Stereoselective Dearomative Formal [3+2] cycloaddition of Indole with Allenols: Access to Structurally Diverse Cyclopenta[b]indoles

Abstract

Dearomative cycloaddition reactions of indoles offer a powerful strategy for rapidly increasing molecular complexity, yet intermolecular variants that proceed with high regio-and diastereocontrol remain uncommon. Herein, we report an iron(III) chloride-mediated dearomative formal [3+2] cycloaddition of indoles with arylsulfonyl allenols, providing direct access to densely functionalized cyclopenta [b]indoles with excellent diastereoselectivity. The reaction proceeds under mild Lewis acidic conditions without the use of precious metal catalysts and displays broad substrate scope, tolerating diverse substitution patterns on the indole core and allenols, including electron-rich, electron-deficient, sterically hindered, and fused systems, affording the desired tricyclic scaffold in moderate to excellent yields. The synthetic utility of this protocol is demonstrated through late-stage functionalization of pharmaceutically relevant indole-containing molecules, Double Cascade Dearomative Cycloaddition, gram-scale synthesis, and downstream product diversification. Mechanistic studies, including DFT energy calculation and isotopic labeling experiments, support an ionic, non-radical pathway involving Lewis acid activation of the allenol to generate a transient electrophilic intermediate, followed by a dearomative cyclization. This operationally simple and sustainable method enables rapid construction of structurally complex, nonplanar cyclopenta[b]indole frameworks of potential relevance in medicinal chemistry.