Mechanistic studies and applications of the Cu-catalyzed three-component reactions

Abstract

Combined analyses of experimental and computational studies on the Cu-catalyzed three-component reactions of sulfonyl azides, terminal alkynes and amines, alcohols, or water are described. A range of experimental data support the validity of a common pathway in the reaction of 1-alkynes and two distinct types of azides substituted with sulfonyl- and aryl(alkyl) groups. The main reason for the different outcome from reactions between sulfonyl and aryl(alkyl) azides is attributed to the fragility of the N-sulfonyl triazolyl copper intermediates. These species are readily rearranged to the another key intermediate, ketenimine, into which various nucleophiles such as amines, alcohols or water add to afford the three-component coupled products; amidines, imidates or amides, respectively. In addition, the proposed mechanistic framework is in a good agreement with the obtained kinetic, competition studies, and computational study (B3LYP/$LACV3P^*$+). Such mechanistic insights and computational studies of the Cu-catalyzed three-component reaction enable to develop a new practical procedure for the preparation of 4-substituted 1-(N-sulfonyl)-1,2,3-triazoles. The important heterocycles are obtained regioselectively in good to excellent yield by suppressing the Dimroth-rearrangement of the N-sulfonyl triazolyl copper intermediates into ketenimine species. To expand the scope of these novel coupling reactions, we have also developed intramolecular reaction for the synthesis of 2-sulfonyliminoindolines upon the reaction of 2-ethynylanilines with sulfonyl azides in the presence of CuI salt. In addition, an efficient procedure for $\alpha$-aryl $\beta$-hydroxy imidates has been developed via Cu-catalyzed four-component reaction. Both of two applications of the Cu-catalyzed MCR offer the important pharmacophores and synthetic intermediates in good yield with a wide substrate scope under mild conditions.