Joanna Wencel-Delord

C-H bond activation enables the rapid construction and late-stage diversification of functional molecules.

The beginning of the twenty-first century has witnessed significant advances in the field of C-H bond activation, and this transformation is now an established piece in the synthetic chemists toolbox. This methodology has the potential to be used in many different areas of chemistry, for example it provides a perfect opportunity for the late-stage diversification of various kinds of organic scaffolds, ranging from relatively small molecules like drug candidates, to complex polydisperse organic compounds such as polymers. In this way, C-H activation approaches enable relatively straightforward access to a plethora of analogues or can help to streamline the lead-optimization phase. Furthermore, synthetic pathways for the construction of complex organic materials can now be designed that are more atom- and step-economical than previous methods and, in some cases, can be based on synthetic disconnections that are just not possible without C-H activation. This Perspective highlights the potential of metal-catalysed C-H bond activation reactions, which now extend beyond the field of traditional synthetic organic chemistry.

Beyond Directing Groups: Transition‐Metal‐Catalyzed CH Activation of Simple Arenes

The use of coordinating moieties as directing groups for the functionalization of aromatic C-H bonds has become an established tool to enhance reactivity and induce regioselectivity. Nevertheless, with regard to the synthetic applicability of C-H activation, there is a growing interest in transformations in which the directing group can be fully abandoned, thus allowing the direct functionalization of simple benzene derivatives. However, this approach requires the disclosure of new strategies to achieve reactivity and to control selectivity. In this review, recent advances in the emerging field of non-chelate-assisted C-H activation are discussed, highlighting some of the most intriguing and inspiring examples of induction of reactivity and selectivity.

High-Yielding, Versatile, and Practical [Rh(III)Cp*]-Catalyzed Ortho Bromination and Iodination of Arenes

We report a uniquely high-yielding, general, and practical ortho bromination and iodination reaction of different classes of aromatic compounds. This reaction occurs by Rh(III)-catalyzed C-H bond activation methodology and is therefore the first example of the application of this cationic catalyst for C-Br and C-I bond formation.

Rhodium(III) and Hexabromobenzene—A Catalyst System for the Cross‐Dehydrogenative Coupling of Simple Arenes and Heterocycles with Arenes Bearing Directing Groups

C(6)Br(six) & drugs! C(6)Br(6) can be used as the cooxidant/catalyst modifier for the [Rh(III)Cp*]-catalyzed (Cp*=C(5)Me(5)) dehydrogenative cross-coupling of benzamides with simple benzene derivatives (see scheme, DG=directing group). Similarly, heterocycles can be coupled and druglike structures formed. Mechanistic studies suggest a unique and multiple role of the Cu(OAc)(2)/C(6)Br(6) system and a nonchelate-assisted C-H activation as the rate-determing step.

Asymmetric C(sp2)H Activation

A niche topic in the past decade, the asymmetric C-H bond activation has been attracting growing interest over the last few years. Particularly significant advances have been achieved in the field of direct, stereoselective transformations of C(sp(2) )-H bonds. This Concept article intends to showcase different types of asymmetric C(sp(2) )-H bond activation reactions, emphasising both the nature of the stereo-discriminating step and the variability of valuable scaffolds that could be rapidly constructed by means of such strategies.

Synthesis of Axially Chiral Biaryls through Sulfoxide-Directed Asymmetric Mild CH Activation and Dynamic Kinetic Resolution†

A mild and robust direct C-H functionalization strategy has been applied to the synthesis of axially chiral biaryls. Such an efficient and stereoselective transformation occurs through an original dynamic kinetic resolution pathway enabling the conversion of diastereomeric mixtures of non-prefunctionalized substrates into atropisomerically pure, highly substituted biaryl scaffolds. The main feature of this transformation is the use of an enantiopure sulfoxide as both chiral auxiliary and traceless directing group. The potential of newly synthesized biaryls as valuable building blocks is further illustrated.

1,1,1,3,3,3-Hexafluoroisopropanol as a Remarkable Medium for Atroposelective Sulfoxide-Directed Fujiwara-Moritani Reaction with Acrylates and Styrenes.

