1,4-Dihydrobenzothieno[3,2-b]pyridine-5,5-dioxides

A series of polycyclic 1,4-dihydropyridines has been synthesized, viz., 1,4-dihydrobenzothieno[3,2-b]pyridine-5,5-dioxides with electron-acceptor substituents at position 3. Their alkylation, chemical oxidation, and reactivity in electrochemical oxidation have been studied. The effect of a sulfonyl group in the indene segment on properties (pK, electrochemical oxidation potential) of the dihydrobenzothienopyridine system is considered.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1563–1567, November, 1986.     

Electrochemical synthesis of 1,2,3,4,4,5,6-substituted 1,4-dihydropyridines

It has been shown that chemical oxidation of the methyl ester of 3,4,5-trimethoxycarbonyl-1,2,6-trimethyl-1,4-dihydropyridine to the pyridinium salt, requiring forcing experimental conditions, may be replaced by electrochemical oxidation. On electrochemical reduction of 3,4,5-trimethoxycarbonyl-1,2,6-trimethylpyridinium perchlorate in the presence of alkylating agents 1,2,3,4,4,5,6-substituted 1,4-dihydropyridines are obtained. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 226–237, February, 2007.     

Gas chromatography/mass spectrometric study of non-commercial C-4-substituted 1,4-dihydropyridines and their oxidized derivatives

A gas chromatography/mass spectrometry (GC/MS) method for the qualitative and quantitative determination of the calcium-channel antagonists C-4-substituted 1,4-dihydropyridines, and their corresponding N-ethyl derivatives, is presented. Also, the electrochemical oxidation and the reactivity of the compounds with alkyl radicals derived from 2,2'-azobis-(2-amidinopropane) were monitored by GC/MS. Mass spectral fragmentation patterns for the C-4-substituted 1,4-dihydropy-ridine parent drugs were significantly different from those of their oxidation products, generated either by electrochemical oxidation or by reaction with alkyl radicals. However, for N-ethyl-1,4-dihydropyridine compounds it was not possible to detect the final products (pyridinium salts) using these experimental conditions.     

Synthesis and electrochemical oxidation of 1-aryl-3,5-diethoxycarbonyl-2,6-unsubstituted 1,4-dihydropyridines

The possibility of obtaining 1-aryl-3,5-diethoxycarbonyl-2,6-unsubstituted 1,4-dihydropyridines with electronacceptor substituents in the N-phenyl radical was demonstrated. The intermediate products of their formation, viz., 2,4-bis(arylaminomethyiene)-3-phenylglutaric acid esters, were established. The electrochemical oxidation potentials of 1-aryl-2,6-unsubstituted 1,4-dihydropyridines are 100–200 mV higher than those of the 2,6-dimethyl analogs. A linear correlation between the electrochemical oxidation potentials and the Taft ⁰ constants of the substituents in the 1-phenyl ring was established.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 373–377, March, 1991.     

Special Features of the Electrochemical Oxidation of Substituted 4-Carboxy-1,4-dihydropyridines

Electrochemical oxidation potentials of 1,4-dihydropyridines substituted with 4-COOH, 4-COOR, and 4-CONRR' groups have been determined in aprotic acetonitrile by the rotating ring-disk electrode method (RRDE). The electrochemical reduction potentials of the resulting products were also determined at the ring electrode. It was established that protonated pyridines are formed in the oxidation of derivatives with and without a substituent in position 4 of the heterocycle. In the case of 4-alkoxycarbonyl substituted compounds the substituent at position 4 is generally retained. 1,4-Dihydrogenated derivatives of isonicotinic acid as a rule loose the substituent at position 4 on oxidation, and both types of product were recorded for the corresponding 4-carbamoyl derivatives. The substituent at position 9 of the heterocycle was mainly retained on electrochemical oxidation of the 3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridine derivatives studi! ed.     

