A convenient new synthesis of fused 1,2,4-triazoles: the oxidation of heterocyclic hydrazones using copper dichloride

A series of 1,2,4-triazoles have been prepared by oxidative intramolecular cyclization of heterocyclic hydrazones with copper dichloride. General applicability of this simple transformation was confirmed by the synthesis of moderate to high yields of 1,2,4-triazolo[4,3-a]pyridines, 1,2,4-triazolo[4,3-a]pyrimidines, 1,2,4-triazolo[4,3-b]pyridazines, 1,2,4-triazolo[4,3-a]phthalazines, and 1,2,4-triazolo[4,3-a]quinoxalines. A 1,2,4-triazolo[4,3-e]purine-6,8(7H)-dione was obtained in a lower yield.     

Serendipitous synthesis of 3-hydroxy tetrahydrofurans from tin catalyzed sulfonylation of acyclic 1,2,4-triols

The reaction of syn-1,2,4-triols under sulfonylation conditions catalyzed by Bu₂SnO (5 mol %) results in cyclization and the formation of 3-hydroxy tetrahydrofurans (56-85%) while the anti-1,2,4-triols react to give C1-O-sulfonyl derivatives in good yields (66-83%) and the cyclization product in poor yield (5-12%). A mechanism that justifies these observations is proposed to occur via the tosylation of the primary hydroxyl followed by an intramolecular tin acetal rearrangement to a 1,3-stannylene which then undergoes a 5-exo-tet-cyclization. The difference in rates of cyclization reactivity is due to the energetically more stable tin acetals of syn-1,3-diols compared to those of anti-1,3-diols.     

Selenium Dioxide–Mediated Synthesis of Fused 1,2,4-Triazoles as Cytotoxic Agents

A series of fused 1,2,4-triazoles has been prepared by oxidative intramolecular cyclization of heterocyclic hydrazones with selenium dioxide. General applicability of this practical protocol was confirmed by the synthesis of moderate to good yields of 1,2,4-triazolo[4,3-a]pyridines, 1,2,4-triazolo[4,3-a]pyrimidines, 1,2,4-triazolo[4,3-a]pyramidines, and 1,2,4-triazolo-[4,3-a]quinoxa lines. All compounds were tested in vitro for their cytotoxic activity against HCT-116, A549, and Colo-205 cell lines. Two compounds, 3-(4-methoxyphenyl)-7-methyl-[1,2,4]triazolo[4,3-a]pyridine and 1-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoxaline, showed potent antiproliferative activity against the three cell lines.     

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

New 4‐aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thiones 3 have been synthesized by the intramolecular cyclization of 4‐aryl‐1‐(1‐phenyl‐5‐methyl‐1,2,4‐triazol‐4‐formyl)thiosemicarbazides 2 with an 8% NaOH solution, and then 3 reacted with ω‐bromo‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenone to afford 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 4 . The preliminary biological test showed that the representative compounds possess some anti fungal activities.     

Chemical and Pharmacological Properties of 3-(Thiophen-2-yl)-4-substituted-Δ 2-1,2,4-triazoline-5-thiones

Three 3-(thiophen-2-yl)-4-substituted-Δ ² -1,2,4-triazoline-5-thiones were synthesized by intramolecular cyclization of 1-(thiophen-2-ylcarbonyl)-4-substituted thiosemicarbazides in alkaline medium. Their effects on the central nervous system (CNS) of mice in some behavioral tests were investigated. All investigated compounds displayed antinociceptive activity. The correlation between the structural features and bioactivity has been discussed.     

Synthesis of New Surfactants Mono and Bipolar Derived from 1,2,4‐Triazole‐5‐thione

Abstract

3‐Phenyl‐1,2,4‐triazole‐5‐thione (PTS) and 3‐methyl‐1,2,4‐triazole‐5‐thione (MTS) are prepared in two steps. The first is a condensation of the thiosemicarbazide with the benzoyl chloride and the acetyl chloride for the PTS and MTS respectively in pyridinic medium. This step leads to the formation of 1‐benzoylthiosemicarbazide and 1‐acetylthiosemicarbazide. The 1‐acetylthiosemicarbazide is also prepared with a new method consisted of a simple solvolysis the thiosemicarbazide in acetic acid for 4 hr. The second is the intramolecular cyclization in methanol with the presence of the sodium methalate leads to the formation of the PTS and the MTS in good yields. The alkylation of MTS and PTS under the conditions of solid–liquid phase transfer catalysis (PTC) allowed us to synthesize some new mono and bipolar surfactants compounds derived from 1,2,4‐triazole‐5‐thione in good yields.     

Synthesis,antibacterial and antifungal activities of new chiral 5-alkyl-3-(1′-benzenesulfonylpyrrolidin-2′-yl)-4,5-dihydro-1,2,4-oxadiazin-6-ones

Chiral α-bromoacid chlorides can be easily prepared from amino acids. Their condensation with new 1-benzenesulfonylpyrrolidin-2-carboxamidoxime derived from proline lead to the corresponding O-(bromoacyl) amidoximes. The latter afforded new chiral 5-alkyl-3-(1′-benzenesulfonylpyrrolidin-2′-yl)-4,5-dihydro-1,2,4oxadiazin-6-ones in good chemical yields via intramolecular cyclization in the presence of one equivalent of NaH. These new compounds were evaluated for their antibacterial and antifungal activities using micro-dilution tests against some strains of bacteria and fungi. Our compounds showed an excellent antibacterial activity, which is better than the drug levofloxacin.     

