6- Methyl-2-pyridine carboxylic acid

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. 

Pyridine yields methyl substitution products which bear the same relationship to it that toluene, xylene and mesitylene do to benzene. These homologues like those of bepzene are easily oxidized and yield corresponding carboxyl derivatives or acids, viz., pyridine carboxylic acids, as just discussed. 

Wt % was obtained from each benzene-ether extract. Determination was made from the gas chromatograms of their methyl esters. Thiophene- and pyridine carboxylic acids for Samples 2-6, and pyridine tricarboxylic acids for Sample 1. 

Methyl-5-ethylpyridine Nicotinic Acid, 3-Pyridine carboxylic acid... 

Reactions of 5-Aminoisothiazoles. 5-Amino-3-methylisothiazole (22) gives 1 1 adducts with nitriles RCN [R = (un)substituted Ph] or EtOCMe=NH to give the thiadiazoles [23 R = (un)substituted Ph or Me]. 5-Amino-3-methylisothiazole-4-carboxyhc acid (24), in benzene that contains pyridine, reacts with CICH2COCI and then with HNR2 to give 5-dialkylamino-acylamino-3-methyl-4-carboxylic acid derivatives (25 R = Me or Et = 1 or 2) ... 

Beilstein Handbook Reference) Arecaidine Areoaine BRN 0112366 Methylguvacine N-Methylguvacine Nicotinic acid, 1,2,5,6-tetrahydro-1-methyl- NSC 76017 3-Pyridinecarboxylic acid, 1,2,5,6-tetrahydro-1-methyl- 1,2,6,6-Tetrahydro-1-methylnioo-tinic acid 1,2,5,6-Tetrahydro-1-methyl-3-pyridine-carboxylic acid. Isolated from betel nuts. Plates or tablets, mp = 232° (dec)insoluble in EtOH, Et20, CeHe, CHCI3, very soluble in H2O. 

A low concentration of nitrogen and sulfur heterocycles also can be found in various petroleums. Coal was for years the major source of pyridine-based heterocycles, obtained by pyrolysis in the absence of oxygen (destmctive distillation). An intriguing new detection of heterocycles in nature has occurred in the field of chemistry of the solar system. Pyridine carboxylic acids have been detected in a meteorite that landed in Canada (near Tagish Lake)." Nicotinic acid and its two isomers were isolated along with 12 methylated and other derivatives. 

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. 

Electron-attracting substituents should assist this reaction. However, with acetic anhydride in acetonitrile, 2-picolinic acid 1-oxide gives mainly pyridine 1-oxide and carbon dioxide, whilst the same reaction carried out under ultra-violet irradiation proceeds similarly but with the formation of a little more 2-hydroxypyridine. The methyl esters of the pyridine-carboxylic acid 1-oxides behave normally, but there is no evidence that the methoxycarbonyl group promotes the reaction, and 2-cyanopyridine 1-oxide does not react with acetic anhydride . The results of a kinetic study of the rearrangement of pyridine 1-oxide in acetic anhydride exclude the intramolecular rearrangement of the free cation (113) and also a free radical process. There remain the two possibilities of nucleophilic substitution by reaction between... 

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 introduction of vapour-phase oxidation of alkylpyridines over vanadium and molybdenum oxides in 1951 made pyridine aldehydes and dialdehydes technically available 2< 278d, With a deficiency of air, pyridoins result 4 > 278e, 294 with a sufficiency, aldehydes result (3-methyl groups are oxidized, but pyridine-3-aldehyde does not appear to have been made by this method 278e, 295) and with an excess, the carboxylic acids, including nicotinic acid, and pyridines are formed by decarboxylation , 296-7, Vapour-phase oxidation in presence of ammonia gives nitriles and pyridine-carboxylic acid amides278/, 296,... 

Pyridine-carboxylic acids have been prepared by the reaction of the 3-pyridyl Grignard reagent 36a and of 2- and 3-pyridyl lithium with carbon dioxide. Nicotinic acid isotopically labelled in the carboxyl group has been obtained in this way . The reaction is especially useful for preparing pyridine-acetic acids and has been applied to 2-2t t and 4-picolyl lithium i. Under conditions where phenyl lithium adds to the azomethine linkage of 4-picoline, 2-phenylpyridine-4-acetic acid i is produced. 2,6-Lutidine gave 6-methylpyridine-2-acetic acid, but the reaction failed with 2-methyl-6-phenoxypyridine . ... 

Ethers of benzenepentol have been obtained by Dakin oxidation of the appropriately substituted acetophenone. Thus, the oxidation of 2-hydroxy-3,4,6-ttimethoxyacetophenone and 2-hydroxy-3,4,5-ttimethoxyacetophenone with hydrogen peroxide ia the presence of alkali gives l,2-dihydroxy-3,4,6-ttimethoxybenzene and l,2-dihydroxy-3,4,5-ttimethoxybenzene, respectively further methylation of these ethers yields the pentamethyl ether of benzenepentol (mp 58—59 degC) (253). The one-step aromatization of myoinositol to produce esters of pentahydroxybenzene is achieved by treatment with carboxylic acid anhydrides ia DMSO and ia the presence of pyridine (254) (see Vitamins). 6-Alkyl- or... 

