New routes to the v-triazolo[1,5-a]pyridine and pyrazolo[1,5-a]pyridine ring systems

New routes to the v-triazolo[1,5-a]pyridine and pyrazolo[1,5-a]pyridine ring systems are described. Treatment of the N-amine salts of 2-picolinealdehyde oxime or 2-pyridyl ketone oximes with polyphosphoric acid gave v-triazolo[1,5-a]pyridines in fair yields. Treatment of 2-picolyl ketones or their oximes with O-mesitylenesulfonylhydroxylamine produced directly pyrazolo-[1,5-a]pyridines. These reactions were extended to the quinoline cases.     

On triazoles XXIV . Synthesis of cycloalka[1,2,4]triazolo[1,5-a]pyrimidinones

The uv and nmr spectral data of some 6,7,8,9,10,11-hexahydrocyclohepta[d][1,2,4]triazolo[1,5-a]pyrimidin-5-one, 5,6,7,8,9,11-hexahydrocyclohepta[e][1,2,4]triazolo[1,5-a]pyrimidin-10-one, 6,7,8,9,10,11-hexahydrocycloocta[d][1,2,4]triazolo[1,5-a]pyrimidin-5(12H)-one, 5,6,7,8,9,10-hexahydrocycloocta[e][1,2,4]triazolo[1,5-a]-pyrimidin-11(12H)-one, 6,7,8,9,10,11,12,13,14,15-decahydrocyclododeca[d][1,2,4]triazolo[1,5-a]pyrimidin-5(16H)-one and 5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[e][1,2,4]triazolo[1,5-a]pyrimidin-15(16H)-one as well as their N-benzylated derivatives representing six novel ring systems were compared to prove their structure. The N-benzylation of the highly insoluble cyclic amides to yield the isomeric N-benzyl derivatives 3/1, 3/2 and 3/3 distinguished by INAPT was performed through their readily soluble tetrabutylammonium salts.     

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.     

Stereoselectivity in the Addition of 1,3-Dipolarophiles to 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes

Thermolysis of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes in the presence of N-arylmaleimides having a substituent in the ortho position of the aromatic ring leads to predominant formation of the corresponding trans-9-arylperhydropyrazolo[1,2-a]pyrrolo[3,4-c]pyrazole-1,3-diones. 6-Aryl-1,5-diazabicyclo[3.1.0]hexanes react with fumaric acid derivatives in a stereoselective fashion, affording perhydropyrazolo[1,2-a]pyrazoles with a trans,trans configuration.     

Reactivity of 7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines: Synthesis of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as potential benzodiazepine receptor ligands. 1

A series of 7-methylpyrazolo[1,5-a]pyrimidines were reacted with dimethylformamide dimethylacetal to give the corresponding dimethylaminovinyl derivatives. These were reacted with ammonium acetate affording, through a ring closure, a number of 6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidines bearing various substituents on the pyrazole ring. The 6-acetyl-2-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine was used as starting material for obtaining some O-alkyl derivatives. Catalytic transfer hydrogenation of 2-benzyloxy-6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine led to the 2-hydroxy derivative.     

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).     

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 .     

The synthesis of [1]benzothieno[2,3-c]quinolines, [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline,and [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline

Photocyclization of 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamide 10 afforded [1]benzothieno[2,3-c]-quinolin-6(5H)-one 11 which was chlorinated to 6-chloro[1]benzothieno[2,3-c]quinoline 12 followed by dechlorination to give [1]benzothieno[2,3-c]quinoline 5 . A series of 6-substituted alkoxy and thioalkoxy[1]benzothieno[2,3-c]quinoline derivatives were prepared along with the N-methyl quaternary salt 13 of 5 . 6-Chloro[1]-benzothieno[2,3-c]quinoline 12 was converted into 6-hydrazino[1]benzothieno[2,3-c]quinoline 23 which upon treatment with formic acid yielded [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline 6 . Treatment of 23 with nitrous acid resulted in [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline 7 . Compounds 6 and 7 are novel heterocyclic ring systems.     

Tautomeric structure of dihydropyrazolo[1,5-a]-pyrimidin-7-one in a solution. A facile synthesis of novel 6-quinoxalinyldihydropyrazolo[1,5-a]pyrimidin-7-ones by ring transformation

6-Quinoxalinyldihydropyrazolo[1,5-a]pyrimidin-7-ones 4a-d were synthesized by the ring transformation of 3-(N,N-dimethylcarbamoyl)furo[2,3-b]quinoxaline hydrochloride 5 . Compounds 4a-d were found to exist as the 4,7-dihydro-7-oxo form E in dimethyl sulfoxide based on the nmr spectral data.     

