Pyridones, acidity

Pyridone Acid Chlorides as Fluorescent Derivatizing Reagents. A second derivatizing reagent, a fluorescent acid chloride, was synthesized from the sodium salt of 3-phenyl-2(lH)pyridone (IV). 

The benzoselenophene phosphonic acid (128) has been obtained from phenyl-ethynylphosphonic acid and Se02-HBr" and classical reactions were employed in the synthesis of the pyridone acids (129) (R = aryl or heteroaryl, R = H or COOMe). ... 

Ethionamide (2-ethylthioisonicotinamide, Trecator SC, 8) is an antibiotic prodrug used in the treatment of tuberculosis. One synthetic pathway involves the condensation of diketo-ester 160 with cyanoacetamide 161 followed by hydrolysis of the resulting pyridone 162 into give pyridone acid 163. Treatment of 163 with POCI3 converts the lactam to imine chloride and simultaneous ester formation in ethanol to give 164. Hydrogenation of 164 to remove the chloride, amide formation, and sequential conversion to the thioamide provided 8." ... 

It is found in practice that for a number of compounds reacting ma the predominant species an almost horizontal plot is obtained. For compounds presumed to be nitrated via the free bases, such as 2,6-lutidine i-oxide and 3- and 5-methyl-2-pyridone, slopes of approximately unity are obtained. Since this type of plot allows for the incomplete ionisation of nitric acid, it can be used at higher acidities than plots using — ( H + logio Hjo) which break down when the condition is no longer true. 

The similarity of their rate profiles, and the similarity of their rate constants for nitration at a particular temperature and acidity show that 4-pyridone, i-methyl-4-pyridone, and 4-methoxypyridine are all nitrated as their cations down to about 85 % sulphuric acid. The same is true of 2-methoxy-3-methylpyridine. In contrast, 3- and 5-methyl-2-pyridone, i,5-dimethyl-2-pyridone and 3-nitro-4-pyridone all react... 

The 2-nitration of 3-hydroxy- and 3-methoxy-pyridine in 85-96% sulphuric acid involves the conjugate acids, whilst the 3-nitration of 6-hydroxy and 6-methoxy-2-pyridone in 70-77 % sulphuric acid involves the free bases, which react at, or near to the encounter rate. ... 

When carried out in dilute acid, diazotization of 2-aminothia2ole may provide unstable diazohydroxides (164, 335, 336), differing in that respect from 2-aminopyridines which give 2-pyridones when the reaction is carried out in weak acids (337). 

These alkaloids include the substituted pyridone ricinine [524-40-3] (53), CgHgN202, which is easily isolated in high yield as the only alkaloid from the castor bean (Ricinus communis L.). The castor bean is also the source of castor oil (qv), which is obtained by pressing the castor bean and, rich in fatty acids, has served as a gentie cathartic. 

Fluoropyridine is readily hydroly2ed to 2-pyridone in 60% yield by reflux in 6 Ai hydrochloric acid (383). It is quite reactive with nucleophiles. For example, the halogen mobiUty ratio from the comparative methoxydehalogenation of 2-fluoropyridine and 2-chloropyridine was 85.5/1 at 99.5°C (384). This labihty of fluorine has been utili2ed to prepare fluorine-free 0-2-pyridyl oximes of 3-oxo steroids from 2-fluoropyridine for possible use as antifertihty agents (385). 

Biosynthetic studies using acetate (Ac), propionate (Pr), and butyrate (Bu) revealed the polyketide nature of aurodox which has the composition Pr(Ac)g for the goldinamine skeleton C-7 to C-25 and the composition Bu(Ac) for the C-27 to C-39 carbon chain of goldinonic acid. In contrast to the methyl branch at C-8, those at C-19 and C-21 are methionine-derived as are all remaining methyl groups (52,53). The biogenetic origin of the pyridone moiety is not clear. 

Mocimycin has been chemically converted to aurodox by protection of the 4-hydroxy group at the pyridone moiety as the benzoylformate, followed by /V-methylation and hydrolytic removal of the protective group (1,55). Whereas aurodox esters are active growth promotors in animals, goldinamines that are A/-acylated by acids other than goldinonic acid, such as acetic, benzoic, or arylsulfonic acids, lack useful antimicrobial or growth-promoting activity (1). 

Pyrans and related compounds react with ammonia to give pyridines. A commercially useful example is the reaction of dehydroacetic acid (derived from diketene) with ammonia to give 2,6-dimethyl-4-pyridinone [7516-31 -6] via 2,6-dimethyl-4-pyridinone-3-carboxyhc acid [52403-25-5]. Chlorination of the pyridone gives clopidol [2971-90-6] (56), a coccidiostat (72,73). 

The result of this biosynthesis is that the product is nicotinic acid mononucleotide rather than free nicotinic acid. Ingested nicotinic acid is converted to nicotinic acid mononucleotide which, in turn, is converted to nicotinic acid adenine dinucleotide. Nicotinic acid adenine dinucleotide is then converted to nicotinamide adenine dinucleotide. If excess nicotinic acid is ingested, it is metabolized into a series of detoxification products (Fig. 4). Physiological metabohtes include /V-methylnicotinamide (19) and A/-methyl-6-pyridone-2-carboxamide (24) (1). 

Pyridazines are formed from pyrones or their thioxo analogs or from appropriate pyridones. Pyrones or pyridones react with diazonium salts to give the corresponding hydrazones (187) and (188) which are rearranged under the influence of acid or base into pyridazinones as shown in Scheme 107. On the other hand, kojic acid is transformed with hydrazine into a 1,4-dihydropyridazine and a pyrazole derivative. 4H-Pyran-4-thiones... 