Methyl Red (4-dimethylaminoazobenzene-2 -carboxylic acid) [493-52-7] M 269.3, m 181-182 , Cl 13020, pK j 2.30, pK2 4.82. The acid is extracted with boiling toluene using a Soxhlel apparatus. The crystals which separated on slow cooling to room temperature are filtered off, washed with a little toluene and recrysld from glacial acetic acid, benzene or toluene followed by pyridine/waler. Alternatively, dissolved in aq 5% NaHC03 soln, and ppted from hot soln by dropwise addition of aq HCl. Repealed until the extinction coefficients did not increase. 

When trigonelline is heated in closed tubes with baryta water at 120°, it gives rise to methylamine, whilst similar treatment with hydrochloric acid at 260° furnishes methyl chloride and nicotinic acid (pyridine-3-carboxylic acid), indicating that it is the methylbetaine of nicotinic acid. 

TABLE XXVn. l-Methyl-l,6-dihydropyrazolo[3,4-c]pyridin-7-ones Prepared by Cyclization of Vicinal 4-(Alkyn- l-yl)pyrazole-5-carboxylic Acid Amides [90IZV2089]. 

Treatment of alkyl 9-benzyloxycarbonyl-3-methyl-6-oxo-2/7,6//-pyr-ido[2,l-f ][l,3]thiazine-4-carboxylates with BBr3 in CH2CI2 at -70 °C for 0.5-1 h and at room temperature for 3h yielded 9-carboxyl derivatives. The decarboxylation of these acids was unsuccessful. Hydrolysis of diethyl cA-3,4-H-3,4-dihydro-3-methyl-6-oxo-2//,6//-pyrido[2,l-f ][l,3]thiazine-4,9-dicarboxylate in aqueous EtOH with KOH at room temperature for 3 days yielded 4-ethoxycarbonyl-3,4-dihydro-3-methyl-6-oxo-2//,6//-pyrido-[2,l-f ] [1,3]thiazine-9-carboxylic acid (00JCS(P1)4373). Alkyl 9-hydroxy-methyl-3-methyl-6-oxo-3,4-dihydro-2//,6//-pyrido[2,l-f ][l,3]thiazine-4-car-boxylates were O-acylated with AC2O and (PhC0)20 in pyridine at room temperature for 12-48h. 

It is only recently that the chloromethylation reaction, well known in the benzene series, has been extended to isoxazoles. It has been thereby found that this reaction results in 4-chloromethyl derivatives (69), their yield decreasing as follows 5-phenyl > 3,5-dimethyl > 5-methyl > 3-methyl isoxazoles > isoxazole. To prove the position of the chloromethyl group these compounds were oxidized to the known isoxazole-4-carboxylic acids (70). It is especially noteworthy that pyridine and its homologs do not undergo chloromethylation. 

By oxidation with chromic acid, this is converted into cyclohexanone-3-carboxylic acid, in which the —CH. OH— group is converted into the —CO— group. This is converted into its ethyl ester and treated with magnesium methyl iodide, and the product, on hydrolysis, yields l-methyl-cyclohexane-l-ol-3-carboxylic acid, which is converted byhydro-bromic acid into 1-bromo-l - methyl - cyclohexane - 3 - carboxylic acid. When this is digested with pyridine, hydrobromic acid is eliminated and yields l-methyl-A -cyclohexane-3-carboxylic acid of the formula—... 

Methyl pyrazine-2-carboxylic acid is refluxed with thionyl chloride in anhydrous benzene for approximately 12 hours. Benzene and thionyl chloride excess is removed by distillation. Then some anhydrous dioxane is added and this acid chloride solution is allowed to drop into p-(/3-aminoethyl)-benzenesulfonamide suspension in dioxane and anhydrous pyridine. The resulting mixture is then refluxed for 3 hours. Dioxane is removed by distillation and then the residue is washed with water and acetic acid. The raw acylated sulfonamide is then filtered and crystallized from 95% ethanol, thus obtaining a product of MP 200 to 203 C. 

There is obtained from 4-[)3-[5-methyl-isoxazolyl-(3)-carboxamido]-ethyl]-benzene-sulfonamide (prepared from 5-methyl-isoxazole-(3)-carboxylic acid chloride and 4-()3-aminoethyl)-benzene-sulfonamide hydrochloride, MP 213° to 214°C in pyridine) and chloroformic acid methyl ester, in a yield of 69%, the compound N-[ [-4-[)3-[5-methyl-isoxazolyl-(3)-carbox-amido] -ethyl] ] -benzene-sulfonyl] ] -methyl-urethane in the form of colorless crystals of MP 173°C. 

In the course of this study, the authors determined /Lvalues for dibenzyl, methyl phenyl, methyl p-nitrophenyl, di-p-tolyl, di-isopropyl and tetramethylene sulphoxides and for diethyl, dipropyl and dibutyl sulphites. The /Lscales are applied to the various reactions or the spectral measurements. The /Lscales have been divided into either family-dependent (FD) types, which means two or more compounds can share the same /Lscale, family-independent (FI) types. Consequently, a variety of /Lscales are now available for various families of the bases, including 29 aldehydes and ketones, 17 carboxylic amides and ureas, 14 carboxylic acids esters, 4 acyl halides, 5 nitriles, 10 ethers, 16 phosphine oxides, 12 sulphinyl compounds, 15 pyridines and pyrimidines, 16 sp3 hybridized amines and 10 alcohols. The enthalpies of formation of the hydrogen bond of 4-fluorophenol with both sulphoxides and phosphine oxides and related derivatives fit the empirical equation 18, where the standard deviation is y = 0.983. Several averaged scales are shown in Table 1588. 

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