1 -methyl-2- -pyridones

Methyl-2-pyridone has been prepared by the methylation of 2-pvridone,1 by the oxidation of i-methylpyridinium iodide 2... 

Nitro- 1-methyl -2-pyridon Methanol 65 24 3-Amino-l-methyl- 2-pyridon -100 ... 

There appear to be no ERE data for pyridones and related compounds, and although Dewar and co-workers18 have calculated the heats of atomization for a number of structures of this type, the results were used for a discussion of tautomeric equilibria rather than for deriving values for the Dewar resonance energies. Empirical studies on tautomeric equilibria have, however, been used to estimate the difference in ERE of pyridones and pyridine (Section II,A, 4). Beak et al 1 studied the gas-phase 1-methyl-2-pyridone 2-methoxypyridine equilibrium and compared the result with the equilibrium constant for the jV-methylvalerolactam ... 

Dewar pyridine, 2-azabicyclo[2.2.0]hexa-2,5-diene (218), thermally reverted to pyridine at room temperature with a half-life time of 2.5 minutes (Ea = 16 kcal/mol).255 Far more stable were 2-azabicyclo-[2.2.0]hex-5-en-3-ones (225).265-267 The kinetics of the thermal (2 + 2)-cycloreversion of 225 (R = Me) in the temperature range of 130° to 160° have been reported (A//J = 33.2 kcal mol-1 ASt = + 2.7 cal mol-1 deg-1).266 An interesting difference in rate was observed between 225 (R = H) and its methyl homolog 225 (R = Me). At 130° the former reverted ten times as rapidly to 2-pyridone as the latter did to 1-methyl-2-pyridone this difference has been related to the intermediacy of the lactim tautomer of 225 (R = H) in the former reaction. Dewar benzene oxide, 2,3-epoxybicyclo[2.2.0]hex-5-ene (266), isomerized to an equilibrium mixture of benzene oxide/oxepin at 115° with a half-life time of 18 minutes.270 The relatively high thermal stability of such strained bicyclic heterocycles has been attributed to the fact that the symmetry-allowed conrotatory process would give rise to an unfavored cis.trans heterocyclic diene.265... 

Selective 7y-methylation of 2-pyridones can be effected indirectly, namely via the exclusively O-directed silylation A -methylation of the silyl ether 7, followed by desilylation of 8, leads to 1-methyl-2-pyridone 9. Specific 7V-alkylation is also observed with dialkyl phosphates [83]. 

Figure 2. Isolated yields of Dewar pyridones (outlined shapes) and [4+4] dimers (filled shapes) as a function of the initial concentration of 1 -methyl-2-pyridone. Note the absence of a solvent effect. Data from reference 8.

First described in I960, the most accessible photoproduct of 1-methyl-2-pyridone 5 is a dimer, with a tr s-head-to-tail structure 6 (Scheme 2). Photoisomerization of 2-pyridone to give the 2-aza-bicy-clo[2.2.0]hex-5-en-3-one 7 competes with dimerization. Both of these products are derived from a shortlived (ca. 0.2 ns) singlet excited state generated by irradiation above 300 nm, typically using a Pyrex... 

Sakurai, N. and Ohmiya, S., Photoaddition reaction of 1,2-dialkylindoles and -pyrroles to 1-methyl-2-pyridone via proton transfer from the 2-methylene group of the indole or pyrrole, /. Chem. Soc., Chem. Commun., 297-298, 1993. 

Chloro-l-methylpyridinium iodide (1) reacts with a mixture of a carboxylic acid and an alcohol, in the presence of two equivalents of base, to form an ester (eq 1). The pyridinium salt (2) is formed rapidly by displacement of chloride from (1) by the carboxylate subsequent reaction with the alcohol results in formation of the ester, along with 1 -methyl-2-pyridone (3). A variety of solvents may be employed, but yields are highest in dichloromethane or pyridine. Tri-n-butylamine or Triethylanune are often used as base. The co-product (3) is insoluble in dichloromethane and so precipitates from this solvent. Good results are obtained even for hindered carboxylic acids and alcohols. 

As shown in Figure 8.3, the principal metabolites of nicotinamide are A( -methyl nicotinamide and methyl pyridone carboxamides. AT -Methyl nicotinamide is actively secreted into the urine by the proximal renal tubules. Nicotinamide A(-methyltransferase is an S-adenosylmethionine-dependent enzyme that is present in most tissues. Very high intakes of nicotinamide may deplete tissue pools of one-carbon fragments - indeed, this was the basis for the use of nicotinamide in the treatment of schizophrenia (Section 8.8). 

Methyl nicotinamide can also be oxidized to methyl pyridone-2-carboxamide and methyl pyridone-4-carboxamide. The extent to which this oxidation occurs, and the relative proportions of the two pyridones formed,... 

Figure 8.3. Metabolites of nicotinamide and nicotinic acid. Nicotinamide deamidase (nicotinamidase), EC 3.5.1.19 nicotinamide Af-methyltransferase, EC 2.1.1.1 aldehyde dehydrogenase, EC 1.1.1.1. Relative molecular masses (Mr) nicotinamide, 123.1 nicotinic acid, 122.1 nicotinamide JV-oxide, 139.1 Af -methyl nicotinamide, 139.1 trigonelline, 137.1 nicotinuric acid, 179.2 and methyl pyridone carboxamides, 154.1.

A number of studies have investigated the equivalence of dietary tryptophan and preformed niacin as precursors of the nicotinamide nucleotides, generally by determining the excretion of -methyl nicotinamide and methyl pyridone carboxamide in response to test doses of the precursors, in subjects maintained on deficient diets. 

Urinary Excretion of N -Methyl Nicotinamide and Methyl Pyridone Carboxamide... 

The most widely used method for assessing niacin nutritional status is measurement of the urinary excretion of niacin metabolites. Table 8.1 shows the excretion of A( -methyl nicotinamide and methyl pyridone carboxamide in niacin adequacy and deficiency. 

Ratio, methyl pyridone carboxamide A/ -methyl nicotinamide ... 

The excretion of methyl pyridone carboxamide is more severely reduced in marginal niacin deficiency than is that of -methyl nicotinamide. The excretion of methyl pyridone carboxamide decreases rapidly in subjects fed on a niacin-deficient diet, and virtually ceases several weeks before the appearance of clinical signs of deficiency by contrast, a number of studies have shown continuing excretion of -methyl nicotinamide even in pellagrins. A better estimate of niacin nutritional status can be obtained by determining the ratio of urinary methyl pyridone carboxamide Ai -methyl nicotinamide, which is relatively constant, despite the administration of loading doses of tryptophan or niacin to adequately nourished subjects (between 1.3 to 4.0), and a ratio of less than 1.0 indicates depletion of niacin reserves (de Eange and Joubert, 1964 Dillon et al., 1992). 

The oxoaporphine alkaloid pontevedrine stands apart from these two subgroups. Its unique feature is that it possesses an A-methyl pyridone moiety. 

Reaction of the keto acid 7, obtained through Friedel-Crafts acylation, with ammonium acetate in acetic acid gives the yellow pyridone 8 as the major product. Compound 8 is amphoteric, forming both a sodium salt and a stable hydrochloride. Alkylation with methyl iodide in alkaline methanol affords a mixture of the N- and 0-methylated products 9 and The iV-methyl-pyridone 9 is unstable and oxidized by air to the bicyclic keto imide... 

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