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.

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

Chemistry of biologically important synthetic organoselenium compounds.

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 cascade oxidative annulation reactions of benzoylacetonitrile with internal alkynes proceed efficiently in the presence of a rhodium catalyst and a copper oxidant to give substituted naphtho[1,8-bc]pyrans by sequential cleavage of C(sp2)–H/C(sp3)–H and C(sp2)–H/O–H bonds. These cascade reactions are highly regioselective with unsymmetrical alkynes. Experiments reveal that the first-step reaction proceeds by sequential cleavage of C(sp2)–H/C(sp3)–H bonds and annulation with alkynes, leading to 1-naphthols as the intermediate products. Subsequently, 1-naphthols react with alkynes by cleavage of C(sp2)–H/O–H bonds, affording the 1:2 coupling products. Moreover, some of the naphtho[1,8-bc]pyran products exhibit intense fluorescence in the solid state.

Rhodium-catalyzed cascade oxidative annulation leading to substituted naphtho[1,8-bc]pyrans by sequential cleavage of C(sp2)-H/C(sp3)-H and C(sp2)-H/O-H bonds.

Many methods have recently been developed to construct C C bonds through direct C H transformations. Among these methods, various transition metals have been shown to be effective in the last two decades. 3] The first-row transitionmetal catalysts, such as iron complexes, 5] have drawn much attention recently as a result of their ready availability, low cost, relatively low toxicity, and unique catalytic abilities. Cases where the catalytic direct C H transformation is mediated by Co catalysis are very rare. On the other hand, various organometallic reagents have been successfully used to facilitate such transformations. However, much more active Grignard reagents have never been successfully applied as an intermolecular coupling partner with C H bonds. Herein, we demonstrated the first successful example of cobalt-catalyzed direct C H transformation with both aryl and alkyl Grignard reagents as nucleophiles to facilitate C C bond formation. In other studies, the directing group orientation was considered useful to control the regioselectivity in C H activation. Among different anchoring groups, nitrogencontained groups were frequently used owing to their good compatibility with transition metals and synthetic applications. 7h, 9] Initially, we chose the benzo[h]quinoline (1a) as the substrate to explore the reactivity of Grignard reagents in the presence of transition-metal catalysts. However, in the absence of any catalyst, the direct nucleophilic attack of pyridine derivatives at the 2-position by Grignard reagents is a big challenge (traditional pathway, Scheme 1). For instance, even much less active organozinc reagents promote such a reaction through nickel catalysis. We propose that the presence of a suitable transition-metal catalyst and lowering the reaction temperature might be the good strategy to decrease the reactivity of RMgBr toward the direct addition to pyridine derivatives. After many trials to achieve the goal, the desired crosscoupling finally took place smoothly with Co(acac)3 as a catalyst in the presence of TMEDA and DCB in THF at room temperature (Table 1, entry 1). Certainly, no desired product 3aa was formed in the absence of catalyst, under otherwise identical conditions with Grignard reagents. Next, the reactivity of various Grignard reagents was investigated (Table 1). Phenyl Grignard reagents bearing different substituents provided the desired products in moderate to excellent yields. The steric effect was important in influencing the reaction outcome. Thus, increase of the steric hindrance dramatically decreased the yield (compare Table 1, entries 2, 3, and 4). Meanwhile, further increase of steric hindrance completely inhibited the transformation (Table 1, entry 14). Importantly, the functional groups MeO (Table 1, entries 8 and 9), F (Table 1, entry 11), and Cl (Table 1, entry 12) are compatible. These findings offer the opportunity for the orthogonal coupling to afford more complicated molecules. This direct cross-coupling can be extended to alkyl Grignard reagents for the constructions of C(sp) C(sp) bonds. Interestingly, MeMgBr showed the best reactivity and the desired methylated product 3aq was isolated in an excellent yield (Table 1, entry 17). However, other alkyl Grignard reagents gave much lower yields and only linear products were obtained (Table 1, entries 18–21). Unfortunately, under the same conditions, vinylMgBr completely failed to facilitate this cross-coupling reaction (Table 1, entry 22). Moreover, different benzo[h]quinoline compounds were investigated (Scheme 2). We found that this transformation was very sensitive to steric effects. When either a Ph or Me group was introduced at the 2-position, the coupling was completely inhibited and only the starting material was recovered (3ba and 3ca). If the substituent was introduced at the 9-position, the cross-coupling indeed took place while Scheme 1. New catalytic pathway beyond the traditional nucleophilic addition of RMgBr in the presence of a Co catalyst.

Direct Cross‐Coupling of CH Bonds with Grignard Reagents through Cobalt Catalysis

The rhodium(III)-catalyzed intermolecular C7-thiolation and selenation of indolines with disulfides and diselenides were developed. This protocol relies on the use of a removable pyrimidyl directing group to access valuable C-7 functionalized indoline scaffolds with ample substrate scope and broad functional group tolerance.

Rh(III)-Catalyzed C7-Thiolation and Selenation of Indolines.

Herein, the catalytic promiscuity of TcCGT1, a new C-glycosyltransferase (CGT) from the medicinal plant Trollius chinensis is explored. TcCGT1 could efficiently and regio-specifically catalyze the 8-C-glycosylation of 36 flavones and other flavonoids and could also catalyze the O-glycosylation of diverse phenolics. The crystal structure of TcCGT1 in complex with uridine diphosphate was determined at 1.85 A resolution. Molecular docking revealed a new model for the catalytic mechanism of TcCGT1, which is initiated by the spontaneous deprotonation of the substrate. The spacious binding pocket explains the substrate promiscuity, and the binding pose of the substrate determines C- or O-glycosylation activity. Site-directed mutagenesis at two residues (I94E and G284K) switched C- to O-glycosylation. TcCGT1 is the first plant CGT with a crystal structure and the first flavone 8-C-glycosyltransferase described. This provides a basis for designing efficient glycosylation biocatalysts.

Bin Li

Papers

Rhodium-catalyzed cascade oxidative annulation leading to substituted naphtho[1,8-bc]pyrans by sequential cleavage of C(sp2)-H/C(sp3)-H and C(sp2)-H/O-H bonds.

Direct Cross‐Coupling of CH Bonds with Grignard Reagents through Cobalt Catalysis

Rh(III)-Catalyzed C7-Thiolation and Selenation of Indolines.

Molecular and Structural Characterization of a Promiscuous C-Glycosyltransferase from Trollius chinensis.

Cp*Co(III)-Catalyzed C-H Acylmethylation of Arenes by Employing Sulfoxonium Ylides as Carbene Precursors.