Cyclization of (1,2,4,5-tetrazin-3-yl)hydrazones to 3,7-dihydro-1,2,4-triazolo[4,3-b]-1,2,4,5-tetrazines

The intramolecular cyclization of (6-R-1,2,4,5-tetrazin-3-yl)hydrazones of ketones (R is 3,5-dimethylpyrazol-1-yl, 4-methylimidazol-1-yl, or 2-alkylidenehydrazino) giving rise to the previously unknown 3,7-dihydro-1,2,4-triazolo[4,3-b]-1,2,4,5-tetrazines, including spiro compounds, was studied. The reactivity and the yields of the reaction products depend on the structure of the alkylidene fragment and the nature of the substituent in the tetrazine ring.

     

Intramolecular heterocyclization of N-(pyrimidin-2-yl)imines of methyl trifluoropyruvate

The reactions of N-(pyrimidin-2-yl)imines of methyl trifluoropyruvate with trimethyl phosphite afforded methyl 3-fluoroimidazo[1,2-a]pyrimidin-2-carboxylates, which were transformed into N-substituted methyl 3-aminoimidazo[1,2-a]pyrimidine-2-carboxylates by the reactions with amines.     

Synthesis and molecular structure of 1-(pyrimidin-2-yl)-2-(4-aryl-1,3-thiazol-2-yl)hydrazines

Reactions of some 2-hydrazinopyrimidine hydrochlorides with potassium thiocyanate gave 1-(pyrimidin-2-yl)thiosemicarbazides which underwent Hantzsch condensation with aryl chloromethyl ketones to produce 1-(pyrimidin-2-yl)-2-(4-aryl-1,3-thiazol-2-yl)hydrazine hydrochlorides. The protonation was accompanied by mutually dependent tautomeric rearrangements of heterocyclic fragments.     

4-(取代嘧啶-2-基)-1-芳磺酰基氨基脲化合物的合成与表征

以取代的苯磺酰肼与(取代嘧啶-2-基)-氨基甲酸苯酯在非亲核性碱存在下合成了12个4-(取代嘧啶-2-基)-1-芳磺酰基氨基脲化合物5和3个5与碱形成的有机盐5as, 5bs和5cs. 所有合成化合物均经过元素分析和¹H NMR的结构确证. ¹H NMR数据证明, 在5as～5cs中, 磺酰氨基脲起到提供质子的作用.     

Reaction of 4-Aryl-1-(4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidin-2-yl)thiosemicarbazides with Dimethyl Acetylenedicarboxylate

4-Aryl-1-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)thiosemicarbazides react with dimethyl acetylenedicarboxylate in methanol to give the corresponding methyl {3-aryl-4-oxo-2-[(4-oxo-3,4-dihydro-thieno[2,3-d]pyrimidin-2-yl)hydrazono]-1,3-thiazolidin-5-ylidene}acetates, whereas in dioxane methyl 5-aryl-amino-2-methoxycarbonylmethyl-3-(4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)-2,3-dihydro-1,3,4-thiadiazole-2-carboxylates are mainly formed.     

Synthesis and tuberculocidic activity of some 4-arylaminomethylene-3-methyl-1-(pyrimidin-2-yl)pyrazol-5(4H)-ones

4-Arylaminomethylene-3-methyl-1-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)pyrazol-5(4H)-ones were synthesized by a three-component reaction between the 6-methyl-2-(3-methyl-5-oxo-2,5-dihydropyrazol-1-yl)pyrimidin-4(1H)-one, triethoxymethane, and an aromatic amine. These compounds were found to exist as aminomethyleneketones regardless of the electronic effects of substituents in the aromatic fragments. The resulting compounds showed pronounced tuberculocidic activity.     

[4+2]-Cycloaddition of 3,6-bis(3,5-dimethyl-4-R-pyrazol-1-yl)-1,2,4,5-tetrazines with alkenes

A number of 1,4-dihydropyridazines and pyridazines were prepared by the Diels-Alder reaction with an inverse electron demand from cyclic heterodiene systems, 3,6-bis(3,5-dimethyl-4-R-pyrazol-1-yl)-1,2,4,5-tetrazines, and some enamines as well as from 4-vinylpyridine, butyl vinyl ether, phenylacetylene, and acrylamide. The reaction of 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with styrene afforded 4,5-dihydropyridazine, which was readily oxidized by atmospheric oxygen to form the corresponding pyridazine. Electron-withdrawing substituents (Br or Cl) in the pyrazole rings accelerate [4+2]-cycloaddition. When heated, 1,4-dihydropyridazines, which were synthesized from tetrazines and enamines, eliminated amine to give pyridazines. The reactivities of tetrazines were evaluated by quantum-chemical methods. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 354–360, February, 2000.     

