Electrophilic Cyclization Reaction Research Articles

Developments in the Construction of Benzo[b]thiophenes from 2‐Alkynylthioanisoles by Electrophilic and Radical Cyclization Reactions

Developments in the Construction of Benzo[b]thiophenes from 2‐Alkynylthioanisoles by Electrophilic and Radical Cyclization Reactions

Synthesis of Dihalonaphthalenes via Silver-Catalyzed Halogenation and Electrophilic Cyclization of Terminal Alkynols.

Herein, we report a silver-catalyzed halogenation and electrophilic cyclization reaction based on the trifunctionalization of terminal alkynols with NBS or iodine monochloride in a step-efficient synthetic way to produce homo/heterodihalogenated naphthalene derivatives bearing two different halogen atoms in moderate to good yields. This methodology readily accommodates various functional groups, including electron-withdrawing nitro, cyano, acid-sensitive dioxazolyl, and alkoxy groups.

SYNTHESIS OF BENZO[B]THIOPHENE-BASED ORGANIC COMPOUNDS AND THEIR HYDRAZINE ELECTROOXIDATION PERFORMANCE AS AN ANODE CATALYST

In this study, 3-iodo-2-(p-tolyl)benzo[b]thiophene (4C) is synthesized by using Sonagashira coupling reactions and electrophilic cyclization reactions. Electrochemical measurements have been performed using electrochemical methods such as cyclic voltammetry (CV), chronoamperometry (CA) and electrochemical impedance spectroscopy (EIS) in the environment of 1 M KOH + 0.5M N2H4 solution. The CV results obtained showed that 4C catalyst promoted the generation of the best current (15.40 mA/cm2), and EIS results confirmed that electrode modifeed with the same derivative presented the lowest charge transfer resistance. Taken together, these results suggest that 4C organocatalyst could be used as an anode efficient catalyst in hydrazine (N2H4) fuel cells.

Hydrazine electrooxidation performance of cyano-substituted indole derivatives as organic anode catalyst

Here we present the new EWG-substituted indole derivatives, namely 2-((5-(1-methyl-2-phenyl-1 H-indol-3-yl)thiophen-2-yl)methylene) malonitrile (IPTM), 2-((5-(1-methyl-2-phenyl-1 H-indol-3-yl)furan-2yl)methyl)malonitrile(IPFM) and 2-((4-(1-methyl-2-phenyl-1 H-indol-3-yl)benzylidene) malonitrile (IPPM) was synthesized by using Sonogashira coupling, electrophilic cyclization, Suzuki-Miyaura coupling and condensation reactions. The isolated yields were obtained as 86 %, 71 %, and 69 % yields, respectively. Cyclic voltammetry(CV), chronoamperometry (CA), and electrochemical impedance spectroscopy (EIS) were used for the electrochemical measurements to observe the electrocatalytic behavior of IPTM, IPFM and IPPM. The results exhibited that the highest-performance organic-based catalyst was 2.601 mA/cm2 (0.073 mA/mg) for IPPM which could be a good candidate as a metal-free electrocatalyst for hydrazine electrooxidation.

Investigation of the performance of (4-(3-iodobenzo[b]thiophen-2-yl)-N,N-dimethyllaniline as an anode catalyst for glucose electrooxidation

In this study (4-(3-iodobenzo[b]thiophen-2-yl)-N,N-dimethyllaniline (4), Sonagashira Coupling Reaction was synthesized using Electrophilic Cyclization Reactions. Then, the anode catalyst performance for glucose electrooxidation was investigated. The electrocatalytic activities of the organic catalyst were investigated by CV, CA and EIS measurements in 1 M KOH + 0.5 M C6H12O6 solution. Interestingly, electrochemical depositing on organic catalyst by Pd metal increased the specific activity, and it was calculated as 0.61 mA/cm2 Consequently, Pd@4 catalyst will be used as an electrocatalyst with high specific and stability and low charge transfer activity.

Mechanistic Insight from Lewis-Acid-Dependent Selectivity and Reversible Haloboration, as Harnessed for Boron-Based Electrophilic Cyclization Reactions.

