Molecular Diversity

, Volume 22, Issue 4, pp 969–977 | Cite as

An efficient and facile synthesis of new tetracyclic fused pyrazolo[4,3-c][1,2,4]triazino[4,5-a]quinolin-4(5H)-ones

  • Mohsen A.-M. GomaaEmail author
  • Huda A. Ali
Original Article


Reaction of amidrazones 1a–1i with (1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene)propanedinitrile (2) in ethyl acetate solution in one-step reaction led to the formation of unprecedented pyrazolo[4,3-c][1,2,4]triazino[4,5-a]quinolin-4(5H)-ones 3a–3g along with pyrazolo[4,3-c][1,2,4]triazino[4,5-a]quinolin-12b-oles 3h–3m in moderate to excellent yields. These novel heterocycles were formed via a Michael addition reaction followed by intramolecular cyclization via a dearomatization process.


Pyrazolo[4,3-c][1,2,4]triazino[4,5-a]quinolone Amidrazone (1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene)propanedinitrile Dearomatization 



We are grateful to Prof. Dr. Jens Christoffers at Institut für Chemie Carl von Ossietzky Universität Oldenburg and Prof. Dr. Georg Manolikakes Fachbereich Chemie-Organische Chemie TU Kaiserslautern for kind help in the measurements of some NMR spectra and HRMS experiments.

Supplementary material

11030_2018_9849_MOESM1_ESM.docx (990 kb)
Supplementary material 1 (DOCX 989 kb)


