Brønsted Acid-Mediated Synthesis of Isocoumarins and Isoquinolines

Abstract Heterocyclic compounds are of significant importance in the fields of organic synthesis and medicinal chemistry. Current synthetic methods for these molecules often rely on specific building blocks or transition-metal catalysis, which impose certain limitations in terms of methodology. Consequently, the development of metal-free synthetic methodologies for heterocycles is of great importance. In this study, readily available and inexpensive additives, TsOH·H₂O and CH₃COOH, were employed as the mediators. By modulating the solvent system, isocoumarin and isoquinoline derivatives were efficiently synthesized in CH₃CN and DMF, respectively. Notably, this method enables a rapid and efficient synthesis of the natural product Thunberginol A under metal-free conditions. This strategy offers a practical and efficient approach for constructing relevant drug-like core skeletons.