Organic reactions that involve the direct functionalization of non-activated C–H bonds represent an attractive class of transformations which maximize atom- and step-economy, and simplify chemical synthesis. Due to the high stability of C–H bonds, these processes, however, have most often required harsh reaction conditions, which has drastically limited their use as tools for the synthesis of complex organic molecules. Following the increased understanding of mechanistic aspects of C–H activation gained over recent years, great strides have been taken to design and develop new protocols that proceed efficiently under mild conditions and duly benefit from improved functional group tolerance and selectivity. In this review, we present the current state of the art in this field and detail C–H activation transformations reported since 2011 that proceed either at or below ambient temperature, in the absence of strongly acidic or basic additives or without strong oxidants. Furthermore, by identifying and discussing the major strategies that have led to these improvements, we hope that this review will serve as a useful conceptual overview and inspire the next generation of mild C–H transformations.

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Mild metal-catalyzed C–H activation: examples and concepts

Transition metal-catalyzed direct functionalization of C–H bonds is one of the key emerging strategies that is currently attracting tremendous attention with the aim to provide alternative environmentally friendly and efficient ways for the construction of C–C and C–hetero bonds. In particular, the strategy involving regioselective C–H activation assisted by various functional groups shows high potential, and significant achievements have been made in both the development of novel reactions and the mechanistic study. In this review, we attempt to give an overview of the development of utilizing the functionalities as directing groups. The discussion is directed towards the use of different functional groups as directing groups for the construction of C–C and C–hetero bonds via C–H activation using various transition metal catalysts. The synthetic applications and mechanistic features of these transformations will be discussed, and the review is organized on the basis of the type of directing groups and the type of bond being formed or the catalyst.

Transition metal-catalyzed C–H bond functionalizations by the use of diverse directing groups

Oxidative Coupling between Two Hydrocarbons: An Update of Recent C–H Functionalizations

Transition metal-mediated C–H bond activation and functionalization represent one of the most straightforward and powerful tools in modern organic synthetic chemistry. Bi(hetero)aryls are privileged π-conjugated structural cores in biologically active molecules, organic functional materials, ligands, and organic synthetic intermediates. The oxidative C–H/C–H coupling reactions between two (hetero)arenes through 2-fold C–H activation offer a valuable opportunity for rapid assembly of diverse bi(hetero)aryls and further exploitation of their applications in pharmaceutical and material sciences. This review provides a comprehensive overview of the fundamentals and applications of transition metal-mediated/catalyzed oxidative C–H/C–H coupling reactions between two (hetero)arenes. The substrate scope, limitation, reaction mechanism, regioselectivity, and chemoselectivity, as well as related control strategies of these reactions are discussed. Additionally, the applications of these established methods in the s...

Oxidative C-H/C-H Coupling Reactions between Two (Hetero)arenes.

The use of directing groups has proven to be a successful strategy to enhance reactivity and control selectivity in C–H functionalization reactions. In the past decade, a multitude of new transformations and new directing groups have been explored, and several recent reviews have discussed directing group approaches for C–H functionalization. This review focuses specifically on the use of monodentate nitrogen-based directing groups published during the past two years, with the aim of covering a body of literature that is complementary to existing reviews.

Recent advances in directed C–H functionalizations using monodentate nitrogen-based directing groups

A Solvent Regulated Hydrogen Bond Crosslinking Strategy to Prepare Robust Hydrogel Paint for Oil/Water Separation

We have developed for the first time a general, concise and highly selective method for the C2-heteroarylation of pyridines and related azines with a broad range of heteroarenes via a two-fold C–H activation, which streamlines the previous approaches that require the activated azine N-oxide as the coupling partner.

Pd-catalyzed oxidative C–H/C–H cross-coupling of pyridines with heteroarenes

An unprecedented catalytic system composed of the Wilkinson catalyst [Rh(PPh3)3Cl] and CF3COOH enabled the highly regioselective cross-coupling of aromatic amines with a variety of heteroarenes through dual CH bond cleavage. This protocol provided a facile and rapid route from readily available substrates to (2-aminophenyl)heteroaryl compounds, which may be conveniently transformed into highly extended π-conjugated heteroacenes. The experimental studies and calculations showed that thianaphtheno[3,2-b]indoles have large HOMO–LUMO energy gaps and low-lying HOMO levels, and could therefore potentially be high-performance organic semiconductors. Herein we report the first use of a rhodium(I) catalyst for oxidative CH/CH coupling reactions. The current innovative catalyst system is much less expensive than [RhCp*Cl2]2/AgSbF6 and could open the door for the application of this approach to other types of CH activation processes.

Use of the Wilkinson catalyst for the ortho-C-H heteroarylation of aromatic amines: facile access to highly extended π-conjugated heteroacenes for organic semiconductors.

Cross-coupling: the "chelation-directed control" and "catalytic-system-based control" strategies effectively switch the C2/C3-site selectivity in the heteroarylation of indoles and pyrroles with N-heteroarenes by a palladium-catalyzed twofold C-H activation to form biheteroarenes and are further extended to the synthesis of complex fused tri- and tetracyclic heteroarenes by a tandem fourfold C-H activation.

Elements of regiocontrol in the direct heteroarylation of indoles/pyrroles: synthesis of bi- and fused polycyclic heteroarenes by twofold or tandem fourfold C-H activation.

Power of two: A widely functional-group tolerant, selective and rapid oxidative cross-coupling between two structurally similar azoles has been carried out by using a palladium/copper co-catalytic twofold C-H activation method (see scheme).

Yumin Huang

Papers

A Solvent Regulated Hydrogen Bond Crosslinking Strategy to Prepare Robust Hydrogel Paint for Oil/Water Separation

Pd-catalyzed oxidative C–H/C–H cross-coupling of pyridines with heteroarenes

Use of the Wilkinson catalyst for the ortho-C-H heteroarylation of aromatic amines: facile access to highly extended π-conjugated heteroacenes for organic semiconductors.

Elements of regiocontrol in the direct heteroarylation of indoles/pyrroles: synthesis of bi- and fused polycyclic heteroarenes by twofold or tandem fourfold C-H activation.

Palladium(II)-catalyzed oxidative C-H/C-H cross-coupling between two structurally similar azoles.