Pick your Pd partners: A number of catalytic systems have been developed for palladium-catalyzed CH activation/CC bond formation. Recent studies concerning the palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle are discussed (see scheme), and the versatility and practicality of this new mode of catalysis are presented. Unaddressed questions and the potential for development in the field are also addressed.

In the past decade, palladium-catalyzed CH activation/CC bond-forming reactions have emerged as promising new catalytic transformations; however, development in this field is still at an early stage compared to the state of the art in cross-coupling reactions using aryl and alkyl halides. This Review begins with a brief introduction of four extensively investigated modes of catalysis for forming CC bonds from CH bonds: PdII/Pd0, PdII/PdIV, Pd0/PdII/PdIV, and Pd0/PdII catalysis. A more detailed discussion is then directed towards the recent development of palladium(II)-catalyzed coupling of CH bonds with organometallic reagents through a PdII/Pd0 catalytic cycle. Despite the progress made to date, improving the versatility and practicality of this new reaction remains a tremendous challenge.

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Palladium(II)-catalyzed C-H activation/C-C cross-coupling reactions: versatility and practicality.

N-Heterocyclic Carbenes in Late Transition Metal Catalysis

The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

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.

The first Suzuki cross-coupling reaction of aryltrimethylammonium triflates based on the use of an IMes·Ni(0) catalyst system is described. A wide range of electron-withdrawing and electron-donating substituents are tolerated on both the aryltrimethylammonium triflate and the boronic acid components of this reaction. In addition to arylboronic acids, the scope of the reaction is extended to encompass both boronate esters and alkenylboranes. This methodology constitutes a novel, mild method to activate anilines for metal-catalyzed cross-coupling reactions.

The first Suzuki cross-couplings of aryltrimethylammonium salts

C H bond amination has emerged as a powerful tool for the synthesis of complex nitrogen-containing molecules. Following the early discoveries by Breslow and Gellman, Du Bois and co-workers revolutionized this area of chemistry by developing protocols for practical, efficient, and predictable reactions for oxidative C H amination. Dirhodium(II) tetracarboxylate catalysts were shown to be particularly effective. Manganese– and ruthenium–porphyrin complexes, silver complexes, and preoxidized nitrogen sources have also been developed as catalysts to carry out this important reaction. Despite these recent advances, general methods for both enantioselective and intermolecular C H amination remain elusive. Although chiral dirhodium(II) complexes have been developed as catalysts for highly enantioselective metallocarbene reactions, their application to C H amination chemistry is yet to produce the same spectacular results. To date, the most effective protocol for asymmetric C H amination requires the combination of enantioenriched sulfoxamines as chiral auxiliaries and a chiral dirhodium(II) catalyst. To address the challenge of catalytic asymmetric C H amination, we chose to study ruthenium(II)–pybox (pybox= pyridine bisoxazoline) complexes (Scheme 1). Despite reports that show complex 1 exhibited limited reactivity and selectivity in C H amination reactions, we felt that the modular nature of the ligand, and the fact that the anionic ligands were independent of the chiral pybox ligand, offered us an opportunity which had not been possible by using either dirhodium(II)or porphyrin-based catalyst systems. Ruthenium(II)–pybox complexes 1–4 were readily prepared by using the method developed by Nishiyama et al. (Scheme 1). In our initial study, the challenging test substrate sulfamate ester 5 was treated with 1.1 equivalents of the oxidant bis(acetoxy)iodobenzene and 5 mol% catalyst 2 to give the desired product of C H insertion 6, albeit in modest yield and enantiomeric excess (Table 1, entries 1–3). Based on the study by Fiori and Du Bois, which demonstrates that rhodium-catalyzed C H amination involves formation of an electrophilic metallonitrene and a build up of positive charge on the carbon center during the insertion process, we rationalized that a cationic catalyst would be more reactive than its neutral analogue. Halide abstraction from the Scheme 1. Synthesis of ruthenium(II)–pybox complexes.

Enantioselective CH Amination Using Cationic Ruthenium(II)–pybox Catalysts

A total synthesis of the marine natural product diazonamide A (1) has been accomplished. This work features a highly stereoselective synthesis of the C(10) quaternary center and the central furanoindoline core enabled by an iminium-catalyzed alkylation–cyclization cascade. Additionally, a magnesium-mediated intramolecular macroaldolization and a palladium-catalyzed tandem borylation/annulation were developed to enable the closure of the two 12-membered macrocycles of diazonamide A. This synthesis involves 20 steps in its longest linear sequence and proceeds in 1.8% overall yield.

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Total synthesis of diazonamide A

A conceptually novel metallonitrene/alkyne metathesis cascade reaction has been developed for the construction of nitrogen-containing compounds from simple alkyne starting materials. Rhodium(II) tetracarboxylate salts are efficient catalysts for this reaction, in which an electrophilic rhodium nitrene is trapped by an alkyne, resulting in the formation of a new C–N bond and the generation of a reactive metallocarbene for cascade reaction. The reaction is tolerant of both alkyl and aryl substituents on the alkyne, and proceeds at room temperature in a variety of common solvents. The modular nature of the reaction allows for the rapid construction of congested bicyclic systems from remarkably simple alkyne starting materials.

Catalytic metallonitrene/alkyne metathesis: a powerful cascade process for the synthesis of nitrogen-containing molecules.

The reaction of a sulfamate ester derived rhodium nitrenoid species with an alkyne produces a versatile intermediate, capable of cascading into a wide variety of secondary transformations. The nature of the intermediate has been probed by reactivity studies, and the synthetic utility of the cascade process, which facilitates the construction of complex heterocyclic structures from remarkably simple acyclic precursors, is highlighted.

Simon B. Blakey

Papers

The first Suzuki cross-couplings of aryltrimethylammonium salts

Enantioselective CH Amination Using Cationic Ruthenium(II)–pybox Catalysts

Total synthesis of diazonamide A

Catalytic metallonitrene/alkyne metathesis: a powerful cascade process for the synthesis of nitrogen-containing molecules.

π-Nucleophile Traps for Metallonitrene/Alkyne Cascade Reactions: A Versatile Process for the Synthesis of α-Aminocyclopropanes and β-Aminostyrenes