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Transition metal-catalyzed cross-coupling with aryl halides has revolutionized the way of diversifying aromatic compounds. Aryl ethers are attractive alternatives to aromatic halides as coupling partners considering the accessibility and potential environmental benefits. The last two decades have witnessed a striking success in the field of C–O bond activation of aryl ethers, including the construction of C–C bond and C–X bond, as well as reductive deoxygenation. Here, we present a comprehensive review of C–O bond activation in the context of aryl, vinyl, and benzylic ethers. This review elaborates on the current state-of-the-art methods, categorized by different catalytic systems, including transition metal catalysis, photoredox catalysis, and other innovative approaches. The newly developed methods allow C–O bond activation under mild conditions with exceptional functional group tolerance, potentially enabling the late-stage functionalization of pharmaceuticals. The limitations and future perspectives of the methods are also presented. [ABSTRACT FROM AUTHOR]

• Synthesis, in-silico and evaluation of anti-inflammatory activity of some new indole substituted aryl ethers were done. • All the synthesized derivatives complied lipinski's rule of five with zero violations. • The synthesized derivatives exhibited excellent COX-2 inhibition when evaluated in-silico. • Compound AG-1 (N-((1H-indol-3yl) methylene)−4-phenoxyaniline) in the dose of 50 mg kg-1 b.w was found to be most potent anti-inflammatory compound. • Indole-aryl ether with r substituent as h results significant anti-inflammatory activity. A number of anti-inflammatory drugs with an aryl-ether part, such as Nimesulide and Rofecoxibs, have been shown to damage cells and kill liver cells. Keeping in view this rationale, the present work was aimed at synthesising new indole-substituted aryl ethers and evaluating their anti-inflammatory effects, which have minimal side effects. New indole substituted aryl ethers were synthesised. Spectral characterisation of these newly synthesised compounds was done using infrared (IR), proton nuclear magnetic resonance (1H NMR), and carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy techniques. Further, In-silico studies were performed with an aim to evaluate the suitability of synthesised compounds as potential bioactive candidates for anti-inflammatory activity. The synthesised compounds were subjected to anti-inflammatory activity evaluation using the carrageenan-induced rat paw edema model. Primarily, the chemical reaction completion was ensured using TLC and M.P. Further, the structures of all synthesised compounds were confirmed by the results of spectra characterization. Results of in-silico study exhibited the docking of compounds on target proteins. On the basis of experimental findings, it was concluded that compound AG-1 (N -(1H-indol-3yl) methylene)-4-phenoxyaniline) is the most potent anti-inflammatory compound amongst all the newly synthesised compounds. Findings of the present study concluded that AG-1 could be used as a viable new lead bioactive compound to serve as a potent candidate for a new anti-inflammatory drug. The novelty of the present work resides in the simplest way of synthesis, a good docking score, and excellent anti-inflammatory potential when evaluated in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • M / β zeolite has a three-dimensional channel-type hierarchical porous texture. • Stable acid sites and abundant defects are favorable for obtaining PCAs. • H 2 can be activated as H+, H · , δ+H ··· Hδ-, and H ··· H over Ni@ M / β. • C–C coupling induced by aromatic α -carbon activation is the key to obtaining PCAs. To produce high-density liquid fuels from lignite, a novel Ni-based bifunctional MCM-41/ β composite zeolite (Ni@ M / β) is reported for the catalytic hydroconversion (CHC) of lignite-derived aryl ethers to high-yield polycyclic alkanes (PCAs). Ni@ M / β has a three-dimensional channel-type hierarchical porous texture with β as the core and MCM-41 as the shell. Stable Brønsted/Lewis acid sites and abundant internal/inter-zeolite defects also effectively promote the CHC of aryl ethers to PCAs. Under optimal conditions (5 MPa initial H 2 pressure and 160 °C), selectivities of 2-(benzyloxy)naphthalene (BON) and benzyloxybenzene derived PCAs are as high as 76.0 and 90.5 %, respectively, with dimers and trimers dominating. DFT calculation based on electrostatic potential distribution on the van der Waals surface and Mulliken charge distribution of BON and derived oxygenated monomers shows that aromatic intermediates with >C aromatic OH have multiple accessible sites and are easy to bind with cation/radical fragments. Therefore, it is speculated that PCAs are mainly derived from C-C coupling induced by cation/radical fragments after the activation of aromatic α -carbon. In addition, the activation of H 2 to H+, H · , δ+H ··· Hδ-, and H ··· H is mainly attributed to the strong Ni- M / β interaction and abundant defects. The whole CHC process is triggered mainly by the adsorption of H+ released by Ni@ M / β at O sites of aryl ethers, and >C aliphatic -O- bridged bond cleavage is dominant. During this period, benzyl cation/radical produced by >C-O- bond cleavage and aromatic α -carbon activation (mainly) is coupled/reformed with adjacent aromatic fragments into corresponding polymers with non-oxygen bridged bonds, which are more easily converted to PCAs. This polycrystalline composite strategy improves the accessibility of large-sized molecules to active centers, and then increases the yields of PCAs, which is attractive for the clean and efficient conversion of lignite-derived oils to high-density liquid fuels. [ABSTRACT FROM AUTHOR]

