Copper‐Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl‐N‐methylimidazole Michael Acceptors: Scope,Limitations and Iterative Reactions

An efficient copper‐catalyzed enantioselective conjugate addition of dimethylzinc to unsaturated 2‐acyl‐N‐methylimidazoles has been achieved using a chiral bidentate hydroxyalkyl‐NHC ligand. The reactions proceed with excellent regioselectivity (1,4 vs. 1,6 and 1,8) in extended conjugated systems to afford the 1,4‐adducts in high enantioselectivities. This regioselectivity could be ascertained by DFT studies highlighting the crucial role of the imidazole ring. Thanks to the development of efficient protocols to regenerate the unsaturated 2‐acyl‐N‐methylimidazole moiety, an iterative process has been developed ultimately leading to 3,5,7 all‐syn or anti‐anti polydeoxypropionate stereodiads.

     

Asymmetric Synthesis with N‐Heterocyclic Carbenes. Application to the Copper‐Catalyzed Conjugate Addition

Chiral N‐heterocyclic carbenes are good ligands for the copper‐catalyzed conjugate addition of dialkylzinc reagents to various Michael acceptors. With as little as 4% of chiral ligand, the enantioselectivity may reach 93% on cycloheptenone.     

Highly Enantioselective Copper‐Phosphoramidite‐Catalyzed Conjugate Addition of Dialkylzinc Reagents to Acyclic α,β‐Unsaturated Imides

A new and practical way to introduce an alkyl fragment in the β‐position of aliphatic carboxylic acid derivatives with high enantioselectivities by the use of a commercially available chiral ligand is reported. N‐Acylpyrrolidinones, as simple derivatives of an α,β‐unsaturated carboxylic acid, were found to be the substrates of choice featuring good reactivity and high enantioselectivities (up to >99% ee).     

Asymmetric One‐Pot Conjugate Addition of Grignard Reagents to α,β‐Unsaturated Compounds Followed by Reaction with Carbenium Ions

Asymmetric catalytic multistep reactions enable the formation of structurally complex compounds from simple starting materials. Enantioselective Cu‐catalyzed 1,4‐additions of Grignard reagents to Michael acceptors form reactive chiral enolates. We show here that these chiral enolates react in a one‐pot fashion with naked carbenium ions, such as tropylium, 1,3‐benzodithiolium, and dianisylmethylium ions. The corresponding products were obtained in good yields, with enantioselectivities up to 96% ee and high diastereomeric purities.

     

Synthesis of 2,5‐Diaminoquinones by One‐Pot Copper‐Catalyzed Aerobic Oxidation of Hydroquinones and Addition Reaction of Amines

The aerobic oxidation of various hydroquinones was achieved by using copper nanoparticles entrapped in aluminum oxyhydroxide [Cu/AlO(OH)] at room temperature. Furthermore, 2,5‐diamino‐1,4‐benzoquinones were synthesized directly from hydroquinone and amines by a one‐pot procedure consisting of the copper‐catalyzed aerobic oxidation of hydroquinones and the double addition of amines to the resulting quinones.     

Enantioselective Copper(II)‐Catalyzed Conjugate Addition of Indoles to β‐Substituted Unsaturated Acyl Phosphonates

The first copper‐catalyzed enantioselective conjugate addition of indoles to β‐substituted unsaturated acyl phosphonates was successfully realized by using a heteroarylidene‐tethered bis(oxazoline) ligand. The reaction features high efficiency, cheap catalyst and broad generality. In the case of either β‐alkyl‐ or β‐aryl‐substituted unsaturated acyl phosphonates, the 3‐indolyl adducts were achieved in high yields with good to excellent enantioselectivities (up to 97% ee). The 3‐indolyl adducts can serve as important intermediates in the synthesis of indole alkaloids.

     

Copper‐Catalysed Conjugate Addition of Grignard Reagents to 2‐Methylcyclopentenone and Sequential Enolate Alkylation

The copper/Rev‐JosiPhos‐catalysed asymmetric conjugate addition of Grignard reagents to 2‐methylcyclopentenone ( 1 ) provides 2,3‐disubstituted cyclopentanones in high yields and enantioselectivities, and good diastereoselectivities. Reaction of the in situ formed enolate with various alkylating reagents in the presence of 1,3‐dimethyltetrahydropyrimidine‐2(1H)‐one (DMPU) affords the corresponding products in a one‐pot reaction. This procedure creates two vicinal stereocentres, one of them quaternary.

