National Engineering Research Center for Process Development of Active Pharmaceutical Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals , Zhejiang University of Technology , Hangzhou 310014 , P.R. China.
J Org Chem. 2020 Jan 17;85(2):1009-1021. doi: 10.1021/acs.joc.9b02951. Epub 2019 Dec 24.
C3-alkenylated and C3-(hetero)arylated 1-indazoles are privileged structural motifs in numerous pharmaceuticals. Direct C3-alkenylation and C3-(hetero)arylation of 1-indazoles have been significantly challenging because of the inert nature of this carbon center. Herein, we present an efficient mechanochemical strategy for palladium-catalyzed C-H/C-H cross-coupling to construct C3-alkenylated and C3-heteroarylated 1-indazoles using low-cost copper oxidants with satisfactory product yields and broad functional group tolerance. The robustness of the developed protocols was further demonstrated by the unprecedented total mechanosynthesis of the intermediate of PLK4 inhibitor CFI-400945 and HIF-1α inhibitor YC-1.
C3-烯基化和 C3-（杂）芳基化的 1-吲唑是许多药物中的重要结构基元。由于这个碳原子中心的惰性，直接 C3-烯基化和 C3-（杂）芳基化 1-吲唑具有很大的挑战性。在此，我们提出了一种有效的机械化学策略，用于钯催化的 C-H/C-H 交叉偶联，使用廉价的铜氧化剂构建 C3-烯基化和 C3-杂芳基化的 1-吲唑，具有令人满意的产率和广泛的官能团耐受性。所开发的方案的稳健性还通过 PLK4 抑制剂 CFI-400945 和 HIF-1α 抑制剂 YC-1 的中间体的前所未有的全机械合成得到了进一步证明。
