Alkyl Phenyl Ethers Research Articles

Synthesis and Molecular Docking Study of Hydrazone Schiff Bases of α‐Naphthalene‐Containing Alkyl Phenyl Ether Fragment as Potent α‐Amylase and α‐Glucosidase Inhibitors

AbstractIn this study, new Schiff base derivatives of α‐naphthalene acetic acid containing alkyl phenyl ether fragment have been effectively synthesized through multistep reaction process, characterized by 1H‐NMR and 13C‐NMR spectroscopy. These derivatives have been tested for their in vitro α‐amylase and α‐glucosidase inhibitory activities. In the series, 8 compounds (2j, 2f, 2e, 2m, 2a, 2b, 2l, and 2c) exhibited promising α‐amylase inhibition with IC50 values from 5.38 ± 0.36 to 14.59 ± 0.64 µg/mL. Similarly, in the case of α‐glucosidase inhibitory activity, 10 derivatives (2e, 2f, 2j, 2m, 2b, 2c, 2i, 2d, 2a, and 2l) exhibited excellent activity having IC50 values from 6.96 ± 0.39 to 16.27 ± 0.31 µg/mL, wheras the remaining derivatives exhibited good‐to‐least antidiabetic potential. The ADME properties were calculated for all Schiff base derivatives using Swiss‐ADME web tool. Furthermore, the docking studies identified the binding modes of the compounds.

Synthesis, characterization, enzyme inhibition and molecular docking studies of benzothiazole derivatives bearing alkyl phenyl ether fragments

Novel benzothiazole derivatives containing alkyl/benzyl phenyl ether fragments have been synthesized through two step reaction process. Initially, 2-hydroxybenzaldehyde was refluxed with 2-aminothiophenol in the presence of sodium metabisulfite (Na2S2O5) in DMF solvent followed by treating it with alkyl and aromatic halides in the presence of triethylamine in dry acetone to get the product derivatives (1–11) in better yields. These products were characterized by means of modern spectroscopic (1H, 13C NMR and HR-ESI-MS) techniques and screened for in vitro tyrosinase inhibitory activity. In the series, three compounds 13 (IC50 = 8.6 ± 0.2 µM), 3 (IC50 = 11.1 ± 0.5 µM), and 12 (IC50 = 18.2 ± 0.1 µM) showed excellent inhibition comparing with the standard kojic acid (IC50 = 17.8 ± 0.6 µM). Likewise, six compounds 9, 10, 11, 2, 4, and 5 attributed significant activity ranging from IC50 22.6 ± 0.8 to 29.2 ± 0.3 µM. Besides, compound 6 (IC50 = 40.6 ± 0.5 µM) was found least active while two compounds 7 and 8 were found inactive. The molecular docking study on molecules and their interaction with tyrosinase protein revealed a consistent pattern in the activity of kojic acid. The electronic characteristics of active derivatives 2, 3, 9–12, and kojic acid were examined using the TD-DFT approach. The study found that the HOMO and LUMO were concentrated on the π-conjugated system of the benzothiazole rings moiety, indicating a significant delocalization of electrons. The study also found that compounds compared to kojic acid, possess chemical hardness and stability properties, with lower electrophilicity index indicating higher bioactivity and lower toxicity. The study also highlighted the importance of comprehensive ADMET profiling in early drug development to ensure safety and efficacy.

