Synthesis of 8,8-R,R-8,9-dihydro[1,2,4]triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]quinazolin-6(7<Emphasis Type="Italic">H</Emphasis>)-ones

Three-component condensation of 3-amino-1,2,4-triazole (or its 5-methyl and 5-methylthio derivatives), dimedone (or cyclohexane-1,3-dione), and dimethylformamide dimethyl acetal afforded 8,8-R, R-8,9-dihydro[1,2,4]triazolo[1,5-a]quinazolin-6(7H)-ones. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2805–2807, December, 2005.     

Cascade cyclization reactions of 3,4,5-triamino-1,2,4-triazole with aromatic aldehydes and cycloalkanones

A three-component condensation of 3,4,5-triamino-1,2,4-triazole (1) with aromatic aldehydes 2a–f and dimedone (3) or cyclohexanone (8) afforded partially hydrogenated 9-aryl-[1,2,4]triazolo[5,1-b]quinazolin-8-ones. The structure of 2-amino-6,6-dimethyl-3-(4-nitrobenzylidene)amino-9-(4-nitrophenyl)-5,6,7,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8-one (4e) was confirmed by X-ray diffraction data. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1178–1182, July, 2006.     

Synthesis of 9-Aryl-6,6-dimethyl-5,6,7,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)ones

The reaction of 3-amino-1,2,4-triazole with arylidene derivatives of dimedone and their potential synthetic equivalents leading to the formation of 9-aryl-6,6-dimethyl-5,6,7,9-tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)ones has been studied. The direction of heterocyclization has been established, and the possible mechanisms for the formation of the pyrimidine heterocycle have been analysed.     

Microwave-assisted three component synthesis of novel bis-fused quinazolin-8(4H)-ones linked to aliphatic or aromatic spacer via amide linkages

Abstract

A novel series of bis(tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8-ones) and bis(tetrahydrobenzo[4,5]imidazo[2,1-b]quinazolinones) containing amide linkages were regionselectively prepared via a three-component reaction of bis(aldehydes) with dimedone and 3-amino-1,2,4-triazole (or 2-aminobenzimidazole) under conventional heating as well as under microwave irradiation.     

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.     

Improved synthesis of 2-amino-1,2,4-triazolo[1,5-a]pyrimidines

An improved procedure is suggested for preparing 2-amino-1,2,4-triazolo[1,5-a]pyrimidines from 3,5-diamino-1,2,4-triazole and unsaturated aromatic ketones, with acetyl protection of the amino group in the step of oxidation of 2-amino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines.     

Reactions of α-aminoazoles with diethyl benzylidenemalonate

Cyclocondensations of diethyl benzylidenemalonate with 3-amino-5-methylpyrazole, 3,5-diamino-1,2,4-triazole, 3,4,5-triamino-1,2,4-triazole, and 2-amino-benzimidazole in alcohols take a single route and lead to the formation of functionally substituted partially hydrogenated pyrazolo-, triazolo[1,5-a]-pyrimidin-5-ones and pyrimido[1,2-a]benzimidazol-2-one respectively. From reaction mixtures involving 3-amino-1,2,4-triazole and its 5-methylsulfanyl analog in methanol the intermediate products of heterocyclization were isolated forming as a result of alkylation with the β-carbon of the unsaturated ester the endocyclic nucleophilic sites of aminoazoles. The structure of one among the products obtained, diethyl(3-amino-5-methylsulfanyl-1,2,4-triazol-2-yl)benzylmalonate was proved by X-ray crystallography. In DMF the same reagents yielded mixtures of partially hydrogenated triazolo[1,5-a]pyrimidin-5-ones.     

Synthesis of [1,2,4]triazoloquinazoline and [1,2,4]-triazolo-1,4-benzodiazepine derivatives

Some [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones 7 , the corresponding isomers [1,2,4]triazolo[4,3-c]quinazo-lin-5(6H)-ones and the 5-amino derivatives 8, 9 and 11 have been synthesized starting from the acylamidrazones 5 . The preparation of 5H-[1,2,4]triazolo[1,5-d]-1,4-benzodiazepin-6(7H)-ones 15 and of 5-cyclicaminomethyl-[1,2,4]triazolo[1,5-c]quinazolines 16 and 17 is also reported.     

