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.     

Candida antarctica lipase B-catalyzed the unprecedented three-component Hantzsch-type reaction of aldehyde with acetamide and 1,3-dicarbonyl compounds in non-aqueous solvent

A direct approach to 1,4-dihydropyridines by lipase-catalyzed unprecedented three-component Hantzsch-type reaction of aldehyde with 1,3-dicarbonyl compounds and acetamide in non-aqueous solvent has been developed. Some control experiments have been performed to demonstrate the specific catalytic effect of CAL-B. Acetamide was utilized as a novel ammonia source in the Hantzsch-type reaction for the first time. An array of 1,4-dihydropyridines was successfully synthesized through this methodology.     

The First Functionalized 6,12-Diazatetrakishomocubanes

The photodimerization of asymmetric 4-aryl-1,4-dihydropyridines results, totally unexpectedly, in the new 6,12-diazatetrakishomocubanes 1. This is in contrast to the previously observed [2+2] photocycloaddition reactions of symmetrical 4-aryl-1,4-dihydropyridines     

Substitution reactions involving the 2,6-methyl groups of 1,4-dihydropyridines

4,4-Disubstituted 1,4-dihydropyridines (I) are brominated with bromine in chloroform to give 2,6-bis(bromomethyl)-4,4-disubstituted 1,4-dihydropyridines (II), whereas 2,6-bis(dibromomethyl)-4,4-disubstituted 1,4-dihydropyridines (III) are obtained in the case of bromination of I in acetic acid. The bromine atoms in II and III are labile and readily undergo nucleophilic substitution.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1519–1524, November, 1978.     

Mass spectra of 4-substituted-1,2,6-trimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridines

The mass spectra of 4-substituted-1,2,6-trimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridines have been studied. The detailed fragmentation mechanisms, supported by high resolution measurements, the study of metastable ions and the use of deuterium labelling, are discussed.     

Microwave-assisted combinatorial synthesis of hexa-substituted 1,4-dihydropyridines scaffolds using one-pot two-step multicomponent reaction followed by a S-alkylation

A sequential one-pot two-step protocol for microwave-assisted synthesis of Hantzsch-type hexa-substituted 1,4-dihydropyridines has been developed. The three-component reactions of beta-aroylthioamides with aldehydes and acetonitrile derivatives produce the intermediates in situ followed by a S-alkylation to afford hexa-substituted 1,4-dihydropyridines. The reaction presumably proceeds via a Knoevenagel condensation-Michael addition-cyclocondensation-rearrangement-S N2 reaction sequence. Target compounds were obtained in high yields and simply purified by recrystallization. The novel method is complementary to the classical Hantzsch synthesis in that it is well-suited to the preparation of hexa-substituted 1,4-dihydropyridines.     

Aromatization of <Emphasis Type="Italic">Hantzsch</Emphasis> 1,4-Dihydropyridines by Hydrogen Peroxide in the Presence of Cobalt(II) Acetate

Summary.  Hydrogen peroxide readily oxidizes Hantzsch type 1,4-dihydropyridines in the presence of cobalt(II) acetate as catalyst at room temperature. No evidence of a dealkylation process for 4-alkyl 1,4-dihydropyridines has been observed. Corresponding author. E-mail: mhashemi@sharif.ac.ir Received January 16, 2002; accepted (revised) April 20, 2002     

Graphite oxide mediated oxidative aromatization of 1,4-dihydropyridines into pyridine derivatives

A new approach utilizing graphite oxide as an oxidizing agent is applied for the oxidative aromatization of 1,4-dihydropyridines. Graphite oxide efficiently aromatized Hantzsch 1,4-dihydropyridines into their corresponding pyridine derivatives in excellent yields. The reaction was carried out in toluene at 100 °C.     

Accelerated Hantzsch electrospray synthesis with temporal control of reaction intermediates

Complex chemical reactions can occur in electrosprayed droplets on the millisecond time scale. The Hantzsch synthesis of 1,4-dihydropyridines was studied in this way using on-line mass spectral analysis to optimize conditions and characterize the product mixture. Changing the distance between the nanospray source and the MS inlet allowed exploration of reaction progress as a function of droplet time-of-flight. Desolvation of the charged microdroplets is associated with transformation from starting material to intermediates and eventually to product as the distance is increased. Results of the on-line experiments require a termination step that discontinuously completes the desolvation process and allows the generated gaseous ions to be used to characterize the state of the system at a particular time. The intermediates seen correspond to those known to occur in the bulk solution-phase reaction. Off-line collection of the sprayed reaction mixture allowed the recovery of 250 mg h^–1 of desired reaction product from a single sprayer, permitting characterization by NMR and other standard methods. A thin film version of the accelerated reaction is described and it could be controlled through the temperature of the collection surface.     

Bromination of 4-aryl-3,5-dialkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines

4-Aryl-3,5-dialkoxycarbonyl-2,6-dimethyl-1,4-dihydropyridines are brominated by N-bromosuccinimide in methanol at room temperature at the methyl groups at positions 2 and 6 to form mono-, di-, tri-, and tetrabromo derivatives. When the N-unsubstituted bromomethyl-1,4-dihydropyridines are heated they are easily converted to tetrahydrofuropyridines, but in the case of the analogous N-substituted-1,4-dihydropyridines cyclization does not occur. The 2,6-bis(bromomethyl)-substituted products easily replace bromine under the influence of nucleophilic reagents.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1230–1235, September, 1991.     

