An Efficient Method for the Synthesis of Benzofused Five-Membered Cyclic Sulfamates

Authors

  • Serhii H. Aleksandrenko Taras Shevchenko National University of Kyiv; Enamine Ltd, Ukraine
  • Bohdan V. Vashchenko Taras Shevchenko National University of Kyiv; Enamine Scientific Research Institute, Ukraine https://orcid.org/0000-0003-4575-2065

DOI:

https://doi.org/10.24959/ophcj.26.358460

Keywords:

heterocycles, organosulfur compounds, sulfamates, building blocks

Abstract

An efficient and scalable method for the synthesis of 1,2,3-benzoxathiazole 2,2-dioxides and related five-membered cyclic sulfamates employing gaseous sulfuryl fluoride (SO2F2) in the presence of Et3N is described. The one-pot cyclization of 2-aminophenol derivatives proceeds at rt and tolerates a variety of substituents on the aromatic ring, including electron-withdrawing groups, as well as N-substituted substrates. The method provides the target heterocycles in improved yields compared to classical SO2Cl2-based protocols and is readily scalable to 50 g without loss of efficiency. A virtual library of 49 cyclic sulfamate derivatives was generated and evaluated using the LLAMA approach. The library members exhibit favorable lead-like physicochemical profiles, with 100% compliance with the Lipinski, Veber, Muegge, and GSK 4/400 filters, supporting the utility of the proposed chemotypes for medicinal chemistry applications.

Supporting Agency

  • This work was funded by Enamine Ltd.

