Pyrones, Diels-Alder, addition reactions

Pyrones, which are the ring-oxygen equivalents of pyridones, are simply a- and y-hydroxy-pyrylium salts from which an 0-proton has been removed. There is little to recommend that 2- and 4-pyrones be viewed as aromatic they are perhaps best seen as cyclic unsaturated lactones and cyclic p-oxy-a,P-unsaturated-ketones, respectively, for example 2-pyrones are hydrolysed by alkali, just like simpler esters (lactones). It is instructive that, whereas the pyrones are converted into pyridones by reaction with amines or ammonia, the reverse is not the case - pyridones are not transformed into pyrones by water or hydroxide. Some electrophilic C-substitutions are known for pyrones and benzopyrenes, the oxygen guiding the electrophile ortho or para, however there is a tendency for electrophihe addition to the C-C double bond of the heterocyclic ring, again reflecting their non-aromatic nature. Easy Diels-Alder additions to 2-pyrones are further evidence for diene, rather than aromatic, character. 

Pyrone reacts readily as a diene in Diels-Alder additions, but the initial adduct often loses carbon dioxide, generating a second diene that then adds a second mole of the dienophile reaction with maleic anhydride, shown below, is typical - a monoadduct can be isolated, which under more vigorous conditions loses carbon dioxide and undergoes a second addition. When the dienophile is an alkyne, methyl propiolate for example, benzenoid products result from the expulsion of carbon dioxide. Primary adducts, which have not lost carbon dioxide, can be obtained from reactions conducted at lower temperatures under very high pressure or in the presence of lanthanide catalysts. A useful example is the reaction of 2-pyrone and substituted derivatives with alkynyl boronates leading to aryl boronates 2-pyrone itself reacts in 86% yield with trimethylsilylethynyl boronate. ... 

The chemistry of compound 115, prepared from the reaction of hexafluoropropene with sulfur and potassium fluoride in DMF, is similar to 110. Diels-Alder addition of 115 to vinyl acetate was accompanied by loss of acetic acid to give the parent pyrone 116 (R=H). The reaction of 115 with butyl- and phenylacetylenes gave 116 (R=Bu, Ph). Addition of 115 to the C=C bond of ketene was accompanied by a 1,3 hydrogen shift to produce the hydroxypyrone and its acetylated product 117. In the presence of a weak base such as dimethylacetamide or dimethylpropionamide, 115 underwent a self-condensation reaction with loss of CO2 to give the pyrone 118 this reaction was not observed for 110 [43] (Scheme 36). 

The 2-pyrones can behave as dienes or dienophiles depending on the nature of their reaction partners. 3-Carbomethoxy-2-pyrone (84) underwent inverse Diels-Alder reaction with several vinylethers under lanthanide shift reagent-catalysis [84] (Equation 3.28). The use of strong traditional Lewis acids was precluded because of the sensitivity of the cycloadducts toward decarboxylation. It is noteworthy that whereas Yb(OTf)j does not catalyze the cycloaddition of 84 with enolethers, the addition of (R)-BINOL generates a new active ytterbium catalyst which promotes the reactions with a moderate to good level of enantio selection [85]. 

Treatment of bicyclic lactones 66, derived from Diels-Alder reaction of 3-carboxy-2-pyrone under standard radical conditions using (TMSlsSiH, leads to bridged lactones 67, which can smoothly be converted to bicyclo[3.3.0]-lactones 68 (Scheme 10). For X = CHaOMe, this cascade of rearrangements took place in a 78% overall yield, providing 68 in diastereomerically pure form. Three additional steps provided a novel route toward Corey s lactone 69. 

Okamura and coworkers151 studied the base catalyzed Diels-Alder reactions between 3-hydroxy-2-pyrone (224) and chiral l,3-oxazolidin-2-one based acrylate derivatives. Catalysis of the reaction between 224 and 225 by triethylamine gave fair to good de values, somewhat dependent on the solvent system used (equation 63, Table 7). Addition of 5% of water to the solvent isopropanol, for example, increased the de of the endo adduct 226 substantially. When the amount of water was increased, however, the triethylamine catalyzed reaction became less endo and diastereofacially selective, a small amount of exo 227 being obtained. Replacing triethylamine by the chiral base cinchonidine also improved the de, but now independently of the solvent system used. 

These phenomena can be illustrated by the cycloaddition reactions of fulvenes with electron-deficient a-pyrones. In general, the Diels-Alder reactions of electron-deficient dienes such as 458 with 6-alkyl substituted fulvenes favor addition across one of the endocyclic... 

Another enantioselective synthesis of longifolene, shown in Scheme 13.27, uses an intramolecular Diels-Alder reaction as a key step. The alcohol intermediate is resolved in sequence B by formation and separation of a menthyl carbonate. After oxidation, the pyrone ring is introduced by y addition of the ester enolate of methyl 3-methylbutenoate. 

As shown in Figure 41, Kobayashi s catalysis was also effective for asymmetric aza Diels-Alder reactions, and in this case 2.4 equiv. of DBU was used instead of 1,3,5-trimethylpiperidine. 2,6-Di-/m-butyl-4-methylpyridine appeared to be most effective additive 95 Mark6 et al. have reported that these catalysts are also effective for asymmetric inverse electron-demand Diels-Alder reactions of 2-pyrone... 

