Solid Phase Synthesis of 3,4,5-Trisubstituted-1,2,4-Triazoles Derivatives from the Resin-Bound Acylhydrazines


An extension of our methodology on solid-phase synthesis of 3,4,5-trisubstituted-1,2,4-triazoles under mild conditions has been developed. Firstly, the resin-bound acylhydrazine is reacted with orthoesters to provide resin-bound 1,3,4-oxadiazoles. Secondly, condensation of 1,3,4-oxadiazoles resin with the corresponding arylamines hydrochloride to form the the resin-bound triazoles. 3,4,5-Trisubstituted-1,2,4-triazoles derivatives were obtained from resin-bound acylhydrazines in several steps providing 78% - 87% overall yields and excellent purity. The advantages of this method include straightforward operation and high yield and purity of the products.

Share and Cite:

R. Xie, X. Liu, C. Mai and Z. Liu, "Solid Phase Synthesis of 3,4,5-Trisubstituted-1,2,4-Triazoles Derivatives from the Resin-Bound Acylhydrazines," International Journal of Organic Chemistry, Vol. 3 No. 1A, 2013, pp. 35-40. doi: 10.4236/ijoc.2013.31A004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. Curtis and N. Jennings, “1,2,4-Triazoles,” In: A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Eds., Comprehensive Heterocyclic Chemistry III, Vol. 5, Elsevier Ltd., New York, 2008, pp. 159-209.
[2] K. D. Patel, B. D. Mistry and K. R. Desai, “Synthesis and Antimicrobial Activity of 1,2,4-Triazoles,” Journal of Indian Chemical Society, Vol. 79, No. 9, 2002, pp. 964-965.
[3] K. Shalini, N. Kumar, S. Drabu and P. K. Sharma, “Advances in Synthetic Approach to and Antifungal Activity of Triazoles,” Beilstein Journal of Organic Chemistry, Vol. 7, 2011, pp. 668-677. doi:10.3762/bjoc.7.79
[4] K. Colanceska-Ragenovic, V. Dimova, V. Kakurinov, D. G. Molnar and A. Buzarovska, “Synthesis, Antibacterial and Antifungal Activity of 4-Substituted-5-Aryl-1,2,4Triazoles,” Molecules, Vol. 6, No. 10, 2001, pp. 815-824. doi:10.3390/61000815
[5] B. S. Holla, K. N. Poorjary, B. S. Rao and M. K. Shivananda, “New Bis-Aminomercaptotriazoles and BisTriazolothia-Diazoles as Possible Anticancer Agents,” European Journal of Medicinal Chemistry, Vol. 37, No. 6, 2002, pp. 511-517. doi:10.1016/S0223-5234(02)01358-2
[6] G. Turan-Zitouni, Z. A. Kaplancikli, A. Özdemir, P. Chevallet, H. B. Kandilci and B. Gümüsel, “Studies on 1,2, 4-Triazole Derivatives as Potential Anti-Inflammatory Agents,” Archiv der Pharmazie, Vol. 340, No. 11, 2007, pp. 586-590. doi:10.1002/ardp.200700134
[7] G. R. Jadhav, M. U. Shaikh, R. P. Kale, M. R. Shiradkar and C. H. Gill, “SAR Study of Clubbed [1,2,4]-Triazolyl with Fluorobenzimidazoles as Antimicrobial and Antituberculosis Agents,” European Journal of Medicinal Chemistry, Vol. 44, No. 7, 2009, pp. 2930-2935. doi:10.1016/j.ejmech.2008.12.001
