Structural Chemistry

, Volume 23, Issue 5, pp 1441–1448

Does dehydrocyclization of 4-benzoylthiosemicarbazides in acetic acid lead to s-triazoles or thiadiazoles?

  • Agata Siwek
  • Paweł Stączek
  • Urszula Kosikowska
  • Anna Malm
  • Piotr Paneth
  • Stefan Jankowski
Original Research


Ever since the recognition of strong pharmaceutical activities of triazoles and thiadiazoles, these scaffolds have been the subject of vigorous studies. One of the best strategies for synthesis of these azoles is dehydrocyclization of 1,4-disubstituted thiosemicarbazides, which leads to s-triazoles in alkaline media, whereas in strong acidic media 1,3,4-thiadiazoles are formed. However, the literature is riddled with contradictory communications regarding the nature of the products of such reactions under mild acidic conditions. As these compounds are not amenable to X-ray analysis, we have resorted to NMR and theoretical modelling to resolve this discrepancy. In this article, we present arguments indicating that dehydrocyclization of 4-benzoylthiosemicarbazides in glacial acetic acid leads to thiadiazole derivatives. These structural findings are augmented by studies of bioactivity of a few members of the studied class of compounds.


Thiadiazole Triazole NMR DFT 


  1. 1.
    Günay NS, Çapan G, Ulusoy N, Ergenç N, Ötük G, Kaya D (1999) 5-Nitroimidazole derivatives as possible antibacterial and antifungal agents. Farmaco 54:826–831CrossRefGoogle Scholar
  2. 2.
    Ikizler AA, Johansson CB, Bekircan O, Çelik C (1999) Synthesis and antibacterial activities of some 1,2,4-triazole derivatives. Acta Polon Pharm Drug Res 56:283–288Google Scholar
  3. 3.
    Demirayak Ş, Benkli K, Güven K (2000) Synthesis and antimicrobial activities of some 3-arylamino-5-[2-(substituted 1-imidazolyl)ethyl]-1,2,4-triazole derivatives. Eur J Med Chem 35:1037–1040CrossRefGoogle Scholar
  4. 4.
    Hui X-P, Zhang L-M, Zhang Z-Y, Wang Q, Wang F (2000) Synthesis and antibacterial activity of s-triazoles, s-triazolo[3,4-b]1,3,4-thiadiazoles and s-triazolo[3,4-b]-1,3,4–thiadiazoles of 5-methylisoxazole. J Chin Chem Soc 47:535–539Google Scholar
  5. 5.
    Gulerman NN, Dogan HN, Rollas S, Johansson C, Celik C (2001) Synthesis and structure elucidation of some new thioether derivatives of 1,2,4-triazoline-5-thiones and their antimicrobial activities. Farmaco 56:953–958CrossRefGoogle Scholar
  6. 6.
    Holla BS, Sarojini BK, Rao BS, Akberali PM, Kumari NS, Shetty V (2001) Synthesis of some halogen-containing 1,2,4-triazolo-1,3,4-thiadiazines and their antibacterial and anticancer screening studies—part I. Farmaco 56:565–570CrossRefGoogle Scholar
  7. 7.
    Kosikowska U, Siwek A, Dobosz M (2004) Antimicrobial activities of 4-substituted-3-(piperidin-4-yl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones. Acta Polon Pharm Drug Res 51:460–463Google Scholar
  8. 8.
    Tozkoparan B, Kupeli E, Yesilada E, Isik S, Ozalp M, Ertan M (2005) Synthesis and evaluation of analgesic/anti-inflammatory and antimicrobial activities of 3-substituted-1,2,4-triazole-5-thiones. Arznei-Forschung 55:533–540Google Scholar
  9. 9.
    Al-Deeb OA, Al-Omar MA, El-Brollosy NR, Habib EE, Ibrahim TM, El-Emam AA (2006) Synthesis, antimicrobial, and anti-inflammatory activities of novel 2-[3-(1-adamantyl)-4-substituted-5-thioxo-1,2,4-triazolin-1-yl]acetic acids, 2-[3-(1-adamantyl)-4-substituted-5-thioxo-1,2,4-triazolin-1-yl]propionic acids and related derivatives. Arznei-Forschung 56:40–47Google Scholar
  10. 10.
    Holla BS, Rao BS, Sarojini BK, Akberali PM, Kumari NS (2006) Synthesis and studies on some new fluorine containing triazolothiadiazines as possible antibacterial, antifungal and anticancer agents. Eur J Med Chem 41:657–663CrossRefGoogle Scholar
  11. 11.
