An efficient one-pot expeditious synthesis of 3-phenyl-1-(6-phenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazin-3-yl)-1H-pyrazol-5-amines via multicomponent approach

An efficient synthesis of 3-phenyl-1-(6-phenyl-7H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazin-3-yl)-1H-pyrazol-5-amines was accomplished by a simple, atom-economical, and multicomponent approach. Reaction of 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol with various phenacyl bromides and benzoylacetonitriles in ethanol and catalytic amount of acetic acid afforded the titled compounds. The structures of newly synthesized compounds were confirmed by their analytical and spectral (IR, ¹H-NMR, ¹³C-NMR, and Mass) data.     

Synthesis and pharmacological evaluation of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles: A condensed bridgehead nitrogen heterocyclic system

A series of 3-diphenylmethyl-6-substituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives (4a–j and 5a–d) were synthesized by condensation of 4-amino-5-diphenylmethyl-4H-1,2,4-triazole-3-thiol with various substituted aromatic acids and aryl/alkyl-isothiocyanates. The structures of synthesized compounds were characterized by elemental analysis, IR, ¹H NMR, ¹³C NMR and mass spectroscopic studies. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen were screened for their analgesic, ulcerogenic, lipid peroxidation and hepatotoxic effects. Compounds 6-(4-chlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (4a) and 6-(2,4-dichlorophenyl)-3-diphenylmethyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole(4c) emerged as the most active compounds of the series and were moderately more potent than the standard drug ibuprofen.     

Synthesis of 3-Alkyl-6-aryl(arylamino)-7H-[1,2,4]triazolo- [3,4-b][1,3,4]thiadiazines

Starting from 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols and substituted chloroacetanilides, the corresponding (5-alkyl-4-amino-4H-1,2,4-triazol-3-ylsulfanyl)acetanilides were synthesized. The products underwent intramolecular cyclization in boiling phosphoryl chloride to afford 3-alkyl-6-arylamino-7H-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazines. 3-Alkyl-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hydrobromides were obtained by reaction of 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols with substituted phenacyl bromides.     

Facile synthesis of 6-hetaryl[1,2,4]triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazoles and 7-hetaryl[1,3,4]thiadiazolo[2,3-<Emphasis Type="Italic">c</Emphasis>][1,2,4]triazines with fungicidal activity

Condensation of 4-amino-4H-1,2,4-triazole-3-thiol and 4-amino-6-methyl-3-sulfanyl-1,2,4-triazin-5(4H)-one with ethyl cyanoacetate gave ethyl [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylacetate and ethyl 3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-ylacetate, respectively. Reactions of the condensation products with 1,3-diphenylprop-2-en-1-one, aromatic aldehydes, and carbon disulfide or N,N-dimethylformamide dimethyl acetal (followed by treatment with hydrazine hydrate) gave the corresponding 6-hetaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and 7-hetaryl-3-methyl-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-ones. Preliminary tests revealed fungicidal activity of the pyrazolyl-substituted derivatives. Published in Russian in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 12, pp. 1813–1818. The text was submitted by the authors in English.     

Intramolecular cyclization of 4-amino-3-alkylsulfanyl-1,2,4-triazoles as a method for annelation of thiadiazine and thiadiazole rings

4-Amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiols reacted with N-substituted isatins to give 2-oxo-3-[5-(pyridin-4-yl)-3-sulfanyl-4H-1,2,4-triazole-4-ylimino]-2,3-dihydro-1H-indoles which were treated with phenacyl bromides to obtain the corresponding S-phenacyl derivatives. The latter underwent base-catalyzed intramolecular cyclization with formation of 6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines spiro-fused to 2-oxo-2,3-dihydro-1H-indole fragment at C³. Analogous cyclization of 2,6-di-tert-butyl-4-[5-hetaryl-3-(2-aryl-2-oxoethylsulfanyl)-4H-1,2,4-triazole-4-ylimino]cyclohexa-2,5-dienones involved the imino nitrogen atom to produce the corresponding 6-aroyl-5-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hetaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles.     

