Molecular Diversity

, Volume 19, Issue 4, pp 759–771 | Cite as

A facile environment-friendly one-pot two-step regioselective synthetic strategy for 3,7-diarylpyrazolo[1,5-a]pyrimidines related to zaleplon and 3,6-diarylpyrazolo[1,5-a]pyrimidine-7-amines assisted by KHSO\(_{4}\) in aqueous media

  • Asem Satyapati Devi
  • Shunan Kaping
  • Jai Narain Vishwakarma
Full-Length Paper


3-Aminopyrazoles required for the synthesis of pyrazolo[1,5-a]pyrimidines were obtained by the reaction of enaminonitriles with hydrazine hydrate. The resulting aminopyrazoles are reacted with formylated acetophenones under reflux at \(60~ ^\circ \hbox {C}\) assisted by KHSO\(_{4}\) in aqueous media to form regioselectively 3,7-diarylpyrazolo[1,5-a]pyrimidines and 3,6-diarylpyrazolo[1,5-a]pyrimidine-7-amines. X-ray crystallography of selected compounds 5b and 7i further confirmed the regioselective formation of these products.


3-Aminopyrazole Michael addition Pyrazolo[1, 5-a]pyrimidines Regioselectivity Zaleplon 



Authors wish to thank Rev. Fr. Dr. Stephen Mavely, Vice Chancellor, Assam Don Bosco University for providing infrastructure for the execution of this work. Authors also wish to express their gratitude to IIT, Guwahati, Tezpur University, Tezpur, SAIF-NEHU, Shillong and SAIF-CDRI, Lucknow for providing spectral and analytical data. Our thanks are also due to the Department of Biotechnology (DBT), Government of India for a research project. SK thanks DBT-GOI for research fellowships.

