Sequential Multicomponent Reaction Research Articles

Synthesis of novel chromeno-tethered imidazolone scaffold through one pot sequential multicomponent reaction mediated cyclization: A structural, computational and in silico investigation

A novel chromeno imidazole-based derivative was synthesized and characterized using single crystal X-ray diffraction technique. The MCR strategical methodology followed by the cyclization and the SN2 mechanism resulted in the formation of chromenoimidazolone molecular scaffold. The structural analysis revealed that the structure crystallizes in P1¯ space group and was stabilized by intra and intermolecular interactions. The dihedral angle of 82.85° indicated the non planarity of the molecule. The molecular interactions exhibited by the crystal structure were analysed by the Hirshfeld surface analysis and the H…H interactions was found to be major contributor to the overall interactions of the compound with the percentage contribution of 52.3%. The theoretical investigations were carried out using density functional theory calculations to predict various electronic properties of the compound. The HOMO-LUMO energy gap of the compound is found to be 1.4534 eV for alpha and 3.9367 eV for a beta spin. The MEP analysis revealed that the C = O exhibit the highest negative electrostatic potential with the value of -0.064 a.u. indicating its nucleophilic nature. Further, natural bond orbital analysis revealed that the LP(1)→π* interaction demonstrates the highest stabilization energy of 53.49 kcal/mol.The results of the molecular docking analysis of the compound against 6FS1 protein showed a docking score of -7.4 kcal/mol, indicating the potential of the compound to be a good anti-cancer agent. Further, the findings of the molecular docking were substantiated by the molecular dynamics simulation studies which showed very good stability of the protein-ligand complex.

Manganese Complex Catalyzed Sequential Multi-component Reaction: Enroute to a Quinoline-Derived Azafluorenes.

The development of innovative synthetic strategies for constructing complex molecular structures is the heart of organic chemistry. This significance of novel reactions or reaction sequences would further enhance if they permitted the synthesis of new classes of structural motifs, which have not been previously created. The research on the synthesis of heterocyclic compounds is one of the most active topics in organic chemistry due to the widespread application of N-heterocycles in life and material science. The development of a new catalytic process that employs first-row transition metals to produce a range of heterocycles from renewable raw materials is considered highly sustainable approach. This would be more advantageous if done in an eco-friendly and atom-efficient manner. Herein we introduce, the synthesis of various new quinoline based azafluorenes via sequential dehydrogenative multicomponent reaction (MCR) followed by C(sp3)-H hydroxylation and annulation. Our newly developed, Mn-complexes have the ability to direct the reaction in order to achieve a high amount of desired functionalized heterocycles while minimizing the possibility of multiple side reactions. We also performed a series of control experiments, hydride trapping experiments, reaction kinetics, catalytic intermediate and DFT studies to comprehend the detailed reaction route and the catalyst's function in the MCR sequence.

An aerobic copper-catalyzed multi-component reaction strategy for N′,N′-diaryl acylhydrazine synthesis: reactions and mechanism

A sequential multi-component reaction of aldehydes and aryl hydrazines for the synthesis of N',N'-diaryl acylhydrazines with high regioselectivity has been achieved via an aerobic copper-catalyzed process.

Facile synthesis of tetrahydroquinoline containing dithiocarbamate derivatives via one-pot sequential multicomponent reaction.

An efficient sequential multi-component method for the synthesis of tetrahydroquinoline containing dithiocarbamates has been developed. This reaction involved a boronic acid-catalysed reduction of quinolines to tertrahydroquinolines, followed by nucleophilic addition reaction with carbon disulphide to form dithiocarbamic acids and subsequent S-arylation via external base-free Chan-Evans-Lam coupling in a one-pot operation. The methodology is compatible with a wide variety of functional groups and also useful in the late-stage functionalization of pharmaceuticals. The dual role of the boronic acid as a catalyst (in the reduction of quinolines) and as a reagent (in the S-arylation) has been demonstrated for the first time herein.

Turn-Mimic Hydantoin-Based Loops Constructed by a Sequential Multicomponent Reaction.

A collection of peptidomimetics characterized by having an aspartic acid motif embedded in a rigid hydantoin heterocycle are synthesized through a sequential multicomponent domino process followed by standard regioselective deprotection/coupling reactions based on acid-base liquid/liquid purification protocols. 1H nuclear magnetic resonance experiments, molecular modeling, and X-ray analysis showed that the resulting hydantoin-based loops I (in particular) and II (to a lesser extent) can be considered novel β-turn inducer motifs being able to project two peptide-like strands in a U-shaped conformation driven by the formation of intermolecular hydrogen bonds.

