Synthesis and chemical transformations of partially hydrogenated [1,2,4]triazolo[5,1-b]quinazolines

The reaction of 5-methyl-7-phenyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine with α,β-unsaturated carbonyl compounds in MeOH in the presence of MeONa affords partially hydrogenated aryl-substituted [1,2,4]triazolo[5,1-b]quinazolines. Hydrolysis, oxidation, reduction, and alkylation of 5,6,8-triphenyl-5,6,7,10-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline were studied. The structure of one oxidation product, viz., 7-hydroxy-5,6,8-triphenyl-6,7-dihydro[1,2,4]triazolo[5,1-b]quinazoline, was established by X-ray diffraction. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 335—340, February, 2006.     

Benzannulation of 5-methyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine with chalcones and their synthetic equivalents as a method for the synthesis of tetrazolo[5,1-b]quinazolines

Derivatives of tetrahydrotetrazolo[5,1-b]quinazolines were synthesized by the reactions of 5-methyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine with α,β-unsaturated carbonyl compounds and their synthetic equivalents in methanol in the presence of sodium methoxide. The spontaneous or specifically target oxidation of these derivatives gives rise to aromatic tetrazoloquinazolines. The reaction pathways and mechanisms were discussed. The structures of the resulting compounds were confirmed by IR and ¹H NMR spectroscopy, mass spectrometry, and elemental analysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1971–1976, September, 2008.     

Partially Hydrogenated Aromatic Substituted Tetrazolo[1,5-a]pyrimidines

By treating 5-aminotetrazole with aromatic ,-unsaturated ketones or with Mannich base hydrochlorides there have been synthesized aromatic substituted 4,7-dihydrotetrazolo[1,5-a]-pyrimidines. They can be reduced to the corresponding 4,5,6,7-tetrahydro derivatives by the action of NaBH₄. The high thermodynamic stability of the 4,7-dihydrotetrazolo[1,5-a]pyrimidines when compared with the 4,5-dihydro isomers has been revealed. Reaction of 5-aminotetrazole both with cyclohexanone as well as with 2-cyclohexylidenecyclohexanone leads to formation of 9,9-pentamethylene-4,5,6,7,8,9-hexahydrotetrazolo[5,1-b]quinazoline, the structure of which was demonstrated using X-ray crystallography.     

Water-Mediated Selective Synthesis of Pyrazolo[1,5-a]quinazolin-5(4H)-ones and [1,2,4]Triazolo[1,5-a]quinazolin-5(4H)-one via Copper-Catalyzed Cascade Reactions

A convenient and sustainable synthesis of pyrazolo[1,5-a]quinazolin-5(4H)-ones and [1,2,4]triazolo[1,5-a]quinazolin-5(4H)-one through copper-catalyzed cascade reactions of 2-bromobenzoates with 1H-pyrazol-5-amines or 1H-1,2,4-triazol-5-amine under ligand-free conditions in water is presented. It is notable that aqueous medium turned out to be crucial for the chemoselective formation of the title compounds. Compared with literature protocols, this new method showed advantages such as simple and sustainable procedure, commercially available starting materials, and convenient reuse of the reaction medium together with the copper catalyst.     

Synthesis of some novel pyrazolo[1,5-a]quinazolines and their fused derivatives

New pyrazolo[1,5-a]quinazoline-3-carbonitriles 4a,b were obtained via cyclocondensation of 5-amino-3-cyanomethyl-1H-pyrazole-4-carbonitrile (1) with enaminones of 1,3-cyclohexanedione derivatives 2a,b in refluxing glacial acetic acid. Condensation of compounds 4a,b with various aromatic aldehydes furnished the corresponding arylidene derivatives 6a–j. On the other hand, condensation of 4a,b with o-hydroxybenzaldehydes yielded the polyheterocyclic compounds 10a–h. Coupling of compounds 4a,b with aryldiazonium chlorides led to formation of 2-arylhydrazono derivatives 12a–h. Also, reaction of compounds 4a,b with phenyl isothiocyanate, followed by addition of ethyl chloroacetate and chloroacetonitrile, afforded the polyheterocyclic compounds based on pyrazolo[1,5-a]quinazoline core. The reaction of compounds 4a,b with phenyl isothiocyanate and elemental sulfur gave the thiazole-2-thione derivatives 25a,b. The reaction of enamines of compounds 4a,b with each of hydrazine hydrate and guanidine hydrochloride afforded pyrazolo[4″,3″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-8-ones 30a,b and pyrimido[5″,4″:5′,6′]pyrido[4′,3′:3,4]pyrazolo[1,5-a]quinazolin-9(10H)-ones 33a,b, respectively. The structures of all the newly synthesized compounds were elucidated by elemental analyses and spectral data. The plausible mechanisms have been postulated to account for their formation.     

