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.