Synthesis and some properties of 5-alkylamino-2-(phthalimidoalkyl)-1,3-oxazole-4-carbonitriles

5-Alkylamino-1,3-oxazole-4-carbonitriles containing a 2-phthalimidoethyl or 3-phthalimidopropyl substituent at position 2 of the oxazole ring were synthesized. In the reaction of 5-(morpholin-4-yl)-2-(2-phthalimidoethy)l-1,3-oxazole-4-carbonitrile with hydrazine hydrate, 2-(2-aminoethyl)-5-(morpholin-4-yl)-1,3-oxazole-4-carbonitrile is formed. In the case of the 3-phthalimidopropyl analog, the recyclization product 3-amino-2-(morpholin-4-ylcarbonyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole is formed.     

Synthesis of some new pyrimidine selanyl derivatives

The targeted synthesis of 2-(methylsulfanyl)-6-(furan-2-yl)-4(3H)-selenoxo -pyrimidine-5-carbonitrile failed due to the formation 1-methyl-2-methylsulfanyl-6-oxo -4-(furan-2-yl)-1,6-dihydropyrimidine-5-carbonitrile. A new series of 5,6,7,8-tetrahydro-1-benzo thieno[2,3-d]pyrimidine-4-yl substituted selanyl derivatives were prepared by the reaction of sodium diselenide with 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine followed by the reaction with chloroacetic acid derivatives such as ethyl chloroacetate, chloroacetamide or chloroacetonitrile. Hydrazinolysis of ethyl (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine- 4-ylselanyl)acetate with hydrazine hydrate gave the corresponding hydrazino derivative. The latter reacted with ethyl acetoacetate, acetylacetone, diethyl malonate, ethoxymethylenemalononitrile or ethyl 2-cyano-3-ethoxyacetate to afford 5-methyl-2-[2-(5,6,7,8-tetrahydro-1-benzothieno [2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazol-3-one, 1-(3,5-dimethylpyrazol-1-yl)-2- (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)ethanone, 1-[2-(5,6,7,8-tetrahydro -1-benzothieno[2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazolidine-3,5-dione and 5-Amino-1-[2-(5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)acetyl]-1H-pyrazol -4-yl substituted carbonitrile or ethyl carboxylate, respectively. The structure of the novel compounds was confirmed by spectroscopic tools (IR, ¹H NMR ¹³C NMR and mass spectra) and elemental analysis.     

Synthesis of maleopimaric and citraconopimaric acids N-[3-(pyrimidin-2-yl)aryl]amides

Acylation of 6-methyl-N-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine, 4-methyl-N-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine, and N-[4-(pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine with maleopimaric and citraconopimaric acid chlorides, with benzotriazolyl maleopimarate afforded N-[3-(pyrimidin-2-yl)aryl]amides of maleopimaric and citraconopimaric acids. By the reaction of substituted N-arylamides of maleopimaric acid with methanesulfonic acid biologically active methanesulfonates were obtained.     

Synthesis of 2-(β-D-ribofuranosyl)pyrimidines,A new class of C-nucleosides

A new C-glycosyl precursor for C-nucleoside synthesis, 2,5-anhydroallonamidine hydrochloride ( 4 ) was prepared and utilized in a Traube type synthesis to prepare 2-(β-D-ribofuranosyl)pyrimidines, a new class of C-nucleosides. The anomeric configuration of 4 was confirmed by single-crystal X-ray analysis. Reaction of 4 with ethyl acetoacetate gave 6-methyl-2-(β-D-ribofuranosyl)pyrimidin-4-(1H)-one ( 5 ). Reaction of 4 with diethyl sodio oxaloacetate gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxylic acid ( 6 ). Esterification of 6 with ethanolic hydrogen-chloride gave the corresponding ester 7 which when treated with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidin-6(1H)-oxo-4-carboxamide ( 8 ). Condensation of 2,5-anhydroallonamidine hydrochloride ( 4 ) with ethyl 4-(dimethylamino)-2-oxo-3-butenoate ( 9 ), gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboxylate ( 10 ). Treatment of 10 with ethanolic ammonia gave 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ). Single-crystal X-ray analysis confirmed the β-anomeric configuration of 11. Acetylation of 11 followed by treatment with phosphorus pentasulfide and subsequent deprotection with sodium methoxide gave 2-(β-D-ribofuranosyl)pyrimidine-4-thiocarboxamide ( 14 ). Dehydration of the acetylated amide 12 with phosphorous oxychloride provided 2-(β-D-ribofuranosyl)pyrimidine-4-carbonitrile ( 15 ). Treatment of 15 with sodium ethoxide gave ethyl 2-(β-D-ribofuranosyl)pyrimidine-4-carboximidate ( 16 ), which was converted to 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamidine hydrochloride ( 17 ) by treatment with ethanolic ammonia and ammonium chloride. Treatment of 16 with hydroxylamine yielded 2-(β-D-ribofuranosyl)pyrimidine-4-N-hydroxycarboxamidine ( 18 ). Treatment of 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide ( 11 ) with phosphorus oxychloride gave the corresponding 5′-phosphate, 19 , Coupling of 19 with AMP using the carbonyldiimidazole activation procedure gave the corresponding NAD analog, 2-(β-D-ribofuranosyl)pyrimidine-4-carboxamide-(5′ ? 5′)-adenosine pyrophosphate ( 20 ).     

