3-Cyano-2-pyridone

Another direct route leads, as we shall now demonstrate, to pyridones. These useful compounds are the basis for nucleophilic substitutions on the ring (Chapter 43). We choose an example that puts a nitrile in the 3-position. This is significant because the role of nicotinamide in living things (Chapter 50) makes such products interesting to make. Aldol disconnection of a 3-cyano pyridone starts us on the right path. 

The cyclocondensation of 1,3-diketones with cyanoacetamide catalysed by base yielding 3-cyano-pyridones 23 (Guareschi synthesis) finds wide application ... 

A third synthesis which has resulted in the preparation of rieinine and a number of its derivatives is due to Schroeter, Seidler, Sulzbacher and Kanitz,i2 who foimd that cyanoacetyl chloride polymerises spontaneously to 6-chloro-2 4-dihydroxy-3-cyano-pyridine. The di-sodium derivative of this with methyl sulphate produces A -methyl-6-chloro-4-hydroxy-3-cyano-2-pyridone (6-chlororicininic acid), the mono-sodium derivative of which, with methyl bromide or sulphate, is converted into 6-chlororicinine and the latter is reduced by zinc and sulphuric acid to rieinine. A fourth synthesis, starting from 3-nitro-4-pyridone, is due to Reitmann. ... 

Bis(trifluoromethyl)-substituted pyrimidines are also available fromtrifluoro-acetonitrde on reaction with enamines and ynamines [d ] With dimethylami-nocrotonates, a cyclocondensation takes place to give 2-pyridones. 5-Cyano-6-trifluoromethyluracil is available via a similar route [95] (equation 18)... 

The cyclization of the 1,3-enyne amines with cyanacetamide in the presence of bases (55°C, H2O, 2 h) leads to 3-cyano-6-methyl-2-pyridones (155), yield 77% (69ZOR1179). 

Cyano-4-Carbethoxy-6-Ethyl-2-Pyridone 205 cc of 60% aicohoi, 22 grams of the product just obtained, 11 grams of cyanacetamide and 4.5 cc of piperidine are refiuxed. 19 grams of product having a melting point of 211°C are obtained. 

B) 3-Cyano-4-Carbethoxy-6-(n)-Propyl-2-Pyridone The 135 grams of the product just obtained are condensed with 62 grams of cyanacetamide in the presence of 24 cc of piperidine in 1200 cc of 95% alcohol. 64 grams of a product, melting at 152°C, are obtained. 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

Hoomaert has studied Diels-Alder reactions of pyridine oquinodimethane analogs generated from functionalized o-bis(chloromethyl)pyridines <96T(52)11889>. The photochemical cycloaddition of 2-alkoxy-3-cyano-4,6-dimethylpyridine with methacrylonitrile gives a bicyclic azetine, 6-alkoxy-3,5-dicyano-2,5,8-trimethyl-7-azabicyclo[4.2.0]octa-2,7-diene, in moderate yield <96CC1349>. Regiospecific hydroxylation of 3-(methylaminomethyl)pyridine to 5-(methylaminomethyl)-2-(17/)-pyridone by Arthrobacter ureafaciens has been reported <96MI173>. 

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... 

N-Cyanoguanidine, 35, 69 Cyanohydrin formation, 33, 7 3-Cyano-6-isobutyl-2(l)-pyridone, 32, 34 3-Cyano-6-methyl-2(1)-pyridone, 32, 32 l-Cyano-3-a-naphthylurea, 36, 11 1-Cyano-3-phenylurea, 36, 8 Cyclic acyloins, 36, 82 Cyclization, (3-aminoethylsulfuric acid to ethylenimine, 30, 38 1,2-benzo-3,4-dihydrocarbazole from phenylhydrazine and a-tetralone,... 

As a general rule, in the case of CSPs featuring hydrophobic pockets, a decrease of mobile phase flow-rate results in an increase of chromatographic resolution (Rs), as a consequence of better stationary phase mass transfer [78]. This change has significant impact mostly in RP mode [17]. In the NP enantioselective separations of two test solutes (4-hexyl-5-cyano-6-methoxy-3,4-dihydro-2-pyridone and... 

Several condensation routes to 2,3 -bipyridinones have been reported. Thus 3-acetylpyridine and nicotinaldehyde were condensed to the a,/ -unsat-urated ketone 45, which reacted in a Michael condensation with l-(car-bamoylmethyl)pyridinium chloride (46) to give 2,4-di(3-pyridyl)-6-pyridone (47). Compound 47 was converted to the alkaloid nicotelline 10 by replacement of the hydroxyl group of 47 by chlorine, followed by reductive dehalogenation. Related condensations have been described, including the synthesis of 4,6-diphenyl-2,3 -bipyridine. Similarly, aldehyde 48 was condensed with cyanoacetamide (49) to afford 2-(3-pyridyl)-5-cyano-6-pyridone (50), the cyano group of which was hydrolyzed and decarbox-ylated to 2,3 -bipyridin-6-one. Several modifications and extensions of... 

Note 5) in 400 ml. of water and piperidine acetate (prepared by adding piperidine to 8 ml. of glacial acetic acid in 20 ml. of water until the solution is just basic to litmus). The flask is equipped with a reflux condenser, and the mixture is heated under reflux for 2 hours. At the end of this time 200 ml. of water is added, and the solution is acidified (to litmus) with acetic acid, causing separation of the product as a voluminous yellow precipitate. The mixture is cooled in an ice bath for 2 hours, and the product is collected on a suction filter, washed on the filter with three 100-ml. portions of ice water, and dried (Note 6). The yield of 3-cyano-6-methyl-2(l)-pyridone is 59-67 g. (55-62%) m.p. 292-294° (dec., cor.) (Notes 7, 8, and 9). 

Analysis of the crude product is approximately 0.9% low in carbon. Analytically pure 3-cyano-6-methyl-2(l)-pyridone, m.p. 296.5-298.5° (dec., cor., under nitrogen), can be obtained by one recrystallization from 50% (by volume) ethanol, using 66 ml. per g. of product and treating the hot solution with Darco. Recovery of the product is 60%, and concentration of the mother liquor yields impure material. 

A similar procedure can be used for preparing other 2(l)-pyr-idones. For example, 3-cyano-6-isobutyl-2(l)-pyridone can be obtained from the sodium salt of formylmethyl isobutyl ketone, and 3-cyano-5,6-dimethyl-2(l)-pyridone can be prepared from the sodium salt of a-formylethyl methyl ketone.5... 

The procedure used for preparing the sodium salt of formyl-acetone is a modification of a previously described procedure.2 3-Cyano-6-methyl-2(l)-pyridone has been prepared by the condensation of /3-ethoxycrotonaldehyde diethyl acetal with cyano-acetamide 6 and by condensation of the sodium salt of formyl-acetone with cyanoacetamide.7... 

Cyano, halo, amino, and nitro groups in the 2- or 4-position of pyridinium ions are susceptible to nucleophilic substitution. Treatment of these compounds with aqueous alkali gives the corresponding pyridones. Since this transformation is not the result of oxidation, it will not be further considered here. 

Two pyridone alkaloids ricinine (238) and nudiflorine (239) have been isolated from Ricinus and TYewia (Euphorbiaceae), respectively (61JBC1186 64CI(L)1524). It has been shown that at least seven species in this family contain enzyme systems that can oxidize 3-cyano-l-methylpyridinium salts in... 

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