Pick your Pd partners: A number of catalytic systems have been developed for palladium-catalyzed CH activation/CC bond formation. Recent studies concerning the palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle are discussed (see scheme), and the versatility and practicality of this new mode of catalysis are presented. Unaddressed questions and the potential for development in the field are also addressed.

In the past decade, palladium-catalyzed CH activation/CC 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 CC bonds from CH bonds: PdII/Pd0, PdII/PdIV, Pd0/PdII/PdIV, and Pd0/PdII catalysis. A more detailed discussion is then directed towards the recent development of palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.

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Palladium(II)-catalyzed C-H activation/C-C cross-coupling reactions: versatility and practicality.

The site-selective formation of carbon-carbon bonds through direct functionalizations of otherwise unreactive carbon-hydrogen bonds constitutes an economically attractive strategy for an overall streamlining of sustainable syntheses. In recent decades, intensive research efforts have led to the development of various reaction conditions for challenging C-H bond functionalizations, among which transition-metal-catalyzed transformations arguably constitute thus far the most valuable tool. For instance, the use of inter alia palladium, ruthenium, rhodium, copper, or iron complexes set the stage for chemo-, site-, diastereo-, and/or enantioselective C-H bond functionalizations. Key to success was generally a detailed mechanistic understanding of the elementary C-H bond metalation step, which depending on the nature of the metal fragment can proceed via several distinct reaction pathways. Traditionally, three different modes of action were primarily considered for CH bond metalations, namely, (i) oxidative addition with electronrich late transition metals, (ii) σ-bond metathesis with early transition metals, and (iii) electrophilic activation with electrondeficient late transition metals (Scheme 1). However, more recent mechanistic studies indicated the existence of a continuum of electrophilic, ambiphilic, and nucleophilic interactions. Within this continuum, detailed experimental and computational analysis provided strong evidence for novel C-H bond metalationmechanisms relying on the assistance of a bifunctional ligand bearing an additional Lewis-basic heteroatom, such as that found in (heteroatom-substituted) secondary phosphine oxides or most prominently carboxylates (Scheme 1, iv). This novel insight into the nature of stoichiometric metalations has served as stimulus for the development of novel transformations based on cocatalytic amounts of carboxylates, which significantly broadened the scope of C-H bond functionalizations in recent years, with most remarkable progress being made in palladiumor ruthenium-catalyzed direct arylations and direct alkylations. These carboxylate-assisted C-H bond transformations were mostly proposed to proceed via a mechanism in which metalation takes place via a concerted base-assisted deprotonation. To mechanistically differentiate these intramolecular metalations new acronyms have recently been introduced into the literature, such as CMD (concerted metalationdeprotonation), IES (internal electrophilic substitution), or AMLA (ambiphilic metal ligand activation), which describe related mechanisms and will be used below where appropriate. This review summarizes the development and scope of carboxylates as cocatalysts in transition-metal-catalyzed C-H functionalizations until autumn 2010. Moreover, experimental and computational studies on stoichiometric metalation reactions being of relevance to the mechanism of these catalytic processes are discussed as well. Mechanistically related C-H bond cleavage reactions with ruthenium or iridium complexes bearing monodentate ligands are, however, only covered with respect to their working mode, and transformations with stoichiometric amounts of simple acetate bases are solely included when their mechanism was suggested to proceed by acetate-assisted metalation.

Carboxylate-assisted transition-metal-catalyzed C-H bond functionalizations: mechanism and scope.

The area of transition-metal-catalyzed direct arylation through cleavage of CH bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with organometallic reagents In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners—including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations

Transition-metal-catalyzed direct arylation of (hetero)arenes by C-H bond cleavage.

The medicinal chemistry community has become increasingly aware of the value of tracking calculated physical properties such as molecular weight, topological polar surface area, rotatable bonds, and hydrogen bond donors and acceptors. We hypothesized that the shift to high-throughput synthetic practices over the past decade may be another factor that may predispose molecules to fail by steering discovery efforts toward achiral, aromatic compounds. We have proposed two simple and interpretable measures of the complexity of molecules prepared as potential drug candidates. The first is carbon bond saturation as defined by fraction sp3 (Fsp3) where Fsp3 = (number of sp3 hybridized carbons/total carbon count). The second is simply whether a chiral carbon exists in the molecule. We demonstrate that both complexity (as measured by Fsp3) and the presence of chiral centers correlate with success as compounds transition from discovery, through clinical testing, to drugs. In an attempt to explain these observations,...

Escape from flatland: increasing saturation as an approach to improving clinical success.

