Mannich Reaction Research Articles

Progress in Catalytic Asymmetric Reactions with 7-Azaindoline as the Directing Group

α-Substituted-7-azaindoline amides and α,β-unsaturated 7-azaindoline amides have emerged as new versatile synthons for various metal-catalyzed and organic-catalyzed asymmetric reactions, which have attracted much attention from chemists. In this review, the progress of research on 7-azaindoline amides in the asymmetric aldol reaction, the Mannich reaction, the conjugate addition, the 1,3-dipole cycloaddition, the Michael/aldol cascade reaction, aminomethylation and the Michael addition-initiated ring-closure reaction is discussed. The α-substituted-7-azaindoline amides, as nucleophiles, are classified according to the type of α-substituted group, whereas the α,β-unsaturated 7-azaindoline amides, as electrophiles, are classified according to the type of reaction.

(3+2) Annulation of 4‐Acetoxy Allenoate with Aldimine Enabled by AgF‐Assisted P(III)/P(V) Catalysis

AbstractA phosphine‐catalyzed (3+2) annulation of 4‐acetoxy allenoate and aldimine with the assistance of AgF is described. The success of this reaction hinges on the metathesis between the enolate‐phosphonium zwitterion and AgF, leading to a key intermediate comprising of silver enolate and a fluorophosphorane P(V)‐moiety. The former is able to undergo a Mannich reaction with aldimine, whereas the latter initiates a cascade sequence of AcO‐elimination/aza‐addition, thus furnishing the P(III)/P(V) catalysis. By taking advantage of the silver enolate, a preliminary attempt at an asymmetric variant was conducted with the combination of an achiral phosphine catalyst and a chiral bis(oxazolinyl)pyridine ligand (PyBox), giving moderate enantioselectivity.

(3+2) Annulation of 4-Acetoxy Allenoate with Aldimine Enabled by AgF-Assisted P(III)/P(V) Catalysis.

A phosphine-catalyzed (3+2) annulation of 4-acetoxy allenoate and aldimine with the assistance of AgF is described. The success of this reaction hinges on the metathesis between the enolate-phosphonium zwitterion and AgF, leading to a key intermediate comprising of silver enolate and a fluorophosphorane P(V)-moiety. The former is able to undergo a Mannich reaction with aldimine, whereas the latter initiates a cascade sequence of AcO-elimination/aza-addition, thus furnishing the P(III)/P(V) catalysis. By taking advantage of the silver enolate, a preliminary attempt at an asymmetric variant was conducted with the combination of an achiral phosphine catalyst and a chiral bis(oxazolinyl)pyridine ligand (PyBox), giving moderate enantioselectivity.

Bi-functional astaxanthin macromolecular nanocarriers to alleviate dextran sodium sulfate-induced inflammatory bowel disease

Dextran sulfate sodium is one of the important members in the field of polysaccharide biotechnology, which can induce inflammatory bowel disease (IBD) in the gastrointestinal tract. Nevertheless, the application of astaxanthin (AST) and epigallocatechin-3-gallate (EGCG), known for their pronounced antioxidant and anti-inflammatory properties, is encumbered by limited stability and bioavailability. To surmount this challenge, dual nutritional macromolecular nanoparticles were provided for alleviating IBD. The forementioned strategy entailed the utilization of EGCG as a wall material via the Mannich reaction, resulting in the creation of specialized nanocarriers capable of mitochondrial targeting and glutathione-responsive AST delivery. In vitro investigations, these nanocarriers demonstrated an enhanced propensity for mitochondrial accumulation, leading to proficient elimination of reactive oxygen species and preservation of optimal mitochondrial membrane potential about 1.5 times stronger than free AST and EGCG. Crucially, in vivo experiments showed that the colon length of IBD mice treated with these nanocarriers increased by 51.29 % and facilitated the polarization of M2 macrophages. Moreover, the assimilation of these nanocarriers exerted a favorable impact on the composition of gut microbiota. These findings underscore the immense potential of dual nutrition nanocarriers in contemporaneously delivering hydrophobic biological activators through oral absorption, thereby presenting a highly promising avenue for combating IBD.