Sequential three-component reactions: synthesis, regioselectivity and application of functionalized dihydropyridines (DHPs) for the creation of fused naphthyridines

Facile and efficient synthesis of tetrasubstituted 1,4- and 1,6-dihydropyridines (DHPs) has been achieved by employing three-component domino reaction using dimethyl acetylenedicarboxylate (DMAD), aliphatic amines, and α,β-unsaturated aldehyde in the presence of 30 mol % trifluoroacetic acid. Interestingly, regioselectivity for the synthesis of 1,4-dihydropyridines can be increased by using 30 mol % triflic acid. In addition, the synthesis of fused-naphthyridine derivatives has been accomplished involving imino-Diels-Alder reaction by employing 1,4-dihydropyridines, aromatic aldehydes, and aromatic amines.     

Some substitution and heterocyclization reactions based on 1,4-dihydropyridines

Data on the bromination, chlorination, and bromolactonization of 4-aryl-1,4-dihydropyridines are correlated. The reactions of the products of bromination of 4-aryl-1,4-dihydropyridines with various nucleophilic agents (amines and iodide, azide, and thiocyanate ions) and reactions involving the heterocyclization of the products of substitution of the 2,6-methyl groups of 4-aryl-1,4-dihydropyridines, which lead to condensed furo-, difuro-, pyrrolo-, dipyrrolo-, furopyrrolo-, and furothiazolopyridines and thiazolopyridothiadiazines are examined.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 781–791, June, 1992.     

Efficient and Rapid Synthesis of Highly Functionalized Novel Symmetric 1,4-Dihydropyridines Using Glacial Acetic Acid as Solvent

A new series of 1,4-dihydropyridines bearing a pyrazole moiety in the 4-position were synthesized by a variation of the classical Hantzsch synthesis. The reaction of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde 4a–n with 3-amino crotononitrile in the presence of glacial acetic acid afforded novel 3,5-dicyano-2,6-dimethyl 1,4-dihydropyridines 5a–n. The procedure has short reaction time (15–20 min), easy workup, and good yield of product. The structures of all synthesized compounds were well characterized by mass, infrared, ¹H and ¹³C NMR, and elemental analysis.     

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.     

Highly regioselective photodimerization of 1,4-dihydropyridines: An efficient synthesis of novel 3,6-diazatetraasteranes

Conventional photocycloaddition of 1,4-dihydropyridines does not afford novel head-to-head 3,6-diazatetraasteranes. Herein, we describe a highly regioselective method to synthesize 3,6-diazatetraasteranes via an intramolecular photodimerization of 1,4-dihydropyridines. First, the 1,4-dihydropyridines were tethered by phthaloyl to direct a proximate parallel arrangement in head-to-head orientation by the rotation of CC single bonds in solution. An intramolecular [2 + 2] photocycloaddition proceeded subsequently to give desired 3,6-diazatetraasteranes in high yield (92–97%) and excellent regioselectivity. Furthermore, two different 1,4-dihydropyridines can also be regiocontrolled by this strategy and produce polysubstituted 3,6-diazatetraasteranes via a cross-photodimerization in a concise and efficient way. In addition, this approach can provide direct access to other polysubstituted polyhedron scaffolds from 1,4-dihydropyridine analogues.     

水相条件下1,4-二氢吡啶衍生物的合成与芳构化

将醛、乙酰乙酸乙酯和醋酸铵的多组分反应引入到水相回流条件下, 合成了一系列具有生物和药物活性的1,4-二氢吡啶化合物. 在此基础之上, 向反应体系中直接加入氧化剂MnO2, “一锅法”生成了芳构化的吡啶衍生物, 将原来Hantzsch酯的合成与芳构化在“一锅”里实现, 缩减了反应步骤, 提高了反应效率.     

Regioselective synthesis of novel 2-chloroquinoline derivatives of 1,4-dihydropyridines

Highly regioselective reaction of some substituted 2,4-dichloroquinolines with symmetrical 1,4-dihydropyridines, leading to novel quinoline derivatives of DHPs, has been achieved in the presence of powdered K₂CO₃, as a mild and efficient base, at moderate temperature. All the synthesized compounds were characterized by use of IR, NMR, and mass spectral data.     

硅胶硫酸:一种在温和及无溶剂条件下一锅法合成1,4-二氢吡啶的高效多相催化剂(英文)

A series of 1,4-dihydropyridines have been prepared by a one-pot condensation of aldehydes,ethyl acetoacetate,and ammonium acetate in the presence of a heterogeneous catalyst silica sulfuric acid at room temperature under solvent-free condition. This new protocol has the advantage of short reaction time and excellent yields,and is an environmentally benign route to the synthesis of 1,4-dihydropyridines.     

Palladium-catalyzed regioselective silaboration of pyridines leading to the synthesis of silylated dihydropyridines

The addition of silylboronic esters to pyridine takes place in toluene at 50 °C in the presence of a palladium catalyst to give N-boryl-4-silyl-1,4-dihydropyridines in high yield. The regioselective 1,4-silaboration also proceeds in the reaction of 2-picoline and 3-substituted pyridines, whereas 4-substituted pyridines undergo 1,2-silaboration to give N-boryl-2-silyl-1,2-dihydropyridines regioselectively.     

An intramolecular journey of a carboxyl group around 1,2-dihydropyridines: multisite δ- versus γ-lactonization reactions

In contrast to substituted 4-acetic acid 1,4-dihydropyridines, giving only δ-lactones upon intramolecular reactions, 2-substituted 1,2-dihydropyridines led, besides to δ-lactones, also to new, structurally interesting γ-lactones as the result of a bromine-induced carbon-carbon double bond ‘Umpolung’.