Migratory Aryl Cross-Coupling

A fundamental property of cross-coupling reactions is regiospecificity, meaning that the site of bond formation is determined by the leaving group’s location on the electrophile. Typically, to achieve a different substitution pattern requires synthesis of a new, corresponding starting-material isomer. As an alternative, we proposed the development of cross-coupling variants that afford access to multiple structural isomers from the same coupling partners. Here, we first demonstrate that a bulky palladium catalyst can facilitate efficient, reversible positional transposition of aryl halides by temporarily forming metal aryne species. Despite the nearly thermoneutral equilibrium governing this process, combining it with gradual addition of a suitable nucleophile results in parallel resolution of the isomers and high yields of unconventional product isomers. The method accommodates a range of oxygen- and nitrogen-centered nucleophiles and tolerates numerous common functional groups. A Curtin–Hammett kinetic scheme is supported by computational and experimental data, providing a general mechanistic framework for extending this migratory cross-coupling concept.