Multicomponent synthesis of 3-(1H-indol-3-yl)-2-phenyl-1H-benzo[f]indole-4,9-dione derivatives.

Herein, we report a one-pot greener methodology for the synthesis of 3-(1H-indol-3-yl)-2-phenyl-1H-benzo[f]indole-4,9-dione derivatives by the multicomponent reaction of arylglyoxal monohydrate, 2-amino-1,4-naphthoquinone, and indole in acetonitrile medium under reflux conditions in the presence of 10 mol% sulfamic acid as a catalyst in 20-30 min of reaction time. Three new bonds have formed (2 C-C, 1 C-N) in this methodology. Bioactive moieties such as indole, pyrrole and naphthoquinone are present in our product. This methodology is also applicable in gram-scale synthesis. A wide variety of substrates were tested to find the generality of the methodology and good yield of the products were obtained in a very short reaction time. Along with the operational simplicity of the methodology, purification process of the products is easier by simple recrystallization process. All the synthesized products were characterized by spectroscopic techniques such as FTIR, 1H NMR, 13C NMR, and HRMS.

An in-depth exploration of six decades of the Kröhnke pyridine synthesis - a review.

The Kröhnke Pyridine Synthesis has been discovered about six decades ago (1961), by Fritz Kröhnke and Wilfried Zecher at the University of Giessen. The original method involved the reaction of α-pyridinium methyl ketone salts with α,ß-unsaturated carbonyl compounds in the presence of a nitrogen source, frequently ammonium acetate. Since its discovery, the Kröhnke methodology has been demonstrated to be suitable for the preparation of mono-, di-, tri- and tetra-pyridines, with important applications in several research fields. Over the years, a number of modifications to the original approach have been developed and reported, enabling for the broad applicability of these methods even in modern days, also for the synthesis of non-pyridine compounds. In this critical and tutorial review, we will thoroughly explore and discuss the potential of the original method, the refinements that have been made over the years, as well as some applications arising from each type of pyridine and/or non-pyridine compounds produced by Kröhnke's approach.

Insight into the hydrophobic functionalization of cellulose microfibrils using the Passerini three-component reaction.

The aqueous catalyst-free one-pot Passerini 3-component reaction (P-3CR) was employed for the functionalization of dialdehyde cellulose (DAC) derived from the periodate oxidation of microfibrillated cellulose (MFC) with insights provided by 13C and 15N CP-MAS NMR and FTIR analyses. The kinetics of the P-3CR revealed rapid progress within the initial 2 h, reaching a plateau between 6 and 18 h. The reaction achieved a maximum degree of substitution (DS) with only 1 equivalent of carboxylic acid and isocyanide with respect to the number of aldehydes, therefore demonstrating the atom economy character of the P-3CR performed on MFC. Variable DS values (0.08 to 0.37) were achieved by altering the degree of oxidation of DAC (ranging from 0.48 to 1.1) when reacted with heptanoic acid and tert-butyl isocyanide. Additionally, aliphatic chain lengths of carboxylic acids from C4 to C11 were successfully used for the functionalization of DAC with distinct hydrophobic chains. Furthermore, while cosolvents negatively affected the DS when using heptanoic acid, a significant increase was observed in the case of undecanoic acid due to an improved solubility of the reagent. The aqueous medium P-3CR can thus be considered a versatile tool to tailor the functionalization of MFC and provide it with hydrophobicity.

Investigation of the Biological Activity of Pyrrolo[1,2-a]imidazole Derivatives Produced by a Green One-Pot Multicomponent Synthesis of Ninhydrins.

