Synlett 2015; 26(13): 1808-1814
DOI: 10.1055/s-0034-1380212
letter
© Georg Thieme Verlag Stuttgart · New York

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
a   Medicinal Chemistry and pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India   eMail: hmmeshram@yahoo.com
,
L. Chandrasekhara Rao
a   Medicinal Chemistry and pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India   eMail: hmmeshram@yahoo.com
,
N. JagadeeshBabu
b   Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India
,
V. Dileep Kumar
c   Biology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India
,
U. S. N. Murthy
c   Biology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India
,
H. M. Meshram*
a   Medicinal Chemistry and pharmacology Division, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India   eMail: hmmeshram@yahoo.com
› Institutsangaben
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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

 
  • References and Notes

    • 1a Ugi I, Dömling A, Horl W. Endeavour 1994; 18: 115
    • 1b Hulme C, Gore V. Curr. Med. Chem. 2003; 10: 51
    • 1c Sunderhaus JD, Dockendorff C, Martin SF. Org. Lett. 2007; 9: 4223
    • 1d Armstrong RW, Combs AP, Tempest PA, Brown SD, Keating TA. Acc. Chem. Res. 1996; 29: 123
    • 1e Muller FL, Constantieux T, Rodriguez J. J. Am. Chem. Soc. 2005; 127: 17176
    • 1f Haurena C, Gall EL, Sengmany S, Martens T, Troupel M. J. Org. Chem. 2010; 75: 2645
    • 2a Tietze LF, Lieb ME. Curr. Opin. Chem. Biol. 1998; 2: 363
    • 2b Dax SL, McNally JJ, Youngman MA. Curr. Med. Chem. 1999; 6: 255
    • 2c Willy B, Müller TJ. J. Eur. J. Org. Chem. 2008; 4157
    • 2d Heravi MM, Baghernejad B, Oskooie HA, Hekmatshoar R. Tetrahedron Lett. 2008; 49: 6101
    • 2e Adib M, Sheikhi E, Kavoosi A, Bijanzadeh HR. Tetrahedron 2010; 66: 9263
    • 2f Dömling A. Comb. Chem. High Throughput Screening 1998; 1: 1
    • 2g Evdokimov NM, Kireev AS, Yakovenko AA, Antipin MY, Magedov IV, Kornienko A. J. Org. Chem. 2007; 72: 3443
    • 2h Chen W.-B, Wu Z.-J, Pei Q.-L, Cun L.-F, Zhang X.-M, Yuan W.-C. Org. Lett. 2010; 12: 3132
    • 4a Jacquemond-Collet I, Benoit-Vical F, ; Mustofa, Valentin A, Stanislas E, Mallie M, Fouraste I. Planta Med. 2002; 68: 68
    • 4b Kouznetsov VV, Melendez Gomez CM, Derita MG, Svetaz L, Olmo ED, Zacchino SA. Bioorg. Med. Chem. 2012; 20: 6506
    • 4c Colotta V, Catarzi D, Varano F, Capelli F, Lenzi O, Filacchioni G, Martini C, Trincavelli L, Ciampi O, Pugliese AM, Pedata F, Schiesaro A, Morizzo E, Moro S. J. Med. Chem. 2007; 50: 4061
    • 4d Huang A, Moretto A, Janz K, Lowe M, Bedard PW, Tam S, Di L, Clerin V, Sushkova N, Tchernychev B, Tsao DH. H, Keith JC. Jr, Shaw GD, Schaub RG, Wang Q, Kaila N. J. Med. Chem. 2010; 53: 6003
  • 5 Lilienkampf A, Mao J, Wan B, Wang Y, Franzblau SG, Kozikowski AP. J. Med. Chem. 2009; 52: 2109
  • 6 Nasveld P, Kitchener S. Trans. R. Soc. Trop. Med. Hyg. 2005; 99: 2
  • 7 Leatham PA, Bird HA, Wright V, Seymour D, Gordon A. Eur. J. Rheumatol. Inflammation 1983; 6: 209
  • 8 Huang F.-C, Galemmo RA. Jr, Campbell HF. US 4918081, 1990
    • 9a Insuasty B, Montoya A, Becerra D, Quiroga J, Abonia R, Robledo S, Vélez ID, Upegui Y, Nogueras M, Cobo J. Eur. J. Med. Chem. 2013; 67: 252