The cores of many types of polymers, ligands, natural products, and pharmaceuticals contain biaryl or substituted aromatic structures, and efficient methods of synthesizing these structures are crucial to the work of a broad spectrum of organic chemists. Recently, Pd-catalyzed carbon−carbon bond-forming processes, particularly the Suzuki−Miyaura cross-coupling reaction (SMC), have risen in popularity for this purpose. The SMC has many advantages over other methods for constructing these moieties, including mild conditions, high tolerance toward functional groups, the commercial availability and stability of its reagents, and the ease of handling and separating byproducts from its reaction mixtures. Until 1998, most catalysts for the SMC employed triarylphosphine ligands. More recently, new bulky and electron-rich phosphine ligands, which can dramatically improve the efficiency and selectivity of such cross-coupling reactions, have been introduced. In the course of our studies on carbon−nitrogen bond-formi...

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Palladium-Catalyzed Suzuki-Miyaura Cross-coupling Reactions Employing Dialkylbiaryl Phosphine Ligands

Suzuki−Miyaura coupling reactions of aryl and heteroaryl halides with aryl-, heteroaryl- and vinylboronic acids proceed in very good to excellent yield with the use of 2-(2‘,6‘-dimethoxybiphenyl)dicyclohexylphosphine, SPhos (1). This ligand confers unprecedented activity for these processes, allowing reactions to be performed at low catalyst levels, to prepare extremely hindered biaryls and to be carried out, in general, for reactions of aryl chlorides at room temperature. Additionally, structural studies of various 1·Pd complexes are presented along with computational data that help elucidate the efficacy that 1 imparts on Suzuki−Miyaura coupling processes. Moreover, a comparison of the reactions with 1 and with 2-(2‘,4‘,6‘-triisopropylbiphenyl)diphenylphosphine (2) is presented that is informative in determining the relative importance of ligand bulk and electron-donating ability in the high activity of catalysts derived from ligands of this type. Further, when the aryl bromide becomes too hindered, an ...

Catalysts for Suzuki−Miyaura Coupling Processes: Scope and Studies of the Effect of Ligand Structure

Despite advances in the Suzuki–Miyaura cross-coupling process, the need for an operationally simple and general system remains. The minimum criteria for an optimum system that must be met include: 1) a broad substrate scope, 2) the ability to make truly hindered biaryls, 3) the ability to operate at low levels of catalyst for a range of substrates not just with the most simple examples (e.g., other than phenyl boronic acid), and 4) the ability to operate at room temperature. Moreover, it is most desirable to develop protocols that do not necessitate the use of a glovebox. Herein we report a catalyst system based on a new ligand that meets the above four criteria, has unprecedented scope, reactivity, and stability, uses only commercially available, air-stable components, and is experimentally simple to employ. Our previous work on cross-coupling methodology demonstrated that dialkylphosphanylbiphenyls were excellent supporting ligands. We have reported that these can be prepared by the addition of an aryl Grignard reagent to an insitu-generated benzyne intermediate, followed by trapping of the newly formed organomagnesium complex with ClPR2. [3] The thought process that led to the design of the new ligand 1 is shown in Scheme 1. Mechanistic studies in our laboratory indicated that the elimination of ortho hydrogens on the bottom ring (that not bearing the dialkylphosphanyl group) was important for catalyst activity and longevity. We believe that this is due to two effects: 1) prevention of cyclometalation (to form a palladacycle), which diminishes catalyst lifetime, and 2) increased steric bulk relative to complexes with two ortho hydrogens. We also feel that it is important that the two methoxy groups are smaller in size than two alkyl groups as in our previously reported ligands. Moreover, the lone pairs of the alkoxy groups might interact with the Pd center and/or add electron density to the ligand backbone. The latter could be important as the interaction of the metal with the bottom ring is well documented and could help stabilize intermediate complexes. Furthermore, the 1,3-dimethoxybenzene moiety offers the advantage that it can be installed by means

http://sites.fas.harvard.edu/~chem253/lit/c253lit3.pdf

A rationally designed universal catalyst for Suzuki-Miyaura coupling processes

Palladium‐Catalyzed Aminocarbonylation of Aryl Chlorides at Atmospheric Pressure: The Dual Role of Sodium Phenoxide

A method for the Pd-catalyzed carbonylation of aryl bromides has been developed using Xantphos as the ligand. This method is effective for the direct synthesis of Weinreb amides, 1° and 2° benzamides, and methyl esters from the corresponding aryl bromides at atmospheric pressure. In addition, a putative catalytic intermediate, (Xanphos)Pd(Br)benzoyl, was prepared and an X-ray crystal structure was obtained revealing an unusual cis-coordination mode of Xantphos in this palladium−acyl complex.

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Joseph R. Martinelli

Papers

Catalysts for Suzuki−Miyaura Coupling Processes: Scope and Studies of the Effect of Ligand Structure

A rationally designed universal catalyst for Suzuki-Miyaura coupling processes

Palladium‐Catalyzed Aminocarbonylation of Aryl Chlorides at Atmospheric Pressure: The Dual Role of Sodium Phenoxide

Palladium-catalyzed carbonylation reactions of aryl bromides at atmospheric pressure: a general system based on Xantphos.

Accelerating reactions with microreactors at elevated temperatures and pressures: profiling aminocarbonylation reactions.