4-Aryl-1,4-dihydropyridines

Aryl-1,4-dihydropyridines.2 These compounds are important calcium channel blockers or enhancers depending on the stereochemistry at C4. An enaritio-selective synthesis of the (S)-isomers (blockers) is based on addition of an aryl-lithium to achiral 3-dihydrooxazolyl-5-methoxycarbonylpyridine (2). Thus addition... 

Khadilkar, B.M., Gaikar, V.G. and Chitnavis, A.A., Aqueous hydrotrope solution as a safer medium for microwave enhanced Hantzsch dihydropyridine ester synthesis, Tetrahedron Lett., 1995, 36, 8083-8083 Khadilkar, B.M. and Chitnavis, A.A., Rate enhancement in the synthesis of some 4-aryl- 1,4-dihydropyridines using methyl 3-aminocrotonate, under microwave irradiation, Indian J. Chem., Sect. B, 1995, 34, 652-653. 

Hilgeroth, A., Baumeister, U. and Heinemann F.W., Solution-dimerization of 4-Aryl- 1,4-dihydropyridines, Eur. J. Org. Chem., 2000, 245-250 Hilgeroth, A., Baumeister, U. and Heinemann F.W., Rotameric properties of novel N acyl and N-acyloxy dimeric 4-phenyl-1,4-dihydropyridines derived from developed solid-state synthesis, Heterocycles, 1999, 51, 2367-2376. 

Balalaie, S. and Kowsari, E., One-pot synthesis of N-substituted 4-aryl-1,4-dihydropyridines under solvent-free conditions and microwave irradiation, Monatsh. Chem., 2001, 132, 1551-1555. 

New 4-aryl-1,4-dihydropyridines and 4-arylpyridines as P-glycoprotein inhibitors. Drug Metab Dispos 33 321-328... 

Correlations with cr+ also exist for 13C=0 and 13CH2 shifts in AT-phenacylpyridinium bromides measured in H20 (77CC119), as well as for H and 13C shifts at the 4-position of 4-aryl- 1,4-dihydropyridines (Hantzsch esters) (70) (77BSB267). This latter type of compound is of interest as an effective model for the NAD/NADH coenzyme system, and this work provides detailed analysis of H and 13C NMR of such compounds. 

Lipophilic 1,4-dihydropyridines, such as 4-aryl-1,4-dihydropyridines, exhibit significant calcium channel antagonist activity. N.R. Natale et al. have synthesized a series of 4-isoxazolyl-1,4-dihydropyridines bearing lipophilic side chains at the C5 position of the isoxazole ring." The Hantzsch synthesis was carried out in an aerosol dispersion tube at 110 °C in ethanol in the presence of 2 equivalents of ethyl acetoacetate and aqueous ammonia solution. 

The reaction of A -phenacylpyridinium bromide with lithium dialkylcuprates (49) results in the isolation of acetophenone. The fate of the heterocyclic moiety has apparently not been determined. It is reasonable to assume, on the basis of the soft nature of these organometallic reagents, that 4-alkylpyridines must have been produced concomitantly. Addition of chloroformate esters to a mixture of pyridine and a cuprate reagent leads predominantly to A -carbo-alkoxy-4-alkyl(aryl)- 1,4-dihydropyridines (50). 

A soln. of startg. 4-aryl-1,4-dihydropyridine in DMF treated with NaCN at 60°, and stirred for 20 min - 3-methyl 5-(isopropyl) 2-(fluoromethyl)-6-methylpyridine-3,5-dicarboxylate and l-chloro-4-fluoro-2-(trifluoromethyl)benzene (Y 72%). This is the first generally applicable fragmentation-type aromatization of a Hantzsch ester under mild, basic, non-oxidative conditions. F.e.s. T. Mclnally, A.C. Tinker, J. Chem. Soc. Perkin Trans. I 1988, 1837-44. 

Gordeev MF, Patel DV, Gordon EM (1996) Approaches to combinatorial synthesis of heterocycles a solid-phase synthesis of 1,4-dihdropyridines. J Org Chem 61 924-928 Breitenbucher JG, Figliozzi G (2000) Solid-phase synthesis of 4-aryl-1,4-dihydropyridines via the Hantzsch three component condensation. Tetrahedron Lett41 4311 315... 

Aryl-l,4-dihydropyridines are of interest since related systems have application as calcium channel antagonists. The energy barrier to rotation about the aryl-dihydropyridine bond is small, with the coalescence temperatures observed by NMR spectroscopy to be well below room temperature <1996T9665>. When the aryl group at the 4-position is replaced with a biaryl group, the antiperiplanar form dominates <1997BML2519>. 

NMR spectra of the solution of 69j and 69k with p-TolLi show a remarkable upheld shift relative to those for 69j and 69k, AS = 182 and 212 ppm, respectively, indicating an increase in the coordination number of tin. It is noteworthy that the organos-tannates 69h and 69i react with l,3-bis(methoxycarbonyl)pyridinium chloride to give the corresponding alkylated(arylated) dihydropyridines. ... 

