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.

Transition-metal-catalyzed, coordination-assisted C(sp3)-H functionalization has revolutionized synthetic planning over the past few decades as the use of these directing groups has allowed for increased access to many strategic positions in organic molecules. Nonetheless, several challenges remain preeminent, such as the requirement for high temperatures, the difficulty in removing or converting directing groups, and, although many metals provide some reactivity, the difficulty in employing metals outside of palladium. This review aims to give a comprehensive overview of coordination-assisted, transition-metal-catalyzed, direct functionalization of nonactivated C(sp3)-H bonds by covering the literature since 2004 in order to demonstrate the current state-of-the-art methods as well as the current limitations. For clarity, this review has been divided into nine sections by the transition metal catalyst with subdivisions by the type of bond formation. Synthetic applications and reaction mechanism are discussed where appropriate.

Transition-Metal-Catalyzed, Coordination-Assisted Functionalization of Nonactivated C(sp3)-H Bonds.

Transition-metal-catalysed direct C(sp3)−H functionalization of primary aliphatic amines is an attractive – but elusive – process that could provide efficient access to biologically and pharmaceutically important compounds. Now, a palladium-catalysed γ-arylation of primary alkylamines is achieved using an inexpensive, catalytic and transient directing group.

Site-Selective C−H Arylation of Primary Aliphatic Amines Enabled by a Catalytic Transient Directing Group

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.

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

Directed C-H functionalization has been realized as a complementary tool to the traditional approaches for a straightforward access of non-proteinogenic amino acids; albeit such a process is restricted mostly up to the γ-position. In the present work, we demonstrate the diverse (hetero)arylation of amino acids and analogous aliphatic amines selectively at the remote δ-position by tuning the reactivity controlled by ligands. An organopalladium δ-C(sp3 )-H activated intermediate has been isolated and crystallographically characterized. Mechanistic investigations carried out experimentally in conjunction with computational studies shed light on the difference in the mechanistic picture depending on the substrate structure.

Iterative Arylation of Amino Acids and Aliphatic Amines via δ-C(sp3 )-H Activation: Experimental and Computational Exploration.

Despite the widespread applications of C–H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing groups (DGs) served as ancillary ligands to ensure ortho-, meta- and para-C–H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C–H functionalization: introduction of DG prior to C–H activation and removal of DG post-functionalization. Here we report a temporary directing group (TDG) for meta-C–H functionalization via reversible imine formation. By overruling facile ortho-C–H bond activation by imine-N atom, a suitably designed pyrimidine-based TDG successfully delivered selective meta-C–C bond formation. Application of this temporary directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the meta position has been explored. Site-selective C–H functionalization still faces some challenges, such as the introduction and removal of an appropriate directing group. Here, the authors introduce a temporary directing group for selective meta-C–H functionalization of 2-arylbenzaldehydes via reversible imine formation.

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Imine as a linchpin approach for meta-C–H functionalization

Overriding the preference for favorable proximal metalation by ortho-directing amide group, a pyrimidine-based directing group (DG) has been demonstrated for diverse remote meta-C–H functionalizati...

Diverse meta-C–H Functionalization of Amides

Despite
the widespread applications of C–H functionalization, controlling site
selectivity remains a significant challenge. Covalently attached directing
group (DG) served as an ancillary ligand to ensure proximal ortho-,
distal meta- and para-C-H functionalization over the
last two decades. These covalently linked DGs necessitate two extra steps for a
single C–H functionalization: introduction of DG prior to C–H activation and
removal of DG post-functionalization. We introduce here a transient directing
group for distal C(sp2)-H
functionalization via reversible
imine formation. By overruling facile proximal C-H bond
activation by imine-N atom, a
suitably designed pyrimidine-based transient directing group (TDG) successfully
delivered selective distal C-C
bond formation. Application of this transient directing group strategy for
streamlining the synthesis of complex organic molecules without any necessary
pre-functionalization at the distal position has been explored.

/pdf/imine-as-a-linchpin-approach-for-distal-c-sp2-h-1apm9z0f58.pdf

Imine as a Linchpin Approach for Distal C(sp2)–H Functionalization

Abstract. This work describes a suitable approach for palladium(II)-catalyzed regioselective C8-H olefination of 1-naphthamides. Interestingly, naphthamide fused lactam 2,3-dihydro-1H-benzo[de]isoquinolin-1-one derivatives were also synthesized in case of a particular class of napthamides. This protocol was found well compatible with a diverse range of acrylates and styrenes, leading product formation in good yields along with a wide functional group tolerance. The developed strategy was further applicable for the synthesis of different drug derivatives. 

Sukumar Pradhan

Papers

Iterative Arylation of Amino Acids and Aliphatic Amines via δ-C(sp3 )-H Activation: Experimental and Computational Exploration.

Imine as a linchpin approach for meta-C–H functionalization

Diverse meta-C–H Functionalization of Amides

Imine as a Linchpin Approach for Distal C(sp2)–H Functionalization

Palladium‐catalyzed amide‐directed ligand free C8‐olefination of 1‐naphthamides for the synthesis of 2,3‐dihydro‐1H‐benzo[de]isoquinolin‐1‐ones