Frank Glorius

An overview of N-heterocyclic carbenes

The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.

Beyond Directing Groups: Transition‐Metal‐Catalyzed CH Activation of Simple Arenes

The use of coordinating moieties as directing groups for the functionalization of aromatic C-H bonds has become an established tool to enhance reactivity and induce regioselectivity. Nevertheless, with regard to the synthetic applicability of C-H activation, there is a growing interest in transformations in which the directing group can be fully abandoned, thus allowing the direct functionalization of simple benzene derivatives. However, this approach requires the disclosure of new strategies to achieve reactivity and to control selectivity. In this review, recent advances in the emerging field of non-chelate-assisted C-H activation are discussed, highlighting some of the most intriguing and inspiring examples of induction of reactivity and selectivity.

The Measure of All Rings—N‐Heterocyclic Carbenes

Quantification and variation of characteristic properties of different ligand classes is an exciting and rewarding research field. N-Heterocyclic carbenes (NHCs) are of special interest since their electron richness and structure provide a unique class of ligands and organocatalysts. Consequently, they have found widespread application as ligands in transition-metal catalysis and organometallic chemistry, and as organocatalysts in their own right. Herein we provide an overview on physicochemical data (electronics, sterics, bond strength) of NHCs that are essential for the design, application, and mechanistic understanding of NHCs in catalysis.

Rh(III)-Catalyzed Directed C−H Olefination Using an Oxidizing Directing Group: Mild, Efficient, and Versatile

An efficient Rh(III)-catalyzed oxidative olefination by directed C-H bond activation of N-methoxybenzamides is reported. In this mild, practical, selective, and high-yielding process, the N-O bond acts as an internal oxidant. In addition, simply changing the substituent of the directing/oxidizing group results in the selective formation of valuable tetrahydroisoquinolinone products.

Extending NHC-Catalysis: Coupling Aldehydes with Unconventional Reaction Partners

Transition metal catalysis is a powerful means of effecting organic reactions, but it has some inherent drawbacks, such as the cost of the catalyst and the toxicity of the metals. Organocatalysis represents an attractive alternative and, in some cases, offers transformations unparalleled in metal catalysis. Unique transformations are a particular hallmark of N-heterocyclic carbene (NHC) organocatalysis, a versatile method for which a number of modes of action are known. The NHC-catalyzed umpolung (that is, the inversion of polarity) of electrophilic aldehydes, through formation of the nucleophilic Breslow intermediate, is probably the most important mode of action. In this Account, we discuss the reaction of Breslow intermediates with unconventional reaction partners. In two traditional umpolung reactions, the benzoin condensation and the Stetter reaction, some selectivity issues represent significant challenges, especially in intermolecular variants of these reactions. In intermolecular cross-benzoin reactions, high levels of selectivity were recently obtained, even in the hydroxymethylation of aldehydes with formaldehyde. The key to success was careful choice of the NHC catalyst and reaction conditions. Among asymmetric Stetter reactions, intermolecular versions have posed a long-standing challenge. Recently, the groups of Enders and Rovis reported the first selective and efficient systems. We have contributed to this field by developing an efficient intermolecular Stetter reaction for the formation of α-amino acid derivatives, with broad aldehyde scope and high enantiomeric excess. Moreover, tailor-made thiazolylidene catalysts allowed the unprecedented use of nonactivated olefins and alkynes as aldehyde coupling partners. The basis for this reactivity is a unique mode of NHC organocatalysis: dual activation. In a concerted but asynchronous transition state, the positively polarized proton of the Breslow intermediate activates the coupling partner (for example, an olefin), while the nucleophilic enamine moiety starts to attack the activated coupling partner. As a consequence of the concerted nature of this mechanism, excellent values for enantiomeric excess were obtained for many substrates in the intramolecular hydroacylation of alkenes. In addition, thiazolylidene catalysts have enabled the coupling of aldehydes with reactive species, for example, with arynes and with activated alkyl bromides. NHC catalysis should continue to flourish and lead to surprising developments. One remaining challenge is the asymmetric intermolecular hydroacylation of unactivated olefins. In this area, metal-based catalysts have shown promising early results, but they are far from being either general or practical. It will be interesting to see which class of catalyst, whether metal-based or NHC-based, eventually develops into the method of choice.

