The synthesis of pyrimido[4,5-d] pyridazines

The synthesis of pyrimido[4,5-d]pyridazin-2-one-4-thione (II), pyrimido[4,5-d]pyridazine-2,4-dithione (VI), 4-aminopyrimido[4,5-d]pyridazine-2-thione (III), 2-aminopyrimido[4,5-d]-pyridazin-4-one (X), 2-methylpyrimido[4,5-d]pyridazin-4-one (XII), and pyrimido[4,5-d]-pyridazin-4-one (XIII) are reported together with several new pyridazine intermediates.     

The synthesis of pyridazino[4,5-d] pyridazines,pyrazino [2,3-d] pyridazines and a pyrimido [4,5-d] pyridazine

The synthetic chemistry of the relatively unknown pyridazino [4,5-d]pyridazine ring system has been extended. 1,4-Diaminopyridazino [4,5-d]pyridazine (VIII) has been prepared by two routes, the most interesting of these being the one-step conversion of 4,5-dicyanopyridazine into VIII with hydrazine. Upon nitration VIII gave only the mononitramine (X). Attempts to prepare 1,4-dichloropyridazino [4,5-d]pyridazine gave only 4-chloro-2H-pyridazino [4,5-d]pyridazin-1-one (XII). Pyrimido [4,5-d]pyridazine-1,3-dione (XIV) was prepared from pyridazine-4,5-dicarboxamide (IV). The hydrolysis of 5,8-dichloropyrazino [2,3-d]pyridazine (XV) gave 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) and likewise the ammonolysis of XV gave 5-amino-8-chloropyrazino [2,3-d]pyridazine (XX). As expected the hydrolysis of 5,8-dibromo-pyrazino [2,3-d]pyridazine (XXI) gave 5-bromopyrazino [2,3-d]pyridazin-8-one (XXII). Attempted catalytic dechlorination of 5-chloropyrazino [2,3-d]pyridazin-8-one (XVII) gave 1,2,3,4-tetrahydropyrazino [2,3-d]pyridazin-5-one (XIX).     

Fused pyrimidines. 5. Methylated pyrimido[4,5-d]pyrimidines

The Mannich reaction has been applied to pyrimidines possessing activating groups at positions 2, 4, and 6 and that have a methyl group attached at a ring nitrogen atom. The corresponding tetrahydropyrimido[4,5-d]pyrimidines were obtained. In one case there was a possibility of isomer formation. Chemical reactivity was not successful in determining the structure but through an nmr program called INAPT, a version of INEPT, we were able to assign the structure as that of 6 .     

Reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride leading to purine,thiazolo[4,5-d]pyrimidine,pyrimido[4,5-e][1,3,4]thiadiazine,pyrazolo[3,4-d]pyrimidine,and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivativese

The reaction of 6-arylidenehydrazino-1,3-dimethyluracils with thionyl chloride in benzene afforded purine, thiazolo[4,5-d]pyrimidine, pyrimido[4,5-e][1,3,4]thiadiazine, pyrazolo[3,4-d]pyrimidine, and [1,2,3]thiadiazolo[4,5-d]pyrimidine derivatives, while the treatment of 6-(benzylidene-1′-methylhydrazino)-1,3-dimethyluracil with thionyl chloride in benzene gave 4-methylpyrimido[4,5-e][1,3,4]thiadiazine and 1-methylpyrazolo-[3,4-d]pyrimidine derivatives. Plausible mechanisms for the formation of these fused pyrimidines are also described.     

