Pyridine homologues, oxidation

S3mthesis of Collidine.—The most important synthesis of pyridine homologues is that of collidine from which pyridine may be obtained by elimination of the methyl groups by oxidation and loss of carbon dioxide. When aldehyde ammonia is heated with aceto-acetic ester a derivative of a di-hydrogenated collidine is obtained, as follows ... 

Like pyridine, pyridine homologues and derivatives are converted into amine oxides. a-Picoline oxide is prepared by oxidation with hydrogen peroxide in acetic acid in 83% yield [1188]. Under identical conditions, 2,5-dimethylpyridine oxide and nicotinamide oxide are obtained in 84% yield [160] and 73-82% yield [162], respectively. Pentachloropyridine is oxidized to its oxide by peroxyacetic or peroxytrifluoroacetic acid (equation 504) [755]. 

Aminopyridine Tosic anhydride is used in activating pyridine-A -oxide and homologues for attack by t-butylamine. The resulting 2-t-butylaminopyridine is dealkylated by CF3COOH. 

The past year has seen the publication of Comprehensive Organic Chemistry, one volume of which contains much information on the six-membered ring systems to be reviewed in this article a monograph on the chemistry of condensed pyrazines has also appeared. Reviews on 1,4-thiazines, l,3-benzothiazines," pyridazines, benzo[c]cinnolines, quinazolines, purines, pyrrolo[3,2-c]quino-lines, 1,10-phenanthroline and its complexes, polyaza-phenanthrenes, and 1,9- and 1,10-diaza-anthracenes have been published. Other specialist reviews are devoted to catalytic methods of obtaining pyridine bases pyridine N-oxides the stereochemistry of quinolizines, indolizines, and pyrrolizines benzothiazinone dioxides 2-quinazolones and their cyclic homologues (e.g. 

Pyridine 1-oxide reacts with adamantane-1-thiol in acetic anhydride to give 2- and 3-(l-adamantanethio)pyridines and their tetrahydropyridine analogues. Corresponding butylthio-substituted pyridines are obtained using Bu SH or Bu SH in this reaction in the presence of a chloroformic acid derivative. No complications arise in the use of 3-bromopyridine 1-oxide and KSH for the synthesis of 3,3 -dipyridyl sulphide. 2-Methyl- or 2-phenyl-pyridine is converted into its 5-alkylthio-homologue by reaction of the pyridine-MeLi adduct with a dialkyl disulphide. ... 

Carboxylic acids. Of these pyridine acids there are mono-, di-, and tri-carboxylic acids known, which are obtained by oxidation of the corresponding mono-, di-, and tri-methyl homologues. One of the mono-carboxylic acids is known as nicotinic acid and is obtained... 

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. 

Homologues of pyridine are converted into the corresponding pyri-dinecarboxylic acids by electrooxidation [117], by oxidation with dilute nitric acid [462], or by treatment with potassium permanganate [503, 555] (equation 187). 

Homologues of Pyridine.—Many homologues of pyridine have been obtained from bone-oil and coal-tar or by syntheses from other compounds. The methyl derivatives of pyridine are called picoUneSy the dimethyl derivatives are called lutidines, and the trimethyl derivatives are called collidines. As in the case of toluene and the xylenes, the side-chains are converted into carboxyl groups by oxidation. The a, /S, and 7 mono-carboxylic acids of pyridine are called picolinic acid, nicotinic acid, and isonicotinic acid, respectively. 

The first experiments were carried out with nicotinic acid (61), and it was found that mitochondrial oxidation of cholesterol was enhanced in rats fed this compound. It was later found (62) that addition of nicotinic acid (8 X 10 moles, 10 mg) to the incubation mixture enhanced oxidation of cholesterol. Of a large series of nicotinic acid and nicotinamide homologues tested, only 3-pyridylacetic acid also stimulated oxidation of cholesterol (62,63). This compound has also been shown to be hypocholesterolemic in man (64,65). Pyridinol carbamate, 2,6-bis(hydroxymethyl)pyridine-di-A -methylcarbamate, fed to rats as 1 % of their diet also enhanced in vitro oxidation of cholesterol by rat liver mitochondria (66). 

Qualitatively, the effect of substituents upon the ease of oxide formation is that which would be expected for the electrophilic process 20a shown. Quantitatively, a limited range of data is available for perbenzoic acid oxidation of pyridine and its homologues and halogen derivatives in 50 per cent aqueous dioxan 20 at 25 . The second-order rate constants for 3- and 4-substituted pyridines fit a Hammett plot with p = — 2-35 and are also roughly linear with pKa Bulky 2-substituents cause deviations but not so markedly as in quaternization (see p. 190). 

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