Preparation of Mannich reaction modified magnetic adsorbent for separation and purification of total flavonoids from Lycium barbarum leaves

Flavonoids are important secondary metabolites, but their separation and enrichment are difficult due to low contents and complex active components. Poly(styrene-divinylbenzene)-based resins are widely used for the separation of natural products, however, they have low adsorption capacity and poor selectivity. To solve these problems, Mannich reaction modified magnetic poly(styrene-divinylbenzene) (MPM-MR) microspheres were synthesized, and used for the separation and purification of flavonoids from Lycium barbarum leaves. Compared with other flavonoids (such as kaempferol, quercetin, naringenin and rutin), MPM-MR exhibited higher adsorption capacity and better selectivity for myricetin, which reached 81.6 mg/g at 298.15 K. Sieving interactions, hydrogen bonds and π-π interactions mainly exist between the MPM-MR and the flavonoids. In addition, the materials showed good enrichment of total flavonoids from actual samples of Lycium barbarum leaves, which increased from 8.17% to 24.99%. The Mannich reaction-modified magnetic poly(styrene-divinylbenzene) would be a promising material for efficient capture of flavonoids from natural plants.

Preparation of waterborne intumescent flame-retardant coatings using adenosine-based phosphonates for wood surfaces

Here, organic solvent-free adenosine-based waterborne flame retardant curing agents were synthesized and introduction into a melamine urea-formaldehyde resin (MUF) to construct flame-retardant coatings for wood surfaces. Adenosine-based phosphonate (APU), composed of adenosine, urea, formaldehyde, and phosphorous acid, was synthesized by the Mannich reaction. The chemical structure of APU was investigated by Fourier-transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and 31P nuclear magnetic resonance (NMR) spectroscopy. In contrast to MAW0, the coatings containing APU exhibited similar physical characteristics. MAW4 achieved a vertical combustion (UL-94) V-0 rating and an impressive limiting oxygen index (LOI) of 54.5 %. Cone calorimetry indicated that the time to ignition (TTI) of MAW4 was 89 s, an increase of 790 % compared with MAW0, which may significantly prolong the escape time from a fire. Scanning electron microscopy (SEM), thermal infrared imaging, and Raman spectroscopy all confirmed that continuous and dense char layers reduced the transport of heat, ignitable gases, and smoke. This limited the further pyrolysis and combustion of wood, showing that the waterborne intumescent flame-retardant coatings proposed in this research endowed wood with excellent flame retardancy.

Synthesis and properties of low viscosity robust biobased benzoxazine resin

The preparation of biobased benzoxazine resin with low melting point and low curing temperature has important significance for environmental sustainable development and practical application in industrial field. In this paper, biobased benzoxazine monomer HA-fa was synthesized from p-hydroxybenzyl alcohol, paraformaldehyde and furfurylamine, and H-fa were prepared by Mannich reaction of hordenine with paraformaldehyde and furfurylamine. The two benzoxazine organic molecules showed different thermodynamic behaviors. HA-fa and H-fa were liquid at room temperature. The viscosity of HA-fa and H-fa at room temperature (25 °C) were 1.683 Pa/s and 0.602 Pa/s, and the curing peak temperature was 220 °C and 208 °C, respectively, both organic molecules showed excellent processability. Then poly(HA-fa) and poly(H-fa) were prepared by two organic molecules through thermal curing procedure. The comprehensive properties of two benzoxazine resins were investigated. The glass transition temperature (Tg) of poly(H-fa) is 223 °C, while the Tg of poly(HA-fa) has two peak temperatures, 225 °C and 281 °C, respectively. This may be due to the existence of two different crosslinking networks in the resin, which leads to the phase separation of the resin, thus reflecting two Tg. Meanwhile, the initial thermal decomposition temperatures Tdi of poly(HA-fa) and poly(H-fa) were 330 °C and 331 °C, respectively, showing excellent thermal stability of the newly prepared resin. In addition, poly(HA-fa) and poly(H-fa) have both high storage modulus (3174 MPa and 2608 MPa, respectively, measured at 25 °C) and good flexural strength (121 ± 2.7 MPa and 96 ± 3.6 MPa). Among the two resins, poly(HA-fa) showed more excellent comprehensive properties, which may be based on the joint action of resin multi-crosslinking sites and hydrogen bond crosslinking network.

