Regioselective Friedel–Crafts Reactions of N-Substituted Glyoxylamide with Indoles Catalyzed by Brønsted Acid

Dedicated with admiration to Professor K. Peter C. Vollhardt

Abstract

An efficient regioselective Friedel–Crafts reaction of a series of N-substituted glyoxylamide with indoles catalyzed by Brønsted acid was developed. The reactions proceeded smoothly at room temperature and the corresponding N-substituted 2-hydroxy-2-(1H-indol-3-yl) acetamides were afforded in moderate to good yields (up to 89%). When 2 M HCl was used, the bisindole compounds were obtained in good to excellent yield (up to 91%) resulting from a double Friedel–Crafts reaction.

Key words

regioselective Friedel–Crafts reaction - Brønsted acid - N-substituted glyoxylamide - indole - N-substituted 2-hydroxy-2-(1H-indol-3-yl) acetamide - bisindole compound

• References and Notes


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Indoles 2 were purchased from ASTATECH and J&K Scientific Ltd. except ethyl 2-[(1-methyl-1H-indol-6-yl)oxy]acetate and 2-[(1-methyl-1H-indol-6-yl) oxy]acetamide. Ethyl 2-[(1-methyl-1H-indol-6-yl)oxy]acetate was synthesized according to the literature procedures, see:
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• 13 N-Substituted 2-Hydroxy-2-(1H-indol-3-yl) Acetamides 3; General Procedure To a stirred mixture of N-substituted glyoxylamide (1.0 mmol), indoles (1.1 mmol) in dioxane (8 mL) was added AcOH (5.0 mmol) at 25 °C for 0.5 h. After the completion of the reaction (monitored by TLC), the mixture was diluted with H₂O and extracted with EtOAc (4 × 20 mL). The organic layer was washed with sat. brine, dried over anhydrous Na₂SO₄, and the solvent was evaporated to dryness. The crude residue was purified by flash chromatography on silica gel (CH₂Cl₂–MeOH, 80:1) to afford pure N-substituted 2-hydroxy-2-(1H-indol-3-yl) acetamides 3 (61–89% yield). 2,2-Di(1H-indol-3-yl)-N,N-phenyl Acetamide Derivatives 4; General Procedure To a stirred mixture of N-substituted glyoxylamide (1.0 mmol), indoles (2.0 mmol) in dioxane (8 mL) was added HCl (2 mol/L, 0.1 mmol) at 25 °C for 0.5 h. After completion of the reaction (monitored by TLC), the mixture was diluted with H₂O and extracted with EtOAc (3 × 20 mL). The organic layer was washed with sat. brine, dried over anhydrous Na₂SO₄, and the solvent was evaporated to dryness. The crude residue was purified by flash chromatography on silica gel (CH₂Cl₂–MeOH, 100:1) to afford pure 2,2-di(1H-indol-3-yl)-N,N-phenyl acetamide derivatives 4 (69–91% yield). Analytical Data of Some Typical Compounds 2-Hydroxy-2-(1H-indol-3-yl)-N-phenylacetamide (3a) Yield 84%; yellow solid, mp 150–152 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.00 (s, 1 H), 9.90 (s, 1 H), 7.70 (s, 3 H), 7.33–7.28 (m, 4 H), 7.03–6.96 (m, 3 H), 6.08 (s, 1 H), 5.32 (s, 1 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 171.9, 138.9, 136.6, 128.8, 128.0, 126.0, 124.3, 123.6, 121.4, 119.9, 118.9, 114.8, 111.7, 68.9. ESI-HRMS: m/z [M + Na⁺] calcd for C₁₆H₁₄N₂O₂Na: 289.0947; found: 289.0961. Anal. Calcd: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.10; H, 5.35; N, 10.53. 2,2-Di(1H-indol-3-yl)-N-phenylacetamide (4a) Yield 89%; yellow solid, mp 139–141 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.90 (s, 2 H), 10.34 (s, 1 H), 7.65–7.57 (m, 4 H), 7.35 (m, 2 H), 7.28 (t, J = 8.0 Hz, 2 H), 7.19 (s, 2 H), 7.07–7.00 (m, 3 H), 6.95 (t, J = 8.0 Hz, 2 H) 5.55 (s, 1 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 171.0, 138.9, 137.0, 128.8, 126.9, 126.1, 124.1, 121.5, 120.4, 119.3, 118.0, 112.8, 111.0, 42.0. ESI-HRMS: m/z [M + Na⁺]: calcd for C₂₄H₁₉N₃ONa: 388.1420; found: 388.1425. Anal. Calcd: C, 78.88; H, 5.24; N, 11.50. Found: C, 78.79; H, 4.23; N, 9.49. 2-[(3-{2-[(4-chlorophenyl)amino]-1-(1H-indol-3-yl)-2-oxoethyl}-1-methyl-1H-indol-6-yl)oxy]acetate (3d′) Yield 84%; brown solid, mp 194–196 °C. ¹H NMR (600 MHz, DMSO-d ₆): δ = 10.92 (s, 1 H), 10.47 (s, 1 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.36–7.18 (m, 2 H), 7.18 (m, 1 H), 7.07–7.04 (m, 2 H), 6.96–6.94 (m, 2 H), 6.69–6.67 (m, 1 H), 5.48 (s, 1 H), 4.77 (s, 2 H), 4.17 (q, J = 7.2 Hz, 2 H), 3.67 (s, 3 H), 1.21 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 171.9, 169.2, 154.5, 139.3, 137.8, 136.9, 132.5, 131.0, 128.5, 127.0, 122.9, 122.1, 121.6, 121.0, 120.7, 119.8, 112.5, 109.9, 98.6, 65.6, 42.6, 40.7, 32.4, 14.2. ESI-HRMS: m/z [M + Na⁺] calcd for C₂₉H₂₆ClN₃O₄Na: 538.1504; found: 538.1501. Anal. Calcd: C, 67.50; H, 5.08; N, 8.14. Found: C, 67.56; H, 5.00; N, 8.19.