Supplementary material

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  1. 1.
    Stefano A, Anna A, Maurizio B, Alessandra T, Francisco O, Francesco O, Silvia S, Chiara B, Matilde Y (2010) Hit identification and biological evaluation of anticancer pyrazolopyrimidines endowed with anti-inflammatory activity. Chem Med Chem 5:1242–1246. doi: 10.1002/cmdc.201000165 CrossRefGoogle Scholar
  2. 2.
    Curran K, Verheijen JC, Kaplan J, Richard DJ, Toral-Barza L, Hollander I, Lucas J, Ayral-Kaloustian S, Yu K, Zask A (2010) Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 1-substituent. Bioorg Med Chem Lett 20:1440–1444. doi: 10.1016/j.bmcl.2009.12.086 CrossRefPubMedGoogle Scholar
  3. 3.
    Al-Adiwish WM, Tahir MIM, Siti-Noor-Adnalizawati A, Hashim SF, Ibrahim N, Yaacob WA (2013) Synthesis, antibacterial activity and cytotoxicity of new fused pyrazolo[1,5-a]pyrimidine and pyrazolo[5,1-c][1,2,4]triazine derivatives from new 5-aminopyrazoles. E J Med Chem 64:464–476. doi: 10.1016/j.ejmech.2013.04.029 CrossRefGoogle Scholar
  4. 4.
    Rashad AE, Hegab M, Megeid FME, Abdel-Megeid RE, Micky JA (2008) Synthesis and antiviral evaluation of some new pyrazole and fused pyrazolopyrimidine derivatives. Bioorg Med Chem 16:7102–7106. doi: 10.1016/j.bmc.2008.06.054 CrossRefPubMedGoogle Scholar
  5. 5.
    Alexander JO, Wheeler GR, Hill PD, Morris MP (1966) Effects of 4-hydroxypyrazolo(3,4-d)pyrimidine upon the catabolism of purines by various tissues of the rat and upon the rate of growth of morris 5123-C hepatoma. Biochem Pharmacol 15:881–889. doi: 10.1016/0006-2952(66)90164-X CrossRefPubMedGoogle Scholar
  6. 6.
    Selleri S, Bruni F, Costagli C, Costanzo A, Guerrini G, Ciciani G, Gratteri P, Besnard F, Costa B, Montali M, Martini C, Fohlin J, Siena GD, Aiello PM (2005) A novel selective gaba\(_{a}\) \(\upalpha \)1 receptor agonist displaying sedative and anxiolytic-like properties in rodents. J Med Chem 48:6756–6760. doi: 10.1021/jm058002n CrossRefPubMedGoogle Scholar
  7. 7.
    Novinson T, Bhooshan B, Okabe T, Revankar GR, Wilson HR, Robins RK, Senga K (1976) Novel heterocyclic nitrofurfural hydrazones. In vivo antitrypanosomal activity. J Med Chem 19:512–516. doi: 10.1021/jm00226a013 CrossRefGoogle Scholar
  8. 8.
    Senga K, Novinson T, Wilson HR, Robins RK (1981) Synthesis and antischistosomal activity of certain pyrazolo[1,5-a]pyrimidines. J Med Chem 24:610–613. doi: 10.1021/jm00137a023 CrossRefPubMedGoogle Scholar
  9. 9.
    Kuribayash S, Goto K, Naito S, Kamataki T, Yamazaki H (2009) Human cytochrome P450 1A2 involvement in the formation of reactive metabolites from a species-specific hepatotoxic pyrazolopyrimidine derivative, 5-n-butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine. Chem Res Toxicol 22:323–331. doi: 10.1021/tx00034a019 CrossRefGoogle Scholar
  10. 10.
    Huang CQ, Wilcoxen KM, Grigoriadis DE, McCarthy JR, Chen C (2004) Design and synthesis of 3-(2-pyridyl)pyrazolo[1,5-\(a\)]pyrimidines as potent CRF\(_{1}\) receptor antagonists. Bioorg Med Chem Lett 1:3943–3947. doi: 10.1016/j.bmcl.2004.05.056 CrossRefGoogle Scholar
  11. 11.
    Wang YD, Honores E, Wu B, Johnson S, Powell D, Miranda M, McGinnis JP, Discafani C, Rabindran SK, Cheng W, Krishnamurthy G (2009) Synthesis, SAR study and biological evaluation of novel pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as anti-proliferative agents. Bioorg Med Chem 17:2091–2100. doi: 10.1016/j.bmc.2008.12.046 CrossRefPubMedGoogle Scholar
