Remote Meta-C–H Activation Using a Pyridine-Based Template: Achieving Site-Selectivity via the Recognition of Distance and Geometry

Abstract

The pyridyl group has been extensively employed to direct transition-metal-catalyzed C–H activation reactions in the past half-century. The typical cyclic transition states involved in these cyclometalation processes have only enabled the activation of ortho-C–H bonds. Here, we report that pyridine is adapted to direct meta-C–H activation of benzyl and phenyl ethyl alcohols through engineering the distance and geometry of a directing template. This template takes advantage of a stronger σ-coordinating pyridine to recruit Pd catalysts to the desired site for functionalization. The U-shaped structure accommodates the otherwise highly strained cyclophane-like transition state. This development illustrates the potential of achieving site selectivity in C–H activation via the recognition of distal and geometric relationship between existing functional groups and multiple C–H bonds in organic molecules.

Ligand-accelerated non-directed C–H functionalization of arenes

“…Extensive research on various directing group designs 1–6 and strategies 19–21 , as well as the development of ligands which accelerate C–H functionalization 22 , has significantly improved the practicality and utility of this approach. Ligand-acceleration has enabled palladium catalysts to functionalize remote C–H bonds of aromatic substrates by recognition of distance and geometry 23–24 . (Figure 1a).…”

Remote site-selective C–H activation directed by a catalytic bifunctional template

“…Though applicability can be severely curtailed by distance from the directing group and the shape of the molecule, a number of approaches have been developed to overcome this limitation 6-12 . For instance, recognition of the distal and geometric relationship between an existing functional group and multiple C–H bonds has recently been exploited to achieve meta -selective C–H activation by use of a covalently attached U-shaped template 13-17 . However, stoichiometric installation of the template is not feasible in the absence of an appropriate functional group handle.…”

“…We chose a bis-amide T1 as the backbone for attaching the U-shaped templates due to their ability to chelate with Pd(II) or Cu(II) centers 23-24 which will be present in our reaction. Since we have recently demonstrated that a properly positioned C-3 pyridyl group could also function as a U-shaped template in a meta -selective iodination reaction 13,17 , we choose C-3 pyridine over the nitrile directing group to enhance the coordination with the small amount of Pd(II) catalyst. With these considerations in mind, we synthesized various templates based on the bis-sulfonamide and bis-amide scaffolds containing the directing C-3 pyridine group as pendant side arms.…”

Palladium(II)‐Catalyzed ortho‐Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold

“…Transformations reported by Hartwig, [7] Yu, [8] Tan, [9] Dong, [10] Zhao, [11] and us [12] demonstrated the feasibility of this concept in C–H functionalization. Specifically, a recent report from Zhao and coworkers [11b] demonstrated the Pd-catalyzed ortho -selective arylation to construct biaryls, using oximes as the surrogate species.…”