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

Abstract

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