Electrocatalytic reductive deuteration of arenes and heteroarenes

• 成果类型: Article
• 署名作者: Bu, Faxiang; Deng, Yuqi; Xu, Jie; Yang, Dali; Li, Yan; Li, Wu; Lei, Aiwen
• 署名单位: Wuhan University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4691
• DOI: 10.1038/s41586-024-07989-7
• 发表日期: 2024-10-17
• 关键词: deuterium; DRUG; hydrogenation; heterocycles; strategies; tritiation

摘要

The incorporation of deuterium in organic molecules has widespread applications in medicinal chemistry and materials science1,2. For example, the deuterated drugs austedo3, donafenib4 and sotyktu5 have been recently approved. There are various methods for the synthesis of deuterated compounds with high deuterium incorporation6. However, the reductive deuteration of aromatic hydrocarbons-ubiquitous chemical feedstocks-to saturated cyclic compounds has rarely been achieved. Here we describe a scalable and general electrocatalytic method for the reductive deuteration and deuterodefluorination of (hetero)arenes using a prepared nitrogen-doped electrode and deuterium oxide (D2O), giving perdeuterated and saturated deuterocarbon products. This protocol has been successfully applied to the synthesis of 13 highly deuterated drug molecules. Mechanistic investigations suggest that the ruthenium-deuterium species, generated by electrolysis of D2O in the presence of a nitrogen-doped ruthenium electrode, are key intermediates that directly reduce aromatic compounds. This quick and cost-effective methodology for the preparation of highly deuterium-labelled saturated (hetero)cyclic compounds could be applied in drug development and metabolism studies. Reductive deuteration and deuterodefluorination of arenes and heteroarenes is achieved through a scalable and general electrocatalytic method using a nitrogen-doped ruthenium electrode and heavy water.