Houben-Hoesch mediated strategies to highly substituted and functionalized bicyclic and tricyclic aromatic scaffolds
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An efficient route for the synthesis of highly-substituted 1-aminonaphthalenes from commercially available benzaldehydes is initially described. The method employs a stereoselective Still-Gennari modification of the Horner-Wadsworth-Emmons olefination to afford (E)-benzylidenesuccinonitrile precursors, which undergo Bronsted acid-mediated Houben-Hoesch type cycloaromatization to afford 1-aminonaphthalene derivatives. The aminonaphthalenes exhibit pH-responsive changes to absorbance and fluorescence emission properties that highlight their potential as fluorescent sensors. Furthermore, the developed olefination then annulation strategy is adapted to divergently and regioselectively access the aminocyanophenanthrene and phenanthrol esters from common precursors, naphthaldehydes and fumaronitriles or diethyl fumarate, through crucial E-alkene intermediates. In contrast to existing strategies, the phenanthrenes afforded by the strategy herein are directly functionalized with primary amino, cyano, hydroxy, and/or ester groups, making them easily amenable to a variety of chemical/physical transformations to afford value-added compounds or materials. Finally, to increase complexity in the scaffolds afforded by the developed Houben-Hoesch type cycloaromatization, an interrupted Houben-Hoesch cascade strategy was developed and is reported for the synthesis of 6,7-oxoannulated indoles, analogs of 6,7-carboannulated indole natural products, from pyrrolylsuccinonitrile silyl ethers. The interrupted Houben-Hoesch cascade proceeds through an initial nucleophilic attack by the pyrrole on a Lewis acid-activated nitrilium, followed by a second nucleophilic attack on the resulting iminium intermediate by an in situ-deprotected alcohol. The cascade strategy enables the synthesis of a broad range of substituted dihydrofurano- and tetrahydropyranoindoles, scaffolds that are synthetically challenging by other means, in a single step.
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Ph. D.