Abstract
Cycloaromatization, via tandem cycloaddition – extrusion of carbon dioxide, between methyl isodehydroacetate or methyl coumalate and a variety of alkyne dienophiles has been investigated. This method provides an efficient synthesis of methyl 4-hydroxymethyl-2,6dimethylbenzoate (1), a key intermediate in the preparation of retinal-based molecular probes.
Highlights
The Diels-Alder chemistry of bromo-2-pyrones has been studied in detail.[1]
Substituted coumalates have been used in total synthesis in two principal ways: cycloaddition with an electron-rich olefin to install a bicyclic lactone[3] and for cycloaromatization.[4]
It is noteworthy that our observations regarding the reactions that produce 10a / 10b and 11a / 11b differ from those reported previously for an extremely similar system.6c Using methyl coumalate with methyl propiolate in one instance and ethyl isodehydroacetate with methyl propiolate in another, Effenberger and Ziegler reported the opposite regioselectivity.6c It is possible that subtle substituent effects account for our differing observations; the regioselectivity reported appears to be in accord with the results expected based on the complementary polarity of the reactants (Scheme 2)
Summary
The Diels-Alder chemistry of bromo-2-pyrones has been studied in detail.[1] The cycloaddition of the related coumalate esters is a process that has been underutilized in organic synthesis and methodology.[2] The reactions of coumalates with olefins typically follow an inverse-electrondemand motif.[2] Substituted coumalates have been used in total synthesis in two principal ways: cycloaddition with an electron-rich olefin to install a bicyclic lactone[3] and for cycloaromatization.[4]. The reaction of α-pyrones with alkynes yields aryl derivatives upon extrusion of carbon dioxide (Figure 2).[6] The most typical alkyne reactive partners are phenylacetylene, a propiolate, or dimethyl acetylenedicarboxylate, which suggests that the electronic requirements of the cycloaddition can follow the usual motif. The work described is aimed at developing a more efficient synthesis of 1 via this cycloaromatization route
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