[
X CrCl2 CrX2
R1CHO R
R1
R X R CrX2
X = I, Br (6)
Scheme 4
Halides 566
CrCl2, THF
I 25 °C, 4.5 h
CHO +
I 94%
96:4 (E):(Z)
I
CHO +
I
Conditions
CrCl2, THF, 24 h, 12%, 72:28 (E):(Z)
CrCl2, DMF (1 equiv.), THF, 1 h, 74%, 93:7 (E):(Z)
Scheme 5
O
I CrCl2, THF
+ (4)
I 25 °C
85%
16:84 (E):(Z)
a!Acetoxybromides react with aldehydes under similar reaction conditions to give alkenes[ Com!
mercial CrCl1 is reported to be unsuccessful for this reaction\ instead the chromium species being
generated using CrCl2:Zn[ A coordinating agent such as DMF is essential for an e.cient reaction^
however\ other complexing agents such as TMEDA or tetraethylethylenediamine ð0\1!bis"di!
ethylamino#ethaneŁ "TEEDA# are also e}ective\ but can a}ect the stereoselectivity of double bond
formation[ Ketones and esters remain una}ected by the reaction conditions[ a\b!Unsaturated and
aromatic aldehydes react with little stereoselectivity and low yields[ In general\ use of higher
temperatures can improve yields but often at the expense of "E#:"Z# selectivity[ A variety of a!
acetoxybromides have been used in this reaction^ one example is shown in Equation "4# ð82SL726Ł[
CHO Br
Zn, CrCl3
+ (5)
CO2Me OAc DMF, THF, 66°C CO2Me
61%
73:27 (E):(Z)
The high "E# selectivity and mild reaction conditions for the condensation of aldehydes and
diiodides using CrCl1 had led to its exploitation in natural product synthesis[ In an approach to the
synthesis of a segment of macbecin I\ condensation of aldehyde "6# with 0\0!diiodoethane using
CrCl1 proceeds in high yield with exclusive formation of the "E#!alkene with no racemisation at the
chiral centre adjacent to the aldehyde group "Equation "5## ð78JCS"P0#089Ł[ Similarly\ the synthesis
of unusual long chain ketones originating from algae has been accomplished using successive CrCl1!
mediated condensations to give the all!"E# pentaene "7# "Scheme 5# ð77TL1488Ł[ The analogous all!
"Z# alkene was prepared\ for comparison with the natural product\ using a salt!free Wittig reaction[
OMe O CrCl2 (8 equiv.) OMe

MeCHI2 (2 equiv.)
Ar H Ar (6)
THF, 25 °C, 2.5 h
O-TBDMS 91% O-TDBDMS
(7) TBDMS = t-butyldimethylsilyl
>99% (E)
The condensation of haloforms with aldehydes using CrCl1 is an excellent method for the
preparation of "E#!vinyl halides ð75JA6397\ 80COS"0#796Ł[ The general reaction is beyond the scope of
this chapter^ however\ it has led to the development of a one!pot procedure for the preparation of
allylic alcohols by CrCl1!mediated condensation of iodoform and benzaldehyde[ The initially formed
"E#!vinyl iodide\ is reacted in situ with another aldehyde using NiCl1 catalyst in DMF\ to give the
allylic alcohol in good overall yield "Scheme 6# ð 72TL4170\ 75JA4533\ 75JA5937\ 75JA6397Ł[
In a di}erent approach to the use of chromium!based reagents for alkene synthesis\ the trans!
O I OMe CrCl2 OMe
+ C7H15
C7H15 H I ( )5 OMe OMe
( ) ( ) COMe
C7H15 5 ( )5 5 ( )5
(8)
Scheme 6
O OH
I
H CHI3, CrCl2 C8H17CHO C8H17
THF, 2 h NiCl2 (cat.)
DMF, 60 °C
62% >92:8 (E):(Z)
Scheme 7
metallation of the Grignard reagent derived from trimethylsilylmethyl chloride using CrCl2 gives
the organochromium reagent "8# which adds e.ciently to aldehydes[ The b!trimethylsilyl alcohols
thus prepared can be isolated and on treatment with dilute mineral acid eliminate to give the alkene
"Scheme 7# in a process related to the Peterson alkeneation "see Section 0[05[1#[ The reaction is
reported to be unsuccessful with ketones ð70TL4920Ł[
i, RCHO
CrCl3 ii, H2O
TMS MgCl TMS CrCl2 R
THF (9) iii, H+
Scheme 8
0[04[1[1 Zinc!mediated Condensation

The methylenation of carbonyl compounds using organozinc reagents derived from dihal!
omethanes works best in the presence of Lewis acids\ typically TiCl3 or AlMe2 ð67TL1306\ 79BCJ0587\
80COS"0#638Ł[ The reaction is successful for aldehydes\ ketones and a\b!unsaturated aldehydes "Sch!
eme 8#[ Because it is an electrophilic reagent\ it is also successful with enolisable aldehydes and
ketones ð74TL4468Ł[ Diiodomethane works best when using AlMe2 or VCl3 as the catalyst^ the
stronger Lewis acid TiCl3 enables dibromomethane to be used ð67TL1306\ 79BCJ0587Ł[ Detailed
experimental procedures are available ð76OS"54#70Ł[ More complex dihalides have also been used in
related reactions ð77TL2246Ł[ Excellent chemoselectivity for aldehydes in the presence of ketones
can be achieved using the much milder Lewis acid\ Ti"OPri#3 "Scheme 09#[ Reversal of such chemo!
selectivity can be achieved by pretreatment of the substrate with Ti"NEt1#3 "Scheme 09# ð74TL4470Ł[
Similarly\ ketones can be methylenated in the presence of esters and free alcohols ð74TL4468Ł[ This
has been exploited in a synthesis of a gibberellin precursor "Equation "6## ð71TL3182Ł[
O H H
CH2Br2–Zn–TiCl4, THF
(7)
OH 90% OH
O O
MeO2C MeO2C
O O
The reaction can also be carried out using dibromo! or diiodomethane in the absence of Lewis
acids^ however\ the use of ultrasound is desirable and greatly accelerates the process "Equation
"7##[ Even so\ yields with ketones and a\b!unsaturated aldehydes are low under these conditions
ð73BCJ1224Ł[
Halides 568
O CH2I2-Zn-Me3Al
C11H23 H 0 °C, 4 h C11H23

81%
CH2Br2-Zn-TiCl4
25 °C, 40 h
92%
O
O
CH2I2-Zn-Me3Al
H
0 °C, 1 h
75%
Scheme 9
O O
i, Ti(NEt2)4, CH2Cl2 CH2I2–Zn–Ti(OPri)4
CHO CHO
( )8 ii, CH2I2–Zn–TiCl4 ( )8 25 °C, 3 h ( )8
THF, 25 °C, 30 min 83%
76%
Scheme 10
O Zn, CH2X2, THF

(8)
25 °C, ultrasound
C6H13 H C6H13
X = I, 20 min, 70%
X = Br, 300 min, 58%
A related reaction involves the generation of a mixed bismetallic reagent from an allylic zinc
bromide and a vinyl!Grignard\ !lithium or !diethylaluminum reagent[ Condensation with an alde!
hyde in the presence of BF2 = OEt1 gives the 0\4!diene in good yield and with very high "E#!selectivity
"Scheme 00# ð75TL0928\ 75TL0932Ł[
ZnBr PhCHO
MgBr
C6H13 ZnBr
C6H13 BF3•OEt2 C6H13 Ph
–90 → –50 °C
MgBr 78% >99:1 (E):(Z)
Scheme 11
0[04[1[2 Condensations Mediated by Other Metals

The condensation of èm!dibromides and !diiodides with carbonyl compounds can be
accomplished using magnesium\ either as a mercury amalgam or\ less e.ciently\ as magnesium
turnings ð69T0170Ł[ The reaction is rapid\ often being complete in a few minutes\ and good yields
can be obtained with both aldehydes and ketones "Scheme 01#[
O
Mg/Hg
MgX R
R R1
CH2X2
Et2O, benzene MgX R1
X = Br, I R = Ph, R1 =
H, X = I, 65%
R, R1 = (CH2)6, X = I, 68%
X = Br, 63%
R, R1 = cholest-4-en-3-one, X = I, 70%
Scheme 12
A series of methylenating agents can be prepared by the action of aluminum on dichloromethane
ð55TL5910\ 56TL0470\ 77JOC1718Ł[ The initial complex "09# is relatively unreactive\ but if treated with
triethyl! or trimethyl!aluminium\ very e}ective ketone methylenating agents "00# and "01# are
obtained[ They convert a broad range of aliphatic\ alicyclic and aromatic ketones to their methylene
derivatives with no competitive alkylation or reduction[ Complexes of these reagents with ethers
"THF or Et1O# are particularly e.cient[ Unfortunately\ related multicarbon alkenylating agents
such as "02# are much less successful\ inducing severe side reactions for substrates other than
aromatic ketones\ which themselves give only fair to good yields "Scheme 02#[
AlCl2 AlR3 AlRCl

CH2Br2
3 CH2Cl2 + 4 Al
AlCl2 CH2Cl2
AlRCl
(10) (11) R = Et
(12) R = Me
(12)•THF EtClAl
Ph O Ph
CH2Cl2 AlClEt
75% (13)
Scheme 13
Organozirconium!based methylenating agents such as "03# can be prepared by treatment of a

dihalomethane with zirconocene dichloride and zinc[ They are usually generated in situ and rapidly
methylenate aldehydes\ ketones and enones\ and are reportedly particularly useful for acid!sensitive
substrates "Scheme 03# ð78TL2816Ł[ Unfortunately\ homologous dihalides such as 0\0!dibro!
mopentane are unsuccessful in this reaction probably owing to b!elimination in the organozirconium
intermediate[
CH2Br2, Zn Cp M
Cp2ZrCl2 Zr
THF Cp Cl
(14)
M = ZrCp2Cl or ZnCl
C8H17 C8H17
Cp2ZrCl2, Zn, CH2Br2
THF, 25 °C, 3 h
64%
O
Scheme 14
Transmetallation of the Grignard reagent derived from trimethylsilylmethyl chloride with TiCl3
gives a reagent "04# which methylenates aldehydes but not ketones "Scheme 04#[ The intermediate
alkoxytitanium complex is not isolated but undergoes in situ elimination to give the corresponding
alkene ð70TL4920Ł[ This is in contrast to the related chromium!based system which needs further
acid treatment before the alkene is formed "Scheme 7#[ Higher yields can be obtained using the
trimethylgermanium reagent "05# under similar conditions\ although the reaction is still poor with
ketones[
TiCl4 R
RCHO Me3X R
Me3X MgCl Me3X TiCl3
THF OTiCl3
(15) X = Si R = C6H13, X = Si, 65%
(16) X = Ge R = C6H13, X = Ge, 88%
Scheme 15
The methylenation of aldehydes and ketones using samarium has been reported ð79JA1582\
75TL2780\ 76CL1090Ł[
Treatment of an aldehyde or ketone with SmI1 and a dihalomethane initially
gives an iodohydrin\ which upon treatment with a further equivalent of SmI1 in hexa!
Oxyèn 570
methylphosphoramide "HMPA# with an additive such as N\N!dimethylaminoethanol "DMAE# or
glutaric anhydride\ eliminates to give the alkene in a useful one!pot procedure "Scheme 05#[
O R1 SmI2, HMPA
CH2I2, SmI2, 5 min
I
R2 R2
R1 R2 OSmI DMAE R1
R1 = C11H23, R2 = H, 73%
R1, R2 = (CH2)11, 80%
Scheme 16
Finally\ chloromethyllithium can be generated readily from chloroiodomethane and methyl!

lithium or lithium powder ð75CC0554Ł[ It is usually generated in situ\ and reacts with aldehydes and
ketones to give the methylenated products in moderate to good yields "Equation "8##[
i, ClCH2I, MeLi, –78 → –60 °C

(9)
ii, Add ketone and warm
to 25 °C overnight
80%
0[04[2 BY CONDENSATION OF OXYGEN FUNCTIONS
0[04[2[0 Synthesis of b!Lactones and Subsequent Decarboxylation

The thermal elimination of carbon dioxide from a b!lactone is generally a stereospeci_c process\
with geometry of the b!lactone being conserved in the alkene product "Equation "09## ð55JOC3932\
61JA1999\ 82S330Ł[ The reaction occurs at temperatures ranging from approximately 79>C to 059>C\
although more extreme conditions are required in some cases ð75T0470\ 80JOC0065Ł[ The reaction can
also be catalysed by SiO1 ð80JOC0065Ł or a carboxylic acid "e[g[\ tri~uoroacetic acid#^ however\ in
the latter case stereoselectivity can be seriously a}ected "Scheme 06# ð70CC780Ł[
O
R3 R4
O heat
+ CO2 (10)
R1 R3 80 → 160 °C
R1 R2
R2 R4
But O But
CF3CO2H (1 mol%) O 100 °C
1,2-dichlorobenzene, 25 °C 1,2-dichlorobenzene
Ar Ar But Ar
98:2 (E):(Z) Ar = 4-(MeO)C6H4 >2:98 (E):(Z)
Scheme 17
The preparation of b!lactones for this reaction is generally carried out by condensation of a
carboxylic acid enolate equivalent with an aldehyde or ketone[ The dianions of carboxylic acids add
to aldehydes ð60JOC0038\ 68CC41\ 70JOC2248Ł and ketones ð61JA1999\ 63JOC0549\ 67JOC3463Ł to give
predominantly the threo!b!hydroxy acids where appropriate "Scheme 07#[ These products are then
readily cyclised to the b!lactones by treatment with phenylsulfonyl chloride:pyridine\ p!tolu!
enesulfonyl chloride:pyridine ð73T0158Ł\ or methanesulfonyl chloride:Na1CO2 ð65JCS"P0#773Ł[ Ther!
molysis "079>C# of b!lactones derived from threo!b!hydroxy acids gives trans!alkenes as the major
products ð70JOC2248Ł[ Alternatively\ if the lactonisation is carried out at slightly elevated tem!
peratures "34Ð44>C#\ alkene products can be isolated directly ð61JA1999Ł[ This procedure is often
limited by the e.ciency of the initial condensation reaction[
R1 R1
i, LDA (2 equiv.) R2 CO2H O R2 R1
R1 R2
THF, –78 °C → RT PhSO2Cl 180 °C
CO2H
ii, R3R4CO, pyridine R4 O –CO2
R2 R4 OH R4 R3
0 °C → RT overnight R3 5 °C R3
iii, HCl (aq.)
threo trans
PhSO2Cl, pyridine, 45–55 °C
Yields (%)
R1 R2 R3 R4 Acid Lactone Alkene Ref.
But H H But 79 82 95 81JOC3359

1-Adb H H 1-Adb 22 43 82 81JOC3359
But H H 1-Adb 64 85 100 81JOC3359
H Ph Ph Ph 81 70 100 72JA2000
H Me Ph Ph 76 37a 100 72JA2000
Me Me –(CH2)5– 75 67 100 72JA2000
–(CH2)5– 61 90 100 74JOC1650
a >50% alkene also isolated. b 1-Ad = 1-Adamantyl.

Scheme 18
The condensation of esters with aldehydes and ketones allows the preparation of b!hydroxyesters\
which may also be considered as precursors to b!lactones[ However\ problems can be encountered as
the conditions required for ester hydrolysis and:or lactone synthesis can induce a retro!Reformatsky
reaction with destruction of the b!hydroxyester ð61JA1999Ł[ Nevertheless\ some b!hydroxyesters
have been used in this manner[ The b!hydroxyester "06# can be stereoselectively alkylated with alkyl
halides ð73T0158Ł[ Hydrolysis\ lactonisation and thermolysis then give the trans!alkene selectively
"Scheme 08#[ Alternatively\ the b!hydroxyester "07#\ synthesised by nonstereoselective reduction
"41 ] 37 mixture# of the corresponding b!keto ester followed by chromatography\ can be processed
similarly to give a trisubstituted alkene "Scheme 19# ð57TL3458\ 65JCS"P0#773Ł[
OH
OH i, LDA (2 equiv.) CO2Et
THF, –50 °C i, KOH, H2O, EtOH, 85%
CO2Et
Ph
ii, BnBr, HMPA ii, TsCl, pyridine, 82%
Ph
–50 → 0 °C iii, 150 °C, 84%
(17) >95:5 selectivity trans
Scheme 19
O O OH O Bun
i, NaBH4, MeOH i, NaOH, H2O, EtOH
Bun OEt ii, separation Bun OEt ii, MsCl, Na2CO3
Bun Bun Bun
pentane
(18) iii, collidine, ∆
Scheme 20
The condensation reaction between a thioester enolate and a ketone occurs with high ster!
eoselectivity^ this provides a direct route to b!lactones\ as the intermediate alkoxide cyclises in situ
Oxyèn 572
with loss of the thiophenolate group "Scheme 10# ð80JOC0065Ł[ In the case of more hindered
thioesters\ improved yields of the b!lactone can be obtained by use of the 1\5!dimethylthiophenyl
ester[ Decarboxylation gives the "E#!alkene in high yield\ the reaction occurring at 79Ð009>C when
catalysed by silica gel "09) w:w#[
OLi O R1 O
O
i, LDA, THF R3 –LiSPh R2
R2
SPh R4 SPh O
ii, R3R4CO R3
R2 R1
R1 R4
O
O i, LDA, THF O
R = Ph, 48%
SR ii, cyclohexanone
R = 2,6-dimethylphenyl, 72%
O O
i, LDA, THF 80–110 °C
O
SPh ii, acetylcyclohexane SiO2
75% H 95%
29:1 selectivity
Scheme 21
The condensation of "1!alkenyl#triphenoxytitanium derivatives with unsymmetrical ketones pro!

vides a highly diastereoselective route to substituted homoallylic alcohols\ which are readily con!
verted into b!lactones\ via b!hydroxy acids "Scheme 11# ð71HCA0861Ł[ Thermolysis again provides
access to the alkene with control of double bond geometry[
OH
O THF KMnO4, NaIO4
+ Ti(OPh)3 Ph
Ph 70–90% dioxane, H2O
60%
83–92% diastereoselectivity
OH i, PhSO2Cl, pyridine, 5 °C,

82% Ph
CO2H
Ph ii, 140–160 °C
76%
Scheme 22
Lithium phenylethynolate can be readily generated by loss of benzonitrile from the lithiated
isoxazole "08#[ It condenses with carbonyl compounds to form the lithiated b!lactone "19# via the
corresponding ketene "Scheme 12#[ The enolate "19# may be reacted with alkyl halides\ aldehydes\
or protonated to give highly substituted b!lactones\ which extrude CO1 on heating to 039>C to form
the expected alkenes ð64AG"E#654Ł[
The synthesis of b!lactones and subsequent decarboxylation provides an alternative process to
the Wittig reaction[ Although examples of synthetic applications are limited ð82S330Ł\ this reaction
has been used for the introduction of the isopropylidene groups in syntheses of terpinolene "10# and
"2#!a!curcumene "11#\ by condensation of the required carboxylic acid dianion with acetone\
followed by b!lactone formation and thermolysis ð63JOC0211Ł[
In addition to forming b!lactones which may subsequently decarboxylate\ b!hydroxy acids can
also undergo elimination via a Grob!type fragmentation\ to give alkenes[ This is particularly useful
as it provides the opposite alkene geometrical isomer to that which would be produced if a b!
lactone intermediate was used "Scheme 13#[ The alcohol is converted into a leaving group\ either a
phosphonium salt using Mitsunobu!type chemistry ð68CC41Ł\ or an imidate by treatment with N\N!
dimethylformamide dimethyl acetal "DMFÐDMA# ð73T0158Ł[ The zwitterionic intermediates thus
formed after deprotonation of the acid then undergo stereocontrolled anti!elimination with loss of
CO1\ generally to give "Z#!alkenes ð64HCA0349Ł[ A related oxidative decarboxylation has been
reported using VOCl2 and other vanadium"V# complexes ð78JA2958Ł[
Ph Ph
N BunLi, THF N –60 °C R1R2CO
O O Ph OLi
–60 °C –PhCN
Ph Ph
Li
(19)
R1 R1 R1
R2 OLi R2 R2 R1 Ph
O BnBr, HMPA O 140 °C
Ph or PhCHO Ph
Ph • O R2 R4
O Li or AcOH R3 O
(20)
Yield (%)a
R1 R2 R3 Lactone Alkene
Ph H Bn 68 95(Z)
Me Me Bn 56 93
–(CH2)5– H 51 92
Me Me H 59 88
But H H 65 —
Ph H PhCH(OH) 79b —
a 75AG(E)765. b based onPhCHO.
Scheme 23
(21) (22)
CO2–
OH
dead, PPh3 80–120 °C/10 mm Hg
CO2H H R1
R2 H R2 68–77% R1 R2
THF, 25 °C, 5 min
R1 +
R1 = Ph, R2 = alkyln
OPPh3
CO2–
OH H Bn
DMF-DMA H Me 87% Ph
CO2H
CHCl3 O
Bn 60 °C >97:3 (Z):(E)
N+
Scheme 24
0[04[2[1 Conversion of Carbonyl Compounds to 0\2\3!Thia! and 0\2\3!Selenadiazolines and Extrusion

of N1 and S or Se and Related Reactions
The two!fold extrusion of nitrogen and sulfur from 0\2\3!thiadiazolines to form alkenes\ was
originally developed by Barton ð61JCS"P0#294\ 63JCS"P0#0683Ł and also independently by Kellogg
Oxyèn 574
ð61JOC3934Ł^ for a review see ð77T5130Ł[ The reaction involves initial loss of N1 to form a thiocarbonyl
ylide which undergoes conrotatory ring closure to a thiirane which loses sulfur\ often induced by a
phosphine "PBu2\ PPh2 or P"NEt1#2# "Scheme 14#[
N N R2 R4 S R1 R4
R2 R4 –N2 conrot. R1 R4 PR3
+
S R1 S – R3 R2 R3 R2 R3
R1 R3
Scheme 25
The 0\2\3!thiadiazolines may be synthesised by a number of routes[ Condensation of hydrazine

hydrate\ hydrogen sul_de\ and a carbonyl compound gives a 0\2\3!thiadiazolidine "12# with low
stereoselectivity[ This can then be oxidised to the 0\2\3!thiadiazoline using diethyl azodicarboxylate
"dead# ð61JOC3934Ł\ lead tetraacetate ð61JCS"P0#294\ 82JOC32Ł or 1\2!dichloro!4\5!dicyano!0\3!benzo!
quinone ð61JCS"P0#294Ł[ Alternatively\ condensation of hydrazine and a carbonyl compound
followed by chlorination and cyclisation provides the most e.cient route to these systems "Scheme
15#[
H H
O NH2NH2 N N
N N dead, LTA or ddq R2 R1
R2 R1
R1 R2 H2S S
S R1 R2
R1 R2
(23)
H H
H2S N N N N N N
dead
R2 N +
N R2 Et2O R R R R R R
S S S
R = But, 1:0.6 trans:cis
R1 R1
Cl2, –70 °C Cl H2S, CHCl3 N N
R2 N R2 N R2 R1
N R2 CH2Cl2
N R2 60–100%
Cl R1 S R2
R1 R1
ddq = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
Scheme 26
0\2\3!Thiadiazolines can also be synthesised directly by cycloaddition of a thioketone and a

diazo compound "Scheme 16# ð61JOC3934Ł[ This has two advantages^ it allows the synthesis of
unsymmetrical alkenes and it alleviates the requirement of a _nal oxidation step[ However\ the
dangers and unpleasantness of working with the diazo and thioketone precursors should also be
taken into consideration[ Both the thioketone and diazo compound are readily synthesised from
the corresponding carbonyl compounds[ The diazo compound is prepared via the hydrazone either
via the triphenylphosphoranylhydrazone ð63JCS"P0#0683\ 64CC428Ł or by oxidation using barium
manganate ð82JOC4899Ł[ The intermediate 0\2\3!thiadiazolines can be isolated\ or directly converted
to alkenes by carrying out the cycloaddition reaction at elevated temperatures "059>C# "Equation
"00## ð64CC428Ł[
O (MeO)3CH, MeOH S N N
R2 R3
R2 R1 H2S, HCl, 0 °C R2 R1 S
R1 R4
i, NH2NH2•H2O, HO(CH2)2OH, ∆
O N2
or NH2NH2(NH2NH3)2•SO4
R3 R4 ii, BaMnO4 or PPh3•Br2 then ∆ R3 R4
Scheme 27
160 °C, 45 h
+ (11)
S N N 72%
PPh3
mainly trans-isomer
0\2\3!Selenadiazolines undergo similar extrusion reactions to the corresponding sulfur systems\

and have the advantage that the selenoketone precursors "also referred to as selones# show greater
reactivity toward diazo compounds^ thus 0\2\3!selenadiazolines may be easier to prepare by the
cycloaddition route "Scheme 17# ð64CC428\ 71JOC2452\ 82JOC4899Ł[ Again\ it is possible to carry
out the reaction at elevated temperatures without isolation of the intermediate selenadiazoline
ð71JOC2452Ł[ The selenoketones are prepared from ketones by heating the triphenyl!
phosphoranylhydrazone derivative with selenium powder ð71JOC2452Ł and a trace of base "e[g[\
NBu2# if necessary "Scheme 18# ð65JCS"P0#1968Ł[
Se N2 N N R1 R4
THF, RT R1 R4 ∆
+
R1 R2 R3 R4 R2 Se R3 R2 R3
Se Se
i, THF, RT 185 °C
+ +
ii, 185 °C 65%
40%
N2 N
N PPh3
Scheme 28
Se, 185 °C
N Se
66%
N PPh3
But Se, NBu3 (trace) But

N Se
But N PPh3 120 °C But
35%
Scheme 29
This reaction has found application in the synthesis of very hindered alkenes including "13#\
"14# and "15# ð63JCS"P0#0683\ 64CC428\ 73CB166Ł\ and potential precursors of the elusive tetra!t!
butylethylene\ and tied back analogues thereof "16# and "17# ð70TL3826\ 75T0582\ 82JOC4899Ł[
More recently\ this reaction has been applied to the synthesis of less sterically congested alkenes\
such as those derived from aldehydes "Scheme 29#[ Previously\ thermolysis of 0\2\3!thiadiazolines
to give relatively nonhindered alkenes resulted in only low yields of thiiranes or alkene products[
This is now believed to be a result of the instability of 0\2\3!thiadiazoline and 0\2\3!thiadiazolidine
precursors\ a problem which has been overcome by improved synthetic procedures ð82JOC32Ł[
A related two!fold extrusion reaction which can also be used for alkene synthesis is the thermolysis
of the oxathiolan!4!ones "20# and "21#[ Both these compounds lose CO1 and sulfur on thermolysis\
with the corresponding alkene formed in good yield ð61JCS"P0#294Ł[ The substrates are readily
prepared by acid!catalysed condensation of an aldehyde or ketone with mercaptodiphenylacetic
acid "Scheme 20#[
Oxyèn 576
X Y
Ph
But Ph
Ph
(26)
But Ph X = S, Y = Me, Me
(24) (25) X = CH2CH2, Y = CH2CH2
S S
S S
S S
(27) (28)
H H
R H2S, THF
R SH N N Pb(OAc)4 N N
NH2NH2
O
OH R S R CaCO3 R S R
H H
CHCl3
∆, THF
PPh3 S
R R
R R
(30) (29)
(29) (30)
R Yield (cis:trans) (%) Yield (cis:trans) (%)
C6H13 75(4:1) 70(4:1)

C9H19 62(4:1) 56(4:1)
66(6:1) 63(6:1)
Scheme 30
Ph S
Ph SH PhCHO Ph 150–160 °C Ph Ph
Ph
CO2H TsOH O 2h
Ph Ph
C6H6 O 95%
94% (31)
Ph Ph S
SH 2-methylcyclohexanone 215–225 °C Ph
Ph 4h
CO2K HCl, AcOH, 5 h O
Ph
74% 88% Ph
O
(32)
Scheme 31
0[04[2[2 McMurry Coupling of Carbonyl Compounds

The titanium induced reductive coupling of carbonyl compounds is an e.cient and widely!used
process for alkene preparation[ It has been the subject of a number of reviews ð79OPP250\ 72ACR394\
72MI 004!90\ 77CRV622\ 77T3184\ 78C28\ 78CRV0402\ B!78MI 004!90\ 78S772Ł[ The reaction has general appli!
cability and is successful for a wide variety of aldehydes and ketones\ including unsaturated\ aryl
and alkyl\ both intermolecular and intramolecular[ Although the reaction is often referred to as the
McMurry reaction ð63JA3697Ł\ it was also independently reported by Mukaiyama ð62CL0930Ł and
Tyrlik ð62BSF1036Ł around the same time\ with slightly di}erent reaction conditions[
McMurry|s initial discovery of this reaction provides a nice example of serendipity in synthetic
chemistry[ While attempting to develop a new procedure for carbonyl reduction\ McMurry inves!
tigated the use of LiAlH3 modi_ed by TiCl2\ and obtained the dimeric alkene "22# in 79) yield\
rather than the desired reduction product "23# "Scheme 21# ð72ACR394Ł[
TiCl3, LiAlH4
80%
O
(34) (33)
Scheme 32
The reactive species in the reaction is almost certainly a Ti"9# species in a _nely divided form
ð70BSB0030\ 71JOC137\ 71MI 004!90Ł[ There are many reported procedures for the generation of such a
species\ the most reactive and reproducible being formed from TiCl2 and a zincÐcopper couple
ð67JOC2144Ł[ In early experiments\ the age\ history and source of TiCl2 caused problems with
reproducibility^ however\ puri_cation by crystallisation as the complex TiCl2"DME#0[4 gives reliable
results\ even from batches of TiCl2 which were previously ine}ectual "Scheme 22# ð78JOC2637Ł[
Higher yields may be obtained if a nonaqueous _ltration procedure is used rather than an
aqueous work!up[ The coupling is believed to occur on the surface of the active titanium particle^
the highly pebbled {Swiss cheese| type of surface generated gives a very high surface!to!mass ratio
ð67JOC2144Ł[
conditions
O
Conditions Yield(%)
TiCl3/LiAlH4 12
TiCl3/Zn-Cu 37
TiCl3(DME)1.5 87
Scheme 33
Many other procedures are also available for the production of low valent titanium species by
reduction of either TiCl2 or\ less commonly\ TiCl3[ These are] TiCl2:K"graphite# ð65JOC785\ 67JOC2144\
71JOC137\ 74JOM"179#296\ 76S0960\ 77JA5803\ 77JCS"P0#0618Ł^ TiCl2:Li ð67JOC2144\ 71JOC137\ 71TL4374\
73LA0894Ł^ TiCl2:Na ð71JOC137Ł^ TiCl2:Zn0Cu ð67JOC2144\ 78JOC2637Ł^ TiCl2:LiAlH3 ð63JA3697\
65TL2154\ 67JOC2598\ 67JOC2138Ł^ TiCl2:LiAlH3:NR2 ð65CL0016\ 66S442\ 72JA0559Ł^ TiCl3:Mg"Hg#
ð62BSF1036\ 71JOC137\ 89AJC0328Ł^ TiCl3:Zn:pyridine ð66S442Ł[ In the case of TiCl3:Zn\ the addition
of an amine induces disproportionation to the active Ti"9# species ð76S0960Ł[
A synthetic approach to the synthesis of mevinolin "28# and compactin "39# gives a good example
for comparison of some of the various procedures available for generation of the active Ti"9# "Scheme
23#[ Under standard conditions no alkene was formed\ possibly due to the highly oxygenated nature
of the substrate[ Addition of a tertiary amine gave a better yield and improved the stability of the
acetal unit^ however\ the best yield was obtained using potassium graphite as the reducing agent[
Importantly\ no racemisation was observed at the position a! to the aldehyde unit in the cyclisation
of compound "25#[ Unfortunately this reagent system is very sensitive to atmospheric moisture
and:or oxygen\ which can lead to low yields with aged reagents ð80JOC5336Ł[
A survey of functionality compatible with reaction conditions has been published ð78CRV0402Ł[
Acetals "best with added amine#\ alcohols "but not allylic alcohols#\ alkenes\ silanes\ amines\ ethers\
halides "but not 0\1!dihalides# and sul_des are una}ected by the reaction[ Alkynes\ amides\ car!
boxylic acids\ esters\ ketones\ nitriles and tosylates will survive in some cases[ Allylic and benzylic
alcohols\ 0\1!diols\ epoxides\ enediones and quinones\ halohydrins\ a!haloketones\ aliphatic and
aromatic nitro compounds\ oximes and sulfoxides are all generally incompatible with the reaction
Oxyèn 578
O OSiButPh2 O OSiButPh2
O O
conditions
Et3SiO Et3SiO
H DME, RT H
R
O R
O
(35) R = H (37) R = H
(36) R = Et (38) R = Et
HO O
O
O
O
H
R
(39) mevinolin R = Me
(40) compactin R = H
(37)
Conditions Yield (%)
TiCl3, Zn-Cu 0
TiCl3, LiAlH4 0
TiCl3, LiAlH4, NEt3 30–35
TiCl3, C8K 71
Scheme 34
conditions[ Reductive coupling of aromatic ketones can lead to further reduction of the new C1C
bond forming the ethane derivative ð71JCS"P1#66Ł[
The reaction is usually e.cient and generally successful[ Symmetrical alkenes are prepared readily
from aldehydes or ketones\ saturated or unsaturated\ using any of the conditions described above
"Scheme 24# ð63JA3697\ 66S442\ 67JOC2144\ 73JOC2507Ł[ Hindered alkenes can also be prepared although
reduced yields are observed[ In extreme cases "e[g[\ di!tert!butylketone#\ reduction of the ketone to
the secondary alcohol is observed with no evidence of coupling ð79JCR"S#285Ł[
TiCl3/K, THF
O
85%
CHO TiCl3/LiAlH4
THF
2
85%
β-carotene
O TiCl3/LiAlH4
THF
85%
TMS
TMS TiCl3/Li, DME
CHO 38%
TMS
Scheme 35 (continued)
O TiCl3/Zn, THF, pyridine
20 h, 51%
3:1 (E):(Z)
TiCl3/Zn, THF, pyridine
3 days, 15%
O
Scheme 35
Unsymmetrical alkenes can also be prepared in some cases\ particularly if one carbonyl compound
"often acetone# is used in excess "Scheme 25# ð67JOC0501\ 67JOC2144Ł\ or if one is a diaryl ketone such
as benzophenone or ~uorenone[ Thioketones also undergo reductive coupling to give alkenes under
similar conditions ð67JOC2144Ł[
R TiCl3/K R R R
O + O + +
THF, 12 h R
R R R
1:1 (41) (42) (43)

R= Pri,ratio (41):(42):(43), 2.5:6:1.5, 29%
R = Et, ratio (41):(42):(43), 1:6.5:2.5, 31%
TiCl3/Li, THF
O
O (4 equiv.)
67% (+26% dimer)
TiCl3/Li, THF
O
(4 equiv.)
OMe OMe
85%
O TiCl3/Li, THF
O
Ph Ph (4 equiv.) Ph Ph
94%
Scheme 36
Intramolecular couplings are also very e.cient for formation of cyclic alkenes[ As well as the
more usual _ve and six!membered rings ð67JOC2144Ł\ highly strained three and four!membered
cycloalkenes have been synthesised "Scheme 26# ð65TL2154\ 67JOC2144\ 67JOC2598Ł[ Macrocyclic
alkenes can also be prepared\ generally under high dilution conditions "Scheme 27# ð67JOC2144\
67JOC2598\ 72BCJ081\ 73JA4907\ 75BCJ1198\ 75JA404\ 75JA1821\ 75JA2402\ 77JA5803Ł[
The McMurry coupling has been extensively used in the synthesis of interesting and unusual
molecules ð68JOC3618\ 70SC784\ 71BCJ1323\ 71CB0123\ 72BCJ1912\ 72JA6060\ 73JA612\ 73JA5349\ 73JOC0516\
73LA239\ 74AG"E#0935\ 75AG"E#619\ 75JCS"P0#364\ 76AG"E#817\ 76CB68\ 76CC270m 76TL2198\ 76TL3854\
77AG"E#187\ 77AG"E#300\ 77BCJ0170\ 77JA2467Ł\ and of natural products ð65CL0016\ 67CL792\ 71TL0666\
71TL1612\ 74CC0171\ 74TL1056\ 74TL1060\ 74TL2282\ 75BCJ0098\ 76JOC1894\ 76JOC3774\ 76T4378\ 77CC243\
77TL3258Ł[ Some of these have already been described "Schemes 23\ 24\ 26 and 27#\ and additional
examples are shown in Scheme 28 ð66JA591\ 72BCJ081\ 73JA4907\ 75JA404\ 75JA1821Ł and Scheme 39
ð71JOC4118\ 73JOC2509\ 75JA2402\ 75TL288\ 76TL2980\ 77JCS"P0#0974Ł[
Oxyèn 580
O O TiCl3/Li, THF
Ph 70%
Ph
O
TiCl3/Li
Ph
Ph
THF, 5 days Ph Ph
O 87%
O O
TiCl3/LiAlH4
Ph Ph THF, 6 days
46%
Ph Ph
Scheme 37
O O TiCl3/Li, THF
( )20 83%
O O TiCl3/LiAlH4 Ph
Ph ( )10 Ph 61%
Ph
TiCl3/LiAlH4
CHO DME, ∆
CHO 14%
Scheme 38
CHO
TiCl4/Zn, THF
Fe Fe
pyridine
CHO 32%
H
TiCl3/LiAlH4
+
THF, 4 h
O ca. 20%
H
TiCl3/Zn-Cu
O O
DME, 90%
2
Scheme 39
TMS
TMS TiCl3/Li or Zn-Cu

+
CHO DME, ∆
50–60%
single stereoisomer vetispirene
OH
HO
TiCl3/Li, DME
OR O OR
(excess)
O 76%
R = TBDMS isomijiol
CHO
OHC
TiCl3/Zn-Cu
DME, ∆
H 20% H
taxane skeleton
H O O
O
CHO TiCl3/Zn-Cu
DME, ∆ CO2Me H
52% O O
CO2Me OH
O
strigol
OHC O O O
O
TiCl3/Zn-Ag
H DME, ∆ H H H
MeO 56%
estrone
Scheme 40
McMurry!type coupling has also been reported using other metal systems ð77CRV622Ł\ including
Cp1Ti"CO#1 ð73JOM"157#C0Ł\ NbCl4:NaAlH3 ð71BSB038\ 71CL046Ł\ NbCl4:K ð81CB038Ł\ low valent
tungsten ð61JA5427\ 67JOC1366\ 71BSB038\ 73CC230\ 78JA1213Ł\ and molybdenum ð67JOC1366\ 71BSB038Ł[
Most of these systems are limited to the synthesis of aromatic alkenes[ A reagent system based on
zinc has also been described "Equation "01## ð81TL2788Ł[
Bun
O
Zn, THF, RT
(12)
Bun Me Me
Si Si
Me Me
Cl Cl
72% Bun
0[04[2[3 Addition of Organometallic Reagents to Carbonyl Compounds and In Situ Dehydration

The dehydration of alcohols is a very general method for the formation of alkenes[ A full
discussion of this reaction is beyond the scope of this chapter and is covered elsewhere "see Section
0[02[3#[ However\ there are examples where an elimination reaction can be carried out in situ
immediately after carbon0carbon bond formation\ and thus represents a method for the direct
synthesis of alkenes[
The preparation of crowded alkenes from hindered ketones can be di.cult using common
methods such as the Wittig reaction\ where often no reaction or electron transfer reduction is
observed[ The addition of organolithium reagents to ketones generates a lithium alkoxide which is
often converted to the alcohol by aqueous workup[ If\ however\ thionyl chloride is added to the
alkoxide slowly at −67>C "the reaction is reported to be extremely exothermic# and the resulting
solution allowed to warm to room temperature\ then direct formation of alkene is observed in high
yield "Scheme 30# ð78JOC0264Ł[ This reaction has been applied to the synthesis of crowded alkenes\
which could otherwise not be prepared in a satisfactory manner using alternative strategies[
O R3CH2Li, Et2O SOCl2, Et2O R1

R3 OLi
R1 R2 –78 °C R1 R2 –78 °C → RT
R2 R3
O
But But
But
O
O O O
(44) (45) (46) (47) (48)
Variation of product yield on use of different alkyllithium reagents

Ketone MeLi PriLi BusLi
(44) 94 94 95
(45) 93 90 88
(46) 82 82 83
(47) 96 95 96
(48) 96 93 90(E)+(Z)
Scheme 41
0[04[3 BY CONDENSATION OF SULFUR\ SELENIUM OR TELLURIUM FUNCTIONS
0[04[3[0 Alkylation of Sulfur"II# Stabilised Carbanions and Elimination

The addition of anions derived from thioethers to carbonyl compounds provides e.cient access
to b!hydroxysul_des[ The anions can be generated by lithiation of the thioether ð56JOC0606\ 55JOC3986\
67JA1039\ 71JA1812Ł or from a halide via the Grignard reagent ð71CL0586Ł[ Conversion of the alcohol
group to a benzoate ester and reductive elimination using TiCl3:Zn:pyridine ð63CL0412Ł\ TiCl2:K
ð70JOC3961Ł\ or Na:naphthalene ð61JA3647Ł then forms the alkene "Scheme 31#[ Related procedures
are also successful using organoselenium chemistry "see Section 0[04[3[3#[ This reaction sequence is
successful for hindered ketones\ b\g!unsaturated ketones which transform without double bond
migration ð61JA3647Ł and a\b!unsaturated ketones without overreduction "Scheme 32# ð70JOC3961Ł[
An alternative procedure for the conversion of b!hydroxysul_des into alkenes has also been
developed ð61TL626Ł[ Alkoxide formation and reaction with ortho!phenylene phosphochloridite
form a phosphorus"III# ester which on thermolysis gives the desired alkene "Scheme 33#[
0[04[3[1 Alkylation of Sulfur"IV# Stabilised Carbanions followed by Elimination

0[04[3[1[0 Alkylation of sulfoxides and elimination
Sulfoxides have been used extensively for alkene synthesis using the syn!elimination of a sulfenic
acid[ Similarly\ alkylation of sulfoxide stabilised carbanions is also used extensively for car!
bon0carbon bond formation[ However\ the two procedures have been rarely linked together to
form simple alkenes[ The related reaction using selenium!based systems has been investigated more
thoroughly "see Section 0[04[3[3#[
i, camphor i, BunLi,
BunLi, THF RT, 15 h ii, (PhCO)2O
PhSMe PhS Li OH
0 °C ii, H2O iii, TiCl3/K, THF
SPh
(49) 67%
(from camphor)
O OCOPh TiCl4/Zn
+ (49) R1
SPh
R1 R2 R2 pyridine R1 R2
(50) (51)
(50)–(51)
R1 R2 Yield (%)
PhCH2CH2 Me 93
Bn Bn 94
PhCH=CH Me 90
Cholestan-3-one 87
Scheme 42
SPh
O OBz
H H H
i, PhSCH2Li, THF Na/naphthalene
ii, BunLi, (PhCO)2O THF

49% 90%
PhSCH2Li BunLi, (PhCO)2O

HO
40% then
O Na/naphthalene
PhS 75–90%
PhSCH2Li BunLi, (PhCO)2O

HO
then TiCl3/K
O
87%
PhS
Scheme 43
O
O i, PhCH2Li OH i, MeLi, THF, 0 °C O P
PhS PhS
ii, H2O R2 O O
R1 R2 R1 ii, R1 R2
P Cl
(52) O
R1 R2 Yield from (52) dioxane, ∆
Ph Ph 83
n-C9H11 H 80
n-C11H23 H 64
R1 R2
Scheme 44
In an approach to the synthesis of the elaeokanines\ the sulfoxide "42# was alkylated and reduced
to give a mixture of products which were separated[ Regeneration of the sulfoxide anion of "43# and
condensation with butanal gave the two epimeric sulfoxides which after separation and thermolysis
gave "−#!elaeokanine B "Scheme 34# ð89JOC1017Ł[
O– O– O–
O– H H
i, LDA S+ NaBH4 S+ S+
S+ N Ar N Ar + N Ar
N Ar ii, I I 81%
(53) (54) 4:1 (55)

i, LDA
CHO
ii,
76%
OH OH
H H
toluene, ∆, 3 h
N N
–
90–92% S+ O
Ar
(–)-elaeokanine B 2:1 mixture of isomers
Scheme 45
0[04[3[1[1 Alkylation of sul_namides and elimination

The addition of a!lithiosul_namides to carbonyl compounds and subsequent thermal elimination
of the b!hydroxysul_namide intermediates provides a route to alkenes "Scheme 35# ð55JA4545\
56PAC08\ 57JA4437\ 57JA4442Ł[ The sul_namide reagent is limited in that the initial anion formed using
N\N!disubstituted sul_namides "45#\ eliminates to give a sul_ne and low yields are obtained[ It is
for this reason that dianions of sul_nanilides are reagents of choice[
O
O O OH O
BunLi ( 2 equiv.) i, R R R
R1 S R2 R1 S R2 S R2
N N R N
THF, –78 °C ii, H2O
H Li Li R1 H
∆
R1
+ SO2 + R2NH2
R R
Scheme 46
O
S
Me N
O
(56)
The dilithio salt of N!methanesul_nyl!p!toluidine\ generated using BunLi\ adds smoothly to

aldehydes and ketones to give b!hydroxysul_namides[ Competing enolate formation can be an
important side reaction although yields\ taking into account recovered ketone\ are high "Equation
"02##[ For example\ 3!t!butylcyclohexanone "46# undergoes approximately 59) addition and 39)
enolate formation[ Thermolysis of the b!hydroxysul_namide adducts gives alkenes in high yield\
although this reaction is considerably slower for adducts derived from aldehydes and moisture
must be excluded to prevent deleterious side reactions occurring ð55JA4545\ 56PAC08Ł[ With N!ethyl!
sul_nyl aniline\ a mixture of "Z#! and "E#!alkenes is formed "Scheme 36#[ This is a result of the non!
stereoselective b!hydroxysul_namide formation[ The elimination reaction itself has been shown
to occur stereospeci_cally by a cis elimination pathway "Equation "03## ð57JA4442Ł[ Further evidence
for this is provided by the trans!1!hydroxycyclohexylsul_nanilide "47#[ Stereospeci_c cis! elimination
would form the highly unstable trans!cyclohexene\ whereas trans elimination would give the cis!
cyclohexene[ Signi_cantly\ "47# is stable under thermolysis conditions which cause complete
decomposition of other b!hydroxysul_nanilides indicating that only the cis elimination mechanism
operates[
O
S p-Tol (13)
Me N O Ph Ph
H ii, Ph Ph then H2O
iii, ∆, benzene
96%
OH
∆, benzene
(14)
95%
S O
PhHN
But O
(57)
O HO O
i, BunLi, THF, –40 °C ∆, 5 h
S p-Tol S p-Tol Ph
N ii, PhCHO Ph N toluene
32% overall
H H
1.6:1 (E):(Z)
Scheme 47
OH
NHPh
S
O
(58)
0[04[3[2 Alkylation of Sulfur"VI# Stabilised Carbanions followed by Elimination

0[04[3[2[0 The Julia reaction and related transformations
The condensation of a sulfone anion with a carbonyl compound and subsequent reductive
elimination of the b!hydroxysulfone "or a derivative thereof# to form an alkene "Scheme 37#\ is
usually referred to as the Julia reaction ð62TL3722Ł\ although the important contributions made by
Lythgoe and Kocienski ð67JCS"P0#718Ł have also been recognised[ It has been the subject of a number
of reviews ð70CI"L#437\ 74PAC652\ 74PS"13#86\ 77BCJ096\ 80COS"0#681\ B!82MI 004!91Ł[ The reaction usually
gives good trans selectivity\ particularly if there is some branching adjacent to the newly formed
double bond "Scheme 38# ð79JCS"P0#0934Ł[
PhO2S H base PhO2S M R4 R3 M = MgX or Li R1 OH

+ R2 R3
R2 R1 RLi or RMgX R2 R1 O PhO2S R4
(59)
Na(Hg)
(60)
R1 R3 R1 OR5
(59) R1 = Me, R2 = R3 = H, R5 Yield (%) Na(Hg)
H 63 R2 R3
R4 = Bun, 70% Ms 80 R2 R4 PhO2S R 4
Ac 79
Ts 64 trans R5 = Ac, Bz, Ms, Ts
(60)
Scheme 48
PhO2S
Na(Hg)
MeOH, THF
–20 °C
OBz >98% (E)
OBz
C5H11 Na(Hg) C5H11
C6H13 C6H13
MeOH, THF
SO2Ph –20 °C 4:1 (E):(Z)
OBz
Na(Hg)
MeOH, THF
SO2Ph –20 °C >97% (E)
OBz
Na(Hg)
MeOH, THF
SO2Ph –20 °C
4:1 (E):(Z)
Scheme 49
The sulfone anion is usually generated using BunLi in THF\ although other reagents have
also been used\ including ButLi ð76JCS"P0#0512\ 76TL4652\ 78T6050\ 89TL4414Ł\ MeLi ð75TL1984Ł\ LDA
ð75JOC2805\ 77JOC3171\ 77TL4058Ł\ and magnesium bases\ which are superior for reactions involving
easily enolisable carbonyl compounds\ including aldehydes ð62TL3722\ 67JCS"P0#718Ł[ An interesting
case\ shown in Scheme 49\ required the use of phenyllithium\ as bases such as LDA and Et1NLi
were not of su.cient strength to deprotonate the sulfone\ whereas stronger bases "BunLi\ ButLi#
caused undesired side reactions ð89JA6396Ł[ In some cases use of the co!solvent HMPA is required
ð72CC529\ 76T3284Ł[ For sulfones with additional acidic protons\ it is possible to avoid protection by
the use of polyanions "Scheme 40# ð75TL1984\ 76TL4648Ł[ The condensation is successful with both
aldehydes and ketones and can be promoted by Lewis acids\ typically Bui1AlOMe\ generated in situ
from diisobutylaluminum hydride and methanol ð75TL1984\ 76JOC2648Ł\ or BF2 = OEt1 "Schemes 40
and 41# ð74TL4486\ 77JA4087Ł[
The initial products of the condensation reaction are b!hydroxysulfones\ which may be eliminated
OH
OMe O
PhO2S O
O
O OR1
O OMe
R2 O CHO
OR1 OR1
(61)
i, PhLi, THF, –78 °C
ii, add (61)
iii, PhCOCl, DMAP, –78 → 25 °C
iv, Na(Hg), MeOH, Na2HPO4, –20 °C
60% overall
OH
O
OR1
O OMe O
OMe
O bryostatin 7
O
OR1
R2 O
OR1
R1 = SiButPh2, R2 = SiEt3
Scheme 50
O
PhO2S
O
OR
i, BunLi (3 equiv.), THF, –78 °C
OH ii, (62) RO OBz
iii, PhCOCl, –78 °C → RT OH
iv, Na(Hg), MeOH, THF
3,4-dihydro-
Na2HPO4, –30 °C
30% milbemycin
HO analogue
R = SiButPh2 OH
O
O
CHO
OBz
(62)
BnO BnO
i, MeLi (2 equiv.), THF, –78 °C
ii, (63), Bui2AlOMe
BOC iii, Na(Hg), MeOH, BOC

N Na2HPO4, 0 °C N OTHP
65% overall
H SO2Ph H
OHC
OTHP
(63)
Scheme 51
OMe
OMe
O
O
PGF2α
ii, BF3•Et2O
iii, RCHO, >90% O-TBDMS
SO2Ph iv, Na(Hg), MeOH, –20 °C TBDMS-O
TBDMS-O R=
70% R
C5H11
(E) only
S S S S
O-THP i, BunLi, THF, –78 °C
PhO2S ii, BF3•Et2O

CHO
iii, (64)
iv, Na(Hg), MeOH O-THP
46% (64)
Brefeldin
Scheme 52
directly using sodium amalgam ð62TL3722\ 66JOC1925\ 74JOC4354\ 74TL4486\ 77JA4087Ł^ see also ð65TL2366\
67TL1514Ł\ often in the presence of the phosphate bu}ers Na1HPO3 ð75TL1984\ 76JOC2648\ 78BCJ2021Ł\
or KH1PO3 ð75JA1665Ł^ electrochemically ð67CL58Ł^ using Bu2SnH:1\1?!azobisisobutyronitrile
"AIBN# ð70TL1564Ł^ or with SmI1 on imidazole!derived sulfones ð89TL6094Ł "Scheme 42#[ The
double bond formed from this reduction is predominantly the trans!isomer\ irrespective of the
stereochemistry in the b!hydroxysulfone[ This implies that any intermediate radical or anion pro!
duced by reduction of the sulfone is su.ciently long!lived to allow the molecule to equilibrate to an
intermediate with the large groups as far apart as possible\ prior to elimination ð67JCS"P0#718\
70CI"L#437Ł[
More commonly\ the hydroxyl group of a b!hydroxysulfone will be converted into an ester prior
to reduction using sodium amalgam[ Again high trans selectivity is observed[ Typical esters are
O-THP
i, Bu nLi, THF AcO
ii, (65)
PhO2S
O-THP iii, Na(Hg), MeOH, Na2HPO4
32%
AcO N
N O
CHO
N
O Ph
AcO
AcO N 1α, 25−dihydroxyvitamin D2

N O
N
O Ph
(65)

PhO2S O BnO O
ii, (66), 40%
O O
iii, Na(Hg), MeOH,
THF, KH2PO4
40% OSiButPh2 OBn
OBn
BnO
O
(+) avermectin B1a

OSiButPh2
(66)
p-TolSO2 i, BunLi, THF p-TolSO2 Bu3SnH, AIBN
R
R ii, (CH2O)n HO R 80 °C
(67) (68)
(67) (68)
R Yield (%) Yield (%)
C8H17 95 92
C6H13 92 63
C4H9 96 53
PhCH2 88 100
O O O
N R N
i, NaHMDS, THF, –78 °C S R SmI2 (3 equiv.)
S R
N ii, R1CHO THF R1
O N (70)
Me R1 OH RT
Me
(69)
R R1 (69) → (70) (E):(Z)
Yield(%)
Ph PhCH2CH2 82 8:1
(CH3)2C=CH PhCH2CH2 84 5:1
PhCH2CH2 PhCH2CH2 55 3:1
PhCH=CH (CH3)2C=CH 78 (E) only
Ph (CH3)2C=CH 85 5:1
Scheme 53
acetates\ prepared using acetic anhydride ð67JCS"P0#723\ 75JOC3739\ 76JOC1727Ł with pyridine and:or 3!
dimethylaminopyridine "dmap# when necessary "Scheme 43# ð76T3284\ 77TL4058\ 78JOC01Ł\ benzoates
prepared using benzoyl chloride "Scheme 44# ð79JCS"P0#0934\ 79JCS"P0#0399\ 71TL3768\ 72CC529\ 75JA3592\
76JCS"P0#0512\ 76TL4644\ 76TL4648\ 76TL4652\ 77JOC0953\ 89JA6396\ 89TL4414Ł\ mesylates "Scheme 45#
ð62TL3722\ 67JCS"P0#718\ 70CI"L#437\ 71TL0852\ 74TL4486Ł or tosylates ð62TL3722\ 67JCS"P0#718Ł[ Ester for!
mation is often carried out in situ on the b!alkoxysulfone intermediate formed from the initial
condensation reaction[ Acetoxy and benzoyloxy groups are better than mesylate and tosylate for
derivatisation of allylic hydroxyl groups leading to the formation of conjugated dienes ð67JCS"P0#718Ł[
Methanol is the solvent of choice for this reaction being superior to EtOH and PriOH ð67JCS"P0#718Ł^
however\ often a co!solvent such as EtOAc ð67JCS"P0#718\ 67JCS"P0#723\ 75JA3592Ł or THF
ð79JCS"P0#0399\ 71TL3768\ 72CC529\ 75JOC3739\ 76TL4652Ł is added to help dissolve the substrate[ The
reduction reaction is usually carried out between −19>C and −39>C ð67JCS"P0#718Ł[ Higher geo!
metrical selectivity is often observed at these low temperatures^ however\ in some cases this can be
at the expense of lower overall yield ð75JOC3739Ł[
OMe OMe
SO2Ar
i, BunLi, THF, HMPA, –90 °C
CHO
O-THP ii, (71)
O-THP
iii, Ac2O, pyridine, DMAP
–90 °C → RT
CO2Me iv, Na(Hg), Na2HPO4, MeOH, –20 °C
30% CO2Me
O-BOM O-BOM
(71)
ingramycin
i, BunLi, THF, –78 °C O O CHO

SO2Ph ii, (72) O
O
iii, Ac2O
iv, Na(Hg), MeOH, THF
O-TBDMS 86% OSiButPh2
OSiButPh2
O-TBDMS (72)
5:3 (E):(Z) at new double bond
(+) milbemycin β3
Scheme 54
Alternative procedures via xanthate esters have also been developed^ these methods give good
yields of alkene\ even in cases where other elimination protocols are unsuccessful[ The xanthates
are prepared from the initially formed b!alkoxysulfone intermediate using CS1 and methyl iodide[
Reduction using Bu2SnH "Scheme 46# ð66TL3112\ 75JOC2805\ 77JOC3171Ł\ or photolysis in the presence
of N!acetyloxy!1!thiopyridine "65# "Scheme 47# ð81T6098\ 80TL1692Ł gives alkenes with high trans
selectivity[ In the latter case\ use of other radical initiators such as AIBN\ Et2B!O1\ or "PhCO1#1 is
also successful[
Procedures closely related to the Julia reaction\ provide additional alternative routes to alkenes[
If the b!hydroxysulfone intermediates are eliminated to the vinylsulfones\ usually by simple base
catalysis on the derived acetates ð71TL1354\ 76JCS"P0#1060\ 76T748Ł^ see also ð73JA2569\ 75JOC2729Ł^ or
dehydration using POCl2:pyridine ð62TL3722Ł\ the sulfone group on these intermediates may be
reductively removed with retention of double bond geometry using sodium dithionite ð71TL2154Ł or
sodium amalgam ð62TL3722Ł[ Alternatively\ it is also possible to use a Grignard reagent "BunMgCl#
which\ in the presence of a nickel"II# or lead"II# catalyst\ acts as a reducing agent "Scheme 48#^ use
of the latter metal often leads to higher yields and better stereochemical control ð72TL3200\ 72TL3208\
75JOC2729\ 76T748Ł[ In some cases\ using nickel"II#\ or more commonly iron"III# catalysis\ it is possible
to replace the sulfone group with a Grignard reagent leading to the formation of trisubstituted
alkenes\ again with complete control of stereochemistry ð71TL1358\ 76JCS"P0#1060Ł\ see also ð71TL1346Ł
"Scheme 59#[
O i, BunLi, THF, HMPA, –78 °C O

PhO2S N ii, (73) N
H SEM iii, PhCOCl H SEM
O
iv, Na(Hg), MeOH,
THF, –20 °C MeO2C
53%
H H
antibiotic X-14547A
O CHO
MeO2C
(73)
PhO2S
i, BunLi, THF, –78 °C to –40 °C
MeO
capsaicin
ii, MeO2C(CH2)4CHO
–78 → 0 °C O
iii, PhCOCl, –78 °C → RT 9:1 (E):(Z)
iv, Na(Hg), MeOH, –20 °C
70–80%
Scheme 55
i, BunLi, Et2O, –70 °C TMS R1

TMS
SO2Ph
ii, R1R2CO R2
iii, MeSO2Cl
iv, Na(Hg) (74)
(74)
R1 R2 Overall yield (%)
Me Me 92
Et Et 92
Ph Ph 95
(CH2)5 94
(CH3)2C=CH H 85 (E)+(Z)
Ph H 92 (E)+(Z)
Scheme 56
OBn
BnO
OSiButPh2
O
SO2Tol-p i, LDA, THF, –60 °C
ii, (75)
p-TolSO2
O OBn O
iii, CS2, MeI
S SMe
OBn
O OBn
BnO
OSiButPh2
Bu3SnH, 100 °C
O 83%
CHO OBn
(75) BnO
OSiButPh2
O
pseudomonic acid C
O OBn
Scheme 57
S MeS
hν
R
O SO2Ar . O SO2Ar
MeS (76) MeS 31–85%
n-C7H15
R n-C7H15 R n-C7H15
high (E)-selectivity
R = n-C6H13 or PhCH2CH2
Ar = Ph or p-Tol
Scheme 58
S
N O
O
(76)
PhO2S Bun POCl3, pyridine Na(Hg)
80% PhO2S Bun EtOH, RT

OH 70% Bun
PhO2S
PhO2S i, BunLi, THF, –78 °C conditions
ii, n-C6H13CHO
iii, Ac2O n-C6H13 n-C6H13
iv, NaOH >97% (E) isomer
Conditions Yield(%)
BunMgCl, THF, RT, Ni(acac)2, DABCO 46
BunMgCl, THF, RT, Pd(acac)2 41
Na2S2O4, cyclohexane-H2O, Adogen 464, NaHCO3, 80 °C 65
Scheme 59
SO2Ph n-C8H17MgBr n-C8H17
+
Bun Fe(acac)3 Bun Bun
63% 18%
97:3 (E):(Z)
O i, PhSO2CH(Li)CH3 O
OHC THF, –78 °C PhO2S
O O
ii, Ac2O, 20 °C
iii, NaOH, dioxane
O-TBDMS 80% O-TBDMS
MgBr
OBn
Fe(acac)3, 20 °C
32%
O
milbemycin β3 O
OBn O-TBDMS
Scheme 60
The Julia reaction has found extensive use in natural product synthesis^ an excellent review has
been published ð80COS"0#681Ł[ The main advantages of the reaction are good trans selectivity\
particularly with more substituted systems\ the ease with which the coupling partners can be
synthesised ð66JOC1925\ 77CJC1759\ 77TL0086Ł\ and the reaction|s success with relatively complex
molecules[ Many important examples have been discussed already to illustrate a particular point
"vide supra# and some further details are summarised in Scheme 50[ These include approaches to
0a!hydroxyvitamin D2 "Scheme 50# ð79JCS"P0#0399Ł\ 0a\14!dihydroxyvitamin D1 "Scheme 42#
ð78BCJ2021Ł\ "¦#!milbemycin b2 "Schemes 43\ 59 and 50# ð74CC0215\ 75JOC3739\ 76JCS"P0#0512\
76JCS"P0#1060\ 76TL4652\ 78T6050Ł and analogues "Scheme 40# ð76TL4644\ 76TL4648Ł\ "¦#!avermectin
B0a "Scheme 42# ð75JA1665Ł\ premonensin ð75JA1365\ 75JA3592Ł\ pseudomonic acid C "Scheme 46#
ð74JOC3206\ 75JOC2805\ 77JOC3171Ł\ methyl deoxypseudomonate B ð73TL1974Ł\ tetronasin "Scheme 50#
ð75JA3592\ 89TL4414Ł\ bryostatin 6 "Scheme 49# ð89JA6396Ł\ brefeldin "Scheme 41# ð77JA4087Ł\ the
antibiotic X!03436A "Schemes 44 and 50# ð71TL3768\ 72CC529Ł\ PGF1a "Scheme 41# ð74TL4486Ł\
trans!D!erythro!sphingosine "Scheme 50# ð76JOC1727Ł\ "2#!trinoranastreptene ð77TL4058Ł^ FK!495
"Scheme 50# ð78JOC01Ł\ ingramycin "Scheme 43# ð76T3284Ł\ capsaicin "Scheme 44# ð77JOC0953Ł and
trans!alkene dipeptide isosteres "Scheme 40# ð75TL1984\ 76JOC2648Ł[
C8H17
CHO
C8H17
ii, (77) H OBz
iii, PhCOCl (77)
H iv, Na(Hg), MeOH, THF, –20 °C
SO2Tol-p 59% 1α-hydroxyvitamin D3
(isolated as 3,5-dinitrobenzoate after
hydrolysis and reesterification) OBz
O O
O O i, BunLi, THF, –50 °C

ii, (78)
OSiButPh2
iii, PhCOCl CO2Me
iv, Na(Hg), MeOH, Na2HPO4
SO2Ph OSiButPh2 76%
OHC
CO2Me
OMe
(+) milbemycin β3
OMe
(78)
i, BunLi, THF, PhMe, –78 °C

ii, (79)
O O
PhO2S O iii, PhCOCl, –78 °C O
H H H H
iv, Na(Hg), KH2PO4, OMe
OMe O
MeOH, –40 °C
52%
O tetronasin
O CHO
O
(79)
S O-TBDMS i, BunLi, THF, –78 °C
ii, (CH3)2CHCHO, 83%
SO2Ph
S iii, Ac2O, pyridine, ∆ OMe
iv, Na(Hg), KH2PO4,
OMe OMe 2.5:1 (E):(Z)
MeOH, THF, –20 °C
33%
FK-506 subunit
ArSO2 i, BunLi, THF, –78 °C

ii, (80)
iii, PhCOCl, pyridine

iv, Na(Hg), THF,
MeOH, –20 °C 10:1, (E):(Z) at ∆5,6 (80) CHO
49%
antibiotic X-14547A
i, BunLi, THF OBn
ii, (81)
iii, Ac2O, 55% O
n-C13H27 trans-D-erythro-
n-C14H29SO2Ph
sphingosine
iv, Na(Hg), MeOH, EtOAc N
51% Bn O
OBn
O
OHC
N
Bn O
(81)
Scheme 61
0[04[3[2[1 The RambergÐBacklund reaction

The base!induced conversion of a!halosulfones to alkenes was _rst reported in 0839 by Ramberg
and Backlund ð39AK"02A#0Ł[ They observed that\ if a!bromoethylsulfone was treated with aqueous
potassium hydroxide\ 1!butene was formed\ predominantly as the "Z#!isomer "Equation "04##[
Br
KOH (aq.), ∆
(15)
S 85%
O O
Since then the reaction has been extensively used for the synthesis of alkenes and an excellent
detailed review has been published ð80COS"2#750Ł[ Earlier reviews are also particularly useful for
discussions on the mechanism ðB!56MI 004!90\ 57ACR198\ 66OR0Ł and for methods of preparing suitable
precursors for the reaction ð66OR0\ 75T2620\ B!77MI 004!90\ B!82MI 004!90Ł[ Other reviews are also of
interest ð66T1908\ 68COC"2#076\ 71T1746\ B!77MI 004!91\ B!77MI 004!92\ 77T5130Ł[
The reaction is believed to proceed by formation of a sulfone anion which cyclises by displacement
of a leaving group "X# to give an episulfone intermediate "71#\ from which sulfur dioxide is lost to
give the alkene "Scheme 51#[ The leaving group "X# is usually a halogen\ although tosyloxy groups
have also been used but give a much slower reaction^ in the latter cases the process is prone to side
reactions\ particularly if NaOMe:MeOH is used as base rather than KOBut:ButOH ð79JOC0608Ł[ A
sul_nate can also be used as the leaving group and p!toluenesul_nate ð75CL322Ł^ see also ð79RTC28Ł
as well as tri~uoromethanesul_nate "tri~inate# "Schemes 52 and 53# have been used ð73TL3506\
74JOC1009\ 75JA1247Ł[ Simple alkylsul_nates require harsh reaction conditions and are of limited use
ð41JA0114Ł[
X R3 X R3 R1 R3
R1 base R1 –SO2 R1 R3
– R2 R4
R2 S R4 R2 S R4 S
O O O O R2 R4
O O
(82)
X = Cl, Br, I, OTs, SO2CF3, SO2Tol-p
Scheme 62
i, base (2 equiv.), R1X 2

ii, base (1 equiv.), R2X R1 R4 R base, ∆ R1 R2
(83) F3C
iii, base (1 equiv.), R3X S S R3
R4 R3
iv, R4X O O O O
Scheme 63
The a!halosulfones can be prepared by a variety of methods "Scheme 54# ð66OR"14#0\ 80COS"2#750Ł\
most commonly from a sul_de by oxidation followed by halogenation ð58JA2769\ 77JA6136Ł\ or by
halogenation ð75T2620Ł and oxidation ð66JA1704\ 66JA5835\ 67JOC3416\ 75JOC1286\ 76JA1746Ł[ Chlori!
nation of bridgehead sul_des and sulfones has been reported "Scheme 55# ð58JOC2769Ł[ Other
miscellaneous preparative procedures are also available "Schemes 60 and 64#[ Reactions related to
the Ramberg!Backlund\ where the a!halosulfone moiety is replaced by an a!halosul_de ð62TL3284Ł\
a!halo sulfoxide ð73CB855\ 75CB0439Ł or an a!halo N!p!toluenesulfonyl sulfoximine ð67JOC3039Ł\ have
also been reported\ and in the particular case of the sulfoxide shown "Equation "05##\ was superior
to the sulfone system[
Li Li
BunLi ( 2 eq.) i, MeI
F3C Me F3C
(83) S S S S n-C5H11
THF, –78 °C ii, BunLi, –78 °C
O O O O iii, I(CH2)4CH3 O O O O
(84) 70%
i, BunLi ( 2 equiv.),
THF, –78 °C
ii, acrolein, 77%
iii, MnO2, CH2Cl2
90%
O O
O
K2CO3
F3C F3C
THF, ∆ S S n-C5H11 S S n-C5H11
n-C5H11 100% O O O O O O O O
dihydrojasmone
Scheme 64
O O
R1 S R3
R2 R4
O O
R1 S R3 R1 S R3
R2 R4 X
R2 R4
R1 S R3
X
R2 R4
Scheme 65
SO2 SO2 SO2

i, BunLi ∆ KOH (aq.), ∆
ii, SO2Cl2 75%

SO2 Cl
Cl
Scheme 66
On
O S O
Cl
KOBut, ButOH
n = 1, 25–90% (16)
n = 2, <10%
The use of tri~uoromethanesul_nate "tri~inate# as a leaving group in the Ramberg!Backlund

reaction has found particular application for alkene synthesis using mesyl tri~one "72#\ which acts
as an alkene polyanion equivalent "Scheme 56# ð73TL3506\ 74JOC1009\ 75JA1247Ł[ The alkene precursors
are prepared by sequential alkylation of mesyl tri~one\ where high regioselectivity can be achieved\
but low stereoselectivity "Scheme 56#[ The reaction succeeds only if the precursor is fully substituted
on the carbon atom between the two sulfone groups so as to prevent deprotonation at this highly
activated position "note formation of dianion "73##\ and thus is best suited to the synthesis of 0\0!
di!\ tri! and tetra!substituted alkenes[
F3C Me
C C
–
C C–
–
≡ S S
–
O O O O
(83)
Scheme 67
One of the most useful improvements on the original Ramberg!Backlund reaction was developed
by Meyers[ Chlorination and alkene formation occur in one pot using KOH\ CCl3\ ButOH and
H1O[ The reaction is a general procedure for the chlorination of compounds with acidic methylene
groups and\ for sulfones\ cyclisation and extrusion of SO1 occurs in situ "Scheme 57# ð58JA6409\
63JA2221\ B!66MI 004!90\ 70ACS"B#152\ 71S493\ 73CL722\ 76JOC0692Ł^ but see ð68CJC0847Ł^ see also
ð67JOC0874Ł[ In the case of simple acyclic dialkyl sulfones\ a signi_cant amount of product resulting
from dichlorocarbene addition to the alkene is formed\ which can be a serious limitation on the
utility of this reaction "Equation "06## ð58JA6409Ł[ However\ these conditions\ in some cases\ are
successful when the more conventional Ramberg!Backlund approach fails[ In the speci_c example
given "Equation "07##\ problems were encountered with the chlorination step ð62CC419Ł[ An alter!
native one!pot procedure allows formation of alkenes directly from sulfones in moderate yield by
oxidation of a\a!dianions with CuCl1 "Equation "08## ð63TL1794Ł^ see also ð77TL898Ł[
O O O O
O O KOH, CCl4
R2 S R1 S R1
R2 S R1 R2
ButOH, H2O
Cl R2 R1
O O KOH, CCl4, ButOH, H2O

Ph
Ph S Ph Ph
100%
(E) only
R Yield (%)
O O
R KOBut, CCl4 O O Bn 84
R n-C5H11 50
ButOH, MeOH, H2O CH2=CHCH2 73
S 50 °C, 20 h EtCH=CHCH2 77
O O Prn 60
Scheme 68
Cl Cl
KOH, CCl4
+ (17)
ButOH, H2O
S
O O 32% 60%
O O
S
KOH, CCl4
(18)
ButOH, H2O
(CH2)n
(CH2)n
n = 5 → 10
18 → 52%
i, BunLi ( 4 equiv.), DME

S (19)
O O ii, CuCl2 ( 5 equiv.)
45% (by GLC) 2:1 (E):(Z)
In addition to Meyers| system\ a number of other bases can be used to induce a Ramberg!
Backlund reaction on an a!halosulfone[ The original literature report ð39AK"02A#0Ł used aqueous
KOH^ however\ ButOK:ButOH is also now widely used[ The two bases show interesting ster!
eoselectivity\ KOH favouring the "Z#!isomer of the alkene\ whereas KOBut favours the "E#!isomer
"Scheme 58# ð70CB898Ł[ Other bases have been used including LiOBut or CsOBut\ which give minor
changes in stereoselectivity relative to KOBut ð75JA3457Ł\ KOCEt2 ð80JA8571Ł\ NaOMe:MeOH
ð69JA1470Ł\ MeLi ð77JA6136Ł\ NaH:KH ð75CL322Ł and LiAlH3 "for 0\1!disubstituted cyclobutenes#
"Equation "10## ð63JA4790Ł[ For the vinylogous Ramberg!Backlund reaction "Scheme 69#\ KOBut
can be used\ the precursors for such a reaction being easily prepared by regiospeci_c photochemical
addition of BrCH1SO1Br to alkenes followed by elimination ð64IJC140\ 72JA5053\ 72JA5054\ 73TL4358\
75JA3457\ 76OS"54#89\ 89JA3961Ł[ Alternatively\ it is possible to induce a Ramberg!Ba
cklund reaction
by Michael addition to an a\b!unsaturated sulfone\ although stereoselectivity can be low "Scheme
60# ð66TL3416\ 70T306Ł[ The vinylogous\ and Michael!induced Ramberg!Backlund reactions are both
useful for the synthesis of conjugated dienes and polyenes "see also ð63JA2221Ł#[
O
O O
Bun Br2, NaOH conditions
HO2C S Bun HO2C
Bun
S O
Br
O Conditions
KOH, H2O, ∆, 65%, 82:18 (Z):(E)
KOBut, ButOH, ∆, 85%, 24:76 (Z):(E)
Scheme 69
i, BrSO2CH2Br, hν O O
CH2Cl2, –20 °C R S KOBut
R
ii, NEt3, –23 °C ButOH, THF R
97% Br 59%
R = n-C5H11 (85)
10:1 (E):(Z) 83:17 (Z):(E)
from pure (E)-(85)
Scheme 70
Cl O O
PhSO2Na
S
S DMSO, RT
O O 65–80%
SO2Ph
2(E), 4(Z), 26%

2(E), 4(Z), 23%
2(E), 4(Z), 20% 4 2 SO2Ph
2(E), 4(Z), 31%
Scheme 71
The use of phase transfer catalysts allows a Ramberg!Backlund reaction to proceed under milder
conditions\ i[e[ with more dilute NaOH solutions\ or employing Na1CO2 and NaHCO2 as base\
which allows base sensitive functional groups such as esters to be present in the substrate ð71S493Ł[
Typically aliquat!225 "tricaprylmethylammonium chloride# or benzyltriethylammonium chloride
are used to catalyse the reaction under conditions similar to those developed by Meyers "NaOH\
CCl3\ H1O# ð71S493Ł\ although in some cases this is less satisfactory "Scheme 61# ð70ACS"B#152Ł[
The main disadvantage of the Ramberg!Backlund reaction is its lack of stereoselectivity[ Although
this can be controlled to a certain extent "Scheme 58#\ the reaction generally produces mixtures of
"E#! and "Z#! isomers whenever possible[ It is known that loss of SO1 from the episulfone occurs
stereospeci_cally\ with retention of con_guration[ It is thus at the cyclisation stage\ which is usually
the rate determining step\ where the geometry of the _nal product is determined\ and lack of
stereocontrol is apparent "Scheme 62# ð57ACR198\ 69JA1470\ 65T0694\ 66OR"14#0\ 74CJC0\ but see B!77MI
004!93Ł[ For this reason\ the reaction is most useful for the synthesis of alkenes where stereoisomerism
is not a problem[ In many cases the methodology is superior to alternative protocols available for
the synthesis of strained or reactive cycloalkenes\ particularly if both allylic positions are fully
substituted\ as this prevents elimination of HX to form a vinylsulfone which in some cases can be
an important competing side reaction "Scheme 63# ð60JOC0904\ 68CJC0847\ 79LA0439\ 72HCA0989Ł[
The Ramberg!Backlund reaction has been used extensively for ring synthesis[ In such cases\ it is
O O
S Cl NaOH (20%), aliquat 336
40 h, ∆, 86%
Br
NaOH (10%), aliquat 336
CO2Et
Ph S CO2Et Ph
2 h, RT, 75%
O O
conditions
Ph S Ph Ph
O O Ph
Conditions
NaOH (10%), CCl4, ∆, no reaction
NaOH (10%), CCl4, aliquat 336, ∆, 94%
Na2CO3 (sat. aq.), CCl4, aliquat 336, ∆, 70%
KOH, CCl4, ButOH, H2O, 100%
Scheme 72
X X O O O O
base – –X–
S + S
R1 S R4 R1 S R2 SLOW
O O O O R1 R2 R1 R2
FAST FAST
R2
R1 R2
R1
Scheme 73
Cl
ButOK, THF 82%
S S S OBut
O O O O O O
Scheme 74
actually a ring contraction rather than a cyclisation reaction\ and stereoselectivity\ which can be a
serious problem in acyclic systems\ is controlled[ It has been used for the synthesis of cyclobutenes
unsubstituted at positions 0 and 1 "Equation "19## ð63CB0804\ 63JA4790\ 65CB682\ 66CB1867\ 66JA1704\
66JA5835\ 67JOC3416\ 79LA0439\ 70AG"E#566\ 72HCA0989\ 73CB0757\ 75TL0784\ 76CB4\ 77JA7086Ł\ and also
related 0\1!disubstituted systems "Equation "10## ð63JA3604\ 63JA4790\ 65JA3825\ 66OS"46#42Ł[ Cyclo!
pentenes can also be prepared "Scheme 55#\ including tricycloð4[2[9[91\7Łdeca!2\4\8!triene "75#\ which
is unstable and prone to isomerisation "Equation "11## ð76JA1746^ see also 64TL836\ 79H"03#0628\ 73HCA323\
76LA568\ 77JA4368Ł[ Cyclopentenones and related systems are also available "Schemes 53\ 57 and 64#
ð66TL0062\ 73CL722\ 74JOC1009\ 75CL322\ 76JOC0692\ 77CC343Ł[
SO2 KOBut, THF

(20)
29%
Cl
LiAlH4
SO2 (21)
dioxane, ∆
37%
Cl KOBut (excess)
THF, –78 → 0°C
O (22)
S then 0 °C, 1 h
O 46%
(86)
O
TMS-I O O
OH
HO
65%
S ( )7 O-TBDMS I S ( )7 O-TBDMS
O O O O
KOBut
–78 °C, 30 min
65%
O
O
O
CO H
( )7 2 ( )7 O-TBDMS
tetrahydrodicranenone B
Scheme 75
The unstable cyclohexene "76# "Equation "12## ð72JA556\ 75JOC1286\ 77TL3792Ł\ other cyclohexenes
ð75JA1247Ł and phenanthrenes ð53JA3974Ł can also be prepared using this reaction[ For the synthesis
of larger rings "Equation "07##\ the Ramberg!Backlund reaction su}ers from low yields and has
considerable drawbacks over alternative procedures ð62CC419\ 65TL0132\ 67TL3158\ 70JOC0636Ł[
However\ the reaction has recently found application for the synthesis of analogues of the DNA
cleaving enediynes related to calicheamicins "Scheme 65# ð77JA3755\ 77JA6136Ł and has also been used
in synthesis of the nine!membered ring macrocyclic alkene "¦#!eremantholide "Equation "13##
ð80JA8571Ł[
Cl
O KOBut (excess)
S (23)
DMSO
O 45%
(87)
O OR
S MeLi, Et2O
OR OR
O OR
–78 °C, 15 min
Cl 20%
R = TBDMS
O KOBut or MeLi
S (CH2)n (CH2)n
O 20–80%
n =2→8
Cl
Scheme 76
O O
O O Et3COK, DME, HMPA O O

(24)
H 70 °C, 5 min H
O 82%
S O O
O
Cl O O
(+)-eremantholide A
0[04[3[2[2 Alkylation of sulfoximine stabilised carbanions followed by elimination Ð the Johnson
"N!methylphenylsulfonimidoyl#methyl lithium method
The anions of alkylaryl sulfoximines "77# readily add to aldehydes and ketones to form b!
hydroxysulfoximines "Scheme 66#[ These compounds can readily undergo reductive elimination
using aluminum amalgam in aqueous THF and acetic acid to give alkenes "Scheme 66# ð62JA5351\
68JA2591^ see also 62JA6313Ł[ The reaction can be carried out without isolation of the b!hyd!
roxysulfoximine intermediate ð68JA2591Ł[ The reaction is successful for the synthesis of mono!\
di!\ and trisubstituted alkenes\ but fails in the initial condensation reaction which would lead to
tetrasubstituted systems owing to problems with enolisation[ Aryl aldehydes are also poor substrates
as the thiophenol biproduct from the reductive elimination reaction can add to the styrene product
resulting in a signi_cant reduction of yield[ Another serious limitation is that\ for the synthesis of
polysubstituted alkenes using alkyl sulfoximines "78# and "89#\ mixtures of cis! and trans!isomers
are produced in the reaction irrespective of the geometry of the b!hydroxysulfoximine ð68JA2591Ł[
R R1
O R O R R R1
BunLi, THF R1R2CO OH Al(Hg)
Ph S Ph S O
S R2
(or MeMgBr) NMe THF, H2O
MeN MeN Li Ph R2
AcOH
(88) R = H (91) (92)
(89) R = Me
(90) R = (CH2)2Me
Reaction of sulfoximines with carbonyl compounds and subsequent elimination

R1R2CO Sulfoximine (91) (92)
Yield (%) Yield (%) (E):(Z)
Me(CH2)14COMe (88) 90 90 (85a)

Me(CH2)6CHO (88) 85 60
O (88) 85 93
Me(CH2)4CHO (89) 75 100 (60:40)

Me(CH2)2CHO (90) 78 78 (64:36)
O
(89) 75 65 (78:22b)
a Yield without isolation of intermediate β-hydroxysulfoximine. b Stereochemistry not determined.
Scheme 77
The initial sulfoximine anions can be considered as being less basic but more nucleophilic than
the corresponding Wittig reagent ð68JOC1779Ł[ As a result\ the reaction using sulfoximine anions
can be successful in cases where the Wittig reaction has failed\ two such cases being during the total
synthesis of gascardic acid "Equation "14## and 5a!carbaprostaglandin I1 "Equation "15## ð68JA4959\
68JOC1779Ł[ Sulfoximines can also show useful chemoselectivity\ the product "82# being formed by
selective attack at the least hindered ketone "Equation "16## ð73JA3436Ł[
O
i, Ph S CH2Li
MeN (5 equiv.)
O gascardic acid (25)
THF, –78 °C
CO2H ii, Al(Hg), THF, H2O CO2Me
AcOH, –78 °C → RT
iii, CH2N2
70%
CO2 H CO2Me
O O-THP
i, THF, –20 °C
(26)
ii, Al(Hg), THF
H2O, AcOH
R = TBDMS
RO OR 48%
RO OR
+
mixture of isomers, ratio not given
MgBr
Ph
S O-THP
MeN O 6a-carbaprostaglandin I2
O O O
Ph S CH2Li
i,
MeN
OMe THF, 0 °C OMe
O O (27)
OR ii, Al(Hg), THF, OR
O H2O, AcOH O
O 67%
(93)
Sulfoximines are chiral\ and can be readily resolved ð74PS"13#420Ł[ If used in an enantiomerically
pure form\ they provide an opportunity for resolution by separation of diastereomeric b!hydroxy!
sulfoximines prior to reductive elimination[ This approach has been used for the synthesis of "−#!
b!Panasinsene "83# and its enantiomer "Scheme 67#[ The resolution procedure is greatly simpli_ed
in this case\ as addition of the sulfoximine anion to the ketone shows complete facial selectivity
resulting in formation of only two diastereomeric b!hydroxysulfoximines\ which were separated by
chromatography ð70JA6556Ł[
O
Ph NMe
Ph O S
O Ph
S HO S O
Li HO
NMe
NMe +
THF
(±) 42% 33%

i, separation
ii, Al(Hg)
THF, H2O, AcOH
96%
(–)-β-panasinsene (94)
Scheme 78
A related process involves the use of resolved sulfoximines adding to symmetrical ketones "Scheme
68 and Equation "17##[ Again\ addition occurs selectively to one face of the ketone to give a b!
hydroxy sulfoximine\ which can undergo asymmetric elimination via its trimethylsilyl ether\ to
give the axially chiral alkenyl sulfoximine "84# with high diastereoselectivity ð75AG"E#824Ł[ The
sulfoximine group can be substituted with full retention of stereochemistry using a nickel!catalysed
cross!coupling reaction with an organozinc reagent\ in the presence of a metal salt "MgBr1\ LiCl#\
allowing access to trisubstituted alkenes ð78JA0014Ł[
O O O O
O
O O
S Ph
Li NMe H H i, TMS-Cl H H
H H THF
ii, BunLi, THF, –78 °C
OH 91%, >98% ds
MeN
O MeN S O S
Ph
Ph O
(95)
Scheme 79
O O-TBDMS
Ph
S H
MeN
2 Zn O-TBDMS
(28)
NiCl2(dppp), MgBr2
O-TBDMS 83%, 99:1 (E):(Z)
O-TBDMS
O-TBDMS O-TBDMS
0[04[3[3 Alkylation of Selenium"II# and Selenium"IV# Stabilised Carbanions Followed By Elimination

There are a number of important ways in which alkylation of selenium stabilised anions can lead
to alkene formation at the new C0C bond[ First\ alkylation of selenide a!anions using alkyl
halides leads to the formation of substituted selenides\ which\ after oxidation to the corresponding
selenoxides\ undergo the well!known syn!elimination reaction to give\ predominantly\ the less
substituted "E#!alkene "Scheme 79#[ A related process is also possible via a selenonium ylide "Scheme
70#[ Alternatively\ selenoxide a!anions can be alkylated and eliminated directly "Scheme 71#[ The
addition of selenide a!anions to carbonyl compounds provides an e.cient method for the prep!
aration of b!hydroxyselenides[ These then undergo a reductive elimination reaction\ induced by a
variety of reagents "vide infra#\ with overall loss of RSeOH to give an alkene "Scheme 72#[ In this
case\ the geometry of the new double bond is controlled by the b!hydroxyselenide stereochemistry[
An excellent extensive review in this area has been published ð80COS"0#518Ł and other reviews are
also available ð67T0938\ 79T1420\ B!75MI 004!91\ B!76MI 004!90\ B!76MI 004!91\ 76TCC0\ 78H"17#0192Ł[
R1 –O + R1
Se R3 R4 X Se [O] Se ∆ R2 R3
R1 R3 R3
R2 –H
Li R2 R2 R4
R4 R4
Scheme 80
–
R1 H2C + R1
Se R3 R4 X Se i, MeX Se R2 R3
R1 R3 R3
R2 ii, base –H
Li R2 R2 R4
R4 R4
Scheme 81
–O + R 1
O– R2 R3
R4 Se
X ∆
Se R3 R3
R1
R2 R2
–H
R4
Li
R4
Scheme 82
O
R1
Se R3 Se R2 R3
R4 R5 –R1SeOH
R1 HO R3
R2
Li R4 R2 R4 R5
R5
Scheme 83
As all these processes begin with the alkylation of a selenium stabilised anion\ the generation of
such species will be brie~y mentioned here^ more detail can be found in the aforementioned reviews[
The most important methods for generating selenium!stabilised anions are summarized in Scheme
73 ð67T0938\ 68TL3122\ 79T1420\ 73IJ014\ B!76MI 004!90\ B!76MI 004!91\ 78H"17#0192\ 80COS"0#518Ł[ These
involve the nucleophile induced "usually BunLi# cleavage of 0\0!selenoacetals ð65TL2632\ 68CC0025\
79TL0886\ 71CC453\ 76CC0439\ 78T1994Ł\ deprotonation of selenides "although C0Se bond cleavage can
be a serious side reaction# ð63CC889\ 64CC689\ 68JA5527\ 73JOC0985\ 78T1912Ł\ Michael addition to
vinylselenides "rarely used# ð67AG"E#415Ł\ and oxidation of selenides to selenoxides and subsequent
deprotonation "which is often carried out in one pot# ð64CC689\ 64JA2149\ 68JA5537\ 72JOC1987Ł[
R1 R2 BunLi R1 R2 LDA R1
RSe
RSe SeR THF or Et2O RSe Li R2
R1 BunLi R1
Li
Bun
SePh SePh
R3 R3
R3 [O] LDA R2
R1 + R1 +
R1 Se R2 Se Li
Se R2
O– O–
Scheme 84
In general\ anions stabilised by an SeCH2 group are more reactive than the corresponding
SePh analogue ð78T1912Ł[ They react well with aldehydes and ketones\ including hindered ketones
ð71CC453\ 75CB0051Ł\ to form b!hydroxyselenides "Scheme 74# ð64CC689\ 65TL0274\ 65TL2632\ 68CC0025\
68JA5527\ 78T1994\ 78T1912\ see also 66LA735\ 67TL0034\ 79TL0886\ 70TL0722\ 71TL3274\ 73TL1218\ 76CC0439Ł\
and will also add in a Michael!type reaction to a\b!unsaturated lactones "Scheme 75# ð76CC095Ł[
Se Li OH MsCl, NEt3
Ph
But O But But
82% 91%
SePh
O
SeMe Ph
SeMe ButLi, Et O SeMe Ph
2 Ph PI3, NEt3
70% Ph CH2Cl2, 20 °C
SeMe Li
OH Ph 72% Ph
O
Me2C(SePh)2 HO SePh PI3, NEt3
R BunLi, –78 °C CH2Cl2, 20 °C R
R
R = H in Et2O, 84%, 95:5 ds R = H, 84%

R = Me in Et2O, 60% R = Me, 95%
R = H or Me in THF, 0%
Me2C(SePh)2 SOCl2, NEt3

O HO
BunLi, THF,
SePh CH2Cl2, 54%
H –78 °C H H
O-TBDMS 85% O-TBDMS O-TBDMS
Scheme 85
For allylic anion systems\ complementary regio! and enhanced stereocontrol can be obtained by
transmetallation of the lithium species with triethylaluminum to form an allylic aluminum {ate|
complex\ which adds to aldehydes selectively at the a!position\ whereas the original organolithium
reagent alkylates predominantly in the g!position "Equation "18## ð73JOC0985Ł[
O O O O
PhSeCH2Li
THF, HMPA
–85 °C
59%
SePh
OMe OMe
i, NaIO4, MeOH,
MeO H2O, 20 °C
MeO
OMe O OMe OMe O OMe
O ii, ∆, C6H6 O
O 85% O
N N
H H iii, LiOH, MeOH, H H
OBz HO
H2O, 50 °C
(benzoate hydrol.)
SePh OBz 92% OH
(±)-pederin
Scheme 86
Li+ SePh SePh

α γ i, Et3Al Et
Ph – Et + Et + PhSe (29)
Se
ii, EtCHO OH
OH OH
(96) (97) (98)
with AlEt3, 90%, ratio (96):(97):(98), 81:19:0
without AlEt3, 91%, ratio (96)+(97):(98), 12:88
Alkylation with alkyl halides is much less general "Scheme 76#\ with only primary alkyl bromides
and iodides reacting e.ciently "Scheme 77# ð63CC889\ 68JA5527Ł with best results being obtained
using THF with HMPA as co!solvent ðB!76MI 004!91\ 76TCC"024#0\ 80COS"0#518Ł[ Allylation can be
achieved by using CuBr = Me1S as a catalyst "Scheme 78# ð73IJ014\ 76TCC0Ł\ although this is not
always necessary "Scheme 89# ð63CC889\ 64JA2149\ 68JA5537Ł[
in Et2O SeMe
OH
44% I
SeMe O Et2O
SeMe
+ OLi
I or THF I
Li SeMe
in THF
56%
O
Scheme 87
Li EtBr H2O2
Ph
Ph SePh THF, H2O
Ph SePh
80% overall
only (E)-isomer
Li Ph Br
Ph
H2O2
Ph
Ph
Ph SePh THF, H2O
Ph SePh
81% overall
only (E)-isomer
Scheme 88
SeMe i, BunLi
ii, CuI•Me2S
SeMe TBHP
R
R SeMe iii, X R Al2O3, THF
75%
R = n-C6H13,
X = Cl, Br, I, OTs
78–90%
Scheme 89
Li Ph
NaIO4
+ Ph
Ph Br Ph
Ph SePh MeOH, H2O
Ph SePh
55% overall
Scheme 90
Selenoxides are much easier to metallate than selenides\ and are often generated by oxidation of
a selenide "m!chloroperoxybenzoic acid# and deprotonated in situ using an excess of base to neutralise
the m!chloroperoxybenzoic acid by!product[ In such cases\ LDA in THF at low temperatures
"−67>C# is successful ð64CC689\ 64JA2149\ 68JA5537\ 72JOC1987\ B!76MI 004!90\ B!76MI 004!91Ł whereas use
of BunLi results in C0Se bond cleavage ðB!76MI 004!91Ł[ Alkylation can be achieved with reactive
alkyl halides "Scheme 80# ð64JA2149\ 68JA5537Ł and carbonyl compounds "Scheme 81# "Equation
"29## ð64CC689\ 72JOC1987Ł[
– i, LDA (2 equiv.)
MCPBA (1 equiv.) O THF, –78 °C
Se
Ph Me THF
Se + ii, Ph Br
Ph
Ph Me 75% overall
i, MCPBA (1 equiv.), THF

Se Ph Ph + Ph
Ph
ii, LDA (2 equiv.), THF,
–78 °C 64 : 36
iii, MeI
59%
O– i, LDA, THF, –78 °C
+ Ph
Se Ph
Ph ii, BunI
81%
Scheme 91
i, MCPBA (1 equiv.) PhSe Ph Ph

ii, LDA (2 equiv.) MeSO2Cl
Se Ph
Ph
iii, EtCHO NEt3
iv, NaI, NaHSO3
Et OH 70% Et
HOAc, 0 °C
87%
i, MCPBA (1 equiv.) OH
Se ii, LDA (2 equiv.)
But MeSO2Cl
Ph SePh But
iii, 4-butyltcyclo- NEt3
hexanone 91%
iv, NaI, NaHSO3
HOAc, 0 °C
82%
Scheme 92
– OH
O O i, THF, –78 °C
+ ii, CH3CO2H
+ Se (30)
Ph
iii, ∆
Li 72%
After alkylation\ there are two routes which can be used for alkene formation[ The _rst involves
loss of RSeOH from a b!hydroxyselenide "Schemes 74 and 81# ð67T0938\ 80COS"0#518Ł[ This can be
induced using a number of reagents including SOCl1:NEt2 ð65TL2116\ 65TL2632\ 71CC453\ 75JOC2097\
76CC0439Ł\ MsCl:NEt2 ð64CC689\ 68JA5527Ł\ TsOH ð65TL0274\ 65TL2116\ 65TL2632\ 73JOC0985Ł^ but see
ð68CC0025\ 89BSF570Ł\ PI2:NEt2 ð68CC0025\ 79TL0886\ 71CC453Ł\ P1I3:NEt2 ð70TL0722Ł\ HClO3 ð65TL0274\
65TL2632Ł\ carbonyl diimidazole ð68CC0025\ 79TL0886Ł\ POCl2 ð67TL1582\ 71CC453Ł\ "CF2CO#1O:NEt2
ð65TL0274\ 65TL2632Ł\ NaH and phosphochloridite "88# ð65TL2632Ł\ and TMS!Cl:NaI ð70JOC120Ł[ b!
Alkoxyselenides undergo a similar elimination using either TMS!Cl:NaI ð70JOC120Ł or Na:NH2
ð68CC72Ł[ Note that the geometry of the alkene produced is dependent on the stereochemistry of
the b!hydroxy! "or alkoxy#selenide precursor\ a mechanism consistent with loss of an RSe¦ equi!
valent from a seleniiranium salt intermediate "Scheme 82# ð65TL0274\ 65TL2632\ 70JOC120Ł[
O
P Cl
O
(99)
R1
R4 SeR1 R4 R2
Se+ –"RSe+"
R5 R2 R4 R2
HO R3 R5 R3
R5 R3
Scheme 93
b!Hydroxyselenides can also be prepared by addition of a!lithioselenoxides to carbonyl com!

pounds and subsequent reduction back to the selenide using NaI:NaHSO2 or P"OMe#2 ð64CC689\
68JA5537Ł[ Elimination "as above# then provides an alkene "Scheme 81#[ Alternatively\ direct elim!
ination of the b!hydroxyselenoxide intermediate generally occurs in the direction away from the
alcohol group to give an allylic alcohol "Equation 29# ð66LA735\ 67TL0034\ 68JA5537\ 79TL0886\ 72JOC1987\
76JOC663Ł[
Substituted selenides\ prepared by alkylation of a!seleno anions with alkyl and allyl halides\ can
be readily converted into selenoxides\ and subsequently alkenes by in situ elimination by oxidation
using many reagents "Schemes 77\ 78 and 89#\ ðB!76MI 004!91\ 80COS"0#518Ł including TBHP:Al1O2
which is reported to be particularly good for primary alkylphenylselenides and dialkylselenides
ð67TL0030\ 73IJ014Ł\ ozone ð68TL3122Ł\ H1O1 ð63CC889\ 74CC0926Ł\ or NaIO3 ð74CC0926\ 76CC095Ł[ In
some cases yields can be low\ and an alternative procedure involving elimination via a selenonium
ylide can be used "Scheme 83#[ The required ylides are readily formed by alkylation of a dialkyl!
selenide with either MeSO1F or MeI:AgBF3 and treatment with KOBut ð68TL3122\ 73IJ014Ł[
SePh i, O3, CH2Cl2
C9H19 ii, toluene C9H19

NEt3, ∆
33%
i, MeSO2F, Et2O Me
SeMe + –
or MeI, AgBF4 Se CH2
C8H17 ii, KOBut, THF C8H17

or DMSO C8H17
60–77% overall
Scheme 94
0[04[3[4 Alkylation of Tellurium Stabilised Anions Followed By Elimination

Although elimination of telluroxides\ analogous to that of selenoxides "see Section 0[04[3[3#\ is
known to produce alkenes ð64CS8\ 72JA1637\ 74CC0926\ 75S0\ 76MI 004!90\ B!76 MI004!91Ł\ it is generally a
much less attractive reaction for a number of reasons ð72TL3236Ł\ including di.culty in controlling
the tellurium oxidation state "overoxidation to tellurones#\ formation of stable hydrates\ reduction
Nitroèn 606
of telluroxide by RTeOH by!product to give the unreactive telluride\ and formation of alcohols via
tellurinic esters "RTe"O#OR#[ In addition\ relatively little is known about the reactivity of a!
telluroorganometallics toward electrophiles ðB!76MI 004!91Ł[ Similarly\ unlike the analogous selenium
reaction\ b!hydroxytellurides do not undergo elimination of RTeOH to form alkenes in a high
enough yield to be synthetically useful ð67TL3288Ł[
0[04[4 BY CONDENSATION OF NITROGEN FUNCTIONS
0[04[4[0 Rhodium Catalysed Dimerisation of Diazo Compounds

There are few examples of simple alkene synthesis by condensation of nitrogen functions^ however\
an interesting reaction involving the rhodium catalysed dimerisation of primary aryl diazoalkanes
results in formation of diarylethylenes\ predominantly as the "Z#!isomers "Scheme 84# ð71TL1166Ł[
The "Z# ] "E# ratio varies according to the catalyst used\ higher "Z# selectivity being observed using
iodorhodium"III#tetraphenyl porphyrin rather than Rh1"OAc#3[ The reaction is unsuccessful with
secondary aryl diazoalkanes[
Y Y Y
Rh2(OAc)4 Y
N2
Y
X Y X X
X = Y = H, 84%, 4:1 (Z):(E)
X = OMe, Y = H, 61%, >2.5:1 (Z):(E)
X = Y = Me, 90%, 0.7:1 (Z):(E)
N2 Rh2(OAc)4
S S S
>38%, 2.7:1 (Z):(E)
Scheme 95
1.16
Formed by Condensation:
Condensation of P, As, Sb,
Bi, Si or Metal Functions
IAN GOSNEY
University of Edinburgh, UK
and
DOUGLAS LLOYD
University of St. Andrews, UK
0[05[0 C1C BONDS BY CONDENSATION OF PHOSPHORUS\ ARSENIC\ ANTIMONY OR
BISMUTH FUNCTIONS 619
0[05[0[0 Alkenation via the Witti` Reaction 619

0[05[0[1 Phosphonium Ylides 610
0[05[0[1[0 Mechanism 610
0[05[0[1[1 Stable ylides 611
0[05[0[1[2 Reactive ylides 615
0[05[0[1[3 Formation of "E#!alkenes via Witti`ÐSchlosser modi_cation 618
0[05[0[1[4 Ylides of intermediate "moderate# reactivity 629
0[05[0[2 Arsonium Ylides 626
0[05[0[2[0 Comparison of stable\ reactive and semi!stabilised "moderately stabilised# ylides 627
0[05[0[3 Stibonium Ylides 631
0[05[0[4 Bismuthonium Ylides 632
0[05[0[5 PO!Activated Alkene Formation 633
0[05[0[5[0 Mechanism 633
0[05[0[5[1 Phosphonate!stabilised carbanions "WadsworthÐEmmons Reaction# 633
0[05[0[5[2 Phosphoryl!stabilised carbanions "Horner Reaction# 641
0[05[1 C1C BONDS BY CONDENSATION OF SILICON\ BORON\ GERMANIUM OR

TELLURIUM FUNCTIONS 647
0[05[1[0 Silicon!Mediated Alkenation] The Peterson Reaction 647

0[05[1[0[0 Mechanism 647
0[05[1[0[1 Preparation of silicon!stabilised carbanions 648
0[05[1[0[2 Methylenation reactions 648
0[05[1[0[3 Stereoselective formation of alkenes 659
0[05[1[1 Boron!mediated Alkenation 653
0[05[1[2 Germanium!mediated Alkenation 654
0[05[1[3 Tellurium!mediated Alkenation 655
608
619 C1C Bond"s# by Condensation of Phosphorus\ etc[ and Silicon\ etc[
0[05[2 METAL!INDUCED METHYLENATION 655
0[05[2[0 Tebbe|s Reaènt 656
0[05[2[1 Oshima|s Reaènt 656
0[05[0 C1C BONDS BY CONDENSATION OF PHOSPHORUS\ ARSENIC\

ANTIMONY OR BISMUTH FUNCTIONS
0[05[0[0 Alkenation via the Wittig Reaction

The Wittig reaction is one of the most important processes in organic synthesis[ It consists of the
formation of carbonÐcarbon double bonds by transfer of an alkylidene group\ in the form of a
carbanion attached to a heteroatom that carries a high degree of positive charge\ to a carbonyl
compound with displacement of the carbonyl oxygen "Equation "0##[
X+ O R1 R3
+ + X O (1)
–
R1 R2 R3 R4 R2 R4
The heteronium group X attached to the alkylidene group usually contains an atom belonging to
Group 04\ commonly phosphorus and arsenic\ and to a lesser used extent\ antimony and bismuth[
Such compounds are de_ned as ylides which may be represented as hybrids of the dipolar "0# or
covalent "1# structures[ For convenience\ in this chapter ylides will commonly be represented by
covalent structures such as "1# but the dipolar contribution to such structures must be taken as
understood[
X+ X
–
R1 R2 R1 R2
(1) (2)
If electron!withdrawing centres are conjugated with the ylidic carbon atom\ further dipolar
structures such as "2# and "3# may make major contributions to the overall structure[ Delocalisation
of the negative charge onto the alkylidene grouping in this way frequently leads to the ylides being
isolable[ Such ylides are commonly described as stable ylides^ in this context stable is\ in e}ect\
usually synonymous with isolable[ Many ylides are not\ however\ isolable\ because of their high
reactivity\ in particular they are very prone to hydrolysis[ In this chapter such ylides will be
called reactive ylides[ Some other ylides notably benzylides "0^ R0 Ph\ R1 H# have a reactivity
intermediate between those ylides which are obviously stable or obviously reactive^ these will be
termed moderately reactive ylides[ This section is organised according to the type of heteronium
group X used in the Wittig reagent[ Section 0[05[0[1 covers phosphorus ylides and is further
subdivided depending on the nature of the alkylidene grouping and its stabilising action[ The
competing bene_ts and disadvantages of the use of arsenic\ antimony and bismuth ylides for
carbonÐcarbon double bond formation are discussed in Sections 0[05[0[2\ 0[05[0[3\ and 0[05[0[4\
respectively[
O–
+X –
+X
(3) (4)
In general\ sulfonium\ selenonium and telluronium ylides either react with carbonyl compounds
to form epoxides\ or\ in the case of the stable ylides\ undergo no reaction at all\ but there has been
a report in 0882\ of the formation of an alkene from a carbonyl compound which may involve a
telluronium ylide as an intermediate "Section 0[05[1[3#[
0[05[0[1 Phosphonium Ylides
While the Wittig reaction is used widely to construct one or more C1C bond"s# in a speci_c
position\ the stereochemical course of the reaction is sometimes less predictable and mixtures of
"Z#! and "E#!alkenes are often produced if the phosphonium ylide and carbonyl compound are both
unsymmetrically substituted[ This lack of stereoselectivity was _rst noted by Wittig and Schollkopf
in the reaction of the allylic ylide "4# with benzaldehyde to give a 0 ] 0 mixture of "Z#!"5# and
"E#!phenylbutadiene "6# "Scheme 0# ð43CB0207Ł[
Ph
+ +
Ph3P Ph3P PhCHO
Br– +
–
Ph
(5) (6) (7)
Scheme 1
Subsequent investigations revealed wide variation in the stereoselectivity of the reaction depending
on the base used ð43CB0207\ 44CB0543Ł\ and the reaction temperature ð46LA"592#004Ł[ In many cases
only the "E#!alkene is formed\ a fact that is frequently put to synthetic use[ For example\ Trippett
ð45CI"L#79Ł was able to prepare the _rst pure sample of all!trans!squalene from the condensation of
two molecules of geranylacetone "7# with the bis ylide derived from 0\3!bis"triphenyl!
phosphonio#butane dibromide "8# "Scheme 1#[
+ O
2BuLi (8)
Ph3P +
Br– PPh3 Br– 35%
THF
(9)
Scheme 2
Bergelson and Shemyakin were the _rst to explore the cis!selectivity in detail and to demonstrate
its synthetic utility ð53PAC160Ł[ Their pioneering work on the e}ect of solvents and additives on the
"Z# and "E# ratio of alkenes laid the foundations for subsequent mechanistic investigations\ notably
by Schlosser ðB!69MI 005!90Ł which revealed subtle ways to bring about a high degree of stereo!
selectivity in the Wittig reaction[
0[05[0[1[0 Mechanism
Any attempt to rationalise the stereochemical outcome of the Wittig reaction hinges on a full
understanding of the mechanism[ This aspect has been extensively studied and the reader is referred
to an excellent article on the subject ð78CRV752Ł[ Over much of its history\ the Wittig reaction has
been described as a stepwise ionic process initiated by nucleophilic attack of the ylide on the carbonyl
carbon atom to give two possible diastereomeric betaine intermediates "09a# and "09b# "Scheme 2#[
Subsequent decomposition then occurs by way of cis! and trans!oxaphosphetanes "structures "00a#
and "00b## ð62JA4667\ 64C230Ł to form the "Z#! or "E#!alkenes by elimination of phosphine oxide in a
syn fashion ð54AG"E#578\ 56LA"697#0Ł[ At least part of the driving force for the second stage of the
reaction appears to be the formation of the very strong phosphorusÐoxygen bond[ Vedejs has shown
that there is no longer a clear need to invoke an ionic intermediate on the way to the covalent
oxaphosphetane intermediate "00# in the Wittig reaction of {reactive| phosphorus ylides ð78JA4750Ł[
For reasons that are not clearly understood there is a decided kinetic preference for oxaphosphetane
formation via a one!step cycloaddition reaction that only under {salt!free| conditions su}ers neg!
ligible reversal to starting materials[ In consequence\ a high proportion of the less thermodynamically
stable "Z#!alkene is formed via the incursion of an early {puckered| transition state that gives a high
ratio of cis! to trans!oxaphosphetanes[ In most\ if not all\ other cases\ oxaphosphetane formation
is reversible\ and consequently stable phosphorus ylides furnish predominantly "E#!alkenes by
allowing interconversion to the thermodynamically more stable threo!isomer "00b# and collapse by
a later almost planar transition state[ It follows that the stereochemistry of the alkene produced will
depend both on the nature of the ylide and on the reaction conditions that a}ect the balance between
the betaine dissociation and formal cycloaddition steps ð78TL0250Ł[ For this reason it is convenient
to deal separately with the three distinct categories of ylides] stable\ reactive and so!called moderately
reactive[
R1 + + +
–
PPh3 Ph3P O– Ph3P O–
betaine structures once thought to be
H H + H R3
key intermediates;
R1 R3 R1 H
(10a) (10b)
erythro threo
R1
PPh3
Ph3P O Ph3P O cis and trans oxaphosphetanes

+ +
H H H R3 observable by NMR
R3 one step four centre
O cycloaddition R 1 R3 R1 H
(11a) (11b)
cis trans
irrev. syn elim. of Ph3PO
R3
R1 R3 R1
(Z) (E)
Scheme 3
0[05[0[1[1 Stable ylides

In general\ reactions employing stabilised ylides favour the formation of the stereoisomer with
the activating group at the a!carbon of the alkene trans to the larger group at the b!carbon[ This
stereoselectivity\ as discussed above\ is attributed to the preferential decomposition of the betaine
intermediate in the threo! rather than the erythro!con_guration since\ in the transition state leading
to the "E#!alkene\ there is less steric interference to conjugative stabilisation of the incipient double
bond[ The condensation of the ethoxycarbonylmethylide "01# with benzaldehyde in Scheme 3 is
illustrative ð52IZV0942Ł[
– +
O PPh3
:
:
: :
: :
Ph : : H
–Ph3PO Ph
CO2Et
+ PhCHO
Ph3P PhH 77% yield
H CO2Et
(12) O 95% of the product
EtO
Scheme 4
Scheme 4\ Equation "1# and Scheme 5 provide three other examples indicating the high degree of
stereoselectivity that may be obtained with stabilised ylides ð61JOC1468\ 64JA2401Ł[ The use of epoxides
as the base in a one!pot synthesis of alkenes by Buddrus is worthy of special note ð57AG"E#425\
61AG"E#0930\ 63CB1949Ł[
S NC
OHC
+ BunLi, THF S
Cl– Ph3P CN S
1 h, RT 63% yield
100% of product
S
Scheme 5
O O O
+ (2)
80%
Ph3P O
O
O EtO2C
Ph3P, Ph
EtO2C Br
CH2Cl2 overnight, RT
91% yield Ph
93% of the product
Scheme 6
As the examples in Scheme 4\ Equation "1# and Scheme 5 indicate\ the "E#!isomer is often
produced with almost complete exclusion of the "Z#!isomer[ It should be recognised that this may
not be a true re~ection of the stereochemistry of the reaction[ In many cases\ "Z#!alkenes having
electron!withdrawing groups at the a!carbon are isomerised to the thermodynamically more stable
"E#!isomer by the elevated temperatures required to e}ect the reaction ðB!69MI 005!91Ł[ In addition\
the reactants or products may catalyse the isomerisation ð52JA2767\ 53JA4930Ł[
The degree of stereoselectivity observed may be in~uenced by the nature of the substituents on
the ylide[ A characteristic feature of stabilised ylides is that replacement of phenyl groups on
phosphorus by alkyl groups such as butyl ð54JOC0185Ł or cyclohexyl ð51CB0783\ 54JOC0185Ł shifts the
isomer ratio further in favour of the "E#!product "Equation "2##[ To account for this e}ect it has
been suggested that alkyl groups "which are more electron!donating than phenyl# reduce the e}ective
charge at phosphorus\ thus allowing equilibration of the intermediate betaines[ However\ it may
equally be due to increased steric interaction preventing the formation of the transition state leading
to "Z#!alkene[
+ i, NaOEt/EtOH, 25 °C Ph
R 3P CO2Et X– CO2Et (3)
ii, PhCHO
X = Br or BPh4
Product
R (Z) (E)
Ph 15 85
Bu 5 95
n-C6H13 2 98
n-C10H21 4 96
c-C6H13 0 100
Substitution of phenyl groups on phosphorus by alkyl groups also results in an increase in the
yields of alkene "Equation "3## ð59T029Ł[ This is because electron!releasing groups attached to
the phosphorus facilitate nucleophilic attack ð52JA2767Ł on the carbonyl group in the _rst "rate!
controlling# step of the Wittig reaction by stabilising the contributing dipolar canonical form\ for
example\ "02b#[ Thus\ ~uorenylidenetriphenylphosphorane "02^ RPh# reacts only with the more
reactive "electrophilic# aldehydes\ whereas the tri!n!butyl ylide "02^ RBun# gives quantitative yields
of alkene with most aldehydes\ and good yields with the more reactive ketones\ for example\
p!nitrobenzophenone[
PR3
(13a)
O PhH
+ (4)
3–24 h, reflux
–
+PR
3
(13b)
Yield (%)
Carbonyl R = Ph R = Bun
p-O2NC6H4CHO 96 99
p-ClC6H4CHO 93 96
PhCHO 84 96
p-MeOC6H4CHO 37 94
p-Me2NC6H4CHO 0 94
(p-O2NC6H4)2CO 0 93
p-O2NC6H4COMe 0 67
p-ClC6H4COMe 0 9
The trans!stereoselectivity of Wittig reactions of stabilised ylides may be adversely a}ected by the
introduction of substituents at the position a to the phosphorus atom[ If the group is su.ciently
large\ the energy di}erence between the two diastereoisomers of the intermediate betaine will be
lowered[ In this case appreciable amounts of "Z#!alkenes are formed in addition to the "E#!isomers[
For example\ reaction of phenacylidenetriphenylphosphorane "03^ RH# with p!nitrobenzaldehyde
gives entirely "E#!alkene\ whereas introduction of an a!bromine atom "03^ RBr# leads to the
formation of 24) of the "Z#!isomer "Equation "4## ð52JA1689Ł[
R CHCl3
Ar R Ar COPh
Ph3P + ArCHO + (5)
COPh 24 h, RT COPh R
(14)
R Yield (%) Product composition
H 72 100 0
Br 64 35 65
Ar = p-O2NC6H4
A similar situation prevails in the preparation of esters related to the insecticide bioresmethrin
"Equation "5## ð63JCS"P0#1369Ł[ Condensation of the aldehyde "05# with the ethoxycarbonylmethylide
"04^ RH# gives a product containing ×89) of the "E#!alkene^ alternatively\ when RBr or Cl\
the condensation produces an isomer mixture in which the "Z#!product predominates "69Ð79)#[
R OHC H
CH2Cl2
Ph3P + H CO2But
CO2Et overnight, RT
(15) (16)
EtO2C R
H H
R EtO2C
H CO2 But
+ H CO2But
(6)
R Product composition
H >90 <10
Cl 30 70
Br 20 80
The e}ect of a!methyl substituents is of interest "Scheme 6#[ As a rule\ the "E#!alkene is formed
almost exclusively as illustrated by the reaction ð50JOC3167Ł of methoxycarbonylethylidenetriphenyl!
phosphorane "06# with acetaldehyde to give practically pure methyl tiglate "07#\ i[e[\ the "E#!isomer\
and with the alkynic aldehyde ð57JCS"C#0886Ł "08# to give a product "19# which was all!trans as
shown by NMR[ Similarly\ the same ylide with 1!hydroxytetrahydropyran "10# ð52T038\ 53IZV1992Ł
a}orded methyl 6!hydroxy!1!methyl!"E#!hept!1!enoate "11# stereospeci_cally[ However\ loss of
stereospeci_city has occasionally been observed ð56TL390\ 69TL30\ 62JCS"P0#0305\ 65LA0364Ł[
MeCHO
CH2Cl2
overnight, reflux CO2Me
90% yield (18)
97% of the product
Ph
Ph CHO
(19)
Ph3P
CH2Cl2, 2 h, RT
CO2Me 64% yield
(17) 100% of the product CO2Me
(20)
O OH
(21) HO ( )4
CO2Me
(22)
Scheme 7
A signi_cant loss of trans!stereoselectivity also occurs in the reactions of stabilised ylides with
aldehydes having a!alkoxy substituents although precise rules to predict the extent of loss are still
di.cult to formulate[ In the case of the aldehydosugar "12# ð68HCA1980Ł\ reaction with
ethoxycarbonylmethylidenetriphenylphosphorane "01# in chloroform gave an isomer mixture "13#
in which the "Z#!product predominates "59)# "Equation "6##[ The loss in stereoselectivity is solvent
dependent and "Z#!alkene formation can be minimised in DMF "03)# and maximised in methanol
"81)#[ This e}ect is general and usually more "Z#!alkene is obtained when an aprotic solvent is
replaced by a protic one\ such as methanol\ or when soluble lithium salts are added[
EtO2C
OHC O O
Ph3P O O
+ (7)
CO2Et
MeO O MeO O
(12) (23) (24)
Product composition
Solvent (Z):(E)
DMF 14:86
CHCl3 60:40
MeOH 92:8
Whereas in the reactions of stabilised ylides with aldehydes\ the "E#!alkene is predominantly
formed\ interaction with unsymmetrical ketones almost always leads to a considerable amount of
"Z#!isomer[ However\ condensation often fails unless an acid catalyst\ for example\ benzoic acid is
present ð56CB0033\ 58JCS"C#1617\ 63CB0662Ł "Equation "7##[
O PhH CO2Et R CO2Et

Ph3P
+ + (8)
CO2Et 5–12 h, 80 °C
R R
(12)
Yield (%) Product composition

without with
R PhCO2H PhCO2H
Et 5 89 66 34
Pr 12 83 60.5 39.5
An alternative\ but often better procedure\ to acid catalysis involves heating a mixture of the
reactants without a solvent to relatively high temperatures "049Ð199>C# ð50MI 005!90\ 50TL468Ł[ For
example\ in the synthesis of abscisic acid "Equation "8##\ the condensation between ethoxy!
carbonylmethylidenetriphenylphosphorane "01# and 0!hydroxy!3!oxo!a!ionone "14# was practically
complete after 09 min at 039Ð069>C and gave approximately equal amounts of the "E\Z#! and "E\E#!
esters "15# and "16# respectively ð57JOC2455Ł[ A comparison of the stereochemical outcome of the
procedure with that obtained in toluene "or ethanol# after prolonged heating revealed little di}erence
in the isomer ratio ð60BSF"1#3440\ 61TL1410Ł although increasing the temperature to about 069>C
appeared to increase the amount of "E\E#!isomer ð57JOC2455Ł[
Ph3P
O +
OH CO2Et
O
(25) (12)
CO2Et
OH + OH (9)
CO2Et
O O
(26) (27)
Product composition
Reaction conditions Yield (%) (E,Z) (E,E)
Melt (10 min, 140-170 °C) 83 50 50
Toluene (4 h, reflux) 77 50 50
EtOH 38 62
0[05[0[1[2 Reactive ylides

From Section 0[05[0[1[1 it can be assumed that\ in the absence of additives or solvent interactions\
the "E#!isomer usually forms the major product in Wittig reactions e}ected with stabilised ylides[
This situation changes profoundly in the case of the so!called {reactive| ylides\ i[e[\ ylides that do
not contain stabilising a!substituents[ For these the thermodynamically less stable "Z#!isomers tend
to dominate the mixture of alkenes obtained\ as illustrated by the two examples ð52JOC261\
62HCA0065Ł in Scheme 7[ The degree of stereoselectivity varies considerably with the reaction
conditions\ especially with the nature of the solvent and the base used[ The decisive in~uence of
dissolved lithium salts is particularly stressed[ It was originally thought that Wittig reactions of
reactive ylides produced largely "E#!alkenes but that the "Z# ] "E# ratio could be increased by the use
of special polar solvents and added lithium salts[
BuLi OHC
+ +
Ph3P 10 °C
Et2O
Br– 82%
84 : 16
CHO
BunLi O O
+ +
Ph3P 85%
Et2O
Br– 0.5 h, RT O
85 : 15
Scheme 8
While these conditions have been used to e}ect striking syntheses of a number of naturally
occurring cis!unsaturated acids it has become apparent that lithium salts have little or no e}ect on
the stereochemistry of reactions involving reactive ylides in dipolar aprotic solvents[ The examples
in Scheme 8 illustrate the generalisation that reactive ylides normally yield alkenes that are ×89)
"Z#\ irrespective of the presence or absence of lithium salts\ if the reaction is carried out in very polar
aprotic solvents such as dimethylformamide ð56T1698Ł\ dimethylsulphoxide "DMSO# ð66JOC1672\
66TL3146Ł\ or hexamethylphosphoramide "HMPA# ð63S687\ 63TL196Ł[ The addition of DMSO or
HMPA as cosolvent to tetrahydrofuran also provides a suitable reaction medium for promoting
the formation of "Z#!alkene ð63JOC2682\ 63OPP158Ł[ It should be stressed that organolithium com!
pounds are unsuitable as bases in dimethylformamide "DMF# since they may react with this solvent
to give aldehydes ð45JCS3580\ 46CI"L#0485Ł[ Sodium hydride is recommended as base if DMF is used
as solvent^ metal alkoxides have also enjoyed widespread use ð53CB2182Ł[
BunLi RCHO R
+
Ph3P Et
DMF 1h
I– Et
0.5 h, 20 °C
R (Z) (E)
Et 95 5
Ph 74 26
+ Na+ –CH2SOMe OHC OCH2Ph CO2H

Ph3P CO2H
DMSO 2.5 h, RT O Ph
Br– 20 min, 20–25 °C 87%; no (E) isomer
Scheme 9
A completely di}erent situation is observed for reactions in nonpolar solvents such as benzene
and ether[ Reactions in solvents of this type show a salt dependence\ giving increased amounts of
the "E#!alkene on addition of relatively soluble lithium salts such as lithium iodide ð55AG"E#556\
56LA"697#0Ł[
In order to explain these e}ects in nonpolar media\ it is argued that when dissolved metal cations\
especially Li¦\ are present in the reaction solution\ the decomposition of both diastereoisomeric
betaine intermediates to alkene is retarded by complex formation with the cation[ As a result\
reversal of the betaine formation step becomes important and more of the kinetically favoured
erythro!betaine is converted into the thermodynamically more stable threo!isomer\ thus reducing
the proportion of "Z#!alkene in the product[ The absence of salt e}ects in more polar media is
regarded as being due to destabilisation of any such betaineÐcation complex due to preferential
solvation of the cation[
It is important\ therefore\ when preparing "Z#!alkenes by the Wittig reaction in nonpolar media\
to ensure that ylide solutions that are free from dissolved salts are used[ Several means of achieving
this have been reported[ For example\ the ylide can be prepared by the use of sodamide in anhydrous
ammonia and then extracted into benzene ð47LA"508#09\ 54AG"E#472Ł[ A variation of this method is
to prepare the ylide with sodamide in boiling tetrahydrofuran and to remove the insoluble inorganic
salts by _ltration ð69LA"628#100Ł[ Potassium t!butoxide ð64JA3216Ł and sodium bis"trimethyl!
silyl#amide ð65CB0583Ł have also been employed as bases in tetrahydrofuran without the tedious
necessity for _ltration[
In another convenient procedure ð69MI 005!93Ł a mixture of the phosphonium salt and the aldehyde
is treated with sodium t!pentoxide dissolved in benzene containing trace amounts of dimethyl
sulphoxide[ Typical {salt!free| "Z# ] "E# distributions are also obtained when 07!crown!5!complexes
of potassium carbonate or potassium t!butoxide are used in THF ð64S673Ł[ Major advantages of
the last two methods are that preformation of the ylide is unnecessary[ Apart from the obvious
advantages of a {one!pot| process\ in situ formation of the ylide gives high yields of alkenes and a
minimum of self!condensation[ Some examples of the use of the {salt!free| Wittig reactions are
shown in Schemes 09\ 00 and Equation "09# ð69MI 005!92\ 64JA3216\ 64S673\ 65CB0583Ł[
K2CO3
18-crown-6
Ph
+ + PhCHO (10)
Ph3P
THF, 18 h, reflux
X– 96%
(Z) : (E) 85 : 15
Although the choice of reaction conditions may exert a signi_cant in~uence on the stereochemical
composition of the product of Wittig reactions\ other factors of importance are the nature of the
substituents both on the carbonyl and on the ylide component[ As the data in Table 0 clearly
demonstrates\ the reaction between homologous unbranched alkylidene ylides and primary aliphatic
ButOK OHC CO2Et

+
Ph3P
THF 50 min, 25 °C
Br– 30 min, 25 °C 69%
+
CO2Et
CO2Et
94 : 6
Scheme 10
+ Na+ –N(TMS)2 +
– –20 °C, crystallize and
Ph3P Ph3P + NaBr
hexane separate by filtration
Br– 3 h, reflux and washing
CO2Me
– OHC
+
Ph3P CO2Me
THF, –78 °C
84%
'salt free' (Z):(E)
98 : 2 –78 °C
94 : 6 20 °C
84 : 16 100 °C
Scheme 11
aldehydes is highly stereoselective in salt!free solution\ yielding products in which the proportion of
the "Z#!isomer exceeds 89) "in most cases 84)#[ However\ when a\b!unsaturated or aromatic
aldehydes serve as the carbonyl component\ some loss of stereoselectivity is observed\ especially in
dipolar aprotic media[ This di}erence in behaviour may best be explained by assuming that betaine
formation with aliphatic aldehyde is essentially irreversible "in the absence of lithium salts#\ whereas
with more electrophilic carbonyl compounds such as p!cyanobenzaldehyde\ reversibility is more
pronounced and the betaine formation and hence the product ratio become thermodynamically
controlled[
Table 0 Yields and "Z# ] "E# ratios of alkenes from {salt!free| Wittig reactions of reactive
ylides in benzene\ toluene or tetrahydrofuran at 9>C ð55AG"E#556\ 56LA"697#0\ B!69MI 005!90\
60BSF"1#342Ł[
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Ph2P¦0−CHR0 ¦R1CH1O:R0CH1CHR1 ¦Ph2P1O
"Z# ] "E# ratio "yield )#
R1 R0 Me R0 Et R0 Pr
*
Et 86 ] 2 "69#
Prn 84 ] 4 84 ] 4 "38# 84 ] 4 "67#
n!C4H00 80 ] 8 "55# 85 ] 3
"E#!PhCH1CH 76 ] 02 "66#
PhC2C 62 ] 16
p!MeOC5H3 89 ] 09 "67# 81 ] 7 "84# 89 ] 09 "79#
p!MeC5H3 78 ] 00 "77# 84 ] 4 "48# 81 ] 7 "60#
Ph 76 ] 02 "87# 85 ] 3 "77# 83 ] 5 "55#
p!ClC5H3 71 ] 07 "66# 82 ] 6 "43# 81 ] 7 "53#
m!ClC5H3 63 ] 15
p!NCC5H3 63 ] 15
p!F2C C5H3 58 ] 20
*
In the case of ketones the isomer ratio depends on the nature of the substituents at the carbonyl
carbon[ With alkyl aryl ketones the "Z#!isomer is still favoured as shown in Scheme 01
ð65JCS"P0#0365Ł[ On the other hand\ cis!stereoselectivity is almost totally lost with unsymmetrical
aliphatic ketones using a variety of reaction conditions[
R
Na+ –CH2SOMe ArCOR R

+
Ar
Ph3P +
DMSO, 0.25 h, 25 °C 1 h, 25 °C Ar
Br–
R Yield (%) Product composition

Me 80 9 : 1
Et 71 9 : 1
Ar = p-MeOC6H4
Scheme 12
An unexpectedly large tendency to form "Z#!alkenes has been observed with aliphatic aldehydes
when the alkyl group is branched ð62JA4667\ 64JA5103Ł[ For example\ reaction of ethylidenetriphenyl!
phosphorane with bulky aldehydes such as pivalaldehyde and 1\1!dimethylbut!2!enal gives pre!
dominantly\ if not exclusively\ "Z#!alkene\ even in the presence of lithium salts[ Steric factors may
also be responsible for the exclusive formation ð58CC292\ 58CC674Ł of the "Z#!alkene "17# from
the reaction of hexylidenetriphenylphosphorane with the endo!aldehyde "18#^ in the case of the
corresponding exo!aldehyde a mixture of "Z#! and "E#!alkenes is obtained in the ratio of 79 ] 19
"Scheme 02# ð58JA4253Ł[ A possible explanation for this surprising selectivity can be formulated
ð58CC292\ 58CC674Ł based on initial coordination of the carbonyl oxygen atom to the phosphorus
atom of the ylide before C0C bond formation takes place[
THP-O
CHO THP-O
BunLi (29) H
+ n-C5H11
Ph3P
PhH PhH
Br– n-C5H11
H
(28)
Scheme 13
This rationale may also explain the loss of cis!selectivity in Wittig reactions of reactive ylides
having branched alkyl substituents at the a!carbon atom[ The example in Scheme 03 illustrates this
e}ect ð60JCS"C#2141Ł[
OHC
+
Ph3P
+
Br–
Reaction conditions Yield (%) Product composition

BunLi, Et2O, 4 h, 35 °C 70 1 : 1
Na+ –CH2SOMe, DMSO, 4 h, 25 °C 71 2.4 : 1
Scheme 14
0[05[0[1[3 Formation of "E#!alkenes via WittigÐSchlosser modi_cation

As mentioned previously\ reactive ylides will a}ord large amounts of "E#!alkenes if equilibration
of the erythro and threo betaines can be accelerated[ A method has been described ð55AG"E#015\
56LA"697#0\ B!65MI 005!90Ł whereby the initially formed betaineÐlithium complex\ with predominantly
the erythro con_guration\ is a!metallated with an equivalent of an organolithium reagent to form a
new b!oxido phosphorus ylide "betaine ylide# "20# "Scheme 04#[ Whereas the initially formed erythro!
complex "29# was relatively stable to inversion\ the diastereoisomeric betaine ylides are rapidly
interconverted\ even at temperatures as low as −67>C[ Signi_cantly\ the equilibrium lies far to the
side of form "20b#\ so addition of one equivalent of a proton donor occurs with remarkable
stereospeci_city to form the Wittig intermediate "21# in the threo con_guration\ which decomposes
selectively to give pure "E#!alkene[ It should be noted that protonation of b!oxido ylides prepared
from salt!free ylides leads to mixture of erythro! and threo!betaines and hence to mixtures of "Z#!
and "E#!alkenes ð69CB1703Ł[
+ + +
Ph3P –O LiX Ph3P –O LiX Ph3P –O LiX
PhLi 1 : 99 H+
H R2 Li R2 R 1 R2
R1 H R1 H Li H
(30) erythro (31a) erythro (31b) threo
+
Ph3P –O LiX R1
R1 R2
H H R1
(32) threo
Scheme 15
Table 1 summarises\ the application of this method\ known as the WittigÐSchlosser reaction\ to
the preparation of "E#!alkenes using reactive ylides in combination with a variety of aliphatic\
unsaturated and aromatic aldehydes[ For comparison\ the conventional Wittig reactions lead to a
"E# ] "Z# distribution that varies between 64 ] 14 "for phenylhexene# and 19 ] 79 "for oct!1!ene#[
Table 1 trans!Stereoselective alkenation of aldehydes R1CH1O with reactive ylides ðPh2P¦!−CHR0Ł

via the WittigÐSchlosser reaction ð55AG"E#015\ 56LA"697#0\ B!65MI 005!90Ł[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Alkene formed R0 R1 Yield "E# ] "Z# ratio
")#
*
Oct!1!ene Me n!C4H00 69 88 ] 0
Oct!1!ene n!C4H00 Me 59 85 ] 3
Oct!3!ene n!C2H6 n!C2H6 61 87 ] 1
PhCH1CHMe Me Ph 58 88 ] 0
{salt!free| 71 65 ] 13
PhCH1CHEt Et Ph 61 86 ] 2
PhCH1CH"CH1#2Me Bun Ph 64 85 ] 3
"E#
PhCH1CHCH1CHMe Me PhCH1CH 52 86 ] 2
*
trans!Stereoselective alkene synthesis by means of the WittigÐSchlosser reaction is not limited

to aldehydes\ as is shown by the reaction of the ethylidene!triphenylphosphorane with the un!
symmetrical ketone acetophenone to give "E#! and "Z#!phenylbut!1!enes in the ratio 78 ] 00
ð56LA"697#0Ł[ When carried out in the conventional manner\ the same reaction led to a ratio of 39 ] 59
ðB!69MI 005!90Ł[ In contrast\ no detectable increase in stereoselectivity was observed ð69JOC454Ł for
the reactions of n!butylidenetriphenylphosphorane with the aliphatic methyl ketone\ methyl!
heptenone\ under the same conditions[
Exaggerated trans!selectivity is also observed with oxido ylides bearing various nucleophilic
groups "OH\ CO1H and CONH1# in the side chain ð74JA106Ł\ relative to a ylide that does not possess
such a group\ upon reaction with both benzaldehyde ""E# ] "Z#82 ] 6# and hexanal ""E# ] "Z#41 ] 37#[
0[05[0[1[4 Ylides of intermediate "moderate# reactivity

As discussed previously\ ylides fall into two main groups according to their reactivity[ The major
group are the so!called {reactive| ylides in which the negative charge is localised on the a!carbon\
whereas the second group includes the {stable| ylides which are much less reactive owing to extensive
delocalisation of negative charge through participation of resonance structures[ Obviously\ a whole
spectrum of reactivity lies in between\ and some ylides stabilised by a!substituents such as vinyl\
aryl or alkynyl show an intermediate {moderate| reactivity which is also re~ected in the stereo!
chemical outcome of their reactions with carbonyl compounds[ Scheme 05\ Equation "00# and
Schemes 06Ð08 illustrate the fact that stereoisomeric mixtures of alkenes are usually produced when
this preparatively important class of ylides are employed in Wittig reactions under a variety of
conditions ð54JOC0362\ 58S64\ 69T0180\ 60CB1774\ 61AJC434\ 62S184\ 63TL1476Ł[ It will be noted that in
most cases a slight preponderance of the "E#!alkene is favoured[
NaOEt PhCHO
Ph Ph Ph
+
Ph3P Ph +
EtOH 50 h, RT Ph
Cl– ~100%
55 : 45
Scheme 16
Ph
Ph 50% aq. NaOH Ph
+
Ph3P Ph + + Ph (11)
CHO CH2Cl2
Cl– 10 min, RT Ph
87%
64 : 36
Na+ –CH2SOMe O CHO

+
Ph3P O + O
DMSO 15 min, 50 °C
Br– 15 min, ca. 30 °C 20%
80 : 20
Scheme 17
MeO
MeO
MeO
NaOEt O CHO
+
Ph3P OMe +
EtOH 2.5 h, RT O
Cl– 15 min, RT 54% O OMe
OMe
1 : 2
Scheme 18
PhLi n-C5H11CHO F n-C5H11 F

+
Ph3P F +
Et2O, THF 0.5 h, –78 °C
n-C5H11
I– 2 h, –78 °C 55%
45 : 55
Scheme 19
Since moderately reactive ylides possess di}erent structural features\ certain of which deserve
special recognition\ it is convenient\ when discussing stereochemical implications as well as pre!
parative applications\ to treat the important types of moderately reactive ylides^ benzylic and allylic
separately[
"i# Benzylic ylides

For Wittig reactions e}ected with triphenylphosphonium benzylides\ the stereochemistry of the
products depends largely on the nature of the substituents in the aryl ring[ In keeping with previous
stereochemical arguments\ electron!releasing groups which enhance the reactivity "nucleophilicity#
of the ylide reduce the trans!selectivity\ whereas the reverse is true for electron!withdrawing groups[
Important advantages may be gained in synthesis from this in~uence to produce a higher proportion
of "Z#!alkene[ For example\ in the preparation of 3!nitro!3?!methoxystilbene\ the reaction of
3!nitrobenzylidenetriphenylphosphorane "22# with anisaldehyde leads to the predominant formation
of the "E#!alkene as shown in Scheme 19 ð51JOC3555\ 55JOC223Ł[ However\ by interchanging the ylide
and aldehyde substituents\ a 0 ] 0 mixture of stereoisomers is obtained "cf[ ylide "23##[
BunLi Ar2CHO Ar1 Ar2 Ar1

+
Ph3P Ar1 +
PhH overnight, RT
Ar2
Cl– 1 h, RT
Ylide Ar1 Ar2 Product composition

(33) p-O2NC6H4 p-MeOC6H4 26(0) : 74(100)
(34) p-MeOC6H4 p-O2NC6H4 44(48) : 56(52)
Scheme 20
Perhaps a more e}ective means of shifting the isomer ratio in favour of the "Z#!product is through
structural alteration of the phosphonium group[ As already noted\ if the phosphorus atom is
rendered more electrophilic by substitution of electron!withdrawing groups\ the betaine intermediate
has less chance to equilibrate to the more stable threo form[ As a consequence greater selectivity for
"Z#!alkene formation is observed ð55JOC223Ł[ Table 2 shows that in the synthesis of 3!nitro!3?!
methoxystilbene\ use of 3!methoxybenzylidenetris"p!chlorophenyl#phosphorane "24# in place of "23#
leads to an increase from 33 ] 45 to 79 ] 19 in the "Z# ] "E# ratio[ In a similar manner\ the "Z# ] "E#
ratio increases in the nitrobenzylidene series as the phosphorus substituent is successively changed
from n!butyl "25# to phenyl "26# to p!chlorophenyl "27#[ As indicated\ the course of the reaction
may be shifted overwhelmingly in favour of either the "Z#! or the "E#!isomer by the appropriate
choice of reactants[
Table 2 Relative yields of "Z#! and "E#!3!nitro!3?!methoxystilbenes
from the reaction of R02P¦CH1C5H3R1Br− with R2C5H3CHO in benzene
at room temperature using n!butyllithium as base ð55JOC223Ł[
*
Ylide R0 R1 R2 "Z# ] "E# ratio
*
23 Ph OMe NO1 33 ] 45
24 p!ClC5H3 OMe NO1 79 ] 19
25 n!C3H8 NO1 OMe 06 ] 72
26 Ph NO1 OMe 15 ] 63
27 p!ClC5H3 NO1 OMe 41 ] 37
*
Apart from the e}ect of the substituents\ the degree of stereoselectivity observed may be in~uenced
by changes in the reaction medium[ As shown in Table 3\ formation of "Z#!alkene is increased by
the use of either protic solvents or dipolar aprotic solvents[ However\ under no circumstances is the
e}ect appreciable\ and "E#!alkene usually dominates the product composition even when salt!free
solutions of the ylide are employed[ This would imply that in general solvation of the betaine
intermediate is not signi_cantly a}ecting its formation or reversible decomposition[ It has been
suggested ðB!69MI 005!90Ł that threo!betaine formation becomes more important under conditions
of kinetic control if the ylide sidechain bears bulky ligands such as phenyl "or cyclohexyl#[ Even so\
it should be noted that use of Schlosser|s modi_cation\ whereby the initially formed betaineÐlithium
complex is a!metallated\ fails to improve the trans!selectivity in the reaction with propionaldehyde[
An interesting change in selectivity is observed ð63JCS"P0#1324Ł when the reaction solvent in the
Wittig condensation between 1!methoxybenzyltriphenylphosphonium bromide and the aldehyde
"28# is changed from methanol to dimethylformamide "Equation "01##[ In methanolic solution "1 h\
re~ux# with lithium methoxide as base the "E#!stilbene predominated\ but in dimethylformamide
"0 h\ 89>C# the "Z#!stilbene predominated[ The reason why opposite stereoselectivities are preferred
in these solvents is not apparent[
+
MeO PPh3 OHC OMe MeO OMe
LiOMe
+ (12)
97–99%
Cl– mixture of isomers
Br Br
(39)
Table 3 E}ect of the reaction medium on the stereoselectivity of the Wittig reaction between
benzyltriphenylphosphonium salts and propionaldehyde[
*
PhCH1CHEt
Reaction medium "salt present# "Z# ] "E# ratio Yield Ref[
")#
*
BunLi0C5H5 "LiBr# 16 ] 62 46 57JCS"C#0873
"LiCl# 12 ] 66 21Ð72 53JOC2216
"LiCl# 10 ] 68 56T1698
"LiBr# 16 ] 62
"LiI# 30 ] 48
Schlosser|s a!metallation product 32 ] 46
BunLi0hexane 11 ] 67
{salt!free| C5H5 14 ] 64 B!69MI 005!90
07 ] 71 50 56T1698
Et1O0NaOEt 20 ] 58 52T038
THF0NaOEt 22 ] 56
DMF0BunLi 33 ] 45 21Ð33 53JOC2216
39Ð34 ] 59Ð44 59Ð63 57JCS"C#0873
DMF0NaOEt 35 ] 43 55 53JOC2216
EtOH0NaOEt 35 ] 43 84
K1CO2007!crown!5!ether0THF 14 ] 64 83 64S673
*
The isomer ratio may be shifted further in favour of the "E#!isomer by replacing the phenyl groups
on phosphorus by alkyl groups as illustrated in Table 4 where a comparison is made of the
distribution of stilbene isomers obtained in ethanol[ It should be noted that substitution of alkyl
groups for phenyl groups on phosphorus leads not only to almost pure "E#!stilbene\ but also to
better yields[ A similar e}ect has been noted previously for stabilised ylides[
Table 4 Yields and "Z# ] "E# ratios for stilbene resulting from the inter!
action of di}erent benzylphosphonium salts R0R1R2P¦CH1PhX− and
benzaldehyde in ethanolÐsodium ethoxide[
*
PhCH1CHPh
R0R1R2 "Z# ] "E# ratio Yield Ref[
")#
*
Ph 42 ] 36 65 44CB0543
Ph1Me 17 ] 61 86 55JCS"C#0989
PhMe1 02 ] 76 80
Bu 8 ] 80 B!69MI 005!90
cyclohexyl 4 ] 84 81 51CB0783
*
In general\ structural changes in the carbonyl co!reactant exert only a minor e}ect on the
stereochemistry of Wittig reactions of benzylidenetriphenylphosphorane[ trans!Selectivity is pre!
served when using a variety of aliphatic\ unsaturated and aromatic aldehydes under aprotic
conditions[ There are some exceptions to this observation\ but one in particular deserves special
attention ð57JCS"C#0886Ł and involves condensation of benzylidenetriphenylphosphorane with the
a\b!unsaturated aldehyde "39# having a carboxylate ion on the b!carbon atom "lactol in disguise# to
give a mixture of pentadienoic acids "30# and "31# "Scheme 10#\ in which a high proportion of the
newly formed double bond has the "Z# con_guration[ Molecular models suggest that this may result
from preferential stabilisation of the erythro form of the intermediate betaine by interaction of
the positively charged phosphorus atom and the carboxylate ion in the staggered conformation
ð57JCS"C#0871\ 57JCS"C#0886Ł[
As might be expected\ in some instances only the "E#!isomer is formed\ especially when it is
strongly favoured on steric grounds[ An example is the conversion of indole!2!aldehyde "32# into
"E#!0!phenyl!1!"2!indolyl#ethylene "33# in 29Ð59) yield by condensation with benzylidenetriphenyl!
phosphorane "Scheme 11# ð65IJC"B#308Ł[
O O OH
Ph
NaOMe (40)
+
Ph3P Ph CO2H + Ph
Et2O 2 h, 20 °C
Cl– 0.5 h, 10 °C 93% CO2H
(41) 66 : 34 (42)
Scheme 21
CHO
N
H
NaNH2 (43)
+
Ph3P Ph
PhH 4 h, RT N Ph
Br– 4–8 h, 80 °C H
(44)
Scheme 22
"ii# Allylic ylides

