Nickel-Catalyzed cis-Arylation of Unactivated gem-Difluoroalkenes: A Pathway for the Construction of a Fluorinated Amino Acid Molecular Library.

Abstract

Because of their intrinsic inertness, the selective functionalization of unactivated gem-difluoroalkenes represents a formidable challenge in organofluorine chemistry. Herein, we report a picolinamide-directed, nickel-catalyzed strategy that enables the stereoselective arylation of unactivated gem-difluoroalkenes incorporated within norvaline-derived scaffolds. The devised protocol has a broad substrate scope and selectively produces cis-arylated monofluoroalkene products in high yields, providing a rapid and efficient pathway to a broad range of nonnatural fluorinated amino acids. Preliminary mechanistic investigations have pointed toward the involvement of a nickel(I) species in the catalytic cycle. This work expands the scope of the synthetic utility of unactivated gem-difluoroalkenes and furnishes a robust platform for the functionalization of difluoroalkenes.