Chiral N-heterocyclic Carbene Research Articles

Highly Enantioselective Cyclizations of Conjugated Trienes with Low Catalyst Loadings: A Robust Chiral N-Heterocyclic Carbene Enabled by Acetic Acid Cocatalyst

Densely functionalized cyclopentenones are useful synthetic intermediates. We report herein a new method to synthesize this important class of compounds through a highly enantioselective (98 → 99% ee) triene cyclization that is cocatalyzed by acetic acid and a chiral N-heterocyclic carbene (NHC). We discovered that acetic acid not only could coexist with NHCs but also could greatly stabilize the active catalyst, which enables a long-lived catalyst with high reactivity and selectivity.

Chiral N-Heterocyclic Carbene Borane Complexes: Synthesis and Structural Analysis

A new family of chiral N-heterocyclic carbene borane complexes was synthesized starting from their corresponding imidazolium salts. The complexes were fully characterized. X-ray crystal structures of the complexes were obtained.

Ruthenium NHC Catalyzed Highly Asymmetric Hydrogenation of Benzofurans

H2-O-T! Aromatic O-heterocycles are a challenging substrates for asymmetric hydrogenation (H2). An in situ formed chiral N-heterocyclic carbene (NHC) ruthenium complex allows the high yielding, completely regioselective, and highly asymmetric hydrogenation of substituted benzofurans at room Temperature, giving valuable 2,3-dihydrobenzofurans (see scheme).

Synthesis and characterization of novel chiral NHC–palladium complexes and their application in copper-free Sonogashira reactions

A new series of chiral N-heterocyclic carbene (NHC) palladium complexes were synthesized from a relatively inexpensive amino acid, l-phenylalanine. All these compounds were fully characterized by (1)H-NMR, (13)C-NMR and elemental analysis. The X-ray molecular structures of two of the complexes were reported. The catalytic activity of the four palladium complexes was successfully tested in the Sonogashira reaction under copper free conditions in air. The palladium complex 3a provided good activity in the Sonogashira coupling reaction.

Axially chiral N-heterocyclic carbene gold(I) complex catalyzed asymmetric Friedel–Crafts/cyclization reaction of nitrogen-tethered 1,6-enynes with indole derivatives

A class of axially chiral NHC–Au(I) complexes has been applied to the asymmetric Friedel–Crafts/cyclization reaction of nitrogen-tethered 1,6-enynes 14 with indole derivatives 15, affording the corresponding Friedel–Crafts and intramolecular cyclization products 16 in good yields and with moderate ee values under mild conditions.

ChemInform Abstract: Chiral N‐Heterocyclic Carbene Catalyzed Annulation of α,β‐Unsaturated Aldehydes with 1,3‐Dicarbonyls.

AbstractChiral N‐heterocyclic carbene catalyzed annulations of ynals (I) and enals (IV) with 1,3‐dicarbonyl compounds (II) and (VII) are described.

Formal Diels–Alder Reactions of Chalcones and Formylcyclopropanes Catalyzed by Chiral N-Heterocyclic Carbenes

Highly enantioselective (formal) hetero-Diels-Alder reactions between chalcones and formylcyclopropanes are disclosed. The challenging N-heterocyclic carbene (NHC)-bounded enolate intermediates from formylcyclopropanes were captured for new C-C bond forming reactions. The reaction products were obtained with high diastereo- and enantioselectivities and could be easily transformed to optically pure multisubstituted cyclohexane derivatives.

Asymmetric Intermolecular Stetter Reaction of Enals with Nitroalkenes

An asymmetric intermolecular ­Stetter reaction of enals 2 with nitroalkenes 3 catalyzed by chiral N-heterocyclic carbenes has been developed. With precatalyst 1, the reaction proceeded with good to high enantioselectivity and afforded good yields of Stetter products 4. The presence of catechol as an additive was crucial for the reaction efficiency. This effect of a bifunctional Brønsted acid has also been observed in the intramolecular Stetter reaction and could be general, enabling lower catalyst loadings in other N-heterocyclic carbene catalyzed transformations. Primary alkyl-substituted nitroalkenes are not suitable substrates for the current catalytic system.

