Bifunctional N-heterocyclic Carbene Research Articles

Amide C–N bonds activation by A new variant of bifunctional N-heterocyclic carbene

We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C–N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a catalyst turnover agent, the resulting thioester synthon can be transformed into several interesting atropisomers. Both control experiments and theoretical calculations reveal the crucial role of the hybrid NHC-HBD skeleton, which activates the amide via H-bonding and brings it spatially close to the carbene centre. This discovery illustrates the potential of the NHC-HBD chimera and demonstrates a complementary strategy for amide bond activation and manipulation.

Bifunctional NHC-Promoted C2-Alkylation of Pyridine via Ni–Al Bimetallic-Catalyzed Hydroarylation of Unactivated Alkenes

Achieving site-selective alkylation with pyridine under transition metal catalysis has remained a long-standing challenge, especially when using unactivated alkene as an alkylating reagent. We herein describe a site-selective C2-alkylation of pyridine under Ni–Al bimetallic catalysis and directing bifunctional N-heterocyclic carbene (NHC) as ligand through hydroarylation of unactivated alkenes. A broad range of C2-alkylated pyridines with various functionalities could be prepared in high efficiency (up to 99% yield) and high C2-selectivity, and the scope of heterocycles is not limited to pyridines but can be expanded to other azines like pyrazines and pyrimidines. Mechanistic studies suggest that a bifunctional NHC–Ni–Al–pyridine complex is responsible for high site selectivity control and that reductive elimination might be the rate-determining step.

Bifunctional NHC-Catalyzed Remote Enantioselective Mannich-type Reaction of 5-(Chloromethyl)furfural via Trienolate Intermediates.

The N-heterocyclic carbene (NHC)-catalyzed enantioselective Mannich-type reactions of the biomass-derived platform compound 5-(chloromethyl)furfural (CMF) with imines were developed. A series of high-value-added chiral amines were afforded in good to high yields with excellent regio- and enantioselectivities. The bifunctional NHC derived from ʟ-pyroglutamic acid was efficient to steer the remote addition of trienolate intermediate to imine in a highly stereocontrolled manner. This represents the first example of enantioselective reactions via NHC-bound trienolate intermediate.

Enantioselective Seleno‐Michael Addition Reactions Catalyzed by a Chiral Bifunctional N‐Heterocyclic Carbene with Noncovalent Activation

The Michael reaction is a conjugate addition and is one of the most powerful methods with which to prepare functional molecules with a β-stereogenic center. Despite its success in the formation of various asymmetric carbon-carbon and carbon-heteroatom bonds, enantioselective seleno-Michael addition remains essentially unexplored. We report here a highly enantioselective Michael addition reaction of alkyl selenols to enones. This method conveniently introduces a Se atom to an electron-deficient double bond asymmetrically. A chiral bifunctional N-heterocyclic carbene (NHC)/thiourea catalyst was developed as a key ingredient that delivers chiral β-seleno ketones with remarkable selectivity. This new catalyst and its mode of action support broad applications in the catalytic activation of nucleophilic reactions.

A Bifunctional N-Heterocyclic Carbene as a Noncovalent Organocatalyst for Enantioselective Aza-Michael Addition Reactions

Chiral N-heterocyclic carbenes (NHCs) have been recently established as powerful catalysts for enantioselective bond-forming processes via noncovalent interactions. The underlying HOMO-raising acti...

Bifunctional N-Heterocyclic Carbenes Derived from l-Pyroglutamic Acid and Their Applications in Enantioselective Organocatalysis.

In nature, enzymes are a powerful medium for the construction of enantiomerically pure chemicals, which always inspires synthetic chemists to explore new catalysts to imitate the enzyme machinery for asymmetric transformations. Vitamin B1, a bifunctional thiazolium N-heterocyclic carbene (NHC) precursor, is the coenzyme for transketolase. In the past two decades, a series of chiral NHCs, including monocyclic, bicyclic, tetracyclic, and even bridged ones, have been synthesized and successfully utilized as efficient organocatalysts for a wide variety of asymmetric organic reactions. The utility of bifunctional catalysts can enhance catalytic activity and improve stereochemical control through their synchronous activation of both reaction partners. However, the NHCs possessing multiple activation sites are far less developed.This Account gives an overview of our research on the design, development, and applications of bifunctional NHCs in organocatalysis. We synthesized a series of l-pyroglutamic acid-derived bifunctional NHCs bearing a free hydroxyl group which can interact with carbonyl or imino groups via hydrogen-bonding. Further studies revealed that these bifunctional catalysts worked well for a variety of reactions. We have developed bifunctional NHC-catalyzed aza-benzoin reactions, [2 + 2], [2 + 3], and [2 + 4] cycloadditions of ketenes, [3 + 2] and [3 + 4] annulations of enals, and aza-MBH and Rauhut-Currier reactions of Michael acceptors. In addition to these reactions via nucleophilic Breslow intermediates, enolates, homoenolates, and zwitterionic azolium intermediates, the bifunctional NHC-catalyzed [3 + 3] annulation via 1,3-biselectrophilic α,β-unsaturated acyl azolium intermediates was also developed.In these reactions, bifunctional NHCs showed amazing effects compared to normal nonbifunctional NHCs. In some cases, the bifunctional NHCs facilitated reactions which did not work under normal NHC catalysis, possibly due to additional activation via H-bonding. More interestingly, the bifunctional NHCs could not only improve but also switch the enantioselectivity to get products with opposite stereochemistry through H-bond controlled stereochemical directing. Furthermore, the reaction mode could be totally changed from [3 + 2] to [3 + 4] annulation to give kinetically favored products when bifunctional NHCs were employed. In future, the applications of bifunctional NHCs in other challenging reactions, such as asymmetric reactions with carbon-carbon unsaturated bonds, and the reactions involving alkyl or heteroatom radicals will be the major focus in our group.

