N-alkylation of 1,4-dihydropyridine-3,5-dicarboxylic acid esters

Alkylation of the anions of 1,4-dihydropyridines (1,4-DHP) formed by treatment of sodium hydride in aprotic solvents gave 1-alkyl(up to C₆H₁₃)-3,5-bis(ethoxycarbonyl)- and 1-alkyl-3,5-bis(aryloxycarbonyl)-1,4-DHP. The presence of a substituent in the 4 position increases the reactivity of the 1,4-DHP anion in the alkylation reaction. The absorption maximum in the UV spectra of the 1,4-DHP anion is shifted 100 nm bathochromically as compared with the neutral molecule. The longwave absorption maximum in the UV spectra of 1-alkyl-1,4-DHP is shifted hypsochromically as compared with the 1-unsubstituted compounds; this is explained by steric hindrance of the conjugation of the C=O groups with the -electron system of the ring. The introduction of an alkyl group at the nitrogen atom facilitates the electrical oxidation of 1,4-DHP.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1508–1513, November, 1978.     

Rapid, efficient, room temperature aromatization of Hantzsch-1,4-dihydropyridines with vanadium(V) salts: superiority of classical technique versus microwave promoted reaction

The aromatization of 1,4-dihydropyridines (1,4-DHPs) employing group 4 (Zr and Hf) and 5 (V, Nb, Ta) elements of periodic system has been studied. The reaction with VOCl₃ in dichloromethane at room temperature afforded products, substituted pyridines, in high-to-excellent yield. For the first time, the formation of charge-transfer complexes (CTCs) has been evidenced in preorganization step between 1,4-DHP and oxidant before electron transfer. The CTC has been formed only in neutral solvents such as dichloromethane and is characterized by intensive coloration. The aromatization of 1,4-DHP with V₂O₅ in refluxing acetic acid has found to be superior over microwave promoted reaction in solventless media. The only reasonable explanation was found in polymeric structure of V₂O₅, which slowly transfer energy of microwaves needed for the activation of the reactants. The solvent polarity dependent oxidative dealkylation of 4-n-propyl-1,4-DHP has been discovered. Unexpectedly, the reaction in acetic acid afforded only 33% of dealkylated product compared to 91% obtained in dichloromethane under the same reaction conditions.     

An umpolung approach to the hydroboration of pyridines: a novel and efficient synthesis of N-H 1,4-dihydropyridines

The first inverse hydroboration of pyridine with a diboron(4) compound and a proton source has been realized under simple basic and catalyst-free conditions. This process consists of a formal boryl anion addition to pyridine, which produces an N-boryl pyridyl anion complex, and the subsequent protonation of the anion complex. This process enables a simple and efficient method for the synthesis of multi-substituted N-H 1,4-dihydropyridine (1,4-DHP) derivatives that are difficult to prepare using established methods. Furthermore, this method allows for facile preparation of 4-deuterated 1,4-DHPs from an easily accessible deuterium ion source. This inverse hydroboration reaction represents a new mode for pyridine functionalization.

Umpolung of pyridine hydroboration was achieved by the reaction between pyridine and diboron(4) with a base and a proton source.     

Cu-catalyzed one-pot multicomponent approach for the synthesis of symmetric and asymmetric 1,4-dihydropyridine (1,4-DHP) linked 1,2,3-triazole derivatives

Abstract

Synthesis of various symmetric and asymmetric 1,4-DHP linked 1,2,3-triazole derivatives from economical and readily available starting materials via a convenient methodology in a single-pot method using CuSO₄·5H₂O as an efficient catalyst has been reported. The reaction proceeded efficiently under the optimized reaction conditions with excellent functional group compatibility providing the desired products in good yields. The method appears to be an efficient combinatorial strategy for the synthesis of new 1,4-DHP linked triazole derivatives.     