Aims & Objective: This study entailed the creation of a new variation of pyrroloimidazoles with exceptional efficacy through chemical synthesis. The synthesis was accomplished by tricomponent reactions utilizing ninhydrins, diamines, and activated acetylenic compounds in an aqueous setting, leading to significant yields. The antioxidant properties of recently synthesized Pyrroloimidazoles derivatives have been ascribed to the existence of NH and OH groups, which were evaluated using two techniques. The antimicrobial effectiveness of recently developed pyrroloimidazoles was evaluated using a disk diffusion technique against both Gram-negative and Gram-positive bacteria. MATERIALS AND METHODS: The study team utilized high-quality starting chemicals, solvents, and reagents with consistent chemical and physical properties. The Shimadzu IR-460 spectrometer was used in a KBr medium to get the Ft-IR spectra of the synthesized nanocatalyst. Furthermore, we employed a Bruker DRX-400 AVANCE spectrometer to acquire 1H-NMR and 13C-NMR spectra of the synthesized compounds. The spectrometer utilized in this investigation functions at a frequency of 400 MHz. The solvent employed for the spectra of produced compounds was CDCl3, with TMS serving as the internal standard. The mass spectra of the produced compounds, which have an ionization potential of 70 eV, were obtained using the Finnigan MAT 8430 spectrometer. Elements of produced compounds were subjected to elemental analysis using the Heraeus CHN-O-Rapid analyzer. RESULTS: This work investigated the three-component reaction involving ninhydrins 1, diamines 2, and electron-deficient acetylenic compounds 3 for the eco-friendly production of pyrroloimidazoles derivatives 4 in water-based solutions at normal temperature. The results indicated that these molecules displayed noteworthy efficacy, similar to that of conventional antioxidants. Also, the results indicated that the synthesized pyrroloimidazoles have bacteriostatic properties. CONCLUSION: In summary, this study aimed to examine the environmentally friendly characteristics of ninhydrins, diamines, and electron-deficient acetylenic compounds when dissolved in water at normal room temperature. The research resulted in the successful production of new pyrroloimidazole derivatives with a high rate of success. This study conducted a more in-depth analysis of the antioxidant properties of the synthesized pyrroloimidazoles 4a-4d by the utilization of two techniques: DPPH radical scavenging and FRAP assays. The results indicated that these molecules displayed noteworthy efficacy, similar to that of conventional antioxidants. Furthermore, we utilized both Gram-positive and Gram-negative bacteria to showcase the antibacterial effectiveness of the synthesized pyrroloimidazoles by the disk diffusion technique. The results indicated that the synthesized pyrroloimidazoles have bacteriostatic properties. These reactions provide benefits, such as efficient utilization of atoms, generation of large quantities of products, and straightforwardness of the reaction.

Melamine phosphate-modified magnetic chitosan: a novel biocompatible catalyst for the synthesis of biological tetrahydrodipyrazolopyridine and pyrazolopyranopyrimidine derivatives.

A novel biocompatible composite was fabricated by the functionalization of magnetic chitosan with the melamine phosphate (MP) ionic compound to serve as a recoverable and bifunctional catalyst, aiming at the diversity-oriented generation of biological tetrahydropyrazolopyridine and pyrazolopyrimidine derivatives. This involved a meticulously orchestrated reaction, exploiting the in situ generated pyrazole alongside aromatic aldehydes, ammonium acetate, and (thio) barbituric acid. The present work manifests outstanding advantages, offering a novel and great method for the optimal synthesis of two valuable heterocyclic series especially five new derivatives. The resulting novel biocompatible composite was comprehensively characterized through a range of analytical techniques, including FT-IR, NH3 and CO2-TPD, XRD, TEM, FE-SEM, VSM, EDX, elemental CHNS analysis, ICP-MS, and NMR spectroscopy. Notably, the study represents a critical step in the preparation of advanced materials from accessible and cost-effective precursors.

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.

Photocatalytic Enantioselective Radical Cascade Multicomponent Minisci Reaction of ß-Carbolines Using Diazo Compounds as Radical Precursors.

Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of ß-carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of ß-carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo-/enantio-selective control, and good functional group tolerance, allowing access to a variety of valuable chiral ß-carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products.

Palladium-Catalyzed Cascade Heck Coupling and Allylboration of Iododiboron Compounds via Diboryl Radicals.

