Asymmetric Henry Reaction Research Articles

Selectivity Control in Nitroaldol (Henry) Reaction by Changing the Basic Anion in a Chiral Copper(II) Complex Based on (S)-2-Aminomethylpyrrolidine and 3,5-Di-tert-butylsalicylaldehyde

This article is a continuation of our previous research on the catalytic capability of a chiral copper complex based on commercially available (S)-2-aminomethylpyrrolidine and 3,5-di-tert-butylsalicylaldehyde with various counter-anions in the asymmetric Henry reaction. Our findings indicate that depending on the type of base used, chiral nitroalcohols with yields up to 98% and ee values up to 77%, as well as β-nitrostyrenes with yields up to 88%, can be produced. Additionally, it has been found that the outcome of the reaction and the catalytic properties of copper (II) complexes (S)-Cu1 and (S)-Cu2 are influenced by the structure of the aldehyde used.

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives.

The new chiral ligands I-III based on derivatives of imidazolidin-4-one were synthesised and characterised. The catalytic activity and enantioselectivity of their corresponding copper(II) complexes were studied in asymmetric Henry reactions. It was found that the enantioselectivity of these catalysts is overall very high and depends on the relative configuration of the ligand used; cis-configuration of ligand affords the nitroaldols with major enantiomer S- (up to 97% ee), whereas the application of ligands with trans-configuration led to nitroaldols with major R-enantiomer (up to 96% ee). The "proline-type" ligand IV was also tested in asymmetric aldol reactions. Under the optimised reaction conditions, aldol products with enantioselectivities of up to 91% ee were obtained.

Partially carbonized chiral polymer with Cu-bis(oxazoline) as an efficient heterogeneous catalyst for asymmetric Henry reaction

Through partially carbonizing the condensation polymer CB, the Cu–CB-180 catalyst achieved excellent enantioselectivity and recyclability in heterogeneous asymmetric Henry reaction.

Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags.

The effect of the presence of fluorous tags in bisoxazoline ligands on the stereoselectivity of the cobalt-catalyzed asymmetric Henry reaction was investigated. In contrast to the stereoselectivity obtained with conventional nonfluorous ligands, using bisoxazoline bidentate ligands featuring two fluorous tags in adjacent positions on the aromatic ring yielded a reversed stereoselectivity. The stereoselectivity also reversed when the fluorous tags were replaced with alkyl chains of equivalent length, albeit to a considerably lesser degree, highlighting the effect of the fluorous tags.

Helical polyether-immobilized chiral aza-bis(oxazolines): Synthesis and synergistic effect on the enantioselectivity of Zn-catalyzed Henry reaction

Novel polyether-immobilized aza-bis(oxazolines) ligands derived from optically pure epichlorohydrin and aza(bisoxazolines) were prepared by anionic polymerization. Through chiral optical studies, it is determined that the chiral polyether ligands can maintain stable helical conformation in the solvent, with controllable molecular weights and low polydispersity index of 1.02–1.06. Asymmetric Henry reactions of aldehydes were performed to investigate the relationship between the catalytic activity and the helical conformation of these polyethers, gave the adducts in up to 97 % yield with high enantiomeric excess(98 % ee). In particular, there is a synergistic effect between the helical chirality of the polyether backbone and the point chirality of the pendant aza-bis(oxazolines) in the asymmetric Herny reaction. Helical polyether-immobilized chiral aza-bis(oxazolines) ligands can be easily recycled at least 10 times without losing their enantioselectivity. It was also found by MALDI-TOF-MS that zinc(II) combined with polyether probably result in a double spiral species in the presence of more than 2.5 mol% Zn(OAc)2, which lead to negative effect on catalytic performance of the polyether.

Highly efficient, asymmetric, and organocatalyst-based Henry reactions between α,β-unsaturated trifluoromethyl ketone and nitromethane

An organocatalyst derived from quinine efficiently promoted an asymmetric Henry reaction between α,β -unsaturated trifluoromethyl ketones and nitromethane, resulting in corresponding and highly functionalized products with excellent yields and high enantioselectivities (up to 94% ee).

Hydroxynitrile lyase engineering for promiscuous asymmetric Henry reaction with enhanced conversion, enantioselectivity and catalytic efficiency.

Arabidopsis thaliana hydroxynitrile lyase (AtHNL) engineering has uncovered variants that showed up to 12-fold improved catalytic efficiency than the wild-type towards asymmetric Henry reaction. The AtHNL variants have displayed excellent enantioselectivity, up to >99%, and higher conversion in the synthesis of 13 different (R)-β-nitroalcohols from their corresponding aldehydes. Using cell lysates of Y14M/F179W, we demonstrated a preparative scale synthesis of (R)-1-(4-methoxyphenyl)-2-nitroethanol, a tembamide chiral intermediate, in >99% ee and 52% yield.

