Straightforward synthesis of pyrimido[4,5-e][1,4]diazepines via 6-aminopyrimidin-5-carbaldehydes

Abstract

A high-throughput method to obtain several pyrimido[4,5-e][1,4]diazepines is described by a two-step acylation/cyclization sequence from key intermediates 6-amino-5-(amino)methylpyrimidines, which were prepared from the precursor 6-aminopyrimidin-5-carbaldehydes. The acylation is accomplished with haloacyl halides to render ((4-aminopyrimidin-5-yl)-methyl)-2-haloamide intermediates. The cyclization step worked successfully, but depending on the substituents, competitive reactions versus the cyclization to pyrimido[4,5-e][1,4]diazepines were found to afford indolinones or acrylamides which were formed via alternative cyclization or elimination respectively. The pyrimido[4,5-e][1,4]diazepines were derivatized by alkylation at N(9), and a two-step one-pot procedure, cyclization/alkylation, from the ((pyrimidin-5-yl)-methyl)-2-haloamide intermediates was optimized to the formation of these N(9)-substituted derivatives. Keywords: 4(6)-Aminopyrimidines, Diazepines, Fused heterocycles, Acylation, Cyclization