Recent developments in metal-catalyzed reactions have unveiled many opportunities for the synthetic chemist, making previously unfeasible disconnections into routine operations. Recent work within the Donohoe group utilizing one such method led to the development of a de novo synthetic route to isoquinolines. Whereas traditional isoquinoline syntheses revolve around the lynchpin of electrophilic aromatic substitution, our approach employed the palladium-catalyzed a-arylation of carbonyl enolates to mediate the key carbon-carbon bond-forming process and hence had much greater substrate flexibility.A range ketone enolates were arylated at the a-position with acetal-protected ortho-halo-benzaldehydes or ortho-halo-arylketones. The resulting intermediates could be converted into isoquinolines by treatment with a mildly acidic source of ammonia, or the corresponding isoquinoline N-oxides by treatment with hydroxylamine hydrochoride. An array of reaction partners were successfully coupled using this approach and significant functional group tolerance was demonstrated (including the incorporation of heteroatom, nitro and ester moieties). Highly-substituted isoquinolines could thus be accessed in two steps from readily-available starting materials.A second generation route was then developed, whereby a three component coupling procedure could be employed in a one-pot operation. This allowed a huge variation of substitution to be incorporated, particularly at the 4-position � an isoquinoline position traditionally difficult to selectively functionalize in the parent heterocycle.This synthetic approach has proven to be highly-versatile in the synthesis of a range of other aryl motifs and under the correct cyclization conditions the intermediates can also be converted into carbocycles such as naphthols and napthylamines. The isoquinoline manifold is also accessible in higher oxidation levels via the a-arylation of nitrile and ester enolates. Work is currently being undertaken applying this methodology to natural product synthesis.

Expedient synthesis of substituted aromatics via the a-arylation of enolates

246th National Meeting (2013)

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