Binaphthyl-Proline Hybrid Chiral Ligands: Modular Design, Synthesis, and Enantioswitching in Cu(II)-Catalyzed Enantioselective Henry Reactions.

Chiral O-N-N tridentate ligands were designed from proline and BINOL. Their design strategy and performance were evaluated using a copper(II)-catalyzed asymmetric Henry reaction as a model. The desired β-nitroalcohols were obtained in up to 94% ee's. Preliminary results suggested that the stereofacial selection of the reactions was mainly controlled by the chiral diamine moiety derived from proline, and matching of the central and axial chiralities was essential for the high stereoselectivity of the reaction. Enantioswitching was observed when an appropriate substituent was introduced to the binaphthyl group. Si-selections were found in reactions using 2a without 3-substituents as chiral ligand, and Re-selections were found with the same high enantioselectivities when 2i bearing the 3-trifluoromethyl group was used as the chiral ligand.

Synthesis of Pd-stabilized chiral conjugated microporous polymer composites as high efficiency heterogeneous asymmetric Henry reaction catalysts

Chiral conjugated microporous polymers (CCMPs) containing amide groups were designed and synthesized by Sonogashira coupling polymerization. CCMPs are reported for the first time as heterogeneous asymmetric catalyst platforms for the stabilization of Pd with applications in asymmetric catalytic synthesis. Four Pd/CCMPs heterogeneous catalysts exhibited efficient catalytic activity (of up to 87% yield) and excellent enantioselectivity (of up to 97% enantiomeric excess value) in the asymmetric Henry reaction, with a wide range of substrates and easy recovery. The Pd/CCMPs composites could be easily recycled and maintained catalytic activity after 3 cycles of reactions. A rational catalytic cycle was proposed to further understand the role of Pd/CCMPs in the Henry reaction. This study greatly extends the application of CCMPs in heterogeneous asymmetric catalysis.

Conformationally locked cis-1,2-diaminocyclohexane-based chiral ligands for asymmetric catalysis

An efficient synthesis for a new conformationally locked chiral cis-1,2-diaminocyclohexane scaffold has been developed. The conformational lock allows for convenient symmetrical derivatization of the amino groups through the reductive amination strategy. A series of optically pure chiral ligands based on the cis-DACH scaffold has been generated to demonstrate a proof-of-concept for these ligands as chiral catalysts in the asymmetric Henry reaction. Excellent yields with moderate enantioselectivity were demonstrated at room temperature, with an increase in enantioselectivity at lower temperatures, showing the potential of this new type of cis-DACH ligand.

Asymmetric Henry reaction using a double fluorous-tagged Co–salen complex

A highly stereoselective asymmetric Henry reaction using a double fluorous-tagged Co–salen complex was conducted. The introduction of two fluorous tags into the Co–salen complex was found to be more effective in terms of improving stereoselectivity than the introduction of a strong electron-withdrawing nitro group into the same position of the salen ligand. The observed stereoselectivity was significantly higher than that when using a Jacobsen-type Co–salen complex bearing the same asymmetric source.

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban.

The human drugs – the antibiotic linezolid (1) and the anticoagulant rivaroxaban (2) – belong among modern pharmaceutics, which contain an oxazolidine-2-one moiety bearing a stereogenic center. The chirality of these drugs is a fundamental attribute for their biological activity. Herein, one of the efficient asymmetric syntheses of these drugs was studied in detail. Highly enantioselective catalysts were tested in the key step of the synthetic procedure, i.e., the asymmetric Henry reaction, under different reaction conditions, using several starting aldehydes. The corresponding nitroaldols as chiral intermediates in the syntheses of these drugs were obtained in high yields and enantiomeric excesses of up to 91% ee.

Development of an Improved Route to a Human Immunodeficiency Virus Maturation Inhibitor by Chromium-Free Allylic Oxidation and an Efficient Asymmetric Henry Reaction

Development of an Improved Route to a Human Immunodeficiency Virus Maturation Inhibitor by Chromium-Free Allylic Oxidation and an Efficient Asymmetric Henry Reaction

Asymmetric Henry Reaction of Trifluoromethyl Enones with Nitromethane Using a N,N-Dibenzyl Diaminomethylenemalononitrile Organocatalyst.

