High acceleration of the direct aldol reaction cocatalyzed by BINAM-prolinamides and benzoic acid in aqueous media

Abstract

The enantioselective direct aldol reaction, organocatalyzed by recoverable BINAM-prolinamide derivatives can be highly accelerated by a catalytic amount of a carboxylic acid without a detrimental of the obtained enantioselectivities. From the study of suitable acids and reaction conditions, benzoic acid in aqueous DMF or in water was shown to give the best results with high yields and enantioselectivities. Thus, the reaction between p-nitrobenzaldehyde and acetone catalyzed by (Sa)-BINAM-L-Pro and benzoic acid can be carried out at -20º C in only 8.5 h to give the expected product with 86% ee. In the case of butan-2-one, the iso- and the anti-isomers are obtained in a 1:1 isomer ratio up to 99% ee. Cyclohexanone gives the anti-aldol in up to 99% dr and 97% ee in only 2 h. The opposite diastereoselectivity is obtained in the case of cyclopentanone with lower ee up to 65% for the syn and 85% for the anti-isomer.