Michael Addition Research Articles

One-pot synthesis of benzothiazole derivatives using bovine serum albumin and Novozym435

This study presents a one-pot synthesis method involving a Michael acceptor formation via condensation reaction between aldehyde and benzothiazole-2-acetonitrile catalyzed by bovine serum albumin (BSA), followed by a decarboxylative Michael addition reaction using keto esters as nucleophiles and immobilized lipase (Novozym435) as a catalyst. This approach enabled the synthesis of 11 derivatives of 2-(benzo[d]thiazol-2-yl)-5-oxo-3-arylhexanenitrile with yields ranging from 54 % to 91 %.

A One-Pot Cascade Strategy toward Organocatalytic Enantioselective Construction of Fused Benzimidazoles.

Herein, we describe an asymmetric assembly of ortho-aromatic diamines and formyl tethered Michael acceptors forming chiral fused benzimidazoles. A cinchona-alkaloid-derived bifunctional squaramide catalyst enables the methodology through on-site dihydrobenzimidazole formation followed by an aza-Michael addition/oxidation cascade. This protocol stands out for its excellent catalytic efficiency over the background reaction and its mild conditions, making it more practical. Various Michael acceptors, including enones, ester, and thioester, were successful substrates in this study. Additionally, this methodology has demonstrated scalability and successfully showcased postsynthetic transformations.

Monomer-Recyclable Polyester from CO2 and 1,3-Butadiene.

Synthesis of monomer-recyclable polyesters solely from CO2 and bulk olefins holds great potential in significantly reducing CO2 emissions and addressing the issue of plastic pollution. Due to the kinetic disadvantage of direct copolymerization of CO2 and bulk olefins compared to homopolymerization of bulk olefins, considerable research attention has been devoted to synthesis of polyester via the ring-opening polymerization (ROP) of a six-membered disubstituted lactone intermediate, 1,2-ethylidene-6-vinyl-tetrahydro-2H-pyran-2-one (𝜹-L), obtained from telomerization of CO2 and 1,3-butadiene. However, the conjugate olefin on the six-membered ring of 𝜹-L leads to serious Michael addition side reactions. Thus, the selective ROP of 𝜹-L, which can precisely control the repeating unit for the production of polyesters potentially amenable to efficient monomer recycling, remains an unresolved challenge. Herein, the first example of selective ROP of 𝜹-L is reported using a combination of organobase and N,N'-Bis[3,5-bis(trifluoromethyl)phenyl]urea as the catalytic system. Systematic modifications of the substituent of the urea show that the presence of electron-deficient 3,5-bis(trifluoromethyl)-phenyl groups is the key to the extraordinary selectivity of ring opening over Michael addition. Efficient monomer recovery of oligo(𝜹-L) is also achieved under mild catalytic conditions.

Reaction Mechanisms of H2S Oxidation by Naphthoquinones.

1,4-naphthoquinones (NQs) catalytically oxidize H2S to per- and polysufides and sulfoxides, reduce oxygen to superoxide and hydrogen peroxide, and can form NQ-SH adducts through Michael addition. Here, we measured oxygen consumption and used sulfur-specific fluorophores, liquid chromatography tandem mass spectrometry (LC-MS/MS), and UV-Vis spectrometry to examine H2S oxidation by NQs with various substituent groups. In general, the order of H2S oxidization was DCNQ ~ juglone > 1,4-NQ > plumbagin >DMNQ ~ 2-MNQ > menadione, although this order varied somewhat depending on the experimental conditions. DMNQ does not form adducts with GSH or cysteine (Cys), yet it readily oxidizes H2S to polysulfides and sulfoxides. This suggests that H2S oxidation occurs at the carbonyl moiety and not at the quinoid 2 or 3 carbons, although the latter cannot be ruled out. We found little evidence from oxygen consumption studies or LC-MS/MS that NQs directly oxidize H2S2-4, and we propose that apparent reactions of NQs with inorganic polysulfides are due to H2S impurities in the polysulfides or an equilibrium between H2S and H2Sn. Collectively, NQ oxidation of H2S forms a variety of products that include hydropersulfides, hydropolysulfides, sulfenylpolysulfides, sulfite, and thiosulfate, and some of these reactions may proceed until an insoluble S8 colloid is formed.

A Squaramide-Based Organocatalyst as a Novel Versatile Chiral Solvating Agent for Carboxylic Acids.

