New approaches to synthesis of tris[1,2,4]triazolo[1,3,5]triazines

Thermal cyclization of 3-R-5-chloro-1,2,4-triazoles (R = Cl, Ph) afforded 2,6,10-tri-R- tris[1,2,4]triazolo[1,5-a:1′,5′c:1″,5″-e][1,3,5]triazines 5 (R = Ph) and 7 (R = Cl). These compounds are first representatives of this class of heterocycles, whose structures were unambiguously established. Treatment of these compounds with nucleophiles (H₂O/NaOH, NH₃) results in the triazine ring opening to give compounds consisting of three 1,2,4-triazole rings linked in a chain. For example, treatment of cyclic compound 5 with aqueous alkali affords 3-phenyl-1-3-phenyl-1-(3-phenyl-1H-1,2,4-triazol-5-yl)-1,2,4-triazol-5-yl-1H-1,2,4-triazol-5-one. Treatment of 3,7,11-triphenyltris[1,2,4]triazolo[4,3-a:4′,3′c:4″,3″-e][1,3,5]triazine (2) with HCl/SbCl₅ leads to the triazine ring opening giving rise to 5-(3-chloro-5-phenyl-1,2,4-triazol-4-yl)-3-phenyl-4-(5-phenyl-1H-1,2,4-triazol-3-yl)-1,2,4-triazole. Thermal cyclization of the latter produces 3,7,10-triphenyltris[1,2,4]triazolo[1,5-a:4′,3′c:4″,3″-e][1,3,5]triazine (13). Thermolysis of both cyclic compound 2 and cyclic compound 13 is accompanied by the Dimroth rearrangement to yield 3,6,10-triphenyl-tris[1,2,4]triazolo[1,5-a:1′, 5′-c:4″,3″-e][1,3,5]triazine (14). Compounds 13 and 14 are the first representatives of cyclic compounds with this skeleton. ¹³C NMR spectroscopy allows the determination of the isomer type in a series of tris[1,2,4]triazolo[1,3,5]triazines.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 706–712, March, 2005.     

A convenient method for the synthesis of 7-amino-substituted 1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amines

A new practical synthesis of 7-amino-substituted 1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amines is developed. The triazine ring closure of 5-guanidino-3-phenyl-1,2,4-triazole with trichloroacetonitrile proceeds chemo- and regioselectively depending on the nature of the solvent. Conducting the reaction in toluene provided 7-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine as the product, which can be further aminated efficiently with replacement of the trichloromethyl group.     

Reaction of 3-acetonyl-5-cyano-1,2,4-thiadiazole with phenylhydrazine hydrochlorides: indolization and phenylpyrazolation

Treatment of 3-acetonyl-5-cyano-1,2,4-thiadiazole (1) with 4-methyl or 4-methoxyphenylhydrazine hydrochloride provided 5-cyano-3-(2,5-dimethylindol-3-yl)-1,2,4-thiadiazole (2) or 5-cyano-3-(5-methoxy-2-methylindol-3-yl)-1,2,4-thiadiazole (3) as the sole product, respectively. In contrast, treatment of 1 with phenylhydrazine hydrochloride resulted in the formation of 5-cyano-3-(2-methylindol-3-yl)-1,2,4-thiadiazole (4) and the unexpected 5-cyano-3-(3,5-dimethyl-1-phenylpyrazol-4-yl)-1,2,4-thiadiazole (5). In a similar manner, when 1 was treated with 4-chlorophenylhydrazine hydrochloride, indolization was suppressed by phenylpyrazolation giving rise to 5-cyano-3-(5-chloro-2-methylindol-3-yl)-1,2,4-thiadiazole (6) and 5-cyano-3-[1-(4-chlorophenyl)-3,5-dimethylpyrazol-4-yl]-1,2,4-thia diazole (7). The reaction mechanism is discussed. Compounds 4, 5 and 6 exhibited weak antimicrobial activity against Helicobacter pylori.     

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.     

Oxidative azacyclization of 1-monosubstituted thioureas in reaction with [bis(acyloxy)iodo]arenes to form 1,2,4-thiadiazole derivatives

For the first time, derivatives of 1,2,4-thiadiazoles have been obtained by the reaction of [bis(acyloxy)iodo]arenes with 1-monosubstituted thioureas. 1-Acetylthiourea is subject to intermolecular azacyclization to form 3,5-bis-(acetylamino)-1,2,4-thiadiazole in reaction with [bis(acyloxy)iodo]benzene. 1-Phenylthiourea forms 3,5-bis-(phenylamino)-1,2,4-thiadiazole in a single-stage reaction with (diacetoxyiodo)benzene. The reaction of 1-phenylthiourea with [bis(trifluoroacetoxy)iodo]benzene leads to the formation of 5-imino-4-phenyl-3-phenylamino-4H-1,2,4-thiadiazoline.     

