Multicomponent Reaction Research Articles

Multicomponent synthesis of stereogenic-at-boron fluorophores (BOSPYR) from boronic acids, salicylaldehydes, and 2-formylpyrrole hydrazones.

This work describes one-step syntheses of various stereogenic-at-boron fluorochromes (BOSPYR) via multicomponent reactions involving readily accessible boronic acids, salicylaldehydes, and 2-formylpyrrole hydrazones. The dyes absorb and emit in the visible region of the electromagnetic radiation, and are characterized by large Stokes shifts (2850-4930 cm-1) with weak fluorescence emissions (Φfl: 1.5-9.1%). Notably, the dimmed fluorescence of BOSPYRs recovers upon transition to viscous media (21-fold for 1a). The representative compound 1a exhibits clear Cotton effects with dissymmetry factors of ca. |gabs| ∼ 1.9 × 10-3 in the visible region, indicating efficient asymmetry induction to the chromophore. The X-ray molecular structure of 1a shows that the chromophore deviates from planarity by 17.2°, which may contribute significantly to the inherent chirality of the fluorophore. A computational examination of excited states by time-dependent density functional theory (TD-DFT) identifies the emission mechanism as arising from a locally-excited (LE) state.

Correction: Carbon nanotubes as heterogeneous catalysts for the multicomponent reaction synthesis of heterocycles

Correction: Carbon nanotubes as heterogeneous catalysts for the multicomponent reaction synthesis of heterocycles

Green synthesis, anti-inflammatory evaluation and molecular docking of novel pyridines via one pot multi-component reaction using ultrasonic irradiation.

In this paper, we present a green application for the synthesis of novel pyridine derivatives 4a-f via one-pot, multicomponent reaction (MCRs) of some aromatic aldehydes 1a-f with malononitrile (2) and N-(4-acetylphenyl)-4-methylbenzenesulfonamide (3) in the presence of ammonium acetate using ultrasonic irradiation (U.S) in an aqueous solvent H2O:EtOH (2:1). The structures of all synthesized pyridines 4a-f were confirmed via elemental analysis and different spectroscopic techniques. This application has many advantages such as avoiding hazardous solvents, excellent yields, inexpensive, simple application, in addition to obtain pure compounds. The anti-inflammatory activity of the newly compounds was examined with the reference drug Ibuprofen. The obtained results showed that most derivatives are promising anti-inflammatory activates. Moreover, compound 4b exhibits the most anti-inflammatory activity with a percentage of inhibition with 51.67% compared with Ibuprofen 53.96%. Furthermore, the newly compounds were studied in their molecular docking simulations against the enzyme Human Cyclooxygenase-2, with Tolfenamic Acid as a reference ligand (PDB ID: 5IKT). Compound 4b demonstrated a robust binding affinity with the target protein 5ikt, evidenced by its binding affinity score of - 11.16 kcal/mol, which is the highest among the studied compounds.

Atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines via asymmetric multicomponent reaction.

Imidazo[1,2-a]pyridines are privileged heterocycles with diverse applications in medicinal chemistry; however, the catalytic asymmetric synthesis of these heterocyclic structures remains underexplored. Herein, we present an efficient and modular approach for the atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines via an asymmetric multicomponent reaction. By utilizing a chiral phosphoric acid catalyst, the Groebke-Blackburn-Bienaymé reaction involving various 6-aryl-2-aminopyridines, aldehydes, and isocyanides gave access to a wide range of imidazo[1,2-a]pyridine atropoisomers with high to excellent yields and enantioselectivities. Extensive control experiments underscored the pivotal role of the remote hydrogen bonding donor on the substrates in achieving high stereoselectivity for these reactions. The versatile derivatizations of these atropisomeric products, especially their role as an analog of NOBINs and their facile conversion into unique 6,6-spirocyclic products, further emphasize the merits of this methodology.

