Studies with polyfunctionally substituted heteroaromatics: New routes for the synthesis of polyfunctionally substituted pyridines and 1,2,4-triazolo[1,5-a]pyridines

The 1-substituted ethylidenemalononitriles 1a–c condensed with triethyl orthoformate in refluxing acetic anhydride to yield the dienes 2a–c . On the other hand, a mixture of N,N-dimethylformamide and triethyl orthoformate condensed with 1a–d to yield the N,N-dimethylaminopentadienonitriles 2d–g . The pentadienonitriles 2d–g were also formed from the reaction of 1a–d with dimethylformamide dimethylacetal in refluxing acetic acid. When compounds 1a–c were treated with dimethylformamide dimethylacetal in refluxing p-xylene, a mixture of 3 , 4 and 2e–g was formed. The reaction of 2a , b with hydrazine hydrate afforded the N-amino-2-iminopyridines 5a , b . These were converted into the triazolo[1,5-a]pyridines 8a–d on treatment with benzoyl chloride and with dimethylformamide dimethylacetal. On the other hand, the reaction of 2c with hydrazine hydrate afforded the pyrazolo[3,4-b]pyridine 7c . Treatment of 2a , c or 2e , g with cyanoethanoic hydrazide afforded the N-(cyanoacetamido)pyridines 9a , b . The dienes 2d , f , g afforded the pyridones 11a–c on treatment with acetic acid and hydrochloric acid mixture. Compounds 11b , c were also formed on treatment of 2b , c with acetic acid hydrochloric acid mixture. The reaction of 2d , g with ethanolic sodium ethoxide gave the ethoxypyridines 13a , b .     

Studies with polyfunctionally substituted heteroaromatics: A facile route for the synthesis of polyfunctionally substituted N-aminopyridines, 1,2,4-triazolo[1,5-a]pyridines and isoquinolines

The reactions of formaldehyde and acetaldehyde with active methylene compounds, followed by reaction with cyanoacetic acid hydrazide 2, afforded N-aminopyridine-2-one derivatives 5a-f. In contrast, the reactions of cyanoacetic acid hydrazide 2 with aliphatic aldehydes and cyanothioacetamide afforded pyridinethione derivatives 11a-b. Also, the reactions of active methylene compounds with formaldehyde and cyanoacetamide afforded pyridin(1H)-2-one derivatives 12a-c. The reactions of 5b with aldehydes and ketones afforded compounds 13a, b, 14, and 15, respectively. The reactions of 5b with arylidinemalononitriles 16a,b afforded isoquinoline derivatives 19a,b. Compound 19b by hydrolysis gave the final product 20. Compound 20 could also be formed by hydrolysis of 5b to give 21, followed by the reaction with 16b. © 1997 John Wiley & Sons, Inc.     

An unequivocal synthesis of some substituted 1,2,4-triazolo[1,5-a]pyrimidines

An unequivocal synthesis of 5-chloro-7-methyl- (8) and 7-methyl-1,2,4-triazolo[1,5-a]pyrimidine (10) from 2-amino-4-chloro-6-methylpyrimidine (5) through the corresponding amidine6 and formamide oxime7 was developed. It was unambigously shown by comparison of the chemical shifts and the magnitude of coupling constants that the compounds obtained by condensation of 3-amino-1,2,4-triazole (12) and ethyl acetoacetate (13) and some further transformations are isomeric 5-methyl substituted 1,2,4-triazolo[1,5-a]pyrimidines1,9, and11.

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Eine eindeutige Synthese einiger substituierter 1,2,4-Triazolo[1,5-a]pyrimidine

Zusammenfassung Es wurde ein eindeutiger Syntheseweg für 5-Chlor-7-methyl- (8) und 7-Methyl-1,2,4-triazolo[1,5-a]pyrimidin (10) ausgehend von 2-Amino-4-chlor-6-methylpyrimidin (5) über das entsprechende Amidin6 und das Formamidoxim7 entwickelt. Durch Vergleich von chemischen Verschiebungen und Kopplungskonstanten konnte eindeutig gezeigt werden, daß die Verbindungen, die bei der Kondensation von 3-Amino-1,2,4-triazol (12) and Ethylacetoacetat (13), sowie einige weitere Transformationsprodukte, isomere 5-Methylsubstituierte 1,2,4-Triazolo[1,5-a]pyrimidine sind (1,9,11).

