Carbene Catalysis Research Articles

N-Heterocyclic Carbene (NHC)/Metal Cooperative Catalysis.

N-Heterocyclic carbene (NHC) catalysis can access umpolung reactivity of carbonyl compounds as acyl anions, enolates and homoenolates. Considerable progress has been made in asymmetric transformation by the introduction of chirality to the NHC scaffold. However, the single catalyst system has limitations in chemo-, regio- and stereoselectivity. A solution to these problems has recently emerged with the synergistic combination of NHC catalysis and metal catalysis. A number of NHC/metal combinations have been found not only to improve reactivity and stereoselectivity, but also to enable access to unprecedented transformations. This paper highlights examples of successful asymmetric NHC/metal cooperative catalysis.

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 ϵ-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 ϵ-multisubstituted-α,β-γ,δ-diunsaturated esters by an unprecedented NHC-catalyzed ϵ-functionalization was also established.

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

AbstractThe merging of photoredox catalysis and N‐heterocyclic carbene (NHC) catalysis for γ‐ and ϵ‐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 ϵ‐multisubstituted‐α,β‐γ,δ‐diunsaturated esters by an unprecedented NHC‐catalyzed ϵ‐functionalization was also established.

Oxidative NHC-Catalysis as Organocatalytic Platform for the Synthesis of Polyester Oligomers by Step-Growth Polymerization.

The application of N-heterocyclic carbene (NHC) catalysis to the polycondensation of diols and dialdehydes under oxidative conditions is herein presented for the synthesis of polyesters using fossil-based (ethylene glycol, phthalaldehydes) and bio-based (furan derivatives, glycerol, isosorbide) monomers. The catalytic dimethyl triazolium/1,8-diazabicyclo[5.4.0]undec-7-ene couple and stoichiometric quinone oxidant afforded polyester oligomers with a number-average molecular weight (Mn ) in the range of 1.5-7.8 kg mol-1 as determined by NMR analysis. The synthesis of a higher molecular weight polyester (polyethylene terephthalate, PET) by an NHC-promoted two-step procedure via oligoester intermediates is also illustrated together with the catalyst-controlled preparation of cross-linked or linear polyesters derived from the trifunctional glycerol. The thermal properties (TGA and DSC analyses) of the synthesized oligoesters are also reported.

The Combination of Lewis Acid with N-Heterocyclic Carbene (NHC) Catalysis

In the last ten years, the combination of Lewis acid with N-heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in a variety of important asymmetric synthesis, due to the ready availability of starting materials, operational simplicity and mild reaction conditions. Recent findings illustrate that Lewis acid could largely enhance the efficiency and enantioselectivity, reverse the diastereoselectivity, and even influence the pathway of the same reaction partners. Herein, this review aims to reveal the recent advances in NHC-Lewis acid synergistically promoted enantioselective reactions for the expeditious assembly of versatile biologically important chiral pharmaceuticals and natural products.

Stereoselective [8 + 2] Cycloaddition Reaction of Azaheptafulvenes with α-Chloro Aldehydes via N-Heterocyclic Carbene Catalysis

A highly efficient [8 + 2] cycloaddition reaction of azaheptafulvenes with α-chloro aliphatic aldehydes enabled by N-heterocyclic carbene catalysis is presented, delivering cis-cycloheptatriene-fused γ-lactams with good yields, moderate to good diastereoselectivies, and excellent enantioselectivies. This higher order cycloaddition reaction can be readily expanded to the gram scale, and the products could be further transformed to other useful compounds via simple operations.

N-Heterocyclic carbene as a Brønsted base catalyst for the amination of naphthol derivatives and alcoholysis of glutaric anhydrides

A non-covalent Brønsted-basic N-heterocyclic carbene catalyzed (NHC) Friedel-Crafts type amination of naphthol derivatives using dialkyl azodicarboxylates as the aminating source and alcoholysis of various glutaric anhydrides using alcohol as pronucleophile is presented. Both of these reactions are performed in the presence of either commercially available free-carbene catalyst or in situ-generated carbene catalyst. Friedel-Crafts type amination reaction is an example of a hydroxy group facilitated amination reaction. Both reactions proceed via in situ activations of –OH group by the carbene catalyst through hydrogen bonding interaction and furnish the relevant products in moderate to excellent yields.

