Syntheses of substituted 1-(2-phenethyl)pyrazoles

Alkylation of 3-methylpyrazole with 2-phenethyl p-toluenesulfonate gave 3-methyl-1-(2-phenethyl)pyrazole ( 2a ) and 5-methyl-1-(2-phenethyl)pyrazole ( 3a ) in low yield. Reaction of 5-chloro-1,3-dimethylpyrazole ( 5 ) with substituted-benzaldehydes afforded compounds 7 . Reduction of the latter afforded compound 2 in high yield. Compound 3 could be obtained from the reaction of substituted-2-(phenethyl)hydrazine hydrochloride 9 with acetoacetaldehyde dimethylacetal in moderate yield.     

An efficient synthesis of the novel triazoloquinazoline adenosine antagonist,CGS 15943

An efficient synthesis of the novel triazoloquinazoline adenosine antagonist, CGS 15943, is reported in five steps in approximately 50% overall yield. A key reaction in the synthetic sequence is the double cyclization of an N-(substituted-2-cyanophenyl)carbamate with a carboxylic acid hydrazide to afford a [1,2,4]triazolo-[1,5-c]quinazolin-5(6H)-one in high yield without either a Dimroth or “translocative” rearrangement occurring. Another key reaction is the condensation of a 2-(1H-1,2,4-triazol-5-yl)benzenamine with cyanamide under acidic conditions to prepare a guanidine.     

Die Acylierung von 5-Amino-1 H-1, 2, 4-triazolen. Eine 13C-NMR.-Studie

The Acylation of 5-Amino-1 H-1,2,4-triazoles. A ¹³C-NMR. Study The acylation of 3-substituted-5-amino-1 H-1,2,4-triazoles (1) with methyl chloroformate or dimethylcarbamoyl chloride yielded mainly 1-acyl-5-amino-1,2,4-triazoles ( 2 and 3 ). Acylation of 3-methyl-, 3-methoxy- and 3-methylthio-5-amino-1 H-1,2,4-triazole ( 1b , 1c and 1d ) with methyl chloroformate gave up to 10% of the 1-acyl-3-amino-1,2,4-triazoles. For the unsubstituted 5-amino-1,2,4-triazole (1a) , a (1:1)-mixture of the 3- and 5-isomers 2a and 4 was obtained in dioxane in the presence of triethylamine. No 4-acylated product was detected in contrast to earlier reports. The structures of the reaction products were determined with the aid of proton coupled ¹³C-NMR. spectra using the corresponding N-methyl-1,2,4-triazoles as reference compounds.     

On Triazoles. XIII. The reaction of 5-benzalimino-1,2,4-triazoles with substituted acetyl chlorides

The reaction of Schiff bases prepared from 1- and 2-substituted-5-amino-1,2,4-triazoles with phenoxyacetyl chlorides in the presence of triethylamine and a mixture of phosphorus oxychloride and dichloroacetic acid in dimethylformamide to yield β-lactam 4 , a dihydro-1,2,4-triazolo[4,3-a]pyrimidine-5(1H)-one 5, a 1,2,4-triazolo[1,5-a]pyrimidin-5(3H)-one 9 and the corresponding 1,2,4-triazolo[4,3-a]pyrimidine-5(1H)-one 10 derivatives was studied.     

On triazoles. I. The reaction of N-cyanocarbonimidodithioic acid diesters with hydrazines

The reaction of N-cyanocarbonimidodithioic acid di(alkyl and aralkyl)esters with different alkyl-, aralkyl- and arylhydrazines to yield 1-substituted-3-R-thio-5-amino-1H-1,2,4-triazoles ( 3 ) and 2-substituted-3-R-thio-5-amino-2H-1,2,4-triazoles ( 4 ) was studied. Isolation of the different types of isomeric pairs of 3 and 4 helped to prove the structure of products obtained which made possible correction of some confusion in the literature. The 3 (R = H) tautomeric structure of the non-substituted derivatives was supported by comparison of their uv and cmr spectra with those of the alkylated and aralkylated derivatives 3 and 4 , respectively, again correcting confusion in the literature. An hplc determination of the ratio of products 3 and 4 formed in the above reactions with different hydrazines made it possible to prove the mechanism of the reaction.     

Reactions of 3-amino-1,2,4-triazoles with cinnamic aldehydes

The reaction of 3-amino- and 3-amino-5-methylthio-1,2,4-triazoles with cinnamaldehyde takes two directions to form mixtures of 5-[N-(3-phenylpropenylideneamino)]-1H-1,2,4-triazoles and 5-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-7-ols.     