[8] S. Borg, G. Estenne-Bouhtou, K. Luthman, I. Csöregh, W. Hesselink and U. Hacksell, “Synthesis of 1,2,4-Oxadiazole-1,3,4-Oxadiazoleand 1,2,4-Triazole-Derived Dipeptidomimetics,” The Journal of Organic Chemistry Vol. 60, No. 10, 1995, pp. 3112-3120. doi:10.1021/ jo00115a029
[9] C. Chen, R. Dagnino, C. Q. Huang, J. R. McCarthy and D. E. Grigoriadis, “1-Alkyl-3-Amino-5-Aryl-1H-[1,2,4]Triazoles: Novel Synthesis via Cyclization of N-Acyl-S-Methylisothioureas with Alkylhydrazines and Their Potent Corticotropin-Releasing Factor-1 (CRF1) Receptor Antagonist Activities,” Bioorganic & Medicinal Chemistry Letters, Vol. 11, No. 24, 2001, pp. 3165-3168. doi:10.1016/S0960-894X(01)00657-6
[10] S. K. Thompson, A. M. Eppley, J. S. Frazee, M. G. Darcy, R. T. Lum, T. A Tomaszek, L. A. Ivanoff, J. F. Morris, E. J. Sternberg, D. M. Lambert, A. V. Fernandez, S. R. J. Petteway, T. D. Meek, B. W. Metcalf and J. G. Gleason, “Synthesis and Antiviral Activity of a Novel Class of HIV-1 Protease Inhibitors Containing a Heterocyclic P1’P2’ Amide Bond Isostere,” Bioorganic & Medicinal Chemistry Letters, Vol. 4, No. 20, 1994, pp. 2441-2446. doi:10.1016/S0960-894X(01)80406-6
[11] F. Kevin, “Triazole Derivatives and Their Preparation and Method for Treating Non-Hodgkin’s Lymphoma,” US Patent No. 2006-808341, 2007.
[12] M. H. Klingele and S. Brooker, “The Coordination Chemistry of 4-Substituted 3,5-Di(2-Pyridyl)-4H-1,2,4-Triazoles and Related Ligands,” Coordination Chemistry Reviews, Vol. 241, No. 1-2, 2003, pp. 119-132. doi:10.1016/S0010-8545(03)00049-3
[13] G. Aromí, L. A. Barrios, O. Roubeau and P. Gamez, “Triazoles and Tetrazoles: Prime Ligands to Generate Remarkable Coordination Materials,” Coordination Chemistry Reviews, Vol. 255, No. 5-6, 2011, pp. 485-546. doi:10.1016/j.ccr.2010.10.038
[14] X. W. Chen, C. Y. Liu, T. H. Jen, S. A. Chen and S. Holdcroft, “Synthesis and Characterization of a Fullerene Bearing a Triazole Group,” Chemistry of Materials, Vol. 19, No. 20, 2007, pp. 5194-5199. doi:10.1021/cm071686y
[15] Z. Y. Zhou, X. W. Chen and S. Holdcroft, “Stabilizing Bicontinuous Nanophase Segregation in πCP-C60 DonorAcceptor Blends,” Journal of the American Chemical Society, Vol. 130, No. 35, 2008, pp. 11711-11718. doi:10.1021/ja802021z
[16] P. L. Wu, X. J. Feng, H. L. Tam and K. W. Cheah, “Efficient Three-Photon Excited Deep Blue Photoluminescence and Lasing of Diphenylamino and 1,2,4-Triazole Endcapped Oligofluorenes,” Journal of the American Chemical Society, Vol. 131, No. 3, 2009, pp. 886-887. doi:10.1021/ja806703v
[17] S. J. Haycock-Lewandowski, N. J. Mawby, A. Wilder and J. Ahman, “Development of a Bulk Enabling Route to Maraviroc (UK-427,857), a CCR-5 Receptor Antagonist,” Organic Process Research & Development, Vol. 12, No. 6, 2008, pp. 1094-1103. doi:10.1021/op8000614
