Multicomponent Reaction Research Articles

Ideas Behind the Tryptophan-Mediated Petasis Reaction (TMPR) Concept for Peptide Stapling.

This Concept short review offers an insightful analysis of pivotal research papers and explores the key synthetic ideas behind the intersection of two realms in peptide chemistry: using tryptophan and Petasis multicomponent reactions for macrocyclisation and labelling of peptides. The recently published tryptophan-mediated Petasis reaction (TMPR) concept represents a critical junction between these two worlds, highlighting how combining such methodologies leads to more effective and versatile synthetic strategies, setting a potentially new direction for future research in the field of peptide-drug conjugates.

Skeletal Formation of Carbocycles with CO2: Selective Synthesis of Indolo[3,2-b]carbazoles or Cyclophanes from Indoles, CO2, and Phenylsilane

Skeletal Formation of Carbocycles with CO₂: Selective Synthesis of Indolo[3,2-<i>b</i>]carbazoles or Cyclophanes from Indoles, CO₂, and Phenylsilane

Synthesis of Polysubstituted Pyridines via Nitrogen-doped Graphene Catalyzed One-Pot Multicomponent Reaction under Solvent-Free Conditions

Abstract: Polysubstituted pyridine derivatives were producedwith high to excellent yields in the presence of nitrogen-doped graphene (NDG) as a dual acid–based catalyst. NDG efficiently catalyzes the multicomponent reaction between arylaldehydes, diethyl-acetylene dicarboxylates, malononitrile, and ammonium acetate under solvent-free conditions at 80°C to afford the polysubstituted pyridines in short reaction times. The structures of the synthesized pyridines were established by Ft-IR, 1H, and 13C NMR spectroscopic analysis. The advantages of this method include the in-situ oxidation of prepared 1,4-dihydropyridines, one-pot procedure, solventless system, operational simplicity, and no column chromatography. Additionally, neither toxic solvents nor catalysts are needed, and the procedure can be very reliable among the reported methodologies. The yields and reaction times in the presence of four times recycled catalyst are in comparable to the fresh catalyst. background: Graphene quantum dots have attracted considerable attention of chemists because of their unique properties such as: stability, non-toxicity, good water solubility, biocompatibility. In continuation of our interest in using ionic liquids, water or solvent-free systems as green reaction media in organic reactions for the synthesis of important compounds , we wish to report here efficient synthesis of polysubstituted pyridine derivatives in high to excellent yields using Nitrogen-doped graphene as efficient catalyst.

Multicomponent Polymerizations of Elemental Sulfur, CH2Cl2, and Aromatic Amines toward Chemically Recyclable Functional Aromatic Polythioureas.

The exploration of new polymer materials required the development of efficient, economic, robust, and scalable synthetic routes, taking energy consumption, environmental benefit, and sustainability into overall consideration. Herein, through retro-polymerization analysis of functional aromatic polythioureas, a multicomponent reaction of elemental sulfur, CH2Cl2, and aromatic amines was designed with the assistance of fluoride, and efficient, economic, and robust multicomponent polymerizations (MCPs) of these three abundantly available cheap monomers, elemental sulfur, CH2Cl2, and aromatic diamines, were developed to realize scalable conversion directly from sulfur to a series of functional aromatic polythioureas with high molecular weights (Mn up to 50,800 g/mol) in excellent yields (up to 98%). The synergistic cooperation of the strong and selective coordination of thiourea with gold ions and the redox property of aromatic polythiourea enable in situ reduction of Au3+ to elemental gold under a normal bench condition. Furthermore, the functional aromatic polythiourea could be chemically recycled through aminolysis with NH3·H2O to afford a diamine monomer in 83% isolated yield. The development of elemental sulfur-based MCP has brought the opportunity to access cost-effective and sustainable sulfur-containing functional polymer materials, which is anticipated to provide a solution for the utilization of sulfur waste and making profitable polymer materials.

