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.     

Syntheses of substituted-oxazolo-1,3,4-thiadiazoles, 1,3,4-oxadiazoles,and 1,2,4-triazoles

Starting from readily available methyl 5-methyloxazole-4-carboxylate ( 1 ) and 4-methyl-5-oxazolylcar-boxylic acid hydrazide ( 11 ) the title compounds were prepared. The reaction of compound 1 with hydrazine hydrate afforded the corresponding hydrazide 2 . The reaction of compound 2 with formic acid yielded 1-formyl-2-(5-methyloxazole-4-carboxyl)hydrazine ( 3 ). Refluxing of the latter with phosphorus pentasulfide in xylene gave compound 5 in 62% yield. The reaction of compound 3 with phosphorus pentoxide afforded compound 4 . Starting from hydrazide 11 , compounds 13 and 14 were prepared similarly. Reaction of compound 2 with substituted isothiocyanate yielded compound 9 which was cyclized in basic medium to 4-alkyl-5-(5-methyl-4-oxazolyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione ( 10 ). The isomer 19 was prepared similarly. Methylation and subsequent oxidation of compound 19 gave compound 21 . Reaction of the acid 7 with thiosemicarbazide in the presence of phosphorus oxychloride gave 2-amino-5-(5-methyl-4-oxazolyl)1,3,4-thiadiazole ( 8 ). 2-Amino-5-(4-methyl-5-oxazolyl)-1,3,4-thiadiazole ( 17 ) was prepared from acyl chloride 15 by the usual method.     

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.     

Synthesis and antimicrobial evaluation of some 1,3-thiazole, 1,3,4-thiadiazole, 1,2,4-triazole, and 1,2,4-triazolo[3,4-b][1,3,4]-thiadiazine derivatives including a 5-(benzofuran-2-yl)-1-phenylpyrazole moiety

Abstract  

Potassium hydrazinecarbodithioate were prepared by treatment of acid hydrazides with carbon disulfide in the presence of potassium hydroxide. Reaction of this potassium salt with hydrazine hydrate, phenacyl bromide, or hydrazonoyl chlorides afforded 1,2,4-triazole, 1,3-thiazole, and 1,3,4-thiadiazoles. Reaction of 1,2,4-triazole with phenacyl bromide or hydrazonoyl chlorides afforded the corresponding 1,2,4-triazolo[3,4-b][1, 3, 4]-thiadiazines. All these new compounds were screened for antibacterial and antifungal activity. Some had promising activity.     

Synthesis of 1,2,4-triazole and thiazole analogs of ketoconazole

The synthesis of 1,2,4-triazole and thiazole analogs of ketoconazole is described in which one of the α azole ring carbons is linked to C-2 of the ketal by means of a three methylene tether. Lithiation of 1-methyl-1,2,4-triazole and thiazole and subsequent alkylation with 2-(2,4-dichlorophenyl)-2-(3-iodopropyl)-1,3-dioxolane produced, after an aqueous acidic workup, 2,4-dichlorophenyl 3-[5-(1-methyl-1,2,4-triazolyl) and 2-thiazolyl]propyl ketones, respectively. Ketalization with glycerol furnished the corresponding diastereomeric pairs of cis and trans 1,3- dioxolanes. The reaction of 2,4-dichlorophenyl 3-[5-(1-methyl-1,2,4-triazolyl)]propyl ketone with 3-mercapto-1,2-propanediol produced the corresponding diastereomeric cis and trans hydroxymethyl 1,3-oxathiolanes. The diastereomeric racemates were separated by column chromatography and their stereochemistry established by nOe nmr experiments. Some of these racemic cis ketal alcohols were converted by benzyl bromide to the corresponding benzyl ethers. Several of these racemic cis-ketals were reacted, first with methanesulfonyl chloride, then with 1-acetyl-4-(4-hydroxyphenyl)piperazine, to furnish the title compounds.     

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.     