     

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.     

Regioselective synthesis of novel polyfunctionally substituted pyrazolo[1,5-a]pyrimidines under solvent-free conditions

A series of 2-(pyrazolo[1,5-a]pyrimidin-5-yl)benzoic acids 5 has been prepared by a novel protocol that uses the fusion method between 5-amino-1H-pyrazoles 4 and 3-(3-oxo-2-benzofuran-1(3H)-ylidene)pentane-2,4-dione 3. The use of this novel protocol renders good to excellent yields along with short reaction times. In addition, this solvent-free cyclocondensation proceeds in a regiospecific fashion by intramolecular ring opening of the furane ring in a Michael-type reaction.     

Synthesis of some substituted tetrahydropyrimido[4,5-b][1,6]naphthyridines as potential antitumor agents

Cyclocondensation of two disubstituted 6-aminopyrimidines 11 and 12 with 1-benzyl-3-hydroxymethylene-4-piperidone afforded new tricyclic, linear disubstituted 6,7,8,9-tetrahydropyrimido[4,5-b][1,6]naphthyridines 4 and 5 respectively. Similar cyclocondensation of 11 with 1-benzoyl-1,2,3,6-tetrahydropyridine-5-carboxalde-hyde gave the corresponding benzoylated tetrahydropyrimido[4,5-b][1,6]naphthyridine 6 . Debenzoylation of 6 afforded 7 . 1-Benzyl-3-aminomethylene-4-piperidone when cyclocondensed with 11 also afforded 4 . The linear structures were established by ¹H nmr and ¹³C nmr. The growth of leukemia L1210 cells in culture was inhibited about 50% by 4,5,6 and 7 at 100 μM.     

Tandem synthesis of functionalized tetrahydro-4aH-benzo[c]isoquino[1,2-t]pyrrolo[1,2-a][1,6]naphthyridines

An effective route to fused hexacyclic derivatives of isoquinoline is described via tandem reaction of isoquinoline, dialkyl acetylenedicarboxylates, and 3-chloropentane-2,4-dione or alkyl 3-chloroacetoacetates.     

A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.     

Synthesis of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines and related heterocycles

The reaction between 5-amino-4-imino-1(2)-substituted-1(2)H-4,5-dihydropyrazolo[3,4-d]pyrimidines and several commercially available reactants afforded new heterocycles with a conserved pyrazolo[3,4-d]pyrimidine nucleus. The key intermediates employed proved to be suitable compounds by virtue of their two vicinal amino and imino groups that were used to obtain five, six and seven-membered rings.     

Pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine: a new ring system through Dimroth rearrangement

Derivatives of the new ring system pyrazolo[3,4-d][1,2,3]triazolo[1,5-a]pyrimidine were synthesized from the corresponding angular isomers, through a Dimroth rearrangement, in quantitative yields. Preliminary computational studies demonstrated that this class of compounds could be a good candidate as DNA intercalating agents.     

Microwave-assisted synthesis of 1-aryl-3-acetyl-1,4,5,6-tetrahydrobenzimidazo[1,2-d][1,2,4]triazine: first example of a novel ring system

Novel highly functionalized benzimidazoles were synthesized in two steps by microwave irradiation: construction of the benzimidazole ring followed by ring closure to the new tricyclic system.     

A one-pot,three-component,microwave-promoted synthesis of 2-amino-substituted 7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazines

A new, efficient, catalyst-free, one-pot, three-component method for the synthesis of 2-amino-substituted 7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazines using 3,5-diamino-1,2,4-triazoles, cyanamide, and triethyl orthoformate is developed. The reaction proceeds smoothly under microwave-assisted heating. Advantages of the method include using easily available reagents, short reaction times, and operational simplicity.     