In contrast to reactions of reactive ylides\ the stereochemistry of Wittig reactions e}ected with
moderately reactive ylides is little a}ected by the presence of dissolved lithium salts[ Scheme 12
shows one example ð58JCS"C#0913Ł in which the stereochemical outcome is not signi_cantly di}erent
under {salt!free| conditions from that obtained under normal Wittig reaction conditions ð66T0734Ł[
Owing to the intrinsic nonstereoselectivity of allylic ylides\ formation of conjugated dienes of de_nite
con_guration is best conducted by reaction of a saturated aliphatic reactive ylide with an
a\b!unsaturated aldehyde\ as exempli_ed by the synthesis of the "8Z\ 00E#!diene "35a# ð64CL092Ł\ a
major component of the sex pheromone of the Egyptian cotton leafworm "Spodoptera littoralis#\ by
the Wittig reaction of 8!acetoxynonyltriphenylphosphonium bromide 34 with "E#!pent!1!en!0!al in
dimethyl sulphoxide using dimsylsodium as the base "Scheme 13#[ This gave a 63) yield of the
dienes containing 74Ð89) of "35a# and 09Ð04) of the "8E\ 00E#!isomer "35b#\ whereas alternative
Wittig condensation of "E#!pent!1!entyltriphenylphosphonium bromide "36# with 8!oxonon!0!
ylacetate produced a mixture of isomers in various ratios depending on the reaction conditions[
( )2
PhH O CHO
NaNH2 –
+ +
Ph3P Ph3P PhH, 25 °C
NH3 (l) reflux
67%
Br– 'salt-free'
( )2 + ( )2
O O
6 parts 4 parts
Scheme 23
A further stereochemical complication sometimes encountered during Wittig reactions with allylic
ylides having a terminal substituent is loss of con_guration in the allylic double bond[ Thus\
the reaction ð55JOC1896\ 61HCA0717Ł between salicylaldehyde and the ylide generated from the
crotylphosphonium salt "37# "Equation "02## gave a mixture of all four geometrical isomers of the
diene "38#[ The same mixture was also obtained starting from pure "E#!crotyl salt[ However\ the
tendency to isomerise is not a general phenomenon[ Preservation of stereochemical integrity has
been demonstrated for both "Z#! and "E#!allylic phosphonium salts during ylide formation and
subsequent reaction with aldehydes ð51LA"547#54\ 64HCA0905Ł[
+
Ph3P OAc
Br– (45)
Na+ –CH2SOMe, DMSO
CHO
OAc + OAc
(46a) (46b)
OAc
OHC
base
+
Ph3P
Br–
(47)
Reaction conditions (46a) : (46b)

KOBut/PhH 40 : 60
GLYME/BunLi 50 : 50
Na+ –CH2SOMe/DMSO 60 : 40
Scheme 24
1 3
CHO
+ NaH
+ Ph3P 2 4 (13)
DMF
OH Br– 58% OH
(48) (49)
(E)-1, (E)-3, 34%
(E)-1, (Z)-3, 15%
(Z)-1, (E)-3, 36%
(Z)-1, (Z)-3, 15%
In some cases\ at least\ stereomutation may be suppressed by an appropriate choice of reaction

conditions[ For example\ the "Z#!allyltriphenylphosphonium bromide "49# with butyllithium and
cyclohexanone in tetrahydrofuran at 39>C gave a mixture of dienes "40a# and "40b# containing 19)
of the "E#!isomer "Scheme 14# ð47JCS732Ł[ By preparing the ylide at −14>C and warming to 4>C
after addition of the ketone the proportion of "E#!isomer was reduced to ³4)[
O
OH BunLi (2 equiv.) OH OH
+
+
THF, –25 °C THF
PPh3
Br–
(50) (51a) (51b)
Scheme 25
Substitution of a methyl group at the b!position usually increases the isomerisation about the
allylic double bond ð60JA2346Ł[ Another di.culty that frequently arises in Wittig reactions of allylic
ylides is concurrent condensation at the g!position[ For example\ reaction of hexanal with the allylic
ylide "41# furnished ð63JOC710Ł not only all four geometric isomers of methyl 2!methyldeca!1\3!
dienoate "42#\ the normal a!condensation product\ but also both geometric isomers of methyl
1!isopropenyl!1!enoate "44#\ the g!condensation product "Scheme 15#[ The latter could have been
formed via the cyclic six!centre phosphorane "43#[
However\ by generating the ylide from its salt\ using diisopropylamine in DMF in the presence
+ +
Ph3P – CO2Me Ph3 P CO2Me
α γ –
(52a) (52b)
C5H11CHO
CH2Cl2, 0.5 h, 25 °C
+
CO2Me + Ph3P CO2Me
C5H11 3
4 2
(53) –O C5H11
(E)-2, (E)-4, 12%
(E)-2, (Z)-4, 7%
(Z)-2, (E)-4, 17%
(Z)-2, (Z)-4, 6% CO2Me
Ph3P
O C5H11
(54)
CO2Me CO2Me
C5H11
+
C5H11
(E)-(55) (Z)-(55)
Scheme 26
of cadmium iodide\ it is possible to minimise g!condensation and obtain fair yields of the
a!condensation product "42# "25)#[
In the case of a\b!unsaturated carbonyl compounds\ condensation at the g!position is highly
speci_c and takes place in a Michael!type fashion to provide a simple and elegant synthesis of
cyclohexa!0\2!dienes ð60HCA0656\ 62CB2668\ 63JOC0207Ł[ A possible mechanism for this transformation
is illustrated in Scheme 16 ð60HCA0656Ł[
O
+
BunLi CO2Et
Ph3P
Et2O 1 h, RT
Cl– 1 h, 5–10 °C
CO2Et CO2Et CO2Et
60%
O– – O
+PPh +PPh
3 3
Scheme 27
As expected increased steric hindrance at the g!carbon atom inhibits g!condensation ð62JOC2514\
62TL3314Ł\ although condensation of 1!methylenecyclohexanone with the ylide derived from the
allylic salt "45# ð44CB0304Ł resulted in the formation of 0!"cyclohex!0!enyl#!2!cyclohexylidenepropene
"46# via a ð0\2Ł!hydrogen shift as shown in Scheme 17[
Finally\ mention should be made of a related {one pot| procedure ð64TL0248Ł for the synthesis of
conjugated polyene esters or ketones involving the condensation of allylidenetriphenylphosphorane
with a\b!unsaturated b!chloro!carbonyl compounds\ for example\ "47#\ in the presence of an alde!
hyde "Scheme 18#[ The reaction is believed to involve analogous conjugate addition to give inter!
mediates such as "48#[ Subsequent loss of chloride and deprotonation by base convert "48# into the
O
PhLi
H
+ Et2O 19 h, RT PPh3
Ph3P 4 h, RT O
Br– (56) (57)
Scheme 28
conjugated ylide "59# which is trapped by the aldehyde[ It should be noted that trapping the ylide
with benzaldehyde gives a high yield of the expected all!"E#!triene "50a# whereas the more bulky
isobutyraldehyde a}ords a 39 ] 59 mixture of "Z#! and "E#!isomers "50b# and "50a#\ respectively[
Cl CO2Et
Cl
+ LiNPri (58) +
2
Ph3P Ph3P CO2Et
Br– THF 2 h, RT –
0.5 h, 20 °C
(59)
+ + RCHO
–H+
Ph3P CO2Et Ph3P CO 2Et
– overnight
(60)
R
CO2Et + CO2Et
R
(61a) (61b)
R Yield (%) (E) (Z)
Ph 84 100 : 0
Me2CH 67 60 : 40
Scheme 29
0[05[0[2 Arsonium Ylides

Comparative studies\ involving acylylides ð71OPP262\ 77JCS"1#0718Ł\ ~uorenylides ð59JOC072Ł and
cyclopentadienylides ð61T232Ł\ show that arsonium ylides are markedly more reactive than their
phosphonium "and sulfonium# analogues[ In many cases reactions proceed only in the case of the
arsonium ylides^ this is especially true the more electron!withdrawing are the substituents on the
ylidic carbon atom\ although some arsonium ylides with two electron!withdrawing substituents will
not react even with aldehydes as reactive as 1\3!dinitrobenzaldehyde ð62T0586Ł[ This di}erence has
commonly been attributed "inter alia\ ð53ACS544\ 57CJC350\ 57JOM"02#152\ 60ACS0341\ 61T242\ 65CB362Ł#
to the lower electronegativity of the arsenic atom\ which leads to a lower electrostatic interaction
between the arsenic and ylidic carbon atoms\ and to a lower e}ectiveness of ppÐdp orbital overlap
between these atoms because of the greater size and di}useness of the arsenic 3d!orbitals compared
with the 2d!orbitals of phosphorus or sulfur[ But it has been pointed out that other factors in
addition to electronegativity and ppÐdp orbital overlap must play a part in determining the relative
acidity of the heteronium salts and the stability of the related ylides ð56LA"696#019Ł^ the involvement
of steric factors has been noted[
Arsonium ylides also di}er in behaviour from their phosphorus counterparts in that in reactions
with carbonyl compounds they may provide alkenes\ or like sulfonium ylides\ epoxides[ The type
of product formed depends on the nature of the substituents on both the ylidic carbon atom and
the arsenic atom\ and also to some extent on the solvent used^ these aspects have been the subject
of an excellent review ðB!83MI 005!90Ł[ The _rst example of a reaction between an arsonium ylide
and a carbonyl compound was recorded in a thesis in 0826 ð53MI 005!90Ł^ it was reported that
triphenylarsonium benzoylylide reacted with benzaldehyde to give benzylideneacetophenone[ Two
publications dealing with the reactions of arsonium ylides appeared in 0859[ One described the
formation of alkenes in high yield\ starting from a ~uorenylide ð59JOC072Ł\ and the other reported
that from triphenylarsonium methylide and benzophenone both 0\0!diphenylethylene and phenyl!
acetaldehyde were obtained\ with the latter predominating "0 ] 2[4#^ it was suggested that the aldehyde
arose from an initially formed epoxide during an acid workup of the reaction mixture ð59JA452Ł[
Similarly a reaction between triphenylarsonium ethylide and p!tolualdehyde gave a mixture of a
small amount of an alkene and\ as principal product\ p!tolylacetone\ again formed by acid induced
rearrangement of an initially formed epoxide ð53MI 005!91Ł[
Thus at an early stage in the study of arsonium ylides it was shown that either alkenes or epoxides
might be formed\ in contrast to the behaviour of phosphonium ylides\ which gave only alkenes\ and
sulfonium ylides\ which gave only epoxides[ It was also apparent that arsonium ylides were more
reactive than their phosphonium analogues\ for while triphenylarsonium ~uorenylide reacted with
p!dimethylaminobenzaldehyde to give an alkene in high yield\ triphenylphosphonium ~uorenylide
did not react with this aldehyde ð59JOC072Ł[ This arsonium ylide reacted in high yield with a number
of substituted benzaldehydes and with acetaldehyde^ it did not react with acetone or acetophenone
but did with the more reactive ketone p!nitroacetophenone ð71OPP262Ł[
The reaction of triphenylarsonium benzylide "51# with p!nitrobenzaldehyde "Scheme 29# provided
an alkene and an epoxide in about equal amounts\ together with equimolar amounts of triphenyl!
arsine and triphenylarsine oxide ð54CI"L#0615Ł[
C6H4NO2
Ph3AsO +
Ph Ph
Ph3As + (1,4)-OHCC6H4NO2
O
(62) Ph3As +
Ph C6H4NO2
Scheme 30
By contrast\ in another investigation of the reactions between arsonium ylides and aldehydes\ it
was found that either an alkene or an epoxide was formed\ depending upon the identity of the ylide\
but not both of them together ð60JCS"C#0003Ł[ Both alkenes and epoxides were always trans[ This
usually appears to be the case[
0[05[0[2[0 Comparison of stable\ reactive and semi!stabilised "moderately stabilised# ylides

The general pattern which has emerged is that stable arsonium ylides provide alkenes whilst
reactive arsonium ylides give epoxides ð54BAU0323\ 54CI"L#0615\ 54IZV0363\ 69JOC1567\ 60JCS"C#0003Ł[
This can be attributed to stabilisation of the transition state leading to alkene formation being
provided by those same electron!withdrawing groups that stabilise the ylides ð54CI"L#0615\
60JCS"C#0003Ł[
Thus arsonium ylides stabilised by acyl groups ð69JOC1567\ 64G098\ 67IJC"B#512\ 67S505\ 68IJC"B#526\
71OPP262Ł\ alkoxycarbonyl groups ð54MI 005!90\ 62T0586\ 74TL5336Ł\ cyano groups ð70MI 005!90\ 72MI
005!90Ł\ and cyclopentadiene rings ð57CI"L#0166\ 61T232\ 61T242Ł all provide alkenes\ predominantly
trans\ as products from reactions with carbonyl compounds[ Most ylides with two electron!
withdrawing substituents do not\ however\ take part in Wittig reactions ð72T186\ 77JCS"P1#0718Ł^ steric
factors may also sometimes inhibit reaction ð72T186Ł[
The arsonium salt Ph1"PhCH1#AsCH1CH1OH Br− requires two equivalents of butyl lithium for
its conversion into an ylide −OCH1CH1"Ph1#As1CHPh^ the presence of the alkoxide group does
not prevent the ylide reacting with aldehydes to form a trans!alkene together with 1!hydroxy!
ethyldiphenylarsine oxide ð89AG"E#0343Ł[ In contrast\ 1!hydroxyethyltriphenylarsonium bromide
reacts with arylaldehydes in the presence of solid potassium hydroxide to give 1!aryl!2!hydroxy!
methyloxiranes ð77TL4184Ł[
Reactive ylides give good yields of trans!epoxides ð70JA0172Ł\ although stereospeci_city may vary
with conditions[ For example\ use of an arsonium tetra~uoroborate as precursor of the ylide\
and potassium bis"trimethylsilyl#amide as base gives 099) trans!epoxide\ whereas with iodide as
counterion and butyl lithium as base\ there is less stereospeci_city ð70JA0172Ł[
Semi!stabilised arsonium ylides are intermediate in behaviour between stable and reactive
ylides\ and may provide alkenes and:or epoxides ð58JCS"C#1353\ 62JOM"59#136\ 64JOM"74#062\
64JOM"85#126\ 65JOM"097#064\ 65JOM"001#168\ 77BSB160\ 78JOC2118Ł[ Allylic arsonium ylides show such a
pattern of reactivity[ Ethoxycarbonylallyl ylides "52#\ wherein the ester group is conjugated with the
ylidic carbon atom\ a}ord dienes in reactions with aldehydes or ketones ð74S46\ 76S269Ł\ whereas
other allylic ylides "53# lacking such an electron!withdrawing substituent give vinylic epoxides in
high yield "Scheme 20# ð72SC0082\ 80TL1802Ł[ In the latter case it is found that the presence of
hexamethylphosphoramide leads to the formation of a diene instead of the epoxide ð72SC0082\
80TL1802Ł[ The ethynyl ylide Ph2As1CHC2C!TMS reacts with ketones to give conjugated enynes\
giving higher yields than its phosphonium analogue ð77JOM"235#070Ł[
O CO2Et
CO2Et
R1 R2 R1
Ph3As Et2O
R2
(63)
O
Ph
R1 R2
R1
Ph
Ph3As Et2O R2
O
(64)
Scheme 31
In these cases\ factors such as the substituent groups on arsenic\ and the nature of the solvent
and of the base\ may become important in determining the nature of the product^ this will be
considered in more detail later[ Small changes in the structure of the ylidic moiety may also have a
marked e}ect^ for example\ whereas triphenylarsonium b!naphthylmethylide reacts to give epoxide\
the presence of a bromine atom at the adjacent a!position of the naphthalene ring results instead in
the formation of alkenes ð65JOM"097#064Ł[ These results may be summarised as shown in Scheme 21[
R1 O
Ph3As +
R2 R4 R4
R1
+
Ph3As R2
EPOXIDE ALKENE
–O R4
R4
Semi-stabilised
reactive ylides, e.g., stable ylides, e.g.,
ylides, e.g.,
R1 = H, R2 = Me R1 = H, R2 = C6H4X R1 = H, R2 = COR3
Increasing reactivity of ylide
Scheme 32
"i# Effect of substituents on arsenic

The _rst report of such e}ects was in a study of the reactions of a series of tris"p!substituted
phenyl#arsonium ylides with benzaldehyde^ all these ylides gave epoxides in high yield save for the
tris"p!dimethylamino# compound which gave instead the trans!alkene ð69MI 005!92Ł[ In further
experiments replacement of a triphenylarsonium group by a tris"p!methoxyphenyl#arsonium group
was found to have little e}ect on the ratio of products ð60JCS"C#0003Ł\ and inclusion of the arsenic
atom in a strained ring also had no e}ect ð65JOM"009#204Ł[
A comprehensive investigation of a series of ylides "54# with benzaldehyde showed that as X\ Y
become more electron!donating\ so the proportion of alkene to epoxide increases ð66AG"E#376Ł[
For example\ the ratios of epoxide ] alkene changed from ¼00 ] 0 "XYH# to ¼5[4 ] 0
"XYMeO#\ ¼5 ] 0 "XH\ YNMe1#\ ¼3 ] 0 "XNMe1\ YH#\ ¼0 ] 0 "XYNMe1#[
Even more striking is the e}ect of replacing these aryl groups by alkyl groups\ viz ratios of
epoxide ] alkene were Ph2As\ ¼00 ] 0^ Et1PhAs\ ¼0 ] 4\ Et2As\ ¼0 ] 76 ð66AG"E#376Ł[
Ph
(p-XC6H4)2(p-YC6H4)As
(65)
These results strongly suggest that remote control of the major pathway followed in reactions of
semi!stabilised arsonium ylides with carbonyl compounds might be achieved by choice of the
appropriate arsonium group[ The reactivity of arsonium ylides is also a}ected by both electronic
and steric e}ects on the arsenic atom[
"ii# Effects of solvent and base

Initial studies of solvent e}ects\ on the reactions of triarylarsonium benzoylylides with p!nitro!
benzaldehyde in N\N!dimethylformamide\ dimethyl sulphoxide or methanol\ indicated little solvent
e}ect in these cases ð60ACS1430Ł\ but later studies of the more _nely balanced reactions of semi!
stabilised ylides have provided examples of strong in~uences due to the e}ect of di}erent base and
solvent when the ylide is generated in the presence of a carbonyl compound ð57IC057\ 72SC0082\
77BSB160\ 78JOC2118\ 80TL1802Ł[ Thus\ when benzyltriphenylarsonium bromide or p!chlorobenzyl!
triphenylarsonium bromide were treated with sodium hydride in benzene in the presence of a
variety of p!substituted benzaldehydes the products were alkenes\ but if sodium ethoxide in ethanol
was used the isolated products were epoxides ð66TL2732\ 68IJC"B#748Ł[ Likewise\ when triphenyl!
arsonium benzylylide was generated by phenyllithium in the presence of either benzaldehyde or
acetaldehyde\ the preponderant product was the epoxide whereas use of sodium amide as base
provided mostly the alkene ð77BSB160Ł[ Similar results were obtained when an allyltriphenyl!
arsonium salt was deprotonated using di}erent hexamethyldisilazide salts at −54>C in tetra!
hydrofuran in the presence of aldehydes ð78JOC2118Ł[ When the potassium salt was used as base the
product was trans!alkene\ but when the lithium salt was used a 1 ] 0 mixture of trans! and cis!
epoxides resulted[ It was suggested that when the potassium salt is used\ the reactants can equilibrate
between the cis and trans form of the conjugated ylide\ but that the lithium ion enhances production
of a betaine and that this cyclises to give the two epoxides[ Again scope for the control of the
reaction\ by suitable choice of solvent and:or base\ at least of semi!stabilised ylides\ is indicated[
"iii# Reactions with conjuàted enones

Arsonium ylides may react with conjugated enones either to give dienes or by conjugate addition
to provide cyclopropane derivatives ð79MI 005!90\ 79MI 005!91Ł as typi_ed in Scheme 22[
Formation of a cyclopropane derivative rather than participation in a Wittig reaction appears to
R2 R2
MeCO R3 R3
R1CO
COR1 R2 = Ph, R3 = H or R2 = R3 = Me
Ph3As R4
COR1
R1 = OMe or Ph PhCO
PhCO R4
R4 = Me, Ph, CO2Me
Scheme 33
be encouraged by the presence of a bulky group adjacent to the carbonyl group of the ketone ð79MI
005!91Ł[ Enals and conjugated enals undergo Wittig reactions with arsonium ylides to give alkenes
and dienes respectively ð76TL1044\ 77TL2838Ł[
"iv# Reactions with other C1X functions

Semi!stabilised arsonium ylides react with thioketones^ with cyclic thioketones triphenylarsonium
benzylides gave only exocyclic alkenes and no thiirans ð79ZN"B#84Ł[ Benzothiopyrones "and\ better\
benzopyrones# also react to give exocyclic alkenes\ in these cases arylidenebenzopyrans ð79SC346Ł[
Reaction of triphenylarsonium benzylide with benzylideneaniline gave 0\1\2!triphenylaziridine
ð60JCS"C#0003Ł[ This reaction is analogous to that of reactive arsonium ylides with carbonyl
compounds[
"v# Mechanism
Since the behaviour of arsonium ylides in Wittig reactions appeared to be intermediate between
that of sulphonium and phosphonium ylides\ it was inferred that mechanisms similar to those
accepted for the respective reactions of the latter ylides were involved "Scheme 23# ð54CI"L#0615Ł[
The energetic driving force to generate an arsenicÐoxygen bond is not as strong as that to form a
phosphorusÐoxygen bond\ so that there is not the same compulsion to alkene formation in the case
of arsonium ylides\ allowing the alternative pathway "b# "Scheme 23# to compete[ It has been
suggested that in the case of stable ylides\ where R1 is an electron!withdrawing group\ the presence
of the latter group\ which becomes conjugated with the carbonÐcarbon double bond in the _nal
alkene\ also stabilises the transition state leading to the formation of the alkene\ thus promoting
pathway "a# with respect to pathway "b# ð54CI"L#0615\ 60JCS"C#0003Ł[
+ R2 R2 R2
R13As R2 R2 R3
R1 3As R2 (a) R13As R2
R13AsO +
O R3 O R3
–O R3 R2 R3
R3 R3 R3
R2
R13As
R2
+
O
R2 R2 R2 R2
R3 R3 R13As R2 +
R2
(b) R13As
R13As +
R3 O– R3 O
R3 O–
R3 R3 R3
Scheme 34
The rates of the reactions of acylylides\ Ph2As1CHCOX with ketones decreases as X is more
electron!withdrawing\ making the ylide less nucleophilic ð61BAU1945\ 61IZV1002Ł[ This observation\
together with the relation between the reactivity and basicity of an ylide ð60ACS1430Ł and the second!
order character of the reaction\ all suggest that the _rst step\ which is slow and reversible\ is the
rate!determining step[ The lack of solvent e}ect on the rates of reactions between benzoylylides and
p!nitrobenzaldehyde led to the suggestion ð60ACS1430Ł that in alkene formation the reaction goes
directly to a four!membered ring transition state without the intermediate formation of a betaine[
This was seen to be consistent with the large negative entropy of reaction and the very low activation
energies observed[
Formation of an epoxide must\ however\ involve an intermediate betaine which reacts further by
intramolecular displacement of an arsine[ When pathways "a# and "b# "Scheme 23# are followed\ the
electrons in the arsenicÐcarbon bond are displaced in an opposite direction in the two mechanisms[
In alkene formation displacement of electrons occurs away from the arsenic atom and in epoxide
formation displacement of electrons is towards the arsenic atom[ The change in pathway\ depending
upon the nature of the substituents at arsenic\ could be associated with this\ for electron!donating
substituents on arsenic should assist displacement of the electrons away from arsenic and favour
alkene formation as observed ð66AG"E#376Ł[ For similar reasons electron!withdrawing substituents
on the ylide carbon atom should favour alkene formation[
The observed solvent e}ects on the type of product formed ð58JCS"C#1353\ 66TL2732\ 68IJC"B#748Ł
could also be associated with the structure of the intermediate[ Formation of alkenes or epoxides
necessitates\ respectively\ cisoid and transoid arrangements of the arsenic and oxygen atoms\ and a
transoid structure is likely to be much more favoured in a polar protic solvent such as ethanol than
in benzene[ Similarly\ as observed\ the presence of lithium ions should favour epoxide formation
compared to the e}ect of sodium or potassium ions since the transoid intermediate is likely to be
stabilised by association of the oxygen with lithium but less so with sodium or potassium ð77BSB160\
78JOC2118Ł[
"vi# Conclusion
Reactions of arsonium ylides with carbonyl compounds take place much more readily than with
phosphonium or sulphonium ylides[ The nature of the products depends upon the character of the
substituents on the ylide carbon atom\ where electron!withdrawing substituents favour alkene
formation\ and of substituents on the arsenic atom\ where electron!donating substituents favour
alkene formation[ This may be summarised as in Figure 0[ However\ choice of appropriate base
and solvent can\ in the case of less stabilised ylides\ have an e}ect on both the product distribution
and on the stereospeci_city of the product[ More detailed analysis is desirable\ but it seems likely
that\ at least in the case of semi!stabilised ylides and possibly for others also\ control over the
product can be achieved by suitable choice of the substituents on arsenic\ and of the solvent and
base\ thus making a valuable addition to the organic chemist|s synthetic armoury[
Type of ylide
R1 R4
R2 As
R5
R3
Push Pull Alkenes
Epoxides Pull Push

(Push, pull refer, respectively, to electron-donating or electron-withdrawing
effects of substituents on the arsenic or carbon atoms)
Figure 1 Formation of alkenes or epoxides in the reaction of arsonium ylides with carbonyl compounds.
Reactions which may initially appear to involve ylides may not in fact do so[ For example\ a
bromomalonic ester reacted with a variety of aldehydes in the presence of tributylarsine to form
alkylideneÐ or arylideneÐmalonic esters\ but no base was required and it was suggested that reaction
proceeded not via an ylide but via an arsonium salt "55# formed by extraction of a bromonium ion
from the malonic ester ð78JOM"264#34Ł[ The malonate anion then makes a nucleophilic attack on the
aldehyde "Scheme 24#[
CO2Et CO2Et
AsBu3 RCHO
RCHO + Br [Bu3AsBr]+ [CH(CO2Et)2]–
CO2Et (66) R CO2Et
Scheme 35
0[05[0[3 Stibonium Ylides

Only limited information is available on the use of stibonium ylides in the Wittig reaction[
Spectroscopic data on triphenylstibonium tetraphenylcyclopentadienylide has established that the
ylide C0Sb bond is more polar and has less double!bond character than in the corresponding
arsonium or phosphonium ylides[ This is attributed to the less e.cient overlap between the 1p
orbitals of the ylide C!atom and the d!orbitals of antimony\ because of the greater size and di}useness
of the d!orbitals in this case ð61T232\ 61T242Ł[ The greater dipolarity of the stibonium ylide compared
to its arsonium\ phosphonium and sulfonium analogues is also in accord with its higher reactivity
towards benzaldehydes\ and as a stable ylide\ it gave alkenes only ð61T232Ł[ By comparison\ as
might be expected for a reactive ylide\ nonisolable triphenylstibonium methylylide reacted readily
with benzophenone and formed an epoxide which\ however\ rearranged to diphenylacetaldehyde
ð59JA452Ł[ Tri!n!butylstibonium benzylide also reacted with aryl aldehydes\ and like its arsonium
analogue\ gave mixtures of alkene and epoxide ð89CC74\ 81ACR071Ł[
Tributylstibonium ylides having one electron!withdrawing substituent "e[g[\ "56##\ react readily
with aldehydes or ketones to give "E#!alkenes[ Since the ylides are sensitive to air they were prepared
in situ and not isolated[ Evidence for their formation was provided by trapping the initial adduct
formed from the ylide and aldehyde with trimethylsilyl chloride as shown in Scheme 25 ð89JCR"S#277Ł[
CO2Me Ar CO2Me TMS-Cl Ar CO2Me

–78 °C ButOK
Bu3Sb + ArCHO Cl–
–O +SbBu –78 °C +SbBu
3 TMS-O 3
(67)
MeO2C MeO2C Ar
ArCHO
SbBu3
TMS-O –78 °C to RT TMS-O
Ar Ar
Scheme 36
Stibonium ylides bearing two electron!withdrawing substituents did not undergo Wittig reactions
ð77JCS"P1#0718Ł[
As with comparable arsenic compounds\ some a!halo esters and amides react with oxo!compounds
in the presence of stibines\ but without the need of base\ to form arylidene or alkylidene derivatives
ð78JOM"255#76Ł[ The mechanism is thought to be the same as for the arsenic analogues\ namely via
initial formation of a stibonium salt "57# "Scheme 26#[
CO2Me CO2Me
Br R2CHO
+ R13Sb [R13SbBr]+ [CH(CO2Me)2]–
CO2Me R2 CO2Me
(68)
Scheme 37
It has also proved possible to make alkenes in a one!pot process from diazo!compounds N1CR1\
where R is an electron!withdrawing group\ and aldehydes or ketones by heating them in the presence
of triphenylstibine^ no base was required ð89TL4786Ł[ The reaction was assumed to proceed through
a stibonium ylide as intermediate\ although it has proved impossible to isolate this ylide\ which
probably reacted further too rapidly to allow this to be accomplished[
0[05[0[4 Bismuthonium Ylides

Relatively little attention has been paid to bismuthonium ylides\ and information on their e}ec!
tiveness as a method of alkene formation from carbonyl compounds is limited[ In the only example
reported so far\ the bismuthonium ylides "58^ XCH1\ O# reacted with aryl or alkyl aldehydes to
give a variety of products\ depending on the ylide\ the aldehyde "RCHO# and the conditions[ The
products included cyclopropane derivatives "69#\ furan derivatives analogous to "69# but with a
furan ring replacing the cyclopropane ring\ and in some cases "from "58^ XO# and p!methoxy!
benzaldehyde or cinnamaldehyde# the straightforward product from a Wittig reaction "60#
ð77CL738Ł[
O O
X OO O
X O R
BiPh3 X O
X O
O O R O O
(69) (70) (71)
0[05[0[5 PO!Activated Alkene Formation

The use of PO!stabilised carbanions has come to challenge the Wittig reaction as the synthetic
method of choice when a speci_c alkene is required[ Two variants exist] the reaction of a phosphonate
carbanion with a carbonyl compound to form an alkene is commonly referred to as the WadsworthÐ
Emmons reaction\ whilst the use of a phosphine oxide stabilised anion is called the Horner reaction
"Equation "03##[ When compared to the Wittig reaction such PO!activated reactions o}er a number
of advantages\ although the lesser stabilising e}ect of the neutral phosphoryl and phosphonate
groups means that electron!withdrawing a!substituents are generally required at the carbanion
centre before preparative yields of alkenes can be obtained[ These advantages include] "i# greater
nucleophilicity than the corresponding phosphonium ylide such that they react\ often exother!
mically\ with both aldehydes and ketones under milder conditions^ "ii# the phosphinic\ phosphonic
and phosphoric acid derivatives obtained from PO!activated syntheses are water!soluble so sep!
aration from the alkene is easily achieved^ and\ "iii# considerable control of stereochemistry is
possible by change of reaction conditions to yield the alkene with either the "E#! or the "Z#!geometry[
O O
i, NaNH2, benzene
Ph
P Ph + P (14)
R R O–
R ii, Ph2CO Ph Ph R
R = Ph, OEt
The scope\ mechanism and stereochemistry of these types of reaction have been extensively
reviewed ð63CRV76\ B!68MI 005!90\ 78CRV752\ 80COS"0#650Ł\ and only a summary of the mechanism will
be presented here\ with a more detailed account of the aspects relating to stereochemistry[
The accepted mechanism for PO!activated alkene synthesis is closely analogous to that of the
Wittig reaction in that the phosphorus!stabilised carbanion reacts with the carbonyl compound in
a reversible step to form a diastereomeric mixture of erythro "61a# and threo "61b# intermediate
alkoxides that irreversibly decompose by syn!elimination of a waterÐphosphorus acid anion to give
an alkene with speci_c geometry "Scheme 27#[ In the case of the Horner reaction\ or the absence of
resonance!stabilising a!substituents\ the initial oxyanion intermediates may be trapped as their
conjugate acids[ The ratio of "E#! to "Z#!alkenes obtained in a given reaction depends largely on the
relative rates of formation and decomposition of the intermediates "61# and to the extent of their
equilibration[ The development of an understanding of the various factors a}ecting these equilibria\
including the e}ect of changing the base\ solvent\ temperature and the nature of the associated
cation has led to successful attempts to control the stereochemical outcome in PO!activated alkene
formation[
0[05[0[5[1 Phosphonate!stabilised carbanions "WadsworthÐEmmons Reaction#

The greater reactivity of phosphonate!stabilised carbanions over the corresponding Wittig reagent
in alkene!forming reactions is ascribed to the fact that the phosphonate group has a lower net
positive charge and accordingly provides less stabilisation for the adjacent carbanion by valence
shell expansion\ "62a#t"62b# "Scheme 28#[ Thus ketones that react sluggishly\ or not at all\ with
Wittig reagents "stabilised by an alkoxycarbonyl or acyl group# ð59CPB708Ł are smoothly converted
into the corresponding alkenes by their phosphonate counterparts under very mild conditions[
Table 5 summarises this striking di}erence in reactivity for reactions of diethyl ethoxycarbonyl!
O O
P R2 +
R1 – R3 R4
R1
O O
H H
P R2 P R2
R1 R1
R1 R1
–O R3 –O R4
R4 R3
(72a) (72b)
R3 R4
R2 R4 R2 R3
Scheme 38
methylphosphonate and its phosphonium analogue with a variety of ketones[ Ketones are generally
less reactive towards phosphonate carbanions than aldehydes\ and usually require much more
vigorous conditions for alkene formation[ This is primarily due to steric e}ects\ and electronic
e}ects seem less important\ although tri~uoromethyl ketones do show enhanced reactivity[
O O O–
P R2 P R2 P R2
R1O R1O –
R1O
RO1 RO1 RO1
(73a) (73b)
R1 = alkyl or phenyl; R2 = stabilizing group, e.g. alkoxycarbonyl, acyl, nitrile, etc.
Scheme 39
A characteristic drawback to the use of phosphonate carbanions for alkene formation is that an
electron!withdrawing a!substituent must be present at the carbanion centre[ With hydrogen or alkyl
groups as the only a!substituent "{unactivated| carbanions#\ reaction with carbonyl compound is
rapid\ but in most cases only poor yields of alkene are obtained ð63CRV76\ B!68MI 005!90Ł\ apparently
because the intermediate alkoxide "61# requires {activating| a!substituents "e[g[\ CO1−\ CO1Et\ CN\
aryl\ vinyl\ SO1R\ OR and NR1#\ before it will decompose\ often only under vigorous conditions[
"i# Formation of "E#!alkenes

Generally speaking "E#!alkene formation is favoured in WadsworthÐEmmons reactions when
groups capable of conjugating with the incipient double bond are present[ For example Royal Jelly
"exclusively "E## has been prepared from the reaction of diethyl ethoxycarbonylmethylphosphonate
and the aldehyde "63# "Equation "04## ð64JIC427Ł[
O NaH
( )7
+ (EtO)2P CO2Et ( )7
(15)
O CHO THF O CO2Et
(74)
Even in those cases where mixtures of "E#! and "Z#!alkenes are almost invariably obtained
with the corresponding Wittig reagent ð53JPR032Ł\ "E#!alkene is formed almost exclusively with
phosphonate anions as in the reaction with a!naphthaldehyde to form the stilbene "64# "Equation
"05## ð58RZC84Ł^ interestingly\ the addition of catalytic amounts of 04!crown!4 to reactions using
NaH in THF as base\ is found to improve the yield of stilbenes substantially ð70JCS"P0#2976Ł[
Table 5 Relative yields of alkenes from the reaction of Wittig and phosphonate reagents with ketones[
635
From From
Ph3P=CHCO2Et (EtO2)2P(O)CH2CO2Et
Ketone Reaction conditions (Yield %) Alkene Ref.
Et2CO NaOEt, DMF

xylene (reflux) (0) Et2C=CHCO2Et 61CI(L)990
(ca. 65), 20 °C
O NaOEt, DMF
C6H6 (reflux) (25) CHCO2Et 61CI(L)990
(ca. 65), 20 °C
O NaOEt, DMF CHCO2Et

xylene (reflux) (0) 61CI(L)990
(ca. 65), 20 °C
EtCOMe xylene (reflux) (40) NaNH2, Et2O (58) Et(Me)C=CHCO2Et 64IZV1341

PhCOMe 170 °C, 10 h (68) NaNH2, Et2O (77) Ph(Me)C=CHCO2Et 72M1651
NaOMe, MeOH
O toluene (<50) 2 d (reflux) 73ACS1401
(90), 40 °C, 10 h CO2Et
(Z) and (E)
C8H17
NaOEt, DMF
no reaction 65JOC505
(93), 20 °C, 20 h
EtO2CCH
O
NaOEt, DMF
xylene, 6–14 h, reflux (15) 64IZV1341
(43), 30 °C, overnight
O EtO2CCH
C1C Bond"s# by Condensation of Phosphorus\ etc[ and Silicon\ etc[
MeO MeO
N N
MeO KOBut, DMF, MeO 66JOC1447
H 152 °C, 3 h (54) H
(99), 20 °C, 30 h 63JCS1461
Et Et
O CHCO2Et
P CHO
+ (16)
(75)
P Reaction conditions Yield (%) (Z) : (E)
PH3P+– NaOMe/MeOH 71 58 : 42
(EtO)2P(O) NaOMe/DMF 67 0 : 100
The use of the WadsworthÐEmmons reaction is generally the method of choice for the preparation
of "E#!a\b!unsaturated carbonyl compounds\ especially in natural product syntheses[ For example\
the C7 side chain in prostaglandins\ such as 09\09!dimethyl prostaglandin E0 "66#\ can be introduced
successfully by reaction of dimethyl 1!oxoheptylphosphonate "65# with the appropriate aldehyde
followed by reduction of the keto group "Scheme 39# ð67JCS"P0#293Ł[
O
O O
( )
6 CO2Me + (MeO)2P
C5H11
–
HO CHO (76)
O O
( ) ( )
6 CO2Me 6 CO2Me
HO HO
C5H11 C5H11
O HO
(77)
Scheme 40
Extensive use has been made of the exclusive trans!stereochemistry shown by ethoxy!
carbonylmethyl phosphonate anions even when the conjugation is extended by unsaturation[ The
dehydro derivative "79# of the C07 juvenile hormone of cecropia has been synthesised by Corey et
al[ in 67) yield "88) stereoselectivity# from the condensation of phosphonate "68# with aldehyde
"67# "Equation "06## ð60TL0710Ł[ A Wittig reaction between the same aldehyde and the corresponding
"E#!triphenylphosphorane a}orded non!stereoselective mixtures of "E#! and "Z#!alkene[
O
(EtO)2P
CO2Me
(79)
(17)
CHO LDA
O
(78) (80) CO2Me
Signi_cant loss of trans!stereoselectivity will occur when steric interactions in the product become
serious ð57BCJ0141\ 57CC0588\ 57CJC1114Ł[ For example\ in the reactions of diethyl ethoxy!
carbonylalkylphosphonates "70# with aliphatic aldehydes "71# "Scheme 30# ð57CC0588Ł\ only "E#!
ester "72# is formed when R0 H[ With the size of R0 increasing together with the branching of the
alkyl group R1 of the aldehyde\ the "Z#!ester "73# becomes the major product of the reaction[
The reverse e}ect is found upon incorporation of an a!~uoro substituent even with bulky alde!
hydes[ For example\ condensation of "EtO#1P"O#CH"F#CO1Me with isobutyraldehyde in the pres!
ence of BunLi:THF"−67>C# a}orded a 89) yield of PriCH1C"F#CO1Me with almost complete
trans!selectivity ð74BSF"1#337Ł[ This higher than expected trans!stereoselection is attributed to elec!
tronic e}ects ð73T1760Ł and has been applied to the synthesis of ~uorinated sex pheromones[
Loss of trans!stereoselectivity does occur in condensations with unsymmetrical ketones ð54IZV0493\
56JA4181\ 57CC432\ 58AJC0626\ 58AJC1034\ 60ABC0005\ 62ACS0390Ł[ Two examples from the synthesis of
O R2CHO CO2Et R1
NaH (82)
(EtO)2P CO2Et +
DME 15 °C, 3 h, RT R2 R1 R2 CO2Et
R1
(81) (83) (84)
R1 R2 % (84) in the product

H Pri 0
H But 0
Me Me 0
Me Et 16
Me Pri 62–73
Me Bui 67
Et Me 18
Et Et 41
Et Pri 84
Scheme 41
natural products are illustrative of this "Equation "07# and Scheme 31#[ Thus\ in the _rst step of
the synthesis of racemic b\g!carotene ð62ACS0390Ł\ condensation of b!ionone "74# with diethyl
methoxycarbonylmethylphosphonate in the presence of sodium methoxide gave an isomer mixture
containing 24) of methyl "Z#!b!ionylidene acetate "75b#[ Likewise\ during the synthesis of the
juvenile hormone isolated from the giant silkworm moth Hyalophora cecropia ð58AJC0626\ 58AJC1034Ł\
treatment of the methyl ketone "76# with the sodium salt of trimethyl phosphonacetate in DME led
to a mixture of the "E\E#! "77a# and "Z\E#!ester "77b# in yield in the ratio 59 ] 39[
O O NaOMe
+
(EtO)2P CO2Et MeOH
10 h, 40 °C
(85) 90%
CO2Me*
+ (18)
CO2Me*
(86a) 65 : 35 (86b)
* ester change
trans!Selectivity can be maximised by increasing the size of the substituents on both the phos!
phonate and stabilising ester groups[ For example\ in the reaction with 1!phenylpropanal\ the a!
methyl substituted ethyl phosphonate "78# gave a ratio of 84 ] 4 of "Z#!"89# and E!"89# "Scheme 32#[
By using bulky isopropyl groupings instead\ the stereoselectivity is dramatically reversed and the
corresponding reaction with "80# occurs to give 4 ] 84 ratio of "Z#!"81# and "E#!"81# ð70T2762\ 71JA0098\
76JA3644Ł[
This approach has been used to ensure trans!alkene formation in natural product syntheses[ One
example of its utility is represented by the synthesis of brefeldin C in which the "E#!alkene "82# was
selectively synthesised in 61) yield without epimerisation "Equation "08## ð78TL3734Ł[
O-MPM O O
O-MPM
H H
(PriO)2P
CHO O-TBDMS OMe CO2Me O-TBDMS
(19)
KOBut, THF
H H
(93)
The same e}ect is observed with a!cyanophosphonates which are usually less stereodemanding
than their carbalkoxy counterparts and produce mixtures of "Z#! and "E#!alkenes in the range 0 ] 3
to 1 ] 0 ð79SC498\ 79ZOB65Ł[ For example\ in the reaction with b!ionone "74#\ "PriO1#1P"O#CHCN−Na¦
is found to be more trans!selective ""Z#:"E#07 ] 04# than the corresponding diethyl phosphonate
O DME
1 h, RT
O O + (MeO)2P CO2Me
– 0.5 h, reflux
Na+ 90%
O
(87)
+ CO2Me
O O
CO2Me
O O
(88a) 60 : 40 (88b)
Scheme 42
O O
(PriO)2P CO2Pri (EtO)2P CO2Me
(91) CHO (89)
CO2 Pri CO2Me

KOBut, THF Ph KOBut, THF
Ph Ph
(92) (Z) : (E) 5 : 95 (90) (Z) : (E) 95 : 5
Scheme 43
""Z#:"E#24 ] 54# ð79SC498Ł "see Equation "07# and Scheme 31#[ Choice of solvent can also play a
role in determining the _nal product ratios^ such an e}ect is ascribed to the extent of intermediate
alkoxide reversibility[ In benzene\ the reaction of diethyl cyanomethylphosphonate with the ketone
"83# is "E#!selective\ whereas in DMF or DMSO\ a moderate level of "Z#!selectivity is obtained
"Equation "19##[
CN NC
O
O
+ + (20)
(EtO)2P CN
(94)
MeLi/benzene 28% 72%
NaH/DMF or DMSO 60% 40%
Bulky ester groups can also induce high "E#!selectivity even in reactions with hindered ketones[
Thus\ condensation of the t!butyl ester phosphonate "85# with ketone "84# a}ords the "E#!product
"86# with only a trace of the "Z#!isomer "Scheme 33# ð75JOC848Ł[ Notably\ when the t!butyl group
is replaced by a large alkyl chain\ selectivity is lost and in the corresponding condensation with
phosphonate "87#\ a 0 ] 3 mixture of "Z#:"E#!"88# is formed ð76JOC0261Ł[
For reactants that racemise easily or are base!sensitive a new protocol devised by Masamune and
co!workers ð73TL1072Ł exists for generating phosphonate carbanions under mild conditions[ This
involves use of lithium chloride and a weak base such as 0\4!diazabicycloð4[3[9Łundec!4!ene "dbu#
or diisopropylamine[ In one exemplary case directed at a key intermediate for the synthesis of
norescurinine\ Heathcock ð76H"64#64Ł demonstrated that potassium t!butoxide gave epimerised
O
(MeO)2P CO2But
(96) O
R O
NaH, THF
83%
CO2But
R = CH2CO2Me O
O
(97) (E) only
R O
O O
O O (MeO)2P ( )
O 8 CO2Me O
(95)
(98)
R O
NaH, THF O
80% ( )
O O 8 CO2Me
R= (99)
O-TBDMS
Scheme 44
material in the reaction of phosphonate anion "099# with the complex aldehyde "090#\ but that
LiCl:dbu circumvented racemisation to produce "091# in 79) yield and 82) ee "Equation "10##[
O O O O O
MeO2C CHO
P(OMe)2 CO2Me
(101)
O O (21)
N OBut LiCl, dbu, MeCN N OBut
O O
(100) (102)
Another example of the utility of this modi_cation is the synthesis of amphotericin!B by Nicolaou
ð77JA3574Ł[
"ii# Formation of "Z#!alkenes

One method for obtaining almost pure "Z#!alkene from the reaction of phosphonate carbanions
with aldehydes makes use of the fact that intermediate alkoxides with magnesium as the cation are
much more stable than the comparable sodium or lithium complexes "Scheme 34# ð61T3198\ 62T3088Ł[
H H
O (PhO)2P(O) CN (PhO)2P(O) CN
PriMgCl i, PhCHO, 5 h, –80 °C
(PhO)2P CN +
THF, 5 h, –80 °C ii, HOAc
HO H HO Ph
(103) Ph H
(104a) (104b)
PhH
30 h, reflux
Ph CN Ph
+
CN
80 : 20
Scheme 45
When hydrolysed\ these reaction mixtures a}ord diastereomeric b!hydroxyphosphonates from
which the erythro component may be separated by fractional crystallisation and stereospeci_cally
converted into the corresponding "Z#!alkene by heating[ For example ð61T3198Ł\ in the direct reaction
between diphenyl cyanomethylphosphonate "092# and benzaldehyde under normal conditions\ the
ratio of "Z#! to "E#!cinnamonitriles is 04 ] 74\ whereas thermal decomposition of the isolated erythro!
adduct "093a# gives a "Z# ] "E# ratio of 79 ] 19[
Incorporation of the phosphonate group into a ring as in structure "094# promotes "Z#!alkene
selectivity in reactions with aromatic aldehydes as well as enhancing reactivity compared to its
acyclic counterpart "EtO1#P"O#CH1CO1Et "Scheme 35# ð72PS"05#228Ł[ This high "Z#!selectivity "54Ð
69)# is attributed ð66TL0026\ 67T886Ł to a more rapid closure to the pentacoordinate intermediate
"095# owing to release of strain in the _ve!membered ring coupled with an increase in the rate of
elimination relative to the equilibration of intermediates[ Replacement of the CO1Et grouping in
"094# by CN brings about a reversal in selectivity to trans "vide supra#\ whereas with the corresponding
t!butyl ester\ very high levels of "Z#!alkenes "×84)# are obtained instead ð75MI 005!90Ł[
O O
O P CO2Et O P CO2Et O
–
+ RCHO O–
O O
O P CO2 Et
–O R O
R
(105) (106)
O O–
R CO2Et
P +
O O
Scheme 46
Dramatically higher levels of cis!selectivity can also be obtained by a variant and introduced by
Still and Gennari ð72TL3394Ł in 0872 that uses bis"tri~uoroethyl#phosphonates "e[g[\ "096# and "097##
in reactions with aldehydes[ The magnitude of selectivity is dependent on the base and solvent
combination used\ and in this respect\ potassium hexamethyldisilazide with 07!crown!5 in THF
appears to be most e}ective by increasing the rate of elimination relative to equilibration due to
minimal complexation of the intermediate alkoxide with its counterion[ For example\ phosphonate
"096# combined with benzaldehyde to give a ×49 ] 0 "Z#:"E#!ratio of alkenes that dropped to 01 ] 0
with octanal ð72TL3394Ł[ The improved cis!selectivity in such reactions is attributed to the electron!
withdrawing e}ect of the tri~uoromethyl groups that forces an increase in the rate of elimination
of alkene from the initially formed b!hydroxyphosphonate adduct before equilibration can take
place "cf[ 61#[ Still|s method has been used extensively in synthesis ð77JA1137\ 77JA2818\ 77JOC3163Ł[ A
typical example of its utility\ with an aldehyde possessing an a!ether functionality\ is represented by
Danishefsky|s synthesis of the ester "098# which was contaminated with only 4) of the "E#!isomer
O O
(CF3CH2O)2P CO2Me (CF3CH2O)2P CO2Et
(107) (108)
O O O
MeO (CF3CH2O)2P CO2Me MeO
(107)
O O (22)
KHMDS, 18-crown-6, THF
80%
TBDMS-O O TBDMS-O
H H
BzO BzO CO2Me
(109)
KHMDS = potassium hexamethyldisilazide (Z) : (E) > 95 : 5
Still|s approach is also e}ective with a variety of carbanion stabilising groups other than esters\
including cyano which normally exhibits poor stereoselectivity when used as a diethylphosphonate[
In one interesting example ð77TL308Ł\ the conjugated cyano phosphonate "000# condensed with the
cis!isomer "009# of b!ionone to produce the highly strained all!cis!retinal "001# "Equation "12##^ the
crude yield was 34) with 61) of the material having the cis!con_guration at the newly formed
double bond "C!00#[
O CN
(CF3CH2O)2P 11
CHO CHO
(111)
(23)
i, KHMDS, 18-crown-6, THF
ii, dibal
(110) (112)
dibal = diisobutylaluminum as a mixture of isomers
Good levels of cis!selectivity are also obtained even with a!methyl substituents[ For example\ the
reaction of tri~uoroethylphosphonate "097# with benzaldehyde a}orded a 29 ] 0 ratio of "Z#:"E#
isomers\ which is reversed to 0 ] 11 in the corresponding reaction with "EtO#1P"O#CH1"Me#CO1Et
ð72TL3394Ł[ The e}ect is general\ and is further exempli_ed by the synthesis of methyl tri!substituted
alkenes from the condensation of "097# with aldehydes "002# ð76TL2964Ł\ "003# ð77H"16#1966Ł and
"004# ð76JOC2772Ł with virtually completely "Z#!selectivity[ In an interesting application to natural
product synthesis\ Roush and Palkowitz ð78JOC2998Ł have synthesised the C"0#ÐC"04# segment of
streptovaricin by applying Still|s phosphonate to form the "Z#!alkene "006# from the a!methyl
substituted aldehyde "005# with greater than 89) selectivity "Equation "13##[ Even with groups
larger than methyl\ cis!stereoselectivity is compromised to only a small extent[
OMe
MeO OBz CHO OAc CHO

NHBOC
CHO
(113) (114) (115)
O
OAc OAc O O
(CF3CH2O)2P CO2Me
CHO
(107)
(24)
KHMDS, 18-crown-6, THF CO2Me
O N 65%
O O
(116) (117)
In a further variant\ Corey and Wiatkowski ð77JA4542Ł have introduced the use of phosphoric
acid bisamides\ for example\ "Me1N#1P"O#CH1R "Ralkyl or aryl# for alkenation reactions[ For
Raryl\ reactions with aldehydes are well controlled to give only erythro!adducts which decompose
stereospeci_cally to "Z#!alkenes[ Reactions with alkyl substituents are not stereoselective[ For
example\ with Rn!C6H04 condensation with pivalaldehyde produced a 2 ] 0 "Z# ] "E# mixture of
alkenes compared to the corresponding reaction of the triphenylphosphonium ylide which gave a
87[4 ] 0[4 mixture in favour of the "Z#!isomer[
0[05[0[5[2 Phosphoryl!stabilised carbanions "Horner Reaction#

As far back as 0847\ Horner ð47CB50Ł discovered the alkene forming reaction that bears his name
by treatment of methyldiphenylphosphine oxide "007# with sodamide and then benzophenone to
give 0\0!diphenylethene "008# in 69) yield together with diphenylphosphinic acid "Scheme 36#[ The
intervention of an alkoxide intermediate corresponding to the conventional Wittig!type betaine was
_rst proved ð48CB1388Ł by isolation of the b!hydroxyphosphine oxide "010# from the reaction of
benzyldiphenylphosphine oxide "019# with phenyllithium and benzaldehyde\ followed by quenching
with acid "Equation "14##[
Ph
O O O Ph O
NaNH2 Ph
P P + P
Ph Me liq. NH3 Ph CH2– Ph OH
Ph Ph Ph Ph
(118) (119)
Scheme 47
O
O
i, PhLi P Ph
P Ph Ph (25)
Ph ii, PhCHO Ph
Ph
HO Ph
(120) (121)
By using potassium t!butoxide as base\ no adduct was obtained\ but 0\1!diphenylethene was
isolated in good yield[ In a further signi_cant discovery in 0853\ Horner ð53TL1356Ł showed that the
b!hydroxyphosphine oxide "010# consisted of a mixture of diastereomers that could be separated by
chromatography into a minor isomer "4)# with the erythro!con_guration "011a# and a major isomer
"89)# with the threo!con_guration "011b# "Scheme 37#[
O O O
H H
Ph P Ph P Ph P Ph Ph
Ph Ph Ph
Ph Ph Ph
Ph HO Ph HO Ph HO Ph Ph
H H
(122b) (121) (122a)
Scheme 48
Assignment of con_guration was based on subsequent decomposition of the adducts by treatment

with phenyllithium and lithium hydride to give "Z#! and "E#!0\1!diphenylethene\ respectively\ by
syn!elimination of diphenylphosphinic acid[ This _nding laid the basis for the use of anions from
phosphine oxides to form alkenes of speci_c geometry^ however the intermediate b!hydroxyphos!
phine oxide can be isolated only if lithium is used as the counterion to the base for deprotonation
ð47CB50\ 48CB1388Ł[ Sodium or potassium bases promote in situ decomposition to form alkenes
directly[ The fact that the Horner reaction can be stopped at the _rst stage and the intermediate
adducts isolated and separated into pure diastereomers\ that are frequently crystalline\ does o}er a
de_nite advantage over the more conventional Wittig reaction in that each diastereomer "erythro
and threo# o}ers direct access to a single geometric isomer of the corresponding alkene
ð74JCS"P0#1296Ł[ An added bonus is that the phosphine oxide reagents do not require an a!stabilising
substituent "cf[ phosphonate reagents# to e}ect alkenation[ The presence of such groups\ for example\
carbonyl\ even when protected as the ethylene acetal\ does place a limitation on the Horner reaction
by inhibiting the decomposition of the intermediate b!hydroxyphosphine oxide and thus preventing
the formation of alkenes ð72JCS"P0#0062Ł[ Furthermore\ such adducts even with moderate stabilising
groups next to Ph1P"O# "e[g[\ phenyl# have to be isolated at low temperatures otherwise the reaction
proceeds stereorandomly to give a mixture of alkenes[
Other complications do exist and speci_cally involve loss of stereospeci_city in the case of erythro!
adducts by equilibration with the starting materials\ a problem that is exacerbated with aromatic
aldehydes ð72TL2820Ł^ however speci_c reaction conditions have been developed to bring about
greater erythro:threo ratios ð72TL2820\ 74JCS"P0#1296Ł[ It is also worth mentioning at this point of an
alternative approach to the intermediate b!hydroxyphosphine oxides by ring!opening of epoxides[
Bridges and Whitham ð63CC031Ł originally used this method to carry out a stereospeci_c cis to
trans alkene conversion by isolating pure diastereomers of b!hydroxyphosphone oxides "012# from
treatment of the derived epoxide with lithium diphenylphosphide "Scheme 38#[ The "E#!alkenes were
then obtained by syn elimination initiated by a strong base\ usually NaH in DMF[
O
R H R
R R i, Ph2PLi P R NaH
Ph
H H ii, H2O2 Ph DMF
R O R
HO R
H
(123)
Scheme 49
In a variant to this method\ epoxidation of allylphosphine oxides followed by ring!opening with

nucleophiles has been employed to generate the intermediate hydroxyphosphine oxides ð73CL0886\
74TL1008\ 74TL4698Ł[ Such oxidations normally proceed in a highly stereoselective manner provided
the allylphosphine oxide is trisubstituted[
"i# Stereoselective formation of "E#! and "Z#!alkenes

The reversibility of the _rst step in the Horner reaction coupled with the diminished rate of
elimination from erythro!adducts can be utilised to synthesise "E#!alkenes without isolation of
intermediates ð65JCS"P0#1275Ł[ Steric factors are important as in the approach by Lythgoe et al[
ð67JCS"P0#489Ł to the synthesis of the diene portion of vitamin D1 "015# "Equation "15##[ Thus\
metallation of the phosphine oxide "013# followed by treatment under mild conditions with the
ketone "014# gave\ after deprotection\ the newly formed trisubstituted double!bond with the desired
"E#!geometry[ The same technique has been used to synthesise other conjugated dienes with speci_c
trans geometry\ including polyene isoprenoids[ For example ð67TL3048Ł\ treatment of the lithiated
derivative of the phosphine oxide "016# with "E#!citral "017# gave rise to the isoprenoid "018# with
almost complete "×87)# trans!selectivity "Equation "16##[ By comparison\ condensation of the
same aldehyde with the corresponding phosphonium ylide led to a 49 ] 49 mixture of "E#! and "Z#!
7!polyenes[ Change of base is often advantageous[ For example\ Nicolaou et al[ ð73CC238Ł syn!
thesised the pentaene "029# with speci_c "E#!geometry by carrying out the initial addition with LDA
followed by use of potassium t!butoxide to e}ect elimination "Equation "17##[ In the total synthesis
of milbemycin\ Smith and co!workers ð75JA1551Ł also found that in the condensation of the phos!
phine oxide "020# with aldehyde "021#\ the sensitivity of the alkene stereochemistry depended
profoundly on the choice of base "Equation "18##[ The use of NaH led to a 0 ] 6 "Z#:"E# ratio\ but
owing to epimerisation at the aldehydic methine\ the yield was only 04)[ This improved to 63)
with potassium hexamethyldisilazide\ but the use of this base\ gave only a 1 ] 2 "Z#:"E# ratio[ These
problems were avoided by the _nding that sodium hexamethyldisilazide e}ected the condensation
almost quantitatively to give the desired "E#!alkene "022# in a 6 ] 0 ratio with its "Z#!isomer[
C9H17 C9H17
O
H
P OR O
Ph (125)
Ph (26)
BunLi
HO
(124) (126)
i, BunLi
(27)
O ii, CHO
Ph2P
(128)
(127) (129)
OSiPh2But i, Ph2(O)P , LDA

ButPh2SiO O
CHO ii, ButOK
55%
OSiPh2But
(28)
ButPh 2SiO O
(130)
H
O
O
Ph2P O
H
CO2Me O
NaN(TMS)2
+ O (29)
CO2Me
THF
CHO 85–95%
OMe
OMe
(131) (132) (133)
Solvent e}ects can also be important in determining the stereochemical outcome[ In an ingenious
synthesis of {gossyplure|\ the insect pheromone that consists of a 49 ] 49 mixture of "Z\Z#! and "E\E#!
dienes "025a# and "025b# "Scheme 49# ð70JOC348Ł\ reaction of the unsaturated diphenylphosphine
oxide "023# with pentanal in a precise 0 ] 0 mixture of THF and Et1O a}orded the b!hydroxyphos!
phine oxide "024# as an equal mixture of diastereomers[ The isomers were not isolated but decom!
posed under basic conditions to give the desired mixture of dienes[
O O
Ph2P Ph2P
BunLi
+ CHO
( )6 ( )6 ( )6
R1O OH R1O R2 R3 R1O
(134) (135) (136)
a; R2 = H, R3 = (CH2)3Me
b; R2 = (CH2)3Me, R3 = H
Scheme 50
In general\ the Horner reaction does not proceed in one step to give essentially pure "E#! or
"Z#!alkenes[ For this purpose it is necessary to isolate the intermediate diasteromeric b!hydroxy!
phosphine oxides\ usually by chromatography\ and e}ect decomposition stereospeci_cally to the
corresponding alkenes via syn elimination of diphenylphosphinic acid[ This methodology has been
used with allylphosphine oxides to prepare dienes and polyenes without undesired double!bond
stereomutation that often accompanies such condensations ð75JA1551\ 77TL1390Ł[ For example\ the
lithio derivative of allylphosphine oxide "026# added to acetaldehyde to form the easily separated
mixture of diastereomeric b!hydroxyphosphine oxides "027a# and "027b# "Scheme 40# ð66JCS"P0#449Ł[
Independent decomposition of these diastereomers led to pure "E#!"028a#! and "Z#!"028b#!dienes[
The synthetic utility of this indirect method is further demonstrated by the construction of a
cis!double bond at C"00# of polyene "030# "Scheme 41# ð68TL4932Ł following chromatographic
separation of the diastereomeric b!hydroxy phosphine oxides and speci_c treatment of the
erythro!isomer "039# with NaH in DMF[
When using this protocol\ decomposition of threo!adducts a}ords "E#!alkenes stereospeci_cally
and in high yields without exception[ Unfortunately\ loss of selectivity can occur with erythro!
adducts\ especially when conjugating groups are present a to the phosphorus ð73JCS"P0#132Ł\ due to
breakdown to starting materials and equilibration with the threo!adduct[ This leads to con!
tamination of the "Z#!alkene\ often with predominating amounts of "E#!alkene[ Equilibration can
be minimised and greater erythro:threo ratios obtained by the use of electron!donating ortho!
substituents in diarylphosphine oxides[ This is demonstrated convincingly by the reaction of
"o!MeOC5H3#1P"O#C−HPriLi¦ with benzaldehyde to form the erythro!adduct only ð75CB1049Ł[
O
NaH/DMF
Ph2P
OH
H
O BunLi (138a) (139a)
Ph2P
MeCHO
(137) O
Ph2P NaH/DMF
OH
H
(138b) (139b)
Scheme 51
OHC
O
Ph2P
BunLi
O
Ph2P
NaH/DMF
HO
(140) (141)
Scheme 52
erythro!Selectivity is also favoured by using very polar solvents such as DMF or DMSO^ in
nonpolar solvents\ reaction occurs with virtually no selectivity ð74JCS"P0#1296Ł[ An excellent measure
of selectivity can also be obtained in THF\ especially in conjunction with the lithium complexing
agent tetramethylene diamine "TMEDA# at low temperatures ð74JCS"P0#1296Ł[ For example\ com!
pared to the poor selectivity reported earlier "see Scheme 37#\ these conditions "−61>C# led to an
77 ] 01 mixture of erythro!"011a# and threo!"011b#[ A di}erent technique employs dibenzophosphole
oxide!stabilised carbanions ð74JCS"P0#0842Ł[ Decomposition of the erythro!adduct "031a^
R0 R1 Ph#\ "generated speci_cally via "E#!stilbene oxide# with dbu led to "Z#!stilbene exclusively
owing to a marked increase in the rate of elimination upon incorporation of phosphorus into a _ve!
membered ring[ Even with NaH:DMSO\ which led to erythro!"011a# giving mostly "E#!alkene\ the
cyclic analogue "031a^ R0 R1 Ph# decomposed to furnish an 78 ] 00 mixture of "Z#:"E#!stilbenes[
In a signi_cant development\ Warren ð75TL534\ 78TL590Ł extended this approach by introducing
selective reduction of the a!ketophosphine oxide "032# to obtain both the erythro!"031a# and threo!
"031b# adducts separately[ Reduction under normal conditions with NaBH3 gave rise to the threo
isomer\ but by addition of CeCl2\ the stereoselectivity is reversed in favour of the erythro isomer\
due to chelation control[ In an excellent example of the utility of this method ð75TL534Ł\ both "E#!
and "Z#!isosafroles were synthesised from a single ketophosphine oxide intermediate "032^ R0 Me\
R1 2\3!"methylenedioxy#phenyl#[
The utility of this modi_cation is general[ trans!Alkenes can be synthesised by acylation of
diphenylphosphinoyl!stabilised anions with carboxylate esters or lactones to furnish a!ketophos!
phine oxides\ which can be reduced with di}erent agents\ including sodium borohydride\ to yield
predominantly threo!b!hydroxyphosphine oxides ð72TL482\ 74JCS"P0#1296Ł[ This general protocol is
exempli_ed in Scheme 42 by the synthesis of alkenol "033#\ a component of the Mediterranean fruit
~y pheromone with speci_c "E#!geometry ð74JCS"P0#1296Ł^ the "Z#!isomer could not be detected by
GLC[
O O O
P H P H P R1
R1 R1
HO R2 HO H O R2
H R2
(142a) (142b) (143)
O
O BunLi, THF, –78 °C
Ph2P NaBH4, EtOH
Ph2P
85%
then CH2[CH2]4OC=O O OH
81%
O
Ph2P H NaH, DMF
OH
H
92%
HO OH
(144)
Scheme 53
By incorporating a carboxylic acid in the side chain\ reduction of the ketophosphine oxide leads
to lactonization[ Separation and treatment with KOH to e}ect elimination provides a route to
unsaturated acids[ In a further extension of this approach\ Warren ð77JCS"P0#1860Ł has synthesised
"E#!homo!allylic alcohols "035# by incorporating an intramolecular acyl transfer to the ketophos!
phine oxide "034# "Scheme 43#[
O
O O LDA Ph2P i, NaBH4, 64% OH
OH
Ph2P 73% ii, NaH, 85%
O OEt
O
(145) (146)
Scheme 54
Stereospeci_c syntheses of trisubstituted alkenes\ for example\ "038# can be achieved by addition
of butyllithium to the ketophosphine oxide "036# with chiral centres to induce high diastereo!
selectivity in the b!hydroxy intermediate "037# "Scheme 44# ð78TL3470Ł[ A more common method
involves reaction of branched phosphine oxides with aldehydes in preference to treatment of
unbranched phosphine oxides with ketones\ which leads to lower yields due to the instability of the
intermediate b!hydroxyphosphine oxides ð72TL000\ 76JCS"P0#1458Ł[ In both approaches\ the initial
condensation occurs stereorandomly and requires separation by chromatography of the two diaster!
omeric phosphine oxides[ Both "Z#!a!bisabolene "049#\ one of the main constituents of Opoponax
oil ð72TL000Ł\ and "040# ð74T2714Ł have been prepared by these two di}erent approaches[
O O
Ph2P Ph2P
Ph BuLi Ph NaH Ph
O Ph HO Ph DMF Bu Ph
Bu
(147) (148) (149)
Scheme 55
O P
O P O-THP
O
(150) (151)
0[05[1 C1C BONDS BY CONDENSATION OF SILICON\ BORON\ GERMANIUM OR

TELLURIUM FUNCTIONS
0[05[1[0 Silicon!Mediated Alkenation] The Peterson Reaction

A valuable alternative to the Wittig and related reactions involves a!silyl carbanions which can
be generated by metallation of weakly acidic organosilanes with butyllithium[ Such anions "041#
react readily with carbonyl compounds as illustrated in Scheme 45 to form lithio derivatives of b!
hydroxysilanes "042#\ which spontaneously eliminate the trimethylsilyloxy group to form alkenes in
excellent yields[ The major driving force for this process\ commonly referred to as the Peterson
reaction after its discoverer in 0857 ð57JOC679Ł\ is provided by the formation of the strong siliconÐ
oxygen bond "DSi!O420 kJ mol−0#[ As ordinarily e}ected\ the Peterson reaction has the practical
advantage in that the by!product hexamethyldisiloxane "043# is volatile\ and consequently is easier
to remove from the product alkene than triphenylphosphine oxide formed in the Wittig reaction[
TMS C4H9Li TMS PhCOPh LiO TMS
Li Ph
TMEDA ether/pentane
Ph Ph Ph Ph
0–35 °C
(152) (153)
O TMS Ph H3O+
Ph + TMS-OLi TMS-O-TMS
Ph 77%
Ph Ph Ph
(154)
Scheme 56
The Peterson reaction has been applied extensively in organic synthesis to convert aldehydes and
ketones into alkenes\ but owing to di.culties in generating the necessary a!silyl carbanions for more
complex applications\ its greatest utility lies in the synthesis of methylene derivatives[ The reaction
has been reviewed by Ager ð73S273Ł\ as well as by Colvin ðB!77MI 005!90Ł[ A review article by Kelly
ð80COS"0#620Ł covers the topic in some depth[
In general\ condensation of an a!silylcarbanion with a carbonyl compound proceeds in a manner
analogous to the Wittig reaction[ The overall transformation is depicted in Scheme 46 and will
proceed directly to alkene if X is an anion!stabilising group "phenyl\ ester\ thio\ sulphonyl\ etc[#[
However\ if X is not anion!stabilising\ the elimination reaction of the b!oxido intermediate "044# is
slow\ and consequently the b!hydroxysilane "045# can be isolated and subsequently converted into
an alkene in a separate step on treatment with either basic "NaH\ KH or KOBut# or acidic
"HOAc\H1SO3 or BF2 = Et1O# reagents ðB!77MI 005!90Ł[
–O HO
O
– SiR3 SiR3 SiR3
X X X X
(155) (156)
Scheme 57
Boron\ Silicon or Germanium 648
0[05[1[0[1 Preparation of silicon!stabilised carbanions
A variety of methods exist for the generation of a!silylcarbanions for use in the Peterson reaction[
Proton abstraction is only feasible provided the organosilane is functionalised with an anion!
stabilising group[ The bases most commonly used for deprotonation are either alkyllithiums\ usually
in conjunction with TMEDA\ or LDA ðB!77MI 005!90Ł[ When an anion!stabilising group is not
present\ access to a!silylcarbanions can be achieved by indirect methods\ including the addition of
an organometallic species to a vinylsilane ð69JA6313Ł\ metalÐhalogen exchange ð69CJC450Ł\ trans!
metallation of an already a!metallated organosilane ð65AG"E#050Ł\ and cleavage of a siliconÐcarbon
bond in bis! or poly!silylated compounds with alkoxide or ~uoride anions ð62TL3082Ł[ The need for
such procedures can be circumvented by taking advantage of alternative approaches\ which o}er
direct access to b!hydroxysilanes\ often in a stereode_ned manner[ These methods involve the
reaction of b!ketosilanes with hydride sources ð63TL0022Ł or organometallic reagents such as alkyl!
lithiums and Grignard reagents ð78OS"56#014Ł\ and the regiospeci_c ring!opening of a\b!epoxysilanes
with dialkylcuprates ð64JOC1153Ł[ Examples of these methods are given in Section 0[05[1[0[3[
0[05[1[0[2 Methylenation reactions

The greatest utility of the Peterson reaction is in the synthesis of methylene derivatives[ For
nonenolizable ketones\ a particularly clean method for the generation of the required a!silyl!
carbanion is by reaction of a bissilylated methane with an alkoxide "Scheme 47# ð62TL3082Ł[ The
driving force for this reaction is the thermodynamically favoured formation of a siliconÐoxygen
bond[
O
TMS Ph
Ph Ph
TMS TMS + ROLi RO-TMS +
53%
Li Ph
Scheme 58
In other methylenation reactions\ the use of a!silyl organometallic reagents\ particularly lithium!
and Grignard!based\ has proved advantageous in comparison to the Wittig reaction for enolizible
ketones\ although exceptions have been reported[ For example\ the bridged ketone "046# reacted
smoothly with methylenetriphenylphosphorane\ whereas trimethylsilylmethylmagnesium chloride
acted as a base and abstracted an a!proton with aldol products being isolated ð65MI 005!90Ł[
Interestingly\ Lewis!acid catalysis could have proved advantageous in this instance as evidenced by
the reaction of b!tetralone "047# with trimethylsilylmethyllithium in the presence of cerium trichlo!
ride[ Under these conditions\ methylenation is virtually complete and occurs without isomerisation\
whereas in its absence the ketone is recovered unchanged[ Improved yields of methylenation are
obtained even with base!sensitive aldehydes by the prior addition of cerium trichloride ð76JOC170Ł[
For example\ octanal can be methylenated to only 45) extent under normal conditions\ but the
cerium!modi_cation approach a}orded 75) of the desired product[ Other additives such as titanium
tetrachloride have been employed\ albeit in conjunction with the Grignard reagent "TMS!CH1MgCl#
ð70TL4920Ł\ but yields of methylenated product are inferior with aldehydes "octanal\ 48)#\ and for
ketones\ the additive virtually prevents reaction[ Typically\ acetophenone gave only 2) methyl!
enation ð70TL4920Ł\ whilst the cerium!modi_cation "TMS!CH1Li:CeCl2# occurred successfully in
82) yield ð76JOC170Ł\ which dropped to 67) under normal conditions[
O
O
(157) (158)
Even in the absence of additives\ such a!silyl organometallic reagents possess a distinct advantage
when compared to the corresponding Wittig reagent by permitting the introduction of a methylene
group into a sterically hindered ketone[ For example\ the "2#!b!gorgonene precursor "048# failed
to react under Wittig conditions ð62TL2386Ł\ whereas methylenation could be achieved with
trimethylsilylmethylmagnesium chloride\ albeit in only 04) yield "Scheme 48#[ Even with less
sterically demanding carbonyl compounds\ the Peterson method for the synthesis of methylene
derivatives o}ers advantages in being compatible with a variety of sensitive functionalities\ including
the anomeric alkoxy group in "059# ð71JOC2437Ł\ the thioacetal group in "050# ð77TL3410Ł\ and an
aziridine moiety in "051# ð77JOC2280Ł[ The latter example is of interest in that the elimination
from the intermediate b!hydroxysilane was e}ected quantitatively by the unusual treatment with
1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq#[
ClMgO
TMS MgCl NaOAc/AcOH
H TMS H
O
(159)
Scheme 59
O O-SiEt3 O
H
Ph O MeO
O O OR
S
O PhOCOOMe S H
N NMe
O OMe
(160) (161) (162)
Hindered ketones can also be transformed into an ethylidene unit by the ingenious use of
a!"trimethylsilyl#vinyllithium "052#\ which is readily accessible by metallation of the corresponding
bromocompound ð79JA1352Ł[ The general procedure is outlined in Scheme 59 and forms the basis
of the synthesis of coronafacic acid by Jung and co!workers ð79JA1352Ł[ The same reagent can also
be utilised for the preparation of terminal allenes\ although in this situation the intermediate adducts
are most reluctant to eliminate\ but can be isolated as the corresponding alcohol and converted into
a better leaving group such as tri~uoroacetate or chloride ð67JOC0415Ł^ treatment with ~uoride ion
results in smooth elimination to give the desired allene as illustrated in Scheme 50 for the synthesis
of 0\0!diphenylallene in 34) yield[
OH
O TMS TMS i, H2, Rh/Al2O3
+
Li ii, BF3•Et2O
(163)
Scheme 60
Ph TMS TMS Ph
i, SOCl2
O + •
HO
Ph Li ii, F–, DMSO Ph
Ph
(163) Ph
Scheme 61
0[05[1[0[3 Stereoselective formation of alkenes

As mentioned earlier\ the presence of an anion!stabilising group facilitates the elimination step
in the Peterson reaction and alkenes are formed directly[ Conversely\ the lack of such a group
permits isolation of the intermediate b!hydroxysilane and elimination of the alkene is carried out in
a separate step[ For this reason\ it is convenient to deal with these two categories of alkene formation
separately[
"i# Formation of aliphatic alkenes
Since alkylsilanes are not readily deprotonated\ access to the required a!metallated silanes is
obtained by the various methods discussed in Section 0[05[1[0[1[ Unlike the Wittig reaction\ when
such a!silylcarbanions react with carbonyl compounds where cis! and trans!alkenes can be produced\
both isomers are formed in almost equal amounts[ This lack of stereospeci_city results from the
formation\ under kinetic control\ of the intermediate b!hydroxysilane as a ca[ 0 ] 0 mixture of threo!
and erythro!diastereomers\ which decompose with a high degree of selectivity[ The ratio is found not
to be a}ected signi_cantly by any change in reaction conditions\ but fortunately\ a preponderance of
either cis! or trans!alkenes can be obtained by other routes that provide a diastereomerically highly
enriched b!hydroxysilane[
In one approach\ illustrated in Scheme 51\ the addition of ethyllithium to trimethylvinylsilane is
used to generate an a!silylcarbanion\ which is quenched with carbon dioxide to form a carboxylic
acid ð64JA0353Ł[ Further steps as indicated a}ord the b!ketosilane "053#\ the reduction of which
using dibal occurs in a manner predicted by the FelkinÐAnh mode to a}ord predominantly the
threo!b!hydroxysilane "054#[ In the second stage\ treatment of "054# with potassium hydride on one
hand\ or with boron tri~uoride etherate or sulfuric acid on the other\ led\ respectively\ to the
stereospeci_c formation of "E#! and "Z#!oct!3!ene "Scheme 52# ð64JA0353Ł[ This di}erence in
geometry of the alkene depending on the type of treatment is a re~ection of the mechanistic
requirement for syn!elimination in the former case\ and the need for an anti!periplanar geometry of
elimination in the latter[
i, EtLi
TMS TMS OH TMS Prn TMS H
ii, CO2 i, (COCl)2 Bui2AlH
H Prn
iii, H3O+ Prn O ii, Prn2CuCl Prn O Prn OH
(164) (165)
Scheme 62
Nu
BF3•Et2O or H+ TMS H
H Prn Prn Prn
Prn O+
TMS H
H Prn
Prn OH
(165)
TMS O– Prn
KH
H Prn
Prn H Prn
Scheme 63
The same method can be utilised to provide a stereoselective synthesis of trisubstituted alkenes
as exempli_ed in Scheme 53 by the addition of methyllithium to b!ketosilane "055# to give pre!
dominantly one diastereomeric form of the two possible b!oxidosilanes ð65JOC1839\ 66TL0796Ł[
Workup under either basic or acidic conditions as discussed earlier allowed stereoselective generation
of the trisubstituted alkene[
Unlike the Horner reaction\ it is not possible to control such processes to produce predominantly
the erythro!adduct[ This is relatively unimportant provided that one of the diastereomeric
b!hydroxysilanes is formed in su.ciently large excess\ since the two complimentary methods of
elimination allow the choice of stereoselective delivery of either geometrical isomer of the alkene[
By analogy to the Horner reaction\ synthetic access to diastereomeric b!hydroxysilanes such as
"054# and "056# can be obtained by regiospeci_c opening of a\b!epoxysilanes with dialkylcuprates
"Scheme 54# ð64JOC1153Ł[ The overall reaction is highly stereoselective and is consistent with the
silyl group facilitating speci_c nucleophilic attack a to silicon\ coupled with treatment by potassium
TMS NaOAc
Prn H
LiO C5H11 AcOH Prn C5H11
TMS 69%
MeLi (E) : (Z) 1 : 9
Prn
C5H11
O LiO TMS Prn
KOBut
(166) Prn H
C5H11 74% C5H11
(E) : (Z) 9 : 1
Scheme 64
hydride to e}ect syn elimination and produce alkenes in ×88) geometric purity[ Unfortunately\
considerable limitations are placed on the synthetic usefulness of this method by the need for
epoxysilanes with de_ned geometry[
TMS O TMS H Prn
Prn2CuLi KH
H OH
Prn Prn Prn Prn
(165)
H+
O H H
Prn2CuLi KH
TMS OH Prn Prn
TMS Prn Prn Prn
(167)
Scheme 65
"ii# Formation of functionalised alkenes

The Peterson reaction can be successfully employed with a!silylallyl anions "057# to synthesise
conjugated alkenes directly provided the addition to the carbonyl compound is carried out in the
presence of magnesium bromide to promote a!attack "Scheme 55# ð67TL1272Ł\ otherwise the sel!
ectivity is inverted and g!attack predominates ð79JA4993Ł[ By incorporating a boronate function at
the g!position as in "058#\ reaction with aldehydes is also directed predominantly towards the
a!position to form the erythro!adduct "069# as the major diastereomer "Scheme 56# ð70TL1640Ł\
which undergoes base!catalysed elimination to form the mono!substituted "Z#!double bond isomer
"060#[
O
R2 R2
ButLi, HMPA R2 R1 R1
TMS TMS
or BusLi, TMEDA – MgBr2 MO R1
Li+
TMS
(168)
HMPA = hexamethylphosphoramide
Scheme 66
OH
TMS B O RCHO KH R
R
O
TMS
(169) (170) (171)
Scheme 67
The same conditions are also required for the synthesis of a\b!unsaturated esters by the addition
of functionalised a!silylcarbanions such as "061# to aldehydes "RCHO#[ The elimination from the
b!oxidosilane intermediate\ which is formed in the presence of magnesium bromide\ is directed
towards the "Z#!isomer "062# by treatment with HMPT\ or alternatively is carried out with BF2 = Et1O
to synthesise the "E#!isomer "063# "Equation "29## ð70CC766Ł[ Even easily enolisable ketones\ for
example\ cyclohexanone\ which often give poor yields in the Wittig reaction\ react readily with
reagents such as "061# to give ×84) yield of the desired alkene[ Such reactions with unsymmetrical
ketones proceed with high kinetic selectivity to form predominantly "Z#!alkenes\ and as such
are complimentary to the corresponding Wittig reaction\ which produces the "E#!isomer as the
predominant product[ The "Z# ] "E# ratio of the derived conjugated alkenes "064#\ "065# and "066#
illustrate this selectivity ð70TL0464\ 73TL4592Ł[
O O O
RCHO
TMS OMe + OMe (30)
OMe
– HMPT or BF3•OEt2
R R
(172) (173) (174)
Conditions RCHO (173) : (174)
HMPT Ph 80 : 20
Bun 85 : 15
BF3•Et2O Ph 1 : 99
Bun 2 : 98
CO2Et
CO2Et CO2Et
(175) (176) (177)

(Z) : (E) 89 : 11 67 : 33 90 : 10
By increasing the size of the ester grouping\ it is possible to raise the "Z# ] "E# ratios of alkenes as
exempli_ed by the butenolide product "067# ð70TL0484Ł[ On changing the ester group "R# from
methyl to propyl and then t!butyl\ the "Z# ] "E# ratio improved from 32 ] 46 to 79 ] 19 and 77 ] 01
without much change in the yield "ca[ 69)#[ Surprisingly\ "Z#!selectivity is maintained even when
the product becomes sterically crowded as in the pseudomonic acid derivative "068# which is
produced in an "Z# ] "E# ratio of 77 ] 01 ð74JCS"P0#430Ł[
O O-TMS CO2But
TMS-O
OR
OMe O
O
OMe O-TMS
(178) (179)
Synthesis of hetero!substituted alkenes using more complex metallated silanes such as "079#\
"070#\ "071# and "072# ð74TL3248Ł have been outlined[ The latter example is of interest in that unlike
the preceding one\ reaction with aldehydes led to a change in selectivity from equal amounts of "E#!
and "Z#!alkenes to formation of "E#!alkenes almost exclusively without any racemisation of the
sulfoximine[ The Peterson reaction is also compatible with a phosphorus substituent as demonstrated
in the original work of Gilman and Tomasi "Scheme 57# ð51JOC2536Ł in which the silyl!substituted
phosphorane "073# reacted with benzophenone to produce tetraphenylallene "074# by the preferential
loss of TMS!O instead of elimination of triphenylphosphine oxide expected under Wittig conditions[
O O
O TMS
TMS B S TMS Ph S* TMS
N Ph
O Li TsN
Li Li Li
(180) (181) (182) (183)
O +
+ –O TMS Ph PPh3
Ph3P TMS Ph Ph TMS-O–
Ph
+
–
Ph PPh3 Ph
(184)
+ O
Ph PPh3 Ph Ph
Ph Ph
•
–
Ph Ph Ph
(185)
Scheme 68
0[05[1[1 Boron!mediated Alkenation

In comparison to the well!established chemistry of silicon!stabilised carbanions that of the cor!
responding boron reagents has received scant attention\ especially in connection with the conversion
of a carbonyl compound into an alkene by addition to an aldehyde or ketone[ Evidence so far shows
that such reactions do occur readily ð55TL3204Ł\ but may lead to products other than alkenes
depending upon the nature of the carbonyl compound[ For example\ the bis"mesitylboryl#stabilised
carbanion "076#\ prepared conveniently by reaction of ~uoride ion with the bis"mesitylboryl#"tri!
methylsilyl#alkane "075# ð72OM125Ł\ condensed with benzophenone in a straightforward manner to
a}ord the corresponding alkene "077# in 69) isolated yield "Scheme 58# ð72TL524Ł[ On the
other hand reaction with benzaldehyde at room temperature led to a mixture of products\ includ!
ing the expected alkene "078# in only 39) yield\ but with 88[8) "E#!selectivity ð74TL4982Ł[ The
reluctance of "076# to be "Z#!selective\ like the corresponding Wittig reagent\ is the result of
anti!elimination from the initially formed and favoured erythro!adduct "089^ see Scheme 69#\
which is formed even at low temperatures "−67>C# and decomposes only on warming to room
temperature[
C7H15
TMS Li
LiF
)2 B + TMS-F
Mes2B C7H15
(186) (187)
O
O
Ph Ph
Ph
Ph C7H15 O OH
+ C7H15 + C7H15
Ph C7H15 Ph Ph Ph
(188) (189)
Scheme 69
By analogy to the Peterson reaction\ the stability of intermediates such as "089# can be utilised to
bring about the stereoselective formation of both geometric forms of the alkene by inducing
decomposition with various reagents selected to promote either anti! or syn!elimination of the boryl
function[ Thus\ treatment of "089# with tri~uoroacetic anhydride "TFAA# at low temperature
H H
C7H15 C7H15
OLi TMS-Cl TMS-O
BMes2 –110 °C BMes2
Ph H Ph H
(190) (191)
TFAA HF/MeCN
CF3 H
C7H15
H 2O +
BMes2
O O
BMes2
Ph H
Ph C7H15 H
H
Ph C7H15 Ph
C7H15
Scheme 70
"−009>C# followed by warming to room temperature resulted in decomposition by a cyclic ester!

type elimination to a 8 ] 0 mixture of "Z#:"E#!alkenes "Scheme 69# ð76CC186Ł[ Alternatively\ prior
reaction of "089# with trimethylsilylchloride produced the silyl ether "080# which fragmented to a
84 ] 4 mixture of "E#:"Z#!alkenes "62) yield# with aqueous HF in acetonitrile ð76CC186Ł[ Inter!
estingly\ substitution of the 3!position of the aromatic aldehyde by electron!withdrawing or
!donating groups caused little variation in yield or selectivity for "E#!alkenes\ but led to a lowering
on both accounts for "Z#!alkenes[
In the reaction of "089# with aliphatic aldehydes it is necessary to premix the aldehyde with a
protic acid\ for example\ acetic acid\ to ensure alkene formation ð78TL4532\ 78TL4536Ł\ which proceeds
with poor selectivity unless the aldehyde is bulky[
Finally\ it is worth noting that boron!stabilised carbanions like their silicon analogues can bring
about methylation of ketones[ For example\ the condensation of "082# with cyclohexanone gave
methylenecyclohexanone in ca[ 44) yield "Scheme 60#\ but deprotonation of b!methyl!8!
borabicycloð2[2[0Łnonane "081# proved di.cult and only occurred to an appreciable degree with the
highly hindered base\ lithium piperidide ð61JA5743Ł[
O
N Li
B Me B
Li
(192) (193)
Scheme 71
0[05[1[2 Germanium!mediated Alkenation

Little information is available on pseudo!Wittig reactions of germenes\ R01Ge1CR11\ compounds
with a germaniumÐcarbon double bond\ due to their transient nature and a propensity to poly!
condense and form oligomers[ This is demonstrated by the reaction of Ph1Ge and N1CHCO1Et
"Carius tube\ copper powder\ 59>C# to generate the transient germene Ph1Ge1CHCO1Et\ which is
only partially trapped by benzaldehyde with the formation of a germoxane "Ph1GeO#n and the
corresponding alkene "PhCH1CHCO1Et\ 6)# ð79JA4302Ł^ the side reaction led to oligomers[
In another report ð80OM0660Ł\ the {free| germene "084# was obtained by thermal decomposition
of the stable adduct "083#\ but upon condensation with benzaldehyde\ the reaction stopped at the
intermediate germaoxetane "085# due to the large steric hindrance of the substituent "Scheme 61#[
In the case of acetone\ reaction occurred with the enolic form\ followed by a germanotropic
rearrangement[
R R
R
Mes2Ge PhCHO Mes2Ge R
Mes2Ge
R O
R
NEt3 Ph
stable
(194) (195) (196)
Mes = CR2 =
Scheme 72
0[05[1[3 Tellurium!mediated Alkenation

The formation of an alkene from a carbonyl compound which may involve a telluronium ylide
as an intermediate has been reported "Equation "20## ð82T5710Ł[
CO2Me O CuI
R1 CO2Me
Bun2Te + N2 + (31)
CO2Me R1 R2 100 °C R2 CO2Me
no solvent
90%
No reaction takes place in the absence of a tellurium compound\ but there is no _rm evidence
that a tellurium ylide is indeed an intermediate^ attempts to isolate an ylide were unsuccessful\ but
0
H!NMR provided evidence for its presence[ The one!pot reaction is simple and proceeds without
base and in high yield[
0[05[2 METAL!INDUCED METHYLENATION

One!carbon homologation of carbonyl compounds can be achieved with certain methylene!
bridged metallic species that act as CH1 transfer agents[ The most useful preparative examples of
such species are the titanium methylenation complex "086# known as Tebbe|s reagent ð67JA2500Ł\
and the zinc divalent complex "087# developed by Oshima ð76JOC3309Ł[ Both of these complexes
have found widespread application in organic synthesis and o}er distinct advantages over the more
conventional Wittig methylenation reagent[ In particular they remove the possibility of enolising
sensitive carbonyl functions\ whilst the more reactive Tebbe|s reagent "086# can be used in the
methylenation of esters and amides for which the conventional Wittig reaction is not suitable[ The
literature on these synthetically useful processes has been reviewed by Pine ð82OR"32#0Ł[
Metal 656
0[05[2[0 Tebbe|s Reagent
The h4!C4H4 "hereafter Cp# complex "086# of titanium is readily made by the reaction of red\
crystalline CpTiCl1 "mp 129>C# with Al1Me5 ð74JOC1275Ł[ In the reaction with carbonyl compounds\
the actual methylene transfer agent is Cp1Ti1CH1\ which is formed from "086# by elimination of
Me1AlCl upon warming or by addition of a Lewis base such as pyridine or 3!dimethylaminopyridine
"dmap#[ In the absence of an added Lewis base\ reaction of "086# with an ester such as methyl
benzoate "Scheme 62# ð79JA2169Ł proceeds slowly in contrast to ketones and amides which react
rapidly[ In each case\ the driving force for methylenation is the formation of titanocene oxide\
Cp1Ti1O ð73AG"E#476Ł[
Ti AlMe2
Cl
(197)
O
Al2Me6 Ph
toluene, 20 °C Me pyridine OMe
Cp2TiCl2 Cp2Ti Al [Cp2Ti CH2] Ph
–Me2AlCl – [Cp2Ti O]n
Cl Me OMe
–CH4 81%
(197)
Scheme 73
Table 6 illustrates the application of this method to the preparation of methylene derivatives from
a wide range of carbonyl!containing compounds\ including enol ethers from esters ð67JA2500Ł\ and
enamines from amides ð78SC1548Ł^ the reaction is not applicable to hindered ketones due to enolate
formation\ nor anhydrides and acid chlorides[
0[05[2[1 Oshima|s Reagent

Unlike Tebbe|s reagent\ the use of Oshima|s reagent "087# ð67TL1306Ł as a methylene transfer!
agent does not require the presence of a base\ but like its counterpart\ it is more e}ective in the
methylenation of enolizable ketones than the Wittig reaction ðB!75MI 005!90Ł[ It is readily prepared
by the treatment of dibromo! or diiodo!methane and zinc with titanium tetrachloride and may
be stored inde_nitely at −19>C ð76OS"54#70Ł[ The procedure is exempli_ed in Scheme 63 by the
methylenation of the b!keto ester "088# in 39) yield ð77BCJ356Ł^ the corresponding Wittig reaction
failed[
BrZn ZnBr/TiCl4
(198)
CO2Et
CH2Cl2 (199)
Zn–CH2Br2–TiCl4
25 °C, 15 min THF, 25 °C, 12 h
40% CO2Et
Scheme 74
Table 6 Yields from methylenation of carbonyl!containing compounds via Tebbe reagent "086# in toluene[
Reaction Conditions Yield Ref.

(%)
1 Aldehydes
O
THF, 0 °C to RT, 30 min 92 78JA3611
Ph
2 Lactones
O THF, 0 °C to RT, 30 min 85 80JA3270

O
O THF, tol, dmap, –40 °C, 30 min; RT, 90 min 88TL4333
Et
3 Esters
O
THF, 0 °C to RT, 30 min 60 83PAC1733
MeO OMe
O
THF, 0 °C to RT, 30 min 47 88JOC1903
n-C5H11 O Ph
O
Ph
THF, 0 °C to RT, 30 min 96 80JA3270
O
4 Ketones
O
THF, 0 °C to RT, 30 min 97 91S165
THF, 0 °C to RT, 30 min 65 82PAC1915
5 Amides
N N THF, 0 °C to RT, 30 min 56 89SC2659

O
N THF, 0 °C to RT, 30 min 74 89SC2659
Ph O
Metal 658
Oshima|s reagent is only suitable for the methylenation of aldehydes and ketones "cf[ Tebbe|s
reagent#\ but this modi_ed reactivity has led to a widespread application in organic synthesis due
to a tolerance of a variety of other functional groups\ including esters\ lactones\ acetates and ketals
as exempli_ed in Table 7[
Table 7 Yields from methylenation of aldehydes and ketones via Oshima|s reagent "087#[
Reactant Conditions Yield Ref.

(%)
O
MeO2C Zn, CH2Br2, TiCl4 40 88CJC1359
CH2Cl2, 20 °C, 1.5 h
O Zn, CH2Br2, TiCl4 35 84TL2035

EtO2C CH2Cl2, 20 °C, 1.5 h
O
Et
CO2Me
Zn, CH2Br2, TiCl4 94 80JOC2005
THF, 25 °C, 12 h
O
Zn, CH2Br2, TiCl4 98 89TL1241

THF, 25 °C, 12 h
O O
O
O
O
AcO Zn, CH2Br2, TiCl4 79 88TL3339
CH2Cl2, 20 °C, 1.5 h
CO2Me O
OMe
OMe Zn, CH2Br2, TiCl4 30 88BCJ467

THF, 25 °C, 12 h
O
O
O
Zn, CH2Br2, TiCl4 95 87CC1008
O CH2Cl2, 20 °C, 1.5 h
O O
O O
O
MeO
Zn, CH2I2, TiCl4 47 90CAR(201)185
THF, 25 °C, 15–60 min
O
O
In a synthetically useful modi_cation of "087#\ the use of Ti"OPri#3 instead of TiCl3 ð74TL4470Ł
allows the exclusive methylenation of an aldehyde in the presence of a ketone[ Moreover\ the reverse
e}ect can be achieved by complexation of the aldehydic carbonyl with Ti"NEt1#3 prior to treatment
with "087#[ Scheme 64 illustrates the bene_t of this chemoselectivity[
Zn–CH2I2–Ti(OPri)4 O
83% ( )8
O O
( )8
O
i, Ti(NEt2)4
( )8
ii, Zn–CH2I2–TiCl4
76%
Scheme 75
Finally\ it is worth mentioning a clever variation of this method that allows the general alkyl!
idenation of esters "and lactones# by use of dibromoalkanes instead of dibromomethane[
Tetramethylethylenediamine is required and the reagents are mixed in a di}erent order to that
normally used for "087#\ but yields are high and the process leads to the formation of "Z#!alkenyl
ethers predominantly ð76JOC3309Ł[ By contrast\ Tebbe|s reagent cannot be extended to the alkyl!
idenation of esters[
1.17
Pericyclic Processes
HAMISH McNAB
University of Edinburgh, UK
0[06[1 FORMATION OF MONOENES BY RETRO!ENE AND RELATED REACTIONS 661

0[06[1[0 Cleavaè of One C0H and One C0C Bond 661
0[06[1[1 Cleavaè of One C0H and One C0O Bond 662
0[06[1[1[0 Pyrolysis of acetates and related esters 662
0[06[1[1[1 Pyrolysis of xanthate esters 664
0[06[1[1[2 Other concerted pyrolytic eliminations 666
0[06[1[2 Cleavaè of One C0H and One C0S Bond\ includin` Pyrolysis of Sulfoxides 667
0[06[1[3 Cleavaè of One C0H and One C0Se Bond*Pyrolysis of Selenoxides 679
0[06[1[4 Cleavaè of One C0H and One C0N Bond\ includin` the Cope Elimination 671
0[06[2 FORMATION OF MONOENES BY RETRO!CYCLOADDITION REACTIONS 673

0[06[2[0 Retro ð1¦1Ł Cycloadditions 673
0[06[2[1 Retro ð3¦1Ł Cycloadditions "Retro!DielsÐAlder Reactions# 674
0[06[3 FORMATION OF DIENES AND POLYENES 676

0[06[3[0 Retro!cycloaddition Reactions 678
0[06[3[1 Retro!cheletropic Reactions 689
0[06[0 INTRODUCTION
This chapter is concerned with the creation of the C1C unit by retro!pericyclic cleavage reactions\
with emphasis on their synthetic utility[ Retro!sigmatropic!shift processes\ which are considered
_rst\ are characterised by cleavage of one C0H and one C0X bond to create the alkene\ whereas
the retro!cycloaddition reactions which form the next section of the chapter are characterised by
cleavage of two C0C "or C0X# bonds[ Formation of dienes and polyenes are considered separately\
and include a consideration of retro!cheletropic reactions[ Concerted rearrangements are covered
in Chapters 0[98 and 0[07[ Within each section\ the mechanism and stereochemistry of the process
under consideration will be covered\ together with an assessment of the scope\ limitations and
reaction conditions^ _nally\ some examples of applications to the syntheses of natural and unnatural
products will be given[
The majority of the relevant reactions are thermal eliminations\ which may be carried out
preparatively either in solution or in the gas phase[ Most chemists have an intuitive {feel| for solution
temperature conditions\ but the same cannot be said for gas phase reactions\ where the contact time
of the substrate in the hot zone is the most important parameter[ This chapter will describe as {~ow
pyrolyses| those reactions which are carried out at atmospheric pressure "often in a stream of
nitrogen# by feeding the substrate\ either neat or in solution\ down a heated tube packed with glass
helices[ Contact times under these conditions are generally of the order of a few seconds[ In contrast\
660
661 C1C Bond"s# by Pericyclic Processes
{~ash vacuum pyrolysis| "FVP# involves vacuum distillation of the substrate through a heated tube\
and contact times are generally a few milliseconds[ Clearly\ much higher temperatures are needed
for FVP and\ as a general rule\ a reaction which proceeds at 079>C in solution may well require in
excess of 799>C under FVP conditions\ with ~ow pyrolyses taking place at intermediate tempera!
tures[
0[06[1 FORMATION OF MONOENES BY RETRO!ENE AND RELATED REACTIONS

The general reactions under consideration are shown in Equations "0# and "1#[ Equation "0#
involves hydrogen transfer via a six!membered ring transition state and is formally a ð1ss ¦1ss ¦1psŁ
reaction[ In certain cases where X and Y are carbon!containing groups\ the formation of the by!
product X1Y0ZH may also be synthetically useful[ Equation "1# is isoelectronic with Equation
"0#\ but involves a _ve!membered ring transition state ð1ss ¦1ss ¦1vsŁ[ A number of general reviews
are available "e[g[\ ð58AG"E#445\ 82S548Ł#\ which include examples of the generation of C0heteroatom
double bonds by this mechanism[
H ZH
Z
+ X Y (1)
Y
X
H
+ X YH (2)
+ Y–
X
0[06[1[0 Cleavage of One C0H and One C0C Bond

Apart from the intramolecular case which results in a rearrangement\ the {all!carbon| retro!ene
reaction "Equation "0#^ XYZC# is of little synthetic value ð82S548Ł[ In part\ this is due to a
mechanistic dichotomy in which concerted and homolytic cleavage mechanisms are in competition
and which therefore leads to mixtures of products[ In the gas phase pyrolysis of hex!0!ene\ for
example\ retro!ene cleavage is most important at lower temperatures\ with radical _ssion of the
C!20C!3 bond being predominant at high temperatures ð68MI 006!90Ł[
Simple ketones decompose on pyrolysis under ~ow conditions to give alkenes "Equation "0#^
ZO#\ but they require temperatures ca[ 049>C higher than the corresponding acetates "see Section
0[06[1[1[0# for comparable conversion ð67JOC0310Ł\ and therefore the reaction is seldom used syn!
thetically[
Decarboxylation of carboxylic acids containing b\g!unsaturation "Equation "2## forms a special
case of Equation "0#\ in which the {useful| product is the HZ0Y1X fragment ðB!68MI 006!91\
B!79MI 006!90Ł[ Pyrolyses are carried out at 239>C in solution "boiling phenanthrene# ð53JCS2786Ł or
at ca[ 319>C in the gas phase under ~ow conditions ð54JCS5191Ł[ The reaction takes place with a
wide variety of substituted acids\ including cyclic examples ð56JCS"B#446Ł\ but it does not appear to
have been exploited in synthesis[
H ZH
O Z
CO2 + X Y (3)
Y
O X
Facile decarboxylation of b!ketoacids and 0\2!diacids ð40QR020Ł is familiar as a key step in the
acetoacetic ester and malonic ester syntheses of methyl ketones and carboxylic acids\ respectively\
in which the initially formed enol tautomerises to the _nal product "Scheme 0#[ In practice\ the
reaction may only require heating of the acid for a few hours in re~uxing aqueous acid solution
ð32OSC"1#305Ł\ or heating at 014Ð029>C in the absence of solvent ð32OSC"1#82Ł[
Monoenes by Retro!ene and Related Reactions 662
H
H O O
O O
CO2 + R1 R1
O R1
R2 R2
R2
R1 = Me or OH; R2 = alkyl
Scheme 1
0[06[1[1 Cleavage of One C0H and One C0O Bond

These cleavage processes are an important group of preparatively useful reactions "Equation "0#^
XO# which di}er in the nature of the other heteroatoms "Y\Z#[ Most have the overall e}ect of
accomplishing an alcohol dehydration\ by _rst modifying the alcohol function and then performing
a pyrolytic syn!elimination ð59CRV320Ł[ The e.ciency of both of these steps is therefore important
in the synthetic applicability of the various methods[
0[06[1[1[0 Pyrolysis of acetates and related esters

Many reviews of this topic "Equation "0#^ XZO# are available ð59CRV320\ 60MI 006!90\
B!68MI 006!91\ B!79MI 006!90\ 80COS0900Ł[
This reaction is traditionally carried out in the gas phase under ~ow conditions\ with temperatures
of 499Ð414>C recommended for preparative purposes ð59CRV320Ł[ FVP conditions are also e}ective\
but require slightly higher temperatures "599Ð699>C#[ The mechanism has been extensively studied
ðB!68MI006!91Ł[ The syn!nature of the elimination was suspected for many years before it was
elegantly proved by pyrolyses of the speci_cally labelled acetates "0# and "1#\ which lead to deuterium
incorporation into\ and deuterium exclusion from\ the alkene product\ respectively "Scheme 1#
ð42JA5900\ 61JCS"P1#054Ł[ These results have been applied to the conformational analysis of steroids
"ð40JCS0937Ł and references therein#[
H
O Ph
flow
Ph + HOAc
O 400 °C
D Ph 74% D Ph
(1)
H
O Ph
flow
Ph + DOAc
O 400 °C
H D 61% Ph
Ph
(2)
Scheme 2
The regioselectivity of the elimination is dependent on a number of factors\ including statistical

e}ects\ thermodynamic stability of the products "arising from steric e}ects# and electronic e}ects\
and the overall stereochemical outcome can be rather modest[ Statistical e}ects dominate the
pyrolyses of simple alkyl acetates^ for example\ but!1!yl acetate gives a 46 ] 32 ratio of but!0!ene to
but!1!enes\ close to the statistical ratio of 59 ] 39 ð52RTC0012Ł "Equation "3##[ Steric e}ects promote
the formation of the "E#! rather than the "Z#!alkenes if either is possible "Equation "3## and may
cause a slight reduction in the amount of terminal alkene in competitive situations[ Cycloalkyl
acetates generally form the alkene unexceptionally^ however\ with large ring sizes\ both "E#! and
"Z#!alkenes are formed "Equation "4## ð44JA0990Ł[ The formation of a double bond endo! to a ring
is generally favoured relative to the exo!isomer\ due to the greater reduction in eclipsing interactions
in the former case ðB!68MI 006!91Ł "e[g[\ Equation "5# ð48JA540Ł#[ Conjugative stabilisation of the
product appears to be unimportant^ even the acetate "2# gives just a 0 ] 0 mixture of conjugated and
unconjugated dienes "Equation "6## ð58MI 006!90Ł[ Large ring lactones\ which can accommodate the
required transition state\ undergo corresponding thermal rearrangement to give v!unsaturated
carboxylic acids ð66JOC2784Ł[
flow
+ + (4)
380–440 °C
OAc 57% 28% 15%
OAc
flow
+ (5)
500 °C
69% 19%
flow
+ (6)
OAc 450 °C
0–16% 84–100%
OAc
'reactor'
+ (7)
300 °C
(3) 50% 50%
Electronic factors are now recognised as being dominant in governing the rate and direction of
alkene formation[ The reaction is aided by electron donation at C!0\ such that the order of reactivity
is tertiary×secondary×primary\ even allowing for statistical correction "e[g[\ the relative rates of
ethyl\ isopropyl and t!butyl acetates are 0 ] 17[7 ] 2204 ð64JCS"P1#0914Ł#[ The reaction is aided by
electron withdrawing groups at C!1\ such that pyrolysis of "E#!methyl 1!acetoxycyclo!
hexanecarboxylate gave the 0!alkene almost exclusively "Equation "7## ð48JA1015Ł[ Bulky electron
donating "alkyl# substituents at this position can also cause a small rate enhancement due to {steric
acceleration| ð65JCS"P1#179Ł\ which reaches a maximum factor of 02 for a t!butyl group relative to a
hydrogen atom[
CO2Me CO2Me CO2Me

flow
+ (8)
435 °C
OAc
97% 3%
The reaction is also accelerated by electron!withdrawing groups at the carbonyl carbon atom^
formates\ chloroacetates\ chloroformates and other functional groups such as carbonates and
carbamates "see Section 0[06[1[1[2# are therefore all in principle more e.cient than acetates
ðB!68MI 006!91Ł\ although the e}ect is often small ð52JCS0135Ł[ However\ cyclohexyl tri~uoroacetate
is some 08 times more reactive than the corresponding acetate ð58JCS"B#076\ 61RTC2Ł[
From a synthetic point of view\ these reactions are attractive despite the relatively high tem!
peratures involved\ because of the ready availability of starting materials\ and because of the absence
of any acidic or basic reagents which might promote rearrangements[ At a practical level\ the use
of benzoates rather than acetates has the advantage that benzoic acid crystallises at the exit point
of the furnace\ well away from the more volatile alkene ð77MI 006!90Ł[ The gas!phase\ short contact
time conditions are particularly e}ective for the synthesis of alkenes which readily polymerise or
decompose unless kept in the cold[ Examples include the generation of reactive dihydrofurans
ð76TL0408\ 82AJC0210Ł or dihydrothiophenes ð75JOC002Ł "Scheme 2#^ in both monocyclic cases the
isolated yield from the pyrolysis step was ×74)[
Acetate pyrolysis continues to be employed as a key step in natural product syntheses[ It was
used selectively by Klaver et al[ en route to the alkaloid peduncularine "3#\ when anionic or cationic
eliminations failed "Scheme 3# ð78JA1477Ł[ The exo!cyclic methylene groups of longifolene "4#
ð89JA3598\ 82JOC1075Ł and sinularene "5# ð68AJC0708Ł were introduced by classic {~ow| pyrolysis
methodology using benzene or toluene solutions of the substrates "Scheme 4#[
FVP
OSiMe2But OSiMe2But
AcO O 510 °C, 0.02 torr O
FVP
S OAc 400 °C, 0.0001 torr S
OH OH
FVP
OAc
O 550 °C, 0.2 torr O
O O
H H
Scheme 3
AcO AcO
Pri OAc FVP Pri Pri

N N N
600 °C, 0.05 torr
O O N
H
(4)
Scheme 4
flow
OAc
525 °C, benzene
(5)
flow
OAc 450 °C
(6)
Scheme 5
0[06[1[1[1 Pyrolysis of xanthate esters

This method follows the general mechanism of Equation "0# "XO\ YC0SR\ ZS#^
invariably the S!methyl derivatives are used[ As well as the reviews cited in the previous subsection\
a specialised account of this transformation*the Chugaev reaction*is available ð51OR"01#46Ł[
The reaction is aided by greater nucleophilicity in the atom Z ðB!68MI 006!91Ł and so\ not
surprisingly\ xanthates are more reactive than acetates and the reaction may be carried out under
relatively mild conditions[ Possible thermal isomerisation of the alkene is therefore minimised[
Typically\ the pure xanthate is heated to ca[ 049>C for a few hours either at atmospheric pressure
or under vacuum^ the product may distil out or remain in the pyrolysis ~ask[ If the xanthate distils
without decomposition\ the elimination can be e}ected by dropwise addition to a high boiling point
solvent such as diphenyl ether or biphenyl ð51OR"01#46Ł[ Two disadvantages of this method vis!a!
vis ester pyrolysis are that xanthates are more di.cult to prepare than acetates and that the products
are frequently contaminated with sulfur!containing impurities "which are traditionally removed by
treatment with metallic sodium# ð51OR"01#46Ł[
The syn!stereochemistry of the process was established by Cram ð38JA2772Ł "e[g[\ Equation "8##\
and this was applied to assign the con_guration of terpene hydroxyl groups in the early days of
conformational analysis ð38JCS1063Ł[ The involvement of the C1S sulfur atom in the elimination
has been proved by 23S and 03C isotope e}ects ð50CJC237Ł[ Statistical\ thermodynamic and steric
factors again govern the direction of the elimination ð51OR"01#46Ł\ and complex mixtures will result
if a variety of decomposition pathways are open "cf[ Section 0[06[1[1[0#[ Where a comparison has
been made\ the results have been found to be closely similar to those of the corresponding acetate\
bearing in mind that the reaction conditions are substantially di}erent ð59CRV320Ł[ Again\ the
formation of "E#!alkenes is favoured over "Z#!alkenes in competitive situations[ "Z#!Cycloalkenes
are formed when the ring size is smaller than eight carbon atoms ð51OR"01#46Ł\ but the proportion
of "E#!isomer increases the larger the ring size ð44JA0990Ł[ The preference for endo! rather than exo!
elimination in cyclic cases is apparently less marked than for the corresponding acetate ð59CRV320Ł[
Electron withdrawing groups attached to sulfur further accelerate the reaction ð42JA1007Ł[
Ph Ph
S 180 °C
(9)
O SMe
H
Xanthate pyrolysis is still used substantially in synthesis[ At a simple level\ b!02C!labelled styrene
was prepared in 19) yield by pyrolysis of the xanthate derived from labelled phenethyl alcohol
ð76JA442Ł[ A comparison of acetate\ tosylate and xanthate pyrolysis as a means of preparing tens
of grams of 5!chlorohex!0!ene has shown that the last method is preferred\ with yields of 64Ð79)
being obtained routinely by FVP at 414>C ð78JOC4700Ł[ Applications in propellane ð76TL1684\
89JA117Ł and triquinancene chemistry ð89TL2398\ 81JOC4010Ł have also been published since the late
0879s\ including a spectacular triple!Chugaev process "Equation "09## which takes place in 80)
yield when carried out at 119Ð129>C in hexamethylphosphoramide "HMPA# ð89TL2398\ 81JOC4010Ł[
OCS2Me
220 °C
OCS2Me (10)
HMPA
OCS2Me 91%
A number of applications in natural product synthesis may be cited[ Pyrolysis of the xanthate "6#
in biphenyl solution at 109>C gave an 79) yield of the alkene "7# en route to racemic lindestrene
"Scheme 5# ð74TL5282Ł[ The method is compatible with the presence of remote chiral centres\ and
the alkene function of the alkaloid "−#anisomycin "8# was introduced by xanthate pyrolysis in
o!dichlorobenzene "Equation "00##^ the 3\4!dehydropyrrolidine isomer was also obtained as a minor
by!product ð78H"18#0750Ł[ Not surprisingly\ heating the xanthate "09# at its sublimation temperature
"109>C# gave regiospeci_c formation of the dihydropyran "00# in high yield "Equation "01##^ structure
"00# has been proposed as a potential intermediate in yohimbine alkaloid synthesis ð75JOC2912Ł[ In
other cases\ a comparison of xanthate and selenoxide methods has come out in favour of the latter
methodology ð89JOC3940Ł[
MeS2CO
O O
O
O Ph2, 210 °C O
16 h
H 80% H H
CO2Me CO2Me
(7) (8)
Scheme 6
MeS2CO OMe OMe

180 °C
H H (11)
N N
CO2Bn R
R = CO2Bn → R =H
(9)
O O
MeS2CO H H
210 °C
(12)
H H 93% H
Ph3CO OMe Ph3CO OMe

(10) (11)
0[06[1[1[2 Other concerted pyrolytic eliminations

Wide structural variation is possible\ and some examples have been summarised ð80JOC735Ł^
Taylor has made extensive studies of the mechanistic e}ects of changing the heteroatoms "e[g[\
ð80JCS"P1#0692Ł and earlier papers in the series#[ Important factors include the nucleophilicity of Z
and the electronegativity of Y "or of atoms attached to Y#\ both of which aid the reaction "Equation
"0## ðB!68MI 006!91Ł[ However\ these variations have\ as yet\ not signi_cantly displaced the traditional
acetate or xanthate methods for preparative purposes[
The heteroatom Z is not required for a successful pyrolytic elimination\ and indeed simple vinyl
ethers "01# "Equation "0#^ XO# can be pyrolysed in a ~ow system at atmospheric pressure
ð66JOC2788Ł\ to give alkenes at a comparable rate to the corresponding acetate\ although the product
distribution is slightly altered "Equation "0#^ XO# ð71JCS"P1#0068\ 77JCS"P1#626Ł[
O
(12)
1!Alkoxypyridines "02# ð71JCS"P1#0064Ł and related heterocycles ð75JCS"P1#0144Ł undergo a similar

decomposition "Equation "0#^ XO\ ZN#[
N O
(13)
Other examples of substrates with two heteroatoms which give alkenes in a similar manner to
ester pyrolyses are thionacetates "03# "and the isomeric thioacetates "04## ð62JCS"P1#0182\ 64JCS"P1#206Ł
and benzimidates "05# ð55TL5168Ł\ whereas examples related to xanthates include the carbonates
"06# ð61JCS"P1#815\ 61JCS"P1#0633\ 61JCS"P1#1248\ 72JCS"P1#180Ł and thiocarbonates "07#[ Within the
series of carbonates and their possible sulfur analogues\ the following order of reactivity has been
found ð77JCS"P1#066Ł] PhOCSOR×PhOCO1R×PhSCSOR×PhSCO1R×PhOCS1R×PhSCS1R×
PhOCOSR×PhSCOSR[ The major rate change occurs when OR is replaced by SR\ with the change
from carbonyl to thiocarbonyl producing a relatively small e}ect ð77JCS"P1#066Ł[
S O NPh O S
O S O Ph O OR O OR
(14) (15) (16) (17) (18)
The ~ow pyrolysis of carbamates "08# ð62AJC0148Ł has attracted some attention[ Empirically\
N\N!dimethylcarbamates require similar conditions to those of acetates\ but their diphenyl ana!
logues react at rather lower temperatures ð70JOC1793Ł[ In one useful application\ decomposition of
the carbamate "19# at the temperature of re~uxing carbon tetrachloride "09 h# gave an 79) yield of
the silole "10# "Equation "02## ð72TL2410Ł^ the method was much superior to earlier methods of
dehydration[ A study of N!aryl!O!alkylselenocarbamate "11# pyrolysis has been made ð83T528Ł[
Conditions are mild "79>C in chloroform solution#\ but the syn!elimination is complicated by a
competing bimolecular "E1# mechanism[
S Se
O NR2 O NHAr
(19) (22)
O
NHPh CCl4
(13)
Si O 10 h Si
Me Me Me Me
(20) (21)
Similar eliminations have been observed from phosphate "12#\ phosphinate "13# or sulfonate "14#
esters[ Phosphates are much more reactive than the corresponding acetate owing to the greater
electronegativity of the phosphorus atom ð50JOC735Ł\ and the rate spread for alkyl diphenyl!
phosphinates "primary ] secondary ] tertiary0 ] 399 ] 095# is much greater than for the cor!
responding acetates ð64JCS"P1#0914Ł[
O O O
OR Ph R
P P S
O OR O Ph O O
(23) (24) (25)
Tosylates have been found to be more reactive than either acetates or xanthates in 0\2!eliminations
in the adamantane series ð61JCS"P0#1422Ł[ Like benzoates\ they have the added practical advantage
for FVP that the co!product condenses at a position in the trap\ well away from the alkene\ allowing
facile separation ð78JOC4700Ł[ As an alternative to gas!phase methods\ 7!quinolylsulfonates or
1!pyridylsulfonates have been found to decompose cleanly at ca[ 049>C to give good to excellent
yields of simple alkenes ð78JOC278Ł[
0[06[1[2 Cleavage of One C0H and One C0S Bond\ including Pyrolysis of Sulfoxides
The cleavage of C0S bonds in ester!type pyrolyses is well known "Equation "0#^ XS\ etc[#[
Examples include thioacetates "04# and S!alkyldimethylthiocarbamates "15#\ which show standard
eliminations to give alkenes "79Ð87) on a 099 mg scale# upon FVP at 459>C ð76JOC2577Ł^ these
compounds are less reactive than their O!alkyl isomers[
S NMe2
(26)
Pyrolysis of sulfoxides has long been known to give alkenes\ but the reaction has only been
developed as a useful synthetic method since the mid 0869s ð67ACR342\ 67CRV252\ 67S602\ 80COS0900Ł[
The availability of the precursors and the mild conditions required for the elimination are two major
attractions of this method "and for the related application of selenoxide pyrolysis "Section 0[06[1[3##[
In particular\ it provides a three!step route from ketones or esters to their a\b!unsaturated analogues
by sequential sulfenylation\ oxidation and thermolysis "Scheme 6# ð67CRV252Ł[ The thermolysis step
usually takes place in solution in the temperature range 14Ð029>C\ with S!arylsulfoxides decom!
posing at the lower temperatures and S!alkylsulfoxides decomposing at the higher temperatures in
the range ð67ACR342Ł[ Electron!withdrawing groups on the S!aryl ring also accelerate the reaction
ð67CL430Ł[ The method is also useful for the preparation of the sulfenic acid co!products ð80COS0900Ł[
Sul_nate esters "16# show similar elimination reactions ð69JCS"C#70Ł[
–O +
SR3 SR3
[O] heat
R1 R2 R1 R2 R1 R2
O O O
R1 R2
+ R3SOH
O
Scheme 7
+ O–
S
OMe
(27)
The standard syn!stereochemistry of the process for acyclic examples was established by Kings!
bury and Cram ð59JA0709Ł and the solvent independence of the reaction rate is consistent with a
concerted mechanism[ Isotope e}ect studies suggest that the hydrogen transfer occurs via a linear
transition state ð67JA1791\ 67JA2816Ł[ Acyclic alkenes are produced with "E# stereochemistry ð62JA5739\
64JOC037Ł[ Fragmentation takes place towards the most acidic b!hydrogen atom\ and the order of
reactivity quoted by Trost ð67ACR342Ł is as follows] C1C0CH1 ×C2C0CH1 ×ArCH1 ½
CH2 ×CH1 ×CH[ The elimination takes place away from b!hydroxy groups to give allylic alcohols
"Scheme 7# ð67TL3892Ł] the equivalent reaction of selenoxides "Section 0[06[1[3# is more useful in
practice[ Where no other reaction is possible\ pyrolysis of b!hydroxysulfoxides gives ketones via
their enol tautomers ð64TL1730Ł[ Chirality at the sulfoxide group can also have an e}ect on the
regiochemistry\ especially in sterically hindered situations where alternative b!hydrogen atoms have
similar acidities ð56JCS"C#421\ 69JCS"C#722\ 65JCS"P0#348Ł[ Early attempts to obtain optically active
alkenes by the use of homochiral sulfoxides have met with only limited success ð56JOC1948Ł[ As
found for acetate and xanthate pyrolysis\ endo!cyclic rather than exo!cyclic elimination takes place
in _ve! and six!membered cyclic systems "Equation "03# and Scheme 8\ where LDA is lithium
diisopropylamide# ð62JA5739\ 64JOC037\ 66HCA1277Ł[
140 °C OH
OH
+
SR
–O
OH
Scheme 8
O–
+
SMe
120 °C
O O + O (14)
O 95% O O
87:13
As the elimination step takes place under such mild conditions\ the synthetic utility of sulfoxide
eliminations is primarily dependent on the availability of the precursors[ The route to a\b!unsatu!
rated carbonyl compounds "Scheme 6# can be extended by regiospeci_c alkylation*either at the
sul_de or the sulfoxide stage ð67S602Ł*to give a combined alkylationÐelimination sequence "e[g[\
Scheme 8# ð66HCA1277Ł[ Dimsyl anion methodology can be used as a route to isolated terminal
alkenes\ although the thermolysis temperatures are comparatively high "e[g[\ Scheme 09#
ð53JOC1588Ł[
O O O
SPh
i, LDA, MeI +
SPh 70 °C
ii, mcpba O–
Scheme 9
O–
NaCH2S(O)Me DMSO
S+
C15H31 OTs C15H31 C15H31
DMSO reflux
Scheme 10
In some applications from the late 0879s\ vinyl ~uorides have been obtained from a!~uoro!
sulfoxides ð76TL2890Ł^ for the corresponding b!~uoro derivatives elimination takes place away
from the ~uorine atom to give a high yield of an allylic ~uoride "Equation "04## ð81JOC603Ł[
Dimethyldioxirane has been advocated for oxidising sterically hindered sul_des to the sulfoxide
prior to the elimination\ for which traditional reagents are ine}ective ð82T6856Ł[ In the _eld of natural
product synthesis\ sulfoxide elimination has been employed in routes to avermectin ð76TL3848Ł and
azadirachtin ð76TL110\ 80T5702Ł subunits "Scheme 00# "see also Chapters 0[02 and 0[03#[
F 80 °C F
(15)
+ Me 20 h
S 95%
O–
CO2Me CO2Me
HO HO
SPh
mcpba
O 110 °C O
H 94% H
OMe OMe
OSiMe2But OSiMe2But
+ 110 °C
SPh
O– 92%
O O
H H
Scheme 11
0[06[1[3 Cleavage of One C0H and One C0Se Bond*Pyrolysis of Selenoxides

Selenoxide elimination is the most recently developed method to be considered in this chapter\
and it occurs under the mildest conditions\ with the {pyrolysis| frequently taking place in solution
between 9>C and room temperature "Equation "1#^ XSe#[ On average\ temperatures for the
elimination are 49Ð019>C lower than those required for sulfoxide pyrolysis ð67T0938Ł[ Alkenes which
are sensitive to nucleophiles\ polymerisation\ enolisation and thermal degradation can be prepared
e.ciently by this method[ Flexible routes to the selenide precursors are available from ketones\
esters\ epoxides or by substitution reactions\ which enhance the synthetic utility of the method\ and
these lead to a\b!unsaturated carbonyl compounds\ allylic alcohols or terminal alkenes\ respectively[
Reviews have been published ð67T0938\ B!75MI 006!90\ 80COS0900Ł[ Detailed practical considerations
are discussed by Clive ð67T0938Ł\ and applications to natural product synthesis are summarised by
Paulmier ðB!75MI 006!90Ł[
The reaction is carried out by oxidation of a selenide precursor "usually a phenylselenide# and
the elimination then takes place directly without isolation of the selenoxide[ A range of possible
reagents may be employed\ but hydrogen peroxide or meta!chloroperoxybenzoic acid are used most
commonly ð67T0938Ł[ The formation of terminal unconjugated alkenes from primary selenides is
slow\ although it can be encouraged by incorporating an electron withdrawing group into the
phenyl ring of the selenide ð64JOC836\ 79TL4926Ł[ Since the precursors are easily made from alcohols
ð65JOC0374Ł\ this provides an alternative to acetate and related pyrolyses for primary alcohol
dehydration[ The generation of acyclic enones is particularly rapid[ Often\ an excess of the oxidising
agent is employed to destroy the selenenic acid co!product\ which could otherwise react with the
alkene "particularly terminal alkenes# or undergo competing disproportionation reactions
ð67JOC0578Ł[ The selenenic acid can also be destroyed by addition of a secondary amine to convert
it into a selenenamide ð65JOC1492Ł\ a strategy which is particularly useful when cyclic enones are
formed ð64JA4323Ł[
The mild conditions employed\ compared with sulfoxides "and amine oxides#\ are due to the
longer Se0O and Se0C bond lengths and to the greater polarisation of the Se0O bond ð70JA0121Ł[
The syn!nature of the elimination was established in 0869 using a steroid example ð69JCS"D#75Ł\ and
later con_rmed for acylic cases ð62TL0868Ł[ As usual\ "E#!alkenes are obtained predominantly
ð63TL1168Ł\ although almost equal amounts of "E#! and "Z#!a\b!unsaturated nitriles may be obtained[
In most cyclic systems a "Z#!alkene is produced\ but for large "−01!membered# rings either pure
"E#! isomer or mixtures of "E#! and "Z#!isomers may be obtained ð67T0938Ł[ As with sulfoxide! or
acetate!type pyrolysis\ endo!alkene formation is favoured over exo!elimination for both _ve! and
six!membered rings\ although in some cases the preference may not be very great "Scheme 01#
ð62JA4702Ł[ Where possible\ the fragmentation occurs away from a b!electronegative substituent
"particularly oxygen atoms# "e[g[\ Equation "05## ð63JOC318Ł\ and this provides an e.cient and
highly e}ective synthetic route to allylic alcohols[ Decomposition takes place towards allylic or
benzylic centres to give the conjugated product ð62JA4702\ 62TL0868\ 64JA2149Ł^ conditions are par!
ticularly mild in these cases ð64JA4323Ł[ The direction of the elimination is also a}ected by statistical
factors\ and if these are in opposition to the above e}ects then the overall regioselectivity may not
be very good[
H2O2, MeOH
67:23
O O O
SePh
+
80:20
H2O2, AcOH, THF, H2O, < 25 °C
Scheme 12
SePh
H2O2
+ (16)
25 °C
OH OH OH
> 99:1
Partly because of the availability of precursors\ selenoxide eliminations are particularly e}ective
for the synthesis of a\b!unsaturated carbonyl compounds\ and for allylic alcohols ð62JA1586Ł and
related compounds ð80COS0900Ł via enolate selenenylation and epoxide ring opening\ respectively[
These methods are of signi_cant importance in contemporary organic synthesis\ and frequently
appear in multistep syntheses of natural products[ Thus the reaction has been employed in quassinoid
chemistry "Equation "06## ð83JOC200Ł\ where it was found that removal of the phenylselenenic acid
co!product was simply e}ected by addition of sodium bicarbonate[ Cases of a\b!unsaturated car!
bonyl compounds being produced include formation of a!alkylidene!b!lactones "17# ð82JOC211Ł
"which can be transformed into allenes by b!lactone thermolysis "Section 0[06[2[0## and a subunit
"18# of the streptogramin antibiotics "Scheme 02# ð78JOC2877Ł[ Some exo!methylene heterocyclic
compounds have been prepared via selenoxide intermediates "e[g[\ Equation "07## ð82JOC0238Ł[
Allylic alcohol formation has been employed in key steps en route to symbioramide "29# ð83LA30Ł\
valienamine "20# ð81TL0914Ł and coriolin "21# ð82LA0022Ł "Scheme 03# "see also Chapter 0[03#[
O O
H2O2, EtOH, NaHCO3

(17)
H H
25 °C
PhSe O-TBDMS 82% O-TBDMS
H H
O O
O O
H2O2
SePh 25 °C
(28)
O-TBDMS O-TBDMS
i, LiNPri2, PhSeBr
ii, H2O2
70%
CO2Me CO2Me
(29)
Scheme 13
EtO2C EtO2C
H2O2
SePh (18)
Ph 20 °C, 25 h Ph
O 71% O
0[06[1[4 Cleavage of One C0H and One C0N Bond\ including the Cope Elimination
Alkenes may be formed by pyrolysis of suitable amides "Equation "0#^ XNR\ ZO#[ Although
the temperatures required are higher "ca[ 099>C# than those for the corresponding acetate
ð59CRV320Ł\ similar isomer distributions are obtained ð48JA540Ł[ Kinetic data for amides and the
corresponding thioamides "Equation "0#^ XN\ ZS# are available ð78JCS"P1#468\ 89JCS"P1#1076Ł[
In a cyclic example\ facile elimination of isobutene from N!t!butylpyridazin!2!ones at 699>C under
FVP conditions has been observed ð71JCS"P0#0734Ł[ Disulfonimides "22# can also be pyrolysed neat
at 059Ð199>C to give alkenes in up to 88) yield[
The most important reaction type in this section is the Cope elimination "Equation "1#^ XNR#\
for which specialised reviews are available ð59OR206\ 82S152Ł in addition to more general surveys
ð59CRV320\ 80COS0900Ł[ The method presents an alternative to the more widely used Hofmann
elimination of quaternary ammonium hydroxides\ and has certain advantages in terms of ease of
manipulation and lack of product isomerisation[ However\ the Meisenheimer rearrangement to
form N\N\O!trisubstituted hydroxylamines may compete ð82S152Ł[
As with the related sulfoxide and selenoxide eliminations\ the reaction is normally carried out with
a mixture of amine and oxidising agent without puri_cation of the amine oxide[ After destruction of
the excess oxidising agent\ the reaction mixture is concentrated and the crude material is pyrolysed
for a few minutes at 099Ð039>C "e[g[\ ð42JA2101Ł#[ These conditions are signi_cantly more severe
than those required for sulfoxide and particularly selenoxide eliminations[ Both the alkene and the
hydroxylamine by!product distil from the reaction mixture and are separated by treatment with
acid[ Signi_cant rate enhancements can be observed if the elimination is carried out in DMSO
solution ð51JA0623Ł[
The syn!stereochemistry of the elimination has been frequently established "e[g[\ Equation "08#
ð62JOC0631Ł#\ but isotope e}ects suggest that there may be subtle di}erences in the mechanism in
OH
OH OH HO ( )14
H2O2
O-TBDMS O-TBDMS N O
( )13 25 °C ( )13
H
SePh
HO ( )13
(30)
BnO BnO BnO
BnO i, PhSeNa BnO BnO

ii, mcpba, 45 °C
86%
HO BnO
O O
BnO HO
BnO HO
BnO HO NH2
OH OH
(31)
HO O
H
O i, PhSeNa O O
O O
O ii, H2O2, EtOH, 78 °C, 4 h
H HO H H O
OH
(32)
Scheme 14
NO2
O 2S
N
R SO2
NO2
(33)
DIGLYME solution "nonlinear hydrogen transfer via a bent transition state# and DMSO solution
"linear hydrogen transfer\ possibly incorporating a molecule of solvent# ð67JA1791\ 67JA2816\ 70JA3549Ł[
03
C!Isotope e}ects indicate that extensive rupture of both the C0N and the C0H bonds has taken
place at the transition state\ with relatively little C1C character ð72JA2603Ł[ In aliphatic systems\
the direction of elimination qualitatively resembles that found for esters\ with the number of
hydrogen atoms on b!positions being the major factor ð59CRV320\ 59OR206Ł^ the formation of "E#!
alkenes is again favoured if both "E# and "Z# isomers can be obtained ð59CRV320\ 59OR206Ł[ In
medium!sized rings "−nine!membered# "E#!alkenes are obtained exclusively ð42JA2101\ 44JA0517Ł[ A
striking di}erence compared with the results of ester\ sulfoxide or selenoxide pyrolyses is that a
double bond exo! to a six!membered ring is obtained in preference to the endo!isomer "Equation
"19## ð46JA3618Ł[ This may be due to the more severe constraints of the _ve!membered ring transition
state with relatively short C0N bonds\ which requires a quasi!boat form in the cyclohexane ring
for endo!elimination[ Five! and seven!membered ring analogues give more of the endo!cyclic alkene
ð46JA3618Ł[
O–
+
NMe2
110 °C
(19)
D D
+
NMe2 160 °C
+ (20)
O–
97.2:2.8
Applications of the Cope elimination to synthesis have been rare[ Following earlier work in thiete
dioxide chemistry ð53JOC2020Ł\ Woolhouse et al[ obtained the conjugated thiete "23# exclusively by
heating a sample of the amine oxide "24# at 89>C "Scheme 04# ð82JHC762Ł^ the isomeric thiete "25#
is thought to be formed initially\ which then isomerises under the reaction conditions[ In a highly
stereoselective\ convergent synthesis of racemic trichodiene "26#\ a Cope elimination was used in the
_nal step to introduce the exo!cyclic alkene function "Equation "10## ð73JOC2769Ł[ Examples of
intramolecular ring cleavage by Cope elimination have been published with simple heterocycles
ð59JA3545Ł and the work has been extended to alkaloid chemistry in the mid 0879s ð73JCS"P0#0690\
74H"12#2974Ł "see also Chapters 0[02 and 0[03#[
+
O–
N H H
90 °C
SO2 SO2 SO2
(35) (36) (34)
Scheme 15
NMe2
mcpba
(21)
distil at 1.5 torr
(37)
0[06[2 FORMATION OF MONOENES BY RETRO!CYCLOADDITION REACTIONS
0[06[2[0 Retro ð1¦1Ł Cycloadditions

Thermal cycloreversions of this type "Equation "11## would formally be ð1ss ¦1saŁ processes and
hence many of these reactions occur thermally by diradical mechanisms ð75T1024Ł and are not
considered in detail here[ The incorporation of a carbonyl group in the four!membered ring
apparently increases the likelihood of a "stereospeci_c# concerted process taking place under thermal
conditions[ The topic has been reviewed ð71AG"E#114Ł[
W Z W Z
+ (22)
X Y X Y
Mechanistic aspects of the formation of alkenes by cyclobutane pyrolysis have been reviewed by
Gajewski ðB!70MI 006!91Ł and Brown ðB!79MI 006!90Ł\ and the weight of evidence is in favour of
diradical intermediates ð83TL1564Ł[ In contrast\ the thermal decomposition of simple cyclobutanones
is probably concerted and proceeds with the retention of stereochemistry predicted for such a
mechanism ð61JA6124Ł[ Under photochemical conditions\ even simple cyclobutanes would be
expected to undergo concerted fragmentation^ one example is shown in Equation "12# ð64TL0224Ł[
Monoenes by Retro!Cycloaddition Reactions 674
Ph O Ph O
hν
+ (23)
N N
Ph Me Ph Me
The photochemical formation of oxetanes followed by thermal cracking in the opposite sense
ð62CC263Ł has been employed as a synthetic method for a\v!enones ð64CC195Ł^ this is probably
another diradical process ð66CRV362Ł[
The facile loss of carbon dioxide from b!lactones is well established ð0772CB1197Ł and has been
reviewed "e[g[\ ð73CHEC"6#252\ 82S330Ł[ The process is of synthetic value for the two!step conversion
of 2!hydroxycarboxylic acids into alkenes\ and since these precursors can be readily obtained from
ketones the method is a viable alternative to the Wittig reaction for the conversion of ketones into
alkenes[ Experimental conditions include heating in water ð47JA2474Ł\ or heating at 039Ð059>C
either neat ð61JA1999Ł or in solution ð82JOC211Ł\ or FVP at 399>C ð80JOC4671Ł[ The decomposition
is accelerated by electron donating substituents at the 3!position\ although it is a}ected little by
substituents at the 2!position ð73CHEC"6#252Ł[ The precise mechanism of the reaction is a matter for
debate ð82S330Ł\ but the syn!nature of the elimination was con_rmed in 0855 "Equation "13##
ð55JOC3932Ł[ This feature\ together with the absence of isomerisation\ is particularly important for
synthetic applications ð61JA1999Ł[ The method has been used as a route to enol ethers ð62CJC870\
68S277Ł\ and applications to the synthesis of allenes are also noteworthy ð80JOC4671\ 82JOC211Ł[ In
exceptional cases where a highly strained alkene would result\ the cycloreversion may take place in
the opposite sense to give a keto!ketene ð75JA6010Ł[
O
H
100 °C
+ CO2 (24)
H O
Ar
Ar
Simple b!lactams can decompose thermally to give isocyanates and alkenes ð48RTC440Ł\ although
the alternative mode of fragmentation to ketene and imine may take place with appropriate
substituents ð52JA2413Ł and under photochemical conditions ð57CB1558Ł[ Upon FVP at 599>C
"01 torr# reaction takes place to give alkenes with almost complete retention of stereochemistry
"Equation "14## ð69JA0652Ł[ This reaction does not appear to have been used synthetically[
O
H FVP
+ (25)
H N 600 °C
H
99.3:0.7
0[06[2[1 Retro ð3¦1Ł Cycloadditions "Retro!DielsÐAlder Reactions#

This ð1ps ¦1ss ¦1ssŁ reaction "Equation "15## has been used extensively as a preparative route to
either monoenes\ dienes "Section 0[06[3[0# or other multiply bonded functional groups containing
heteroatoms[ For the preparation of alkenes "Equation "15#^ YZC#\ the transformation almost
always involves cleavage of two C0C single bonds "i[e[\ UXC#[ It can be carried out in
solution\ usually at temperatures in excess of 049>C ð80COS"4#440Ł\ although in appropriate cases
acceleration by cation\ anion or radical substitution has been predicted ð67T0766Ł[ Indeed\ oxy!
anionic substitution may cause the reaction to proceed rapidly at room temperature "Equation "16##
ð79TL1688Ł[ Cycloreversion of endo!adducts may be substantially faster than that of exo!adducts
ð67JOC407Ł[ Increasingly\ FVP methods are employed to accomplish the transformation for neutral
species\ using temperatures in the range 399Ð599>C ð80COS"4#440Ł[ Cyclopentadiene or anthracene
adducts ""27# and "28#\ respectively# have been commonly used as alkene precursors[ The former
has the advantage that its low molecular weight causes the precursor "and the cyclopentadiene co!
product# to be relatively volatile and it is commonly used for complex alkenes\ although relatively
high temperatures may be required[ In contrast\ anthracene is less volatile and condenses near the
exit point of the furnace^ it is often used for simple alkenes from which it is readily separated[
U U
V Z heat V Z
+ (26)
W Y W Y
X X
MeO2C
MeO2C 25 °C
+ (27)
H t1 < 1 min
/2
MeO2C MeO2C
O– H
O–
R2
R1 R1
R2
(38) (39)
These methods have been used to prepare a wide range of both simple and functionalised alkene
systems\ and some typical examples are given below[ In many cases reactive alkenes are released at
a late stage of a synthesis and so the DielsÐAlder adduct serves as a protecting group[ A number of
comprehensive reviews of retro!DielsÐAlder processes are available\ covering mechanistic features
ð57CRV304\ 79AG"E#668Ł\ preparative aspects ð67T08\ 74S010\ 80COS"4#440Ł and application to natural
product synthesis ð76S196Ł[
The vinylimidazole "39# is a good example of a simple alkene best prepared by retro!DielsÐAlder
reactions[ A yield of 74Ð89) is claimed for ~ow pyrolysis "methanol solution# at 499>C "Equation
"17## ð72AG"E#459Ł[ The method is also useful for releasing sensitive a\b!unsaturated carbonyl
functionality[ The example shown in Equation "18# is noteworthy\ since the chiral centres and the
alcohol protecting group are both una}ected\ despite the apparently severe conditions of the retro!
DielsÐAlder reaction ð75TL2400Ł[ Zwanenburg and co!workers have used FVP methodology "499>C#
to generate the alkene unit of cyclopentenones "e[g[\ Equation "29#\ which are important inter!
mediates in the synthesis of quinane natural products^ once again\ optically active products can be
obtained under these conditions "e[g[ ð76TL246\ 83TL1676Ł#[ A large number of methylidenemalonic
esters have been generated in situ by reaction of malonic ester with formaldehyde\ trapped with
anthracene\ and then released again by pyrolysis of the adducts "30# in solution at 199Ð149>C in the
presence of maleic anhydride "which reacts with the anthracene formed#[ For most esters\ yields are
in the 39Ð59) range ð77JOC3748Ł[ Natural products containing an allylic alcohol unit*such as "31#\
a ~avour component of mushrooms*have been made in high enantiomeric purity by a method
which requires an FVP cycloreversion to create the alkene function "Scheme 05# ð76TL072Ł[
N
FVP
+ (28)
500 °C N
N
H N H
(40)
FVP Ph
Ph + (29)
500 °C
O O-TMS O O-TMS
R1 R1 R2
H R2
FVP
+ (30)
500 °C
O O
Dienes and Polyenes 676
R1O2C
CO2R2
(41)
O-TMS
FVP O-TMS
+
660 °C
OH
(42)
Scheme 16
The retro!DielsÐAlder cleavage of anthracene cycloadducts has been used very e}ectively by
Ripoll and co!workers ð74S010Ł to generate unstable or highly reactive tautomers such as enols
ð68NJC084Ł\ simple enamines ð79T1386Ł or vinyl phosphines ð79T1386Ł\ as shown in Equation "20#[ In
many cases\ these products were trapped or were characterised by spectroscopy at low temperatures[
FVP X
+ (31)
660 °C
X = OH, NH2, PH2, etc.
In certain cases where strained alkenes may be formed\ an alternative free!radical ring expansion
may take place rather than the retro!DielsÐAlder process[ Certain cyclopropeneÐanthracene adducts\
for example\ have been shown to behave in this way ð83CC778Ł[
0[06[3 FORMATION OF DIENES AND POLYENES

