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 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.
The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
Yossi
Y
Zafrani
The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
Dafna
D
Amir
The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
Lea
L
Yehezkel
The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
Moran
M
Madmon
The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
Sigal
S
Saphier
The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
Naama
N
Karton-Lifshin
The Department of Organic Chemistry, Israel Institute for Biological Research , Ness-Ziona 74100, Israel.
Eytan
E
Gershonov