Synthesis of 3-methyl-4-cyano-3-butenoic acid amides and their cyclization into 6-amino-2-pyridones

Two groups of amides, derivatives of 3-methyl-4-cyano- and 3-methyl-4-cyano-4-carbethoxy-3 acids were obtained from acetoacetamides in the form of mixtures of Z, E-isomers and the pure E-isomers were isolated. It was shown that amides from the first group are cyclized by bases into the corresponding 6-amino-4-methyl-2-pyridones and amides from the second group are cyclized into 6-hydroxy-5-cyano-4-methyl-2-pyridones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1636–1640, December 1992.     

The synthesis of annelated 3-cyano-2-pyridones

Annelated tricyclic 3-cyano-2-pyridones were synthesized from cyanoacetamide adducts using a thermal cyclization process which had previously been reported to afford an annelated pyrimidone product.     

Amino-functionalized SBA-15 catalyzed one-step synthesis of 2-amino-5-cyano-4-hydroxy-6-aryl pyrimidines

A simple and efficient approach towards one-step synthesis of 2-amino-5-cyano-4-hydroxy-6-aryl pyrimidines has been developed. It is based on three-component condensation of aliphatic, aromatic or heterocyclic aldehydes, ethyl cyanoacetate and guanidinium carbonate in the presence of amino-functionalized SBA-15 catalyst in ethanol. In this chemical process, the tautomeric interconversion of pyrimidine derivatives has been observed. This efficient technique has the advantage to give 2-amino-pyrimidine derivatives using a heterogeneous catalyst in high yields, to be completed in short reaction times and to offer a simple product isolation procedure.     

Preparation of 3-hydroxy- and 3-methoxy-N-heteroaryl-2-methyl-4-pyridones

A number of new 3-hydroxy- and 3-methoxy-2-methyl-4-pyridones substituted on the nitrogen atom with selected heterocycles has been prepared. Novel chelating properties of the hydroxy-compounds are expected.     

Preparative synthesis of 3-cyano-4-difluoromethyl- and 3-cyano-4-trifluoromethyl-2(1H)-pyridones

An efficient procedure for the synthesis of 3-cyano-4-difluoromethyl- and 3-cyano-4-trifluoromethyl-2(1H)-pyridones was developed. The structure of one of the resulting compounds was established by X-ray diffraction analysis.     

Regioselective photoalkylation of 2-cyano-6-methoxynaphthalene by methoxy-substituted 1,2-diarylcyclopropanes

Photoreactions of 2-cyano-6-methoxynaphthalene with methoxy-substituted 1,2-diarylcyclopropanes in benzene give 2-cyano-1-(1,3-diarylpropyl)-6-methoxynaphthalenes. The excellent regioselectivity seen in these processes can be explained by initial formation of singlet exciplexes, in which the dipoles of each component are oriented in opposite directions.     

Regioselective synthesis and properties of 3-cyano-6-thienylpyridine-2(1H)-thiones

Reactions of sodium derivatives of 2- and 3-thenoylacetaldehydes with cyanothioacetamide gave 2- and 3-cyano-6-thienylpyridine-2(1H)-thiones, which were used in the synthesis of substituted 2-alkylthiopyridines, thieno[2,3-b]pyridines, and other fused heterocycles. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 365–368, February, 1998.     

Synthesis of substituted 2-amino-3-cyano-4-methylpyrroles

A facile route for the synthesis of substituted 2-amino-3-cyano-4-methylpyrroles from N-acetyl-α-amino ketones and malononitrile is reported.     

Synthesis of 6-substituted 5-cyano-7-hydroxy-2-carboxybenzofurans

Methods for the synthesis of 5-cyano-7-hydroxy-2-carboxybenzofurans bearing a variety of substituents at the 6-position are outlined. The scope and limitations of lithiation processes, electrophilic substitutions, and pericyclic reactions are investigated.     

New synthesis of 2-amino-3-cyano-4,5-tetramethylenethiophene

We have shown that 2-amino-3-cyano-4,5-tetramethylenethiophene (IV) is formed in the reaction of cyclohexanethione (I) with malononitrile (II) and sulfur in the presence of triethylamine. The reaction proceeds through a step involving the formation of cyclohexylidenemalononitrile (III) and occurs via attack by the malononitrile anion on the sulfur atom of the thiocarbonyl group of I. Δ^2,α-Bornanylmalononitrile (V) was similarly obtained from thiocamphor and II; the latter reaction cannot be realized with camphor because of the steric hindrance of the carbonyl carbon atom.     

Synthesis of N-substituted 3-hydroxy-2-methyl-4-pyridones and -pyridonimines

Carbohydrates with 1,4 glycosidic bonds like maltose, lactose, dextrin or starch react with primary amines as well as amino acids or proteins to give i.e. 3-hydroxy-2-methyl-4-pyridones 5 and 3-hydroxy-2-methyl-4-pyridonimines 7. A generally applicable synthesis of compounds of this type is described. The pyridones 5 and pyridonimines 7 are strongly complexing agents. Molybdenum-derivatives, for instance, are suitable as fairly stable oxidation catalysts.     

