Synthesis of Isochromans by Palladium-Catalyzed C-H Olefination

Significance

The synthesis of isochromans 3 from tertiary alcohols 1 and alkenes 2 via a palladium-catalyzed hydroxyl-directed C-H olefination-intramolecular oxidative cyclization sequence is described. Optimization of the reaction conditions showed that the amino acid ligand shown is critical for high conversion. Instructively, hexafluoro­benzene is preferred to toluene to avoid competing olefination of the solvent. In general, yields were higher with electron-rich arenes (R^¹ = Me, OMe) compared to electron-poor ones (R^¹ = Hal, CF₃). The EWG on the alkene is required since only the uncyclized olefins 4 were isolated with electron-neutral alkenes (R⁴ = alkyl, aryl). The methodology was extended to secondary and primary alcohols (5-8), although the yields were somewhat low due to competing decomposition of the starting materials.