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Synthesis of 3,3-Diarylazetidines

Diaryl heterocyclic amines are important building blocks in medicinal chemistry. While diarylpyrrolidine and diarylpiperidine structures are found in a variety of compounds used in drug discovery studies1, the 4-membered ring diarylazetidines are much less prominent in the medicinal chemistry literature. Presumably this is due to limited availability of diarylazetidine derivatives and few methods for the preparation of diarylazetidines. Herein, we describe a short and convenient method for the preparation of 3,3-diarylazetidines. Commercially available N-Boc-azetidin-3-one was readily converted into N-Boc-3-phenylazetidin-3-ol by the addition reaction of phenyllithium in THF at -78 °C. The N-Boc-3-phenylazetidin-3-ol was obtained in a high yield and high purity. Subsequent arylation of N-Boc-3-phenylazetidine-3- ol using a Friedel-Crafts reaction conditions (toluene/AlCl3) afforded the desired 3,3- diarylazetidine ring system in good yields. The scope and limitations of this new synthetic sequence for the preparation of 3,3-diarylazetidines will be presented.