N‐Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β‐Unsaturated Amides

AbstractConcerted nucleophilic aromatic substitution (CSNAr) has emerged as a powerful mechanistic manifold, in which nucleophilic aromatic substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CSNAr reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N‐heterocyclic carbene (NHC)‐catalyzed intramolecular cyclization of acrylamides that contain a 2‐fluorophenyl group on the nitrogen through a CSNAr reaction. By using this catalytic method, it is possible to synthesize an array of quinolin‐2‐one derivatives, which are common structural motifs in pharmaceuticals and organic materials. DFT calculations unambiguously revealed that this reaction proceeds through the concerted nucleophilic aromatic substitution of aryl fluorides, in which a stereoelectronic σ (Cipso‐Cβ)→ σ*(Cipso‐F) interaction critically contributes to the stabilization of the transition state for the cyclization.

N-Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated Amides.

Concerted nucleophilic aromatic substitution (CSN Ar) has emerged as a powerful mechanistic manifold, in which nucleophilic aromatic substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CSN Ar reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of acrylamides that contain a 2-fluorophenyl group on the nitrogen through a CSN Ar reaction. By using this catalytic method, it is possible to synthesize an array of quinolin-2-one derivatives, which are common structural motifs in pharmaceuticals and organic materials. DFT calculations unambiguously revealed that this reaction proceeds through the concerted nucleophilic aromatic substitution of aryl fluorides, in which a stereoelectronic σ (Cipso -Cβ )→ σ*(Cipso -F) interaction critically contributes to the stabilization of the transition state for the cyclization.

Enantioselective N‐Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut–Currier Reaction

AbstractWhile the enantioselective Rauhut–Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high‐nucleophilicity N‐heterocyclic carbenes, it is possible to achieve Rauhut–Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).

Enantioselective N-Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut-Currier Reaction.

While the enantioselective Rauhut-Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high-nucleophilicity N-heterocyclic carbenes, it is possible to achieve Rauhut-Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).

N-Heterocyclic Carbene Catalyzed (5+1) Annulations Exploiting a Vinyl Dianion Synthon Strategy.

Direct polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N-heterocyclic carbene (NHC) catalyzed reactions, in which β-unsubstituted conjugate acceptors undergo homoenolate formation and C-C bond formation twice, have been developed. Specifically, the all-carbon (5+1) annulations give a range of mono- and bicyclic cyclohexanones (31 examples). In the first family of annulations, β-unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.

N‐Heterocyclic Carbene Catalyzed (5+1) Annulations Exploiting a Vinyl Dianion Synthon Strategy

AbstractDirect polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N‐heterocyclic carbene (NHC) catalyzed reactions, in which β‐unsubstituted conjugate acceptors undergo homoenolate formation and C−C bond formation twice, have been developed. Specifically, the all‐carbon (5+1) annulations give a range of mono‐ and bicyclic cyclohexanones (31 examples). In the first family of annulations, β‐unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.

N-Heterocyclic Carbene Catalyzed Stereoselective Synthesis of 2-Nitro-thiogalactosides

A highly selective NHC-catalyzed Michael addition of alkanethiols or thiophenol to 2-nitro-d-galactal compounds for the synthesis of 2-nitro-thiogalactoside derivatives has been developed for the first time. A wide variety of 1,2-cis-2-nitro-thiogalactosides can be prepared in good to excellent yields and high to excellent α-selectivities.

Asymmetric Synthesis of C2-Quaternary Indolin-3-ones Enabled by N-Heterocyclic Carbene Catalysis.

