β-Nitroacrylates as Useful Building Blocks for the Synthesis of Alkyl Indole-2-Carboxylates

Abstract

Polyfunctionalized alkyl indole 2-carboxylates can be easily synthesized starting form β-nitroacrylates and o-bromoanilines through an addition–elimination process followed by an intramolecular palladium-catalyzed Heck reaction.

Key words

indoles - Heck reaction - β-nitroacrylates - cyclization - Michael addition

• References and Notes

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• 13 The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) bound to polystyrene (3 mmol/g) was purchased from Sigma–Aldrich (01961-5G-F) and used directly without any manipulation.
• 14 Synthesis of Indoles 5; General Procedure: o-Bromoaniline 1 (0.5 mmol) and β-nitroacrylate 2 (0.5 mmol) were stirred at 70 °C for 24 h, then MeCN (3 mL) and TBD (1 mmol, 333 mg) were added and the resulting solution was stirred at r.t. for 5 h. Finally, after TBD filtration (washing with EtOAc) and solvent evaporation, the crude material 4 was dissolved in DMF (4 mL), treated with Pd₂(dba)₃ (32 mg, 0.034 mmol), P(o-Tol)₃ (42 mg, 0.138 mmol), Et₃N (0.96 mL, 6.9 mmol), and heated at 110 °C for 12 h. After cooling, the reaction was quenched with 2 M HCl (10 mL), extracted with Et₂O (3 × 30 mL) and the organic extracts were dried over Na₂SO₄. After filtration and solvent evaporation at reduced pressure, the crude indole 5 was purified by flash chromatography (hexane–EtOAc). Ethyl 3-Ethyl-1H-indole-2-carboxylate (5a): White solid; mp 91–93 °C. IR (Nujol): 747, 1257, 1673, 3329 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.29 (t, J = 7.7 Hz, 3 H), 1.44 (t, J = 7.3 Hz, 3 H), 3.14 (q, J = 7.7 Hz, 2 H), 4.43 (q, J = 7.3 Hz, 2 H), 7.14 (t, J = 7.7 Hz, 1 H), 7.32 (t, J = 8.1 Hz, 1 H), 7.38 (d, J = 7.7 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 1 H), 8.78 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.7, 15.7, 18.3, 60.9, 111.9, 120.1, 121.0, 123.0, 125.7, 127.1, 127.9, 136.2, 162.7. MS (EI, 70 eV): m/z (%) = 217 (100) [M]⁺, 202, 188, 171, 170, 156, 143, 128, 115, 101, 89, 77, 63, 51, 39, 29. Anal. Calcd for C₁₃H₁₅NO₂ (217.26): C, 71.87; H, 6.96; N, 6.45. Found: C, 71.91; H, 7.00; N, 6.41. Ethyl 3-Methyl-1H-indole-2-carboxylate (5b): Pale-orange solid; mp 128–130 °C. IR (Nujol): 744, 780, 1257, 1683, 3326 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.45 (t, J = 7.3 Hz, 3 H), 2.63 (s, 3 H), 4.44 (q, J = 7.3 Hz, 2 H), 7.08–7.44 (m, 3 H), 7.68 (d, J = 8.1 Hz, 1 H), 8.73 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 10.1, 14.7, 60.9, 111.8, 120.1, 120.4, 121.0, 123.6, 125.8, 128.8, 136.0, 162.9. MS (EI, 70 eV): m/z (%) = 203 [M]⁺, 174, 157 (100), 129, 102, 77, 51, 29. Anal. Calcd for C₁₂H₁₃NO₂ (203.24): C, 70.92; H, 6.45; N, 6.89. Found: C, 70.98; H, 