Synthèse de nouvelles 7 (5)-〚benzimidazol-2-yl〛méthyl-2 (7)-méthyl-1,2,4-triazolo〚1,5-a〛(〚4,3-a〛)pyrimidines

Condensation of 4-hydroxy-6-methyl pyran-2-one 2 with 3-amino-1,2,4-triazole 1 in refluxing alcohol afforded 5-alkoxycarbonylmethyl-7-methyl-1,2,4-triazolo〚1,5-a〛pyrimidines and their isomers 5-alkoxycarbonylmethyl-7-methyl-1,2,4-triazolo〚4,3,-a〛pyrimidines 4. Reaction of hydrazine hydrate with compounds 4 and 5 yielded the corresponding hydrazid acids 6 and 7. Condensation of o-phenylenediamines 8 with esters 3(4) in refluxing xylol or with hydrazid acid 6(7) by melting reagents afforded 7(5)-〚benzimidazol-2-yl〛methyl-5(7)methyl-1,2,4-triazolo〚1,5-a〛(〚4,3-a〛)pyrimidines 9(10). The structures of the annealed compounds have been elucidated by their ¹H, ¹³C NMR and Mass Spectroscopy data.     

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.     

A new method for the synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines

The reaction of 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 4 with o-chlorobenzenediazonium chloride gave 3-[α-(o-chlorophenylhydrazono)-2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethyl]-2-oxo-1,2-dihydroquinoxaline 6 , whose refluxing in phosphoryl chloride/pyridine afforded 1-(o-chlorophenyl)-3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 7. The reactions of 6 and 7 with nitrous acid resulted in sulfur extrusion to provide 1-(o-chlorophenyl)-3-(4-methyl-4H-1,2,4-triazol-5-yl)1H-pyrazolo[3,4-b]quinoxaline 8 and 3-[α-(o-chlorophenylhydrazono)-4-methyl-4H-1,2,4-triazol-5-ylraethyl]-2-oxo-1,2-dihydroquinoxaline 9 , respectively.     

Synthesis and antimicrobial evaluation of some 1,3-thiazole, 1,3,4-thiadiazole, 1,2,4-triazole,and 1,2,4-triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]-thiadiazine derivatives including a 5-(benzofuran-2-yl)-1-phenylpyrazole moiety

Abstract  Potassium hydrazinecarbodithioate were prepared by treatment of acid hydrazides with carbon disulfide in the presence of potassium hydroxide. Reaction of this potassium salt with hydrazine hydrate, phenacyl bromide, or hydrazonoyl chlorides afforded 1,2,4-triazole, 1,3-thiazole, and 1,3,4-thiadiazoles. Reaction of 1,2,4-triazole with phenacyl bromide or hydrazonoyl chlorides afforded the corresponding 1,2,4-triazolo[3,4-b][1, 3, 4]-thiadiazines. All these new compounds were screened for antibacterial and antifungal activity. Some had promising activity. Graphical abstract        

Syntheses of substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines

Reaction of N-methyl-2-amino-4-nitroaniline ( 1 ) with lactic acid afforded 2-(1-hydroxyethyl)-1-methyl-5-nitrobenzimidazole ( 2 ). Oxidation of compound 2 with chromic acid in acetic acid gave 2-acetyl-1-methyl-5-nitrobenzimidazole ( 3 ). Reaction of compound 3 with substituted 2-aminobenzaldehyde ( 4 ) under basic conditions yielded substituted 2-(1-methyl-5-nitro-2-benzimidazolyl)quinolines ( 5 ). Condensation and cyclization of o-aminoacetophenone (or substituted o-aminobenzophenones) with compound 3 under acetic condition afforded compound 7 . Condensation and cyclization of compound 1 with indole-3-carboxaldehyde ( 11 ) in ethanol in the presence of excess nitrobenzene gave 3-(1-methyl-5-nitro-2-benzimidazolyl)indole ( 12 ).     