Electrochemical Oxidation of Compounds Containing 1,4-Dihydropyridine and Pyridinium Rings — Analogs of Gene Transfection Agents

A study was carried out on the electrochemical oxidation of 1,4-dihydropyridines, found as substituents in pyridinium salts, which are strong electron acceptors. The potentials for their oxidation in acetonitrile were determined. NMR spectroscopy was used to find the relative acidity of the N–H and C–H protons and the oxidation potentials were determined for the anionic products of the ionization of the N–H bond in dihydropyridine. The only product of the preparative electrolysis, in contrast to chemical oxidation, is the corresponding pyridine, namely, the oxidized dihydropyridine form.     

CARO'S ACID SUPPORTED ON SILICA GEL. PART 7: A VERSATILE REAGENT FOR THE AROMATIZATION OF HANTZSCH 1,4-DIHYROPYRIDINES UNDER NON-AQUEOUS CONDITION AND MICROWAVE IRRADIATION

Efficient oxidation of 1,4-dihydropyridines with Caro's acid on silica gel is achieved under nonaqueous conditions and in a domestic microwave oven. The reactions under microwave irradiation were shorter in duration and higher in yields than the reactions in conventional method, confirming the potentiality of microwave heating in aromatization of Hantzsch 1,4-dihydropyridines.     

Electrochemical oxidation of C4-vanillin- and C4-isovanillin-1,4-dihydropyridines in aprotic medium: Reactivity towards free radicals

This work reports the electrochemical oxidation of two new synthetic C4-vanillin and -isovanillin-1,4-dihydropyridines in aprotic medium. Its reactivity with alkylperoxyl radicals ABAP-derived at pH 7.4 is also studied. Voltammetry, coulometry, controlled-potential electrolysis, UV–visible spectroscopy and GC–MS techniques were employed to collect data that permitted us to study its oxidation. Effect of TBA-OH addition on the oxidation was electrochemically and spectroscopically followed. In aprotic medium, the oxidation mechanism involves the formation of the pyridine derivative, which was generated by controlled-potential electrolysis (CPE) at 1270 mV and identified by GC–MS technique as the final product of the electrolysis. Spectroelectrochemical experiments also support the formation of the pyridine derivative from the oxidation of both 1,4-dihydropyridines. Direct reactivity of synthesized compounds towards alkylperoxyl radicals ABAP-derived was determined. Results reveal that the inclusion of vanillin radical or its positional isomer, isovanillin in the 4-position of the dihydropyridine ring produced a significant positive effect on the reactivity towards alkylperoxyl radicals, even compared with commercial dihydropyridine drugs with a well-known antioxidant ability. Scavenging mechanism involves the electron-transfer and the formation of a pyridine derivative, which was identified by GC–MS.     

Oxidation of cationic 1,4-dihydropyridine derivatives as model compounds for putative gene delivery agents

A new synthetic approach to cationic pyridine derivatives is described here. Two different strategies for the synthesis of 1,1′-{[3,5-bis(ethoxycarbonyl)-4-phenylpyridine-2,6-diyl]dimethylene}bispyridinium salts have been developed. The key step of the first strategy relies on electrochemical and chemical oxidation of cationic 1,4-dihydropyridines; the second one involves nucleophilic substitution of pyridine dibromo derivatives.     

Electrochemical oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines

The electrochemical oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines has been studied in an aprotic medium and in the presence of pyridine. In an aprotic medium the products of oxidation are both 4-alkyl-substituted and 4-unsubstituted pyridines or mixtures of them. On oxidation in acetonitrile of 4-Et-, 4-n-Pr-, and 4-i-Bu-substituted dihydropyridines, 2-methylene-1,2,3,4-tetrahydropyridines were obtained in addition to the oxidized forms. In the presence of base the products of preparative electrolysis of the studied compounds were 4-alkyl-substituted pyridines. The exception was the 4-i-Pr- substituted dihydropyridine which was dealkylated on oxidation even in the presence of base. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1829–1838, December 2008.     