Synthesis of 5H-Pyrrolo[3,4-b]Pyridin-5-Ones via a Cerium Chloride Catalyzed Multicomponent Cascade Process: A One-Pot Approach Incorporating Ugi-Zhu 3CR, Aza Diels–Alder, N-Acylation, and Aromatization Reactions

We have synthesized α-isocyano-β-phenylpropionamides 5 (a–c) using a two-step process and then created a new series of poly-substituted 5H-pyrrolo[3,4-b]pyridin-5-ones 12 (a–o) via a multi-component reaction. Most of the reported literature used scandium triflate and either benzene or toluene as solvents, which are not good for the environment. We have identified cerium(III) chloride as the catalyst and acetonitrile as the solvent for conversion, which is harmless to the environment. The synthetic strategy involved Ugi-Zhu 3CR (UZ-3CR), Aza Diels–Alder, N-acylation, and aromatization steps, yielding products in the range of 65–85%.

Design and synthesis of PDSPTCF as an influential Brønsted-Lewis acidic catalyst for the producing benzo[a]benzo[6,7]chromeno[2,3-c]phenazines

Initially, 4,4'-(1,4-phenylene)di(sulfonic)pyridinium tetrachloroferrate (PDSPTCF) as a novel organic–inorganic hybrid salt was synthesized and identified by elemental mapping, energy-dispersive X-ray spectroscopy, inductively coupled plasma atomic emission spectrometer, Raman spectroscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, field emission scanning electron microscopy, vibrating-sample magnetometry, and thermal gravimetric (TG) techniques. Then, the catalytic performance of this hybrid salt was assessed for the producing benzo[a]benzo[6,7]chromeno[2,3-c]phenazine derivatives via one-pot multicomponent domino reaction (MDR) of benzene-1,2-diamine, 2-hydroxynaphthalene-1,4-dione and aldehydes under optimal conditions (70 °C, solvent-free, 5 mol% PDSPTCF) in short reaction times and high yields. Highly efficacy of the PDSPTCF for the production of benzo[a]pyrano[2,3-c]phenazines can be assigned to the synergistic effect of Lewis and Brønsted acids, and having two positions of each acid (i.e., FeCl4ˉ and –SO3H). In addition, this catalyst showed good reproducibility with six cycles of recycling.

Biginelli Reaction: A Multi-Component Type of Reaction and Synthetic Advancement in the Synthesis of Bioactive Dihydropyrimidinone Derivatives

Background: In synthetic and medicinal chemistry, multi-component reactions (MCRs) are considered an essential tool in synthesizing bioactive heterocyclic scaffolds. These reactions have been strategically used in drug discovery and development because of ease and economy. Objective: The current manuscript aims to highlight the importance of the Biginelli reaction in the synthesis of diverse dihydropyrimidinones with medicinal applications. Methods: We searched various keywords, including “multicomponent reaction”, “Biginelli reaction” and “dihydropyrimidinone” on “PubMed, PubChem, and google scholar” and collected the relevant articles for including the current work. Results: Biginelli reaction involving ketoester, aldehyde, and urea is a high-yielding, atomeconomical, environmentally benign reaction for developing a library of new dihydropyrimidinones to drive the process of drug discovery. Several developments were achieved with modifications of synthetic techniques, including C-H activation, coupling, cycloaddition, etc. Inclusively, these modifications give access to a wide range of dihydropyrimidinones. Conclusion: The current review provides an overview of recent developments in the Biginelli reaction and insights into synthesizing bioactive dihydropyrimidinones.

Application of Metal–Organic Frameworks in Multicomponent Reactions

AbstractMetal-catalyzed multicomponent reactions are versatile synthetic protocols often used to prepare a range of different products. These reactions provide complete molecular diversity and high atom efficiency while saving energy. Recently, metal–organic frameworks have attracted attention as environmentally friendly catalytic systems as they possess an abundance of catalytic sites in ordered crystal skeletons. In this graphical review, we highlight the recent progress made utilizing metal–organic frameworks to facilitate multicomponent reactions.

