aza-Michael Addition Reaction Research Articles

Polyamidoamine Dendrimer Microgels: Hierarchical Arrangement of Dendrimers into Micrometer Domains with Expanded Structural Features for Programmable Drug Delivery and Release.

In this paper, we report on the fabrication of micron-sized dendrimer hydrogels (μDHs) using the water-in-oil (w/o) inverse microemulsion method coupled with the highly efficient aza-Michael addition. EDA core polyamidoamine (PAMAM) dendrimer G5 (10 w%) and polyethylene glycol diacrylate (PEG-DA, M n = 575 g/mol) (the molar ratio of amine/acrylate = 1/1) were dissolved in the water phase and added to hexane in the presence of surfactants span 80/tween 80 (5/1, w/w) (volume ratio of hexane to surfactants: 70:1) to form w/o microemulsions, in which PAMAM G5 cross-links with PEG-DA via the aza-Michael addition reaction. The resulting microgels are within 3-5 μm with relatively narrow size distribution. μDHs are pH-responsive degradable. They show good cytocompatibility and do not cause acute toxicity in vivo. Furthermore, they can realize a high loading of the hydrophobic drug CPT and enter the cells in the form of particles. The CPT and CPT/dendrimer complex can be slowly released following the zero-order release kinetics. Taken together, μDHs possessing hierarchically ordered dendrimers in micron domains represent a new class of microparticles with expanded structural features for programmable drug delivery and release.

Superelastic and pH-Responsive Degradable Dendrimer Cryogels Prepared by Cryo-aza-Michael Addition Reaction

Dendrimers exhibit super atomistic features by virtue of their well-defined discrete quantized nanoscale structures. Here, we show that hyperbranched amine-terminated polyamidoamine (PAMAM) dendrimer G4.0 reacts with linear polyethylene glycol (PEG) diacrylate (575 g/mol) via the aza-Michael addition reaction at a subzero temperature (−20 °C), namely cryo-aza-Michael addition, to form a macroporous superelastic network, i.e., dendrimer cryogel. Dendrimer cryogels exhibit biologically relevant Young’s modulus, high compression elasticity and super resilience at ambient temperature. Furthermore, the dendrimer cryogels exhibit excellent rebound performance and do not show significant stress relaxation under cyclic deformation over a wide temperature range (−80 to 100 °C). The obtained dendrimer cryogels are stable at acidic pH but degrade quickly at physiological pH through self-triggered degradation. Taken together, dendrimer cryogels represent a new class of scaffolds with properties suitable for biomedical applications.

Catalyst-Free One-Pot Synthesis of Chromeno-Imidazo-Pyridinones by an Aza-Michael Addition/Rearrangement/Heterocyclization Tandem Reaction

A one-pot synthesis of a novel series of chromeno-imidazo-pyridinone derivatives from 3-[(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl]chromones and ethane-1,2-diamine at room temperature under catalyst-free conditions has been successfully developed. This approach involves a tandem aza-Michael addition reaction, a chromone-to-chromanone rearrangement, and a heterocyclization sequence, leading to chromeno-imidazo-pyridinone polyheterocycles. The structure and absolute configurations of the new compounds were elucidated by a combination of 1D- and 2D-NMR analyses and single-crystal X-ray diffraction.

Ethylenediamine Grafting to Functionalized NH2–UiO-66 Using Green Aza-Michael Addition Reaction to Improve CO2/CH4 Adsorption Selectivity

Three versions of zirconium-based metal organic frameworks, NH2–UiO-66, GMA-UiO-66, and EDA-UiO-66, were synthesized and employed as adsorbent for CO2/CH4 separation. GMA-UiO-66 was synthesized via a ring opening reaction between the amine species in the framework and epoxy groups in glycidyl methacrylate (GMA), while the green aza-Michael addition reaction was used for the first time to functionalize GMA-UiO-66 with ethylenediamine (EDA). The products were characterized by BET, XRD, TGA, FESEM, ICP-OES, 1H NMR, mass spectroscopy, and FTIR-ATR methods to monitor their textural properties before and after functionalization. The results indicated that GMA was successfully grafted to the NH2–UiO-66 framework, and most of the alkene groups were grafted with EDA, which indicated that the Michael addition reaction was very effective. The experimental gas adsorption results indicated that the EDA-grafted UiO-66 possessed the highest CO2 adsorption capacity as well as CO2/CH4 selectivity due to the introduction o...

1-[1-(4-Chlorobenzenesulfonyl)-1H-indole-3-yl]-3-[4-(pyridin-2-yl)piperazin-1-yl]propan-1-one

The title compound was prepared by an aza-Michael addition reaction between 1-[1-(4-chlorobenzenesulfonyl)-1H-indole-3-yl]prop-2-en-1-one and 2-piridylpiperazine catalyzed by SiO2. The structural identity of the title compound was proven by elemental analysis and spectroscopic methods (IR, NMR). The compound was assayed in a binding assay at the 5-HT6 receptor, showing poor affinity.

