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.

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

The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure The schemes feature typical substrates used, the products obtained as well as the required reaction conditions Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them Accordingly, this review should be of particular interest also for scientists from industrial R&D sector Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date

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A comprehensive overview of directing groups applied in metal-catalysed C-H functionalisation chemistry.

Catalytic C–H activation has emerged as a powerful tool for sustainable syntheses. In the recent years, notable success was achieved with the development of cobalt-catalyzed C–H functionalizations with either in situ generated or single-component cobalt-complexes under mild reaction conditions. Herein, recent progress in the field of organometallic cobalt-catalyzed C–H activation is reviewed until November 2015.

Cobalt-Catalyzed C―H Activation

The first cobalt-catalyzed cyanation, halogenation, and allylation via C–H activation have been realized. These formal SN-type reactions generate valuable (hetero)aryl/alkenyl nitriles, iodides, and bromides as well as allylated indoles using a bench-stable Co(III) catalyst. High regio- and mono-selectivity were achieved for these reactions. Additionally, allylation proceeded efficiently with a turnover number of 2200 at room temperature, which is unprecedented for this Co(III) catalyst. Alkenyl substrates and amides have been successfully utilized in Cp*Co(III)-catalyzed C–H activation for the first time.

Co(III)-Catalyzed C–H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation

The reactivity and selectivity of 1,3-diynes in transition-metal-catalyzed CH activation is exploited to quickly assemble diverse polysubstituted bisheterocycles, which are highly important but difficult to access. By using the CH activation/1,3-diyne strategy, we overcame the challenges of selectivity (chemo-, regio-, and mono-/diannulation) and constructed seven kinds of adjacent bisheterocycles through the formation of four strategic bonds with high efficiency and high selectivity.

The C-H activation/1,3-diyne strategy: highly selective direct synthesis of diverse bisheterocycles by Rh(III) catalysis.

α-Halo and pseudohalo ketones are used for the first time as C(sp(3))-based electrophiles in transition-metal-catalyzed C-H activation and as oxidized alkyne equivalents in Rh(III)-catalyzed redox-neutral annulations to generate diverse N-heterocycles. This transformation is efficient and scalable. Due to the mild reaction conditions, a variety of functional groups could be tolerated.

α-MsO/TsO/Cl ketones as oxidized alkyne equivalents: redox-neutral rhodium(III)-catalyzed C-H activation for the synthesis of N-heterocycles.

Citronellal as key compound in organic synthesis

PhenAll: Recent breakthroughs in site-selective and direct functionalization of free phenols by transition-metal-catalyzed C-O or C-H bond activation are highlighted here as role models for the complete and switchable positional control of transformations of important core structures.

Francisco de Azambuja

Papers

Co(III)-Catalyzed C–H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation

The C-H activation/1,3-diyne strategy: highly selective direct synthesis of diverse bisheterocycles by Rh(III) catalysis.

α-MsO/TsO/Cl ketones as oxidized alkyne equivalents: redox-neutral rhodium(III)-catalyzed C-H activation for the synthesis of N-heterocycles.

Citronellal as key compound in organic synthesis

Direct Functionalization with Complete and Switchable Positional Control: Free Phenol as a Role Model