Aminomethylation of enals through carbene and acid cooperative catalysis: Concise access to β²-amino acids

A convergent, organocatalytic asymmetric aminomethylation of α,β-unsaturated aldehydes by N-heterocyclic carbene (NHC) and (in situ generated) Brønsted acid cooperative catalysis is disclosed. The catalytically generated conjugated acid from the base plays dual roles in promoting the formation of azolium enolate intermediate, formaldehyde-derived iminium ion (as an electrophilic reactant), and methanol (as a nucleophilic reactant). This redox-neutral strategy is suitable for the scalable synthesis of enantiomerically enriched β²-amino acids bearing various substituents. Harmonious cooperation: An N-heterocyclic carbene (NHC) and (in situ generated) Brønsted acid cooperatively catalyze the aminomethylation of α,β-unsaturated aldehydes. This cooperative catalytic reaction provides a redox neutral strategy for quick access to β²-amino esters in an enantioselective manner.