In the past year, reviews on 1,8-naphthyridines, perimidines, polyazaphen-anthrenes, 3-azabicyclo[3.3.1]nonanes, and 1,2- and 2,1-benzothiazines have appeared. Reviews on specialist aspects of pyridine chemistry are devoted to the reactions of newly available pyridines, a,a -disubstituted pyridines, the reactions of pyridines with nucleophiles, the electrochemistry of IjT-disubstituted 4,4 -bipyridinium ions (the viologens such as paraquat), dihydropyridines, and 4-aryl-dihydropyridines (a new class of calcium antagonists). Reviews have been published on the cyclization of oximes and amides to quinolines and isoquinolines, quinoline- and isoquinoline-diones, benzo[fl ]- and benzo[c]-quinolizinium ions, azachrysene preparation, quinazolines with plant-growth-regulating and biocidal activities, quinazolines in pharmaceutical research, isotopic hydrogen exchange in... 

Certain aryl-dihydropyridines [e.g. (12)], prepared by conventional Hantzsch synthesis, have been found to be highly effective calcium antagonists and are used to reduce blood pressure and in the treatment of angina pectoris. ... 

A limitation of this approach was the fact that the cyclization could not be accomplished on the resin. This would preclude further functionalization of the core. Therefore an alternate approach was to link the resin to the core via an aminoalcohol spacer as in 93. Furthermore, since linkage was conducted through the P-ketoester component rather than through the nitrogen atom, dihydropyridines 94 could now be formed on the solid support. When the 4-aryl substituent of 94 was nitro, on-resin reduction to the corresponding amine was possible. This allowed for further addition of diversity elements to the core scaffold before cleavage from the resin. 

An important extension of this work deals with the preparation of N-substituted l,4-dihydropyridine-3,5-diearboxylates. Tliirty examples have been deseribed (92SC3291). In most eases the reported yields (10-95%) are higher than those mentioned in the literature. Tire most signifieant results eoneern the synthesis of 1-aryl derivatives, whieh are hardly aeeessible by elassie methods. One should mention that the aminoeyelohexadiene 84 has been isolated as a by-produet when starting from ethyl A-benzylaminobut-3-enoate (Seheme 26). 

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

A one-pot synthesis of N-substituted 4-aryl-l,4-dihydropyridines (Scheme 8.34) was recently [52] mentioned at the Fifth International Electronic Conference on Syn-... 

Most of the cardiotonic pyridazine derivatives discussed in the preceding chapter also exhibit vasodilator effects. In addition, various dihydropyrida-zine derivatives like (52), structurally closely related to calcium-antagonistic Hantzsch-type dihydroypyridines, have been patented as coronary vasodilators [169-171]. Another type of pyridazine analogue of the previously mentioned dihydropyridines, namely compounds of type (53), in which the aryl substituent at C-4 is represented by a pyridazine nucleus, has been claimed in a patent [172]. Quite recently, pyridazinyldihydropyridine-3,5-dicarboxyl-ates (54,55) have been prepared in Austria [173]. 

Enantioselective reduction of 3-aryl-2//-l,4-benzothiazines using a dihydropyridine as the reducing agent has been reported (Equation 11) <2006AGE6751>. 

Aromatic aldehydes react very easily with tetramic acid under acidic conditions to give 3-benzylidene compounds (41). The yields are moderate, because often there are subsequent reactions. As a,/3-unsaturated carbonyl compounds, (41) react in a Michael addition with excess tetramic acid to form (67), but it can also react with other acyclic and cyclic 1,3-dicarbonyl compounds. In these reactions the aryl substituents may vary over a wide range. Thus, (67) and (68) can be cyclized with ammonium acetate to afford pharmacologically interesting compounds (70) and (71) (90TH1). The latter are dihydropyridines. Curiously, (69) does not cyclize under these conditions. (See Fig. 32.)... 

A fairly general route to 1,2-dihydroazocines (64) is provided by the [2+2] cycloaddition of DMAD to 1,2-dihydropyridines (62) (74JCS(Pi)2496,77JOC2903). The reaction gives good yields of the dihydroazocine-6,7-dicarboxylates with N- alkyl, -aryl or functionally substituted removable protective groups. Other substituents can be present at C-3 or -4 in the pyridine, but carboxyl substituents at N-l or C-5 of the pyridine reduce the enamine character, and Diels-Alder addition of the acetylene occurs at the diene system. The [4.2.0] bicyclic intermediates (63) can be detected at -10 to 0°C by NMR warming to 20 °C causes complete conversion to (64). 

Pyrans 69 and 326 (R = Pr) provide dihydropyridines with aryl-hydrazines,311,313 but a structure proof is lacking. 

They have been recognized as hydride donors for effectively reducing, as in the case of l-lithio-2-butyl-l,2-dihydropyridine, benzophenone and other aryl ketones to the corresponding alcohols.142... 

Pyridine reacts with lithium alkyls and aryls under rather vigorous conditions (e.g. xylene at 100°C) to afford 2-alkyl- and 2-aryl-pyridines. The reaction proceeds by way of the corresponding dihydropyridines (e.g. 275 or a tautomer), and these may be isolated at lower temperatures. The less reactive Grignard reagents give poorer yields of the same products. 

The classical Hantzsch reaction, the formation of dihydropyridines from an aldehyde, a 5-keto ester and an amine, was first described in 18826. In the 1940s, the interest for this substance class increased due to its pharmacological activity, for example, 4-aryl-1,4-dihydropyrdines form an important class of calcium channel antagonists such as Nifedipin. 

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