Low aromaticity and a large number of oxygen-bridged bonds among the aromatic structural units of lignin make it possible to obtain chemicals directly. A novel Co/C@N catalyst with high activity towards hydrogenolysis of lignin-derived aryl ethers was synthesized according to the pyrolysis process of a predesigned ZIF-67. According to the results of characterization by powder X-ray diffraction (XRD), N 2 adsorption-desorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS), Co was reduced by the carbonized organic linker of ZIF-67, and N was doped into the carbon skeleton of the catalyst. The effects of holding time, temperature, and initial H 2 pressure on the catalytic performance of Co/C@N were evaluated in the selective hydrogenolysis of benzyl phenyl ether (BPE). BPE was completely converted and the selectivity of monomer reached to 98.2% under optimized reaction conditions. The C alk -O bond in BPE was first dissociated to form toluene and phenol, and then phenol was rapidly hydrogenated to form cyclohexanol. Furthermore, the Co/C@N catalyst shows high activity for hydroprocessing and selective cleavage of other lignin-derived aryl ethers, including phenylethyl phenyl, diphenyl ether, dibenzyl ether, dinaphthalene ether, guaiacol, anisole and veratrole. Image 1 • A novel Co/C@N catalyst was prepared by one-step pyrolysis of ZIF-67. • Co/C@N catalyst showed high activity in the hydrogenolysis of benzyl phenyl ether. • The selectivity of monomers remained above 92% at temperatures investigated. • C alk- O bond in benzyl phenyl ether was first dissociated during hydrogenolysis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mulliken charge distribution difference affects the adsorption of H+ and H ·. • AR hydrogenation and *C al –O– bond cleavage dominated the CHC early stage. • Lowering temperature is favorable for cracking >C ar –O– under certain conditions. • Sufficient H+ release facilitates the direct dehydroxylation and dehydration. This paper focused on the complementary advantages of density functional theory (DFT) calculation and catalytic reaction regulation. Based on the effective identification of intermediates, the possible catalytic hydroconversion (CHC) pathways of lignite-derived aryl ethers over Ni/mordenite were discussed. Bond dissociation energy (BDE) calculations of >C–O– bonds in different substrates and intermediates show that BDEs of >C ar –O– bonds are generally higher than those of >C al –O– bonds, and there is obvious electron aggregation near O atoms. Mulliken charge distribution analyses of different atomic sites further revealed the possible adsorption sites of active hydrogen, especially H · and H+. Possible cleavage pathways were further speculated by evaluating the stability of different leaving groups. In the early stage of CHC, aromatic ring hydrogenation and >C al –O– bond cleavage dominate, rather than >C ar –O– bond cleavage. Enthalpy change analyses combined with the CHC of real substrates further indicate that lowering temperature is beneficial to the cleavage of >C ar –O– bonds under the premise of inhibiting H ··· H transfer and obtaining H · effectively. Appropriately increasing the support acidity to ensure sufficient H+ release is conducive to >C al –O– bond cleavage, especially direct dehydroxylation/dehydration. The analysis of synergetic transfer pathways of active hydrogen during the CHC provides theoretical guidance for the pathway optimization of converting lignite into high-quality clean liquid fuels. [ABSTRACT FROM AUTHOR]