The synthesis of pyrimido[4,5-c]pyridazines and pyrimido[5,4-c]pyridazines

The Hofmann reaction on 6-methylpyridazine-3,4-dicarboxamide (1) gave a mixture of 3-methylpyrimido[4,5-c]pyridazine-5,7-dione (2), 3-methylpyrimido[5,4-c]pyridazine-6,8-dione (3) and an acid (4) of unknown structure. The Hofmann reaction on pyridazine-3,4-dicarboxamide (9) gave a mixture of pyrimido[4,5-c]pyridazine-5,7-dione ( 10 ) and an acid ( 11 ) of unknown structure. The reaction of 3-amino-6-methylpyridazine-4-carboxamide ( 18 ) with ethyl orthoformate gave 3-methylpyrimido[4,5-c]pyridazin-5-one ( 21 ). 4-Aminopyridazine-3-carboxamide ( 36 ) upon fusion with urea gave pyrimido[5,4-c]pyridazine-6,8-dione ( 37 ) while with ethyl orthoformate 36 gave pyrimido[5,4-c]pyridazin-8-one ( 38 ). Pyrimido[5,4-c]-pyridazine-8-thione ( 39 ) was obtained by the action of phosphorus pentasulfide on 38. 4-Amino-3-cyanopyridazine ( 16 ) when treated with formamide produced 8-aminopyrimido[5,4-c]-pyridazine ( 41 ). The synthesis of 4-aminopyridazine-3-carboxamide ( 36 ) and 4-amino-3-cyanopyridazine ( 16 ), both key intermediates in the synthesis of the novel pyrimido[5,4-c]pyridazine ring system was accomplished by the Reissert reaction of 4-aminopyridazine-2-oxides and subsequent conversion of the nitrile to the amide.     

Clean synthesis and antibacterial activities of spiro[pyrimido[4,5-b]quinoline-5,5'-pyrrolo[2,3-d]pyrimidine]-pentaones

A simple, clean and efficient method for the synthesis of spiro[pyrimido[4,5-b]quinoline-5,5'-pyrrolo[2,3-d]pyrimidine]-pentaone derivatives by condensation reaction of 6-amino-uracils and isatins in aqueous media is reported. These products were evaluated in vitro for their antibacterial activities.     

The synthesis of lmidazo[4,5-d] pyridazines. VI. v-Triazolo[4,5-d] pyridazines,pyrazino[ 2,3-d ] pyridazines and 7H-Imidazo [4,5-d] tetrazolo[ 1,5-b] pyridazine

Several pyridazines have been prepared as intermediates in the synthesis of monosubstituted imidazo[4,5-d]pyridazines, monosubstituted v-triazoIo[4,5-d]pyridazines and monosubstituted pyrazino [2,3d] pyridazines. The new ring system, 7H-imidazo[4,5-d]tetrazolo[l,5-b] pyridazine (XIV) has been prepared unsubstituted. Furthermore, unsubstituted imidazo[4,5-d]pyridazine (XI) has been prepared. Calculations for XI and XIV were made by approximate SCF LCAO-MO with CNSO II theory.     

Reactions of tetrahydropyrido[4,5-d][1,2,4]triazolo[1,5-a]-pyrimidin-4-ones with activated alkynes. Synthesis of [1,2,4]triazolo[1′,5′:1,2]pyrimido[4,5-d]azocines

Triazolo[1′,5′:1,2]pyrimido[4,5-d]azocines were synthesized by the tandem expansion of the tetrahydropyridine ring in tetrahydropyridotriazolopyrimidines by the action of activated alkynes. Under these conditions, triazolopyridopyrimidines benzylated at the nitrogen atom of the pyrimidine moiety undergo the Hofmann cleavage of the tetrahydropyridine ring to form 5-vinyltriazolo[1,5-a]pyrimidines.     

Glycolic acid-supported cobalt ferrite-catalyzed one-pot synthesis of pyrimido[4,5-b]quinoline and indenopyrido[2,3-d]pyrimidine derivatives

Herein, one-pot synthesis of pyrimido[4,5-b]quinoline and indenopyrido[2,3-d]pyrimidine derivatives was developed by the three-component reaction of aldehydes, 6-amino-1,3-dimethyluracil, and 1,3-dicarbonyl compounds in the presence of glycolic acid-supported cobalt ferrite CoFe₂O₄@SiO₂@Si (CH₂)₃NHCOOCH₂COOH as a novel magnetic catalyst in ethanol at reflux conditions. Glycolic acid-supported cobalt ferrite was characterized via Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), and vibrating sample magnetometer (VSM). Moreover, the catalyst was easily recovered with magnetic separation and recycled at least for five times without significant loss of its catalytic activity. The products were formed in excellent yields over appropriate reaction times under environmentally friendly conditions. The high efficiency and easy isolation of catalyst from products with an external permanent magnet are some of the remarkable advantages of this method.     