Synthesis of heterocycles based on arylation products of unsaturated compounds: XVII. Arylation of 2-acetylfuran and synthesis of 3-R-6-(5-aryl-2-furyl)-7<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazines

Reaction of 2-acetylfuran with arenediazonium chlorides under Meerwein reaction conditions led to the formation of 5-aryl-2-acetylfurans. The bromination of these compounds gave 2-bromo-1-(5-aryl-2-furyl)-ethanones that reacted with 4-amino-4H-5-R-1,2,4-triazole-3-thiols to form 3-R-6-(5-aryl-2-furyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines.     

Ultrasound-assisted,one-pot,three-component synthesis and antibacterial activities of novel indole derivatives containing 1,3,4-oxadiazole and 1,2,4-triazole moieties

Thirteen novel indole derivatives were efficiently synthesized through ultrasound irradiation by using 4-amino-5-(1H-indol-3-yl)-4H-[1,2,4]triazole-3-thiol (8) and 2-mercapto-5-substituted-1,3,4-oxadiazoles (5a–m). Compared with conventional and microwave methods, yields increased to 82–93%, and reaction times decreased to 15–35 min. The structures of these novel compounds were characterized by spectral data and elemental analysis. Two out of the synthesized compounds (10f and 10l) exhibited excellent activity against Staphylococcus aureus and Escherichia coli, and thus warrant further research.     

Synthesis of a new class of azathia crown macrocycles containing two 1,2,4-triazole or two 1,3,4-thiadiazole rings as subunits

A series of new 1,2/1,3-bis[o-(N-methylidenamino-5-aryl-3-thiol-4H-1,2,4-triazole-4-yl)phenoxy]alkane derivatives 3a-d and bis[o-(N-methylidenamino-2-thiol-1,3,4-thiadiazole-5-yl)phenoxy]alkanes 6a-c were prepared by condensation of 4-amino-5-(aroyl)-4H-1,2,4-triazole-3-thiols 2a-b or 2-amino-5-mercapto-1,3,4-thiadiazole with bis-aldehydes 1a-c. Further reaction of compounds 3a-d and 6a-c with dibromoalkanes afforded the new macrocycles 5a-f and 8a-d. The cyclization does not require high dilution techniques and provides the expected azathia macrocycles in good yields, ranging from 55% to 68%.     

C–H Arylation using acyl thiourea ligands: Applications in the synthesis of 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

Synthesis of a series of new 3,6-diaryl-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles(5a–o) was achieved by phophine free, C–H arylative cross-coupling of 6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles(4a–o)with suitably substituted iodoanilines using 1-(2-naphthoyl)-3-(4-bromophenyl)thiourea as a ligand.The requisite triazolothiadiazoles(4a–o) were obtained by the condensation of 4-amino-1,2,4-triazole-3-thiol(3) with suitably substituted aromatic acids in the presence of phosphoryl chloride.     

Design and synthesis of novel quinoline derivatives bearing oxadiazole,isoxazoline, triazolothiadiazole,triazolothiadiazine, and piperazine moieties

A new series of 2,3-disubstituted quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2-chloroquinoline-3-carbaldehyde 1 , which was transformed to 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 by reaction with 4-phenylpiperazine in DMF-containing anhydrous K₂CO₃; then, compound 2 was oxidized by iodine in methanol, and methyl 2-(4-phenylpiperazin-1-yl)quinoline-3-carboxylate 3 was synthesized. The key intermediate 4 , 4-amino-5-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 6a-c , respectively. Moreover, compound 2 condensed with o-phenylenediamine to give 2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimidazole 7 . Interaction of 7 and 2-chloromethyl-5-aryl-1,3,4-oxadiazoles in the presence of K₂CO₃ led to the title compounds 8a-c . Furthermore, 4,5-dihydroisoxazoline derivatives 9a-c were obtained by the reaction of readily accessible starting materials including 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 , 1-phenyl-2-(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et₃N. The hydrazone intermediates 10a-c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3-acetyl-5-aryl-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazoles 11a-c . Structures of these compounds were established by their elemental analysis, IR, ¹H NMR, and mass spectral data.     

