The synthesis of 7,8-dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]triazines

Cyclic hydrazino amidines were converted to the corresponding aminopyrazolyl derivatives. Ring closure between the amino groups of pyrazoline moieties and NH groups of cyclic amidines afforded the following ring systems: 7,8-Dihydroimidazo[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines, 8,9-dihydro-7H-pyrimido[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines and 7,8,9,10-tetrahydro[1,3]diazepino[1,2-e]pyrazolo[1,5-a]-1,3,5-triazines.     

Synthesis of unsymmetrical 2,4-dialkylpyrazolo[1,5-a]-1,3,5-triazines

The reaction of 3-aminopyrazole with imidate esters such as ethyl acetimidate, gave N-(pyrazol-3-yl)acetamidine (1) rather than the isomeric 2-acetamidoyl-3-aminopyrazole. Ring closure of 1 with orthoesters such as ethyl propionimidate, afforded unsymmetrically substituted 2.4-dialkylpyrazolo[1,5-a]-1,3,5-triazines such as 4-ethyl-2-methylpyrazolo[1,5-a]-1,3,5-triazine (3). The structure of 1 was confirmed by several alternate syntheses. The unique feature of this two-step synthetic approach to the synthesis of pyrazolo[1,5-a]-1,3,5-triazines is that it is a convenient method of preparing fused triazines based on available pyrazoles rather than the less accessible dialkyltriazines.     

The synthesis and chemical reactions of certain pyrazolo[1,5-a]-1,3,5-triazines

3-Aminopyrazole was utilized as a starting material for the preparation of certain pyrazolo-[1,5-a]-1,3,5-triazines. 4-Chloro-2-methylthiopyrazolo[1,5-a]-1,3,5-triazine was prepared and used for studies of nucleophilic displacement reactions, and it has been found that both the chloro and methylthio groups may be displaced by nucleophiles. By modifications of these procedures we have prepared the adenine, hypoxanthine, and xanthine analogs of the pyrazolo-[1,5-a]-1,3,5-triazine ring system. Electrophilic substitution occurs in the 8-position of this ring system. The methyl group was introduced into the 4-position by a novel ring opening and ring closing of the 1,3,5-triazine ring.     

A general approach toward the synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines

An expedient synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines was developed by treating 8-amino-4-[N-(4-aminophenyl)-N-(methyl)amino]pyrazolo[1,5-a]-1,3,5-triazine with various acyl chlorides following by the displacement of the so-formed N-(methyl)-N-[4-(acylamido)phenyl]amino leaving group with various amines. Applications to high-throughput synthesis are suggested.     

The chemistry of 4-hydrazino-7-phenylpyrazolo[1,5-a] -1,3,5-triazines

The reaction of 4-hydrazino-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 4 ) with nitrous acid gave 8-phenyltetrazolo[1,5-e]pyrazolo[1,5-a]-1,3,5-triazine ( 5b ), which was determined by pmr and ir spectra to be in equilibrium with 4-azido-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 5a ). The equilibrium between the tetrazolo ( 5b ) and azido ( 5a ) forms was studied by pmr and an attempt was made to determine if substituents in the pyrazole nucleus could sufficiently stabilize the tricyclic tetrazolo form ( 5b ) over the bicyclic azido form ( 5a ). Thermal degradation of 5 (a ? b) in an aprotic solvent gave 4-amino-7-phenylpyrazolo[1,5-a]-1,3,5-triazine ( 7 ), indicating the probability of a nitrene mechanism involved in the decomposition. Heating 5 in aqueous base gave both 7 and the “hydroxy” analog, 7-phenylpyrazolo[1,5-a]-1,3,5-triazin-4(3H)one ( 6 ), further substantiating the existence of a nitrene intermediate with a competing nucleophilic displacement of the azido group by a hydroxyl group. Cyclization of 4 with diethoxymethylacetate (DEMA) gave 8-phenyl-s-triazolo[4,3-e]pyrazolo[1,5-a]-1,3,5-triazine ( 8 ), which underwent thermal rearrangement to 8-phenyl-s-triazolo[2,3-e]pyrazolo[1,5-a]-1,3,5-triazine ( 9 ). Acid catalyzed ring opening of 9 with formic acid gave 3-N-formamido-5-phenyl-2(2-s-triazolyl)pyrazole ( 10 ). The failure of 10 to recyclize to 9 with the resultant loss of water, supported the theory that the rearrangement of 8 to 9 might occur simply as a concerted, thermally induced “anhydrous” rearrangement rather than via a covalently hydrated intermediate or a Dimroth type mechanism (in the base catalyzed rearrangement).     