Highly Efficient and One-pot New Betti Bases: PEG-400 and Al2O3 Mediated Synthesis, Optimizations, and Cytotoxic Studies

Background: Multicomponent reactions (MCRs) have proven as one of the best alternatives to minimize several environmental consequences, mainly the use of hazardous chemicals, byproducts, and severe production processes. Literature reveals that MCRs with PEG-400 and metal oxide-based greener media provide a new and useful strategy for the construction of biologically potent organic systems. Objective: The present study aimed to synthesize newer Betti bases by a modified Betti reaction employing a highly efficient catalyst for the direct synthesis of a novel class of non-racemic amino benzyl naphthol ligands under green solvent media. The involvement of the articulated framework (4a-4j) was studied against nine cancer panels (NCI-60 cell lines) in terms of inhibiting/killing cancer cells. Methods: For the modification of the Betti reaction, we used 2-aminopyridin-3-ol, aromatic aldehydes, and a naphthol system using greener media employing PEG-400 and alumina as a prime active and highly selective catalyst. Furthermore, the antiproliferative activity against NCI-60 human cancer cell lines (GI50) was used for the development of pharmacologically active compounds and exhibited the single dose (10-5 M) study. Results: Based on greener media synthesis, recompenses of ease of workup, less reaction time, higher yield, and higher atom economy, as well as environmentally friendly, were reported. Betti bases were obtained at a yield of 87-98% and characterized by spectroscopic techniques. Among the synthesized scaffolds, compound 4b was found to be extra potent in melanoma cancer [MDAMB- 435], while compound 4h showed promising inhibition in leukemic cancer cell lines [HL- 60(TB) and MOLT-4]. Conclusion: A straightforward way for an efficient synthesis of Betti bases was developed via the reaction of naphthol and aldehydes with amines in PEG-400 media. An Al2O3 was effectively catalyzed in the Betti reaction in excellent yields without the formation of any other by-product in atom economy and environmentally benign way. The newly synthesized hybrids were tested in vitro against a panel of cancer cell lines, and some of the compounds exhibited significant inhibitory anti-proliferative effects. The most potent compounds (4b and 4h) showed interesting results, and compound 4b was found extra potent in melanoma cancer cell lines with -62% GI values.

Green synthesis of novel aryl sulfonyl-chromenones via one-pot, multi-component reaction using V2O5-FAp@MWCNT nanocomposite

A new, facile, environmentally friendly catalyst, V2O5-FAp@MWCNT, has been successfully synthesized. This catalytic material was characterized using various spectroscopic techniques, including FT-IR, P-XRD, SEM, EDS, and TEM. The catalytic activity of this nanomaterial was employed in the synthesis of aryl sulfonyl-chromenones under mild reaction circumstances. Further, the greener protocol offers numerous benefits, such as straightforwardness, inexpensive, use of a green solvent, eco-friendliness, an easy work-up process, less reaction times (under 30 min), waste minimization, straightforward purification, and excellent product yields (92–96%). Importantly, the catalyst material can be simply detached from the reaction via easy filtration and can be recycled multiple times without any loss in activity.

Multicomponent Synthesis of Structurally Diverse Spiroheterocycles using Bio-organic Catalyst in Aqueous Medium

