Three‐Component Coupling of α‐Trifluoromethyl Carbonyls, Azides and Amines for the Regioselective Synthesis of 1,4,5‐Trisubstituted 1,2,3‐Triazoles

Abstract A metal‐free three‐component coupling of α‐CF 3 carbonyls, azides and amines for the regioselective synthesis of 1,4,5‐trisubstituted 1,2,3‐triazoles in the air is established. Various substituted 4‐amide 1,2,3‐triazoles were obtained when the enolizable α‐CF 3 ketones were applied in aqueous reaction medium. Control and 18 O‐labelling experiments revealed that the in situ generated β‐oxo amide was responsible for the formal oxygen‐shift and the subsequent [3+2] cycloaddition reaction, with amine as both the catalyst and reactant. In the case of non‐enolizable α‐CF 3 esters, the densely functionalized 5‐amino 1,2,3‐triazoles were achieved exclusively, which could enable the late‐stage functionalization of complex biological molecules. magnified image