Selective defluorinative [4 + 3] annulation to access fluorinated oxazepines and thiazepines

Abstract

Fluorinated seven-membered heterocycles are rare yet highly valuable motifs in drug discovery due to their conformational diversity and improved pharmacological profiles. Here, we present a novel, practical, and mild base-mediated S_N2′/S_NV and ipso-/γ-selective defluorinative annulation of heteroaryl-based bis-nucleophiles with α-CF₃-styrenes. This regio- and chemo-selective dual C–F bond activation enables the direct synthesis of fluorinated thiazepine, oxazepine, and oxazepino-indole compounds, where C–N, C–O, and C–S bonds are formed simultaneously. This protocol offers a broad substrate scope (45 examples) with moderate to excellent yields up to 92%, without the need for metals, ligands, or harsh conditions, and provides quick access to fluorinated medium-ring scaffolds of pharmaceutical relevance. Mechanistic studies and further product derivatization are also provided.