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.     

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.     

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.     

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.     

Mass spectra of substituted pyrazolo[1,5-a]-1,3,5-triazines

High resolution electron impact mass spectrometric measurements have been made on twelve pyrazolo[1,5-a]-1,3,5-triazines. Substituents attached to carbon atoms 2, 4, 7, and 8 were used to label the various fragments. Three major ions were observed (a) the molecular ion, (b) an ion corresponding to M-RCN where R is the substituent attached to C-4 and (c) an aryl cyclopropenyl cation which was observed in 7-aryl derivatives. Intensities and accurate mass-measurements are given for all ions having intensities exceeding 2% of the base peak. Nine of the twelve pyrazolo-[1,5-a]-1,3,5-triazines included in this study are described here for the first time.     

Reaction of ethyl 3-ethoxymethylene-2,4-dioxovalerate and ethyl ethoxymethyleneoxaloacetate with 3-aminopyrazole analogs. Synthesis and chemistry of 3,6,7-trisubstituted pyrazolo[1,5-a]pyrimidine derivatives

The chemical reactivity of a series of 3-substituted-6-acetyl-7-carbethoxypyrazolo[l,5-a]pyrimidines ( 6a,b,c ) and 3-substituted-6,7-dicarbethoxypyrazolo[1,5-a]pyrimidines ( 7a,b,c ), prepared by the condensations of the 3-aminopyrazole analogs ( 3a,b,c ) with ethyl 3-ethoxymethylene-2,4-dioxovalerate ( 1 ) or ethyl 3-ethoxymethyleneoxaloacetate ( 2 ), was investigated. Catalytic hydrogenation of 6 or 7 afforded 4,7-dihydro derivatives ( 8 or 9 ). Treatment of 6a,b with acetic acid and water underwent ring transformation into 6H-pyrazolo[1,5-a][1,3]diazepin-6-ones ( 17a,b ). By treatment with phenylhydrazine compounds of type 6 underwent cyclization to yield 2H-dipyrazolo[1,5-a:4′,3′-e]pyrimidines ( 18a,b,c ). Compounds 6 or 7 were treated with an excess of diazomethane at room temperature to give 5-methyl-6H-cyclopropa[5a,6a]pyrazolo-[1,5-a]pyrimidines ( 24 and 25 ) in excellent yields. However, when this reaction was carried out under ice cooling, only compounds of type 23 were isolated. Reaction of 6a with ethyl diazoacetate is also described.     

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).     

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.     

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.     

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.     

Reaction of 5-aminopyrazole derivatives with ethoxymethylene-malononitrile and its analogues

A one-pot synthesis using 5-aminopyrazole derivatives 1 with ethoxymethylenemalononitrile (EMMN), ethyl ethoxymethylenecyanoacetate (EMCA) or diethyl ethoxymethylenemalonate (DEMM) gave pyrazolo-[1,5-a]pyrimidine compounds 2,4,8 . Also, the one step reaction of EMCA with hydrazine hydrate afforded ethyl(4-ethoxycarbonyl-5-pyrazolyl)aminomethylenecyanoacetate 3c . On the other hand, the reaction of 1-substituted 5-aminopyrazole-4-carboxamide 9 with EMMN afforded pyrazolo[3,4-d]pyrimidine compounds 10 .     

Synthesis of pyrazolo[1′,5′:1,2]-1,3,5-triazino[5,6-a]benzimidazoles

The synthesis of a new class of tetracyclic bridgehead heterocycle pyrazolo[1′,5′:1,2]-1,3,5-triazino[5,6-a] benzimidazoles is reported. The key intermediate 2-(3-aminopyrazol-2-yl)benzimidazoles were prepared by the reaction of 2-hydrazinobenzimidazole with an appropriate reagent such as ethyl ethoxymethylenecyanoacetate, ethoxymethylenemalononitrile, β-cyanoacetophenone or α-formylphenylacetonitrile. The treatment of these key intermediates with triethylorthoesters afforded the corresponding pyrazolo[1′,5′:1,2]-1,3,5-triazino[5,6-a]benzimidazoles.     

