Mass spectral fragmentation pattern of 4-carboxy-and 4-methoxycarbonyl-5-methyl(or phenyl)-2-aryl-2H-1,2,3-triazoles

4-Carboxy-5-methyl-2-aryl-2H-1,2,3-triazoles undergo considerable fragmentation on electron impact including loss of OH and H₂O from the molecular ions and rupture of the triazole ring. 4-Carboxy-5-phenyl-2-aryl-2H-1,2,3-triazoles, on the other hand, show no loss of H₂O from the molecular ions.     

Synthesis and properties of 1-dinitromethyl-3-R-1,2,4-triazoles

Reductive denitration of 1-trinitromethyl-3-R-1,2,4-triazoles by KI or NH₂OH followed by the treatment of the formed 1-dinitromethyl-3-R-1,2,4-triazoles salts with sulfuric acid yielded dinitromethyl compounds (R = H, N₃, Cl, NO₂), sufficiently strong CH-acids (pK_a 1.37–0.12) whose typical reactions are similar to those of gem-dinitrocompounds from the aliphatic series. The spectral data and the analysis of correlation relations between pK_a of 1-dinitromethyl-3-R-1,2,4-triazoles and the substituent constants confirm that their structure is analogous to that of the majority of compounds belonging to the mentioned series.     

Heterylation of 3-R1-5-R2-1,2,4-Triazoles with Derivatives of 3,5-Dinitro-1,2,4-Triazole

Heterylation of 3-R¹-5-R²-1'2'4-triazoles (pK _a 3-12) with N-alkyl-, N-alkenyl-, N-alkoxy-carbonyl-, N-oxoalkyl-, N-nitroxyalkyl, N-nitroaminoalkyl-3'5-dinitro-1'2'4-triazoles results insubstitution of a nitro group in 5 position of the dinitro compound yielding 1-R-methyl-3-nitro-5-(3-R¹-5-R²-1,2,4-triazolyl)-1,2,4-triazoles. The side processes: Hydroxide-ion attack on C⁵ and (or) N¹ of the ring both in the substrate and in the target compound afford 1-R-methyl3-nitro-1,2,4-triazol-5-ones, 3,5-dinitro-1,2,4-triazole and NH-acids of N-C-bitriazole series. Optimal reaction media are aprotic dipolar substances, and for compounds prone to heterolysis ethyl acetate-water systems. The azole pK _a is the decisive factor controlling the composition and the ratio of reaction products. The process is promising for azoles with pK _a > 5, and the optimal range of pK _a is 8-10.     

3-Nitro-1,2,4-triazol-5-one derivatives

3-Nitro-1,2,4-triazol-5-one and its monomethyl derivatives react with methyl vinyl ketone to give products of addition to the ring N₁ and N₄ atoms. The reaction with formaldehyde and N-methylolacetamide proceeds only at the N₁ atom. The keto derivatives of 3-nitro-1,2,4-triazol-5-one undergo the Schmidt reaction to give the corresponding acetamides. A number of compounds that include functional groups in the N₁-alkyl substituent of the 3-nitro ring were obtained by treatment of the bases of N₁-substituted 3,5-dinitro-1,2,4-triazoles in aprotic media.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 552–558, April, 1981.     

Formation of derivatives of 5,6-dihydrooxazino- and 5,6-dihydrooxazolo[3,2-b]-1,2,4-triazole in the reaction of 1-oxoalkyl-3,5-dinitro-1,2,4-triazoles with potassium cyanide

1,3-Dihydrooxazino- and 1,3-dihydrooxazolol[3,2-b]-1,2,4-triazoles were obtained instead of the expected 3-nitro-5-cyano-1,2,4-triazole derivatives in the reaction of 1-oxoalkyl-3,5-dinitro-1,2,4-triazoles with potassium cyanide. Their formation is due to the fact that primary attack by the cyanide anion is not directed at the ring C₅ atom but rather at the carbonyl group with subsequent intramolecular replacement of the nitro group.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1403–1405, October, 1981.     

