Deoxygenation of

Aliphatic Alcohols
Caitlin McMahon
Alexanian Group Meeting
June 12, 2014

Importance of Deoxygenation
Ubiquitous in total synthesis & modification of natural products
Deoxygenation in synthesis of potent insecticide (functional group tolerant)

Deoxygenation/elimination in Mukaiyamas Taxol synthesis

Frank, S. A.; Roush, W. R. J. Org. Chem. 2002, 67, 43164324.

Mukaiyama, T., et al; Chem. Eur. J. 1999, 5, 121161.

Importance of Deoxygenation
Carbohydrate & aminoglycoside chemistry
Enzymes deactivate hydroxy-group of antibiotics

Deoxygenation of nucleosides

Deoxygenations of carbohydrates often used to obtain

intermediates from the chiral pool

Arya, D. P. Aminoglycoside Antibiotics: From Chemical Biology to Drug Discovery; 2007
Saito, I., et al J. Am. Chem. Soc. 1986, 108, 31153117.

Outline
Overview of historical methods of deoxygenation
Barton-McCombie Deoxygenation & Variations
Photochemical Deoxygenation

Direct Deoxygenation
Areas for exploration

Methods of Deoxygenation
Challenge: Strong C-O bond (85-91 kcal/mol)

Herrmann, J. M.; Knig, B. Eur. J. Org. Chem. 2013, 2013, 70177027.

Historical Methods & Limitations

Conversion to alcohol derivatives

Conversion to halide or thiolate

Dehydration

reduction

reduction

hydrogenation

Substitution reactions limited to 1 alcohols

(or unhindered 2)
Rearrangements and undesired eliminations common
Hartwig, W. Tetrahedron 1983, 39, 26092645.

Benchmark Discovery
Barton-McCombie Deoxygenation (1975)

Derek H.R. Barton

1918-1998
Imperial College
Nobel Laureate (1969)

Widely utilized
Radical mechanism avoids elimination and

rearrangement pathways
Barton, D. H. R.; McCombie, S. W. J. Chem. Soc. [Perkin 1] 1975, 15741585.

Stuart W. McCombie
Imperial College
(Post-doc)

Limitations & Drawbacks

Problems
Organotin hydrides are toxic
Organotin hydrides are expensive
Tin byproducts are difficult to separate from products

Solution
Make it catalytic in tin

Solution
Use different H-source

Issues with stability with 3 xanthates

McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. In Organic Reactions; John Wiley & Sons, Inc., 2004.

Improving the Barton Deoxygenation

Alternative H-donors
Silanes

Phosphines

Hypophosphorous acid

Barton, D. H. R.; et al Tetrahedron Lett. 1990, 31, 4681-4684.

Barton, D. H. R.; Jacob, M. Tetrahedron Lett. 1998, 39, 13311334.
Izawa, K. et al Tetrahedron Lett. 2001, 42, 76057608.

Improving the Barton Deoxygenation

Alternative H-donors
Diphenylphosphine oxide

Borane/H2O

Jang, D.; HyanCho, D.; Kim, J. Synth. Commun. 1998, 28, 35593565.
Wood, J. L. et al J. Am. Chem. Soc. 2005, 127, 1251312515.

Catalytic Barton Deoxygenation

First report - Fu (1997)

Proposed catalytic cycle:

Examples of polymer-supported catalytic tin hydrides

used to further aid in separation

Lopez, R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 69496950.
Dumartin, G.; Pereyre, M.; et al Tetrahedron Lett. 2000, 41, 33773380.

Alcohol Derivatives Beyond Xanthates

Trifluoroacetates:

Toluates:

Jang, D. O.; Cho, D. H. Tetrahedron Lett. 2002, 43, 59215924.

Kim, J.-G.; Cho, D. H.; Jang, D. O. Tetrahedron Lett. 2004, 45, 30313033.
Lam, K.; Mark, I. E. Org. Lett. 2008, 10, 27732776.

Alcohol Derivatives Beyond Xanthates

Phosphites:
Site-selective peptide-catalyzed phosphitylation

Jordan, P. A.; Miller, S. J. Angew. Chem. Int. Ed. 2012, 51, 29072911.

Electrochemical Deoxygenation
Reduction of phosphinate derivatives

Probable mechanism:

Lam, K.; Marko, I. E. Org. Lett. 2011, 13, 406409.

Photo-catalyzed Deoxygenation
Early example:

Proposed mechanism

Saito, I.; et al J. Am. Chem. Soc. 1986, 108, 31153117.

Photo-catalyzed Deoxygenation
Batch to flow deoxygenation via iodide intermediate

Deoxygenation & functionalization of N-phthalimidoyl oxalates

Stephenson, C. R. J.; et al Chem. Commun. 2013, 49, 43524354.

Overman, L. E.; et al J. Am. Chem. Soc. 2013, 135, 15342-15345.

Direct Reductions of Alcohols

Lewis acid-catalyzed direct deoxygenation

Chemoselective deoxygenation of a primary alcohol in the

presence of a secondary alcohol:

Gevorgyan, V.; Rubin, M.; Benson, S.; Liu, J.-X.; Yamamoto, Y. J. Org. Chem. 2000, 65, 61796186.
Denanc, M.; Guyot, M.; Samadi, M. Steroids 2006, 71, 599602.

Direct Reductions of Alcohols

InCl3-catalyzed direct dehydroxylation

Chemoselectivity:

Iridium-catalyzed direct dehydroxylation

(via oxidation/Wolff-Kishner sequence)

Baba, A.; et al J. Org. Chem. 2001, 66, 77417744.
Huang, J.-L.; Dai, X.-J.; Li, C.-J. Eur. J. Org. Chem. 2013, 2013, 64966500.

Direct Reductions of Alcohols

Titanium(III)-mediated direct deoxygenation

Proposed mechanism:

Barrero, A. F. et al J. Am. Chem. Soc. 2010, 132, 254259.

Conclusions
Deoxygenation is important in chemical synthesis,

especially useful in carbohydrate chemistry.

The Barton-McCombie deoxygenation was a benchmark

discovery and countless variations and improvements

have been reported, making it extremely useful in
synthesis.
Various other photoredox and metal-catalyzed methods

for deoxygenation have emerged as useful instruments in

the chemical toolbox.
The C-O bond remains an interesting target for activation

and functionalization.