The methods described in the previous sections have been applied*often unexceptionally*to
generate dienes and polyenes\ and some typical examples of each will be given below[ The major
advantage of these methods vis!a!vis ionic eliminations is that the reactions usually proceed with a
notable lack of isomerisation\ and so nonconjugated alkenes can often be obtained if desired[
Standard ~ow pyrolysis of an acetone solution of the diacetate "32# gave the diene "33# in up to
74) yield on a 149 g scale "Equation "21## ð76JOC4923Ł[ Trahanovsky and co!workers have made
extensive application of ester pyrolysis under FVP conditions as a route to heteroaromatic analogues
of o!xylylenes "e[g[\ ð70JA5580\ 75JOC3197Ł#[ The mechanism may involve a direct d!elimination\ or a
ð2\2Ł!sigmatropic shift of the ester function prior to standard b!elimination "Scheme 06#[ These
xylylenes are stable at −59>C but form dimers at room temperature[
AcO OAc
flow
(32)
460 °C
O O O O
(43) (44)
OCOPh
FVP
dimers
O 635 °C O
Scheme 17
Facile Chugaev eliminations can take place instead of the expected reduction when appropriate
xanthate!type compounds are heated to 79Ð009>C in the presence of tributyltin hydride ð82JA1157Ł[
Allylic alcohols have been transformed into conjugated dienoic esters by a one!pot process
involving sequential ortho!ester exchange\ ð2\2Ł!sigmatropic shift and sulfoxide pyrolysis "Scheme
07# ð80JOC5870Ł[ Although mixtures of isomers may be obtained\ the method has been usefully
applied in synthesis ð89JOC2856\ 80JOC3228Ł[ In a more esoteric application\ a quadruple sulfoxide
elimination was employed to generate four alkene units in the novel cyclophane "34# "Equation "22##
ð80AG"E#0062Ł[ The use of sulfoxide and particularly selenoxide pyrolysis to give conjuàted dienes
is complicated by the possibility of a competitive ð1\2Ł!sigmatropic shift to give the isomeric sulfenate
or selenenate\ respectively "Scheme 08#\ which may be trapped to give an allylic alcohol ð63ACR036Ł[
As a result of the reversibility of the process in the case of sulfur\ the diene may also be obtained if
desired ð71JOC3790Ł\ especially if the S!aryl ring contains electron!withdrawing groups which accel!
erate the elimination ð67CL430Ł[ With selenoxides\ the equilibrium lies much further towards the
selenenate\ and dienes have only been obtained in a few special cases and in modest yield ð72JA1492Ł[
Ph + OEt H+ 100 °C
+ S
OH OEt Ph + O
O– OEt S 4–18 h
–O OEt
Ph + 45–95%
S CO2Et CO2Et
–O
Scheme 18
SOMe
MeOS
300 °C
(33)
MeOS SOMe
(45)
Ph
+
S O–
P(OMe)3
OSPh OH
Scheme 19
The Cope elimination has been employed to prepare penta!0\3!diene and allylbenzene^ both
were obtained in the absence of their conjugated isomers penta!0\2!diene and b!methylstyrene\
respectively ð46JA859Ł[ Although the overall yield is often high\ isomerisation may be a problem in
amine oxide pyrolysis ð81TL1350Ł\ and traditional Hofmann elimination can be more selective[ A
spontaneous {sila!Cope| elimination\ leading speci_cally to a "Z#\"Z#!diene\ has been reported to
take place under particularly mild conditions ð71JA6555Ł[
0[06[3[0 Retro!cycloaddition Reactions

Photochemical cleavage of cyclobutanes has been used to achieve some spectacular syntheses of
unnatural target molecules such as bullvalene "Equation "23## ð53CB2039Ł\ and*in conjunction with
matrix isolation*reactive polyenes such as pentalenes ð62AG"E#226Ł and cyclobutadienes
ð63AG"E#314Ł have been obtained[
hν
(34)
The pyrolytic cleavage of b!lactones has been employed as a convenient route to arene oxides
and related dihydroaromatic compounds ð67JA241Ł\ since the precursors can be easily obtained in
a few steps from benzoic acid[
The retro!DielsÐAlder reaction can be used to release a single alkene of a diene "or polyene# unit[
The general conditions of the reaction are described in Section 0[06[2[1\ and a typical example is
shown in Equation "24# ð75TL0334Ł[
MeO2C
FVP
+ (35)
550 °C
CO2Me MeO2C
CO2Me 100%
Clearly\ dienes can also be generated directly by utilising the other product of the retro!DielsÐ
Alder process "Equation "15#^ UVWXC#[ When the {diene| released forms part of a
benzenoid system\ the reactions may be especially facile[ Much variation in the precursor structure
is possible\ and useful syntheses have been developed in which the diene is formed by cleavage of
either two C0C bonds\ or one C0C bond together with a C0O or C0N bond\ or by cleavage of
two C0N bonds[ By way of illustration\ some typical examples of each of these classes are given
below[
The retro!DielsÐAlder cleavage of ethylene from 0\3!epoxytetrahydronaphthalenes "35# under
FVP conditions has been developed into a highly e.cient synthesis of the highly reactive iso!
benzofuran system "Equation "25## ð70MI 006!90Ł[ The parent compound\ which is a useful DielsÐ
Alder diene\ can be accumulated in quantitative yield at a rate of 4Ð09 g h−0 from a commercially
available precursor ð61CC236Ł[
FVP
O O + (36)
650 °C
(46)
Cycloadducts derived from a!pyrones "e[g[\ "36## acting as dienes often lose CO1 under the
conditions of their formation to generate diene products by cleavage of one C0C and one C0O
bond "e[g[\ Scheme 19# ð61TL3540Ł[ When the original dienophile is an alkyne\ substituted benzene
systems are obtained directly "e[g[\ ð76T4134Ł#[
O
O
O 150 °C –CO2
+
O O MeO2C O
H
CO2Me O MeO2C
(47)
Scheme 20
In a similar fashion to the examples in the preceding paragraph\ retro!DielsÐAlder cleavage of
one C0C and one C0N bond "usually as RCN#\ or two C0N bonds "usually as N1# frequently
takes place in situ following cycloaddition reactions of azines and alkynes\ leaving an alternative
heteroaromatic system as the _nal product of the reaction[ Typical examples of the many possibilities
are given in Scheme 10 ð62LA326\ 63LA0089Ł[ This area of heterodiene reactions has been com!
prehensively reviewed ð72T1758Ł[
CO2Et CO2Et
Et2N
MeCN
+ NEt2
N N 20 min N
90%
CO2Me CO2Me
CO2Me
N N 140 °C, 15 h N
+ MeO2C CO2Me
N N 53% N
CO2Me
CO2Me CO2Me
Scheme 21
0[06[3[1 Retro!cheletropic Reactions

Retro!cheletropic processes are applicable to the stereospeci_c formation of conjugated dienes
"Equation "26##[ The extruded group "X# is most often CO\ N1 or SO1[ The cleavage of SO1 from
2!sulfolenes is of particular importance in synthesis\ and this topic has been reviewed ð82PHC0Ł[
Both the thermal extrusion of sulfur dioxide from "37# ð55JA1746\ 55JA1747Ł and of nitrogen from
"38# ð55JA0224Ł have been shown to take place stereospeci_cally with disrotatory motions of the
terminal methylene groups "e[g[\ Scheme 11#[ Carbon monoxide extrusion is particularly important
when an aromatic product is formed ð56TL3834Ł[
X X + (37)
–SO2 + –
SO2 –N2 N N
155 °C
(48) (49)
Scheme 22
The formation of butadiene derivatives by pyrolysis of 2!sulfolenes takes place readily at 099Ð
049>C in solution or in a sealed tube\ at 249>C under ~ow conditions\ or at ca[ 499>C by FVP[ The
_rst conditions may be used to generate a reactive diene in situ in the presence of a dienophile\
whereas the last conditions are often more e.cient for the isolation of the diene itself[ 0!Substituted
or 0\3!disubstituted butadienes can be made by alkylation of the sulfolene at its acidic a!positions
prior to the pyrolysis\ although special conditions must be used to avoid the ring opening of the
anion to butadienyl sul_nate[ Therefore\ nonnucleophilic bases have been used so that the anion
may be generated in the presence of the alkylating agent ð75JCS"P0#0928Ł[ Alternatively\ the protection
and subsequent pyrolytic "FVP# release of the sulfolene as a formal DielsÐAlder adduct has the
signi_cant advantage that alkylation"s# take place exclusively on the exo!face and therefore lead to
a stereospeci_c diene synthesis "Equation "27## ð71TL2166Ł[ This method has been employed exten!
sively by Bloch et al[ as a route to insect sex pheromones "e[g[\ ð72TL0136\ 75T3864Ł#[ 1!Trimethyl!
silylsulfolene can be used to achieve a\a!dialkylation and hence give a potential route to
0\0!disubstituted butadienes ð76CC823Ł[
R2 FVP
+ R2 (38)
R1
600 °C
SO2
R1
Reaction of the anion derived from 2!methyl!2!sulfolene with prenyl or geranyl bromides followed
by extrusion of SO1 has been reported as a stereo! and regioselective means of introducing an
isoprene unit onto an existing skeleton ð73CC0212Ł[ Many functionalised 1!substituted butadienes
have been obtained by pyrolysis of the corresponding 2!substituted sulfolene[ For example\
1!trimethylsilylbuta!0\2!diene was generated by sealed!tube "059>C# pyrolysis of the appropriate
sulfolene\ and underwent in situ DielsÐAlder reaction with dimethyl acetylenedicarboxylate
"DMAD# ð76JOC133Ł[
In applications of sulfolene pyrolysis to alkaloid synthesis\ the butadiene released is often in place
to undergo an intramolecular DielsÐAlder reaction and hence create a new six!membered ring[ Two
examples are given in Scheme 12 ð79JOC2261\ 83TL0960Ł^ in the _rst of these\ the heteroene component
was also generated by a pyrolytic method[
O
TMS-O
O-TMS
N H 390 °C O
N
SO2 OAc
H
N
N
110 °C
O
3.5 h O H
N MeO C SO2 CO2Me
2 79%
N
H
H
(E):(Z) 4:1
Scheme 23
Pyrolysis of 1\6!dihydrothiepin!0\0!dioxides "49# leads to 0\2\4!trienes by an analogous concerted

process ð58JA4571Ł[
SO2
(50)
1.18
One or More 1CH, 1CC,
and/or C1C Bonds Formed
by Rearrangement
PATRICK J. MURPHY
University of North Wales, Bangor, UK
0[07[0 GENERAL INTRODUCTION AND METHOD OF CATEGORISATION 682
0[07[1 REARRANGEMENTS INVOLVING 0\1!SHIFTS AND 0\ j MIGRATION 683
0[07[1[0 Where YH 683
0[07[1[0[0 ð0\ jŁ Mi`rations of hydroèn 683
0[07[1[1 Where YC 688
0[07[1[1[0 ð0\ jŁ Rearranèments involvin` C mi`ration 688
0[07[1[2 Where YC0C 795
0[07[1[3 Where YC0C0C 795
0[07[1[3[0 Cope rearranèment 795
0[07[1[4 Where YC0Z "ZHeteroatom# 705
0[07[1[4[0 Where Zchalcoèn 705
0[07[1[4[1 Where Znitroèn 712
0[07[1[4[2 Miscellaneous rearranèments 714
0[07[1[5 Where YC0C0Z 714
0[07[1[5[0 Where Zchalcoèn 714
0[07[1[5[1 Where ZN^ the aza!Claisen rearranèment and related processes 724
0[07[1[6 Other Heteroatom Variants 725
0[07[1[7 Where YZ0C0Z? 725
0[07[1[7[0 Where Z and Z?chalcoèn 725
0[07[1[7[1 Where Z and:or Z?nitroèn 725
0[07[1[8 Where YZ 726
0[07[1[09 Where YZ0Z? 727
0[07[1[09[0 Where Z\ Z?chalcoèn 727
0[07[1[09[1 Where Z and:or Z?nitroèn 728
0[07[1[00 Where YZ0Z0Z 739
0[07[2 OTHER REARRANGEMENTS 739
0[07[2[0 Tandem and Hi`her Si`matropic Rearranèments 739
0[07[2[1 Rearranèments That Involve Rin` Openin` 730
0[07[2[1[0 Rin` openin` of cyclopropanes 730
0[07[2[1[1 Photochemical rin` openin` of cyclic ketones 730
0[07[2[1[2 Rearranèments of epoxides 731
0[07[0 GENERAL INTRODUCTION AND METHOD OF CATEGORISATION

Rearrangement reactions lie at the heart of modern synthetic organic chemistry\ and in their
highest form they can e}ect complex but predictable manipulations of carbon frameworks and
associated functionality[ This chapter is complementary to other discussions in this work and the
682
683 1CH\ 1C0C or C1C Bonds by Rearranèment
reader is speci_cally referred to Chapters 0[98\ 0[06 and 0[19 "Sections 0[19[0[2 and 0[19[2[1[#
for other information[ Allylic rearrangement during substitution\ aromatic rearrangements\ and
reductive transposition\ will not be dealt with in this chapter[ Two works edited by Mayo ðB!52MI
007!90\ B!79MI 007!90Ł and the chapter on rearrangements in the excellent annual series Orànic
Reaction Mechanisms currently edited by Knipe and Watts ðB!55MI 007!90Ł provide useful back!
ground information[
The order of discussion is based upon the generalised transformation found in Equation "0#
involving the formation of product "1# from a precursor "0#^ the organisational principles apply to
the function Y[
(1)
X Y
(1) (2)
For example\ the _rst section deals with rearrangements involving ð0\jŁ!processes "jodd numeral^
these are not necessarily sigmatropic in their nature# and the case where YH hydrogen is
discussed _rst\ followed sequentially by Ycarbon!containing and _nally with hetero! or chalcogen!
containing substituents[ Several other comments are also necessary at this point[ First\ hetero!
substituted alkenes "enol ethers\ enamines etc[# will not be covered in this section\ and recourse
should be made to the relevant chapters[ Stereochemical and mechanistic considerations will be
included as\ and where\ necessary[
0[07[1 REARRANGEMENTS INVOLVING 0\1!SHIFTS AND 0\ j MIGRATION

This section forms the bulk of the chapter and deals with rearrangements involving a 0\1!shift of
a double bond\ together with the concomitant migration of the group X to give the new function Y
"in many cases XY# "Equation "0##[ These reactions are discussed in the following order] sig!
matropic "the molecular orbital considerations for these processes are covered in general texts
ðB!69MI 007!90\ B!65MI 007!90Ł#\ acid!catalysed\ base!catalysed\ and metal!catalysed[
0[07[1[0 Where YH
0[07[1[0[0 ð0\jŁ Migrations of hydrogen

"i# Si`matropic mi`rations of hydroèn
Many examples of thermal or photochemical rearrangements have been reported in which a
hydrogen migrates along a p!system^ these have been reviewed on several occasions ðB!69MI 007!90\
60ACR161\ 60AG"E#650\ 60MI 007!90\ 65CRV076\ 70RCR555Ł[ The most commonly encountered rearrange!
ments of this type are ð0\2Ł "photochemical and suprafacial#\ ð0\4Ł "thermal and suprafacial# and
ð0\6Ł "thermal and antarafacial or photochemical and suprafacial# hydrogen shifts "Scheme 0#[ The
ð0\2Ł process is the least common\ though the photochemical transformations in Scheme 1 show
typical examples ð52HCA567\ 53PAC428\ 54TL2844\ 65JA739Ł[
[1, 3] [1, 5]
[1, 7]
Scheme 1
In contrast\ ð0\4Ł hydrogen shifts are quite common "for excellent reviews of early work\ see
ð58CRV092\ 65CRV076Ł# and are thermal in nature "Scheme 2# ð52RTC630\ 53TL0998\ 54T1218\ 58CJC0444\
69CB315\ 62T2670\ 65CRV076\ 71T456\ 73MI 007!90Ł[ Some photochemical antarafacial ð0\4Ł hydrogen shifts
are also known ð58TL882\ 69JA6397Ł[
The ð0\6Ł hydrogen shift has been studied extensively and is known to proceed antarafacially
0\1!shifts 684
hν hν
( )n ( )n
83% n = 0, 83%
n = 1, 85%
OH OH
H hν H
H 21% H
H H
O O
Scheme 2
H
480 °C 298 °C
Ph Ph
393 °C
Scheme 3
under thermal conditions ð53RTC0062\ 69HCA062\ 61BSF3127\ 61HCA0274\ 61HCA0717\ 65CRV076Ł\ and
suprafacially under photochemical conditions ð58RTC155\ 69BCJ0019Ł[ This rearrangement has
attracted considerable interest\ owing to the presence of a conjugated triene in vitamin D2 "chole!
calciferol# "2# which can undergo a reversible ð0\6Ł!hydrogen shift to a minor previtamin form "3#
"Scheme 3# ð53RTC0062\ 72ACR70\ 76TL5910Ł[ Some interesting work reported in 0880 has involved the
thermolysis of "6Z#!analogues of vitamin D ð80JA0244\ 80JOC2461Ł[
Several similar processes exist\ in particular the ð0\4Ł hydrogen shift found in vinyl cyclopropanes
"Scheme 4#\ which is competitive with the rearrangement of vinyl cyclopropanes to cyclopentenes
"see Section 0[07[1[1[0"ii##[ The ð0\4Ł shift generally occurs at lower temperatures than cyclopentene
formation and signi_es the lowest energy pathway for rearrangement ð58CRV092\ 61MI 007!90\
65RCR358Ł^ the reaction is thought to proceed via a chair!like transition state with an activation
energy of 29Ð24 kcal mol−0 ð61MI 007!90\ 65RCR358\ 74OR"22#136Ł^ most of the reactions are stereo!
speci_c yielding only the cis!alkene[ The process has also been shown to be reversible ð54CB645\
54LA"577#17\ 79TL1376Ł[ The reaction has many examples of theoretical and synthetic interest "Scheme
5# ð53JCS4467\ 54LA"577#17\ 56JA0393\ 57CC24\ 61TL014\ 62RTC594Ł and has been used in the total synthesis
of sarkomycin "4# "Scheme 6# ð79TL1376\ 72JOC2470Ł[ 1!Vinyl cycloalkanols are also known to undergo
a thermal ð0\4Ł hydrogen shift ð59JA3807Ł[
"ii# Acid! and base!catalysed mi`rations of a hydroèn atom

Rearrangement of double bonds is possible under both proton and Lewis acid catalysis[ The
reaction is not generally useful as carbocations are involved as intermediates and these give rise to
many side products[ Also\ where several double bond isomers are possible\ mixtures are obtained\
generally favouring the thermodynamic product ð69S394Ł[ Examples are known of mineral acid
ð25CB771\ 52JCS3980Ł\ alumina ð44JA4055\ 54JA3096Ł\ p!toluene sulfonic acid ð51BSF0214Ł\ oxalic acid
ð42JA4310Ł and Lewis acid!catalysed isomerisations ð56CC286Ł[ The reaction generally proceeds well
when conjugation is present in the product ð42JA4310\ 54JA2117Ł[
The base!mediated or !catalysed migration of double bonds is a well!documented procedure
which has been reviewed on several occasions ðB!53MI 007!90\ B!54MI 007!90\ 57ACR120\ 58S86\ B!69MI
007!91\ 69S394\ B!66MI 007!90Ł[ Excellent results can be obtained when amide bases ð76OS"54#113Ł or
alkali metals absorbed on to alumina are used "Scheme 7# ð74AG"E#219Ł^ potassium t!butoxide has
Ph Ph
363 °C 331 °C
OH
Ph Ph
OH
H H
HO HO
(3) (4)
Ph Ph Ph
hν hν
Scheme 4
Scheme 5
300 °C
O
150 °C
89%
O
CO2Me
280 °C CO2Me
(E):(Z) 82.5:17.5
CHO CHO
120 °C
Scheme 6
0\1!shifts 686
O O O
<400 °C steps
>450 °C
CO2H
H H
H H
(5)
Scheme 7
also been used to good e}ect ð57JOC110\ 79JOC899Ł[ The process normally leads to equilibrium
mixtures favouring the thermodynamic product[ The mechanism of the reaction\ often referred to
as prototropic rearrangement\ is an example of electrophilic substitution with allylic rearrangement
of an intermediate carbanion[ It has been demonstrated to be partially intramolecular in some
instances\ in which case the base {leads| the proton from one site to another ð53JA4355\ 58JA3348Ł[
K+ –NH(CH2)3NH2
93%
K/Al2O3/20 °C
H H
10 : 90
H H
Scheme 8
Rearrangement is possible under relatively mild conditions when conjugation is possible in the
product[ Many examples are known using nitrogen bases and potassium t!butoxide and the criteria
for the position of the equilibrium "shown in Scheme 8# has been studied extensively ð71JOC3647\
71JOC3655\ 72JOC473Ł^ two examples are also shown in Scheme 8 ð75S810\ 82HCA307Ł[ The isomerisation
of b\g!enones to a\b!enones under acidic\ basic and enzymatic conditions has been extensively
studied ðB!78MI 007!90\ 89CR0192Ł[ In the majority of cases the equilibrium lies on the side of the
conjugated product but steric factors can\ in some cases\ reverse this trend[ In small ring "_ve! or
six!membered# enones the conjugated product also prevails "×88 ] 0# but\ in medium rings\ a cross!
over is observed eventually favouring the unconjugated product "i[e[ seven!membered\ 62 ] 16^ eight!
membered\ 19 ] 79^ nine!membered\ ³9[2 ] ×88[6# "Scheme 09#^ this is probably due to unfavourable
transannular interactions in the conjugated product ð55JCS"B#053\ 65JA6208Ł[ It is also possible to
e}ect the reverse reaction\ i[e[ an overall rearrangement of conjugated esters via a two!step
procedure\ involving lithium amide base generation of an enolate which is then protonated to
give the kinetic\ deconjugated product^ excellent stereocontrol is generally observed "Scheme 00#
ð70HCA0912\ 71JOC052\ 73CL0430Ł[
A ð0\2Ł hydrogen shift is also invoked in the SommeletÐHauser rearrangement "see Section
0[07[1[4[1"ii##^ iodine!catalysed alkene isomerisation is also known ð76JOC1475Ł[
"iii# Metal!catalysed mi`rations of hydroèn

Double!bond migrations are also possible under metal catalysis^ common techniques utilise
supported metals "on alumina\ silica or carbon#\ metal salts\ metal complexes and also ZieglerÐ
Natta conditions[ The most commonly used metals are palladium and rhodium ð57ACR075Ł\
although examples are known of platinum\ nickel and iridium!based catalysis ð55MI 007!91\ 56MI 007!90\
69S394\ B!63MI 007!90Ł^ typical examples are shown in Scheme 01 ð57TL2686\ 72S841\ 74JA6241\ 76TL4362\
83T2028Ł[ The reaction proceeds either via a metal hydride additionÐelimination process or a p!allyl
complex ð62JA1137Ł[ Metal carbonyls are also known to e}ect alkene isomerisations ð62JA1137\
78BSF688Ł[
base
X Y X Y
X = Ph, Me, CN, CO2Et

Y = H, aryl, alkyl, CN, OPh, Cl
NEt3 (0.5 equiv.), PhH, 60 °C, 6 h
O O 80% O O
N
, RT, CH2Cl2
O O N N O O
H
CO2Et 97% CO2Et
Scheme 9
O O
O O
99 : 1 20 : 80
Scheme 10
i, LDA, HMPA, THF

CO2Et ii, H+, H2O
98% CO2Et
i, LDA, HMPA, THF

ii, H+, H2O
CO2Et 98% CO2Et

Scheme 11
OMe OMe
ClRh(PPh3)3 (0.01 equiv.)
CHCl3, reflux, 1 h
80%
H H RhCl3, EtOH, reflux H H

N N
H H
OH OH PdCl2(PhCN)2 OH OH
PhH, reflux, 1 h
90%
O O
Scheme 12
0\1!shifts 688
"iv# Anion accelerated mi`rations of hydroèn atoms
Paquette demonstrated that oxyanion substituents facilitate rapid ð0\4Ł sigmatropic shifts\ with
rate increases of ×094^ for example the rearrangement of 1\3!cycloctadienol to 2!cycloctenone
proceeds rapidly at room temperature on addition of potassium hydride "Equation "1## ð79JA2861Ł[
OH O
KH, THF, RT
(2)
0[07[1[1 Where YC
0[07[1[1[0 ð0\jŁ Rearrangements involving C migration

"i# Si`matropic mi`rations of carbon centres
Sigmatropic rearrangements involving the migration of alkyl or aryl groups are well known
despite evidence which suggests a lower migratory aptitude for alkyl and aryl groups when compared
with the corresponding hydrogen migrations ð58JA0467\ 60JA549Ł[ The sigmatropic parameters for
these reactions are known to be that the thermal suprafacial ð0\2Ł rearrangement occurs with
inversion of con_guration at the migrating carbon atom\ while the thermal suprafacial ð0\4Ł shift
occurs with retention of con_guration^ photochemical suprafacial ð0\2Ł shifts occur with retention
of con_guration[ Various articles have been published on this matter ð58TL1596\ 69CC0057\ 60CC096\
60CC097\ 61ACR395\ 65CRV076Ł and many exceptions to these observations are known ð56JA4492\
57ACR041\ 61ACR395\ 64JA2726\ 79JA1358\ 79JA3730Ł[
Much work has been performed on ð0\2Ł!rearrangements involving the migration of a carbon
centre[ The thermal rearrangement of substituted bicycloð2[1[9Łhept!1!enes "5# and bicyclo ð1[0[0Łhex!
1!enes "6# are known to proceed with inversion of con_guration ð56JA4492\ 58CC0958\ 58JA3211\ 58TL1596\
69JA0985\ 69JCS"B#0309\ 61CC605Ł^ studies on the rearrangement of "7# to "8# have shown the reaction
to proceed with retention[ The aza!anion "7# Li undergoes an accelerated rearrangement\ the reaction
being complete in one minute at 29>C ð64JA2726Ł[ An interesting tandem ð0\2Ł!ð2\2Ł!rearrangement
has been reported for the 6!vinylbicyclohept!1!ene "09#\ which leads to the formation of the tetra!
hydroindene "00# "Scheme 02# ð75TL3096Ł[ Photochemical examples of this rearrangement are also
known "Scheme 03# ð54TL2844\ 89CJC0850\ 81JA4767Ł[
290 °C
AcO
OAc
(6)
Z
Z
∆
H H
(7) Z = Me, Ac, MeO, N3, MeOCH2CO2
∆
NR
NR
(8) R = H, Me, CO2Ph, CO2Me, Li (9)
168 °C [3,3]
(10) (11)
Scheme 13
Ar Ar
hν
85%
O O
hν CF3
CF3
Scheme 14
Anion!accelerated examples of thermal ð0\2Ł!rearrangements are known\ including reactions of

lithium\ sodium\ magnesium and zinc alkoxides ð55LA"587#79\ 58JA4051\ 63BSF0813\ 66TL1448\ 67JA1023\
71JOC3675Ł\ with the best examples generally being rearrangements of potassium alkoxides "Scheme
04# ð68TL1668Ł[
BunLi/THF
reflux, 2.5 h
HO HO
98%
OH OH
KH, HMPA
75 °C, 16 h
Ph Ph
Scheme 15
A formal ð0\2Ł!shift is also observed in the oxa!di!p!methane and aza!di!p!methane rearrangement

ðB!72MI 007!90Ł[ For example\ irradiation of the oxime acetate of 1\1!dimethyl!2!phenylbut!2!enal
"01# has been shown to a}ord the oxime acetate of 3!methyl!2!phenylpent!2!enal "02#\ presumably
via a free radical pathway "Equation "2## ð89CC823Ł[ Many examples of the related photochemical
0\2!acyl migration are also known ðB!79MI 007!90Ł[
Ph Ph
hν
(3)
N N
OAc OAc
(12) (13)
There are also many examples known of thermal ð0\4Ł!migration of alkyl and aryl substituents
particularly in cyclic systems "Scheme 05# ð57RTC187\ 69TL1644\ 61JOC1590\ 62JOC376\ 63JA0851\
65CRV076Ł[ These reactions again require extreme conditions\ which limit their synthetic application[
Anion!accelerated versions of this reaction which illustrate migration of alkyl\ vinyl and cyclopropyl
groups have been reported "Equation "3## ð73CC889Ł[
HO O
KH/HMPA
Ph Ph 20 °C, 30 min Ph
Ph (4)
76%
Ph Ph Ph Ph
Several ð0\6Ł migrations of carbon substituents are known\ the thermal processes occurring with
inversion ð61AG"E#721Ł and the photochemical processes with retention of con_guration ð89JOC0495Ł^
the subject has been reviewed ðB!70MI 007!90Ł[
0\1!shifts 790
625–660 °C
+
550–718 °C
∆
Ph
Ph
Ph Ph
Scheme 16
"ii# Rearranèment of vinylcyclopropanes

The conversion of vinylcyclopropanes to cyclopentenes is a frequently encountered rearrangement
"see also Section 0[07[1[0[0"i##\ and can be considered as a formal ð0\2Ł!migration of a carbon
centre "Equation "4## ð50JCS2436\ 51JPC0560\ 71TL125Ł[ The reaction is conducted under thermal\
photochemical and metal!catalysed conditions and the topic has been reviewed on several occasions
ð74OR"22#136\ B!76MI 007!90\ 77CSR118\ 77TCC62\ 80COC"4#788\ 82SL764Ł[
(5)
"a# Thermal rearranèment of vinylcyclopropanes[ Two mechanisms have been invoked to explain
the selectivity found in the thermal reaction\ which was _rst reported by Neureiter ð48JOC1933Ł\ either
a concerted ð1ps ¦1ssŁ reaction or via diradical intermediates ð61MI 007!90\ 65RCR358\ 74OR"22#136\
B!76MI 007!91\ 78CRV054Ł[ The majority of this experimental evidence suggests a diradical cleavage of
the cyclopropane with subsequent reclosure of the allylic diradical[ Despite the nature of this
mechanism\ the reaction is known to proceed with a high degree of stereochemical integrity^ for
example\ the optically pure cyclopropane "03# rearranges to give the expected product ""−#04#\ as
well as ""¦#04#\ ""−#05# and ""¦#05#^ these additional products suggest a biradical mechanism\
with intermediates that cannot freely rotate "Equation "5## ð65JA5694\ B!76MI 007!92Ł[
+ + + (6)
(14) ((–) 15) ((+) 15) ((–) 16) ((+) 16)

65% 8% 22% 5%
The reaction has been investigated thoroughly from a synthetic standpoint\ and some general
conclusions can be drawn[ In general\ increased carbon substitution\ extended conjugation or
heterosubstitution all lower the activation barrier for rearrangement to the cyclopentene\ thus the
transformation of vinylcyclopropanes "06#Ð"10# into the corresponding cyclopentenes all occur more
freely than for the parent system "Scheme 06# ð53JCS848\ 53JCS4467\ 61JA1433\ 61MI 007!90\ 62TL1434\
65TL464\ 70JOC495Ł[ Other facile transformations are the interesting tandem rearrangement of 0\0!
bis"cyclopropylethene# "11# and the rearrangement of methylene cyclopropane "12# "Scheme 07#
ð55JCS"A#0231\ 61JA7823\ 62JA7985\ 71CB1497\ 71JA1387Ł[
Reports from the 0879s and 0889s have highlighted the potential for this rearrangement\ and have
also shown the possibility for catalysis of the reaction "Scheme 08#[ Davies has reported the facile
thermal rearrangement of the {pushÐpull| vinylcyclopropanes "13# and "14#^ an even better method
employed a diethylaluminum chloride!catalysed rearrangement\ which proceeded at −67>C with
excellent stereocontrol and in high yield ð81TL342Ł[ A similar rearrangement was reported byCorey in
his synthesis of antheridiogen!An ð74JA4463\ 75CL510Ł[ The thermal rearrangement of spirovinylcyclo!
propanes "15# has also been reported ð81TL0534Ł[ The transformation can also be mediated in other
ways^ for example by free radical ð77TL0432Ł and Li:DMF ð80TL3480Ł promoted rearrangements[
(17) (18)
X
X
(19) X = OMe, NMe2
(20) (21)
Scheme 17
(22)
(23)
F F F F F F
+
96 : 4
S S S S
Scheme 18
"b# Photochemical rearranèment of vinylcyclopropanes[ The photochemical rearrangement of

vinylcyclopropanes under direct and sensitised conditions has also proved synthetically useful\ and
has been reviewed ð74OR"22#136\ B!76MI 007!93\ 77CSR118\ 78CRV054\ 82SL764Ł[ Several intermediates
have been proposed for the reaction including diradicals\ zwitterions and carbenes ð54JA4153Ł[ Some
representative examples are given in Scheme 19[ Notable examples include the formation of the
novel tricyclic carbon skeletons "16# and "17# via this rearrangement\ the reaction being subject to
a remarkable substituent e}ect ð73TL0144Ł[ A similar thermal rearrangement has also been reported
in the synthesis of the structurally complex sesquiterpene longifolene ð74JOC804Ł[ The conversion
of vinylcyclopropanes "18# into the bicycloð2[1[9Łheptene "29# "a precursor for "−#!D8"01#!capnellene
"20## has also been reported ð80T7148\ 80TL0096Ł[ A similar transformation has also been observed for
vinylcyclopropenes which rearrange to give substituted cyclopentadienes "Equation "6## ð66JA1231\
66JA1233\ 67JOC0382Ł[
Ph Ph
hν
(7)
87%
Ph Ph Ph Ph
0\1!shifts 792
CO2Et
Et2AlCl, CH2Cl2, –78 °C
CO2Et
EtO 93%
EtO
(24)
H CO2Me
CO2Me H
Et2AlCl, CH2Cl2, –78 °C
60%
O H O
(25) H
H H
500 °C
88%
H H
(26)
Scheme 19
X X
O O
hν hν
X = CH2, O H H
O
O
But
R = But R = Me
O
R
(27) (28)
H
OH OH
hν
H H H
(29) (30) (31)
Scheme 20
"c# Metal!catalysed rearranèment of vinylcyclopropanes[ The transition metal!catalysed

rearrangement of vinyl cyclopropanes is of much importance\ as the reaction generally occurs
under mild conditions ð67ACR193\ 77CSR118Ł[ The reaction is catalysed by several transition metal
complexes\ the most common being those of rhodium"I# ð60CC0137\ 65CC78\ 68JCS"P1#851\ 79JOC4919Ł\
nickel"9# ð68CL816Ł\ nickel"II# ð52T604Ł and palladium"9# ð71TL1160\ 73MI 007!91Ł[ One prerequisite
for the reaction is the presence of an additional site of coordination for the metal since\ if this is
not available\ then b!hydride elimination is the predominant reaction pathway ð65CC78\ 68CL816\
68JCS"P1#851Ł^ representative examples of this reaction are shown in Scheme 10[
"d# Charè!accelerated rearranèment of vinylcyclopropanes[ As with many rearrangement pro!
cesses ð80COC"4#888\ 82OR"32#82Ł the introduction of a charged substituent into a vinylcyclopropane
leads to an acceleration of the reaction with the e}ect that the transformations are generally easily
performed under very mild conditions[ Examples are known of oxyanion "21# ð79JOC0239\ 70JA1332Ł
and carbanion "22# and "23# ð74JA3468Ł acceleration and the Lewis acid!catalysed examples "Scheme
08# are essentially carbocation accelerated ð74JA4463\ 75CL510Ł[ Dinnocenzo and Conlon ð77JA1213Ł
O O
H
(C2H4)2Rh(acac)
H
H
Ni(COD)2
P(Bun)3, 70 °C
99%
[Pd(PPh3)4]
50 °C CO2Me CO2Me
+
CO2Me 85% CO2Me CO2Me
CO2Me
3:1
Scheme 21
have demonstrated a catalytic\ one electron oxidation of vinyl cyclopropanes "24# which e}ects a
rapidly accelerated rearrangement "Scheme 11#[
BunLi, 25 °C, 1 h
Ph Ph OH
O OLi
Cl 90% Ph
(32)
BunLi, THF/HMPA
SO2Ph
–78 °C to 25 °C
SO2Ph
97%
(33)
H BunLi, THF/HMPA
SO2Ph SO2Ph
–78 °C to 25 °C
87%
H
(34)
MeO
(p-BrC6H4)3N+ SbF6– (cat.)
MeCN, RT, 5 min
MeO
86%
(35)
Scheme 22
"e# Natural product synthesis usin` the rearranèment of vinylcyclopropanes[ Much work has been
done on the synthesis of natural products using the vinylcyclopropane to cyclopentene rearrange!
ment[ Notable work is by Hudlicky on hirsutene ð79JA5240\ 79JOC4919Ł\ isocumene ð73TL1336Ł\
pentalene and related structures ð72JOC3342\ 76JOC3530Ł[ The thermal rearrangement of cyclopropane
"25#\ for example\ leads to a 55 ] 23 mixture of cyclopentene "26# and diene "27#\ the former being
further converted to pentalene "28#[ Corey has reported the Lewis acid!catalysed conversion of
cyclopropane "39# to the fused cyclopentene "30#\ in his synthesis of the plant hormone anther!
idiogen!An "Scheme 12# ð74JA4463Ł[ Related work worthy of note is by Piers and co!workers en
route to zizaene ð68CC0027Ł and hinesol ð72CJC2116Ł[
0\1!shifts 794
H H H
OMe OMe OMe
585 °C
+
EtO2C H
H
CO2Et
CO2Et
(36) (37) 66% (38) 34%
(39)
Et2AlCl, CH2Cl2, 0 °C H
TBS-O H TBS-O
80%
H H H
O O O O
(40) (41)
Scheme 23
"iii# Rearranèment of vinylcyclobutanes

Since its discovery ð59JA0996Ł\ the vinylcyclobutane to cyclohexene rearrangement has been the
subject of a considerable number of mechanistic studies ð55MI 007!92\ 56JA4492\ 57ACR041\ 61ACR395\
61JA7806\ B!70MI 007!91Ł[ Despite this large quantity of work\ the thermal rearrangement has found
limited applications in synthesis\ as high temperatures are generally required to e}ect the trans!
formation\ and the reaction is further limited by competitive decomposition ð52MI 007!91Ł[ Some of
the more successful examples are given in Scheme 13 ð66TL0668\ 79JCR0440Ł[
330 °C
O
O
300 °C
55%
O O O
Scheme 24
The most signi_cant contributions in vinylcyclobutane rearrangement are the anion!accelerated

cases ð67CC368Ł[ The basic reaction is the rearrangement of a 1!vinylcyclobutanol to a 2!
hydroxycyclohexene\ as exempli_ed in the rearrangement of exo!bicycloð2[1[9Łheptane "31# to a 7 ] 0
mixture of exo and endo!norbornenol "32# when treated with potassium hydride "Equation "7##
ð67CC368Ł[ Many examples are known in which lithium ð70T2832Ł and sodium ð72TL1820Ł alkoxides
have also been used[ The reaction has also been applied to the synthesis of several fused carbocyclic
systems ð79JA5899\ 70T2832\ 72JA419\ 72JA5687\ 73JA1629\ 77JOC0737Ł[ Representative examples of these
reactions are given in Scheme 14 including the formation of "33# which was subsequently converted
into "−#b!selinene "34#[ The topic has been the subject of a short review ð82OR"32#82Ł[
H
KH, THF OH
+ (8)
3 h, 25 °C
OH OH
H
(42) exo-(43) 8:1 endo-(43)
OH
H
KH, THF, HMPA
OH 25 °C
73%
OH
KH, THF, reflux
H
60%
OH
H H
OH
H H
HO KH, THF, reflux steps
(44) (45)
Scheme 25
0[07[1[2 Where YC0C

Baldwin has reported an anionic ð1\2Ł!rearrangement of an all!carbon system\ which\ depending
on reaction temperature\ is thought to proceed via either a sigmatropic or a dissociative mechanism\
or a combination of both ð69CC054Ł[
0[07[1[3 Where YC0C0C
0[07[1[3[0 Cope rearrangement

The Cope rearrangement in its generalised form\ can be considered as the interconversion of two
0\4!dienes "Equation "8##[ The conditions for this conversion are numerous and include thermal\
photochemical\ metal!catalysed\ acid!catalysed and charge!accelerated examples[ The reaction has
also been reviewed ð52AG"E#004\ 64OR"11#0\ 79T2\ 73CRV194\ B!73MI 007!92\ 89AG"E#598\ 89SL56\ 80COC"4#674\
81OR"30#0Ł[ The reaction proceeds via a six!membered cyclic transition state\ with a preference for a
chair conformation ð66JA0388\ 79JA2045Ł\ structural features permitting ð63JA2694\ 74JA4628\ 77CC243Ł[
This\ in combination with a marked preference for sp2 carbon centres to occupy equatorial\ rather
than axial\ positions in the transition state\ leads to the formation of products with "E# double bond
geometry[ This also has the e}ect that transfer of chirality from a stereogenic centre in the substrate
to a new centre in the product is possible with excellent levels of integrity\ generally greater than
86) ð56CC508\ 79JOC0061\ 71JA6114Ł[
(9)
"i# Thermal Cope rearranèment

The thermal Cope rearrangement ð39JA330Ł can be considered as the parent member of a large
family of related 2\2!sigmatropic rearrangements[ The thermal reaction has been used in synthesis
0\1!shifts 796
on many occasions and selected examples serve to illustrate this point and to highlight the reaction|s
drawbacks[ The reaction is reversible\ but several factors can be applied and shift the position of
the equilibrium in a predictable manner[ In general terms\ and in the absence of any other con!
tributing factors\ the equilibrium will tend to favour the formation of the most highly substituted
alkenes "Scheme 15#^ this is exempli_ed by the equilibrium mixture obtained on heating "35# and
"36# ð57MI 007!90Ł[ Numerous further examples are known ð66JA0388\ 79JA1281\ 77CC243Ł including a
report ð81JA1524Ł which demonstrates that DL!"37# and meso!"37# require di}erent conditions to
e}ect Cope rearrangement and illustrates the marked preference for a chair conformation "which
DL!"37# is forced to adopt# over a boat conformation "which meso!"37# is forced to adopt# in the
transition state of the reaction[
210 °C to 260 °C 160 °C
1 : 5.6 99%
(46) (47)
H H H H
40–70 °C 240–280 °C
DL-(48) meso-(48)
Scheme 26
An important driving force for the rearrangement is if one or both of the double bonds enters
into conjugation[ Examples are known in which this conjugation is provided by ester ð30JA0732\
68JA0500Ł\ ketone ð59TL18\ 50T02\ 51TL494\ 52MI 007!92\ 70TL0472Ł\ nitrile ð79TL1014\ 70TL0068\ 73JA607Ł
and aryl ð56CC508Ł functions "Scheme 16#[ In certain cases the preference for polyalkyl substitution
takes precedence over the stabilisation that is possible through conjugation "Equation "09##
ð68JA0500\ 75TL4812Ł[ The rearrangement is highly favoured when one of the double bonds of the
product is incorporated into an aromatic ring\ and examples include the formation of indoles and
pyrazoles "Equation "00## ð58CC88Ł[
275 °C
5 : 95
CO2Me CO2Me
O O
Ph Ph
O-TMS
CN
O-TMS 210 °C
CN
Scheme 27
SO2R SO2R
135 °C, 47 h
(10)
81% SO2R
SO2R
110 °C
(11)
N N
Me Me
The Cope product may also be able to tautomerise to form an aromatic ring and thus move the
position of equilibrium to the aromatic product[ Many examples are known of this phenomenon
and these include the well!known para!Claisen rearrangement of aryl allyl ethers "see Section
0[07[1[5[0["i#[b#[ For example\ 4!allyl!1\3!cyclohexadieneone "38#\ rapidly rearranges at relatively
low temperature to give the phenol "49# via its keto tautomer "Scheme 17# ð64ACR134Ł[ With the
similarities between the Cope and Claisen reactions\ one might envisage a Cope analogue of the
aromatic Claisen rearrangement^ however\ the reaction is not possible using simple homoallyl
benzene derivatives\ even in the presence of conjugating substituents ð23JA336\ 55BSF170\ 66MI 007!91\
68JA0682\ 79JOC3682Ł[ Some of the rare examples of this reaction are shown in Scheme 18 ð45JA1436\
45JA1440\ 79CB2568\ 75JOC072Ł and include the rearrangement of the aryl vinyl cyclopropane "40# to
give the annulated product "41#\ in which the cyclopropane assists in lowering the activation energy
required for disruption of aromaticity ð67JA766Ł[ Other factors that a}ect the position of equilibrium
in the Cope rearrangement are ring strain "see Section 0[07[1[3[0[v# and some conformational e}ects
ð48T08\ 79JA1686Ł[
O O OH
(49) (50)
Scheme 28
EtS–/DMF/∆
45%
OMe O– OH
(51) (52)
250 °C to 260 °C
CO2Et
S CO2Et 49%
EtO2C S
CO2Et
Scheme 29
Alkynes and allenes participate in the Cope rearrangement[ Cope rearrangement of 0\4!enynes
provides a useful route to allenes ð54JCS5673\ 55JA4735\ 57JOC3302Ł and the oxy!Cope variant leads
to the formation of a\b!unsaturated ketones ð67CC540Ł[ Allenes also participate readily in Cope
rearrangements\ leading to the formation of conjugated dienes ð67TL0792\ 77JOC085Ł\ and examples
are known where the allene and isolated double bond are both incorporated into a large ring
ð54JA3490\ 54JA3495\ 54TL0248Ł[ Bisallenes participate in Cope rearrangements ð54JA3490\ 54JA3495\
54TL0248Ł[ Some examples are illustrated in Scheme 29[
"ii# Catalysis of the Cope rearranèment

The Cope rearrangement is often accelerated by the presence of a catalyst\ particularly acids and
metals[ For example\ the thermal rearrangement of ketone "42# takes several hours at 79>C\ whereas
0\1!shifts 798
O
160 °C • OH
HO
DIGLYME, ∆
•
70%
COMe
OH
Scheme 30
under acid catalysis the reaction produces good yields in 04 minutes "Equation "01## ð70TL0472Ł[
This acid catalysis is largely restricted to 0\4!dienes that contain carbonyl substituents^ other
examples are known involving catalysis by mineral acids ð54JA4004\ 60HCA826\ 62HCA64\ 64ACR134\
70TL0472Ł\ Lewis acids ð59TL18\ 50T02Ł\ alumina ð65JOC1937Ł and weak acids such as ammonium
salts and iodine ð79TL0236Ł[
O O
CF3CO2H (1 equiv.)
15 min, CH2Cl2
(12)
74%
(53)
Several metal complexes are known to act as catalysts for the Cope rearrangement[ Palladium
dichloride was originally found to e}ect the rearrangement when a stoichiometric amount was used
ð55JOM"5#301\ 56AG"E#799\ 62JOM"38#372Ł^ however\ subsequent investigation has shown that catalytic
quantities of palladium"II# complexes can be used in a wide range of rearrangements "Scheme
20# ð71JA6114\ 72TL2646\ 73AG"E#468Ł[ Other metals are also known to accelerate the rate of Cope
rearrangement\ for example Rh1"CO#3Cl1 ð62JCS"P0#0802Ł and also silver and mercury salts ð73T2166\
75T0222Ł[ A few examples of photochemically initiated Cope rearrangements are also known\
although the factors a}ecting the rearrangement are not thoroughly understood ð54TL2844\ 56TL116\
58JA411\ 74JOC2282Ł[
Z PdCl2(MeCN)2 (0.1–0.3 equiv.) Z

CH2Cl2, 40 °C
Z = CO2Et, CO2H,
COMe, CN, 64–94%
(E):(Z) ca. 7:3
PdCl2(MeCN)2 (0.09 equiv.)

Ph Ph + Ph
86%, >90% ee
7:3
Scheme 31
"iii# Oxy!Cope rearranèment

The most important development in the synthetic applications of the Cope rearrangement was
the discovery of the oxy!Cope variant ð53JA4908Ł[ In this type of reaction\ a C!2 hydroxy!0\4!diene
undergoes Cope rearrangement to give an intermediate enol\ which on tautomerism leads to a d\o!
unsaturated carbonyl compound "Scheme 21#[ This reaction has several advantages over the normal
Cope reaction\ in that the precursors to the reaction are easily prepared via a Grignard!type protocol
and the product contains two easily distinguishable and useful functional groups[ Another very
important consideration is that\ by generating an enol which will rapidly tautomerise to a carbonyl
compound\ the reaction removes the product from the equilibrium and this drives the rearrangement
to completion "for a reversible case see ð80TL208Ł#[ This allows the formation of the ther!
modynamically unfavoured product in many cases and this protocol has been used on many
occasions[ "This factor is also evident in the anionic oxy!Cope reaction^ see next section[# One major
drawback of the reaction is the possibility of a competing thermal retro!ene reaction ð69JOC745Ł[
This problem is often circumvented by the use of ether ð57JA3618Ł or ester ð57FRP0408690Ł derivatives[
Some examples of this reaction are given in Scheme 22 ð56JA2351\ 65TL566\ 81JCS"P0#1616Ł[ Pal!
ladium"II# catalysis of the oxy!Cope rearrangement is also known ð72TL0046Ł[
OH R
R COR
OH
Scheme 32
OH O
CHO
HO
CO2Et
CO2Et
∆, o-DCB
90%
OH
O
Scheme 33
"iv# Anionic oxy!Cope rearranèments

The major drawback of all the previous methods for Cope rearrangements is the requirement for
extreme reaction conditions to e}ect the transformation[ It was thus of major synthetic importance
when Evans and Golob reported ð64JA3654Ł that rate enhancements of 0909Ð0906 were possible in
oxy!Cope rearrangements if 0\4!diene alkoxides were used[ This anionic oxy!Cope rearrangement
"Scheme 23# of a lithium\ sodium or potassium alkoxide "43# normally proceeds to give an inter!
mediate enolate "44# as the rearranged product under considerably milder conditions than are
required for the thermal variant[ Additionally\ the analogous anion!accelerated Cope rearrange!
ments of 2!amino!0\4!dienes has also been demonstrated and was found to be considerably more
facile than those of the corresponding 2!hydroxy!0\4!dienes ð82TL136Ł[
Synthetic applications illustrating the importance of this reaction include approaches to the
taxane diterpenes^ for example\ the AB ring system model "46# was constructed using the oxy!
Cope rearrangement of divinylcyclobutane alkoxides "45# ð80JOC210\ 81HCA0644\ 82JOC3841Ł[ A short
synthesis of the tricyclic ring system of vinigrol "48#\ has been reported using the anionic oxy!Cope
rearrangement of "47# ð82JOC1238Ł\ and the rearrangement of ether "59# has been used in the
enantiospeci_c synthesis of ajmaline!related alkaloids "Scheme 24# ð82JOC550Ł^ see also ð80CJC66\
82JOC3134\ 82JOC4371\ 82SC200\ 82T0914Ł[
0\1!shifts 700
O– M+ R
R H2O COR
O – M+
(54) (55)
M = Li, Na, K
Scheme 34
OLi O
–78 °C to RT, THF
57%
(56) (57)
OH
HH KH, 18-crown-6
H
HO
THF, reflux
OH 80%
O
(58)
(59)
H OH H O
H
Et KH, dioxane, cumene, reflux Et
N NR N NR
52% + other isomers (R = Bn)
Me H Me H H
Et Et
(60)
Scheme 35
"v# Cope reaction of divinyl cycloalkanes

The Cope reaction of divinyl cycloalkanes has been an area of considerable investigation[ The
basic conversion is shown in Equation "02# and can be represented as the equilibrium between the
divinyl cycloalkane "50# and a cyclic diene "51#[ The primary factor that a}ects the position of this
equilibrium is the strain associated with the ring sizes present[ In the case of cis!0\1!divinylcyclo!
propanes "n0# and cyclobutanes "n1#\ the rearrangement lies completely on the side of the less!
strained seven! and eight!membered ring dienes\ and very low temperature are required for this
transformation "Scheme 25# ð47LA"504#0\ 50LA"533#061\ 53TL1492\ 54CC115\ 69CC0408\ 62CC208\ 65JA4826\
71CC0053\ 75JA4890Ł[ However\ it is known that\ for bridged 0\4!cycloctadienes\ the equilibrium can
lie on the side of the cyclobutane ð69JA692\ 61JA8117\ 68JA6488\ 70CC675Ł[
n( ) n( ) (13)
(61) n = 1–10 (62)

The Cope rearrangements of 0\1!divinylcyclopropanes have been used extensively in organic
synthesis ð80COC"4#674\ 81OR"30#0Ł^ early work concentrated on the synthesis of cycloheptane!con!
taining natural products such as the dictyopterenes ð58HCA779\ 58TL2348\ 60JA2976\ 65JOC2389\
71TL0394Ł[ Many synthetic strategies have been developed to prepare the precursors] these include
conjugate addition:elimination of vinylcyclopropyl organometallic reagents to b!substituted cyclo!
alkenones ð65JOC2389\ 65TL2134\ 67JOC2529\ 72CJC0115\ 72CJC0128\ 82T4192Ł\ construction of cyclo!
propanes from sulfur ylides ð69JA1047\ 69JA5530\ 69JA5532\ 62TL2860\ 62TL2864\ 63JOC2064\ 70JCS"P0#2114Ł\
transition metal!catalysed addition of vinylcarbenes to cyclic dienes ð76T3154\ 76TL0742\ 77TL864Ł and
5–20 °C 120 °C
H
33 °C
H
H
Scheme 36
generation of enol derivatives ð73TL2848\ 74TL1624Ł[ Examples of these methods are shown in Scheme
26 and include the Cope rearrangement of divinylcyclopropane "52#\ prepared via the conjugate
addition:elimination protocol\ which led to the cycloheptadiene "53#\ a precursor of b!himachalene
ð72CJC0128Ł[ A rhodium!catalysed intermolecular cyclopropanationÐCope rearrangement approach
to the synthesis of hydroaxulenes has been described ð80JOC612Ł\ as well as a similar sequence for the
synthesis of various seven!membered carbocycles ð80JOC2706Ł and tropane derivatives ð80JOC4585Ł\
including the enantioselective route for the preparation of cyclopropane "54# which rearranges to
tropane "55# ð81TL5824Ł[ Both cis! and trans!0\1!divinylcyclopropanes give the same products on
Cope rearrangement "the trans!isomer undergoes isomerisation via a diradical intermediate to
the cis!isomer ð52AG"E#0\ 61JA4809Ł and consequently higher temperatures are necessary to e}ect
rearrangement#[ A similar e}ect is seen with trans!0\1!divinylcyclobutanes\ but side reactions are
known to occur ð53JA788Ł[
O O
xylene, ∆
90%
(63) (64)
O
CO2R*
CO2R*
O CO2R BOCN
N2 H H
BOCN BOCN
Rh2(OOct)4 82%, 66% de
pentane, reflux
(65) (66)
Scheme 37
Many examples of Cope rearrangement are known for divinylcyclobutanes\ particularly the
oxy!Cope variant\ as several methods for the preparation of 1!vinylcyclobutanones are available
ð78OS"56#109Ł[ For example\ addition of a vinyl group to the cyclobutanone "56#\ leads to divinylcyclo!
butanol "57#\ which undergoes oxy!Cope rearrangement ð71JOC1157\ 73HCA663Ł[ Many other stra!
tegies are available for the preparation of divinylcyclobutane Cope precursors including ð1¦1Ł
cycloadditions and ~uoride ion!assisted conjugate additions "Scheme 27# ð79TL3436\ 70JOC1088\
71HCA340\ 71JA6569\ 74JOC190\ 77TL1662\ 80TL5858Ł[
The position of equilibrium is totally reversed in the rearrangement of 0\1!divinylcyclopentanes
"n2# and cyclohexanes "n3# "Equation "02##\ as the small amount of ring strain in _ve! and six!
membered rings is preferred to the considerable strain found in medium!sized rings "eight! to eleven!
membered#[ In the parent ring systems\ 0\4!cyclononadiene "58# and cyclodecadiene "69# rearrange
completely to the corresponding divinylcycloalkanes "Scheme 28# ð52AG"E#628\ 52HCA372\ 62JOC3006Ł^
see also ð57JOC3147\ 58LA"616#083Ł[ The germacrane class of sesquiterpenes displays this characteristic
rearrangement as many of them contain the 0\4!cyclodecadiene skeleton^ for example\ the thermal
conversion of "¦#!hedycaryol "60# to "−#!elemol "61# takes place readily "Equation "03## ð57CC0118\
69CC781Ł[ Many other examples are known ð48CCC1260\ 48LA"514#195Ł and information is available
on the e}ect of substituents on the conformation adopted for rearrangement ð57CC0118\ 69CC781\
0\1!shifts 702
O
O HO
KH, THF, RT
62%
(67) (68) (E):(Z) 21:79

H O
150 °C O
+
• 55%
O
H
TMS
F–, DMF, RT
O –O O
O
H H O
H
H SMe
PhH, ∆
SMe H
100% O
O H
O H
Scheme 38
69JCS"C#1586\ 69JCS"C#1693\ 63T0414Ł[

It is also possible to observe equilibrium mixtures when highly
substituted cyclodecadienes are used ð53JCS3467\ 79JA0645Ł^ and it is also possible to reverse the
position of equilibrium completely ð76CC0085Ł[
100 °C
(14)
OH OH
H H H
(71) (72)
(69) (70)
Scheme 39
Furthermore\ it is possible to reverse the position of this equilibrium to favour the medium!sized
ring if the oxy! or anionic oxy!Cope rearrangement is employed\ and this methodology has been
used to good e}ect[ Several examples exist of 0\1!divinylcyclopentane to cyclononenone rearrange!
ments under oxy!Cope conditions\ many of these in the synthesis of natural products "Scheme 39#
ð70JOC8\ 70JOC1088\ 75TL108Ł[ In a similar manner\ cyclodecenones can be prepared by oxy! or anionic
oxy!Cope rearrangement of 0\1!divinylcyclohexanols ð69TL498Ł[ The reaction has found widespread
application in the synthesis of cyclodecane natural products "germacranolides ð74BCJ035Ł#\ peri!
planone B ð68JA1382\ 73JA3927\ 75TL0204Ł\ eucannabinolide ð66JA3075\ 72JA514Ł#\ as well as many other
polycyclic systems "Scheme 30# ð70JOC1088\ 74TL5026\ 77JA789\ 81TL812Ł[
The smaller ring product is also favoured in the thermal rearrangement of divinylcycloheptanes
"n4# ð56TL116Ł\ but again the large ring product is favoured in the oxy!Cope rearrangement
ð79BCJ1847Ł[ In the Cope rearrangement of 0\1!divinylcyclooctanes "n5# and larger rings "n6Ð09#\
OH O
KH, THF, reflux
83%
O O
KOH, MeOH, RT
46%
H OH O
Scheme 40
220 °C, 3 h
90%
OH O
OH O–
KH, THF
18-crown-6 steps
periplanone B
THP-O THP-O
H KH, 18-crown-6
OH THF, reflux O H
53%
H
H H
H
Scheme 41
the equilibrium position shifts again\ leading to the preferential formation of twelve! to sixteen!
membered rings[ The determining factor in these equilibria is the strain present in medium!sized
rings "eight! to eleven!membered#[ Examples are known of divinylcyclooctane rearrangements to
twelve!membered rings ð68HCA1529\ 71AG"E#575\ 71JOC0521Ł and also rearrangements of divinylcyclo!
undecanes ð75AG"E#0915Ł and cyclododecanes "Scheme 31# ð79BCJ1847\ 71JOC0521Ł[
130 °C
63%
O O
CO2R CO2R
250 °C
82%
Scheme 42
"vi# Cope rearranèments of vinylbicycloalkenes

The Cope rearrangement of vinylbicycloalkenes leads to the formation of a fused bicyclic diene^
the most frequently reported cases are the bicycloð1[1[0Łheptenes "62# and bicycloð1[1[1Łoctenes "63#\
0\1!shifts 704
which lead to the formation of indene and decalin skeletons respectively "Scheme 32#[ This powerful
methodology can be used to rapidly assemble complex polycyclic skeletons\ and has been used in
the synthesis of several natural products[ Representative examples of indene ð65BCJ1906\ 75JA6762\
77CC428Ł and decalin formation are given in Scheme 33 ð53JA4908\ 57JA3618\ 67JA7069\ 68CC095\ 73TL4092\
77CC0170\ 77T2028\ 81TL812Ł including the formation\ via anionic oxy!Cope rearrangement\ of a
precursor "64# for the indacene subunit of ikarugamycin ð76TL20\ 77JA768Ł[ The rearrangement of 6!
vinylbicycloð2[2[0Łheptenes also leads to the formation of indenes\ but can be problematic in some
cases ð63JA2357\ 71JOC3704\ 76JA4620Ł[ Larger ring ð71JOC3704Ł and tricyclic ð55CC664\ 56TL3426\
60JCS"C#869\ 66T0416Ł variants are also known[
(73)
H
(74)
Scheme 43
H
KH
OH
92%
O
H
H
KH, 18-crown-6
DME, RT, 14 h
OH
O
H
MeO OMe
O
H H OMe
OH KH, THF, 20 °C
H OMe
83%
Et
H H
H
(75)
Scheme 44
The preparation of several strained polycyclic systems using the oxy!Cope reaction is also possible[
For example\ the rearrangement of 1!exo!methylene!5!vinylbicycloð1[1[1Łoctane "65#\ has led to a
synthesis of the taxane model "66# which contains a bridgehead double bond "Equation "04##
ð71JOC2089\ 77TL162Ł^ examples in which an additional ring is present have also been reported
ð77JOC3497\ 77TL162Ł[
KH, THF, 20 °C
(15)
83%
OH O
(76) (77)
0[07[1[4 Where YC0Z "ZHeteroatom#
0[07[1[4[0 Where Zchalcogen

"i# Witti` rearranèment "YC0O#
The 1\2!Wittig rearrangement ð75CRV774\ 80S483Ł involves the rearrangement of the anion of a
substituted methyl allyl ether to a 0!alkoxybut!2!ene "Equation "05##^ this reaction proceeds under
relatively mild conditions in generally good yield and with predictable stereochemistry ð68AG"E#452\
81AG"E#536Ł[ Several methods are available for the generation of carbanions in these systems and
much depends on the nature of the substituent E\ which is employed to promote formation of the
anion ð89JOC0310Ł[ A list of literature examples of di}erent types of group E is given in Table 0[
(16)
– O O–
E E
Table 0 Examples of group E[

Type Ref[
*
H 67JA0816\ 74TL3848\ 74TL4902\ 74TL4906\ 74TL4910\ 75JA2730\
76JA2906\ 76JA5088\ 76JOC1859\ 76TL1988\ 76TL3882\ 89CB042\ 89CB806\
89TL3290\ 89TL3314\ 82TL1486\ 82TL4106
aryl:heteroaryl 55LA"587#79\ 55TL5282\ 69CC3\ 69TL242\ 60JA2445\ 72JOC168\
73JOC0731\ 78TL1438\ 82CL0286
vinylic 40JA0326\ 69CC3\ 70JA5381\ 71TL2820\ 72JOC168\ 73JOC0696\
73JOC0731\ 74JA2804\ 75JOC3204\ 80CL32\ 80JOC0074\ 83T2576
alkynyl 72CL0268\ 72JOC168\ 73CL144\ 73JOC0731\ 73T1292\ 73TL454\ 74CL0608\
74CL0612\ 74JOC0032\ 74TL4688\ 75JOC3205\ 76JOC2759\ 76JOC2772\
76TL612\ 76TL2212\ 77TL3476\ 89JOC0310\ 80CL32\ 81CC249\ 81T3976
oxazolines and oxamines 72TL402\ 73TL5900\ 75TL3074\ 77JOC3520\ 77JOC4078\ 82TL638\ 82TL642
R0C1O 63HCA1973\ 74JA4461
0 1
R 0C1N"R # 78JOC4304
CO1− 70TL58\ 75JOC3989\ 75TL3788
CO1R 75TL0446\ 75TL3400\ 75TL3470\ 76CL58\ 76TL792\ 77TL3652\ 80TL4026
CONR1 74CL0618\ 75TL3466
CN 63TL1966\ 66BSF814
*
The stereochemical implications of the reaction are governed to a large extent by the con_guration
of the double bond in the allyl ether^ for example\ rearrangement of the isomeric benzyl crotyl ethers
"67# and "68#\ which proceeds with excellent syn selectivity for the cis!crotyl ether "67#\ whereas the
selectivity is lower for the trans!isomer "68# "Scheme 34# ð69CC3\ 69LA"623#095\ 65CC573Ł[
BuLi, THF, TMEDA

hexane, –80 °C to –25 °C
O 100% HO Ph
Ph
(78)
+
O Ph
HO Ph HO Ph
(79) 66 : 33
Scheme 45
0\1!shifts 706
A nonstabilised variant of the 1\2!Wittig rearrangement employs an unstabilised lithiomethyl
allylic ether generated in situ through transmetallation of a "trialkylstannyl#methyl allylic ether
ð67JA0816Ł[ The reaction has been used extensively in synthesis and several examples serve to
illustrate the selectivity inherent in the process "Scheme 35#[ In acyclic systems\ the stereochemistry
of the rearranged double bond depends upon the substitution pattern of the allylic ether "structures
"79# and "70## ð67JA0816Ł[ In addition\ high stereoselectivity ð74TL4902Ł and absolute stereoinduction
ð89CB042\ 89CB806Ł are also known\ for example\ the StillÐWittig rearrangement of the carbohydrate!
derived stannane "71# gave the homoallylic alcohol "72# as a single diastereoisomer[ The reaction
has also found application in natural product synthesis\ including the preparation of steroidal
side chains ð74TL3848\ 74TL4906\ 74TL4910Ł\ the sesquiterpene punctatin A ð75JA2730Ł\ hydroxylated
vitamin D2 analogues ð76TL1988Ł and dipeptide isosteres ð80TL4390\ 82TL4106Ł[
n-C7H15 BunLi, THF n-C7H15
–78 °C, 30 min
O 91% HO
SnBu3
(80)
Bu
O 95%, 97 : 3 Bu
OH
SnBu3
(81)
BunLi, THF, 3.5 h

SnBu3 –78 °C
O O
O O OH
O 79%, >99 : 1
(82) (83)
Scheme 46
Probably the most studied substrates for 1\2!Wittig rearrangement are allyl propargyl ethers^
these are selectively deprotonated at the propargylic position to give anions which readily undergo
1\2!rearrangement[ A high degree of diastereoselectivity is often seen in this rearrangement and\ in
general\ "E#!allylic ethers a}ord anti!homoallylic alcohols "73#\ and "Z#!allylic ethers rearrange to
syn!homoallylic alcohols "74# ð73TL1292Ł^ however\ many exceptions are known "Scheme 36#
ð73T1292\ 75TL3078Ł "for mechanistic considerations\ see ð72JOC168\ 89JOC0310Ł#[ Stereocontrolled
transformations have also been reported "Equation "06## ð73CL144\ 73JOC0731\ 73TL454\ 74CL0608\
74CL0612\ 74JOC0032\ 77TL3476Ł[
BuLi, THF, –85 °C to 0 °C
O 72%; 99:1 HO
(84)
BuLi, THF, –85 °C to 0 °C
O 56%; 9:1
HO
(85)
Scheme 47
O O
O O
O
(17)
77%; >99:1
HO
TMS
TMS
The reaction has also found extensive use in natural product synthesis\ for example\ Nakai has
employed the propargylic 1\2!Wittig rearrangement for elaboration of side chains in steroidal
systems ð74CL0608\ 74TL4688Ł and both he and Takahashi have reported approaches to substituted
cyclopentenes as prostaglandin precursors ð82SL416\ 82TL4812Ł[ Perhaps the most synthetically impor!
tant application of this reaction is found in the reports by Marshall ð75JOC3205\ 76JOC2759Ł of the
synthesis of medium! and large!ring carbocycles by 1\2!Wittig ring contraction of allylpropargyl
ethers[ Thus\ treatment\ of the seventeen!membered allylpropargyl ether "75# using BunLi in pen!
taneÐTHFÐTMEDA gave "76# as the major diastereomer in excellent yield ð77TL2436Ł^ this reaction
demonstrates the ability of remote stereocentres to e}ect chirality transfer in these macrocyclic
systems "Equation "07## ð77TL3802\ 89JOC116Ł[ This chemistry presents a powerful route for the
synthesis of cembranoid diterpenes ð76JOC2772\ 89JOC116Ł\ with similar rearrangements to ten!
membered rings having been used in a synthetic approach to the germacranolide sesquiterpene
aristolactone ð76JOC2772\ 77JOC3097Ł^ homochiral lithium amide base methodology has also been
applied to the latter reaction ð76TL2212\ 77JA1814Ł[ A similar strategy has been applied to the synthesis
of neocarzinostatinÐchromophore analogues and esperamicinÐcalichemicin analogues^ for example\
the transannular ð1\2Ł!Wittig rearrangement of a twelve!membered cyclic ether led to the diyne "77#
"Equation "08## ð80JOC2354\ 81TL3452Ł[
O-THP O-THP
O OH
BunLi, –20 °C
(18)
73%; >4:1 selectivity
(86) (87)
ButLi, THF
–100 °C, 10 min
(19)
O 67%
OH
TBDMS-O TBDMS-O
(88)
Similar ring contractions of diallylic macrocyclic ethers are also known^ Takahashi et al[ reported
1\2!Wittig ring contractions of thirteen!membered diallylic ethers "Equation "19## ð75JOC3204\
76H"14#028Ł^ a similar 1\2!Wittig ring expansion protocol has also been reported ð82TL7342Ł[ Acyclic
diallyl ethers also undergo 1\2!Wittig rearrangement and a systematic study of these reactions has
been performed^ the regioselectivity of the rearrangement was found to be related to the stability of
the presumed allylic anion intermediates and\ in general\ the less!substituted allylic anion was
preferred "Scheme 37# ð70JA5381\ 72JOC168Ł^ in addition\ the stereoselectivity of the process is highly
dependent upon the geometry of the intermediate allylic anion ð83T2576Ł[ Tertiary allyl ethers
derived from "¦#!camphor and "−#!fenchone also impart a high degree of absolute stereochemical
control to the ð1\2Ł!Wittig rearrangement ð80JOC0074Ł[ Many examples of aryl stabilised anions have
also been reported ð69CC3\ 69TL242\ 60JA2445\ 73JOC0731\ 78TL1438Ł[
BunLi, THF
–78 °C, 10 h
(20)
94%
O OH
One area of considerable interest is where the anion that initiates a 1\2!Wittig rearrangement is
derived from an enolate[ Numerous examples have been reported and include enolates derived from
a!allyloxy or a!propargyloxy ketones\ hydrazones\ nitriles\ acids\ esters\ amides and also oxazoles
"see Table 0#[ In general\ such anions are easily formed under mild conditions and lead to highly
functionalised products with great synthetic potential^ other advantages include the possibility of
incorporation of chiral auxiliary groupings and the opportunity to e}ect changes in the counterion[
Some representative examples are shown in Scheme 38\ which includes methodology for the modi!
_cation of the 11!hydroxy substituent found in ecdysone and brassinolide natural products "78#
0\1!shifts 708
BunLi, THF
–85 °C to 0 °C, 10 h
O 79%
HO
BunLi, THF
–85 °C to 0 °C
O 79%; syn:anti 92:8

HO
Scheme 48
ð75JOC3989\ 75TL3788Ł and in the synthesis of an advanced intermediate for the preparation of
rapamycin "89# ð82TL638\ 82TL642\ 82TL0092Ł[ Ester enolates show a high propensity for 1\2!rearrange!
ment\ and chiral auxiliaries have been used to e}ect high levels of diastereoselectivity and asymmetric
induction in the transformation "80# "Equation "10## ð76CL58Ł[ Examples using amides of homochiral
pyrrolidines ð74CL0618Ł and oxazoline derivatives ð73TL5900\ 75TL3074\ 77JOC3520Ł are also known[
CO2H OH
H O LDA, THF, –78 °C CO2H

82%
H H
H
OMe (89)
O-MOM OH O-MOM
O OMe O OMe
BunLi, THF, –78 °C O
O 74% N
BnO BnO
N O (90)
Scheme 49
O
LHMDS, THF
HMPA, –70 °C
O O O (21)
75% HO
Ph OR*
syn:anti 93:7, 96% ee (91)
Transmetallation of enolates has been used to good e}ect and it is well known that zirconium
and titanium enolates improve the e.ciency and stereoselectivity of the Wittig rearrangement of
allylic glycolate esters ð75TL3470\ 77CL3657\ 77TL3652Ł^ similar results are also obtained with boron or
tin enolates ð80TL3536Ł[ A high erythro!selectivity is observed when silyl ketene acetals of a!allyloxy
esters are treated with TiCl3 or SnCl3 to induce a ð1\2Ł!sigmatropic shift "Scheme 49# ð80SL518Ł[ A
titanium!mediated ð1\2Ł!Wittig rearrangement of glycolate ester "81# gave the hexenoate "82# with
excellent stereocontrol and diastereoselectivity "Equation "11## ð81BCJ0730Ł[
OH
LDA, THF, Cp2TiCl2
O CO2Pri –20 °C
BnO CO2Pri (22)
72%
OBn
(92) syn:anti 29:1 (93)
Bun
LDA, THF, Cp2ZrCl2
–100 °C
O Bun O
81% HO
O OPri OPri
syn:anti 98:2, 96% ee
SnCl4, CH2Cl2, –50 °C

O O
73% HO
TMS-O OMe OMe

syn:anti 92:8
Scheme 50
"ii# Rearranèment of oxonium ylides "YC0O#

The 1\2!rearrangement of oxonium ylides e}ects a similar transformation to that found in the
ð1\2Ł!Wittig reaction[ Various methods are available for the generation of the ylide ð80CRV152Ł^
these include metal!catalysed decomposition of a!diazo ketones ð75JA5959\ 75JA5951\ 77TL4008\
81TL5082Ł with intramolecular 1\2!rearrangement and similar intermolecular versions using a!diazo!
malonate! ð61JA2769Ł and a!diazoacetate!based ð60JOC0621Ł rearrangements of allylic ethers[
Trimethylsilyloxonium ylides can also be generated in situ by treatment of a!allyloxyacetic esters
with TMSO!Tf and triethylamine ð75TL3400Ł[ Representative examples are given in Scheme 40[
Prn O O O
0.02% Cu(acac)2
O THF, reflux – 83%; >97:3

N2 Prn O Prn O
+
N2CHCOPh O O
+
Ph OMe Rh2(OAc)4 (0.01 equiv.) Ph Ph Ph Ph
CH2Cl2, RT
OMe OMe
(Z) 91:9
(E) 19:87
TMS-OTf
+
O TMS-O
NEt3 83%; 92:8
– HO CO2Me
CO2Me CO2Me
Scheme 51
"iii# ThiaÐWitti` rearranèment "YC0S#

Allylic sul_des undergo 1\2!Wittig rearrangement\ but at a slower rate than their oxygen counter!
parts[ Several anion stabilising groups have been utilised including cyano ð65JA6004Ł\ vinyl
ð60HCA628Ł\ aryl ð60HCA628Ł\ ester ð79CL0950Ł\ thiolether ð66SC092Ł and sulfoxide ð64CR"C#0120Ł^
rearrangements in which no stabilising group is used ð81TL6212Ł have been reported and can be
considered a direct heterologue of the Still 1\2!Wittig variant "Scheme 41# ð67JA0816Ł[
0\1!shifts 710
HS
BunLi, THF
Bu3Sn –78 °C, 5 min
OBn 90%
S
BnO
anti:syn >96:4
i, LDA, THF, HMPA, –20 °C

S ii, MeI
SMe
NC SMe 77%
SMe
CN
Scheme 52
"iv# Rearranèment of sulfur ylides "YC0S#

The 1\2!rearrangement of allylic sulfur ylides has been studied extensively ð80COC"2#802Ł[ It is a
facile process occurring readily under mild conditions\ proceeding in a concerted fashion with
inversion at the allyl centre[ A high degree of stereocontrol is observed for the alkene geometry and\
in the absence of any special e}ects\ such as conformational or steric factors ð70JOC2204Ł\ the
rearrangement is "E#!selective ð58CC88\ 61CC691\ 62JOC1461\ 68JOC3017Ł[
Several methods exist for the preparation of the intermediate ylide and a common method is the
deprotonation of sulfonium salts "Scheme 42# ð60CC0528\ 61CC646\ 61TL2476\ 67T206\ 79CC0985Ł[ This
prototypic reaction has also found application in ring contraction ð61JA7821\ 70JCS"P0#0842Ł and
expansion methodologies ð64JA5767\ 66HCA0250\ 67JOC0074\ 67JOC3715\ 67JOC3720\ 67TL408\ 68JOC3017\
73TL2444Ł including impressive total synthetic work towards erythronolide A ð72JA016Ł\ cytochalasin
ð73JA3506Ł\ zygosporin ð77JA3711Ł and a precursor of methynolide "83# ð76JA4767Ł performed by
Vedejs and co!workers "Scheme 43#[ Examples are also known of asymmetric transfer using homo!
chiral sulfonium salts ð62JA851\ 62JOC2327\ 66TL0226\ 67JOC1407\ 80TL224Ł although\ in the majority of
cases\ the reaction proceeds with low enantiomeric excess[ Enantioselective deprotonation of a
prochiral sulfonium salt using a chiral base has also been reported ð62JOC2327Ł\ but asymmetric
induction was low[
PhSCH2Cl
SPh KOBut +
SPh
– 80%
PhS SPh
SPh
S BunLi, THF S S
–
–78 °C
+ +
S S 80%
S
Br–
Scheme 53
Regiospeci_c generation of ylides using ~uoride ion!catalysed desilylation of trimethylsilyl sul!

fonium salts has been explored ð68JA5341Ł^ this technique has the advantage over the previous
method in that 1\2!rearrangement usually takes place before any equilibration to thermodynamically
more stable ylides can occur^ examples include a rearrangement that was important in the total
synthesis of sarkomycin "Scheme 44# ð74JOC1854Ł[ The direct formation of sulfur ylides is also
possible by the addition of a carbene or benzyne to a sul_de^ this has been an area of exceptional
development ð66ACR068\ B!67MI 007!90\ 75ACR237Ł[ Several methods are available for the generation
of carbene intermediates in these reactions\ the most common being the light!promoted ð61JA2769\
61JOC2680Ł or metal!catalysed generation of carbenes from diazonium compounds\ the
NaOH selectivity >25:1
+
S +
S
H2O, CH2Cl2
S COPh
Ph – Ph
Br–
O O
O-MOM O-MOM
TfO CO2Et
K2CO3 + 40%
S EtO2C S
–
O-MOM OBn OBn

steps TfO CO2Et
2,6-lutidine + 76%
EtO2C S S
S
–
OBn
steps
methynolide
S
CO2Et
(94)
Scheme 54
latter method giving better results ð61JA2769Ł[ Copper ð61TL4010\ 61JA2769\ 61JOC2680\ 61TL1812\ 79TL288\
71JCS"P0#1646Ł or rhodium ð70JOC4983\ 73ACR247\ 76CL0458\ 89CC307\ 89CL502\ 89T3776Ł catalysis is gen!
erally used[ Carbenes generated under phase transfer ð61TL4010Ł or SimmonsÐSmith!type ð71TL2908Ł
conditions have been used\ as have carbenes from the Lewis acid mediated decomposition of
diazopenicillins ð79TL288\ 71JCS"P0#1646Ł[ Several examples of these methods are given in Scheme
45\ including methodology by which treatment of a tosylhydrazone with hydride generates the
intermediate ylide which then rearranges to the dithiolester "84#\ a synthetic precursor of the natural
product bakkenolide ð61CC243\ 66JA4342Ł[ In addition\ Yoshikoshi and co!workers describe a novel
ring contraction strategy directed towards the preparation of highly substituted lactones "85#
ð78TL0464\ 89CC307\ 89CL502\ 89T3776\ 80TL5048Ł\ see also ð61JA2769\ 61TL1812\ 83CC678Ł[
O O O
CsF, PhCHO
+ MeCN +
SPh SPh
94%
–
SPh
TMS
Scheme 55
Some noteworthy work has been reported using benzyne for generating sulfur ylides "including a
total synthesis of squalene ð58CC88Ł#^ however\ competitive rearrangements are frequently observed
ð52LA"551#077\ 57CC075Ł[ Sulfoxonium ylides also undergo 1\2!sigmatropic rearrangements ð55TL0676\
57CPB682\ 62TL1240Ł as do selenonium ylides ð79TL288\ 71JCS"P0#1646Ł[
0\1!shifts 712
CO2Et
N2
BnO CO2Et BnO BnO
Rh2(OAc)4 + 83%
SPh EtO2C – SPh
PhH, reflux EtO2C SPh
CO2Et
CO2Et
S
THF, NaH
reflux Me
62%
+
S H S – H H
TosHNN SMe (95)
SMe
O O O O
O Rh2(OAc)4 O
PhH, reflux SPh
CO2Et – CO2Et
N2 S+ CO2Et
Ph
PhS
(96)
Scheme 56
0[07[1[4[1 Where Znitrogen
"i# Aza!Witti` rearranèment "YC0N#

Some examples of the 1\2!aza!Wittig rearrangement are known utilising basic conditions to
generate the requisite anion "Equation "12## ð61JA8150\ 89CL1958Ł[
LDA, THF
–78 °C
(23)
N 100%
O Ph O N Ph
H
"ii# Rearranèment of nitroèn ylides "YC0N#

The 1\2!rearrangement of nitrogen ylides "the 1\2!Stevens rearrangement# has been used exten!
sively in synthesis and has many parallels with the corresponding rearrangement of sulfur ylides
ð66ACR068\ 75ACR237\ 80COC"2#802Ł[ The rearrangement is a concerted\ symmetry!allowed process\
proceeding with inversion at the allylic centre and showing high regio!\ diastereo! and enantio!
selectivities[
Several methods exist for the preparation of nitrogen ylides\ the most commonly used being the
deprotonation of quaternary ammonium salts under basic conditions ð60JA1231\ 62JOC1804\ 63JA6462\
79JCS"P0#0325\ 79JCS"P0#1922\ 70JCS"P0#0852\ 89JA0888Ł[ Other methods include the ~uoride!catalysed
desilylation of trimethylsilyl ammonium salts ð68JA5341\ 72JOC3662\ 89JA0888Ł\ rhodium!catalysed
reaction of allylic amines with diazo!compounds ð70JOC4983\ 73JOC0806Ł and silyl tri~ate!mediated
rearrangements "Scheme 46# ð89CL1958Ł[
High levels of diastereo!control are possible in acyclic rearrangements\ particularly with pro!
pargylic ammonium ylides\ the stereochemistry being dependent on the double!bond geometry in
the starting material ð58CC183\ 61CC51\ 79JCS"P0#0325Ł[ In contrast\ acyclic\ nonpropargylic ammonium
ylides give mixtures of diastereoisomers ð70JCS"P0#0842Ł with steric factors playing a signi_cant role
"Scheme 47# ð70JCS"P0#0852Ł[ E.cient transfer of con_guration is also possible ðB!73MI 007!93Ł as is
asymmetric induction by remote chiral centres ð60JA1231Ł[ Ring contraction ð70JCS"P0#0842\ 77TL2882Ł
and ring expansion ð67TL412Ł reactions are also known^ these generally proceed with higher dia!
stereoselectivity than is observed in acyclic cases "Scheme 48#[
CN
KOBut, DMSO, THF
+
N selectivity >9:1 N
But But
NC
N2CHCO2Et
+
NMe2 Rh2(OAc)4 NMe2 82%
– EtO2C NMe2
CO2Et
TMS-OTf
Me +
N N 69%
Me NEt3 – MeHN CO2Me
syn:anti 4:1
TMS
CO2Me CO2Me
Scheme 57
+ Ph Ph
NMe2
+
– 85–91%
Ph NMe2 NMe2
Ph Ph Ph
6 (E); ratio; 86:14

6 (Z); ratio; 10:90
Scheme 58
But But But
dbu
+
H +
H
20 °C 90%
N N N
Ph Ph CO2Et
– Bn
EtO2C TfO– EtO2C
Br– NaOH, PhH

+ Ph reflux
N COPh
N
Me
O Me
Scheme 59
The SommeletÐHauser rearrangement ð26CR"194#45\ 40JA3011Ł is also a 1\2!rearrangement\ but

one in which a benzylic quaternary ammonium ylide is employed[ The reaction proceeds via an
intermediate triene "for example "86## which on most occasions undergoes re!aromatisation\ via a
0\2!hydrogen shift^ however\ on some occasions these intermediates have been intercepted and
isolated "Equation "13## ð77CC269\ 83JCS"P0#282Ł[
0\1!shifts 714
+
N I– CsF, DMF, RT
N (24)
Me
74%
TMS Me
(97)
0[07[1[4[2 Miscellaneous rearrangements
"i# YC0Hal
Rhodium!catalysed decomposition of diazoacetates in the presence of allylic halides allows the
preparation of halonium ylides^ these compounds undergo sigmatropic rearrangement to homo!
allylic halides\ with iodides giving the best results "Scheme 59# ð70JOC4983Ł[
Rh2(OAc)4 (0.005 equiv.)

I EtO2CCHN2, 25 °C
I+ 98%
– EtO2C I
CO2Et
Scheme 60
0[07[1[5 Where YC0C0Z
0[07[1[5[0 Where Zchalcogen

"i# Claisen rearranèment "YC0C0O#
The Claisen rearrangement can be represented simply as the ð2\2Ł sigmatropic conversion of allyl
vinyl ethers "87# into g\d!unsaturated carbonyl compounds "88# "Equation "14##[ Since its discovery
ð01CB2046Ł the reaction has been the subject of several modi_cations\ which have led to it becoming
one of the most powerful synthetic operations available for carbonÐcarbon bond formation ð79T2\
B!70MI 007!90\ 73CRV194\ 76AHC"31#192\ 77CRV0312\ 78S60Ł[ The common variants of the Claisen
rearrangement are shown in Equation "14# and\ in addition to the parent rearrangement of allyl
vinyl ethers "XH\ R\ Ar#\ the Johnson orthoester "XOR# and the Eschenmoser amide acetal
"XNR1# modi_cations are facile processes which have increased the potential of this methodology[
Possibly the most important developments in this area are the enolate Claisen rearrangement
"XOM#\ the Ireland rearrangement of silyl ketene acetals "XOSiR2# being the most widely
used[ An aromatic version of the reaction is also known\ where the vinyl ether portion of the
molecule is contained within an aromatic ring[ In addition\ anion!accelerated examples of the Claisen
rearrangement are known\ as are several other versions\ for example where XF ð70CL0178Ł\ XSi\
Ge ð89JA6680Ł and XFe ð76OM1138Ł[ The reaction\ in accord with related processes\ is generally
considered to be an exothermic\ intramolecular and concerted process ð68JA1635\ 77CRV0312Ł[
X X
X = H, R, Ar, Aliphatic
O O X = OR, Johnson
X = NR2, Eschenmoser (25)
X = OM, Ireland
(98) (99)
"a# Claisen rearranèment of allyl vinyl ethers[ The Claisen rearrangement of allyl vinyl ethers
has been used extensively in synthesis^ this is despite the fact that the uncatalysed thermal reaction
generally requires temperatures of 099Ð199>C and thus limits the process to thermally stable
compounds[ Thermal Claisen rearrangement of ethers normally results in high "E#!selective product
formation ð48JA2268\ 59JA3570Ł[ The reaction has found considerable application in the total synthesis
of natural products\ particularly those which contain multiple contiguous quaternary carbon centres
ð77TL0558\ 82JOC6640Ł[ Many ring expansion reactions have also been reported\ the precursors
being prepared via Tebbe alkeneations of lactones or esters ð74JA6241\ 89TL5688\ 80JA1509\ 80JOC2730\
82TL0610Ł or via selenoxide elimination ð89TL3930\ 89TL5868Ł[ High levels of stereocontrol ð78JOC3167\
89JA3924Ł and chirality transfer ð78HCA885\ 89JCS"P0#00Ł are also observed[ Speci_c examples of these
transformations are shown in Scheme 50 and include the formation of contiguous quaternary centres
in the rearrangement of allyl vinyl ether "099# ð77TL0558Ł\ the two!carbon ring contraction of
macrocyclic ether "090# "prepared using the Tebbe methodology# ð82TL0610Ł and the tandem selenox!
ide eliminationÐClaisen rearrangement of substrate "091# ð89TL5868Ł "for a related sulfoxide elim!
inationÐClaisen protocol\ see ð89TL3930Ł#[ Numerous other synthetic examples are known
ð78HCA885\ 78JOC3167\ 89JA2141\ 89JA3924\ 89T2590\ 89T3376\ 82TL2412Ł[
O O-TBS O
O O
151 °C, nonane, 4 h
O O
47%
CN 16:1 diastereoselectivity CN O-TBS
(100)
O
O 190 °C, decalin
67%
(101)
O H O H O H
O O– Et2NH O
O + O O
SePh mesitylene >66%
reflux
H H H H
O
(102)
Scheme 61
The chorismate mutase catalysed ð2\2Ł!sigmatropic rearrangement of chorismate to prephenate

in the shikimic acid pathway ð52NAT277\ 62B2381\ 68AJC0810Ł presents a biosynthetic example of this
versatile process[ Transition!state analogues have been prepared in order to study both enzyme
inhibition ð74JA6681\ 77JOC2084Ł and the preparation of catalytic monoclonal antibodies ð77JA4482\
77SCI315Ł[
Catalysis of the Claisen reaction of allyl vinyl ethers "and of many of the Claisen variants# has
received considerable attention[ Catalysis by Bronsted and Lewis acids ð89JA205\ 89JA6680\ 89TL266\
89TL2130Ł\ bases\ metal salts ð78BCJ2724\ 80JCR"S#061Ł\ transition metal complexes ð73AG"E#468\
75TL5156\ 76TL4768\ 78SC1098Ł\ and microwave methodology ð75TL3834Ł have been reported and early
work in this _eld has been reviewed ð73CRV194Ł[ Later work has concentrated on aspects of
organoaluminum catalysis of the reaction\ and high levels of stereocontrol and chiral transmission
have been reported ð77JA6811\ 78TL0154\ 89JA205\ 80JA1651\ 80JOC2730Ł[ In addition\ chiral organo!
aluminum reagents have also been shown to e}ect asymmetric rearrangements in enantiomeric
excesses as high as 82) "Scheme 51# ð89JA6680Ł[ The rate of reaction in the aliphatic Claisen
rearrangement of allyl vinyl ethers has been shown to be highly dependent on solvent with a rate
acceleration occurring in polar solvents\ particularly water:alcohol mixtures ð82CRV1912Ł^ see also
ð69JOC2474\ 76JA0059\ 76JA0069\ 76JA4997\ 78JOC404\ 78JOC4738\ 89TL3036\ 82T1982Ł[
Unlike the Cope rearrangement the Claisen reaction is not generally reversible[ However\ several
examples are known of the so!called retro!Claisen rearrangement\ where the allyl vinyl ether product
is favoured^ these cases generally occur where excessive strain is present in the ketonic system
ð54HCA0874\ 57CC476\ 58JA1704\ 60HCA0478\ 68CC473\ 71JA5018\ 72CC821\ 74JA3248Ł[
"b# Aromatic Claisen rearranèment[ The aromatic Claisen rearrangement is the thermal ð2\2Ł!
sigmatropic rearrangement of an allyl aryl ether to give initially an ortho!dienone\ which on
0\1!shifts 716
H Bui3Al, –78 °C to RT H
O CH2Cl2
H
76%
H H
HO
SiPh2But
AlMe
Ph SiPh2But Ph
(1.1–2.0 equiv.), CHCl3
–40 °C, 8 h
O SiMe2Ph 70%, 90% ee O SiMe2Ph
Scheme 62
enolisation yields an ortho!allylphenol[ This is referred to as the ortho!Claisen rearrangement and

is typi_ed by the rearrangement of the allyl ether "092# "Scheme 52# ð82CC682Ł[ When both ortho
positions are substituted\ a second 2\2!sigmatropic shift "Cope rearrangement# occurs\ which\ on
enolisation\ generates a para!allylphenol in the so called para!Claisen rearrangement "see 0[07[1[3[0[i\
Scheme 17#[ These products are also obtained occasionally when one or both ortho positions are
unsubstituted^ however\ no reaction occurs when all ortho and para positions are substituted
ð52HCA1333\ 57HCA0592Ł[ These reactions have been used extensively in synthesis ð33OR"1#0\ 73CRV194Ł
and remain the best synthetic route for the formation of allyl or phenyl substituted aromatic
compounds ð77TL5686\ 78JOC2026\ 89SC0326\ 80JCS"P0#1978\ 80SC0344\ 83CC140\ 83TL0550Ł[ A further com!
plicating factor in this rearrangement is the {abnormal| Claisen rearrangement ð60MI 007!91\ 62JA2237Ł^
this results in the formation of mixtures of isomeric allyl phenols via a homodienyl 0\4!sigmatropic
H!shift ð64OR"11#0Ł[ This process can be suppressed by the introduction of a trapping agent for
the intermediate phenol\ N!O!bis"trimethylsilyl#acetamide "bsa# and hexamethyldisilazane being
particularly e}ective ð83TL1034Ł[
MeO MeO MeO

200 °C
91%
O O OH
(103)
Scheme 63
"c# The Eschenmoser amide acetal and Johnson orthoester Claisen rearranèments[ The discoveries
of the Johnson orthoester ð69JA630Ł and the Eschenmoser amide acetal ð53HCA1314\ 68HCA0811Ł
rearrangement protocols were major developments in this area[ The formation of vinyl ketene
acetals and ketene N\O!acetals\ by treatment of allylic alcohols with ortho or amide acetals and
their subsequent in situ sigmatropic rearrangement facilitated the stereoselective synthesis of g\d!
unsaturated amides "093# and esters "094# "Scheme 53#[ The reactions generally require high tem!
peratures to e}ect conversion^ these conditions are required for the alcohol exchange reaction\ and
not for the actual rearrangement which occurs at signi_cantly lower temperatures ð74JOC4898Ł[ Both
reactions have been used extensively in synthesis and are known to proceed with high levels of
chirality transfer and stereoselectivity ð69JA630\ 66TL0514\ 78CPB1936Ł[ In addition\ the Eschenmoser
rearrangement produces stereochemically well!de_ned ketene N\O!acetals with a thermodynamic
preference for the "Z#!isomer ð60CB2568Ł^ for the formation of "E#!ketene N\O!acetals\ see
ð68JOC771Ł[ This is not the case for the Johnson variant and mixtures of diastereomers are obtained
where a!substituents are present in the orthoester ð60JCS"C#1849\ 76JOC0190\ 77JOC2757\ 77TL544\
78JOC0112Ł[ Nevertheless\ the reaction has found considerable synthetic application ð68TL2946\
79TL3224\ 70JOC0374\ 72T2620\ 75JOC012\ 78TL2266\ 78TL5160\ 78TL5466\ 89SC312Ł[
MeC(OMe)2NMe2
xylene, reflux, 4 h 91%

OH O O NMe2
NMe2
(104)
MeC(OEt)3
138 °C, 1 h
92%
HO EtO O EtO O
(105)
Scheme 64
The Eschenmoser rearrangement of the allylic alcohol "095# was a crucial step in the total synthesis
of DL!stenine ð89JOC5125Ł and similar transformations have been used in the synthesis of branched!
chain D!myo!inositols ð82CC859Ł and in the stereoselective construction of the C"10#ÐC"31# fragment
of rapamycin ð82CC508Ł[ Many additional examples are known\ including the Eschenmoser
rearrangement of alcohol "096# to amide "097#\ a key step in the total synthesis of thromboxane B1
"Scheme 54# ð66TL0514Ł[ Approaches to carbohydrate!derived carbocycles ð78JOC4249Ł\ alkaloids
ð80JCS"P0#450Ł and optically active ~uorine compounds ð80TL3156Ł have also been reported using
the Eschenmoser protocol\ as have many other examples ð68HCA0811\ 71JA6063\ 71TL098\ 73JOC1571\
75TL2942\ 76JOC0261\ 76TL1930\ 78CPB1936Ł[
Me2N
H H
MeC(OMe)2NMe2
xylene, reflux
N 90% N
HO
H CO2Me H CO2Me
TBS-O TBS-O
(106)
i, MeC(OMe)2NMe2
HO xylene, reflux, 4 h
ii, K2CO3, MeOH CONMe2
OH OH
MeO O 75% MeO O
(107) (108)
Scheme 65
Several modi_ed Eschenmoser procedures are also known\ including the ynamineÐClaisen
rearrangement ð55TL5314\ 68JOC771\ 70JOC2785\ 70TL3986Ł\ where the reactive N\O!ketene acetal
intermediates are formed at ambient temperature by treatment of an ynamine with an allylic
alcohol[ Methods for the preparation of N!silylketene N\O!acetals from allyl N!phenylimidates
by deprotonation and subsequent N!silylation have been reported ð89SL86Ł\ as have N\N!dialkyl!
alkoxymethyleneiminium salts which\ in combination with lithium alkoxides\ generate the requisite
intermediates for the Claisen rearrangement "Scheme 55# ð74JOC4898\ 76JA5605\ 80TL3088Ł[
Similar progress has been made with the Johnson rearrangement\ and the rearrangement of allylic
alcohol "098#\ using orthoacetate "009#\ illustrates both the absolute transfer of con_guration in this
reaction but\ due to the formation of both "Z#! and "E#!ketene acetals\ the product "000# is formed
as an epimeric mixture ð65JA0472Ł[ The Johnson rearrangement of "001# has been used in the total
synthesis of the alkaloid "−#!mesembranol ð83CC890Ł\ and a similar transformation was used in an
0\1!shifts 718
CH2=CHCH2O–Li+
+
N OMe THF, reflux, 12 h N O 65% N O
Me Me Me
OH O NMe2
NEt2
H
xylene, reflux 62%
>90:10 selectivity
H CONMe2
Scheme 66
approach to the thapsane sesquiterpenes ð82JCS"P0#556Ł[ A recent synthetic approach to pyrrolizidine

alkaloids uses the JohnsonÐClaisen rearrangement of alcohol "002# as a key transformation\ the
reaction proceeding with complete chirality transfer "Scheme 56# ð82S504Ł[ Other examples are
worthy of note ð76JA2914\ 76JOC0190\ 76JOC2430\ 76TL1486\ 77CC0420\ 77JOC0811\ 78JOC625\ 89JOC1097\
80CC0468\ 80TL4414\ 82T3678\ 82TL0740Ł[
O
O MeO CO2Me 160 °C, 1 h
MeO2C + MeO
O
MeO >75%
OH
(109) (110)
O
O
MeO2C
O
CO2Me
MeO2C H
(111)
OEt
OEt
HO OMe OEt O
EtCO2H
135 °C
MOM-O OMe MOM-O OEt
56%
(112) OMe
OEt
OMe
OEt
OEt
OH EtCO2H
CO2Et
100 °C
OTr OTr
90%
O-MOM O-MOM
(113)
Scheme 67
The related rearrangements of vinyl ketene acetals have been reported\ including a key step in
the total synthesis of the marine metabolite "¦#!laurencin via a tandem selenoxide eliminationÐ
Claisen rearrangement of selenide "003# to give lactone "004# ð82JA09399Ł^ similar examples are
known "Scheme 57# ð80T6060\ 82JA4704Ł[
"d# The Ireland ester enolate Claisen rearranèment[ The rearrangement of metal enolates gen!
erated from allylic esters has long been known to be a viable variant of the Claisen reaction ð38JA0049\
38JA1328\ 59JOC0704\ 61SC16Ł^ however\ it was not until Ireland and co!workers reported ð61JA4786\
64TL2864\ 65JA1757Ł the e}ective ð2\2Ł sigmatropic rearrangement of silyl ketene acetals that the full
SePh
NaIO4, dbu
O O m-xylene, reflux O O
73%
O
O
O-TBS O-TBS O-TBS
(114) (115)
Scheme 68
potential of the reaction was realised[ Treatment of an allylic ester "005# with a lithium amide base\
followed by O!silylation "normally with t!butyldimethylsilyl "TBDMS# chloride to limit competitive
C!silylation ð61JA4786\ 62SC56Ł# generates a silyl ketene acetal "006# which\ on warming\ undergoes
sigmatropic rearrangement to yield a g\d!unsaturated silyl ester "007# "Scheme 58#[ In the 0879s and
0889s this simple procedure has been developed into a general way to e}ect stereocontrolled Claisen
rearrangements and represents one of the most powerful methodologies available to the synthetic
chemist ð82MI 007!90Ł[
O OSiR3 OSiR3
O O O
(116) (117) (118)
Scheme 69
The most important aspects of this process are those which allow control of the stereochemistry
of the intermediate enolate\ as the geometry of the products of the IrelandÐClaisen rearrangement
can be predicted by consideration of con_guration of the double bonds involved in the ketene acetal
rearrangement[ The formation of "E#!silyl ketene acetal "008# is favoured when THF is used in the
formation of the lithium enolate\ while the use of 12) hexamethylphosphoramide "HMPA#:THF
favours the formation of the "Z#!silyl ketene acetal "019#^ on rearrangement these intermediates give
the erythyro! "010# and threo!products "011#\ respectively "Scheme 69# ð64TL2864Ł[ Other additives
such as N\N?!dimethylpropyleneurea "DMPU# or TMEDA can also have a profound e}ect
ð80JOC549\ 82MI 007!90Ł as can other factors such as the choice of base ð82JOC4290\ 82MI 007!90\ 83T2988Ł[
Several other conditions\ such as treatment of the ester precursor with silyl tri~ates in the presence
of a nitrogen base\ can also be used to generate the intermediate silyl ketene acetal ð77JA2187\ 78TL404\
82TL1140Ł[ The reaction has been extensively studied from a mechanistic standpoint and the factors
a}ecting the transition!state geometry "boat versus chair shaped six!membered rings# for both
acyclic and cyclic cases have been examined ð80JOC2461Ł[
LDA, TBS-Cl 87:13
THF O 79% O
O
TBS-O TBS-O
O
(119) (121)
THF, 23%HMPA 81:19

O LDA, TBS-Cl O 73% O
O TBS-O TBS-O
(120) (122)
Scheme 70
0\1!shifts 720
The IrelandÐClaisen rearrangement has been used extensively in synthesis[ Applications include
the synthesis of polyether antibiotics ð79JA0044\ 72JA0877\ 74JA2174Ł\ sesquiterpenes ð79JA5780\ 70JA1335\
73CC716\ 78CC0554Ł\ alkaloids ð82TL2874Ł\ steriods ð89CC0990Ł\ iridoids ð71JA3929Ł\ tetronates
ð75JOC524\ 77JA743\ 89TL3322Ł\ marine natural products ð78JA1624Ł\ amino acids ð71JOC2822\ 78CC0701Ł\
carbocycles ð79JA5778\ 72HCA1597\ 73JOC3219\ 74TL0052\ 77JOC3812\ 77TL0260\ 78JA7120\ 78JOC8Ł\ nitrogen
heterocycles ð74JOC696\ 75JOC2136\ 75T1720\ 76CC0119\ 76TL2920\ 78TL404\ 80JCS"P0#694Ł\ oxygen hetero!
cycles ð89TL4174Ł\ macrocyclic lactones ð72HCA1597Ł\ C!glycosides ð68CJC0632Ł\ substituted cyclo!
hexanes ð74JOC4068\ 78JOC8\ 83TL0206Ł\ chiral stannanes ð77JOC4078\ 89TL758Ł silanes ð74JOC4068\
75JCS"P0#050\ 77JOC4078Ł and numerous other examples ð77T2968\ 89TL0866\ 80JOC242\ 80TL2198\
82JOC4762Ł[
Other notable applications include the total synthesis of ebelactone A\ wherein the ester "012#\ is
treated under the IrelandÐClaisen conditions to generate an "E#!O!silylketene acetal which
rearranges to give the ester "013#\ with excellent stereocontrol ð89TL6402Ł[ The reaction has also
been developed into a double IrelandÐClaisen reaction for stereocontrolled two!directional chain
synthesis ð80TL6590Ł[ Complementary to this\ iterative enolate Claisen rearrangements have proved
to be a versatile route to synthetically useful 1\6!nonadiene!4!carboxylic acids\ proceeding with high
enantioselectivity ð82JOC3478Ł[ The methodology lends itself well to the stereoselective synthesis of
contiguous quaternary centres ð79T308\ 75JOC3374\ 89JA4590Ł as illustrated by the rearrangement of
ester "014# under Ireland conditions to give predominantly "015#\ a precursor of trichodiene
ð82JOC5144\ 83T0540Ł[ The IrelandÐClaisen rearrangement has also been used in syntheses involving
the ring contraction of lactones ð77JA2187Ł[ Knight and co!workers have used this strategy for the
enantiospeci_c total synthesis of "−#kainic acid via IrelandÐClaisen ring contraction of lactone
"016# to the pyrrolidine "017# in 44) overall yield "Scheme 60# ð76CC0119\ 76TL2920Ł[
TMS-Cl, LDA, Et3N
–20 °C to –60 °C, 4 h
MeO2C
78%
O O O-TBS O O-TBS
O (123) (124)
i, reflux, 12 h
OMe O OMe O-TBS
LDA, TMS-Cl ii, H3O+
TEA, THF, –100 °C iii, CH2N2 MeO
O O
75%
92:8 selectivity CO2Me
(125) (126)
O
LDA, TBS-Cl, THF OSiPri3 CO2H
–100 °C to 20 °C CO2Et H+
O TBS-O N OSiPri3
OSiPri3 55%
N O N
CO2Et CO2Et
(127) (128)
Scheme 71
Several other enolates also participate in Ireland!type ð2\2Ł!sigmatropic rearrangements and

indeed the use of zinc enolates derived from a!halo esters in the ReformatskyÐClaisen rearrangement
was reported shortly after Ireland|s original report ð62CC006\ 77TL2180Ł[ The selective formation and
rearrangement of "E#!enol dialkylboronates has also been reported ð78JA2330Ł^ the process has been
extended to a}ord an enantioselective and diastereoselective Ireland rearrangement of achiral allylic
esters utilising a recyclable chiral boron reagent "018# "Scheme 61# ð80JA3915Ł[ A procedure for
e}ecting the Claisen rearrangement of allyl esters or lactones via the corresponding dialkoxyphos!
phinyl ketene acetals has also been reported as being more facile than the analogous Ireland
rearrangement ð82JA7736Ł[
"e# The Carroll rearranèment[ The Carroll variant of the Claisen rearrangement is the base!
catalysed or thermal rearrangement of b!keto esters and allylic alcohols to alkenic ketones with
concomitant decarboxylation "Scheme 62# ð39JCS693\ 39JCS0155\ 30JCS496\ 32JA0881Ł[ The intermediates
Ph Ph R2BO
OBR2 O
NEt3, –78 °C
NEt2Pri, –78 °C
O ArO2SN NSO2Ar + O O
toluene, hexane
CH2Cl2 B
Br
(129)
75%, 97% ee 65%, 96% ee
H+ H+
99:1 90:10
TBS-O OH
O O
Scheme 72
in the Carroll reaction are easily prepared with well!de_ned double!bond con_guration\ and many
synthetic applications of the reaction have been reported ð58LA"618#41\ 58TL2142\ 60LA"636#59\
61JCS"P0#256\ 63HCA660\ 79JA751\ 70SC126\ 71TL098\ 72JOC1011Ł\ including some of industrial relevance
ð64PAC416Ł[ The reaction has been improved further with the discovery of the ester enolate Carroll
rearrangement ð73JOC611Ł\ where dianions of allylic acetoacetates are rearranged at elevated tem!
peratures to yield b!keto acids[ This methodology has been used in an approach to the PrelogÐ
Djerassi lactone framework wherein the dianion generated from b!keto ester "029# undergoes
rearrangement and decarboxylation to give cyclopentanone "020# "Scheme 63# ð82TL0038Ł[ The
reaction has also been used in the synthesis of the sesquiterpene isocomene ð77JOC3497Ł\ and a
modi_ed silyl ketene acetal variant has been used for the diastereoselective formation of contiguous
quaternary centres ð77T6476Ł[
Bui O Bui O Bui O
O OH
220 °C –CO2
O O 65%
Scheme 73
O O OLi LiO O
2LDA, THF trans:cis 4:1 H
O –78 °C O 71%
(130) (131)
Scheme 74
"f# Charè!accelerated Claisen rearranèments[ Since the _rst report of a carbanion!accelerated

Claisen rearrangement ð71JA3861\ 72JOC2258\ 73TL0432Ł considerable work has been performed on
this and other charge!accelerated rearrangements ð74JOC3553Ł[ Several anion stabilising groups have
been utilised and the most successful have proved to be arylsulfonyl groups ð78JA7767Ł\ phosphine
oxides and phosphonates ð70JCS"P0#1016\ 80JOC0992Ł as well as phosphonamide groups ð80JOC4952Ł^
in contrast\ ethoxycarbonyl! \ cyano! \ and cyanohydrin!groups do not promote the rearrangement
ð78JA7767Ł[ Examples are given in Scheme 64\ including an asymmetric example utilising the phos!
phorus!stabilised carbanion "021# ð76JOC4631\ 78TL1358Ł[
Remarkable rate accelerations are observed for the rearrangement of substituted allyl cyclo!
hexenyl ethers "022#[ The thermal rearrangement of ketone "022a# is slow\ having a half!life of 239 h\
0\1!shifts 722
O O K-DMSO O O O O
LiCl, RT 90:10 selectivity
O P P O P
N – 78% N
But But
(132)
O
–
O KH, LiCl
O
95:5 selectivity TolSO2
TolSO2 TolSO2
DMSO, 50 °C 85%
Scheme 75
whilst the rearrangement of carbomethoxyhydrazone "022b# and its sodium salt "022c# are con!
siderably accelerated with half!lives of 11 h and 0[4 h\ respectively ð79JOC3302\ 79TL3792\ 72JOC2755\
72TL2Ł[ The metal enolate "023# ð74JA4461Ł also undergoes accelerated rearrangement\ and this
methodology has also found synthetic application ð77TL3118Ł^ related accelerated rearrangements
of vinyl ~uorides ð63BSF1961Ł and enamines are also known ð73CC0316Ł[ Though not necessarily a
charge!accelerated reaction\ the ketene Claisen rearrangement of allylic ethers "024# also proceeds
with good yields "Scheme 65# ð67HCA2985\ 72JOC759Ł[
THF, reflux
O O
X X
(133) a; X = O
b; X = NNHCO2Me
c; X = NN– CO2MeNa+
O M+ O–
HO
O Me2CuLi O 0 °C, 15 min O
THF, –78 °C ~100%
(134)
Zn, Cl3CCOCl
+ ~60%
Et2O
O O O
Cl
–O O
(135) Cl Cl
Cl
Scheme 76
"ii# Thia!Claisen rearranèment

The ð2\2Ł sigmatropic rearrangement of allyl vinyl thioether\ the thia!Claisen rearrangement
"commonly referred to as the thio!Claisen rearrangement# is a facile process which has many
parallels with the parent reaction ð68PS"6#58Ł[ The acyclic and aromatic rearrangements occur under
relatively mild conditions^ however\ the thioaldehydes that are formed are unstable and undergo
further reaction to generate cyclised products[ Thermal rearrangement of allyl vinyl thioether "025#
leads to the formation of bicyclic product "026#^ if\ however\ the reaction is performed in the
presence of an acid anhydride\ the intermediate thioketone is trapped\ to give "027#\ and the
cyclisation step is averted "Scheme 66# ð76TL5350Ł[ An alternative strategy is to conduct the reaction
under conditions which will e}ect hydrolysis of the thioaldehyde to the corresponding aldehyde
ð69JA4411\ 61CC51\ 62JA1582Ł^ many other examples of the reaction are known ð63JOC0464\ 66JOC061\
68PS"6#58\ 70JA0646\ 75H"13#2236\ 76JOC269\ 78CC303\ 89TL412Ł[ Similar reactions have been reported for
allyl vinyl sulfoxide rearrangements to give g\d!unsaturated sul_nes\ which again undergo hydrolysis
to furnish the corresponding aldehydes ð74JA5620\ 80JCS"P0#2088Ł^ the corresponding sulfone
rearrangement to a}ord unstable g\d!unsaturated sulfenes is also known ð65JA2201Ł[
Pr
NMe
Pr Pr S
120 °C (137)
NMe NMe
DME, 60 min Pr
S S
(136) (PrCO)2O NMe
PrCOS
(138)
Scheme 77
Reports have highlighted chirality transfer and asymmetric induction in the reaction^ for example\
the diketene thia!Claisen rearrangement of allylic sulphide "028# proceeds with complete 0\1!induc!
tion via the transition state shown in Scheme 67 ð70JOC1117\ 73JOC0739\ 78TL2406\ 80AG"E#0354Ł[
Correspondingly high levels of syn!stereoselectivity have been observed for the rearrangement
of allyl ketene dithioacetals ð80T5164Ł and\ in the thia!Claisen rearrangement of S!crotyl ketene
dithioacetals such as "039#\ it is possible to control the formation of three contiguous stereogenic
centres ð81T09204\ 82T2020Ł[ S!Allylation of thioamides\ for example "030#\ followed by treatment
with base e}ects the formation of allyl vinyl thioether "031# which undergoes rapid rearrangement
under remarkably mild conditions "Scheme 67# ð79JA1281Ł^ attempts at developing an asymmetric
version of this reaction have also been reported ð76JA5605Ł[
Cl3CCOCl TBS-O
TBS-O Zn/Cu/Et2O Cl TBS-O Cl Cl
S+ Pri
SPri 87%, 94% de
SPri
R reflux, 3–5h R R
Cl
(139) O– O
HO S
H
cyclohexane
OH S 80 °C, 3–5 h R SMe
R SMe R = Me, But, Pri, 52–95%

63–94% selectivity
(140)
Br dbu
N N
ButOH RT
S S+ Br–
(141)
N N
81%
S S
(142)
Scheme 78
0\1!shifts 724
0[07[1[5[1 Where ZN^ the aza!Claisen rearrangement and related processes
Many examples of the aza!Claisen rearrangement have been reported and have proved useful
in synthesis[ The aliphatic aza!Claisen reaction is known\ requiring high temperatures to e}ect
rearrangement ð64OR"11#0Ł^ however\ the use of both Bronsted and Lewis acids results in e}ective
catalysis of the reaction[ For example\ the rearrangement of allylic enamines "032# to imines "033#
is easily e}ected under mild conditions using a range of catalysts "Equation "15## ð67TL3226\ 72TL0910\
81JOC6077Ł[ The 2!aza!Cope rearrangement of N!alkyl!N!allylanilines has also been the subject of
extensive study ð46JOC0307\ 60TL3550\ 62HCA094\ 66HCA867\ 73TL2048Ł\ and this process is again easily
promoted by Lewis acid catalysis which generally lowers the temperature required for the reaction
by over 099>C ð82JOC4984Ł[
A powerful extension of the rearrangement is found in the rearrangement of homochiral N!alkyl!

N\O!ketene acetals\ for example "034#^ this intermediate undergoes rapid rearrangement under very
mild conditions with excellent diastereocontrol ð74JA332\ 74JOC4658\ 75JOC0266\ 76TL0920\ 77S251Ł[ A
further variant is the zwitterionic aza!Cope rearrangement which involves the treatment of tertiary
amines\ for example "035#\ with propiolate esters to e}ect the formation of the zwitterionic enamine
intermediates "036# which undergo facile rearrangement to give enamines "037# "Scheme 68#
ð72JOC3151Ł[ Many examples of this reaction are known and it has found extensive use in alkaloid
synthesis ð73JOC1697\ 73TL1292\ 78JOC1782\ 89JA6571\ 89JCS"P0#0382Ł[ The rearrangement of N!allyl ket!
enimines "038#\ readily generated from N!allyl amides\ provides a useful synthesis of b\g!unsaturated
nitriles ð80TL068Ł and several alternative methods are also available for the generation of the
intermediates required for the reaction "Scheme 79# ð80JOC869\ 80TL3930\ 80TL6122Ł[ A 2!aza!IrelandÐ
Claisen rearrangement has also been reported ð89TL616Ł[
i,
OTos
N O ii, LiPri, THF, –78 °C N O 70%, >97:3 N O
Ph Ph Ph
H
(145)
O O CO2Et
H
O O
CO2Et
+ In N
MeCN, reflux N 68%
In
In O O H
N –
CO2Et
(146) (147) (148)
In = indole
Scheme 79
0[07[1[6 Other Heteroatom Variants
Many heteroatom variants of the Claisen rearrangement "2!hetero!Cope rearrangement# have
been reported[ Possibly the most remarkable of these is the metallo!Cope rearrangement ð75TL0928\
75TL0932\ 75TL3316\ 75TL3320\ 80TL4858Ł[ For example\ lithiation of Z!vinyl iodide "049# followed by
treatment with crotyl magnesium bromide and transmetallation with zinc bromide generates the
organozinc intermediate "040#^ this then undergoes rearrangement to the stable bimetallic species
"041# which on hydrolysis gives the product "042# with excellent diastereocontrol "Scheme 70#[
Examples of the 2!phospha! ð75CL490Ł and 2!sila!Cope ð62JOC2547Ł rearrangements are also
known[
But But
OBut Pr CrotylMgBr Pr
ButLi O O
Pr I
Li ZnBr2
Zn
H H
(150) (151)
M M
H2O
75%, >95:5
OBut OBut
(152) (153)
Scheme 81
0[07[1[7 Where YZ0C0Z?

A variety of 0\2!diheteroanalogues of the ð2\2Ł!sigmatropic Cope rearrangement are known and
have been reviewed ð79T2\ 73AG"E#468\ 73CRV194\ 77CRV0312\ 78S60Ł[
0[07[1[7[0 Where Z and Z?chalcogen

The ð2\2Ł!rearrangement of allylic acetates is a palladium catalysed ð79JA6476\ 73AG"E#468\ 89JOC3503\
82JCS"P0#1802Ł or thermal process] this process normally leads to equilibrium mixtures which slightly
favour primary allylic acetates where possible[ Either reaction usually proceeds with complete
transfer of absolute or relative stereochemistry as illustrated by the rearrangement of the acetates
"043# or "044# "Scheme 71# ð89JOC3503\ 82JCS"P0#0738Ł[ The related mercury"II# catalysed rearrange!
ments of allyl!N\N!dimethylcarbamic esters is also of considerable synthetic importance ð67JA3711Ł[
O!Allylic dithiocarbonates\ for example "045#\ also undergo facile rearrangement ð76TL4862Ł and
this particular example\ which is catalysed via a b!cyclodextrin complex\ proceeds to give the
isomeric S!allylic dithiocarbonate "046# in a remarkable 35) ee ð80TL6446Ł[ Examples of the reaction
are also known to e}ect ring expansions ð80CPB0548Ł and a thiolcarbonate variant has been used in
pheremone synthesis ð82T6546Ł[ The corresponding rearrangement of allylic dithiocarbamates has
found considerable synthetic application and a typical example is the thermal rearrangement of
"047# "Scheme 72# ð89TL3044Ł[
0[07[1[7[1 Where Z and:or Z?nitrogen

The rearrangement of trichloroimidates "Overman|s methodology# has been used extensively in
synthesis ð79ACR107Ł[ For example\ the thermal rearrangement of trichloroimidate "048# generated
0\1!shifts 726
Ar Ar
O O 190 °C, PhCN O O

C5H11 82% C5H11
Ph2OP Ph2OP
(154)
O O OAc
O O
C6H6, Pd(MeCN)2Cl2, RT, 14–72 h
R1 R1
90–96%
R2 R3 R2 R3
(155) R1 = H, Me, fused aryl (Z):(E) 3:1–20:1
R2 = Me, TMS, Bun, OEt, fused aryl
R3 = H, Me, Cl
Scheme 82
S O beta-cyclodextrin S O
Me H2O, 2–5 °C, 7 d Me
S S
80%, 46% ee
Ph Ph H
(156) (157)
HO HO
R CCl4, reflux, 5 h R
S S S S
R = alkyl, aryl, 84–89%
N N
(158)
Scheme 83
the amide "059# with complete transfer of chirality^ the product subsequently being used for the
total synthesis of the alkaloid "R\R#!crinan ð82T4066Ł[ The reaction is also facilitated by palladium
catalysis ð73AG"E#468\ 82S618Ł and generally proceeds with complete stereocontrol\ although excep!
tions are known ð81TL3202Ł[ The related rearrangement of O!tetrahydropyranylhydroximates\ for
example "050#\ has also been reported "Scheme 73# ð83TL04Ł[ N!Allyl!1!thiones are also formed
from the ð2\2Ł!sigmatropic rearrangement of 1!allylthioimadazoles ð57ZOR0003Ł[ The preparation of
allylic isocyanates "052# has been reported using the sigmatropic rearrangement of allylic cyanates
"051# "Scheme 74# ð80SL127Ł^ a 0\2!diphospha!Cope rearrangement has also been reported ð76CB020Ł[
0[07[1[8 Where YZ

The acid!catalysed rearrangement of allylic alcohols is a process of some importance in organic
chemistry ð38JCS285\ B!52MI 007!93\ B!53MI 007!91Ł[ The reaction is typi_ed by the sulfuric acid!catalysed
rearrangement of allylic alcohol "053# to its conjugated isomer "054# ð34JCS89Ł\ as was used in the
original synthesis of vitamin!A "Equation "16## ð36HCA378\ 36HCA0800Ł[ In favourable cases the use
of Bronsted or Lewis acids can e}ect the transformation cleanly and in high yield^ however\ many
side reactions can also occur including elimination "to produce dienes#\ skeletal rearrangements\
cyclisations and polymerisation[ These problems have led to the development of other methodology
toluene, reflux
O NH 75% O NH
CCl3 CCl3
(159) (160)
Ph O Ph O
xylene, reflux
N 68% N
THP-O THP-O
(161)
Scheme 84
O N
N O
Tf2O • N
H2N O EtPri2N, CH2Cl2 O N H HN O
–78 °C 83%
Ph Ph Ph Ph
(162) (163)
Scheme 85
for e}ecting oxygen transposition including metal!catalysed rearrangements of allylic acetates "see
Section 0[07[1[7[0# and related systems ð67JA3711Ł[ ð0\4Ł!sigmatropic rearrangements of oxygen
"ethers# and nitrogen functions "tertiary amines# are also known ð65CRV076Ł[
H2SO4, RT, 48 h
OH (27)
80%
OH
(164) (165)
The ð0\2Ł!sigmatropic migration of boron is a facile process ð57ACR041\ B!79MI 007!91Ł and this
leads to a ~eeting existence for simple allyl boranes[ The rearrangement is accelerated by Lewis
acids ð63PAC494Ł and is inhibited by complexation of the borane with amines ð66JOM"021#8Ł[ Brown
has reported the facile rearrangement of a!substituted allyl boronate esters "055# to the more
thermodynamically stable primary boronates "056# "Equation "17## ð89TL6004Ł[ The thermal
rearrangement of allylic halides has been observed ð48JCS1619Ł\ and some ð0\4Ł!sigmatropic
migrations are also known ð65CRV076Ł[ The thermal ð0\2Ł!rearrangement of allylsilanes is known to
proceed with inversion at silicon\ favouring the most highly substituted alkene product but leading
to mixtures of stereoisomers ð61JA1404\ 62JA7567Ł[ Tin and germanium analogues of this process are
also known\ as are some ð0\4Ł!rearrangements of these systems ð65CRV076Ł[
R R
reflux, toluene
B 24–36 h B
O O O O (28)
84–92%, mostly (E)
(166) (167)
0[07[1[09 Where YZ0Z?
0[07[1[09[0 Where Z\ Z?chalcogen

The rearrangement of allylic peroxides via intermediate peroxy radicals is catalysed by free!
radical intermediates or light and has been shown to proceed by a concerted ð1\2Ł!process ð89JA0155Ł^
0\1!shifts 728
the reaction was _rst observed by Schenck ð47LA"507#191Ł for cholesterol hydroperoxides but has
limited synthetic use[
Perhaps the most important rearrangement in this area is the reversible ð1\2Ł sulfoxideÐsulfenate
rearrangement[ This reaction is of considerable importance in the synthesis of allylic alcohols by in
situ decomposition of the sulfenate to destroy the equilibrium process ðB!77MI 007!90Ł[ A rep!
resentative example of each reaction is shown in the tandem ð1\2ŁÐð1\2Ł rearrangement of the diester
"057# "Scheme 75# ð71TL2352Ł[ A similar process is also observed for the ð1\2Ł sigmatropic selenoxideÐ
selenate rearrangement^ an integral process in the selenium dioxide oxidation of allylic carbon
centres ð65OR"13#150Ł[
Ph
–O + S O
SPh RT O PhS
( ) 3h ( ) >60% ( )
4 CO2Me 4 CO2Me 4 CO2Me
OCOPh OCOPh OCOPh
(168)
Scheme 86
0[07[1[09[1 Where Z and:or Z?nitrogen

The ð1\2Ł!sigmatropic rearrangement of amine oxides to the corresponding hydroxylamine has
been shown to be a particularly facile process ð33JA0818Ł and proceeds with exceptionally high levels
of asymmetric transfer ð62CC737Ł[ For example\ oxidation of homochiral g!N\N!dibenzylamino!a\b!
unsaturated esters "058# e}ects formation of an intermediate amine oxide "069#\ which undergoes
low temperature ð1\2Ł!sigmatropic rearrangement with complete 0\2!transfer of chirality ð80TL3370Ł[
The reaction has also been used in a nonasymmetric sense for the preparation of naturally occurring
terpene alcohols ð89BCJ0217Ł[ In a related process allyl ethers of oximes\ for example "060#\ are also
known to undergo a reversible formal ð1\2Ł!shift with the corresponding N!allyl nitrone "061# via
radical pair intermediates\ the example given being best e}ected using palladium catalysis ð80TL168Ł^
a sulfur heterologue of this reaction is also known ð80JA2415Ł[ The Stevens!like ð1\2Ł!rearrangement
of allylic aminoamidates\ for example "062#\ has also been observed "Scheme 76# ð72JCS"P0#0918Ł[
R CO2Et R CO2Et R CO2Et

mcpba, CH2Cl2 TBSOCH2
NBn2 –50 °C, 48 h Bn2N + 70–80%, >95% ee O

O– Bn2N
(169) (170) R = Me, Bn, Bui
Ph
O PdCl2(MeCN)2 (15 mol%) + O–
Ph N reflux CH2Cl2 N
70%
(171) (172)
Ph
Ph
+ PhH, reflux
Me N
N– 68% Me N NHPh
Me N
O NHPh Me O
(173)
Scheme 87
0[07[1[00 Where YZ0Z0Z
A duality of mechanisms is possible in trihetero!ð2\2Ł!rearrangements\ for example\ the rearrange!
ment of the allylic!p!nitrophenylsulfonyl derivative "063# is thought to proceed via a concerted
ð2\2Ł!sigmatropic process involving a chair!like transition state ð80JOC0903Ł\ whereas the related
rearrangement of allylic thionophosphates involves ion!paired intermediates "Equation "18##
ð80JA3784Ł[
O O
OEt reflux, PhMe, 24 h OEt

O O (29)
O 100% O
S S
O Ar
Ar O
(174)
0[07[2 OTHER REARRANGEMENTS
0[07[2[0 Tandem and Higher Sigmatropic Rearrangements

The _eld of tandem sigmatropic rearrangements is one of considerable interest and represents a
powerful synthetic application of rearrangement methodology ð80COC"4#764Ł[ The para!Claisen
rearrangement is an early example of the tandem ClaisenÐCope rearrangement ð15LA"338#70Ł "see
also Sections 0[07[1[3[0["i# and 0[07[1[5[0["i#"b##\ and this process has also found considerable
application in aliphatic systems\ as exempli_ed by the synthesis of b!sinesal "064# ð58JA2170Ł[ The
CopeÐClaisen sequence is also known[ For example\ the substrate "065# is transformed into the
aldehyde "066# as the major product^ the latter compound was subsequently used in natural product
synthesis "Scheme 77# ð71JA6070Ł[
OEt
O
Claisen
OH Hg(OAc)2
100 °C, 48 h
O
Cope
CHO
(175)
H
selectivity
306 °C ~4:1
40 min 85%
O
CHO
O
(176) (177)
Scheme 88
Numerous higher order sigmatropic rearrangements are known and have been the subject of
many theoretical studies^ however\ they have found limited application in synthesis ðB!55MI 007!90Ł[
A ð2\4Ł!sigmatropic rearrangement has been put forward to rationalise the rearrangement of
Other Rearranèments 730
vinylcyclopropane "067# to dihydroindene "068# ð75CC0796Ł\ and a ð4\4Ł!sigmatropic process is
thought to occur in the oxy!Cope rearrangement of "079# "Scheme 78# ð70T2856\ 70TL1360Ł[ A ð6\6Ł
rearrangement has also been reported ð74TL0946Ł[
CO2Et
H CO2Et
80 °C
Ph
H Ph
(178) (179)
OH KH, THF O
1 h, RT
90%
H
(180)
Scheme 89
0[07[2[1 Rearrangements That Involve Ring Opening
0[07[2[1[0 Ring opening of cyclopropanes

Many rearrangement processes are known in cyclopropane chemistry[ These can be e}ected under
a variety of conditions including thermal\ photochemical or metal!catalysed ðB!76MI 007!93Ł[ The
photochemical irradiation of arylcyclopropanes provides an example of a typical rearrangement
which in general leads to a mixture of many products\ including variable amounts of substituted
propenes "Scheme 89# ð68MI 007!90Ł[ Indeed\ yields of products are not generally good or predictable
in such reactions\ as several mechanistic pathways are known to operate ð72JOC1191\ 77JA2590\
77JOC1695\ 77JOC1600Ł[ An example of a Rh"I#!catalysed rearrangement is also given in Scheme 89
ð61JA6646\ 62TL1616Ł[
hν, MeOH AcO

OAc
18%
Tol Tol
hν, cyclohexane
+
Ph 65%; 16% Ph Ph
CO2Me CO2Me CO2Me

[Rh(CO)2Cl]2 (5 mol%)
+
CHCl2, 65 °C, 22 h
69%
H
~1:1
Scheme 90
0[07[2[1[1 Photochemical ring opening of cyclic ketones

The photochemical ring cleavage of cyclic ketones to yield v!unsaturated aldehydes is a useful\
if somewhat unpredictable\ process ð69TL0064\ B!79MI 007!92Ł[ Synthetic examples of note include the
ring opening of macrocyclic ketone "070# ð66TL652Ł and the formation of medium ring lactones
from epoxy ketone "071# ð62CC112Ł^ a reaction using a cyclopropane in place of the epoxide has
been used in the synthesis of medium ring ketones ð58CC0938\ 61BCJ0666Ł[ The reaction has also
found an application in the total synthesis of insect pheromones "Scheme 80# ð62TL2348Ł[
O O
hν
75%
(181)
O O O O
hν, hexane O O
+
42%; 20%
(182)
Scheme 91
0[07[2[1[2 Rearrangements of epoxides

Several fragmentation reactions of epoxides result in the formation of unsaturated alcohols[ The
rearrangement of epoxides to allylic alcohols has been well documented and occurs under a variety
of conditions ð72T1212\ 73S518Ł[ Base!mediated rearrangement of epoxides is a common process and
the use of the hindered bases such as LDA can result in excellent regioselectivity\ for example\ in
the rearrangement of epoxide "072# "Scheme 81#[ Homochiral bases have also been used in the
enantioselective rearrangement of meso!epoxides ð80TA0\ 82CC773Ł[ Fragmentation with ring open!
ing is also known and perhaps the most elegant application is found in the two epoxide rearrange!
ments reported by Holton ð73JA4620\ 73TL3344Ł[ Treatment of b!patchouline oxide "073# with boron
tri~uoride etherate e}ects rearrangement with a ð0\1Ł carbon shift to give homoallylic alcohol "074#^
epoxidation of "074# leads to the intermediate "075# which rearranges in situ with ring _ssion\ to
give the taxane AB!ring model "076#^ extension of this chemistry led to the _rst total synthesis of
taxol ð83JA0486\ 83JA0488Ł[
O
LDA, THF OH
–50 °C, 3 h
95%
(183)
BF3•OEt2 ButO2H, Ti(OPri)4
65% 0 °C, 1 h
OH
O
(184) (185)
DMS, reflux
HO
83%
OH
O O
(186) (187)
Scheme 92
1.19
Tricoordinate Anions, Cations,
and Radicals
JULIAN O. WILLIAMS
University of Exeter and White Knight Chemicals Ltd, Paignton, UK
and
MICHAEL J. KELLY
University of Exeter, UK
0[08[0 TRICOORDINATE CARBANIONS 733
0[08[0[0 General Aspects of Carbanion Formation 733
0[08[0[0[0 General literature survey 733
0[08[0[0[1 Different types of carbanion 734
0[08[0[0[2 Simple alkyl carbanion formation 734
0[08[0[0[3 Carbanions stabilised by conjuàtion 736
0[08[0[1 Carbanions by Proton Loss 737
0[08[0[1[0 Carbanion formation by proton loss stabilised by hybridization effects 737
0[08[0[1[1 Carbanion formation by proton loss stabilised by conjuàtion 738
0[08[0[1[2 Carbanion formation by proton loss stabilised by induction 740
0[08[0[1[3 Carbanion formation by proton loss stabilised by multiple substituents 741
0[08[0[1[4 Kinetics of base!catalysed formation of carbanions 742
0[08[0[1[5 Carbanion formation stabilised by conjuàtion with heterocyclic systems 748
0[08[0[1[6 Carbanion formation by proton loss stablised in accordance with the Huckel "3n¦1# rule 750
0[08[0[1[7 Destabilised carbanion formation by proton loss viewed in the context of the Huckel
"3n¦1# rule 753
0[08[0[1[8 Formation of homoaromatic carbanions by proton loss 754
0[08[0[1[09 Formation of the phenalene anion by proton loss 755
0[08[0[1[00 Carbanions derived from unsaturated acidic hydrocarbons involvin` stabilisation by very
extensive delocalisation 755
0[08[0[1[01 Carbanion stabilization by a nonadjacent p!bond] the formation of homoenolate anions 756
0[08[0[1[02 Kinetic versus thermodynamic factors determinin` the course of enolisation 758
0[08[0[1[03 Factors determinin` the course of ketone and aldehyde enolate formation 762
0[08[0[1[04 Factors determinin` the course of ester and amide enolate formation 765
0[08[0[1[05 Structural effects on the enerètics of s!cis and s!trans dienolates 766
0[08[0[1[06 Chiral auxiliaries conferrin` stereocontrol over enolate reactions 767
0[08[0[1[07 Stereoelectronic effects in the formation of enolates and related functions 767
0[08[0[1[08 Dicarbanion formation by proton loss 768
0[08[0[1[19 Choice of base and solvent for the formation of various types of carbanion stabilised
by conjuàtion 779
0[08[0[1[10 Metallation of N!alkylimines 770
0[08[0[1[11 Carbanion formation with concomitant double!bond rearranèment 771
0[08[0[2 Carbanions by Scission of C0C or C0X Bonds 772
0[08[0[2[0 General considerations of carbanion formation by C0C bond scission 772
0[08[0[2[1 Formation of carbanions by decarboxylation 772
0[08[0[2[2 Formation of carbanions durin` cleavaè of alkoxides 772
0[08[0[2[3 Carbanion formation by acyl cleavaès 772
732
733 Tricoordinate Anions\ Cations\ and Radicals
0[08[0[2[4 Carbanions derived from orànometallic species 774
0[08[0[2[5 Formation of carbanions by scission of C0O and C0haloèn bonds 775
0[08[0[2[6 Formation of carbanions by scission of C0N bonds 776
0[08[0[3 Carbanions by Addition to C1C Bonds 777
0[08[0[3[0 Nucleophilic addition to C1C bonds resultin` in carbanion formation 777
0[08[0[3[1 Carbanion formation durin` sin`le electron transfer to C1C bonds 778
0[08[1 TRICOORDINATE CARBOCATIONS 789
0[08[1[0 General Aspects of Carbocation Formation 789
0[08[1[0[0 Nomenclature 789
0[08[1[0[2 General features of carbocation formation and structural stability 780
0[08[1[1 Carbocations by Bond Scission 786
0[08[1[1[0 Aryl!substituted carbocations by bond scission 786
0[08[1[1[1 Alkyl carbocations by bond scission 788
0[08[1[1[2 Enyl carbocations by bond scission 890
0[08[1[1[3 Ynyl and cyano carbocations by bond scission 893
0[08[1[1[4 Nonclassical carbocations "carbonium ions# by bond scission 893
0[08[1[1[5 Formation by bond scission of carbocations stabilised in accordance with the Huckel
"3n¦1# rule 895
0[08[1[1[6 Phenalene cations by bond scission 809
0[08[1[2 Carbocations by Addition to C1C Bonds 800
0[08[1[2[0 Stable carbocations by protonation of alkenes 800
0[08[1[2[1 Stable carbocations by protonation of dienes 800
0[08[1[2[2 Dienylic and polyenylic cations by protonation of trienes and polyenes 801
0[08[1[2[3 Arenonium and phenonium ions 803
0[08[1[2[4 Azulenyl carbocations 805
0[08[1[2[5 Homotropylium and homoaromatic carbocations 806
0[08[1[2[6 m!Hydrido!bridèd carbocations 807
0[08[2 TRICOORDINATE RADICALS 808
0[08[2[0 General Features of Radical Formation 808
0[08[2[0[1 Description of the different character of carbon!centred radicals 808
0[08[2[0[2 Stability and structure of carbon!centred radicals 810
0[08[2[0[3 Solvent and concentration effects 812
0[08[2[0[4 Initiation 813
0[08[2[0[5 Vicinal substituent 814
0[08[2[1 Radicals by Bond Scission 814
0[08[2[1[0 CarbonÐhydroèn bond scission 814
0[08[2[1[1 CarbonÐcarbon bond scission 817
0[08[2[1[2 CarbonÐhaloèn bond scission 824
0[08[2[1[3 CarbonÐchalcoèn bond scission 827
0[08[2[1[4 CarbonÐnitroèn bond scission 833
0[08[2[1[5 CarbonÐboron bond scission 835
0[08[2[1[6 CarbonÐcobalt bond scission 835
0[08[2[1[7 CarbonÐmercury bond scission 837
0[08[2[2 Radicals by Addition to C1C 837
0[08[2[2[0 The addition of oxyèn!centred radicals to C1C 837
0[08[2[2[1 The addition of sulfur!centred radicals to C1C 838
0[08[2[2[2 The addition of nitroèn!centred radicals to C1C 849
0[08[2[2[3 The addition of `roup IV!centred radicals to C1C 849
0[08[0 TRICOORDINATE CARBANIONS
0[08[0[0 General Aspects of Carbanion Formation
0[08[0[0[0 General literature survey

Since the 0859s\ a number of monographs have been published covering general aspects of
carbanion chemistry ðB!79MI 008!90\ B!72MI 008!92\ B!73MI 008!90\ B!76MI 008!90Ł[ Cram discussed in
general the relationship between carbanion structure and reactivity ðB!54MI 008!90Ł[ Synthetic appli!
cations were speci_cally described by Stowell ðB!68MI 008!90Ł[ Streitwieser and Hammons surveyed
the estimation of hydrocarbon acidity by kinetic and thermodynamic methods ð54MI 008!95Ł[ Ex!
change reactions in liquid ammonia have been reviewed ð52APO"0#044Ł[ Albery ð56MI 008!96Ł\ Eigen
ð53AG"E#0Ł and Grunwald ð54MI 008!96Ł dealt with rapid proton!transfer reactions[ Fischer and
Rewicki considered the chemistry of acidic hydrocarbons ð57MI 008!94Ł[ Carbocyclic nonbenzenoid
Carbanions 734
aromatic carbanions have been reviewed by Lloyd ðB!55MI 008!90Ł[ The subject of saturated "sp2#
carbanions adjacent to both heterocyclic and nonheterocyclic nitrogen has been reviewed ð77PIA076\
81T1478Ł[ General reviews on carbanions have appeared frequently ðB!57MI 008!90\ 57MI 008!95\
58FCF276\ B!62MI 008!90\ B!62MI 008!93\ 67MI 008!90\ 67RCR314\ 68COC"1#300\ B!67MI 008!90\ 70MI 008!90\
74MI 008!90\ B!81MI 008!90Ł[ The subject of carbanions in general and electrophilic aliphatic substitu!
tion in particular has been reviewed at yearly intervals\ the latest in the series being in 0880
ðB!80MI 008!90Ł[
0[08[0[0[1 Different types of carbanion

Carbanions may be divided broadly into two classes ðB!76MI 008!91Ł]
"i# Short!lived reactive intermediates in solution in basic conditions\ found in base!catalysed
deuterium exchange\ ElcB eliminations and a!eliminations[ In these cases\ another substance in the
solution "often the solvent# acts as proton donor^ such a carbanion exists in equilibrium with its
conjugate acid or is present only as a stationary!state intermediate and is probably in low con!
centration with a brief lifetime[
"ii# Carbanions\ or the closely related organometallic compounds\ which occur in solution at
higher concentration with longer lifetimes[ The solvent must be markedly less acidic than the
conjugate acid of the carbanion and not vulnerable to nucleophilic attack[ Typically anhydrous
ether proves to be a suitable solvent for such carbanions[
The occurrence of carbanions in moderate to high concentration in aqueous solution is somewhat
limited because a C0H bond will dissociate appreciably in aqueous solution only if substituted by
two or three strongly electron!withdrawing groups[ However\ dipolar aprotic solvents such as
acetonitrile\ hexamethylphosphoramide "HMPA# or DMSO can sustain signi_cant concentrations
of less strongly stabilised carbanions[ In such solvents carbanions may sometimes exist as free ions\
but more often they will exist in the form of solvent!separated or contact ion pairs[ In the less!acidic
solvents\ such as THF\ 1!Me!THF\ DME and the higher glymes\ diethyl ether and pentane\ strong
ion pairing of a carbanion with its gegenion will be normal[ When not stabilised by an electron!
delocalising group\ the anion is likely to bond covalently to the cation\ forming a polar covalent
compound[
In organometallic compounds a carbanion provides a s!electron pair and is said to be a s!donor
ligand of the metal\ as in for example alkyllithium and alkyl magnesium compounds[ Certain
carbanions also bond strongly to transition metals\ particularly those in low oxidation states\
through a combination of s! and p!bonding\ with the ligand carbanion donating an unshared pair
to form a s!bond "or in the case of alkenes\ one or more pairs of p!electrons to give dpÐpp!bonding#
to the metal and receiving electron density from _lled metal d!orbitals into empty p!orbitals to
give dpÐpp!bonding[ Such complexes undergo a variety of reactions useful in synthetic organic
chemistry[
0[08[0[0[2 Simple alkyl carbanion formation

