Ligand-enabled meta-C-H activation using a transient mediator

Abstract

Achieving site selectivity in C-H functionalization reactions is a significant challenge, especially when the target C-H bond is distant from existing functional groups. Coordination of a functional group to a metal is often a key driving force and control element in many important reactions including asymmetric hydrogenation, epoxidation and lithiation. Exploitation of this effect has led to the development of a broad range of directed C-H activation reactions. However, these C-H activation methods are limited to proximal C-H bonds, which are spatially and geometrically accessible from the directing functional group. The development of meta-selective C-H functionalizations remains a significant challenge. We recently developed a U-shaped template that can be used to overcome this constraint and have shown that it can be used to selectively activate remote meta-C-H bonds. Although this approach has proved to be applicable to various substrates and catalytic transformations, the need for a covalently attached, complex template is a substantial drawback for synthetic applications. Here we report an alternative approach employing norbornene as a transient mediator to achieve meta-selective C-H activation with a simple and common ortho-directing group. The use of a newly developed pyridine-based ligand is crucial for relaying the palladium catalyst to the meta position by norbornene after initial ortho-C-H activation. This catalytic reaction demonstrates the feasibility of switching ortho-selectivity to meta-selectivity in C-H activation of the same substrate by catalyst control.

Figure 1. Design of a new approach for meta-C–H activation

a, Previously reported remote meta-C–H activation directed by a U-shaped template. b, The norbornene-mediated Catellani reaction functionalizes ortho-positions of aryl iodides. c, The development of a tailor-made ligand that switches the ortho-selectivity to meta-selectivity using norbornene as a transient mediator (this work). Ar_F, 4-(CF₃)C₆F₄. The activated C–H bonds (blue) and the newly formed bonds (red) are highlighted.

Figure 2. Discovery of a ligand that enables meta-C–H alkylation using norbornene as a transient mediator

a, Pyridine promotes Pd-catalyzed reaction of phenylacetic amide with norbornene to afford benzocyclobutene via a Catellani pathway. DCE, 1,2-dichloroethane. b, A modified pyridine-type ligand enables selective meta-C–H methylation. Yields are determined by crude ¹H NMR analysis. c, meta-C–H alkylation with ethyl iodoacetate.

Figure 3. meta-C–H alkylation of phenylacetic amides

R-I, methyl iodide or ethyl iodoacetate; X, Y, generic substituents; Ac, acetyl; Bn, benzyl; Phth, phthaloyl; Ts, 4-toluenesulfonyl.

Figure 4. Scope of organohalide coupling partners

a, meta-C–H Alkylation with alkyl halides. Alkyl-X, iodoethane or benzyl bromides. b, meta-C–H arylation with aryl iodides. TBME, t- butyl methyl ether.