    Dogan HN, Duran A, Rollas S, Sener G, Uysal MK, Gülen D (2002) Synthesis of new 2,5-disubstituted-1,3,4-thiadiazoles and preliminary evaluation of anticonvulsant and antimicrobial activities. Bioorg Med Chem 10:2893–2898CrossRefGoogle Scholar
  12. 12.
    Mamolo MG, Vio L, Banfi E (1996) Synthesis and antimicrobial activity of some 2,5-disubstituted 1,3,4-thiadiazole derivatives. Farmaco 51:71–74Google Scholar
  13. 13.
    Rollas S, Karakus S, Durgun BB, Kiraz M, Erdeniz H (1996) Synthesis and antimicrobial activity of some 1,4-disubstituted thiosemicarbazide and 2,5-disubstituted-1,3,4-thiadiazole derivatives. Farmaco 51:811–814Google Scholar
  14. 14.
    Dogan HN, Rollas S, Erdeniz H (1998) Synthesis, structure elucidation and antimicrobial activity of some 3-hydroxy-2-naphthoic acid hydrazide derivatives. Farmaco 53:462–467CrossRefGoogle Scholar
  15. 15.
    Zamani K, Faghihi K, Tofighi T, Shariatzadeh MR (2004) Synthesis and antimicrobial activity of some pyridyl and naphthyl substituted 1,2,4-triazole and 1,3,4-thiadiazole derivatives. Turk J Chem 28:95–100Google Scholar
  16. 16.
    Wood TC, Johnson KL, Naylor S, Weinshilboum RM (2002) Cefazolin administration and 2-methyl-1,3,4-thiadiazole-5-thiol in human tissue: possible relationship to hypoprothrombinemia. Drug Metab Dispos 30:1123–1128CrossRefGoogle Scholar
  17. 17.
    Zamani K, Faghihi K, Mehranjani MS (2003) Synthesis of some new 2,5-disubstituted 1,3,4-thiadiazoles containing isomeric pyridyl as potent antimicrobial agents. Pol J Pharmacol 55:1111–1117Google Scholar
  18. 18.
    Carvalho SA, Da Silva EF, Santa-Rita RM, De Castro SL, Fraga CAM (2004) Synthesis and antitrypanosomal profile of new functionalized 1,3,4-thiadiazole-2-arylhydrazone derivatives, designed as non-mutagenic megazol analogues. Bioorg Med Chem Lett 14:5967–5970CrossRefGoogle Scholar
  19. 19.
    Gürsoy A, Ates Ö, Karali N, Cesur N, Kiraz M (1996) Synthesis and antifungal activity of new carbamodithioic acid esters derived from 3-acetylcoumarin. Eur J Med Chem 31:643–646CrossRefGoogle Scholar
  20. 20.
    Chu Ch-H, Hui X-P, Zhang Y, Zhang Z-Y, Li Z-Ch, Liao R-A (2001) Synthesis and antifungal activities of ω-[4-aryl-5-(1-phenyl-5-methyl-1,2,3-triazol-4-yl)-1,2,4-triazol-3–thio]-ω-(1H-1,2,4-triazol-1-yl)acetophenones. J Chin Chem Soc 48:121–125Google Scholar
  21. 21.
    Wujec M, Pitucha M, Dobosz M, Kosikowska U, Malm A (2004) Synthesis and potential antimycotic activity of 4-substituted-3-(thiophene-2-yl-methyl)-Δ2-1,2,4-triazoline-5–thiones. Acta Pharm 54:251–260Google Scholar
  22. 22.
    Modzelewska-Banachiewicz B, Kamińska T (2001) Antiviral activity of the products of cyclization of dimethyl 2-[(1-arylamino-1-arylmethylidene)hydrazo]succinate. Eur J Med Chem 36:93–99CrossRefGoogle Scholar
  23. 23.
    De La Rosa M, Kim HW, Gunic E, Jenket C, Boyle U, Koh YH, Korboukh I, Allan M, Zhang W, Chen H, Xu W, Nilar S, Yao N, Hamatake R, Lang SA, Hong Z, Zhang Z, Girardet JL (2006) Tri-substituted triazoles as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase. Bioorg Med Chem Lett 16:4444–4449CrossRefGoogle Scholar
  24. 24.
    Todoulou OG, Papadaki-Valiraki A, Filippatos EC, Ikeda S, De Clercq E (1994) Synthesis and anti-myxovirus activity of some novel N,N′-disubstituted thioureas. J Med Chem 29:127–131CrossRefGoogle Scholar
  25. 25.
