Thiourea Organocatalyst Research Articles

Novel chiral thiourea organocatalysts for the catalytic asymmetric oxaziridination

Catalytic enantioselective oxaziridination is one of the challenging reactions in the oxidation of organic molecules. In this article, a series of novel chiral thiourea moleculars were synthesized from natural cinchona alkaloids and primary amines. By using these molecules as organocatalysts and m-chloroperoxybenzoicacid (m-CPBA) as the oxidant, a methodology on highly enantioselective epoxidation of aldimines has been developed. Several optically active oxaziridines have been constructed in good yields (up to 95%) and moderate to excellent enantioselectivities (up to 99% ee). A plausible transition state was also proposed.

Enantioselective Synthesis of Highly Substituted Chromans via the Oxa-Michael-Michael Cascade Reaction with a Bifunctional Organocatalyst.

A highly enantioselective synthesis of chiral chroman derivatives via an oxa-Michael-Michael cascade reaction has been developed using a bifunctional thiourea organocatalyst. The products were obtained with excellent enantioselectivities (up to >99%), good yields (up to 95%), and diastereoselectivities (up to 5:1).

Iterative Coupling of Two Different Enones by Nitromethane Using Bifunctional Thiourea Organocatalysts. Stereocontrolled Assembly of Cyclic and Acyclic Structures.

An organocatalytic iterative assembly line has been developed in which nitromethane was sequentially coupled with two different enones using a combination of pseudoenantiomeric cinchona-based thiourea catalysts. Application of unsaturated aldehydes and ketones in the second step of the iterative sequence allows the construction of cyclic syn-ketols and acyclic compounds with multiple contiguous stereocenters. The combination of the multifunctional substrates and ambident electrophiles rendered some organocatalytic transformations possible that have not yet been realized in bifunctional noncovalent organocatalysis.

ChemInform Abstract: Enantioselective α‐Amination of 1,3‐Dicarbonyl Compounds in Batch and Flow with Immobilized Thiourea Organocatalysts.

AbstractThe polymer‐supported bifunctional thiourea organocatalyst PSTU is not irreversibly deactivated by the azodicarboxylates (II) used.

ChemInform Abstract: Organocatalytic Asymmetric Addition of Naphthols and Electron‐Rich Phenols to Isatin‐Derived Ketimines: Highly Enantioselective Construction of Tetrasubstituted Stereocenters.

A quinine-derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral 3-amino-2-oxindoles with a quaternary stereocenter in high yields (up to 99 %) with excellent enantioselectivity (up to 99 % ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.

Enantioselective Synthesis of Spiro[1,3‐­indanedione–tetrahydrothiophene]s by ­Organocatalytic Sulfa‐Michael/Michael Domino Reaction

AbstractThe organocatalytic asymmetric domino reaction between 2‐arylidene‐1,3‐indanediones and 4‐mercapto‐2‐butenoates for the construction of chiral spiro[indane‐1,3‐dione–tetrahydrothiophene] skeletons was developed. In the presence of a tertiary amine–thiourea organocatalyst, a series of 2‐arylidene‐1,3‐indanediones reacted with tert‐butyl 4‐mercapto‐2‐butenoate smoothly to furnish chiral spiro heterocycles in good yields (75–99 %) with high enantioselectivities (89–99 % ee) and diastereoselectivities (75.4:24.6 to 97.1:2.9 dr). Notably, functionalized chiral spiro heterocycles were also built in one pot through an aldol condensation/sulfa‐Michael/Michael domino reaction in similarly high yields with high asymmetric induction.

