Keary M. Engle

Palladium(II)-Catalyzed C―H Activation/C―C Cross- Coupling Reactions: Versatility and Practicality

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. A more detailed discussion is then directed towards the recent development of palladium(II)-catalyzed coupling of C-H bonds with organometallic reagents through a Pd(II)/Pd(0) catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.

Ligand-Enabled Reactivity and Selectivity in a Synthetically Versatile Aryl C–H Olefination

Heck of an Alternative The Mizoroki-Heck reaction is widely used in organic synthesis to link together unsaturated carbon fragments such as olefins and arenes. However, one of its drawbacks is the need to append a reactive group such as a halogen to one of the reagents beforehand. Wang et al. (p. 315, published online 26 November) present an alternative palladium-catalyzed reaction that links olefins directly to aryl acids. Oxygen added to the reaction medium concurrently oxidizes the aryl C-H bond at the linkage site, eliminating the need for prior halogenation. Introducing amino acid–derived ligands tunes the aryl site at which the reaction takes place, and efficient reactivity can be achieved across a diverse range of substrates. A palladium-based catalyst eliminates the need for halogenated compounds for the formation of carbon-carbon bonds. 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 position-selective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl carbon-hydrogen (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. 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 syntheses of 2-tetralone and naphthoic acid natural product cores.

Ligand-Accelerated C−H Activation Reactions: Evidence for a Switch of Mechanism

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.

Catalytic Hydrotrifluoromethylation of Unactivated Alkenes

A visible-light-mediated hydrotrifluoromethylation of unactivated alkenes that uses the Umemoto reagent as the CF(3) source and MeOH as the reductant is disclosed. This effective transformation operates at room temperature in the presence of 5 mol % Ru(bpy)(3)Cl(2); the process is characterized by its operational simplicity and functional group tolerance.

Bystanding F+ Oxidants Enable Selective Reductive Elimination from High‐Valent Metal Centers in Catalysis

Reductive elimination from partially or completely oxidized metal centers is a vital step in a myriad of carbon-carbon and carbon-heteroatom bond-forming reactions. One strategy for promoting otherwise challenging reductive elimination reactions is to oxidize the metal center using a two-electron oxidant (that is, from M((n)) to M((n+2))). However, many of the commonly used oxidants for this type of transformation contain oxygen, nitrogen, or halogen moieties that are subsequently capable of participating in reductive elimination, thus leading to a mixture of products. In this Minireview, we examine the use of bystanding F(+) oxidants for addressing this widespread problem in organometallic chemistry and describe recent applications in Pd(II) /Pd(IV) and Au(I) /Au(III) catalysis. We then briefly discuss a rare example in which one-electron oxidants have been shown to promote selective reductive elimination in palladium(II)-catalyzed C-H functionalization, which we view as a promising future direction in the field.

Pd(II)-Catalyzed Olefination of sp3 C−H Bonds

The first Pd(II)-catalyzed sp(3) 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 gamma-lactams. Notably, this method was effective with substrates containing alpha-hydrogen atoms and could be applied to effect methylene C-H olefination of cyclopropane substrates.

Pd(II)-Catalyzed Hydroxyl-Directed C−H Olefination Enabled by Monoprotected Amino Acid Ligands

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 Activation of Cyclopropanes

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 can be used as coupling partners, and the reaction proceeds under mild conditions. These results provide a new retrosynthetic disconnection for the construction of enantioenriched cis-substituted cyclopropanecarboxylic acids.

Pd(0)/PR3-Catalyzed Intermolecular Arylation of sp3 C–H Bonds

Pd(0)-catalyzed intermolecular arylation of sp(3) C-H bonds has been achieved using PR(3)/ArI. This protocol can be used to arylate a variety of aliphatic carboxylic acid derivatives, including a number of bioactive drug molecules. The use of fluorinated aryl iodides also allows for the introduction of fluorine into a molecule of interest.

Ligand-enabled meta-C-H activation using a transient mediator

Achieving site selectivity in C–H functionalization reactions is a significant challenge, especially when the target C–H bond is distant from existing functional groups. Coordination of a functional group to a metal is often a key driving force and control element in many important reactions including asymmetric hydrogenation, epoxidation and lithiation. Exploitation of this effect has led to the development of a broad range of directed C–H activation reactions. However, these C–H activation methods are limited to proximal C–H bonds, which are spatially and geometrically accessible from the directing functional group. The development of meta-selective C–H functionalizations remains a significant challenge. We recently developed a U-shaped template that can be used to overcome this constraint and have shown that it can be used to selectively activate remote meta-C–H bonds. Although this approach has proved to be applicable to various substrates and catalytic transformations, the need for a covalently attached, complex template is a substantial drawback for synthetic applications. Here we report an alternative approach employing norbornene as a transient mediator to achieve meta-selective C–H activation with a simple and common ortho-directing group. The use of a newly developed pyridine-based ligand is crucial for relaying the palladium catalyst to the meta position by norbornene after initial ortho-C–H activation. This catalytic reaction demonstrates the feasibility of switching ortho-selectivity to meta-selectivity in C–H activation of the same substrate by catalyst control.