Ullmann Ether Synthesis Research Articles

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Total synthesis of kehokorins A and B

The total synthesis of a dibenzofuran rhamnoside, kehokorin A, and its aglycone, kehokorin B, was achieved via a route including Suzuki-Miyaura cross-coupling followed by Ullmann ether synthesis to form a dibenzofuran, stepwise bromination at C7 of the dibenzofuran, a second Suzuki-Miyaura cross-coupling to install a 4-methoxyphenyl group at C7, and rhamnosylation.

Structure Elucidation of the Main Tetrahydroxyxanthones of Hypericum Seeds and Investigations into the Testa Structure.

Seeds from Hypericum species have recently been identified as an interesting source of xanthone derivatives. Extraction of seeds from H. perforatum with MeOH and subsequent concentration via polyamide adsorption yielded a fraction enriched in tetrahydroxyxanthones (THX), which were further semipurified by silica gel chromatography. Based on tentative structure assignment of the two main THX X1 and X2 by NMR a total synthesis was performed for both compounds (THX 1 and 2, respectively), starting with an Ullmann ether synthesis. The synthesized 1 and 2 were characterized via 1D- and 2D-NMR methods as well as by LC/HR-MS analysis and proven to be 1,4,6,7-THX (1) and 1,2,6,7-THX (2). Final structure assignment of the natural Hypericum THX constituents was accomplished by comparing chromatographic and spectroscopic data (LC/MSn and GC/MS) with those of 1 and 2 which were obtained by synthesis. Beyond, investigations into the seeds of H. perforatum and H. tetrapterum by scanning electron microscopy (SEM) provided insights of the structure of the testa (seed coat), which is established by two cell layers, with the lignified sclerenchyma presumably being the depository of the xanthones.

The structure proposed for apteniol D is different from that of the compound obtained by total synthesis

We describe the synthesis of 4,4′-oxyneolignan, the proposed structure for naturally occurring apteniol D. The diphenyl ether moiety in 4,4′-oxyneolignan was formed via classical Ullmann ether synthesis using excess copper powder in N,N-dimethylacetamide. The spectral data of synthesised apteniol D show differences compared to those of naturally occurring apteniol D.

Synthesis and degranulation-inhibiting activities of the proposed apteniols B, C, and G.

The synthesis of compounds with the structures proposed for the oxyneolignan apteniols B, C, and G is described. The diphenyl ether skeletons of the proposed apteniols were formed via Ullmann ether synthesis. In particular, the spectral data for the synthesized apteniols B, C, and G did not agree with those previously reported for the isolated compounds. Furthermore, the synthesized proposed apteniol B did not show degranulation-inhibiting activity, while the prepared proposed apteniols C and G exhibited activities considerably weaker than that of the methyl ester of proposed apteniol A.

Syntheses and biological activities of the proposed structure of apteniol A and its derivatives.

We describe the syntheses of the proposed structure of diphenyl ether oxyneolignan, apteniol A and its derivatives. The diphenyl ether moiety of proposed apteniol A was formed via Ullmann ether synthesis, but the spectral data of the synthesized apteniol A did not agree with that in previous studies. The dimethyl ester derivative of the proposed apteniol A was found to enhance neurite outgrowth in PC12 cells and inhibit antigen-induced degranulation in RBL-2H3 cells.

Syntheses of the Fungal Metabolites Boletopsins 7, 11, and 12 from the Papua New Guinea Medicinal Mushroom Boletopsis sp.

Boletopsins 7 (1), 11 (2), and 12 (3) are p-terphenyl dibenzofuran compounds, isolated from the Papua New Guinean medicinal mushroom Boletopsis sp. The first syntheses of these fungal metabolites are reported, allowing for an investigation of their antibiotic activity. The key steps include sequential Suzuki-Miyaura couplings to rapidly form the p-terphenyl backbone and an Ullmann ether synthesis on a formate ester to create the dibenzofuran moiety. Biological evaluation of the synthetic compounds and intermediates against a panel of bacterial nosocomial pathogens was performed.

KF/Clinoptilolite, an effective solid base in Ullmann ether synthesis catalyzed by CuO nanoparticles

Download options Please wait... Article information DOI https://doi.org/10.1039/C3NJ00834G Article type Letter Submitted 25 Jul 2013 Accepted 08 Oct 2013 First published 11 Oct 2013 Download Citation New J. Chem., 2014,38, 42-45 BibTex EndNote MEDLINE ProCite ReferenceManager RefWorks RIS Permissions Request permissions KF/Clinoptilolite, an effective solid base in Ullmann ether synthesis catalyzed by CuO nanoparticles M. A. Khalilzadeh, H. Keipour, A. Hosseini and D. Zareyee, New J. Chem., 2014, 38, 42 DOI: 10.1039/C3NJ00834G To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page. If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given. If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page. Read more about how to correctly acknowledge RSC content. Social activity Tweet Share Search articles by author Mohammad A. Khalilzadeh Hoda Keipour Abolfazl Hosseini Daryoush Zareyee

Microwave-assisted Cu-catalyzed Ullmann ether synthesis in a continuous-flow milli-plant

The combination of milli-scale processing and microwave heating has been investigated for the Cu-catalyzed Ullmann etherification in fine-chemical synthesis, providing improved catalytic activity and selective catalyst heating. Wall-coated and fixed-bed milli-reactors were designed and applied in the Cu-catalyzed Ullmann-type CO coupling of phenol and 4-chloropyridine. In a batch reactor the results show clearly increased yields for the microwave heated process at low microwave powers, whereas high powers and catalyst loadings reduced the benefits of microwave heating. Slightly higher yields were found in the Cu/ZnO wall-coated as compared to the Cu/TiO2 fixed-bed flow-reactor. The benefit here is that the reaction occurs at the surface of the metal nanoparticles confined within a support film making the nano-copper equally accessible. Catalyst deactivation was mainly caused by Cu oxidation and coke formation; however, at longer process times leaching played a significant role. Catalyst activity could partially be recovered by removal of deposited by-product by means of calcination. After 6h on-stream the reactor productivities were 28.3 and 55.1kgprod/(mR3h) for the fresh Cu/ZnO wall-coated and Cu/TiO2 fixed-bed reactor, respectively. Comparison of single- and multimode microwaves showed a threefold yield increase for single-mode microwaves. Control of nanoparticles size and loading allows to avoid high temperatures in a single-mode microwave field and provides a novel solution to a major problem for combining metal catalysis and microwave heating. Catalyst stability appeared to be more important and provided twofold yield increase for the CuZn/TiO2 catalyst as compared to the Cu/TiO2 catalyst due to stabilized copper by preferential oxidation of the zinc. For this catalyst a threefold yield increase was observed in single-mode microwaves which, to the best of our knowledge, led to a not yet reported productivity of 172kgprod/(mR3h) for the microwave and flow Ullmann CO coupling.

Potassium Fluoride Supported on Natural Nanoporous Zeolite: A New Solid Base for the Synthesis of Diaryl Ethers

AbstractAn efficient and inexpensive synthesis of diaryl ethers has been developed. The process involves the nucleophilic aromatic substitution of electron‐deficient aryl halides and phenols and is mediated by potassium fluoride/Clinoptilolite (KF/CP) in dimethyl sulfoxide (DMSO). The approach affords good to excellent yields of the arylated products without the need for additional cation capture. The solid base is also efficient in the Ullmann ether synthesis.

Copper(I) phenoxide complexes in the etherification of aryl halides.

Copper-catalyzed Ullmann ether synthesis has been studied for many years because aryl ethers comprise important classes of medicinally active compounds and agrochemicals.[1,2] The traditional Ullmann-type reactions required high temperatures, use of polar and high-boiling solvents, and stoichiometric quantities of the copper salt. Recently, by combining the copper with a variety of different ligands, milder catalytic Ullmann reactions have been developed [Eq. (1)]. Examples

Copper(0) in the Ullmann heterocycle-aryl ether synthesis of 4-phenoxypyridine using multimode microwave heating

The action of nanoparticulate copper catalysts with a mean particle size of 10 nm in the Ullmann ether synthesis is reported using multimode microwave heating and employing stable chloropyridine salts and unactivated phenol, with stabilized copper nanoparticles outperforming other copper catalysts in terms of stability and reusability.

