Nucleophilic Reagents Research Articles

Novel candidates synthesis of indenopyrazole, indenoazine and indenothiophene, with anticancer and in silico studies.

Aim: The indandione nucleus, is one of the most amazing nuclei in medicinal chemistry,is used to design new derivatives.Methods & materials: Novel indandione derivatives are prepared with different electrophilic and nucleophilic reagents to yield 3, 4, 8, 11, 14, 16, 19, 20, 21, 22 and 23. Compounds 8, 11, 16, 20 and 23 are investigated against OVCAR-3 and HeLa, using LLC-MK2 and cis-Pt as references. in silico and spectral studies were analyzed for the selected compounds.Results: Compounds 20 and 23 at 100ns were the most potent compounds, so molecular dynamics studies were performed.Conclusion: Compound 23 was the most active toward the HeLa cervical cell line, and compound 20 was the most active toward the Ovcar-3 cell line.

SYNTHESIS AND STUDY OF ANTINOCICEPTIVE ACTIVITY OF SUBSTITUTED 2-(3-CYANO-4,5,6,7-TETRAHYDROBENZO[B]THIOPHEN-2-YLAMINO)-4-OXOBUT-2-ENOATES

In the current work, we present results the study of synthetic transformations of substituted 3-thienylimino-3H-furan-2-one derivatives containing a nitrile substituent in the third position of the thiophene ring under the action of nucleophilic reagents. This class of compounds is of great for study due to the presence of several reaction centers in its structure, which makes it possible to obtain products of various structures, while retaining important pharmacophore groups - fragments of 2-aminothiophene and a fragment of 2,4-dioxobutanoic acid. We have synthesized and studied for biological activity substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates, which were obtained by a multistep synthesis method. The proposed method provides high yields of target compounds and includes the reaction of 4-aryl-2-hydroxy-4-oxobutanoic acids with 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile, followed by intramolecular cyclization of the resulting products under the action of propionic anhydride, as well as decyclization of the resulting substituted 3-thienylimino-3H-furan-2-ones under the action of primary alcohols. The structure of the finally isolated compounds was confirmed by 1H and 13C NMR spectroscopy and the elemental analysis. The resulting compounds were screened in vivo to detect and evaluate their biological activity and acute toxicity. Antinociceptive activity was studied in white outbred mice of both sexes by the hot plate test with intraperitoneal injection. Acute toxicity was studied according to the Pershin method, based on monitoring the condition of mice for 10 days after intraperitoneal injection of the test compounds. According to the results obtained, the tested compounds have a pronounced antinociceptive activity, and the assessment of acute toxicity indicates that they belong to the V class of practically non-toxic drugs. The high values of antinociceptive activity in combination with low toxicity make the considered substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates a highly promising class for further study in order to search for and develop new biologically active compounds with analgesic effect. For citation: Sharavyeva Yu.O., Makhmudov R.R., Shipilovskikh D.A., Silaichev P.S., Gorbunova I.A. Synthesis and study of antinociceptive activity of substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 7. P. 19-27. DOI: 10.6060/ivkkt.20246707.7029.

Origin of Chemoselectivity of Halohydrin Dehalogenase-Catalyzed Epoxide Ring-Opening Reactions.

By performing molecular dynamics (MD), quantum mechanical/molecular mechanical (QM/MM) calculations, and QM cluster calculations, the origin of chemoselectivity of halohydrin dehalogenase (HHDH)-catalyzed ring-opening reactions of epoxide with the nucleophilic reagent NO2- has been explored. Four possible chemoselective pathways were considered, and the computed results indicate that the pathway associated with the nucleophilic attack on the Cα position of epoxide by NO2- is most energetically favorable and has an energy barrier of 12.9 kcal/mol, which is close to 14.1 kcal/mol derived from experimental kinetic data. A hydrogen bonding network formed by residues Ser140, Tyr153, and Arg157 can strengthen the electrophilicity of the active site of the epoxide substrate to affect chemoselectivity. To predict the energy barrier trends of the chemoselective transition states, multiple analyses including distortion analysis and electrophilic Parr function (Pk+) analysis were carried out with or without an enzyme environment. The obtained insights should be valuable for the rational design of enzyme-catalyzed and biomimetic organocatalytic epoxide ring-opening reactions with special chemoselectivity.

