Alkyl 1,4-dihydropyridine-3,5-dicarboxylates

An interesting result has been observed when 4-formylantipyrine 89 was converted into the corresponding pyridinium salt 90 and reacted with alkyl 3-aminobut-2-enoates. Tire expected 1,4-dihydropyridines 91 are transient species in these syntheses and readily lose the 4-substituent (antipyrine, 93) so that dialkyl 2,6-dimethylpyridine-3,5-dicarboxylates 92 are obtained (85-95%) (94H815). Protonation of the pyrazole ring by the evolved hydrochloric acid accounts for this particular behavior (Scheme 29). 

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). 

Cycloaddition of 1-alkyl-1,4-dihydropyridines and DMAD gives cyclobutapyridines which are stable and do not undergo ring opening. However the cycloadducts (65) formed from thiocarbamoylmethylenepyridines lead to azocines (66) in 40-70% yields (75CPB2749). Similarly, l-methyl-l,4-dihydroquinoline gives l,6-dihydrobenzazocine-3,4-dicarboxylate (67). 

A brief discussion of some aspects of alcohol dehydrogenase will be used to illustrate the potential for catalysis. This system is chosen for illustration because it has been studied so extensively. Lessons drawn can be applied in a broader context. The 1,4-dihydropyridine (2a) is the reductant and this affords a nico-tinium ion (1) on transfer of hydride, as illustrated in equation (1). This process is mimicked in many abiotic systems by derivatives of (2 R = alkyl or benzyl), by Hantzsch esters (7), which are synthetically readily accessible, and 1,4-dihydro derivatives (8) of pyridine-3,5-dicarboxylic acid. A typical abiotic reaction is the reduction of the activated carbonyl group of an alkyl phenylglyoxylate (9), activated by a stoichiometric amount of the powerful electrophile Mg(CI04)2, by, for example, (2b equation 8). After acrimonious debate the consensus seems to be that such reactions involve a one-step mechanism (i.e. equation 5), unless the reaction partner strongly demands a radical intermediate, as in the reduction of iron(II) to iron(III). 

Derivatives of 1,4-dihydronicotinamide (2) and l,4-dihydropyridine-3,5-dicarboxylic acid (8) are obtained from the corresponding pyridines by alkylation followed by reduction with sodium dithionite, as illustrated for (76) in equation (33). The absolutely regioselective reduction by dithionite of pyridinium salts to 1,4-dihydropyridines is true synthetic good fortune most other reducing agents reduce pyridinium salts nonregioselectively and often with reduction beyond the dihydro stage. 

We have reported syntheses of 1-substituted 1,4-dihydropyridines and their fused analogues by treatment of primary amines with bis-enaminones, derived from alkyl acetone-1,3-dicarboxylates (00H2033), and ethyl 2-(5-oxo-4,5-dihydro-lH-pyrazol-3-yl)acetates (07H657,06T8126, 05TA2187, 04H609, 02H791). 

The apparent ionization constants and ultraviolet absorption spectra of the three isomeric pyridine monocarboxylic acids were determined at 25 in aqueous KCI. As expected, it was confirmed that these acids exist in aqueous isoelectric solutions mainly in the dipolar ion form. Similar data for monocarboxylic and monosulfonic acids and polyvalent acids were obtained more recently. The dissociation constants and electrophoretic mobilities of fifteen substituted alkyl-, nitro-, and chloropyiidine carboxylic acids were also determined. The ultraviolet absorption spectra of a series of dihydropyridine-3, S-dicarboxylic acids were correlated with electronic and steric factors. ... 

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