Imidazo[1,2-α]pyrimidines and 1,2,4-triazolo[1,5-α]pyrimidines: Two new examples of mesoionic xanthine analogs

Several derivatives of mesoionic imidazo[1,2-α]pyrimidine-5,7-dione and 1,2,4-triazolo[1,5-α]pyrimidine-5,7-dione, two new examples of mesoionic xanthine ring systems, were prepared and characterized. These compounds were conveniently prepared by the condensation of bis-(2,4,6-trichlorophenyl) malonates with the appropriately substituted alkylaminoimiazole or 1,2,4-triazole.     

13C-NMR-Untersuchungen zur Azido-Tetrazol-Valenzisomerie. Tetrazolo[1,5-α]pyrimidine

¹³C NMR has been used to study the azido-tetrazolo valence isomerism of three tetrazolo[1,5-α]pyrimidines. Large chemical shift variations of C-4 carbons were found to be useful to distinguish between azido and tetrazolo isomers. Furthermore, the structure of new heterocycles has been proved and the report of LaNoce and Giuliani concerning 9-methyl-s-triazolo[4,3-c]tetrazolo[1,5-α]pyrimidine is shown to be incorrect.     

Synthesis and reactions of tetrazolo[1,5-α]pyrimidines

The reaction of “magic malonates” (bis-2,4,6-trichlorophenyl malonates, 1 ) with 5-aminotetrazole ( 2 ) in the presence of triethylamine yields the ammonium salts 3 . Upon treatment of 3 with strong acids compounds 4a-d were obtained as a mixture of isomeric tetrazolopyrimidines ( A ) and 2-azidopyrimidines ( B ). Reaction of 4d with bromine or sulfuryl chloride leads by ring opening and decarboxylation to the halogenated tetrazole derivatives 5 or 7 , respectively. The action of acetic anhydride in pyridine on 3d yields the zwitterionic tetra-mic acid derivative 10.     

Crystal and molecular structure of 7-phenyl-1,2,4-triazolo[1,5-a]-1,3,5-triazine

The crystal and molecular structure of 7-phenyl-1,2,4-triazolo[1,5-a]-1,3,5-triazine were determined. It was shown that the amine nitrogen atom (N¹) of the triazole ring acts as a nucleophilic center in the cyclization of N-(1,2,4-triazol-5-yl)amidines with electrophilic reagents.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, 117913 Moscow. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 6, pp. 1386–1389, June, 1992.     

Convenient Synthesis of Some 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines Bearing 3-Methylthio{7H-1,2,4-triazolo[1,5-d]tetrazol-6-yl}moiety as Possible Antimicrobial Activity

4-Amino-4H-3-methylthio{7H-1,2,4-triazolo[1,5-d]tetrazol-6-yl}-1,2,4-triazole-5thi-ol (1) was condensed with various substituted aromatic aldehydes or acid chlorides to yield a series of arylideneamines 2 or aroylamines 3. These were easily cyclized to the corresponding 6-aryl-3-methylthio7H-1,2,4-triazolo[1,5-d]tetrazol-6-yl-1,2,4-triazolo [3,4-b]-1,3,4-thiadiazoles (4) on treatment with palladium-on-charcoal or phosphorus oxychloride. Compounds 4 were also prepared directly via the reaction of 1 with aromatic carboxylic acids in the presence of phosphorus oxychloride. Cyclocondensation of 1 with a variety of two-carbon cyclizing reagents, namely chloroacetone, pyruvic acid, benzoylformic acid, and benzoin led to the formation of 3-methylthio{7H-1,2,4-triazolo[1,5-d]tetrazol-6-yl}-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (5?8). Some of the newly synthesized compounds were tested for their antibacterial and antifungal activity against a variety of microorganisms.     

Oxidative cyclization of 2-amino-1-arylideneaminobenzimidazoles into 1,2,4-triazolo[1,5-a]benzimidazoles

When heated in nitrobenzene, 1-arylideneamino-2-methylaminobenzimidazoles convert in a 20...30% yield into 2-aryl-3-methyl-1,2,4-triazolo[1,5-a]benzimidazoles. In addition, 2-methylaminobenzimidazole and the corresponding benzonitrile are formed as a result of a thermal splitting of the N-N bond. Under the same conditions, 2-amino-1-arylideneaminobenzimidazoles and 1-arylideneamino-3-methylbenzimidazoline-2-imines give only products of splitting off of the nitrile. In several cases, the subsequent reaction of the nitrile with 2-amino-1-methylbenzimidazole leads to the formation of benzamidines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1226–1231, September, 1988.     

Synthesis of a new 1,4-dihydropyridine containing the imidazo[1,5-α]pyridine nucleus

The synthesis of the new dihydropyridine diethyl 1,4-dihydro-4-(imidazo[1,5-α]pyridin-8-yl)-2,6-dimethyl-pyridine-3,5-dicarboxylate ( 1 ) is described. After many attempts to prepare the key intermediate aldehyde 2a by different approaches, this compound has been obtained in good yields from methyl 2-cyano-3-pyridinecar-boxylate ( 10 ). A three-step procedure involving reduction to the amine, formylation with concomitant cyclization and reduction of the ester group was used.     