High-Performing Biodegradable Waterborne Polyester/Functionalized Graphene Oxide Nanocomposites as an Eco-Friendly Material.

The development of high-performing nanocomposites of homogeneously dispersed graphene oxide in a waterborne polyester matrix with controlled interfacial interactions is a daunting challenge owing to the presence of strong cohesive energy in both. Thus, in this study, graphene oxide was functionalized with toluene diisocyanate and butane diol through a simple method and incorporated into the waterborne polyester matrix through a facile in situ bulk polymerization technique without using any compatibilizing agent or organic solvent for the first time. The thermoset of the nanocomposite was formed by curing it with hyperbranched epoxy of glycerol and poly(amido amine). The resultant thermosetting nanocomposites with 0.1–1 wt % functionalized graphene oxide exhibited significant enhancement in mechanical properties such as elongation at break (245–360%), tensile strength (7.8–39.4 MPa), scratch hardness (4 to >10 kg), toughness (17.18–86.35 MJ/m3), Young’s modulus (243–358 MPa), impact resistance (8.3 to >9.3 kJ/m), and thermostability. Further, the Halpin–Tsai model was used to predict the alignment of graphene oxide. The nanocomposite was also biodegradable against the Pseudomonas aeruginosa bacterial strain. Furthermore, this nanocomposite exhibited strong catalytic activity for the aza-Michael addition reaction. Thus, the nanocomposite can be utilized as a high-performing sustainable material in different potential applications including as heterogeneous catalysts.

Surface Aligned Main-Chain Liquid Crystalline Elastomers: Tailored Properties by the Choice of Amine Chain Extenders

A promising way to induce shape transformation in soft materials is via spatial variation in the orientation of the alignment of liquid crystalline elastomers (LCEs). Here, we improve the nascent thermomechanial shape transformation in main-chain LCEs prepared via aza-Michael addition reactions. Specifically, increasing the alkyl length in the n-alkylamine chain extender effectively reduces the actuation temperature by destabilizing the nematic phase as well as reduces the glass transition temperature (Tg) by increasing the free volume. In addition, incorporating a hydroxyl end-group in the amine chain extender (i.e., n-alkanolamine) increases the actuation strain and improves the film quality by preventing side-chain aggregates of n-alkylamine-functionalized LCEs. Interestingly, uniaxially aligned n-alkanolamine-functionalized LCEs exhibit an unprecedentedly large elongation and an enhanced toughness even along the loading direction likely due to hydrogen bonding between chains. Thus, our study highlight...

Design and preparation of a new polyurea–polysiloxane–polyether copolymer with a block soft segment prepared by utilizing aza-Michael addition reaction

A novel polyurea–polysiloxane–polyether copolymer has been prepared which displays mild microphase separation and high mechanical strength.

Mildly Cross-Linked Dendrimer Hydrogel Prepared via Aza-Michael Addition Reaction for Topical Brimonidine Delivery.

In this work, we developed a mildly cross-linked dendrimer hydrogel (mcDH) via aza-Michael addition of polyamidoamine (PAMAM) dendrimer G5 and polyethylene glycol diacrylate (PEG-DA, Mn=575 g/mol). We chose the antiglaucoma drug brimonidine tartrate as a model drug and developed a new antiglaucoma drug formulation on the basis of mcDH. Cytotoxicity of the mcDH formulation to NIH3T3 fibroblasts, in vitro drug release kinetics and ex vivo drug permeability across the rabbit cornea were examined. We also studied interactions between PAMAM dendrimer and the drug using 1H NMR spectroscopy for a mechanistic understanding of brimonidine release from the mcDH. mcDH was found to be efficient unionizing brimonidine tartrate to form and encapsulate brimonidine free base for sustained release and enhanced corneal permeation.

Ferrocene-Based Nonphosphorus Copolymer: Synthesis, High-Charring Mechanism, and Its Application in Fire Retardant Epoxy Resin

A novel nonphosphorus copolymer poly((3,3′-diphenyl diacetylethylenediamino)-1,1′-ferrocene) (PDPFDE) was synthesized, with the aim of reducing the fire hazards of epoxy resin (EP), via an aza-Michael addition reaction and was well characterized. A high char yield of about 62.9 wt % was obtained for PDPFDE from thermogravimetric analysis results, and a charring mechanism has been suggested that involves iron-cored carbon nanotubes as catalysts. An EP composite containing 5.0 wt % PDPFDE reached a low limiting oxygen index value of 29.1% and V-1 rating in the UL-94 test. On comparison with neat EP, the peak of the heat release rate and the total smoke production of the composite were reduced by 36.0% and 24.0%, respectively. Scanning electron microscopy and energy dispersive X-ray analysis results indicated the formation of coherent, dense, and nitrogen-rich char residues due to the incorporation of PDPFDE. Furthermore, the addition of an appropriate amount of PDPFDE improved the mechanical properties comp...

