中科院上海有机化学研究所马大伟团队报道了铜催化的磺酰胺与(杂)芳基氯化物/溴的偶联反应。相关研究成果于2022年9月6日发表在《德国应用化学》。

N-（杂）芳基磺酰胺单元是药物开发的关键骨架之一。磺酰胺的直接N-芳基化是制备N-（杂）-芳基磺酰胺的一种非常有吸引力的方法，因为它避免了先前缩合方法导致的潜在遗传毒性问题。尽管已经开发了许多催化体系，但大多数已知方法存在反应范围有限和金属催化剂和配体可用性不方便的问题。

该文中，研究人员描述了铜和草酰胺（或4-羟基吡啶酰胺）的组合，为磺胺与富电子和贫电子（杂）芳基卤化物的偶联提供了强大的催化体系。在100℃下，在2-5mol%的铜盐和草酰胺类存在下，多种伯磺胺和仲磺胺能够与一系列（杂）芳基溴化物偶联。在10mol%的Cu₂O和4-羟基吡啶酰胺的作用下，伯磺胺与（杂）芳基氯化物的偶联效果良好，得到了具有良好多样性的N-芳基磺酰胺。催化方法使四种含氯市售药物直接磺酰胺化，并由相应的芳基卤化物制备两种磺酰胺药物。

附：英文原文

Title: Cu-Catalyzed Coupling Reactions of Sulfonamides with (Hetero)Aryl Chlorides/Bromides

Author: Qiaoli Li, Lanting Xu, Dawei Ma

Issue&Volume: 2022-09-06

Abstract: The  N  -(hetero)aryl sulfonamide unit is one of the privileged skeletons for drug development. Direct  N  -arylation of sulfonamides is a very attractive approach for preparing  N  -(hetero)- aryl sulfonamides because it avoids the potential genotoxic problem resulted from the previous condensation method. Although a number of catalytic systems have been developed, most known methods suffer from limited reaction scope and inconveniency on metal catalyst and ligand availability. Here we described that the combination of copper and oxalamides (or 4-hydroxypicolinamides) offers a powerful catalytic system for coupling of sulfonamides with both electron-rich and electron-poor (hetero)aryl halides. A wide range of primary and secondary sulfonamides were able to couple with a series of (hetero)aryl bromides in the presence of 2-5 mol% copper salts and oxalamides at 100  o  C. Coupling of primary sulfonamides with (hetero)aryl chlorides worked well under the action of 10 mol% Cu  2  O and a 4-hydroxypicolinamide to afford  N  -aryl sulfonamides in excellent diversity. The catalytic method enabled direct sulfonamidation of four chloro-containing marketed drugs and preparation of two sulfonamide drugs from the corresponding aryl halides.

DOI: 10.1002/anie.202210483

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202210483