A One-Pot, Three-Component Synthesis of 3-(1H-Pyrazol-1-yl)-4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones under Solvent-Free Conditions

Abstract

A one-pot, three-component synthesis of 3-(1H-pyrazol-1-yl)-4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones is described which involves heating a mixture of 1,2-dihydro-3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine, aldehydes, and dimedone in the presence of a catalytic amount of p-toluenesulfonic acid under solvent-free conditions. The bridgehead-fused 6:6:6 systems with one ring-junction nitrogen atom were obtained in excellent yields.

Key words

[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones - 1,2-dihydro-3,6-bis(1H-pyrazol-1-yl)-1,2,4,5-tetrazine - solvent-free reaction - multicomponent reactions - cyclizations - heterocycles

• References and Notes

• 1a Multicomponent Reactions . Zhu J, Bienaymé H. Wiley-VCH; Weinheim: 2005
• 1b Dömling A. Chem. Rev. 2006; 106: 17
• 1c Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3169
• 1d Ramón DJ, Yus M. Angew. Chem. Int. Ed. 2005; 44: 1602
• 1e Ma C, Yang Y. Org. Lett. 2005; 7: 1343
• 1f Cheng Y, Meth-Cohn O. Chem. Rev. 2004; 104: 2507
• 1g Ruijter E, Scheffelaar R, Orru RV. A. Angew. Chem. Int. Ed. 2011; 50: 6234
• 2a Solvent-Free Organic Synthesis . Tanaka K. Wiley-VCH; Weinheim: 2004. 1st print
• 2b Tanaka K, Toda F. Chem. Rev. 2000; 100: 1025
• 2c Singh MS, Chowdhury S. RSC Adv. 2012; 2: 4547
• 2d Zhao YN, Li J, Li CJ, Yin K, Ye DY, Jia XS. Green Chem. 2010; 12: 1370
• 2e Martins MA. P, Frizzo CP, Moreira DN, Buriol L, Machado P. Chem. Rev. 2009; 109: 4140
• 3a Bleehen NM, Newlands ES, Lee SM, Thatcher N, Selby P, Calvert AH, Rustin GJ. S, Brampton M, Stevens MF. G. J. Clin. Oncol. 1995; 13: 910
• 3b Newlands ES, Blackledge GR. P, Slack JA, Rustin GJ. S, Smith DB, Stuart NS. A, Quarterman CP, Hoffman R, Stevens MF. G, Brampton MH, Gibson AC. Br. J. Cancer 1992; 65: 287
• 4a Audebert P, Sadki S, Miomandre F, Clavier G. Electrochem. Commun. 2004; 6: 144
• 4b Li Z, Ding JF, Song NH, Du XM, Zhou JY, Lu JP, Tao Y. Chem. Mater. 2011; 23: 1977
• 4c Ding J, Song N, Li Z. Chem. Commun. 2010; 46: 8668
• 4d Li Z, Ding J, Song N, Lu J, Tao Y. J. Am. Chem. Soc. 2010; 132: 13160
• 5a Kaim W. Coord. Chem. Rev. 2002; 230: 127
• 5b Kaim W, Berger S, Greulich S, Reinhardt R, Fiedler J. J. Organomet. Chem. 1999; 582: 153
• 5c Parimal K, Witlicki EH, Flood AH. Angew. Chem. Int. Ed. 2010; 49: 4628
• 6a Benson FR. The High Nitrogen Compounds . Wiley-Interscience; New York: 1984
• 6b Neunhoeffer H In Comprehensive Heterocyclic Chemistry I . Vol. 3. Katritzky AR, Rees CW. Chapt. 2.21 Pergamon Press; Oxford: 1984: 531-572
• 6c Hurst DT In Comprehensive Heterocyclic Chemistry II . Vol. 6. Katritzky AR, Rees CW, Scriven EF. V. Chapt. 6.22 Pergamon Press; London: 1996: 957-965
• 6d Churakov AM, Tartakovsky VA. Chem. Rev. 2004; 104: 2601
• 6e Saracoglu N. Tetrahedron 2007; 63: 4199
• 7a Cioslowski J, Sauer J, Hetzenegger J, Karcher T, Hierstetter T. J. Am. Chem. Soc. 1993; 115: 1353
• 7b Panek JS, Zhu B. Tetrahedron Lett. 1996; 37: 8151
• 7c Müller K, Sauer J. Tetrahedron Lett. 1984; 25: 2541
• 7d Burg B, Dittmar W, Reim H, Steigel A, Sauer J. Tetrahedron Lett. 1975; 16: 2897