3－苄基－6－（1－氨基烃基）－1，2，4－三唑并[3,4-b]-1,3,4-噻二唑的合成与波谱表征

3－苄基－4－氨基－5－巯基－1，2，4－三唑与氨基酸在三氯氧磷存在下反应 ，合成3－苄基－6－（1－氨基烃基）－1，2，4－三唑并[3,4-b]－1，3，4－噻二 唑，其结构经元素分析、红外光谱、核磁共振氢谱、碳谱、质谱等确证。这是稠杂 环接氨基酸残基的首次报道。     

Reactions of 1,2-Dimethyl-5-nitroimidazole,novel methods of conversion of the 2-Methyl group to a nitrile

1, 2-Dimethyl-5-nitroimidazole( 1 )and N,N-dimethylformamide dicyclohexylacetal gave the 2-(β-dimethylaminovinyl) analog 2 and with iodine and pyridine gave the 2-(1-pyridinium)methyl compound 3 . Benzoyl chloride-triethylamine and 1 led to benzoylation of the 2-methyl group to give ketone 9 as the enol benzoate. Nitrous acid or nitrosylsulfuric acid with 9 or its enol ester afforded the oximinoketone 10 which was cleaved with thionyl chloride to give 2-cyano-1-methyl-5-nitroimidazole ( 11 ) in high overall yield. 1-Ethyl-2-methylbenzimidazole ( 22 ) was converted to 2-cyano-1-ethylbenzimidazole ( 25 ) similarly. Reaction of 1 with ethyl oxalyl chloride and triethylamine afforded ethyl 1-methyl-5-nitro-2-imidazolepyruvate ( 19 ) as the enol oxalate. Nitrous acid and 19 gave the oximino pyruvate 20 which effervesced on mild heating to give 2-cyano-1-methyl-5-nitroimidazole ( 11 ). The preparation of 1-methyl-5-nitro-2-imidazoleacetonitrile ( 39 ) is reported.     

Iodocyclization of S-allyl derivatives of 3-mercapto-4-methyl-1,2,4-triazole

It has been established that iodocyclization of 3-(2-methyl-2-propenyl)thio-4-methyl-1,2,4-triazole occurs regioselectively with annelation of the thiazole ring, 3-(3-methyl-2-butenyl)thio-4-methyl-1,2,4-thiazole with annelation of the thiazine ring, and 3-allylthio-4-methyl-1,2,4-triazole with annelation of both rings to form derivatives of [1,3]thiazolo[3,2-b][1,2,4]triazolium and [1,2,4]triazole[5,1-b][1,3]thiazinium iodides.     

5-乙氧羰基甲硫基-1,2,4-三唑席夫碱的合成及杀菌活性

以3-甲基-4-氨基-5-乙氧羰基甲硫基-1,2,4-三唑为原料,与取代芳醛合成9种3-甲基-4-(X-取代基苯亚甲基氨基)-5-乙氧羰基甲硫基-1,2,4-三唑席夫碱化合物a～i。 产物结构经1H NMR、IR和MS等技术手段确证。 其中化合物3-甲基-4-(4-羟基苯亚甲基氨基)-5-乙氧羰基甲硫基-1,2,4-三唑h进一步经X射线单晶衍射得到其晶体结构（CCDC：910927）：C14H16N4O3S,Mr=320.37,Orthorhombic,P2(1)2(1)2(1)/n,a=0.9220(10) nm,b=1.5823(17) nm,c=2.1667(2) nm,V=3.161(6) nm3,Z=8,F(000)=1344。 化合物对4种植物病原菌的初步生物活性测试结果(EC95值)表明,化合物d、e、f对供试菌种西瓜枯萎病和小麦赤霉病的抑菌活性优于对照原药三唑酮。     

Synthesis and Antimicrobial Activities of Some 6-Methyl-3-Thioxo-2,3-Dihydro-1,2,4-Triazine Derivatives

