Scalable Synthesis of 6-Functionalized 1,4-Oxazepanes

Seven-membered heterocycles like 1,4-oxazepanes are strikingly scarce in compound libraries, despite their privileged position at the interface of diazepane, morpholine, and azepane scaffolds. The lack of reliable synthetic routes has long hindered their exploration, leaving a clear gap between potential and practical use. In this study, we revisit classical heterocyclization toward 1,4-oxazepanes and demonstrate that careful optimization transforms it into a robust protocol suited for multigram synthesis. The strategy accommodates both unsubstituted and methyl-substituted precursors, providing access to a diverse array of functionalized oxazepanes that are underrepresented in the literature otherwise. Alongside synthetic advances, the work provides a deeper understanding of how steric effects, transannular interactions, and substitution patterns govern the reactivity of this medium-sized scaffold.