Organocatalytic Enantioselective Synthesis of Polysubstituted Spirooxindoles using a Tandem Michael–Michael Reaction

AbstractA highly efficient stereoselective method for the synthesis of functionalized spirooxindole derivatives with four contiguous stereogenic centers, including two adjacent quaternary stereogenic centers, was realized through an organocatalytic tandem Michael–Michael reaction. By employing a quinidine‐derived thiourea organocatalyst, the reaction between (E)‐2‐cyano‐2‐(2‐oxo‐1‐tritylindolin‐3‐ylidene)acetates and (E)‐1‐alkyl‐6‐nitro‐hex‐2‐en‐1‐ones yields the desired spirooxindole products in good yields (up to 90%) and with excellent stereoselectivities (up to 95:5 dr and 98% ee).magnified image

2-Amino-1,3,5-triazine chemistry: hydrogen-bond networks, Takemoto thiourea catalyst analogs, and olfactory mapping of a sweet-smelling triazine

The chemistry of 4,6-dialkyl-2-amino-1,3,5-triazines with bulky alkyl substituents was investigated and their use as building blocks for preparing chiral thiourea organocatalysts explored. Reaction of ammonia with 4,6-di-tert-butyl-2-chloro-1,3,5-triazine gave 4,6-di-tert-butyl-1,3,5-triazin-2-amine which formed extended hydrogen-bond networks in the solid state according to X-ray crystallography. Selected heterocyclic amines were converted to isothiocyanates, and the latter reacted with (S,S)-2-(dimethylamino)cyclohexylamine to give enantiopure 1-hetaryl-3-[2-(dimethylamino)cyclohexyl]thioureas, with hetaryl representing either 4,6-dimethyl-1,3-diazin-2-yl, 4,6-diisopropyl-1,3,5-triazin-2-yl, or 4,6-di-tert-butyl-1,3,5-triazin-2-yl groups. These compounds are structural analogs of Takemotos’s chiral thiourea organocatalysts (1-[3,5-bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-(dimethylamino)cyclohexyl]thiourea) with an aza-aryl instead of the 3,5-bis(trifluoromethyl)phenyl group. They feature a strong intramolecular N–H to N-1 hydrogen bond, as shown by X-ray crystallography of 1-(4,6-di-tert-butyl-1,3,5-triazin-2-yl)-3-[2-(dimethylamino)cyclohexyl]thiourea in the solid state and by 1H NMR spectroscopy of all derivatives in CDCl3 solution, which prevents them from acting as bifunctional organocatalyst. In the reaction of 4,6-di-tert-butyl-2-chloro-1,3,5-triazine with ammonia, 4,6-di-tert-butyl-2-ethoxy-1,3,5-triazine was identified as side-product displaying a mildly sweet, floral odor that is unusual for a 1,3,5-triazine. Analogs (>35) of 4,6-di-tert-butyl-2-ethoxy-1,3,5-triazine were prepared to define the important structural factors of the olfactophore.

ChemInform Abstract: Enantioselective Assembly of Functionalized Carbocyclic Spirooxindoles Using an L‐Proline Derived Thiourea Organocatalyst.

AbstractMultifunctional spirooxindole scaffolds are synthesized by enantioselective multi‐component reactions involving sequential vinylogous Michael addition and cyclization.

Synthesis and Applications of (-)-(S)-3-Aminoquinuclidine- Derived Thiourea

A synthesis of enantiopure thiourea organocatalyst based on (-)-(S)-3-aminoquinuclidine dihydrochloride was developed with quantitative product yield. The catalyst was tested in different reactions: asymmetric Michael addition of ketones and malonates to nitroalkenes, nitromethane 1,4-addition to trans-chalcone, and Friedel-Crafts alkylation of indoles with trans-β-nitrostyrene. The novel thiourea proved to catalyze the aforementioned reactions and expected products were obtained in mediocre yields and low enantioselectivities.

Diphenylprolinol silyl ether-derived thioureas as highly efficient catalysts for the asymmetric Michael addition of aldehydes to nitroalkenes

This Letter described the synthesis of the first diarylprolinol silyl ether-derived bifunctional thiourea organocatalysts. The catalysts were applied to the asymmetric Michael addition of aldehydes to nitroalkenes to give the desired adducts in good yields (up to 99%) with excellent enantioselectivities (up to 99% ee) and excellent diastereoselectivities (up to 99:1). The spatial placement of C-4 substituent is of importance to the reaction activity and stereoselectivity.

Organocatalytic asymmetric addition of naphthols and electron-rich phenols to isatin-derived ketimines: highly enantioselective construction of tetrasubstituted stereocenters.

A quinine-derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral 3-amino-2-oxindoles with a quaternary stereocenter in high yields (up to 99%) with excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.