  12. 12.
    Fraley ME, Hoffman WF, Rubino RS, Hungate RW, Tebben AJ, Rutledge RZ, McFall RC, Huckle WR, Kendall RL, Coll KE, Thomas KA (2002) Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: A new class of KDR kinase inhibitors. Bioorg Med Chem Lett 12:2767–2770. doi: 10.1016/S0960-894X(02)00525-5 CrossRefPubMedGoogle Scholar
  13. 13.
    Compton DR, Carlson KE, Katzenellenbogen JA (2004) Pyrazolo[1,5-a]pyrimidines as estrogen receptor ligands: defining the orientation of a novel heterocyclic core. Bioorg Med Chem Lett 14:5681–5684. doi: 10.1016/j.bmcl.2004.08.046 CrossRefPubMedGoogle Scholar
  14. 14.
    Ahmetaj S, Velikanje N, Grošelj U, Šterbal I, Prek B, Golobič A, Kočar D, Dahmann G, Stanovnik B, Svete J (2013) Parallel synthesis of 7-heteroaryl-pyrazolo[1,5-a]pyrimidine-3-carboxamides. Mol Divers 17:731–743. doi: 10.1007/s11030-013-9469-3 CrossRefPubMedGoogle Scholar
  15. 15.
    Thurairajah P (1998) Process improvement in the synthesis of N->3-(3-cyano-pyrazolo(1,5-a)pyrimidin-7-yl)phenyl-N-ethylacetamide. US Patent 5714607Google Scholar
  16. 16.
    George CFP (2001) Pyrazolopyrimidines. Lancet 358:1623–1626. doi: 10.1016/S0140-6736(01)06656-9 CrossRefPubMedGoogle Scholar
  17. 17.
    Weitzel KW, Wickman JM, Augustin SG, Strom JG (2000) Zaleplon: a pyrazolopyrimidine sedative-hypnotic agent for the treatment of insomnia. Clin Ther 22:1254–1267. doi: 10.1016/S0149-2918(00)83024-6 CrossRefPubMedGoogle Scholar
  18. 18.
    Dusza JP, Tomcufcik AS, Albright JD (1985) [7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines. US Patent 4626538Google Scholar
  19. 19.
    Baraldi PG, Fruttarolo F, Tabrizi MA, Romagnoli R, Preti D, Ongini E, El-Kashef H, Carrion MD, Boreab PA (2007) Synthesis of a new series of pyrazolo[1,5-a]pyrimidines structurally related to zaleplon. J Heterocycl Chem 44:355–361. doi: 10.1002/jhet.5570440212 CrossRefGoogle Scholar
  20. 20.
    Frey RR, Curtin ML, Albert DH, Glaser KB, Pease LJ, Soni NB, Bouska JJ, Reuter D, Stewart K, Marcotte P, Bukofzer G, Li J, Davidsen SK, Michaelides MR (2008) 7-Aminopyrazolo[1,5-a]pyrimidines as potent multitargeted receptor tyrosine kinase inhibitors. J Med Chem 51:3777–3787. doi: 10.1021/jm701397k CrossRefPubMedGoogle Scholar
  21. 21.
    Kim I, Song JH, Park CM, Jeong JW, Kim HR, Ha JR, No Z, Hyun YL, Cho YS, Kang NS, Jeon DJ (2010) Design, synthesis, and evaluation of 2-aryl-7-(3\(^\prime \),4\(^\prime \)-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidines as novel PDE-4 inhibitors. Bioorg Med Chem Lett 20:922–926. doi: 10.1016/j.bmcl.2009.12.070 CrossRefPubMedGoogle Scholar
  22. 22.
    Dwyer MP, Paruch K, Labroli M, Alvarez C, Keertikar KM, Poker C, Rossman R, Fischmann TO, Duca JS, Madison V, Parry D, Davis N, Seghezzi W, Wiswell D, Guzi TJ (2011) Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach–Part 1. Bioorg Med Chem Lett 21:467–470. doi: 10.1016/j.bmcl.2010.10.113 CrossRefPubMedGoogle Scholar
  23. 23.
    Sadek KU, Mekheimer RA, Mohamed TM, Moustafa MS, Elnagdi MH (2012) Regioselectivity in the multicomponent reaction of 5-aminopyrazoles, cyclic 1,3-diketones and dimethylformamide dimethylacetal under controlled microwave heating. Beilstein J Org Chem 8:18–24. doi: 10.3762/bjoc.8.3 PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Wu Y-C, Li H-J, Liu L, Wang D, Yang H-Z, Chen Y-J (2008) Efficient construction of pyrazolo[1,5-\(a\)]pyrimidine scaffold and its exploration as a new heterocyclic fluorescent platform. J Fluoresc 18:357–363. doi: 10.1007/s10895-007-0275-0 CrossRefPubMedGoogle Scholar
