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Synlett 2015; 26(16): 2261-2266
DOI: 10.1055/s-0035-1560462
DOI: 10.1055/s-0035-1560462
letter
Regioselective Friedel–Crafts Reactions of N-Substituted Glyoxylamide with Indoles Catalyzed by Brønsted Acid
Further Information
Publication History
Received: 10 June 2015
Accepted after revision: 17 July 2015
Publication Date:
25 August 2015 (online)
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 compoundSupporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1560462.
- Supporting Information
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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.
For reviews on indoles, see:
For selected examples, see:
For selected examples, see:
For selected examples, see:
For selected examples, see:
For selected examples, see:
For selected examples, see:
N-Substituted glyoxylamides 1 were prepared according to the reported procedures, see:
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:
2-[(1-methyl-1H-indol-6-yl) oxy]acetamide was synthesized from ethyl 2-[(1-methyl-1H-indol-6-yl)oxy]acetate according to the literature procedures, see: