4-Hydroxy-6-methyl-2 -pyridones, reaction

Reactions between triacetic acid lactone (MI-243) and ammonia or amines to give 4-hydroxy-6-methyl-2-pyridones are well known. For example, glycine and XII-243 give l-carboxymethylene-4-hydroxy-6-methyl-2-pyii-done. This latter 4-hydroxy-2-pyridone has also been formed from diketene and glycine in aqueous base via XU-244, which can be deacetylated in concentrated sulfuric acid. Dehydroacetic acid does not appear to be an intermediate in the formation of xn-244. Under these conditions it reacted with glycine to form an isomeric product, which, however, was not characterized. ... 

The nitro group in quaternary salts of 4-nitropyridine is easily replaced. Recrystallization of the methiodide from undried acetone gives l-methyl-4-pyridone . Reaction of 4-nitropyridine with benzyl chloride yields 1-benzyl-4-pyridone, and with benzyl bromide, l-benzyl-3,5-dibromo-4-pyridone (nuclear bromination is thought to result from the oxidation of hydrobromic acid by nitrous acid) the experimental description suggests that in these reactions nucleophilic replacement of nitro by halide may occur initially . The consequences of the autoquaternization of 4-nitropyridine have already been mentioned. The formation of 4-hydroxypyridine from 4-nitropyridine and acetic anhydride a presumably involves the acetyl-pyridinium salt. 4-Nitropyridine 1-oxides give with acetic anhydride mainly 4-hydroxy-or 4-acetoxy-3-nitropyridine l-oxides sic but the presence... 

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). 

N-Methyl-4-hydroxy-2-quinolone 183 in a three-component reaction gives spiro pyrano[3,2-c]qionoline-2-ones (02MI2), but indolones 213 with 4-hydroxy-6-methyl-2-pyridone 177 react in a complicated way (97BCJ1625). Ethoxycarbonyl-methylene indolone (Z = COOEt) forms pyrans 224, while dicyano analogs (Z = CN) yield substituted quinoline 225 (Scheme 85). 

The reaction of ethyl acetoacetate with cyclopentanone in the presence of excess ammonium acetate gives 2-hydroxy-4-methyl-6,7-dihydro-5/7-1-pyr incline (127) in 23.5% yield.20,86 The spectral evidence available is not conclusive, but by anology with simpler systems, it seems certain that the pyridone form (127b) is predominant. 

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-hydroxy-4-methyl-6-cyclohexyl-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. 

Nucleophilic substitution of the hydroxyl group in 4-hydroxy-6-methyl-2(l//)-pyridones 184 using an excess of aralkyl amine without any solvent under MWI for 14—20 min gave the 4-aralkylamino-2(l//)-pyridones 185 in 60-91% yields. However, under the same conditions, aliphatic and aromatic amines gave no reaction (Scheme 39) (99SL1747). 

To a solution of 100 mg (2R)-2-((lR)-hydroxy-l-hept-3-yn-2-one)-l-[((15, 2R)-2-(1-methyl- 1-phenylethyl) cyclohexyoxy) carbonyl]-5-(triisopropylsilyl)-2,3-ciihydro-4-pyridone (0.161 mmol) in 7 mL methanol was added 66 mg cerium(III) chloride heptahydrate (CeCl3 7H20, 0.177 mmol) in one portion. After being stirred for 10 min, the mixture was cooled to —50°C, and 9 mg sodium borohydride (0.241 mmol) was added. The reaction mixture was stirred for an additional 10 min, quenched with 10 mL water, and extracted with CH2CI2 (3 x 10 mL). The combined extracts were dried over MgS04 and concentrated under reduced pressure. The residue was purified by radial PLC (silica gel, 30% EtOAc/hexanes) to give 96 mg (2R)-2-((lR,25)-dihydroxy-hept-3-yne)- -[((15,2R)-2-( 1-methyl- 1-phenylethyl)-cyclohexyloxy)carbonyl]-5-(triisopropylsilyl)-2,3-dihydro-4-pyridone as a colorless oil, in a yield of 96%. 

The hydroxy adducts can be oxidized into the Sn products. Indeed, the oxidative hydroxylation of Al-alkylpyridinium salts into pyridones is a well-known Sn transformation, as illustrated by the reaction of 3-methoxycarbonyl-l-methylpyridinium iodide with the hydroxide ion in the presence of potassium ferricyanide, affording the corresponding l-methyl-6-pyridone (Scheme 37) [2, 11, 139]. 

