Pyrrolidine-thiourea as a bifunctional organocatalyst: highly enantioselective Michael addition of cyclohexanone to nitroolefins

[reaction: see text] Asymmetric Michael additions of cyclohexanone to both aryl and alkyl nitroolefins in the presence of 20 mol % of organocatalyst 2b and 10 mol % of n-butyric acid afford adducts 5 with high diastereoselectivities and enantioselectivities.     

Highly enantioselective Michael addition reactions in water catalyzed by an insoluble MPS-supported 4-sulfonamidyl prolinol tert-butyldiphenylsilyl ether

The development of a highly efficient, insoluble, and non-swelling MPS-supported organocatalyst for the direct asymmetric Michael reaction of ketones and aldehydes to nitrostyrenes at room temperature in water is described. Excellent yields (up to 100%) and high stereoselectivities (up to 94% dr and 93% ee) were achieved with 10 mol % of the catalyst. The resin-bound catalyst was simply separated and recovered by filtration, and reused for six consecutive trials without significant loss of activity and enantioselectivity.     

A highly enantioselective organocatalyst for the Michael addition of cyclic ketones to nitroolefins

Enantiomerically pure triamine 2, which catalyses the Michael addition of cyclic ketones to nitroolefins with high diastereoselectivity (up to 99:1) and enantioselectivity (up to 91% ee), was designed and prepared.     

Highly efficient bifunctional organocatalysts for the asymmetric Michael addition of ketones to nitroolefins

A type of secondary-secondary-tertiary triamine bifunctional organocatalysts have been properly designed and synthesized. In our study, the designed catalyst (S)-N-(pyrrolidin-2-ylmethyl)pyridin-2-amine 5 has been shown to be highly efficient to promote the asymmetric Michael addition of ketones to nitroolefins at room temperature, which afforded the corresponding adducts in excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to >99% ee).     

Pyrrolidine-carbamate based new and efficient chiral organocatalyst for asymmetric Michael addition of ketones to nitroolefins

The novel ((S)-pyrrolidin-2-yl)methyl phenylcarbamate was synthesized and used as an efficient organocatalyst for the asymmetric Michael addition of cyclic/acyclic ketones to nitroolefins. Interestingly, the resulting Michael adducts were obtained in good to high yields (up to 96%) with excellent stereoselectivity (ee up to >99%, dr up to >99:1) without using any additive.     

Ionic-liquid-supported organocatalyst for the enantioselective Michael addition of ketones to nitroolefins

Ionic-liquid-supported triazole-pyrrolidine 2, for the direct asymmetric Michael reaction was successfully synthesized. The supported catalyst demonstrated good activity and high enantioselectivity in the addition of cyclohexanone to nitroolefins. Furthermore, the supported catalyst can be readily recovered and reused four times without significant loss of catalytic activity.     

A new type of organocatalyst for highly stereoselective Michael addition of ketones to nitroolefins on water

(S)-2-((Naphthalen-2-ylsulfonyl)methyl)pyrrolidine, prepared in three steps from (S)-N-Boc-2-[((4-toluenesulfonyl)oxy)methyl]pyrrolidine in 62% overall yield, was used as a new type of organocatalyst bearing a pyrrolidine and a sulfone moiety. It shows very high catalytic activity toward the direct asymmetric Michael reaction of cyclohexanone and nitroolefins. All the corresponding adducts can be furnished in 90-99% yields and with up to 98% ee and over 99:1 dr on water in the presence of this catalyst (15 mol %) without any additive.     

l-Proline derived triamine as a highly stereoselective organocatalyst for asymmetric Michael addition of cyclohexanone to nitroolefins

l-Proline derived triamine 4 has been developed as a highly efficient and stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroolefins. In the presence of (CF₃SO₂)₂NH, 4 catalyzed the reaction of cyclohexanone to a variety of nitroolefins with high yields (up to 99%) and excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to 98% ee).     

Enantioselective Michael addition of cyclic ketones to nitroolefins catalyzed by a novel fluorine-insertion organocatalyst

A novel fluorine-insertion organocatalyst, which was designed based on the fluorine–ammonium ion gauche effect, was synthesized and used successfully to catalyze the asymmetric Michael addition of cyclic ketones to nitroolefins. High yields and excellent diastereo- and enantioselectivities were achieved under mild conditions. A possible stereochemical model is also proposed.     

Polystyrene-immobilized pyrrolidine as a highly stereoselective and recyclable organocatalyst for asymmetric Michael addition of cyclohexanone to nitroolefins

Polystyrene-immobilized pyrrolidine 4 has been developed as a highly efficient, reusable, and stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroolefins. In the presence of trifluoroacetic acid, 4 catalyzed the reaction of cyclohexanone to a variety of nitroolefins with high yields (up to >99%) and excellent diastereoselectivities (up to >99:1 dr), and enantioselectivities (up to >99% ee). Furthermore, 4 could be recovered and recycled by a simple filtration of the reaction solution and used for more than 10 consecutive trials without significant loss of its catalytic activity.     

