Synthesis of 2‐(Trifluoromethyl)Azetidines by Strain‐Release Reactions of 2‐(Trifluoromethyl)‐1‐Azabicyclo[1.1.0]Butanes

Abstract Substituted azetidines are privileged heterocyclic scaffolds in medicinal chemistry and have become synthetic targets of high interest in recent years. With the goal of developing a new access to azetidines incorporating the pharmaceutically relevant trifluoromethyl group, the reactivity of 2‐(trifluoromethyl)‐1‐azabicyclo[1.1.0]butanes was investigated in polar strain‐release reactions. By using benzyl chloroformate or trifluoroacetic anhydride as reacting partners, diversely substituted 3‐chloroazetidines, 3‐substituted azetidines and azetidin‐3‐ols bearing a trifluoromethyl group at C2 could be readily synthesized. In addition, palladium‐catalyzed hydrogenolysis reactions provided an entry to cis‐ 3‐aryl‐2‐trifluoromethyl azetidines.