In the past decade, palladium-catalyzed C-H activation/C-C bond forming reactions have emerged as promising new catalytic transformations; however, development in this field is still at an early stage compared to the state of the art in cross-coupling reactions using aryl and alkyl halides. This Review begins with a brief introduction of four extensively investigated modes of catalysis for forming C-C bonds from C-H bonds: Pd(II)/Pd(0), Pd(II)/Pd(IV), Pd(0)/Pd(II)/Pd(IV) and Pd(0)/ Pd(II) catalysis. More detailed discussion is then directed towards the recent development of Pd(II)-catalyzed coupling of C-H bonds with organometallic reagents through a Pd(II)/Pd(0) catalytic cycle. Despite much progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.

The use of preformed sodium carboxylates as substrates led to the first observation of facile Pd-insertions into sp3 β-C−H bonds in simple aliphatic acids. Consequently, Pd-catalyzed methylation and arylation of o-C−H bonds in benzoic acids and β-C−H bonds in aliphatic acids using either a phenylboronate, methylboronic acid, or ArI have been achieved via a C−H activation/C−C coupling sequence.

The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch together the carbogenic cores of numerous complex organic molecules. Given that the positionselective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl C-H bonds would obviate the inefficiencies associated with generating halide precursors or their equivalents; however, methods for carrying out such a reaction have suffered from narrow substrate scope and low positional selectivity. Here we report an operationally simple, atom-economical, carboxylate-directed Pd(II)-catalyzed C-H olefination reaction with phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atmospheric pressure as the oxidant. The positional selectivity can be tuned by introducing amino acid derivatives as ligands. We demonstrate the versatility of the method through direct elaboration of commercial drug scaffolds and efficient synthesis of 2-tetralone and naphthoic acid natural product cores.

Initial rate studies have revealed dramatic acceleration in aerobic Pd(II)-catalyzed C–H olefination reactions of phenylacetic acids when mono-N-protected amino acids are used as ligands. In light of these findings, systematic ligand tuning was undertaken, which has resulted in drastic improvements in substrate scope, reaction rate, and catalyst turnover. We present evidence from intermolecular competition studies and kinetic isotope effect experiments that implies that the observed rate increases are a result of acceleration in the C–H cleavage step. Furthermore, these studies suggest that the origin of this phenomenon is a change in the mechanism of C–H cleavage from electrophilic palladation to proton abstraction.

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.

Unactivated CH3 groups in 2‐oxazolines are oxidized by inexpensive oxidants, such as tert‐butyl peroxyacetate and lauroyl peroxide, in the presence of a catalytic amount of Pd(OAc)2. Carboxylic anhydrides are essential for both the oxidation of the PdC bonds and regeneration of Pd(OAc)2. The use of [D6]Ac2O as the solvent shows that the acetyl group incorporated into the product is from acetic anhydride rather than the oxidant (see scheme).

A novel Pd(II)-catalyzed ortho-C-H olefination protocol has been developed using spatially remote, unprotected tertiary, secondary, and primary alcohols as the directing groups. Mono-N-protected amino acid ligands were found to promote the reaction, and an array of olefin coupling partners could be used. When electron-deficient alkenes were used, the resulting olefinated intermediates underwent subsequent Pd(II)-catalyzed oxidative intramolecular cyclization to give the corresponding pyran products, which could be converted into ortho-alkylated alcohols under hydrogenolysis conditions. The mechanistic details of the oxidative cyclization step are discussed and situated in the context of the overall catalytic cycle.

Pd(II)-catalyzed enantioselective C-H olefination of diphenylacetic acid substrates has been achieved through the use of mono-protected chiral amino acid ligands. The absolute configuration of the resulting olefinated products is consistent with that of a proposed C-H insertion intermediate.Despite substantial progress in developing various Pd-catalyzed C-heteroatom and C-C bond forming reactions via C-H activation,1 achieving enantioselectivity in these reactions through a stereoselective Pd insertion step remains a significant challenge.2 -9 In our ongoing studies to design and evaluate new ligands to effect asymmetric C-H cleavage, two major problems have become apparent. First, the simultaneous binding of both the substrate and the chiral ligand to the Pd(II) center is often difficult to achieve. Second, even if such complexes are assembled, the ligand often strongly inhibits C-H activation, either because it induces an unwanted conformational change or adversely affects the electronic properties of the Pd(II) center.yu200@scripps.edu. Supporting Information Available: X-ray diffraction analysis for 2e, experimental procedure and characterization of all new compounds (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2011 January 20. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe have recently found that mono-protected amino acid ligands and 2-benzylpyridine substrates coordinate with Pd(II) in a one-to-one ratio with high fidelity. 3 Importantly, the resulting chiral Pd(II) complexes were found to induce asymmetric C-H cleavage with high enantioselectivity (up to 95% ee). Of critical importance for the viability of this process is the precise match between the binding ability of the pyridine substrate and the chiral ligand. This observation, however, calls into question whether this chiral ligand scaffold is broadly applicable to synthetically useful substrates, including those that contain weakly coordinating functional groups. Herein, we report an enantioselective C-H olefination reaction of α,α-diphenylacetic acids using mono-protected amino acids as chiral ligands. This new development represents an encouraging step towards the realization of synthetically useful Pdcatalyzed enantioselective C-H activation reactions.We previously reported that both inorganic and organic cations dramatically accelerate carboxyl-directed C-H activation reactions.10 Our current hypothesis, based on the structure of a C-H insertion intermediate, 10b is that the σ-chelation of the carbonyl oxygen of the carboxylate salt with Pd(II) is responsible for the facile C-H cleavage promoted by the complexinduced proximity effect. Following this hypothesis, we anticipated that a chiral carbon-Pd intermediate B could be formed in analogy to intermediate A, which is formed following enantioselective C-H activation using a pyridyl directing group. Subsequently, we envisioned t...