N‐Heterocyclic Carbene Catalysis via Azolium Dienolates: An Efficient Strategy for Remote Enantioselective Functionalizations

N‐heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in organic synthesis. In recent years a number of reviews have been published on NHC‐catalyzed transformations involving Breslow intermediates, acyl azoliums, α,β‐unsaturated acyl azoliums, homoenolate equivalents, and azolium enolates. However, the azolium dienolate intermediates generated by NHCs have been employed in asymmetric synthesis only very recently, especially in cycloadditions dealing with remote functionalization. This Minireview highlights all the developments and the new advances in NHC‐catalyzed asymmetric cycloaddition reactions involving azolium dienolate intermediates.     

Visible‐Light‐Driven N‐Heterocyclic Carbene Catalyzed γ‐ and ϵ‐Alkylation with Alkyl Radicals

The merging of photoredox catalysis and N‐heterocyclic carbene (NHC) catalysis for γ‐ and ?‐alkylation of enals with alkyl radicals was developed. The alkylation reaction of γ‐oxidized enals with alkyl halides worked well for the synthesis γ‐multisubstituted‐α,β‐unsaturated esters, including those with challenging vicinal all‐carbon quaternary centers. The synthesis of ?‐multisubstituted‐α,β‐γ,δ‐diunsaturated esters by an unprecedented NHC‐catalyzed ?‐functionalization was also established.     

Cooperative Catalysis and Activation with N‐Heterocyclic Carbenes

N‐Heterocyclic carbene (NHC) catalysis has emerged as a powerful stratagem in organic synthesis to construct complex molecules primarily by polarity reversal (umpolung) approaches. These unique Lewis bases have been used to generate acyl anions, enolates, and homoenolates in catalytic fashion. Recently, a new strategy has emerged that dramatically expands the synthetic utility of carbene catalysis by leveraging additional activation modes: cooperative catalysis. The careful selection and balance of cocatalysts have led to enhanced reactivity, increased yields, and improved stereoselectivity. In certain cases, these catalytic additives have changed the regioselectivity or diastereoselectivity. This Minireview highlights new advances in NHC cooperative catalysis and surveys the evolution of this field.     

Chiral N‐Heterocyclic Carbene Ligands Enable Asymmetric C−H Bond Functionalization

The asymmetric functionalization of C?H bond is a particularly valuable approach for the production of enantioenriched chiral organic compounds. Chiral N‐heterocyclic carbene (NHC) ligands have become ubiquitous in enantioselective transition‐metal catalysis. Conversely, the use of chiral NHC ligands in metal‐catalyzed asymmetric C?H bond functionalization is still at an early stage. This minireview highlights all the developments and the new advances in this rapidly evolving research area.     

Enantioselective N‐Heterocyclic Carbene Catalysis that Exploits Imine Umpolung

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine.     

Enantioselective Synthesis of Tertiary Propargylic Alcohols under N‐Heterocyclic Carbene Catalysis

A straightforward procedure to carry out the enantioselective benzoin reaction between aldehydes and ynones by employing a chiral N‐heterocyclic carbene (NHC) as catalyst was developed. Under the optimized reaction conditions, these ynones undergo a clean and selective 1,2‐addition with the catalytically generated Breslow intermediate, not observing any byproduct arising from competitive Stetter‐type reactivity. This procedure allows the preparation of tertiary alkynyl carbinols as highly enantioenriched materials, which have the remarkable potential to be used as chiral building blocks in organic synthesis.     

An N-heterocyclic carbene/Lewis acid strategy for the stereoselective synthesis of spirooxindole lactones

A cooperative catalysis approach for the enantioselective formal [3+2] addition of α,β-unsaturated aldehydes to isatins has been developed. Homoenolate annulations of β-aryl enals catalyzed by an N-heterocyclic carbene (NHC) require the addition of lithium chloride for high levels of enantioselectivity. This NHC-catalyzed annulation has been used for the total synthesis of maremycin B.     

N‐Heterocyclic‐Carbene‐Catalyzed Umpolung of Imines

N‐Heterocyclic carbene (NHC) catalysis has been widely used for the umpolung of aldehydes, and recently for the umpolung of Michael acceptors. Described herein is the umpolung of aldimines catalyzed by NHCs, and the reaction likely proceeds via aza‐Breslow intermediates. The NHC‐catalyzed intramolecular cyclization of aldimines bearing a Michael acceptor resulted in the formation of biologically important 2‐(hetero)aryl indole 3‐acetic‐acid derivatives in moderate to good yields. The carbene generated from the bicyclic triazolium salt was found to be efficient for this transformation.     

