Synthesis and some transformations of 5-isoxazolylsulfonyl chlorides

P. S. Lebed, A. O. Tolmachov, Yu. O. Zubchuk, O. M. Boyko, M. V. Vovk


The effect of the structure of 5-(benzylthio)isoxazoles on selectivity of the synthesis of 5-(chlorosulfonyl)isoxazoles has been determined. The chemical behavior in relation to amines has been described.

Aim. To develop the methods for the synthesis of 5-(chlorosulfonyl)- isoxazoles and 4-chloro-5-(chlorosulfonyl)isoxazoles as promising reagents for construction of prospective bioactive compounds.

Results and discussion. The number of 5-(benzylthio)isoxazoles was obtained by cyclocondensation of N-hydroxyimidoyl chlorides or 2-chloro-2-(hydroxyimino) acetates with benzylethynylsulfide. Their oxidative chlorination with gaseous chlorine led to formation of the mixture of isoxazole-5-sulfonyl chlorides and 4-chloroisoxazole-5-sulfonyl chlorides. The ratio between these products in the mixture depended on the nature of the substitution group in position 3 of the isoxazole ring. For the synthesis of 4-chloro-5-(chlorosulfonyl)isoxazoles with acceptable yields the approach of an advance chlorination of 5-benzylthioisoxazoles by N-chlorosuccinimide with further oxidative chlorination was used.

Experimental part. The synthesis of the starting and target compounds was performed in classic preparative conditions; flesh-chromatography; elemental analysis; LCMS; 1H and 13C NMR-spectroscopy were used.

Conclusions. The reaction of oxidative chlorination of 5-(benzylthio)-3-isoxazoles has been studied. The synthetic approach for the previously unknown representatives of isoxazole-5-sulfonylchlorides has been developed.


N-hydroxyimidoyl chlorides; benzylethynyl sulfide; 5-(benzylthio)-3-isoxazoles; oxidative chlorination; isoxazole-5-sulfonylchlorides

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GOST Style Citations

1.         Pinho e Melo, T. Recent advances on the synthesis and reactivity ofisoxazoles / T. Pinho e Melo // Curr. Org. Chem. – 2005. – Vol. 9, Issue 10. – P. 925–958. doi: 10.2174/1385272054368420

2.         Recent advances in isoxazole chemistry / A. V. Galenko, A. F. Khlebnikov, M. S. Novikov et al. // Russ. Chem. Rev. – 2015. – Vol. 84, Issue 4. – P. 335–377. doi: 10.1070/rcr4503

3.         Hu, F. Recent developments in the synthesis and reactivity of isoxazoles : method catalysis and beyond / F. Hu, M. Szostak // Adv. Synth. Catal. – 2015. – Vol. 357, Issue 12. – P. 2583–2614. doi: 10.1002/adsc.201500319

4.         A review on synthesis and reactivity of isoxazoles and pyrazolines / K. Manna, U. Banik, P. S. Grosh, M. Dos //NirmaUniversityJ. Pharm. Sci. – 2014. – Vol. 1, Issue 1. – P. 37–49.

5.        Goodman and Gilman`s the pharmacological basis of therapeutics / eds. L. Brunton, B. A. Chabner, B. Knollman. – McGrow–Hill, 2011.

6.         Lee, C. C. 3,5–Isoxazoles from α–bromopentafluorophenylvinyl sulfonates : synthesis of sulfonates and sulfonamides / C. C. Lee, R. J. Fitzmaurice,S. Caddik// Org. Biomol. Chem. – 2009. – Vol. 7, Issue 21. – P. 4349–4351. doi: 10.1039/b911098d

7.         Unexpected heterocyclization of electrophilic alkenes by tetranitromethane in the presence of triethylamine. Synthesis of 3–nitroisoxazoles / Y. A. Volkova, E. B. Averina, Y. K. Grishin et al. // J. Org. Chem. – 2010. – Vol. 75, Issue 9. – P. 3047–3052. doi: 10.1021/jo100319p

8.        Nematocidal sulfonamides. Pat. WO 2010129500(A2) / Lahm G. P., Lett R. M., Smith B. T., Smith B. K., Tyler C. A. – declared 04.05.2009; published 11.10.2010.

9.         Benzofuryl pyrone derivatives. Pat. US 6589984(B1) / Nanyva Y., Ymai H., Ida T., Muratoni E., Kitaki K., Sugimoto Y., Kosugi T., Takeuchi A., Watanabe K., Tokuyama T., Takeuchi T., Hamada M. – declared 11.09.2000; published 08.07.2003.

10.       Hydroxy steroid dehydrogenaze inhibitors. Pat. US 20060223829(A1) / Aertgeerts K., Breennan N.,Cao S., ChangE., Kiryanova A., Liu X. – declared 31.03.2005; published 05.10.2006.

11.       3,4–Diarylpyrazoles as proteinkinase inhibitors. Pat. WO 2010010154(A1) / Pulici M., Zuccoto F., Badari A., Nuvoloni S., Cervi G., Traqeandi G., Bionrado S., Trifiro P., Marchionni C., Moduguo M. – declared 24.07.2008; published 28.01.2010.

12.       Adembri, G. Oxidation products of 5–isoxazolthiolsand 5–ethylisoxazoles : sulfoxides, sulfones, sulfonicacids and derivatives / C. Ademri, R. Nesi // J. Heterocycl. Chem. – 1972. – Vol. 9, Issue 3. – P. 695–697. doi: 10.1002/jhet.5570090336

13.       Synthesis of isomeric fluorobenzene–sulfonylchlorides /S. Zhersh, O. Lukin, V. Matvienko, A. Tolmachev // Tetrahedron. – 2010. – Vol. 66, Issue 32. – P. 5982–5986. doi: 10.1016/j.tet.2010.06.036

14.       Baker, R. H. The cleavage of organic sulfides with chlorine / R. H. Baker, R. M. Dodson, B. Riegel // J. Am. Chem. Soc. – 1946. – Vol. 68, Issue 12. – P. 2636–2639.doi: 10.1021/ja01216a063

15.       Barry, W. J. Derivatives of 5–o–merkaptophenyl–3–methyl–1–phenylpyrazole / W. J. Barry, J. L. Finar // J. Chem. Soc. – 1954. – P. 138–140.doi: 10.1039/jr9540000138

16.       Preparation of novel antibacterial agents. Replacement of the central aromatic ring with heterocycles / J. Li, B. D. Wakefild, J. C. Ruble et al. // Bioorg. Med. Chem. Lett. – 2007. – Vol. 17, Issue 8. – P. 2347–2350. doi:10.1016/j.bmcl.2006.12.055

17.       Liu, K–C. A particularly convenient preparation of benzohydroximinoil chlorides (nitrile oxide precursors) / K–C. Liu, B. R. Shelton, R. K. Howe // J. Org. Chem. – 1980. – Vol. 45, Issue 19. – P. 3916–3918. doi: 10.1021/jo01307a039

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19.       In pursuit of an acetylen dithiolate synthesis / W. W. Seidel, M. J. Meel, M. Schaffrath, T. Pape // Eur. J. Org. Chem. – 2007. – Vol. 2007, Issue 21. – P. 3526–3532. doi: 10.1002/ejoc.200601107


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