Thermal electron-transfer-induced oxidation of 2-pyrazolines


Various 3,5-diaryl-1-phenyl-2-pyrazolines were synthesized, and their thermal oxidation to their corresponding 2-pyrazoles was investigated using tetrabutylammonium peroxydisulfate in acetonitrile solution. Compared to the reported oxidative methods, this oxidizing agent provides a clean and non-expensive oxidative reaction in a short reaction time. Based on the proposed reaction mechanism, the extent of co-planarity of the C3-aryl ring toward C3=N2 double bond of the heterocyclic ring affects the electron-donating ability of the heterocyclic ring and decreases the time of oxidative reaction. The experimental results are supported by cyclic voltammetric measurements.

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  1. 1.

    Ali MA, Shaharyar M, Siddiqui AA (2007) Synthesis, structural activity relationship and anti-tubercular activity of novel pyrazoline derivatives. Eur J Med Chem 42:268–275.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Ozdemir Z, Kandilci HB, Gumusel B, Calıs U, Bilgin AA (2007) Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives. Eur J Med Chem 42:373–379.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Jainey PJ, Bhat IK (2012) Antitumor, analgesic, and anti-inflammatory activities of synthesized pyrazolines. Pharm Chem 4:82–87.

    CAS  Article  Google Scholar 

  4. 4.

    Ramesh B, Sumana T (2010) Synthesis and anti-inflammatory activity of pyrazolines. Chem Eur J 7:514–516.

    CAS  Article  Google Scholar 

  5. 5.

    Karabacak M, Altıntop MD, Çiftçi Hİ, Koga R, Otsuka M, Fujita M, Özdemir A (2015) Synthesis and evaluation of new pyrazoline derivatives as potential anticancer agents. Molecules 20:19066–19084.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Kumar V, Sareen V, Khatri V, Sareen S (2016) Recent applications of pyrazole and its substituted analogs. Int J Appl Res 2:461–469. ISSN Online: 2394-5869

  7. 7.

    Dai H, Li Y-Q, Du D, Qin X, Zhang X, Yu H-B, Fang J-X (2008) Synthesis and biological activities of novel pyrazole oxime derivatives containing a 2chloro-5-thiazolyl moiety. J Agric Food Chem 56:10805–10810.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Keter FK, Darkwa J (2012) Perspective: the potential of pyrazole-based compounds in medicine. Biometals 25:9–21.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Ouyang G, Cai X-J, Chen Z, Song BA, Bhadury PS, Yang S, Jin LH, Xue W, Hu D-Y, Zeng S (2008) Synthesis and antiviral activities of pyrazole derivatives containing an oxime moiety. J Agric Food Chem 56:10160–10167.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Abrigach F, Touzani R (2016) Pyrazole derivatives with NCN junction and their biological activity: a review. Med Chem 6:292–298.

    Article  Google Scholar 

  11. 11.

    Evai LA, Patonay T, Silva AMS, Pinto DCGA, Cavaleiro JAS (2002) Synthesis of 3-aryl-5-styryl-2-pyrazolines by the reaction of (E, E) cinnamylideneacetophenones with hydrazines and their oxidation into pyrazoles. J Heterocycl Chem 39:751–758.

    Article  Google Scholar 

  12. 12.

    Levai A, Silva Artur MS, PintoDiana CGA, Cavaleiro Jose AS, Alkorta I, Elguero J, Jekö J (2004) Synthesis of pyrazolyl-2-pyrazolines by treatment of 3-(3aryl-3-oxopropenyl)chromen-4-ones with hydrazine and their oxidation to bis(pyrazoles). Eur J Org Chem 2004:4672–4679.

    CAS  Article  Google Scholar 

  13. 13.

    Sabitha G, Reddy GSKK, Reddy CS, Fatima N, Yadav JS (2003) Zr(NO3)4: a versatile oxidizing agent for aromatization of Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines. Synthesis 8:1267–1271.

    Article  Google Scholar 

  14. 14.

    Azarifar D, Zolfigol MA, Maleki B (2004) Silica-supported 1,3-dibromo-5,5dimethylhydantoin (DBH) as a useful reagent for microwave-assisted aromatization of 1,3,5-trisubstituted pyrazolines under solvent-free conditions. Synthesis 11:1744–1746.

    Article  Google Scholar 

  15. 15.

    Han B, Liu Z, Liu Q, Yang L, Liu Z-L, Yu W (2006) An efficient aerobic oxidative aromatization of Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines. Tetrahedron 62:2492–2496.

    CAS  Article  Google Scholar 

  16. 16.

    Zolfigol MA, Azarifar D, Maleki B (2004) Trichloroisocyanuric acid as a novel oxidizing agent for the oxidation of 1,3,5-trisubstituted pyrazolines under both heterogeneous and solvent free conditions. Tetrahedron Lett 45:2181–2183.