Thiamine Hydrochloride: A Highly Efficient Organo-Catalyst for the One-Pot Synthesis of 2, 4, 5-Triaryl Imidazole Derivatives

Abstract: In this study, we have developed an expeditious and efficient method for the synthesis of 2,4,5–triaryl imidazole derivatives using thiamine hydrochloride as a catalyst. The one-pot, solventfree- multicomponent reaction of an aromatic/heterocyclic aldehyde with benzyl and ammonium acetate at reflux conditions leads to the formation of title compounds in extremely good yields. This protocol offers several features, such as safe, simple, atom efficient, economical, mild conditions, minimum waste, easy work-up procedures, shorter reaction time (40-45 min), catalyst recyclability, etc. The developed methodology is operationally simple and eco-friendly.

Trihaloisocyanuric Acids: Useful Reagents for Halogenation Reactions and Heterocyclic Scaffold Construction

Abstract: Trihaloisocyanuric acids [1,3,5-trihalo-1,3,5-triazine-2,4,6-(1H,3H,5H)-triones] are commercially available or easily prepared solids. They are highly reactive, stable, easily handled, and have an excellent atom economy, transferring up to three halogen atoms to organic substrates. In these regards, the present review summarizes their synthetic applications as safe and convenient reagents. Therefore, electrophilic halogenation reactions of alkenes, alkynes, arenes, heteroarenes, carbonyl compounds, and heteroatoms, as well as radical halogenation involving saturated substrates and in situ halogenated intermediates for Appel-type reactions are presented and discussed. Remarkably, applications of trihaloisocyanuric acids in processes for the construction of heteroarene scaffolds based on electrophilic halo- and oxidative cyclization, multicomponent reactions, and telescopic reactions are also given.

Organoselenium-Catalyzed C2,3-Diarylation of N-H Indoles.

An organoselenium-catalyzed C2,3-diarylation of unprotected N-H indoles with electron-rich aromatics has been developed. This one-pot multicomponent tandem cross-dehydrogenation coupling reaction allows for the incorporation of two different aromatic groups to indoles. More importantly, this approach offers significant advantages, including a high atom and step economy, eliminating the need for prepreparation of the reaction substrates, streamlining the synthetic process and enhancing its practicality. Overall, this organoselenium-catalyzed C2,3-diarylation reaction presents an efficient and versatile strategy for the functionalization of indole derivatives.

Recent Advancement in Multicomponent Synthesis of Fused Coumarin Derivatives.

The synthesis of coumarin derivatives has been an essential topic since its discovery in 1820. In bioactive compounds, the coumarin moiety serves as a backbone, as many such bioactive compounds with the coumarin moiety play a significant role in their bioactivities. Given this moiety's relevance, several researchers are developing fused-coumarin derivatives to create new drugs. Mostly the approach done for this purpose was a multicomponent reaction based. Over the years, the multicomponent reaction has gained enormous popularity, and this approach has evolved as a replacement for conventional synthetic methods. Because of all these perspectives, we have reported the various fused-coumarin derivatives synthesized using multicomponent reactions in recent years.

One pot green synthesis of Biginelli reaction catalysed by bio-waste metal-free super acid lignin sulphonate

A Bio-waste metal-free super acid catalyst (BWC) has been synthesized at higher temperature and used as a catalyst for synthesis of 3,4-dihydropyrimidine-2-(1H)-ones (DHPMs) via one pot three component Biginelli reaction. The multicomponent reactions are very complex and involves more than two reagents. In the present study, sulfonated carbonaceous material called a green catalyst was utilized for three component reaction. Catalyst was synthesized from sodium lignosulfonate which is obtained from the wastage of paper-making industries from the sulfite pulping process. The synthesized green catalyst was characterized by FT-IR, Thermal Gravimetric Analysis (TGA) scanning electron microscopy (SEM), Thermal Electronic microscopy (TEM), and elemental analysis. The three component Biginelli synthesis the catalyst was optimized to 8 mol % quantity which was sufficient to complete the reaction within 1–4 hrs. The yield of reaction ranges from 70-90 %. Separation was easy and recycling ability of catalyst was also tested with good retention of catalytical activity. Catalytic activity was performed as an acid-catalyzed reaction in ethanol. The synthesis of all the compounds were confirmed by 1H NMR (Nuclear magnetic resonance), MS (Mass Spectra), FT-IR (Fourier Transform Infrared), CHNS (Carbo, Hydrogen, Nitrogen, Sulphur) analysis. The satisfactory results were obtained with good yields, shorter reaction time and simplicity in the experimental procedure. The catalysts could be recycled and reused three times without decrease in the catalytic activity significantly.