Каталитическое циклоалкилирование метилового эфира 4-гидроксифенилпропионовой кислоты метилциклоалкенами

Research has been carried out in the field of catalytic cycloalkylation of phenol derivatives. In the course of research, was developed the method for the synthesis of hindered phenols by cycloalkylation of 4-hydroxyphenylpropionic acid methyl ester with 1-methylcyclopentene, 1- and 3-methylcyclohexenes in the presence of a KU-23 cation exchanger catalyst. The influence of different kinetic parameters (temperature, time of the reaction, molar ratio of the initial components, amount of catalyst) on the yield and selectivity of the target product was determined, thereby determining the optimal process mode. It has been established that at low temperatures (60-80°C) of the reaction of cycloalkylation of phenol with 1(3)-methylcycloalkenes in the presence of a KU-23 catalyst, O-alkylation of phenol is observed, with the formation of alkylphenyl ethers. With an increase in the temperature of the cycloalkylation reaction, the concentration of alkylphenyl ethers gradually decreases, and the alkyl substituent migrates to the ortho position (Claisen rearrangement). The optimal conditions for the reaction of cycloalkylation of methyl ester of 4-hydroxyphenylpropionic acid with methylcyclenes are: temperature 90-110ºС, reaction time 5-5.5 h, molar ratio of ether to cyclene 1:1, amount of catalyst - 10% per taken ether. Under these conditions, the yield of target products is 68.7-79.5% of theory per taken ether, and the selectivity is 93.4-97.3% for the target product. The structure and composition of the products of the cycloalkylation reaction were confirmed by spectral and chromatographic methods of analysis. Synthesized methyl esters of 3-mono-cycloalkyl-substituted 4-hydroxyphenylpropionic acid were tested as stabilizers for polyurethane polymer, the tests gave positive results.

Catalytic SNAr Hydroxylation and Alkoxylation of Aryl Fluorides

AbstractNucleophilic aromatic substitution (SNAr) is a powerful strategy for incorporating a heteroatom into an aromatic ring by displacement of a leaving group with a nucleophile, but this method is limited to electron‐deficient arenes. We have now established a reliable method for accessing phenols and phenyl alkyl ethers via catalytic SNAr reactions. The method is applicable to a broad array of electron‐rich and neutral aryl fluorides, which are inert under classical SNAr conditions. Although the mechanism of SNAr reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addition followed by elimination), experimental data that support this hypothesis is still under exploration. Mechanistic studies and DFT calculations suggest either a stepwise or stepwise‐like energy profile. Notably, we isolated a rhodium η5‐cyclohexadienyl complex intermediate with an sp3‐hybridized carbon bearing both a nucleophile and a leaving group.

Catalytic SN Ar Hydroxylation and Alkoxylation of Aryl Fluorides.

Nucleophilic aromatic substitution (SN Ar) is a powerful strategy for incorporating a heteroatom into an aromatic ring by displacement of a leaving group with a nucleophile, but this method is limited to electron-deficient arenes. We have now established a reliable method for accessing phenols and phenyl alkyl ethers via catalytic SN Ar reactions. The method is applicable to a broad array of electron-rich and neutral aryl fluorides, which are inert under classical SN Ar conditions. Although the mechanism of SN Ar reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addition followed by elimination), experimental data that support this hypothesis is still under exploration. Mechanistic studies and DFT calculations suggest either a stepwise or stepwise-like energy profile. Notably, we isolated a rhodium η5 -cyclohexadienyl complex intermediate with an sp3 -hybridized carbon bearing both a nucleophile and a leaving group.

A comprehensive review on catalytic O-alkylation of phenol and hydroquinone

ABSTRACT The alkylation process involves two competitive paths of O- and C-alkylation and achieving better selectivity for desired products is a very challenging problem. The development of new process for synthesis of O-methylated products of phenol and dihydric phenols is a subject of high industrial and academic interest. Alkyl phenyl ethers, especially anisole and 4-methoxyphenol, have captivated significant interest due to their increasing applications in pharmaceutical industries. The main emphasis of the present review is to explore the recent development in two catalytic O-alkylation processes. The first process is O-methylation of phenol into anisole and another is selective mono O-methylation of hydroquinone into 4-methoxyphenol. The present article covers O-alkylation methods with methanol and dimethyl carbonate as alkylating agent over various acidic and basic catalytic systems. The catalyst systems analyzed involves Bronsted and Lewis acidic and basic ionic liquids, conventional acids, metal oxides, solid acid and basic catalysts, hydrotalcites, various zeolites and heteropolyacids. The mechanistic behavior of alkylation reactions in presence of different catalytic system is reviewed critically which is important to design new and/or modified catalyst in order to maximize the yield of desired product. Additionally, an influence of reaction parameters, role of catalyst and their active sites on product distribution is described. The review paper gives useful insight for researchers in the field of catalysis and reaction engineering of alkylation reactions. Understandings of the reaction pathways will help in developing reliable kinetic models necessary for process scale-up to industrial scale reactor system.