Synthesis of di- and trisubstituted 1,2,4-triazoles containing indole fragments

The reaction of imino esters of indole-series acids with acid hydrazides gave N₍₁₎-acylamidrazones, which, during heating, were converted to 3,5-disubstituted 1H-1,2,4-triazoles containing indole fragments. Compounds of this type were also synthesized by the reaction of indolyl-containing 2,5-disubstituted 1,3,4-oxadiazoles with formamide. Condensation of 2,5-disubstituted 1,3,4-oxadiazoles with aniline gave 3,4,5-trisubstituted 4H-1,2,4-triazoles containing indolyl radicals. Cyclocondensation of N₍₁₎-phenylamidrazones of indole-series acids with benzoyl chloride gave 1,3,5-trisubstituted 1H-1,2,4-triazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 189–196, February, 1993.     

Molecular modeling of the mechanisms of thermolysis of nitramino-1,2,4-triazoles

Modeling of the probable mechanisms of the thermolysis of C-and N-nitramino-1,2,4-triazoles has been carried out by methods of mathematical chemistry. It was established that the formation is possible of a more diverse spectrum of products in their destruction than was previously recorded by different experimental methods. Subsequent assessment of the thermochemical preference for pathways of decomposition of the compounds was carried out by the density functional method in the B3LYP/6-31G* approach. It was determined that the thermal destruction of C-and N-nitramino-substituted polynitrogen heterocycles, capable of tautomeric conversion, was most probably through the thermochemically least stable nitramine form. Thermal decomposition of the considered tautomers is preferred at the NNO₂ fragment and not at the triazole ring. The direction of the structural stabilization of the investigated compounds has been clarified by comparison of the geometric, electronic, and thermochemical characteristics of C-NNO₂-and N-NNO₂-substituted 1,2,4-triazoles. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1467–1495, October, 2006.     

Ring-chain-transformations : Synthesis of ω-functionalized alkylthio-1,2,4-triazoles by reaction of cyclic S-analogous N-cyano or N-aroylcarbonimidoesters with hydrazines

Cyclic N-cyanocarbonimidodithioesters 4 or N-aroylcarbonimidothioic acid esters 10 react regioselectively with arylhydrazines and methylhydrazine by a ring chain transformation reaction forming ω-functionalized 3-alkylthio-1,2,4-triazoles 8 and 11 or 5-alkylthio-1,2,4-triazoles 9 .     

Cascade reactions for constructing heterocycles containing a pyrimidino-pyrazino-pyrimidine core using 1,2,4-triazole scaffolds

The regioselective cyclocondensation of aminoethyl-1,2,4-triazoles and glyoxal provides pentacyclic heterocycles in which two 7,8-dihydro-5H-6λ²-[1,2,4]triazolo[1,5-c]pyrimidine systems are connected through CH(OH) bridges generating a central piperazine-2,5-diol ring. The structure of the new compounds was elucidated based on ¹H, ¹³C and ¹⁵N NMR spectroscopic methods. The molecular structure of the parent compound generated from aminoethyl-1,2,4-triazole was established by single crystal X-ray diffraction.     

Reactions of 3-nitro-1,2,4-triazoles with alkylating agents. 6*. Alkylation of a neutral heterocycle by alcohols in acid media*

Reaction of 3-nitro-1,2,4-triazole and 5-methyl-3-nitro-1,2,4-triazole with secondary and tertiary alcohols in conc. H₂SO₄ takes place at the N(2) atom. Alkylation by 2-propanol occurs regioselectively to form the 1-isopropyl-3-nitro-and 1-isopropyl-3-methyl-5-nitro-1,2,4-triazoles. As a consequence of isomerization the alkylation using cyclohexyl or tert-butyl alcohols gives respectively a mixture of regioisomers substituted at atom N(1) (1-cyclohexyl-3-nitro-and 1-cyclohexyl-5-methyl-3-nitro-1,2,4-triazoles) and at atom N(2) (5-nitro-1-cyclohexyl-and 1-cyclohexyl-3-methyl-5-nitro-1,2,4-triazoles) and, in the second case, to 1-tert-butyl-3-nitro-1,2,4-triazole. * For Communication 5 see [1]. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1680–1687, November, 2008.     

