Catalytic Cascade Cyclization and Regioselective Hydroheteroarylation of Unactivated Alkenes

A Pd(II)-catalyzed directed, regio-controlled hydroheteroarylation of unactivated alkenes via a cascade intramolecular amino/oxy/carbo-palladation of alkynes followed by cis-migratory insertion of alkenes has been developed for the construction of γ-heteroaryl-substituted carbonyl compounds. 8-Aminoquinoline was employed as a cleavable bidentate directing group to stabilize the nucleopalladated vinylpalladium(II) intermediate and also to control the regioselectivity of the carbopalladation step. The reaction sequence proceeds under operationally simple conditions using 5 mol % Pd(OAc)2 in hexafluoroisopropanol and is compatible with a variety of nucleophiles to deliver structurally divergent heterocyclic skeletons including indoles, chromenes, 1,4-oxazines, 1,3-oxazines, pyrroles, isochromenones, and spirocyclohexadienones. The synthetic utility of this methodology is further demonstrated by carrying out gram-scale synthesis, directing group removal, and late-stage modification of drugs and natural products. Control studies indicated that the carbopalladation is selective toward the unactivated alkene in the presence of an activated one.