Multicomponent Mannich Reaction Research Articles

A Multicomponent Mannich Reaction Catalyzed by Hydrolases Immobilized on Titanate Nanotubes.

This study presents an innovative method for synthesizing β-amino carbonylated compounds, specifically 2-[phenyl(phenylamino)methyl] cyclohexanone, achieving high conversions and diastereomeric ratios. Using trypsin or α-chymotrypsin in both free and immobilized forms on titanate nanotubes (NtsTi), synthesized through alkaline hydrothermal methods, successful immobilization yields were attained. Notably, α-chymotrypsin, when free, displayed a diastereoselective synthesis of the anti-isomer with 97 % conversion and 16 : 84 (syn : anti) diastereomeric ratio, which slightly decreased upon immobilization on NtsTi. Trypsin, in its free form, exhibited diastereoselective recognition of the syn-isomer, while immobilization on NtsTi (trypsin/NtsTi) led to an inversion of diastereomeric ratio. Both trypsin/NtsTi and α-chymotrypsin/NtsTi demonstrated significant catalytic efficiency over five cycles. In conclusion, NtsTi serves as an effective support for trypsin and α-chymotrypsin immobilization, presenting promising prospects for diastereoselective synthesis and potential industrial applications. Furthermore, it offers promising prospects for the diastereoselective synthesis of 2-[phenyl(phenylamino)methyl] cyclohexanone through multicomponent Mannich reaction and future industrial application.

Multicomponent synthesis of α-branched amines using organozinc reagents generated from alkyl bromides.

The use of alkylzinc bromides in the multicomponent Mannich reaction is described. Heteroleptic organozinc compounds were obtained in THF or 2-MeTHF by direct insertion of zinc dust into the C-Br bond of alkyl bromides. It was found that the presence of a stoichiometric amount of LiCl was essential for the efficiency of the subsequent three-component coupling with aldehydes and amines. A variety of primary, secondary, and tertiary organozinc reagents as well as secondary amines and aromatic aldehydes could be used for the straightforward preparation of α-branched amines. Interestingly, whereas previously reported work describing the preparation and reaction of organozinc iodides in acetonitrile showed higher reactivity of secondary organozinc reagents over primary ones, reactions in THF in the presence of LiCl led to opposite results, with higher reactivity of primary organozinc reagents.

Construction of covalent organic frameworks via the Mannich reaction at room temperature for light-driven oxidative hydroxylation of arylboronic acids.

An increasing variety of organic reactions have been developed for the synthesis of more structurally stable and multifunctional COFs. Here, we report a class of β-ketamine linked covalent organic frameworks that were constructed through the CeCl3-catalyzed multi-component Mannich reaction at room temperature. And the TAD-COF obtained based on this method could significantly promote the light-driven oxidative hydroxylation of arylboronic acids.

Current Pharmaceutical Research on the Significant Pharmacophore Mannich bases in Drug Design.

A multitude of distinct Mannich bases have been synthesized and evaluated as potential therapeutics for a wide variety of diseases and medical conditions, either in the form of prodrugs or as molecules that trigger a biological response from specific targets. The Mannich reaction has been utilized to enhance the biological activity of numerous compounds, resulting in notable progress in various areas such as anticonvulsant, antimalarial, anticancer, anti-inflammatory, antiproliferative, antibacterial, antimicrobial, antitubercular, antiprotozoal, topoisomerases I and II inhibition, α-glucosidase inhibition, carbonic anhydrase inhibition, as well as research related to anti-Alzheimer's disease and anti-Parkinson's disease. Bioactive semisynthetic Mannich bases derived from natural compounds such as chalcone, curcumin, and thymol have also been identified. Pharmaceutical compounds characterized by low solubility may encounter challenges related to their oral bioavailability, half-life, distribution within tissues, rapid metabolism, toxicity, and various other relevant variables. Mannich bases have the ability to undergo protonation under physiological circumstances, facilitating interactions between ligands and receptors, and enhancing their solubility in water. The experimental findings indicate that the solubility of Mannich base prodrugs is higher compared to that of the parent compound. The use of the multicomponent Mannich reaction has been established as a valuable synthetic methodology for the construction of multifunctional compounds through the application of diverse synthetic strategies under varying reaction conditions. The continuous investigation of synthetic techniques for Mannich reactions involves several approaches, such as employing protocols in aquatic environments, utilizing catalysts that are both biodegradable and reusable, exploring the use of ionic liquids, investigating solvent-free and/or catalyst-free media, and exploring reaction conditions involving microwave and ultrasound irradiation. Consequently, the Mannich reaction has emerged as a powerful technique in the field of medicinal chemistry. It is utilized for the creation of new chemical compounds that possess diverse and attractive biologic features. Additionally, this reaction is employed to alter the physicochemical properties of a potential drug candidate, thereby influencing its bioavailability, efficacy, and pharmacological activity. Due to their favorable bioactivities and synthesis techniques, Mannich bases remain a subject of ongoing attention in the field of medicinal/pharmaceutical chemistry.

