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.     

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.

     

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.

     

Catalytic Enantioselective Addition of Alkyl Grignard Reagents to Aliphatic Aldehydes

Herein, we report an efficient catalytic system for the enantioselective addition of alkyl Grignard reagents to a broad range of aliphatic aldehydes with good yields and enantioselectivities. Remarkably, the challenging methylmagnesium bromide (MeMgBr) can also be added to a variety of aliphatic aldehydes, providing versatile chiral methyl carbinol units with unprecedented yields and enantioselectivities in a simple one‐pot procedure under mild conditions.     

Iron‐Catalyzed Regio‐ and Stereoselective Conjugate Addition of Aryl‐Grignard Reagents to α,β,γ,δ‐Unsaturated Sulfones and its Synthetic Application

The iron‐catalyzed δ‐addition of aryl‐Grignard reagents to α,β,γ,δ‐unsaturated sulfones proceeded in a regio‐ and stereoselective manner to give cis‐4‐aryl‐2‐alkenyl sulfones. Allylic alkylation of the resultant products was performed without isomerization of the cis‐olefin to give cis‐4‐aryl‐1,1‐dialkyl‐2‐alkenyl sulfones, which upon intramolecular Friedel–Crafts reaction with aluminum chloride gave 1,4‐dihydronaphthalenes having a quaternary carbon center.     

Iron‐Catalyzed Synthesis of Allenes from 2‐Alken‐4‐ynoates and Grignard Reagents

Treatment of 2‐alken‐4‐ynoates with methyl‐ or aryl‐Grignard reagents and iron(II) chloride (10 mol%) afforded 5‐methyl‐ or 5‐aryl‐3,4‐alkadienoates in good yields as a single isomer after aqueous work‐up. Likewise, (2‐alken‐4‐ynoyl)oxazolidinones afforded (5‐methyl‐3,4‐alkadienoyl)oxazolidinones. The aldol‐type reaction with acetone was also possible in place of the hydrolytic work‐up.     

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.     

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).     

Copper‐Catalyzed Asymmetric Allylic Alkylation of Halocrotonates: Efficient Synthesis of Versatile Chiral Multifunctional Building Blocks

The highly enantioselective synthesis of α‐methyl‐substituted esters is reported in up to 90% yield and up to 99% ee using copper‐TaniaPhos as chiral catalyst. The transformation proved scalable to at least 6.6 mmol (1.7 g scale). The products of this transformation have been further elaborated to multifunctional building blocks with a single (branched esters and acids) or multiple stereogenic centers (vicinal dimethyl esters, as well as, hydroxy‐ or iodo‐substituted lactones).     

Regio‐ and Stereoselective Preparation of β,γ‐Unsaturated Carboxylic Acids by One‐Pot Sequential Double 1,6‐Addition of Grignard Reagents to Methyl Coumalate

An efficient regio‐ and stereoselective metal‐catalyzed addition of two Grignard reagents (homo‐coupling, 2 RMgX or hetero‐coupling, R¹MgX+R²MgX) to methyl coumalate (methyl 2‐oxo‐2H‐pyran‐5‐carboxylate) is described. This synthetic approach opens the access to a wide variety of functionalized β,γ‐unsaturated carboxylic acids in a modular way. Control of the chemo‐ and stereoselectivity of this one‐pot procedure is discussed.

     

Rhodium‐Catalyzed Enantioselective Conjugate Addition of Arylboronic Acids to Dihydronitronaphthalenes

A highly enantioselective (up to 91% ee) rhodium‐catalyzed asymmetric addition of arylboronic acids has been achieved leading to the challenging dihydro‐3‐nitronaphthalenes using one equivalent of phosphoramidite ligand to rhodium catalyst. A concise formal asymmetric synthesis of the dopamine D1 agonist, dihydrexidine was accomplished using the method.     

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.     

Copper(I)‐Catalysed Multicomponent Reaction: Straightforward Access to 5‐Hydroxy‐1H‐pyrrol‐2(5H)‐ones

A copper‐catalysed multicomponent coupling reaction between readily available (Z)‐3‐iodoacrylic acids, terminal alkynes, and primary amines was developed to smoothly access a small library of 5‐hydroxy‐1H‐pyrrol‐2(5H)‐ones in good yields. This practical and general process was applied to a short‐steps synthesis of the natural product pulchellalactam.

     

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.

     

Regioselective Addition of Organometallic Reagents to 2‐(1‐Alkynyl)‐2‐alken‐1‐ones for an Efficient Synthesis of Substituted 1,2‐Allenyl Ketones

Highly substituted 1,2‐allenyl ketones can be easily and efficiently prepared from organometallic reagents and readily available 2‐(1‐alkynyl)‐2‐alken‐1‐ones. The synthetic application of 1,2‐allenyl ketone products was also showcased by palladium‐catalyzed further transformation.     

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.     

Organocatalytic Asymmetric Sulfa‐Michael Addition to α,β‐Unsaturated Ketones

The highly enantioselective organocatalytic sulfa‐Michael addition to α,β‐unsaturated ketones has been accomplished using benzyl and tert‐butyl mercaptans as the sulfur‐centered nucleophiles. Optically active products are obtained in high yields and good to excellent stereocontrol (up to 96 % ee) from a large variety of enones. Central to these studies has been the use of the catalytic primary amine salt A , derived from 9‐amino‐(9‐deoxy)‐epi‐hydroquinine and D ‐N‐Boc‐phenylglycine, in which both the cation and the anion are chiral, that exhibits high reactivity and selectivity for iminium ion catalysis with enones.     

pseudo Enantiomeric Carbohydrate Olefin Ligands – Case Study and Application in Kinetic Resolution in Rhodium(I)‐Catalysed 1,4‐Addition

In order to investigate significant differences in asymmetric induction for pseudo enantiomeric carbohydrate olefin ligands in rhodium(I)‐catalysed 1,4‐addition reactions, we designed a set of new olefin ligands differing in relative configuration and pyranoside conformation. With these, we have successfully elucidated structural requirements for metal binding and also identified an improved alternative for one pseudo enantiomer. Furthermore, we report the efficient kinetic resolution of a racemic 4‐hydroxycyclopentenone derivative by 1,4‐addition.