Axially Chiral N-Heterocyclic Carbene Gold(I) Complex Catalyzed Asymmetric Cycloisomerization of 1,6-Enynes

A new class of axially chiral NHC-Au(I) complexes (1–11) has been developed from optically active BINAM and fully characterized by NMR, ESI-MS, and IR spectroscopic data, where structures of complexes 1, 2a, and 6 have been further determined by X-ray diffraction studies of their single crystals, exhibiting a nearly linear coordination geometry around the gold(I) center. Within the carried out investigations herein, the sterically less hindered gold(I) complex (aR)-6, having a pyrrolidin-1-yl group, has been realized to be the best catalyst in gold(I)-catalyzed asymmetric acetoxycyclization of 1,6-enyne 52a, giving product 53a in >99% yield with −59% ee at 0 °C, and the sterically less hindered gold(I) catalyst (aS)-2a is the best catalyst in the asymmetric oxidative rearrangement of 1,6-enynes, affording the corresponding aldehydes 56a,c–h in excellent yields (up to >99%) and modest enantioselectivities (3.1–70% ee) using PhCl as the solvent at 10 °C.

Catalytic Asymmetric Intermolecular Stetter Reaction of Enals with Nitroalkenes: Enhancement of Catalytic Efficiency through Bifunctional Additives

An asymmetric intermolecular Stetter reaction of enals with nitroalkenes catalyzed by chiral N-heterocyclic carbenes has been developed. The reaction rate and efficiency are profoundly impacted by the presence of catechol. The reaction proceeds with high selectivities and affords good yields of the Stetter product. Internal redox products were not observed despite of the protic conditions. The impact of catechol has been found to be general, facilitating far lower catalyst loadings than were previously achievable.

Oxidative Esterification, Thioesterification, and Amidation of Aldehydes by a Two‐Component Organocatalyst System Using a Chiral N‐Heterocyclic Carbene and Redox‐Active Riboflavin

Flavin of the month! Triazolium-derived N-heterocyclic carbenes (NHCs) and a flavin catalyzed the oxidative esterification, thioesterification, and amidation of aldehydes with various alcohols, thiols, and amines, respectively, with O2 as the terminal oxidant (see scheme; R1=aryl; R2, R3=alkyl or aryl). By using a chiral NHC catalyst, the enantioselective acylation promoted the kinetic resolution of racemic alcohols and the desymmetrization of a meso-diol. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Ligand-Controlled Highly Regioselective and Asymmetric Hydrogenation of Quinoxalines

The research group of Glorius developed a ligand-controlled hydrogenation of quinoxalines. Selecting the right N-heterocyclic carbene ligand facilitates the regioselective hydro-genation of either the heterocyclic or the carbocyclic ring of a substituted quinoxaline. The hydrogenated products were generally obtained in quantitative yields and by employing chiral N-heterocyclic carbene ruthenium complexes, the 5,6,7,8-tetrahydroquinoxalines were furnished with good enantioselectivities.

Metal-Free Catalytic C–Si Bond Formation in an Aqueous Medium. Enantioselective NHC-Catalyzed Silyl Conjugate Additions to Cyclic and Acyclic α,β-Unsaturated Carbonyls

A metal-free method for enantioselective conjugate addition of a dimethylphenylsilyl group to α,β-unsaturated carbonyls is reported. Transformations are catalyzed by a chiral N-heterocyclic carbene (NHC), performed in an aqueous solution (3:1 mixture of water and tetrahydrofuran) and are operationally simpler to perform than the NHC-Cu-catalyzed variant. The chiral catalyst is generated from an enantiomerically pure imidazolinium salt (prepared in three steps) and a common organic amine base (dbu). NHC-catalyzed processes proceed with 5.0-12.5 mol % catalyst loading at 22 °C within 1-12 h, affording the desired β-silyl carbonyls in 85:15 to >98:2 enantiomeric ratio and in 50% to >98% yield. Cyclic enones or lactones and acyclic α,β-unsaturated ketones, esters, and aldehydes can be used as substrates.

