The synthesis and cyclofunctionalization of (1,3-thiazolidin-2-ylidene)ketones


  • M. B. Litvinchuk Lesya Ukrainka East European National University; Institute of Organic Chemistry of the NAS of Ukraine, Ukraine
  • A. V. Bentya Institute of Organic Chemistry of the NAS of Ukraine, Ukraine
  • N. Yu. Slyvka Lesya Ukrainka East European National University, Ukraine
  • M. V. Vovk Institute of Organic Chemistry of the NAS of Ukraine, Ukraine



N-allylthioamides, electrophilic cyclization, (1, 3-thiazolidin-2-ylidene)ketones, tautomerism, pyrrolo[2, 1-b][1, 3]thiazoles, [1, 3]thiazolo[3, 2-a]pyridines


Aim. To develop a new approach to the design of (1,3-thiazolidin-2-ylidene)ketones and expansion of their synthetic potential as convenient building blocks in the reactions of [3+2]- and [3+3]-cyclization.

Results and discussion. Еlectrophilic intramolecular cyclization (EIC) of N-allythioamides of β-ketoacids using phosphoric acid or iodine is a convenient synthetic method to obtain new (5-methyl- and 5-iodomethyl-1,3-thiazolidine-2-ylidene)ketones. Cyclization of ketones with maleic anhydride leads to derivatives of 2,3-dihydropyrrolo[2,1-b][1,3]thiazole. [3+3]-Cyclocondensation with methyl propiolate and dimethyl acetylenedicarboxylate results in formation of the functionalized [1,3]thiazolo[3,2-a]pyridine derivatives.

Experimental part. (5-Methyl- and 5-iodomethyl-1,3-thiazolidin-2-ylidene)ketones were synthesized from N-allylthioamides using phosphoric acid or iodine in chloroform. (1,3-Thiazolidin-2-ylidene)ketones react with maleic anhydride, methyl acetylenecarboxylate or dimethyl acetylenedicarboxylate resulting in a 2,3-dihydropyrrolo[2,1-b][1,3]thiazole-5(6H)-one and 2,3-dihydro-5H-[1,3]thiazolo[3,2-a]pyridine derivatives.

Conclusions. A convenient method of [5-methyl- and 5-iodomethyl-1,3-thiazolidin-2-ylidene]ketones preparation based on the EIC of N-allylthioamides of β-ketoacids has been developed using phosphoric acid and iodine. The (1,3-thiazolidin-2-ylidene)ketones synthesized can be useful in cyclization reactions leading to functional pyrrolo[2,1-b][1,3]thiazole and [1,3]thiazolo[3,2-a]pyridine derivatives.


Download data is not yet available.


