Chiral Thiourea Research Articles

Asymmetric aza-Michael additions of 4-nitrophthalimide to nitroalkenes and preliminary study of the products for herbicidal activities

The first application of 4-nitrophthalimide as nitrogen nucleophile for enantioselective aza-Michael addition to nitroalkenes has been developed. The process is promoted by chiral thiourea catalyst derived from cinchonine to give corresponding Michael adducts with up to 87% ee. Activity test showed that some products of the reaction have moderate or good herbicidal activity against cole and barnyard grass at 100 μg/ml.

Stereoselective Organocatalytic Alkylations with Carbenium Ions

Diastereoselective SN1-type reactions have been known for many years and have been used in the synthesis of many natural products. It has recently been shown that chiral nucleophiles, obtained using organocatalytic methodologies, can react with highly reactive carbenium ions in a stereoselective fashion. Based on this, carbenium ions can be applied in asymmetric catalytic reactions. 1 Introduction 1.1 Reaction of Ferrocenyl Alcohols with Lewis Acids 2 Reaction of Alcohols ‘on Water’ 2.1 Stability of Carbenium Ions and the Mayr Scale 3 Organocatalytic Stereoselective SN1-Type Reactions of Aldehydes and Isolated Carbenium Ions 3.1 Attempts at the Related Asymmetric SN1-Type α-Alkylation of Ketones 3.2 Organocatalytic Stereoselective SN1-Type Reactions under Oxidative Conditions 4 Organocatalytic SN1-Type Reactions Involving Lewis Acids 5 Alkylation of Aldehydes Made Simple with the Benzodithiolylium Ion 6 Organocatalytic SN1-Type Reactions Involving Bronsted Acids 7 SN1-Type Reactions Promoted by Chiral Thioureas 8 Conclusion and Perspectives

Asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with β-nitroalkenes catalyzed by chiral bifunctional thioureas

The first asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with nitroolefins catalyzed by chiral bifunctional thioureas was reported and 2,3-dihydrofuro[3,2-c]-coumarin adducts have been obtained in moderate yields (53-75%) and good enantioselectivities (64-90% ee).

Recognition of chiral carboxylates by 1,3-disubstituted thioureas with 1-arylethyl scaffolds

Chiral thioureas with 1-arylethyl and 1-arylethyl-2-2-2-trifluoroethyl (Ar = Ph, 1-Napht, 9-Anthr) scaffolds were used as hosts to recognize acetate and chiral mandelates. The higher binding obtained with the trifluoromethyl analogue is also reflected in the higher selectivity factor for one enantiomer. The C2 symmetry was also indispensable to obtain selectivity.

Chiral thiouronium salts: synthesis, characterisation and application in NMR enantio-discrimination of chiral oxoanions

Chiral thioureas and functionalised chiral thiouronium salts were synthesised starting from the relatively cheap and easily available chiral amines: (S)-methylbenzylamine and rosin-derived (+)-dehydroabietylamine. The introduction of a delocalised positive charge to the thiourea functionality, by an alkylation reaction at the sulfur atom, enables dynamic rotameric processes: hindered rotations about the delocalised CN and CS bonds. Hence, four different rotamers/isomers may be recognised: syn–syn, syn–anti, anti–syn and anti–anti. Extensive 1H and 13C NMR studies have shown that in hydrogen-bond acceptor solvents, such as perdeuteriated dimethyl sulfoxide, the syn–syn conformation is preferable. On the other hand, when using non-polar solvents, such as CDCl3, the mixture of syn–syn and syn–anti isomers is detectable, with an excess of the latter. Apart from this, in the case of S-butyl-N,N′-bis(dehydroabietyl)thiouronium ethanoate in CDCl3, the 1H NMR spectrum revealed that strong bifurcated hydrogen bonding between the anion and the cation causes global rigidity without signs of hindered rotamerism observable on the NMR time scale. This suggested that these new salts might be used as NMR discriminating agents for chiral oxoanions, and are indeed more effective than their archetypal guanidinium analogues or the neutral thioureas. The best results in recognition of a model substrate, mandelate, were obtained with S-butyl-N,N′-bis(dehydroabietyl)thiouronium bistriflamide. It was confirmed that the chiral recognition occurred not only for carboxylates but also for sulfonates and phosphonates. Further 1H NMR studies confirmed a 1 : 1 recognition mode between the chiral agent (host) and the substrate (guest); binding constants were determined by 1H NMR titrations in solutions of DMSO-d6 in CDCl3. It was also found that the anion of the thiouronium salt had a significant influence on the recognition process: anions with poor hydrogen-bond acceptor abilities led to the best discrimination. The presence of host–guest hydrogen bonding was confirmed in the X-ray crystal structure of S-butyl-N,N′-bis(dehydroabietyl)thiouronium bromide and by computational studies (density functional theory).