A squaramide-based organocatalyst for asymmetric Michael reactions has been tested as a chiral solvating agent (CSA) for 26 carboxylic acids and camphorsulfonic acid, encompassing amino acid derivatives, mandelic acid, as well as some of its analogs, propionic acids like profens (ketoprofen and ibuprofen), butanoic acids and others. In many cases remarkably high enantiodifferentiations at 1H, 13C and 19F nuclei were observed. The interaction likely involves a proton transfer from the acidic substrates to the tertiary amine sites of the organocatalyst, thus allowing for pre-solubilization of the organocatalyst (when a chloroform solution of the substrate is employed) or the simultaneous solubilization of both the catalyst and the substrate. DOSY experiments were employed to evaluate whether the catalyst-substrate ionic adduct was a tight one or not. ROESY experiments were employed to investigate the role of the squaramide unit in the adduct formation. A mechanism of interaction was proposed in accordance with the literature data.

Dearomative [2 + 1] Spiroannulation of Bromophenols with Electron-Deficient Alkenes.

A base-assisted dearomative [2 + 1] spiroannulation of p/o-bromophenols with activated olefins (methylenemalonates) to construct various cyclopropyl spirocyclohexadienone skeletons is reported. Furthermore, several other halophenols (X = Cl, I) were also tolerated in this process. Control experiments reveal a dearomative Michael addition of phenols at their halogenated positions to methylenemalonates, followed by intramolecular radical-based SRN1 dehalogenative cyclopropanation. However, according to the density functional theory (DFT) calculations, an SN2 dehalogenative cyclopropanation with the same low activation energy barrier should not be excluded. The utility of this method is showcased by gram-scale syntheses and transformations of the dearomatized products.

2,3-Epoxyamide-alcohols in Domino Reactions: En Route to Molecular Diversity.

The synthesis of polycyclic γ- and δ-lactams bearing up to four contiguous fully controlled stereocenters is presented. For that purpose, we developed an original approach based on the use of 2,3-epoxyamides in domino reactions by taking advantage of the nucleophilic nitrogen atom and electrophilic epoxide. In reaction with enol ethers bearing gem bis-electrophiles on the double bond as Michael acceptors, four different reaction pathways were observed. They all started with a domino oxa-Michael/aza-Michael/epoxide opening sequence and depending on substrates engaged could be followed either by a lactonization or a hemiketalization/retro-aldol cascade. Thus, four original fully-substituted piperidine- or pyrrolidine-2-one scaffolds were selectively synthesized in good to high yields. Moreover, these polycyclic lactams were obtained in high stereo- and chemo-selectively highlighting the efficiency and molecular diversity offered by this new methodology that should offer various synthetic opportunities in the future.

Cover Image, Volume 62, Issue 10

This cover illustrates the curing process of a novel anionic UV‐curable adhesive. The onecomponent adhesive is based on the Michael addition of acetoacetic acid esters and acrylates, using trans‐o‐coumaric acid‐type photobase generators to release organic superbases. After exposing the adhesive on the substrate to UV light, another adherend is attached, allowing for gradual curing at room temperature. The Delayed‐onset UV‐curable system enables bonding of light‐proof adherends. The illustration was provided by Art Action Inc. DOI: 10.1002/pol.20230840 image

Tannic acid-crosslinked gelatin composite microspheres adsorbed with CQAS or Ca2+ for rapid hemostasis

In the case of massive blood loss due to natural disasters and wars, timely and rapid hemostasis is of great significance to improve the survival rate of injured people. Nevertheless, uncontrolled, noncompressible, and irregular bleeding wounds remain a giant challenge for rapid hemostasis. In this study, the tannic acid-crosslinked gelatin was first obtained by Michael addition reaction, and then the tannic acid-crosslinked gelatin composite microspheres (TGMs) were prepared by the emulsion cross-linking method. TGMs could significantly improve the water absorption and hemostatic performance compared with single component gelatin microspheres (GMs). Increasing the water absorption ratio and introducing blood coagulation factors into composite materials are simple and effective strategies to enhance the hemostatic properties. Therefore, chitosan quaternary ammonium salt (CQAS) and Ca2+ were electrostatic adsorbed to obtain two kinds of functional TGMs, which were respectively CQAS-absorbed TGMs (T2GMs-CQAS) and calcium ion-absorbed TGMs (T2GMs-Ca2+). Notably, T2GMs-CQAS, and T2GMs-Ca2+ could absorb water rapidly within 3 seconds, in addition, especially the water absorption ratio of T2GMs-CQAS could reach 2.95 times compared with GMs. Benefited from rapid water absorption, coagulation pathway activation, and red blood cells aggregation of T2GMs-CQAS and T2GMs-Ca2+, resulting in rapid blood coagulation in vitro. In addition, CQAS and Ca2+ provided strong and intrinsic antibacterial activity due to positive charge. Moreover, in the tail amputation and liver hemostatic models, T2GMs-CQAS and T2GMs-Ca2+ demonstrated superior hemostatic effects compared to commercial Yunnan Baiyao®. In conclusion, T2GMs-CQAS and T2GMs-Ca2+ have potential applications as hemostatic dressings in uncontrolled, noncompressible, and irregular bleeding wounds.