  1. Huang, Z.–T., & Shi, X. (1990). Synthesis of Heterocyclic KeteneN,S–Acetals and Their Reactions with Esters of α,β–Unsaturated Acids. Synthesis, 1990 (02), 162–167.
  2. Huang, Z.–T., & Shi, X. (1990). Synthesis, Reactions, and Tautomerism of Ketene N,S–Acetals with Benzothiazoline Ring. Chemische Berichte, 123 (3), 541–547.
  3. Åberg, V., Sellstedt, M., Hedenström, M., Pinkner, J. S., Hultgren, S. J., & Almqvist, F. (2006). Design, synthesis and evaluation of peptidomimetics based on substituted bicyclic 2–pyridones—Targeting virulence of uropathogenic E. coli. Bioorganic & Medicinal Chemistry, 14 (22), 7563–7581.
  4. Åberg, V., Das, P., Chorell, E., Hedenström, M., Pinkner, J. S., Hultgren, S. J., & Almqvist, F. (2008). Carboxylic acid isosteres improve the activity of ring–fused 2–pyridones that inhibit pilus biogenesis in E. coli. Bioorganic & Medicinal Chemistry Letters, 18 (12), 3536–3540.
  5. Åberg, V., Norman, F., Chorell, E., Westermark, A., Olofsson, A., Sauer–Eriksson, A. E., & Almqvist, F. (2005). Microwave–assisted decarboxylation of bicyclic 2–pyridone scaffolds and identification of Aβ–peptide aggregation inhibitors. Organic & Biomolecular Chemistry, 3 (15), 2817.
  6. Kulén, M., Lindgren, M., Hansen, S., Cairns, A. G., Grundström, C., Begum, A., … Almqvist, F. (2018). Structure–Based Design of Inhibitors Targeting PrfA, the Master Virulence Regulator of Listeria monocytogenes. Journal of Medicinal Chemistry, 61 (9), 4165–4175.
  7. Glennon, R. A., Gaines, J. J., & Rogers, M. E. (1981). Benz–fused mesoionic xanthine analogs as inhibitors of cyclic–AMP phosphodiesterase. Journal of Medicinal Chemistry, 24 (6), 766–769.
  8. Manfroni, G., Meschini, F., Barreca, M. L., Leyssen, P., Samuele, A., Iraci, N., … Cecchetti, V. (2012). Pyridobenzothiazole derivatives as new chemotype targeting the HCV NS5B polymerase. Bioorganic & Medicinal Chemistry, 20 (2), 866–876.
  9. Džambaski, Z., Marković, R., Kleinpeter, E., & Baranac–Stojanović, M. (2013). 2–Alkylidene–4–oxothiazolidine S–oxides: synthesis and stereochemistry. Tetrahedron, 69 (31), 6436–6447.
  10. Marković, R., Baranac, M., Džambaski, Z., Stojanović, M., & Steel, P. J. (2003). High regioselectivity in the heterocyclization of β–oxonitriles to 4–oxothiazolidines: X–ray structure proof. Tetrahedron, 59 (39), 7803–7810.
  11. Marković, R., Vitnik, Ž., Baranac, M., & Juranic, I.(2002). Mechanism of stereoselective synthesis of push–pull (Z)–4–oxothiazolidine derivatives containing an exocyclic double bond. A MNDO–PM3 Study. Journal of Chemical Research, 2002 (10), 485–489.
  12. Marković, R., Baranac, M. (2000) Regioselective Synthesis of New 5–Ethoxycarbonylmethyl–4–oxothiazolidin–2–ylidene Bromides and Rearrangement Reaction Thereof. Synlett, 2000 (05), 607–610.
  13. Elghandour, A. H. H., Ibrahim, M. K. A., Elshikh, S. M. M., & Ali, F. M. M. (1992). Studies with polyfunctionally substituted heteroaromatics: synthesis of several new thiazoles, pyrazolo[5,1–c]triazines and of polyfunctionally substituted pyridines and pyrimidines. Tetrahedron, 48 (42), 9295–9304.
  14. Kambe, S., Saito, K., Sakurai, A., & Midorikawa, H. (1980). A Simplified Procedure for the Preparation of 2–Alkoxycarbonyl–5–aryl–4–cyano–3–hydroxy–3–phenyltetrahydrothiophenes. Synthesis, 1980 (10), 839–840.
  15. Satzinger, G. (1978). Heterocyclen durch Reaktion von Mercapto– und Hydroxycarbonsäureestern mit aktivierten Nitrilen. Justus Liebigs Annalen Der Chemie, 1978 (3), 473–511.
  16. Satzinger, G. (1963). Substituierte 2–Methylen–thiazolidone–(4). Justus Liebigs Annalen Der Chemie, 665 (1), 150–165.
  17. Dixit, A. N., Venodhar Reddy, K., Deshmukh, A. R. A. S., Rajappa, S., Ganguly, B., & Chandrasekhar, J. (1995). Conformational preferences of α–functionalised keten–S,N–acetals: Potential role of SO and SS interactions in solution. Tetrahedron, 51(5), 1437–1448.
