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

Abstract

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.

Multicomponent Synthesis of Biologically Relevant S‐Diarylmethane Dithiocarbamates Using p‐Quinone Methides

“…To our delight, we found that all of the tested compounds demonstrated promising anti‐cancer activity, and in the case of compounds 3 aa , 3 ak , 3 an and 3 ea , IC 50 value less than 10 μ M was observed (Figure 2). Importantly, all these four compounds demonstrated anti‐proliferative activity comparable to the reported activity of anti‐cancer drugs Doxorubicin and Etoposide in the A549 cell line [25] . These findings explicitly underline the importance of the developed method, enabling straightforward synthesis of novel S ‐diarylmethane dithiocarbamates that could serve as a promising scaffold for designing effective anti‐cancer drugs.…”

“…Importantly, all these four compounds demonstrated anti-proliferative activity comparable to the reported activity of anti-cancer drugs Doxorubicin and Etoposide in the A549 cell line. [25] These findings explicitly underline the importance of the developed method, enabling straightforward synthesis of novel Sdiarylmethane dithiocarbamates that could serve as a promising scaffold for designing effective anti-cancer drugs.…”

Electron Donor‐Acceptor (EDA) Complex Enabled C−C Cross‐Coupling Reactions of α‐Amino Radicals

“…The method included the reaction of tetrahydroisoquinolines 15 a with silyl enol ether of furan 15 b in the presence of organic photocatalyst which is an organic dye (fluorescein), thiourea, and blue LEDs to give lactone-substituted tetrahydroquinoline motifs 15 c in good to excellent yield (Scheme 15). [84] The detailed optimization study revealed that thiourea is essential for the higher yield of the desired 15 c (though without this additive, a maximum 84 % yield could be achieved). The proposed mechanism included a SET between excited fluorescein and amine to generate radical cation intermediate Int-15 d, which was then reacted with molecular oxygen to give The role of thiourea is to scavenge the hydroxy radical, which would most likely interfere in the catalytic cycle.…”