Heterolytic cleavage of one of the bonds of a tetrahedrally coordinated carbon atom in molecule
"0# can occur in such a way as to leave a net negative charge on the resultant tricoordinate carbon
atom "1#\ "Equation "0##[
R1 R1
R2 X R2 – X+ (1)
R3 R3
(1) (2)
Although the evidence for the existence for such species as "1# is overwhelming\ they are usually
highly unstable\ transient and not given to direct observation[ Their existence and physical charac!
teristics can frequently only be inferred by examination of the products or kinetics of a given
reaction ðB!81MI 008!91Ł[
Every carbanion possesses an unshared pair of electrons and is therefore\ by de_nition\ a Lewis
base[ When a carbanion "e[g[\ 1# "Equation "1## is protonated\ it is converted into its conjugate acid
"e[g[\ 2#[ The stability of the carbanion is proportional to the strength of the conjugate acid[ The
weaker the acid\ the greater the strength of the base and the lower the stability of the carbanion[
Determination of the strengths of the conjugate acids immediately determines the order of stability
of a series of carbanions[
R1 R1
H+
R2 – R2 (2)
R3 R3
(2) (3)
The aliphatic C0H bond is relatively strong and largely covalent ðB!59MI 008!90Ł[ The removal
of a proton from a simple alkane consequently proves di.cult[ Consideration may be given to the
equilibrium between methane and its conjugate base in basic medium "Equation "2##[ A number of
factors combine to make the methyl anion an energetically unfavourable species\ and this equilibrium
lies overwhelmingly to the left[ Not least of the factors which destabilise the methyl anion is the
absence of any means to delocalise the negative charge[
CH4 + B– CH3– + BH (3)
There is no doubt that carbanions derived from simple alkanes are very unstable in solution[
There is even some evidence that simple carbanions such as ethyl and isopropyl degenerate to
radicals through the loss of an electron ð75TL3300\ 77JA596Ł[ However\ indirect methods have enabled
a study to be made of these species[ Applequist and O|Brien investigated ð52JA632Ł the position of
the equilibrium for the reaction in ether and ether:pentane "Equation "3##[
R1Li + R2I R1I + R2Li (4)
The rationale underlying these experiments was that the R group which forms the more stable
carbanion would be more likely to be bonded to lithium rather than iodine[ Carbanion stability was
found by this method to be in the order] vinyl×phenyl×cyclopropyl×ethyl×n!propyl×
isobutyl×neopentyl×cyclobutyl×cyclopentyl[ Later\ using a similar method\ Dessy et al[ set up
the equilibrium\ shown in Equation "4#\ treating a number of alkyl magnesium compounds with
various alkyl mercury compounds in THF solution ð55JA359Ł[
R12Mg + R22Hg R12Hg + R22Mg (5)
The group of greater carbanion stability is associated with the magnesium cation[ The order
of carbanionic stability\ determined by this method was] phenyl×vinyl×cyclopropyl×
methyl×ethyl×isopropyl\ which was in broad agreement with the work of Applequist and O|Brien[
It may be concluded that the stability of alkyl carbanions decreases in the order] methyl
×primary×secondary[ Dessy et al[ were unable to obtain data for the t!butyl anion\ but there can
be little doubt that it is even less stable[ This observed order of stability may be attributed to
inductive e}ects transmitted through the s!framework[ The ¦I methyl groups a to the isopropyl
carbanion serve to increase charge density at the central carbanionic atom\ leading to a decrease in
stability[ The results of Applequist and O|Brien show that b!branching also reduces carbanion
stability[ The cyclopropyl carbanion seems anomalously stable\ but this may be viewed as due to
ring strain promoting a large amount of s!character in the C0H bond[
There is no direct evidence as to the structure of unsubstituted alkyl carbanions\ since such species
have not been isolated[ However\ it is plausible that the charge!carrying carbon atom may be
regarded as sp2!hybridised with the lone pair of electrons directed towards one vertex of the
tetrahedron\ as shown in structure "3# "Equation "5##[ Such carbanions may be regarded as iso!
electronic with amines[ When R0 R1 R2 in structure "3# the carbanion may be viewed as chiral[
However\ such species undergo lone!pair pyramidal inversion with concomitant racemisation in
much the same way as tertiary amines "Equation "5##[
R3 2
R1 R
(6)
R1 R3
R2
(4)
Typically\ Letsinger ð49JA3731Ł found that in light petroleum:diethyl ether 1!octyllithium race!
mised slowly at −69>C\ but within minutes at 9>C[ Contrastingly\ Curtin and Koehl reported that
Carbanions 736
the compound required hours to racemize at −5>C in pentane ð59CI"L#151Ł[ The catalysis of the
racemisation by diethyl ether may be attributed to the coordination of the oxygen atom to the
lithium atom to promote ion!pair formation by the normally covalent organolithium compound
"Scheme 0#[
d-C8H17Li (OEt2)n d-C8H17– •Li(OEt2)n+
l-C8H17Li (OEt2)n l-C8H17– •Li(OEt2)n+
Scheme 1
Carbon atoms at bridgeheads form carbanions relatively easily and stable bridgehead carbanions
are known ð55MI 008!96Ł[ The pyramidal structure of unsubstituted alkyl carbanions is further
supported by Streitwieser et al[ ð58JA418Ł and Peoples and Grutzner ð79JA3698Ł[
0[08[0[0[3 Carbanions stabilised by conjugation

When a multiple bond is located a to the charge!bearing carbon atom\ the carbanion "4# "Equation
"6## is stabilised by conjugation between the unshared pair of electrons and the p!electronic system
of the multiple bond[
Z Z–
R3 R3 (7)
R1 – R1
R2 R2
(5a) (5b)
This phenomenon is responsible for the stability of the allylic ðB!69MI 008!90Ł and benzylic
ð63JA4697Ł carbanions "see Equation "7# and Scheme 1 respectively#[
– –
R R (8)
– –
Scheme 2
Diphenylmethyl and triphenyl anions are even more stable than the benzylic anion and
can be kept in solution inde_nitely\ provided anhydrous conditions are rigorously maintained
ðB!79MI 008!91Ł[ The diphenylmethyl and triphenyl carbanions enclosed by crown ethers have been
the subject of x!ray crystallographic analyses ð74JA1063Ł[
Methyl and alkyl anions have proved too reactive to have any well!characterised solution chem!
istry\ and even when the gegenion is a very electropositive metal like lithium\ the carbonÐmetal
bond is largely covalent[ Most of the existing knowledge of carbanion chemistry has been derived
from the study of more stable species[ It is certainly of importance to quantify relative carbanion
stability ðB!60MI 008!90Ł[ A suitable fundamental approach has been to measure acidÐbase equilibria\
in which both components are carbon acids[ By selecting anions that are highly coloured\ McEwen\
Conant and Wheland\ working in the 0829s\ were able to measure their concentrations spec!
trometrically and even colorimetrically[ They were able to draw up a hydrocarbon pKa scale
measured in ethereal solutions[ Typically\ a solution of the orange!coloured sodium salt of diphenyl!
methane\ Ph1CH− = Na¦\ on treatment with triphenylmethane\ was gradually converted into
diphenylmethane by proton transfer and the solution assumed a red colour due to the predominance
of the triphenylmethyl anion Ph2C−[ Quantitatively\ it was ascertained that triphenylmethane was
the more acidic by at least 1 pKa units[ By taking as a standard\ at one extreme\ a compound whose
pKa could be measured independently\ for example in aqueous solution\ this spectrometric technique
was used to obtain data for a range of hydrocarbon compounds with pKa values in the range 04 to
29 ð21JA0101\ 25JA0013\ 36JA1914Ł[ Simple colorimetric techniques were used to rank hydrocarbons in
a series of increasing acidity in ethereal solution ð21JA0101Ł[
Subsequently more re_ned work was carried out by Streitwieser et al[ in the polar protic solvent
cyclohexylamine\ which has very low acidity ð56JA52Ł[ These results served in general to con_rm
the earlier studies by McEwen et al[ ð25JA0013Ł[
When the negative charge of a carbanionic carbon atom is conjugated with a C1O double bond
or a carbonÐnitrogen multiple bond "Equation "6#^ ZO or N#\ the carbanion is stabilised to an
even greater extent than even triarylmethyl anions\ since such electronegative heteroatoms are more
able to accommodate the excess negative charge than carbon atoms[
For the anion "5# "Equation "8## the canonical form "5b# is the major resonance canonical\
contributing more to the hybrid than canonical "5a#\ because of the high electron a.nity of the
oxygen atom[ Nevertheless\ for the purposes of this chapter\ resonance hybrids such as that depicted
in Equation "8# are regarded as tricoordinate carbanions[
O O–
R3 R3
R1 R1 (9)
–
R2 R2
(6a) (6b)
Using both equilibrium and kinetic data\ a comparison of hydrocarbon acidities may be made
"Table 0# ð57JA0680\ B!60MI 008!91\ B!67MI 008!94Ł[ It should be noted\ however\ that even the most
acidic compounds tabulated form conjugate anions which are more strongly basic than aqueous
sodium hydroxide solution[
0[08[0[1 Carbanions by Proton Loss
0[08[0[1[0 Carbanion formation by proton loss stabilised by hybridization effects

The foregoing discussion in Section 0[08[0[0[2 has given an indication of the di.culties of
formation of tricoordinate alkyl carbanions\ which do not bene_t from resonance stabilisation[
There are\ however\ some factors which can conspire to stabilise such carbanions[
Within the context of the molecular orbital version of the quantum mechanical molecular model\
the shapes and distribution of electron density for 1s! and 1p!carbon orbitals and the characteristics
of various hybridised s:p mixtures may be calculated[ As the percentage of s!character of a carbon
spn!hybridised orbital increases\ the average distance\ measured over time\ between electron and
nucleus decreases\ and the coulombic term relating to stabilisation by electron cloud with carbon
nucleus electrostatic interaction increases[ Accordingly\ the acidity of a C0H bond is enhanced by
increasing s!character\ a phenomenon exempli_ed by the facile conversion of alkynes into alkynyl
carbanions\ and one which has wide implications in organic synthesis[
It has been found that the percentage of s!character in a C0H bonding orbital plays a major role
in determining the NMR spinÐspin coupling constant between 0H and 02C[ By taking alkyne\
ethylene and ethane as reference points\ it is possible to derive an empirical relationship between
percentage s!character and J02C*H\ as shown in Equation "09#[
J13C–H = 500 – 5(100 – %SC–H) (10)
Streitwieser et al[ measured the rates of hydrogen!isotope exchange of a series of C2 to C7 cyclic

hydrocarbons in cyclohexylamine containing caesium cyclohexylamide ð58JA416Ł and showed a
close correlation with J02C*H[ Highly strained hydrocarbons are su.ciently acidic to be deprotonated
by methyl lithium in ether ð54TL176Ł\ and reaction rates correlate with J02C*H values[ The increase
in kinetic acidity with decreasing ring size undoubtedly results from the increase in s!character of
the carbon orbital in the C0H bond ð54MI 008!95Ł[ Hydrogen!isotope exchange of cyclobutane with
caesium cyclohexylamide in cyclohexylamine in somewhat faster than that of cyclohexane\ and
cyclopropane reacts faster by a factor of approximately 094 ð50JCS62Ł[
The highly strained hydrocarbon\ tricyclo!ð3[0[9[91\6Ł!heptane "6#\ has been found to undergo
Carbanions 738
Table 0 Approximate pKa values for various hydrocarbons[
Compound pKa Compound pKa
H
~16 Ph2CH2 31b
H
Ph H
16.4a PhMe 35b
17.8b 35c
H
H
H H
20.6b 39c
H
Ph Ph
24.4b PhCHMe2 39c
Ph
Ph3CH 29b H 39c
43c
CH4 44c
48c
a 'Anchored' in aqueous solution. b Obtained from equilibrium data. c Extrapolated from isotopic exchange rates.
Reproduced by permission of John Wiley and Sons, Ltd. from 'Mechanism in Organic Chemistry' by R.W. Alder, R. Baker
and J. M. Brown © 1971.
rapid deuterium exchange with potassium t!butoxide in t!butyl alcohol at 88[4>C ð59JA2541Ł[ This
remarkable kinetic acidity is presumably a consequence of the high degree of s!character in the
C0H bond\ estimated from the J02C*H coupling constant to be 39)[
(7)
0[08[0[1[1 Carbanion formation by proton loss stabilised by conjugation

The above discussion implies that the lone!pair orbital of a localised carbanion will be most stable
when it has the maximum possible s!character[ It might be expected that an alkyl carbanion would
have strong preference for sp2!hybridisation over sp1 in which the lone pair is forced to occupy a
p!orbital[ In fact\ a pyramidal con_guration with sp2!hybridisation and C2n symmetry is predicted
for the CH2− anion theoretically by CNDO!type calculations ð57JA1360\ 58T3006Ł[ Such calculations
predict an energy barrier to pyramidal inversion of approximately 04 kcal mole−0[ The inversion
barriers of substituted\ and in some cases conjugated\ carbanions have been studied theoretically
by Niemeyer utilising CNDO:1 and STO!2G calculations ð66T1156Ł\ while the so!called {gauche
e}ect|\ with its stereochemical consequences for adjacent electron pairs and polar bonds\ was
reviewed by Wolfe\ with respect to ab initio molecular!orbital calculations ð61ACR091Ł[ A planar
sp1!hybridised trigonal conformation with D2h symmetry was predicted as an energy minimum for
the "N2C#2C− carbanion ð65AJC0524Ł[
Consideration of the benzyl anion reveals the operation of two opposing e}ects[ The tendency to
maximise the s!character of the orbital carrying the negative charge is opposed by the potential
energy bene_ts to be gained by increased delocalisation of the negative charge made possible if the
carbanionic lone pair is associated with a p!orbital[ There is no way of predicting a priori which
e}ect will predominate[ Recourse to the valence bond model "Scheme 1# indicates the possibility of
extensive resonance stabilisation and implies at least qualitatively that ppÐpp!delocalisation will be
a signi_cant stabilising factor[ Physical properties of the benzyl anion are consistent with the picture
of a highly delocalised species as depicted in Figure 0[ Signi_cantly\ the 02C!NMR chemical shift
and J02C*H "027 Hz for the PhCH1 methylene group\ compared with a coupling of 80 Hz for MeLi#
ð55JA0161Ł indicate the conformation with the atom centres coplanar is energertically favoured[
–
Figure 0 Stabilisation by ppÐpp delocalisation of the negative charge in the benzyl anion[
It would appear that there exists a considerable degree of stabilisation attributable to ppÐpp!
electron delocalisation in an sp1 carbanion of this type[ The relevant data in Table 0 indicate that
the successive substitution of phenyl groups for hydrogen atoms in methane increases the acidity
and decreases the pKa value in stepwise fashion by 8\ 02 and 04 pKa units[ The values imply that the
triphenylmethyl anion is 10 kcal mole−0 "RT loge0904# more stable than the methyl anion at 14>C[
It may be seen from the data that proportionately less energetic stabilisation is gained with each
sequential replacement of a hydrogen atom by a phenyl group[ As has been argued above\ the most
e}ective stabilisation occurs when all the atom centres are coplanar\ i[e[\ when the p!orbital of the
sp1!hybridised carbanionic carbon atom lies parallel to the p!orbitals which constitute the p!clouds
of the phenyl ring"s#[ This condition becomes increasingly di.cult to ful_l due to unfavourable
steric interactions as the number of phenyl substituents increases[ In fact\ the triphenylmethyl anion
is thought to be propeller!shaped "7#\ a structure which re~ects a compromise between energetically
favourable conjugative e}ects and unfavourable steric interactions[
–
(8)
Should a carbanionic carbon atom be adjacent to a ppÐpp!bond orbital whose remote conjugated
atom is oxygen or nitrogen\ a stable system may result[ In species such as enolate anions\ a!nitro!
carbanions\ and a!cyano!carbanions\ it is to be expected that most of the negative charge will reside
on the oxygen or nitrogen atom\ each of which is more electronegative than carbon[ The pKa values
observed for this type of system are generally much lower than those of analogous hydrocarbons[
Pearson and Dillon ð42JA1328Ł measured the acidities of various compounds and obtained the
following series of pKa values] CH2NO1 09[1^ CH2COCH2 19^ CH2CN 14^ CH2CO1Et 14^
CH2CH1CH1 24 "the active protons are italicised#[
The signi_cance of the role of resonance in the stabilisation of anions was quanti_ed by Belanger
et al[ who measured the rates of exchange of a!substituted phenylacetates in alkaline D1O "Scheme
2# ð58CC0956Ł[ With a carbanion of this type\ the degree of deformation from coplanarity of the
atoms involved in conjugation will vary with the steric interactions between the ortho protons of
Carbanions 740
the phenyl ring and the substituent R[ It is clear from the experimental evidence that the rate of
deuterium exchange increases with diminishing steric bulk of the group R[ In the case where RPri
there are considerable unfavourable steric interactions[
O O–
–
R
(8)
Relative rates of deuterium exchange as a function of the size of substituent R:
Pri = 1; Et = 18; Me = 155; H = 42 000
O O– O O–
H
H D2O, DO– –
H H
O O– –O O– –O O –O O
– –
R R R R
–
(8a) (8b) (8c) (8d)
Resonance stabilisation of the dianion (10)
Variation of steric inhibition of resonance stabilisation in the formation of planar or near-planar carbanions
Scheme 3
The base!catalysed isotope exchange of a hydrogen a to a −M substituent such as a carbonyl or

cyano functionality will normally result in the loss of chirality at that site since the intermediate will
be planar due to sp1!hybridisation at the carbanionic carbon centre[ However\ this general rule does
not apply in the case of an acidic proton bonded to either a cyclopropane ð51JA1354Ł or cyclopropene
ð57JA1587Ł ring[ For these two systems\ a nonplanar anion would seem to be preferred because of
the extra stabilisation inherent in the small three!carbon ring "see Section 0[08[0[1[0# and also
because of the additional bond angle strain needed to attain sp1!hybridisation in a three!carbon
ring[ The nitrile "8# undergoes deuterium exchange more than 3999 times faster than it racemises in
NaOMe:MeOD "Scheme 3#[
Consistent with the above observation\ a structurally related cyclopropyllithium was shown to
be con_gurationally stable under conditions where optically active alkyllithium compounds rapidly
racemise ð53JA2172Ł[
0[08[0[1[2 Carbanion formation by proton loss stabilised by induction

Almost all substituents which stabilise carbanions by conjugation also o}er signi_cant stabil!
isation by _eld and inductive e}ects ðB!60MI 008!92Ł^ alkyl substituents interact with carbanions by
_eld and inductive mechanisms alone[ Thus alkyl substitution at an sp2!hybridised carbanion causes
very marked destabilisation[ Methyllithium is stable for months in ethereal solution\ whereas
t!butyllithium can be kept only in hydrocarbon solvents in the absence not only of oxygen but also
of nitrogen[ Conversely tri~uoromethyl substituents are strongly stabilizing of carbanions and
"CF2#2CH has an estimated pKa 00 ðB!60MI 008!93Ł[ There is no doubt that in this case the nine
~uorine atoms combine to stabilise the resultant carbanion by induction as shown in structure "09#[
Additionally\ carbanion "09# may be regarded as being stabilised by resonance in the manner
–
Ph Ph – Ph Ph D
MeO– MeOD
≡
Ph Ph Ph C Ph
k1 (fast)
N N N N
(9) (nonplanar)
k2 (slow) k1 >> k2
–
N MeOD Ph N
Ph C N Ph C
Ph Ph D
Ph
–
(planar) (nonplanar)
Deuterium exchange and racemisation of a cyclopropyl-nitrile in MeONa/MeOD
Scheme 4
F CF3
F C C–
F CF3
(10)
shown in Scheme 4 ð49JA397\ B!48MI 008!90\ B!59MI 008!91\ 68COC"0#414\ 72T0030Ł[ Von R[ Schleyer and
Kos refer to this type of e}ect as {negative "anionic# hyperconjugation| and have investigated the
theoretical rationalisation using molecular orbital theory ð72T0030Ł[
F–
F F– F–
F F F+
:
F F F F F–
• etc.
–
F3C CF3 F3 C CF3 F3C CF3
F 3C CF3
(10a) (10b) (10c) (10d)
Scheme 5
0[08[0[1[3 Carbanion formation by proton loss stabilised by multiple substituents

As might be expected\ a multiplicity of suitably positioned substituents\ of the requisite type\
serve to increase the stabilisation of a carbanion over the corresponding monosubstituted case[
When a dilute solution of aqueous sodium hydroxide is added to a solution of a b!diketone "e[g[\
acetyl acetone "00# "Scheme 5#\ or to a b!keto ester "e[g[\ ethyl acetoacetate "02# "Scheme 6##\ proton
abstraction from the active methylene group takes place[ In both cases\ ionisation by loss of a
proton is facilitated by two factors] _rst\ the presence of adjacent −I substituents\ caused by the
high electronegativity of the oxygen atoms and second\ that the −M carbonyl groups are able to
stabilise the resultant carbanions "01# and "03# by mesomeric delocalisation of the negative charge[
O O –H+ O O O– O O O–
+H+
–
(11) (12a) (12b) (12c)
Scheme 6
Carbanions 742
O O –H+
OEt +H+
(13)
O O O– O O O– O– O–
+
–
OEt OEt OEt OEt
(14a) (14b) (14c) (14d)
Scheme 7
Substitution of three electron!attracting ~uorine atoms for methyl hydrogen atoms in acetyl
acetone "00# increases its acidity by a factor of 3 pKa units[ Conversely\ substitution of a methyl
group on the centre carbon of diketone "00# "i[e[\ taking the value for 2!methyl!1\3!pentanedione#
lowers its acidity by a factor of 1 pKa units\ an e}ect partly due to steric inhibition of resonance in
the anion\ which may _nd di.culty in attaining coplanarity of the conjugated system due to methylÐ
methyl interactions[ Ethyl acetoacetate "02#\ in which one of the carbonyl groups is bound to an
ethoxy group\ is a weaker acid than acetylacetone "00# by 9[2 pKa units[ Since the ester carbonyl
group of carbanion "03# acquires electron density from conjugation with the ethoxy group\ as shown
in canonical form "03d#\ it can absorb a correspondingly smaller amount of negative charge from
the carbanionic carbon in the manner represented by canonical "03c#[ Thus the ester carbonyl group
is less e}ective in stabilizing the carbanion than the ketone carbonyl group[ Further comparisons
of {activated| dicarbonyl compounds can be made from Tables 1 and 2[
The bridged bicyclic diketone "04# is not appreciably more acidic than ordinary monoketones
"with pKa values approaching 08 or 19#\ since canonical form "05b# "Scheme 7# would necessitate a
double bond at a bridgehead\ in violation of Bredt|s rule ð13LA"326#0\ 39JA1822Ł[ The preferred mode
of ionisation of diketone "04# giving enolate carbanion "06# is shown in Scheme 8[
Similarly\ although there are three benzene rings a to the C0H bond in trypticine "07#\ the
compound is not appreciably more acidic than unsubstituted alkanes ð49JA0994Ł[ Canonical forms
such as "08b# "Scheme 09#\ which might be expected to stabilise the trypticide anion "08#\ are
precluded by Bredt|s rule ð13LA"326#0Ł[
0[08[0[1[4 Kinetics of base!catalysed formation of carbanions

The bromination of almost any enolisable ketone "e[g[\ "19# "Scheme 00# or aldehyde in the
position a to the carbonyl group is accelerated by the addition of bases[ Such base!promoted
halogenations of carbonyl compounds are kinetically similar to reactions subject to general base
catalysis ðB!48MI 008!91Ł[ A simple example ð35JCS525Ł is the bromination of acetone "19#\ promoted
by the hydroxide anion giving "10^ XBr# via carbanion "11#[ The rate of the reaction is proportional
to the concentration of ketone and base\ but is independent of the concentration of bromine[
Chlorination ð35JCS525Ł and iodination ð23JA856Ł of acetone "19# in the presence of hydroxide take
place in a similar manner[
If the mechanism proposed for acetone also applies to the bromination of the optically active
ketone "12# "Scheme 01#\ a basic solution of this ketone should undergo racemisation in the absence
of bromine at the same rate as in the presence of bromine\ since the presumed rate!determining step
in the bromination reaction\ speci_cally the conversion of ketone "12# to the carbanion "13#\ destroys
the chiral centre[ The rates of bromination and racemisation of ketone "15# have been compared in
aqueous acetic acid\ with acetate ion added as the base\ and found to be the same ð25JCS512Ł[ Since
the concentration of anion "13# is small\ its rate of destruction should equal its rate of formation\
once the initial step is underway[ When anion "13# is generated in D1O it incorporates a deuterium
atom a to the carbonyl group\ to give "16#[ It has been found that\ within the limits of experimental
error\ the rates of racemisation and deuteration of ketone "12# are equal in D1O:dioxane mixtures
catalysed by the presence of NaOD ð27JCS67Ł[ It is worthy of note that the speci_c rates of
deuteration of ketone "12# in D1O:dioxane and of racemisation in H1O:dioxane are found to be
di}erent[ The strength of a given base is slightly di}erent in each medium\ because their solvation
characteristics are not identical[
Table 1 Rate of transfer of protons to water at 14 >C ð42JA1328Ł[
Compound k1 Compound k1
(min–1) (min–1)
O O
O H
~2 x 10–12 1.4 x 10–1
H2 N OEt
(methyl hydrogen)
O O
Me CN ~4 x 10–12 ~1.7 x 10–1
HO OH
(methylene hydrogen)
O O O
2.0 x 10–11 5.0 x 10–1
HO Ph CF3
(methyl hydrogen)
O O
O
2.8 x 10–8 S 6.0 x 10 –1
CF3
O O
O O
EtO OEt 2.0 x 10–5 6.6 x 10–1
Ph
Et
O O
4.5 x 10–4 NC CN 9.0 x 10–1

OEt
Et
O O
H O O
OEt 5.8 x 10–4 9.0 x 10–1
F3C CF3
O O O O
1.5 x 10–3 1.0
EtO OEt
O O
O O
5.0 x 10–3 7.8
OH
(methylene hydrogen)
O
NC 7.0 x 10–2
OEt
O O
7.2 x 10–2
OEt
The mechanisms shown in Schemes 00 and 01 are classed as SE0] initially a slow ionisation and
a fast subsequent addition[ First!order kinetics are observed and the IUPAC designation is DE ¦AE[
Carbanions generated from optically active compounds during hydrogen exchange can give
products implying either inversion or retention of con_guration or racemisation or an intermediate
result ð50JA2577\ 52JA2789\ 53JA4334\ 53JA4346\ 54MI 008!97\ B!54MI 008!91\ 60JA1114\ 60JA1120\ 62MI 008!19Ł[
The ratio of ke "rate constant for isotopic exchange# to ka "rate constant for racemisation# may be
considered[ When ke:ka Ł0\ deuterium exchange proceeds with retention of con_guration[ When
ke:ka ½0 racemisation results\ while ke:ka ½9[4 leads to inversion[ All three types of behaviour occur
and are dependent on the structure and substitution pattern of the anion\ the base and the solvent[
Retention is generally found in solvents of low dielectric constant\ racemisation is favoured in polar
aprotic solvents and inversion in protic solvents[ Finally\ a fourth type of behaviour is encountered
Carbanions 744
Table 2 Ionisation constants of some carbon acids at 14 >C ð42JA1328Ł[
O O O
20 9
O O O O
H
EtO OEt 15 8
Et
O O O O
13 7
EtO OEt Ph CF3
O O O O
13 S 6
OEt CF3
Et
O O
H O O
OEt 12 6
O O
NC CN 11 6
O
O O
O O
11 5
CF3
O O
H O O
10 1
O O
10
OMe
O O
9
Ph
–H+
–
O O O
O O O–
(15) (16a) (16b)
Scheme 8
in aprotic solvents with aprotic bases like tertiary amines\ the ratio ke:ka ³9[4\ indicating that
racemisation takes place faster than isotopic exchange[ Cram termed this process {isoracemisation|\
during which the conjugate acid of the amine remains associated with the carbanion as an ion pair
ðB!54MI 008!91Ł[ Occasionally\ the ion pair dissociates long enough for the carbanion to rotate and
recapture the deuteron[
For 1!carboxamido!8!deuterio!8!methyl~uorene "17#\ it was found that retention of con_gura!
tion "ke:ka 037# occurs in THF with ammonia or a primary amine as base ð52JA2789Ł[ Similar
–H+
–
O O O
O O O–
(15) (17a) (17b)
Scheme 9
–H+
–
–
(18) (19a) (19b)
Scheme 10
O HO– O O– X2 O
X + X–
(slow) – (fast)
(20) (22a) (22b) (21)
Scheme 11
O
Et
Ph
H
H2O or HOAc
(fast) (25)
O O O– O
B– Br2 (fast)
Et * Et – Et Et
Ph Ph Ph Ph
(slow) Br
D2O (fast)
(26)
(23) (24a) (24b)
O
Et
Ph
D
Products (25)–(27) are racemic
(27)
Scheme 12
results were obtained with the benzyl system in cyclohexylamine using cyclohexylamide as base
ð54MI 008!97Ł[ Cram|s proposed mechanism is shown in Scheme 02[ In the low!dielectric solvent\ the
carbanion is closely paired with the ammonium cation\ so that reprotonation occurs from this same
ammonium cation that was formed in the original dedeuteration and from the same face[
Another process that can lead to retention of con_guration occurs with the chiral substrate "17#
in benzene solution containing 09) phenol with potassium phenoxide as the base[ The carbanion
remains paired to the potassium cation\ which is also coordinated to phenol molecules[ Rotation of
the potassium phenol complex deploys a phenol molecule into a position to protonate the anion
with retention "ke:ka 07#\ as shown in Scheme 03[
Carbanions 746
H H
H H H H
N +N
:
THF, NH3
D D
O – O
NMe2 NMe2
(28)
Retention: ke/kα >> 1
D D
H H H H
N +N
H H
O – O
NMe2 NMe2
Scheme 13
Ph H
O Ph H
O
K +
K+
O Ph
– 90% PhH O Ph
10% PhOH
D D
O PhOK – O
NMe2 NMe2
(28)
Retention: ke/kα >> 1
Ph D Ph D
O O
+ –
K O Ph K+
H O Ph
O H
– O
NMe2
NMe2
Scheme 14
The stereochemistry of the exchange reaction of benzylic systems has been studied using optically
active ethylbenzene!a!d^ each replacement of an a!H by hydrogen was found to proceed with about
71) net retention of con_guration ð51JA147Ł[ On the basis of this kinetic and stereochemical data\
the mechanism of this type of exchange reaction was formulated by Streitwieser as proceeding from
"18# "Scheme 04# through a highly polar four!centre transition state "29# to yield a benzyllithium
intermediate\ which reacts with solvent ð54MI 008!97Ł[ The dotted lines in intermediate "29# denote
bonds which may be largely or totally ionic[ The experimental results require that the organic
moieties in "29# embody a substantial degree of negative charge[ The high primary isotope e}ect
implies that the intermediate organolithium compound survives long enough for the deuteriated
cyclohexylamine to di}use away[
For similar benzyl systems in DMSO\ the rates of deuterium exchange and racemisation are more
H H D+
D –
– + NHC6H11
H2NC6H11 H
+ LiNHC6H11
(29)
(30)
PhCH2– •Li+ + C6H11NHD PhMe
C6H11 = cyclohexyl
Scheme 15
nearly equal "ke:ka ½0#[ The more polar solvent presumably allows dissociation of the paired ions[
The newly created free carbanion then enters a symmetric solvation environment[ The lone pair of
the carbanion is then free to rehybridise to an sp1 orbital\ and in this symmetrical form the carbanion
may be protonated from either face with equal probability ð54MI 008!97Ł[
In methanolic solution\ as shown in Scheme 05\ there are protons readily available from the
surrounding solvent sheath[ As the proton departs from one side of the molecule\ it can be replaced
concertedly from the opposite face[ Predominance of this pathway dictates that a majority of the
product will result from inversion at the chiral centre\ as shown in Scheme 05[ The exchange of
nitrile "20# in methanol with tri!n!propylamine as the base gave ke:ka 9[73 ð53JA4346Ł[
HOMe – –OMe
OMe
Ph Ph H H
MeOH, NPrn3 Et
Et CN Et CN CN Et CN
D Ph
D D Ph
–
OMe
(31) OMe DOMe
Inversion: ke/kα ~ 0.5
Scheme 16
When a base that possesses no exchangeable protons induces carbanion formation in a solvent
of low polarity and low proton concentration\ the ion pair formed will revert to base and substrate
without deuterium exchange[ However\ the carbanion will sometimes rotate while still a partner in
the ion pair[ Inversion\ proceeding by way of two changes in hybridisation of the orbital containing
the carbanionic lone electron pair\ followed by redeuteration\ forms the enantiomer[ This constitutes
isoracemisation as shown in Scheme 06\ whereby nitrile "20#\ in THF containing tri!n!propylamine
as base and 0[4 M t!butyl alcohol\ undergoes isoracemisation to give a mixture of "20# and its
enantiomer "21# such that ke:ka 9[94 ð53JA4346Ł[ The mechanism explains how inversion occurs
without deuterium exchange leading to racemisation\ which results from repeated inversion[ A
single act of inversion without deuterium exchange is termed {isoinversion|[
Cram has identi_ed a second process\ which gives values of ke:ka ³l involving carbanions with a
strategically placed substituent capable of undergoing tautomerism or having high electron density[
Chiral 1!nitro!6!carboxamido!8!deutero!8!methyl~uorene "22# "Scheme 07# is dedeuterated to form
the plane symmetric ion pair "23#[ Redeuteration may occur\ with equal probability onto either
face\ via either transition state "24#\ which recreates the original substrate "22# or via transition
state "25#\ which results in the formation of enantiomer "26# ð57JA1487\ 57JA1595\ 57JA1501\ 60JA1124\
78AG"E#62Ł[ This process is termed the {conducted tour| mechanism\ since the positive species
migrates in a stepwise fashion around the periphery of the substrate from one nucleophilic position
to another[ At 14>C in THF\ chiral!substituted ~uorene "25# with 05) t!butyl alcohol with 09
mole) tri!n!propylamine as base gives rise to ke:ka 9[09[
In conclusion\ it is unlikely that free carbanions exist in solution^ they are usually in ion pairs or
else solvated ð66APO"04#042\ 66T1626Ł[ This assertion was supported by studying the treatment of
PhCOCHMe− = M¦ with ethyl iodide\ where M¦ was Li¦\ Na¦ or K¦[ The half!lives of the reaction
"Li\ 20×09−5^ Na\ 9[28×09−5^ K\ 9[9934×09−5# demonstrates that the species involved were not
Carbanions 748
THF, ButOH carbanion
Et Et Et rotation Et
NPrn3
Ph D Ph D :NPrn3 Ph
– +DNPrn
3 ≡ –
Ph +DNPrn
3
NC NC NC CN
(31)
rehybridisation:
Isoracemisation: ke/kα ~ 0 sp3 to sp2
Et rehybridisation Et
Et Et sp2 to sp3
– +DNPrn – +DNPrn
NC D – +NPrn NC
NC D 3 3 3
Ph Ph Ph NC Ph
(32)
Base-catalysed isoracemisation of (31) involving inversion of configuration
Scheme 17
:NPrn3 +
NPrn3
D THF, ButOH, NPrn3 D
O O– O O–
N+ N+
Me2N O Me2N O
(33) (35)
+
NPrn3 +
NPrn3
D
O – D O–
O O–
N+
N+
Me2N O
Me2N O
(36) (34)
Conducted tour: ke/kα ~ 0
:NPrn3
D
O O–
N+
Me2N O
(37)
Scheme 18
identical ð59JA0275Ł[ Similar results were reported with Li\ Na and Cs triphenylmethides Ph2C− = M¦
ð70JOU270Ł[ Alternatively\ where ion pairs do not play an important role\ carbanions are solvated[
Cram has shown evidence of solvation of carbanions in many solvents[ The _eld of carbanionic
pair formation has been extensively investigated ð55JA296\ 55JA207\ 58JA3479\ 66JA7151\ 66MI 008!90\
67JA2403\ 68JA522\ 68JOC206\ 68TL216Ł[
0[08[0[1[5 Carbanion formation stabilised by conjugation with heterocyclic systems

Alkyl groups situated in the a! and g!positions of pyridine rings show reactions which result from
the relatively easy loss of a proton from the alkyl carbon atom ðB!56MI 008!90\ 73CHEC"1#204\ 77PIA076\
81T1478\ B!81MI 008!92Ł[ Such strategically placed alkyl groups a and g to the ring nitrogen of a
pyridine ring are signi_cantly more reactive than alkyl groups attached to a benzene ring in base!
catalysed processes involving deprotonation of the alkyl substituent ð68JOM018Ł[ The carbanion
thus produced is stabilised by charge delocalisation into the heterocyclic ring\ whereby one of the
canonical forms "28b# "Scheme 08# accommodates the negative charge on the electronegative nitro!
gen atom[ Strong bases\ such as sodamide "NaNH1:NH2\ −39>C# or organometallic compounds
"PhLi:Et1O\ 39>C#\ convert 1!alkylpyridines "27# essentially completely into the corresponding
anions "28# as is the case with 3!alkylpyridines[ Anions such as "28# react readily with electrophilic
reagents "Equation "00##[
B–
N N CH2– N
–
(38)
(39a) (39b)
Scheme 19
E+ E (11)
N N
–
(39b)
3! and 1!Alkylpyridines can undergo base!catalysed substitution at the alkyl position in the
following ways "Scheme 19#]
"i# Alkylation\ e[g[\ 1!picoline "27# to give 1!n!propylpyridine\ conyrine\ "39# ð40JA2297\ 45JA0612\
48JA1457\ 59JCS3343Ł[
"ii# Reaction with carbonyl compounds to give alcohols\ e[g[\ 1!picoline "27# gives the tertiary
alcohol "30#[
"iii# Carboxylation\ e[g[ 1!picoline "27# gives 1!pyridineacetic acid "31#\ which must be esteri_ed
before isolation[
"iv# Acylation\ e[g[\ 1!picoline "27# gives ketone "32# ð40JA3290\ 63JOC1995Ł[
"v# Aldol condensation followed by dehydration\ e[g[\ 1!picoline "27# gives stilbazole "33#
ð34JOC10\ 63JA7984Ł[
N
(40)
i, NaNH2
ii, EtI
OH
N Ph Ac2O i, NaNH2 N Ph
PhCHO ii, PhCOMe
(44) (41)
N
(38)
i, PhLi i, PhLi
ii, PhCO2Et ii, CO2
O
CO2H
N Ph N
(43) (42)
Scheme 20
Carbanions 750
Similarly\ the anion derived from 3!methyl quinoline\ by the action of sodamide\ reacts with
benzoyl chloride to give 3!phenacylquinoline[
2!Methyl pyridine is less acidic than either 1!methylpyridine "27# or 3!methylpyridine and will
not undergo base!catalysed aldol reactions as easily as either of the latter[ It can\ however\ be
deprotonated by very strong bases such as sodamide in liquid ammonia and the anions can then be
alkylated ð40JA2297Ł[ 1!Methyl groups can be selectively functionalised in the presence of 2!methyl
groups\ an example of which is the selective formation of the sul_de "35# "Equation "01## in high
yield from 1\2!dimethylpyridine "34#\ butyllithium and diphenyl disul_de ð70JOC1948Ł[
BuLi, PhSSPh
(12)
SPh
N N
(45) (46)
Proton removal from methyl groups on either the 1! or 3!position of the pyridine nucleus is
rendered even easier when the heterocyclic nitrogen bears a formal positive charge\ as in quaternary
salts "36# "Equation "02## and N!oxides "Scheme 10#\ both of which require only mild base catalysis
to e}ect deprotonation[
PhCHO, piperidine, MeOH

(13)
N+ 70% N+ Ph
I– Me I– Me
(47)
Cl
N
(49)
POCl3, Et3N
90%
O
(CO2Et)2, KOEt PhCHO, 5% KOMe, MeOH
N+ CO2Et N+ 56% N+ Ph
O– O– O–
(51) (48) (50)
Scheme 21
Reaction of 1!methylpyridine!N!oxide "37# with p!toluenesulfonyl chloride or phosphorus oxy!

chloride gives 1!pyridylmethyl chloride "38# "Scheme 10#\ and related reactions with reactive halides
have also been studied ð51JOC2745\ 70JHC828Ł[ Condensation of benzaldehyde with "37# gives alkene
"49#[ Reaction of "37# with diethyl oxalate under basic conditions furnishes the a!keto ester "40#[
0[08[0[1[6 Carbanion formation by proton loss stablised in accordance with the Huckel "3n¦1# rule
The formation of aromatic monocyclic carbanions has been reviewed ð68COC"1#250Ł[ Cyclo!
pentadiene "41# has apparently anomolously high acidic properties with pKa ½05 since\ with the
loss of a methylene proton\ the resultant carbanion "42# is stabilised by resonance and has attained
a sextet of delocalised electrons thus conforming to the Huckel "3n¦1# p!electron rule "Scheme 11#
ðB!54MI 008!92Ł[ The resonance stabilisation of the cyclopentadienyl anion is greater than that
accorded to pyrrole\ thiophene or furan\ since all _ve canonical forms are equivalent ðB!81MI 008!
93Ł[ The resonance energy stabilisation for "42# has been estimated at 13Ð16 kcal mole−0 ð70JOC521Ł[
The chemistry of the cyclopentadienide anion has been reviewed by Lloyd ðB!55MI 008!91Ł[
Webster observed that electrophilic substitution could not ordinarily employ strongly acidic
conditions because of the basicity of the cyclopentadienyl anion ð56JOC28Ł[ However\ when the
negative charge was dispersed over peripheral nitrile groups\ strongly acidic conditions could be
–
–H+
etc. ≡ –
–
–
(52) (53)
Scheme 22
employed[ Tetracarbomethoxycyclopentadiene can be isolated ð50PCS006Ł\ but the more strongly

acidic tetracyanocyclopentadiene "pKaMeCN¼9# or monosubstituted tetracyanocyclopentadienes
are elusive[ The tetracyanocyclopentadienyl anion "43# "Scheme 12# could be compared in reactivity
to anisole ð54JA0719\ 55AG"E#319\ 55JA2935\ 55JA3944Ł[ The studies were conducted on the tetra!
ethylammonium\ potassium and silver tetracyanocyclopentadienide salts[ All three salts were sur!
prisingly soluble in organic solvents and changes in cation had little e}ect on the course of reaction[
The most convenient cation was found to be tetraethylammonium\ the salts of which were found to
be in general water insoluble and crystalline[
The tetracyanocyclopentadienyl anion "43# "Scheme 12# reacts with concentrated nitric acid\
formaldehyde\ bromine\ chlorine\ tri~uoromethylsulphenyl chloride and acetic anhydride to give
nitro!\ methylidene!\ bromo!\ chloro!\ tri~uoromethylthio! and acetyl!tetracyanocyclopentadienyl
anions[ The chlorotetracyanocyclopentadienyl anion and chlorine produce 4\4!dichloro!0\1\2\3!
tetracyanocyclopentadiene\ an enophile which undergoes DielsÐAlder cycloaddition with ethylene
at atmospheric pressure and room temperature[
Suitably positioned substituents such as the tri~uoromethyl groups of 0\1\2\3\4!penta!
kis"tri~uoromethyl#cyclopentadiene "44# "Scheme 13# render the compound more acidic than nitric
acid ð79JA5522Ł[
Fulvenes such as "45# form cyclopentadienide salts on treatment with lithium alkyls ð47CI"L#0478\
47PCS178Ł\ or with sodamide in liquid ammonia "Scheme 14# ð47PCS178\ 50JCS3509Ł[
Indene "46# and ~uorene "47# "Scheme 15# are also acidic\ but less so than cyclopentadiene "see
Table 1#[ The negative charge\ formed initially on the _ve!membered ring of either indene or
~uorene\ is delocalised onto a fused six!membered ring only at the expense of the loss of aromatic
stability of the fused six!ring electron system as depicted in canonical "48b# "Scheme 15#[ However\
the tribenzopentalene derivative ~uoradene "59# is su.ciently acidic "pKa 02[5#\ that it will dissolve
in aqueous sodium hydroxide ð59JA823Ł[
The cyclopentadienyl anion may be stabilised by complexation with an Fe1¦ ion to form the
{sandwich compound| "a descriptive designation originated by Dunitz and Orgel ð42NAT010\
B!76MI 008!92Ł# dicyclopentadienyl iron\ Fe"C5H5#1 "50# "dubbed {ferrocene| by Woodward et al[
ð41JA2347Ł#\ which was _rst reported almost simultaneously by two groups of workers ð40NAT0928\
41JCS521Ł[ The _rst preparation by Kealy and Pauson used the reaction of cyclo!
pentadienylmagnesium bromidewith FeCl2 in diethyl etherÐbenzene[ X!ray analyses of ferrocene
and its simple derivatives have revealed that this complex exists in the staggered or antiprismatic
conformation shown in structure "50# ð41JA1014\ 41ZN"B#266Ł[ In solution the rings rotate quite freely\
with the barrier to ring rotation estimated at 1Ð4 kcal mole−0 ð68ACR304Ł[
Ferrocene is exceptionally stable[ It is not only una}ected by air\ moisture and heat up to
369>C\ but it can also be boiled in concentrated hydrochloric acid or 09) caustic soda without
decomposition[ The dicyclopentadienyl derivatives\ Cp1M\ of the other metals in the _rst transition
series from V to Ni have been synthesised ð48MI 008!93\ 48MI 008!94Ł[ Metallocenes containing two
metal atoms and three cyclopentadienyl anion rings have been prepared and are known as {triple!
decker sandwich| compounds ð66AG"E#0Ł[ Tetradecker\ pentadecker and hexadecker sandwich com!
pounds have been reported ð74AG"E#832Ł[ For a bibliography of reviews on metallocenes see Bruce
ð61AOC"09#162Ł[
The cyclopentadienyl anions of ferrocene\ in common with other metallocenes\ readily undergo
substitution reactions underlining their aromatic character ð51AG"E#201\ 51AG"E#283Ł[ The _rst exam!
ple of such a reaction was reported by Woodward et al[ ð41JA2347Ł[ When ferrocene in carbon
disul_de was treated with acetyl chloride in the presence of aluminum chloride\ it was smoothly
converted to the diacetyl derivative "51# "Equation "03##[
Treatment of benzocycloheptratrienes "52# or "53# with potassium amide in liquid ammonia
cleanly a}ords solutions of the benzocycloheptatrienyl anion "54# "Scheme 16# ð62JA2271Ł[ Such
solutions can be quenched with wet ether to produce isomers "52# and "53# in about equal
proportions[
Carbanions 752
The cyclononatetraenide anion "56# has been prepared from bicycloð5[0[9Łnona!1\3\5!triene "55#
in moderate yield by deprotonation with the methylsul_nyl carbanion "Equation "04## ð54JA0830Ł[
NC CN NC CN NC CN
vi
– – –
NC CN NC CN NC CN
57%
S NO2 NH2
CF3
iv, v
i–iii 67%
82.5%
NC CN NC CN
NC CN CN NC
vii
–
NC CN NC – – CN
– 95%
NC CN
OH NC CN
(54)
viii, ix
40%
NC CN
NC CN NC CN NC CN
–
x xi NC CN xii
– – –
NC CN NC CN NC CN
83% 75% + quantitative
N
O OH
xiii
polymer
i, [Et4N]+•[Cp(CN)4]– (starting material), AlCl3, 0 °C to 50 °C; ii, CF3SCl (g), RT to 40 °C; iii, reflux, 1.5 h, RT,
overnight; iv, K+•[Cp(CN)4]– (starting material), HNO3 (conc.), RT, 15 min; v, H2O, Et4N•Cl, 0 °C; vi, Zn, H2O,
6M HCl, reflux, 15 min; vii, [Et4N]+•[Cp(CN)4]– (starting material), paraformaldehyde, CF3CO2H, RT, 1 h; viii,
K+•[Cp(CN)4]– (starting material), Ac2O, CF3CO2H, reflux, 1 h; ix, Et4N•Cl, H2O; x, NaBH4, EtOH, reflux, 1 h;
xi, pyridine, SOCl2, RT, 2.5 h; xii, pyridine, reflux, 15 h; xiii, 135–140 °C, 15 min.
Scheme 23
F3C CF3 F3C CF3

F3C CF3
base
– F3C CF3 etc.
F3C CF3 F3C CF3
H CF3 CF3
F F
(55)
F–
Scheme 24
RLi or –
etc. ≡
NaNH2, NH3 (l)
–
(56)
Scheme 25
(57)
–
base
–
(58) (59a) (59b)
Scheme 26
(60)
– – COMe
MeCOCl, AlCl3, CS2
Fe2+ Fe2+ (14)
– –
MeOC
(61) (62)
KNH2, NH3 Et2O, H2O

– +
(63) (65) (63) (64)
Scheme 27
NaCH2SOMe
– Na+ (15)
(66) (67)
The preparation from triene system "57# of the stable 0\4!methanocyclononatetraenyl 09p!electron
anion "58# has been reported "Equation "05## ð55JA2350Ł[ The down_eld 0H!NMR signals of the
ring protons "7−d−5# combined with the strong shielding of the methylene protons indicated the
induction of a ring current and suggested that "58# was a 09p!electron delocalised homoaromatic
system[
NaCH2SOMe, DMSO, N2, RT

– (16)
(68) (69)
0[08[0[1[7 Destabilised carbanion formation by proton loss viewed in the context of the Huckel
"3n¦1# rule
If proton removal from a molecule results in formation of an anti!aromatic p!electron system\
this may prove a great disincentive to carbanion formation[ It has been found that "69# loses its
Carbanions 754
proton about 5×092 more slowly than the saturated analogue "60# ð56JA3272Ł[ For the similar pair
"61# and "62# the observed ratio is approximately 093 ð57JA1587Ł[ This illustrates that "69# and "61#
are much more reluctant to form carbanions\ which would be unstable 3p!electron antiaromatic
cyclopropenyl carbanions\ than "60# and "62# which form simple carbanions[ Although derivatives
of the cyclopropenyl anion have been inferred as transient intermediates\ all attempts to prepare
the ion or any of its derivatives as relatively stable intermediates have been in vain ð71TL684Ł[ A
triphenylcyclopropyl anion has been prepared in the gas phase\ with a lifetime of 0Ð1 seconds
ð75TL4820Ł[
H COPh H COPh H CN H CN
Ph Ph Ph Ph Ph Ph Ph Ph
(70) (71) (72) (73)
In marked contrast to cyclopentadiene "41# cycloheptatriene "63# displays no unusual acidity[ The
cycloheptatrienyl anion "64# has been prepared in solution albeit in modest yield by the action of
benzyl potassium on cycloheptatriene "Scheme 17# ð52JA2930Ł[ The anion "64# is less stable than the
cyclopentadienyl anion "42#\ having an 7p!electron system as discussed in detail by Dauben and Ri_
ð52JA2930Ł[ The formation of antiaromatic monocyclic carbanions has been reviewed ð68COC"1#280Ł[
CO2H
BnK, toluene, 25 °C, 7 h CO2
– + BnCO2H + polymer
(74) (75) 30 : 30 : 40
Scheme 28
0[08[0[1[8 Formation of homoaromatic carbanions by proton loss

A bishomocyclopentadienyl anion "66# has been prepared\ in which delocalisation of the negative
charge appears to take place to a signi_cant degree[ Brown and Occolowitz originally proposed "66#
as being involved in the deprotonation of bicycloð2[1[0Łocta!1\5!diene "65# "Equation "06##\ which
occurs 093[4 times faster than the deprotonation of the analogous monoene "67# ð54CC265\ 56CC527\
57JCS"B#300\ 69JA2710Ł[ Paquette has reviewed the concept of extended homoaromaticity ð67AG"E#095Ł[
Carbanion "68# ð62JA5338Ł and the heterocyclic carbanion "79# ð64CC190Ł exhibit comparable
0
H!NMR spectral properties to "66#\ suggesting a sustained ring current[
DMSO, KOBut
(17)
–
(76) (77)
– –
N
(78) (79) (80)
The instability of bishomocyclopentadienyl anions was underlined by the _nding that the
1!bromobishomocyclopentadienyl anion "71# is not obtained by the treatment of the bromide "70#
with base\ the _nal product of the reaction being the bicyclic alkyne "72#[ Bergman and Rajadhyaksha
suggested that carbanion "71# is formed\ but that it subsequently loses Br− and rearranges to give
"72# "Scheme 18# ð69JA1052Ł[
ButOK, DMSO, RT
–
29%
Br Br
(81) (82) (83)
Scheme 29
It should be noted that the precise realities of carbanionic homoaromaticity is an area of contro!
versy[ However\ a balanced account of the debate is given by Lee and Squires ð75JA4967Ł\ who
present evidence\ derived from gas!phase experiments\ supporting the bishomoaromatic charge
delocalisation of carbanion "66#[
0[08[0[1[09 Formation of the phenalene anion by proton loss

The chemistry of phenalenes has been reviewed ð47T228\ 54QR163\ 62MI 008!08Ł[ Phenalene "73# is
remarkable\ in that it gives rise to a relatively stable anion "74#\ cation "75# and radical "76#[
– + •
(84) (85) (86) (87)
Quantum mechanical studies have provided a satisfactory explanation for their observed stability[
Huckel molecular orbital "HMO# calculations indicate that all three species possess the same
p!electron delocalisation energy ð45CI"L#0295\ 46DOK"006#0910\ 59JA0861\ 53CCC0821Ł[ In simple terms\
the phenalenyl anion "74# "derived from phenalene using phenyllithium ð49JA0134Ł or potassium
methoxide ð45CI"L#0493\ 47T228Ł# can be represented as having a 01p!electron periphery\ with the
negative charge formally assigned to the central carbon atom[ Phenalene is more acidic than
triphenylmethane "pKa 14# and less so than cyclopentadiene "pKa 05# ð49JA0134Ł[
0[08[0[1[00 Carbanions derived from unsaturated acidic hydrocarbons involving stabilisation by very
extensive delocalisation
6H!Dibenzoðc\`Ł~uorene "77# is about 093 times more acidic than ~uorene[ Tris"biphenyl!
enevinyl#methane "78# had the highest acidity of any of the ~uorene!substituted hydrocarbons
described prior to 0855 ð51LA"543#53\ 53AG"E#201\ 54LA"578#0Ł[
(88) (89)
Carbanions 756
In 0856\ however\ Kuhn and Rewicki reported the preparation of tris!"6H!dibenzoðc\`Ł!
~uorenylidenemethyl#methane "89# and hydrocarbon "80# which were obtained as a tautomeric
mixture by the method shown in Scheme 29 ð56AG"E#524Ł[
+
+ (Me2N=CH)2C=CH–NMe2•(ClO4)2–
(88)
NaOMe, pyridine, warm
80%
NMe2
Li+ –
65%
(ethereal solution)
reflux, 1 h
CH
3 2
(90) (91)
Scheme 30
When treated with DMSO containing a base "e[g[\ NaOH or tri!n!propylamine#\ the hydrocarbons
"89# and "80# gave a deep green carbanion "81# now known as Kuhn|s anion[ As might be expected\
hydrocarbons "89# and "80# are highly acidic[ A 09−4 M solution in DMSO is almost completely
dissociated even without addition of base ð56AG"E#524Ł[
Okamoto et al[ have published detailed experimental techniques for the preparation of two further
hydrocarbon salts both consisting of Kuhn|s anion as the carbanion moiety ð89JOC885Ł[
0[08[0[1[01 Carbanion stabilization by a nonadjacent p!bond] the formation of homoenolate anions

Under certain circumstances "Scheme 20# a carbonyl group can activate a distant proton "e[g[\ on
a b!carbon atom as in "82# when n0# su.ciently to allow conversion to an anion "83# stabilised
(92)
by homoconjugation[ Such an anion is called a {homoenolate carbanion| "83# and the cyclic alcohol
derived by protonation on oxygen is the homoenol "84#[
– O– OH
O O
n n
n n
(93) (94) (95)
Scheme 31
In the simplest case "Scheme 20^ n0#\ the homoenol formed is a cyclopropyl alcohol[ The
archetypal example of homoenolisation is that of "¦#!camphenilone "85#\ which\ when treated with
potassium t!butoxide\ underwent racemisation "Scheme 21# ð55JA0894Ł[ The experimental evidence
pointed to the formation of the symmetrical intermediate "86#[
O O
–O
(+)-(96) (97) (–)-(96)

≡
+H+ –H+ +H+ –H+
–
O – –O O
Scheme 32
g!Homoenolate formation "Scheme 20^ n1# has been observed in {half!cage| ketones ð54JA803\
54JA804\ 54JA805Ł[Winstein and Fukunaga both found that the hexachloro half!cage ketone "87a#
was converted\ in good yield\ to the corresponding hexachlorohomoenol "88a# in re~uxing pyridine
at 099>C "k1[8×09−4 s−0#[ Winstein also studied the g!enolisation of the parent ketone "87b# at
a range of temperatures and found\ for example\ that "87b# rearranged to "099# in 9[8 M
t!BuOK:t!BuOH with a rate constant of 6[47×09−4 at 084>C "k074>C ½2[7×09−4 s−0#[ The subject
of homoenolisation has been reviewed ð72T195Ł[
Carbanions 758
O OH
X X
O
X X
X X
X X
X X
(98a) X = Cl (99a) X = Cl (100)
(98b) X = H (99b) X = H
0[08[0[1[02 Kinetic versus thermodynamic factors determining the course of enolisation

The presence of certain unsaturated substituents at a saturated carbon atom\ for example\
carbonyl\ cyano or phenyl groups renders any hydrogen atoms bonded to that carbon relatively
acidic as shown in Table 3[ As indicated in Table 3\ the e}ectiveness of these activating groups
follows the approximate order] COR×CO1R½CN×Ph[ The presence of two such activating
groups further enhances the acidity of an active methylene compound^ conversely\ acidity is
decreased by about 0Ð1 pKa units by an alkyl substituent[ The values or ranges of values given in
Table 3 for weakly acidic substances should be viewed as approximate[ The values listed are not
corrected for deviations in pKa values which result from the measurements being made in di}erent
solvents with a variety of bases and cations present ð21JA0101\ 25JA0013\ 42JA1328\ 48JOC698\ 54JA271\
54JA273\ B!54MI 008!93\ 54JCS"B#0641\ 56JA0610\ 56JA1641\ 56JA1640\ 56JA1859\ 56JA2894\ 56JCS"B#716\ 57JA1710\
57JA2304\ 57JOC1111\ 57JOC2366\ 57MI 008!95\ 58JA5638\ 58JA1686\ 69JCS"B#062\ 69JCS"B#068\ 69JCS"B#083\
69JA3578\ 69JA4815\ 69JA4822\ 69JA4828Ł[
Table 3 Approximate pKa values of some active methylene compounds[

Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
CH1"CN#CO1Et 8 MeCOCH2 19
CH1"COMe#1 8 Indene 10
MeCOCH1CO1Et 00 ButCOCH2 10
MeCH"COMe#1 00 ButCOCHMe1 12
CH1"CN#1 00 CH2CO1Et 14
CH1"CO1Et#1 02 CH2CN 14
CpH 04 Ph2CH 17Ð12
PhCH1COPh 05 Ph1CH1 22Ð24
MeCOCH1Cl 06 PhCH2 26
PhCOCH2 08
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Much attention has been devoted to the determination of rate and equilibrium constants for
enolate formation by the loss of protons a to a carbonyl group ðB!89MI 008!90Ł[ Synthetic routes
that involve the formation and subsequent reaction of carbanions "enolate anions# derived from
active methylene compounds constitute very important and synthetically useful classes of organic
chemical and enzymatic reactions\ including eliminations\ aldol condensations and alkylations
ð64T1868\ 80JA8556Ł[ Although studies on the acid! and base!catalysed conversion of aldehydes and
ketones to their enols were reported as early as the 0899s ð71APO"07#0\ 78T3802Ł\ the inaccessiblity
of these enols in aqueous solution hampered studies of their ketonisations[ Keefe and Kresge
ðB!89MI 008!91Ł and Capon ðB!89MI 008!92Ł developed techniques for producing enols in su.ciently
high concentration to enable their ketonisation reactions to be examined[ Aqueous pKa values\
ketoÐenol equilibrium constants and rate constants for ketoÐenol interconversions are now available
for a variety of aldehydes and ketones ð71APO0\ 78T3802\ B!89MI 008!91\ B!89MI 008!93Ł[
In the case of most monoketones and esters the amount of enol present at equilibrium is small[
Conversely 0\1! and 0\2!dicarbonyl compounds often contain a large proportion "×49)# of their
enol tautomers at equilibrium ð43JOC0859\ B!59MI 008!92\ 50JOC2045\ 52T0514\ 54JOC2101\ 55JCS"B#130\
56JOC0883\ 56JOC1051\ 69T1916\ 69T1924Ł[
Scheme 22 illustrates the general rule that the enol tautomer is more acidic than the keto tautomer
by 3Ð4 pKa units ð55JCS"B#130Ł[ This acidity di}erence is attributable to the fact that the rate of
proton abstraction from a C0H bond usually proceeds slowly relative to the very fast "frequently
di}usion!controlled# rate of proton removal from OH bonds or proton addition to either oxygen
or a carbanionic carbon atom "Scheme 23# ðB!48MI 008!92\ 51JA3713\ 53AG"E#0\ 56JA1715\ 58JA0035\
58JOC3972Ł[
O O– H
O
–H+ +H+
+H+ –H+
pKa = 16.7 pKa = 11.3
Scheme 33
O base (slow) O O–
+H+ –
+H+ base (fast) +H+ base (fast)
+ H
O H
–H+ (slow) O
+H+
H :OH2
(water or another
Lewis base)
Scheme 34
The degree of enolisation and the structure and stereochemistry of the enols obtained from
0\2!dicarbonyl compounds are dependent both on the structure of the dicarbonyl compound and
the solvent in which the equilibria are measured ðB!59MI 008!93Ł[ The positions and compositions of
the equilibrium mixtures involving 0\2!dicarbonyl compounds are measured from NMR experiments
ð52JA0585\ 54JA494\ 55JCS"B#050\ 56JA0072\ 56JCS"C#0605\ 56TL18\ 56TL3414\ 57JCS"B#021\ 57JCS"C#565\ 57T0540\
57T0758\ 58JOC1706Ł[ Furthermore\ the stabilisation of dienol tautomers as their tricarbonyliron
complexes has been studied ð57CC0114\ 58TL2878Ł[
0\2!Dicarbonyl compounds in nonpolar\ aprotic solvents usually favour the cisoid enol form\
which normally exists as a monomer with an intramolecular hydrogen bond as shown in Scheme 24[
transoid conformation cisoid conformation
favoured in water favoured in carbon
tetrachloride
O O
O OH O O
H
Scheme 35
Dimeric and polymeric hydrogen!bonded species are formed by cyclic 0\2!diketones where intra!
molecular hydrogen bonding in the enol is prevented by the geometry of the molecule ð56JOC1051Ł[
The percentage of enol present in such cases is dependent on both the concentration and the
temperature of the solution[ In relatively polar solvents\ and particularly in polar protic solvents\
the percentage of the keto form is usually enhanced\ since this tautomer is more subject to solvation
through a process of intermolecular hydrogen bonding with proximate solvent molecules[ It should
be noted\ however\ that cyclic 0\2!diketones represent an exception to this generalisation[
The presence of substituents\ especially sterically bulky substituents\ in the 0\2!dicarbonyl system
usually serves to depress the percentage of enol present at equilibrium\ since formation of a planar
enol tautomer incorporating an intramolecular hydrogen bond results in adjacent substituents being
forced into sterically unfavourable eclipsed conformations[
The ratio at equilibrium between the pairs of isomeric enols\ shown in Equation "07# and listed
in Table 4 is evidently a consequence of the stabilising e}ects resulting from conjugation with the
Carbanions 760
carbonyl group set against the requirement for minimisation of unfavourable steric interactions and
torsional strains ð52JA0585\ 58JOC1706Ł[
O O O
CCl4 H H
(CH2)n (CH2)n + (CH2)n (18)
O 25 °C O O
(101) (102) (103)
Table 4 Percentage composition of enol mixtures derived

from Equation "07#[
*
Value of n Tautomer "091# Tautomer "092#
*
2 11 67
3 65 13
4 23 55
5 45 33
6 58 20
7 71 07
*
Measurements of the rates of proton removal from C0H bonds a to carbonyl groups are
somewhat more plentiful in the literature than data concerning the equilibrium dissociation con!
stants for such weak acids ð39JA002\ 40JCS1329\ 40JCS1331\ 45JA5158\ 48JOC698\ 59HCA0804\ 50JA2567\
51JA1788\ 51JA1894\ 51JA2053\ 51JA2391\ 51TL558\ 52JA0427\ 52JOC2251\ 52MI 008!93\ 53JA0886\ 53JA1721\ 53JA4346\
54JA2117\ 54JA4381\ 54JA4382\ 54JA4402\ 54JCS"B#0641\ 54JOC0230\ 54JOC1491\ 55JA0221\ 55JOC419\ 56JA1553\
56JCS"B#716\ 56JCS"B#0062\ 56JOC381\ 56JOC2699\ 56JOC3016\ 56RCP88\ 57MI 008!95\ 57JOC1111\ 57JOC2366\
57JOC0290\ 57JOC0649\ 57JCS"C#227\ 57T5176\ 57TL1206\ 57TL1810\ 57JA3518\ 57JOC824\ 57JOC832\ 57JA5638\
57JA5980\ 57CRV264\ 58JA1686\ 58CC181\ 58JA429\ 58JOC2969\ 58CC0387\ 58CC0386\ 58JOC1213\ 69JCS"B#083\
69JA3578\ 69JA4815\ 69JA4822\ 69JA4828\ 69JA1334\ 69JA2586Ł[
In base!catalysed enolisations\ alkyl substituents appear invariably to decrease the rate of depro!
tonation from ketones at both a!positions "Table 5# ð56JA1553\ 56JOC2699\ 56JOC3016\ 57TL1206\ 57TL1810\
57T5176\ 57JA3518\ 58CC181Ł[ This phenomenon may be attributed in part to enhanced steric hindrance
towards the approach of the base engaged in proton abstraction[
Table 5 Relative ratesa of H:D exchange for a series of ketones R!CO!

Me catalysed by Na1CO2 or NaOD in D1O or D1O:dioxane mixtures[
R Rate of exchanè Rate of exchanè at an
at Me a!C0H bond on R
*
Me0 099 099
MeCH10 34Ð49 17
EtCH10 22Ð30 01Ð02
Me1CHCH10 16 6
Me2CCH10 4Ð10 9[2Ð9[6
Me1CH0 22Ð34 9[0Ð9[8
Me2C0 05Ð16
*
a
These values represent the total rate of exchange at each group and are not corrected for the
number of hydrogen atoms at each a!position[ From {Modern Synthetic Reactions|\ 1nd edn[\
by Herbert O[ House\ Copyright "Þ# 0861 by W[ A[ Benjamin\ Inc[
Furthermore\ in the case of methylene groups or a!protons activated by one or more carbonyl
groups\ the presence of alkyl substituents at either carbon atom may interfere by steric overcrowding
with the attainment of a transition state during proton removal that would otherwise permit e.cient
overlap of the p!orbitals involved "Scheme 25# ðB!61MI 008!90Ł[
Ketones can be totally converted to their enolate anions in a kinetically controlled process by
adding the ketones slowly to an excess of a strong base in an aprotic solvent "Scheme 25#[
In a\b!unsaturated ketones\ nitriles and esters "e[g[\ "093# "Scheme 26## the g!proton assumes the
acidity\ which is normally a prerogative of the proton a to the carbonyl or nitrile group\ especially
when R0 is other than a proton and cannot compete[ Alkylation at the a!position to give "094#\
ketone added to Bun H Bun
O excess Pri2NLi
O H H
+ H H O
Bun 1,2-DME, 0 °C
Li NPri2 Pri2N Li
Bun H Bun O– Li+ Bun

+ +
Li+ –O H H H O– Li+
84 : 7 : 9
Scheme 36
competes with alkylation at the g!position "leading to product "095#\ and usually predominates
ðB!81MI 008!94Ł[
O–
R2
OEt
R1
O O O
R2 γ α R2 R3X R2
OEt OEt OEt
–
R1 R1 R3 R1
(104) (106)
O O
R2 R3X R2
–
OEt OEt
R1 R3
R1
(105)
Scheme 37
For ketone enolates the question of the regioselectivity may be summarised ð65T1868\ 73MI 008!91Ł[
Under kinetic conditions "low temperature\ −67>C\ excess base\ small cation#\ the less!substituted
enolate is formed[ More hindered bases give higher selectivity[ Under conditions designed to provide
an equilibrium mixture of product enolates "relatively higher temperature\ excess ketone\ larger
cation# the more substituted enolate is usually formed[
The required one of two possible enolates\ derived from an unsymmetrical ketone\ may be
selectively prepared and such methods have been reviewed ð64PAC442\ 65T1868Ł[ The two isomeric
carbanions "096# and "097# interconvert rapidly only in the presence of the parent ketone or any
stronger acid "Scheme 27# ð54JOC0230Ł[
i, +H+
O– O ii, –H+
O– O
Bun Bun –
Bun Bun
–
(107) (108)
Scheme 38
In the absence of such acids\ it is possible to prepare either "096# or "097# and thus in some cases
to carry out selective alkylation at the a!position on either ~ank of the ketone functionality
ð54JOC1491\ 58JOC0851\ 60JOC1250Ł[ The regioselective formation of enolates derived from unsym!
metrical ketones and their subsequent alkylation have been the subject of extensive research[
Whereas numerous e}ective and ingenious methods have been reported for the regioselective
formation of the anion\ the alkylation step has frequently encountered serious di.culties[ Equi!
libration of enolates accompanying the alkylation process has resulted in loss of regioselectivity and
Carbanions 762
in the formation of polyalkylated products ð65T1868\ 66T1626\ B!68MI 008!91Ł[ An especially notorious
example of this phenomenon is the benzylation of the kinetic lithium enolate mixture derived either
from 1!heptanone directly or from a mixture of the corresponding silyl enol ethers "098# and "009#\
which gave as the major products "000# and "001# in 42) and 26) yield\ respectively\ along with
dibenzylated isomers in 09) yield ð60JOC1250Ł[
O
O-TMS O-TMS O
Bun
Bun Bun Bun Bn
Bn
(109) (110) (111) (112)
Liotta and Caruso argued that if the kinetic enolate mixture could be substantially activated
towards alkylation\ then proton transfer and the resulting equilibration and polyalkylation might
no longer be an e}ective competing process in the presence of excess alkylating agent ð74TL0488Ł[
They reported the use of various Li¦ complexing agents to accomplish these objectives[ All the
ligands reported produced more terminal than internal alkylation[ The order of e}ectiveness was
found to be HMPA "3[8 equiv[#×DMF "neat#×benzo!03!crown!3 "0[50 equiv[#×DMF "5[07
equiv[#×triglyme "0[83 equiv[#[ HMPA was found to give\ starting from a mixture of silyl enol
ethers "098# and "009# a ratio of terminal "000# to internal "001# benzylation products of 81 ] 7\ with
an absolute yield of "000# of 66) "a percentage yield quite close to the absolute amount of terminal
enolate "009# initially present#[ The rates of reaction in the presence of each of the ligands were
enhanced^ in the presence of benzo!03!crown!3\ DMF or HMPA the reactions were complete in
less than one minute[ Since benzyl bromide may be considered to be a relatively reactive electrophile\
the regiochemistry obtained using the less!reactive alkylating reagent\ n!butyl iodide was examined[
In the presence of HMPA\ not only was the rate accelerated but the product mixture showed a
de_nite preference for the terminal n!butylated product[ In a preparative scale run using HMPA\ a
39) absolute yield of mono!n!butylated products was obtained in which 45) was the terminal
isomer[ Thus\ even with a poorer electrophile the presence of a suitable complexing agent gave
greater regioselectivity[ Liotta and Caruso discussed these observations in the light of NMR work
concerning organolithium complexes formed in various ethereal solutions ð62JA2576\ 66JA3843\ 66T1626\
70HCA1506\ 70JA3383Ł[
0[08[0[1[03 Factors determining the course of ketone and aldehyde enolate formation
The subject of enolate anion formation has been reviewed by Mekelburger and Wilcox
ð80COS"1#88Ł[ Sterically encumbered amide bases are employed to retard nucleophilic attack on the
carbonyl group[ The most frequently employed bases are lithium diisopropylamide "LDA#\ lithium
isopropylcyclohexylamide "LICA#\ lithium tetramethylpiperidine "LITMP#\ lithium hexa!
methyldisilylamide "LHMDS# and lithium tetramethyldiphenyldisilylamide "LTDDS#[ Other useful
bases include sodium hydride\ potassium hydride and triphenylmethyllithium[ The stereochemical
course of an enolate reaction frequently depends on the geometry of the enolate anion[ The structures
of enolates have been studied through NMR studies and by x!ray crystallography ð66JA3843\ 66T1626\
70JA3383\ 74CB653\ 74HCA0262\ 74JA2234\ 74JA4392\ 74TL2820\ 75HCA0930\ 75JA351\ 76JA4428Ł[
Aldehyde enolates and aldehydes are extremely reactive and therefore\ to avoid undesirable side
reactions\ fast and quantitative conversion of aldehydes to enolates is necessary[ Strong bases are
required\ e[g[\ potassium amide in liquid ammonia ð69RTC0042Ł or potassium hydride in THF
ð67TL380Ł[ As a consequence of their excessive reactivity\ aldehyde enolates are infrequently used
in organic synthesis[
For all types of enolates either "E#! or "Z#!geometry is possible and this has been the subject of
much study ð71TS0\ B!73MI 008!92\ B!73MI 008!93Ł[ Such information is pertinent to predicting the
outcome of aldol reactions because "Z#!enolates tend to give syn products\ whereas "E#!enolates
tend to give anti products with varying degrees of stereoselectivity[
Under equilibrium conditions\ the "Z#!enolate is invariably the major product except in the case
of three!to!nine membered ring systems\ where the "E#!enolate is favoured[ The investigations of
Rathke and co!workers are consistent with this observation "Equation "08##\ where the use of LDA
gives rise to a product ratio determined largely by kinetic factors ð79JA2848Ł[
OLi
O LDA OLi
+ (19)
(E) 87% (Z) 13%

Corey and Gross| studies on enolate selectivity led to the conclusion that the use of sterically
hindered bases like lithium t!octyl butyl amide "LOBA# gave superior selectivity to "E#!enolates as
compared to LDA ð73TL384Ł[ He argued that the stereochemical outcome in the presence of HMPA
was not a kinetic e}ect\ but was due to equilibration to the more thermodynamically stable
"Z#!enolate[ Corey and Gross| conclusion was founded on their experiments using TMS!Cl as an
internal quenching agent during the enolisation with a lithium amide base "Equation "19##[
O-TMS
O LOBA
O-TMS
+ (20)
(E) (Z)
Method Solvent (E) : (Z)
Internal quench THF 98 : 2
Internal quench (8 equiv. TMS-Cl) HMPA, THF 37 : 63
Internal quench (17 equiv. TMS-Cl) HMPA, THF 46 : 54
Two-step procedurea HMPA, THF 18 : 82
a Slow addition of ketone to LDA followed by silylation.
LOBA = Lithium t-octyl butylamide
Rathke and co!workers found that the addition of 0Ð3 equivalents of HMPA or TMEDA did
not change the "E# ] "Z# ratio "Scheme 28#\ but the addition of 9[1 equivalents of 2!pentanone caused
rapid isomerisation to an equilibrium mixture of enolates with an "E# ] "Z# ratio of 05 ] 73[ He
suggested as explanation the mechanism illustrated in Scheme 28 ð79JA2848Ł[ Rathke and co!workers
found it was possible to control the deprotonation of 2!pentanone in THF solution so as to produce
predominantly the "E#!isomer by addition of the ketone to 09) excess LITMP at 9>C ""E# ] "Z#
ratio 76 ] 02#\ or to produce predominantly the "Z#!isomer by addition of the ketone to a slight
de_ciency of LITMP ""E# ] "Z# ratio 05 ] 73#[ He concluded that the formation of the "E#!enolate
could be the result of kinetically controlled deprotonation\ but the formation of the "Z#!enolate is
thermodynamically favoured[
OLi OLi O
O Et OLi O
+ +
Et
(E) 16% (Z) 84%
Scheme 39
Ketone enolate stereochemical assignments have been determined by Ireland et al[ ð65JA1757Ł[
The preponderance of "E#!enolate observed with LDA as the base in THF solution in these and
related studies with esters can be rationalised by the consideration of the nonbonding interactions
in the alternative pericyclic transition states "002# and "003# "Scheme 39#[ Unfavourable steric
interactions between R0 and R1 disfavour transition state "002# and promote enolisation via the
transition state "003# to give "Z#!geometry\ whereas dominant R1 versus L "R2# nonbonded inter!
actions should militate against transition state "003# in favour of "002#[
If lithium dialkylamide bases are used in a mixture of THF and HMPA\ or if silylamide bases
are employed\ then "Z#!enolates prove to be the major products[ Prediction of the outcome of
kinetic product control necessitates a more precise study of the reactants and bases[ Reactions of
ketones\ esters or thioesters with lithium dialkylamides "e[g[\ LDA\ LICA or LITMP# in THF favour
the "E#!enolate[ Larger\ sterically encumbered bases give predominantly "Z#!selectivity "Table 6#
ð66JA7098\ 79JOC0955Ł[
However\ if a bulky group "e[g[ t!butyl or phenyl# is located a to the carbonyl group\ the
Carbanions 764
O
R2
R1
R32NLi, THF
+
+
R1 R1
O O
R2 R2
Li Li
R3 R3
H H
N N
R3 R3
(113) (114)
OLi
OLi
R1 R2
R1
R2
(E) (115) (Z) (116)
Scheme 40
Table 6 Kinetic enolisation of aldehydes and ketones where

R1 Et "Scheme 39#[
R0 Basea Enolate ratio "Z# ] "E#
*
Et LDA 29 ] 69
Et LCPA 24 ] 54
Et LHMDS 55 ] 23
Et LITMP 19 ] 79
Pri LDA 59 ] 39
Pri LCPA 48 ] 30
i
Pr LHMDS ×87 ] 1
Pri LITMP 21 ] 57
But LDA ×87 ] 1
0!Adamantyl LDA ×87 ] 1
TMS LDA 27 ] 51
Ph LDA ×87 ] 1
Ph LCPA ×87 ] 1
Ph LHMDS ×87 ] 1
Ph LITMP ×87 ] 1
Mesityl LDA 4 ] 84
Mesityl LCPA 3 ] 85
Mesityl LHMDS 76 ] 02
*
a
LCPA lithium cyclohexylisopropylamide\ LHMDS lithium hexamethyl!
disylamide\ LDA lithium diisopropylamide\ LITMP lithium tetramethyl!
piperidine[
"Z#!enolate is preferred ð66JA136Ł[ As has been discussed\ ketones enolise under kinetic conditions
regioselectively towards the less!substituted carbon atom\ and stereoselectively to the "Z#!enolate\
if the enolates are formed by a bulky base and trapped with dialkyl boron tri~ates\ R1BOSO1CF2\
at low temperatures ð68JA5019Ł[ Both types of "Z#!enolates can be generated for future application
in stereoselective aldol reactions as shown in Equations "10# and "11#[
O LDA, THF, 15 min, –72 °C OLi
(21)
But 100% But
trans ≡ (Z)
O Bu
F 3C S O B
O Bu
O i, Et2O, –78 °C, 0.5 h Bu

ii, 0 °C, 0.5 h B
O Bu (22)
–[Pri +
2EtNH] •CF3SO3
–
H
trans ≡ (Z)
N: (>99%)
0[08[0[1[04 Factors determining the course of ester and amide enolate formation
The subject of ester enolate anion formation has been reviewed by Wipf ð80COS"4#716Ł[ It was
initially proposed that the "E# ] "Z# ratio of the enolate esters was kinetically determined\ regardless
of whether THF or a mixture of HMPA:THF was used ð64TL2864\ 65JA1757Ł[ Two possible transition
states "002# and "003# leading to lithium ester enolate formation are shown in Scheme 39\ where in
this case R0 OR[ In the absence of the solvating ligand HMPA or DMPU the lithium atom is
strongly coordinated to the ester carbonyl oxygen atom leading to strongly unfavourable interaction
between R0 and R2 in transition state "003#[ Although transition state "002# is energetically dis!
favoured by unfavourable interaction between R0 and R1\ this transition state leads preferentially
to "E#!enolate formation in the absence of HMPA or DMPU "N\N?!dimethylolpropyleneurea#[
Contrastingly\ in the presence of HMPA or DMPU\ the lithium atom is highly solvated resulting
in a weakened coordination of the Li¦ by the carbonyl oxygen atom[ In this case\ unfavourable
steric interactions between R0 and R2 are reduced by such solvation\ which lengthens the Li¦ to
carbonyl oxygen bond\ while steric repulsion between R0 and R1 is relieved by rotation about the
methylene carbon to carbonyl carbon C0C bond[ These two factors combine to lower the potential
energy of transition state "003# relative to the unsolvated case and leads preferentially to "Z#!enolate
formation[ It should also be noted in this latter solvated situation\ that a decrease in polarisation
of the carbonyl oxygen also results in a signi_cantly less reactant!like transition state\ as the a!C0H
bond becomes more di.cult to break ð74JA1153\ 80JOC549Ł[ In the presence of a slight excess of ester
in the enolisation mixture\ there is a change in the "E# ] "Z# ratio of the lithium enolate in favour of
the "Z#!enolate ð80COS"4#716\ 80JOC549Ł[
Tertiary carboxylic acid amides always give "Z#!enolates with high selectivity[ Ireland et al[ have
proposed a cyclic six!membered transition state between the carbonyl group and the dialkylamide
base to explain this phenomenon ð65JA1757Ł\ and in the mid 0879s the validity of this model was
bolstered by theoretical calculations by Moreland and Dauben ð74JA1153Ł[ As summarised in Table
7\ under {apparent| ð71TS0Ł kinetic control\ esters and thioesters a}ord largely "E#!enolates\ while
dialkylamides exhibit predominant to exclusive "Z#!enolisation[
Evans et al[ have postulated ð79TL2864\ 79TL3122\ 70THŁ that the high "Z#!stereoselection observed
in the deprotonation of dialkylamides is a consequence of ground state allylic strain considerations
ð55AG"E#788\ 57CJC710\ 57CRV264\ 67JOC1694Ł that disfavour deprotonation via transition state "002#
"Scheme 39^ R0 NR1#[ Thus the formation of "E#!enolates "004# is disfavoured\ whereas formation
of "Z#!enolates "005# via transition state "003# "Scheme 39^ R0 NR1# is perforce the preferred
reaction pathway[ Investigations indicate that the enolisation process catalysed by LDA in THF
a}ords enolates "004# and "005# with at least 86) "Z#!stereoselection ð79TL3122Ł[ Related obser!
vations have been reported on the stereoselective enolisation of dialkylthioamides ð79JA6795Ł[ In
this latter study\ the IrelandÐClaisen strategy ð65JA1757Ł was employed to assign enolate geometry[
Studies on the role of base structure and solvent have appeared in the literature ð67TL1968\
79JA2848Ł and the Ireland enolisation model for lithium amide bases\ involving a chair!con_gured
six!centre pericyclic mechanism\ has now been widely accepted[ The stereoselectivity of enolisation
has been well reviewed by Evans\ Nelson and Taber ð71TS0Ł and also\ particularly with respect to
the IrelandÐClaisen rearrangement\ by Pereira and Srebnik ð82MI 008!90Ł[ The e}ect of ~uorine
substituents on the structure and reactivity of enolates and enolate equivalents has been reviewed
ðB!77MI 008!90Ł[ Structural investigations of lithium enolates and related species have been reviewed
ð77AG"E#0513\ 78AG"E#166Ł and also\ speci_cally\ NMR investigations ð76AG"E#0101Ł[
Carbanions 766
Table 7 Kinetic enolisation of carboxylic acid esters and amides[
Enolate ratio
R1 R2 Base (E):(Z) Ref.
OMe Me LDA 95:5 80JOC1066

OMe Et LDA 91:9 76JA2868
OMe Ph LDA 29:71 76JA2868
OMe But LDA 97:3 76JA2868
OBut Me LDA 95:5 80JOC1066
OBut Et LDA 95:5 76JA2868
SBut Me LDA 90:10 80TL3975
NEt2 Me LDA <3:97 81TH
N(CH2)4 Me LDA <3:97 80TL4233
NPri2 Me LDA 19:81 80JOC1066
OLi
O LDA, THF, –70 °C OLi
R2 R1 + R2
R1 R1
R2
(E) (Z)
0[08[0[1[05 Structural effects on the energetics of s!cis and s!trans dienolates

Eldin\ Whalen and Pollack have examined the acidifying e}ect of the positioning of either a
phenyl or vinyl substituent at the a!carbon of a carbonyl compound ð77JA0870\ 78JA5308\ 89JOC0908\
80JA0233\ 80JA2722Ł[ Both a phenyl substituent and a vinyl substituent can increase the aqueous
acidity of a simple ketone by as much as 096!fold[ The aqueous acidities of 1!tetralone "006#
ð77JA0870Ł and 4!androstene!2\06!dione "007# ð78JA5308Ł are comparable "Equations "12#Ð"15##\
which implies a quantitatively similar acidifying e}ect for a phenyl group and a double bond on the
a!carbon of carbonyl compounds[ However\ the double bonds in the b\g!unsaturated ketones
4"09#!androstene!2\06!dione "008# and 2!cyclohexenone "019# are approximately 091Ð092 less e}ec!
tive in promoting the ionisation of the a!hydrogen atom than in compound "007#[
–H+
pKa = 12.9 (23)
O –O
(117) (121)
O O
–H+
pKa = 12.7 (24)
O –O
(118) (122)
O O
–H+
pKa >> 14 (25)
O –O
(119) (123)
–H+
pKa ~ 15.2 (26)
O –O
(120) (124)
The most salient di}erences between enolate "011# and enolates "012# and "013# are _rstly\ that
"011# has an s!trans conformation of the conjugated double bonds\ whereas the anions of "012# and
"013# possess an s!cis geometry and secondly\ "011# has an exocyclic double bond that is not present
in "012# and "013#[
Pollack and co!workers have reported an 0H!NMR investigation of the relative kinetic acidities
of the cis and trans g!protons of 1!cyclopentylidenecyclopentanone "014# "Scheme 30# ð82JOC6099Ł[
In this system the in~uence of endocyclic versus exocyclic double bonds is eliminated\ rendering it
possible in theory to isolate the e}ect of orientation of the double bonds of a dienolate ion "s!cis
versus s!trans# on the acidifying e}ect of a b\g!double bond[ Both the kinetic and quenching
experiments indicated that the transition state for the formation of the s!cis dienolate "015# is higher
than that for the s!trans dienolate "016# by a factor of about four!fold "ca[ 9[7 kcal mol−0#[ Pollack
and co!workers estimated that thermodynamically the s!trans dienolate "016# was about 0[6 kcal
mol−0 more stable than the s!cis dienolate\ corresponding to a di}erence in pKa of 0[1 units[
O– O O–
–H+ –H+
(127) (125) (126)
Scheme 41
Pollack and co!workers concluded that cyclic s!cis dienolates were considerably less stable than
the corresponding s!trans dienolates due to two factors^ _rst\ greater strain caused by the presence
of two double bonds in the same ring in the case of the s!cis dienolate and second\ an inherent
energy di}erence between s!cis and s!trans geometries[ The authors ascribed predominance to the
_rst e}ect[
0[08[0[1[06 Chiral auxiliaries conferring stereocontrol over enolate reactions

Valinol! and ephedrine!derived auxiliaries\ to be found incorporated in structures "017# and "018#
respectively\ both possess similar characteristics as chiral controllers for a wide range of asymmetric
transformations ð70PAC0098\ 71MI 008!90Ł[ "Z#!Enolates\ derived from N!acyl imides of chiral oxazo!
lidinones react with aldehydes in a highly stereoregulated fashion yielding a!substituted!b!hyd!
roxyamides in high yields "Equations "16# ð70JA1016Ł and "17# ð71TL796Ł#[
O O i, Bu2BOTf, CH2Cl2, 0 °C
O O OH
ii, Et3N
O N iii, PhCHO, –78 °C O N Ph
(27)
81%
(128)
i, Bu2BOTf, CH2Cl2, 0 °C
ii, Et3N O O OH
O O iii, CHO
O N
O N (28)
86%
Ph
Ph
(129)
Equations "16# and "17# are illustrative of the vast and growing literature describing the reactions
of chiral enolate anions[ The reader is directed to the authoritative texts of Evans ðB!73MI 008!91Ł
and Heathcock ðB!73MI 008!94Ł for reviews of this topic[
0[08[0[1[07 Stereoelectronic effects in the formation of enolates and related functions

The subject of such stereoelectronic e}ects has been reviewed by Deslongchamps ðB!72MI 008!93Ł[
Corey observed ð42E218Ł that the kinetically controlled bromination of ketosteroids always gives
Carbanions 768
the epimer in which the bromine atom is {polar| "i[e[ axial# ð43JA064Ł[ In a subsequent publication\
Corey and Sneen ð45JA5158Ł mentioned that this was an example of a stereochemical!electronic
e}ect[
Fraser and Champagne have observed a marked selectivity in the exchange of the con!
formationally _xed substrate "029#\ a bridged biaryl ketone in which the C0H0 bond is parallel to
the pp!orbitals of the carbonyl group^ the H0 ] H1 ratio of rates of exchange was found to be 62
using sodium methoxide and 29 using sodium phenoxide ð65CJC2798Ł[
H1
C
O H2
(130)
Fraser and Champagne also studied the base!catalysed H:D exchange reaction of 3!twistanone
"020# ð67JA546Ł[ One C0H bond alignment "H0# gives maximum overlap with the adjacent
pp!orbital of the carbonyl function\ whereas the dihedral angle between the C0H1 bond and that
pp!system is 29>[ Accordingly\ when 3!twistanone was treated with sodium methoxide in methanol!
O!d\ the relative rates of exchange of the diastereotopic protons H0 and H1 were found to be in the
ratio 189 ] 0[ Using ab initio molecular orbital calculations Wolfe and Schlegel have predicted that
the enolate derived from the removal of H0 from "020# should be more stable than that derived by
abstraction of H1 by 07 kcal mole−0 ð64CJC2254Ł[
C
H1 H2
O
(131)
0[08[0[1[08 Dicarbanion formation by proton loss

Compounds of the type MeCO0CH10CO0 can release two protons\ if treated with 1 moles of
a su.ciently strong base "e[g[\ LDA or BuLi#\ to give dicarbanions "e[g[\ "021# "Scheme 31##[ Such
dianions are ambident carbon nucleophiles\ in addition to an attack capability involving the oxygen
atoms[ For such species the electrophilic attack is almost invariably on the more basic carbon atom[
However\ counter!examples do exist\ for example the work of Trimitsis et al[ ð72JOC1846Ł[ Since a
proton on a carbon bonded to two carbonyl groups is more acidic than that on a carbon adjacent
to just one carbonyl group\ it follows that the CH− group of "021# is more acidic than the CH1−
group\ so it is the latter group which is attacked by an electrophile to give "022# ð47JA5259\ 54JOC1823Ł[
The subject has been reviewed ð58OR"06#044\ 66S498\ 80COS"1#070\ 80T3112Ł[
O O O O i, RX O O
2 moles base
R
OEt OEt ii, H+ OEt
– –
(132) (133)
Scheme 42
The hydrocarbon analogue "024# of the squarate dianion "025# has been prepared by metallation
of 0\1!dimethyl!2\3!bismethylenecyclobutene "023# with BunLi\ ButOK or BunLi\ TMEDA "Scheme
32# ð78JOC662\ B!78MI 008!90Ł[
– 2– 2–
O O
–2H+
≡ cf.
O O
–
(134) (135) (135) (136)
Scheme 43
Methylated biphenylene dianions have been characterised by NMR spectroscopy and their direc!
tion of ring!opening has been rationalised by molecular orbital calculations ð78TL048Ł[
0[08[0[1[19 Choice of base and solvent for the formation of various types of carbanion stabilised by
conjugation
C0H bonds are polarised by attached unsaturated carbon substituents[ Such groups activate the
neighbouring CH2\ CH1 or CH in the following order] CR1NR1¦ ×COR×C2N×CO1R×
CR1NR×Ph×CR1CR1[
The formation of the carbanions described in Scheme 33 depends on equilibria between the
carbon acid\ its conjugate base and the solvent[ To ensure a substantial concentration of the
carbanion in solution the pKa of both the conjugated acid of the base and of the solvent must be
higher than the pKa value of the carbon acid[ Alkali hydroxides in water "pKa ½05#\ alkoxides
in the corresponding alcohols "pKa ½19#\ sodium amide in liquid ammonia "pKa ½24#\ sodium
methylsul_nylmethylide in dimethyl sulfoxide "pKa ½24#\ alkali metal hydrides ð75AG"E#354Ł\ lithium
amides or lithium alkyls in ether or hydrocarbon solvents "pKa ×39# are common combinations
used in synthesis "Table 8#[
pKa ~ 35 OEt pKa ~ 11 OEt

–
–
BuLi NaOH, H2O
O O O O
pKa ~ 35 pKa ~ 11
–
N N N –
N
BuLi NaOH, H2O
O O pKa ~ 9 O
–
O
pKa ~ 25 – O O
LDA, THF K2CO3, H2O
OEt OEt
LDA (2 equiv.)
O pKa ~ 20 O Y or Y
– –
LDA, THF BuLi (2 equiv.) O
O O – O
O O
OEt pKa ~ 13
OEt
–
OEt NaOEt, EtOH OEt
O O
Scheme 44
Sometimes\ unfortunately\ the bases "e[g[\ methoxides\ amides\ lithium alkyls# react as nucleo!
philes\ rather than carry out the desired proton abstraction\ with the result that the nucleophile
undergoes an addition and:or substitution reaction with the carbon compound[ In order to avoid
this undesirable situation\ nonnucleophilic sterically hindered bases are popular\ e[g[\ potassium
t!butoxide\ LDA\ sodium bisðtrimethylsilylŁamide\ potassium 2!aminopropylamide "KAPA#\
Carbanions 770
Table 8 Common combinations of bases and solvents used for the conversion of weakly acidic methylene
compounds to their anions[
Base Frequently used solvents References to preparation and use
*
ButOK ButOH\ DMSO\ Et1Oa\ 0\1!DME\ 40JA4669\ 40OR"5#30\ 46JA1895\ 46JOC591\
PhHa\ THF 47JA4119\ 47JA5185\ 47JOC730\ 59JA1736\
50JA2567\ 51JA2053\ 51JA2391\ 51TL558\
52JA0427\ 52OSC"3#021\ 53JA0886\ 53JA4346\
54JA2117\ 54OS"34#78\ 55JA0221\ 56JCS"C#0759
ðFor crystal structure of ButOK see 56AG"E#790Ł
EtMe1CONa Et1O\ PhH\ PhMe 49BSF422\ 49BSF426\ 45BSF0939\ 50BSF725\
50T34\ 51TL494\ 52BSF0814\ 52BSF0829\
52RCP31
NaNH1 liq[ NH2\ Et1Oa\ PhHa\ PhMea\ 30JA1864\ 44OSC"2#33\ 44OSC"2#108\
0\1!DME 44OSC"2#667\ 59OS"39#27\ 51JOC2725\
53AG"E#360\ 54JOC1826\ 54JOC3024\ 55JOC871\
55JOC878\ 56OS"36#61\ 56OS"36#81\
57OS"37#42\ 57OS"37#79
KNH1 liq[ NH2\ Et1Oa 47JA5259\ 48JA0043\ 48JA0059\ 48OS"28#62\
59JOC047\ 51JOC1626\ 52JOC0835\ 53AG"E#360\
54JA71\ 55JOC0924\ 57OS"37#39
Et1NLi 0\1!DME\ Et1O 21LA"384#73\ 34JA1095\ 34JA1009\ 49JOC749\
40JA3047\ 53CB2437\ 53JOM"0#365\
54JOC0230\ 54JOC1491\ 57JOC824\ 57JOC832\
69JA2111\ 69OS"49#55
Pri1NLi 0\1!DME\ Et1O\ THF 56JA1499\ 58JOC1213\ 69JA0285\ 69JA0286\
69OS"49#47\ 69OS"49#55
"TMS#1NNa THF\ Et1O\ PhH 53JOM"0#365\ 58CC0386\ 58CC0387\ 69JA2111
NaH Et1Oa\ PhHa\ PhMea\ C5H3Me1a\ 34JA0162\ 49JA2693\ 41JA720\ 48JOC698\
0\1!DMEa\ DMFa 59JA0275\ 59JA0573\ 59JA1784\ 59JA4693\
50JOC533\ 50OS"30#4\ 51OS"31#17\ 52JOC2251\
52OSC"3#150\ 54JOC0230\ 54JOC1491\
56OR"04#0\ 56OS"36#19\ 57JOC824\ 57JOC832\
57JOC1111\ 57JOC2314\ 57JOC2366\ 69TL2892 "For
the preparation of a very reactive form of sodium
hydride by reaction of hydrogen with sodium
naphthelenide in THF solution\ see ð57JA3494Ł#
LiH Et1Oa 48JOC698\ 59JA0275\ 57JOC1111\ 57JOC2366
MeSOCH1Na DMSO 50JOC3001\ 51JA755\ 53JOC110\ 53PCS097\
54JA0234\ 58MI 008!90
Ph2CLi Et1O\ 0\1!DME 48JOC118\ 52JOC2251\ 52JOC0614\ 54JOC0230\
54JOC1491\ 57JOC824\ 57JOC832\ 69CC0214
Ph2CNa Et1O\ PhH\ PhMe\ liq[ NH2 32OSC"1#157\ 32OSC"1#595\ 43JOC0389\
44JOC0420\ 46JA770\ 48JOC698
Ph2CK 0\1!DME 43JOC0389\ 44JOC0420\ 51JOC3035\ 52JOC2251\
54JOC0230\ 54JOC1491\ 57JOC824\ 57JOC832
Sodium naphthelenide and 0\1!DME 25JA1331\ 59BSF243\ 51JOC2634
related carbanions
*
a
Solvents in which the base is either insoluble or only partially soluble[ From {Modern Synthetic Reactions|\ 1nd edn[\ by Herbert O[ House\
Copyright "Þ# 0861 by W[ A[ Benjamin\ Inc[
lithium 0\0!bis"trimethylsilyl#!2!methylbutoxide and the weak bases 0!"dimethylamino#naphthalene

and poly"3!"diisopropylaminomethyl#styrene# ðB!61MI 008!91\ 65TL0706Ł[
0[08[0[1[10 Metallation of N!alkylimines

A carbonyl function may be converted into an amino group by condensation with a primary
amine[ The resulting N!alkylimine "{Schi} base|# "026# "Scheme 34# can be metallated with LDA in
ethereal solvents at 9>C[ At temperatures below −69>C such lithiated Schi} bases are stable
against self!addition[ These carbanions are useful in selective aldol additions ð57AG"E#6Ł[ Metallated
dimethyl hydrazones have also been used extensively[ They permit stereo! and regioselective car!
banion formation since the dimethylamino group orients away from large substituents and tends to
locate the metal ion proximate to the less substituted carbon atom ð67CB0226Ł[
Li+
N LDA, THF, –78 °C no self-addition and
R1 – N
R1 no proton exchange
R2
(137) R2
Me
O +Li N Me
i, Me2NNH2
R1
– N
R2 ii, BuLi or LDA, THF, –78 °C R1
R2
MeI
N – + N
Li+ N
N NMe2
Me NMe2
Me
90 : 10
Scheme 45
0[08[0[1[11 Carbanion formation with concomitant double!bond rearrangement

The double bonds of many unsaturated compounds are shifted on treatment with strong bases
ðB!78MI 008!91Ł and there have been numerous reviews ð57ACR120\ 58S86\ 69RCR748\ 69S394Ł[ In many
cases equilibrium mixtures are obtained and the thermodynamically most stable isomer predom!
inates[ Lists of which double bonds are more stable in conversions of XCH1CH1CHY to
XCH1CHCH1Y are to be found in the literature ð71JOC3655\ 72JOC473Ł[ If formation of the new
double bond places it in conjugation with an existing double bond or an aromatic ring\ this pathway
will usually be favoured\ although there are counter!examples ð51TL558\ 54JOC1402Ł[ If formation of
the new double bond promotes resonance stabilisation with a lone electron pair then\ similarly\ this
pathway will be favoured ð53TL0080\ 55JCS"C#71\ 57JCS"C#0892\ 61JCS"P0#0424\ 62JCS"P0#0747\ 76TL4776Ł[
An example of the isomerisation of alkenes by base is furnished by the synthetically useful
Varrentrapp reaction ð59T135Ł[ Despite the vigorous conditions\ the reaction can be quite speci_c[
The product "027# "Scheme 35# is derived in high yield and results from at least nine successive
isomerisations followed by base!catalysed cleavage[
O– NaOH, 300 °C O–
O 80% O
O–
O
(138)
Scheme 46
Terminal alkenes react with potassium t!butoxide in DMSO to give internal alkenes of pre!
dominantly cis!con_guration "e[g[\ "039# "Scheme 36## as the favoured product via the cis!allylic
anion "028# ð54JA2133Ł[
Carbanions 772
KOBut, DMSO
–
(preferred pathway)
(139) (140)
Scheme 47
0[08[0[2 Carbanions by Scission of C0C or C0X Bonds
0[08[0[2[0 General considerations of carbanion formation by C0C bond scission

In these reactions\ the substrate may be regarded as the moiety that retains the electron pair[ The
resultant carbanion is usually quenched by a proton[ The reactions are sometimes termed {anionic
cleavages| ð76RCR872Ł and usually proceed via an SE0 carbanionic mechanism[ Such reactions are
facilitated kinetically by any inherent stabilisation of the nascent carbanion[
0[08[0[2[1 Formation of carbanions by decarboxylation

The elimination of carbon dioxide from a carboxylic acid is an important reaction in organic
chemistry[ However\ decarboxylation of simple aliphatic acids requires high temperatures and is of
limited synthetic value\ although acetic acid in the form of the acetate salt\ when heated with base\
gives good yields of methane ð52JCE101Ł[ Contrastingly\ decarboxylation readily occurs when certain
structural features are present[ When the acid possesses a suitably situated electron!withdrawing
substituent as in oxalic\ nitroacetic or trichloroacetic acid\ carbon dioxide is readily eliminated on
heating and the resultant carbanion is protonated[ The facile elimination of carbon dioxide from
b!ketonic esters to yield ketones probably proceeds via an e}ectively concerted mechanism involving
a cyclic transition state without formation of a carbanion ð50JA0840\ 52PCS142Ł[ However\ mono!
carboxylic acids or their alkali salts on heating with sodium hydroxide\ calcium hydroxide or other
metallic hydroxides give an alkane and a metal carbonate "Equation "18## ð0745MI 008!90Ł[ This
pyrolysis presumably involves transient carbanion formation[
heat
(RCO2)2Ca + Ca(OH)2 2RH + 2CaCO3 (29)
0[08[0[2[2 Formation of carbanions during cleavage of alkoxides

Alkoxides of tertiary alcohols can be cleaved by thermolysis "Equation "29## ð48JA0506\ 66JOM334\
67JA1023Ł[ The reaction fails when the R groups are unbranched alkyl groups[ Branched alkoxides\
such as those derived from diisopropylneopentylcarbinol or tri!t!butylcarbinol\ can be cleaved
ð67JOC704Ł[ Allylic ð76HCA0747\ 76HCA0768Ł\ benzylic ð77JCS"P1#872Ł and aryl groups also cleave[
Gas!phase studies indicate that cleavage proceeds via carbanion formation ð77JA1603\ 78CC050Ł[
However\ with some substrates ð78JOC4933\ 78JOC4943Ł and hindered alcohols "not the alkoxides# a
radical pathway is suspected ð89JOC0941Ł[ Mechanistic studies have examined the inversion and the
subsequent degree of racemisation of carbanions thus formed ð48JA4639\ 58JA0998\ B!81MI 008!95Ł[
R1 i, heat
R1
R2 O– R2H + O (30)
R3 ii, H+ R3
0[08[0[2[3 Carbanion formation by acyl cleavages
"i# Formation of carbanions durin` the retro!aldol reaction

The factors a}ecting reversibility of the aldol reaction have been reviewed ð80COS"1#022Ł[ The
entire aldol reaction "including the possible dehydration step giving the a\b!unsaturated carbonyl
compound "030## is an equilibrium "Scheme 37# and a\b!unsaturated and b!hydroxy aldehydes and
ketones can be cleaved by treatment with hydroxide anion[ However\ there is evidence that an SET
"single electron!transfer reaction# mechanism can participate when the substrate is an aromatic
ketone ð71JA5677\ 75JOC361Ł[
O
O O O R2 –
R2 R2 R3
R2 HO–, H2O R1 HO–, H2O R1
R3 R3 R3 R1
R1 = H
R4 R5 R4 R5 R4 R5
R4 R5 OH O–
(141) O
Scheme 48
Aldol reactions in which aldehydes are receptors "i[e[\ R3 H# are often easily reversible under
mild conditions while aldol reactions in which ketones are receptors are more readily reversible than
the analogous reactions with aldehyde receptors[ The main structural factor that favours reversibility
is steric compression of the aldol[ Branching at the hydroxy carbon in the aldol favours reversibility\
as does branching at the carbon situated between the hydroxy and carbonyl functions in the aldol
ð72JA0487Ł[ The degree of stereoselectivity of aldol reactions can be adversely a}ected by the
retrograde reaction[ In most cases\ aldolate equilibration must be avoided\ because it usually
degrades the kinetically established stereoisomer ratio ð80COS"1#123Ł[
The cleavage of cyanohydrins is mechanistically similar to the retrograde aldol reaction
ð44OSC"2#090Ł[ The retrograde Michael reaction also gives rise to carbanions via C0C bond scission
"see Section 0[08[0[3[0[0#[
"ii# Base!induced cleavaè of b!keto esters

When b!keto esters are treated with concentrated base\ cleavage occurs via a tetrahedral inter!
mediate with concomitant carbanion formation "Scheme 38# ð26JA0712Ł^ see also ðB!81MI 008!96Ł
although there is evidence that in some cases a SET mechanism is involved ð72TL0556Ł[
O O
R1 R 2O O– O O O
OR2 R1 +
OR2 R1 R1
R1 OR2 OR2
R1 –
R2O–
Scheme 49
The ready reversibility of the closely related Dieckmann condensation combined with the tendency
to form the least hindered metal enolate usually determine the structure of the cyclised product
from an unsymmetrical diester ð32OSC"1#005\ 49JA1284\ 41JA0693\ 53JOC1670\ 54JOC070\ 54OS"34#14\ 55CC779\
55T174\ 56JOC1146\ 56OR"04#0\ 57JOC359\ B!61MI 008!92Ł[
"iii# Carbanion formation resultin` from cleavaè of ketones

Carbanion formation resulting from the heterolytic C0C bond scission is of pivotal importance
to the mechanism of the synthetically useful Favorskii rearrangement "see Section 0[98[0[1[4#
ð69RCR621\ B!81MI 008!97Ł[
"iv# Cleavaè of nonenolisable ketones

Ordinary ketones are generally much more di.cult to cleave than trihaloketones or b!diketones\
because the carbanionic intermediates in these latter cases are more stable than simple unsubstituted
carbanions ðB!81MI 008!98Ł[ However\ nonenolizable ketones can be cleaved by treatment with a
09 ] 2 mixture of ButOK:H1O in an aprotic solvent such as ether "Scheme 49#\ DMSO\ 0\1!DME
Carbanions 774
ð37JCS0397\ 56JA835Ł or with solid t!BuOK in the absence of a solvent ð66JCS"P0#359Ł[ In certain cases\
cyclic ketones can be cleaved by treatment with base\ even if they are enolisable ð47T77Ł[
O
O O–
ButOK, H2O, Et2O H2O
R1 R2 R1H + R2CO2But
R1 R2 R1 OBut
R2
ButO–
(alkyl carbanion
formation)
Scheme 50
Cleavage of ketones with sodium amide is called the HallerÐBauer reaction ð64S284\ 89OPP056Ł[
As in the preceding case\ the reaction is usually applied only to nonenolisable ketones\ and most
frequently to ketones of the form ArCOCR2\ where the products R2CCONH1 are not easily attain!
able by other methods[ However\ a diversity of ketones can be cleaved by this method[ It has been
shown that the con_guration of optically active R0 is retained "Scheme 40# ð51JA3727\ 51JOC3041\
77JOC3861\ 77JOC3867Ł[
–
NH2 NH
O – NH O
2 R1 R2 –H+ R1 R2 H+
R 1H +
R1 R2 R2 NH–
O– O–
Scheme 51
0[08[0[2[4 Carbanions derived from organometallic species

The nature of the carbon0metal bond may be ionic or polar!covalent depending chie~y on the
electronegativity of the metal and the structure of the organic moiety[ Ionic bonding is especially
favoured when the negative charge on the carbanionic carbon is stabilised by resonance or _eld
e}ects[ Thus the sodium salt of acetoacetic ester is more ionic than methylsodium[ The enormous
literature of organometallic chemistry has been reviewed ðB!56MI 008!91\ B!74MI 008!91\ B!78MI 008!92\
B!81MI 008!09Ł[ Organometallic chemistry involving species either p!bonded or s!bonded to metals
has been reviewed by Pearson ðB!74MI 008!90Ł[ The structures of organodialkali compounds have
been speci_cally reviewed ðB!76MI 008!93Ł[ The synthesis and structural characterisation of car!
banions of alkali and alkaline earth cations has been reviewed ð80COS"0#0Ł\ along with organo!
aluminum reagents ð80COS"0#66Ł\ organocopper reagents ð80COS"0#096Ł\ organotitanium and
organozirconium reagents ð80COS"0#028Ł\ organochromium reagents ð80COS"0#062Ł\ organozinc\
organocadmium and organomercury reagents ð80COS"0#100Ł\ organocerium reagents ð80COS"0#120Ł\
organosamarium and organoytterbium reagents ð80COS"0#140Ł[ In 0880 developments in synthetic
organic chemistry via organometallics were reviewed by Dotz and Ho}mann ðB!80MI 008!91Ł[
Most organometallic bonds are polar!covalent^ only the alkali metals have electronegativities low
enough to form truly ionic bonds ðB!81MI 008!09Ł with carbon\ while even lithium alkyls show
considerable covalent character[ X!ray crystallographic studies of organoalkali compounds have
been reviewed ð76AOC"16#058Ł[ X!ray crystallographic examination of potassium\ rubidium and
caesium methyls indicates completely ionic lattices ð69CB154\ 66CB606Ł[ The simple alkyls of sodium\
potassium\ rubidium and caesium are insoluble in benzene or other nonpolar organic solvents\
whereas alkyllithiums are soluble in such media[
Metal!associated alkyl carbanions are usually produced from the corresponding halides by metalÐ
halogen exchange[ Standard procedures may be found in\ besides others\ the text by Fieser and
Fieser ðB!56MI 008!92Ł[ Halides at sp2!hybridised carbon atoms are more reactive than sp1!hybridised
carbon atoms[ The scissile ionic carbonÐmetal bonds "e[g[\ C0Na\ C0Li or C0Mg# may sub!
sequently be replaced by a more covalent carbonÐmetal bond "e[g[\ C0Cu# by metalÐmetal inter!
change ðB!75MI 008!90Ł[ The metal ion may be strongly associated with the carbanion centre and
modify its behaviour[ However\ carbanion chemistry and the chemistry of organometallic
compounds\ especially of Li\ Mg\ Na and K are closely related ð55MI 008!97\ B!62MI 008!92\ B!63MI 008!90\
B!77MI 008!91Ł[ Their chemical reactions are similar[ Synthetic chemistry\ however\ takes advantage
of two important phenomena] _rst lithium forms more covalent structures than other alkali metals
and second\ carbanions with a {soft| copper"I# gegenion tend to be highly nucleophilic[ Organo!
metallics\ as either reactants:reagents\ or reaction intermediates\ can exhibit fascinating reactivity
pro_les[ The assessment of the diverse reactivity patterns is of great theoretical and practical interest[
In a generalisation of the Lewis acidÐbase concept and by dividing the acids and bases into two
categories "{hard| and {soft|#\ Pearson formulated the Hard and Soft Acids and Bases "HSAB#
principle ð52JA2422\ 56JA0716Ł[ Tse!Lok Ho has surveyed a number of organometallic reactions\
useful in organic synthesis\ in terms of the HSAB principle ð74T0Ł[
Carbanions are much less prone to rearrangement than are carbocations ðB!76MI 008!94Ł[ The
analogue of the most common type of carbocation rearrangement\ which would be migration of an
alkyl group to an adjacent electron!rich centre leaving its bonding pair of electrons behind\ does
not occur at all readily\ although a rare example is shown in Equation "20# ð66JA0770Ł[ Pericyclic
rearrangements of carbanions have been reviewed ð67AG"E#202Ł[
Ph Li Ph
(31)
Ph Ph Li
With the exception of pericyclic rearrangements\ carbanion rearrangements usually occur stepwise
either via intramolecular addition of a carbanion to a neighbouring unsaturated group or by
nucleophilic attack by the carbanion at a neighbouring substitution site ðB!52MI 008!90\ B!54MI 008!94\
B!64MI 008!90\ B!79MI 008!92Ł[
Scheme 41 shows an anionic rearrangement in which a phenyl group migrates from an adjacent
centre\ leaving a more stable carbanion ð50JA301\ 50JA1426Ł[ Such reactions are termed GrovensteinÐ
Zimmerman rearrangements[ The intermediate carbanion is Ph2C0CH1−\ and the phenyl group
moves without its electron pair[ Aryl and vinyl\ but not alkyl groups\ migrate in this type of
rearrangement ð78JOC0560Ł[
Ph Cl Ph Li Li Ph
–30 °C 0 °C
Ph + Li Ph Ph
Ph Ph Ph
Scheme 52
Zimmerman and Zweig have demonstrated that when there is a choice between a phenyl group
and a tolyl group\ the phenyl group migrates preferentially "Equation "21## ð50JA0085Ł[ This is
consistent with a mechanism in which the migrating aryl group interacts with the carbanion centre
through its p!electron system to give a transition state "or perhaps an intermediate# structure "031#
or "032# "Scheme 42#[ The phenyl migration involving "031# would be favoured because carbanion
"032# is destabilised by the electron!donating methyl group[ Anion "033# can be detected in solution
at low temperature ð65JA6724\ 71JA5570\ 71JOC1817Ł[
Ph Li Ph
Tol Tol + Tol (32)
Li Ph
Li
major product minor product
0[08[0[2[5 Formation of carbanions by scission of C0O and C0halogen bonds

Standard procedures for the preparation of organometallic species from halogenated carbon
compounds may be found in the text by Fieser and Fieser ðB!56MI 008!92Ł and are also covered in
Chapter 1[00 of this work[
Cleavage of C0O and C0Cl bonds by metals dissolved in an aprotic solvent can facilitate the
preparation of a variety of aromatic ð67CB1379Ł and homoaromatic ð57JA5451Ł carbanions and
carbanionic annulenes[ In 0867\ Boche et al[ found "Equations "22# and "23## that the reaction of
8!anti!methoxy! or 8!anti!chlorobicycloð5[0[9Łnona!1\3\5!triene "034# or "035# with Li\ Na or K in
THF at −29>C to −19>C led stereoselectively to the aromatic cis\cis\cis\trans!ð8Łannulene anion
"036# ð67CB1379Ł[ The isomeric syn!8!methoxy! "037# or syn!8!chloro!cis!bicycloð5[0[9Łnona!1\3\5!
triene "038# on the other hand\ gave the all!cis!anion "56#[ Boche et al[ concluded that 8!syn!
lithio! and 8!anti!lithio!cis!bicycloð5[0[9Łnona!1\3\5!trienes "037^ XLi# and "034^ XLi# were not
intermediates in the formation of "56# and "036#[ They presumed that electron transfer\ giving
Carbanions 776
–
–
Tol H
Ph H
H
H
(142) (143)
Cl Cs-K-Na* CO2
–75 °C, THF –
Ph
Ph Ph CO2–
(144)
* alloy of eutectic composition
Scheme 53
bicycloð5[0[9Łnonatriene anion radicals followed by stereoselective ring!opening of these species\

was responsible for the course of these reactions[
H alkali metal
H
– M+ (33)
X conrotation
H
(145) X = OMe (147)
(146) X = Cl
H alkali metal
X
– M+ (34)
H disrotation
H
(148) X = OMe (67)
(149) X = Cl
Substrate Reagent(s) Product Carbanion Yield(s) (%)

(145) Li or Na or K (147) >97%
(146) Li (147) 68%
(146) Na (147) 75%
(146) K (147) 82%
(146) Li-naphthelenide (147) 68%
(146) Na-naphthelenide (147) 67%
(148) Li or Na or K (67) >97%
(149) Li or Na or K (67) >97%
0[08[0[2[6 Formation of carbanions by scission of C0N bonds

The mechanism of the Wol}ÐKishner reduction of aldehydes and ketones involves transient
carbanion formation as a result of the cleavage of a C0N bond leading to the evolution of a
molecule of nitrogen[ This and related reactions have been reviewed ð37OR"3#267\ 57AG"E#019\
B!61MI 008!93\ 80COS"7#216\ B!81MI 008!00Ł[ The Wol}ÐKishner reduction of the a\b!unsaturated ketone
"049# "Scheme 43# results in a mixture of products "041# and "042#\ which demonstrates the role of
the intermediate allylic carbanion "040#\ but also highlights one of the limitations of the procedure
ð53JA4492Ł[
N2H4•H2O, KOH –N2
1,2-DME, reflux
N N
O NH2 N–
–
(150)
–
ROH
+
(152) 30 : 70 (153) (151)
Scheme 54
0[08[0[3 Carbanions by Addition to C1C Bonds
0[08[0[3[0 Nucleophilic addition to C1C bonds resulting in carbanion formation

"i# Carbanion formation durin` nucleophilic addition to C1C bonds
Nucleophilic addition to C1C bonds has been reviewed ðB!53MI 008!90Ł[ In the _rst step of the
addition the nucleophile Nu− attacks\ with its pair of electrons\ one carbon atom of the double
bond\ creating a carbanion "Scheme 44#[ The second step is combination of this carbanion with an
electrophile E¦[
Z Z step 2
Z
step 1
Nu– Nu – Nu E
+E+
Scheme 55
"ii# Carbanion formation durin` the Michael!type nucleophilic addition to C1C bonds
In the special case of addition "Scheme 44# of NuE to a substrate of the form 0C1C0Z\ where
Z is an electron!withdrawing group\ e[g[\ CHO\ COR "including quinones#\ CO1R\ CONH1\ CN\
NO1\ SOR\ SO1R\ etc[\ addition nearly always follows a mechanism involving a tetrahedral inter!
mediate ð78T3906Ł\ with Nu− attacking the sp1!hybridised carbon atom furthest from the carbonyl
group "Scheme 45#[ For reviews of the reactions of C1C0C1O compounds see ðB!78MI 008!93\
B!78MI 008!94Ł and for quinones see ðB!63MI 008!91\ B!77MI 008!92\ 80RCR61Ł[
O–
Nu
O OH O
Nu– Nu Nu
O
Nu
–
(154)
Scheme 56
Protonation of the enolate ion "043# occurs chie~y at the oxygen atom to give the enol which
tautomerises to the keto form[ When the nucleophile Nu− takes the form Z0CH−0Z?\ or
R0R1C−0Z\ the addition is called the Michael reaction ð48OR"09#068\ B!61MI 008!95\ 73RCR633\
Carbanions 778
80COS"3#0\ B!81MI 008!01Ł\
the importance of which in synthetic organic chemistry cannot be over
emphasised^ a simple example is shown in Scheme 46[
EtO2C
CN
EtO2C
–
EtO2C EtO2C CN EtO2C
NaOEt, EtOH H2O
–
CN
EtO2C 25–30 °C EtO2C EtO2C
(155) EtO2C 57–63% overall yield
CN
EtO2C –
(156)
Scheme 57
The rate!limiting step in the reaction "i[e[\ "044# into "045##\ is reversible giving rise to the possibility
of retrograde Michael reactions\ wherein the key step is formation of a carbanion by C0C bond
scission ð51JCS285\ 51JCS0630\ 54JOC0180\ 56JOC1667\ 57TL3298\ 69JCS"B#358Ł[
0[08[0[3[1 Carbanion formation during single electron transfer to C1C bonds
"i# Dissolvin` metal reduction of a\b!unsaturated ketones

Upon treatment with lithium in liquid ammonia\ an a\b!unsaturated ketone is reduced to the
enolate anion which may\ in turn\ react with an alkyl halide\ frequently giving regiospeci_c alkyl!
ation ð60JA0916\ 63HCA0206\ 67JA181Ł[ Exploitation of this synthetic strategy has been reviewed
ðB!61MI 008!94\ 65OR"12#0\ B!81MI 008!02Ł and an example is given by Scheme 47 ð54JA164Ł[
Li, NH3 (l), Et2O BunI, NH3 (l)
43% overall yield O

O Li+ –O H
H
Bun
Scheme 58
"ii# Dissolvin` metal reduction of aromatic systems

Alkali metals are used to partially reduce aromatic systems ð49QR58\ 47QR06\ 69S050\ 61S280\ 78T0468Ł[
Illustrative of this is the reduction of benzene to 0\3!cyclohexadiene with lithium "or sodium or
potassium# and ethanol in liquid ammonia "Scheme 48# ð48JA2541\ 48JA2547\ 53JA0985\ 89SC1054Ł[ Such
reactions are referred to as Birch reductions[ One important function of the alcohol in this type of
reaction is to provide a proton source that is more acidic than ammonia[
–
M, EtOH EtOH M EtOH
NH3 (l), Et2O
• • –
M = Li, Na or K
Scheme 59
A number of polycyclic aromatic systems\ which have less negative reduction potentials than
benzene\ are reduced with an alkali metal in liquid ammonia in the absence of an alcohol\ or even
by less!reactive metals such as calcium or magnesium ð51OS"31#37\ 53JOC0150\ 55JCS"C#043Ł[ When
substituted aromatic compounds are subjected to the Birch reduction\ electron!donating groups
such as alkyl or alkoxyl decrease the rate of the reaction and are generally found in the nonreduced
positions of the product[ For example\ anisole gives 0!methoxy!0\3!cyclohexadiene[ Conversely\
electron!withdrawing groups such as CO1H or CO1NH1 increase the rate of reaction and are found
in the reduced positions of the product[ Such regioselectivities have been rationalised by molecular
orbital theory ð79JA2269\ 79JA3963\ 79JA5329\ 70JA173\ 89JA0179Ł[ Methods do exist\ however\ to reverse
these regioselectivities ð75TL0358\ 76TL1370Ł[ The mechanism of Birch reductions involves solvated
electrons ð76TCC"027#038Ł which are transferred from the metal atom via the solvent to the aromatic
ring ð48T037Ł[ The generation of ions and diions from aromatic compounds has been reviewed
ð63CRV132Ł[ Internal alkenes are not normally reduced by metals in ammonia^ however\ certain
nonconjugated alkenes with low!lying antibonding orbitals represent exceptions ð56JA2254Ł[
"iii# Dissolvin` metal reduction of annulenes to ìve aromatic dianions

The cyclooctatetraenyl dianion "048# can be prepared by treatment of solutions of cyclo!
octatetraene "046# in ether\ THF or liquid ammonia with alkali metals[ The reaction was originally
reported by Reppe et al[ ð37LA"459#0Ł[ Their investigations showed that a dialkali metal salt was
formed[ The reduction of cyclooctatetraene "046# to form the radical anion "047# and then the
dianion "048# was _rst achieved by Katz "Scheme 59# ð59JA2673\ 59JA2674\ 68COC"1#287Ł[ Subsequent
work has con_rmed that the radical anion and the dianion are planar\ delocalised systems
ð63AX"B#722\ 63JA0237\ 70JOC2814\ 73CC0543\ 75CC836\ 78JOM"260#168Ł[ The chemistry of dianions and
polyanions has been reviewed by Bates ðB!79MI 008!93Ł[
+e– +e–
–
• 2–
–e– –e–
(157) (158) (159)
Scheme 60
"iv# Reversible electron transfer with C59

One of the most remarkable properties associated with buckminsterfullerene C59\ and a property
that has profoundly in~uenced scienti_c activity\ is its tremendous electron a.nity ð82CI"L#115Ł[
Electrochemically\ C59 is seen to accept six electrons ð81CC671\ 81JA2867Ł[ Electron addition to C59 is
reversible[ Multiple and reversible electron addition is possible because the resulting C59 anions
"such as C− 1− 2−
59\ C59 or C59 # exhibit unique stability relative to other multiply charged organic ions[
Such labile behaviour suggests that C59 should engage in reversible electron transfer with many
electron donors including metals and:or metal complexes as well as organic reducing agents[
0[08[1 TRICOORDINATE CARBOCATIONS
0[08[1[0 General Aspects of Carbocation Formation
0[08[1[0[0 Nomenclature
For many years species of the type "059# were called {carbonium ions|\ although as long ago as
0891 Gomberg had suggested that this nomenclature was inappropriate because {!onium| usually
referred to a covalency higher than that of the neutral atom ð91CB1286Ł[ Nevertheless the term
{carbonium ion| became well established ð75JCE829Ł until 0860\ when Olah found evidence for
another type of intermediate\ in which there is a positive charge at a carbon atom\ but in which the
formal covalency of the carbon atom is _ve rather than three[ The simplest example is the methanon!
ium ion CH¦ 4 ð60CT455\ 61JA797Ł[ Olah proposed that the title {carbonium ion| be reserved for such
pentacoordinate positive carbon species\ and that species of the type "059# be called {carbenium
Carbocations 780
ions|[ He also proposed the term {carbocation| to encompass both types\ and these de_nitions have
been accepted by IUPAC[ While some authors still refer to "059# as a carbonium ion and others call
it a carbenium ion\ the general practice is to refer to it simply as a carbocation and this latter method
will be employed in this chapter[
R
R +
R
(160)
The species shown by structure "050# contains a two!electron\ three!centre bond and is known as
a {non!classical carbonium ion|\ although strictly speaking it is simply a {carbonium ion|[ Harwood
has clari_ed the situation by stating that] a carbenium ion only contains two!electron\ two!centre
bonds\ whereas a carbonium ion contains a two!electron\ three!centre bond and the cationic centre
has a coordination number of _ve ðB!81MI 008!03Ł[
R
R +
R
(161)

Between 0857 and 0865\ a _ve!volume treatise edited by Olah and von R[ Schleyer was published
ðB!57MI 008!91\ B!69MI 008!91\ B!61MI 008!96\ B!62MI 008!93\ B!65MI 008!90Ł[ Monographs have been written
by Bethell and Gold ðB!56MI 008!93Ł and Vogel ðB!74MI 008!92Ł and reviews have been published
ð55APO"3#294\ 62AG"E#062\ 62TS142\ B!62MI 008!94\ 63MI 008!93\ B!63MI 008!92\ 67MI 008!93\ 68COC"1#300\
68TCC"79#08\ 70MI 008!91\ 70CS86\ 76MI 008!09\ 80CRV264Ł^ see also the series Advances in Carbocation
Chemistry[ For a review of carbocations in superacid solutions\ see Olah et al[ ðB!74MI 008!93Ł[ The
chemistry of carbocyclic nonbenzenoid aromatic carbocations has been reviewed by Lloyd
ðB!55MI 008!90Ł[ Over the years\ carbocations have been periodically reviewed by Cox\ the latest
being ðB!89MI 008!94Ł[ Dicarbocations have been speci_cally reviewed ð72AG"E#289\ 73T3050\
78AG"E#0210Ł[ Intramolecular cationic rearrangements have been reviewed by Lowry and Richardson
ðB!76MI 008!95Ł[
0[08[1[0[2 General features of carbocation formation and structural stability
"i# Introduction to carbocation formation by bond scission

By 0824 it had become evident through the investigations of Hughes et al[ ð22JCS415\ 22JCS0460\
24JCS144Ł that nucleophilic!substitution reactions could proceed by what appeared to be two distinct
paths[ In the _rst of these\ the new bond is being formed simultaneously as the old bond is breaking\
the SN1 mechanism\ and this is the path by which the basic hydrolysis of methyl iodide proceeds[
In the second path\ the SN0 route\ the bond to the leaving group is broken before the new bond with
the nucleophile is created\ and the reaction proceeds ostensibly through the intermediacy of a free
carbocation[ Reactions proceeding by this mechanism may be represented in two steps\ for example\
the hydrolysis of t!butyl chloride "Scheme 50#[
–Cl– H 2O
But Cl +But But OH + H+
Scheme 61
This path has been variously called the {dissociation|\ {heterolysis| or {carbocation| mechanism\
or {solvolytic displacement|[ In the {dissociation mechanism|\ the initial step is generally the slow one[
"Although some evidence has been obtained that in a few SN reactions proceeding via preliminary
dissociation\ the initial step is more rapid than the subsequent attack on the carbocation ð43JCS1807\
44JA0011Ł[ "These cases\ it must be stressed\ are exceptions[#
In general\ nucleophilic substitutions on primary carbon atoms tend to proceed via the SN1
mechanism\ while those on tertiary carbon atoms tend to proceed via the SN0 mechanism\ and those
on secondary carbon atoms often constitute borderline cases[ For the SN0 mechanism\ the activated
complex in the slow "bond!breaking# step assumes some of the character of an ion pair\ implying
its formation necessitates considerable separation of charge[ Alkyl groups are more e}ective electron
releasers than a hydrogen atom[ It would seem reasonable to expect that the leaving group ]L "with
its pair of bonding electrons# would depart more easily from R2C ] L than from RCH1 ] L\ "where
Ralkyl# and this proves to be the case[ Two additional e}ects may account\ in part\ for the ease
of unimolecular substitution on tertiary carbon atoms[ First\ since the tertiary carbon atom generally
su}ers from steric crowding\ it may be expected that relief from such strain will be more pronounced
on expulsion of the leaving group from a tertiary carbon\ than from a primary carbon[ Such crowded
halides as But1PriCCl are known to undergo unimolecular solvolysis extremely rapidly ð44JA1790Ł[
Second a carbocation "and presumably an activated complex having much of the character of a
carbocation# should be stabilised by hyperconjugation[ At present\ the weight of evidence is against
hyperconjugation in the ground states of neutral molecules\ although this is not an entirely unani!
mous verdict ð76AJC0426Ł[ However\ for carbocations and free radicals ð51T222Ł there is evidence
that hyperconjugation is important[ In hyperconjugation in the ground state of neutral molecules\
which Muller and Mulliken called {sacri_cial hyperconjugation| ð47JA2378Ł\ the canonical forms
involve not only {no!bond resonance|\ but also charge separation not extant in the main undisturbed
form[ In carbocations\ the canonical forms display no more charge separation than the main form\
and this has been called {isovalent hyperconjugation|[
Such hyperconjugation would be expected to be more important if there are three alkyl groups
on the a!carbon than if there is only one alkyl group[ Such canonical forms as in "051# "Equation
"24## imply that the b C0H bonds are loosened during the formation of the activated complex[
Since C0H bonds are {looser| "or longer# than C0D bonds\ it might be supposed that substitution
of deuterium for b!hydrogen atoms would lower the extent of hyperconjugation slightly\ thus
retarding SN0 substitution at the a!carbon atom[ Such an e}ect has indeed been observed ð42JA1814\
43JA680\ 47JA1215Ł[ Further evidence of hyperconjugation being the cause of this b secondary isotope
e}ect is provided by the observation that the equilibrium constant for the reaction depicted by
Equation "25# is such that K187 0[8629[19\ indicating that "053# is more stable than "052#
ð76JA6836Ł[
R1 R1
+
:L H+ :L (35)
R2 R2
(162)
(CD3)3C+ + ButH +But + (CD3)3CH (36)

(163) (164)
Aryl groups linked to the a!carbon atom are even more e}ective in facilitating SN0 substitution
than are alkyl groups\ for such groups stabilise the carbocation "and the carbocation!like activated
complex# by supplying p!electron density from the ring "Scheme 51#[
R1 R1 R1
+
:L :L + :L
R2 R2 R2
+
Scheme 62
The ease of both SN0 and SN1 reactions is a}ected by the polarity of the solvent[ For the SN0
reactions of alkyl halides and sulfonate esters\ activation requires separation of opposite charges
and\ in general\ such reactions are more rapid in solvents of high dielectric constant "e[g[\ water or
formic acid# than in solvents of low dielectric constant "e[g[\ acetone or dioxane#[
There is substantial theoretical and experimental evidence that the optimum structure for a
carbocation is such that the three sp1!orbitals lie in the same plane at angles of 019> ð58JA0926Ł[ Any
distortion of this optimum geometry will be strongly resisted by a carbocation\ since both the
Carbocations 782
necessary rehybridisation of the cationic carbon centre and the resultant greater steric repulsion
increase the energy of the system[
Two types of distortion are possible] deformations in which the cationic carbon centre and the
three attached atoms remain in the same plane\ and distortions leading to nonplanar structures
"Figure 1#[ This latter type of distortion is unavoidable during carbocation formation in some
bridged systems in which\ for structural reasons\ planar ions cannot form[ The variation in reactivity
of a range of ring systems is shown in structures "054#Ð"058# ð55MI 008!90Ł[
R R
+
120° 120° +
+
R R 120° > R
R R R R
120°
Optimum geometry Strain from loss Coplanar bond
of coplanarity angle strain
Figure 1 Sources of strain in carbocations[
1.0 0.5 10–3 10–6 10–13
Br But
Br Br Br Br
(165) (166) (167) (168) (169)
Both bridged bromides "057# and "058# are unreactive\ with the latter yielding the corresponding
alcohol only after treatment with aqueous silver nitrate at 049>C for 1 days[ With similar reagents\
"056# produces alcohol after reaction at room temperature for 3 hours[ It may be inferred that
0!bromoadamantane "056# can achieve a greater degree of coplanarity at the nascent cationic carbon
centre\ but it is still markedly less reactive than t!butyl bromide "054#[ Only bromide "055# proves
to be of comparable reactivity to "054# since its extra methylene group gives the molecule much
greater ~exibility than the more rigid adamantane skeleton[ For discussions of the stereochemistry
of carbocations see ð62CSR286\ 64ACR258Ł[
Carbocations prove to be intermediates in diverse types of reaction and the more stable types can
be kept in solution or in some cases isolated as solid salts[ In solution the carbocation may be free\
especially in polar solvents\ or it may be part of an ion pair\ which is more prevalent in nonpolar
solvents ðB!61MI 008!97\ B!63MI 008!94Ł[
Among simple alkyl carbocations\ the order of stability is tertiary×secondary×primary
ð60CT455\ 61JA797Ł[ Many examples of rearrangements of primary or secondary carbocations to
tertiary carbocations are known both in solution and gaseous phases[ The _eld of intramolecular
cationic rearrangements has been reviewed by Lowry and Richardson ðB!76MI 008!94Ł[ Simple alkyl
cations are not stable in conventional strong!acid solutions\ for example\ H1SO3[ However\ it
was discovered that many of them could be kept stable inde_nitely in solution with mixtures of
~uorosulfuric acid and antimony penta~uoride[ Such mixtures\ usually dissolved in SO1 or SO1ClF\
are often called {superacids|[ Although the term {superacid| was _rst used by Conant in 0816
ð16JA2936Ł\ the technology was systematically developed by Olah\ whose early experiments involved
the reaction of alkyl ~uorides with SbF4 which might more accurately be termed a {super Lewis
acid| "Equation "26## ð53JA0259\ 53PCS036\ 58JA3708Ł[
SO2 or SO2ClF
RF + SbF5 R+•SbF6– (37)
It was found later by Olah that similar carbocations could also be generated from alcohols in
superacid in sulfur dioxide solution at −59>C ð54JA1886\ 56JA2465Ł[ Indeed even alkanes can be
induced to give carbocations in superacid solution by loss of H− "Equation "27## ð56JA3628Ł[ In
accordance with the observed stability order\ H− is abstracted from alkanes by superacid most
readily from tertiary carbons and least readily from primary carbons[
FSO3H, SbF5
ButH +But + SbF5•FSO3– + H2 (38)
As of 0884\ no primary carbocation has survived long enough to be detected[ Neither methyl nor
ethyl ~uoride gave observable Me¦ or Et¦ ions when treated with SbF4[ A number of benzylic
carbocations have been obtained in solution as SbF− 5 salts ð56JA4576\ 61JA1933Ł[ Diarylmethyl and
triarylmethyl carbocations are further stabilised[ It has long been known that in SO1\ triphenyl!
chloromethane ionises to give the equilibrium shown in Equation "28#[
Ph3C Cl Ph3C+ + Cl– (39)
Both triphenylmethyl and diphenylmethyl carbocations have been isolated as solid salts
ð52AG"E#511\ 54AG"E#762Ł[ Arylmethyl carbocations are further stabilised when they have electron!
donating groups in the ortho and:or para positions ð38JCS0613\ 44JA2940Ł[
Cyclopropyl groups have an even greater stabilising e}ect on carbocations than aryl groups[
Carbocation "069# has been prepared by dissolving the corresponding alcohol in 85) sulfuric acid
ð51JA1905Ł\ while "060# and "061# have been similarly prepared in FSO2H:SO1:SbF4 ð54JA1887\
54JA2999Ł[
+ +
+
(170) (171) (172)
This special ability to stabilise carbocations\ which increases with each additional cyclopropyl
ring\ results from conjugation between the bonding orbitals of the cyclopropyl rings and the empty
p!orbital of the cationic carbon atom[ NMR studies indicate that this vacant p!orbital lies parallel
to the C20C3 bond of the cyclopropane ring\ as shown in structure "062#\ and not orthogonal to it
ð51JA1905\ 69JA0559\ 69JA2123\ 60JA2816\ 63JA6480\ 89JA7801Ł[ In solvolysis of primary cyclopropylmethyl
systems\ the rate is enhanced because of this overlap of the s!bonds of the ring with the empty
p!orbital of the cationic carbon atom ð68JOC1759Ł[ The ion that is formed initially is an unrearranged
cyclopropylmethyl cation that is symmetrically stabilised as represented in Scheme 52 ð57JA52Ł[
Evidence that "062# is orientated as shown is provided by the fact that substitution of one or more
methyl groups in the 2! and 3!positions increases the rate of solvolysis of cyclopropylcarbinyl 2\4!
dinitrobenzoates by approximately a factor of 09 for each methyl group ð55JA1210Ł[ If only one of
the s!bonds of the cyclopropyl ring was involved in stabilisation "e[g[\ the 1\2 bond#\ then methyl
substitution at the 2!position should increase the rate\ and a second methyl group at the same
position should enhance it further\ but placing the second methyl group at the 3!position should
have little e}ect^ such is not the case[ It may thus be inferred that both the C10C2 bond and the
C10C3 bond contribute electron density towards the stabilisation of positive charge on the C0
atom[
+
1
3 +
2 +
2 H ≡ +
≡
1
4
3 +
4
(173)
Scheme 63
Numerous methods have been employed for the examination of factors governing the stability of
carbocations[ {Stability|\ however\ is only a relative term\ since in chemical systems\ carbocations
are frequently associated with anions and solvent[ Intermolecular ionÐsolvent interactions can be
eliminated if studies are undertaken in the gas phase\ and scales of stabilities have been obtained by
the measurement of ionisation potentials "Table 09# ðB!52MI 008!91Ł[
An important technique for the investigation of carbocation stability and structure is measurement
of the 02C!NMR chemical shift of the cationic carbon atom ð64APO"00#012\ 68MI 008!94Ł[ 02C!NMR
chemical shifts for a range of carbocations are given in Table 00 ð57JA0773\ 58JA4790\ 66JA4915\
66JOC1555Ł[
However\ the 02C!NMR chemical shifts do not always re~ect the precise order of carbocation
stabilities as determined by other methods^ for example\ the chemical shift shows that the triphenyl!
Carbocations 784
Table 09 Ionisation potentials "kcal mol−0# of radicals derived from electron!impact studies[
Ð*ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
Radical Ionisation potential Radical Ionisation potential
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
Me 118[3 2 9[6 Me1CH 071[1 2 0[1
MeCH1 191[4 2 0[1 PhCH1 067[8 2 0[7
MeCH1CH1 199[3 2 0[1 MeCH1CHCH1 066[7 2 0[1
p!NCC5H3CH1 086[8 2 1[2 Me2C 060[7 2 0[1
HC2CCH1 089[1 2 0[7 Ph1CH 057[7 2 1[2
CH11CHCH1 077[1 2 9[6 p!MeOC5H3CH1 046[6 2 1[2
ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ
*
02
Table 00 C!NMR chemical shift values\ in ppm from 02CS1\ for the cationic carbon in some carbocations
in SO1ClF:SbF4\ SO1:FSO2H:SbF4\ or SO1:SbF4 ð60JA353Ł[
Carbocation Chemical shift Temp[ Carbocation Chemical shift Temp[
">C# ">C#
*
Et1MeC¦ −028[3 −19 Me1"cyclopropyl#C¦ −75[7 −59
Me1EtC¦ −028[1 −59 PhMeCH¦ −39a
Me2C¦ −024[3 −19 Ph2C¦ −07[0 −59
Me1CH¦ −014[9 −19 Ph1CH¦ −4[5 −59
PhMe1C¦ −50[0 −59
*
methyl carbocation has a more positive cationic carbon than the diphenylmethyl carbocation\
despite the fact that the former is known to be more stable[ The 1!cyclopropylpropyl and
1!phenylpropyl carbocations have shifts of −75[7 ppm and −50[0 ppm\ respectively\ despite the
fact that according to other experimental evidence a cyclopropyl group is more e.cient than a
phenyl group at stabilising a carbocation ð60JA353\ 62JA1399\ 63JA2437\ 64JA1891\ 64APO"00#012\ 65CJC1728\
66JA0601\ 68JOC1541\ 68MI 008!96Ł[
"ii# Introduction to carbocation formation by electrophilic addition to C1C bonds

