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.

Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

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Chalcone: A Privileged Structure in Medicinal Chemistry.

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 combination of Ag2CO3 with Pd(O-Ac)2/PCy3 or Pd(O-CO-CF3)2/PCy3 is found to efficiently promote the title reaction.

Palladium-catalyzed decarboxylative C-H bond arylation of thiophenes.

The first copper-catalyzed direct β-functionalization of saturated ketones is reported. This protocol enables diverse ketones to couple with a wide range of nitrogen, oxygen and carbon nucleophiles in generally good yields under operationally simple conditions. The detailed mechanistic studies including kinetic studies, KIE measurements, identification of reaction intermediates, EPR and UV–visible experiments were conducted, which reveal that this reaction proceeds via a novel radical-based dehydrogenation to enone and subsequent conjugate addition sequence.

Cu-Catalyzed Sequential Dehydrogenation–Conjugate Addition for β-Functionalization of Saturated Ketones: Scope and Mechanism

The direct alkynylation of a variety of thiophenes and some other heterocyclic systems proceeds best with using Ag2O as the oxidant and affords structural motifs of bioactive products and pharmaceuticals.

Xiaoming Jie

Papers

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

Palladium-catalyzed decarboxylative C-H bond arylation of thiophenes.

Cu-Catalyzed Sequential Dehydrogenation–Conjugate Addition for β-Functionalization of Saturated Ketones: Scope and Mechanism

Palladium-catalyzed oxidative cross-coupling between heterocycles and terminal alkynes with low catalyst loading.

Pd-Catalyzed C–H Olefination of (Hetero)Arenes by Using Saturated Ketones as an Olefin Source