aza-Michael Reaction Research Articles

Debondable Epoxy-Acrylate Adhesives using β-Amino Ester Chemistry.

The reuse of multilayered materials, which are held together by structural epoxy adhesives, is a major challenge since the bonded substrates cannot be easily separated for recycling. In this research, we explore a one-pot strategy based on β-amino ester chemistry for the development of modified epoxy adhesives with on-demand debonding potential. For this, a formulation of commercially available acrylate, epoxy and amine compounds is used. The research starts with a systematic study, demonstrating the influence of the different compounds on the thermal and adhesive properties of the materials. Subsequently, the potential for debonding is demonstrated using rheological measurements and tensile tests. The fast, catalyst-free Aza-Michael reaction enables the straightforward preparation of such epoxy-based adhesives, while the reverse reaction allows for debonding at 120 °C. In general, a chemical design is demonstrated for producing an industrially attractive generation of debondable epoxy-based adhesives.

Cobalt(II) catalyzed Michael-type hydroamination of activated olefins

The aza-Michael addition reaction of primary and secondary amines to α,β-unsaturated olefins viz; acrylonitrile, phenyl vinyl sulfone and dimethyl maleate has been carried out using 5–10 mol% Co(NO3)2.6H2O as a catalyst in t-BuOMe at 80–100 °C, giving rise to the desired β-aminocarbonyl compounds or sulfones in moderate to good yields. A wide range of aromatic amines, even those bearing electron withdrawing groups could be added to activated olefins via this strategy. Addition of (hetero)aromatic amines were also feasible, while in case of 2-aminopyridine the reaction was found to be effective only when AgOTf was added along with the catalyst. The aliphatic amines; benzylamine, dibenzylamine, di-n-butylamine were also smoothly added to acrylonitrile and phenyl vinyl sulfone. The methodology describes cobalt(II) nitrate as an eco-friendly, cheap and shelf available catalyst suitable for performing the Michael-type hydroamination reactions.

Non-destructive visual detection of fresh food spoilage

Two coumarin derivatives SWJT-33 and SWJT-34 were synthesized as probes for the detection of cadaverine (Cad). Among them, SWJT-34 exhibits high selectivity and low detection limits for Cad using fluorescence or UV–vis spectrum. The detection limits for Cad were calculated to be 0.018 μM by fluorescence spectrum and 0.34 μM by UV–vis spectrum, which was much lower than those of most of reported probes. The probe could realize colorimetric and ratiometric detection of Cad because an aza-Michael addition reaction occurred between SWJT-34 and Cad to form the Schiff base compound as a product. In addition, SWJT-34 could be fabricated as portable test strips for the selective detection of Cad in vapor, and the corresponding detection limits were calculated to be 1.88 ppm in the fluorescent mode and 57 ppm in UV–vis mode, respectively. Additionally, these test strips could be used to test the freshness of Rottweiler shrimp and pork at different temperatures.

Gold(I)-Catalyzed Rautenstrauch/Hetero-Diels-Alder/Retro-aza-Michael Cascade Reaction for the Synthesis of α-Hydrazineyl-2-cyclopentenones.

A one-pot synthesis of ring-fused, α-hydrazineyl-2-cyclopentenone derivatives is achieved by a gold(I)-catalyzed Rautenstrauch/hetero Diels-Alder/ring opening tandem reaction of suitable propargyl esters. By mixing the latter with a dialkylazodicarboxylate in the presence of a gold(I) catalyst, the 1,2-acyloxy migration/cyclization process (Rautenstrauch reaction) leads to cyclopentadienyl ester intermediates which are trapped by the heterodienophile present in situ. This provides strained intermediates which spontaneously undergo highly regioselective ring opening by a retro aza-Michael reaction promoted by the gold(I) catalyst, eventually yielding the target compounds. Six- and seven-membered ring-fused cyclopentenones bearing a pendant α-hydrazineyl moiety can be obtained in moderate to excellent yield (50-98%) by this approach, with a minimal erosion of the initial optical purity when using enantioenriched substrates.

Synthesis of Azabicyclic Isosteres of Piperazine 2S-Carboxylic Acid.

Methods have been developed for the stereocontrolled synthesis of bicyclic diaza [3.3.0] octane carboxylic acids as possible isosteres of piperazine 2S-carboxylic acid. In the first approach, l-pyroglutamic acid was functionalized adopting new as well as documented reaction sequences via Michael and aza-Michael reactions, leading to two of the four intended isosteres. An alternative shorter route relying on enolate chemistry starting with N-Pf 4-keto l-proline methyl ester led to two other isosteres. Calculated pKa values and density functional theory (DFT) calculations have provided some insights into the relative basicities of the nitrogen atoms in these diaza [3.3.0] octane carboxylic acids in relation to piperazine 2S-carboxylic acid.

