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‐CF3 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‐CF3 ketones were applied in aqueous reaction medium. Control and 18O‐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‐CF3 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