Pyrrole Synthesis via Allylic sp3 C−H Activation of Enamines Followed by Intermolecular Coupling with Unactivated Alkynes

A conceptually novel pyrrole synthesis is reported, efficiently merging enamines and (unactivated) alkynes under oxidative conditions. In an intermolecular Rh catalyzed process, the challenging allylic sp(3) C-H activation of the enamine substrates is followed by the cyclization with the alkyne (R(3) = CO(2)R). Alternatively, in some cases (R(3) = CN), the enamine can be utilized for a vinylic sp(2) C-H activation. A total of 17 examples with yields above 60% is presented, together with the results of an initial mechanistic investigation.

N-Heterocyclic Carbenes in Transition Metal Catalysis

N-Heterocyclic Carbenes in Catalysis-An Introduction.- N-Heterocyclic Carbenes in Catalysis-An Introduction.- N-Heterocyclic Carbenes as Ligands for High-Oxidation-State Metal Complexes and Oxidation Catalysis.- N-Heterocyclic Carbenes as Ligands for High-Oxidation-State Metal Complexes and Oxidation Catalysis.- Palladium-catalyzed Reactions Using NHC Ligands.- Palladium-catalyzed Reactions Using NHC Ligands.- Routes to N-Heterocyclic Carbene Complexes.- Routes to N-Heterocyclic Carbene Complexes.- Chiral N-Heterocyclic Carbenes as Stereodirecting Ligands in Asymmetric Catalysis.- Chiral N-Heterocyclic Carbenes as Stereodirecting Ligands in Asymmetric Catalysis.- Transition Metal-Catalyzed Reactions Using N-Heterocyclic Carbene Ligands (Besides Pd- and Ru-Catalyzed Reactions).- Transition Metal-Catalyzed Reactions Using N-Heterocyclic Carbene Ligands (Besides Pd- and Ru-Catalyzed Reactions).- N-Heterocyclic Carbenes as Ligands for Olefin Metathesis Catalysts.- N-Heterocyclic Carbenes as Ligands for Olefin Metathesis Catalysts.

Dual Catalysis Sees the Light: Combining Photoredox with Organo-, Acid, and Transition-Metal Catalysis

The photoredox activation of organic substrates with visible light is a powerful methodology that generates reactive radical species under very mild conditions. When combined with another catalytic process in a dual catalytic system, novel, visible-light-promoted transformations have been realized that do not proceed using either catalyst in isolation. In this minireview, the state of the art in organic reactions mediated by dual catalytic systems merging photoredox activation with organo-, acid or metal catalysis is discussed.

Rh Catalyzed Olefination and Vinylation of Unactivated Acetanilides

In the catalyzed oxidative olefination of acetanilides (oxidative-Heck coupling), Rh offers great advantages over more common Pd catalysts. Lower catalyst loadings, large functional group tolerance (in particular to halides), and higher reactivity of electron-neutral olefins (styrenes) are some of the attractive features. Most interestingly, even ethylene reacts to yield the corresponding acetanilido-styrene. Moreover, the Cu(II) oxidant can also be utilized in catalytic amounts with air serving as the terminal oxidant.

Co(III)-Catalyzed C–H Activation/Formal SN-Type Reactions: Selective and Efficient Cyanation, Halogenation, and Allylation

The first cobalt-catalyzed cyanation, halogenation, and allylation via C-H activation have been realized. These formal SN-type reactions generate valuable (hetero)aryl/alkenyl nitriles, iodides, and bromides as well as allylated indoles using a bench-stable Co(III) catalyst. High regio- and mono-selectivity were achieved for these reactions. Additionally, allylation proceeded efficiently with a turnover number of 2200 at room temperature, which is unprecedented for this Co(III) catalyst. Alkenyl substrates and amides have been successfully utilized in Cp*Co(III)-catalyzed C-H activation for the first time.