Copper nitrate-enabled ring expansion reaction of cyclopropanes: a direct approach to 3-cyano-isoxazoline N-oxides

Abstract

A novel copper nitrate-enabled ring expansion reaction of cyclopropanes with a nitro group exchange was described, affording pharmacologically interesting isoxazoline N-oxide skeletons. A series of 3-cyano-isoxazoline N-oxide compounds were efficiently synthesized from 1,1-dicyano-2-arylcyclopropane derivatives with copper nitrate as the nitro source. The given approach features a wide substrate scope, mild conditions, good yields and operational simplicity. The produced isoxazoline N-oxides could be successfully converted into nitrogen-containing heterocycles such as isoxazolines, isoxazoles and nitrosoacetals, which are significant drug analogues. Further mechanistic investigation reveals a distinctive ionic nitration pathway with the assistance of copper nitrate, and indicates a concerted but not synchronous nitro-shift with the rebound of stepwise cyano-shift as an unprecedented functional group exchange process.