Pyridone acid chlorides

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). 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

The Liebeskind group cross-coupled 4-chloro-2-cyclobutenone 69 with 2-tribuylstannyl-benzothiazole to synthesize a-pyridone-based azaheteroaromatics [48], The adduct 70 underwent a thermal rearrangement to afford a transient vinylketene 71, which then intramolecularly cyclized onto the C—N double bond of benzothiazole, giving rise to thiazolo[3,2-a]pyridin-5-one 72. In another case, 2-acetyl-4-trimethylstannylthizaole (73) was coupled with an acid chloride 74 to form the desired ketone 75 [49]. 

Treatment of the thallous salt of 2-pyridone (6) with an acyl or aroyl chloride in ether suspension, at room temperature, results in quantitative conversion to a 2-acyloxy- or 2-aroyloxypyridine (7). The latter compounds are extremely reactive acylating and aroylating agents which possess the advantage over the starting acid chlorides of eliminating 2-pyridone rather than chloride ion in the acylation step.5... 

Hydroxypyridine protonates on nitrogen, with a typical pyridine p/faH of 5.2 the pyridones are much less basic and, like amides, protonate on oxygen.However, the reaction of 4-pyridone with acid chlorides produces A-acyl derivatives. l-Acetyl-4-pyridone subsequently eqnilibrates in solution affording a mixtnre with 4-acetoxypyridine. ... 

A slightly different synthesis was used for preparation of Ipalbidine and Ipalbine from the enaminone 262, which was acylated with the acid chloride 263 and cyclized in base. The resulting pyridone 264 was hydrolyzed and decarboxylated followed by reduction to give the racemic Ipalbidine 265, Scheme 71. Resolution of 265 and further chemical transformations led to Ipalbine (71HCA513). 

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." ... 

N-Condensed 2-pyridone ring from carboxylic acid chlorides... 

Heterocyclics from a-dicarboxylic acid chlorides 4-Hydroxy-2-pyridones from enamines... 

For instance, the anion 5, derived from 2-pyridone, undergoes acylation by acid chlorides on oxygen with ester formation 4, while carboxylation by CO2 occurs on C-5 with formation of the carboxylic acid 6 ... 

With carboxylic acid chlorides, 2-ethoxypyridine 1-oxide gives ethyl chloride and l-acyloxy-2-pyridones. The latter are acylating agents, and the corresponding sulphonyl compounds, formed similarly, sulphonylate... 

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. ... 

Methyl- and 3-phenyl-4-hydroxy-2-oxo-2//-pyrido[2,1 -Z)]oxazinium inner salts were prepared in the reaction of 2-pyridone and 2-substituted malonyl chloride, prepared in situ from 2-substituted malonic acid with PCI5 in CH2CI2 (00JCS(P2)2096). 

The reaction mixture was then dissolved in methylene chloride, the amine was removed by shaking with dilute hydrochloric acid, the reaction product was extracted from the organic phase by means of dilute sodium hydroxide solution and the alkaline solution was acidified with acetic acid to a pH value of 6. The 1 -hvdroxv-4-methyl-6-cvclohexvl-2-pyridone precipitated in crystalline form. It was filtered off with suction, washed with water and dried. The yield was 1.05 g (49% of theory) melting point 143°C. 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

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