Molecular level model for the agonist/antagonist selectivity of the 1,4-dihydropyridine calcium channel receptor

Summary Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxylate], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5-carboxylate], and Bay O 9507 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(4-nitrophenyl)-pyridine-5-carboxylate] were determined. The conformations of the 1,4-DHP rings of these activator analogues of Bay K 8644 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5- carboxylate] do not suggest that their activator properties are as strongly correlated with the degree of 1,4-DHP ring flattening as was indicated for members of the corresponding antagonist series. The solid state hydrogen bonding of the N(1)-H groups of the activators is not, unlike that of their antagonist counterparts, to acceptors that are directly in line with the donor. Rather, acceptor groups are positioned within ± 60 degrees of the N(1)-H bond in the vertical plane of the 1,4-DHP ring. Previously determined structure-activity relationships have indicated the importance of this N(1)-H group to the activity of the 1,4-DHP antagonists. Based on these observations, a model is advanced to describe the 1,4-DHP binding site of the voltage-gated Ca²⁺ channel and its ability to accommodate both antagonist and activator ligands.     

Fluorescence of 3,5-diethoxycarbonyl-1,4-dihydropyridine derivatives and their anions

The fluorescence spectra of a group of 3,5-diethoxycarbonyl-1,4-dihydropyridine (1,4-DHP) derivatives were investigated. The introduction of electron-acceptor N-substituents and 2,6-methyl groups decreases Q markedly. The fluorescence spectra of 1,4-DHP anions are shifted bathofluorically, and the Q values are higher than for the corresponding 1,4-DHP. The fluorescence spectra have large Stokesian shifts, which are decreased for 1,4-DHP anions. A good correlation exists between the _max values of the fluorescence bands of 1,4-DHP anions and the Hammett _p ⁺ constants of the 4-R-aryl substituents.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 67–70, January, 1988.     

1,4-二氢吡啶衍生物与DNA相互作用的电化学与圆二色谱研究

用电化学和圆二色谱(CD)技术研究了5个1,4-二氢吡啶(1,4-DHP)衍生物与小牛胸腺DNA(CT-DNA)的相互作用.结果表明,1,4-DHP衍生物与CT-DNA相互作用是通过嵌入的方式进行的,相互作用的强弱与1,4-DHP衍生物的立体结构有关.1,4-DHP衍生物4-取代基空间位阻越小,嵌入到CT-DNA的程度越大.相反,空间位阻较大的1,4-DHP衍生物嵌入CT-DNA程度较小.非平面结构的1,4-DHP衍生物使CT-DNA双螺旋链结构松散程度增大.     

1,4-Dihydropyridine derivatives as deactivators of singlet oxygen

The constants of deactivation (k_q) of ¹O₂ by 1,4-dihydropyridine (1,4-DHP) derivatives were determined by quenching of the luminescence of singlet oxygen (¹O₂). The k_q values for 1,4-DHP derivatives range from 10⁶ to 10⁷ litersmole^–1-sec^–1 and depend to a considerable extent on the nature of the substituents in the 1,4-DHP ring. The presence of a substituent in the 4 position decreases k_q, while conversion of the 1,4-DHP system to the corresponding pyridine system deprives the compound of its ability to deactivate ¹O₂. As a result of tests of 12 1,4-DHP derivatives it was found that 2,6-dimethyl-3,5-di (phenylcarbamoyl)-1,4-dihydropyridine deactivates ¹O₂ most effectively.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 924–926, July, 1981.     

Intercepted-Knoevenagel condensation for the synthesis of unsymmetrical fused-tricyclic 4H-pyrans

4H-Pyrans (4H-Pys) and 1,4-dihydropyridines (1,4-DHPs) are important classes of heterocyclic scaffolds in medicinal chemistry. Herein, an indium(III)-catalyzed one-pot domino reaction for the synthesis of highly functionalized 4H-Pys, and a model of 1,4-DHP is reported. This alternative approach to the challenging Hantzsch 4-component reaction enables the synthesis of fused-tricyclic heterocycles, and the mechanistic studies underline the importance of an intercepted-Knoevenagel adduct to achieve higher chemoselectivity towards these types of unsymmetrical heterocycles.     

Organocatalyzed regioselective and enantioselective synthesis of 1,4- and 1,2-dihydropyridines

Abstract

Herein, we introduce one of the first examples of asymmetric organocatalyzed synthesis of 1,2-dihydropyridines, affording enantioselective access to and partially solving regioselectivity challenges in the synthesis of dihydropyridines. We demonstrate that through modification of organocatalysts both 1,2- and 1,4-dihydropyridines (1,2- and 1,4-DHPs) can be obtained with high regioselectivity (ratio of 1,2-DHP/1,4-DHP from 95/5 to 0/100) and enantioselectivity (33% ee for 1,2-DHPs and up to 98% ee for 1,4-DHPs) in good yields (up to 87%).     

