Cu(II)-Catalyzed Unsymmetrical Dioxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-phenoxyketones

A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver alpha,alpha-difluorinated-alpha-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of alpha,alpha-difluorinated ketone and alpha,alpha-difluorinated ether moieties, these compounds have rarely been reported as a synthetic intermediate. Computational predictions and later experimental corroboration suggest that the phenoxy-substituted fluorinated ketone's sp(3)-hybridized hydrate form is energetically favored relative to the respective nonether variant and that perturbation of the electronic character of the ketone can further encourage the formation of the hydrate. The more facile conversion between ketone and hydrate forms suggests that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.

Automated summary

A Cu-based catalyst system is used to couple gem-difluoroalkenes with phenols under aerobic conditions, resulting in the formation of alpha,alpha-difluorinated-alpha-phenoxyketones, a previously unstudied hybrid fluorinated functional group. Computational predictions and experimental evidence suggest that the phenoxy-substituted fluorinated ketone favors the sp(3)-hybridized hydrate form over the nonether variant, and that modulation of the ketone's electronic character promotes hydrate formation. This study is significant as it provides insights into the covalent inhibition of proteases and other enzymes, and also offers possibilities for accessing other useful fluorinated functional groups.