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.

Visible Light Promoted Site-Specific Functionalization of α-Acyloxy Carboxamides: Unlocking a Forbidden Chemical Space in the Passerini Reaction.

The facile generation of the α-acyloxy carboxamide radical is hereby reported for the first time, utilizing a photoredox catalyzed reaction of Passerini adducts synthesized using a 4-formyl-1,4-dihydropyridine as the carbonyl component. This radical effectively engages in a Giese reaction with a range of olefins, ultimately leading to the synthesis of novel Passerini-derived products not previously amenable to direct aldehyde-based transformations. Consequently, the resulting strategy, developed both in batch and in flow, offers a promising opportunity to expand the chemical space accessible through the Passerini reaction, virtually incorporating "impossible" aldehydes.

An In-Depth Exploration of Six Decades of the Kröhnke Pyridine Synthesis.

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.

High-Shear Enhancement of Biginelli Reactions in Macromolecular Viscous Media.

Chemical reactions and transformations in non-traditional vessels have gained significant interest in recent years. Flow chemistry, with its advantages in mixing, mass transfer, scalability, and automation, is a driving force behind this paradigm shift. In particular, the Vortex Fluidic Device (VFD) has emerged as a versatile tool across various applications, from organic synthesis to materials science. In this study, the role of the VFD in performing the Biginelli reaction, a multicomponent reaction widely used in pharmaceutical and polymer science, for a post-polymerization modification is explored. By conducting the Biginelli reaction in the VFD, rapid product formation with low catalyst loading and without the need for high temperatures is achieved. However, the critical need to understand and know solution viscosity, especially within the context of modifying macromolecules is highlighted.

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.

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.

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.

Multicomponent reaction for synthesis, molecular docking, and anti-inflammatory evaluation of novel indole-thiazole hybrid derivatives.

In this article, novel thiazol-indolin-2-one derivatives 4a-f have been synthesized via treatment of thiosemicarbazide (1) with some isatin derivative 2a-f and N-(4-(2-bromoacetyl)phenyl)-4-tolyl-sulfonamide (3) under reflux in ethanol in the presence of triethyl amine (TEA). The structures of new products were elucidated by elemental and spectral analyses. Moreover, all compounds were investigated for their in vivo anti-inflammatory activity using celecoxib as a reference drug. The target compound 4b was the most active anti-inflammatory candidate and exhibited higher edema inhibition (EI = 38.50%) than that recorded by celecoxib (EI = 34.58%) after 3 h. Furthermore, the most active compounds 4b and 4f were subjected to a molecular docking study inside COX-2 enzyme to show their binding interactions. Both compounds 4b and 4f showed good fitting into COX-2 binding site with docking energy scores - 11.45 kcal/mol and - 10.48 kcal/mol, respectively which indicated that compound 4b revealed the most promising and effective anti-inflammatory potential.

Green synthesis and cytotoxic activity of functionalized naphthyridine.

A multicomponent synthesis of 1,8-naphthyridine with high yields utilizing benzaldehydes, malononitrile, phenol, and acetylenic esters in aqueous solution at room temperature in the presence of SiO2/Fe3O4 as a reusable catalyst is reported. Using the MTT test, the cytotoxic properties of all the produced compounds were assessed in vitro against cancer cell lines (MCF-7 and A549) and normal cell lines (BEAS-2B). It was discovered that the most effective cytotoxic agent, doxorubicin-like in its lack of selectivity, was the derivative 5h. On the other hand, the compound 5c might be regarded as an equipotent molecule with greater selectivity in relation to doxorubicin. Also, this study investigates the antioxidant effects of 1,8-naphthyridine carboxylates, along with other studies conducted in this study.

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.

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.

Highly Potent and Intestine Specific P-Glycoprotein Inhibitor to Enable Oral Delivery of Taxol.

