Building Up a Piperazine Ring from a Primary Amino Group via Catalytic Reductive Cyclization of Dioximes

Abstract

Piperazine is one of the most frequently found scaffolds in small-molecule FDA-approved drugs. In this study, a general approach to the synthesis of piperazines bearing substituents at carbon and nitrogen atoms utilizing primary amines and nitrosoalkenes as synthons was developed. The method relies on sequential double Michael addition of nitrosoalkenes to amines to give bis(oximinoalkyl)amines, followed by stereoselective catalytic reductive cyclization of the oxime groups. The method that we developed allows a straightforward structural modification of bioactive molecules (e.g., α-amino acids) by the conversion of a primary amino group into a piperazine ring.

The medicinal chemistry of piperazines: A review

“…In 2023, Sukhorukov with his coworkers reported a strategy for the synthesis of piperazines, in which the double Michael addition of nitroso alkenes (NSA) (32) converts primary amines (31) into bis(oximino alkyl) amine (33). Then dioxime unit of compound 33 undergoes reductive cyclization in the presence of different catalysts such as Pd or Ni and yields substituted piperazines 34(a-d) (Scheme 11) (Pospelov et al, 2022;Pospelov & Sukhorukov, 2023).…”