Geminal bis(boronates) are versatile synthetic building blocks in organic chemistry. The fact that they predominantly serve as nucleophiles in the previous reports, however, has restrained their synthetic potential. Herein we disclose the ambiphilic reactivity of α-halogenated geminal bis(boronates), of which the first catalytic utilization was accomplished by merging a formal Heck cross-coupling with a highly diastereoselective allylboration of aldehydes or imines, providing a new avenue for rapid assembly of polyfunctionalized boron-containing compounds. We demonstrated that this cascade reaction is highly efficient and compatible with various functional groups, and a wide range of heterocycles. In contrast to a classical Pd(0/II) scenario, mechanistic experiments and DFT calculations have provided strong evidence for a catalytic cycle involving Pd(I)/diboryl carbon radical intermediates.

Isocyanide-Based Multicomponent Reactions Coupled One-Pot Process: Efficient Tools to Diversity-Oriented Synthesis of Structural Peptidomimetics.

Multicomponent diversity-oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5-diketopiperazines (2,5-DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3-triazoles and 1,5-disubstituted tetrazoles (1,5-DS-T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide-based multicomponent reactions (IMCRs): Ugi-4CR and Ugi-Azide (UA), followed by a one-pot process: SN2/intramolecular alkyne-azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5-DKP. Herein, the 1,2,3-triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of UA reaction generates scaffold diversity at the N-1 α-carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere such as 1,5-DS-T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.

Green synthesis and investigation of antioxidant and antibacterial activity of new derivatives of chromenoazepines employing CuO/TiO2@MWCNTs.

The synthesis of novel, high-yield derivatives of chromenoazepine was investigated in this work. CuO/TiO2@MWCNTs was used as a nanocatalyst in a multicomponent reaction involving 4-aminocumarine, activated acetylenic chemicals, and alkyl bromide in room temperature water to create these novel compounds. Using MCRs of 4-aminocumarine, isothiocyanate, and alkyl bromide in the presence of CuO/TiO2@MWCNTs as nanocatalysts in room-temperature water, chromenothiazepines were synthesized under comparable conditions. The freshly synthesized azepine exhibits antioxidant activity since its NH group has undergone two evaluation processes. Additionally, using two types of Gram-negative bacteria in a disk distribution procedure, the antibacterial activity of recently developed azepines was evaluated, and these compounds also inhibited the growth of Gram-positive bacteria. This method's benefits include quick reaction times, large product yields, and straightforward catalyst and product separation through easy steps.

Highly Conductive Imidazolate Covalent Organic Frameworks with Ether Chains as Solid Electrolytes for Lithium Metal Batteries.

Poly(ethylene oxide) (PEO)-based electrolytes are often used for Li+ conduction as they can dissociate the Li salts efficiently. However, high entanglement of the chains and lack of pathways for rapid ion diffusion limit their applications in advanced batteries. Recent developments in ionic covalent organic frameworks (iCOFs) showed that their highly ordered structures provide efficient pathways for Li+ transport, solving the limitations of traditional PEO-based electrolytes. Here, we present imidazolate COFs, PI-TMEFB-COFs, having methoxyethoxy chains, synthesized by Debus-Radziszewski multicomponent reactions and their ionized form, Li+@PI-TMEFB-COFs, showing a high Li+ conductivity of 8.81 mS cm-1 and a transference number of 0.974. The mechanism for such excellent electrochemical properties is that methoxyethoxy chains dissociate LiClO4, making free Li+, then those Li+ are transported through the imidazolate COFs' pores. The synthesized Li+@PI-TMEFB-COFs formed a stable interface with Li metal. Thus, employing Li+@PI-TMEFB-COFs as the solid electrolyte to assemble LiFePO4 batteries showed an initial discharge capacity of 119.2 mAh g-1 at 0.5 C, and 82.0 % capacity and 99.9 % Coulombic efficiency were maintained after 400 cycles. These results show that iCOFs with ether chains synthesized via multicomponent reactions can create a new chapter for making solid electrolytes for advanced rechargeable batteries.

Novel SK channel positive modulators prevent ferroptosis and excitotoxicity in neuronal cells.

