EDUCATION

1994.09-1998.07  Zhejiang University of Technology

2000.09-2003.06  Zhejiang University of Technology

2003.09-2006.07 Nankai University, SKLEOC, Ph. D.

2006.12-2009.09  University of Geneva

CONTACT

Tel: 0571-88320890

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Address: Zhejiang University of Technology, No.18 Chao Wang Road, Hangzhou, Zhejiang University School of Materials

DISSERTATION

Abstract

    The chiral Lewis acid catalyzed asymmetric Freidel-Crafts reaction has received extensively study and has become one of the most important methods for the preparation of enantiomerically enriched alkylated arenes. However, this reaction is still at initial stage. The scope of the substrates is limited and only the bidentate chelating substrates can be used to provide high enantioselectivity. In the literature, the 1,4-binding and 1,5-binding modes of the substrates coordinated to metal in the catalyst have been developed extensively. In this thesis, we intend to introduce 1,3-binding mode to this reaction and expand the scope of the substrates.

    Firstly, we choose nitroalkenes as substrates to establish 1,3-binding chelating mode, and after screening the Lewis acid, chiral ligands and optimizing the reaction conditions, we found that the (S)-Ph-Bisoxazoline/Zn(OTf)₂ catalyst system was very efficient for this asymmetric Friedel-Crafts reaction of indoles with nitroalkenes. Under the optimal reaction conditions, i.e. 10 mol% Zn(OTf)₂, 12 mol% (S)-Ph-bisoxazoline, and toluene as solvent at 0 oC, a series of arylnitroalkenes, alkylnitroalkenes and -nitro acrylate reacted well with indoles to give the corresponding products with high enantioselectivities (up to 90% ee) in excellent yields. Furthermore, by the help of Chemdraw 3D MM2, we confirm that our 1,3-binding chelating mode of tnitroalkene coordinated to zinc through two oxygen atoms of nitro group is critical to enantiocontrol. The indole attacks nitroalkene from the Re face and produce the product with S configuration.

    To further testify this newly 1,3-binding mode, we developed a new Friedel-Crafts reaction of indoles with N-sulfonyl aldimines. By optimization the reaction conditions, we found that the reactions can be performed smoothly at room temperature (20 ^oC) with DCM as solvent and in the presence of 10 mol% Cu(OTf)₂ and 17 mol% (S)-Bn-bisoxazoline, providing the Friedel-Crafts products in excellent enantioselectivities (up to 96% ee) and high yields. The configuration of the products can be interpreted by 1,3-binding chelating mode and further determined by single-crystal X-ray analysis. 

   To improve the ee values of these transformations, we synthesize a series of non-symmetric chiral bisoxazoline ligands with different substituents in the 4-position of the oxazolines, and found that the ee values of the products in the reaction of indole react with nitrostyrene, can be improved to 88% by using these new ligands. For the substrate of benzylidene malonate, the ee values of product were increased to 80%, which is close to the best results in the literature.

    In all of this study, 63 new compounds, including 18 ligands and related intermediates and 45 Friedel-Crafts products, were synthesized and confirmed by 1H NMR, 13C NMR, microanalysis, MS or HRMS analysis. 

Keywords: asymmetric Friedel-Crafts reaction, 1,3-binding mode, indole, nitroalkenes,  imines

PUBLICATION

1.Yi-Xia Jia, Jun Zhong, Shou-Fei Zhu, Can-Ming Zhang, Qi-Lin Zhou*, Chiral Βrønsted acid catalyzed enantioselective Friedel-Crafts reaction of indoles and α-aryl enamides: construction of chiral quaternary carbons, Angew. Chem. Int. Ed.2007, 46, 5565-5567.

2.Yi-Xia Jia, Jian-Hua Xie, Hai-Feng Duan, Li-Xin Wang, Qi-Lin Zhou*, Asymmetric Friedel–Crafts addition of indoles to N-sulfonyl aldimines: Α simple approach to optically active 3-indolylmethanamine derivatives, Org. Lett. 2006, 8, 1621-1624.

3.Hai-Feng Duan, Yi-Xia Jia, Li-Xin Wang, Qi-Lin Zhou*, Enantioselecitive Rh-catalyzed arylation of N-tosylarylimines with arylboronic acids,Org. Lett. 2006, 8, 2567-2569.

4.Yi-Xia Jia, Shuo-Fei Zhu, Yun Yang, Qi-Lin Zhou*, Asymmetric Friedel–Crafts alkylations of indoles with nitroalkenes catalyzed by Zn(II)-bisoxazoline complexes, J. Org. Chem. 2006, 71, 75-80.