Nitrogen-containing heterocycles are prevalent motifs in pharmaceutical compounds. Elaboration of halogenated heteroaromatic cores can be achieved through cross-coupling reactions, which are among the most widely used methods in organic synthesis. However, when two or more halides are present on the substrate, controlling site selectivity becomes critical. In most cases, dihalogenated heteroarenes react with predictable selectivity in Pd-catalyzed cross-couplings, and it is very challenging to invert the conventional selectivity. Here we demonstrate a ligand-controlled strategy to achieve selective cross-coupling at the conventionally disfavored site of 2,4-dichloropyridine derivatives. DFT studies support the hypothesis that selectivity relates to controlling palladium's ligation state, and provide insight into the role of frontier molecular orbitals on selectivity preferences.

Origin of ligand-controlled selectivity in cross-coupling of dichloroheteroarenes

ACS Spring 2022

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