New Simple Synthesis of Quinoline-4-carbonitriles

Abstract

Alkylation of 2-nitrobenzyl cyanides with α-halomethyl ketones furnishes ketonitriles which upon reduction with tin(II) chloride form quinoline-4-carbonitriles in good yields.

Key words

quinolines - reduction - nitriles - alkylation - ketones - tin

• References and Notes

• 1a Solomon VR, Lee H. Curr. Med. Chem. 2011; 18: 1488
• 1b Kaur K, Jain M, Reddy RP, Jain R. Eur. J. Med. Chem. 2010; 3245
• 2a Madapa S, Tusi Z, Batra S. Curr. Org. Chem. 2008; 12: 1116
• 2b Kouznetsov VV, Méndez LY. V, Gomez CM. M. Curr. Org. Chem. 2005; 9: 141
• 3a Okamoto T, Tani H. Chem. Pharm. Bull. 1959; 7: 925
• 3b Vu AT, Cohn ST, Manas ES, Harris HA, Mewshaw RE. Bioorg. Med. Chem. Lett. 2005; 15: 4520
• 4a Banini SR, Turner MR, Cummings MM, Soederberg BC. G. Tetrahedron 2011; 67: 3603
• 4b Wróbel Z, Kwast A, Mąkosza M. Synthesis 1993; 31
• 4c Wróbel Z, Mąkosza M. Tetrahedron 1993; 49: 5315
• 4d Zimmermann T, Sicker D, Pink M. J. Prakt. Chem. 1993; 335: 390

