Synthesis of N-methyl 3-alkyl-isothiazolidine- 1,1-dioxo-3-methylcarboxylates through the intramolecular Michael reaction




sulfonamides, amino acids, cyclization, the Michael addition


An efficient and common method for the synthesis of N-methyl 3-alkyl-isothiazolidine-1,1-dioxo-3-methylcarboxylates has been developed. Readily available 2-monosubstituted β-amino acid esters hydrochlorides and β-chloroethylsulfonyl chloride were used as starting reagents. Methyl 2-alkyl-2-(vinylsulfonamido)ethanoates obtained on the first step were alkylated at the Nitrogen atom and converted into methyl 2-alkyl-2-(N-methylvinylsulfonamido) ethanoates. The latter were subjected to NaH-mediated intramolecular Michael addition thus affording the target methyl 3-alkyl-isothiazolidine-1,1-dioxo-3-methylcarboxylates. This class of compounds is considered as sulfonamide bioisostere of natural pyroglutamic acid (pGlu) and thus can be used in the synthesis of compounds with potential biological activity.


Download data is not yet available.


Ajeet, Mishra, A. K. & Kumar, A. (2015). Recent аdvances in development of sulfonamide derivatives and their pharmacological effects — a review. Am. J. Pharmacol. Sci., 3, No. 1, pp. 18-24.

Carta, F., Scozzafava, A. & Supuran, C. T. (2012). Sulfonamides: a patent review (2008—2012). Expert Opin. Ther. Pat., 22, No. 7, pp. 747-758.

Lücking, U. (2019). Neglected sulfur(VI) pharmacophores in drug discovery: exploration of novel chemical space by the interplay of drug design and method development. Org. Chem. Front., 6, No. 8, pp. 1319-1324.

Patani, G. A. & LaVoie, E. J. (1996). Bioisosterism: a rational approach in drug design. Chem. Rev., 96, No. 8, pp. 3147-3176.

Langdon, S. R., Ertl, P. & Brown, N. (2010). Bioisosteric replacement and scaffold hopping in lead generation and optimization. Mol. Inform., 29, No. 5, pp. 366-385.

Olkkola, K. T., Brunetto, A. V. & Mattila, M. J. (1994). Pharmacokinetics of oxicam nonsteroidal antiinflammatory agents. Clin. Pharmacokinet., 26, No. 2, pp. 107-120.

Scozzafava, A., Owa, T., Mastrolorenzo, A. & Supuran, C. (2003). Anticancer and antiviral sulfonamides. Curr. Med. Chem., 10, No. 11, pp. 925-953.

Panday, S. K. (2020). Pyroglutamic acid and its derivatives: the privileged precursors for the asymmetric synthesis of bioactive natural products. Mini. Rev. Org. Chem., 17, No. 6, pp. 626-646.

Gazme, B., Boachie, R. T., Tsopmo, A. & Udenigwe, C. C. (2019). Occurrence, properties and biological significance of pyroglutamyl peptides derived from different food sources. Food Sci. Hum. Wellness., 8, No. 3, pp. 268-274.

Qian, Y., Bolin, D. R., Conde-Knape, K., Gillespie, P., Hayden, S., Huang, K.-S., Liu, M., Olivier, A. R., Ren, Y., Sergi, J., Xiang, Q., Yi, L., Yun, W., Zhang, X. (2013). N-substituted sultam carboxylic acids as novel glycogen synthase activators. MedChemComm., 4, No. 5, pp. 833-838.

Cherney, R. J., Mo, R., Meyer, D. T., Hardman, K. D., Liu, R.-Q., Covington, M. B., Qian, M., Wasserman, Z. R., Christ, D. D., Trzaskos, J. M., Newton, R. C., Decicco, C. P. (2004). Sultam hydroxamates as novel matrix metalloproteinase inhibitors. J. Med. Chem., 47, No. 12, pp. 2981-2983.



How to Cite

Izhyk В. ., Dobrydnev О. ., Popova М. ., & Volovenko Ю. . (2022). Synthesis of N-methyl 3-alkyl-isothiazolidine- 1,1-dioxo-3-methylcarboxylates through the intramolecular Michael reaction. Reports of the National Academy of Sciences of Ukraine, (6), 73–78.