Solvatochromism and halochromism in nitro lophine derivatives: Photophysical study, computational calculations and applications as pH sensing material

Nitro Lophines were readily synthesized via multicomponent reaction of benzil, nitro benzaldehyde and ammonium acetate. All three nitro Lophines were isolated in good yields and were also characterized by various analytical and spectroscopic techniques. A distinctive solvatochromism was observed in case of ortho and para nitro containing Lophines in their absorbance spectra. In particular, naked eye solvatochromism was observed, in case of para nitro Lophine, in the form of yellow and red coloured solution in methanol and DMSO respectively. Halochromism studies revealed the hypsochromic shift under acidic pH while bathochromic shift under alkaline pH for both nitro Lophines. Again the para nitro Lophine demonstrated wonderful distinctive colour change under acidic and alkaline pH in both methanol and DMSO as solvents. The measurement of absorbance at different pH values was carried out and the data obtained were used for calculation of dissociation constants employing several graphical methods. Computational calculations were carried out using TD-DFT for UV–Vis absorption calculation while graph-convolutional neural network model was utilized for calculation of dissociation constants. Ultimately, a reusable naked eye pH detection paper could be developed using para nitro Lophine as a sole indicator.

The effect of carbon chain length of cross-linking agent on the functionality of carrier- free immobilized Thermomyces lanuginosa lipase particles

The cross-linked enzyme (CLEs) of Thermomyces lanuginosa lipase (TLL) was prepared in an isocyanide-based multi-component reactions (ICMRs) platform by applying three di-acidic cross-linkers to unveil more factors contributing to the functional properties of CLEs. The linkers were 1,11-undecanedicarboxylic acid, azelaic acid, and adipic acid with 11, 7, and 4 carbon lengths, respectively, providing a proper tool to investigate the effect of linker length on the activity, stability, and selectivity of the resulting CLEs. The immobilization yields of 60–90 % and the specific activities of 168, 88.4 and 49 U/mg were obtained for the CLEs of 1,11-undecanedicarboxylic acid, azelaic acid, adipic acid, respectively. The lower activity of azelaic and adipic acid-mediated CLEs compared to the soluble TLL (110 U/mg) was explained by in silico calculations. The results revealed that as opposed to 1,11-undecanedicarboxylic acid, both linkers tended to penetrate the enzyme active site, thus resulting in a major inhibitory effect on the enzyme functionality. The thermal and co-solvent stability of the immobilized derivatives improved compared to those of free TLL. The selectivity of CLEs was also examined by catalytic release of main omega-3 fatty acids from fish oil, presenting the highest selectivity of 22 for the CLEs of azelaic acid.

One-pot multicomponent reaction: An efficient synthesis of 4-(HET)Aryl-substituted pyrazolo-quinolinones.

Pyrazolo-quinolinones (PQs) are a versatile class of Organic chemistry and it was found that they have very advanced functionally promising as selective compounds due to their scaffold and demonstrated low toxicity and considerable clinical promise. Moreover, these compounds have an important role in different applications such as analytical reagents, technical, pharmaceutical development, and biological markers. So, we aimed to synthesize and characterize new 4-(Het)aryl-substituted Pyrazole-quinolinones. Synthesis of One-Pot Multicomponent Reaction was carried out with the reaction of 5-amino-3-methyl-1H-pyrazole 1a, and 5-amino-3-phenyl-1H-pyrazole 1b and dimedone 2 with some (het)aryl aldehydes 3 using ethanol. Characterizations such as the linear structures and the regiospecificity of the reactions were determined by using NMR, GC-MS, IR, and UV measurements. This research will be very useful for all methods and procedures using multi-one-point reactions which are very popular in the synthesis of heterocyclic systems for pyrazole- quinoline skeleton synthesis.

