Photochemical Organocatalytic Synthesis of Thioethers from Aryl Chlorides and Alcohols

• Published in: Journal of the American Chemical Society Vol. 146; no. 5; pp. 2907 - 2912
• Main Authors: Wu, Shuo, Wong, Thomas Hin-Fung, Righi, Paolo, Melchiorre, Paolo
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07-02-2024
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.3c13900

Thioethers, often found in pharmaceuticals and natural compounds, typically involve metal cross-coupling reactions, high temperatures, and the use of disagreeable thiols for their synthesis. Here we present a straightforward, thiol-free organocatalytic protocol that uses mild conditions to stitch together inexpensive alcohols and aryl chlorides, yielding a diverse array of aryl alkyl thioethers. Central to this approach was the discovery that tetramethylthiourea can serve as a simple sulfur source upon intercepting photochemically generated aryl radicals. To form radicals, we used a readily available indole thiolate organocatalyst that, when excited with 405 nm light, gained a strongly reducing power, enabling the activation of typically unreactive aryl chlorides via single-electron transfer. Radical trapping by the thiourea, followed by an alcohol attack via a polar path, resulted in the formation of thioether products.