Application of PhSCF₂CF₂SiMe₃ as a Tandem Anion and Radical Tetra­fluoroethylene Equivalent: Fluoride-Catalyzed Addition to N-Substituted Cyclic Imides Followed by Radical Cyclization

Abstract

PhSCF₂CF₂SiMe₃ undergoes a fluoride-catalyzed nucleophilic addition to N-substituted cyclic amides affording adducts in moderate to good yields. Reductive cleavage of the phenylsulfanyl group of N-methylated adducts under radical conditions yields the corresponding tetrafluoroethyl-containing adducts in excellent yields. Under the same reduction conditions, N-allylated adducts undergo 6-exo radical cyclization to afford the corresponding tetrafluorinated 1-azabicyclic compounds in moderate to good yields and cis selectivities.

Key words

nucleophilic addition - radical reaction - fluorine - heterocycles - imides

• References

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• 13a 5-Hydroxy-1-methyl-5-[1,1,2,2-tetrafluoro-2-(phenylthio)ethyl]pyrrolidin-2-one (2a′)A solution of TBAT (108 mg, 10 mol%) in dry THF (2 mL) was added dropwise to a solution of PhSCF₂CF₂SiMe₃ (1.13 g, 4 mmol) and 1a (226 mg, 2 mmol) in dry THF (10 mL). The mixture was stirred at r.t. under argon for 1 h, followed by the addition of aq HF (4 mL, 1 M), and stirred at 35 °C for another hour. The reaction product was extracted in Et₂O (3 × 25 mL), the combined organic phase was washed with brine (15 mL), dried (MgSO₄), and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (SiO₂, PE–EtOAc) to give the desired product 2a (349 mg, 54% yield); white solid; mp 116–118 °C; R_f = 0.26 (PE–EtOAc, 50:50). ¹H NMR (400 MHz, CDCl₃): δ = 2.10–2.18 (m, 1 H), 2.39–2.45 (m, 2 H), 2.67–2.74 (m, 1 H), 2.87 (s, 3 H), 5.34 (br s, 1 H), 7.38–7.43 (m, 2 H), 7.46–7.50 (m, 1 H), 7.62–7.65 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.3, 28.8, 29.5, 90.7–91.2 (m), 116.0 (tt, ¹ J _CF = 262.2 Hz, ² J _CF = 30.9 Hz), 123.8, 124.8 (tt, ¹ J _CF = 289.0 Hz, ² J _CF = 35.1 Hz), 129.2, 130.6, 137.2, 175.7. ¹⁹F NMR (376 MHz, CDCl₃): δ = –118.7 (dd, 1 F, ² J _FF = 273.2 Hz, ³ J _FF = 8.0 Hz), –117.5 (dd, 1 F, ² J _FF = 273.2 Hz, ³ J _FF = 3.4 Hz), –85.4 (dd, 1 F, ² J _FF = 224.5 Hz, ³ J _FF = 8.0 Hz), –83.6 (d, 1 F, ² J _FF = 224.5 Hz, ³ J _FF = 3.4 Hz). IR (film): ν_max = 3191, 1680, 1578, 1105, 753, 691 cm^–1. MS (EI): m/z (%) = 190 (5), 114 (100), 109 (11), 86 (9), 58 (13). HRMS (ESI⁺): m/z calcd for C₁₃H₁₄F₄NO₂S [MH]⁺: 324.06759; found: 324.06760
• 14a 5-Hydroxy-1-methyl-5-(1,1,2,2-tetrafluoroethyl)- pyrrolidin-2-one (3a)A solution of n-Bu₃SnH (470 μL, 1.75 mmol) and AIBN (25 mg, 0.15 mmol) in dry toluene (3 mL) was added over 1 h using a syringe pump to a refluxing solution of 2a (323 mg, 1 mmol) in dry toluene (5 mL). The resulting mixture was refluxed under argon for 3 h, followed by concentration under reduced pressure and purification by flash column chromatography (SiO₂, PE–EtOAc) to give product 3a (202 mg, 94% yield); colorless oil; R_f = 0.23 (PE–EtOAc, 60:40). ¹H NMR (400 MHz, CDCl₃): δ = 1.90–2.00 (m, 1 H), 2.26–2.38 (m, 2 H), 2.41–2.50 (m, 1 H), 2.73 (d, 3 H, J = 2.5 Hz), 6.59 (tdd, 1 H, ² J _HF = 51.5 Hz, ³ J _HF = 9.6, 3.5 Hz), 7.36 (br d, 1 H, J = 2.8 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 25.8, 28.4, 28.8, 88.7–90.2 (m), 173.8. ¹⁹F NMR (376 MHz, CDCl₃): δ = –138.3 (ddd, 1 F, ² J _FF = 301.0 Hz, ³ J _FF = 10.7, 7.1 Hz), –134.3 (ddd, 1 F, ² J _FF = 301.0 Hz, ³ J _FF = 12.5, 1.3 Hz), –130.6 (ddd, 1 F, ² J _FF = 265.8 Hz, ³ J _FF = 12.5, 7.1 Hz), –126.8 (ddd, 1 F, ² J _FF = 265.8 Hz, ³ J _FF = 10.7, 1.3 Hz). IR (film): ν_max = 3204, 1687, 1110 cm^–1. MS (EI): m/z (%) = 198 (6), 114 (100), 101 (8), 86 (20), 58 (45). HRMS (ESI⁺): m/z calcd for C₇H₁₀F₄NO₂ [MH]⁺: 216.06422; found: 216.06417
