NHC Catalyst Research Articles

Radical N-heterocyclic carbene catalysis for β-ketocarbonyl synthesis

N-Heterocyclic carbene-catalyzed radical cross-coupling between aldehydes and α-bromoesters or α-bromoamides is described. β-Ketocarbonyl compounds having a quaternary carbon center at the α-position can be synthesized under mild reaction conditions. Both aromatic and aliphatic aldehydes are suitable acyl donors by employing proper NHC catalyst precursors.

Asymmetric Anisoin Synthesis Involving Benzoin Condensation Followed by Deracemization

The highly enantioselective synthesis of p-anisoin was achieved via the benzoin condensation of a prochiral p-anisaldehyde using achiral NHC catalysts such as vitamin B1. In this reaction, p-anisoi...

Ultrarapid Cerium(III)–NHC Catalysts for High Molar Mass Cyclic Polylactide

Cyclic polyesters could improve the properties of degradable plastics, but routes to them that provide a product with faster rates, higher molar mass, and greater selectivity for cyclic vs linear p...

Suzuki-Miyaura Cross-Coupling of Esters by Selective O-C(O) Cleavage Mediated by Air- and Moisture-Stable [Pd(NHC)(μ-Cl)Cl]2 Precatalysts: Catalyst Evaluation and Mechanism.

The cross-coupling of aryl esters has emerged as a powerful platform for the functionalization of otherwise inert acyl C-O bonds in chemical synthesis and catalysis. Herein, we report a combined experimental and computational study on the acyl Suzuki-Miyaura cross-coupling of aryl esters mediated by well-defined, air- and moisture-stable Pd(II)-NHC precatalysts [Pd(NHC)(μ-Cl)Cl]2. We present a comprehensive evaluation of [Pd(NHC)(μ-Cl)Cl]2 precatalysts and compare them with the present state-of-the-art [(Pd(NHC)allyl] precatalysts bearing allyl-type throw-away ligands. Most importantly, the study reveals [Pd(NHC)(μ-Cl)Cl]2 as the most reactive precatalysts discovered to date in this reactivity manifold. The unique synthetic utility of this unconventional O-C(O) cross-coupling is highlighted in the late-stage functionalization of pharmaceuticals and sequential chemoselective cross-coupling, providing access to valuable ketone products by a catalytic mechanism involving Pd insertion into the aryl ester bond. Furthermore, we present a comprehensive study of the catalytic cycle by DFT methods. Considering the clear advantages of [Pd(NHC)(μ-Cl)Cl]2 precatalysts on several levels, including facile one-pot synthesis, superior atom-economic profile to all other Pd(II)-NHC catalysts, and versatile reactivity, these should be considered as the 'first-choice' catalysts for all routine applications in ester O-C(O) bond activation.

Synthesis of 1,10-decanediol diacetate and 1-decanol acetate from furfural

Furfural was converted into furoin by immobilized NHC catalyst, and then furoin was upgraded into 1,10-decanediol diacetate and 1-decanol acetate by Pd/C catalytic hydrodeoxygenation reaction promoted with Sc(OTf)3 in acetic acid.

Vitamin B1-catalyzed aerobic oxidative esterification of aromatic aldehydes with alcohols.

A straightforward aerobic oxidative esterification of aryl aldehydes with alcohols has been developed for the synthesis of substituted esters by employing vitamin B1 as a cost-effective, metal-free, and eco-friendly NHC catalyst. Air is used as a green terminal oxidant. The reaction is a useful addition to the existing NHC-catalytic oxidative esterification.

A non-ionic surfactant based catalyst tablet: a reusable gold–NHC catalyst system for alkyne hydration reactions

Herein, we report the encapsulation of IPrAuCl (Au-1) in Synperonic®F108 (Syn), acting as both a catalyst tablet medium and surfactant for dispersion of hydrophobic alkyne substrates and gold–NHC complexes in aqueous media.

Bifunctional N‐Heterocylic Carbene‐Catalyzed Highly Enantioselective Trans‐Cyclopentannulation of Enals and Enones via Homoenolate

AbstractAn efficient and flexible synthesis of a new class of chiral bifunctional NHC catalyst has been reported. These new imidazolylidene NHCs, bearing a (thio)urea function as a hydrogen bond donor promoted efficiently highly diastereoselective trans‐cyclopentannulation of enals and enones in moderate to good yields (up to 69 % yield) along with excellent enantioselectivity (up to 96 % ee). This methodology could be applied to a large variety of substrates (30 examples).

Au(I)‐Catalyzed Hydration of 1‐Iodoalkynes Leading to α‐Iodoketones

A catalytic protocol for the Au(I)‐catalyzed hydration of 1‐iodoalkynes is disclosed. The use of Au(I)–NHC catalyst enabled the straightforward synthesis of a variety of α‐iodomethyl ketones in good to excellent yields. The utility of this simple method is further highlighted by showcasing iodination/hydration and hydration/oxidation sequential protocols leading to the construction of molecular complexity.

