Construction of Difluoro-Functionalized Heterocycles via Annulation and Concomitant Fluorine Incorporation

Abstract Herein, we report a novel cascade annulation strategy for the expedient synthesis of difluoro-functionalized quinolines and quinoxalines. This protocol is compatible with both 2-aryl and 2-vinyl anilines, enabling the controllable incorporation of various fluorine-containing functionalities, including CF2H, SCF2H, and SeCF2H. For CF2H installation, the annulation of 2-aryl/vinyl anilines with BrCF2CO2Et was developed, in which BrCF2CO2Et serves as a C1 building block and a difluorocarbene precursor. Notably, in the presence of external sulfur or selenium sources, a one-pot reaction with S/Se and BrCF2CO2Et was realized, providing a diverse array of valuable fluoromethylthio(seleno)-functionalized N-heterocycles under metal-free conditions. Furthermore, the direct introduction of the SCF2H moiety into quinoxalines was achieved via difluoromethyl thiolation under the same reaction conditions.