Asymmetric Michael Addition Reaction Research Articles

ChemInform Abstract: Asymmetric Michael Addition Reactions of Nitroalkanes to 2‐Furanones Catalyzed by Bifunctional Thiourea Catalysts.

AbstractHighly functionalized γ‐lactones with two or three consecutive stereogenic carbons are synthesized with diastereoselectivities up to <20:1 dr and enantioselectivities up to <99% e.e.

Optically active helical polymers with pendent thiourea groups: Chiral organocatalyst for asymmetric michael addition reaction

ABSTRACTThis article reports a novel category of helical substituted polyacetylenes bearing pendant thiourea groups and showing remarkable asymmetric catalysis ability. Thiourea‐based monomer and another chiral monomer underwent copolymerization, affording copolymers with considerable optical activity. The copolymers were used as chiral organocatalyst to homogeneously catalyze the asymmetric Michael addition of diethyl malonate to trans‐β‐nitrostyrene. During catalysis, a synergetic effect occurred between the pendant thiourea moieties and the helical structures in the polymer backbones. The enantioselectivity of the reaction was governed by the thiourea moieties. Meanwhile, the concaves along the helices provided specific domains where the substrates and catalytic groups were packed together, leading to a remarkable enhancement of product yield and enantioselectivity. Product with high yield (85%) and satisfactory ee (up to 72%) can be obtained. The present helical polymers open up new opportunities for developing macromolecules as mimetic enzymes catalyzing asymmetric reactions. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 1816–1823

Asymmetric Base‐Free Michael Addition at Room Temperature with Nickel‐Based Bifunctional Amido‐Functionalized N‐Heterocyclic Carbene Catalysts

AbstractA series of nickel‐based chiral bifunctional catalysts (1d–3d) with N‐heterocyclic carbene (NHC) ligands derived from (1R)‐(–)‐menthol, (1S)‐(–)pinene, and (1R)‐(+)‐camphor have been successfully designed for asymmetric Michael addition reactions under base‐free conditions. The NHC complexes, namely, [1‐R‐3‐{N‐(phenylacetamido)}imidazol‐2‐ylidene]2Ni [R = (1S)‐menthyl (1d), (1S)‐pinane (2d), and (1R)‐isobornyl (3d)], bearing chiral ancillaries on the amido‐functionalized side arms of the NHC ligands, performed the bifunctional catalysis of the asymmetric base‐free Michael addition reaction of the α‐methyl cyano ester substrates ethyl 2‐cyanopropanoate (4), isopropyl 2‐cyanopropanoate (5), and tert‐butyl 2‐cyanopropanoate (6) with the activated olefinic substrates methyl vinyl ketone (7) and acrylonitrile (8) in 63–98 % yields with enantiomeric excess (ee) values of 2–75 % at room temperature in 8 h. More interestingly, only the longest of the three catalysts, the menthol derivative 1d, showed significant chiral induction of up to 75 % ee; this has been attributed to the reduction of the steric influence owing to the relatively distant dispositions of the chiral ancillaries from the catalytically active metal center that arise as a consequence of the cis geometries of 1d–3d.

POSS supported diarylprolinol silyl ether as an efficient and recyclable organocatalyst for asymmetric Michael addition reactions

The POSS supported (S)-α,α-diphenylprolinol trimethylsilyl ether catalyst was synthesized and applied in the asymmetric Michael addition reactions of aldehydes and arylnitroalkenes, providing the products in good yields with excellent enantioselectivities and good diastereoselectivities. The POSS supported catalyst can be readily recycled and reused for further transformations at least eight cycles without observing significant decrease in yield and stereoselectivity.

Asymmetric Michael addition reactions of nitroalkanes to 2-furanones catalyzed by bifunctional thiourea catalysts.

The first bifunctional thiourea catalyzed asymmetric Michael addition reactions of nitroalkanes to 2-furanones are described. The highly functionalized γ-lactones with two or three consecutive stereogenic carbons were obtained in high yields (up to 99%), high diastereoselectivities (up to >20 : 1 dr) and enantioselectivities (up to >99% ee).