1,4-二氢吡啶衍生物合成方法的改进和芳构化研究

改进了Hantzsch合成法,通过一锅煮合成1,4-二氢吡啶衍生物,大大缩短了反应时间,操作简便,发现氯化铁是一个较好的1,4-二氢吡啶衍生物芳构化的氧化剂。     

Reductive ability of 1,4-dihydropyridine derivatives in relation to ions of trivalent iron

3,5-Dicarbonyl derivatives of 2,6-dimethyl-1,4-dihydropyridine (1,4-DHP) can reduce Fe³⁺ to Fe²⁺ depending on the nature of the substituents at position 4 and in the 3,5-ester group. This ability is less pronounced for the 1,4-DHP derivatives investigated than for ascorbic acid, but among derivatives possessing antioxidant activity it is less than that of the known antioxidants ionol (BOT) and trolox. Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 661–663, May, 1999.     

Influence of 1,4-dihydropyridine derivatives on the generation of hydroxyl radicals

It was shown that a series of 1,4-dihydropyridine (1,4-DHP) derivatives in the NAD-H-Cu²⁺ -H₂O₂ system inhibit the formation of the hydroxyl radical (HO), while derivatives of 1,4-DHP with electron-donor substituents in the molecule are themselves capable of generating HO in the presence of Cu²⁺ and H₂O₂.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 519–521, April, 1992.     

Nitro radical anion formation from nitrofuryl substituted 1,4-dihydropyridine derivatives in mixed and non-aqueous media

Three new nitrofuryl substituted 1,4-dihydropyridine derivatives were electrochemically tested in the scope of newly found compounds useful as chemotherapeutic alternative to the Chagas' disease. All the compounds were capable to produce nitro radical anions sufficiently stabilized in the time window of the cyclic voltammetric experiment. In order to quantify the stability of the nitro radical anion we have calculated the decay constant, k2. Furthermore, from the voltammetric results, some parameters of biological significance as E7(1) (indicative of in vivo nitro radical anion formation) and KO2 (thermodynamic indicator of oxygen redox cycling) have been calculated. From the comparison of E7(1), KO2 and k2 values between the studied nitrofuryl 1,4-DHP derivatives and well-known current drugs an auspicious activity for one of the studied compounds i.e. FDHP2, can be expected.     

FERRIC CHLORIDE HEXAHYDRATE: A CONVENIENT REAGENT FOR THE OXIDATION OF HANTZSCH 1,4-DIHYDROPYRIDINES

A general and practical route for the moderate yield oxidative conversion of readily accessible 1,4-dihydropyridines (1,4-DHPs) to the corresponding pyridines was described using a relatively benign oxidant, i.e. ferric chloride hexahydrate (FeCl₃·6H₂O). The reaction was carried out under mild and convenient condition. However, oxidation of 4-isopropyl-1,4-DHP 1b with FeCl₃·6H₂O afforded the dealkylated pyridine 2a.     

Reactions of Peroxynitrite with Phenolic and Carbonyl Compounds: Flavonoids are not Scavengers of Peroxynitrite

Peroxynitrite (ONOO⁻, oxoperoxonitrate(1−)), an isomer of nitrate that oxidizes and nitrates biomolecules, is likely to be formed in vivo from the reaction of superoxide with nitrogen monoxide. To determine whether flavonoids scavenge peroxynitrite as postulated in the literature, we studied the reactions of peroxynitrite with phenol, hydroquinone, catechol, and the flavonoid monoHER. These reactions are first‐order with respect to peroxynitrous acid and zero‐order with respect to the organic compounds, and proceed as fast as the isomerization of peroxynitrous acid to nitrate. In vivo, a large fraction of all peroxynitrite is likely to react with carbon dioxide to form an unstable adduct, the 1‐carboxylato‐2‐nitrosodioxidane anion (ONOOCO). The presence of phenolic compounds did not influence the rate of disappearance of this adduct, which was ca. 4×10² s⁻¹. On the basis of these kinetic studies, it can be concluded that flavonoids are not scavengers of peroxynitrite. The products from the reaction of peroxynitrite with hydroquinone (benzene‐1,4‐diol) and catechol (benzene‐1,2‐diol) are para‐benzoquinone and ortho‐benzoquinone, respectively; no nitrated products were found. In a subsequent reaction, ortho‐quinone reacted with nitrite, a common contaminant of peroxynitrite preparations to form 1,2‐dihydroxy‐4‐nitrobenzene. We also investigated whether carbonyl compounds could redirect the reactivity of peroxynitrite toward nitration, as carbon dioxide does. The reaction with acetone is first‐order with respect to peroxynitrite and first‐order with respect to the carbonyl compound. The rate constant is 1.8 M ⁻¹s⁻¹ at neutral pH and 20°; peroxynitrite does not react with the carbonyl compounds dimethyl acetamide, L ‐alanylalanine, or methyl acetate. It is not likely that the carbonyl compounds or the mono‐, di‐, or polyphenolic compounds can scavenge peroxynitrite in vivo.     