Advances in the Synthesis of Fused 1,2,3-Triazoles via a MCR-Intramolecular Azide-Alkyne Cycloaddition Approach

The present review narrates several reports which deal with the synthesis of fused 1,2,3-triazole containing scaffolds following a sequential multicomponent reaction (MCR)-intramolecular azide-alkyne cycloaddition (IAAC) approach. The reviewed reactions were cleverly designed so as to incorporate azide and alkyne functionalities in the MCR product which was then subjected to IAAC. The review is divided into two sections based on the number of components in the multicomponent reaction. We have aimed at a critical discussion and also have highlighted either advantages or disadvantages of each methodology.

Synthesis, in vitro biological evaluation and molecular docking study of coumarin-1,4-dihydropyridine derivatives as potent anti-inflammatory agents

The green chemistry approach provides for the synthesis of coumarin-1,4-dihydropyridine scaffolds 6a-o via sequential multi-component reaction using catalytic amount of triethylamine (TEA). These new coumarin scaffolds have been successfully explored for the effective inflammatory as well as microbial infection inhibitors. The antimicrobial activity results of the title compounds show potent activity against both Gram positive and Gram negative bacterial and fungal stains. Additionally, anti-inflammatory activity of all the compounds have been found to be quite promising in comparison with standard Diclofenac sodium. Furthermore, the in silico docking study has been performed for all the compounds with S. aureus DNA gyrase and cyclooxygenase-2 (PDB ID 4PH9). The computational results are in good agreement with the in vitro antibacterial and anti-inflammatory findings.

Synthesis, Molecular Docking and Mosquitocidal Efficacy of Lawsone and its Derivatives Against the Dengue Vector Aedes aegypti L. (Diptera: Culicidae).

Aedes aegypti is the primary vector of dengue, a significant public health problem in many countries. Controlling of Ae. aegypti is the biggest challenge in the mosquito control programe, and there is a need for finding bioactive molecules to control Ae. aegypti in order to prevent dengue virus transmission. To assess the mosquitocidal property of lawsone and its 3-methyl-4H-chromen-3-yl-1- phenylbenzo[6,7]chromeno[2,3,c]pyrazole-dione derivatives (6a-6h) against various life stages of Ae. aegypti. Besides, to study the mode of action of the active compound by molecular docking and histopathological analysis. All derivatives were synthesized from the reaction between 2-hydroxy-1,4-naphthoquinone, chromene-3-carbaldehyde, and 1-phenyl-3-methyl-pyrazol-5-one by using one pot sequential multicomponent reaction. The mosquito life stages were subjected to diverse concentrations ranging from 1.25, 2.5, 5.0, and 10 ppm for lawsone and its derivatives. The structure of all synthesized compounds was characterized by spectroscopic analysis. Docking analysis was performed using autodock tools. Midgut sections of Ae. aegypti larvae were analyzed for histopathological effects. Among the nine compounds screened, derivative 6e showed the highest mortality on Ae. aegypti life stages. The analyzed LC<50 and LC90 results of derivative 6e were 3.01, 5.87 ppm, and 3.41, 6.28 ppm on larvae and pupae of Ae. aegypti, respectively. In the ovicidal assay, the derivative 6e recorded 47.2% egg mortality after 96-hour post-exposure to 10 ppm concentration. In molecular docking analysis, the derivative 6e confirmed strong binding interaction (-9.09 kcal/mol and -10.17 kcal/mol) with VAL 60 and HIS 62 of acetylcholinesterase 1 (AChE1) model and LYS 255, LYS 263 of kynurenine aminotransferase of Ae. aegypti, respectively. The histopathological results showed that the derivative 6e affected the columnar epithelial cells (CC) and peritrophic membrane (pM). The derivative 6e is highly effective in the life stages of Ae. aegypti mosquito and it could be used in the integrated mosquito management programe.

One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas, X-ray, and In Silico ADME/Tox Profiling Studies

Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.

