[4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones

Abstract

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels–Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI2 is an effective catalyst in the Diels–Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH2Cl or Boc2O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH2Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H2O2 or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2.

[3+2]-Cycloaddition of Nitrile Imines to Parabanic Acid Derivatives—An Approach to Novel Spiroimidazolidinediones

“…It can also be pointed out that the presence of a halogen atom in the R 1 position of the compound 5c led to a slight increase in cytotoxicity compared to 5f (R 1 = CH 3 ). As can be seen from the IC 50 measurements, the cytotoxicity of the presented compounds belongs to the region of micromolar concentrations, which is a good but insufficient value compared to the known lead compounds [ 12 , 30 ]. This result may be explained by the high lipophilicity of compounds containing 3–5 aromatic fragments within a relatively small volume of the molecule.…”

“…If necessary, this isomer mixture may be repeatedly separated. Based on [30], the observed phenomena can be explained by the atropoisomerism conferred by the repulsive interactions of ortho-substituent R 1 (the halogen atom) and the aromatic substituent R 2 at the neighboring nitrogen atom of the triazoline cycle (Figure 6). stituent was a donor or acceptor.…”

“…If necessary, this isomer mixture may be repeatedly separated. Based on [30], the observed phenomena can be explained by the atropoisomerism conferred by the repulsive interactions of ortho-substituent R1 (the halogen atom) and the aromatic substituent R2 at the neighboring nitrogen atom of the triazoline cycle (Figure 6). In conclusion, it is worth noting that the 1,3-dipolar cycloaddition of nitrile imines to compounds 2 containing an exocyclic bond C=N resulted in the formation of a heterocyclic product 5 with the jointed imidazolidine and 1,2,4-triazoline fragments.…”

Special Issue “Development and Synthesis of Biologically Active Compounds”

“…Several publications concern the study of the cytotoxic and antibacterial, antiaggregation, or antiphytopathogenic activities of synthesized compounds. In the investigation by Shybanov et al [20], the regio-and stereoselective synthesis of novel hydantoin and thiohydantoin-based spiro-compounds was developed. The obtained compounds showed moderate cytotoxicity to MCF7, A549, HEK293T, and VA13 cell lines.…”