Transition Metal Catalyzed Coupling Reactions under C−H Activation

C−C coupling by transition metal catalyzed C−H activation has developed into a diverse area of research. The applicable catalysts are manifold, and the variety of products obtained range from basic chemicals to pharmaceuticals and building blocks for carbon networks. One reaction, in which several C−C bonds are formed under C−H activation of a methyl group, is the conversion of ortho-iodoanisole according to Equation (1).     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Rhodium‐Catalyzed Enantioselective Silylation of Cyclopropyl C−H Bonds

Hydrosilyl ethers, generated in situ by the dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo asymmetric, intramolecular silylation of cyclopropyl C?H bonds in high yields and with high enantiomeric excesses in the presence of a rhodium catalyst derived from a rhodium precursor and the bisphosphine (S)‐DTBM‐SEGPHOS. The resulting enantioenriched oxasilolanes are suitable substrates for the Tamao–Fleming oxidation to form cyclopropanols with conservation of the ee value from the C?H silylation. Preliminary mechanistic data suggest that C?H cleavage is likely to be the turnover‐limiting and enantioselectivity‐determining step.     

Chiral N‐Heterocyclic Carbene Ligands Enable Asymmetric C−H Bond Functionalization

The asymmetric functionalization of C?H bond is a particularly valuable approach for the production of enantioenriched chiral organic compounds. Chiral N‐heterocyclic carbene (NHC) ligands have become ubiquitous in enantioselective transition‐metal catalysis. Conversely, the use of chiral NHC ligands in metal‐catalyzed asymmetric C?H bond functionalization is still at an early stage. This minireview highlights all the developments and the new advances in this rapidly evolving research area.     

Mild C−H/C−C Activation by Z‐Selective Cobalt Catalysis

Cationic cobalt complexes enable unprecedented cobalt‐catalyzed C?H/C?C functionalizations with unique selectivity features. The versatile cobalt catalyst proved broadly applicable, enabled efficient C?H/C?C cleavage at room temperature, and delivered Z‐alkenes with excellent diastereocontrol.     

Chemically Non‐Innocent Cyclic (Alkyl)(Amino)Carbenes: Ligand Rearrangement,C−H and C−F Bond Activation

A cyclic (alkyl)(amino)carbene (CAAC) was found to undergo unprecedented rearrangements and transformations of its core structure in the presence of Group 1 and 2 metals. Although the carbene was also found to be prone to intramolecular C?H activation, it was competent for intermolecular activation of a variety of sp‐, sp²‐, and sp³‐hybridized C?H bonds. Double C?F activation of hexafluorobenzene was also observed in this work. These processes all hold relevance to the role of these carbenes in catalysis, as well as to their use in the synthesis of new and unusual main group or transition metal complexes.     

Chiral Bifunctional Phosphine‐Carboxylate Ligands for Palladium(0)‐Catalyzed Enantioselective C−H Arylation

Previous enantioselective Pd⁰‐catalyzed C?H activation reactions proceeding via the concerted metalation‐deprotonation mechanism employed either a chiral ancillary ligand, a chiral base, or a bimolecular mixture thereof. This study describes the development of new chiral bifunctional ligands based on a binaphthyl scaffold which incorporates both a phosphine and a carboxylic acid moiety. The optimal ligand provided high yields and enantioselectivities for a desymmetrizing C(sp²)?H arylation leading to 5,6‐dihydrophenanthridines, whereas the corresponding monofunctional ligands showed low enantioselectivities. The bifunctional system proved applicable to a range of substituted dihydrophenanthridines, and allowed the parallel kinetic resolution of racemic substrates.     

A Chiral Nitrogen Ligand for Enantioselective,Iridium‐Catalyzed Silylation of Aromatic C−H Bonds

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C−H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C−H bond cleavage is irreversible, but not the rate‐determining step.     

Two Stereoinduction Events in One C−H Activation Step: A Route towards Terphenyl Ligands with Two Atropisomeric Axes

Herein we disclose the synthesis of original chiral scaffolds—ortho‐orientated terphenyls presenting two atropisomeric Ar–Ar axes. These unusual structures were built up by using the C?H activation approach, and remarkably, both chiral axes were controlled with excellent stereoselectivity in a single transformation. During the reaction, not only does atroposelective functionalization of a biaryl precursor occur to establish one stereogenic axis, but an unprecedented atropo‐stereoselective C?H arylation also takes place to generate the second stereogenic element. These enantiomerically pure ortho‐terphenyls show an original tridimensional structure and thus constitute a unique foundation for building up a library of enantiomerically pure bidentate ligands, such as the new ligands S/N‐Biax and diphosphine BiaxPhos.     

