Novel Synthetic Strategies and Mechanistic Insights in the Synthesis of Trifluoromethoxylated Compounds

ABSTRACT

As a highly efficient and versatile structural modification tactic, the installation of the trifluoromethoxy (‐OCF ₃ ) group enables precise tuning of the metabolic stability, lipophilicity, and binding affinity of organic molecules, thereby rendering it a privileged motif widely adopted in modern drug discovery, agrochemical development, and functional materials research. Nevertheless, conventional synthetic strategies toward OCF ₃ ‐functionalized molecules have long suffered from prominent drawbacks: the inherent instability of trifluoromethoxide anions, the paucity of bench‐stable OCF ₃ reagents, and inadequate chemo‐ and regioselectivity. Over the past few decades, pioneering progress in reagent engineering, catalytic system development, and reaction pathway modulation has broken through these persistent limitations, affording selective and efficient routes toward a broad spectrum of OCF ₃ ‐functionalized molecular frameworks. In this review, the significant progress in trifluoromethoxylation chemistry is summarized, which can be systematically categorized into five categories: (1) Transition metal‐catalyzed trifluoromethoxylation; (2) visible‐light‐mediated trifluoromethoxylation; (3) direct installation of the trifluoromethoxy unit via reagent‐mediated processes; (4) heteroatom‐involved trifluoromethoxylation; (5) in situ‐generated OCF ₃ sources.