Copper‐Catalyzed Three‐Component Coupling of Terminal Alkyne,Dihalomethane and Amine to Propargylic Amines

The direct C H and C halogen activation for C C bond formation is one of the most interesting reactions in organic chemistry. C C bond formation using alkynes as a carbon nucleophilic source is a very useful method in synthesis. Herein, a copper(I) chloride catalyzed three‐component coupling reaction of alkynes, dihalomethanes and amines through C H and C halogen activation to form propargylic amines under mild conditions has been established. The reaction can be conducted in water, in neat or in common organic solvents and it was applicable to both aromatic and aliphatic alkynes with good functional groups tolerance. It represents an excellent example of multi‐component reactions (MCRs), provides an elegant method for the synthesis of propargylic amines which are frequent skeletal components and synthetically versatile key intermediates for the preparation of many nitrogen‐containing biologically active compounds. From the mechanism point of view, this chemistry offers not only a new approach to propargylic amines with new C C and C N bonds formation through C H and C halogen activation, but also provides valuable mechanistic insight into the novel multi‐component reactions.     

Synthesis of Isoquinolines via Rhodium(III)‐Catalyzed Dehydrative C?C and C?N Coupling between Oximines and Alkynes

Isoquinolines have been synthesized from the redox‐neutral dehydrative C N and C C cross‐coupling between oximines and alkynes using a catalytic amount of (pentamethylcyclopentadiene)rhodium dichloride dimer {[RhCp*Cl₂]₂} and cesium acetate (CsOAc), a process that involves ortho C H activation of oximines and subsequent functionalization with alkynes. This redox‐neutral catalytic isoquinoline synthesis operates under mild conditions, and is insensitive to moisture or air. A broad scope of coupling partners has been established, and a likely mechanism has been suggested.     

Gold-Catalyzed Polycyclization Toward Natural Products Synthesis

Over the last years, gold catalysis has gained considerable significance in organic synthesis, since it allows atom economy and synthetic efficiency for the transformation of relatively simple substrates into valuable, highly complex molecular architectures. The gold-catalyzed polycyclization reactions of alkynes and enynes have been particularly successful toward the synthesis of natural products. This review highlights the recent developments in polycyclization area according to the key gold-catalyzed step.     

Recent Developments in the Synthesis and Reactivity of Isoxazoles: Metal Catalysis and Beyond

Isoxazoles are important five‐membered aromatic heterocycles in organic chemistry. Recently, many exciting advances in the synthesis and functionalization of isoxazoles have been reported. New transition metal‐catalyzed reactions have resulted in the development of attractive and highly efficient synthetic approaches to densely functionalized isoxazoles. Complete control of regioselectivity can be achieved on the basis of a judicious choice of metal catalyst and reaction partners using dipolar cycloaddition and cycloisomerization reactions, while more recent studies have focused on the site‐selective functionalization of isoxazoles via C H functionalization. New strategies for the use of isoxazoles as scaffolding templates in asymmetric synthesis have emerged, thus opening new prospects for the synthesis of enantioenriched motifs under the conditions that are orthogonal to other transformations. In this review, recent advances involving the synthesis and reactivity of isoxazoles are summarized. The review covers the period from January 2005 to June 2015.

     

Copper‐Catalyzed or ‐Mediated C?H Bond Functionalizations Assisted by Bidentate Directing Groups

Copper salts, which are abundant, relatively inexpensive and possess low toxicity, have long been used as versatile catalysts for various reactions in organic synthesis. Recently, the development of Cu‐catalyzed or ‐mediated C H functionalization reactions has gained significant attention. Since the pioneering work of Daugulis on the introduction of 8‐aminoquinoline and picolinic acid auxiliaries as removable directing groups in transition metal‐catalyzed C H bond activations, the combination of copper salts with these bidentate directing groups has emerged as an innovative strategy for the construction of carbon‐carbon or carbon‐heteroatom bonds through C H bond cleavage. In addition to the 8‐aminoquinoline and picolinamide systems, several other bidentate directing groups including the 2‐aminophenyloxazoline group by Yu and Dai and the PIP system by Shi, have been developed as well. This review intends to cover most of the recent advances on copper‐catalyzed or ‐mediated direct sp² and sp³ C H bond functionalizations assisted by these bidentate directing groups. The major achievements in this area are discussed and catalogued by the type of bonds formed (C C, C O, C N, C S, C P etc.). Special attention is paid to the reaction mechanisms. Selected examples of substrates are listed as well. In addition, a personal outlook is given at the end.

     

Practical Synthesis of Polysubstituted Imidazoles via Iodine‐ Catalyzed Aerobic Oxidative Cyclization of Aryl Ketones and Benzylamines

A practical synthetic method for polysubstituted imidazoles via iodine‐catalyzed aerobic oxidative cyclization of aryl ketones and benzylamines has been developed. It was found to tolerate a broad range of substrates to prepare polysubstituted imidazole derivatives in a one‐pot manner, and thus importantly allowed product diversity for imidazole chemistry. Additionally, the resultant 1,2,4‐trisubstituted imidazoles could be conveniently transformed to functionalized 1,2,4,5‐tetrasubstituted imidazoles via electrophilic substitution or direct C H functionalization, or 2,4‐diaryl‐1H‐imidazoles by debenzylation reaction, which further indicates potential applications of this method in synthetic and pharmaceutical chemistry.     

