Transition metal-catalyzed aryl C-H activation is a powerful synthetic tool as it offers step and atom-economical routes to site-selective functionalization. Compared with proximal ortho-C-H activation, distal (meta- and/or para-) C-H activation remains more challenging due to the inaccessibility of these sites in the formation of energetically favorable organometallic pretransition states. Directing the catalyst toward the distal C-H bonds requires judicious template engineering and catalyst design, as well as prudent choice of ligands. This review aims to summarize the recent elegant discoveries exploiting directing group assistance, transient mediators or traceless directors, noncovalent interactions, and catalyst and/or ligand selection to control distal C-H activation.

Arene diversification through distal C(sp2)-H functionalization.

The elaboration of simple arenes in order to access more complex substitution patterns is a crucial endeavor for synthetic chemists, given the central role that aromatic rings play in all manner of important molecules. Classical methods are now routinely used alongside stoichiometric organometallic approaches and, most recently, transition metal catalysis in the range of methodologies that are available to elaborate arene C–H bonds. Regioselectivity is an important consideration when selecting a method and, of all those available, it is arguably those that target the meta position that are fewest in number. The rapid development of transition metal-catalysed C–H bond functionalisation over the last few decades has opened new possibilities for meta-selective C–H functionalisation through the diverse reactivity of transition metals and their compatibility with a wide range of directing groups. The pace of discovery of such processes has grown rapidly in the last five years in particular and it is the purpose of this review to examine these but in doing so to place the focus on metals other than palladium, the specific contributions of which have been very recently reviewed elsewhere. It is hoped this will serve to highlight to the reader the breadth of current strategies and mechanisms that have been used to tackle this challenge, which may inspire further progress in the field.

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Access to the meta position of arenes through transition metal catalysed C–H bond functionalisation: a focus on metals other than palladium

Transition metal catalyzed C-H activation has developed a contemporary approach to the omnipresent area of retrosynthetic disconnection. Scientific researchers have been tempted to take the help of this methodology to plan their synthetic discourses. This paradigm shift has helped in the development of industrial units as well, making the synthesis of natural products and pharmaceutical drugs step-economical. In the vast zone of C-H bond activation, the functionalization of proximal C-H bonds has gained utmost popularity. Unlike the activation of proximal C-H bonds, the distal C-H functionalization is more strenuous and requires distinctly specialized techniques. In this review, we have compiled various methods adopted to functionalize distal C-H bonds, mechanistic insights within each of these procedures, and the scope of the methodology. With this review, we give a complete overview of the expeditious progress the distal C-H activation has made in the field of synthetic organic chemistry while also highlighting its pitfalls, thus leaving the field open for further synthetic modifications.

Toolbox for Distal C-H Bond Functionalizations in Organic Molecules.

Strategic evolution in transition metal-catalyzed directed C–H bond activation and future directions

Transition metal-catalysed functionalizations of inert C–H bonds to construct C–C bonds represent an ideal route in the synthesis of valuable organic molecules. Fine tuning of directing groups, catalysts and ligands has played a crucial role in selective C–H bond (sp2 or sp3) activation. Recent developments in these areas have assured a high level of regioselectivity in C–H olefination reactions. In this review, we have summarized the recent progress in the oxidative olefination of sp2 and sp3 C–H bonds with special emphasis on distal, atroposelective, non-directed sp2 and directed sp3 C–H olefination. The scope, limitation, and mechanism of various transition metal-catalysed olefination reactions have been described briefly.

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Recent development in transition metal-catalysed C–H olefination

Direct catalytic transformation of C–H bonds to new functionalities has provided a powerful strategy to synthesize complex molecular scaffolds in a straightforward way. Unstinting efforts of the sy...

Transition Metal Catalyzed Enantioselective C(sp2)–H Bond Functionalization

Rhodium catalysis has been extensively used for ortho-C-H functionalization reactions, and successfully extended to meta-C-H functionalization. Its application to para-C-H activation remains an unmet challenge. Herein we disclose the first example of such a reaction, with the Rh-catalyzed para-C-H olefination of arenes. The use of a Si-linked cyanobiphenyl unit as a traceless directing group leads to highly para-selective arene-olefin couplings.

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Rhodium catalyzed template-assisted distal para-C–H olefination

Iridium catalyzed direct C–H borylation has provided a powerful strategy to construct a complex molecular architecture in a relatively straightforward way. Controlling regioselectivity is one of the most challenging issues in these transformations. Enormous efforts of the synthetic community have helped to overcome the selectivity issue in the case of proximal C–H borylation by introducing a directing group concept along with noncovalent interaction. However, selectively targeting a remote C–H bond is a formidable challenge and often requires special designing of the directing template. In this highlight, we aim to provide a recent update on noncovalent interaction enabled Ir-catalyzed remote C–H borylation, with a special emphasis on the corresponding enantioselective variant.

Sudip Maiti

Papers

Arene diversification through distal C(sp2)-H functionalization.

Toolbox for Distal C-H Bond Functionalizations in Organic Molecules.

Transition Metal Catalyzed Enantioselective C(sp2)–H Bond Functionalization

Rhodium catalyzed template-assisted distal para-C–H olefination

Noncovalent interactions in Ir-catalyzed remote C–H borylation: a recent update