Main content area

The Difluoromethyl Group as a Masked Nucleophile: A Lewis Acid/Base Approach

Geri, Jacob B., Wade Wolfe, Michael M., Szymczak, Nathaniel K.
Journal of the American Chemical Society 2018 v.140 no.30 pp. 9404-9408
Lewis acids, Lewis bases, ambient temperature, aromatic hydrocarbons, drugs, lipophilicity, moieties, pharmacokinetics
The difluoromethyl group (R–CF₂H) imparts desirable pharmacokinetic properties to drug molecules and is commonly targeted as a terminal functional group that is not amenable to further modification. Deprotonation of widely available Ar–CF₂H starting materials to expose nucleophilic Ar–CF₂– synthons represents an unexplored, yet promising route to construct benzylic Ar–CF₂–R linkages. Here we show that the combination of a Brønsted superbase with a weak Lewis acid enables deprotonation of Ar–CF₂H groups and capture of reactive Ar–CF₂– fragments. This route provides access to isolable and reactive Ar–CF₂– synthons that react with a broad array of electrophiles at room temperature. The methodology is highly general in both electrophile and difluoromethyl (hetero)arene and can be applied directly to the synthesis of benzylic difluoromethylene (Ar–CF₂–R) linkages, which are useful lipophilic and metabolically resistant replacements for benzylic linkages in medicinal chemistry.