An N-heterocyclic carbene (NHC)-catalyzed formal [4 + 2] annulation of 2-aryl-3 H-indol-3-ones with α,β-unsaturated carboxylic acids bearing γ-H was developed via an in situ activation strategy. The reaction involves the γ-addition of vinyl enolates to the unique cyclic ketimines to afford chiral tricyclic indolin-3-ones with a quaternary carbon center at 2-position. This protocol provides a rapid and enantioselective pathway to access a novel class of structurally important C2-quaternary indolin-3-ones that might be useful for drug discovery.

Stereodivergent Synthesis of Chiral Paraconic Acids via Dynamic Kinetic Resolution of 3-Acylsuccinimides.

A direct N-heterocyclic carbene (NHC) catalysis of maleimides with alkyl aldehydes is established for the synthesis of 3-acylsuccinimides. The first dynamic kinetic resolution of 3-acylsuccinimides is accomplished through asymmetric transfer hydrogenation. These two catalytic methodologies are utilized for the synthesis of each enantiomer of trans-paraconic acids in three steps and cis-paraconic acids in four steps with good yields and high stereoselectivities. This stereodivergent synthetic methodology is applied for the synthesis of seven bioactive paraconic acid natural products.

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.

Correction to Fischer Carbene Catalysis of Alkynol Cycloisomerization: Application to the Synthesis of the Altromycin B Disaccharide.

Correction to Fischer Carbene Catalysis of Alkynol Cycloisomerization: Application to the Synthesis of the Altromycin B Disaccharide.

Ruthenium(II) Porphyrin Quinoid Carbene Complexes: Synthesis, Crystal Structure, and Reactivity toward Carbene Transfer and Hydrogen Atom Transfer Reactions.

Reactivity study of novel metal carbene complexes can offer new opportunities in catalytic carbene transfer reactions as well as in other synthetic protocols. Metal complexes with quinoid carbene (QC) ligands are assumed to be key intermediates in a variety of metal-catalyzed QC transfer reactions using diazo quinones, which demands development of the chemistry of QC transfer of well characterized metal-QC complexes. Herein we report the isolation and QC transfer of ruthenium porphyrins [Ru(Por)(QC)] which contribute the first examples of (i) structurally characterized metal-QC complex (by X-ray crystallography) and (ii) isolated metal-QC complex that undergoes QC transfer reaction. The complexes [Ru(Por)(QC)] were prepared from reaction of [Ru(Por)(CO)] with diazo quinones and exhibited dual reactivity, i.e., hydrogen atom transfer (HAT) as well as QC transfer. The stoichiometric QC transfer reactions from these Ru-QC complexes to nitrosoarenes (ArNO) afforded nitrones in up to 90% yield, and the corresponding catalytic reactions were also developed. Both the stoichiometric and catalytic reactions for a series of QC ligands bearing electron-donating and -withdrawing substituents showed a reverse substituent effect on the QC transfer reactivity. Complexes [Ru(Por)(QC)] are also reactive toward C-H and X-H (X = N, S) bonds and can catalyze aerobic oxidation of 1,4-cyclohexadiene; their stoichiometric HAT reactions with unsaturated hydrocarbons gave product yields of up to 88%. The unique dual reactivity and electronic feature of [Ru(Por)(QC)] were studied by spectroscopic means and density functional theory (DFT) calculations.

Enantio‐ and Diastereoselective Hydrofluorination of Enals by N‐Heterocyclic Carbene Catalysis

AbstractIn contrast to well‐established asymmetric hydrogenation reactions, enantioselective protonation is an orthogonal approach for creating highly valuable methine chiral centers under redox‐neutral conditions. Reported here is the highly enantio‐ and diastereoselective hydrofluorination of enals by an asymmetric β‐protonation/α‐fluorination cascade catalyzed by N‐heterocyclic carbenes (NHCs). The two nucleophilic sites of a homoenolate intermediate, generated from enals and an NHC, are sequentially protonated and fluorinated. The results show that controlling the relative rates of protonation, fluorination, and esterification is crucial for this transformation, and can be accomplished using a dual shuttling strategy. Structurally diverse carboxylic acid derivatives with two contiguous chiral centers are prepared in a single step with excellent d.r. and ee values.