For reviews on VNS, see:
• 5a Mąkosza M. Synthesis 2011; 2341
• 5b Mąkosza M. Chem. Soc. Rev. 2010; 39: 2855
• 5c Mąkosza M, Wojciechowski K. Chem. Rev. 2004; 104: 2631
• 5d Mąkosza M, Wojciechowski K. Heterocycles 2001; 54: 445
• 6a Leardini R, Nanni D, Tundo A, Zanardi G. Gazz. Chim. Ital. 1989; 119: 637
• 6b Miyashita A, Taido N, Sato S, Yamamoto K.-i, Ishida H, Higashino T. Chem. Pharm. Bull. 1991; 39: 282
• 7 Alkylation of 2-Nitrophenylacetonitriles 1 with α-Halomethyl Ketones: Synthesis of 2-(5-Chloro-2-nitrophenyl)-4-oxo-4-phenylbutyronitrile (2c) – Typical Procedure To a solution of 5-chloro-2-nitrophenylacetonitrile (2 mmol) in DMF (15 mL) NaH (55 mg, 2.3 mmol) was added. The reaction mixture was stirred for 20 min and then α-bromoacetophenone (0.80 g, 4 mmol) was added (in the case of α-chloro ketones an equimolar amount of KI was also added). The reaction mixture was stirred at 80 °C for 12–24 h until the starting material 1 had disappeared (TLC). The reaction mixture was then poured into dilute HCl, extracted with EtOAc (3 × 30 mL) and dried with Na₂SO₄. After filtration and evaporation of solvent, the residue was purified by column chromatography (SiO₂, hexane–EtOAc, 4:1); yield 91%; yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 3.70, 3.73, 5.29 (ABX, J = 17.9, 8.2, 5.1 Hz, 3 H), 7.46–7.53 (m, 2 H), 7.52 (dd, J = 8.8, 2.2 Hz, 1 H), 7.59–7.64 (m, 1 H), 7.88 (d, J = 2.2 Hz, 1 H), 8.07 (d, J = 8.8 Hz, 1 H). ¹³C NMR (100 MHz): δ = 29.04, 43.47, 118.99, 127.25, 128.12, 128.89, 129.87, 130.89, 132.36, 134.12, 135.19, 140.86, 193.56. ESI-HRMS: m/z calcd for C₁₆H₁₁N₂O₃ClNa: 337.0350; found: 337.0367. Selected Data 2-(5-Chloro-2-nitrophenyl)-4-oxopentanenitrile (2a) Pale yellow crystals; mp 113–115 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.22 (s, 3 H), 3.14, 3.17, 5.06 (ABX, J = 18.2, 8.2, 5.1 Hz, 3 H), 7.51 (dd, J = 8.8, 2.1 Hz, 1 H), 7.79 (d, J = 2.1 Hz, 1 H), 8.05 (d, J = 8.8 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 28.77, 29.40, 47.56, 118.74, 127.26, 129.89, 130.79, 132.07, 140.90, 145.90, 201.85. ESI-HRMS: m/z calcd for C₁₁H₉N₂O₃ClNa: 275.0194; found: 275.0197. 2-(5-Fluoro-2-nitrophenyl)-4-oxo-4-phenylbutyronitrile (2d) Orange-red oil. ¹H NMR (500 MHz, CDCl₃): δ = 3.71, 3.75, 5.32 (ABX, J = 18.0, 7.9, 5.3 Hz, 3 H), 7.24 (ddd, J = 9.2, 6.8, 2.7 Hz, 1 H), 7.46–7.51 (m, 2 H), 7.59–7.63 (m, 2 H), 7.91–7.95 (m, 2 H), 8.19 (dd, J = 9.2, 5.1 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 29.35, 43.37, 116.80 (d, J = 22.4 Hz), 118.17 (d, J = 24.8 Hz), 119.05, 128.12, 128.84 (d, J = 9.8 Hz), 128.89, 133.94 (J = 8.3 Hz), 134.12, 135.22, 143.86, 163.06 (d, J = 272 Hz), 193.57. ¹⁹F NMR (470 MHz, CDCl₃): δ = –100.44 (ddd, J = 8.6, 6.8, 5.1 Hz). ESI-HRMS: m/z calcd for C₁₆H₁₁N₂O₃Na: 321.0646; found: 321.0654. 5,5-Dimethyl-1-(1-octyl-4-nitro-2-phenyl-1H-indol-5-yl)-5-oxohexanenitrile (15a) Yield 76%; orange-red oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.85 (t, J = 6.8 Hz, 3 H),1.17 (s, 9 H), 1.09–1.30 (m, 10 H), 1.61–1.70 (m, 2 H), 3.25, 3.27, 5.10 (ABX, J = 18.1, 8.1, 5.0 Hz, 3 H), 4.21 (t, J = 7.6 Hz, 2 H), 6.96 (s, 1 H), 7.46–7.53 (m, 5 H), 7.55 (d, J = 8.5 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.02, 22.53, 26.20, 26.55, 28.88, 28.95, 29.45, 29.99, 31.62, 42.81, 43.97, 44.40, 102.06, 115.45, 120.59, 121.80, 122.85, 123.34, 128.79, 129.10, 129.35, 131.45, 138.79, 139.44, 146.39, 210.31. ESI-HRMS: m/z calcd for C₃₀H₃₇N₃O₃Na: 510.2727; found: 510.2736.
