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Communication

Intermolecular hydroacylation of acrylate esters: a new route to 1,4-dicarbonyls

Michael C. Willis* and Selma Sapmaz Department of Chemistry, University of Bath, Bath, UK BA2 7AY. E-mail: m.c.willis@bath.ac.uk; Fax: (+44) (0)1225 826231; Tel: (+44) (0)1225 826568 Received (in Cambridge, UK) 31st August 2001, Accepted 15th October 2001 First published as an Advance Article on the web 22nd November 2001
1,4-Dicarbonyl compounds can be prepared using a Rh(I) mediated hydroacylation reaction between (2-aminopicolyl)imines and acrylate esters followed by acid hydrolysis. The transition metal catalysed hydroacylation reaction in which an aldehyde and an alkene are combined to generate a ketone is a relatively unexplored process. The main limitation of this reaction is the instability of the proposed acyl-metal intermediates and the resulting competitive decarbonylation pathway.1 Intramolecular variants of the process utilising pent-4-en1-als as substrates, leading to cyclopentanones as products, have been extensively studied,2 however reports leading to larger ring sizes3 or intermolecular examples are scarce.4 Recently the Jun group have reported the use of a reaction system employing Wilkinsons complex and 2-aminopicoline as catalysts that allows intermolecular hydroacylation to proceed.5 The success of the Jun system is attributed to the intermediacy of a picolylimine capable of forming a chelate stabilised acylrhodium species.6 The majority of hydroacylation reactions reported to date utilise unfunctionalised alkenes as substrates thus generating simple ketones as products. We speculated that the use of alkenes substituted directly with either an ester or ketone group would provide direct access to the synthetically challenging 1,4-dicarbonyl array (Scheme 1). These 1,4-difunctionalised motifs are synthetically useful intermediates for the preparation of substituted furans,7 butyrolactones8 and succinate derivatives.9 Such 1,4-dicarbonyl systems are not straightforward to prepare and the approach presented here can be considered as the equivalent of an acyl-anion addition to an enoate.10 The related hydroformylation reaction has been reported although in these cases, by definition, only a single carbon unit corresponding to the CO molecule is introduced.11 Using variously substituted and functionalised aldehydes in the corresponding hydroacylation reaction would allow the addition of functionalised carbon chains.12 In this communication we report our progress towards this goal. To assess the feasibility of the process we elected to study the reactions of imine 1 as an aldehyde equivalent and thus limit decarbonylation. The reaction of 1 with methyl acrylate under a variety of reaction conditions is summarised in Table 1. Reactions were conducted in a sealed tube using Wilkinsons complex as the catalyst. Upon completion the reaction mixtures were treated directly with 1.0 M HCl to liberate the required 1,4-dicarbonyl adducts. Optimal conditions involved heating a THF solution of the substrates at 135 C for 6 hours with 10 mol% catalyst (entry 1). Under these conditions the desired

product was isolated in 73% yield as a single regioisomer. Lowering the catalyst loading or reaction temperature or decreasing the reaction time resulted in less efficient processes (entries 24). The reaction also proceeds if toluene is employed as solvent although a more complex reaction mixture is produced resulting in lower yields (entry 5). Chlorobenzene was also evaluated but resulted in only low conversion to product. The use of 1,4-dioxane allowed a reasonable yield of the desired product to be isolated however solubilty problems were encountered that were not observed with THF. In order to probe the generality of the process a range of substituted enoates were evaluated in the reaction with imine 1 (Table 2). Variation in the ester group is tolerated well, with Me and tBu esters both delivering the expected adducts in good yields (entries 1 and 2).13 Entry 3 demonstrates the tolerance towards amides with N,N-dimethylacrylamide generating the corresponding product in 74% yield. The introduction of substituents to the b-position of the alkene significantly reduces the reaction efficiency with methyl crotonate and cinnamate delivering the desired adducts in 24% and 10% yield respectively (entries 4 and 5). Substitution at the a-position has a similar effect on the reaction efficiency with methyl methacrylate yielding 16% of the requisite product (entry 6). A bsubstituent could be successfully introduced if it was sufficiently activating, thus the use of N-methyl maleimide as the alkene component generated the desired hydroacylation product in 81% yield (entry 7). The generality with respect to the imine component was next explored; we were particularly interested in assessing the influence of electron withdrawing and donating substituents on the aryl ring. A selection of 2-amino-3-methylpyridylimines bearing a range of substituents were readily prepared and evaluated in the reaction with methyl acrylate (Table 3). Electron withdrawing groups such as -NO2 and -CN had a beneficial effect on the rate of the reaction with good yields of the desired products being obtained in only 20 and 80 min respectively (entries 2 and 3). Electron donating substituents
Table 1 Reaction of imine 1 with methyl acrylatea