  1. 1.
    Abdel-Rahman RM (1991) Synthesis and anti human immune virus activity of some new fluorine containing substituted-3-thioxo-1,2,4-triazin-5-ones. Farmaco 46:379–389PubMedGoogle Scholar
  2. 2.
    Sidwell RW, Dixon GJ, Sellers SM, Schable FM (1968) In vivo antiviral properties of biologically active compounds. II. Studies with influenza and vaccinia viruses. Appl Microbiol 16:370–392PubMedPubMedCentralGoogle Scholar
  3. 3.
    Abdel-Rahman RM, Seada M, Fawzy M, El-Baz I (1994) Synthesis of some new 1,6-dihydro-3-substituted- 6-spiro(9′-fluorine)-1,2,4-Triazine-5-(4H)ones as potential Anti HIV and Anti cancer drugs. Pharmazie 49:729–733PubMedGoogle Scholar
  4. 4.
    Abdel-Rahman RM, Seada M, Fawzy M, El-Baz I (1994) Synthesis of some new heterobicyclic compounds containing spiro-1,2,4-triazin e moiety as potential anti-HIV and anticancer agents. Pharmazie 49:811–814PubMedGoogle Scholar
  5. 5.
    El-Gendy Z, Morsy JM, Allimony H, Abdel-Monem WR, Abdel-Rahman RM (2005) Synthesis of heterobicyclic nitrogen systems bearing a 1,2,4-triazine moiety as anticancer drugs. Phosphorus Sulfur Silicon 173:2055–2071. CrossRefGoogle Scholar
  6. 6.
    El-Gendy Z, Morsy JM, Allimony H, Abdel-Monem WR, Abdel-Rahman RM (2001) Synthesis of heterobicyclic nitrogen systems bearing the 1,2,4-triazine moiety as anti-HIV and anticancer drugs. Pharmazie 56:376–383PubMedGoogle Scholar
  7. 7.
    Abdel-Rahman RM (1992) Synthesis of new fluorine bearing trisubstituted 3-thioxo-1,2,4-triazin-5-ons as potential anticancer agents. Farmaco 47:319–326PubMedGoogle Scholar
  8. 8.
    Abdel-Rahman RM, Seada M, Fawzy M, El-Baz I (1993) Synthesis and anti-cancer anti human immune virus activities of some new thioether bearing a 1,2,4-triazine-3-hydrazones. Farmaco 48:397–406PubMedGoogle Scholar
  9. 9.
    Ibrahim MA, Abdel-Rahman RM, Abdel-Halim AM, Ibrahim SS, Allimony HA (2009) Synthesis, chemical reactivity and fungicidal activity of pyrido[1,2-b][1,2,4]triazine derivatives. J Braz Chem Soc 20:1275–1286. CrossRefGoogle Scholar
  10. 10.
    Ibrahim MA, Abdel-Rahman RM, Abdel-Halim AM, Ibrahim SS, Allimony HA (2008) Synthesis and antifungal activity of novel polyheterocyclic compounds containing fused 1,2,4-triazine moiety. ARKIVOC 21:202–215Google Scholar
  11. 11.
    Ali TE, Ibrahim MA (2010) synthesis and antimicrobial activity of chromone-linked 2-pyridone fused with 1,2,4-triazoles, 1,2,4-triazines and 1,2,4-triazepines ring systems. J Braz Chem Soc 21:1007–1016. CrossRefGoogle Scholar
  12. 12.
    Wittman MD, Carboni JM, Yahg Z, Lee FY, Attar R, Baliman P, Vyas DM (2010) Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. J Med Chem 52:7360–7363. CrossRefGoogle Scholar
  13. 13.
    Mullick P, Khan SA, Begum T, Verma S, Kaushik S, Alam O (2009) Synthesis of 1,2,4-triazine derivatives as potential anti-anxiety and anti-inflammatory agents. Acta Poloniae Pharm Drugs Res 66:379–385Google Scholar
  14. 14.
    Abdel-Rahman RM, Morsy JM, Hanafy F, Amene HA (1999) Synthesis of heterobicyclic nitrogen systems bearing the 1,2,4-triazine moiety as anti-HIV and anticancer drugs. Pharmazie 54:347–351PubMedGoogle Scholar
  15. 15.
    Sangshette JN, Shinde DB (2010) One pot synthesis and SAR of some novel 3-substituted 5,6-diphenyl-1,2,4-triazines as antifungal agents Bioorg. Med Chem Lett 20:742–745. CrossRefGoogle Scholar
  16. 16.
    Zhao Z, Leister WH, Strauss KA, Wisnosk DD, Lindsley CW (2003) Broadening the scope of 1,2,4-triazine synthesis by the application of microwave technology. Tetrahedron Lett 44:1123–1127. CrossRefGoogle Scholar
  17. 17.
    Shi B, Lewis W, Campbell IB, Moody C (2009) A concise route to pyridines from hydrazides by metal carbene N–H insertion, 1,2,4-triazine formation, and Diels–Alder reaction. J Org Lett 11:3686–3688. CrossRefGoogle Scholar
  18. 18.
    Rostamizadeh S, Sadeghi K (2002) One-pot synthesis of 1,2,4-triazines. Synth Commun 32:1899–1902. CrossRefGoogle Scholar
