Michael Addition Products Research Articles

Three-component carbonylative Michael addition of aryl bromides using abundant metal-carbonyl under light

Carbonyl compounds are widely found in various chemical reactions and natural products. Herein, a light-driven carbonylative cross-coupling reaction of bromobenzene was reported. Co2(CO)8 was used as an abundant solid carbonyl source to synthesize various Michael addition products with high yields. This reaction has broad substrates scope with good functional group tolerance. The mechanism study indicated that the reaction is achieved by the formation of benzoyl radical from homolytic C–Co cleavage under irradiation.

Solvent solute interaction (IEFPCM model), Michael addition-based anticancer drug synthesis, FTIR, NMR, and UV–visible investigations of spirooxindole-pyranoindole (2AIPC) − in vitro and in silico anti-cancer activity

Herein, click chemistry was chosen to synthesize 2AIPC using Knoevenegel and Michael addition reactions. In this synthesis, Lewis base was attracted by the generation of sp3 hybridized carbanion at active methylene group in the reactants for propagation reaction proceeding towards conducting the Michael addition product. The synthesized 2AIPC was characterized by NMR(13C and 1H), UV, FTR and FT-IR analytical tools; it was also evaluated utilizing density functional theory. According to DFT analyses, the comparative study of the functional groups of 2AIPC molecule was successfully described using Raman and FT-IR spectra with simulated spectra. NLO behaviour and charge exchange utilizing the hyperpolarizability and FMO band gap characteristics were also investigated. Through computational studies using MEP, FUKUI, RDG, and NBO, intermolecular interaction and the reactive area of the synthesized molecule were demonstrated.Moreover, the anticancer activity under the in-vitro analysis was tested, and the molecule showed 61.04 % GI against the K-562 leukemia cells at 10-5 M. Molecular docking also evaluated cytotoxicity by in silico study against leukemia-related proteins (60QN, 6OQC, 1EMR, and 606F). The docked complexes showed binding affinities of −7.82, −7.1, −6.9, and −6.71 kcal/mol. A nucleophile elimination process at 2AIPC’s main amino group may also increase the molecule’s potential to be a more effective lead medication.

Asymmetric Metal‐Templated Approach to Amino Acids with a CF3‐Containing 3,2’‐Pyrrolidinyl Spirooxindole Core via a Michael/Mannich [3+2]‐Cycloaddition Reaction

AbstractWe report here a practical protocol for the asymmetric synthesis of amino acids (AAs) with a CF3‐containing 3,2’‐pyrrolidinyl spirooxindole skeleton with three defined carbon stereocenters via a sequential Michael/Mannich [3+2]‐cycloaddition reaction. The coupling of a robust and stereochemically stable chiral dehydroalanine Ni(II) complex with various N‐2,2,2‐trifluoroethylisatin ketimines in the presence of triethylamine afforded a library of single diastereomeric complexes with a 3,2’‐pyrrolidinyl spirooxindole moiety in 36–71% yields. In particular, the change of base to LiOH allowed to obtain predominantly the Michael addition product in 76% yield. Finally, the decomposition of the obtained Ni(II) complexes with 3 N HCl provided the target complex AA with a 3,2’‐pyrrolidinyl spirooxindole core and (2S,4R)‐2,4‐diamino‐5,5,5‐trifluoropentanoic acid – an (S)‐norvaline derivative, together with easy recovery of the chiral auxiliary ligand for the synthesis of the starting dehydroalanine complex.

Reaction of Nitro‐Substituted Donor‐Acceptor Cyclopropanes with Pyrazoles in DMSO: Unexpected Formation of Tandem Kornblum‐Type Ring‐Opening Oxidation/Aza‐Michael Addition Products

AbstractThe ring‐opening reaction of nitro‐substituted donor‐acceptor cyclopropanes with pyrazoles in DMSO was investigated. Unexpectedly, the cyclopropanes underwent Kornblum‐type ring‐opening oxidation with DMSO to form aroylmethylidene malonates as intermediates in the reactions. The intermediates further underwent aza‐Michael addition with pyrazoles in tandem manner to give the corresponding aza‐Michael adducts. The highlights of the methodology include the occurrence of ring‐opening/oxidation under neutral conditions with DMSO and formation of aza‐Michael adducts with pyrazoles under catalyst‐free conditions.