    CAS  Article  Google Scholar 

  17. 17.

    Chai L, Zhao Y, Sheng Q, Liu Z-Q (2006) Aromatization of Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines with HIO3 and I2O5 in water. Tetrahedron Lett 47:9283–9285.

    CAS  Article  Google Scholar 

  18. 18.

    Nakamichi N, Kawashita Y, Hayashi M (2002) Oxidative aromatization of 1,3,5-trisubstituted pyrazolines and Hantzsch 1,4-dihydropyridines by Pd/C in acetic acid. Org Lett 4:3955–3957.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Aggarwal R, Kumar V, Singh SP (2007) Synthesis of some new 1-(6-fluorobenzothiazol-2-yl)-3-(4-fluorophenyl)-5-arylpyrazolines and their iodine(III) mediated oxidation to corresponding pyrazoles. Indian J Chem 46B:1332–1336.

    CAS  Article  Google Scholar 

  20. 20.

    Huang YR, Katzenellenbogen JA (2000) Regioselective synthesis of 1,3,5-triaryl-4-alkylpyrazoles: novel ligands for the estrogen receptor. Org Lett 2:2833–2836.

    CAS  Article  Google Scholar 

  21. 21.

    Ananthnag GS, Adhikari A, Balakrishna MS (2014) Iron-catalyzed aerobic oxidative aromatization of 1,3,5-trisubstituted pyrazolines. Catal Commun 43:240–243.

    CAS  Article  Google Scholar 

  22. 22.

    Kumar A, Maurya RA, Sharma S (2009) Oxidative aromatization of 1,4-dihydropyridines and pyrazolines using HbA–H2O2: an efficient biomimetic catalyst system providing metabolites of drug candidates. Bioorg Med Chem Lett 19:4432–4436.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Pérez-Aguilar MC, Valdés C (2015) Synthesis of chiral pyrazoles: a 1,3-dipolar cycloaddition/[1,5]sigmatropic rearrangement with stereoretentive migration of a stereogenic group. Angew Chem Int Ed 54:13729–13733.

    CAS  Article  Google Scholar 

  24. 24.

    Zhang Q, Meng L-G, Wang K, Wang L (2015) nBu3P-catalyzed desulfonylative [3 + 2] cycloadditions of allylic carbonates with arylazosulfones to pyrazole derivatives. Org Lett 17:872–875.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Zheng Y, Zhang X, Yao R, Wen YC, Huang J, Xu X (2016) 1,3-Dipolar cycloaddition of alkyne-tethered N-tosylhydrazones: synthesis of fused polycyclic pyrazoles. J Org Chem 81:11072–11080.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    O’Connor MJ, Sun C, Guan X, Sabbasani VR, Lee D (2016) Sequential 1,4-/1,2-addition of lithium(trimethylsilyl)diazomethane onto cyclic enones to induce C–C fragmentation and N–Li insertion. Angew Chem Int Ed 55:2222–2225.

    CAS  Article  Google Scholar 

  27. 27.

    Chen F-E, Li Y-Y, Xu M, Jia H-Q (2002) Tetrabutylammonium peroxydisulfate in organic synthesis; XIII. A simple and highly efficient one-pot synthesis of nitriles by nickel-catalyzed oxidation of primary alcohols with tetrabutylammonium peroxydisulfate. Synthesis 13:1804–1806.

    Article  Google Scholar 

  28. 28.

    Chen F-E, Peng Z-Z, Fu H, Liu J-D, Shao L-Y (1999) Tetrabutylammonium peroxydisulfate in organic synthesis. Part 8. An efficient and convenient nickel catalyzed oxidation of primary amines to nitriles with tetrabutylammonium peroxydisulfate. J Chem Res (S) 12:726–727.

    Article  Google Scholar 

  29. 29.

    Choi HC, Cho KI, Kim YH (1995) Novel direct tetrahydropyranylation of alcohols with tetrahydropyran and tetra-n-butylammonium peroxydisulfate. Synlett 2:207–208.

    Article  Google Scholar 

  30. 30.

    Jung JC, Kim YH, Lee K (2011) Practical β-masked formylation and acetylation of electron-deficient olefins utilizing tetra(n-butyl)ammonium peroxydisulfate. Tetrahedron Lett 52:4662–4664.

    CAS  Article  Google Scholar 

  31. 31.

    Yang SG, Park MY, Kim YH (2002) Facile and chemo-selective cleavages of allyl ethers utilizing tetrabutylammonium sulfate radical species. Synlett 3:492–494.

    Article  Google Scholar 

  32. 32.

