Lithium Chloride‐Promoted Brønsted Acid‐Catalyzed Friedel‐Crafts Alkylation Reaction of Indoles with Aldehydes and Ketones “on Water”

Abstract The Friedel‐Crafts reaction between indoles and ketones poses a significant challenge. In this study, we developed an efficient and environmentally friendly approach for the synthesis of bis(indolyl)methanes bearing all‐carbon quaternary and tertiary centers at room temperature under “on water” conditions. Notably, the utilization of saturated lithium chloride as a solvent greatly enhances the Brønsted acid‐catalyzed double additions of indoles to ketones and aldehydes by promoting hydrophobic interactions. Additionally, LiCl acts as a Lewis acid catalyst for carbonyl activation and facilitates dehydration. This methodology demonstrates compatibility with various ketone substrates such as alkyl alkyl ketones and aryl alkyl ketones, along with aldehyde substrates. Furthermore, gram‐scale productions were successful, and the LiCl solutions demonstrate reusability.