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 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.

Fluorogenic and chromogenic chemosensors and reagents for anions.

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.

Abstract The three-dimensional structure of carbohelicenes has fascinated generations of molecular chemists and has been exploited in a wide range of applications. Their strong circularly polarized luminescence has attracted considerable attention in recent years due to promising applications in new optical materials. Although the enantioselective synthesis of fused carbo- and heterohelicenes has been achieved, a direct catalytic enantioselective method allowing the synthesis of lower, non-fused carbo[ n ]helicenes ( n = 4–6) is still lacking. We report here that Pd-catalysed enantioselective C–H arylation in the presence of a unique bifunctional phosphine-carboxylate ligand provides a simple and general access to these lower carbo[ n ]helicenes. Computational mechanistic studies indicate that both the C–H activation and reductive elimination steps contribute to the overall enantioselectivity. The observed enantio-induction seems to arise from a combination of non-covalent interactions and steric repulsion between the substrate and ligand during the two key reductive elimination steps. The photophysical and chiroptical properties of the synthesized scalemic [ n ]helicenes have been systematically studied. 

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A C–H activation-based enantioselective synthesis of lower carbo[n]helicenes

Corrigendum: Functionalization of Organic Molecules by Transition‐Metal‐Catalyzed C(sp3)H Activation

An efficient catalytic system has been developed for the synthesis of benzocyclobutenes by C−H activation of methyl groups. The optimal conditions employed a combination of Pd(OAc)2 and PtBu3 as catalyst, K2CO3 as the base, and DMF as solvent. A variety of substituted BCB were obtained under these conditions with yields in the 44−92% range, including molecules that are hardly accessible by other methods. The reaction was found limited to substrates bearing a quaternary benzylic carbon, but benzocyclobutenes bearing a tertiary benzylic carbon could be obtained indirectly from diesters by decarboxylation. Reaction substrates bearing a small substituent para to bromine gave an unexpected regioisomer that likely arose from a 1,4-palladium migration process. The formation of this “abnormal” regioisomer could be suppressed by introducing a larger subsituent para to bromine. DFT(B3PW91) calculations on the reaction of 2-bromo-tert-butylbenzene with Pd(PtBu3) with different bases (acetate, bicarbonate, carbonate)...

Synthesis of Benzocyclobutenes by Palladium-Catalyzed C—H Activation of Methyl Groups: Method and Mechanistic Study.

C ? H Bond Alkylation (Including Hydroarylation of Alkenes)

Polycyclic molecules were obtained in good yields by double C(sp2)−H/C(sp3)−H arylations mediated by a single palladium/phosphine catalyst. Both double intermolecular/intramolecular and intramolecular/intramolecular C−C couplings were performed successfully, which indicates that this concept has a broad applicability for the rapid construction of molecular complexity.

Olivier Baudoin

Papers

A C–H activation-based enantioselective synthesis of lower carbo[n]helicenes

Corrigendum: Functionalization of Organic Molecules by Transition‐Metal‐Catalyzed C(sp3)H Activation

Synthesis of Benzocyclobutenes by Palladium-Catalyzed C—H Activation of Methyl Groups: Method and Mechanistic Study.

C ? H Bond Alkylation (Including Hydroarylation of Alkenes)

Synthesis of Polycyclic Molecules by Double C(sp2)—H/C(sp3)—H Arylations with a Single Palladium Catalyst.