    Chen F-E, Liu J-D, Fu H, Peng Z-Z, Shao L-Y (2000) Tetrabutylammonium peroxydisulfate in organic synthesis; VII. A facile and efficient method for the regeneration of carbonyl compounds from semicarbazones by tetrabutylammonium peroxydisulfate. Synth Commun 30:2295–2299.

    CAS  Article  Google Scholar 

  33. 33.

    Yang SG, Hwang JP, Park MY, Lee K, Kim YH (2007) Highly efficient epoxidation of electron-deficient olefins with tetrabutylammonium peroxydisulfate. Tetrahedron 63:5184–5188.

    CAS  Article  Google Scholar 

  34. 34.

    Whang PJ, Gak Yang S, Hae Kim Y (1997) Novel α-iodination of functionalized ketones with iodine mediated by bis(tetra-n-butylammonium) peroxydisulfate. Chem Commun 15:1355–1356.

    Article  Google Scholar 

  35. 35.

    Park MY, Yang SG, Jadhav V, Kim YH (2004) Practical and regioselective brominations of aromatic compounds using tetrabutylammonium peroxydisulfate. Tedrahedron Lett 45:4887–4890.

    CAS  Article  Google Scholar 

  36. 36.

    Yang SG, Kim YH (1999) A practical iodination of aromatic compounds using tetrabutylammonium peroxydisulfate and iodine. Tetrahedron Lett 40:6051–6054.

    CAS  Article  Google Scholar 

  37. 37.

    Chen F-E, Lu Y-W, He Y-P, Luo Y-F, Yan M-G (2002) Tetrabutylammonium peroxydisulfate in organic synthesis. XII. A convenient and practical procedure for the selective oxidation of thiols to disulfides with tetrabutylammonium peroxydisulfate under solvent-free conditions. Synth Commun 32:3487–3492.

    CAS  Article  Google Scholar 

  38. 38.

    Memarian HR, Soleymani M (2011) Ultrasound assisted dehydrogenation of 2-oxo-1,2,3,4-tetrahydrpyrimidine-5-carboxamides. Ultrason Sonochem 18:745–752.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Park HS, Lee HY, Kim YH (2005) Facile Barton–McCombie deoxygenation of alcohols with tetrabutylammonium peroxydisulfate and formate ion. Org Lett 7:3187–3190.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Memarian HR, Ghahremani S (2017) Electron transfer-induced oxidation of 2,3-dihydroquinazolin-4(1H)-ones. Z Naturforsch 72b:403–408.

    CAS  Article  Google Scholar 

  41. 41.

    Memarian HR, Kalantari M (2017) Steric and electronic substitution effects on the thermal oxidation of 5-carboethoxy-2-oxo-1,2,3,4-tetrahydropyridines. J Iran Chem Soc 14:143–155 and references cited therein.

    Article  Google Scholar 

  42. 42.

    Memarian HR, Sanchooli E (2017) Photo-dehydrogenation of 4,6-diaryl-2-oxo-1,2,3,4-tetrahydropyrimidines. J Iran Chem Soc 14:1335–1346 and references cited therein.

    CAS  Article  Google Scholar 

  43. 43.

    Soltani M, Memarian HR, Sabzyan H (2018) Spectroscopic studies of aryl substituted 1-phenyl-2-pyrazolines: steric and electronic substitution effects. J Mol Struct 1173:903–917.

    CAS  Article  Google Scholar 

  44. 44.

    Zhenglin Y, Shikang W (1993) A study on the photoinduced charge transfer process of triaryl-2-pyrazoline compounds. J Lumin 54:303–308.

    CAS  Article  Google Scholar 

  45. 45.

    Bozkurt E, Gul HI, Mete E (2018) Solvent and substituent effect on the photophysical properties of pyrazoline derivatives: a spectroscopic study. J Photochem Photobiol A Chem 352:35–42.

    CAS  Article  Google Scholar 

  46. 46.

    Fahrni CJ, Yang L, VanDerveer DG (2003) Tuning the photoinduced electron-transfer thermodynamics in 1,3,5-triaryl-2-pyrazoline fluorophore: X-ray structures, photophysical characterization, computational analysis, and in vivo evaluation. J Am Chem Soc 125:3799–3812.

    CAS  Article  PubMed  Google Scholar 

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We are thankful to the Research Council and Office of Graduate Studies of the University of Isfahan for their financial support.

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Correspondence to Hamid Reza Memarian.

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Memarian, H.R., Minakar, R. Thermal electron-transfer-induced oxidation of 2-pyrazolines. Mol Divers 23, 953–964 (2019).

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  • Electron transfer
  • Oxidation
  • Peroxydisulfates
  • 2-Pyrazolines
  • Substituent effects