     

Spiro‐Pyrrolidine‐Catalyzed Asymmetric Conjugate Addition of Hydroxylamine to Enals and 2,4‐Dienals

A spiro‐pyrrolidine‐catalyzed tandem aza‐1,4‐addition/hemi‐acetalization reaction was developed with excellent enantioselectivity (12 examples of ≥99% ee), and several substrates proceeded with higher ee (up to 10% increase) compared with the literature data. Particularly, an interesting and unusual aza‐1,6‐/oxa‐1,4‐addition for some substrates was also observed.

     

Efficient Catalytic Asymmetric Synthesis of trans‐5‐Aryl‐2‐substituted Cyclohexanones by Rhodium‐Catalyzed Conjugate Arylation of Racemic 6‐Substituted Cyclohexenones

Catalytic asymmetric conjugate arylation of racemic 6‐substituted cyclohexenones with arylboronic acids was catalyzed by 3 mol % of chiral amidophosphane‐[RhCl(C₂H₄)]₂ in a 10:1 mixture of 1,4‐dioxane and water at 70 °C to afford a nearly 1:1 mixture of trans‐ and cis‐5‐aryl‐2‐substituted cyclohexanones in high enantioselectivity, which was subsequently epimerized with sodium ethoxide in ethanol to give thermodynamically stable trans‐5‐aryl‐2‐substituted cyclohexanones with 99–97 % ee in high two‐step yields.     

Conjugate Reduction of α,β‐Unsaturated Carbonyl and Carboxyl Compounds with Poly(methylhydrosiloxane) Catalyzed by a Silica‐Supported Compact Phosphane–Copper Complex

A silica‐supported, cage‐type, compact phosphane (Silica‐SMAP) was used for the copper‐catalyzed conjugate reduction of α,β‐unsaturated carbonyl and carboxyl compounds with poly(methylhydrosiloxane) (PMHS). The heterogeneous catalyst system showed high activity and chemoselectivity, and was easily separable from the reaction mixture after the reaction. Furthermore, the catalyst was reusable without loss of its high catalytic activity or selectivity.     

Synthesis of Diastereomeric 1,4‐Diphosphine Ligands Bearing Imidazolidin‐2‐one Backbone and Their Application in Rh(I)‐Catalyzed Asymmetric Hydrogenation of Functionalized Olefins

The diastereomeric 1,4‐diphosphine ligands, (S,S,S,S)‐ 1a , (R,S,S,R)‐ 1b and (R,S,S,S)‐ 1c , with the imidazolidin‐2‐one backbone were synthesized, and utilized for an investigation of the effects of backbone chirality on the enantioselectivity in the Rh(I)‐catalyzed hydrogenation of various functionalized olefinic substrates. It was found that the catalytic efficiencies are largely dependent on the configurations of the α‐carbons to phosphine. Thus, the Rh complex of the pseudo‐C₂‐symmetrical diphosphine, (R,S,S,S)‐ 1c , showed excellent enantioselectivities (93.0–98.6% ees) in the hydrogenations of a broad spectrum of substrates, and especially in the hydrogenations of methyl α‐(N‐acetyamino)‐β‐arylacrylates (95.3–97.0% ees). However, the enantioselectivities obtained with the C₂‐symmetrical (R,S,S,R)‐ 1b were largely dependent on the substrate (19.8–97.3% ees). The Rh complex of ligand 1a having the (S,S,S,S)‐configuration showed the lowest catalytic efficiency for all of the substrates examined (0–84.8% ees).     

Highly Efficient Copper(I) Iodide‐Tolyl‐BINAP‐Catalyzed Asymmetric Conjugate Addition of Methylmagnesium Bromide to α,β‐Unsaturated Esters

A highly efficient asymmetric conjugate addition of methylmagnesium bromide (MeMgBr) to α,β‐unsaturated esters catalyzed by copper(I) iodide‐tolyl‐BNIP (CuI‐Tol‐BINAP) is described.     