    Duran A, Dogan HN, Rollas S (2002) Synthesis and preliminary anticancer activity of new 1,4-dihydro-3-(3-hydroxy-2-naphthyl)-4-substituted-5H-1,2,4-triazoline-5–thiones. Farmaco 57:559–564CrossRefGoogle Scholar
  26. 26.
    Holla BS, Poojary KN, Rao BS, Shivanada MK (2002) New bis-aminomercaptotriazoles and bis-triazolothiadiazoles as possible anticancer agents. Eur J Med Chem 37:511–517CrossRefGoogle Scholar
  27. 27.
    Pomarnacka E, Gdaniec M (2003) Synthesis and anticancer activity of 2-amino-8-chloro-5,5-dioxo[1,2,4]triazolo[2,3-b][1,4,2]benzodithiazine derivatives. Bioorg Med Chem 11:1259–1267CrossRefGoogle Scholar
  28. 28.
    Lin R, Connolly PJ, Huang S, Wetter SK, Lu Y, Murray WV, Emanuel SL, Gruninger RH, Fuentes-Pesquera AR, Rugg CA, Middleton SA, Jolliffe LK (2005) 1–Acyl-1H-[1,2,4]triazole-3,5-diamine analogues as novel and potent anticancer cyclin-dependent kinase inhibitors: synthesis and evaluation of biological activities. J Med Chem 48:4208–4211CrossRefGoogle Scholar
  29. 29.
    Lu K, Loo TL (1980) The pharmacologic fate of the antitumor agent 2-amino-1,3,4-thiadiazole in the dog. Cancer Chemoth Pharm 4:275–279CrossRefGoogle Scholar
  30. 30.
    Stewart JA, Ackerly CC, Myers CF, Newman RA, Krakoff IH (1986) Clinical and clinical pharmacologic studies of 2-amino-1,3,4-thiadiazole (A-TDA:NSC 4728). Cancer Chemoth Pharm 16:287–291CrossRefGoogle Scholar
  31. 31.
    Invidiata FP, Grimaudo S, Giammanco P, Giammanco L (1991) Synthesis and pharmacological properties of 6-substituted 3-(pyridine-4-yl)-1,2,4-triazole[3,4-b]-[1,3,4]thiadiazoles. Farmaco 46:1489–1495Google Scholar
  32. 32.
    Modzelewska-Banachiewicz B, Banachiewicz J, Chodkowska A, Jagiełło-Wójtowicz E, Mazur L (2004) Synthesis and biological activity of new derivatives of 3-(3,4-diaryl-1,2,4-triazole-5-yl)propenoic acid. Eur J Med Chem 39:873–877CrossRefGoogle Scholar
  33. 33.
    Sun X-Y, Jin Y-Z, Li F-N, Li G, Chai K-Y, Quan Z-S (2006) Synthesis of 8-alkoxy-4,5–dihydro-[1,2,4]triazole[4,3-a]quinoline-1-ones and evaluation of their anticonvulsant properties. Arch Pharm Res 29:1080–1085CrossRefGoogle Scholar
  34. 34.
    Misra U, Hitkari A, Saxena AK, Gurtu S, Shanker K (1996) Biologically active indolylmethyl-1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 4H-1,3,4-triazoles and 1,2,4-triazines. Eur J Med Chem 31:629–634CrossRefGoogle Scholar
  35. 35.
    Varvaresou A, Siatra-Papastaikoudi T, Tsotinis A, Tsantili-Kakoulidou A, Vamvakides A (1998) Synthesis, lipophilicity and biological evaluation of indole-containing derivatives of 1,3,4-thiadiazole and 1,2,4-triazole. Farmaco 53:320–326CrossRefGoogle Scholar
  36. 36.
    Clerici F, Pocar D, Guido M, Loche A, Perlini V, Brufani M (2001) Synthesis of 2-amino-5-sulfanyl-1,3,4-thiadiazole derivatives and evaluation of their antidepressant and anxiolytic activity. J Med Chem 44:931–936CrossRefGoogle Scholar
  37. 37.
    Savini L, Chiasserini L, Pellerano C, Filippelli W, Falcone G (2001) Synthesis and pharmacological activity of 1,2,4-triazolo[4,3-a]quinolines. Farmaco 56:939–945CrossRefGoogle Scholar
  38. 38.
    Tozkoparam B, Yesilada E, Ertan M (2007) Preparation of 5-aryl-3-alkylthio-1,2,4-triazoles and corresponding sulfones with anti-inflammatory-analgesic activity. Bioorg Med Chem 15:1808–1814CrossRefGoogle Scholar
  39. 39.
