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.

Thermal C-C bond cleavage reactions allow the construction of structurally diverse molecular skeletons via predictable and efficient bond reorganizations. Visible light photoredox-catalyzed radical-mediated C-C bond cleavage reactions have recently emerged as a powerful alternative method for overcoming the thermodynamic and kinetic barrier of C-C bond cleavage in diverse molecular scaffolds. In recent years, a plethora of elegant and useful reactions have been invented, and the products are sometimes otherwise inaccessible by classic thermal reactions. Considering the great influence and synthetic potential of these reactions, we provide a summary of the state of art visible light-driven radical-mediated C-C bond cleavage/functionalization strategies with a specific emphasis on the working models. We hoped that this review will be useful for medicinal and synthetic organic chemists and will inspire further reaction development in this interesting area.

Visible Light-Driven Radical-Mediated C-C Bond Cleavage/Functionalization in Organic Synthesis

It is textbook knowledge that carboxamides benefit from increased stabilisation of the electrophilic carbonyl carbon when compared to other carbonyl and carboxyl derivatives This results in a considerably reduced reactivity towards nucleophiles Accordingly, a perception has been developed of amides as significantly less useful functional handles than their ester and acid chloride counterparts However, a significant body of research on the selective activation of amides to achieve powerful transformations under mild conditions has emerged over the past decades This review article aims at placing electrophilic amide activation in both a historical context and in that of natural product synthesis, highlighting the synthetic applications and the potential of this approach

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Amide activation: an emerging tool for chemoselective synthesis

Herein, we report a nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes through reductive decarboxylation of redox-active esters. The present reaction enables the preparation of functionalized gem-difluoroalkenes with the formation of sterically hindered C(sp3)–C(sp3) bonds under very mild reaction conditions, while tolerating many sensitive functional groups and requiring minimal substrate protection. Therefore, this method provides an efficient and convenient approach for late-stage modification of biologically interesting molecules.

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Nickel-catalyzed allylic defluorinative alkylation of trifluoromethyl alkenes with reductive decarboxylation of redox-active esters

The Suzuki–Miyaura cross-coupling has been widely recognized as one of the most important methods for the construction of C–C bonds. However, in contrast to traditional aryl halide or pseudohalide electrophiles, coupling reactions with unactivated C–N and C–O electrophiles have proven significantly more challenging. Here we report the first general palladium-catalyzed Suzuki–Miyaura cross-coupling of both common amides and aryl esters through the selective cleavage of the C–N and C–O bonds under exceedingly mild conditions. Notably, for the first time we demonstrate selective C(acyl)–N and C(acyl)–O cleavage/cross-coupling under the same reaction conditions. The reaction uses a commercially available, bench-stable and operationally-convenient (η3-1-t-Bu-indenyl)Pd(IPr)(Cl) precatalyst. Furthermore, we demonstrate that the reactivity of generic amides and aryl esters can be correlated with barriers to isomerization around the C(acyl)–X (X = N, O) bond, thus providing a blueprint for the development of a broad range of novel coupling reactions of ester and amide electrophiles by the selective activation of C–O and C–N bonds.

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Suzuki–Miyaura cross-coupling of amides and esters at room temperature: correlation with barriers to rotation around C–N and C–O bonds

Organoboron reagents are important synthetic intermediates that have a key role in the construction of natural products, pharmaceuticals and organic materials1. The discovery of simpler, milder and more efficient approaches to organoborons can open additional routes to diverse substances2-5. Here we show a general method for the directed C-H borylation of arenes and heteroarenes without the use of metal catalysts. C7- and C4-borylated indoles are produced by a mild approach that is compatible with a broad range of functional groups. The mechanism, which is established by density functional theory calculations, involves BBr3 acting as both a reagent and a catalyst. The potential utility of this strategy is highlighted by the downstream transformation of the formed boron species into natural products and drug scaffolds.

Metal-free directed sp 2 -C–H borylation

Rhodium-catalyzed C7-selective decarbonylative arylation, olefination, and methylation of indoles with carboxylic acids or anhydrides by C-H and C-C bond activation have been developed. Furthermore, C7-acylation products can also be generated selectively at a lower reaction temperature in the developed system. The key to the high reactivity and regioselectivity of this transformation is the appropriate choice of an indole N-PtBu2 chelation-assisted group. This method has many advantages, including easy access and removal of the directing group, the use of cheap and widely available coupling agents, no requirement of an external ligand or oxidant, a broad substrate scope, high efficiency, and the formation of a sole regioisomer.

PIII -Chelation-Assisted Indole C7-Arylation, Olefination, Methylation, and Acylation with Carboxylic Acids/Anhydrides by Rhodium Catalysis.

A copper-catalyzed system has been introduced for the enantioselective defluoroalkylation of linear 1-(trifluoromethyl)alkenes through C–F activation to synthesize various gem-difluoroalkenes as carbonyl mimics. For the first time, arylboronate-activated alkyl Grignard reagents were uncovered in this cross-coupling reaction. Mechanistic studies confirmed that the tetraorganoborate complexes generated in situ were the key reactive species for this transformation.

Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents.

Modification of commercially available monophosphine ligands with either aryl bromides or chlorides by rhodium(I)-catalyzed, tertiary phosphine directed C−H activation is described A series of ligand libraries containing mono- and diaryl-substituted groups, having different steric and electronic properties, were obtained in high yields Based on the outstanding properties of their parent scaffolds, the modified ligands have been found to be powerful in organic reactions

Rhodium(I)‐Catalyzed Tertiary Phosphine Directed C−H Arylation: Rapid Construction of Ligand Libraries

Amide and olefins are important synthetic intermediates with complementary reactivity which play a key role in the construction of natural products, pharmaceuticals and manmade materials. Converting the normally highly stable aliphatic amides into olefins directly is a challenging task. Here we show that a Ni/NHC-catalytic system has been established for decarbonylative elimination of aliphatic amides to generate various olefins via C-N and C-C bond cleavage. This study not only overcomes the acyl C-N bond activation in aliphatic amides, but also encompasses distinct chemical advances on a new type of elimination reaction called retro-hydroamidocarbonylation. This transformation shows good functional group compatibility and can serve as a powerful synthetic tool for late-stage olefination of amide groups in complex compounds.

Minyan Wang

Papers

Metal-free directed sp 2 -C–H borylation

PIII -Chelation-Assisted Indole C7-Arylation, Olefination, Methylation, and Acylation with Carboxylic Acids/Anhydrides by Rhodium Catalysis.

Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents.

Rhodium(I)‐Catalyzed Tertiary Phosphine Directed C−H Arylation: Rapid Construction of Ligand Libraries

Nickel-catalysed retro-hydroamidocarbonylation of aliphatic amides to olefins.