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.

Bifunctional N-heterocyclic carbene catalyzed [3 + 4] annulation of enals with azadienes: enantioselective synthesis of benzofuroazepinones

The bifunctional N-heterocyclic carbene catalyzed [3 + 4] annulation of enals with aurone-derived azadienes was developed to afford benzofuroazepinones with excellent enantioselectivities.

Ligand Dynamics and Aerobic Allylic Oxidation with Bifunctional Ni(NHC) Complexes

AbstractThe synthesis of three new NiCl(allyl/cinnamyl)(NHC) complexes, containing a bifunctional NHC (N‐heterocyclic carbene) ligand is described. Two different NHCs were utilized that contain a secondary amine (HNR; R=t‐Bu or Mes) moiety on one of the N‐imidazolylidene arms. Complexes with allyl (2 a) and cinnamyl (3 a and 3 b) were each crystallographically characterized and η3‐allyl and κ1‐C NHC ligand coordination modes were found in the solid‐state. In the solution‐state, each of the ligands shows highly fluxional behaviour. Halide substitution of the chloro ligand for iodo effectively slows the ligand dynamics and permits solution‐state characterization that is in agreement with the solid‐state structures. The complexes react with oxygen to ultimately oxidize the allyl or cinnamyl ligands to acrolein (AC) or cinnamaldehyde (CA) and phenyl vinyl ketone (PVK), respectively. The bifunctional nature of the NHC has limited influence on oxidation reactivity, but preliminary evidence suggests it plays a role in the stability of the nickel oxidation products.

Acceptorless Alcohol Dehydrogenation: OH vs NH Effect in Bifunctional NHC–Ir(III) Complexes

Bifunctional complexes bearing N-heterocyclic carbene (NHC) ligands functionalized with hydroxy or amine groups were synthesized to measure the beneficial effect of different modes of metal–ligand cooperation in the acceptorless dehydrogenation of alcohols. In comparison to complexes with an amine moiety, hydroxy-functionalized iridium catalysts showed superior activity. In contrast to alcohols, 1,4-diols underwent cyclization to give the corresponding tetrahydrofurans without involving dehydrogenation processes. Mechanistic investigations to rationalize the “OH effect” in these types of complexes have been undertaken.

Bifunctional N-heterocyclic carbene ligands for Cu-catalyzed direct C–H carboxylation with CO2

A copper-catalyzed direct C–H carboxylation of heteroarene compounds using diethylene glycol-functionalized imidazo[1,5,a] pyridin-3-ylidene (DEG-ImPy) ligands has been developed.

ChemInform Abstract: N‐Heterocyclic Carbene‐Catalyzed [3 + 4] Annulation of Enals and Alkenyl Thiazolones: Enantioselective Synthesis of Thiazole‐Fused ε‐Lactones.

The bifunctional N-heterocyclic carbene catalyzed [3 + 4] annulation of enals and 5-alkenyl thiazolones was developed, giving the corresponding thiazole-fused e-lactones in high yields with excellent diastereoselectivties and enantioselectivities. The thiazole-fused e-lactone could be isomerized to the spirocyclic thiazolone–cyclopentanone without erosion of enantioselectivity.

N-Heterocyclic Carbene-Catalyzed [3 + 4] Annulation of Enals and Alkenyl Thiazolones: Enantioselective Synthesis of Thiazole-Fused ε-Lactones.

The bifunctional N-heterocyclic carbene catalyzed [3 + 4] annulation of enals and 5-alkenyl thiazolones was developed, giving the corresponding thiazole-fused ε-lactones in high yields with excellent diastereoselectivties and enantioselectivities. The thiazole-fused ε-lactone could be isomerized to the spirocyclic thiazolone-cyclopentanone without erosion of enantioselectivity.

Nickel‐Catalyzed Cross‐Coupling of Aryl Bromides with Tertiary Grignard Reagents Utilizing Donor‐Functionalized N‐Heterocyclic Carbenes (NHCs)

One, two or three? The utilization of sterically hindered alkyl substrates represents a major challenge of the present cross-coupling methodology. The nickel-catalyzed Kumada cross- coupling of tertiary alkyl Grignard reagents with aryl bromides allows this difficult reaction with numerous different substrates. Optimal results were obtained using sterically demanding, bifunctional N-heterocyclic carbene ligands.

Two metal–organic frameworks based on a double azolium derivative: post-modification and catalytic activity

A new bifunctional N-heterocyclic carbene (NHC) precursor was used to construct two metal-organic frameworks, which can anchor palladium(II) sites by post-modification, presenting remarkable framework dependent catalytic activities.

Chiral Bifunctional N-Heterocyclic Carbenes: Synthesis and Application in the Aza-Morita-Baylis-Hillman Reaction

A series of chiral bifunctional N-heterocyclic carbene (NHC) precursors with a proximal hydroxy group were smoothly prepared from l-pyroglutamic acid. Promising enantiomeric excesses (up to 44% ee) were achieved for the bifunctional NHC-catalyzed­ enantioselective aza-Morita-Baylis-Hillman reaction of cyclopent-2-enone with N-tosylphenylmethanimine.