Oxygen Atom Insertion Into Tetrahydroquinolines: A Skeletal Editing Approach To Unexplored 2,3-Benzoxazepines

Since the introduction of chlordiazepoxide (Librium) and diazepam (Valium), 1,4-benzodiazepines have become established privileged scaffolds in medicinal chemistry due to their anxiolytic, sedative, and anticonvulsant properties. Despite their clinical success, prolonged use is associated with adverse effects such as tolerance, dependence, and cognitive impairment, prompting continued efforts to identify related frameworks with improved safety profiles. Exploration of the benzodiazepine chemical space has mainly followed two directions: regiomeric adjustment to access 2,3-benzodiazepines, and heteroatom replacement to generate 1,4-benzoxazepines (Scheme 1A). In contrast, the combined implementation of these approaches—leading to 2,3- benzoxazepines—remains largely unexplored. Reported syntheses of 2,3-benzoxazepines typically suffer from regioselectivity issues, competing dimerizations, and limited scope (Scheme 1B). As an alternative, direct atom insertion into abundant cyclic precursors—recently referred to as molecular skeletal editing—could provide a more straightforward solution. Among the reported skeletal reorganization strategies, oxygen atom insertions have been explored less frequently due to competing peripheral oxidations. One possible approach is the Meisenheimer rearrangement of tertiary amine N-oxides, as the N–O bond is preserved throughout the transformation. Herein, we revisit the [1,2]-Meisenheimer rearrangement as a skeletal editing strategy to selectively access 2,3-benzoxazepines from readily available tetrahydroquinolines, including derivatives from natural sources (Scheme 1C).