The effect of pyrolysis temperature on the characteristics of biochar, pyroligneous acids, and gas prepared from cotton stalk through a polygeneration process

The biochar (BC), pyroligneous acid (PA), and gas were collected from cotton stalks based on a polygeneration process, and this study was systematically focused to develop and process biochar and its byproducts obtained with various pyrolysis temperatures (300, 350, 400, 450, 500, and 550 °C). The results showed that the yield of biochar decreased from 46.71 % to 30.26 % as the pyrolysis temperature was increased from 300 to 550 °C, and this was accompanied by an increase in carbon content from 71.32–78.02%. Heatmap analysis on the correlation among pyrolysis temperature of biochar and elements illustrated that the content of C, H, and O were highly correlated with pyrolysis temperature of biochar. The ketones, phenols, alcohols, acids, and alkyl phenyl ethers were the major chemical constituents. The maximum total content of amino acids reached 647.1 mg/kg when the pyroligneous acids were collected at 450 °C. Moreover, the volume fractions of gas (CO and CH4) content increased with increasing pyrolysis temperature, leading to an increase in the gas heating value. Overall, the outcomes presented above indicated that the polygeneration system would be environmentally benign and effective in producing biochar, pyroligneous acids, and gas, which provides economic benefits and suggests a potential industrial application for cotton stalk.

Chirality, Gelation Ability and Crystal Structure: Together or Apart? Alkyl Phenyl Ethers of Glycerol as Simple LMWGs

Chiral recognition plays an important role in the self-assembly of soft materials, in particular supramolecular organogels formed by low molecular weight gelators (LMWGs). Out of 14 pairs of the studied racemic and enantiopure samples of alkyl-substituted phenyl ethers of glycerol, only eight enantiopure diols form the stable gels in nonane. The formation of gels from solutions was studied by polarimetry, and their degradation with the formation of xerogels was studied by the PXRD method. The revealed crystalline characteristics of all studied xerogels corresponded to those for crystalline samples of the parent gelators. In addition to those previously investigated, crystalline samples of enantiopure para-n-alkylphenyl glycerol ethers [alkyl = pentyl (5), hexyl (6), heptyl (7), octyl (8), nonyl (9)] and racemic 3-(3,5-dimethylphenoxy)propane-1,2-diol (rac-14) have been examined by single crystal X-ray diffraction analysis. Among 22 samples of compounds 1–14 studied by SC-XRD, seven different types of supramolecular motifs are identified, of which only two are realized in crystals of supramolecular gelators. An attempt was made to relate the ability to gel formation with the characteristics of the supramolecular motif of a potential gelling agent, and the frequency of formation of the motif, required for gelation, with the chiral characteristics of the sample.