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.     

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.     

Reactivity of 7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines: Synthesis of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as potential benzodiazepine receptor ligands. 2

A series of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-6-ones was obtained by reaction of ammonium acetate with ethyl 7-dimethylaminovinylpyrazolo[1,5-a]pyrimidine-6-carboxylates and these had been prepared from ethyl 7-methylpyrazolo[1,5-a]pyrimidine-6-carboxylates by reaction with dimethylformamide dimethylacetal. Under these conditions the compounds bearing a 2-hydroxy group were also O-alkylated. During the preparation of the ethyl 2-hydroxy-7-methyl-3-phenylpyrazolo[1,5-a]pyrimidine-6-carboxylate the corresponding 5-methyl isomer was isolated and identified.     

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 .     

Aza-2-dienes-1,3. Partie 5. Préparation de N-aminoimidazoles, 3H-pyrroles,triazolo[1,2,4][1,5-a]pyrazines et imidazo[1,2-a]pyrazines

2-Aza-1,3-dienes. Access to N-Aminoimidazoles, 3H-Pyrroles, [1,2,4]Triazolo[1,5-a]pyrazines, or Imidazo[1,2-a]pyrazines Nucleophilic attack of 5-(dialkylamino)-2-aza-1,3-diene-1,1-dicarbonitriles (or their 1-methoxycarbonyl analogous) by hydrazines or hydrazdes gives substituted N-aminoimidazoles, [1,2,4]triazolo-[1,5-a]pyrazines, or α-dihydrazino derivatives. With α-amino esters (or analogous), imidazo[1,2-a]pyrazines are produced. Addtion of cyanide anions occurs also with formation of substituted 3H-pyrroles. Structures and rationalisation of this nucleophilic attack are discussed.     

1,2,4-Triazoles. XXV. The effect of pyridine substitution on the isomerization of s-Triazolo[4,3-a] pyridines into s-Triazolo[1,5-a] pyridines

The isomerization of s-triazolo[4,3-a]pyridines into s-triazolo[1,5-a]pyridines is greatly facilitated by electron withdrawing nitro substituents in the pyridine ring and retarded by electron donating amino groups.     

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 ).     

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.     

Synthesis of N-Alkylated Derivatives of Pyrazolo[1,5-a]pyrimidine and Their Reaction with Methylamine

With the object of studying the factors influencing the course of enamine rearrangements, we have carried out the N-alkylation of alkyl- and aryl-substituted pyrazolo[1,5-a]pyrimidines. Using the NOEDIF NMR spectroscopic method for the cases of 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidines it was found that addition of the alkyl group occurs at the N₍₄₎ atom of the pyrimidine fragment in the pyrazolo[1,5-a]pyrimidine. It was shown that, when reacting with an alcoholic solution of methylamine, the 5,7-dimethyl-2-phenyl- and 2,5,7-triphenylpyrazolo[1,5-a]pyrimidine iodomethylates undergo decomposition to give 5-methylamino-3-phenylpyrazole and 5-(1,3-diphenyl-3-methylamino-2-propenylid-1-ene)amino-3-phenylpyrazole.     

Polarized ethylene. V. Synthesis of 1-substituted indolizine,pyrazolo[1,5-a]pyridine,and their related compounds using methoxyethylene derivatives

The reaction of pyridinium or isoquinolinium N-ylides with methoxy-substituted ethylenes gave the corresponding indolizine and pyrrolo[2,1-a]isoquinoline derivatives bearing acetyl, aroyl, cyano, ester group at the 1-position in one step. Pyrazolo[1,5-a]pyridine, pyrazolo[1,5-a]quinoline, and pyrazolo[5,1-a]isoquinolines were also synthesized in good yields from the corresponding aromatic N-imines and methoxyethylene derivatives.     

A synthesis of 6-functionalized 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines

6-Unsubstituted 7-R-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines (R = H or Me) were synthesized via two pathways: (a) deacylation of the corresponding 5-acetyl Biginelli-like precursors in KOH/H₂O and (b) reduction of the corresponding 1,2,4-triazolo[1,5-a]pyrimidines using LiAlH₄. The products could be easily formylated at position 6, which is promising for the further synthesis of functionalized 6-substituted derivatives of 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. In contrast, 6-acetyl-7-(4-(N,N-dimethylaminophenyl))-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine undergoes a cascade process in KOH/H₂O, leading to the formation of a 4,5,8,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline derivative.