Catalytic Difluoromethylation of Alkenes with Difluoroacetic Anhydride: Reactivity of Fluorinated Diacyl Peroxides and Radicals.

Given the importance of difluoromethylated molecules for drug and agrochemical development, much attention has been drawn to the establishment of related synthetic protocols, as exemplified by the CF2H radical‐mediated catalytic difluoromethylation of alkenes. However, most of these difluoromethylations proceed under photocatalytic conditions, whereas those requiring thermal conditions are few. Herein, we developed a general and practical method of Cu‐catalyzed alkene difluoromethylation with difluoroacetic anhydride (DFAA) as a CF2H source, showing that the thus realized amino‐, allylic‐, and oxy‐difluoromethylations involve bis(difluoroacetyl) peroxide (BDFAP) in situ generated from DFAA and H2O2 and further demonstrating the occurrence of carbo‐difluoromethylation under catalyst‐free conditions. The obtained results pave the way to the simple and efficient synthesis of a broad range of difluoromethylated species and thus facilitate their practical applications, including those in medicinal and agricultural chemistry. Moreover, we probed the mechanisms of the observed transformations, rationalized the extraordinary fast decomposition of BDFAP compared to that of diacyl peroxides containing CF3 or CF2Cl groups, and performed DFT calculations to shed light on the low stability and decomposition mode of BDFAP. Finally, we examined the influence of fluorinated radical philicity on the reaction outcome. [ABSTRACT FROM AUTHOR]