MODIFIED WILLIAMSON METHOD IN THE SYNTHESIS OF NEW THIOETHERS
DOI:
https://doi.org/10.32782/naturaljournal.14.2025.14Keywords:
thioether, sulfide, sulphon, nucleophilic substitution, Williamson reactionAbstract
The possibility of the application of a modified version of the Williamson reaction, that involves the interaction of thiols with substituted alkyl halides in the presence of a base without the intermediate isolation of thiolates, has been investigated to obtain new compounds that combine a sulfide bond with other types of functional groups. Thioethers are known for their diverse biological activities, including antitumor, antimicrobial, antiviral, antioxidant effects etc. Many of the commonly used methods for obtaining thioethers require strong bases, moisture-sensitive organolithium compounds or Grignard reagents or organometallic catalysts, which complicate the synthesis procedure and limit its practical applicability. The reaction of thiolates as nucleophilic reagents with alkyl halides remains a simple and accessible method for the synthesis of thioethers. An application of thiols and halogen derivatives as reagents in the presence of an equimolar amount of alkali simplifies the synthesis procedure and avoids the isolation of mercaptides in an individual state. One group of the obtained thioethers contains an acetanilide fragment. Acetanilide derivatives are known for their wide range of biological activities, including antipyretic, antimicrobial, anti-inflammatory, antitumor, and antihyperglycemic effects. The combination of this fragment with a thioether group makes the obtained products promising for further investigation of their biological activity. Another direction of the study was the alkylation of 2-mercaptobenzoxazole, leading to the formation of sulfides containing a benzoxazole fragment. Derivatives of this heterocycle are of interest as potential antitumor, antibacterial, antiviral, and fungicidal agents. The described method also proved suitable for obtaining benzothiazole derivatives. Compounds containing a benzothiazole fragment are primarily known for their antitumor activity, but they also show promise in other fields of medicine, particularly in cardiology.
References
Cramer N.B., Bowman C.N. Chemoselective and Bioorthogonal Ligation Reactions ( Concepts and Applications) / W.R. Algar, P.E. Dawson, I.L. Medintz ( ed.). Chapter : Thiol-Ene Chemistry, 2017. P. 117–145. https://doi.org/10.1002/9783527683451.ch5
Ghoshal T., Patel T.M. Anticancer activity of benzoxazole derivative (2015 onwards): a review. Future Journal of Pharmaceutical Sciences. 2020. Vol. 6. P. 94. https://doi.org/10.1186/s43094-020-00115-0
Han M.İ., Küçükgüzel G. Thioethers: An Overview. Current Drug Targets. 2022. Vol. 23(2). P. 170–219. https://doi.org/10.2174/1389450122666210614121237
Li C., Liu Y., Ren X., Tan Y., Jin L., Zhou X. Design, Synthesis and Bioactivity of Novel Pyrimidine Sulfonate Esters Containing Thioether Moiety. International Journal of Molecular Sciences. 2023. Vol. 24(5). P. 4691. https://doi.org/10.3390/ijms24054691
Liu T., Peng F., Zhu Y. et al. Design, synthesis, biological activity evaluation and mechanism of action of myricetin derivatives containing thioether quinazolinone. Arabian Journal of Chemistry. 2022. Vol. 15(8). P. 104019. https://doi.org/10.1016/j.arabjc.2022.104019
Mu S., Liu H., Zhang L., Wang X., Xue F., Zhang Y. Synthesis and Biological Evaluation of Novel Thioether Pleuromutilin Derivatives. Biological and Pharmaceutical Bulletin. 2017. Vol. 40(8). P. 1165–1173. https://doi.org/10.1248/bpb.b16-00160
Nair D.P., Podgórski M., Chatani S., Gong T., Xi W., Fenoli C.R., Bowman C.N. The Thiol-Michael Addition Click Reaction: A Powerful and Widely Used Tool in Materials Chemistry. Chemistry of Materials. 2014. Vol. 26(1). P. 724–744. https://doi.org/10.1021/cm402180t
Naskar R., Ghosh P., Manna C.K., Murmu N., Mondal T.K. Palladium(II) complexes with thioether based ONS donor ligand: Synthesis, characterization, X-ray structure, DFT study and anti-cancer activity. Inorganica Chimica Acta. 2022. Vol. 534. P. 120802. https://doi.org/10.1016/j.ica.2022.120802
Ruan X., Zhang C., Jiang S. et al. Design, Synthesis, and Biological Activity of Novel Myricetin Derivatives Containing Amide, Thioether, and 1,3,4-Thiadiazole Moieties. Molecules. 2018. Vol. 23(12). P. 3132. https://doi.org/10.3390/molecules23123132
Sattar R., Mukhtar R., Atif M., Hasnain M., Irfan A. Synthetic transformations and biological screening of benzoxazole derivatives: A review. Journal of Heterocyclic Chemistry. 2020. Vol. 57(5). P. 2079–2107. https://doi.org/10.1002/jhet.3944
Singh R.K., Kumar A., Mishra A.K. Chemistry and Pharmacology of Acetanilide Derivatives: A Mini Review. Letters in Organic Chemistry. 2019. Vol. 16(1). P. 6–15. https://doi.org/10.2174/1570178615666181129150925
Sinha A.K., Equbal D. Thiol-Ene Reaction as a Sharping Stone of Click Chemistry: Recent Advances in Synthetic Aspects and Mechanistic Studies of Anti-Markovnikov-selective Hydrothiolation of Olefins. Asian Journal of Organic Chemistry. 2018. Vol. 8(1). P. 32–47. https://doi.org/10.1002/ajoc.201800639
Smolyaninov I., Pitikova O., Korchagina E. et al. Electrochemical behavior and anti/prooxidant activity of thioethers with redox-active catechol moiety. Monatshefte für Chemie. 2018. Vol. 149. P. 1813–1826. https://doi.org/10.1007/s00706-018-2264-1
Song X., Li P., Li M. et al. Synthesis and investigation of the antibacterial activity and action mechanism of 1,3,4-oxadiazole thioether derivatives. Pesticide Biochemistry and Physiology. 2018. Vol. 147. P. 11–19. https://doi.org/10.1016/j.pestbp.2017.10.011
Tunel H., Er M., Alici H., Onaran A., Karakurt T., Tahtaci H. Synthesis, structural characterization, biological activity, and theoretical studies of some novel thioether-bridged 2,6-disubstituted imidazothiadiazole analogues. Journal of Heterocyclic Chemistry. 2021. Vol. 58(6). P. 1321–1343. https://doi.org/10.1002/jhet.4260
Yadav K.P., Rahman M.A., Nishad S., Maurya S.K., Anas M., Mujahid M. Synthesis and biological activities of benzothiazole derivatives: A review. Intelligent Pharmacy. 2023. Vol. 1(3). P. 122–132. https://doi.org/10.1016/j.ipha.2023.06.001
Zhao M., Zhou Z., Tang P. Synthesis of α-trifluoromethoxy-sulfide through the Pummerer rearrangement. Organic & Biomolecular Chemistry. 2025. Vol. 25. P. 6127–6132. https://doi.org/10.1039/D5OB00673B
Zheng Y., Qin C., Li F. et al. Self-assembled thioether-bridged paclitaxel-dihydroartemisinin prodrug for amplified antitumor efficacy-based cancer ferroptotic-chemotherapy. Biomaterials Science. 2023. Vol. 9. P. 3321–3334. https://doi.org/10.1039/D2BM02032G