Alkenes dissolved in aqueous acid are in rapid\ reversible equilibrium with a cation formed by
addition of a proton ð41JA4261Ł[ This cation has to be nonclassical in nature in view of the behaviour
of the isomeric pentenes "063# and "064#\ "Scheme 53# ð42JA0142\ 42JA2844Ł[ Both pentenes react with
dilute nitric acid to give the same tertiary alcohol "068#[ If the reaction is interrupted\ when half the
alkene has been converted to the alcohol\ the remaining alkene has the starting structure in each
case[ The initial product of protonation is therefore of such a structure that loss of a proton gives
only the starting alkene[ The reversibly formed carbocations are the p!complexes "065# and "066#\
which are precursors to the hydration of the alkenes in a relatively mild acidic medium and\ have
the proton embedded in the p!electron cloud[ They are therefore reasonable intermediates to expect
from reactions in which a classical carbocation "067# is subsequently formed ð41JA4832Ł[
It has been found that if the hydration of an alkene "068# is conducted in D1O but terminated in
its early stages\ the unreacted alkene has acquired no deuterium and has undergone no isomerisation
ð45JA4796\ 46JA2613Ł\ whereas both deuteration and isomerisation should be expected if the reversible
formation of a classical carbocation were involved[
Tertiary cycloalkyl cations\ such as the 0!methyl!0!cyclopentyl cation "079# show high stability in
superacid media and can be derived from a number of precursors\ e[g[\ "070# and "071# ð57JA822Ł[
Cyclohexene "072# also gives cation "079# via isomerisation of the secondary cyclohexyl cation to
the more thermodynamically stable tertiary methylcyclopentyl cation[ Under such extreme
conditions\ the cation "079# undergoes both carbon and hydrogen scrambling[ Sorensen and co!
workers have prepared tertiary cycloalkyl cations of di}erent ring sizes\ 3−n−19 and these cations
were found to undergo various expansion or contraction reactions ð67JA4023Ł[
In contrast to simple alkenes\ aryl!substituted alkenes dissolve in sulfuric acid to give com!
paratively stable carbocations\ as indicated by the spectra and the recovery of the alkene on dilution
ð41JCS1056Ł[ Because of the similarity of their spectra it is believed that the carbocations "073#Ð"075#
are best represented by the classical structures shown ð41JCS1061Ł[
The addition of a proton to an unsaturated molecule can sometimes lead to the same carbocation
H+
H+
(174) (176)
+ H2O
HO
H+ (178) (179)
H+
(175) (177)
D3O+ + D
D
(179)
(183)
HF, SbF5, SO2
HF, SbF5, SO2 + HF, SbF5, SO2
(181) (180) (182)
Scheme 64
+
Ph Ph
+ +
Ph Ph Ph
(184) (185) (186)
as the loss of an anionic group from a saturated species\ as shown by the two routes to the
0\0!diphenylethyl cation "076# "Scheme 54# ð41JCS1061Ł[
Ph +H+
Ph Ph
+ +H+
OH
Ph –H2O Ph Ph
(187)
Scheme 65
The formation of transient carbocations is thought to be an intermediate step in electrophilic

addition reactions\ for example the hydration of certain alkenes ð53JA3616\ 54JA1046\ 54JCS5607\
55JA019Ł\ though it is not the only mechanism for such reactions ð59JA3618\ 52JA1134\ 52JCS0829\
54JCS5908Ł[
Carbocation formation will clearly be favoured by the strength of the source of the protons as an
acid\ and this consideration should be foremost in deciding the choice of the reaction medium\ in
addition to the usual desiderata of power for anion stabilisation\ chemical inertness and high
dielectric constant ðB!56MI 008!94Ł[ Concentrated sulfuric acid\ and to a lesser extent\ other strong
mineral acids were therefore the _rst media employed in such reactions[ Sulfuric acid is in many
respects a very suitable solvent\ but presents problems connected with its high reactivity both as a
sulfonating agent and as an oxidant[ For this reason MSA ð49JA052Ł\ chlorosulfonic acid ð53JA823Ł\
Carbocations 786
~uorosulfonic acid ð53CJC491Ł and liquid hydrogen halides\ especially hydrogen ~uoride\ have been
used[
The protonating power of a Bronsted acid can be increased by stabilising the gegenion formed
alongside the carbocation[ If the Bronsted acid is a hydrogen halide\ the proton donating power of
the medium can be increased by adding a substance with a strong speci_c a.nity for the relevant
halide ion[ Acid:halide combinations that have been used extensively as media for the generation
of stable carbocations include HCl:AlCl2\ HCl:BCl2 ð51JCS599Ł\ HF:BF2 ð49IEC1092Ł\ HF:SbF4
ð54JA0092Ł and FSO2H:SbF4 ð54JA1886Ł[ Such media are superior to sulfuric acid both in acidity
and chemical inertness[ Furthermore\ they can be used at low temperatures[ The solutions can be
diluted with sulfur dioxide to facilitate work at even lower temperatures ð54JA0092Ł[
In a case where the cationic carbon centre is in conjugation with a double bond the stability of
the system is enhanced due to resonance and because the positive charge is delocalized over two
atoms "Equation "39##[ If the substituents R are equivalent\ then each of the two terminal allylic
carbon atoms will bear a charge of exactly ¦9[4[
R R R R R R
+ + +
R R R R ≡ R R (40)
R R R
Stable allylic carbocations have been prepared by dissolving conjugated dienes in concentrated
sulfuric acid "Equation "30## ð51JA0387\ 52JA1880Ł[
H2SO4
+ (41)
0[08[1[1 Carbocations by Bond Scission
0[08[1[1[0 Aryl!substituted carbocations by bond scission

The triphenylmethyl carbocation "077# represents not only the _rst stable carbocation to be
discovered ð91CB0078\ 91CB2920Ł\ but also the _rst to be studied by x!ray di}raction ð54AX326Ł[
Carbocation "078# has proved to be propeller!shaped with threefold "D2# symmetry] the cationic
carbon atom and the three adjacent ring carbons are coplanar\ while the three benzene rings\ due
to steric crowding of the ortho hydrogens\ are twisted out of coplanarity\ reducing the degree of
resonance stabilisation of the system and resulting in a slightly {feathered| propeller geometry[ In
the perchlorate salt of "077#\ the aromatic rings of the cation are mutually twisted at an angle of 43>
to each other[ These twist angles are in the range 34Ð50> in the platinum salts ð61JA4400Ł[
NH2
B
+ +
A
H2N C NH2
(188) (189)
The tri!"p!aminophenyl#methyl carbocation "078# is propeller!shaped\ but does not exhibit three!
fold symmetry ð60AX"B#0394Ł[ The three exocyclic bonds adjoining the central cationic carbon are
coplanar indicating strong electron delocalisation from the aryl rings[ The carbocation "078# has
the rings A\ B and C twisted by 23[3>\ 22[7> and 16[2>\ respectively\ from the plane formed by the
cationic carbon and the three atoms attached to it[ Despite these large angles\ there is evidence of
appreciable p!electron delocalisation[
para!Methoxy or amino substituents have a powerful stabilising e}ect on the cation\ as illustrated
by the various ionic triphenylmethane dyes bearing these groups\ e[g[\ derivatives of malachite
green "089#[ Extensive data on the stability of substituted triphenylmethyl carbocations have been
tabulated by Freedman ðB!62MI 008!95Ł[
NMe2
+ R
Me2N
(190)
The degrees of ionisation of triphenylmethyl chloride\ p\p?!dimethoxybenzhydryl chloride and

dimesitylmethyl chloride in liquid sulfur dioxide are about the same ð10JPR0\ 26RTC424Ł[ Appar!
ently one ring of the triphenylmethyl carbocation may be dispensed with\ if the other two rings are
adequately substituted[ 0!Phenyl!1\1\1!tri~uoroethyl cations\ purportedly highly unstable\ in fact
have fairly long lifetimes ð78JA6548Ł[ They are generated by the solvolysis of YC3H3CH"CF2#X
"Ye[g[\ MeS^ XOTs\ OMs or Br# in 0 ] 0 H1O:F2CCH1OH and solvolysis rate constants are
almost identical with those for the non~uorinated analogues YC3H3CH"CH2#X^ only SN0 mech!
anisms were observed\ even with nucleophiles such as N− 2 \ 0
−
and Br−[
The tripticyl carbocation "080# is a system in which the bridged structure ensures that all three
rings will always deviate from coplanarity with the bonds leading to the cationic carbon atom to
the maximum possible extent[ Tripticyl bromide exhibits none of the tendency to ionise that is
shown by the closely analogous triphenylmethyl bromide ð49JA0994Ł[ It seems likely that the major
reason for the instability of carbocation "080# is structural inhibition of resonance stabilisation by
the aromatic rings and prevention of the cationic carbon atom adopting planar sp1!hybridisation[
(191)
The work of Walden is remarkable for his early utilisation of a nonaqueous solvent\ liquid sulfur
dioxide\ possessing an exceptional ionising power ð91CB1907Ł[ The importance of the choice of
solvent had also been noticed by Gomberg ð91CB1286Ł\ who showed that in some solvents such as
benzene and ether\ triphenylmethyl chloride is nonionised and colourless\ while in solutions of
{dissociating solvents| such as SO1\ MeCOCl and SO1Cl1\ are conductors and exhibit a yellow colour[
Both properties were correctly attributed to Ph2C¦[ Ionisation occurs also when triphenylmethyl
chloride is complexed with inorganic halides\ e[g[\ SnCl3\ ZnCl1 or AlCl2 ð91CB0078Ł[
Using the modern superacid technology\ developed by Olah\ the following stable triphenylmethyl
carbocationic salts have been prepared and are commercially available] Ph2C = SbCl5 ðB!61MI 008!98\
B!89MI 008!95Ł\ Ph2C = PF5 ðB!63MI 008!95Ł\ Ph2C = SnCl4\ Ph2C = BF3 "ðB!56MI 008!95\ B!75MI 008!91Ł and
references therein#[
The structures of such exotic species as the biscyclobutadienyliron tricarbonyl phenylmethyl
carbocation "081# ð60JA5577Ł have been determined by x!ray crystallography as have those of the
dicarbocations "082# ð56JA2394Ł and "083# ð60JCS"B#807Ł\ and all show the propeller!type structures
depicted[
The synthesis of the tri"0!azulenyl#methyl carbocation "084^ RH# has been reported by two
methods] one by the reaction of azulene with tetraethyl ortho!carbonate ðC"OEt#3Ł in the absence of
Carbocations 788
MeO OMe
+ + + +
+
Fe(CO)3
(OC)3Fe
MeO OMe
(192) (193) (194)
acid ð50LA"549#51Ł and the other by the hydride abstraction from tri"0!azulenyl#methane by the
triphenylmethyl carbocation ð76BCJ2610\ 77NKK046Ł[ Substituted tri"0!azulenyl#methyl carbocations
"084^ RMe\ OMe\ CO1Me# were obtained by Asao by treatment of the triazulenylmethanes with
1\2!dichloro!4\5!dicyano!0\3!benzoquinone "ddq# in CH1Cl1\ followed by addition of hexa!
~uorophosphoric acid to give the crystalline products ð89PAC496Ł[ The chemistry of the perchlorate
salt of the tri"1!thiophenyl#methyl carbocation "085# has been examined ð89TL1512Ł[
R
S
+
+
R S
S
R
(195) (196)
0[08[1[1[1 Alkyl carbocations by bond scission

Some carbocations are stable only as salts of complex anions\ for example\ AlCl− − 1−
3 \ BF3 \ SnCl5
−
or SbF5 [ The alkylcarbocationic salts belong to this class ðB!57MI 008!92Ł[
Remarkably stable alkylcarbocationic hexa~uoroantimonates R¦SbF− 5 have been obtained by
Olah and co!workers ð52JA0217\ 53JA0259Ł[ Such ionisations can be accompanied by extensive
rearrangements ð62ACR42Ł[ Through hydride and methide shifts\ the thermodynamically most stable
carbocations are formed[ n!Propyl and i!propyl ~uorides give the identical isopropyl cation "086#
and n!butyl\ sec!butyl\ i!butyl and t!butyl ~uorides all lead to the formation of the same tertiary
carbocation complex "087# while each of the seven isomeric pentyl ~uorides including neopentyl
~uoride\ gives the same tertiary carbocation complex "088#[
SbF6– SbF6– SbF6–

+ + +
(197) (198) (199)
The alkyl carbocation hexa~uoroantimonates are generally stable only if an excess of SbF4 is
present[ The role of this excess of Lewis acid is undoubtedly to solvate the organic salt or ion pair[
Such solvated tertiary alkyl cation hexa~uoroantimonates are soluble without decomposition in
cold SO1[ Their optical 0H! and 02C!NMR spectra and chemical behaviour have been studied by
Olah and co!workers ð52JA0217\ 53JA0259\ 57JA0773\ 58JA4790\ 66JA4915\ 66JOC1555\ 70PNA"67#0887Ł[ The
crystal structure of the t!butyl cation has been determined by x!ray crystal analysis of its Sb1F−
00 salt
at −79>C ð82JA6139Ł[ The cation was found to be planar^ the C0C¦ bonds had an average length
ý and the C0C¦0C bond angles were 019"0#>[
of 0[331"4# A
Attempts to obtain alkyl carbocation complexes by dissolving alkyl chlorides in other liquid
Lewis acid halides "e[g[\ SnCl3\ TiCl3\ SbCl4# have proved unsuccessful\ either because the Lewis
acids are too weak to cause ionisation of the C0Cl bond or the solvating e}ect of the halides is not
su.cient to stabilise any carbocations formed[ However\ the sec!butyl cation has been prepared by
slow addition of sec!butyl chloride to SbF4:SO1ClF solution at −009>C ð57JA5771Ł[ Alkyl carbo!
cations are not stable in sulfuric acid solutions as has been observed by Deno and co!workers
ð51JA1905Ł[
A wide range of phenyl\ alkyl and cyclopropylcarbinyl cations have been prepared by Olah from
alcohols by treatment with superacids FSO2H:SBF4 "0 ] 0# or FSO2H:SO1ClF solution at −67>C
ð66JOC1555Ł[
Carbocations are di.cult or impossible to form at bridgehead carbon atoms in ð1[1[0Ł systems
ðB!62MI 008!96Ł and bridgehead adamantane carbocation reactivities have been studied by
von R[ Schleyer et al[ ð53JA3083Ł[ However\ von R[ Schleyer et al[ have reported the preparation of
the adamantyl cation "199^ RH# as the hexa~uoroantimonate salt ð53JA3084Ł and subsequently
that of the 2\2?!"0\0?!biadamantyl# dication "190# and the 3\8!diamantyl dication "191# in superacid
media ð74JA1653Ł[ In 0889\ Olah prepared the tris"0!adamantyl#methyl cation "192#\ which is stable
for about 29 min at −69>C in FSO2H:SbF4 "0 ] 0#\ and is the most crowded carbocation yet
synthesised ð89JA5311Ł[ Its relatively high stability is attributed to the structural constraint of the
adamantyl cage framework producing a high barrier to decomposition[ The _rst crystal structure
of an alkyl carbocation ðthe Sb1F−00 salt of "199^ RMe#Ł was reported by Laube ð75AG"E#238Ł[ The
cationic centre was found to be almost planar[
+ +
R R + +
+
R
(200) (201) (202) (203)
A striking example of bridgehead unreactivity is furnished by compound "193#\ which resisted

hydrolysis when boiled for 10 hours in 29) KOH:EtOH or for 37 hours in H1O:AgNO2 ð28JA2073Ł[
ð1[1[1Ł!Bicyclic systems undergo SN0 reactions much faster than smaller bicyclic systems\ although
the reactions are retarded compared to open!chain analogues[ Synthetic use has been made of the
former type of reaction ð74JOC3594Ł[ The relatively larger and more ~exible structure permits
formation of cation "194#\ which is su.ciently stable to be kept in solution with SbF4:SO1ClF below
−49>C[ The brominated ð2[0[0Łsystem "195# undergoes SN0 reaction ð76CC722Ł as does the cubyl
tri~ate "196# ð89JA2114\ 89JA2117Ł[ Ab initio calculations show that the cubyl carbocation\ though
permanently constrained to be nonplanar requires less energy to form than the 0!norbornyl cation
ð89JA2116Ł[
Br
+
OSO2CF3
Cl SbF6–
(204) (205) (206) (207)
The 0!trishomobarrelyl "197# and 0!trishomobullvalyl "198# cations have been prepared in the
superacid media "SbF4:SO1ClF# ð62AG"E#288Ł[ In these two cations\ the inherent instability of the
bridgehead position is ameliorated by the stabilisation derived from conjugation with the three
cyclopropyl groups[ The dodecahedryl carbocation "109# and the 0\05!dodecahedryl dication "100#
have been prepared in superacid media "SbF4:SO1ClF# by Olah and co!workers ð77JA7488Ł[
Timberlake and co!workers have prepared the pentacyclopropylethyl carbocation "101# "Equation
"31## ð75JOC1858Ł[ 02C!NMR spectra revealed all _ve cyclopropyl rings to be equivalent down to
−099>C[ Further spectroscopic evidence showed species "101# to be a classical cation undergoing
rapid interchange[
Carbocations 890
+ +
+ +
+
dodecahedryl cation dodecahedryl dication
(208) (209) (210) (211)
+ + (42)
(212)
The C0C bonds of alkanes can be cleaved by superacids and primary\ secondary and tertiary
hydrogens of alkanes can be exchanged under such conditions ð56CC524\ 57RTC208\ 58JA2150\ 58RTC260\
62JA3859Ł and these topics have been reviewed ð60CT455\ 61MI 008!02\ 62AG"E#062Ł[ Typically neo!
pentane in FSO2H:SbF4 can cleave to give CH3 and the t!butyl cation "Equation "32##[ C0H
cleavage is a competing reaction and\ for example\ neopentane can give H1 and the t!pentyl cation
"formed by rearrangement of the initially formed neopentyl cation# by this type of pathway[
FSO3H, SbF5
Me4C Me3C+ + CH4 (43)
Alkanes can give carbocations in superacid by loss of a hydride ion "Equation "33## ð56JA3628Ł[
However\ Herlem has later asserted that the mechanism is somewhat more complex than mere
hydride abstraction alone\ invoking oxidation by both SbF4 and SO2 in the presence of HSO2F and
electrochemical oxidation of the hydrocarbon ð66PAC096Ł[
FSO3H, SbF5
ButH Me3C+ + SbF5•FSO3– + H2 (44)
0[08[1[1[2 Enyl carbocations by bond scission

Unlike alkyl carbocations\ allylic cations are stable in concentrated sulfuric acid provided that
the termini of the allylic system are completely alkylated "the contributing resonance canonical
forms should be those of tertiary carbocations# ðB!57MI 008!92Ł[ The simplest ion of this type "102#
was obtained by Deno and co!workers ð51JA0387\ 52JA1880\ 52JA1884\ 52JA1887Ł[ Enyl carbocations are
stable for a relatively long time in 85) sulfuric acid\ but they quickly disappear in more dilute
solutions\ due to hydration and polymerisation[ Allylic cations possessing a cyclopentane skeleton
are more stable than the cyclohexane analogues[
Ph Ph
+ +
Ph Ph
HSO4– ClO4–
(213) (214)
Ziegler found allylic carbocations are additionally stabilised by the introduction of phenyl groups\
e[g[\ the 0\0\2\2!tetraphenylpropenylium cation "103#\ which is formed from tetraphenylallyl alcohol
and perchloric acid ð12LA"323#23Ł[
A cyclobutenium carbocation "104# was obtained ð51JA2088Ł by treating 0\1!dichloro!0\1\2\3!
tetramethylcyclobutene!2 with SbF4:SO1 at −69>C[ The analogous tetraphenylated compound
"105# was obtained as a crystalline SnCl− 4 complex ð51JA3054\ 53JA622Ł[
Allylic\ acyclic dienyl or polyenyl cations are usually obtained by addition of a proton to the
terminal carbon in the array of C1C bonds[ However\ by treating certain diphenyl!
polyvinylcarbinols with HF and BF2\ Hafner obtained crystalline ~uoroborates of a series of
Cl Ph Cl
+ Ph + Ph
SnCl5 –
SbF6–
Ph
(215) (216)
diphenylmethine carbocations "106#\ the colour of which varies from orange "n9#\ to blue "n3#
ð50AG231Ł[
n
(217)
Carbocation "108#\ resulting from alcohol "107#\ has a half life of only a few seconds in 85)
sulfuric acid at 14>C\ quantitatively rearranging to the monoenylic cation "119# "Scheme 55#
ð53JA0760Ł[
OH H2SO4
+ +
(218) (219) (220)
Scheme 66
Stable allylic cations have been prepared by Olah and co!workers in superacid media by the
reaction of alkyl halides\ alcohols\ or alkenes "via hydride abstraction# with SbF4 in SO1 or SO1ClF
"Equations "34#Ð"36#\ Schemes 56 and 57\ Equations "37#Ð"41## ð53JA4571\ 60JA3108\ 61JA2433\ 61JA5323\
64JA0428Ł[
R SbF5, SO2, –60 °C R

(45)
F
+
R = H, Me
Cl FSO3H, SO2, –80 °C

+ (46)
Cl Cl
R1 R2 SbF5, SO2 R1
R3 OH or SbF5, SO2ClF
R2 R2 or R2 R2 (47)
+
OH R3 R1 –80 °C
R3 R3 R2 R3 R3
R1 = R2 = R3 = Me
R1 = H; R2 = R3 = Me
R1 = R2 = Me; R3 = H
R1 = Ph; R2 = Me; R3 = H
OH
SbF5, SO2, –78 °C SbF5, SO2ClF, –100 °C
+
Scheme 67
Carbocations 892
Cl(Br)
Cl(Br)
SbF5, SO2
FSO3, SbF5
OH SO2ClF
SbF5, SO2
FSO3, SbF5
SO2ClF SbF5, SO2
SbF5, SO2
OH or SbF5, SO2ClF
Br
Cl Cl
All reactions carried out at reduced temperature
Scheme 68
SbF5, SO2
R2 or SbF5, SO2ClF
R2
or FSO3H, SbF5, SO2
or FSO3H, SbF5, SO2ClF
(48)
R1 –78 °C
+
R3 R3 R1
X
R1 = R2 = R3 = H; X = OH, Br or Cl
R1 = Me; R2 = R3 = H; X = OH
R1 = R2 = Me; R3 = H; X = OH
R1 = R3 = Me; R2 = H; X = OH
R1 = R2 = R3 = Me; X = OH
FSO3H, SbF5
or SbF5, SO2ClF
or SbF5, SO2
R (49)
+
–78 °C
OH R
R = H or Me
FSO3H, SbF5, SO2ClF, –78 °C

(50)
+
OH
R1 R2 FSO3H, SO2, –78 °C

R1 R2 (51)
or FSO3H, SO2ClF, –120 °C +
OH
R1 = R2 = Me
R1 = Prc; R2 = Me
R1 = Ph; R2 = Me
R1 = R2 = Prc
R1 = Prc; R2 = Ph
R1 = R2 = Ph
(Prc = cyclopropyl)
R1 FSO3H, SO2, –78 °C R1

+ (52)
HO or FSO3H, SO2ClF, –120 °C
R2 R2
R1 = R2 = Me
R1 = Me; R2 = Prc
R1 = Me; R2 = Ph
R1 = R2 = Prc
R1 = Prc; R2 = Ph
R1 = R2 = Ph
0[08[1[1[3 Ynyl and cyano carbocations by bond scission

Diarylalkynyl cations "R0C2C0C¦Ar1# and other alkynic cations have been formed ð54JA0270\
¦
54JA3906Ł[ Stable propargyl cations "R0C2C0CR1 # have been prepared in superacid media by
Olah and co!workers ð54JA4521\ 63JA4744Ł[ The tris"ethynyl#methyl cations "111^ RMe\ But\ TMS\
Ph# can be obtained by treating the parent alcohols "110# "Scheme 58# with FSO2H:SO1ClF at
−67>C[ Signi_cant participation of resonance canonicals "111b# with allenyl character is envisaged
by Olah and co!workers\ and the electronic e}ects due to changing R were found to be only slight
ð89JOC5950Ł[ Unsubstituted\ p!Me! and p!MeO!0\0!diphenyl!1!butynyl cations "Me0C2C0C!Ar¦ 1 #
have also been studied by Olah et al[ ð75JA0464Ł[
R R R
FSO3H, SO2ClF +
R OH R + R • etc.
–78 °C
R R R
(221) (222a) (222b)
Scheme 69
Solvolytic studies ð79JA0103\ 79JA3027\ 79JA6502Ł have shown that a cyano group bonded to a
cationic carbon atom stabilises it through resonance\ despite the strong −I e}ect[ This model
is supported by 04N!NMR spectroscopy of cyanodiarylmethyl cations "N2C0CAr¦ 1 # ð79JA5539\
71JA0517Ł[
0[08[1[1[4 Nonclassical carbocations "carbonium ions# by bond scission

The subject of nonclassical carbocations "carbonium ions# has been reviewed ðB!61MI 008!09\
B!61MI 008!00\ B!76MI 008!96\ B!81MI 008!04Ł[ Overlap of the vacant orbital of a carbocation with
nonconjugated\ distant p! or s!bond orbitals within the same molecule may produce a stabilisation
of the ion which can be recognised by kinetic and stereochemical behaviour[ The extreme of
stabilisation would be to ensure the existence of a carbonium ion in protic acid solutions or in the
form of crystalline salts[ In 0848\ Leal and Pettit reported the preparation of a crystalline perchlorate
"113# "Scheme 69# from the tertiary benzyl chloride "112# ð48JA2059Ł[ The stability of the salt "113#
was attributed to the overlap of the empty pz!orbital of cationic carbon atom C1 with the
p!molecular orbital of the double bond[
+
H H Ph Ph
ClO4–
Cl 2
AgClO4 2
+ Ph ≡ + ≡ ClO4–
Ph
H H ClO4–
(223) (224)
Scheme 70
Carbocations 894
1!p!Anisyl!camphenilol and its epimer iso!1!p!anisyl!camphenilol yield in sulfuric\ hydrochloric
or formic acid solutions a stable nonclassical carbocation\ characterised by a strong absorption in
the visible and near!UV spectra and by its conductivity "in formic acid solution#[ On solvolysis\
rearranged reaction products are formed^ therefore carbocation "114# may be considered to be an
example of the isolation of a carbonium ion acting as an intermediate in a WagnerÐMeerwein
rearrangement ð48LA"512#106Ł[
X–
OMe
(225)
X = HSO4–, Cl– or HCO2–
A prodigious quantity of work has been published on the solvolysis of the 1!norbornyl system in
an e}ort to determine whether the 0\5!bond participates and if the carbonium ion "115# "Scheme
60# is a true intermediate ð41JA0036\ 41JA0043\ 54JA265\ 55PAC14\ 72ACR315\ 72ACR321\ 72ACR337\
77JOC550Ł[ The controversy was for many years dominated by the con~icting views of Winstein\
who proposed the nonclassical ion\ and Brown\ who argued in favour of a classical carbocation
ð74MI 008!95Ł[
HOAc –H+ ≡
:
AcO AcO
1 +
OBs
6 –H+
:
O HOAc
OAc
Bs = brosyl, S Br (226)
O
7 5
4
H 4
5
1 3
≡ 7 6
H + H 3 +
1 +
6 2 R
2
H
(227) (226) (228)
7
+
3
+
(229) (230)
Scheme 71
A majority of scientists now acknowledge the validity of the carbonium ion "115# ð68JA411\
79JCS"P1#0336\ 71TL2008\ 72JA849\ 72JA6012\ 73CB1409\ 73JA709\ 73TL2392\ 74ACR143\ 74JA2636\ 76JA6152\
77JOC550Ł\ but this view is by no means unanimous[ For evidence since the late 0869s against
a nonclassical carbocation "115# see ð66JA266\ 67JA1490\ 67JCR"S#51\ 67JOC2556\ 68JOC022\ 68JOC2425\
68TCC"79#0\ 79JCR"S#041\ 79JOC1002\ 72CJC1392\ 74JOC715\ 74JOC0054\ 75JOC2625Ł[ The 1!norbornyl cation
"115# has also been extensively studied at low temperatures and these studies tend to support the
nonclassical model[ Olah and co!workers have prepared the 1!norbornyl cation in stable solutions
at temperatures below −049>C in SbF4:SO1 and FSO2H:SbF4:SO1\ when the structure is static and
hydride shifts are absent[ Raman spectra\ 02C!NMR and x!ray analysis indicated the ion was
nonclassical ð69JA3516\ 61JA797\ 62JA7587\ 65ACR30\ 79JA572\ 79JA5756\ 71JA6094\ 72ACR339\ 72JA2460\
77JA3001Ł[ There are\ however\ those who still challenge the nonclassical view ð63JA6527\ 64APO"00#066\
71JOC1978\ 78MI 008!98Ł\ which Olah continues to defend ð72JOC1035Ł[ The nonclassical model is
supported by the fact that 02C!NMR spectra of the 1!norbornyl cation in the solid state at 66K and
even 4K gave no evidence of {freezing out| a single classical ion ð71BSB311\ 71JA896\ 71JA6279\ 89JA7880Ł[
Olah represents the nonclassical structure as nortricyclane "116# protonated at the apex[ Olah
concluded that all the positive charge resides on C0 and C1 with a negligible amount on C5 in
carbonium ion "115#[
Ab initio calculations show that the nonclassical model "115# corresponds to an energy minimum
ð78JA0416Ł[ At low temperatures the spectra of "117^ RMe or Et# show reduced charge delocal!
isation ð58JA2847Ł\ and "117^ RPh# is e}ectively classical ð63JA084Ł\ as are "117^ ROMe#
ð58JA5750Ł and "117^ RCl# ð58JOC1203Ł[ 02C!NMR studies show that electron!withdrawing sub!
stituents on a phenyl ring at C1 render the cation less classical\ whereas electron!donating groups
confer greater classical character ð66JA4572\ 67JA2736\ 71JOC2892Ł[
The _rst crystal structure of a norbornyl cation was reported by Laube for the Sb1F− 00 salt of the
anti!0\1\3\6!tetramethyl!1!norbornyl cation "118#\ which was found to have no symmetry
ð76AG"E#459\ 80CRV264Ł[ Attempting to assess the nonclassical character of 6!norbornenyl cations\
Laube isolated the SbF− 5 salt of the 1\2!dimethyl!6!phenyl!1!norbornen!6!yl cation "129# ð78JA8113\
−
80CRV264Ł[ The crystal structure of "129# showed the carbon skeleton surrounded by two SbF5
anions\ with no overall symmetry[ It was felt the unexpectedly strong bending of the C6 bridge
toward the C1 to C2 bridge was indicative of the formation of a three!centre\ two!electron bond
between C1\ C2 and C6[
0[08[1[1[5 Formation by bond scission of carbocations stabilised in accordance with the Huckel
"3n¦1# rule
Aromatic and antiaromatic monocyclic ions have been reviewed by Garratt ð68COC"1#289Ł[
"i# Cyclic carbocations with "3n¦1# p!electrons\ where n0

In 0826 Huckel ð26MI 008!90\ 26MI 008!91Ł {predicted| a stable cycloheptatrienyl carbocation\
unaware that such a species had already been prepared by Merling without its structure being fully
understood ð0780CB2097Ł[ Doering and Knox subsequently proved ð43JA2192Ł that the crystals
obtained by Merling from cycloheptatriene "tropylidene# "63# "by addition of bromine and elim!
ination of hydrobromic acid# were cycloheptatrienium bromide "tropylium bromide# "120^ XBr#
"Equation "42##[ Dauben et al[ later obtained tropylium salts by a hydride transfer from cyclo!
heptatriene "63# to the triphenylcarbonium ion in acetonitrile or in liquid SO1 solution at −19>C
ð46JA3446\ 59JOC0331Ł[
+ Ph3C+•X– + X– + Ph3CH (53)

quantitative
(74) (231)
This method is satisfactory for a wide range of substituent groups\ gegenions "X−# and solvents
and generally gives nearly quantitative yields of high!purity salts\ from which the by!product tri!
phenylmethane is easily separated[ Tropenylium cation chemistry has been reviewed ðB!55MI 008!92\
56RCR624\ 62MI 008!19\ 62CRV182\ B!62MI 008!97Ł[ The benzotropylium ion "121# ð44CI"L#304Ł\ sym!
and asym!dibenzotropylium ions "122# ð48JCS2028Ł and "123# ð49LA"457#52Ł\ respectively\ and the
tribenzotropylium ion "124# ð46JOC0132\ 47HCA303Ł have been synthesised[ The relatively high stab!
Carbocations 896
ility decreases as indicated in Scheme 61\ apparently because the 6!membered ring is distorted from
planarity by steric crowding of phenyl protons\ which increases through the series[
+ + +
> + > >
(232) (233) (234) (235)
Scheme 72
The heptaphenyltropylium cation "125# was prepared by Battiste as the bromide ð50CI"L#449\
50JA3090Ł[ The stable 0\2\4!tricyclopropyltropylium cation "126# has been reported ð71BCJ2146Ł[ One
of the most stable carbocations ever produced\ the 0\1 ] 2\3 ] 4\5!tris"bicycloð1[1[1Łocteno#tropylium
ion "127#\ has been described by Komatsu et al[ ð77JA522Ł[ Its stability is attributed to inductive
e}ects and enhanced hyperconjugation of the aromatic system with twelve of the C0C s!bonds of
the cyclohexyl side groups[ These bonds lie almost orthogonal to the plane of the 6!membered ring
and are thus almost parallel to the p!orbitals of the aromatic system[
Ph
Ph Ph
+
Ph Ph +
+
Ph Ph
(236) (237) (238)
"ii# Cyclic carbocations with "3n¦1# p!electrons\ where n9

For reviews of two!electron aromatic systems see ð54AG"E#09\ 55MI 008!98\ B!55MI 008!93\ 56RCR446\
62TCC36\ 63CRV078\ B!76MI 008!97Ł[The Huckel "3n¦1# rule predicts that in general cyclopropenyl
cations "128# should possess aromatic stability\ and this prediction is validated by the fact that a
large number of such cations have been reported[ Even the unsubstituted archetype "139# has been
prepared "Equation "43## ð56JA4937a\ 56JA4937b\ 69JA873Ł[
R1 R2
+ +
+ + ≡ (54)
+
R3 (240)
(239)
The majority of preparations of cyclopropenyl salts have involved carbene addition to an acetyl!
enic bond[ The _rst example of such a salt "130# was prepared by Breslow and co!workers using a
carbene generated by decomposition of a diazo compound[ This synthesis and other examples are
shown in Scheme 62 ð46JA4207\ 47JA4880Ł\ Scheme 63 ð50JA1256Ł\ Scheme 64 ð50JA1264Ł\ Equation
"44# ð59JA1533\ 59JA1540\ 51JA2057Ł\ Scheme 65 ð53JA0348Ł\ Scheme 66 ð51JA2057Ł and Equation "45#
ð51JA2057Ł[
Ph CN Ph Ph
Ph Ph
+
N2 BF3•Et2O, trace H2O X– is mostly BF4–
Ph Ph X–
and some BF3OH–
Ph CN Ph
(241)
Scheme 73
Cl Ph Ph
KOBut Ph Cl Ph Ph ButO–
Ph
:
Cl Ph Cl
Ph Ph Ph Ph
HBr +
Br–
Ph OBut
Ph
Scheme 74
Ph
Ph Cl Ph Ph H2O
ButO–
:
Ph OBut
Ph Ph Ph Ph
HBr
+ Br–
Ph O Ph
Scheme 75
R R
Ac2O, HClO4 R R
+ ClO4– (55)
CO2H
Cl Cl Cl
Cl Cl Cl Cl Cl
:CCl2 KOH SbCl5 +
Cl SbCl6–
Cl Cl Cl
Cl Cl Cl
Scheme 76
Prn Prn Prn Prn

Prn Prn
PrnLi Ph3C+•ClO4– +
+ X– ClO4–
Prn Prn
Scheme 77
Ph Ph Ph Ph
i, PrnMgBr +
2 ClO4– (56)
ii, Ph3C+•ClO4–
Ph O Ph Prn
Cyclopropenium salts "128# are soluble and stable in acid solution\ but neutral aqueous solutions
become turbid owing to the equilibration with a covalent carbinol "131#[
R1 R2
R3 OH
(242)
It has been suggested ð51JA2057Ł that the pH value at which there is 49) ionisation of the carbinol
"131# to the cyclopropenium ion "128#\ described as pKR¦\ can be taken as a criterion of the stability
Carbocations 898
of the cation[ Some values have been determined experimentally by potentiometric titration or
spectrophotometrically "Table 01#[
Table 01 pKR¦ values of some cyclopropenyl cations[
Compound Medium Method pKR+
Prn Prn
+
ClO4– 50% MeCN/H2O potentiometric titration 7.2
Prn
p-MeOC6H4 p-MeOC6H4
+
Br– 50% MeCN/H2O potentiometric titration 6.5
p-MeOC6H4
p-MeOC6H4 p-MeOC6H4
+ 50% MeCN/H2O potentiometric titration 5.2
Br–
Ph Ph
+
Br– 50% MeCN/H2O potentiometric titration 3.1
Ph
Prn Prn
+ 50% MeCN/H2O potentiometric titration 2.7
ClO4–
Ph Ph
+ H2O spectrophotometric titration 0.32
Br–
A number of factors other than p!electron stabilisation a}ect the position of equilibrium so that
the absolute values of pKR¦ are much less easy to interpret than their relative values[ The pKR¦
values in Table 01 suggest that n!propyl groups stabilise the cation more e}ectively than do phenyl
groups[ An alternative explanation is that the covalent carbinol is more e}ectively stabilised by
phenyl than by propyl groups[ On comparing the diphenyl and diphenylpropyl compounds\ the
pKR¦ value is greater for the latter[ This suggests that the n!propyl group does indeed have a
stabilising e}ect on the cyclopropenium cation^ it seems likely that this is an inductive rather than
hyperconjugative e}ect[
The syn!triphenylcyclopropenium perchlorate "132# was _rst synthesised by Breslow and Yuan
ð46JA4207\ 47JA4880Ł[ Due to the steric compression of the ortho!hydrogens\ the phenyl rings cannot
lie coplanar with the 2!ring and the molecule adopts a propeller!like arrangement with the benzene
rings twisted at a shallow average angle of 02[5> ð52JA2291\ 55JA087Ł[ The tripropylcyclopropenyl
ð51JA2057Ł and the tricyclopropylcyclopropenyl "133# ð79TL836\ 75JA023Ł cations rank amongst the
most stable carbocations known and are even stable in aqueous solution[ The tri!t!butylcyclo!
propenyl cation is also very stable ð57JA3384Ł\ as is the tris!0!"4!isopropyl!2\7!dimethyl!
azulenyl#cyclopropenylium cation "Agranat|s cation# ð65JOC1268\ 89PAC496Ł[
+
+
ClO4–
(243) (244)
The dications "134^ RMe or Ph# have been prepared ð53JA623\ 58JA2556\ 69JA0329\ 65JA5189Ł and
their aromaticity discussed ð63JOC267\ 67JA3290Ł[ The IGLO "individual gauge for localised molecular
orbitals# method has been used by von R[ Schleyer and co!workers to study the cyclobutadiene
cation ð78JA0036Ł[ These and earlier ab initio calculations ð75JA450Ł and x!ray studies ð73AG"E#260Ł
of derivatives suggest that the puckered ring "135# is more stable than the planar con_guration
implied by structure "134#[
R R 2+ R R 2+
R R R R
(245) (246)
"iii# Cyclic carbocations with "3n¦1# p!electrons\ where n1

0\5!Methanoð09Łannulene "136# reacts with diazomethane in the presence of cuprous chloride to
give bicycloð4[3[0Łdodecapentene "137#\ from which a hydride ion may be abstracted producing a
bridged cation "138# "Scheme 67# having a delocalised system of 09p!electrons ð54AG"E#243\
55AG"E#593\ 57HCA114\ 69TL0830Ł[ The observed 0H!NMR ring current ð54AG"E#243Ł and x!ray analysis
ð65JA0888\ 68AX"B#0735Ł favour the delocalised 09p!electron system "138# rather than a benzo!
homotropylium structure "149#[ The distance between C0 and C5 is long "1[2 A
ý # and the rather ~at
nature of the peripheral carbon system combine to suggest that transannular interactions in this
carbocation are not important ð73ACR236Ł[
1
CH2N2 Ph3C+•BF4–
+ BF4– +
CuCl MeCN
6
(247) (248) (249) (250)
Scheme 78
For discussions relating to factors a}ecting paramagnetic ring currents in the analogous bicyclo!
ð4[3[0Łdodecapentaenyl anion see ð62JA2273Ł[
0[08[1[1[6 Phenalene cations by bond scission

The stability of the phenalenium cation "75# was mentioned in Section 0[08[0[1[09[ The cation
was _rst prepared by Pettit as its perchlorate salt ð45CI"L#0295\ 59JA0861Ł[ A general synthesis of
phenalenium salts features hydride abstraction from phenalenes by high potential quinones in the
presence of perchloric acid ð52JCS2184Ł or by triphenylmethyl perchlorate ð48JCS1662Ł[ Several alkyl
phenalenium perchlorates have been prepared by this method "e[g[\ "140## as well as benzoðaŁphen!
alenium perchlorate "141# ð54QR163Ł[
ClO4–
ClO4–
+ +
(251) (252)
Although not conforming to the "3n¦1# rule the perinaphthenylium cation is remarkably stable[
According to molecular orbital theory ðB!50MI 008!91Ł the positive charge is distributed between
positions 0\2\3\5\6 and 8 "but not on the central position 02#[ These six positions are equivalent and
vulnerable to nucleophilic attack[ The solid yellow perchlorate is stable in dry nitrogen\ but in the
presence of water it yields perinaphthenone and perinaphthylene denoting the intermediate for!
mation of a secondary alcohol which subsequently disproportionates ð45CI"L#0295\ 59JA0861Ł[ Certain
Carbocations 800
hydrocarbons\ e[g[\ pyrene and perilene\ whose conjugate acids contain the perinaphthenylium
cation\ are highly reactive towards electrophiles at the positions predicted by molecular orbital
theory ðB!50MI 008!90Ł[
0[08[1[2 Carbocations by Addition to C1C Bonds
0[08[1[2[0 Stable carbocations by protonation of alkenes

Cationic polymerisation generally occurs when treating reactive alkenes with strong acids
ðB!52MI 008!92Ł[ However\ Olah and Halpern discovered conditions which allowed the formation of
stable monomeric carbocations as the only or predominant product in high yields by the protonation
of alkenes with superacids "Scheme 68\ Equation "46#\ Scheme 79\ Equations "47# and "48##
ð60JOC1243Ł[ However\ it was emphasised that no single general procedure could be applied to any
alkene\ but speci_c conditions had to be employed in each case[
HSO3F, SO2
Ph Ph KOH, H2O, –80 °C
Ph
or HSO3F, SO2ClF +
HO
Ph Ph –80 °C Ph Ph 80% overall yield Ph Ph
Scheme 79
HSO3F, SO2
Ph Ph
or HSO3F, SO2ClF +
(57)
Ph –80 °C Ph
HF, SbF5, SO2ClF, –120 °C +

hydride shift
+
Scheme 80
HF, SbF5, SO2ClF, –80 °C +

(58)
Ph Ph
SO2ClF + + +
+ HF + SbF5 + + (59)
–80 °C
0[08[1[2[1 Stable carbocations by protonation of dienes

The formation of the allyl cation by protonation of dienes has been reviewed by Deno
ðB!69MI 008!92Ł and his work is referred to in Section 0[08[1[1[2\ ð51JA0387\ 52JA1880Ł[ Deno empha!
sised the importance of the measurements of freezing!point depression in sulfuric acid leading the
initial con_rmation of the existence of conjugated alkenyl cations ðB!69MI 008!92Ł[ The demonstration
that 0\2\4\4!tetramethyl!cyclohexadiene "142# produces a twofold depression in freezing point in
sulfuric acid combined with quantitative regeneration of the starting diene gave the strongest
evidence for the validity of Equation "59# and the formation of carbocation "143#[
H2SO4
HSO4– (60)
+
(253) (254)
An idea of the thermodynamic stability of various allylic cations derived from protonated dienes
may be derived from Table 02[ It may be noted that stability is conferred on the allylic cation by
the cyclopropyl group\ a phenomenon discussed by Deno et al[ ð54JA3422Ł[
0[08[1[2[2 Dienylic and polyenylic cations by protonation of trienes and polyenes

This topic has been reviewed by Sorensen ðB!69MI 008!93Ł[ The interaction of polyenes with strong
acids has long been a recognised colour test\ dating back to early days of the dye industry\ when it
was observed that the colour of many compounds could be enhanced or shifted to longer wavelengths
by the addition of acid[ The great majority of compounds\ in which colour enhancement occurred\
contained an {auxochromic| group\ but some "e[g[\ the purely hydrocarbon polyenes# probably
derived their enhanced colours from carbocation formation ð27CB331Ł[ Hexaene "144# has been
protonated under strongly acidic conditions and the NMR spectrum indicates the formation of the
carbocation "145#\ which gives a blue colour in dilute solution "Equation "50## ð54JA4964Ł[ Treatment
of "146# with acid gave the magenta tetraenylic cation "147# ð50JA1281Ł\ which is rendered particularly
stable by the heavily alkylated terminal cyclopentenyl rings[ Treatment of the triene "148# with acid
also gave the dimeric cation "147# "Scheme 70# ð50JA1281Ł[
c. H2SO4
+ (61)
(255) (256)
c. H2SO4 + c. H2SO4
2
(257) (258) (259)
Scheme 81
The dienylic cations "159# ð53JA0760Ł and "150# "Scheme 71 ð53JA0760Ł\ Equation "51# ð54CJC1633\
54JA1042Ł# are stable in 85) H1SO3^ compound "150# results from cyclisation and:or rearrangement
of either "151# or "152#[ The _rst direct observation of a dienylic cation "154# of the type which is in
equilibrium with an aliphatic triene "153# was made by von Doering and Saunders et al[ who
discovered the heptamethylcyclohexadienyl cation "154# as a product of the exhaustive methylation
of benzene ð47T067Ł[ Cation "154# is an example of an {arenonium ion|\ the formation of which type
of species is reviewed in Section 0[08[1[2[3 "Equation "52## ð47T067Ł[
i, LiAlH4
O ii, –H2O 96% H2SO4
+
72%
(260)
Scheme 82
96% H2SO4
or (62)
+
(262) (263) (261)

Carbocations 802
Table 02 pK values for the protonation of some dienes[
Concentration of H2SO4 (%)

Alkenyl cationa required for half-protonation pKb Ref.
1.2 0.6 65JA4533

+
+ 12 –0.46 65JA4533
33 –1.9 63JA2998
+
+ 35 –2.1 63JA2998
+ 42 –2.6 63JA2998
+ 42 –2.6 63JA2998
+
Ph 45 –2.9 65TH
+
But 47 –3.1 65TH
50 –3.4 63JA2998
+
+ 50 –3.4 65JA4533
Ph
52 –3.6 65JA4533
+
Ph
+ 54.5 –3.8 65JA4533

Ph Ph
+ 73 6.3 63JA2998
80 –7.3 63JA2998
+
+
82 7.7 63JA2998
a The structure of the cation is given instead of that of the diene because in most cases a single cation is in equilibrium with several dienes.
b Values of pK were calculated from the equation: Ho = pK + log([CB]/[CBH+]) where Ho = Hammett's acidity function.
c. HCl
+ (63)
(264) (265)
0[08[1[2[3 Arenonium and phenonium ions
"i# Arenonium ions

The early history of arenonium ions was outlined by Nenitzescu ðB!57MI 008!92Ł\ and the _eld has
been subsequently reviewed ðB!69MI 008!94\ 63BAU0920\ 71ACR35\ 73TCC0Ł[ Until about 0839\ the
s!complexes of aromatic compounds\ also called {Wheland intermediates|\ were only hypothetical
entities[ In 0847\ Olah and Kuhn achieved the decisive breakthrough by isolating crystalline cyclo!
hexadienyl ~uoroborates "155#Ð"158# from the reaction between an aromatic hydrocarbon "toluene\
m!xylene\ mesitylene or isodurene#\ HF\ and BF2 at low temperature "see Scheme 72#\ which are
salts of arenonium ions ð47JA5424Ł[ The resulting coloured complexes had a high speci_c conductivity
and de_nite decomposition points\ varying from −54>C for the toluene complex to −04>C and
−09>C for the complexes of mesitylene and isodurene[ Using similar techniques Olah and co!
workers prepared the related PF− −
5 and SbF5 complexes of methylbenzenes ð51JOC2330Ł[ A classic
paper by MacLean and Mackor reported the NMR spectra of a number of stable arenonium ions\
including those formed by protonation of toluene\ mesitylene and hexamethylbenzene ð50MP130Ł[
H H H H H H H H H H
6
+
BF4– +
BF4– +
BF4– +
BF4– 5
+
1 BF4–
3
(266) (267) (268) (269) (270)
H H
HF, SbF5, SO2ClF, SO2F2, –134 °C
5 6 1
SbF6–
+ 2
4
3
(271)
Scheme 83
The archetypal arenonium ion\ the benzenonium ion "160#\ has been prepared at low temperature
in superacid media "Scheme 72# ð61JA1923Ł[ The 02C!NMR spectra of the benzenonium ion "160#
ð67JA5188Ł and the pentamethylbenzenonium ion "169# ð68JA3669Ł both indicate that the unit positive
charge is distributed approximately equally between C0\ C2 and C4[
Olah and Kuhn were the _rst to isolate typical intermediates of the FriedelÐCrafts aromatic
alkylation reactions\ for example\ the crystalline complex of the type "160a# obtained from the
reaction of EtF:BF2 with mesitylene "Scheme 73#\ along with similar results with toluene\ m!xylene\
and asym!tetramethylbenzene ð47JA5430Ł[ Olah and Kuhn also isolated crystalline complexes of the
type "161# which\ according to theory\ are intermediates in aromatic formylation\ acetylation
and nitration reactions ð47JA5430\ 59JA1279Ł[ Contemporaneously\ von Doering and co!workers
introduced\ by exhaustive methylation of benzene with AlCl2 and MeCl\ a seventh methyl group to
hexamethylbenzene^ the resultant chloroaluminate "162# was obtained^ this compound gave meth!
anol and hexamethylbenzene upon hydrolysis ð47T067Ł[
It should be noted ðB!69MI 008!94Ł that the stability of an arenonium ion is determined by two
factors] "i# its resistance toward isomerisation and decomposition reactions^ and "ii# its resistance
towards deprotonation\ which is related to the basicity of the parent molecule[ Cations of the less
basic isomers of the di!\ tri! and tetramethylbenzenes are chemically unstable owing to their tendency
to isomerise to the more stable cations of m!xylene\ mesitylene and isodurene\ respectively[ These
isomerisations proceed by successive intramolecular 0\1!hydrogen and 0\1!methyl shifts[ In
benzenonium ions\ the 0\1!methyl shift is a very slow process relative to the 0\1!hydrogen shift[
Carbocations 804
H Et Et
EtF, BF3, –80 °C heat

+
BF4–
(271a)
Scheme 84
H X
R1 R1
+
BF4– AlCl4–
+
R1 R1
R1
(272) (273)
R1 = Me or H; X = CHO, R2CO, NO2
"ii# Phenonium ions

The topic of phenonium ion formation has been reviewed by Lancelot\ Cram and von R[ Schleyer
ðB!61MI 008!01Ł and by Lowry and Richardson ðB!76MI 008!98Ł[ Several stable phenonium ions have
been prepared by Olah in superacid media Scheme 74 ð56JA4148\ 60JA5766\ 65JA5173Ł\ Scheme 75
ð58JA0347\ 73JA2154Ł\ whereby their NMR spectra could be studied[
H H
HF, SbF5, SO2ClF –HCl, several h + –HCl, several h

+
–78 °C –60 °C –30 °C
Cl +
Cl
R1 R2 R1 R2
SbF5, SO2 or SbF5Cl–
X HF, SbF5, SO2
R3 + R3
–78 °C or –60 °C
R5 R4 R5 R4
X = OH or Cl
R1 = R2 = R3 = R4 = R5 = H
R1 = R2 = R4 = R3 = H; R5 = Me
R1 = R2 = R4 = H; R3 = R5 = Me
R2 = R4 = H; R1 = R3 = R5 = Me
R1 = R2 = R3 = R4 = R5 = Me
Scheme 85
Cl SbF5, SO2 SbF5, SO2

+
–78 °C –78 °C
Cl
R
R
SbF5, SO2ClF
+
–90 °C
R = H or Me
Scheme 86
X X
X
intermolecular
PhH, AlCl3•MeNO2 alkylation
20 °C δ–
Cl Cl AlCl3
δ+
oriented π-complex
X = Me or H
Scheme 87
Investigations by Olah et al[ concerning the phenylethylation of benzene and toluene with
b!phenylethyl chlorides\ in more nearly normal FriedelÐCrafts conditions\ indicated p!aryl par!
ticipation in polarised donor!acceptor b!phenylethylating complexes rather than the formation of
phenonium ions "s!complexes# "Scheme 76# ð81PNA"78#804Ł[
0[08[1[2[4 Azulenyl carbocations

The chemistry of azulene "163# and its derivatives has been reviewed ðB!55MI 008!94\ 66RCR429\
74HOU"V:1c#016Ł[ Azulene is an unusual hydrocarbon molecule in that it has a permanent dipole
moment "0[97D#[ Canonicals "163b and c# "Scheme 77# reveal how the dipolarity occurs and may be
summarised by structure "163d#[ The molecule "163# is readily protonated at C0\ or its equivalent
C2\ to give carbocation "164# "Scheme 78#\ which may be portrayed by canonicals "164aÐe#[ The
seven!membered ring takes on the characteristics of an aromatic tropylium cation and the system
may be described by structure "164f#\ which implies partial _xation of the C11C2 double bond[ It
is this ability of the seven!membered ring of the azulenyl system to accommodate a positive charge\
which enables the three guaiazulene substituents to stabilise the cyclopropenium ion in the tris!0!"4!
isopropyl!2\7!dimethylazulenyl#cyclopropenylium cation "Agranat|s cation# "Section 0[08[1[1[5["ii##[
7 8
1 1
+
6 2 + etc. ≡ + –
5 3 – – 3
4
(274a) (274b) (274c) (274d)
Scheme 88
+
+
H+
+
(274) (275a) (275b) (275c)
+ 2
1
+ +
(275f)
(275e) (275d)
Scheme 89
An impression of the relative stability of various azulenyl cations may be derived from Table 03\
which re~ects the work of Schulze and Long ð53JA211\ 53JA216\ 53JA220Ł[ Worthy of note is the
Carbocations 806
unusual behaviour of 0!nitrotrimethylazulene\ which protonates at C0 as opposed to the C2 position
favoured by the other 0!substituted azulenes[ It is thought that this anomolous C0 protonation
relieves steric crowding between the 0!nitro group and the 7!methyl group[
Table 03 Spectrophotometric measurements of the formation of azulenyl carbocations[
Molarity of HClO4
Azulene Azulenyl cation required for half-protonation
1.22
+
p-Me2N-Bn p-Me2N-Bn
2.16
+
+ 2.30
Cl Cl
4.17
+
NO2 NO2
+ 5.06
CN CN
8.36
+
0[08[1[2[5 Homotropylium and homoaromatic carbocations

The subject of homoaromaticity has been reviewed by Childs ð73ACR236Ł\ Paquette ð67AG"E#095Ł\
Winstein ð58QR030\ B!61MI 008!09Ł\ Story and Clark ðB!61MI 008!00Ł\ Olah\ Prakash and Sommer
ðB!74MI 008!93Ł and Garratt ð68COC"1#359\ B!75MI 008!92Ł[
Cyclooctatetraene "046# undergoes protonation\ when dissolved in concentrated H1SO3[ The
proton adds to one of the double bonds of "046# to give the homotropylium cation "165# "Equation
"53## ð54JA2156\ 55JA593\ 55JA595\ 55JA1936\ 72JOC0320\ 77JA0097Ł[ Carbocation "165# may be isolated as
a solid salt\ C7H8¦ = SbCl−5 ð51JA1731Ł[ In cation "165# an aromatic sextet of electrons is delocalised
over seven sp1!hybridised carbons C0 to C6 somewhat analogously to the aromatic tropylium cation[
The remaining carbon C7 is sp2!hybridised and takes no part in the delocalisation of the positive
charge[ NMR spectra show the presence of a ring current[ In order to maximise the overlap of the
C0 and C6 p!orbitals\ the C7 methylene group is constrained to lie almost vertically above the plane
of the seven!carbon aromatic ring formed by C0 to C6[
(δ –0.3)
H
8
7 H (δ 5.1)
H2SO4
(δ 8.5) H 4
+ (64)
1
3 2 H (δ 6.4)
(δ 8.5) H
H (δ 8.5)
(157) (276)
Paquette has stated ð67AG"E#095Ł that "166# and "167# "Scheme 89# ð67AG"E#095Ł are examples of
bishomoaromatic cations\ while Childs ð73ACR236Ł\ being somewhat more stringent in his de_nition
of homoaromaticity\ is sceptical of this assertion[ Jonsall and Ahlberg have used 0JC*C values as a
test for homoaromaticity in "166^ RH# ð75JA2708\ 80CRV264Ł[ 02C!NMR spectroscopy in superacid
media supports its aromatic character\ although solvolytic studies suggest that "166^ RH# has the
planar dihydroindenyl structure "168# ð61JA6952\ 64JOC699Ł[ Semiempirical and ab initio "STO!2G#
calculations _nd both structures "166^ RH# and "168# to represent energy minima ð72JCS"P1#294\
74T5944Ł[
R
super acid super acid
medium medium
OH
+ (gives R = Me)
R
R = H or Me (277)
super acid
medium
+
(278)
Scheme 90
(δ 7.38) (δ 1.04) H H (δ 0.0)

(δ 3.63) H H R H (δ 4.40)
H
H (δ 8.23) (δ 6.95) H (δ 6.62)
+ +
H (δ 6.40) H (δ 6.87)
H (δ 7.52) H (δ 8.03)
(277) (278)
(279)
Olah and co!workers have reported the preparation of the unusual pagodyl dication "170# "Scheme
80# from pagodane "179# ð78JA635Ł^ see also ð72TL4746\ B!76MI 008!90Ł[ The dication was described
as homoaromatic[
SbF5
SO2ClF +
etc. ≡ 2+
+ + +
–78 °C
(280) (281)
Scheme 91
0[08[1[2[6 m!Hydrido!bridged carbocations

Three!centre\ two!electron C0H0C bonds occur only rarely in organic chemistry[ However\
Sorensen has shown that the 0\5!dimethyl!0!cyclodecyl cation "171# "Equation "54## and related ions
contain transannular three!centre C0H0C bonds\ when generated from the corresponding alcohols
at −019>C in superacid media ð70JA477Ł[ These ions are not stable\ rearranging and ultimately
Tricoordinate Radicals 808
decomposing above −69>C[ However\ McMurry et al[ have prepared the relatively stable in!
bicycloð3[3[3Ł!0!tetradecyl cation "172# "Scheme 81#\ which is comparable in acidity to acetic acid
ð78JA7756\ B!78MI 008!95\ 80CRV264Ł[ Sorensen and Whitworth have subsequently prepared a series of
m!hydrido!bridged tricycloalkyl cations "173# varying the acid media with the value of n\ where
4−n−7 "Equation "55## ð89JA7024Ł[
HO
HSO3F, SO2ClF
H H+ (65)
–120 °C
(282)
Ti0 H+
H H+
O
(283)
Scheme 92
(n = 8); FSO3H, SbF5, SO2ClF, –80 °C

(n = 7); FSO3H, SbF5, SO2ClF, –112 °C to –10 °C
H + (66)
(n = 6); FSO3H (1 drop), TFA, –10 °C to RT H
(n = 5); TFA, H2O, RT
(CH2)n–1 (CH2)n
0[08[2 TRICOORDINATE RADICALS
0[08[2[0 General Features of Radical Formation

The generation of radicals has been known since 0899 when Gomberg _rst investigated the
triphenylmethyl radical ð99CB2049\ 99JA646Ł[ The following 69 years saw a steady increase in the
available information regarding these intermediates ðB!35MI 008!90\ B!46MI 008!90\ 52OR"02#80\
52OR"02#049\ B!53MI 008!91\ B!55MI 008!95\ B!69MI 008!95\ 60ACR275\ B!60MI 008!94\ B!60MI 008!95Ł[ Research
in this period culminated with an excellent two!volume work edited by Kochi ðB!62MI 008!98\
B!62MI 008!09Ł[ Since 0869 there has been a dramatic increase in the generation\ understanding and
use of radicals in synthesis and this is re~ected in the number of literature reviews[ General texts in
the _eld include] Barton and Parekh ðB!81MI 008!05Ł\ Motherwell and Crich ðB!81MI 008!06Ł\ Regitz
and Giese ð78HOU"0#0\ 78HOU"1#0Ł\ Curran ð77S306\ 77S378Ł\ Ramaiah ð76T2430Ł\ Giese ðB!75MI 008!93Ł\
Walling ð74T2776Ł\ Tedder ð71AG"E#390Ł\ Nonhebel et al[ ðB!68MI 008!95Ł\ Davies and Parrott
ðB!67MI 008!94Ł and Hay ðB!63MI 008!96Ł[ Reviews on more speci_c topics are] bridgehead radicals
ð78CRV864\ 81CSR094Ł\ the captodative*or synergistic ð78JA6447Ł*e}ect ð74ACR037\ 77PAC0524Ł\
cyclisations ðB!79MI 008!94\ 70T2962\ 73SCI772\ 77PAC0534\ 77BCJ038\ 89T0274\ 80ACR028\ 80COS"3#668Ł\ cyclo!
propylmethyl radical ð81MI 008!07\ 82CSR236Ł\ diastereofacial selection in intermolecular reactions
ð80ACR185\ 83SL0Ł\ organosilane ð81ACR077Ł and organotin reagents ðB!75MI 008!94\ 76S554Ł\ persistent
radicals ð65ACR02Ł\ retrosynthetic planning ð80SL52Ł and ring expansions ð82CRV1980Ł[
0[08[2[0[1 Description of the different character of carbon!centred radicals

Much of the research in the previous sections concerning carbanion formation "see 0[08[0# and
carbocation formation "see 0[08[1# was carried out from the perspective of mechanistic studies
roughly during the period 0859 to 0874[ However\ many of the most important developments in the
formation of carbon!centered radicals have been motivated by the needs of synthetic organic
chemistry and this is re~ected in the approach used in section 0[08[2[
Radicals are species that contain at least one unpaired electron[ Although they are neutral species\
radicals may be de_ned as nucleophilic "even though they are electron de_cient#\ electrophilic or
ambiphilic in character[ These tendencies have been rationalised using the frontier molecular orbital
theory ðB!65MI 008!91\ 72AG"E#642\ 80COS"3#604Ł and are in~uenced by the functional group"s# attached
to the carbon holding the unpaired electron[ Thus\ interaction of the singly occupied molecular
orbital "SOMO# with the lowest unoccupied "LUMO# and:or the highest occupied molecular orbital
"HOMO# of its reaction partner will be in~uenced by the relative energy of the SOMO[
"i# Nucleophilic radicals

Carbon!centred radicals that add more rapidly to electron!poor alkenes\ such as acrylonitrile and
methyl acrylate\ are de_ned as nucleophilic[ Alkyl!substituted radicals have a nucleophilic tendency
and increasing the number of alkyl substituents serves to raise the relative energy of the SOMO[
This reduces the energy di}erence between the SOMO and LUMO "Figure 2# and is re~ected in the
slight increase in relative reaction rates[ Thus\ the relative reaction rates of alkyl radicals with
dimethyl fumarate\ an electron!de_cient alkene\ follows the order tertiary×secondary×primary
"Table 04# "Equation "56## ð72TL692Ł[ For other information see chapters 0[97 and 0[01[
LUMO
∆E
SOMO
Figure 2 Interaction of nucleophilic radical SOMO with LUMO of alkene[
Table 04 Relative rates of radical addition to dimethyl fumarate

"Equation "56##
R
CO2Me krel
R• + MeO2C CO2Me (67)
MeO2C
•
R• krel
n-C7H15• 1
c-C6H11• 1.1
But• 1.6
"ii# Electrophilic radicals

Electrophilic radicals have a reaction pro_le directly opposite to that of nucleophilic radicals[
Hence\ these species react with electron!rich alkenes\ such as enol ethers and enamines\ more rapidly
than with electron!de_cient alkenes[ Electron!withdrawing substituents enhance the electrophilic
character and the frontier molecular orbital interaction is that of the SOMO with the HOMO^ an
energy decrease in the SOMO leads to a lower DE and an increased rate of reaction "Figure 3#[
However\ unlike their nucleophilic counterparts\ information relating to absolute rate constants for
electrophilic radicals is scarce ð75JOC4996\ 75CB333\ 76JOC194\ 78JOC297Ł[
SOMO
∆E
HOMO
Figure 3 Interaction of electrophilic radical SOMO with HOMO of alkene[
"iii# Ambiphilic radicals

On considering the frontier molecular orbital theory\ one might expect a certain group of radicals
to have a SOMO of intermediate energy[ In this scenario\ the relative energy di}erence between
interactions of the SOMO\ with either the LUMO or HOMO of the alkene\ would be similar[ Thus\
both electron!donating and !releasing substituents attached to the alkene would accelerate the
reaction rate[ Ambiphilic radicals fall into this grey category separating nucleophilic and electrophilic
character[ However\ very little is known about these species and the borders of ambiphilic and both
nucleophilic and electrophilic radicals are very poorly de_ned[ Recent research suggests that a
carbon!centred radical substituted by one weakly electron!withdrawing group has ambiphilic tend!
encies "Table 05# "Equation "57## ð77CB1952\ B!78MI 008!97Ł[
Table 05 Relative rates of ambiphilic radical addition to alkenes
"Equation "57##
krel •
ButO2C CH2• + R (68)
ButO2C R
R krel
CO2Me 12
Et 1
Ph 40
0[08[2[0[2 Stability and structure of carbon!centred radicals

One of the major di}erences between radicals and their ionic counterparts is that radicals will
undergo direct radicalÐradical coupling\ forming a dimer "Equation "58##[ For simple alkyl radicals\
this reaction typically occurs at the di}usion!controlled rate\ hence their lifetime is extremely short
in solution[ However\ these transient species may be trapped in a frozen lattice and kept for relatively
long periods\ allowing spectral measurements to be made ð52JA273\ 57AG"E#496\ 60ARP098\ 79CSR0Ł[
Transient radicals are the most useful in synthesis[ In analogous fashion to carbocations\ the stability
order of free radicals is tertiary×secondary×primary and this can be explained in terms of
hyperconjugation and inductive e}ects "Scheme 82#[ The most simple and useful method of assessing
radical stabilisation is that of bond dissociation energy ðD"C0H#Ł\ a high value indicating lower
stability ð71ARP382\ 71JA2544\ 74JA1761\ 75TCC"029#0\ 77JA6228\ 77JA6232\ 78JOU338Ł^ see also ð89ACR264\
82ACR409\ 82JOC5956Ł[ However\ Nicholas and Arnold have disputed the usefulness of this measure
ð73CJC0749\ 73CJC0759Ł[
R1 R1 R1
2 R2 R2 (69)
R2 • R3 R3 R 3
R • •
> • > >
R R R
R R
•
Scheme 93
On introducing conjugation at the carbon!centred radical\ delocalisation of the unpaired electron
can occur and this results in a more stable species ðB!57MI 008!93\ 75JA2113Ł[ Increasing the number
of substituents that allow conjugation enhances the stability of the radical "Scheme 83#[ It has also
been postulated that radicals have enhanced stability "via resonance# when substituted by both an
electron!donating and electron!withdrawing group\ the so!called {captodative| or {synergistic| e}ect
ð74ACR037\ 77TL5728\ 77TL0326\ 77PAC0524\ 77JPO086\ 77JA7053\ 78JA6447\ 89APO"14#020Ł[ However\ it is
important to note that there is also evidence\ both theoretical and experimental\ against this
enhancement ð76AG"E#669\ 78JA4734\ 89JOC47\ 89CJC0603Ł[ For example\ evidence suggests that\ while
both mono! and di~uoromethyl radicals are more stable than a methyl radical\ the tri~uoromethyl
radical is less stable ð78JOC4537Ł[ However\ although these electronic e}ects increase relative stability\
radicals generally remain transient species[
•
> >
•
Scheme 94
With respect to radical chemistry\ the opposite of a transient species is a persistent one and the
important factor to consider here is not that of electronic stabilisation but of steric hindrance
ð79TCC"77#0Ł[ Hence\ although the benzyl radical is more stable than the methyl radical\ it remains a
transient species[ The triphenylmethyl radical "174#\ however\ exists in solution at room temperature
ð62RCR0900Ł[ This species is one example of a persistent radical and occurs\ at a concentration of
approximately 1)\ in equilibrium with its dimer "175# "Equation "69## ð57TL138\ 69T4232\ 69CB0090\
63T1998Ł[ The greater importance of steric hindrance to the dimerisation of persistent radicals was
elegantly demonstrated by Sabacky et al[ ð56JA1943Ł[ This group prepared the radicals "176# and
"177# and compared the ability of these compounds to dimerise with that of the triphenylmethyl
radical "174#[ The carbon containing the radical in compound "174# is sp1!hybridised and\ to
maximise delocalisation\ all three phenyl rings must be simultaneously coplanar[ X!ray crys!
tallographic measurements\ however\ have shown that this is not the case[ In reality the triphenyl!
methyl radical is propeller!shaped and the extent of delocalisation is similar to that in both the
diphenylmethyl and phenylmethyl radicals[ Compound "176# is a planar species and maximum
interaction "resonance stabilisation# occurs between the p!orbital on the central carbon atom and
the p!orbital systems of the three aromatic rings[ Conversely\ the ortho!methoxy groups in compound
"177# increase the steric bulk around the central carbon atom\ resulting in an increased deviation
from a planar geometry and a decrease in resonance stability[ Thus\ compounds "176# and "177#
will have similar electronic character with compound "176# having greater delocalisation and com!
pound "177# having greater steric bulk[ Thus\ if resonance is the major factor in~uencing the stability
of compound "174#\ compound "176# would dimerise and not compound "177#[ The opposite would
occur if steric hindrance is the major in~uence on stability[ In actuality\ there is no evidence for
dimerisation of compound "177# either in solution or the solid state[ Compound "176#\ however\
exists as a dimer and dissociates only slightly in solution ð56TL2766\ 67TL3760Ł[ Similar e}ects are
observed with the di!t!butylmethyl radical "178# where steric e}ects alone retard the rate of dim!
erisation ð65ACR02\ 67CB61\ 68TL818Ł[
There are two possible shapes for simple alkyl radicals[ If the unpaired electron were to be
2 (70)
• H
(285) (286)
MeO OMe
O O OMe OMe
• •
But But
O MeO •
OMe
(287) (288) (289)
accommodated in a p!orbital\ the carbon would have planar geometry "189#[ Alternatively\ if an
sp2!orbital were occupied\ the carbon would adopt a pyramidal shape "180# "Figure 4#[ Direct
physical evidence was gained from both electron spin resonance "ESR# and infrared spectroscopy
of the methyl radical and other simple alkyl radicals ð56JCP"36#2526\ 56JCP"36#4035\ 66JA7237\ 67AG"E#483Ł[
This information\ and the known loss of optical activity on generation of a radical at a chiral
carbon\ indicate the geometry to be essentially planar[ However\ if the carbon!centred radical
contains a highly electronegative substituent\ the con_guration becomes more pyramidal and this
deviation increases with the number of electronegative substituents ð54JCP"32#1693\ 56JCP"35#2082\
58JCP"40#1656\ 63JA1190\ 65JA129Ł[ Thus\ the geometry changes from essentially planar to pyramidal
across the series shown in Scheme 84\ though the barrier to inversion is low[ In contrast to
this\ bridgehead radicals are pyramidal and their rigid structure prevents inversion ð76JOC1516\
77JCS"P1#0878\ 78CRV864\ 89CC0478\ 81CSR094Ł[ This geometry results in an increased s!character of the
SOMO and reduced stability of the radical\ when compared to their simple alkyl counterparts[
(290) (291a) (291b)
Figure 4 Pyramidal nature of tricoordinate C!centred radical[
Me• < FH2C• < F2HC• < F3C•
Scheme 95
0[08[2[0[3 Solvent and concentration effects

In contrast to carbanion and carbocation chemistry\ carbon!centred radicals are neutral species
and therefore their reactions are virtually independent of solvent e}ects ð56JA1543\ B!62MI 008!00\
74T2776\ 80COS"3#604Ł[ Thus\ the rate of a radical reaction is similar over a wide range of solvent
polarities[ When selecting the solvent\ it is more important to consider the rate of a potential
radicalÐsolvent side reaction[ Typical solvents used in radical chemistry are aromatic hydrocarbons\
particularly benzene\ ethers and alcohols "see ð75JA292Ł#[ However\ it is important to note that alkyl
radicals will both abstract a!hydrogen atoms from THF and diethyl ether and add to benzene\ with
pseudo _rst!order rate constants of approximately 093 s−0\ 092 s−0 and 091 s−0\ respectively ð66JA6859\
74MI 008!96\ 77ACR195Ł[ Halocarbons should also be avoided when tin!\ silicon! and phosphorus!
centred radicals are involved as intermediates\ since abstraction of either a halogen or a hydrogen
atom may occur[
As with the choice of solvent\ concentrations become very important when considering the relative
rates and e.ciency of radical reactions[ For example\ Giese et al[ and Barclay et al[ have both
demonstrated that\ on altering the concentration of tributyltin hydride "TBTH#\ reactions can a}ord
di}erent products ð73JA0682\ 89OS"57#55\ 82JOC0972Ł[ Thus\ on generating the anomeric radical "181#
using a high concentration of TBTH\ the product of deoxygenation "182# is observed[ However\ on
slow addition of TBTH\ in a solution containing 1\1?!azobisisobutyronitrile "AIBN^ 291# the initial
radical undergoes rearrangement of the acetyl moiety\ generating radical "183#[ This second radical
is subsequently quenched with TBTH to a}ord the 1!deoxyglucose derivative "184# "Scheme 85#[
Phosphate groups have also been shown to rearrange in this manner ð82JOC0972Ł[
OAc OAc
high TBTH concentration
AcO O AcO O
AcO • AcO
OAc OAc
(292) (293)
AIBN, low
TBTH concentration
OAc OAc
O low TBTH concentration O

AcO AcO
AcO • AcO
OAc OAc
(294) (295)
Scheme 96
0[08[2[0[4 Initiation
The homolytic cleavage of a chemical bond requires an energy input and there are four methods
by which this energy may be supplied] thermolysis\ photolysis\ redox reactions and sonication[
Thermolysis may be achieved at high temperatures in the gas phase^ however\ this is not a useful
process for synthetic applications ðB!79MI 008!95Ł[ Thus\ to generate a radical in solution at moderate
temperatures\ it is usually necessary to kick!start the process by adding an initiator[ The selection
of an initiator is generally dictated by the operating temperature\ although the character of the
bond being cleaved should also be considered ð52OR"02#80\ 74T2776Ł[ Commonly utilised initiators at
elevated temperatures include azo compounds ð54JA2302\ 69JA3284\ 79CRV88\ 75JA6824\ 76JA1649Ł\ diacyl
peroxides and peroxides ðB!68COC"0#898\ 77JA1766Ł[ In the late 0879s\ the bulky hexa!
organodistannanes "185\ 186 and 187#\ via the intermediary stannyl radical "Equation "60## ð78T840\
B!80MI 008!92Ł\ and the bis"trialkylstannyl#benzopinacolates "188 and 299# ð77JA0520\ 82TL6708Ł have
been shown to generate\ under thermolytic conditions\ carbon!centred radicals e.ciently "290#[ The
mechanism of the latter reaction is uncertain\ though the initial fragmentation is thought to be that
outlined in Equation "61#[ Although there are many thermal initiators\ the most frequently used in
synthetic applications is AIBN "291#[ This compound has an e}ective temperature range of 59Ð009>C
and its decomposition pathway is well understood "Equation "62## ð53JA0800\ 79CRV88\ 74T2776Ł[
heat
(R3Sn)2 2 R3Sn• (71)
Et Pri
R= Et Pri
Et Pri
(296) (297) (298)
RO OR RO OR
heat
Ph Ph Ph • • Ph (72)
Ph Ph Ph Ph
(299) R = Bun3Sn (301)
(300) R = Me3Sn
CN
heat
N N 2 + N2 (73)
• CN
NC
(302)
Photoinitiation is the most applicable technique for low temperature work ð68JOC3012\ 74JOC2387Ł[
However\ Oshima and co!workers have reported a triethylborane!tin hydride method of generating
radicals e}ectively even at −67>C ð77TL5016\ 78BCJ032Ł[ The most useful photoinitiators are diben!
zoyl peroxide and AIBN^ however\ Neumann and co!workers have reported the use of hexa!
butyldistannane under mild conditions\ with triplet sensitisers ð54JA2302\ 69JA3284\ 79CRV88Ł[ Thus\
on irradiation of a solution containing hexabutyldistannane and the sensitiser\ either acetone\
diphenyl ether or 3!methoxy acetophenone\ with a 014 W daylight lamp\ selective homolytic cleavage
of the tinÐtin bond was observed ð82SL175Ł[
Redox reactions are emerging as useful processes for the generation of carbon!centred radicals[
The most important techniques from a synthetic viewpoint are reactions involving transition metals\
though electrolysis is also useful "e[g[\ Kolbe reactions^ section 0[08[2[1[1"iii##[ The use of transition
metals has been reviewed by Iqbal et al[ ð83CRV408Ł[ Sono!initiation is also emerging as a potentially
useful method ð78JOC5090\ 78JA5738\ 82TL0206Ł^ see also ð76CSR128Ł[
0[08[2[0[5 Vicinal substituent

As with ionic chemistry\ certain vicinal moieties may cause undesirable elimination reactions to
occur "Equation "63##[ Functional groups to beware of are halogens\ xanthates\ nitro\ isonitrile\
selenides\ sul_des and sulfoxides "see Chapters 0[02 and 0[03#[
R3
R4 R1 R3
R1 + X• (74)
• X
R2 R4
R2
0[08[2[1 Radicals by Bond Scission
0[08[2[1[0 CarbonÐhydrogen bond scission

Simple hydrocarbons may undergo carbonÐhydrogen bond scission by either thermolysis or
abstraction together with a radical species generated from an initiator "e[g[\ Cl=\ Br=\ RO=\ R=#[ These
processes have been extensively studied and the order of hydrogen atom abstraction generally
parallels their bond dissociation energies ð71ARP382Ł[ Thus\ the relative susceptibility for abstraction
is tertiary×secondary×primary ðB!62MI 008!01\ 71AG"E#390\ 71T202Ł[ However\ the regioselectivity is
variable and dependent on both the abstracting radical and the reaction temperature ð60JA1954\ 62S0\
70TL0780\ 78JOC2460\ 82ACR108Ł[ Also\ on the introduction of a carbonÐcarbon double bond\ the
preferred site of abstraction is at the allylic position[ This is ascribed to resonance stabilisation of
the resultant radical^ allylic rearrangements are frequently observed "Equation "64## ðB!62MI 008!02Ł[
Similarly\ on introduction of an aromatic ring\ the abstraction usually\ but not always\ occurs at
the benzylic position ðB!62MI 008!01Ł[
R4 R4
R1 • R1
R5 R5
(75)
•
R2 R3 R2 R3
Electron!donating and withdrawing groups reduce the a!carbonÐhydrogen bond strength hence
radicals are generated with a high degree of regioselectivity ð62HCA0405\ 71ARP382\ 72CB0931\ 72JA3690\
72TL074Ł[ Thus\ on treatment with di!t!butyl peroxide "DTBP#\ ketones and carboxylic acids\ esters
and lactones readily form the radical at the carbon atom a to the electron!withdrawing moiety
"Equations "65#Ð"68## ð59DOK"020#479\ 50DOK"025#0988\ 50IZV1954\ 54CC6\ 74JOC2119Ł[ Higher regio!
selectivities are facilitated when two electron withdrawing groups are present "Equation "79##
ð51JCS3357\ 60BSF350\ 75JA0697Ł[ Furthermore\ although it is possible to generate a radical at the
alkoxy carbon atom of an ester or lactone\ this generally does not occur[ This is in stark contrast
to amides and lactams\ where the radical is preferentially generated at the carbon atom a to the
nitrogen atom "Equation "70## ð57T3498Ł[
O O
DTBP, ∆
• (76)
or hν
•
DTBP, ∆
C5H11 CO2H C5H11 CO2H (77)
DTBP, ∆
•
C5H11 CO2Me C5H11 CO2Me (78)
O O
DTBP, ∆
• (79)
O O
or hν
NC NC
CO2Et • CO Et
2
DTBP, 150 °C
(80)
O O O
hν, acetone
HN HN + HN • (81)
•
major minor
A superior procedure to the DTBP method is the use of metal salts in an oxidative process[
Several metals in high oxidation states\ including Ag1¦\ Co2¦\ Ce3¦\ Fe2¦\ Ir3¦\ Mn2¦ and V4¦ are
e}ective in generating a radical at the carbon atom a to an electron!withdrawing group "Equations
"71# and "72## ð61JOU1404\ 63JA6866\ 71TL4476\ 77JA1109\ 82TL0690\ 83CRV408Ł[ Of these\ manganese has
been studied most intensively and a simpli_ed mechanism is depicted in Scheme 86 ð63JA6866\
77JOC1026\ 77PAC0548\ 80CRV0126Ł[ A representative selection of substrates is depicted in Equations
"73# and "74#\ Scheme 87\ Equations "75Ð77# ð73SC0080\ 73JOC0592\ 74TL3180\ 82JOC6509\ 82JOC6539Ł[
O O
Mn(OAc)3
(82)
or Ag+/S2O82– •
X XH XH
Mn3+
Mn2+ +
R1 R2 R1 R2 R1 • R2
X = CO2H, CO2R, COR, CN, NO2
Scheme 97
O O
dilute KOH
•
NH NH
(83)
K3Fe(CN)6 –O
HO O N O O N O
H H
Mn(OAc)3
O AcOH, ∆
+ (84)
40% O
Mn(OAc)3
AcOH, ∆ NO2
+ NO2 (85)
78%
Mn(OAc)3, AcOH, Ac2O, ∆ HCO2H, ∆
43%
O
HO2C O
Scheme 98
O
OAc CN Mn(OAc)3
+ AcOH, RT CN
O (86)
Ph CO2H 77%
Ph OAc
Mn(OAc)3, AcOH
CO2Et AcONa, 70 °C
+ CO2Et (87)
OHC OHC
N CO2Et 80% N
H H CO2Et
Ph
O O Mn(OAc)3, Cu(OAc)2 O
AcOH, RT O
O O (88)
90%, de 86%
Ph
The regioselective intramolecular formation of a remote carbon!centred radical may also be

achieved by initially generating\ for example\ a heteroatom radical\ typically based on nitrogen or
oxygen ð53AG"E#414\ B!62MI 008!02\ B!79MI 008!94\ B!81MI 008!06Ł[ Heteroatom!centred radicals may
e}ect a 0\4!hydrogen atom abstraction with concomitant generation of the desired carbon radical
"Equations "78# and "89##[ These reactions have been the subject of many investigations and are
now well understood ð52CRV44\ 57PAC0\ 60S0\ 75JA1270\ 76JA1084\ 77JCS"P0#2144\ 77TL726\ 77TL0330\ 77TL1104\
B!78MI 008!96\ 81TL4802Ł[ Curran and co!workers developed this methodology to include the use of
aryl and vinyl radicals as the initially formed reactive species "Schemes 88 and 099# ð77JA4899\
89JA785\ 80JOC3224\ 82JA5940Ł[ It should\ however\ be noted that this method is not con_ned to 0\4!
abstractions^ Breslow and co!workers have elegantly demonstrated that 0\n!abstraction may occur
in steroid systems^ an example and the proposed mechanism is shown in Scheme 090 ð77MI 008!93\
89CC0963\ 89CC0965\ 89JA5731\ 80JA7866Ł[
NO
hν, PhH
ONO + OH (89)
ON
OH
PhI(OAc)2, I2, hν
cyclohexane, 80 °C
(90)
77% N NO2
H H
NHNO2
Bu3SnH, AIBN, PhH

MeO2C 80 °C, 24 h MeO2C
•
MeO2C I MeO2C
87%
CN CN
MeO2C
•
MeO2C MeO2C MeO2C
MeO2C • MeO2C
CN CN CN
Scheme 99
•
I Bu3SnH, AIBN, PhH, 80 °C
N N
Me Me
O O
• •
N 75%
Me Me
Me N
O O
N
O Ph
Ph
Me
N
O
Ph
Scheme 100
0[08[2[1[1 CarbonÐcarbon bond scission

The homolytic _ssion of a carbonÐcarbon bond is a useful preparative method for the formation
of carbon!centred radicals[ Typically\ this process proceeds via a heteroatom!centred radical which
subsequently su}ers b!carbonÐcarbon bond scission with simultaneous formation of the desired
carbon!centred radical and expulsion of either a ketone\ aldehyde or carbon dioxide[ However\
other methods including decarbonylation\ addition to cyclopropanes as well as cyclopropyl! and
cyclobutylcarbinyl fragmentation reactions have been investigated ð61JA290\ 62JA745\ 62JA5617\
65JOC412\ 68ACR55\ 75TL0442\ 77CC0279\ 77JA2299\ 78CC221\ 89CJC0587\ 80JOC2790\ 81MI 008!07\ 81T7920\
81TL070\ 82CRV1980\ 82CSR236Ł[
O p-NO2C6H4ICl2, hν, CH2Cl2

H
O
O O •
H –HCl
O >90%
O
•I I
Cl
O
Cl
O
Scheme 101
"i# b!Fra`mentation of oxyèn!centred radicals

There are several factors including ring strain\ stereoelectronic e}ects and relative stability of the
adduct radical\ that in~uence the direction of b!fragmentation in unsymmetrical molecules[ The
observed fragmentation results from a combination of these determinants and cannot be deduced
by simple analysis of individual e}ects[
Several methods have been developed for the generation of alkoxy radicals ðB!62MI 008!03\
B!68MI 008!92\ 73TL0842\ 76T2430Ł[ Booker!Milburn has reported that slow addition of a solution of
iron"III# chloride in DMF to the cyclopropyl silyl ether "292# a}ords the alkoxy radical "293#
ð81SL798Ł[ This species subsequently fragments\ to a}ord the ring!expanded carbon!centred radical
"294#[ Intramolecular addition followed by chlorine!atom abstraction generated the bicyclic com!
pound "295# "Scheme 091#[ A similar reaction was observed by Snider et al[ when a cyclopropyl silyl
ether was treated with cupric tetra~uoroborate ð81JOC1288Ł[
A number of systems have been developed to generate the precursor alkoxy radical from the
parent alcohol[ On reacting cyclopropyl alcohol derivatives with either copper"II#\ iron"III#\ lead"IV#
or manganese"IV# salts\ the alkoxy radical undergoes a facile b!fragmentation with concomitant
relief of ring strain ð57RTC0290\ 62TL716\ 73TL4224\ 80CL0082\ 82CL434Ł[ Hence\ on treatment of the
bicyclic compound "296# with silyl enol ether "297# and manganese"III# 1!pyridinecarboxylate
"Mn"pic#2#\ diketones "298# and "209# are formed in 66 and 4) yield respectively "Scheme 092#
ð82BCJ708Ł[ Similarly cyclobutyl\ cyclopentyl and cyclohexyl alcohols are suitable substrates for this
reaction[ Typical substrates and reagents are illustrated in Equations "80#Ð"83# ð61JA0198\ 76TL2852\
82JCS"P0#2996\ 82JOC6117Ł[ A related method involves the facile homolytic _ssion of an epoxide
carbonÐoxygen bond at the b!position to the carbon!centred radical[ The chemistry of the initial
radical intermediate "200#\ generated by the tin hydride mediated dehalogenation or deoxygenation\
is however dependent on the reagent concentration and substrate substitution patterns "Scheme
093# ð70JCS"P0#1252\ 75CC0308\ 76CC0127\ 77TL726\ 77TL844\ 78T6724\ 78TL2232\ 80TL6382\ 81T5772\ 82CRV1980\
82JOC0104\ 82TL756\ 82TL3494\ 82TL4086Ł[
TMS-O •O
O
FeCl3, DMF, RT •
(303) (304) (305)
• Cl
O O
64%
(306)
Scheme 102
OH O-TBDMS O•
Mn(pic)3, DMF, 0 °C
+
Ph
(307) (308)
O O O O
•
• + • Ph +
O-TBDMS Ph • O-TBDMS
O O
+
Ph
O Ph O
(309) (310)
Scheme 103
O
H OH H
Ph Mn(OAc)3 Ph
(91)
H H •
OH
CAN CHO (92)
•
O
HO CO2Et CO2Et
HgO, I2, hν
(93)
•
Bu OH
O SnBu3
Pb(OAc)4
(94)
SnBu3 Bu
•
•O R O R HO R
R + R• + R
R R R R R R
O
R R
R •
R
(311) R R
R
•
R O
Scheme 104
A b!fragmentation reaction\ analogous to that of the alkoxy version has been developed for
lactols[ The method generally involves the use of either a mercury"II# oxide\ iodine and hn or
"diacetoxyiodo#benzene "DIB# and iodine system ð75TL272\ 76CL022\ 76TL2286\ 81JCS"P0#0726\ 82TL3754Ł[
Thus Suginome and Yamada demonstrated that treatment of the lactol "201# with mercury"II# oxide
and iodine followed by irradiation\ produced the 09!membered iodolactone "202# in 68) yield
"Scheme 094#[ This method was also demonstrated to be useful for the synthesis of 8!\ 09! and
00!membered iodolactones ð76T2260Ł[ The related method involving use of DIB and iodine was
shown to be useful in generating formate esters from deoxypentose derivatives ð81AG"E#661Ł[ Accord!
ingly\ the sugar derivative "203# a}orded the formate ester "204# "Equation "84##[
O
O OH OH
O HgO, I2, hν O
79%
I
(312) (313)
Scheme 105
O OH
DIB, I2, cyclohexane, RT O O2CH

O (95)
O
58% O I
(314) (315)
Beckwith and Hay reported the use of N!"cyclopentyloxy#pyridine!1!thione "205# as a clean source
of generating alkoxy radicals for a kinetic study of the reversible b!scission reaction[ In this study
they showed that the distribution of products "206# and "207# is dependent on the concentration of
the TBTH indicating a reversible reaction "Scheme 095# ð77JA3304\ 78JA129Ł[ Hartung and Giese
have also reported on the formation of carbon!centred radicals via the b!scission of alkoxy radicals\
generated by photolysis of tertiary "alkylperoxy#"pyridine#cobaloximes "Scheme 096# ð80CB276Ł[
Hirao et al[ have demonstrated that cyclobutanone "208#\ on treatment with VO"OEt#Cl1\ under!
goes carbonÐcarbon bond scission to a}ord compounds consistent with the radical intermediate
"219#[ The proposed mechanism is outlined in Scheme 097 ð80JOC1153Ł[ The intramolecular addition
of carbon!centred radicals to ketones\ with subsequent b!scission\ has been investigated in greater
depth ð82CRV1980Ł[ As can be seen in Scheme 098\ this ring!expansion reaction has a wide substrate
tolerance and ring expansions of one\ three and four methylene units can be achieved in moderate!
to!high yields[ This methodology has been developed to include cyclisation onto imines ð82TL5676Ł^
see also ð80JA0944Ł[ Heterocyclic ring systems are also suitable substrates for the formation of
carbon!centred radicals via ring expansion ð80T3736\ 81T2274\ 81T3916Ł[ An interesting development
S O• OH
O Bu3SnH, PhH
N
(316) (318)
CHO CHO
•
(317)
Scheme 106
But
O
O
H
O O–
N N
Co hν O
N N O• + Me •
–O O
H
N
But
Scheme 107
is the use of the azido moiety "as in compounds "210## as an aminyl radical precursor[ Cyclisation
followed by b!scission of the intermediate "211# a}orded high yields of ring!expanded lactams "212#
"Scheme 009# ð82JA2217Ł[
O
O V O
VO(OEt)Cl2, CuCl2
+ O
CN OEt OEt
•
(319) (320)
O O
• OEt 63%
OEt
Cl
CN CN
Scheme 108
O •O O
• ( )m
( )m ( )m
•
CO2R CO2R CO2R
( )n ( )n ( )n
n = 0–11; m = 0, 2, 3
Scheme 109
N3 SnBu3 SnBu3 H
O• O O
O
( )m TBTH, AIBN
N N N
( )m • ( )m ( )m
CO2Et
( )n ( )n ( )n
( )n CO2Et CO2Et CO2Et
(321) (322) (323)
n = 1,2; m = 1, 2
Scheme 110
"ii# Decarbonylation
This has been demonstrated to be a preparatively useful method of generating carbon!centred
radicals and three complementary procedures exist[ Pfenninger et al[ treated the phenyl selenoester
"213# with TBTH\ initiated with AIBN\ in an inert aromatic solvent to a}ord the acyl radical "214#[
At higher temperatures\ secondary and tertiary acyl substrates undergo decarbonylation to form
the alkyl radical "215#^ primary and arylacyl substrates do not su}er decarbonylation "Scheme 000#
ð79HCA1217\ 78JOC0666Ł[ Similarly\ Patel and Pattenden demonstrated that\ on sunlamp irradiation\
arylmethyl! and allylacylcobalt salophens "216# undergo homolysis of the acylÐcobalt bond with
subsequent decarbonylation "Scheme 001# ð77TL696Ł[ Unfortunately\ primary and secondary acyl
radicals are stable to decarbonylation ð76TL4838\ 77CSR250Ł[ A noteworthy development involves the
formation of acyl radicals "218# via dehalogenation of acid chlorides mediated by tris"trimethyl!
silyl#silane "TTMSS#[ Thus\ on treatment of primary\ secondary and tertiary acid chlorides "217#
with TTMSS and AIBN in toluene at 79>C\ the nor!alkanes "229# are obtained in high yields
"Scheme 002# ð68JCS"P0#0026\ 89JOM"270#044\ 81TL0676Ł[
O O
OAc •
OAc OAc •
SePh
Bu3Sn• –CO
AcO
AcO AcO
(324) (325) (326)

Scheme 111
Co(salophen)py •
•
hν –CO
O O
N N N
H H H
(327)
N N
Co
O O
CoII(salophen)
Scheme 112
"iii# Decarboxylation
The formation of alkyl radicals via the decarboxylation of carboxylic acids has been known for
some time[ Several methods are outlined below[
O TTMSS, AIBN, toluene, 80 °C O
• R• R H
R Cl R
(328) (329) (340)
Scheme 113
The electrolytic Kolbe decarboxylation generates alkyl radicals which undergo recombination to
form dimers "Equation "85## ð52JA2308\ 52MI 008!93\ 67JA3892\ 70AG"E#800Ł[ If two di}erent acids are
employed\ unsymmetrical compounds result\ the yields of which are increased when an excess of
one acid is used ð67AG"E#36\ 77TL1686\ 77TL1790Ł[ The procedure is\ however\ only useful for primary
and allylic carboxylic acids and overoxidation is a problem[ Diacylperoxides may also be used as
the source of alkyl radicals\ either under thermolytic or photolytic conditions[ This procedure has
very limited advantages over the Kolbe electrolysis[ These advantages include a greater selectivity
under low!temperature photolysis in the solid state\ and the fact that tertiary acids undergo decar!
boxylation ðB!62MI 008!04\ 68COC"0#898\ 74T3102\ 77JA1766Ł[
H H
OAc
CO2H H
O
O
–e–
H (96)
AcO 40%
H O
H
H
AcO
H H
Decarboxylation may be e}ected in the presence of high oxidation!state metals ð53JOC810\

B!62MI 008!05\ 78H"17#378\ 89JHC68\ 80JOC1755Ł[
Thus\ in the presence of catalytic quantities of silver"I#
nitrate or acetate and a peroxo compound "e[g[\ aroylperoxide\ perborate\ percarbonate and per!
oxydisulfate# homolytic alkylation of protonated heteroaromatic systems occurs[ Primary\ sec!
ondary and tertiary carboxylic acids are suitable substrates for this method and a mechanism has
been proposed in Scheme 003 ð60T2464\ 65TCC"51#0\ 67TL508\ 72ACR16\ 74TL3792Ł[ A similar method\
adopting the use of hypervalent iodine compounds\ has been reported by Togo et al[ ð80CL0580\
80TL5448\ 82JCS"P0#1306Ł[ Thus\ on treatment with either "bis"tri~uoroacetoxy#iodo#benzene or
"bis"tri~uoroacetoxy#iodo#!penta~uorobenzene\ tertiary "230# and secondary "231# acids decar!
boxylate to generate the alkyl radical which can subsequently alkylate a heteroaromatic base in
good yields "233 and 234# "Equation "86##[ Primary carboxylic acids "232# are poor substrates for
this procedure and\ with respect to the hypervalent iodine compound\ a three!fold excess of both
acid and base is required[
RCO2H
(PhCO2)2 + Ag+ PhCO2• + PhCO2– + Ag2+ R• + CO2 + H+ + Ag+
Scheme 114
O C6F5I(O2CCF3)2
+ (97)
R OH hν, CH2Cl2
N R N
(341) R = adamantyl (344) R = adamantyl, 85%

(342) R = cyclohexyl (345) R = cyclohexyl, 72%
(343) R = 2-phenylethyl (346) R = 2-phenylethyl, 28%
In 0879\ Barton introduced a novel method suitable for the radical decarboxylation of primary\
secondary\ tertiary\ a\b!unsaturated and aromatic acids ð79CC621Ł[ The procedure involved a TBTH!
mediated dehalogenation of chlorodihydrophenanthrene esters "236#\ to a}ord the radical species
"237#[ Rapid aromatisation followed by decarboxylation a}orded phenanthrene "238# and the
desired alkyl radical "Scheme 004#[ Although there is a broad substrate compatibility\ formation of
the ester was problematic and this instigated further research[ Barton et al[ subsequently discovered
that O!esters of thiohydroxamic acid derivatives\ e[g[\ "249# were reduced\ in a radical chain manner\
on treatment with TBTH "Scheme 005# ð74T2890\ 74TL4832\ 80CRV366\ B!81MI 008!06Ł[ The commercially
available sodium salt of N!hydroxypyridine!1!thione was chosen since both the potential for aro!
matisation and reduction of the thiocarbonyl moiety would assist the fragmentation process
ð64JCS"P0#0463\ 70PAC04Ł[ The O!acyl derivatives of several thio! and selenohydroxamic acid com!
pounds "249Ð246# have since been prepared and their radical fragmentation studied ð72TL4778\
73TL0944\ 75JCS"P0#28\ 81T6980\ 81T6010\ 82TL3494Ł[ The N!hydroxypyridine!1!thione derivative however\
remains the most popular choice and has been utilised frequently in both functional!group trans!
formations and in synthesis ð75PAC564\ 76MI 008!00\ 76S554\ 76T2430\ 77S306\ 77S378\ 78CRV0302\ 81T1418Ł[
A number of simple methods are available to prepare these O!esters "249# in high yields ð72CC828\
73CC0187\ 74T2890\ 77T4368\ 81T6972Ł[ The radical chain process is usually initiated by either thermolysis\
in re~uxing benzene or toluene\ or photolysis using a 149 W tungsten lamp[ On photolysis at low
temperature\ thiohydroxamic ester derivative "249# produces radicals without a subsequent chain
process at −29>C\ while derivative "243# continues a radical chain process at −59>C ð76T1622Ł[
Zard and co!workers have demonstrated that a combination of both heating and irradiating leads
to higher product yields in some addition reactions ð80TL088Ł[ Sonication of thiohydroxamic esters
in carbon tetrachloride has also been reported as a useful method of inducing the halogenative
decarboxylation ð78JOC5090Ł[ Ultrasound is reported to generate the trichloromethyl radical "247#
which initiates fragmentation of the thiohydroxamic ester "249# "Scheme 006#[
O O
R O R O
Cl Bu3Sn•
• + Bu3SnCl R• + CO2 +
PhH, 80 °C
(347) (348) (349)
Scheme 115
Bu3Sn• Bu3SnH
O
O –CO2
N R• R H
R O
R O•
S Bu3SnSpy Bu3Sn•
(350)
Scheme 116
0[08[2[1[2 CarbonÐhalogen bond scission

The homolysis of a carbonÐhalogen bond is an important method of forming carbon!centred
radicals and many procedures have been described[ The most important involves removal of the
halogen atom by trialkyltin radicals\ themselves formed via one of the initiation procedures described
above "Equation "87## ð57ACR188\ 74AG"E#442\ 75PAC564\ 76S554\ 77S306\ 77PAC0548\ 80CRV0126Ł[ The
halogen atom can be chlorine\ bromine or iodine\ ~uorine being essentially inert "see ð57CJC522\
62JCS"P1#0469\ 74JOC1038Ł#[ The reactivity follows the order iodine×bromine×chlorine\ with rate
constants in the order of ½ 098\ 096 and 091 M−0 s−0\ respectively ðB!72MI 008!90Ł[ Thus\ it is possible
to selectively generate a carbon radical by homolysis of a carbonÐbromine bond in the presence of
a carbonÐchlorine bond "Equation "88## ð68JOC040Ł[ The nature of the alkyl group is also an
in~uential factor and the ease of radical formation for simple alkyl substrates follows the expected
order\ tertiary×secondary×primary[ Several tin reagents are available for this reaction^ however\
tributyl! and to a lesser extent\ triphenyltin hydride\ are most frequently used ð77OM1119Ł[ The
R1 MeS S
RCO2 N N RCO2
R2CO2 N RCO2 N N
S Ph
Se
Se Ph R1 N
S
(351) (352) R1 = Me or Ph (353) (354) R1 = Ph, 4-MeOPh or 1-naphthyl
O
O S
Me
N RCO2 Me
N N
S N N O2CR
N
O2CR
(355) (356) (357)
ultrasound
CCl4 Cl3C• + Cl•
(358)
O CCl4
O –CO2
N R• R Cl
R O
R O•
S Cl3CSpy Cl3C•
(350) (358)
Scheme 117
reactions are generally performed in re~uxing benzene or toluene solution under AIBN initiation\
although other solvents\ with polarities ranging from cyclohexane to methanol\ have been used[
Light and Breslow have developed a water!soluble tin hydride reagent which reduces alkyl halides
in either water or organic solvents ð89TL1846\ 82OS"61#088Ł[ Tributylgermanium hydride is also
e}ective in the formation of carbon!centred radicals from alkyl halides\ though the germyl radical
has a reduced rate of halogen atom abstraction which can result in a poor chain propagation step
ð72JA2467\ 73JA232\ 74TL5178\ 74JA3484\ 75JA4782\ 76JOC2498\ 77T5184Ł[ Removal of the tin residues from
the reaction mixture is a major problem with the use of these reagents^ however\ several work!up
procedures have been developed ð68S360\ 68JOC338\ 70JCS"P0#1252\ 78JOC2039Ł[ The use of catalytic
quantities of a tin reagent\ in conjunction with either lithium aluminum hydride\ sodium borohydride
or diisobutylaluminum hydride\ has been developed to reduce this problem ð52JOC1054\ 62JOC2944\
64JOC1443\ 66TL3180\ 67MI 008!92\ 73CL1958\ 75JA292Ł[ Organotin reagents have also been immobilised
on polymers\ alumina and silica\ thus allowing removal of the tin residues by simple _ltration
ð64JOC0855\ 70AG"E#0932\ 71JA4453\ 80JOC4860\ 81JCS"P0#2054\ 82SL172Ł[
k
R3Sn• + R–X R3Sn–X + R• (98)
AcO AcO
O O
OH OH
F F
Bu3SnH, AIBN
(99)
Br H
O O
Cl Cl
Chatgilialoglu has introduced tris"trimethylsilyl#silane "TTMSS# as an excellent alternative to tin

hydrides[ Although the siliconÐhydrogen bond strength is greater\ comparative studies have shown
this reagent to be equally e}ective in the formation of carbon!centred radicals for use in synthesis
ð76JA4156\ 77JOC2530\ 78JOC1381\ 78TL1622\ 78TL570\ 80JOC567\ 82SL032Ł[ The use of both tris!
"alkylthio#silane and a triethylsilane:thiol system have also been shown to be useful alternatives
ð78CC0276\ 89SL108\ 81ACR077Ł[ A solution developed by Barton et al[ adopts the use of dialkyl
phosphites and hypophosphorous acid[ This method has been demonstrated to be useful for sec!
ondary and tertiary alkyl iodides and bromides ð81TL4698\ 82JOC5727Ł[ Giese and Thoma have shown
that the dimeric metal complex dicarbonyl "h4!cyclopentadienyl#iron "248# undergoes metalÐmetal
bond cleavage on irradiation with a 149 W sunlamp to generate the iron!centred radical species
"259#[ This subsequently abstracts a halide atom to a}ord the carbon!centred radical "Equations
"099# and "090##[ However\ the reaction is limited to alkyl iodides and activated bromides ð78TL1896\
80HCA0032Ł[ Decacarbonyldimanganese "250# also generated carbon!centred radicals via this metalÐ
metal bond homolysis and subsequent iodine atom abstraction process ð80HCA0024Ł[
O
Cp CO hν
2 Cp(CO)2Fe• (100)
Fe Fe
OC Cp
O
(359) (360)
Cp(CO)2Fe• + R–X Cp(CO)2FeX + R• (101)
(360)
CO CO
CO CO
OC Mn Mn CO
OC OC
CO CO
(361)
Samarium"II# iodide reacts with alkyl halides to generate radicals^ however the method is
extremely solvent!dependent[ When the reaction is performed in THF\ only primary alkyl iodides
and bromides are e}ective substrates\ but on addition of HMPA\ primary\ secondary and tertiary
halides become e.cient radical precursors ð81CRV18\ 81SL832Ł[ Some bimolecular rate constants for
the reduction of primary alkyl radicals have been reported[ These constants were dependent on the
amount of HMPA added\ varying from 4×094 to 6×095 M−0 s−0 ð82TL0606Ł[ Low oxidation state
salts of chromium ð81CB176\ 82CB0648Ł\ iron ð77T3560Ł and nickel ð82JCS"P0#1228Ł have also been
shown to be e}ective in the homolytic dehalogenation of alkyl bromides and iodides[ Representative
examples are given in Equations "091#Ð"093# "see also ð83CRV408Ł#[
PO(OEt)2
Br
CrCl2, (CH2NH2)2, DMF

+ (102)
PO(OEt)2 84%
CO2Me
Cl
FeCl2, P(OEt)3 Cl
PhH, 165 °C
+ O (103)
88%
CO2Me
O
64 : 36
Br
Br
Ni+, MeCN, Ph2PH
+ + (104)
78% N O N O
N O N O
Ts Ts Ts Ts
86 : 10 : 4
0[08[2[1[3 CarbonÐchalcogen bond scission
"i# CarbonÐoxyèn bond scission

Homolytic cleavage of the carbonÐoxygen bond of alcohols was initially investigated by Barton
and McCombie ð64JCS"P0#0463\ 70PAC04\ B!81MI 008!06Ł[ A number of secondary alcohols were con!
verted into thiocarbonyl derivatives "251Ð258# which were subsequently transformed into the parent
hydrocarbon\ on treatment with TBTH[ It has been demonstrated that the mechanism involves the
reversible addition of a tributyltin radical to the thiocarbonyl moiety "e[g[\ 258# to form the
intermediate radical "263#\ followed by homolytic scission of the carbonÐoxygen bond\ generating
the carbon!centred radical and a carbonyl species "264# "Scheme 007#[ The tin intermediate "264#
subsequently fragments to the tin sul_de "265# and COS ð77JCS"P0#0406\ 78CRV0302\ 89TL2880\
80JCS"P0#0062Ł[ Since this initial work\ several alternative derivatives have been demonstrated to be
useful carbon centred radical precursors "269Ð262# ð72T1598\ 75PAC564\ 76S554\ B!81MI 008!06Ł[
S
S X S
R
O N R R R1 R2
O O Ar O X
N
(362) (363) (364) X = S, Ar = Ph (369) X = S, R2 = Me
(365) X = S, Ar = 4-MeOPh (370) X = S, R2 = Ph
(366) X = S, Ar = 4-MeSO2Ph (371) X = O, R2 = Me, Ph or aryl
(367) X = S, Ar = 2,4-MeO2Ph
(368) X = Se, Ar = Ph
S O
R R O
O N O N
O
O O
(372) (373)
S SnBu3 SnBu3
S S
R + •SnBu3 R• +
O SMe R
O • SMe O SMe
(369) (374) (375)
MeSSnBu3 + COS
(376)
Scheme 118
Primary alcohol derivatives\ as might be expected\ require the most forcing conditions to fragment^
hence it is necessary to heat a solution of xanthate esters "258# to 049>C[ Thus\ on slow addition of
TBTH in p!cymene at 049>C\ the hederagenin xanthate derivative "266# a}orded methyl oleanolate
"267#\ via the primary radical species "Scheme 008#[ The use of thiocarbonyl imidazolide "251# and
thiobenzoate "253# derivatives\ in conjunction with TBTH\ however\ is e}ective at the slightly lower
temperature of 029>C "compare ð70S632Ł with ð89TL1454Ł#[ Barton et al[ have since systematically
investigated the use of a variety of silanes in alliance with thionocarbonate derivatives of type "260#[
Hence\ on initiation with triethylborane:oxygen in the presence of diphenylsilane\ these primary
alcohol derivatives are reduced to the parent hydrocarbon in high yields at 79>C ð89TL3570\ 80T7858\
80SL324\ 80TL6076Ł[ Thus\ not only is the reaction temperature lowered but the use of toxic TBTH is
eliminated[ AIBN and benzoyl peroxide may also be used to initiate this silane chemistry^ however\
large quantities are required\ indicating a short radical chain process ð81ACR077Ł[ Similarly\
dialkylphosphites and hypophosphorus acid e}ect the reaction in re~uxing dioxan solution
ð81TL4698\ 82JOC5727Ł[ A cautionary note should be mentioned with regard to the generation of
carbon!centred radicals from the precursory primary thiocarbonyl derivatives[ If the substrate
contains homoallylic unsaturation\ the radical intermediate may be captured to a}ord a lactone[
Three groups have developed synthetically useful lactonisation procedures that adopt this meth!
odology "Equations "094# and "095## ð77TL5016\ 78JOC0123\ 78CC0154\ 80JCS"P0#0062\ 81JOC5792Ł[
CO2Me TBTH
p-cymene
H
150 °C 65%
HO HO HO
H H H
•
O (378)
S
SMe
(377)
Scheme 119
H S
TBTH, AIBN
O (105)
O SMe TolH, 80 °C
71% H
S
TMS TMS
i, TBTH, TolH, –78 °C
S SMe ii, H3O+
O (106)
O 98%
O
The formation of carbon!centred radicals from the corresponding secondary alkyl derivatives
"251Ð260# is an exceptionally facile process that has been utilised frequently in synthesis[ The
reactions proceed at a lower temperature to that of their primary analogues\ even at −19>C
with the triethylborane:oxygen initiation procedure ð74SC390\ 75JOC1502\ 77TL5014\ 89JA1923\ 81TL5518\
81T1418Ł[ Although all of the methods available for the generation of primary radicals are applicable
to the generation of secondary radicals\ xanthate "258# and thionocarbonate derivatives "260# are
more commonly used "Equation "096## ð70JA821\ 72JA3948\ 78TL1508\ 81T6324\ B!81MI 008!06\ 82JOC4917Ł[
An interesting and potentially useful development is the use of O!acetyl thiohydroxamic ester "268#
in place of the alkyltin or alkylsilane reagent ð80TL1692\ 81T6098Ł[ Irradiation with visible light at
39>C a}orded the methyl radical which reacts with the thiocarbonyl moiety of xanthate "279#[
Subsequent b!scission of the carbonÐoxygen bond a}orded the secondary cyclododecyl radical "270#
which\ on reaction with a second molecule of the thiohydroxamic ester derivative "268#\ carries the
chain "Scheme 019#[ A polystyrene!supported organotin hydride has also been reported to e}ect the
radical deoxygenation of secondary alcohols after conversion to either their methyl xanthate "258#
or thionocarbonate derivatives "260# ð81SL790Ł[
C5F5O
S O
O O
OSiEt3 OSiEt3
TBTH, TolH
AIBN, 90 °C
HO HO (107)
99%
HO O HO O
BzO BzO
AcO AcO
The thiocarbonyl derivatives "251\ 253Ð261# work well for primary and secondary carbonÐoxygen
bonds\ but due to the facile Chugaev reaction at elevated temperatures\ their use is limited with
tertiary substrates[ Four methods have now been reported for the formation of carbon!centred
radicals from tertiary alcohols[ The _rst solution\ reported by Pfenninger et al[\ adopted the use of
a selenocarbonate derivative "271# ð79HCA1217Ł[ Treatment with TBTH and AIBN in a re~uxing
benzene solution e}ected deselenylation\ to a}ord the formyl radical "272# which subsequently
decarboxylated to generate the carbon!centred radical "273#[ Hydrogen atom abstraction from
S O
N visible light O
S•
O N
N
O S
+ Me•
(379) (379)
O S • S N
SMe
(380) O (381)
Me•
MeS SMe
Scheme 120
TBTH gave the deoxygenated compound "274#[ Trapping of the intermediate formyl radical with
TBTH also occurred\ to give the formate "275# "Scheme 010#[ Barton|s initial solution for the
generation of carbon!centred radicals from tertiary alcohols was to use the thermally more stable
thioformate ester derivatives "252# ð71TL1908Ł[ However\ the synthesis of these radical precursors is
not easy[ Thus\ Barton and Crich have developed a facile method which incorporates the radical
chemistry of O!esters of thiohydroxamic acids ð73CC663\ 74TL646\ 75JCS"P0#0592Ł[ The mixed half
esters of oxalic acid "262# are conveniently prepared from the tertiary alcohol\ oxalyl chloride and
the sodium salt of N!hydroxypyridine!1!thione[ As with the radical decarboxylation procedure
either heating or irradiation with a tungsten lamp is su.cient to initiate the radical chain process\
a}ording the tertiary carbon radical\ the thiyl radical and two equivalents of carbon dioxide
"Equation "097##[ Barton et al[ have also demonstrated the utility of the O!acetyl thiohydroxamic
ester "261# derivative in the formation of tertiary carbon!centred radicals from methyl xanthate
derivatives[ The fragmentation is e}ected by photolysis with a 499 W tungsten lamp at 9Ð39>C\
hence the competing Chugaev elimination is suppressed "Scheme 019# ð82TL1622Ł[
O Et3CSH
R–H + 2CO2 + (108)
O N heat or hν SCEt3
R O N S
O S
(372)
Selective formation of carbon!centred radicals parallels the stability of the generated radical[
Thus\ Dolan and MacMillan have shown that deoxygenation of the secondary allylic derivative
"276# does not occur under the conditions required to transform the tertiary allylic compound "277#
into the deoxy compound "278# ð74CC0477Ł[ A similar deoxygenation of a tertiary centre was e}ected
in the presence of a secondary\ cyclic thionocarbonate moiety "Equation "098## ð77TL170Ł[
S S
O O
O S TBTH, xylene O
N 140 °C
N (109)
H O H H
74%
O O
O O
In general\ when cyclic thionocarbonates are formed from a primary and either a secondary or
tertiary alcohol moiety\ the radical is generated at the most substituted centre ð66JCS"P0#0607\ 74T3142\
82TL7134Ł[ There are\ however\ exceptions to this generality and the cleavage of a primary over a
secondary carbonÐoxygen bond was explained in terms of the bond!angle strain energy ð89JOC0305Ł[
With cyclic thionocarbonate systems involving secondary and either secondary or tertiary carbonÐ
oxygen bonds\ product mixtures may arise "Equations "009#Ð"001## ð66JCS"P0#0607\ 67HCA589\ 74T3142\
76TL4862\ 78CRV0302Ł[
O
SePh O
O •
TBTH, AIBN O •
PhH, 80 °C 81%
O
(382) (383) (384) (385)
15%
(386)
Scheme 121
O O O
OMe
O
O O O O
MeO O
OAc O
O AcO AcO
O
CO2Me CO2Me CO2Me

(387) (388) (389)
O O
O O O O
(110)
O O
O O O O
HO
S
O O O
O O O O O O
+ (111)
O O O
O O O O HO O
OH
S
AcO OMe
O HO OMe HO OMe
O O
+ (112)
O O
OH OH
S
Lowinger and Weiler have developed a novel method for the generation of carbon!centred radicals
from epoxides ð89CJC0525\ 83CRV408Ł[ Treatment of the epoxide "289#\ in THF solution\ with two
mole equivalents of bis"cyclopentadienyl#titanium"III# chloride e}ected homolytic scission of one
carbonÐoxygen bond to form a carbon radical "Scheme 011#[ The reaction seems to proceed\ as one
would predict\ via the radical intermediate "280#[
O •
• Cp2(Cl)TiO
Cp2TiCl Cp2(Cl)TiO Cp2TiCl
(390) (391)
Cp2(Cl)TiO Ti(Cl)Cp2
Scheme 122
"ii# CarbonÐsulfur bond scission

Unlike their alcohol counterparts\ thiols readily undergo desulfurisation via a radical chain
mechanism[ Hence\ on treatment of the thiol with trialkyl phosphite\ in the presence of either AIBN
or light\ reductive desulfurisation occurs according to the mechanism described in Scheme 012
ð45JA5303\ 46JA4215\ 48JA0132Ł[ Thiols are similarly desulfurised on treatment with two equivalents of
TBTH and AIBN "Equation "002## ð71JA1935\ 74TL024Ł[ The ability of a substrate to undergo
desulfurisation mirrors the relative stability of the generated radical\ benzyl¼allyl×
tertiary×secondary×primary×methyl ð71TL332\ 73JOC4195\ 75AJC66Ł[ The formation of carbon!
centred radicals from the corresponding sul_de is a more energetically demanding process and these
compounds are rarely used as radical precursors[ Phenyl sul_de derivatives\ however\ have been
applied in a limited number of synthetically useful reactions since the phenylÐsulfur bond is not
a}ected under the reaction conditions "Equation "003## ð72JCS"P0#392\ 76S554\ 81CC502Ł[
AIBN •
RSH + P(OEt)3 RS• + P(OEt)3 RS P(OEt)3
∆ or hν
RSH
R• + SP(OEt)3 RH + RS•
Scheme 123
TBTH, AIBN
PhH, ∆
(113)
O 80% O
HS
O O
TBTH, AIBN AcO

O O
AcO PhH, ∆
(114)
O O
92%
MeO
MeO
SPh
"iii# CarbonÐselenium bond scission

In contrast to their sulfur analogues\ the homolytic scission of carbonÐselenium bonds is a
relatively easy process and has frequently been adopted for the generation of carbon!centred radicals
ð67CC30\ 76S554\ 77PAC0548\ 80JCS"P0#0322\ 82JOC5746Ł[ Primary\ secondary and tertiary radicals have
been generated from their phenylselenyl precursors[ Typically\ the selenide substrate is treated with
triphenyltin hydride in re~uxing toluene^ however\ a more facile reaction occurs at lower tem!
peratures under AIBN initiation "Equation "004## ð79JA3327Ł[ Tributyltin hydride and tris"trimethyl!
silyl#silane "TTMSS# may also be used ð89CC0464\ 89T434\ 80JCS"P0#1686\ 80JOC567\ 81ACR077Ł[ A novel
photosensitised one!electron reduction of primary and secondary phenylselenyl compounds has
been reported ð82CC0525Ł[ The selenides were irradiated with a 349W Hanovia medium pressure
lamp "l×179 nm# in an isopropanol solution containing 0\4!dimethoxynaphthalene "DMN# as
sensitiser and ascorbic acid as co!reductant[ Yields of the reduced compounds were in the range
79Ð89) "Scheme 013#[ Kataoka et al[ have also demonstrated that single electron transfer "SET#
can e}ect the reductive cleavage of seleniumÐ and sulfurÐcarbon bonds of cyclic onium salts via a
carbon!centred radical "Scheme 014# ð89JCS"P0#2906Ł[
O-TBDMS O-TBDMS
Me2OC Me2OC
Ph3SnH, AIBN
PhH, ∆
(115)
Ph 78% Ph
H H
SePh
–•
O PriOH, λ 280 nm, 3 h O
+ DMA* DMA+• +
SePh 90%
SePh
Degradation e– (AA)
O O
• + PhSe– + PhSeSePh
Scheme 124
Mg, SET
+ sonication SeMe
THF, RT
BF4– •
Se Se
Me 86% Me •
SeMe
Scheme 125
"iv# CarbonÐtellurium bond scission

The homolytic cleavage of a carbonÐtellurium bond is an even more facile process than that with
selenides[ The formation of carbon!centred radicals occurs either at room temperature for secondary
or at 79>C for primary substrates\ on treatment with triphenyltin hydride[ Addition of any initiator
to the reaction mixture is unnecessary ð79JA3327Ł[ Although information in the literature is limited\
the homolytic cleavage of a carbonÐtellurium bond appears to be very selective and seems to parallel
the ease of radical formation[ An understanding of this selectivity has been successfully applied by
Barton et al[ in an elegant extension of the thiohydroxamic ester chemistry[ A methyl radical
generated from the O!acetyl thiohydroxamic ester derivative "268# generated under standard
conditions\ was allowed to react with anisyltelluride derivatives "281#\ liberating the more stable
secondary radical "282#[ This radical subsequently undergoes typical radical addition and:or sub!
stitution reactions "Scheme 015# ð77TL5470\ 89JA780\ 81JA4893\ 81T8150\ 82JA7949Ł[
S
N visible light
O N
O
•S
(379) + Me•
R1 R1
Te OMe •
R2 R2
(392) (393)
MeTe OMe
Scheme 126
0[08[2[1[4 CarbonÐnitrogen bond scission
"i# Azoalkanes
Homolysis of the carbonÐnitrogen bond in azoalkanes "283# can be e}ected either by thermolysis
or photolysis over a wide temperature range\ to a}ord a carbon!centred radical or biradical and
nitrogen gas ð79CRV88Ł[ They are therefore\ probably the cleanest and most convenient source of
radicals and are frequently used as initiators in radical reactions[ The ease of homolysis\ as expected\
parallels the relative stability of the formed radical\ benzyl×tertiary×secondary×primary[ With
cyclic azoalkanes\ release of ring strain is also a contributory factor[ There are two mechanistic
possibilities for this fragmentation\ either simultaneous or stepwise carbonÐnitrogen bond scission[
It is now believed that for symmetrical azoalkanes\ the simultaneous pathway is followed while\ for
unsymmetrical compounds\ there is a continuum between the two[ The more unsymmetrical the
compound\ the greater the tendency to proceed via a diazenyl radical "284# "Scheme 016#[ The
synthetic potential of this method for generating carbon!centred radicals has been demonstrated by
Little and co!workers in the synthesis of several ring systems "Equation "005## ð68JA6018\ 70JA1633\
70TL3278\ 74TL2306\ 74JOC1399\ 74JOC2839\ 81SL096Ł[ Taber et al[ have proposed a radical chain mech!
anism for the reductive cyclisation of a ketone tosylhydrazone "Scheme 017#[ They propose the
monoalkyl diazene "286# is formed on reduction of the hydrazone "285# with NaBH2CN:ZnCl1\
which subsequently fragments to form the carbon radical intermediate "287# ð82TL5198Ł[
hν or ∆ R1 hν or ∆ R1
2R1• + N2 N N R2• + R1• + R2• + N2
R1 = R2 R1 ≠ R2 N N•
R2
(394) (395)
Scheme 127
OMe
MeO MeO
OMe OMe
THF, ∆, NH4Cl, H2O, acetone
OMe (116)
70%
O
N
N
CO2Et CO2Et CO2Et

NaBH3CN, ZnCl2
THF, ∆
N 66% N N
HN N N•
Ts H
(396) (397)
CO2Et CO2Et
CO2Et
•
•
(398)
Scheme 128
"ii# Isocyanides\ isothiocyanates and isoselenocyanates

Primary\ secondary and tertiary isocyanides react with TBTH to generate carbon!centred radicals
ð57JA3071\ 68TL1180\ 79JCS"P0#1546\ 79S57Ł[ This process is initiated with AIBN and is temperature!
dependent^ however\ very little is known about the mechanism ð67JCS"P1#0202Ł[ As noted with
previous radical precursors\ ease of radical formation parallels the stability of the generated radical[
Consequently\ while tertiary and secondary isocyanides a}ord radicals in either re~uxing benzene
or toluene solution\ primary substrates require the higher temperatures a}orded by a re~uxing
xylene solution[ Barton et al[ demonstrated that this phenomenon allowed selective formation of
secondary and tertiary radicals over their primary counterparts ð79JCS"P0#1554Ł[ In a re~uxing
benzene solution\ the tetraisocyanide derivative "288# was completely deaminated\ however\ at 69Ð
61>C\ the primary isocyanide moiety was una}ected "Scheme 018#[ It should be noted that the
formation of the primary radical is at an unusually low temperature and this was attributed to the
b!oxygen e}ect ð71CC336Ł[ Chatgilialoglu and co!workers have investigated the ability of silanes to
e}ect the generation of radicals from isocyanides ð89SL108\ 89TL5902\ 80JOC567\ 81ACR077Ł[ With these
silane reagents\ there is no temperature dependence and a facile reductive homolysis of primary\
secondary and tertiary isocyanides occurs at about 64>C[ A tertiary isocyanide has also been
reduced via a radical chain process using hypophosphorus acid ð82JOC5727Ł[ Isothiocyanates and
isoselenocyanates also form carbon!centred radicals\ via the intermediary of the isocyanide
ð79JCS"P0#1546\ 79JCS"P0#1554\ 70CC890Ł[
NC
NC
AcO O O
AcO O
AcO AcO AcO
TBTH, AIBN TBTH, AIBN AcO
O PhH, ∆ CN PhH, 70–72 °C
O
AcO AcO NC O
81% 63% AcO
AcO AcO
AcO
NC
(399)
Scheme 129
"iii# Nitroalkanes
The reduction of aliphatic nitro compounds with TBTH has been reported ð70JA0446\ 70TL0694Ł[
Tertiary nitro compounds are the most e}ective in generating radicals\ though secondary systems
are also useful[ However\ a primary nitro moiety is inert to this TBTH!mediated reaction[ Typically\
tertiary and allylic substrates react with about one equivalent TBTH and AIBN at 79>C while
secondary substrates require the higher temperatures a}orded by toluene and about _ve equivalents
of hydride ð72HCA1109\ 74T3902\ 75S582\ 76S554\ 82T4078Ł[ The mechanism has been the subject of several
studies and is now believed to proceed via addition of the tributyltin radical to the nitro compound
"399# to a}ord the nitroxide radical "390#[ Subsequent b!scission of the carbonÐnitrogen bond
a}orded the carbon!centred radical "Scheme 029# ð76CB0086\ 77BCJ2518\ 89JOC2210\ 82T8968^ compare
with 70JA0446Ł[
SnBu3
NO2 •O O •
Bu3Sn•
N + ONOSnBu3
R1 R3
R1 R3 R2
R2 R1 R3
R2
(400) (401)
Scheme 130
0[08[2[1[5 CarbonÐboron bond scission

Homolytic scission of a carbonÐboron bond may be induced thermally\ on initiation with either
AIBN or diacylperoxides\ photochemically and by the slow addition of air "oxygen# ð69JA601\
69JA603\ 61AG"E#581\ 68COC"2#680\ B!75MI 008!93Ł[ The latter method is becoming an important low!
temperature method for the initiation of radical reactions associated with other functional groups
ð77TL5014\ 77TL5016\ 78BCJ032\ 89JA1923\ 89TL2880\ 89TL3570\ 80T7858\ 81T1418\ 82JA09353\ 82TL0206Ł[ Again\
the ease of radical formation parallels the stability of the generated radical\ tertiary×
secondary×primary[ Thus\ with B!alkylborinanes\ it has been demonstrated that generation of
either a secondary or tertiary carbon!centred radical occurs in preference to the primary radical
"Scheme 020# ð60JA2666Ł[ This phenomenon was utilised to circumvent the ine.ciency of free!
radical addition reactions[ With simple trialkylboranes\ only one of the three alkyl groups participate
in the reaction\ thus any reaction can only be 22) e.cient ð57JA3054Ł[ However\ if two sacri_cial
substituents are introduced\ as in B!alkylborinanes and alkyldiphenylboranes\ the reaction can
achieve a 099) e.ciency with respect to the synthetically useful alkyl group ð60JA2666\ 67JOM"045#090^
see also 60JA0913\ 75T4412Ł[
O
O
THF, O2
B •
90%
Scheme 131
0[08[2[1[6 CarbonÐcobalt bond scission

Carbon!centred radicals are e.ciently generated from a variety of alkylcobalt"III# species
ð72ACR232\ 77CSR250\ 77S378\ 83CRV408Ł[ Pioneering work by Sche}old established the use of vitamin
B01 catalysis in the chemical\ electrochemical and photoelectrochemical reduction of alkyl halides[
Homolytic scission of an intermediary cobaltÐcarbon bond generates the carbon!centred radical
"Equations "006#Ð"019## ð79JA2531\ B!72MI 008!94\ 76OM0595\ 76PAC252\ 89T2044Ł[ This facile homolytic
cleavage has now been extended to include the more readily available bis"dimethylglyoximato#
"dmgH# "391#\ N\N!ethylenebis"salicylidaminato# "salen# "392# and N\N!phenylenebis!
"salicylidaminato# "salophen# "393# derivatives[ Typically\ carbon!centred radicals are a}orded on
either sunlamp irradiation or thermolysis and the value of this method has been demonstrated
by several groups "Equations "010# and "011## ð71JOC0664\ 74JOC4764\ 75JA3689\ 78JOC0219\ 89SL055\
89JCS"P0#1580\ 89JCS"P0#1692\ 89JCS"P0#1698\ 81T8262\ 82CB0076Ł[
O Br O O H
( )n ( )n
B12a
( )n + (117)
electrolysis
90% n = 3; 0:100
95% n = 4; 100:0
80% n = 5; 88:12
Br H
( )n ( )n
B12a ( )n
+ (118)
electrolysis
O O O
90% n = 3; 0:100
95% n = 4; 100:0
85% n = 5; 53:47
EtO OEt
O
O O B12a, hν
Br
electrolysis
+ (119)
C5H11 47% C5H11
TBDMS-O O
TBDMS-O
Br
B12a, Zn EtO
(120)
EtO O O
R
H
O O– R
R
N N N N
Co Co N N
N N O O Co
–O O N O O
H N
N
(402) (403) (404)
CO2Et
Co(salophen)py
CO2Et hν, CH2Cl2

+ (121)
O 65% O
OEt
O OBn OEt O OBn
py(dmgH)2Co hν, EtOH NC
+ (122)
HO OH CN 81% HO OH
OH OH
0[08[2[1[7 CarbonÐmercury bond scission
The generation of free radicals via homolysis of a carbonÐmercury bond\ often called {the mercury
method|\ is a well!documented and important process^ however\ it has now largely been surpassed
by the use of tin hydrides ð74AG"E#442\ B!75MI 008!93\ 77CRV376\ 78ACR0\ 80COS"3#604Ł[ The importance
of the former method lies in both the ease of alkylmercurial preparation\ especially in relation to
the solvomercuration reaction and subsequent radical formation ðB!75MI 008!95Ł[ Alkyl radicals may
be generated by both photolysis and thermolysis\ on addition of AIBN^ however\ the most common
method is reduction in the presence of hydrogen donors such as sodium borohydride or tributyltin
hydride\ to the unstable mercuric hydride "Scheme 021# ð66CB1477\ 73CB2064\ 73TL4128Ł[ Primary\
secondary and tertiary alkylmercuric halides\ acetates and nitrates are compatible with this
procedure[ Representative examples are depicted in Equation "012#\ Schemes 022 and 023 ð71CB1415\
73TL1632\ 73JCS"P0#610Ł[ More speci_c methods that involve mercury in the generation of alkyl radicals
include electrochemical\ autoxidation\ halodemercuration and the use of photosensitised mercury
and metallic salts ð77CRV376Ł[
NaBH4
RHgX RHgH RHg• R• + Hg
Scheme 132
i, Hg(NO3)2
ii, NaBH4
or + TsNH2 N (123)
97–99%
Ts
O O OMe CN O OMe
HO HO i, TBTH, HO
Hg(OAc)2, MeOH ii, Ac2O
HO HO HgOAc 72% HO CN
OH OH OH
Scheme 133
HgOAc CO2Me
Hg(OAc)2, MeOH NaBH4, CO2Me
OMe 74% OMe
Scheme 134
0[08[2[2 Radicals by Addition to C1C

The addition of heteroatom!centred radicals to carbonÐcarbon double bonds\ with concomitant
formation of a carbon!centred radical\ has been known for many years[ This anti!Markovnikov
addition process is well understood and there are several review articles that discuss this process
ð52OR"02#80\ 52OR"02#049\ 69AG"E#162\ B!62MI 008!06\ 77S378\ 80CRV0126\ 80COS"3#604Ł[ However\ many of
these reactions are not useful\ being superseded by the hydroboration and heteroatom mercuration
methods "Sections 0[08[2[1[5 and 0[08[2[1[7\ respectively#[ Outlined below are some of the preferred
methods of forming carbon!centred radicals by the addition of heteroatom radicals to carbonÐ
carbon double bonds[
0[08[2[2[0 The addition of oxygen!centred radicals to C1C

Oxygen!centred radicals are high energy species that typically undergo b!scission and atom
abstraction reactions "see Sections 0[08[2[1[0 and 0[08[2[1[1"i##[ Intramolecular cyclisations\
however\ are possible when a C1C double bond is suitably positioned within the substrate[ Thus\
oxygen!centred radicals a}ord _ve! and six!membered ring systems in high yielding cyclisation
reactions "Equations "013#Ð"015## ð64JOC2503\ 73JOC0234\ 76TL3900\ 80TL34\ 80TL38Ł[
O O
O hν
(124)
N 70%
O O
S
S
N
OH HgO, I2, hν O O I
O
(125)
68%
di-t-butyl peroxalate, PhH
HOO
+ + + (126)
H O H O O O
OH OH HO H HO H
68 : 21 : 8 : 3
0[08[2[2[1 The addition of sulfur!centred radicals to C1C

Thiyl radicals are readily generated from thiols either on photolysis or treatment with radical
initiators[ These radicals are known to undergo reversible addition to alkenes at the least!hindered
carbon atom[ These properties have been used by the groups of Singleton and Feldman in syntheses
of cyclopentane and cyclohexane systems\ respectively\ from cyclopropyl substituted alkenes
ð89TL712\ 89TL4440\ 82SL716Ł[ Feldman has also demonstrated the utility of this additionÐelimination
process in the preparation of the brefeldin ring system ð82JOC5740Ł[ Sulfonyl radicals also add to
carbonÐcarbon double bonds to a}ord the carbon!centred radical in preparatively useful reactions
"Equations "016#Ð"029## ð75JA3457\ 89T2950\ 80T4314\ 80JCR"S#0\ 80JOC1068\ 81JOC5007Ł[
ButO
SO2Ph
(BunS) 2, hν
+ OBut (127)
81%
SO2Ph
O
(PhS)2, AIBN
O Ph PhCl, hν
CO2But
+ (128)
O Ph 51%
CO2But
O
O O
Cl (PhS)2, AIBN H
Cl H O PhH, hν Cl (129)
O 61%
Cl
O H
EtO2C CO2Et EtO2C CO2Et
TsBr, hν
MeCN
(130)
69%
Ts CO2Me
CO2Me
Br
0[08[2[2[2 The addition of nitrogen!centred radicals to C1C

It has been demonstrated that the addition of nitrogen!centred radicals to carbonÐcarbon double
bonds is a reversible process[ The intramolecular aminyl radical cyclisation is also substrate!
dependent and has been shown to require an activated carbonÐcarbon double bond ð81TL3882\
82TL4412Ł[ However\ dialkylamminium radicals participate in both facile and high!yielding radical
addition reactions[ These reactions can be either intramolecular additions "with unactivated double
bonds# or intermolecular additions "with electron!rich alkenes# ð76JA2052\ 89TL0564\ 89T1206\ 89T1218\
89T1234\ 80JOC0298Ł[ Amidyl radicals have a similar reaction pro_le ð81TL4802\ 82CB0060\ 82TL5766\
82JOC3822Ł[ Representative examples of amminium and amidyl radical addition reactions are
depicted in Equations "020#Ð"023#[
S ButSH, PhH
O 50 °C
+ + Spy (131)
N 80% H N N
O N N Bu Bu
Bu Bu
100 : 0 : 0
S ButSH, PhH
O 50 °C
+ + Spy (132)
N 87–100% H N N
O N N Bu Bu
Bu Bu
acid = CH3CO2H, CH2(CO2H)2, 4–100 : 0–43 : 0–69
CF3CO2H
S hν, MeCN
O CH2(CO2H)2 Bu OEt
+ OEt (133)
N Bu 58% N N
O N Bu S
Bu
O Ph
S
Ph hν, (PhSe)2 N
(134)
N 70% SePh
O N
0[08[2[2[3 The addition of group IV!centred radicals to C1C

The addition of carbon!centred radicals to a carbonÐcarbon double bond is arguably the most
synthetically useful of these processes and Chapter 0[97 discusses this in detail[ The addition of
stannyl\ germyl and silyl radicals to carbonÐcarbon double bonds\ to a}ord the adduct carbon!
centred radical\ are preparatively useful procedures ð52OR"02#049\ B!62MI 008!06\ 77JOM"239#206\
80JCR"S#105\ 81JOC2883Ł[ The precursory Group 3 radicals\ generated by the typical initiation pro!
cedures described above\ add regioselectively to the least!hindered terminus of the double bond[
The addition of stannyl radicals to carbonÐcarbon double bonds has also been demonstrated to be
reversible[ With respect to silyl radicals\ Chatgilialoglu et al[ have illustrated that the addition
process is extremely facile and both electron!rich and electron!de_cient alkenes participate equally
well in this reaction\ to generate a carbon!centred radical "Equations "024#Ð"026## ð81JOC2883Ł[
CO2Me CO2Me
SnBu3
Bu3SnH
(135)
OAc
CO2Me (Bu3Sn)2, hν
+ (136)
CO2Me 92%
AcO CO2Me
MeO2C
TIMSS, AIBN (TMS)3Si H

X PhMe, 80–90 °C
(137)
X = CN, 85% X
X = OAc, 80%
1.20
Allenes and Cumulenes
CHRISTIAN BRUNEAU and PIERRE H. DIXNEUF
Universite de Rennes 1, France
1.20.1 INTRODUCTION 953
1.20.2 BY C—H BOND FORMATION 954
1.20.2.1 Isomerization of Alkynic Compounds 954
1.20.2.I.I Isomerization of alkynes and diynes 954
1.20.2.1.2 Isomerization of enynes 955
1.20.2.1.3 Propargylic rearrangement 955
1.20.2.1.4 Rearrangement into a-allenic ketoncs 957
1.20.2.1.5 Photorearrangement 957
1.20.2.2 Reduction of Carbon-carbon Triple Bonds 958
1.20.2.2.1 Dehalogenation of alkynic halides 958
1.20.2.2.2 Reduction of polyunsalurated hydrocarbons 959
1.20.2.2.3 Reduction of propargylic derivatives 961
1.20.2.2.4 Palladium catalyzed reduction of propargylic derivatives 962
1.20.2.2.5 Elimination involving H migration 962
1.20.2.2.6 Hydrolysis of alkynic silanes 963
1.20.2.2.7 Allenes via hydroboration 963
1.20.2.2.8 Hydrohalogenation of enyne derivatives 965
1.20.3 BY C—C BOND FORMATION 966
1.20.3.1 Nucleophilic Substitution with Organocopper Compounds from Propynyl Derivatives 966
1.20.3.2 Nucleophilic Substitution with Organomagnesium Reagents 970
1.20.3.3 Reaction of Electrophiles with Propargyl and Allenyl Organometallics 971
1.20.3.4 Catalytic Formation of Allenes via Allenyl-Metal Intermediates 975
1.20.3.5 Allene Synthesis via Boron Derivatives 976
1.20.3.6 Specific Reactivity of Propargyl Silanes 977
1.20.3.7 C—C Bond Formation via Sigmatropic Rearrangements 979
1.20.4 BY C—C BOND FORMATION 981
1.20.4.1 Elimination Reactions 981
1.20.4.2 Reduction of Unsaturated Alcohols and Halides 986
1.20.4.3 Wittig and Related Reactions 986
1.20.4.4 Addition of Carbene Moieties to Double Bonds 988
1.20.4.5 Dehalogenation 990
1.20.4.5.1 Dehalogenation of gem-dihalocyclopropancs 990
1.20.4.5.2 Dehalogenation of gem-dihaloalkenes 990
1.20.4.6 Reactions Involving Coordinated Organomelallic Species 991
1.20.4.7 Metal-catalyzed Homocoupling of Alkynes or Cumulenes 992
1.20.4.8 Intramolecular Rearrangement with Formation of a Heteroatom-carbon Bond 993
1.20.4.9 Miscellaneous Reactions 995
1.20.1 INTRODUCTION
The preparation and reactivity of allenes and cumulencs have received special attention in several
reviews. After the first reviews on allenes <64RCRl, B-69MI120-01) and cumulenes <61BSF2176>, general
information on methods for preparation was given by Murray <77HOU(5)967>, Hopf <B-80MI 120-01),
953
954 Allenes and Cumulenes
Landor <B-82MI 120-01), and Brandsma <B-84MI 120-01 >. More specialized reviews have appeared
dealing with propargylic rearrangements <B-69MI 120-02), allenic ketones <80T33l>, strained cumu-
lenes <89CRVllll>, and reactivity of allenes <B-84MI 120-02, 84T2805).
1.20.2 BY C—H BOND FORMATION
1.20.2.1 Isomerization of Alkynic Compounds
1.20.2.1.1 Isomerization of alkynes and diynes

Allenes were initially prepared by isomerization of the RCH 2 —C^C— moiety by a strong base
catalyst such as an alkali metal amide (NaNH 2 ) at high temperature <B-69MI 120-01) or, when the a
hydrogen is more acidic, at 20°C with a tertiary amine <65CB2611> or basic alumina <64T2177>.
Coordination of the triple bond to a metal like Mn can help the isomerization with A12O3
<79AG(E)688>. This method can be applied to the formation of allenyl sulfides from alkynyl thioethers
<70QRSl). Internal alkynes containing a hydroxy group can be isomerized regioselectively into
allenic alcohols with BuLi/TMEDA (Scheme 1) <86TL4599>. For diynes in the presence of Bu'OK
the prototropic rearrangement leads to bisallenyl derivatives <73TL318l>, while for 1,4-diynes milder
conditions can be used (NaOH/EtOH) for the preparation of alkynyl allenes (Scheme 2) <58JA1376>.
Scheme 1
Scheme 2
By C—H Bond Formation 955
1.20.2.1.2 Isomerization ofenynes
1,4-Enynes can be isomerized using Bu'OK to produce conjugated ene-allenes <65JOC2983>. Cross-
conjugated ene-allenes and ene-diallenes have been produced by prototropic shift from a 1,4-
enediyne <87TL2697>. 1,4-Enynes containing a hydroxy group are transformed into conjugated
vinylallenyl alcohol derivatives in the presence of 5% methanolic sodium hydroxide (Scheme 3)
<53JA1O5O>.
1.20.2.1.3 Propargylic rearrangement

Propargyl derivatives with a heteroatom X attached to the spi carbon ( R ' — C =
C—CHR 3 —X—R 2 ) easily undergo a ready base-catalyzed rearrangement leading to stable allenes
R 1 —CH=C=CR 3 —X—R 2 . Allenyl ethers, efficient building blocks in organic synthesis
<92AG(E)1033, 93JOC5709, 93S165, 93SL1O5>, are generally obtained in 80-100% yields by reaction of
propargyl ethers with Bu'OK <68RTC916, 93JOC5702). Catalytic amounts of Bu'OK are used for the
selective transformation of 2-alkynyl ethers (1) (containing a bromine atom) into allenyl ethers (2)
<88CC237>. This reaction can also be applied to the generation of alkenyl allene (4) (precursor for
Diels-Alder cycloadditions) from the enyne (3) <93CC270>. 2-Alkynyl ethers with an internal triple
bond usually give complete conversion into allenyl ethers on treatment with NaNH 2 <65RTC3l>.
Bispropargylic ethers and thioethers have been converted into bispropadienyl ethers and sulfides
with various base systems (Scheme 4) <76TL318l, 78TL691).
Scheme 4
The isomerization of /5-alkynic alcohols is less common but occurs in the presence of AgNO 3 to
afford a-allenic alcohols <59HCA719>. The isomerization of propargylic derivatives into allenes
containing a SR <63RTC1O4O>, SeR, or TeR group is achieved with strong bases (Scheme 5). Thioether
derivatives generally isomerize faster than the corresponding selenium or tellurium compounds
<66BSF3016, 66BSF3024). Novel cyclic enyne allene sulfones (6) have been prepared by oxidation of
cyclic enediyne sulfides (5) with w-chloroperbenzoic acid (Scheme 5) <93CC14O6>. 2-Alkynyl amines
(7) can be converted into iV,./V-dialkylalienyl amines (8) by treatment with potassium amide or
alumina; they are stable except in the case where R = H and are precursors of 1-alkynyl amines
<68JCS(C)228>. Heterocyclic allenyl amines have been prepared in only moderate yields by this
method <68JCS(C)606>. However, allenyl benzotriazole can be prepared in satisfactory yield by
treatment of propargyl benzotriazole with NaOH (Scheme 5) <93JOC3038>.
The mild isomerization of the prop-2-ynyl into the allenyl group within phosphine ligands
coordinated to metal complexes can also be achieved (Scheme 6) <93CB1O77>.
Scheme 5
Scheme 6
1.20.2.1.4 Rearrangement into a-allenic ketones
The rearrangement of ^-alkynic ketones into a-allenic ketones can be achieved with base as in
the transformation of (9) to (10) <55JCS174O>, or under milder conditions by using NaHCO 3 in water
for (11) to (12) <B-84MI 120-01), or basic alumina for (13) to (14) and (15) to (16) <86JOC2623>.
A similar isomerization takes place with jS-alkynic esters in the presence of K 2 CO 3 <72TL4249>.
Homopropargylic alcohols give a-allenic ketones upon oxidation with Jones reagent via the for-
mation of /?-alkynic ketones, followed by isomerization <57CR(C)179O>. A good method to produce
allenynone (19) from alkynyl homopropargylic alcohol (17) involves first, the Swern oxidation into
(18) followed by thermal rearrangement into (19); Jones reagent converts alcohol (17) into the
y-pyrone (20) in low yield (Scheme 7) <93TL449>. The oxidation of homopropargylic alcohols by the
Dess-Martin periodinane reagent also affords allenones in good yields <90JOC3450>.
Scheme 7
1.20.2.1.5 Photorearrangement
Irradiation of 1,1,3-triphenylpropyne in methanol, in the presence of 1,4-dicyanonaphthalene
(1,4-DCN) as photosensitizer, gives a rearrangement leading to triphenylallene as the major product
<85JA6615>. A stereoisomerization with no proton migration has been observed during the irradiation
(at 230 nm) of alkenyl allenes (21) and (22) in hexane (Scheme 8) <76RTC80>.
Scheme 8
1.20.2.2 Reduction of Carbon-carbon Triple Bonds
1.20.2.2.1 Dehalogenation ofalkynic halides

Hydrodehalogenation of a-alkynic halides by reducing agents such as ZnCu/ROH or LiAlH4
constitutes a general means of access to allenic derivatives (see Table 1). Since the direct reduction
of propargylic alcohols is not possible under these conditions, a-allenyl alcohols can be prepared
from a-halo-oe'-hydroxyalkynic compounds <55JOC1337>. For example, in the synthesis of the first
fluoroallenylamino acid (25), the fluoroallenyl group is formed by reduction of the chloro-
fluoropropargyl synthon (23) into the fluoroallenic alcohol (24) (Scheme 9) <87JA349l>. The Hiyama
reagents, CrCl2 generated from CrCl, and LiAlH4, or CrCl2 in the presence of AcOH <83T2185>, are
also useful reducing systems that allow the obtention of allenes and vinyl allenes from propargylic
halides <78TL380l> and l-bromo-4-ene-2-ynes <79NJC321> (Table 1). The utilization of a chiral
protonating agent like (-)menthol or (-)borneol in the reduction of l-bromo-2-alkynes leads to the
formation of enantiomerically enriched allenes <81TL1O3>.
Table 1 Reduction of ot-alkynic halides.
R' R2 R3 X Reducing agent Yield Ref.