    Schenone S, Brullo C, Bruno O, Bondavalli F, Ranise A, Filippelli W, Rinaldi B, Capuano A, Falcone G (2006) New 1,3,4-thiadiazole derivatives endowed with analgesic and anti-inflammatory activities. Bioorg Med Chem 14:1698–1705CrossRefGoogle Scholar
  40. 40.
    Varandas LS, Fraga CAM, Miranda ALP, Barreiro EJ (2005) Design, synthesis and pharmacological evaluation of new nonsteroidal anti-inflammatory 1,3,4-thiadiazole derivatives. Lett Drug Des Discov 2:62–67CrossRefGoogle Scholar
  41. 41.
    Önkol T, Çakir B, Şahin MF, Yildirim E, Erol K (2004) Synthesis and antinociceptive activity of 2-[(2-oxobenzothiazolin-3-yl)methyl]-5-aminoalkyl/aryl-1,3,4-thiadiazole. Turk J Chem 28:461–468Google Scholar
  42. 42.
    Kulkarni MV, Patil VD, Biradar VN, Nanjappa S (1981) Synthesis and biological properties of some 3-heterocyclic substituted coumarins. Arch Pharm Res 34:435–439Google Scholar
  43. 43.
    Palaska E, Şahin G, Kelicen P, Durlu NT, Altinok G (2002) Synthesis and anti-inflammatory activity of 1-acylthiosemicarbazides, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles and 1,2,4-triazole-3-thiones. Farmaco 57:101–107CrossRefGoogle Scholar
  44. 44.
    Labanauskas L, Kalcas V, Udrenaite E, Gaidelis P, Brukštus A, Daukšas V (2001) Synthesis of 3-(3,4-domethoxyphenyl)-1H-1,2,4-triazole-5-thiol and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole derivatives exhibiting anti-inflammatory activity. Pharmazie 56:617–619Google Scholar
  45. 45.
    Labanauskas L, Udrenaite E, Gaidelis P, Brukštus A (2004) Synthesis of 5-(2-, 3- and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity. Farmaco 59:255–259CrossRefGoogle Scholar
  46. 46.
    Awhey SN, Gupta A (1991) Synthesis of some 2-(5-substituted 1,3,4-oxadiazol-2-yl), 2-(5-substituted-1,3,4-thiadiazol-2-yl)- and 2-(3-mercapto-4-substituted-4H-1,2,4-triazol-5-yl)-benzimidazoles as potential anti-inflammatory agents. Indian J Chem B 20B:407–412Google Scholar
  47. 47.
    Fahmy AF, Ali N, Abdelhamid HS, Hemdan MM (2010) The utility of p-N-succinimidobenzoyl isothiocyanate in synthesis of benzoxazole, quinazoline, pyrimidine, 1,2,4-triazoline, 1,3-thiazolidine, and thiourea derivatives. Phosphorus Sulfur Silicon 185:1536–1542CrossRefGoogle Scholar
  48. 48.
    Shams HZ, Mohareb RM, Helal MH, Mahmoud AE (2007) Synthesis, structure elucidation, and biological evaluation of some fused and/or pendant thiophene, pyrazole, imidazole, thiazole, triazole, triazine, and coumarin systems based on cyanoacetic 2-[(benzoylamino)thioxomethyl]hydrazide. Phosphorus Sulfur Silicon 182:237–263CrossRefGoogle Scholar
  49. 49.
    Zhang W-Q, Li Y-P, Liu Ch-J, Wang J-D (2008) Synthesis of 2-[(aroyl)amino]-5-[[2-(trifluoromethyl)-1-benzimidazolyl]methyl]-1,3,4-thiadiazole under microwave irradiation. Youji Huaxue 28:2166–2169Google Scholar
  50. 50.
    Wei T-B, Liu H, Hu J-H, Li M-L, Xu W-X, Yang L-Z, Zhang Y-M (2006) Microwave-promoted efficient synthesis of 2,5-disubstituted 1,3,4-thiadiazole. Indian J Chem B 45B:2754–2756Google Scholar
  51. 51.
    Wei T-B, Li M-L, Liu H, Yang L-Z, Xu W-X, Zhang Y-M (2005) Synthesis and biological activity of 2,5-disubstituted 1,3,4-thiadiazoles. Hecheng Huaxue 13:219–222Google Scholar
  52. 52.
