Synthesis of Some Halogen- and Nitro-substituted Nicotinic Acids and Their Fragmentation Under Electron Impact

Features of electrophilic and nucleophilic substitution under chlorination and nitration reactions conditions have been investigated for 6-hydroxy- and 6-methyl-substituted derivatives of 3-cyano-4-methyl-2(1H)-pyridones. The polychloro- and nitro-substituted 3-cyano-4-methylpyridines obtained were used as synthons in the synthesis of some polyhalo- and nitro-substituted nicotinic acids and their amides. The fragmentation pathways of the synthesized compounds under electron impact have been studied.     

4(3H)-Quinazolinones containing heterocyclic group in position 3

The corresponding 2,3-substituted 4(3H)-quinazolinones were obtained in the reactions of 2-methyl- and 2-phenyl-4-oxo-3,1-benzoxazines with 1-amino-1,2,4-triazole, 4-amino-2,3-dimethyl-1-phenyl-5-pyrazolone, 2-amino-5-ethyl-1,3,4-thiadiazole, 3-amino-6,6-dimethyl-4-oxo-4,5,6,7-tetrahydroindazole, 1-amino-3-cyano-4,6-dimethyl-2-pyridone, and 1-amino-3-cyano-6-phenyl-4-trifluoromethyl-2-pyridone. The formation of N-benzolyanthranilamides in the reactions of 2-phenyl-4-oxo-3,1-benzoxazine with 2-amino-5-ethyl-1,3,4-thiadiazole and 1-amino-3-cyano-6-phenyl-4-trifluoromethyl-2-pyridones was exceptional. The structures of two of the products have been confirmed by X-ray crystallography.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 936–943, July, 2000.     

3-[Amino(methylthio)methylene]pentane-2,4-dione in the synthesis of functionalized pyridines

New syntheses of functionalized pyridines from 3-[amino(methylthio)methylene]-2,4-pentanedionevia its boron chelates were proposed. The products of condensation of dimethylformamide dimethylacetal with the latter chelates were converted into 3-acetyl-2-methylthio-4-hydroxypyridine by refluxing in BuOH and into 1-alkyl-3-cyano-2-methyl-4-pyridones by treatment with primary amines.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1118–1121, June, 1995.This study was financially supported by the International Science Foundation (Grant M5Q 000).     

Synthesis and chemical properties of 8-aryl-7-acyl-1-6-dimethyl-6-hydroxy-4-cyano-5,6,7,8-tetrahydro-3(2H)-isoquinolinones and isoquinolinethiones

8-Aryl-7-acetyl-1, 6-dimethyl-6-hydroxy-4-cyano-5, 6, 7, 8-tetrahydro-3(2H)-isoquinolinones and -isoquinolinethiones and their sodium salts were obtained by the reaction of cyanoacetamide and cyanothioacetamide with 3-aryl-2, 4-diacetyl-5-methyl-5-hydroxycyclohexanonesinbasicrnedium. 8-Aryl-7-acetyl-6-methoxycarbonyl-1, 6-dimethyl-4-cyano-5, 6, 7, 8-tetrahydro-3(2H)-isoquinolinones were obtained by the reaction of acetyl chloride and the above isoquinolinone sodium salts. The reaction of iodoacetamide and the above isoquinolinethione sodium salts yielded 8-aryl-7-acetyl-3-carbamoylmethylthio-1, 6-dimethyl-4-cyano-5, 6, 7, 8-tetra-hydroisoquinolines, which were cyclized into 1-amino-6-aryl-7-acetyl-2-carbamoyl-5, 8-dimethyl-8-hydroxy-6, 7, 8, 9-tetrahydrothiophene[2,3-c]isoquinolines in basic medium.     

