Phosphorus oxychloride , reaction with pyridone

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

A First, a reaction with phosphorus oxychloride and phosphorus pentachioride can be used to convert 2-pyridone into 2-chloropy= ridine. and then this compound is subjected to an addition-elimination reaction with methoxide ion (from sodium methoxide) (Scheme 2,26). Note chloride is a much better leaving group than methoxide. 

Both pyridones can react with electrophiles at positions ortho and para to the activating oxygen atom. For instance, 4-pyridone reacts with electrophiles at the C3 position (the mechanism can be formulated from either mesomeric representation) to give intermediate 5.24. As with pyridine N-oxides, reaction with phosphorus oxychloride gives useful chloropyridines 5.25. We shall see the utility of 2- and 4-chloropyridines in the next section. 

Nitration of 4-pyridone 5.23 gives 5.28, and reaction with phosphorus oxychloride affords chloropyridine 5.29. This pyridone-chloropyridine conversion activates the system to nucleophilic attack by hydrazine, affording 5.30. The nitro group also facilitates nucleophilic attack by delocalisation of negative charge in the intermediate. 

Although the mechanism of chlorination of pyridine A-oxides by the action of phosphorus oxychloride, phosphorus pentachloride, or sulfuryl chloride has not been established, it seems most likely that some of these reactions involve intra- or inter-molecular attack by chloride ion or potential chloride ion following complexing at oxygen (see Sections II and IV). With a few exceptions, they are therefore more appropriately discussed under the heading of nucleophilic substitutions (Section IV, A, 3). One such exception may be the reaction of A-hydroxy-4-pyridone with sulfuryl chloride, which ultimately gives l,2,2,3,3,5,6-heptachloro-2,3-dihydro-4-pyridone (65). It has been proposed that the first step in this reaction is the formation of 3,5-dichIoro-AT-hydroxy-4-pyridone.157 If this is so, then it must involve electrophilic attack at the two /3-positions, followed by the more usual nucleophilic substitutions. 

Chlorination of the pyridone (436 R = 4-pyridinyl) with phosphorus oxychloride followed by a reaction with hydrazine gave a low yield of the corresponding 2-amino-3-hydroxypyridine (437). Cyclization of this product was carried out by a reaction with l,r-carbonyldiimidazole in DMF at room temperature to give the oxazolo[4,5-6]pyridine (438 R = 4-pyridinyl) (Scheme 51) <94JMC248>. 

Dolby and Biere (252, 253) adopted a quite different tactic to produce these systems. The key step is the trapping of a Vilsmeier salt with sodium borohydride. All the functionality required to effect the condensation reactions is built into a 2-pyridone derivative 612. This compound is produced by the route outlined in Scheme 38. Treatment of 612 with indole in the presence of phosphorus oxychloride gives a Vilsmeier salt, which is reduced with sodium borohydride to the piperidylindole 613. Hydrolysis of the ester group and cyclization with polyphosphoric acid gave a mixture consisting mainly of epidasycarpidone (608) (54% yield) together with some 607 (15% yield). The 608 was converted to the carbinol 614 with methyllithium and dehydrated to 611 with alumina. 

The conversion of the carbonyl group in pyridones into a leaving group has a very important place in the chemistry of these compounds, the most frequently encountered examples involving reaction with phosphorus oxychloride and/or pentachloride leading to the chloropyridine, via an assumed chloro-phosphate... 

Attempts to prepare the 2-chloro-derivatives (57 R = 2-Cl X = NO2 or Cl) by heating pyridones (58 R = N02 or Cl) with phosphorus oxychloride or thionyl chloride failed, but gave instead the pyrido[2,3-Z>]benzofurans (59 R = NO2 or Cl) in 70% and 42% yield respectively. Possible reaction pathways are elaborated in Scheme 13. 

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