Synthesis of 7-Alkyl(aryl)-6-alkoxycarbonyl-5-fluoroalkyl-1,2,4-tri(tetr)azolo[1,5-a]pyrimidines

Fluorinated 3-oxo esters react with aldehydes and 3-amino-1,2,4-triazoles and 5-aminotetrazoles to give, respectively, 7-alkyl(aryl)-6-alkoxycarbonyl-5-fluoroalkyl-1,2,4-triazolo[1,5-a]pyrimidines and -tetra-zolo[1,5-a]pyrimidines. The same heterocyclic products can be obtained by reaction of 2-benzylidene-2-fluoroacyl esters with the corresponding aminoazoles.     

Preparation of imidazo[2,1-b]quinazolin-5(3H)-ones and related tricyclic systems using a novel,double displacement reaction

New methodology is described for the construction of tricyclic heterocycles. Thus, a double displacement reaction of l-(2-fluorobenzoyl)-2-methylthio-2-imidazoline ( 8a ) with 1,1-dialkylhydrazines gave 10-substituted 2,10-dihydroimidazo[2,1-b]quinazolin-5(3H)-ones in good yield. The corresponding 1-(2-nitrobenzoyl)-2-meth-ylthio-2-imidazolines also underwent double displacement reactions with hydrazines. Other tricyclics made using double displacement reactions were pyrimido[2,1-b]quinazolines, imidazo[1,2-a]pyrido[2,3-d]pyrimidines, and imidazo[1,2-a]pyrazolo[3,4-d]pyrimidines. Treatment of 8a with hydrazine hydrate or methylhydrazine gave products resulting from displacement, but did not afford fused benzotriazepinones.     

Reaction of ethyl 3-ethoxymethylene-2,4-dioxovalerate and ethyl ethoxymethyleneoxaloacetate with 3-aminopyrazole analogs. Synthesis and chemistry of 3,6,7-trisubstituted pyrazolo[1,5-a]pyrimidine derivatives

The chemical reactivity of a series of 3-substituted-6-acetyl-7-carbethoxypyrazolo[l,5-a]pyrimidines ( 6a,b,c ) and 3-substituted-6,7-dicarbethoxypyrazolo[1,5-a]pyrimidines ( 7a,b,c ), prepared by the condensations of the 3-aminopyrazole analogs ( 3a,b,c ) with ethyl 3-ethoxymethylene-2,4-dioxovalerate ( 1 ) or ethyl 3-ethoxymethyleneoxaloacetate ( 2 ), was investigated. Catalytic hydrogenation of 6 or 7 afforded 4,7-dihydro derivatives ( 8 or 9 ). Treatment of 6a,b with acetic acid and water underwent ring transformation into 6H-pyrazolo[1,5-a][1,3]diazepin-6-ones ( 17a,b ). By treatment with phenylhydrazine compounds of type 6 underwent cyclization to yield 2H-dipyrazolo[1,5-a:4′,3′-e]pyrimidines ( 18a,b,c ). Compounds 6 or 7 were treated with an excess of diazomethane at room temperature to give 5-methyl-6H-cyclopropa[5a,6a]pyrazolo-[1,5-a]pyrimidines ( 24 and 25 ) in excellent yields. However, when this reaction was carried out under ice cooling, only compounds of type 23 were isolated. Reaction of 6a with ethyl diazoacetate is also described.     

Synthesis and structure of some thienopyrimidine derivatives

A series of substituted thieno[2,3-d]pyrimidines was synthesized starting from ethyl-2-amino-4-isopropylthiophene-3-carboxlate. Reaction of 2-hydrazino-5-isopropyl-thieno[2,3-d]pyrimidin-4(3H)-one and its 3-methyl analogue with different reagents afforded thieno[2,3-d]triazolo[4,3-a]pyrimidines and thieno[3,2-e]triazolo[4,3-a]pyrimidines, beside open chain derivatives. Correspondence: Atef A. Hamed, Department of Chemistry, Faculty of Science, Menoufia University, Shebin El Koam, Egypt.     

