A γ-Fluoro β-Acetoxypropyl Sulfonium Salt as an Equivalent of a (Fluoromethyl)vinyl Sulfonium Salt: Reagent for the Facile Synthesis of Monofluoromethylated Cyclopropanes or Aziridines

Abstract

A β-monofluoromethylated vinyl sulfonium salt, prepared in situ from a precursor γ-fluoro β-acetoxypropyl sulfonium salt under mild basic conditions, reacted with a lvariety of active methylene compounds or a primary sulfone amide under basic conditions to provide the corresponding monofluoromethylated three-membered rings in good-to-excellent yields. This new sulfonium reagent should permit easy access to a variety of important monofluoromethylated organic compounds.

Key words

monofluoromethylation - vinyl sulfonium salt - cyclopropanes - aziridines

• References and Notes

• 1a Chen DY.-K. Pouwer RH. Richard J.-A. Chem. Soc. Rev. 2012; 41: 4631
• 1b Pellissier H. Tetrahedron 2008; 64: 7041
• 1c Aziridines and Epoxides in Organic Synthesis . Yudin AK. Wiley-VCH; Weinheim: 2006
• 1d Lebel H. Marcoux J.-F. Molinaro C. Charette AB. Chem. Rev. 2003; 103: 977
• 2a Ojima I. J. Org. Chem. 2013; 78: 6358
• 2b Kirk KL. Org. Process Res. Dev. 2008; 12: 305
• 2c Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 2d Müller K. Faeh C. Diederich F. Science 2007; 317: 1881
• 2e Isanbor C. O’Hagan D. J. Fluorine Chem. 2006; 127: 303

For the CF₃ salt, see:
• 3a Kasai N. Maeda R. Furuno H. Hanamoto T. Synthesis 2012; 44: 3489
• 3b Maeda R. Ooyama K. Anno R. Shiosaki M. Azema T. Hanamoto T. Org. Lett. 2010; 12: 2548

For the CF₂H salt, see:
• 3c Ishikawa T. Kasai N. Yamada Y. Hanamoto T. Tetrahedron 2015; 71: 1254

For the F salt, see:
• 3d Hirotaki K. Takehiro Y. Kamaishi R. Yamada Y. Hanamoto T. Chem. Commun. 2013; 49: 7965

