Applications 2-pyridones

Posner G. H. Stereocontrolled Synthesis of Functionalized Cyclohexenes Via Diels-Alder Cycloadditions of 2-Pyrones and 2-Pyridones-Applications to Synthesis of Physiologically Active Compounds in Stereocontrolled Org. Synth. 1994 177, Ed. Trost B. M., Pb. Blackwell Oxford... 

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...

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

Water-Tracing Compounds. Another application of these fluorescent pyridones has been the development of a series of coaipounds useful as ground-water tracers. Smart and Laidlaw have outlined several qualities desirable in fluorescent water-tracing compounds (.18). 

Wetai Ion Analysis. We have reported a sensitive trace-metal analysis based upon HPLC separation of p-aminophenyl EDTA chelates and fluorescence detection by postcolumn reaction with fluorescamine (23). An application of the pyridone chemistry already discussed leads to a fluorescent-labeled EDTA (VIII). 

Since 2-pyridone (24a, Table 3) exists as an equilibrium mixture with 2-hydroxy-pyridine (25a)14), it is difficult to isolate 24a in a pure state. However, the complexation method using inclusion hosts is applicable for the isolation of keto-form 24a in a pure state. For example, 24a was isolated by inclusion complexation (1 2 complexes) with 1 (26a) (Table 3) and with 3 (27a) (mp 151-153 °C), respectively. Both 26a and 27a do not contain the enol form (25a). The structure of 26a was studied by X-ray crystal analysis (Figs. 7, 8)12>. Inclusion of the keto-form is understandable, because 1 and 3 form more stable hydrogen bonds with the carbonyl oxygen of the... 

The freeze of the equilibrium by complexation with 1 is applicable to various 2-pyridone derivatives such as those summarized in Table 3 l5). IR spectra show that all complexes consist of the keto-form only (24). 

In a recent review [83], the present authors discussed the tautomeric equilibria of 2-hydroxypyridine/2-pyridone and the 5-(2//)-isoxazolone system in considerable detail, focusing on the application of several different continuum solvation models. The following presentation will be somewhat more broad in terms of the different equilibria discussed and will not recapitulate all of the analysis previously presented for the above two systems. 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

The British usage is less likely to lead to misunderstanding and is also more consistent. However, exceptions to it are made, especially in the case of contracted trivial names, where its application would result in lack of clarity or of euphony, e.g., 8-quinolyl, 2-pyridone, and 1-naphthoic acid are used rather than quinol-8-yl, pyrid-2-one, and naphth-l-oic acid. 

The aza-Diels-Alder reaction of Danishefsky s diene with imines provides a convenient method for the synthesis of 2-substituted 2,3-dihydro-4-pyridones, a compound class that has important synthetic applications. Kobayashi and co-workers have studied the reaction in detail using ytterbium (III) triflate as the Lewis acid30. Although the reaction is often run at low temperature (—78°C to 0°C) for a number of hours, we have found that the reaction also worked well at elevated temperatures (150°C) in the microwave for a few minutes (J. Westman and A. Hurynowics, unpublished results) (see Scheme 5.15). The imines could either be preformed prior to the addition of the Danishefsky s diene or the reaction could be performed as a multi-component protocol, where all components were added at once. 

A convenient one-step conversion of moderately activated nitroarenes to phenols was achieved in DMSO via nucleophilic nitrite displacement by the anion of an aldoxime.153 TTie resulting O-arylaldox-ime is rapidly cleaved to the phenol derivative under the reaction conditions. The reaction is also applicable to activated fluorides and even to 2-chloropyridine which, at 110 °C, is converted to 2-pyridone in 72% yield.153 A somewhat related process concerns the synthesis, in 82-92% yield, of 4-alkoxybenzoni-triles (45 R = Me, CH2-oxirane, CHrfh, CHMeCTfcMe from O-alkyl-4-nitrobenzaldoximes (44) via hydride-induced elimination of the alkoxide followed by alkoxy denitration (Scheme 17).154... 

