Palladium-catalyzed enolate arylation as a key C-C bond-forming reaction for the synthesis of isoquinolines.

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.

Short and efficient syntheses of protoberberine alkaloids using palladium-catalyzed enolate arylation.

A concise synthesis of the biologically active alkaloid berberine is reported, and a versatile palladium-catalyzed enolate arylation is used to form the isoquinoline core. The overall yield of 50 % is a large improvement over the single, previous synthesis. By design, this modular route allows the rapid synthesis of other members of the protoberberine family (e.g., pseudocoptisine and palmatine) by substitution of the readily available aryl bromide and ketone coupling partners. Moreover, by combining enolate arylation with in situ functionalization, substituents can be rapidly and regioselectively introduced at the alkaloid C13 position, as demonstrated by the total synthesis of dehydrocorydaline. The avoidance of electrophilic aromatic substitution reactions to make the isoquinoline allows direct access to analogues possessing more varied electronic properties, such as the fluorine-containing derivative synthesized here.

Modular isoquinoline synthesis using catalytic enolate arylation and in situ functionalization.

A methyl ketone, an aryl bromide, an electrophile, and ammonium chloride were combined in a four-component, three-step, and one-pot coupling procedure to furnish substituted isoquinolines in overall yields of up to 80%. This protocol utilizes the palladium catalyzed α-arylation reaction of an enolate, followed by in situ trapping with an electrophile, and aromatization with ammonium chloride. tert-Butyl cyanoacetate participated in a similar protocol; after functionalization and decarboxylation, 3-amino-4-alkyl isoquinolines were prepared in high yield.