Research on Chemical Intermediates

, Volume 45, Issue 4, pp 1707–1719 | Cite as

Catalyst-free grinding method: a new avenue for synthesis of 6-amino-3-methyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and DFT studies on the mechanistic pathway of this category of compounds

  • Mohammad NikpassandEmail author
  • Leila Zare Fekri
  • Parissa Naddaf Rahro


A novel, efficient, one-pot, catalyst-free grinding procedure for synthesis of 6-amino-3-methyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile is reported. The condensation of substituted benzaldehydes, 3-amino-5-methylpyrazole, and malononitrile according to a three-component reaction was investigated using density functional theory (DFT) at B3LYP/6-311G level to explore the reaction mechanism. All the routes were studied, the structure of the intermediates was optimized, and all the respective transition states were found. The results of the calculations show that the proposed mechanism relies on four intermediates.


Grinding reaction DFT Mechanism Intermediate Transition state 



Financial support from the Research Council of Islamic Azad University, Rasht Branch is sincerely acknowledged.


  1. 1.
    A.M. Li, Y. Ouyang, Z.Y. Wang, Y.Y. Cao, X.Y. Liu, L. Ran, C. Li, L. Li, L. Zhang, K. Qiao, J. Med. Chem. 56, 3593 (2013)CrossRefPubMedGoogle Scholar
  2. 2.
    A.H. Shamroukh, A.E. Rashad, H.H. Sayed, J. Phosphorus Sulfur Silicon Rel. Elem. 180, 2347 (2005)CrossRefGoogle Scholar
  3. 3.
    L. Commeiras, S.C. Woodcock, J.E. Baldwin, R.M. Adlington, A.R. Cowley, P. Wilkinson, Tetrahedron 60, 933 (2004)CrossRefGoogle Scholar
  4. 4.
    A. Cappelli, C. Nannicini, A. Gallelli, G. Giuliani, S. Valenti, G.P. Mohr, M. Anzini, L. Mennuni, F. Ferrari, G. Caselli, A. Giordani, W. Pereis, F. Makovec, G. Giorgi, S. Vomero, J. Med. Chem. 51, 2137 (2008)CrossRefPubMedGoogle Scholar
  5. 5.
    R. Lin, P.J. Connolly, Y. Lu, G. Chin, S. Li, Y. Yu, S. Huang, X. Li, S.L. Emanuel, S.A. Middleton, R.H. Gruninger, M. Adams, A.R. Fuentes-Pesquera, L.M. Greenberger, J. Bioorg. Med. Chem. Lett. 17, 4557 (2007)CrossRefGoogle Scholar
  6. 6.
    H. de Mello, A. Echevarria, A.M. Bernardino, M. CantoCavalheiro, L.L. Leon, J. Med. Chem. 47, 5427 (2004)CrossRefPubMedGoogle Scholar
  7. 7.
    F. Manetti, S. Schenone, F. Bondavalli, C. Brullo, O. Bruno, A. Ranise, L. Mosti, G. Menozzi, P. Fossa, M.L. Trincavelli, C. Martini, A. Martinelli, C. Tintori, M. Botta, J. Med. Chem. 48, 7172 (2005)CrossRefPubMedGoogle Scholar
  8. 8.
    B.A. Johns, K.S. Gudmundsson, E.M. Turner, S.H. Allen, V.A. Samano, J.A. Ray, G.A. Freeman, F.L. Boyd, C.J. Sexton, D.W. Selleseth, K.L. Creech, K.R. Moniri, J. Bioorg. Med. Chem. 13, 2397 (2005)CrossRefGoogle Scholar
  9. 9.
