This Review summarizes the advancements in Pd-catalyzed C(sp3)–H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C–H bonds, many C(sp3)–H activation/C–C and C–heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chemistry. A number of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)–H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C–H functionalization reactions.

Metrics & MoreArticle Recommendations CONSPECTUS:The functionalization of unactivated carbon− hydrogen bonds is a transformative strategy for the rapid construction of molecular complexity given the ubiquitous presence of C−H bonds in organic molecules. It represents a powerful tool for accelerating the synthesis of natural products and bioactive compounds while reducing the environmental and economic costs of synthesis. At the same time, the ubiquity and strength of C−H bonds also present major challenges toward the realization of transformations that are both highly selective and efficient. The development of practical C−H functionalization reactions has thus remained a compelling yet elusive goal in organic chemistry for over a century. Specifically, the capability to form useful new C−C, C−N, C−O, and C−X bonds via direct C−H functionalization would have wide-ranging impacts in organic synthesis. Palladium is especially attractive as a catalyst for such C−H functionalizations because of the diverse reactivity of intermediate palladium−carbon bonds. Early efforts using cyclopalladation with Pd(OAc) 2 and related salts led to the development of many Pd-catalyzed C−H functionalization reactions. However, Pd(OAc) 2 and other simple Pd salts perform only racemic transformations, which prompted a long search for effective chiral catalysts dating back to the 1970s. Pd salts also have low reactivity with synthetically useful substrates. To address these issues, effective and reliable ligands capable of accelerating and improving the selectivity of Pd-catalyzed C−H functionalizations are needed.In this Account, we highlight the discovery and development of bifunctional mono-N-protected amino acid (MPAA) ligands, which make great strides toward addressing these two challenges. MPAAs enable numerous Pd(II)-catalyzed C(sp 2 )−H and C(sp 3 )−H functionalization reactions of synthetically relevant substrates under operationally practical conditions with excellent stereoselectivity when applicable. Mechanistic studies indicate that MPAAs operate as unique bifunctional ligands for C−H activation in which both the carboxylate and amide are coordinated to Pd. The N-acyl group plays an active role in the C−H cleavage step, greatly accelerating C−H activation. The rigid MPAA chelation also results in a predictable transfer of chiral information from a single chiral center on the ligand to the substrate and permits the development of a rational stereomodel to predict the stereochemical outcome of enantioselective reactions. We also describe the application of MPAA-enabled C−H functionalization in total synthesis and provide an outlook for future development in this area. We anticipate that MPAAs and related next-generation ligands will continue to stimulate development in the field of Pd-catalyzed C−H functionalization.

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The enzymatic β-C–H hydroxylation of the feedstock chemical isobutytic acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transitionmetal catalyzed enantioselective β-C–H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline (MPAO) ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation and -alkynylation of isobutyric acid/2-amino-isobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.

Enantioselective carbon-hydrogen (C-H) activation reactions by asymmetric metallation could provide new routes for the construction of chiral molecules. However, current methods are typically limited to the formation of five- or six-membered metallacycles, thereby preventing the asymmetric functionalization of C-H bonds at positions remote to existing functional groups. Here we report enantioselective remote C-H activation using a catalytic amount of a chiral norbornene as a transient mediator, which relays initial ortho-C-H activation to the meta position. This was used in the enantioselective meta-C-H arylation of benzylamines, as well as the arylation and alkylation of homobenzylamines. The enantioselectivities obtained using the chiral transient mediator are comparable across different classes of substrates containing either neutral σ-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis.