Three-component Mannich Reaction Research Articles

Hen egg white lysozyme encapsulated in ZIF-8 for performing promiscuous enzymatic Mannich reaction

Hen egg white lysozyme (HEWL) was exploited for the synthesis of β-amino carbonyl compounds through a direct and three-component Mannich reaction in aqueous, confirming high chemoselectivity toward imine. In order to further extend the applications of the enzyme, HEWL was encapsulated using a metal-organic framework (MOF). The reactivity, stereoselectivity, and reusability of the encapsulated enzyme were investigated. The reaction was significantly enhanced as compared to the non-encapsulated enzyme. A mutated version of the enzyme, containing Asp52Ala (D52A), lacking important catalytical residue, has lost the bacterial site activity against Micrococcus luteus (M. luteus) while the D52A variant displayed an increased rate of the Mannich reaction, indicating a different catalytical residue involved in the promiscuous reaction. Based on site-directed mutagenesis, molecular docking, and molecular dynamic studies, it was proposed that π-stacking, H-bond interactions, and the presence of water in the active site may play crucial roles in the mechanism of the reaction.

A Heterogeneous, Highly Efficient, and Reusable Mo-Al2O3 Composites Based Organocatalyst for One Pot Three-Component Mannich Reaction for the Synthesis of β-aminocarbonyl Compounds

We have successfully developed a new Mo-Al2O3/p-TSA organocatalyst which has improved the yield of the Mannich reaction. This protocol has the advantage of mild conditions, high yield, easy work-up, environmentally friendly procedure, and the solid catalyst was recycled. The catalyst was analysed by XRD, SEM, and EDS techniques. The synthesized Mo-Al2O3composites were used in the presence of p-toluene sulfonic acid (p-TSA) conducts the one-pot three-component Mannich reaction and various β-amino ketones prepared with good yields and characterized by IR, 1H, and 13C NMR Techniques.

Оптимизация процесса получения аминометоксипроизводных ментола

On the basis of experimental data, a regression mathematical model of the process of obtaining aminomethoxy derivatives of the menthol series based on the three-component Mannich reaction with the participation of menthol, formaldehyde and secondary amines was developed, reflecting the influence of the main technological factors (ratio of initial reagents (mol/mol), temperature (0C), reaction time (h)) on the yield of the target product (%). A statistical analysis of the obtained model was carried out, and the adequacy of the developed model to the experimental data was proved. The optimal values of the input parameters are found, at which the maximum value of the yield of menthol aminomethoxy derivatives is achieved.

Mechanochemical asymmetric three-component Mannich reaction involving unreactive arylamines.

We report here a mechanochemical protocol for an asymmetric three-component Mannich reaction involving unreactive arylamines with simple cyclic ketones and arylaldehydes catalyzed by (S)-proline with a chiral diol. In this mechanochemical protocol, ball milling enables reaction acceleration and enantioselectivity control. The reported asymmetric three-component Mannich reactions usually involve reactive arylamines such as p-anisidine and phenylamine, while the catalytic asymmetric Mannich reactions involving unreactive arylamines in solution did not proceed smoothly or gave low yields and enantioselectivities. However, the use of ball-milling techniques overcomes the deficiency of the batch systems in solution and avoids the use of toxic organic solvents. The desired products were obtained in moderate-to-good yields (49%-80%) with good-to-high enantioselectivities (up to 99% ee). This is the first example of a mechanochemically activated catalytic asymmetric three-component Mannich reaction involving unreactive arylamines.

Two silver–containing polyoxometalate–based inorganic–organic hybrids as heterogeneous bifunctional catalysts for construction of C–C bonds and decontamination of sulfur mustard simulant