Enantioselective Synthesis of Spirocyclohexadienones by NHC‐Catalyzed Formal [3+3] Annulation Reaction of Enals

The enantioselective synthesis of pyrazolone‐fused spirocyclohexadienones was demonstrated by the reaction of α,β‐unsaturated aldehydes with α‐arylidene pyrazolinones under oxidative N‐heterocyclic carbene (NHC)catalysis. This atom‐economic and formal [3+3] annulation reaction proceeds through a vinylogous Michael addition/spiroannulation/dehydrogenation cascade to afford spirocyclic compounds with an all‐carbon quaternary stereocenter in moderate to good yields and excellent ee values. Key to the success of the reaction is the cooperative NHC‐catalyzed generation of chiral α,β‐unsaturated acyl azoliums from enals, and base‐mediated tandem generation of dienolate/enolate intermediates from pyrazolinones.     

Polyhalides as Efficient and Mild Oxidants for Oxidative Carbene Organocatalysis by Radical Processes

Simple and inexpensive polyhalides (CCl₄ and C₂Cl₆) have been found to be effective and versatile oxidants in removing electrons from Breslow intermediates under N‐heterocyclic carbene (NHC) catalysis. This oxidative reaction involves multiple single‐electron‐transfer (SET) processes and several radical intermediates. The α, β, and γ‐carbon atoms of aldehydes and enals could be readily functionalized. Given the low cost of the oxidants and the broad applicability of the reactions, this study is expected to greatly enhance the feasibility of oxidative NHC catalysis for large‐scale applications. Also this new SET radical process with polyhalides as single‐electron oxidants will open a new avenue in the development of NHC‐catalyzed radical reactions.     

N‐Heterocyclic Carbene Catalyzed γ‐Dihalomethylenation of Enals by Single‐Electron Transfer

An N‐heterocyclic carbene (NHC) catalyzed dihalomethylenation of enals is described. It is a rare example of merging NHC catalysis with single‐electron chemistry, a challenging topic with limited previous success. The versatile carbon‐centered trihalomethyl radicals have been demonstrated, for the first time, to be compatible with an NHC‐bound intermediate, thus leading to efficient and regioselective intermolecular C?C bond formation. The mild process provides straightforward access to unsaturated δ,δ‐dihalo esters.     

An Upstream By‐product from Ester Activation via NHC‐Catalysis Catalyzes Downstream Sulfonyl Migration Reaction

A sequential reaction combining N‐heterocyclic carbene (NHC) and N‐hydroxyphthalimide (NHPI) catalysis allowed for the upstream by‐product NHPI, which was generated in the NHC‐catalyzed cycloaddition reaction, to act as the catalyst for a downstream nitrogen‐to‐carbon sulfonyl migration reaction. Enantiomeric excess of the major product in the cycloaddition reaction remained intact in the follow‐up sulfonyl migration reaction.     

N‐Heterocyclic Carbene Catalyzed Oxidative Coupling of Alkenes/ α‐Bromoacetophenones with Aldehydes: A Facile Entry to α,β‐Epoxy Ketones

A novel, N‐heterocyclic carbene (NHC) catalyzed direct oxidative coupling of styrenes with aldehydes has been described for the synthesis of α,β‐epoxy ketones in good yields. This unprecedented regioselective oxidative coupling employs NBS/DBU/DMSO (DBU=1,8‐diazabicyclo [5.4. 0] undec‐7‐ene, DMSO=dimethylsulfoxide, NBS=N‐bromosuccinimide) as an oxidative system at ambient conditions. Additionally, first NHC‐catalyzed Darzens reaction of α‐bromoketones and aldehydes under mild reaction conditions has also been described. Interestingly, mechanistic studies have revealed the preferred reactivity of NHC with alkene/α‐bromoketone rather than aldehydes, thus proceeding via the ketodeoxy Breslow intermediate.     

Silver‐Catalyzed Amidiniumation of Alkynes: Isolation of a Silver Intermediate,Synthesis of Enamine Amido Carbene Precursors,and an Unprecedented Umpolung of Propiolamide

A silver‐catalyzed amidiniumation of N‐propiolic formamidines for the synthesis of novel enamine amido carbene precursors is reported. Isolation of a first silver intermediate in silver‐catalyzed amidiniumation of alkynes and other organogold intermediates supports our proposed mechanisms. Several control experiments reveal the unexpected effects of both HOTf and substrate substituents on the choice of either a π or σ,π silver activation mode and the cyclization fashion. Bis(hydroxyimidazol)ium salts were obtained through an unprecedented umpolung of propiolamides. The byproduct Ag₂O as either an oxidant or silver source promotes the syntheses of N‐heterocyclic carbene (NHC) precursors or Ag/NHC complexes.     