A convenient,rapid microwave assisted synthesis of some novel 3-[(4-chloro-3-methylphenoxy)methyl]-6-aryl-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles using acidic alumina

A facile synthesis of 3-[(4-chloro-3-methylphenoxy)methyl]-6-aryl-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 3a–n has been achieved by microwave promoted condensation of 3-mercapto-4-amino-5-[(4-chloro-3-methylphenoxy)methyl]-4H-1,2,4-triazole 1 with various aromatic aldehydes 2a–n in presence of catalytic amount of p-TsOH (para-toluenesulphonic acid). The structures of 3a–n are supported by IR and ¹H and ¹³C NMR spectral data.     

Synthesis of novel heterocycles using 1,2,3-triazole-4-carbohydrazides as precursors

Herein, we report the synthesis of various heterocyclic ring systems containing 1,2,3-triazole from the reactions of acid hydrazides and commercially available reagents, using efficient and simple procedures. Reactions of certain 1,2,3-triazole-4-carbohydrazides and α-bromoketones in boiling ethanol afforded the corresponding hydrazones rather than the expected triazines. The hydrazones could also be synthesized in 85-90% yield via an alternative pathway that involved the reaction of 1,2,3-triazole-4-carbohydrazides and 4-acetyl-1,2,3-triazoles in boiling ethanol containing glacial acetic acid. Reaction of one of the 4-carbohydrazides with carbon disulfide, followed by the reaction with hydrazine hydrate, gave 4H-1,2,4-triazole-3-thiol in 73% yield, which further reacted with other α-bromoketones in boiling ethanol to afford 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines in 82-84% yields. Additionally, reactions of certain carbohydrazides with ethyl 2-cyano-3,3-bis(methylthio)acrylate gave 1-aryl-1H-1,2,3-triazole-4-carbohydrazides rather than the expected 1H-pyrazole-4-carboxylates.     

Synthesis of 1,2,4-triazole, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives of benzotriazole

A novel series of 1-(1-carbonylmethyl-1H-benzotriazole) thiosemicarbazides 3a-e was synthesized and then cyclized with sodium hydroxide to afford 1-(4-substituted-4H-1,2,4-triazole-3-thion-5-yl)methyl-1H-benzotriazoles 4a-e , which were alkylated with ethyl iodide to l-(3-ethylthio-4-substituted-4H-1,2,4-triazol-5-yl)-methyl-1H-benzotriazoles 5b-e . The reaction of 1H-benzotriazol-1-acetic acid hydrazide ( 2 ) with carbon disulphide and potassium hydroxide followed by hydrazine hydrate gave 1-(4-amino-4H-1,2,4-triazole-3-thion-5-yl)methyl-1H-benzotriazole ( 6 ). Its subsequent condensation with carboxylic acids in the presence of phosphorus oxychloride or with phenacyl bromides afforded two series of fused heterocycles namely; 6-substituted-3-[1-(1H-benzotriazole)methyl]-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 7a-e and 6-substituted phenyl-3-[1-(1H-benzotriazole)methyl]-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 8a-e respectively. The structure of the newly synthesized compounds was elucidated by elemental analyses, ir and nmr spectra.     

Reaction of azolethiones with diacetylene

Reactions of 2,3-dihydro-1H-benzimidazole-2-thione, 2,3-dihydro-1H-1,2,4-triazole-3-thione, 4-amino-5-phenyl-3,4-dihydro-2H-1,2,4-triazole, and 6-aminopurine-2-thiol with diacetylene in DMSO gave the corresponding 1-(azolylsulfanyl)but-1-en-3-ynes having Z configuration of the double bond.     

The efficient synthesis of 3-[6-(substituted)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl]-1H-indazole

This study presents an efficient synthesis of 3-[6-(substituted-phenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-yl]-1H-indazole via dehydrative condensation with cyclization of 4-amino-5-(1H-indazol-3-yl)-4H-[1,2,4]triazole-3-thiol and fluorinated or nonfluorinated carboxylic acids in presence of phosphorous oxychloride. The multistep reaction pathway proceeds through different compounds. Present synthesis has the advantages of easily accessible starting materials, convenient synthesis, simple reaction condition, wider substrate scope, and higher yield (75% to 90% isolated).     

