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.

An overview of N-heterocyclic carbenes

Over the last decade, substantial research has led to the introduction of an impressive number of efficient procedures which allow the selective construction of CC bonds by directly connecting two different CH bonds under oxidative conditions. Common to these methodologies is the generation of the reactive intermediates in situ by activation of both CH bonds. This strategy was introduced by the group of Li as cross-dehydrogenative coupling (CDC) and discloses waste-minimized synthetic alternatives to classic coupling procedures which rely on the use of prefunctionalized starting materials. This Review highlights the recent progress in the field of cross-dehydrogenative C sp 3C formations and provides a comprehensive overview on existing procedures and employed methodologies.

The Cross-Dehydrogenative Coupling of C sp 3H Bonds: A Versatile Strategy for CC Bond Formations

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes.

Metal–organic frameworks (MOFs), established as a relatively new class of crystalline porous materials with high surface area, structural diversity, and tailorability, attract extensive interest and exhibit a variety of applications, especially in catalysis. Their permanent porosity enables their inherent superiority in confining guest species, particularly small metal nanoparticles (MNPs), for improved catalytic performance and/or the expansion of reaction scope. This is a rapidly developing interdisciplinary research field. In this review, we provide an overview of significant progress in the development of MNP/MOF composites, including various preparation strategies and characterization methods as well as catalytic applications. Special emphasis is placed on synergistic effects between the two components that result in an enhanced performance in heterogeneous catalysis. Finally, the prospects of MNP/MOF composites in catalysis and remaining issues in this field have been indicated.

Metal–organic frameworks meet metal nanoparticles: synergistic effect for enhanced catalysis

The umpolung strategy encompasses all the methods that make organic molecules react in an inverse manner compared to their innate polarity-driven reactivity. This concept entered the field of organocatalysis when it was recognized that N-heterocyclic carbenes (NHCs) can provide catalytic access to acyl anion equivalents. Since then, tremendous efforts have followed to develop a broad variety of NHC-catalyzed reactions. In addition to this, more recent research developments have shown that other families of organocatalysts are also able to mediate transformations in which inversion of polarity is involved. This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.

Organocatalytic umpolung: N-heterocyclic carbenes and beyond

The encapsulation of noble-metal nanoparticles (NPs) in metal-organic frameworks (MOFs) with carboxylic acid ligands, the most extensive branch of the MOF family, gives NP/MOF composites that exhibit excellent shape-selective catalytic performance in olefin hydrogenation, aqueous reaction in the reduction of 4-nitrophenol, and faster molecular diffusion in CO oxidation. The strategy of using functionalized cavities of MOFs as hosts for different metal NPs looks promising for the development of high-performance heterogeneous catalysts.

A family of metal-organic frameworks exhibiting size-selective catalysis with encapsulated noble-metal nanoparticles.

An oxidative γ-functionalization of enals under N-heterocyclic carbene (NHC) catalysis to give unsaturated δ-lactones is disclosed. Enantioselectivity control involving the relatively remote enal γ-carbon was achieved via Lewis acid [Sc(OTf)3 or combined Sc(OTf)3/Mg(OTf)2] and NHC cooperative catalysis.

Oxidative γ-addition of enals to trifluoromethyl ketones: enantioselectivity control via Lewis acid/N-heterocyclic carbene cooperative catalysis.

Direct β-carbon activation of saturated carbonyl compounds represents a significant fundamental challenge in organic chemistry. Here, the catalytic activation of saturated ester β-sp3 carbon as nucleophile via N-heterocyclic carbene organocatalysis is reported. The catalytically generated nucleophilic β-carbon undergoes enantioselective reactions with various electrophiles.

β-Carbon activation of saturated carboxylic esters through N -heterocyclic carbene organocatalysis

The first N-heterocyclic carbene (NHC)-catalyzed [3+4] cycloaddition of azomethine imines and enals is disclosed. Oxidative catalytic remote activation of enals affords 1,4-dipolarophile intermediates that react with 1,3-dipolar azomethine imines to generate dinitrogen-fused seven-membered heterocyclic products with high optical purities. Our approach also provides effective kinetic resolution of azomethine imines, in which the substrate chiral center that is remote from the NHC catalyst can be well resolved.