Traceless liquid-phase synthesis of 3-alkylamino-4,5-disubstituted-1,2,4-triazoles on polyethylene glycol (PEG)

A liquid-phase route to 3-alkylamino-4,5-disubstituted-1,2,4-triazoles has been developed, which permits the incorporation of three elements of diversity. The heterocycle was constructed upon PEG6000 (soluble polymer) modified by 4-hydroxy-2-methoxybenzaldehyde, from which a traceless cleavage could be realized with TFA/CH₂Cl₂. This method provided a library of 3-alkylamino-4,5-disubstituted-1,2,4-triazoles with reasonable yields and excellent purity.     

Reactions of 3-nitro-1,2,4-triazole derivatives with alkylating agents. 5. Selective synthesis of 1,4-dialkyl-and 1,4,5-trialkyl-3-nitro-1,2,4-triazolium salts from 1-alkyl-and 4,5-dialkyl-3-nitro-1,2,4-triazoles and dialkyl sulfates

Interaction of N₍₁₎-alkyl-substituted 3-nitro-5-R-1,2,4-triazoles with dialkyl sulphates proceeds selectively and results in the respective salts of 1,4-dialkyl-, 1,4,5-trialkyl-3-nitro-1,2,4-triazoliums. The reaction of N₍₄₎-alkyl-substituted 3-nitro-5-R-1,2,4-triazoles yields the mixtures of the salts of 1,4-dialkyl-, 1,4,5-trialkyl-3-nitro-1,2,4-triazoliums and 1,4-dialkyl-, 1,3,4-trialkyl-1,2,4-triazol-5-ones with predominance of quaternary salts. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 927–934, June, 2007.     

Heterocyclic nitro compounds. 28. 1-(Oxoalkyl)-3-nitro-5-r-1,2,4-triazoles in reactions with hydrazine and hydroxylamine

The reaction of 1-(oxoalkyl)-3-nitro-5-R-1,2,4-triazoles with hydroxylainine and hydrazine takes place at the keto group to give azines and oximes (R = H, CH₃), with reduction of the nitro group (R = NO₂, hydroxylamine), or with participation of both reaction centers with annelation and conversion to triazolo[3,2-c]-1,2,4-triazines and -1,2,4-triazepines, depending on the character of the substituent in the 5 position of the triazole ring and the type of reagent.See [1] for Communication 27.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1113–1117, August, 1982.     

5-Substituted 3-Nitro-1-vinyl-1,2,4-triazoles

A series of 5-substituted 3-nitro-1-vinyl-1,2,4-triazoles were synthesized by alkaline treatment of the corresponding 1-(2-haloethyl- or 2-nitroxyethyl)-3-nitro-1,2,4-triazoles and by transvinylation of NH acids of the same series with vinyl acetate. The scope of applicability of the transvinylation procedure was established with respect to the azole pK _a value. The vinylic double bond on the nitrogen was shown to be inactive toward both nucleophilic and electrophilic reagents, whereas the halogen atom in position 5 exhibits enhanced reactivity. The latter factor provides the possibility for versatile structural modification via nucleophilic replacement of the 5-halogen atom by various groups, including triazolate ion.     

Spectroscopic identification of some derivatives of 3,4-diamino-4H-1,2,4-triazole and 3-Hydrazino-4H-1,2,4-triazole

Spectroscopic methods (ir, ¹H- and ¹³C-nmr, ms and uv) have been used for the structural elucidation and identification of different isomeric 1,2,4-triazole derivatives, obtained by cyclisation reactions from appropriate diaminoguanidines. The four compounds 3,4-diamino-4H-1,2,4-triazole, 3-hydrazino-4H-1,2,4-triazole, 3-amino-4-(2,6-dichlorobenzylideneamino)-4H-1,2,4-triazole and 3-(2,6-dichlorobenzylidenehydrazino)-4H-1,2,4-triazole, were chosen as representative structures to illustrate the general spectroscopic properties for 3,4-diamino- and 3-hydrazino-substituted 4H-1,2,4-triazoles and the corresponding hydrazones, with different substituents in the 5-position of the triazole ring (alkyl-, aralkyl-, mercapto-, hydroxy- and amino-groups). Nmr and uv spectroscopy were found to be the best methods for confirmation of the different series of hydrazones, while ir and nmr were found to be suitable for the structural elucidation of compounds in the series of 3,4-diamino- and 3-hydrazino-4H-1,2,4-triazoles, respectively.     