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.     

4(3H)-Quinazolinones containing heterocyclic group in position 3

The corresponding 2,3-substituted 4(3H)-quinazolinones were obtained in the reactions of 2-methyl- and 2-phenyl-4-oxo-3,1-benzoxazines with 1-amino-1,2,4-triazole, 4-amino-2,3-dimethyl-1-phenyl-5-pyrazolone, 2-amino-5-ethyl-1,3,4-thiadiazole, 3-amino-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole, 1-amino-3-cyano-4,6-dimethyl-2-pyridone, and 1-amino-3-cyano-6-phenyl-4-trifluoromethyl-2-pyridone. The formation of N-benzolyanthranilamides in the reactions of 2-phenyl-4-oxo-3,1-benzoxazine with 2-amino-5-ethyl-1,3,4-thiadiazole and 1-amino-3-cyano-6-phenyl-4-trifluoromethyl-2-pyridones was exceptional. The structures of two of the products have been confirmed by X-ray crystallography.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 936–943, July, 2000.     

1,2,4-Triazines. 5. Regioselective N2-amination of 3-methylthio-1,2,4-triazin-5(2H)-ones. A new efficient synthesis of [1,2,4]triazolo[2,3-b][1,2,4]triazin-7(1H)-one

A regioselective synthesis of 2-amino-1,2,4-triazinones ( 3a-b ) is reported, by reaction of 3-methylthio-1,2,4-triazinones ( 1a-b ) 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-triazinone ( 8a ) has shown the site of amination to be N2 of the 1,2,4,-triazinone ring. Subsequent reaction of 2-amino-1,2,4-triazinone ( 3b ) with ammonium hydroxide, followed by ring closure with formic acid provided [1,2,4]triazolo[2,3-b][1,2,4]triazin-7 (1H)-one ( 10 ).     

Synthesis of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione and its reactions with C-electrophiles

4-Amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-trazole-3-thione is formed from the reaction of 4,6-diphenylpyrimidinecarboxylic acid or its ethyl ester with thiocarbonyl hydrazide. Alkylation of the product leads to S-alkyl derivaties or 6-substituted 3-(4,6-diphenyl-2-pyriimidinyl)-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine. Acetylation of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione gave under different conditions monoacetyl-, diacetyl, and triacetyl derivatives at the amino group and the N₍₂₎ atom, whereas benzoylation gave a benzoyl group at the amino group and 3-(4,6-diphenyl-2-pyrimidinyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1088–1094, July, 2007.     

Fused polycyclic nitrogen-containing heterocycles: IX. Synthesis and molecular structure of methyl 3-(2-R-5-phenylthiazol-4-yl)-7-phenyl-7<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazolo-[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazine-6-carboxylates

4-Amino-3-(2-R-5-phenylthiazol-4-yl)-1,2,4-triazole-5-thiones react with methyl 3-chloro-2-oxo-3-phenylpropionate to give methyl 3-(2-R-5-phenylthiazol-4-yl)-7-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-carboxylates. According to the X-ray diffraction data, the thiazole ring in the products is planar, while the thiadiazine ring has a distorted unsymmetrical boat conformation. Depending on the substituent in the thiazole ring, methyl 3-(2-R-5-phenylthiazol-4-yl)-7-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-6-carboxylates in crystal give rise to different supramolecular structures, lamellar and cylindrical.Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 9, 2004, pp. 1358–1365.Original Russian Text Copyright © 2004 by Mamedov, Mustakimova, Gubaidullin, Litvinov, Levin.     

Chemistry of acyl(imidoyl)ketenes. 8*. Thermolysis of 3-alkoxycarbonyl- 5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]- quinoxaline-1,2,4-triones. Structure of 2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)- 2,4-di(ethoxycarbonyl)-6-phenyl-2,3,5,6-tetrahydro- 1h-pyrido[1,2-a]quinoxaline-1,3,5-trione

3-Alkoxycarbonylmethylene-1-phenyl-1,2,3,4-tetrahydro-2-quinoxalones, obtained by the interaction of dialkyl esters of oxaloacetic acid and N-phenyl-o-phenylenediamine, react with oxalyl chloride with the formation of 3-alkoxycarbonyl-5-phenyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4-triones. Alkoxycarbonyl(2-oxo-1-phenyl-1,2-dihydro-3-quinoxalinyl)ketenes, generated on thermal decarbonylation of the latter, are stabilized by participation in a [4+2] cyclodimerization reaction with the formation of 2,4-di(alkoxycarbonyl)-2-(3-oxo-4-phenyl-3,4-dihydro-2-quinoxalinyl)-6-phenyl-2,3,5,6-tetrahydro-1H-pyrido[1,2-a]quinoxaline-1,3,5-triones. The crystal and molecular structure of the di(ethoxycarbonyl) derivative have been investigated by X-ray structural analysis.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1501–1506, October, 2004.     

