Directed C–H activation has emerged as a major approach for developing synthetically useful reactions, owing to the proximity-induced reactivity and selectivity enabled by coordinating functional groups1–6. In contrast, development of palladium-catalyzed non-directed C–H activation has faced significant challenges associated with the lack of sufficiently active palladium catalysts7–8. Current palladium catalysts are only reactive with electron-rich arenes unless an excess of arene is used9–18, which limits synthetic applications. Herein, we disclose a 2-pyridone ligand that significantly enhances the reactivity of a palladium catalyst, allowing for Pd(II)-catalyzed non-directed C–H activation of a broad range of aromatic substrates using the various arenes as the limiting reagent. The significance of this finding is demonstrated by the direct functionalization of advanced synthetic intermediates, drug molecules, and natural products that cannot be utilized in excessive quantities. The potential of this methodology to be expanded to a variety of transformations is indicated by the development of both C–H olefination and C–H carboxylation protocols. Furthermore, the site selectivity in this transformation is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C–H functionalization.

The ability to differentiate between highly similar C−H bonds in a given molecule remains a fundamental challenge in organic chemistry. In particular, the lack of sufficient steric and electronic differences between C−H bonds located distal to functional groups has prevented the development of site-selective catalysts with broad scope. An emerging approach to circumvent this obstacle is to utilize the distance between a target C−H bond and a coordinating functional group, along with the geometry of the cyclic transition state in directed C−H activation, as core molecular recognition parameters to differentiate between multiple C−H bonds. In this Perspective, we discuss the advent and recent advances of this concept. We cover a wide range of transition-metalcatalyzed, template-directed remote C−H activation reactions of alcohols, carboxylic acids, sulfonates, phosphonates, and amines. Additionally, we review eminent examples which take advantage of non-covalent interactions to achieve regiocontrol. Continued advancement of this distance-and geometry-based differentiation approach for regioselective remote C−H functionalization reactions may lead to the ultimate realization of molecular editing: the freedom to modify organic molecules at any site, in any order.

The development of a Pd(II)-catalyzed enantioselective fluorination of C(sp3)–H bonds would offer a new approach to making chiral organofluorines. However, such a strategy is particularly challenging because of the difficulty in differentiating prochiral C(sp3)–H bonds through Pd(II)-insertion, as well as the sluggish reductive elimination involving Pd–F bonds. Here, we report the development of a Pd(II)-catalyzed enantioselective C(sp3)–H fluorination using a chiral transient directing group strategy. In this work, a bulky, amino amide transient directing group was developed to control the stereochemistry of C–H insertion step and selectively promote C(sp3)–F reductive elimination pathway from Pd(IV)–F intermediate. Stereochemical analysis revealed that while the desired C(sp3)–F formation proceeds via an inner-sphere pathway with retention of configuration, the undesired C(sp3)–O formation occurs through an SN2-type mechanism. The elucidation of the dual mechanism allows us to rationalize the profound ligand effect on controlling reductive elimination selectivity from high-valent Pd species.

Saturated aza-heterocycles are highly privileged building blocks that are commonly encountered in bioactive compounds and approved therapeutic agents. These N-heterocycles are also incorporated as chiral auxiliaries and ligands in asymmetric synthesis. As such, development of methods to functionalize the α-methylene C–H bonds of these systems enantioselectively is of great importance, especially in drug discovery. Currently, enantioselective lithiation with (–)-sparteine followed by Pd(0) catalyzed cross coupling to prepare α-arylated amines is largely limited to pyrrolidines. Here we report a Pd(II)-catalyzed enantioselective α-C–H coupling of a wide range of amines, including ethyl amines, azetidines, pyrrolidines, piperidines, azepanes, indolines, and tetrahydroisoquinolines. Chiral phosphoric acids are demonstrated as effective anionic ligands for the enantioselective coupling of methylene C–H bonds with aryl boronic acids. This catalytic reaction not only affords high enantioselectivities, but also provides exclusive regioselectivity in the presence of two methylene groups in different steric environments.

