Download PDF
Synlett 2025; 36(04): 347-352
DOI: 10.1055/a-2351-4900
letter

Attempts on Fluorinative Transformation of Selected Functionalized Cycloalkene Scaffolds through Aziridination/Aziridine-Opening Protocol

Tamás T. Novák
a   Institute of Organic Chemistry, Stereochemistry Research Group, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Magyar Tudósok krt. 2, Hungary
b   Department of Organic Chemistry and Technology, Faculty of Chemical Technology and Biotechnology, Budapest University of Technology and Economics, 1111 Budapest, Műegyetem rkp. 3, Hungary
,
Ágnes Gömöry
c   Institute of Organic Chemistry, MS Proteomics Research Group, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Magyar Tudósok krt. 2, Hungary
,
Melinda Nonn∗
d   MTA TTK Lendület Artificial Transporter Research Group, Institute of Materials and Environmental Chemistry, HUN-REN Research Center for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Magyar Tudósok krt. 2, Hungary
,
Jianlin Han 
e   Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, P. R. of China
,
Loránd Kiss∗
a   Institute of Organic Chemistry, Stereochemistry Research Group, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Magyar Tudósok krt. 2, Hungary
› Author AffiliationsThe authors gratefully acknowledge financial support from the Nemzeti Kutatási Fejlesztési és Innovációs H (National Research, Development and Innovation Office of Hungary, NKFIH/OTKA FK 145394 and K 142266). Project no. RRF-2.3.1-21-2022-00015 has been implemented with the support provided by the European Union. This work was supported by the János Bolyai Research Scholarship to M.N. of the Magyar Tudományos Akadémia (Hungarian Academy of Sciences).
› Further Information
    Permissions and Reprints All articles of this category


Abstract

Studies on the transformations of some functionalized cycloalkene derivatives through their ring olefin-bond aziridination/aziridine opening with fluoride are presented. The selected model compounds submitted to fluorinative functionalization were an amino ester and diesters with a cyclohexene skeleton as well as a cyclopentene-fused β-lactam. Functionalization proceeded across a substrate-directed diastereoselective olefin-bond aziridination, followed by fluoride-mediated aziridine opening or intramolecular lactonization giving some fluorinated amino ester or amino lactone derivatives.

Key words

amino ester - aziridine - fluorination - lactam - lactone

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2351-4900.
  • Supporting Information


Publication History

Received: 22 May 2024

Accepted after revision: 24 June 2024

Accepted Manuscript online:
24 June 2024

Article published online:
08 July 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References and Notes

