1.1 Introduction to Pd-catalyzed directed C–H functionalization
The development of methods for the direct conversion of carbon–hydrogen bonds into carbon-oxygen, carbon-halogen, carbon-nitrogen, carbon-sulfur, and carbon-carbon bonds remains a critical challenge in organic chemistry. Mild and selective transformations of this type will undoubtedly find widespread application across the chemical field, including in the synthesis of pharmaceuticals, natural products, agrochemicals, polymers, and feedstock commodity chemicals. Traditional approaches for the formation of such functional groups rely on pre-functionalized starting materials for both reactivity and selectivity. However, the requirement for installing a functional group prior to the desired C–O, C–X, C–N, C–S, or C–C bond adds costly chemical steps to the overall construction of a molecule. As such, circumventing this issue will not only improve atom economy but also increase the overall efficiency of multi-step synthetic sequences.

Direct C–H bond functionalization reactions are limited by two fundamental challenges: (i) the inert nature of most carbon-hydrogen bonds and (ii) the requirement to control site selectivity in molecules that contain diverse C–H groups. A multitude of studies have addressed the first challenge by demonstrating that transition metals can react with C–H bonds to produce C–M bonds in a process known as “C–H activation”.1 The resulting C–M bonds are far more reactive than their C–H counterparts, and in many cases they can be converted to new functional groups under mild conditions.

The second major challenge is achieving selective functionalization of a single C–H bond within a complex molecule. While several different strategies have been employed to address this issue, the most common (and the subject of the current review) involves the use of substrates that contain coordinating ligands. These ligands (often termed “directing groups”) bind to the metal center and selectively deliver the catalyst to a proximal C–H bond. Many different transition metals, including Ru, Rh, Pt, and Pd, undergo stoichiometric ligand-directed C–H activation reactions (also known as cyclometalation).2,3 Furthermore, over the past 15 years, a variety of catalytic carbon-carbon bond-forming processes have been developed that involve cyclometalation as a key step.1b–d,4

The current review will focus specifically on ligand-directed C–H functionalization reactions catalyzed by palladium. Palladium complexes are particularly attractive catalysts for such transformations for several reasons. First, ligand-directed C–H functionalization at Pd centers can be used to install many different types of bonds, including carbon-oxygen, carbon-halogen, carbon-nitrogen, carbon-sulfur, and carbon-carbon linkages. Few other catalysts allow such diverse bond constructions,5,6,7 and this versatility is predominantly the result of two key features: (i) the compatibility of many PdII catalysts with oxidants and (ii) the ability to selectively functionalize cyclopalladated intermediates. Second, palladium participates in cyclometalation with a wide variety of directing groups, and, unlike many other transition metals, promotes C–H activation at both sp2 and sp3 C–H sites. Finally, the vast majority of Pd-catalyzed directed C–H functionalization reactions can be performed in the presence of ambient air and moisture, making them exceptionally practical for applications in organic synthesis.

While several accounts have described recent advances, this is the first comprehensive review encompassing the large body of work in this field over the past 5 years (2004–2009). Both synthetic applications and mechanistic aspects of these transformations are discussed where appropriate, and the review is organized on the basis of the type of bond being formed.

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Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions

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 direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

This communication describes a new and highly practical Pd(II)-catalyzed method for the regio- and chemoselective oxidative functionalization of arenes and alkanes. Carbon−hydrogen bonds of substrates that contain a variety of directing groups (e.g., pyridine, azobenzene, pyrazole, and imine derivatives) are selectively transformed into esters, ethers, and aryl-halides under mild conditions. The scope of this reaction in terms of substrate, directing group, and oxidant is described, and a preliminary catalytic cycle is proposed.

A Highly Selective Catalytic Method for the Oxidative Functionalization of C−H Bonds

Transition metal catalyzed oxidative functionalization of carbon-hydrogen bonds

This communication describes the synthesis of a family of unusually stable palladium(IV) complexes containing two chelating 2-phenylpyridine ligands and two benzoates. These complexes undergo clean C−O bond-forming reductive elimination upon heating, and the mechanism of this catalytically relevant process has been studied in detail. Solvent effects, crossover experiments, Eyring plots (which show ΔS⧧ of −1.4 ± 1.9 and 4.2 ± 1.4 in CDCl3 and DMSO, respectively), and Hammett analysis (which shows ρ = −1.36 ± 0.04 upon substitution of the para-benzoate substituent) all suggest that reductive elimination does not proceed via initial dissociation of a benzoate ligand. Instead, an unusual mechanism involving pre-equilibrium dissociation of the N-arm of the phenylpyridine ligand is proposed.

Unusually stable palladium(IV) complexes: detailed mechanistic investigation of C-O bond-forming reductive elimination.

This paper describes the synthesis of a series of PdIV complexes of general structure (N∼C)2PdIV(O2CR)2 (N∼C = a rigid cyclometalated ligand; O2CR = carboxylate) by reaction of (N∼C)2PdII with PhI(O2CR)2. The majority of these complexes undergo clean C−O bond-forming reductive elimination, and the mechanism of this process has been investigated. A variety of experiments, including Hammett plots, Eyring analysis, crossover studies, and investigations of the influence of solvent and additives, suggest that C−O bond-forming reductive elimination proceeds via initial carboxylate dissociation followed by C−O coupling from a 5-coordinate cationic PdIV intermediate. The mechanism of competing C−C bond-forming reductive elimination from these complexes has also been investigated and is proposed to involve direct reductive elimination from the octahedral PdIV centers.

Allison R. Dick

Papers

A Highly Selective Catalytic Method for the Oxidative Functionalization of C−H Bonds

Transition metal catalyzed oxidative functionalization of carbon-hydrogen bonds

Unusually stable palladium(IV) complexes: detailed mechanistic investigation of C-O bond-forming reductive elimination.

Detailed Study of C−O and C−C Bond-Forming Reductive Elimination from Stable C2N2O2−Ligated Palladium(IV) Complexes

A simple catalytic method for the regioselective halogenation of arenes