Carbene‐Catalyzed Enantioselective Aldol Reaction: Post‐Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers

AbstractThe dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon–carbon bond‐forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post‐aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non‐enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post‐aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.

Carbene-Catalyzed Enantioselective Aldol Reaction: Post-Aldol Stereochemistry Control and Formation of Quaternary Stereogenic Centers.

The dominated approaches for asymmetric aldol reactions have primarily focused on the aldol carbon-carbon bond-forming events. Here we postulate and develop a new catalytic strategy that seeks to modulate the reaction thermodynamics and control the product enantioselectivities via post-aldol processes. Specifically, an NHC catalyst is used to activate a masked enolate substrate (vinyl carbonate) to promote the aldol reaction in a non-enantioselective manner. This reversible aldol event is subsequently followed by an enantioselective acylative kinetic resolution that is mediated by the same (chiral) NHC catalyst without introducing any additional substance. This post-aldol process takes care of the enantioselectivity issues and drives the otherwise reversible aldol reaction toward a complete conversion. The acylated aldol products bearing quaternary/tetrasubstituted carbon stereogenic centers are formed in good yields and high optical purities.

Pd(NHC)(μ-Cl)Cl]2: Versatile and Highly Reactive Complexes for Cross-Coupling Reactions that Avoid Formation of Inactive Pd(I) Off-Cycle Products.

SummaryThe development of more reactive, general, easily accessible, and readily available Pd(II)–NHC precatalysts remains a key challenge in homogeneous catalysis. In this study, we establish air-stable NHC–Pd(II) chloro-dimers, [Pd(NHC)(μ-Cl)Cl]2, as the most reactive Pd(II)–NHC catalysts developed to date. Most crucially, compared with [Pd(NHC)(allyl)Cl] complexes, replacement of the allyl throw-away ligand with chloride allows for a more facile activation step, while effectively preventing the formation of off-cycle [Pd2(μ-allyl)(μ-Cl)(NHC)2] products. The utility is demonstrated via broad compatibility with amide cross-coupling, Suzuki cross-coupling, and the direct, late-stage functionalization of pharmaceuticals. Computational studies provide key insight into the NHC–Pd(II) chloro-dimer activation pathway. A facile synthesis of NHC–Pd(II) chloro-dimers in one-pot from NHC salts is reported. Considering the tremendous utility of Pd-catalyzed cross-coupling reactions and the overwhelming success of [Pd(NHC)(allyl)Cl] precatalysts, we believe that NHC–Pd(II) chloro-dimers, [Pd(NHC)(μ-Cl)Cl]2, should be considered as go-to precatalysts of choice in cross-coupling processes.

Phosphine Free Catalytic Selective Dehydrative Etherification of Secondary Alcohols by Using Ag(I)-Nhc Complexes

We herein report the phosphine-free catalytic selective dehydrative etherification of secondary alcohols into symmetrical/ unsymmetrical ethers under mild conditions by using well-defined, air-stable, Ag(I)-NHC complexes. We have synthesized several novel Ag(I) complexes bearing NHC- ligands, namely, [(S)-7-(R1)-6-(R2)2-2-(R3)-6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-3-ylidene}AgCl (1−2)b, (Scheme 3), were isolated for the first time and structurally characterized through various spectroscopic techniques including single crystal X-ray diffraction analyses. All of these novel Ag(I)-NHC complexes have shown an excellent catalytic activity to produce value added ethers from various secondary alcohols through dehydration process by using Ag(I)-NHC catalysts under mild conditions, respectively.

Development of Multi-functional NHC Catalysts bearing Pyridine Moiety: Application to Catalytic Asymmetric Reactions

Development of Multi-functional NHC Catalysts bearing Pyridine Moiety: Application to Catalytic Asymmetric Reactions

Carbazole‐Based N‐Heterocyclic Carbenes for the Promotion of Copper‐Catalyzed Palladium‐Free Homo‐/Hetero‐Coupling of Alkynes and Sonogashira Reactions

AbstractAlkynes are useful synthetic building blocks that occur in many naturally occurring molecules and have the potential to be easily modified for further natural products and drug synthesis applications. Given the‐versatility of the alkyne functionality,‐various synthetic methods (mostly palladium‐based) are known in the literature, allowing the installation to take place under different reaction conditions. A single catalytic system (without Pd) however, if developed could provide a single point solution for the installation of the alkyne moiety and keeping this in mind, we report herein a highly active palladium‐free Cu/carbazole‐based NHC catalyst system allowing homocoupling and heterocoupling of alkynes at ambient temperature. Using a combination of Cu/NHC‐catalyzed homocoupling/deprotection/heterocoupling sequence tetraynes have also been synthesized in good yields. The Cu/NHC catalyst system was also able to catalyze a palladium‐free Sonogashira reaction of synthetically useful nucleosides.