Highly efficient and enantioselective Michael addition of acetylacetone to nitroolefins catalyzed by chiral bifunctional organocatalyst bearing multiple hydrogen-bonding donors

A new efficient catalyst system for the asymmetric addition of acetylacetone to nitroolefins using a chiral bifunctional organocatalyst bearing multiple hydrogen-bonding donors was developed. When using the organocatalyst 2c derived from natural cinchona alkaloid in optimal conditions, up to 98% chemical yield and 98% ee were observed with a variety of aromatic nitroolefins.     

Highly enantioselective water-compatible organocatalyst for Michael reaction of ketones to nitroolefins

A chiral diamine was found to catalyze enantioselective addition of ketones to nitroolefins in aqueous/saline/organic media. The products were obtained with excellent diastereoselectivities (syn/anti = 99:1) and enantioselectivities up to 99%. The reaction could be facilitated using a mild acid. [reaction: see text]     

Self-assembled proline-amino thioureas as efficient organocatalysts for the asymmetric Michael addition of aldehydes to nitroolefins

A small co-catalyst library of amino thioureas has been established from chiral 1,3-diamines. These bifunctional thioureas can form assemblies with proline to cooperatively catalyze the asymmetric Michael addition of aldehydes to nitroolefins. Both the reaction rate (up to 98% yield for 18 h) and the enantioselectivity (up to 94% ee) were significantly improved upon in less polar solvents.     

Pyrrolidine-thioxotetrahydropyrimidinone as an efficient organocatalyst for the enantioselective Michael addition of cyclic ketones to nitrodienes

Among the various Michael additions, the enantioselective reaction between cyclic ketones and nitrodienes has received little attention in comparison to the corresponding reaction with nitroolefins. A bifunctional organocatalyst consisting of the pyrrolidine moiety and a thioxotetrahydropyrimidinone ring successfully catalyzed this asymmetric transformation. The products of the reaction between various ketones and nitrodienes were obtained in high yields (up to 96%) with excellent diastereo- (up to >98:2 dr) and enantioselectivities (up to 99:1% er).     

Novel chiral ammonium ionic liquids as efficient organocatalysts for asymmetric Michael addition of aldehydes to nitroolefins

Two chiral ammonium ionic liquids 1a and 1b have been newly synthesized from commercially available (+)-cis-2-benzamidocyclohexanecarboxylic acid. These CILs have been demonstrated to be efficient organocatalysts for asymmetric Michael addition of aldehydes to nitroolefins with excellent yields (up to 99%), high enantioselectivities (up to 90%) and modest to high diastereoselectivities (syn/anti ratio up to 99/1).     

A recyclable organocatalyst for asymmetric Michael addition of acetone to nitroolefins

Based on different chiral diamine skeletons, a series of bifunctional primary amine-thiophosphoramides were synthesized and screened as the catalysts for the asymmetric Michael addition of acetone to both aromatic and aliphatic nitroolefins. Under the catalysis of a thiophosphoramide derived from 1,2-diphenylethane-1,2-diamine, the corresponding adducts were obtained in high yields (up to >99%) with excellent enantioselectivities (97-99% ee) under mild reaction conditions. Moreover, the catalyst could be recovered via simple phase separation and reused at least five times without any loss of both catalytic activity and stereocontrol.     

Organocatalytic Michael addition of aldehydes to trisubstituted nitroolefins

The combination of O-TMS protected diphenyl-prolinol and benzoic acid was found to be effective to catalyze the Michael addition of aldehydes to 3-substituted 3-nitroacrylates. The reaction provided syn,anti-Michael adducts with good diastereoselectivity and excellent enantioselectivity. Some β-aryl and α-methyl substituted nitroolefins also worked under these conditions, although prolonging reaction time was required. These adducts could be used for assembling 2,3,4-trisubstituted pyrrolidines through simple hydrogenation.     

Pyrrolidine-linker-camphor assembly: bifunctional organocatalysts for efficient Michael addition of cyclohexanone to nitroolefins under neat conditions

A simple and convenient strategy was developed to synthesize a new class of pyrrolidinyl-camphor based bifunctional organocatalysts possessing varying functional linkers. Catalytic screening of these camphor-pyrrolidine linked derivatives for asymmetric Michael reaction of cyclohexanone with β-nitrostyrene was carried out. Various aryl- and heteroaryl-nitroolefins, ketones as well as aldehydes gave the corresponding Michael adducts in high chemical yields (up to 95%) and exceptionally high diastereo-(syn/anti up to 99:1) and enantioselectivity (up to 95%) using catalyst 6 under solvent-free conditions.     

Novel and highly efficient bifunctional calixarene thiourea derivatives as organocatalysts for enantioselective Michael reaction of nitroolefins with diketones

New bifunctional calixarene thiourea organocatalysts were synthesized and applied in catalytic asymmetric Michael addition of acetylacetone to various nitroolefins at room temperature. The corresponding adducts were obtained in good to excellent yields with excellent enantioselectivities (up to 92% ee). The present research demonstrates the advantages of incorporating two stereocontrolling structures into a single catalyst. Notably, it offers a simple and convenient doubly stereocontrolled approach for the catalytic asymmetric synthesis of a chiral organic molecule.