Substituted 2-Pyridones

2- pyridones indicate the positional reactivity order 3 5 4 6, regardless of the location of the substituents (68CCC394). 

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When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

Table 3 Highly substituted 2-pyridones were aminomethylated by utilizing a microwave-assisted Mannich reaction...

Halogen-substituted 2-pyridones are key intermediates for further metal-catalyzed coupling reactions and the halogenation of these scaffolds has already been described in previous sections. In the following section, a variety of C - C and C - N cross-coupling reactions under microwave-assisted conditions are described with some illustrative examples. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

Fig. 9 Examples of Buchwald-Hartwig amination of bromo-pyridines and subsequent hydrogenolysis leading to amino-substituted 2-pyridones...

Due to the importance of substituted 2-pyridones, many preparative methods have been reported (see Sect. 2.1), and some of these, but for from all, have been further developed into methods suitable for microwave-assisted organic synthesis (MAOS). Here we describe mainly methods performed with instruments specially designed for MAOS, thus excluding synthesis per-... 

Fig. 1 Heterocycles bearing a 2-pyridone moiety with wide range of medicinal applications. Amrinone WIN 40680 1 is a cardiotonic agent for the treatment of heart failure. ZAR-NESTRA 2 is a selective farnesyl protein inhibitor and NP048 3 is a pilicide with novel antibacterial properties. The 2-pyridones 4, 5 and 6 are schematic representations of the three categories of 2-pyridones that wiU be covered in this chapter i.e., substituted 2-pyridones 4, 2-quinolones 5 and other ring-fused 2-pyridones 6...

M-substituted 2-pyridones can be prepared by N-alkylation, under basic conditions (pfCa of the amide proton is 11). The resulting anion can then react on either nitrogen or oxygen depending on the conditions employed [24-27]. Also, several direct methods for the construction of N-substituted 2-pyridones have been reported. Two such examples can be seen in Scheme 3 where the first example (a) is an intramolecular Dieckmann-type condensation [28] and the second (b) is a metal-mediated [2 -I- 2 + 2] reaction between alkynes with isocyanates [29,30]. 

Fig. 3 Tentative mechanism for the formation of substituted 2-pyridones in the reaction between enaminones and methylene-activated nitriles...

The availability of functionalized 2(lH)-pyrazinone in combination with the use of microwave accelerated solid-phase chemistry constitutes a sohd foundation for generating large libraries of compoimds suitable for medicinal chemistry. The authors have also shown that the scaffold can be further functionalized using the principles of cUck-chemistry , thereby paving the way towards highly substituted 2-pyridone structures [45-47]. 

Microwave-Assisted Synthesis of Ring-Fused /V-Substituted 2-Pyridones... 

Pyridones have not been considered previously because the reaction site can undergo resonance effects involving more than one type of interaction. Localized effects, assuming they are field effects, will not be affected. If the localized effect were an inductive effect, which seems very unlikely, then there would be two paths to the reaction site. Consider the pyridones for which data are available. Three sets are extant. They are the 3-substituted 4-pyridones, 33 the 5-substituted 2-pyridones, 34 and the 3-substituted 2-pyridones, 35. In each of these systems, the substituent is conjugated with the nitrogen atom by one path and in... 

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

The Kappe group has described a multicomponent, one-pot, two-step pathway to 3,5,6-substituted 2-pyridones (Scheme 6.229) [410], In the first step, equimolar mix-... 

A non-dissociative mechanism for interconversion of the tautomers of 6-substituted-2-pyridones (116) has been found (Bensaude et al., 1977). In... 

Neo AG, Carrillo RM, Barriga S, Moman E, Marcaccini S, Marcos CE (2007) Multicomponent synthesis of highly substituted 2-pyridones. Synlett 2 327-329... 

Studies on sulfur-substituted 2-pyridones have shown (99M545) that unsaturated phenylthio ketones 90 can yield aminopyrans 91 with MN 27a, while enaminone (X = NMe2) gives 2-pyridones 92 (Scheme 26). 

Substituted 2-pyridones were obtained from enamines with appropriate functional groups. Phenyl isocyanates and phenyl isothiocyanates... 

As expected, macroscale reduction gave products corresponding to those from reduction of the parent pyridine, that is, piperideines and piperidines. Electrolysis of a series of N-alkyl-substituted 2-pyridones, for example N-methyl-(79), yielded a mixture of A-methylpiperidine and -piperideine 80.126 Reduction of the methyl ether of 2-pyridone gave piperidine only.127... 

In a manner similar to N-substituted 2-pyridones, 2-methylene analogs such as 74, were found to react stereoselectively with various dienophiles to give endo adducts 75 [79,80]. This approach allowed for the synthesis of isoquinuclidines having a carbon side chain at the 3-position ... 

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