New tetrahydro-isoquinoline derivatives as cholinesterase and α-glycosidase inhibitors: Synthesis, characterization, molecular docking & dynamics, ADME prediction, in vitro cytotoxicity and enzyme inhibition studies

In the presented work, it was reported about the synthesis procedure of new isoquinoline derivatives starting from chalcones and acetoacetanilide, a multi-step synthesis pathway yielded four isoquinoline derivatives (5a-d). At the first stage of our research, corresponding cyclohexanone derivatives are synthesized from the Michael addition reaction of chalcones with acetoacetanilide. After that, on the based cyclohexanone derivative was obtained novel isoquinoline derivatives. According to the structures, a plausible reaction mechanism was suggested. The structure of the synthesized compounds was confirmed by NMR spectroscopy method and X-Ray analysis. Additionally, to determine cholinesterase and α-glycosidase inhibition activity compounds 5(a-d) were tested against AChE, BChE and α-Gly as in vitro. In this work, the novel isoquinoline derivatives 5(a-d) demonstrated encouraging inhibitory action against α-glucosidase, as seen by their IC50 values ranging from 9.95 to 19.25 nM. This indicates that they were approximately 1–3 times more active than acarbose (IC50 = 23.07 nM). Also, the molecular docking IFD XP Gscores, dynamics simulations and MM-GBSA ΔG binding free energies of the isoquinoline derivatives on hAChE, hBChE and α-Gly are determined. The molecular dynamics (MD) simulations conducted in this study provided valuable insights into the dynamic behaviors, stabilities, and interaction profiles of ligand–protein complexes involving the R and S isomers of compounds 5c-hAChE, 5c-hBChE, and 5a-αGly. The MD simulations were crucial for understanding the complex stabilities and dynamic mechanisms of the ligand–protein interactions, shedding light on the potential inhibitory roles of these compounds..

Proline-derived carboxylic acid as a bifunctional organocatalyst for highly efficient asymmetric Michael addition of aldehydes to nitroalkenes

A novel bifunctional proline amide–carboxylic acid catalyst was used for the highly stereoselective Michael reaction of various aldehydes with different nitroalkenes. This catalyst was easily prepared using commonly available anhydrides and proline linked with a diamine spacer. The asymmetric catalytic Michael reactions afforded high yields (up to 98 %), diastereoselectivities (syn/anti ratio: up to 86:14), and enantioselectivity (up to 99 % ee) when 5 mol% of the catalyst is used with N-methylmorpholine as a base in a dichloromethane solvent at room temperature.

Programmable, Self-Healable, and Photochromic Liquid Crystal Elastomers Based on Dynamic Hindered Urea Bonds for Biomimetic Flowers.

Recently, researchers have been exploring the use of dynamic covalent bonds (DCBs) in the construction of exchangeable liquid crystal elastomers (LCEs) for biomimetic actuators and devices. However, a significant challenge remains in achieving LCEs with both excellent dynamic properties and superior mechanical strength and stability. In this study, a diacrylate-functionalized monomer containing dynamic hindered urea bonds (DA-HUB) is employed to prepare exchangeable LCEs through a self-catalytic Michael addition reaction. By incorporating DA-HUB, the LCE system benefits from DCBs and hydrogen bonding, leading to materials with high mechanical strength and a range of dynamic properties such as programmability, self-healing, and recyclability. Leveraging these characteristics, bilayer LCE actuators with controlled reversible thermal deformation and outstanding dimensional stability are successfully fabricated using a simple welding method. Moreover, a biomimetic triangular plum, inspired by the blooming of flowers, is created to showcase reversible color and shape changes triggered by light and heat. This innovative approach opens new possibilities for the development of biomimetic and smart actuators and devices with multiple functionalities.

