Trifluoromethylated Heterocycles via Intramolecular Cyclisation: Evolution From Traditional to Green Synthesis

Abstract

The principles of green chemistry have driven modern organic synthesis toward processes that are more efficient, less toxic, and atom‐economical. This review systematically summarizes recent advances in the synthesis of trifluoromethylated heterocycles. The review outlines the structural characteristics and reactivity profiles of electrophilic, nucleophilic, and radical trifluoromethylating reagents. It then explores traditional synthetic strategies, including transition‐metal catalysis (Pd, Cu, and Ag) and metal‐free thermal/chemical oxidant‐mediated reactions. Subsequently, a strong emphasis is placed on emerging green synthetic methodologies. These encompass visible‐light photocatalysis (involving homogeneous Ru/Ir complexes, organic photocatalysts, heterogeneous photocatalysis, and catalyst‐free photochemistry), electrochemistry (anodic oxidation and cathodic reduction), as well as photoelectrocatalysis, mechanochemical and enzymatic catalysis for constructing trifluoromethylated heterocyclic frameworks via cascade cyclisation. Each of these approaches exhibits distinct advantages in terms of reaction efficiency, substrate scope, stereoselectivity, and environmental friendliness. Notably, electrochemical and photocatalytic methods stand out due to their avoidance of chemical oxidants and mild conditions. Meanwhile, enzymatic catalysis offers a novel route for the asymmetric synthesis of chiral trifluoromethylated heterocycles. This review aims to provide a valuable reference for the green, efficient, and precise synthesis of trifluoromethylated heterocycles.