Abstract: Palladium on carbon catalyzes C−O bond cleavage of aryl ethers (diphenyl ether and cyclohexyl phenyl ether) by alcohols (R−OH) in H2. The aromatic C−O bond is cleaved by reductive solvolysis, which is initiated by Pd‐catalyzed partial hydrogenation of one phenyl ring to form an enol ether. The enol ether reacts rapidly with alcohols to form a ketal, which generates 1‐cyclohexenyl−O−R by eliminating phenol or an alkanol. Subsequent hydrogenation leads to cyclohexyl−O−R. [ABSTRACT FROM AUTHOR]

A mechanistic study of arylations of aliphatic alcohols and hydroxide with diaryliodonium salts, to give alkyl aryl ethers and diaryl ethers, has been performed using experimental techniques and DFT calculations. Aryne intermediates have been trapped, and additives to avoid by-product formation originating from arynes have been found. An alcohol oxidation pathway was observed in parallel to arylation; this is suggested to proceed by an intramolecular mechanism. Product formation pathways via ligand coupling and arynes have been compared, and 4-coordinated transition states were found to be favored in reactions with alcohols. Furthermore, a novel, direct nucleophilic substitution pathway has been identified in reactions with electron-deficient diaryliodonium salts. [ABSTRACT FROM AUTHOR]

A simple protocol for reductive cleavage of C-O bond in diaryl and aryl methyl ethers was reported, in which NaH served as a reducing agent and KO tBu as a base and a radical initiator. The combination of NaH and KO tBu displayed high efficiency for reductive cleavage of C-O bond in diaryl and aryl ethers ( e.g., dibenzofuran, diphenyl ether, anisole) without the hydrogenation of the aryl rings, in the absence of any other catalysts or ligands at 140 °C, producing corresponding arenes and phenols. It was indicated that the reaction was under a radical mechanism. [ABSTRACT FROM AUTHOR]

Metallic palladium surfaces are highly selective in promoting the reductive hydrolysis of aromatic ethers in aqueous phase at relatively mild temperatures and pressures of H2. At quantitative conversions, the selectivity to hydrolysis products of PhOR ethers was observed to range from 50 % (R=Ph) to greater than 90 % (R= n-C4H9, cyclohexyl, and PhCH2CH2). By analysis of the evolution of products with and without incorporation of H218O, the pathway was concluded to be initiated by palladium metal catalyzed partial hydrogenation of the phenyl group to an enol ether. Water then rapidly adds to the enol ether to form a hemiacetal, which then undergoes elimination to cyclohexanone and phenol/alkanol products. A remarkable feature of the reaction is that the stronger Ph−O bond is cleaved rather than the weaker aliphatic O−R bond. [ABSTRACT FROM AUTHOR]

In a heretofore-unreported reaction, 1,2-cyclohexandione reacts with a variety of alcohols under mild acid-catalyzed dehydration conditions to afford not only ethers of 1,2- cyclohexanedione but the corresponding aryl ethers as well in moderate to good yield. [ABSTRACT FROM AUTHOR]

