One-Pot Chemoselective Synthesis of Arylated Benzo[h]quinolines

Abstract

A one-pot chemoselective synthesis of 2-aminobenzo[h]quinolines has been delineated by the reaction of 6-aryl-4-sec-amino-2H-pyran-2-one-3-carbonitriles and 2-cyanomethylbenzonitrile using sodamide as a base in DMF. The synthesis involves sequential intermolecular C–C and intramolecular C–C and C–N bond formation. This reaction has delivered benzo[h]quinolines chemoselectively in excellent yield under microwave irradiation. The structure of one product was confirmed by single-crystal X-ray crystallography.

Key words

chemoselectivity - quinolones - fused-ring systems - nucleophiles

• References and Notes

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• 26 Crystal Data for 3l (CCDC 994354) C₂₄H₁₉BrN₄O, CHCl₃, triclinic, space group: P-1, a = 12.4071(5), b = 13.8990(6), c = 15.3973(7) Å, α = 108.420(4)°, β = 93.430(4)°, γ = 113.596(4)°, V = 2254.92 (18) ų, T = 293(2) K, Z = 2, m = 2.026 mm^–1, F(000) = 1052.0, D _c = 1.529 Mg m^–1, colorless rectangular crystal, crystal size: 0.26 × 0.20 × 0.11 mm, R1 =0.0712 for 7159 F ₀ > 4σ(F ₀) and 0.1111 for all 10874 data and 593 parameters with goodness of fit GooF = 1.023. Unit cell determination and intensity data collection (2θ range = 8-133.2°) was performed with 88.4% completeness at 293(2) K. Structure solutions by direct methods and refinements by full-matrix least-squares methods on F2. CCDC 994354 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
• 27 General Procedure for the Synthesis of 2-Amino-5-aryl-4-sec-amino-1-yl-benzo[h]quinoline-6-carbonitriles 3a–3l by Conventional Heating A mixture of 6-aryl-2-oxo-4-sec-amino-1-yl-2H-pyran-3-carbonitrile (0.5 mmol), 2-cyanomethylbenzonitrile (0.5 mmol, 71.0 mg), and NaNH₂ (1.0 mmol, 39.0 mg) in dry DMF (4.0 mL) was stirred at 100 °C for 35–50 h. After completion of reaction, the mixture was poured onto crushed ice followed by neutralization with 10% HCl. The solid material formed was filtered, washed with water, dried, and purified by silica gel column chromatography using hexane–EtOAc (7:3) as eluent. General Procedure for the Microwave-Assisted Synthesis of 2-Amino-5-aryl-4-piperidine-1-yl-benzo[h]quinoline-6-carbonitriles 3a–3l (Except 3d and 3j) A mixture of 2-oxo-6-aryl-4-piperidin-1-yl-2H-pyran-3-carbonitrile (1.0 mmol), 2-cyanomethylbenzonitrile (1.0 mmol, 142.0 mg), and NaNH₂ (2.0 mmol, 78.0 mg) in dry DMF (2.0 mL) was heated at 100 °C for 55 min under microwave irradiation. Completion of reaction was monitored by TLC. After completion, the reaction mixture was poured onto crushed ice and neutralized with 10% HCl. The precipitate obtained was filtered, washed with H₂O, dried, and purified by silica gel column chromatography using hexane–EtOAc (7:3) as eluent. 