Approximately 1,3-Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with promising anticancer activity. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were first investigated as dipolarophiles in the reactions with nitrile imines. The generation of nitrile imines was carried out either by the addition of tertiary amine to hydrazonoyl chlorides «drop by drop» or using the recently proposed diffusion mixing technique, which led to ~5–15% increases in target compound yields. It was found that the addition of nitrile imines to C=S or C=N exocyclic double bonds led to 1,2,4-thiazolines or triazolines and occurred regioselectively in accordance with the ratio of FMO coefficients of reactants. The yield of the resulting spiro-compound depended on the presence of alkyl substituents in the nitrile imine structure and was significantly decreased in reactions with imines with strong electron donor or electron-withdrawing groups. Some of the obtained compounds showed reasonable in vitro cytotoxicity. IC50 values were calculated for HCT116 (colon cancer) cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test.

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.

The cycloaddition of 1,3-dipoles at C=N bonds is a relatively rare process, in contrast to the widespread cycloaddition reactions at C=C, C≡C, and C=S bonds. In this study, we present the syntheses of novel hydantoin/1,2,4-oxadiazoline spiro-compounds using a 1,3-dipolar cycloaddition of nitrile oxides to C=N bonds of 5-iminohydantoins. The efficiency of the approach was demonstrated by varying the substituents at four positions of the resulting spirocyclic molecules. Cytotoxicity of the target hydantoin/1,2,4-oxadiazolines was shown to exceed previously known spiro-compounds bearing only hydantoins or 1,2,4-oxadiazolines (IC₅₀ values were 30–50 μM, HCT116 cell lines).

1,3 Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with the promising anticancer active. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were firstly investigated as dipolarophiles in the reactions with nitrile imines. The generation of nitrile imines was carried out either by the addition of tertiary amine to hydrazonoyl chlorides «drop by drop» or using recently proposed diffusion mixing technique, which led to ~5-15% increasing of target compounds yields. It was found that the addition of nitrile imines to C=S or C=N exocyclic double bonds led to 1,2,4-thiazolines or triazolines and occurred regioselectively in accordance to the ratio of FMO coefficients of reactants. The yield of the resulting spiro-compound depended on the presence of alkyl substituents in nitrile imine structure and was significantly decreases at the reactions with imines with strong electron donor or electron-withdrawing groups. Some of the obtained compounds showed reasonable in vitro cytotoxicity. IC50 values were calculated for HCT116 (colon cancer) cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test.