1.5- dimethyl-2-pyridone

The similarity of their rate profiles, and the similarity of their rate constants for nitration at a particular temperature and acidity show that 4-pyridone, i-methyl-4-pyridone, and 4-methoxypyridine are all nitrated as their cations down to about 85 % sulphuric acid. The same is true of 2-methoxy-3-methylpyridine. In contrast, 3- and 5-methyl-2-pyridone, i,5-dimethyl-2-pyridone and 3-nitro-4-pyridone all react... 

Pyrans and related compounds react with ammonia to give pyridines. A commercially useful example is the reaction of dehydroacetic acid (derived from diketene) with ammonia to give 2,6-dimethyl-4-pyridinone [7516-31 -6] via 2,6-dimethyl-4-pyridinone-3-carboxyhc acid [52403-25-5]. Chlorination of the pyridone gives clopidol [2971-90-6] (56), a coccidiostat (72,73). 

Unexpectedly strong intermolecular hydrogen bonding has been reported by IR spectroscopic studies for tetrahydro-4,7-phenanthroline-l,10-dione-3,8-dicarboxylic acids, which exist in the oxo-hydroxy form 165 in both solid state and in solution [78JCS(CC)369].Tlie conclusion was based on comparison of B-, C-, and D-type bands for 165 and their dimethyl esters (detection of hydrogen bonding) and on analysis of IR spectra in the 6 /xm region (pyridine- and pyridone-like bands). 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

By contrast, the rate-acidity profiles for nitration of 3-nitro-4-pyridone, 3-and 5-methyl-2-pyridone and l,5-dimethyl-2-pyridone resemble each other and differ from the above-indicated reaction upon the free base, and correction of the observed rates to allow for the concentration of free base actually present gave rate-acidity profiles of the expected form the corrected entropies of activation then turned out to be positive. Furthermore, if the logarithms of the corrected rate coefficients obtained in media of low acidity were plotted against +log aHlQ, then slopes of near unity were obtained (see above, p. 18), but not otherwise. A similar result was obtained from the nitration data for 4-pyridone in media of low acidity suggesting that here it reacts as the free base. A further test which was applied was to calculate the concentration of nitronium ions in the various media and to correct the observed rate coefficients for this the logarithms of these coeffi-... 

Similar reasoning was applied to determination of the reacting form of 1-hy-droxy-2,6-dimethyl-4-pyridone, its rate being compared to that of 4-methoxy-... 

Methoxy-2,6-dimethylpyridine 4-Hydroxy-2,6-diraethylpyridine-l-oxide anion l-Hydroxy-2,6-dimethyl-4-pyridone 4-Methoxy-2,6-dimethylpyridine-l-oxide... 

The rate-acidity profile for pyrimidin-2-one indicated reaction on the free base but since the derived second-order rate coefficient is 104 times greater than that for 2-pyridone, and the acidity dependence in the H0 region was also greater, the slope of log kt versus —H0 plot being 0.45, cf. 0.15 for 2-pyridone reaction was, therefore, postulated as occurring via a covalent hydrate, hydration taking place at the 4 position. Methyl substitution increased the rate as expected and N-methyl substitution produced a larger effect than 4,6-dimethyl substitution and this may be due to alteration of the amount of covalent hydration at equilibrium. The data... 

It was shown in the same article that the decarboxylation could also be performed by conventional heating but then copper cyanide was required and a mixture of saturated and imsaturated 2-pyridones 65 and 66 was obtained in a ratio of 1 10 (Fig. 10). A tentative mechanism was suggested for the reagent-free MAOS method where the carbonyl in the 2-pyridone ring is supposed to assist in the decarboxylation yielding an yUde 67 (Fig. 11). The decarboxylated bicyclic 2-pyridone 68 is thereafter obtained after protonation by the solvent. In agreement with the mechanistic suggestion, it was shown that a selective deuteration occurred when deuterated dimethyl sulfoxide (DMSO-de) was used as solvent. 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

Bicyclic 2-pyridones fused over the nitrogen is another important heterocyclic scaffold. In the quest towards the total synthesis of Camptothecin, Danishefsky and co-workers developed a method where a vinylogous urethane was reacted with 1,3-dicarboxymethoxyallene generated in situ from dimethyl 3-chloroglutaconate to a bicyclic 2-pyridone intermediate [31-34]. This method has later been successfully applied in the synthesis of other... 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

Reaction of 1,3-dicarbonyl compounds with IVJV-dimethylformamide dimethyl acetal followed by malonamide in the presence of sodium hydride gives 5,6-disubstituted 1,2-dihydro-2-oxopyridine-3-carboxamides, whereas reaction of the intermediate enamines with cyanothioacetamide or cyanoacetamide in the presence of piperidine provides 2-thioxopyridine-3-carboxamides and 4,5-disubstituted l,2-dihydro-2-oxopyridine-3-carboxamides, respectively <95S923>. P-Enaminonitriles 14 react with p-ketoesters and alkyl malonates, in the presence of stoichiometric amounts of tin(IV) chloride, to afford 4-aminopyiidines 15 and 4-amino-2-pyridones 16 <95T(51)12277>. 

