Regioselective Transition-Metal-Free Synthesis of Diverse Benzothiazoles by Thermally Induced Cyclization of ortho-Halobenzanilides

摘要

The highly regioselective and efficient synthesis of diverse substituted-benzothiazoles, including heterocyclic units and amino groups, was achieved in moderate to high yields from ortho-bromothiobenzanilides, ortho-bromoarylthioureas, orthobromobenzanilides, and ortho-dibromobenzanilides, regardless of the electron density and substituted positions, via the prevalent carbon-sulfur bond formation by thermally induced intramolecular cyclization reaction without using any metal sources or other additives. Polysubstituted-benzothiazoles, particularly 2,4-, 2,6-disubstituted, and 2,4,6-trisubstituted benzothiazoles, could be efficiently synthesized by a facile cascade reaction from appropriate ortho-bromobenzanilides under general thiolation conditions. This benign reaction represents a straightforward and practical approach toward diverse substituted- benzothiazoles. In addition, the remaining bromine substituent of the resulting products was further utilized as a functional handle for the additional diversification and exploited as a complementary solution for the adjustment of harsh reaction condition. This methodology not only allows for the elaboration of benzothiazole molecules, but also provides a new valuable synthetic tool for a range of pharmaceutical applications.