Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds

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Aryl-aryl bond formation one century after the discovery of the Ullmann reaction.

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

This critical review discusses historical and contemporary research in the field of transition metal-catalyzed carbon–hydrogen (C–H) bond activation through the lens of stereoselectivity. Research concerning both diastereoselectivity and enantioselectivity in C–H activation processes is examined, and the application of concepts in this area for the development of novel carbon–carbon and carbon–heteroatom bond-forming reactions is described. Throughout this review, an emphasis is placed on reactions that are (or may soon become) relevant in the realm of organic synthesis (221 references).

Transition metal-catalyzed C–H activation reactions: diastereoselectivity and enantioselectivity

Three different mechanisms have been identified for the CuCl 2 -mediated oxidative coupling of naphthols to binaphthyls in the presence of chiral amines (sparteine or α-methylbenzylamine); fair to excellent enantioselection has been observed (up to 100 % ee). The choice of the dominant mechanism appears to be critically dependent on the structure of the partners to be coupled. Thus, for the self-coupling of 2-naphthol (1) the enantioselection is mainly controlled of via a second-order asymmetric transformation of the product 4 (up to 100 % ee). The same mechanism is responsible for the formation of enantiomerically enriched biphenanthrol 9 (76% ee). By contrast, enantiodifferentiation in the formation of 5 and 7 results from the diastereoselective crystallization of the corresponding Cu(II)-amine-binaphtyl complex, wheras an enantioselective coupling operates in the preparation of 6. A catalytic cycle has been designed, employing 10 mol% of CuCl 2 (with AgCl to regenerate Cu II ) and sparteine(20 mol%); when applied to the asymmetric cross-coupling 1+3→6, the product (-)6 was obtained in 41%yield

Synthesis of enantiomerically pure binaphthyl derivatives. Mechanism of the enantioselective, oxidative coupling of naphthols and designing a catalytic cycle

Synthesis of enantiomerically pure 2,2'-dihydroxy-1,1'-binaphthyl, 2,2'-diamino-1,1'-binaphthyl, and 2-amino-2'-hydroxy-1,1'-binaphthyl. Comparison of processes operating as diastereoselective crystallization and as second order asymmetric transformation

The novel 1,1'-binaphthyls with OH and/or NHR (R=H or Ph) groups in the 2,2'-positions and with additional methoxycarbonyl group(s) in the 3- or 3,'-positions (13-18) have been synthesized from their respective precursors 1-5 by the CuCl 2 /t-BuNH 2 -mediated oxidative cross-coupling. In most cases, the chemoselectivity was good, and the cross-coupled products 11-18 were obtained in fair to excellent yields. Binaphthyls 6-10, resulting from the self-coupling, and carbazoles 10-23 have been identified as byproducts. Ab initio calculations and electrochemical measurements have been employed to account for the observed selectivity

Selective Cross-Coupling of 2-Naphthol and 2-Naphthylamine Derivatives. A Facile Synthesis of 2,2',3-Trisubstituted and 2,2',3,3'-Tetrasubstituted 1,1'-Binaphthyls

Enantioselective reduction of ketimines 6−10 with trichlorosilane can be catalyzed by the N-methyl valine-derived Lewis-basic formamide (S)-23 (Sigamide) with high enantioselectivity (≤97% ee) and low catalyst loading (1−5 mol %) at room temperature in toluene. The reaction is efficient with ketimines derived from aromatic amines (aniline and anisidine) and aromatic, heteroaromatic, conjugated, and even nonaromatic ketones 1−5, in which the steric difference between the alkyl groups R1 and R2 is sufficient. Simple nitrogen heteroaromatics (8a,b,d) exhibit low enantioselectivities due to the competing coordination of the reagent but increased steric hindrance in the vicinity of the nitrogen (8c,e) results in a considerable improvement. Cyclic imines 32d-d exhibited low to modest enantioselectivities.

Asymmetric reduction of imines with trichlorosilane, catalyzed by sigamide, an amino acid-derived formamide: scope and limitations.

Allylation of aromatic and heteroaromatic aldehydes 1a−k with allyltrichlorosilane 2 can be catalyzed by the new heterobidentate, terpene-derived bipyridine N-monoxides 4, 6a,b, and 8−11 (≤10 mol %) to afford (S)-(−)-3 with high enantioselectivities (≤99% ee). The stereochemical outcome has been found to be controlled by the axial chirality of the catalyst, which in turn is determined by the central chirality of the annulated terpene units. Solvent effects on the conversion and the level of asymmetric induction have been elucidated, and MeCN has been identified as the optimal solvent for these catalysts.

Pavel Kocovsky

Papers

Synthesis of enantiomerically pure binaphthyl derivatives. Mechanism of the enantioselective, oxidative coupling of naphthols and designing a catalytic cycle

Synthesis of enantiomerically pure 2,2'-dihydroxy-1,1'-binaphthyl, 2,2'-diamino-1,1'-binaphthyl, and 2-amino-2'-hydroxy-1,1'-binaphthyl. Comparison of processes operating as diastereoselective crystallization and as second order asymmetric transformation

Selective Cross-Coupling of 2-Naphthol and 2-Naphthylamine Derivatives. A Facile Synthesis of 2,2',3-Trisubstituted and 2,2',3,3'-Tetrasubstituted 1,1'-Binaphthyls

Asymmetric reduction of imines with trichlorosilane, catalyzed by sigamide, an amino acid-derived formamide: scope and limitations.

New Lewis-basic N-oxides as chiral organocatalysts in asymmetric allylation of aldehydes.