Palladium-Catalyzed Stitching of 1,3-C(sp³)-H Bonds with Dihaloarenes: Short Synthesis of (±)-Echinolactone D

Palladium-catalyzed C(sp³)-H functionalization presents an efficient strategy to construct a variety of carbon-carbon bonds. However, application of this approach toward the preparation of five-membered benzo-fused carbocycles via the most simplifying C-H activation logic has not been realized. In this Article, we report a palladium-catalyzed annulation reaction between gem-dimethyl-containing amides and 1-bromo-2-iodoarenes that effectively constructs two C_alkyl-C_aryl bonds and provides access to a variety of five-membered benzo-fused compounds. In this transformation, the dihaloarene is stitched to the gem-dimethyl moiety via two sequential β-C(sp³)-H arylations utilizing the differential reactivity of the 1,2-difunctionalized electrophile. This annulation reaction is enabled by a dual-ligand system comprising of an N-acyl glycine and a pyridine-3-sulfonic acid that synergistically promotes the palladium stitching and provides the bicyclic products. This method displays a broad substrate scope and shows excellent amide compatibility. We also demonstrate the synthetic potential of this annulation by synthesizing echinolactone D.