Three-component Synthesis of Trifluoromethyl Compounds: A DecadeReview

This review surveys the rapidly expanding toolbox of three-component reactions that introduce a CF3 group into organic scaffolds, with emphasis on protocols that are simultaneously lowcost, operationally simple, and environmentally sustainable. A decade of innovation has transformed the synthesis of trifluoromethyl compounds into mild, green, and broadly applicable tactics. Radical cascades, transition-metal catalysis, and polar (nucleophilic/electrophilic) manifolds now allow chemists to assemble complex fluorinated molecules directly from three inexpensive, commercially available fragments. Constructing C-C bonds with pre-fluorinated building blocks has emerged as the most general strategy, tolerating a wider substrate scope than de-novo C-F bond formation. Collectively, these advances deliver rapid molecular complexity while minimizing waste, solvent, and energy input. The next frontier lies in merging reaction with photo- and electrochemical activation to achieve CF3 incorporation under even greener conditions, and in developing robust asymmetric variants that can install multiple contiguous stereocenters in a single flask.