Amine Thiourea Research Articles

Enantioselective Distal Functionalization of 3-Cyano-4-methylcoumarins through Direct Vinylogous Conjugate Addition to Maleimides.

An unprecedented organocatalyzed asymmetric vinylogous Michael reaction between 3-cyano-4-methylcoumarins and maleimides with an excellent enantiomeric ratio (up to 99.5:0.5) and yield (up to 95%) is reported. This remarkable selectivity is attributed to the hydrogen bonding ability of l-tert-leucine-derived amine thiourea catalyst. The versatility, practical applicability, and scalability are demonstrated by the generation of γ-functionalized coumarin derivatives.

Primary amine–thiourea grafted graphene–based heterogeneous chiral catalysts for highly enantioselective Michael additions

Heterogeneous asymmetric catalysis based on earth-abundant carbon materials put together the advantages for the ease of separation, simple regeneration, and high stability of solid catalysts as well as acts as low-cost, environmentally friendly metal-free alternative to the metal-based catalysts. Two new bifunctional carbocatalysts [(S,S) and (R,R) GO-PATU] were prepared by anchoring enantiomerically pure organosilanes bearing primary amine and thiourea groups to the graphene oxide (GO) skeleton covalently via silane coupling reaction. The surface modification of GO was analyzed by a combination of Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron spectroscopy (TEM) techniques. The catalytic performances of graphene-based materials were investigated in the asymmetric Michael addition reactions of α,α-disubstituted-aldehydes to nitrostyrenes and N-substituted-maleimides. The effects of solvents and Brønsted basic or acidic additives were evaluated using both catalysts and good yields (up to 85%) and stereoselectivities (up to 95% ee) were obtained in dichloromethane at room temperature in the presence of l- and d-camphorsulfonic acid. Besides, recycling and reusing studies of the catalysts were successfully performed.

Synthesis of Chiral Tertiary Amine–Thioureas Based on Spirobi­indane and Application in Catalytic Asymmetric Michael Addition Reaction

A series of novel chiral bifunctional tertiary amine–thioureas based on spirobiindane were designed and synthesized as organo­catalysts. One of these catalysts was shown to promote the asymmetric Michael addition reaction of 1,3-diphenylpropane-1,3-dione to nitro­olefins, affording the desired products in good yields (up to 95%) and enantioselectivities (up to 98% ee).

Is the iminium ion mechanism viable in the piperidine-catalyzed 1,4-conjugate addition reaction of nitroalkanes to α,β-unsaturated ketones?

Reactions leading to carbon–carbon bond formation, such as the addition of nitroalkanes to α,β-unsaturated ketones, are very important for organic transformations. In the past 15 years, an asymmetric version using amine–thiourea catalysts has been developed. While tertiary amines work via base catalysis, primary and secondary amines are believed to work through iminium catalysis. In this work, we have investigated theoretically the iminium ion catalysis of a model system: the addition of nitromethane to 4-phenylbut-3-en-2-one catalyzed by piperidine in methanol solution. Our results point out that for this system, the iminium mechanism has a very unfavorable transition state with a free energy barrier of 39 kcal mol−1, involving elimination of the hydroxide ion from the carbinolamine intermediate to form the iminium ion.

Highly enantioselective sequential vinylogous aldol reaction/transesterification of methyl-substituted olefinic butyrolactones with isatins for the construction of chiral spirocyclic oxindole-dihydropyranones.

A highly stereoselective sequential vinylogous aldol reaction/transesterification of methyl-substituted olefinic butyrolactones and isatins was developed. With this developed protocol, a series of chiral spirocyclic oxindole-dihydropyranones were obtained in good to excellent yields (73-99%) and enantioselectivities (71-97% ee).

Solvent-Free Enantioselective Michael Reactions Catalyzed by a Calixarene-Based Primary Amine Thiourea.

An upper-rim functionalized calix[4]arene-based thiourea installed onto the ( R, R)-1,2-cyclohexanediamine scaffold was synthesized with a view to investigate its catalytic ability in enantioselective Michael additions. The reactions were found to conveniently proceed under solvent-free conditions, observing good to high enantioselectivities. From this preliminary study, the calix[4]arene unit is likely to play a role in affecting the conversion and to a lesser extent to the stereochemical outcome of the reactions through van der Waals contacts and C-H···π interactions with the substrates.

13 C Kinetic Isotope Effects as a Quantitative Probe To Distinguish between Enol and Enamine Mechanisms in Aminocatalysis.

A combination of experimental 13 C kinetic isotope effects (KIEs) and high-level density functional theory (DFT) calculations is used to distinguish between "enamine" and "enol" mechanisms in the Michael addition of acetone to trans-β-nitrostyrene catalyzed by Jacobsen's primary amine thiourea catalyst. In light of the recent findings that the widely used 18 O-incorporation probe for these mechanisms is flawed, the results described in this communication demonstrate an alternative probe to distinguish between these pathways. A key advantage of this probe is that quantitative mechanistic information is obtained without modifying experimental conditions. This approach is expected to find application in resolving mechanistic debates, while providing valuable information about the key transition state of organocatalyzed reactions involving the α-functionalization of carbonyls.

