Facile and Highly Chemoselective N-Difluoromethylation of Functionalized Tertiary Amines

Synthesis of organic compounds containing fluorine atoms has become one of the more important issues in the field of organic synthesis because of the central role fluorinated functions play as bioisosteres in agrochemicals and drugs, leading to changes in affinity, metabolic stability, hydrophobicity and bioavailability of various bioactive compounds. In the world of organic synthesis, the incorporation of a fluorine atom/s is also frequently employed for various other applications to modify both chemical and physical properties of molecules. Among various fluorinated moieties, difluoromethyl (-CF₂H) is one of the most promising. Quaternary ammonium salts are a well-known and abundant family of compounds used in medical applications, cosmetics, agriculture, and chemical catalysis. Since the charged moiety is responsible for the unique properties of these compounds, the influence of a difluoromethyl group adjacent to the cationic center may be of interest. In this work, we present a practical, convenient and general method for the difluoromethylation of tertiary amines, using diethyl bromodifluoromethylphosphonate and fluoride. We found that 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 a-difluoromethyl ammonium 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 (e.g. drugs, ionic liquids, polymers). Combining the two highly important issues of fluorinated organic compounds and quaternary ammonium salts may lead to interesting changes in chemical and physical properties. A preliminary assessment of the effects an a-difluoromethyl group has on hydrogen bonding and log P of quaternary ammonium salts is also described.