2-Amino-5-phenyl-4-piperidin-1-yl-benzo[h]quinoline-6-carbonitrile (3a) Yield 75% (142.0 mg); R_f = 0.28 (30% EtOAc–hexane); orange solid; mp 140–142 °C. IR (KBr): 3338, 3050, 2941, 2854, 2212 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.58–0.71 (m, 2 H, CH₂), 1.20–1.41 (m, 4 H, CH₂), 2.32–2.42 (m, 2 H, CH₂), 2.83–2.94 (m, 2 H, CH₂), 4.88 (s, 2 H, NH₂), 6.28 (s, 1 H, ArH), 7.37–7.44 (m, 3 H, ArH), 7.47–7.53 (m, 2 H, ArH), 7.62–7.74 (m, 2 H, ArH), 8.23 (d, J = 8.0 Hz, 1 H, ArH), 9.08 (d, J = 7.3 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.4, 24.5, 52.7, 98.9, 105.6, 112.6, 118.6, 125.0, 125.2, 126.9, 127.2, 127.9, 129.2, 130.0, 130.2, 131.6, 138.8, 145.0, 150.7, 158.9, 161.3. ESI-HRMS: m/z calcd for C₂₅H₂₂N₄: 379.1917 [M + H⁺]; found: 379.1916. 2-Amino-4-piperidin-1-yl-5-p-tolyl-benzo[h]quinoline-6-carbonitrile (3b) Yield 65% (128.0 mg); R_f = 0.25 (30% EtOAc–hexane); orange solid; mp 182–184 °C. IR (KBr): 3369, 2926, 2855, 2209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.19–1.46 (m, 6 H, CH₂), 2.35–2.52 (m, 5 H, CH₂, CH₃), 2.87 (d, J = 11.7 Hz, 2 H, CH₂), 5.03 (s, 2 H, NH₂), 6.27 (s, 1 H, ArH), 7.20–7.28 (m, 2 H, ArH), 7.39 (d, J = 8.0 Hz, 2 H, ArH), 7.62–7.76 (m, 2 H, ArH), 8.24 (d, J = 7.3 Hz, 1 H, ArH), 9.10 (d, J = 8.0 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 21.3, 23.4, 24.5, 52.6, 98.5, 105.3, 112.5, 118.8, 125.0, 125.2, 126.9, 127.8, 129.2, 129.7, 130.1, 131.6, 135.7, 137.7, 145.2, 150.4, 158.7, 161.1. ESI-HRMS: m/z calcd for C₂₆H₂₄N₄: 393.2074 [M + H⁺]; found: 393.2074. 2-Amino-5-(4-methoxyphenyl)-4-piperidin-1-yl-benzo[ h ]quinoline-6-carbonitrile (3c) Yield 71% (145.0 mg); R_f = 0.14 (30% EtOAc–hexane); orange solid; mp 180–182 °C. IR (KBr): 3437, 3171, 2924, 2852, 2208 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.60–0.80 (m, 2 H, CH₂), 1.20–1.46 (m, 4 H, CH₂), 2.36 (t, J = 10.9 Hz, 2 H, CH₂), 2.86 (d, J = 11.9 Hz, 2 H, CH₂), 3.85 (s, 3 H, OCH₃), 4.96 (s, 2 H, NH₂), 6.23 (s, 1 H, ArH), 6.93 (d, J = 8.7 Hz, 2 H, ArH), 7.42 (d, J = 8.7 Hz, 2 H, ArH), 7.55–7.74 (m, 2 H,ArH), 8.21 (d, J = 7.3 Hz,1 H, ArH), 9.09–9.11 (m, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.4, 24.6, 52.6, 53.3, 98.4, 105.1, 112.3, 112.5, 118.9, 125.0, 125.1, 126.7, 129.1, 129.8, 131.1, 131.5, 131.6, 144.8, 150.7, 158.8, 159.5, 160.9. ESI-HRMS: m/z calcd for C₂₆H₂₄N₄O: 409.2023 [M + H⁺]; found: 409.2000. 