Solid‐State Radical C−H Trifluoromethylation Reactions Using Ball Milling and Piezoelectric Materials

Abstract

The application of piezoelectricity for the generation of trifluoromethyl (CF3) radicals is reported together with the development of a method for the mechanochemical C−H trifluoromethylation of aromatic compounds. As compared to conventional solution‐based approaches, this mechanoredox C−H trifluoromethylation enables cleaner and more sustainable access to a wide range of trifluoromethylated N‐heterocycles and peptides, which are important structural motifs in modern drug discovery. This study thus represents an important milestone for future applications of mechanoredox systems to medicinal and pharmaceutical science.

Sustainability Assessment of Mechanochemistry by Using the Twelve Principles of Green Chemistry

“…An additional area of opportunity for mechanocatalysis consist in the use of piezoelectric materials to drive mechanochemical reactions by ball milling (Scheme 13). [186–189] This approach was initially demonstrated in 2015 when the mechanical activation of ZnO nanoparticles in ball mills enabled the synthesis of benzimidazoles 57 [186] . More recently, ZnO and BaTiO 3 were used as additives to drive mechanoredox arylation, borylation and trifluoromethylation reactions, [187,188] as well as to control copper‐catalyzed ATRC reactions [189] .…”