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.

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

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 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 direct carbonylation of C-H bonds in the benzene ring of N-phenylpyrazoles via catalysis by ruthenium or rhodium complexes is described. The reaction of N-phenylpyrazoles with carbon monoxide and ethylene in the presence of Ru(3)(CO)(12) or Rh(4)(CO)(12) resulted in the site-selective carbonylation of the ortho C-H bonds in the benzene ring to give the corresponding ethyl ketones. A variety of functional groups on the benzene ring can be tolerated. N-Phenylpyrazoles have higher reactivities than would be expected, based on the pK(a) values of the conjugate acid of pyrazole. The choice of solvent for this reaction is significant, and N, N-dimethylacetamide (DMA) gives the best result.

Ruthenium- and rhodium-catalyzed direct carbonylation of the ortho C-H bond in the benzene ring of N-arylpyrazoles.

In contrast to a number of examples of stoichiomemc reactions involving C-H bond cleavage by transition metal complexes, the use of this chemistry in practical catalytic reactions is still rare. The catalytic reactions of this type generally suffer from low efficiency (low chemical yields, low catalyst turnover, necessity of the use of one of the reactants in large excess, often as the solvent, and necessity of extra energy input by photo irradiation etc.), low selectivity, and lack generality. During the past 30 years, the research in these fields has been very active and as much as 50 review articles have been published (refs. 1 and 2). Recently, exceptionally efficient catalytic reactions involving C-H bond cleavage were reported. Jordan and Taylor found a Zr-catalyzed addition of a-picoline to olefins in 1989 (ref. 3). Although the presence of molecular hydrogen was necessary to keep the catalyst turnover high and thus it inevitably forced the consumption of olefin by hydrogenation as a competing reaction, a quantitative yield of the product could be obtained. In 1992, Moore and co-workers reported on the coupling together of three reactants, pyridine, CO, and an olefin, using Ru,(CO),,as the catalyst (ref. 4). The oxygen atom of CO could not carry a substituent at the oxygen but the nitrogen in isoelectronic isonitrile could be envisioned to bear such and the plausibility of an intramolecular a-addition can be thus recognized. This was realized by Jones and Kosar (ref. 5 ) . It should be noted that various types of C-H bonds can react with the aid of transition metals through a variety of mechanisms ranging from oxidative addition to deprotonation. Some of these reactions are useful in organic synthesis. The selected examples are Pd-catalyzed functionalization of unsaturated and allylic C-H bonds (ref. 6) , Ru-catalyzed functionalization of C-H bonds a to hetero atoms (ref. 7), Ru-, Rh-, and Pd-catalyzed addition of active methylene compounds to unsaturated functions (ref. 8), Rhand Ru-catalyzed hydroacylation of olefins with aldehydes (ref. 9), Rh-catalyzed decarbonylation of aldehydes (ref. lo), and catalytic functionalization of olefins via addition-elimination mechanism (ref. 11).

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Catalytic addition of CH bonds to multiple bonds

Ruthenium- and rhodium-catalyzed intramolecular C–H/olefin coupling reactions of 1-(2-pyridyl)-, 1-(2-imidazolyl)-, and 1-(2-oxazolyl)-1,5-dienes proceeded in a regiospecific manner to give 5-membe...

Transition Metal-Catalyzed Intramolecular Cyclization of 1,5- and 1,6-Dienes via Direct Cleavage and Addition of the Carbon–Hydrogen Bond

The palladium-catalyzed ortho-selective chlorination of N-quinolinylbenzamide derivatives with hydrochloric acid was achieved under anodic oxidation conditions. The use of 5,7-dichloro-8-quinolinyl group as directing group was effective for the selective chlorination, and the reaction was applicable to benzamide derivatives bearing various functional groups. Synthesis of vismodegib was also completed using the palladium-catalyzed electrochemical C–H chlorination in two different steps.

Palladium-Catalyzed ortho-Selective C-H Chlorination of Benzamide Derivatives under Anodic Oxidation Conditions

The ruthenium-catalyzed carbonylation at the C−H bond of five-membered N-heteroaromatic compounds is described. The reaction of imidazoles with CO and olefins in toluene in the presence of a catalytic amount of Ru3(CO)12 results in carbonylation of the C−H bond at the 4-position (adjacent to the sp2-nitrogen) of the imidazole ring to give acylated imidazoles in good to high yields. A wide range of olefins can be utilized in the carbonylation reaction, and a variety of functional groups are compatible under the reaction conditions. Other five-membered N-heteroaromatic compounds, such as pyrazoles, oxazoles, and thiazoles, can also be used for the carbonylation reaction, and in all cases, carbonylation takes place exclusively at a C−H bond α to the sp2 nitrogen. The reactivity of the five-membered heterocycles corresponds to the pKa of the conjugate acid of these heterocycles. The higher the pKa of the substrate, the higher is the reactivity. This indicates that the pKa values are related to the ability of ...

Fumitoshi Kakiuchi

Papers

Ruthenium- and rhodium-catalyzed direct carbonylation of the ortho C-H bond in the benzene ring of N-arylpyrazoles.

Catalytic addition of CH bonds to multiple bonds

Transition Metal-Catalyzed Intramolecular Cyclization of 1,5- and 1,6-Dienes via Direct Cleavage and Addition of the Carbon–Hydrogen Bond

Palladium-Catalyzed ortho-Selective C-H Chlorination of Benzamide Derivatives under Anodic Oxidation Conditions

Acylation of Five-Membered N-Heteroaromatic Compounds by Ruthenium Carbonyl-Catalyzed Direct Carbonylation at a C−H Bond