Reaction of N-cyanoformimidates with some heterocyclic compounds. A new synthesis of 5-azaadenine and related compounds

3-Amino-1,2,4-triazoles and 2-aminobenzimidazole were reacted with N-cyanoimidates to give 5-amino-1,2,4-triazolo[2,3-a]-1,3,5-triazines (5-azaadenines) and 4-aminobenzimidazo[1,2-a]-1,3,5-triazines, respectively. The structures of the compounds obtained were confirmed through the comparison with some of the possible isomers prepared by independant methods.     

1,2,4-Triazines. VI. Imidazo[1,2-b]-as-triazines

Imidazo[1,2-b]-as-triazines were obtained in high yields by heating substituted glyoxaldoximes with 1,2-diaminoimidazoles in the presence of hydrochloric acid. Phenylglyoxal hydrate in a similar reaction afforded a mixture of 2- and 3-diphenyl-6-arylimidazo[1,2-b]-as-triazines. α-Ketoacids and 1,2-diaminoimidazoles in the presence of hydrochloric acid afforded 2,6-disubstituted-4H-imidazo[1,2-b]-as-triazin-3-ones.     

Condensed imidazo-1,24-azines. 28. Synthesis and transformations of 2-aroylmethyl-6,7.-diphenylimidazo-[1,2-b]-1,2,4-triazin-4H-3-ones

The reaction of 1,2-diamino-4,5-diphenylimidazole with 3-aroyl-2-propanonoic acid yields 2-aroylmethyl-6,7-diphenylimidazo[1,2-b]-1,2-4-triazin-4H-3-one. The cyclization pathways of these imidazoriazines leading to condensed furo[2,3-e]-, thieno[2,3-e]-, pyrrolo[2,3-e]-, and furo[3,2-e]limidazo[1,2,-b]-1,2,4-triazines were studied. A mass spectrometric study was carried out on the decomposition of these products upon electron impact. For Communication 27, see [1]. Kherson Industrial Institute, 325008 Kherson, Ukraine. A. N. Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences, 117071 Moscow. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 258–262, February, 1998.     

Bromination of Substituted 5H-Imidazo[1,2-b]-1,2,4-triazepin-4-ones and -thiones

The reactions of substituted 5H-imidazo[1,2-b]-1,2,4-triazepin-4-ones and -thiones with bromine and N-bromosuccinimide have been studied. Derivatives of 3- and 8-bromo-, 3,8-dibromoimidazo[1,2-b]-1,2,4-triazepine and 5H-2-bromomethyl-3-methyl-7,8-diphenylimidazo[1,2-b]-1,2,4-triazepin-4-one are formed, depending on the degree of substitution, the nature of the brominating agent, and the reaction conditions.     

Convenient synthesis of fused heterocycles from α-ketohydroximoyl chlorides and heterocyclic amines

Nitroso derivatives of imidazo[1,2-a]pyridine ( 11, 13, 14 ), imidazo[1,2-a]pyrimidine ( 15 ), imidazo[1,2-a]pyrazine ( 16 ), imidazo[1,2-b]pyrazole ( 17 ), and imidazo[1,2-b]-1,2,4-triazole ( 19 ) were obtained in good yields from α-ketohydroximoyl chlorides 3 and 2-aminopyridines ( 4–6 ), 2-aminopyrimidine ( 7 ), 2-aminopyrazine ( 8 ), 5-amino-3-phenylpyrazole ( 9 ), and 3-amino-2H-1,2,4-triazole ( 10 ), respectively. Under different conditions, the reaction of 3 with 3-amino-2H-1,2,4-triazole ( 10 ) and 2-aminopyrazine ( 8 ) afforded the noncyclized substitution products 18 and 22 , respectively. The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectral data, and alternate synthesis wherever possible.     

Regioselectivity of cyclization of 3-allyl(propargyl)sulfanyl-5<Emphasis Type="Italic">H</Emphasis>-[1,2,4]triazino[5,6-<Emphasis Type="Italic">b</Emphasis>]indoles

The interaction of 3-allylsulfanyl-5H-[1,2,4]triazino[5,6-b]indole with iodine led to 1-iodomethyl-1,2-dihydro[1,3]thiazolo[2',3':3,4][1,2,4]triazino[5,6-b]indol-11-ium pentaiodide with an angular structure, on the basis of which 1-iodomethyl-1,2-dihydro[1,3]thiazolo-, 1-methylidene-1,2-di-hydro[1,3]thiazolo, and 1-methyl[1,3]thiazolo derivatives were obtained. The intramolecular cyclization of 3-propargyl(allyl)sulfanyl-5H-[1,2,4]triazino[5,6-b]indoles under the influence of concentrated sulfuric acid led to linear annelated products:3-methyl[1,3]thiazolo[3',2':2,3][1,2,4]tri-azino[5,6-b]indole or its 2,3-dihydro derivative.     

