Radical trifluoromethoxylation of fluorinated alkenes for accessing difluoro(trifluoromethoxy)methyl groups†

Abstract

In this study, we explore the potential of the difluoro(trifluoromethoxy)methyl group, CF₂–O–CF₃, an underexplored but promising structural analog of the trifluoromethoxy group (OCF₃). This moiety offers unique electronic properties and enhanced chemical stability due to its multiple C–F bonds, along with the added advantage of C–O bond cleavage, making it an attractive option in fluorine chemistry. We have succeeded in synthesizing difluoro(trifluoromethoxy)methyl compounds via radical amino- and hydroxy-trifluoromethoxylations of β,β-difluorostyrenes. Control experiments, including radical clock experiments, support a free radical mechanism. The synthetic utility of the resulting difluoro(trifluoromethoxy)methyl compounds is also demonstrated through transformations into bioactive analogs, such as pyrrole derivatives, fendiline analogs, and carpropamid analogs, highlighting their potential in drug development.