  19. 19.
    Kidwai M, Sapra P, Bhushan KR, Misra P (2001) Microwave assisted synthesis of novel 1,2,4-triazines “dry media”. Synth Commun 31:1639–1645. CrossRefGoogle Scholar
  20. 20.
    Morsy JM, Hanafy IF, Abdel-Rahman RM, Amine HA (2000) Synthesis and chemical reactivity of novel functionally substituted 5,6-diphenyl-1,2,4-triazines Pak. J Sci Ind Res 43:208–213Google Scholar
  21. 21.
    Edmont D, Chenault J (2003) 8-Fluoro-4-hydroxy-1H-[1,2,4]triazino[4,5-a]quinoline-1,6(2H)-dione: synthesis and reactivity. J Heterocyclic Chem 40:789–793. CrossRefGoogle Scholar
  22. 22.
    Aly AA, Brown AB, Hassan AA, Gomaa MA-M, Nemr FM (2015) Reaction of ethyl 2-cyano-3,3-bis(methylthio)acrylate with amidrazones; synthesis of new mercapto pyrazoles and NMR investigation. J Sulfur Chem 36:502–510. CrossRefGoogle Scholar
  23. 23.
    Aly AA, Hassan AA, Bräse S, Gomaa MA-M, Nemr FM (2017) Reaction of amidrazones with diaminomaleonitrile: synthesis of 4-amino-5-iminopyrazoles. J Heterocyclic Chem 54:480–483. CrossRefGoogle Scholar
  24. 24.
    Aly AA, Gomaa A-MM, Nour El-Din AM, Fahmi MS (2006) Amidrazones in the synthesis of 1H-1,2,4-Triazoles. Z Naturforsch 61B:1239–1242CrossRefGoogle Scholar
  25. 25.
    Aly AA, Gomaa A-MM, Nour El-Din AM, Fahmi MS (2007) Reactions of amidrazones with 1,4-quinones. ARKIVOC (xvi):41–50Google Scholar
  26. 26.
    Aly AA, Nour El-Din AM, Gomaa A-MM, Fahmi MS (2008) Rapid and facile synthesis of 4-aryl-5-imino-3-phenyl-1H-naphtho[2,3-f]-1,2,4-triazepine-6,11-diones via the reaction of amidrazones with dicyanonaphthoquinone. Z Naturforsch 63B:223–228CrossRefGoogle Scholar
  27. 27.
    Gomaa MA-M (2001) Reaction of N1, N2-diarylamidines with 2-(3-methyl-5-oxo-1-phenyl-1H-pyrazol-4(5H)-ylidene)-propanedinitrile. J Chem Res (S). CrossRefGoogle Scholar
  28. 28.
    Zhang Y-C, Zhao J-J, Jiang F, Sun S-B, Shi F (2014) Organocatalytic asymmetric arylative dearomatization of 2,3-disubstituted indoles enabled by tandem reactions. Angew Chem Int Ed 53:13912–13915. CrossRefGoogle Scholar
  29. 29.
    Shi F, Zhu R-Y, Dai W, Wang C-S, Tu S-J (2014) Catalytic asymmetric formal [3 + 3] cycloaddition of an azomethine ylide with 3-indolylmethanol: enantioselective construction of a six-membered piperidine framework. Chem Eur J 20:2597–2604. CrossRefPubMedGoogle Scholar
  30. 30.
    Wang CS, Zhu R-Y, Zheng J, Shi F, Tu S-J (2015) Enantioselective construction of spiro[indoline-3,2′-pyrrole] framework via catalytic asymmetric 1,3-dipolar cycloadditions using allenes as equivalents of alkynes. J Org Chem 80(1):512–520. CrossRefPubMedGoogle Scholar
  31. 31.
    Dai W, Jiang X-L, Tao J-Y, Shi F (2016) Application of 3-methyl-2-vinylindoles in catalytic asymmetric povarov reaction: diastereo- and enantioselective synthesis of indole-derived tetrahydroquinolines. J Org Chem 81(1):185–192. CrossRefPubMedGoogle Scholar
  32. 32.
    Wang Y-M, Zhang H-H, Li C, Fan T, Shi F (2016) Catalytic asymmetric chemoselective 1,3-dipolar cycloadditions of an azomethine ylide with isatin-derived imines: diastereo- and enantioselective construction of a spiro[imidazolidine-2,3′-oxindole] framework. Chem Commun 52:1804–1807. CrossRefGoogle Scholar
  33. 33.
    Davison JS (1979) A preparation of 3-Amino-4,5-diaryl-1,2,4-triazoles. Synthesis. CrossRefGoogle Scholar
  34. 34.
    Junek H, Klade M, Sterk H, Fabian W (1988) Syntheses with nitriles, LXXX. Dicyanomethylenepyrazolinones and their chromophoric properties. Monatsh Chem 119:993–1010. CrossRefGoogle Scholar
  35. 35.
    Furniss BS, Hannaford AJ, Smith PWG, Tatchell AR (1989) Vogel’s text book of practical organic chemistry, 5th edn. Longman Scientific & Technical Longman Group UK Limited House, Harlow Essex. CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemistry, Faculty of ScienceMinia UniversityEl-MiniaEgypt

Personalised recommendations