Electrochemical Hofmann Rearrangement for Modular Synthesis of Unsymmetrical Ureas and Late‐Stage Modification of Drugs

Due to the poor compatibility of amines under oxidative conditions and the low chemoselectivity between two different amides, the Hofmann rearrangement of amides involving amine or other amide nucleophiles poses significant challenges. Herein, we present a versatile electrochemical reaction that achieves highly chemoselective Hofmann rearrangement of two different amides with the addition of only sodium iodide, enabling the efficient synthesis of single N ‐acylureas. Additionally, under similar electrochemical conditions, both primary and secondary amines can also efficiently react with amides to produce unsymmetrical ureas. This electrosynthetic method exhibits good functional group tolerance and has been successfully employed to synthesize five herbicides, as well as to facilitate the late‐stage functionalization of over twenty amine‐containing drugs. Furthermore, mechanism studies indicated that the use of NaI guaranteed the feasibility and compatibility of the reaction.