Different reaction selectivity occurs with the Lewis acids B-chlorocatecholborane (ClBcat), B-bromocatecholborane (BrBcat), and BBr3, favoring either alkyne haloboration, electrophilic cyclization of a tethered nucleophilic sulfur onto the alkyne, or group transfer of the nucleophile. This reaction selectivity also depends on the chain length of the tethered nucleophile, revealing a subtle interplay of relative kinetics and thermodynamics. In all cases, BBr3 reacts readily with alkynes to form haloborated products; however, this process is reversible, and this reversibility can be harnessed to ultimately access regio- and stereodefined cyclic sulfonium zwitterions via the slower but thermodynamically favored electrophilic cyclization pathway. Reversibility was noted by following the reaction by NMR spectroscopy, and by characterizing the kinetic and thermodynamic products by a combination of 2D NMR spectroscopy and single-crystal X-ray diffraction. The "mixed" reagent bromocatechol borane (BrBcat) displayed reactivity between ClBcat and BBr3, producing bromoboration in some cases and electrophilic cyclization in others. With this enhanced understanding of the reaction dynamics, it becomes possible to use boron Lewis acids in a predictable manner in cases where haloboration is the kinetic product but in which the reversibility of this reaction maintains access to eventual alternative reactivity leading to desired building blocks in organic synthesis.

TELLURO-INDUCED CYCLISATION 2-(BUT-2-ENYLTHIO)QUINOLINECARBALDEHYDE AND QUINOLINE-4-ONE

Aryltellurium trichlorides have proven themselves as good cyclizing reagents in electrophilic intramolecular cyclization reactions, mainly of propenyl derivatives of heterocycles. On the other hand, information on the use of butenyl derivatives in reactions with p-alkoxyphenyltellurtrichlorides is limited. In this work, the regioselectivity of the process of electrophilic intramolecular cyclization of but-2-enyl thioethers of quinoline-3carbaldehyde and quinazolin-4-one with p-methoxyphenyltellurium trichloride was investigated.
 It was established that, as a result of the tellurium-induced cyclization with p-methoxyphenyltellurium trichloride of but-2-enyl thioethers of quinoline and quinazoline, angular tricyclic chlorides – 2-(dichloro(4-methoxyphenyl)-tellanyl)-1-methyl-5-formyl-2,3- dihydro-1H-[1,3]thiazino[3,2-a]quinolin-11-ium and 2-(dichloro(4-methoxyphenyl)-tellanyl)-1-methyl-6-oxo-5-phenyl-2, 3,5,6-tetrahydro-1H-[1,3]thiazino[3,2-a]quinazolin-11-ium, respectively, with an annealed six-membered ring in the form of complexes with p-methoxyphenyltellurium trichloride. Optimal conditions for the electrophilic intramolecular cyclization reaction were selected.
 Keywords: electrophilic heterocyclization; p-methoxyphenyltellurium trichloride; organotellurium compounds; chloride 2-(dichloro(4-methoxyphenyl)-tellanyl)-1-methyl-5-formyl-2,3-dihydro-1H-[1,3]thiazino[3,2 -a]quinolin-11-ium, chloride 2-(dichloro(4-methoxyphenyl)-tellanyl)-1-methyl-6-oxo-5-phenyl-2,3,5,6-tetrahydro-1H-[1,3]thiazino[3,2-a]quinazolin-11-ium

Thiazol-2-ylidenes as N-Heterocyclic carbene ligands with enhanced electrophilicity for transition metal catalysis.

Over the last 20 years, N-heterocyclic carbenes (NHCs) have emerged as a dominant direction in ligand development in transition metal catalysis. In particular, strong σ-donation in combination with tunable steric environment make NHCs to be among the most common ligands used for C-C and C-heteroatom bond formation. Herein, we report the study on steric and electronic properties of thiazol-2-ylidenes. We demonstrate that the thiazole heterocycle and enhanced π-electrophilicity result in a class of highly active carbene ligands for electrophilic cyclization reactions to form valuable oxazoline heterocycles. The evaluation of steric, electron-donating and π-accepting properties as well as structural characterization and coordination chemistry is presented. This mode of catalysis can be applied to late-stage drug functionalization to furnish attractive building blocks for medicinal chemistry. Considering the key role of N-heterocyclic ligands, we anticipate that N-aryl thiazol-2-ylidenes will be of broad interest as ligands in modern chemical synthesis.

Synthesis of Benzo[b]thiophenes via Electrophilic Sulfur Mediated Cyclization of Alkynylthioanisoles.

A stable dimethyl(thiodimethyl)sulfonium tetrafluoroborate salt was employed for the electrophilic cyclization reaction of o-alkynyl thioanisoles for the synthesis of 2,3-disubstituted benzo[b]thiophenes. The reaction described herein works well with various substituted alkynes in excellent yields, and a valuable thiomethyl group was introduced with ease. The reaction utilizes moderate reaction conditions and ambient temperature while tolerating various functionalities. To elucidate the mechanism, electrophilic addition reactions using the dimethyl(thiodimethyl)sulfonium tetrafluoroborate salt with diphenylacetylene was demonstrated.