Silver‐Catalyzed Amidiniumation of Alkynes: Isolation of a Silver Intermediate,Synthesis of Enamine Amido Carbene Precursors,and an Unprecedented Umpolung of Propiolamide

A silver‐catalyzed amidiniumation of N‐propiolic formamidines for the synthesis of novel enamine amido carbene precursors is reported. Isolation of a first silver intermediate in silver‐catalyzed amidiniumation of alkynes and other organogold intermediates supports our proposed mechanisms. Several control experiments reveal the unexpected effects of both HOTf and substrate substituents on the choice of either a π or σ,π silver activation mode and the cyclization fashion. Bis(hydroxyimidazol)ium salts were obtained through an unprecedented umpolung of propiolamides. The byproduct Ag₂O as either an oxidant or silver source promotes the syntheses of N‐heterocyclic carbene (NHC) precursors or Ag/NHC complexes.     

N-heterocyclic carbene-catalysed intermolecular Stetter reactions of acetaldehyde

A facile method for the intermolecular Stetter reaction of various Michael acceptors with acetaldehyde as a biomimetic acylanion source was realized using N-heterocyclic carbene catalysis. This catalytic system has also been applied to the enantioselective Stetter reaction and resulted in moderate to good enantioselectivities for the corresponding Stetter products.     

NHC‐Catalyzed Asymmetric Synthesis of Functionalized Succinimides from Enals and α‐Ketoamides

The efficient asymmetric synthesis of highly substituted succinimides from α,β‐unsaturated aldehydes and α‐ketoamides via NHC‐catalyzed [3+2] cycloaddition has been developed. The new scalable protocol significantly expands the utility of NHC catalysis for the synthesis of heterocycles and provides easy access to assemble a wide range of succinimides from simple starting materials.     

N-heterocyclic carbene-catalyzed radical reactions

While N-heterocyclic carbene(NHC)catalyzed electron-pair-transfer processes have been developed into an important tool for synthetically important bond formations during the past decades,the corresponding radical reactions via NHC catalysis have only received growing attention in the past six years.Taking into account the advantages NHC-catalyzed radical reactions might bring,such as creating new activation modes that were previously unobtainable,it is worthwhile to provide a conceptual understanding of this emerging area.Therefore,herein we give an overview of NHC-catalyzed radical reactions via different synthetic techniques.     

N‐Heterocyclic Carbene Catalyzed Radical Coupling of Aldehydes with Redox‐Active Esters

N‐Heterocyclic carbene catalyzed radical reactions are challenging and underdeveloped. In a recent study, Ohmiya, Nagao and co‐workers found that aldehyde carbonyl carbon centers can be coupled with alkyl radicals under NHC catalysis. An elegant aspect of this study is the use of a redox‐active carboxylic ester that behaves as an single‐electron oxidant to convert the Breslow intermediate into a radical adduct and concurrently release an alkyl radical intermediate as a reaction partner.     

Chiral iridium(I) bis(NHC) complexes as catalysts for asymmetric transfer hydrogenation

The common use of NHC complexes in transition‐metal mediated C–C coupling and metathesis reactions in recent decades has established N‐heterocyclic carbenes as a new class of ligand for catalysis. The field of asymmetric catalysis with complexes bearing NHC‐containing chiral ligands is dominated by mixed carbene/oxazoline or carbene/phosphane chelating ligands. In contrast, applications of complexes with chiral, chelating bis(NHC) ligands are rare. In the present work new chiral iridium(I) bis(NHC) complexes and their application in the asymmetric transfer hydrogenation of ketones are described. A series of chiral bis(azolium) salts have been prepared following a synthetic pathway, starting from L ‐valinol and the modular buildup allows the structural variation of the ligand precursors. The iridium complexes were formed via a one‐pot transmetallation procedure. The prepared complexes were applied as catalysts in the asymmetric transfer hydrogenation of various prochiral ketones, affording the corresponding chiral alcohols in high yields and moderate to good enantioselectivities of up to 68%. The enantioselectivities of the catalysts were strongly affected by the various, terminal N‐substituents of the chelating bis(NHC) ligands. The results presented in this work indicate the potential of bis‐carbenes as stereodirecting ligands for asymmetric catalysis and are offering a base for further developments. Copyright © 2010 John Wiley & Sons, Ltd.