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

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