Facile synthesis of some novel triazolo[3,4-b]thiadiazines and triazolo[4,3-b]tetrazines

4-Amino-5-ethyl-4H-1,2,4-triazole-3-thiol was used as a key intermediate for the synthesis of triazolo[3,4-b][1,3,4]thiadiazines, triazolo[4,3-b][1,2,4,5]tetrazines and Schiff’s base via reactions with various hydrazonoyl halides and salicyaldehyde, respectively. Moreover triazolyl-N-N′-triazole derivatives were prepared from reaction of Schiff’s base with various hydrazonoyl halides. The structures of all the newly synthesized heterocyclic compounds were established by considering elemental analysis and spectral data.     

Synthesis of heterocycles from arylation products of unsaturated compounds: XVIII. 5-Arylfuran-2-carboxylic acids and their application in the synthesis of 1,2,4-thiadiazole, 1,3,4-oxadiazole,and [1,2,4]triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazole derivatives

Arylation of furan-2-carboxylic acid or its methyl ester with arenediazonium chlorides in the presence of copper(II) chloride gave the corresponding 5-arylfuran-2-carboxylic acids or methyl 5-arylfuran-2-carboxylates. 5-Arylfuran-2-carbonyl chlorides reacted with potassium thiocyanate and then with 5-methyl-1,2-oxazol-3-amine to give 5-aryl-N-[3-(2-oxopropyl)-1,2,4-thiadiazol-5-yl]furan-2-carboxamides as a result of recyclization of intermediate isoxazolylthiourea derivatives. The reactions of 5-arylfuran-2-carbonyl chlorides with 5-(2-furyl)-1H-tetrazole involved opening of the tetrazole ring with elimination of nitrogen molecule and led to the formation of 2-(5-arylfuran-2-yl)-5-(2-furyl)-1,3,4-oxadiazoles. 3-Substituted 6-(5-arylfuran-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles were obtained by condensation of 5-arylfuran-2-carboxylic acids with 5-substituted 4-amino-4H-1,2,4-triazole-3-thiols in phosphoryl chloride.     

6-Arylamino-3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines: Novel N-Arylamidine Structures

We propose a method for obtaining derivatives of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine by alkylation of 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol by substituted -chloroacetanilides, followed by cyclization of the intermediate by phosphorus oxychloride.     

Pyrolytic desulfurization ring contraction of condensed thiadiazines as a general route towards pyrazoloazines and pyrazoloazoles with a bridgehead (ring junction) nitrogen atom

Pyrolytic conversion of [1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, [1,3,4]thiadiazino[2,3-b]quinazolin-10-ones and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines into their corresponding pyrazolo[5,1-c][1,2,4]triazin-4-ones, pyrazolo[4,3-b]quinazolin-9-ones and pyrazolo[5,1-b][1,2,4]triazoles via desulfurization ring contraction is described. The starting condensed 1,3,4-thiadiazines were prepared from the corresponding readily available 4-amino-3-thioxo-1,2,4-triazin-5(4H)-ones, 3-amino-2,3-dihydro-2-thioxoquinazolin-4(1H)-one and 4-amino-3(2H)-thioxo-1,2,4-triazoles upon reaction with the appropriate α-haloketones in two steps, or directly in one step in ethylpyridinium tetrafluoroborate (ionic liquid, IL).     

Synthesis of new 4-amino-5-(1,4-benzodioxan-2-yl)-4<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazole-3-thiol derivatives

Acylation and cyclization reactions of 4-amino-5-(1,4-benzodioxan-2-yl)-4H-1,2,4-triazole-3-thiol were studied. Acylation of the title compound with substituted benzoyl chlorides gave the corresponding amides, whereas its reactions with substituted benzoic acids in the presence of POCl3 were accompanied by cyclization with formation of triazolothiadiazoles containing a 1,4-benzodioxane substituent. 4-Amino-5-(1,4-benzodioxan-2-yl)-4H-1,2,4-triazole-3-thiol reacted with substituted benzaldehydes to afford the corresponding Schiff bases, and its alkylation with chloroacetic acid in ethanol in the presence of sodium acetate gave S-ethoxycarbonylmethyl derivative.