Background: MCRs are one of the most significant tools in the synthesis of organic compounds. MCR is a rapid chemical technique that uses three or more reactants to produce products that sustain all structural and substructural properties of the initial components. MCRs are useful in all fields of synthetic chemistry because of their rapid rate of reaction, simple procedure and excellent yields. We reported an efficient and environmentally friendly domino approach for the synthesis of spiroheterocycles spiro annulated with indeno[1,2-b]quinoline. Method: The spiroheterocycles with privileged heterocyclic substructures have been synthesized using taurine (2-aminoethanesulfonic acid) as a green, sustainable, bio-organic and recyclable catalyst in a three-component reaction of isatins, 1,3-diketones, and 1-napthylamine in aqueous media. The present synthetic method is probably the first report to synthesize spiroheterocycles, spiroannulated with indeno[1,2-b]quinoline. Furthermore, the approach is valuable because of the excellent yield that results from the reaction in 15-20 min. Result: The optimization of reaction conditions is an important case of efficient synthesis. The solvent, temperature, time and catalyst loading were all examined. The reusability of the catalyst was also investigated experimentally. The used catalyst taurine has a high activity as well as good reusability. The present synthetic protocol will be extended to synthesise a library of hybrid compounds. The present synthetic approach is cost-effective, and time-efficient with an easy-workup methodology that gives outstanding yields (80–95%) in 15–20 min. Conclusion: Taurine-catalyzed multicomponent reaction is a novel and efficient method for the synthesis of spiroannulated indeno[1,2-b]quinolines. The high catalytic activity of taurine as a catalyst with water as a green solvent makes the process environmentally friendly. The special features of the synthetic protocol include synthetic efficiency, operational simplicity, and reusability of the catalyst and it is expected to make significant contributions not only to drug discovery studies but also to pharmaceutical and therapeutic chemistry in view of introducing molecular diversity in the synthesized molecules.

1,3-Naphthoxazine derivatives: Synthesis, in silico pharmacokinetic studies, antioxidant and photoprotective properties

Investigation into the interactions between photoprotective agents and skin can offer a precise understanding of their biological behaviors in vitro and in vivo, providing crucial insights for generating new substances. For this purpose, we designed and synthesized a series of naphthoxazine derivatives and examined their photoprotective properties. 1,3-naphthoxazine derivatives were synthesized through the multi-component reaction of 2-naphthol, arylamines and aromatic aldehydes in the presence of copper(II) trifluoromethanesulfonate (Cu(OTf)2) and (±)-Camphor-10-sulfonic acid ((±)-CSA) catalyst system under sonication. The potential of these synthesized 1,3-naphthoxazine derivatives as antioxidants and viable organic structural-based sunscreen ingredients has been investigated. Sun protection factor (SPF) assay results showed that especially compounds 4i, 4c, 4k, 4d, 4r, and 4h had remarkably high activity (23.65, 23.57, 23.04, 21.94, 20.80, and 20.26, respectively at 900 µg/mL concentration). Additionally, antioxidant activity of the synthesized compounds was evaluated and compounds 4h, 4e, 4b, and 4j exhibited the highest activities in DPPH scavenging activity assay (86.46 %, 82.83 %, 80.78 %, and 80.65 % respectively at 400 µg/mL concentration). The synthesized compounds exhibit promising characteristics for effective UV radiation absorption, suggesting their suitability for inclusion in sunscreen formulations. Cytotoxic activity of compound 4k against normal human fibroblast cell line (MRC-5) was determined by CVDK-8 method. The results revealed that the compound provided remarkable viability (87.55 %) of MRC-5 cells at concentration of 100 µM. The study explores their efficacy in providing broad-spectrum protection against UVA and UVB rays, degradation and photostability, ADMET profile, and other pharmacokinetic properties.

10-camphor sulfonic acid: A simple and efficient organocatalyst to access anti-SARS-COV-2 Benzoxanthene derivatives

10-Camphor sulfonic acid (10-CSA) has gained popularity as an organocatalyst due to its broad range of solubility and user-friendliness. Affordable multicomponent reactions (MCRs) for the preparation of benzoxanthenes (4a-4 h) (5a-5i) are presented in this work. Extensive investigations and records have been conducted on the diverse biological features exhibited by xanthenes and benzoxanthenones, such as their antiviral, antibacterial, and anti-inflammatory capabilities.Using β-naphthol, dimedone, and aldehydes, we demonstrate a cost-effective and environmentally friendly catalytic method. Under ideal circumstances, the 10-CSA catalyzes one-pot reaction, procuring impressive amounts of benzoanthenes (85–95 %). All the synthesized compounds were characterized by 1H NMR and 13C NMR. A wide variety of suitable chemicals, simple work-up procedures, and solvent-free synthesis outperforms numerous existing methods for procuring biologically relevant benzoxanthene derivatives are some of the interesting features of this organocatalyzed bronsted acid process. Therefore this synthesis is industrially inevitable. Furthermore, computational studies such as molecular docking and ADMET data analysis were performed on a number of the synthesized benzoxanthene molecules. This has led to the identification of the most potent synthetic against the SARS-CoV-2 spike protein. Additionally, to mimic how medicinal compounds interact to target proteins, computational docking and dynamics techniques were used. These studies showed that, in terms of binding affinity and other crucial traits, 4a, 4b, and 5a are potential possibilities. Overall, the current study should be of great help in the development of benzoxanthene analogs which can be potential drugs for treatment of COVID-19.