Catalytic etherification of phenolic oil with methanol was investigated to decrease the polarity and acidity of the product oil. The catalyst KH2PO4/activated alumina (AA) provided the best performance due to its excellent dehydration and anticoking property. When catalyzed by KH2PO4-AA, the content of aryl ethers increased with rising temperature during the early stage but decreased at 500 °C. Alkoxy phenols had an inhibiting effect on etherification of alkyl phenols due to adsorption competition. Aryl ethers were mostly generated from alkyl phenols, while alkoxy phenols also contributed by simultaneous conversion to dialkoxybenzenes and diphenols, with a higher selectivity to diphenols. This explained the reduced alkoxy phenols and more generated alkyl phenols and aryl ethers at 350 °C. [ABSTRACT FROM AUTHOR]

ortho-Quinones are underutilized six-carbon-atom building blocks. We herein describe an approach for controlling their reactivity with copper that gives rise to a catalytic aerobic cross-coupling with phenols. The resulting aryl ethers are generated in high yield across a broad substrate scope under mild conditions. This method represents a unique example where the covalent modification of an ortho-quinone is catalyzed by a transition metal, creating new opportunities for their utilization in synthesis. [ABSTRACT FROM AUTHOR]

The metabotropic glutamate receptors (mGlu receptors) have emerged as attractive targets for number of neurological and psychiatric disorders. Recently, mGluR5 negative allosteric modulators (NAMs) have gained considerable attention in pharmacological research. Comparative molecular field analysis (CoMFA) was performed on 73 analogs of aryl ether which were reported as mGluR5 NAMs. The study produced a statistically significant model with high correlation coefficient and good predictive abilities. [ABSTRACT FROM AUTHOR]

We describe the first total syntheses of two ellagitannins, laevigatins A and E. Laevigatin A comprises a 2,3- O-( S)-hexahydroxydiphenoyl-α- D-glucose unit, whose anomeric oxygen atom forms a dehydrodigalloyl ester. Laevigatin E is a dimeric ellagitannin with structural motifs similar to those of laevigatin A. A recently developed method for synthesizing C-O digallates allowed the synthesis of more than 1 g of laevigatin A. The abundant supply allowed the synthesis of laevigatin E, an achievement that implies that more complex ellagitannins could be accessible. [ABSTRACT FROM AUTHOR]

Catalytic hydrogenolysis of aryl ethers is a green way to utilize lignin-derived biomass resources or aromatic plastics with ether bonds for producing important chemicals and biofuels, but is also a challenging issue. In this work, we synthesized several cobalt-yttrium bimetallic catalysts via a simple co-precipitation method. One of them with a Co/Y molar ratio of 12/1 could catalyze the reaction with good performances in the absence of a promoter under relatively mild conditions, especially as low as 140 °C. The interaction between Co and Y species contributed to the high activity. The Y species inhibited the reduction of cobalt oxides and enhanced the adsorption capacity of hydrogen. The results of recycling and gram-scale experiments showed the present catalyst possesses great potential for industrial application. The present finding not only builds an efficient Co–Y bimetallic catalyst for hydrogenolysis of aryl ethers emanated from lignin-derived biomass or aromatic plastics with ether bonds, but also widens the application range of the rarely used yttrium metal in catalysis. [Display omitted] • A Co–Y bimetal can efficiently catalyze the hydrogenolysis of diphenyl ethers. • The incorporated Y enhanced the H 2 adsorption amount of the Co-based catalyst. • The Co 12 Y 1 O x could be reused at least 8 times with high activities. • The Co 12 Y 1 O x catalyst showed good universality in the reaction. • The catalyst could catalyze the gram-scale experiment with a high activity. [ABSTRACT FROM AUTHOR]

Ferrocenyl aryl ethers can be synthesized in good yields by Cu(I)/phosphine-catalyzed coupling reactions from iodoferrocene or 1,1′-dibromoferrocene and various phenols in toluene, using Cs2CO3 or K3PO4 as a base. For the first time a solid-state structure of a ferrocenyl-1,1′-diaryl ether [1,1′-di(4-tert-butylphenoxy)ferrocene] has been determined from single-crystal X-ray data. The mixed ferrocenyl aryl ether 1-(4-tert-butylphenoxy)-1′-(2,4-dimethylphenoxy)ferrocene was prepared in a two-step synthetic protocol. [ABSTRACT FROM AUTHOR]

