Flow Synthesis of C2‐Alkylated Indoline Enabled by Convergent Cation–Anion Direct Reaction

ABSTRACT The dearomatization of indoles is a useful strategy for synthesizing indolines. Acidic activation of indoles is crucial for regioselective substitution at the C2 position. In this approach, indolium cations are generated from indoles and subsequently react with nucleophiles to afford C2‐substituted indolines. However, the reaction requires acidic activation in the presence of the nucleophiles, thereby limiting it to acid‐stable nucleophiles. Alkyl nucleophiles are unstable under acidic conditions, making the synthesis of C2‐alkylated indolines challenging. In this study, a flow microreactor (FMR) was used to handle unstable species under the given reaction conditions, enabling instantaneous C sp3 –C sp3 bond formation between highly reactive indolium cations and alkyllithium species. Rapid mixing enabled precise control over the reactive intermediates, leading to selective bond formation between the highly reactive cationic and anionic sites. Furthermore, the integrated reaction in FMR systems enables the introduction of functional groups that are difficult to install using conventional methods.