[18] S. Fustero, J. Gonzalez and C. Del Pozo, “1,4-Benzodiazepine N-Nitrosoamidines: Useful Intermediates in the Synthesis of Tricyclic Benzodiazepines,” Molecules, Vol. 11, No. 8, 2006, pp. 583-588. doi:10.3390/11080583
[19] K. B. Hansen, J. Balsells, S. Dreher, Y. Hsiao, M. Kubryk, M. Palucki, N. Rivera, D. Steinhuebel, J. D. Armstrong III, D. Askin and E. J. Grabowski, “First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin,” Organic Process Research & Development, Vol. 9, No. 5, 2005, pp. 634-639. doi:10.1021/op0500786
[20] A. Moulin, M. Bibian, A. L. Blayo, S. E. Habnouni, J. Martinez and J. A. Fehrentz, “Synthesis of 3,4,5-Trisubstituted-1,2,4-Triazoles,” Chemical Reviews, Vol. 110, No. 4, 2010, pp. 1809-1827. doi:10.1021/cr900107r
[21] N. I. Korotkikh, A. V. Kiselev, A. V. Knishevitsky, G. F. Raenko, T. M. Pekhtereva and O. P. Shvaika, “Recyclization of 1, 3, 4-Oxadiazoles and Bis-1,3,4-Oxadiazoles into 1,2,4-Triazole Derivatives. Synthesis of 5-Unsubstituted 1,2,4-Triazoles,” Chemistry of Heterocyclic Compounds, Vol. 41, No. 7, 2005, pp. 866-871. doi:10.1007/s10593-005-0240-2
[22] N. A. Meanwell, J. L. Romine, M. J. Rosenfeld, S. W. Martin, A. K. Trehan, J. J. K. Wright, M. F. Malley, J. Z. Gougoutas, C. L. Brassard, J. O. Buchanan, M. E. Federic, J. S. Fleming, M. Gamberdella, K. S. Hartl, G. B. Zavoico and S. M. Seiler, “Nonprostanoid Prostacyclin Mimetics 5. Structure-Activity-Relationships Associated with [3-[4(4,5-Diphenyl-2-Oxazolyl)-5-Oxazolyl] Phenoxy] Acetic Acid,” Journal of Medicinal Chemistry, Vol. 36, No. 24, 1993, pp. 3884-3903. doi:10.1021/jm00076a018
[23] M. J. Stocks, D. R. Cheshire and R. Reynolds, “Efficient and Regiospecific One-Pot Synthesis of Substituted 1,2, 4-Triazoles,” Organic Letters, Vol. 6, No. 17, 2004, pp. 2969-2971. doi:10.1021/ol048863a
[24] J. Lindström and M. H. Johansson, “Synthesis of 3-Aryl5-Methyl 4-Substituted [1,2,4] Triazoles,” Synthetic Communications, Vol. 36, No. 15, 2006, pp. 2217-2229. doi:10.1080/00397910600638994
[25] A. J. Duplantier, E. L. Bachert, J. B. Cheng, V. L. Cohan, T. H. Jenkinson, K. G. Kraus, M. W. McKechney, J. D. Pillar and J. W. Watson, “SAR of a Series of 5,6-Dihydro-(9H)-Pyrazolo [3,4-c]-1,2,4-Triazolo[4,3-Alpha]Pyridines as Potent Inhibitors of Human Eosinophil Phosphodiesterase,” Journal of Medicinal Chemistry, Vol. 50, No. 2, 2007, pp. 344-349. doi:10.1021/jm060904g
[26] B. Modzelewska-Banachiewicz, J. Banachiewicz, A. Chodkowska, E. Jagiello-Wojtowicz and L. Mazur, “Synthesis and Biological Activity of New Derivatives of 3-(3,4-Diaryl-1,2,4-Triazole-5-yl)Propenoic Acid,” European Journal of Medicinal Chemistry, Vol. 39, No. 10, 2004, pp. 873-877. doi:10.1016/j.ejmech.2004.07.002