Entry 1 2b 3 4 5 a Conditions: RhCl(PPh3)3 mol%).

Temp./C

Solvent

Time/h

Yield (%)

Scheme 1 Electronic supplementary information (ESI) available: experimental details. See http://www.rsc.org/suppdata/cc/b1/b107852f/

135 THF 6 73 135 THF 6 47 70 THF 7 48 135 THF 4 59 135 PhMe 6 56 imine 1 (1.0 eq.), methyl acrylate (2.0 eq), sealed tube, (10 mol%) followed by HCl (1.0 M). b RhCl(PPh3)3 (5

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Chem. Commun., 2001, 25582559

This journal is The Royal Society of Chemistry 2001

DOI: 10.1039/b107852f

had a smaller influence on the rate of reaction; a -OMe substituent had minimal effect compared to the parent phenyl system with an 83% yield being achieved after 6 h (entry 4). para-Methyl and -bromo groups are also well tolerated delivering the corresponding 1,4-dicarbonyls in 98% and 85% yield respectively (entries 5 and 6). Exchange of a phenyl for the more electron rich naphthyl derived imine again showed little difference with the naphthyl derived adduct being obtained in 86% yield after 6 h reaction (entry 7). The reason for the rate accelerations observed with the nitroand cyano-substituted imines is unclear although destabilisation of the chelated intermediate is a possibility. Given these rate accelerations we were interested to see if these more reactive imines would allow a- and b-substituted acrylate esters to be employed as substrates. Unfortunately, although a rate acceleration was observed little difference in yield was obtained, with the nitro-substituted imine delivering products from reaction with methyl crotonate and methyl methacrylate in only 22% and 14% yield respectively. The use of diimine 2, prepared in good yield from benzene1,4-dicarboxaldehyde, offers a potential starting point for two directional synthesis14 and allowed a double hydroacylation to
Table 2 Reaction between 1 and various alkenes using RhCl(PPh3)3a Entry Alkene Product Time/h Yield (%)

be attempted. Pleasingly, the required tetracarbonyl product 3 was isolated in 76% yield after 6 hours reaction.15

In conclusion, we have demonstrated the general viability of the intermolecular hydroacylation of acrylate esters as a new regioselective route to 1,4-dicarbonyl systems. The imine component of the reaction can tolerate a range of substituents including electron donating and electron withdrawing groups. The enoate component can contain a variety of ester groups as well as amide functionalities with little effect on yield, however, introduction of simple a- or -substituents reduces the efficiency of the reactions. Efforts to expand the substrate tolerance, to identify more efficient catalyst systems and to develop a process that can utilise aldehydes directly are underway in our laboratory and will be reported in due course. The EPSRC are thanked for financial support of this project. We also thank the EPSRC Mass Spectrometry service at the University of Wales, Swansea, for analyses and Johnson Matthey PLC for the loan of rhodium salts.