Recent Advances in the Domino Annulation Reaction of Quinone Imines.

Quinone imines are important derivatives of quinones with a wide range of applications in organic synthesis and the pharmaceutical industry. The attack of nucleophilic reagents on quinone imines tends to lead to aromatization of the quinone skeleton, resulting in both the high reactivity and the unique reactivity of quinone imines. The extreme value of quinone imines in the construction of nitrogen- or oxygen-containing heterocycles has attracted widespread attention, and remarkable advances have been reported recently. This review provides an overview of the application of quinone imines in the synthesis of cyclic compounds via the domino annulation reaction.

One-Step Transformation of Aryl Diazonium Salts into Aryl Indium(III) Reagents.

A method for the conversion of diazonium salts into intrinsically nucleophilic aryl indium reagents is described. The reaction is performed using indium(I) bromide with the C-In bond being formed by the interaction of aryl radicals with the indium salt. The obtained aryl indium(III) reagents work well in the Liebeskind-Srogl cross-coupling with thioesters, affording a wide variety of aryl ketones. This two-step transformation is a general method for the acylation of diazonium salts.

Decarboxylative Nucleophilic Fluorination of Aliphatic Carboxylic Acids.

Herein, we present a decarboxylative nucleophilic fluorination of carboxylic acids with a silver catalyst. This strategy enables the synthesis of a myriad of diverse and valuable fluorinated motifs under mild conditions, demonstrating good functional-group tolerance and utility in late-stage functionalization. In contrast to traditional electrophilic fluorination, this nucleophilic method utilizes a more readily available nucleophilic fluorinating reagent, providing substantial advantages in terms of cost efficiency, broad substrate scope, and functional-group compatibility.

4-Pyridyl perfluoroalkyl sulfide as a practical nucleophilic perfluoroalkylation reagent

4-Pyridyl perfluoroalkyl sulfide as a practical nucleophilic perfluoroalkylation reagent

Effect of isopropyl chloride addition in AlCl3 catalytic system on the formation of coal tar pitch-based mesophases

Mesophase pitch is a high-quality precursor for the synthesis of high-performance pitch-based carbon fibers. The mesophase content, texture and softening point are the most important factors for the structure, properties and spinnability of mesophase pitch (MP). Herein, we report a novel approach for the preparation of mesophase pitch with high anisotropic content and low softening point by AlCl3 catalytic pyrolysis in the presence of isopropyl chloride (PrCl). The variation of anisotropic content and mesophase texture under different PrCl additions and the effect of the introduction of isopropyl on the molecular stacking of aromatic lamellar molecules were investigated. The results confirmed that, except for their role in improving catalytic activity, carbocation co-catalysts can improve the structure and molecular assembly of aromatic molecules through the introduction of alkyl groups. The reaction of isopropyl chloride (PrCl) as a co-catalyst catalyzed pyrolysis of medium-temperature coal pitch at 370 ℃ for 8 h produced a bulk mesophase with a content close to 100 %. Compared to the AlCl3 system (without PrCl), the AlCl3-PrCl system can catalyze the preparation of mesophases at lower temperatures. In addition, it is logical that the introduction of isopropyl group significantly increases the stacking spacing of the mesophase pitch layer molecules, which can effectively improve the mobility of the aromatic layer molecules resulting in the growth of mesophase. The fusion texture and anisotropic content of mesophase pitch were significantly improved by replacing the nucleophilic reagent of the AlCl3-catalyzed system. This work provides feasible ideas for the preparation of high-performance coal tar based mesophase pitch.

Regio- and Diastereoselective Hydrophosphination and Hydroamidation of gem-Difluorocyclopropenes.

In this study, concise, efficient, and modular hydrophosphinylation and hydroamidation of gem-difluorocyclopropenes were disclosed in a mild and transition-metal-free pattern. Through this approach, phosphorus, and nitrogen-containing gem-difluorocyclopropanes were produced in moderate to good yields with excellent regio- and diastereoselectivity. Readily available gem-difluorocyclopropenes and nucleophilic reagents, along with inexpensive inorganic bases, were employed. Multiple synthetic applications, including gram-scale and derivatization reactions and modification of bioactive molecules, were subsequently elaborated.