    • 9b Sun J, Zhu H, Yang Z.-M, Zhu H.-L. Eur. J. Med. Chem. 2013; 60: 23
  • 10 Mahamoud A, Chevalier J, Davin-Regli A, Barbe J, Pages J.-M. Curr. Drug Targets 2006; 7: 843
  • 11 Muruganantham N, Sivakumar R, Anbalagan N, Gunasekaran V, Leonard JT. Biol. Pharm. Bull. 2004; 27: 1683
    • 12a Wilson WD, Zhao M, Patterson SE, Wydra RL, Janda L, Strekowski L, Schinazi RF. Med. Chem. Res. 1992; 2: 102
    • 12b Strekowski L, Mokrosz JL, Honkan VA, Czarny A, Cegla MT, Wydra RL, Patterson SE, Schinazi RF. J. Med. Chem. 1991; 34: 1739
  • 13 Musiol R, Jampilek J, Buchta V, Silva L, Niedbala H, Podeszwa B, Palka A, Majerz-Maniecka K, Oleksynd B, Polanski J. Bioorg. Med. Chem. 2006; 14: 3592
  • 14 Podeszwa B, Niedbala H, Polanski J, Musiol R, Tabak D, Finster J, Serafin K, Milczarek M, Wietrzyk J, Boryczka S, Mol W, Jampilek J, Dohnal J, Kalinowsik DS, Richardson DR. Bioorg. Med. Chem. Lett. 2007; 17: 6138
    • 15a Zamboni R, Belley M, Champion E, Charette L, DeHaven R, Frenette R, Gauthier JY, Jones TR, Leger S. J. Med. Chem. 1992; 35: 3832
    • 15b Nakayama H, Loiseau PM, Bories C, Torres de Ortiz S, Schinini A, Serna E, Rojas de Arias A, Fakhfakh MA, Franck X, Figadere B, Hocquemiller R, Fournet A. Antimicrob. Agents Chemother. 2005; 49: 4950
    • 15c Mekouar K, Mouscadet J.-F, Desmaele D, Subra F, Leh H, Savoure D, Auclair C, d’Angelo J. J. Med. Chem. 1998; 41: 2846
    • 15d Franck X, Fournet A, Prina E, Mahieux R, Houquemiller R, Figadere B. Bioorg. Med. Chem. Lett. 2004; 14: 3635
    • 15e Fournet A, Mahieux R, Fakhfakh MA, Franck X, Hocqumeiller R, Figadère B. Bioorg. Med. Chem. Lett. 2003; 13: 891
    • 15f Fakhfakh MA, Fournet A, Prina E, Mouscadet J.-F, Franck X, Hocquemiller R, Figadere B. Bioorg. Med. Chem. 2003; 11: 5013
    • 15g Chang FS, Chen WC, Wang CH, Tzeng CC, Chen YL. Bioorg. Med. Chem. 2010; 18: 124
    • 16a Komai H, Yoshino T, Matsunaga S, Kanai M. Org. Lett. 2011; 13: 1706
    • 16b Li H.-Y, Xing L.-J, Xu T, Wang P, Liu R.-H, Wang B. Tetrahedron Lett. 2013; 54: 858
    • 16c Yan Y, Xu K, Fang Y, Wang Z. J. Org. Chem. 2011; 76: 6849
    • 16d Qian B, Shi D, Yang L, Huang H. Adv. Synth. Catal. 2012; 354: 2146
    • 16e Qian B, Guo S, Shao J, Zhu Q, Yang L, Xia C, Huang H. J. Am. Chem. Soc. 2010; 132: 3650
    • 16f Qian B, Xie P, Xie Y, Huang H. Org. Lett. 2011; 13: 2580
    • 16g Qian B, Guo S, Xie C, Huang H. Adv. Synth. Catal. 2010; 352: 3195
    • 17a Martins MA. P, Frizzo CP, Moreira DN, Buriol L, Machado P. Chem. Rev. 2009; 109: 4140
    • 17b Cave GW. V, Raston CL, Scott JL. Chem. Commun. 2001; 2159
    • 17c Cheng C, Jiang B, Tu S.-J, Li G. Green Chem. 2011; 13: 2107
    • 18a Meshram HM, Ngeswara Rao N, Chandrasekhara Rao L, Satish Kumar N. Tetrahedron Lett. 2012; 53: 3963
    • 18b Meshram HM, SatishKumar N, Jagadeesh Babu N, Chandrasekhara Rao L, Ngeswara Rao N. Tetrahedron Lett. 2013; 54: 5941
  • 19 Linday ME. Practical Introduction to Microbiology. E. and F. N. Spon; U.K.: 1962: 177
  • 20 P Clinical And Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Tests; Eighteen informational supplement M100-S18 (2008).
  • 21 CCDC number of the 4f is 952999. These data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223336033; email: deposit@ccdc.cam.ac.uk].
  • 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.