Chiral Carboxylic Acid Enabled Achiral Rhodium(III)‐Catalyzed Enantioselective C−H Functionalization

Reported is an achiral Cp^xRh^III/chiral carboxylic acid catalyzed asymmetric C?H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4‐dihydroisoquinolin‐3(2H)‐one. Secondary alkylamines as well as nonprotected primary alkylamines underwent the transformation with high enantioselectivities (up to 98.5:1.5 e.r.) by using a newly developed chiral carboxylic acid as the sole source of chirality to achieve enantioselective C?H cleavage by a concerted metalation‐deprotonation mechanism.     

Enantioselective Access to 1H‐Isoindoles with Quaternary Stereogenic Centers by Palladium(0)‐Catalyzed C−H Functionalization

A catalytic enantioselective method for the synthesis of chiral 1H‐isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)‐catalyzed C?H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H‐isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.     

Solvent‐Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII‐Catalyzed C−H Activation

The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N‐methoxy benzamides and α,α‐difluoromethylene alkynes is enabled by C?H activation with a chiral CpRh^III catalyst. Remarkably, product formation is solvent‐dependent; alkynyl isoindolinones are afforded in MeOH (up to 86 % yield, 99.6 % ee) whereas monofluoroalkenyl isoindolinones are generated in ⁱPrCN (up to 98:2 Z/E, 93 % yield, 86 % ee). Mechanistic studies revealed chiral allene and E‐configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z‐configured monofluoroalkene upon protonation in the ⁱPrCN system and into an alkyne by an unusual anti β‐F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z‐monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.     

Enantioselective Pallada‐Electrocatalyzed C−H Activation by Transient Directing Groups: Expedient Access to Helicenes

Asymmetric pallada‐electrocatalyzed C?H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C?H activations were realized with high position‐, diastereo‐, and enantio‐control under mild reaction conditions to obtain highly enantiomerically‐enriched biaryls and fluorinated N?C axially chiral scaffolds. Our strategy provided expedient access to, among others, novel chiral BINOLs, dicarboxylic acids and helicenes of value to asymmetric catalysis. Mechanistic studies by experiments and computation provided key insights into the catalyst's mode of action.     

Arene‐Limited Nondirected C−H Activation of Arenes

The nondirected C(sp²)−H activation of simple arenes has advanced significantly in recent years through the discovery of new catalyst systems that are able to perform transformations with the arene as the limiting reagent. Important developments in catalyst and ligand design that have improved reactivity and selectivity are reviewed.     

Micellar Catalysis for Ruthenium(II)‐Catalyzed C−H Arylation: Weak‐Coordination‐Enabled C−H Activation in H2O

Chemoselective C?H arylations were accomplished through micellar catalysis by a versatile single‐component ruthenium catalyst. The strategy provided expedient access to C?H‐arylated ferrocenes with wide functional‐group tolerance and ample scope through weak chelation assistance. The sustainability of the C?H arylation was demonstrated by outstanding atom‐economy and recycling studies. Detailed computational studies provided support for a facile C?H activation through thioketone assistance.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

Cobalt‐Catalyzed Tandem C−H Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides with Alkylidenecyclopropanes

A cobalt‐catalyzed chelation‐assisted tandem C?H activation/C?C cleavage/C?H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C?C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C?N bonds. Here the inexpensive catalyst system exhibits good functional‐group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m‐CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C?H cobaltation, β‐carbon elimination, and intramolecular C?H cobaltation sequence.     

Directing‐Group‐mediated C−H‐Alkynylations

C?C triple bonds are amongst the most versatile functional groups in synthetic chemistry. Complementary to the Sonogashira coupling the direct metal‐catalyzed alkynylation of C?H bonds has emerged as a highly promising approach in recent years. To guarantee a high regioselectivity suitable directing groups (DGs) are necessary to guide the transition metal (TM) into the right place. In this Focus Review we present the current developments in DG‐mediated C(sp²)?H and C(sp³)?H modifications with terminal alkynes under oxidative conditions and with electrophilic alkynylation reagents. We will discuss further modifications of the alkyne, in particular subsequent cyclizations to carbo‐ and heterocycles and modifications of the DG in the presence of the alkyne.     

Increasing Catalyst Efficiency in C−H Activation Catalysis

C?H activation reactions with high catalyst turnover numbers are still very rare in the literature and 10 mol % is a common catalyst loading in this field. We offer a representative overview of efficient C?H activation catalysis to highlight this neglected aspect of catalysis development and inspire future effort towards more efficient C?H activation. Examples ranging from palladium catalysis, Cp*Rh^III‐ and Cp*Co^III‐catalysis, the C?H borylation and silylation to methane C?H activation are presented. In these reactions, up to tens of thousands of catalyst turnovers have been observed.