Conspectus Reactions that convert carbon–hydrogen (C–H) bonds into carbon–carbon (C–C) or carbon–heteroatom (C–Y) bonds are attractive tools for organic chemists, potentially expediting the synthesis of target molecules through new disconnections in retrosynthetic analysis. Despite extensive inorganic and organometallic study of the insertion of homogeneous metal species into unactivated C–H bonds, practical applications of this technology in organic chemistry are still rare. Only in the past decade have metal-catalyzed C–H functionalization reactions become more widely utilized in organic synthesis. Research in the area of homogeneous transition metal–catalyzed C–H functionalization can be broadly grouped into two subfields. They reflect different approaches and goals and thus have different challenges and opportunities. One approach involves reactions of completely unfunctionalized aromatic and aliphatic hydrocarbons, which we refer to as “first functionalization.” Here the substrates are nonpolar and hydrophobic and thus interact very weakly with polar metal species. To overcome this weak affinity and drive metal-mediated C–H cleavage, chemists often use hydrocarbon substrates in large excess (for example, as solvent). Because highly reactive metal species are needed in first functionalization, controlling the chemoselectivity to avoid over-functionalization is often difficult. Additionally, because both substrates and products are comparatively low-value chemicals, developing cost-effective catalysts with exceptionally high turnover numbers that are competitive with alternatives (including heterogeneous catalysts) is challenging. Although an exciting field, first functionalization is beyond the scope of this Account. The second subfield of C–H functionalization involves substrates containing one or more pre-existing functional groups, termed “further functionalization.” One advantage of this approach is that the existing functional group (or groups) can be used to chelate the metal catalyst and position it for selective C–H cleavage. Precoordination can overcome the paraffin nature of C–H bonds by increasing the effective concentration of the substrate so that it needn't be used as solvent. From a synthetic perspective, it is desirable to use a functional group that is an intrinsic part of the substrate so that extra steps for installation and removal of an external directing group can be avoided. In this way, dramatic increases in molecular complexity can be accomplished in a single stroke through stereo- and site-selective introduction of a new functional group. Although reactivity is a major challenge (as with first functionalization), the philosophy in further functionalization differs—the major challenge is developing reactions that work with predictable selectivity in intricately functionalized contexts on commonly occurring structural motifs. In this Account, we focus on an emergent theme within the further functionalization literature: the use of commonly occurring functional groups to direct C–H cle...

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.

O-Methyl hydroxamic acids, readily available from carboxylic acids, are found to be extremely reactive for beta-C-H activation by Pd(OAc)2. This reactivity is exploited to develop the first example of cross-coupling sp3 C-H bonds with sp3 boronic acids. Air was shown to be a suitable stoichiometric oxidant for the catalytic oxidative coupling reaction. A biologically active natural product is readily converted to its novel analogues through this coupling reaction.

Pd(II)-catalyzed intramolecular amination of sp2 and sp3 C-H bonds are developed using a combination of CuCl2 and AgOAc as the oxidant. The reaction protocol tolerates the presence of a double bond in the substrates. This catalytic reaction provides practical access to a wide range of beta-, gamma-, and delta-lactams.

The first Pd(II)-catalyzed sp3 C–H olefination reaction has been developed using N-arylamide directing groups. Following olefination, the resulting intermediates were found to undergo rapid 1,4-addition to give the corresponding γ lactams. Notably, this method was effective with substrates containing α-hydrogen atoms and could be applied to effect methylene C–H olefination of cyclopropane substrates.

Pd(0)-catalyzed intermolecular arylation of sp 3

Systematic ligand development has led to the identification of novel mono-N-protected amino acid ligands for Pd(II)-catalyzed enantioselective C–H activation of cyclopropanes. A diverse range of organoboron reagents could be used as coupling partners, and the reaction was found to proceed under mild conditions. These results provide a new retrosynthetic disconnection for the construction of enantioenriched cis-substituted cyclopropanecarboxylic acids.

An enantioselective method for Pd(II)-catalyzed cross-coupling of methylene β-C(sp3)–H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing α-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective β-C(sp3)–H activation of acyclic amides.