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Domino reaction of (2-haloethyl)polyfluorophenyl sulfides, sulfoxides, and sulfones with ammonia or amines: one-pot synthesis of 3,4-dihydro-2H-1,4-benzothiazines polyfluorinated at the benzene ring and the corresponding 1-oxides and 1,1-dioxides

5,7,8-Trifluoro-3,4-dihydro-2H-1,4-benzothiazine, corresponding 1-oxide and 1,1-dioxide, as well as some of their 4- and 6-substituted derivatives were prepared in 39–88% yields via the reaction of ammonia or primary aliphatic amines with (2-haloethyl)-2,3,5,6-tetrafluorophenyl sulfides, sulfoxides, or sulfones. Formation of the heterocyclic moiety was shown to proceed as a two-stage process starting from halogen replacement at the side chain followed by intramolecular aminodefluorination. The ratio of the reaction rates of the two processes depends on the nature of the reagent used. Chemical structures of the cyclization products were proved by precise analysis of the NMR spectra and by comparing the experimental NMR parameters with those calculated by an empirical additivity scheme and quantum chemistry methods (DFT).

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Figure 1.


  1. To provide correct comparison of calculated and experimental data, we measured fluorine chemical shifts for 5% solutions in 95% aq EtOH, so the fluorine chemical shifts in Table 1 and in the Experimental are not the same (the chemical shifts given in the Experimental were measured for solutions in CDCl3 or CDCl3–DMSO-d6).


  1. Fringuelli, R.; Milanese, L.; Schiaffella, F. Mini-Rev. Med. Chem. 2005, 5, 1061.

    Article  CAS  Google Scholar 

  2. Ajani, O. O. Arch. Pharm. 2012, 345, 841.

    Article  CAS  Google Scholar 

  3. Gupta, R. R.; Ojha, K. C. In Phenothiazines and 1,4-Benzothiazines – Chemical and Biochemical Aspects, Gupta, R. R., Ed.; Elsevier: Amsterdam, 1988, p. 163.

    Google Scholar 

  4. (a) Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications; Filler, R.; Kobayashi, Y.; Yagupolskii, L., Eds.; Elsevier: Amsterdam, 1993. (b) Organofluorine Chemistry. Principles and Commercial Applications; Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds.; Plenum Press: New York, 1994. (c) Davis, R.; Bryson, H. M. Drugs 1994, 47, 677. (d) Furin, G. G. Fluorine-containing Heterocyclic Compounds [in Russian]; Nauka: Novosibirsk, 2001, p. 9.

  5. Armenise, D.; Muraglia, M.; Florio, M. A.; De Laurentis, N.; Rosato, A.; Carrieri, A.; Corbo, F.; Franchini, C. Arch. Pharm. 2012, 345, 407.

    Article  CAS  Google Scholar 

  6. Vysokov, V. I.; Charushin, V. N.; Chupakhin, O. N.; Pashkevich, T. K. Zh. Org. Khim. 1998, 34, 455.

    Google Scholar 

  7. Culbertson, T. P. J. Heterocycl. Chem. 1991, 28, 1701.

    Google Scholar 

  8. Cecchetti, V.; Fravolini, A.; Schiafella, F.; Tabarrini, O.; Zhou, W.; Pagella, P. G. J. Heterocycl. Chem. 1992, 29, 375.

    Article  CAS  Google Scholar 

  9. (a) Gupta, R. R.; Kumar, R.; Gautam, R. K. J. Fluorine Chem. 1985, 28, 381. (b) Gupta, R. R.; Thomas, A.; Gautam, R. K.; Gupta, V. J. Fluorine Chem. 1989, 44, 1. (c) Hamadi, M. Y.; Gupta, R.; Gupta, R. R. J. Fluorine Chem. 1999, 94, 169.

  10. (a) Yakobson, G. G.; Petrova, T. D.; Kobrina, L. S. In Fluorine Chemistry Reviews; Tarrant, P., Ed.; Marcel Dekker: New York, 1974, vol. 7, p. 115. (b) Nosova, E. V.; Lipunova, G. N.; Charushin, V. N.; Chupakhin, O. N. J. Fluorine Chem. 2010, 131, 1267. (c) Hargreaves, C. A.; Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. Tetrahedron 2007, 63, 5204. (d) Cargill, M. R.; Linton, K. E.; Sandford, G.; Yufit, D. S.; Howard, J. A. K. Tetrahedron 2010, 66, 2356. (e) Ranjbar-Karimi, R.; Mousavi, M. J. Fluorine Chem. 2010, 131, 587.

