Homogenous Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles: Scope and Mechanistic Studies

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• 作者：Ying Duan ; Lu Li ; Mu-Wang Chen ; Chang-Bin Yu ; Hong-Jun Fan ; Yong-Gui Zhou
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：May 28, 2014
• 年：2014
• 卷：136
• 期：21
• 页码：7688-7700
• 全文大小：854K
• 年卷期：v.136,no.21(May 28, 2014)
• ISSN：1520-5126

文摘

An efficient palladium-catalyzed asymmetric hydrogenation of a variety of unprotected indoles has been developed that gives up to 98% ee using a strong Br酶nsted 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鈺怌 bond of indoles was the significant intermediate in this reaction. The important proposed active catalytic Pd鈥揌 species was observed with ¹H NMR spectroscopy. It was found that proton exchange between the Pd鈥揌 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鈥揌 generation step. The strong Br酶nsted acid activator can remarkably decrease the energy barrier for both Pd鈥揌 generation and hydrogenation. The high enantioselectivity arises from a hydrogen-bonding interaction between N鈥揌 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.