Effects of additional ring-fusion site on dual reactivity based dynamic covalent chemistry

Tautomers are widespread in organic chemistry, and their unique reactivity allows diverse transformations. In this work, the incorporation of nearby amide ring-fusion site offered a versatile platform for controlling dual reactivity based dynamic covalent chemistry (DCC) of aldehyde ring-chain tautomers. A suite of 2-formylbenzosulfonamide derived tautomers were prepared, and the intramolecular ring-chain equilibrium and intermolecular dynamic covalent reactions along the underlying mechanistic foundation were investigated. By regulating the substituent electronic effect and solvent effect, ring-chain tautomerization equilibrium was readily regulated in solution. The adjacent amide NH participates in intramolecular hydrogen bonding, as revealed by crystal analysis. Furthermore, the addition of acid and the change of solvent allowed turning on/off the intramolecular cyclization from the amide group to create fused ring scaffolds. Finally, the reversible covalent reactions with amine nucleophile reagents maintained the intermolecular reactivity successfully. The molecular and pathway diversity reported herein sets the scene for future design and applications.

The study of the interaction of 1,2- and 1,4-naphthoquinones with aminophosphonic esters

A number of new biologically active phosphorus-containing quinones were prepared by the reaction of 2,3-dichloro-1,4-naphthoquinone and sodium 1,2-naphthoquinone-4-sulfonate with phosphonate nucleophilic reagents, aminophosphonic acid esters. The structures of the synthesized compoumds were confirmed by ESI-MS, 1H NMR, IR-spectroscopies and elemental analysis. It was shown that aminophosphonic esters form products of nucleophilic substitution of a chlorine atom of 1,4-naphthoquinone or a sulfonyl group of 1,2-naphthoquinone on an aminophosphonic fragment. The products of the interaction of sodium 1,2-naphthoquinone-4-sulfonate with primary aminophosphonates existed in solution in 1,2-quinoid or 2-hydroxy-1,4-quinonimine tautomeric form depending on pH. The antimicrobial activity of the prepared compounds was investigated against Escherichia coli В-906, Staphylococcus aureus 209-Р, Mycobacterium luteum В-917, Candida tenuis VKM Y-70 and Aspergillus niger VKM F-1119 strains by the method of diffusion in agar of their 0.1% and 0.5% solutions. 1,2-Naphthoquinone derivatives showed good activity against S. aureus at a concentration of 0.1%, in its turn 1,4-napthoquinone derivatives showed activity against M. luteum at a concentration of 0.5%.

Transition Metal and Photocatalyst Free Arylation via Photoexcitable Electron Donor Acceptor Complexes:Mediation and Catalysis

AbstractVisible‐light‐activated organic reactions unlock novel avenues for complex molecular transformations, impossible under standard “thermal” conditions, which makes them powerful tools in the arsenal of synthetic chemistry. However, transition metal‐based or organic photoredox catalysts are often used to ensure productive absorption of visible light, which might be not desirable to medicinal chemistry and industry due to toxicity, low sustainability, and high cost of most photocatalysts. A more environmentally and economically benign approach is based on the formation of transient electron donor‐acceptor (EDA) complexes between two reagents or a reagent and an additive, that readily absorb visible light, acting as internal photosensitizers. Within the EDA complex‐based arylation strategies, chemical transformations are mediated by noncovalent interaction between two molecules, namely between electron‐poor aryl halides or their synthetic equivalents and electron‐rich nucleophilic reagents or additives. Moreover, besides stoichiometric EDA complexes between two molecules, EDA complex based organocatalysis can be achieved in certain cases through regeneration of the donor molecules in the course of the reaction. Photoexcitation of the EDA complexes induces a single electron transfer (SET) process to generate aryl radical species for the arylation step. This Review will focus on the state‐of‐the‐art EDA complex‐based arylation strategies utilizing aryl halides, aryldiazonium, diaryliodonium, arylsulfonium and arylphosphonium salts as reactants, published mainly in the last five years.

