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.

In recent years, the olefin metathesis reaction has attracted widespread attention as a versatile carbon−carbon bond-forming method. Many new applications have become possible because of major advances in catalyst design. State-of-the-art ruthenium catalysts are not only highly active but also compatible with most functional groups and easy to use. This Account traces the ideas and discoveries that were instrumental in the development of these catalysts, with particular emphasis on (PCy3)2Cl2RuCHPh and its derivatives. The discussion includes an analysis of trends in catalyst activity, a description of catalysts coordinated with N-heterocyclic carbene ligands, and an overview of ongoing work to improve the activity, stability, and selectivity of this family of L2X2RuCHR complexes.

http://web4.uwindsor.ca/users/j/jlichaa/reference.nsf/0/10ff8b04ff3a317885256d88005720f6/$FILE/acr-2001-34-18-metath-grubbs.pdf

The Development of L2X2RuCHR Olefin Metathesis Catalysts: An Organometallic Success Story

The biaryl structural motif is a predominant feature in many pharmaceutically relevant and biologically active compounds. As a result, for over a century 1 organic chemists have sought to develop new and more efficient aryl -aryl bond-forming methods. Although there exist a variety of routes for the construction of aryl -aryl bonds, arguably the most common method is through the use of transition-metalmediated reactions. 2-4 While earlier reports focused on the use of stoichiometric quantities of a transition metal to carry out the desired transformation, modern methods of transitionmetal-catalyzed aryl -aryl coupling have focused on the development of high-yielding reactions achieved with excellent selectivity and high functional group tolerance under mild reaction conditions. Typically, these reactions involve either the coupling of an aryl halide or pseudohalide with an organometallic reagent (Scheme 1), or the homocoupling of two aryl halides or two organometallic reagents. Although a number of improvements have developed the former process into an industrially very useful and attractive method for the construction of aryl -aryl bonds, the need still exists for more efficient routes whereby the same outcome is accomplished, but with reduced waste and in fewer steps. In particular, the obligation to use coupling partners that are both activated is wasteful since it necessitates the installation and then subsequent disposal of stoichiometric activating agents. Furthermore, preparation of preactivated aryl substrates often requires several steps, which in itself can be a time-consuming and economically inefficient process.

http://aether.cmi.ua.ac.be/artikels/Artikels%20Gitte/Artikels/Reviews/Heck-Type-lautens.pdf

Aryl-aryl bond formation by transition-metal-catalyzed direct arylation.

Although homogeneous gold catalysis was known previously, an exponential growth was only induced 12 years ago. The key findings which induce that rise of the field are discussed. This includes early reactions of allenes and furanynes and intermediates of these conversions as well as hydroarylation reactions. Other substrate types addressed are alkynyl epoxides and N-propargyl carboxamides. Important vinylgold intermediates, the transmetalation from gold to other transition metals, the development of new ligands for gold catalysis, and significant contributions from computational chemistry are other crucial points for the field highlighted here.

Gold-Catalyzed Organic Reactions

Despite the impressive progress achieved in asymmetric catalysis during the last decade, an increasing number of new catalysts, ligands, and applications are reported every year to satisfy the need to embrace a wider range of reactions and to improve the efficiency of existing processes. Because of their availability, unique stereochemical aspects, and wide variety of coordination modes and possibilities for the fine-tuning of the steric and electronic properties, ferrocene-based ligands constitute one of the most versatile ligand architectures in the current scenario of asymmetric catalysis. Over the last few years ferrocene catalysts have been successfully applied in an amazing variety of enantioselective processes. This Review documents these recent advances, with special emphasis on the most innovative asymmetric processes and the development of novel, efficient types of ferrocene ligands.

Recent applications of chiral ferrocene ligands in asymmetric catalysis.

Novel dipolarophiles and dipoles in the metal-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides.