Synthesis of 2,8-disubstituted 1,2,4-triazolo[5,1-i]purines

This paper describes the preparation of 2-aryl-8-fluorobenzyl-1,2,4-triazolo[5,1-i]purines 2 , starting from 2-aryl-7,8-diamino-1,2,4-triazolo[1,5-c]pyrimidines 9 . Our synthetic procedure represents the first example of a feasible approach for the synthesis of 2,8-disubstituted triazolo[5,1-i]purines. New syntheses of 5-amino-3-arylpyrimido[5,4-e]1,2,4-triazines 12 and 8-fluorobenzyl-6-hydrazinopurines 15 are also reported.     

Chlorotrimethylsilane-promoted synthesis of 1,2,4-triazolopyrimidines from 3,5-diamino-1,2,4-triazoles and pentane-2,4-diones

An efficient synthesis of 2-amino-1-R-[1,2,4]triazolo[1,5-a]- pyrimidinium or 3-amino-2-R-[1,2,4]triazolo[4,3-a]pyrimidi- nium chloride derivatives by heterocyclization of 3,5-diamino- 1-R-1,2,4-triazoles (R = Alk or Ar) with pentane-2,4-diones was developed. The process is promoted by chlorotrimethyl- silane which plays the dual role of carbonyl-activating agent and water scavenger.     

1,2,4-triazines. 7. Regioselective n2-amination of 3-methylthio-1,2,4-triazin-5(2H)-ones.A novel synthesis of [1,2,4]triazolo[2,3-b][1,2,4]triazinones and -triazine

A regioselective synthesis of 2-aminotriazinones 6a-d is reported, by reaction of 3-methylthio-1,2,4-triazinones 5a-d with O-(2,4-dinitrophenyl)hydroxylamine (2) as an amino-transfer agent. A spectroscopic study and an unequivocal synthesis of 2-amino-4-methyl-6-phenyl-1,2,4-triazinedione ( 11a ) has shown the site of amination to be N2 of the 1,2,4-triazinone ring. Subsequent reaction of 2-amino-1,2,4-triazinones 6a-b with amines, followed by ring closure with aliphatic acids provided [1,2,4]triazolo[2,3-b][1,2,4]triazine-7(1H)ones 13a-e. Conversion of [1,2,4]triazolo[2,3-b][1,2,4]triazinone 13c to unsubstituted [1,2,4]triazolo[2,3-6][1,2,4]triazine (15) was attained.     

N-Nitroimines: I. Synthesis,Structure, and Properties of 3,5-Diamino-1-nitroamidino-1,2,4-triazole

The reaction of 3,5-diamino-1,2,4-triazole with 2-methyl-1-nitroisothiourea gives 3,5-diamino-1-nitroamidino-1,2,4-triazole instead of the expected 1-[5(3)-amino-1,2,4-triazol-3(5)-yl]-2-nitroguanidine. Almost planar structure of the molecule of 3,5-diamino-1-nitroamidino-1,2,4-triazole gives rise for direct polar conjugation which is responsible for the low basicity of the amino groups.     

Cyclocondensation of 3-Amino-1,2,4-triazoles with Esters of Substituted Cinnamic Acids and Aromatic Unsaturated Ketones

We have studied the reactions of 3-amino, 3,5-diamino-, and 3-amino-5-trifluoromethyl-1,2,4-triazole with esters of substituted cinnamic acids and aromatic unsaturated ketones; we have established the directionality of formation of the tetrahydrooxopyrimidine ring. We have carried out hydrolysis and hydrazinolysis of 7-phenyl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-5-one. We have conducted an X-ray diffraction study of isopropylidene hydrazide of 3-(5-amino-1,2,4-triazol-1-yl)-3-phenylpropionic acid.     

Unexpected Direction of Iodocyclization of 3-Allylthio-5-phenyl-4H-1,2,4-triazole

The reaction of 3-allylthio-5-phenyl-4H-1,2,4-triazole with iodine to give a mixture of 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine, 5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole, and 6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine has been studied. The structure of the products obtained was established using ¹H NMR spectroscopy of their dehydriodination products.     

