Chiral N-heterocyclic Carbene Research Articles

Iron-catalyzed stereoselective C–H alkylation for simultaneous construction of C–N axial and C-central chirality

The assembly of chiral molecules with multiple stereogenic elements is challenging, and, despite of indisputable advances, largely limited to toxic, cost-intensive and precious metal catalysts. In sharp contrast, we herein disclose a versatile C–H alkylation using a non-toxic, low-cost iron catalyst for the synthesis of substituted indoles with two chiral elements. The key for achieving excellent diastereo- and enantioselectivity was substitution on a chiral N-heterocyclic carbene ligand providing steric hindrance and extra represented by noncovalent interaction for the concomitant generation of C–N axial chirality and C-stereogenic center. Experimental and computational mechanistic studies have unraveled the origin of the catalytic efficacy and stereoselectivity.

Crystallization-Induced Chirality Transfer in Conformationally Flexible Azahelicene Au(I) Complexes with Circularly Polarized Luminescence Activation.

Flexible and twisted annulated π-systems exhibit numerous unique and desirable features, owing to their ability to display chirality. However, preventing their racemization due to the dynamic nature of their chirality remains a challenge. One promising approach to stabilize homochirality in such systems is chirality transfer from a chiral auxiliary to a moiety displaying dynamic chirality. Herein, we introduce a new approach for dynamic chirality stabilization in conformationally flexible azahelicene species via crystallization-induced intermolecular chirality transfer in Au(I) complexes featuring azahelicene (dibenzo[c,g]carbazole and benzo[c]carbazole) and enantio-pure chiral N-heterocyclic carbene (NHC) ligands with a complementary tailored shape. Crystallization of these azahelicene Au(I) complexes not only suppresses the dynamic chirality of the dibenzocarbazole species but also stabilizes their homochirality through the intermolecular conjunction between the chiral NHC and dibenzocarbazole ligands. In the Au(I) benzocarbazole complexes, the intermolecular conjunction and chirality transfer in the crystals induce chirality in the initially achiral benzocarbazole ligand. Furthermore, the crystallization of the studied complexes activates their circularly polarized luminescence (CPL) properties, which were suppressed in solution. Importantly, chirality transfer leads to significant CPL enhancement; the complexes that feature chirality transfer within the crystal structure exhibit luminescence dissymmetry factors 5 to 10 times higher than those of the complexes without chirality transfer.

Asymmetric Synthesis of Planar Chiral Carbonitriles and Amines via Carbene-Catalyzed Kinetic Resolution.

We have developed a catalytic method using chiral N-heterocyclic carbene (NHC) as the sole organic catalyst to synthesize planar chiral carbonitriles asymmetrically, resulting in optically pure, multifunctional compounds. The method demonstrates remarkable tolerance toward diverse substituents and substitution patterns through kinetic resolution (KR) or desymmetrization processes. The resulting optically pure planar chiral products hold significant potential for applications in asymmetric synthesis and antibacterial pesticide development.

Boryl radical catalysis enables asymmetric radical cycloisomerization reactions.

The development of functionally distinct catalysts for enantioselective synthesis is a prominent yet challenging goal of synthetic chemistry. In this work, we report a family of chiral N-heterocyclic carbene (NHC)-ligated boryl radicals as catalysts that enable catalytic asymmetric radical cycloisomerization reactions. The radical catalysts can be generated from easily prepared NHC-borane complexes, and the broad availability of the chiral NHC component provides substantial benefits for stereochemical control. Mechanistic studies support a catalytic cycle comprising a sequence of boryl radical addition, hydrogen atom transfer, cyclization, and elimination of the boryl radical catalyst, wherein the chiral NHC subunit determines the enantioselectivity of the radical cyclization. This catalysis allows asymmetric construction of valuable chiral heterocyclic products from simple starting materials.

Carbene-stabilized enantiopure heterometallic clusters featuring EQE of 20.8% in circularly-polarized OLED

Bright and efficient chiral coinage metal clusters show promise for use in emerging circularly polarized light-emitting materials and diodes. To date, highly efficient circularly polarized organic light-emitting diodes (CP-OLEDs) with enantiopure metal clusters have not been reported. Herein, through rational design of a multidentate chiral N-heterocyclic carbene (NHC) ligand and a modular building strategy, we synthesize a series of enantiopure Au(I)-Cu(I) clusters with exceptional stability. Modulation of the ligands stabilize the chiral excited states of clusters to allow thermally activated delayed fluorescence, resulting in the highest orange-red photoluminescence quantum yields over 93.0% in the solid state, which is accompanied by circularly polarized luminescence. Based on the solution process, a prototypical orange-red CP-OLED with a considerably high external quantum efficiency of 20.8% is prepared. These results demonstrate the extensive designability of chiral NHC ligands to stabilize polymetallic clusters for high performance in chiroptical applications.

