Chiral NHC Research Articles

Synthesis, Characterization, and Catalysis of Planar Chiral Ferrocene‐based N‐Heterocyclic Carbene Ligands and Its Metal Complexes

AbstractThis study presents the development of a novel planar chiral ferrocene‐based NHC ligand and its corresponding metal complexes. The key unit of the imidazolium backbone, planar chiral ortho‐isopropyl ferrocenyl amine, was synthesized starting from (S)‐Ugi's amine. Imidazolium was obtained through the sequential condensation of glyoxal with ferrocenyl amine, followed by the ring‐closure of 1,3‐diferrocenyldiimine with chloromethylethyl ether. Chiral imidazolylidene NHC (IFcPr) metal complexes were prepared by treating imidazolium with silver oxide or base followed by transmetalation with appropriate metal salts. The steric and electronic properties of the IFcPr ligand were assessed using %Vbur and TEP, respectively. These assessments indicated that the ligand was as bulky as the adamantyl NHC ligand and exhibited strong donor ability similar to that of a triazolylidene NHC ligand. The catalytic performance of the copper and palladium complexes was evaluated in the asymmetric borylation of ethyl cinnamate and Suzuki–Miyaura coupling reactions, respectively. The IFcPr−Cu complex catalyzed the borylation of ethyl cinnamate with bis(pinacolato) diboron, followed by oxidation to yield the hydroxy ester with 58 % yield and 30 % ee. In contrast, the IFcPr−Pd‐PEPPSI complex provided the axial chiral binaphthyl compound with 59 % yield and 51 % ee at a low catalyst loading (0.1 mol %, TON=590).

Dual NHC/HAT‐Promoted Esterification to Access α‐Aryl Glycines

α‐Aryl glycines are among the more important carbonyl compounds, particularly as nonproteinogenic α‐amino acids present in many pharmacophores. As such, many strategies have been developed to access this motif, but direct carboxylation methods remain underdeveloped. Herein, we employ a dual NHC/HAT catalysis strategy to access 2‐azaallyl radicals, which subsequently couple with in situ generated ester azolium radical intermediates. Base‐mediated collapse of the ensuing tetrahedral intermediate liberates the NHC catalyst and benzophenone protected aryl glycine. This methodology was employed to esterify obtain a variety of aryl substituted glycine derivatives, as well as allylic and benzylic sites. Mechanistic studies reveal that this radical process operates under both oxidative and reductive quenching cycles, while preliminary experiments employing a chiral NHC and Lewis acid additive demonstrate modest enantioselectivity.

N-Heterocyclic Carbene Enabled Copper Catalyzed Asymmetric Synthesis of Pyrimidinyl Phosphine with both Axial and P-Stereogenicity.

P-stereogenic phosphines, renowned for their utility as ligands and catalysts, have been instrumental in the field of asymmetric catalysis. However, the catalytic asymmetric synthesis of chiral ligands possessing both axial and phosphine chirality remains a significant challenge. Here, we present the successful demonstration of a Cu-catalyzed asymmetric C-P construction using in situ generated secondary phosphine and heteroaryl chloride. By introducing a chiral NHC ligand and an achiral diphosphine auxiliary ligand, we effectively alleviated the poisoning effect caused by phosphine(III) compounds and suppressed the nonenantioselective background reaction. The reaction exhibited excellent enantioselectivity, with up to 96 % ee, and good diastereoselectivity, with up to 14 : 1 dr, when employing less sterically hindered secondary phosphines. This particular substrate poses a significant challenge due to its strong poisoning effect in copper catalysis.

Increasing enantioselectivity and reactivity in Ir-Catalysed intramolecular hydroamination reactions

A series of axially chiral NHC ligands bearing dialkylated naphthyl side arms and electron-rich substituted phenyl groups in the backbone have been employed in the synthesis of neutral NHC-Ir(COD)Cl complexes. When the halide ligand was abstracted from these compounds by appropriate silver salts AgX (X = PF6, NTf2), chiral cationic, formally 14-electron iridium complexes [(NHC)Ir(COD)][X] were formed. When these species were applied as catalysts for asymmetric intramolecular hydroamination of unactivated, amino-olefin substrates, chiral 5- and 6- membered N-heterocyclic products were obtained with moderate to excellent enantioselectivities. By tuning the substrate through variation of the N-protecting group on the amino-olefin substrates, remarkable improvements in enantioselectivity were obtained.

