Catalytic transformation of ubiquitous C–H bonds into valuable C–N bonds offers an efficient synthetic approach to construct N-functionalized molecules. Over the last few decades, transition metal catalysis has been repeatedly proven to be a powerful tool for the direct conversion of cheap hydrocarbons to synthetically versatile amino-containing compounds. This Review comprehensively highlights recent advances in intra- and intermolecular C–H amination reactions utilizing late transition metal-based catalysts. Initial discovery, mechanistic study, and additional applications were categorized on the basis of the mechanistic scaffolds and types of reactions. Reactivity and selectivity of novel systems are discussed in three sections, with each being defined by a proposed working mode.

Transition Metal-Catalyzed C–H Amination: Scope, Mechanism, and Applications

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

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.

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

Significance: Reported is a remarkable synthesis of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles. The reaction of readily available N-tosylhydrazones with anilines is mediated by copper(II) and pivaloic acid. The reaction involves cyclization through C–N and N–N bond formation. This method enables an azide-free access to 1,2,3-triazoles with high efficiency under mild conditions. It exhibits a broad scope tolerating anilines with either electron-withdrawing or -donating groups and a variety of N-tosylhydrazones. More significantly, the two-step synthesis starting from aryl ketones to the desired triazoles can also be executed in a one-pot fashion without compromising the yield. An exclusive high regioselectivity – 1,4-disubstituted or 1,4,5-trisubstituted products – constitutes another advantage of this method. Comment: The most common route to build 1,2,3-triazoles is through Huisgen-type [3+2] cycloadditions. Although numerous methods for the improvement of the Huisgen reaction were reported recently, it is inevitable that an azide (which may sometimes not be readily available) will be involved. To the best of our knowledge, this paper is the first report to synthesize 1,2,3-triazoles without using toxic and potential explosive azide species. A possible tosylhydrazone intermediate (see structure above) of the reaction was proposed and synthesized. Its subsequent treatment with a catalytic amount of copper resulted in the formation of the expected produc. Examples of utilizing heterocyclic amines (e.g., 3-aminopyridine) as substrates in this reaction may be anticipated. Ar1 O

Copper-mediated synthesis of 1,2,3-triazoles from N-tosylhydrazones and anilines.

K2CO3 promoted direct sulfenylation of indoles: a facile approach towards 3-sulfenylindoles

Nickel-catalyzed direct amination of arenes with alkylamines

CuI-catalyzed aerobic oxidative synthesis of imidazoheterocycles has been achieved. Four hydrogen atoms were removed in one step. This protocol was compatible with a broad range of functional groups, and it has been also successfully extended to unsaturated ketones, bringing about the formation of alkenyl-substituted imidazoheterocycles, which were difficult to prepare by previous means. Preliminary mechanistic studies indicated that this reaction was most likely to proceed through a catalytic Ortoleva–King reaction. By using this method, the marketed drug Zolimidine could be prepared with 90% yield on a gram scale from commercially available materials.

Zhengkai Chen

Papers

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

Copper-mediated synthesis of 1,2,3-triazoles from N-tosylhydrazones and anilines.

K2CO3 promoted direct sulfenylation of indoles: a facile approach towards 3-sulfenylindoles

Nickel-catalyzed direct amination of arenes with alkylamines

CuI-Catalyzed Aerobic Oxidative α-Aminaton Cyclization of Ketones to Access Aryl or Alkenyl-Substituted Imidazoheterocycles