    • 3a Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
      CrossrefPubMedSearch in Google Scholar
    • 3b Dykstra KD, Ichiishi N, Krska SW, Richardson PF. Emerging Fluorination Methods in Organic Chemistry Relevant for Life Science Application, In: Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals. Haufe G, Leroux FG. Academic Press; London: 2019: 1-90
      Search in Google Scholar
  • 9 Nonn M, Kiss L, Forró E, Sillanpää R, Fülöp F. Tetrahedron 2014; 70: 8511
    CrossrefSearch in Google Scholar
  • 10 Nonn M, Kiss L, Haukka M, Fustero S, Fülöp F. Org. Lett. 2015; 17: 1074
    CrossrefPubMedSearch in Google Scholar
  • 11 Remete AM, Novák TT, Nonn M, Haukka M, Fülöp F, Kiss L. Beilstein J. Org. Chem. 2020; 16: 2562
    CrossrefPubMedSearch in Google Scholar
    • 13a General Procedure for Aziridination Reactions The appropriate starting material 1 mmol was dissolved in 10 mL MeCN and then cooled down to 0 °C. After that, 1.2 equiv (1.2 mmol, 338 mg) chloramine-T·3H2O and 15 mol% PTAB (0.15 mmol, 56 mg) were added. The mixture was stirred to the appropriate time and then was cooled down. When the reaction was completed, MeCN was evaporated from the mixture and the residue was dissolved in 30 mL EtOAc. The mixture was then washed with 3 ( 10 mL water, and the organic and water phases were separated. The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated under vacuum. Purification of the crude product by column chromatography on silica gel afforded the products as oils or solids.
    • 13b Benzyl (1S*,3R*,4S*,6R*)-4-[(tert-Butoxycarbonyl)amino]-7-tosyl-7-azabicyclo[4.1.0]heptane-3-carboxylate (11) Prepared according to aziridination general procedure from benzyl (1R*,6S*)-6-[(tert-butoxycarbonyl)amino]cyclohex-3-ene-1-carboxylate (331 mg, 1.00 mmol) for 5 h. Purification of the crude product by column chromatography on silica gel afforded the product as white-yellowish solid 235 mg; yield 50%. R f = 0.20 (H/E n-hexane/EtOAc, 3:1); mp 50–52 °C. 1H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz, 2 H), 7.39–7.28 (m, 7 H), 5.48 (d, J = 10.1 Hz, 1 H), 5.09 (d, J = 12.2 Hz, 1 H), 4.94 (d, J = 12.3 Hz, 1 H), 3.98 (d, J = 8.0 Hz, 1 H), 3.07 (td, J = 4.9, 2.4 Hz, 1 H), 2.98 (ddd, J = 6.8, 5.2, 1.1 Hz, 1 H), 2.58–2.54 (m, 1 H), 2.54–2.50 (m, 1 H), 2.42 (s, 3 H), 2.16–2.06 (m, 2 H), 2.01 (dt, J = 15.1, 7.4 Hz, 1 H), 1.40 (s, 9 H). 13C NMR (75 MHz, CDCl3): δ = 172.4, 155.0, 144.6, 135.3, 129.8, 128.5, 128.3, 128.2, 127.4, 126.3, 79.4, 66.8, 45.2, 40.3, 38.8, 38.3, 28.3, 27.1, 23.9, 21.6. HRMS: m/z calcd for C26H32N2O6SNa+ [M + Na]+: 523.1879; found: 523.1878.
    • 13c General Procedure for Fluorination Reactions The appropriate starting material 1 mmol was dissolved in 15 mL anhydrous 1,4-dioxane, and the temperature was set to the boiling point of the solvent. Then 4 equiv fluorinating reagent (either Xtal-Fluor-E 4.00 mmol, 916 mg or Xtal-Fluor-M 4.00 mmol, 972 mg) was added and the reaction mixture was stirred to the appropriate time. When the reaction was completed, the flask was cooled down to room temperature and 15 mL EtOAc were added to the mixture. It was poured to a separation funnel and washed with 3 ( 15 mL saturated NaHCO3 solution. The organic phase was dried with anhydrous Na2SO4, filtered, and evaporated under vacuum. Purification of the crude product by column chromatography on silica gel afforded the products as oils or solids.
    • 13d Benzyl (1R*,5S*,6R*,8R*)-8-Fluoro-3-oxo-2-tosyl-2,4-diazabicyclo[3.3.1]nonane-6-carboxylate (13) Prepared according to the general procedure of fluorination reactions from benzyl (1R*,3R*,4S*,6S*)-4-[(tert-butoxycarbonyl)amino]-7-tosyl-7-azabicyclo[4.1.0]heptane-3-carboxylate 250 mg (0.50 mmol) for 35 min and 4.00 equiv (2.00 mmol, 486 mg) Xtal-Fluor-M were used as fluorinating agent. Purification of the crude product by column chromatography on silica gel afforded the product as orange-yellowish solid 60 mg; yield 33%. R f = 0.50 (H/E n-hexane/EtOAc, 1:1); mp 170 °C. 1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 8.4 Hz, 2 H), 7.40–7.25 (m, 4 H), 5.54 (d, J = 3.2 Hz, 1 H), 5.11 (d, J = 4.7 Hz, 2 H), 4.98 (d, J = 3.3 Hz, 1 H), 4.82 (t, J = 3.5 Hz, 1 H), 3.98 (s, 1 H), 2.85 (ddd, J = 12.9, 4.7, 2.0 Hz, 1 H), 2.41 (s, 3 H), 2.31 (d, J = 2.8 Hz, 1 H), 2.26 (t, J = 2.4 Hz, 1 H), 1.86 (dtd, J = 10.0, 5.6, 2.3 Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 171.9, 151.3, 144.7, 136.6, 135.2, 129.3, 128.7, 128.6, 128.3, 89.0, 86.7, 67.0, 51.5, 51.0, 46.5, 42.5, 24.5, 24.2, 21.6. 19F NMR (282 MHz, CDCl3): δ = –183.6. HRMS: m/z calcd for C22H24FN2O5S+ [M + H]+: 447.1390; found: 447.1389.