Cascade Alkynyl Prins Cyclization and Aza-Michael Reaction: En Route to Regioselective Pyrano- and Isochromenoquinoline Scaffolds.

A metal-free, Lewis acid approach for the regioselective synthesis of dihydropyranoquinoline scaffolds has been unveiled. The methodology employs a cascade alkynyl Prins-aza-Michael reaction sequence to deliver the products in good to excellent yields. The strategy features mild reaction conditions, broad substrate scope, and high functional group tolerance. The protocol has been further extended to include isochromenoquinoline derivatives. The utility of the reaction lies in the synthesis of highly fused polycyclic N,O-heterocycles via intramolecular Heck coupling. Additionally, a Rh(III)-catalyzed annulation results in the formation of highly fluorescent pentacyclic ammonium salts in excellent yields. Photophysical studies reveal that these pentacyclic ammonium salts exhibit strong emission in the green region (500-550 nm).

Design and Evaluation of a Reprocessable Bismaleimide Thermoset: Enhancing Functionality and Sustainability Compatibility.

Bismaleimide (BMI) resins are high-performance thermosets that are primarily used in aerospace because of their exceptional heat resistance and physical properties. However, their growing demand has led to significant environmentally unfriendly waste. To address this, our research proposes a reprocessable BMI system using a newly synthesized BMI vitrimer (BMIV) with functional groups that form covalent adaptable networks (CANs). To enhance the properties, a symmetrical BMI with two ester groups introduced into the rigid rod molecule was designed as a CAN component. After confirming the structure using various spectroscopic techniques, BMIV was coupled with aromatic diamines via an additional aza-Michael reaction to obtain the cured resins. Subsequently, the mechanical properties and reprocessing behavior of the thermally stable and optimized thermosetting material with the best performance were evaluated, and the evidence, mechanism, and activation energy of the topology rearrangement are reported in detail.

Total synthesis of (-)-2-oxo epimesembranol and (+)-dihydromaritidine via a key Johnson-Claisen rearrangement.

A general approach to Sceletium alkaloids of the family Aizoaceace following a key Johnson (orthoester)-Claisen rearrangement of an enantioenriched allylic alcohol has been disclosed. The tricyclic core (1c) of cis-3a-octahydroindoline skeleton was achieved via an ester-aminolysis followed by an intramolecular aza-Michael reaction with amine under elevated temperature. Utilizing aforementioned strategy, a collective total syntheses of Sceletium alkaloids, such as (-)-2-oxo-epimesembranol (1d) [the first total synthesis], (-)-6-epimesembranol (1b), and (-)-mesembrine (1a) were shown. Further this strategy was applied for total synthesis of (+)-dihydromaritidine (2c) sharing [5,11b]-ethanophenanthridine skeleton.

The synthesis of novel unnatural amino acid by intramolecular aza-Michael addition reaction as multitarget enzyme inhibitors.

Synthesis of novel unnatural amino acids (UAAs) from 4-oxo-4-phenylbut-2-enoic acid derivatives with intramolecular aza-Michael addition reaction in the presence of chlorosulfonyl isocyanate (CSI) was reported in soft conditions without any metal catalyst. Acids and base as a catalyst, and solvents effects were investigated for the synthesis of novel UAAs. This novel method provides inexpensive, practicable, and efficient approach to generate UAAs. The use of UAAs has attracted great interest in the development of therapeutic agents and drug discovery to improve their properties. In this context, in addition to the synthesis of new UAAs, their inhibition effects on important metabolic enzymes of acetylcholinesterase (AChE) and carbonic anhydrases I and II (hCA I and II) enzymes were investigated. The compound 2g showed the best inhibition for CA I and AChE enzymes, while compound 2i exhibited the best inhibition profile against CA II isoenzyme. The inhibition values of these compounds were found as 1.85 ± 0.64 for AChE, 0.53 ± 0.07 for hCA I, 0.44 ± 0.15 µM for hCA II, respectively, and they showed a stronger inhibitory property than acetazolamide (standard inhibitor for hCA I and II) and tacrine (standard inhibitor for AChE) molecules. The activity of the studied molecule against different proteins that are hCA I (PDB ID: 2CAB), hCA II (PDB ID: 5AML), and AChE (PDB ID: 1OCE) was examined. Finally, the drug properties of the studied molecule were examined by performing absorption, distribution, metabolism, excretion, and toxicity analysis.

