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

Nandigama Satish Kumar; L. Chandrasekhara Rao; N. JagadeeshBabu; V. Dileep Kumar; U. S. N. Murthy; H. M. Meshram

doi:10.1055/s-0034-1380212

Synlett, Table of Contents

Synlett 2015; 26(13): 1808-1814
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

Nandigama Satish Kumar

^aMedicinal Chemistry and pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India Email: hmmeshram@yahoo.com

,

L. Chandrasekhara Rao

^aMedicinal Chemistry and pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India Email: hmmeshram@yahoo.com

,

N. JagadeeshBabu

^bLaboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India

,

V. Dileep Kumar

^cBiology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India

,

U. S. N. Murthy

^cBiology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India

,

H. M. Meshram*

^aMedicinal Chemistry and pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India Email: hmmeshram@yahoo.com

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Abstract

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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.

Key words

quinoline - multicomponent reaction - medicinal chemistry - azaarene - antibacterial

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References

References and Notes

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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): ν_max = 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): ν_max = 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): ν_max = 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.

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