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 chemistry of copper is extremely rich because it can easily access Cu0, CuI, CuII, and CuIII oxidation states allowing it to act through one-electron or two-electron processes. As a result, both radical pathways and powerful two-electron bond forming pathways via organmetallic intermediates, similar to those of palladium, can occur. In addition, the different oxidation states of copper associate well with a large number of different functional groups via Lewis acid interactions or π-coordination. In total, these feature confer a remarkably broad range of activities allowing copper to catalyze the oxidation and oxidative union of many substrates.

Oxygen is a highly atom economical, environmentally benign, and abundant oxidant, which makes it ideal in many ways.1 The high activation energies in the reactions of oxygen require that catalysts be employed.2 In combination with molecular oxygen, the chemistry of copper catalysis increases exponentially since oxygen can act as either a sink for electrons (oxidase activity) and/or as a source of oxygen atoms that are incorporated into the product (oxygenase activity). The oxidation of copper with oxygen is a facile process allowing catalytic turnover in net oxidative processes and ready access to the higher CuIII oxidation state, which enables a range of powerful transformations including two-electron reductive elimination to CuI. Molecular oxygen is also not hampered by toxic byproducts, being either reduced to water, occasionally via H2O2 (oxidase activity) or incorporated into the target structure with high atom economy (oxygenase activity). Such oxidations using oxygen or air (21% oxygen) have been employed safely in numerous commodity chemical continuous and batch processes.3

However, batch reactors employing volatile hydrocarbon solvents require that oxygen concentrations be kept low in the head space (typically <5–11%) to avoid flammable mixtures, which can limit the oxygen concentration in the reaction mixture.4,5,6 A number of alternate approaches have been developed allowing oxidation chemistry to be used safely across a broader array of conditions. For example, use of carbon dioxide instead of nitrogen as a diluent leads to reduced flammability.5 Alternately, water can be added to moderate the flammability allowing even pure oxygen to be employed.6 New reactor designs also allow pure oxygen to be used instead of diluted oxygen by maintaining gas bubbles in the solvent, which greatly improves reaction rates and prevents the build up of higher concentrations of oxygen in the head space.4a,7 Supercritical carbon dioxide has been found to be advantageous as a solvent due its chemical inertness towards oxidizing agents and its complete miscibility with oxygen or air over a wide range of temperatures.8 An number of flow technologies9 including flow reactors,10 capillary flow reactors,11 microchannel/microstructure structure reactors,12 and membrane reactors13 limit the amount of or afford separation of hydrocarbon/oxygen vapor phase thereby reducing the potential for explosions.

Enzymatic oxidizing systems based upon copper that exploit the many advantages and unique aspects of copper as a catalyst and oxygen as an oxidant as described in the preceding paragraphs are well known. They represent a powerful set of catalysts able to direct beautiful redox chemistry in a highly site-selective and stereoselective manner on simple as well as highly functionalized molecules. This ability has inspired organic chemists to discover small molecule catalysts that can emulate such processes. In addition, copper has been recognized as a powerful catalyst in several industrial processes (e.g. phenol polymerization, Glaser-Hay alkyne coupling) stimulating the study of the fundamental reaction steps and the organometallic copper intermediates. These studies have inspiried the development of nonenzymatic copper catalysts. For these reasons, the study of copper catalysis using molecular oxygen has undergone explosive growth, from 30 citations per year in the 1980s to over 300 citations per year in the 2000s.

A number of elegant reviews on the subject of catalytic copper oxidation chemistry have appeared. Most recently, reviews provide selected coverage of copper catalysts14 or a discussion of their use in the aerobic functionalization of C–H bonds.15 Other recent reviews cover copper and other metal catalysts with a range of oxidants, including oxygen, but several reaction types are not covered.16 Several other works provide a valuable overview of earlier efforts in the field.17 This review comprehensively covers copper catalyzed oxidation chemistry using oxygen as the oxidant up through 2011. Stoichiometric reactions with copper are discussed, as necessary, to put the development of the catalytic processes in context. Mixed metal systems utilizing copper, such as palladium catalyzed Wacker processes, are not included here. Decomposition reactions involving copper/oxygen and model systems of copper enzymes are not discussed exhaustively. To facilitate analysis of the reactions under discussion, the current mechanistic hypothesis is provided for each reaction. As our understanding of the basic chemical steps involving copper improve, it is expected that many of these mechanisms will evolve accordingly.

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Aerobic Copper-Catalyzed Organic Reactions

The selective oxidation of C-H bonds and the use of O(2) as a stoichiometric oxidant represent two prominent challenges in organic chemistry. Copper(II) is a versatile oxidant, capable of promoting a wide range of oxidative coupling reactions initiated by single-electron transfer (SET) from electron-rich organic molecules. Many of these reactions can be rendered catalytic in Cu by employing molecular oxygen as a stoichiometric oxidant to regenerate the active copper(II) catalyst. Meanwhile, numerous other recently reported Cu-catalyzed C-H oxidation reactions feature substrates that are electron-deficient or appear unlikely to undergo single-electron transfer to copper(II). In some of these cases, evidence has been obtained for the involvement of organocopper(III) intermediates in the reaction mechanism. Organometallic C-H oxidation reactions of this type represent important new opportunities for the field of Cu-catalyzed aerobic oxidations.

