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

Abstract

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.

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

“…Whereas the same arylation reactions with KFalumina/18-crown-6 in acetonitrile proceeded very sluggishly (1-84 h) as has been shown in the previous study, 9 the reactions at the present reaction conditions exhibited dramatic rate acceleration. As can be seen in the Table 1, all of the reactions are completed in 10 min with very high yields.…”

“…Noteworthy among these are very rapid and efficient reactions of bulky 2-tert-butylphenol with 2-fluoronitrobenzene and 4-fluoronitrobenzene, which required 68 h and 84 h of reaction times respectively in previous conventional method in solvents (entries 5 and 13). 9 Electron deficient phenols such as 4-chlorophenol and 4-nitrophenol were reacted smoothly with aryl fluoride to give the corresponding diaryl ethers (entries 7-8 and 15-16), which would not proceeded effectively under classical Ullmann type diaryl ether synthesis. These results coupled with environmentally benign conditions clearly demonstrate the advantage of the present new protocol.…”

“…6 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. 8,9 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.…”

A modified, economical and efficient synthesis of variably substituted pyrazolo[4,3-d]pyrimidin-7-ones

“…Nucleophilic aromatic substitution S N Ar reactions are of importance due to their use in industrial chemistry including the synthesis of N-alkyl aminoheterocycles [8], bioactive diarylethers [9] and N,N-disubstituted-5-aminothiophene-2-carboxaldehyde [9][10]. S N Ar reactions are also used to functionalize the pyrrole nucleus [11,12] and in the preparation of quinoxalinedione [13], which are AMPA receptor antagonists, as well as in synthesis of labeled 2'-deoxyinosine and 2'-deoxyadenosine [14].…”

Synthesis of novel fluorophenylaryl / heteroaryl ether derivatives

“…Nitration of 6 under relatively mild conditions gave a mixture of two regioisomers 5-fluoro-4-nitrobenzimidazole 7 and 5-fluoro-6-nitrobenzimidazole 8. The 4-nitro compound 7 was subjected to KF-Al 2 O 3 12 mediated coupling with o-fluorophenol and p-fluorophenol in the presence of catalytic amount of 18-crown-6-ether 13 in MeCN to give fluorophenyl benzimidazole (heteroaryl) ethers 9a-9b. Pd-C catalyzed hydrogenation of 9a-9b at atmospheric pressure afforded compounds 1a-1b, respectively in excellent yields.…”