ChemInform Abstract: Highly Enantioselective Asymmetric Michael Addition Reactions with New Chiral Multisite Phase‐Transfer Catalysts.

AbstractThe synthesis of the catalysts (I) is described.

Amide groups switch selectivity: C-H trifluoromethylation of α,β-unsaturated amides and subsequent asymmetric transformation.

The first direct C-H β-trifluoromethylation of unsubstituted or α-alkyl-substituted α,β-unsaturated carbonyl compounds under metal-free conditions was realized with excellent regio- and stereoselectivity as well as a very broad substrate scope. Both olefinic and allylic trifluoromethylation products are accessible with high selectivities by altering the substrate substitutions. The resultant olefinic products, namely (E)-β-trifluoromethyl (CF3) α,β-unsaturated hydroxamic acid derivatives, served as acceptors in organocatalytic asymmetric Michael addition reactions to give hydroxamic acid derivatives bearing a chiral CF3-substituted stereocenter with high enantioselectivities.

Syntheses of Chiral Ferrocenophanes and Their Application to Asymmetric Catalysis

AbstractN‐Substituted 2‐aza‐[3]‐ferrocenophanes were easily synthesized from 1,1′‐ferrocenedicarbaldehyde and aliphatic amines in high yields. One of the ferrocenophanes served as a ligand for the copper‐catalyzed oxidative coupling of 2‐naphthol derivatives to give the products in good yields with up to 92 % ee, and it also efficiently catalyzed the asymmetric Michael addition reaction as an organocatalyst.

ChemInform Abstract: An Alternative Synthesis of Chiral (S)‐Proline Derivatives that Contain a Thiohydantoin Moiety and Their Application as Organocatalysts in the Asymmetric Michael Addition Reaction under Solvent‐Free Conditions.

A convenient synthetic procedure for the preparation of chiral thiohydantoins derived from natural α-amino acids is reported. Salient features of this method include ready availability of the starting materials, mild reaction conditions, and high yields of the desired products. The prepared thiohydantoins were tested as organocatalysts in asymmetric Michael addition reactions, under solvent-free reaction conditions. Thiohydantoin 10 d turned out to be the most efficient catalyst, and its catalytic activity can be significantly enhanced by the use of an equimolar amount of salicylic acid as additive. Furthermore, highest diastereo- and enantioselectivity is achieved when the reaction is carried out at −5.5 °C, without detriment of the reaction rate. Regarding the reaction’s scope, the asymmetric Michael reaction catalyzed by 10 d was found to maintain its efficiency with various Michael acceptors. Se reporta un procedimiento conveniente para la preparacion de las tiohidantoinas quirales 10 a–f derivadas de α-aminoacidos y conteniendo el segmento de (S)-prolina. Caracteristicas sobresalientes de esta metodologia incluyen la alta disponibilidad de las materias primas, las condiciones de reaccion suaves y los altos rendimientos de los productos deseados. Los compuestos 10 a–f se probaron como organocatalizadores en la reaccion de adicion de Michael asimetrica, bajo condiciones de reaccion sin disolvente. La tiohidantoina 10 d resulto ser el catalizador mas eficiente, y su actividad catalitica mejora significativamente con el uso de una cantidad equimolar de acido salicilico como aditivo. Ademas, se consigue una mayor diastereo- y enantioselectividad cuando la reaccion se lleva a cabo a −5.5 °C, sin detrimento de la velocidad de reaccion. En cuanto al alcance de la reaccion, se encontro que en general la reaccion de Michael asimetrica catalizada por 10 d mantiene su eficacia con varios aceptores de Michael.

ChemInform Abstract: A Chiral Benzoylthiourea—Pyrrolidine Catalyst for the Highly Enantioselective Michael Addition of Ketones to Chalcones.

AbstractThe catalytic asymmetric Michael addition reaction of cyclic ketones with a variety of chalcones is presented.

