Asymmetric Alkylation of α-Cyanoketimines with Alkyl Bromides Catalyzed by Bis-Cinchonium Salts

Abstract

The SN2 reaction constitutes one of the most fundamental bond-forming transformations in organic chemistry, finding numerous synthetic applications across pharmaceutical, agrochemical, and materials science. However, the development of new catalysts for asymmetric SN2 reactions with nucleophiles beyond enolate derivatives remains a formidable challenge. Herein, we report the development of a new class of bis-cinchonium catalysts for an unprecedented enantioselective SN2 alkylation of cyanoketimines with alkyl bromides. This reaction features a broad substrate scope with respect to both reaction partners, thereby providing a useful approach to enantioenriched α,α-dialkyl aminonitriles. Computational studies revealed that the bis-cinchonium catalyst, through a network of weak bonding interactions, activated both cyanoketimines and alkyl bromides and preorganized them along the trajectory toward the transition state of an SN2 reaction.