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References

  1. Andersen, K. K.; Bray, D. D.; Chumpradit, S.; Clark, M. E.; Habgood, G. J.; Hubbard, C. D.; Young, K. M. 1,2,3-Benzoxathiazole 2,2-Dioxides: Synthesis, Mechanism of Hydrolysis, and Reactions with Nucleophiles. J. Org. Chem. 1991, 56 (23), 6508–6516. https://doi.org/10.1021/jo00023a012.
    |
  2. Andersen, K. K.; Kociolek, M. G. Acidity of Cyclic Sulfamates: Study of Substituted 1,2,3-Benzoxathiazole 2,2-Dioxides and Theoretical Investigation of the Effect of Conformation on Acidity. J. Org. Chem. 1995, 60 (7), 2003–2007. https://doi.org/10.1021/jo00112a022.
    |
  3. Kim, S. J.; Park, H. B.; Lee, J. S.; Jo, N. H.; Yoo, K. H.; Baek, D.; Kang, B.; Cho, J.-H.; Oh, C.-H. Novel Lβ-Methylcarbapenems Having Cyclic Sulfonamide Moieties: Synthesis and Evaluation of in Vitro Antibacterial Activity. Eur. J. Med. Chem. 2007, 42 (9), 1176–1183. https://doi.org/10.1016/j.ejmech.2007.02.001.
    | |
  4. Kim, S. J.; Jung, M.-H.; Yoo, K. H.; Cho, J.-H.; Oh, C.-H. Synthesis and Antibacterial Activities of Novel Oxazolidinones Having Cyclic Sulfonamide Moieties. Bioorg. Med. Chem. Lett. 2008, 18 (21), 5815–5818. https://doi.org/10.1016/j.bmcl.2008.09.034.
    | |
  5. Moss, T. A.; Alonso, B.; Fenwick, D. R.; Dixon, D. J. Catalytic Enantio‐ and Diastereoselective Alkylations with Cyclic Sulfamidates. Angew. Chem. Int. Ed. 2010, 49 (3), 568–571. https://doi.org/10.1002/anie.200905329.
    | |
  6. Kok, K.; Kuo, C.-L.; Katzy, R. E.; Lelieveld, L. T.; Wu, L.; Roig-Zamboni, V.; Van Der Marel, G. A.; Codée, J. D. C.; Sulzenbacher, G.; Davies, G. J.; Overkleeft, H. S.; Aerts, J. M. F. G.; Artola, M. 1,6- Epi -Cyclophellitol Cyclosulfamidate Is a Bona Fide Lysosomal α-Glucosidase Stabilizer for the Treatment of Pompe Disease. J. Am. Chem. Soc. 2022, 144 (32), 14819–14827. https://doi.org/10.1021/jacs.2c05666.
    | |
  7. Benltifa, M.; Kiss, M. D.; Garcia-Moreno, M. I.; Mellet, C. O.; Gueyrard, D.; Wadouachi, A. Regioselective Synthesis and Biological Evaluation of Spiro-Sulfamidate Glycosides from Exo-Glycals. Tetrahedron: Asymmetry 2009, 20 (15), 1817–1823. https://doi.org/10.1016/j.tetasy.2009.07.012.
    |
  8. Hanson, S. R.; Whalen, L. J.; Wong, C.-H. Synthesis and Evaluation of General Mechanism-Based Inhibitors of Sulfatases Based on (Difluoro)Methyl Phenyl Sulfate and Cyclic Phenyl Sulfamate Motifs. Bioorg. Med. Chem. 2006, 14 (24), 8386–8395. https://doi.org/10.1016/j.bmc.2006.09.002.
    | |
  9. Lawrence Woo, L. W.; Leblond, B.; Purohit, A.; Potter, B. V. L. Synthesis and Evaluation of Analogues of Estrone-3-O-Sulfamate as Potent Steroid Sulfatase Inhibitors. Bioorg. Med. Chem. 2012, 20 (8), 2506–2519. https://doi.org/10.1016/j.bmc.2012.03.007.
    | |
  10. Clarke, B.; Cutler, L.; Demont, E.; Dingwall, C.; Dunsdon, R.; Hawkins, J.; Howes, C.; Hussain, I.; Maile, G.; Matico, R.; Mosley, J.; Naylor, A.; O’Brien, A.; Redshaw, S.; Rowland, P.; Soleil, V.; Smith, K. J.; Sweitzer, S.; Theobald, P.; Vesey, D.; Walter, D. S.; Wayne, G. BACE-1 Hydroxyethylamine Inhibitors Using Novel Edge-to-Face Interaction with Arg-296. Bioorg. Med. Chem. Lett. 2010, 20 (15), 4639–4644. https://doi.org/10.1016/j.bmcl.2010.05.111.
    | |
  11. Yan, Z.; Kahn, M.; Qabar, M.; Urban, J.; Kim, H.-O.; Blaskovich, M. A. Design and Synthesis of Phosphotyrosine Mimetics. Bioorg. Med. Chem. Lett. 2003, 13 (12), 2083–2085. https://doi.org/10.1016/S0960-894X(03)00253-1.
    | |
  12. Saitoh, T.; Seki, K.; Nakajima, R.; Yamamoto, N.; Kutsumura, N.; Nagumo, Y.; Irukayama-Tomobe, Y.; Ogawa, Y.; Ishikawa, Y.; Yanagisawa, M.; Nagase, H. Essential Structure of Orexin 1 Receptor Antagonist YNT-707, Part V: Structure-Activity Relationship Study of the Substituents on the 17-Amino Group. Bioorg. Med. Chem. Lett. 2020, 30 (3), 126893. https://doi.org/10.1016/j.bmcl.2019.126893.
    | |
  13. Haftchenary, S.; Nelson, S. D.; Furst, L.; Dandapani, S.; Ferrara, S. J.; Bošković, Ž. V.; Figueroa Lazú, S.; Guerrero, A. M.; Serrano, J. C.; Crews, D. K.; Brackeen, C.; Mowat, J.; Brumby, T.; Bauser, M.; Schreiber, S. L.; Phillips, A. J. Efficient Routes to a Diverse Array of Amino Alcohol-Derived Chiral Fragments. ACS Comb. Sci. 2016, 18 (9), 569–574. https://doi.org/10.1021/acscombsci.6b00050.
    | |
  14. Armarego, W. L. F.; Chai, C. Purification of Laboratory Chemicals, 6th ed.; Butterworth-Heinemann: Burlington, 2009.

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Published

2026-05-01

How to Cite

(1)
Aleksandrenko, S. H.; Vashchenko, B. V. An Efficient Method for the Synthesis of Benzofused Five-Membered Cyclic Sulfamates. J. Org. Pharm. Chem. 2026, 24, 38-45.

Issue

Vol. 24 No. 1 (2026)

Section

Original Researches

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