FEATURES OF PHENOL ALKYLATION WITH HIGHER ALPHA – OLEFINS ON MACROPOROUS SULFOCATIONITES

The features of phenol alkylation by higher alpha-olefins to obtain monoalkylphenols (MAP) using commercial industrial samples of macroporous sulfocationites are considered: Tulsion-66 and Amberlist 36 dry, which are in different price categories and differ significantly in geometric dimensions: pore diameter at Tulsion-66 = 450-500 A; at Amberlist 36 dry =240 A; pore volume (cm3/g) 0.35 and 0.2, respectively. The thermodynamic analysis of a complex mixture of simultaneously occurring reversible reactions of the formation of target monoalkylphenols (the sum of ortho - and para - isomers) and by-products (dialkylphenols and alkylphenyl ether) in the range of 383-408 K was performed. It was found that to obtain 97-98% equilibrium monoalkylphenols yield, it is necessary to have a 4-6 fold molar excess of phenol with respect to olefins. It is not recommended to raise the temperature above 408 K, as this leads to a significant increase in by-products. In the course of kinetic studies, the optimal concentration of sulfocationites was established - 20% for the initial mixture, providing maximum rates for the selected samples under the same conditions while maintaining selectivity for the target monoalkylphenols at the level of 97-98%. Thus, at T=383 K, the phenol/olefin ratio =6: 1, the reaction rate on Tulsion-66 is 1.6-1.7 times higher than on Amberlist 36 dry. The activation energies estimated from experimental data in the studied temperature range had values (kJ/mol) : 14.64±1.89 on Tulsion-66 and 26.53±3.2 on Amberlist 36 dry. Differences in the reactivity of the investigated sulfocationites confirm the known theoretical positions, according to which the reaction rate during ion exchange catalysis depends on the ratio of the sizes of reacting molecules and catalyst pores.

Mesoporous aromatic frameworks modified by metal chlorides in phenol alkylation with oct-1-ene

Mesoporous polyaromatic frameworks (PAF) based on tetraphenylmethane were synthesized. The PAF/AlCl3 and PAF/FeCl3 catalysts were prepared by impregnating the synthesized products with aluminum and iron chlorides, respectively. The resulting materials were characterized by low-temperature adsorption—desorption of nitrogen, IR spectroscopy, and transmission electron microscopy. The catalytic activity of PAF/AlCl3 and PAF/FeCl3 was tested in the phenol alkylation with oct-1-ene. The tests showed that the use of these catalysts gave both alkylphenols (C-alkylates) and alkyl phenyl ethers (O-alkylates) in the total yields up to 78 and 65% for PAF/AlCl3 and PAF/FeCl3, respectively. The fraction of alkylphenols depends on both the catalyst amount and reaction temperature.

Synthesis and characterization of poly(N-isopropylacrylamide-co-N,N′-methylenebisacrylamide-co-acrylamide) core – Silica shell nanoparticles by using reactive surfactant polyoxyethylene alkylphenyl ether ammonium sulfate

We report a novel approach based on using polyoxyethylene alkylphenyl ether ammonium sulfate (HS10) as an anion reactive surfactant, which greatly reduced the size of poly(N-isopropylacrylamide-co-acrylamide-co-N,N′-methylenebisacrylamide) [P(NIPAM/AM/MBA)] microgel core – silica shell particles. First, the microgel cores were synthesized by copolymerization of N-isopropylacrylamide (NIPAM), N,N′-methylenebisacrylamide (MBA) with a variation of acrylamide (AM) and HS10 concentration in water. It followed by silica encapsulation of the microgel cores via the addition of 3-glycidyloxypropyltrimethoxysilane (GLYMO) and tetraethyl orthosilicate (TEOS) at alkaline environment (pH 12). It is interesting to note that the size of both PNIPAM-based microgel cores and PNIPAM-based microgel core – silica shell particles were well-controlled by using a small level of HS10. Furthermore, SEM images of the hybrid core – shell particles show the well-defined spherical morphology with monodisperse particle size distribution. As expected, HS10-containing samples are covered by the porous silica shell layer, instead of continuous silica shell obtained from HS10-free samples observed in TEM images. This novel incorporation not only well controls the core size and shell morphology, leading to increase their specific surface area but also does not greatly affect the thermo-sensitivity of final products. The resultant thermo-responsive microgel core – silica shell particles with controlled particle morphology and physicochemical properties are useful for biomedical application fields.