  11. Amosova, S. V.; Gostevskaya, V. I.; Gavrilova, G. M.; Nesterov, V. N.; Struchkov, Yu. T.; Il’icheva, L. N. Chem. Heterocycl. Compd. 1996, 32, 1023. [Khim. Geterotsikl. Soedin. 1996, 1195.]

    Article  Google Scholar 

  12. Amosova, S. V.; Gavrilova, G. M.; Gostevskaya, V. I.; Afonin, A. V.; Larina, L. I. Chem. Heterocycl. Compd. 1998, 34, 625. [Khim. Geterotsikl. Soedin. 1998, 706.]

    Article  CAS  Google Scholar 

  13. (a) Bernotas, R. C., Dooley, R. J. Tetrahedron 2010, 66, 2273. (b) Parai, M. K.; Panda, G. Tetrahedron Lett. 2009, 50, 4703.

  14. (a) Langille, K. R.; Peach, M. E. J. Fluorine Chem. 1972, 1, 407. (b) Musial, B. C.; Peach, M. E. J. Fluorine Chem. 1976, 7, 427. (c) Testaferri, L.; Tingoli, M.; Tiecco, M. J. Org. Chem. 1980, 45, 4376. (d) Crowell, T. R.; Peach, M. E. J. Fluorine Chem. 1982, 21, 469. (e) MacNicol, D. D.; Mallison, P. R.; Murphy, A.; Sym, G. J. Tetrahedron Lett. 1982, 23, 4131. (f) Pastor, S. D.; Hessell, E. T. J. Org. Chem. 1985, 50, 4812.

  15. Kizner, T. A.; Shteingarts, V. D. Zh. Org. Khim. 1989, 25, 2424.

    CAS  Google Scholar 

  16. Litvak, V. V.; Kondrat'ev, A. S.; Shteingarts, V. D. Russ. J. Org. Chem. 2009, 45, 1637. [Zh. Org. Khim. 2009, 45, 1648.]

    Article  CAS  Google Scholar 

  17. Krulikovskaya, E. A.; Dozmorov, S. V. Zh. Obshch. Khim. 1972, 42, 2248.

    CAS  Google Scholar 

  18. (a) González, J. P.; Edgar, M.; Elsegood, M. R. J.; Weaver, G. W. Org. Biomol. Chem. 2011, 9, 2294. (b) Kolchina, E. F. Dis. kand. khim. nauk; Novosibirsk, 2004.

  19. Bruce, M. I. J. Chem. Soc. A 1968, 1459.

  20. Pushkina, L. N.; Stepanov, A. P.; Zhukov, V. S.; Naumov, A. D. Zh. Org. Khim. 1972, 8, 586.

    CAS  Google Scholar 

  21. Sheppard, W. A.; Foster, S. S. J. Fluorine Chem. 1972, 2, 53.

    Article  CAS  Google Scholar 

  22. Marriott, J. H.; Moreno Barber, A. M.; Hardcastle, I. R.; Rowlands, M. G.; Grimshaw, R. M.; Neidle, S.; Jarman, M. J. Chem. Soc., Perkin Trans. 1 2000, 24, 4265.

  23. Sandford, G.; Tadeusiak, A.; Yufit, D. S.; Howard, J. A. K. J. Fluorine Chem. 2007, 128, 1216.

    Article  CAS  Google Scholar 

  24. Petrova, T. D.; Savchenko, T. I.; Kukovinets, O. S.; Yakobson, G. G. Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk. 1974, 2, 117.

    Google Scholar 

  25. Petrov, V. P.; Barkhash, V. A. Chem. Heterocycl. Compd. 1970, 6, 357. [Khim. Geterotsikl. Soedin. 1970, 385.]

    Article  Google Scholar 

  26. Konstantinova, A. V.; Gerasimova, T. N.; Kozlova, M. M.; Petrenko, N. I. Chem. Heterocycl. Compd. 1989, 25, 451. [Khim. Geterotsikl. Soedin. 1989, 539.]