BCMIM][Cl] ionic liquid catalyzed diastereoselective synthesis of β‐amino ketones via facile, one‐pot, multicomponent Mannich reaction under solvent‐free condition

AbstractIn this work, by utilizing 6 mol% of 1,3‐bis(carboxymethyl)imidazolium chloride [BCMIM][Cl] ionic liquid as a catalyst, a highly effective diastereoselective one‐pot multicomponent Mannich reaction has been established. The three components, namely, cyclohexanone, substituted aromatic aldehydes, and substituted aromatic amines, underwent the Mannich reaction efficiently under the solvent‐free condition at room temperature in the presence of 6 mol% [BCMIM][Cl] catalyst to afford the desired β‐amino ketones. Excellent diastereoselectivity, rapid reaction times, high yields, and no purification by column chromatography are the key characteristics of this process. All synthesized derivatives were thoroughly characterized and confirmed using 1H NMR, 13C NMR, and Fourier‐transform infrared spectral methods. Moreover, the catalytic activity of the [BCMIM][Cl] ionic liquid catalyst was maintained after being reprocessed and used three times.

Amidoalkyl Naphthols as Important Bioactive Substances and Building Blocks: A Review on the Current Catalytic Mannich-Type Synthetic Approaches

Currently, 1-amidoalkyl-2-naphthol derivatives are of increasing interest due to their biological activities and further use in the preparation of other important bioactive molecules, such as aminoalkyl naphthols and oxazines. The synthesis of 1-amidoalkyl-2-naphthol moiety is usually achieved by employing one-pot multicomponent Mannich reactions. This review covers the recent reports on 1-amidoalkyl-2-naphthols’ preparation with the use of different catalysts and summarizes the available published data for the period of the last 3 years. It also puts emphasis on the structure, synthetic transformation and biological importance of this class of products.

Catalytic, Theoretical, and Biological Investigations of Ternary Metal (II) Complexes Derived from L-Valine-Based Schiff Bases and Heterocyclic Bases.

A new series of ternary metal complexes, including Co(II), Ni(II), Cu(II), and Zn(II), were synthesized and characterized by elemental analysis and diverse spectroscopic methods. The complexes were synthesized from respective metal salts with Schiff's-base-containing amino acids, salicylaldehyde derivatives, and heterocyclic bases. The amino acids containing Schiff bases showed promising pharmacological properties upon complexation. Based on satisfactory elemental analyses and various spectroscopic techniques, these complexes revealed a distorted, square pyramidal geometry around metal ions. The molecular structures of the complexes were optimized by DFT calculations. Quantum calculations were performed with the density functional method for which the LACVP++ basis set was used to find the optimized molecular structure of the complexes. The metal complexes were subjected to an electrochemical investigation to determine the redox behavior and oxidation state of the metal ions. Furthermore, all complexes were utilized for catalytic assets of a multi-component Mannich reaction for the preparation of -amino carbonyl derivatives. The synthesized complexes were tested to determine their antibacterial activity against E. coli, K. pneumoniae, and S. aureus bacteria. To evaluate the cytotoxic effects of the Cu(II) complexes, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MCF-7) cells compared to normal cells, cell lines such as human dermal fibroblasts (HDF) were used. Further, the docking study parameters were supported, for which it was observed that the metal complexes could be effective in anticancer applications.