N-Arylation of Heterocycles by a Tandem Aza-Michael Addition Reaction and Aromatization Sequence

Cyclohexa-2,4-dien-1-one derivatives, upon reaction with N-heterocycles in the presence of scandium(III) triflate, underwent a tandem Michael addition reaction followed by aromatization of the ­Michael adduct generated in situ to give N-aryl heterocycles in good yields. Because of the ready accessibility of variously substituted cyclohexa-2,4-dien-1-ones, a range of N-aryl heterocycles have become available.

Recyclable Fe3O4 Nanoparticles Catalysts for Aza-Michael Addition of Acryl Amides by Magnetic Field

A nanostructure-based catalytic system has the advantages of both homogeneous and heterogeneous catalysis. It is of great significance to develop the sustainable and green process of homogeneous catalytic reaction. We report a novel, efficient and recyclable magnetic Fe3O4 nanoparticles-catalyzed aza-Michael addition reaction of acryl amides, and the magnetic nanoparticles catalysts can be recovered by external magnetic field. Both primary amine and secondary amine can react with various acryl amides providing a good output to target products successfully at room temperature. Further experiments reveal that the magnetic Fe3O4 nanoparticles-based catalyst shows excellent yields, which can be recycled 10 times, and, at the same time, it maintains a high catalytically activity. In this catalytic system, the tedious separation procedures are replaced by external magnetic field, which gives us a different direction for choosing a catalyst in a nanostructure-based catalytic system.

Mechanisms and kinetics of isothermal polymerization of N,N′-bismaleimide-4,4′-diphenylmethane with 5,5-dimethylbarbituric acid in the presence of triphenylphosphine

Mechanisms and kinetics of isothermal polymerization of N,N′-bismaleimide-4,4′-diphenylmethane (BMI) with 5,5-dimethylbarbituric acid (55BTA) in the presence of triphenylphosphine (Ph3P, as a base catalyst for aza-Michael addition reaction) were investigated. Both model-free and model-fitting methods were used to determine triplet kinetic parameters, and comparable kinetic parameters obtained. Based on the model-free method, average activation energy (Eα) and pre-exponential factor (Aα) are 33±1kJmol−1 and 8267±2min−1 in the α range 0.1–0.9, respectively, with g(α)=[(1−α)−0.1−1]/0.1 [i.e. f(α)=(1−α)1.1]. As to the model-free method, overall activation energy (E) and pre-exponential (A) are 32±1kJmol−1 and 4583±1min−1 with the g(α)=[(1−α)−0.1−1]/0.1. Aza-Michael addition reaction mechanism played an important role in the polymerization of BMI/55BTA in the presence of Ph3P at low temperature. By contrast, free radical polymerization predominated in the BMI/55BTA system at higher temperature.

Synthesis of 4-hydroxyquinoline-2,3-dicarboxylates using N-(2-aminobenzoyl)benzotriazoles

A method for the preparation of 4-hydroxyquinoline-2,3-dicarboxylates has been developed by aza-Michael addition reaction of N-(2-aminobenzoyl)benzotriazoles with dimethyl acetylenedicarboxylate. 4-Hydroxyquinoline-2,3-dicarboxylates were obtained in moderate to good yields (53–87%).

Functionalized Tetrahydropyridines by Enantioselective Phosphine-Catalyzed Aza-[4 + 2] Cycloaddition of N-Sulfonyl-1-aza-1,3-dienes with Vinyl Ketones.

The development of electron-demand disfavored [4 + 2] cycloaddition of two electron-deficient reacting partners poses a considerable challenge. An enantioselective aza-[4 + 2] cycloaddition of electron-deficient N-sulfonyl-1-aza-1,3-dienes is possible with vinyl ketones via phosphine catalysis, which provides facile access to a wide range of enantioenriched trifluoromethylated tetrahydropyridines in up to 97% yield with 97% ee and >20:1 dr. The mechanistic study indicated that this cycloaddition proceeds via a tandem intermolecular aza-Rauhut-Currier/intramolecular aza-Michael addition reaction.

In Situ-Forming Polyamidoamine Dendrimer Hydrogels with Tunable Properties Prepared via Aza-Michael Addition Reaction.