An amphiphilic organic catalyst for the direct asymmetric Michael addition of cycloketone to nitroolefins in water

A series of amphiphilic proline-derived mercapto imidazole organic catalysts were synthesized and shown to be very effective with an acid cocatalyst for the asymmetric Michael addition reaction of ketones to nitroolefins with high diastereoselectivity (up to 99:1) and execellent enantioselectivity (up to 96%) using water as solvent.

Highly Enantioselective Asymmetric Michael Addition Reactions with New Chiral Multisite Phase-Transfer Catalysts

Highly enantioselective Michael addition reactions of diethyl malonate to various chalcones have been achieved under mild chiral multisite phase-transfer reaction conditions by the successful utilization of 2,4,6-(triscinchoniummethyl)phenyl-1,3,5-triazines as new chiral quaternary ammonium catalysts. This simple asymmetric Michael addition process was found to be quite effective and to obtain Michael adducts with very good yields and enantiomeric excesses.

Organocatalysis with Chiral Ionic Liquids

This mini-review reports an overview of the most promising applications of chiral ionic liquids as organocatalysts for asymmetric reactions such as the asymmetric direct aldol, Michael addition, Diels-Alder and Baylis-Hillman reactions, as well as future perspectives for industrial applications. Recent publications have reported the development of novel chiral ionic liquids and their potential application as unique chiral reaction media or just as alternative chiral organocatalysts. The number of chiral ionic liquids efficiently tested for asymmetric catalysis to date is small but new perspectives can be considered in the future. The peculiar properties of ionic liquids, including chiral ones, combined with the possibility to recycle and reuse them, can be particularly relevant for some catalytic reactions. Keywords: Chiral Ionic Liquids, Organocatalysis, Asymmetric reactions.

An Alternative Synthesis of Chiral (S)‐Proline Derivatives that Contain a Thiohydantoin Moiety and Their Application as Organocatalysts in the Asymmetric Michael Addition Reaction under Solvent‐Free Conditions.

AbstractA convenient synthetic procedure for the preparation of chiral thiohydantoins derived from natural α‐amino acids is reported. Salient features of this method include ready availability of the starting materials, mild reaction conditions, and high yields of the desired products. The prepared thiohydantoins were tested as organocatalysts in asymmetric Michael addition reactions, under solvent‐free reaction conditions. Thiohydantoin 10 d turned out to be the most efficient catalyst, and its catalytic activity can be significantly enhanced by the use of an equimolar amount of salicylic acid as additive. Furthermore, highest diastereo‐ and enantioselectivity is achieved when the reaction is carried out at −5.5 °C, without detriment of the reaction rate. Regarding the reaction’s scope, the asymmetric Michael reaction catalyzed by 10 d was found to maintain its efficiency with various Michael acceptors.

ChemInform Abstract: Recyclable Cinchona Alkaloid Catalyzed Asymmetric Michael Addition Reaction.

AbstractThe applied catalyst can be recovered by fluorous solid‐phase extraction and reused for at least two cycles.

Asymmetric Michael addition of ketones to nitroolefins: pyrrolidinyl-oxazole-carboxamides as new efficient organocatalysts

Chiral pyrrolidinyl-oxazole-carboxamides were synthesized and used as efficient new organocatalysts for the asymmetric Michael addition of ketones with nitroalkenes under solvent-free conditions. Gratifyingly, the corresponding Michael adducts were obtained in higher yields (up to 99%) and excellent stereoselectivities (up to >99/1 dr and 99% ee). Transition state models have been proposed to account for the high enantio- and diastereoselectivity of these Michael addition reactions and also the energetics have been investigated using density functional methods. These results support the preferential formation of syn-products by the approach of trans-β-nitrostyrene through the re-face of anti-enamine.

High Diastereoselectivity Induced by a Fluorous Alkyl Group in the Asymmetric Michael Reaction of Nitroalkenes Catalyzed by a Prolinol Methyl Ether

AbstractThe fluorous prolinol methyl ether was prepared through the perfluorohexylethylation of (S)‐1‐tert‐butyl 2‐methyl pyrrolidine‐1,2‐dicarboxylate using commercially available perfluorohexylethyl iodide, methylation, and deprotection in three steps in 19 % overall yield. In the asymmetric Michael addition reaction of nitrostyrene with propanal, the diastereoselectivity (syn/anti=92:8) with the prepared fluorous prolinol methyl ether was much higher than that (syn/anti=87–80:13–20) with nonfluorinated prolinol methyl ethers that have two n‐octyl groups or two phenyl groups in place of perfluorohexylethyl groups.