A novel N,N-dibenzyl diaminomethylenemalononitrile organocatalyst efficiently promoted asymmetric Henry reactions of trifluoromethyl enones with nitromethane, affording corresponding highly functionalized products in high yields with excellent enantioselectivities (up to 90% ee). This study is the first to report the successful example of the asymmetric 1,2-additions of nitromethane to trifluoromethyl enones.

Cellulose-supported hyper-crosslinked l-tryptophan as an efficient chiral catalyst support for improved catalytic performance

Catalyst supports were modified using a variety of matrices, and cellulose showed the best modification effect, with an enantioselectivity up to 99% in the asymmetric Henry reaction.

Recent advances in catalysts for the Henry reaction

The Henry reaction, the coupling of a nitro alkane and a carbonyl group, is an important C–C bond-forming reaction giving nitro alkanols, which are useful, versatile intermediates in synthetic organic chemistry and for the pharmaceutical industry. Among the catalysts employed in the Henry reaction, transition metal complex catalysts play an important role. Transition metal complexes, including small molecules and nanoparticles, catalyze the asymmetric Henry reaction efficiently and in most of the cases give chiral nitro alkanol products in good yield and enantiomeric excess. This review summarizes transition metal complex catalysts, metal-free organic catalysts and nanoparticle catalysts for the Henry reaction.

Synthesis of Pd-Stabilized Chiral Conjugated Microporous Polymer Composites as High Efficiency Heterogeneous Asymmetric Henry Reaction Catalysts

Synthesis of Pd-Stabilized Chiral Conjugated Microporous Polymer Composites as High Efficiency Heterogeneous Asymmetric Henry Reaction Catalysts

Asymmetric Henry Reaction of Nitromethane with Substituted Aldehydes Catalyzed by Novel In Situ Generated Chiral Bis(β-Amino Alcohol-Cu(OAc)2·H2O Complex

Novel chiral thiophene-2,5-bis(β-amino alcohol) ligands (L1–L5) were designed and synthesized from thiophene-2,5-dicarbaldehyde (3) with chiral β-amino alcohols (4a–e) in 4 steps with overall 23% yields. An in situ generated L-Cu(OAc)2·H2O catalyst system was found to be highly capable catalyst for the asymmetric Henry reaction of nitromethane (7) with various substituted aromatic aldehydes (6a–m) producing chiral nitroaldols product (8a–m) with excellent enantiomeric purity (up to 94.6% ee) and up to >99% chemical yields. 20 mol% of L4-Cu(OAc)2 catalyst complex in EtOH was effective for the asymmetric Henry transformation in 24 h, at ambient temperature. Ease of ligand synthesis, use of green solvent, base free reaction, mild reaction conditions, high yields and excellent enantioselectivity are all key factors that make this catalytic system robust and highly desirable for the access of versatile building block β-nitro alcohol in practical catalytic usage via asymmetric Henry reaction.

Valmet Chiral Schiff‐Base Ligands And Their Copper(II) Complexes as Organo, Homogeneous and Heterogeneous Catalysts for Henry, Cyanosilylation and Aldol Coupling Reactions

AbstractCyanosilylation, aldol coupling and asymmetric Henry reactions were carried out with L‐ and D‐valmet ligands in different configurations: i) coordinated to sodium ions, as organocatalysts, with week base properties, ii) complexes with copper(II), as homogeneous catalysts, and iii) immobilized copper(II) complexes onto graphene oxide (GO) as heterogeneous catalysts. For the reaction of benzaldehyde and nitromethane in water these afforded an asymmetric Henry reaction, with a spectacular increase of the conversion and ee (92.5 and 95.8 %, respectively) after the deposition on GO. Ligand complexed copper was also effective for cyanosilylation and Aldol coupling reaction.

Application of asymmetric Henry reaction by copper(II) complexes containing (R,R)-1,2-diaminocyclohexane with naphthyl and thiophenyl substituents

A series of Cu(II) complexes containing C1-symmetric thiophene derivatives of (1R,2R)-N1-(naphthalen-2-ylmethyl)cyclohexane-1,2-diamine, namely L1, L2 and L3 were synthesized and characterized. These complexes had distorted square-planar geometries around the Cu(II) center. High yield (99%) and excellent enantioselectivity (>99%) for (S)‐1‐nitro‐4‐phenylbutan‐2‐ol from the reaction of 3‐phenylpropanal and nitromethane was obtained using [L1Cu(OAc)2] or [L3Cu(OAc)2] with 10 mol% of diisopropylethylamine (DIPEA) within 24 h. The catalytic systems also demonstrated good activity and moderate to high enantioselectivity for aliphatic aldehydes.