Bromopyridine has been made by direct bromination of pyridine - from N-methyl-2-pyridone with phosphorus penta-bromide and phosphorus oxybromide from 2-aminopyridine by diazotization with amyl nitrite in 20% hydrobromic acid from sodium 2-pyridinediazotate by solution in concentrated hydrobromic acid and from 2-aminopyridinc by diazotization in the presence of bromine and concentrated hydrobromic acidd The method described here is essentially that of Craig. 

The procedure for preparing 6-hydroxynicotinic acid is also based on a method described by von Pechmann. 6-Hydroxynico-tinic acid has also been prepared by decarboxylation of 6-hy-droxy-2,3-pyridinedicarboxylic acid by heating 6-hydra-zinonicotinic acid or its hydrazide with hydrochloric acid by the action of carbon dioxide on the sodium salt of a-pyridone at 180-200 and 20 atmospheres by heating the nitrile of 6-chlo-ronicotinic acid with alcoholic sodium hydroxide or hydrochloric acid from 6-aminonicotinic acid and by the prolonged action of concentrated ammonium hydroxide on methyl cou-malate. ... 

Certain molecules that can permit concerted proton transfers are efficient catalysts for reactions at carbonyl centers. An example is the catalytic effect that 2-pyridone has on the aminolysis of esters. Although neither a strong base (pA aH+ = 0.75) nor a strong acid (pJsfa = 11.6), 2-pyridone is an effective catalyst of the reaction of -butylamine with 4-nitrophenyl acetate. The overall rate is more than 500 times greater when 2-pyridone acts... 

R-methyl-2-pyridone- N-methyl-2-pyridone-3-carboxylic acid 3-carhoxylic acid amide... 

A third synthesis which has resulted in the preparation of rieinine and a number of its derivatives is due to Schroeter, Seidler, Sulzbacher and Kanitz,i2 who foimd that cyanoacetyl chloride polymerises spontaneously to 6-chloro-2 4-dihydroxy-3-cyano-pyridine. The di-sodium derivative of this with methyl sulphate produces A -methyl-6-chloro-4-hydroxy-3-cyano-2-pyridone (6-chlororicininic acid), the mono-sodium derivative of which, with methyl bromide or sulphate, is converted into 6-chlororicinine and the latter is reduced by zinc and sulphuric acid to rieinine. A fourth synthesis, starting from 3-nitro-4-pyridone, is due to Reitmann. ... 

In 1931 Ing pointed out that formula (II) and (III) do not contain methyl or potential methyl groups in j ositions 6 and 8 which they occupy in cytisoline. Further, a partially reduced quinoline ought to oxidise easily to a benzenecarboxylic acid and so far the only simple oxidation, products recorded from cytisine were ammonia, oxalic acid and isovaleric acid. Distillation of cytisine with zinc dust or soda-lime yields pyrrole and pyridine, but no quinoline. On these grounds Ing suggested that cytisine should be formulated without a quinoline nucleus, and that the reactions which indicate the presence of an aromatic nucleus in the alkaloid can be accounted for by an a-pyridone ring. This a-pyridone nucleus can... 

The importance of ring size holds also for tautomerism of -pyrrol-5-ones and. d -dihydro-6-pyridones. While the former compounds behave as cyclic 1-methyl-2-alkyl-2-hydroxy-5-pyrrolidones 179) (76) [or, on distillation, as the dehydrated l-methyl-2-alkyl-J -pyrrolones (77)], the latter compounds exist as acyclic N-methylamides of 8-oxo-acids (78) [as shown by infrared spectroscopy (/80)j. The dehydration of 78 during distillation to form l-methyl-2-alkyl-. -dihydro-6-pyridones (79) is achieved only with difficulty. 

In their acidity, basicity, and the directive influence exerted on electrophilic substitution reactions in benzenoid nuclei, acylamino groups show properties which are intermediate between those of free amino and hydroxyl groups, and, therefore, it is at first surprising to find that the tautomeric behavior of acylaminopyridines closely resembles that of the aminopyridines instead of being intermediate between that of the amino- and hydroxy-pyridines. The basicities of the acylaminopyridines are, indeed, closer to those of the methoxy-pyridines than to those of the aminopyridines, the position of the tautomeric equilibrium being determined by the fact that the acyl-iminopyridones are strong bases like the iminopyridones and unlike the pyridones themselves. Thus, relative to the conversion of an... 

The name hydroxamic acid was first used by Losseii in 1869, in the case of oxalohj droxamic acid, obtained from diethyl oxalate and hydroxylamine. Where this grouping forms part of the main cyclic system, however, the compound is named as a derivative of this system. In this review, 2 and 3 would be named as 1-hydroxy-2-pyrrolidone and l-hydroxy-2-pyridone, respectively. 

Fluoro and 3- or 5-nitro-2-chloropyridine A-oxides may be converted to the corresponding l-benzoyloxy-2-pyridones by reaction with benzoic acid alone. 

Cyclic hydroxamic acids and V-hydroxyimides are sufficiently acidic to be (9-methylated with diazomethane, although caution is necessary because complex secondary reactions may occur. N-Hydroxyisatin (105) reacted with diazomethane in acetone to give the products of ring expansion and further methylation (131, R = H or CH3). The benzalphthalimidine system (132) could not be methylated satisfactorily with diazomethane, but the V-methoxy compound was readil3 obtained by alkylation with methyl iodide and potassium carbonate in acetone. In the pyridine series, 1-benzyl-oxy and l-allyloxy-2-pyridones were formed by thermal isomeriza-tion of the corresponding 2-alkyloxypyridine V-oxides at 100°. 

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