Preparation of Diaryl Ethers

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185], 

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Ullman reaction The synthesis of diaryls by the condensation of aromatic halides with themselves or other aromatic halides, with the concomitant removal of halogens by a metal, e.g. copper powder thus bromobenzene gives diphenyl. The reaction may be extended to the preparation of diaryl ethers and diaryl thio-ethers by coupling a metal phenolate with an aryl halide. 

Fig. 16.6. Copper-mediated nucleophilic substititon reactions with aryl iodides or bromides for the preparation of diaryl ethers, diaryl sulfides, diaryl amines and arylmalonic esters (A). Often, these reactions are also referred to as Ullmann reactions.

Aranyos, A., Old, D. W., Kiyomori, A., et al. (1999) Novel electron-rich bulky phosphine ligands facilitate the palladium-catalyzed preparation of diaryl ethers. Journal of the American Chemical Society, 121, 4369 4378. 

Cuprous oxide was found superior to other copper species as reagent and catalyst for (he preparation of diaryl ethers by a modified Ullmann condensation, ... 

In an effort to eliminate heavy metals (Pd, Cu) from the preparation of diaryl ethers, a procedure using a sterically hindered proazaphosphatrane promoter has recently been reported using microwave heating (Scheme 2.23). Using TBDMS-protected phenols, aryl halides, 1-10% of the promoter and toluene as a solvent, this... 

Pearson AJ, Bruhn PR, Hsu S-Y (1986) Preparation of diaryl ethers from tyrosine or 4-hydroxyphenylglycine using organomanganese chemistry. J Otg Chem 51 2137-2139. doi 10.102 l/jo00361a043... 

S.L. Buchwald et al. - Electron-Rich Bulky Phosphine Ligands Facilitate the Pd-Catalyzed Preparation of Diaryl Ethers, J. Am. Chem. Soc. 121,4369,1999 ... 

Discrete copper compounds can also be used as catalysts for the synthesis of arylamines (Scheme 3.52) [58]. Venkataraman used a neocuproine-ligated copper(I) species to promote the coupling of aryl halides with secondary amines. A practical advantage to this chemistry was that only air-stable materials were needed to construct the catalyst needed for the cross-coupling. A base was needed to promote the reaction, and potassium tert-butoxide was found to be more effective in the cross-coupling than other common bases including potassium phosphate, sodium methoxide, or cesium carbonate. Curiously, cesium carbonate was not as active in this chemistry, but it was quite effective in the preparation of diaryl ethers. Several aryl halides were screened for activity, and aryl bromides and iodides afforded moderate to good yields of the arylamines. It should be noted that an electron-neutral aryl chloride was converted into the triarylamine, albeit in lower yield (49%). 

SNAr reactions also provide an important strategy for the preparation of various kinds of diaryl ethers. p-Dinitrobenzene reacts with even sterically hindered phenols to give the corre-... 

Treatment of diaryl ethers with dichloromethyl methyl ether in the presence of tin(lV) chloride leads to xanthylium salts (Scheme 268) (73JCS(Pl)ll04). It is necessary that the diaryl ether is so designed that electrophilic attack occurs ortho to the potential heteroatom. The thienopyrylium salts (673) and (674) have been prepared in the same manner. 

The structural relevance of diaryl ethers and the lack of a convenient, mild and general method for their preparation has resulted in increased efforts towards filling this gap in the synthetic methodology during the past decade. 

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. ... 

This procedure has been used by White (31) to prepare substituted diaryl ethers, many of them not readily available by other routes. 

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. 

As part of the studies of ligand effects on the reductive elimination of diaryl ethers, arylpalladium phenoxide complexes containing a DPPF analog that had P-CF3 substituents on each of the ligand aryl groups was prepared. This CF3-DPPF complex underwent reductive elimination of diaryl ether only twice as fast as the simple DPPF complex (Eq. 7). ... 

In 2007,Wan and coworkers prepared the diaryl ether via direct etherification of the tautomerizable heterocycle using BOP in the presence of DBU in MeCN (07JOCI0I94). 

Scheme 3.28 Pd-catalyzed C-H carbonylation of diaryl ethers to prepare xanthones.

In Figure 13.2, the intensity of the ion at m/z 170 represents a molecular ion of an aromatic compound. The characteristic losses from the molecular ion (M - 1, M - 28, and M - 29) suggest an aromatic aldehyde, phenol, or aryl ether. The molecular formula of Ci2H 0O is suggested by the molecular ion at m/z 170, which can be either a biphenyl ether or a phenylphenol. The simplest test to confirm the structure is to prepare a TMS derivative, even though m/z 11 strongly indicates the diaryl ether. 

This reaction is similar to 13-1 and, like that one, generally requires activated substrates. With unactivated substrates, side reactions predominate, though aryl methyl ethers have been prepared from unactivated chlorides by treatment with MeO in HMPA. This reaction gives better yields than 13-1 and is used more often. A good solvent is liquid ammonia. The compound NaOMe reacted with o- and p-fluoronitrobenzenes 10 times faster in NH3 at — 70°C than in MeOH. Phase-transfer catalysis has also been used. The reaction of 4-iodotoluene and 3,4-dimethylphenol, in the presence of a copper catalyst and cesium carbonate, gave the diaryl ether (Ar—O—Ar ). Alcohols were coupled with aryl halides in the presence of palladium catalysts to give the Ar—O—R ether. Nickel catalysts have also been used. ... 

A selective heating in liquid/liquid systems was exploited by Strauss and coworkers in a Hofmann elimination reaction using a two-phase water/chloroform system (Fig. 2.10) [32]. The temperatures of the aqueous and organic phases under micro-wave irradiation were 110 and 55 °C, respectively, due to the different dielectric properties of the solvents (Table 2.3). This temperature differential prevented decomposition of the final product. Comparable conditions would be difficult to obtain using traditional heating methods. A similar effect has been observed by Hallberg and coworkers in the preparation of /3,/3-diarylated aldehydes by hydrolysis of enol ethers in a two-phase toluene/aqueous hydrochloric acid system [33],... 

Trifluoroborane-etherate was used in this reaction. The same route seems to be quite convenient for the preparation of many other (diphenylmethylene-amino)boranes including dihaloborane derivatives. Similarly, B-monohalo derive atives such as [(C6Hs)2ON—B(C6H5)C1] and B-diaryl derivatives were synthesized by the cited method 47)... 

Xing, X. et al.. Utilization of a copper-catalyzed diaryl ether synthesis for the preparation of verbenachalcone. Tetrahedron, 58, 7903, 2002. 

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