Enantioselective Synthesis of 4‐Substituted Dihydrocoumarins through a Zinc Bis(hydroxyamide)‐Catalyzed Conjugate Addition of Terminal Alkynes

A new enantioselective catalyst for the conjugate addition of terminal alkynes has been developed. Terminal alkynes react with 3‐alkoxycarbonylcoumarins in the presence of diethylzinc and bis(hydroxyamide) ligands to give chiral non‐racemic dihydrocoumarins substituted with an alkynyl group on the C‐4 position with good yields and enantiomeric excesses up to 95%.     

Copper‐Catalyzed Chloroamination of Alkynes: Highly Regio‐ and Stereoselective Synthesis of (E)‐β‐Chloro‐Enesulfonamides

An efficient copper catalysis system for the chloroamination of alkynes with chlorosulfonamide at room temperature is described, providing a highly regio‐ and stereoselective procedure for the synthesis of (E)‐β‐chloro‐enesulfonamides in moderate to good yields.     

Excess Phosphine Ligand Plays a Critical Role in the Asymmetric Copper(I) Iodide‐Catalyzed Conjugate Addition of Grignard Reagents to α,β‐Unsaturated Esters

The role of excess ligand in the asymmetric 1,4‐conjugate addition (ACA) of Grignard reagents to α,β‐unsaturated esters compounds catalyzed by copper(I) iodide‐2,2′‐bis(di‐p‐tolylphosphino)‐1,1′‐binaphthyl (CuI‐Tol‐BINAP) is explored herein. In addition, this methodology allows asymmetric induction to be carried out using a non‐chiral phosphine copper complex with excess of a chiral phosphine ligand.     

Enantioselective Copper‐Catalyzed Intramolecular N−H Bond Insertion: Synthesis of Chiral 2‐Carboxytetrahydroquinolines

The first highly enantioselective intramolecular N−H bond insertion was realized by using copper catalysts modified with chiral spirobisoxazoline ligands, which provides a novel strategy for the synthesis of chiral 2‐carboxytetrahydroquinolines. This reaction features fast reaction rate, high yield, high enantioselectivity, and mild reaction conditions.

     

Phosphoramidite Ligands Based on Simple 1,2‐Diols: Synthesis,Use in Copper‐Catalyzed Asymmetric Additions,and Achirotopic Stereogenic Phosphorus Centres

Phosphoramidite ligands are widely used in catalysis and normally constructed from large C₂‐symmetrical diols such as BINOL or TADDOL. We report here on new ligands based on a set of simple diols that had been previously overlooked. Ligands based on (S,S)‐trans‐cyclohexanediol and (R,R)‐(+)‐1,2‐diphenyl‐1,2‐ethanediol, in combination with both chiral and achiral amines, were tested in 3 different copper‐catalyzed asymmetric reactions and up to 89% ee was observed. A different ligand gave the best results in each reaction examined. Using meso‐cis‐cyclohexanediol and meso‐cis‐diphenyl‐1,2‐ethanediol with a chiral non‐racemic amine gave diastereomeric ligands bearing achirotopic stereogenic phosphorus atoms which were characterized with the assistance of X‐ray crystallography and variable temperature NMR studies. This work provides a new set of ligands that may be useful in some asymmetric reactions when phosphoramidites based on BINOL and TADDOL are ineffective. We also identify a novel stereochemical feature of phosphoramidites that may be useful in asymmetric catalysis and ligand design.

     

Palladium‐Catalysed Enantioselective Conjugate Addition of Aromatic Amines to α,β‐Unsaturated N‐Imides. Effect of the Chelating Moiety

Palladium‐catalysed enantioselective additions of aromatic amines to α,β‐unsaturated N‐imides 4 – 6 are reported. The N‐substituent of the Michael acceptor appears to have an unusual modulating effect on the amine activity. The effects of introducing different substituents are examined. Overall, the yield and selectivity of the system appear to be less sensitive to environmental effects than previous systems. The importance of the counteranion is revealed.     

Copper‐Catalyzed Activation of Dioxygen: Oxidative Cyclization of 2‐Arylindoles

A series of unusual six‐ring‐fused heterocycles containing indole and quinoline skeletons was successfully synthesized by a copper‐catalyzed reaction from 2‐arylated indoles. Two new bonds were regioselectively formed from C H and C H coupling. ¹⁸O‐Labelled experiments revealed that the dioxygen is not only the oxidant but also the reactant.