The use of picolinic acid amide derivatives as an effective family of bidentate ligands for copper-catalysed aryl ether synthesis is reported. A fluorine-substituted ligand gave good results in the synthesis of a wide range of aryl ethers. Even bulky phenols, known to be very challenging substrates, were shown to react with aryl iodides with excellent yields using these ligands. At the end of the reaction, the first examples of end-of-life Cu species were isolated and identified as CuII complexes with several of the anionic ligands tested. A preliminary mechanistic investigation is reported that suggests that the substituents on the ligands might have a crucial role in determining the redox properties of the metal centre and, consequently, its efficacy in the coupling process. An understanding of these effects is important for the development of new efficient and tunable ligands for copper-based chemistry. [ABSTRACT FROM AUTHOR]

The direct replacement of aromatic methoxy groups with activated carbon nucleophiles would give rise to novel synthetic pathways for targeted and diversity-oriented syntheses. We demonstrate here that this transformation can be achieved in a one-step reaction involving a bifunctional organolithium nucleophile in combination with a CArOMe bond-cleaving nickel catalyst. The resulting products are stable, α-CH active, and suitable for various further modifications. [ABSTRACT FROM AUTHOR]

Highlights: [•] Semifluorinated arylene ether, esters and their combinations are prepared at RT. [•] Organic compounds possessing various functional groups. [•] Organic molecules include azo units, allyl, vinyl, nitro, etc. [•] Fundamental understanding of reactivity of starting materials. [ABSTRACT FROM AUTHOR]

Using Bi2(SO4)3 as the catalyst and TMSCl as the additive, a wide variety of aldehydes, ketones, and acetals were smoothly condensed with aryl ethers at room temperature to provide the corresponding diarylmethanes and triarylmethanes selectively in good to excellent yields. [ABSTRACT FROM AUTHOR]

One in, one out: In the presence of a copper/silver bimetallic catalyst system, aromatic carboxylate salts undergo ortho CH alkoxylation with concomitant loss of the carboxylate directing group in a protodecarboxylation step (see scheme, FG=functional group). This process provides a convenient synthetic access to the important class of aromatic ethers from widely available carboxylic acids. [ABSTRACT FROM AUTHOR]

The diaryl ether moieties have attracted considerable attention of medicinal chemists as they are endowed with a wide range of diverse biological activities. The present study involves synthesis, characterization of some new aryl ethers and evaluation of their antiinflammatory and analgesic activity. A series of new aryl ether derivatives [4(a-h), 5] were prepared by Ullmann's ether condensation. The structures of new compounds are supported by their IR, ¹H NMR and Mass spectra. The new derivatives were evaluated for their antiinflammatory and analgesic activity. Among the tested, compound 3 has shown better antiinflammatory and analgesic activity. [ABSTRACT FROM AUTHOR]

The reaction of aryl fluorides with silyl reagents has been shown to be efficiently promoted by tetrabutylammonium fluoride, providing aryl ethers with good to excellent yields under solvent-free conditions. The efficiency of this reaction was demonstrated by the compatibility with aldehyde, nitro, cyano and acetyl groups. Moreover, the rigorous exclusion of air/moisture was not required in these transformations which proceeded under milder conditions than previously reported reactions of this type. [ABSTRACT FROM AUTHOR]

Copper iodide was utilized as a relatively inexpensive catalyst for the synthesis of podocarpic acid ether derivatives in excellent yields through the one-step cross-coupling reaction of methyl 13-iodo-O-methylpodocarpate with alcohols. [ABSTRACT FROM AUTHOR]

