Brønsted Acids as Additives for the Direct Asymmetric Aldol Reaction Catalyzed by l-Prolinethioamides. Direct Evidence for Enamine−Iminium Catalysis

The use of protonated l-prolinethioamide instead of the free base derivative 1 as the organocatalyst for
the direct aldol addition has a profound and appreciable effect on both the yield and the stereochemical
course of the reaction. 4-Nitrobenzaldehyde (2) reacts with acetone in the presence of the protonated
catalyst 1·TFA, affording aldol product 3 with a yield up to 99% and an ee up to 98%. The catalyst
loading can be lowered to 2.5 mol %. More than 20 different acids were investigated as an additive, and
its role as cocatalyst has been discussed. Furthermore, reactions of l-prolinethioamide salts with acetone
have been monitored using ESI-MS and 1H NMR techniques, giving insight into the mechanism of the
direct aldol reaction. The presumed formation of the iminium salt 10 has been unambiguously confirmed.