Synthesis of 1,3-dialkylpyrazolo [1,5-a]-1,3,5-triazine-2,4-diones isomers of 1,3-dialkylxanthines

The synthesis of a new series of alkylxanthine analogs containing a bridgehead nitrogen atom is reported. 1,3-Dialkylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones, were prepared by the treatment of 3-methylpyrazolo[1,5-a]-1,3,5-triazine-2,4-dione (3) with the corresponding alkyl iodide. Similarly, the reaction of 3-methyl-7-phenylpyrazolo[1,5-a]-1,3,5-dialkyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones. The starting materials, 3 and 17 , were prepared via the reaction of an appropriate 3-aminopyrazole with ethoxycarbonyl isothiocyanate. Several 8-bromo derivatives were prepared by direct bromination of the 1,3-dialkylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones.     

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.     

Purine analog inhibitors of xanthine oxidase - structure activity relationships and proposed binding of the molybdenum cofactor

A number of new hypoxanthine analogs have been prepared as substrate inhibitors of xanthine oxidase. Most noteworthy inhibitory new hypoxanthine analogs are 3-(m-tolyl)pyrazolo[1,5-a]pyrimidin-7-one ( 47 ), ID₅₀ 0.06 μM and 3-phenylpyrazolo[1,5-a]pyrimidin-7-one ( 46 ), ID₅₀ 0.40 μM. 5-(p-Chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-one ( 63 ) and the corresponding 5-nitrophenyl derivative 64 exhibited an ID₅₀ of 0.21 and 0.23 μM, respectively. 7-Phenylpyrazolo[1,5-a]-s-triazin-4-one ( 40 ) is shown to exhibit an ID₅₀ of 0.047 μM. The structure-activity relationships of these new phenyl substituted hypoxanthine analogs are discussed and compared with the xanthine analogs 3-m-tolyl- and 3-phenyl-7-hydroxypyrazolo[1,5-a]pyrimidin-5-ones ( 90 ) and ( 91 ), previously reported from our laboratory to have ID₅₀ of 0.025 and 0.038 μM, respectively. The presence of the phenyl and substitutedphenyl groups contribute directly to the substrate binding of these potent inhibitors. This work presents an updated study of structure-activity relationships and binding to xanthine oxidase. In view of the recent elucidation of the pterin cofactor and the proposed binding of this factor to the molybdenum ion in xanthine oxidase, a detailed mechanism of xanthine oxidase oxidation of hypoxanthine and xanthine is proposed. Three types of substrate binding are viewed for xanthine oxidase. The binding of xanthine to xanthine oxidase is termed Type I binding. The binding of hypoxanthine is termed Type II binding and the specific binding of alloxanthine is assigned as Type III binding. These three types of substrate binding are analyzed relative to the most potent compounds known to inhibit xanthine oxidase and these inhibitors have been classified as to the type of inhibitor binding most likely to be associated with specific enzyme inhibition. The structural requirements for each type of binding can be clearly seen to correlate with the inhibitory activity observed. The chemical syntheses of the new 3-phenyl- and 3-substituted phenylpyrazolo[1,5-a]pyrimidines with various substituents are reported. The syntheses of various 8-phenyl-2-substituted pyrazolo-[1,5-a]-s-triazines, certain s-triazolo[1,5-a]-s-triazines and s-triazolo[1,5-a]pyrimidine derivatives prepared in connection with the present study are also described.     

Reaction of enol type acyl cyanide with o-aminophenol

The reaction of 7-chloro-4-(2-cyano-2-hydroxyvinyl)tetrazolo[1,5-a]quinoxaline 2a with o-aminophenol gave 7-chloro-4-(b-hydroxyphenylcarbamoylmethylene)4,5-dihydrotetrazolo[1,5-a]quinoxaline 4 , while the reaction of compound 2a with o-aminophenol hydrochloride afforded 4-[2-(2-benzoxazolyl)-2-hydroxyvinyl]-7-chlorotetrazolo[1,5-a]quinoxaline 5 , whose acetylation provided 4-[2-acetoxy-2-(2-benzoxazolyl)vinyl]-7-chlorotetrazolo[1,5-a]quinoxaline 6 . The behavior in a deuteriodimethyl sulfoxide or deuteriotrifluoroacetic acid solution is described for compounds 4–6 .     

Condensed tetrazolo-1,3,5-triazines. 4. Synthesis of salts of 5-aminotetrazolo[1,5-a]-1,3,5-triazin-7-one

2-Amino-4-azido-1,3,5-triazin-6(1H)-ones were synthesized by successive substitution of the trinitromethyl groups in 2-amino-4,6-bis(trinitromethyl)-1,3,5-triazines under the influence of azide and nitrite ions. Interaction of 2-amino-4-azido-1,3,5-triazin-6(1H)-ones with bases led to the azido-tetrazole tautomeric conversion give salts of 5-aminotetrazolo[1,5-a]-1,3,5-triazin-7-one. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1211–1219, August, 2006.     

