Reactions of Pyridones

3-Hydroxypyridine protonates on nitrogen, with a typical pyridine p/faH of 5.2 the pyridones are much less basic and, like amides, protonate on oxygen.However, the reaction of 4-pyridone with acid chlorides produces A-acyl derivatives. l-Acetyl-4-pyridone subsequently eqnilibrates in solution affording a mixtnre with 4-acetoxypyridine.  

Electrophilic substitution at carbon can be effected much more readily with the three oxy-pyridines than with pyridine itself, and it occnrs ortho and para to the oxygen fnnction, as indicated below. Acid catalysed exchange of 4-pyridone in denterinm oxide, for example, gives 3,5-didenterio-4-pyridone, via C-protonation of the neutral pyridone.  

Substitutions usually proceed via attack on the neutral pyridone, but in very strong acid, where there is almost complete 0-protonation, 4-pyridone undergoes a slower nitration, via attack on the salt, but with the same regioselectivity.  

Electrophilic substitutions of 3-hydroxypyridine take place at C-2, for example nitration, Mannich substitution and iodination. Its phenol-like character is nicely illustrated by efhcient 2,4,6-tribromination with Af-bromosuccinimide. 2-Methoxypyridine brominates at C-5 and 4-methoxypyridine at C-3.  

The conversion of the carbonyl group in pyridones into a leaving group has a very important place in the chemistry of pyridones, the most frequently encountered examples involving reaction with phosphoryl chloride and/or phosphorus pentachloride leading to the chloro-pyridine, via an assumed dichlorophosphate 

---

RATE COEFFICIENTS AND PARAMETERS FOR REACTION OF PYRIDONES WITH... 

A useful reaction of pyridones is conversion into chloropyridines by the use of phosphoras oxychloride POCI3 in the presence of PCI5. This... 

Cyclizing ca-chloro Reissert compound 136 gives rise to tricyclic lactam 137 (72JHC541). In a study of the cobalt-mediated reaction of pyridones with alkynes, in the case of the N-hexynyl compound, C-H activation with... 

Reaction of pyridones with diazoalkanes involves deprotonation as the first step, forming an alkyldiazonium cation which then rapidly alkylates the pyridone anion 2-pyridone gives mainly 0-methyl derivatives, but 4-pyridone gives mixed 0- and A-methyl derivatives. 

In this reaction, another mechanism can be proposed as illustrated in Scheme 9. Namely, the ring opening reaction of pyridone 1 proceeds after addition of enolate 13 to form the open-chain intermediate 17 instead of bicyclic one 16, and then its cyclization yields nitrophenol 14. However, this mechanism is excluded by the following experimental facts. When the reaction is conducted at a low temperature, the bicyclic compound 18 is isolated, which is transformed to nitrophenol 14 upon heating with base (Scheme 10) [39]. 

As shown in the previous section, N-alkyl nitroanilines 23 are obtained in the reaction of pyridone 1 with ketones 22 in the presence of amines. In this case, amines are introduced as the dialkylamino substituents. On the contrary, different reactivity is observed when ammonia is used instead of amines. The TCRT reaction proceeds to afford 2,3-dialkyl-5-nitropyridines 24 upon treatment of pyridone 1 with ketones 22 in the presence of ammonia (Table 2) [42,43]. The C4 - C5 - C6 unit is derived from pyridone 1, the C2 - C3 unit is derived from ketone, and the ring nitrogen (Nl) is from ammonia, namely the new ring consists of three components. As electrophilic nitration of pyridines is quite difficult, the present TCRT will be an alternative method for preparation of nitropyridine derivatives. 

Substituted furo[2,3-fc]pyridones were assembled by a Pd-mediated sequential crosscoupling Sonogashira reaction-Wacker-type heteroannulation and deprotection reactions of pyridones, aUcynes and organic halides in an one-pot operation <03OL2441>. The coupling products of pyridones and alkynes could be separated and a single palladium catalyst intervened in three different transformations. 

The Rh(II)-catalyzed reaction of pyridone 96 with DMAD was also found to give cycloadducts derived from an intermediate azomethine ylide. The initial reaction involves generation of the expected carbonyl ylide by intramolecular cyclization of the keto carbenoid onto the oxygen atom of the amide group. A subsequent proton shift generates the thermodynamically more stable azomethine ylide, which is trapped by DMAD. This is an example of subsequent formation of ylides of two types, a phenomenon termed a dipole cascade (93JOC1144). 

Mechanism of reaction of pyridones with phosphoryl chloride, illustrated for 2-pyridone... 

The most important method for the introduction of halogen substituents into pyrido[2,3-c/]-pyrimidines 5 is the reaction of pyridone or pyrimidone functions with halogenating agents such as phosphoryl halides39-77,79 131, l34,200,237,332 or thionyl chloride238,333,569 to furnish the corresponding halogen compounds 6. 

