Radical conjugate addition to 2-substituted chromones via an electron donor-acceptor complex

Abstract

A novel photocatalyst-free radical conjugate addition to 2-substituted chromones has been developed, utilizing Hantzsch esters and TMSOTf to efficiently access diverse 2,2-disubstituted chroman-4-ones under mild conditions. Mechanistic studies, including UV-vis spectroscopy and 1H NMR titration, indicate that the reaction proceeds via an electron donor-acceptor (EDA) complex, which is formed in situ through the reaction of TMSOTf with chromones to generate 4-siloxy-1-benzopyrylium salts. This versatile method enables late-stage functionalization of natural chromones, affording structurally diverse scaffolds with promising biological activity. The resulting chroman-4-one derivatives suppress cGAMP-induced immune responses in ISRE assays, whereas their parent chromones enhance these responses. These results highlight chroman-4-ones as promising immunosuppressive scaffolds for therapeutic development.