Pentacoordinate Phosphoranes as Versatile Reagents in Fluoroalkylation Reactions

A general method for the synthesis of bench-stable bis(difluoromethyl) pentacoordinate phosphoranes has been developed. The reaction is rapid, operationally simple, and easily scalable. The pentacoordinate phosphoranes can generate both difluoromethyl radical (·CF₂H) and difluorocarbene (:CF₂) intermediates. Thus, a variety of fluoroalkylation transformations have been achieved by ·CF₂H, such as oxidative difluoromethylation of electron-deficient heterocycles, nickel/photoredox dual-catalyzed difluoromethylation of aryl bromides, and photoredox difluoromethylation of alkenes, or by:CF₂, such as gem -difluorocyclopropanation of alkenes, base-promoted difluoromethylation of heteroatom nucleophiles, Pd-catalyzed difluoromethylation of arylboronic acids, and Cu-mediated trifluoromethylation of aryl iodides (via:CF₂ and recombined CF₃⁻). These fluoroalkylation methods have been successfully applied to late-stage fluoroalkylation of drugs and drug-like molecules.