Copper-Catalyzed Aerobic Oxidative C ? H Functionalizations: Trends and Mechanistic Insights

Copper-catalyzed C-H functionalization reactions: efficient synthesis of heterocycles.

Nitrogen containing compounds are of great importance because of their interesting and diverse biological activities. The construction of the C–N bond is of significant importance as it opens avenues for the introduction of nitrogen in organic molecules. Despite significant advancements in this field, the construction of the C–N bond is still a major challenge for organic chemists, due to the involvement of harsh reaction conditions or the use of expensive catalysts in many cases. Thus, it is a challenge to develop alternative, milder and cheaper methodologies for the construction of C–N bonds. Herein, we have selected some prime literature reports that may serve this purpose.

C–N bond forming cross-coupling reactions: an overview

An efficient method for the transformation of N-benzyl bisarylhydrazones and bisaryloxime ethers to functionalized 2-aryl-N-benzylbenzimidazoles and 2-arylbenzoxazoles is described. The protocol involves a copper(II)-mediated cascade C–H functionalization/C–N/C–O bond formation under neutral conditions. Substrates having either electron-donating or -withdrawing substituents undergo the cyclization to afford the target heterocycles at moderate temperature.

Copper-Mediated Synthesis of Substituted 2-Aryl-N-benzylbenzimidazoles and 2-Arylbenzoxazoles via C–H Functionalization/C–N/C–O Bond Formation

An unprecedented copper(II)-catalyzed aerobic oxidative synthesis of 2,4,5-triaryl-1,2,3-triazoles and 1,3,5-triaryl-1,2,4-triazoles from bisarylhydrazones as the common starting precursor has been achieved via cascade C–H functionalization/C–C/N–N/C–N bonds formation under mild reaction conditions. One of the enthralling outcomes of this strategy is the copper(II)-catalyzed room temperature C–H functionalization/C–N bond formation in presence of air, which has been accomplished during the synthesis of substituted 1,2,4-triazoles. This new class of compounds could give prospective luminescence as an iconic component in the area of pharmaceutical and biological sciences. The intermediates for both the processes have been isolated to elucidate the mechanistic scenario.

Copper(II)-Catalyzed Aerobic Oxidative Synthesis of Substituted 1,2,3- and 1,2,4-Triazoles from Bisarylhydrazones via C–H Functionalization/C–C/N–N/C–N Bonds Formation

Copper(II)-Catalyzed Conversion of Bisaryloxime Ethers to 2-Arylbenzoxazoles via C−H Functionalization/C−N/C−O Bonds Formation

Activation and functionalization of N2 : A mixed diimide/dinitride tetranuclear titanium complex formed by activation of dinitrogen served as a unique platform for the synthesis of nitriles. Functional groups such as aromatic C-X (X=Cl, Br, I) bonds, nitro groups, and ammonia-sensitive aldehyde and chloromethyl moieties were compatible with the synthetic method.

Conversion of Dinitrogen to Nitriles at a Multinuclear Titanium Framework

Tris(pentafluorophenyl)borane-catalyzed dehydrogenative-cyclization of N-tosylhydrazones with aromatic amines has been disclosed. This metal-free catalytic protocol is compatible with a range of functional groups to provide both symmetrical and unsymmetrical 3,4,5-triaryl-1,2,4-triazoles. Mechanistic experiments and density functional theory (DFT) studies suggest an initial Lewis adduct formation of N-tosylhydrazone with B(C6F5)3 followed by sequential intermolecular amination of the borane adduct with aniline, intramolecular cyclization and frustrated Lewis pair (FLP)-catalyzed dehydrogenation for the generation of substituted 1,2,4-triazoles.

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B(C6F5)3-catalyzed dehydrogenative cyclization of N-tosylhydrazones and anilines via a Lewis adduct: a combined experimental and computational investigation

Murali Mohan Guru

Papers

Copper-Mediated Synthesis of Substituted 2-Aryl-N-benzylbenzimidazoles and 2-Arylbenzoxazoles via C–H Functionalization/C–N/C–O Bond Formation

Copper(II)-Catalyzed Aerobic Oxidative Synthesis of Substituted 1,2,3- and 1,2,4-Triazoles from Bisarylhydrazones via C–H Functionalization/C–C/N–N/C–N Bonds Formation

Copper(II)-Catalyzed Conversion of Bisaryloxime Ethers to 2-Arylbenzoxazoles via C−H Functionalization/C−N/C−O Bonds Formation

Conversion of Dinitrogen to Nitriles at a Multinuclear Titanium Framework

B(C6F5)3-catalyzed dehydrogenative cyclization of N-tosylhydrazones and anilines via a Lewis adduct: a combined experimental and computational investigation