Are There Carbenes in N‐Heterocyclic Carbene Organocatalysis?

Azolium cations are widely employed in organocatalysis to catalyse highly valuable synthetic processes in the presence of a base. These reactions are called “N‐heterocyclic carbene catalysis”, based on the assumption that they are initiated by the formation of a free carbene through deprotonation, which can then react with the substrates and thereby affect their reactivity to obtain the desired products. However, we herein provide evidence that an electrophilic aromatic substitution mechanism is energetically more favourable, in which the azolium cation reacts directly with the substrate, avoiding the formation of the free carbene in solution.     

Single-Electron Transfer Reactions Enabled by N-Heterocyclic Carbene Organocatalysis

Over the past decades, N-heterocyclic carbene (NHC) organocatalysis has undergone a flourish of development on the basis of closed-shell reaction paths. By contrast, the emerging area of single-electron transfer (SET) reactions enabled by NHC catalysis still remain underdeveloped, but offer plenty of opportunities to develop new catalytic modes and useful synthetic methods. A number of interesting transformations were triggered by the SET process from the electron-rich Breslow intermediates to various single-electron acceptors. In additions, recent studies revealed that the Breslow radical cations could also be generated by single-electron reduction of the electron-deficient acyl azolium intermediates. These discoveries open a new avenue for NHC organocatalysis to harness radical reactions. The present review will focus on the exciting advancements in the dynamic area of radical NHC organocatalysis.     

N-heterocyclic carbene catalyzed reaction of phthalaldehydes: controllable stereoselective synthesis of polyhydroxylated spiro- and fused indenones dictated by the structure of NHC catalysts

The N-heterocyclic carbene catalyzed stereoselective dimerization reactions of phthalaldehydes produced polyhydroxylated spiro- or fused indenones. The reaction pathways were dictated by the structures of NHC catalysts. Under the catalysis of a imidazole carbene, phthalaldehydes produced dihydroxylspiro[indene-2,1'-isobenzofuran]-3-ones in good to excellent yields, whereas a triazole carbene catalyzed reaction of phthalaldehydes afforded fully cis-trihydroxylindeno[2,1-a]inden-5-ones in high yields. This work not only provides a highly efficient method for the construction of valuable polyhydroxyl substituted indene derivatives that are not easily assembled by other synthetic means but also reflects the versatility of organocatalysis using N-heterocyclic carbenes.     

Radical Acylfluoroalkylation of Olefins through N-Heterocyclic Carbene Organocatalysis

Fluorinated ketones are widely prevalent in numerous biologically interesting molecules, and the development of novel transformations to access these structures is an important task in organic synthesis. Herein, we report the multicomponent radical acylfluoroalkylation of a variety of olefins in the presence of various commercially available aromatic aldehydes and fluoroalkyl reagents through N-heterocyclic carbene organocatalysis. With this protocol, over 120 examples of functionalized ketones with diverse fluorine substituents have been synthesized in up to 99 % yield with complete regioselectivity. The generality of this catalytic strategy was further highlighted by its successful application in the late-stage functionalization of pharmaceutical skeletons. Excellent diastereoselectivity could be achieved in the reactions forging multiple stereocenters. In addition, preliminary results have been achieved on the catalytic asymmetric variant of the olefin difunctionalization process.     

Radical Acylfluoroalkylation of Olefins through N‐Heterocyclic Carbene Organocatalysis

Fluorinated ketones are widely prevalent in numerous biologically interesting molecules, and the development of novel transformations to access these structures is an important task in organic synthesis. Herein, we report the multicomponent radical acylfluoroalkylation of a variety of olefins in the presence of various commercially available aromatic aldehydes and fluoroalkyl reagents through N‐heterocyclic carbene organocatalysis. With this protocol, over 120 examples of functionalized ketones with diverse fluorine substituents have been synthesized in up to 99 % yield with complete regioselectivity. The generality of this catalytic strategy was further highlighted by its successful application in the late‐stage functionalization of pharmaceutical skeletons. Excellent diastereoselectivity could be achieved in the reactions forging multiple stereocenters. In addition, preliminary results have been achieved on the catalytic asymmetric variant of the olefin difunctionalization process.     

