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

Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds

Once considered the 'holy grail' of organometallic chemistry, synthetically useful reactions employing C-H bond activation have increasingly been developed and applied to natural product and drug synthesis over the past decade. The ubiquity and relative low cost of hydrocarbons makes C-H bond functionalization an attractive alternative to classical C-C bond forming reactions such as cross-coupling, which require organohalides and organometallic reagents. In addition to providing an atom economical alternative to standard cross - coupling strategies, C-H bond functionalization also reduces the production of toxic by-products, thereby contributing to the growing field of reactions with decreased environmental impact. In the area of C-C bond forming reactions that proceed via a C-H activation mechanism, rhodium catalysts stand out for their functional group tolerance and wide range of synthetic utility. Over the course of the last decade, many Rh-catalyzed methods for heteroatom-directed C-H bond functionalization have been reported and will be the focus of this review. Material appearing in the literature prior to 2001 has been reviewed previously and will only be introduced as background when necessary. The synthesis of complex molecules from relatively simple precursors has long been a goal for many organic chemists. The ability to selectively functionalize a molecule with minimal pre-activation can streamline syntheses and expand the opportunities to explore the utility of complex molecules in areas ranging from the pharmaceutical industry to materials science. Indeed, the issue of selectivity is paramount in the development of all C-H bond functionalization methods. Several groups have developed elegant approaches towards achieving selectivity in molecules that possess many sterically and electronically similar C-H bonds. Many of these approaches are discussed in detail in the accompanying articles in this special issue of Chemical Reviews. One approach that has seen widespread success involves the use of a proximal heteroatom that serves as a directing group for the selective functionalization of a specific C-H bond. In a survey of examples of heteroatom-directed Rh catalysis, two mechanistically distinct reaction pathways are revealed. In one case, the heteroatom acts as a chelator to bind the Rh catalyst, facilitating reactivity at a proximal site. In this case, the formation of a five-membered metallacycle provides a favorable driving force in inducing reactivity at the desired location. In the other case, the heteroatom initially coordinates the Rh catalyst and then acts to stabilize the formation of a metal-carbon bond at a proximal site. A true test of the utility of a synthetic method is in its application to the synthesis of natural products or complex molecules. Several groups have demonstrated the applicability of C-H bond functionalization reactions towards complex molecule synthesis. Target-oriented synthesis provides a platform to test the effectiveness of a method in unique chemical and steric environments. In this respect, Rh-catalyzed methods for C-H bond functionalization stand out, with several syntheses being described in the literature that utilize C-H bond functionalization in a key step. These syntheses are highlighted following the discussion of the method they employ.

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Rhodium-Catalyzed C-C Bond Formation via Heteroatom-Directed C-H Bond Activation

Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of "microwave flash heating" in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200400655

Controlled microwave heating in modern organic synthesis.

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.

Ru-, Rh-, and Pd-Catalyzed C-C Bond Formation Involving C-H Activation and Addition on Unsaturated Substrates: Reactions and Mechanistic Aspects

Cyclometallated compounds, obtained by direct intramolecular C–H activation of a ligand by transition metals, are fairly reactive [especially those derived from palladium(II)] towards insertion of internal alkynes into their metal-carbon bond. This reaction leads to either new organometallic compounds by inclusion of one to three alkynes into the M-C bond, or organic compounds which are either carbocyclic or heterocyclic, their nature depending upon the alkyne substituents as well as upon the cyclometallated ligand.

Reactions of cyclopalladated compounds and alkynes: New pathways for organic synthesis?

The syntheses of cycloruthenated compounds by several methods, and especially by the C–H activation pathway, have been reviewed. Many ruthenium-containing starting materials lead to these interesting organometallic compounds, which have found various applications in different fields of chemistry. Their reactivity highlights both thevariety of reactions that were found to occur at the Ru–C bonds as well as the inertness of the organometallic moiety when these species are exposed to strongly oxidizing molecules or to reactive halogenation reagents. Their use as catalyst precursors showed them to be particularly efficient for hydrogenation reactions, either by H2 or by hydride transfer. Physicochemical characteristics of cycloruthenated complexes include: (i) a cathodic shift of the electrochemical potentials corresponding to various redox couples, (ii) a bathochromic shift of UV/Vis absorption bands, (iii) valuable luminescence properties. Dinuclear cycloruthenated complexes display specific properties connected to interactions between the metals, such as strong electronic coupling, evidenced by intervalence bands of mixed-valence species, or efficient energy transfer.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Cycloruthenated Compounds – Synthesis and Applications

Cisplatin-derived anticancer therapy has been used for three decades despite its side effects Other types of organometallic complexes, namely, some ruthenium-derived compounds (RDC), which would display cytotoxicity through different modes of action, might represent alternative therapeutic agents We have studied both in vitro and in vivo the biological properties of RDC11, one of the most active compounds of a new class of RDCs that contain a covalent bond between the ruthenium atom and a carbon We showed that RDC11 inhibited the growth of various tumors implanted in mice more efficiently than cisplatin Importantly, in striking contrast with cisplatin, RDC11 did not cause severe side effects on the liver, kidneys, or the neuronal sensory system We analyzed the mode of action of RDC11 and showed that RDC11 interacted poorly with DNA and induced only limited DNA damages compared with cisplatin, suggesting alternative transduction pathways Indeed, we found that target genes of the endoplasmic reticulum stress pathway, such as Bip, XBP1, PDI, and CHOP, were activated in RDC11-treated cells Induction of the transcription factor CHOP, a crucial mediator of endoplasmic reticulum stress apoptosis, was also confirmed in tumors treated with RDC11 Activation of CHOP led to the expression of several of its target genes, including proapoptotic genes In addition, the silencing of CHOP by RNA interference significantly reduced the cytotoxicity of RDC11 Altogether, our results led us to conclude that RDC11 acts by an atypical pathway involving CHOP and endoplasmic reticulum stress, and thus might provide an interesting alternative for anticancer therapy

http://cancerres.aacrjournals.org/content/canres/69/13/5458.full.pdf

A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP

Cyclometallated compounds obtained via the well-known intramolecular C-H activation by transition metals of N- or S- containing ligands may lead to organic heterocycles through reaction with alkynes. The mechanistic implications of the formation of both C-C and C-Y bonds are discussed. A reaction pathway involving insertion of the alkyne into the metal- carbon bond of the starting material followed by intramolecular addition of the Y atom to the resulting metallated-vinyl unit is proposed based on both the regioselectivity of the insertion and the existence of genuine isolated intermediates for the formation of the heterocyclic compounds.

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Michel Pfeffer

Papers

Ru-, Rh-, and Pd-Catalyzed C-C Bond Formation Involving C-H Activation and Addition on Unsaturated Substrates: Reactions and Mechanistic Aspects

Reactions of cyclopalladated compounds and alkynes: New pathways for organic synthesis?

Cycloruthenated Compounds – Synthesis and Applications

A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP

Selected applications to organic synthesis of intramolecular C-H activation reactions by transition metals