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. 2023 Mar 6;24(5):5037.
doi: 10.3390/ijms24055037.

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

Dmitry E Shybanov  1 , Maxim E Kukushkin  1 , Yanislav S Hrytseniuk  1 , Yuri K Grishin  1 , Vitaly A Roznyatovsky  1 , Viktor A Tafeenko  1 , Dmitry A Skvortsov  1 , Nikolai V Zyk  1 , Elena K Beloglazkina  1
Affiliations

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

Dmitry E Shybanov et al. Int J Mol Sci. .

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.

Keywords: 2-thiohydantoins; Diels–Alder reaction; [4+2]-cycloaddition; antibacterial activity; cytotoxicity; hydantoins; spiro-compounds.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Diels–Alder reactions with methylenehydantoins and methylenethiohydantoins [15,16,17].
Scheme 2
Scheme 2
Starting dienophiles and synthesis of compounds 12-21 from methylideneimidazolones 1,2.
Scheme 3
Scheme 3
Reactions of methyleneimidazolones with cyclopentadiene.
Figure 1
Figure 1
(a) Characteristic doublets of doublet set of HC=CH protons of compounds 35a and 35b in their 1H NMR spectra (CDCl3). (b) Characteristic correlations observed in 1H-1H NOESY NMR spectrum of the compounds 35a. (c) 1H NOESY NMR spectrum of compound 35b.
Scheme 4
Scheme 4
Reactions of methylidenethiohydantoins 1-3, 5, 6, 8-10 with cyclohexadiene.
Figure 2
Figure 2
Molecular structure of compound 51a. Thermal ellipsoids are given a 30% probability.
Scheme 5
Scheme 5
Reactions of methylideneimidazolones 1-12 with 2,3-dimethylbutadiene.
Scheme 6
Scheme 6
Reactions of methylideneimidazolones1, 2, 4-6, 8, and 9 with isoprene.
Scheme 7
Scheme 7
Alkylation and acylation of spirocyclic imidazolones.
Scheme 8
Scheme 8
Desulfurization of spiro-thiohydantoins by H2O2.
Scheme 9
Scheme 9
1 This product was isolated as an inseparable mixture with the addition products of nitrile oxide at the C=C bond. Desulfurization of spiro-thiohydantoins by the nitrile oxide action.
See this image and copyright information in PMC

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