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Synlett 2015; 26(13): 1808-1814
DOI: 10.1055/s-0034-1380212
DOI: 10.1055/s-0034-1380212
letter
A Catalyst-Free, One-Pot, Three-Component Approach for the Synthesis of 2-[1-Aryl-2-(azaaryl)ethyl]malononitriles via sp3 C–H Activation of 2-Methyl Azaarenes
Weitere Informationen
Publikationsverlauf
Received: 09. Februar 2015
Accepted after revision: 20. April 2015
Publikationsdatum:
18. Juni 2015 (online)
Abstract
Combinatorial libraries of 2-[1-aryl-2-(azaaryl)ethyl]malononitriles derivatives have been synthesized by catalyst-free, one-pot, three-component protocol and employing water as a solvent. Simple reaction, open air reaction, and easy isolation are added advantages of this method. The method is applicable for aryl as well as heteroaryl systems and provides a convenient access for the synthesis of novel quinoline derivatives. All the 2-[1-aryl-2-(azaaryl)ethyl]malononitrile derivatives were evaluated for their antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus cereus) and Gram-negative bacteria (Pseudomonas aeruginosa). Eleven compounds exhibited good antibacterial activity against both Gram-positive pathogens and Gram-negative species.
Supporting Information
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0034-1380212.
- Supporting Information
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- 22 General Procedure A 5 mL round-bottom-flask containing 2-methylquinoline (1a, 1 mmol), benzaldehyde (2a, 1.0 mmol), and malononitrile (3, 1 mmol), and H2O (2 mL) was placed in an oil bath and refluxed for the appropriate time at 100 °C (temperature monitored by a thermometer). The progress of reaction was monitored by TLC. After completion of the reaction, the flask was removed from the oil bath, and the solid product obtained was filtered, washed with H2O (2 × 10 mL) and n-hexane (3 × 10 mL). The reaction mixture was diluted with H2O and extracted with EtOAc. The combined EtOAc extracts were then dried over Na2SO4, and after removal of the solvent the mixture was purified by column chromatography (silica gel; hexane–EtOAc, 90:10) to give pure products.
- 23 Analytical Data for a Few Typical Compounds 2-[1-(1,3-Diphenyl-1H-pyrazol-4-yl)-2-(quinolin-2-yl)ethyl]malononitrile (4i) Pale grey solid; yield 75%; mp 149–151 °C. IR (KBr): νmax = 3443, 3063, 2867, 2258, 1745, 1597, 1546, 1503, 1450, 1418, 1362, 1312, 1245, 1153, 1062, 960, 914, 829, 753, 695, 514 cm–1. 1H NMR (500 MHz, CDCl3): δ = 3.53 (m, 2 H), 4.48 (m, 1 H), 4.93 (d, J = 4.8 Hz, 1 H), 7.21 (d, J = 8.3 Hz, 1 H), 7.29 (t, J = 7.4 Hz, 1 H), 7.39 (m, 5 H), 7.52 (t, J = 7.9 Hz, 1 H), 7.61 (d, J = 6.7 Hz, 2 H), 7.71 (t, J = 8.0 Hz, 3 H), 7.78 (d, J = 8.2 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 8.08 (d, J = 8.3 Hz, 1 H), 8.27 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 29.15, 35.40, 41.40, 112.47, 112.74, 118.73, 119.42, 121.85, 126.05, 126.77, 127.07, 127.16, 127.82, 128.72, 128.94, 129.01, 129.08, 129.63, 130.12, 132.46, 137.17, 139.80, 147.81, 152.69, 157.02. ESI-MS: m/z = 440 [M + H]+. HRMS: m/z calcd for C29H22N5: 440.18697 [M + H]+; found: 440.18478. 2-[2-(6-Bromoquinolin-2-yl)-1-phenylethyl]malononitrile (5c) Pale grey solid; yield 75%; mp 118–120 °C. IR (KBr): νmax = 3422, 3032, 2901, 2853, 2252, 1592, 1488, 1451, 1324, 1190, 1054, 831, 771, 698 cm–1. 1H NMR (500 MHz, CDCl3): δ = 3.48 (dd, J = 4.8, 16.1 Hz, 1 H), 3.66 (dd, J = 9.7, 16.1 Hz, 1 H), 4.09 (m, 1 H), 5.05 (d, J = 5.0 Hz, 1 H), 7.24 (d, J = 5.3 Hz, 1 H), 7.33 (m, 3 H), 7.45 (d, J = 8.2 Hz, 2 H), 7.79 (dd, J = 2.2, 9.0 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.95 (d, J = 2.1 Hz, 1 H), 7.99 (d, J = 8.3 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 28.52, 39.35, 44.02, 111.81, 112.28, 120.07, 122.46, 127.76, 127.86, 128.69, 128.92, 129.42, 130.40, 133.00, 135.61, 136.78, 145.90, 157.59. ESI-MS: m/z = 376 [M + H]+. HRMS: m/z calcd for C21H15N3Br: 376.0444 [M + H]+; found: 376.0445. 2-{1-[3-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-2-(6-methylpyridin-2-yl)ethyl}malononitrile (6f) White solid; yield 70%; mp 89–91 °C. IR (KBr): νmax = 3447, 3138, 3066, 2926, 1592, 1500, 1453, 1410, 1340, 1228, 1152, 1070, 963, 843, 749, 686, 588, 550, 494 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.51 (s, 3 H), 3.33 (m, 2 H), 4.25 (m, 1 H), 4.56 (d, J = 4.7 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 7.02 (d, J = 7.5 Hz, 1 H), 7.15 (t, J = 8.6 Hz, 1 H), 7.33 (t, J = 7.3 Hz, 1 H), 7.47 (m, 3 H), 7.56 (m, 2 H), 7.71 (d, J = 7.7 Hz,), 8.21 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 21.35, 24.50, 29.08, 35.89, 40.93, 112.20, 112.46, 117.74, 119.22, 120.84, 121.85, 125.74, 126.83, 128.66, 129.31, 129.47, 137.08, 138.39, 139.69, 152.58, 155.85, 158.52. ESI-MS: m/z = 422 [M + H]+. HRMS: m/z calcd for C27H23N5: 422.17755 [M + H]+; found: 422.17680.