  18. Ohsugi, E., Fujioka, T., Harada, H., Nakamura, M., & Maeda, R. (1989). Synthetic studies on diuretics. 5–(3,3–n,s–substituted–2–propenoyl)–2,3–dihydro–2–benzo(b)furancarboxylic acids. Chemical & pharmaceutical bulletin, 37 (5), 1268–1278.
  19. Chandrasekharam, M., Singh, O. M., Ila, H., & Junjappa, H. (1998). Reaction of β–Oxodithioesters With Propargylamine: A Facile Entry to Novel 2–(Acylalkylidene)–5–(Methylene)Thiazolidines. Synthetic Communications, 28 (16), 3073–3079.
  20. Saravanan, S., Mohan, P., & Muthusubramanian, S. (2011). Formation of reagent–selective products from 2–(4,5–dihydrothi– azol–2–ylthio)–1–arylethanone with different nucleophiles. Journal of Sulfur Chemistry, 32 (1), 71–84.
  21. Litvinchuk, M. B., Bentya, A. V., Slyvka, N. Y., & Vovk, M. V. (2017). Halocyclization of products of allyl isothiocyanate addition to acyclic methylene active compounds. Russian Journal of Organic Chemistry, 53 (5), 709–716.
  22. Żankowska–Jasińska, W., Burgieł, M., Danel, A., Syguła, A. (1988) A novel synthesis of 1,3 Thiazetidine–2–one and 1,3–Oxazine–2–one Derivatives. Journal für Praktische Chemie. 330 (5), 795–800.
  23. Nishio, T. (1998) Sulfur–Containing Heterocycles Derived by Reaction of ω–Keto Amides withLawesson’s Reagent. Helvetica Chimica Acta. 81 (5–8), 1207–1214.
  24. Gupta, A. K., Reddy, K. R., Ila, H., & Junjappa, H. (1995). Cuprous bromide–promoted cyclization of ketene N,S–acetals with prop–2–ynyl bromide: synthesis of regiospecifically substituted and annelated 3–acyl(or nitro)–5–methyl pyrroles. Journal of the Chemical Society, Perkin Transactions 1, (13), 1725.
  25. Gupta, A. K., Chakrasali, R. T., Ila, H., & Junjappa, H. (1989). Reaction of Polarized KeteneS,N–Acetals with Bromoacetaldehyde Diethyl Acetal: Synthesis of 1–Substituted 3–Acyl– and 3–Nitro–2–methylthiopyrroles and 1,2–Annulated 3–Acylpyrroles. Synthesis, 1989 (02), 141–142.
  26. Gupta, A. K., Ila, H., & Junjappa, H. (1988). Cyclocondensation of Acylketene S,N– and N,N–acetals with Maleic Anhydride and Maleimide: A Facile One–Step Synthesis of Pyrano [3,4–c]pyrrole, Pyrrolo [3,4–c]pyridine and Condensed Pyrrole Derivatives. Synthesis, 1988 (04), 284–286.
  27. Chakrasali, R. T., Ila, H., & Junjappa, H. (1988). Cycloaddition of Aroyl/Acylketene S,N–Acetals with Tosyl Azide: Synthesis of Novel 4–Aroyl/Acyl–5–amino–1H–1,2,3–triazoles and 3,4–Annulated 1,2,3–Triazoles. Synthesis, 1988 (11), 851–854.
  28. El–Shafei, A. K., El–Saghier, A. M. M., & Soliman, A. M. (1995). Synthesis of Heterocyclic Ketene N,S–Acetals and Their Reactions with α,β–Unsaturated Nitriles. Collection of Czechoslovak Chemical Communications, 60 (6), 1065–1069.
  29. Yan, S., Chen, Y., Liu, L., He, N., & Lin, J. (2010). Three–component solvent–free synthesis of highly substituted bicyclic pyridines containing a ring–junction nitrogen. Green Chemistry, 12 (11), 2043.
  30. Ila, H., Junjappa, H., Chakrabarti, S., Panda, K., & Misra, N. C. (2005). Aza–Annulation of Polarized N,S– and N,N–Ketene Acetals with Itaconic Anhydride: Synthesis of Novel Functionalized 1,2,3,4–Tetrahydro–2–pyridones and Related Azabicycles. Synlett, (9), 1437–1441.
  31. Singh, A., Srivastava, A., & Singh, M. S. (2018). Metal–Free One–Pot Four–Component Cascade Annulation in Ionic Liquids at Room Temperature: Convergent Access to Thiazoloquinolinone Derivatives. The Journal of Organic Chemistry, 83 (15), 7950–7961.



How to Cite

Litvinchuk, M. B.; Bentya, A. V.; Slyvka, N. Y.; Vovk, M. V. The Synthesis and Cyclofunctionalization of (1,3-Thiazolidin-2-ylidene)ketones. J. Org. Pharm. Chem. 2018, 16, 18-27.



Original Researches