High performance quaternary ammonium-functionalized polybenzoxazine-based anion exchange membranes

Two kinds of benzoxazine monomers were synthesized by Mannich reaction with N,N-dimethyl-p-phenylenediamine and N,N-dimethylethylenediamine using polyformaldehyde, 4,4′-dihydroxydiphenylmethane as raw materials. Subsequently, quaternary ammonium functionalization was realized by Menshutkin reaction. The aromatic amine-based quaternary ammonium-functionalized polybenzoxazine (AQPBZ) and aliphatic amine-based quaternary ammonium-functionalized polybenzoxazine (LQPBZ) were synthesized by ring-opening polymerization. Polybenzoxazine anion exchange membrane (AEM) was prepared by solution casting method. The AQPBZ and LQPBZ AEMs exhibit micro-phase separated morphology clearly. LQPBZ AEM displays more large ion clusters and ion conductive channels due to the flexible alkyl connection between QA group and polybenzoxazine skeleton. AQPBZ and LQPBZ AEMs have the ionic conductivity of 75.5 mS/cm and 86.3 mS/cm at 80 °C and 100% relative humidity, respectively. AQPBZ and LQPBZ AEMs show excellent alkaline stability. After treated with 6 M sodium hydroxide solution at 80 °C for 240 h, they manitained the 49.8 mS/cm and 50.2 mS/cm, respectively. They also exhibit good oxidation stability and thermal stability. Their oxidation weight losses are 4.1% and 7.2% through Fenton test, respectively. Their Td5s are 325 °C and 289 °C, respectively.

Synthesis, biological evaluation and in silico studies of some new analogues of 3,5-vdisubstituted thiazolidin-2,4-dione.

Background: A new series of 3,5-disubstituted thiazolidin-2,4-dione molecules werederived and characterized using various spectral techniques (1H NMR, IR, carbon, hydrogen, nitrogen, etc.) and physicochemical parameters. Materials & methods: The molecules were derived using Knoevenagel condensation followed by Mannich reaction and further synthesized analogues were screened for their antioxidant and antimicrobial potential using 2,2-diphenyl-1-picrylhydrazyl free radical scavenging method and serial tube dilution method, respectively, along with in silico studies (docking and absorption, distribution, metabolism and excretion parameters) to explore the drug-receptor interaction and druglikeness. Results & conclusion: In antimicrobial screening, the analogs MP2, MM6, MM7 and MM8 displayed promising activity while molecule MM4 exhibited better antioxidant potential in the series. In molecular docking analysis, the best-fitted analogs, namely, MM6 and MM7, showed good interactions.

Development and characterisation of highly specific monoclonal antibody-based immunoassays for the detection and quantification of genistein-7-O-[α-rhamnopyranosyl-(1→6)]-β-glucopyranoside in Derris scandens (Roxb.) Benth.

The stem of the plant species Derris scandens (Roxb.) Benth. (DS) contains genistein-7-O-[α-rhamnopyranosyl-(1→6)]-β-glucopyranoside (GTG), which is a unique marker. Previous analyses of GTG using antibody-based immunoassays were compromised because of their high cross-reactivity with structurally related compounds of DS, thereby limiting their applicability in DS quality control. Conjugation of GTG with carrier proteins was achieved using the Mannich reaction to produce a highly specific monoclonal antibody (mAb) targeting GTG (anti-GTG mAb). The anti-GTG mAb was generated using hybridoma technology and characterised using an indirect competitive enzyme-linked immunosorbent assay (icELISA). Both lateral-flow immunoassay (LFIA) and icELISA were developed to detect and quantify GTG in DS raw materials and associated products. icELISA using the anti-GTG mAb showed 100% specificity for GTG, with only 1.77% cross-reactivity with genistin and less than 0.01% cross-reactivity with other compounds. icELISA demonstrated a linear range for GTG determination between 62.5 and 2000 ng/mL. The limits of detection (LOD) and quantification were 49.68 and 62.50 ng/mL for GTG, respectively. The precision of the analysis ranged from 1.28% to 4.20% for repeatability and from 1.03% to 7.05% for reproducibility. The accuracy of the analysis ranged from 101.97% to 104.01% for GTG recovery. GTG levels determined via icELISA were consistent with those confirmed via high-performance liquid chromatography (HPLC) (R2 = 0.9903). Moreover, the LOD of LFIA for GTG was 500 ng/mL. Immunoassays utilising specific anti-GTG mAbs were successfully developed, including LFIA for rapid GTG detection and icELISA for GTG quantification.