Taxol is widely used in cancer chemotherapy; however, the oral absorption of Taxol remains a formidable challenge. Since the intestinal p-glycoprotein (P-gp) mediated drug efflux is one of the primary causes, the development of P-gp inhibitor is emerging as a promising strategy to realize Taxol's oral delivery. Because P-gp exists in many tissues, the non-selective P-gp inhibitors would lead to toxicity. Correspondingly, a potent and intestine specific P-gp inhibitor would be an ideal solution to boost the oral absorption of Taxol and avoid exogenous toxicity. Herein, we would like to report a highly potent and intestine specific P-gp inhibitor to enable oral delivery of Taxol in high efficiency. Through a multicomponent reaction and post-modification, various benzofuran-fused-piperidine derivatives were achieved and the biological evaluation identified 16 c with potent P-gp inhibitory activity. Notably, 16 c was intestine specific and showed almost none absorption (F=0.82 %), but possessing higher efficacy than Encequidar to improve the oral absorption of Taxol. In MDA-MB-231 xenograft model, the oral administration of Taxol and 16 c showed high therapeutic efficiency and low toxicity, thus providing a valuable chemotherapy strategy.

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.

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.

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.

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.

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps.

Pyrazoles are rarely found in nature but are traditionally used in the agrochemical and pharmaceutical industries, while other areas of use are also actively developing. However, they have also found numerous other applications. The search for new and efficient syntheses of these heterocycles is therefore highly relevant. The modular concept of multicomponent reactions (MCR) has paved a broad alley to heteroaromatics. The advantages over traditional methods are the broader scope and increased efficiency of these reactions. In particular, traditional multistep syntheses of pyrazoles have considerably been extended by MCR. Progress has been made in the cyclocondensation of 1,3-dielectrophiles that are generated in situ. Limitations in the regioselectivity of cyclocondensation with 1,3-dicarbonyls were overcome by the addition-cyclocondensation of α,ß-unsaturated ketones. Embedding 1,3-dipolar cycloadditions into a one-pot process has additionally been developed for concise syntheses of pyrazoles. The MCR strategy also allows for concatenating classical condensation-based methodology with modern cross-coupling and radical chemistry, as well as providing versatile synthetic approaches to pyrazoles. This overview summarizes the most important MCR syntheses of pyrazoles based on ring-forming sequences in a flashlight fashion.

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.

O,S,Se-containing Biginelli products based on cyclic ß-ketosulfone and their postfunctionalization.

A one-pot three-component Biginelli synthesis of dihydropyrimidinones/thiones/selenones via acetic acid or solvent-free Yb(OTf)3-catalyzed tandem reaction of ß-ketosulfone (dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide), an appropriate urea, and arylaldehyde has been developed. The reaction proceeds with high chemo- and regioselectivity to give diverse DHPMs in reasonable yields up to 95%. Moreover, an SO2-containing analogue of anticancer drug-candidate enastron (SO2 vs C=O) was obtained by using the here reported method in gram scale. We also demonstrate the reactivity of the Biginelli product in various directions - synthesis of condensed thiazoles and tetrazoles. In silico assessment of ADMET parameters shows that most compounds meet the lead-likeness requirements. The biological profiles of new compounds demonstrate high probability levels of activity against the following pathogens/diseases: Candida albicans, Alphis gossypii, Tripomastigote Chagas, Tcruzi amastigota, Tcruzi epimastigota, Leishmania amazonensis, and Dengue larvicida.

Ugi bisamides based on pyrrolyl-ß-chlorovinylaldehyde and their unusual transformations.

By one-pot four- and three-component Ugi reactions involving convertible isocyanides and unexplored pyrrole-containing ß-chlorovinylaldehyde, a small library of 20 bisamides with unusual behavior in post-Ugi transformations was prepared and characterized. Surprisingly, a well-documented approach to obtain peptide-containing carboxylic acids through acid hydrolysis of the convertible isocyanide moiety in the Ugi bisamides proceeded in an unexpected manner in our case, leading to the formation of derivatives of amides of heterylidenepyruvic acid. An optimized synthetic protocol for this transformation was elaborated and a plausible sequence involving the elimination of the 2-chloroacetamide moiety and the conversion of the ß-chlorovinyl fragment into a vinyl one is provided.