Diazoacetonitrile in modern organic synthesis: recent advances, reactivity, and future directions

Diazoacetonitrile is a historically significant yet long-underutilized diazo compound whose synthetic potential has only recently begun to be realized. Since its discovery, this reagent remained largely unexplored owing to its high nitrogen content and associated safety concerns. Recent advances in in situ generation and continuous-flow technologies, however, have enabled the safe handling and controlled use of diazoacetonitrile, leading to a renewed surge of interest in its chemistry. Owing to its unique ability to function as a carbene precursor while simultaneously introducing a synthetically versatile nitrile group, diazoacetonitrile provides efficient access to a wide range of structurally diverse molecular frameworks. This review summarizes recent developments in the preparation, reactivity, and synthetic applications of diazoacetonitrile, with particular emphasis on cycloaddition reactions (3 + 2, 4 + 1, and 2 + 1), C-H insertion reactions, and other metal-carbene-mediated processes. Beyond carbene chemistry, diazoacetonitrile can generate additional reactive intermediates, including nitrone ylides, nitrile ylides, and ketenimines, and may also act as a carbon-centered nucleophile. Special attention is given to the construction of biologically relevant heterocyclic and carbocyclic scaffolds. Current limitations and future opportunities, particularly in asymmetric synthesis and medicinal chemistry, are also discussed.