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Synthesis of 1H-1,2,4-triazoles

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A simple, efficient, and mild method for the synthesis of substituted 1,2,4-triazoles from hydrazines and formamide proceeds smoothly under microwave irradiation in the absence of a catalyst and shows excellent functional-group tolerance.
G. M. Shelke, V. K. Rao, M. Jha, T. S. Cameron, A. Kumar, Synlett, 2015, 26, 404-407.


An electrochemical multicomponent reaction of aryl hydrazines, paraformaldehyde, NH4OAc, and alcohols provides 1,5-disubstituted and 1-aryl 1,2,4-triazoles. Alcohols act as solvents as well as reactants and NH4OAc is used as the nitrogen source. With the assistance of reactive iodide radical or I2 and NH3 electrogenerated in situ, this process effectively avoids the use of strong oxidants and transition-metal catalysts.
N. Yang, G. Yuan, J. Org. Chem., 2018, 83, 11963-11969.


A multicomponent process enables the synthesis of 1-aryl 1,2,4-triazoles directly from anilines, amino pyridines, and pyrimidines. The reaction scope was explored with 21 different substrates.
A. Tam, I. S. Armstrong, T. E. La Cruz, Org. Lett., 2013, 15, 3585-3589.


A copper-catalyzed reaction under an atmosphere of air provides 1,2,4-triazole derivatives by sequential N-C and N-N bond-forming oxidative coupling reactions. Starting materials and the copper catalyst are readily available and inexpensive. A wide range of functional groups are tolerated.
S. Ueda, H. Nagasawa, J. Am. Chem. Soc., 2009, 131, 15080-15081.


A cascade addition-oxidative cyclization of nitriles with 2-aminopyridines or amidines was achieved in the presence of 1,10-phenanthroline-functionalized MCM-41-supported copper(I) complex [Phen-MCM-41-CuBr] as the heterogeneous and recyclable catalyst and air as the oxidant. The approach provides a wide range of 1,2,4-triazole derivatives in high yields.
J. Xia, X. Huang, M. Cai, Synthesis, 2019, 51, 2014-2022.


A facile and versatile catalytic system involving copper catalyst, K3PO4 as the base, and O2 as the oxidant enables an efficient synthesis of 2,4,6-trisubstituted and 2,6-disubstituted 1,3,5-triazines and 1,3-disubstituted 1,2,4-triazoles from amidines with trialkylamines, DMSO, and DMF as the reaction partners, respectively. This protocol features an inexpensive catalyst, a green oxidant, good functional group tolerance, and high regioselectivity.
H. Huang, W. Guo, W. Wu, C.-J. Li, H. Jiang, Org. Lett., 2015, 17, 2894-2897.


A highly regioselective one-pot process provides rapid access to highly diverse 1,3,5-trisubstituted 1,2,4-triazoles from reaction of carboxylic acids, primary amidines, and monosubstituted hydrazines.
G. M. Castanedo, P. S. Seng, N. Blaquiere, S. Trapp, S. T. Staben, J. Org. Chem., 2011, 76, 1177-1179.


A general and metal-free synthesis of 1,3,5-trisubstituted 1,2,4-triazoles from hydrazones and aliphatic amines has been achieved under oxidative conditions via a cascade C-H functionalization, double C-N bonds formation, and oxidative aromatization sequence in the presence of iodine as catalyst.
Z. Chen, H. Li, W. Dong, M. Miao, H. Ren, Org. Lett., 2016, 18, 1334-1337.


1,5-Disubstituted 1,2,4-triazoles were formed by Cu(II) catalysis in high yield, whereas 1,3-disubstituted 1,2,4-triazoles were selectively obtained under Ag(I) catalysis. These regioselective catalytic methodologies provide a facile access to 1,2,4-triazole scaffolds with high efficiency, broad substrate scope, and excellent functional group compatibility.
J.-Q. Liu, X. Shen, Y. Wang, X.-S. Wang, X. Bi, Org. Lett., 2018, 20, 6930-6933.


1,5-Disubstituted 1,2,4-triazoles were formed by Cu(II) catalysis in high yield, whereas 1,3-disubstituted 1,2,4-triazoles were selectively obtained under Ag(I) catalysis. These regioselective catalytic methodologies provide a facile access to 1,2,4-triazole scaffolds with high efficiency, broad substrate scope, and excellent functional group compatibility.
J.-Q. Liu, X. Shen, Y. Wang, X.-S. Wang, X. Bi, Org. Lett., 2018, 20, 6930-6933.


An effective 1,3-dipolar cycloaddition for the synthesis of 1,3,5-trisubstituted 1,2,4-triazole derivatives by reaction of oximes with hydrazonoyl hydrochlorides using triethylamine as a base gave the desired 1,3,5-trisubstituted 1,2,4-triazoles in good yields. The reaction was applicable to aliphatic, cyclic aliphatic, aromatic and heterocyclic oxime substrates.
L.-Y. Wang, W.-C. Tseng, H.-Y. Lin, F. F. Wong, Synlett, 2011, 1467-1471.


A series of new oxamide-derived amidine reagents can be accessed in excellent yield with minimal purification necessary. A subsequent reaction of these reagents with various hydrazine hydrochloride salts efficiently generates 1,5-disubstituted-1,2,4-triazole compounds in good yields. Both aromatic and aliphatic hydrazines react readily with the amidine reagents under very mild reaction conditions.
Y. Xu, M. McLaughlin, E. N. Bolton, R. A. Reamer, J. Org. Chem., 2010, 75, 8666-8669.


A three-component reaction of readily available 2-diazoacetonitriles, nitriles, and aryldiazonium salts provides a wide range of 1-aryl 5-cyano-1,2,4-triazoles. This regiospecific synthesis relies on a dipolar [3 + 2] annulation of an in situ formed nitrile ylide with the aryldiazonium salt.
L.-N. Zhou, F.-F. Feng, C. W. Cheung, J.-A. Ma, Org. Lett., 2021, 23, 739-744.


Readily accessible N'-nitro-2-hydrocarbylidene-hydrazinecarboximidamides can be cyclized to disubstituted 1H- and 4H-1,2,4-triazoles in good yields under mild reaction conditions. Whereas intramolecular redox reactions under acidic conditions provide amino-1,2,4-triazoles, neutral conditions with water as the solvent and air as oxidant give nitroimino-1,2,4-triazoles.
F. Zhao, T. Singh, Y. Xiao, W. Su, D. Yang, C. Jia, J.-Q. Li, Z. Qin, Synthesis, 2021, 53, 1901-1910.


Hexafluorophosphoric acid promotes the formation of 1,3,4-oxadiazolium hexafluorophosphate salts from N′-acyl-N-aroyl-N-arylhydrazides or N′-acyl-N-acyl-N-arylhydrazides under mild conditions. A subsequent reaction with cyanamide in propan-2-ol in the presence of triethylamine generates 1,5-disubstituted 3-amino-1H-1,2,4-triazoles in good yields.
B. Wong, A. Stumpf. D. Carrera, C. Gu, H. Zhang, Synthesis, 2013, 45, 1083-1093.


A mild, one-pot cyanoimidation of aldehydes using cyanamide as a nitrogen source and NBS as an oxidant was achieved in high yields without the addition of a catalyst. Subsequently, the substituted N-cyanobenzimidate products may also undergo a cyclization reaction to give 1,2,4-triazole derivatives in high yields.
P. Yin, W.-B. Ma, Y. Chen, W.-C. Huang, Y. Deng, L. He, Org. Lett., 2009, 11, 5482-5485.