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.

A catalytic asymmetric synthesis of the axially chiral bridged biaryl (-)-2, a structural analogue of natural (-)-rhazinilam possessing original antimitotic properties, is described. The key step is an intermolecular asymmetric Suzuki coupling, furnishing the nonbridged biaryl (-)-6, precursor of (-)-2, with up to 40% ee using binaphthyl ligand 7a. Various known or new binaphthyl and ferrocenyl phosphines as well as phosphetanes were screened as ligands in this reaction, the conditions of which were optimized. The comparison with another Suzuki coupling system showed that 7a is the most versatile ligand described to date for this type of transformation. This work gives the first application of the asymmetric Suzuki coupling to a biologically relevant target.

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Asymmetric Synthesis of an Axially Chiral Antimitotic Biaryl via an Atropo‐Enantioselective Suzuki Cross‐Coupling.

The immunosuppressive agent sanglifehrin A has been prepared for the first time by total synthesis. The construction of the macrocyclic unit of the target molecule was achieved through a selective intramolecular Stille coupling, and the spirolactam unit by Paterson-aldol reactions. The final steps involve an intermolecular Stille coupling and the opening of the internal acetal unit. This convergent synthesis opens the way for the synthesis of libraries of novel sanglifehrin analogues for biological screening.

Total Synthesis of Sanglifehrin A.

Palladium-Catalyzed Borylation of Ortho-Substituted Phenyl Halides and Application to the One-Pot Synthesis of 2,2′-Disubstituted Biphenyls.

3-Arylpiperidines are important building blocks in pharmaceutical research. They are usually synthesized through the construction of the piperidine ring or the reduction of a 3-arylpyridine precursor, because the inert character of the C–H bonds in β-position to the nitrogen atom is commonly thought to preclude direct β-functionalization. Palladium-catalyzed migrative Negishi coupling was developed to directly access 3-aryl-N-Boc-piperidines in good to excellent selectivity, and with yields between 43 and 76%. The design of a new flexible phenylpyrrole-based phosphine ligand proved to be a key element to induce both efficiency and β-selectivity.


Keywords:

n-Butyllithium;
tert-Butyl 3-(3-methoxyphenyl)piperidine-1-carboxylate;
Degassed methanol;
2-(Diisoproylphosphanyl)-1-phenylpyrrole;
n-Hexane;
Palladium-catalyzed β-selective C(sp3)-H arylation;
N-Boc-Piperidines;
Teflon-coated magnetic stirbar;
Toluene

Palladium-catalyzed β -Selective C(sp3)-H Arylation of N-Boc-Piperidines

The copper-catalyzed C(sp2)¢H trifluoromethylation of N,N-disubstituted hydrazones using the Togni reagent is demonstrated to proceed efficiently for aliphatic aldehyde-derived substrates. The success of the reactions relied on the choice of the N,N-diphenylamino group as the terminal hydrazone amino group where N,N-dialkylamino groups were preferred for (hetero)aromatic aldehyde-derived substrates. In addition, the trifluoromethylated N-arylhydrazones are shown to be ideal substrates for Fischer indole synthesis allowing a straightforward, three-step access to 2-trifluoromethylindole derivatives from simple aldehydes.

Olivier Baudoin

Papers

Asymmetric Synthesis of an Axially Chiral Antimitotic Biaryl via an Atropo‐Enantioselective Suzuki Cross‐Coupling.

Total Synthesis of Sanglifehrin A.

Palladium-Catalyzed Borylation of Ortho-Substituted Phenyl Halides and Application to the One-Pot Synthesis of 2,2′-Disubstituted Biphenyls.

Palladium-catalyzed β -Selective C(sp3)-H Arylation of N-Boc-Piperidines

Copper-Catalyzed Trifluoromethylation of Aliphatic N-Arylhydrazones: A Concise Synthetic Entry to 2-Trifluoromethylindoles from Simple Aldehydes.