Effect of microwave heating on Ullmann-type heterocycle-aryl ether synthesis using chloro-heterocycles

Ullmann ether synthesis was conducted on a variety of chloro-heterocycles with different phenols using optimized conditions involving copper powder and cesium carbonate. On many substrates, microwave heating afforded higher yields in significantly shorter reaction times compared to conventional heating conditions. These findings provide a facile method for aryl ether synthesis from chloropyridines, chloroquinolines, and chlorobenzothiazoles.

Microwave‐Assisted Synthesis of Diaryl Ethers from Reactions of Phenols with Nitroaryl Fluorides under Solvent‐Free Conditions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Microwave-assisted Synthesis of Diaryl Ethers from Reactions of Phenols with Nitroaryl Fluorides under Solvent-free Conditions

Diaryl ethers are frequently found in substructures of many biologically important natural products. Diaryl ethers can be commonly synthesized via two general ways which include Ullmann ether synthesis and aromatic nucleophilic substitution (SNAr) based addition reactions. In general, classical Ullmann diaryl ether synthesis required high boiling solvents, stoichiometric amount of organocuprate catalyst, and long reaction times. In recent years, diaryl ether synthesis based on SNAr addition reactions have received considerable attention. For example, various diaryl ethers have been synthesized from the method utilizing the reaction of phenols with electron deficient aryl halides in the presence of potassium fluoride-alumina and 18-crown-6. However, in this method the reactions usually required longer reaction times ranged from hours to several days in refluxing acetonitrile which limit its practical utlilization. Recently, microwave-assisted organic synthesis in various solvents as well as under solvent-free conditions have received tremendous investigation. By applying microwave irradiation to certain organic reactions, it is often possible to reduce reaction times from many hours to a few minutes. In addition, recent large demand for environmentally-friendly and less hazardous chemical reaction processes have stimulated the development of clean reactions that avoid use of excess amount of toxic and volatile organic reaction solvents. In particular, microwave-assisted reactions coupled with solvent-free conditions that involve the exposure of neat reactants to microwaves received great attention. This ecofriendlier technique has many practical advantages over conventional methods in terms of rapid reaction, operational simplicity, cleaner reaction, and increased yield. A couple of methods for the preparation of diaryl ethers using refluxing solvents under microwave irradiation conditions are recently reported. However, to the best of our knowledge, the only previous example for the microwaveassisted synthesis of diaryl ethers via SNAr based reaction under solvent-free conditions was reported briefly by the reaction of 4-fluoronitrobenzene with phenol in the presence of potassium hydroxide. As part of our ongoing program for the development of microwave-assisted organic reactions, we need to develop an efficient and facile synthetic method for diaryl ethers in solvent-free conditions using microwaves. Herein, we report our preliminary results on the microwave promoted synthesis of diaryl ethers under solvent-free phase transfer catalysis (PTC) conditions. Treatment of phenols with nitroaryl fluorides, KF-alumina and Aliquat 336 under microwave irradiation in a domestic microwave oven provided the corresponding diaryl ethers in high yields. When the reactions were conducted in the absence of the PTC catalyst, the negligible amounts of the diaryl ethers were detected. After careful screening of several phase transfer catalysts (TBAB, 18-crown-6, and

Application of n.c.a. 4‐[18F]fluorophenol in diaryl ether syntheses of 2‐(4‐[18F]fluorophenoxy)‐benzylamines

AbstractThe availability of no‐carrier‐added (n.c.a.) 4‐[18F]fluorophenol offers the possibility of introducing the 4‐[18F]fluorophenoxy moiety into potential radiopharmaceuticals. Besides alkyl–aryl ether synthesis using n.c.a. 4‐[18F]fluorophenol the diaryl ether coupling is an attractive synthetic method to enlarge the spectrum of interesting labelling procedures. As examples the syntheses of n.c.a. 2‐(4‐[18F]fluorophenoxy)‐N,N‐dimethylbenzylamine and n.c.a. 2‐(4‐[18F]fluorophenoxy)‐N‐methylbenzylamine were realized by an Ullmann ether synthesis of corresponding 2‐bromobenzoic acid amides using tetrakis(acetonitrile)copper(I) hexafluorophosphate as catalyst and a subsequent reduction of the amides formed. The radiochemical yield of the coupling varied between 5 and 65% based on labelled 4‐[18F]fluorophenol. Both compounds are structural analogues of recently published radiotracers for imaging the serotonin reuptake transporter sites (SERT). However, in vitro binding assays of both molecules showed only a low affinity towards monoamine transporters. Copyright © 2004 John Wiley & Sons, Ltd.

