Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.; New York University (NYU)-East China Normal University Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China.
Sci Adv. 2017 Mar 8;3(3):e1602467. doi: 10.1126/sciadv.1602467. eCollection 2017 Mar.
Multicomponent reactions (MCRs) represent an ideal organic synthesis tool for the rapid construction of complex molecules due to their step and atom economy. Compared to two-component reactions, the development of new MCRs has been greatly limited during the 170 years since the first MCR was reported. Theoretically, the trapping of an active intermediate generated from two components by a third component could change the traditional two-component reaction pathway, leading to the discovery of MCRs. We report an example of the trapping of α-imino enols generated in situ from 1-sulfonyl-1,2,3-triazoles via α-imino metal carbene species by vinylimine ions using C(2)-substituted indoles and paraformaldehyde as precursors in the presence of a rhodium(II) catalyst. The traditional enol-ketone transformation pathway was suspended by the trapping procedure and efficiently switched to an MCR pathway to produce α-amino-β-indole ketones in moderate to good yields. Unexpectedly, the resulting products and the theoretical density functional theory (DFT) calculation results indicated that the enolic carbon had a stronger nucleophilicity than the well-known traditional enamic carbon in the trapping process. The reaction mechanism was investigated using control experiments and detailed DFT calculations, and the synthetic application of the products was also illustrated. The developed strategy provides a mild and rapid access to α-amino-β-indole ketones and suggests a rationale for the discovery of MCRs by trapping an active intermediate with a third component in a traditional two-component reaction pathway.
多组分反应 (MCRs) 因其具有步骤经济性和原子经济性，是快速构建复杂分子的理想有机合成工具。与二组分反应相比，自第一个 MCR 被报道以来的 170 年中，新 MCR 的发展受到了极大的限制。理论上，通过第三组分捕获由两个组分生成的活性中间体可以改变传统的二组分反应途径，从而发现 MCRs。我们报告了一个通过α-亚氨基金属卡宾物种原位捕获由 1-磺酰基-1,2,3-三唑生成的α-亚氨基烯醇的实例，使用 C(2)-取代的吲哚和多聚甲醛作为前体，在铑(II)催化剂的存在下，乙烯亚胺离子作为第三组分。通过捕获程序，传统的烯醇-酮转化途径被暂停，并有效地切换到 MCR 途径，以中等至良好的产率生成α-氨基-β-吲哚酮。出乎意料的是，所得产物和理论密度泛函理论 (DFT) 计算结果表明，在捕获过程中，烯醇碳的亲核性比众所周知的传统烯胺碳更强。通过对照实验和详细的 DFT 计算研究了反应机理，并说明了产物的合成应用。所开发的策略为通过在传统的二组分反应途径中用第三组分捕获活性中间体来提供温和快速地制备α-氨基-β-吲哚酮的方法，并为通过捕获活性中间体发现 MCRs 提供了理论依据。
