Amination of Isonitriles in Water: Urea Synthesis under Biocompatible Conditions

Abstract Bioorthogonal reactions have been widely used to track biomolecules in living systems. Due to stringent requirements of physiological conditions, enriching the toolkit of bioorthogonal reactions remains the most important and challenging issue. Herein, the biocompatible ligation of isonitriles and amines to ureas in neutral aqueous medium was developed for the first time. The ligation showed benign nature of biocompatibility, broad substrate scope, and specific chemoselectivity. Meanwhile, urea as a natural linkage, its derivatives played an important role in medicinal chemistry. The second‐order reaction rate constant ( k 2 ) was determined, which was higher or comparable to that of Staudinger ligation and strain‐promoted azide‐alkyne cycloaddition (SPAAC). Direct labeling of Ac 4 GlcN has been achieved in Hep G2 cells.