Phosphonium and benzotriazolyloxy (and related) intermediates are easily prepared by the reactions of cyclic amides and ureas with (1H-benzotriazol-1-yloxy)triaminophosphonium hexafluorophosphate related reagents. The former intermediates could also be made available using analogous phosphonium reagents prepared in situ or from commercial sources. These intermediates efficiently lead to carbon-nitrogen, carbon-oxygen, carbon-sulfur, and carbon-carbon bond formations through nucleophilic aromatic substitution reactions with various nucleophiles. A new �reaction involving the generation of phenols in situ from arylboronic acids and oxygen under palladium(0) catalysis or with boronic acids and hydrogen peroxide is reviewed. 1 Introduction 2 Phosphonium-Mediated Nucleophilic Aromatic Substitution Reactions of Heterocyclic Systems 2.1 Phosphonium-Mediated Carbon-Nitrogen Bond Forming Reactions via Modified Appel Conditions 2.2 Phosphonium-Mediated Carbon-Nitrogen Bond Forming Reactions via Commercially Available Phosphonium Reagents 2.2.1(1H-Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium Hexafluorophosphate as an Activating Agent 2.2.2(1H-Benzotriazol-1-yloxy)tripyrrolidinylphosphonium Hexafluorophosphate and Bromotripyrrolidinylphosphonium Hexafluorophosphate as Activating Agents 2.2.3 Solvent and Base Effects 2.3 Reactivity of Various Phosphonium Reagents 2.4 Phosphonium-Mediated Carbon-Oxygen, Carbon-Sulfur, and Carbon-Carbon Bond Forming Reactions 3 Benzotriazolyloxy-Mediated and Related Bond-Forming Reactions of Heterocyclic Systems 4 Phosphonium-Mediated Reaction Mechanisms 4.1 Stepwise Pathways via Phosphonium and 1H-Benzotriazol-1-ol (or Pyridotriazol-1-ol) Adducts 4.2 1H-Benzotriazol-1-ol (or Pyridotriazol-1-ol) Adduct Independent Pathway 5 Palladium-Catalyzed Heteroaryl Ether Formation from Benzotriazolyloxy- or Pyridotriazolyloxy-Substituted Heterocycles with Arylboronic Acids 6 Unusual 1H-Benzotriazol-1-ol Adduct Rearrangement 7 A Tentative Protection and Amination Strategy Involving a 1H-Benzotriazol-1-ol Adduct 8 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

This review covers the application, mechanisms and limitations of simple alkylating agents that can be used for the conversion of carboxylic acids to esters, phenols to aryl ethers, enols to enol ethers and thiols to thioethers. Specific recent examples are provided to show the selectivity (regio or chemo) in these transformations. It is important to have access to these methods when considering alternatives to classical alkylating techniques. [ABSTRACT FROM AUTHOR]

Abstract: A wide range of commercial diazodicarboxylates and phosphines were screened in an attempt to find purification-free conditions for application in parallel synthesis. The combination of immobilized triphenylphosphine and TMAD proved to be suitable for the synthesis of aryl ethers via the Mitsunobu reaction. Nine ethers were synthesized in good yield and excellent purity, the purification being limited to a filtration step. [Copyright &y& Elsevier]

Chiral 3-methanesulfonyl-1-Boc-pyrrolidine and piperidine were reacted with sodium phenolates, resulting in a mixture of displacement and elimination products. Following carbamate deprotection and pH adjustment, the 3-pyrroline and tetrahydropyridine by-products resulting from elimination were easily removed through aqueous partitioning and/or concentration. Although the pyrrolidines were formed with a high degree of optical purity, slight racemization was observed for the piperidine case because elevated temperatures were required to effect displacement. [ABSTRACT FROM AUTHOR]

Abstract: The combination of 2-phosphino-substituted N-arylpyrroles or related indoles (cataCXium®P) and Pd(OAc)2 allows for efficient cross-coupling reactions of aryl chlorides and phenols to give diaryl ethers. A variety of aryl and heteroaryl chlorides can be coupled with substituted phenols showing unprecedented catalyst turnover numbers. [Copyright &y& Elsevier]

The copper-catalyzed Ullmann C-O coupling reactions between phenols and aryl/vinyl halides have been efficiently performed by employing ( E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one, an easily available enaminone, as ligand. This new ligand is advantageous for its easy availability, broad applicability and good efficiency. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]