Photocatalytic Intramolecular [2 + 2] Cycloaddition of Indole Derivatives via Energy Transfer: A Method for Late-Stage Skeletal Transformation

Abstract

Visible light-promoted dearomative [2 + 2] cycloaddition of indole derivatives tethered with olefins at the N1 position has been considered thermodynamically unfeasible due to the high triplet excited-state energies. We describe visible light-promoted [2 + 2] cycloaddition with concomitant dearomatization of indole derivatives tethered with olefins at the N1 position via the energy transfer process, providing cyclobutane-fused polycyclic indoline derivatives that are potentially useful in drug design and discovery. These cyclobutane-fused indoline-based polycycles are obtained in high yields and with good diastereoselectivities (>99:1). The key to the success of the reaction is the formation of H-bond(s) between N-alkenoylindole and solvent, enabling the reduction of the triplet energy of the indole derivatives, which greatly improved the efficiency of the protocol. The applicability of the method is demonstrated by late-stage skeletal diversification of indole-containing bioactive molecules, which provides a powerful strategy for the rapid skeleton remodeling. DFT calculations were used to give a deep understanding of the reaction pathways.