Skeleton Editing of 2‐Aryloxazines with CF ₃ ‐ynones Leading to Isoindolone Fused CF ₃ ‐Benzooxazocines Possessing Potent Anti‐ ZIKV and Anti‐Cancer Activities

Comprehensive Summary One of the most profound goals of modern organic chemistry is to enrich synthetic method and compound library serving as the foundation of pharmaceutical and material sciences. Presented herein is a concise construction of privileged isoindolone fused CF 3 ‐benzooxazocine scaffold based on the cascade reaction of 2‐aryl‐4 H ‐benzo[ d ][1,3]oxazine 1 with CF 3 ‐ynone 2 . This novel reaction is initiated by aryl C−H alkenylation of 1 with 2 followed by intramolecular aza ‐Michael addition to form the isoindoline ring, water‐promoted oxazine ring‐opening and intramolecular oxo ‐nucleophilic addition to form the oxazocine ring. In forming the isoindoline scaffold, 1 acts as a C3N1 synthon and 2 acts as a C1 synthon. In forming the oxazocine skeleton, 1 acts as another version of C3N1 synthon while 2 acts as a C3 synthon and water acts as an O1 synthon. To our knowledge, this is the first example of one‐pot tandem generation of both isoindolone and CF 3 ‐oxazocine scaffold through directing group‐assisted C−H bond activation‐initiated skeleton editing of easily obtainable substrates. Importantly, some of the products thus obtained showed excellent in vitro anti‐Zika virus (ZIKV) activity and moderate to good anti‐proliferative activity against three human cancer cell lines.