Copper-Catalyzed Regio- and Enantioselective Hydroamination of gem-Difluoroalkenes to Access Chiral Difluoromethyl Amines.

The difluoromethyl group (CF2H) is an important motif in medicinal chemistry. We report the efficient synthesis of a range of optically pure α-difluoromethyl amines via copper-catalyzed regio- and enantioselective hydroamination of gem-difluoroalkenes. The application of a chiral pyridine-derived ligand inhibits β-F elimination from the chiral α-CF2H organocopper intermediate. The proposed chiral Cu catalyst promotes the production of chiral α-difluoromethyl amines by an enantioselective Cu-H insertion and a reductive C-N bond elimination using readily available materials. The findings of this study establish a new synthetic strategy to access chiral α-difluoromethyl motifs.