Synthesis and characterization of 4-(2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)benzaldehyde for carbohydrate antigen 125 electrochemical detection and molecular docking modeling

4-(2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)benzaldehyde (MPBB)-based chemical antibody is developed to detect CA125 (MUC-16) level more effectively via electrochemical methods. Novel MPBB is synthesized by using Pd-catalyst coupling reactions and electrophilic cyclization reactions. New benzothiophene structure is dispersed in Nafion solution and CA125 antigen was incubated on this electrode. Optimum conditions are found as 3 μL MPBB loading, 30 ng/mL CA125 antigen concentration, and 90 min incubation time. Two distinct linear ranges of the electrode prepared at optimum conditions are determined by DPV as 5–50 ng/ml and 100–500 ng/ml. Limit of detection and limit of quantification values have been obtained as 0.03385 ng/mL and 0.10155 ng/mL, respectively. Interference and artificial serum results reveal that this electrode is a promising electrode for CA125 antigen determination for ovarian cancer. Binding energy is investigated by employing a molecular docking modeling study between CA125 antigen and MPBB. Electrochemical results and molecular docking results revealed that the MPBB is a promising alternative to marketed CA125 immunoassays.

A novel electrochemical sensor for monitoring ovarian cancer tumor protein CA 125 on benzothiophene derivative based electrodes

COVID-19 crisis affects ovarium cancer patients seriously. Thus, it is vital to diagnose ovarium cancer, one of the most common types of cancer diagnosed and the causes of death of women around the world, at early stages. Herein, 5-(2-phenylbenzo[b]thiophen-3-yl) thiophene-2-carbaldehyde (PTTC)-based sensor is designed to detect CA-125 more precisely and rapidly via electrochemical methods. PTTC, novel benzothiophene derivative, is synthesized by electrophilic cyclization reactions and Pd-catalyst coupling reactions. Then, PTTC is dispersed homogeneously in Nafion solution, and an ink is obtained. This ink is transferred onto the glassy carbon electrode and CA-125 is incubated on this electrode. Cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy measurements are employed to determine sensitivity and reliability of CA-125 on PTTC based GCE electrode. The effect of CA 125 concentration, incubation time, scan rate studies are performed by CV to determine the optimum conditions. Optimum conditions are found as 3 μL PTTC loading, 5000 ng/mL CA125 antigen concentration and 30 min incubation time. Linear range of the PTTC based GCE electrode prepared at optimum conditions are obtained by DPV as 1–100 ng/ml.Limit of detection and limit of quantification values were obtained as 0.0096 ng/mL and 0.0288 ng/mL, respectively. Interference and artificial serum results reveal that this electrode is a promising electrode for CA125 antigen determination for the ovarium cancer. PTTC is a novel and unique material for the detection of ovarium cancer antigen CA-125 and promising for CA-125 antigen detection.

Electrochemically-initiated intramolecular 1,2-amino oxygenation of alkynes: facile access to formyl- and acyl-substituted indolizines

An environmentally benign electrooxidative approach to the intramolecular aminooxygenation of alkynes through an electrophilic cyclization reaction has been developed, providing an efficient approach toward diverse formyl- and acyl-substituted indolizines.

Metal‐Free Synthesis of Selenodihydronaphthalenes by Selenoxide‐Mediated Electrophilic Cyclization of Alkynes

AbstractA transition‐metal‐free, selenium mediated electrophilic cyclization reaction was realized through a one‐pot procedure between simple alkynes and triflic anhydride‐activated selenoxides to give selenium containing dihydronaphthalene products. This method gave good to very high yields for all products, including selenium‐substituted phenanthrene, dihydroquinoline, 2H‐chromene, and coumarin, which can be further transformed to other functionalized compounds.

The Use of Electrophilic Cyclization for the Preparation of Condensed Heterocycles

AbstractCondensed heterocycles are well-known for their excellent biological effects and they are undeniably important compounds in organic chemistry. Electrophilic cyclization reactions are widely used for the synthesis of mono-heterocyclic compounds. This review highlights the utility of electrophilic cyclization reactions as an effective generic tool for the synthesis of various condensed heterocycles containing functional groups that are able to undergo further chemical transformations, such as nucleophilic substitution, elimination, re-cyclization, cleavage, etc. This review describes the reactions of unsaturated derivatives of different heterocycles with various electrophilic agents (halogens, arylsulfanyl chlorides, mineral acids) resulting in annulation of an additional partially saturated heterocycle. The electrophilic reaction conditions, plausible mechanisms and the use of such transformations in organic synthesis are also discussed. The review mainly focuses on research published since 2002 in order to establish the current state of the art in this area.1 Introduction2 Electrophilic Cyclization Pathways Involving a Nitrogen Nucleo­philic Center3 Electrophilic Cyclization Pathways Involving a Chalcogen Nucleophilic Center3.1 Sulfur Centers3.2 Oxygen Centers3.3 Selenium Centers4 Strategies and Mechanisms5 Conclusion