Organocatalytic Asymmetric Addition of Naphthols and Electron‐Rich Phenols to Isatin‐Derived Ketimines: Highly Enantioselective Construction of Tetrasubstituted Stereocenters

AbstractA quinine‐derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral 3‐amino‐2‐oxindoles with a quaternary stereocenter in high yields (up to 99 %) with excellent enantioselectivity (up to 99 % ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.

ChemInform Abstract: Organocatalytic Desymmetrization of Cyclic meso‐Anhydrides Through Enantioselective Alcoholysis with Functionalized Primary Nitroallylic Alcohols.

Abstract The direct organocatalytic desymmetrization of cyclic meso-anhydrides was achieved by alcoholysis with nitroallylic alcohols. The reaction between primary nitroallylic alcohols and cyclic meso-anhydrides catalyzed by cinchonidine derived thiourea organocatalyst II (10 mol %) proceeded smoothly. The corresponding hemiesters were obtained in high chemical yields with high to excellent levels of stereoselectivity (up to 90% yield and 99% ee). On the other hand, the reversal of enantioselectivity was observed when an amino cinchonidine derivative (III) was used as the organocatalyst under the similar reaction conditions. This demonstrated an example of activation of the nucelophilic component in the desymmetrization of cyclic meso-anhydrides.

ChemInform Abstract: Recent Advances in Asymmetric Organocatalysis Mediated by Bifunctional Amine—Thioureas Bearing Multiple Hydrogen‐Bonding Donors

AbstractReview: [50 refs.

Enantioselective α-amination of 1,3-dicarbonyl compounds in batch and flow with immobilized thiourea organocatalysts

A PS-immobilized thiourea catalyses the enantioselective α-amination of dicarbonyl compounds at room temperature. It is not deactivated by azodicarboxylate reagents, allowing multiple recycling in batch as well as use in flow (21 min residence time).

Recent advances in asymmetric organocatalysis mediated by bifunctional amine-thioureas bearing multiple hydrogen-bonding donors.

Organocatalysis has proven to be one of the most rapidly developing and competitive research areas in asymmetric catalysis since 2000, and has become a third branch besides biocatalysis and transition metal catalysis. In this feature article, recent progress from our research group on asymmetric organocatalysis, focusing on fine-tunable amine-thiourea catalysis, is described. Design of novel bifunctional amine-thiourea organocatalysts based upon the synergistic activation strategy via multiple hydrogen bonds and their applications in asymmetric C-C, C-N, and C-S bond-forming reactions under mild conditions are discussed in detail. The most attractive feature of the newly designed fine-tunable amine-thiourea catalysts is the incorporation of multiple hydrogen bonding donors and stereogenic centers.

Enantioselective assembly of functionalized carbocyclic spirooxindoles using anl-proline derived thiourea organocatalyst

Enantioselective sequential vinylogous Michael addition–cyclization reactions of vinyl malononitriles with isatylidene malononitrile were accomplished usingl-proline derived bifunctional thiourea.

ChemInform Abstract: New Simple Primary Amine—Thiourea Organocatalysts and Their Application in Asymmetric Conjugate Addition.

Abstract1‐((1R,2R)‐2‐aminocyclohexyl)‐3‐(9H‐fluoren‐9‐yl)thiourea in combination with 4‐methylbenzoic acid as additive catalyzes the reaction of 2‐aryl‐1‐nitroethylenes (I) with acetone (II) to give 4‐aryl‐2‐oxo‐5‐nitropentanes (III) in moderate yields and with good enantioselectivities.

The Novel Activation Model of Multifunction Thiourea Organocatalysts

The novel activation model of multifunction thiourea organocatalysts is examined using density functional theory calculations. The key feature of this model is that the two N-H of thiourea group play different roles in activating substrates, one N-H activates cyclohexenone, and the other N-H and tertiary amine of epiquinine activate the hydroxyl of diphenylphosphine oxide together. More importantly, there is a hydrogen bond between one hydrogen atom in primary amine of catalyst with phenyl ring of diphenylphosphine oxide via a NH-π interaction.