A directive Ni catalyst overrides conventional site selectivity in pyridine C–H alkenylation

Achieving the transition metal-catalysed pyridine C3−H alkenylation, with pyridine as the limiting reagent, has remained a long-standing challenge. Previously, we disclosed that the use of strong coordinating bidentate ligands can overcome catalyst deactivation and provide Pd-catalysed C3 alkenylation of pyridines. However, this strategy proved ineffective when using pyridine as the limiting reagent, as it required large excesses and high concentrations to achieve reasonable yields, which rendered it inapplicable to complex pyridines prevalent in bioactive molecules. Here we report that a bifunctional N-heterocyclic carbene-ligated Ni–Al catalyst can smoothly furnish C3–H alkenylation of pyridines. This method overrides the intrinsic C2 and/or C4 selectivity, and provides a series of C3-alkenylated pyridines in 43–99% yields and up to 98:2 C3 selectivity. This method not only allows a variety of pyridine and heteroarene substrates to be used as the limiting reagent, but is also effective for the late-stage C3 alkenylation of diverse complex pyridine motifs in bioactive molecules. Selective C–H alkenylation of pyridines at the C3 position, with the pyridine as the limiting reagent, is a long-standing synthetic challenge. Now, it has been shown that this can be achieved using a bifunctional N-heterocyclic carbene-ligated Ni–Al catalyst that overrides the intrinsic C2/4 selectivity of pyridines and enables the selective late-stage functionalization of a range of complex pyridyl-containing motifs.