Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights

Abstract

This report describes a detailed study of Ni phosphine catalysts for the Suzuki–Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands, these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPh2Me and PPh3 afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid. Several key observations were made regarding the selectivity of these reactions, including: (1) phosphine ligands that afford high selectivity for monoarylation fall within a narrow range of Tolman cone angles (between 136 and 157°); (2) more electron-rich trialkylphosphines afford predominantly diarylated products, while less electron-rich di- and triarylphosphines favor monoarylation; (3) diarylation proceeds via intramolecular oxidative addition; and (4) the solvent (MeCN) plays a crucial role in achieving high monoarylation selectivity. Experimental and density functional theory studies suggest that all of these data can be explained based on the reactivity of a key intermediate: a Ni0–π complex of the monoarylated product. With larger, more electron-rich trialkylphosphine ligands, this π complex undergoes intramolecular oxidative addition faster than ligand substitution by the MeCN solvent, leading to selective diarylation. In contrast, with relatively small di- and triarylphosphine ligands, associative ligand substitution by MeCN is competitive with oxidative addition, resulting in the selective formation of monoarylated products. The generality of this method is demonstrated with a variety of dichloropyridines and chloro-substituted aryl boronic acids. Furthermore, the optimal ligand (PPh2Me) and solvent (MeCN) are leveraged to achieve Ni-catalyzed monoarylation of a broader set of dichloroarene substrates.