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

R. Zhu; Q. Y. Liang; Y. M. Gong; Q. Y. Pu; Z. Y. Wang; C. Wang; L. Zhou; J. Sun

doi:10.1055/s-0036-1590953

Synlett, Table of Contents

Synlett 2018; 29(04): 452-456
DOI: 10.1055/s-0036-1590953

letter

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

R. Zhu

^aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China

^bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. of China

,

Q. Y. Liang

^aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China

^bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. of China

,

Y. M. Gong

^aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China

^bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. of China

,

Q. Y. Pu

^aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China

^bUniversity of Chinese Academy of Sciences, Beijing 100049, P. R. of China

,

Z. Y. Wang

^cDepartment of Chemistry, Xihua University, Chengdu 610039, P. R. of China Email: wangchao@cib.ac.cn Email: sunjian@cib.ac.cn

,

C. Wang*

^aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China

,

L. Zhou

^aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China

,

J. Sun*

^aNatural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. of China

› Author Affiliations

Abstract

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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

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References

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.

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