The potential of d6 non-noble metal NHC catalysts for carbon dioxide hydrogenation: group and row effects

Group VIB NHC-complexes as promising non-noble catalysts for CO2 hydrogenation benefiting by the weak electronegativity and low oxidation state.

NHC‐catalyzed Redox‐Neutral Aza‐Benzoin Reaction of Aldehydes with Tetrahydroisoquinolines

Summary of main observation and conclusionTetrahydroisoquinoline derivatives are useful synthetic intermediates, which play an important role in the preparation of natural products, pharmaceuticals and other materials. Herein, we report an unprecedented redox‐neutral aza‐benzoin protocol to construct such scaffold. Upon exposure of tetrahydroisoquinolines to aromatic aldehydes in the presence of an NHC catalyst, the C‐1 acylated tetrahydroisoquinolines were obtained in moderate to good yields.

Thiolate Bridged Gold(I)–NHC Catalysts: New Approach for Catalyst Design and its Application to Trapping Catalytic Intermediates

New dinuclear N-heterocyclic gold complexes with bridging thiolate ligands have been designed as catalytic precursors with desired properties such as stability, recyclability and that do not require additives. The dinuclear compound [(AuNHC)2 (μ-SC6 F5 )]OTf could slowly release the active catalytic species [Au(NHC)]+ and the precursor [Au(SC6 F5 )(NHC)] in solution, which means that both species would remain stable throughout the catalytic cycle and the pre-catalyst could easily be recovered. The properties exhibited by the complexes have been taken advantage of to gain new insights on the gold-catalyzed hydroalkoxylation of alkynes, with the aim of clarifying all the steps of the catalytic cycle, together with the characterization of intermediates and final products. Isolation and characterization of the pure final spiroketals and the thermodynamic intermediate have been achieved for the first time. Moreover, the kinetic intermediate has also been detected for the first time.

Theoretical understanding mechanisms and stereoselectivities of [2+2] cycloaddition of ketenes with ketimines catalyzed by bifunctional N-heterocyclic carbene

Reaction mechanism of NHC-catalyzed asymmetric [2+2] cycloaddition reaction between ketenes and isatin-derived ketimines for the formation of spirocyclic indolo-β-lactams has been investigated using density functional theory (DFT). The catalytic cycle for the title reaction included three possible mechanisms: the “ketene preferential mechanism” (mechanism A) and the “imine preferential mechanism” (mechanisms B and C). They have three similar steps: the first step is the nucleophilic attack of the NHC catalyst, the second one is ring-closure proceed, and the last one is catalyst regeneration and product formation. This work adopted the two different N-heterocyclic carbene catalysts (named as NHC-I and NHC-II) involved in experiment. The calculated results indicate that the Gibbs free energy barriers of mechanism A are remarkably lower than those of mechanisms B and C, and the reaction pathway leading to the SS-configured product has the lowest Gibbs free energy barrier, which agrees with the experiments. It is worth noting that in mechanism A, NHC-I has a free-rotating hydroxyl group which can form a hydrogen bond and ketene, which greatly reduces the energy of the enolate intermediate and affects the cycloaddition process, improving the stereoselectivity of the reaction. Furthermore, the special role of the catalysts and origin of stereoselectivity of the title reaction were also identified by global reactivity index and frontier molecular orbital analyses. The new insights obtained in this study might provide clues for understanding the reaction mechanism of the high stereoselective reaction catalyzed by bifunctional N-heterocyclic carbene catalysts.

Synthesis of podophyllotoxin-glycosyl triazoles via click protocol mediated by silver (I)-N-heterocyclic carbenes and their anticancer evaluation as topoisomerase-II inhibitors

Herein we report the regioselective synthesis of podophyllotoxin-Glycosyl triazole hybrids catalysed by Ag(I)-N-heterocyclic carbene (Ag(I)-NHC) in a short reaction time (∼30 min) at ambient conditions. In principle, it is the first report of Click alkyne-azide cycloaddition catalysed by Ag(I)-NHC catalyst and moreover, this new methodology yielded good results when compared with traditional CuAAC in terms of reaction time and selectivity. The synthesised compounds were further explored for in vitro anticancer activity against four human cancer cell lines Du145, HeLa, A-549, and MCF-7 and found that these synthesised compounds possess significant anticancer activity. Further, the compounds 5a and 5e were identified as promising leads due to their better activity across all cell lines than that of the standard drug etoposide. Molecular docking studies of 5a & 5e with DNA Topoisomerase-II were revealed that the free energy calculations of active compounds were in good agreement with observed IC50 values.