Convenient synthesis of 6,7-dihydroazolo[5,1-b]quinazolin-8(5H)-one derivatives

Three-component condensation of 3(5)-aminoazoles with benzaldehydes and dimedone in acetonitrile in the presence of montmorillonite KSF as heterogeneous catalyst regioselectively afforded 5,6,7,9-tetrahydroazolo[5,1-b]quinazolin-8(4H)-one derivatives in good yields. Oxidation of the condensation products with ceric ammonium nitrate in acetone gave the corresponding 6,7-dihydroazolo[5,1-b]quinazolin-8(5H)-ones.     

Synthesis of 6-Acyl-7-aryl-4,7-dihydrotetrazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidine-5-carboxylic acids and their methyl esters

6-Acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylic acids and methyl 6-acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylates were synthesized by fusion of 4-aryl-2,4-dioxobutanoic acids and their methyl esters, respectively, with 1H-tetrazol-5-amine and aromatic aldehydes. The reaction of methyl 2,4-dioxopentanoate with 1H-tetrazol-5-amine and 2-fluorobenzaldehyde in boiling acetic acid gave methyl 6-acetyl-5-hydroxy-7-(2-fluorophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine-5-carboxylate.     

Fluorine-Containing Heterocycles: XII. Fluorine-Containing Quinazolin-4-ones and Azolo[<Emphasis Type="Italic">a</Emphasis>]quinazolinone Derivatives

Methods for the synthesis of fluorine-containing derivatives of 2-imino-1,3-diphenylquinazolin-4-one, imidazo[1,2-a]quinazolin-5-one, pyrazolo[1,5-a]quinazolin-5-one, and [1,2,4]triazolo[1,5-a]quinazolin-5-one were developed on the basis of the reaction of tetrafluorobenzoyl chloride with N,N′-diphenylguanidine and aminoazoles.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 7, 2005, pp. 1092–1100.Original Russian Text Copyright © 2005 by Lipunova, Nosova, Laeva, Kodess, Charushin.     

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.     

Cascade cyclization reactions of 3,4,5-triamino-1,2,4-triazole with aromatic aldehydes and cycloalkanones

A three-component condensation of 3,4,5-triamino-1,2,4-triazole (1) with aromatic aldehydes 2a–f and dimedone (3) or cyclohexanone (8) afforded partially hydrogenated 9-aryl-[1,2,4]triazolo[5,1-b]quinazolin-8-ones. The structure of 2-amino-6,6-dimethyl-3-(4-nitrobenzylidene)amino-9-(4-nitrophenyl)-5,6,7,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazolin-8-one (4e) was confirmed by X-ray diffraction data. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1178–1182, July, 2006.     

Cascade cyclization of 3(5)-aminopyrazoles with aromatic aldehydes and cyclohexanediones

Three-component condensation of 5(3)-amino-3(5)-methylpyrazole with aromatic aldehydes and 1,3-cyclohexanedione afforded mixtures of 3-methyl-4-aryl-2,4,6,7,8,9-hexa hydro-5H-pyrazolo[3,4-b]quinolin-5-ones and 2-methyl-9-aryl-5,6,7,9-tetrahydro pyrazolo[5,1-b]quinazolin-8(4H)-ones. The reaction of 3-aminopyrazolo-4-carbonitrile and ethyl 3-aminopyrazolo-4-carboxylate with aldehydes and cyclo hexanedione or dimedome is regioselective and leads to the formation of partially hydrogenated pyrazolo [5,1-b]quinazolin-8-one systems. In all compounds the dihydroazine ring exists in the enamine tautomeric form.     