Chemical Transformation of 4-Hydroxyquinoline-2(1H)-Onestosome New Simple Derivatives: Synthesis and Spectral Characterization

In the first part of the present study, five substituted 4-hydroxyquinolin-2(1H)-ones (1-5) were prepared and then subjected to the reactions with various nucleophilic and electrophilic reagents including alkyl halides, dimethyl sulfate, bromine, anhydride acetic, and anilines to synthesize some new products (6-30). In the second part of this study, 6-chloro-4-hydroxyquinolin-2(1H)-one and/or 6,8-dichloro-4-hydroxyquinolin-2(1H)-one were employed in a catalyst-free, environmentally friendly, and simple procedure for the efficient synthesis of new derivatives (31-36) from one-pot three-component condensation with aryl-aldehydes and piperidine. The structures of the compounds were characterized by physical and spectral data.. KEYWORDS :4-Hydroxyquinolin-2(1H)-one, Alkylation, Aryl-amination, Methylation, Three-component condensation.

New Insights into the Dependence of CPEB3 Ribozyme Cleavage on Mn2+ and Mg2.

CPEB3 ribozyme is a self-cleaving RNA that occurs naturally in mammals and requires divalent metal ions for efficient activity. Ribozymes exhibit preferences for specific metal ions, but the exact differences in the catalytic mechanisms of various metal ions on the CPEB3 ribozyme remain unclear. Our findings reveal that Mn2+ functions as a more effective cofactor for CPEB3 ribozyme catalysis compared to Mg2+, as confirmed by its stronger binding affinity to CPEB3 by EPR. Cleavage assays of CPEB3 mutants and molecular docking analyses further showed that excessive Mn2+ ions can bind to a second binding site near the catalytic site, hindering CPEB3 catalytic efficiency and contributing to the Mn2+ bell-shaped curve. These results implicate a pivotal role for the local nucleobase-Mn2+ interactions in facilitating RNA folding and modulating the directed attack of nucleophilic reagents. Our study provides new insights and experimental evidence for exploring the divalent cation dependent cleavage mechanism of the CPEB3 ribozyme.

Photoredox Catalyzed Radical Fluoroalkylation with Non-Classical Fluorinated Reagents.

The emergence of photocatalysis has greatly advanced radical fluoroalkylation reactions. Central to this advancement is the introduction and refinement of radical reagents, which play a pivotal role in driving these reactions forward. Intriguingly, some of these reagents, previously not recognized for their radical properties, have emerged as key players in this area. In this Perspective, we provide an overview of four representative reagents pioneered by our laboratory, which have subsequently garnered extensive application in broader research contexts, including difluorocarbene precursors bromodifluoromethylphosphonium bromide, electrophilic sulfonylation reagent triflic anhydride, and nucleophilic trifluoromethylation reagent methyl fluorosulfonyldifluoroacetate (Chen's reagent). The integration of phosphonium reagents, triflic anhydride, and methyl fluorosulfonyldifluoroacetate into photocatalysis has enabled some unexpected reactivities and now notably expanded the capabilities in radical difluoromethylation, trifluoromethylation, and difluoroalkylation. Our discussion highlights how these atypical reagents have enriched the toolkit available for radical fluoroalkylations, offering insights that could inspire future research and application in this area.

Ligand- and metal-exchange reactions of robust nickel complexes with pentagonal bipyramidal structures.

The coordination chemistries of transition metal complexes with pentagonal bipyramidal geometries were investigated, and the highly stable nature of a cyclic pentapyridyl ligand was disclosed. A NiCl2 complex with the pentapyridyl ligand was found to be stable toward water and acidic conditions. The stable complex underwent ligand-exchange reactions with nucleophilic reagents, and a series of pentagonal bipyramidal complexes with different apical ligands was prepared. Crystallographic analyses with the aid of theoretical calculations revealed that the complexes were constructed by electrostatic threading of a divalent linear nickel complex into the ring of the neutral, cyclic pentapyridyl, which resulted in robust water- and acid-resistant complexes with unique pentagonal bipyramidal structures. A reductive metal exchange reaction was then discovered, which enabled "linear divalent metal + electrostatic ring" formulations with different metal atoms.