(Invited) Design of Reduced Shear Force Cu Cleaning Processes Via α-β-Unsaturated Chemistries for Enhanced BTA Residue Removal

As integrated circuit and logic devices continue to decrease, limiting induced defectivity during Chemical Mechanical Planarization (CMP) processes (polishing and substrate cleaning) is imperative. Defects resulting from the CMP process can be classified as mechanical (i.e., scratching), chemical (i.e., corrosion), or physiochemical (i.e., adsorbed contaminants) according to the mechanism of formation. Traditionally, a contact cleaning method implements a polyvinyl alcohol (PVA) brush to transfer cleaning chemistry to the substrate of interest and provides the necessary mechanical energy for defect removal. While this process effectively removes contaminants, its reliance on shear forces can induce secondary defect modes, such as scratching. One major challenge for the post-CMP cleaning of Cu substrates is the polymeric residue film comprised of BTA-Cu+ complexes that propagate during the CMP polishing process. The current and most effective mode to mitigate this “residue defect” is coupling brush-induced shear force with additives that promote interfacial redox reactions to remove residues through an undercutting mechanism. This work focuses on developing a “softer” and additive structure-based approach that drives less aggressive interfacial shear between the brush and wafer substrate. More specifically, α-β-unsaturated additives with diverse functionality (i.e., -unsaturated carboxylic acids, carboxylic acids, and unsaturated benzaldehydes) will be tested to evaluate their efficacy to “overcut” the organic residue via a proposed aza-Michael addition reaction pathway. This “overcutting” mechanism relies on additional modes of interaction (i.e., p-stacking, H-bonding, conformational relationships, etc.) with the BTA- Cu+ polymeric residue film. A suite of dynamic techniques (i.e., Tafel analysis, OCP vs. time, contact angle, additive diffusion analysis, and shear force) will attempt to correlate the additive structure and reaction mechanism to organic residue removal efficiency and measured interfacial shear forces. Initial results have shown that implementing an “overcutting” mechanism will decrease the overall shear force and significantly reduce the generation of secondary defects without sacrificing overall defect removal efficiency.

Lewis Acid Mediated Synthesis of 4-Aminoquinoline Derivatives from 2-Aminobenzonitriles and Activated Alkynes via Aza-Michael and Annulation Reactions

AbstractAn efficient methodology for the synthesis of highly diverse 4-aminoquinoline derivatives from activated alkynes and 2-aminobenzonitriles mediated by Lewis acid is described. The reaction proceeds via sequential aza-Michael addition/intramolecular annulation to afford highly substituted 4-aminoquinolines in good yields. The reaction is operationally simple and has high atom-economy with broad substrate scope. The post synthetic application of the reaction provides 4H-benzo[de][1,6]naphthyridines.

Abstract We012: Sheet like extracellular matrix secreting single cell microvesicles for reprogrammed endothelial cell therapy towards vascular regeneration

To enhance cell survival and engraftment for cell therapy, cell encapsulated injectable biomaterials have been widely used. However, the challenges were hypoxia and nutrient shortage in the core, inflammatory cell infiltration and limited distribution of cells from injection sites. Encapsulation of single cells in sub-100-micron microgels with higher surface to volume ratios provides more efficient oxygen and mass exchange. However, typical production of single-cell-laden microgels by microfluidics devices results in cell damage and compromised biological properties. We hypothesized that stimuli responsive amphiphilic copolymer bearing RGD peptides may self-assemble around single cells induced by cell adhesion moieties would result in single cell microvesicles (MV). A stimuli responsive amphiphilic copolymer GPM (Gelatin Poly glycerol sebacate Methacrylate) was synthesized by grafting hydrophobic synthetic polymer PGS into hydrophilic natural polymer gelatin via methacrylation followed by aza-Michael addition reaction. Single cell microvesicles of endothelial cells (EC-MVs) were fabricated by self-assembly of GPM at room temperature. For in vivo studies, sub-50-micron EC-MVs made of reprogrammed endothelial cells (rECs) were clustered into 200 micron spheres (mGPM) using sodium alginate and injected into a hindlimb ischemia model to investigate cell survival and biological function. The mGPM microspheres functioned as a barrier from immune cell infiltration and also enhanced cellular distribution. The encapsulated rECs were released over 2-4 wks in vivo and were shown robust engraftment, migration, and survival in limb tissues, promoting blood flow recovery and sustained vascular regeneration over 6 months. Interestingly, in in vitro culture, rEC-MVs secreted sheet like extra cellular matrix (ECM) which appeared to make an important role for vessel formation (neovascularization) in vivo (Figure 1). The current study clearly demonstrated the favorable biological applicability of GPM single cell MVs toward vascular regeneration by reprogrammed ECs.

