Ultrasound-Accelerated Amide Coupling Reactions Directed toward the Synthesis of 1-Acetyl-3-carboxamide-β-carboline Derivatives of Biological Importance

Abstract

Several biologically important 1-acetyl-3-carboxamide-β-carboline derivatives were rapidly synthesized by ultrasound-promoted amide coupling of 1-acetyl-9H-pyrido[3,4-b]indole-3-carboxylic acid with substituted aromatic amines. The major advantages of the proposed method are that use of ultrasound irradiations afforded the desired products in a drastically reduced reaction time and in excellent yields compared with conventional stirring.

Key words

ultrasound - β-carboline - amide coupling - polycyclic indoles

• References and Notes

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• 33 Conventional method for the synthesis of 9H-pyrido[3,4-b]indole-3-carboxamide derivatives (3a–k); General procedure: To a stirred solution of 1 (1 equiv) in DMF were added EDC·HCl (1.1 equiv) and HOBt (1.1 equiv), followed by addition of DIPEA (2.1 equiv). The resulting reaction mixture was stirred at r.t. for 30 minutes. The requisite amine 2a–c was added portionwise and the reaction was stirred at r.t. for 15–18 h (Table 1). Progress of reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water, and the precipitate filtered. Column chromatography on silica (100–200 mesh), eluting with 30–40% ethyl acetate/hexane gave the pure 1-acetyl-3-carboxamide-β-carboline derivatives 3a–c.Ultrasound method for the synthesis of 1-acetyl-3-carboxamide-β-carboline derivatives (3a–k); General procedure: To a stirred solution of 1 (1equiv) in DMF were added EDC·HCl (1.1 equiv) and HOBt (1.1 equiv), followed by addition of DIPEA (2.1 equiv). The resulting reaction mixture was stirred at r.t. for 10 minutes. The requisite amine 2a–k was added portionwise and the reaction was stirred at r.t. under sonication for the time detailed in Table 1 and Table 2. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold water, and the precipitate filtered. Column chromatography on silica (100–200 mesh), eluting with 30–40% ethyl acetate/hexane gave the pure 1-acetyl-3-carboxamide-β-carboline derivatives 3a–k.Representative Spectroscopic Data1-Acetyl-N-phenethyl-9H-pyrido[3,4-b]indole-3-carboxamide (3a): Pale-yellow solid; mp 172–174 °C; IR (KBr): 3349, 2914, 1683, 1534 cm^–1; ¹H NMR (400 MHz, CDCl₃): δ = 10.31 (s, 1 H, -NH), 9.00 (s, 1 H), 8.12 (d, J = 7.63 Hz, 1 H), 8.00 (t, 1 H, -NH), 7.56–7.50 (m, 2 H), 7.31–7.18 (m, 6 H), 3.78 (q, J = 6.78 Hz, 2 H), 2.93 (t, J = 6.78 Hz, 2 H), 2.67 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 202.2, 164.4, 141.4, 139.1, 139.0, 136.1, 133.4, 132.5, 129.6, 128.8, 128.7, 126.5, 122.2, 121.4, 120.9, 118.2, 112.1, 40.4, 35.8, 25.6; HRMS (ESI): m/z [M+H]⁺ calcd for C₂₂H₁₉N₃O₂: 358.1555; found: 358.1545.1-Acetyl-N-(2,4-difluorophenyl)-9H-pyrido[3,4-b]indole-3-carboxamide (3j): Yellow solid; mp 210–212 °C; IR (KBr): 3350, 2916, 1665, 1539 cm^–1; ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.29 (s, 1 H, -NH), 10.39 (s, 1 H, -NH), 9.19 (s, 1 H), 8.12 (q, J = 6.10 Hz, 1 H), 7.83 (d, J = 7.63 Hz, 1 H), 7.63 (t, J = 8.39 Hz, 1 H), 7.46–7.41 (m, 1 H), 7.34 (t, J = 7.63 Hz, 1 H), 7.17 (t, J = 8.39 Hz, 1 H), 2.93 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 200.6, 162.5, 145.1, 142.9, 142.4, 137.2, 135.0, 133.9, 133.9, 132.2, 129.5, 122.4, 121.0, 120.2, 118.4, 113.4, 111.4, 104.5, 104.2, 25.9; HRMS (ESI): m/z [M+H]⁺ calcd for C₂₀H₁₃F₂N₃O₂: 366.1054; found: 366.1061
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