Small conductance calcium-activated potassium (SK) channel activity has been proposed to play a role in the pathology of several neurological diseases. Besides regulating plasma membrane excitability, SK channel activation provides neuroprotection against ferroptotic cell death by reducing mitochondrial Ca2+ uptake and reactive oxygen species (ROS). In this study, we employed a multifaceted approach, integrating structure-based and computational techniques, to strategically design and synthesize an innovative class of potent small-molecule SK2 channel modifiers through highly efficient multicomponent reactions (MCRs). The compounds' neuroprotective activity was compared with the well-studied SK positive modulator, CyPPA. Pharmacological SK channel activation by selected compounds confers neuroprotection against ferroptosis at low nanomolar ranges compared to CyPPA, that mediates protection at micromolar concentrations, as shown by an MTT assay, real-time cell impedance measurements and propidium iodide staining (PI). These novel compounds suppress increased mitochondrial ROS and Ca2+ level induced by ferroptosis inducer RSL3. Moreover, axonal degeneration was rescued by these novel SK channel activators in primary mouse neurons and they attenuated glutamate-induced neuronal excitability, as shown via microelectrode array. Meanwhile, functional afterhyperpolarization of the novel SK2 channel modulators was validated by electrophysiological measurements showing more current change induced by the novel modulators than the reference compound, CyPPA. These data support the notion that SK2 channel activation can represent a therapeutic target for brain diseases in which ferroptosis and excitotoxicity contribute to the pathology.

A versatile approach for one-pot synthesis of hybridized quinolines linked to fused N-containing heterocycles in water.

Here, highly efficient one-pot protocols for the synthesis of structurally diverse fused N-containing heterocycles containing 2-chloroquinoline employing 1,1-bis(methylsulfanyl)-2-nitroethene, diamines, 2-chloroquinoline-3-carbaldehydes and dimedone/Meldrum's acid in green media in the absence of catalyst are reported. The current report proposes sustainable, simple, four-component and straightforward strategies for generating interesting N-containing heterocyclic compounds from a range of diamines and 2-chloroquinoline-3-carbaldehydes. The utilization of water as green media furnishes sustainability by preventing the usage of toxic solvent. A range of quinoline-containing aldehydes and diamines can be converted to two types of products with respect to using dimedone or Meldrum's acid via an inexpensive, one-pot and easy route.

Green preparation of new pyrimidine triazole derivatives via one-pot multicomponent reactions of guanidine.

In this research the goal was to produce novel pyrimidine triazole compounds in high yields using triethylamin as an efficient catalyst. These new compounds were synthesized by using multicomponent reaction of aldehydes, guanidine, electron deficient acetylenic compounds, tert-butyl isocyanide and hydrazonoyle chloride in aqueous media. Due to the presence of an NH group, which was assessed using two different methodologies, newly synthesized pyrimidine triazoles have antioxidant properties. Additionally, the antibacterial activity of newly created pyrimidine triazoles was assessed using the disk distribution method with two different types of Gram-positive bacteria and Gram-negative bacteria, demonstrating that the use of these compounds prevented the growth of bacteria. Applied to the preparation of pyrimidine triazole derivatives, this method has short reaction times, high product yields, and the ability to separate catalyst and product using simple procedures.

Advances in Difunctionalization of Olefins with Diorganyl Dichalcogenides.

Organochalcogen molecules have extensive applications in various fields. They serve as pharmaceuticals, ligands, organocatalysts, agrochemicals, and other functional materials. Difunctionalization of olefins, which belong to a class of multicomponent reactions, is a successful technique for introducing two functional moieties in a single-step reaction, both in terms of atom economy and step economy. The difunctionalization of olefins with diorganyl dichalcogenides may effectively increase the molecular complexity, which has achieved significant advancements in recent decades. This article describes recent advancements in the difunctionalization of olefins with diorganyl diselenides and diorganyl disulfides.

Brook Rearrangement as Trigger for Dearomatization Reaction: Synthesis of Non-Aromatic N-Heterocycles.

The [1,2]-Brook rearrangement stands as a potent technique for constructing complex molecules. In this study, we showcase its power in the dearomatization of aromatic N-heterocycles. Through a concise four-step process that integrates lithiation, nucleophilic addition, Brook rearrangement and dearomatization reaction, we demonstrate a versatile strategy for generating diverse non-aromatic N-heterocycles which exhibit ambident reactivities. Various acyl silanes, halo-pyridines, and quinolines have been explored within this context. The synthetic utility of this methodology is demonstrated through the construction of complex architectures.

