Visible Light-driven Metal-free C–H Functionalization: Access to New Bioactive Tetrahydroisoquinoline-Butenolide Hybrids via Domino Amine Oxidation/Vinylogous Mannich Reaction

An efficient metal-free visible light-driven two-step domino reaction towards new bioactive tetrahydroisoquinoline-butenolide hybrid compounds was developed for the first time. Combination of fluorescein as photosensitizer and thiourea as an additive was found to be the most effective way to promote an aerobic amine oxidation/vinylogous Mannich domino reaction sequence with yields up to 97% for a broad substrate scope. While fluorescein without thiourea additive gave product in 84% yield, it was even observed that thiourea in absence of fluorescein is also able to promote formation of product with good yield of 75%, which is explained by a potential role of thiourea as an electron-transfer mediator in light-induced amine oxidation. Both experimental and computational evidence supported the crucial role of singlet oxygen in the developed C–H functionalization reaction. In addition, in vitro studies of tetrahydroisoquinoline-butenolide hybrid compounds demonstrated their high antischistosomal and anti-cancer activities.