Divergent Synthesis of <scp> CF ₃ </scp> ‐Polycyclic Compounds with Potent Anticancer Activity <i>via</i> <scp>CHA</scp> ‐Initiated Double or Triple Annulation of 3‐Alkenyl‐1,2,4‐oxadiazolones with <scp> CF ₃ </scp> ‐Ynones ^†

Comprehensive Summary The pivotal roles of fused carbo‐/heterocyclic skeletons in medicinal chemistry and fine chemical industry are best exemplified by their ubiquitous presence in marketed drugs and wide applications in organic electronics and luminescence materials. Among them, azafluoren(ol)e, pyridopyrimidin(on)e and isoindole derivatives possess a wide spectrum of biological activities. Moreover, they have also demonstrated strong absorption and emission properties, thus qualifying their uses in dyes and light‐emitting materials. Presented herein is a divergent synthesis of CF 3 ‐azafluorenol or CF 3 ‐pyrido[1,2‐ a ]pyrimidine fused isoindole through condition‐ controlled cascade reactions of 3‐alkenyl‐1,2,4‐oxadiazolone with CF 3 ‐ynone. The formation of the former product involves a C−H activation (CHA)‐initiated formal [4 + 2] annulation followed by an intramolecular enamine aldol‐type reaction. The formation of the latter product firstly goes through a formal [4 + 2] annulation but with different regio‐selectivity, followed by an intermolecular condensation and an intramolecular Friedel‐Crafts type reaction, or followed by C−H alkenylation, N ‐intramolecular Michael addition, N ‐nucleophilic addition and water elimination. To our knowledge, this is the first report on CHA‐initiated double or triple annulation of 3‐alkenyl‐1,2,4‐oxadiazolone with CF 3 ‐ynone to furnish different polycyclic products. In general, these synthetic protocols feature redox‐neutral reaction conditions, good compatibility with labile functional groups, excellent step‐/atom‐economy, valuable products, intriguing reaction pathways, diverse structural derivation and ready scalability. To explore the potential application of the products thus obtained in pharmaceutical field, the anti‐cancer activity of selected products against two human cancer cell lines (HCT‐116 and Hela) was evaluated by using 5‐fluorouracil (5‐FU) as the positive control. The results showed that most of them possess moderate to good anti‐cancer activity.