Enantioselective 1,3-Dipolar Cycloaddition of Methyleneindolinones with α-Diazomethylphosphonate to Access Chiral Spiro-phosphonylpyrazoline-oxindoles Catalyzed by Tertiary Amine Thiourea and 1,5-Diazabicyclo[4.3.0]non-5-ene

A methodology to access chiral 3,3'-spiro-phosphonylpyrazoline oxindoles via an asymmetric 1,3-dipolar cycloaddition reaction of substituted methyleneindolinones with α-diazomethylphosphonate in the catalysis of tertiary amine thiourea and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) has been established. This method exhibits high functional group compatibility, where a wide range of methyleneindolinones with various substituents and heterocyclic rings are accommodated by this reaction. The resulting chiral 3,3'-spiro-phosphonylpyrazoline oxindoles can be further transformed into spiro-phosphonylcyclopropane oxindoles by ring contraction.

A ratiometric fluorescent probe for hypochlorous acid determination: Excitation and the dual-emission wavelengths at NIR region

An interesting ratiometric fluorescent probe with unique optical performance was reported in this work. By modifying on the bridge-head of heptamethine cyanine chromophore with an N-phenyl-N’-ethylene amine thiourea substituent as a chemodosimetric recognition unit, the probe exhibited ratiometric fluorescent response towards hypochlorous acid (HClO). Upon addition of HClO, the absorbance spectra showed a great red shift as large as 150nm from 650nm to 800nm. Employing the isosbestic absorption point at 730nm as an excitation wavelength, a ratiometric fluorescent sensing mode with two long emission wavelengths at 760nm and 820nm was acquired, and thus the probe displayed significant behavior with both the excitation wavelength and the dual-emission wavelengths located at NIR (650–900nm) region exclusively. Also, the probe showed excellent performance in high sensitivity and good selectivity towards HClO over other reactive oxygen species and a wide variety of coexist species in biological pH condition and had been successfully used to detect hypochlorous acid in serum samples and tap water samples.

Amine Thiourea Catalysed Double Michael Reaction: An Approach for the Asymmetric Synthesis of Spiro[pyrazolone-4,3′-tetrahydrothiophenes

A domino reaction, based on an organocatalysed sulfa-Michael­/Michael sequence, is demonstrated as being useful for the asymmetric synthesis of spiro[pyrazolone-4,3′-tetrahydrothiophenes] bearing three consecutive stereocentres. This new class of spirocyclic compounds has been synthesised in good yield and fairly good diastereo- and enantioselectivity by reacting α,β-unsaturated pyrazolones and <i>tert</i>-butyl (<i>E</i>)-4-mercapto-2-butenoate in the presence of a readily available secondary amine thiourea derived from (<i>R</i>,<i>R</i>)-1,2-diphenylethylenediamine.

Concentration Effect in the Asymmetric Michael Addition of Acetone to β-Nitrostyrenes Catalyzed by Primary Amine Thioureas

Bifunctional primary amine thiourea (PAT) organocatalysts show remarkable improvement in enantioselectivity and catalytic activity (turnover frequency) in the asymmetric Michael addition of acetone to β-nitrostyrenes upon dilution. Mechanistic investigations indicate that this behavior corresponds to the inhibition of off-cycle catalyst deactivation at low concentration, rather than to the operation of aggregation phenomena at high concentration. Reaction at low concentration (≤0.2 M in β-nitrostyrene) leads to the minimization of catalyst deactivation and, thus, to the optimization of yield and ee of the Michael­ addition products.

A Modular Strategy for the Direct Catalytic Asymmetric α-Amination of Carbonyl Compounds

Summary Direct catalytic methods for the stereoselective introduction of various non-protected amines at the carbon atom adjacent to a carbonyl group remain elusive in synthetic chemistry, even though they offer the most straightforward entry to chiral α-aminocarbonyl compounds. Here, we demonstrate that the in situ activation of hydroxylamines with trichloroacetonitrile enables direct transfer of their amine moieties to the C-3 position of oxindoles with rigorous enantiocontrol under the catalysis of chiral 1,2,3-triazolium salts. This protocol provides a powerful and practical means of accessing optically active 3-aminooxindoles with a wide array of alkyl and aryl substituents on nitrogen. Other carbonyl compounds, such as β-ketoesters and α-cyanoesters, can also be directly transformed into the corresponding α-aminocarbonyls with high enantioselectivity.