Reaction of diketene with cyanothioacetamide: A convenient and regioselective method for the preparation of new 4(1H)-pyridone derivatives

The reaction of diketene with cyanothioacetamide in dry dioxane in the presence of triethylamine gives triethylammonium 3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinethiolate. The regioselective S-alkylation of this thiolate is a convenient method for the preparation of substituted 4(1H)-pyridones and also derivatives of thiazolo[3,2-a]pyridine and thieno[2,3-b]pyridine. The action of 2-amino-1,1,3-tricyanopropene on this thiolate leads to its transformation into a new heterocyclic system, namely, 5H-pyrido[2′,3′:4,5]thiopyrano[2,3-b]pyridine; treatment with iodine yields the oxidation product, namely, the corresponding bis(2-pyridyl) disulfide. The structure of isopropyl (3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thioacetate was confirmed by X-ray diffraction structural analysis. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 716–725, May, 2007.     

A convenient synthesis of nicotinate esters from 3-cyanopyridones

A convenient synthesis of alkyl-substituted ethyl nicotinates 8 was devised, using 3-cyano-2(1H)-pyridones 4. These were converted to the corresponding 2-bromo-3-cyanopyridines 5 with boiling phosphorus tribromide. The resulting 5 were smoothly debrominated to 3-cyanopyridines 6 with zinc dust in boiling ethanolic acetic acid. The nitrile function was hydrolyzed in boiling 6N hydrochloric acid, and the resulting nicotinic acid hydrochlorides 7 esterified with refluxing triethyl orthoformate, to give the ethyl nicotinates 8. A modified formylation of 2-butanone led to the sodium salt of 2-methyl-3-oxobutanal ( 3a ) of enhanced purity.     

N-3-Oxoalkylamides and -Thioamides in the Synthesis of Heterocyclic Compounds. 7. Study of the Cyclization of N-(3-Oxoalkyl)amides of Tosylacetic Acid

Alkyl-substituted N-(3-oxoalkyl)amides of tosylacetic acid are cyclized under the action of bases with the formation of 3-tosyl-3,6-dihydropyridin-2(1H)-ones. In the presence of a phenyl substituent at position C₍₁₎ of the 3-oxoalkyl chain the reaction proceeds with the formation of 2-pyridones. The principles influencing the regiodirection of cyclization are explained.     

Syntheses of 2-acetyl-3-hydroxy-1-n-propylpyrrole from isomaltol and 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones from maltol

2-Acetyl-3-hydroxyfuran (2) reacts with n-propylamine affording 2-acetyl-3-hydroxy-1-n-propylpyrrole (3) in 63% yield. The transformation of 2-methyl-3-hydroxy-4-pyrone (4) into 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones is achieved by benzylation of the 3-hydroxyl group whereupon the product reacts with ammonia and the corresponding pyridone is obtained. The pyridone is alkylated with alkyl bromides and after hydrobromic acid in acetic acid cleavage of the 3-position ether function, 1-n-alkyl-3-hydroxy-2-methyl-4-pyridones are obtained in 48% overall yield.     

6-Amino-5-cyano-1H,4H-pyrazolo[3,4-b]pyrans

The reaction of 3-methyl-1-phenyl-5-pyrazolene with arylideneamino nitriles in alcohol leads to the formation of 3-methyl-4(1-aryl-2,2-dicyanoethyl)-5-pyrazolones, which are readily cyclized in the presence of bases to the corresponding 6-amino-5-cyano-3-methyl-4-aryl- 1H,4H-pyrazolo[3,4-b]pyrans. The structures of the intermediate and final products were confirmed by the IR, UV, PMR, and mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 801–806, June, 1982.     

Reactions of α,β-unsaturated ketones with cyanoacetamide

3-Aryl-1-phenyl-2-propen-1-ones Ia-f and aroylphenylacetylenes Va-d reacted under reflux for 3 hours with cyanoacetamide in the presence of sodium ethoxide to give the corresponding 4-aryl-3-cyano-6-phenyl-2-(1H)pyridones VI. However, when ketones Ia-e were refluxed with cyanoacetamide for one hour in the presence of sodium ethoxide or piperidine, they gave the corresponding 4-aryl-3-cyano-3,4-dihydro-6-phenyl-2-(1H)pyridones IIIa-e, which upon heating with selenium gave the corresponding 2-pyridones VI. The structures of the products are based on chemical and spectroscopic evidence.     

