Imidazoline-fused [1,4]oxazepines ( prepared in two simple steps from methyl 2-hydroxyaroates, ethylene diamine and bis-electrophilic aromatics) undergo a facile, good-yielding hydrolytic imidazoline ring expansion (HIRE) upon N-alkylation and treatment with aqueous K 2 CO 3 . The resulting arene-fused ten-membered lactams significantly add to the contemporary arsenal of smallmolecule scaffolds where medium-sized ring systems are severely underrepresented.Small molecule libraries containing medium-sized (8-to 11-membered) rings are currently recognized as a drug discovery platform with many advantages compared to linear scaffolds or those based on flat heteroaromatic rings.1 The introduction of a cycle drastically reduces the rotatable bond count (compared to a linear molecule), which improves permeability through cell membranes and intestinal absorption.

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 (11to 12-membered) diarene-fused rings were obtained via the homo-HIRE and homo 2 -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.

A four‐step approach to the “hydrated imidazoline ring expansion” (HIRE) is presented. In most cases, the ring expansion was the sole process. However, for the first time, an alternative course of the hydrated imidazoline evolution was discovered which gave N‐aminoethyl derivatives. These can, in principle, be converted into the target HIRE products under sufficiently forcing conditions. The approach offers improved flexibility with respect to the peripheral substituents and is also applicable to the synthesis of eleven‐membered lactams. We observed that the latter can exist in two stable isomeric forms due to lactam–amide bond isomerization. The latter finding further demonstrates the value of medium‐sized rings as multiple‐conformer probes for biological target interrogation.

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