Cyclic dienes also react readily with ADC compounds although in many cases the initial adducts are not isolable. 1-Substituted pyrid-2-ones give Diels-Alder adducts with ADC compounds, although 2-pyridone itself gives only the substitution product (e.g., 113).174 2-Pyrone gives a 1 2 adduct with PTAD, since the initial adduct (114) rapidly loses C02 to generate a diene which then reacts with more PTAD.175 The initial adducts of ADC compounds with cyclopentadienones,176 and 3,4-dimethyl-1-phenylphos-phole 1-sulfide (115)177 also regenerate a diene by loss of CO and PhP=S, respectively. 

In Scheme 6.230, the multistep synthesis of 2,3-dihydro-4-pyridones is highlighted [411]. The pathway described by Panunzio and coworkers starts from a dioxin-4-one precursor, which is readed with 2 equivalents of benzyl alcohol under solvent-free microwave conditions to furnish the corresponding /1-diketo benzyl esters. Subsequent treatment with 1 equivalent of N,N-dimethylformamide dimethyl acetal (DMFDMA), again under solvent-free conditions, produces an enamine, which is then cyclized with an amine building block (1.1 equivalents) to produce the desired 4-pyridinone produds. All microwave protocols were conducted under open-vessel conditions using power control. 

This was significant in the preparation of l,2-dimethyl-3-hydroxy-4-pyridone, employed clinically as an iron chelating agent. The aminoreductone is obtained by reaction of methylamine with maltol. Traces of metal within the system readily form highly colored complexes with reactant or product and these are difficult to remove. With the CMR, the preparation was achieved in 65 % yield without the need for decolorizing charcoal and the product was crystallized by collecting the effluent in acetone (Scheme 2.10) [22]. 

Scheme2.10 Microwave preparation of l,2-dimethyl-3-hydroxy-4-pyridone.

Creosol, 33, 17 Crotonaldehyde, 33, IS 34, 29 diethyl acetal, 32, 5 Cupric acetate monohydrate, 36, 77 Cuprous oxide-silver oxide, 36, 36, 37 Cyanamide, 34, 67 36, 8 Cyanoacetamide, 32, 34 Cyanoacetic acid, 31, 25 Cyanoacetylurea, 37, 16 >-Cyanobenzaldehyde, 30, 100 >-Cyanobenzaldiacetate, 36, 59 3-Cyano-5,6-dimethyl-2(l)-pyridone, 32,34 N-2-Cyanoethylaniline, 36, 6 N-2-Cyanoethyl- -anisidine, 36, 7 Cyanoethylation, of aniline, 36, 6 of ethyl phenylcyanoacetate, 30, 80 N-2-Cyanoethyl-m-chloroaniline, 36, 7 Cyanogen, 32, 31 Cyanogen iodide, 32, 29 Cyanogen iodide, complex with sodium iodide, 32, 31... 

Reduction of o /i-unsatin-ated lactams, S,6-dihydro-2-pyridones, with lithium aluminum hydride, lithium alkoxyaluminum hydrides and alane gave the corresponding piperidines. 5-Methyl-5,6-dihydro-2-pyridone (with no substituent on nitrogen) gave on reduction with lithium aluminum hydride in tetrahydrofuran only 9% yield of 2-methylpiperidine, but l,6-dimethyl-5,6-dihydro-2-pyridone and 6-methyl-l-phenyl-5,6-dihydro-2-pyridone afforded 1,2-dimethylpiperidine and 2-methyl-1-phenylpiperidine in respective yields of 47% and 65% with an excess of lithium aluminum hydride, and 91% and 92% with alane generated from lithium aluminum hydride and aluminum chloride in ether. Lithium mono-, di- and triethoxyaluminum hydrides also gave satisfactory yields (45-84%) [7752]. 

Starting material for the synthesis is the enaminoaldehyde obtainable by some version of the Villsmeyer reaction on pi coline derivative 9. Condensation of that with cyanoacetamide in the presence of methoxide leads to pyridone J. The reaction can be rationalized by assuming that the initial step consists in Michael addition of the anion from acetamide to the acrolein elimination of dimethyl amine would afford the intermediate Conden-... 

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