Driven by its synthetic power and environmental friendliness, C C bond-forming reactions through catalytic activation of Csp2 H bonds constitutes a hot area of research. Since the pioneering work by Murai et al. and Fujiwara and coworkers, remarkable progress has been made in this field, with palladium occupying a prevalent position. Most of these procedures rely on the use of a coordinating functionality that aids in the transition metal mediated functionalization of a proximal C H bond. However, from a synthetic viewpoint, the practicality of the directing groups can be compromised when the target molecule does not contain such functionality. Therefore, the discovery of efficient and removable directing groups is in high demand. Owing to the prevalence of the indole unit in pharmaceuticals and bioactive natural products, its regioselective C H functionalization represents an important challenge in this area. In contrast to the much more developed C H arylation reactions, direct alkenylations have received much less attention. A particularly challenging transformation is the intermolecular direct alkenylation at the C2-position, for which only three protocols have been reported. Ricci and co-workers reported the palladium(II)-catalyzed regiocontrolled C2 alkenylation of indole directed by a nonremovable N-2-pyridylmethyl group. Gaunt and co-workers described a practical method for the palladium(II)-catalyzed alkenylation of indoles (without an N-protecting group) in which the regioselectivity can be switched from C3 to C2 by varying the nature of the solvent and additives. However, decreased reaction yield was found in C2 alkenylation. Miura, Satoh et al. disclosed the palladium(II)-catalyzed C H alkenylation/decarboxylation of indole-3-carboxylic acids to afford exclusively 2-alkenyl indoles, where the carboxyl group blocks the C3-position and acts as a removable directing group. Despite these important advances there is room for innovation, both in increasing the efficiency of the reaction and in improving the current limited scope with regard to both the alkene component and directing group. To date, only monosubstituted electrophilic alkenes (mainly acrylates) have been applied in the C2 alkenylation of indoles, except for one isolated example of coupling with styrene. We disclose herein a highly efficient and structurally versatile palladium(II)-catalyzed C2 alkenylation of indoles and pyrroles employing the easily installed and removed N-(2pyridyl)sulfonyl directing group. Given the electrophilic nature of the palladium(II) center, our first challenge was to find an N-protecting group for the C2 functionalization of indole instead of the more nucleophilic C3-position. A set of potential directing groups were examined in the reaction of derivatives 2–7 with methyl acrylate under [Pd(CH3CN)2Cl2] catalysis (10 mol%) using Cu(OAc)2·H2O (1 equiv) as an oxidant in DMA at 110 8C (Table 1). Not unexpectedly, under such conditions the indole 1 cleanly underwent C3 alkenylation with complete regiocontrol (Table 1, entry 1). In contrast, the Bocprotected derivative 2 led to a 68:32 mixture of C2/C3 alkenylation products, in very low conversion (Table 1, entry 2). Both C2 regioselectivity and conversion were enhanced by switching to a Ts group (Table 1, entry 3) or a p-Ns group (Table 1, entry 4), albeit at an unpractical level. NHeteroarylsulfonyl groups strongly influenced the reactivity and regiocontrol. For example, the N-(2-thienyl)sulfonyl group in 5 led to low conversion and no regiocontrol

Palladium(II)‐Catalyzed Regioselective Direct C2 Alkenylation of Indoles and Pyrroles Assisted by the N‐(2‐Pyridyl)sulfonyl Protecting Group

Recent advances in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides

Optically active α,β-diamino acids are very attractive targets in organic synthesis because of their wide-ranging biological significance and high versatility as synthetic building blocks. Efficient synthesis of such non-proteinogenic amino acid derivatives must face the challenge of generating two contiguous stereocenters with complete diastereo- and enantiocontrol in flexible, acyclic molecules. The catalytic asymmetric direct Mannich reaction has provided elegant and efficient solutions for the stereocontrolled assembly of both syn- and anti-α,β-diamino acid derivatives, including those with a α-tetrasubstituted carbon stereocenter, with the aid of either organometallic or purely organic chiral catalysts (or the combination of both). This tutorial review highlights progress in this area, which has recently been boosted through two complementary strategies: the direct Mannich reaction of glycine ester Schiff bases with imines and the direct aza-Henry reaction between nitro compounds and imines.

Juan C. Carretero

Papers

Recent applications of chiral ferrocene ligands in asymmetric catalysis.

Novel dipolarophiles and dipoles in the metal-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides.

Palladium(II)‐Catalyzed Regioselective Direct C2 Alkenylation of Indoles and Pyrroles Assisted by the N‐(2‐Pyridyl)sulfonyl Protecting Group

Recent advances in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides

Catalytic asymmetric direct Mannich reaction: a powerful tool for the synthesis of alpha,beta-diamino acids.