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

Abstract

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.

Figure 1

Unreactive substrates for sp³-C–H oxygenation.

Figure 2

Products of 2° sp³-C–H functionalization.

Figure 3

Influence of pyridine (pyr) to Pd(OAc)₂ ratio on the rate of benzene acetoxylation.

Scheme 1

Transformation of C–H bonds into diverse functional groups.

Scheme 2

Strategies for controlling site selectivity.

Scheme 3

Catalytic cycle for ligand-directed C–H acetoxylation.

Scheme 4

Representative products of ligand-directed C–H oxygenation.

Scheme 5

Representative products of ligand-directed C–H halogenation.

Scheme 6

Representative products of ligand-directed C–H arylation.

Scheme 7

Major site for C–H acetoxylation of 3′-substituted 2-arylpyridines.

Scheme 8

Selectivity for isomer A in diverse C–H functionalizations.

Scheme 9

Selectivity in ligand-directed sp³-C–H acetoxylation.

Scheme 10

Relative reactivity of directing groups toward C–H acetoxylation in competition studies.

Scheme 11

Complementary site selectivity of halogenation in the presence and absence of Pd.

Scheme 12

Pd-catalyzed C-2 arylation of indoles and pyrroles with [Ar₂I]BF₄.

Scheme 13

Pd-catalyzed C-3 arylation of 2,5-disubstituted pyrroles.

Scheme 14

Catalyst control of selectivity with ancillary ligands.

Scheme 15

Catalyst control of selectivity in napthalene arylation.

Scheme 16

Proposed mechanism for oxidative coupling between benzo[h]quinoline and aryl–H.