The macrocyclic diaryl ether motif is commonly found in both synthetic and naturally occurring molecules, which were reported to mediate a wide range of biological activities. One of the most straightforward methods for the synthesis of macrocyclic diaryl ethers is the copper-catalyzed intramolecular Ullmann reaction of appropriate phenols with aryl halides. However, the scope and generality of Ullmann coupling has been limited by the harsh reaction conditions and low reaction yields. Therefore, much effort has been devoted to the modifications of this classical coupling reaction. During the course of our continuing effort on the synthesis of diaryl ether macrocycles, microwave heating has been applied for the intramolecular Ullmann macrocyclization reaction. Using our optimized conditions, a panel of diaryl ether macrocycles of different ring sizes, with different substitution patterns and linkers, was successfully synthesized under microwave irradiation using CuO as catalyst, K2CO3 as suitable base, and pyridine as solvent. Improved yields and shorter reaction times were noted compared with conventional heating and sealed pressure tube. To the best of our knowledge, this represents the first example of microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular Ullmann coupling.

Microwave-assisted synthesis of macrocyclic diaryl ethers via intramolecular Ullmann reaction

244th National Meeting (2012)

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