Mechanistic Dichotomy in Sulfate Radical Anion-Mediated Oxidative Synthesis of Activated <i>N</i> -Hydroxysuccinimide Esters

A sustainable, transition-metal-free approach for the oxidative esterification of aldehydes with <i>N</i>-hydroxysuccinimide has been developed using ammonium persulfate as the sole oxidant. The protocol affords <i>N</i>-hydroxyimide esters in quantitative yields under mild aqueous acetonitrile conditions, displaying broad substrate scope and high functional group tolerance. These esters serve as versatile intermediates and have been directly transformed, either telescopically or in one pot, into a wide range of pharmaceutically relevant amides. The synthetic utility was demonstrated by the preparation of marketed drugs, including moclobemide, procainamide, acecainide, and bezafibrate, with moclobemide further synthesized on a 100 g scale, highlighting the practicality and industrial relevance of the process. Mechanistic studies, supported by radical trapping and density functional theory calculations, provide unprecedented evidence for sulfate radical anion (SO₄^·-)-mediated hydrogen atom abstraction from aromatic aldehydes. The results suggest that the generation and subsequent radical-radical coupling of acyl and succinimide-N-oxyl radicals constitute the most favorable pathway, while alternative radical and cationic routes may also contribute under reaction conditions. This study not only advances an efficient and scalable amide synthesis but also broadens the mechanistic understanding of sulfate radical anion reactivity in aromatic systems.