  25. 25.
    Hussein AM (2010) Synthesis of some new purine-related compounds: regioselective one-pot synthesis of new tetrazolo[1,5-a]pyrimidine, pyrazolo[1,5-a]pyrimidine and pyrimido[1,6-a]pyrimidine derivatives. J Sau Chem Soc 14:61–68. doi: 10.1016/j.jscs.2009.12.010 CrossRefGoogle Scholar
  26. 26.
    Elmaati TMA, El-Taweel FMA (2003) Routes to pyrazolo[3,4-e][1,4]thiazepine, pyrazolo[1,5-a]pyrimidine and pyrazole derivatives. J Chin Chem Soc 50:413–418. doi: 10.1002/jccs.200300063 CrossRefGoogle Scholar
  27. 27.
    Alcade E, De Mendoza J, Garcia-Marquina JM, Almera C, Elguero J (1974) Elude de la réaction du \(\upbeta \)-aminocrotonitrile et du \(\upalpha \)-formyl phénylacétonitrile avec l’hydrazine: Synthèse d’amino-7 pyrazolo[1,5-a]pyrimidines. J Heterocycl Chem 11:423–429. doi: 10.1002/jhet.5570110330 CrossRefGoogle Scholar
  28. 28.
    Khalil KD, Al-Matar HM, Al-Dorri DM, Elnagdi MH (2009) Studies with enaminones and enaminonitriles: synthesis of 3-aroyl and 3-heteroaroyl-pyrazolo-[1,5-a]pyrimidines. Tetrahedron 65:9421–9427. doi: 10.1016/j.tet.2009.08.084 CrossRefGoogle Scholar
  29. 29.
    Stepanuik OO, Matviienko VO, Kondratov S, Vitruk IV, Tolmachev AO (2013) Synthesis of new pyrazolo[1,5-\(a\)]pyrimidines by reaction of \(\upbeta \),\(\upgamma \)-unsaturated \(\upgamma \)-alkoxy-\(\upalpha \)-keto esters with n-unsubstituted 5-aminopyrazoles. Synthesis 45:925–930. doi: 10.1055/s-0032-1318329
  30. 30.
    Elfahham HA, Abdel-Galil FM, Ibraheim YR, Elnagdi MH (1983) Activated nitriles in heterocyclic synthesis. A novel synthesis of pyrazolo[1,5-a]pyrimidines and pyrano[2,3-c]pyrazoles. J Heterocycl Chem 20:667–670. doi: 10.1002/jhet.5570200331 CrossRefGoogle Scholar
  31. 31.
    Aggarwal R, Rani C, Kumar R, Garg G, Sharma J (2014) Synthesis of new bi(pyrazolo[1,5-a]pyrimidinyl)-7-one derivatives from dehydroacetic acid and its analogues as antibacterial agents. Arkivoc ii:120–134. doi: 10.3998/ark.5550190.p008.089 Google Scholar
  32. 32.
    Mokhtara M, Saleha TS, Basahel SN (2012) Mg–Al hydrotalcites as efficient catalysts for aza-Michael addition reaction: a green protocol. J Mol Catal A 353–354:122–131. doi: 10.1016/j.molcata.2011.11.015 CrossRefGoogle Scholar
  33. 33.
    Shaaban MR, Saleh TS, Farag AM (2007) Synthesis and antimicrobial evaluation of novel pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine and pyrimido[1,2-a]benzimidazole derivatives. Heterocycles 71:1765–1777. doi: 10.3987/COM-07-11060 CrossRefGoogle Scholar
  34. 34.
    Behbehani H, Ibrahim HM, Makhseed S (2010) Synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides as potential non benzodiazepine hypnotics. Arkivoc ii:267–282. doi: 10.3998/ark.5550190.0011.222 Google Scholar
  35. 35.
    Salaheldin AM, Alphy MK (2008) Studies with enaminonitriles: synthesis and chemical reactivity of 2-phenyl-3-piperidin-1-yl acrylonitrile under microwave heating. J Heterocycl Chem 45:307–310. doi: 10.1002/jhet.5570450202 CrossRefGoogle Scholar
  36. 36.
    Ishak CY, Metwally NH, Wahbi HI (2013) In-vitro antimicrobial and antifungal activity of pyrimidine and pyrazolo-[1, 5-a] pyrimidine. Int J Pharm Phytopharmacol Res 2:407–411 issn: 2249–6084Google Scholar
