Converting C–H bonds directly into carbon-carbon and carbon-heteroatom bonds can significantly improve step-economy in synthesis by providing alternative disconnections to traditional functional group manipulations. In this context, directed C–H activation reactions have been extensively explored for regioselective functionalization1-5. 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 limitation6-12. 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 template13-17. However, stoichiometric installation of the template is not feasible in the absence of an appropriate functional group handle. Here we report the design of a catalytic, bifunctional template that binds heterocyclic substrate via reversible coordination instead of covalent linkage, allowing remote site-selective C–H olefination of heterocycles. The two metal centers coordinated to this template play different roles; anchoring substrates to the proximity of catalyst and cleaving the remote C–H bonds respectively. Using this strategy, we demonstrate remote site-selective C–H olefination of heterocyclic substrates which do not have functional group handles for covalently attaching templates.

Site-selective functionalization of C–H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, developing strategies to activate C–H bonds that are distal from a functional group is essential. In this context, distinguishing remote C–H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C–H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukemia agent, and hydrocinnamic acid substrates.

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.

A quinoline-based ligand was shown to promote palladium-catalyzed β-C(sp3)–H fluorination for the first time. A range of unnatural enantiopure fluorinated α-amino acids were obtained through sequential β-C(sp3)–H arylation and subsequent stereoselective fluorination from readily available L-alanine.

Pd-catalyzed C(sp 3 )−H activation of alcohol typically shows β-selectivity due to the required distance between the chelating atom in the attached directing group and the targeted C−H bonds. Herein we report the design of a hemilabile directing group which exploits the chelation of a readily removable benzyl ether moiety to direct γor δ-C−H carbonylation and olefination of alcohols. The utility of this approach is also demonstrated in the late-stage C−H functionalization of β-estradiol to rapidly prepare desired analogues that required multi-step syntheses with classical methods.