Controlling site selectivity in palladium-catalyzed C-H bond functionalization.

Effective methodology to functionalize C-H bonds requires overcoming the key challenge of differentiating among the multitude of C-H bonds that are present in complex organic molecules. This Account focuses on our work over the past decade toward the development of site-selective Pd-catalyzed C-H functionalization reactions using the following approaches: substrate-based control over selectivity through the use of directing groups (approach 1), substrate control through the use of electronically activated substrates (approach 2), or catalyst-based control (approach 3). In our extensive exploration of the first approach, a number of selectivity trends have emerged for both sp(2) and sp(3) C-H functionalization reactions that hold true for a variety of transformations involving diverse directing groups. Functionalizations tend to occur at the less-hindered sp(2) C-H bond ortho to a directing group, at primary sp(3) C-H bonds that are β to a directing group, and, when multiple directing groups are present, at C-H sites proximal to the most basic directing group. Using approach 2, which exploits electronic biases within a substrate, our group has achieved C-2-selective arylation of indoles and pyrroles using diaryliodonium oxidants. The selectivity of these transformations is altered when the C-2 site of the heterocycle is blocked, leading to C-C bond formation at the C-3 position. While approach 3 (catalyst-based control) is still in its early stages of exploration, we have obtained exciting results demonstrating that site selectivity can be tuned by modifying the structure of the supporting ligands on the Pd catalyst. For example, by modulating the structure of N-N bidentate ligands, we have achieved exquisite levels of selectivity for arylation at the α site of naphthalene. Similarly, we have demonstrated that both the rate and site selectivity of arene acetoxylation depend on the ratio of pyridine (ligand) to Pd. Lastly, by switching the ligand on Pd from an acetate to a carbonate, we have reversed the site selectivity of a 1,3-dimethoxybenzene/benzo[h]quinoline coupling. In combination with a growing number of reports in the literature, these studies highlight a frontier of catalyst-based control of site-selectivity in the development of new C-H bond functionalization methodology.