A Comprehensive Insight into the Synthetic Pathways to Tetrahydrobenzoxazepines, Tetrahydrobenzothiazepines, and Tetrahydrobenzoimidazoazepines

Abstract:: Multiple heteroatom-containing fused seven-membered heterocyclestetrahydrobenzoxazepines, tetrahydrobenzothiazepines, and tetrahydrobenzoimidazoazepines serve as privileged scaffolds in a wide array of pharmacologically active compounds. Over the past two decades, significant strides have been made in efficient, selective, and sustainable synthetic routes to access these heterocyclic molecular frameworks. Prominent among them are cyclodehydration of properly substituted diols, transition metal-catalyzed intramolecular C-N bond formation, cyclization with N-protected amino alcohols with bromoethyl sulfonium salts, Michael-initiated ring-closure (MIRC) reactions, intramolecular Rh-catalyzed hydrofunctionalization of internal alkynes and allenes, etc., to construct tetrahydrobenzoxazepine cores under green chemistry metrics. These stepwise, mildcondition processes have facilitated the rapid diversification of heterocyclic libraries. On the other hand, transition metal-catalyzed intramolecular C-N bond formation of thioether derivatives, photochemical cyclization of arene-linked phthalimides containing a thioether donor group at the terminal SMe functionality, intramolecular cyclization of N-tethered aromatic thioalkenols, and reduction of benzothiazepinones have been key in accessing various tetrahydrobenzothiazepine architectures. The synthesis of tetrahydrobenzoimidazoazepines often relies on ring-expansion strategies using aziridine precursors, as well as intramolecular C-N coupling cascades that provide high regio- and stereocontrolably, the SN2-type stereoselective ring opening of activated aziridines with 2-bromobenzyl alcohols, 2-bromobenzyl mercaptans, and 2-bromobenzyl amines, followed by Cumediated C-N bond formation, efficiently gives rise to tetrahydrobenzoxazepines, tetrahydrobenzothiazepines, and tetrahydrobenzoimidazoazepines, respectively, in high yields. This review provides a comprehensive overview of advances in the synthesis of these three frameworks, with a focus on key methodologies, including cycloaddition reactions, ring expansion strategies, C-N coupling reactions, and other diverse synthetic approaches explored during this period.