Cleavage of Catechol Monoalkyl Ethers by Aluminum Triiodide–Dimethyl Sulfoxide

Using eugenol and vanillin as model substrates, a practical method is developed for the cleavage o-hydroxyphenyl alkyl ethers. Aluminum oxide iodide (O=AlI), generated in situ from aluminum triiodide and dimethyl sulfoxide, is the reactive ether cleaving species. The method is applicable to catechol monoalkyl ethers as well as normal phenyl alkyl ethers for the removal of methyl, ethyl, isopropyl, and benzyl groups. A variety of functional groups such as alkenyl, allyl, amide, cyano, formyl, keto, nitro, and halogen are well tolerated under the optimum conditions. Partial hydrodebromination was observed during the demethylation of 4-bromoguaiacol, and was resolved using excess DMSO as an acid scavenger. This convenient and efficient procedure would be a practical tool for the preparation of catechols.

Alkylation of Aromatic Compounds in the Presence of Catalysts Based on Mesoporous Phenol–Formaldehyde Polymers

A catalyst based on a mesoporous phenol–formaldehyde polymer (MPF) as an organic support modified with the IMHSO4 ionic liquid has been synthesized. The catalytic activity of the sample has been studied in the alkylation of aromatic compounds with octene-1. It has been found that the use of the catalyst in phenol alkylation leads to the formation of both alkylphenols (C-alkylates) and alkyl phenyl ethers (O-alkylates) with a total yield of up to 60%. In the case of alkylation of benzene and benzene derivatives, significant conversion values (45–50%) are achieved only for toluene and anisole.

Oxidative coupling of sp2 and sp3 carbon\u2013hydrogen bonds to construct dihydrobenzofurans

Metal-catalyzed cross-couplings provide powerful, concise, and accurate methods to construct carbon–carbon bonds from organohalides and organometallic reagents. Recent developments extended cross-couplings to reactions where one of the two partners connects with an aryl or alkyl carbon–hydrogen bond. From an economic and environmental point of view, oxidative couplings between two carbon–hydrogen bonds would be ideal. Oxidative coupling between phenyl and “inert” alkyl carbon–hydrogen bonds still awaits realization. It is very difficult to develop successful strategies for oxidative coupling of two carbon–hydrogen bonds owning different chemical properties. This article provides a solution to this challenge in a convenient preparation of dihydrobenzofurans from substituted phenyl alkyl ethers. For the phenyl carbon–hydrogen bond activation, our choice falls on the carboxylic acid fragment to form the palladacycle as a key intermediate. Through careful manipulation of an additional ligand, the second “inert” alkyl carbon–hydrogen bond activation takes place to facilitate the formation of structurally diversified dihydrobenzofurans.

Role of Polymerized Micelles on the Calcium Carbonate Mineralization of Nanofibers

Calcium carbonate (CaCO3) is a well-known chemical adsorbent. In this study, anthraquinone dye adsorption by CaCO3-mineralized nanofibers was evaluated with respect to the chemistry and structure of ionic particles that were seeded into the fibers. Reacted and unreacted surfmers of polyoxyethylene-1-(alkyloxylmethyl) alkyl ether sulfuric ester ammonium salt (PAMS) and polyoxyethylene alkylphenyl ether ammonium sulfate (PAPS) were added to aqueous poly(vinyl alcohol) (PVA) solutions at concentrations above their critical micelle concentration prior to electrospinning. The roles of these polymerized micelles on CaCO3 mineralization (produced by dipping PVA nanofibers into alternating solutions of aqueous CaCl2 and NaCO3) were compared to the roles of calcium chloride (CaCl2) and unseeded PVA nanofibers. Seeding nanofibers with reacted PAMS and PAPS resulted in higher degrees of CaCO3 mineralization than those with unreacted surfmers. PAPS caused even greater degrees of CaCO3 mineralization than other seeds,...

