C–H activation has surfaced as an increasingly powerful tool for molecular sciences, with notable applications to material sciences, crop protection, drug discovery, and pharmaceutical industries, among others. Despite major advances, the vast majority of these C–H functionalizations required precious 4d or 5d transition metal catalysts. Given the cost-effective and sustainable nature of earth-abundant first row transition metals, the development of less toxic, inexpensive 3d metal catalysts for C–H activation has gained considerable recent momentum as a significantly more environmentally-benign and economically-attractive alternative. Herein, we provide a comprehensive overview on first row transition metal catalysts for C–H activation until summer 2018.

3d Transition Metals for C-H Activation.

This Review summarizes the advancements in Pd-catalyzed C(sp3)–H activation via various redox manifolds, including Pd(0)/Pd(II), Pd(II)/Pd(IV), and Pd(II)/Pd(0). While few examples have been reported in the activation of alkane C–H bonds, many C(sp3)–H activation/C–C and C–heteroatom bond forming reactions have been developed by the use of directing group strategies to control regioselectivity and build structural patterns for synthetic chemistry. A number of mono- and bidentate ligands have also proven to be effective for accelerating C(sp3)–H activation directed by weakly coordinating auxiliaries, which provides great opportunities to control reactivity and selectivity (including enantioselectivity) in Pd-catalyzed C–H functionalization reactions.

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Palladium-Catalyzed Transformations of Alkyl C-H Bonds.

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

Iron Catalysis in Organic Synthesis

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

Direct ortho-Thiolation of Arenes and Alkenes by Nickel Catalysis

Palladium(II)-catalyzed ortho-olefination of arenes applying sulfoxides as remote directing groups.

A novel 1,7-palladium migration-cyclization-dealkylation sequence for the regioselective synthesis of benzotriazoles has been developed. These reactions proceed in excellent yields with high regioselectivities. The mechanism of the reaction has also been investigated.

1,7-Palladium Migration via C−H Activation, Followed by Intramolecular Amination: Regioselective Synthesis of Benzotriazoles

Because of their special optical and electronic properties, the efficient synthesis of unsymmetrical and functionalized polycyclic aromatic hydrocarbons (PAHs) is becoming much more important. The transitionmetalcatalyzed cross-coupling reactions of organometallic reagents with organic halides are popular methods for the formation of Csp2 Csp2 bonds. Thus, transition-metal-catalyzed annulation reactions of functionalized precursors, such as intramolecular direct arylations (Scheme 1, path a), the annulation of arynes (path b), double-coupling reactions of organodimetallic reagents with dihalides (paths c and d), sequential C H arylation with o-biphenylboroxin and FeCl3 oxidation (path e), and [2+2+2] or [4+2] cycloaddition reactions, provide effective synthetic transformations for the synthesis of functionalized PAHs. Moreover, oxidative dehydrogenation coupling reactions are also a feasible way to construct PAHs, and FeCl3 is a popular oxidant. [8]

Friedel–Crafts Arylation for the Formation of C sp 2C sp 2 Bonds: A Route to Unsymmetrical and Functionalized Polycyclic Aromatic Hydrocarbons from Aryl Triazenes

Binjie Wang

Papers

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

Direct ortho-Thiolation of Arenes and Alkenes by Nickel Catalysis

Palladium(II)-catalyzed ortho-olefination of arenes applying sulfoxides as remote directing groups.

1,7-Palladium Migration via C−H Activation, Followed by Intramolecular Amination: Regioselective Synthesis of Benzotriazoles

Friedel–Crafts Arylation for the Formation of C sp 2C sp 2 Bonds: A Route to Unsymmetrical and Functionalized Polycyclic Aromatic Hydrocarbons from Aryl Triazenes