Chemoselective N-Difluoromethylation of Functionalized Tertiary Amines

A practical, convenient, and general method for the difluoromethylation of tertiary amines, using diethyl bromodifluoromethylphosphonate and fluoride, is described. This commercially available phosphonate smoothly reacts with a fluoride ion to liberate a difluorocarbene intermediate that in the presence of a proton source and a tertiary amine generates the corresponding alpha-difluoromethylammonium compound in good to excellent yields. Despite the involvement of a difluorocarbene intermediate, this difluoromethylation occurs almost exclusively on the nitrogen atom with diverse molecular structures, including drugs, surfactants, chiral phase transfer catalysts, polymers, ionic liquids, and other fine chemicals. A preliminary assessment of the effects that an alpha-difluoromethyl groupT has on hydrogen bonding and logP of quaternary ammonium salts is also described.