Enantioselective Alkylation of Aldehydes with Organoborons Enabled by Nickel/N‐Heterocyclic Carbene Catalysis†

Comprehensive SummaryTransition‐metal‐catalyzed asymmetric alkylation of aldehydes represents a straightforward strategy for the synthesis of chiral secondary alcohols. However, efficient methods using organoborons as coupling reagents are rare. Herein, we report a highly enantioselective nickel‐catalyzed alkylation reaction of aldehydes, using readily available alkylborons as nucleophiles. A wide variety of chiral secondary alcohols were prepared from commercially available aldehydes with high yields. The key to the excellent enantioselectivity and chemoselectivity was the employment of a bulky C2‐symmetric chiral NHC ligand. This protocol features excellent enantiocontrol, mild conditions, and good functional group compatibility.

Mechanisms, regio- and stereoselectivities involved in NHC[sbnd]catalyzed dearomatizing annulation of ester with ylide: A computational study

The catalytic mechanism for dearomatizing annulation of ester with ylide by a chiral NHC catalyst is investigated by density functional theory (M06–2X) computations. After precatalyst activation giving active NHC, the transformation proceeds via five steps: (1) nucleophilic addition of the NHC to ester, (2) α−CH deprotonation to generate acylazolium intermediate, (3) coupling acylazolium intermediate with ylide to form a new C − C bond, (4) ring closure and (5) elimination of the NHC with formation of the annulation product tricyclic dihydroisoquinoline. The regio- and stereoselectivity controlling step is C − C bond formation. For regioselectivity, local reactivity index analysis indicates that the C1-addition is more favorable than either C3 or C4 addition. The stereoselectivity for the formation of SS-configurational product is ascribed to a number of noncovalent interactions (C–H·O, C–H·N and C–H·π). Electron localization function (ELF) analyses reveal the important role of the NHC in Ccarbonyl−Ocarbonyl bond breaking. These results enable both in-depth understanding of NHC catalysis and rational design of catalytic reactions.

Studies towards the Enantioselective Synthesis of Cryptowolinol via Pd0-Catalyzed C(sp3)-H Arylation/Parallel Kinetic Resolution.

We report a model study towards the enantioselective synthesis of the dibenzopyrrocoline alkaloid (-)-cryptowolinol. The key step involves a challenging enantioselective Pd0-catalyzed C(sp3)-H arylation performed with a chiral NHC ligand, which proceeds via parallel kinetic resolution (PKR). A very efficient PKR process was achieved on a deoxygenated model substrate and was successfully transposed to a potential intermediate en route to (-)-cryptowolinol.

Chiral NHC Ligands for Enantioselective Gold(I) Catalysis Under Aerobic Conditions: the Importance of Conformational Flexibility and Steric Hindrance of NHC Ligand on Reactivity.

Gold(I) catalysis has been recognized as a valuable tool for the unique transformation of multiple carbon-carbon bonds. Enantioselective π-catalysis based on gold(I) complexes is, however, still underdeveloped due to lack of privileged ligands. Herein, we present an accessible method to a new family of stable yet catalytically active chiral NHC-Au(I)-Cl complexes. The key to preserving a simultaneous fine balance between reactivity and stability in this newly developed family appears to be sterically hindered, but conformationally flexible NHC ligands. These could be easily accessed on a multigram scale by merging sterically hindered anilines with commercially available amino alcohols and amines via a four-steps synthetic sequence without the need for chromatographic purification. Further investigations of the catalytic activity of NHC-Au-Cl complexes identified the OH functionality incorporated into the NHC core as crucial for the level of enantioselectivity as well as the TsO- anion responsible for the activation of NHC-Au(I)-Cl. Finally, NMR studies and X-ray investigations revealed for the first time that the widely accepted ion metathesis (NHC-Au-Cl to NHC-Au-OSO2 R) responsible for the activation of NHC-Au-Cl complexes does not take place (or it is very slow) in commonly used MeNO2 in contrast to DCM.

Chiral Bifunctional NHC–Guanidine Ligands for Asymmetric Hydrogenation

AbstractWe report the synthesis of chiral N-heterocyclic carbene/guanidine bifunctional ligands from readily available amino alcohols. The resulting chiral bifunctional copper(I) complexes are active catalysts in an asymmetric hydrogenation of ketones. We show that the chiral linker unit can be employed for the transfer of stereoinformation.

