Chemoselective N‑Difluoromethylation of Functionalized Tertiary Amines

• Published in: Journal of organic chemistry Vol. 81; no. 19; pp. 9180 - 9187
• Main Authors: Zafrani, Yossi, Amir, Dafna, Yehezkel, Lea, Madmon, Moran, Saphier, Sigal, Karton-Lifshin, Naama, Gershonov, Eytan
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.10.2016; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; QUATERNARY AMMONIUM; MEDICINAL CHEMISTRY; NUCLEOPHILES; REAGENT; BRUSHES; PHOSPHATE-ESTERS; SUPPORTED AMMONIUM FLUORIDES; REACTIVITY; SALTS; CATALYSTS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.6b01728

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 α-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 α-difluoromethyl groupT has on hydrogen bonding and logP of quaternary ammonium salts is also described.