Organo‐Catalyzed Enantioselective [4+2] Annulation of Glutaraldehyde and C3‐Indolyl‐imines To Access Indol‐3‐yl‐piperidines

AbstractA simple and straightforward method is developed for the enantioselective synthesis of indol‐3‐yl‐piperidine. The reaction proceeds through a proline‐catalyzed direct Mannich reaction between glutaraldehyde and C3‐indolyl‐imines, followed by intramolecular reductive cyclization as an overall [4+2] annulation in one‐pot fashion. A series of indol‐3‐yl‐piperidine have been accessed with good yields up to 71 % and high enantioselectivity up to >99 % ee.

One‐Pot Stereoselective Synthesis of Different Fused Multicyclic Iminosugars Based on the Iminium‐Ion Intermediate

Comprehensive SummaryDifferent novel fused multicyclic iminosugars were synthesized from D‐ribose tosylate, aniline and vinyl ethyl ether by one‐pot three‐component stereoselective [4+2] reaction at different temperatures. The iminium‐ion is the key intermediate for the reaction. As a result, several complex fused iminosugars 3a were obtained by aza‐Diels‐Alder mechanism at 60 °C, while a series of aza‐C‐glycosides 5a were prepared by Mannich reaction at room temperature accompanied by another tetrahydroquinoline‐fused iminosugars 4a (tricyclic derivatives) through aza‐Diels‐Alder cycloaddition. This strategy will help to construct structurally diverse and bioactive iminosugar analogues.

Construction of three-dimensional porous organic polymers with enhanced CO2 uptake performance via solid-state thermal conversion from tetrahedral benzoxazine-linked precursor

Porous organic polymers (POPs) with three-dimensional (3D) linkages have drawn great interest due to their potential applications in separation, adsorption, and sensing fields. Herein, a new 3D benzoxazine (BZ)-linked porous organic polymer (TPM-BZ-Py POP) was synthesized by linking a tetrahedral benzoxazine (TPM-BZ-Br4) with tetraethynylpyrene (Py-T) via Sonogashira coupling. Specifically, the synthesis of the tetrahedral benzoxazines with four oxazine rings in a single monomer involved the utilization of Schiff base formation, NaBH4 reduction as well as Mannich condensation reactions. To confirm the chemical structure of the benzoxazine monomers and their corresponding polybenzoxazines, Fourier transform infrared (FTIR), proton nuclear magnetic resonance (1H NMR), and carbon nuclear magnetic resonance (13C NMR) spectroscopy techniques were employed. The pore volume and specific surface area of the 3D TPM-BZ-Py POP were determined through N2 adsorption/desorption isotherms, and they were found to be 0.52 cm3/g and 185 m2/g, respectively. In addition, the solid-state chemical transformation occurred during thermal ring-opening polymerization (ROP), and the resulting 3D poly(TPM-BZ-Py) POP displayed higher CO2 capture ability (1.81 mmol/g) compared with TPM-BZ-Py POP (0.60 mmol/g) at room temperature. Such enhancement observed in poly(TPM-BZ-Py) POP was proposed to be caused by the formation of phenolic units and Mannich bridges within the polymer network by taking into consideration the structural transformation during the ring-opening polymerization (ROP). The functionalities in poly(TPM-BZ-Py) have great potential to interact with CO2 molecules through strong intermolecular hydrogen bonding or acid/base interactions, which further supports the benefit of incorporating oxazine rings into POP frameworks.

Reaction-induced liquid crystalline polybenzoxazine thermosets using aryl ester bonds as cross-linkages

