Strategic installation of the –CH2CF3 motif via transition-metal-catalyzed C–H functionalization

Abstract

Fluorinated alkyl groups play a crucial role in medicinal chemistry by modulating molecular conformation, metabolic stability, lipophilicity, and biological activity. Among these, the trifluoroethyl (−CH₂CF₃) group has emerged as a valuable motif due to its unique electronic properties and its presence in bioactive molecules and drug candidates. Conventional trifluoroethylation methods typically rely on pre-functionalized substrates, limiting step economy and synthetic efficiency. In contrast, transition-metal-catalyzed C−H functionalization offers a direct and atom-economical alternative for installing this group from simple precursors. This review systematically summarizes recent advances in C−H trifluoroethylation across C(sp), C(sp²), and C(sp³)−H bonds, with emphasis on catalyst design, site selectivity, mechanistic pathways, and synthetic scope, and discusses current challenges and future opportunities in this developing area.