Pyridine dicarboxylic acids

This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

Pyridine-3,5-dicarboxylic acid, 2,6-dimethyl-synthesis, 2, 457 Pyridinedicarboxylic acids synthesis... 

Similar compounds to those described above have been prepared by the same group using the bis-cesium salts of pyridine-3,5-dicarboxylic acids. In a number of experiments Piepers and Kellogg showed that Cs plays an irreplacable role as compared with Na", K and Rb for the formation of [the macrocycle shown below] . 

Bemtsson, P. B., Carlsson, S. A. I., Gaarder, J. O., and Ljung, B. R. (1981). 2,6-Dimethyl-4-2, 3-disubstituted pbenyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-as3mimetric diesters... 

Pyridine-3,5-dicarboxylic acid X-ray, 2, 113 <73CL1089, 73BCJ2020, 73BCJ2292, 73BCJ2372, 73BCJ2669)... 

Dimethyl-4-phenyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester... 

Derivatives of pyridine-3,5-dicarboxylic acid have been shown to undergo reaction with lithium aluminum hydride by attack on the pyridine ring to form 1,4-dihydropyridines.57,58 Presumably the decrease in electron-density at the ring carbon atoms due to these substituents causes the ring to be extremely susceptible to hydride attack. Similar results were obtained with 3,5-dicyanopyridine derivatives. Methyl nicotinate, however, underwent reaction with LAH with exclusive reduction of the ester function.57 Recently the 3,5-dicyanopyridines have been reported to give mixtures of 1,2- and 1,4-dihydropyridines on reduction with LAH or sodium boro-hydride.20 ... 

Anodic treatment of 3,5-lutidine (35) on BDD electrodes also turned out to be challenging. Only traces of the desired pyridine-3,5-dicarboxylic acid (36) could be detected. As electrolyte a dilute NaOH solution was employed. The mineralization and decomposition seem to be the dominant reaction pathways (Scheme 16). 

Cesium salts of substituted pyridine-3,5-dicarboxylic acids were used first by Krui-zinga and Kellogg for the synthesis of macrocyclic lactones [51]. Kellogg obtained the bis-lactone 46 in a one-pot reaction of the cesium carboxylate 44 and the dibro-mo compound 45 in 85 % yield without application of high dilution conditions [1]. By comparison with other alkali metal carbonates he proved the yield-increasing effect of the cesium ions ... 

Two-dimensional structures result when pyridine-dicar-boxylic acids are used. The complex trans-VACliLi (L = 2,6-dimethyl pyridine-3,5-dicarboxylic acid) (149) self-assembles to yield a two-dimensional sheet structure that involves hydrogen bonding between the carboxylic acid groups mediated by methanol solvent molecules (Scheme 31). 

Our work with dipicolinate derivatives also indicates that nitrogen donors can be preferred over oxygen donors in certain cases. To better understand the binding behavior of dipicolinate, we explored the coordination geometries of various DPA analogues with Tb. Three structural isomers were examined pyridine-2,4-dicarboxylic acid (2,4-DPA), pyridine-3,5-dicarboxylic acid (3,5-DPA), and dipicolinate itself (pyridine-2,6-dicarboxylic acid, DPA). Picolinic acid (Pic) and Pyr, which have one and both carboxyl arms eliminated, respectively, were also included. As DPA usually coordinates in a tridentate fashion with the two... 

Olefin-containing esters of pyridine-3,5-dicarboxylic acid are able to form macrocycles using a ring-closing metathesis reaction if the pyridine was protected with complexing Pt. The method was applied to 69- and 75-membered macrocycles <03ZOR449>. An example of a 17-membered ring formation is shown below. 

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). 

Figure U.1D. Nicotinamide analogs tested in pellagra or animal models of pellagra. The active compounds include (1,2, 6, 11, 12, 13,15,18, and 20). Compounds active in some models or in pellagrainclude (7,17,21), pyrazine-2,3-dicarboxylic acid, NAD, pyridyl-3-aldehyde,pyridyl-3-carbi-nol, tryptophan, and 3-hydroxyanthranilicacid. The inactive compounds are (3,4,5,8,9,10,14,16, 19), 3-arninopyridine,thiazole-5-carboxylicacid, 2-methylpyridine, 3-methylpyridine, 2,6-dimethyl-pyridine-3,5-dicarboxylic acid, pyridine-3,5-dicarboxylic acid, kynurenine, 3-hydroxykynurenine, and formylkynurenine. This figure is from Ref 33 and is used with permission.

Oxidation of 3,5-dialkyIpyridines.1 3,5-Dialkylpyridines are oxidized to pyridine-3,5-dicarboxylic acids in very good yields by sulfur trioxide or oleum when catalyzed by 1-4% selenium. 

S02,403 on the photoreduction of quinones,404 on acetyl and acetyl peroxide radicals in gas-phase reactions,405 on fluoroalkyl radicals in solution,408 on the photochemistry of 2,2-dimethoxy-2-phenylacetophenone,407 on pyridine-3,5-dicarboxylic acid,408 on photolytically reduced pyrazine,409 410 on the dimerization... 

The chief synthetic problem in an approach to (5d) would be the incorporation of the bridge thereby creating a macrocyclic ring. Numerous approaches to bridged pyridines have been described but none met our needs. We therefore developed an independent route. We had been struck by the report that cesium-carboxylates in DMF are powerfully nucleophilic. We were well rewarded on applying this report to commercially available pyridine-3,5-dicarboxylic acid (57), which could be converted into, for example, (55) in 90% yield (eq. 27)... 

The sodium enolate of acetoacetaldehyde (X-6) could be condensed with formaldehyde and ammonolyzed to yield the dihydropyridine (X-7). Subsequent nitric acid oxidation gave pyridine-3,5-dicarboxylic acid (X-8). When this... 

The diamide of pyridine-3,5-dicarboxylic acid pf-154) was prepared by oxidizing 3,5-diacetyl-l,4-dihydropyridine (X-153) with dilute nitric acid followed by treatment with thionyl chloride and dimethylformamide. ... 

Oxidation of plantagonine gave pyridine-3,5-dicarboxylic acid ( ) (mp 312°) methyl ester (mp 84°) identical with a synthetic specimen. On this evidence and on that derived from mass and NMR-spectra structure LXVIII is ascribed to this alkaloid (181). 

Oxindolylmethyl) pyridine-3,5-dicarboxylic acid 5-methyl ester refluxed 1 min. in acetic anhydride enollactone (Y 94%) added below 5° to a mixture of hydrazine hydrate and methanol, shaken until dissolved hydrazide (Y 90%). F. e. s. H. Plieninger, M. Schach von Wittenau, and B. Kiefer, B. 91, 2095 (1958). 

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