The synthesis of pyrimido[4,5-c] pyridazines and pyrido[2,3-d]pyrimidines related to toxoflavin and fervenulin

4-Deazatoxoflavin (1,6-dimethyl-1,5,6,7-tetrahydropyrimido[4,5-c]-5,7-pyridazinedione) ( 7 ) and several other 4-deazatoxoflavin and 4-deazafervenulin analogs have been prepared with the required intermediates. 3,5,7-Trimethyl-1,2,3,4-tetrahydropyrido[2,3-d]-2,4-pyrimidinedione ( 19 ) and 8-phenyl-3,5,7-trimethyl-2,3,4,8-tetrahydropyrido[2,3-d]-2,4-pyrimidinedione ( 20 ) were also prepared.     

Pyrido[2,3-d]pyrimidines,II. One step synthesis of pyrido[2,3-d]pyrimidines and pyrimido[4,5-b]quinolines from 6-amino uracils

Summary Reduction of 6-azidouracils2 with hydrogen palladium or sodium dithionite afforded the corresponding 6-aminouracils5 which could also be obtained by reaction of2 with triphenylphosphanevia phosphazenes and subsequent hydrolysis (Staudinger reaction). The use of trimethylphosphite instead of phosphanes yields with2b the expected trimethoxyphosphazene3c, whereas2a reacts to the phosphonoaminopyrimidine4. The syntheses of 5-hydroxy pyrido[2,3-d]pryimidine-2,4,7-triones6, pyrido[2,3-d]pyrimidine-2,4,5-triones8, cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-triones7a,c, and tetrahydro-pyrimido[4,5-b]quinolin-2,4,5-triones7b,d by condensation of 6-aminouracils5 with malonates, ethylaceto/benzoylacetate, ethyl 2-oxocyclopentanecarboxylate and ethyl 2-oxocyclohexanecarboxylate, respectively, are described.

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Pyrido[2,3-d]pyrimidine, 2. Mitt. Einstufige Synthese von Pyrido[2,3-d]pyrimidinen und Pyrimido[4,5-b]chinolinen aus 6-Aminouracilen

Zusammenfassung Reduktion der 6-Azidouracile2 mit Wasserstoff/Palladium oder Natriumdithionit ergibt die entsprechenden 6-Aminouracile5, die auch durch Reaktion von2 mit Triphenylphosphin und anschließende Hydrolyse erhalten werden können (Staudinger-Reaktion). Die Verwendung von Trimethylphosphit anstelle von von Trimethylphosphin ergibt mit2b das erwartete Trimethoxyphosphazin3c, während2a zum Phosphonoaminopyrimidin4 reagiert. Die Synthesen der 5-Hydroxy-pyrido[2,3-d]pyrimidin-2,4,7-trione6, der Pyrido[2,3-d]pyrimidin-2,4,5-trione8, der Cyclopenta[e]pyrido[2,3-d]pyrimidin-2,4,5-trione7a,c und der Tetrahydro-pyrimido[4,5-b]chinolin-2,4,5-trione7b,d durch Kondensation der 6-Aminouracile5 mit Malonat, Acetat, Ethyl-2-oxocyclopentancarboxylat und Ethylcyclohexancarboxylat werden beschrieben.

     

Syntheses of Oxazolo [4,5-b]pyridines and [4,5-d]pyrimidines

Oxazolo [4, 5-b] pyridines and [4, 5-d] pyrimidines and their 2-substituted compounds have been prepared respectively by condensation of orthoesters or thioimidates derivatives with 2-amino-3-hydroxypyridine and 4-amino-5-hydroxypyrimidine.     

Synthesis of pyrimido[4,5-b] indole derivatives

Chemistry of Heterocyclic Compounds -     

1,4-disubstituted pyridazino[4,5-d] pyridazines

1,4-Bis(methyIthio)pyridazino[4,5-d]pyridazine (IV) was synthesized from 4,5-pyridazinedi-carboxylic acid in three steps. By employing IV as an intermediate, various 1,4-disubstituted pyridazino[4,5-d]pyridazine derivatives of classes 1,4-N,S; 1,4-N,O; 1,4-O,S; and 1,4-O,O were prepared by one-step or two-step nucleophilic substitution reactions. Steric, polar and resonance effects were observed in some of these reactions and are discussed.