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The Baylis–Hillman reaction is a carbon-carbon bond forming reaction between the α-position of an activated alkene and an aldehyde, or generally a carbon electrophile. Employing a nucleophilic catalyst, such as tertiary amine and phosphine, this reaction provides a densely functionalized product (e.g. functionalized allyl alcohol in the case of aldehyde as the electrophile).〔Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972.〕〔Ciganek, E. ''Org. React.'' 1997, ''51'', 201. 〕 This reaction is also known as the Morita–Baylis–Hillman reaction or MBH reaction.〔K. Morita, Z. Suzuki and H. Hirose, Bull. Chem. Soc. Jpn.,1968, 41, 2815.〕 It is named for the Japanese chemist Ken-ichi Morita, the British chemist Anthony B. Baylis and the German chemist Melville E. D. Hillman. DABCO is one of the most frequently used tertiary amine catalysts for this reaction. In addition, nucleophilic amines such as DMAP and DBU as well as phosphines have been found to successfully catalyze this reaction. MBH reaction has several advantages as a useful synthetic method: 1) It is an atom-economic coupling of easily prepared starting materials. 2) Reaction of a pro-chiral electrophile generates a chiral center, therefore an asymmetric synthesis is possible. 3) Reaction products usually contain multiple functionalities in a proximity so that a variety of further transformations are possible. 4) It can employ a nucleophilic organo-catalytic system without the use of heavy metal under mild conditions. Several reviews have been written.〔''Recent Advances in the Baylis−Hillman Reaction and Applications'' Deevi Basavaiah, Anumolu Jaganmohan Rao, and Tummanapalli Satyanarayana Chem. Rev., 2003, 103 (3), pp 811–892 2003 (Article) 〕〔Masson, G., Housseman, C. and Zhu, J. (2007), ''The Enantioselective Morita–Baylis–Hillman Reaction and Its Aza Counterpart''. Angewandte Chemie International Edition, 46: 4614–4628. 〕〔''aza-Baylis−Hillman Reaction'' Valerie Declerck, Jean Martinez and Frederic Lamaty Chem. Rev., 2009, 109 (1), pp 1–48, 2009 (Review) 〕〔''Recent Contributions from the Baylis−Hillman Reaction to Organic Chemistry'' Deevi Basavaiah, Bhavanam Sekhara Reddy and Satpal Singh Badsara Chemical Reviews 2010 110 (9), 5447-5674 〕〔''The Baylis–Hillman reaction: a novel concept for creativity in chemistry'' Deevi Basavaiah and Gorre Veeraraghavaiah Chem. Soc. Rev., 2012, Advance Article 〕 ==Reaction mechanism== Hoffmann first proposed a mechanism for the MBH reaction.〔Angew. Chem., Int. Ed. Engl. 1983, 22, 795.〕 The first reaction step involves 1,4-addition of the catalytic tertiary amine to the activated alkene to generate the zwitterionic aza-enolate. In the second step, this enolate adds to an aldehyde via an aldol addition. The third step involves intramolecular proton shift, which subsequently generates the final MBH adduct and releases the catalyst via E2 or E1cb elimination in the last step. Hill and Isaacs performed kinetic experiments to probe the mechanistic details.〔J. Phys. Org. Chem. 1990, 3, 285.〕 The rate of reaction between acrylonitrile and acetaldehyde was first order in concentrations of acrylonitrile, acetaldehyde, and DABCO. Hill and Isaacs proposed that the aldol addition step, which involves all three reactants, thus is the rate determining step. That they did not observe kinetic isotope effect using α-deutrated acrylonitrile also supported this statement. However, this initial mechanistic proposal had been criticized because of several points. The rate of MBH reaction was accelerated by the build-up of product (autocatalytic effect), which could not be rationalized by the mechanism. Also the formation of a considerable amount of ‘unusual’ dioxanone byproduct in the MBH reaction of aryl aldehydes with acrylates was not expected. McQuade et al. and Aggarwal et al. have reevaluated the MBH mechanism using both kinetics and theoretical studies, focusing on the proton-transfer step.〔Organic Letters, 2005, 7, 1, 147-150.〕〔Angew. Chem., Int. Ed. 2005, 44, 1706-1708.〕 According to McQuade, the MBH reaction between methyl acrylate and p-nitrobenzaldehyde is second order relative to the aldehyde and shows a significant kinetic isotope effect at the α-position of the acrylate (5.2 in DMSO). Interestingly, regardless of the solvents the KIE were found to be greater than 2, indicating the relevance of proton abstraction in the rate-determining step. Based on these new data, McQuade proposed a new mechanism, suggesting that the proton transfer step is the RDS. First and second steps are not changed, but after the first aldol addition the second addition of aldehyde occurs to form a hemiacetal alkoxide. Then the rate-determining proton transfer step via six-membered transition state releases the adduct A, which further reacts to produce MBH product B or dioxanone byproduct C. This mechanism accounts for the formation of dioxanone byproduct. Aggarwal focused on the autocatalytic effect and observed that the catalytic quantities of MBH product or methanol removed this effect. Thus he proposed that at early stage of the reaction non-alcohol catalyzed mechanism, equivalent to McQuade's proposal, operates, while after 20% conversion alcohol-catalyzed mechanism dominates. In this later stage, alcohol R'OH assists the rate-determining proton transfer step via six membered transition state. Aggarwal and Harvey modeled the two pathways using density functional theory calculations and showed that the computed energy profile matches well with the experimental kinetic isotope effect and observed rate of reaction.〔J. Am. Chem. Soc. 2007, 129, 15513.〕 Also they showed that the overall enthalpic barrier of the alcohol-catalyzed pathway is slightly smaller than that of the non-alcohol-catalyzed pathway, rationalizing that as the alcohol (MBH product) concentration increases the alcohol-catalyzed pathway starts to dominate, exhibiting the autocatalysis. While McQuade's and Aggarwal's studies are receiving much attention recently, there are a number of issues not resolved yet. First, McQuade's proposal for the role of the intermediate A is not clearly proven. Because A could be formed simply by addition of B to an aldehyde, formation of A and C could be happening outside of the MBH mechanism. McQuade asserts that the rate determining step involves two molecules of aldehyde because the reaction rate is second order in aldehyde, but does not explain why Hill and Isaac observed first order for their substrates. Indeed the enormous variability of substrates for MBH reaction is a constraint for probing the general mechanism of MBH reaction in a unified manner. Also, Aggarwal previously suggested that RDS of the reaction changes from proton transfer to aldol addition over the course of the reaction, based on the fact that primary kinetic isotope effect disappears after 20% conversion,〔 but the subsequent computational studies concluded that the proton transfer step still has the highest barrier in the late stage of reaction. The discrepancy between kinetic and computational results implies that there still are mechanistic aspects of MBH reaction not understood well. Recently, Coelho and Eberlin et al. have used ESI-MS data to provide experimental data to support the dualistic nature of the reaction's proton transfer step, thus granting the first structural evidence for both McQuade's and Aggarwal's mechanistic propositions for this RDS step of the reaction.〔J. Org. Chem., 2009, 74(8), 3031-3037〕 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Baylis–Hillman reaction」の詳細全文を読む スポンサード リンク
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