6.48; N, 6.86. Propyl 3-Methyl-1H-indole-2-carboxylate (5c): Pale-yellow solid; mp 102–105 °C. IR (Nujol): 744, 780, 1242, 1682, 3328 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.06 (t, J = 7.3 Hz, 3 H), 1.77–1.89 (m, 2 H), 2.62 (s, 3 H), 4.33 (t, J = 6.8 Hz, 2 H), 7.14 (t, J = 7.3 Hz, 1 H), 7.29–7.40 (m, 2 H), 7.67 (d, J = 8.1 Hz, 1 H), 8.70 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 10.2, 10.9, 22.4, 66.6, 111.8, 120.1, 120.3, 121.0, 123.7, 125.8, 128.8, 136.1, 163.1. MS (EI, 70 eV): m/z (%) = 217 [M]⁺, 174, 157 (100), 129, 102, 77, 51, 41, 29. Anal. Calcd for C₁₃H₁₅NO₂ (217.26): C, 71.87; H, 6.96; N, 6.45. Found: C, 71.84; H, 6.93; N, 6.47. Methyl 3-Nonyl-1H-indole-2-carboxylate (5d): White solid; mp 65–67 °C. IR (Nujol): 749, 1250, 1675, 3326 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.07–1.43 (m, 12 H), 1.62–1.73 (m, 2 H), 3.06–3.14 (m, 2 H), 3.95 (s, 3 H), 7.11–7.16 (m, 1 H), 7.28–7.40 (m, 2 H), 7.69 (dd, J = 0.9, 9.0 Hz, 1 H), 8.75 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.4, 22.9, 24.9, 29.6, 29.8, 29.9, 30.0, 31.3, 32.2, 51.9, 111.9, 120.1, 121.2, 123.0, 125.8, 126.0, 128.2, 136.2, 163.1. MS (EI, 70 eV): m/z (%) = 301 [M]⁺, 242, 188 (100), 156, 128. Anal. Calcd for C₁₉H₂₇NO₂ (301.42): C, 75.71; H, 9.03; N, 4.65. Found: C, 75.74; H, 9.05; N, 4.64. Ethyl 3-(4-Cyanobutyl)-1H-indole-2-carboxylate (5e): White solid; mp 115–117 °C. IR (Nujol): 752, 1021, 1250, 1697, 2248, 3374 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.44 (t, J = 7.3 Hz, 3 H), 1.67–1.78 (m, 2 H), 1.81–1.92 (m, 2 H), 2.36 (t, J = 6.8 Hz, 2 H), 3.17 (t, J = 7.3 Hz, 2 H), 4.43 (q, J = 7.3 Hz, 2 H), 7.12–7.18 (m, 1 H), 7.29–7.42 (m, 2 H), 7.66 (d, J = 8.1 Hz, 1 H), 8.81 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.7, 17.3, 23.9, 25.3, 29.9, 61.1, 112.1, 120.0, 120.5, 120.8, 123.5, 124.0, 125.9, 128.0, 136.1, 162.4. MS (EI, 70 eV): m/z (%) = 270 [M]⁺, 224, 202, 197, 156 (100), 128, 101, 77, 29. Anal. Calcd for C₁₆H₁₈N₂O₂ (270.33): C, 71.09; H, 6.71; N, 10.36. Found: C, 71.06; H, 6.70; N, 10.40. Cyclopentyl 3-Ethyl-5-methyl-1H-indole-2-carboxylate (5f): White solid; mp 113–115 °C. IR (Nujol): 783, 799, 1255, 1679, 3314 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.26 (t, J = 7.7 Hz, 3 H), 1.58–2.06 (m, 8 H), 2.45 (s, 3 H), 3.06 (q, J = 7.7 Hz, 2 H), 5.44–5.50 (m, 1 H), 7.14 (dd, J = 1.3, 8.5 Hz, 1 H), 7.24–7.28 (m, 1 H), 7.45 (s, 1 H), 8.61 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.8, 18.4, 21.8, 24.0, 33.2, 77.8, 111.6, 120.2, 123.5, 126.1, 127.6, 128.1, 129.4, 134.5, 162.7. MS (EI, 70 eV): m/z = 271 [M]⁺, 203, 188, 186, 185 (100), 170, 142, 115, 41 Anal Calcd. for C₁₇H₂₁NO₂ (271.35): C, 75.25; H, 7.80; N, 5.16. Found: C, 75.29; H, 7.82; N, 5.13. Ethyl 5-Methyl-3-phenethyl-1H-indole-2-carboxylate (5g): White