Axially chiral biaryls are ubiquitous structural motifs of biologically active molecules and privileged ligands for asymmetric catalysis. Their properties are due to their configurationally stable axis, and therefore, the control of their absolute configuration is essential. Efficient access to atropo-enantioenriched biaryl moieties through asymmetric direct C-H activation, by using enantiopure sulfoxide as both the directing group (DG) and chiral auxiliary, is reported. The stereoselective oxidative Heck reactions are performed in high yields and with excellent atropo-stereoselectivities. The pivotal role of 1,1,1,3,3,3-hexafluoropropanol (HFIP) solvent, which enables a drastic increase in yield and stereoselectivity of this transformation, is evidenced and investigated. Finally, the synthetic usefulness of the herein disclosed transformation is showcased because the traceless character of the sulfoxide DG allows straightforward conversions of the newly accessed, atropopure sulfoxide-biaryls into several differently substituted axially chiral scaffolds.

Enantiopure Sulfinyl Aniline as a Removable and Recyclable Chiral Auxiliary for Asymmetric C(sp3)−H Bond Activation

An original and recyclable chiral bidentate aniline-sulfoxide-based directing group has been developed. This auxiliary allows challenging stereoselective Pd-catalyzed direct functionalization of small cycloalkanes through C-aryl and C-alkyl bond formation. Although moderate diastereoselectivities are observed, both optically pure enantiomers of the highly functionalized products can be obtained separately by simple silica gel chromatography and cleavage of the chiral auxiliary. This strategy was further applied to the preparation of enantiomerically pure 1,2,3-trisubstituted cyclopropane carboxylic acid derivatives, with three stereogenic centers and bearing both alkyl and aromatic substituents. These molecular scaffolds are not yet reported in the literature. The synthetic utility of this approach is validated by the chiral auxiliary being readily cleaved and recovered posteriori to the C-H activation step, without deterioration of its optical purity. Finally, an unprecedented palladacycle intermediate generated through C-H activation of the cyclopropane moiety has been isolated and fully characterized. Initial DFT calculations shed additional light on the reactivity of this original intermediate.

Rh(III)- and Ir(III)-Catalyzed C–C Bond Cross Couplings from C–H Bonds

Over the recent years, dicationic [Cp*Ir(III)] and more particularly [Cp*Rh(III)] complexes have established themselves as extremely powerful catalysts enabling direct C–H activation of various aromatic and vinylic compounds. During such transformations, a common metallacyclic intermediate [Cp*M(C^X)] (M=Ir, Rh) is formed and undergoes further transformations, according to the nature of the coupling partner, to finally afford a myriad of valuable, often complex, and otherwise difficult to access scaffolds like heterocycles and polyunsaturated skeletons. The major advances achieved in this field clearly showcase the potential of these catalysts to functionalize latent C–H bonds under surprisingly mild reaction conditions. The aim of this chapter is to present the latest and most representative contributions in the field of Rh(III)- and Ir(III)-catalyzed C–H activation by focusing on the reactivity of the corresponding metallacyclic intermediates.

Stereoselective Sulfinyl Aniline-Promoted Pd-Catalyzed C−H Arylation and Acetoxylation of Aliphatic Amides

Stereoselective functionalization of aliphatic C-H bonds presents a great challenge. Following this target, we disclose herein an original strategy towards direct arylation of aliphatic chains at ß-methylene position based on a use of amide-sulfoxide bicoordinating directing group. Although moderate to high chiral induction (up to 9:1u2005d.r.) is achieved, diastereomerically pure compounds may be afforded by simple separation of diastereomeric products by silica gel chromatography. Accordingly, this reaction allows preparation of a large scope of high-value scaffolds in synthetically useful yields while recyclable character of our chiral auxiliary brings an additional benefit. A potential of this methodology to build up original molecules by sequential diarylation and expedient (two step) synthesis of a biologically active compound are further disclosed. Finally a first example of stereoselective direct acetoxylation of aliphatic chains is reported.