Hypervalent Chalcogen Bonds Catalysis on the Intramolecular Aza-Michael Reaction of Aminochalcone: Catalytic Performance and Chalcogen Bond Properties.

Chalcogen bond (ChB) catalysis, as a new type in the field of non-covalent bond catalysis, has become a hot research topic in the field of organocatalysis in recent years. In the present work, we investigated the catalytic performance of a series of hypervalent ChB catalysis based on the intramolecular Aza-Michael reaction of aminochalcone. The reaction includes the carbon-nitrogen bond coupling step (key step) and the proton transfer step. The catalytic performance of mono-dentate pentafluorophenyl chalcogen bond donor ChB1 was comparable to that of bis-dentate chalcogen bond donor ChB4, and stronger than that of mono-dentate chalcogen bond donors ChB2 and ChB3. The formation of the chalcogen bond between the catalyst and the carbonyl oxygen atom of the reactant, causing the charge rearrangement of the reactant and C(1) charge of the -C-Ph group to become more positive, thereby the ChB catalysis promoted the nucleophile reaction. The electron density of the chalcogen bond of the pre-complex, the most positive electrostatic potentials of the catalyst, and the NPA charge of the key atom are proportional to the Gibbs energy barrier of the C-N bond coupling process, which provides an idea to predict the catalytic activity of the ChB catalysis.

Bio-based non-isocyanate poly(urea)-PEG hybrids for VOC-free waterborne dispersions and fast UV-curable film application

Poly(urethane)-acrylate hybrids are often used to yield high-performing fast UV-curable coatings thanks to their highly reactive acrylate moieties. However, they are usually manufactured from toxic and petro-based isocyanate (e.g. isophorone diisocyanate, hexamethylene diisocyanate) monomers and are dispersed in water using toxic volatile neutralization agent (e.g. triethylamine). To tackle those issues, hydrophobic and bio-based non-isocyanate poly(urea) (NIPUrea) blocks have been synthesized and coupled with hydrophilic poly(ethylene glycol) diacrylate (PEGdA) via aza-Michael reaction to yield VOC-free non-ionic waterborne NIPUrea-acrylate dispersions. Those amphiphilic NIPUrea-PEG hybrids enabled the development of low particle-size waterborne dispersions for fast UV curable films (curing time < 1 min) with high gel content (>98 %) and tunable mechanical properties.

Identification of Dihydropyrazolo[1,5-a]pyrazin-4(5H)-ones as Cyclic Products of β-Amidomethyl Vinyl Sulfone Alphavirus Cysteine Protease Inhibitors.

Optimized syntheses of (E)-5-(2-ethoxyphenyl)-N-(3-(methylsulfonyl)allyl)-1H-pyrazole-3-carboxamide (RA-0002034, 1), a promising antiviral covalent cysteine protease inhibitor lead, were developed. The syntheses avoid the contamination of 1 with the inactive cyclic dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 2, which is formed by the intramolecular aza-Michael reaction of the vinyl sulfone warhead under basic conditions and slowly at pH 7.4 in phosphate buffer. The pure cysteine protease inhibitor 1 could be synthesized using either modified amide coupling conditions or through the introduction of a MOM-protecting group and was stable as a TFA or HCl salt. Although acyclic 1 demonstrated poor pharmacokinetics with high in vivo clearance in mice, inactive cyclic 2 showed improved plasma exposure. The potential use of cyclic dihydropyrazolo[1,5-a]pyrazin-4(5H)-ones as prodrugs for the acyclic β-amidomethyl vinyl sulfone warhead was demonstrated by GSH capture experiments with an analog of 2.

Energetic Nitrate-Based Polymer-Bonded Explosives Derived from Sustainable Aza-Michael Reactions.