Alkylation of phenol with olefins in the presence of catalysts based on mesoporous aromatic frameworks

Mesoporous polyaromatic frameworks (PAFs) based on tetraphenylmethane were obtained and modified with sulfonic acid groups. The compounds were characterized by solid-state 13C NMR and IR spectroscopy, low-temperature nitrogen adsorption-desorption, and transmission electron microscopy. The acidities of the PAF-1-SO3H and PAF-2-SO3H samples determined by titration were 3.99 mmol g–1 and 0.91 mmol g–1, respectively. The catalytic activity of PAF-SO3H for alkylation of phenol with linear terminal olefins was investigated. The reaction products were isomeric monoalkylphenols (C-alkylates), and alkyl phenyl ethers (O-alkylates).

ChemInform Abstract: Tandem Reaction of Arynes with Tertiary Amines and Aldehydes: Formation of 9‐ and 10‐Membered Dibenzo[1,5]oxaza Heterocycles.

AbstractIn situ generated arynes react with aldehydes and tertiary aromatic amines to give 2‐morpholinophenyl substituted phenyl alkyl ethers of type (IV).

Ether analogues of DPA-714 with subnanomolar affinity for the translocator protein (TSPO)

Sixteen new phenyl alkyl ether derivatives (12, 14–28) of the 5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-ylacetamide (DPA) class were synthesized and evaluated in a competition binding assay against [3H]PK11195 using 18 kDa translocator protein (TSPO) derived from rat kidney mitochondrial fractions. All analogues showed superior binding affinities for TSPO compared to DPA-713 (5) and DPA-714 (6). Picomolar affinities were observed for this class of TSPO ligands in this assay for the first time, with phenethyl ether 28 showing the greatest affinity (Ki = 0.13 nM). Additionally, all analogues increased pregnenolone biosynthesis (134–331% above baseline) in a rat C6 glioma cell steroidogenesis assay.

Simple and Economical Synthesis of Alkyl Phenyl Ethers by the Reaction of Phenols and Alkyl Esters Using Nanocrystalline Beta

A simple, economical, and recyclable catalytic route is developed for the synthesis of alkyl phenyl ethers by the liquid phase reaction of phenol derivatives with alkyl esters using conventional and nanocrystalline zeolite Beta. A wide range of alkyl phenyl ethers can be prepared using this catalytic protocol. Nanocrystalline zeolite Beta exhibited higher activity than conventional zeolite Beta.

Ultrasound-assisted polymerization of methyl methacrylate using the reactive surfactant Hitenol BC10 in a semicontinuous heterophase process

Semicontinuous heterophase polymerization was used to polymerize methyl methacrylate (MMA) with the reactive surfactant Hitenol BC10 (polyoxyethylene(10)alkylphenyl ether ammonium sulfate, HBC10) in the presence of ultrasound at 50 °C. The effects of HBC10 concentrations and the monomer addition rate (R a) on kinetics, colloidal behavior, and molar masses were studied. Latexes with polymer content between 20 and 24 % were obtained. Particle size distributions (PSD) of latexes without HBC10 were bimodal, whereas those obtained in the presence of HBC10 were mono-modal in all cases. The average particle diameters (D p) were in the range of 39–63 nm decreasing with the HBC10 concentration and increasing with R a. Polymerization rates (R p) were decreased, by increasing the HBC10 concentration, which was ascribed to chain transfer events to HBC10. It was also observed that R p increased with R a; however, monomer-starved conditions were favored at lower R a values. Very high-average molecular weights were observed (1.63 × 106 ≤ M w ≤ 2.34 × 106 g/mol) which decreased when HBC10 concentration increased, and increased with R a. The corresponding polydispersity indexes (M w/M n) were in the range of 1.55–2.30, showing relatively wide molar masses distributions. It was observed from differential scanning calorimetry that polymers with HBC10 presented two T g (123 and 178 °C) which was ascribed to HBC10 incorporated to PMMA chain, corroborated by 1H NMR.