solid; mp 132–134 °C. IR (Nujol): 755, 779, 798, 1601, 1678, 3309 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.44 (t, J = 7.3 Hz, 3 H), 2.47 (s, 3 H), 2.91–2.99 (m, 2 H), 3.34–3.41 (m, 2 H), 4.41 (q, J = 7.3 Hz, 2 H), 7.13–7.33 (m, 7 H), 7.41 (s, 1 H), 8.75 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.8, 21.8, 27.4, 37.6, 60.9, 111.7, 120.2, 123.6, 123.8, 126.1, 127.7, 128.2, 128.5, 128.8, 129.6, 134.5, 142.6, 162.7. MS (EI, 70 eV): m/z (%) = 307 [M]⁺, 216 (100), 170, 142, 115, 91, 65, 39, 29. Anal. Calcd for C₂₀H₂₁NO₂ (307.39): C, 78.15; H, 6.89; N, 4.56. Found: C, 78.19; H, 6.91; N, 4.53. Ethyl 5-Methoxy-3-[(2-phenyl-1,3-dioxolan-2-yl)methyl]-1H-indole-2-carboxylate (5h): White solid; mp 144–146 °C. IR (Nujol): 752, 762, 779, 1022, 1258, 1539, 1668, 3326 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.37 (t, J = 7.3 Hz, 3 H), 3.68–3.85 (m, 9 H), 4.27 (q, J = 7.3 Hz, 2 H), 6.96 (dd, J = 2.5, 8.5 Hz, 1 H), 7.11 (d, J = 2.5 Hz, 1 H), 7.22–7.30 (m, 4 H), 7.36–7.42 (m, 2 H), 8.72 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.6, 36.5, 55.9, 60.8, 64.9, 102.9, 110.7, 112.4, 117.0, 117.7, 125.8, 126.2, 127.9, 129.5, 131.2, 142.9, 154.4, 162.5. MS (EI, 70 eV): m/z (%) = 381 [M]⁺, 232, 186, 149 (100), 105, 77. Anal. Calcd for C₂₂H₂₃NO₅ (381.42): C, 69.28; H, 6.08; N, 3.67. Found: C, 69.32; H, 6.10; N, 3.66. Ethyl 3-(3-Acetoxypropyl)-5-methoxy-1H-indole-2-carboxylate (5i): Pale-yellow solid; mp 74–76 °C. IR (Nujol): 782, 1220, 1674, 1732, 3327 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.42 (t, J = 7.3 Hz, 3 H), 1.97–2.07 (m, 2 H), 2.05 (s, 3 H), 3.11–3.18 (m, 2 H), 3.87 (s, 3 H), 4.12 (t, J = 6.8 Hz, 2 H), 4.41 (q, J = 7.3 Hz, 2 H), 6.97–7.04 (m, 2 H), 7.27 (d, J = 8.5 Hz, 1 H), 8.73 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.7, 21.3, 21.4, 29.7, 56.0, 61.0, 64.5, 101.0, 113.0, 117.3, 123.2, 124.1, 128.4, 131.4, 154.6, 162.4, 171.4. MS (EI, 70 eV): m/z (%) = 319 [M]⁺, 259, 231, 213, 186 (100), 158, 115, 43. Anal. Calcd for C₁₇H₂₁NO₅ (319.35): C, 63.94; H, 6.63; N, 4.39. Found: C, 63.98; H, 6.65; N, 4.37. Ethyl 6-Methoxy-3-pentyl-1H-indole-2-carboxylate (5j): White solid; mp 108–110 °C. IR (Nujol): 781, 1247, 1671, 3311 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, J = 6.8 Hz, 3 H), 1.33–1.39 (m, 4 H), 1.41 (t, J = 7.3 Hz, 3 H), 1.61–1.71 (m, 2 H), 3.02–3.07 (m, 2 H), 3.85 (s, 3 H), 4.40 (q, J = 7.3 Hz, 2 H), 6.76–6.82 (m, 2 H), 7.52–7.55 (m, 1 H), 8.61 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.3, 14.7, 22.8, 25.0, 31.0, 32.2, 55.7, 60.6, 93.7, 111.5, 122.0, 122.2, 122.8, 126.3, 137.1, 159.2, 162.2. MS (EI, 70 eV): m/z (%) = 289 [M]⁺, 243, 232, 216, 204, 186 (100), 160, 158, 115, 89, 41, 29. Anal. Calcd for C₁₇H₂₃NO₃ (289.37): C, 70.56; H, 8.01; N, 4.84. Found: C, 70.60; H, 8.00; N, 4.82.