Temperature affects the kinetics but not the products of the reaction between 4-methylbenzoquinone and lysine

Quinones are electrophilic compounds that can undergo Michael addition or Schiff base reaction with nucleophilic amines, but the effect of temperature has not been systematically studied. The aim of this study was to characterize how temperature affects the reaction mechanism and kinetics of 4-methylbenzoquinone (4MBQ) with lysine (Lys), Nα-acetyl Lys or Nε-acetyl Lys. The products were identified and characterized by LC-MS/MS, which revealed formation of Michael addition products, Schiff base, and a di-adduct in Lys and Nα-acetyl Lys-containing reaction mixtures. The product profiles were not affected by temperature in the range of 15–100 °C. NMR analysis proved that Michael addition of Nα-acetyl Lys occurred on the C5 position of 4MBQ. Rate constants for the reactions studied by stopped-flow UV–vis spectrophotometry under pseudo-first-order conditions where the amines were present in excess in the range 15 °C to 45 °C showed the α-amino groups of Lys are more reactive than the ε-groups. The kinetics results revealed that the temperature dependence of reaction rates followed the Arrhenius law, with activation energies in the order: Lys < Nε-acetyl Lys < Nα-acetyl Lys. Our results provide detailed knowledge about the temperature dependence of the reaction between Lys residues and quinones under conditions relevant for storage of foods.

Enantioselective Conjugate Addition of Boronic Acids to α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Diols.

Herein, we report the enantioselective conjugate addition of organic boronic acids to α,β-unsaturated 2-acyl imidazoles using (R)-3,3'-I2-BINOL as the catalyst. The catalytic system shows high efficiency and tolerance to alkenylboronic acids and heteroarylboronic acids. The corresponding Michael addition products were obtained in moderate to excellent yields and with moderate to excellent enantioselectivities (up to 97% ee). A gram-scale reaction was also conducted, and the desired product was obtained in high yield with no erosion in enantioselectivity. Finally, the synthetic utility of the methodology was demonstrated by transforming the 2-acyl imidazole moiety to the corresponding aldehyde, carboxylic acid, ester, and amide derivatives.

Horseradish peroxidase catalyzed grafting of chitosan oligosaccharide with different flavonols: structures, antioxidant activity and edible coating application.

Enzymatic catalyzed grafting of oligosaccharides with polyphenols is a safe and environmentally friendly approach to simultaneously enhance the bioactivity of oligosaccharides and the solubility of polyphenols. In this study, chitosan oligosaccharide (COS) was grafted with three different flavonols including myricetin (MYR), quercetin (QUE) and kaempferol (KAE) by horseradish peroxidase (HRP) catalysis. The structures, antioxidant activity and edible coating application of COS-flavonol conjugates were investigated. The total phenol content of COS-MYR, COS-QUE and COS-KAE conjugates was 59.89, 68.37 and 53.77 mg gallic acid equivalents g-1 , respectively. Thin layer chromatography showed the conjugates did not contain ungrafted flavonols. COS-flavonol conjugates showed ultraviolet absorption peak at about 294 nm, corresponding to the A-ring of flavonols. Fourier-transform infrared spectra of conjugates confirmed the formation of Schiff-base and Michael-addition products. The proton-nuclear magnetic resonance spectrum of COS-KAE conjugate exhibited phenyl proton signals of KAE. X-ray diffraction patterns of conjugates showed some diffraction peaks of flavonols. COS-flavonol conjugates presented rough and porous morphologies with sheet-like and/or blocky structures. The conjugates showed higher water solubility, free radical scavenging activity and reducing power than flavonols. Moreover, fish gelatin/COS-flavonol conjugate coatings effectively prolonged the shelf life of refrigerated largemouth bass (Micropterus salmoides) fillets from 5 days to 7-8 days. COS-flavonol conjugates prepared by HRP catalysis have great potentials as novel antioxidant agents. © 2022 Society of Chemical Industry.