Novel Reaction of Nitrosonium(NO~ ) with Hantzsch Dihydropyridines

OurinterestinthereactionofHantzschl,4-dihydropyridinewithnitrosoniumtetrafluoroborate(NO BF#-)wasraisedfromtwoaspects.Thefirstwasbiologicalactivitiesandcytotoxicrolesofnitricoxideandnitrosonium(NO )"2.NO isaredoxpartnerofNO,butitsnatureisinstarkcontrasttoNO2'3.ThesecondwasthatHantzschl,4-dihydropyridinesareanaloguesofNADHcoenZymes.TheoxidationofHantzschl,4-dihydropyridinesisanoldreaction.Ithasbeenattractedmoreattentionofchemistsinrecentyears,essentiallysincethediscoverythattheirmetabol…     

Synthesis, Cardiovascular Activity, and Electrochemical Oxidation of Nitriles of 5-Ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic Acid

Nitriles of 4-aryl-5-ethoxycarbonyl-2-methylthio-1,4-dihydropyridine-3-carboxylic acid have been obtained by the methylation of 1,4-dihydropyridine-2-thiolates; of 1,4-dihydropyridine-2(3H)-thiones in the presence of a stoichiometric amount of piperidine, and of a mixture of 1,4,5,6-tetrahydro- and 1,4-dihydropyridine-2-thiolates with methyl iodide. One-pot multicomponent synthesis has also been used in the condensation of ethyl 2-arylmethyleneacetoacetate, 2-cyanothioacetamide, piperidine, and methyl iodide; of ethyl acetoacetate, 3-aryl-2-cyanothioacrylamide, piperidine, and methyl iodide; and of ethyl acetoacetate, an aromatic aldehyde, 2-cyanothioacetamide, piperidine, and methyl iodide. The latter, a five-component method, takes place rapidly and under mild conditions, it is efficient (yields of 75-96%, economy of time, labour, and resources) and green (there is no need to synthesize lachrymators, such as 3-aryl-2-cyanothioacrylamides).The cardiovascular activity and the electrochemical oxidation of the synthesized 2-methylthio-1,4-dihydropyridines have been investigated. A comparative analysis has been carried out of the ability towards electrochemical oxidation as a function of the electronic properties of the substituent at position 4 of the heterocycle.     

Catalytic aromatization of Hantzsch 1,4-dihydropyridines by ferric perchlorate in acetic acid

Catalytic oxidation of Hantzsch 1,4-dihydropyridines is described using a catalytic amount of ferric perchlorate in acetic acid at room temperature.     

Catalytic aromatization of 1,4-dihydropyridines by radical cation salt prompted aerobic oxidation

Aromatization of Hantzch 1,4-dihydropyridines was achieved under radical cation salt induced conditions, in which triarylamine radical cation acts as an efficient catalyst to prompt the aerobic oxidation of 1,4-DHPs in a catalytic way.     

Electrochemical conversions of 5-oxo-1,4-dihydroindeno[1,2-b]pyridine derivatives

The electrochemical oxidation and reduction potentials of 9 derivatives of 5-oxo-1,4-dihydroindeno[1,2-b]pyridine in acetonitrile on a glassy graphite disk electrode have been established. Indenodihydropyridines are oxidized with considerably greater difficulty and reduced considerably more easily than the corresponding 3,5-diethoxycarbonyl derivatives of 1,4-dihydropyridines which is explained by the presence of the cyclopentane fragment which ensures the coplanarity of the carbonyl groups with the aminovinyl system of the heterocycle. The mechanism of electrooxidation has been studied by the rotating disk electrode with a ring method which revealed the reasons for the process.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1992 pp. 1223–1229, September, 1992.     