For the preparation of the vinyl sulfonium salt from the corresponding alkyl sulfonium salt, see:
• 4a Hirotaki K. Irie A. Nakamura Y. Hanamoto T. Synthesis 2017; 49: 2488
• 4b Gopinath P. Chandrasekaran S. J. Org. Chem. 2011; 76: 700
• 4c Yar M. McGarrigle EM. Aggarwal VK. Org. Lett. 2009; 11: 257
• 5 Yamazaki T. Asai M. Ohnogi T. Lin JT. Kitazume T. J. Fluorine Chem. 1987; 35: 537
• 6 Gu X.-P. Ikeda I. Okahara M. Bull. Chem. Soc. Jpn. 1987; 60: 667
• 7a Yan N. Lei Z.-W. Su J.-K. Liao W.-L. Hu X.-G. Chin. Chem. Lett. 2017; 28: 467
• 7b Adam J.-M. Foricher J. Hanlon S. Lohri B. Moine G. Schmid R. Stahr H. Weber M. Wirt B. Zutter U. Org. Process Res. Dev. 2011; 15: 515
• 7c Haufe G. J. ­Fluorine Chem. 2004; 125: 875
• 7d Akiyama Y. Fukuhara T. Hara S. Synlett 2003; 1530
• 7e Van Hijfte L. Heydt V. Kolb M. Tetrahedron Lett. 1993; 34: 4793
• 7f Landini D. Albanese D. Penso M. Tetrahedron 1992; 48: 4163
• 7g Landini D. Penso M. Tetrahedron Lett. 1990; 31: 7209
• 8 1-Fluoro-3-(phenylthio)propan-2-ol (8; see ref. 5) A heavy-walled borosilicate glass tube [17.8 cm (height) × 13 mm (diameter)], equipped with a screw cap and a magnetic stirrer bar, was successively charged with KHF₂ (2.4 g, 30.8 mmol), a 1 M solution of TBAF in THF (3.8 mL, 3.8 mmol), sulfide 9 (ref. 6; 1.28 g, 7.70 mmol), and TBADT (240 μL, 0.77 mmol). The tube was immersed in a preheated oil bath at 85 °C, and the mixture as stirred at this temperature for 16 h then cooled to r.t. Sat. aq NaHCO₃ (10 mL) and EtOAc (10 mL) were added and the organic layer was separated. The aqueous layer was extracted twice more with EtOAc, and the extracts were combined. 1 M HCl (15 mL) was added, and the organic layer was separated once more and extracted twice with EtOAc. The combined organic phases were mixed with H₂O (15 mL), and the organic layer was separated again and extracted twice with EtOAc. The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure to give a colorless oil; yield: 1.38 g (97%). ¹H NMR (400 MHz, CDCl₃): δ = 7.43–7.20 (m, 5 H), 4.59–4.47 (m, 1 H), 4.47–4.34 (m, 1 H), 4.00–3.85 (m, 1 H), 3.14 (dd, J = 14.0, 5.1 Hz, 1 H), 3.03 (ddd, J = 14.0, 7.7, 0.9 Hz, 1 H), 2.52 (d, J = 4.6 Hz, 1 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –232.8 (dt, J = 18.6, 47.3 Hz).
• 9 2-Fluoro-1-[(phenylthio)methyl]ethyl Acetate (7; see ref. 5) A 100 mL, two-necked, round-bottomed flask equipped with a magnetic stirrer bar, a stopcock, and a three-way stopcock was successively charged with CH₂Cl₂ (18.2 mL), sulfide 8 (1.18 g, 6.34 mmol), Ac₂O (0.78 mL, 8.2 mmol), and DMAP (38.7 mg, 0.317 mmol). The mixture was cooled to 0 °C, pyridine (0.77 mL, 9.5 mmol) was added, and the resultant mixture was stirred at 0 °C for 15 min then allowed to warm to r.t. After the usual workup, the residue was purified by chromatography [silica gel, hexane–EtOAc (3:1)] to give a colorless oil; yield: 1.31 g (90%). ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.15 (m, 5 H), 5.22–4.98 (m, 1 H), 4.72–4.47 (m, 2 H), 3.26–3.10 (m, 2 H), 2.05 (d, J = 13.7 Hz, 3 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –234.5 (dt, J = 22.7, 47.3 Hz).
• 10 For the preparation of nanoparticulate Cu₂O, see: Guo D. Wang L. Du Y. Ma Z. Shen L. Mater. Lett. 2015; 160: 541