[27] B. Modzelewska-Banachiewicz, M. Ucherek, M. Zimecki, J. Kutkowska, T. Kaminska, B. Morak-Mlodawska, R. Paprocka, M. Szulc, G. Lewandowski, J. Marciniak and T. Bobkiewicz-Kozlowska, “Reactions of N3-Substituted Amidrazones with Cis-1,2-Cyclohexane Dicarboxylic Anhydride and Biological Activitiesof the Products,” Archiv der Pharmazie, Vol. 345, No. 6, 2012, pp. 486-494. doi:10.1002/ardp.201100333
[28] S. Olson, S. D. Aster, K. Brown, L. Carbin, D. W. Graham, A. Hermanowski-Vosatka, C. B. LeGrand, S. S. Mundt, M. A. Robbins, J. M. Schaeffer, L. H. Slossberg, M. J. Szymonifka, R. Thieringer, S. D. Wright and J. M. Balkovec, “Adamantyl Triazoles as Selective Inhibitors of 11 Beta-Hydroxysteroid Dehydrogenase Type 1,” Bioorganic & Medicinal Chemistry Letters, Vol. 15, No. 19, 2005, pp. 4359-4362. doi:10.1016/j.bmcl.2005.06.040
[29] M. A. García, S. Martín-Santamaría, M. Cacho, F. M. Llave, M. Julian, A. Martínez, B. Pascual-Teresa and A. Ramos, “Synthesis, Biological Evaluation, and ThreeDimensional Quantitative Structure-Activity Relationship Study of Small-Molecule Positive Modulators of Adrenomedullin,” Journal of Medicinal Chemistry, Vol. 48, No. 12, 2005, pp. 4068-4075. doi:10.1021/jm050021+
[30] M. Saitoh, J. Kunitomo, E. Kimura, H. Iwashita, Y. Uno, T. Onishi, N. Uchiyama, T. Kawamoto, T. Tanaka, C. D. Mol, D. R. Dougan, G. P. Textor, G. P. Snell, M. Takizawa, F. Itoh and M. Kori, “2-{3-[4-(Alkylsulfinyl)Phenyl]1-Benzofuran-5-yl}-5-Methyl-1,3,4-Oxadiazole Derivatives as Novel Inhibitors of Glycogen Synthase Kinase-3 Beta with Good Brain Permeability,” Journal of Medicinal Chemistry, Vol. 52, No. 20, 2009, pp. 6270-6286. doi:10.1021/jm900647e
[31] A. Brown, D. Ellis, D. Pearce, M. Ralph and N. Sciammetta, “Aryloxypyrazines as Highly Selective Antagonists of Oxytocin,” Bioorganic & Medicinal Chemistry Letters, Vol. 19, No. 10, 2009, pp. 2634-2636. doi:10.1016/j.bmcl.2009.03.160
[32] T. Sugane, T. Tobe, W. Hamaguchi, I. Shimada, K. Maeno, J. Miyata, T. Suzuki, T. Kimizuka, A. Kohara, T. Morita, H. Doihara, K. Saita, M. Aota, M. Furutani, Y. Shimada, N. Hamada, S. Sakamoto and S. Tsukamoto, “Synthesis and Biological Evaluation of 3-Biphenyl-4-yl4-Phenyl-4H-1,2,4-Triazoles as Novel Glycine Transporter 1 Inhibitors,” Journal of Medicinal Chemistry, Vol. 54, No. 1, 2011, pp. 387-391. doi:10.1021/jm101031u
[33] P. H. J. Carlsen and K. B. JØrgensen, “Synthesis of Unsymmetrically Substituted 4H-1,2,4-Triazoles,” Journal of Heterocyclic Chemistry, Vol. 31, 1994, pp. 805-807.
[34] X. F. Chen, R. Liu, Y. Xu and G. Zou, “Tunable Protic Ionic Liquids as Solvent-Catalysts for Improved Synthesis of Multiply Substituted 1,2,4-Triazoles from Oxadiazoles and Organoamines,” Tetrahedron, Vol. 68, 2012, pp. 4813-4819. doi:10.1016/j.tet.2012.03.114
[35] P. Seneci, “Solid Phase Synthesis and Combinatorial chemistry,” Wiley InterscienceJohn, Wiley & Sons, New York, 2000.