N-heterocyclic carbene-catalyzed [3+4] cycloaddition and kinetic resolution of azomethine imines

a,b-Unsaturated carbonyl compounds are basic building blocks in organic synthesis. Lewis acid catalysts bearing chiral ligands have traditionally been used for the asymmetric catalytic activation of this class of molecules as Michael acceptors. 2] Indeed, Lewis acid catalysis continues to be a powerful approach in which innovative solutions are still emerging. Representative examples of chiral Lewis acid catalysts include the metal–bisoxazoline complexes introduced by the research groups of Evans and Corey, the multimetallic bifunctional catalysts developed by Shibasaki and co-workers, the bifunctional Lewis acid/base catalysts described by Lectka and co-workers, and the metal–N,N’dioxide catalysts developed by Feng and co-workers. In another direction, organocatalytic methods have received intense attention in the last decade or so. By iminium catalysis, pioneered by MacMillan and co-workers, a,bunsaturated aldehydes and ketones can be activated as electrophiles for a set of highly enantioselective reactions (Scheme 1a). The related equally useful ester substrates, on the other hand, are outside the scope of iminium/enamine catalysis, which has proved to be versatile for aldehyde and ketone substrates. We are interested in the organocatalytic activation of readily available esters for asymmetric synthesis. N-Heterocyclic carbenes (NHCs, typically imidazolium-based NHCs) have been studied previously for the catalysis of transesterification reactions (Scheme 1b). Two mechanisms were proposed for NHC-catalyzed transesterification; one involves ester activation, and the other involves alcohol activation, in which NHC behaves as a base catalyst. Recently, we disclosed the HOMO activation of saturated a-aryl acetic esters through catalysis with NHCs to generate enolate intermediates for enantioselective reactions. Herein we report the formal LUMO activation of a,b-unsaturated esters by NHC catalysis for highly enantioselective reactions with enamides (Scheme 1c). The key step involves the addition of the NHC catalyst to the ester substrate I to form an a,b-unsaturated acyl azolium intermediate II. Unsaturated acyl azolium intermediates of this type were previously generated from enals, a-hydroxyenones, a-bromoenals, ynals, and a,b-unsaturated acid fluorides by (oxidative) NHC catalysis. Lupton and co-workers reported an NHC-catalyzed enol ester rearrangement, which was proposed to proceed by addition of the NHC to the carbonyl group of the ester, followed by Claisen rearrangement. They suggested that an a,b-unsaturated acyl azolium intermediate (such as II) was unlikely to be involved as a key intermediate (Scheme 1b). In a related approach, Smith and co-workers recently reported the use of anhydrides as a,b-unsaturated acyl ammonium precursors with isothiourea catalysts. Each of these elegant methods has its own merits and limitations. For example, with a,b-unsaturated aldehyde substrates, relatively expensive organic oxidants 19] need to be used in the asymmetric oxidative NHC catalysis. The use of ynals as substrates is constrained by the limited substitution patterns (e.g. disubstitution at the a and b carbon atoms is not possible) and somewhat high cost of the ynal compounds. In our approach, the ester substrates are readily available, inexpensive, and stable (easy to handle). Various Scheme 1. a,b) Previously reported related approaches for the activation of carbonyl substrates with organocatalysts. c) LUMO activation of a,b-unsaturated carbonyl compounds by NHC catalysis. Ts = p-toluenesulfonyl.

Yonggui Robin Chi

Papers

A family of metal-organic frameworks exhibiting size-selective catalysis with encapsulated noble-metal nanoparticles.

Oxidative γ-addition of enals to trifluoromethyl ketones: enantioselectivity control via Lewis acid/N-heterocyclic carbene cooperative catalysis.

β-Carbon activation of saturated carboxylic esters through N -heterocyclic carbene organocatalysis

N-heterocyclic carbene-catalyzed [3+4] cycloaddition and kinetic resolution of azomethine imines

NHC Organocatalytic Formal LUMO Activation of α,β‐Unsaturated Esters for Reaction with Enamides