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

• Published in: International journal of molecular sciences 2023-03, Vol.24 (5), p.5037
• Main Authors: Shybanov, Dmitry E, Kukushkin, Maxim E, Hrytseniuk, Yanislav S, Grishin, Yuri K, Roznyatovsky, Vitaly A, Tafeenko, Viktor A, Skvortsov, Dmitry A, Zyk, Nikolai V, Beloglazkina, Elena K
• Format: Article
• Language: English
• Subjects: 2-thiohydantoins; [4+2]-cycloaddition; Acylation; Alkylation; Antibacterial activity; Biological activity; Catalysis; Catalysts; Cell lines; Cycloaddition; Cycloaddition Reaction; Cyclopentadiene; Cyclopentanes; Cytotoxicity; Diels-Alder reactions; Diels–Alder reaction; Escherichia coli; HEK293 Cells; Humans; Hydantoin; Hydantoins; Hydrogen Peroxide; Isomers; Isoprene; Lewis acid; Nitrogen atoms; Olefins; spiro-compounds; Thiohydantoins; Toxicity testing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24055037

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 ZnI 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 PhCH Cl or Boc O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H O 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 ( ) BW25113 DTC-pDualrep2 but were almost inactive against BW25113 LPTD-pDualrep2.