Abstract

4-Arylidene-imidazole derivatives (4a,b) were readily prepared by reacting 4-am- ino-6-methyl-3–thioxo-2,3–dihydro[1,2,4]triazin-5(4H)-one (1) with 4-arylidene-2-phenyl- 4H-oxazol-5-one (2). Reaction of 1 with some aromatic aldehydes in presence of triethylphosphite exclusively afforded the corresponding aminophosphonates 5a-c. Reaction of 1 with 3-phenyl-1H-quinazoline-2,4-dione (6a) and/or 3-phenyl-2-thioxo-2,3-dihydro- 1H-quinazolin-4-one (6b) gave 2-(6-methyl-5-oxo-3-thioxo-2,5-dihydro-3H-[1,2,4]triazin-4-ylimino)-3-phenyl-2,3-dihydro-1H-quinazolin-4-one (7). Moreover, on treating 1 with 2-phenylbenzo[d][1,3]thiazine-4-thione (8), 6-methyl-4-(2-phenyl-4-thioxo-4H-quinazolin-3-yl)-3-thioxo-3,4-dihydro-2H-[1,2,4]triazine-5-one (9) was obtained in 65% yield. Reaction of 1 with 4-sulfonylaminoacetic acid derivatives (10a,b) afforded the corresponding sulfonamides (11a,b), respectively. Acid hydrolysis of 11a afforded 7-aminomethyl-3-methyl[1,3,4]thiadiazole[2,3-c][1,2,4]triazin-4-one (12). 4-Amino-6-methyl-3-(morpholine-4-ylsulfanyl)-4H-[1,2,4]triazin-5-one (14) was prepared by reacting compound 1 with morpholine in presence of KI/I₂, while 3,3′-bis(4-amino-6-methyl-5-oxo-triazinyl)disulfide (16) was obtained by oxidation of 1 with lead tetraacetate. The antimicrobial activity of the products was evaluated against Gram-positive and Gram-negative bacteria as well as the fungus Candida albicans.

[Supplementary materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental files: Additional text, figures, and tables.]     

Reactions with diazoazoles. Part VI. Unequivocal synthesis of 3-methyl-3h-azolotetrazoles. Correction of the formerly described 3-methylazolotetrazoles in favour of mesoionic 2-methylazolotetrazoles

3-Methyl-3H-pyrazolo[1,5-d]tetrazoles 2 and 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) have been unequivocally synthesized by annulation of the tetrazole moiety to the pyrazole resp. 1,2,4-triazole system. The constitution of some N-methyl substituted azolotetrazoles, formerly described as 3-methyl-3H-pyrazolo[1,5-d]tetrazoles 2, 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) and 1-methyl-6-phenyl-1H-1,2,4-triazolo[4,3-d]tetrazole (5), has to be revised in favour of the corresponding mesoionic 2-methyl derivatives 2′, 4′, 5′. The structures of 3-methyl-3H- as well as of 2-methyl-2H-pyrazolo[1,5-d]tetrazole derivatives 2a, 2c, 2′a have been determined by X-ray analyses. The azapentalenic system is aromatic in all three measured compounds and mesoionic in the case of the 2-methyl-2H- substitution pattern. The phenyl and ester substituents are coplanar with the azapentalene system. 3-, 2-, and 1-Methylpyrazolo[1,5-d]tetrazoles exhibit different behaviour when allowed to react with stannous chloride or sodium ethoxide. Azolotetrazoles with a methyl substituent at N-1, N-2 or N-3 of the tetrazole moiety can be distinguished by a combination of ¹H and ¹³C nmr with respect to the chemical shifts of the N-methyl group and the bridgehead carbon. Results of semiempirical calculations of the pyrazolo[1,5-d]tetrazole anion and of its N-methyl derivatives are discussed.     

