Pyridone, formation

A series of bromoalkyl sulfonates was therefore needed to form the N-alkyl sulfonated 2-pyridones. Formation of bromoalkyl sulfonates has not been described extensively in the literature (19). 

Pyridone formation from the condensation of cyanoacetic ester with diketone in the presence of ammonia. 

When 4-alkylated pyridinium salts are exposed to ferricyanide, oxidation at the 4-a-carbon atom competes with pyridone formation and all possible oxidation products 104-109 are produced as complex reaction mixtures. In the case of complete substitution of the 4-a-H atoms (110), pyridones 111 result as unique products in almost quantitative yields. 

Pyridone Formation by Alkaline Ferricyanide Oxidation or 3-Substituted Pyridinium Salts... 

The number of these sites, as measured by Fink (246, 262), vary between 1.2 and 1.8 X 1013/cm2. This value nicely coincides with the number of sites that convert pyridine to the pyridone species (see Section IV.D.l). Thus, the X-sites certainly contain reactive and strongly basic OH groups and they may be identical with the sites responsible for the pyridone formation and the hydrolysis of ketones and nitriles. The highest-frequency OH group vanishes preferentially in all these surface reactions. Because the X-sites are Al-OH pair sites created by the formation of oxide vacancies in the immediate vicinity of the reactive OH groups, the above result lends some support to the interpretation of Dunken and Fink (116) that the reactive OH groups (3800 cm-1) are surrounded by four oxide vacancies rather than Peri s (120) assumption that they are surrounded by four O2- ions (see Section IV.A.l). Rosynek (267a) thinks that a free carbonate ion also exists on the surface and contributes to the band at 1480 cm-1. 

The presence of electron withdrawing groups at the a position (R3) of the acrylate derivative increases the reactivity of the reagent toward conjugate addition, while substituents in the ( position (R4) tend to provide steric constraints that hinder carbon-carbon bond formation (Scheme 3). Of the various acrylate derivatives employed in these reactions, the most frequently used have electron withdrawing functionality such as a carboxylic acid, amide, ester, or nitrile group or a combination of these. Direct pyridone formation can be achieved primarily through the use of either a,(J acetylenic esters or acrylate derivatives with P substituents (Y = SR, OR, NR2) that eliminate under the reaction conditions. 

Other methods for one-step pyridone formation include aza-annulation with either 57 or 86. The reaction of tetralone 83 and ammonia generated an imine that underwent aza-annulation with 57 to give 84, which was used as a key intermediate in the synthesis of derivatives of antitumor and antiviral alkaloid fagaronine (eq. 22).35 Reagent 86 converted 85 to the corresponding pyridone 87 by aza-annulation and subsequent elimination of MeSH (eq. 23).6 Reaction of 86 with other aryl alkyl ketones, such as a-tetralone and 2-acetyl thiophene, only produced yields of 28% and 36%, respectively. 

When the reactivity of hydrazine imine 218 was investigated through aza-annulation with 205, pyridone formation also occurred with the least substituted nitrogen to form 219 (eq. 49).72 Hydrolysis of 219 led to the formation of 220 in good yield. 

Pyridone formation could also be accomplished by reaction of 208 with 86 in the presence of K2CO3 to yield 265 upon elimination of MeSH (eq. 55).6 Alternatively, reaction of 267 with fi-enamino ester 266 led to the formation of the pyridone 268 in good yield (eq. 56).78... 

An interesting acrylate derivative, 277/278, was also used for pyridone formation (eq. 57).81 Treatment of 221 with 277/278 resulted in formation of the corresponding a-acyl substituted pyridone 279. 

Pyridone formation was achieved through a two step process, by sequential conjugate addition and cyclization (eq. 60). 6 Conjugate addition was accomplished through extensive heating of 296 with 57, and cyclization of 298 to 299 was facilitated by the subsequent addition of NaH. 

Formation of the corresponding a-substituted 5-lactams was accomplished by reaction of 296 with itaconic anhydride (316) to give dihydropyridone 317, 6 while pyridone formation was accomplished by aza-annulation with diester 47 to generate pyridone 318 (eq. 62).87... 

Scheme 16 Late stage 2-pyridone formation in the total synthesis of cytosine 54.

Treatment of 2-, 3-, and 4-substituted pyridine-1-oxides (XtJ-360) with 2-bromopyridine gives l-(substituted-2-pyridyl)-2-pyridones, usually in low yields, 2,3 -dipyridyl ethers, and 2-pyridones (see also Chapter IV). In several instances, the 7V-(2-pyridyl)-2-pyridones have been hydrolyzed to aminopyridine with aqueous sodium hydroxide. Electron donating substituents, particularly at the 3-position, favor, and electron withdrawing groups on the 2- or 4-position prevent, pyridyl-2-pyridone formation. 

To close, it is worth mentioning the work of Bonaga et al. regarding the formation of macrocycles via cobalt-catalyzed pyridine or pyridone formation (Scheme 1.30) [3k,46c and d,51]. Using long-tethered diynes, only two pyridinophanes are actually... 

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