Design of 2-(4-(2-pentyllbenzo[b]thiophen-3-yl)benzylidene)malononitrile based remarkable organic catalyst towards hydrazine electrooxidation

Abstract Herein, 2-(4-(2-pentyllbenzo[b]thiophen-3-yl)benzylidene)malononitrile (6B) is synthesized by using coupling reactions, electrophilic cyclization reactions, and condensation reactions. Then, these materials are employed as anode catalysts for hydrazine electrooxidation reactions with electrochemical methods such as cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) in 1 M KOH + 0.5 M N2H4 solution on different benzothiophene derivates. 6B catalyst exhibits the best catalytic activity in hydrazine electrooxidation reaction with 3.22 mA cm−2 (16.72 mA mg−1 6B) value. Thus, for the electrodes obtained from 6B, the electrode preparation stage is optimized by the response surface methodology (RSM) and the hydrazine electrooxidation current under optimum conditions is found as 4.95 mA cm−2. EIS results reveal that 6B modified electrode has the lowest charge transfer resistance. In conclusion, 6B catalyst could be used as anode catalysts in hydrazine fuel cells instead of expensive catalysts such as Pt, Pd, and Au.

Development of Heterocycle-Substituted and Fused Azulenes in the Last Decade (2010-2020).

Azulene derivatives with heterocyclic moieties in the molecule have been synthesized for applications in materials science by taking advantage of their unique properties. These derivatives have been prepared by various methods, involving electrophilic substitution, condensation, cyclization, and transition metal-catalyzed cross-coupling reactions. Herein, we present the development of the synthetic methods, reactivities, and physical properties for the heterocycle-substituted and heterocycle-fused azulenes reported in the last decade.

Design, Synthesis, and In vitro Evaluation of Thieno[a]dibenzothiophene Derivatives

AbstractA variety of highly substituted thieno[2,3‐a]dibenzothiophenes and thieno[3,2‐a]dibenzothiophenes are readily prepared via cascade electrophilic cyclization reaction. The reaction was tolerated a variety of compounds. In the present study, antimicrobial and antifungal activities were investigated for all synthesized molecules against A. niger ATCC 16404, C. albicans ATCC 10231, S. aureus ATCC 25923 and B. subtilis ATCC 6633, respectively.

Halo-heterocyclization of butenyl(prenyl)thioethers of 4,5-diphenyl-1,2,4-triazol-3-thiole into triazolo[5,1-b] [1,3]thiazinium systems: experimental and theoretical evolution

A facile and highly efficient regioselective synthesis of partially saturated triazolo[5,1-b][1,3]thiazinium salts by the electrophilic heterocyclization of the butenyl thioethers of 4,5-diphenyl-1,2,4-triazol-3-thiol with halogens was developed. Under developed conditions, electrophilic cyclization reactions proceeded smoothly and cleanly and the corresponding fused products were obtained in high yields in all cases examined. Herein, we also report the studying of the regiochemistry of this process using computer simulation methods, XDR, and spectral investigations for explaining of electrophilic cyclization mechanism and solving of final products structure.

Synthesis of 3-Halo-7-azaindoles through a 5-endo-dig Electrophilic Cyclization Reaction

Biologically useful 7-azaindoles were synthesized by electrophilic cyclization of 3-alkynyl-N,N-dimethylpyridine-2-amines with molecular iodine. By this simple atom-economical approach under ambient reaction conditions, a library of interesting 3-iodo-7-azaindoles were synthesized in high yields. To synthesize the corresponding 3-bromo- and 3-chloro-7-azaindoles, an environmentally benign copper-mediated cyclization was employed, with inexpensive, nontoxic, and noncorrosive sodium chloride and sodium bromide as the sources of chlorine and bromine, respectively.

Synthesis of Novel Bis-pyrazoles via Electrophilic Cyclization

Efficient steps towards the synthesis of novel (phenyl)(1'-aryl-1,5,5'-triphenyl[3,3'-bi-1Hpyrazol]- 4-yl)methanones 4a-e were developed. The procedure starts from 1-(4-benzoyl-1,5-diphenyl- 1H-3-pyrazolyl)-3-phenyl-2-propyn-1-one (2) which was synthesized by a palladium catalyzed crosscoupling reaction. Compound 2 reacted with various hydrazines to give (E)-(phenyl)[1,5-diphenyl-3- [3-phenyl-1-(2-arylhydrazono)-2-propyn-1-yl]-1H-4-pyrazolyl]methanones E-3a-e. The bis-pyrazole derivatives 4a-e were synthesized from electrophilic cyclization reaction of α,β-acetylenic hydrazones E-3a-e and copper(I) iodide. All synthesized compounds were characterized by FT-IR, 1H, 13C NMR and Mass spectral analyses.