ORGN 104

We describe here several novel routes to 5-alkyl isoquinolines. We employed 5-bromoisoquinoline in copper-mediated and palladium-catalyzed α-arylations of malonate esters to give the dicarboxylate adducts that underwent facile thermal monodecarboxylation to the acetate product. In a second route, 5-bromoisoquinoline underwent metal-halogen exchange to give the 5-lithiated intermediate, which was acylated with diethyl oxalate to give the α-keto ester. The final route utilized a palladium-catalyzed addition of acetate using the reagent tributylstannyl acetic acid ethyl ester.

Treatment of the 5-acetyl derivative with lithium diisopropylamide afforded an enolate that underwent alkylation and hydroxylation in high yields.