Transition-Metal-Free Synthesis of Enantioenriched Tertiary and Quaternary α-Chiral Allylsilanes.

Access to enantioenriched tertiary and quaternary α-chiral allysilanes without any transition-metal catalyst is reported. This was achieved by enantioselective allylic displacement of γ-silylated allylic bromides through Lewis base activation of Grignard reagents by a bidentate chiral NHC ligand. The process afforded both high γ-regio- and enantioselectivity and is compatible with a wide range of silyl groups on the substrates.

C–H Functionalization of Arenes via NHC-Supported Ni/Al Bimetallic Catalysis

AbstractDespite the C–H functionalization of arenes offering an efficient synthetic route towards functionalized aromatic compounds with high atom- and step-economy, the low reactivity of the C–H bond makes this transformation rather challenging. Compared with mono-metal catalysis, the introduction of bimetallic catalysis would greatly enhance the reactivity and selectivity of this transformation. In this review, we highlight recent progress in the C–H functionalization of arenes via NHC-Ni/Al catalysis. The added aluminum as a co-catalyst would activate arene through Lewis acid-base interaction, and regioselectivity could be controlled through the synergism of NHC-Ni and Al. This strategy could be also applied in enantioselective C–H alkylation with well-designed chiral NHC ligands.1 Introduction2 C–H Addition to Alkynes via C–H Activation3 C–H Alkylation via Ni/Al Bimetallic Catalysis3.1 Racemic Hydroarylation with Alkenes3.2 Asymmetric Hydroarylation with Alkenes4 Conclusion and Outlook

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors.

We present here a stereoselective tandem reaction based on the asymmetric conjugate addition of dialkylzinc reagents to unsaturated acylimidazoles followed by trapping of the intermediate zinc enolate with carbocations. The use of a chiral NHC ligand provides chiral zinc enolates in high enantiomeric purities. These enolates are reacted with highly electrophilic onium compounds to afford densely substituted acylimidazoles. DFT calculations helped to understand the reactivity of the zinc enolates derived from acylimidazoles and allowed their comparison with metal enolates obtained by other conjugate addition reactions.

Asymmetric Catalytic Transformations of Aza‐ortho‐ and Aza‐para‐Quinone Methides

AbstractThe catalytic methodologies for the derivatization of aza‐QM have recently appeared in the literature and involve organocatalytic and organometallic approaches. This review aims at analyzing the diverse catalytic systems involving chiral NHC carbenes, phosphoric acids, phosphoramidites, phosphine and copper and palladium catalysis showing its applicability for the synthesis of a diverse away of N‐containing compounds which in many cases have biological activity.

Mechanisms and origins of stereoselectivity involved in NHC-catalyzed [3 + 3] Annulation of 2-bromoenals and β-ketothioamides: A DFT study

We reported a density functional theory (M06–2X) study of the possible mechanisms operating in a chemo- and stereoselective [3+3] annulation reaction of 2-bromoenal with β-ketothioamide catalyzed by a chiral NHC catalyst. DFT computations suggest the catalytic reaction involves nucleophilic addition, [1,2]-proton transfer, debromination, [1,3]-proton transfer, Michael addition, [1,5]-proton transfer, ring closure and catalyst dissociation, in which Michael addition is the chemo- and stereoselectivity-determining step and provides the SR-configured sipro-piperidinone predominantly. This result is consistent with the stereoselectivity observed in experiment. Nonconvalent interaction (NCI) analysis reveals that the origin of stereoselectivity is the different weak interactions (C–H···π, LP···π and π···π). The computational results should deepen our understanding of NHC catalysis, and may thus contribute to the design of new catalytic systems.

Rhodium and iridium NHC complexes from chiral NHC precursors: Synthesis, structure, transfer hydrogenation catalysis and method validation

Heteroleptic [RhIIICp*(NHC)] and [IrIIICp*(NHC)] complexes bearing a N-amino acid functionality derived from imidazolium salts were synthesized and characterized by NMR, IR, HR-MS, and single-crystal X-ray diffraction. A discussion of the structure of the [RhCp*{κ2(C,O)–NHC}Cl] complex 3f as a pair of diastereomers is presented. Catalysts were assessed for the transfer hydrogenation (TH) of ketones in basic propan-2-ol, obtaining good yields for the reduction products. A chromatographic method applied for measurements of compounds in TH as analytes was validated. The Rh and Ir complexes described here offer an original approach in the development of catalysts based in classic NHC precursors.

