Trifluoromethylation-Induced Lactonization: A Novel Transformation of Unsaturated Carboxylic Acids

Fluorinated drugs are highly important, and one of their common structural motifs is the trifluoromethyl group. As a result, there is an increasing demand for new or improved synthetic pathways toward trifluoromethylated compounds. One such route, developed less than one and a half decades ago, is trifluoromethylation-induced lactonization of unsaturated carboxylic acids. Initial successes (including the only known enantioselective protocol for this reaction) were achieved using Togni's reagent II in the presence of a Cu(I) catalyst (mechanism: radical trifluoromethylation, then Cu-assisted lactonization), then the focus shifted to photocatalytic methods (mechanism: radical trifluoromethylation, single-electron oxidation, then lactonization). Later, electrocatalytic methods were developed too (mechanism: radical trifluoromethylation, single-electron oxidation, then lactonization). Recently, the first CF₃ ⁺ transfer-induced lactonization was finally realized as well. The purpose of this review is to provide a comprehensive overview of the current state of this field of research. First, the importance of trifluoromethylation, CF₃-containing drugs, and lactonizations is explained briefly. Then, possible reaction mechanisms of trifluoromethylation-induced lactonizations are discussed. Finally, I will present known trifluoromethylative lactonizations, grouped according to their mechanisms and the type of chemistry involved.