Facile Multicomponent Mannich Reaction towards Biologically Active Compounds

AbstractThe Mannich reaction is one of the most broadly used organic reactions for constructing C−N and C−C bonds in synthetic chemistry. This review focuses on the multicomponent Mannich reaction and its variants for the synthesis of biologically active moieties such as anticancer, antimicrobial, antimalarial, antitubercular, anti‐inflammatory and anticonvulsant molecules. A few organocatalyzed asymmetric Mannich reactions are also incorporated.

Chiral Water-Soluble Molecular Capsules With Amphiphilic Interiors.

We present the synthesis of new chiral water-soluble dimeric capsules by the multicomponent Mannich reaction between charged amino acids (glutamic acid or arginine), resorcinarene, and formaldehyde and by subsequent self-assembly. The zwitterionic character of the backbones enables electrostatic interactions between arms and induces self-assembly of dimeric capsules, namely, (L-ArgR)2 and (L-GluR)2, in water with a wide range of pH, as demonstrated by NMR, diffusion coefficient measurement, and circular dichroism. The assembly/disassembly processes are fast on the NMR timescale. This mode of dimerization leaves side chains available for additional interactions and creates chiral cavities of mixed hydrophobic/hydrophilic character. According to this characteristic, capsules do not bind fully nonpolar or fully polar guests but effectively encapsulate a variety of chiral molecules with mixed polar/apolar characters (aliphatic and aromatic aldehydes, epoxides, alcohols, carboxylic acids, amines, and amino acids) with moderate strength. We also demonstrate the formation of heterocapsules (GluR) (ArgR) (homo- and heterochiral) that utilize additional interactions between charged acidic and basic side chains and have better encapsulation properties than those of the homodimers.

Mixed Aliphatic Organozinc Reagents as Nonstabilized Csp3-Nucleophiles in the Multicomponent Mannich Reaction.

The use of mixed aliphatic organozinc reagents in the multicomponent Mannich reaction is described. A large variety of primary, secondary, and tertiary organozinc reagents, secondary amines and aromatic or aliphatic aldehydes could be used for the straightforward preparation of densely substituted amines. The three-component reaction could additionally be performed starting from alkyl halides under reductive (Barbier-type) conditions.

Bifunctional C2-symmetric ionic liquid-supported (S)-proline as a recyclable organocatalyst for Mannich reactions in neat condition

A bi-functional C2-symmetric ionic liquid-supported (S)-Proline organocatalyst [BHEDIMP][CF3CO2] has been designed and synthesized for the first time. The novel C2-symmetric organocatalyst [BHEDIMP][CF3CO2] (4 mol%) was employed for the one-pot multi-component Mannich reactions comprising of substituted acetophenones, arylamines, and aryl aldehydes to yield racemic β-amino ketones derivatives in neat conditions. This present synthetic method is highlighted by numerous advantages such as low catalyst loading percentage, solvent-free synthesis, short reaction times, easily accessible substrates, and devoid of chromatography purification. The supported C2-symmetric organocatalyst was recycled and reused six times without substantial damage to its catalytic efficiency.

Ionic liquid-immobilized proline(s) organocatalyst-catalyzed one-pot multi-component Mannich reaction under solvent-free condition

A highly efficient clean and simple methodology has been established for the one-pot Mannich reaction using ionic liquid-immobilized proline(s) organocatalyst under solvent-free conditions. The three components comprising substituted acetophenones, substituted aromatic aldehydes and substituted aromatic amines underwent Mannich reactions in the presence of 7 mol% of ionic liquid-immobilized proline(s) organocatalyst to provide β-amino carbonyl compounds in 2–3 h at room temperature with excellent yields. This methodology provides several advantages such as mild reaction conditions, short reaction time, low catalyst loading percentage, multi-component approach, transition metal-free and solvent-free synthesis. The ionic liquid-immobilized proline(s) organocatalyst was recycled and reused five times without a significant loss of its catalytic activity.

Multicomponent Mannich Reaction through C–H Activation of Azabiaryls

Multicomponent Mannich Reaction through C–H Activation of Azabiaryls

Multicomponent Aromatic and Benzylic Mannich Reactions through C-H Bond Activation.

