Theoretical Study of Mechanism and Product Selectivity of Metal-Catalyzed Reactions of Alkynyl Thioethers with Isoxazoles/Anthranils

Density functional theory (DFT) calculations were performed to investigate the detailed mechanisms of metalcatalyzed reactions of alkynyl thioethers with isoxazoles/anthranils. The origins of the product selectivities were also explored. The results show that when [IPrAu(CH3CN)]+ was used as the catalyst, beta-selective addition gave a sulfenylated pyrrole/indole as the primary product. However, the major product was a sulfur-substituted beta-keto enamide, which was formed via alpha-addition, when [Zn(OTf)]+ was used. The product selectivity was determined by the first nucleophilic attack step. We found that the catalyst and substrate both played crucial roles in guiding the product selectivity. The electronic effects of ligands on the catalyst and substituents on the substrate were the dominant factor. For the anthranil substrate, the preference for C1-C6 bond coupling rather than C1-C4 bond coupling can be attributed to effective conjugation between the carbonyl group and the phenyl moiety during C1-C6 bond coupling. These insights into the mechanisms of metal-catalyzed reactions of alkynyl thioethers with isoxazoles/anthranils will facilitate the design of new catalytic reactions of isoxazoles with electron-deficient alkynes.