Rethinking Hydrolytic Imidazoline Ring Expansion: A Common Approach to the Preparation of Medium-Sized Rings via Side-Chain Insertion into [1.4]Oxa- and [1.4]Thiazepinone Scaffolds

The
previously reported ring-expansion strategy involving hydrolytically
prone imidazoline rings was thought to include the formation of a
hydrated imidazoline intermediate. In this work, we accessed the latter
via the addition of a 2-aminoethyl side chain onto a lactam moiety.
This led to an efficient three-atom ring expansion of diarene-fused
[1.4]­oxazepines and [1.4]­thiazepines and led us to propose to term
this common approach the hydrated imidazoline ring expansion (HIRE)
reaction. The strategy was extended to the insertion of longer (containing
up to five atoms) side chains, and thus, larger (11- to 12-membered)
diarene-fused rings were obtained via the homo-HIRE and homo2-HIRE reactions, respectively. This underscores the utility of the
HIRE reaction for the preparation of medium-sized rings, an important
class of chemical tools for interrogation of various biological targets.