One-step synthesis of substituted 2-amino-4H-chromenes and 2-amino-4H-benzo[f]chromenes. Molecular and crystal structure of 2-amino-3-cyano-6-hydroxy-4-phenyl-4H-benzo[f]chromene

Substituted 2-aminochromenes were synthesized by three-component condensation of aromatic aldehydes, derivatives of cyanoacetic acid, and phenols or naphthols. The molecular and crystal structure of 2-amino-3-cyano-6-hydroxy-4-phenyl-4H-benzo[f]chromene was established by X-ray diffraction analysis.     

Synthesis of 6-arylazo-substituted 5-hydroxy-2-hydroxymethyl-4-pyridones and related compounds

5-Hydroxy-2-hydroxymethyl-4-pyridone ( 1 ) and 5-hydroxy-2-hydroxymethyl-1-methyl-4-pyridone ( 2 ) reacted with arenediazonium salts to give 6-arylazo-substituted compounds 3a-d and 4a-d , respectively. Compounds 3a-d were methylated with diazomethane to afford 6-arylazo-2-hydroxymethyl-4,5-dimethoxypyridines 5a-d .     

Synthesis of acetylenic β-diketones and their conversion into 4H-pyran-4-ones,pyrazoles, and 1-hydroxy-4-pyridones

A simple method for the synthesis of acetylenic β-diketones is described. They can be cyclized to the corresponding 4H-pyran-4-ones with acids. Their reaction with hydrazine hydrate gave pyrazole derivatives isomeric with those obtained from 4H-pyran-4-ones. With hydroxyl-amine hydrochloride in ethanol, 1-hydroxy-4-pyridones are formed.     

A novel synthesis of 5-aryl-3-cyano-2-pyridones by using vinamidinium salts

A variety of vinamidinium salts were condensated with cyanoacetamide in refluxing methanol that contained sodium methoxide to produce 5-aryl-3-cyano-2-pyridones in good yield.Simple experimental conditions were used to prepare ten different 5-aryl-3-cyano -2-pyridones,four of which are new compounds.     

Regioselective synthesis of 6-amino- and 6-amido-6-deoxypullulans

Hydrophobically modified polysaccharides that contain amine and amide groups possess valuable features for drug delivery and other applications. These chemical groups are known to play a fundamental role in the biological activity of important polysaccharides. Pullulan is known for its non-toxicity and biocompatibility, therefore, we have applied the versatile Staudinger reaction for the synthesis of regioselectively substituted pullulan derivatives containing amine or amide groups with promise for biomedical applications. The synthesis began with the regioselective bromination of pullulan at C-6 with N-bromosuccinimide and triphenylphosphine, providing 6-bromo-6-deoxy-pullulan, which is soluble in a range of organic solvents and therefore is a dynamic intermediate for the synthesis of other pullulan derivatives. Azide displacement of bromide from 6-bromo-6-deoxy-pullulan esters yielded the corresponding 6-azido-6-deoxy-pullulan esters. Staudinger reduction of these azides efficiently and chemoselectively afforded the corresponding amino- or amidopullulans.     

Regioselective synthesis and properties of 3-cyano-6-methyl-4-trifluoromethylpyridine-2(1H)-thione. Molecular and crystal structure of 3-cyano-2-ethylthio-6-methyl-4-trifluoromethylpyridine

The reaction of trifluoroacetylacetone with cyanothioacetamide proceeded regioselectively to form 3-cyano-6-methyl-4-trifluoromethylpyridine-2(1H)-thione from which the corresponding 2-alkylthiopyridines and 3-aminothieno[2,3-b]pyridines were obtained. The crystal and molecular structure of 3-cyano-2-ethylthio-6-methyl-4-trifluoromethylpyridine was established by X-ray diffraction analysis.     

Preferential inhibition of xanthine oxidase by 2-amino-6-hydroxy-8-mercaptopurine and 2-amino-6-purine thiol

Background  

The anticancer drug, 6-mercaptopurine (6MP) is subjected to metabolic clearance through xanthine oxidase (XOD) mediated hydroxylation, producing 6-thiouric acid (6TUA), which is excreted in urine. This reduces the effective amount of drug available for therapeutic efficacy. Co-administration of allopurinol, a suicide inhibitor of XOD, which blocks the hydroxylation of 6MP inadvertently enhances the 6MP blood level, counters this reduction. However, allopurinol also blocks the hydroxylation of hypoxanthine, xanthine (released from dead cancer cells) leading to their accumulation in the body causing biochemical complications such as xanthine nephropathy. This necessitates the use of a preferential XOD inhibitor that selectively inhibits 6MP transformation, but leaves xanthine metabolism unaffected.