Diketene and glycine in a basic solution ve 3-acetyl-1-carboxymethylene-4-hydroxy-6-methyl-2-pyridone (XII-189) by a reaction path in which dehydroacetic acid is not an intermediate. However, W-acetoacetylglycine was not detected. Deacylation of XII-189 to XII-190 occurs in sulfuric acid. 

Nicotinic Add Metabolism. The sequence of reactions leading to the formation of pyridine compounds is of particular interest as a source of nicotinic acid. Nutritional, isotopic, and genetic experiments have all shown that tryptophan and its metabolic derivatives including 3-hydroxy-anthranilic acid are precursors of nicotinic acid in animals and in Neuro-spora. The terminal steps in this sequence are not known. Under certain physiological conditions an increase in picolinic carboxylase appears to reduce nicotinic acid synthesis. This implies a common pathway as far as the oxidation of 3-hydroxyanthranilic acid. Whether quinolinic acid is a precursor of nicotinic acid is still uncertain. The enzyme that forms the amide of nicotinic acid also has not been isolated. Subsequent reactions of nicotinamide include the formation of the riboside with nucleoside phosphorylase and methylation by nicotinamide methyl-kinase. In animals W-methylnicotinamide is oxidized to the corresponding 6-pyridone by a liver flavoprotein. Nicotinic acid also forms glycine and ornithine conjugates. Both aerobic and anaerobic bacteria have been found to oxidize nicotinic acid in the 6-position. ... 

Orthopalladation of (3 )-a-methyl-4-nitrobenzylamine has been reported. The reaction of [PdGl(G6H4GH2-NMe2)]2 with the anion of A-methyl-3-hydroxy-2-methyl-4-pyridone afforded 67The first six-membered palladacycles such as 68 (X = Br, Gl, OAc Y = G1, F, NO2) synthesized from primary phenethylamines with electron-withdrawing substituents on the aryl ring were reported by Vicente et al ... 

In a further elaboration of the structure Wiesner et al. (70, 71) converted hydroxy acid XIV to its methyl ester XXXII which was treated with phosphorus pentoxide in boiling xylene. From this reaction a product, C17H20NO3CI (XXXIII), was isolated which was apparently a simple dehydration product since its UV-spectrum was identical with that of XXXII. A second product (XXXIV) CieHigNOsCl, isolated after hydrolysis to the acid w as distinctly different, showing the properties of an a-pyridone. They showed that the pyridone was tricyclic and apparently formed in a ring-opening reaction with introduction of a double bond but its structure was not elucidated. They pointed out that the formation of a pyridone in this reaction is indicative that the lactam ring is six-membered. 

If 2-hydroxyacetophenone analogues such as 3-acetyl-4,6-dimethyl-2-pyridone and 4-acetyl-5-hydroxy-3-methyl-l-phenylpyrazole are used as the methylene component in the condensation with R COaEt in the presence of LiH in THE or dioxane, the reaction gives the corresponding R -containing p-diketones 132 and 134, whose dehydration under the action of concentrated H2SO4 affords 8-aza-2-(polyfluoroaIkyl) chromones 133 [58] and 6-(polyfluoroalkyl)-3-methyl-l-phenylpyrano[2,3-c] pyrazol-4(17/)-ones 135 [59] (Scheme 41). 

In an Initio study of the tautomerism of 2- and -hydroxy-pyridines, 4 -hydroxypyridine was calculated to be 2.4 kcal/mol more stable than 4-pyridone. 2-Pyridone was calculated to be 0.3 kcal /mol more stable than 2-hydroxypyridine and this is in good agreement with experimental values obtained from tautomeric studies in the gas phase.A study of the bromination of the 2-pyridone/2-hydroxypyridine system has revealed that reaction occurs via the principal "one" tautomer at pH<6 and via the conjugate anion at pH>6. Attack on the "one" occurs preferentially at the 3-position, whereas on the anion it probably occurs mainly at the 5-position. The facile formation of 3f5-dibromo-2-pyridone results from the comparable reactivity of the monobromopyridones at pH<1 and pH>4- Practical procedures have been reported for the preparation of 3-bromo-2-pyridone and 3,5-dibromo-2-pyridone Cycloaddition of 2-substituted pyridinium betaines with unsymmetrical alkenes gives products of mixed orientation for example, treatment of (40) with methyl... 

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