In this work, we describe synthesis and characterization of novel in situ-forming polyamidoamine (PAMAM) dendrimer hydrogels (DHs) with tunable properties prepared via highly efficient aza-Michael addition reaction. PAMAM dendrimer G5 was chosen as the underlying core and functionalized with various degrees of acetylation using acetic anhydride. The nucleophilic amines on the dendrimer surface reacted with α, β-unsaturated ester in acrylate groups of polyethylene glycol diacrylate (PEG-DA, Mn = 575 g/mol) via aza-Michael addition reaction to form dendrimer hydrogels without the use of any catalyst. The solidification time, rheological behavior, network structure, swelling, and degradation properties of the hydrogel were tuned by adjusting the dendrimer surface acetylation degree and dendrimer concentration. The DHs were shown to be highly cytocompatible and support cell adhesion and proliferation. We also prepared an injectable dendrimer hydrogel formulation to deliver the anticancer drug 5-fluorouracil (5-FU) and demonstrated that the injectable formulation efficiently inhibited tumor growth following intratumoral injection. Taken together, this new class of dendrimer hydrogel prepared by aza-Michael addition reaction can serve as a safe tunable platform for drug delivery and tissue engineering.

Bisphosphonate‐functionalized poly(β‐amino ester) network polymers

Three novel bisphosphonate-functionalized secondary diamines are synthesized and incorporated into poly(β-amino ester)s (PBAEs) to investigate the effects of bisphosphonates on biodegradation and toxicity of PBAE polymer networks. These three novel amines, BPA1, BPA2, and BPA3, were prepared from the reactions of 1,4-butanediamine, 1,6-hexanediamine, or 4,9-dioxa-1,12-dodecanediamine with tetraethyl vinylidene bisphosphonate, respectively. The PBAE macromers were obtained from the aza-Michael addition reaction of these amines to 1,6-hexane diol diacrylate (HDDA) and poly(ethylene glycol) diacrylate (PEGDA, Mn = 575) and photopolymerized to produce biodegradable gels. These gels with different chemistries exhibited similar degradation behavior with mass loss of 53-73% within 24 h, indicating that degradation is mostly governed by the bisphosphonate group. Based on the in vitro cytotoxicity evaluation against NIH 3T3 mouse embryonic fibroblast cells, the degradation products do not exhibit significant toxicity in most cases. It was also shown that PBAE macromers can be used as cross-linkers for the synthesis of 2-hydroxyethyl methacrylate hydrogels, conferring small and customizable degradation rates upon them. The materials reported have potential to be used as nontoxic degradable biomaterials. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1412-1421, 2017.

Asymmetric hydroazidation of α-substituted vinyl ketones catalyzed by chiral primary amine

We report herein the first example of asymmetric hydroazidation of α-substituted vinyl ketones by using chiral primary amines as the catalysts. A simple chiral primary-tertiary diamine catalyst derived from l-phenylalanine was found to readily promote this aza-Michael addition reaction with enamine protonation as the key stereogenic step, thus enabling the effective synthesis of α-chiral β-azido ketones with good yields and moderate enantioselectivities.

介孔分子筛MCM-41固载磷钨酸催化苯并三氮唑与查尔酮的氮杂迈克加成反应研究

以介孔分子筛MCM-41固载磷钨酸为催化剂，对苯并三氮唑与查尔酮进行了氮杂迈克加成的催化研究。经过条件筛选，发现MCM-41中的磷钨酸负载量对该反应体系有很大的影响，其中50 wt%的磷钨酸负载量更有利于反应的进行，产率可达98%。通过NMR对产物结构进行了表征，并且催化剂具有一定的回收再利用效果。 In this paper, mesoporous siliceous material MCM-41 supported H3PW12O40 (PW) could act as an efficient catalyst for the aza-Michael addition reaction of chalcone with benzotriazole. As can be seen from a serial of reaction conditions, the ratio of PW and MCM-41 plays a critical role in the reaction, and the best catalyzed result was achieved when using 50 wt% PW/MCM-41, and the yield was up to 98%. All the products were confirmed by NMR techniques. Moreover, the catalyst was also found to exhibit better recyclability.

Polymer coated magnetically separable organocatalyst for C[sbnd]N bond formation via aza-Michael addition

A polyacrylamide coated magnetite (PAM@MNP) catalyst was synthesized by following a two step approach involving the reaction of magnetite (Fe3O4) particles with coupling agent 3-(trimethoxysilyl)propyl methacrylate followed by grafting of acrylamide and subsequent polymerization via surface initiated radical polymerization technique. The synthesized organocatalyst was used for a one-pot aza-Michael addition reaction of amines with electron deficient alkenes to give β-amino carbonyls. The magnetic properties of the synthesized organocatalyst provide it a facile recovery by external magnet which eliminates the problems arising during catalyst separation by conventional filtration.