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.     

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-based chiral pyridinium ionic liquids (ILs) as recyclable and highly efficient organocatalysts for the asymmetric Michael addition reactions

A novel series of pyrrolidine-based chiral pyridinium ionic liquids (ILs) have been developed by using commercially available (S)-(2-aminomethyl)-1-N-Boc-pyrrolidine. These chiral ILs have been found to be recyclable and efficient organocatalysts for the asymmetric catalytic Michael addition reactions of ketones to nitroolefins with high yields, high enantioselectivies, and diastereoselectivies.     

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.     

Highly enantioselective Michael addition of aldehydes to nitroolefins catalyzed by primary amine thiourea organocatalysts

Asymmetric Michael addition reactions of aldehydes to nitroolefins have been successfully initiated by a series of primary amine thiourea bifunctional catalysts, with high enantioselectivities (90-98% ee) and excellent yields (80-96%). The privileged quinine scaffold was found to be essential to the reaction efficiency and enantioselectivity.     

Chiral amine-thioureas bearing multiple hydrogen bonding donors: highly efficient organocatalysts for asymmetric Michael addition of acetylacetone to nitroolefins

New bifunctional organocatalysts amine-thioureas bearing multiple hydrogen bonding donors were synthesized and applied in catalytic asymmetric Michael addition of acetylacetone to aryl and alkyl nitroolefins. Multiple hydrogen bonding donors play a significant role in accelerating reactions, improving yields and enantioselectivities.     

Chiral squaramide as multiple H-bond donor organocatalysts for the asymmetric Michael addition of 1,3-dicarbonyl compounds to nitroolefins

A series of chiral bifunctional squaramide multiple H-bond donor organocatalysts have been designed and synthesized by the rational assembly of chiral privileged scaffolds of indanol and cinchona alkaloids. In the presence of 1 mol % 1a, the asymmetric Michael addition reaction of 1,3-dicarbonyl compounds to nitroolefins proceeded to provide the product in high yields (up to 92%) and with good to high ee values (up to 96%). The additional H-bond in this squaramide system plays a crucial role in enhancing the enantioselectivity.     

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.     

Asymmetric Michael addition reactions of aldehydes with nitrostyrenes catalyzed by functionalized chiral ionic liquids

A new class of pyrrolidine-based functionalized chiral ionic liquids (FCILs) has been developed and shown to be effective and reusable catalysts for the asymmetric Michael addition reactions. For the Michael addition reaction involving various aldehydes and nitrostyrenes, FCIL 6, in combination with trifluoroacetic acid as an additive, was found to be a very effective catalyst, compared to FCIL 3, which varied slightly in structure. Excellent yields (up to 99%), good enantioselectivities (up to 85% ee), and high diastereoselectivities (syn/anti ratio up to 97:3) were obtained for these reactions. The FCIL catalysts were easily recycled and reused for at least five times without significantly losing their ability to affect the outcome of the asymmetric reactions.     

Michael addition of thiols to alpha-enones in ionic liquids with and without organocatalysts

Seventeen organocatalyts were tested for their ability to catalyst the addition of thiophenols to chalcones in [bmim]PF6. The products were isolated in high yield after a short reaction time, but no stereoselectivity was observed. The reactions also proceeded (without any stereoselectivity) in four other ionic liquids. In contrast, 16% and 26% ee were observed when L-proline and cinchonine, respectively, were used as the catalysts in CH2Cl2. Addition of thiophenols is also catalysed by HCl, as well as D-mandelic and L-tartaric acids. Addition of thiophenols to chalcones also occurred in neat ionic liquids, without any additional catalyst, but the rate of the reaction depended considerably on the structure of ionic liquid. The scope of the non-catalysed reaction in ionic liquids was tested by the reactions of 5 different thiols and 3 different alpha-enones.     

Highly efficient asymmetric Michael addition of aldehydes to nitroalkenes with 4,5-methano-l-proline as organocatalysts

The 4,5-methano-l-prolines were used as chiral organocatalysts in asymmetric Michael addition of aldehydes to nitroolefins. These proline-like catalysts are unique for their rigid bicyclic structure with a cyclopropane and two H atoms attached to the bridgehead C atoms lying on the same side of the ring. They therefore showed high efficiency in asymmetric Michael addition of aldehydes to nitroolefins. Under the optimal conditions, excellent diastereo- and enantioselectivities (up to 97/3 dr and 98% ee) were obtained in high yields for a series of aldehydes and nitroolefins using only 5 mol % catalyst loading. The methodology features easily available catalysts, high catalytic efficiency and environmentally friendly procedures.     

Novel carbohydrate-based bifunctional organocatalysts for nucleophilic addition to nitroolefins and imines

Glucosamine has been selected as a cheap and readily available chiral scaffold for the synthesis of a series of novel enantiomerically pure bifunctional organocatalysts bearing a tertiary amino group in proximity to a (thio)urea group. The catalytic behaviour of these compounds, both as neutral and N-protonated species, was investigated using the addition of acetylacetone to β-nitrostyrene as a model reaction. Under optimized experimental conditions, chemical yields up to 93% and enantioselectivities up to 89% were obtained. Semiempirical (AM1) computational studies allowed to find a theoretical rationale for the chemical and stereochemical behaviour of the catalyst of choice. These catalysts were also preliminarily investigated as promoters in the addition of diethyl malonate to the N-Boc imine of benzaldehyde, affording the product in up to 81% ee.     

A highly efficient asymmetric Michael addition of anthrone to nitroalkenes with cinchona organocatalysts

A highly efficient asymmetric Michael addition of anthrone to nitroalkenes catalyzed by cinchona alkaloids was described. Up to 99% ee of the corresponding adduct was obtained.     

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.     

Asymmetric organocatalyzed Michael addition of aldehydes to β-nitrostyrene in ionic liquids

The addition of aliphatic aldehydes to β-nitrostyrene, catalyzed by proline-derived organocatalysts, proceeded well in various ionic liquids. Products were obtained in high yields and syn/anti diastereoselectivity. However, the enantioselectivity was only mediocre, even though some analogous reactions in organic solvents were highly enantioselective. We also evaluated the temperature effect on the diastereoselectivity as well as on the enantioselectivity of the Michael addition.     

Organocatalytic asymmetric Michael addition of 2,4-pentandione to nitroolefins

[reaction: see text] A novel binaphthyl-derived amine thiourea organocatalyst has been developed and demonstrated to efficiently catalyze Michael addition reactions (using as low as 1 mol % loading) of diketones to nitroalkenes with remarkably high enantioselectivities.