Synthesis of diaryl ether

Diaryl ethers are an important class of compounds in pharmaceuticals and agricultural chemicals. The Ullmann ether formation reaction provides direct access to diaryl ethers. However, harsh reaction conditions, such as high temperatures (125-220 °C), stoichiometric quantities of the copper catalyst, and low to moderate yields, have greatly limited the utility of the reaction. The use of soluble copper salts and some effective ligands made it possible to carry out these reactions under mild reaction conditions. 

Entry X [Cu] Ligand Base Reaction conditions Yidd (%) Ref. 

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A variant for the synthesis of diaryl ethers—e.g. diphenyl ether 9, where an aryl halide and a phenoxide are reacted in the presence of copper or a copper-(I) salt, is called the Ullmann ether synthesis. ... 

Sjwyer and coworkers have developed an efficient alternative UUmann synthesis of diaryl ethers, diaryl thioethers, and diarylamines using the SnAt reaction. Phenol, thiophenol, or aniline reacts v/ith an appropriate aryl halide, In the presence of KF-aliunina and 18-crovm-6 In acetonitrile or DMSO to give the corresponding diaryl ether or diaryl thio ether as shovm In Eqs. 9.6 and 9.7. ... 

Fig. 10. Synthesis of diaryl ethers under sonication conditions...

A useful reaction for investigation is the Ullmann synthesis of diaryl ethers, which has potential importance for synthesis of a number of commercial products in the agrochemical and pharmaceutical fields, but which suffers from serious drawbacks, particularly high temperatures... 

Figure 15. Ultrasound-assisted synthesis of diaryl ethers.

Synthesis of Diaryl Ethers A Long-Standing Problem Has Been Solved... 

Until quite recently the synthesis of diaryl ethers has not been an easy task unless the target molecule was not sensitive towards the very harsh reaction conditions employed. 

The recent development directed towards the synthesis of diaryl ethers in a milder and more efficient manner was mainly driven by the synthesis of complex natural products. 

The base or nucleophile in the Dow phenol process is aqueous NaOH that needs to be heated to 300° C, which is only possible at a pressure of 200 bar. This conconction is only just capable of deprotonating chlorobenzene to benzyne or of adding to the latter subsequently. Thus, there is no analogous synthesis of diaryl ethers from sodium phenolates and haloben-zenes. And as expected, the product resulting from the Dow process did not contain more than 15% of diphenyl ether. 

The name Ullmann is not only associated with the biaryl synthesis (Figure 16.4, 16.5), but is also known from the synthesis of diaryl ethers (Ullmann synthesis of diaryl ethers). An example is given in the topmost reaction of Figure 16.6. Remember Side Note 5.6, where we asked the following question How can diphenyl ethers be prepared Now you are ready to give a correct answer, which is By way of Ullmann synthesis. ... 

Vttmann diaryl ether synthesis. This copper(I) derivative is recommended as the condensing reagent in the Ullmann synthesis of diaryl ethers from phenols and bromoarenes in refluxing pyridine (equation I). 

Schmittling, E. A., Sawyer, J. S. Synthesis of diaryl ethers, diaryl thioethers, and diarylamines mediated by potassium fluoride-alumina and 18-crown-6. J. Org. Chem. 1993, 58, 3229-3230. 

Evans, D. A., Katz, J. L., West, T. R. Synthesis of diaryl ethers through the copper-promoted arylation of phenols with arylboronic acids. An expedient synthesis of thyroxine. Tetrahedron Lett. 1998, 39, 2937-2940. 

Li, F., Wang, Q., Ding, Z., Tao, F. Microwave-Assisted Synthesis of Diaryl Ethers without Catalyst. Org. Lett. 2003, 5, 2169-2171. 

Zhao, J. K., Wang, Y. G. An efficient synthesis of diaryl ethers by coupling aryl halides with substituted phenoxytrimethylsilane in the presence of TBAF. Chin. Chem. Lett. 2003, 14, 1012-1014. 

Cristau, H.-J., Cellier, P. P., Hamada, S., Spindler, J.-F., Taillefer, M. A General and Mild Ullmann-Type Synthesis of Diaryl Ethers. Org. Lett. 2004, 6, 913-916. 

Ullmann ether reaction The synthesis of diaryl ethers by the coupling of an aroxide anion with an aryl halide in the presence of copper. 

Arylation. Traditionally, arylation of nucleophiles is carried out in the presence of copper catalysts, the use of FeCls as an alternative, with its scope has now been delineated. In the synthesis of diaryl ethers, l,3-di-t-butyl-l,3-propanedione serves an additive (ligand for the Fe ion) and CS2CO3 as base. A,A -Dimethylethylenediamine appears to be an excellent ligand in the reaction with A-nucleophiles (A-heterocycles, amides" ) in a nonpolar solvent (toluene) where a milder base (K3PO4) suffices, arylation of alkanethiols calls for t-BuONa. ... 

Diaryl ethers. This electron catalyzed synthesis of diaryl ethers f... 

Diaryl ethers. This electron-rich and bulky / iV-ligand (1) facilitates the Pd-catalyzed synthesis of diaryl ethers from phenols and aryl halides. 

As base. Numerous reactions that are initiated by deprotonation have been conducted with KF-AI2O3. These include the synthesis of diaryl ethers, amines, and sulfides by nucleophilic aromatic substitutions, AJ-alkylation of 2,4-dinitrophenyl-hydrazones, condensation of 3-phenylisoxazol-5-one with aldehydes, and ring closure of /V-(w-chloroalkyl) carboxamides to afford 1,3-oxazolines and 1,3-oxazines. ... 

The reaction of nucleophiles with chloroarene-Mn(CO)3 and fluoro arene-Cr(CO)3 complexes has been employed for the synthesis of diaryl ethers and has been particularly applied (ref. 55) to the selective arylation of polyfunctional phenols by reaction of the phenoxide formed from NaH in dimethylformamide with the 4-chlorotoluene-manganese tricarbonyl cation (as the hexafluorophosphate) in acetonitrile at ambient temperature over 18 hours. 

A high yield synthesis of diaryl ethers involves nucleophilic attack by phenoxide on arynes generated from iodobenzenes. The arynic nature was established with substituted iodobenzenes ( -MePhI and phenol, for example, gave 35% m-tolyl phenyl ether as well as 25% of t -tolyl phenyl ether). Diaryl sulfides were similarly prepared from thiophenols and iodoarenes. 

Scheme 15.65. Copper(l)-catalyzed synthesis of diaryl ethers from aryl iodides and bromides.

TheU F (2003) Synthesis of diaryl ethers a long-standing problem has been solved. In ... 

Synthetic Methodology Derived from the DoM-Cross-Coupling Nexus 11099 Table 14.19 The DoM-Ullmann synthesis of diaryl ethers [12]. 

Synthesis of diaryl ethers. Dimerization or polymerization reactions may proceed by phenolic oxidation, which is initiated by one-electron oxidation of the phenol 7 to give the radical 8. The radicals react successively with each other to yield dimeric structures. When the radicals are further oxidized, the cation 9 is produced, and reacts with nucleophiles, leading to nonphenolic dienones. 

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