Remote Electronic Tuning of Chiral N-Heterocyclic Carbenes.

Our recent efforts to develop novel N-Heterocyclic carbene (NHC)-catalyzed asymmetric reactions are described. During our investigation for development of the acylation reactions via acylazoliums generated by the reactions of NHCs and α-oxidized aldehydes, we have observed significant effects of substitution at a remote site of the carbene carbon of NHCs. In addition, we also observed a significant enhancement of the enantioselectivity by the addition of carboxylate anions. From this observation, we proposed a novel working hypothesis involving a formation of a complex of the substrate and additive to reinforce the recognition of the catalyst for enhancement of the catalytic performance of the asymmetric N-heterocyclic carbene system. By applying this concept, we achieved the kinetic resolutions of both cyclic and acyclic alcohols in excellent enantioselectivities. The effects of the remote substitution were also observed in intramolecular Stetter reaction and intermolecular benzoin reaction. In these reactions, the comparison of the catalytic performance of the NHCs bearing variable remote substitutions provided insights into the reaction mechanism because the remote substitution tuned the electronic nature of NHCs without affecting the steric and electrostatic factors around the reaction site. We also developed an intramolecular benzoin condensation involving two aldehydes, which is challenging to realize. Using the substrates bearing proper protecting groups, we succeeded in the stereo divergent synthesis of a variety of inososes, which are important intermediates for the synthesis of biologically active cyclitols.

Remote Electronic Effect of Chiral N-Heterocyclic Carbene Catalyst on an Asymmetric Benzoin Reaction.

A remote electronic effect of chiral aminoindanol-derived N-heterocyclic carbene catalyst on an asymmetric benzoin reaction was investigated. The catalyst bearing remote electron-withdrawing substituents increased enantioselectivity of the reaction at the cost of the reaction rate. DFT calculations rationalized the increased enantioselectivity.

Concise Synthesis of Chiral Tricyclic Lactams by Tandem Dynamic Kinetic Asymmetric Reductive Amination/Lactamization Using Ammonium Salts.

The atom- and step-efficient synthesis of chiral fused tricyclic lactams from readily available ketoesters using cheap ammonium salts as the nitrogen source is reported. This ruthenium-catalyzed system operates through an efficient tandem dynamic kinetic asymmetric reductive amination (ARA)/lactamization and produces chiral fused tricyclic lactams in high yields with excellent diastereo- and enantioselectivity (up to >99 % ee, >20 : 1 dr and 98 % yield). The robust method was also applied to the concise synthesis of key intermediates in the synthesis of rivastigmine analogues and chiral N-heterocyclic carbene catalysts.

Highly Efficient Circularly Polarized Luminescence from Chiral Au13 Clusters Stabilized by Enantiopure Monodentate NHC Ligands.

Chiral Au nanoclusters have promising application prospects in chiral sensing, asymmetric catalysis, and chiroptics. However, enantiopure superatomic homogold clusters with crystallographic structures emitting bright circularly polarized luminescence (CPL) remain challenging. In this study, we designed chiral N-heterocyclic carbenes (NHCs), and for the first time enantioselectively synthesized a pair of monovalent cationic superatomic Au13 clusters. This new enantiomeric pair of clusters has a quasi-C2 symmetric core and exhibited CPL with an unprecedent solution-state quantum yield (QY) of 61 % among those of the atomically precise Au nanoclusters. DFT calculations provided insights into the circular dichroism behavior, and revealed the origin of CPL from superatomic Au clusters. This work opens a new avenue for developing novel homochiral nanoclusters using chiral NHC ligands and provides fundamental understanding of the origin of the chiroptics of metal clusters.

Highly Efficient Circularly Polarized Luminescence from Chiral Au13 Clusters Stabilized by Enantiopure Monodentate NHC Ligands

AbstractChiral Au nanoclusters have promising application prospects in chiral sensing, asymmetric catalysis, and chiroptics. However, enantiopure superatomic homogold clusters with crystallographic structures emitting bright circularly polarized luminescence (CPL) remain challenging. In this study, we designed chiral N‐heterocyclic carbenes (NHCs), and for the first time enantioselectively synthesized a pair of monovalent cationic superatomic Au13 clusters. This new enantiomeric pair of clusters has a quasi‐C2 symmetric core and exhibited CPL with an unprecedent solution‐state quantum yield (QY) of 61 % among those of the atomically precise Au nanoclusters. DFT calculations provided insights into the circular dichroism behavior, and revealed the origin of CPL from superatomic Au clusters. This work opens a new avenue for developing novel homochiral nanoclusters using chiral NHC ligands and provides fundamental understanding of the origin of the chiroptics of metal clusters.

Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition

ConspectusConjugate acceptors are one of the most common electrophilic functional groups in organic synthesis. While useful in a diverse range of transformations, their applications are largely dominated by the reactions from which their name is derived (i.e., as an acceptor of nucleophiles in the conjugate position). In 2014, we commenced studies focused on their ability to undergo polarity inversion through the conjugate addition of Lewis base catalysts. The first step in this process provides an enolate, from which the well-developed Rauhut-Currier (RC) and Morita-Baylis-Hillman (MBH) reactions can occur; however, tautomerization to provide a species in which the β-carbon of the conjugate acceptor can now act as a donor is also possible. When we commenced studies on this topic, reaction designs with this type of species, particularly when accessed using N-heterocyclic carbenes (NHCs), had been reported on only a handful of occasions. Despite a lack of development, conceptually it was felt that reactions taking advantage of polarity switching by Lewis base conjugate addition have a number of desirable features. Perhaps the most significant is the potential to reimagine a ubiquitous functional group as an entirely new synthon, namely, a donor to electrophiles from the conjugate position.Our work has focused on catalysis with both simple conjugate acceptors and also those embedded within more complicated substrates; the latter has allowed a series of cycloisomerizations and annulation reactions to be achieved. In most cases, the reactions have been possible using enantioenriched chiral NHCs or organophosphines as the Lewis base catalysts thereby delivering enantioselective approaches to novel cyclic molecules. While related chemistry can be accessed with either family of catalyst, in all cases reactions have been designed to take advantage of one or the other. In addition, a fine balance exists between reactions that exploit the initially formed enolate and those that involve the polarity-inverted β-anion. In our studies, this balance is addressed through substrate design, although catalyst control may also be possible. We consider the chemistry discussed in this Account to be in its infancy. Significant challenges remain to be addressed before our broad aim of discovering a universal approach to the polarity inversion of all conjugate acceptors can be achieved. These challenges broadly relate to chemoselectivity with substrates bearing multiple electrophilic functionalities, reliance upon the use of conjugate acceptors, and catalyst efficiency. To address these challenges, advances in catalyst design and catalyst cooperativity are likely required.

(NHC)Ni(II)-Directed Insertions and Higher Substituted Olefin Synthesis from Simple Olefins

ConspectusWell-controlled olefin insertion is critical for achieving catalytic and productive bulk and fine-chemical synthesis. Developing efficient and selective methods for meeting diverse insertion demands is extremely noteworthy, as it supports numerous transformations. The challenges are related to improving catalyst performance and selectivity control and uniting previously unreactive substrate pairs to achieve higher molecular structural complexity and utility. Nickel catalysts have received persistent attention in higher substituted olefin synthesis and polymerization, and numerous new strategies have been established to fulfill the ever-changing demands. This Account focuses on the recent progress based on N-heterocyclic carbene (NHC) ligands and nickel catalysts in our laboratory in using simple terminal olefins as olefin donors or acceptors.It begins with a brief history of olefin codimerization and the major advances in hydrovinylation achieved by other research groups using ethylene as an olefin donor. It then describes problems related to the reductive elimination that can occur when both the hydrometalated alkene and NHC are on the catalyst. It emphasizes the impact of NHC catalyst generation methods on the competing reactivity. Next, it explains the principal challenges and great opportunities in using our method (with α-olefins as olefin donors and alkenyl sources) to replace intermolecular reductive hydroalkenylation reactions (which require rare and more expensive alkenyl halides and boronic acids as reactants, alongside a stoichiometric amount of metallic reagents). The Account then illustrates the potential uses of our method for solving challenging organic synthesis problems using tailor-made (NHC)Ni(II) catalysts to allow redox-neutral catalytic cycles based on high chemo- and regioselective cross-insertion controls. It shows that upon optimal steric and electronic cooperation between the NHC, olefin donor, and olefin acceptor, regiodivergent insertion and convergent synthesis can be achieved easily.In the course of our work, we uncovered several unique insights into regulating (anti-)Markovnikov hydronickelation, carbonickelation, hydrocarbonation, ring closure, 1,3-allyl shift, isomerization, and catalyst regeneration under green, neutral, and mild-temperature conditions. These insights are also outlined here, along with theoretical calculations that offer additional understandings of the insertion reactivity and selectivity differences observed between the NHC and the highly related phosphorus-based Ni(II) hydride-catalyzed cross-hydroalkenylation and cycloisomerization systems.Compared to traditional olefin and cyclic structure synthesis technology, such as olefin cross-metathesis, enyne cyclization, and cross-coupling reactions, the new catalyst systems often offer previously inaccessible product structural characteristics, substrate scope, and outcomes. In particular, the method is effective for the catalytic synthesis of unsymmetrical and functionalized 1,1-disubstituted olefins (a.k.a. gem-olefins), 1,4-dienes (a.k.a. skipped dienes), conjugated dienes, endo- and exocyclic olefins, fused and spiro rings, and aromatic products. These syntheses are variously achieved by cross-hydroalkenylation, insertion-induced rearrangement, cycloadditions, and other approaches inspired by our investigations and detailed in this Account. Cross-hydroalkenylation can be achieved with high enantioselectivity by application of carefully designed and structurally flexible C1 and C2 chiral NHC ligands, yielding a pool of chiral branched alkenes and 1,4-dienes directly from simple chemical feedstocks used in industry. This Account will draw further attention to green alkenylation and the related development of redox-neutral catalytic cycles.