Synthesis and Physicochemical Properties of Heterocyclic Compounds Based on 5,7-Diimino-2,5,6,7-tetrahydro-1H-cyclopenta[cd]phenalene

N,N'-Bis(7-amino-2,5-dihydro-1H-cyclopenta[cd]phenalen-5-ylidene)-substituted derivatives of 2,5-diamino-1,3,4-thiadiazole, 2,6-diaminopyridine, and 3,5-diamino-1-phenyl-1,2,4-triazole were synthesized. The products are soluble in water, and they attract interest as potential biologically active substances.     

On triazoles. VII Synthesis of novel tri- and tetracyclic ring systems

The ring-closure of the 5-amino-1-(2-aminophenyl)-3-methylthio-1H-1,2,4-triazole derivatives 3 and 4 with different simple and cyclic C₁ components lead to the formation of 1,2,4-triazolo[1,5-α]-1,3,5-benzotriazepines 5–6 , their 4,5-dihydro- 7 , different 5-spiro-homocyclic- 8–13 , and 5-spiro-heterocyclic- 14-15 analogues. The structure of the compounds obtained was proved with the use of their ir, uv, ¹H-nmr and ¹³C-nmr spectra.     

Study of the Products of Iodocyclization of 4-Allyl-5-phenyl-1,2,4-triazole-3-thione

The interaction of 4-allyl-5-phenyl-1,2,4-triazole-3-thione with iodine proceeds with the formation of a mixture of 6-iodomethyl-3-phenyl-5,6-dihydrothiazolo[2,3-c]-1,2,4-triazole and 6-iodo-3-phenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine. The structures of the cyclization products obtained were established on the basis of the ¹H NMR spectra of their dehydroiodinated derivatives. 6-Methyl-3-phenylthiazolo[2,3-c]-1,2,4-triazole, 3-phenyl-5H-1,2,4-triazolo[3,4-b]-1,3-thiazine, and 3-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3-thiazine are formed on eliminating HI from the cyclization products.     

On triazoles. XXXIII. The reaction of potassium triazolyldithiocarbonates with dihaloalkanes

The reaction of potassium (5-amino-3-Q-1,2,4-triazolyl)dithiocarbonates 2 with 1,ω-dihaloalkanes 7-10 to yield ω-haloalkyldithiocarbonates 11-12 , ω-alkylene-bis(dithiocarbonates) 13-15 and different by-products as the corresponding 7,8-dihydro[1,2,4]triazolo[1,5-c][1,3,5]thiadiazepine-5(9H)-thione ( 16 ), 7,8,9,10-tetrahy-dro[1,2,4]triazolo[1,5-c][1,3,5]thiadiazocine-5-thione ( 17 ) and 1,7-dihydro-5H-1,2,4-triazolo[1,5-c][1,3,5]thiadi-azine-5-thione ( 22 ) derivatives all three representing novel ring systems were obtained. Repeating the reactions with dipotassium salts 3 the corresponding iminodithietans 18 , imino-1,3-dithiolanes 19 and imino-1,3-dithianes 20 were obtained. Unexpectively, the imino-1,3-dithiolanes ( 19 ) rearranged to the corresponding thiazolidines 24-27 under rather mild conditions. A possible mechanism is proposed for this rearrangement.     

Part 1: Synthesis of Polyfused Heterocyclic Systems Derived From 3-Phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione

3-Phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione ( 1 ) was condensed with o -aminothiophenol, 2-amino-ethanol or cystamine to afford compounds 2-4 respectively. Treatment of compound 1 with dimethylthiomethylenemalononitrile yielded the corresponding pyrano[3,2- f ][1,2,4]triazolo[3,4- b ]-[1,3,4]thiadiazepine derivative 5 . 7-[5-Amino-1,3-dithiolan-2-ylidene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione ( 6 ) was obtained by treating compound 1 with CS 2 and chloroacetonitrile. Thiation of compound 1 gave the corresponding thioanalog 7 , which in turn was condensed with malononitrile to give 3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6-one-8-ylidenemalononitrile ( 8 ). On treating compound 8 with benzaldehyde or p -nitrobenzaldehyde, pyrano[1,2,4]triazolo[1,3,4]thiadiazepin derivatives 9a , b , respectively, were obtained. Compound 8 was treated with CS 2 and methyl iodid to give the corresponding dithiomethylmethylene derivative 10 which was subjected to react with aniline to give pyrido[1,2,4]triazolo[1,3,4]thiadiazepine derivative 11 . Compound 8 was treated with 3-aminopyridine, o -aminothiophenol, or o -phenylenediamene to yield compounds 12 and 13a , b respectively. Finally, tertiary amines or activated phenols were condensed with compound 8 to yield compounds 14 and 15a , b respectively.     

