Peroxide-Initiated Hydrophosphinylation of gem-Difluoroalkenes

The installation of fluorine and fluorinated functional groups into drug-like scaffolds can perturb the physicochemical, pharmacokinetic, and pharmacodynamic properties of compounds. However, some potentially useful fluorinated substructures reside predominantly outside the realm of the current synthetic methodologies. One such substructure, the a,a-difluorophosphine oxide, might be convergently prepared by the reaction of a gem-difluorinated alkene with a P-H bond, though such nucleophilic reactions instead proceed through a C-F substitution pathway that delivers monofluorovinyl products. In contrast, we report a peroxide-initiated hydrophosphinylation reaction of gem-difluoroalkenes that avoids C-F substitution and produces a wide range of a,a-difluorophosphine oxides and functions using readily available reagents and green solvents.

Automated summary

The installation of fluorine and fluorinated functional groups into drug-like scaffolds can greatly affect the properties of compounds. However, current synthetic methods are limited in their ability to incorporate certain potentially useful fluorinated substructures, such as the α,α-difluorophosphine oxide. This study presents a new approach using peroxide-initiated hydrophosphinylation reactions to prepare a wide range of α,α-difluorophosphine oxides and functions, utilizing readily available reagents and green solvents.