Electron ionization mass spectra and crystal structures of some [1,2,4]triazolo[1,2-b]- and [1,3,4]thiadiazolo[3,4-b]phthalazines

The mass spectra of ten 1,3-dithioxo[1,2,4]triazolo[1,2,-b]phthalazines, five 3-iminosubstituted 1-thioxo-[1,3,4]thiadiazolo[3,4-b]phthalazines, three 3-iminosubstituted-1-thioxo[1,2,4]triazolo[1,2-b]phthalazines, and 1,3-dithioxo-5,10-dihydro[1,3,4]thiadiazolo[3,4-b]phthalazine were recorded under electron ionization. The fragmentation pathways were elucidated by metastable ion analysis and exact mass measurements. The changes in the ring-system had little effect on the fragmentation mechanism, but the effect on peak intensities was considerable. The most important fragmentations began with the opening of the triazole ring. Substituents at nitrogen atoms also had a marked effect on the mass spectral behavior. The aryl substituents prompted a whole new fragmentation. The X-ray crystal structure was determined for a few compounds. Two of the three structures of the 1,3-dithioxo[1,2,4]triazolo[1,2-b]phthalazines that were studied proved to be relatively planar, whereas the structure of 1,3-dithioxo-5,10-dihydro[1,3,4]thiadiazolo[3,4-b]phthalazine was considerably bent similarly to the 2-(4-chlorophenyl)-1,3-dithioxo-2,3,5,10-tetrahydro[1,2,4]triazolo[1,2-b]-phthalazine. The triazole and the thiadiazole rings had a strong double bond nature.     

Heterocyclization of 3-(R-amino)-3-methylthio-1-phenylpropenones and 5-benzoyl-6-methylthio-1,2-dihydropyridin-2-ones with 1,2- and 1,3-dinucleophilic reagents

The interaction of 3-(R-amino)-3-methylthio-1-phenylpropenones and 1-alkyl-5-benzoyl-3-ethoxy-carbonyl-6-methylthio-1,2-dihydropyridin-2-ones with N,N- and N,C-1,2- and 1,3-dinucleophiles proceeded regioselectively by [3 + 2] and [3 + 3] cyclocondensation with the formation of derivatives of pyrazole, benzimidazo[1,2-a]-pyridine, benzimidazo[1,2-a]pyrimidine, imidazo[1,2-a]pyrimidine, [1,2,4]triazolo[4,3-b]pyridazine, and 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine. The regioselectivity of the reactions carried out was analyzed.     

The synthesis of 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles,11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles and 1,2,4-triazolo[3,4-f]-1,2,4-triazino[4,5-a]indoles

This paper describes the synthesis of the previously unknown 11H-1,2,4-triazolo[4,3-b]pyridazino[4,5-b]indoles (2) and 11H-tetrazolo[4,5-b]pyridazino[4,5-b]indoles (3) from 4-hydrazino-5H-pyridazino[4,5-b]indoles (1) , as well as the synthesis of 1,2,4-triazolo[3,4-f]-1,2,4-triazino-[4,5-a]indoles (10) from 2-indolecarbohydrazide (4) . Compounds 2 were obtained by acylation of compounds 1 , followed of thermal cyclization and compounds 3 by treating compounds 1 with nitrous acid. The reactions of compound 4 with formic acid or ethyl orthoformiate gave 1,2-dihydro-1-oxo-1,2,4-triazino[4,5-a]indole (6) . Treating this last compound with phosphorus oxychloride or phosphorus pentasulfide, followed by hydrazine, gave 1-hydrazino-1,2,4-triazino-[4,5-a]indole (9) . Acylation of this last compound, followed of cyclization gave compounds 10 . All the compounds were characterized by elemental analysis and ir and ¹H-nmr spectra.     