Enantioselective Nitroso Aldol Intramolecular Transesterification Cyclization Domino Reaction for Highly Effective Construction of Chiral Spirooxindoles

A catalytic asymmetric nitroso aldol intramolecular transesterification cyclization domino reaction between a C3 alkyl ester substituted oxindole and nitrosobenzene for the construction of chiral spirooxindoles was achieved in the presence of a chiral bifunctional tertiary amine thiourea catalyst and water. Optically active spirooxindoles were obtained in moderate yields (up to 76 %) and excellent enantioselectivities (up to 95 % ee).

Dynamic Kinetic Resolution of Biaryl Lactones via a Chiral Bifunctional Amine Thiourea-Catalyzed Highly Atropo-enantioselective Transesterification.

A solution to the unmet synthetic challenge of achieving highly atropo-enantioselective transesterification of Bringmann's lactones has been realized, employing a chiral bifunctional amine thiourea as promoter. The synergistic activation of the lactones and alcohols/phenols by the respective thiourea and amine groups is crucial for achieving the highly enantioselective, high-yielding dynamic kinetic resolution process. This protocol gives highly optically pure, axially chiral biaryl compounds with a broad substrate scope under mild reaction conditions.

Construction of Stereogenic α,α-Disubstituted Cycloalkanones via 1° Amine Thiourea Dual Catalysis: Experimental Scope and Computational Analyses.

The mechanistic exploration and an expanded experimental discussion of the organocatalyzed, asymmetric Pfau-d'Angelo reaction by exploiting a bifunctional 1° amine thiourea catalyst system is disclosed. Notable breadth in substrate scope has been demonstrated on both the cyclic ketone moiety and the α,β-unsaturated electrophile. Exploration into the matched and mismatched selectivity of this process with a ketone containing pre-existing stereocenters has been demonstrated. Computational analyses of the reaction mechanism are reported. In concert with kinetic isotope effect (KIE) experiments, these computational results provide a detailed understanding of the likely mechanism, including the aspects of the organocatalyst scaffold that are critical for stereoselectivity.

Asymmetric Conjugate Addition of Benzofuran‐2‐ones to Alkyl 2‐Phthalimidoacrylates: Modeling Structure–Stereoselectivity Relationships with Steric and Electronic Parameters

A highly predictive model to correlate the steric and electronic parameters of tertiary amine thiourea catalysts with the stereoselectivity of Michael reactions of 3-substituted benzofuranones and alkyl 2-phthalimidoacrylates is described. As predicted, new 3,5-bis(trifluoromethyl)benzyl- and methyl-substituted tertiary amine thioureas turned out to be highly suitable catalysts for this reaction and enabled the synthesis of enantioenriched α-amino acid derivatives with 1,3-nonadjacent stereogenic centers.

Asymmetric Conjugate Addition of Benzofuran‐2‐ones to Alkyl 2‐Phthalimidoacrylates: Modeling Structure–Stereoselectivity Relationships with Steric and Electronic Parameters

AbstractA highly predictive model to correlate the steric and electronic parameters of tertiary amine thiourea catalysts with the stereoselectivity of Michael reactions of 3‐substituted benzofuranones and alkyl 2‐phthalimidoacrylates is described. As predicted, new 3,5‐bis(trifluoromethyl)benzyl‐ and methyl‐substituted tertiary amine thioureas turned out to be highly suitable catalysts for this reaction and enabled the synthesis of enantioenriched α‐amino acid derivatives with 1,3‐nonadjacent stereogenic centers.

Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

An investigation on the stereoselective cascade sulfa-Michael/aldol reaction of nitroalkenes and commercially available 1,4-dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thiourea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-β-methyl-β-nitrostyrenes affording the heterocyclic products in good yields and moderate stereoselectivities.

Calixarene-derived chiral tertiary amine–thiourea organocatalyzed asymmetric Michael additions of acetyl acetone and dimethyl malonate to nitroolefins

Novel bifunctional chiral thiourea-tertiary amines bearing a calix[4]arene scaffold were synthesized and applied in catalytic asymmetric Michael addition of acetyl acetone and dimethyl malonate to nitroolefins. The corresponding adducts were obtained in excellent yields (up to 99%) and with high enantioselectivities (up to 94% ee).

Enantioselective Construction of Aryl‐Substituted All‐Carbon Quaternary Stereocenters by Using Tertiary Amine–Thiourea‐Catalyzed Michael Additions

AbstractA catalytic enantioselective synthetic strategy for the aryl‐substituted all‐carbon quaternary stereocenters of bioactive hydrodibenzofuran alkaloids was achieved by the Michael addition reaction of α‐cyano ketones and acrylates using a chiral tertiary amine–thiourea catalyst. This method can tolerate steric bulkiness and multiple functional groups, and 32 Michael adducts were prepared in good to excellent yields with moderate to good enantioselectivities. The enantiopurity of the products could also be enriched up to 99 % ee after one recrystallization. This enantioselective Michael addition features a low cost, metal‐free, and easily operable procedure that can provide multifunctionalized enantiopure Michael adducts on a four‐gram scale and supply sufficient amounts of potential precursors for a number of hydrodibenzofuran natural products.