(%)
Me Et H Cl LiAlH4 63 55JOC95
H H CH2OH Cl LiAlH4 94 87TL2697
Pr H H Cl ZnCu 71 49JA1964
H H CH(Me)OAc Br Zn 45 67CR(C)1492
H H C5H11 Br CrCl2 75 78TL3801
H H CH2=CH Br CrCl2 40 79NJC321
H «-C7H15 CH2=CMe Br CrCl2 95 79NJC321
H Me 1-cyclohexenyl Br CrCl2 95 79NJC321
Scheme 9
Alkynic halides of different structures, with the halogen separated from the triple bond by an
unsaturated conjugated chain, have been reduced by generation of vinylallenyl metal intermediates
which release the allene o n hydrolysis (Scheme 10) <60JCS34l, 72TL4465,72CC866,74BSF1119,74CR(C)149,
76S755, 77T2813, 79TL1845>.
Scheme 10
1.20.2.2.2 Reduction of polyunsaturated hydrocarbons

The formal 1,4-addition of hydrogen to conjugated enynes affords allenes as illustrated by the
reduction of dicyclohexen-1-yl acetylene with hydrogen in the presence of an iron/aluminum catalyst
(Scheme 11) <42JA363>. Conjugated 2-en-4-yn-l-ols are reduced to 3,4-dien-l-ols by LiAlH4 in
refluxing diethyl ether <75BSF14O7>. Enynes containing an allenyl group and either an hydroxy (26)
or an acetate (27) group have been reduced into diallenes (28) by reaction with LiAlH4 (26) or
LiAlH 3 OMe (26)-(27). With this latter reagent, less competing hydroxy substitution by the hydride
ion takes place. This reduction corresponds to a 1,4-addition of H /H + and the presence of a
960 Allenes and Cwnulenes
Scheme 11
hydroxy group in (26) is expected to facilitate the hydride transfer via an alkoxyhydridoaluminate
—OA1H3 intermediate <74TL1593>. The reduction of tetraphenylbutatriene with aluminum amalgam
in THF containing water gives l,l,4,4-tetraphenyl-l,2-butadiene in 70% yield <6lCB3060>, but this
strategy has been scarcely used for allene preparation (Scheme 11). A specific reduction of the enyne
(29), with the double bond linked to an ester group, has been achieved by treatment with a
cyanocuprate in ether. After protonation with pivalic acid, the allene (30) is obtained; the carbo-
cupration product (31) is formed when the reaction is performed in THF (Scheme 11) <91TL7229>.
It has also been shown that a low temperature favours C—H rather than C—C bond formation in
the reaction of propargylic acetates with organocuprates and LiAlH4 <76CC183>.
A reduction sequence, formally with R~ and H + , is exemplified by the addition of an organo-
lithium <77HOU(5)1030> or a Grignard reagent <74BSFl 119> to enynes followed by hydrolysis (Scheme
12). A similar strategy was applied to the formation of aminomethyl allenes, by addition of
amines to 1,3-enynes, or by reaction with lithium amides followed by protonation (Scheme 12)
<77HOU(5)1037>. Under similar conditions, lithium phosphide leads to dialkylphosphinomethyl all-
enes (Scheme 12) <60ZOB1056>.
Scheme 12
1.20.2.2.3 Reduction ofpropargylic derivatives
x-Allenyl alcohols (33) are obtained in good yields from the mono-O-tetrahydropyranyl ethers of
but-2-yn-I,4-diols (32) by reduction with LiAlH4 under mild conditions (Scheme 13). This reaction
is expected to produce first a =C—CH 2 —O—A1H— intermediate (34) able to intramolecularly and
stereoselectively substitute the leaving group O—THP by transfer of hydride <73JCS(Pl)720)'. /?-
Allenic alcohols can be obtained under similar conditions by reduction of mono-0-tetra-
hydropyranyl ethers of pent-3-yn-l,5-diols with LiAlH4 in THF at 65°C <74ACS(B)765>. a-Allenyl
ethers and tertiary amines have been prepared by reduction of 1,4-dialkoxybut-2-ynes and 4-
dialkylamino-l-methoxybut-2-ynes, respectively, with lithium aluminum hydride and a Lewis acid
(MgBr2 or A1CI3) <85S768>. An analogous transformation can be achieved from (35) which bears a
quaternary ammonium group as the leaving group at the a.' position of the internal triple bond
(Scheme 13) <74S344>. It is, however, possible to transform propargylic alcohols with no leaving
groups such as the steroid (36) into the corresponding allene (37), but the reaction requires the
presence of LiAlH4/AlCl3 (3/1) in THF (Scheme 13) <75CC362>. The regioselective reduction of
aryloxymethylethynyl carbinols (38) into aryloxymethyl allenes (39) can be achieved using only
LiAlH 4 in THF; in this case, the observed regioselectivity is thought to result from the coordination
of both oxygen atoms to the aluminum centre (Scheme 13) <86TL3777>. A versatile method to
produce a variety of hydroxymethyl allenes of type (41) results from reduction of hydroxymethyl
alkynes (40) with LiAlH 4 in THF followed by treatment with solid iodine at — 78CC. The reaction
proceeds via the alanate (42); treatment of (42) with iodine in a THF solution affords allylic iodo
alcohols (43) (Scheme 13) <82TL305l>-
The reaction of propargylic ether or acetate (44) with ethylcuprate generated from an excess of
EtMgBr with CuBr • Me2S in THF gives a reaction mixture containing allenes (45), (46) resulting
from reduction and alkylation, respectively, together with the alkynic isomers (Scheme 14)
<84JOC4120>.
Scheme 13
Cumulenes have been obtained from 4,5-dien-2-yn-l-ols (47) (or the corresponding acetates), by
reduction with LiAlH4. The addition of hydride to the central allenyl carbon atom with elimination
of the hydroxy (or acetate) group leads to the formation of cumulenes (48) (Scheme 14) <75BSF2159,
75BSF2166).
Scheme 14
1.20.2.2.4 Palladium catalyzed reduction of propargylic derivatives

Propargylic derivatives bearing a good leaving group (carboxylate, carbonate or halide) are
known to be transformed by palladium(O) complexes to afford allenyl palladium intermediates.
Their hydrogenolysis by an alcohol <86TL5237>, or various sources of hydride, like metal hydride
<84TL845> or ammonium formates <87S603, 86CC922) leads to the formation of allenes (Scheme 15).
a-Hydroxy allenes have been obtained by a similar strategy, by reduction of alkynic epoxides with
triethylammonium formate in the presence of Pd2(dba)3 • CHC13 as the catalyst precursor, but the
selectivity was not good, and homopropargylic alcohol isomers were also formed (Scheme 15)
<86CC922>. a-Hydroxy allenes are formed more selectively starting from alkynyl cyclic carbonates
in the presence of Pd(dba)2/1,2-bis(diphenylphosphino)ethane <94SL457>. Palladium-catalyzed
decarboxylation-hydrogenolysis of propargylic formates, which have a terminal triple bond, cleanly
gives allenes at room temperature <93TL2161>.
1.20.2.2.5 Elimination involving H migration

Rearrangement of propargylic diazene (50), involving the loss of nitrogen and the regioselective
1,5-migration of hydride, leads to 1,3-disubstituted allenes. The intermediates (50) can be formed
from a-alkynic ketones, by reduction of the corresponding tosylhydrazone derivatives (49) with
catecholborane, to afford alkyl and aryl allenes <78CC726>, or with NaBH 3 CN to produce silylated
allenes <80JOC3925>. The same type of intermediate (50) is involved in the direct oxidation (by
diethylazodicarboxylate (dead) at 0°C) of hydrazines (51), obtained in two steps from a-alkynic
alcohols; this process generates trienynes (52) with complete stereospecificity from optically active
propargylic alcohols (Scheme 16) <89TL5747>.
Scheme 15
Another example of elimination-rearrangement involving a sigmatropic 1,5-migration is illus-

trated by the formation of allenes with loss of SO2 via sulfinic acids (54) generated by hydrolysis of
propargylic sulfinamides (53) (Scheme 16) <9OTL213>.
1.20.2.2.6 Hydrolysis ofalkynic silanes

Electrophilic desilylation of propargylic silanes TMS-CH 2 C=CR (55), in the presence of car-
boxylic acids such as CF 3 CO 2 H <80JOC5006> or BF 3 -2 CH 3 CO 2 H <87JOM(319)333> provides a regio-
selective synthesis of monosubstituted allenes (56) under mild conditions (Scheme 17). Selective
cleavage of the propargylic trimethylsilyl group from TMS-C(Me) 2 C=C—TMS (57) leads to the
substituted allenyl silane (58) on treatment with CF 3 CO 2 H at 0°C <8lCClO94,8lTL340l> or MeSO3H
at 25 CC <72JOM(39)C44>. Alcohols (61), containing a terminal allenyl group, have been obtained
under similar conditions from alcohols (59) or their trimethylsilyl derivatives (60) (Scheme 17). The
protection of the alcohol functionality by a tetrahydropyranyl group gives rise to the formation of
the two possible allenols <87JOM(319)333>. 1-Trimethylsilylpropargyl alcohols are converted into
trimethylsilyloxy allenes in 63-96% yields by reaction with BuLi, via migration of the trimethylsilyl
group and protonation <80TL623>.
The cleavage of a = C — S i bond leads to a terminal allene via proton transfer and protonolysis.
This method has been used to access, respectively, 1,2,4,6-tetraenes (64) and (65) from a free (63)
or coordinated (62) trimethylsilyldienyne by cleavage with fluoride. During this procedure, the
propargylic proton transfer induces a cis-trans isomerization of the diene system (Scheme 18)
<92BSF151>.
1.20.2.2.7 Allenes via-hydroboration

Hydroboration of l-chloro-2-alkynes with diisoamyl or dicyclohexylborane in THF at 0°C gives
a-chloromethylvinyl boranes which undergo easy elimination on treatment with sodium hydroxide
to produce terminal allenes in good yields (Scheme 19) <7OJA1427>.
Scheme 16
Scheme 17
Scheme 18
Scheme 19
1.20.2.2.8 Hydrohalogenation ofenyne derivatives

1,4-Addition of HX (X = Cl, Br) to vinylalkyne or enynols leads to halogenated allenes; yields
are improved in the presence of Lewis acids, e.g. A1C13 or ZnCl2 (Scheme 19) (32JA4066, 63IZV499,
66JCS(C)1223>.
966 Allenes and Cumulates
1.20.3 BY C—C BOND FORMATION
1.20.3.1 Nucleophilic Substitution with Organocopper Compounds from Propynyl Derivatives

Since the first use of organocopper reagents to synthesize allenes from propargylic derivatives via
selective SN2' displacement of a leaving group <68JA4733>, many examples of this strategy have been
reported involving a variety of labile groups and copper derivatives.
Lithium cuprates allow the selective formation of allenes from propargylic acetates containing a
spirocycloalkyl substituent at the propargylic carbon <75TL4615>. Pasto et al. <78JOC1389> have
shown the preferred formation of alkyl allenes from mixed methyl alkyl cuprates and alkyl allenyl
cuprates, and pointed out the competition between reduction and substitution in the case of terminal
chloropropargylic derivatives (Scheme 20). Chiral allenes, precursors of natural pheromones, have
been obtained with lithium dialkylcuprates starting from optically active propargylic carbamates
(66) (Scheme 21) <78JOC1950,78JOC2091). a-AUenyl alcohols, precursors of dihydrofurans, have been
prepared by treatment of epoxy propargylic alcohols with methylcuprate <93JOC7180>. The reaction
of the epoxy alcohol (67) with organocuprates leads to a mixture of ami and syn diols (68) and (69)
at 35 °C, whereas the presence, of dimethyl sulfide at — 60°C selectively directs the nucleophilic
substitution to the formation of the anti isomer (68) <83TL5587>.
Scheme 20
Scheme 21
However, diorganocuprates are known to racemize optically active allenes, and other organo-
copper derivatives have been used for the synthesis of optically active allenes from chiral propargylic
derivatives. Chiral 1 -phenyl-3-alkyl and 1,3-dialkyl allenes have thus been obtained from propargylic
sulfinates or sulfonates and (RCuBr)MgBr • LiBr at — 65°C <89JOC3726>. Dienylallene tricarbonyl
iron complexes (71) have been obtained from dienylpropargylic carbonate (70) or mesylate com-
plexes and (RCuBr)MgBr-LiBr (R = Et, Bu') with very high diastereoselectivity <92AG(E)224,
93T9775). These organoheterocuprates are also suitable reagents for the synthesis of siiylated allenes
By C—C Bond Formation 967
(72) from trimethylsilyl propargylic sulfinates, mesylates or tosylates <79S390>. 5-Trimethylsilyl-2-
methylpenta-2,3-dien-l-ol (74) has been produced by opening the epoxide (73) with a trimethyl-
silylmethyl copper(I) species formed from trimethylsilylmethyl magnesium chloride and LiCuBr2
<85JOC5143>. Pure butatriefies (76) have been obtained from 3-bromo-alk-3-en-l-ynes (75), as a
result of o«n-l,3-substitution, on treatment with a copper(I) species in THF at — 50°C (Scheme 22)
<82JOM(240)329>.
Scheme 22
Other organocopper(I) reagents have been prepared by using Grignard reagents in the presence
of catalytic amounts of Cu(I) halides. This procedure usually avoids the parallel formation of
alkynic derivatives resulting for simple nucleophilic substitution. Propargylic derivatives bearing an
alkoxy group as the leaving group have been used to gain access to polyalkylpropa-l,2-dienes
<76JOM(108)159>, 1,2,4,6-tetraenes (77) <79TL7> and a-allenyl amines <87TL2207>. Chiral allenes are
obtained with high stereoselectivity from optically active propargylic ethers <90JA8042> and cyclic
acetals <85TL4197> by using RMgBr, CuBr (5%), and P(OEt)3 to inhibit racemization. Cyclic allenes
(79) can be obtained from cyclic propargylic esters (78) <86TL4845>, and the use of CuX catalyst
also allows the diastereoselective synthesis of a-allenols from epoxides <91T1677> or cyclic carbonates
(or sulfates) in the presence of a Lewis acid (Scheme 23) <92TA15O9>.
More simple organocoppcr(I) derivatives promote 1,3-substitution reactions with propargylic
derivatives. Fluorinated allenes (80) and bisallenes (81) have been prepared from propargylic halides
or tosylates and perfluoroalkyl copper(I) compounds (Scheme 24) <90TL3699,90TL3703). The synthesis
of a-allenic alcohols (82), of high optical purity, has been carried out starting from the appropriate
chiral propargylic bromide or tosylate and functional Cu(I) derivatives <9UOC1083>. Another route,
Scheme 23
based on the use of propargyl chloride and alkyl copper reagents arising from optically active amino
acids, has allowed the formation of enantiomerically pure protected amino acids containing an
allenyl group <93SL219>. Similar syntheses of allenic amino acids (83) are based on the use of zinc-
copper reagents (Scheme 24) <92CC319, 93SL499). Stannyl alkynes (84) react with alkyl copper(I)
species at — 60CC to give stannyl allenes (85) in high yields, but quantitative transmetallation
of (84) takes place with MeCu, C H ^ C H — C u , Ph—Cu and TMS—C=C—Cu (Scheme 25)
<84TL3019>. The copper(I) enolate generated from the lithium enolate of acetylacetate and Cul at
— 78°C is able to substitute propargylic esters to produce j5-allenyl esters <78JOC555>.
X R'F R2 R3 Yield {%) Ref.

OTs CF3, C3F7, C 6 F, 3 H H 68,41,49 90TL3699
Cl CF3, C3F7, C 6 Fi 3 , C 8 F 17 H Me 73,68,66,60
Cl CF 3 EtO2C Me 57 90TL3699
Cl CF 3 TMS Me 52 90TL3699
Br C 6 F 13 , CgFn H H 70-75 90TL3703
Scheme 24
The direct 1,3-substitution of the hydroxy group of propargylic alcohols has been performed
successfully by an organocuprate formed in situ from Cul, RLi, and (methyl phenylamino)
tributylphosphonium iodide (Scheme 25) <80JOC4536>.
Scheme 25
Coupling either two propargylic acetates or two allenyl bromides in the presence of CuCl in DMF
at room temperature, furnishes symmetrical diallenes (86) via allenyl radical intermediates (Scheme
25) <75CC174>.
The l,3-alkadien-2-yl diethyl phosphate (87) reacts with an organocuprate reagent formed in situ
from RMgX and CuX to afford the allene (88) in moderate yield; suitable conditions have to be
found to avoid nucleophilic substitution giving the 1,3-diene (89) (Scheme 26) <83TL1297>.
Scheme 26
The generation of allenyl enolates by 1,6-addition of lithium dimethylcuprate to conjugated

functional enynes makes possible access to allenyl esters (90) by C—C bond formation, and to
allenyl enol ethers (91) by C—O bond formation, on addition of electrophiles <93CB25i, 93LA521).
When the starting alkyne is substituted by a bulky group like Bu', these allenyl enolates can be
trapped to selectively afford allene derivatives (92) (Scheme 26) <93CB26l>.
1.20.3.2 Nucleophilic Substitution with Organomagnesium Reagents

The reaction of propargyl derivatives with Grignard reagents is well documented, but the com-
petition between alkyne and allene formation has brought some restriction to its utilization.
However, the selectivity of the 1,3-substitution has been improved by the use of specific leaving
groups or catalytic systems involving transition metals. Thus, propargylic alcohols, protected in situ
by l-chloro-2-methyl-Af,iV-tetramethylenepropenyl amine, lead to the selective formation of allenes
at 0°C with alkyl, phenyl, vinyl, and allyl Grignard reagents in very good yields (Scheme 27)
<84TL4007>.
Palladium(O) is an efficient catalyst for the cross-coupling of propargylic and allenic halides with
Grignard reagents to selectively produce alkyl and aryl allenes <80TL5019>. The nickel-catalyzed
reaction of propargylic alcohols (93) with organomagnesium bromides selectively gives silyl allenes
(94) (Scheme 27) <85JOC1122>. Pasto et al. <76JOC3496, 78JOC1382, 78JOC1385) have shown that iron
(especially FeCl3) and cobalt derivatives were good catalysts for the production of allenes from
propargylic halides and Grignard reagents.
A similar nucleophilic substitution involving triethylaluminum and tris(trimethylsilylethynyl)
methyl acetate (95) gave compound (96) in low yield (20%) (Scheme 27) <88CC748>.
It must be noted that vinylic allenes have been obtained via selective 1,5-substitution of chloride
from 5-chloropent-3-en-l-ynes on treatment with MeMgl <72CC866>.
Scheme 27
1.20.3.3 Reaction of Electrophiles with Propargyl and Allenyl Organometallics

Propargylic and allenic organometallics are usually prepared by reaction of a metal or an alkyl
lithium with either the corresponding halide or the hydrocarbon. Metallation of allenic hydro-
carbons or halogen-lithium exchange from haloallenes with butyllithium at — 78 °C generates
carbanions capable of reacting with electrophiles to produce allenyl derivatives via C—C bond
formation <9lCOS(2)8l>. Various electrophiles have been used leading to the synthesis of various
functional allenes.
The selective formation of mono-, di-, tri- and tetraalkyl allenes (84-94%) is possible with alkyl
halides (75CC561,82SC739). The cross-coupling between allenyl lithium compounds and aryl or vinyl
halides, catalyzed by Pd(PPh 3 ) 4 makes possible the preparation of vinyl and aryl allenes <82S738>.
The reaction of allenyl lithium with ketones and epoxides, respectively, leads to oc-allenic and
/?-allenic alcohols <81S875, 83CC1133), the selective formation of the latter being improved in the
presence of hexamethylphosphorotriamide. When CO 2 is used as the electrophile, allenic carboxylic
acids are formed in good yields <77JA7632,81S875, 85JA6046). Whereas the reaction with amides gives
allenic ketones <77NJC373>, the cross-coupling with ureas provides an efficient route to allenic
amides in satisfactory yields (Scheme 28) <81S875>. The ambident alkynic-allenic nature of
3,3-dimethylallenyl lithium has been discussed by Creary on the basis of hard and soft acidity
<77JA7632>.
Functional allenic compounds have been prepared from y-lithio-y-alkoxyallenes <68RTCH79>,
silyl allenes <80TL3987>, y-methoxy-y-alkyl allenes <78TL1137>, and the synthesis of the first primary
helicoidal molecule (97) was based on the reaction of y-methoxy-y-lithio allene with tetra-
hydrofuranone moities (Scheme 29) <8OJA2134>. The use of enantiopure alkoxy allenes has allowed
the preparation of enantiomerically enriched allenols by reaction with aldehydes <93SL1O5>. Sily-
loxypropargyl lithium reagents (98), generated either by alkylation of silylated ketones or alky-
nylation of silyl ketones, react with electrophiles to produce allenol silyl ethers (99) (Scheme 29)
<80JA1423, 86JA7791).
Allenyl Grignard reagents have not been used extensively because of their lack of selectivity.
However, y-allenyl ketones have been produced from allenyl magnesium bromide and esters
(69BSF898, 70BSF3157).
The organoaluminum derivative (100), generated by reaction of aluminum with trimethyl-
silylpropargyl bromide selectively affords allenyl alcohols (101) and (102), on reaction with carbonyl
compounds, whereas magnesium or zinc propargyl derivatives selectively give homopropargylic
alcohols (81TL1579,9UOM(403)299>. Reaction of (100) with triethyl orf/io-formate affords the aldehyde
Scheme 28
Scheme 29
(103), a useful intermediate for the access to functionalized allenic alcohols on reaction with
organomagnesium, zinc, or aluminum reagents (Scheme 30) <92JOM(440)277>. Propargylic lithium
alanates generated from methylacetylenes, selectively afford allenes, a-allenic alcohols and acids
by reaction with allyl halide, carbonyl compounds and carbon dioxide, respectively. Similarly,
methoxyallenyl aluminum reagents react with aldehydes to produce methoxyhydroxy allenes (104)
which cyclize into furans under acidic conditions with loss of methanol <82CL1O29>. With organo-
aluminum derivatives arising from substituted propargyl bromides, a-allenic tertiary amines have
been produced with high selectivity (>90%) when the electrophile is an iminium salt <8UOM(2l8)l>
or a #em-aminoether (Scheme 30) <80JOM(198)l>.
Scheme 30
Stable organotin compounds react with activated aldehydes to produce y-allenyl alcohols in good
yields <73JOM(54)153>. The in situ formation of organotin derivatives by stirring stannous chloride
with propargylic halides leads to allenic alcohols on reaction with aldehydes at 0°C <81CL621,
93TL449). The best selectivity in allenols is observed when y-substituted propargyl iodides are used
(Scheme 31).
Transmetallation of 1-trimethylsilyl (or 1-methyl) propynyl lithium with titanium isopropoxide
Scheme 31
at — 78 °C gives access to a titanium reagent which reacts with carbonyl compounds at — 78°C to
specifically afford allenic alcohols, whereas similar reactions from l-trimethylsilyl-3-substituted
propynyl lithium lead to alkynic alcohols (Scheme 32) <82JOC2225>. Highly regio- and dias-
tereoselective syntheses of 4-hydroxy-l,2-alkadienyl carbamates (105) have been obtained from
propargylic carbamates by using the corresponding titanium derivative, whereas no selectivity was
observed with the lithium reagent <87T2457>.
Scheme 32
By reaction of aldehydes or ketones in the presence of hexamethylphosphoramide (HMPA), a

very selective formation of allenols has been observed when chromium(II) derivatives were used to
generate the allenyl organometallic intermediate from propargylic bromides <81T1359). This system
allows the use of propargylic halides containing other functionalities such as esters, halides and
nitriles <92JOC4070>.
The organocupration of methyl propynoate by an allenyl cuprate selectively affords trans-2,4,5-
trienyl methyl esters in good yields (Scheme 33) <76TL275>.
Allenic ketones have been synthesized by reaction of propargyl mercury iodide with acyl chlorides
in the presence of A1C13 at - 4 0 ° C (Scheme 33) <86JOC2623>.
Organozinc compounds prepared from propargylic halides usually give no selectivity on reaction
with carbonyl electrophiles, but after treatment with zinc, -/-substituted a-alkynic bromides react
with N-chloromethyl-N-methylformamide to afford allenic methyl formamides, which are easy to
convert into secondary allenyl amines with BuLi <86BSF449>. On hydrolysis with D 2 O, allenic zinc
Scheme 33
reagents, generated from propargylic mesylates or chlorides and triorganozincates, give allenes in
high yields via C—C and C—D bond formations <93JOC6166>.
Nucleophilic organosamarium derivatives, formed by electron transfer from Sml2 to allenyl
palladium species, react with carbonyl compounds to afford homopropargylic and allenic alcohols,
the proportions of which depend on the substitution pattern of the starting prop-2-yn-l-yl acetate
<87CL2275>.
1.20.3.4 Catalytic Formation of Allenes via Allenyl-Metal Intermediates

The reaction with palladium(O) catalysts probably proceeds via oxidative addition of a propargylic
carboxylate, halide, or carbonate to produce an allenyl organopalladium(II) moiety. Subsequent
reaction with electrophiles gives 1,2-diene derivatives.
Starting from propargylic halides or esters and hard nucleophilcs such as R—ZnCl, in the presence
of catalytic amounts of Pd(PPh 3 ) 4 , functionalized allenes and bisallenes have been obtained with
high regio- <81TL1451> and stereoselectivity <83JOCH03> except in the case of 1-alkynylcyclopropyl
derivatives which led to alkynic cyclopropanes as major compounds <92JA405i>. Conjugated para-
allenyl styrenes and vinyl allenes have thus been obtained from various nucleophiles including zinc,
aluminum and tin organomctallics <86JOC4006>. Allenynes have been synthesized in one step from
propargylic halides or acetates and terminal alkynes in the presence of tetrakis(triphenylphos-
phine)palladium, copper iodide and a base <93TL3853>. The cross-coupling is also possible from
allenyl halides and organozinc <84TL5571>, magnesium <80TL50l9> or copper <83S32> species as
nucleophiles, catalyzed by palladium(O) complexes (Scheme 34). Gore has recently shown the direct
access to functionalized vinyl allenes (106) by coupling of propargylic acetates and penty-
noates based on the efficient activation of both substrates by palladium complexes <93TL3129>
(Scheme 34). Since they are easily transformed into allenyl—Pd(ll) intermediates, CO 2 and alkoxide,
propargylic carbonates are especially good substrates for various transformations into allenic
derivatives via palladium(O) catalysis. In alcohol, under CO pressure, propargylic carbonates
are easily converted into allenic esters (107) (86TL731, 93JA5865, 93JOM(45i)i5>. Mono- and
[R'-M] = R'ZnCl; R'OCH/CuI/base

X = Br, Cl, OAc, OTs
R2 = H, Me, Ph; R3, R4 = H, Me, Ph, PhCH2CH2, PhCH=CH, Ar
R1 = Ph, TMS-OC, PhCsC, H2C=C(Me)C=C, H O C - O C , H2C=CH, BulCH=CH
R'M = Ph2Zn; R2 = H; R3 = Ph, Bu', 20 °C, 98%

R'M = RMgX; R2 = H, Me; R3 = Me, 60-98%
R'M = R'OCH/Cul (2%)/Et2NH; R2 = H, Me; R3 = Pr", Me, 20 °C, 70-94%
Scheme 34
dicarbonylation of propargyl halides are also possible under phase transfer conditions, with
Ni(CN) 2 • 4H 2 O as the catalyst precursor to produce allenyl mono- and dicarboxylic acids (92OM493,
93OM1871). The carbonylation in the presence of carbanions generated from active methylene
compounds with NaH gives allenyl ketones (108) <91SL697>. From 4-amino-2-alkynyl carbonates,
the carbonylation leads directly to allenic /Mactams via subsequent intramolecular C—N bond
formation <91TL7683>. Based on the easy formation of alkynyl copper derivatives from terminal
alkynes, Cul and a base, l,2-dien-4-ynes, l,2-dien-4-yn-6-ols or their tetrahydropyranyl ethers (109)
have been obtained in good yields in the presence of palladium catalyst precursors with KBr or LiCl
<90TL7179,9UOM(417)305>. Alkenyl allenes (110) have been synthesized in one step from propargylic
carbonates and activated olefins via the Heck reaction, in the presence of Pd(OAc)2, PPh 3 and KBr
in DMF at 70°C (Scheme 35) <91TL3397>.
Scheme 35
1.20.3.5 Allene Synthesis via Boron Derivatives

Organoboranes react with lithium chloro- or acetatopropargylides at low temperature to produce
allenyl boranes. Further treatment with acetic acid gives the allenes (111) ( > 7 0 % yields),
corresponding to the migration of an alkyl group from the boron atom to the terminal carbon of
the initial alkyne (Scheme 36) <74JA5620,77JOC2650). Propargylic organoborane intermediates react
with carbonyl compounds to produce allenic alcohols in good yields <78JA5561,82JOC3364,83JOC5376),
with CO 2 to give allenic acids, and with allylic halides to form 1,2,5-trienes <82JOC3364>. 3-Alk-
enylpropargylic boranes (112) react at — 78 °C with aldehydes to afford the conjugated 1,2,4-trienols
(113) in more than 60% yield (Scheme 36) <8UOC829>. Recently, the enantioselective synthesis of
chiral a-allenols via reaction of aldehydes with an enantiopure propargyl borane, generated from
bromoborane (114), has been described <90JA878>. The formation of allenols is also possible by
reaction of trialkylborane with 3,4-epoxybut-l-ynes in the presence of oxygen <73S305>.
Scheme 36
1.20.3.6 Specific Reactivity of Propargyl Silanes

In the presence of a Lewis acid as catalyst, propargyl trialkyl silanes react regioselectively with
electrophiles to afford allenic derivatives via a stabilized vinylic carbocation according to Equation (1).
(i)
This strategy has allowed the preparation of a variety of allenes using electrophiles such as
acyl chlorides (80JOC5006, 81TL3401>, acetals <81TL3609, 85OM333), aldehydes <75JOM(93)43, 81TL455,
81TL1327, S4TL651), and ketones (Scheme 37) <81TL455>. For propargyl trimethyl silanes containing
a silyl ether or a hydroxy group, the reaction with aldehydes leads to vinylidene cyclic compounds
(115), (116), (117) (Scheme 37) <84TL651, 86T2017, 86T2501, 88JOM(349)43>.
Scheme 37
Iminium salts, generated from formaldehyde and secondary amines in the presence of CF 3 CO 2 H,
react with propargyl silanes to afford tertiary allenyl amines (118) (Scheme 37) <90JOM(396)289>.
Similarly, vinylidene cyclic amines have been prepared from amino propargyl trimethyl silanes via
a regiospecific intramolecular reaction <87TL4689>.
Allenyl lactams (119) have been produced by reaction of propargyl silanes with acyl iminium
cations used as electrophiles <83TL14O7,84JOC1149,84TL3115,86TL1411,88TL4253,92T3445). Under similar
conditions, allenyl ethers (120) have been obtained from oxonium derivatives, formed in situ
with BF 3 • Et 2 O (Scheme 38) <87JOC1370,88JOC2450). The acetolysis of 8-(trimethylsilyl)-6-octyn-2-ol
tosylate led to an exocyclic allene via an electrophilic intramolecular reaction <8OJA512O>.
Propargyl silanes react smoothly with the activated double bond of alkylidene malonates in the
presence of TiCl4 at 20°C to produce allenes in moderate to good yields <82JOM(236)177>. Allenyl
acyl cyanides (121) are obtained in good yields from a-unsaturated acyl cyanides and 3-trimethyl-
silylprop-1-yne (Scheme 38) <86JOCl 199>. Intramolecular addition of propargyl silanes to conjugated
Scheme 38
enones, in the presence of TiCl4 or EtAlCl2 at very low temperature ( — 70 °C) gives rise to anneladon
compounds (122) containing the exocyclic allenic moiety (Scheme 38) <85TL1831, 86CC829, 88S263).
Other examples of acid-catalyzed or Lewis acid-promoted cyclizations from trimethylsilyl propargyl
derivatives, leading to the exocyclic terminal allenyl group, have been reported <91CB247, 92TL8017,
93TL7849).
1.20.3.7 C—C Bond Formation via Sigmatropic Rearrangements

Claisen-Cope rearrangement of propargyl vinyl ethers is a method of choice for the access to fi-
allenic aldehydes, ketones, esters and amides according to the general equation A -> B (Equation
(2)).
(2)
A classical route for access to intermediates of type (A) is the condensation, under acidic
conditions, of prop-2-yn-l-ols with enol ethers <67HCAH58> or orô-csters (Scheme 39) (77JOC353,
82JOC4478,92TL1057). The good diastereoselectivity of this reaction has been used for the preparation
of chiral methylmalonaldehyde derivatives <88JOC4736>. The reaction of amide acetals with prop-2-
yn-l-ols in refluxing benzene made possible the preparation of allenic pyrrolidines (123) and pi-
peridine amides in more than 54% yield (Scheme 39) <82JOC389, 84JOC1204). The Claisen rearrange-
ment can also be extended to propargyl allyl ethers <80JOC2080> and 2-propargyloxy imines
<92TL4447>. Allenic acids (124) have been obtained in 47-88% yields starting from propargyl
glycolates via enolates generated on treatment with TMS 2 NLi (Scheme 39) <85CL1457>. Furans
undergo ring opening in the presence of BuLi, and the subsequent rearranged intermediate can
be trapped by electrophiles to give allenyl ketones <79JA2208>. Other examples of sigmatropic
rearrangements involving C—C bond formation have been described, among them the aza-Cope
rearrangement involving 2-(./V-succinimidyl)-4-pentyne derivatives (125) <84JA1877>, or the for-
mation of the allenic thioether (128) from the allylic sulfide (126) and 3-chloro-3-methylbut-2-yn-l-
yl lithium (127) <74CC1O>. Allenyl sulfones have been obtained by nucleophilic substitution of a
phenylsulfonyl group from 2,3-bis(phenylsulfonyl)-l,3-butadiene by soft carbanions <93JA3776>.
Scheme 39
The thermal ene reaction between terminal alkynes and indane-l,2,3-trione involving C—C
bond formation and H migration gives rise to 2-allenyl-2-hydroxy indane-l,3-diones (Scheme 39)
<92JCS(P1)2355>.
By C=C Bond Formation 981
1.20.4 BY C=C BOND FORMATION
1.20.4.1 Elimination Reactions

1,2-Elimination from an unsaturated molecule or 1,4-elimination from both sides of a triple bond,
provide simple routes to allenes and cumulenes. The sterically hindered tetra-terJ-butyl allene has
been obtained by elimination of water under acid catalysis from l,l,3,3-tetra-?er?-butyIprop-2-en-
l-ol <82AG(E)924>. However, there are only a small number of examples of direct elimination
of water from alcohols. In most cases, ester type derivatives like trifluorosulfonates <75JOC657>,
trifluoroacetates <78JOC1526,88TU355), or sulfinates <85AG(E)85l> facilitate the elimination (Scheme
40).
Scheme 40
1,2,3-Butatrienc derivatives have been formed by 1,4-elimination of methanol, by treatment of

propargylic methyl ether with two equivalents of Bu'Li. The intermediate lithiobutatriene (129)
allowed access to a-silyl a-silyloxy butatrienes (130) on reaction with TMS-C1, to allenyl ketones
and aldehydes (131) on hydrolysis <8ITL2827>, or to allenyl amines (132), (133) starting from
l-dialkylamino-4-methoxy-4-methylpent-2-ynes (Scheme 41) <82JOM(233)C25>. Butatrienyl ethers
have been obtained from l-trimethylsilyloxy-4-alkoxybut-2-ynes by 1,4-elimination of Me3SiOH on
treatment with ethyllithium <81RTC34>. Dehydrohalogenation by strong bases has been widely used
to prepare allenes in good yields from unsaturated halopropanes with release of HX (Scheme 42)
<6UCS2687>. The reactive allenyl diazomethyl ketone (135) has been obtained from the bromo-
derivative (134) on treatment with l,5-diazabicyclo[4.3.0]non-5-ene (dbn) at —20°C <76JOC3326>.
Elimination of HC1 from the /J-chlorovinyl aldehydes (136) gave allenyl aldehydes (137) <70TL4315>,
whereas the elimination of HC1 from (138) using pyridine led to a 'push-pull' type cumulene (139)
Scheme 41
982 Ailenes and Cumulenes
containing the fulvene and heptafulvene units linked by a cumulative double bond <87AG(E)335>.
Similarly, l,3-di-ter/-butyl-5-vinylidene cyclopentadiene was obtained at low temperature by elim-
ination of HC1 from 6-chloro-6-methylpentafulvene using 2,2,6,6-tetramethylpiperidine lithium as
a base <86AG(E)466>. y-Ketoallenes have been prepared in 34—40% yield by reaction of dialkyl
ketones with 1,4-dibromobut-2-ene in the presence of NaH in DMSO at room temperature via a
process involving elimination of HBr <91CC294>. Tris(arylthio)butatrienes (141) have been obtained
by elimination of HC1 from l,2-dichlorobuta-l,3-dienes (140); these compounds rearrange at room
temperature into enyne derivatives <84LA1873>. Unsaturated /?-chlorosilanes (142) can eliminate one
molecule of chlorosilane in the presence of a fluoride (KF or Et 4 NF) to afford ailenes (143) <74TL17l,
84S384). The elimination of HX (X = Cl, C1O4) from l,l,3,3-tetrakis(dialkylamino) allylic chlorides
or perchlorates (144) with BuLi yields l,l,3,3-tetrakis(dialkylamino) ailenes (145) in good yields
(Scheme 42) <73AG(E)566>.
Scheme 42
The elimination of sulfur-containing units provides another route to cumulenes. Thus, desul-
furization of 4-vinylidene-l,3-dithiolane-2-thione (146) by l,3-dimethyl-2-phenyl-l,3,2-diazaphos-
pholidine (147) gives butatriene derivatives under very mild conditions (Scheme 43) <91S1151,
92AG(E)i6il>. Treatment of episulfides (148) with PBu3 at 130°C, or with dimethyl diazomalonate
in the presence of a rhodium catalyst, leads to desulfurization and gives cumulenes (Scheme 43)
<86T1989>. 1,2,3,4-Pentatetraenes (151) have been obtained in fair yields (>50%) by thermolytic or
photolytic desulfurization of episulfides (149), (150) (Scheme 43) <87TLl803, 89TL427I). Thermal
elimination of sulfur dioxide from the alkylidene sulfones (152) at 650°C affords vinyl allenes (153)
in states of good purity and high yields (Scheme 43) <83TL4691>.
Scheme 43
Addition of a ketone or a diketone to dibromotriphenylphosphine gives access to a bromide salt;

its treatment with Et 3 N leads to elimination of triphenylphosphine oxide and formation of terminal
allenes and allenyl ketones (72TL3257).
The thermal elimination of ArSeOH from vinyl selenoxides leads to allenes when the syn-
elimination to form a carbon-carbon triple bond is not possible (80JA5967). Based on the same
principle, the asymmetric oxidation of vinyl selenides (154) by David oxidants, or Bu'O2H in the
presence of Sharpless catalysts, leads to chiral allenic sulfones (155) (Scheme 44) <92CC46,93JOC3697).
Cyclic allenic esters (157) have been produced by oxidation of 3,4-polymethylene-2-pyrazolin-5-
ones (156) by thallium nitrate followed by ring opening with MeOH (Scheme 44) <80JOC3522>.
Allenes have been formed by acylation of/V-nitroenamines (158) with concomitant elimination of
N 2 O, but the reaction is not specific (depending on the site of deprotonation), and only low yields
of allenes have been obtained (Scheme 44) <79JOC4H6>.
Treatment of allylic mesylates (159) activated by a chiral sulfoxide group with Me2CuLi • Lil in
THF at — 78 CC gave allenes (160) corresponding to the formal elimination of MsOS(O)/>-Tol
(Scheme 45) <92TL4985>.
Butatrienes (162) have been obtained from 1-iodohex-l-yne and ?£?r?-hexyl boranc on reaction with
MeONa via the intermediate divinyl boranes (161) (Scheme 45) <91T343>. Oxidation of cumulenes by
w-chloroperbenzoic acid leads to alkylidene cyclopropanones, which photochemically release car-
bon monoxide to produce new cumulenes containing one double bond less (Scheme 45) (87JA4338,
92JA5998).
The reaction of propargyl alcohol with SOBr2 affords an example of intramolecular nucleophilic
substitution with formation of a carbon-carbon double bond. Bromoallenes (163) are thus formed
preferentially when the reaction is carried out in the presence of propylene oxide (Scheme 46)
<84TL3055>. Similarly, acyl allenes have been obtained by reaction of SOC12 with acyl propargylic
alcohols <85TL63l>.
The rearrangement of alkynic disilanes (164) initiated by FeCl3 or TiCl4 leads to 1,1 -bissilyl allenes
Scheme 44
Scheme 45
Scheme 46
on elimination of TMS-O-TMS (Scheme 46) <90TL5607>. Treatment of 2-halo-2-alkenoyl silanes

(165) with organolithium gives trimethylsilyloxy allenes after migration of the silyl group to the
oxygen atom and elimination of LiX <86JA779l>. A similar base-induced Brook rearrangement and
elimination of an ether group is observed in the formation of 4-[(benzyloxy)(terf-butyl)(methyl)
silyloxy]penta-l,2,3-triene on reaction of the corresponding acyl silane with lithium or bromo-
magnesium 3-tetrahydropyranyloxyprop-l-ynide <94TL1161>.
Treatment of chlorinated vinylic phosphirenes (166) with BuLi at — 78 °C gives phos-
phinobutatrienes (167) in good yields via C—P bond formation, rearrangement and elimination of
LiCl <92SL635>. Deprotonation of the benzothiophenium perchlorate (168) by MeONa leads to ring
opening and formation of the allene (169) (Scheme 46) <92CL1357>.
a-Hydroxyallenes have been prepared from 3-phenylselenobuta-l,3-dienes by oxidation with
H 2 O 2 , followed by sigmatropic rearrangement and elimination <84TL1987>.
The hetero-Cope rearrangement involved in the reaction of propargyl esters of N-acyl amino
acids (170) with phosgene leads to allenyl oxazolinones (171) after elimination of water through
prolonged heating at 50-70°C (Scheme 46) <75AG(E)58>.
1.20.4.2 Reduction of Unsaturated Alcohols and Halides
Reduction of 1,4-dihydroxy-2-butynes (172) by various reducing agents (e.g., PBr3, SnCl2/HCl)
has been used to prepare tetrasubstituted butatrienes <66BSF2885, 59CB1849). Reaction of the diols
(172) with EtOH in the presence of hot H 2 SO 4 leads to the synthesis of butatrienes <87IZV695>. The
extension of this reaction to 1,6-dihydroxy-2,4-hexadiynes (173) <66BSF2885> has recently been used
for the preparation of hexapentaenes (174) and bishexapentaenes as potential molecular materials
for nonlinear optics <93CM357> or as host molecules (Scheme 47) <91BCJ659>.
Scheme 47
Reductive dehalogenation of l,4-dihalo-2-butynes by zinc dust or even by an excess of Nal in

DMSO are simple routes to butatrienes. The reaction is possible under phase transfer conditions
<84AKZU6>, and when one halogen is replaced by an alkoxy group, a 1:1 mixture of an allenyl
ether and an alkynyl ether is obtained <67RTC129>. If the starting compound has a 2,5-dihalopent-
l-en-3-yne structure like (175), the reductive cleavage of halogen-carbon bonds with zinc dust leads
to pentatetraenes of type (176) <86AG(E)340> (Scheme 47).
It is also possible to generate butatrienes in good yields and high stereoselectivity by reduction of
2,3-diiodobuta-l,3-dienes using BuLi at —70°C <84CL131>.
1.20.4.3 Wittig and Related Reactions

The formation of allenes from phosphorus ylides and carbonyl compounds can be considered
either starting from an alkylidene phosphorane and a ketene <63CB1535> or from a vinylidene
phosphorane and carbonyl compounds. Both these strategies have been used to gain access to a
variety of functionalized allenes.
Terminal allenes have been obtained in 59-80% yields by reaction of stable phosphorus ylides
with C H 2 = C = O at 0-5 C C (Scheme 48) <70S543>. Electron-deficient allenes such as l,l,3,3-(tetra-
alkoxycarbonyl) allenes have also been prepared in more than 60% yield by treatment of alkylidene
phosphoranes with ketenes in refluxing benzene (79LA1388).
A similar process, based on the use of carboxylic acids or acyl chlorides that are able to give a
/^-elimination reaction in place of a ketene, can be used to prepare allenes (Scheme 48). Thus, ethyl
allenyl carboxylates have been obtained from [(ethoxycarbonyl)methylidene] phosphoranes (177)
and acids, in the presence of Bu3N and 2-chloro-l-methylpyridinium iodide <85HCA2244>. From
unsaturated acids like acrylic or propargylic acids, the formation of vinyl allenes takes place but
only in low yields (6-18%). In dichloromethane at room temperature, and in the presence of
Et 3 N, acyl halides react with [(alkoxycarbonyl)methylidene] phosphoranes (177) to provide allenes
<80HCA438, 92CPL243) and alkenyl allenes from a,/?-unsaturated acyl chlorides <85HCA2249>.
Scheme 48
l-Alkyl-3-bromo-l-pentafluorophenyl allenes (179) have been prepared from phosphoranes (178)

and bromoacetyl bromide at —20°C in THF <9UCS(Pl)665>. Unsymmetrical pentatetraenes (180)
have been prepared in good yields (50-75%) on reaction of a phosphorus ylide with allenyl acyl
chloride in the presence of Et 3 N at room temperature (Scheme 48) <86CB12O8>. Photolysis of
stabilized phosphoranes ylides with alkoxycarbene chromium complexes (181) under a carbon
monoxide atmosphere leads to allenes via formation of a ketene (Scheme 49) <92JA4079>. The
coordination of vinyl ketenes to a Fe(CO)3 moiety makes possible the direct synthesis of coordinated
vinyl allenes (182) <91CC129O, 92JCS(Pl)259> on reaction with phosphonoacetate in a Wadsworth-
Emmons type reaction <6UA1733> (Scheme 49). On reaction with phosphonium ylides, carbon
Scheme 49
dioxide allows the formal coupling of two carbenic moieties with the carbon atom of CO 2 <74TL1275>.
Alkynic phosphine oxides (or the corresponding sulfur-containing compounds) (183) react with
organomagnesium reagents in the presence of Cul to give nucleophilic species which couple with
aldehydes to afford alcohols of type (184). On treatment with NaH, the latter compounds give
allenes via a Wittig-Horner type elimination (Scheme 49) <74TL19O5>.
The other strategy based on the use of vinylidene triphenylphosphoranes can be exemplified by
the synthesis of push-pull allenes of type (185) from cyclic 1,2-diketones and 2,2-diethoxy vinylidene
phosphorane (Scheme 50) <73TL3985,75TL4405>.
Scheme 50
A new allene synthesis involving a boron-Wittig reaction of aldehydes with boron stabilized
carbanions at — 78°C has been recently reported (Scheme 50) <92JCS(Pl)747>. Regioselective halide
displacement from halogenated phosphonium salts gives rise to phosphacumulenes, which react
with ketones to afford butatriene derivatives <69JA6ll2>. The bromoalkenylphosphonium bromide
(186) gave a 53% yield of the cumulene diester (187) <87AJC1675>, whereas on reaction with ketones
in the presence of (Me3Si)2NLi at low temperature dibromo- or dichlorophosphonium salts (188)
led to halogenated butatrienes (189) (Scheme 51) (84CC152,87JOC443, 88TL4U, 90JOC2983).
The symmetrical butatriene (191) has been obtained in 7 1 % yield by reaction of fluorenone
with a propylidene phosphorane produced from methylidene triphenyl phosphorane and the gem-
dihaloalkene (190) (Scheme 51) <75TL4025). The Horner-Emmons type reaction starting from allenyl
diphenylphosphine oxide (192) <90TL7469>, or allenyl phosphonates (193) <85U136, 86JA343) and
aldehydes or ketones, makes possible the synthesis of butatrienes derivatives and bicyclic cumulenes
(194) via an intramolecular reaction (Scheme 52). Another strategy based on the intermediate
formation of a cumulenyl diylide is exemplified by the synthesis of 1,4-diphenylbutatriene from
benzaldehyde and the diphosphonium bistriflate (195) <91T4539>. Higher symmetrical cumulenes
have been obtained by Wittig reaction of carbon suboxide with 2 equivalents of phosphorus ylide
at room temperature (Scheme 52) <86AG(E)93,87G625>.
1.20.4.4 Addition of Carbene Moieties to Double Bonds

Unsaturated carbenes generated in situ by treatment of propargylic halides or esters with Bu'OK
react with alkenes to produce alkenylidene cyclopropanes (196) in moderate yields (10-52%)
(Scheme 53) (61JA4990, 7UA4527). Extended unsaturated carbenes like alkadienylidene, alka-
trienylidene and alkatetraenylidene carbenes have been generated from 1-ethynylvinyl triflates
<79JA4772, 82ACR348>, (l,3-diynyl)alkyl mesylate or halide <81JA4638, 88CC3O1, 88JOC3122), and
(l-butadiynyl)vinyl triflates (81JA6437, 82ACR348), respectively. These unsaturated carbenes give
access to a variety of cyclopropyl cumulenes and dimerized cumulenic compounds <87JA782>.
Silicon-, germanium-, and tin functionalized cumulenes have been prepared in good yields
(26-88%) on interaction of alkadienylidene <8UA5429> and alkatetraenylidene <8UA6437> carbenes
with Group 4 hydrides.
Scheme 51
Scheme 52
cw-Cumulenes (197) have also been prepared in 20-50% yields via homocoupling of two carbenes
generated from (a-methylthiovinyl) copper reagents and CH3I at 0°C in THF (Scheme 53)
<75TL2923>.
scheme 5J
1.20.4.5 Dehalogenation
1.20.4.5.1 Dehalogenation ofgem-dihalocyclopropanes

Treatment of #em-dihalocyclopropanes by alkyllithium at low temperature ( — 30 °C to room
temperature) gives allenes in good yields <63ACS1683,84CJC1558,84TL2887,85CC1812). Butatrienes have
also been prepared in approximately 75% yields by reaction of BuLi with #em-dibromo methylene
cyclopropanes <67JCS(C)194>. This strategy has been used for the synthesis of cyclic allenes (198)
<73JOC864, 86TL4679) and bisallenes (199) <90TLl84l>, bicyclic allenes (200) <82JOC1435>, and small
ring cyclic cumulenes such as cyclonona-l,2,3-triene (Scheme 54) <84JOC2880>.
Scheme 54
1.20.4.5.2 Dehalogenation ofgem-dihaloalkenes

Dimerization of #em-dihaloalkenes on treatment with alkyllithium leads to butatrienes via
1-halo-1-lithium alkene intermediates. Cumulenic thioesters (201) <83CPB3306> and tetra(2-thi-
enyl)butatrienes (202) <92CC778> were prepared in this way (Scheme 55). From these intermediates,
lithium can be exchanged with copper <86JA537l> to produce functionalized alkoxy (203) <88JA5567>,
alkynyl (204) <93AG(E)1187> and fluorinated (205) <91CC566> butatrienes (Scheme 55). 1-Halo-l-
lithio alkenes intermediates have also been generated on treatment of terminal monohalogenated
n
alkenes with Bu Li <84JOM(264)135, 84JOM(271)18l>. Aryl-substituted butatrienes have been con-
veniently prepared from 1,1-dibromoethenes using a nickel(O) catalyst at 50 °C (Scheme 55)
(84CL2005, 89CC1690).
Scheme 55
1.20.4.6 Reactions Involving Coordinated Organometallic Species

Coordinated cumulenes can be generated by reaction of suitable substrates with organometallic
complexes. The cumulene moiety can be eliminated from the metal centre by ligand exchange from
(206) <89CB1237>, oxidation of (207) with Me 3 NO <93OM397l> or protonation of (208) (Scheme 56)
<93AG(E)1315>. Cumulenic systems can also be formed from metal-vinylidene intermediates by
dimerization of the vinylidene ligand on thermal treatment <85U131, 90JOC1874, 87CC981) or ligand
exchange (Scheme 56) <92CB2667>.
Titanium complexes (209) or mixed titanium aluminum complexes (210) react with aldehydes or
ketones to afford allenes (8UA1276, 83JA5490, 93AG(E)554, 93JOC1298). Under similar conditions,
1-zinc-1-zirconium alkene reagents (211), (generated by reaction of zinc acetylides with H(Cl)Zr(Cp)2)
react with aldehydes in dichloromethane at 25 CC to smoothly produce allenes (Scheme 57) <9UA9888,
94OM94).
Scheme 56
Scheme 57
1.20.4.7 Metal-catalyzed Homocoupling of Alkynes or Cumulenes

Activation of terminal alkynes by metal complexes, via a vinylidene intermediate, makes possible
the catalytic synthesis of cumulenes. Ruthenium complexes such as H 2 Ru(CO)(PPh 3 ) 3 <76CC84l>,
or Ru(cod)(cot) <93BCJ987, 9UA9604) catalyze the dimerization of bulky terminal alkynes such as
to7-butylacetylene or trimethylsilylacetylene into the corresponding 1,4-disubstituted butatrienes
(Scheme 58).
Iyoda et al. have shown that the nickel(O)-catalyzed cyclodimerization of tetraarylhexapentaenes
led to new cumulenes such as the head-to-head dimers of type (212) <89JA376i>. Hexapentaenes
bearing bulky alkyl substituents gave the head-to-tail dimer (213) in good yield using a nickel(O)
catalyst in refluxing benzene (Scheme 58) <9OCL2149>.
Scheme 58
1.20.4.8 Intramolecular Rearrangement with Formation of a Heteroatom-carbon Bond

Intramolecular rearrangement involving heteroatom-carbon and carbon-carbon double bond
formation can take place from various functionalized propargyl derivatives. Thus, the condensation
of Ph 2 PCl with prop-2-yn-l-ol derivatives leads to the formation of alkynyl phosphinites (214),
which undergo rearrangement into allenes via intramolecular addition of the phosphorus atom to
the triple bond <62JOC1828, 89JA1770, 89TL4995).
Similarly, allenyl dihalophosphine oxides (215) were obtained at room temperature from pro-
pargylic alcohols and phosphorus trihalide via dihalopropargyl phosphites <76JOC3l9l>; the latter
compounds are useful intermediates for access to allenyl phosphonic derivatives and oxaphos-
pholenes. Allenyl dialkyl phosphates (216) have been prepared in 43-62% yields on rearrangement
of stable propargylic phosphates with AgClO 4 as catalyst (Scheme 59) <77JOC1804>. The same type
of silver-catalyzed reaction allows the efficient conversion of alkynyl esters into allenyl esters
<73HCA875, 77JOC1804).
The reaction of propargylic alcohols with sulfenyl chloride at low temperature in the presence of
a base leads to allenyl sulfoxides via unstable propargyl sulfenates <71JCS(C)153O, 88JA4062,93SL931).
This method has been used for the preparation of allenyl chloromethyl sulfones (217) as dienophiles
<90JA4072>, and in a key step for the modification of steroids <79JOC1582> (Scheme 60). The utilization
of sulfinyl chloride allows the obtention of allenyl sulfones via a similar intramolecular rearrange-
ment <87JOC403l>. Treatment of propargylic diol monothionocarbonates with (TMS)2NLi has been
used to produce heterocyclic allenes (218) <94TL1255>.
Allenyl trichloroacetamides (219) are formed by thermal interconversion of propargylic trichloro-
acetimidate, which isomerize into trichloroacetamidodienes on prolonged heating <(8OACR218>. Pro-
padienyl isothiocyanates (221) have been prepared by thermolysis of propynyl thiocyanates (220)
via a sigmatropic rearrangement in 7-20% yield in dilute solution at 60-100°C, or better in
95-100% yield in the gas phase at 400°C <92AG(E)90>.
Scheme 59
Scheme 60
1.20.4.9 Miscellaneous Reactions
Push-pull butatrienes like l,l-bis(dimethylamino)-4,4-dicyanobutatriene (222) <93TL1779> and
1,1 -bis(dimethylamino)-4,4-bis(methoxycarbonyl)butatriene (223) <78TL4263> have been synthesized
by coupling 1,1 -dimethylaminoethylene with 1,1-dichloroethylene compounds. Homologation of
alkynic compounds to allenes has been performed with formaldehyde and diisopropylamine in the
presence of CuBr as catalyst in refluxing dioxan <79CC859>. On bromination, divinylalkyne deriva-
tives containing naphthyl substituents lead to 1,6-dibromocumulatrienes (224) via 1,6-addition of
bromine (Scheme 61) <9OPJC123>. Deprotonation of the bisallene (225) by 2,2,6,6-tetra-
methylpiperidine lithium, followed by oxidation with CuCl2 at — 80 °C gives the hexapentaene (226)
<90PAC531>.
Scheme 61
1-21
Alkynes
MARK FURBER
Astra Charnwood, Loughborough, UK
INTRODUCTION 998
1.21.1 ALKYNES BY C—H BOND FORMATION 998
1.21.1.1 Reduction ofAlkynyl-Heteroatom Functions 998
1.21.1.1.1 Reduction of alkynyl hatides 998
1.21.1.1.2 Reduction of alkynyl-oxygen, -sulfur, -selenium or -tellurium functions 999
1.21.1.1.3 Reduction of alkynyl-nitrogen, -phosphorus, -arsenic, -antimony or -bismuth functions 999
1.21.1.2 Reduction of Alkynyl-Metalloid Functions 999
1.21.1.3 Reduction of Alkynyl-Metal Functions 1000
1.21.2 ALKYNES BY C—C BOND FORMATION 1000
1.21.2.1 Substitution Reactions of Alkynyl Carbanions 1000
1.21.2.1.1 Substitution of halogen 1000
1.21.2.1.2 Substitution of oxygen functions 1021
1.21.2.1.3 Substitution of sulfur, selenium or tellurium functions 1031
1.21.2.1.4 Substitution of nitrogen, phosphorus, arsenic, antimony or bismuth functions 1032
1.21.2.1.5 Substitution of boron, silicon or germanium functions 1033
1.21.2.1.6 Oxidative homocoupling reactions of terminal alkynes and their derivatives 1034
1.21.2.2 Addition Reactions of Alkynyl Carbanions 1036
1.21.2.2.1 Addition to carbon-carbon multiple bonded functions 1036
1.21.2.2.2 1,2-Addition to carbon-oxygen double bonded functions 1037
1.21.2.2.3 1,2-Addition to other carbon-chalcogen double bonded functions 1040
1.21.2.2.4 1,2-Addition to carbon-nitrogen multiple bonded functions 1040
1.21.2.2.5 1,2-Addition-elimination reactions 1044
1.21.2.2.6 1,4-Addition reactions 1048
1.21.2.3 Substitution Reactions of PropargyliAllenyl Carbanions 1051
1.21.2.3.1 Substitution of halogen 1052
1.21.2.3.2 Substitution of oxygen functions 1053
1.21.2.4 Addition Reactions of PropargyljAllenyl Carbanions 1054
1.21.2.4.1 1,2-Addition to carbon—oxygen double bonded functions 1054
1.21.2.4.2 1,2-Addition to other carbon-chalcogen double bonded functions 1058
1.21.2.4.3 1,2-Addition to carbon-nitrogen multiple bonded functions 1059
1.21.2.4.4 1,2-Addition-elimination reactions 1060
1.21.2.4.5 1,4-Addition reactions 1061
1.21.3 ALKYNES BY C = C BOND FORMATION 1062
1.21.3.1 Elimination Reactions 1062
1.21.3.1.1 Elimination of hydrogen 1063
1.21.3.1.2 Elimination of carbon functions 1063
1.21.3.1.3 Elimination of halogen 1063
1.21.3.1.4 Elimination of oxygen functions 1069
1.21.3.1.5 Elimination of sulfur, sellenium or tellurium functions 1072
1.21.3.1.6 Elimination of nitrogen functions 1075
1.21.3.1.7 Elimination of phosphorus, arsenic, antimony or bismuth functions 1079
1.21.3.1.8 Elimination of boron, silicon or germanium functions 1080
1.21.3.1.9 Elimination of metal functions 1080
1.21.3.2 Formation by Fragmentation Reactions 1081
1.21.3.3 Formation by Pericyclic Reactions 1083
1.21.3.4 Formation by Isomerisation Reactions 1084
997
998 Alkynes
INTRODUCTION
Alkynes are of enormous value both as products in their own right and, more importantly, as
synthetic intermediates from which the triple bond can be readily converted into a number of other
functional groups. Consequently, a number of synthetic methods have been developed for the
introduction of alkyne units into organic molecules. Many of these methods have been described,
for example in books by Raphael <B-55MI I2l-Ol>, Rutledge <B-68MI I2l-Ol>, Viehe <B-69MI I2l-Ol>
and Brandsma <B-71MI 121-01, B-88MI121-01) and in reviews by Ben-Efraim <B-78MI 121-03), Friedrich
<B-83MI 121-03) and Jones and Stanforth <B-91MI 121-01 >. In addition, more specialised reviews are
available and these are referenced in the appropriate sections of this chapter.
For the purpose of this review the preparation of alkynes is divided into methods of C—H bond
formation, C—C single bond formation and C—C triple bond formation (Figure 1). C—H bond
formation is clearly only applicable to terminal alkynes and even then has little practical value aside
from alkyne protection-deprotection sequences. C—C single bond formation encompasses the large
class of substitution and addition reactions of terminal alkynes and their anions, and also the
somewhat smaller class of substitution and addition reactions of propargyl/allenyl anions. C—C
triple bond formation is dominated by elimination reactions, although fragmentation, isomerisation
and electrocyclic reactions are also included within this section.
Figure 1
Figure 1 Methods of Alkyne Formation.
1.21.1 ALKYNES BY C—H BOND FORMATION

Aside from the production of ethyne and propyne by the hydrolysis of carbides, terminal alkynes
can be prepared by the cleavage of alkynyl-heteroatom and alkynyl-metalloid/metal bonds (Equa-
tion (1)). In most cases the reaction is of little synthetic value since most effort has been devoted to
the reverse transformation, that is, the conversion of 1-alkynes into the corresponding 1-substituted
derivatives. Exceptions are the usually trivial hydrolysis of alkynylmetal compounds and the cleavage
of alkynyl-silicon bonds in alkyne protection/deprotection sequences.
R = x - R ^ ^ (l)
X = heteroatom, metalloid or metal function
1.21.1.1 Reduction of Alkynyl-Heteroatom Functions
1.21.1.1.1 Reduction of alkynyl halides

1-Alkynyl halides are most commonly converted into the corresponding free alkynes by treatment
with organolithium reagents followed by hydrolysis of the intermediate alkynyllithium. The reaction
is applicable to alkynyl chlorides, bromides and iodides. Similar halogen-metal exchange reactions
are observed on treatment of 1-bromo- and 1-iodoalkynes with Grignard reagents or with the
sodium salt of diethylmalonate <63RTC183>. 1-Alkynyl halides have also been converted into the
free alkynes by treatment with metallic sodium in ether <B-69MI I2l-O5>, copper metal in acetic acid
<82TL2373> and with a copper hydride reagent derived from potassium tri-j-butylborohydride and
copper(I) iodide <74CC762>.
1,21.1.1.2 Reduction of alkynyl-oxygen, -sulfur, -selenium or -tellurium functions

1-Alkynyl ethers can be reduced to 1-alkynes by diisobutylaluminum hydride, as illustrated by
the conversion of 1-methoxyhexyne into hexyne in 32% yield <66JOC329>. 1-Alkynylthioethers are
most commonly cleaved by reaction with alkali metal amide and alkyllithium reagents (64RTC307,
B-69MI 121-06). The course of the reaction depends on the structure of the thioether, but in the
absence of an acidic y-proton exclusive nucleophilic substitution at sulfur occurs to furnish the
1-alkyne on hydrolysis. 1-Alkynyl selenides display an even greater propensity to undergo sub-
stitution at the heteroatom with organolithium reagents, and generally afford 1-alkynes on hydroly-
sis of the intermediate alkynyllithium. In comparison, 1-alkynyl ethers undergo addition—elimination
reactions with organolithium reagents (see Section 1.21.3.1.2(iii)). Alkynyl tellurides have been
reduced with sodium borohydride in ethanol to afford 1-alkynes <88OM84>.
1-Alkynyl sulfoxides afford 1-alkynes on treatment with Grignard reagents (74RTC240). The
reaction presumably proceeds by attack of the Grignard reagent at the sulfur atom of the sulfoxide.
1-Alkynyl phenylselenoxides undergo hydrolysis with aqueous base to afford 1-alkynes and, in view
of their ready removal by mcpba oxidation and hydrolysis, phenylselenoethers have been proposed
as protecting groups for 1-alkynes <86SC283>. In an isolated example phenyl (/Mnethoxyphenyl-
telluro)ethyne has been reported to afford phenylethyne as the sole product on oxidation with
mcpba <90SC2l8i>.
1.21.1.1.3 Reduction of alkynyl-nitrogen, -phosphorus, -arsenic, -antimony or -bismuth functions

1-Alkynyl amines are not readily converted into 1-alkynes. In contrast, 1-alkynyl phosphines
undergo cleavage of the carbon-phosphorus bond on treatment with strong alkali <63N403), organo-
lithium reagents <62RTC993> and lithium metal <66JOM(5)205>. In a similar manner, the action of
PhLi on the oxide of diphenylethynylphosphine leads to the formation of phenylethyne <66BSF97l>.
Alkynyl derivatives of arsenic <57ZAAC(290)348>, antimony <61ZAAC(312)186> and bismuth
<62ZAAC(317)54> readily undergo cleavage of the carbon-heteroatom bond affording the 1-alkyne
with water or aqueous base.
Alkynyl phosphonium and arsonium salts are readily cleaved by water <(62CB319,64TL983), aqueous
base <87IJC(B)77> or basic alumina <56ZAAC(287)26i>.
1.21.1.2 Reduction of Alkynyl-Metalloid Functions

The alkynyl-boron bond of 1-alkynylboranes and 1-alkynylboronates is cleaved by a variety of
proton donors, that is, proton acids, alcohols and water <83COMC-I337, 88TL2631). The reaction of
alkynylborates with proton donors is dependent on the acidity of the reagents and the migratory
aptitude of the other ligands on boron. Weak proton donors and ligands of low migratory aptitude
favour protonolysis of the alkynyl-boron bond. Strong acids and ligands of high migratory aptitude
favour protonation of the alkynyl group followed by 1,2-migration of an organic group from boron
to the alkynyl oc-carbon atom <83COMC-I337,88TL4181).
The cleavage of alkynyl-silicon bonds is a valuable reaction in organic synthesis since silyl
protection is commonly used for the storage, protection and selective functionalisation of terminal
alkynes. Commonly employed deprotection conditions include: tetrabutylammonium fluoride in
THF or DMF <73TL1495>, potassium fluoride dihydrate in methanol <67JOM(8)239>, silver nitrate
in aqueous methanol followed by potassium cyanide <67RTC1138, 68TL5041) or potassium iodide
<87TL3923>, methanolic alkoxide <5UA5864> and carbonate <92AG(E)124O> solutions, aqueous solu-
tions of sodium hydroxide with <86SC983> and without <65JOM(4)217> phase-transfer catalysis and
aqueous solutions of sodium bicarbonate <69JCS(C)2273>, potassium carbonate <73T883> and sodium
1000 Alkynes
borate <72JOM(37)45>. The rate of protodesilylation depends on both the nature of the cleavage
reagent and on the particular silicon and carbon substituents. Through appropriate choice of
substituents, selective cleavage reactions can be achieved.
The cleavage of alkynyl-germanium bonds has been accomplished under aqueous base (63RTC183,
65JOM(4)217> and acid conditions <60BSF856,64JOM(l)420>.
1.21.1.3 Reduction of Alkynyl-Metal Functions

Alkynyl-metal bonds are cleaved by acid hydrolysis. For active metals such as Mg, Li, etc., water
is sufficiently acidic. For alkynyl derivatives of less electropositive metals such as copper <72S63>,
tin <65BSF35> and lead <68BSF1O85>, stronger acid conditions are required. Alkynylmercury com-
pounds have been cleaved with cyanide ion <58JA6626>.
1.21.2 ALKYNES BY C—C BOND FORMATION

Alkynes are frequently prepared by substitution, addition and addition-elimination reactions.
Many of these reactions can be further categorised into reactions of alkynyl carbanions and reactions
of propargyl/allenyl carbanions.
1.21.2.1 Substitution Reactions of Alkynyl Carbanions

The coupling of sp and sp3 centres can be achieved by the alkylation of an alkynyl carbanion or
by alkynylation of an alkyl organometallic reagent (see Section 1.21.2.1.l(iii)). In practice, by far
the most important process involves the use of a deprotonated alkyne as the nucleophile. Detailed
procedures for the preparation of alkynyl carbanions are described in two excellent books by
Brandsma <B-71MI 121-01, B-88MI121-01 >.
1.21.2.1.1 Substitution of halogen
(i) Substitution involving alkyl halides

The alkylation of terminal alkynes has traditionally been carried out using sodamide suspended
in liquid ammonia to form a sodium alkynide, which is then alkylated with the appropriate alkyl
halide <B-71M1 I2l-Ol>. Essentially the reaction is limited to primary alkyl halides with a carbon
chain unbranched at the ^-position. /^-Branched primary alkyl halides give a mixture of substitution
and elimination products while secondary and tertiary alkyl halides (and also primary alkyl halides
containing an electron-withdrawing group at the /^-position) undergo almost exclusive elimination.
Even with primary alkyl halides variable yields have been observed due to the low solubilities of
higher alkyl halides (greater than C5) in liquid ammonia. To overcome this problem other solvents
have been investigated both alone and as cosolvents with liquid ammonia (Scheme 1) <37JOCl,
5OJCS115, B-71MI 121-01, 74S441, 86TL573, 88S250>.
The use of lithium alkynides in liquid ammonia with THF as the cosolvent has been reported to
give good yields with alkyl bromides <J7T1845>. Dipolar aprotic solvents such as DMF, hexa-
methylphosphoramide (HMPA) and DMSO have been used successfully. DMF has been used as
solvent alone <59AG245,61T18> or as a cosolvent with THF <65BSF859> or xylene <59JOC840>. HMPA
has been used very successfully as solvent alone (73SC245, 74SC199) or as a cosolvent with THF
(65BSF859, 65BSF1872, 72S567, 75S423). Reactions occur rapidly at or below room temperature and
yields are high even with alkyl chlorides. Since the early 1980s, however, HMPA has been shown
to be highly carcinogenic and the HMPA substitute A^-ZV-dimethylpropyleneurea (DMPU) might
prove preferable since it has been observed to promote the alkylation of lithium alkynides with
equal effect <88S250>. DMSO has been used successfully as solvent alone or as a cosolvent with
liquid ammonia, but due to competing metallation of this solvent <73JOC3588>, the use of DMSO is
best restricted to alkylations using ethynyllithium itself (or the commercially available ethy-
nyllithium-ethylenediamine complex) <74S441> or lithium alkynides possessing inductively sta-
bilising electron-withdrawing groups <86TL5445>. Dioxan has also been used as a solvent at
temperatures of 100-150°C and gives moderate yields of branched alkynes from secondary alkyl
Scheme 1
bromides <58LA37,68JMC371,68JMC373). Lithium salts in refluxing THF have been recommended for
the cyclisation of acyclic diterminal diynes with dihaloalkanes (Equation (2)) <(93S558>. Magnesium
alkynides are inert towards even primary alkyl halides in the absence of catalysis by other metals.
(2)
Unprotected co-hydroxy-1-alkynes (63JCS5889,64BSF2477,68AJC2989, B-71MI121-01) and co-carboxy-

1-alkynes <74SC199> can be selectively monoalkylated by treatment of the dilithium compounds with
one equivalent of alkyl halide. Similarly, unprotected co-haloalkanols <63JCS5889> and
co-haloalkanoic acids <63JCS775,63JCS5889,65JCS894,67TL401,74SC199,74TL423) can be used to alkylate
lithium and sodium alkynides in the presence of an extra equivalent of the metal alkynide. Carbonyl
groups in either coupling partner are protected as acetal, ketal or ortho-ester functions. Rep-
resentative examples of the alkylation of alkynyl carbanions in multifunctional substrates are given
in Scheme 2 <84CC350, 89CB193, 90JOC791).
The alkylation of ethyne itself is complicated by disproportionation of the monoanion driven by
precipitation of the dianion from many organic solvents. The monoanion is stabilised by liquid
ammonia but in this solvent alkylation is poor. The commercially available complex of ethynyl-
lithium and ethylenediamine is stable and soluble in DMSO, and alkylations occur in good yield in
this solvent <74S44i>. As expected, 1-bromoalkanes and 1-iodoalkanes are more reactive and give
the same or higher yields than 1-chloroalkanes, which require forcing conditions for complete
reaction.
The reaction of Group 1 alkynides with allylic and propargylic halides is complicated by multiple
alkylation, isomerisation and polymerisation reactions. For example, in a study of the reaction of
sodium alkynides with allylic halides in liquid ammonia it was found that complex isomeric mixtures
of mono-, di- and tri-allylation products were obtained <75LA2130>. Surprisingly, addition of lithium
iodide has been reported to improve matters and allows the high yield coupling of lithium hexynide
with crotyl chloride <80CL669>. This procedure is reported to be applicable to other allylic halides
1002 Alky ties
Scheme 2
and lithium alkynides, and has been applied in an intramolecular reaction to produce the
14-membered ring of the marine natural product crassin acetate (Equation (3)) <91TL3605>. Group 2
alkynides show little reactivity in the absence of other metal catalysts. The use of copper(I) alkynides
has, however, proven successful in these reactions <B-69MI 121-03, 72S63). Good results have been
obtained using preformed copper(T) alkynides, or copper(I) alkynides generated in situ from terminal
alkynes or lithium and magnesium alkynides (Scheme 3) (83TL5185, 92TL135). Propargylic and
unsymmetrically substituted allylic halides have the potential to produce regioisomeric products
and the factors governing product regiochemistry are often unclear. Propargylic halides generally
afford 1,4-diynes as the main products when R2 = alkyl and allenynes when R2 = H (Scheme 4),
although exceptions are known. In a similar manner, allylic halides generally undergo substitution
at the least hindered end of the allyl system although the ratio of normal allylation product to
isomeric allylic rearrangement product can be strongly influenced by the reaction conditions
<77T1845>. High regioselectivities have been described for the coupling of allylic and propargylic
halides with 1-alkynes in the presence of copper(I) halides and l,5-diazabicyclo[5.4.0]undec-5-ene
(dbu) or l,5-diazabicyclo[4.3.0]non-5-ene (dbn) to afford 1,4-enynes and 1,4-diynes respectively
<78LA658>. 1,4-Enynes and 1,4-diynes have also been formed in high yield from the coupling of
allylic <89TL2225> and propargylic <92TL5757> halides with 1-alkynes in the presence of copper(I)
iodide, sodium or potassium carbonate and tetra-n-butylammonium chloride, in DMF or aceto-
nitrile. The mild reaction conditions (room temperature, 2-24 h) are compatible with a number
of functional groups, including esters and unprotected hydroxys. Allylic bromides also undergo
substitution by 1-alkynes under more classical phase-transfer conditions, using a concentrated
alkali-dichloromethane biphasic system, copper(I) chloride and Aliquat-336 or triethyl-
benzylammonium chloride <92JOC2188>.
(3)
Alkynylboron reagents do not undergo substitution reactions with alkyl halides although highly
successful methods are available for preparing alkylated alkynes using these reagents (see Section
Scheme 3
Scheme 4
1.21.3.1.5). Alkynylaluminum reagents do, however, undergo alkylation and provide one of the few
satisfactory methods available for direct tertiary alkyl-alkynyl coupling. Thus, treatment of lithium
alkynides with aluminum trichloride leads to trialkynylaluminum intermediates which undergo
coupling with tertiary alkyl chlorides and bromides in high yield (Equation (4)) <75JA7385>. Primary
and secondary alkyl halides do not undergo substitution reactions with these reagents. The yields
obtained through this procedure are much higher than those observed in the reactions of tertiary
alkyl chlorides with 1-alkynes in the presence of Friedel-Crafts catalysts, where the yields of
the coupling products are, in general, disappointingly low <B-64MI 121-01). An exception to this
generalisation is the reaction of alkynylsilanes with tertiary alkyl chlorides and bromides in the
presence of aluminum trichloride which can proceed in high yield <82CC959>. This 'Friedel-Crafts
like' reactivity of alkynylsilanes has been applied intramolecularly in the cyclisation of homo-
conjugated polyalkynes <85JA6546>.
(4)
Examples of substitution by alkynyltin reagents are also known. Thus treatment of mixed halo
acetals containing O, N and S heteroatoms with tri-«-butyltinalkynides in the presence of zinc
1004 Alkynes
chloride leads to the formation of a-alkynyl ethers, amines and sulfides. This methodology has been
applied to the synthesis of amino acids and C-glycosides <88JA2501>.
Transition metal mediated cross-coupling reactions have been limited to allylic and propargylic
halides <82ACR340>. The coupled product is obtained in almost quantitative yield when a copper(I)
salt of phenylethyne is reacted with allyl bromide in HMPA in the presence of tetra-«-butyl-
ammonium iodide and (PPh3)2Pd(I)Ph <81IZV2836>. Alkynylzinc, copper, silver and magnesium
reagents undergo palladium-catalysed cross-coupling reactions with propargyl bromides to afford
high yields of conjugated allenynes <81TL1451,82RTC405). Similarly, propargylic halides couple with
1-alkynes themselves in the presence of a base and Pd(PPh3)4 and copper(I) iodide catalysts to
afford substituted allenynes, including 1,1-disubstituted, 1,3-disubstituted, tri- and tetrasubstituted
allenynes <93TL3853>. Alkynyltin reagents, alkynylsilanes and 1-alkynes themselves have been
observed to undergo more complicated palladium-catalysed reactions with allylic halides (Equation
(5)) <79JOC55, 82CL1485, 90JOC5833>.
(5)
(ii) Substitution involving alkenyl, allenyl or aryl halides

The coupling between sp and sp2 carbon atoms is most commonly achieved by the reaction of an
alkenyl, allenyl or aryl halide with a 1-alkyne or an alkynyl organometallic reagent (Scheme 5). The
reverse process, involving alkynylation of an alkenyl, allenyl or aryl organometallic, is discussed in
Section 1.21.3.1.1 (iii).
Scheme 5
Traditionally, the coupling between sp and sp2 centres has been achieved through the use of
alkynylcopper reagents. The Castro-Stephens reaction between an aryl iodide and a copper(I)
alkynide in refluxing pyridine has been used with particular success for the preparation of diaryl
alkynes (Equation (6)) (63JOC3313,64JA4358). The copper(I) alkynide is usually preformed by reaction
of the terminal alkyne with copper(I) chloride in an appropriate solvent <72S63>, but it can also be
generated in situ by reaction of the terminal alkyne with copper(I) iodide in the presence of an amine
base such as dbu <93JOC2694>, by reaction with copper powder in the presence of an inorganic base
such as K 2 CO 3 <83JCR(M)167> or by reaction of a preformed metal alkynide with a copper(I) halide
<77JOC2626>. Halogen reactivity follows the order 1 > Br > C l » F and, when the reaction is carried
out under nitrogen to avoid oxidative coupling of the alkyne, yields are usually high. Diverse
functional groups can be tolerated in both the halide and the alkyne, although nucleophilic sub-
stituents (OH, SH, NH 2 , CO 2 H, NO2) in the ortho position of aryl halides give rise to cyclisation
products <66JOC407l>. Electron-withdrawing groups in the halide accelerate the reaction although
high temperatures (ca. 100°C) and stoichiometric quantities of copper are generally still required
for the reaction. Several reviews of the reaction have been published <75OR(22)253, B-74MI 121-01,
B-80MI 121-01, 84T1433); representative examples are provided in Scheme 6 <64JA4358, 77JOC2626,
78TL3195, 83JCR(M)167>.
(6)
Scheme 6
Although relatively few examples have been reported, alkenyl and allenyl halides will undergo
coupling reactions with copper(I) alkynides under certain conditions (Scheme 7) <67CC1259,73TL1019,
89SC2199). Successful couplings have been achieved with /?-bromostyrenes and with the iodine
bearing carbon atoms of l-chloro-2-iodoethylene and 1,2-diiodoethylene in refluxing pyridine or
DMF <67CC1259, 68JOU21, 72JCS(Pl)639>. In JV-methylpyrrolidone or in the absence of solvent at
220 °C, alkenyl halides have been reported not to react with copper(I) alkynides <69JA6464>. A more
generally applicable procedure is the reaction of terminal alkynes with alkenyl iodides or bromides
in the presence of copper(I) iodide or bromide in HMPA <89SC2199>. This reaction is stereospecific
and is applicable to both alkyl and aryl substituted alkynes. Allenyl bromides have been reported
to couple with terminal alkynes in the presence of copper(I) bromide and an amine base <73TL1O19,
75JCS(P1)1628>.
Scheme 7
Terminal alkynes can be prepared through the use of protecting groups. Ethyne, protected at one
terminus, can be introduced on to the alkene, allene or aryl nucleus via coupling at the free terminus.
Subsequent removal of the protecting group generates a terminal alkyne. Commonly used protecting
1006 Alkynes
groups are acetals <77JOC1480,77JOC2626), ketones <74JOU1990>, ketals <67JCS(C)20l l>, hydroxymethyl
<67JCS(C)578, 75JOM(93)253>, tetrahydropyran-protected hydroxymethyl <67JCS(C)578, 70IZV1144),
dimethylcarbinol and ethyl vinyl ether-protected carbinol <71IZV1534, 72IZV472) and ethyl ester
<69JCS(C)2173>. The conditions required for removal of these protecting groups can be incompatible
with sensitive functionality elsewhere in the product. Trimethylsilyethynyl copper is reported to be
unstable under the usual Castro-Stephens conditions <75JOC131> while trimethylsilylbutadiyne
undergoes coupling with allenyl bromides in moderate yield <73TL1O19>.
Although the use of stoichiometric quantities of copper(I) salts can be limiting, it has been
reported that the coupling of alkenyl and aryl halides with terminal alkynes proceeds efficiently with
catalytic copper(I) iodide in the presence of potassium carbonate and triphenylphosphine (Equation
(7)) <92TL5363>. Yields are high in the quoted examples, but the required reaction temperatures are
also relatively high and it seems unlikely that this process will compete with the now widely used
palladium-catalysed coupling reaction which proceeds at or below room temperature (see below).
Cul (cat.), 2PPh3, K2CO3

R'X + R2^SE - R2 — R' (7)
DMF or DMSO
80-120 °C, 5-26 h
85-96%
Transition metal-catalysed cross-coupling reactions, particularly those based on palladium, have

dominated the area of sp-sp1 carbon-carbon bond formation in recent years and have been used
with remarkable success in natural product synthesis. Palladium mediated sp-sp1 coupling processes
have emerged involving either the terminal alkyne or its metallated counterpart.
(a) Reaction of metallated alkynes with alkenyl, allenyl or aryl halides in the presence of catalytic
quantities of Pd(II) or Pd(0) compounds (Equation (8)). By appropriate choice of metal, palladium
catalyst and solvent, very high yields of coupling product can be obtained under mild conditions
(Scheme 8) <77CC683, 78JOC358, 82RTC405, 83JOM(250)55l, 87JA2138). With alkenyl and allenyl halides
the reaction proceeds with retention of the double bond geometry, although inappropriate choice
of catalyst can lead to long reaction times and to product isomerisation. Terminal alkynes can be
prepared without recourse to protecting groups. With respect to the metal, the reactivity of met-
allated alkynes shows an interesting trend. Highly electropositive metals such as sodium, lithium
and magnesium are often less effective than metals of intermediate electronegativity, possibly due
to the formation of stable tetraalkynylpalladates with the former reagents <87CC477>. In most cases
alkynyltin (81JOU18, 83DOK(272)1384, 83JOM(250)551, 87JA2138), alkynylzinc <77CC683, 78JOC358) and
alkynylcopper <81IZV2836, 83JOM(250)55l> reagents appear to be optimal with respect to reactivity
and toleration of functionality in both coupling partners. With organotin reagents alkyl groups
have the slowest transfer rate, thus by using a trimethyl- or tributylalkynyltin reagent the alkynyl
group is transferred exclusively. Although the trimethyltin reagents are more reactive and allow for
easier product purification (Me3Snl is water soluble), the tributyltin reagents are more stable and
can be purified by chromatography and stored. The preparation of alkynylcopper reagents has
already been described; alkynyltin and alkynylzinc reagents are generally prepared by reaction of
the lithium or magnesium alkynide with a trialkyltin chloride or with zinc chloride. Alkynyltin
reagents have also been prepared by the condensation of a terminal alkyne with bis(triethyltin)oxide
or by reaction with an ,/V-trialkylstannylamine <92SLI99>. Alkynylmagnesium reagents have been
used successfully but their scope is limited <84T2773>.
(8)
Coupling rates and yields are frequently very sensitive to the particular transition metal catalyst
employed. In contrast to sp1sp1 and sp3sp2 coupling reactions, the product yields in nickel-catalysed
sp-sp2 coupling processes are substantially lower than those realised under palladium catalysis,
presumably because the alkyne-containing starting compounds and/or products tend to react more
readily with nickel catalysts than with similar palladium catalysts to form polymers, most notably
cyclic trimers and tetramers. In practice, therefore, palladium catalysts are used almost exclusively.
The rate of the coupling reaction and/or the reaction temperature can also be very sensitive to the
particular palladium catalyst used. Higher ratios ofphosphine ligand to palladium slow the reaction
and higher temperatures are generally required to achieve the same yields of products. Thus, in the
Scheme 8
reaction of alkynyltin reagents with alkenyl halides, higher reaction temperatures and/or longer
reaction times are required for tetrakis(triphenylphosphine)palladium than for bis(triphenyl-
phosphine)palladium dichloride <87JA2138>. Bis(acetonitrile)dicnloropalladium in the weakly coor-
dinating solvent DMF is also a very active catalyst, giving high yields of coupled products
instantaneously at ambient temperatures and within 3 min at — 50°C <87JA2138>.
Reactivity of the alkenyl, allenyl or aryl halide follows the order 1 > Br > C l » F and with respect
to the sp2 centre, alkenyl > allenyl > aryl. Iodides and bromides generally undergo coupling reactions
under mild conditions, although unactivated aryl bromides can require elevated temperatures.
Chlorides are generally unreactive unless activated by electron-withdrawing substituents. Fluorides
are inert.
Marked reactivity differences between stereoisomeric alkenyl halides have been observed with the
£-isomers showing the highest reactivity. This observation has been used very effectively in highly
diastereoselective mono- and dialkynylation of a commercial mixture of E/Z-dibromoethylenes
(Equation (9)) <86TL435l> and in the monoalkynylation of a commercial mixture of is/Z-bromo-
trimethylsilylethylenes <88TL2239>.
(9)
A potentially very useful one-pot synthesis of stereodefined l,5-diene-3-ynes has been described
involving the sequential coupling of trimethylstannyl(trimethylsilyl)ethyne with two different alkenyl
iodides (Scheme 9) <89TL2403>. The greater reactivity of the carbon-tin bond in the presence of
Pd(PPh3)4 allows selective coupling with an alkenyl iodide to give a trimethylsilyl-substituted enyne
intermediate (1). The carbon-silicon bond is normally inert under the usual palladium-catalysed
carbon-carbon bond forming conditions, but in situ activation with tris(diethylamino)sulfonium
trimethyldifluorosilicate (tasf) enables a palladium-catalysed cross-coupling reaction with a second
alkenyl iodide <88JOC918>. Transmetallation presumably proceeds due to the enhanced nucleo-
philicity of a pentacoordinated silicate, or even a naked anion, generated on treatment with the
fluoride ion source.
1008 Alkynes
Scheme 9
Alkynylzinc reagents undergo palladium-catalysed coupling with Z-bromoalkenyl boranes gen-

erated in situ from terminal alkynes and boron tribromide (Scheme 10) <88TL1811 >. The intermediate
alkenylborane can be further transformed by protonolysis or by palladium-catalysed coupling with
an organic halide in the presence of a base.
R1 = n-C6H13, R2 = Bu"C=C, R3 = H, 61%

R1 = n-C6H13, R2 = BunC=C, R3 = Ph, 54%
Scheme 10
Although the potential of this general approach to the formation of sp-sp2 carbon-carbon bonds
is well recognised, its use for the preparation of complicated natural products and their analogues
has been limited (Equation (10)) <87JMC193>. Two reasons for this are apparent. In the first instance,
the reaction requires the prior formation of a metal alkynidc under conditions (strong base) which
might not be compatible with functionality elsewhere in the molecule. Secondly, a milder procedure
involving the palladium-catalysed coupling of terminal alkynes themselves with alkenyl, allenyl and
aryl halides, and related electrophiles, is available and has been used with great success in the natural
products area.
(10)
(b) Reaction of terminal alkynes with alkenyl, allenyl or aryl halides in the presence of catalytic
quantities of Pd(II) or Pd(0) compounds and a base (Equation (11)). Terminal alkynes can be
coupled directly to alkenyl, allenyl and aryl halides in the presence of a palladium catalyst and a
base. The reaction was independently reported by three groups. Cassar demonstrated that alkenyl
and aryl bromides and iodides undergo a palladium-catalysed alkynylation in the presence of sodium
methoxide at 40-100°C, over 3-8 h <75JOM(93)253>. Dieck and Heck carried out similar reactions
using amine bases at 100°C, the reaction times ranging from 0.5 h to 2.25 h <75JOM(93)259>.
Sonogashira et al. used a Pd(PPh3)2Cl2/CuI/Et2NH system at room temperature to provide a range
of alkenyl and aryl substituted alkynes after 3-6 h <75TL4467>. Both copper(I) iodide and bromide
have been demonstrated to accelerate these reactions significantly, and this variant of the procedure
is used in most cases. In the absence of copper(I) co-catalysis no reaction generally occurs at room
temperature unless the substrate is highly activated. An additional advantage to the use of copper(I)
co-catalysis is the diminished triphenylphosphine contamination of the reaction products
<89JOC4453>.
(ll)
The most commonly employed palladium catalysts are Pd(PPh3)4, Pd(PPh3)2Cl2 and
Pd(OAc)2/PPh3, although other systems such as 10% Pd on carbon/PPh 3 have been used with
success. Amine bases are used almost exclusively. A wide variety of amine bases including n-
propylamine, «-butylamine, diethylamine, piperidine and triethylamine has been used successfully,
often as the reaction solvent.
Reactivity follows the usual order 1 > Br > C l » F and alkenyl > allenyl > aryl. With unactivated
aryl rings, iodides and bromides can be used although the iodides are substantially more reactive,
requiring lower temperatures and shorter reaction times. Chlorides generally show poor reactivity
unless electron-withdrawing substituents are present on or within the ring. Fluorides are inert. The
reaction shows a marked sensitivity to substituent effects; the relative reaction rates for the reaction
of substituted bromobenzenes with 1-heptyne catalysed by 2 mol % Pd(PPh,) 4 and 3 mol % CuBr
are:/>-NO2 (1800), p-CN (1190),^-CHO (313),/>-H (38) and/7-OCH3 (1) <89JOC4453>. With prolonged
reaction times, however, even hindered and highly electron-rich aryl iodides undergo successful
coupling reactions with terminal alkynes <89JOC249>. Electron-withdrawing groups directly attached
to the alkyne adversely affect the coupling reaction. For example, the reaction of iodopyrimidincs
with ethylpropiolate fails to give the cross-coupling product, while the reaction with an alkyl or
arylethyne gives the desired ethynylpyrimidines <78H(9)27i>. Similar results in the palladium-cat-
alysed reaction of iodobenzenes with perfluoroalkylethynes have been described <90BCJ2124>. To
overcome this problem 3,3,3-trifluoro-l-pentynylzinc chloride was used in the place of 3,3,3-
trifluoro-1-pentyne itself, and was successfully coupled to iodobenzene in high yield. 3,3,3-Tri-
ethoxypropyne has been used successfully as a replacement for ethyl propiolate <92S|46>.
A wide variety of heteroarylalkynes have been prepared under palladium and copper co-catalysis
(Table 1). Yields are invariably high and a wide variety of functional groups is tolerated in both the
halidc and the alkyne.
Aryl and heteroaryl dihalides and polyhalides can undergo selective mono-, di- and poly-
substitution under appropriate conditions. As expected, 1,2-dibromo-4-nitro- and l,2-dibromo-3-
nitrobenzenes undergo alkynylation to rapidly provide the product in which the bromine para or
ortho to the nitro group is replaced, whereas the corresponding dibromoaminobenzenes slowly
provide the product otmeta substitution <89JOC4453>. 1,2-Dibromo- and diiodobenzene will undergo
selective monoalkynylation under the appropriate conditions; the second alkynylation proceeds at
approximately one-tenth the rate of the initial alkynylation, allowing a subsequent alkynylation
using a different alkyne (Scheme 11) <92TL2315>. Mixed bromoiodoaromatics were found to undergo
alkynylation reactions more rapidly at the iodo positions, and some selective reactions have been
achieved (Scheme 12) <90JOC63>. Peralkynylation of polyhaloaromatic and polyhaloheteroaromatic
systems is readily achieved. For instance, hexaethynylbenzene is prepared from either hexabromo-
or hexaiodobenzene in moderate yield by cross-coupling with trimethylsilylethyne, followed by
desilylation (Scheme 12) <86AG(E)268,90JOC63>.
Alkenyl and allenyl halides are more reactive than the corresponding aryl halides and undergo
stereospecific cross-coupling reactions with terminal alkynes (Scheme 13) <75JOM(93)253,75JOM(93)259,
75TL4467, 81TL1451, 83S32>. Both bromides and iodides react readily at room temperature under
copper(I) co-catalysis. As seen with aryl systems, electron-withdrawing groups on the alkenyl halide
accelerate the reaction; thus coupling with a range of 3-bromopropenoates has been observed at
room temperature in the absence of copper co-catalysis <8()JOC4926>. Although chlorides are less
reactive, activated systems such as 1,1-dichloroalkenes <87TU649> and (£)- and (Z)-l,2-dichloro-
alkenes (85TL709, 85TL3811) undergo facile coupling reactions (Scheme 14) <81TL315, 85TL3811,
86TL5857). The commercial availability of pure (E)- and (Z)-l,2-dichloroethylene and the ability to
perform two successive and different stereospecific alkynylation reactions at the termini of these
systems, has been utilised with great success in the synthesis of a number of polyene and eneyne
containing natural products, particularly the eicosanoids <89TL495l, 93SL217) and the enediyne
antibiotics <9lAG(E)i387>. The preparation of intermediates in the synthesis of lipoxin B4 and in the
synthesis of dynemicin and calicheamicin/esperamicin models (2) and (3) is illustrated in Scheme 15
and Equations (12) and (13) (88JA1626,91CL1271,93SL217).
1010 Alkynes
Table 1 Palladium catalysed formation of heteroarylalkynes.
Scheme 11
Scheme 12
Scheme 13
Scheme 14
1012 Alkynes
Scheme 15
(12)
(13)
Unactivated alkenyl chlorides can undergo rapid coupling reactions at room temperature using
a weakly ligated palladium catalyst and the appropriate choice of amine base and solvent. Opti-
misation of the conditions for the coupling of heptyne with (l£)-chloroheptene gave a very efficient
system comprising PdCl 2 (MeCN) 2 or PdCl2(PhCN)2 (5%), Cul (10%) and piperidine as solvent
<91TL6109>. Under these conditions the coupling product was isolated in 93% yield after 1 h at
room temperature. A similar yield of product was obtained after 6 h by employing 20 equivalents
of piperidine in tetrahydrofuran as solvent, whereas other solvents and amine bases gave low yields
of product. Alkenyl iodides under the same conditions gave lower yields of products. As an
interesting comparison, when heptynyl tributylstannane was treated with (l£)-chloroheptene in the
presence of PdCl2(MeCN)2, no reaction had occurred after 20 h at room temperature.
Terminal alkynes are most conveniently prepared by cross-coupling reactions with trimethyl-
silylethyne <80S627>. Alternative procedures are available based upon coupling reactions with
propargyl alcohol or 2-methylbut-3-yn-2-ol, followed by oxidative decarbonylation with
MnO 2 /KOH/18-crown-6 or base cleavage <81S364, 84S728). With ethyne itself, reaction occurs at
both termini to give dialkenyl-, diallenyl- and diarylalkynes (Scheme 16) <75TL4467,88TL3651).
In addition to intermolecular alkynylations, ring closures have been successfully achieved by
intramolecular alkynylation (Scheme 17) <88T6337,94SL766). Closure of the 11-membered ring of the
cahcheamicin model system (4) was achieved by a palladium-catalysed intramolecular cross-coupling
reaction <92SL766>. In a similar fashion, the dehydro [12] annulene (5) was formed by an inter-
molecular followed by an intramolecular palladium-catalysed alkynylation reaction employing
(Z)-l,2-diiodoethylene; the corresponding dichloride failed to give any of the desired macrocycle
<88T6337>.
The palladium-catalysed cross-coupling of alkenyl and aryl halides with terminal alkynes has
Scheme 16
Scheme 17
been achieved both under phase-transfer catalysis and in aqueous solvent systems with water-soluble
palladium catalysts. The phase-transfer conditions typically employ benzyltriethylammonium chlor-
ide (1 mol%) as the phase-transfer agent, a large excess of 2.5 N aqueous sodium hydroxide as the
base, and a mixture of Pd(PPh3)4 (1 mol%) and Cul (0.5-2 mol%) as the catalyst <82T63l>.
Yields are reportedly higher than those obtained under the standard anhydrous conditions, but the
procedure has not been extensively used. The conditions are such that alkynyltrimethylsilanes
undergo deprotection/cross coupling in a one-pot reaction <84T2773>. In a similar manner, the
monoprotected alkyne 2-methyl-3-butyn-2-ol will successfully undergo two successive arylation
reactions (Scheme 18) <84S57l, 88T6337).
Water soluble palladium catalysts based on the sulfonated phosphines PPh2(w-C6H5SO3M)
(M = N a + , K + ) <90JA4324> and P(m-C6H5SO3Na)3 <92SL715> have been successfully applied to the
coupling of alkenyl and aryl halides in acetonitrile/water mixtures. The reported yields are high, the
reactions are carried out at room temperature, and in the case of the Pd(OAc)2/P(w-C6H5SO3Na)3
system, copper(I) co-catalysis is unnecessary.
The mechanism of the palladium-catalysed cross-coupling reaction of alkenyl, allenyl and aryl
halides with terminal alkynes or alkynylmetal reagents has not been determined, presumably
because, in common with most other transition metal-catalysed reactions, the transient nature of
the intermediates makes mechanistic studies extremely difficult. A plausible mechanistic scheme is
shown in Scheme 19. A stereospecific oxidative addition of, for instance, an alkenyl iodide to Pd(0)
gives an alkenylpalladium(II) iodide (6). The subsequent reaction between (6) and a terminal alkyne
gives a new alkenylpalladium(II) iodide (7) which undergoes elimination of HPdl at elevated
temperatures to produce the cross-coupled product. Alternatively, with preformed alkynylmetal
reagents, or with alkynylcopper compounds generated in situ from terminal alkynes and copper(I)
1014 Alkyne s
Scheme 18
halides, a preferable mechanism might involve transmetallation with the alkenylpalladium iodide
(6), followed by reductive elimination of the cross-coupled product and regeneration of the Pd(0)
catalyst.
Scheme 19
It is interesting to note that in the absence of copper co-catalysis and in the presence of excess
alkyne, alkenyl iodides undergo a sequence of reactions to give, not the expected enynes, but
substituted fulvenes <90JA9330>. The reaction can be understood if it is assumed that in the presence
of excess alkyne the alkenylpalladium(II) iodide (7) is converted to the triene (8) (Scheme 20)
<90JA9330>. A suprafacial insertion at C-5 followed by cis /Mvydride elimination then generates the
(£)-fulvene. In the presence of copper(I) co-catalysis the normal cross-coupling product is obtained.
Scheme 20
In addition to these direct coupling reactions of metal alkynides and terminal alkynes, more
complicated coupling reactions are known, in which insertion of an additional unsaturated function
(such as carbon monoxide, an alkene, or another alkyne) into the alkenyl- or arylpalladium bond
occurs prior to insertion of the terminal alkyne.
The palladium-catalysed carbonylation of alkenyl and aryl halidcs in the presence of a terminal
alkyne gives mixed alkenyl/alkynyl and aryl/alkynyl kctoncs in fair to moderate yields (Equation
(14)) <81CC333>. The reaction works well with aryl iodides, but not with aryl bromides possessing
strong electron-withdrawing substituents. In these cases the arylalkyne is produced exclusively. The
reactions with 2-bromo-2-butene, /J-bromostyrene and 2-ethoxyvinyllbromide give the phenyl-
ethynyl ketones in 47, 81 and 58% yields respectively. Isolated examples of the carbonylative
coupling reaction of alkynyltin reagents with alkenyl and aryl halides have been reported. With aryl
iodides the use of (>73-C3H5PdCl)2 in HMPA, DMF or acetone allows extremely mild conditions to
be used; 20°C and 1 atmosphere of carbon monoxide <8iDOK(26l)ll4l>. Cyclopentenyliodide has
been coupled with pentynyltributylstannane in the presence of (PPh3)2PdCl2 (50psi CO, 50°C, 7 h)
to give the corresponding ketone in 54% yield <84JA64i7>.
(14)
The palladium-catalysed cross-coupling of an alkenyl, allcnyl or aryl halide and a terminal alkyne
with the additional insertion of an alkene (Heck reaction), is a very desirable goal. In practice, the
problem of rapid /J-hydride elimination from the intermediate alkylpalladium species has limited
this reaction to those alkenes from which /?-hydride elimination is less facile, most notably nor-
bornene and norbornadiene (Equation (15)) <82TL4517,92TL3503). In contrast with the direct coupling
reaction, alkenyl iodides undergo alkene isomerisation in this reaction.
(15)
The palladium-catalysed cross-coupling of an alkenyl, allenyl or aryl halide and a terminal alkyne
with the additional insertion of a second alkyne has been more successful, the crucial difference being
the greater resistance of alkenylpalladium intermediates to /?-hydride elimination. The palladium-
catalysed reaction of alkenyliodide (9) with hexynylmetal reagents demonstrates a strong dependence
on the metal, with the highest proportion of insertion product being obtained with hcxynyltrimethyl-
stannanc (Equation (16)) <90TL4393>. Applications of this reaction to the preparation of both
carbocyclic (91TL5243, 93TL2139) and heterocyclic (88TL5565) systems have been reported. In work
directed towards a synthesis of the neocarzinostatin chromophore, the dibromoalkcnc (10) was
treated with an alkynyltin reagent under palladium catalysis to give the product derived from cross-
coupling with insertion (Scheme 21) <93TL2139>. In a subsequent step, the insertion product was
subjected to a second cross-coupling reaction.
(16)
Finally, it should be noted that in addition to direct substitution, allenyl halides are able to
undergo 1,3-substitution reactions with nucleophiles, particularly organocopper reagents, to afford
alkynes (Equation (17)) <8UA4618, 82TL1651, 83TL3291, 84TL3059,86JOC2230). Although the alkyne is
formed in a substitution reaction, this process is quite different to those discussed so far, in that the
alkyne unit is not present in the nucleophile but is introduced by a reorganisation of the allene. The
regiochemistry of substitution by organocopper reagents, and hence the balance between alkynic
and allenic products, is dependent on the substitution pattern of the allenyl halide and the nature
of the organocopper reagent. In particular, it has been observed that 3-substituted- and
3,3-disubstituted-l-haloallenes react with lithium dialkylcuprates to afford 1-alkylallenes via direct
substitution <73JCS(P1)1347>, while cyanocuprates R(CN)CuLi react with 1-substituted- and
1,3-disubstituted-l-haloallenes to give mainly internal alkynes <84TL3059>. With 3,3-disubstituted-l-
haloallenes H-alkyl cyanocuprates afford alkynes, whereas a-branched primary, secondary and
1016 Alkynes
Scheme 21
tertiary alkyl cyanocuprates afford allenic products <87TL6073>. Employing optically active
1,3-disubstituted-l-bromoallenes, SNT organocuprate displacements have been shown to proceed
with very high a«;/-selectivity <84TL3059>. The reaction has been applied as a key step in the synthesis
of hybridalactone (Equation (18)) <84JA2735> and ll(/?)-HETE <8UA4618>, and in the synthesis of
prostaglandin <83TL329l> and arachidonic acid <82TL1651> analogues.
(17)
(18)
(Hi) Substitution involving alkynyl halides

This section is concerned with the reaction of alkynyl halides with stabilised and unstabihsed
carbon nucleophiles. Although many of these reactions appear to involve electrophilic substitution
of an sp carbon atom, simple substitution mechanisms are rarely involved. In many cases the
reactions proceed through an addition-elimination mechanism. More general reviews covering the
reactions of alkynyl halides with nucleophiles are available <B-69MI 121-05, B-78MI121-02).
Relatively few examples of the reaction of alkynyl halides with stabilised carbon nucleophiles
have been reported. Tertiary enolates undergo a substitution reaction with alkynyl chlorides bearing
an anion stabilising substituent, for example, phenyl or trimethylsilyl (Equation (19)) <43CB80,
84JA3551); primary and secondary enolates give rise to unidentifiable product mixtures. In the
absence of an anion-stabilising group no reaction occurs, supporting an addition-elimination
mechanism. Alkynyl(phenyl)iodonium salts react with soft nucleophiles, such as /?-dicarbonyl and
aminomalonate enolates, to give the corresponding alkynylated products (90CC118, 9UOC3912);
alkynylation of simple enolates does not occur. Alkynyl bromides react with methyl-
ene(triphenyl)phosphorane to afford propargylidene(triphenyl)phosphoranes <80LA206l). The ylides
have been reacted with aldehydes to afford a wide range of enynes (Scheme 22).
(19)
ByC- Bond Formation 1017
Scheme 22
The reaction of alkynyl halides with Grignard and organolithium reagents is dependent upon a
number of factors including the halide, the solvent and the nature of the organometallic ligand. In
the absence of catalysis by other metals, alkynyl chlorides only undergo effective coupling with
Grignard reagents when activating substituents are present on the alkyne, for example,
3-alkoxychloroalkynes (63BSF1876,63BSF1888). With organolithium reagents the most common reac-
tion observed is halogen-metal interconversion with formation of an alkynyllithium. Alkynyl
bromides have been observed to undergo moderately effective coupling reactions with alkyl-
magnesium halides in polar solvents, although competing halogen-metal interconversion does still
occur. The influence of solvent polarity is demonstrated by the reaction of bromophenylethyne with
pentylmagnesium bromide. In diethyl ether, phenylethyne is formed almost quantitatively. In
tetrahydrofuran the yield drops to 83%, and in HMPA to 20%, with a 55% yield of substitution
product being obtained in the latter solvent (63BSF1876, 63BSF1888). Similarly, a 50% yield of
6-dodecyne was obtained from the reaction of 1-bromoheptyne and pentylmagnesium bromide in
HMPA. The reaction with Grignard reagents in polar solvents is, however, limited to alkyl-
magnesium halides. With either alkenyl or aryl reagents metal-halogen interchange occurs, even in
HMPA. Alkynylmagnesium halides do effect substitution but the yields are inferior to those obtained
with alkynyl iodides. With organolithium reagents rapid bromine-lithium exchange occurs. Alkynyl
iodides generally undergo metal-halogen exchange with Grignard and organolithium reagents. An
exception is the reaction with alkynylmagnesium halides which provides a convenient and high-
yielding route for the preparation of symmetrical 1,3-diynes <B-69MI 121-04). For the preparation of
unsymmetrical 1,3-diynes, the route is inferior to the Cadiot-Chodkiewicz method since it gives a
mixture of both symmetrical and unsymmetrical products. Alkynyl fluorides, perhaps surprisingly,
undergo very effective coupling reactions with both types of organometallic reagent. Fluoroethyne
itself has been prepared from 1,1-difluoroethylene at low temperatures, and coupled in situ with
alkyl, alkenyl and aryl Grignard and organolithium reagents (Scheme 23) <82TL4325>. In a similar
manner, aryl-substituted alkynyl fluorides have been coupled with alkyl- and aryllithium reagents
(Scheme 24) <82TL4329>.
Scheme 23
Scheme 24
Organocopper(I) compounds undergo successful substitution reactions with alkynyl halides

(Scheme 25) (72TL5209, 79S826, 8UOM(217)267, 89TL4799). Alkylcopper reagents of the type
RCu-MgX 2 <8OT1215> and alkylcopper/zinc reagents of the type RCu(CN)ZnX react, under mild
conditions, with alkynyl bromides and iodides to afford disubstituted alkynes <89TL4799>. Alkenyl
1018 Alkynes
<75TL1465, 79S826, 8OT1215>, allenyl <81JOM(217)267, 88T6699> and arylcopper(I) reagents <72TL5209>
also undergo successful substitution reactions with alkynyl bromides and iodides in tetrahydrofuran
or tetrahydrofuran/TMEDA mixtures; the chlorides give very low yields. Alkenylcopper(I) reagents
react with retention of configuration. Interestingly, the reactions can proceed at a sufficiently fast
rate that a hydroxy group in the alkynyl halide need not be protected <79S826>. Alkenylcoppcr/zinc
reagents have also been coupled with functionalised alkynyl halides <9iTL6085>. Alkenylcopper(I)
reagents can be generated from alkenylboranes providing a method that is stereochemically comp-
lementary to the carbometallation route (Equation (20)) <81JOC645>. The derived alkenylcopper(I)
reagents couple effectively with alkynyl bromides and iodides with retention of configuration
<81JOC645>. The reaction can also be successfully achieved with bis(acetylacetonato)copper catalysis
<83BCJ2855,84CL1029). Terminal alkynes can be prepared using iodoethynyltrimethylsilane followed
by brief treatment of the product with dilute aqueous alkali <72TL5209>. Reactions of alkynyl halides
with lithium diorganocuprate reagents or with organomagnesium halide reagents in the presence of
copper(I) catalysis, proceed mainly by metal-halogen exchange and poor yields of enynes are
obtained <72TL5209, 79S826>.
Scheme 25
(20)
Organocopper(I) compounds also undergo successful substitution reactions with alkynyl iodon-
ium salts. Treatment of alkynyl(phenyl)iodonium tosylates with dialkylcuprate <9UCS(Pi)2892>,
alkenylcopper <87JA7561> and alkynylcyanocuprate <9UCS(Pi)2892> reagents affords disubstituted
alkynes, 1,3-enynes and unsymmetrical 1,3-diynes respectively (Scheme 26).
Terminal alkynes undergo coupling with alkynyl bromides in the presence of an aliphatic amine
and a catalytic amount of a copper(I) salt to give unsymmetrical diynes. A reducing agent, such as
hydroxylamine, is often added to maintain the level of cuprous ion. Alkynyl chlorides show low
reactivity, although some chloroalkynols have been successfully employed. Alkynyl iodides have a
strong tendency to undergo self-coupling to give symmetrical diynes. The reaction, commonly
known as the Cadiot-Chodkiewicz coupling, is particularly valuable for the preparation of unsym-
metrical diynes (B-69MI i2i-04>. Coupling almost certainly proceeds through in situ formation of the
copper(I) alkynide and, indeed, a variant of the procedure involves the use of preformed copper(I)
alkynides in pyridine <68TL2919,7UCS(C)186>. Some examples of the reaction are illustrated in Scheme
27 <87JMC254, 92TL5355). Polyalkynes are also accessible by employing the Cadiot Chodkiewicz
Scheme 26
reaction, although protecting group strategies are required for successful couplings (Equation
(21)) <90JA4054>. Without recourse to protecting groups polymerisation and symmetrical coupling
reactions are unavoidable, employing the parent alkyne H(C=C),,H or bromoaikyne H(C=C) n Br.
Carboxylate, primary and tertiary carbinol, and trialkylsilyl protecting groups have been successfully
applied to this reaction, most commonly in the bromoaikyne <B-69MI 121-04). A particularly con-
venient and high yielding procedure employs the coupling of preformed copper(I) alkynides with
(bromoethynyl)trimethylsilane <83S128>.
Scheme 27
(21)
Terminal alkynes undergo a facile palladium/copper-catalysed coupling with alkynyl bromides

and iodides (Equation (22)) (90TL7227, 91SC977). In THF, this palladium-catalysed version of the
Cadiot-Chodkiewicz reaction proceeds rapidly at room temperature to give moderate to high yields
of coupling products.
Transition-metal catalysis has also been successfully applied to the alkynylation of organometallic
reagents. Alkynyl bromides react with trialkylaluminum reagents in the presence of bis(JV-methyl-
salicylaldimine)nickel to give the substitution products in 42-90% yield (Equation (23)) <78TL283l>.
1020 Alkynes
Similarly, alkenyldiisobutylalanes, derived from hydroalumination of terminal alkynes, react with
alkynyl halides in the presence of zinc chloride and a palladium catalyst to afford the cross-coupling
product (Equation (24)) <78JA2254>.
(23)
(24)
Alkenylboranes undergo palladium-catalysed cross-coupling reactions with alkynyl bromides in

the presence of a base such as alkoxide, hydroxide or acetate (Equation (25)) <79TL3437, 85JA972).
Normally transition metal transmetallation processes do not occur readily with organoboranes, due
to the weak carbanionic character of organic groups in the organoborane. However, the reaction is
facilitated in the presence of base through the formation of an organoborate, and 1,3-enynes can
be formed in high yield.
(25)
Alkenyltin compounds undergo cross-coupling reactions with alkynyl bromides and iodides in
the presence of palladium(II) catalysts (Equation (26)) <92TL3647>. Copper(I) co-catalysis has been
reported to accelerate this reaction <90JOC5359>.
(26)
More complicated reactions have been reported in which a cyclisation process accompanies the
cross-coupling reaction. Ethynylidene cyclopentanes have been formed with high stereoselectivity,
in 35-71% yield, from the reaction of <5-ethynyl malonate enolates (and related enolates) with
alkynyl halides (Equation (27)) <91TL654l>. The reaction requires catalysis by both palladium(O)
and copper(I) species. Ynenol lactones are formed with high stereoselectivity when the potassium
salts of y-alkynylcarboxylic acids are reacted with alkynyl bromides in the presence of a
palladium/triarylphosphine catalyst (Equation (28)) <92TL28ll>. The nature of the phosphine is
important; only tri-o-tolylphosphine and tri-(2-furyl)phosphine promote an efficient transformation.
(27)
(28)
Heck-type alkenylation of alkynyl halides would represent a very simple route for the preparation
of 1,3-enynes. Unfortunately, very low yields are obtained under the normal conditions.
1-Bromophenylethyne does react normally, but a large amount of diphenylbutadiyne is also produced
<82OR(27)345>. Under solid-liquid phase-transfer conditions (potassium or sodium carbonate/tetra-
n-butylammonium chloride/DMF) alkynyl iodides do undergo a palladium-catalysed reaction with
methyl-2-propenoate or 3-buten-2-one, at room temperature, to give methyl (£)-enynoates and
(£)-enynones respectively in 40-70% yield (Equation (29)) <87S70>. Application of the conditions
to unactivated alkenes has not been reported.
(29)
1.21.2.1.2 Substitution of oxygen functions
(i) Substitution of alkyl-oxygen functions

The substitution of ester and ether functions by alkynylmetal reagents, in particular the sub-
stitution of sulfonate esters and epoxides, is an extremely important method for carbon-carbon
bond formation.
Dialkyl sulfates and aryl-, alkyl- and perfluoroalkylsulfonate esters have all been successfully
employed in substitution reactions with alkynylmetal reagents. Whereas the use of dialkyl sulfates
is limited to lower members of the group (methyl, ethyl, propyl and isopropyl) <B-69MI 121-03),
sulfonate esters of primary alkanols are generally applicable alkylating agents (Schemes 28
<86JOC3098,88CPB4337,91TL53> and 29 (80TL4047,86TL4913,90TL4609». The sulfonate esters are readily
prepared and often give yields of substitution product comparable to, or better than, those obtained
with the corresponding halide. In addition, the wide reactivity range of the various substituted
sulfonate esters (detailed studies establish triflates to be some 104-105 times more reactive than the
corresponding tosylates <82S85» can allow selective substitution reactions. For example, whereas
the coupling reactions of alkynyllithium reagents with tosylates and iodides bearing /?-oxygen
functions do not generally proceed well, the corresponding triflates often allow successful sub-
stitution (Equation (30)) <86TL6133,90TL4609).
(30)
Alkynylaluminum reagents undergo substitution reactions with secondary alkyl sulfonates.

Trihexynylaluminum has been reported to afford the substitution products with isopropyl and
cyclopentyl mesylates in 60 and 99% yields respectively (Equation (31)) <75JA7385>. 3-Methyl-2-
butyl mesylate affords the isomerization product, 3,3-dimethyl-4-nonyne, as the only coupling
product (60%). Although alkynyldialkylalanes, such as those derived from diethylaluminum chlor-
ide, were reported not to be dependable alkynylating reagents, such reagents have since been
employed successfully (Equation (32)) <86JMC230>. Interestingly, trialkynyl- and alkynyldiethyl-
alanes have been observed to undergo direct substitution reactions with a secondary homoallylic
1022 Alkynes
Scheme 28
Scheme 29
tosylate whereas the corresponding alkyl- and alkenylaluminum reagents afford cyclopropanes
through homoallylic rearrangement <85IZV11O9>. Reactions with tertiary alkyl sulfonates have not
been reported.
(31)
(32)
Oxiranes (epoxides) undergo substitution reactions with alkynylmetal reagents to yield jS-hy-
droxyalkynes. With unsymmetrical oxiranes the ring opening by Group 1 metal alkynides usually
occurs at the less substituted carbon atom <78JOU1095>. In liquid ammonia, oxirane itself and
homologues react rather slowly, although high yields of homopropargylic alcohols can be obtained
when a mixture of lithium alkynide and the oxirane in ammonia is allowed to stand for 12-24 hours
<B-88MI 121-02). With sodium alkynides, there is some risk of product O-alkylation when the oxirane
is used in excess. Alkynylmagnesium halides also undergo substitution reactions with oxiranes,
although the reaction is generally unsatisfactory since impure products are often obtained
<(68RTC1249>. The Lewis acidity of the reagents can cause S^l-like attack of the alkynide ion on
both ring carbons, and can cause the formation of halohydrins. It can also cause rearrangement of
the oxirane to an aldehyde or ketone which, in turn, can couple with the alkynylmetal. Since the
reaction with alkali metal alkynides in liquid ammonia is reported to be limited to terminal oxiranes
<56CB853,58JA4593, 60JA4918), a variety of improved procedures have been developed to expand the
scope of this reaction. The use of strongly coordinating solvents such as DMSO <(67CR(C)839,69CC674,
78S26>, HMPA <75TL5l, 76TL1539, 81S490) or DMPU <92SL29l> enhances the nucleophilicity of the
alkynide ion and can afford good yields of substitution products with nonterminal oxiranes. Exam-
ples are illustrated in Scheme 30 <74TL2615, 87S139, 89TL2153). The coupling of oxiranes with alky-
nyllithium reagents can be accelerated by the addition of boron trifluoride etherate either to the
oxirane/alkynyllithium mixture (84CC202, 92JOC6344, 93SL37) or to the alkynyllithium reagent prior
to addition of the epoxide <83TL391>. Although these two procedures would appear to be quite
different, it has been established that RLi and BF 3 -OEt 2 are reasonably stable together at low
temperatures and react independently as potent nucleophile and strong Lewis acid <84JA3693>.
Reactions with oxiranes are rapid at — 78CC and functional groups such as halogen, ester or ketal
are unaffected under the reaction conditions (Scheme 31) <83TL39l>. Alkynyl groups are introduced
regioselectively at the less hindered site in the case of monoalkyl-substituted oxiranes, but with low
regioselectivity with styrene oxide, indicating cationic character in the transition state. Epoxy
alcohols derived from (£)-allylic alcohols react with lithium alkynides in the presence of boron
trifluoride etherate to give mixtures of rearranged and unrearranged products with the former
predominating in most cases (Equation (33)) <84CC202>.
Scheme 30
Scheme 31
(33)
Alkynylaluminum reagents also undergo effective substitution reactions with oxiranes in nonpolar
(68CC634, 69TLI379, 70TL2695, 73TL3899> or ethereal solvents (76CC907, 78JOC353). The Lewis acidic
1024 Alkynes
nature of the alanes and their consequent ability to coordinate oxirane oxygen atoms (initial
electrophilic attack) facilitates alkynyl transfer. The choice of solvent can have a dramatic effect on
the outcome of the reaction. For example, the reaction of diethylhexynylaluminum with 3,4-
epoxycyclopentene in an ether solvent resulted in predominant opening of the oxirane ring by attack
at the allylic carbon, while use of a hydrocarbon solvent led to rearrangement of the oxirane to
cyclopent-3-enone followed by further reaction of the carbonyl group <75CC287>. The reaction of a
dimethylaluminum alkynide with the diol oxirane (11) has been successfully applied to the prep-
aration of prostaglandins and the sesquiterpene vernolepin (Scheme 32) <73TL3899, 76TL1769,
80JCS(Pl)852>. Different sources of dimethylaluminum chloride were found to give variable regio-
selectivities in this reaction, the difference being traced to the formation of methoxymethylaluminum
chloride through air oxidation. Deliberate formation of the methoxymethylaluminum alkynide gave
complete regioselectivity. The opening of oxiranes with an unsubstituted ethynylalane R 2 A1C=CH
has been accomplished with dimethylethynylaluminum etherate <76CC907, 78JOC353, 8UA7520) and
also with trimethylsilyl protection/deprotection <76TL1769>. Alkynylalanate reagents will also
undergo substitution reactions with oxiranes in the presence of boron trifluoride etherate (89T6197,
92SL266) and have been used successfully in cases where the corresponding alane has failed
<90TL7145>.
Scheme 32
Alkynylgallium reagents undergo substitution reactions with oxiranes. A reagent prepared from
1-lithio-l-octyne and equimolar trimethylgallium in THF-hexane underwent a rapid reaction with
oxirane at room temperature to afford 3-decyn-l-ol in 95% yield <84TL5423>. Furthermore, reaction
with a variety of oxiranes can be accomplished in good yield employing catalytic trimethylgallium,
substitution occurring at the less substituted position of the epoxide.
Triisopropoxytitanium alkynides react with aryl-, alkenyl-, alkynyl- and trimethylsilyl-substituted
oxiranes to afford moderate to good yields of adduct resulting from attack at the more substituted
carbon of the oxirane ring (Equation (34)) <88CB1315>. Further substitution on the oxirane ring or
at the alkenyl group increases the yield. Alkyl substituted oxiranes give very low yields of substitution
product. The reaction with alkenyl- and alkynyl-substituted oxiranes is particularly interesting since
these systems invariably undergo substitution with migration of the multiple bond.
(34)
Oxetane and substituted oxetanes undergo substitution reactions with alkynyllithium reagents in
the presence of boron trifluoride etherate to afford y-hydroxyalkynes (Equation (35)) <83TL5l2l,
84T4261). In a related reaction, /?-propiolactones undergo substitution reactions with dimethyl-
alkynylaluminum reagents to afford /?-alkynylpropionic acids (Equation (36)) <86TL87>.
(35)
(36)
Allylic and propargylic oxygen functions undergo 1,1- and 1,3-substitution reactions with terminal
alkynes and alkynylmetal reagents. As with the corresponding halides, the regiochemistry of sub-
stitution depends on a number of factors, particularly the substitution pattern of the substrate and
the nature of the alkynylmetal reagent. In compound (12) the C—OMs carbon atom is sufficiently
hindered towards direct nucleophilic attack that a regioselective copper-catalysed 1,3-substitution
occurs with phenylethynylmagnesium chloride (Equation (37)) <88CBI461>. More generally, allylic
ethers of 2-hydroxybenzothiazole undergo stereo- and regioselective substitution reactions with
copper(I) alkynides in THF or DMF at 40-60°C, reaction occurring at the less substituted terminus
of the allyl system (Equation (38)) <79TL3873>. Unsubstituted propargyl toluenesulfonate undergoes
a copper-catalysed 1,1-substitution reaction with alkynylmagnesium halide reagents in THF to
afford 1,4-diynes in good yield <79S292>. In contrast, propargyl acetates <73TL336l, 82RTC405),
methanesulfmates <82RTC405>, methanesulfonates <74S573> and toluenesulfonates <65TL1953> have
been reported to undergo 1,3-substitution reactions with copper(I) alkynides to afford allenynes in
good yield. The Pd(PPh,)4-catalysed reaction of propargylic acetates, diethylphosphates, methyl-
sulfinates, methanesulfonates and epoxides affords allenynes with a wide range of alkynylmetal
reagents (Scheme 33) <82RTC97, 82RTC405, 86JOC4006). Propargylic acetates, carbonates and tolu-
enesulfonates also react with terminal alkynes in the presence of Pd(PPh,)4, copper(I) iodide, an
amine base and lithium chloride to afford allenynes by 1,3-substitution <9OTL7179, 93TL3853). Pro-
pargyl acetates undergo substitution reactions with trialkynylalanes when activated as their dicobalt
hexacarbonyl complexes, the free 1,4-diynes being recovered from their Co2(CO)6 complexes by
oxidation with eerie ammonium nitrate at — 78°C <83TL2239>.
(37)
(38)
Acetals, ortho-esters, ./V,/V-dialkylformamide acetals and 0/7/70-carbonates have also been reacted
with alkynes or alkynylmetal reagents to afford products formally derived from substitution reac-
tions. The reaction mechanisms are more complicated in these cases, often involving Friedel-Crafts
1026 Alkynes
Scheme 33
type alkylation of the alkyne <B-69MI 121-03). Alkynyltrimethylsilanes (83JA2904, 87HCA448) and
alkynyltributylstannanes (86JA7116) undergo coupling reactions with acetals in the presence of
stoichiometric titanium(IV) chloride to give propargyl ethers in high yield. Very high diastereo-
selectivities are observed by employing acetals derived from chiral 1,3-diols (Equation (39))
(83JA2904, 86JA7116). Propargyl ethers are also formed from acetals and alkynyltrimethylsilanes in
the presence of catalytic quantities of zinc chloride and tin(IV) chloride <87CL1975>, and, under the
same conditions, directly from aldehydes in the presence of alkoxytrimethylsilanes (Scheme 34)
<88BCJ4037>. C-Glycosylated alkynes have been prepared by the reaction of Z)-glucal acetates with
alkynyltrimethylsilanes in the presence of tin(IV) chloride <93SL413>, and by the reaction of an
O-glycoside with ethynylmagnesium bromide in the presence of zinc bromide (89TL6027).
(39)
Scheme 34
Orô-formates, or;/io-acetates and orr/jo-carbonates react with alkynyl magnesium halides

<B-69MI 121-03, 84JOC2031) and with 1-alkynes in the presence of a zinc halide catalyst (58JA4607,
86JOC2607) to afford propargyl acetals, ketals and ortho-esters respectively. jV,7Y-Dialkylformamide
acetals condense with 1 -alkynes in the absence of catalysts simply on heating the two components
together <60AG836>.
(ii) Substitution involving alkenyl-, allenyl- and aryl-oxygen functions

The formation and trapping of an enolate, allenolate or phenolate ion, followed by substitution
of the enol derivative with a terminal alkyne or alkynylmetal reagent, allows the regiospecific
formation of enyne, allenyne or arenyne products (Scheme 35). In practice, enol substitution
reactions of this type have only been successfully achieved under transition metal catalysis. Although
a wide range of diorganocuprate reagents do undergo successful substitution reactions with alkenyl
and aryl triflates <80TL43l3>, alkynyl groups are not transferred. Substitution by an alkynyl group
is most successfully achieved by the palladium-catalysed cross coupling of a terminal alkyne, or
alkynylmetal reagent, with an alkenyl/aryl phosphate or sulfonate. As with the corresponding
halides, distinct palladium mediated sp-sp2 coupling processes have emerged involving either the
terminal alkyne or its metallated counterpart.
Scheme 35
(a) Reaction of metallated alkynes with alkenyl/aryl phosphates or sulfonates in the presence of
catalytic quantities of Pd(II) or Pd(0) compounds. With appropriate choice of metal, palladium
catalyst and solvent, very high yields of coupling product have been obtained under mild conditions
with both alkenyl and aryl sulfonates, and with alkenyl phosphates. Metals of intermediate elec-
tronegativity such as Al, Sn and Zn are most successful; organolithium and magnesium reagents do
not effect carbon-oxygen bond cleavage in these systems, rather they effect attack at the phosphorus
or sulfur atom with regeneration of the metallic cnolate <8OTL2531>. Diethylalkynylalanes undergo
palladium-catalysed cross-coupling reactions with alkenyl phosphates with exclusive transfer of the
alkyne (Scheme 36) <84BCJ108>. (PPh3)4Pd was found to be the most effective catalyst. The reaction
has also been successfully applied to alkenyl phosphates derived from thiocarboxylic S-esters
<81TL1609>.
Scheme 36
The palladium-catalysed cross-coupling reaction of alkynyltrialkyltin reagents with alkenyl and

aryl triflates provides a useful route to enynes and arynes (Scheme 37) <84JA4630,86JA3033,87JA5478).
The reaction has been applied to both highly functionaliscd <89JA54t7> and highly hindered alkenyl
and aryl triflates (Scheme 38) <89JOC5828, 92JOC678>, and to a limited number of heteroaryl systems
<89AJC279>. At least one equivalent of lithium chloride is required for the reaction to proceed to
completion, indicating that the initial oxidative addition product, an alkenyl- or arylpalladium(II)
triflatc, is incapable of entering a catalytic cycle. In the presence of lithium chloride, an alkenyl- or
arylpalladium(II) chloride is generated which reacts with the organotin reagent to afford coupled
products with regeneration of the palladium(O) catalyst. Lithium bromide and iodide can also be
used, but catalyst decomposition leads to longer reaction times and, in the case of lithium iodide,
to incomplete reaction. Sodium and potassium salts are unsuitable for the reaction. Zinc chloride
can accelerate the reaction, presumably by transmetallation to the organozinc chloride, but it cannot
replace the use of lithium chloride. (PPh3)4Pd and (PPh3)2PdCl2 both give good results with alkenyl
and aryl triflates, although different selectivities have been observed. For instance, with 4-halo-
aryltriflates a change in selectivity is observed on going from (PPh3)4Pd (1 > Br > OTf) to (PPh3)2PdCl2
(1 > OTf > Br). The coupling reaction works well in a number of solvents including THF and other
ethers; those solvents able to solubilise lithium chloride and act as good ligands (HM"PA, DMPU,
DMF and DMSO) arc particularly effective. Low concentrations of water do not adversely affect
1028 Alkynes
the reaction, nor does the presence of oxygen, although reactions are usually carried out under an
inert atmosphere.
Scheme 37
Scheme 38
Alkynylzinc chlorides undergo palladium-catalysed cross-coupling reactions with aryl fluoro-

alkanesulfonates in the presence of lithium chloride (Equation (40)) <87TL2387>. Alkynylzinc chlor-
ides also undergo nickel- or palladium-catalysed cross-coupling reactions with diketene (Equation
(41)) <83CPB4346>.
(40)
(41)
In the presence of fluoride ion, various types of organosilicon compounds undergo palladium-
catalysed cross-coupling with alkenyl and aryl triflates under mild conditions <9OTL2719>. A single
example of the coupling of an alkynyltrimethylsilane with an alkenyl triflate has been reported
(Equation (42)).
(42)
(b) Reaction of terminal alkynes with alkenyl and aryl sulfonates in the presence of catalytic
amounts of Pd(II) or Pd(0) compounds and a base. Terminal alkynes can be coupled directly to
alkenyl and aryl sulfonates in the presence of a palladium catalyst and a base (Scheme 39). The
palladium-catalysed cross-coupling of alkenyl triflates with terminal alkynes was independently
reported by two groups. Stille et al. used (PPh3)4Pd or (PPh,)2PdCl2 in DMF at 70°C in the presence
of triethylamine <85JOC2302>. Yields are considerably improved by the addition of lithium chloride.
Cacchi el al. carried out similar reactions using amine bases or sodium acetate in DMF at 60 °C,
and also using an amine base and copper(I) iodide at room temperature <86S320>. The presence of
copper co-catalysis is essential for the reaction to proceed at room temperature. Aryl fluoro-
alkanesulfonates, including aryl triflates, similarly undergo palladium-catalysed cross-coupling with
terminal alkynes in the presence of triethylamine in DMF at 90°C <86TL1171> and with copper(I)
iodide co-catalysis at room temperature <89TL2581>. Heteroaryl triflates, including pyridines
(88JOC386,89TL258l> and isoquinolines <89JMC1820>, undergo similar reactions. An interesting prep-
aration of a [5.6] spiro ring system has been reported employing the palladium-catalysed reaction
of 4-/-butyl-l-cyclohexene triflate with an excess of trimethylsilylethyne (Equation (43)) <90JA9330>.
The attempted use of the less reactive mesylate and tosylate functions, where reported, has been
unsuccessful (86TL1171, 87H(26)355>.
Scheme 39
(43)
The palladium-catalysed cross-coupling of alkenyl triflates with terminal alkynes has been exten-
sively used for the synthesis of analogues of vitamin D (calciferol) and its hydroxylated metabolites
<86TL1523, 88JOC1790, 88TL1203, 9UA3873, 9UMC2452>, for the synthesis of Z-enediyncs related to the
neocarzinostatin chromophore <9iTL3405,93TL4177), and in a total synthesis of ginkgolide B (Scheme
40) <88JA649, 92CB271).
Scheme 40
Carbonylative coupling reactions of alkenyl and aryl triflates with terminal alkynes and alkynyltin
reagents have been reported. Alkenyl triflates undergo carbonylative coupling with alkynyltin
reagents in the presence of (PPh3)4Pd and lithium chloride <84JA7500>. In the presence of bidentate
phosphine ligands and palladium(II) acetate, alkenyl triflates undergo carbonylative coupling with
1030 Alkynes
terminal alkynes to afford l-alken-4-yn-3-ones in good yields (Equation (44)) <91TL6449>. Mono-
dentate phosphine ligands are not effective in the reaction, and the conditions are unsuccessful with
electron deficient alkynes such as ethyl propynoate and 3,3-diethoxy-l-propyne, and with aryl
triflates. Aryl triflates do, however, undergo successful carbonylative coupling reactions with
alkynylstannanes in the presence of dichloro(l,r-bis(diphenylphosphino)ferrocene)palladium(II),
lithium chloride and carbon monoxide (1 atm.) <88JA1557>.
(44)
(c) Substitution involving alkynyl-oxygen functions. The use of alkynyl ethers as electrophilic
alkynylation reagents has been reported although these reactions have seen little use compared to
the more commonly employed nucleophilic alkynylation reagents (alkynylmetals). A range of
disubstituted alkynes has been produced from the reaction of 1-ethoxy-l-hexyne with organolithium
reagents (Equation (45)) <68RTC69>. Phenylmagnesium bromide, when employed instead of phenyl-
lithium, gave a poor result. Ethynylation is also possible, as in the preparation of phenylethyne
from ethoxyethyne. Strong evidence for an addition-elimination mechanism was obtained from the
reaction of ethoxyhexyne with hexynyllithium in dioxan. Prolonged heating of the solution of these
compounds at 100°C and subsequent hydrolysis afforded the diyne (14), in addition to a small
amount of the ether (13) (Scheme 41) <68RTC69>. Ether (13) became the main product when the
reaction time was shortened.
(45)
Scheme 41
Allylboranes and substituted allylboranes undergo an addition-elimination reaction with ethoxy-

ethyne in the presence of triethylalane to afford the products of a formal substitution reaction
(Scheme 42) <80S904>. The initial addition reaction is exothermic and proceeds at a low temperature,
yielding a thermally stable alkenylborane. Elimination to 1,4-pentenynes is achieved by treating the
alkenylboranes with triethylaluminum at 80-110°C.
Scheme 42
1.21.2.1.3 Substitution of sulfur, selenium or tellurium functions
The substitution of sulfur, selenium and tellurium functions by 1-alkyncs or alkynylmetal reagents
is generally much more difficult than substitution of the corresponding oxygen functions. In part,
this is due not only to the weaker inductive effects of SR, SeR and TeR functions compared to their
oxygen counterparts, but also to the increased propensity for nucleophilic substitution to occur at
the chalcogen atom rather than at carbon (B-67M1 121-02). This is particularly true for Se and Tc
functions and direct replacement of selenium and tellurium groups by alkynes has not been described.
Some success has been achieved employing sulfur functions, particularly sulfones.
Simple alkyl and aryl sulfides do not undergo substitution reactions with alkynylmetal reagents.
Even the more activated thioacetals (CH2(SR)2) and orj/io-thioesters are stable to alkynylmagnesium
halides in contrast to their oxygen counterparts (B-67MI 121-02). Successful substitution reactions
have been reported with episulfonium tetrafluoroborates generated in situ from alkenes and
dimethyl(thiomethyl)sulfonium tetrafluoroborate. Alkynyldiethylalanes and lithium dialkynyl-
diethylaluminates were found to afford the highest yields of homopropargyl thiomethyl ethers
(Scheme 43) <84JA4263>. Alkynyldiethylalanes have also been reported to effect successful sub-
stitution of a range of allylic sulfones in the presence of aluminum trichloride (Scheme 44) <86JA1O98>.
Using the more Lewis acidic alkynylethylaluminum chloride obviates the need for an exogeneous
Lewis acid. The reaction is regioselective, substitution occurring at the less substituted side of the
allyl system, and is compatible with ester and hydroxyl functions. The mechanism most likely
involves ionisation to a carbenium ion followed by capture by the nucleophile. 2-Arylsulfonyl
substituted cyclic ethers <89T4293> and amides <90SL48> react with alkynylzinc reagents to afford
substitution products in high yield (Scheme 45).
Scheme 43
Scheme 44
Direct substitution of alkenyl and aryl sulfides or sulfones by alkynylmetal reagents has not been
reported. Alkenyl sulfides are well known to undergo nickel-catalysed cross-coupling reactions with
Grignard reagents, but reactions with the corresponding alkynylmagnesium halides have not been
described, perhaps due to the known propensity of alkynes to undergo polymerisation under nickel
catalysis. Substitution of a /?-sulfonyl-a,/?-unsaturated ester by 1-octynylmagnesium bromide has
been reported, but the reaction proceeds by a conjugate addition-elimination mechanism (Equation
(46)) <89TL173>.
1032 Alkynes
Scheme 45
(46)
Alkynyl sulfones undergo substitution reactions with Grignard and organolithium reagents
(Equation (47)) <79JOC3444>. The reaction is limited to alkynyl sulfones not having propargylic
hydrogen atoms and is believed to proceed by a mechanism involving single electron transfer (SET)
<84TL4851>.
(47)
1.21.2.1.4 Substitution of nitrogen, phosphorus, arsenic, antimony or bismuth functions

The groups NH 2 , NHR and NR 2 are extremely poor nucleofuges and direct substitution reactions
with alkynide anions have not been reported. Successful substitution reactions of NR 2 functions
have been achieved in aminals but these reactions presumably involve iminium ion intermediates
(see Section 1.21.3.2.4).
The leaving-group ability of NH 2 and NHR can be improved by conversion to ./V-sulphonyl
derivatives, but the reaction with alkynide ions has only been used scarcely. An example is the ring
cleavage of bis(aziridine) (15) with lithium heptynide (Equation (48)) <89JOC5324>. Even with this
highly activated system no reaction is observed in the absence of HMPA. The leaving-group ability
of NR 2 can also be improved by quaternisation of the nitrogen atom, although elimination reactions
predominate with such substrates and substitution can only be achieved under special circumstances
(Equation (49)) <63JCS2990>.
(48)
(49)
Amine diazotisation provides the very powerful leaving group (N2) and substitution of a diazo-
nium group is an effective method for the introduction of many functional groups into an aromatic
ring. Up to 1995, alkynes have not been introduced, although palladium-catalysed substitution
reactions of arenediazonium salts have been reported <87JCS(Pl)151l>, offering the potential for
substitution with alkynes and alkynylmetal reagents. Substitution adjacent to a carbonyl group has
been effected; thus ethyl diazoacetate reacts with trialkynylboranes to provide propargylic esters in
good yield (Equation (50)) <72CJCllO5>.
(50)
Nitro functions do not generally undergo substitution reactions. However, oe-nitroalkynes can be
obtained by the reaction of alkynyllithium reagents with 2,2-dinitropropane (Equation (51))
(79CC488, 82SC557). The reaction with 2,2-dinitropropane has been successfully extended to alky-
nyllithium reagents derived from propargyl acetals and amines <(82SC557).
(51)
No examples of the substitution of phosphorus, arsenic, antimony or bismuth functions by

alkynes/alkynylmetal reagents have been reported.
1.21.2.1.5 Substitution of boron, silicon or germanium functions

