Double Isocyanide Insertion with 3‐Indolylmethanols Enabled by C–O Bond Cleavage

Comprehensive Summary The efficient construction of valuable N ‐heterocycles is one of the most important tasks in organic synthesis. Pyrrolo[2,3‐ b ]indoles represent a privileged skeleton, which are extensively found in natural products, pharmaceuticals and luminescent materials. Nevertheless, their synthesis suffers from pre‐functionalized starting materials and multi‐step synthesis. On the other hand, despite significant progress in isocyanide insertions, it remains underdeveloped for multiple isocyanide insertion initiated from inert C–O bond activation. Herein, we report an unprecedented TMSOTf‐catalyzed domino reaction enabled by C–O bond activation, where double isocyanide insertion with 3‐indolylmethanols and sequential intramolecular cyclization are involved to afford cyano‐substituted pyrrolo[2,3‐ b ]indoles. Isocyanides, which have generally been utilized as the sole C1 building block, are employed as both C ‐nucleophiles and masked N ‐nucleophiles to produce the cyano‐substituted pyrrole skeleton. The crucial chloranil oxidant assists the electronic property variation of the indole motif, facilitating the nucleophilic attack at both benzylic and C2 positions of 3‐indolylmethanols. This newly established protocol features mild conditions, good functional group tolerance and broad substrate scope. Depending on the substituent of the isocyanide, corresponding amide and cyclopenta[ b ]indole scaffold could also be accessed. Moreover, diverse transformations of the obtained product are illustrated, including deprotection and hydrolysis. The successful formation of various types of N ‐containing polycyclic compounds further demonstrates the remarkable synthetic potential inherent of the given protocol. After careful mechanistic studies, the enamine compound, generated from double isocyanide insertion with 3‐indolylmethanols, is proposed as the key intermediate for this reaction.