Energetic quaternary salts containing bi(1,2,4-triazoles)

New energetic salts (2, 3, 9, 10, and 11) were synthesized via the protonation of 4,4'-bi(1,2,4-triazole) or N-4-(1,2,4-triazole)-N-3-(4-methyl-1,2,4-triazole)amine with nitric acid or perchloric acid or 5-nitro-tetrazole. The structures of 4,4'-bi(1,2,4-triazolium) nitrate (2), N,N-dimethyl-N'-(5-methyl-tetrazole)methanimidamide (8), and N-4-(1,2,4-triazole)-N-3-(4-methyl-1,2,4-triazolium)amine perchlorate (10) were confirmed by a single-crystal X-ray analysis. The physical properties and heats of combustion of the new ionic salts were measured, and the heats of formation were also determined.     

Synthesis and single-crystal X-ray diffraction studies of 1-β-D-ribofuranosyl-1,2,4-triazole-3-sulfonamide and certain related nucleosides

1-β-D-Ribofuranosyl- 21 , 1-(2-deoxy-β-D-erytftro-pento fur anosyl)- 27 and 1-β-D-arabinofuranosyl- 29 derivatives of 1,2,4-triazole-3-sulfonamide ( 19 ) have been prepared. Glycosylation of the silylated 19 with 1,2,3,5-tetra-0-acetyl-β-D-ribofuranose ( 5 ) in the presence of trimethylsilyl triflate gave the corresponding blocked nucleoside ( 20 ), which on ammonolysis afforded 1-β-D-ribofuranosyl-1,2,4-triazole-3-sulfonamide ( 21 ). Stereospecific glycosylation of the sodium salt of 19 with either 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranose ( 22 ) or 1-chloro-2,3,5-tri-0-benzyl-α-D-arabinofuranose ( 23 ) provided the corresponding protected nucleosides 26 and 28. Deprotection of 26 and 28 furnished 1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,2,4-triazole-3-sulfonamide ( 27 ) and 1-β-D-arabinofuranosyl-1,2,4-triazole-3-sulfonamide ( 29 ), respectively. 2-0-D-Ribofuranosyl-1,2,4-triazole-3(4H)-thione ( 7 ) and 4-β-D-ribofuranosyl-1,2,4-triazole-3(2H)-thione ( 9 ) were also prepared utilizing either an acid catalyzed fusion of 1,2,4-triazole-3(1H,2H)-thione ( 4 ) with 5 , the reaction of 5 with silylated 4 in the presence of trimethylsilyl triflate, or by ring closure of 4-(2,3,5-tri-0-benzoyl-β-D-ribofuranosyl)thiosemicarbazide ( 10 ) with mixed anhydride and subsequent deacylation. The synthesis of 1-β-D-ribofuranosyl-3-benzylthio-1,2,4-triazole ( 15 ) has also been accomplished by the silylation procedure employing 3-benzylthio-1,2,4-triazole ( 13 ) and 5 to give 1-(2,3,5-tri-0-acetyl-β-D-ribofuranosyl)-3-benzylthio-1,2,4-triazole ( 14 ). Deacetylation of 14 furnished 15 . The structural assignments of 7, 14 and 21 were made by single-crystal X-ray diffraction analysis and their hydrogen bonding characteristics have been studied. The sulfonamido-1,2,4-triazole nucleosides are devoid of any significant antiviral or antitumor activity in cell culture.     

Synthesis of certain 1,2,4-triazole nucleoside derivatives

The syntheses of 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and its 2′-deoxy analog 8b as well as 5-amino-2-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-3-one ( 12 ) have been accomplished. Compounds 8a and 8b were synthesized via glycosylation of 3-bromo-5-nitro-1,2,4-triazole which was followed by replacement in three steps of the 3-bromo function to yield 3-nitro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 4a ) and its 2′-deoxy analog 4b . Compounds 4a and 4b were methylated at N², hydrogenated and deblocked to give 3-amino-4-methyl-1-(β-D-ribofuranosyl)-1,2,4-triazolin-5-one ( 8a ) and the 2′-deoxy analog 8b . Compound 12 was synthesized by glycosylation of 3-amino-1-methyl-1,2,4-triazolin-5(2H)-one ( 10 ). The structures of 8b and 12 were confirmed by single crystal X-ray diffraction analysis.