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.

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.

During the past decades, synthetic organic chemistry discovered that directing group assisted C–H activation is a key tool for the expedient and siteselective construction of C–C bonds. Among the v...

Bidentate Directing Groups: An Efficient Tool in C-H Bond Functionalization Chemistry for the Expedient Construction of C-C Bonds.

Achieving selective C−H activation at a single and strategic site in the presence of multiple C−H bonds can provide a powerful and generally useful retrosynthetic disconnection. In this context, a directing group serves as a compass to guide the transition metal to C−H bonds by using distance and geometry as powerful recognition parameters to distinguish between proximal and distal C−H bonds. However, the installation and removal of directing groups is a practical drawback. To improve the utility of this approach, one can seek solutions in three directions: 1) Simplifying the directing group, 2) using common functional groups or protecting groups as directing groups, and 3) attaching the directing group to substrates via a transient covalent bond to render the directing group catalytic. This Review describes the rational development of an extremely simple and yet broadly applicable directing group for PdII, RhIII, and RuII catalysts, namely the N-methoxy amide (CONHOMe) moiety. Through collective efforts in the community, a wide range of C−H activation transformations using this type of simple directing group have been developed.

A Simple and Versatile Amide Directing Group for C-H Functionalizations.

The functionalization of C(sp3 )-H bonds streamlines chemical synthesis by allowing the use of simple molecules and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C-H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths and weaknesses of three main approaches: transition-metal-catalyzed C-H activation, 1,n-hydrogen atom transfer, and transition-metal-catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3 )-H bonds. For each strategy, the scope, the reactivity of different C-H bonds, the position of the reacting C-H bonds relative to the directing group, and stereochemical outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C-H functionalization reactions and inspire future research in this area.

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Complementary Strategies for Directed C(sp3 )-H Functionalization: A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer.

Pd-catalyzed β-C–H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C–H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct β-C–H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of β-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands.

Ligand-Enabled β-C–H Arylation of α-Amino Acids Using a Simple and Practical Auxiliary

Palladium-catalyzed enantioselective C(sp2)-H arylation of ferrocenyl ketones enabled by a chiral transient directing group.

Pd-Catalyzed Direct ortho-C–H Arylation of Aromatic Ketones Enabled by a Transient Directing Group

The use of a template as a linchpin motif in directed remote C–H functionalization is a versatile yet relatively underexplored strategy. We have developed a template-directed approach to realizing one-pot sequential palladium-catalyzed meta-selective C–H olefination of phenols, and nickel-catalyzed ipso-C–O activation and arylation. Thus, this bifunctional template converts phenols to synthetically useful 1,3-disubstituted arenes.

Sequential Functionalization of meta-C-H and ipso-C-O Bonds of Phenols

Palladium-catalyzed activation of remote meta-C-H bonds in arenes containing tethered alcohols was achieved with high regioselectivity by using a nitrile template. Computational studies on the macrocyclic transition state of the regioselectivity-determining C-H activation steps revealed that both the C-N-Ag angles and gauche comformations of phenyl ether play an extremely important role in the meta selectivity.

Zhong Jin

Papers

Ligand-Enabled β-C–H Arylation of α-Amino Acids Using a Simple and Practical Auxiliary

Palladium-catalyzed enantioselective C(sp2)-H arylation of ferrocenyl ketones enabled by a chiral transient directing group.

Pd-Catalyzed Direct ortho-C–H Arylation of Aromatic Ketones Enabled by a Transient Directing Group

Sequential Functionalization of meta-C-H and ipso-C-O Bonds of Phenols

Activation of Remote meta‐C−H Bonds in Arenes with Tethered Alcohols: A Salicylonitrile Template