A Convenient Approach for the Synthesis of 1,3-Diphenyl-1H-pyrazole-5-carbonitrile

Abstract

An operationally simple and efficient protocol for the synthesis of unsymmetrical substituted 1,3-pyrazole derivatives has been developed via a three-component coupling reaction involving hydrazonoyl chloride, 4-oxo-4H-chromene-3-carbaldehyde, and hydroxylamine hydrochloride.

Key words

hydrazonoyl chloride - hydroxylamine hydrochloride - 4-oxo-4H-chromene-3-carbaldehyde - pyrazole - multicomponent reaction

• References and Notes

• 1a Joule JA, Mills K. Heterocyclic Chemistry. 4th ed. Blackwell; Oxford: 2000
• 1b Eicher T, Hauptmann S. The Chemistry of Heterocycles. Wiley-VCH; Weinheim: 2003
• 1c Katrizky AR, Pozharskii AF. Handbook of Heterocyclic Chemistry. 2nd ed. Pergamon Press; Amsterdam: 2000
• 2a Fischer DS, Allan GM, Bubert C, Vicker N, Smith A, Tutill HJ, Purohit A, Wood L, Packham G, Mahon MF, Reed MJ, Potter BV. J. Med. Chem. 2005; 48: 5749
• 2b Yang YS, Li QS, Sun S, Zhang YB, Wang XL, Zhang F, Tang JF, Zhu HL. Bioorg. Med. Chem. 2012; 20: 6048
• 3 Elguero J, Goya P, Jagerovic N, Silva AM. S In Pyrazoles as Drugs: Facts and Fantasies in Targets in Heterocyclic Systems . Vol. 6. Attanasi OA, Spinelli D. Italian Society of Chemistry; Roma: 2002: 52
• 4a Lamberth C. Heterocycles 2007; 71: 1467
• 4b Nikolaus M. Pharma Chem. 2007; 6: 25
• 5a Navarro JA. R, Lippert B. Coord. Chem. Rev. 2001; 222: 219
• 5b Danel A, He Z, Milburn GH. W, Tomasik PJ. Mater. Chem. 1999; 9: 339
• 6a Klingele J, Dechert S, Meyer F. Coord. Chem. Rev. 2009; 253: 2698
• 6b Dias HV. R, Lovely CJ. Chem. Rev. 2008; 108: 3223
• 7a Strecker A. Justus Liebigs Ann. Chem. 1850; 75: 27
• 7b Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
• 7c Kappe CO. Acc. Chem. Res. 2000; 33: 879
• 8a Elguero J, Goya P, Jagerovic N, Silva AM. S. Targets Heterocycl. Syst. 2002; 6: 52
• 8b Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, Anderson GD, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY, Isakson PC. J. Med. Chem. 1997; 40: 1347
• 8c Terrett NK, Bell AS, Brown D, Ellis P. Bioorg. Med. Chem. Lett. 1996; 6: 1819
• 8d Elguero J In Comprehensive Heterocyclic Chemistry II . Vol. 6. Katritzky AR, Rees CW, Scriven EF. V. Pergamon Elsevier Science; Oxford: 1996: 1
• 8e Singh SK, Reddy PG, Rao KS, Lohray BB, Misra P, Rajjak SA, Rao YK, Venkatewarlu A. Bioorg. Med. Chem. Lett. 2004; 14: 499
• 9a Elguero J In Comprehensive Heterocyclic Chemistry II . Vol. 3. Katritzky AR, Rees CW, Scriven EF. V. Pergamon Press; Oxford: 1996: 1
• 9b Kost AN, Grandberg II In Advances in Heterocyclic Chemistry . Vol. 6. Katritzky AR, Boulton AJ. Academic Press; New York: 1966: 347
• 10a Grotjahn DB, Van S, Combs D, Lev DA, Schneider C, Rideout M, Meyer C, Hernandez G, Mejorado L. J. Org. Chem. 2002; 67: 9200