• 8a Kovalev EG, Postovskii IY, Rusinov GL, Shegal IL. Chem. Heterocycl. Compd. 1981; 17: 1063
• 8b Tolshchina SG, Ishmetova RI, Ignatenko NK. Chem. Heterocycl. Compd. 2013; 49: 604
• 9a Latosh NI, Rusinov GL, Ganebnykh IN, Chupakhin ON. Russ. J. Org. Chem. 1999; 35: 1363
• 9b Rusinov GL, Latosh NI, Ganebnykh IN, Ishmetova RI, Ignatenko NK, Chupakhin ON. Russ. J. Org. Chem. 2006; 42: 757
• 9c Chavez DE, Hiskey MA. J. Heterocycl. Chem. 1998; 35: 1329
• 10a Chari MA, Karthikeyan G, Pandurangan A, Naidu TS, Sathyaseelan B, Zaidi SM. J, Vinu A. Tetrahedron Lett. 2010; 51: 2629
• 10b Hasaninejad A, Zare A, Shekouhy M. Tetrahedron 2011; 67: 390
• 10c Subba Reddy BV, Umadevi N, Narasimhulu G, Yadav JS. Chem. Lett. 2013; 42: 927
• 10d Bazgir A, Seyyedhamzeh M, Yasaei Z, Mirzaei P. Tetrahedron Lett. 2007; 48: 8790
• 10e Azarifar D, Nejat-Yami R, Akrami Z, Sameri F, Samadi S. Lett. Org. Chem. 2012; 9: 128
• 10f Tavakoli HR, Moosavi SM, Bazgir A. J. Korean Chem. Soc. 2013; 57: 472
• 11a Sayyafi M, Seyyedhamzeh M, Khavasi HR, Bazgir A. Tetrahedron 2008; 64: 2375
• 11b Ghorbani-Vaghei R, Karimi-Nami R, Toghraei-Semiromi Z, Amiri M, Ghavidel M. Tetrahedron 2011; 67: 1930
• 12 Scott FL. Angew. Chem. 1957; 69: 506
• 13a Coburn MD, Buntain GA, Harris BW, Hiskey MA, Lee KY, Ott DG. J. Heterocycl. Chem. 1991; 28: 2049
• 13b Gong YH, Miomandre F, Méallet-Renault R, Badré S, Galmiche L, Tang J, Audebert P, Clavier G. Eur. J. Org. Chem. 2009; 35: 6121
• 13c Li Y, Asadi A, Perrin DM. J. Fluorine Chem. 2009; 130: 377
• 14a Adib M, Sheikhi E, Bagheri M, Bijanzadeh HR, Amanlou M. Tetrahedron 2012; 68: 3237
• 14b Adib M, Sheikhi E, Rezaei N. Tetrahedron Lett. 2011; 52: 3191
• 14c Adib M, Ansari S, Bijanzadeh HR. Synlett 2011; 619
• 14d Adib M, Karimzadeh M, Mahdavi M, Sheikhi E, Mirzaei P. Synlett 2011; 834
• 14e Adib M, Sheikhi E, Kavoosi A, Bijanzadeh HR. Tetrahedron 2010; 66: 9263
• 14f Adib M, Sheikhi E, Kavoosi A, Bijanzadeh HR. Synthesis 2010; 4082
• 14g Adib M, Mohamadi A, Sheikhi E, Ansari S, Bijanzadeh HR. Synlett 2010; 1606
• 15 Typical Procedure for the Preparation of Compounds 8a–kA mixture of DHBPTz (0.272 g, 1.0 mmol), benzaldehyde (0.127 g, 1.2 mmol), dimedone (0.140 g, 1.0 mmol) and PTSA (0.052 g, 0.3 mmol) was heated at 120 °C for the time indicated in Table 1. After completion of the reaction as indicated by TLC monitoring, the reaction mixture was cooled to r.t., and the residue was purified by column chromatography using n-hexane–EtOAc (5:1) as eluent. The solvent was removed and the pure product 8a was obtained.3-(3,5-Dimethyl-1H-pyrazol-1-yl)-9,9-dimethyl-6-phenyl-6,8,9,10-tetrahydro-4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]-benzoxazin-7-one (8a)Yield 0.372 g (92%); yellow powder; mp 167 °C. IR (KBr): 3255 and 3144 (NH), 1709 (C=O), 1642 (C=N), 1601, 1491, 1370, 1318, 1270, 1219, 1113, 1028, 971, 911, 773, 744 cm^–1. