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 reacting (3+2)-cycloadditions with various dipolarophiles with double and triple carbon-carbon, carbon-heteroatom or heteroatom-heteroatom. As a result of these reactions, five-membered heterocyclic compounds are formed. When cyclic dipolarophiles with an to exocyclic carbon-nitrogen bond double bonds (exo-C=N) are introduced into the reaction with these dipoles, 1,2,4-triazoline or 1,2,4-oxadiazoline cycles are formed, spiro-coupled with the initial dipolarophile cycle. Using such rectations, it is possible to effectively synthesize spiro 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 the spiro compounds synthesis. The research area covers reactions of both saturated and unsaturated dipolarophiles, monocyclic and polycyclic structures, as well as compounds containing one to three heteroatoms, with special attention to systems containing biologically significant heterocyclic pharmacophores. Based on the collected literature sources, the high regio- and chemoselectivity characteristic of this type of reaction, as well as high tolerance to labile substrates, are shown. Recent advances in reaction conditions, including microwave and ultrasonic activation, as well as one-pot and diffusion protocols were highlighted.