Abstract
The palladium-catalyzed coupling of an enolate with an ortho-functionalized aryl halide (an α-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 α-arylation with carbon or heteroatom-based electrophiles, or by performing an α,α-heterodiarylation to install aryl groups at this position. The α-arylation of nitrile and ester enolates gives access to 3-amino and 3-hydroxyisoquinolines and the α-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.
Highlights
It has been over a century since the first synthetic routes to isoquinolines were published
A number of notable recent contributions have exploited the versatility provided by modern synthetic methodology to access this motif, in particular the scope afforded by transition metal catalysis,[9] and in so doing have vastly expanded the synthetically-accessible isoquinoline motifs, those containing electron-deficient core structures which were unobtainable via the traditional methods
Our contribution to this area began when we embarked on a research program employing the palladium-catalyzed crosscoupling of a ketone enolate with an aryl halide to construct the C4–C4′ bond en route to the isoquinoline nucleus.[10]
Summary
It has been over a century since the first synthetic routes to isoquinolines were published. A number of notable recent contributions have exploited the versatility provided by modern synthetic methodology to access this motif, in particular the scope afforded by transition metal catalysis,[9] and in so doing have vastly expanded the synthetically-accessible isoquinoline motifs, those containing electron-deficient core structures which were unobtainable via the traditional methods Our contribution to this area began when we embarked on a research program employing the palladium-catalyzed crosscoupling of a ketone enolate with an aryl halide to construct the C4–C4′ bond en route to the isoquinoline nucleus.[10] This α-arylation reaction has become a powerful addition to the arsenal of the synthetic chemist[11] since its discovery in 199712 and is a well-established, albeit underutilized, palladiumcatalyzed coupling procedure. We have presented these together with our previous results to provide proper context and allow the full scope (and limitations) of this research program to be discussed in detail
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