Melanie S. Sanford

Palladium-Catalyzed Ligand-Directed C–H Functionalization Reactions

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.

Controlling Site Selectivity in Palladium-Catalyzed C–H Bond Functionalization

Effective methodology to functionalize C-H bonds requires overcoming the key challenge of differentiating among the multitude of C-H bonds that are present in complex organic molecules. This Account focuses on our work over the past decade toward the development of site-selective Pd-catalyzed C-H functionalization reactions using the following approaches: substrate-based control over selectivity through the use of directing groups (approach 1), substrate control through the use of electronically activated substrates (approach 2), or catalyst-based control (approach 3). In our extensive exploration of the first approach, a number of selectivity trends have emerged for both sp(2) and sp(3) C-H functionalization reactions that hold true for a variety of transformations involving diverse directing groups. Functionalizations tend to occur at the less-hindered sp(2) C-H bond ortho to a directing group, at primary sp(3) C-H bonds that are β to a directing group, and, when multiple directing groups are present, at C-H sites proximal to the most basic directing group. Using approach 2, which exploits electronic biases within a substrate, our group has achieved C-2-selective arylation of indoles and pyrroles using diaryliodonium oxidants. The selectivity of these transformations is altered when the C-2 site of the heterocycle is blocked, leading to C-C bond formation at the C-3 position. While approach 3 (catalyst-based control) is still in its early stages of exploration, we have obtained exciting results demonstrating that site selectivity can be tuned by modifying the structure of the supporting ligands on the Pd catalyst. For example, by modulating the structure of N-N bidentate ligands, we have achieved exquisite levels of selectivity for arylation at the α site of naphthalene. Similarly, we have demonstrated that both the rate and site selectivity of arene acetoxylation depend on the ratio of pyridine (ligand) to Pd. Lastly, by switching the ligand on Pd from an acetate to a carbonate, we have reversed the site selectivity of a 1,3-dimethoxybenzene/benzo[h]quinoline coupling. In combination with a growing number of reports in the literature, these studies highlight a frontier of catalyst-based control of site-selectivity in the development of new C-H bond functionalization methodology.

High-valent organometallic copper and palladium in catalysis

Copper and palladium catalysts are critically important in numerous commercial chemical processes. Improvements in the activity, selectivity and scope of these catalysts could drastically reduce the environmental impact, and increase the sustainability, of chemical reactions. One rapidly developing strategy for achieving these goals is to use ‘high-valent’ organometallic copper and palladium intermediates in catalysis. Here we describe recent advances involving both the fundamental chemistry and the applications of these high-valent metal complexes in numerous synthetically useful catalytic transformations.

Merging Visible-Light Photocatalysis and Transition-Metal Catalysis in the Copper-Catalyzed Trifluoromethylation of Boronic Acids with CF3I

This communication describes the development of a mild method for the cross-coupling of arylboronic acids with CF(3)I via the merger of photoredox and Cu catalysis. This method has been applied to the trifluoromethylation of electronically diverse aromatic and heteroaromatic substrates and tolerates many common functional groups.

Synthetic and mechanistic studies of Pd-catalyzed C-H arylation with diaryliodonium salts: evidence for a bimetallic high oxidation state Pd intermediate.

This contribution describes the substrate scope and mechanism of Pd-catalyzed ligand-directed C-H arylation with diaryliodonium salts. This transformation was applied to the synthesis of a variety of different biaryl products, using directing groups including pyridines, quinolines, pyrrolidinones, and oxazolidinones. Electronically and sterically diverse aryl groups (Ar) were transferred in high yield using iodine(III) reagents of general structure [Mes-I-Ar]BF(4). Mechanistic investigations have been conducted that establish the kinetic order of the catalytic reaction in each component, determine the resting state of the catalyst and the iodine(III) reagent, quantify the electronic influence of the arylating reagent on the reaction rate, and establish the intra- and intermolecular 1 degree H/D kinetic isotope effect. On the basis of these studies, this transformation is proposed to proceed via turnover-limiting oxidation of the Pd dimer [Pd(N~C)(OAc)](2) (N~C = 3-methyl-2-phenylpyridine) by [Mes-I-Ph]BF(4). This mechanism implicates a bimetallic high oxidation state Pd species as a key catalytic intermediate. The significance of this and other aspects of the proposed mechanism are discussed in detail.

Room-Temperature C–H Arylation: Merger of Pd-Catalyzed C–H Functionalization and Visible-Light Photocatalysis

This communication describes the development of a room-temperature ligand-directed C-H arylation reaction using aryldiazonium salts. This was achieved by the successful merger of palladium-catalyzed C-H functionalization and visible-light photoredox catalysis. The new method is general for a variety of directing groups and tolerates many common functional groups.

Cascade Catalysis for the Homogeneous Hydrogenation of CO2 to Methanol

This communication demonstrates the homogeneous hydrogenation of CO(2) to CH(3)OH via cascade catalysis. Three different homogeneous catalysts, (PMe(3))(4)Ru(Cl)(OAc), Sc(OTf)(3), and (PNN)Ru(CO)(H), operate in sequence to promote this transformation.

Detailed study of C-O and C-C bond-forming reductive elimination from stable C2N2O2-ligated palladium(IV) complexes

This paper describes the synthesis of a series of Pd(IV) complexes of general structure (N~C)(2)Pd(IV)(O(2)CR)(2) (N~C = a rigid cyclometalated ligand; O(2)CR = carboxylate) by reaction of (N~C)(2)Pd(II) with PhI(O(2)CR)(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 Pd(IV) 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 Pd(IV) centers.

Insights into directing group ability in palladium-catalyzed C-H bond functionalization.

This paper describes a detailed investigation of factors controlling the dominance of a directing group in Pd-catalyzed ligand-directed arene acetoxylation. Mechanistic studies, involving reaction kinetics, Hammett analysis, kinetic isotope effect experiments, and the kinetic order in oxidant, have been conducted for a series of different substrates. Initial rates studies of substrates bearing different directing groups showed that these transformations are accelerated by the use of electron-withdrawing directing groups. However, in contrast, under conditions where two directing groups are in competition with one another in the same reaction flask, substrates with electron-donating directing groups react preferentially. These results are discussed in the context of the proposed mechanism for Pd-catalyzed arene acetoxylation.

Aryl−CF3 Bond-Forming Reductive Elimination from Palladium(IV)

This communication describes oxidatively induced Ar-CF(3) bond-forming reductive elimination from new Pd(II) complexes of general structure (L approximately L)Pd(II)(Ar)(CF(3)). The electrophilic fluorinating reagent N-fluoro-2,4,6-trimethylpyridinium triflate promotes these reactions in good to excellent yields. The palladium(IV) intermediate ((t)Bu-bpy)Pd(IV)(CF(3))(F)(OTf)(C(6)H(4)F) has been isolated, characterized, and demonstrated to undergo high yielding Ar-CF(3) coupling upon thermolysis. This work provides an attractive conceptual framework for the development of Pd(II/IV)-catalyzed arene trifluoromethylation reactions.