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.     

Condensed Tetrazolo-1,3,5-triazines. 1. Synthesis of 5-Polynitromethyltetrazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]-1,3,5-triazin-7-one Salts

The aziridation of 2-R-4,6-bis(trinitromethyl)-1,3,5-triazines containing electron-donor substituents has been studied. It was found that the corresponding 4-azido-2-dialkylamino-6-trinitromethyl-1,3,5-triazines are formed when R = NMe₂, NEt₂. When R = O^–NMe₄ ⁺ a novel reaction route was discovered leading to the tetramethylammonium salt of 5-polynitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-one which is formed as a result of azido-tetrazole and lactim-lactam tautomeric conversion. Denitration of this salt at the trinitromethyl group occurs with retention of the tetrazolo-1,3,5-triazine structure. An X-ray analysis was carried out for the denitration product which was the dipotassium salt of 5-dinitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-one.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 259–266, February, 2005.     

Reactions of 4-oxobenz[1,3-e]oxazinium perchlorates with α-aminoazoles

Reactions of 4-oxo benz[1,3-e]oxazinium perchlorates with 1-R¹-3-R²-5-aminopyrazoles lead to the formation of derivatives of pyrazolo[3,4-d]pyrimidine and pyrazolo[1,5-a]1,3,5]triazine series, and with 3-amino-1,2,4-triazole, to [1,2,4]triazolo[1,5-a][1,3,5]triazines.     

Neue Synthesen von Pyrazolo[1,5-a]-s-triazinen

Two new syntheses of pyrazolo[1,5-a]-s-triazines are reported: (a) Addition of acetyl isocyanate to 5-amino-3-methyl-pyrazole followed by hydrolysis yields N-(3-methyl-5-pyrazolyl)-urea ( 15 ), which on cyclisation with triethyl orthoacetate gives 2-hydroxy-4,7-dimethylpyrazolo[1, 5-a]-s-triazine ( 16 ). (b) Condensation of aminoguanidine with β-oxo-nitriles affords 1-amidino-5-aminopyrazoles 18 . These are cyclised to pyrazolo[1,5-a]-s-triazines 19--21 by reaction with orthoesters, acetic-formic anhydride, phenylisocyanide dichloride, dimethyl oxalate, N, N′-carbonyldiimidazole, and N, N′-thiocarbonyldiimidazole. The 4-amino group in 19 is converted by standard procedures to OH, SH, SCH₃, Cl and NRR′. Reaction of pyrazolo[1,5-a]-s-triazines 30 with electrophiles leads to compounds substituted at position 8, e.g. 32a--e .     

A synthesis of new 7-amino-substituted 4-aminopyrazolo[1,5-a][1,3,5]triazines via a selective three-component triazine ring annulation

3-Amino-substituted 5-aminopyrazoles were found to be suitable substrates for the synthesis of new 4-aminopyrazolo[1,5-a][1,3,5]triazines (5-aza-9-deaza-adenines) when used in the one-pot, three-component reaction with cyanamide and triethyl orthoformate under microwave irradiation. The reaction proceeded selectively and its scope was demonstrated by the preparation of a library of 4-aminopyrazolo[1,5-a][1,3,5]triazines. Some structural aspects of the prepared compounds were investigated using dynamic NMR spectroscopy and X-ray crystallography. The operational simplicity, short reaction time, and good reproducibility are attractive features of the developed robust and practical approach for the synthesis of 7-amino-substituted 4-aminopyrazolo[1,5-a][1,3,5]triazines.     

Nucleosides CV. Synthesis of the 8-((β-D-ribofuranosyl)pyrazolo[1,5-a]-1,3,5-triazine isosteres of adenosine and inosine

Reaction of ethyl N-cyanoformimidate ( 3 ) and of ethyl N-carbelhoxyformimidate ( 5 ) with 3-aminopyrazole ( 2 ) gave 4-amino- and 4-oxo-3H-pyrazolo[1,5-a]-1,3,5-triazine ( 4 and 7 ), respectively. Reaction of 3-amino-4-(2,3-O-isopropylidene-5-O-trityl-β-D-ribofuranosyl)pyrazole ( 8 ) with the same reagents similarly gave the blocked 4-amino-8-ribosyl- and 4-oxo-3H-8-ribosyl-pyrazolo[ 1,5-a]-1,3,5-triazine ( 9 and 15 ), respectively. Deblocking in acid finally afforded the unblocked products 10 (an isostere of adenosine and formycin) and 16 (an isostere of inosine and formycin B). The corresponding derivatives in the a series were made by identical procedures for confirming all structural assignments. Preliminary in vitro testing results of 10 are included.     

