Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 14, Issue 3, Pages 1065-1090Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5ob02320c
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- St. John's College Oxford
- EPSRC
- GlaxoSmithKline
- CAPES, Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brazil
- Engineering and Physical Sciences Research Council [1112322] Funding Source: researchfish
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The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an alpha-arylation) furnishes a protected 1,5-dicarbonyl moiety that can be cyclized to an isoquinoline with a source of ammonia. This fully regioselective synthetic route tolerates a wide range of substituents, including those that give rise to the traditionally difficult to access electron-deficient isoquinoline skeletons. These two synthetic operations can be combined to give a three-component, one-pot isoquinoline synthesis. Alternatively, cyclization of the intermediates with hydroxylamine hydrochloride engenders direct access to isoquinoline N-oxides; and cyclization with methylamine, gives isoquinolinium salts. Significant diversity is available in the substituents at the C4 position in four-component, one-pot couplings, by either trapping the in situ intermediate after alpha-arylation with carbon or heteroatom-based electrophiles, or by performing an a, alpha-heterodiarylation to install aryl groups at this position. The alpha-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the alpha-arylation of tert-butyl cyanoacetate followed by electrophile trapping, decarboxylation and cyclization, C4-functionalized 3-aminoisoquinolines. An oxime directing group can be used to direct a C-H functionalization/bromination, which allows monofunctionalized rather than difunctionalized aryl precursors to be brought through this synthetic route.
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