Pyridine carboxylic acids, reduction

Derivatives of the pyridine carboxylic acids are polarographically reducible both in acid and alkaline solution in the latter solvent the nucleus is reduced.127 In the few cases where a macroscale reduction at a mercury electrode127,128 has been made, the 1,4-dihydropyridine has been isolated [e.g., Eq. (3)].127... 

When the reduction is performed without control of the potential, a mixture of products results. Thus, reduction in sulfuric acid at lead or mercury cathodes of the pyridine carboxylic acids leads to a mixture of picolines andtetra- and hexahydropyridine derivatives.284-287 Derivatives of nicotinic acid are more apt to be reduced in the ring than the 2- and 4-carboxypyridines. Reduction of the corresponding pyridylcarbinoles under identical conditions produces a similar reaction mixture.287... 

R te Constants for Reduction of IsOnicotinamide (4-Pyridine Carboxylic Acid Amide) Complexes by [Cr(H20)6] ... 

The reduction of acyl hydrazines has been investigated very little. Polarography of 4-pyridine carboxylic acid hydrazide in acid and neutral solution shows that it is reduced in two, two-electrons steps [141]. The result of controlled potential electrolysis is cleavage of the N-N bond to form 4-pyridine-carboxamide, which then undergoes reduction to the aldehyde in the second step. Other hydrazides of heterocyclic carboxylic acids behave analogously. 

Anion radical from anion of pyridine-4-carboxylic acid Reduction with solvated electrons/ Liquid NHj (flow system) EPR/ 213 H(2,6) 0.196 H(3,5) 0.196 N 0.551 ... 

Derivatives of pyridine carboxylic acids form 1 1 complexes with Eu + in strongly acidic conditions. Whereas the complexes with nicotinic and picolinic acids are stable with respect to further reaction, isonicotinic acid and its Af-methyl derivative undergo reduction with an Eu + substrate stoicheiometry of 2 1. 

Ladenburg 38 described the reduction of pyridine and some of its homologues to piperidines by sodium and alcohol, and the method has occasionally been used for this purpose it is useful with pyridine-carboxylic acids and their side-chain vinylogues which give piperidine-carboxylic acidsi 40 Esters of pyridine-carboxylic and vinylogous side-chain acids give the fully saturated alcohols. ... 

The reduction of pyridine-carboxylic acids has been mentioned already (pp. 258, 263), and it has been seen that electrolytic reduction or reduction with zinc and acetic acid can give methyl- or hydroxymethylpyridines. Whilst the electrolytic reduction of benzoic acid to benzyl alcohol is well known, benzene-carboxylic acids are generally not so readily reduced as the pyridine-carboxylic acids. Two other additional cases might be quoted. A dichloropyridine-carboxylic acid has been reduced by phosphorus and hydriodic acid to a dichloromethylpyridine , and 2,6-dichloropyridine-4-carboxylic acid with zinc and acetic acid gives 2,6-dichloro-4-hydroxy-methylpyridine . Isonicotinic acid is reduced to the alcohol by tin and hydrochloric acid . 

The amides and hydrazides of pyridine-carboxylic acids arc of some importance, though their chemistry is not marked by unusual properties. Nicotinamide is, of course, an important compound, and isonicotinic acid hydrazide (isoniazid) is an antitubercular drug. Substituted derivatives are used as antidepressants. In general, however, these compounds show normal chemical behaviour. The amides undergo hydrolysis, dehydration and Hofmann bromination without difficulty. Their reduction has been much studied as a route to pyridine aldehydes. The Sonn-Muller reduction is not very satisfactory in this series, but the McFadyen-Stevens reaction is useful . Nicotinic acid diethylamide gives only poor yields of the aldehyde upon reduction with lithium aluminium hydride, but yields from the methyl-phenylamide are high. Most satisfactory is the reduction of nicotinic acid dimethylamide with lithium diethoxyaluminium hydride . 

The general reactions of the esters of pyridine-carboxylic acids are in no way exceptional their reduction has been mentioned (pp. 258, 263). 

Pyridine-carboxylic acid chlorides, usually prepared by the use of thionyl chloride [a reaction in which nuclear chlorination sometimes occurs (p. 227)], are in most respects normal though rather unstable. Their reactions with alcohols provide some of the best ester preparations in this series. The Rosen-mund reduction fails with all three of the pyridoyl chlorides i though it... 

A more general route to 4-acetoxy-l,3-dioxanes utilizes the reductive acylation of l,3-dioxane-4-ones [46] (Scheme 21). l,3-Dioxane-4-ones 126 are prepared from the corresponding -hydroxy carboxylic acids. Low temperature reduction with DIBALH generates a diisobutylaluminum hemiacetal (127) which undergoes acylation in situ with AC2O in the presence of pyridine and DMAP. This method allows for the preparation of a wide range of 4-acetoxy-l,3-dioxanes, without the problem of a-epimerization. This method also represents a general approach to acylic a-acetoxy ethers, which are themselves useful synthetic intermediates [47,48]. 

Reduction of the carboxylic acid group passes through the intermediate aldehyde. For a number of examples in the heterocyclic series, the aldehyde becomes a major product because it is trapped as the hydrated vfc.-diol form. Examples include imidazole-2-caiboxylic acid [139], thiazole-2-carboxylic acid [140] and pyridine-4-carboxylic acid [141] reduced in dilute aqueous acid solution. Reduction of imidazole-4-carboxylic acid proceeds to the primary alcohol stage, the aldehyde intermediate is not isolated. Addition of boric acid and sodium sulphite to the electrolyte may allow the aldehyde intermediate to be trapped as a non-reducible complex, Salicylaldehyde had been obtained on a pilot plant scale in this way by... 

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