• 10b Jackowski O, Lecourt T, Micouin L. Org. Lett. 2011; 13: 5664
• 10c Hari Y, Tsuchida S, Sone R, Aoyama T. Synthesis 2007; 3371
• 10d Ma C, Li Y, Wen P, Yan R, Ren Z, Huang G. Synlett 2011; 1321
• 10e Martín R, Rodríguez Rivero M, Buchwald SL. Angew. Chem. Int. Ed. 2006; 45: 7079
• 10f Babinski DJ, Aguilar HR, Still R, Frantz DE. J. Org. Chem. 2011; 76: 5915
• 11a Yet L In Comprehensive Heterocyclic Chemistry III . Vol. 4. Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Elsevier; Oxford: 2008: 1
• 11b Stanovnik B, Svete J. Science of Synthesis, Houben-Weyl Methods of Molecular Transformations. Vol. 12, Category 2. Chap. 12.1 Thieme; Stuttgart: 2002: 15
• 11c Stanovnik B, Svete J. Chem. Rev. 2004; 104: 2433
• 11d Gerstenberger BS, Rauckhorst MR, Starr JT. Org. Lett. 2009; 11: 2097
• 11e Zhang X, Kang J, Niu P, Wu J, Yu W, Chang J. J. Org. Chem. 2014; 79: 10170
• 12a Huisgen R. Angew. Chem. 1963; 75: 604
• 12b Nájera C, Sansano JM. Angew. Chem. Int. Ed. 2005; 44: 6272
• 12c Nájera C, Sansano JM. Org. Biomol. Chem. 2009; 7: 4567
• 12d Adrio J, Carretero JC. Chem. Commun. 2011; 47: 6784
• 12e Longmire JM, Wang B, Zhang X. J. Am. Chem. Soc. 2002; 124: 13400
• 12f Yan XX, Peng Q, Zhang Y, Zhang K, Hong W, Hou XL, Wu YD. Angew. Chem. Int. Ed. 2006; 45: 1979
• 12g Lévesque F, Bélanger G. Org. Lett. 2008; 10: 4939
• 12h He Z, Liu T, Tao H, Wang C.-J. Org. Lett. 2012; 14: 6230
• 13a Huisgen R. Angew. Chem., Int. Ed. Engl. 1963; 2: 565
• 13b Huisgen R. Angew. Chem., Int. Ed. Engl. 1963; 2: 633
• 14 Donohue AC, Pallich S, McCarthy TD. J. Chem. Soc., Perkin Trans. 1 2001; 2817
• 15 Oh L. Tetrahedron Lett. 2006; 47: 7943
• 16 Deng X, Mani NS. Org. Lett. 2006; 8: 3505
• 17 Chiericato M, Croce PD, Carganico G, Maiorana S. J. Heterocycl. Chem. 1979; 16: 383
• 18a Katritzky AR, Wang M, Zhang S, Voronkov MV. J. Org. Chem. 2001; 66: 6787
• 18b Elguero J In Comprehensive Heterocyclic Chemistry II . Vol. 3. Katritzky AR, Rees CW, Scriven EF. V. Pergamon Press; Oxford: 1996: 1
• 19 Khlopushina TG, Krinskaya AV, Kirsanova ZD, Zykov DA, Zagorevskii VA. Pharm. Chem. J. 1991; 25: 760
• 20 Hassaneen HM, Ead HA, Elwan NM, Shawali AS. Heterocycles 1988; 27: 2857
• 21 Alizadeh A, Moafi L, Zhu LG. Synlett 2016; 27: 595
• 22 Alizadeh A, Moafi L, Ghanbaripour R, Abadi MH, Zhu Z, Kubicki M. Tetrahedron 2015; 71: 3495
• 23 Alizadeh A, Ghanbaripour R, Zhu LG. Synlett 2013; 24: 2124
• 24 Alizadeh A, Ghanbaripour R. Res. Chem. Intermed. 2015; 41: 8785
