Synthesis of α,α-difluoro-β-amino amides using aldimines and bromodifluoroacetamides via the Reformatsky reaction

Abstract

α,α-Difluoro-β-amino amides are attractive building blocks of biologically active compounds such as fluorinated pharmaceutical mimics and oligopeptides. Herein, we describe the zinc-promoted Reformatsky reaction of aldimines using bromodifluoroacetamides which provides a direct synthetic approach to α,α-difluoro-β-amino amides. This method gave various N-PMP protected α,α-difluoro-β-amino-β-aryl amides in 64–95% yields. Furthermore, these amides were efficiently converted into 2,2-difluoropropane-1,3-diamines under reductive conditions using a combination of NaBH₄ and BF₃.