Chain branching during the polycondensation of isophthalic aldehyde and 1,1′‐diacetylferrocene by the Claisen–Schmidt reaction

AbstractN‐methyl‐2‐pyrrolidone‐soluble ferrocene‐containing polychalcones, which are promising as a platform for the formation of ferromagnetic coatings after pyrolysis in an inert atmosphere is synthesized through the polycondensation of isophthalic aldehyde and 1,1′‐diacetylferrocene by the Claisen–Schmidt reaction. The structure and the molecular weight distribution of the polychalcones is characterized by NMR, IR spectroscopy, and size exclusion chromatography. It is shown that the formation of polychalcones is accompanied by chain branching via the Michael reactions and the aldol‐croton condensation. The structure of the linear fragments of the polychalcone chains is simulated with a tailored low‐molecular model compound, that is 1,3‐bis(3‐ferrocenyl‐1‐propen‐2‐one)benzene, which is characterized by the NMR and IR spectroscopy as well as the X‐ray diffraction analysis. The obtained results indicate an increasing tendency for polychalcone chain branching with the temperature growth during the Claisen–Schmidt reaction. The weight loss and the increase in magnetization under the conditions of pyrolysis of polychalcones at different temperatures is studied. The assumptions regarding the possible mechanisms of thermal destruction of ferrocene‐containing macromolecules are put forward.

Reaction of β-Nitrostyrene with Diethyl Malonate in the Presence of Bispidines: The Unusual Role of the Organocatalyst

The aim of this work was the investigation of novel organocatalysts for the Michael addition of diethyl malonate to β-nitrostyrene. The methodology of the study included NMR titration, reaction monitoring by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS), product characterization by MALDI, IR spectroscopy, scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), and elemental analysis. As a result, evidence of supramolecular interactions between two pairs of components of the reaction was found. In addition to the supramolecular complexes, an unusual reaction, i.e., the Michael addition of NH-bispidines to β-nitrostyrene, was found, which led to previously unknown oligomers of β-nitrostyrene. A new mechanism for the catalytic action of NH-bispidine was proposed, which involved catalysis not by the initial organocatalyst but rather by its adduct with β-nitrostyrene. Thus, in this reaction, N-benzylbispidine acted as an initiator, and the real catalyst was the betaine formed during the initiation stage.

Synthesis of Spiro[indoline-pyridine]-dicarboxylates and Substituted Alkylidene Oxindoles by Azomethine Ylides and MBH Carbonates of Isatins.

We have developed an efficient protocol for the synthesis of spiro[indoline-pyridine]dicarboxylates and substituted alkylidene oxindoles through [3 + 3] cycloaddition and Michael addition individually by azomethine ylides and various MBH carbonates of isatins. The selective generation of cyclic products and chain products was achieved by changing the substituents at the 3-position of the oxindoles. The features of this method include convenient catalysts, mild reaction conditions, and broad substrate scopes.

An improved microwave‐assisted facile one‐pot synthesis of novel pyrazolylphosphonates via Knoevenagel‐phospha‐Michael protocol

AbstractIn this study, a highly effective microwave‐assisted method employing a multicomponent domino Knoevenagel/phospha‐Michael reaction has been established. This approach facilitates the synthesis of a novel set of pyrazolylphosphonate derivatives in good yields by combining aryl aldehydes with pyrazolones and trialkylphosphites, utilizing piperidine as a Bronsted base catalyst. All pyrazolylphosphonates have been characterized by means of IR, 1H‐NMR, 13C‐NMR, and HRMS analyses and physical methods. This protocol can be characterized by its eco‐friendly nature, exceptional efficiency in terms of product yields, and short reaction times.