  37. 37.
    Zhang X, Song Y, Gao L, Guoa X, Fan X (2014) Highly facile and regio-selective synthesis of pyrazolo[1,5-a]pyrimidines via reactions of 1,2-allenic ketones with aminopyrazoles. Org Biomol Chem 12:2099–2107. doi: 10.1039/C3OB42445F CrossRefPubMedGoogle Scholar
  38. 38.
    Ming L, Shuwen W, Lirong W, Huazheng Y, Xiuli Z (2005) A convenient, rapid, and highly selective method for synthesis of new pyrazolo[1,5-a]pyrimidines via the reaction of enaminones and 5-amino-1H-pyrazoles under microwave irradiation. J Heterocycl Chem 42:925–930. doi: 10.1002/jhet.5570420526
  39. 39.
    Sanz D, Claramunt RM, Saini A, Kumar V, Aggarwal R, Singh SP, Alkorta I, Elguero J (2007) Pyrazolo[1,5-a]pyrimidines. A combined multinuclear magnetic resonance (1H, 13C, 15N, 19F) and DFT approach to their structural assignment. Mag Reson Chem 45:513–517. doi: 10.1002/mrc.1992
  40. 40.
    Kiessling A, Wiesinger R, Sperl B, Berg T (2007) Selective inhibition of c-myc/max dimerization by a pyrazolo[1,5-a]pyrimidine. Chem Med Chem 2:627–630. doi: 10.1002/cmdc.200600294 CrossRefPubMedGoogle Scholar
  41. 41.
    Gregg BT, Tymoshenko DO, Razzano DA, Johnson MR (2007) Pyrazolo[1,5-a]pyrimidines. Identification of the privileged structure and combinatorial synthesis of 3-(hetero)arylpyrazolo [1,5-a]pyrimidine-6-carboxamides. J Comb Chem 9:507–512. doi: 10.1021/cc0700039 CrossRefPubMedGoogle Scholar
  42. 42.
    Devi AS, Dutta MC, Nongkhlaw R, Vishwakarma JN (2010) KHSO\(_{4}\) assisted Michael addition-elimination reactions of formylated acetophenones in warer: A facile general green synthetic route to (alkyl/aralkyl/aryl)amino-1-arylprop-2-en-1-ones. J Indian Chem Soc 87:739–742Google Scholar
  43. 43.
    Devi AS, Helissey P, Vishwakarma JN (2011) Synthesis of novel bis-enaminones by KHSO\(_{4 }\)-assisted Michael addition-elimination reaction of 3-(dimethylamino)-1-phenylprop-2-en-1-ones with diamines in water. Green Sustain Chem 1:30–34. doi: 10.4236/gsc.2011.12006 CrossRefGoogle Scholar
  44. 44.
    Radl S, Blahovcova M, Tkadlecová M, Havlicek J (2010) Synthetic studies connected with the preparation of n-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)phenyl]-n-ethylacetamide, a zaleplon regioisomer. Heterocycles 80:1359–1379. doi: 10.3987/COM-09-S(S)129 CrossRefGoogle Scholar
  45. 45.
    Anwar HF, Fleita DH, Kolshorn H, Meier H, Elnagdi MH (2006) 2H-Pyrazol-3-ylamines as precursors for the synthesis of polyfunctionally substituted pyrazolo[1,5-a]pyrimidines. Arkivoc xv:133–141. doi: 10.3998/ark.5550190.0007.f16 Google Scholar
  46. 46.
    Martins MAP, Scapin E, Frizzo CP, Rosa FA, Bonacorso HG, Zanatta N (2009) 2-Methyl-7-substituted pyrazolo[1,5-\(a\)]pyrimidines: highly regioselective synthesis and bromination. J Braz Chem Soc 20:205–213. doi: 10.1590/S0103-50532009000200003 CrossRefGoogle Scholar
  47. 47.
    Chanda K, Dutta MC, Karim E, Vishwakarma JN (2004) An efficient microwave assisted solvent-free synthesis of polarized enamines. J Indian Chem Soc 81:791–793Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Asem Satyapati Devi
    • 1
  • Shunan Kaping
    • 1
  • Jai Narain Vishwakarma
    • 1
  1. 1.Organic Research Lab., Department of Chemical ScienceAssam Don Bosco UniversityGuwahatiIndia

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