ABSTRACT The increasing tendency to develop integration in electronic devices lead to the demand for thermally conductive polymeric materials. We offered a simple synthetic route to thermally conductive polybenzoxazine thermosets bearing liquid crystalline structures without the addition of any filler. Benzoxazine monomer of BZ-COOH was synthesized via Mannich reaction of p-hydroxy benzoic acid, p-formaldehyde, and dodecyl amine. After ring-opening polymerization of BZ-COOH, the obtained benzoxazine oligomer of OBZ-COOH was converted into acetoxy-bearing benzoxazine oligomer of OBZ-AC. Through self-crosslinking reaction of acetoxy group and carboxyl group in OBZ-AC using Zn(CH3COO)2 as a catalyst, the polybenzoxazine thermosets of OBZ-PES were produced. The liquid crystalline behavior of OBZ-AC was studied by POM, SAXS, and DSC. The results show that OBZ-AC formed the LC mesophase during isothermal and non-isothermal curing. The LC mesophase displays a layered arrangement of the smectic C phase. The formation mechanism is esterification reaction-induced. Owing to the formation of liquid crystalline structure, the TC of OBZ-PES is found to be 0.284 W/m. K, which is 21% and 16% greater than those of OBZ-COOH and OBZ-AC, respectively. In addition, the OBZ-PES shows excellent thermal performance. Its Tg(G”) is up to 269°C. Its 5% weight loss temperature (Td5) and 10% weight loss temperature (Td10) are 383°C and 410°C, respectively.

Plant polyphenol surfactant construction with strong surface activity and chelation properties as efficient decontamination of UO22+ on cotton fabric

Chemically synthesized surfactants have promising applications in the treatment of uranium, however, their hazardous environmental effects, non-biodegradability, and numerous drawbacks prevent them from being widely used in practice. Herein, we successfully synthesized a green chelating and foaming integrated surfactant (BTBS) by Mannich reaction and acylation of bayberry tannin for the effective removal of UO22+ from aqueous environments or solid surfaces. The as-prepared surfactant was systematically characterized by FT-IR, showing that the hydrophobic groups were successfully grafted onto tannin. The modified material showed better foaming and emulsifying properties, which proved this method could improve the amphiphilicity of tannin. Moreover, for the first time, a foam fractionation method in conjunction with a tannin-based surfactant was applied for UO22+ removal from water. This surfactant was used as a co-surfactant and could readily remove 90 % of UO22+ (20 mg L−1) from water. The removal of UO22+ could be completed in a short time (30 min), and the maximum adsorption capacity was determined as 175.9 mg g−1. This surfactant can also be used for efficient decontamination of uranium-contaminated cotton cloth with a high removal rate of 94.55 %. In addition, the mechanism studies show that the adsorption of BTBS for UO22+ can be mainly attributed to a chelating mechanism between UO22+ and the adjacent phenolic hydroxyls. The novel biomass-derived BTBS with advantages such as high capture capacity, environmental friendliness, and cost-effectiveness suggests that it plays an important role in the remediation of radionuclide pollution.

Dual preservative strategy for facilitating bamboo durability using cinnamaldehyde and diethylenetriamine and its reaction characteristics on bamboo cell wall

Cinnamaldehyde exhibits excellent anti-mold properties that can preserve bamboo. However, establishing a stable bonding linkage (CN) requires cinnamaldehyde modification, which can be used to manipulate cell wall characteristics and improve bamboo durability. In this study, cinnamaldehyde's chemical fixation into bamboo through the Mannich reaction was successfully achieved, resulting in enhanced anti-mold capacity and dimensional stability. The modified bamboo exhibited remarkable anti-mold properties, with a 40.0% increase in resistance to swelling caused by moisture fluctuations. Nanoindentation analysis also revealed that the internal bamboo cell wall's mechanical properties improved following modification, including a significant improvement in surface hydrophobicity from 13.9° to 67.3°. Concerning the impact of the modification on bamboo cells, the sclerenchyma cell of bamboo was determined to be the focus. We used guaiacol as a lignin model compound to elucidate the potential mechanism of cinnamaldehyde modification, specifically Schiff base formation, using nuclear magnetic resonance spectra. This study shows a viable dual preservative strategy to extend bamboo lifespan.