Synthesis of m-Phenoxybenzaldehyde Starting from Chlorobenzene and m-Cresol: Some Aspects of Process Development

m-Phenoxybenzaldehyde (MPB) is an important intermediate for synthetic pyrethroids. In the present paper, an economic process scheme was developed to synthesize MPB starting from cheaper reactants. The process scheme was started with the synthesis of m-phenoxytoluene (MPT). Oxidation of MPT by air gave MPB, but the selectivity was found to be high at low conversions of about 10%, and if the conversion level was increased, then large amounts of the undesired m-phenoxybenzoic acid (MPBA) was formed. To obtain the desired aldehyde, Rosenmund reduction of MPBA was carried out to give high yields of the MPB. The effects of different parameters such as catalyst, substrate concentration, temperature, etc., were studied for all three of the reactions, viz., Ullmann ether synthesis, oxidation, and Rosenmund reduction. MPT was prepared from chlorobenzene, a relatively cheaper starting material, in the presence of poly(ethylene glycol) as cosolvent and cuprous chloride as the catalyst. A selectivity of 97% was obtained with 86% conversion to the product. Oxidation of MPT was carried out by air in the presence of cobalt acetate as catalyst and sodium bromide as catalyst promoter. The selectivity with respect to the aldehyde and the ester was 37.4 and 30.6%, respectively, at a restricted overall conversion of 24%. The process parameters were controlled to achieve high selectivity towards the aldehyde. The acid, formed as the side product, was reduced to the aldehyde by Rosenmund reduction via the acyl chloride. At a conversion level of 85%, a selectivity of 87% to MPB was obtained using Pd/C.

Synthesis of Diaryl Ethers, Diaryl Thioethers, and Diarylamines Mediated by Potassium Fluoride−Alumina and 18-Crown-6: Expansion of Scope and Utility1

An efficient alternative to the Ullmann ether synthesis of diaryl ethers, diaryl thioethers, and diarylamines involving the S(N)Ar addition of a phenol, thiophenol, or aniline to an appropriate aryl halide, mediated by potassium-fluoride alumina and 18-crown-6 in acetonitrile or DMSO, is described. Expansion of the reaction conditions to include DMSO as solvent has resulted in a far greater range of substitution patterns permitted on the electrophile. For example, it was found that electronically unfavorable 3-chlorobenzonitrile could be condensed with 3-methoxyphenol to form the corresponding diaryl ether in 66% yield, a combination not normally amenable to Ullmann coupling. Electron-withdrawing groups present on the electrophile may be as diverse as nitro, cyano, formyl, acetyl, ester, amide, and even aryl. The method features a simple reaction procedure that provides products in generally good to excellent purified yields.

Synthesis and characterization of fluorinated poly(aryl ether ketone)s containing 1,4-naphthalene moieties

The new monomer 2,2-bis[4-(4-(4-fluorobenzoyl}-1-naphthoxy)phenyl]hexafluoropropane (2) was synthesized in a two-step reaction sequence. 2,2-bis[4-(1-naphthoxy)phenyl]-hexafluoropropane (1) was prepared using the Ullmann ether synthesis reaction of 4,4-(hexafluoroisopropylidiene)diphenol with 1-bromonaphthalene. Friedel-Crafts acylation of 1 with 4-fluorobenzoyl chloride in methylene chloride containing dimethylsulfone selectively afforded 2 in 82% yield. The polycondensation of 2 with various bisphenols in DMAc in the presence of an excess of potassium carbonate as a condensation reagent was carried out at 165°C to quantitatively afford the corresponding fluorinated poly(aryl ether ketone)s containing 1,4-naphthalene moieties. Thermal analysis of the polymers showed them to have T g s ranging from 194 to 230°C and to be thermally stable in air up with initial weight losses at about 500°C. In addition, these novel polymers exhibited excellent solubility in organic solvents including NMP, DMAc, and chloroform.

An easy access to functionalized diaryl ethers: Formal total synthesis of K-13

As an alternative to the Ullmann ether synthesis, the S NAr reaction led to an efficient one step synthesis of chiral bis-aminoacid diaryl ethers, important intermediates in the synthesis of K-13.