A Facile and Efficient Synthesis of Novel 1,2,4-Triazolo[5,1-b]quinazolin-9-one Derivatives

Summary.  A facile and efficient synthesis of a series of novel 1,2,4-triazolo[5,1-b]quinazolines is described. 2,3-Diaryl-2,3-dihydro-1H-1,2,4-triazolo[5,1-b]quinazolin-9-ones were obtained by reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic aldehydes as well as by ring closure of the corresponding anils. Treatment of 3-amino-2-arylamino-3H-quinazolin-4-ones with aromatic carboxylic acids afforded 2,3-diaryl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones which could also be synthesized by dehydrogenation of the corresponding dihydro derivatives. Reaction of 3-amino-2-arylamino-3H-quinazolin-4-ones with diethyl malonate and acetylacetone gave 3-aryl-3,9-dihydro-9-oxo-1,2,4-triazolo[5,1-b]quinazolin-2-yl-acetic acid ethyl ester and 3-aryl-2-methyl-3H-1,2,4-triazolo[5,1-b]quinazolin-9-ones, respectively. The latter compounds were also prepared via reaction with acetic anhydride, whereas acetylation with acetic anhydride in the presence of pyridine afforded the acetyl derivatives. Received March 22, 2001. Accepted (revised) May 11, 2001     

Ionic Liquid–Mediated One-Pot Synthesis of 5-(Trifluoromethyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine Derivatives

A facile one-pot synthesis of 5-(trifluoromethyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine derivatives is described via a three-component reaction of aldehydes with 5-aminotetrazole and ethyl 4,4,4-trifluoro-3-oxobutanoate or 4,4,4-trifluoro-1-phenylbutane-1,3-dione in ionic liquid. This method has the advantages of short synthetic route, operational simplicities, good yields, ecofriendliness, and recyclability of the solvent.     

Synthesis of a New Series of Imidazo-[1,5-a]pyrido[2,3-e]pyrazines as Potential Ligands for the GABA Receptor Complex

Summary.  Starting from 2-chloro-3-nitropyridine, 2-isopropyl-1,4-dihydropyrido[2,3-b]pyrazin-2(3H),3-dione was synthesized. This compound was reacted with potassium tert-butoxide and diethyl chlorophosphate to afford an intermediate dihydropyrido[2,3-b]pyrazin-2-ylphosphate derivative which in turn furnished the desired 1,2,4-oxadiazolylimidazo[1,5-a]pyrido[2,3-e]pyrazine derivatives with 5-alkyl-3-isocyanomethyl-1,2,4-oxadiazoles in the presence of additional tert-butoxide. The title compounds are potential ligands for the γ-aminobutyric acid A/benzodiazepine receptor complex. Received November 26, 2001. Accepted December 3, 2001     

Synthesis and antimicrobial activity of new derivatives of pyrano[4',3':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine and new heterocyclic systems

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains.     

Partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines as synthons for the preparation of polycondensed heterocycles: reaction with chlorocarboxylic acid chlorides

Partially hydrogenated 2-amino[1,2,4]triazolo[1,5-a]pyrimidines and 2-amino[1,2,4]triazolo[5,1-b]quinazolines react with the chlorides of chloroacetic, 3-chloropropanoic, and 4-chlorobutanoic acids at 0–5 °C to give amides through acylation of the 2-amino group. Heating the corresponding 3-chloropropanoyl derivatives at 80–90 °C in DMF leads to selective intramolecular alkylation at N-3 to form the chlorides of partially hydrogenated [1,2,4]triazolo[1,5-a:4,3-a′]dipyrimidin-5-ones and pyrimido[2′,1′:3,4][1,2,4]triazolo[5,1-b]quinazolin-12-ones. It may be more convenient to prepare such compounds through one-pot processes. Some reactions of the synthesized chlorides of polycondensed heterocycles have been studied. Conditions have been found to effect the selective synthesis of free bases, oxidative aromatization or hydrolysis of the dihydropyrimidine cycle, and the selective hydrolytic cleavage or elimination of the pyrimidone ring. Some of the resulting compounds represent new mesoionic heterocycles.     