Rearrangement reactions of heterocycles. 12. Rearrangement of 6-substituted pyrido[1,2-a]pyrimidines to isomeric 1,8-naphthyridines and some of their further reactions

2-Amino-6-methylpyridine ( 4 ) reacts with active malonates 2a-d or 3a-d either in acetone solution with triethylamine as catalyst at room temperature or with active malonates 2a-d in acetone solution at reflux temperature to yield the pyrido[1,2-a]pyrimidines 5a-d . 2,6-Diaminopyridine ( 8 ) already reacts without triethylamine with 2a-d at room temperature to afford the pyrido[1,2-a]pyrimidines 9a-d . At higher temperatures pyrido[1,2-a]pyrimidines 5 and 9 are rearranged via ketene intermediates [1] to yield the 1,8-naphthyridines 6a-d , and 10a-d , respectively. The naphthyridines 6 and 10 can also be synthesized directly from 4 or 8 using either diethyl malonates 1 or — with better results — the active malonates 2 at 240–250°. Further reaction of 10a-e with 2c,d leads to the pyridonaphthyridines 12a-f . Nitration of 6c yields the nitro derivative 16 and chlorination of 6c,d gives 15c,d , while the chlorination of 10c affords the di-chloro derivative 17 .     

Transformations of the pyrido[1,2-a]pyrazine ring system into imidazo[1,2-a]pyridines,imidazo[1,2-a]pyrimidines and 2-oxa-6a, 10c-diazaaceanthrylenes

Transformations of methyl 3-dimethylamino-2-(1-methoxycarbonyl-4-oxo-4H-pyrido[1,2-a]pyrazin-3-yl)acrylate with some cyanomethylenecarbonyl group containing compounds or cyanamide into imidazo-[1,2-a]pyridines, irmdazo[1,2-a]pyrimidines and 2-oxa-6a, 10c-diazaaceanthrylenes are described.     

Synthesis of Structurally Related Purines: Benzimidazo[1,2-a]pyridines, Benzimidazo-[1,2-c]pyrimidines, and Pyrazolo-[1,5-a]pyrimidines

Summary.  Reactions of sodium salts of 3-hydroxymethylene-2-alkanones with 2-cyanomethylbenzimidazole afforded benzimidazo[1,2-a]pyridines. Analogues reactions with 2-aminobenzimidazole and 5-aminopyrazoles afforded benzimidazo[1,2-c]pyrimidines and pyrazolo[1,5-a]pyrimidines. Received December 12, 1999. Accepted (revised) February 12, 2000     

One-step reaction leading to new pyrazolo[1,5-a]pyrimidines by condensation of 2-pyrone with 5(3)-amino-3(5)-arylpyrazoles

Condensation of 5(3)-amino-3(5)-arylpyrazoles with 4-hydroxy-6-methylpyran-2-one leads to 5,7-dimethyl-2-arylpyrazolo[1,5-a]pyrimidines, 5-alkoxycarbonylmethyl-7-methyl-2-arylpyrazolo[1,5-a]pyrimidines and their isomeric 7-alkoxycarbonylmethyl-5-methyl-2-arylpyrazolo[1,5-a]pyrimidines. These compounds result from competitive reactions and from different cyclization pathways. Structure and mechanism of formation of these new products are reported.     

A synthesis of 6-functionalized 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines

6-Unsubstituted 7-R-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines (R = H or Me) were synthesized via two pathways: (a) deacylation of the corresponding 5-acetyl Biginelli-like precursors in KOH/H₂O and (b) reduction of the corresponding 1,2,4-triazolo[1,5-a]pyrimidines using LiAlH₄. The products could be easily formylated at position 6, which is promising for the further synthesis of functionalized 6-substituted derivatives of 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. In contrast, 6-acetyl-7-(4-(N,N-dimethylaminophenyl))-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine undergoes a cascade process in KOH/H₂O, leading to the formation of a 4,5,8,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline derivative.     