2-Amino-5-(4-fluorophenyl)-4-piperidin-1-yl-benzo[h]quinoline-6-carbonitrile (3d) Yield 73% (145.0 mg); R_f = 0.24 (30% EtOAc–hexane); orange solid; mp 203–205 °C. IR (KBr): 3341, 2926, 2853, 2208 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.63–0.83 (m, 2 H, CH₂), 1.17–1.50 (m, 4 H, CH₂), 2.30–2.52 (m, 2 H, CH₂), 2.83–2.90 (m, 2 H, CH₂), 4.90 (s, 2 H, NH₂), 6.28 (s, 1 H, ArH), 7.05–7.18 (m, 2 H, ArH), 7.44–7.52 (m, 2 H, ArH), 7.62–7.77 (m, 2 H, ArH), 8.22 (d, J = 8.0 Hz, 1 H, ArH), 9.10 (d, J = 7.3 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.3, 24.6, 52.7, 98.8, 105.8, 112.3, 114.2 (d, J _C–F = 22.0 Hz), 118.5, 125.0, 125.2, 127.2, 129.4, 131.5, 131.9 (d, J _C–F = 7.6 Hz), 134.6, 134.7, 143.7, 150.2, 158.7, 161.0, 162.6 (d, J _C–F = 250.1 Hz). ESI-HRMS: m/z calcd for C₂₅H₂₁FN₄: 397.1823 [M + H⁺]; found: 397.1823. 2-Amino-5-(4-chlorophenyl)-4-piperidin-1-yl-benzo[h]quinoline-6-carbonitrile (3e) Yield 82% (169.0 mg); R_f = 0.25 (30% EtOAc–hexane); golden solid; mp 127–129 °C. IR (KBr): 3474, 3151, 2929, 2853, 2207 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.66–0.77 (m, 2 H, CH₂), 1.22–1.48 (m, 4 H, CH₂), 2.35–2.45 (m, 2 H, CH₂), 2.81–2.91 (m, 2 H, CH₂), 4.91 (s, 2 H, NH₂), 6.29 (s, 1 H, ArH), 7.37–7.47 (m, 4 H, ArH), 7.62–7.75 (m, 2 H, ArH), 8.21 (d, J = 8.0 Hz, 1 H, ArH), 9.08 (d, J = 7.3 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.3, 24.5, 52.6, 99.1, 105.4, 112.3, 118.4, 125.1, 125.1, 127.1, 127.3, 129.3, 130.0, 131.4, 131.4, 133.8, 137.2, 143.5, 150.7, 158.9, 160.9. ESI- HRMS: m/z calcd for C₂₅H₂₁ClN₄O: 413.1527 [M + H⁺]; found: 413.1527. 2-Amino-5-(4-bromophenyl)-4-piperidin-1-yl-benzo[h]quinoline-6-carbonitrile (3f) Yield 66% (151.0 mg); R_f = 0.26 (30% EtOAc–hexane); light yellow solid; mp 216–218 °C. IR (KBr): 3368, 2924, 2853, 2209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.60–0.82 (m, 2 H, CH₂), 1.22–1.50 (m, 4 H, CH₂), 2.32–2.51 (m, 2 H, CH₂), 2.81–2.89 (m, 2 H, CH₂), 4.90 (s, 2 H, NH₂), 6.29 (s, 1 H, ArH), 7.38 (d, J = 8.7 Hz, 2 H, ArH), 7.56 (d, J = 8.7 Hz, 2 H, ArH), 7.63–7.76 (m, 2 H, ArH), 8.22 (d, J = 8.0 Hz, 1 H, ArH), 9.10 (m, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.3, 24.6, 52.7, 99.1, 105.4, 112.3, 118.4, 122.0, 125.1, 125.2, 127.2, 129.3, 130.1, 130.3, 131.4, 131.8, 137.7, 143.5, 150.7, 159.0, 161.0. ESI-HRMS: m/z calcd for C₂₅H₂₁BrN₄: 457.1022 [M + H⁺]; found: 457.1024. 