Pyridinethiones. VIII. The aldol and wittig condensations of 3-formyl-2(1H)-pyridones, -thiones and -selones. Preparation of new cyanopyridones

Condensations of 1-substituted-3-formyl-2(1H)-pyridones, -thiones and -selones with methyl ketones such as acetophenone give the corresponding chalcones in high yields. Geometry at the vinyl hydrogens is E. These chalcones can be cyclized with ethyl cyanoacetate in the presence of ammonium acetate to form new 3-cyano-2(1H)-pyridones. An effective “one-pot” preparation is worked out and an intermediate from the cyclization reaction is isolated. Via the Wittig reaction it is possible to prepare condensation products from 1-substituted-3-formyl-2(1H)-pyridinethiones and -selones with mainly Z geometry at the vinyl hydrogens.     

Oxidative cyclization of 3-oxopropanenitriles with α,β-unsaturated amides by manganese(III) acetate. Regio- and stereoselective synthesis of 4-cyano-2,3-dihydrofuran-3-carboxamides

4-Cyano-2,3-dihydrofuran-3-carboxamides were obtained from the oxidative cyclization of 3-oxopropanenitriles with unsaturated amides using manganese(III) acetate. Treatment of 3-oxopropanenitriles with (2E)-3-(5-methyl-2-furyl)acrylamide and (2E)-3-(2-thienyl)acrylamide gave 2-(5-methyl-2-furyl) and 2-(2-thienyl) substituted 4-cyano-2,3-dihydrofuran-3-carboxamides in moderate yields, respectively. However, (2E)-3-(2-furyl)acrylamide and (2E)-3-phenylacrylamide did not produce any product under the same conditions. On the other hand, reaction of a dienamide such as (2E,4E)-5-phenylpenta-2,4-dienamide with 3-oxopropanenitriles gave diastereomeric mixtures of 2-(2-vinylphenyl)-4-cyano-2,3-dihydrofuran-3-carboxamides. Mechanisms are proposed for the formation of all of these compounds.     

Synthesis and stereoisomerism of derivatives of <Emphasis Type="Italic">tert</Emphasis>-butyl 7-alkylideneceph-3-em-4-carboxylate

By condensation of tert-butyl 3-methyl-7-oxoceph-3-em-4-carboxylate and its 3-acetoxymethyl analog with acetylmethylenetriphenylphosphorane and 3-trimethylsilylpropyn-2-ylindenetriphenylphosphorane tert-butyl 7Z-acetylmethylene-3-methylceph-3-em-4-carboxylate and also 7Z-and 7E-isomers of tert-butyl 3-acetoxymethyl-7-(3-trimethylsilylpropyn-2-ylidene)ceph-3-em-4-carboxylates were synthesized. Oxidation of these compounds with 1 equivalent of meta-chloroperbenzoic acid gave their 1R-and 1S-sulfoxides, and oxidation with 2 equivalents gave the corresponding sulfones. According to data from ¹H NMR spectroscopy, the carbonyl of the β-lactam descreens proton H-9 of the alkylidene group in the 7Z-isomers more strongly than in the 7E-isomers, shifting their signals to weaker field. Analogous shifts of the H-6 signal to weaker field was observed in the 1R-sulfoxides in comparison with that for the 1S-sulfoxide. These results were confirmed by X-ray crystallography of tert-butyl 7Z-acetylmethylene-3-methyl-1S-oxoceph-3-em-4-carboxylate and tert-butyl 7Z-acetylmethylene-3-methyl-1,1-dioxoceph-3-em-4-carboxy-late. In memory of Professor A.A. Potekhin __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 618–626, April, 2008.     

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.     