Multicomponent Mannich reactions through C-H bond activation are described. These transformations allowed for the straightforward generation of densely substituted benzylic and homo-benzylic amines in good yields. The reaction involves a reaction between two transient species: an organometallic species, generated by transition-metal-catalyzed sp2 or sp3 C-H bond activation and an in situ generated imine. The use of an acetal as an aldehyde surrogate was found essential for the reaction to proceed. The process could be successfully applied to RhIII -catalyzed sp2 C-H bond functionalization and extended to CuII -catalyzed sp3 C-H bond functionalization.

Betti base and its modified phthalonitrile derivative for the turn on fluorimetric detection of Hg2+ and Cr3+ ions

The Betti Base Phenyl-(2-pyridinylamino)-methyl-2-naphthalenol (BB) derived by the multicomponent Mannich aminoalkylations reaction from 2-naphthol, 2-aminopyridine and benzaldehyde. The modified phthalonitrile 4-((1-(phenyl(pyridin-2-ylamino)methyl)naphthalen-2-yl)oxy)phthalonitrile BBPN was obtained by aromatic nucleophilic coupling reaction of 4-nitrophthalonitrile with BB. The compounds were successfully characterized by common spectroscopic and single crystal XRD techniques. The compounds BB and BBPN was exhibited a selective and sensitive fluorescence detection tendency towards mercuric Hg2+ and chromium Cr3+ ions respectively by the fluorescence turn on processes. Job’s plot method is employed to obtain idea about the stoichiometric interaction of metal ions with fluorescent probes. Theoretical calculation was done by Density Functional Theory DFT-B3YLP in order to get atomistic insights into the coordination geometry of Hg2+ and Cr3+ with BB and BBPN respectively. The limit of detection (LOD) of Hg2+ with BB and Cr3+ with BBPN was estimated respectively as 9.7 × 10−7 mol/L and 7.03 × 10−6 mol/L. The fluorescence enhancement of both compounds were induced by the inhibition of Photoinduced Electron Transfer (PET) process in which electron transfer happens from amino group to the fluorophore naphthol unit. The PET process was blocked upon binding of the sensors BB and BBPN with Hg2+ and Cr3+ respectively.

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.

Multicomponent Mannich‐Like Reactions of Organometallic Species

A century after the pioneering works of Carl Mannich in 1917, the aminoalkylation of carbonylated compounds has become a classical reaction of organic chemistry. Thanks to its modular character, the so‐called multicomponent Mannich reaction has found numerous applications throughout the fields of chemistry, especially for synthetic and biomedical purpose. After 100 years of good service, recent developments involving nucleophile diversification through the use of stoichiometric or even catalytic amounts of organometallic species have greatly revitalized this venerable reaction and expanded its scope, thus opening the way to a new world of possibilities. This Microreview on the organometallic Mannich reaction aims to highlight seminal contributions to the field as well as the major progress recently made in this area.

First synthesis of aminonaphthoquinones derived from lawsone in a colloidal dispersion system created by a Brønsted acid-surfactant-combined catalyst in water: An environmentally friendly protocol

Environmentally friendly one-pot protocol was developed for the first synthesis of aminonaphthoquinones derived from 2-hydroxy-1,4-naphthoquinone (lawsone) via a multicomponent Mannich reaction in aqueous media using a catalytic amount of dodecyl benzenesulfonic acid (DBSA), exploring a Brønsted acid-surfactant catalyst (BASC) concept, at room temperature.

ChemInform Abstract: A Simple and Convenient Method for Synthesis of New Aminonaphthoquinones Derived from Lawsone by Catalytic Multicomponent Mannich Reaction.

AbstractImproved reaction conditions are developed for the three component Mannich reaction of lawsone (I) with aldehydes and amines to give new aminonaphthoquinones.

A rapid access to novel and diverse 3-oxothiazolo[3,2-c]pyrimidine-8-carboxylates using multicomponent Mannich cyclisation reactions.

An efficient synthesis of novel 3-oxotetrahyrothiazolo[3,2-c]pyrimidine-8-carboxylate derivatives was developed by reacting 4-oxothiazolidines with formaldehyde and amines under very mild conditions. A variety of novel thiazolopyrimidine carboxylates were attained rapidly by double Mannich/intramolecular cyclisation reactions in very good yields.