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.04 and 1.05 (2 × s, 6 H, 2 × CH₃), 1.83 (s, 2 H, CH₂), 2.21 (d, ² J = 16.5 Hz, 1 H, CH _CCH_D), 2.28 (d, ² J = 16.5 Hz, 1 H, CH_CCH _D), 2.31 and 2.40 (2 × s, 6 H, 2 × CH₃), 6.08 (s, 1 H, pyrazole CH), 6.42 (s, 1 H, NCH), 7.31 (t, J = 7.5 Hz, 1 H, CH), 7.39 (t, J = 7.5 Hz, 2 H, 2 × CH), 7.53 (d, J = 7.5 Hz, 2 H, 2 × CH), 7.95 (s, 1 H, NH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 11.9 and 13.7 (2 × pyrazole CH₃), 28.4 and 28.6 [C(CH₃)₂], 34.6 (CH₂C=C), 34.7 [C(CH₃)₂], 50.8 (CH₂C=O), 64.0 (NCH), 109.7 (pyrazole CH), 114.0 (C), 127.1, 128.2 and 128.7 (3 × CH), 135.8, 139.2, 143.0, 150.2, 152.5 and 157.8 (6 × C), 191.5 (C=O). MS: m/z (%) = 404 (58) [M⁺], 368 (6), 339 (6), 327 (100), 243 (25), 227 (36), 202 (10), 179 (23), 163 (22), 149 (36), 122 (20), 95 (32), 77 (32). Anal. Calcd (%)for C₂₂H₂₄N₆O₂ (404.47): C, 65.33; H, 5.98; N, 20.78. Found: C, 65.30; H, 6.05; N, 20.72.6-(4-Chlorophenyl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)-9,9-dimethyl-6,8,9,10-tetrahydro-4H,7H-[1,2,4,5]tetraazino-­[6,1-b][1,3]benzoxazin-7-one (8e)Yield 0.404 g (92%); yellow powder; mp 207 °C. IR (KBr): 3220 and 3124 (NH), 1695 (C=O), 1648 (C=N), 1593, 1492, 1458, 1370, 1321, 1272, 1220, 1115, 1087, 1018, 970, 909, 831, 791, 743, 680 cm^–1. ¹H NMR (400.1 MHz, CDCl₃): δ = 0.99 and 1.00 (2 × s, 6 H, 2 × CH₃), 1.79 (d, ² J = 17.3 Hz, 1 H, CH _ACH_B), 1.80 (d, ² J = 17.3 Hz, 1 H, CH_ACH _B), 2.18 (d, ² J = 16.4 Hz, 1 H, CH _CCH_D), 2.23 (d, ² J = 16.4 Hz, 1 H, CH_CCH _D), 2.28 and 2.35 (2 × s, 6 H, 2 × CH₃), 6.05 (s, 1 H, pyrazole CH), 6.36 (s, 1 H, NCH), 7.31 (d, J = 8.8 Hz, 2 H, 2 × CH), 7.45 (d, J = 8.8 Hz, 2 H, 2 × CH), 8.51 (s, 1 H, NH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 11.9 and 13.6 (2 × pyrazole CH₃), 28.2 and 28.6 [C(CH₃)₂], 34.6 (CH₂C=C), 34.7 [C(CH₃)₂], 50.7 (CH₂C=O), 63.3 (NCH), 109.7 (pyrazole CH), 113.5 (C), 128.5 and 128.8 (4 × CH), 133.9, 135.6, 137.9, 143.1, 150.5, 152.6 and 157.8 (7 × C), 191.6 (C=O). MS: m/z (%) = 440 (20) [M⁺, ³⁷Cl], 438 (65) [M⁺, ³⁵Cl], 353 (2), 342 (4), 327 (100), 271 (5), 243 (42), 179 (30), 163 (45), 95 (28), 67 (18), 55 (17). Anal. Calcd (%) for C₂₂H₂₃ClN₆O₂ (438.92): C, 60.20; H, 5.28; N, 19.15. Found: C, 60.18; H, 5.32; N, 19.11.3-(3,5-Dimethyl-1H-pyrazol-1-yl)-9,9-dimethyl-6-propyl-6,8,9,10-tetrahydro-4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-one (8k)Yield 0.322 g (87%); yellow powder; mp 189 °C. IR (KBr): 3237 (NH), 1713 (C=O), 1670 (C=N), 1628, 1593, 1493, 1439, 1382, 1323, 1279, 1223, 1134, 1110, 1085, 1028, 970, 934, 904, 850, 814, 773, 716, 670 cm^–1. ¹H NMR (400.1 MHz, CDCl₃): δ = 0.96 (t, J = 7.3 Hz, 3 H, CH₂CH ₃), 0.98 and 1.01 (2 × s, 6 H, 2 × CH₃), 1.40–1.51 (m, 2 H, CH₂), 1.62 (d, J = 17.4 Hz, 1 H, CH _ACH_B), 1.63–1.71 (m, 1 H, CH), 1.72 (d, J = 17.4 Hz, 1 H, CH_ACH _B), 1.81–1.88 (m, 1 H, CH), 2.18 (d, J = 16.3 Hz, 1 H, CH _CCH_D), 2.24 (d, J = 16.3 Hz, 1 H, CH_CCH _D), 2.27 and 2.36 (2 × s, 6 H, 2 × CH₃), 5.37 (br d, J = 6.3 Hz, 1 H, NCHCH₂), 6.04 (s, 1 H, pyrazole CH), 7.55 (s, 1 H, NH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 11.8, 13.6 and 13.8 (2 × pyrazole CH₃ and CH₂ CH₃), 18.3 (CH₂CH₃), 28.1 and 28.7 [C(CH₃)₂], 34.4 (CH₂C=C), 34.5 [C(CH₃)₂], 36.2 (CHCH₂), 50.8 (CH₂C=O), 62.3 (NCH), 109.6 (pyrazole CH), 113.9, 135.8, 142.9, 150.5, 152.4 and 158.6 (6 × C), 191.7 (C=O). MS: m/z (%) = 370 (5) [M⁺], 327 (100), 273 (3), 243 (22), 163 (20), 95 (12), 67 (8), 55 (7). Anal. Calcd (%) for C₁₉H₂₆N₆O₂ (370.45): C, 61.60; H, 7.07; N, 22.69. Found: C, 61.51; H, 6.93; N, 22.57.