5-Bromo-2-pyrone

The base-promoted ring contraction of 3-bromo-2-pyrones to 2-furoic acids cf. Scheme llOd) is a well exemplified reaction 01CB1992,69JCS(C)1950,73JCS(P1)1130> which has also been applied to the obtention of benzofuran-2-carboxylic acids frorn 3-bromocoumarins 08CB830,70KGS(S2)166), Similar base treatment of 3-amino-2-pyrones provides pyrrole-2-carboxylic acids (Scheme IlOe) 75JHC129). 

Because of their low reactivity, a Diels-Alder reaction of 2-pyrones usually requires such a high temperature that the initial bicyclic lactone adducts often undergo cycloreversion [30,33] with loss of CO2. In some cases this limitation has been overcome by carrying out the reaction imder high pressure conditions. Posner and coworkers have shown [34-36] that the presence of a tolylthio group or a bromine atom at the 3- or 5-position increases the reactivity of 2-pyrones. 3-Bromo-2-pyrone (35) (Scheme 2.15), as well as its regioisomer 5-bromo (36)... 

Bromo-2-pyrones and 3-bromocoumarins give furan- and benzofuran-2-carboxylic acids by ring fission and subsequent closure, e.g. (228) — (229) (116) or (117) — (230). Pyrone rings are opened by aqueous acid in some cases, probably by successive protonation and attack of a water molecule, e.g. dehydroacetic acid (231) gives (233) which immediately forms (232) or (234) with HC1 or H2S04, respectively. 

Bromo-2-pyrone sublimes in high vacuum at relatively low temperature. Thus, the material should not be subjected to high vacuum for long periods of time. 

The procedure described above allows a more efficient and convenient synthesis of 3-bromo-2-pyrone than previously described in the literature.5 This procedure avoids making and handling 2-pyrone, a sensitive compound. The major by-product of the reaction is 5-bromo-2-pyrone. We postulate that the formation of this by-product results from prototropic migration in basic medium followed by elimination of HBr (Scheme 1). 

Bromo-2-pyrone is not only a valuable precursor for the synthesis of various 3-substituted 2-pyrones,7 but it is also a reactive unsymmetrical diene.8 3-Bromo-2-pyrone undergoes Diels-Alder cycloadditions with a regioselectivity and stereoselectivity that is superior to that of 2-pyrone. Furthermore, 3-bromo-2-pyrone is a chameleon (i.e., ambiphilic) dienophile, undergoing cycloaddition to both electron deficient and electron rich dienophiles. The cycloadducts of bromopyrone with dienophiles are isolable and are useful in the synthesis of diastereomerically pure cyclohexene carboxylates (Scheme 2).8... 

Scheme 4. Diels-Alder cycloadditions of 3-bromo-2-pyrone 4 and 5-bromo-2-pyrone 5...

Both 3-bromo-2-pyrone 4 and 5-bromo-2-pyrone 5 can also be prepared from 2-pyrone-3-carboxylic acid 40 and coumalic acid 39 in one step, albeit in moderate yields, utilizing the same protocol, varying only the equivalents of NBS employed in the reaction (Scheme 14). 

A series of 5-substituted-3-bromo-2-pyrones can be thus readily synthesized as summarized in Figure 3. The resultant 2-pyrones are expected to be potent ambident dienes as exemplified by the cycloadditions of 5-phenyl-3-bromo-2-pyrone with methyl acrylate and benzyl vinyl ether (Scheme 34). 

With bromine, 2-pyrone forms an nnstable addnct that gives the substitution product 3-bromo-2-pyrone on warming," however this can also be obtained satisfactorily by bromodecarboxylation of 2-pyrone-3-carboxylic acid coumalic acid (2-pyrone-5-carboxylic acid) gives 5-bromo-2-pyrone"" or 3,5-dibromo-2-pyrone" (See also 11.2.2.3 and 11.4.2 for syntheses of halo-2-pyrones). 

Bromo-2-pyrone does not undergo exchange (or C-H-deprotonation) with n-butyllithium, however it has been transformed into a cuprate, albeit of singularly less nucleophilic character than typical cuprates. ... 

Diels-Alder reaction of pymn-2-ones. Diels-Alder reaction of 2-pyrones, if successful, can provide unusual cyclohcxcnecarboxylic acids, but thermally promoted cycloadditions with these electron-deficient dienes usually result in decarboxylation and aromatization of the adducts as a result of the required high temperatures (6,291-292). Successful Diels-Alder reactions of 3-bromo-2-pyrone (1) with the electron-rich dioxolc... 

With bromine, 2-pyrone forms an unstable adduct, which gives the substitution product 3-bromo-2-pyrone on warming. " With nitronium tetrafluoroborate, the electrophile is assumed to attack first at carbonyl oxygen leading subsequently to 5-nitro-2-pyrone. Simple examples of electrophilic substitution of 4-pyrones are remarkably rare, however bis-dimethylaminomethylation of the parent heterocycle takes place under quite mild conditions. 

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. 

Based on competition experiments, 3-bromo-2-pyrone is more reactive toward both electron-poor and electron-rich dienophiles than unsubstituted 2-pyrone. It is, however, less reactive toward electron-deficient dienophiles than 3-sulfenyl-2-pyrone. 

More recently it was demonstrated that Lewis acid catalysis combined with high pressure coaxes 3-bromo-2-pyrone into [4+2] cycloadditions with unactivated terminal alkenes leading to cycloadducts, as shown in Table 5. As in the case of 3-methoxycar-bonyl-2-pyrone vide supra), reaction with unactivated dienophiles generally leads to decreased levels of stereocontrol compared to reaction with activated dienophiles. 

The synthetic utility of 3-bromo-2-pyrone has been demonstrated by the conversion of bicyclic lactones 56-58 into differently functionalized A-ring fragments for a number of biologically interesting novel vitamin D analogs. ... 

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