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.

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.

The development of new methods for the direct functionalization of unactivated C–H bonds is ushering in a paradigm shift in the field of retrosynthetic analysis. In particular, the catalytic enantioselective functionalization of C–H bonds represents a highly atom- and step-economic approach toward the generation of structural complexity. However, as a result of their ubiquity and low reactivity, controlling both the chemo- and stereoselectivity of such processes constitutes a significant challenge. Herein we comprehensively review all asymmetric transition-metal-catalyzed methodologies that are believed to proceed via an inner-sphere-type mechanism, with an emphasis on the nature of stereochemistry generation. Our analysis serves to document the considerable and rapid progress within in the field, while also highlighting limitations of current methods.

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Catalytic Enantioselective Transformations Involving C-H Bond Cleavage by Transition-Metal Complexes.

Phenols are widely used as starting materials in both industrial and academic society. Dearomatization reactions of phenols provide an efficient way to construct highly functionalized cyclohexadienones. The main challenge to make them asymmetric by catalytic methods is to control the selectivity while overcoming the loss of aromaticity. In this tutorial review, an up to date summary of recent progress in CADA reactions of phenol and aniline derivatives is presented.

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Catalytic asymmetric dearomatization (CADA) reactions of phenol and aniline derivatives

BACKGROUND The ultimate goal of synthetic chemistry is the efficient assembly of molecules from readily available starting materials with minimal waste generation. The synthesis of organic molecules—compounds containing multiple carbon-hydrogen (C–H) and carbon-heteroatom (such as oxygen or nitrogen) bonds—has greatly improved our quality of life. Pharmaceuticals that can treat disease, agrochemicals that enhance crop yields, and materials used in computer engineering are but three illustrative examples. And yet more often than not, the syntheses of these substances have proved challenging because of restrictions on how molecules can be constructed. Major advances in organic chemistry have relied on the discovery of reactions that dramatically altered chemists’ approach to building molecules. Canonical organic reactions typically rely on the high reactivity of functional groups (with respect to a C–H bond) in order to introduce new functionality in a target molecule. However, there are times when the accessibility of certain functional groups at particular carbon centers may be restricted; in these cases, the installation of functionality may require several steps and can lead to undesired side reactions, delaying the production of as well as decreasing the overall yield of a synthetic target. Considering that organic molecules possess an abundance of C–H bonds, it should be unsurprising that C–H functionalization (the conversion of C–H bonds into C–X bonds, where X ≠ H) has garnered considerable attention as a technique that could alter synthetic organic chemistry by enabling relatively unreactive C–H bonds to be viewed as dormant functionality. And yet, to date applications of C–H functionalization logic are hindered by considerable limitations in terms of regioselectivity and stereoselectivity (the construction of chiral centers). ADVANCES Although numerous approaches to regioselective C–H functionalization have been extensively reported, only recently has attention been placed on addressing the issues of stereoselectivity. One such solution entails chiral transition metal catalysts in which a metal complexed to a chiral ligand reacts directly with a C–H bond, forming a chiral organometallic intermediate that is then diversely functionalized. A variety of transition metal catalysts have been shown to affect the asymmetric metallation of C–H bonds of enantiotopic carbons (C–H bonds on different carbons) or enantiotopic protons (C–H bonds on the same carbon). The major driving force behind the development of enantioselective C–H activation has been the design of chiral ligands that bind to transition metals, creating a reactive chiral catalyst while also increasing the reactivity at the metal center, accelerating the rate of C–H activation. OUTLOOK In order for enantioselective C–H activation to become a standard disconnection in asymmetric syntheses, the efficiency of catalyses and breadth of transformations must be improved. Although the specific requirements to achieve these goals are unclear, we argue that improved ligand design will be instrumental to further progress until any C–H bond of any molecule can be converted into any functionality in high yields with high enantioselectivity. The impact of such progress will no doubt have rippling effects in seemingly disparate fields, such as medicine, by enabling the syntheses of previously inaccessible forms of matter.

Enantioselective C(sp3)‒H bond activation by chiral transition metal catalysts.

A Rh-catalyzed enantioselective dearomatization of 1-aryl-2-naphthols with internal alkynes via C–H functionalization reaction was achieved. In the presence of a chiral Cp/Rh catalyst and combined oxidants of Cu(OAc)2 and air (oxygen), various highly enantioenriched spirocyclic enones bearing an all-carbon quaternary stereogenic center could be synthesized in 33–98% yields with up to 97:3 er.

Asymmetric Dearomatization of Naphthols via a Rh-Catalyzed C(sp²)-H Functionalization/Annulation Reaction.

Rhodium-catalyzed C(sp2)−H functionalization reactions of 4-aryl-5-pyrazolones followed by [3+2] annulation reactions with alkynes provide rapid access to highly enantioenriched five-membered-ring 4-spiro-5-pyrazolones. The use of a chiral SCpRh catalyst enabled the synthesis of a large range of spiropyrazolones with all-carbon quaternary stereogenic centers in up to 99 % yield and 98 % ee from readily available substrates.

Asymmetric Synthesis of Spiropyrazolones by Rhodium-Catalyzed C(sp2 )-H Functionalization/Annulation Reactions.

An intermolecular asymmetric dearomatization reaction of β-naphthols with nitroethylene through a chiral-thiourea-catalyzed Michael reaction is described. Enantioenriched functionalized β-naphthalenones with an all-carbon quaternary stereogenic center could thus be easily constructed from simple naphthol derivatives in good yields and excellent enantioselectivity (up to 79% yield, 98% ee).

Asymmetric Dearomatization of β‐Naphthols through a Bifunctional‐Thiourea‐Catalyzed Michael Reaction

Cp*RhIII-Catalyzed C–H Amidation of Ferrocenes

Rapid access to mono- or dialkynylation of ferrocene with ethynylbenziodoxolones as the alkynylation reagents was achieved via rhodium-catalyzed direct C–H bond functionalization at room temperature. Mono- and dialkynylation were easily modulated by varying the sterical volume of the directing group, such as pyridine and isoquinoline, and amount of hypervalent iodine reagents. A wide range of ferrocene-based alkynylation products could be obtained in up to 94% yield, and a gram-scale reaction also proceeded smoothly with high efficiency.

Shao-Bo Wang

Papers

Asymmetric Dearomatization of Naphthols via a Rh-Catalyzed C(sp²)-H Functionalization/Annulation Reaction.

Asymmetric Synthesis of Spiropyrazolones by Rhodium-Catalyzed C(sp2 )-H Functionalization/Annulation Reactions.

Asymmetric Dearomatization of β‐Naphthols through a Bifunctional‐Thiourea‐Catalyzed Michael Reaction

Cp*RhIII-Catalyzed C–H Amidation of Ferrocenes

Rhodium(III)-Catalyzed C–H Alkynylation of Ferrocenes with Hypervalent Iodine Reagents