Reactions of cyclic enaminoketones with benzylidenemalononitriles. Synthesis of new fused heterocyclic systems containing the 1,4-dihydropyridine fragment

The reactions of cyclic enaminoketones with benzylidenemalononitriles were examined and a new procedure was developed for the synthesis of fused heterocyclic systems containing the 1,4-dihydropyridine ring, viz., thienopyrimidoquinolines and furopyrimidoquinolines. The characteristic features of the reactions and the structures of the resulting compounds were investigated.     

Reactivity of bis-vinylphosphates obtained from imide derivatives. Synthesis of 2,6-disubstituted 1,4-dihydropyridines

The Pd-catalyzed functionalization of lactam-derived vinyl phosphates has become an important tool in the last decade for the synthesis of nitrogen-containing heterocycles. By using this method, we were able to introduce alkenyl, aryl and heteroaryl groups on bis-vinylphosphate derivatives to provide efficient access to 2,6-disubstituted 1,4-dihydropyridines.     

Synthesis and study of novel fulleropyrrolidines bearing biologically active 1,4-dihydropyridines

New fulleropyrrolidines endowed with chlorine-containing biological active 1,4-dihydropyridines (1,4-DHPs) have been synthesised from the respective formyl substituted 1,4-DHPs by following Prato's procedure. The presence of the chlorine atom on C2 of the 1,4-DHP ring brings about important spectroscopical and structural differences in compounds 10a-f related to the parent hydrogen-containing 11a. The mass spectroscopy study reveals different fragmentation patterns for fulleropyrrolidines 10a-f and their precursors 1,4-DHPs, as well as with 11a. Semiempirical calculations (AM1 and PM3) predict a most stable stereoisomer in all cases (RS for 10a-f) and the same RR for 11a. The presence of chlorine atom in 10a-f is responsible for the higher calculated conformational energy barriers in comparison with 11a. The geometry of the 1,4-DHP shows that the presence of fullerene unit does not significantly alter the required conformation for biological activity.     

Rearrangement of 2-amino-1-aryl-1,4-dihydropyridines

Heating of 2-amino-1-aryl-1,4-dihydropyridines in acidic aqueous media gives 2-arylamino-1,4-dihydropyridines. The reaction formally involves the migration of the aryl substituent from the endo-to exocyclic N atom. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1259–1260, July, 2006.     

Synthesis and theoretical study of pyrrole formiate derivatives through ring contraction of 1,4-dihydropyridines

Pyrrole formiate derivatives were synthesized through ring contraction of corresponding 3-carboxylate-1,4-dihydropyridines (3-CDHPs) mediated by 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO). 2-Carboxylate-3-aryl-1H-pyrroles (2) and 3-carboxylate-4-aryl-1H-pyrroles (3) were obtained under readily accessible reaction conditions. To gain deep insights into this transformation, DFT calculations were carried out to establish the plausible reaction mechanism. The result revealed that the processes, including release of hydrogen, coupling with TEMPO, ring-opening of DHP scaffold, cleavage of ON bond in TEMPO moiety, fabrication of pyrrole scaffold and dissociation of formyl were incorporated in the transformation, which was confirmed further by the characterization of a byproduct and the detection of key intermediates using the LC-MS method.     

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.     

Photochemistry of Hantzsch 1,4-dihydropyridines and pyridines

The photochemistry of some Hantzsch 4-phenyl-1,4-dihydropyridines bearing a substituent on the phenyl ring (the three isomeric chloro derivatives and the 4′-nitro derivative) has been studied. All of these compounds underwent inefficient aromatization to the corresponding pyridines (quantum yield <10⁻⁴ at 366 nm, <10⁻² at 254 nm). This process is scarcely affected by molecular oxygen and is initiated by proton transfer (from C₄-H), probably to the solvent, from the excited singlet. In turn, the thus formed pyridines were photoreactive with comparable or higher efficiency. Thus, the 4-(3′-chlorophenyl) and 4-(4′-chlorophenyl) Hantzsch pyridines underwent positional rearrangement to form two isomers each. The reaction occurs via Dewar benzene--prismane path. In the case of the minor isomer a further 1,3-shift take place at the Dewar benzene level. The 4-(2′-chlorophenyl) derivative underwent C-Cl bond homolysis, which led to cyclization of the phenyl group onto one of the ester groups forming a pyrane ring.     

A clean procedure for the synthesis of 1,4-dihydropyridines via Hantzsch reaction in water

A clean and efficient procedure was established to synthesize 1,4-dihydropyridines via one-pot Hantzsch reactions in aqueous medium without the use of a catalyst and/or organic solvent. The reaction with stoichiometric molar ration could be carried out in a sealed vessel with a water steam, air, or nitrogen atmosphere to afford Hantzsch esters in good to excellent yields and purities. After the simple filtration, the 1,4-dihydropyridines were isolated, and the filtrate could be recycled and reused without significantly decreasing the yields and purities. The novel and clean methodology offers the advantages including short reaction time, good yields, operational simplicity, less leaks, and environmentally benign.     

