Three-Component Friedel-Crafts Reaction of Indoles, Glyoxylate, and Amine under Solvent-Free and Catalyst-Free Conditions - Synthesis of (3-Indolyl)glycine Derivatives

Jun-Ling Zhao; Li Liu; Hai-Bo Zhang; Yan-Chao Wu; Dong Wang; Yong-Jun Chen

doi:10.1055/s-2005-922764

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Synlett 2006(1): 0096-0100
DOI: 10.1055/s-2005-922764

LETTER

Three-Component Friedel-Crafts Reaction of Indoles, Glyoxylate, and Amine under Solvent-Free and Catalyst-Free Conditions - Synthesis of (3-Indolyl)glycine Derivatives

Jun-Ling Zhao^a,b, Li Liu*^a, Hai-Bo Zhang^a,b, Yan-Chao Wu^a,b, Dong Wang*^a, Yong-Jun Chen*^a
^a Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, P. R. of China
Fax: +86(10)62554449; e-Mail: yjchen@mail.iccas.ac.cn; e-Mail: dwang210@mail.iccas.ac.cn;
^b Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100080, P. R. of China

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Publication History

Received 21 September 2005
Publication Date:
16 December 2005 (online)

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Abstract

Solvent-free and catalyst-free three-component reactions of indoles, amines, and ethyl glyoxylate gave alkylation products in good to high yields (61-93%), providing a convenient synthesis of (3-indolyl)glycine derivatives.

