Synthesis of Amide-Functionalized Isoquinoline Derivatives by Photo-Induced Carbamoyl Radical Cascade Amidation/Cyclization

Abstract

Isoquinoline-1,3-dione derivatives are of paramount importance in pharmaceutical research due to their versatile bioactivities, including notable anti-tumor and antibacterial properties. This study developed a novel method to synthesis of amide-functionalized isoquinoline derivatives by a cascade amidation/cyclization of N-(methacryloyl)benzamide with carybamonyl radical, generated from oxamic acids with the organic photosensitizer 4CzIPN. Mechanistic investigations, supported by radical scavenger experiments and HRMS analysis, unequivocally established a radical-mediated reaction pathway, with control studies validating the proposed cyclization cascade. This protocol offers distinct advantages including mild reaction conditions, environmental benignity, and broad substrate scope for the synthesis of amide-functionalized isoquinoline-1, 3-diones. Furthermore, this synthetic platform has been successfully extended to the synthesis of amide-functionalized oxindoles and succinimides bearing α-quaternary carbon centers, underscoring its broad synthetic utility.