Catalyst-Free Regioselective 1,6-Aza-Michael Addition of para-Quinone Methides with Tetrazoles in Water

A facile catalyst-free regioselective 1,6-aza-Michael addition of para-quinone methides with tetrazoles was efficiently developed using water as a green solvent. This process exhibited broad substrate compatibility, including benzotriazole, pyrazole, and indazole, yielding the corresponding N-substituted azoles with excellent efficiency and regioselectivity. To demonstrate the practicality of this methodology, gram-scale reactions were successfully conducted. The possible mechanistic pathway is elucidated based on the preliminary results from control experiments as well as discrete fourier transform (DFT) calculations, which reveal that the solvent water plays a crucial role in facilitating the reaction by forming hydrogen bonds with the substrate, thereby enhancing the reaction progress.