Ligand design for dual enantioselective control in Cu-catalyzed asymmetric conjugate addition of R2Zn to cyclic enone

A new chiral N-heterocyclic carbene (NHC) ligand derived from a natural α-aminoester has been designed and synthesized. The coupling of N-methylbenzimidazole with an α-chloroacetamide derivative, which was prepared from chloroacetyl chloride and (S)-serine methyl ester, gave the corresponding ester/amide-functionalized azolium compound 20. The reaction of 2-cyclohexen-1-one (17) with Et2Zn in the presence of catalytic amounts of Cu(OTf)2 and 20 produced (R)-3-ethylcyclohexanone (18) as a major product. In contrast, the enantioselective conjugate addition (ECA) reaction catalyzed by Cu(OTf)2 under the influence of a hydroxy-amide-functionalized azolium compound 15, which was derived from (S)-tert-leucinol, produced (S)-18 in preference to (R)-18. A series of azolium salts were synthesized from (S)-serine esters, and the reaction conditions for the ECA reaction were optimized to produce (R)-18 with 69% ee. The best results were obtained in the case of the reaction of 4,4-dimethyl-2-cyclohexen-1-one (34) with Et2Zn catalyzed by Cu(OTf)2 in combination with azolium compounds. When the reaction of 34 with Et2Zn was carried out in the presence of catalytic amounts of Cu(OTf)2 and 20, (S)-3-ethyl-4,4-dimethylcyclohexanone (35) was obtained with 97% ee, whereas the ECA reaction under the influence of hydroxy-amide-functionalized azolium 15 afforded (R)-35 with >99% ee. In this manner, the reversal of enantioselectivity was achieved by controlling the structure of chiral ligands.

ChemInform Abstract: Axially Chiral C2‐Symmetric N‐Heterocyclic Carbene (NHC) Palladium Complex‐Catalyzed Asymmetric α‐Hydroxylation of β‐Keto Esters.

AbstractThe asymmetric hydroxylation of indan‐1‐one‐2‐carboxylates using phenyloxaziridine as oxidant is catalyzed by a novel axially chiral NHC—Pd catalyst (BINCAP).

Ligand‐Controlled Highly Regioselective and Asymmetric Hydrogenation of Quinoxalines Catalyzed by Ruthenium N‐Heterocyclic Carbene Complexes

Inflating flat bicycles: Proper choice of the N-heterocyclic carbene (NHC) ligand in Ru NHC complexes allows the completely regioselective ligand-controlled hydrogenation of either the heterocyclic or the carbocyclic ring of a substituted quinoxaline in quantitative yields. Chiral NHC ligands allow the challenging asymmetric hydrogenation of the carbocyclic ring of quinoxalines, yielding enantioenriched 5,6,7,8-tetrahydroquinoxalines with an enantiomeric ratio of up to 94:6.

Synthesis of Chiral N-Heterocyclic Carbene Ligands with Rigid Backbones and Application to the Palladium-Catalyzed Enantioselective Intramolecular α-Arylation of Amides

Chiral N-heterocyclic carbene (NHC) ligands having a 2,2'-bisquinoline-based C(2) symmetric skeleton were developed. The ligands exhibited good enantioselectivity in palladium-catalyzed intramolecular α-arylation of amides to give 3,3-disubsituted oxindoles.

Chiral N-Heterocyclic Carbene−Copper(I)-Catalyzed Asymmetric Allylic Arylation of Aliphatic Allylic Bromides: Steric and Electronic Effects on γ-Selectivity

Chiral N-heterocyclic carbene ligands were electronically and sterically tuned to improve γ-selectivity in copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides with several aryl Grignard reagents. High γ-selectivity was realized when either the aryl group of the Grignard reagent or the aryl group on the N-substituent of the carbene ligand was electron-deficient or when either the carbene ligand or allylic bromide was bulky. The results indicated that electron deficiency and steric hindrance of the initially formed σ-allyl copper intermediate enhance the rate of the reductive elimination to give γ-products as major isomers.

ChemInform Abstract: Copper‐Catalyzed Asymmetric Addition of Arylboronates to Isatins: A Catalytic Cycle Involving Alkoxocopper Intermediates.

AbstractThe title reaction affords 3‐aryl‐3‐hydroxy‐2‐oxoindoles (III) under mild conditions.

Chiral N-heterocyclic carbene catalyzed annulation of α,β-unsaturated aldehydes with 1,3-dicarbonyls

Chiral N-heterocyclic carbene catalyzed annulations of ynals and enals with 1,3-dicarbonyls have been described. The two reactions provided direct and efficient methods for enantioselective synthesis of functionalized dihydropyranones. Comparatively, the reactions starting from ynals were atom-economical; furthermore the reactions of enals demonstrated broader substrate compatibility.