Imidazole Morita-Baylis-Hillman

The most efficient catalyst system for the Morita-Baylis-Hillman reaction of methyl vinyl ketone has been reported by Miller [183, 184], Use of L-proline (58) (10 mol%) in conjunction with the A-methyl imidazole containing hexapeptide 131 (10 mol%) provided an efficient platform for the reaction of 125 with a series of aromatic aldehydes 127 (52-95% yield 45-81% ee) (Scheme 52). Importantly, it was shown that the absolute configuration of the proline catalyst was the major factor in directing the stereochemical outcome of the reaction and not the complex peptide backbone. 

Intramolecular versions of the Morita-Baylis-Hillman reaction have also met with success using a dual Lewis acid/Lewis base catalyst system. Miller has shown that a combination of A-methyl imidazole (132) (10 mol%) and... 

A highly enantioselective proline-catalysed intramolecular Morita-Baylis-Hillman reaction of hept-2-enedial (111) has been reported. Addition of imidazole to the mixture resulted in an unusual inversion of enantioselectivity.149 The first example of a TiCU-mediated Morita-Baylis-Hillman-type reaction of cy-acetyl cyclic ketene dithioacetals with arylaldehydes has been described.150... 

Peptide-based imidazole catalyst 63 in the presence of L-proline as a cocatalyst promoted asymmetric Morita-Baylis-Hillman reactions between methyl vinyl ketone and aromatic aldehydes (Scheme 22.14). The combination... 

As an extension of this work, the same authors have used polystyrene-supported proline as a recyclable catalyst in the Morita-Baylis-Hillman reaction of a range of aryl aldehydes with methyl or ethyl vinyl ketone. These reactions were performed in the presence of imidazole and provided a series of Morita-Baylis-Hillman adducts in moderate to high yields (17 88%) combined with high enantioselectivities of up to 95% ee (Scheme 2.55). This study represented the first example of supported proline as heterogeneous catalyst for the Morita-Baylis-Hillman reaction. In addition, Zhou et al. reported that these reactions could be eatalysed by combinations of L-proline with chiral tertiary amines derived from various readily available chiral sources, such as L-proline or (5)-a-phenylethylamine. In these conditions, the Morita-Baylis-Hillman adducts were obtained in reasonable chemical yields (34-97%) and low to good enantioselectivities (12 83% ee). In this study, it was demonstrated that the proline stereochemistry was the sole factor to determine the eonfiguration of the newly formed chiral centre. 

The Morita-Baylis-Hillman (MBH) reaction is described as the coupling between the a-position of an activated double bond and an sp electrophilic carbon (typically an aldehyde, but also an imine) using an appropriate catalyst, normally Lewis bases [21]. Shi and coworkers showed that imidazole and proline formed an efficient co-catalytic system for carrying out the MBH reaction, but with low ee [22]. 

The Morita-Baylis-Hillman (MBH) reaction is a powerful carbon-carbon bondforming reaction that has found widespread application in organic synthesis. In 2005, Miller and Hong independently reported the highly enantioselective intramolecular MBH reaction. The Miller group applied a combination of (S)-pipecohc acid 79 and N-methylimidazole to catalyze the cychzation of heptenal derivatives 80 in aqueous THF (Scheme 36.21a) [27a]. In contrast, Hong and coworkers used simple L-proline and imidazole as the catalysts (Scheme 36.21b) [27b]. 

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