Synthesis,Reactions, and Antimicrobial Evaluation of Some Polycondensed Thienopyrimidine Derivatives

Some novel indeno[2,1-b]thiophenes, indeno[1′,2′:4,5]thieno[2,3-d][1,2,3]triazines, indeno[1′,2′:4,5]thieno[2,3-d]pyrimidines, indeno[1′,2′:4,5]thieno[2,3-d][1,3]thiazolo[3,2-a]pyrimidines, and indeno[1′,2′:4,5]thieno[2,3-d][1,2,4]triazolo[4,3-a]pyrimidines 2–16 were prepared starting with 2-aminoindeno[2,1-b]thiophene-3-carboxylic acid amide ( 1 ). Furthermore, the antimicrobial evaluation of the prepared products showed that many of them revealed promising antimicrobial activity.     

Reactivity of 7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines: Synthesis of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as potential benzodiazepine receptor ligands. 1

A series of 7-methylpyrazolo[1,5-a]pyrimidines were reacted with dimethylformamide dimethylacetal to give the corresponding dimethylaminovinyl derivatives. These were reacted with ammonium acetate affording, through a ring closure, a number of 6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidines bearing various substituents on the pyrazole ring. The 6-acetyl-2-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine was used as starting material for obtaining some O-alkyl derivatives. Catalytic transfer hydrogenation of 2-benzyloxy-6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine led to the 2-hydroxy derivative.     

Synthesis,characterization and in vitro anthelmintic activity against Nippostrongylus brasiliensis of new 5-aryl-2-phenyl-6,7-dihydropyrazolo[1,5-a]pyrimidines

Several new pyrazolo[1,5-a]pyrimidines were obtained from the reaction of 1H-5-amino-3-phenylpyrazole ( 1 ) with β-dimethylaminopropiophenones 2 in pyridine. The structure elucidation of 6,7-dihydropyrazolo[1,5-a]pyrimidines 3 is based on nmr measurements. These compounds showed moderate anthelmintic in vitro activity against the Nipposirongylus brasiliensis model.     

Syntheses of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines from methyl tetrahydro-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-3-oxo-2-thiophenecarboxylate,respectively

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 13 ) was condensed with 6-aminonicotinic acid ( 18 ) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 19 ). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 17 ). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate ( 21 ) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid ( 25 ) by an analogous route.     

Synthesis of N-Alkylated Derivatives of Pyrazolo[1,5-a]pyrimidine and Their Reaction with Methylamine

With the object of studying the factors influencing the course of enamine rearrangements, we have carried out the N-alkylation of alkyl- and aryl-substituted pyrazolo[1,5-a]pyrimidines. Using the NOEDIF NMR spectroscopic method for the cases of 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidines it was found that addition of the alkyl group occurs at the N₍₄₎ atom of the pyrimidine fragment in the pyrazolo[1,5-a]pyrimidine. It was shown that, when reacting with an alcoholic solution of methylamine, the 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidine iodomethylates undergo decomposition to give 5-methylamino-3-phenylpyrazole and 5-(1,3-diphenyl-3-methylamino-2-propenylid-1-ene)amino-3-phenylpyrazole.     

Preparation of 2-aryl and 2-aryloxymethyl imidazo[1,2-a]pyridines and related compounds

A series of substituted 2-aryl imidazo[1,2-a]pyridines has been prepared in which a variety of substituents are introduced on the 4′-position of the phenyl ring and on the 3, 5 , 6 or 7 position of the heterocyclic ring. Most examples have acetamido, bromo, cyano, or formyl substituents at the 4′-position. Analogous imidazo-[2,1-b]fhiazoles and imidazo[1,2-a]pyrimidines have also been prepared. Another series of compounds consisting of 4′-formylphenoxymethyl derivatives of imidazole, the three positional isomers of pyridine, thiazole, benzimidazole and ring-substituted imidazo[1,2-a]pyridines has been prepared. 2-(4′-Formylphenylethenyl) derivatives of imidazole and imidazo[1,2-a]pyridine were also prepared.     

