Direct asymmetric α C(sp3)‒H alkylation of benzylamines with MBH acetates enabled by bifunctional pyridoxal catalysts

Abstract

Abstract Organocatalytic allylic substitution of Morita-Baylis-Hillman (MBH) adducts is widely regarded as one of the most powerful transformations in organic synthesis. A range of activated carbon nucleophiles have been successfully employed in this reaction, enabling the incorporation of diverse functional moieties. Despite its potential, the use of inert C–H nucleophiles—critical for broadening the reaction’s versatility and synthetic utility—remains a significant challenge in the field. Direct α-C–H functionalization of benzyl amines with MBH adducts offers a promising route to form a new C–C bond while simultaneously establishing a chiral amine moiety, a feature highly attractive from the perspective of organic synthesis. However, this transformation is particularly challenging due to the inherent inertness of the α-C( sp ³)–H bonds, significant nucleophilic interference from the NH₂ group, and the complexity of selectivity control. Herein, we have successfully achieved an asymmetric direct α-C–H allylic alkylation of NH₂-unprotected benzylamines with MBH adducts using a bifunctional chiral pyridoxal catalyst, producing biologically important chiral γ-amino acid derivatives in good yields with excellent diastereo- and enantioselectivities. The reaction offers a distinct strategy for synthesizing multiply functionalized compounds from readily available starting materials, significantly expanding access to complex chiral architectures.