Fluorinated [1,2,4]triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidines and [1,2,4]triazolo[5,1-<Emphasis Type="Italic">c</Emphasis>][1,2,4]triazines*

The reaction of 3-R-5-amino-1,2,4-triazoles with the ethyl ester of 2-fluoroacetoacetic acid gave 2-R-fluoro[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-ones. The reaction of a 3-R-1,2,4-triazolyl-5-diazonium salt with the ethyl ester of 2-fluoroacetoacetic acid and subsequent cyclization of the triazolylhydrazones lead to 7-R-3-fluoro[1,2,4]triazolo[5,1-c][1,2,4]triazin-4(1H)-ones.     

Syntheses of substituted-1,2,4-triazoles

Starting from the readily available 3-phenylpropionitrile, 3-(or 5-)(2-phenethyl)-1,2,4-triazole 3 was prepared. Reaction of compounds 3 with diazomethane afforded 1-methyl-3-(2-phenethyl)-1,2,4-triazole (4) and 1-methyl-5-(2-phenethyl)-1,2,4-triazole (5) . Reaction of compound 3 with methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride afforded only one of the expected isomer; namely compounds 6 , 7 and 8 respectively.     

On triazoles XVI. The reaction of 5-amino-1,2,4-triazoles with β- and γ-oxo esters. A novel N-carbonylation reaction

5-Amino-1,2,4-triazoles reacted with alifatic β-oxo-esters to yield besides the unexpected 1,2,4-triazolo-[1,5-a]-1,3,5-benzotriazepin-5-one derivative 7 either the corresponding esters 5 and 6 or a 1:2 condensation product 8. To the contrary alicyclic and heterocyclic β-oxo-esters formed in the above reaction only derivatives 7. The proposed mechanism of the formation of 7 involving a novel N-carbonylation reaction was proved by the isolation of the by-products and the intermediate of the reaction. Repeating the above reaction with a γ-oxo-ester, namely the ethyl levulinate, derivatives 17 and 18 , respectively, representing two new ring systems were obtained.     

A study on ester formylhydrazones

A series of ester formylhydrazones 2 were synthesized from the reaction of alkyl imidate hydrochlorides 1 with formylhydrazine. Treatment of 2 with hydrazine hydrate, ethyl carbazate and tert-butyl carbazate led to the formation of 3-alkyl-4-amino-, 3-alkyl-4-ethoxycarbonylamino- and 3-alkyl-4-tert-butoxycar-bonylamino-4H-1,2,4-triazoles 3–5 , respectively. Reaction of compounds 2 with formylhydrazine gave N,N'-diformylhydrazine 6 . Compounds 2 were reacted with 2,5-dimethoxytetrahydrofuran to afford 3-alkyl-4-(1H-pyrrol-1-yl)-4H-1,2,4-triazoles 8 .     

Notiz über die Reaktion von Methylhydrazin mit N-Cyano-azomethinen. Abhängigkeit des Reaktionsverlaufs von der Natur der Abgangsgruppe

The reaction of methylhydrazine with N-cyanoazomethines 1 containing a thioalkyl leaving group yields the 3-amino-1,2,4-triazole derivatives 2 , whereas the N-cyanoazomethines 1 containing an alkoxy leaving group give the isomeric 5-amino-1,2,4-triazoles 3. The yields are excellent and the position selectivity is high. The structures of the 1,2,4-triazole derivatives were determined with the aid of proton-coupled ¹³C-NMR. spectra.     

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.     

Synthesis of 1-aryl-3-trifluoromethyl-5-methylthio-1,2,4-triazoles from 2-arylmethylisothiosemicarbazides and 1,1,1-trichloro-3,3,3-trifluoroacetone

The reaction of 1,1,1-trichloro-3,3,3-trifluoroacetone with S-methyl-2-arylisothiosemicarbazides affords an unusual synthesis of 1-aryl-3-trifluoromethyl-5-methylthio-1,2,4-triazoles from which 1-aryl-3-trifluoromethyl-1,2,4(4H)-triazole-5-ones are obtained on treatment with base.     