With regard to heterocyclic compounds as coupling components, the importance of the formerly widespread pyrazolone-, aminopyrazole-, and 4-hydroxy -quinolone-based yellow azo dyes has greatly diminished with the advent of the tinctorially superior and therefore more economical pyridone azo dyes. Only a few examples have survived and then only for special applications such as for dyeing of acetate fibers. Examples are C.I. Disperse Orange 56 and C.I. Disperse Yellow5. (for structure, see Section 3.2.5). 

Since photochemical reactions in inclusion compounds have been described in one chapter of the previous book [1], enantioselective (3-lactam formation reactions are summarized in this present chapter as a typical application of the inclusion technique for enantioselective photosynthesis. In addition, as a representative enantioselective single-crystal-to-single-crystal photoreaction, the photodimerization reactions of coumarin and thiocoumarin in their inclusion compound with a chiral host are also described. Furthermore, a host-catalyzed photodimerization reaction of chalcone and 2-pyridone in the solid state is also added to this chapter as a unique example of the application of inclusion techniques to selective photoreaction. 

S. M. Sieburth in Advances in Gycloaddition. The Inter- and Intra-Molecular [4+4]-Photocycloaddition of 2-Pyridones and Its Applications to Natural Product Synthesis , M. Harmata, Ed. Jai Press, Greenwich, CT, 1999, vol. 5, p. 85. 

Pyridine jV-oxides undergo isomerism to the 2-pyridone when heated under reflux in acetic anhydride. In a recent application of this methodology, pyridine iV-oxide 113 was treated with acetic anhydride followed by sodium methoxide to give 6-hydroxypyridine 114 in 60% yield <2002T6951> (Equation 79). 3-Acetylpyridine Ar-oxide can be converted to the 2-pyridone under similar conditions in 28% yield <2001T8841>. 

In a novel application of 2-azetidinanes, the ready availability of chiral versions enables their reductive ring opening and subsequent functional group manipulation to give chiral versions of 2-pyridones in excellent yields (Scheme 117) <2003T6445>. 

Assuming that the general methodology in Scheme 62 would be applicable, catechol precursors were required for the C-4 pyridone substituents of 5 and 6. This led (using analogies to the catechol cleavages illustrated in Schemes 4 and 5) to a requirement for boronic acids 178 and 179 for use in the Suzuki cross-coupling step (Scheme 64). 

CONTENTS The Synthesis of Seven-Membered-Rings General Strategies and the Design and Development of a New Class of Cycloaddition Reactions, Paul A. Wender and Jennifer A. Love. Recent Advances in Diels -Alder Cycloadditions of 2-Pyrones, Benjamin T. Woodard and Gary H. Posner. The Inter- and Intramolecular [4 + 4] Photocycloaddition of 2-Pyridones and Its Application to Natural Product Synthesis, Scott McN. Sieburth. 3 + 4 Annulations Between Rhodi- J s... 

Sieburth S McN. The inter- and intramolecular [4+4] photocycloaddition of 2-pyridones and its application to natural product synthesis. In Advances of Cycloaddition. Harmata M, ed. Greenwich, CT JAI, 1999 85-118. 

Recently, many investigations have been carried out on the [4 + 4] photocycloaddition of 2-pyridones and its application to organic synthesis. Although the studied reactions involved only racemic materials, high diastereoselectivities have been obtained with chiral substrates. This makes this type of cycloaddition very promising for asymmetric synthesis [93]. 

Of lesser relevance to this discussion are halogenation methods involving the modification of the carbon skeleton (synthesis and degradation). The Hunsdiecker reaction, as applied to certain heterocyclic acids, has had limited application for the synthesis of halogen derivatives. The preparation of 3-bromo-4,6-dimethyl-2-pyridone from the silver salt of the respective 3-carboxylic acid by treatment with bromine in carbon tetrachloride is a rare example of success.13 The interaction of carbenes with heterocycles also has been employed infrequently, but recent advances in carbene generation may reactivate this approach.14 The Ciamician-Dennstedt ring expansion of pyrrole to / -halopyridines is a case in point18 [Eq. (4)] ... 

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