Synthesis of bioactive heterocyclic compounds using camphor

The aim of the work was to synthesize novel heterocyclic compounds derived from camphor with antibacterial activity. The pyridazine, xanthene, pyranothiazole, pyridinothiazole, thiophene and pyrazole derivatives were produced from 4,11,11-trimethyl-9-phenyl-7-(2-phenylhydrazono)-3,4,5,6,7,9-hexahydro-1H-1,4-methanoxanthen-8(2H)-one (1). Thiophene derivatives 6a,b were produced according to the Gewald’s reaction for  thiophene synthesis. On the other hand, pyranothiazol derivatives 8a,b were synthesized by the multicomponent reactions between xanthene derivative 5, benzaldehyde and ethylcyanoacetate or malononitrile in ethanol/triethylamine. Whereas, pyridinothiazole derivative 9 was produced in ethanol/ammonium acetate by the multicomponent reaction between xanthene derivative 5, benzaldehyde and malononitrile. The antibacterial activity of the synthesized compounds was evaluated against E. coli bacteria. All synthesized compounds showed moderate activity against E. coli bacteria.    KEY WORDS: Anti-microbial, Camphor, Heterocyclic, Pyrazol-3(2H)-one, Thiazol-4(5H)-one, Thieno[3,2-d]thiazole, Xanthenes Bull. Chem. Soc. Ethiop. 2024, 38(4), 1069-1076.                                                          DOI: https://dx.doi.org/10.4314/bcse.v38i4.20

TCS/ZnCl2 as a controlled reagent for the Michael addition and heterocyclic cyclization based on the phenyl pyrazolone scaffold with docking validation as a Covid-19 protease inhibitor

TCS/ZnCl2 is presented as a new catalyst for achieving the Michael addition adduct 5a-g by the reaction of phenyl pyrazolone 4 as the Michael donor and arylidene derivatives 3a-g as the Michael acceptor. The one-pot multi-component reaction of the same fragments' scaffolds as aldehydes 1a-g, malononitrile (2), and phenyl pyrazolone 4 with the same catalyst gives pyrano[2,3-c]pyrazole derivatives 6a-g as final products. The prepared compounds undergo docking validation as COVID-19 protease inhibitors and are compared with hydroxychloroquine as a reference drug. KEY WORDS: Pyranopyrazole, multi-component reactions, TCS/ZnCl2 catalyst, COVID-19, the energy score, hydroxychloroquine Bull. Chem. Soc. Ethiop. 2024, 38(4), 1119-1127.                                                       DOI: https://dx.doi.org/10.4314/bcse.v38i4.24                                                      

In silico and in vitro study of pyrimidones synthesized with ethylenediamine- modified β-cyclodextrin: potential against ESBL E. coli

Modern organic synthesis is primarily focused on developing environmentally benign synthetic protocols by employing green chemistry principles. Accordingly, in our recent research work, we herein report the use of modified supramolecular host cyclodextrin as an effective solid based green catalyst for accessing structurally diverse and medicinally relevant pyrimidone architectures. The catalyst and the synthesized compounds 4 (a-r) were characterized using FT-IR, NMR and GC-mass spectroscopy. Major highlights of the reported work include the economical atom process, remarkably gentler reaction conditions, ease of operation, high isolated yields, and excellent catalyst turnover numbers. The molecular docking studies suggest that the compound 4n has hydrogen bonding, hydrophobic and π-pair interactions with the active site of the CXT M 15 receptor. Further, the in-vitro antibacterial study as well as the screening of anti-biofilm activity resulted in a BIC value of 76.79 ± 0.785% at a concentration of 10 µg/mL and morphological alterations induced by DHPMs against the ESBL E. coli strain aggregated with a good result. KEY WORDS: Ethylenediamine modified β-CD, Multicomponent reaction, 3,4-dihydropyrimidin-2(1H)-ones DHPM derivatives, Solvent-free conditions, Reusability, Antibactercidal Bull. Chem. Soc. Ethiop. 2024, 38(4), 1103-1118.                                                           DOI: https://dx.doi.org/10.4314/bcse.v38i4.23

Aqueous extract of Sea buckthorn berries: A greener and ecofriendly medium for synthesis of pyrazolopyranopyrimidines

