Heterocycles pyridone

Ultraviolet irradiation of pyridines can prodnce highly strained species that can lead to isomerised pyridines or can be trapped. The three picolines and the three cyano-substituted pyridines constitute photochemical triads irradiation of any isomer, in the vaponr phase at 254 nm, results in the formation of all three isomers. From pyridines and from 2-pyridones 2-azabicyclo[2.2.0]-hexadienes and -hexenones can be obtained in the case of pyridines these are nsnally nnstable and revert thermally to the aromatic heterocycle. Pyridone-derived bicycles are relatively stable, 4-alkoxy- and -acyloxy-pyridones are converted in particnlarly good yields. Irradiation of iV-methyl-2-pyridone in aqueous solution prodnces a mixture of regio- and stereoisomeric 4n pins 4n photo-dimers. ... 

Hydroxy-, Hydroxyall l-, and Aminoall lpyridines. A full discussion of the tautomerism occurring in heterocycles with oxygen and sulfur substituents has been pubUshed (38). Equation 2 shows the tautomerism expected in 2-pyridone (16) and 4-pyridone (38). 

The chemistry of dye intermediates maybe conveniendy divided into the chemistry of carbocycles, such as benzene and naphthalene, and the chemistry of heterocycles, such as pyridones and thiophenes. 

As discussed in Section 4.01.5.2, hydroxyl derivatives of azoles (e.g. 463, 465, 467) are tautomeric with either or both of (i) aromatic carbonyl forms (e.g. 464,468) (as in pyridones), and (ii) alternative non-aromatic carbonyl forms (e.g. 466, 469). In the hydroxy enolic form (e.g. 463, 465, 467) the reactivity of these compounds toward electrophilic reagents is greater than that of the parent heterocycles these are analogs of phenol. 

It is common for names of simple heterocyclic carbonyl derivatives to be contracted, with loss of the -ine ending of the parent name, e.g. pyridone, quinolone, acridone, pyrrolidone, thiazolidone. 

Many heterocyclic compounds exist as mixtures of tautomers. For example, 2-hydroxypyridine exists in equilibrium with 2-pyridone. 

The mechanism of recognition of most supramolecular entities (such as abiotic receptors) is the formation of several hydrogen bonds. Since heterocyclic tautomers possess both strong HBA and HBD properties (see Sections III,G, V,D,2, and VI,G), they are often used for this purpose. For instance, the hydrogen bond network formed by 5,5 -linked bis(2-pyridones) has been used by Dickert to obtain sensors (96BBG1312). 

We do not discuss in detail the cases of tautomerism of heterocycles embedded in supramolecular structures, such as crown ethers, cryptands, and heterophanes, because such tautomerism is similar in most aspects to that displayed by the analogous monocyclic heterocycles. We concentrate here on modifications that can be induced by the macrocyclic cavity. Tire so-called proton-ionizable crown ethers have been discussed in several comprehensive reviews by Bradshaw et al. [90H665 96CSC(1)35 97ACR338, 97JIP221J. Tire compounds considered include tautomerizable compounds such as 4(5)-substituted imidazoles 1///4//-1,2,4-triazoles 3-hydroxy-pyridines and 4-pyridones. 

Nitroenamines and related compottnds have been used for synthesis of a variety of heterocyclic compottnds. Rajappahassummaiized the chemistry of nltroenamines fseeSecdon4.2. Anga and coworkers have developed the synthesis of heterocycles based on the reacdon of nltropytidones or nltropyrimldmone v/ith nucleophiles. For example, 2-subsdntted 3-nltro-pyridmes are obtained by the reacdon of l-methyl-3,5-dinitro-2-pyridones wiih ketones in the presence of ammonia fEq. 10.82. ... 

The Suzuki reaction has been successfully used to introduce new C - C bonds into 2-pyridones [75,83,84]. The use of microwave irradiation in transition-metal-catalyzed transformations is reported to decrease reaction times [52]. Still, there is, to our knowledge, only one example where a microwave-assisted Suzuki reaction has been performed on a quinolin-2(lH)-one or any other 2-pyridone containing heterocycle. Glasnov et al. described a Suzuki reaction of 4-chloro-quinolin-2(lff)-one with phenylboronic acid in presence of a palladium-catalyst under microwave irradiation (Scheme 13) [53]. After screening different conditions to improve the conversion and isolated yield of the desired aryl substituted quinolin-2( lff)-one 47, they found that a combination of palladium acetate and triphenylphosphine as catalyst (0.5 mol %), a 3 1 mixture of 1,2-dimethoxyethane (DME) and water as solvent, triethyl-amine as base, and irradiation for 30 min at 150 °C gave the best result. Crucial for the reaction was the temperature and the amount of water in the... 

This chapter has taken the reader through a number of microwave-assisted methodologies to prepare and further functionalize 2-pyridone containing heterocycles. A survey of inter-, intramolecular-, and pericyclic reactions together with electrophilic, nucleophilic and transition metal mediated methodologies has been exemplified. Still, a number of methods remain to be advanced into microwave-assisted organic synthesis and we hope that the smorgasbord of reactions presented in this chapter will inspire to more successful research in this area. 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

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...

Synthesis of 2-Pyridone Containing Heterocycles Using Conventional Heating... 

The broad range of applications of 2-pyridone containing heterocycles has led to the development of numerous synthetic methods [3,4], which dates back... 

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... 

Hence, microwave irradiation in DMA for 12 min at 120 °C or 30 min at 140 °C, depending on the substrate, resulted in 20 or 21 in 90-96% yields, compared to yields around 50% and a 24 h reaction time for conventional heating. As can be seen in Eq. 2 in Fig. 5, two possibilities exist to connect the heteroaryl bromide part with the five-membered heterocycle (indicated by a and fi. Table 2) that results in a six-membered 2-pyridone ring. Still, a very high selectivity was obtained yielding the 2-pyridones 21, in which the new bond had been introduced at Ca. It should be noted that the obtained structures 20 and 21 represent heterocyclic derivatives of 2-quinolones rather than true 2-quinolones. 

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-... 

The previous sections have described methods to obtain 2-pyridone scaffolds. Both in the construction of new materials and especially in drug design and development, there is a desire to be able to derivatize and optimize the lead structures. In the following sections, some recent developments using MAOS to effectively substitute and derivatize 2-pyridone heterocycles are described. The reaction types described range from electrophilic-, and nucleophilic reactions to transition metal-catalyzed transformations (Fig. 7). To get an overview of how these systems behave, their characteristics imder conventional heating is first described in brevity. 

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. ... 

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>. 

Some heterocyclic amides, in principle similar to those described above, were shown to cyclize in a Michael type reaction to give anellated pyridones in excellent yield 1-1393... 

Michael addition of (benzotriazol-l-yl)acetonitrile 557 to a,[)-unsatu rated ketones followed by heterocyclization provides new means for preparation of 2,4,5-trisubstituted pyridines. The reaction is catalyzed by bases. In the presence of secondary amines, a nucleophilic attack of amine on the CN group in adduct 556 initiates the cyclization to tetrahydropyridine 558 that subsequently eliminates water and benzotriazole to give pyridine 559. Analogously, in the presence of NaOH, pyridone 560 forms, via intermediate 561 (Scheme 88) <1997JOC6210>. 

Linke, S., Kurz,., Lipinski, D., and Gau, W., Annealation reactions of N-heterocycles to condensed pyridones with bridgehead nitrogen, Ann. Chem., 542, 1980. 

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