Synthesis and some properties of N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]pyrazinones

Reactions of methyl 2-(2-formyl-1H-pyrrol-1-yl)alkanoates with unsubstituted aliphatic 1,2-, 1,3-, and 1,4-diamines gave N-unsubstituted pyrrolo[2,1-c]-1,3-diazacycloalkano[1,2-a]-pyrazinones. Some of them show ring-chain tautomerism. Transformations of these compounds led to a number of novel heterocyclic systems: 2,10-dihydro-3H,5H-imidazo[1,2-a]-pyrrolo[1,2-d]pyrazines, 2,3,4,11-tetrahydro-6H-pyrrolo[1??,2??:4,5]pyrazino[1,2-a]pyrimidines, 1,2,3,5,6,10b-hexahydroimidazo[1,2-a]pyrrolo[2,1-c]pyrazines, 1,3,4,6,7,11b-hexahydro-2H-pyrrolo[2??,1??:3,4]pyrazino[1,2-a]pyrimidines, and 2,3,4,5,6,7-hexahydro-1H-pyrrolo[2,1-c]-[1,4,7]triazacycloundecin-8(9H)-one.     

2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物的合成

以2-溴丙酸甲酯、α,α-二氯甲基甲醚和胍唑为原料, 经缩合以及环化反应制得2-氨基-6-甲基-5-氧代-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶. 为了提高其在有机溶剂中的溶解性, 该化合物再同1-溴丁烷发生亲核取代反应得到了2-氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶, 然后与芳基醛和叔丁基异氰发生Ugi多组分反应, 合成了一系列具有潜在催吐活性的2-取代氨基-6-甲基-5-氧代-4-正丁基-4,5-二氢-1,2,4-三氮唑并[1,5-a]嘧啶类衍生物, 产品结构经质谱、核磁共振谱及元素分析确认.     

Condensed Pyridopyrimidines. 7. Synthesis of Condensed Triazolo[4,3-c]- and Tetrazolo[1,5-c]pyrimidines

Novel dihydro-5H-pyrano[3',4':5',6']pyrido[2,3-d]-1,2,4-triazolo[4,3-c]pyrimidines and 1,2,3,4-tetrazolo[1,5-c]pyrimidines have been synthesized from 2-amino-3-cyano-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine.     

Synthesis and reactions of “biginelli-compounds”. Part I

Various reactions of 2-oxo(or thioxo)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid derivatives (Biginelli-compounds) were investigated. The site of methylation and acylation on 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester 1a and its 2-oxo derivative 9a was studied. The synthesis of pyrimido[2,3-b]thiazines and thiazolo[3,2-a]pyrimidines was accomplished by condensation of 1a with 1,3-and 1,2-dielectrophiles. A Dimroth-like rearrangement yielding 6H-1,3-thiazines can be observed when 1a was treated with dimethylformamide and phosphorus oxychloride. The formation of indeno[1,2-d]pyrimidines can be achieved by intramolecular Friedl-Crafts acylation of 9a and 13 , respectively. Finally a route for the preparation of 4,6-disubstituted-pyrimidine-5-carbonitriles is presented, starting with Biginelli-compound 25 .     

Synthesis and chemical reactivity of some 1,2,4-Thiadiazolo[2,3-a]-pyrimidines and related compounds

A novel synthetic approach for 1,2,4-thiadiazolo[2,3-a]pyrimidines, 1,2,4-thiadiazolo[2,3-c]-pyrimidines and 1,2,4-thiadiazolo[2,3-b] indazoles is described. Several transformations of these heterocyclic systems are presented. 1,2,4-Thiadiazolo[2,3-a] pyrimidines undergo a very facile ring cleavage to give 3-amino-5-carbethoxyamino-1,2,4-thiadiazole and similar ring opening was observed also with the isomerie [2,3-c] system. On the other hand, 1,2,4-thiadiazolo[2,3-a]-pyridines undergo under similar conditions cleavage of the thiadiazole part of the bicycle.