Synthesis and Reactions of 5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7 H -thiazolo[3,2- a ]pyrimidine-6-carbonitrile

5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile was synthesized via the reaction of 4-(2-aminothiazol-4-yl)-3-methyl-1-phenyl-2-pyrazolin-5-one with benzylidene malononitrile and was then transformed to related fused heterocyclic systems. The antifungal and antibacterial studies revealed in some cases excellent biocidal properties.     

N′-(取代嘧啶-2-基)-N-菊酰硫脲的合成与生物活性研究

采用活性基团拼接法, 将第一菊酸构型中的最高活性组分(＋)-反式菊酸以及二氯菊酸引入到含取代嘧啶环的酰基硫脲结构中, 合成了5个未见文献报道的N′-(取代嘧啶-2-基)-N-(＋)-反式菊酰硫脲衍生物(3a～3e)和3个均未见文献报道的N′-(取代嘧啶-2-基)-N-二氯菊酰硫脲(3f～3h), 结构经元素分析、IR和¹H NMR得到确证. 初步的生物活性测试结果表明: 大部分化合物具有较好的杀菌活性, 有的化合物兼具除草和杀菌活性, 有的化合物兼具杀虫和杀菌活性.     

Utility of [4-(3-methoxyphenyl)pyrimidin-2-yl]cyanamide in synthesis of some heterocyclic compounds

N-[4-(3-Methoxyphenyl)pyrimidin-2-yl]cyanamide ( 1 ) was reacted with morpholine and respective binuclephilic reagents namely: ethylenediamine, o-phenylenediamine, o-aminothiophenol, or o-aminophenol to give the corresponding carboximidamide 2 , imidazolidine 3 , and benzazoles 4–6 . While its reaction with hydrazides in DMF at 90°C, gave the corresponding 1,2,4-triazols 7–11 . Also, treatment of cyanamide 1 with heterocycles having both nucleophilic and electrophilic groups (─NH₂/─COOEt) in iso-propanol in presence of catalytic amount of Conc. HCl, gave the corresponding thieno[2,3-d]pyrimidinone 12 and unexpected thieno[3,2-d]pyrimidine 13 instead of bis-thieno[3,2-d]pyrimidine 14 , respectively. While, its reaction with ethyl 5-amino-1,3-thiazole-4-carboxylate yielded the unexpected N-(pyrimidin-2-yl)urea 15 rather than the corresponding thiazolo[5,4-d]pyrimidine 16 . Unexpected N-(pyrimidin-2-yl)thiourea 17 was obtained, when cyanamide 1 reacted with potassium thiolates in iso-propanol with catalytic amount of Conc. HCl.     

Synthesis and antimalarial effects of N,N-dialkyl-6-(substituted phenyl)-1,2,4,5-tetrazin-3-amines

The synthesis of a series of N,N-dialkyl-6-(substituted phenyl)-1,2,4,5-tetrazin-3-amines (IV) by two routes is described. The first route (Scheme I) involved the oxidative cyclization of formazans (II) to 3-bromo-6-(substituted phenyl)-1,2,4,5-tetrazines (III), followed by treatment with amines. The second (Scheme II) utilized the treatment of 3-(methylthio)-6-(substituted phenyl)-1,2,4,5-tetrazines (VII) with amines to provide the desired products. The intermediate 3-(methylthio)-6-(substituted phenyl)-1,2,4,5-tetrazines (VII) were obtained by thiobenzoylation of hydrazinecarbohydrazonothioic acid methyl ester with [[(substituted phenyl)thioxomethyl]thio]-acetic acids (V) to afford the 1,2-dihydro-3-(methylthio)-6-(substituted phenyl)-1,2,4,5-tetrazines (VI). Oxidation with bromine in acetic acid provided the desired intermediates. The target 6-(substituted phenyl)-1,2,4,5-tetrazin-3-amines (IV) displayed modest antimalarial activity.     