Merging organocatalysis and gold catalysis-a critical evaluation of the underlying concepts

While both organocatalysis and gold catalysis have their roots deeply entrenched in the landscape of modern organic chemistry, an exciting trend in the complementary merging of organocatalysis and especially Au(I) catalysis has emerged in the last four years. This niche area has been developing rapidly and this minireview serves to pin-point the fundamental concepts guiding reaction design in these binary catalytic systems. Moreover, the proven synthetic utility of organo/Au(I) multicatalytic systems in accessing molecular frameworks, previously a challenge to single catalytic systems, has resulted in this new concept permeating numerous areas of organocatalysis, such as primary/secondary amine, Br?nsted acid, hydrogen-bonding as well as N-heterocyclic carbene (NHC) catalysis. The first detailed account of these recent developments is systematically presented.     

Recent Advances in Organocatalytic Methods for Asymmetric C?C Bond Formation

Beyond a doubt organocatalysis belongs to the most exciting and innovative chapters of organic chemistry today. Organocatalysis has emerged not only as a complement to metal‐catalyzed reactions and to biocatalysis over the last decade, but also provides new asymmetric organocatalyzed reactions that cannot be accomplished by metal‐ or biocatalyzed reactions so far. A large number of organocatalytic processes are already well established in organic synthesis. Nevertheless, the number of publications in this field is still on the increase; new important results are produced constantly. This review gives a detailed overview of the latest developments and main streams in organocatalyzed asymmetric C? C bond formation processes of the last three years. It is intended to outline the most important current findings focused on especially new synthetic methodologies.     

One‐Pot Consecutive Catalysis by Integrating Organometallic Catalysis with Organocatalysis

The present study integrates two types of catalysis, namely, organometallic catalysis and organocatalysis in one reaction pot. In this process, the product of the first catalytic cycle acts as catalytic component for next catalytic cycle. The abnormal N‐heterocyclic carbene–copper‐based organometallic catalyst acts as an efficient catalyst for a click reaction to provide triazole, which, in turn, acts as an efficient organocatalyst for different organic transformations, for example, aza‐Michael addition and multicomponent reactions, in a consecutive fashion in the same reaction pot.     

Nucleophilic β‐Carbon Activation of Propionic Acid as a 3‐Carbon Synthon by Carbene Organocatalysis

Direct β‐carbon activation of propionic acid (C₂H₅CO₂H) by carbene organocatalysis has been developed. This activation affords the smallest azolium homoenolate intermediate (without any substituent) as a 3‐carbon nucleophile for enantioselective reactions. Propionic acid is an excellent raw material because it is cheap, stable, and safe. This approach provides a much better solution to azolium homoenolate synthesis than the previously established use of acrolein (enal without any substituent), which is expensive, unstable, and toxic.     

Atroposelective Access to 1,3-Oxazepine-Containing Bridged Biaryls via Carbene-Catalyzed Desymmetrization of Imines

We disclose herein an atroposelective synthesis of novel bridged biaryls containing medium-sized rings via N-heterocyclic carbene organocatalysis. The reaction starts with addition of the carbene catalyst to the aminophenol-derived aldimine substrate. Subsequent oxidation and intramolecular desymmetrization lead to the formation of 1,3-oxazepine-containing bridged biaryls in good yields and excellent enantioselectivities. These novel bridged biaryl products can be readily transformed into chiral phosphite ligands. Preliminary density function theory calculations suggest that the origin of enantioselectivity arises from the more favorable frontier molecular orbital interactions in the transition state leading to the major product.     

N‐Heterocyclic Carbene Catalyzed Synthesis of δ‐Sultones via α,β‐Unsaturated Sulfonyl Azolium Intermediates

A limited array of reactive intermediates have enabled a wealth of discoveries in N‐heterocyclic carbene organocatalysis. In this study, the viability of α,β‐unsaturated sulfonyl azoliums as double electrophiles in new reactions is examined. Specifically, the (3+3) annulation of such species with the trimethylsilyl enol ethers of various 1,3‐dicarbonyl compounds has been developed. This reaction provides access to a range of novel unsaturated δ‐sultones (18 examples) in good yields (40–88 %) under mild reaction conditions. Mechanistic studies and the development of an enantioselective variant (55 % yield, 73:27 e.r.) support the intermediacy of an α,β‐unsaturated sulfonyl azolium species.     