Key words

solvent-free - catalyst-free - indole - three-component alkylation - amine

References and Notes

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13

4b: colorless oil. IR: 3399, 3051, 2981, 1732, 1602, 1547, 1504, 1239, 1185, 1023 cm^-1. ¹H NMR: δ = 7.88 (d, J = 7.8 Hz, 1 H), 7.37-7.16 (m, 6 H), 6.77 (t, J = 7.3 Hz, 1 H), 6.70 (d, J = 8.6 Hz, 2 H), 5.44 (s, 1 H), 4.35-4.15 (m, 2 H), 3.75 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 172.7, 146.7, 137.4, 129.3, 127.7, 126.4, 122.1, 119.7, 119.6, 118.1, 113.4, 111.0, 109.6, 61.6, 54.3, 32.9, 14.2. HRMS: m/z calcd for C₁₉H₂₀N₂O₂ (M⁺): 308.1525, found: 308.1521.
4c: colorless oil. IR: 3400, 2958, 2870, 1729, 1602, 1503, 1460, 1306, 1200, 1020 cm^-1. ¹H NMR: δ = 7.97 (s, 1 H), 7.83-7.81 (m, 1 H), 7.26-7.10 (m, 5 H), 6.74 (t, J = 7.2 Hz, 1 H), 6.65 (d, J = 7.8 Hz, 2 H), 5.30 (s, 1 H), 4.32-4.07 (m, 2 H), 2.43 (s, 3 H), 1.20 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 172.5, 146.7, 135.2, 133.4, 129.3, 126.8, 121.4, 119.9, 118.8, 118.0, 113.2, 110.6, 107.5, 61.5, 54.1, 14.2, 12.1. HRMS: m/z calcd for C₁₉H₂₀N₂O₃ (M⁺): 308.1525, found: 308.1528.
4d: light yellow oil. IR: 3407, 2983, 2832, 1729, 1603, 1503, 1487, 1309, 1211, 1024 cm^-1. ¹H NMR: δ = 8.24 (s, 1 H), 7.28-7.12 (m, 5 H), 6.89 (dd, J = 8.8, 2.4 Hz, 1 H), 6.76 (t, J = 7.3 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 2 H), 5.37 (s, 1 H), 4.32-4.17 (m, 2 H), 3.88 (s, 3 H), 1.25 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 172.8, 154.3, 146.7, 131.6, 129.4, 126.2, 123.9, 118.2, 113.5, 112.9, 112.0, 101.1, 61.6, 55.9, 54.4, 21.1, 14.2. HRMS: m/z calcd for C₁₉H₂₀N₂O₃ (M⁺): 324.1474, found: 324.1476.
4e: white solid; mp 123-125 °C. IR: 3409, 3381, 2985, 1710, 1602, 1506, 1455, 1314, 1270, 1021 cm^-1. ¹H NMR: δ = 8.27 (s, 1 H), 7.95 (d, J = 1.8 Hz, 1 H), 7.24 (dd, J = 8.6, 1.8 Hz, 1 H), 7.16-7.04 (m, 4 H), 6.72 (m, 1 H), 6.60 (dd, J = 8.6, 1.0 Hz, 2 H), 5.29 (s, 1 H), 4.26-4.08 (m, 2 H), 1.20 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 172.5, 146.4, 135.2, 129.4, 127.5, 125.4, 124.5, 122.2, 118.4, 115.3, 113.6, 113.3, 113.0, 112.1, 61.9, 54.2, 14.1. HRMS: m/z calcd for C₁₈H₁₇N₂O₂ (M⁺): 372.0473, found: 372.0477.
4f: light yellow oil. IR: 3381, 2982, 2221, 1730, 1604, 1506, 1471, 1230, 1195, 1099 cm^-1. ¹H NMR: δ = 8.65 (s, 1 H), 8.22 (s, 1 H), 7.44-7.43 (m, 2 H), 7.36 (d, J = 2.0 Hz,
1 H),7.16-7.12 (m, 2 H), 6.75 (t, J = 7.3 Hz, 1 H), 6.63 (d, J = 8.1 Hz, 2 H), 5.37 (s, 1 H), 4.30-4.11 (m, 2 H), 1.22 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 171.8, 146.0, 129.3, 125.7, 125.6, 125.5, 125.4, 120.5, 118.6, 113.8, 113.6, 112.4, 103.3, 62.1, 54.1, 14.1. HRMS: m/z calcd for C₁₉H₁₇N₃O₂ (M⁺): 319.1321, found: 319.1326.
4j: white solid; mp 117-119 °C. IR: 3311, 3280, 2978, 2835, 1732, 1565, 1452, 1230, 1196, 1099 cm^-1. ¹H NMR: δ = 8.70 (s, 1 H), 7.82 (d, J = 1.8 Hz, 1 H), 7.35-7.22 (m, 6 H), 7.11-7.07 (m, 2 H), 4.66 (s, 1 H), 4.26-4.11 (m, 2 H), 3.86 (d, J = 13.0 Hz, 1 H), 3.81 (d, J = 13.0 Hz, 1 H), 2.60 (br s, 1 H), 1.23 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 173.2, 139.1, 135.0, 128.6, 128.5, 127.7, 127.4, 125.2, 124.3, 122.1, 113.2, 112.9, 112.5, 61.4, 57.2, 51.7, 14.2. HRMS: m/z calcd for C₁₉H₂₀N₂O₂Br (M + H): 387.0702, found: 387.0708.
4m: light yellow oil. IR: 3409, 2979, 2932, 1729, 1592, 1495, 1450, 1187, 1025, 747 cm^-1. ¹H NMR: δ = 8.09 (s, 1 H), 7.56 (d, J = 7.6 Hz, 1 H), 7.36-7.22 (m, 6 H), 7.08-7.00 (m, 2 H), 4.70 (s, 1 H), 4.25-4.09 (m, 2 H), 3.84 (d, J = 13.0 Hz, 1 H), 3.79 (d, J = 13.0 Hz, 1 H), 2.46 (s, 3 H), 1.94 (s, 1 H), 1.21 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 173.5, 139.7, 136.0, 128.4, 128.4, 127.1, 125.7, 122.9, 122.7, 120.4, 120.1, 117.2, 113.8, 61.1, 57.6, 51.5, 16.6, 14.2. HRMS: m/z calcd for C₂₀H₂₂N₂O₂ (M⁺): 322.1681, found: 322.1677.
4n: white solid; mp 98-99 °C. IR: 3403, 3182, 2960, 2858, 1729, 1495, 1460, 1301, 1221, 1183 cm^-1. ¹H NMR: δ = 7.97 (s, 1 H), 7.74 (d, J = 7.3 Hz, 1 H), 7.30-7.22 (m, 6 H), 7.13-7.07 (m, 2 H), 4.67 (s, 1 H), 4.23-4.00 (m, 2 H), 3.78 (d, J = 13.2 Hz, 1 H), 3.72 (d, J = 13.2 Hz, 1 H), 3.24-3.13 (m, 1 H), 2.20 (s, 1 H), 1.29-1.26 (m, 6 H), 1.14 (t, J = 7.1 Hz, 3 H). ¹³C NMR: δ = 173.2, 143.2, 140.0, 135.2, 128.3, 127.0, 126.8, 121.3, 119.8, 119.5, 110.5, 106.5, 60.9, 56.5, 51.0, 25.4, 23.2, 22.1, 14.1. HRMS: m/z calcd for C₂₂H₂₆N₂O₂ (M⁺): 350.1994, found: 350.1999.

14

The scale-up experiment was performed on a gram scale: To a stirred mixture of 1a (1.0 g, 8.5 mmol) and benzylamine (3b; 1.43 mL, 1.4 g, 12.8 mmol), 2 (1.3 g, 12.8 mmol) was added at ambient temperature. The reaction mixture was stirred for 40 min. The crude product was purified by flash chromatography on silica gel (petroleum ether-EtOAc, 4:1) to give ethyl 2-(1H-indol-3-yl)-2-(benzylamino)acetate (4g, [4] 2.06 g, 78%).