    Article  Google Scholar 

  27. Gerasimova, T. N.; Kargapolova, I. Yu. Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk. 1986, 5, 112.

    Google Scholar 

  28. Hogben, M. G.; Graham, W. A. G. J. Am. Chem. Soc. 1969, 91, 283.

    Article  CAS  Google Scholar 

  29. Abraham, R. J.; Macdonald, D. B.; Pepper, E. S. J. Am. Chem. Soc. 1968, 90, 147.

    Article  CAS  Google Scholar 

  30. Furin, G. G.; Yakobson, G. G. Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk. 1977, 2, 109.

    Google Scholar 

  31. Furin, G. G., Yakobson, G. G. Izv. Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk. 1976, 3, 120.

    Google Scholar 

  32. Andreevskaya, O. I.; Furin, G. G.; Yakobson, G. G. Zh. Org. Khim. 1977, 13, 1684.

    CAS  Google Scholar 

  33. Cohen, E. A.; Bourn, A. J. R.; Manatt, S. L. J. Magn. Reson. 1969, 1, 436.

    CAS  Google Scholar 

  34. Neese, F. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2, 73.

    CAS  Google Scholar 

  35. Dalton, a Molecular Electronic Structure Program, Release Dalton2015.0 (2015);

  36. Aidas, K.; Angeli, C.; Bak, K. L.; Bakken, V.; Bast, R.; Boman, L.; Christiansen, O.; Cimiraglia, R.; Coriani, S.; Dahle, P.; Dalskov, E. K.; Ekström, U.; Enevoldsen, T.; Eriksen, J. J.; Ettenhuber, P.; Fernández, B.; Ferrighi, L.; Fliegl, H.; Frediani, L.; Hald, K.; Halkier, A.; Hättig, C.; Heiberg, H.; Helgaker, T.; Hennum, A. C.; Hettema, H.; Hjertenæs, E.; Høst, S.; Høyvik, I.-M.; Iozzi, M. F.; Jansik, B.; Jensen, H. J. Aa.; Jonsson, D.; Jørgensen, P.; Kauczor, J.; Kirpekar, S.; Kjærgaard, T.; Klopper, W.; Knecht, S.; Kobayashi, R.; Koch, H.; Kongsted, J.; Krapp, A.; Kristensen, K.; Ligabue, A.; Lutnæs, O. B.; Melo, J. I.; Mikkelsen, K. V.; Myhre, R. H.; Neiss, C.; Nielsen, C. B.; Norman, P.; Olsen, J.; Olsen, J. M. H.; Osted, A.; Packer, M. J.; Pawlowski, F.; Pedersen, T. B.; Provasi, P. F.; Reine, S.; Rinkevicius, Z.; Ruden, T. A.; Ruud, K.; Rybkin, V.; Salek, P.; Samson, C. C. M.; Sánchez de Merás, A.; Saue, T.; Sauer, S. P. A.; Schimmelpfennig, B.; Sneskov, K.; Steindal, A. H.; Sylvester-Hvid, K. O.; Taylor, P. R.; Teale, A. M.; Tellgren, E. I.; Tew, D. P.; Thorvaldsen, A. J.; Thøgersen, L.; Vahtras, O.; Watson, M. A.; Wilson, D. J. D.; Ziolkowski, M.; Ågren, H. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2014, 4, 269.

    CAS  Google Scholar 

  37. Foresman, J. B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J.; Frisch, M. J. J. Phys. Chem. 1996, 100, 16098.

    Article  CAS  Google Scholar 

  38. Ovenall, D. W.; Chang, J. J. J. Magn. Reson. 1977, 25, 361.

    CAS  Google Scholar 

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The research described was supported in part by the Russian Foundation for Basic Research (grant No. 14-03-00108 А). The authors thank the Chemical Service Center, SB RAS, Novosibirsk, for recording spectra of the compounds described and the Information Technology Centre of the Novosibirsk State University for providing access to the cluster computational resources to carry out quantumchemical calculations.

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Correspondence to Andrey S. Kondratyev.

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Vitalij D. Shteingarts and Vladimir V. Litvak are deceased

Published in Khimiya Geterotsiklicheskikh Soedinenii, 2017, 53(12), 1350–1361

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Kondratyev, A.S., Shteingarts, V.D., Litvak, V.V. et al. Domino reaction of (2-haloethyl)polyfluorophenyl sulfides, sulfoxides, and sulfones with ammonia or amines: one-pot synthesis of 3,4-dihydro-2H-1,4-benzothiazines polyfluorinated at the benzene ring and the corresponding 1-oxides and 1,1-dioxides. Chem Heterocycl Comp 53, 1350–1361 (2017).

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