Zhang Jianye, Yang Zhaoliang, Liu Chunlei, Wan Hao, Hao Zizhao, Ji Xinrui, Wang Pengjie, Yi Hong, Lei Aiwen
National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang, 330022, P. R. China.
Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P. R. China.
Nat Commun. 2024 Aug 13;15(1):6954. doi: 10.1038/s41467-024-51327-4.
Phenolic compounds have long captivated the interest of organic synthesis, particularly in their quest for selective hydroxylation of arenes using HO as a hydroxyl source. However, the inherent high reactivity and low redox potential of phenols often lead to undesirable overoxidation byproducts. To address this challenge, herein, we develop an electrophotochemical approach, finetuning substrate oxidative potential and enabling para-selective hydroxylation of anilides. This method showcases versatility, accommodating a wide array of substrates, while revealing high regional selectivity and compatibility with diverse functional groups. Moreover, the protocol allows facile late-stage functionalization of biologically active molecules. Mechanistic investigations demonstrate the activation of anilides by the excited state photocatalyst, effectively decreasing their oxidative potential and enhancing regional selectivity during hydroxylation. By using this protocol, important drug molecules such as Paracetamol, Fenretinide, Practolol, and AM404 could be synthesized, demonstrating the applicability of this approach in drug synthesis and late-stage functionalization.
酚类化合物长期以来一直吸引着有机合成领域的关注，特别是在利用HO作为羟基源对芳烃进行选择性羟基化的研究中。然而，酚类固有的高反应活性和低氧化还原电位常常导致产生不需要的过氧化副产物。为应对这一挑战，在此我们开发了一种光电化学方法，微调底物的氧化电位并实现酰胺的对位选择性羟基化。该方法展现出了通用性，适用于多种底物，同时具有高区域选择性以及与多种官能团的兼容性。此外，该方案还允许对生物活性分子进行便捷的后期功能化修饰。机理研究表明，激发态光催化剂可激活酰胺，有效降低其氧化电位并增强羟基化过程中的区域选择性。通过使用该方案，可以合成对乙酰氨基酚、芬维A胺、心得宁和AM404等重要药物分子，证明了该方法在药物合成和后期功能化中的适用性。
