Zhou Tongliang, Zhao Chaoyue, Yang Shiyi, Bisz Elwira, Dziuk Błażej, Lalancette Roger, Szostak Roman, Hong Xin, Szostak Michal
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States.
Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou 310027, P.R. China; School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, P.R. China.
ACS Catal. 2025 Jul 29;15(16):13846-13859. doi: 10.1021/acscatal.5c03458. eCollection 2025 Aug 15.
Developments in organic synthesis over the past century have greatly enabled the discovery of life-saving medicines. In this context, over the past two decades, palladium-catalyzed cross-coupling reactions have transformed the exploration of emerging therapeutics. However, the cross-coupling between aryl halides and hydrazine, NHNH, the smallest bis-nitrogen nucleophile, has been a long-standing challenge due to the reducing capacity of hydrazine and the presence of multiple N-H bonds. These advances have significantly lagged behind modern cross-coupling technologies despite the broad utility of arylhydrazines to serve as a springboard for the discovery of innovative medicines. Herein, we report a general platform for the diversification of pharmaceuticals by late-stage hydrazination. By designing biaryl, sterically demanding biaryl and flexible N-heterocyclic carbene ligands with strong σ-donation and controlled architecture of the catalytic pocket, we have established selective palladium-catalyzed cross-coupling of aryl halides with hydrazine to give highly valuable arylhydrazines. By using this method, we have achieved direct cross-coupling of a variety of complex pharmaceuticals covering various metabolic diseases ranging from life-changing anticancer to blockbuster antiallergic drugs to give broadly useful arylhydrazines that can be converted into heterocyclic frameworks. The developed class of ligands shows notably high %V, while retaining the full flexibility of the catalytic pocket. In this catalysis approach, a remarkably broad range of aryl chlorides and aryl bromides can be systematically applied as cross-coupling partners using mild carbonate bases. The developed ligands feature biaryl-controlled steric environment of the catalytic pocket in combination with strong σ-donicity, which facilitates and integrates individual elementary steps of the catalytic cycle, such as oxidative addition, reductive elimination from Pd center, as well as protection of Pd-(II) intermediate from overreduction. Extensive computational studies have been conducted to gain insight into the mechanism of the coupling and elucidate the key role of biaryl and sterically flexible N-heterocyclic carbene ligands. The presented reactivity establishes a powerful entry into the late-stage cross-coupling with challenging nucleophiles for drug discovery and development.
过去一个世纪有机合成领域的发展极大地推动了救命药物的发现。在此背景下，在过去二十年中，钯催化的交叉偶联反应改变了新型治疗药物的探索方式。然而，芳基卤化物与肼（最小的双氮亲核试剂NHNH）之间的交叉偶联，由于肼的还原能力以及多个N - H键的存在，一直是一个长期存在的挑战。尽管芳基肼作为发现创新药物的跳板具有广泛用途，但这些进展明显落后于现代交叉偶联技术。在此，我们报告了一个通过后期肼化实现药物多样化的通用平台。通过设计具有强σ供电子能力和可控催化口袋结构的联芳基、空间位阻大的联芳基以及柔性N - 杂环卡宾配体，我们实现了芳基卤化物与肼的选择性钯催化交叉偶联，得到了非常有价值的芳基肼。通过使用这种方法，我们实现了多种复杂药物的直接交叉偶联，这些药物涵盖了从改变生活的抗癌药物到重磅抗组胺药物等各种代谢疾病药物，得到了用途广泛的芳基肼，它们可以转化为杂环骨架。所开发的配体类别显示出显著高的%V，同时保留了催化口袋的完全灵活性。在这种催化方法中，使用温和的碳酸盐碱，可以系统地将范围广泛的芳基氯化物和芳基溴化物用作交叉偶联伙伴。所开发的配体具有联芳基控制的催化口袋空间环境以及强σ供电子性，这促进并整合了催化循环的各个基本步骤，如氧化加成、从钯中心的还原消除以及保护钯（II）中间体不被过度还原。已经进行了广泛的计算研究，以深入了解偶联机制并阐明联芳基和空间柔性N - 杂环卡宾配体的关键作用。所展示的反应性为药物发现和开发中与具有挑战性的亲核试剂进行后期交叉偶联提供了有力途径。