Theoretical Investigations of Bioactive Substituted 2‐Amino‐3,5‐dicarbonitrile‐6‐thiopyridine Derivatives

AbstractThis study utilizes the density functional theory (DFT) (B3LYP method and 6–31 + G* basis set)‐based method to theoretically investigate substituted 2‐amino‐3,5‐dicarbonitrile‐6‐thiopyridine derivatives within a prevalent multicomponent reaction involving aldehyde, malononitrile, and thiophenol. Various reactivity descriptors, including frontier molecular orbitals, dipole moment, polarizability, and molecular electrostatic potential, are computed to understand the variations in reactivity and stability of these compounds. The results demonstrate the reliability of DFT‐derived descriptors in predicting chemical reactivity and provide valuable insights for further research and practical applications in the field of chemical reactivity and reaction mechanisms. Geometric parameters, along with thermodynamic variables, such as standard enthalpies (ΔH), entropies (ΔS), Gibbs free energy (ΔG), and global reactivity descriptors (ionization potential (I), electron affinity (A), chemical hardness (η), softness (σ), global softness (S), chemical potential (μ), global electrophilicity (ω), and nucleophilicity index (N), are calculated to gain insight into the dynamics of these interactions and variations in reactivity and stability.

Estimation of multicomponent reactions’ yields from networks of mechanistic steps

This work describes estimation of yields of complex, multicomponent reactions (MCRs) based on the modeled networks of mechanistic steps spanning both the main reaction pathway as well as immediate and downstream side reactions. Because experimental values of the kinetic rate constants for individual mechanistic transforms are extremely sparse, these constants are approximated here using Mayr’s nucleophilicity and electrophilicity parameters fine-tuned by correction terms grounded in linear free-energy relationships. With this formalism, the model trained on the mechanistic networks of only 20 – but mechanistically- and yield-diverse MCRs – transfers well to newly discovered MCRs that are based on markedly different mechanisms and types of individual mechanistic transforms. These results suggest that mechanistic-level approach to yield estimation may be a useful alternative to models that are derived from full-reaction data and lack information about yield-lowering side reactions.

Systematic, computational discovery of multicomponent and one-pot reactions

Discovery of new types of reactions is essential to organic chemistry because it expands the scope of accessible molecular scaffolds and can enable more economical syntheses of existing structures. In this context, the so-called multicomponent reactions, MCRs, are of particular interest because they can build complex scaffolds from multiple starting materials in just one step, without purification of intermediates. However, for over a century of active research, MCRs have been discovered rather than designed, and their number remains limited to only several hundred. This work demonstrates that computers taught the essential knowledge of reaction mechanisms and rules of physical-organic chemistry can design – completely autonomously and in large numbers – mechanistically distinct MCRs. Moreover, when supplemented by models to approximate kinetic rates, the algorithm can predict reaction yields and identify reactions that have potential for organocatalysis. These predictions are validated by experiments spanning different modes of reactivity and diverse product scaffolds.