• 25 General Procedure A mixture of 4-oxo-4H-chromene-3-carbaldehyde (1 mmol) and hydroxylamine hydrochloride (1 mmol) in EtOH (2 mL) was stirred at reflux for 12 h. Then hydrazonoyl chloride 1 (1 mmol) was added to the mixture followed by the dropwise addition of Et₃N (1 mmol). The mixture was stirred at room temperature until completion (2 h), monitoring by TLC. The solvent was removed, and the residue purified by column chromatography (hexane–EtOAc, 1:10) to afford the pure products 2a–g. Representative Analytical Data 1,3-Diphenyl-1H-pyrazole-5-carbonitrile (2a) White powder, mp 135–137 °C, 0.20 g, yield 82%. IR (KBr): ν_max = 3131 (CH), 2227 (CN), 1593 (C=N), 1496 (Ar) cm^–1. Anal. Calcd (%) for C₁₆H₁₁N₃ (245.28): C, 78.35; H, 4.52; N, 17.13. Found: C, 78.39; H, 4.57; N, 17.10. ¹H NMR (300 MHz, CDCl₃): δ = 7.32 (1 H, s, CH⁴), 7.42 (2 H, t, ³ J _HH = 6.9 Hz, 2 CH _para of 2 Ph), 7.48 (2 H, t, ³ J _HH = 8.7 Hz, 2 CH _meta of Ph), 7.58 (2 H, t, ³ J _HH = 7.5 Hz, 2 CH _meta of Ph), 7.81 (2 H, d, ³ J _HH = 8.1 Hz, 2 CH _ortho of Ph), 7.89 (2 H, d, ³ J _HH = 7.8 Hz, 2 CH _ortho of Ph). ¹³C NMR (75.0 MHz, CDCl₃): δ = 111.07 (CCN), 113.08 (CH⁴), 114.97 (CN), 122.84 (2 CH _ortho of Ph), 125.94 (2 CH _ortho of Ph), 128.90 (CH _para of 2 Ph), 128.94 (2 CH _meta of Ph), 129.08 (CH _para of Ph), 129.62 (2 CH _meta of Ph), 131.08 (C _ipso C³), 138.63 (C _ipso N), 152.72 (C³). 3-(4-Chlorophenyl)-1-phenyl-1H-pyrazole-5-carbonitrile (2b) Cream powder, mp 150 °C, 0.22 g, yield 77%. IR (KBr): ν_max = 3129 (CH), 2228 (CN), 1596 (C=N), 1601 and 1495 (Ar) cm^–1. Anal. Calcd (%) for C₁₆H₁₀ClN₃ (279.73): C, 68.70; H, 3.60; N, 15.02. Found: C, 68.77; H, 3.64; N, 15.06. ¹H NMR (300 MHz, CDCl₃): δ = 7.28 (1 H, s, CH⁴), 7.43 (2 H, d, ³ J _HH = 8.5 Hz, 2 CH of Ar), 7.51 (1 H, t, ³ J _HH = 7.2 Hz, CH _para of Ph), 7.57 (2 H, t, ³ J _HH = 7.9 Hz, 2 CH _meta of Ph), 7.78 (2 H, d, ³ J _HH = 7.4 Hz, 2 CH of Ar), 7.81 (2 H, d, ³ J _HH = 7.4 Hz, 2 CH _ortho of Ph). ¹³C NMR (75.46 MHz, CDCl₃): δ = 111.07 (CCN), 113.06 (CH⁴), 115.31 (CN), 122.97 (2 CH _ortho of Ph), 127.30 (2 CH of Ar), 129.21 (CH _para of Ph), 129.30 (2 CH _meta of Ph), 129.70 (C _ipso C³), 129.79 (2 CH of Ar), 135.10 (C _ipso Cl), 138.61 (C _ipso N), 151.74 (C³). 3-(4-Methylphenyl)-1-phenyl-1H-pyrazole-5-carbonitrile (2d) White powder, mp 124–126 °C, 0.22 g, yield 85%. IR (KBr): ν_max = 3131 (CH), 2228 (CN), 1593 (C=N), 1500 and 1430 (Ar) cm^–1. Anal. Calcd (%) for C₁₇H₁₃N₃ (259.31): C, 78.74; H, 5.05; N, 16.20. Found: C, 78.70; H, 5.09; N, 16.25. ¹H NMR (300 MHz, CDCl₃): δ = 2.42 (3 H, s, CH₃), 7.28 (1 H, s, CH⁴), 7.283 (2 H, d, ³ J _HH = 8.7 Hz, 2 CH of Ar), 7.50 (1 H, t, ³ J _HH = 7.2 Hz, CH _para of Ph), 7.57 (2 H, t, ³ J _HH = 7.3 Hz, 2 CH _meta of Ph), 7.78 (2 H, d, ³ J _HH = 8.7 Hz, 2 CH of Ar), 7.81 (2 H, d, ³ J _HH = 7.4 Hz, 2 CH _ortho of Ar). ¹³C NMR (75.46 MHz, CDCl₃): δ = 21.37 (CH₃), 111.21 (CCN), 112.91 (CH⁴), 114.83 (CN), 122.81 (2 CH _ortho of Ph), 125.83 (2 CH of Ar), 128.29 (C _ipso C³), 128.83 (CH _para of Ph), 129.59 (2 CH _meta of Ph), 129.62 (2 CH of Ar), 138.68 (C _ipso N), 139.08 (C _ipso Me), 152.80 (C³).