The Road Less Traveled: Unconventional Site Selectivity in Palladium-Catalyzed Cross-Couplings of Dihalogenated -Heteroarenes.

The vast majority (≥90%) of literature reports agree on the regiochemical outcomes of Pd-catalyzed cross-coupling reactions for most classes of dihalogenated -heteroarenes. Despite a well-established mechanistic rationale for typical selectivity, several examples reveal that changes to the catalyst can switch site selectivity, leading to the unconventional product. In this Perspective, we survey these unusual cases in which divergent selectivity is controlled by ligands or catalyst speciation. In some cases, the mechanistic origin of inverted selectivity has been established, but in others the mechanism remains unknown. This Perspective concludes with a discussion of remaining challenges and opportunities for the field of site-selective cross-coupling. These include developing a better understanding of oxidative addition mechanisms, understanding the role of catalyst speciation on selectivity, establishing an explanation for the influence of ring substituents on regiochemical outcome, inverting selectivity for some "stubborn" classes of substrates, and minimizing unwanted over-reaction of di- and polyhalogenated substrates.