Azolo[5,1-<Emphasis Type="Italic">c</Emphasis>]-1,2,4-triazines as a new class of antiviral compounds

Synthetic methods, reactivity, and the properties of a new class of antiviral compounds, pyrazolo-, imidazo-, 1,2,4-triazolo[5,1-c]-1,2,4-triazinones, tetrazolo[5,1-b]-1,2,4-triazinones, and azoloannulated amino-1,2,4-triazines having structural similarity with biogenic purines and capable of mimicking them in metabolic processes are considered. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 967–995, May, 2008.     

Cyclocondensation of 3-amino-2-iminonaphtho[1,2-d]thiazole with oxalic acid derivatives

Refluxing 3-amino-2-iminonaphtho[1,2-d]thiazole ( 1 ) with diethyl oxalate ( 2a ) in a 2:1 molar ratio in dry pyridine provided 2,2′-binaphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole ( 3 ). On the other hand, when 1 was treated with excess amount of 2a in dimethylformamide, it afforded ethyl naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole-2-carboxylate ( 4a ) on heating and ethyl N-(2-iminonaphtho[1,2-d]thiazol-3-yl)oxamate ( 5 ) by stirring at room temperature. Cyclization of 5 upon fusion led to the formation of 3-hydroxy-2H-naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazin-2-one ( 6 ). Compound 6 could also be prepared directly from 1 by refluxing either with 2a neatly, in glacial acetic acid or with oxalic acid ( 2b ) in the same medium. The acid form of 4a might be obtained from 1 and 2b on heating in dimethylformamide, but it was decarboxylated to naphtho-[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazole ( 4b ) during the reaction.     

Ring transformation of 1,5-benzoxazepines into spirobenzoxazoles. Synthesis of pyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines and spiro[benzoxazole-2′(3′H),4(1H)-pyrazolo[5,1-c][1,2,4]triazines]

The reactions of the 3-substituted 4-amino-8-ethoxycarbonyl[5,1-c][1,2,4]triazines 1 and 2 with o-amino-phenol hydrochloride gave the pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines 5 and 8 . The alkylation of 5 with methyl iodide and isopropyl iodide afforded the 6-alkoxylpyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines 6a and 6b , respectively. Refluxing of 5, 6a, 6b and 8 in hydrochloric acid/acetic acid resulted in ring transformation to produce the spiro[benzoxazole-2′(3′H),4(1H)pyrazolo[5,1-c][1,2,4]-triazines] 7a, 7b and 9 . The screening data of the above compounds was described.     

6- and 7-aryl-1,2,4-triazolo[4,3-b]-1,2,4-triazines. Synthesis and characterization

Synthetic methods for the preparation of 6-aryl-1,2,4-triazolo[4,3-b]-1,2,4-triazines ( 1 ) and the 7-aryl isomers ( 2 ) are described. Compounds 1 were prepared from aryl glyoxaldoximes 76 via 6-aryl-1,2,4-triazin-3(2H)ones ( 75 ). A simple procedure for the preparation of the 7-aryl isomers was effected using arylglyoxals 11 and the triazoles ( 4, 12a and 12b ). However, complete regioselectivity was not realized in all cases, especially when the triazoles were substituted at the C-5 position. A regiospecific synthesis of the 7-aryl isomers 2 was developed via the 3-methylthio-5-aryl-1,2,4-triazines ( 61 ). The structure of the parent 6-phenyl derivative 5 was confirmed by x-ray crystallography.     

Synthesis and conversions of 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline

The reaction of the hydrazone 3a with hydrazine hydrate in DBU/ethanol conveniently gave 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 6 . The reactions of 6 with an equimolar and 2-fold molar amount of nitrous acid afforded 3-(α-hydroxyimino-4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethyl)-2-oxo-1,2-dihydroquinoxaline 9 and 3-(α-hydroxyimino-5-methyl-2H-1,2,4-triazol-3-ylmethyl)-2-oxo-1,2-dihydroquinoxaline 10 , respectively, which were converted into the 3-heteroarylisoxazolo[4,5-b]quin-oxalines 13a,b and 11 , respectively. Compound 9 was also cyclized into the 8-quinoxalinyl-1,2,4-triazolo-[3,4-f][1,2,4]triazines 14a,b .     

