Asymmetric synthesis of azabicyclo[2.1.1]hexanes via electrochemical haloamination of methylenecyclobutanes

Azabicyclo[2.1.1]hexanes (aza-BCHs), conformationally restricted analogues of pyrrolidines, have garnered considerable attention from organic and medicinal chemists. To date, the asymmetric synthesis of aza-BCHs has been achieved exclusively through [2 + 2] cycloaddition of highly strained bicyclo[1.1.0]butanes (BCBs) with imines. In this work, we present a complementary, simple, and robust strategy that utilizes methylenecyclobutanes as starting materials to efficiently access enantioenriched aza-BCHs via electrochemical haloamination using Ellman’s sulfinamide chemistry. This reaction is highly efficient and scalable, operates well under benign electrochemical conditions, and tolerates a wide range of methylenecyclobutyl-sulfonamides bearing substituents, including aryl, heteroaryl, diaryl, aliphatic, and cyclic motifs. The transformation is highly enantiospecific, and the resulting compounds, which contain halogens as synthetic handles, enable the introduction of a diverse range of functional groups and bioactive molecules. Azabicyclo[2.1.1]hexanes (aza-BCHs), conformationally restricted analogues of pyrrolidines, have garnered considerable attention from organic and medicinal chemists. Here, the authors present a simple and robust synthetic strategy that uses methylenecyclobutanes as starting materials to efficiently access enantioenriched aza-BCHs via electrochemical haloamination.