Solid-state fluorescence of a quasi-isostructural polymorphic biphenyl based Michael addition product

Dimorphic biphenyl based Michael addition product displayed AIE in ethanol–water system and solid state owing to its highly twisted conformation. The quasi-isostructural nature of the two polymorphs resulted in identical photo-physical behaviours.

Organocatalyzed Enantioselective Conjugate Addition of Boronic Acids to β,γ-Unsaturated α-Ketoesters.

We report herein the (R)-3,3'-Br2-BINOL-catalyzed enantioselective conjugate addition of organic boronic acids to β,γ-unsaturated α-ketoesters to generate the corresponding Michael addition products in moderate to high yields and with moderate to excellent enantioselectivities (up to 99% ee). This catalytic system features characteristics of mild reaction conditions, high efficiency, and tolerance to alkenylboronic acids and heteroarylboronic acids.

Domino Reaction for Synthesis of Spiro[pyrazole‐4,5′‐pyrrolo[3,4‐c]carbazoles] and Spiro[pyrrolo[3,4‐c]carbazole‐5,5′‐thiazoles

AbstractThe concentrated hydrochloride catalyzed reaction of 3‐(indol‐3‐yl)maleimides with (E)‐4‐arylidene‐5‐methyl‐2‐phenylpyrazol‐3‐ones in acetonitrile at room temperature afforded unexpected Michael addition product in high yields, which could be easily converted to the cis/trans‐diastereoisomers of spiro[pyrazole‐4,5′‐pyrrolo[3,4‐c]carbazoles] with the nearly 2 : 1 ratios by further oxidation with DDQ. On the other hand, the similar one‐pot two‐step reaction of 3‐(indol‐3‐yl)maleimides with (E)‐5‐arylidene‐2‐phenylthiazol‐4‐one predominately gave cis‐diastereoisomers of spiro[pyrrolo[3,4‐c]carbazole‐5,5′‐thiazoles] in satisfactory yields. The reaction mechanism included domino acid catalyzed Michael addition and DDQ oxidative coupling process

Identification of Potential Drug Targets of Broad-Spectrum Inhibitors with a Michael Acceptor Moiety Using Shotgun Proteomics.

The Michael addition reaction is a spontaneous and quick chemical reaction that is widely applied in various fields. This reaction is performed by conjugating an addition of nucleophiles with α, β-unsaturated carbonyl compounds, resulting in the bond formation of C-N, C-S, C-O, and so on. In the development of molecular materials, the Michael addition is not only used to synthesize chemical compounds but is also involved in the mechanism of drug action. Several covalent drugs that bond via Michael addition are regarded as anticarcinogens and anti-inflammatory drugs. Although drug development is mainly focused on pharmaceutical drug discovery, target-based discovery can provide a different perspective for drug usage. However, considerable time and labor are required to define a molecular target through molecular biological experiments. In this review, we systematically examine the chemical structures of current FDA-approved antiviral drugs for potential Michael addition moieties with α, β-unsaturated carbonyl groups, which may exert an unidentified broad-spectrum inhibitory mechanism to target viral or host factors. We thus propose that profiling the targets of antiviral agents, such as Michael addition products, can be achieved by employing a high-throughput LC-MS approach to comprehensively analyze the interaction between drugs and targets, and the subsequent drug responses in the cellular environment to facilitate drug repurposing and/or identify potential adverse effects, with a particular emphasis on the pros and cons of this shotgun proteomic approach.

Synthesis and Spectral Study of Some New 4-substituted but-2-enolide Derivatives

A variety of some new substituted 4-amino-4-(bromomethyl)butolides (4a-g) have been synthesized by reactions 4-(Bromomethyl)but-2-enolide (2) with some (substituted benzylidene) benzene-1,4-diamine (3a-g) in the presence of absolute ethanol as a solvent to give the Michael addition products, while in the case of its reaction in the presence of pyridine as a solvent and base be added to the β- and - positions to be yield substituted 4-amino-4-(aminomethyl)butolides (5a-g). 4-(Bromomethyl)but-2-enolide (2) is prepared by the reaction 3,3-dimethylacrylic acid and N-bromo succinimide with benzoyl peroxide to give 3,3-Bis(bromomethyl)acrylic acid (1) and then the ring-closure reaction is carried out in basic media. All newly synthesized compounds were confirmed by spectral analysis and the corresponding reactions were monitored by TLC.