The construction of C–C bonds and degradation of chemical warfare agents (CWAs) are two central organic conversions for future sustainable development. Herein, two remarkable silver-containing polyoxomolybdates-based hybrids (Ag-POMos), [Ag(L)(H2O)2]2[HPMo12O40] (1) and [Ag2(L)2]2[HPMo10V2O40]·4DMSO (2) (L ​= ​4,6-bis(2-pyridyl)-2-aminopyrimidine) were designed and prepared by using silver cation, polyoxomolybdates and multiple N-donors ligand (L). The structure of compound 1 is constructed from an independent Ag center and a keggin-type POMs; compound 2 is composed of two independent Ag centers and a keggin-type POMs, which displays intriguing POM-incorporated 1-D chain structure with hydrogen bonding. Additionally, Ag-POMos catalysts can be severed as the efficient bifunctional catalysts for the three-component Mannich reaction to achieve the construction of C–C bonds and decontamination of sulfur mustard 2-chloroethyl ethyl sulfide (CEES). As bifunctional heterogeneous catalyst, particularly compound 2, exhibits satisfying catalytic performances in the Mannich reaction (conv. 99%; sele. 99%) and the oxidation of CEES (conv. 96%; sele. 96%). Notedly, after three runs, compound 2 maintains excellent catalytic properties, demonstrating its remarkable cycling stability.

S-(+) Camphorsulfonic Acid Glycine (CSAG) as Surfactant-Likes Brønsted Acidic Ionic Liquid for One-Pot Synthesis of ß-Amino Carbonyl

A rapid and efficient S-(+) camphor sulfonic acid Glycine (CSAG), catalyzed, one-pot three-component Mannich reaction has been performed to synthesize ß-amino carbonyl compound at room temperature. The reaction gave desired products in good yield and excellent diastereoselectivity. Products in the presence of CSAG (15 mol%) with yields of 52–89% were obtained. This method offers a new modification and easy working process in mild reaction conditions with a low amount and catalyst recyclability up to at least three periods without significant reduction in performance (efficiency 88–77%). This report describes for the first time the preparation of CSAG catalysts for the synthesis of Mannich products.

SNsipmim]Cl a new and highly effective, recyclable nano catalyst for single-pot three-component Mannich type reaction

SNsipmim]Cl a new and highly effective, recyclable nano catalyst for single-pot three-component Mannich type reaction

Regioselective synthesis, physicochemical properties and anticancer activity of 2-aminomethylated estrone derivatives

The unique estrogen receptor (ER)-independent antiproliferative and apoptotic activity of 2-methoxyestradiol (2ME2) is well known, however, its use has been limited because of its poor oral bioavailability. In this study, novel 2-aminomethylated estrone (E) and estradiol (E2) derivatives structurally related to 2ME2 were synthesized, and their physicochemical properties as well as their in vitro cytotoxic effects were investigated in the hope of finding more selective antiproliferative agents with improved pharmacokinetic profile. The target compounds were synthesized from 2-dimethylaminomethylated E obtained regioselectively by a three-component Mannich reaction. Quaternization with methyl iodide followed by reacting the ammonium salt with various dialkyl and alicyclic secondary amines afforded the desired products in good yields. The reactions proceeded via a 1,4-nucleophilic addition of the applied secondary amines to the ortho-quinone methide (o-QM) intermediates, generated in situ from the salt by base-promoted β-elimination. The compound library has been enlarged with structurally similar E2 analogues obtained by stereoselective reduction and with some 17β-benzylamino derivatives prepared by reductive amination. The potential values of the novel E and E2 derivatives were characterised by means of three different approaches. At the first step compounds were virtually screened using physicochemical parameters. Physicochemical characterization was completed by kinetic solubility and in vitro intestinal-specific permeability measurement. Antiproliferative effects were additionally determined on a panel of malignant and non-cancerous cell lines. The evaluation of the pharmacological profile of the novel E and E2 derivatives was completed with the calculation of lipophilic efficacy (LiPE).

Ammonium Chloride Promoted One-Pot, Three-Component Mannich Reaction: An Efficient Synthesis of β-Amino Ketones and β-Amino Esters

Ammonium chloride was found to efficiently reagent for the one pot-three component Mannich reaction between aromatic aldehyde, ketone and amine in ethanol at room temperature to furnish β-amino ketones in good to excellent yields. The said protocol was further applied for the direct synthesis of β-amino esters, which are important precursors for the synthesis of β-amino acids. This protocol is potentially applicable for the development of a clean and environment-friendly strategy for the synthesis of β-amino ketones and found applications in the synthesis of potent biologically active molecules due to its simple experimental conditions, inexpensive reagents and straight forward product isolation procedure.