Multicomponent Cyclizative 1,2-Rearrangement Enabled Enantioselective Construction of 2,2-Disubstituted Pyrrolinones.

The 1,2-rearrangement reaction is one of the most important approaches to construct carbon-carbon bonds in organic synthesis. However, the development of catalytic asymmetric 1,2-rearrangements is still far from mature and often suffers from problems such as complex substrates, single product structure, and lack of synthetic application. Multicomponent reaction has been recognized as a robust tool for the synthesis of diverse and tunable products from readily available starting material. Conceptionally and practically, the development of multicomponent asymmetric 1,2-rearrangements is highly desirable. In this regard, we report herein a three-component benzilic acid-type rearrangement of 2,3-diketoesters, aromatic amines and aldehydes for the asymmetric construction of synthetically challenging pyrrolinones bearing aza-quaternary stereocenters. To the best of our knowledge, this reaction represents the first example of organocatalyzed multicomponent asymmetric 1,2-rearrangements.

Palladium-Catalyzed Carbonylative Multicomponent Fluoroalkylation of 1,3-Enynes: Concise Construction of Diverse Cyclic Compounds.

Multicomponent reactions, particularly those entailing four or more reagents, have presented a longstanding challenge due to the inherent complexities associated with balancing reactivity, selectivity, and compatibility. In this study, we describe a palladium-catalyzed multi-component fluoroalkylative carbonylation of 1,3-enynes. A series of products featuring three active functional groups-allene, fluoroalkyl, and carboxyl, were efficiently and selectively integrated in a single chemical operation. Furthermore, more intricate fluoroalkyl-substituted pyrimidinones can be constructed by simply altering the 1,3-bisnucleophilic reagent. This approach also provides a valuable strategy for the late-stage modification of naturally occurring molecules and concise construction of diverse cyclic compounds.

Perfluoroalkyl-Decorated Noble-Metal-Free MOFs for the Highly Efficient One-Pot Four-Component Coupling between Aldehydes, Amines, Alkynes, and Flue Gas CO2.

The non-noble-metal catalysed-multicomponent reactions between flue gas CO2 and cheap industrial raw stocks into high value-added fine chemicals is a promising manner for the ideal CO2 utilization route. To achieve this, the key fundamental challenge is the rational development of highly efficient and facile reaction pathway while establishing compatible catalytic system. Herein, through the stepwise solvent-assisted linker installation, post-synthetic fluorination and metalation, we report the construction of a series of perfluoroalkyl-decorated noble-metal-free metal-organic frameworks (MOFs) PCN-(BPY-CuI)-(TPDC-Fx ) [BPY=2,2'-bipyridine-5,5'-dicarboxylate, TPDC-NH2 =2'-amino-[1,1':4',1''-terphenyl]-4,4''-dicarboxylic acid] that can catalyze the one-pot four-component reaction between alkyne, aldehyde, amine and flue gas CO2 for the preparation of 2-oxazolidinones. Such assembly endows the MOFs with superhydrophobic microenvironment, superior water resistance and highly stable catalytic site, leading to 21 times higher turnover numbers than that of homogeneous counterparts. Mechanism investigation implied that the substrates can be efficiently enriched by the MOF wall and then the adsorbed amine species act as an extrinsic binding site towards dilute CO2 through their strong preferential formation to carbamate acid. Moreover, density functional theory calculations suggest the tetrahedral geometry of Cu in MOF offers special resistance towards amine poisoning, thus maintaining its high efficiency during the catalytic process.

Photoinduced Synthesis of Sulfonyl-Containing Phosphorothioates via a Three-Component Reaction.

Both sulfonyl and phosphorothioate are important privileged structural motifs which are widely presented in pharmaceuticals and agrochemicals. Herein, we describe an efficient approach to synthesizing sulfonyl-containing phosphorothioates by merging photoredox and copper catalysis at room temperature. This protocol is compatible with a wide range of substrates and can be applied to the late-stage modification of complex molecules. Control experiments are conducted to demonstrate the generation of the sulfonyl radical in the transformation.