Chemistry of N-Heterocyclic Sulphur Compounds: Part II: Regioselective Synthesis of N,N'-Diaminotriazolophanes Containing Oxygen and Sulphur Heteroatoms

4-Amino-3,5-dimercapto-1,2,4-triazole has been selectively S-alkylated by bis (2-iodoethyl) ether followed by intramolecular cyclization through regioselective S-alkylation with 1,ω-dihaloalkanes to afford 16-20 membered N,N'-diamino-triazolophanes.     

Antimicrobial Properties of 4-Aryl-3-(2-methyl-furan-3-yl)-Δ2-1,2,4-triazoline-5-thiones

Four 4-aryl-3-(2-methyl-furan-3-yl)-Δ²-1,2,4-triazole-5-thiones were synthesized by intramolecular cyclization of 4-aryl-1-[(2-methyl-furan-3-yl)carbonyl]thiosemicarbazides in alkaline medium. The antimicrobial activity of the synthesized triazoles was evaluated. Semiempirical calculations of geometries, energies, and QSAR parameters have been determined in the hope of gaining insight into different biological activities of closely related isomers. New RM1 parameterization has been shown to perform very well for this class of compounds.     

Solution-phase parallel synthesis of new 2H-pyrimido-[4,5-e][1,2,4]triazin-3-ylidenecyanamides

A practical synthesis of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides has been developed. The key step is the coupling reaction of an aryldiazonium salt with 1-cyano-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylamino)-2-methylisothiourea followed by intramolecular cyclization. A library of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides was prepared in two steps from 6-aminouracils using this method.     

Studies on the oxidative cyclization of 3-hydroxyalkyl-1,2,4-trialkoxynaphthalenes and synthetic application for the biologically active natural compound rhinacanthone

The oxidative intramolecular cyclization of 3-hydroxyalkyl-1,2,4-trimethoxynaphthalenes was investigated. A series of 1,2-naphthoquinone fused cyclic ethers were synthesized directly from 3-hydroxyalkyl-1,2,4-trimethoxynaphthalenes by exposure to diammonium cerium (IV) nitrate. To understand the reaction mechanism, the intramolecular cyclization of 3-hydroxyalkyl-naphthoquinones that were formed as reaction intermediates was also examined. The results suggested that the reaction proceeds by a stepwise oxidation–cyclization mechanism. Using this methodology, five-step synthesis of rhinacanthone was achieved with high yield.     

Facile and Efficient Synthesis of 3,10-Disubstituted-bis-1,2,4-triazolo[4,3-a][3′,4′-c]quinoxalines Using Copper Dichloride as an Oxidant

Various 3,10-disubstituted-bis-1,2,4-triazolo[4,3-a][3′,4′-c]quinoxalines (4) have been synthesized in a facile and efficient manner by copper dichloride mediated oxidative intramolecular cyclization of bis-arylidene derivatives of 2,3-dihydrazinoquinoxaline (3).     

Synthesis and Tuberculostatic Activity of 1,3-Thiazacycloalkyl[3,2-b]-1,2,4-triazoles

The 4-hydroxyalkyl-1,2,4-triazole-3-thiones cyclization allowed us to work out the effective method of 1,3-thiazacycloalkyl[3,2-b]-1,2,4-triazoles synthesis. Some of the compounds that were obtained were tested for their tuberculostatic activity.     

Condensed Thienopyrimidines. 14. Synthesis of 10H-Thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines

Reaction of a substituted 2-aminothienothiopyran with methyl(phenyl) isothiocyanate, intramolecular cyclization of the obtained N'-methyl(phenyl) thioureido derivatives, and work up of the cyclization products with hydrazine hydrate gave 2-hydrazinodihydrothiopyranothienopyrimidines. Treatment of the latter with pyruvic acid gave the novel 10H-thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines.     

Studies on the Reaction of α‐Chloroformylarylhydrazine Hydrochloride with Imidazole and 1,2,4‐Triazole