Polyaniline-Lemon Juice@Silica Nanocomposities an Efficient Catalyst for Synthesis of β-Amino Ketone

The lemon juice anchored polyaniline nanoparticles were synthesized using aniline as a monomer and lemon juice as acid dopant with potassium persulfate as the oxidant. The synthesized nanoparticles were characterized by XRD, FESEM and EDX. The XRD pattern of polyaniline-lemon juice has been shown crystalline nature and the average size found to be 2.998 nm. The polyaniline-lemon juice nanoparticles were immobilized on column silica by grinding method. The polyaniline-lemon juice@silica nanocomposite were characterized by XRD and FESEM. The XRD pattern of polyanilinelemon juice@silica nanocomposite has been shown amphorous nature. This study has explored the catalytic application of these nanocomposites in the synthesis of various β-amino ketones via a onepot three-component Mannich reaction of aldehydes, ketones and aromatic amines. This method provides a novel and enhanced amendment of three-component Mannich reaction in terms of mild reaction conditions and clean reaction profiles, using a small quantity of catalyst and simple workup procedure.

Direct Asymmetric Three-Component Mannich Reaction Catalyzed by Chiral Counteranion-Assisted Silver

Direct asymmetric three-component Mannich reaction involving simple ketones (such as cyclohexanone, acetone, and acetophenone) as donors and catalyzing by silver tartaric acid-derived phosphate was realized to afford a series of optically active β-amino-ketone derivatives in high yields (up to 96%) and good-to-high enantioselectivities (up to 97%) with moderate-to-good diastereoselectivities. This is the first example of direct catalytic asymmetric three-component Mannich reaction via a chiral counteranion-directed strategy.

Organocatalytic enantioselective one-pot synthesis of β-aminoketones via Mannich reaction

An effective protocol for the asymmetric synthesis of β-amino carbonyl compounds using pyrrolidine based organocatalyst has been developed via one-pot three-component Mannich reaction. The organocatalyst (S)-N-(2,4-dinitrophenyl) pyrrolidine-2-carboxamide 3b confirmed to be the superior organocatalyst in solvent acetonitrile to obtain corresponding products in up to 89% yield and with excellent ee (90%). This organocatalytic reaction reveals productive result with a range of other aldehydes. Aromatic aldehydes having electron withdrawing substituent show the best results. Excellent yields, high enantioselectivity, mild reaction condition, and simple experimental work-up procedure are some of the advantages of this method.

Synthesis and characterization of Mannich bases of lawsone and their anticancer activity

Natural and synthetic naphthoquinones are known for a large number of biological activities. Lawsone (2-hydroxy-1, 4-naphthoquinone) is a simplest naturally occurring compound obtained from dried henna (Lawsonia inermis) leaves. In literature, some lawsone derivatives have been reported to exhibit anticancer activity. Hence, a clean and facile one-pot protocol was developed for the synthesis of new aminonaphthoquinones derived from lawsone by three-component Mannich reaction, at room temperature for potential anti-cancer application. Herein we present a small library of Mannich bases with different amines and aromatic aldehydes with moderate to high yield. Synthesized compounds were characterized using various spectroscopic techniques. The anticancer activity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay) along with nuclear morphology assessment (4′,6-diamidino-2-phenylindole or DAPI staining), apoptosis assessment (acridine orange/ ethidium bromide staining), hemolysis and DNA ladder assay evaluated on human liver carcinoma cell line HepG2 are presented.

Hf(OTf)4 as a Highly Potent Catalyst for the Synthesis of Mannich Bases under Solvent-Free Conditions.

Hf(OTf)4 was identified as a highly potent catalyst (0.1–0.5 mol%) for three-component Mannich reaction under solvent-free conditions. Hf(OTf)4-catalyzed Mannich reaction exhibited excellent regioselectivity and diastereoselectivity when alkyl ketones were employed as substrates. 1H NMR tracing of the H/D exchange reaction of ketones in MeOH-d4 indicated that Hf(OTf)4 could significantly promote the keto-enol tautomerization, thereby contributing to the acceleration of reaction rate.

