A facile synthesis of 1-substituted 3-alkoxy-1h-isoindoles based on the reaction of 2-(dialkoxymethyl)phenyllithiums with nitriles, followed by acid-catalyzed cyclization

Abstract

A two-step synthesis of 1-substituted 3-alkoxy-1H-isoindoles 4 has been developed. Thus, the reaction of 2-(dialkoxymethyl)phenyllithium compounds, which are easily generated in situ by Br/Li exchange between 1-bromo-2-(dialkoxymethyl)benzenes 1 and BuLi in THF at -78°, with nitriles afforded [2-(dialkoxymethyl)phenyl]methanimines 2, which were treated with a catalytic amount of TsOH·H2O in refluxing CHCl3 to give the desired products in reasonable yields. Similarly, 3-aryl-1-ethoxy-1-methyl-1H-isoindoles 7 have been prepared starting from 1-bromo-2-(1,1-diethoxyethyl)benzenes 5.