Ring transformations of 4H-pyrans. Pyridines from 2-amino-4H-pyrans

Ring transformations of 4H-pyrans into pyridines are reported. Treatment of 2-amino-4,6-diaryl-3,5-dicyano-4H-pyrans (I) with nitrosylsulfuric acid brings about their transformation into 3,5-dicyano-4,6-diaryl-2-pyridones (VI) which can also be obtained from α-benzoylcinnamonitriles (IX) and cyanoacetamide. Similarly, 2-amino-4,6-diaryl-5-carbethoxy-3-cyano-4H-pyrans (II) lead to 4,6-diaryl-5-carbethoxy-3-cyano-2-pyridones (VII). Treatment of both series of pyrans with sulfuric acid results in the formation of the corresponding 3,4-dihydro-2-pyridones (IV and V). Reaction of pyrans II with ammonium acetate in acetic acid yields 2-amino-4,6-diaryl-5-carbethoxy-3-cyanopyridines (XII). Pyrans I undergo an entirely different type of reaction upon treatment with this reagent leading to 2,4,6-triaryl-3,5-dicyano-1,4-dihydropyridines (XV).     

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.     

Synthesis and DABCO-induced demethylation of 3-cyano-4-methoxy-2-pyridone derivatives

An efficient method for synthesis and demethylation of 3-cyano-4-methoxy-2-pyridone derivatives has been developed. DABCO-induced demethylation can lead to 3-cyano-4-hydroxy-2-pyridones in DMF at 90°C with high yield. The protocol is applicable for the synthesis of 3-cyano-4-hydroxy-2-pyridone derivatives. The method is simple, efficient, and practical.     

Synthesis of 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-3,4′-bipyridine-3′-carboxylic and 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-4,4′-bipyridine-3′-carboxylic esters and investigation of their stability. 2. Esters of 6′-carbamoylmethyl-thio-5′-cyano-1′,4′-dihydro-4,4′-bipyridine-3-carboxylic acids

The stability of solutions of esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4,4′-bipyridine-3′-carboxylic acids was investigated by HPLC. The corresponding esters of 6′-carbamoylmethylthio-5′-cyano-4,4′-bipyridine-3′-carboxylic acids,esters of 8-cyano-5-methyl-3-oxo-7-(4-pyridyl)-2,3-dihydro-7H-thiazolo-[3,2-a]pyridine-6-carboxylic acids, methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate, and methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-thieno[2,3-b]pyridine-5-carboxylate were synthesized as standard compounds (typical impurities). Analysis by HPLC was realized under the conditions of reverse-phase chromatography. It was established that solutions of the investigated compounds (with mixtures of acetonitrile with phosphate buffer, having pH values of not less than 3 and not more than 5, as solvents) are stable for one month when the solutions are stored in a place protected against light. It is also necessary to use chromatographic systems in which the aqueous components have pH 3–5 during determination of the purity of the esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4, 4′-bipyridine-3′-carboxylic acid by HPLC in order to separate the analyzed sorbates and their typical impurities more completely. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 841–848, June, 2007.     

Synthesis of substituted 2-pyridones and 4-aza-3-fluoridones

Substituted N-methyl-2-pyridones and N-methyl-4-aza-3-fluoridones, a previously unknown group of heterocyclic compounds, were obtained by oxidation of 3-methyl-2-phenylpyridine, 3-methyl-2-phenyl-5-(3-methyl-2-phenylpyridin-6-yl)pyridine iodomethylates, as well as of 4-aza-fluorenes substituted at the 9-position.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 939–942, July, 1986.     

New approach to the synthesis of substituted 5-arylcarbamoyl-3-cyano-6-methylpyridine-2(1h)-thiones. Molecular and crystal structure of 2-allylthio-3-cyano-5-(2-methoxyphenylcarbamoyl)-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine

Morpholinium 5-arylcarbamoyl-3-cyano-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine-2-thiolates have been obtained by the interaction of enamines of acetoacetanilides with 5-methyl-2-furfurylidenecyanothioacetamide. Alkylation of the salts gives thioethers and oxidation gives the corresponding substituted pyridine-2(1H)-thiones. The structure of 2-allylthio-3-cyano-5-(2-methoxyphenylcarbamoyl)-6-methyl-4-(5-methyl-2-furyl)-1,4-dihydropyridine was studied by X-ray crystallographic analysis. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 51–58, January, 2006.