Bi(NO3)3•5H2O-catalyzed Mannich Reaction: A Potent Catalyst for Synthesis of β-Aminocarbonyl Compounds

Biologically active compounds containing nitrogen, natural molecules and drugs are important for organic synthesis. Mannich reaction is one of the most common methods used for the synthesis of these compounds. Bi(NO3)3 was used as an efficient catalyst for the one-pot three-component Mannich reactions of ketones with different aromatic amines and aromatic aldehydes at room temperature. It is a good method to prepare β-amino carbonyl compounds in excellent yield. The high efficiency using simple starting materials and a catalytic amount of a reusable catalyst is especially noteworthy.

Stereoselective Synthesis of syn-γ-Hydroxynorvaline and Related α-Amino Acids

The total syntheses of three enantiomerically pure non-proteinogenic amino acids, l-norvaline, γ-oxonorvaline, and syn-γ-hydroxynorvaline, are reported. The chromatography-free route pivoted on the construction of highly enantiomerically enriched substituted α-amino-γ-oxopentanoic acid, from which all three members were accessed divergently via chemoselective and stereoselective reductions. The rapid synthesis of this key α-amino-γ-oxopentanoic acid was achieved by a highly diastereoselective crystallisation-driven three-component Mannich reaction from the readily available building blocks acetone, glyoxylic acid monohydrate, and (S)-(4-methoxyphenyl)ethylamine. The enantiomeric purity of all target molecules was confirmed by HPLC analysis, either of the amino acids or their derivatives.

Asymmetric Mannich Reaction: Synthesis of Novel Chiral 5-(substituted aryl)-1,3,4-Thiadiazole Derivatives with Anti-Plant-Virus Potency

Abstract A series of novel chiral 5-(substituted aryl)-1,3,4-thiadiazole derivatives was synthesized in an enantioselective three-component Mannich reaction using cinchona alkaloid squaramide catalyst with excellent enantioselectivities (up to >99% enantiomeric excess (ee)). The bioassay results showed that these derivatives possessed good to excellent activities against tobacco mosaic virus (TMV).

Acetophenone Mannich bases: study of ionic liquid catalysed synthesis and antioxidative potential of products.

Three-component Mannich reaction of acetophenone or 4-iodoacetophenone with a variety of substituted anilines and benzaldehyde, catalysed with diethanolammonium chloroacetate, was performed under mild conditions. Mannich bases (MBs), of which five are new, were obtained in good to excellent yields. All compounds were characterized using elemental analysis, NMR and IR. In addition, detailed experimental and simulated UV–Vis spectral characterization of these compounds is presented here for the first time. In vitro antioxidative potential of synthetized MBs was evaluated using 2,2-diphenyl-1-picryl-hydrazyl radical and density functional theory (DFT) thermodynamical study. It was shown that compounds with anisidine moiety express moderate antioxidative activity. Mechanism of the organocatalysed Mannich reaction was thoroughly inspected by means of DFT. The reaction undergoes the hydrogen bonding-assisted mechanism. Moreover, the proposed rate determining step of the overall reaction is water elimination in the process of iminium ion formation. To the extent of our knowledge, this is the first detailed report on the influence of this type of catalyst on the formation of iminium ion, as a crucial intermediate for the whole reaction.

Chiral phosphoric acid-catalyzed enantioselective three-component Mannich reaction of acyclic ketones, aldehydes and anilines

Chiral phosphoric acid-catalyzed enantioselective three-component Mannich reaction of acyclic ketones, aldehydes and anilines

Synthesis of β-fluoro(dicarbonyl)ethylamines from 2-fluoro-ethylacetoacetate and dimethyl-2-fluoromalonate ester by batch and semi-continuous flow three-component Mannich reactions

Multi-component Mannich reactions between 2-fluoro-ethylacetoacetate or dimethyl-2-fluoromalonate ester, aldehyde and amine components allowing convenient synthesis of β-fluoro(dicarbonyl)ethylamine systems using both batch and continuous flow techniques are reported.