[36] R. E. Dolle, “Comprehensive Survey of Combinatorial Library Synthesis,” Journal Combintorial Chemistry, Vol. 6, No. 5, 2004, pp. 623-679. doi:10.1021/cc0499082
[37] P. H. Toy and Y. Lam, “Solid-Phase Organic Synthesis Concepts, Strategies, and Ap-plications,” John Wiley & Sons, Inc., Hoboken, 2012.
[38] A. R. Katritzky, M. Qi, D. Feng, G. Zhang, M. C. Griffith and K. Watson, “Synthesis of 1,2,4-Triazole-Functionalized Solid Support and Its Use in the Solid-Phase Synthesis of Trisubstituted 1,2,4-1,2,4-Triazoles,” Organic Letters, Vol. 1, No. 8, 1999, pp. 1189-1191. doi:10.1021/ol990186a
[39] S. D. Larsen and B. A. DiPaolo, “Traceless Solid-Phase Synthesis of 1,2,4-Triazoles Using a Novel Amine Resin,” Organic Letters, Vol. 3, No. 21, 2001, pp. 3341-3344. doi:10.1021/ol016578a
[40] Y. G. Wang, W. M. Xu and X. Huang, “Selenium-Based SafetyCatch Linker: Solid-Phase Synthesis of Vinyl-Substituted Oxadiazoles and Triazoles,” Journal of Combinatorial Chemistry, Vol. 9, No. 3, 2007, pp. 513-519. doi:10.1021/cc0700187
[41] Z. X. Liu, J. L. Zhao and X. Huang, “Solid-Phase Synthesis of 1,3,4-Oxadiazoline-5-Thione Derivatives from Resin Bound Acylhydrazines,” Bioorganic & Medicinal Chemistry Letters, Vol. 16, No. 7, 2006, pp. 1828-1830. doi:10.1016/j.bmcl.2006.01.002
[42] Z. X. Liu, Y. Y. Mu, J. Lin and Y. Y. Chen, “Traceless Solid-Phase Synthesis of 1, 2, 3-Thiadiazole Derivatives from Resin-Bound Acylhydrazine,” Synthetic Communications, Vol. 38, No. 24, 2008, pp. 4407-4414. doi:10.1080/00397910802369521
[43] Z. X. Liu, Y. Y. Mu and Z. S. Song, “Solid Phase Synthesis of 4,5-Disubstituted 1, 2, 4-Triazol-3-One Derivatives from Resin-Bound Acylhydrazines,” Journal of Chemical Research, No. 4, 2008, pp. 216-217.
[44] Z. X. Liu, Z. S. Song, J. L. Zhao and J. Y. Zheng, “SolidPhase Synthesis of 2-Arylamino-5-(4-Hydroxyphenyl)-1, 3,4-Thiadiazole Derivatives Based on Resin-Bound Acylhydrazines,” Phosphorus, Sulfur and Silicon and the Related Elements, Vol. 185, No. 11, 2010, pp. 2375-2381. doi:10.1080/10426501003664176
[45] Z. X. Liu, Y. R. Yi, J. L. Zhao and M. X. Tang, “SolidPhase Synthesis of 4,5-Disubstituted-1,2,4-Triazole-3-Thione Derivatives Based on the Resin-Bound Acylhydrazines,” Synthetic Communications, Vol. 42, No. 1, 2012, pp. 5561. doi:10.1080/00397911.2010.521609
[46] M. Dabiri, P. Salehi, M. Baghbanzadeh and M. Bahramnejad, “Alum (KAl(SO4)2.12H2O): An Efficient and Inexpensive Catalyst for the One-Pot Synthesis of 1,3,4Oxadiazoles under Solvent-Free Conditions,” Monatshefte für Chemie-Chemical Monthly, Vol. 138, No. 12, 2007, pp. 1253-1255. doi:10.1007/s00706-007-0724-0

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.