In cross-coupling reactions, dihaloheteroarenes are usually most reactive at C–halide bonds adjacent to a heteroatom. This selectivity has been previously rationalized. However, no mechanistic explanation exists for anomalous reports in which specific ligands effect inverted selectivity with dihalopyridines and -pyridazines. Here we provide evidence that these ligands uniquely promote oxidative addition at 12e– Pd(0). Computations indicate that 12e– and 14e– Pd(0) can favor different mechanisms for oxidative addition due to differences in their HOMO symmetries. These mechanisms are shown to lead to different site preferences, where 12e– Pd(0) can favor oxidative addition at an atypical site distal to nitrogen.

Halides adjacent to nitrogen are conventionally more reactive in Pd-catalyzed cross-couplings of dihalogenated Nheteroarenes. However, a very sterically hindered N-heterocyclic carbene ligand is shown to promote room-temperature crosscoupling at C4 of 2,4-dichloropyridines with high selectivity (∼10:1). This work represents the first highly selective method with a broad scope for C4-coupling of these substrates where selectivity is clearly under ligand control. Under the optimized conditions, diverse substituted 2,4-dichloropyridines and related compounds undergo cross-coupling to form C4−C (sp2) and C4− C (sp3) bonds using organoboron, -zinc, and -magnesium reagents. The synthetic utility of this method is highlighted in multistep syntheses that combine C4-selective cross-coupling with subsequent nucleophilic aromatic substitution reactions. The majority of the products herein (71%) have not been previously reported, emphasizing the ability of this methodology to open up underexplored chemical space. Remarkably, we find that ligand-free "Jeffery" conditions enhance the C4 selectivity of Suzuki coupling by an order of magnitude (>99:1). These ligand-free conditions enable the first C5-selective cross-couplings of 2,5-dichloropyridine and 2,5-dichloropyrimidine.

The vast majority (≥90%) of literature reports agree on the regiochemical outcomes of Pd-catalyzed cross-coupling reactions for most classes of dihalogenated N-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.

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