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.

Pd(II)-catalyzed α-C(sp3)–H arylation of pyrrolidines, piperidines, azepanes and N-methyl amines with arylboronic acids has been developed for the first time. This transformation is applicable to both a wide array of pyrrolidines and boronic acids, including heteroaromatic boronic acids. A diastereoselective one-pot hetero-diarylation of pyrrolidines is also achieved.

Transition metal-catalyzed C-H bond halogenation is an important alternative to the highly utilized directed-lithiation methods and increases the accessibility of the synthetically valuable aryl halide compounds. However, this approach often requires impractical reagents, such as IOAc, or strong co-oxidants. Therefore, the development of methodology utilizing inexpensive oxidants and catalyst containing earth-abundant transition metals under mild experimental conditions would represent a significant advance in the field. Success in this endeavor requires a full understanding of the mechanisms and reactivity governing principles of this process. Here, we report intimate mechanistic details of the Pd(II)-catalyzed C-H iodination with molecular I2 as the sole oxidant. Namely, we elucidate the impact of the: (a) Pd-directing group (DG) interaction, (b) nature of oxidant, and (c) nature of the functionalized C-H bond [C(sp(2))-H vs C(sp(3))-H] on the Pd(II)/Pd(IV) redox and Pd(II)/Pd(II) redox-neutral mechanisms of this reaction. We find that both monomeric and dimeric Pd(II) species may act as an active catalyst during the reaction, which preferentially proceeds via the Pd(II)/Pd(II) redox-neutral electrophilic cleavage (EC) pathway for all studied substrates with a functionalized C(sp(2))-H bond. In general, a strong Pd-DG interaction increases the EC iodination barrier and reduces the I-I oxidative addition (OA) barrier. However, the increase in Pd-DG interaction alone is not enough to make the mechanistic switch from EC to OA: This occurs only upon changing to substrates with a functionalized C(sp(3))-H bond. We also investigated the impact of the nature of the electrophile on the C(sp(2))-H bond halogenation. We predicted molecular bromine (Br2) to be more effective electrophile for the C(sp(2))-H halogenation than I2. Subsequent experiments on the stoichiometric C(sp(2))-H bromination by Pd(OAc)2 and Br2 confirmed this prediction.The findings of this study advance our ability to design more efficient reactions with inexpensive oxidants under mild experimental conditions.

One of the core challenges in developing C-H activation reactions is to distinguish multiple C-H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp 2)-H bonds have been selectively activated in the presence of proximate ones 1-2. Yet achieving such unconventional site selectivity with C(sp 3)-H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid derived directing group and a 2-pyridione ligand that enables the preferential activation of the distal γ-C(sp 3)-H bond over the proximate β-C(sp 3)-H bonds for a wide range of alcohol derived substrates. Competition experiment of five-and six-membered cyclopalladation step as well as kinetic experiments demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp 3)-H activation. Developing C-H activation reactions as new retrosynthetic disconnections could offer a multitude of novel synthetic strategies due to the abundance of positionally diverse C-H bonds 3-4. On the other hand, the great resemblance between these C-H bonds in terms of bond strength and electronic properties presents a tremendous challenge for achieving regioselectivity. This difficulty escalates with metalation chemistry because in such processes, the numerous primary or secondary C-H bonds are nearly indistinguishable by the metal. For example, despite the recent advances in developing a wide range of Pdcatalyzed C(sp 3)-H activation reactions, their regioselectivity is largely restricted to the cleavage of the C-H bond that will result in five-membered cyclopalladation 5-12. Therefore, it is fundamentally important to develop strategies to switch the selectivity of the key metalation step from five-membered to six-membered cyclopalladation (Fig. 1b). Such Reprints and permissions information is available at www.nature.com/reprints.