An asymmetric approach toward chiral multicyclic spirooxindoles from isothiocyanato oxindoles and unsaturated pyrazolones by a chiral tertiary amine thiourea catalyst

The first organocatalytic Michael-cyclization cascade reaction between isothiocyanato oxindoles and unsaturated pyrazolones has been developed. The multicyclic spiro[oxindole/thiobutyrolactam/pyrazolone] core structures containing three contiguous stereogenic centers, including two spiro quaternary centers, were prepared with excellent diastereo- (up to >20 : 1) and enantioselectivities (up to 99% ee).

Highly Efficient Asymmetric Michael Addition Reaction of Malonates to α,β-Unsaturated Ketones Promoted by a Chiral Thiourea/PPY Dual-Catalyst System

The enantioselective Michael addition reaction of malonates to α,β-unsaturated ketones is efficiently promoted by a combined dual-catalyst system composed of chiral thiourea and 4-pyrrolidinopyridine (PPY) in toluene. The expected Michael adducts with cyclic and acyclic enones are obtained in excellent yields and with excellent enantioselectivities.

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis.

For the first time, chiral sulfoximine derivatives have been applied as asymmetric organocatalysts. In combination with a thiourea-type backbone the sulfonimidoyl moiety leads to organocatalysts showing good reactivity in the catalytic desymmetrization of a cyclic meso-anhydride and moderate enantioselectivity in the catalytic asymmetric Biginelli reaction. Straightforward synthetic routes provide the newly designed thiourea-sulfoximine catalysts in high overall yields without affecting the stereohomogeneity of the sulfur-containing core fragment.

Corrigendum: Modular Bifunctional Chiral Thioureas as Versatile Organocatalysts for Highly Enantioselective Aza‐Henry Reaction and Michael Addition

Corrigendum: Modular Bifunctional Chiral Thioureas as Versatile Organocatalysts for Highly Enantioselective Aza‐Henry Reaction and Michael Addition

Enantioselective Friedel–Crafts Alkylation of N‐Methylindoles with Nitroalkenes Catalyzed by Chiral Bifunctional Abietic‐Acid‐Derived Thiourea‐ZnII Complexes

AbstractThe catalytic asymmetric Friedel–Crafts alkylation of N‐methylindoles with nitroalkenes catalyzed by bifunctional abietic‐acid‐derived thiourea‐ZnII complexes was investigated. Various types of the nitroalkylated indoles were synthesized under mild conditions and obtained with excellent yields (up to 99 %) and good enantioselectivities (up to 86 % ee). These chiral thiourea catalysts are easily available from the commercial abietic acid.

ChemInform Abstract: Organocatalytic Enantioselective Michael Addition of a Kojic Acid Derivative to Nitro Olefins.

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Noncovalent Organocatalytic Synthesis of Enantioenriched Terminal Aziridines with a Quaternary Stereogenic Center

A high-yielding and enantioselective access to novel N-Boc terminal aziridines, bearing a quaternary stereogenic center, has been developed via an aza-Michael initiated ring-closure (aza-MIRC) reaction of α-acyl acrylates with an N-tosyloxy tert-butyl carbamate catalyzed by a chiral amino thiourea. The feasibility of the aziridine regioselective ring-opening to valuable α,α-disubstituted α-amino acid esters has been demonstrated.