Cooperative Catalysis with Aldehydes and Copper: Development and Application in Aerobic Oxidative C?H Amination at Room Temperature

A conceptually new cooperative catalytic system via a synergistic combination of aldehyde and copper catalysis has been established based on systemic mechanistic studies. This new cooperative catalysis has been successfully applied in the direct aerobic oxidative C H amination of azoles at room temperature, which was previously realized under harsh conditions. Mechanistic studies including isotopic labeling experiments and kinetic isotope effect (KIE) experiments support a reaction pathway that involves formation of an aminal, hydrolysis of the aminal to generate the copper‐amide species, subsequent C H amination and re‐oxidation of copper(I) to copper(II) by oxygen. It not only provides an efficient method to realize the oxidative C H amination of benzoxazoles with free amines at room temperature, but also paves the way for establishing new C N bond formation reactions by using this efficient cooperative catalysis.     

Polyheterocycles by Palladium(II)‐Catalyzed Oxidative Domino Reactions Involving Direct C?H Functionalization

A novel palladium(II)‐catalyzed oxidative domino reaction sequence of diyne‐enones and substituted indoles to afford polyheterocycles involving direct C H functionalization using air as oxidant has been developed.     

Iron‐Catalyzed C?H Fuctionalization of Indoles

An easily available iron catalyst was developed to accomplish the C H functionalization of indoles with α‐aryl‐α‐diazoesters in high yields under mild conditions. The asymmetric C H functionalization of indoles was also realized by using iron complexes of chiral spiro bisoxazolines with up to 78% ee.     

Regioselective Access to Sultam Motifs through Cobalt‐Catalyzed Annulation of Aryl Sulfonamides and Alkynes using an 8‐Aminoquinoline Directing Group

The use of cobalt as catalyst in direct C H activation protocols as a replacement for more expensive second row transition metals is currently attracting significant attention. Herein we disclose a facile cobalt‐catalyzed C H functionalization route towards sultam motifs through annulation of easily prepared aryl sulfonamides and alkynes using 8‐aminoquinoline as a directing group. The reaction shows broad substrate scope with products obtained in a highly regioselective manner in good to excellent isolated yields. Mechanistic insights suggest the formation of a Co(III)‐aryl key species via a rate‐determining arene C H activation during the annulation reaction.

     

Copper‐Catalyzed Cross‐Dehydrogenative Coupling (CDC) of Alkynes and Benzylic C?H Bonds

The activation of benzylic C H bonds and subsequent coupling with terminal alkynes in the presence of 2,3‐dichloro‐5,6‐dicyanoquinone (DDQ) and a catalytic amount of copper(I) triflate is presented. Good to moderate yields of disubstituted alkynes are obtained for this cross‐dehydrogenative coupling (CDC) reaction between a variety of aromatic alkynes and diphenylmethane derivatives.     

Cyclopropanes and hypervalent iodine reagents: high energy compounds for applications in synthesis and catalysis

One of the major challenges faced by organic chemistry is the efficient synthesis of increasingly complex molecules. Since October 2007, the Laboratory of Catalysis and Organic Synthesis (LCSO) at EPFL has been working on the development of catalytic reactions based on the Umpolung of the innate reactivity of functional groups. Electrophilic acetylene synthons have been developed using the exceptional properties of ethynyl benziodoxolone (EBX) hypervalent iodine reagents for the alkynylation of heterocycles and olefins. The obtained acetylenes are important building blocks for organic chemistry, material sciences and chemical biology. The ring-strain energy of donor-acceptor cyclopropanes was then used in the first catalytic formal homo-Nazarov cyclization. In the case of aminocyclopropanes, the method could be applied in the synthesis of the alkaloids aspidospermidine and goniomitine. The developed methods are expected to have a broad potential for the synthesis and functionalization of complex organic molecules, including carbocycles and heterocycles.     

Understanding the C?H activation of methane over single-atom alloy catalysts by density functional theory calculations

As an important rate-determining step in the oxidation of methane, the catalytic behaviors of single-atom alloys (SAAs) on the C H activation reactions have not been fully understood. In this work, density functional theory calculations are performed to investigate the C H activation of methane on a series of SAAs with Cu(111/100) and Ag(111/100) as hosts. The reaction energies and the barriers for the C H dissociation reaction follow the traditional Brønsted–Evans–Polanyi (BEP) relationship, but the deviation from this linearity fitting is relatively large. To better describe the catalytic activity, a new nonlinear binary function is proposed to correlate the reaction barrier with the adsorption energies of *H and *CH₃ products, which has higher correlation than the BEP relationship, and showed more accurate predictions of the C H activation reaction for unknown SAAs catalysis. Such mode might be able to extend to other catalyst systems to achieve large-scale catalyst screening.     