• 8 Reduction of Ketonitriles – General Procedure To a solution of ketonitrile 2, 12, 15, or 20 (1 mmol) in EtOAc (5 mL) and EtOH (1 mL) was added SnCl₂ (0.76 g, 4 equiv). The reaction mixture was stirred at r.t. until the starting material disappeared (12–24 h, TLC). After completion, the reaction mixture was diluted with EtOAc (20 mL) washed with 10% aq KF (2 × 10 mL) dried with Na₂SO₄, filtered, and evaporated. The residue was purified by column chromatography (SiO₂, hexane–EtOAc, 2:1). Selected Data 2-tert-Butyl-6-chloroquinoline-4-carbonitrile (3b) Colorless crystals; mp 137–140 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.47 (s, 9 H), 7.73 (dd, J = 9.0, 2.3 Hz, 1 H), 8.07 (d, J = 9.0 Hz, 1 H), 8.11 (d, J = 2.3 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 29.80, 38.49, 115.65, 117.87, 123.28, 123.37, 124.51, 131.76, 131.77, 134.33, 145.74, 169.18. IR (KBr): ν = 2953, 2227, 1588, 1548, 1480, 1461, 1445, 1364, 1206, 1150, 1108, 1078, 924, 893, 834 cm^–1. MS (EI, 70 eV): m/z (%) = 244 (24) [M⁺], 243 (12), 231 (42), 229 (100), 202 (20), 188 (6). HRMS (EI): m/z calcd for C₁₄H₁₃ ³⁵ClN₂: 246.0767; found: 244.0760. 6-Chloro-2-phenylquino-line-4-carbonitrile (3c) Yellow crystals; mp 176–179 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.50–7.58 (m, 3 H), 7.78 (dd, J = 8.9, 2.5 Hz, 1 H), 8.11–8.18 (m, 3 H), 8.20 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 115.36, 118.66, 123.59, 123.63, 125.15, 127.37, 129.20, 130.58, 132.04, 132.41, 134.97, 137.28, 146.59, 156.83. IR (KBr): ν = 3056, 2229, 1590, 1542, 1484, 1445, 1384, 1341, 1234, 1089, 1026, 891, 826, 774, 762 cm^–1. MS (EI, 70 eV): m/z (%) = 266 (35) [M⁺ + 2], 264 (100), 229 (40), 201 (7). HRMS (EI): m/z calcd for C₁₆H₉N₂ ³⁵Cl: 264.0454; found: 264.0443. 2-tert-Butyl-6-methoxyquinoline (4e) Colorless crystals. ¹H NMR (500 MHz, CDCl₃): δ = 1.45 (s, 9 H), 3.91 (s, 3 H), 7.03 (d, J = 2.9 Hz, 1 H), 7.31 (dd, J = 9.2, 2.9 Hz, 1 H), 7.47 (d, J = 8.7 Hz, 1 H), 7.95 (d, J = 9.2 Hz, 1 H), 7.96 (d, J = 8.7 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 30.18, 37.80, 55.45, 104.93, 118.39, 121.41, 127.19, 130.76, 134.74, 143.40, 157.16, 166.78. IR (CHCl₃): ν = 2961, 1625, 1601, 1563, 1498, 1471, 1378, 1229, 1163, 1102, 1032, 852, 834 cm^–1. 2-Phenyl-6-(trifluoromethyl)quinoline (4g) Colorless crystals; mp 119–120 °C (lit.¹⁶ mp 120–122 °C). ¹H NMR (500 MHz, CDCl₃): δ = 7.47–7.61 (m, 3 H), 7.90 (dd, J = 9.1, 1.8 Hz, 1 H), 7.98 (d, J = 8.6 Hz, 1 H), 8.15 (s, 1 H), 8.18–8.22 (m, 2 H), 8.28 (d, J = 9.1 Hz, 1 H), 8.31 (d, J = 8.6 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 120.05, 124.07 (q, J = 273 Hz), 125.31 (q, J = 3.0 Hz), 125.43 (q, J = 4.4 Hz), 126.06, 127.66, 128.00 (q, J = 32.8 Hz), 128.95, 129.94, 130.85, 137.46, 138.90, 149.24, 159.32. ¹⁹F NMR (470 MHz, CDCl₃): δ = –62.27. 2-Phenylbenzo[h]quinoline-4-carbonitrile (13) Yield 55%; yellow crystals, mp 177–180 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.46–7.60 (m, 3 H), 7.72–7.80 (m, 2 H), 7.88–7.95 (m, 2 H), 7.99 (d, J = 9.4 Hz, 1 H), 8.20 (s, 1 H), 8.24–8.30 (m, 2 H), 9.39 (d, J = 7.8 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ =116.21, 118.97, 121.32, 121.79, 123.56, 124.91, 127.32, 127.84, 128.10, 129.10, 129.32, 130.14, 130.36, 131.20, 133.93, 137.85, 146.68, 155.03. IR (KBr): ν = 3059, 2225, 1621, 1582, 1548, 1499, 1442, 1375, 1333, 1275, 1027, 894, 821, 759, 681 cm^–1. MS (EI, 70 eV): m/z (%) = 280 (100) [M⁺], 253 (5), 252 (5), 251 (6). HRMS (EI): m/z calcd for C₂₀H₁₂N₂: 280.1001; found: 280.1009. 