A -Pyridone

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. ... 

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... 

Katada, working in the labs of Ochiai, first described the reaction of N-oxide 3 with acetic anhydride. The resultant rearrangement produced a-pyridone 4. Shortly... 

COR group decreases the basicity of a pyridone form much... 

In this solvent the reaction is catalyzed by small amounts of trimethyl-amine and especially pyridine (cf. 9). The same effect occurs in the reaction of iV -methylaniline with 2-iV -methylanilino-4,6-dichloro-s-triazine. In benzene solution, the amine hydrochloride is so insoluble that the reaction could be followed by recovery. of the salt. However, this precluded study mider Bitter and Zollinger s conditions of catalysis by strong mineral acids in the sense of Banks (acid-base pre-equilibrium in solution). Instead, a new catalytic effect was revealed when the influence of organic acids was tested. This was assumed to depend on the bifunctional character of these catalysts, which act as both a proton donor and an acceptor in the transition state. In striking agreement with this conclusion, a-pyridone is very reactive and o-nitrophenol is not. Furthermore, since neither y-pyridone nor -nitrophenol are active, the structure of the catalyst must meet the conformational requirements for a cyclic transition state. Probably a concerted process involving structure 10 in the rate-determining step... 

It is well accepted that tautomerism relates to the equilibrium between two or more different tautomers e.g., it corresponds to determining if the structure of a compound is, for instance, a pyridone or an hydroxypyridine. The kinetic aspects are often neglected and when the tautomeric equilibrium constant, Kt, is equal to 1 (e.g., for imidazole), the problem may seem... 

Phenylethylamme and its substituted derivatives with methoxybutenone in glacial acetic acid afford the salts of the type 236, which, when oxidized with potassium permanganate, decompose to a-pyridone, whereas in an aqueous medium the compound 237 is formed (80MI1 62AG161). 

Figure 3.36 Structure of the a-pyridone complex [Pt2(NH3)4(pyridone)2]2(N03)5. (Reprinted with permission from/. Am. Chem. Soc., 1978,100,3785. Copyright (1978) American Chemical Society.)...

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. 

The first structural information was obtained for an a-pyridone complex [Pt2(NH3)4(pyridone)2]2(N03)5 (Figure 3.36). 

The Boehringer Ingelheim group chose a pyridone-based core structure to replace the -Glu-Glu-Ile- tripeptide of the generic SH2 domain recognition sequence [130]. From a series of more than 200 analogues, pyridones with mutually different decoration patterns were identified to result in pTyr derivatives with submicromolar affinities (e.g., 55,56) for the Lck SH2 domain [130]. 

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]. 

The first direct evidence for the structure of platinum-blues was provided by the single-crystal X-ray studies of cis-diammineplatinum a-pyridonate-blue, [Pt(2.25+)4(NH3)8(/x-a-pyridonato-N,0)4] (N03)5 H20 (48, 49). In the study, Barton and Lippard selected a-pyridone as a simplified model of pyrimidine bases (see Fig. 3), which must be the primary reason of their success in obtaining the first crystalline-blue material. 

Under the influence of zinc chloride, Danishefsky s diene 4 reacts with simple imines to give dihydro-y-pyridones 100 (e.g. R1 = n-Bu, Ph, Bn R2 = Pr, i-Pr, Ph) in 62-76% yields (equation 58)51. In contrast, the Et2AlCl-catalyzed reaction of the diene 86 with benzylidenemethylamine (101) results in the formation of the dihydro-a-pyridone 102 (equation 59)52. 

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