Skeleton Editing of 2-Aryloxazines with CF₃-ynones Leading to Isoindolone Fused CF₃-Benzooxazocines Possessing Potent Anti-ZIKV and Anti-Cancer Activities

Abstract

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. Meanwhile, the synthesis of structurally complex compounds necessitates tedious multistep procedures. This is certainly not in line with the requirements of green chemistry. Therefore, there is a strong impetus for the development of more concise and sustainable approaches to obtaining such compounds. So far, a number of state-of-the-art strategies for this purpose have been developed. Among them, molecular skeleton editing stands out for its capability of rapidly building or pruning functional molecules. Given the ubiquity of rings in drugs, skeletal editing leading to the generation of biologically privileged cyclic systems is particularly useful. Presented herein is a concise construction of privileged isoindolone fused CF₃-benzooxazocine scaffold based on the cascade reaction of 2-aryl-4H-benzo[d][1,3]oxazine 1 with CF₃-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 CF₃-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.

Keywords

Isoindolone fused benzooxazocines / Skeleton editing / 2-Aryl-4H-benzo[d][1,3]oxazine / CF₃-ynone / C−H bond activation / Anti-ZIKV activity / Anti-cancer activity / Cascade reaction

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2025 SIOC, CAS, Shanghai, & WILEY-VCH GmbH