8-tert-Butyl-3-octyl-2-phenyl-3H-pyrrolo[2,3-h]quinoline (17a) Yield 49%; yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 0.84 (t, J = 7.2 Hz, 3 H), 1.10–1.27 (m, 10 H), 1.51 (s, 9 H), 1.62–1.72 (m, 2 H), 4.28 (t, J = 7.7 Hz, 2 H), 7.38 (s, 1 H), 7.38 (s, 1 H), 7.39–7.58 (m, H), 7.44 (d, J = 8.5 Hz, 1 H), 8.10 (d, J = 8.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.04, 22.57, 26.62, 29.01, 30.37, 30.48, 31.70, 38.12, 44.21, 102.49, 111.50, 115.47, 121.03, 121.45, 124.63, 127.68, 128.45, 129.54, 133.52, 135.94, 136.26, 139.74, 142.91, 168.02. IR (KBr): ν = 2955, 2927, 2856, 1604, 1517, 1478, 1465, 1404, 1362, 1335, 1130, 833, 761, 699 cm^–1. 3-Octyl-2,8-diphenyl-3H-pyrrolo[2,3-h]quinoline-6-carbonitrile (16b) Yield 60%; yellow solid; mp 103–105 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.82 (t, J = 7.6 Hz, 3 H), 1.10–1.30 (m, 10 H), 1.70–1.80 (m, 2 H), 4.30 (t, J = 6.8 Hz, 2 H), 7.42–7.60 (m, 9 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.90 (d, J = 8.8 Hz, 1 H), 8.10 (s, 1 H), 8.24–8.28 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 14.05, 22.57, 26.60, 28.96, 29.03, 30.58, 31.67, 44.46, 103,16, 114.77, 116.92, 117.56, 118.85, 119.51, 120.52, 124.90, 127.33, 128.23, 128.66, 128.96, 129.53, 129.78, 132.72, 136.83, 138.40, 141.19, 143.96, 154.87. IR (KBr): ν = 2918, 2850, 2229, 1584, 1539, 1466, 1422, 1399, 1343, 1299, 1170, 1024, 888, 816, 773, 752, 693 cm^–1. ESI-HRMS: m/z calcd for C₃₂H₃₂N₃: 458.2591; found: 458.2613.3-(Benzyloxymethyl)-2-methyl-7-phenylpyrrolo[3,2-h]quinoline-9-carbonitrile (21) Pale yellow crystals; mp 190–192 °C. ¹H NMR (500 MHz, CDCl₃): δ = 2.59 (d, J = 0.9 Hz, 3 H), 4.47 (s, 2 H), 5.68 (s, 2 H), 7.25–7.38 (m, 6 H), 7.46–7.58 (m, 4 H), 7.85 (d, J = 9.1 Hz, 1 H), 7.96 (d, J = 9.1 Hz, 1 H), 8.15–8.18 (m, 2 H), 8.19 (s, 1 H). ¹³ C NMR (125 Hz, CDCl₃): δ = 12.69, 69.76, 71.95, 103.44, 115.45, 116.16, 118.86, 120.65, 122.56, 123.82, 127.10, 127.77, 128.15, 128.60, 128.73, 129.02, 129.54, 134.57, 136.72, 137.09, 138.29, 146.17, 153.24. HRMS (EI): m/z calcd for C₂₇H₂₁N₃O: 403.1685; found: 403.1682.
• 9 Ramesh C, Kavala V, Kuo C.-W, Yao C.-F. Tetrahedron Lett. 2010; 51: 5234
• 10 Kuhn A, von Eschwege KG, Conradie J. J. Phys. Org. Chem. 2012; 25: 58
• 11a Barros AI. R. N. A, Silva AM. S. Tetrahedron Lett. 2003; 44: 5893
• 11b Okuma K, Seto J.-i, Nagahora N, Shioji K. J. Heterocycl. Chem. 2010; 47: 1372
• 12 Mąkosza M, Winiarski J. J. Org. Chem. 1984; 49: 1494
• 13 The starting materials 14 and 19 were obtained from the corresponding nitroindoles following the procedure described in: Wojciechowski K, Mąkosza M. Synthesis 1989; 106
• 14 6-Methoxy-2-phenyl-1,2,3,4-tetrahydroquinoline-4-carbonitrile (22): Selected Data ¹H NMR (500 MHz, CDCl₃): δ = 2.32 (ddd, J = 13.0, 12.1, 11.3 Hz, 1 H), 2.48 (ddd, J = 12.2, 5.4, 2.6 Hz, 1 H), 3.77 (s, 3 H), 4.27 (dd, J = 11.3, 2.6 Hz, 1 H), 4.34 (dd, J = 12.1, 5.4 Hz, 1 H), 6.53 (d, J = 8.6 Hz, 1 H), 6.74 (dd, J = 8.6, 2.7 Hz, 1 H), 6.93 (d, J = 2.7 Hz, 1 H), 7.32–7.42 (m, 5 H). ¹³C NMR (125 MHz, CDCl₃): δ = 29.98, 35.03, 55.89, 56.08, 112.97, 116.37, 120.51, 126.53, 126.65, 128.35, 128.83, 128.87, 141.96, 152.58. IR (KBr): ν = 3379, 3341, 2237, 1503, 1343, 1286, 1245, 1231, 1165, 1113, 1034, 811, 765, 702 cm^–1. MS (EI, 70 eV): m/z (%) = 264 (100) [M⁺], 263 (34), 224 (10), 187 (27), 160 (7). HRMS (EI): m/z calcd for C₁₇H₁₆N₂O: 264.1263; found: 264.1270.
• 15 Bunce RA, Schammerhorn JE, Slaughter LM. J. Heterocycl. Chem. 2007; 44: 1051
• 16 Shindoh N, Tokuyama H, Takemoto Y, Takasu K. J. Org. Chem. 2008; 73: 74