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, while also discussing current challenges and future opportunities in this developing area