Synthesis of 5H‐indeno[1,2‐b]pyridine derivatives: Antiproliferative and antimetastatic activities against two human prostate cancer cell lines

This study describes the direct synthesis of 2-amino-4-(phenylsubstituted)-5H-indeno[1,2-b]pyridine-3-carbonitrile derivatives 5-21, through sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-indanone in the presence of ammonium acetate and acetic acid (catalytic). The biological study showed that compound 10 significantly impeded proliferation of the cell lines PC-3, LNCaP, and MatLyLu. The antimetastatic effects of compound 10 could be related with inhibition of MMP9 in the PC-3 and LNCaP human cell lines. On the basis of a study of the structure-activity relationship of these compounds, we propose that the presence of two methoxy groups at positions 6 and 7 of the indeno nucleus and a 4-hydroxy-3-methoxy phenyl substitution pattern at position 4 of the pyridine ring is decisive for these types of molecules to exertvery good antiproliferative and antimetastatic activities.

A sequential multicomponent reaction (SMCR) strategy: Synthesis of novel pyrazolo-1,4-dioxaspiro[4,5]decane grafted spiro-indenoquinoxaline pyrrolidine heterocycles

A facile and expedient one-pot sequential five-component synthesis of highly substituted trispiro-pyrrolidine heterocycles is described. The key step involves [3 + 2]-cycloaddition of azomethine ylide. This multicomponent reaction (MCR) strategy provides a mild reaction condition, high yield of the products, high regioselectivity, and operational simplicity to assemble complex structural entity in a single operation. The structure of product was confirmed by IR, 1H-NMR, 13C-NMR, and high-resolution mass spectroscopic analysis. A theoretical insight is provided through MM2 calculation for the formation of the observed products.

Synthesis, in vitro biological evaluation and molecular docking study of coumarin-1,4-dihydropyridine derivatives as potent anti-inflammatory agents

The green chemistry approach provides for the synthesis of coumarin-1,4-dihydropyridine scaffolds 6a-o via sequential multicomponent reaction using catalytic amount of triethylamine (TEA). These new coumarin scaffolds have been successfully explored for the effective inflammatory as well as microbial infection inhibitors. The antimicrobial activity results of the title compounds have shown potent activity against both gram positive and gram negative bacterial, and fungal stains. Additionally, anti-inflammatory activity of all the compounds has been found to be quite promising in comparison with standard Diclofenac sodium. Furthermore, the in silico docking study has been performed for all the compounds with S. aureus DNA gyrase and cyclooxygenase-2 (PDB ID 4PH9). The computational results are in good agreement with the in vitro antibacterial and anti-inflammatory experimental results.

Iodide-Catalyzed Selenium-Assisted Sequential Multicomponent Synthesis of a Luminescence Benzo-Oxazino-Isoindole Framework.

We have described an unexpected pathway using the R-NC/Se system for the synthesis of the unreported benzo-oxazino-isoindole framework by the iodide-catalyzed selenium-assisted sequential multicomponent reaction of the Knoevenagel adduct of ninhydrin and malononitrile, isocyanide, amine, and elemental selenium under mild reaction conditions. The photophysical properties of the products were investigated by absorption and emission spectroscopy, revealing that the new heterocyclic system has good fluorescence properties.

An easy access to highly substituted trispiroheterocycles – Synthesis of novel pyrazolo-1,4-dioxa-spiro[4,5]decane grafted spiro-oxindolopyrrolidines via a sequential multicomponent reaction

A facile one-pot sequential four-component synthesis of highly substituted trispiro heterocyclic system involving [3 + 2]-cycloaddition of azomethine ylides as the key step is described. The protocol provides a mild reaction condition, high yield of the products, high regioselectivity, and operational simplicity to assemble complex structural entity in a single operation. The structure of the product was confirmed by spectroscopic techniques, elemental and high-resolution mass spectrum analysis.

Dienaminodiones, new push-pull alkenes, from 3,4-dihydroxysalicylaldehyde-derived Schiff base

An atom-economical one-pot synthesis of a new push-pull dienaminodiones from a 3,4-dihydroxysalicylaldehyde-derived Schiff base and indoles in the presence of phenyliodine(III) diacetate is described. Variation of indoles and anilines constitute a broad substrate scope of the methodology with good to moderate yields. Formation of Schiff base followed by an indole addition to afford dienaminodione takes place in one-pot; thus, the present method serves as a sequential multicomponent reaction. The present work also serves as a methodology to afford indole variants of natural product talaroenamine B.

