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Synlett 2018; 29(04): 452-456
DOI: 10.1055/s-0036-1590953
letter
© Georg Thieme Verlag Stuttgart · New York

HMPA-Catalyzed One-Pot Multistep Hydrogenation Method for the Synthesis of 1,2,3-Trisubstituted Indolines

R. Zhu
a   Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
b   University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
,
Q. Y. Liang
a   Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
b   University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
,
Y. M. Gong
a   Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
b   University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
,
Q. Y. Pu
a   Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
b   University of Chinese Academy of Sciences, Beijing 100049, P. R. of China
,
Z. Y. Wang
c   Department of Chemistry, Xihua University, Chengdu 610039, P. R. of China   Email: wangchao@cib.ac.cn   Email: sunjian@cib.ac.cn
,
C. Wang*
a   Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
,
L. Zhou
a   Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
,
J. Sun*
a   Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
› Author AffiliationsWe are grateful for the financial support from the Western Light ­Talents Training Program of Chinese Academy of Sciences, the National Natural Science Foundation of China (Project No. 21402185).
Further Information

Publication History

Received: 18 September 2017

Accepted after revision: 11 October 2017

Publication Date:
19 December 2017 (online)

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Abstract

A convenient and facile method was developed for the synthesis of 1,2,3-trisubstituted indolines. Starting from indole derivatives and ketones/aldehydes, the corresponding indoline products could be obtained with high yield by the hexamethylphosphoramide (HMPA) catalyzed indole Friedel–Crafts reaction, reduction and direct reductive amination process.

Key words

cascade reaction - reductive animation - HMPA - trichloro­silane - indole - indoline

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1590953.
  • Supporting Information
 

