Pyridones fused

Bicyclic 2-pyridones fused over the nitrogen is another important heterocyclic scaffold. In the quest towards the total synthesis of Camptothecin, Danishefsky and co-workers developed a method where a vinylogous urethane was reacted with 1,3-dicarboxymethoxyallene generated in situ from dimethyl 3-chloroglutaconate to a bicyclic 2-pyridone intermediate [31-34]. This method has later been successfully applied in the synthesis of other... 

Scheme 4 Synthesis of bicyclic 2-pyridones fused over the nitrogen...

The reaction of 2- and 4-pyridones, fused as part of a variety of 6,6-heterocyclic systems, is a recurring theme in many publications for example, conversion of diethyl 4-oxo-l,5,7,8-tetrahydro-4//-[l,6]naphthyridine 3,6-dicarboxy-late into the 4-chloro derivative <2004BML3441>, and others will appear through the chapter. 

Figure 8.9 Quinolinone (pyridone) fused-ring SARMs from Ligand Pharmaceuticals, Inc.

In the development of pyridone fused acridines, Kennedy et al. used a sulfoxide-based route to produce 3,7-dimethyl-5-methoxy-l-phenylthio-... 

Thieno[3,4-< ]-l-thia-2,4-diazine 1,1-dioxides 281 (R = alkyl R = H, Cl, F) are inhibitors of HIV-1 reverse transcriptase and have significant anti-HIV-1 activity <1998AAC618>. Pyridone-fused 3,4-dihydro-2//-l-thia-2,4-diazine... 

The reaction of phenol-linked 1,6-diyne with isocyanate afforded 2-pyridone-fused benzofuran in good yield as a single regioisomer (Scheme 4.76) [48]. 

The use of microwave irradiation for this reaction, compared to conventional thermal heating, was investigated. Chloroform used as solvent under the conventional heating did only allow a temperature of 60 °C and a direct comparison between the two methods is therefore somewhat unfair imder these circumstances. Nevertheless, the microwave-assisted method is attractive and proved useful for both primary and secondary amines resulting in highly substituted pyrazolo ring-fused pyridones 40 in 68-86% yields within only 10 min. 

Fig. 11 A tentative mechanism for the reagent-free decarboxylation of ring-fused 2-pyridones obtained under MAOS conditions...

Pemberton N, Chorell E, Almqvist F (2006) Microwave-Assisted Synthesis and Functionalization of 2-Pyridones, 2-Quinolones and Other Ring-Fused 2-Pyridones. T. 1-30... 

Keywords 2-Pyridone 2-quinolone Ring-fused 2-pyridone... 

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...

Scheme 3 Examples of Dieckmann-type condensation (a) and [2 + 2 + 2] cycloaddition (b) leading to functionalized and ring-fused 2-pyridones...

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

Ring-fused 2-pyridone structures where the additional ring is fused over the nitrogen will be covered in this section. Other ring-fused systems can be obtained simply by using suitable cychc starting materials or by conducting intramolecular reactions, examples for the preparation of such systems can be found in the papers discussed in Sect. 2.2 [42,43]. 

This method has been extended to include imines other than A -thia-zolines, hence enabling the synthesis of multi ring-fused 2-pyridones (28,30, and 33, Scheme 8). Thus, by reacting dihydroisoquinoUnes 27 or /1-carboUnes 29 with acyl Meldrum s acid derivatives 24, a set of new ring-fused heterocycles was prepared in moderate to excellent yields (a and b. Scheme 8). These systems were prepared by using trifluoro acetic acid (TFA) as a proton source instead of solutions saturated with HCl (g). The switch of acid proved to be advantageous since it reduced the formation of by-products and increased the isolated yields. From a practical point of view, TFA is also su-... 

Scheme 9 Synthesis of ring-fused 2-pyridones via aminopropenoates using both solution-phase and solid-phase conditions...

The site of dihydroxylation in heterocycles depends on the nature of the heteroaromatic system (Scheme 9.31) usually, electron-rich heterocycles like thiophene are readily biooxidized but give conformationally labile products, vhich may undergo concomitant sulfoxidation [241]. Electron deficient systems are not accepted only pyridone derivatives give corresponding cis-diols [242]. Such a differentiated behavior is also observed for benzo-fused compounds biotransformation of benzo[b] thiophene gives dihydroxylation at the heterocyclic core as major product, while quinoline and other electron-poor systems are oxidized at the homoaromatic core, predominantly [243,244]. 

For most simple phenols this equilibrium lies well to the side of the phenol, since only on that side is there aromaticity. For phenol itself, there is no evidence for the existence of the keto form. However, the keto form becomes important and may predominate (1) where certain groups, such as a second OH group or an N=0 group, are present (2) in systems of fused aromatic rings and (3) in heterocyclic systems. In many heterocyclic compounds in the liquid phase or in solution, the keto form is more stable, although in the vapor phase the positions of many of these equilibria are reversed. For example, in the equilibrium between 4-pyridone (118) and 4-hydroxypyridine (119), 118 is the only form detectable in ethanolic solution, while 119 predominates in the vapor phase. " In other heterocycles, the hydroxy-form predominates. 2-Hydroxypyridone (120) and pyridone-2-thiol (122) are in equilibrium with their tautomers, 121 and 123, respectively. In both cases, the most stable form is the hydroxy tautomer, 120 and 122. ... 

Scheme 6.236 /V-Acyliminium ion-based cyclizations leading to fused pyridones.

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