Homogenous Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope and Mechanistic Studies
Homogenous Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope and Mechanistic Studies
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均相钯催化未保护吲哚的不对称氢化：范围和机理研究
DOI：
10.1021/ja502020b
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发表时间：
2014-05-28
影响因子：
15
通讯作者：
Zhou, Yong-Gui
中科院分区：
文献类型：
--
作者：
Duan, Ying;Li, Lu;Zhou, Yong-Gui
利用强布朗斯特酸作为活化剂，钯催化多种无保护吲哚的不对称加氢反应可产生高达98%的ee。该方法应用于含手性吲哚骨架的生物活性产物的简易合成。研究了钯催化不对称氢化反应的机理。同位素标记反应和ESI-HRMS证实，由吲哚的C=C键质子化形成的一种铝盐是该反应的重要中间体。用H-1核磁共振光谱观察了重要的活性催化物质Pd-H。研究发现，Pd-H活性物质与溶剂三氟乙醇（TFE）之间没有发生质子交换，尽管以前在金属氢化物和酒精溶剂之间观察到这种质子交换。密度泛函理论计算进一步揭示了pd催化吲哚不对称加氢反应的机理。实验和理论研究的结合表明，钯催化的氢化过程经历了一个逐步的外球加氢和离子加氢机制。氢气的活化是由Pd配合物的三氟乙酸通过六元环过渡态辅助的异裂解过程。由于极性溶剂TFE能够稳定Pd-H生成步骤中的离子中间体，该反应在极性溶剂TFE中进行得很好。强Bronsted酸活化剂能显著降低Pd-H生成和加氢的能垒。高对映选择性是由于在八元环过渡态上，铝盐的N-H与配位三氟乙酸的氧之间的氢键相互作用导致氢化物转移，而活性手性Pd配合物是典型的双功能催化剂，既影响铝盐与Pd配合物的配位三氟乙酸之间的氢键相互作用，也影响其氢键相互作用。值得注意的是，pd催化的不对称氢化反应相对耐受氧、酸和水。
An efficient palladium-catalyzed asymmetric hydrogenation of a variety of unprotected indoles has been developed that gives up to 98% ee using a strong Bronsted acid as the activator. This methodology was applied in the facile synthesis of biologically active products containing a chiral indoline skeleton. The mechanism of Pd-catalyzed asymmetric hydrogenation was investigated as well. Isotope-labeling reactions and ESI-HRMS proved that an iminium salt formed by protonation of the C=C bond of indoles was the significant intermediate in this reaction. The important proposed active catalytic Pd-H species was observed with H-1 NMR spectroscopy. It was found that proton exchange between the Pd-H active species and solvent trifluoroethanol (TFE) did not occur, although this proton exchange had been previously observed between metal hydrides and alcoholic solvents. Density functional theory calculations were also carried out to give further insight into the mechanism of Pd-catalyzed asymmetric hydrogenation of indoles. This combination of experimental and theoretical studies suggests that Pd-catalyzed hydrogenation goes through a stepwise outer-sphere and ionic hydrogenation mechanism. The activation of hydrogen gas is a heterolytic process assisted by trifluoroacetate of Pd complex via a six-membered-ring transition state. The reaction proceeds well in polar solvent TFE owing to its ability to stabilize the ionic intermediates in the Pd-H generation step. The strong Bronsted acid activator can remarkably decrease the energy barrier for both Pd-H generation and hydrogenation. The high enantioselectivity arises from a hydrogen-bonding interaction between N-H of the iminium salt and oxygen of the coordinated trifluoroacetate in the eight-membered-ring transition state for hydride transfer, while the active chiral Pd complex is a typical bifunctional catalyst, effecting both the hydrogenation and hydrogen-bonding interaction between the iminium salt and the coordinated trifluoroacetate of Pd complex. Notably, the Pd-catalyzed asymmetric hydrogenation is relatively tolerant to oxygen, acid, and water.