Transformations of tetrahydrobenzo[b][1,6]naphthyridines and tetrahydropyrido[4,3-b]pyrimidines under the action of dimethyl acetylene dicarboxylate

10-Cyanotetrahydrobenzo[b][1,6]naphthyridines 3, 4 undergo addition of DMAD, followed by a Stevens rearrangement of the intermediate ylide to yield methyl dioates 8 and 9. An alternative transformation sequence starts with migration of the dimethyl butenedioate anion to the carbon of the CN group, followed by the addition of 1 mol of water, to provide succinates 10 and 11. In contrast, tetrahydropyrido[4,3-b]pyrimidines 5-7 undergo a tandem cleavage process, involving one molecule of solvent. The resulting enamines are easily cleaved by strong acids, to give dihydropyrymidinylethylamines, which are scarcely available by other synthetic means.     

A Convenient Synthesis and Herbicidal Activity of N-phosphonoalkylpyrazolo[4,3-e][1,2,4]-triazolo[1,5-d]pyrimidines

An important building block, diethyl [(5-amino-4-cyano-3-methylsulfanyl-pyrazol-1-yl)–(4-fluorophenyl)methyl] phosphonate (3) was efficiently synthesized via the condensation of 1-hydrazino-1-(4-fluorophenyl)methyl phosphonate (1) with 2-[bis(methylthio)methylene]malononitrile (2).3 reacted with triethyl orthoformate to afford diethyl [(4-cyano-5-ethoxymethyleneamino-3-methylsulfanyl-pyrazol-1-yl)-(4-fluorophenyl)methyl] phosphonate (4), which reacted with various acyl hydrazines in refluxing 2-methoxyethanol to provide the target compounds (5) in good yields directly. The results of preliminary bioassay indicated that compounds 5 possess potent herbicidal activity against the roots of monocotyledonous (barnyard grass) and dicotyledonous (oil rape) plants, and could be further developed as potential herbicides.     

Intramolecular Heck reaction: A facile sequential one-pot synthesis of 1,2,3,4-tetrahydrobenzo[b][1,6]naphthyridines

A simple and convenient sequential one-pot synthesis of 1,2,3,4-tetrahydrobenzo[b][1,6] naphthyridines has been developed. The reductive amination of 2-chloro-3-formylquinolines with various amines in the presence of sodium borohydride provided the corresponding secondary amines in high yields. Further, a sequential one-pot reaction involving N-allylation and intramolecular Heck type 6-exo-trig cyclization was performed on the secondary amines to afford a range of desired 1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine derivatives in good to high yields.     

Synthesis of some 3-substituted [1,8]naphthyrido[3,2-c][1,8]naphthyridines. A new heterocyclic ring system

Some 3-substituted-5,6-dihydro[1,8]naphthyrido[3,2-c][1,8]naphthyridines (V) were obtained by the condensation of 7-substituted-2,3-dihydro-1,8-naphthyridin-4-(1H)ones (IV) with 2-aminonicotinaldehyde. All of the 5,6-dihydro derivatives V were transformed into the fully aromatic compounds VI by refluxing with nitrobenzene.     

Densely functionalized 1,2-dihydrobenzo[b][1,6]naphthyridines: one-pot synthesis via sequential Ugi and Heck reactions

A facile one-pot synthesis of functionalized 1,2-dihydrobenzo[b][1,6]naphthyridines is described via sequential Ugi four components using 2-chloroquinoline-3-carboxaldehydes, allyl amine, acetic acid, isocyanides and ligand free Heck reactions in good yields.     

Synthesis of the bi-heterocyclic parent ring system 1,2,4-triazolo[4,3-b][1,2,4,5]tetrazine and some 3,6-disubstituted derivatives

The synthesis of the previously unknown parent ring system was developed. Treatment of 3-hydrazino-1,2,4,5-tetrazine ( 4 ) with diethoxymethyl acetate gave the parent ring system. Similar treatment of 3-(3,5-dimethylpyrazol-1-yl)-6-hydrazino-1,2,4,5-tetrazine ( 2 ) with one carbon cyclizing reagents gave 3,6-di-substituted derivatives of the 1,2,4-triazolo-1,2,4,5-tetrazine ring system.