Subsequently, Posner published the completely regioselective and highly stereoselective cyclo additions of racemic 3-(p-tolylsulfinyl)-2-pyrone (141) (Scheme 70) with 1,1-dimethoxyethylene [133],vinylether,and vinylthioethers [134]. With the first dienophile, the best diastereoselectivity (an 88 12 ratio of the two endo-adducts) was achieved at room temperature in toluene or hexane as the solvent (48 h). A 10 1 endo/exo mixture of cycloadducts was obtained with vinyl-ether in the presence of ZnBr2 as the catalyst, whereas a total endo selectivity was observed in reactions of 141 with vinylthioethers [134] conducted under high pressures. The bridged bicyclic lactone cycloadducts 142 have been used as versatile synthons in the synthesis of shikimic acid derivatives. Although enantio-merically pure samples of compound 141 could be obtained [134] it was not used as a starting material for asymmetric Diels-Alder reactions (the low yield of (S)-141 precluded this). 

A dihydro-derivative (4) of strobiline (M+ 193) was also obtained. In the mass spectrometer, the pyrrolidine ring is opened to give fragments of m/z 165 and 164 (base peak), followed by a retro-Diels-Alder reaction to give fragments of m/z 137 and 136, respectively. The location of the two additional hydrogen atoms was deduced from the relative u.v. extinctions of (3) and (4), which is consistent with the dihydro-y-pyrone skeleton in the latter compound. This was confirmed by 3H n.m.r. spectra that showed no vinylic protons. 

Diels-Alder reactions. This pyrone does not react with moderately reactive dienophiles (ethyl acrylate), but does react with reactive symmetrical alkenes to give adducts resulting from addition of 2 equiv. of the dienophile with loss of CO2 from the primary cycloadduct. It also reacts with acetylenic dienophiles to form m-tliincthoxyarencs. 

Diels-Alder reactions of thiete 1,1-dioxides occur readily as exemplified by the syntheses of 151 ° and 152. Adducts of thiete 1,1-dioxide with tetraphenylcyclopentadienone or a-pyrone ° are thermally unstable. Thiete 1,1-dioxides also undergo 1,3-dipolar additions with diazoalkanes, (e.g., the formation of 153 from which the strained bicyclic thietane sulfone 154 is obtained) " nitrile oxides, and cycloadditions with the MA -dimethylenamine of isobutyraldehyde (e.g., the formation of 155). ° ... 

Ditertiary phosphane complexes of nickel were found to be effective in the formation of pyrone 108 by cyclocotrimerization of alkynes with carbon dioxide. The formation of the nickelacyclopentadiene 105 from two moles of alkyne and a nickel complex is followed by CO2 insertion into a nickel-carbon bond to give the oxanickelacycloheptadienone 106, which then eliminates 108 with intramolecular C—O coupling. Another route involving [4 + 2] cycloadditions of 105 with CO2 in a Diels - Alder reaction to give 107 cannot be ruled out but is less probable because CO2 does not undergo [4 + 2] cycloaddition with dienes. Addition of another alkyne to 105 results in the formation of a benzene derivative (Scheme 38). ... 

Based on the experiences on the Diels-Alder reaction of 2-pyrones [20], Deng et al. have investigated the stereoselective Diels-Alder reaction of 2-pyrones and a,(3-unsaturated ketones. They also found that primary amines lo and lp derived from quinine and quinidine, respectively, werethe optimal iminium catalysts (5 mol%). The acid additive has a crucial effect on the efficiency of the reaction. TFA (20 mol%) gave the best results, and the Michael reaction, as a side reaction, could also be prohibited. 

Danishefsky and coworkers have synthesized the algylcon of avermectin based on a hetero Diels-Alder reaction between trimethylsilyloxy diene (8) and chiral aldehyde (175 Scheme 49). The pyrone must come from an anti Cram-Felkin addition, so MgBr2 is used as the catalyst in this reaction. The cycloaddition reaction gives the expected product (176) and the CF diastereomer in a ratio of 3 1. The target compound (178) is obtained after a series of reactions outlined in Scheme 49. - ... 

In the second hetero Diels-Alder reaction an anti pyrone derived from Cram-Felkin addition was needed, so trimethylsilyloxy diene (14) was allowed to react with aldehyde (190) in CH2CI2 using BF.vOEt2 as the catalyst. Under these conditions, anti-CF pyrone (191) is obtained in 57% yield, accompanied by 13% of the syn-CF pyrone. Through further manipulations compound (192), a key intermediate in the Kishi synthesis of the ansa bridge of rifamycin S, was obtained. 

Although the bicycloadducts 2 resulting from the Diels-Alder reaction of 2-pyrones and alkenes are generally more stable than the diene bicycloadducts 7 formed from alkyne dienophiles, at elevated temperatures they may still undergo CO2 extrusion to form cyclo-hexadienes 3. These cyclohexadienes may themselves undergo elimination of HX, either spontaneously or after the addition of a base to the reaction mixture, to yield aromatic products 4. Many examples of this reaction type are shown in the 1992 review, and more examples may be found in the carbazole and indole references. ... 

Bromo-2-pyrone. Based on literature precedent and also on the C NMR chemical shift data in Table 1, our expectation was that 3-bromo-2-pyrone (55) would be unexciting as a diene in Diels-Alder reactions. We were pleasantly surprised to find that pyrone 55 undergoes [4+2] cycloadditions with both electron-rich and electron-poor dienophiles under relatively mild reaction conditions. It has the additional advantage of being considerably more stable than 2-pyrone. The bicyclic lactone adducts formed typically undergo reductive debromination, therefore making 3-bromo-2-pyrone a synthetic equivalent of 2-pyrone. 

An intermolecular Diels-Alder reaction of 3,4-pyridyne has been used in a short synthesis of the important anticancer alkaloid eUipticine. In this case the diene is an a-pyrone the initial Diels-Alder adduct is not isolated since it spontaneously aromatizes by loss of carbon dioxide. Unfortunately, the Diels-Alder reaction is not regioselective and an equal amount of the product arising from the alternative direction of addition to 3,4-pyridyne is formed (Scheme 7.35). 

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