A facile synthesis of 6-chloro-2-methylene-2,3-dihydro-1,4-oxazepines from N-propargylic β-enaminones

Abstract

A new and efficient method for the synthesis of 6-chloro-substituted 2-methylene-2,3-dihydro-1,4-oxazepines has been demonstrated. Upon treatment with N -chlorosuccinimide in acetonitrile, N -propargylic β-enaminones underwent chlorination to afford α-chlorinated N -propargylic β-enaminones, which was then subjected to electrophilic cyclization with zinc chloride in refluxing chloroform to yield 6-chloro-2-methylene-2,3-dihydro-1,4-oxazepines. It was shown for the first time that on N -propargylic β-enaminone systems, α-chlorination exclusively preponderates over the formation of chloronium ion. The method was found to be general for a diversity of N -propargylic β-enaminones and tolerated the presence of a wide range of aryl, heteroaryl and alkyl groups with electron-donating and electron-withdrawing substituents. The method was also applicable as the one-pot two-step process without isolating the intermediate α-chlorinated N -propargylic β-enaminones. This operationally easy method may provide a rapid entry to a library of highly functionalized 6-chloro-2-methylene-2,3-dihydro-1,4-oxazepines with potential medicinal applications for human health. • A new and practical method for synthesis of 6-chloro-substituted 1,4-oxazepines. • One-pot conversion of N-propragyl β-enaminones to 6-chloro-substituted 1,4-thiazepines. • High efficiency, large substrate scope and broad functional group tolerance. • Synthesis of chlorine-bearing 1,4-thiazepines as potential scaffolds and pharmacophores.