A facile atom – economical synthesis of highly substituted pyrazolo-N-methyl-piperidine grafted spiro-indenoquinoxaline pyrrolidine heterocycles via a sequential multicomponent reaction

An expedient one-pot sequential five component synthesis of highly substituted pyrazolo-N-methyl-piperidine grafted spiro-indenoquinoxaline pyrrolidine heterocycles involving [3 + 2]-cycloaddition of azomethine ylides as the key step is described. The protocol provides a mild reaction condition, high yield of the products, high regioselectivity and operational simplicity to assemble complex structural entity in a single operation. The structure of the product was confirmed by spectroscopic techniques and elemental analysis.

Synthesis of Chromeno[4,3-b]pyrrol-4(1H)-ones through a Multicomponent Reaction and Cyclization Strategy.

A novel three-component reaction of 2-oxo-2H-chromene-3-carbaldehydes with isocyanides and anilines was developed for one-pot assembly of biologically intriguing chromeno[4,3-b]pyrrol-4(1H)-ones, which can also be transferred into diverse polycyclic fused scaffolds through further synthetic manipulations. The described method tolerates a broad substrate scope and proceeds in moderate to good yield via a sequential multicomponent reaction and intramolecular Michael cyclization.

Synthesis of new functionalized thiazolo pyridine-fused and thiazolo pyridopyrimidine-fused spirooxindoles via one-pot reactions

A sequential multi-component reaction of the nitroketene dithioacetals, cysteamine hydrochloride, isatin and different CH-acids is described. This efficient method provides new functionalized thiazolo pyridine-fused spirooxindoles and thiazolo pyridopyrimidine-fused spirooxindoles in good yields. In the case of using isatin derivatives (5-bromoisatin and 5-chloroisatin), the reaction was carried out by using nano-SiO2 (20 mol%) as an effective heterogeneous Lewis acid promoter. This type of reaction provides a range of skeletally different polycyclic spiro thiazole-based heterocyclic structures and represents attractive advantages including straightforward one-pot operation under the catalyst-free condition and simple workup procedures without using tedious purification procedure.

Sulfonic acid-functionalized graphitic carbon nitride composite: a novel and reusable catalyst for the one-pot synthesis of polysubstituted pyridine in water under sonication

Graphitic carbon nitride as an interesting sustainable soft nanomaterial has drawn broad interdisciplinary attention because of unique electronic structure and chemical stability. An ultrasound-assisted preparation of a series of polysubstituted pyridines in the presence of a polar and strongly acidic sulfonated magnetic graphitic carbon nitride (Fe3O4@g-C3N4-SO3H) under milder and faster reaction conditions in water as a green medium was reported. One-pot sequential multicomponent reaction of aromatic aldehydes with acyclic and cyclic ketones, malononitrile and ammonium acetate was afforded the pyridine derivatives in good-to-excellent yields. In view of eco-friendly and economic considerations, this approach offers a straightforward and convenient route to generate biologically active pyridine derivative in an environmentally friendly manner. The Fe3O4@g-C3N4-SO3H showed high stability and reusability over several reaction sets without noteworthy loss of activity, and thus, this method is a cheap and eco-friendly procedure.

Synthesis of sequence-controlled polymers via sequential multicomponent reactions and interconvertible hybrid copolymerizations

Synthesizing artificial polymers with precise sequence structures, such as their biological analogues, is a serious challenge and of great importance in polymer science. Recently, step-growth polymerization and chain growth polymerization have been the main synthesis methods for preparing artificial sequence-regulated polymers. However, it is difficult to obtain sequence-controlled polymers with sufficient molecular diversity via step-growth polymerization; on the other hand, chain-growth polymerization generally requires laborious repetitive monomer feeding. In this focus review, the sequential multicomponent reactions for preparing periodic sequence-controlled polymers with sufficient molecular diversity and complexity and the interconvertible hybrid copolymerizations producing hybrid multiblock copolymers rapidly in one pot are highlighted. We have developed sequential multicomponent reaction and interconvertible hybrid copolymerization methods to prepare sequence-controlled polymers. The sequential multicomponent reaction combines more than two different multicomponent reactions in one pot to prepare periodic sequence˗controlled polymers with sufficient molecular diversity. The interconvertible hybrid copolymerization method uses trithiocarbonate compounds to combine radical polymerization of vinyl monomers and anionic ring-opening polymerization of thiirane monomers, resulting in hybrid multiblock sequence-regulated polymers.