Enantioselectivity Investigation of Short Polar Peptides with Different Positions in the Michael Reaction

This work reports the effectiveness of short polar peptides as asymmetric catalysts in Michael reactions to attain good yields of enantio- and diastereoselective isomers. In a comparison, glutamic acid and histidine produced greater ee and yields when they were applied as the second amino acid in short trimeric peptides. These short polar peptides were found to be efficient organocatalysts for the asymmetric Michael addition reaction in water. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file.

Mechanistic study of asymmetric Michael addition of malonates to enones catalyzed by a primary amino acid lithium salt

A mechanistic study was carried out for the asymmetric Michael addition reaction of malonates to enones catalyzed by a primary amino acid lithium salt to elucidate the origin of the asymmetric induction. A primary β-amino acid salt catalyst, O-TBDPS β-homoserine lithium salt, exhibited much higher enantioselectivity than that achieved with the corresponding catalysts derived from α- and γ-amino acids for this reaction. Detailed studies of the transition states with DFT calculations revealed that the lithium cation and carboxylate group of the β-amino acid salt catalyst have important roles in achieving high enantioselectivity in the Michael addition reaction of malonates to enones.

ChemInform Abstract: Organocatalytic Asymmetric Michael Addition of 4‐Hydroxycoumarin to β,γ‐Unsaturated α‐Keto Esters.

The coumarin core is present as a characteristic structural motif in a large number of natural products and biologically active molecules. 1 Particularly, many of these naturally occurring 4-hydroxycoumarin and their synthetic analogues are important precursors for the synthesis of natural products and pharmaceuticals. 2 Enantioselective organocatalytic conjugate addition of 4-hydroxycoumarin to α,β-unsaturated ketones is a straightforward method to access warfarin which is an effective anticoagulants. 3 Although a number of reactions of α,β-unsaturated ketones as Michael acceptors have been reported, 3,4 the corresponding β,γ-unsaturated αketo esters have received relatively little attention as Michael acceptors. Recently, several groups have reported the asymmetric Michael addition of 4-hydroxycoumarin to β,γ-unsaturated α-keto esters catalyzed by Cu(II)-bisoxazoline, N,N'-dioxide-Ni(II) complexes, thiourea catalysts. 5 Although several efficient methods have been achieved by these systems, an effective method for the synthesis of warfarin analogues is still a challenge. In the framework of our research program for the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, 6 we recently reported asymmetric Michael addition reaction of active methylenes and methines using chiral catalysts. 7 Herein, we wish to describe the enantioselective asymmetric conjugate addition of 4-hydroxycoumarin to β,γ-unsaturated α-keto esters promoted by binaphthyl-modified thiourea organocatalyst. We initially investigated a reaction system with 4-hydroxycoumarin (1) with (E)-ethyl 2-oxo-4-phenylbut-3-enoate (2a) in the presence of 10 mol % bifunctional organocatalysts (Fig. 1) at room temperature. As shown in Table 1, Takemoto’s catalyst I and quinine-derived thiourea catalyst II effectively promoted the reaction with moderate enantioselectivities (entry 1-2). While both of binaphthyl-modified (thio)urea catalysts III-IV and squaramide organocatalysts V-VI bearing both central and axial chiralities gave high enantioselectivities (entries 3-6). The best result has been obtained with binaphthyl-modified thiourea catalyst III. We studied the effect of the ester group of (E)-4-phenylbut-3-en2-one 2 using catalyst III in CH2Cl2 (entries 3 and 7). When employing synthetically attractive, methyl ester of (E)-2oxo-4-phenylbut-3-enoate (2b), the corresponding Michael adduct 3b was obtained with high enantioselectivity of 93% ee (entry 7). Among the solvents probed, the best results