Cooperative Asymmetric Dual Catalysis Involving a Chiral N-Heterocyclic Carbene Organocatalyst and Palladium in an Annulation Reaction: Mechanism and Origin of Stereoselectivity

The increasing number of examples on cooperative dual catalysis involving organocatalysts and transition metal catalysts indicate their wider acceptance and utility in synthetic applications. In such reactions, the concurrent activation of substrates is likely to present mechanistic complexities. In one of the studies, designed for intermolecular annulation aimed at making a biologically important class of benzazepines, chiral N-heterocyclic carbenes engage an enal in the form of a Breslow intermediate (nucleophilic partner) and Pd(0) activates rac-vinyl benzoxazinanone as a Pd-π-allyl intermediate (electrophile). Given the current importance and the lack of molecular insights on the origin of high enantio-/diastereoselectivities and cooperativity in such dual catalytic reactions, we have undertaken a detailed computational investigation using density functional theory. The kinetically most accessible Pd-π-allyl intermediate from the (S)- and (R)-vinyl benzoxazinanone is found to be Cre and Csi (where re and si denote the open prochiral faces through which the nucleophile can add), respectively. An energetically favorable change in configuration from Csi to Cre, via a PPh3-induced π–σ–π isomerization, suggests that an enantioconvergent mechanism was responsible for the enrichment of the desired Cre Pd-π-allyl species. Ready availability of Cre and the higher energy transition state (TS) for the alternative nucleophilic addition to the Csi is responsible for the high ee (computed >99%, experimental 99%). Improved shape complementarity between the chiral electrophile and nucleophile in the most preferred C–C bond formation TS as well as the noncovalent interactions (C–H··· π, π···π, and H-bonding) therein dictates the diastereoselectivity. An intramolecular C–N bond formation to the final annulated product is the turnover-determining TS. Molecular insights and energetic features, as obtained through our computations, are found to be in concert with several experimental observations, even beyond the sense and extent of stereoselectivities.

Remote electronic effect on the N-heterocyclic carbene-catalyzed asymmetric intramolecular Stetter reaction and structural revision of products.

The remote electronic effects of chiral N-heterocyclic carbene catalysts on the asymmetric intramolecular Stetter reaction are investigated. The reaction rate and enantioselectivity were markedly influenced by a substituent at a remote position of the catalyst. The absolute configurations of the products are revised on the basis of X-ray diffraction. Density-functional theory calculations rationalize the improvement of the enantioselectivity using an electron-deficient catalyst.

Understanding the Reaction Mechanism of Nickel-Catalyzed Enantioselective Arylative Activation of the Aromatic C–O Bond

Mild synthetic methods to transform aromatic carbon–oxygen (C–O) bonds into useful molecules have great potential in renewable biomass conversion. Recently, a Ni–NHC (N-heterocyclic carbene) complex catalyzing an asymmetric ring-opening reaction of dinaphthofuran with PhMgCl at room temperature was reported. In this work, we carried out density functional theory (DFT) calculations to investigate the detailed mechanism. The DFT results reveal a novel mechanism that involves Mg(II)–O coordination followed by migration of the phenyl nucleophile to the Ni(0) metal center prior to oxidative addition of a C–O bond to Ni(0). Insights into how the chiral NHC ligand helps induce the enantioselectivity have been obtained.

