Electrochemical amino- or methoxymethylation of weak nucleophiles with methoxamine hydrochloride

The in-situ generation of iminium ions from amines and aldehyde compounds, followed by nucleophilic attack (Mannich reaction), represents a powerful strategy for the formation of Mannich bases. However, the participation of weakly nucleophilic compounds, such as amides and indoles with electron-withdrawing functional groups, poses significant challenges. Herein, we represent an electrochemical amino- or methoxymethylation of weak nucleophiles with methoxamine hydrochloride. In this electrosynthetic approach, methoxamine hydrochloride serves as both a methylene source and a methoxy or amine source, enabling weakly nucleophilic amides, sulfonamides, and heteroaryl compounds bearing electron-withdrawing groups to engage in the Mannich reaction, resulting in the formation of corresponding aminoalkyl derivatives in moderate yields. Furthermore, by increasing the current and prolonging the reaction time, primary amides can be converted into N -(methoxymethyl)amide derivatives. A practical electrochemical method for the amino- or methoxymethylation of weak nucleophiles with methoxamine hydrochloride has been developed. In this process, methoxamine hydrochloride serves as both the source of methylene and the source of methoxy or amine.