Pyridone derivs

The condensation of ketones with 3-aminonitriles or S-aminoesters ai cyclization to 4-pyridone derivatives was expanded (717-719). 

Marazano and co-workers have also applied the reactions of tryptamine with various Zincke salts, including 115 (Scheme 8.4.39), in the synthesis of pyridinium salts such as 116. This type of product is useful for further conversion to dihydropyridine or 2-pyridone derivatives. For example, in a different study, Zincke-derived chiral pyridinium salts could be oxidized site-selectively with potassium ferricyanide under basic conditions as a means of chiral 2-pyridone synthesis (117 —> 118, Scheme 8.4.40). 

Synthesis, pharmacology, and molecular modeling of 2-pyridone derivatives as inotropic agents 97F331. 

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]. 

Two new pyridone derivatives (14) and (15) have been prepared by cycloaddition of saccharin pseudochloride (16 R = Cl) with Danishefsky s diene and by treatment of (16 R = Me) with ciimamoyl chloride. The synthesis of two more ting expanded derivatives (17) and (18) via cycloaddition to benzisothiazoles was also described <96T3339>. 

As in the case of Diels-Alder reactions, aqueous aza-Diels-Alder reactions are also catalyzed by various Lewis acids such as lanthanide triflates.113 Lanthanide triflate-catalyzed imino Diels-Alder reactions of imines with dienes or alkenes were developed. Three-component aza-Diels-Alder reactions, starting from aldehyde, aniline, and Danishefsky s diene, took place smoothly under the influence of HBL4 in aqueous media to afford dihydro-4-pyridone derivatives in high yields (Eq. 12.46).114... 

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). 

Heteroatom transfer in metallacyclopentadienes was first developed in the context of cobalt chemistry in the mid-1970s [27]. Cobaltacyclopentadienes were converted into various five-membered heterocyclic compounds such as pyrrole and thiophene, and into six-mem-bered heterocyclic compounds such as pyridine and pyridone derivatives. In the case of zirconacydopentadienes, the heteroatom compound must bear at least two halide substituents, since the Cp2Zr moiety is re-converted to the stable Cp2ZrX2. Indeed, this is the driving force behind the heteroatom transfer of zirconacydopentadienes. 

The 4-hydroxypyridine (or 4-pyridone) derivatives are obtained by the use of ethoxymethylenemalonate and acetoacetate (59NKZ534) or acetylenedicarboxylate (78USP4130649). In analogy to these reactions, cyclizations starting from 5-aminotropolone ethers (83USP4382088) or 2-aminotropones (83USP4381304) were claimed. 

The synthesis of cis-1,4 polymers was also tried by e use of monomers with an s-cis conformation. The solid-state photopolymerization of pyridone derivatives, which is a six-membered cyclic diene amide and is a tautomer of 2-hydroxypyridine, was attempted [100]. Pyridones make hydrogen-bonded cocrystals with a carboxylic acid in the crystalline state. Because the cyclic structure fixes its s-cis conformation, if the polymerization proceeds, a cis-2,5 polymer would be obtained. Actually, however, the photopolymerization did not occur, contrary to our expectation, but [4-1-4] photodimerization proceeded when the carbon-to-carbon distance for the dimerization was small (less than 4 A) [101]. A closer stacking distance of the 2-pyridone moieties might be required for the topochemical polymerization of cychc diene monomers. 

Ciclopirox olamine (Loprox) is a pyridone derivative available for the treatment of cutaneous dermatophyte infections, cutaneous C. albicans infections, and tinea versicolor caused by Malassezia furfur. It interferes with fungal growth by inhibiting macromolecule synthesis. 

Thioisomiinchnones prepared by classical methods (Section 5.1.3) have also been extensively used in [3-1-2] cycloadditions with olefinic dipolarophiles (145-148). In general, the initially formed cycloadducts are isolable. In some instances (Scheme 5.32), they extrude H2S to afford 2-pyridone derivatives of type 88 (148,149). In another example, the double extrusion of H2S and CO occurred to give a pyrrole derivative (150). 

The cyanoenamino ketoester 4 reacts with hydrazines to form the pyridone derivative 5 <99H(50)791>. A -Arylsulfonylamino-2-pyridones have been prepared via the reaction of acetohydrazides with arylidenecyanoacetate derivatives <99JCR(S)6>. 

For ring systems that incorporate a pyridine ring, chemistry and reactivity of pyridone derivatives have been incorporated into Sections 10.06.5-10.06.9, wherever appropriate. For crystalline products, which represent most of the derivatives contained within this chapter, the compounds exist as the pyridone tautomer. 

Reaction of 2-oxopyrido[l,2-a]pyrimidines (33) with /f-oxo esters in dimethylformamide in the presence of l,5-diazabicyclo[4,3,0]non-5-ene at room temperature, or with /Toxo amides in the presence of zinc chloride in boiling ethanol, affords the pyridone derivatives (199). Cleavage of the pyrimidine ring can also be effected with amines.28... 

Three equivalents of FeCl3 are required for the reaction of chalcone 41 j with ethyl cyanoacetate to give a-pyridone derivative 72 (Scheme 8.32) [100]. The reaction is carried out at 140 °C under strongly acidic conditions (FeCl3 dissolved in propionic acid). It proceeds presumably by an initial Michael addition yielding intermediate 73. Excess of iron(III) is required, because this is the oxidizing reagent for the introduction of the second C—C double bond in intermediate 74. 

Scheme 8.32 Iron-mediated synthesis of 2-pyridone derivatives.

Among the possible cyclohexanone derivatives, the choice fell on 4-substituted ones (which would not lead to enantiometric mixtures) and to substituents that would yield convenient lipophilicities <2006BMC6368, 2006BML5542, 2007BML1260>. A few such compounds are shown below, and they are derived from 4-substituted cyclohexanones or from 4-pyridone derivatives (Scheme 86). 

Trifluoromethyl-2-pyridone derivative (13) can be prepared in modest yield using polyphosphoric acid (PPA) (Scheme 9) <95JCR(S)476>. 

Compounds (21) and (23) have been synthesized from ethyl azidoacetate and thiophene-2,3-dialdehyde (80). Blocking one formyl group ultimately led to the corresponding pyridone derivatives. Overall yields are approximately 40% for each reaction sequence (Scheme 29) <76CJC1066>. 

Fused pyranone derivatives are converted into the corresponding fused pyridone derivatives by the action of an appropriate amine. Thus, heterocycle (308) yields naphthyridone (417) in moderate yield when reacted with ethanolic ammonia solution <62JCS4528>. Compound (418) and tryptamine gives the indole derivative (419) (82% yield) <76H(4)247>, which was used in the synthesis of nauclefine (420), and compound (421) and tryptamine gave heterocycle (422) (80% yield) <75H(3)627>, which was used in the synthesis of angustine (423). 

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