Bifunctional Thiourea Research Articles

How Do Substrates Bind to a Bifunctional Thiourea Catalyst? A Vibrational CD Study on Carboxylic Acid Binding

AbstractInvited for the cover of this issue are Nora M. Kreienborg and Christian Merten from Ruhr‐University Bochum. They report a vibrational CD study on substrate binding of a thiourea catalyst during which they have encountered some interesting obstacles. Read the full text of the article at 10.1002/chem.201804230.

How Do Substrates Bind to a Bifunctional Thiourea Catalyst? A Vibrational CD Study on Carboxylic Acid Binding.

Knowledge about the active conformation of an asymmetric catalyst is highly valuable in order to understand its stereoinductive power, but spectroscopic access to these structures is often limited. For the example of Takemoto's bifunctional thiourea, we demonstrate the capability of VCD spectroscopy to characterize the conformational preferences of the catalyst with and without having a reactant bound to it. In particular we show that the binding orientation of carboxylic acids can easily be derived from a computationally guided analysis of the spectra. Moreover, we identify characteristic marker bands, which are only visible in the VCD spectra of the catalyst/acid mixtures but not in the corresponding IR spectra. Lastly, we also discuss the problem that the popular DFT functional M06-2X, which we found to perform exceptionally well in the calculations of vibrational frequencies for fluorinated molecules, predicts incorrect structures of the molecular clusters. We relate this poor performance in predicting the structure of the binding topologies to an overestimation of dispersive CH-π and π-π interactions, which occur due to a neglect of the solvent molecules in the clusters. VCD spectroscopy is thus shown to be a powerful tool to identify and subsequently correct such mispredictions of solution-phase structures.

New Strategy To Access Enantioenriched Cyclohexadienones: Kinetic Resolution of para-Quinols by Organocatalytic Thiol-Michael Addition Reactions.

Existing stereoselective routes to 2,5-cyclohexadienones involve either desymmetrization of an achiral substrate or have attempted to perform an asymmetric dearomatization of a phenol. Herein, we report proof-of-principle experiments aimed at developing a kinetic resolution as an alternative method for accessing enantioenriched 2,5-cyclohexadienones. More specifically, chiral bifunctional thiourea catalysts were used to promote the addition of 2-thionapthalene into unsymmetric para-quinols. The selectivity of the kinetic resolution was found to be quite sensitive to substitution around the substrate.

New bifunctional carbohydrate-like thiourea derivatives – design and first application in organocatalysis

From easily available aminopyran and aminooxepane derivatives and 2,5-bis(trifluoromethyl)phenyl isothiocyanate the corresponding thiourea derivatives were prepared. One compound was further modified by introducing a tertiary amino group. The four catalysts were then examined as catalysts in a Michael addition of acetylacetone to β-nitrostyrene. A 1:1 mixture of one of these thioureas with an (S)-prolinol derivative was also tested as catalyst, but no synergetic effect was found. The best yield achieved was 88% and the highest ee amounted to 39%. In a preliminary experiment, the aldol reaction of acetone with isatin was investigated. One catalyst provided the expected aldol product in low yield, but in excellent enantioselectivity.

Chiral Bifunctional Thioureas and Squaramides and Their Copolymers as Recoverable Organocatalysts. Stereoselective Synthesis of 2-Substituted 4-Amino-3-nitrobenzopyrans and 3-Functionalized 3,4-Diamino-4 H-Chromenes.

Novel styryl-substituted thioureas and squaramides were obtained in three steps from commercially available 4-hydroxy-3,5-dichloroaniline. These organocatalysts promote cascade reactions in high yields and excellent stereoselection. By using only a 5 mol % loading of catalyst, it is possible to obtain 2,3,4-trisubstituted benzopyrans by reaction of α-amido sulfones derived from salicyladehydes and nitrostyrenes or 2,3,4-trisubstituted 4 H-chromenes by reaction of the same α-amido sulfones with (phenylsulfonyl)acetonitrile in excellent diastereo- and enantioselectivities. Two polymeric thioureas and squaramides were prepared by copolymerization of the best monomeric catalysts with styrene and divinylbenzene and used for the same transformations. These polymers behave also as excellent stereoselective catalysts that can be recovered and reused for five cycles.