Lewis Acid‐Catalyzed C?H Functionalization for Synthesis of Isoindolinones and Isoindolines

The Lewis acid‐catalyzed C H functionalization of 2‐substituted azaarenes with N‐sulfonylaldimines has been developed, which provides a rapid and efficient approach for synthesis of heterocycle‐containing isoindolinones and isoindolines.     

Synthesis of Propiolic Acids via Copper‐Catalyzed Insertion of Carbon Dioxide into the C?H Bond of Terminal Alkynes

A highly effective copper catalyst has been developed that promotes the insertion of carbon dioxide into the C H bond of terminal alkynes under unprecedentedly mild conditions. For the first time, propiolic acids can thus be synthesized in excellent yields from alkynes and carbon dioxide in the presence of the mild base cesium carbonate. The catalyst, (4,7‐diphenyl‐1,10‐phenanthroline)bis[tris(4‐fluorophenyl)phosphine]copper(I) nitrate, is easy accessible and relatively stable against air and water.     

Polymer Cocktail: A Multitask Supported Ionic Liquid‐Like Species to Facilitate Multiple and Consecutive C?C Coupling Reactions

Polymer‐supported ionic liquid‐like species (SILLPs) with different functionalities have been combined to obtain new catalytic systems (polymer cocktail) with improved properties towards their application for C C coupling reactions. The SILLPs have been synthesized in a simple way and combined to play different functions in the reaction medium. Those roles involve simultaneously (or consecutively) their actuation as supported reagents, precatalysts and scavengers of undesired reaction side‐products. The system has been tested by employing three different C C coupling reactions for 8 consecutive cycles. Moreover, different aryl bromides and iodides have proved to be efficiently transformed by the catalytic cocktail. Finally, the Heck reaction has been conducted in continuous‐flow conditions using a packed bed of this polymer cocktail and employing supercritical carbon dioxide (scCO₂) as a solvent, which cannot be carried out with the use of soluble bases as this would lead to the clogging of the reactor. Finally, the SILLPs cocktail enables one to combine different reaction steps and purification in a single vessel, which represents a significant improvement in terms of process intensification and green chemistry. This is particularly true in the case of the use of scCO₂ as this allows the direct production of crude materials not contaminated either by salts or by solvents.     

Transition Metal‐Catalyzed C?H Activation of Indoles

The last decades have seen a tremendous expanse in the application of C H activation of many different substrate classes, including the invaluable indole scaffold. Following the exciting emergence of C H activation as a multi‐faceted platform for functionalization, a versatile tool box has been developed for the preparation of structurally diverse indoles. This review article discusses recent advances and strategies for transition metal‐catalyzed C H activation of indoles.

     

N‐Heterocyclic Carbene Ligands and Iron: An Effective Association for Catalysis

Although iron has been known and widely used in coordination and organometallic chemistry for decades and N‐heterocyclic carbenes (NHCs) have also been used for about half a century, their combination surprisingly did not become a hot topic in chemistry until this last decade. This review presents several recent and stimulating developments in homogeneous catalysis done mainly using iron/NHC‐based catalysts. Of particular interest are the roles of iron/NHC complexes in cross‐coupling Kochi reactions, C C bond formation reactions and hydrofunctionalization, and more particularly in hydrosilylation. Our review summarizes the key developments in these fields.     

Discrete Molecular Catalysts for Methane Functionalization

The implementation of selective, energy efficient, direct alkane oxidation chemistry could lead to a new paradigm in materials and energy technologies for the 21^st century that is environmentally and economically superior to current processes. Such processes would allow the vast reserves of natural gas to be directly employed as feedstocks for fuels and chemicals. Molecular catalysts that activate and functionalize the C H bonds of unactivated hydrocarbons are of particular interest, from both a scientific and economic viewpoint. This results from the unique properties of these engineered materials, which allow them to carry out oxidative hydrocarbon functionalization, with high atom and energy efficiency, under relatively mild conditions. Despite the large body of work on the activation of C H bonds over the last three decades, relatively few catalyst systems based on this approach present a viable route to functionalize hydrocarbons. This dilemma is largely due to the large gaps in our fundamental knowledge to allow rational design of such catalysts. Addressed in this paper are some of the key challenges and approaches to the de novo design of alkane functionalization molecular catalysts based on the C H activation reaction, with an emphasis on our own research.     

Synthesis of [60]Fullerene‐Fused Tetralones via Palladium‐ Catalyzed Ketone‐Directed sp2 C?H Activation and sp3 C?H Functionalization

The palladium‐catalyzed ketone‐directed dual sp² C H activation and sp³ C H functionalization has been applied for fullerene functionalization for the first time. The sec‐alkyl aryl ketones have been exploited to react with [60]fullerene (C₆₀) to provide the novel and scarce C₆₀‐fused tetralones. The combined use of a highly active cationic palladium(II) catalyst and trifluoromethanesulfonic acid is crucial for the improvement of the reaction yield. A plausible reaction mechanism leading to the observed products has been proposed, and the electrochemistry of the fullerene products has also been investigated.