Dinickel-catalyzed regio- and enantioselective α-alkylation of cyclic ketones with unactivated alkyl halides

Abstract

The asymmetric α-alkylation of simple ketones with unactivated alkyl halides remains a longstanding challenge in organic synthesis. Herein, we report a dinickel-catalyzed asymmetric α-alkylation of cyclic ketones using unactivated alkyl halides as alkylating agents. This methodology accommodates a broad range of substrates, including benzo-fused cyclic ketones, α-aryl and α-alkyl cyclic ketones, and diverse alkyl halides, enabling the construction of chiral ketones with α-quaternary centers with high regio- and enantioselectivity. Mechanistic studies, combining experimental and computational approaches, reveal that this transformation proceeds via a redox-neutral S_N2 pathway catalyzed by nickel(I) species instead of the commonly observed Ni(II) salt. The unique bimetallic ligand framework plays a dual role: (1) stabilizing adjacent dinickel(I) centers through halogen-bridging interactions, thereby enabling the formation of a highly nucleophilic nickel(I) enolate, and (2) providing a chiral pocket to control the stereochemistry of the reaction.