Highly Enantioselective Michael Addition of Dithiomalonates to Nitroolefins Catalyzed by New Bifunctional Chiral Thioureas

We report a highly efficient asymmetric Michael addition of dithiomalonates to trans-β-nitroolefins catalyzed by versatile cinchona-based bifunctional thioureas, which provides the corresponding adducts in high yields (up to 92%) and with excellent enantioselectivities (up to 99% ee) under mild conditions. Replacement of the catalyst with its pseudo-enantiomer gives the Michael adducts with opposite configuration in similar yields and enantioselectivities.

Asymmetric Reaction of p-Quinone Diimide: Organocatalyzed Michael Addition of α-Cyanoacetates.

Hitherto unknown catalytic enantioselective transformation of p-quinone diimides is achieved using chiral bifunctional organic molecules. Bifunctional thiourea compounds catalyze the Michael addition of cyanoacetates with excellent yields and enantioselectivities. The initially formed Michael adducts undergo cyclization to yield functionally rich, fused cyclic imidines bearing a quaternary benzylic chiral center. Density functional theory calculations of the competing transition states (TSs) were carried out to explain the observed stereochemical outcome.

Diastereo- and enantioselective conjugate addition of 3-substituted oxindoles to enones via bifunctional catalysts

This paper presents a synthetically challenging vicinal quaternary-tertiary C–C forming reaction of 3-substituted oxindoles and chalcones by a simple aryl substituted bifunctional thiourea catalyst. The reactions work with a broad range of chalcones, giving chiral 3,3′-substituted oxindoles type compounds with adjacent quaternary-tertiary stereocenters in high yields (up to 99%), very good dr (up to >98:2) and very good ee (up to 96%).

Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc-Catalyzed Asymmetric Hydrosilylation.

A diastereo- and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc-catalyzed hydrosilylation of the carbonyl group, thus leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid-base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl group. The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N-ligands or appealing axially chiral, bifunctional thiourea organocatalysts.

Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc‐Catalyzed Asymmetric Hydrosilylation

AbstractA diastereo‐ and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc‐catalyzed hydrosilylation of the carbonyl group, thus leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid–base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl group. The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N‐ligands or appealing axially chiral, bifunctional thiourea organocatalysts.

Synthesis and Characterization of Complexes of Some Transition Metals with Two Bifunctional Thiourea Derivatives

Synthesis and Characterization of Complexes of Some Transition Metals with Two Bifunctional Thiourea Derivatives

Asymmetric Organocatalytic Approach to 2,4-Disubstituted 1,2,3-Triazoles by N2-Selective Aza-Michael Addition.

Despite the fact that N1-functionalization of NH-1,2,3-triazoles has been known for several decades, enantioselective variants of this reaction have only recently been developed. Nevertheless, functionalization at the N2-position of NH-1,2,3-triazoles leading to optically active N2-substituted triazoles is not yet developed. In this article, we report, for the first time, the asymmetric aza-Michael reaction of 4-aryl-NH-1,2,3-triazoles to cyclic enones under the catalytic influence of chiral bifunctional thiourea organocatalysts for the enantioselective generation of 2,4-disubstituted 1,2,3-triazoles. The cinchonine-derived thiourea catalyst III worked efficiently in the current transformation to produce N2-functionalized 1,2,3-triazoles as major products in optical yields up to >99.9% along with minor 1,4-disubstitued 1,2,3-triazoles.

Bifunctional Thiourea-Ammonium Salt Catalysts Derived from Cinchona Alkaloids: Cooperative Phase-Transfer Catalysts in the Enantioselective Aza-Henry Reaction of Ketimines.