Naphthyridines. Part 3: First example of the polyfunctionally substituted 1,2,4-triazolo[1,5-g][1,6]naphthyridines ring system

Treatment of 1,2,4-triazoles (1) with diethylmalonate in bromobenzene gave 1,2,4-triazolo-[1,5-a]pyridines 2. Chlorination of 2 using POCl₃/DMF (Vilsmeier reagent) led to the isolation of 7-chloro-6-formyl-1,2,4-triazolo[1,5-a]pyridine derivative 4, which reacted with the stabilized ylid 5 to afford 6-ethoxycarbonylvinyl-1,2,4-triazolo[1,5-a]-pyridines 6. Azidation of 6 yielded the corresponding azido compound 7, (Scheme 2). Reduction of 7 with Na₂S₂O₄ gave the corresponding 7-amino compound 8, which cyclized in boiling DMF to give the novel 1,2,4-triazolo[1,5-g][1,6]naphthyridines 9. On the other hand, reacting 7 with one equivalent of PPh₃ (aza-Wittig reaction) in CH₂Cl₂ gave 7-imino-phosphorane derivative 10, and subsequent cyclization in boiling DMF afforded the new 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 11 (Scheme 3). However, treatment of 10 with phenyl isothiocyanate in 1,2-dichlorobenzene at reflux temperature gave the new 1,2,4-triazolo[1,5-g][1,6]naphthyridine derivative 14 (Scheme 4). Refluxing 6 with excess of a primary amines 15a,b in absolute. EtOH yielded the corresponding 7-alkyl-amino-1,2,4-triazolo[1,5-a]pyridines 16a,b. These obtained amines 16a,b underwent intramolecular heterocyclization in boiling DMF to give the novel 9-alkyl-1,2,4-triazolo[1,5-g][1,6]-naphthyridines 17a,b, in excellent yields (Scheme 5).     

Synthesis and antimicrobial activity of some new pyrazole, fused pyrazolo[3,4-d]-pyrimidine and pyrazolo[4,3-e][1,2,4]-triazolo[1,5-c]pyrimidine derivatives

Hydrazonyl bromides 2a,b reacted with active methylene compounds (dibenzoylmethane, acetylacetone, ethyl acetoacetate, phenacyl cyanide, acetoacetanilide, ethyl cyanoacetate, cyanoacetamide and malononitrile) to afford the corresponding 1,3,4,5- tetrasubstituted pyrazole derivatives 5-12a,b. Reaction of 12a,b with formamide, formic acid and triethyl orthoformate give the pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4- d]pyrimidin-4(3H)one and 5-ethoxymethylene-aminopyrazole-4-carbo-nitrile derivatives 13-15a,b, respectively. Compounds 15 a,b reacted with benzhydrazide and hydrazine hydrate to afford pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine and [4-iminopyrazolo- [3,4-d]pyrimidin-5-yl]amine derivatives 16 a,b and 17 a,b. Reactions of compounds 17 a,b with triethyl orthoformate and carbon disulfide give the corresponding pyrazolo[4,3-e]- [1,2,4]triazolo[1,5-c]pyrimidine derivatives 18a,b and 19 a,b, respectively.     

Molecular and crystal structure of 5,7-diphenyl-7-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine

The molecular and crystal structures of 5,7-diphenyl-7-methyi-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine have been studied by X-ray structural methods. The crystal is monoclinic,a=16.112(3),b=13.489(3),c=14.480(3)Å, =101.62(2)°,Z=8, space groupC2/c,R=0.071. The presence of short intermolecular contacts indicates considerable steric strain in the molecule. The dihydropyrimidine ring exists in an unevenly planar boat conformation. Increasing the steric strain of the dihydrocycle leads to a twisted conformation.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1912–1914, November, 1993.     

Synthesis and antiviral evaluation of some novel [1,2,4]triazolo[4,3-β][1,2,4]triazole nucleoside analogs

Ribosylation of 3-amino-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 1 ) with l-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose and stannic chloride resulted in the following protected nucleoside analogs: 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 4 ), 3-amino-1-(2,3,5-tri-O-benzoyl-α-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), and 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) amino-5H-[1,2,4]triazolo[4,3-b]-[1,2,4]triazole ( 7 ). Compounds 4–6 were deprotected to 3-amino-1-β-D-ribofuranosyl[1,2,4]triazolo[4,3-b][1,2,4]-triazole ( 3 ), 3-amino-1-α-D-ribofuranosyl[1,2,4]triazolo[4,5-b][1,2,4]triazole ( 8 ), and 3-imino-2H-2-β-D-ribo-furanosyl[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 9 ), while 7 could not be deprotected without decomposition. Compounds 1, 4, 6, 7 , and 9 were screened and found to have no antiviral activity.     

Synthesis of 5-Thioxo-hexahydrobenzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines and Related Compounds Based on Cyclocondensations of 2-Isothiocyanato-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene

5-Thioxo-4,6,8,9,10,11-hexahydro-benzo[b]thiopheno[2,3-d]-1,2,4-triazolo[1,5-c]pyrimidines and related compounds were prepared based on cyclizations of 2-isothiocyanato-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene with aminoketones and carboxylic hydrazides.     

Nitroazines 18. Arylation and destruction of 6-nitro-1,2,4-triazolo[1,5-a]pyrimidines

6-Ntiro-7-aryl-1,2,4-triazolo[1,5-a]pyrimidines were synthesized by treatment of the corresponding 7-oxo compounds with phosphorus oxychloride in the presence of N,N-dialkylanilines. The 7-(N-methyl-p-methoxyphenylamino) derivatives were formed under the same conditions with N,N-dimethyl-p-anisidine. The nitroarylazolopyrimidines produced underwent destruction to give -nitroacetophenones on treatment with water. The influence of substituenis on the course of the reaction is shown and the mechanism is discussed.For Communication 17 see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1546–1554, November, 1992.     

Synthesis of substituted pyrrolo[1,2-α]pyrimidines

A facile route for the synthesis of pyrrolo[ 1,2-α]pyrimidine derivatives and data for structural assignment are reported.