N-Heterocyclic Carbene-Catalyzed Stereoselective [3 + 2] Cycloaddition of N,N'-Cyclic Azomethine Imines with Aryl Acetaldehydes.

A highly stereoselective [3 + 2] cycloaddition reaction of N,N'-cyclic azomethine imines with aryl acetaldehydes enabled by a chiral N-heterocyclic carbene catalyst is accomplished, giving efficient access to a plethora of enantioenriched N,N'-bicyclic pyrazolidinones featuring aromatic substituents at the C2 position. The current strategy can be directly conducted on a gram scale, and the product could be further reduced to bicyclic pyrazolidine without loss of enantiopurity.

Palladium, iridium, and rhodium complexes bearing chiral N‐heterocyclic carbene ligands applied in asymmetric catalysis

The field of asymmetric catalysis is rapidly developing and the chiral ligands play a key role in enantioselective transition‐metal catalysis. The electron‐rich chiral N‐heterocyclic carbenes (NHCs) have established themselves as a popular class of stereodirecting ancillary ligands to catalyze enantioselective organic transformations in more efficient ways. Several novel transition‐metal complexes in combination with tailored ligand design have emerged during last few decades in asymmetric catalysis. The tailor‐made NHCs can easily be accessed due to the modular synthesis of their parent azolium salt precursors. Their donor capability and the molecular shape can easily be tuned by changing substituent at N‐atom or by changing the cyclic backbone framework. This review article aims to describe the recent advances in this rapidly evolving research area of enantioselective catalysis using well‐defined transition‐metal complexes possessing chiral NHC donor ligands.

Carbene-Catalyzed Activation of C-Si Bonds for Chemo- and Enantioselective Cross Brook-Benzoin Reaction.

The first carbene-catalyzed asymmetric chemoselective cross silyl benzoin (Brook-Benzoin) reaction has been developed. Key steps of this reaction involve activation of the carbon-silicon bond of an acylsilane by a chiral N-heterocyclic carbene (NHC) catalyst to form a silyl acyl anion intermediate. These acyl anions then undergo an addition reaction with indole aldehydes in a highly chemo- and enantioselective manner to afford α-silyloxy ketones with excellent optical purities. The reaction mechanism of this cross Brook-Benzoin reaction was investigated through both experimental and computational methods. The chiral α-hydroxy ketone derivatives obtained by this approach show promising, agrochemically interesting activity against harmful plant bacteria.

Enantioselective alkylative cross-coupling of unactivated aromatic C–O electrophiles

Nonpolar alkyl moieties, especially methyl group, are frequently used to modify bioactive molecules during lead optimization in medicinal chemistry. Thus transition-metal catalyzed alkylative cross-coupling reactions by using readily available and environmentally benign C–O electrophiles have been established as powerful tools to install alkyl groups, however, the C(sp3)–C(sp2) cross-coupling via asymmetric activation of aromatic C–O bond for the synthesis of alkylated chiral compounds remains elusive. Here, we unlock a C(sp3)–C(sp2) cross-coupling via enantioselective activation of aromatic C–O bond for the efficient synthesis of versatile axially chiral 2-alkyl-2’-hydroxyl-biaryl compounds. By employing a unique chiral N-heterocyclic carbene ligand, this transformation is accomplished via nickel catalysis with good enantiocontrol. Mechanistic studies indicate that bis-ligated nickel complexes might be formed as catalytically active species in the enantioselective alkylative cross-coupling. Moreover, further derivation experiments suggest this developed methodology holds great promise for complex molecule synthesis and asymmetric catalysis.

N-Heterocyclic Carbene (NHC)-Catalyzed Transformations Involving Azolium Enolates.

The recent advances in the N-heterocyclic carbene (NHC)-organocatalyzed generation of azolium enolate intermediates and their subsequent interception with electrophiles are highlighted. The NHC-bound azolium intermediates are generated by the addition of NHCs to suitably substituted aldehydes, acid derivatives or ketenes. A broad range of coupling partners can intercept the azolium enolates to form [2+n] cycloadducts (n=2,3,4) and various α-functionalized compounds. The enantioselective synthesis of the target compounds are achieved with the use of chiral NHCs. Herein, we summarized the development that occurred in this subclass of NHC catalysis.