Facile synthesis of 3,5-diaryl-1,2,4-triazoles via copper-catalyzed domino nucleophilic substitution/oxidative cyclization using amidines or imidates as substrates

Two methods for the synthesis of 3,5-diaryl-1,2,4-triazoles, both domino reactions, are reported. The first procedure, the Cu(OTf)₂-catalyzed reaction between two amidines using NaHCO₃ as a base, 1,10-phenanthroline as an additive and K₃[Fe(CN)₆]/atmospheric oxygen as the oxidant, delivers 3,5-diaryl-1,2,4-triazoles with yields up to 68%. The second procedure for the synthesis of 3,5-diaryl-1,2,4-triazoles with yields up to 64% rests on the Cu(OTf)₂-catalyzed reaction between two imidates and ammonium carbonate. This method features the formation of three bonds in a single synthetic step.     

Thermal decomposition mechanisms of nitro-1,2,4-triazoles: A theoretical study

Possible decomposition mechanisms of C-nitro-and N-nitro-1,2,4-triazoles were simulated. We showed that in addition to the experimentally detected thermolysis products including N₂, N₂O, NO, CO₂, HCN, HNCO, 1,2,4-triazole, 3(5)-nitroso-1,2,4-triazole, and 1,2,4-triazolone, some other decompositon products (H₂O, CO, NO₂, cyanamide, cyanuric acid, and melamine) can be formed. Using the density functional approach (B3LYP/6-31G* approximation), we assessed the most favorable thermal decomposition pathways of nitrotriazoles and studied the relationships between the thermolysis pathways of these substances and their molecular and electronic structures. We found a correlation between the energy gap width (energy difference between the frontier molecular orbitals) and the stabilities of the C-nitro-1,2,4-triazole tautomers to thermal decomposition. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1338–1358, August, 2006.     

5-substituted 3-nitro-1-trinitromethyl-1,2,4-triazoles

A number of 5-R-substituted 3-nitro-1-trinitromethyl-1H-1,2,4-triazoles (R = Me, Cl, Br, N₃, NH₂, NO₂) were synthesized by nitration of the corresponding ω-(5-R-3-nitro-1H-1,2,4-triazol-1-yl)alkan-2-ones with mixtures of concentrated sulfuric and nitric acids.     

Chloro derivatives of 1,2,4-triazole

5-Substituted 3-chloro-1,2,4-triazoles were synthesized by diazotization of 5-substituted 3-amino-1,2,4-triazoles in hydrochloric acid. In addition to replacement of the amino group by a chloro group, diazotization of 5-aryl-3-aminotriazoles at high temperatures leads to chlorination of the aromatic ring.Translated from Khimiya Geterotsiklicheskikh Soedinenli, No. 3, pp. 421–423, March, 1976.     

Structure based approach for twin-enzyme targeted benzimidazolyl-1,2,4-triazole molecular hybrids as antifungal agents

Agri-vitality of benzimidazoles and 1,2,4-triazoles against ergosterol and β-Tubulin prompted and “lead hybridization” based novel series of benzimidazolyl-1,2,4-triazoles (1–32) were designed as twin-enzyme targeted inhibitors. In silico computational tools viz. molecular docking, Lipinski parameters, Frontier molecular orbital approach and Toxicity analysis screened three benzimidazoly-1,2,4-triazoles out of 32 designed molecules, which were synthesised by multistep protocol and characterized by spectroscopic techniques. Antimycotic activity against F. verticillioides, D. oryzae, C. lunata and F. fujikuroi indicated deca fold enhanced potency of all the synthesised compounds, than the standard commercial benzimidazole fungicide, carbendazim. Compounds 8 exhibited ED₅₀ values lower than triazole fungicide, propiconazole. Remarkably, compound 8 inflicted the most promising activity against all the test fungi with ED₅₀ value ranging from 16 to 21 μg/ml better than the standard commercial fungicides used (Tilt: 20–25 μg/ml and Carbendazim:150–230 μg/ml). Ultra microscopic details revealed compound 8 not only caused aberrant distortions resulting in collapsed hyphae but also efficiently shrunken the spores resulting in reproduction inhibition, as possible cause of fungal growth inhibition.