On triazoles. VIII The reaction of 5-amino-1,2,4-triazoles with ethyl 2-cyano-3-ethoxyacrylate and 2-cyano-3-ethoxyacrylonitrile

The reaction of different 5-amino-3-Q-1H-1,2,4-triazoles 1 with ethyl 2-cyano-3-ethoxyacrylate ( 5a ) and 2-cyano-3-ethoxyacrylonitrile ( 5b ) to yield either the a type 5-amino-, or the b type 7-amino-1,2,4-triazolo[1,5-a]-pyrimidine derivatives 6–10 was studied. The structure of compounds 6 and 9 was proved by their degradation to the corresponding derivatives 17a and 18a , respectively, through intermediates 11a, 12a, 13a, 14a, 15a and 16a , respectively. The structure of derivatives 7, 8 and 10 was proved on the basis of the analogy of their uv spectra with those of 6a and 9a , respectively. The isolation of the intermediates 19 and 20 helped to prove the mechanism of the reactions leading to the formation of 6a and 9a , respectively. In the reaction of the N-substituted 5-amino-1,2,4-triazoles with 5a the expected condensed ring products were not formed. Instead the aminoacrylates 22 and 24 were obtained. The “Z”-“E” isomeric structure of derivatives 19, 20, 22 and 24 was proved with the help of their pmr spectra. The “Z” isomeric structure of the thermodynamically stabile 22 was corroborated with the help of its proton coupled cmr spectra, too.     

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 .     

Heterocycles from N-benzoylthioamides and dinucleophilic reagents

N-Benzoylthioamides ( 1 ) react with hydrazines and hydroxylamine to form 1H-1,2,4-triazoles and 1,2,4-oxadiazoles, respectively. A similar treatment of the S-methyl derivatives of 1 with amidines leads to 1,3,5-triazines. Ethyl ZV-benzoylthiocarbamate undergoes analogous reactions to yield the corresponding ethoxyheterocycles.     

Synthesis and photochemical degradation of N-arylmethyl derivatives of the herbicide 3-amino-1,2,4-triazole

Reaction of an arylmethyl halide with 3-amino-1,2,4-triazole ( 1 ) allows the preparation of the three N-aryl-methyl derivatives of 1 bearing the substituent on the heterocyclic nitrogen atoms. In basic medium (methoxide anion in DMF or methanol, or in benzene by phase transfer catalysis), the isomers 3 and 5 substituted at N-1 and N-2 respectively are obtained, while the isomer 4 is isolated from neutral medium (DMF). The isomers 3 and 4 may be also prepared by cyclization of appropriate formylguanidinium derivatives. 3-Arylmethylamino-1,2,4-triazoles 2 may be obtained through reaction of 3-chloro-1,2,4-triazole ( 6 ) with arylmethylamines. Photolysis of the N-arylmethyl-3-amino-1,2,4-triazoles 2-5 in methanol or water-methanol mixture, induces homolytic and heterolytic cleavage of the arylmethyl-C-N bond giving rise to 3-amino-1,2,4-triazole ( 1 ). Thus, compounds 2-5 with arylmethyl groups able to absorb solar light may be considered as potential photoactivatable herbicides.     

Reaction of 1,3,4-thiadiazolo and 1,3,4-triazolo[3,2-c]quinazoline derivatives with active methylene compounds

Fused quinazoline derivatives 1 and 4 react with active methylene compounds and depending on the annelated five-membered ring, two types of transformations have been observed. The 1,3,4-thiadiazolo[3,2-c]quinazoline 1 , underwent the five-membered ring opening reaction to afford the 3,4-dihydroquinazolines 2 in good yields, whereas the 1,3,4-triazolo[3,2-c]quinazoline 4 underwent nucleophilic attack at 2-position of the quinazoline ring to yield the corresponding 1,2,4-triazoles 5 .     

Synthesis of heterocycles. Part VI. Synthesis and antimicrobial activity of some 4-amino-5-aryl-1,2,4-triazole-3-thiones and their derivatives

4-Amino-5-aryi-1,2,4-triazole-3-thiones I react with acid chlorides to yield 4-acylamino-5-aryl-1,2,4-triazole-3-thiones II. Compounds I also react with methylene iodide, chloroacetonitrile and methyl bromoacetate to give bis-(4-amino-5-aryl-1,2,4-triazol-3-ylthio)methanes III, 4-amino-5-aryl-3-cyanomethylthio-1,2,4-triazoles IV and 4-amino-5-aryl-3-carbomethoxymethylthio-1,2,4-triazoles V, respectively. Compounds V react with hydrazine hydrate to give the corresponding acid hydrazides VI which in turn condenses with acid chlorides and aldehydes to afford respectively 1-[(4-amino-5-aryl-1,2,4-triazol-3-ylthio)acetyl]-2-aroylhydrazines VII and aryl methylene (4-amino-5-aryl-1,2,4-triazol-3-ylthio)acethydrazones VIII. The antimicrobial activities of the above compounds were screened against different strains of bacteria and fungi.     

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.