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.