Hantzsch synthesis of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-methoxyphenyl)-1,4-dihydropyridine; a novel cyclisation leading to an unusual formation of 1-amino-2-methoxy-carbonyl-3,5-bis(o-methoxyphenyl)-4-oxa-cyclohexan-1-ene

Hantzsch condensation of two equivalents of methyl-3-aminocrotonate with (m- and p)-methoxybenzaldehyde afforded the expected products 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(m-methoxyphenyl)-1,4-dihydropyridine and 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(p-methoxyphenyl)-1,4-dihydropyridine, whereas o-methoxy-benzaldehyde produced mainly 1-amino-2-methoxycarbonyl-3,5-bis(o-methoxy-phenyl)-4-oxa-cyclohexan-1-ene. The structure of the product, not previously reported in the literature, was determined by 1D and 2D NMR spectra and its MS fragmentation. This is the first example of cyclisation leading to a substituted pyran rather than 1,4-DHP under typical Hantzsch reaction conditions. A plausible mechanism for its formation is postulated.     

Fe3O4@SiO2@ADMPT/H6P2W18O62: a novel Wells–Dawson heteropolyacid-based magnetic inorganic–organic nanohybrid material as potent Lewis acid catalyst for the efficient synthesis of 1,4-dihydopyridines

A novel Wells–Dawson heteropolyacid-based magnetic Inorganic–organic nanohybrid, Fe₃O₄@SiO₂@ADMPT/H₆P₂W₁₈O₆₂, was fabricated and used as a green, efficient, eco-friendly, and highly recyclable catalyst for the one-pot and multi-component synthesis of 1,4-Dihydopyridine (1,4-DHP) derivatives from the reaction of various aromatic aldehydes with ethyl acetoacetate and ammonium acetate with good to excellent yields and in a short span of time. The nanohybrid catalyst was prepared by the chemical anchoring of Wells–Dawson heteropolyacid H₆P₂W₁₈O₆₂ onto the surface of functionalized Fe₃O₄ nanoparticles with 2,4-bis(3,5-dimethylpyrazol)-triazine (ADMPT) linker. These nanocatalysts were identified by using scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), infrared spectroscopy (IR) and vibrating sample magnetometer (VSM). This protocol is developed as a safe, cost-effective and convenient alternate method for the synthesis of 1,4-DHP derivatives utilizing an eco-friendly, and a highly reusable catalyst.     

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.     

Sensitization of Peroxynitrite Chemiluminescence by the Triplet Carbonyl Sensitizer Coumarin-525. Effect of CO2

Abstract— The flash of spontaneous chemiluminescence (CL) that reflects the formation of electronically excited intermediates during the decay of peroxynitrite (ONOO) to nitrate was investigated. The half-decay time of the CL flash (0.5 ± 0.1 s) was in agreement with the half-life of peroxynitrite obtained in stopped-flow experiments. The spontaneous CL intensity was linearly dependent on peroxynitrite concentration. The yield of spontaneous CL from peroxynitrite decay, 2 × 10^-9 photons/peroxynitrite at pH 9.5, was strongly enhanced by a sensitizer of triplet carbonyl CL, coumarin-525 (C-525). The maximal yield of sensitized CL was calculated to be 3 × 10^-6 photons/ peroxynitrite molecule for infinite concentration of C-525. The dependence of both spontaneous and sensitized CL on pH has a maximum at about pH 9.5. Bubbling with CO₂ or addition of NaHCO₃ considerably enhanced the flash of CL, and it is concluded that the reaction of the peroxynitrite anion with CO₂ is a major pathway leading to the formation of an electronically excited intermediate of peroxynitrite.