2-Amino-5-(3-bromophenyl)-4-piperidin-1-yl-benzo[h]quinoline-6-carbonitrile (3g) Yield 65% (149.0 mg); R_f = 0.23 (30% EtOAc–hexane); yellow solid; mp 204–206 °C. IR (KBr): 3368, 3199, 3058, 2936, 2854, 2210 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.40–0.62 (m, 1 H, CH₂), 0.76–0.95 (m, 1 H, CH₂), 0.95–1.10 (m, 1 H, CH₂), 1.16–1.30 (m, 1 H, CH₂), 1.33–1.51 (m, 2 H, CH₂), 2.28 (t, J = 10.9 Hz, 1 H, CH₂), 2.50 (t, J = 10.9 Hz, 1 H, CH₂), 2.80 (d, J = 11.7 Hz, 1 H, CH₂), 2.95 (d, J = 11.7 Hz, 1 H, CH₂), 4.95 (s, 2 H, NH₂), 6.32 (s, 1 H, ArH), 7.29–7.38 (m, 1 H, ArH), 7.49–7.60 (m, 3 H, ArH), 7.63–7.76 (m, 2 H, ArH), 8.23 (d, J = 8.0 Hz, 1 H, ArH), 9.10 (d, J = 7.3 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.3, 24.4, 51.9, 53.4, 99.6, 105.4, 112.3, 118.3, 121.0, 125.1, 127.2, 128.4, 128.8, 129.2, 130.0, 130.7, 131.3, 133.3, 140.6, 142.9, 150.6, 159.0, 161.0. ESI-HRMS: m/z calcd for C₂₅H₂₁BrN₄: 457.1022 [M + H⁺]; found: 457.1023. 2-Amino-5-furan-2-yl-4-piperidin-1-yl-benzo[h]quinoline-6-carbonitrile (3h) Yield 82% (151.0 mg); R_f = 0.60 (40% EtOAc–hexane); brown solid; mp 212–214 °C. IR (KBr): 3356, 2926, 2856, 2212 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.90–1.25 (m, 4 H, CH₂), 1.26–1.45 (m, 2 H, CH₂), 2.36 (t, J = 10.6 Hz, 2 H, CH₂), 2.96 (d, J = 10.2 Hz, 2 H, CH₂), 4.87 (s, 2 H, NH₂), 6.25 (s, 1 H, ArH), 6.51–6.58 (m, 1 H, ArH), 6.86 (d, J = 2.5 Hz, 1 H, ArH), 7.46 (s, 1 H, ArH), 7.57–7.70 (m, 2 H, ArH), 8.17 (d, J = 7.3 Hz, 1 H, ArH), 9.00 (d, J = 8.0 Hz, 1 H, ArH). ¹³C (100 MHz, CDCl₃): δ = 23.7, 25.0, 53.1, 99.1, 105.2, 111.0, 111.2, 112.9, 118.1, 125.0, 125.4, 127.4, 129.2, 130.4, 131.3, 133.0, 142.5, 150.3, 150.9, 159.2, 161.5. ESI-HRMS: m/z calcd for C₂₃H₂₀N₄O: 369.1710 [M + H⁺]; found: 369.1689. 2-Amino-4-piperidin-1-yl-5-thiophen-2-yl-benzo[h]quinoline-6-carbonitrile (3i) Yield 76% (146.0 mg); R_f = 0.64 (40% EtOAc–hexane); orange solid; mp 218–220 °C. IR (KBr): 3394, 2925, 2853, 2215 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.80–1.10 (m, 2 H, CH₂), 1.21–1.52 (m, 4 H, CH₂), 2.37 (t, J = 10.9 Hz, 2 H, CH₂), 2.96 (d, J = 11.7 Hz, 2 H, CH₂), 4.95 (s, 2 H, NH₂), 6.28 (d, J = 1.4 Hz, 1 H, ArH), 7.11–7.16 (m, 1 H, ArH), 7.42–7.47 (m, 1 H, ArH), 7.49–7.53 (m, 1 H, ArH), 7.61–7.74 (m, 2 H, ArH), 8.21 (d, J = 8.0 Hz, 1 H, ArH), 9.06 (d, J = 8.0 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 23.4, 24.8, 52.8, 99.4, 106.1, 113.5, 118.3, 125.0, 125.3, 125.6, 127.1, 127.3, 128.0, 129.2, 130.2, 131.4, 137.0, 141.0, 150.3, 159.1, 161.2. ESI-HRMS: m/z calcd for C₂₃H₂₀N₄S: 385.1481 [M + H⁺]; found: 385.1457. 