α-CF3 radical chemistry: from generation to application in organic synthesis
Zhenlei Zou1, Jie Dong1, Yuxia Yang2
1Biomimetic Energy Laboratory, School of Electrical and Information Engineering, Tongling University Tongling 244000 China.
Abstract:
The α-trifluoromethyl (α-CF3) group represents a privileged bioisostere whose strategic incorporation into pharmaceuticals and agrochemicals markedly improves lipophilicity, bioavailability, and metabolic stability, thereby underpinning its status as a cornerstone of modern molecular design. Despite its significance, the installation of the α-CF3 group is often impeded by the poor stability of traditional nucleophilic α-trifluoromethyl anion precursors. These species are highly susceptible to deleterious β-fluoride elimination, thereby complicating their generation and practical application. Radical pathways bypass traditional polarity mismatches and enable the mild homolytic activation of inert C-H bonds, facilitating the high-value transformation of precursors such as trifluoropropanoic acid and trifluoroethanol. This review systematically summarizes advances from 2015 to 2026 in constructing trifluoroethylated compounds via three core strategies: transition metal-catalyzed cross-coupling, radical addition, and leaving-group-assisted transformations. Special emphasis is put on various transformation paths and proposed mechanisms.
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