化学学报 ›› 2012, Vol. 70 ›› Issue (24): 2484-2488.DOI: 10.6023/A12100821 上一篇    下一篇

研究论文

通过对映选择性质子化实现吲哚的不对称C—H官能团化反应研究

邱晃, 张丹, 刘顺英, 邱林, 周俊, 钱宇, 翟昌伟, 胡文浩   

  1. 华东师范大学上海市分子治疗与新药创制工程技术研究中心 上海 200062
  • 收稿日期:2012-10-25 出版日期:2012-12-28 发布日期:2012-11-29
  • 通讯作者: 胡文浩 E-mail:whu@chem.ecnu.edu.cn
  • 基金资助:

    项目受国家自然科学基金(Nos. 20932003, 21125209)和中国科技部“973”计划(No. 2011CB808600)资助.

Asymmetric C—H Functionalization of Indoles via Enantioselective Protonation

Qiu Huang, Zhang Dan, Liu Shunying, Qiu Lin, Zhou Jun, Qian Yu, Zhai Changwei, Hu Wenhao   

  1. Shanghai Engineering Research Centre of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai, 200062
  • Received:2012-10-25 Online:2012-12-28 Published:2012-11-29
  • Supported by:

    Project supported by the National Natural Science Foundation of China (Nos. 20932003 and 21125209) and the Ministry of Science and Technology of the People’s Republic of China (No. 2011CB808600).

研究了醋酸铑[Rh2(OAc)4]与手性磷酸共催化的芳基重氮乙酸酯对吲哚化合物的不对称C—H官能团化反应, 通过对吲哚C—H官能团化反应质子转移机制的研究, 提出了通过不对称质子化实现金属卡宾与吲哚的C—H不对称官能团化反应的新策略. 通过吲哚C—H官能团化反应氘代实验证明, 在金属卡宾对N-烷基吲哚的碳氢官能团化中, 质子迁移是一个分子间的反应, 需要借助一个“质子梭”试剂完成, 因此通过应用“手性质子梭”催化的不对称质子化有望实现反应的对映选择控制. 通过选用手性磷酸作为“手性质子梭”实现了吲哚C—H官能团化反应的不对称催化, 重氮化合物在醋酸铑的催化下形成金属卡宾, 金属卡宾与吲哚反应生成潜手性的离子对中间体, 在催化剂量的手性磷酸存在下, 质子迁移通过双功能的手性磷酸完成, 通过手性磷酸对潜手性的离子对中间体的不对称质子化实现了反应的对映选择性控制. 反应给出了优秀的产率(最高可达99%), 良好到优秀的对映选择性(最高可达94% ee), 且此反应对其他N-芳基和N-硅基吲哚也有良好的反应兼容性.

关键词: C—H官能团化, 共催化, 吲哚衍生物, 不对称质子化

Asymmetric C—H functionalization of indoles from Rh2(OAc)4 and chiral phosphoric acid co-catalyzed reactions of aryl diazoacetates with indoles has been investigated. Through mechanistic study regarding to the proton transfer pathway of the C—H functionalization of indoles, a new strategy to achieve the asymmetric C—H functionalization of indoles from metal carbenoids via enantioselective protonation has been proposed. We initially carried out a deuterium isotope experiments in order to obtain more insight into the proton transfer process of the C—H functionalization of indoles, and the experiments indicated an “indirect proton transfer” in the reaction. A proton-transfer shuttle such as H2O was needed to complete the reaction. The observation provides us an opportunity to design a chiral proton-transfer shuttle to achieve the asymmetric C—H functionalization. In this paper, Rh2(OAc)4 catalyzed diazo decomposition of a aryl diazoacetate generates a metal carbenoid. Reaction of the metal carbenoid with an indole at C-3 position generates a zwitterionic intermediate. A bifunctional chiral phosphoric acid serves as a chiral proton shuttle and helps the proton transfer process via an enantioselective protonation to finish the reaction in high yield and enantioselectivity. A number of indoles including N-alkyl, aryl , silyl and a number of α-aryl-α-diazoesters are well tolerated under the established catalytic conditions, providing good to high enantioselectivity (up to 94% ee) in excellent yield (up to 99% yield). A representative procedure for the enantioselective C—H functionalization of indoles is as following: A mixture of 6-chloro-N-methyl indole (1e) (41 mg, 0.25 mmol), transition metal catalyst Rh2(OAc)4 (1 mg, 0.0025 mmol, 1 mol%), chiral phosphoric acid co-catalyst (R)-4j (3.8 mg, 0.005 mmol, 2 mol%) and 4? MS (100 mg) in 1 mL of toluene was stirred at the 0 ℃. Methyl phenyldiazo acetate (2a) (53 mg, 0.3 mmol) in 1 mL of toluene was added over 1 h period of time via a syringe pump. After completion of the addition, the reaction was stirred for additional 5 min at the same temperature. Solvent was evaporated under reduced pressure to give corresponding crude product. The crude product was purified by flask chromatography on silica gel (eluent: EtOAc/light petroleum ether, VV=1∶40~1∶10) to give the pure product 3q in 92% yield with 94% ee.

Key words: C—H functionalization, cooperative catalysis, indoles, enantioselective protonation