2-Amino-5-(4-methoxyphenyl)-4-morpholin-4-yl-benzo[h]quinoline-6-carbonitrile (3j) Yield 68% (140.0 mg); R_f = 0.15 (40% EtOAc–hexane); orange solid; mp 278–280 °C. IR (KBr): 3357, 2925, 2854, 2209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.55–2.72 (m, 4 H, CH₂), 2.77–2.83 (m, 2 H, CH₂), 3.46–3.58 (m, 2 H, CH₂), 3.87 (s, 3 H, OCH₃), 4.94 (s, 2 H, NH₂), 6.27 (s, 1 H, ArH), 6.95–7.00 (m, 2 H, ArH), 7.39–7.47 (m, 2 H, ArH), 7.57–7.75 (m, 2 H, ArH), 8.22 (d, J = 8.0 Hz, 1 H, ArH), 9.06–9.11 (m, 1 H, ArH). ¹³C (100 MHz, CDCl₃): δ = 51.5, 55.3, 65.7, 98.6, 106.0, 112.0, 112.8, 118.6, 125.1, 125.2, 127.0, 129.4, 129.8, 131.2, 131.5, 131.6, 144.1, 150.8, 158.7, 159.8, 160.0. ESI-HRMS: m/z calcd for C₂₅H₂₂N₄O₂: 411.1816 [M + H⁺]; found: 411.1816. 2-Amino-5-(4-chlorophenyl)-4-morpholin-4-yl-benzo[h]quinoline-6-carbonitrile (3k) Yield 66% (137.0 mg); R_f = 0.21 (40% EtOAc–hexane); golden solid; mp 258–260 °C. IR (KBr): 3351, 2924, 2853, 2211 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.56–2.60 (m, 4 H, CH₂), 2.71–2.79 (m, 2 H, CH₂), 3.50–3.60 (m, 2 H, CH₂), 4.97 (s, 2 H, NH₂), 6.30 (s, 1 H, ArH), 7.36–7.51 (m, 4 H, ArH), 7.63–7.78 (m, 2 H, ArH), 8.22 (d, J = 8.0 Hz, 1 H, ArH), 9.09 (d, J = 8.0 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 51.5, 65.6, 99.2, 106.2, 112.0, 118.1, 125.2, 125.3, 127.4, 127.6, 129.6, 130.0, 131.4, 131.4 134.3, 137.4, 142.8, 151.0, 158.9, 159.9. ESI-HRMS: m/z calcd for C₂₄H₁₉ClN₄O: 415.1320 [M + H⁺]; found: 415.1326. 2-Amino-5-(4-bromophenyl)-4-morpholin-4-yl-benzo[h]quinoline-6-carbonitrile (3l) Yield 63% (145.0 mg); R_f = 0.22 (40% EtOAc–hexane); orange solid; mp 260–262 °C. IR (KBr): 3340, 2925, 2855, 2209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.57–2.68 (m, 4 H, CH₂), 2.70–2.76 (m, 2 H, CH₂), 3.49–3.59 (m, 2 H, CH₂), 5.00 (s, 2 H, NH₂), 6.30 (s, 1 H, ArH), 7.34–7.40 (m, 2 H, ArH), 7.56–7.62 (m, 2 H, ArH), 7.64–7.77 (m, 2 H, ArH), 8.22 (d, J = 7.3 Hz, 1 H, ArH), 9.07–9.12 (dd, J = 0.9 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 51.5, 65.6, 99.3, 106.1, 112.0, 118.1, 122.4, 125.1, 125.3, 127.4, 129.6, 130.0, 130.6, 131.4, 131.6, 137.9, 142.8, 150.8, 158.9, 159.9. ESI-HRMS: m/z calcd for C₂₄H₁₉BrN₄O: 459.0815 [M + H⁺]; found: 459.0816