Pyridines have also been used in cyclization reactions. Two noteworthy examples are shown in scheme 3. The reaction of substituted pyridine 32 with a nitrile affords imidazo[l -ajpyridine 33 in excellent yield <01JOC2862>. Oku and co-workers have reported the use of tetrahydroquinolizinium ylides in a 13-dipolar cycloaddition reaction (34- 35) <01JOC1638>. Sieburth has also published an account of the [4+4] photocyclization reaction of pyridones on route to fusicoccin <01S1185>. 

Scheme 14.74 Ni-catalysed intramolecular and intermolecular reaction of pyridone derivative with alkenes.

In addition to dimerizations, 2-pyridones undergo [4-f4]-photocycloadditions with other aromatics and with 1,3-dienes (Schemes 9 and 10). Triazolopyridine 71 will photodimerize, but when mixed with pyridone 18 yields significant amounts of cross product 72. Intermolecular reactions of pyridones with... 

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). 

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). 

Certain molecules that can permit concerted proton transfers are efficient catalysts for reactions at carbonyl centers. An example is the catalytic effect that 2-pyridone has on the aminolysis of esters. Although neither a strong base (pA aH+ = 0.75) nor a strong acid (pJsfa = 11.6), 2-pyridone is an effective catalyst of the reaction of -butylamine with 4-nitrophenyl acetate. The overall rate is more than 500 times greater when 2-pyridone acts... 

Katada, working in the labs of Ochiai, first described the reaction of N-oxide 3 with acetic anhydride. The resultant rearrangement produced a-pyridone 4. Shortly... 

Marazano and co-workers have also applied the reactions of tryptamine with various Zincke salts, including 115 (Scheme 8.4.39), in the synthesis of pyridinium salts such as 116. This type of product is useful for further conversion to dihydropyridine or 2-pyridone derivatives. For example, in a different study, Zincke-derived chiral pyridinium salts could be oxidized site-selectively with potassium ferricyanide under basic conditions as a means of chiral 2-pyridone synthesis (117 —> 118, Scheme 8.4.40). 

In this solvent the reaction is catalyzed by small amounts of trimethyl-amine and especially pyridine (cf. 9). The same effect occurs in the reaction of iV -methylaniline with 2-iV -methylanilino-4,6-dichloro-s-triazine. In benzene solution, the amine hydrochloride is so insoluble that the reaction could be followed by recovery. of the salt. However, this precluded study mider Bitter and Zollinger s conditions of catalysis by strong mineral acids in the sense of Banks (acid-base pre-equilibrium in solution). Instead, a new catalytic effect was revealed when the influence of organic acids was tested. This was assumed to depend on the bifunctional character of these catalysts, which act as both a proton donor and an acceptor in the transition state. In striking agreement with this conclusion, a-pyridone is very reactive and o-nitrophenol is not. Furthermore, since neither y-pyridone nor -nitrophenol are active, the structure of the catalyst must meet the conformational requirements for a cyclic transition state. Probably a concerted process involving structure 10 in the rate-determining step... 

Methyl- and 3-phenyl-4-hydroxy-2-oxo-2//-pyrido[2,1 -Z)]oxazinium inner salts were prepared in the reaction of 2-pyridone and 2-substituted malonyl chloride, prepared in situ from 2-substituted malonic acid with PCI5 in CH2CI2 (00JCS(P2)2096). 

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)... 

Reaction of diphenylcyclopropanone with tutroketene aimnals gives 6-amino-2-pyridones fEq 10 88 ... 

A kinetic study of the deuteration of pyridones and quinolones by deuterated sulphuric acid yielded the data in Table 148sl0. For the 4-pyridones, the rapid rise in rate with increasing acidity in strongly basic solutions, and the levelling off in rate at about H0 = 0 is consistent with reaction on the free base as is the small negative entropy of activation. The similarity in rate between 4-pyridone and its 1-methyl derivative shows reaction to take place on the form (XII) and not (XIII), viz. 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

The fluoboric acid-catalyzed aza-Diels-Alder reaction of aldimine and Danishefsky s diene proceeds smoothly to afford dihydro-4-pyridones in high yields [90] (Equation 4.16). Unstable aldimines generated from aliphatic aldehydes can be prepared in situ and allowed to react under one-pot reaction conditions. This one-pot Bronsted acid-catalyzed three-component aza-Diels-Alder reaction affords the adducts in good to high yields. 

High-pressure Diels-Alder reaction of 1-methyl-2-(1H)-pyridones having a phenyl group with N-phenylmaleimide [94]... 

---