1,3-Dipolar Cycloaddition of Nitrile Imines and Nitrile Oxides to Exocyclic C=N Bonds—An Approach to Spiro-N-Heterocycles

Nitrile imines and nitrile oxides are capable of undergoing (3+2)-cycloaddition reactions at double and triple carbon–carbon, carbon-heteroatom, or heteroatom–heteroatom bonds of various dipolarophiles, forming five-membered heterocyclic compounds. When cyclic dipolarophiles bearing an exocyclic carbon–nitrogen double bond (exo-C=N) are introduced into the reaction with these dipoles, spiro-fused 1,2,4-triazoline or 1,2,4-oxadiazoline cycles are formed. Such reactions can provide efficient synthetic approaches to spiro-heterocyclic compounds with enhanced biological activity. This review comprehensively summarizes the literature data on the 1,3-dipolar cycloaddition of nitrile imines and nitrile oxides to exo-C=N bonds for spiro compound synthesis. The research area covers reactions of both saturated and unsaturated dipolarophiles, monocyclic and polycyclic molecules, as well as compounds containing one to three heteroatoms, with special emphasis on systems containing biologically significant heterocyclic pharmacophores. Recent advances in reaction techniques, such as microwave and ultrasonic activation, as well as one-pot and diffusion protocols, are also mentioned. © 2025 Elsevier B.V., All rights reserved.