Dicarbonyl pyridones

More general processes rely on variations of the Guareschi-Thorpe reaction [14] where condensations between 1,3-dicarbonyls and cyanoacetamide yield functionalized monocyclic 2(lff)-pyridones (a and b. Scheme 2) [15, 16]. Unless the carbonyls are sufficiently different in reactivity, the reaction suffers from poor regioselectivity. The use of 3-alkoxy or 3-amino enones instead of 1,3-dicarbonyls has proven to be a versatile and reliable synthetic methodology where the 1,4-addition controls the regioselective outcome (c and d. Scheme 2) [17-19]. 

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>. 

Although pyridones are usually resistant to alkali, pyrone rings are often easily opened. Pyran-2-ones are reversibly ring-opened by aqueous alkali to acid anions (222). Hydroxide ions convert coumarins (223) reversibly into salts of coumarinic acids (224) which can be converted into the trans isomers (225), and chromones (226) into 3-dicarbonyl compounds (227). 

Since simple ketones 22 are less reactive compared to 1,3-dicarbonyl compounds 19, improvement of the nucleophilicity of the a-carbon is required by conversion to enamines. When dinitropyridone 1 is treated with acetone 22a in the presence of amines, 2,6-disubstituted 4-nitroanilines 23a-c are produced in good yields (Table 1). In this reaction, the enamine is formed in situ, and attacks stepwise at the 4- and the 6-position of pyridone 1 to afford bicyclic intermediate from which anionic nitroacetamide is eliminated leading to nitroaniline derivative 23. It is possible to synthesize unsymmetri-cal nitroanilines having different substituents at the 2- and the 6-positions by changing ketones 22, and modification of the amino group is also achieved by using other amines [41]. 

When pyrimidinone 3 is allowed to react with 1,3-dicarbonyl compounds 19 in the presence of piperidine, polyfunctionalized pyridones 12 are prepared (Table 12) [62], In the present reaction, /3-keto esters 19b and 19i, diester 19k and cyanoacetate 191 are usable as the reagent to give corresponding pyridones 12, however /J-dikc tones 19c and 19j affords no RTF product, which is due to further decomposition of produced pyridones 12c and 12j under the employed conditions. 

N-methyl-a-nilroacrylamide 46 to afford polyfunctionalized pyridones 12 in reactions with 1,3-dicarbonyl compounds 19 in the presence of piperidine. As a result, versatile azaheterocyclic compounds can be easily prepared from pyridone 1 and pyrimidinone 3, and the synthetic utility of the RTF reaction has been considerably improved. 

These heterocycles are commonly prepared by the cyclization of appropriate 1,5-dicarbonyl precursors 1,5-diones yield 4//-pyrans or dihydropyridines (206 207, Z = O, S, or NH) (which are sometimes oxidized in situ) 1,3,5-triones 208 give -pyrones (209 Z = 0) by dehydration and -pyridones (209 Z = NH) by the action of ammonia (Scheme 115). 

From 1,3-Dicarbonyl Compounds (or Synthons) and 3-Amino-Enones or -Nitriles Pyridines are formed from the interaction between a 1,3-dicarbonyl compound and a 3-amino-enone or 3-amino-acrylate 3-cyano-2-pyridones result if cyanoacetamide is used instead of an amino-enone. 

There have been several reports of the use of cyano-acetamides as C-C-N synthons in pyridone synthesis. The C-C-C component that is required for the formation of a six-membered ring may be either an 0 /3-unsaturated carbonyl compound or a dicarbonyl compound. Alternatively, pyridones have been formed by base-promoted cyclocondensation of cyano-acetamides with a-keto-ketene 5,A -acetals (Scheme 10). ... 

Pyrido[3,4-b]pyrazines substituted in the pyridine ring are available from the reactions of suitably substituted 3,4-diaminopyridines and the appropriate dicarbonyl compounds. No problems are encountered with diamines substituted with halogen or hydroxy groups. Similarly the pyridones 7 provide the oxo compounds 8 and 9. In contrast, 3,4-diamino-5-nitropyridine did not react with glyoxal, and only a low yield of 2,3-dimethyl-8-nitropyrido[3,4-b]pyrazine could be obtained using diacetyl. ... 

Retroanalysis of 2-pyridones via routes a and b suggests p-dicarbonyl compounds 21 or P-substituted acrylic acids 22 as building blocks. These 1,3-biselectrophiles have to be linked by... 

Cyclocondensation of dianions of p-dicarbonyl compounds 35 with nitriles offers a possibility for the formation of asymmetrically 2,6-disubstituted 4-pyridones 36, e.g. ... 

A new pyridone synthesis was developed to form the basis of the second synthesis (Scheme 27) to be announced. This new heterocyclic method involves, in essence, the interaction of a 1,3-dialkoxycarbonylallene with a P-aminocrotonate [in the present context, (95)] or mono-enamine of a 1,3-dicarbonyl... 

Since it is known that a-protons of the acylacetonitriles are more acidic than those of the methyl ketones, it was logical to use the acylacetonitrile building blocks during the first stage of the aldol-like condensation for the synthesis of heterocyclic compounds such as the 4H-pyran, 2-pyridone, and furan derivatives [85-95]. Therefore, it was expected that acylacetonitriles would be oxidized by manganese(III) acetate in a similar manner to the oxidation of a-cyanoacetic acid [65,96-99] and 1,3-dicarbonyl compounds [100] to give acylcyanomethyl radicals, CH(COR)CN, which would attack the alkenic double bonds to produce heterocyclic compoimds in one step [73,75,77,80,101-... 

The reaction between P-dicarbonyl compounds and cyanoacetamide to form the corresponding 3-substituted pyridines (MI-121). Acetoacetamide and... 

The enamine can be formed in situ in a 4CR as well (Scheme 13.36). A primary amine 128 [57] or, in most cases, ammonium acetate [58-61] is reacted with a 1,3-dicarbonyl compound to yield the corresponding enamine. This undergoes nucleophilic addition to the formed Michael acceptor (by reaction of Meldrum s acid 112 with the corresponding aldehydes) followed by cyclization with the Meldrum s acid moiety present in the Michael acceptor molecule. Thus, pyridones are accessible in a 4CR starting from simple, readily available substances. Mostly, acidic conditions are applied for their syntheses, but microwave irradiation under neutral reaction conditions works fine as well. 

Retrosynthesis of 2-pyridones via routes a and b suggests (l-dicarbonyl compounds 22 or C -substituted acrylic acids 23 as building blocks for their synthesis [147]-... 

Chavan and Degani [198] reported a green protocol for the synthesis of 4,6-disubstituted-3-cyano-2-pyridones 107 108 from cyanoacetamides and 1,3-dicarbonyl compounds or chalcones using IL xmder solvent-free conditions... 

The addition of singlet oxygen to 2-pyridones leads to oxygenated products derived from intermediates 163 (Scheme 16). All reported examples carry alkyl substitution of the pyridone at C3 (164) or C6 (26). Acidic hydrolysis (methanolysis) of these intermediates yield dicarbonyl products 165 and 166. ... 

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