The substitution of silicon and germanium functions is not commonly employed for the prep-
aration of alkynes. The substitution of boron functions, however, provides a convenient and general
route for the preparation of various alkyl-, alkenyl- and aryl-substituted alkynes. Lithium
(l-alkynyl)organoborates (readily prepared from the reaction of an organoborane with an alkynyl-
lithium) react with a variety of electrophiles to induce the transfer of an alkyl, alkenyl or aryl
group from boron to the alkynyl C-l carbon atom. With the proper choice of electrophile the
resulting alkenyl borane can be induced to undergo /^-elimination (Scheme 46) <86JOC4507>.
Although the reaction mechanism involves a complicated addition-migration-elimination sequence
the overall result is the substitution of the boron function. The most commonly employed elec-
trophile is iodine (73JA3080, 86JOC4507, 91T343), although methanesulphinyl chloride <73TL1847,
74T2159) and tributyltin chloride <84JOC5175> have also been used.
Scheme 46
Primary alkyl groups are readily introduced as are secondary alkyl groups such as j-butyl,
cyclopentyl and cyclohexyl, in marked contrast to their problematic introduction by conventional
substitution reactions employing alkynylmetal reagents. Tertiary alkyl groups appear to undergo B
to C migration with difficulty and are not generally introduced by this method. Aryl and alkenyl
groups are both readily inserted, the latter being particularly convenient in view of the facile and
highly stereoselective preparation of is-alkenyl boranes by hydroboration of alkynes (Equation (52))
<91T343>. Conjugated 1,3-diynes can also be formed by transfer of an alkynyl group (see Section
1.21.3.1.6). Transfer of both alkyl and alkenyl groups occurs with complete retention of stereo-
1034 Alkynes
chemistry. Only one R group is transferred from organoboranes (R3B) and a more satisfactory
utilisation of the R group is achieved employing thexylmonomethoxyboron <86JOC452l> or bis(l,2-
dimethylpropyl)boron blocking groups <91T343>. Certain functionalities in the organoborane are
compatible with the reaction provided the alkynyllithium reagent is added at low temperature. For
example, methyl ester and acetate functions survive intact.
(52)
Ethynyllithium itself affords low yields of 1-alkynes, although the ethylenediamine complex gives
good results with most alkylboranes <86JOC4507>. Attempted preparation of symmetrical alkynes
employing dilithium ethynide is unsuccessful, but the same overall transformation can be achieved
employing chloroethynyllithium, itself generated in situ from (£)-l,2-dichloroethene <75TL1961>.
Two alkyl groups are transferred from the organoborane in this reaction (Equation (53)).
(53)
a-Chiral mono- and disubstituted alkynes have been prepared employing optically active mono-
alkylthexyborinates (88JA1529,9UOC1500), the latter being obtained in very high enantiomeric excess
by asymmetric hydroboration of prochiral alkenes.
1.21.2.1.6 Oxidative homocoupling reactions of terminal alkynes and their derivatives

Interest in the chemistry of butadiynes and poly-ynes has led to the development of methods for
the oxidative coupling of terminal alkynes and their derivatives. Reviews are available covering
various aspects of oxidative coupling reactions of alkynes <B-69MI 121-04, B-83MI121-02,9iCOS(5)55l>.
Most commonly, oxidative homocoupling is carried out with copper(I) (Glaser reaction) or cop-
per(II) (Eglington reaction) salts in the presence of oxygen (Equation (54)).
Cu'orCu". O,
R^S - R—^ SEE—R (54)
The Glaser reaction, as originally reported, is carried out in two stages. The copper(I) alkynide
is formed in the first stage and then oxidised in the second stage to the diyne. Air and oxygen are
most frequently employed as oxidising agents, although potassium ferricyanide, hydrogen peroxide
and copper(II) salts are also used. Isolation of the copper alkynide is inconvenient and the procedure
was modified to allow in situ formation of the copper(I) derivative. The method further evolved
into that reported in 1960 by Hay (60JOC1275, 62JOC3320). In the Hay procedure, oxygen or air is
passed through a solution of the alkyne and a catalytic quantity of a copper(I) salt in a complex
forming solvent, such as pyridine or TMEDA (Scheme 47). The reaction is of wide scope and is
compatible with a wide variety of functional groups in the alkyne <B-69MI 121-04). Yields are
generally high, although the less acidic alkyl substituted alkynes require the presence of a stronger
base, such as dbu, to promote the reaction <B-88MI 121-01 >.
In the Eglington reaction, the terminal alkyne is heated with a stoichiometric quantity of a
copper(II) salt, most commonly copper(II) acetate, in pyridine or a similar base. Again, the reaction
is of wide scope and is compatible with a variety of functional groups. The reaction is readily
adapted to high dilution conditions and is particularly valuable for the preparation of large ring
poly-ynes by intramolecular oxidative coupling of co-diynes (Scheme 48) <74OS(54)l, 88H(27)475>.
Scheme 47
Scheme 48
Both the Glaser and Eglington oxidative coupling reactions are most suitable for the preparation
of symmetrical butadiynes and poly-ynes. In general, both procedures give unsatisfactory results in
unsymmetrical coupling reactions. Unsymmetrical 1,3-diynes are most conveniently prepared by
the Cadiot-Chodkiewicz procedure, as described in Section 1.21.3.1.1 (iii).
Symmetrical diaryl substituted butadiynes can also be prepared in high yield by reacting benzene
solutions of aryl substituted terminal alkynes with chloroacetone in the presence triethylamine and
a (PPh3)4Pd/CuI catalyst mixture <85TL523>. Under similar conditions, aliphatic 1-alkynes afford
mixtures of symmetrically disubstituted l,4-dialkyl-l,3-butadiynes and 3-alkyl-4-(l-alkynyl)hexa-
l,5-diyn-3-enes (Equation (55)). The oxidative coupling of phenylethyne has been reported employ-
ing a Pd-Cu catalyst in the presence of 4-iodo-(3//)-phenothiazin-3-one <89JOM(364)245>.
(55)
Alkynylmetal reagents and a number of other derivatives of terminal alkynes also undergo
dimerisation in the presence of a suitable oxidant. Alkynyl Grignard reagents afford conjugated
diynes in the presence of iodine or other oxidants <52JCS2O14, 54JCS147), with thionyl chloride
<72JOC3749> or with TV-substituted isocyanide dichlorides in the presence of a palladium catalyst
<88TL5379>. Alkynyllithium reagents undergo oxidative coupling in the presence of stoichiometric
palladium and nickel complexes (69TL4593,87CC477). Alkynylborates undergo oxidative coupling in
the presence of iodine to afford both symmetrical and unsymmetrical 1,3-butadiynes (Equation
(56)) <75CC857, 76JOC1078, 76TL4385>. Alkynyltin <87JOC4296>, alkynylselenium <86CC1O67> and
alkynyl tellurium <90SC2l8l> compounds also undergo symmetrical coupling reactions in the pres-
ence of a suitable oxidant.
1036 Alkynes
(56)
1.21.2.2 Addition Reactions of Alkynyl Carbanions
1.21.2.2.1 Addition to carbon-carbon multiple bonded functions

Terminal aliphatic alkynes react with 1,3-butadienes in the presence of catalytic quantities of a
ruthenium(0)-trialkylphosphine complex to afford linear codimers in good to excellent yield (Scheme
49) (85JOC565,86BCJ3201). 1,3-Butadiene itself undergoes a highly regio- and stereoselective reaction
with straight chain and branched terminal alkynes to afford linear conjugated (£)-enynes. Phenyl-
ethyne also affords the corresponding enyne, but in low yield, the major product being a mixture
of homodimers of phenylethyne. 1,3-Cyclohexadiene affords 1,5-enynes through a regioselective
1,2-addition to the cyclohexadiene. Methyl (£,£)-2,4-hexadienoate similarly undergoes highly regio-
selective and stereoselective reactions to give (£)-l,5-enynes.
Scheme 49
The homocoupling (Scheme 50) and cross-coupling (Scheme 51) of alkynes to furnish 1,3-enynes
has been achieved in high yield employing catalytic Pd(OAc)2 and the hindered phosphine ligand
tris(2,6-dimethoxyphenyl)phosphine <87JA3486>. Homocoupling to afford 1,3-enynes of opposite
regiochemistry has been observed in the protonolysis of alkynylzirconocene derivatives (Scheme 52)
<91JA1440>.
Scheme 50
Scheme 51
Scheme 52
1.21.2.2.2 1,2-Addition to carbon-oxygen double bonded functions

The addition of alkynylmetal reagents to carbonyl compounds, including aldehydes, ketones,
carbon dioxide and carbon monoxide affords primary, secondary or tertiary alkynols, alkynoic
acids or alkynoic esters depending on the carbonyl compound employed. The literature up to 1969
has been comprehensively reviewed <B-69MI 121-03). Group 1 and 2 alkynylmetal reagents are most
commonly employed in these reactions. Liquid ammonia and THF are the most commonly used
solvents.
Aldehydes and ketones react with alkynylmetal reagents to afford propargyl alcohols (Equation
(57)). Reduced yields of coupling products can be caused by enolisation of the carbonyl compound,
the extent to which this occurs depending upon the acidity of the carbonyl compound, the basicity
of the alkynide (kinetic basicity K > Na > Li > Mg) and the polarity of the solvent. The use of ether
solvents and alkynyllithium or alkynylmagnesium halides is preferable with readily enolisable
carbonyl compounds, although in general the latter offer little practical advantage over the more
conveniently prepared alkynyllithium reagents. In some cases, addition of anhydrous lithium bro-
mide has the favourable effect of solubilising poorly soluble alkynyllithium reagents <81S459>.
Addition of ethyne itself is achieved employing the readily prepared amine-free ethynyllithium
<75JOC2250> or the commercially available complex with ethylenediamine <64JOC1872>. High yields
of addition product are obtained even with a number of readily enolised ketones. Addition of
dimetalloethynides to aldehydes has been reported <75JOC1131>. Hydroxymethylation of alky-
nyllithium and magnesium reagents can be achieved employing paraformaldehyde in diethyl ether
or THF as solvent, depolymerisation occurring in situ <65RTC1200>.
O i, R'^^Met OH
II R ' ^ = (-R3 (57)
Met = Li, Na, K, MgX
Alkynylboron and aluminum reagents undergo addition reactions with aldehydes and ketones.
5-l-Alkynyl-9-borabicyclo[3.3.1]nonanes smoothly add to aldehydes and ketones at room tem-
perature to provide propargyl alcohols in high yield (Equation (58)) <85JOC1577>. The reagents are
nonbasic and are essentially inert at 25 °C toward alkyl halides, acid chlorides, amides, anhydrides,
esters, nitriles, acetals and ketals. Furthermore, the reagents can discriminate between aldehydes
and ketones and even between two ketone functions. Ethyne itself is introduced employing the
trimcthylsilyl protected reagent <92JOC2941>. Alkynyldiethylalanes <65CR(261)1992, 68BSF205) and
trialkylalanes <66CR(C)289> undergo addition to aldehydes and ketones although the procedure
seems to offer little advantage, particularly with the latter reagents where only one of the three
alkynyl groups is utilised in the reaction.
(58)
1038 Alkynes
Alkynylcerium <84TL4233>, titanium <87CB1845>, chromium <85TL5585>, vanadium <86TL933>,
manganese <77TL3383>, ytterbium <8UOM(205)4> and zinc <87TL1O19> reagents have been coupled
with aldehydes and ketones. Alkynylcerium dichloride reagents have been used with particular
success for readily enolised ketones such as /J,y-enones and benzyl ketones (Scheme 53) <84TL4233,
9UA694,91TL1707, 92TL4653). These ketones undergo extensive enolisation even with alkynyllithium
and magnesium reagents, but afford high yields of the addition product in the presence of one
equivalent of cerium trichloride. Alkynyltitanium triisopropoxides react smoothly with aldehydes
at - 5 0 ° C but very slowly with ketones even at 0°C (Equation (59)) <87CB1845>. The reagents also
allow highly diastereoselective reactions with some chiral aldehydes. Alkynylchromium reagents,
prepared by treatment of alkynyl iodides (and less commonly alkynyl bromides) with anhydrous
chromium(II) chloride, also undergo highly chemoselective reactions with aldehydes <85TL5585>.
Catalytic quantities of nickel(II) chloride are commonly employed in the addition reactions to
overcome the variable results sometimes observed with different sources of Cr(II)Cl2 <86JA5644>.
Alkynylchromium reagents have been applied with particular effect for cyclisations mediated by
intramolecular addition to enolisable aldehydes (Scheme 54) <9lTL3i7i, 92JA9279,92TL75H, 93TL1467).
Although conditions have been described for achieving such cyclisations with alkynyllithium
<88TL4217> and alkynylcerium reagents <91JA694>, the chromium(II)-mediated reaction of alkynyl
iodides provides a more general solution.
Scheme 53
(59)
Alkynyltin <67TL495,86CC102) and silicon <76AG(E)498,76TL2449,83T975> reagents undergo addition

reactions with aldehydes and ketones in the presence of a Lewis acid or fluoride ion. 1-Alkynes
themselves undergo addition to aldehydes and unhindered ketones in the presence of Sn(OTf)2 and
an amine <9UOC409l>.
1-Alkynes will undergo addition reactions with aldehydes and ketones in the presence of basic
reagents such as alkali metal hydroxides and alkoxides. The reaction is limited to less base-sensitive
carbonyl compounds and is more successful with ketones than aldehydes. Phase-transfer catalysis
is beneficial <82LA175O>. The reaction has been comprehensively reviewed <B-69MI 121-03).
Scheme 54
In addition to chemoselectivity considerations, stereoselectivity issues including diastereo-

selectivity and enantioselectivity usually arise in the addition of alkynylmetal reagents to aldehydes
and ketones. Diastereoselective additions to chiral aldehydes and ketones and to substituted cyclic
ketones have been reported. For acyclic compounds, with a carbonyl unit as the only polar group,
Cram's rule applies and stereoselectivities are generally moderate. A comparison of alkynyllithium
and alkynyltitanium triisopropoxides showed little difference in diastereoselectivities for the addition
to chiral aldehydes <87CB1845> whereas considerable improvements were observed with the TiCl4-
promoted addition of alkynyltin reagents <86CC1O2>. Low diastereoselectivities are frequently
observed in the addition of alkynyllithium and magnesium reagents to ot-alkoxy aldehydes, although
improved diastereoselectivities have been reported with alkynylzinc bromides and alkynyltitanium
triisopropoxides in the presence of TiCl4 (84CL405,87TL1019,93JOC2468). In the absence of overriding
steric constraints, alkynylmetal reagents undergo moderate to complete axial additions to cyclo-
hexanones and cyclohexenones <83TL4887>. The presence of an axial substituent at C-3 or C-5 in
either system results in a shift to complete selectivity for equatorial addition <75CRV52l, 89JOC4072).
Generalisations are less easy to make in the cyclopentanone series. 2-Alkylcyclopentanones undergo
CK-addition with ethynylmetal reagents. 2-Methoxycyclopentanone undergoes predominantly trans-
addition with ethynyllithium in liquid ammonia, but predominantly cw-addition in THF <75CRV52l >.
Interestingly, a complete reversal of stereoselectivity was observed with the 3-hydroxy-
cyclopentanone (16) on changing from monolithium ethynide to the bis magnesium ethynide (Sch-
eme 55) <81CC363>.
Scheme 55
Enantioselective additions to aldehydes and ketones have been achieved with trialkyl-
silylethynyllithium reagents which undergo addition to aromatic and aliphatic aldehydes in the
presence of a chiral amino alcohol ligand (ee 40-92%) (Equation (60)) (79CL447,80CL255). Moderate
enantiomeric excesses have also been achieved in the alkynylation of alkyl and aryl aldehydes
with alkynylzinc reagents in the presence of catalytic quantities of the amino alcohols (— )-N,N-
dibutylnorephedrine <90JCS(Pl)937> and (-)-Af-methylephedrine (Equation (61)) <90SL547>.
1040 Alkynes
(60)
(61)
2-Alkynoic acids are prepared by the carboxylation of alkynylmetal reagents (Equation (62))
(B-88MI I2i-oi>. Group 1 and 2 alkynylmetal reagents are employed almost exclusively, the reaction
being performed with solid carbon dioxide <54JOC1580> or, preferably, with anhydrous gaseous
carbon dioxide. The choice of solvent can be important; for instance, dioxan solutions of dial-
kynylmagnesium reagents afford higher yields of alkynoic acids than ethereal solutions of alky-
nylmagnesium halides <56JA1221>. In general, the use of alkynyllithium reagents in THF is optimal
providing alkynoic acids in very high, often quantitative, yields (B-88M1121-01 >.
i, CO2, THF
R = Li R—:^^CO2H (62)
ii, H 3 O +
Esters of 2-alkynoic acids are conveniently obtained by the oxidative carbonylation of terminal
alkynes (Equation (63)) <80TL849>. The reaction is carried out at atmospheric pressure and room
temperature in an alcoholic solvent with catalytic palladium(ll) chloride, a stoichiometric quantity
of copper(II) chloride and a base.
(63)
1.21.2.2.3 1,2-Addition to other carbon-chalcogen double bonded functions

In contrast to their carbonyl counterparts, thioaldehydes and thioketones usually undergo
1,2-addition reactions with carbanions through thiophilic attack; that is, nucleophilic attack occurs
at the heteroatom end of the C = S bond <B-90MI 12.1-01 >. Alkynylmetal additions have been little
studied but appear to conform to this mode of reactivity. Thus, thiobenzophenone reacts with
ethynyl sodium to give 1,2-bis(benzhydrylthio)ethyne (Equation (64)) <65CB33il>.
(64)
1.21.2.2.4 1,2-Addition to carbon-nitrogen multiple bonded functions

This section will deal with the reaction of 1-alkynes and alkynylmetal reagents with imines and
imine derivatives, heteroaromatic nitrogen compounds (e.g., pyridincs), isocyanates, isothio-
cyanates, carbodiimides and nitriles.
Aldimines and ketimines do not generally undergo addition reactions with alkynyllithium and
magnesium reagents <48JA3868>, although exceptions are known <86AKZ306, 89S33>. The poor rcac-
tivity of imines is presumably due to the low electrophilicity of the imine carbon atom and competing
deprotonation. Imines can be activated towards nucleophilic addition by removal of electron density
from the imine carbon atom. This has been achieved by coordination of a Lewis acid to the nitrogen
lone pair, by quaternisation of the nitrogen atom (iminium salts and Af-acyliminium salts) and by
incorporation of an electron-withdrawing group on the imine nitrogen (Af-acylimines and
jV-sulphonylimines).
Aldimines undergo 1,2-addition reactions with alkynyllithium reagents, in the presence of stoi-
chiometric boron trifluoride etherate, to afford secondary amines in reasonable yield. The reaction
has been applied to acyclic aldimines (Equation (65)) <84TL1O83> and to substituted 3-thiazolines
<83TL4503>. Ketimines do not undergo addition reactions under these conditions but are presumably
intermediates in the formation of propargyl amines by trialkynylaluminum-induced Beckmann
rearrangement of oxime carbonates (Equation (66)) <84TL2367>. Other Lewis acids, for example
TMS-OTf <88CC439> have been applied to the reaction of organometallic reagents with imines, but
the use of alkynylmetal reagents has not been reported.
(65)
(66)
Iminium salts have long been used as activated imines. The Mannich reaction of an alkyne with
formaldehyde and a secondary amine affords good yields of l-amino-2-alkynes (Equation (67))
<73S703>. The reaction can be viewed as a nucleophilic attack of the alkynide anion on an iminium
ion generated in situ. Conjugated alkynes including 1,3-enynes, 1,3-diynes and arylethynes react
more readily than do the less acidic alkylethynes. Copper salts markedly accelerate the reaction
through the formation of an alkynylcopper(I) reagent. Unfortunately the reaction is limited to the
preparation of tertiary amines in which the alkyne and N-atom are connected by a methylene group.
This limitation is overcome by the use of l-(l-dialkylaminoalkyl)benzotriazoles prepared from
benzotriazole, an aldehyde and a secondary amine. The latter compounds react with alkynyllithium
reagents to afford high yields of propargyl amines (Equation (68)) <89S3l>. An alternative to
the Mannich reaction for the preparation of tertiary amines is the reaction of AÂf-disubstituted
aminoalkyl ethers with alkynylmagnesium halides (Scheme 56) <63CPB1O49> or with 1-alkynes in the
presence of copper(I) iodide <85TL3203>. Primary propargyl amines are not available from the
conventional Mannich reaction but have been prepared employing ./V-triphenylphosphorylidene-1-
(benzotriazol-l-yl)methylamine (Scheme 57) <89TL3303> and A^N-bis^rimethylsilyOmethoxy-
methylamine <84AG(E)53, 84CC794,87S848).
(67)
(68)
Preformed iminium salts also undergo reaction with alkynylmetal reagents although only a few
examples have been reported <70JA6676, 83BSF(2)2l>. 5-Alkylthioamidinium salts of thiolactams
react with alkynyllithium reagents to afford a-alkynylazacycloalkanes after reduction with lithium
aluminum hydride (Scheme 58) <89JCS(Pl)12ll>.
1042 Alkynes
Scheme 56
Scheme 57
Scheme 58
/V-Acylimines and iV-acyliminium salts are also powerful electrophiles <70S49,84S85>. The reagents,
usually generated in situ, undergo 1,2-addition reactions with a variety of alkynylmetal reagents
<80CC736, 84T811, 86S372, 86TL4241, 88T5425, 88T5451, 88TL5391, 90JOC4657, 90S115>. A few examples are
illustrated in Scheme 59.
7V-Sulphonyl aldimines undergo addition reactions with alkynyllithium reagents to generate
N-protected primary amines <90JOC393>. The N-sulphonyl imines can be generated in situ by
treatment of aldehydes with JV-sulphinyl sulphonamides (Scheme 60).
Oximes and hydrazones generally show low reactivity towards alkynylmetal reagents. For exam-
ple, (S)-( — )-l-amino-2-methoxymethylpyrrolidine (SAMP)-hydrazones have been reported to
undergo addition reactions with a wide variety of organocerium reagents (alkyl, alkenyl, aryl), but
alkynylcerium reagents fail to give any addition products <87JA2224>. Boron trifluoride-activated
oxime ethers do undergo addition reactions with alkynyllithium reagents to afford O-alkyl hydroxyl-
amines (Equation (69)) <88TL3455>. Similarly, 2-isoxazolines undergo addition reactions with alky-
nyllithium reagents in the presence of boron trifluoride etherate provided the C-3 ring carbon atom
is unsubstituted <89CL1O79,91COS(l)355>.
(69)
Pyridine and other heteroaromatic nitrogen compounds possessing a formal azomethine linkage
undergo addition of alkynylmetal reagents when converted into iminium salts. Pyridine and sub-
stituted pyridines undergo smooth 1,2-addition reactions with alkynylmagnesium halides in the
presence of methyl chloroformate (Equation (70)) <83H(20)60l. 83TL18O1, 87JOC2094). Where other
Scheme 59
Scheme 60
electrophilic functions are present, such as carbonyl groups, chemoselectivity has been controlled
employing alkynyltin reagents. For example, 3-acyl substituted pyridines afford reasonable yields
of 2,3-disubstituted 1,2-dihydropyridines with alkynyltin reagents, whereas the corresponding mag-
nesium reagents display poor selectivity (88TL1785). N-Benzyloxypyridinium chloride, generated in
situ from pyridinc TV-oxide and benzoyl chloride, undergoes 1,2-addition of alkynylsilver reagents
to afford the C-2 addition product <89CL773>. The reaction is applicable to a wide range of substituted
pyridine TV-oxides and to quinoline, isoquinoline and pyrimidine TV-oxides.
(70)
Addition of alkynylmetal reagents to heterocumulenes such as isocyanates, isothiocyanates and

carbodiimides have not been studied extensively and only a few examples are available. Isocyanates
have long been known to react with alkynylmetal reagents and have often been used for charac-
terisation purposes (31JA4192, 33JA1094, 59CB1950); representative examples are given in Scheme 61
(33JA1094, B-88MI 121-20). Primary carboxylic amides are available from the reaction of alky-
nylmagnesium bromides with trimethylsilyl isocyanate or chloroacetyl isocyanate <75TL981> and
from the reaction of alkynylsilanes with chlorosulfonyl isocyanate <88S621>. A single example of the
reaction of an alkynyltin reagent with phenyl isocyanate in the presence of aluminum trichloride
has been reported <90CB2i9i>. 9-(l-Alkynyl)-9-borabicyclo[3.3.1]nonanes react with isocyanates to
afford 7V,7^'-disubstituted-Ar-(2-alkynoyl)-ureas (Equation (71)) <79SiO4>.
1044 Alkynes
Scheme 61
(71)
Isothiocyanates <8UCS(P1)4O, B-88MI 121-03> and carbodiimides <72BCJ1846, 84LA85> react with
group 1 and 2 alkynylmetal reagents to afford thioamides and amidines respectively (Scheme 62)
<72CPB1846, B-88MI 121-03>.
Scheme 62
Although nitriles do not undergo addition reactions with alkynyllithium reagents, and Lewis acid
promoted reactions have not been reported, nitrilium ions are presumably intermediates in the
Beckmann rearrangement of oxime sulfonates induced by alkynylmagnesium halides (Equation
(72)) <82TL3395>. Reduction of the intermediate imine with diisobutylaluminum hydride allows the
preparation of propargyl amines in reasonable yield.
(72)
1.21.2.2.5 1,2-Addition-elimination reactions

This section deals with the reaction of alkynylmetal reagents with electrophiles of the form
C(X)=Y, where both X and Y represent heteroatom functions. Substrates include carboxylic acid
chlorides, anhydrides and imides, carboxylic esters, thiol esters and lactones, amides and lactams,
alkyl chloroformates, alkyl chlorothionoformates and alkyl chlorodithioformates, imidoyl chlorides,
/V,iV-dialkylcarbamoyl and A^^-dialkylthiocarbamoyl chlorides, and cyanogen chloride. Although
the overall transformation for these reactions is one of substitution, the mechanism, at least of the
nontransition metal-mediated reactions, is better represented as an addition-elimination reaction.
Carboxylic acid chlorides react with alkynylmetal reagents to afford conjugated alkynones (Equa-
tion (73)). Group 1 and 2 alkynylmetal reagents do not generally give satisfactory results and
the less reactive alkynylcopper reagents are more successfully employed <70TL2659, 75OR(22)253>.
Although ethynylcopper itself does hot undergo this reaction, trimethylsilylethynylcopper can be
used successfully <75JOC131 >. Alkynylzinc halides also give very good results with saturated aliphatic
acid chlorides <88JOM(338)289>; with unsaturated acid chlorides the palladium-catalysed process is
more successful. Alkynylsilver <56JA1675>, manganese <89TL3545> and cadmium <67ZOR219> reagents
have also been employed successfully. More conveniently, 1-alkynes themselves react with acid
chlorides in the presence of catalytic copper(I) iodide, (PPh3)2PdCl2 and triethylamine at room
temperature to afford alkynones in high yield (Equation (74)) <77S777>. Unfortunately the reaction
is not applicable to acid chlorides such as acetyl, propanoyl and butanoyl chloride which react
readily with triethylamine. Alkynylzinc <83TL518l> and alkynyltin <86AG(E)508> reagents both
undergo smooth palladium-catalysed coupling reactions with acid chlorides, affording high yields
of conjugated ynones under very mild conditions and in the presence of a wide variety of other
functional groups. Alkynylsilanes undergo aluminum trichloride-catalysed reactions with acid chlor-
ides <63CB3280, 72JOM(37)45>. The intramolecular reaction has been applied to the preparation of a
number of cyclic alkynones <78TL23Ol>.
(73)
(74)
Carboxylic anhydrides undergo more effective coupling reactions with group 1 and 2 alkynylmetal
reagents <71M214>. Lithium alkynyltrifluoroborates also react smoothly with carboxylic acid anhy-
drides to afford conjugated alkynones in high yield (Equation (75)) <84TL24ll>. Cyclic imides, such
as succinimide, react with alkynylmagnesium halides to afford 4-ketoamides in yields of 40-69%
<71CPB391>.
(75)
Carboxylic acid esters generally afford tertiary alcohols with alkynylmetal reagents; exceptions
include formate, oxalate and trichloroacetate <78S3O7, 78TL937). Tertiary alcohol formation can be
prevented by employing alkynyllithium reagents in the presence of boron trifiuoride etherate (Equa-
tion (76)) <86S42l>. Under these conditions aliphatic esters afford conjugated alkynones in good
yield, whereas aromatic and a,j6-unsaturated esters do not react. Thiol esters such as 5-ethyl
carbothioates react with 1-alkynyltrimethylsilanes in the presence of silver tetrafluoroborate to give
the corresponding alkynones in good yield <83TL5131>. Lactones undergo addition-elimination
reactions with alkynyllithium reagents to afford conjugated alkynones, generally in good yield,
although this is dependent on the lactone ring size (Equation (77)) <78TL937>. The products are
often in equilibrium with their ring-closed hemiketal forms, the position of equilibrium depending
on the ring size and substitution pattern. Successful monoaddition of the alkynylmetal reagent
appears to be dependent on the stability of the intermediate ketal alkoxide which in turn is related
to ring size; 6 > 5 > 7 » acyclic. 6-Membered ring lactones invariably afford conjugated alkynones
in very high yield and numerous examples have been reported demonstrating the generality of this
reaction (Scheme 63) <81CL1415, 92JOC5818). In certain cases the initial addition product can be
induced to undergo a ring enlargement to an oxocene when warmed to room temperature in the
presence of HMPA (Equation (78)) <84TL1757>.
1046 Alkynes
(76)
(77)
Scheme 63
(78)
Carboxylic amides acylate alkynylmetal reagents with variable success <B-69MI 121-03).
A^TV-Disubstituted formamides, in particular A^JV-dimethylformamide <B-88MI 121-01 > and formyl
piperidine <81AG925>, react with alkynyllithium reagents to afford good yields of conjugated ynals.
The reaction intermediate is reasonably stable in ether solvents and further attack of the alky-
nyllithium reagent does not occur. Alkynylmagnesium halides give somewhat lower yields
<58JCS1O54>. A number of methyl and phenyl alkynones can be prepared in high yield from an
alkynyllithium reagent and AîV-dimethylacetamide or A^./V-dimethylbenzamide. However, weakly
basic alkynides such as phenylethynyllithium give unsatisfactory results <88JOM(338)289, B-88MI121-01).
The amides from other aliphatic carboxylic acids react incompletely. In the presence of boron
trifluoride etherate a wide variety of ,/V,./V-dialkylamides react with alkynyllithium reagents to
afford conjugated ynones in high yield (Equation (79)) <83CL35>. An interesting chemoselectivity is
observed under these reaction conditions with dimethylaminocarbonyl being far more reactive than
methoxycarbonyl and comparable to a ketone group. Secondary amides such as acetanilide are
recovered unchanged under the reaction conditions.
(79)
N-Methoxy-TV-methylamides are more effective acylating agents than the corresponding N,N-
dialkylamides and afford high yields of conjugated ynones with alkynyllithium reagents (Equation
(80)) (81TL3815,88JA2301). An evaluation of a variety of carboxylic acid derivatives in the preparation
of ynones showed that JV-methoxy-Ar-methylamides are very resistant to excess nucleophilic attack
as compared to acid chlorides, lithium carboxylates, 2-pyridylthioate esters and iV-acylpyrazoles,
and result in no tertiary alcohol products <85JOC3972>. In addition, the iV,0-dimethylhydroxylamine
unit appears to enhance the reactivity of the carbonyl group such that selective displacement
reactions can be achieved even in the presence of ester functions <88JA2301>. This methodology has
been usefully applied to the preparation of a number of ^-lactam ynones (Equation (81)) <87TL1857>.
The symmetrical urea Ar,Af/-dimethoxy-jV,Ar'-dimethylurea has been used as a carbonyl dication
equivalent in its reaction with phenylethynyllithium <9UOC29li>.
(80)
(81)
The reaction of lactams with alkynylmetal reagents has been little reported. Alkynyl azacyclo-
alkanes have been prepared in good yields by the reaction of alkynyllithium reagents with lactams
in the presence of boron trifluoride etherate followed by lithium aluminum hydride reduction of the
adducts (Equation (82)) <83TL1719>.
(82)
Alkyl chloroformates (17) react with alkynyllithium reagents to form esters of 2-alkynoic acids
(Equation (83)) <B-69MI 121-03 >.. The reaction is normally carried out by adding the lithiated alkyne
to an excess of the chloroformate in order to avoid the formation of tertiary alcohols <B-88MI
121-01). Esters of 2-alkynoic acids are also formed in a palladium-catalysed reaction of alkyl
chloroformates with alkynylzinc chlorides <83TL5l8l>. Alkyl chlorothionoformates (18) react with
alkynylmagnesium bromides and with 1-alkynes under palladium catalysis to afford thionoesters
<89TL1073,91LA903). Alkyl chlorodithioformates (19) similarly afford dithioesters <89TL1O73, 91LA903).
Imidoyl chlorides (20) react with alkynylcopper reagents <72S63, 91LA903) and, under palladium
catalysis, with 1-alkynes and alkynyltin reagents to afford alkynyl imines in high yield (85TL3463,
91S235,91TL1459). In a similar manner isocyanide dichlorides afford dialkynyl imines <88TL5379>.
1048 Alkynes
(83)
-/V,7V-Dialkylcarbamoyl chlorides (21) react with alkynylmetal reagents <55CR989> and with
1-alkynes in the presence of a palladium catalyst (iisill, 91LA903) to afford amides of 2-alkynoic
acids. N,./V-Dialkylthiocarbamoyl chlorides (22) afford thioamides (Equation (83)) <9lLA903>.
Cyanogen chloride reacts with alkynyllithium reagents to afford conjugated alkynyl nitriles
(73RTC667, 80S150). In the early 1990s, these compounds have been obtained from the reaction of
1-alkynes themselves with CuCN/bis(trimethylsilyl)peroxide <91TL2169> or with CuCN/TMS-Cl/cat.
Nal (Equation (84)) <93TL59ll>.
R ^ =
Cl—SEN RÊSEE SEN (84)
CuCN, TMS-C1, Nal
orCuCN,TMS-O-O-TMS
1.21.2.2.6 1,4-Addition reactions

A limited number of methods is available for the 1,4-addition of afkynylmetal reagents (or
terminal alkynes themselves) to cc,/?-unsaturated ketones, esters, sulfones, nitro compounds, etc.
Group 1 and 2 metal alkynides do not, in general, undergo successful 1,4-addition reactions.
Exceptions include the purely sterically controlled addition of lithium alkynides to 1,1,1-triphenyl-
3-penten-2-one <81AG(E)569> and the 1,4-addition of lithium and magnesium alkynides to a-silyl-
a,/?-unsaturated sulfones (Equation (85)) (90SL701, 90TL5499). The use of alkynylcopper reagents to
effect the 1,4-addition of an alkynyl group is precluded due to the tenacity with which copper binds
alkynyl ligands <69JOC3616>. One possible solution to this problem employs a cuprate reagent
derived from (£)-l,2-bis(tri-«-butylstannyl)ethylene as a nucleophilic ethynyl group equivalent in
the conjugate addition to a,/J-unsaturated ketones (Scheme 64) <74JA558l>. Unfortunately, extension
of this procedure to higher alkynes would appear to present major difficulties. More generally
applicable 1,4-addition reactions of alkynylmetal reagents have to date been limited to alkynyl-
aluminum, alkynylboron, alkynylzinc and alkynyltin reagents.
(85)
Scheme 64
Diethylalkynylalanes react with conjugated enones to give the 1,4-addition products (Scheme 65)
<7UA7320>. The reaction is believed to proceed through a cyclic six-mem bered transition state, and
in the absence of other proximal coordinating functionalities, the reaction is limited to enones
capable of adopting a cisoid conformation. Cyclic enones in which the enone system is rigidly
constrained to a transoid geometry, such as 2-cyclohexenone or isophorone, react with the alane
reagent to provide the tertiary carbinol derived from 1,2- rather than 1,4-addition of the alkyne
unit. This constraint can be overcome by preferential coordination of the aluminum reagent to
a neighbouring hydroxyl or amino group. For example, 2-(6-carbomethoxyhexyI)-4-hydroxy-2-
cyclopentenone (23) reacts with trialkynyl- and alkynyldimethylalanes to afford the 1,4-addition
product, the alkynyl group being delivered to the same face as the directing hydroxyl group
(Equation (86)) (72TL2627,75TL4217). Protection of the hydroxyl group of (23) by a tetrahydropyranyl
group prevents reaction with the aluminum reagent. In a similar system, the stereochemistry of the
conjugate addition has been reversed by providing a coordinating group exocyclic to the cyclo-
pentene ring (Equation (87)) <91JOC3205>. Conjugated enals and ynones do not afford 1,4-addition
products with diethylalkynylalanes, but rather give the 1,2-addition product <7UA7320>. Conjugated
nitro alkencs undergo 1,4-addition giving y-alkynylnitro compounds in good yield (Equation (88))
<89JOC2391>.
Scheme 65
(86)
(87)
(88)
A more general procedure for the 1,4-addition of an alkynyl unit to conjugated enones is the
nickel-catalysed reaction with dimethylalkynylalanes (Equation (89)) <78JA2244>. The reaction has
been successfully applied to a range of cyclic s-trans enones using a catalyst derived from treatment
of Ni(acac)2 with diisobutylaluminum hydride. 1,4-Addition of an ethyne unit is most readily
achieved by the use of a trimethylsilylethynyl reagent, since reaction with an unprotected aluminum
ethynide is complicated by product decomposition.
1050 Alkynes
(89)
1,4-Addition of alkynylalanes followed by in situ alkylation is not readily achieved due to the
poor reactivity of aluminum enolates. However, a protocol has been described whereby addition of
alkynylalanes to alkylidenemalonates is followed by palladium-catalysed allylation, permitting
vicinal /J-alkynylation a-allylation in a single operation (Scheme 66) <93TL227i).
Scheme 66
Alkynylboron reagents similarly undergo 1,4-addition to conjugated enones. Thus, tri-

octynylboron undergoes successful 1,4-addition to pregnenolone acetate yielding the 16-octynyl
derivative <72TL2627>. A trialkynylboron reagent has also been successfully added to methyl vinyl
ketone <76TL235>. Unfortunately, only one of the three alkynyl groups is transferred in the reaction,
constituting a serious disadvantage where the alkyne moiety is valuable. Extension of this reaction
to 5-]-alkynyl-9-BBN provides a solution to this problem <77JA954>. Reaction with conjugated
enones occurs rapidly at room temperature and gives high yields of the 1,4-addition product.
Analogous to the uncatalysed 1,4-addition of alkynylalanes, the reaction is believed to proceed
through a cyclic transition state, consistent with the observation that the reaction is retarded by
steric bulk at the /?-position of the enone and fails with cyclic enones which are incapable of adopting
a cisoid geometry. Alkynyldiisopropoxyboranes also react with conjugated enones in the presence
of boron trifluoride etherate to give 1,4-addition products in good yields (Equation (90)) <92CL695>.
A disproportionation reaction is believed to occur with boron trifluoride to give the more Lewis
acidic alkynylfluoroisopropoxyborane reagent; in the absence of boron trifluoride etherate no
reaction occurs.
(90)
Alkynylzinc bromides undergo 1,4-addition to conjugated enones in the presence of

r-butyldimethylsilyltriflate to give >',d-alkynyl silyl enol ethers (Equation (91)) <90TL7627>. The reaction
is successful with both s-cis and s-trans enones and yields are high with /S-monosubstituted
a,/?-enones. With /?-unsubstituted enones, such as methyl vinyl ketone, yields are reduced due to
further reaction of the initially formed 1,4-addition product (a zinc enolate) with the enone.
Furthermore, the method is unsuccessful with /J,#-disubstituted enones, yielding a mixture of 1,2-
and 1,4-addition products along with unreacted starting material.
(91)
Alkynyltrichlorotin reagents, prepared from terminal alkynes and a combination of tin(IV)

chloride and a trialkylamine, undergo 1,4-addition to conjugated enones (Equation (92)) <92CL2479>.
Cyclic enones were not examined. With methyl vinyl ketone, addition of two equivalents of the
alkyne has been reported under almost identical conditions (Equation (93)) <93JA3362>.
(92)
(93)
Transition metal-catalysed reactions of terminal alkynes with conjugated enones and enoates
have been reported. A very efficient addition of terminal alkynes to methyl vinyl ketone has been
realised with a RhCl(PMe3)3 catalyst (Equation (94)) <90TL7063>. Very few examples were reported
and it remains to be seen whether this potentially very useful reaction will prove general. Unfor-
tunately, at temperatures significantly above 20 °C, dimerisation of the terminal alkyne occurs as a
competing reaction, and this might hinder attempts to extend the reaction to ^-substituted enones.
(94)
A palladium-catalysed reaction of terminal alkynes with methyl 2,3-pentadienoate has been

reported (Equation (95)) <9OJA2816>. An unusual dependence of product regioselectivity on the
choice of catalyst is observed with the conjugated enoate (24) being favoured by more electron
deficient catalyst systems and the nonconjugated enoate (25) being favoured by more electron rich
catalysts. The ratio of (24): (25) was optimised at 81:19 using a catalyst comprising tetra-
kis(carbomethoxy)palladacyclopentadiene and tris(2,6-dimethoxyphenyl)phosphine. The ratio of
(25): (24) was optimised at 91:9 using a catalyst comprising palladium acetate and triphenyl-
phosphine. A possible explanation for the catalyst-dependent regioselectivity might relate to the
preferential coordination of an active palladium intermediate to the 2,3-double bond with a more
electron rich catalyst (leading to the nonconjugated ester products) and to the 3,4-double bond with
a more electron deficient catalyst (leading to the conjugated ester product). Steric effects override
these electronic effects such that further substitution at position 2 or 4 gives the conjugated addition
product (24) regardless of the catalyst used.
(95)
1.21.2.3 Substitution Reactions of Propargyl/AUenyl Carbanions

While alkynylmetal reagents are generally used for the introduction of the carbon-carbon triple
bond, a number of propargylation methods have been developed employing propargyl/allenyl metal
reagents <B-80Ml 121-02). Almost all of the reported examples of this type of substitution reaction
can be categorised as substitutions of halogen or oxygen functions. In addition, the reported
reactions have been limited to alkyl, allyl, propargyl and benzyl electrophiles. Nevertheless, this
alternative strategy is particularly well suited for the preparation of a-branched alkynes.
1052 Alkvnes
1.21.2.3.1 Substitution of halogen
Propargyl and allenyl organometallic reagents are powerful nucleophiles and undergo a variety
of substitution reactions. Unfortunately, the reagents frequently exist in equilibrium with each other
and display ambident behaviour in their reactions with electrophiles. Substitution reactions of alkyl
halides are no exception. Indeed, one of the main problems associated with the use of these reagents
is controlling the balance between allenic and propargylic products (Scheme 67).
M _ _ M RX R + R
Scheme 67
Allenylmagnesium halides display poor reactivity towards unactivated alkyl halides, but couple
effectively with allylic halides, propargylic halides and a-haloethers to afford mixtures of alkynes
and allenes. In some cases alkynes are formed almost exclusively, as in the coupling with allyl and
propargyl bromides (26) and (27) (Scheme 68) <75T1846>. In other cases substantial quantities of
allene are formed. The resulting separation problems can be overcome by silylation of the crude
product, and this procedure has been successfully applied to the reaction of allenylmagnesium
bromide with allylic and benzylic halides <70TL2247>. Allenyllithium reagents generally afford sub-
stituted allenes by a-alkylation <75CC56l>, whereas allenylalanates have been reported to undergo
regioselective y-alkylation reactions with allylic bromides, affording 1,5-enynes in high yield (Equa-
tion (96)) <83S883>.
Scheme 68
(96)
Lithium and magnesium derivatives of l-(trimethylsilyl)propyne <68TL504l>, l-(triisopropylsilyl)-

propyne <82TL719> and l-(trimethylsilyl)butyne <84Slll> have been used very effectively for the
regioselective substitution of allyl, benzyl and unactivated alkyl halides (Scheme 69) (70JA6314,
86JA1359). The trialkylsilyl group functions both as a readily removable protecting group and as a
steric shielding group reducing the level of substitution at C-1.
Scheme 69
An alternative and very effective solution to the regioselectivity problem is provided by the use
of 1,3-dilithiopropyne. The allenyl dianion is presumably destabilised relative to the propargyl
dianion allowing the reagent to undergo highly regioselective monosubstitution (Scheme 70) and
1,3-disubstitution (Scheme 71) reactions with primary alkyl bromides <(75CC817,76S32l>. The reaction
can be readily extended to other terminal alkynes and provides a convenient route to a-branched
alkynes, compounds which are not readily available by substitution of alkynylmetal reagents.
Reactions with allylic halides have been reported to be problematic and reagents derived from
dilithiation of allene <85TL27l> and phenyl propargyl sulphide <81JOC5041> have been recommended
as alternatives.
Scheme 70
Scheme 71
1.21.2.3.2 Substitution of oxygen functions

Allenylmagnesium bromide reacts with 1,2-epoxybutane (Equation (97)) <B-80Ml 121-02), whereas
allenyllithium reagents afford allenes predominantly or exclusively <81S875>. Regioselective prop-
argylation of epoxides can be achieved employing lithiated 1-triisopropylsilylpropyne (Equation
(98)) <82TL719>. The corresponding Grignard reagent undergoes substitution reactions with allylic
epoxides <84JA6006> and allylic phosphates <87TL527> in the presence of copper(I) iodide (Scheme
72). Allenyltrialkylstannanes react with allylic acetates in the presence of catalytic Pd(PPh3)4
<83JOC5302> and with acetals and ketals in the presence of titanium(IV) chloride <87CL1345> to afford
1,5-enynes and propargyl ethers respectively.
(97)
(98)
Scheme 72
1054 Alkynes
1.21.2.4 Addition Reactions of Propargyl/Allenyl Carbanions
The 1,2-addition reaction of propargyl/allenyl organometallics to C = X functions provides an
alternative strategy for introduction of the carbon-carbon triple bond, one which is particularly
well suited for the preparation of /?-functionalised alkynes (B-78MI 121-01, B-80MI121-02, 9icos(2)8i>.
The reactions can, however, be complicated by equilibration of the isomeric propargyl/allenyl
organometallics with the associated formation of a mixture of propargylic and allenic adducts. In
general, at least with carbonyl functions, it is believed that the reactions proceed by a cyclic SE\'
(or SE2') process and that allenylmetals lead mainly to alkyne-containing adducts whereas the
corresponding propargylic isomers lead to allenic adducts (Scheme 73). The overall regioselectivity
is governed by the equilibrium concentration and relative reactivities of the organomctallic nucleo-
philes, and is therefore highly dependent on the nature of the substituents on both the organometallic
reagent and on the electrophile.
Scheme 73
In addition to the problem of regioselectivity, problems of enantioselectivity and diastereo-

selectivity (syn and anti isomers) can arise, depending on the substitution pattern of the organo-
metalhc reagent.
1.21.2.4.1 1,2-Addition to carbon-oxygen double bonded functions

The 1,2-addition of propargyl/allenyl metal and metalloid reagents to aldehydes and ketones
provides a convenient method for the preparation of homopropargyl alcohols. Through appropriate
choice of the metal and the reaction conditions, regioselectivc and stereoselective propargylation
methods have been developed for particular substitution patterns of the organometallic reagents. It
therefore seems most useful to arrange this section according to the substitution pattern of the
target homopropargylic alcohol (Figure 2).
Figure 2
Figure 2 Substituted homopropargyl alcohols.

Type I alcohols can be prepared very effectively by the addition of unsubstituted allenylboron,
tin and silicon reagents to aldehydes and ketones. These reagents are relatively stable towards
isomerisation and generally afford predictable results in their reactions with carbonyl compounds.
9-Allenyl-9-BBN undergoes a highly regioselective addition to aldehydes and ketones, and even
to relatively hindered ketones, affording high yields of type I alcohols (Scheme 74) <93TL15>.
Allenylboronic esters have also been successfully applied to the regioselective <74JOM(76)297,
74JOM(76)305> and enantioselective <82JA7667, 86JA483, 86TL1175) propargylation of aldehydes and
/J-hydroxyketones (although not to ketones in general) (Scheme 75). Enantioselective propargylation
of aldehydes has also been achieved with propargyl triphenylslannane in the presence of a chiral
bromoborane reagent derived from the bis-/>-toluenesulphonamide of (R,R)- 1,2-diphenyl-1,2-
diaminoethane and boron tribromide (Equation (99)) <90JA878>. The reaction proceeds through the
intcrmediacy of an allenylborane. Diallenyltin dibromide <84CL1939> and allenyltrimethyl-
silane/titanium(IV) chloride <8()JOC3925> also react with aldehydes to afford type I alcohols.
Scheme 74
Scheme 75
(99)
Allenyl/propargyl metal reagents derived from more electropositive metals (Li, Mg, Zn, Al)
frequently undergo rapid equilibration and the outcome of their addition reactions is less predictable.
However, some generalisations can be made. Allenylmagnesium halides and unsubstituted allenyl-
aluminum reagents usually react with carbonyl derivatives to furnish predominantly or exclusively
type I alcohols <70BSF2175>, whereas, with the exception of some aromatic aldehydes and ketones
<89SC17O5>, allenyllithium and zinc reagents generally afford mixtures of allenic and homo-
propargylic alcohols <B-8OMI 121-02). Highly regioselective propargylation of aldehydes and ketones
can be achieved employing the lithium derivative of l-(triisopropylsilyl)propyne (Equation (100))
<82TL7I9>.
(100)
Type II homopropargyl alcohols have been prepared by the regioselective reaction of aldehydes
and ketones with 3-substituted allenylmagnesium <73BSF337l> and aluminum <83S883> reagents. In
the reaction of aldehydes with 1,2-butadienylmagnesium halides, the antr.syn product ratio is
related to the size of the aldehyde substituent and has been rationalised as shown in Figure 3
<69CR(C)342>. With aldehydes a«//-diastereoselectivity can be improved to 96-98% employing the
1056 Alkynes
corresponding allenylzinc chlorides (Equation (101)) <84JOC4565>. Allenyltitanium reagents also
give improved a«//-selectivity in certain cases <82JOC2225>. Type II sy«-homopropargyl alcohols are
obtained selectively from the reaction of aldehydes and ketones with 3-substituted allenylsilanes in
the presence of titanium(IV) chloride (Equation (102)) <86JOC3870>. a-Substituted propargyl bro-
mides are reported to undergo addition to aldehydes in the presence of chromium(II) chloride to
afford homopropargyl alcohols exclusively, albeit with little diastereoselectivity <92JOC4070>.
Figure 3
Figure 3 Steric effects in the addition of allenyl Grignard reagents to aldehydes.
(101)
(102)
Type III homopropargylic alcohols can be formed by the reaction of 3,3-disubstituted allenyl-
lithium and magnesium reagents with carbonyl compounds; steric factors play a large part in
determining the outcome of the reaction. Thus, while the homopropargyl alcohol (28) was formed
according to Scheme 76 <62CR(255)l750>, an analogous Grignard derivative furnished none of the
corresponding alcohol but gave (29) as the principal product <75T3073>. It has since been shown
that 3,3-dialkyl substituted allenyllithium <75CC561, 77JA7632, 81S875> and alanate <83S883> reagents
react with aldehydes and unhindered aryl ketones to afford type III alcohols, whereas dialkyl ketones
and hindered aryl ketones afford predominantly allenic alcohols. Small quantities of alkynols
corresponding to (29) are also formed in many of these reactions, presumably by rearrangement of
the allenyllithium.
Scheme 76
Type IV homopropargylic alcohols can be prepared selectively through the reaction of aldehydes
and ketones with 1-substituted allenylboranes (Scheme 77) <78JA556l> or with 1-substituted allenyl-
silanes in the presence of titanium(IV) chloride <86JOC3870>. In contrast, 1-substituted allenyl/
propargyl metal reagents generally afford allenic alcohols as the major products <84BCJ2768>. An
exception is the selective formation of homopropargyl alcohols from the reaction of hindered
ketones with 1-substituted allenyltin/alkyllithium combinations <90JOC44l>. The limitation to hin-
dered ketones can be overcome using indirect methods. Thus, acyl silanes condense with the
allenyllithium reagents to afford almost exclusively the homopropargylic alcohols after desilylation
with tetrabutylammonium fluoride (Equation (103)).
Scheme 77
(103)
Type V homopropargylic alcohols have been prepared by the regioselective reaction of

1,3-disubstituted allenyltitanium reagents with aldehydes (Equation (104)) <84BCJ2768>. The reaction
is highly diastereoselective affording tf«f/-homopropargylic alcohols. Allenylzirconium reagents,
generated by treating propargylic ethers with biscyclopentadienylzirconium, have also been shown
to undergo regioselective and diastereoselective reactions with aldehydes in the presence of boron
trifluoride etherate to afford a«»'-homopropargylic alcohols <92TL3769>. Complementary syn
diastereocontrol, and also enantiocontrol, is obtained in the Lewis acid-catalysed reaction of enantio-
merically enriched 1,3-disubstituted allenylsilanes <93TL2383> and stannanes <92JOC1242> with
a-branched aldehydes (Scheme 78). Intramolecular cyclisations of allenylstannane aldehydes have
been successfully applied to the preparation of 12-14 membered rings (Equation (105)) (92JOC3387).
(104)
Scheme 78
(105)
Type VI homopropargylic alcohols can be prepared by the addition of propargyl/allenyl metal

reagents to carbonyl compounds, but few examples have been reported. Whereas 1,3,3-trisubstituted
allenyllithium reagents seem to show a strong preference for the formation of allenic alcohols
<81S875>, the corresponding allenyl-9-BBN <93JOC165l> and allenylzirconium (Scheme 79)
<92TL3769> reagents afford homopropargylic alcohols with high selectivity. 1,3,3-Trisubstituted
1058 Alkynes
allenylsilanes also afford type VI alcohols selectively, but the reaction is complicated by the for-
mation of 4,5-dihydrofurans (Equation (106)) <86JOC3870>.
Scheme 79
(106)
Reaction of propargyl/allcnyl zinc, magnesium and lithium reagents with carbon dioxide affords
mixtures of alkynoic and allenic acids, with the latter predominating <(B-80MI 121-02, 81S875). In
contrast, regioselective formation of 3-alkynoic acids has been achieved by carbonation of allenyl-
alanates (Equation (107)) <83S883>.
(107)
1.21.2.4.2 1,2-Addition to other carbon-chalcogen double bonded functions

Thioaldchydes are generally unstable at ambient temperatures and their reactions with prop-
argyl/allenyl organometallics have not been reported. Di-?-butyl thioketone reacts with allen-
ylmagnesium bromide to afford a mixture of homopropargylic thiol (30) and the heterocycle (31)
(Equation (108)) <77JOM(i40)257>. Adamantane thione reacts similarly.
(108)
Dithioesters react with allenylmagnesium bromide to afford dithioacetals after methylation (Equa-
tion (109)) <77T2949>. Carbon disulfide similarly undergoes carbophilic addition with allcnyllithium
reagents to afford methyl 3-alkynedithioates after methylation (Equation (110)) <81S551).
(109)
(110)
1.21.2.4.3 1,2-Addition to carbon-nitrogen multiple bonded functions
Most of the information available for the reaction of propargyl/allenyl organometallics with
C-N multiple bonded functions concerns the reactions of aldimines and their iminium salts. Little
or no information is available for reactions with ketimines, ketiminium salts, iV-heterosubstituted
imines (oxime ethers, phenylhydrazones, etc.) or nitriles.
The addition of unsubstituted propargyl/allenyl aluminum, zinc, magnesium and lithium reagents
to aldimines has been reported (Equation (111)) <64BSF952,71BSF3071). Homopropargylamines (32)
are obtained exclusively with the aluminum reagent, whilst mixtures of alkynic (32) and allenic
products (33) are formed with the zinc and lithium reagents. Propargyl/allenyl magnesium reagents
do not give useful yields of (32).
(111)
Direct additions of unsubstituted propargyl/allenyl organometallics to ketimines have not been

reported. There is, however, no reason why reactions of this type should not be successful since
indirect additions have been achieved in the Beckmann rearrangement of oxime sulfonates promoted
by Grignard reagents <82TL3395>. Thus, treatment of oxime sulfonates with Grignard reagents
furnishes imines which can be further alkylated with allenylmagnesium bromide and lithium reagents
(Scheme 80).
Scheme 80
Substituted propargyl/allenyl organometallics bearing a C-l trimethylsilyl group (34) undergo

highly regio- and diastereoselective reactions with aliphatic aldimines affording an/z'-homopropargyl
amines (Equation (112)) <84CC1OO4>. Yields are optimal employing the titanium reagent derived
from addition of ClTi(Pr'O)3 to the lithiated allene. The stereoselectivity is readily explained by a
cyclic transition state in which the a-substituent of the imine and the methyl group of the allenylmetal
reagent are aligned in a less sterically congested anti relationship (Figure 4). a-Aryl imines are
exceptions in that they react with little stereoselectivity. Related addition reactions of a-silyl-
allenylboranes have been reported <85JOC2193>.
(112)
Propargyl/allenyl organometallics also undergo addition reactions with iminium salts, both pre-
formed iminium salts <81JOM(218)275> and those generated in situ from gem amino ethers (Equation
(113)) <80JOM(l98)l, 87BSF93). As with the corresponding imines, aluminum reagents are more
selective than the corresponding lithium, magnesium or zinc compounds. Regardless of the metal,
however, the regiochemical outcome is markedly affected by the nature of R1. Alkynic products are
favoured with unsubstituted propargyl/allenyl metal reagents (R1 = H) and allenic products are
favoured with the corresponding substituted reagents (R1 = alkyl).
1060 Alkynes
Figure 4
Figure 4 Regioselective and diastereoselective formation of anti-homopropargylamines.
(113)
The increased electrophilicity of iminium salts can allow reactions with propargyl/allenyl organo-
metallics derived from less electropositive metals such as tin and silicon. An example is the reaction
of propargyl/allenyl tin reagents with iminium salts derived from quinoline or isoquinoline and
chloroformate esters. Addition is regioselective affording l-alkoxycarbonyl-2-(2-alkynyl)-l,2-dihy-
droquinolines and dihydroisoquinolines (Equation (114)) <87CL1519>. An /Y-acyl iminium ion is also
a presumed intermediate in the titanium(IV) chloride-promoted reaction of 1 -methyl- l-(trimethyl-
silyl)allene with 5-ethoxy-2-pyrrolidinone (Equation (115)) <85JA7233>.
(114)
(115)
1.21.2.4.4 1,2-Addition-elimination reactions

Relatively few examples of 1,2-addition-elimination reactions of propargyl/allenyl organo-
metallics have been reported. Carboxylic esters undergo addition-elimination reactions with prop-
argyl/allenyl magnesium reagents to afford mixtures of the bis-addition products (35) and (36)
(Equation (116)), even at low temperatures (B-80MI 121-02). The allenic alcohol (36) derives from
isomerisation of the initially formed propargylic ketone. Regioselective monoaddition is observed
in the reaction of allenic organomercurials with acid chlorides (Equation (117)) <86JOC2623>;
however, the propargylic ketones are relatively unstable and readily isomerise to allenones. 7Y,7Y-
Disubstituted carboxylic acid amides react with propargyl/allenylmagnesium reagents to afford
mixtures of propargylic and allenic ketones <56CR(243)1895>.
(116)
(117)
Benzoxazoles and benzothiazole react with allenylmagnesium bromide to afford products (37)
and (38) by an initial addition-elimination reaction (Equation (118)) <86S638>.
(118)
1.21.2.4.5 1,4-Addition reactions

Few examples of the 1,4-addition reactions of propargyl/allenyl organometallics have been
reported, perhaps due to difficulties associated with controlling both the addition mode (1,2-addition
vs. 1,4-addition) and the ambident behaviour of the reagents. Although, in general, propargyl/allenyl
lithium reagents undergo • 1,2-addition reactions with a,/?-unsaturated carbonyl compounds
(77JA7632,90JOC441), lithiated l-(triisopropylsilyl)propyne has been reported to effect regioselective
conjugate propargylation of 2-cyclohexenone in a THF-HMPA solvent mixture (Equation (119))
<82TL719>. 1,2-Addition occurs in THF alone. Organocopper reagents have met with limited success
<74TL4467>.
(119)
Silylallenes and stannylallenes have proven more successful. For instance, trimethylsilylallene and
3,3-dimethyl-l-trimethylsilylallene undergo successful 1,4-addition reactions with a,/?-unsaturated
acyl cyanides in the presence of TiCl4 (Equation (120)) <86JOC1199>. With ot,/?-unsaturated ketones
reactions can be more complicated. For example, the reaction of trimethylsilylallene with 2-cyclo-
hexenone in the presence of TiCl4 provides a 1.6:1 mixture of the 1,4-adduct, 3-propargylcyclo-
hexanone and a cyclopentene derivative (Scheme 81) <83T935>. The minor product, presumably
derived via 1,2-silyl migration in an intermediate vinyl cation, can be avoided by using triphenyl-
stannylallene <90JOC4853>. The weaker C-Sn bond allows a more rapid elimination of the stannyl
group and the high yield formation of conjugate propargylation products. Similarly, 3-methyl-l-
(triphenylstannyl)allene reacts with 2-cyclohexenone to afford the 1,4-addition product (R1 = Me)
as a 1:1 mixture of diastereomers.
(120)
1062 Alkyne s
Scheme 81
The TiCl4-promoted reaction of stannylallenes with a-nitro alkenes has also been reported
<90JOC4853>. Using (tri-«-butylstannyl)allene, two types of products, /?-propargylic nitroalkanes (39)
and a-propargylic ketones (40) are obtained. The selectivity depends on the presence or absence of
an a-substituent on the nitro alkene (Scheme 82).
Scheme 82
1.21.3 ALKYNES BY C s C BOND FORMATION

All alkyne carbon-carbon triple bond formation reactions can be classified as elimination reac-
tions. However, for the purpose of this review it is convenient to make some distinctions and to
classify the reactions into three categories: elimination, fragmentation and electrocyclic reactions.
In addition, a fourth category of reaction, isomerisation reactions, has been added to account for
those processes in which a triple bond is introduced by migration of a preexisting triple bond along
a carbon chain.
1.21.3.1 Elimination Reactions

The alkyne carbon-carbon triple bond is most commonly introduced by elimination of a stable
molecule or molecules from a more saturated substrate, either an alkene or an alkane. Eliminations
most commonly involve the loss of groups from adjacent carbon atoms (1,2-eliminations) although
alkynes can also be formed by 1,1-eliminations and, with more highly unsaturated systems, by
1,4- and 1,6-eliminations.
1.21.3.1.1 Elimination of hydrogen
Thermolytic elimination of hydrogen from alkenes is known to occur, but requires severe con-
ditions and does not represent a convenient laboratory procedure for the preparation of alkynes
<60AG39l>. 1-Alkenes have been observed to undergo dehydrogenation with lithium dispersion to
afford lithium alkynides and lithium hydride <67JOC105>. With 1-hexene the yield reached 6 5 %
although lower yields were obtained with other 1-alkenes. A number of diaryl substituted alkynes
have been prepared in moderate yields by dehydrogenation of the corresponding alkenes with
KOBu' in oxygenated D M F , but the reaction is of limited scope <91CC948>.
In contrast to the severe conditions required for the thermal dehydrogenation of alkenes, pal-
ladium-catalysed dehydrogenation of both terminal and internal monoalkenes occurs under very
mild conditions. Employing a supported palladium acetate catalyst and perchloric acid in an aerated
ethanol-water solvent system, a range of straight chain 1-alkenes has been reported to undergo
dehydrogenation to afford 1-alkynes in very high yields (Equation (121)) <85CC1571>. Moreover,
internal trans alkenes give nearly quantitative yields of disubstituted alkynes with complete regio-
selectivity. N o isomerisation occurs and provided an aqueous ethanolic solvent system is employed,
no hydration of the alkene or alkyne is observed.
R' [T]— Pd(OAc)2 (4mol %)

1
\=\ R —= R2 + H2O (121)
\ 2 air, HC104, EtOH, H2O
Ri = H; R2 = Prn, Bun, n-C 5 H n , H - C 6 H B , n-C 7 H 15 , «-C 8 H 17 89-92%

R1 = Me, Et, Prn; R2 = Pr", Bu", n-C 5 H n 95-98%
1.21.3.1.2 Elimination of carbon functions

Although alkynes are frequently prepared by the elimination of carbon functions, these reactions
are more adequately described as fragmentations or electrocyclic reactions and as such are treated
in Sections 1.21.4.2 and 1.21.4.3. A unique alkene-alkyne transformation has been reported on
treatment of a variety of terpenoids containing a terminal isopropylidene unit with sodium nitrite
in aqueous acetic acid (Scheme 83) <86TL267>. The reaction produces 2-alkynes in 30-98% yields
and appears to involve an unprecedented elimination of a CH 4 unit from the double bond of the
2-methylpropenyl group. On closer examination, however, it has been determined that the original
methyl group is lost as carbon dioxide, and a mechanism involving a complicated series of nitrations,
ring closure to an isoxazoline /V-oxide and fragmentation to the alkyne, carbon dioxide and NO
has been proposed <87TL492l>. Thus, the reaction is more adequately described as a fragmentation
reaction.
Scheme 83
1.21.3.1.3 Elimination of halogen
(i) Dehydrohalogenation
Alkynes have been prepared from organic halides by 1,1-, 1,2-, 1,4- and even 1,6- eliminations of
hydrogen halide, although by far the most important type of elimination from the preparative point
of view is 1,2-dehydrohalogenation.
1064 Alkynes
1,2-Elimination of hydrogen halide from 1,1- and 1,2-dihaloalkanes (Equations (122) and (123))
and from haloalkenes (Equation (124)) represents the most common method for introducing the
carbon-carbon triple bond. The starting materials are readily accessible; 1,2-dihaloalkanes are
prepared by halogenation of alkenes and 1,1-dihaloalkanes are available from halogenation of
aldehydes or ketones with, for example, phosphorus pentachloride or another acid halide. Alkenyl
halides, including 1,1-dihaloalkenes, can be prepared by a variant of the Wittig reaction or by
dehydrohalogenation of dihaloalkanes with bases not strong enough to accomplish full elimination
to alkynes.
(122)
(123)
(124)
A priori, numerous complementary and opposing factors will govern the course of base-induced
1,2-dehydrohalogenations. Among these are the nature of the leaving group, the base and the
solvent, and also the electronic and steric effects of the substituents in the a and /? positions. For a
given substrate the choice of base, solvent and temperature is often critical for successful alkyne
formation, as illustrated in Scheme 84 (60JCS3614, 64JCS115 L >. This sequence demonstrates; (i) the
elimination of hydrogen halide from 1,2-haloalkanes is faster than the corresponding elimination
from haloalkenes; (ii) trans elimination from alkenyl halides is more rapid than cis elimination; and
(iii) sodium amide in liquid ammonia is a much more effective base than potassium /-butoxide.
Scheme 84
Tertiary amines such as dbu and dbn which smoothly dehydrohalogenate dihaloalkanes to
haloalkenes are generally inert towards the latter compounds. Similarly, alkali metal carbonates do
not effect elimination in unactivated haloalkenes. Alkali metal hydroxides and alkoxides in solvents
such as alcohols, dioxan and DMSO have been used with some success as illustrated in Scheme
85 <76JA2667, 87CB187, 92JOC651). The greater basicity of potassium f-butoxide and its reduced
nucleophilicity due to steric encumbrance have led to its successful use in elimination reactions. In
particular, the dehydrobromination of alkenyl bromides by potassium /-butoxide used in com-
bination with the Wittig reaction of aldehydes with bromomethylenetriphenylphosphorane provides
a convenient preparation of terminal alkynes (Equation (125)) <80TL402l, 92JOC651). The product
alkynes can, however, be contaminated with unreacted (£)-alkenyl bromide. Indeed, oxygen bases
generally suffer from the disadvantage that only trans eliminations proceed smoothly with alkenyl
By C~C Bond Formation 1065
halides. Isomers with H and X in a cis relationship react very slowly, do not react at all, or evade
cis elimination by a side reaction (Scheme 86) (54JA4558,62JOC3688).
Scheme 85
(125)
Scheme 86
The use of oxygen bases can be further limited by isomerisation and addition reactions of the
product alkyne. The preparation of straight chain terminal alkynes is particularly affected by
isomerisation reactions; using sodium ethoxide in ethanol the yield rapidly drops off with increasing
chain length <27CB950>. One very effective solution to this problem is the use of potassium /-butoxide
and catalytic amounts of 18-crown-6 in petroleum ether <80LAi >. Very high yields of alkyl substituted
alkynes are formed with no residual alkenyl halide or isomerisation/addition products being formed.
1,2-Dihalides (from alkenes) and 1,1-dihalides (from aldehydes) yield 1-alkynes and internal
1,1-dihalides (from symmetrical ketones) give internal alkynes in excellent yield (Scheme 87).
2,2-Dihalides (from methyl ketones) yield homogeneous 1-alkynes only if the 3-position is blocked.
A similar high yielding procedure for the preparation of alkyl and aryl substituted alkynes from
1,2-dibromoalkanes has been reported using potassium hydroxide and catalytic amounts of lipo-
philic phase-transfer catalysts in petroleum ether (81T1653,86T3569).
The fluoride ion can promote elimination from alkenyl halidcs to afford alkynes <74JCS(Pl)340>.
A mild synthesis of 1,3-diynes ; s provided by a two step sequence involving a palladium(O)-catalysed
coupling of a 1-alkyne with (Z)-1,2-dichloroethene, followed by dehydrochlorination of the inter-
mediate (Z)-chloroenyne with tetrabutylammonium fluoride (Scheme 88) <88JOC2655>. The cor-
responding (£)-chloroenynes give only traces of 1,3-diynes even under vigorous conditions,
consistent with the observation that syn eliminations generally require a stronger base.
Alkali metal amides are stronger bases than alkoxides or fluoride ion and are frequently used in
elimination reactions. Sodium amide in liquid ammonia is most commonly employed although
other solvents such as DMSO and HMPT, and other amides such as lithium amide and lithium
diisopropylamide are frequently used. In liquid ammonia, three equivalents of sodium amide base
1066 Alkynes
Scheme 87
Scheme 88
are generally employed for the preparation of 1-alkynes from dihaloalkanes. In this manner the
sodium salt of the 1 -alkyne is precipitated, thus avoiding prototropic isomerisations. In DMSO, the
sodium salts are soluble but isomerisation to the thermodynamically more stable 2-alkynes can be
prevented if prolonged reaction times are avoided <7OT2127>. A further advantage to the use of
amide bases is that both (£)- and (Z)-haloalkenes are smoothly converted to the alkyne. The
intermediate alkynylmetal reagent can also be used in situ for further reactions, for example with
ketones or carbon dioxide. In spite of the frequently successful preparation of acyclic alkynes
employing amide bases, the latter have not been used to a significant extent in cycloalkyne chemistry.
One exception is the generation of arynes where one of the most commonly used procedures is the
reaction of an aryl chloride or bromide with sodium amide or a lithium dialkylamide <B-83MI 121-01 >.
Alkali metal amides have been used very successfully for the preparation of alkynols from
1,2-haloethers. The reaction is illustrated by the preparation of 4-pentyn-l-ol from tetra-
hydrofurfuryl chloride and sodium amide (Equation (126)) <53OS(33)6S>. Related eliminations have
been very successfully employed for the preparation of optically active 3-hydroxyalkynes (Scheme
89) (89TL5455, 90SL591, 90T7033). All of these eliminations appear to proceed through an initial
deprotonation a to the chlorine atom followed by elimination of the ether oxygen, affording an
alkenyl chloride intermediate, the alkyne-forming reaction involving a dehydrohalogenation reac-
tion. If less than three equivalents of base are employed the alkenyl chloride intermediates can be
isolated.
(126)
Organolithium compounds are very effective reagents for the dehydrohalogenation of dichloro-
alkanes and certain haloalkenes. The course of these organolithium-induced elimination reactions
is governed by the relative rates of deprotonation and lithium halogen exchange reactions in the
haloalkene. With chloroalkenes, initial deprotonation geminal to the chlorine atom is followed by
a rapid dehydrochlorination reaction induced by a second equivalent of organolithium (Scheme 90)
(73TL1495,92TL2681). With bromo- and iodoalkenes lithium halogen exchange usually predominates
and alkynes are not formed with these substrates. In a similar manner 1,1-dichloro- and
1,1-dibromoalkenes also undergo a rapid lithium-halogen exchange reaction, activated by the
second halogen atom. However, with these substrates the intermediate lithiated alkenyl halides are
able to undergo a further 1,2-dehydrohalogenation reaction to afford an alkynyllithium species. Very
Scheme 89
successful formyl to ethynyl conversion reactions have been developed, based on the organolithium
induced dehydrohalogenation of 1,1-dichloroalkanes (Scheme 91) <79S502>, 1,1-dichloroalkenes
(Scheme 92) <74BSF(2)i73i, 75S458) and 1,1-dibromoalkenes (Scheme 93) <72TL3769>. The com-
bination of aldehyde alkenation employing dibromomethylenetriphenylphosphorane (prepared in
situ from carbon tetrabromide and triphenylphosphine) and organolithium-induced dehy-
drohalogenation of the intermediate 1,1-dibromoalkene has been used extensively, and represents
one of the most commonly employed methods for introducing the alkyne unit. The intermediate
alkynylmetal reagent can be used in situ for further reactions, for example alkylation and car-
boxylation (Scheme 94) (91TL4115, 92JA10654, 92JA10653, 92JOC5060). Dehydrofluorination of 1,1-
difiuoroethene using organolithium reagents also provides a route to mono- and disubstituted
alkynes <82TL4325>.
Scheme 90
Scheme 91
The preparation of alkynes by the 1,1-elimination of hydrogen halide from alkenyl halides is
commonly known as the Fritsch-Buttenberg-Wiechell rearrangement (Equation (127)). Alkynes
are formed successfully from monoaryl and diaryl substituted alkenyl halides. The low tendency of
alkyl groups to undergo migration usually leads to intermolecular carbenoid reactions with
2,2-dialkyl substituted alkenyl halides. Rearrangement is highly stereoselective, migration of the
trans aryl group occurring simultaneously with elimination of the halogen in a carbenoid inter-
mediate. Where the trans substituent is an alkyl group, a preferential cis migration of an aryl residue
1068 Alkynes
Scheme 92
Scheme 93
Scheme 94
occurs. The whole spectrum of bases, including hydroxide, alkoxide, amide and organolithium
bases, has been employed in the Fritsch-Buttenberg-Wiechell rearrangement. The reaction has been
extensively reviewed <B-69MI 121-02, B-78MI 121-03). In a variant of this rearrangement, alk-
enyliodonium tetrafluoroborates have been reported to undergo 1,1-elimination reactions with
migration of the /?-substituent under very mild conditions (Equation (128)) <88JA6565>.
(127)
(128)
By C^C Bond Formation 1069
The preparation of alkynes by 1,4- and 1,6-elimination of hydrogen halides is also known where
unsaturation is present between the eliminating atoms. For example, 1,3-butadiyne and 1,3-butenyne
have been prepared by dehydrohalogenation of 1,4-dichloro-2-butyne and 1,4-dichloro-2-butene
respectively <54JA17OO>. Similarly, 1,3,5-hexatriyne has been prepared by the 1,6-dehydro-
chlorination of 1,6-dichloro-2,4-hexadiyne <51CB785, 52JCS2010, 53CB657, B-88MI I2l-Ol>.
(ii) Dehalogenation
Dehalogenation of 1,2-dihaloalkenes and 1,1,2,2-tetrahaloalkanes has been effected with zinc or
organolithium reagents, and less commonly with magnesium or sodium. Other reagents such as
sodium sulfide <81S879> and lithium diphenylphosphide <83JCS(P1)1689> have also been used. Exam-
ples can be found in reviews by Ben-Efraim <B-78MI 121-03> and Kobrich and Buck (B-69MI121-02).
Considered in isolation, the reaction is of limited preparative value since the substrates for
dehalogenation are themselves generally prepared by halogenation of alkynes. Of considerably more
synthetic utility is the combination of dehalogenation with C-C bond formation. An example is
found in a two-step reaction sequence for the conversion of organolithium and magnesium com-
pounds into lithium and magnesium alkynides having two more carbon atoms (Scheme 95)
<76JOC1487>. In the first step, the organometallic reagent is treated with l,l-dichloro-2,2-difluoro-
ethene to afford an intermediate l,l-dichloro-2-fluoroalkene which, in a second step, is treated with
«-butyllithium to effect dehalogenation. Although alkyllithium and alkylmagnesium halide reagents
do not afford alkynes by this method, a wide variety of aryl, heteroaryl and alkynyl organometallic
reagents have been successfully employed. The reaction sequence has also been employed iteratively
to afford diynes, triynes and even tetraynes.
Scheme 95
Another example of C-C bond formation/dehalogenation is the preparation of cyclopropyl-

substituted alkynes by thermal ring-opening of tetrachlorocyclopropene in the presence of an alkene,
followed by dehalogenation of the intermediate trichloroalkene with an organolithium reagent
(Scheme 96) (86CB2995, 89CB377).
Scheme 96
1.21.3.1.4 Elimination of oxygen functions

The elimination of oxygen functions from enol derivatives represents an attractive route for the
preparation of alkynes (Equation (129)), especially in view of the ready availability of enol derivatives
from carbonyl compounds. Although, in 1995, the reaction appears more limited than the cor-
responding elimination of halogen derivatives, a number of successful methods has been developed
for the 1,2-elimination of alkenyl phosphate and sulfonate esters.
1070 Alkynes
R1 R2
\=( ^?^ Rl^^-R2 (129)
ox
Alkenyl phosphates undergo elimination reactions with sodium amide in liquid ammonia
<63JCS3712>, and with lithium dialkylamides <80JOC2526>, to afford alkynes. The reaction has been
applied most successfully to the conversion of methyl ketones into terminal alkynes (Scheme 97)
<80JOC2526, 85OS(65)44, 87TL5793>. Using lithium diisopropylamide (LDA) as the base, good results
are obtained where the group (R) of the methyl ketone (RCOCH3) is either bulky or does not
contain an a-methylene or methine proton. In other cases, LDA produces alkyne/allene mixtures,
and the more sterically hindered lithium 2,2,6,6-tetramethylpiperidide gives superior results.
Scheme 97
Alkenyl triflates have been converted to alkynes by treatment with pyridine <74JOC58l>,
NaH/DMSO <84JA462>, potassium 2,6-di-/-butyl phenoxide <81CC459> and LDA <85S962> (Scheme
98). Under certain circumstances, alkyne formation has also been observed with higher-order
cuprate reagents (Equation (130)) <88TL1197>. Detailed comparisons of the effectiveness of phosphate
and triflate groups have not been reported, but in a single example the triflate group afforded higher
yields of alkyne (Equation (131)) <93TL5257>.
Scheme 98
(130)
(131)
Other enol derivatives affording alkynes by elimination reactions include enol phosphonium
<89S217> and enol benzoxazolium salts <79CL48l>. The former only undergo successful elimination
reactions when the system is activated, (Equation (132)) <89S217>. Enol benzoxazolium salts afford
alkynes on treatment with a large excess of triethylamine at room temperature (Equation (133))
<79CL481>.
(132)
(133)
With the exception of benzyne, cycloalkynes have not generally been formed by the elimination
of enol derivatives. Aryl triflates undergo elimination with LDA to afford diisopropylanilines
through aryne intermediates <91JOC2045>. o-Haloaryl triflates afford aryne intermediates on treat-
ment with H-butyllithium <91TL6735>.
Alkenyl triflates possessing a ^-hydrogen or /?-aryl group can undergo 1,1-elimination with
rearrangement on treatment with a strong base such as potassium f-butoxide (Equation (134))
<74JA4562>. j3,/3-Dialkyl substituted alkenyl triflates afford carbene derived products under identical
conditions. Similar Fritsch-Buttenberg-Wiechell type rearrangements of alkenyl carbamates have
been reported (Equation (135)) <91SL611>.
(134)
(135)
1072 Alkynes
1.21.3.1.5 Elimination of sulfur, sellenium or tellurium functions
Although of little practical importance, alkenyl thioethers eliminate thiols on treatment with
strong bases. Examples include the preparation of 1,3-diynes and 1,3,5-triynes from the cor-
responding alkenyl thioethers in the presence of KNH 2 in liquid ammonia (Equation (136))
<71RTC265, B-88MI 121-01). Alkenyl thioethers also undergo elimination and in situ isomerisation
(Section 1.21.4.4) in the presence of potassium 3-aminopropylamide to afford 1-alkynes in high
yield <78JOC3083>. 1,4-Elimination of thiols is known, as illustrated by the preparation of 1,3-enynes
from allenyl thioethers of the type CH 3 CH=C=C(R)SR' and potassium amide (Equation (137))
<64RTC456>. Analogous elimination reactions of alkenyl/allenyl selenoethers and telluroethers have
not been reported.
(136)
(137)
Thiophene and its 2-alkyl derivatives undergo intramolecular thiol eliminations (ring-opening) in
the presence of BunLi and HMPA to afford enynethiolates (Scheme 99) <76RTC264>. The reaction
proceeds by abstraction of the C-3 proton in an intermediate 2-thienyllithium. In a similar manner
3-halothiophenes undergo ring-opening in the presence of organolithium reagents. The reaction has
been extensively investigated by Gronowitz and co-workers <84JOC2018>. Representative examples
are given in Scheme 100 <76ACS(B)34i, 83JHC729). 3-Haloselenophene and tellurophene derivatives
also afford alkynes, but through an alternative mechanistic pathway involving an initial attack of
the organolithium reagent at the chalcogen atom <79TL15O9>.
Scheme 99
Scheme 100
Alkenyl sulfonium salts afford alkynes on treatment with aqueous alkali <69ZC229>. Alkyl dithio-
acetals of 3-oxocarboxylic acids undergo elimination in the presence of excess dimethyl sulfate and
aqueous alkali to afford 2-alkynoic acids (Scheme 101) <65AG(E)l080>.
The elimination of alkenyl sulfoxides has scarcely been reported. In an isolated example the
tetrahydrofuran (41) undergoes successive elimination and isomerisation reactions in the presence
Scheme 101
of potassium 3-aminopropylamide to afford a terminal alkyne (Equation (138)) (90SC2733). The

reaction presumably proceeds via an intermediate alkenyl sulfoxide. Analogous alkenyl selenoxides
undergo elimination in the presence of bases such as l,4-diazabicyclo[2.2.2]octane (dabco), qui-
nuclidine and hexamethyldisilazane to afford alkynes <80JA5967>. The utility of this elimination is
enhanced when combined with the alkylation of deprotonated alkenyl selenides (Scheme 102).
Elimination is believed to proceed by a pericyclic syn mechanism, as evidenced by the predominant
formation of allenes from (Z)-selenoxides. An interesting elimination/[2,3]-sigmatropic rearrange-
ment of l,2-bis(phenylseleno)-l-alkenes is reported to occur in the presence of dabco affording
propargyl alcohols (Scheme 103) <91CL1805>.
(138)
Scheme 102
Scheme 103
/?-Acetoxy and alkoxy sulfones undergo a double elimination reaction to afford enynes or polyenes
depending on the substitution pattern of the substrate (Scheme 104) <84JA3670>. The initial elim-
ination step involves loss of the acetoxy or alkoxy group furnishing an alkenyl sulfone. Alkenyl
sulfones with no allylic y-hydrogen atoms undergo elimination in the presence of excess BulOK to
afford alkynes. Where an allylic y-hydrogen atom is present 1,3-dienes are formed through iso-
merisation to an allylic sulfone and 1,4-elimination <86JOC3830>. In practice, this limitation restricts
the Julia coupling-double elimination sequence, (illustrated in Scheme 105) <84JA3670>, to aldehydes
R 2 CHO where R2 = aryl, heteroaryl, /?-silyl substituted ethenyl or jS-silyl substituted ethynyl.
Of more general applicability is the reductive elimination of enol phosphates derived from /?-keto
sulfones (Scheme 106) <78JA4852, 78TL2625). The reaction has been successfully applied to mono-
and disubstituted alkynes bearing alkyl, functionalised alkyl, alkenyl and aryl substituents (Scheme
107) (78JA4852, 78TL2625, 79JCS(P1)2429>. Reductive elimination can be carried out using sodium in
liquid ammonia, or by using sodium amalgam in a mixture of THF and DMSO. The latter conditions
are milder and are more suitable where, for example, benzyl ether or ester functions are present.
1074 Alkynes
Scheme 104
Scheme 105
Aryl substituted alkynes can be prone to overreduction, as found during the attempted synthesis of
6'-arylethynyl-6'-dethia analogues of S-adenosylhomocysteine <90JOC3i47).
Scheme 106
Scheme 107
a,a-Dichlorodibenzyl sulfones undergo Ramberg-Backlund rearrangement in the presence of

dabco to afford diaryl substituted alkynes (Scheme 108) <71CC22>. The reaction proceeds through
the intermediacy of thiiren-1,1 -dioxides which can be isolated if desired. a,a-Dichlorodibenzyl
sulfides similarly undergo rearrangement to afford diaryl substituted alkyncs in the presence of
triphenylphosphine and KOBu' (Equation (139)) <73CC955>. The mechanism is likely to be quite
different from that of the Ramberg-Backlund rearrangement.
(139)
Scheme 108
1.21.3.1.6 Elimination of nitrogen functions

Alkynes have been formed by the Hofmann elimination of tertiary amines from quaternised
enamines, although yields are generally low and the method is of very limited usefulness <75TL1513>.
Higher yields of alkynes have been obtained by the pyrolysis of bis quaternary ammonium salts,
but again the method is of little value. Of far greater utility is the preparation of alkynes by
elimination of molecular nitrogen from functional groups possessing two directly bonded nitrogen
atoms. Such functional groups include hydrazones, 1,2-dihydrazones and a variety of nitrogen-
containing heterocycles such as 1-amino- and l-sulfonylamino-l,2,3-triazoles, 5-pyrazolones,
3-nitroso-2-oxazolidones, 2-nitroso-5-isoxazolones, 1,2,3-selenodiazoles and 1,2,3-thiadiazoles.
Additionally, alkynes have been prepared through the elimination of molecular nitrogen from
/>-toluenesulfonylhydrazones, tetrazoles and diazo compounds possessing an adjacent leaving group,
and by the base-induced condensation of carbonyl compounds with trimethylsilyldiazomethane or
dimethyl (diazomethyl)phosphonate.
Hydrazones of benzyl ketones react with mercury(II) trifluoroacetate to afford alkynes in mod-
erate yield <66JOC624>. More generally, 1,2-dihydrazones undergo reaction with a variety of oxidants,
including mercury(II) oxide <63OSC377>, silver trifluoroacetate <58JOC665>, lead(IV) acetate
<68TL45ll> and iodine/Ar-?-butyl-Ar/,Ar',A^",7V"-tetramethylguanidine <88T147>, to afford alkynes. A
very effective system employing catalytic copper(I) chloride, pyridine and oxygen has also been
reported and appears to be superior to the other oxidants (Equation (140)) <83T3279>.
(140)
l-Amino-l,2,3-triazoles, which are sometimes observed as by-products in the mercury(II) oxide

oxidation of 1,2-dihydrazones, can be oxidized with lead(IV) acetate to give alkynes. Cyclooctyne
has been prepared <68LA46> and cycloheptyne and cyclohexyne <68LA65> have been generated
by this method. The salts of l-tosylamino-l,2,3-triazoles undergo photolytic decomposition with
evolution of two mole equivalents of nitrogen and the formation of a metal toluenesulfinate and
the corresponding alkyne (Scheme 109) <64AG(E)138, 71S215>. The starting materials are readily
available from 1,2-bistosylhydrazones and need not be isolated if the latter are photolysed in
aqueous methanolic NaOH <71S215>.
Scheme 109
1076 Alkynes
4,4-Dihalo-5-pyrazolones (42), readily available from /?-ketoesters, afford conjugated alkynoic
acids on treatment with aqueous alkali (Scheme 110) <66JOC2867>. A modification of this reaction
using 3,4-disubstituted-4-monohalo-5-pyrazolones (43) in the presence aqueous alkali and pot-
assium ferricyanide allows the preparation of disubstituted alkynes <76JOC3650>. 3-Alkyl- and
3-aryl-5-pyrazolones (44) afford 2-alkynoic esters on treatment with thallium(III) nitrate
<72AG(E)48>, lead(IV) acetate <82S1100> or (diacetoxyiodo)benzene <87CC7U>.
Scheme 110
5,5-Diaryl, 5,5-alkylaryl- and 5-aryl-3-nitroso-2-oxazolidones afford aryl substituted alkyncs

quantitatively on treatment with n-butylamine (Equation (141)) <72JOC4466, 72JOC4468>. When an
aryl group is not present in the 5-position little alkyne is produced. Hydroxide and alkoxide bases
have also been used but afford lower yields of alkyne <5i JA4199,72JOC4467). 2-Nitroso-5-isoxazolones,
generated in situ from readily available 5-isoxazolones, undergo elimination of nitrous oxide and
carbon dioxide to afford alkynes (Equation (142)) <9iTL532l>. The procedure is applicable to the
preparation of both alkyl and aryl substituted alkynes. 5-Isoxazolones have also been used as
precursors to a variety of aryl substituted terminal alkynes through flash vacuum pyrolysis of their
condensation products with aryl aldehydes (Scheme 111) <78AG(E)609>. A'-Nitroso derivatives of
5-aminoisoxazoles undergo decomposition with loss of nitrogen, carbon dioxide and water to afford
alkynes in moderate to good yield (Equation (143)) <85JOC2372>.
(141)
(142)
Scheme 111
(143)
1,2,3-Selenodiazoles, readily available from oxidation of the semicarbazones of aliphatic and

aromatic aldehydes and ketones with selenium dioxide, are cleaved by the action of strong bases
<72S235> or by thermolysis <7UOC2836>, to afford alkynes, usually in high yield (Scheme 112)
<70AG(E)464>. The reaction is generally applicable and has been used for the preparation of alkyl,
aryl and heteroaryl mono- and disubstituted alkynes <70AG(E)464, 75JHC8O1, 77JHC567), non-
conjugated diynes <73JHC655>, alkynoic acids and esters <73JHC655> and for the preparation of
strained cycloalkynes and cycloalkenynes <86Ti7ll, 88LA221). Although less frequently used,
4,5-disubstituted 1,2,3-thiadiazoles also afford disubstituted alkynes on treatment with organo-
lithium reagents (71OPP163,78S536>, and by photolysis (Scheme 113) <78S736,79CB3728>. In the absence
of a 5-substituent lithium alkynylthiolates are obtained <68CJC1O57>.
Scheme 112
Scheme 113
Diazo compounds possessing an adjacent leaving group, such as a hydroxyl, thioether, sulfone,
sulfonate, carboxylate, halogen or epoxy group, have been used for the preparation of alkynes
(Scheme 114). The opening of epoxides represents a special case of the reaction in that it involves a
subsequent fragmentation and as such is reviewed in Section 1.21.4.2. Most commonly, the diazo
compound is generated in situ from an arylsulfonylhydrazone, although aminoaziridine hydrazones
and N-acetylnitrosamides (88CC83O, 90JA3717) have also been employed. As illustration, treatment
of the tosylhydrazones of benzoin and its acetate and benzoate with alkoxides in protic or aprotic
solvents affords diphenylalkyne in 13%, 94% and 98% yields respectively <69TL4447>. Similarly, the
tosylhydrazones of 20-oxo-21-fluoro- and 21-methanesulfonyloxypregnenes have been converted to
pregnenynes <70HCAi7l>. Tosylhydrazones of a-thiomethylketones have been converted into alkyl
and aryl monosubstituted and disubstituted alkynes in high yield by treatment with methyl lithium
<78JOC4366, 78S305). In a synthesis of tetraethynylmethane (45), incorporation of the final
ethyne unit was achieved employing a phenylsulfone leaving group in combination with a
(2,4,6-triisopropylphenyl)sulfonylhydrazone and the hindered base lithium tetramethylpiperidide
Equation (144)) <93JA3846>. Tosylhydrazones of a-furyl ketones and aldehydes undergo thermolysis
as their sodium salts to afford (£)- and (Z)-2-alken-4-ynals and ynones (46) through cleavage of the
furan ring (Equation (145)) <78JA7927>. In an analogous reaction a-thienyl and a-oxazolyl ketones
1078 Alkynes
and aldehydes afford the corresponding thiocarbonyl compounds (47) and JV-acyl-3-alkyn-2-one
imines (48) respectively <79TL296l>.
Scheme 114
(144)
(145)
2-Alkynones and alkynoates are conveniently prepared by the base-catalysed condensation of

diazoketones and esters with aldehydes. The intermediate a-diazo-/?-hydroxycarbonyl compounds
undergo elimination on treatment with boron trifluoride etherate (Scheme 115) (72JA8084,72SC331).
Scheme 115
Substituted tetrazoles (49; X = Cl, N3, OH, NH 2 ) liberate nitrogen on heating at 110-200 °C to
furnish alkynes in moderate to good yield (Scheme 116) <66TL1663>.
Scheme 116
1-Alkynes have been prepared by the base-promoted reaction of dimethyl (diazomethyl)

phosphonate and trimethylsilyldiazomethane with aldehydes and aryl ketones (Equation (146))
(73CC151, 77JCS(Pi)869>. By operating at low temperatures enolisable aldehydes, aryl ketones and
enals can be transformed successfully <82JOC1837>. Dialkyl ketones do not form alkynes but instead
give cyclopentenes <92CC72l>. The reaction has been applied to the preparation of chiral propargyl
amines from aminoaldehydes <92TL3715> and to the preparation of the immunosuppressive agent
FK506 <89JOC4267, 92JOC5071). The reaction mechanism is believed to involve the loss of nitrogen
from diazoalkene intermediates.
(146)
1.21.3.1.7 Elimination of phosphorus, arsenic, antimony or bismuth functions

Although alkynes are frequently prepared by Wittig-type reactions of phosphorus ylides with
aldehydes and ketones, these invariably precede a further heteroatom elimination, and as such are
treated under the appropriate heteroatom. Elimination reactions involving the loss of a phosphorus
function in the alkyne forming step are more limited in number.
One commonly employed method of alkyne synthesis involves the coupling of phosphorus ylides
with carboxylic acid chlorides followed by thermal extrusion of triphenylphosphine oxide from the
intermediate oxoalkylidenetriphenylphosphorane (50) (Scheme 117). Using conventional pyrolysis
techniques the elimination step is only successful when R1 is an electron-withdrawing group (e.g.,
Ar <59JCS3874, 62JCS2333, 64JCS543, 82TL343>, C O R <65JOC1015>, C O , R (61CB3OO5, 62JCS2333, 64JCS543,
77LA282) and C N (62JCS2333, 64JCS543, 81TL5283). Purely aliphatic alkynes and terminal alkynes are
obtained from the corresponding ylides (R1 = alkyl or H) under flash vacuum pyrolysis (FVP)
conditions (Scheme 118) <85CCll40>. Terminal alkynes can also be prepared by acylation of
ethoxycarbonylmethylenetriphenylphosphorane with acid chlorides followed by FVP at 750°C
<90SL2ll>. Loss of Ph3PO is followed by loss of the ethoxycarbonyl group to afford the 1-alkyne
(Scheme 118). At lower temperatures ethyl 2-alkynoates (51) are obtained. The reaction has been
applied iteratively to the preparation of diynes and triynes <90SL2ll, 90SL212). Where ester (or
thioloester) and keto (or 1,2-diketo) carbonyl groups are both present, oxygen is eliminated exclus-
ively from the latter, giving alkynyl esters <93TL562l>. Room temperature eliminations have been
reported in the presence of organotin halides <74JOM(77)C22>.
Scheme 117
Scheme 118
Dephosphorylation of 2-fluoroalkenylphosphonates in the presence of fluoride ion can afford

1-alkynes, although the reaction has only been applied to perfluoroalkyl substituted alkynes and is
of limited use <84TL1377>.
1080 Alkynes
1.21.3.1.8 Elimination of boron, silicon or germanium functions
Few elimination reactions of this type have been described for the preparation of alkynes. Those
methods which have been reported invariably involve nucleophilic attack at the heteroatom with
expulsion of a /J-leaving group. Alkenylboranes possessing a /Mialogen atom or sulfinate group
undergo alkyne forming elimination reactions, but these eliminations invariably form part of a
sequence of reactions in which the overall transformation can be categorised as one of substitution,
at least for the purpose of this review (Section 1.21.3.1.5). Alkenylsilanes possessing a jS-halogen
atom also undergo elimination reactions in the presence of nucleophiles, most commonly fluoride
ion. The reaction represents an important method for the preparation of arynes and other strained
cycloalkynes, such as 1,3-cyclohexenyne (Scheme 119) <90JA8578>, but has been little used for
the preparation of simple alkynes. j8-Silylalkenyl sulfinates undergo sjw-stereospecinc elimination
reactions to form alkynes (Scheme 120) <82JCS(Pl)1563>. The reactions are analogous to the boron
sulfinate elimination reaction (Section 1.21.3.1.5).
Scheme 119
Scheme 120
Dehydrosilylation of alkenylsilanes has been achieved by employing boron trifluoride activated

iodosylbenzene <85CC697>. The reaction proceeds by halodesilylation followed by elimination of an
intermediate alkenyl(phenyl)iodonium salt (Scheme 121). Both (£)- and (Z)-alkenylsilanes afford
alkynes by this method, although an additional base is required in the former case.
Scheme 121
1.21.3.1.9 Elimination of metal functions

While many of the elimination reactions described in Section 1.21.4 proceed through organo-
metallic intermediates, without exception these alkyne syntheses involve the coelimination of a
By C^=C Bond Formation 1081
heteroatom function (Equation (147)). Dchydrometallation reactions (Equation (148)), which rep-
resent an important source of instability for metal alkyls, are less well described for alkenyl metals.
Aside from the possible involvement of dehydropalladation processes in the catalytic coupling of
unsaturated organic halidcs with terminal alkynes (Section 1.21.3.l.l(ii)), the only dehydro-
metallation reaction of practical importance for the preparation of alkynes is the lead(IV) acetate
induced elimination of trialkyltin hydrides from alkenylstannanes (Scheme 122). The reaction has
been used to prepare terminal alkynes and to introduce the ethynyl group into the ^-position of
a,/?-unsaturated ketones <74JA558l,82TL4607>.
(147)
(148)
Scheme 122
1.21.3.2 Formation by Fragmentation Reactions

Fragmentation reactions, according to the definition of Grob and Schiess <67AG(E)i>, arc pro-
cesses in which the reacting molecule breaks into three fragments according to Equation (149). The
electrofugal group Y-B forms a stable cation or neutral molecule, the central group becomes an
unsaturated fragment and the nucleofugal group X departs with an electron pair. Alkynes are most
commonly formed in fragmentation reactions with substrates of the form Y-C-C=C-X, where X is
the nucleofuge (e.g., halogen, OSO2Ar, SeO2Ar, N 2 + ) and Y is a heteroatom able to stabilise the
positive charge on carbon. Most commonly, the electrofugal fragment is a carbonyl compound or
carbon dioxide.
(T^-B-rc'D'^r —" Y=B + C=D + x (i49)
Many examples of decarboxylative and decarbonylativc fragmentations have been reported where
3-halo-2-alkcnoic acids, esters and aldehydes are treated with aqueous base (Scheme 123) <B-69MI
121-02). Decarbonylative fragmentation requires the addition of a nucleophile, invariably hydroxide,
to the carbonyl carbon atom prior to fragmentation. Decarboxylative fragmentation has also been
successfully applied to the preparation of alkynes from enol sulfonates <69AG(E)429, 7UCS(C)2O13>.
As expected, fragmentation occurs more readily when the nucleofuge and elcctrofuge have a trans
orientation. Arynes have also been prepared by decarboxylative fragmentation of 2-haloar-
ylcarboxylic acids, 2-carboxyaryl tosylates and aryldiazonium-2-carboxylic acids <B-83MI 121-01,
90JOC3808,91COS(4)483> and by decarbonylative fragmentations <B-67MI 121-01).
Scheme 123
1082 Alkynes
Tosylhydrazones of a,/?-epoxy ketones undergo fragmentation to afford an alkyne, a ketone (or
aldehyde), nitrogen and toluenesulfinate ion (Eschenmoser fragmentation) (Scheme 124) (67HCA2101,
67TL3739,67TL3943,71HCA2896). The reaction is of most value with epoxyketones derived from cyclic
enones, where the product alkyne and carbonyl functions are connected. In general, the reaction
involves treating the cyclic enone with />-toluenesulfonylhydrazine in dichloromethane-acetic acid
1:1 to form an intermediate tosyl hydrazone which decomposes to give the alkynal or alkynone. A
number of representative examples are illustrated in Scheme 125 (71HCA2896, 90TL6205,
92JOC50). 2,4-Dinitrobenzenesulfonylhydrazones <75JOC579> and mesityl- and triisopropyl-
sulfonylhydrazones <81S276> have also been found to be advantageous in difficult cases, especially
in instances where the product is an alkynal. Other preparative variations include the use of oximes
<67HCA21O8>, 1,3,4-oxadiazolin derivatives <78CJC308> and 2-phenylaminoaziridine and trans-2,3-
diphenylaminoaziridine hydrazones <72HCA1276, 76OS(55)114>. The aminoaziridine hydrazones of
a,/?-epoxy ketones decompose thermally and afford alkynones in higher yield than the corresponding
tosylhydrazones. In addition, only inert and volatile by-products are formed and the reaction takes
place in a neutral medium.
Scheme 124
Scheme 125
The formation of epoxy ketones from sterically crowded enones is often difficult, but this step
can be avoided by fragmentation of a,/?-unsaturated tosylhydrazones using NBS in alcohol solvents.
The reaction has been applied to the preparation of the natural products muscone and exaltone
(Scheme 126) <79HCA2655>.
A variant of the Eschenmoser fragmentation employing the cleavage of a cyclopropyl substituted
tosylhydrazone has been reported to afford moderate yields of cyclic alkenynes, sometimes con-
taminated with the isomeric allene (Scheme 127) <71HCA1789>. The reaction can be undesirable, as
in the formation of alkyne (52) during a synthesis of sesquicarene <70T3487>.
The nucleofuge in the Eschenmoser fragmentation is N 2 (and toluenesulfinate ion). Analogous
fragmentations employing an allylic alkoxide with halide <77JOC2380>, tosylate (84JA2735,86JOC3214)
By CSEEC Bond Formation 1083
Scheme 126
Scheme 127
or selenone <84JOC1230> leaving groups have been reported (Scheme 128) <77JOC2380, 84JA2735,
84joci230>. The allylie alkoxide intermediate has been generated by base treatment of the alcohol
or by organometallic addition to the corresponding ketone.
Scheme 128
1.21.3.3 Formation by Pericyclic Reactions

Alkynes have occasionally been prepared by pericyclic reactions, generally retrodiene cleavage
reactions. Aside from the trivial case where an alkyne is regenerated from ils cycloaddition adduct,
reversal of the Diels-Alder reaction can lead to products where the diene and dienophile have
exchanged substituents (Scheme 129). An example is the formation of dicyanoethyne and dimethyl-
1084 Alkynes
furandicarboxylate from the reaction of dimethylethynedicarboxylate with 3,4-dicyanofuran at 175-
180°C <62JOC3520>.
Scheme 129
The ketene-anthracene cycloaddition adduct serves as a good precursor in a synthesis of mono-

and disubstituted alkynes (Scheme 130) <81CL1241>. The key step, a retro Diels-Alder reaction, is
achieved by flash vacuum pyrolysis at 500-550°C. A retrodiene cleavage of (53) has also been used
to generate cyclohexyne <63CB342).
Scheme 130
1.21.3.4 Formation by lsomerisation Reactions

Alkynes are able to undergo isomerisation reactions in the presence of strong bases as long as
there is at least one hydrogen atom attached to a carbon atom adjacent to the triple bond. The
equilibrium in linear alkynes has been shown to heavily favour the internal isomers and 1-alkynes
can often be cleanly isomerised to the thermodynamically more stable 2-alkynes using, for example,
NaH or KOBu' in DMSO (Scheme 131) <7OT2127,87CL1905, B-88MI121-01 >. Isomerisation to 3-alkynes
can be achieved employing stronger bases although the comparable energies of 2- and 3-alkynes
leads to product mixtures.
Scheme 131
Contrathermodynamic isomerisations of internal to terminal alkynes are dependent on dis-

placement of the equilibrium by precipitation of the metal alkynide ion. The isomerisation of
2-alkynes to 1-alkynes has been achieved with strong bases such as NaNH, in aromatic hydrocarbons
at high temperature, and with KNH2/NH3/HMPA at room temperature, but isomerisations over
two or more carbon atoms are less successful. Highly effective multipositional isomerisations of
alkynes are possible employing potassium 3-aminopropylamide (KAPA) in excess amine solvent
(the 'Acetylene Zipper Reaction') (Equation (150)) <75JA89l>. Addition of internal alkynes to this
base system at room temperature generally results in almost instantaneous precipitation of the
potassium alkynide in very high yields. Alkynols <76CC959>, alkynyl boranes <77CC318> and some
alkynyl ethers <88S707> also undergo successful isomerisation reactions. The isomerisation of
optically-active secondary propargyl alcohols to terminal alkynols proceeds without loss of con-
figuration at the hydroxyl centre <8lTL4l7l>. A slight variation of the procedure employing pot-
assium r-butoxide and the lithium salt of either 1,2-diaminoethane or 1,3-diaminopropane has been
reported <84CJC1333>.
Y H i. KAPA, APA v
\ — ( /" - \ — (150)
X=H m = 2-6, n = 2-6 74-100%

X = OH m= 1-6, n = 2-8 83-98%
X = BR2 m = 3, n = 3 >95%
KAPA = potassium 3-aminopropylamine

APA = 3-aminopropylamine
Alkenyl sulfides undergo elimination and concomitant multipositional isomerisation to 1-alkynes

in the presence of KAPA (Equation (151)) <78JOC3083>. In a related reaction thiophenyl a-substituted
tetrahydrofurans afford <M-alkyn-l-ols on treatment with KAPA in 3-aminopropylamine <90SC2733>.
(151)
1.22
Ions, Radicals, Carbenes and
Other Monocoordinated Systems
JULIA M. DICKINSON
Manchester Metropolitan University, UK
0[11[0 DICOORDINATE CARBANIONS "i[e[\ VINYLIC CARBANIONS# 0977
0[11[0[0 General Aspects of Carbanion Formation 0977
0[11[0[1 Formation of Vinylic Carbanions by Proton Loss 0978
0[11[0[2 Formation of Vinylic Carbanions by C0C and C0X Bond Scission 0989
0[11[0[2[0 Alkenyllithium reaènts 0989
0[11[0[2[1 Alkenylma`nesium reaènts 0981
0[11[0[2[2 Alkenylcopper reaènts 0982
0[11[0[2[3 Alkenylmercury reaènts 0984
0[11[0[2[4 Alkenylpalladium reaènts 0985
0[11[0[2[5 Alkenylzinc reaènts 0986
0[11[0[2[6 Alkenylcerium reaènts 0987
0[11[0[2[7 Alkenylchromium reaènts 0988
0[11[0[2[8 Alkenylboron reaènts 0099
0[11[0[3 Formation of Vinylic Carbanions by Addition to Acetylenes and Allenes 0099
0[11[0[3[0 Alkenylboron reaènts 0099
0[11[0[3[1 Alkenylzirconium reaènts 0093
0[11[0[3[2 Alkenylma`nesium reaènts 0094
0[11[0[3[3 Alkenylaluminum reaènts 0095
0[11[0[3[4 Alkenylsilicon reaènts 0095
0[11[0[3[5 Alkenylpalladium reaènts 0096
0[11[0[3[6 Alkenylcopper reaènts 0096
0[11[0[3[7 Alkenylmercury reaènts 0097
0[11[0[3[8 Alkenyllithium reaènts 0097
0[11[1 DICOORDINATE CARBOCATIONS "i[e[\ VINYLIC CATIONS# 0098

0[11[1[0 General Aspects of Carbocation Formation 0098
0[11[1[0[0 Structures of vinyl cations 0098
0[11[1[0[1 Relative stabilities of vinylic and triònal cations 0098
0[11[1[0[2 Routes competin` with vinyl cation formation 0009
0[11[1[1 Formation of Vinylic Cations by Bond Scission 0000
0[11[1[1[0 Vinyl cation formation via solvolysis 0000
0[11[1[1[1 Vinyl cation formation via deamination of diazonium salts 0007
0[11[1[1[2 Vinyl cation formation via fra`mentation 0008
0[11[1[1[3 Vinyl cation formation via photolysis 0019
0[11[1[1[4 Vinyl cation formation via oxidative decarboxylation 0010
0[11[1[1[5 Vinyl cation formation via electrooxidation 0010
0[11[1[1[6 Vinyl cation formation via mass spectrometry 0011
0[11[1[2 Formation of Vinylic Cations by Addition to Alkynes and Allenes 0011
0[11[1[2[0 By addition to alkynes 0011
0[11[1[2[1 By addition to allenes 0014
0[11[2 DICOORDINATE RADICALS "i[e[\ VINYLIC RADICALS# 0015

0[11[2[0 General Aspects of Radical Formation 0015
0[11[2[1 Formation of Vinylic Radicals by Bond Scission 0018
0[11[2[2 Formation of Vinylic Radicals by Addition to Alkynes and Allenes 0029
0976
0977 Ions\ Radicals and Carbenes
0[11[3 MONOCOORDINATED ALKYNIC IONS AND RADICALS 0022
0[11[3[0 Alkynic Carbanions 0022
0[11[3[0[0 Lithium acetylides 0022
0[11[3[0[1 Ma`nesium acetylides 0023
0[11[3[0[2 Tin acetylides 0024
0[11[3[0[3 Copper acetylides 0024
0[11[3[0[4 Silver acetylides 0026
0[11[3[0[5 Palladium acetylides 0026
0[11[3[0[6 Silicon acetylides 0027
0[11[3[0[7 Aluminum acetylides 0028
0[11[3[0[8 Zinc acetylides 0028
0[11[3[0[09 Cerium acetylides 0039
0[11[3[0[00 Chromium acetylides 0039
0[11[3[0[01 Nickel acetylides 0030
0[11[3[1 Alkynic Carbocations 0030
0[11[3[2 Alkynic Radicals 0031
0[11[4 VINYLIDENE CARBENES 0032
0[11[0 DICOORDINATE CARBANIONS "i[e[\ VINYLIC CARBANIONS#
0[11[0[0 General Aspects of Carbanion Formation

A number of reviews and monographs that discuss carbanion chemistry in general\ also discuss
various aspects of vinylic carbanions\ such as their formation\ stability\ stereochemistry and reac!
tivity ðB!54MI 011!90Ł[ The following subsections will deal principally with methods of vinyl anion
formation and reactivity[
The method of formation of vinylic "alkenyl# carbanions\ and their subsequent reactivity is
dependent largely on the nature of the countercation[ A number of metals have been found to act
as the cationic component in these species\ with alkenyllithium and alkenyl Grignard reagents being
the most widely studied^ other metals that have been employed include copper\ aluminum\ boron
and tin[ The nature of the metal counterion\ as is to be expected\ markedly alters the stability and
reactivity of the alkenyl carbanion\ but only those organometallic reagents that have found sub!
sequent use in synthesis will be discussed[ In addition\ vinylic carbanions are often implicated as
intermediates in elimination reactions during the conversion of alkenes to alkynes[ A number of
monographs exist which deal with this aspect of vinyl carbanion chemistry^ such reactions will only
be discussed brie~y[
No matter what the method chosen for the generation of the vinylic carbanion\ or the nature of
the countercation in reactions employing such anions\ a number of features are general to these
processes[ The most important of these features from a synthetic chemist|s point of view is the
nonlinearity of the vinylic carbanion and its overall retention of con_guration[ Carbonation reac!
tions have been used to demonstrate this latter property[ For example\ the reaction of "Z#!1!
bromobut!1!ene "0# with lithium to give the corresponding alkenyl carbanion "1#\ followed by
treatment with carbon dioxide gave "Z#!1!methylbut!1!enoic acid "2# as the major isomer in a yield
of ½64)\ with the geometrical isomer being formed in ³4) yield "Scheme 0#[ The nonlinearity of
vinyl anions has also been demonstrated\ for example\ cyclopropene is able to exchange its vinylic
protons readily ð60RTC0009Ł[ A few vinyl carbanions have been characterised by x!ray di}raction
analysis ð74CB0493\ 77JA5922Ł[
In general there are three main methods by which vinylic carbanions may be formed\ and these
will be discussed in more detail in the following sections[
Br CO2– Li+
Li – CO2
Li+
(1) (2) (3)
Scheme 1
Vinylic Carbanions 0978
0[11[0[1 Formation of Vinylic Carbanions by Proton Loss
The increase in s character of the sp1 carbon atom of an alkene\ as compared to an alkyl sp2
carbon\ leads to an increase in acidity of the attached proton[ This proton can thus be removed by
suitable bases to give the corresponding alkenyl carbanion[ The presence of heteroatom!containing
substituents on the double bond can lead to increased stabilisation of the vinylic carbanion\ with
some substituents stabilising a negative charge in the a position\ whilst others stabilise a b carbanion[
For example\ methylvinyl ether reacts with t!butyllithium to give the a!lithio species ð63JA6014\
64JA2711Ł^ higher homologues are also available if the methoxymethyl "MOM# analogue is employed
and n!butyllithium in TMEDA is the lithiating species ð76JOC3706Ł[ Cyclic analogues such as
5!lithio!1\2!dihydropyran can be obtained using the same methodology ð66TL3076\ 73H"11#0378Ł[ Sulfur
and selenium containing substituents are often used to stabilise carbanionic centres but\ whereas
sulfur is more stabilising than selenium for sp2 hybridized carbanionic centres\ the reverse is true
for sp1 hybridized anions\ i[e[\ the seleno moiety is more stabilising than the thio moiety ð79JOC4116Ł^
this is attributed to the greater polarisability of the selenium atom[ The stabilising e}ect of the
heteroatom is modi_ed further by the other groups attached ð72TL3714Ł^ a!lithiovinylsulfones have
also been prepared by direct deprotonation of the corresponding alkenes ð76TL3016\ 76TL5698Ł[
Vinyl selenide has been prepared\ and alkylated in good yield with n!octyl bromide ð67AG"E#415\
71AG"E#309Ł[ Vicinal! and geminal!dihalides can undergo elimination to give vinyl halides which\ in
the presence of a second equivalent of base\ either undergo loss of a vinylic proton to give the
corresponding anion "quenching with an electrophile then gives a substituted alkene# or eliminate a
second halide ion to give an alkyne[ An example of the former can be seen in the reaction of the
carbamate "3# with two equivalents of lithium tetramethylpiperidine "LITMP# ð72JA5044Ł\ followed
by reaction of the intermediate a!lithiodi~uorovinyl carbamate "4# with a series of electrophiles
"Scheme 1# ð82TL304Ł[ An example of alkyne formation via the above mentioned elimination
sequence is seen in the synthesis of an analogue of 2?!azido!2?!deoxythymide "AZT# "5# "Scheme 2#
ð89TL486Ł[ Elimination of HX from vinyl halides via an E1 mechanism is well!documented[
F OCONEt2 F OCONEt2 F OCONEt2

LDA or LITMP E+
F
F F Li F E
(4) (5)
E+ E Yield (%)
TMS-Cl TMS 80
PhSeBr SePh 58
MeOTf Me 71

LITMP = lithium tetramethylpiperidine
Scheme 2
H H
O N O O N O
Br2 Na/DMSO
O N CCl4
O N
TBS-O TBS-O or KOH/H2O
59% 49%
Br Br
H H
O N O O N O
Bu4NF
O N O N
TBS-O THF HO
85%
(6)
Scheme 3
When secondary allylic amines are treated with t!butyllithium\ lithiation occurs at the vinylic
position to give a g!aminated organolithium compound "6#[ With tertiary amines\ however\ lithiation
occurs at the allylic position\ for example\ "7# ð77CC0024\ 77TL3748\ 78JCR"S#199\ 89CC476\ 89CC0410\
80CC0990\ 81TL720Ł[ To overcome this problem\ the ability of a sulfone group to direct metallations
and stabilise the resulting sp1 hybridised organolithium compound has been utilised[ This allowed
the reaction of "E#!N!"2!tosyl!1!propenyl#morpholine "8# with s!butyllithium at −67>C to take
place\ giving the g!functionalised organolithium compound "09# "Scheme 3# ð82TL1992Ł[ Deuterolysis
of "09# with deuterium oxide showed the decreasing stability of the anion with increasing tempera!
ture\ such that at −67>C\ 79) of deuteriated product "00^ ED# was obtained^ at −19>C the
yield had decreased to 69)\ with only decomposition products being obtained at 9>C[ Other
electrophiles were also reacted with "00# to give\ on samarium iodide reduction of the tosyl group\
g!substituted allylic amines[ The regio! and stereoselective lithiation of vinyl sulfones has been
reported on a number of occasions ð68JOC2166\ 68JOC2168\ 76TL878\ 76TL3012\ 76TL3016\ 76TL5698\
78JCS"P0#0276\ 78JOC0646Ł[
NR2 ≡ O
–
Li N R –
Li+
Li
(7) (8)
Ts
O BusLi, –78 °C E+, then H2O O
Ts N Li N Ts N
O
E
(9) (10) (11)
Scheme 4
0[11[0[2 Formation of Vinylic Carbanions by C0C and C0X Bond Scission

Vinylic halides are the common precursors to a number of alkenylmetallic reagents[ However\
vinylic halides are often less reactive than the corresponding alkyl halides because of the overlap
between the _lled p orbital of a halogen atom\ and the p orbital of the double bond\ leading to
resonance stabilisation[ Although the vinyl halides are less reactive than expected\ they will undergo
either metalÐhalogen exchange to give the corresponding alkenylmetallic reagents\ or a metal may
insert into the vinylic carbonÐhalogen bond to give an alkenylmetal halide[ As in the case of
carbanion formation through proton loss "Section 0[11[0[1#\ heteroatom!containing substituents
have been found to stabilise the carbanion formed[ Other alkenylmetal reagents can be prepared
through metalÐmetal exchange\ in which a preformed alkenylmetal derivative "usually the alkenyl!
lithium or alkenyl Grignard reagent# reacts with another metal containing reagent "with or
without additional organic substituents#\ usually a halide\ to give the new alkenylmetal and the
corresponding lithium or magnesium halide[ These new alkenylmetallic reagents often exhibit
modi_ed reactivity as compared to the lithium or magnesium precursors\ namely enhanced chemo!
or regioselectivity[
0[11[0[2[0 Alkenyllithium reagents

Vinyllithium compounds may be prepared stereospeci_cally using dispersed lithium ð64S323\
65OS"44#092Ł[ Certain vinyllithium reagents that are unstable towards elimination or rearrangement
at ordinary temperatures can be prepared at low temperatures\ with terminal vinyllithium reagents
being prepared stereospeci_cally from the corresponding 0!iodo!0!alkenes ð65S134\ 65S650\ 66JOC159Ł[
HalogenÐmetal exchange of vinyl halides is also achieved e.ciently using t!butyllithium as the
source of lithium ð65TL3728\ 67CB1674Ł[ The lithiated derivatives are generated using two equivalents
of t!butyllithium at −019>C in a THFÐpentane solvent mixture\ followed by quenching of the
anion at −67>C with a suitable nucleophile[ Such a method has been used\ for example\ to generate
alkenylsilanols which were then employed e.ciently in a Sharpless epoxidation process which did
not require an allylic alcohol for a display of stereoselectivity "Scheme 4# ð77CC0179Ł[ Alkenyllithium
reagents generated from alkenyl halides and butyllithium will undergo intramolecular cyclisations
to give 2!\ 3!\ 4! and 5!membered rings ð67TL4082\ 75CL348Ł "e[g[\ Equation "0##[ Arylsulfonyl
hydrazones have also been employed as precursors to vinyl anions^ treatment of hydrazone "01#\
with s!butyllithium gave the corresponding alkenyllithium reagent "02# which could be treated with
various electrophiles "Scheme 5# ð67JOC036Ł[
Ph i Ph
Li Si Cl
Me Me
ii
iv
Ph Ph
SiMe2H Si N
v Me Me
iii
Ph vi O vii O
SiMe2OH Ph Ph
SiMe2OH
i, Me2Si(Cl)CH2Cl, Et2O, –25 °C; ii, Me2SiHCl, Et2O, –20 °C; iii, AgNO3, Ag2O (1:6), THF, RT; iv, pyrrolidine, 80 °C;
v, ButO2H, VO(acac)2, acetone; vi, Ti(OPri)4, (+)-DET, ButO2H, CH2Cl2, –20 °C; vii, Et4NF, MeCN, RT
Scheme 5
OSiMe2But
BunLi
(1)
I 86% OSiMe2But
Br
SO2NHNH2
O Pri Pri Pri Pri
MeOH, HCl BusLi, hexane
+ H
N –78 °C to 0 °C
N S
O2
Pri Pri
(12)
Li CHO
DMF, RT
(13)
Scheme 6
Alkenyllithium reagents can also be obtained via a transmetallation process\ vinyllithium itself
may be prepared from the corresponding tin compounds by\ for example\ treatment of tetravinyltin
with phenyl! or butyllithium ð50JA2472Ł[ Substituted alkenyllithium reagents can be prepared from
the products of hydrostannation of alkynes by exchange with n!butyllithium "Scheme 6# ð66JA6254\
66TL2736Ł[ Exchange of tin for lithium in "03# generated the corresponding alkenyllithium derivative
"04# which was alkylated in good yields by 0\7!dibromooctane "Equation "1## ð64JOC1154Ł[ A
cyclopentenyllithium reagent has been generated via this method ð70TL0326Ł\ whilst trans!0\1!bis"tri!
n!butylstannyl#ethylene\ on treatment with butyllithium\ gives the corresponding alkenyllithium
reagent which is readily alkylated by a range of electrophiles ð63JA4470Ł^ such methodology has
been applied to the synthesis of 4\5!dehydroarachidonic acid ð73TL2326Ł[ The b!lithiosilane has been
generated by SnÐLi exchange\ and can be alkylated in good yields\ without showing any tendency
to undergo elimination ð65JOC0379Ł[ Other examples of the generation of alkenyllithium reagents via
tinÐlithium exchange have been reported in the literature ð68JOC2326\ 79JOC3152\ 73JOC2327\ 73TL2044Ł[
BunLi, THF
Bun3SnH, AIBN
Bu3Sn –78 °C
O O 90 °C O O 72%
Li
O O
Scheme 7
Br Br
( )8
Met O-THP THP-O ( )8 O-THP (2)
(14) Met = SnBu3

(15) Met = Li
0[11[0[2[1 Alkenylmagnesium reagents

The usual methods of obtaining Grignard reagents\ using ether as a solvent\ are not applicable
to the vinyl halides\ because of competing elimination reactions leading to alkenes and alkynes[ The
use of tetrahydrofuran as solvent has greatly improved the process\ due to its stronger basicity as
compared to ether\ helping to solvate the vinylmagnesium halides as they form[ Reaction conditions
are otherwise similar to the normal protocol adopted for Grignard reactions\ with the best results
being found with alkenyl bromides\ and on utilising saturated ammonium chloride solution for
workup procedures ð59MI 011!90Ł[ As already mentioned\ subsequent reactions of these vinylic
carbanions proceed with retention of con_guration about the double bond[ For example\ vinyl\
0!alkenyl and 1!alkenyl Grignard reagents couple with alkyl bromides or iodides in the presence of
CuI or AgNO2 to give the corresponding alkenes "Equations "2# and "3#\ Scheme 7 and Equation
"4## ð60JA0372\ 65TL2114\ 68TL0962\ 72TL0930Ł[ The 1!butadienyl Grignard reagent "05# couples with
alkyl bromides and iodides in the presence of functional groups such as esters\ in the presence of a
copper catalyst "Equation "5## ð72JOC0801Ł[ Coupling reactions between vinyl Grignard reagents
and 1!oxy secondary alkyl bromides are catalysed by copper or iron salts "Equations "6# and "7##
ð67TL2600\ 72CB771Ł[ Alkenyl\ silylalkenyl and 1!butadienyl Grignard reagents have been used for
the coupling of primary alkyl tosylates in the presence of a copper catalyst "Equation "8## ð65TL2114\
68TL0962\ 72TL0992Ł^ the coupling of optically active tosylates proceeds without racemisation "Equa!
tion "09## ð72TL0352Ł[ Ring opening of epoxides by alkenyl Grignard reagents is greatly assisted by
copper catalysis "Equations "00# and "01## ð68TL0492\ 71JOC2529\ 71TL0156Ł[
CuI (10%)
MgBr + n-C8H17I n-C8H17 (3)
THF, 0 °C
96%
(E):(Z) 12:88
CuI (10%)
TMS TMS
MgBr + n-C8H17I
(4)
n-C8H17
THF, 0 °C
77%
Cp2TiCl2 TMS BunI, CuI (10%) TMS

Bun TMS + BuiMgBr Bun Bun
MgBr THF, 0 °C Bun
Scheme 8
MgBr AgNO3 (0.1%)

+ MeBr (5)
THF, 25 °C
94%
PhCO2CH2CH2I, Li2CuCl4
(6)
MgCl THF, 20 °C O2CPh
(16) 86%
Br CuBr
MgCl + OMgCl OH (7)
THF
62%
O O
FeCl3
MgBr + O O (8)
62%
Br
R CuI or Li2CuCl4 R
+ n-C8H17OTs (9)
MgBr THF n-C8H17
R = Me, 80%
R = TMS, 83%
R = CH=CH2, 55%
Li2CuCl4
MgBr + TsO OBn OBn (10)
* THF, RT *
O * CuI (10%)
+ * (11)
MgBr Et2O, RT OH
OH
CuI (1.5%)
+ O (12)
MgBr THF, 0 °C
88%
0[11[0[2[2 Alkenylcopper reagents

Alkenyllithium cuprates ð70S730Ł are formed readily from reaction of the corresponding alkenyl!
lithium reagents with copper"I# iodide\ and will undergo conjugate additions to a\b!unsaturated
carbonyl systems[ This methodology has been employed in\ for example\ the synthesis of a cis!fused
d!lactone "06# "Scheme 8# ð64JOC1869Ł and prostaglandin synthesis^ treatment of the lithium reagent
with an alkynylcopper complex gave the mixed cuprate "07# which was employed in a conjugate
addition to cyclopentenone\ for the eventual synthesis of 00!deoxy!prostaglandin E1 "08# "Scheme
09# ð64JOC1154Ł[ Ultrasonication has also been used to generate alkenyllithium cuprates from the
alkenyl bromide\ lithium metal and copper"I# iodide ð71JOC2794Ł[ The corresponding magnesium
cuprates can be formed from a Grignard reagent and copper"I# iodide\ and will undergo similar
reactions ð65JOC2033Ł[ Lithium divinylcuprate itself has been prepared using dimethyl sul_de as
solvent\ giving a soluble complex with the cuprous halide[ The copper complex CuBr = Me1S may
also be conveniently used in excess dimethyl sul_de ð64JOC0359\ 65JOC0285Ł[
i, (CH2=CH–)2CuLi i, O3
ii, TMS-Cl ii, BH4– O
O TMS-O
iii, H3 O+
O
H H H
(17)
Scheme 9
C3H7
CH3(CH2)2C≡CCu, THF 2-cyclopentenone
Li O-THP Cu O-THP
Li
(18)
CO2H
O O
O-THP
OH
(19)
Scheme 10
3 MeCu
2 (13)
0 °C
2 BCl
Dialkenylchloroboranes undergo coupling to dienes in excellent yields "and with a high degree of
retention of con_guration# in the presence of methylcopper "Equation "02## ð65JA0674Ł^ the reaction
presumably proceeds via an alkenylcopper intermediate[ Milder conditions can be employed through
the use of a sodium methoxide addition compound of an alkenyldialkylborane ð79JOC438Ł[ When
such reactions are carried out at low temperatures\ the vinylcopper intermediate is su.ciently
stabilised for it to be trapped by allylic halides\ thus allowing the stereochemically de_ned synthesis
of 0\3!dienes "Equation "03## ð79JOC449Ł^ a variety of functional groups can be tolerated in these
reactions[ Copper reagents formed in this way also undergo 0\3!conjugate addition to a\b!unsatu!
rated carbonyl systems to give g\d!unsaturated carbonyl compounds ð70MI 011!90Ł[ Reaction between
a dialkylvinylborane and CuBr = Me1S also generates vinylcopper boranes ð79BCJ0360\ 79JOC449Ł[
AcO AcO
i, NaOMe
ii, CuBr•SMe2, –15 °C
(14)
B iii, Br
2 73% isolated yield
a!Silylvinylcuprates have been found to be useful synthetic intermediates[ They can be prepared
either by the addition of an organomagnesiocuprate reagent to a silylalkyne "Equation "04## ð66TL048\
66TL0794\ 66TL0712Ł or by a boronÐlithium exchange in the presence of copper"I# iodide to give the
alkenylcuprate of complementary stereochemistry "Equation "05## ð65JOC1830\ 66T1876Ł[ These silicon
substituted alkenyl carbanions can be alkylated in good yields by primary alkyl halides and tosylates\
and allylic halides[ Intramolecular cyclizations are also possible ð65S790\ 65TL1176\ 65TL1836\ 66TL3034\
67JOC036\ 68S33\ 70JOC3599\ 70JOC3597\ 72ACR44\ 72JA5233\ 73TL3890\ 75CL348\ 76TL4682Ł\ with one example
being illustrated "Equation "06## ð74TL4560Ł[ Reactions of vinylic carbanions with epoxides usually
rely on either catalytic or stoichiometric amounts of copper to be present\ THF or ether being the
solvents of choice[ Copper"I# iodide or copper"I# cyanide can be employed in the catalytic reactions\
whilst organolithiocuprates are used for stoichiometric reactions ð64T1624\ 73T530\ 76JOC3301Ł[ An
example of such an epoxide opening is the addition of the vinylsilane "19# to an epoxide in the
presence of copper"I# iodide\ to give the homoallylic alcohol "10# "Equation "07## ð67CL662Ł[ A
number of vinyllithium reagents react with epoxides in good yields\ if converted to the lithium
divinylcuprate _rst "Equation "08## ð72TL2894\ 73CC040Ł[
SiR13
R2CuMgBr
SiR13 Cu (15)
R2
SiR13
R2 SiR13
B MeLi
R2 (16)
CuI Cu
TMS
R TMS
I BunLi
(17)
Cl R
BrMg CuI
(18)
O
TMS HO TMS
(20) (21)
O OH
+ (19)
O-THP
O CuLi O
2
O-THP
0[11[0[2[3 Alkenylmercury reagents

Alkenylboranes can be mercurated with\ for example\ mercuric acetate to give the corresponding
alkenylmercurials\ with retention of con_guration about the double bond "Equation "19## ð61JA3260\
61JOM"25#0Ł[ The resultant organomercurials can be utilised in a number of synthetic processes such
as carbonÐcarbon bond forming reactions ð67AG"E#16Ł[
O i, Hg(OAc)2
B (20)
ii, NaCl HgCl
O
Vinylic mercurials react in a similar manner to the arylmercurials ð71T0602\ B!74MI 011!90Ł[ For
example\ in the presence of PdCl1\ coupling occurs to give symmetrical 0\2!dienes\ presumably via
a divinylpalladium species which reductively eliminates the diene "Equation "10## ð65JOC1130Ł[
Lithium chloride is a necessary component for such reactions\ which are stoichiometric in pal!
ladium"II#\ and are usually carried out in hexamethylphosphoramide "HMPA# solution at 9>C[ As
has been seen in other cases the stereochemistry of the original alkene is retained in the _nal
coupling product[ However\ the reaction is of limited use because alkenylboranes\ from which
alkenylmercurials are obtained\ also undergo such reactions\ the reaction is not catalytic\ and there
is the inherent toxicity of the mercurials and HMPA to be considered[ These coupling reactions
may be carried out catalytically with some rhodium catalysts\ however\ with mercury"II# acting as the
reoxidant ð66JOC0579Ł[ Another useful procedure is the bis"0\4!cyclooctadiene#!nickel"9# coupling of
alkenyl halides ð61JA8123Ł[
HMPA
+ PdCl2 + Pd + HgCl2 (21)
HgCl LiCl
In the absence of added nucleophiles\ and in the presence of a rhodium catalyst\ alkenylmercurials
dimerise onto carbon monoxide to give divinyl ketones\ which are otherwise very di.cult to prepare
"Equation "11## ð79JOC2739Ł[ Enol esters can be obtained in reasonable yields on reaction of
alkenylmercurials with mercuric carboxylates "Equation "12## ð60JOC0775Ł[
R CO, Rh(CO)Cl(PPh3)2 R R
(22)
HgCl >95% O
R = But, cyclohex-2-enyl, Ph
But Pd(OAc)2, 25 °C, THF But

+ Hg(OAc)2 + HgI (23)
HgCl OAc
0[11[0[2[4 Alkenylpalladium reagents

Vinyl halides will undergo Heck!type coupling reactions\ exhibiting the same high stereoselectivity
and generality as found in the reactions of aryl halides ð75AG"E#497Ł[ A number of palladium
catalysts can be utilised\ although typically Pd"OAc#1 is used in conjunction with tri!o!tolylphos!
phine^ triethylamine is added to scavenge the HX produced[ Other triarylphosphines can also be
used in these reactions\ but the aforementioned phosphine is found to give faster reaction rates
ð67JOC1830Ł[ The reaction is thought to proceed via an alkenylpalladium halide species which
undergoes syn addition to an unsaturated system\ followed by syn b!elimination of palladium
hydride\ leading to overall retention of con_guration of both the alkenes employed "Equations "13#Ð
"15## ð70JOC0950\ 70JOC0956Ł[ The regiochemistry of addition of the organopalladium species to the
alkene is mainly sterically controlled\ with addition taking place at the less substituted carbon atom[
However\ in some cases electronic factors may also become important\ and occasionally oppose the
steric e}ect\ leading to mixtures of regioisomers[ If an electron!withdrawing group is present on the
alkene\ addition is usually b to this moiety\ with the product obtained being the "E# isomer[
Coupling with allylic alcohols\ in the presence of piperidine or morpholine\ gives 3!enones or 3!enals
ð71JOC0156Ł[ Reaction with acrolein acetals under similar conditions gives 1\3!dienals\ mainly as the
"E\E#!isomers "Scheme 00#\ whilst reaction with 2!buten!1!one ethylene ketal gives the corresponding
dienones ð70JOC0950Ł[
Br R
+ CO2Me (24)
R >75% CO2Me
OMe OMe
Br + (25)
MeO2C OMe MeO2C OMe
Pd(PPh3)4
+ MeLi + LiBr (26)
Br 88%
Vinylic halides will also couple with various vinylic organometallic reagents in the presence of a
palladium catalyst[ Again\ the reaction is thought to proceed by way of oxidative addition of the
vinylic halide to a palladium"9# catalyst to give the alkenylpalladium halide\ followed by vinylation
by the organometallic "Scheme 01#[ Vinylic Grignard reagents\ alanes\ boranes\ copper and zir!
conium reagents have all been employed in such reactions\ and some will have been dealt with in
the appropriate sections[
H
Pd(OAc)2, P(o-tol)3
OMe N
+ + 100 °C, 24 h
Br
OMe
OMe
OMe (CO2H)2, H2O, ∆
+ N OMe
OMe 79%
CHO
Scheme 11
M
+ Pd0 + Pd0
Pd
X Pd-X
Scheme 12
Vinylic halides will couple directly with alkyllithium and alkyl Grignard reagents at re~ux
temperature in benzene solution in the presence of Pd"PPh2#3 catalyst to give alkenes in good yield\
and with retention of con_guration about the double bond ð68JOC1397Ł[ Again the reaction is
thought to proceed via an alkenylpalladium halide species[ The reaction has been applied to the
synthesis of several pheromones ð72S029Ł[ Chiral coupling products can be formed from secondary
alkyl Grignard reagents and vinylic halides when a chiral ferrocenylphosphine palladium chloride
"or nickel chloride# catalyst is employed^ enantiomeric excesses of up to 57) have been reported
ð71JA079Ł[ Vinylic iodides couple with vinylic Grignard reagents with high stereoselectivity in the
presence of Pd"PPh2#3 catalyst\ allowing the preparation of "E\E#! and "E\Z#!dienes ð67TL080\ 72S029Ł[
Vinyl halides will undergo palladium!catalysed coupling with alkenylboranes "prepared from
alkynes\ Section 0[11[0[3[0# to give dienes[ This approach has been employed in the synthesis of
"S#!"−#!solanone "11# "Equation "16## ð70CC840Ł[ The alkene geometry of the intermediate alkenyl!
borane is retained in the coupling reaction[
i, catecholborane
O ii, H2C=C(Me)Br, Pd(PPh3)4 O
(27)
iii, Jones oxidation
(22)
0[11[0[2[5 Alkenylzinc reagents

Grignard reagents have been used extensively to prepare alkenyl and dialkenylzinc reagents
"Equation "17## ð77TL4534Ł[ Alkenylzinc compounds\ obtained from the corresponding alkenyl!
aluminum or alkenylzirconium compounds and zinc chloride\ couple with aryl iodides in the
presence of a Pd"PPh2#3 catalyst to give the corresponding aryl alkenes "Equations "18# and "29##
ð67JA1143Ł[ Lithium dialkenylcuprates will couple with vinyl halides in the presence of zinc bromide
and a Pd"PPh2#3 catalyst\ with high yield and stereoselectivity\ presumably via the alkenylzinc
reagent "Equation "20##[ Alkenylzinc reagents have also been prepared from the corresponding
alkenylcuprates in situ\ and coupled to aryl iodides stereospeci_cally using Pd"PPh2#3 as catalyst
i, THF, 55 °C, 12 h
MgBr + ZnCl2 Zn (28)
ii, distillation
10–25%
Et Et
Et Et ZnCl2, Pd(PPh3)4
+ (29)
AlBui2 25 °C, 1 h
I 88%
Bun Bun ZnCl2, Pd(PPh3)4

Bun Bun
+ PhI (30)
ZrCp2 25 °C, 1 h Ph
80%
Cl
ZnBr2, Pd(PPh3)4
+ n-C5H11 (31)
I n-C5H11 –10 °C to –5 °C, 2 h
CuLi
2 92%, 99.6% (Z)
Et
Et2CuLi i, ZnBr2, THF, methyl o-iodobenzoate
H H Et CuLi CO2Me
Et ii, 5% Pd(PPh3)4, –10 °C to –20 °C, 2 h
81%
Scheme 13
0[11[0[2[6 Alkenylcerium reagents

Alkenylcerium reagents are prepared by treating the corresponding organolithium compounds
with cerium chloride or cerium iodide "Equation "21##[ The chloride is used in preference\ as it is
more readily available[ The organocerium reagent obtained is represented as RCeX1\ although the
exact structure is unknown ð71CC0931\ 73JOC2893\ 73TL3122Ł[
THF
RLi + CeX3 RCeX2 + LiX (32)
X = Cl, I
Alkenylcerium reagents add to ketones to generate the corresponding alcohols with high diastereo!
selectivity "Equation "22## ð73JOC2893\ 73TL3122Ł\ and have been employed in the stereoselective
synthesis of polycyclic molecules "Scheme 03# ð77JA768\ 78JOC1167\ 89JA166\ 89JA4451Ł[ a!Trimethyl!
silylvinylcerium reagents add to readily enolisable ketones in high yields^ this property has allowed
the synthesis of "−#!eldanolide "12# "Scheme 04# ð74TL750Ł[ b!Silylvinylcerium reagents have also
been employed in synthesis "Equation "23## ð78TL536Ł^ in the example given\ the "E#!cerium reagent
adds to the ketone "13# as shown to give the alcohol "14# as a single adduct\ whereas the "Z#!cerium
reagent does not react\ presumably due to steric e}ects[
OH
O
+ (33)
88%
CeCl2
O
O O
O OH
O
+ (34)
SiMe2Ph
N CN NMe
Me
Cl2Ce CN
SiMe2Ph
(24) (E):(Z) 50:50 (25)
MeS
O-TBDMS CeCl2
THF, –78 °C, 2 h
+
MeS MeS
O-TBDMS O-TBDMS O
H H SMe
OSiButMe2
OH OH BunLi, THF, –20 °C
+
H H
Scheme 14
TMS
O HO
H2C=C(TMS)CeCl2
O THF-Et2O-hexane (4:1:1) O
EtO –78 °C, 0.5 h EtO
O O
(23)
Scheme 15
0[11[0[2[7 Alkenylchromium reagents

Anhydrous chromium"II# chloride transforms vinyl halides to the corresponding alkenyl!
chromium compound which undergoes addition reactions to aldehydes "Equation "24## ð72TL4170Ł[
Aldehydes react more readily than ketones^ the stereochemistry of the original alkenyl halide is
retained[ Alkenylchromium reagents can also be obtained from enol tri~ates in the presence of a
nickel catalyst "Equation "25## ð75JA4533\ 75JA5937Ł^ a catalytic cycle for such reactions has been
proposed ð61JA8123\ 68JA6436Ł[ When vinyl iodides are employed\ palladium"II# salts also catalyse
the reaction[ The use of vinyl tri~ates as precursors to vinyl anions is unusual\ and so this method
is particularly useful ð73TL1160Ł[ Alkenylchromium reagents have been employed in the synthesis
of palytoxin ð76CS462Ł\ and glycosides and C!methyl glycoside analogues "Equation "26## ð76JOC3708\
76JOC3712\ 76JOC3714\ 77JOC2272\ 77JOC3040\ 77JOC4479Ł\ with intramolecular addition reactions being
studied for the synthesis of brefeldin analogues ð77JA4087Ł and ophibolins "Equation "27##
ð77TL3898Ł[
O CrCl2, DMF
+ Ph (35)
I Ph 15 min, 25 °C
100% OH
O CrCl2 R2
+ R1 (36)
R1 OTf R2 NiCl2 (cat.)
DMF OH
O OBn
BnO OBn CrCl2, 1% NiCl2
I + BnO
O O DMF/DMS
OMe
OHC O
OBn
BnO OBn
O BnO
OMe (37)
O
O O OH
HO
CHO H
Ph2ButSiO I NiCl2 (1%)/CrCl2 H

H Ph2ButSiO (38)
DMS, DMSO
56%
O O
0[11[0[2[8 Alkenylboron reagents

Alkenyl Grignard reagents react with trialkylboranes to give an intermediate borate^ decompo!
sition of this complex results in overall alkylation of the vinylic carbanion centre by B:C alkyl
migration "Scheme 05# ð66T0834Ł[
–OH/H
2O
– +
MgBr + R3B BR3 MgBr R
I2
Scheme 16
0[11[0[3 Formation of Vinylic Carbanions by Addition to Acetylenes and Allenes
0[11[0[3[0 Alkenylboron reagents