An efficient enantioselective aza-Henry reaction of aryl α-ketoester-derived ketimines has been realized by using bifunctional thiourea-ammonium salt phase-transfer catalysts, which were derived from quinine. A variety of aryl α-ketoester-derived N-Ts ketimines were investigated, and the corresponding products were obtained in high to excellent yields (up to 99%) with good to high enantioselectivities (up to >99% ee).

Catalytic enantioselective one-pot approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines.

The first enantioselective catalytic approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines has been conveniently developed in a one-pot fashion, starting from α,β-unsaturated acyl pyrazoles and 2-aminothiophenol. The organocatalytic two-step sulfa-Michael/lactamization sequence is promoted by a readily available bifunctional thiourea and p-toluenesulfonic acid, respectively. The protocol enables access to both N-unprotected cis- and trans-diastereoisomers in moderate to satisfactory overall yields (up to 84%) and good to excellent ee values (up to 99%). Mechanistic investigations helped to shed light on the regio- and stereoselective outcome of the process.

Organocatalytic asymmetric synthesis of compounds bearing both isoxazole and pyrazole moieties via 1,6-addition of pyrazol-5-ones to 3-methyl-4-nitro-5-alkenylisoxazoles

Bifunctional thiourea catalyzed 1,6-addition of pyrazol-5-ones to 3-methyl-4-nitro-5-alkenylisoxazoles to provide the desired products in 72–90% yield and 83–94% ee.

Organocatalytic Asymmetric Dimerization of γ‐Hydroxyenones to Acetals and Theoretical Investigations into the Diastereoselection

A method for the organocatalytic, highly enantioselective, and moderately diastereoselective dimerization (redox isomerization/acetal formation) of γ‐hydroxyenones is disclosed. The stereogenic acetal products were obtained via hemiacetal intermediates followed by a cyclization reaction. With bifunctional thiourea catalysts, high yields and excellent enantioselectivities were achieved for a variety of acetal products under mild reaction conditions. In addition, detailed DFT calculations were performed to investigate the mechanism of this reaction, and these calculations suggested that the diastereoselectivity was due to a kinetically controlled process.

Organocatalytic Asymmetric Synthesis of Pentasubstituted Tetrahydrothiopyrans Bearing a Quaternary Centre through a Double Michael Reaction

An organocatalytic, asymmetric, double-Michael strategy has been developed employing trans-α-cyano-α,β-unsaturated ketones for the synthesis of pentasubstituted tetrahydrothiopyrans bearing a quaternary center. A proline-derived bifunctional thiourea was found to be the most effective catalyst for this reaction. With 10 mol% of catalyst, good yields and good to high diastereomeric ratios, as well as excellent enantioselectivities, were obtained with a variety of tetrahydrothiopyrans under mild reaction 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.

Asymmetric Vinylogous Aldol Reaction of α‐ketoesters with 3‐alkylidene oxindoles

AbstractAn efficient enantioselective vinylogous aldol reaction of 3‐alkylidene oxindoles with α‐ketoesters by a bifunctional thiourea catalyst derived from cinchona alkaloid has been disclosed here. The simultaneous H‐bond directing dual activation of vinylogous nucleophile and electrophile afforded high yield (upto 92%) while obtaining excellent stereocontrol (upto 99% ee).magnified image

Multiple Hydrogen-Bonding Bifunctional Thiourea-Catalyzed Asymmetric Dearomative [4 + 2] Annulation of 3-Nitroindoles: Highly Enantioselective Access to Hydrocarbazole Skeletons.

A method for the enantioselective construction of hydrocarbazole skeletons through dearomative [4 + 2] annulation of 3-nitroindoles with Nazarov reagents is reported. The reactions use multiple hydrogen-bonding bifunctional thiourea as catalyst and are highly diastereo- and enantioselective (up to >20:1 dr and >99% ee). The protocol was demonstrated by preparative-scale experiment and the versatile conversion of the products. The multiple hydrogen-bonding in the catalyst plays a pivotal role in the reactivity and stereoselectivity.