Cyclocondensation of methyl 2-(5-methylisoxazol-3-yl)imino-3,3,3-trifluoropropionate with 1,3-binucleophiles

Cyclocondensation of methyl 2-(5-methylisoxazol-3-yl)imino-3,3,3-trifluoropropionate with 1,3-binucleophiles such as benzamidines, aminothiazoline, and 2-aminocrotonic acid nitrile results in trifluoromethyl-containing 3,5-dihydro-4-ones, 2,3-dihydro-6H-imidazo[2,1-b]thiazol-5-one, and 4,5-dihydro-1H-pyrrole-3-carbonitrile.     

Synthesis and Reactions of 5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7<Emphasis Type="Italic">H</Emphasis>-thiazolo[3,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidine-6-carbonitrile

Summary. 5-Amino-3-(3-methyl-5-oxo-1-phenyl-2-pyrazolin-4-yl)-7-phenyl-7H-thiazolo[3,2-a]pyrimidine-6-carbonitrile was synthesized via the reaction of 4-(2-aminothiazol-4-yl)-3-methyl-1-phenyl-2-pyrazolin-5-one with benzylidene malononitrile and was then transformed to related fused heterocyclic systems. The antifungal and antibacterial studies revealed in some cases excellent biocidal properties.     

New convenient synthesis of 2,3-diaminothieno[2,3-d]pyrimidin-4(3H)-one derivates from substituted alkyl 2-(1H-tetrazol-1-yl)thiophene-3-carboxylates

4,5-Disubstituted and 4-substituted alkyl 2-amino-thiophene-3-carboxylates react with triethyl orthoformate and sodium azide in acetic acid to yield new 2-(1H-tetrazol-1-yl)-4-R¹-5-R²-thiophene derivates. It was established that the reaction of these tetrazoles with hydrazine generates the insufficiently studied 2,3-diaminothieno[2,3-d]pyrimidin-4(3H)-one system. It is significant that the reaction mentioned above is the unique tetrazole ring cleavage under the action of hydrazine.     

Synthesis of methyl esters of 5-amino-4-(substituted amino)-2-methylthio-7H-pyrrolo[2,3d]-pyrimidine-6-carboxylic acids

The optimum route for the synthesis of methyl esters of N-[(4-substituted amino)-5-cyano-2-methylthiopyrimidin-6-yl]amino acids (which are starting materials for preparing the methyl esters of the corresponding 5-amino-4-(substituted amino)pyrrolo[2,3-d]pyrimidine-6-carboxylic acids) is via subsequent reactions of 4,6-dichloro-2-methylthiopyrimidine-5-carbonitrile with amines and methyl glycinate. In some examples, the reaction of methyl N-(4-chloro-2-methylthio-6-pyrimidinyl)aminoacetate with amines occurs to give the corresponding acid amides. The previously unknown synthesized derivatives of pyrimidin-6-yl amino acids and 4,5-diaminopyrrolo[2,3-d]pyrimidine- 6-carboxylic acids possess fungicidal properties.Vilnius University, Vilnius 2006, Lithuania. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No 7, pp. 955–961, July, 2000.     

Synthesis and study of 3-(pyrimidin-2-yl)amino-1(2)H-1,2,4-triazole derivatives

The previously unknown 3-[4(3H)-pyrimidinon-2-yl]amino-1H-1,2,4-triazoles, which were converted to 3-[4-chloro-, 3-(4-ethoxy)-, 3-(4-hydrazinopyrimidin-2-yl)]-amino-2(4)H-1,2,4-triazoles, were obtained by the reaction of 2-nitroamino-4(3H)-pyrimidinones with 3-amino-5-hexyl-1H-1,2,4-triazole. The condensation of the initial products with -diketones gave 3-[4-(1H-pyrazol-1-yl)pyrimidin-2-yl]-amino-2(4)H-1,2,4-triazoles. The IR, UV, and PMR spectra of the synthesized compounds were studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1678–1681, December, 1980.