The hydroboration of alkynes with diborane to give vinylboranes is of limited use\ with internal
alkynes giving only moderate yields of trialkenylboranes\ whilst terminal alkynes give little or none
of the required borane ð50JA2723Ł[ However\ the use of more sterically demanding hydroborating
agents\ for example\ 8!borabicycloð2[2[0Łnonane "8!BBN!H#\ or heterosubstituted boranes\ for
example\ catecholborane\ has allowed the preparation of a vast array of vinylboranes from the
corresponding alkynes ð70MI 011!90Ł[
When diisoamylborane is used as the hydroborating agent\ reaction with either internal or
terminal alkynes proceeds rapidly at 9>C\ allowing hydroboration to occur selectively\ even in the
presence of alkenes "Equation "28## ð52JA1952Ł[ Reaction of thexylborane with either 0!chloro! or
0!bromoalkynes gives a thexyl!0!halo!0!alkenylborane "15# which can then either react with an
alkyne to yield a mixed thexyldialkenylborane "16#\ or with an alkene to give a thexylalkyl!
alkenylborane "17# "Scheme 06# ð62CC595Ł[ trans!a!Halovinylboranes have also been prepared from
the reaction of 0!bromo! or 0!iodoalkynes with dicyclohexylborane^ the alkenylborane undergoes a
number of transformations "Scheme 07# ð56JA4975Ł[
+ Sia2BH (39)
BSia2
Cl
Cl
(27)
+ B
Cl
BH2 H Cl
(26) B
(28)
Scheme 17
MeCO2H R1 Br, I
NaOMe
R1
R1 Br, I MeCO2H R2
BR22 NaOH
O
R1
H2O2 R2
NaOMe R1 Br, R2
or NaOH
R2
Scheme 18
8!BBN reacts with internal alkynes to give the corresponding alkenyl derivatives in good yields
ð68JA85Ł[ However\ terminal alkynes can undergo further reaction to give 0\0!diboraalkanes[ This
problem can be overcome by using an excess of the alkyne "usually 099) excess#\ the unreacted
alkyne being recovered at the end of the reaction[ The resulting alkenylboranes are stable\ and can
be recovered by vacuum distillation[ Unlike the previous examples\ 8!BBN shows increased reactivity
towards terminal alkenes which react more readily than alkynes^ terminal alkynes react more readily
than internal alkynes "Equation "39## ð68JOC1217Ł[ Catecholborane reacts with alkynes in re~uxing
THF to give alkenylcatecholboranes in excellent yields "Equation "30## ð61JA3269\ 64JA4138Ł[ These
alkenylboranes are air!stable and can be puri_ed by distillation or recrystallisation[ Yields of
hydroboration can be increased by the use of ultrasonication in place of the prolonged heating that
is often required ð74TL1076Ł[
+ 9-BBN (40)
B
O
+ BH O (41)
O B
O
Dialkenylchloroboranes can be obtained from the reaction of monochloroborane!etherate with

two equivalents of an internal alkyne "Equation "31##[ Reaction with 0!alkynes is only possible if
an excess "½39)# of the alkyne is used ð65JA0674Ł[ The rate of the hydroboration reaction can be
increased by addition of one equivalent of boron trichloride to the reaction mixture ð45JA1062\
65JA0687Ł[ Hydrolysis or alcoholysis of the dialkenylchloroborane provides dialkylborinic acids or
esters[
+ H2BCl•OEt2 (42)
2 BCl
The dibromoborane!methyl sul_de complex reacts cleanly with 0!alkynes to give the cor!
responding alkenyldibromoboranes in excellent yields\ without the problems of competing dihy!
droboration "Equation "32## ð79JOC278Ł[ Reaction of dibromoborane!dimethyl sul_de is unusually
rapid with internal alkynes\ allowing their selective hydroboration in the presence of terminal
alkynes or alkenes[ This selectivity in hydroboration complements that exhibited by 8!BBN\ and so
a judicious choice of hydroborating reagent should allow the preparation of either 0!substituted or
n!substituted alkenylboranes "Equation "33##[
+ HBBr2•SMe2 (43)
BBr2•SMe2
HBBr2•SMe2 R ( )x
R ( )x (44)
BBr2•SMe2
Due to the hydroboration of alkynes occurring to give exclusively the trans!alkenylborane many
subsequent reactions can be carried out in a stereode_ned manner\ allowing the precise prediction
of the stereochemistry of the product[ Examples of the reactions of alkenylboranes will be discussed
later in this section[ The regioselectivity of hydroboration is\ however\ in~uenced by stereo and
electronic e}ects imposed by the alkyne\ and on the nature of the hydroborating agent employed[
However\ appropriate choice of reagent should allow regiospeci_c hydroborations to take place as
required[ When 0!alkynes are used\ nearly all of the available reagents react such that the boron
adds to the terminal carbon atom ð70MI 011!90Ł[ With internal alkynes\ nearly all the reagents have
been shown to be in~uenced to some extent by steric e}ects\ with boron preferring to add to the
less sterically hindered position^ 8!BBN and HBBr1 = SMe1 appear to be the more selective than
hindered reagents such as diisoamylborane and dicyclohexylborane[ Electronic e}ects are also
signi_cant^ when 0!cyclohexyl!0!propyne is hydroborated\ all the reagents show a tendency to add
boron to the least hindered position of the alkyne\ i[e[\ b to the ring[ This tendency is reversed in
0!phenyl!0!propyne\ when 8!BBN and HBBr1 = SMe1 are the reagents used\ with addition to the
position a to the ring being preferred[ However\ the more hindered reagents still show a preference
to add to the b position\ steric in~uences remaining the dominant factor ð70MI 011!90Ł[
The alkenylboranes have found a number of applications as intermediates in organic synthesis[
Their conversion to other organometallic reagents has already been discussed "Section 0[11[0[2#\
but the boron atom can also be displaced by other electrophiles[ Addition of acetic acid to an
alkenylborane results in protonolysis of the carbonÐboron bond to give an alkene ð50JA2723Ł[
Retention of con_guration is observed\ and the reaction thus provides a method for the noncatalytic
hydrogenation of an alkyne to a cis!alkene\ with a number of other functional groups being tolerated[
This has been exploited in the synthesis of the sex pheromone of Lobesia botrana "Equation "34##
ð66TL300Ł[ The use of deuterioacetic acid provides a method for the stereospeci_c preparation of
deuteriated alkenes ð60JA2284Ł[
i, Sia2BH
(45)
ii, HOAc, 0 °C
6( ) OAc
6( ) OAc
Stereochemically pure cis!alkenyl halides can be prepared on reaction of the alkenylborane with
halogen followed by the addition of base "Equation "35## ð62JA5345Ł[ For the formation of trans!
alkenyl halides base is added to the reaction mixture prior to addition of the halogen "Equation
"36## ð62JA4675\ 79JOC278Ł[
Br
O i, Br2, –40 °C
B (46)
ii, NaOMe, MeOH
O 95%
i, 5 NaOH
+ HBBr2•SMe2 (47)
ii, I2
I
67% isolated yield
Methods for the preparation of cis!alkenes from alkenylboranes have been reported ð56JA2541Ł
and applied to the synthesis of prostaglandin analogues ð65JOC2836Ł[ The utilisation of alkenyl!
boranes in the preparation of trans!alkenes is also the subject of a number of publications
ð56JA4975\ 61JA3902\ 61JA5459\ 61S444Ł[ Alkenylboranes have also been used to prepare conjugated
trans\trans!dienes ð62CC595Ł\ cis\trans!dienes ð57JA5132\ 62JOC0506\ 67JOM"045#048Ł\ and cis\cis!dienes
ð54OS"34#28\ 69JA3957\ 65JOC0967\ 65TL3274Ł[
Alkenylboranes will add to aldehydes to give allylic alcohols of known stereochemistry about the
double bond "Equation "37## ð66JOC468Ł[ Functional groups such as esters\ halogens and nitriles are
tolerated by hydroboration\ and so this 0\1!addition to carbonyl groups provides a useful alternative
to the Grignard reaction\ in that reactive substituents can be present in both the substrate and the
organometallic component[ 0\3!Addition of alkenylboranes to a\b!unsaturated ketones occurs to
give g\d!unsaturated ketones as products\ with the con_guration about the vinylic double bond
being retained "Equation "38##[ Transoid enones such as 1!cyclohexenone do not react\ implying
that the reaction proceeds through a cyclic transition state^ on the other hand cisoid enones react
readily ð65JA6721Ł[
Cl Cl
O
+ (48)
B
HO
O
+ (49)
Alkenylboranes are readily oxidised by alkaline hydrogen peroxide to give the corresponding
carbonyl compounds "Equation "49## ð68JA85Ł[ When aldehydes are the expected products "i[e[\
from 0!alkenylboranes#\ a pH 6 bu}er prevents base!catalysed condensation reactions occurring
ð79JOC278Ł[ 0!Alkynes can be converted into carboxylic acids by formation of the 0!trimethylsilyl
derivative\ hydroboration of the resultant 0!trimethylsilylalkyne\ and then oxidation "Scheme 08#
ð66JA6986Ł[
NaOH O
B (50)
H2O2
i, BunLi
ii, TMS-Cl TMS i, NaOH, H2O
iii, Chx2BH ii, H+ CO2H

B 91%
2
Scheme 19
Haloboration of alkynes has also been reported\ and employed in a carboxyole_nation reaction
I i, RCHO
EtO + I B EtO2C
B R
EtO ii, H2O
Scheme 20
Alkenylboranes will undergo a number of reactions mediated by palladium catalysis[ For example\
"E#!disubstituted alkenes can be obtained from alkenyldialkylboranes in the presence of Pd"OAc#1
and triethylamine "Scheme 10# ð79BCJ0569Ł\ whilst Pd"PPh2#3 catalysed coupling with aryl halides
yields arylated alkenes "Equation "40## ð68CC755Ł[ Coupling with allylic chlorides with Pd"OAc#1 as
the catalyst leads to 0\3!dienes "Equation "41## ð79BCJ0569Ł^ allylic bromides require Pd"PPh2#3 as
the catalyst and aqueous sodium hydroxide ð79TL1754Ł[ Alkenylboranes will couple with benzyl
bromides in the presence of Pd"PPh2#3 and sodium hydroxide\ with retention of con_guration
Ph
Pd(OAc)2
Ph
Ph + HB B
Et3N
2 2
Scheme 21
R2 O R1 R2 O
ArX, NaOEt, Pd(PPh3)4
B + NaH + EtO B (51)
R1 O Ar O
Bun Bun
Bun Bun
Cl
Pd(OAc)2 Bun Bun
+ + (52)
B-(9-BBN)
70% 13%
Et Et Pd(PPh3)4 Et
NaOH
+ Br Ph Et Ph (53)
B(Sia)2 PhH, 80 °C
86%
0[11[0[3[1 Alkenylzirconium reagents

Alkenylzirconium reagents o}er some advantages over their magnesium\ aluminum and mercury
counterparts in terms of preparation\ stability and functional group compatibility ð67JA1143\
67TL0916Ł\ and are comparable to alanes with regard to reaction rates[ Alkenylzirconium reagents
are capable of discriminating between aldehydes and ketones\ and may also di}erentiate between
similar functional groups that di}er only in their steric and:or electronic environment[ Epoxides\
ethers\ carboxylic acid esters and thioesters\ nitriles and alkyl halides are all tolerated[ Because of
the lower basicity of alkenylzirconium reagents\ they can be used for addition to readily enolisable
carbonyl compounds[ Alkyltitanium reagents show similar reactivity to their zirconium counter!
parts^ however\ alkenyltitanium reagents cannot be exploited for nucleophilic additions because of
their propensity to undergo oxidative coupling reactions[
Alkenylzirconium compounds are commonly prepared from an alkyne via hydrozirconation\
the zirconium reagent most commonly used being Cp1ZrClH "Equation "43## ð60JA0268\ 64JA568Ł[
Vinylzirconium"IV# complexes are stable\ and can be used in conjugate additions to a\b!unsaturated
ketones\ usually in the presence of a nickel"9# catalyst "Scheme 11# ð66JA7934\ 70JA3355Ł and this
methodology has been used in the preparation of prostaglandin precursors ð67TL3270Ł[ A mech!
anistic investigation of the addition reaction of alkenylzirconium reagents to carbonyl compounds
has been reported ð70JA3355Ł[ They have also been employed in the formation of a!"phenyl!
selenenyl#ketones "Scheme 12# ð79TL0386Ł[
R1 R2
Cp2ZrClH
R2 R1 (54)
ZrCp2Cl
O
O
But O
ZrClCp2
But O But
Scheme 22
Cl
O Cp2Zr O-ZrCp2Cl
O O Ph PhSeBr
Ni(acac)2, dibal-H PhSeSePh

Ph Ph
O O O O Ph
O O
SePh SePh
+
Ph Ph
O O O Ph O O O Ph
31% 50%
Scheme 23
0[11[0[3[2 Alkenylmagnesium reagents

Alkylmagnesium bromides add across an alkyne under nickel"9# catalysis to give vinylmagnesium
bromides which then react as previously discussed[ This approach has been used in a synthesis of
geraniol "18# "Scheme 13# ð67JA3513Ł[ a!Silylvinylmagnesium bromides have also been prepared by
the addition of an alkyl Grignard reagent to a silylalkyne under nickel catalysis\ and subsequently
undergo alkylation by methyl iodide or allyl bromide "Equation "44## ð67JA3513Ł[ a! and b!silylvinyl
Grignard reagents can be alkylated under palladium catalysis ð68JOC044\ 68TL0962\ 72TL0930Ł[
MeMgBr MgBr i, (CH2O)x OH
TMS Ni(acac)2, AlMe3 ii, F–

TMS
(29)
Scheme 24
n-alk n-alk
Br
TMS TMS (55)
63%
MgBr
0[11[0[3[3 Alkenylaluminum reagents

The preparation and reactions of alkenylaluminum reagents have been reviewed ð70S730\ 73OR264\
74AG"E#557Ł[ Alkenylalanes prepared by the addition of diisobutylaluminum hydride "dibal!H# to a
terminal alkyne ð65CC06Ł can be alkylated in respectable yields\ after conversion to an {ate| complex
using\ for example\ n!butyllithium "Equation "45## ð73OR"21#264Ł[ Addition of trimethylaluminum
to alkynes will take place under zirconium catalysis to give the corresponding alkenylaluminum
compounds ð79S0923Ł[ a!Silylalkenylalanes and b!stannylalkenylalanes have also been prepared
ð65JOC1104\ 75TL5050Ł\ and require conversion to an {ate| complex before alkylation can occur[ The
corresponding alkenylaluminum complex\ on the other hand\ alkylates a number of primary and
secondary halides without prior conversion to the {ate| complex ð76JOC0513Ł\ although problems
arise with substrates that can undergo both SN1 and SN1? displacements\ for example\ crotyl bromide[
Vinylic alanes couple with vinylic halides in the presence of PdCl1"PPh2#1 catalyst\ that had been
prereduced with dibal!H\ at 14>C in THF[ Nickel also catalysed the reaction\ but was not as good at
stereocontrol as the palladium catalyst\ for which the reaction was greater than 88) stereoselective
"Equation "46## ð65JA5618Ł[ Alkenylalanes\ prepared as described above\ will react with epoxides if
converted to their {ate| complexes\ by treatment with n!butyllithium "Scheme 14# ð65CC06\ 79S0923Ł[
BunLi
AliBu2 R2 (56)
R1 R 2X R1
n-C5H11
n-C5H11 n-C4H9 HAlBui2
+ (57)
PdCl2(PPh3)2
AlBui2 I 25 °C n-C4H9
74%
R2 R2
dibal-H, Cl2ZrCp2 BunLi
R1 AlR3 R4
or Me3Al, Cl2ZrCp2 R1 O R1
R4 OH
Scheme 25
0[11[0[3[4 Alkenylsilicon reagents

Palladium!catalysed hydrosilylation of alkynes has been used for the preparation of trichloro!
silylalkenes\ which were then converted to the ~uoro derivatives prior to coupling with an allylic
chloride\ again under palladium catalysis[ The product was a 0\3!diene "Scheme 15# ð67TL1050Ł[
Trimethylsilylalkenes will also undergo palladium!catalysed coupling with allylic halides to give
0\3!dienes "Equation "47## ð60TL3690\ 68JOM"068#C6Ł[ Although the palladium"II# used as catalyst for
this reaction should not be reduced in a formal sense\ side reactions can cause reduction to the
metal\ and so cupric chloride is added as a reoxidant[
R
HSiCl3, H2PtCl6 R i, KF, H2O
R
SiCl3 ii, CH2=CHCH2Cl, Pd(OAc)2
Scheme 26
Li2PdCl4
Ph + Ph (58)
TMS Cl CuCl2, MeCN
30%
0[11[0[3[5 Alkenylpalladium reagents
The formation of alkenylpalladium reagents from the addition of a palladium salt across an
alkyne has been reported\ and used in the formation of 0\3!dienes through coupling to an allylic
halide "Scheme 16# ð63TL0956\ 68JOC44Ł[ PdX1"PhCN#1 can be used as the catalyst and\ if an excess
of the allylic halide is also used\ the products are mainly the "Z#!isomers[
Ph
Ph Cl
Cl
PdCl2 + Ph Cl
ClPd Cl ClPd
Ph
PdCl2 +
Cl
Scheme 27
0[11[0[3[6 Alkenylcopper reagents

The preparation of alkenylcopper reagents has been reported ð67JOC2307\ 74CC0525Ł[ Dialkyl!
lithium cuprates will add across an alkyne to give the corresponding alkenylcuprates "Scheme 17#
ð70TL2740Ł[ Grignard reagents also add across alkynes in the presence of stoichiometric amounts of
copper"I# to give the corresponding alkenylmagnesiocuprates\ an approach that has been employed
in the synthesis of insect pheromones "Scheme 18# ð68JOC2777\ 71TL2476Ł[ "Z#!Divinylcuprates derived
from such alkylcuprate additions to alkynes can be alkylated by amino sul_des to give "Z#!allyl!
amines "Equation "48## ð79TL2652Ł[ Alkenylmagnesiocuprates obtained via the addition of Grignard
reagents to alkynes in the presence of copper"I#\ react well with ethylene oxide and monosubstituted
epoxides to give homoallylic alcohols\ although yields can be improved by prior conversion to the
{ate| complexes using a lithium acetylide "Equation "59## ð66JA142\ 67TL0252\ 67TL1354\ 67TL1862\
68JOC0234\ 68JOC2777Ł[
Et
Et2CuLi i, ZnBr2, THF, methyl o-iodobenzoate CO2Me
H H
Et CuLi ii, 5% Pd(PPh3)4, –10 °C to –20 °C, 2 h
81%
Scheme 28
Cl
O H H O 'CuMgBrI' I
CuI
O MgBr O
O Cl
Scheme 29
PhS NEt2 NEt2

CuLi (59)
60–90%
R R
O
R1 R1
R3
'CuMgBr2' OH (60)
R2 R2
R3
Primary alkylcopper reagents add across terminal alkynes both regio! and stereospeci_cally in
ether in the presence of magnesium bromide or iodide[ The alkenylcopper reagents thus obtained
can then be protonated\ alkylated\ halogenated\ carbonated or oxidised to the dimeric diene "Scheme
29# ð63JOM"66#158\ 63JOM"66#170\ 66TL2434Ł[
Br MgBr Cu
Mg, ether CuBr, ether, –35 °C
–35 °C to –15 °C
i, HMPT, –30 °C, (EtO)3P

ii, CO2, –20 °C to 25 °C LiAlH4, ether
Cu iii, 5N HCl, –30 °C
CO2H
OH
Scheme 30
0[11[0[3[7 Alkenylmercury reagents

Mercuric chloride adds across alkynes to give the corresponding alkenylmercury chloride[ This
methodology has been employed in the synthesis of b!chlorolactones\ in which a propargylic alcohol
was the alkyne component\ and the intermediate alkenylmercury derivative was then carbonylated
in the presence of a palladium salt "Scheme 20# ð67JOC020Ł[ The reaction was limited to relatively
low molecular weight propargylic alcohols\ but could be made catalytic in palladium by adding
cupric chloride without a}ecting the yields[
Cl Cl
HO Li2PdCl4, CO
+ HgCl2 HgCl
ether O O
OH
Scheme 31
0[11[0[3[8 Alkenyllithium reagents

Tertiary lithium enolates add to haloalkynes in special cases\ i[e[\ when the other alkyne substituent
is halo\ aryl\ or similar\ and can stabilise a negative charge[ The intermediate vinylic carbanion thus
obtained eliminates halide ion to regenerate an alkyne "Equations "50# and "51## ð32CB79\ 73JA2440Ł[
i, LDA
CO2Et Cl CO2Et (61)
ii, Cl Cl
TMS
OLi
OMe Cl TMS CO2Me

(62)
Vinylic Cations 0098
0[11[1 DICOORDINATE CARBOCATIONS "i[e[\ VINYLIC CATIONS#
0[11[1[0 General Aspects of Carbocation Formation

Reviews and monographs dealing with general aspects of carbocations also discuss vinyl cations\
including theoretical aspects\ preparations and reactions\ as do general reviews on alkene chemistry
ðB!53MI 011!90\ B!56MI 011!90\ 58APO"6#0\ 60ACR62Ł[ A monograph devoted entirely to the discussion of
vinyl cations has also appeared ðB!68MI 011!90Ł[
0[11[1[0[0 Structures of vinyl cations

Three types of structures have been considered for vinyl cations] "i# a {bent| geometry involving
sp1 hybridisation at C"0#\ which retains the structural features of the solvolysis precursors^ "ii# a
linear geometry involving sp hybridisation at C"0#\ which retains the features of electrophilic addition
precursors^ and\ "iii# a bridged species with three substituents attached to C"0#[ Two dynamic
equilibria also need to be considered^ bent cations may rapidly interconvert "Equation "52##\ thus
showing behaviour similar to that of the linear cation\ and rapid rearrangement of an R group
across the double bond of a linear cation must be considered "Scheme 21#[
R1 R3 R1 +
(63)
+
R2 R2 R3
R1 R3 R1 + R2 R1
+ +
R2 R3
R2 R3
Scheme 32
Many MO calculations have been performed on the parent vinyl cation[ In all cases\ the bent
structure was excluded as a possibility\ and so the main argument has been as to whether the linear
or bridged structure is preferred ð53JCP"39#1379\ 57JA0128\ 58JA4249\ 69JA1030\ 60JA797\ 60JCP"44#2724\
60TCA54\ 61CPL274\ 62CPL298\ 65JA764\ 65JCP"53#3048\ 66JA6321\ 67JA4186Ł[ The general conclusion is that
the parent vinyl cation is probably bridged[ a!Substituted vinyl cations are nearly linear at C"0#\
although some deviation from linearity is to be expected when the two b substituents are di}erent[
The relative stabilities of a b!thiovinyl cation and its bridged isomer have attracted special interest
in view of the evidence for b!sulfur participation in solvolysis reactions "Section 0[11[1[1#[ The
bridged structure was calculated to be more stable than the linear structure ð61CC7\ 63JCS"P1#0797\
66JCS"P1#431Ł[ Addition of methyl groups either to the sulfur atom\ or to the vinylic carbon atoms
increases the stability of the thiirenium ion still further ð67G432Ł[ Similar calculations carried out
on the oxygen analogues have shown that\ on the contrary\ it is an open ion that is more stable
than the bridged ion ð66JCS"P1#431Ł[ Bridged selenirenium ions and probably iodonium ions are
more stable than the open chain ions\ whereas the reverse is true for the b!~uoro! and b!chloro!
substituted vinyl cations[ The b!bromovinyl cation is bridged or linear depending on other sub!
stituents present[ In all cases\ a bent vinyl cation may be formed under certain geometrical
constraints\ such as in cyclic structures[
0[11[1[0[1 Relative stabilities of vinylic and trigonal cations

Relative gas phase stabilities have been examined for the heats of formation "DH9f# of several
vinyl cations using mass spectrometric and ion cyclotron resonance spectroscopic techniques\ and
the appropriate thermochemical cycles^ the parent vinyl cation was determined to be 14 kcal mol−0
more stable than the methyl cation and 03[4 kcal mol−0 less stable than the ethyl cation\ whilst the
1!propenyl ion is 04 kcal mol−0 less stable than the secondary isopropyl cation ð58CRV168\ 69CJC844\
60CJC246\ 61CJC2862\ 65JA5699Ł[ Along with the other DH9 values obtained\ it was found that the
di}erences in stability between analogous vinylic and trigonal cations is much lower when the ions
are generated by addition of an electrophile to a multiple bond\ than in the solvolysis reaction\
owing to the higher ground state energies of alkynes[ The relative stabilities of vinylic and trigonal
cations in solution have also been determined through comparison of solvolysis rates ð69JA4346Ł\
or of addition rates to multiple bonds of the appropriate precursors ð55JA3889\ 62JA059\ 63JA2463\
63TL1192\ 64JA0866\ 64TL1660\ 64TL3444\ 65JOC1220\ 66JA189\ 66JOC1910\ 66JOC1578\ 67JOC0410\ 68JOC2911\
B!68MI 011!90Ł[
0[11[1[0[2 Routes competing with vinyl cation formation

Vinyl cations are now accepted as intermediates in many addition and solvolysis reactions and
the transformations discussed in the following sections are all postulated to proceed via these
reactive intermediates[ However\ the relative unreactivity of many vinylic systems in solvolytic
reactions increases the probability of alternative reaction mechanisms operating[ Although the
products obtained are frequently identical to those from the expected SN0 and E0 routes\ it is
essential to exclude these other mechanisms\ by kinetic and isotope labelling methods\ before it is
safe to assume vinyl cation formation[ Simply changing the geometry or substituents in the vinylic
system\ and:or the medium and:or the nucleophile being employed may be su.cient to divert the
course of the reaction from the SN0:E0 pathways ð58APO"6#0\ 60ACR62Ł[ Some of the principle
pathways will now be discussed[
An important vinylic substitution route proceeds via nucleophilic additionÐelimination "Scheme
22# ð58APO"6#0\ 60ACR62\ 66T0100\ 68JA4984Ł[ This process is strongly dependent on the nature of the
nucleophile\ proceeds mainly with retention of con_guration\ and is the most probable route when
the vinylic system contains b!electron!withdrawing substituents ð57G256\ 60JCS"B#760\ 60JCS"B#0350\
61JOC0063\ 62JCS"P1#1967\ 79JOC3298Ł[
R1 R2 R1 R2 R1 R2
–X–
+ Nu– X –
X R3 Nu R3 Nu R3
Scheme 33
In carboxylic acids or acidic media the electrophilic additionÐelimination "AdE!E# route may
compete with the SN0 route "Scheme 23#[ Because most solvolysis reactions are carried out in acidic
media\ HX is a reaction product which may donate a proton for the addition step[ The structural
features that enhance the SN0 route also enhance the AdE!E route\ so this particular mechanism is
of importance when considering vinyl cation formation[ A number of examples of its co!occurrence
have been reported ð57JA5404\ 58JA5083\ 69JA196\ 69JA3874\ 60HCA1959\ 60JA0402\ 62JCS"P1#290\ 64JA710\
67CB0142Ł[ A radical additionÐelimination route has been suggested for the silver nitrate assisted
solvolysis of b!bromostyrenes in aqueous acetonitrile "Scheme 24# ð58JOC0384Ł[
R1 R2 R1 R2 Nu R2 R1 R2 R1 R3
H+ + Nu–
R1 +
X R3 X R3 X R3 Nu R3 Nu R2
Scheme 34
2 AgNO3 2 Ag + 2 NO2 + O2
Ph Br Ph Br Ph NO2
–Br•
NO2 + •
R R NO2 R
2 Br• + 2 NO3– 2 Br– + 2 NO2 + O2
Scheme 35
When a vinyl sulfonate or carboxylate is employed in a solvolysis reaction\ attack on the leaving
group by the solvent or its conjugate base may occur which\ when followed by SÐO or CÐO bond
cleavage gives ketones of identical structure to those obtained via the vinyl cation route "Schemes
25 and 26#[ This solvolysis mechanism may be operating in those cases where the vinylic systems is
unactivated ð58CC0933\ 69JCS"C#1514\ 61AG"E#603\ 63JA0099\ 65TL2496\ 66JOC063\ 67LA0783Ł[
R2 R1 R2 R1 R2 R1 R2 O
–OR5 –R5OSO2R4 H+
–
R3 OSO2R4 R3 O SO2R4 R3 O– R3 R1
OR5
δ–
Scheme 36
R2 R1 R2 R1 R2 R1 R2 O
–OR5 –R5OCOR4 H+
O–
R4
R3 OCOR4 R3 O R3 O– R3 R1
OR5
δ–
Scheme 37
Vinylic solvolysis products may be obtained in some cases by a process involving an initial rate!
determining solvolysis at a nonvinylic position ð68JA0232\ 68JA2856Ł[ Substitution products formed
by the SN0 route from vinylic systems carrying b!hydrogen atoms are often accompanied by
acetylenic products\ the latter being formed by an E0 process on deprotonation of the intermediate
cation[ In certain cases\ however\ when the proper geometry\ substituents and base are present\ E1
reactions may also compete ð53HCA083\ 58JA3599\ 60HCA1959\ 61JA2518\ 63JCS"P1#732Ł[
0[11[1[1 Formation of Vinylic Cations by Bond Scission

There are a number of methods involving bond scission by which vinyl cations can be generated\
including deamination\ fragmentation\ photolysis\ decarboxylation and electrooxidation^ these will
be discussed towards the end of this section[ However\ by far the most widely studied method for
vinyl cation formation is solvolysis\ in which a suitable vinyl derivative is reacted with a solvent
such as methanol\ ethanol or tri~uoroethanol under acid or base catalysis[
0[11[1[1[0 Vinyl cation formation via solvolysis

Vinylic systems are fairly resistant to solvolysis\ their low reactivity being attributed to a com!
bination of the high energy of the vinyl cation and the transition states leading to it\ and to the sp1
hybridisation at C"0# which makes the CÐX bond stronger than is found in aliphatic sp2!hybridised
analogues ð57JA6171Ł[ However\ consideration of a number of factors\ such as the nature of the
leaving group\ and the presence of other substituents on the vinylic system\ can a}ect the rate of
the reaction and the _nal product distribution[ In general\ simple alkylvinyl halides do not react
readily\ and so extremely good leaving groups such as tri~ate or nona~uorobutanesulfonate are
required in place of the halide[ These derivatives can be prepared from the corresponding carbonyl
compound\ via the enol or enolate[ The reaction is also aided by the presence of strongly activating
substituents\ especially p donors "aryl\ vinyl\ allyl# on C"0#\ or by substituents at C"1# that are
capable of positive charge dispersal[ The presence of such activating substituents is essential for
solvolysis of the less reactive vinylic derivatives\ such as the halides or even tosylates[ Kinetic studies
on the rates of solvolysis of vinylic derivatives have been carried out giving much information on
the relative e}ects of activating substituents and:or leaving groups[ Many of these results have been
discussed in detail in an excellent review\ and so only those general points which need to be
considered when generating vinyl cations by the solvolysis method will be considered here[
The solvolysis of a!bromostyrenes in aqueous ethanol bu}ered by triethylamine "Scheme 27#
represents the _rst example of vinyl cation generation by this method ð53HCA083Ł[ The intermediacy
of the vinyl cation was indicated by a number of factors\ such as the _rst!order kinetics\ the strong
e}ect of the aromatic substituent Y\ the faster reaction rate in 49) ethanol as compared with 79)
ethanol\ the independence of base concentration\ and the products obtained\ i[e[\ acetophenones[
The stabilisation of the vinyl cation by the aryl group is nicely illustrated in this reaction\ the
corresponding unsubstituted or alkylvinyl bromides being unreactive under these conditions[ The
presence of other substituents at the C"1# or b position can further enhance the reactivity of the
vinylic derivative by inductive\ steric and participation e}ects[ Charge dispersal onto the b carbon
atom of a b substituted vinyl cation has been shown to be quite considerable by ab initio calculations
ð66JOC2993Ł\ and this is also true for the a!aryl!b!substituted vinyl cation\ although to a smaller
extent[ The steric and inductive e}ects of b substituents are not easily separated[ Anchimeric
assistance by the b!substituents "e[g[\ sulfur derivatives# has been found in the solvolysis of
a!arylvinyl derivatives^ this e}ect has been studied extensively ð57CC0252\ 57CC0565\ 57TL3928\
60JCS"B#263\ 61JCS"P1#1915Ł[ The intermediacy of the thiirenium ion is implicated in\ for example\ the
solvolysis of the vinyl ethers "29# and "20#[ Reaction with methanol of "29# ] "20# in the ratios of
2[0 ] 0 or 0 ] 1[0 gave an identical mixture of products "21# "71)# and "22# "07)#\ indicating that the
reaction had proceeded via a thiirenium ion "23# "Scheme 28# ð58CC0419\ 60JCS"B#263\ 60JCS"B#270Ł[
Solvolysis of trans!0\1!diphenyl!1!"phenylthio#vinyl tosylate "24# in acetic acid would be expected
to proceed via the formation of a vinyl cation intermediate "25#\ to give the corresponding vinyl
acetate[ However\ studies in which the tosylate was 02C labelled at the 0 position showed that 02C
was distributed evenly between the two alkenic carbons of the corresponding acetates "26# and "27#\
leading to the postulated mechanism shown\ in which a thiirenium ion "28# is involved "Scheme 39#
ð71CJC624Ł[ Further examples have been reported in which the intermediacy of thiirenium ions is
implicated ð60JCS"B#270\ 60JCS"C#2907Ł[ In contrast\ there is no evidence for nitrogen or oxygen
anchimeric assistance on the basis of kinetic data^ such reactions are thought to proceed via the
open chain vinyl cations ð61JCS"P0#105\ 61JCS"P0#0025\ 65BCJ1459\ 65CC501Ł[ The e}ect of the leaving
group on the rate of solvolysis of a!arylvinyl derivatives is similar in most cases to its e}ect on
the solvolysis of saturated systems ð58JA4135\ 69TL2122\ 60JCS"B#0458\ 60TL3928\ 61JOC0063\ 62JCS"P1#290\
63JA475\ 63JA3407\ 64JA710\ 64JA725\ 65BCJ1459Ł[
O
p-YC6H4 80% EtOH p-YC6H4 H2O
+Y •
+
p-YC6H4
Et3N
Br
Scheme 38
PhS Tol PhS Tol
Ph O-TNB Ph Ph OMe
(30) S+ (32)
Ph Tol
PhS Ph PhS Ph
(34)
Tol O-TNB Tol OMe

(31) (33)
Scheme 39
TsO Ph Ph
+
Ph SPh Ph SPh
(35) (36)
Ph Ph
TsO 13C AcO Ph
Ph Ph OAc
13C S+ 13C + 13C
Ph SPh Ph Ph SPh PhS Ph

:
(39) (37) (38)
Scheme 40
When a double or triple bond is attached to the vinyl system at either C"0# or C"1#\ two opposing
e}ects on solvolysis are observed[ On the one hand\ unsaturated groups have a negative inductive
e}ect thereby slowing the rate of reaction\ whilst on the other hand they exhibit a positive resonance
"mesomeric# e}ect through allylic type delocalisation and so enhance reaction rates^ the greater the
e.ciency of overlap between the p system and the vacant p orbital\ then the more dominant is this
latter e}ect[ Solvolysis of these systems is therefore strongly geometry dependent[
The _rst example that could be considered under this category is where the vinylic system is
substituted at the C"0# position by another vinyl group "Scheme 30#[ Here\ stabilisation of the
intermediate hybrid cation depends on the deconjugation of the two double bonds and on their
ortho!gonality in the cation[ Solvolysis of acyclic unsubstituted and methyl substituted 1!bromo!
0\2!dienes in 79) ethanol gave three products ð58TL0328\ 69HCA1008Ł "Equation "53##[ Each can be
derived formally from the hybrid cation in Scheme 30[ Successive methyl substitution enhances the
reactivity of the system appreciably\ through a combination of steric and electronic e}ects[ When
considering small ring systems such as 1!substituted 0\2!cyclohexadienes where the double bonds
are incorporated into the ring itself\ overlap of the p and the p orbitals is geometrically restricted[
Under these conditions the negative inductive e}ect of the double bond predominates\ and the
vinyl cation is not formed ð69HCA1029\ 67LA0783Ł[ As ring size increases\ however\ approach to co!
planarity of the vinyl cation is possible\ allowing its formation from 0\2!cycloheptadienyl deriva!
tives ð62CB2105Ł\ 0\2!cyclooctadienyl derivatives ð62CB2105Ł\ and cyclooctatetraenyl derivatives
ð67JA6955Ł[ Ab initio calculations provide further evidence for the importance of geometry in vinyl
cation formation ð66JOC2993Ł[ When the two double bonds are orthogonal\ the a!vinyl substituent
stabilises the vinyl cation "39# by 03[2 kcal mol−0 as compared with the 1!propenyl cation "30#
"Equation "54##[ The conformation with the p"C1C# and p"C¦# orbital orthogonal is\ by contrast\
11[1 kcal mol−0 less stable than the conformation when the two orbitals are in the same plane\ thus
re~ecting the negative inductive e}ect of the double bond[
R4 X R4 R1
R1 +
R1 R4 + R2
R5 R5 •
R3 R2 R3 R2 R5 R3
Scheme 41
R4 Br R3 R1 R3 R1 R3 R1
R1 80% EtOH
+ + OEt (64)
R5 Et3N O R2 R2 • R2
R3 R2
+ + (65)
+ +
(40) (41)
The a!ethynylvinyl system provides the second example of p!bond stabilisation of the vinyl cation
"Scheme 31#[ Ab initio calculations have shown that the stability of the a!ethynyl substituted vinyl
cation "31# in the gas phase is nearly the same as that of the 1!propenyl cation "32#\ re~ecting the
compensation of the electron!donating p character and the electron!withdrawing inductive e}ect of
the triple bond "Equation "55## ð66JOC2993Ł[ These results have been veri_ed experimentally ð79CC092\
79TL492Ł[
R2 X R2
+ R2 R1
R3 R3 • •
+
R3
R1 R1
Scheme 42
+ + (66)
+ +
(42) (43)
The third example of p!bond stabilisation of the vinyl cation is found when the vinyl group is
part of an allenyl system "Scheme 32#[ In this system\ the two double bonds are ortho!gonal to one
another and overlap of the C"1#0C"2# bond with the vacant orbital is at a maximum in the hybrid
ion[ "The generation of vinylic cations by addition of electrophiles to allenyl groups will be considered
in Section 0[11[1[2[1#[ The allenic system has a high ground state energy which\ coupled with the
perfect disposition of the double bond for overlap with the vacant p orbital\ makes the allenyl
system highly reactive[ The solvolysis of a!haloallenes has been studied ð69JA0971\ 60JA5878\ 61JA4950\
62JOC2943\ 62JA6805\ 65JOC570\ 66JA2658Ł showing that reaction rates are reasonable\ with even a
primary allenyl cation being generated solvolytically[ Allylic stabilisation by the additional double
bond in these systems is similar regardless of whether it is attached to C"0# or C"1#[ Solvolysis of
haloallenes gives both propargylic and allenic products\ with the latter tautomerising in aqueous
organic media to give the a\b!unsaturated ketones "Scheme 33# ð54JOC0797\ 69JA0971\ 60JA5878\ 61JA4950\
67JOC652Ł[
R2 X R2 R2
+ +
• • R1
R3 R1 R3 R1 R3
Scheme 43
O
R2 X R2 + R2 R2 R1
H2O
• • HO R1 +
R3 R1 R3 R1 R3 R3
Scheme 44
Relative solvolytic reactivities of vinylic and saturated halides and tri~ates for all three systems
"vinyl!substituted\ ethynyl!substituted and allenyl# have been determined ð37JA735\ 40JA1699\ 46JA3035\
58JA4135\ 69HCA1008\ 69JA1427\ 69JA1439\ 69JA2678\ 60JA5878\ 60TL1060\ 60TL1408\ 61JA881\ 61JOC0063\
63JA0099\ 65JA6547\ 65JA6556\ 65JOC570\ 79CC092\ 79TL492Ł[
Closely related to the above systems are those vinyl derivatives that are substituted by a cyclo!
propyl group\ either as a substituent at the a position\ or directly attached to the b position[ Silver
salt promoted acetolysis of cyclopropylvinyl iodide is several orders of magnitude more rapid than
that of the corresponding acyclic analogue ð58JA1006Ł[ a!Cyclopropylvinyl chloride reacts similarly
ð58JA1004Ł[ Cyclopropyl vinyl cations can rearrange to give cyclobutyl cations^ a!cyclopropylvinyl
halides\ on solvolysis\ give cyclobutenyl and methylenecyclobutyl derivatives amongst the products
ð60JA0814Ł[ Thus acetolysis of the isomeric vinyl iodides "33# and "34# gave identical mixtures of
products "Scheme 34# ð60JA0830Ł[ The "E# isomer "34# is more reactive by a factor of 09[2 than the
"Z# isomer "33#[ This is a general trend ð62CC478Ł[ This di}erence in reactivity is attributed to the
relief of steric strain between the a!cyclopropyl and the b!alkyl group[ The distribution of the
cyclopropyl\ cyclobutyl and homoallyl products depends on the substituents both on C"1# and on
the cyclopropyl ring ð62CC478\ 63T132\ 64JA0420Ł[
When cyclopropylidenemethyl bromide "35# is solvolysed in bu}ered 49) methanol\ cyclo!
butanone "36# was obtained as the sole product "Scheme 35# ð60TL1060Ł[ The formation of the vinyl
cation "37# is indicated by the independence of the reaction rate on base concentration and on
solvent e}ects ð63JA5575Ł[ A methyl substituent on the cyclopropyl ring changes both the products
formed and the reaction rate[ Thus\ when the isomeric bromides "38# and "49# are solvolysed in
49) ethanol the same product mixture distribution is observed\ in which the open chain alcohol
"40# predominates ð63CB0565Ł "Scheme 36#[ The stabilising e}ect of the methyl group is re~ected in
the 09!fold rate increase of "38# and the 16!fold rate increase of "49# over "35# in 59) ethanol
ð63CB0565Ł[ When the methyl substituent is in the a position\ as in vinyl bromide "41# solvolysis in
various solvents "aqueous ethanol\ TFE\ DMF# gives "42# and "43# as the main products\ with
cyclopropyl methyl ketone "44# a minor component "Scheme 37# ð63JA5575Ł[ In contrast\ aryl!
AcOH AcOH
AgOAc AgOAc
+
I I
(44) (45)
+ + +
O
AcO AcO
30–34% 31–36% 0.5–2.5% 16–20%
OAc
+ + +
OAc •
10–13% 2–4% 0.5%
Scheme 45
substituted vinyl bromides "45^ ArPh\ Tol\ An# give predominantly arylcyclopropyl ketones "46#
and 3!arylbut!0!en!2!ynes "47# with only a few percent of any cyclobutyl derivatives "Scheme 38#
ð63JA5575\ 64JOC0883Ł[ This product distribution is due to the extensive charge delocalisation on the
aryl group in vinyl cation "48# which is absent in vinyl cation "59#[ The same behaviour is observed
in a!cyclopropyl substituted vinyl bromides ð68CB1342Ł[
50% MeOH +
Br Et3N
+
OH O
(46) (48) (47)
Scheme 46
Br
50% EtOH + 50% EtOH
Br
(49) (50)
+ +
HO
O O Br
3% 15% 5% (51) 56%
Scheme 47
In all the previous examples\ the vinyl cation has been stabilised by a suitable a substituent\ thus
increasing the rate of reaction[ It is when investigating a!alkylvinyl systems that the relatively low
solvolytic reactivity of vinylic derivatives is found[ Both acyclic and cyclic vinyl halides are unre!
active\ whilst the brosylates and tosylates react slowly ð58JA5083Ł[ It is only when highly nucleofugal
leaving groups are employed that reaction rates are convenient for kinetic and product distribution
+
Br +
(52)
Br O
(55) <1% (53) 32–70% (54) 15–35%
Scheme 48
Ar Ar
+
Br +
Ar
(56) (59) (60)
Ar
Ar Ar Br
(57) 49–54% (58) 34–48%
0–8%
Scheme 49
studies[ The e}ect of various alkyl groups "RMe\ Et\ Bun\ But\ Pri# on C"0# and C"1# was
investigated for substituted vinyl tri~ates in aqueous ethanol\ 86) TFE\ and AcOH with the main
products in almost all cases being the alkynes\ along with smaller quantities of ketones and allenes
"e[g[\ Equation "56##[ An ionic transition state is implicated in these reactions by the e}ect of the
substituents\ by the increase in solvolysis rate on addition of LiClO3 or LiBr\ and by capture
experiments ð63JA0099Ł[ Although E1 and SN1 routes were excluded\ there is a solvent e}ect indi!
cating that the solvent plays some role in the solvolysis ð37JA735\ 40JA1699\ 46JA3035\ 61JA881\ 65JA6547\
65JA6556Ł[ Larger substituent e}ects are exhibited in systems where two alkyl groups are cis to each
other[ When a better stabilising group is present on C"1# of an a!alkylvinyl system\ rearrangements
may occur across the double bond such that the more stable vinyl cation is obtained[ For example\
when a b!cyclopropyl substituent is present as in the "E#! and "Z#!isomers of "50#\ although the
major products are derived from the unrearranged cation "51#\ 00Ð06) of cyclopropyl ethyl ketone
"52# is also formed\ presumably from hydride migration across the double bond of "51# to give the
more stable cation "53# "Scheme 49# ð63TL0526Ł[ A similar extent of hydride migration is found in
solvolysis of the b!phenyl substituted vinyl derivative "Equation "57## ð66CB088Ł[ In the b\b!diphenyl
substituted vinyl derivative "54#\ phenyl migration occurs to such an extent as to give exclusively
the rearranged ketone "55# "Scheme 40# ð69JA2791Ł[
OTf O
90% EtOH
Bu + + (67)
Bun • Bu
73% 18% 9%
Ph O
(68)
OTf Ph
O
TFE (aq.) H–
+ migration +
OTf
(61) (62) (64) (63) 11–17%
Scheme 50
O
Ph OTf 80%
Ph Ph
Ph Ph
Ph
+ Ph
EtOH + migration
Ph Ph
(65) (66)
Scheme 51
In cyclic vinyl tri~ates\ the a!alkyl group is part of the ring system "Equation "58##[ When the ring
is small "n1Ð3#\ the cation derived from solvolysis would be strained\ leading to decreased reaction
rates[ This has been found to be the case ð61AG"E#603\ 66JOC063Ł[ Increasing the ring size leads to an
increase in solvolytic reactivity up to n8\ after which the relative reaction rates are roughly the
same[ This is the case whether 49) ethanol or 69) TFE is used for the solvolysis ð60JA0402\ 61CB2678\
65T26Ł[ For the smaller ring sizes\ the lower reaction rates are attributed to the fact that the vinyl
cation cannot achieve the preferred linear geometry at C"0#[ The larger rings\ however\ are more
~exible allowing them to achieve linearity\ thus giving rates similar to or greater than acyclic systems\
strong evidence for the sp hybridisation of vinyl cations[ The ring strain found in smaller ring
systems such as cyclohexyl cations leads to alkyl rearrangement to the unsaturated centre from both
the saturated position ð60JA0402Ł "Scheme 41# and vinylic positions "Scheme 42# ðB!68MI 011!90Ł[
Ring strain can also be relieved in cyclic vinyl cations by rearrangement to a cation within a larger
ring[ Thus solvolysis of "56# in 59) MeOH gives both "57# and "58# the latter presumably being
derived from rearrangement of cyclohexenyl cation "69# to cycloheptenyl ion "60# "Scheme 43#
ð68AG"E#769\ B!68MI 011!90\ 79CB1904Ł[
OTf +
(CH2)n (CH2)n (69)
OTf +
50% EtOH + Me 38%
Et3N migration
OEt
OEt O 18%
19% 16%
Scheme 52
OTf + O
50% EtOH
+
Et3N
35%
50%
Scheme 53
OTf O
+ +
60% MeOH
Et3N
(67) (70) (71) (69) 7%
(68) 93%
Scheme 54
0[11[1[1[1 Vinyl cation formation via deamination of diazonium salts

There are three main precursors that allow vinyl cation formation via deamination of a diazonium
ion^ amines\ 2!nitroso!1!oxazolidones\ and triazenes[ One of the _rst attempts to generate a vinyl
cation involved treatment of 1\1!diphenylvinyl amine "61# with nitrosyl chloride in methylene
chloride "Scheme 44# ð54JA752Ł[ The products obtained can be rationalised as being formed from
the diazonium ion "62#\ expelling nitrogen to form the vinyl cation "63#\ which then undergoes
phenyl migration "see 0[11[1[1[0# to give the more stable vinyl cation "64#[ It is also possible\ however\
that the reaction proceeds by a!elimination to the vinylidene carbene rather than via a vinyl cation
ð67CRV272Ł[
N
Ph NH2 Ph +N Ph Ph
NOCl + +
Cl–
Ph CH2Cl2 Ph Ph Ph
(72) (73) (74) (75)
Ph Ph Ph Cl
Ph Ph + + + other products from competing reactions
Cl Ph
11% 4% 6%
Scheme 55
2!Nitroso!1!oxazolidones "65# decompose in aqueous or alcoholic media under basic conditions

to give aldehydes\ ketones\ alkynes and vinyl ethers ð40JA3088\ 45JA3543\ 58JA4566\ 69JA6453Ł[ The
reaction can be envisaged as proceeding via the diazonium ion "66# which then expels nitrogen to
yield vinyl cation "67# "Scheme 45#[ In aprotic media\ however\ it is again thought likely that the
reaction proceeds via unsaturated carbenes ð58JOC0119Ł[
R3 R3 R3
O O O O
–OH/H
2O CO2H CO2H
R1 R1 R1
N
R2 NO R2 NH-NO R2 N2OH
(76)
R3 R2 R3 R2
Products
+
R1 +N R1
N OH–
(77) (78)
Scheme 56
Aliphatic triazenes react with acid to give products which are derived from the corresponding
diazonium salts\ and so the same method has been used with vinylic systems[ Thus\ reaction of "68#
with acetic acid gives products which can be rationalised to have been derived from vinyl cations
"79# and "70# "Scheme 46# ð56JA0859Ł[
NHPh N
Ar N N Ar +N Ar R Ar Ar
AcOH –N2 Ar
Products
+ migration +
Ar R Ar R Ar R
(79) (80) (81)
Products
Scheme 57
0[11[1[1[2 Vinyl cation formation via fragmentation

Thermal decarboxylation of "Z#!b!bromo!a\b!unsaturated acids "71# gives alkynes "72# and
ketones "73# as the products[ The zwitterion "74# has been suggested to be the probable intermediate
"Scheme 47# ð53HCA0489Ł[
–CO2
R
–O
O–
2C Br –Br– (83)
O
+
R H2O
R i, H2O O
(82) (85)
ii, –CO2 R
(84)
Scheme 58
Reaction of oxime tosylates "75# with 79) ethanol gave the ketone "76# and the enol ethers "77#
and "78# ""E# ] "Z# 0 ] 0# "Scheme 48# ð65TL3080\ 65TL3084Ł[ The latter were postulated to be derived
from vinyl cation "89# via a fragmentation pathway[ Electron!donating substituents on the aryl ring
increased the fragmentation rate\ and hence the yields of "77# and "78#\ such that it is the predominant
pathway when Arp!Me1NC5H3[
Ar Ar
NC
δ+
N 80% EtOH N Ar
OTs OTs
+
(86) (90)
+ X Ar NC NC
OEt Ar
O +
N
Ar OEt
(87) (88) (89)
Scheme 59
0[11[1[1[3 Vinyl cation formation via photolysis

Vinyl cations have been suggested as intermediates in a number of photolytic reactions[ For
example\ photolysis of pyrazoline "80# is postulated to proceed via a vinyl cation to give allene "81#
and diene "82# as products "Scheme 59# ð56JCS"B#880Ł[
O
O R1 OC(O)R2
N N hν OC(O)R2
R1 R2 +
R1 R1
R1 ether • R1 +
R1 R1
(91) (92) (93)
Scheme 60
Photolysis of vinyl iodide "83# in methylene chloride was suggested to form initially a radical pair
which then underwent electron transfer to give a vinyl cation iodide ion pair "84#[ Alkyl shift
followed by abstraction of chloride from the solvent gives cycloheptenyl chloride "85#\ one of the
products from this photolysis reaction "Scheme 50# ð65JA3208Ł[ A similar mechanism has been
invoked to explain the formation of alkynes "87# and benzofurans "88# on irradiation of 0\0!
diarylethylenes "86# "Equation "69## ð65CC079Ł\ and for alkyne formation from "E#!0\1!dianisylvinyl
bromide "099# "Equation "60## ð68TL0508Ł[ Evidence that these reactions proceed via a vinyl cation
has been obtained from capture experiments ð68TL0508Ł\ and from ~ash photolysis ð79T2118Ł[
Cl
+
hν +
I–
I CH2Cl2 I
(94) (95) (96)
Scheme 61
R
Ar
hν
Ar Ar + Ar (70)
Ar Br O
(97) (98) (99)
An An
hν
An An (71)
Br
(100)
0[11[1[1[4 Vinyl cation formation via oxidative decarboxylation
Oxidative decarboxylation of b!anisyl!a\b!unsaturated acids "090# by lead tetraacetate is thought
to proceed in a similar manner to that discussed above for photolysis reactions "Scheme 51#
ð62CI"L#0956Ł[
An CO2H + Pb(OAc)4 An An •
CO2PbIV
(101)
OAc
An + An An
OAc OAc
OAc
Scheme 62
0[11[1[1[5 Vinyl cation formation via electrooxidation

Electrooxidation of "091# in aqueous t!butanol was suggested to involve formation of the cation
radical "092#\ followed by disproportionation to vinyl cation "093# and cation "094#\ yielding the
ketone "095#\ benzoin "096# and benzil "097# as products "Scheme 52# ð60TL0274Ł[
Ph Ph+ • Ph Ph
electro-
oxidation HClO4 O
N N
Ph
H2O Ph
O O 26–31%
(103) (102)
disproportionation
H2O
Ph Ph Ph Ph
+ +
N + N
O O
(104) (105)
H2O
Ph O
O
H2O
N Ph Ph
Ph
20–34%
OH
O
(106) (107)
work up
[O]
O
Ph
Ph
O
(108)
Scheme 63
0[11[1[1[6 Vinyl cation formation via mass spectrometry
The mass spectra of many vinyl halides and tosylates show peaks with m:e values corresponding
to those of the derived vinyl cations ð57JA1321\ 70JA1669Ł[
0[11[1[2 Formation of Vinylic Cations by Addition to Alkynes and Allenes
0[11[1[2[0 By addition to alkynes

The addition of an electrophile to an alkyne results in the formation of a new s bond and a vinyl
cation "Scheme 53#[ Attack can occur at either carbon atom of the alkyne to give\ in theory\ two
possible products[ In practice\ however\ it is found that one product predominates often to the
exclusion of the other^ the product ratios can usually be rationalised by considering the stability of
the intermediate carbocations[ In most cases\ R0 and R1 are of su.ciently di}erent stabilising ability
that only one product is obtained[ For terminal alkynes\ for example\ it is the internal carbon atom
which bears the positive charge "Schemes 54 and 55 and Equation "61## ð33JA575\ 59RTC0991\ 50RTC686\
52RTC264\ 52RTC283\ 52RTC309\ 54JCS273\ 57JA0919\ 57JA0912\ 65JA2184Ł[ When R0 R1\ the product
obtained can be rationalised by assuming the more stable carbocation is formed^ thus\ alkynyl
ethers and thioethers give the corresponding esters and thioesters\ and not the isomeric ketoethers
ð50RTC0174\ 52RTC394\ 54JCS273\ 57JA0919\ 57JA0912Ł "Equation "62##[ Ynamines yield amides as the
only product "Equation "63## ð63JA5581Ł[ t!Butyl and benzyl cations\ generated under FriedelÐCrafts
conditions\ add to alkylphenylalkynes to give the products derived from a!phenylvinyl cations
"Scheme 56# ð65JA2184Ł[ When R is electron withdrawing\ an a!arylvinyl cation is formed pref!
erentially ð57JA261Ł[ The direction of addition of electrophiles to disubstituted alkynes is consistent
with the relative rates of addition to the individual monosubstituted alkynes\ although caution
should be exercised when applying rate data for the prediction of the regiospeci_city of a reaction
ð54JA1184\ 63JA0009\ 63JOC0327\ 64JA0734\ 68JOC2965Ł[ The importance of substituents and their ability
to control carbocation formation can be seen in the synthesis of steroids "Scheme 57# ð62JA3305\
67TL1438Ł[ When RMe\ _ve!membered ring formation is observed via a linear vinylic carbocation^
this is attributed to the higher stability of the linear over the bent vinyl carbocations and to
higher nonbonded interactions in the transition state[ When RTMS\ however\ six!membered ring
formation is observed\ attributable possibly to the tendency of a silicon atom to stabilise a positive
charge at a b!position ð67TL1438Ł[
R1 R1 Nu
+ Nu–
E R2 E R2
R1 R2 + E+
R2 R1 E
+ Nu–
R1 E Nu R2
Scheme 64
OH O
H2O
OR + H3O+
OR
OR
Scheme 65
OH O
H2O
Ph + H3O+
Ph
Ph
Scheme 66
ZnCl2
Cl But
Ph + ButCl (72)
CH2Cl2 Ph
O
H2O, H+
But OR But (73)
OR
O
H2O, H+
Ph NR2 + H2O Ph (74)
NR2
ZnX2 R1 R1 X
+
Ph R1 + R2X
CH2Cl2 R2 Ph R2 Ph
Scheme 67
R R
+
R
+
H CF3CO2H CF3CO2H H
HO
CHF2Me ClCH2CH2Cl
H H H H
ethylene carbonate ethylene carbonate
H H
R = Me R = TMS
O
O
H H
H H H H
H Scheme 68 H
The addition of halogens and of sulfenyl and selenenyl halides to alkynes is thought to involve
the formation of a bridged species[ Evidence for this has been obtained from the reaction of sulfenyl
halides with an unsymmetrical alkyne to give two regioisomers\ presumably via a thiirenium ion
"Scheme 58# ð54TL3288\ 57JA2355Ł[ Such ring openings are subject to electronic and steric e}ects as
well as to solvent e}ects ð54TL3288\ 54TL3394\ 65CJC2934\ 65CS65\ 65JOC1220Ł[
R2 R1 SR2 R1 Cl
Cl–
R1 + R2SCl S+ +
Cl R2S
R1
Scheme 69
The attacking electrophile does not necessarily have to be an external species\ but could be a
carbocation located in the alkyl chain containing the triple bond[ The intermediate vinylic carbo!
cations formed in these reactions often undergo rearrangements ð50LA"635#100\ 54TL764\ 55TL2736\
56TL2760\ 69JA1431\ 69LA"622#4Ł[ For example\ homopropargyl derivatives such as deuteriated
2!pentyn!0!yl m!nitrobenzenesulfonate\ when solvolyzed in bu}ered tri~uoroacetic acid\ give cyclo!
butanone derivatives deuterated equally at C"2# and C"3#^ this result suggests the intermediacy of
the cyclopropylidenevinyl cation which undergoes bond migration\ rather than direct cyclization to
yield a four!membered ring "Scheme 69# ð57TL3506Ł[ A number of reports of this homopropargyl
rearrangement can be found in the literature ð58JA2127\ 61TL1872\ 62TL3656\ 63JA5575\ 63TL1346\ 65JA751\
66JA0558\ 66JOC063Ł[
D
D CF3CO2H
OSO2C6H4NO2-m +
CF3CO2Na D
D
D D D D
D D D D
+ +
+ +
O O
Scheme 70
Cyclisation to give larger rings has been observed in systems where the triple bond is at an even
more remote position[ Which end of the triple bond is attacked is dependent on the substitution of
the alkyne\ the intermediate vinyl cation then being either endo! or exo!cyclic "Scheme 60#[ For
example\ when 4!hexyn!0!yl tri~ate "098^ RH\ XOTf# is solvolyzed in bu}ered TFE\ the open
chain ether "009# is obtained in 47) yield\ along with the cyclohexenyl derivatives "002^ XOTf\
01)# and "002^ XOCH1CF2\ 13)#[ The latter compounds are presumably derived from the
intermediate endo!cyclic vinyl cation "001#[ In this instance\ there is no trace of products derived
from the exo!cyclic carbocation "000#[ On the other hand\ when 4!heptyn!0!yl tri~ate "098^ RMe\
XOTf# is solvolysed\ both six!membered and _ve!membered ring products are obtained with the
cyclopentene derivatives predominating[ When the substituent is a phenyl group as in 5!phenyl!4!
hexyn!0!yl acetate "098^ RPh\ XOAc# the only cyclic products obtained are cyclopentene
derivatives presumably derived from the exo!cyclic vinyl cation "000^ RPh#[ Similar behaviour is
shown by analogous systems ð55JA2041\ 58JA3410Ł[ Seven!membered rings have been formed from
heptyn!5!yl derivatives\ although to a much lesser extent[ Transannulation reactions involving
cyclodec!4!ynols have also been reported in the literature\ the cyclisations proceeding by way of a
vinyl cation intermediate "Equations "64#Ð"66## ð60CJC2024\ 60TL816\ 61CB310\ 66TL3266Ł[
X +
O
R R R CF3
(109) (110)
R
+
+
+
R
(111) (112)
R X
X
R
(113)
Scheme 71
O O
H H
+ (75)
RO
H H
R=H HCl, MeOH 75%
R = Ts 80% EtOH, 2,6-lutidine 93% 7%
R = PNB 50% EtOH, 2,6-lutidine 92% 8%
O CF3 O F
CF3
+ + (76)
HO
abs. TFE 96% 4% 0%

BF3•OEt2, CH2Cl2 0% 0% 65%
BF3•OEt2
(77)
CH2Cl2
HO
0[11[1[2[1 By addition to allenes

Addition of an electrophile to an unsymmetrical allene can occur at any one of the three
unsaturated carbon atoms[ Attack at C"0# or C"2# results in vinyl cation formation\ whilst attack at
C"1# generates an allylic cation[ The position of attack is dependent mainly on the nature of the
substituents R0\ R1\ R2\ R3\ and their ability to stabilise the intermediate transition state[ When both
the terminal carbon atoms are disubstituted\ that is when R0\ R1\ R2\ R3 H\ then electrophilic
attack occurs preferentially at the central carbon atom of the allene system generating a tertiary
allylic carbocation "Equation "67## ð58CC011Ł[ Aryl substituted allenes also give products arising
from attack at the central carbon atom yielding\ eventually\ the more stable cinnamyl derivatives
"Scheme 61# ð38JA0853Ł[ Initial protonation of the central carbon atom has been reported for a
number of other substrates\ for example\ R0\ R1 Me ð59JA5286Ł\ R1\ R3 Me ð58CC011Ł\ R0
alkyl\ R3 OEt ð54RTC20Ł\ and R0 Me\ R2 Et ð57BSF1019Ł[ It should be pointed out that\
although allyl cation formation is eventually achieved in some cases\ the initially formed allyl cation
is not stabilised by resonance owing to the orthogonality of the two p orbitals and the perpendicular
direction of attack of E¦ on the double bond[ The vacant p orbital and the double bond in the
initially formed ion "and in the transition state leading to it# are orthogonal^ the stabilised allyl
cation is achieved upon rotation by 89> about the s bond[
FSO3D/SbF5 +
• (78)
–70 °C
D
Ar H+ +
• Ar Ar Cl
Scheme 72
Vinyl cation formation is observed in the reaction of hydrogen chloride with 0\1!butadiene
"Scheme 62# ð59JA5286Ł\ whilst in other systems the reaction products suggest competing vinyl:allyl
cation formation ð52JGU2497Ł[ Addition of halogens to allenic systems is reported to proceed via
a bridged halonium ion intermediate ð57JA5630\ 60JA4647\ 63JOC1144Ł "e[g[\ Scheme 63#[ Bridged
intermediates have also been suggested for the addition of arylsulfenyl halides to allenes ð62JA3989Ł[
H+ Cl–
•
+
+
Cl
(E)/(Z) 60% 40%
Scheme 73
As in the formation of vinyl cations by intramolecular addition of a carbocation to an alkyne\

similar processes have been observed for allenes ð53CR"148#1140\ 53TL1080\ 58JA3713Ł[ The product dis!
tribution is strongly dependent on the substituents present in the system\ and on the ionising power
Br2 Br
Br+
•
MeOH
H H
OMe
Scheme 74
of the solvent[ The enol esters or ethers which are the initial products frequently tautomerise to give
the corresponding ketone[ Further examples of participation of allenes in solvolysis reactions\
including kinetic studies\ have been reported ð57CC607\ 58JA2181\ 58JA2188\ 58TL2588\ 63T116\ 63T124Ł[
When the leaving group is suitably positioned on a cyclic system\ bicyclic products may be obtained
"Equation "68## ð58JA3713\ 58TL2588Ł[ Bicyclic products are also obtained when the allenic group is
part of the cyclic system\ presumably via a vinylic cation "Scheme 64# ð62BSF0799Ł[
• i, AcOH • OH
+ + (79)
OTs ii, LiAlH4 OH OH
O
+
OTs
Scheme 75
When additional methylene groups are placed between the allenyl group and the leaving group\
cyclisation occurs\ but usually via the allyl cation "attack at sp allenyl carbon#\ rather than via a
vinyl cation "attack at terminal sp1 allenyl carbon atoms# ð62CC568Ł[ There are\ however\ exceptions
to this generalisation^ the intermediacy of a vinyl cation has been reported in the cyclisation of
cyclohexene "003# to give the cis!octalone "004# "Scheme 65# ð67JA882Ł[
HO i, HCO2H + O
• • +
ii, H3O+
H
(114) (115)
Scheme 76
0[11[2 DICOORDINATE RADICALS "i[e[\ VINYLIC RADICALS#
0[11[2[0 General Aspects of Radical Formation

A number of general reviews and monographs on free radical chemistry\ and the generation of
carbon!centred radicals have been published\ with many of these making reference to vinyl radicals
ð74AG"E#442\ B!75MI 011!90\ 76T2430\ 77S306Ł[ The aim of this discussion\ therefore\ will be to highlight
those methods of vinyl radical formation which have found subsequent use in organic synthesis[
The intermediacy of vinyl radicals has been demonstrated by ESR studies\ with the large 02C
coupling constants observed demonstrating that the unpaired electron is in an orbital possessing
considerable s!character[ They also suggest that vinyl radicals adopt a bent structure "i[e[\ 005#
rather than a linear structure "006#[ Inversion of con_guration of these radicals is rapid even at
temperatures as low as −079>C "Equation "79##[ Some vinyl radicals have been shown to adopt a
linear structure\ but these are sterically congested[
R1 R1
• •
R3
R2 R3 R2
(116) (117)
Vinylic Radicals 0016
R1 R1 R3
•
(80)
•
R2 R3 R2
Vinyl radicals and their reaction with O1 play a crucial role in the combustion of hydrocarbons
ð73JA3245\ 75JPC391\ 81JPC1040Ł[ A number of computational predictions of possible mechanisms\
based on quantum mechanical calculations\ have been made ð82JA8795Ł[
In synthesis\ vinyl radicals can be formed by C0X bond scission\ most commonly where X is a
halogen\ or by addition of another radical to a multiple bond as found in an alkyne or an allene[
Vinyl radicals are higher in energy than the corresponding alkyl radicals^ the formation of vinyl
radicals from the corresponding vinyl halides requires higher reaction temperatures\ with the bro!
mides or iodides being the necessary halogen precursors[ Once formed\ the vinyl radicals can
undergo a number of reactions\ depending on the nature of the other reactants present[ Inter!
molecular additions to unsaturated systems have been reported "Equation "70##\ as have intra!
molecular cyclizations onto a suitably positioned multiple bond "Equation "71##^ intramolecular
hydrogen atom abstraction is also a possibility "Equation "72##[ Examples of these processes will be
given in the following sections[ In the case of intramolecular cyclisations\ the 4!exo!trig mode usually
predominates to give methylenecyclopentanes "007# as the major product[ However\ methyl!
enecyclohexanes "008# can also form\ as a result of what at _rst glance appears to be an overall
5!endo!trig process^ the latter become the major products under appropriate conditions "Equation
"73## ð71JA1210Ł[ Substituting the internal position of the alkene acting as the radical acceptor with
a radical stabilising group is one method of obtaining high yields of the methylenecyclohexanes
"Equation "74## ð75TL0244\ 78CC379Ł[ The formation of the methylenecyclohexanes has been ration!
alised as proceeding via kinetic cyclisation in the expected exo!mode followed by rapid rearrange!
ment "Scheme 66# ð75TL3414\ 75TL3418\ 76JA1718\ 77JA1454Ł[ Cyclohexane formation can be eliminated\
however\ if a high concentration of stannane is used^ because vinyl cyclisations of this type are fast\
the reduced "open chain# product is not obtained in signi_cant amounts even under these conditions
ð75TL3414\ 75TL3418Ł[ The cyclopropane intermediate in these reactions can be trapped when a
suitable substrate is employed "Equation "75## ð70JOC1216\ 82TL1980Ł[ When the vinyl radical gen!
erated is part of a diene system\ cyclisation onto a pendent alkene generates a homoallylic radical
which can then give either the cyclopropane ring or the cyclohexane ring\ the _nal product being
determined by the nature of substituents attached to the diene "Scheme 67# ð82JOC4463Ł[ Whether it
is the _ve! or six!membered ring that is obtained\ vinyl radical cyclisations of this type o}er the
advantage over alkyl radical cyclisations in that there is the retention of some functionality in the
product in the form of an exo!cyclic double bond^ this has been exploited on a number of occasions
ð71JA1210\ 72TL0760\ 73CL0326\ 74TL846\ 75TL0244\ 76JCS"P0#0126\ 76TL1784\ 78JCS"CC#0989Ł[
+ R2 (81)
R1 • R2 R1
•
•
•
(82)
•
(83)
•
Br
Bu3SnH
+ (84)
(118) 65% (119) 22%

CO2Me
MeO2C H
I
CO2Me Bu3SnH
CO2Me (85)
O 80 °C O
85% O-TBDMS
H
O-TBDMS
•
• low •
[Bu3SnH]
high
[Bu3SnH]
Scheme 77
Br
+ (86)
R R R
R=H 100%
R = O-TBDMS 100%
R = Ph 39% 45%
(Yields based on NMR spectroscopy)
SiMe2R2 SiMe2R2 SiMe2R2

SiMe2R2
Bu3SnH • •
Br AIBN, C6H6
R1 R1 R1 R1
O O O
O
a; R1 = Me, R2 = Ph, 58%
b, R1 = Ph, R2 = Me, 54%
c, R1 = hexyl, R2 = Me, 48%
But (E) (Z) But
Br
O O
(Z) 60%, (E) 30%
Scheme 78
Vinyl radicals are much more reactive towards cyclisations than the corresponding alkyl radicals^
in 4!exo cyclisations the rate di}erence is −0999 ð71JA1210\ 75TL3414\ 75TL3418Ł[
0[11[2[1 Formation of Vinylic Radicals by Bond Scission

A number of reagents can be utilised in the homolytic cleavage of vinyl halides to give vinylic
radicals\ with tri!n!butyltin hydride being the most widely used[ The reaction conditions employed
re~ect those already well!established in alkyl radical chemistry\ for example\ use of 1\1?!azo!
bisisobutyronitrile "AIBN#\ thermolysis\ or photolysis as initiators^ the choice of solvent and opera!
ting temperature varies considerably\ but in all cases it is the vinyl bromide or iodide\ and not the
chloride\ that acts as the precursor to the vinyl radical^ the stereochemistry of the vinyl halide is
unimportant as inversion about the radical centre occurs rapidly at the operating temperatures
normally employed[ Other radical precursors include\ for example\ the vinylselenides "Equation
"76## ð76CC675Ł\ whilst trialkylsilanes are just one example of a number of other reagents to have
been utilised[ The following examples have been chosen to illustrate methods of generation of vinyl
radicals by bond scission\ and their subsequent utility in synthesis[
SeMe
( )9 ( )9
Bu3SnH
(87)
HO AIBN HO
80%
There are a number of reports in which vinyl halides can be used to generate vinyl radicals that
subsequently undergo 5!exo cyclisation to give a six!membered ring "cf[ the 5!endo cyclisations
mentioned previously#^ examples include the formation of "019# and "010# "Equations "77# and "78##
ð71JA1210\ 74TL4816Ł[
OH OH
Bu3SnH
(88)
I 80 °C
72%
(120)
Bu3SnH
O O
(89)
Br 80 °C
70%
(121)
The tendency of vinyl radicals to abstract a hydrogen atom rather than undergo cyclisation is
illustrated in Scheme 68[ In this case\ the vinyl radical "012# was generated from the corresponding
vinyl iodide "011# and tri!n!butyltin hydride under photolytic conditions ð77JCS"CC#70Ł[ Hydrogen
atom abstraction from the d position leads to the formation of an allylic radical "013# which cyclises
back onto the original vinylic double bond to generate the tricyclic system "014#[
I •
H
H H H • H
N Bu3SnH, N N quench
N
C6H6, hν
CO2Me CO2Me CO2Me CO2Me
R R R R
(122) (123) (124) (125)
Scheme 79
Vinyl radicals have been generated in a number of tandem radical cyclisation sequences^ the
synthesis of silphiper_l!5!ene "016# "from the bromoketone "015## "Scheme 79# ð71JA1210\ 76T4552Ł\
angular triquinanes ð75JA0095Ł and the southern part of the milbemycin system "Equation "89##
ð77CC172Ł are just a few examples that illustrate this type of process[
O OEt Br
O O
(126) (127)
Scheme 80
CO2Me Bu3Sn CO2Me
Br Bu3SnH
(90)
80 °C O
O 43%
OBn
OBn
0[11[2[2 Formation of Vinylic Radicals by Addition to Alkynes and Allenes

The formation of vinyl radicals from alkynes has been employed on a number of occasions in
synthesis^ quite simply\ a preformed radical adds to a triple bond forming a s bond\ with the vinyl
radical being generated at the b position[ The radical that initially attacks can be carbon centred
"alkyl\ aryl or vinyl#\ or heteroatom centred "e[g[\ tin\ sulfur or selenium#[ Once formed\ the vinyl
radical generated in this way can undergo the same type of reactions as seen in the previous
section\ i[e[\ intermolecular additions\ intramolecular cyclisations or hydrogen atom abstraction[
The following examples serve to illustrate the utility of alkynes as precursors to vinyl radicals in
synthesis[
The principles applied to the addition of radicals to alkenes can also be extended to alkynes\ with
nucleophilic radicals adding preferentially to electron poor alkynes\ whilst electrophilic radicals add
to electron rich alkynes[ Addition to mono! and disubstituted alkynes can lead to mixtures of both
cis!alkenes "from syn!addition to the alkyne#\ and trans!alkenes "anti!addition#\ although it has been
reported that in intermolecular processes\ syn!addition is preferred unless the incoming radical is
sterically bulky\ for example\ But ð78TL716Ł[ A number of di}erent methods for the intermolecular
addition of radicals to alkynes have been reported ð71TL1464\ 74TL2200\ 74TL5990\ 77TL280\ 78TL716\
78JOC0127Ł to give alkenes as products[ Allenes have also been formed from appropriately substituted
alkynes\ via an intermediate vinyl radical "Equations "80# and "81## ð73CL0326\ 75TL1722Ł\ and from
addition of radicals to cyclopropylacetylene ð75JCS"P0#28Ł[
I SnBu3 •
H H (91)
AIBN, 80 °C
BOC CO2PMB 55% BOC CO2PMB
EtO2C [Co]
•
Br (92)
hν EtO2C
EtO2C 70% CO2Et
The formation of per~uoroalkyl analogues is of considerable importance for a number of synthetic

targets\ with the per~uoroalkylation of alkynes and alkenes being a major process for the intro!
duction of a per~uoroalkyl group[ Methods that have been utilised to achieve this include photolysis
ð42JCS0088\ 43JCS0523Ł\ pyrolysis ð40JCS477Ł\ electrolysis ð71CC322Ł\ free radical initiation ð71JOC1140Ł
and transition!metal catalysis ð73TL292\ 74CL0578\ 74JA4075\ 75CL0784Ł[ Triethylborane!induced radical
addition has been employed in synthesis on a number of occasions ð76JA1436\ 77BCJ1582\ 77TL5014\
77TL5016Ł\ and was found to exhibit extremely good catalytic activity in the intermolecular addition
of per~uoroalkyl iodides to both terminal and internal alkynes[ The reaction proceeded with high
regio! and stereoselectivity\ with the trans product being formed exclusively\ whilst the mild reaction
conditions employed allowed the use of the more volatile ~uorides "Equation "82## ð78TL2048Ł[
Et3B
R1 RF
R1 R2 + RFI (93)
hexane I R2
4!Hexynyl cyclizations "Kexo "14>C#1[7×093 s−0^ Kendo "14>C#³5×091 s−0# are slower than
the corresponding 4!hexenyl cyclisations but\ nevertheless\ have found extensive use in synthesis[
As previously mentioned\ one advantage of these types of reactions is that the double bond formed
in the process can be manipulated further\ thus permitting the introduction of other functionalities
ð58TL0542\ 73CL0326\ 74CC0194\ 74T2848\ 74T3902\ 75CC767\ 75TL530\ 76TL1998\ 76TL1526\ 76TL1776\ 77TL46\
77TL0974\ 78TL4906Ł[ The addition of carbon!centred radicals to a pendent alkyne has also been
employed in a number of 5!exo cyclisations\ the resultant vinyl radical abstracting a hydrogen atom
from the tin hydride to continue the chain process "Equations "83# and "84## ð68JOC435\ 73JOC0202\
76CJC093\ 76JA1718Ł[ Tri!n!butyltin hydride is most commonly used in these cyclisation processes
with\ in general\ a solution of the tin hydride and a catalytic amount of AIBN "½4 mol)# in the
chosen solvent being added dropwise to a solution of the radical precursor at re~ux temperature
under nitrogen[ Syringe pump addition to maintain low concentrations of tin hydride has been
employed in those cases where the cyclisation is slow[
Ph Ph
CbzNH Br CbzNH
Bu3SnH
(94)
N PhH, ∆ N
O 75% O
Bu3SnH
(95)
Cl hexane, ∆
72% O
O
TMS
TMS
The addition of a carbon!centred radical onto an alkyne directly attached to a sulfur atom has
been applied to the synthesis of cephalosporins "Scheme 70# ð78H"17#36Ł[ Although fragmentation
and reduction products were obtained as by!products in this process\ there was no evidence for
penem:penam formation\ suggesting that endo!addition was favoured over exo!addition^ this was
attributed to the relative ring strains "3:4 versus 3:5 fused rings# found in such systems[
GHN S
O
N
O Cl
O
ButO 2C
GHN S GHN S GHN S

+ + O
N OH N N
O O O O
CO2But CO2But ButO2C
Scheme 81
Vinyl radicals generated from alkynes have found an important role in tandem cyclisation
processes[ In the synthesis of hirsutene "017#\ for example\ the vinyl radical "018# is formed in the
last cyclisation step\ and acquires a hydrogen atom from the tri!n!butyltin hydride to generate
the tin radical needed for halogen atom abstraction "Scheme 71# ð74JA0337\ 74T2832Ł[ The same
methodology has been applied to the synthesis of D8"01#!capnellene ð74TL3880Ł[ In both cases\ the
second cyclisation step involves the addition of an alkyl radical onto an alkyne to generate a vinyl
radical[ Alkyl radicals are more stable than vinyl radicals and so\ at _rst glance\ this appears to be
an unfavourable process^ however\ a s bond is formed in this cyclisation at the expense of a p bond\
and so the transformation is exothermic[ Vinyl radical cyclisation as the ultimate step in a tandem
process has also been utilised in the synthesis of linear triquinanes "Equation "85## ð72T2832Ł[ In the
construction of the C:D ring of steroidal butenolides through a tandem cyclisation process a vinyl
radical is generated in the _rst cyclisation step\ and subsequently adds to an adjacent alkene
I
H
Bu3SnH
•
H H H H
•
H H
H H H H
(129) (128)
Scheme 82
TMS TMS
I H
Bu3SnH
(96)
80 °C
H H
O O
O O Cl
Cl
Br
Bu3SnH
(97)
75%
H
When tri!n!butyltin hydride is employed as the reagent in radical!forming reactions\ and when
no halogen atom is present in the substrate\ the tin radicals generated as a result of either thermolysis
or photolysis can add to a multiple bond^ in the case of alkynes\ vinyl radicals result[ This tin radical
addition has been utilised in the synthesis of natural products such as seychellene "029# "Scheme 72#
ð78TL114Ł\ amongst others ð76JA1436\ 76JA1718\ 78TL716\ 78TL0886Ł[ The stannyl group can be removed
after cyclisation either by protodestannylation with silica gel and dichloromethane or by trans!
metallation with butyllithium and subsequent quenching[
MeO2C MeO2C MeO2C
CO2Me OH OH
SnBu3 (130)
Scheme 83
Alkynic Ions and Radicals 0022
0[11[3 MONOCOORDINATED ALKYNIC IONS AND RADICALS
0[11[3[0 Alkynic Carbanions

As in the case of vinylic carbanions\ there are a number of reviews and monographs dealing with
general aspects of carbanion chemistry\ which include discussions on acetylide anion formation^
monographs concerned speci_cally with alkyne chemistry also discuss acetylide anions ðB!58MI 011!90\
B!72MI 011!90\ B!67MI 011!91\ B!77MI 011!90Ł[
The increasing s character of the hybrid orbital involved in the s bond to H in the sp orbital of
an alkyne\ as compared to sp1 "alkenes# and sp2 "alkanes#\ results in a corresponding increase in
acidity of the alkynic proton[ Thus\ alkynes RC2CH\ and ethyne HC2CH "pKa 14#\ can be
converted by strong bases such as −NH1 in liquid ammonia\ into the corresponding anions\ which
are somewhat more nucleophilic than cyanide ions[ The low acidity of 0!alkynes means that strong
bases must be used to form the corresponding anions and that water is not a suitable solvent^ a very
low concentration of alkynide ions is present in aqueous solutions[ However\ some transition metal
alkynides can be prepared by precipitation from aqueous solution because of their low solubility in
water[ In general\ the solvent of choice for the preparation of alkynide ions should be less acidic
than the alkyne\ and allow the solvation of both the alkyne and the alkynide ion^ liquid ammonia\
tetrahydrofuran\ ether and hydrocarbons have all been employed[ Ammonia is most often used\
because the alkynide ion is readily formed by metal amides[ Acetylide anions do not require the
presence of electron!withdrawing groups for stabilisation\ the carbanion being stabilised su.ciently
as a result of the high s character of the carbon atom[ Addition of acetylide anions to electrophilic
centres constitutes an important method in synthetic chemistry\ with the added advantage that the
C2C linkage present in the product can be modi_ed further\ for example\ reduction by hydrogen
in the presence of Lindlar catalyst to give the alkene[ However\ acetylide ions are also strong bases
and so\ in certain cases\ can induce elimination reactions as well as nucleophile displacement[ For
example\ reaction with tertiary halides is often found to result in alkenes being formed\ rather than
in alkylation of the acetylide[ As in the case of vinylic carbanions\ acetylide anion reactivity can be
tailored to meet speci_c needs by the judicious choice of the counter cation[ A number of metallated
alkynes have been reported in the literature\ with those that have been found to be of some synthetic
utility being discussed in this article[ The most widely reported alkynides are those of Group 0 and 1
metals\ particularly lithium and magnesium\ and these have been employed principally in alkylation
reactions[ Other metals utilised include copper"I#\ silver\ gold"I#\ zinc\ mercury and aluminum[ In
general\ these metallated acetylides are prepared via transmetallation of the corresponding lithium
or magnesium acetylide with the halide of the metal required[ Palladium!catalysed reactions have
also been employed\ particularly in the reactions of alkynides of metals other than those of Groups
0 and 1[ Alkynic carbanion structures incorporating the t!butylacetylide or phenylacetylide anion
have been characterized by x!ray di}raction analysis ð72CB2101Ł[
In addition to the metallated acetylides mentioned above\ acetylides have also been prepared
through electrochemical reduction of the corresponding alkyne^ when the reaction is carried out in
the presence of an alkyl halide\ the disubstituted alkynes can be obtained in high yields "Scheme 73#
ð65CC595Ł[
Bun4N+ F–, HMPA EtI
Ph + e– Ph – Ph Et
Scheme 84
0[11[3[0[0 Lithium acetylides

Monometallation of ethyne itself can be achieved under special conditions[ Addition of pieces of
lithium or sodium metal to boiling ammonia whilst introducing ethyne gives ammoniacal solutions
of LiC2CH and NaC2CH\ respectively[ The dianion can be prepared as a _ne suspension by
introducing ethyne into a solution of BunLi in ether or THF at 9>C[ Ammonia or other amines
stabilise the monoanion[ Thus\ when ethyne is introduced into a BuLi!TMEDA solution at low
temperatures\ a clear solution of the monolithium salt is obtained[ Other alkynyllithium complexes
are most readily prepared by treating the corresponding 0!alkyne with butyllithium\ in a solvent
such as THF or DIGLYME[ The lithium reagents thus obtained have been employed in alkylation
reactions\ to give a range of natural products such as pheromones "Scheme 74# ð61AG"E#59Ł\
macrolides ð66CL848\ 67CC643\ 67JA3507\ 67JA3519\ 68TL2910\ 79HCA1315\ 72AG"E#679Ł "e[g[\ Scheme 75#\
sesquiterpenes ð58JA3207\ 69TL1134\ 89JOC680Ł "e[g[\ Equation "87##\ and leukotrienes and pro!
staglandins ð68JCS"P0#1843\ 79JA4314\ 79JCS"P0#741\ 72JA2545\ 72TL4074\ 78S787Ł "e[g[\ Scheme 76#[
i, BuLi, DIGLYME H2, Pd/CaCO3, Pb(OAc)4

C10H21 C10H21
ii
Br
130 °C, 8 h
O
mcpba
C10H21
C10H21
Scheme 85
i, BuLi
ii, Br(CH2)7O-THP O
O-THP HO ( )6 O-THP
iii, H3O+
Scheme 86
O-THP
Li
(98)
Br THF
O-THP
Me2SCu
CO2Me
+
OR
Br
n-C5H11
CO2Me OH
OR CO2H
5-HETE
Scheme 87
The tetrahydropyranyl ether of propargyl alcohol "020# is readily metallated at the alkynic carbon
by n!butyllithium\ or ethylmagnesium bromide to give the corresponding anion "021#\ which reacts
with a variety of electrophiles "Scheme 77# ð71OS"59#70\ 73JOC0787\ 73T1426\ 74T1258\ 74TL1126Ł[ Lithium
amide in liquid ammonia has also been used as a base for the generation of an anion from a
substituted propargyl alcohol^ subsequent addition to ethylene oxide allowed the eventual synthesis
of the C!01 to C!07 segment of rhizoxin\ an antitumour macrolide antibiotic ð82TL696Ł[
0[11[3[0[1 Magnesium acetylides

The most common method for the generation of magnesium acetylides is to treat the cor!
responding alkyne with ethylmagnesium bromide\ resulting in deprotonation and metallation\ with
ethane being produced as a side!product ð71OS70Ł[ The preparation of the dianion of ethyne can be
achieved simply by introducing ethyne into a solution of ethylmagnesium bromide in THF at
THP-O
(131)
EtMgBr
or BunLi
O
R2 R2X M ClCO2Me
OMe
THP-O THP-O THP-O
(132) i, (CH2O)n
R1CHO
ii, MnO2
OH O O
R1
THP-O THP-O
OH
THP-O
Scheme 88
×39>C[ Preparation of the monoanion is more di.cult\ although BrMgC2CH can be prepared
by adding a solution of EtMgBr to a solution of ethyne in THF kept below 29>C[
Alkynyl Grignard reagents react stereospeci_cally with alkenyl iodides in the presence of a
palladium catalyst\ Pd"PPh2#3 "Equation "88## ð67TL080Ł[
Pd(PPh3)4
n-C6H13 + MgBr n-C6H13 + MgBrI (99)
I
0[11[3[0[2 Tin acetylides

Trialkyltin acetylides have been used in the synthesis of chiral b\g!unsaturated amino acids\ a
class of compounds some of which have been shown to exhibit neuroexcitatory\ antimicrobial
and enzyme inhibitory properties "e[g[\ ð64ACR170\ 65ACR202Ł#[ An oxazinone "Scheme 78# was
brominated and then condensed with the required trialkyltin acetylide in the presence of zinc
chloride in warm carbon tetrachloride[ The alkyne thus obtained is reduced directly to provide
exclusively the "E#!vinylglycine derivatives in good to excellent ee ð77JA1490\ 77T4314Ł[ Trialkyltin
acetylides will also couple with acid chloride in the presence of a palladium catalyst\ PdCl1"PPh2#1\
with 0\1!dichloroethane as solvent\ to give alkynyl ketones as products "Equation "099## ð71JOC1438Ł[
Ph H
H
Ph H O CO2H
H Ph O
i, NBS, CCl4
Ph O N O N
ii, ZnCl2, CCl4, ∆ t-BOC O H
N H
t-BOC O R23Sn R1
Scheme 89
O
PdCl2(PPh3)2, ClCH2CH2Cl
COCl + Bun3Sn Ph + Bun3SnCl (100)
2 h, 84 °C
Ph
0[11[3[0[3 Copper acetylides

One of the drawbacks often encountered in the use of organocuprates in synthesis is that one of
the organic ligands is invariably {wasted|\ "i[e[\ only one of the ligands is transferred during the
reaction#[ The comparative strength of the sp carbonÐcopper bond has led to the use of copper
acetylides in the preparation of mixed organocuprates\ in which it is the other organic group\ and
not the acetylide\ which participates in reactions[ This has allowed the preparation of a number of
organocuprates in which a synthetically more valuable and less readily available organic group\
usually as its lithium salt\ is coupled with copper acetylide to give the corresponding alkyl!
ethynyllithium cuprate\ which then reacts with electrophiles in a similar manner to that described
elsewhere for dialkyllithium cuprates[ The alkyl component can also be vinylic or aryl\ and the
corresponding Grignard reagents can be used in place of the organolithium reagents[ Thus enami!
dines "022# can be metallated at the 1!position to furnish the alkenyllithio derivatives "023#\ which
are then transformed into the mixed organocuprate "024# prior to alkylation by an allylic halide
"Scheme 89# ð74JOC0908Ł[ This methodology has been applied to other systems[ A mixed organo!
cuprate was employed in the synthesis of a trans!fused a!methylene!g!lactone "025#\ via a conjugate
addition "Scheme 80# ð64JOC0821Ł\ and in an epoxide ring opening to give the precursor to another
a!methylene!g!lactone "026# "Scheme 81# ð65JOC2102Ł[
Pr
BunLi or
ButLi Br
N N Li Cu Pr N Cu N
–78 °C Li 76%
N N N N
But But But But
(133) (134) (135)
Scheme 90
O EtO OEt O O
i,
But Cu i, Ag2O, OH–
ii, H3O+ CHO ii, dcc, pyridine
O-TMS OH O
O
(136)
Scheme 91
O
O O
OH
Li OEt H
OEt
Cu
OEt
OEt
But
(137)
Scheme 92
Copper acetylides prepared from copper"II# sulfate:hydroxylamine hydrochloride have been

utilised in coupling reactions to aryl halides[ Both euparin "027# "Scheme 82# ð66JCS"P0#89Ł and the
antibiotic frustulosin ð68CC013Ł have been synthesized via this method[
Copper acetylides may also be prepared from the corresponding terminal alkyne and copper
Br
O
Cu
HONH2•HCl, CuSO4•5H2O HO OH O
NH4OH, EtOH, RT pyridine, ∆ O
HO
(138)
Scheme 93
t!butoxide^ the anions prepared in this way will react with carbon dioxide to give copper alkynoates
which can be converted into their methyl esters "e[g[\ 028# on treatment with methyl iodide "Scheme
83# ð63CC279Ł[
i, Bun3P, THF, 80 °C
ButOCu, RT ii, CO2
Ph Ph Cu Ph CO2Me
iii, MeI
50% (139)
Scheme 94
0[11[3[0[4 Silver acetylides

Silver acetylides can be prepared from the corresponding terminal alkynes and silver nitrate
ð45JA0564Ł[ These silver salts are of low nucleophilic character\ as evidenced by their inability to
react with either acetone or t!butyl bromide^ however\ they will react with acyl halides in either
carbon tetrachloride\ chloroform\ or benzene to give a\b!alkynic ketones in reasonable yields
"Equation "090## ð45JA0564Ł[ In the presence of pyridine\ the expected acylation does not occur^
instead\ a dihydropyridine addition product "039# is obtained "Scheme 84#\ which can undergo a
number of reactions ð50JA338Ł[ Silver acetylides generated from silver nitrate and phenyl ethyne in
aqueous ethanol react with puri_ed arenediazonium salts "as their chlorides or bromides# to give
phenylazoethynylaromatic compounds "Equation "091## ð64JOC013Ł[
O O
R1 Ag + AgX + (101)
X R2 R2
R1
R1 Ag (140)
R1
R2COCl KOH, Br2
N N N N
Br
R1 R1
O R2 O R2
(140) OH–
Scheme 95
ArN
ArN2+ X– + Ag Ph + AgX (102)
N Ph
Silver acetylides can also be prepared from a terminal alkyne and silver t!butoxide[ Subsequent
reaction with carbon dioxide gives the corresponding silver alkynoate which can be methylated with
methyl iodide to yield the ester ð63CC279Ł[
0[11[3[0[5 Palladium acetylides

Organic halides will couple with ethyne in the presence of a palladium catalyst and base to give
disubstituted alkynes "Equation "092## ð64JOM"82#142\ 64JOM"82#148\ 64TL3356Ł[ As the reaction does
not proceed in the absence of base\ attack of acetylide ion on an intermediate organopalladium
halide is implicated[ Vinyl bromides react to give enynes\ whilst bromoallenes will react with terminal
alkynes to give allenynes "Equation "093## ð72S21Ł[ Monosubstituted alkynes can be obtained by
reaction of trimethylsilylethyne with an organic halide followed by removal of the silyl group
"Scheme 85# ð79S516\ 70JOC1179Ł[ 0!Alkynes can also be coupled to heterocyclic halides in the presence
of a palladium catalyst\ Pd"PPh2#1Cl1\ CuI and triethylamine^ coupling to bromopyridines was used
in the design of ruthenium"II# complexes which spectrochemically recognised Group 0 and 1 metal
cations ð82JCS"D#1518Ł[
N Br N N
Pd(PPh3)2Cl2
+ H H + 2Et2NH + 2Et2NH+ Br– (103)
CuI, 25 °C, 6 h
Pd(PPh3)4, CuI
• + Ph + Et2NH • (104)
25 °C, 2–3 h
Br
78%
Ph
TMS
Br
Pd(PPh3)2Cl2, CuI KOH, MeOH

+ TMS + Et2NH
25 °C, 4 h 25 °C
92% 88%
NO2 NO2 NO2
Scheme 96
Alkynylpalladium complexes are implicated when aryl or vinyl halides are reacted with terminal
alkynes and norbornene ð71TL3406Ł[ It is proposed that the aryl! or vinylpalladium halide formed
initially adds across the alkene in norbornene to give an alkylpalladium adduct which then undergoes
substitution of the bromide ligand by acetylide[ Reductive elimination of the complex then gives
the alkyne derivative "Scheme 86#[ This reaction sequence has also been applied to norbornadiene[
Pd(PPh3)4 Ph
PhBr + PdBr Pd
Ph MeCO2K Ph Ph
Ph
Ph
Scheme 97
0[11[3[0[6 Silicon acetylides

Alkynylsilanes react with electrophiles such that the electrophile attaches itself to the carbon
atom bearing silicon\ the vinylic carbocation thus forming b to the silicon "Scheme 87#[ Subsequent
loss of the silyl group regenerates an alkyne[ A number of examples of this type of reaction are to
be found in the literature ð52CB2179\ 61JOM"26#34\ 62JOC1143\ 65TL1338\ 67TL0470\ 67TL1290Ł\ including
the formation of a D!homosteroid from a trienyne "Scheme 57#[ The directing e}ect of the silicon
group in such reactions is demonstrated very nicely in this example\ for if the silyl group is replaced
by methyl then cyclisation occurs to give the _ve!membered D!ring normally encountered in steroids
ð67TL1438Ł[
R TMS
E+
R TMS R E
+
E
Scheme 98
0[11[3[0[7 Aluminum acetylides
Reviews discussing the preparation and reactions of aluminum acetylides have been published
ð70S730\ 73OR"21#264Ł[ Aluminum acetylides can be prepared by the reaction of lithium acetylides
with a dialkylaluminum halide[ Dimethylaluminum chloride has been used in the preparation of
acetylides for conjugate addition to a\b!unsaturated ketones "Scheme 88# ð67JA1133\ 79JOC2942Ł\
whilst methoxymethylaluminum chloride was used in a route to a!"phenylselenenyl#ketones "030#
"Equation "094## ð79TL0386Ł[ Although organocuprates are more commonly employed in conjugate
additions to enones\ the strength of the C2C!Cu bond precludes the use of copper acetylides in
conjugate alkynylation reactions[ Aluminum acetylides thus o}er the same advantages of chemo!
selectivity over lithium reagents as would be expected from an organocuprate\ and are a useful source
of g!alkynones from the corresponding a\b!enones ð60JA6219Ł[ Alkynylalanes undergo conjugate
addition to enones "e[g[\ 031# under nickel"9# catalysis "Equation "095## ð79JOC2942Ł[
O
i, BuLi i, Ni(acac)2, dibal-H

R R AlMe2
ii, Me2AlCl ii, cycloalk-2-en-1-one
R
Scheme 99
O O O
SePh SePh
i, AlMe(OMe)Cl, LiC≡CBut
+ (105)
ii, PhSeBr, PhSeSePh
But But
(141) 33%
10%
H
Ni(acac)2
+ But AlMe2 (106)
dibal-H
O 67% O
(142)
But
The selectivity of aluminum acetylides has been demonstrated in the ring opening of cyclohexane
oxide^ when the lithium salt of ethoxyethyne was employed\ the required product was not obtained[
However\ conversion of this lithium acetylide to the corresponding diethylaluminum acetylide in
situ\ followed by addition of epoxide gave the alkynol in excellent yield "Scheme 099# ð65JOC0558Ł[
The ring opening of an epoxide by a dialkylaluminum acetylide has been exploited in the synthesis
of a cis!fused hydroxy!g!lactone "032# "Scheme 090# ð64TL40\ 65TL0658Ł[
EtO
toluene cyclohexane epoxide

Li OEt + Et2AlCl Et2Al OEt
–40 °C to RT HO
95%
Scheme 100
0[11[3[0[8 Zinc acetylides

Alkynylzinc reagents are obtained from the reaction of zinc chloride with the corresponding
lithium acetylide[ Zinc acetylides react with vinyl iodides or bromides in the presence of a palladium
catalyst\ Pd"PPh2#3\ to give alkenynes in which the stereochemistry about the original double bond
O-TBDMS O-TBDMS OH
Et2Al TMS i, PdCl2, CO
AgNO3, CN– ii, Bun4N+ F–

H O H H
OH O
O
(143)
Scheme 101
is retained "Equation "096## ð66CC572Ł[ Because zinc acetylides are less reactive than their Grignard
counterparts\ they can also be used in palladium!catalysed coupling reactions with vinyl halides
that contain an ester group "Equation "097##[
Pd(PPh3)4
Bun
+ ClZn Bun + ZnClI (107)
I THF, 25 °C
Bun
Pd(PPh3)4
Br + ClZn Bun (108)
MeO2C THF, 25 °C MeO2C
87%
0[11[3[0[09 Cerium acetylides

Cerium acetylides are prepared by the reaction of the corresponding lithium reagents with cerium
chloride or cerium iodide ð71CC0931\ 73JOC2893\ 73TL3122Ł[ As with the alkenylcerium reagents\ cerium
acetylides add to ketones and aldehydes to yield the corresponding alcohols in good yields "much
improved over those obtained using the lithium acetylide directly# "Equations "098# and "009##
ð73JOC2893\ 73TL3122\ 77TL1812\ 77TL4906\ 77TL5840\ 78TL1516\ 89CL0300Ł[ The trimethylsilylethynylcerium
reagent has been found to be particularly useful for the addition of ethynyl groups to carbonyl
compounds ð73CL0432Ł\ and has been employed successfully in a number of syntheses "Scheme 091#
ð75CPB0420\ 75TL084\ 76CPB0394\ 76TL3472Ł^ readily enolisable ketones are also alkynylated by this
reagent to give homoallylic alcohols in good yields "Equation "000## ð74TL0438\ 77CPB2786\ 80TL0696Ł[
O HO
+ CeCl2 (109)
Ph Ph 95% Ph Ph
OH
O + Ph CeCl2 (110)
89%
Ph
TMS
O
EtO2C TMS CeCl2 EtO2C OH (111)
THF, –78 °C, 2 h
EtO2C 82% EtO2C
0[11[3[0[00 Chromium acetylides

Alkynylchromium reagents can be prepared by the treatment of the corresponding haloalkyne
with chromium"II# chloride in dimethylformamide ð74TL4474Ł[ The carbanions thus obtained react
readily with ketones and aldehydes to give the corresponding alcohols "Equations "001#Ð"003##[
TMS
O OH O OH
O
TMS CeCl2
OH
–78 °C
R O OH R O OH
O OH
COMe
OH
R O OH
Scheme 102
O O Bu I Ph Ph
+ Bu + Bu OH (112)
Ph Ph CrCl2, DMF, 25 °C
OH
96% 4%
O Bu I Br O
(113)
OHC ( )3 CrCl2, DMF, 25 °C ( )3
76%
OH
Ph
Ph I
(114)
OHC CrCl2, DMF, 25 °C
83% OH
0[11[3[0[01 Nickel acetylides

Bromoalkynes treated with trialkylaluminum reagents in the presence of bis"N!methyl!
salicylaldimine#nickel are converted to the corresponding alkyl!substituted alkynes "Equation "004##
ð67TL1720Ł[ It is suggested that the reaction proceeds via insertion of nickel into the alkyne halide
bond to generate an alkynyl nickel complex which undergoes exchange of the halide for an alkyl
group^ the _nal step is elimination of the nickel\ yielding the alkylated product[
Ni(mesal)2
Et3Al + Bus Br Bus Et (115)
pentane, 25 °C
81%
0[11[3[1 Alkynic Carbocations

As has already been discussed\ vinyl cations are accepted organic intermediates generated by\ for
example\ solvolytic processes^ some have been characterised by 0H and 02C NMR spectroscopy
ð74TL0382Ł[ On the other hand\ alkynyl cations are rare^ some have been observed by mass spec!
trometry ð64JOC013\ 73JA410Ł\ but attempts to generate these species by solvolysis have been unsuc!
cessful\ due mainly to the alkynyl cation HC2C¦ being ca[ 029 kcal mol−0 less stable than the
H2C¦ cation[ Even the use of an excellent leaving group\ N1\ as in the decomposition of the
alkynyldiazonium salts has not yielded the required carbocation[ Ab initio calculations have provided
a rationale for this situation ð76JA3126Ł[
The tritium decay method ð82CRV1822Ł has\ however\ allowed products to be isolated which
suggest the intermediacy of an alkynyl carbocation[ Thus\ when 0\3!bis"tritioethynyl#benzene was
allowed to decay in the presence of a nucleophile NuA\ in both liquid and gaseous phase\ for six
months\ signi_cant yields of tritiated derivatives were obtained "Scheme 092# ð64MI 011!90\
66JCP"55#3560\ 67MI 011!92Ł[
+
β decay –3He
T T T 3He
+NuA
T + T Nu
–A+
Nu-A Yield (%)

Ph–H 96
Br–(CH2)4Br 36
Br–But 31
Scheme 103
0[11[3[2 Alkynic Radicals

Although the formation of alkyne radicals is nowhere near as well documented as vinyl radical
formation\ there are nevertheless some methods of alkyne radical formation worthy of mention[
These principally occur under copper catalysis and have been employed in a number of coupling
reactions[ The two classical examples of these are the Glaser reaction\ and the CadiotÐChodkiewicz
coupling[
In the Glaser reaction an alkyne such as 0!phenylpropyne "033# reacts with basic CuCl1 to give a
diyne "034# upon oxidation in air "Equation "005## ð0758CB311\ 0769LA026Ł[ Other copper derivatives
and bases can be employed in place of the copper"II# chloride and hydroxide used in the original
procedures[ For example\ "035# was converted to a 0 ] 1 mixture of "036# and "037# in 27) yield
using copper acetate and pyridine "Equation "006## ð78JA2539Ł[
i, CuCl2, NH4OH
Ph Ph Ph (116)
ii, air
(144) (145)
O
O O
O
O
Cu(acac)2•H2O, 42 °C
OH + (117)
pyridine
O
O O
O
(147) (148)
(146)
In the CadiotÐChodkiewicz coupling\ a bromoalkyne "049# reacts with a monoalkyne "038# in the
presence of cupric chloride and an amine to yield a diyne "Equation "007## ð44CR0944\ 46AC"P#708Ł[
Alkynyl copper derivatives will also couple with aryl halides or other aromatic derivatives ð52JOC1052\
52JOC2202\ 55CB0531\ 56CB0082\ 56CB0199\ 62JOC2782\ B!79MI 011!90Ł[
Vinylidene Carbenes 0032
OH CuCl2, BunNH2
EtO OH
EtO
+ Br Ph Ph (118)
Ph 90% Ph
(149) (150)
0[11[4 VINYLIDENE CARBENES

The simplest unsaturated carbene is vinylidene\ H1C1C]\ which is tautomeric with ethyne[
Reviews concerning this and related species have appeared in the literature ðB!62MI 011!90\ B!64MI 011!
90\ 67ACR096\ 67CRV272\ 67MI 011!92\ 71ACR237\ 80CRV086Ł[ Theoretical studies of the ethyne:vinylidene
system have been made on numerous occasions ð62TCA072\ 64JCP"52#2127\ 65JCP"53#3433\ 66JA1808\
67JA0267\ 67JA0817\ 68ACR177\ 79JA2223\ 70CPL301\ 71CPL382\ 72CPL013Ł\ and the results have been sum!
marised in other reviews ð70CPL397\ 70JA0893Ł[
Vinylidenes have been generated via a number of di}erent routes\ the three most important being]
"i# alkoxide or alkyllithium!induced decomposition of vinyl halides "Equation "008## ð46JOC0137\
48JA3608\ 52JA2411\ 60JA0433\ 61CB1189Ł^ "ii# alkoxide!induced decomposition of 4\4!disubstituted
N!nitrosooxazolidones "Equation "019## ð57JA3078\ 58JA5350\ 58JOC0119\ 62JOC436\ 63JOC650Ł^ "iii# from
vinyl tri~ates and potassium t!butoxide\ this method being the superior choice in terms of yield\
simplicity\ and ~exibility "Equation "010## ð63JA3451\ 64CC06\ 64JA0348\ 64JA2743\ 64JA5367Ł[ The
required tri~ates can be obtained from the corresponding aldehydes via their trimethylsilyl enol
ethers[ The geometry of the starting tri~ate does not a}ect the product distribution\ suggesting an
identical and symmetrical intermediate is being formed[ Small amounts of the t!butyl ethers always
accompany the major products[ Deuterium incorporation ð63JA3451Ł and trapping experiments
ð64CC06Ł also provide evidence for the intermediacy of a methylene carbene in the above reactions[
The ground state has been assigned a singlet multiplicity ð64JA0348\ 66JA1808\ 67JA5829Ł\ and the
carbenes generated by the above methods appear electrophilic in character ð61JOC0442\ 63JA3451Ł\
comparable to the dihalocarbenes[
THF
+ KOBut + (119)
Cl
O O
+ Ar (120)
N
NO Ar
OTf KOBut
OBut Et OBut
+ + + + (121)
Et –20 °C, 36 h Et Et Et
42% 32% 19% 7%
Photolysis of arylsubstituted methylenecyclopropanes has been found to generate methylene

carbenes by fragmentation "Equation "011## ð69JA6382\ 69JA6595Ł[ Methylenecyclopropane will
undergo mercury!sensitised photofragmentation to ethene and ethyne ð57JPC210Ł\ whilst organo!
mercurial "040# undergoes photolysis to generate the dichloromethylene carbene "041# "Scheme 093#
ð57TL492Ł[
hν
+ (122)
Ph
Ph
Methylene carbenes\ once formed\ undergo a number of reactions\ of which the most important
are alkyne formation\ insertion reactions\ addition to alkenes and coupling reactions[
Alkyne formation occurs readily when aryl substituents are present\ and hydrogen migration is
also very rapid ð61JA0467\ 61JA6751Ł\ although with aliphatic and halogen substituents the reaction
Cl HgPh Cl Cl
hν
:
Cl Cl Cl Cl
(151) (152)
Scheme 104
is slowed to such an extent that only minor amounts of alkynic products are obtained[ The
cyclopropyl group is intermediate in its migratory aptitude "Scheme 094# ð61JOC2119Ł[
R R
O O OR– R
:
N
NO
Scheme 105
In the FritschÐButtenbergÐWiechell rearrangement ð54AG"E#38Ł\ a 0\0!diaryl!1!chloroethylene

"042# rearranges to a diarylethyne on treatment with sodium ethoxide in ethanol at 079Ð199>C^
the mechanism was originally proposed to proceed via a vinylidene carbene "043# "Scheme 095#
ð0783LA"168#208\ 0783LA"168#213\ 0783LA"168#226Ł[ Alkali metal amides in liquid ammonia ð25JA1209Ł\
and metal alkyls in nonpolar solvents ð48JA3603\ 56CB1900Ł also induce this rearrangement[ Work in
the early 0859s has demonstrated that a vinyl carbanion intermediate is more probable ð44JA2182\
59JPS0160\ 50G778\ 52G646\ 52JA1162Ł^ in fact\ in diethyl ether\ halovinyllithium compounds generated
by this method can be trapped as their carboxylation derivatives on treatment with CO1
ð52ZN"B#0014Ł[ MetalÐhalogen exchange may compete with metalÐhydrogen exchange\ but only
when the halogen is bromine or iodine ð48JA3603Ł[ Other factors which govern metalÐhydrogen vs[
metalÐhalogen exchange are the choice of metal alkyl\ salt e}ects and the substituents present in the
aryl groups ð48JA3603\ 48JA3608Ł[
Ar Ar δ+
–
Ar Ar
Ar X Ar X δ–
Ar X
(153) (154)
Scheme 106
Insertion reactions of methylene carbenes occur on reaction with trialkylsilanes^ insertion into
the Si0H bond gives vinyl silanes as products "Scheme 096# ð69JA3298\ 69JA3201Ł[ Insertion into CH
bonds is also possible in some cases ð54JA0031\ 57TL492\ 69JA6382Ł\ although intramolecular insertion
reactions appear to occur more readily into C0H bonds a to heteroatoms ð69JOC0975Ł[
R
R R R SiEt3
LiOR Et3SiH
:
O N
NO R R
O
Scheme 107
A number of examples of additions of methylene carbenes to alkenes to give methylene!

cyclopropanes have already been mentioned\ as has the apparent electrophilic character of these
intermediates[ Higher yields of addition products are obtained with vinyl ethers than with hydro!
carbon alkenes ð53JA415\ 58JOC0119Ł[ In addition to electronic e}ects\ steric e}ects also in~uence the
addition reaction\ with cyclohexene reacting 49 times faster than tetramethylethene[ Coupling
reactions are found to occur in those methylene carbenes where rearrangements to alkynes are
Vinylidene Carbenes 0034
sterically unfavourable "Scheme 097# ð46JOC0137\ 48JA3608\ 53AG"E#540\ 54AG84\ 56T454Ł[ The enolate
anions derived from b!dicarbonyl compounds react with either ethynyl"phenyl#iodonium tetra!
~uoroborate or with ethynyl!lead tetraacetate to give the corresponding a!ethynyl!0\2!dicarbonyl
compounds ð78JCS"P0#222\ 89CC007Ł[ When the tetra~uoroborate reagent is employed\ the reaction is
thought to proceed by way of a 0\1!hydrogen migration of an alkylidenecarbene intermediate
"Scheme 098#[
Cl
: • •
Scheme 108
:
H
O
base
+ I+ BF4– O O
O O O O O O
Scheme 109
The stabilisation of a reactive intermediate by complexation to a metal centre has been exploited
for many systems over the years\ and this is also the case for vinylidene carbenes ð80CRV086Ł[ The
most commonly exploited metal centres include Mo\ Fe\ Pd\ Rh\ Ru\ Ir and Os[ Several methods
have been employed for the preparation of these complexes] "i# from 0!alkynes via a formal
0\1!hydrogen shift^ "ii# by addition of electrophiles to metal alkynyl complexes^ "iii# by deprotonation
of carbyne complexes^ and "iv# by formal dehydration of acyl complexes[ Alkenes\ preformed vinyl
complexes\ and disubstituted alkynes have been utilised as precursors^ transfer of vinylidene ligands
between metal centres and modi_cation of existing vinylidene ligands are reactions that have also
been reported ð80CRV086Ł[ The metal complexes once formed\ can undergo a variety of reactions\
including electrophilic or nucleophilic attack\ oxidations\ cycloaddition reactions or dis!
proportionation[
Finally\ mention should be made of extended unsaturated carbenes or cumylenylidenes which
have received attention as reactive intermediates[ They are generated in a similar way\ by base!
catalysed a!elimination of tri~ates with KOBut as was mentioned for the parent methylene carbenes
ð68JA3881\ 79JA5702\ 70JA4318Ł\ and they undergo similar reactions to that of the parent compound\
such as insertion reactions and addition to alkenes[
References to Volume 1
EXPLANATION OF THE REFERENCE SYSTEM
Throughout this work\ references are designated by a numberÐlettering coding of which the _rst
two numbers denote tens and units of the year of publication\ the next one to three letters denote
the journal\ and the _nal numbers denote the page[ This code appears in the text each time a
reference is quoted^ the advantages of this system are outlined in the Introduction[ The system has
been used previously in {{Comprehensive Heterocyclic Chemistry\|| eds A[ R[ Katritzky and C[ W[
Rees\ Pergamon\ Oxford\ 0873 and is based on that used in the following two monographs] "a# A[ R[
Katritzky and J[ M[ Lagowski\ {{Chemistry of the Heterocyclic N!Oxides\|| Academic Press\
New York\ 0860^ "b# J[ Elguero\ C[ Marzin\ A[ R[ Katritzky and P[ Linda\ {{The Tautomerism of
Heterocycles\|| in {{Advances in Heterocyclic Chemistry\|| Supplement 0\ Academic Press\ New
York\ 0865[
The following additional notes apply]
0[ A list of journal codes in alphabetical order\ together with the journals to which they refer\ is
given immediately following these notes[ Journal names are abbreviated throughout using the
CASSI "Chemical Abstracts Service Source Index# system[
1[ Each volume contains all the references cited in that volume^ no separate lists are given for
individual chapters[
2[ The list of references is arranged in order of "a# year\ "b# journal in alphabetical order of
journal code\ "c# part letter or number if relevant\ "d# volume number if relevant\ "e# page number[
3[ In the reference list the code is followed by "a# the complete literature citation in the con!
ventional manner and "b# the number"s# of the page"s# on which the reference appears\ whether in
the text or in tables\ schemes\ etc[
4[ For nontwentieth!century references the year is given in full in the code[
5[ For journals which are published in separate parts\ the part letter or number is given "when
necessary# in parentheses immediately after the journal code letters[
6[ Journal volume numbers are not included in the code numbers unless more than one volume
was published in the year in question\ in which case the volume number is included in parentheses
immediately after the journal code letters[
7[ Patents are assigned appropriate three!letter codes[
8[ Frequently cited books are assigned codes[
09[ Less common journals and books are given the code {{MI|| for miscellaneous with the whole
code for books pre_xed by the letter {{B!||[
00[ Where journals have changed names\ the same code is used throughout\ e[g[ CB refers to
both Chem[ Ber[ and to Ber[ Dtsch[ Chem[ Ges[
Journal Codes
AAC Antimicrob[ Agents Chemother[
ABC Agric[ Biol[ Chem[
AC Appl[ Catal[
AC"P# Ann[ Chim[ "Paris#
AC"R# Ann[ Chim[ "Rome#
ACH Acta Chim[ Acad[ Sci[ Hung[
0036
0037 References
ACR Acc[ Chem[ Res[

ACS Acta Chem[ Scand[
ACS"A# Acta Chem[ Scand[\ Ser[ A
ACS"B# Acta Chem[ Scand[\ Ser[ B
AF Arzneim[!Forsch[
AFC Adv[ Fluorine Chem[
AG Angew[ Chem[
AG"E# Angew[ Chem[\ Int[ Ed[ Engl[
AHC Adv[ Heterocycl[ Chem[
AHCS Adv[ Heterocycl[ Chem[ Supplement
AI Anal[ Instrum[
AJC Aust[ J[ Chem[
AK Ark[ Kemi
AKZ Arm[ Khim[ Zh[
AM Adv[ Mater[ "Weinheim\ Ger[#
AMLS Adv[ Mol[ Spectrosc[
AMS Adv[ Mass[ Spectrom[
ANC Anal[ Chem[
ANL Acad[ Naz[ Lncei
ANY Ann[ N[ Y[ Acad[ Sci[
AOC Adv[ Organomet[ Chem[
AP Arch[ Pharm[ "Weinheim\ Ger[#
APO Adv[ Phys[ Org[ Chem[
AQ An[ Quim[
AR Annu[ Rep[ Prog[ Chem[
AR"A# Annu[ Rep[ Prog[ Chem[\ Sect[ A
AR"B# Annu[ Rep[ Prog[ Chem[\ Sect[ B
ARP Annu[ Rev[ Phys[ Chem[
ASI Acta Chim[ Sin[ Engl[ Ed[
ASIN Acta Chim[ Sin[
AX Acta Crystallogr[
AX"A# Acta Crystallogr[\ Part A
AX"B# Acta Crystallogr[\ Part B
B Biochemistry
BAP Bull[ Acad[ Pol[ Sci[\ Ser[ Sci[ Chim[
BAU Bull[ Acad[ Sci[ USSR\ Div[ Chim[ Sci[
BBA Biochim[ Biophys[ Acta
BBR Biochim[ Biophys[ Res[ Commun[
BCJ Bull[ Chem[ Soc[ Jpn[
BEP Belg[ Pat[
BJ Biochem[ J[
BJP Br[ J[ Pharmacol[
BMC Bioorg[ Med[ Chem[ Lett[
BP Biochem[ Biopharmacol[
BPJ Br[ Polym[ J[
BRP Br[ Pat[
BSB Bull[ Soc[ Chim[ Belg[
BSF Bull[ Soc[ Chim[ Fr[
BSF"1# Bull[ Soc[ Chim[ Fr[\ Part 1
C Chimia
CA Chem[ Abstr[
CAN Cancer
CAR Carbohydr[ Res[
CAT Chim[ Acta Turc[
CB Chem[ Ber[
References 0038
CBR Chem[ Br[

CC J[ Chem[ Soc[\ Chem[ Commun[
CCA Croat[ Chem[ Acta
CCC Collect[ Czech[ Chem[ Commun[
CCR Coord[ Chem[ Rev[
CE Chem[ Express
CEN Chem[ Eng[ News
CHE Chem[ Heterocycl[ Compd[ "Engl[ Transl[#
CHEC Comp[ Heterocycl[ Chem[
CI"L# Chem[ Ind[ "London#
CI"M# Chem[ Ind[ "Milan#
CJC Can[ J[ Chem[
CJS Can[ J[ Spectrosc[
CL Chem[ Lett[
CLY Chem[ Listy
CM Chem[ Mater[
CMC Comp[ Med[ Chem[
COC Comp[ Org[ Chem[
COMC!I Comp[ Organomet[ Chem[\ 0st edn[
COS Comp[ Org[ Synth[
CP Can[ Pat[
CPB Chem[ Pharm[ Bull[
CPH Chem[ Phys[
CPL Chem[ Phys[ Lett[
CR C[ R[ Hebd[ Seances Acad[ Sci[
CR"A# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ A
CR"B# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ B
CR"C# C[ R[ Hebd[ Seances Acad[ Sci[\ Ser[ C
CRAC Crit[ Rev[ Anal[ Chem[
CRV Chem[ Rev[
CS Chem[ Scr[
CSC Cryst[ Struct[ Commun[
CSR Chem[ Soc[ Rev[
CT Chem[ Tech[
CZ Chem[!Ztg[
CZP Czech[ Pat[
DIS Diss[ Abstr[
DIS"B# Diss[ Abstr[ Int[ B[
DOK Dokl[ Akad[ Nauk SSSR
DP Dyes Pigm[
E Experientia
EC Educ[ Chem[
EF Energy Fuels
EGP Ger[ "East# Pat[
EJM Eur[ J[ Med[ Chem[
EUP Eur[ Pat[
FCF Forschr[ Chem[ Forsch[
FCR Fluorine Chem[ Rev[
FES Farmaco Ed[ Sci[
FOR Forschr[ Chem[ Org[ Naturst[
FRP Fr[ Pat[
G Gazz[ Chim[ Ital[
GAK Gummi Asbest Kunstst[
GEP Ger[ Pat[
GEP"O# Ger[ Pat[ O}en[
0049 References
GSM Gen[ Synth[ Methods

H Heterocycles
HAC Heteroatom Chem[
HC Chem[ Heterocycl[ Compd[
HCA Helv[ Chim[ Acta
HOU Methoden Org[ Chem[ "Houben!Weyl#
HP Hydrocarbon Process
IC Inorg[ Chem[
ICA Inorg[ Chim[ Acta
IEC Ind[ Eng[ Chem[ Res[
IJ Isr[ J[ Chem[
IJC Indian J[ Chem[
IJC"A# Indian J[ Chem[\ Sect[ A
IJC"B# Indian J[ Chem[\ Sect[ B
IJM Int[ J[ Mass Spectrom[ Ion Phys[
IJQ Int[ J[ Quantum Chem[
IJS Int[ J[ Sulfur Chem[
IJS"A# Int[ J[ Sulfur Chem[\ Part A
IJS"B# Int[ J[ Sulfur Chem[\ Part B
IS Inorg[ Synth
IZV Izv[ Akad[ Nauk SSSR Ser[ Khim[
JA J[ Am[ Chem[ Soc[
JAN J[ Antibiot[
JAP Jpn[ Pat[
JAP"K# Jpn[ Kokai
JBC J[ Biol[ Chem[
JC J[ Chromatogr[
JCC J[ Coord[ Chem[
JCE J[ Chem[ Ed[
JCED J[ Chem[ Eng[ Data
JCI J[ Chem[ Inf[ Comput[ Sci[
JCP J[ Chem[ Phys[
JCPB J[ Chim[ Phys[ Physico!Chim[ Biol[
JCR"M# J[ Chem[ Res[ "M#
JCR"S# J[ Chem[ Res[ "S#
JCS J[ Chem[ Soc[
JCS"A# J[ Chem[ Soc[ "A#
JCS"B# J[ Chem[ Soc[ "B#
JCS"C# J[ Chem[ Soc[ "C#
JCS"D# J[ Chem[ Soc[\ Dalton Trans[
JCS"F0# J[ Chem[ Soc[\ Faraday Trans[ 0
JCS"F1# J[ Chem[ Soc[\ Faraday Trans[ 1
JCS"P0# J[ Chem[ Soc[\ Perkin Trans[ 0
JCS"P1# J[ Chem[ Soc[\ Perkin Trans[ 1
JCS"S1# J[ Chem[ Soc[ "Suppl[ 1#
JEC J[ Electroanal[ Chem[ Interfacial Electrochem[
JEM J[ Energy Mater[
JES J[ Electron[ Spectrosc[
JFA J[ Sci[ Food[ Agri[
JFC J[ Fluorine Chem[
JGU J[ Gen[ Chem[ USSR "Engl[ Transl[#
JHC J[ Heterocycl[ Chem[
JIC J[ Indian Chem[ Soc[
JINC J[ Inorg[ Nucl[ Chem[
JLC J[ Liq[ Chromatogr[
References 0040
JMAS J[ Mat[ Sci[

JMC J[ Med[ Chem[
JMOC J[ Mol[ Catal[
JMR J[ Magn[ Reson[
JMS J[ Mol[ Sci[
JOC J[ Org[ Chem[
JOM J[ Organomet[ Chem[
JOU J[ Org[ Chem[ USSR "Engl[ Transl[#
JPC J[ Phys[ Chem[
JPJ J[ Pharm[ Soc[ Jpn[
JPO J[ Phys[ Org[ Chem[
JPP J[ Pharm[ Pharmacol[
JPR J[ Prakt[ Chem[
JPS J[ Pharm[ Sci[
JPS"A# J[ Polym[ Sci[\ Polym[ Chem[\ Part A
JPU J[ Phys[ Chem[ USSR "Engl[ Transl[#
JSC J[ Serbochem[ Soc[
JSP J[ Mol[ Spectrosc[
JST J[ Mol[ Struct[
K Kristallogra_ya
KFZ Khim[ Farm[ Zh[
KGS Khim[ Geterotsikl[ Soedin[
KO Kirk!Othmer Encyc[
KPS Khim[ Prir[ Soedin[
L Langmuir
LA Liebigs Ann[ Chem[
LC Liq[ Cryst[
LS Life Sci[
M Monatsh[ Chem[
MAC Macromol[ Chem[
MC Mendeleev Chem[ J[ "Engl[ Transl[#
MCLC Mol[ Cryst[ Liq[ Cryst[
MI Miscellaneous ðbook:journalŁ
MIP Miscellaneous Pat[
MM Macromolecules
MP Mol[ Phys[
MRC Magn[ Reson[ Chem[
N Naturwissenschaften
NAT Nat[
NEP Neth[ Pat[
NJC Nouv[ J[ Chim[
NKK Nippon Kagaku Kaishi "J[ Chem[ Soc[ Jpn[#
NKZ Nippon Kagaku Zasshi
NZJ N[ Z[ J[ Sci[ Technol[
OCS Organomet[ Synth[
OM Organometallics
OMR Org[ Magn[ Reson[
OMS Org[ Mass Spectrom[
OPP Org[ Prep[ Proced[ Int[
OR Org[ React[
OS Org[ Synth[
OSC Org[ Synth[\ Coll[ Vol[
P Phytochemistry
PA Polym[ Age
PAC Pure Appl[ Chem[
0041 References
PAS Pol[ Acad[ Sci[

PB Polym[ Bull[
PC Personal Communication
PCS Proc[ Chem[ Soc[
PHA Pharmazi
PHC Prog[ Heterocycl[ Chem[
PIA Proc[ Indian Acad[ Sci[
PIA"A# Proc[ Indian Acad[ Sci[\ Sect[ A
PJC Pol[ J[ Chem[
PJS Pak[ J[ Sci[ Ind[ Res[
PMH Phys[ Methods Heterocycl[ Chem[
PNA Proc[ Natl[ Acad[ Sci[ USA
POL Polyhedron
PP Polym[ Prepr[
PRS Proceed[ Roy[ Soc[
PS Phosphorus Sulfur
QR Q[ Rev[\ Chem[ Soc[
QRS Quart[ Rep[ Sulfur[ Chem[
QSAR Quant[ Struct[ Act[ Relat[ Pharmacol[ Chem[ Biol[
RC Rubber Chem[ Technol[
RCM Rapid Commun[ Mass Spectrom[
RCP Rec[ Chem[ Prog[
RCR Russ[ Chem[ Rev[ "Engl[ Transl[#
RHA Rev[ Heteroatom Chem[
RJ Rubber J[
RP Rev[ Polarogr[
RRC Rev[ Roum[ Chim[
RS Ric[ Sci[
RTC Recl[ Trav[ Chim[ Pays!Bas
RZC Rocz[ Chem[
S Synthesis
SA Spectrochim[ Acta
SA"A# Spectrochim[ Acta\ Part A
SAP S[ Afr[ Pat[
SC Synth[ Commun[
SCI Science
SL Synlett
SM Synth[ Met[
SR Sulfur Reports
SRI Synth[ React[ Inorg[ Metal!Org[ Chem[
SS Sch[ Sci[ Rev[
SST Org[ Compd[ Sulphur\ Selenium\ Tellurium ðR[ Soc[ Chem[ seriesŁ
SUL Sulfur Letters
SZP Swiss Pat[
T Tetrahedron
T"S# Tetrahedron\ Suppl[
TA Tetrahedron Asymmetry
TAL Talanta
TCA Theor[ Chim[ Acta
TCC Top[ Curr[ Chem[
TCM Tetrahedron\ Comp[ Method
TFS Trans[ Faraday Soc[
TH Thesis
TL Tetrahedron Lett[
TS Top[ Stereochem[
References 0042
UK Usp[ Khim[
UKZ Ukr[ Khim[ Zh[ "Russ[ Ed[#
UP Unpublished Results
URP USSR Pat[
USP US Pat[
WCH Wiadom[ Chem[
YGK Yuki Gosei Kagaku Kyokaishi
YZ Yakugaku Zasshi "J[ Pharm[ Soc[ Jpn[#
ZAAC Z[ Anorg[ Allg[ Chem[
ZAK Zh[ Anal[ Khim[
ZC Z[ Chem[
ZN Z[ Naturforsch[
ZN"A# Z[ Naturforsch[\ Teil A
ZN"B# Z[ Naturforsch[\ Teil B
ZOB Zh[ Obshch[ Khim[
ZOR Zh[ Org[ Khim[
ZPC HoppeÐSeyler|s Z[ Physiol[ Chem[
ZPK Zh[ Prikl[ Khim[
VOLUME 0 REFERENCES
0740LA"67#142 A[ W[ Hofmann^ Justus Liebi`s Ann[ Chem[\ 0740\ 67\ 142[ 516
0745MI 008!90 R[ Piria^ Ann[ Chim[ Phys\ 0745\ 37\ 002[ 772
0759LA"003#43 R[ Fittig^ Justus Liebi`s Ann[ Chem[\ 0759\ 003\ 43[ 273
0758CB311 C[ Glaser^ Ber[ Dtsch[ Chem[ Ges[\ 0758\ 1\ 311[ 0031
0769LA"043#026 C[ Glaser^ Justus Liebi`s Ann[ Chem[\ 0769\ 043\ 026[ 093
0763CB241 M[ P[ von Wilde^ Ber[ Dtsch[ Chem[ Ges[\ 0763\ 6\ 241[ 60
0772CB1197 A[ Einhorn^ Ber[ Dtsch[ Chem[ Ges[\ 0772\ 05\ 1197[ 674
0772LA"107#034 T[ Komnenos^ Justus Liebi`s Ann[ Chem[\ 0772\ 107\ 034[ 295
0773AC"P#338 C[ Friedel and J[ M[ Crafts^ Ann[ Chim[ Phys[ 0773\ 0\ 338[ 351
0776JPR238 A[ Michael^ J[ Prakt[ Chem[\ 0776\ 24\ 238[ 295

0776MI 096!90 A[ Michael^ Am[ Chem[ J[\ 0776\ 8\ 004[ 295
0780CB2097 G[ Merling^ Ber[ Dtsch[ Chem[ Ges[\ 0780\ 13\ 2097[ 895
0783LA"168#208 P[ Fritsch^ Justus Liebi`s Ann[ Chem[\ 0783\ 168\ 208[ 0033
0783LA"168#213 W[ P[ Buttenberg^ Justus Liebi`s Ann[ Chem[\ 0783\ 168\ 213[ 0033
0783LA"168#226 H[ Wiechell^ Justus Liebi`s Ann[ Chem[\ 0783\ 168\ 226[ 0033
0783MI 098!90 A[ E[ Favorskii^ Zh[ Russ[ Fiz[!Khim[ O!va[\ 0783\ 15\ 445[ 280
0784MI 092!90 F[ B[ Ahrens^ Z[ Elektrochem[\ 0784\ 1\ 466[ 092
0786MI 092!90 P[ Sabatier and J[ B[ Senderens^ Compt[ Rend[\ 0786\ 013\ 0247[ 60
0787CB0442 W[ Wernick and R[ Wol}enstein^ Ber[ Dtsch[ Chem[ Ges[\ 0787\ 20\ 0442[ 512
0788CB1296 G[ Wagner and W[ Brickner^ Ber[ Dtsch[ Chem[ Ges[\ 0788\ 21\ 1296[ 279
99CB2049 M[ Gomberg^ Ber[ Dtsch[ Chem[ Ges[\ 0899\ 22\ 2049[ 808
99JA646 M[ Gomberg^ J[ Am[ Chem[ Soc[\ 0899\ 11\ 646[ 808
91CB1907 P[ Walden^ Ber[ Dtsch[ Chem[ Ges[\ 0891\ 24\ 1907[ 787
91CB1286 M[ Gomberg^ Ber[ Dtsch[ Chem[ Ges[\ 0891\ 24\ 1286[ 789\ 787
91CB2920 A[ Baeyer and V[ Villiger^ Ber[ Dtsch[ Chem[ Ges[\ 0891\ 24\ 2920[ 786
0043 References
93BSF090 P[ Sabatier and J[ B[ Senderens^ Bull[ Soc[ Chim[ Fr[\ 0893\ 20\ 090[ 76
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96CB3848 N[ J[ Demjanow^ Ber[ Dtsch[ Chem[ Ges[\ 0896\ 39\ 3848[ 272
09CB0417 H[ Finkelstein^ Ber[ Dtsch[ Chem[ Ges[\ 0809\ 32\ 0417[ 096
00CB1023 H[ Thoms and W[ Siebling^ Ber[ Dtsch[ Chem[ Ges[\ 0800\ 33\ 1023[ 321
01CB2046 L[ Claisen^ Ber[ Dtsch[ Chem[ Ges[\ 0801\ 34\ 2046[ 303\ 714
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02CB0726 E[ Clemmensen^ Ber[ Dtsch[ Chem[ Ges[\ 0802\ 35\ 0726[ 07
03BSF117 P[ Sabatier and L[ Espil^ Bull[ Soc[ Chim[ Fr[\ 0803\ 04\ 117[ 76
05CB14 H[ Rope and M[ Iselin^ Ber[ Dtsch[ Chem[ Ges[\ 0805\ 38\ 14[ 358
05CB1111 W[ Borsche^ L[ Stackmann and J[ Makaro}!Semijanski^ Ber[ Dtsch[ Chem[ Ges[\ 0805\ 38\
1111[ 363
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19MI 009!90 F[ Swarts^ Bull[ Acad[ Res[ Bel`[\ 0819\ 288[ 315
10JPR0 F[ Straus and A[ Dutzmann^ J[ Prakt[ Chem[\ 0810\ 092\ 0[ 787
11CB0859 B[ Nybergh^ Ber[ Dtsch[ Chem[ Ges[\ 0811\ 44\ 0859[ 273
11CB1499 H[ Meerwein and K[ Van Emster^ Ber[ Dtsch[ Chem[ Ges[\ 0811\ 44\ 1499[ 279
12LA"323#23 K[ Ziegler^ Justus Liebi`s Ann[ Chem[\ 0812\ 323\ 23[ 890
13CB0523 P[ Schorigin^ Ber[ Dtsch[ Chem[ Ges[\ 0813\ 46\ 0523[ 285\ 286
13LA"326#0 J[ Bredt^ Justus Liebi`s Ann[ Chem[\ 0813\ 326\ 0[ 742
14CB1917 P[ Schorigin^ Ber[ Dtsch[ Chem[ Ges[\ 0814\ 47\ 1917[ 285
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15MI 093!90 B[ V[ Tronov and E[ A[ Kruger^ J[ Russ[ Phys[!Chem[ Soc[\ 0815\ 47\ 0169^ Chem[ Abstr[\
0816\ 10\ 2776[ 096
16CB849 J[ Loevenich\ J[ Losen and A[ Dierichs^ Ber[ Dtsch[ Chem[ Ges[\ 0816\ 59\ 849[ 0954
17CB0649 K[ Freudenberg\ H[ Toep}er and C[ C[ Andersen^ Ber[ Dtsch[ Chem[ Ges[\ 0817\ 50\ 0649[ 10
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18JA0380 F[ C[ Whitmore and E[ N[ Thurman^ J[ Am[ Chem[ Soc[\ 0818\ 40\ 0380[ 017
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29JCS694 G[ W[ Fenton and C[ K[ Ingold^ J[ Chem[ Soc[\ 0829\ 694[ 501

29JCS1096 T[ S[ Stevens^ J[ Chem[ Soc[\ 0829\ 1096[ 287
29JCS1060 D[ A[ Ainley and F[ G[ Challenger^ J[ Chem[ Soc[\ 0829\ 1060[ 336
20CB1432 E[ Benary^ Ber[ Dtsch[ Chem[ Ges[\ 0820\ 53\ 1432 "Chem[ Abstr[\ 0821\ 15\ 319#[ 375
20JA3081 H[ Gilman\ A[ P[ Hewlett and G[ F[ Wright^ J[ Am[ Chem[ Soc[\ 0820\ 42\ 3081[ 0932
21JA0101 J[ B[ Conant and G[ W[ Wheland^ J[ Am[ Chem[ Soc[\ 0821\ 43\ 0101[ 737\ 758
21JA3955 W[ H[ Carothers\ G[ J[ Berchet and A[ M[ Collins^ J[ Am[ Chem[ Soc[\ 0821\ 43\ 3955[ 854
21JCS44 T[ Thomson and T[ S[ Stevens^ J[ Chem[ Soc[\ 0821\ 44[ 287
21JCS58 T[ Thomson and T[ S[ Stevens^ J[ Chem[ Soc[\ 0821\ 58[ 288
21JCS0815 J[ L[ Dunn and T[ S[ Stevens^ J[ Chem[ Soc[\ 0821\ 0815[ 287
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22JCS0460 E[ D[ Hughes and C[ K[ Ingold^ J[ Chem[ Soc[\ 0822\ 0460[ 780
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23JA336 C[ T[ Hurd and H[ T[ Bollman^ J[ Am[ Chem[ Soc[\ 0823\ 45\ 336[ 797
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References 0044
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25CB771 A[ Butenandt\ J[ Schmidt!Thome^ Ber[ Dtsch[ Chem[ Ges[\ 0825\ 58\ 771[ 684
25CB1095 C[ Mannich and H[ Davidsen^ Ber[ Dtsch[ Chem[ Ges[\ 0825\ 58\ 1095[ 71
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63AG"E#191 D[ Seebach and K[!H[ Geiss^ Anèw[ Chem[\ Int[ Ed[ En`l[\ 0863\ 02\ 191[ 039
63AG"E#396 K[ Kondo\ A[ Negishi and D[ Tunemoto^ Anèw[ Chem[\ Int[ Ed[ En`l[\ 0863\ 02\ 396[ 048
63AG"E#314 G[ Maier^ Anèw[ Chem[\ Int[ Ed[ En`l[\ 0863\ 02\ 314[ 678
63AG"E#357 W[ Bannwarth\ R[ Eidenschink and T[ Kau}mann^ Anèw[ Chem[\ Int[ Ed[ En`l[\ 0863\
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63AG"E#368 K[ Geiss\ B[ Seuring\ R[ Pieter and D[ Seebach^ Anèw[ Chem[\ Int[ Ed[ En`l[\ 0863\ 02\ 368[ 039\ 030
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(Alan R. Katritzky, Otto Meth-Cohn, and Charles W.

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Comprehensive Organic Functional

Part I: Tetracoordinated Carbon with No Attached Heteroatoms

Part II: Tricoordinated Carbon with No Attached Heteroatoms

1.13 One or More C=C Bond(s) by Elimination of Hydrogen, Carbon, Halogen or

Part III: Dicoordinate and Monocoordinate Carbon with No Attached

1.21 Alkynes, Pages 997-1085, Mark Furber

Volume 1. Synthesis: Carbon with No Attached Heteroatoms

Volume 2. Synthesis: Carbon with One Heteroatom Attached by a Single Bond

Volume 3. Synthesis: Carbon with One Heteroatom Attached by a Multiple Bond

Volume 6. Synthesis: Carbon with Three or Four Attached Heteroatoms

OTTO METH-COHN CHARLES W. REES

VOLUME 1 SYNTHESIS: CARBON WITH NO ATTACHED HETEROATOMS

VOLUME 2 SYNTHESIS: CARBON WITH ONE HETEROATOM ATTACHED BY A

VOLUME 3 SYNTHESIS: CARBON WITH ONE HETEROATOM ATTACHED BY A

VOLUME 4 SYNTHESIS: CARBON WITH TWO HETEROATOMS, EACH ATTACHED

VOLUME 5 SYNTHESIS: CARBON WITH TWO ATTACHED HETEROATOMS WITH AT

VOLUME 6 SYNTHESIS: CARBON WITH THREE OR FOUR ATTACHED

0[90[0 REDUCTION OF C0HALOGEN BONDS TO CH

0[90[0[0 General Methods

AcO Pd–C AcO

a!Haloketones are readily dehalogenated with no competing carbonyl reduction ð47JOC0827\

i, LiI, BF3•Et2O, THF

0[90[0[2 Reduction of Chloroalkanes

O i, LiI, BF3•OEt2, THF O

0[90[0[3 Reduction of Bromoalkanes

AcO N N AIBN AcO N N

i, NaI, TMS-Cl, MeCN

0[90[0[4 Reduction of Iodoalkanes

0[90[1 REDUCTION OF C0OXYGEN BONDS TO CH

0[90[1[0 General Methods

AcO Pd–C AcO

0[90[1[1 Reduction of C0OX Bonds

0[90[1[1[0 Reduction of C0OH bonds

i, TMS-Cl, NaI, MeCN

0[90[1[1[1 Reduction of C0O0C bonds

"i# Reduction of oxiranes

"ii# Reduction of other ethers

"iii# Reduction of esters

"iv# Reduction of thionoethers

0[90[1[1[2 Reduction of C0O0heteroatom bonds

0[90[1[2[0 Reduction of aldehydes

EtOH, H2O Me2N

0[90[1[2[1 Reduction of ketones

0[90[1[3 Reduction of "C1O#X to CH2

CO2H i, SiHCl3, MeCN

iii, KOH, (aq.) MeOH

iii, KOH, (aq.) MeOH

0[90[1[4 Reduction of C"OX#n Systems

0[90[2 REDUCTION OF C0SULFUR\ C0SELENIUM AND C0TELLURIUM BONDS TO

0[90[2[0 General Methods

0[90[2[1 Reduction of C0SX Bonds

SePh Ra-Ni, EtOH

SePh Ph3SnH, PhMe, ∆

0[90[2[2 Reduction of C1S to CH1

0[90[2[3 Reduction of C"1S#X to CH2

0[90[2[4 Reduction of C"SX#n Systems

SMe Ra-Ni, EtOH

0[90[2[5 Reduction of C0Se Systems

0[90[2[6 Reduction of C0Te Systems

C10H21 SeMe Ra-Ni, EtOH, ∆

SePh Ph3SnH, PhMe, ∆

0[91[1 REDUCTION OF CARBONÐPHOSPHORUS\ ÐANTIMONY AND ÐBISMUTH BONDS

0[91[3 REDUCTION OF CARBONÐBORON\ ÐSILICON AND ÐGERMANIUM BONDS