Thermo‐responsive block copolymer micelle‐supported (S)‐α,α‐diphenylprolinol trimethylsilyl ether for asymmetric Michael addition of nitroalkenes and aldehydes in water

AbstractAn amphiphilic block copolymer PNIPAM53‐b‐(PS30‐co‐P4AMS10) was facilely prepared by reversible addition‐fragmentation chain transfer (RAFT) polymerization. The immobilization of (S)‐α,α‐diphenylprolinol trimethylsilyl ether onto the block copolymers was then performed through using copper‐catalyzed alkyne‐azide cycloaddition (CuAAC), and the generating amphiphilic diblock copolymer supported chiral catalyst PNIPAM53‐b‐(PS30‐co‐P4AMS10)/proTMS was self‐assembled into micelles with regular diameters about 50 nm in aqueous solution. The micellar catalyst was further used for the asymmetric Michael reaction between propanal and trans‐β‐nitrostyrene in water. Using only 1 mol% micellar catalyst, the corresponding Michael addition products could be obtained in good yields and high enantioselectivities as well as good diastereoselectivities. In addition, this micellar catalyst could be reused at least for four times. Moreover, the micellar catalyst could be applied for the asymmetric addition reaction of 4‐chlorocinnamyl aldehyde and nitromethane, and thus constructing the baclofen pharmaceutical intermediate.

Olefin‐Oriented Selective Synthesis of Linear and Branched N‐Alkylated Heterocycles by Hydroamination

An effective base‐induced selective approach for the synthesis of linear and branched N‐alkylated heterocycles by hydroamination of olefins has been described. The designed C–N bond formation method was directed through the olefin, as with styrenes only linear N‐alkylated product was obtained, and acrylates gave linear as well as branched alkylated heterocycles. This protocol provided the synthesis of exclusive N‐alkylated product instead of the C‐3 Michael addition product. The reaction was also compatible with phenyl vinyl sulfone, thus leading to the formation of sulfone substituted heterocycles in good yield. Further, the method was utilized for the synthesis of medicinally important analogs of CB1 Cannabinoid receptor and Dimebon analogue in short reaction sequence.

Rapid and Reversible Reaction-Based Ratiometric Fluorescent Probe for Imaging of Different Glutathione Levels in Living Cells.

Glutathione (GSH) serves many cellular functions, within the range of 1-10 mM in mammalian cells, abnormal levels of which have been related to many pathological processes. Until now, many researches have been devoted to qualitative sensing of intracellular GSH. However, it is still quite difficult to determine the dynamic GSH levels in living cells. To solve this problem, we designed and synthesized a ratiometric fluorescent probe RP-1 for the detection of different GSH levels based on a reversible Michael addition reaction. The Michael addition product RP-GSH was characterized by ESI-MS. The reversibility and kinetics of the reaction of RP-1 with GSH were studied by spectroscopic methods. According to the concentration dependence of the ratio F405/F488 (F405 and F488 are the fluorescence intensities at 505 and 571 nm when RP-1 in the presence of GSH was excited at 405 and 488 nm, respectively), GSH in the range of 0.1-50 mM could be detected by a very low concentration of 2.5 μM RP-1 in the PBS buffer, indicating that the interference of RP-1 to the biological system in living cell imaging would be minimized. Simultaneously, the dissociation constant (Kd) was obtained as 4.89 mM, suggesting its capability to accurately quantify the GSH concentration in the range of 1-10 mM in cells. Moreover, to improve the cell permeability, we converted RP-1 with a carboxylic acid group into RP-ester with an acetoxymethyl ester group. It is noteworthy that the rapid cell uptake rate of the RP-ester made it very promising because the living cells were efficiently stained with high brightness after incubation with RP-ester for only 1 min. Furthermore, the successful ratio imaging (merged image of 405 channel and 488 channel) of different GSH levels by RP-ester in living cells demonstrated the further development and utilization in the future.