1 2 3 4 5 6 7b

X = OMe X = OtBu X = NMe2

R1 = R2 = H R1 = R2 = H R1 = R2 = H R1 = Me, R2 = H X = OMe R1 = Ph, R2 = H X = OMe R1 = H, R2 = Me X = OMe

6 6 6 18 12 12 6

73 71 74 24 10 16 81

Notes and references

1 J. M. OConnor and M. Junning, J. Org. Chem., 1992, 57, 5075. 2 For leading refs, see: (a) R. W. Barnhart, D. A. McMorran and B. Bosnich, Inorg. Chim. Acta, 1997, 263, 1; (b) B. Bosnich, Acc. Chem. Res., 1998, 31, 667; (c) M. Fujio, M. Tanaka, X.-M. Wu, K. Funakoshi, K. Sakai and H. Suemune, Chem. Lett., 1998, 881. 3 For examples, see: A. D. Aloise, M. E. Layton and M. D. Shair, J. Am. Chem. Soc., 2000, 122, 12610; K. P. Gable and G. A. Benz, Tetrahedron Lett., 1991, 32, 3473. 4 For leading refs, see: H. Lee and C.-H. Jun, Bull. Korean Chem. Soc., 1995, 16, 66; C. P. Lenges, P. S. White and M. Brookhart, J. Am. Chem. Soc., 1998, 120, 6965; T. Kondo, M. Akazome, Y. Tsuji and Y. Watanabe, J. Org. Chem., 1990, 55, 1286; T. Kondo, N. Hiraishi, Y. Morisaki, K. Wada, Y. Watanabe and T.-A. Mitsudo, Organometallics, 1998, 17, 2131. 5 C.-H. Jun, D.-Y. Lee, H. Lee and J.-B. Hong, Angew. Chem., Int. Ed., 2000, 39, 3070. 6 J. W. Suggs, J. Am. Chem. Soc., 1979, 101, 489. 7 W. Friedrichsen, Furans and their benzo derivatives: synthesis, in Compr. Heterocycl. Chem. II, ed. C. W. Bird, Elsevier, Oxford, 1996. 8 E.-I. Negishi and M. Kotora, Tetrahedron, 1997, 53, 6707. 9 R. E. Babine and S. L. Bender, Chem. Rev., 1997, 97, 1359. 10 D. Seebach, Angew. Chem., 1979, 91, 259; Umpoled Synthons. A Survey of Sources and Uses in Synthesis, ed. T. A. Hase, Wiley, New York, 1987. 11 For examples, see: G. Fremy, E. Monflier, J.-F. Carpentier, Y. Castanet and A. Mortreux, Angew. Chem., Int. Ed. Engl., 1995, 34, 1474; C. W. Lee and H. Alper, J. Org. Chem., 1995, 60, 499; Y. Hu, W. Chen, A. M. B. Osuna, J. Xiao, A. M. Stuart and E. G. Hope, Chem. Commun., 2001, 725. 12 For an example of an intramolecular hydroacylation of an acrylate ester see ref. 2(a). 13 All new compounds have been characterised, see ESI for details. 14 For a review, see: S. R. Magnuson, Tetrahedron, 1995, 51, 2167. 15 The preparation of 3 serves as a general procedure: a solution of imine 2 (282 mg, 1.79 mmol) in THF (1 mL) was added to a solution of RhCl(PPh3)3 (167 mg, 10 mol %) in THF (1 mL) at room temperature and stirred for 1 h. Methyl acrylate (480 mL, 5.37 mmol) in THF (2 mL) was added and the reaction vessel flushed with argon. The reaction tube was sealed and then heated at 135 C for 6 h. The reaction was cooled to room temperature, diluted with EtOAc (20 mL), poured into aqueous HCl (1 M, 20 mL) and extracted with EtOAc (3 3 20 mL). The organic portions were washed with brine (20 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (SiO2, 25% EtOAcpetrol) to give 3 (212 mg, 76%) as pale yellow plates.

a Conditions: imine 1 (1.0 eq.), alkene (2.0 eq), THF, 135 C, sealed tube, RhCl(PPh3)3 (10 mol%) followed by HCl (1.0 M). b Product isolated as enamine. pic = 3-picolin-2-yl.

Table 3 Variation in imine substituenta

Entry

Time/h

Yield (%)

1 2 3 4 5 6 7

X X X X X X

= = = = = =

H NO2 CN OMe Me Br

6h 20 min 80 min 6h 6h 6h 6h

73 80 80 83 98 85 86

Conditions: imine (1.0 eq.), methyl acrylate (2.0 eq), THF, 135 C, sealed tube, RhCl(PPh3)3 (10 mol%) followed by HCl (1.0 M).

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