4-Pyridone rings pyridine ring

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

In 1931 Ing pointed out that formula (II) and (III) do not contain methyl or potential methyl groups in j ositions 6 and 8 which they occupy in cytisoline. Further, a partially reduced quinoline ought to oxidise easily to a benzenecarboxylic acid and so far the only simple oxidation, products recorded from cytisine were ammonia, oxalic acid and isovaleric acid. Distillation of cytisine with zinc dust or soda-lime yields pyrrole and pyridine, but no quinoline. On these grounds Ing suggested that cytisine should be formulated without a quinoline nucleus, and that the reactions which indicate the presence of an aromatic nucleus in the alkaloid can be accounted for by an a-pyridone ring. This a-pyridone nucleus can... 

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)... 

The most efficient routes to the cationic oxazolo[3,2- ]pyridine ring system 351 rely on the method of Bradsher and Zinn <1967JHC66> involving the cyclocondensation of iV-phenacyl-2-pyridones 349 obtained by alkylation of readily available 2-pyridones 347 (Scheme 95). This method has been used by Babaev et al. to prepare a series of 6-nitro-oxazolo[3,2- ]pyridines 355 from 5-nitro-2-pyridone 352 in excellent yields <2003MOL460>. Similarly, tricyclic oxazolo[3,2- ]pyridines 359 have been prepared from the corresponding quinolin-2(177)-ones 356 <2003H(60)131>. 

Crystal-structure-sensitive bond-forming and -breaking processes other than ring-chain tautomerism are also known. For example, acetylation of 4-pyridone in pyridine gives rise to crystalline A-acetyl-4-pyridone. When this is dissolved in CH2C12 it gives a nearly 1 1 equilibrium mixture of this acetyl pyridone and 4-acetoxypyridine. The A-acetyl derivative is obtained by crystallization (79). 

The presence of substituents on the pyridine ring, which reduce the basicity of the annular nitrogen atom, not only shifts the pyridone-hydroxypyridine equilibrium towards the hydroxy form [62], but they also inhibit A-alkylation. Thus, for example, 3,5,6-trichloro-2-hydroxypyridine is alkylated preferentially on the oxygen atom. Predictably, alkylation of 3-hydroxypyridine and of 2-amino-3-hydroxypyridine leads to the 3-alkoxypyridines in high yield under basic conditions [63] (see Chapter 3). 

Many analogs of 75 with substituents in the pyridine rings have also been prepared ° although 6-alkoxy-2,2 -bipyridines react with ethylene dibromide to afford the pyridone 76 rather than 4-alkoxy analogs of 75. Derivatives of 75 with alkyl substituents on the ethylene bridge (i.e., 6 and/or 7 positions) can likewise be prepared from 2,2 -bipyridines and appropriate dibromoalkanes. " " 6-Hydroxy-substituted derivatives of 75, for example, compound 78, are accessible by ring closure of j8-carbonyl monoquaternary salts of 2,2 -bipyridine, such as compound 77, with acid. 

For ring systems that incorporate a pyridine ring, chemistry and reactivity of pyridone derivatives have been incorporated into Sections 10.06.5-10.06.9, wherever appropriate. For crystalline products, which represent most of the derivatives contained within this chapter, the compounds exist as the pyridone tautomer. 

Fuhrhop et al. (81 LA 1367) have investigated the oxidation of tneso-(3-carbamoylpyridinio)porphyrins, in which the redox systems of porphyrins and nicotinamide have been combined. In derivative 13, the substituent R is sensitized to visible light and additions to C-4 of the pyridine ring are extraordinarily favored above attack on C-2 and C-6. Thus, photooxidation of 13 gave the 4-pyridone 14, whereas HgO produced the 2-pyridone 15 (Scheme 4). 

The reduced pyridones 96 were obtained in good yield from the aldehydes 95a directly106 or via the phenylhydrazones 95b.107 Platinum oxide-catalyzed hydrogenation of the pyridine ring in 16 gave tetrahydro products (97 R2 = Me,H R4 = H,Me).61... 

Apart from these structurally related alkaloids, P. Lyallii contains a number of other compounds exhibiting, instead of a pyridine unit, either a dihydropyridine ring or a pyridone ring, both of which have a characteristic methylcarboxy group at the C-16 position. Lyaline (10) and lyadine (11) (79), which are representative of the dihydropyridine-bearing class of compounds, are found in all parts of P. Lyallii, while lyalidine (12) and hydroxylyalidine (13) (20) are extracted exclusively from root bark. 

B. Nitrogen-Containing Rings 1. 2-Pyridone and Pyridine-2-thione... 

The most efficient route to the cationic oxazolo[3,2- ]pyridine ring system 69 relies on the cyclocondensation of N-phenacyl-2-pyridones 68 obtained by alkylation of 2-pyridones 67 (Scheme 41) <1967JHC66, CHEC-III(11.10.7.8) 479>. The use of this method is exemplified by the preparation of tricyclic oxazolo[3,2- ]pyridines 71 from the corresponding quinolin-2(l//)-ones 70 (Scheme 42) <2003H131>. 

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