    Wang X, Li Z, Da Y, Chen J, Wang X (2001) Synthesis of 2-(4-bromobenzoylamino)-5-aryloxymethyl-1,3,4-thiadiazoles. Indian J Chem B 40B:422–425Google Scholar
  53. 53.
    Li Z, Wang X, Da Y (2000) Microwave assisted synthesis of 2-(4-methoxybenzoylamido)-5-aryloxymethyl-1,3,4-thiadiazoles. Synth Commun 30:3971–3983CrossRefGoogle Scholar
  54. 54.
    Erian AW, Manhi FM, Zayed SE-G, Ali FA, Elnagdi MH (1998) Hydrazones in heterocyclic synthesis; synthesis of 1,3,4-thiadiazole derivatives. Phosphorus Sulfur Silicon 133:127–139CrossRefGoogle Scholar
  55. 55.
    Siwek A, Stączek P, Wujec M, Stefańska J, Kosikowska U, Malm A, Jankowski S, Paneth P (2011) Biological and docking studies of topoisomerase IV inhibition by thiosemicarbazides. J Mol Model 17:2297–2303CrossRefGoogle Scholar
  56. 56.
    Clinical and Laboratory Standards Institute (2006) Performance standards for antimicrobial disc susceptibility tests; approved standard M2-A9. Clinical and Laboratory Standards Institute, WayneGoogle Scholar
  57. 57.
    Clinical and Laboratory Standards Institute (2006) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard M7-A7. Clinical and Laboratory Standards Institute, WayneGoogle Scholar
  58. 58.
    Hariharan PC, Pople JA (1973) Influence of polarization functions on MO hydrogenation energies. Theor Chim Acta 28:213–222CrossRefGoogle Scholar
  59. 59.
    Francl MM, Pietro WJ, Hehre WJ, Binkley JS, Gordon MS, DeFrees DJ, Pople JA (1982) Self‐consistent molecular orbital methods. XXIII. A polarization‐type basis set for second‐row elements. J Chem Phys 77:3654–3665CrossRefGoogle Scholar
  60. 60.
    Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian, Inc., Wallingford CT (2009)Google Scholar
  61. 61.
    Becke DA (1996) Density-functional thermochemistry. IV. A new dynamical correlation functional and implications for exact- exchange mixing. J Chem Phys 104:1040–1046CrossRefGoogle Scholar
  62. 62.
    Becke AD (1988) Density-functional exchange-energy approximation with correct asymptotic behavior. Phys Rev A 38:3098–3100CrossRefGoogle Scholar
  63. 63.
    Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652CrossRefGoogle Scholar
  64. 64.
    Perdew JP, Wang Y (1992) Accurate and simple analytic representation of the electron gas correlation energy. Phys Rev B 46:6671–6687CrossRefGoogle Scholar
  65. 65.
    Lynch BJ, Truhlar DG (2003) Robust and affordable multicoefficient methods for thermochemistry and thermochemical kinetics: the MCCM/3 suite and SAC/3. J Phys Chem A 107:3898–3906CrossRefGoogle Scholar
  66. 66.
    Zhao Y, Pu J, Lynch BJ, Truhlar DG (2004) Tests of second-generation and third-generation density functionals for thermochemical kinetics. Phys Chem Chem Phys 6:673–676CrossRefGoogle Scholar
  67. 67.
    Siwek A, Paneth P (2007) Computational studies of the cyclization of thiosemicarbazides. J Phys Org Chem 20:463–468CrossRefGoogle Scholar
  68. 68.
    Siwek A, Wujec M, Dobosz M, Jagiełło-Wójtowicz E, Kleinrok A, Chodkowska A, Paneth P (2008) Chemical and pharmaceutical properties of 3-(thiophen-2-yl)-4-substituted-∆2-1,2,4-triazoline-5-thiones. Phosphorus Sulfur Silicon 183:2669–2677CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Agata Siwek
    • 1
  • Paweł Stączek
    • 2
  • Urszula Kosikowska
    • 3
  • Anna Malm
    • 3
  • Piotr Paneth
    • 4
  • Stefan Jankowski
    • 5
  1. 1.Department of Organic Chemistry, Faculty of PharmacyMedical UniversityLublinPoland
  2. 2.Department of Genetics of MicroorganismsUniversity of LodzLodzPoland
  3. 3.Department of Pharmaceutical Microbiology, Faculty of PharmacyMedical UniversityLublinPoland
  4. 4.Institute of Applied Radiation ChemistryTechnical University of LodzLodzPoland
  5. 5.Institute of Organic ChemistryTechnical University of LodzLodzPoland

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