Access to Enantioenriched Organosilanes from Enals and β‐Silyl Enones: Carbene Organocatalysis

Herein, an efficient route to enantioenriched organosilanes, containing two consecutive stereogenic centers, from enals and β‐silyl enones under carbene organocatalysis is described. Under mild reaction conditions, this transition‐metal‐free strategy exhibits a broad substrate scope, and excellent diastereo‐ and enantioselectivity.     

Synergy,Compatibility, and Innovation: Merging Lewis Acids with Stereoselective Enamine Catalysis

In recent years there has been an accelerated rate of development in the field of organocatalysis, with asymmetric organocatalysis now reaching full maturity. The invention of new organocatalytic reactions and the exploration of new concepts now appear in tandem with the application of organocatalytic techniques in the synthesis of natural products and active pharmaceutical ingredients (APIs). After a “golden rush” in organocatalysis, researchers are now starting to combine different methods, thereby taking advantage of the significant benefits of synergy. Metals are used in combination with organocatalytic processes, thus reaching complexity that is found in nature, where enzymes take advantage of the presence of certain metals to increase the arsenal of organic transformations available. In this Focus review, we illustrate the possibility of a “happy marriage” between Lewis acids and organocatalytic stereoselective processes. Questions have been raised about the combination of Lewis acids and organocatalysis owing to the presence of water and/or strong bases in these processes. Some Lewis acids have been shown to be compatible with organocatalysis and concepts relating to their use will be illustrated herein. To summarize the fruitful use of Lewis acids in stereoselective organocatalytic processes, we will draw attention to the advantages and selectivity achieved using this method.     

Asymmetric organocatalysis: from infancy to adolescence

After an initial period of validating asymmetric organocatalysis by using a wide range of important model reactions that constitute the essential tools of organic synthesis, the time has now been reached when organocatalysis can be used to address specific issues and solve pending problems of stereochemical relevance. This Review deals with selected studies reported in 2006 and the first half of 2007, and is intended to highlight four main aspects that may be taken as testimony of the present status and prospective of organocatalysis: a) chemical efficiency; b) discovery of new substrate combinations to give new asymmetric syntheses; c) development of new catalysts for specific purposes by using mechanistic findings; and d) applications of organocatalytic reactions in the asymmetric total synthesis of target natural products and known compounds of biological and pharmaceutical relevance.     

Ambident Reactivity of Imidazolium Cations as Evidence of the Dynamic Nature of N-Heterocyclic Carbene-Mediated Organocatalysis

This work reveals ambident nucleophilic reactivity of imidazolium cations towards carbonyl compounds at the C2 or C4 carbene centers depending on the steric properties of the substrates and reaction conditions. Such an adaptive behavior indicates the dynamic nature of organocatalysis proceeding via a covalent interaction of imidazolium carbenes with carbonyl substrates and can be explained by generation of the H-bonded ditopic carbanionic carbenes.     

Pd-catalyzed inter- and intramolecular carbene transfer from group 6 metal-carbene complexes.