Modular Bifunctional Chiral Thioureas as Versatile Organocatalysts for Highly Enantioselective Aza‐Henry Reaction and Michael Addition

AbstractA series of new modular bifunctional chiral thiourea organocatalysts were synthesized from natural Cinchona alkaloids and amino acids, and their performance in the aza‐Henry reaction of nitroalkanes to imines, the Michael addition of acetylacetone to nitroolefins and the Michael addition of acetone to nitroolefins was investigated. Under the mild conditions, the important building blocks β‐nitro amines and γ‐nitro carbonyl compounds could be obtained in good yields (up to 95%) with excellent enantioselectivities (up to 99% ee) and diastereoselectivity (up to 17:1).

ChemInform Abstract: Enantioselective Synthesis of Optically Active cis‐β‐Thio‐α‐amino Acid Derivatives Through an Organocatalytic Cascade Thio‐Michael/Ring Opening Process.

Non-naturally enantioenriched cis-β-thio-α-amino acid derivatives were synthesized through one pot, cascade thio-Michael/ring opening reaction of aromatic thiols with (Z)-olefinic azlactones in good yields with high levels of diastereoselectivities and enantioselectivities, which was catalyzed by a chiral bifunctional thiourea–tertiary amine catalyst.

ChemInform Abstract: Activation of 1,2‐Keto Esters with Takemoto′s Catalyst Toward Michael Addition to Nitroalkenes.

AbstractThe use of the chiral thiourea catalyst provides the addition products with < 90% antiselectivity and up to 98% enantioselectivity.

ChemInform Abstract: Enantioselective Organocatalytic Michael Addition of Aliphatic Ketones to Nitrodienes.

Abstract A highly enantioselective Michael addition of aliphatic ketones to nitrodienes has been achieved that is catalyzed by readily available chiral thioureas derived from (1R,2R)-diphenylethane-1,2-diamine. Treatment of ketones with nitrodienes in the presence of 10 mol% thiourea 1a and 10 mol% benzoic acid in toluene provided the desired Michael adducts with excellent enantioselectivities (up to 99% ee) and modest to excellent yields (up to 97%).

ChemInform Abstract: Organocatalytic Enantioselective Pyrazol‐3‐one Addition to Maleimides: Reactivity and Stereochemical Course.

AbstractThe title reaction is catalyzed by a chiral bifunctional thiourea catalyst and affords the addition products in a diastereo‐ and enantioselective manner with up to <82% d.e.

Enantioselective Synthesis of Imidazolines with Quaternary Stereocenters by Organocatalytic Reaction of N-(Heteroarenesulfonyl)imines with Isocyanoacetates

An organocatalytic enantioselective Mannich-type reaction of isocyanoacetate with N-sulfonylimines catalyzed by chiral thioureas derived from quinine yielded 2-imidazolines with high diastereo- and enantioselectivities (up to >99:1 dr. and 96% ee). This reaction provided a convenient route to access various imidazolines and related α,β-diamino acids having a quaternary carbon center in high enantiomeric purities.

Chiral enantiopure bis(thio)ureas derived from TADDOL and their carboxylate complexation capacity

Abstract New chiral enantiopure ureas and thioureas with (R,R)-TADDOL backbone were synthesized. Bis-(thio)ureas with C2 symmetry were obtained from TADDOL iso(thio)cyanates and bifunctional amino-(thio)ureas from TADDAMINE, respectively. These were tested for carboxylate recognition capacity and the association constant was determined for the most stable complex.

ChemInform Abstract: Thiourea‐Catalyzed Enantioselective Fluorination of β‐Keto Esters.

Bifunctional chiral thioureas have been successfully used as organocatalysts in enantioselective fluorinations of β-keto esters. The corresponding products could be obtained with good to excellent enantioselectivity in high yields by using N-fluorobisbenzenesulphonimide (NFSI) as fluorination reagent.