• 11 [2-(Acetoxy)-3-fluoropropyl](diphenyl)sulfonium Triflate A two-necked, 100 mL, round-bottomed flask equipped with a Teflon-coated magnetic stirrer bar was successively charged with sulfide 7 (1.10 g, 4.81 mmol), Ph₂IOTf (1.73 g, 4.01 mmol), nanoparticulate Cu₂O (ref. 7; 11.2 mg, 0.08 mmol), and DCE (12 mL). The flask was then immersed in a preheated oil bath at 65 °C for 0.5 h, before the mixture was cooled to r.t. and concentrated in vacuo. The residue was purified by chromatography [silica gel, CH₂Cl₂–acetone (2:1)] to give a white solid; yield: 622 mg (92%); mp 90.1–92.5 °C. IR (ATR): 1737, 1256, 1230, 1164, 968, 762, 742, 634, 574, 514 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.12–8.04 (m, 4 H), 7.79–7.66 (m, 6 H), 5.36–5.22 (m, 1 H), 5.03 (d, J = 13.7 Hz, 1 H), 4.88–4.61 (m, 2 H), 4.39 (dd, J = 13.7, 9.3 Hz, 1 H), 1.99 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 170.4, 135.0, 134.8, 131.7, 131.5, 131.0, 130.5, 124.8, 124.1, 120.7 (q, J = 321.1 Hz), 82.4 (d, J = 176.5 Hz), 67.3 (d, J = 20.0 Hz), 45.5 (d, J = 6.9 Hz), 20.3. ¹⁹F NMR (376 MHz, CDCl₃): δ = –79.7 (s, 3F), –232.6 (dt, J = 23.2, 46.3 Hz, 1 F); HRMS (ESI-TOF): m/z [M – OTf]⁺ calcd for C₁₇H₁₈FO₂S: 305.1012; found: 305.1007.
• 12 2-(Fluoromethyl)-1-tosylaziridine (11) A 50 mL, two-necked, round-bottomed flask equipped with a stopcock, a magnetic stirrer bar, and a three-way stopcock, was charged with CH₂Cl₂ (2.4 mL) under argon. TsNH₂ (42.9 mg, 0.25 mmol) was added, the flask was cooled to 0 °C, and the mixture was stirred for 10 min at 0 °C. Salt 6 (100.9 mg, 0.22 mmol) and DBU (72.4 μL, 0.48 mmol) were added and after 5 min, the reaction was quenched with sat. aq NH₄Cl (3 mL) and the mixture was extracted with EtOAc (×3). The combined organic layers were dried (Na₂SO₄) and concentrated under reduced pressure, and the residue was purified by column chromatography [silica gel, hexane–EtOAc (3:1)] to give a white solid; yield: 48.6 mg (96%); mp: 53.6–54.0 °C. IR (ATR): 1596, 1321, 1133, 1004, 924, 713, 686, 669, 572, 548 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.84 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 4.53 (dd, J = 10.3, 4.0 Hz, 1 H), 4.27 (dd, J = 10.4, 5.9 Hz, 1 H), 3.16–3.05 (m, 1 H), 2.73 (d, J = 6.9 Hz, 1 H), 2.45 (s, 3 H), 2.27 (d, J = 4.3 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 145.2, 134.9, 130.1, 128.3, 81.6 (d, J = 173.2 Hz), 38.0 (d, J = 25.2 Hz), 30.5 (d, J = 6.9 Hz), 22.0. ¹⁹F NMR (376 MHz, CDCl₃): δ = –226.4 (dt, J = 10.4, 46.7 Hz); GC-MS (EI, 70 eV): m/z (%), 229 (5, M⁺), 155 (14), 91 (67), 74 (100), 65 (27); HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₁₀H₁₂FNNaO₂S: 252.0465; found: 252.0456.

For CFH₂-aziridines, see:
• 13a Minicone F. Rogers WJ. Green JF. J. Khan M. Smith GM. T. Bray CD. Tetrahedron Lett. 2014; 55: 5890
• 13b Wang Z. Li F. Zhao L. He Q. Chen F. Zheng C. Tetrahedron 2011; 67: 9199
• 13c Van Brabandt W. Verniest G. De Smaele D. Duvey G. De Kimpe N. J. Org. Chem. 2006; 71: 7100

For CFH₂-cyclopropanes, see:
• 14a de Meijere A. Kozhushkov SI. Yufit DS. Grosse C. Kaiser M. Raev VA. Beilstein J. Org. Chem. 2014; 10: 2844
• 14b Bray CD. Minicone F. Chem. Commun. 2010; 46: 5867
• 14c Riss PJ. Hummerich R. Schloss P. Org. Biomol. Chem. 2009; 7: 2688
• 14d Riss PJ. Rösch F. Org. Biomol. Chem. 2008; 6: 4567
• 15 Jiang B. Zhang F. Xiong W. Chem. Commun. 2003; 536
• 16 CCDC 1863286 contains the supplementary crystallographic data for compound 13b. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.