Synthesis of [1,5-A]Pyrimidinone Ring Derivatives

Cyclodehydrogenation of the benzalhydrazino derivatives 5 and 6 gave 6-cyano-7-(4-methoxyphenyl)- 2-phenyl-5-oxo-1,2,4-triazolo[1,5-a]pyrimidine (8) and 6-cyano-7-(4-methoxyphenyl)-4-methyl-2-phenyl- 5-oxo-1,2,4-triazolo[1,5-a]pyrimidine (9) respectively. Melhylation, acetylation and benzylation of 8 gave the corresponding N-methyl, acetyl and benzyl derivatives 10-12 . Methylation of 5 with dimethylsulfate gave 2-benzalhydrazino-5-cyano-3-methyl-6-(4-methoxyphenyl)-3,4-dihydropyrimidin-4-one (6) , of which the reaction with acetic anhydride in pyridine afforded the N-acetylbenzalhydrazino derivative 15 . The latter was also prepared from acetylation of 5 followed by medthylation with iodomethane. Acetylation of 5 with boiling acetic anhydride afforded the diacetyl derivative 16 , whereas its benzylation gave the mono-N-benzyl derivative 14 .     

<Emphasis Type="Italic">N</Emphasis>-acylimino-substituted 2-oxa-7-azaspiro[4.4]nona-3,6,8-trienes in the synthesis of 3-(1<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazol-3-yl)-3<Emphasis Type="Italic">H</Emphasis>-pyrrole-4-carbonitriles

Reaction with phenylhydrazine of 3Н-pyrroles spirobound to a furan ring, N-acylimino-substituted 2-oxa-7-azaspiro[4.4]nona-3,6,8-trienes, occurs with a diasteroselective formation of previously unknown derivatives of 1,2,4-triazole: 5-amino-3-(5-alkyl-1-phenyl-1H-1,2,4-triazol-3-yl)-2-morpholin-4-yl-3H-pyrrole-4-carbonitriles.     

Thermolysis of 3-phenyl-5-arylamino-1,2,4-oxadiazole and thiadiazole derivatives

Thermal reactions of 3-phenyl-5-arylamino-1,2,4-oxadiazoles I and II were investigated. Neat heating at ca. 250°C for 6 hours afforded H₂O, benzonitrile, arylcyanamides, arylamines, azobenzene, benzimidazole derivatives, and 3,3′-diphenyl-5,5′-bis[1,2,4-oxadiazolyl]. Analogous results were obtained by the thermolysis of 3-phenyl-5-anilino-1,2,4-thiadiazole III at ca. 200°C for 2 hours. In addition to H₂S, NH₃, and HNCS, phenyl isothiocyanate and thiocarbanilide were obtained. Thermolysis of III in quinoline as a radical trap gave analogous resuLts but also 2-anilinoquinoline. A free-radical mechanism has been suggested to account for the identified products. © 1997 John Wiley & Sons, Inc.     

Ring closure reaction of 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride. Synthesis of pyrimido[5,4-c] [1,5]benzoxazepin-5(11H)ones

Syntheses of 11-acety1-2-phenylpyrimido[5,4-c][1,5]benzoxazepin-5(11H)one ( 16a ) and analogs ( 16b,c, 22 ) were described. The reaction of 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 7 ) with 2-aminophenol afforded 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidine-carboxylic acid ethyl ester ( 8a ). The latter was also prepared by catalytic reduction of 4-(2-nitrophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 9 ), which was obtained from 7 and 2-nitrophenol. Involvement of 4-(2-aminophenoxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester ( 12a ) in this reduction as an intermediate was demonstrated by an independent synthesis of 12a and its subsequent rearrangement to 8a. Hydrolysis of 8a or 12a gave 4-(2-hydroxyanilino)-2-phenyl-5-pyrimidinecarboxylic acid ( 15a ). Reaction of 15a with acetic anhydride afforded 16a , the first member of a novel ring system, the pyrimido[5,4- c ][1,5]-benzoxazepin. Additional examples ( 16b,c ) were prepared similarly. The corresponding 11-ethyl derivative ( 22 ) was prepared in similar fashion, starting with 7 and 2-ethylaminophenol. A possible reaction mechanism for the formation of 16a-c from 15a-c and acetic anhydride was discussed.