Structural characterization of 1,3,4-thiadiazolo[3,2-a][1,3,5]triazines by electron impact mass spectrometry

The electron-impact-induced fragmentation of eleven 1,3,4-thiadiazolo[3,2-a][1,3,5]triazines was investigated with the aid of exact mass measurements, B/E and B²/E linked scans, and deuterated compounds. The dominating breakdown process in the electron impact mass spectra of 2-substituted 6-phenyl-1,3,4-thiadiazolo[3,2-a]-[1,3,5]triazine-5,7-diones (1–5) is a retro-Diels-Alder reaction. This process gives rise to the base peak, whereas the molecular ions are of very low intensity. In the mass spectra of 2-substituted 7-methylthio-1,3,4-thiadiazolo-[3,2-a][1,3,5]triazine-5-ones (6–11) in which this fragmentation cannot occur because of the two conjugated double bonds in the triazine ring, the molecular ions are very intense. The mass spectral data permits an unequivocal structure assignment to these compounds, which are otherwise difficult to characterize.     

The synthesis of certain 8-cyano-2,4-disubstituted-imidazo[1,5-a] pyrimidines

A number of imidazo[1,5-a]pyrimidine-8-carboxamides were synthesized by reacting various β-dicarbonyl compounds with 5(4)-aminoimidazole-4(5)carboxamide (AICA, 1 ), the non-ribosylated form of AICAR, a key intermediate in the metabolic pathway of purine biosynthesis. Cyclization of 1 with ethylacetoacetate yielded 2-methylimidazo[1,5-a]pyrimidin-1H-4-one-8-carboxamide ( 2 ). The treatment of 2 with phosphorus oxychloride gave 4-chloro-8-cyano-2-methylimidazo[1,5-a]pyrimidine ( 3 ). Various nucleophiles displaced the 4-chloro substituent of 3 under mild conditions. However, the 4-methylthio group of 8-cyano-2-methyl-4-methylthioimidazo[1,5-a)pyrimidine ( 8a ) was also displaced under very mild conditions. Even more strangely, the 4-diethylamino group of 8-cyano-4-diethylamino-2-methylimidazo[1,5-a]pyrimidine ( 5a ) was displaced by ammonia to give 4-amino-8-cyano-2-methylimidazo[1,5-a]pyrimidine ( 7 ).     

A facile synthesis of enol type acyl cyanides via a 1,3-dipolar cycloaddition reaction and a cyano group migration

The reaction of 7-chlorotetrazolo[1,5-a]quinoxaline 5-oxide 4a or 7-chloro-1,2,4-triazolo[4,3-a]quinoxaline 5-oxide 4b with 2-chloroacrylonitrile gave 7-chloro-4-(2-cyano-2-hydroxyvinyl)tetrazolo[1,5-a]quinoxaline 5a or 7-chloro-4-(2-cyano-2-hydroxyvinyl)-1,2,4-triazolo[4,3-a]quinoxaline 5b , respectively. Alcoholysis of compound 5a or 5b afforded 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydrotetrazolo[1,5-a]quinoxaline 6a or 7-chloro-4-ethoxycarbonylmethylene-4,5-dihydro-1,2,4-triazolo[4,3-a]quinoxaline 6b , respectively. Compounds 5a,b were found to exist as a syn and anti mixture of the enol form, while compounds 6a,b occurred as the enamine and methylene imine forms. The tautoraeric character and/or D-H exchange of the vinyl protons are described for compounds 5a,b and 6a,b .     

Synthesis of nitrogen-containing heterocycles. 5. A new route to 5-amino-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives

Treatment of certain diaminomethylenehydrazones 1 of aromatic carbonyl compounds with ethyl N-cyanoimidate ( 2 ) in acetonitrile in the presence of a tertiary amine at room temperature gives the corresponding amino(N-cyanoiminomethyl)aminomethylenehydrazones 3 in high yields. The intermediate 3 can readily be cyclized to the corresponding 5-amino-2,3-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines 4 in moderate to good yields by brief heating in acetonitrile. When the reaction of diaminomethylenehydrazones 1 with ethyl N-cyanoimidate ( 2 ) is performed at reflux temperature in the presence of a tertiary amine, 5-amino-2,3-dihydro[1,2,4]triazolo[1,5-a]1,3,5]triazines 4 can be directly obtained in moderate yields. The yields of triazolotriazine produced by the one-step synthesis are generally comparable or even higher than the overall yields from the two-step procedure.