Azinones acidity

Ethyl 4,5-difluoro-7-oxo-2,3-dihydro-7//-pyrido[3,2,l-i)][2,l]benzox-azinone-6-carboxylate (98) was formed when ethyl 6,7-fluoro-4-hydroxy-8-(2-hydroxyethyl)quinoline-3-carboxylate (97) was treated with m-chloro-peroxybenzoic acid in chloroform [92JAP(K)92/208287, 92JAP(K)92/ 210656],... 

In this section several azinone derivatizing reactions are collected which do not occur at an anion formed by initial deprotonation of the azinone, because they occur in neutral medium, acidic medium, or via metal-mediated processes. 

Some pK values are collected in Table 2. Thiones are ca. 2 pK units more acidic than the corresponding azinones. Fused benzene rings have little effect except in the 3-substituted isoquinoline series where partial bond fixation lowers the acidity. Additional aza substitution increases the acidity significantly. 

Hydroxypyridines (776) are both weak acids and bases and can therefore exist as zwitterions (777) (see Section 2.2.5.1). The zwitterions of 2- and 4-hydroxypyridines are known as 2- and 4-pyridones because of their uncharged canonical forms, e.g. (778) and (779). a- and y-Hydroxypyridines exist in aqueous solution very predominantly as the oxo or pyridone form. For a- and y-hydroxy-benzopyridines and -benzazines, the equilibrium favors the benzopyridone form still more, with the exception of 3-hydroxyisoquinoline. The reactivity of the pyridones and azinones is considered in Sections 3.2.3.7.2-4. 

Carbamate, thiocar-bamate, pheny-lureas, triazines, acetanilide, uracil, propionalide, benzonitrile, benzamide, di-carboximide, dinitroaniline, pyrethroid, thiadi-azinone, metoxy-benzoic, phenol, phenoxy acid, coumarin... 

Pyridones, pyrones, and azinones. 2- and 4-Pyridone and their 1-alkyl derivatives are readily nitrated to form first the 3- or 5-mono- (H2S04/HN03, 30C) and then the 3,5-di-nitro derivatives. These nitrations involve reactions of the neutral pyridone species. The proportions of 3- and 5-nitration in 2-pyridone vary with the conditions. 3-Nitration is favored at low acidity and high temperature and 5-nitration by the reverse. 

Pyridones, pyrones, azinones, and A/-Oxides. 2- and 4-Pyridones and 2- and 4-pyrones readily give their 3-mono- and 3,5-dihalo derivatives even chelidamic acid 125 reacts in this way. Bromination of pyran-2-one 58 gives the substitution product 126 or the addition product 127 depending on the conditions. 

Pyridones, pyrones, azinones, etc. Although pyridones are usually resistant to alkali, pyrone rings are often easily opened. Pyran-2-one 58 is reversibly ring-opened by aqueous alkali to carboxylate anions 236. Hydroxide ions convert coumarin 97 reversibly into salts of coumarinic acids 237 which can be converted into the trans isomers 238, and chromones 239 into -dicarbonyl compounds 240. 

Subsequent investigations have reinforced earlier evidence for the wide occurrence of hydrogen bonding of azines. Bonding of all the monocyclic azines,many substituted azines, and azinones with water, alcohols, and dilute acids has been studied by electronic absorption spectra and the variation of the effect with changes in the position of the substituent noted. Quinolines and acridines with chloroform, alcohols, phenols, carboxylic acids, aniline, and pyrrole show the influence of hydrogen bonding on... 

POCI3 chlorinations (Eq. (8)) are acid-catalyzed reactions of such reaction products]. The hydrogen bonding of azinones is related to that of iV-oxides, discussed below, and to that of ketones (with water and alcohols) and has been demonstrated by infrared measurements on pjn-idinethione in alcohols and by the electronic absorption spectra of azinones in water. 6-Chloro-l,3-dimethyl-pyrimidine-2,4-dione is rapidly aminated at 20° (with heat evolution) by methyl- or ethyl-amines, etc., in protic media (water or alcohols). 

Another type of pyridazine synthesis from pyrones involves coupling of the latter with diazonium salts and rearrangement of the intermediate hydrazones with either aqueous base or acid to pyrid-azinones. Thus, 4-hydroxy 6-methyl-2-pyrone (triacetic lactone) (44)... 

Halopyridazines were likewise successfully iV -oxidized. 3-Chloro-pyridazine gives the corresponding 1-oxide with perbenzoic acid, whereas the isomeric 2-oxide is prepared indirectly by adding powdered copper to a diazotized solution of 3-aminopyridazine 2-oxide in hydrochloric acid-. " After earlier reported - failures to prepare 3,6-dichloropyridazine A-oxide from 3,6-dichloropyrid-azine and hydrogen peroxide in acetic acid [6-chloro-3(2/ )-p3nrid-azinone was isolated due to hydrolysis], the desired A-oxide was later obtained in low yield. " The yield of 3,6-dichloropyridazine A-oxide can be improved when using monoperphthalic acid in ethereal solution or perbenzoic acid in chloroform. ... 

Other, more complex halopyridazine A-oxides are known. 5-Amino-3,4- and 4-amino-3,5-dichloropyridazine form the corresponding 1-oxide, but 3,6-dichloro-4-methoxypyridazine is oxidized with monoperphthalic acid in ethereal solution to yield a mixture of the 1-oxide (12%), 2-oxide (5%), and 6-chloro-4-methoxy-3(2A)-pyrid-azinone and 6-chloro-4-methoxy-3(2A)-pyridazinone (up to 7%). Of aminopyridazines, the 3 isomer gives a resin with monoperphthalic acid, while the 2-oxide resulted from oxidation with... 

The title compounds are stable tautomers of the corresponding 2-hydroxypyrazine 1-oxides, and in fact l-acetoxy-2(lH)-pyrazinones, not 2-acetoxypyrazine A -oxides, are obtained on treatment with acetyl chloride in the presence of pyridine at room temperature <87JHC187>. Nevertheless, these compounds resemble the N-oxides in most of their reactions. Representative examples are deoxidative acetoxylation and chlorination. Treatment of l-hydroxy-3,5-diphenyl-2(l//)-pyr-azinone (100) with a refluxing mixture of acetic anhydride and acetic acid affords 2,6-diacetoxy-3,5-diphenylpyrazine (101), which is deacetylated with potassium hydrogen carbonate to give 2,6-dihydroxy-3,5-diphenylpyrazine (102) (or tautomer) (Scheme 23) <7UCS(C)2977>, Acetoxylation of a methyl substituent occurs exclusively and then that of the pyrazine ring is suppressed completely. 

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