Atroposelective Three-Component (Fluoro)methylative Alkylation of Terminal Alkynes

The development of synthetic methods for the selective installation of methyl and fluoromethyl groups is highly desired due to their critical role in drug development. While significant advances have been made in the methylation and difluoromethylation of aromatic compounds, the catalytic atroposelective (fluoro)methylative functionalization of alkynes to forge axially chiral alkenes remains underexploited. Herein, we report an enantioselective cross-electrophile strategy for the efficient 1,2-carbo-(fluoro)methylation of alkynes with two different alkyl halides via nickel catalysis. By integrating a one-electron radical process with a two-electron organometallic process, this protocol employs a simple chiral nickel catalyst to effectively discriminate between secondary and tertiary alkyl groups and (fluoro)methyl groups for alkyne difunctionalization. This protocol demonstrates good compatibility of activated secondary/tertiary alkyl bromides, terminal alkynes, and (fluoro)methyl halides, permitting the straightforward synthesis of a broad range of synthetically valuable axially chiral (fluoro)methyl-substituted alkenes with high chemo-, regio-, trans-, and atropo-selectivity. Preliminary mechanistic studies provide insight into the potential reaction pathway.