Ring transformation reactions of C-nucleosides: Facile synthesis of pyrazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]triazine C-nucleosides

1,3-Dimethyluracil ( 1 ), a versatile synthon for the synthesis of various heterocycles, reacted readily with 3-aminopyrazoles 2 in sodium ethoxide to give pyrazolo[1,5-a]pyrimidines 3 . Under similar conditions, 3-aminopyrazole C-nucleosides 4 and the synthon 1 gave a mixture of pyrazolo[1,5-a]pyrimidine C-nucleosides, which was separated on a silica gel column. Attempts to remove the protecting groups yielded pyranose derivative 10 . Another synthon 1,3-dimethyl-5-azauracil and 3-aminopyrazoles 12 gave pyrazolo[1,5-a]triazines 13 . In a similar reaction with 3-aminopyrazole C-nucleosides 4 gave the corresponding pyrazolo[1,5-a]-triazine C-nucleosides 14 and 15 .     

Ring transformation of 6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine. IV (1). Reduction and reaction of 5a-acetyl-6a-ethoxycarbonyl-5a,6a-dihydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine-3-carbonitriles with primary amines

The reaction of 5a-acetyl-6-ethoxycarbonyl-5a,6a-dihydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine-3-carbonitrile ( 1a ) with benzylamine gave ethyl l-benzyl-5-cyano-8a,9-dihydro-2-methyl-1H-pyrrolo[3,4-e]-pyrazolo[1,5-a]pyrimidine-8a-carboxylate ( 2a ), in addition to 5-acetyl-3-benzylamino-1-(4-cyanopyrazol-3-yl)- 2-pyridone ( 3 ). Reaction of 1a with aniline gave ethyl 6-acetyl-8-anilino-3-cyano-7,8-dihydro-4H-pyrazolo-[1,5-a][1,3]diazepine-8-carboxylate ( 4 ), in addition to ethyl 3-cyano-7-methyl-6-pyrazolo[1,5-a]pyrimidine-acrylate ( 5 ). On the other hand, the same reactions of 1b with benzylamine or aniline gave 2b or 8b , respectively. Though catalytic hydrogenation of 1a over 5% palladium-carbon proceeded by ring fission of cyclopropane ring to give 9 , 1a (or 1b ) afforded 4,5-dihydro derivatives ( 13 or 15 ) by catalytic hydrogenation over platinum oxide. The reactivity of 5-methoxy-4,5,5a,6a-tetrahydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine ( 16 ), which are related analogs of 1a,b , is also described.     

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.     

Synthesis of some fused triazoloquinolines

The reaction of 3 -amino-1,2,4-triazolo[4,3-a]quinoline ( II ) with diethyl ethoxymethylenemalonate and ethyl acetoacetate/ethyl trifluoroacetoacetate afforded 10-carboethoxy-9-oxo-9H-pyrimido[1′,2′:1,5][1,2,4]triazolo-[4,3-a]quinoline ( III ) and 11-methyl/trifluoromethyl-9-oxo-9H-pyrimido[1′,2′:1,5][1,2,4]triazolo[4,3-a]quinoline ( IV/V ) respectively. 2-Chloropyridine-3-carboxylic acid chloride reacted with II to yield 5-oxo-5H-pyrido-[3″,2″:5′,6′]pyrimido[1′,2′:1,5][1,2,4]triazolo[4,3-a]quinoline ( VII ), a new ring system.     

Synthesis of New Pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidines and Their Use in the Preparation of Tetraheterocyclic Systems

8,10-Dimethyl-3-(unsubstituted, methyl, ethyl, n-butyl, phenyl)-4-hydroxypyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidin-2(1H)-ones and 3-(2-hydroxyethyl)-2,8,10-trimethylpyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidin-4-ol were synthesized by cyclocondensation of 3-amine-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine with ethyl malonates and α-acetyl-γ-butyrlolactone. Dichloro- and diazido- derivatives were obtained from the reaction of pyridopyrazlopyrimidine derivatives with POCl₃ followed by NaN₃. The tetrahetrocyclic systems were formed by cyclization of 4-chloro-3-(2-chloroethyl)-2,8,10-trimethylpyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine with the appropriate primary amines. The structures of all compounds were established by NMR and mass spectra.     

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.     

Heterocycles of biological importance. Part 1. Novel synthesis and biological activity study of 5-Alkyl and 5-Aryl-7-aminopyrazolo[1,5-a]-pyrimidines from allenic or acetylenic nitriles and 3-aminopyrazole

Allenic nitriles react with 3-aminopyrazole in ethanol or dimethylformamide to give 5-alkyl-7-aminopyrazolo[1,5-a]pyrimidines 5 of pharmaceutical interest in good yields. 3-Phenylpropynenitrile reacts with 3-aminopyrazole in a similar manner to give the aryl compound 8 .     

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.