Cu(II) Catalyzed Unsymmetrical Di-oxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-Phenoxyketones, an Unstudied Substructure

Abstract

A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver α,α-difluorinated-α-phenoxy ketones, an unstudied hybrid fluorinated functional group. Composed of α,α-difluorinated ketone and α,α-difluorinated ether moieties, these have only once been previously reported as a synthetic intermediate en route to pharmacologically active compounds. Computational predictions and later experimental corroboration suggest that the sp3-hybridized hydrate adduct of the phenoxy-substituted fluorinated ketone is energetically accessible. The more facile conversion between ketone and hydrate forms suggest that covalent inhibition of proteases and other enzymes may be possible. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.