• 15a 7,7,8,8-Tetrafluoro-8a-hydroxy-6-methylhexa-hydroindolizin-3(2H)-one (3b)A solution of n-Bu₃SnH (470 μL, 1.75 mmol) and AIBN (25 mg, 0.15 mmol) in dry toluene (3 mL) was added over 3 h using a syringe pump to a refluxing solution of 2b (349 mg, 1 mmol) in dry toluene (5 mL). The resulting mixture was refluxed under argon overnight, followed by concentration under reduced pressure and purification by flash column chromatography (SiO₂, PE–EtOAc) to give product 3b (188 mg, 78% yield); white solid; cis/trans = 76:24; mp (cis) 160–162 °C; R_f = 0.42 (PE–EtOAc, 25:75). ¹H NMR (400 MHz, CDCl₃): δ = 0.91 (dd, 3 H, ³ J _HH = 7.3 Hz, ⁴ J _HH = 3.8 Hz, trans), 1.02 (d, 3 H, ³ J _HH = 6.7 Hz, cis), 1.88–1.97 (m, 2 H, cis + trans), 2.10–2.25 (m, 2 H, cis + trans), 2.28–2.35 (m, 1 H, cis), 2.37–2.40 (m, 1 H, trans), 2.42–2.53 (m, 2 H, cis + trans), 2.69–2.79 (m, 1 H, cis), 3.16–3.23 (m, 1 H, trans), 3.61–3.69 (m, 1 H, trans), 3.77–3.88 (m, 1 H, cis), 7.08 (s, 1 H, trans), 7.11 (s, 1 H, cis). ¹³C NMR (100 MHz, CDCl₃): δ (cis) = 8.0 (d, J = 5.6 Hz), 25.9, 28.6, 35.3 (t, ² J _CF = 21.4 Hz), 36.1 (d, J = 8.3 Hz), 88.1–88.7 (m), 171.8. ¹⁹F NMR (376 MHz, CDCl₃): δ = –140.9 (ddd, 1 F, ² J _FF = 252.4 Hz, ³ J _FF = 16.1, 10.4 Hz, cis), –135.8 (ddd, 1 F, ² J _FF = 257.8 Hz, ³ J _FF = 16.3, 12.1 Hz, trans), –124.7 (ddd, 1 F, ² J _FF = 255.1 Hz, ³ J _FF = 16.1, 14.6 Hz, cis), –121.2 (ddd, 1 F, ² J _FF = 255.1 Hz, ³ J _FF = 18.1, 10.4 Hz, cis), –121.1 (ddd, 1 F, ² J _FF = 252.4 Hz, ³ J _FF = 18.1, 14.6 Hz, cis), –120.4 (ddd, 1 F, ² J _FF = 257.4 Hz, ³ J _FF = 17.9, 12.1 Hz, trans), –117.2 (ddd, 1 F, ² J _FF = 257.8 Hz, ³ J _FF = 17.9, 12.4 Hz, trans), –106.1 (ddd, 1 F, ² J _FF = 257.4 Hz, ³ J _FF = 16.3, 12.4 Hz, trans). IR (film): ν_max = 3252, 1699, 116 cm^–1. MS (EI): m/z (%) = 241 (2) [M]⁺, 221 (58), 201 (22), 173 (12), 112 (100), 84 (77), 55 (35). HRMS (EI⁺): m/z calcd for C₉H₁₁F₄NO₂ [M]⁺: 241.0726; found: 241.0731
• 16 CCDC-860878 (for cis-3b) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
• 17 Bootwicha T, Panichakul D, Kuhakarn C, Prabpai S, Kongsaeree P, Tuchinda P, Reutrakul V, Pohmakotr M. J. Org. Chem. 2009; 74: 3798
• 18a 1-Methyl-5-[1,1,2,2-tetrafluoro-2-(phenylthio)-ethyl]pyrrolidin-2-one (4a)To a solution of 2a (323 mg, 1 mmol) in CH₂Cl₂ (5 mL) was added dropwise triethylsilane (0.8 mL, 5 mmol) and BF₃ ·OEt₂ (377 μL, 3 mmol) under argon atmosphere. The mixture was refluxed for 2.5 h, followed by the addition of sat. NaHCO₃ solution (10 mL), and extracted with CH₂Cl₂ (3 × 25 mL). The combined extracts were washed with brine and dried over anhyd MgSO₄. Filtration followed by evaporation gave a crude product, which was purified by flash column chromatography (SiO₂, PE–EtOAc) to give the desired product 4a (282 mg, 92% yield); colorless oil; R_f = 0.26 (PE–EtOAc, 80:20). ¹H NMR (400 MHz, CDCl₃): δ = 2.15–2.34 (m, 3 H), 2.44–2.59 (m, 1 H), 2.95 (d, 3 H, J = 2.0 Hz), 4.04–4.13 (m, 1 H), 7.37–7.43 (m, 2 H), 7.44–7.51 (m, 1 H), 7.56–7.68 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 19.6–19.8 (m), 29.0, 30.9–31.0 (m), 60.8–61.4 (m), 129.3, 130.7, 137.2. ¹⁹F NMR (376 MHz, CDCl₃): δ = –120.7 (dd, 1 F, ² J _FF = 270.9 Hz, ³ J _FF = 20.1 Hz), –111.0 (d, 1 F, ² J _FF = 270.9 Hz), –86.3 (s, 2 F). IR (film): ν_max = 3063, 1707, 1577, 1108 cm^–1. MS (EI): m/z (%) = 109 (6), 98 (100), 42 (5). HRMS (ESI⁺): m/z calcd for C₁₃H₁₃F₄NNaOS [MNa]⁺: 330.05453; found: 330.05462