Efficient Synthesis of 8-Membered Fused Indoles via Intramolecular Friedel-Crafts Reaction of...

Synthesis of 8-membered rings is one of the most challenging transformations in organic chemistry because of entropic hindrance and ring strain. Azocino[4,3-b]indole frameworks are characterized by fused indole-azocane systems and are vital structural components of many natural products and bioactive compounds. We propose a concise and efficient method for constructing these medium-sized rings via Lewis acid-catalyzed intramolecular Friedel-Crafts cyclization of N-(2,2-dimethoxyethyl)sulfonamides. We synthesized cyclization precursors from indolylpropanol derivatives. Treatment of C2-substituted tosyl precursor 4a with catalyst trimethylsilyl trifluoromethanesulfonate (TMSOTf) (0.5 equivalent) at 0°C provided the desired 8-membered product 8a in 96% yield. The mesyl analog 4b is efficiently cyclized to produce 8b and 9b in 77 and 20% yield, respectively. In contrast, the C3-substituted precursor 7a produces the corresponding 8-membered products 10a and 11a in 41 and 23% yield, respectively. The mesyl analog 7b is cyclized to produce 10b at only 20% yield, demonstrating that the tether geometry remarkably affects ring formation. X-ray crystallographic analysis of the elimination product 11a confirms the formation of the fused 8- membered ring system and reveals a distorted boat-chair conformation. This synthesis route provides a mild, chemoselective approach for accessing synthetically valuable indole-fused 8-membered rings, laying the groundwork for future development of natural product derivatives and functionalized analogs.