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.

Photochemical intermolecular dearomative cycloaddition of bicyclic azaarenes with alkenes

“…As such, the reaction has mostly been limited to electron-rich arenes or their prefunctionalized derivatives, and intramolecular variants (Fig. 1D), which require multi-step substrate synthesis and offer limited generality (19)(20)(21)(22)(23)(24)(25)(26)(27). Additionally, inferior selectivity has been observed in both the intra-and intermolecular DAC reactions (Fig.…”

Protonation-Enhanced Reactivity of Triplet State in Dearomative Photocycloaddition of Quinolines to Olefins

“…Dearomatization of arenes is challenging because of the high chemical stability inherent due to aromaticity. Despite this, chemists have developed various dearomative transformations of arenes, which are currently indispensable tools for synthesizing complex molecules. − Photochemical methods are a common approach to induce the loss of aromaticity. − In particular, visible-light photocatalysis has emerged as an efficient and environmentally friendly tool for utilizing energy transfer − and electron transfer, − enabling sustainable reactions, including various dearomative reactions. − …”

Stereodivergent synthesis of β-iodoenol carbamates with CO2viaphotocatalysis

“… 27 Moreover, the reaction was significantly inhibited by addition of 1.0 equivalent of 2,5-dimethylhexa-2,4-diene, which is a well-known triplet quencher. 28 In this case, only little amount of ( Z )- 3aa was formed along with intermediate 12 in 35% yield ( Scheme 8B ). The above results suggested that electron transfer between 12 and eosin Y might not be involved in the reaction, precluding a photoinduced redox process.…”