Water versus Solvent-Free Conditions for the Enantioselective Inter- and Intramolecular Aldol Reaction Employing L-Prolinamides and L-Prolinethioamides as Organocatalysts

Organocatalysts 1, derived from L-proline and (1S,2R)-cis-1-aminoindan-2-ol or (R)-1-aminoindane, are evaluated as promoters in the direct asymmetric aldol reaction between ketones and aromatic aldehydes in the presence of water and under solvent-free reaction conditions. L-Prolinethioamides 1c and M exhibited higher enantioselectivity than the corresponding prolinamides 1a and 1b in the model aldol reaction between cyclohexanone and 4-nitrobenzaldehyde in the presence of 4-nitrobenzoic acid as cocatalyst. In particular, L-prolinethioamide 1d (5 mol%), derived from L-proline and (R)-1-aminoindane, is shown as the most efficient organocatalyst Studied Promoting the direct aldol reaction of cycloalkyl, alkyl and alpha-functionalized ketones with aromatic aldehydes in the presence of water and under solvent-free reaction conditions employing only 2 equivalents Of nucleophile. Generally, anti-aldol products are obtained in high yields and excellent diastereo- and enantioselcctivities (up to >98/2 anti/syn, up to 98% ee). Solvent-free conditions give slightly higher dr and ee than using water as solvent. In addition, organocatalyst 1d can be easily recovered by extractive work-up and reused. Prolinethioamide 1d (5 mol%) in combination with 4NO(2)C(6)H(4)CO(2)H (5 mol%) is also a very effective organocatalytic system for the asymmetric solvent-free intramolecular Hajos-Parrish-Eder-Sauer-Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to other reported catalysts in organic solvents.