Synthesis and DFT calculations of mono‐ and di‐methylated cucurbit[7]uril based on imidazole derivatives

AbstractNowadays, functionalized cucurbit[n]urils are considered one of the most important examples of macromolecules and have attracted a lot of attention due to their potential applications in several sectors. In the present work monomethyl‐cucurbit[7]uril (3) was synthesized for the first time through facile synthetic route with high purity form by the reaction of monomethylglycoluril (3a‐methyltetrahydroimidazo[4,5‐d]imidazole‐2,5(1H,3H)‐dione) with glycoluril (tetrahydroimidazo[4,5‐d]imidazole‐2,5(1H,3H)‐dione) in the ratio of 1:6, respectively, and formaldehyde in the presence of hydrochloric acid as a catalyst for 24 h at 95°C through Mannich reaction. Moreover, dimethyl‐cucurbit[7]uril (5) was successfully synthesized through the reaction of dimethylglycoluril (3a,6a‐dimethyltetrahydroimidazo[4,5‐d]imidazole‐2,5(1H,3H)‐dione) with glycoluril (tetrahydroimidazo[4,5‐d]imidazole‐2,5(1H,3H)‐dione), following the same procedure as for the monomethyl‐cucurbit[7]uril. The chemical structures of the obtained compounds were established by mass spectrometry, NMR spectroscopy, and quantum‐chemical calculations.

Synthesis, Characterization and Biological Evaluation of Some Novel N-Mannich Bases of Benzimidazole Derivative

Over the past few decades, Mannich bases of heterocyclic molecules have been grabbing the attention of the synthetic chemists for their wide gamut of biological activities ranging from antibacterial, anticancer, antiparkinson to anticonvulsant, anti-inflammatory, analgesic and anti-HIV. Using the knowledge of important features a novel series was designed to obtain improved antibacterial and antifungal activity. Therefore in the present research, we decided to synthesize 2-substituted benzimidazole derivatives by conventional method. Further the study will extended to introduce sulphanilamide and piperazine group substitution on N-1 position of 2-substituted benzimidazole by Mannich reaction and to screen the newly synthesized compounds for their antibacterial and antifungal activity.

Supramolecular self-assembly of EGCG-selenomethionine nanodrug for treating osteoarthritis

Osteoarthritis (OA) has emerged as a significant health concern among the elderly population, with increasing attention paid to ferroptosis-induced OA in recent years. However, the prolonged use of nonsteroidal anti-inflammatory drugs or corticosteroids can lead to a series of side effects and limited therapeutic efficacy. This study aimed to employ the Mannich condensation reaction between epigallocatechin-3-gallate (EGCG) and selenomethionine (SeMet) to efficiently synthesize polyphenol-based nanodrugs in aqueous media for treating OA. Molecular biology experiments demonstrated that EGCG-based nanodrugs (ES NDs) could effectively reduce glutathione peroxidase 4 (GPX4) inactivation, abnormal Fe2+ accumulation, and lipid peroxidation induced by oxidative stress, which ameliorated the metabolic disorder of chondrocytes and other multiple pathological processes triggered by ferroptosis. Moreover, imaging and histopathological analysis of the destabilization of the medial meniscus model in mice confirmed that ES NDs exhibiting significant therapeutic effects in relieving OA. The intra-articular delivery of ES NDs represents a promising approach for treating OA and other joint inflammatory diseases.

Reaction-Induced Liquid Crystalline Polybenzoxazine BearingAromatic Amide Side Branches.

In this study, a nematic phase structure is incorporated into polybenzoxazine to increase its thermal conductivity. A simple route for the synthesis of a thermally conductive polybenzoxazine containing liquid crystalline (LC) structure by grafting oligomeric p-sulfophenylene-terephthalamide (PSTA) is offered. Benzoxazine monomer of pHBA-da is synthesized via Mannich reaction of p-hydroxy benzoic acid, p-formaldehyde, and dodecyl amine. After ring-opening polymerization, the oligomer benzoxazine of OBZ─COOH is obtained. The OBZ─COOH/PSTA mixture is prepared by mixing PSTA with OBZ─COOH. Afterward, the grafted copolymer is named OBZ─PSTA copolymer. The liquid crystalline behavior of OBZ─COOH/PSTA is studied by polarized optical microscopy and small angle X-ray scattering analysis. The results show that the OBZ─PSTA forms the LC structure during isothermal and non-isothermal curing. The LC structure displays a floral textured nematic phase. The phase formation is induced by an amidation reaction. Due to the grafts of LC PSTA, the thermal conductivity of OBZ─PSTA is 0.296W m-1 K-1 , which is 26% greater than OBZ─COOH. The glass transition temperature (Tg ) of OBZ─PSTA is 241°C. The 5% (Td5 ) and 10% weight loss temperatures (Td10 ) of OBZ─PSTA are 346 and 362°C, respectively.