Enantioselective Michael Addition of Aldehydes to β‐Nitrostyrenes Catalyzed by (S)‐N‐(D‐Prolyl)‐1‐triflicamido‐3‐phenylpropan‐2‐amine

A new organocatalyst for the asymmetric Michael addition reaction of aldehydes with β‐nitrostyrenes is developed by coupling D‐proline with (S)‐1‐triflicamido‐3‐phenylpropan‐2‐amine, which in turn is prepared from L‐phenylalaninol. The Michael addition products were obtained in very high yields (up to 93 %) and with excellent enantioselectivity (up to 97 % ee) and high diastereoselectivity (up to &gt;99:1 dr). The catalyst is effective for reactions between α‐branched aldehydes and β‐nitrostyrenes.

Kinetic Resolution of Axially Chiral 2‐Nitrovinyl Biaryls Catalyzed by a Bifunctional Thiophosphinamide

AbstractAn efficient kinetic resolution of axially chiral 2‐nitrovinyl biaryls was realized through organocatalytic asymmetric Michael addition of acetone to the nitroolefin moiety. Under the catalysis of a chiral thiophosphinamide derived from (1R,2R)‐1,2‐diphenylethane‐1,2‐diamine, racemic 2‐nitrovinyl biaryls were converted into highly enantiomer‐enriched 2‐nitrovinyl biaryls in 13–44% yields and a pair of separable Michael addition products bearing both axial and central chiralities in excellent stereocontrol. This represents the first successful application of asymmetric Michael addition of nitroolefins in kinetic resolution of axially chiral biaryls.magnified image

Chiral Hydroxytetraphenylene-Catalyzed Asymmetric Conjugate Addition of Boronic Acids to Enones.

( S)-2,15-Br2-DHTP-catalyzed asymmetric conjugate addition of boronic acids to β-trifluoromethyl α,β-unsaturated ketones and enones was studied. The reaction afforded the corresponding Michael addition products in moderate to high yields with excellent enantioselectivities (up to 99:1 er). This catalytic system features mild reaction conditions, high efficiency, and tolerance to heteroarylboronic acids.

Chiral copper-catalyzed enantioselective Michael difluoromethylation of arylidene meldrum's acids with (difluoromethyl)zinc reagents

The catalytic enantioselective difluoromethylation of arylidene Meldrum's acids with (difluoromethyl)zinc reagent, easily prepared through zinc/iodide exchange reaction of difluoroiodomethane and diethylzinc with co-solvent such as pyridines, by a chiral phosphoramidite-Cu catalyst is shown to provide highly enantioselective sp [3]-difluoromethyl Michael addition product in good yields and high levels of enantioselectivity.

Fe(OTf)3: An Efficient Catalyst for Michael Addition Reactions of Homoaromatic C‐H Nucleophiles with Nitrostyrenes under Microwave Irradiation in Solvent‐Free Condition

AbstractAvailable procedures for Michael addition reaction of homoaromatic C−H nucleophiles (N,N‐dialkylanilines and their cyclic analogues) with nitrostyrenes are observed to be very time consuming (18‐72 h). So, a gentle effort has been made to reduce the time requirement, which is reported herein. Our developed methodology makes use of commercially available Fe(OTf)3 as an efficient catalyst (5 mol%) under microwave irradiation (700 W, 120 °C) and solvent‐free condition and found to be capable of furnishing the Michael adducts in 40–98% yields within 10–20 minutes (19 examples). The regioselectivity of addition of N,N‐dialkylanilines and their cyclic analogues to nitrostyrene derivatives is observed to be exclusively para. The methodology can be extended to the use of cinnamaldehyde as Michael acceptor (2 examples). Three of our Michael addition products are denitrohydrogenated to achieve their corresponding alkylated arenes which paves an effective two‐step synthetic route for p‐alkylated N,N‐dilalkylanilines. Ability to reduce the time requirement by a huge margin (from days to minutes), exclusion of solvent system, exclusive para addition of the homoaromatics to nitrostyrenes are the features of attraction of the developed methodology. The proposed two‐step procedure for regioselective synthesis of p‐alkylated N,N‐dialkylanilines should attract readers’ attention.