α‐Imidazolformylarylhydrazine 2 and α‐[1,2,4]triazolformylarylhydrazine 3 have been synthesized through the nucleophilic substitution reaction of 1 with imidazole and 1,2,4‐triazole, respectively. 2,2′‐Diaryl‐2H,2′H‐[4,4′]bi[[1,2,4]‐triazolyl]‐3,3′‐dione 4 was obtained from the cycloaddition of α‐chloroformylarylhydrazine hydrochloride 1 with 1,2,4‐triazole at 60 °C and in absence of n‐Bu₃N. The inducing factor for cycloaddition of 1 with 1,2,4‐triazole was ascertained as hydrogen ion by the formation of 4 from the reaction of 3 with hydrochloric acid. 4 was also acquired from the reaction of 3 with 1 and this could confirm the reaction route for cycloaddition of 1 with 1,2,4‐triazole. Some acylation reagents were applied to induce the cyclization reaction of 2 and 3.1 possessing chloroformyl group could induce the cyclization of 2 to give 2‐aryl‐4‐(2‐aryl‐4‐vinyl‐semicarbazide‐4‐yl)‐2,4‐dihydro‐[1,2,4]‐triazol‐3‐one 6. 7 was obtained from the cyclization of 2 induced by some acyl chlorides. Acetic acid anhydride like acetyl chloride also could react with 2 to produce 7D . 5‐Substituted‐3‐aryl‐3H‐[1,3,4]oxadiazol‐2‐one 8 was produced from the cyclization reaction of 3 induced by some acyl chlorides or acetic acid anhydride. The 1,2,4‐triazole group of 3 played a role as a leaving group in the course of cyclization reaction. This was confirmed by the same product 8 which was acquired from the reaction of 1 , possessing a better leaving group: Cl, with some acyl chlorides or acetic acid anhydride.     

α-Oxides in reactions with N-H acids of the heterocyclic series

The reaction of epoxides with 3-nitro-5-bromo-1,2,4-triazole gave a series of 1-(β-hydroxyalkyl)-3-nitro-5-bromo-1,2,4-triazoles, which, under the influence of bases, undergo intramolecular cyclization with HBr elimination to give an ew heterocyclic system — 2-nitro-5,6-dihydrooxazolo[2,3-e]-1,2,4-triazole.     

含1,2,4-三唑-5-硫酮席夫碱的新型1,2,4-三唑并[1,5-a]嘧啶衍生物的合成及生物活性研究

以2-苄硫基-5-甲基-7-羟基-1,2,4-三唑并[1,5-a]嘧啶为原料,经醚化、肼解、成盐、关环和席夫碱反应合成了20个新型的含1,2,4-三唑-5-硫酮席夫碱的1,2,4-三唑并[1,5-a]嘧啶类化合物,通过IR,1H NMR,MS和元素分析对所合成的化合物进行了结构表征.初步生物活性测试结果表明,部分化合物表现出一定的抑菌或较好的抗烟草花叶病毒(TMV)活性.在500μg/mL浓度下,化合物6b,6f和6p对TMV的抑制率分别为41%,43%和40%.     

Chloromethyl-, dichloromethyl-, and trichloromethyl-1,2,4-triazines and their 4-oxides: method for the synthesis and tele-substitution reactions with C-nucleophiles

A simple procedure was developed for the synthesis of 1,2,4-triazines and their 4-oxides containing the ClCH₂, Cl₂CH, or CCl₃ group at position 3 by cyclization of 2-aryl-2-hydrazono-1-oximinoethanes with the corresponding chloroacetonitriles. The reaction pathway depends on the number of halogen atoms in the acetonitrile used. The reactions with trichloroacetonitrile, monochloroacetonitrile, and dichloroacetonitrile afford 3-trichloromethyl-1,2,4-triazines, 3-chloromethyl-1,2,4-triazine 4-oxides, and a mixture of the corresponding dichloromethyltriazines and their 4-oxides, respectively. The reactions of 3-trichloromethyl-1,2,4-triazines with indoles and phenols are accompanied by tele-substitution with elimination of halogen from the trichloromethyl group to give 5-indolyl- (or 5-hydroxyphenyl)-3-dichloromethyl-1,2,4-triazines.     

Study of the Products of Iodocyclization of 4-Allyl-5-phenyl-1,2,4-triazole-3-thione

The interaction of 4-allyl-5-phenyl-1,2,4-triazole-3-thione with iodine proceeds with the formation of a mixture of 6-iodomethyl-3-phenyl-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole and 6-iodo-3-phenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine. The structures of the cyclization products obtained were established on the basis of the ¹H NMR spectra of their dehydroiodinated derivatives. 6-Methyl-3-phenylthiazolo[2,3-c]-1,2,4-triazole, 3-phenyl-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine, and 3-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3-thiazine are formed on eliminating HI from the cyclization products.     

An Energetic Triazolo‐1,2,4‐Triazine and its N‐Oxide

The reaction of 3‐amino‐5‐nitro‐1,2,4‐triazole with nitrous acid produces the corresponding diazonium salt. When the diazonium salt is treated with nitroacetonitrile, a subsequent condensation and cyclization reaction occurres to produced 4‐amino‐3,7‐dinitrotriazolo‐[5,1‐c][1,2,4] triazine (DPX‐26). X‐ray crystallographic analysis shows that the DPX‐26 has a density of 1.86 g cm^?3, while it is calculated to have a heat of formation of 398.3 kJ mol^?1. DPX‐26 is predicted to approach the explosive performance of RDX but displays significantly better safety properties. Oxidation of DPX‐26 using hypofluorous acid produces 4‐amino‐3,7‐dinitrotriazolo‐[5,1‐c][1,2,4] triazine 4‐oxide (DPX‐27), which is also predicted to be a high‐performance material with enhanced safety properties.