1,2,4-Triazines. Synthesis of selected members of the s-triazolo[3,4-f]- [1,2,4] triazine and tetrazolo[1,5-f] [1,2,4] triazine ring systems

A convenient synthesis of 3-amino-6-hydrazino-5(2H)[1,2,4]triazinone 4 has been developed and a study of the reactions of 4 with aliphatic acids, orthoesters and miscellaneous active carbonyl reagents has been undertaken. When 4 was refluxed in either neat acid or orthoester in dimethylformamide, a facile ring closure reaction with the N-1 nitrogen of the 1,2,4-triazine ring occurs affording a novel series of 3-aIkyl(aryl)-8(5H)-s-triazolo[3,4-f] [1,2,4]triazinones ( 6–11 ). Ring closure with carbon disulfide and cyanogen bromide is also reported affording 6-amino-3(2H)thio-8(5H)-s-triazolo[3,4-f] [1,2,4]triazinone 12 and 3,6-diamino-8(5H)-s-triazolo-[3,4-f] [1,2,4]triazinone 14 , respectively. In addition 4 has been converted into 3-amino-6-azido-5(2H)-1,2,4-triazinone 15 which was employed in a study of azide-tetrazole equilibrium affording 6-amino-8(5H)tetrazolo[1,5-f][1,2,4]triazinone 16 . Rates for interconversion at various temperatures were measured and an activation energy for the process determined.     

Interaction of aminoazoles with Meldrum’s acid and dialkyl ketones or cyclohexanone

Interaction of 3-amino-5-methylpyrazole, 3-amino-5-methylthio-, and 3,5-diamino-1,2,4-triazole with Meldrum’s acid, acetone, ethyl methyl ketone, and cyclohexanone leads to alkyl-substituted pyrazolo[3,4-b]pyridin-6-ones and 1,2,4-triazolo[1,5-a]pyrimidin-7-ones respectively. The structure of 5,5-dimethyl-2-methylthio-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-7-one was demonstrated by an X-ray structural investigation. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 595–601, April, 2007.     

Reactions of 3-aroylacrylates with α-aminoazoles*

Dihydro derivatives of pyrazolo[3,4-b]pyridine-, pyrazolo[1,5-a]pyrimidine-, and [1,2,4]triazolo-[1,5-a]pyrimidinecarboxylates have been prepared by cyclocondensation of β-aroylacrylates with 5-aminopyrazoles and 3-amino-1,2,4-triazole. Heating dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylates with hydrazine hydrate led to recyclization of the pyrimidine ring to form 6-arylpyridazin-3(2H)-ones.     

Cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine with hydroxylamine and hydrazine

The cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine (3) with hydroxylamine or hydrazine leads to 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenylisoxazolo-[5,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4a ) and 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenyl-1H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4b ), respectively. In the presence of methanolic hydrogen chloride, 4b undergoes a cleavage of the pyrimidine ring to yield (5-amino-1,2,4-triazol-1-yl)(3,5-dimethylpyrazol-4-yl)phenylmethane ( 5 ). The structure determination of the compounds obtained is based on ¹H and ¹³C nmr spectra including NOE measurements.     

Reactions of 3,5-dibromo-1-(thiiran-2-ylmethyl)-1,2,4-triazole with NH-azoles

Reactions of 3,5-dibromo-1-(thiiran-2-ylmethyl)-1,2,4-triazole with 3,5-dimethylpyrazole, 1,3-dimethyl-3,7-dihydropurine-2,6-dione, 3,5-dibromo-1,2,4-triazole, 2,4,5-tribromoimidazole, and 2-chlorobenzimidazole lead to the formation of 5-azolylmethyl-2-bromo-5,6-dihydrothiazolo[3,2-b]-1,2,4-triazoles. In the case of 8-bromo-1,3-dimethyl-3,7-dihydropurine-2,6-dione the intermediate thiolate anion undergoes cyclization into 7-[(3,5-dibromo-1,2,4-triazol-1-yl)methyl]-1,3-dimethyl-6,7-dihydrothiazolo[2,3-f]purine-2,4(1H,3H)-dione. The structure of reaction products depends on the relative rate of substitution of leaving groups in the reagents.     

Cyclecondensation of 3-amino-1,2,4-triazole with substituted methyl cinnamates

The reaction of 3-amino-1,2,4-triazole ( 1 ) with substituted methyl cinnamates 2a-h leads selectively to the formation of 7-aryl-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones 3a-h . The structure eluci dation of the products is based on ir, ¹H and ¹³C nmr measurements and X-ray diffraction.