  • References and Notes

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  • 26 General Procedure for the Synthesis of 1-Alkykl-2-methyl-3-alkylindolines 4: A solution of aromatic aldehyde 2 (0.24 mmol, 1.2 equiv) in CH2Cl2 (0.2 mL) was added dropwise to a solution of indole 1 (0.2 mmol), ketone 3 (0.2 mmol) and HMPA (0.04 mmol, 0.2 equiv) in CH2Cl2 (0.6 mL) in a fully dried reaction tube at –20 °C, and then trichlorosilane in CH2Cl2 (0.2 mL, 6 mol/L) was added dropwise to the solution. The solution was stirred at –20 °C for 48 h, then at 0 °C for 18 h. The reaction was then quenched with sat. aq solution of NaHCO3 (2 mL) and basified with NaHCO3 powder. Then the mixture was extracted with EtOAc (10 mL) three times. The combined extracts were washed with brine and dried over anhyd Na2SO4. The combined solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc) to afford pure indoline 4.
  • 27 Analytical data of compound 4a: light yellow oil; yield: 84%; purification by flash chromatography (PE/EA = 125:1). 1H NMR (400 MHz, CDCl3; 2:1 diastereomers): δ = 7.40–7.47 (m, 2 H, ArH, for two diastereomers), 7.11–7.37 (m, 8.4 H, ArH, for two diastereomers), 6.93–7.02 (m, 0.4 H, ArH, minor), 6.79 (t, J = 6.9 Hz, 0.6 H, ArH, major), 6.41–6.54 (m, 2 H, ArH, for two dia­stereomers), 5.97 (d, J = 7.0 Hz, 0.6 H, ArH, major), 4.79 (q, J = 6.9 Hz, 0.3 H, CH, minor), 4.53 (q, J = 6.9 Hz, 0.6 H, CH, major), 3.84–4.02 (m, 1 H, CH, for two diastereomers), 3.42–3.59 (m, 1 H, CH, for two diastereomers), 2.78–3.06 (m, 2 H, CH2, for two diastereomers), 1.62 (d, J = 6.9 Hz, 1 H, CH3, minor), 1.51 (d, J = 6.9 Hz, 2 H, CH3, major), 1.26 (d, J = 6.6 Hz, 2 H, CH3, major), 0.95 (d, J = 6.6 Hz, 1 H, CH3, minor). 13C NMR (101 MHz, CDCl3): δ = 149.49, 143.79, 140.55, 133.11, 129.36, 128.54, 128.30, 127.02, 126.94, 126.67, 126.02, 124.21, 116.80, 109.64, 60.93, 53.18, 45.84, 34.66, 15.78, 13.56 (major), 150.67, 143.97, 140.62, 132.33, 129.35, 128.26, 128.20, 127.53, 126.71, 125.98, 124.58, 116.44, 107.27, 60.65, 53.39, 46.03, 34.60, 15.83, 15.69 (minor).
  • 28 Analytical data of compound 4b: light yellow oil; yield: 88%; purification by flash chromatography (PE/EA = 100:1). 1H NMR (400 MHz, CDCl3; 2:1 diastereomers): δ = 7.12–7.37 (m, 7 H, ArH, for two diastereomers), 6.94–7.02 (m, 0.4 H, ArH, minor), 6.74–6.91 (m, 2.5 H, ArH, for two diastereomers), 6.41–6.50 (m, 2 H, ArH, for two diastereomers), 6.01 (d, J = 8.0 Hz, 0.6 H, ArH, major), 4.76 (q, J = 6.8 Hz, 0.3 H, CH, minor), 4.50 (q, J = 6.8 Hz, 0.6 H, CH, major), 3.89 (m, 1 H, CH, for two diastereomers), 3.79 (s, 3 H, CH3, for two diastereomers), 3.42–3.58 (m, 1 H, CH, for two diastereomers), 2.77–3.05 (m, 2 H, CH2, for two diastereomers), 1.59 (d, J = 6.9 Hz, 1 H, CH3, minor), 1.49 (d, J = 6.9 Hz, 2 H, CH3, major), 1.25 (d, J = 6.8 Hz, 2 H, CH3, major), 0.94 (d, J = 6.8 Hz, 1 H, CH3, minor). 13C NMR (101 MHz, CDCl3): δ = 158.36, 149.59, 140.58, 135.74, 133.09, 129.37, 128.29, 127.74, 126.97, 126.00, 124.21, 116.72, 113.85, 109.57, 60.81, 55.31, 52.57, 45.83, 34.67, 15.80, 13.69 (major), 150.68, 140.65, 135.90, 132.38, 129.35, 128.26, 128.11, 127.52, 125.97, 124.56, 116.38, 113.50, 107.31, 60.54, 52.85, 46.04, 34.57, 15.94, 15.69 (minor).
  • 29 Analytical data of compound 4c: yellow oil; yield: 88%; purification by flash chromatography (PE/EA = 80:1). 1H NMR (400 MHz, CDCl3; 2:1 diastereomers): δ = 8.17 (t, J = 8.5 Hz, 2 H, ArH, for two diastereomers), 7.61 (d, J = 8.8 Hz, 2 H, ArH, for two diastereomers), 7.08–7.35 (m, 5 H, ArH, for two diastereomers), 7.00 (t, J = 7.0 Hz, 0.3 H, ArH, minor), 6.78 (t, J = 7.0 Hz, 0.6 H, ArH, major), 6.46–6.61 (m, 2 H, ArH, for two diastereomers), 6.38 (d, J = 7.0 Hz, 0.3H, ArH, minor), 5.80 (d, J = 7.0 Hz, 0.6 H, ArH, major), 4.83 (q, J = 7.0 Hz, 0.3 H, CH, minor), 4.54 (q, J = 7.0 Hz, 0.6 H, CH, major), 3.79–4.21 (m, 1 H, CH, for two diastereomers), 3.40–3.66 (m, 1 H, CH, for two diastereomers), 2.66–3.12 (m, 2 H, CH2, for two diastereomers), 1.66 (d, J = 6.9 Hz, 1 H, CH3, minor), 1.54 (d, J = 6.9 Hz, 2 H, CH3, major), 1.28 (d, J = 6.9 Hz, 2 H, CH3, major), 0.97 (d, J = 6.9 Hz, 1 H, CH3, minor). 13C NMR (101 MHz, CDCl3): δ = 151.92, 148.67, 146.99, 140.18, 133.30, 129.33, 128.35, 127.79, 127.46, 126.12, 124.48, 123.89, 117.67, 109.67, 61.20, 53.16, 45.85, 34.61, 15.77, 13.21 (major), 152.15, 150.11, 140.22, 132.32, 129.34, 128.29, 127.61, 126.93, 126.09, 124.91, 123.48, 117.26, 107.15, 60.81, 46.00, 34.68, 15.92, 15.42 (minor).
  • 30 Analytical data of compound 10c: light yellow oil; yield: 89%; purification by flash chromatography (PE/EA = 100:1). 1H NMR (400 MHz, CDCl3): δ = 7.23–7.41 (m, 4 H), 7.05 (d, J = 7.3 Hz, 2 H), 6.60 (t, J = 7.3 Hz, 1 H), 6.29 (d, J = 6.9 Hz, 1 H), 4.64 (q, J = 6.9 Hz, 1 H), 3.19–3.49 (m, 2 H), 3.93 (t, J = 8.3 Hz, 2 H), 1.49 (d, J = 6.9 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 151.22, 141.61, 132.64, 130.21, 128.60, 128.47, 127.22, 124.52, 117.35, 107.37, 54.24, 48.14, 28.28, 16.73.