A novel nontoxic method for processing energetic binder, namely, polyglycidyl nitrate (PGN), using Aza-Michael reactions for deriving high-performance explosive formulations is being reported. The polyol binders used in polymer-bonded explosives (PBX) including PGN are usually cross-linked using isocyanate leading to polyurethane (PU)-based cured solid networks. These reactions require mild reaction conditions and yield good mechanical properties for the PBX but remain challenging due to extraneous reactions of isocyanate resulting in defects in the cured blocks. In addition, the presence of nitrato groups in the vicinity of terminal hydroxyl groups of PGN results in the decuring of cross-linked urethane that affects the storage life of PBX, though PGN-based binder can provide an 18% improvement in the velocity of detonation of PBX at lower solid loadings of 70%. This prevents researchers from exploiting the major performance advantage of using PGN for PBX compositions. This article herein features a green and mild aza-Michael reaction for functional modification of PGN using readily available substrates and triethylene tetramine to form a cross-linked β-aminocarbonyl network. The methodology ensures a void-free, stable, cured network and offers an effective replacement for toxic cure chemistry currently employed for processing of PBX.

Ruthenium(II)-Catalyzed Sequential C-H/N-H Alkene Annulation Cascade of Phenanthroimidazoles: Synthesis and Photophysical Studies.

We report ruthenium(II)-catalyzed sequential C-H/N-H alkenylation cascade of phenanthroimidazole and alkenes to form novel phenanthroimidazoisoindol acrylates via dual C-H activation and aza-Michael reaction. The two nitrogen atoms of the imidazole ring act as directing groups for regioselective dual sequential ortho C-H activation. These polycyclic N-heterocycles were evaluated for their photophysical properties.

Deciphering the Microdroplet Acceleration Factors of Aza-Michael Addition Reactions.

Microdroplet chemistry is emerging as a great tool for accelerating reactions by several orders of magnitude. Several unique properties such as extreme pHs, interfacial electric fields (IEFs), and partial solvation have been reported to be responsible for the acceleration; however, which factor plays the key role remains elusive. Here, we performed quantum chemical calculations to explore the underlying mechanisms of an aza-Michael addition reaction between methylamine and acrylamide. We showed that the acceleration in methanol microdroplets results from the cumulative effects of several factors. The acidic surface of the microdroplet plays a dominating role, leading to a decrease of ∼9 kcal/mol in the activation barrier. We speculated that the dissociation of both methanol and trace water contributes to the surface acidity. An IEF of 0.1 V/Å can further decrease the barrier by ∼2 kcal/mol. Partial solvation has a negligible effect on lowering the activation barrier in microdroplets but can increase the collision frequency between reactants. With acidity revealed to be the major accelerating factor for methanol droplets, reactions on water microdroplets should have even higher rates because water is more acidic. Both theoretically and experimentally, we confirmed that water microdroplets significantly accelerate the aza-Michael reaction, achieving an acceleration factor that exceeds 107. This work elucidates the multifactorial influences on the microdroplet acceleration mechanism, and with such detailed mechanistic investigations, we anticipate that microdroplet chemistry will be an avenue rich in opportunities in the realm of green synthesis.

Fully Biobased Self-Healing and Recyclable Covalent Adaptable Networks Prepared via a Catalyst-Free Aza-Michael Reaction

Fully Biobased Self-Healing and Recyclable Covalent Adaptable Networks Prepared via a Catalyst-Free Aza-Michael Reaction

Fabrication of gelatin-polyester based biocomposite scaffold via one-step functionalization of melt electrowritten polymer blends in aqueous phase

The rapid manufacturing of biocomposite scaffold made of saturated-Poly(ε-caprolactone) (PCL) and unsaturated Polyester (PE) blends with gelatin and modified gelatin (NCO-Gel) is demonstrated. Polyester blend-based scaffold are fabricated with and without applying potential in the melt electrowriting system. Notably, the applied potential induces phase separation between PCL and PE and drives the formation of PE rich spots at the interface of electrowritten fibers. The objective of the current study is to control the phase separation between saturated and unsaturated polyesters occurring in the melt electro-writing process and utilization of this phenomenon to improve efficiency of biofunctionalization at the interface of scaffold via Aza-Michael addition reaction. Electron-deficient triple bonds of PE spots on the fibers exhibit good potential for the biofunctionalization via the aza-Michael addition reaction. PE spots are found to be pronounced in which blend compositions are PCL-PE as 90:10 and 75:25 %. The biofunctionalization of scaffold is monitored through CN bond formation appeared at 400 eV via X-ray photoelectron spectroscopy (XPS) and XPS chemical mapping. The described biofunctionalization methodology suggest avoiding use of multi-step chemical modification on additive manufacturing products and thereby rapid prototyping of functional polymer blend based scaffolds with enhanced biocompatibility and preserved mechanical properties. Additionally one-step additive manufacturing method eliminates side effects of toxic solvents and long modification steps during scaffold fabrication.