Electrochemical transformations of 4-(nitroaryl)-1,2- and -1,4-dihydropyridines in acetonitrile

The potentials of the electrolytic oxidation and reduction of 3,5-diethoxycarbonyl- 1,2- and -1,4-dihydropyridines with a nitroaryl substituent in the 4 position and their oxidized forms were determined by the method of a rotating disk electrode with a ring. The mechanism of the electrochemical oxidation of the starting dihydropyridines in acetonitrile on a graphite electrode was ascertained. The first step in the electrolytic reduction of the starting dihydropyridines is the addition of an electron to the nitro group to give anion radicals, the fine electronic structures and the hyperfine structure (hfs) constants of which were determined by EPR spectroscopy. The pyridinium fragment in the electrolytic oxidation products is reduced more readily than the nitro group in the aryl substituent.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1099–1105, August, 1985.     

Synthesis and Electrochemical Oxidation of Nitriles of 4-Aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic Acids

Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-6-hydroxy-1,4,5,6-tetrahydropyridine-3-carboxylic acids were obtained by the alkylation of 1,4,5,6-tetrahydropyridine-2-thiolate with iodoacetamide or by a three-component synthesis by condensing 2-arylmethylene-1,3-dicarbonyl compounds with 2-cyanothioacetamide in the presence of piperidine with subsequent reaction with iodoacetamide. Nitriles of 4-aryl-2-carbamoylmethylthio-5-ethoxycarbonyl-1,4-dihydropyridine-3-carboxylic acids were obtained by the dehydration of 6-hydroxy-1,4,5,6-tetrahydropyridines or with a one-reactor three-component system from 2-cyano-3-(4-methoxyphenyl)thioacrylamide, 1,3-dicarbonyl compounds, and iodoacetamide. The electrochemical oxidation of the synthesized nitriles was investigated and it was established that derivatives of 1,4,5,6-tetrahydropyridine as a rule are oxidized readily to the corresponding 1,4-dihydropyridines. A comparative analysis has been carried out of the ability of hydrogenated pyridines to be oxidized electrochemically depending on the electron-withdrawing properties of the substituents in the heterocycle.     

4-Phenyl-1,2,4-triazole-3,5-dione as a novel and reusable reagent for the aromatization of 1,4-dihydropyridines under mild conditions

4-Substituted 1,3,4-triazole-3,5-diones were used as effective and recyclable oxidizing agents for the oxidation of 1,4-dihydropyridines to the corresponding pyridine derivatives under mild conditions with good to excellent yields.     

Rapid and efficient aromatization of Hantzsch 1,4-dihydropyridines with Potassium peroxomonosulfate catalyzed by manganese(III) Schiff base complexes

Rapid and efficient oxidation of Hantzsch 1,4-dihydropyridine with Potassium peroxomonosulfate is reported. The Mn(III)-salophen/monopersulfate catalytic system converts 1,4-dihydropyridines to their corresponding pyridine derivatives at room temperature in a 1:1, CH₃CN/H₂O mixture. The ability of various Schiff base complexes in the oxidation of 1,4-dihydropyridine was also investigated.     

One-step synthesis of heterocyclic privileged medicinal scaffolds by a multicomponent reaction of malononitrile with aldehydes and thiols

Heterocyclic privileged medicinal scaffolds involving pyridine, 1,4-dihydropyridine, chromeno[2,3-b]pyridine, and dihydro-1,4-dithiepine frameworks are prepared via a single-step multicomponent reaction of structurally diverse aldehydes with various thiols and malononitrile. Mechanistic studies of the synthetic pathway leading to pyridines reveal that 1,4-dihydropyridines undergo oxidation by the intermediate Knoevenagel adducts rather than by air oxygen. The use of o,o'-disubstituted aromatic aldehydes leads to the corresponding 1,4-dihydropyridines, whereas salicylic aldehydes result in chromeno[2,3-b]pyridines. Reactions of ethanedithiol as a thiol component produce dimeric pyridines with sterically unencumbered aldehydes, while o,o'-disubstituted aromatic aldehydes give dihydro-1,4-dithiepines. Thus, depending on the aldehyde and thiol types, diverse libraries of medicinally relevant compounds can be prepared by a simple one-step process involving no chromatography.