    K.S. Gudmundsson, B.A. Johns, Z. Wang, E.M. Turner, S.H. Allen, G.A. Freeman, F.L.B. Jr, C.J. Sexton, D.W. Selleseth, K.R. Monirib, K.L. Creech, J. Bioorg. Med. Chem. 13, 5346 (2005)CrossRefGoogle Scholar
  10. 10.
    F.E. Goda, A.A.M. Abdel-Aziz, O.A. Attef, J. Bioorg. Med. Chem. Lett. 12, 1845 (2004)CrossRefGoogle Scholar
  11. 11.
    N.M. Parekh, K.C. Maheria, J. Res. Chem. Intermed. 38, 885 (2012)CrossRefGoogle Scholar
  12. 12.
    L. Zare, N.O. Mahmoodi, A. Yahyazadeh, M. Mamaghani, Syn. Commun. 41, 2323 (2011)CrossRefGoogle Scholar
  13. 13.
    P.A. Wender, J. Nat. Prod. Rep. 31, 433 (2014)CrossRefGoogle Scholar
  14. 14.
    A.Z. Halimehjani, I.N. Namboothiri, S.E. Hooshmand, RSC Adv. 4, 48022 (2014)CrossRefGoogle Scholar
  15. 15.
    A.Z. Halimehjani, I.N. Namboothiri, S.E. Hooshmand, RSC Adv. 4, 51794 (2014)CrossRefGoogle Scholar
  16. 16.
    V. Estévez, M. Villacampa, J.C. Menéndez, J. Chem. Soc. Rev. 43, 4633 (2014)CrossRefGoogle Scholar
  17. 17.
    A. Domling, W. Wang, K. Wang, J. Chem. Rev. 112, 3083 (2012)CrossRefGoogle Scholar
  18. 18.
    M. Nikpassand, L. Zare Fekri, M. Nabatzadeh, Comb. Chem. High Throughput Screen. 20, 533 (2017)CrossRefPubMedGoogle Scholar
  19. 19.
    L. Zare Fekri, M. Nikpassand, J. Chil. Chem. Soc. 57, 1415 (2012)CrossRefGoogle Scholar
  20. 20.
    M. Nikpassand, L. ZareFekri, S. Sanagou, Dyes Pigm. 136, 140 (2017)CrossRefGoogle Scholar
  21. 21.
    H. Taherkhorsand, M. Nikpassand, Comb. Chem. High Throughput Screen. 21, 65 (2018)CrossRefPubMedGoogle Scholar
  22. 22.
    L. Zare Fekri, M. Nikpassand, M. Goldoost, Russ. J. Gen. Chem. 83, 2352 (2013)CrossRefGoogle Scholar
  23. 23.
    L. Zare Fekri, M. Nikpassand, Russ. J. Gen. Chem. 83, 2395 (2013)CrossRefGoogle Scholar
  24. 24.
    M. Nikpassand, L. Zare Fekri, K. Hematinezhad, J. Polycycl. Arom. Comp. in press (2018)Google Scholar
  25. 25.
    M.J. Frisch, et al., GAUSSIAN09, Gaussian, Inc., Revision B. 05, Pittsburgh PA (2009)Google Scholar
  26. 26.
    J.G. Ma, J.M. Zhang, H.H. Jiang, W.Y. Ma, J.H. Zhou, Chin. Chem. Lett. 19, 375 (2008)CrossRefGoogle Scholar
  27. 27.
    S. Karmakar, A. Datta, J. Org. Chem. 82, 1558 (2017)CrossRefPubMedGoogle Scholar
  28. 28.
    S. Karmakar, A. Datta, J. Phys. Chem. B 121, 7621 (2017)CrossRefPubMedGoogle Scholar
  29. 29.
    K. Bhattacharyya, S. Karmakar, A. Datta, Phys. Chem. Chem. Phys. 19, 22482 (2017)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Mohammad Nikpassand
    • 1
    Email author
  • Leila Zare Fekri
    • 2
  • Parissa Naddaf Rahro
    • 1
  1. 1.Department of Chemistry, Rasht BranchIslamic Azad UniversityRashtIran
  2. 2.Department of ChemistryPayame Noor UniversityTehranIran

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