Enantioselective Synthesis of Spiro Heterocyclic Compounds Using a Combination of Organocatalysis and Transition-Metal Catalysis.

Over the last ten years, the combination of organocatalysis with transition metal (TM) catalysis has become one of the most important toolboxes used for synthesizing optically pure compounds containing chiral quaternary centers, including spiro heterocyclic molecules. The dominant method in the enantioselective synthesis of spiro heterocyclic compounds based on synergistic catalysis includes chiral aminocatalysis and NHC catalysis, as already established covalent organocatalytic strategies. Another area of organocatalysis widely combined with TM catalysis producing enantiomerically enriched spiro heterocyclic compounds is non-covalent catalysis, dominated by chiral phosphoric acids, thiourea, and squaramide derivatives. This review article aims to summarize enantioselective methods used for constructing spirocyclic heterocycles based on a combination of organocatalysis and transition metal catalysis.

Asymmetric synthesis of spirofuro[2,3-b]azepine-5,3′-indoline derivativesviacycloisomerization/[4 + 3] annulation process under Au/N-heterocyclic carbene relay catalysis

A variety of enantioenriched spirofuro[2,3-b]azepine-5,3’-indoline derivatives were synthesizedviaAu(I)/chiral NHC relay catalyzed cycloisomerization/asymmetric [4+3] annulation.

NHC-catalyzed [3 + 4] annulation between 2-dromoenal and aryl 1,2-diamine: Insights into mechanisms, chemo and stereoselectivities

We present a DFT study of the mechanisms, chemo- and stereoselectivities in the reaction of 2-bromoenal with aryl 1,2-diamine enabled by a chiral NHC. The catalytic reaction starts with NHC addition to 2-bromoenal, subsequent [1,2]-proton transfer results in the Breslow intermediate, which then undergoes sequential CBr bond breaking and [1,3]-proton transfer. The resulting acylazolium can transform to the [3 + 4] cycloadduct through subsequent CN bond formation, [1,3]-proton transfer and cyclization. Finally, elimination of catalyst provides 1,5-benzodiazepin-2-one. DFT results reveal that OAc− and HOAc play important roles respectively in the [1,2]- and [1,3]-proton transfer process. The CN bond formation step controls the enantioselectivity of the reaction, and preferably provides access to (R)-1,5-benzodiazepin-2-one. The computed enantioselectivity (97.5% ee) agrees well with experimental report (97% ee). Non-covalent NH···π, CH···N and CH···π interactions are the key factors for controlling the stereoselectivity. The NHC is demonstrated to play a role in CBr bond activation through reduce the electron density between the C and Br atoms, thus increases 2-bromoenal's electrophilicity and facilitates its subsequent reaction with diamines.

Palladium‐Catalyzed Dual Catalytic Synthesis of Heterocycles

AbstractIn recent years, synergistic dual catalysis has been in the spotlight as a robust strategy for carbon−carbon and carbon−heteroatom bond formation. This review highlights the unique strategies of dual catalysis achieved in the past two decades, involving Pd‐catalyst combined with various first‐ and second‐row transition metals (like Cr, Fe, Cu, Ru, etc.), Lewis acids (based on Yb, Mg, Ti, Al, etc.) or organocatalysts (like squaramide, CPA, and NHC) to achieve valuable heterocyclic cores. Heterocycles find wide applications in pharmaceutical and agrochemical industries. Several organocatalysts like chiral phosphoric acid, NHC, squaramide, etc., and metal salts work in synergy with palladium to provide high‐value products taking advantage of the vast development in cross‐coupling reactions. This review is a comprehensive collection of such dual‐catalysis strategies.

Enantio‐ and Diastereoselective Copper‐Catalyzed Allylboration of Alkynes with Allylic gem‐Dichlorides

AbstractAllylic gem‐dichlorides are shown to be efficient substrates for catalytic asymmetric allylboration of alkynes. The method employs a chiral NHC−Cu catalyst capable of generating in a single step chiral skipped dienes bearing a Z‐alkenyl chloride, a trisubstituted E‐alkenyl boronate and a bis‐allylic stereocenter with excellent levels of chemo‐, regio‐ enantio‐ and diastereoselectivity. This high degree of functionalization makes these products versatile building blocks as illustrated with the synthesis of several optically active compounds. DFT calculations support the key presence of a metal cation bridge ligand–substrate interaction and account for the stereoselectivity outcome.