3- Bromo-2-pyrone, synthesis

The palladium-catalyzed Suzuki-Miyaura reaction of 3,5-dibromo-2-pyronc 100 with benzo[, ]furan-2-boronic acid 101 was applied to the synthesis of 3-(benzo[ ]furan-2-yl)-5-bromo-pyrone 102 in 50% yield (Equation 92) <2004SL2197>. 

The main problem with the original synthetic route to tridachiahydropyrone (9) was the Suzuki coupling step of the boronic ester 84 with the bromo-pyrone fragments 85 and 39 to form the biomimetic precursors 43 and 44 (see Sect. 1.3, Schemes 16 and 18) [1, 2]. In addition to being fairly low yielding the yields themselves were found to be inconsistent. As this occurred at such a late stage in the synthesis it was thought preferable to improve upon this reaction if possible. 

In the total synthesis of nalanthalide, the crucial coupling of the 7-pyrone moiety with the diterpenoid core was achieved by lithium halogen exchange of 3-bromo-2-methoxy-5,6-dimethyl-4/7-pyran-4-one 353 and addition of the resulting 3-lithio-7-pyrone 354 to aldehyde 355 to produce 356 in an impressive 87% yield (Scheme 53) <2005OL3745, 2006TL3251>. 

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 14. Synthesis of 3-bromo-2-pyrone 4 and 5-bromo-2-pyrone 5...

Scheme 26. Synthesis and coupling reactions of 3-(Me3Sn)-5-bromo-2-pyrone 91., 0 Pd(PPh3)4, (Me3Sn)2...

Pyrone itself can be prepared via Prins alkylation of but-3-enoic acid with subsequent lactonisation, giving 5,6-dihydro-2-pyrone, which, via allylic bromination and then dehydrobromination, is converted into 2-pyrone. Alternative manipulation of the dihydropyrone affords a convenient synthesis of a separable mixture of the important 3- and 5-bromo-2-pyrones (see 11.2.2.4). 

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