A novel oxidation-ring-contraction of Hantzsch 1,4-dihydropyridines to polysubstituted furans

A novel oxidation-ring-contraction reaction took place when 4-substituted Hantzsch 1,4-dihydropyridines were treated with Oxone. This reaction pattern provided a convenient method for the synthesis of polysubstituted furans.     

Reactions of cyclic enehydrazino ketones with arylidenemalononitriles. Synthesis of 11-aryl-1-oxo-2,3,4,5,10b,11-hexahydro-1H-indolo[2,3-b]quinoline-10b-carbonitriles

A general and convenient method for the synthesis of 11-aryl-1-oxo-2,3,4,5,10b,11-hexahydro-1H-indolo[2,3-b]quinoline-10b-carbonitriles was elaborated. The method is based on the novel stereoselective rearrangement of fused N-arylamino-substituted 1,4-dihydropyridines. The structures of the synthesized compounds were studied using ¹H NMR spectroscopy and X-ray diffraction analysis.     

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.     

A novel TMSI-mediated synthesis of Hantzsch 1,4-dihydropyridines at ambient temperature

The synthesis of various substituted Hantzsch 1,4-dihydropyridines has been achieved using the classical Hantzsch procedure and modified Hantzsch conditions for the first time at room temperature in the presence of iodotrimethylsilane (TMSI) generated in situ in CH₃CN, in excellent yields.     

Oxidative aromatization of Hantzsch 1,4-dihydropyridines by aqueous hydrogen peroxide-acetic acid

A simple method for the oxidative aromatization of Hantzsch 1,4-dihydropyridines to the corresponding pyridines is achieved by using hydrogen peroxide as green oxidant and acetic acid as catalyst in aqueous solution.     

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.     

Tetrabutylammonium hydrogen sulfate catalyzed eco-friendly and efficient synthesis of glycosyl 1,4-dihydropyridines

An efficient and eco-friendly synthesis of glycosyl 1,4-dihydropyridines has been achieved by a three-component reaction of β-keto esters or ketones, enamines and glycosyl aldehydes in the presence of tetrabutylammonium hydrogen sulfate as catalyst in diethylene glycol.     

An Environmentally Benign Catalytic Method for Versatile Synthesis of 1,4-Dihydropyridines via Multicomponent Reactions

The synthesis of diverse 1,4‐dihydropyridines have been achieved via the multicomponent reactions of aldehydes, enaminones and amines. The reactions have been smoothly performed in water to provide all products with moderate to excellent yields by using lactic acid as a green catalyst.     

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.     

Synthesis of novel unsymmetrical coumarinyl-1,4-dihydropyridines

The novel unsymmetrical 3,5-dialkoxycarbonyl-2,6-dimethyl-4-(7′,8′-dimethoxycoumarin-4′-yl)-1,4-dihydropyridines and 5-acetyl-3-alkoxycarbonyl-2,6-dimethyl-4-(7′,8′-dimethoxycoumarin-4′-yl)-1,4-dihydropyridines (coumarinyl-1,4-dihydropyridines) have been synthesized by Knoevenagel condensation of 4-formyl-7,8-dimethoxycoumarin with alkyl acetoacetates in the presence of AlCl₃ followed by cyclization of the resulted Knoevenagel product with other alkyl acetoacetate or acetyl acetone and ammonium acetate. The structure of the intermediate Knoevenagel product and the cyclized unsymmetrical coumarinyl-1,4-dihydropyridines has been established on the basis of their spectral data analysis and single-crystal X-ray diffraction analysis. The observed conformation of the coumarinyl-1,4-dihydropyridines holds the key to promising calcium antagonistic activity of the synthesized coumarinyl-1,4-dihydropyridines.     

Organocatalyzed highly efficient synthesis of densely functionalized pyrrole-fused 1,4-dihydropyridine derivatives

Abstract

An organo base catalyzed diverse pyrrole-fused 1,4-dihydropyridines were synthesized. This one-pot, three-component domino reaction of enamino imides, aromatic aldehydes, and malononitrile/ethyl cyanoacetate was achieved by 10?mol% of DMAP under refluxing ethanol. In addition, novel bis-pyrrole-fused 1,4-dihydropyridine derivatives were also prepared by using terephthalaldehyde as a linker instead of simple aromatic aldehydes. This transformation proceeds via Knoevenagel condensation/Michael addition and N-cyclization reaction sequence and have some salient features including the use of a cost-effective catalyst, short reaction time and high atom economy. Moreover, the reusability of the catalyst was also performed up to five runs without any significant loss in activity.     

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.