Sustainable development and environmental consciousness have become increasingly important, leading to a revolution of industrial processes and organic synthesis methods. The use of organic solvents and their associated emissions has emerged as a significant environmental issue. Consequently, there is a growing emphasis on finding substitutes for volatile solvents and halogenated organic solvents in various synthetic processes. This study focuses on a greener and more eco-friendly approach to synthesizing pyrazolopyrimidine derivatives using sea buckthorn aqueous extract as a sustainable medium. Sea buckthorn berries, rich in phenolic compounds, fatty acids, and vitamins A, C, E, along with high organic acid content, are conducive to multicomponent reactions. Pyrazolyl derivatives are of particular interest due to their role as essential components in various biologically active compounds. Overall, this methodology offers a green and environmentally sustainable alternative to current protocols, with positive implications for both sustainability and economic factors. Additionally, Sea buckthorn berry extract proves to be a recyclable medium, with minimal decrease in product yields upon recycling.

Innovative synthesis of drug-like molecules using tetrazole as core building blocks.

Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, tetrazoles are introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further showcase the versatility of these new tetrazole building blocks by integrating the tetrazole moiety into various multicomponent reactions (MCRs), which are already significantly employed in drug discovery. This technique represents a unique and complementary method to existing tetrazole synthesis processes. It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods.

Gallium Sulphide (Ga2S3): Green, Reusable, and Efficient Nanocatalyst for the Synthesis of 3,3-(arylmethylene)-bis-(4-hydroxycoumarin) Under Solvent-free Condition

Abstract:: Our current work's primary goal is to create novel heterogeneous gallium sulfide (Ga2S3) nanocatalysts and investigate their catalytic activity in the synthesis of 3,3-(arylmethylene)-bis-(4- hydroxycoumarin) derivatives without use of solvent. FT-IR, XRD, SEM, and EDX analysis characterized the synthesized gallium sulfide (Ga2S3) nanomaterial catalysts. This method's main benefits are its short reaction time, solvent-free conditions, extremely mild reaction conditions, good product yield, and, most importantly, its ability to recover catalysts after at least four runs. background: Use nanocatalyst in multicomponent reaction. objective: To enhance the catalytic activity of nanocatalyst.

Ionic Liquids Immobilized Synthesis of New Xanthenes Derivatives and their Antiproliferative, Molecular Docking, and Morphological Studies.

Xanthenes and benzoxanthenesare are highly valuable compounds in organic chemistry and medicinal chemistry. Xanthene derivatives were found to have many applications in medicinal chemistry. This work aims to explore the synthesis of xanthene derivatives with various substituents and find the possibility of their uses as anticancer agents. The basic starting compound through this work was the 2,3-dihydro-1H-xanthen-1-one (3), which was synthesized from the reaction of cyclohexan-1,3-dione and 2-hydroxybenzaldehyde. Compound 3 synthesized new thiophene, pyrimidine, isoxazole, and thiazole derivatives based on the xanthenes nucleus. Fused xanthene derivatives were obtained through further heterocyclization reactions. Multicomponent reactions expressed in this work were carried out in the presence of solvent catalyzed by Et3N and in solvent-free ionic liquid immobilized catalyst. Cytotoxicity for the newly synthesized compounds toward cancer cell lines was measured, and the results revealed that many compounds exhibited high inhibitions. The antiproliferative activity of the synthesized compounds was studied on six selected cancer cell lines. The nature of the heterocyclic ring and the variations of substituted groups showed a high effect through the inhibitions of the tested compound.

Photocatalytic Bicyclization of Indole-Tethered 1,6-Enynes for Diastereoselective Synthesis of Pyrrolo[3,2,1-jk]carbazoles.

A visible-light-driven photocatalytic protocol is established for the diastereoselective synthesis of pyrrolo[3,2,1-jk]carbazoles via a radical-triggered multicomponent bicyclization reaction starting from readily available indole-tethered 1,6-enynes and α-benzyl-α-bromomalonates under mild conditions. This photocatalytic approach exhibits a wide substrate compatibility and excellent tolerability toward various functional groups and boasts the benefit of efficient ring formation and chemical bond creation.