Efficient use of 1,2-dihaloazine synthons in transition-metal-free preparation of diverse heterocycle-fused 1,4-oxazepines

Abstract

A previously reported condensation reaction of ambiphilic 2-(1H-pyrazol-5-yl)phenols with various o-chloro-substituted nitroaromatic synthons to provide medicinally important tetracyclic pyrazolo[1,5-d][1,4]oxazepines was extended to more readily available and convenient-to-use 1,2-dihaloazines. Although 4,5-dichloropyridazin-3(2H)-ones and 2,3-dichloropyrazine are popular bis(electrophilic) partners in various SNAr-type condensations and also were efficiently used in the reaction reported herein, the facility with which various 3-bromo-2-chloropyridines underwent the same cyclization was unexpected. These reactions are presumed to occur as sequential intermolecular SNAr/Smiles rearrangement/intramolecular SNAr tandem reactions and provide a rare example of the transition-metal-free substitution of a bromine atom at the 3-position of a pyridine ring.