Skeletal Ring Expansion of Indoles to Quinolin-2-ones by Copper-Catalyzed Oxygenative Single-Carbon Migratory Insertion Reaction

Abstract

In skeleton editing, the development of ring expansion of indoles through catalytic single-atom insertion reaction is highly desirable with significant synthetic value. Since the 1960s, indole–quinoline transmutation via inter- or intramolecular single-carbon insertion has been extensively explored for the construction of 3-functionalized quinolines and quinolones. However, the direct oxygenative transformation of indoles to quinolin-2-ones remains underdeveloped. Herein, we report a copper-catalyzed aerobic oxygenative skeletal ring expansion of indoles to prepare highly oxygenated quinolin-2-ones via intramolecular single-carbon migratory insertion. With a readily available copper catalyst and H2O/air (O2) as oxygen sources, cyclic and acyclic 2,3-dialkylindoles were investigated. The reactions proceeded with the selective incorporation of the 2-benzyl or 3-benzyl carbon atom, along with the formation of multiple peripheral C–O bonds. Mechanistic studies revealed that single-electron transfer-induced sequential aerobic oxygenation and ketol-type rearrangement were responsible for the final oxygenated quinolin-2-one products. The highly oxygenated quinolin-2-one 6j exhibited good antitumor activities in vitro, thus demonstrating its potential applications in medicinal chemistry.