Green Synthesis and Biological Study of Novel Cyclopenta[b]pyrrolizine: One‐Pot Multicomponent Reactions via Ag/Fe3O4@MWCNTs

ABSTRACTIn this study, the cyclopenta[b]pyrrolizine was produced via using a nanocatalyst consisting of Ag/Fe3O4@MWCNTs in a multicomponent reaction that involved 2‐arylidenemalononitrile, ethyl 2‐amino‐4‐dioxo‐4‐arylbutanoates, alkyl bromides, and dimethyl acetylenedicarboxylate. The reaction was conducted in water at room temperature, resulting in the synthesis of new compounds. The synthesized compounds demonstrate antioxidant activity due to the occurrence of assessment procedures on its OH group. Moreover, an assessment was conducted on the antibacterial efficacy of recently synthesized pyridines using a disk diffusion method, employing two distinct strains of Gram‐negative bacteria. Notably, the tested compounds exhibited inhibitory effects on the growth of Gram‐positive bacteria as well.

One-Pot Three-Component Access to Furan and Thiophene Derivatives

AbstractThe furan and thiophene skeleton structures are widely present in natural products and synthetic drugs, and display multiple bioactivities. An effective one-pot three-component reaction to access furan and thiophene derivatives from 2-bromo-5-(dichloromethyl)furan or -thiophene; cyanoacetate esters, cyanoacetamides, or malononitrile; and aliphatic secondary amines has been developed. The multicomponent reaction for the construction of new C–N and C–C bonds in one pot is simple, mild, and efficient, and the yield of the target product is as high as 96%.

Core-shell structured magnetite carboxymethyl cellulose for cervical cancer treatment by maintaining methotrexate serum concentration

In this work, we attempted to improve the properties of magnetite carboxymethyl cellulose nanoparticles (Mag CMC NPs) through Ugi multicomponent reaction (MCR) to obtain magnetite carboxymethyl cellulose@functionalized carboxamide nanoparticles (Mag CMC@FCA NPs) as a new nano bio-carrier. Typically, at first Mag CMC NPs prepared by the co-precipitation method. Then by performing the Ugi MCR on Mag CMC NPs, the Mag CMC@FCA NPs achieved better properties in swelling ratio, loading efficiency and loading capacity. The prepared Mag CMC@FCA NPs characterized in detail. Evaluation of the prepared system functionality showed the swelling rate increased from 294 % to 1472 %. Furthermore, for methotrexate (MTX), loading efficiency increased from 24.62 % for Mag CMC NPs to 57.25 % for Mag CMC@FCA NPs, and the drug loading capacity increased from 1.23 % to 2.86 %. The loading of Ampicillin (AMP) and MTX has been observed to have a beneficial effect. When AMP is placed in the metabolic pathway of MTX, it prevents biodegradation of MTX up to 35 %, which results in a longer duration of high MTX concentration in the blood. Consequently, the toxicity of the prepared medication on healthy cells of the body is reduced, and the death rate is decreased to some extent.

Synergistic photobiocatalysis for enantioselective triple radical sorting.

Multicomponent reactions - those where three or more substrates combine into a product - have been highly useful in rapidly building chemical building blocks of increased complexity4, but achieving this enzymatically has remained rare.5 This limitation primarily arises because an enzyme's active site is not typically set up to address multiple substrates, especially in cases involving multiple radical intermediates6. Recently, chemical catalytic radical sorting has emerged as an enabling strategy for a variety of useful reactions7,8. However, making such processes enantioselective is highly challenging due to the inherent difficulty in the stereochemical control of radicals9. Here, we repurpose a thiamine-dependent enzyme10,11 through directed evolution, combine it with photoredox catalysis, to achieve a photobiocatalytic enantioselective three-component radical cross-coupling. This approach combines three readily available starting materials - aldehydes, α-bromo-carbonyls and alkenes - to give access to enantioenriched ketone products. Mechanistic investigations provide insights into how this dual photo-/enzyme system precisely directs the three distinct radicals involved in the transformation, unlocking new enzyme reactivity. Our approach has achieved exceptional stereoselectivity, with 25 out of 33 examples achieving ≥97% enantiomeric excess.