Reactivities of Photoredox Generated Nickel‐Nucleophilic Reactive Organometallic Species

AbstractDual photoredox catalysis has revolutionized the field of cross‐coupling reactions, enabling the discovery of numerous highly efficient reactions. This breakthrough is attributed to the exceptional combination of nickel catalysis with photoredox catalysis. Nickel exhibits both oxidative addition and reductive elimination processes, and a wide range of oxidation states (ranging from I to IV) accessible within a single catalytic cycle. Furthermore, nickel complexes are capable of catalyzing various processes through radical mechanisms. The latest feature has proven to be incredibly potent in facilitating the formation of new C−C and C−X bonds (X=H, O, S, N). The powerful combination of photoredox and nickel catalysis reveals an expansive domain of unexplored possibilities. It offers unparalleled opportunities for improving reactions and exploring innovative pathways. Under photoredox conditions, it is possible to form nucleophilic reactive organometallic intermediates, useful in reaction with electrophiles. We have devoted a research program towards the rediscovery and use of organometallic reagents, introduced by Corey, Hegedus, and Semmelack many years ago. The results unveiled the extraordinary capabilities of photoredox catalysis, enabling the creation and efficient utilization of potent nucleophilic organometallic reagents under mild conditions, free from the need for strong bases or stoichiometric metal reductants.

Quaternary ammonium fluorides and difluorosilicates as nucleophilic fluorination reagents.

TBAT (tetrabutylammonium difluorotriphenylsilicate) is an excellent homogeneous nucleophilic fluorination reagent, but a high excess of the reagent was reported to be essential. We hence optimized the reaction conditions and compared its nucleophilic fluorination reactivity with that of other common commercial nucleophilic fluorination reagents, such as anhydrous TBAF and TASF (tris(dimethylamino)sulfonium difluorotrimethylsilicate). As the substrates, we employed a standard set of primary and secondary octyl substrates under identical conditions. To eliminate the possibility of hydrogen fluoride elimination in the above reagents, we prepared four quaternary ammonium fluorides lacking β-elimination possibility in the hydrocarbon chain, transformed them to the corresponding difluorotriphenylsilicates, and compared their reactivity with that of the commercial reagents. Furthermore, attempts to isolate analogous tetrabutylammonium difluoromethyldiphenylsilicate or difluorodimethylphenylsilicate failed, as was confirmed by comparison of the published experimental data with computed 19F NMR spectra. Finally, we studied the transition states of decomposition of various tetramethylammonium methylphenyldifluorosilicates by DFT methods and found that their relative energies increase with an increasing number of phenyl groups. The formation of difluorosilicates is a nearly barrierless process.

New quinazolin-2,4-dione derivatives incorporating acylthiourea, pyrazole and/or oxazole moieties as antibacterial agents via DNA gyrase inhibition.

This article contributes to the search for new therapeutic agents for treatment of diseases caused by bacterial pathogens. In this study, a new series of compounds incorporating numerous bioactive moieties such as quinazolin-2,4-dione, acylthiourea linkage, and/or five membered nitrogen heterocycles (pyrazole and oxazole) 2-5a-c was described to identify new antibacterial drug candidates via inhibition of DNA gyrase enzyme. The precursor N-[N'-(2-cyano-acetyl)-hydrazinocarbothioyl]-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-benzamide 2 was prepared by treatment of compound 1 with ammonium thiocyanate and cyanoacetic acid hydrazide through multicomponent reaction (MCR). In addition, compounds 3a-d and 4a-b were synthesized by treatment of 2 with aromatic aldehydes and/or ketones through Knoevenagel reaction, affording high purity products in satisfactory yields. Moreover, new heterocyclic moieties such as pyrazole and/or oxazole attached to quinazolin-2,4-dione core 5a-c were synthesized by treatment of 3c with different nucleophilic reagents like hydrazine, phenyl hydrazine and hydroxyl amine, respectively. Subsequently, the obtained products were structurally characterized by IR, 1H-, 13C-NMR, and MS analyses. The minimum inhibitory concentration (MIC) and antibacterial potency of all compounds were estimated against two G-ve (E. coli and P. aeruginosa), and two G+ve bacteria (B. subtilis and S. aureus). Encouragingly, compound 3c demonstrated the best antibacterial activity against all the strains of the tested pathogenic bacteria at low concentrations compared with the standard drug, Ciprofloxacin. Electron withdrawing groups such as -NO2 and -Cl enhance the antibacterial activity. Next, a molecular docking study between the synthesized derivatives and the target enzyme, DNA gyrase enzyme (PDB: 2xct) was undertaken to investigate intermolecular interactions between the compounds and target enzyme.

Controllable tertiary amine-promoted photoactivation metal-free carbonylation of aryl sulfonium salts to aryl carboxylic acid derivatives

This paper describes a new method for the activation of aryl radicals via EDA complexes without metals and photosensitizers for carbonylation with various nucleophilic reagents under visible light.