The effect of the azole ring on the conformational mobility of the dihydropyrimidine ring in 4,7-dihydroazolo[1,5-a]pyrimidines as judged from MNDO calculations

The equilibrium geometries of 4,7-dihydropyrazolo[1,5-a]pyrimidine, 4,7-dihydrotetrazolo [1,5-a]pyrimidine, 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, and 1,4-di-hydropyrimido [1,2-a]imidazole were calculated by the semiempirical quantum-chemical MNDO method. The dihydropyrimidine ring exhibits high conformational mobility in all of these compounds. The change in the energy occurring in the transition of the molecule to the boat conformation with an angle between the planar fragments of ±20° does not exceed 1 kcal mol^–1. The mobility of the dihydro ring increases as interactions between the -systems of the azole ring and the C=C double bond separated by an imino group and a methylene bridge decrease.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1418–1420, August, 1994.     

Synthesis and in vitro anticancer activity of pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-d][1,2,3]triazines

A novel series of pyrazolo[1,5-a]pyrimidines 14a–j and pyrazolo[1,5-a]quinazolines 18a, b were synthesized via condensation of 5-amino-1H-pyrazoles 10a, b with 3-(dimethylamino)-1-aryl-prop-2-en-1-ones 11a–e and 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (15), respectively, in glacial acetic acid. Finally, treatment of 10a, b with sodium nitrite (NaNO₂) afforded pyrazolo[3,4-d]triazines 20a, b. Structures of compounds were confirmed by their spectral data. These compounds were screened for their in vitro cytotoxic activities against human cancer cell lines (HepG-2 and MCF-7) using 3-[4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The results reveal that, the compounds 14b and 14h were the most potent in comparison with doxorubicin. The structure–activity relationship was discussed.     

Studies on the Synthesis of New 3-(3,5-Diamino-1-substituted-pyrazol-4-yl)azo-thieno[2,3-b]pyridines and 3-(2-Amino-5,7-disubstituted-pyrazolo[1,5-a]pyrimidine-3-yl)azothieno[2,3-b]pyridines

Coupling the diazonium salt of 3-amino-2-cyano-4,6-dimethylthieno[2,3-b]pyridine 1 with malononitrile 2 gave 2-cyano-3-(hydrazonomalononitrile)-4,6-dimethylthieno[2,3-b]pyridine 3 which then reacted with hydrazine compounds 4a-4h to yield corresponding 2-cyano-3-(3,5-diamino-1-substituted-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 5a-5h. The 2-cyano-3-(2-amino-5,7-disubstituted-pyrazolo-[1,5-a]pyrimidine-3-yl)azo-4,6-dimethylthieno[2,3-b]pyridines 7a-7f were obtained in good yield by the cyclocondensation reaction of 2-cyano-3-(3,5-diamino-pyrazol-4-yl)azo-4,6-dimethylthieno[2,3-b]pyridine 5a with the appropriate 1,3-diketones 6a-6f under acidic condition.     

Regioselective formylation of pyrazolo[3,4-b]pyridine and pyrazolo[1,5-a]pyrimidine systems using Vilsmeier-Haack conditions

Regioselective formylation behavior has been found in the reaction of pyrazolo[3,4-b]pyridines and pyrazolo[1,5-a]pyrimidines via Vilsmeier-Haack conditions. While the 4,5- and 6,7-dihydro derivatives afforded pyrazolo[3,4-b]pyridine-5-carbaldehydes and 4,7-dihydropyrazolo[1,5-a]pyrimidine-3,6-dicarbaldehydes, respectively, the aromatic analogs rendered the pyrazolo[1,5-a]pyrimidine-3-carbaldehyde only, and no reaction took place at the pyrazolopyridine derivatives.