The palladium-catalyzed site-selective cross-coupling of identical halogen groups with minimal electronic and steric bias remains a formidable challenge, especially for simple benzene derivatives. Here, we report a cooperative phosphine/olefin ligand system that allows the unprecedented C2-selective Suzuki–Miyaura cross-coupling of 2,4-dibromoaryl ethers; regioselective reactions of these substrates are typically difficult to accomplish due to the small steric and electronic differences between the two bromo groups. The electron-deficient ligand JackiePhos facilitates the selective oxidative addition of the slightly-more-negatively-charged C2–Br bond, while 1,5-cyclooctadiene (1,5-cod) stabilizes the sensitive monomeric palladium species, preventing the in-situ formation of ligand-less dense and large palladium aggregates that lead to nonselective cross-coupling. This unique ligand effect is more pronounced under solid-state ball-milling conditions than conventional solution-based conditions. Moreover, we demonstrate that by starting with the C2-selective cross-coupling, a sequential assembly of different aryl groups to the C2, C4, and even C1-site of the benzene core is possible, thus providing a straightforward and efficient strategy to construct multi-functionalized arene scaffolds.
