Pyridine carboxylic acid derivatives

The involvement of zinc in nicotinamide-based hydride-transfer reactions has led to numerous studies of Group IIB complexes of pyridine carboxylic acid derivatives. Cadmium complexes of 2-pyridinecarboxylic acid, 5 3-pyridinecarboxylic add497 and 3-pyridinecarboxamide498 have been reported. The crystal structure of [Cd(HC02)2L2(H20)2] (L = 3-pyridinecarboxamide) has also been described the metal is in an octahedral environment in which the amide acts as a monodentate N donor.498... 

The Pesticide Manual describes 5 pyridine carboxylic acid derivatives, 3 benzoic acids, and 10 aryloxyalkanoic acids in current use as herbicides. 2,4,5-T seems to be banned worldwide and is not included in the current issue (Tomlin, 2000) but is described in earlier issues (e.g., Worthing, 1979). It was first registered in 1948 by Amchem Products, Inc., Pennsylvania, and the Dow Chemical Company, and was mainly used to control shrubs and trees, for example, in forests and along railways. Although the content of dioxin was eventually controlled, with a limit of <0.05 mg/kg in the preparation, it was banned soon after the termination of its use in Vietnam. Other products with 2,4,5-trichlorophenol were also banned or restricted after the Seveso accident (see Hay, 1978a, 1978b). 2,4-D is also produced from a chlo-rophenol and may contain dioxins, but of the much less toxic congeners. It... 

The Pesticide Manual describes 5 pyridine carboxylic acid derivatives, 3 benzoic acids, and 10 aryloxyalkanoic acids in current use as herbicides. 

Pyridine carboxamide [98-92-0] (nicotinamide) (1) and 3-pyridine carboxylic acid [59-67-6] (nicotinic acid) (2) have a rich history and their early significance stems not from their importance as a vitamin but rather as products derived from the oxidation of nicotine. In 1867, Huber prepared nicotinic acid from the potassium dichromate oxidation of nicotine. Many years later, Engler prepared nicotinamide. Workers at the turn of the twentieth century isolated nicotinic acid from several natural sources. In 1894, Su2uki isolated nicotinic acid from rice bran, and in 1912 Funk isolated the same substance from yeast (1). 

Fluorinated derivatives of 191 have been prepared from chlorofluoro-pyridine carboxylic acids (92JMC518). 

In the early days, greatest interest was focused on the acid-catalyzed hydrolysis (by hydrochloric acid in the presence of 2,4-dinitrophenylhydrazine) of Reissert compounds to aldehydes and the corresponding heterocyclic carboxylic acid derivatives. This reaction is fairly general for compounds of quinoline (178) and isoquinoline (179) (Table 18), but it is not applicable to pyridines as they rarely form Reissert compounds. The 3-hydroxyquino-line Reissert compound does not yield benzaldehyde, probably because acylation of the 3-hydroxy group prevents formation of the required cyclic intermediate (180). Some nitroquinolines and isoquinolines give low yields of benzaldehyde. Rather curiously, disub-stituted quinoline Reissert compounds yield less of the aldehyde than of the corresponding... 

Nicotinamide (8.45) and nicotinic acid (8.46, niacin)—which have also been referred to as vitamin B3 or B5—are simple pyridine-3-carboxylic acid derivatives occurring in liver, yeast, and meat. In the form of nicotinamide-adenine dinucleotide (NAD" ) or its phosphorylated form (NADP+), nicotinamide is the most important electron carrier in intermediary metabolism. Unlike FAD, it adds a hydride ion (i.e., one pair of electrons and one hydrogen) only. 

D. E. Peters Dr. Taube and Dr. Gould have presented evidence for electron transfer at a nitrogen site (5). Using pentaamminecobalt(III) complexes of various pyridine carboxylic acids these workers found two paths in the rate expression which they call the acidic and basic paths. For the alkylpyridinium complexes, namely the iV-methyl derivatives, only one term in the rate was found. 

The clean conversion of support-bound, primary amines into sulfonamides by treatment with sulfonyl chlorides is more difficult to perform than the acylation of amines with carboxylic acid derivatives, probably because of the oxidizing properties of sulfonyl chlorides and because primary amines can be doubly sulfonylated. Weak bases (pyridine, 2,6-lutidine, NMM, collidine), short reaction times, and only a slight excess of sulfonyl chloride should therefore be used to convert primary amines into sulfonamides (Table 8.7). 

Various approaches can be used to synthesize pyridines and partially saturated pyridines on insoluble supports. Dihydropyridines can be readily prepared by cyclocondensation of amines with ketones and aldehydes (Hantzsch pyridine synthesis, Figure 15.12). This synthesis proceeds particularly smoothly when using a 3-keto carboxylic acid derivative as the ketone component. This cyclocondensation has been realized on... 

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

On the basis of the above experimental facts, enaminones 42 are considered to be usable as the dinucleophilic reagents for the RTF reaction leading to 4-aminopyridine-3-carboxylic acid derivatives 41 (Table 11) [60]. Enaminones 42 are readily prepared by only mixing 1,3-dicarbonyl compounds 19 and amines without solvent. When enaminone 42i derived from ethyl ace-toacetate 19a and propylamine is used, the RTF reaction proceeds to afford ethyl AT-propyl-4-aminopyridine-3-carboxylate 41i in 88% yield. The amino group of 41 is easily modified by changing amine, and pyridine-3-carboxylic... 

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

In most of their reactions, the pyridine- and azinecarboxylic acids and their derivatives behave as any other acid (cf. Scheme 86). However, some acid chlorides can be obtained only as hydrochlorides, and we must also consider decarboxylation. Esterification of pyridine carboxylic acids can be usefully achieved via in situ generation of the acid fluoride. For example, treatment of picolinic acid with a stoichiometric amount of N,N,N,A-tetramethylfluoroformami-dinium hexafluorophosphate (TFFH) in dichloromethane and triethylamine leads to generation of the acid fluoride, which reacts with (3-methyloxetan-3-yl)methanol to give the corresponding ester in 95% yield <2004S2485>. 

Aminocrotonate ester or aminocrotonitriles are cyclocondensed with vinylogous amidinium salts or enaminone ketals to give pyridine-3-carboxylic acid derivatives via electrocyclic ring closure of an intermediate adduct68-70 (equation 50). 

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... 

In acid solution the carbinol might be reduced further. Pyridine carboxylic acids,2812-carboxythiazoles,282and 2-carboxyimidazoles263 and their amide derivatives have been reduced in this way. The yields of aldehydes in some of these reactions are given in Table I.283... 

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... 

Various chemical classes of auxin herbicides with different weed spectra and types of selectivity have been synthesized and commercially introduced over the years. They include phenoxycarboxylic acids, benzoic acids, pyridine carboxylic acids, aromatic carboxymethyl derivatives and a relatively new category, the quinolinecarboxylic acids (Figure 1). These compounds basically act as synthetic mimics of indole-3-acetic acid (lAA), which is the principal natural auxin in higher plants [2,3,5,7]. 

Electroreduction of pyridine derivatives bearing carboxylic acid derivatives (117 Scheme 23) leads to a variety of products from substituent transformation through ring reduction to ring cleavage. ... 

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