The use of group 6 metal-carbene complexes in inter- and intramolecular carbene transfer reactions has been studied. Thus, pentacarbonyl[(aryl)(methoxy)carbene]chromium(0) and tungsten complexes, 10, efficiently dimerize at room temperature in the presence of diverse Pd(0) and Pd(II)/Et(3)N catalysts. The effect of additives (PPh(3), AsPh(3), or SbPh(3)) on the nature and the isomeric ratio of the reaction products is negligible. The nature of the reaction products is more catalyst-dependent for metal carbenes 12 bearing alkyl groups attached to the carbene carbon. In these cases, either carbene ligand dimerization or beta-hydrogen elimination reactions are observed, depending on the catalyst. The carbene ligand dimerization reaction can be used to prepare conjugated polyenes, including those having metal moieties at both ends of the polyene system, as well as enediyne derivatives. The intramolecular carbene ligand dimerization of chromium bis-carbene complexes 28 and 30 allows the preparation of mono- and bicyclic derivatives, with ring sizes from six to nine members. For bis-carbene derivatives the beta-hydrogen elimination reaction is inhibited, provided that both metal centers are tethered by an o-xylylene group. Other alkyl complexes 32 form new mononuclear carbene complexes 37 or decompose to complex reaction mixtures. The results obtained in these reactions may be explained by transmetalation from Cr(0) to Pd(0) and the intermediacy of Pd-carbene complexes. Aminocarbene-chromium(0) complexes 15, need harsher reaction conditions to transfer the carbene ligand, and this transfer occurs only in the presence of deactivated olefins. The corresponding insertion/hydrolysis products 48 resulted in these cases. A catalytic cycle involving transmetalation from a chromacyclobutane to a palladacyclobutane is proposed to explain these results.     

In the golden age of organocatalysis

The term "organocatalysis" describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound. The interest in this field has increased spectacularly in the last few years as result of both the novelty of the concept and, more importantly, the fact that the efficiency and selectivity of many organocatalytic reactions meet the standards of established organic reactions. Organocatalytic reactions are becoming powerful tools in the construction of complex molecular skeletons. The diverse examples show that in recent years organocatalysis has developed within organic chemistry into its own subdiscipline, whose "Golden Age" has already dawned.     

Non-asymmetric organocatalysis

Asymmetric organocatalysis is now an established methodology for the preparation of chiral compounds. However, these are not the only valuable molecules which can be conveniently obtained. Organocatalytic reactions affording achiral compounds are gaining momentum, opening unexplored pathways in the synthesis of densely functionalized aromatic moieties, olefins and useful molecules such as natural substances.     

The enantioselective Morita-Baylis-Hillman reaction and its aza counterpart

The development of asymmetric Morita-Baylis-Hillman (MBH) reactions has evolved dramatically over the past few years, parallel to the emerging concept of bifunctional organocatalysis. Whereas organocatalysis is starting to compete with metal-based catalysis in several important organic transformations, the MBH reaction belongs to a group of prototypical reactions in which organocatalysts already display superiority over their metal-based counterparts. This Minireview summarizes recent mechanistic insights and advances in the design and synthesis of small organic molecules for enantioselective MBH and aza-MBH reactions.     

A computational study of the reactivities of four-membered heavy carbene systems

The potential energy surfaces for the chemical reactions of four-membered N-heterocyclic group 14 heavy carbene species have been studied using density functional theory (B3LYP/LANL2DZ). Five four-membered group 14 heavy carbene species, (i-Pr)(2) NP(NR)(2) E:, in which E = C, Si, Ge, Sn, and Pb, were chosen as the model reactants in this work. Also, four kinds of chemical reactions, C-H bond insertion, water addition, alkene cycloaddition, and dimerization, have been used to study the chemical reactivities of these group 14 four-membered N-heterocyclic carbene species. Basically, our present theoretical work predicts that the larger the ∠NEN bond angle of the four-membered group 14 heavy carbene species, the smaller the singlet-triplet splitting, the lower the activation barrier, and, in turn, the more rapid, its chemical reactions to various chemical species. Moreover, our theoretical investigations suggest that the relative carbenic reactivity decreases in the order: C > Si > Ge > Sn > Pb. That is, the heavier the group 14 atom (E), the more stable is its four-membered carbene toward chemical reactions. As a result, our results predict that the four-membered group 14 heavy carbene species (E = Si, Ge, Sn, and Pb) should be more kinetically stable than the observed carbene species and, thus, can be also readily synthesized and isolated at room temperature. Furthermore, the singlet-triplet energy splitting of the four-membered group 14 carbene species, as described in the configuration mixing model attributed to the work of Pross and Shaik, can be used as a diagnostic tool to predict their reactivities. The results obtained allow a number of predictions to be made.