Theoretical Study of the Formation of Benzofurotriazines by Reaction of 3-Substituted 1,2,4-Triazines and Fused Azolo[1,2,4]triazines with Resorcinol

3-Methylthio- and 3-amino-1,2,4-triazines react with resorcinol to give benzofurotetrahydrotriazine derivatives, while reactions of [1,2,4]triazolo[4,3-b]- and tetrazolo[1,5-b][1,2,4]triazines with resorcinol stop at the stage of resorcinol addition. According to the results of quantum-chemical calculations, the possibility for further cyclization of the resorcinol addition products is determined by the following factors: tautomeric and conformational states of the compounds, which ensure spatial proximity of the hydroxy group to the cyclization center (C⁶); charges on the C⁶ atom of the triazine ring and oxygen atom of the resorcinol fragment in the conformation most favorable for cyclization; and energies of the highest occupied and lowest unoccupied molecular orbitals of the resorcinol addition products.     

Pyrrolo[1,2-d]triazines-1,2,4. II. Etude des pyrrolo[1,2-d]triazinones-1 et -4

The synthesis of 1,2-dihydro-1-oxopyrrolo[1,2-d]-1,2,4-triazines was achieved by rearrangement of 2-pyrrolyloxadiazoles under alkaline conditions or by cyclisation of pyrrole N-ethoxymethylidene hydrazides. The cyclisation of the N-carbethoxy hydrazone of the pyrrole-2-carboxaldehyde gave the 3,4-dihydro-4-oxopyrrolo[1,2-d]-1,2,4-triazine. Electrophilic substitution reactions of the 1- and 4-pyrrolotriazinones were made either on the lactam nitrogen with methyl sulphate, benzyl chloride and monochloroacetic acid or on the pyrrole ring with bromine and nitric acid. The structure of the derivatives was determined by ¹H nmr.     

Reactions with 5-aminopyrazoles. I. Synthesis of halogen-containing fused pyrazoles

5-Amino-3-phenylpyrazole (I) and 5-amino-4-bromo-3-phenylpyrazole (II) reacted with ethyl acetoacetate and acetylacetone to give various pyrazolo[1,5-a]pyrimidines IV-VI and with benzoins to give different fused pyrazoles, namely, imidazo[1,2-b]pyrazoles IX, pyrrolo[2,3-c]pyrazoles X and pyrazolo[4,3-b][1,4]oxazines XII. Diazotized II was coupled with active methylene-containing nitriles to afford pyrazolo[5,1-c]-as-triazines XIV.     

A new method for the synthesis of novel 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines

The reaction of 3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 4 with o-chlorobenzenediazonium chloride gave 3-[α-(o-chlorophenylhydrazono)-2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-ylmethyl]-2-oxo-1,2-dihydroquinoxaline 6 , whose refluxing in phosphoryl chloride/pyridine afforded 1-(o-chlorophenyl)-3-(2,3-dihydro-4-methyl-3-thioxo-4H-1,2,4-triazol-5-yl)-1H-pyrazolo[3,4-b]quinoxaline 7. The reactions of 6 and 7 with nitrous acid resulted in sulfur extrusion to provide 1-(o-chlorophenyl)-3-(4-methyl-4H-1,2,4-triazol-5-yl)1H-pyrazolo[3,4-b]quinoxaline 8 and 3-[α-(o-chlorophenylhydrazono)-4-methyl-4H-1,2,4-triazol-5-ylraethyl]-2-oxo-1,2-dihydroquinoxaline 9 , respectively.     

A new approach to the synthesis of lamotrigine and other 3,5-diamino-1,2,4-triazine derivatives

A new in principle method for the synthesis of 6-aryl(hetaryl)-3,5-diamino-1,2,4-triazines by decomposition of pre-synthesized tetrazolo[1,5-b][1,2,4]triazines was developed. The advantages of this method over traditional methods were demonstrated using the synthesis of a modern antiepileptic preparation lamotrigine, as an example.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 713–719, March, 2005.     

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines via microwave-activated inverse electron demand Diels-Alder reactions

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines have been synthesized from 1,2,4-triazines using the inverse electron Diels-Alder reaction. For this purpose, 3-methylsulfanyl-1,2,4-triazines were reacted with several nucleophiles allowing the formation of appropriately substituted alkynes to undergo the intramolecular inverse electron demand Diels-Alder reaction. Sealed-tube microwave activation of the cycloaddition reaction has proved to be very efficient and allowed shorter reaction times. This strategy enabled an efficient synthesis of 3-hydroxy-2,3-dihydrofuro[2,3-b]pyridines and 4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridines with several points of diversity on the bicyclic scaffold.