A four-in-one multifunctional self-assembly hydrogel composed of natural drugs for repairing myocardial infarction

To meet the multiple demands of myocardial repair, it would be a novel strategy for myocardial repair if multiple drugs could be constructed into an integrated multifunctional drug formulation. In this study, four drugs with different functions (thioctic acid with antioxidant effects, quercetin with anti-inflammatory and antioxidant effects, arginine with pro-angiogenic effects, and Mn2+ with imaging functions) were selected to construct a four-in-one injectable hydrogel (thioctic acid-arginine-quercetin-Mn2+) through chemical bonding and supramolecular interactions. First, thioctic acid polymerized to a redox-sensitive degradable polymer—poly(thioctic acid) containing disulfide bonds in the main chains through ring-opening polymerization. Quercetin was conjugated to the main chain of the poly(thioctic acid) molecules via thiyl radical-polyphenol Michael addition. Arginine cross-linked the carboxyl groups side chains of the poly(thioctic acid) molecules through hydrogen bonding. Mn2+ further cross-linked the carboxyl groups' side chains of the poly(thioctic acid) molecules through ionic bonding. The hydrogel has antioxidant properties, promotes neovascularization, inhibits inflammatory, improves intracellular Ca2+ overload and mitochondrial dysfunction, protects adenosine triphosphatase (ATPase) activity, and maintains intracellular energy supply, which can reduce the size of myocardial infarcts, and improves cardiac function. This construction method of preparing integrated multifunctional hydrogels from natural drugs will provide a new therapeutic strategy for myocardial repair.

Cu(I)‐Catalyzed Coupling Reactions of β‐Nitrostyrene, 1,3‐Dicarbonyl compound & Aryl amine: An Efficient Method For the Synthesis of Polysubstituted Pyrroles

AbstractA convenient Cu(I) Catalyzed three‐component coupling strategy for the synthesis of polysubstituted pyrroles is developed using simple and readily available building blocks like, 1, 3‐dicarbonyl compound, aryl amine, and β‐nitrostyrene. CuI has been rarely explored for the pyrrole ring synthesis and a comparative analysis of our current catalyst with a range of previously reported catalysts suggested that, CuI is one of the best catalysts for the multicomponent synthesis of polysubstituted pyrrole derivatives. Notably, this process has several advantages, including a simple and practical set‐up with hassle free reaction conditions, extensive substrate scope, short reaction time, high atom economy and environmentally favorable approach. This methodology provides an alternative approach to the highly substituted pyrroles and under optimized reaction conditions, polysubstituted pyrroles were formed in good to excellent yields. Cu(I) catalyzed Mannich reactions followed by Michael addition reactions along with subsequent intramolecular cyclization are believed to be the key steps of this reaction process.

Synthesis and in silico inhibitory action studies of azo-anchored imidazo[4,5-b]indole scaffolds against the COVID-19 main protease (Mpro)

The present work elicits a novel approach to combating COVID-19 by synthesizing a series of azo-anchored 3,4-dihydroimidazo[4,5-b]indole derivatives. The envisaged methodology involves the l-proline-catalyzed condensation of para-amino-functionalized azo benzene, indoline-2,3-dione, and ammonium acetate precursors with pertinent aryl aldehyde derivatives under ultrasonic conditions. The structures of synthesized compounds were corroborated through FT-IR, 1H NMR, 13C NMR, and mass analysis data. Molecular docking studies assessed the inhibitory potential of these compounds against the main protease (Mpro) of SARS-CoV-2. Remarkably, in silico investigations revealed significant inhibitory action surpassing standard drugs such as Remdesivir, Paxlovid, Molnupiravir, Chloroquine, Hydroxychloroquine (HCQ), and (N3), an irreversible Michael acceptor inhibitor. Furthermore, the highly active compound was also screened for cytotoxicity activity against HEK-293 cells and exhibited minimal toxicity across a range of concentrations, affirming its favorable safety profile and potential suitability. The pharmacokinetic properties (ADME) of the synthesized compounds have also been deliberated. This study paves the way for in vitro and in vivo testing of these scaffolds in the ongoing battle against SARS-CoV-2.

Investigations on the Use of Deep Eutectic Solvents (DESs) as Promoters for the Conjugate Addition of α‐Nitroketones to Electron‐Poor Alkenes

AbstractDESs were profitably investigated as solvents and promoters of the conjugate reaction addition of cyclic and acyclic α‐nitroketones to a variety of electron‐poor alkenes. The best results were obtained conducing the reaction in betaine:1,2‐propanediol (1 : 5 molar ratio) DES at room temperature, and enones were demonstrated to be the most effective Michael acceptors. The same reaction conducted by using different molar ratios of the components in this DES showed the eutectic point to be the most effective in terms of the yields observed.