Sequential Deconjugative Electrophilic Fluorination/Cross-Metathesis: Toward the Synthesis of Fluoro Analogues of Biologically Active Compounds

Abstract

For the first time, a deconjugative electrophilic fluorodesilylation reaction was accomplished. γ-Silyl butenamides were treated with Selectfluor to provide α-fluoro-β,γ-unsaturated amides. Other sources of electrophilic fluorine were not efficient or gave protodesilylated side products. The electrophilic fluorodesilylation reaction was followed by a ruthenium-catalyzed cross-metathesis of the resulting functionalized allylic fluoride. The fluorodesilylation/cross-metathesis sequence is ideal for the synthesis of fluoro analogues of symbior­amide.

Key words

fluorinations - desilylations - allylic fluorides - ruthenium - ­catalysis - cross-metathesis

• References

• 1a Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
• 1b Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432
• 2a Kobayashi J, Ishibashi M, Nakamura H, Hirata Y, Yamasu T, Sasaki T, Ohizumi Y. Experientia 1988; 44: 800
• 2b Kobayashi J. J. Nat. Prod. 1989; 52: 225
• 2c Azuma H, Takao R, Niiro H, Shikata K, Tamagaki S, Tachibana T, Ogino K. J. Org. Chem. 2003; 68: 2790
• 3 Gratais, A.; BouzBouz, S. Submitted future work. In this article, we describe the synthesis of symbioramide and its isomer by using the cross-metathesis reaction of hydroxyamides.
• 4 BouzBouz S. Synlett 2011; 1888

For an example of a deconjugative electrophilic fluorination of an α,β-unsaturated imide, see:
• 5a Davis FA, Qi H. Tetrahedron Lett. 1996; 37: 4345
• 5b Davis FA, Qi H, Sundarababu G. Tetrahedron 2000; 56: 5303

For an example of photodeconjugation of vinyl fluorides, see:
• 5c Piva O. Synlett 1994; 729
• 6a Greedy B, Paris J.-M, Vidal T, Gouverneur V. Angew. Chem. Int. Ed. 2003; 42: 3291
• 6b Thibaudeau S, Gouverneur V. Org. Lett. 2003; 5: 4891
• 6c Tredwell M, Tenza K, Pacheco MC, Gouverneur V. Org. Lett. 2005; 7: 4495
• 6d Giuffredi G, Bobbio C, Gouverneur V. J. Org. Chem. 2006; 71: 5361
• 6e Purser S, Odell B, Claridge TD. W, Moore PR, Gouverneur V. Chem. Eur. J. 2006; 12: 9176
• 6f Lam Y.-h, Bobbio C, Cooper IR, Gouverneur V. Angew. Chem. Int. Ed. 2007; 46: 5106
• 6g Sawicki M, Kwok A, Tredwell M, Gouverneur V. Beilstein J. Org. Chem. 2007; 3: No. 34 ; doi: 10.1186/1860-5397-3-34
• 6h Giuffredi GT, Purser S, Sawicki M, Thompson AL, Gouverneur V. Tetrahedron: Asymmetry 2009; 20: 910
• 6i Reginato G, Mordini A, Tenti A, Valacchi M, Broguiere J. Tetrahedron: Asymmetry 2008; 19: 2882
• 6j Barrio P, Rodriguez E, Saito K, Fustero S, Akiyama T. Chem. Commun. 2015; 51: 5246
• 7 Fustero S, Simón-Fuentes A, Barrio P, Haufe G. Chem. Rev. 2015; 115: 871
• 8a Imhof S, Randl S, Blechert S. Chem. Commun. 2001; 1692
• 8b Thibaudeau S, Fuller R, Gouverneur V. Org. Biomol. Chem. 2004; 2: 1110
• 8c Teare H, Huguet F, Tredwell M, Thibaudeau S, Luthra S, Gouverneur V. ARKIVOC 2007; (x): 232
• 8d For a review, see: Hunter L, O’Hagan D. Org. Biomol. Chem. 2008; 6: 2843
• 9a Fürstner A, Thiel OR, Lehmann CW. Organometallics 2002; 21: 331
• 9b Feldman J, Murdzek JS, Davis WM, Schrock RR. Organometallics 1989; 8: 2260
• 10 Chatterjee AK, Choi T.-L, Sanders D, Grubbs RH. Angew. Chem. 2001; 40: 1277
• 11a Schwab P, France MB, Ziller JW, Grubbs RH. Angew. Chem., Int. Ed. Engl. 1995; 34: 2039
• 11b Schwab P, Grubbs RH, Ziller JW. J. Am. Chem. Soc. 1996; 118: 100
• 11c Belderrain TR, Grubbs RH. Organometallics 1997; 16: 4001
• 12a Kingsbury JS, Harrity JP. A, Bonitatebus PJ. Jr, Hoveyda AH. J. Am. Chem. Soc. 1999; 121: 791
• 12b Harrity JP. A, Visser MS, Gleason JD, Hoveyda AH. J. Am. Chem. Soc. 1997; 119: 1488
• 12c Harrity JP. A, La DS, Cefalo DR, Visser MS, Hoveyda AH. J. Am. Chem. Soc. 1998; 120: 2343
• 13a Scholl M, Ding S, Lee CW, Grubbs RH. Org. Lett. 1999; 1: 953
• 13b Chatterjee AK, Grubbs RH. Org. Lett. 1999; 1: 1751
• 13c Chatterjee AK, Morgan JP, Scholl M, Grubbs RH. J. Am. Chem. Soc. 2000; 122: 3783
• 14a Garber SB, Kingsbury JS, Gray BL, Hoveyda AH. J. Am. Chem. Soc. 2000; 122: 8168
• 14b Gessler S, Randl S, Blechert S. Tetrahedron Lett. 2000; 41: 9973
• 15 Methyl (2S)-3-{[tert-Butyl(diphenyl)silyl]oxy}-3-[(2-fluorobut-3-enoyl)amino]propanoate (4f); Typical Procedure A solution of the allyltrimethylsilane 3f (912 mg, 1.8 mmol, 1 equiv) and Selectfluor (970 mg, 2.7 mmol, 1.5 equiv) in MeCN (22 m, 0.2 M) was refluxed under argon until the reaction was complete. The reaction was quenched with sat. aq NH₄Cl, and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography [silica gel, cyclohexane–EtOAc (8:2)] to give a colorless oil; yield: 640 mg (80%). IR (neat): 3440, 2953, 2857, 1748, 1692, 1520 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.64–7.36 (m, 11 H), 6.10–5.96 (m, 1 H), 6.05–5.80 (m, 1 H), 5.58 (d, J = 17 Hz, 1 H), 5.42 (d, J = 10.8 Hz, 1 H), 5.35 (dt, J = 5.2, 1.58 Hz, 0.5 H, CH–F), 5.35 (dt, J = 5.17, 1.56 Hz, 0.5 H, CH–F), 4.70 (dt, J = 8.2, 3.02 Hz, 1 H), 4.17 (dd, J = 10.3, 2.8 Hz, 1 H), 3.92 (dd, J = 10.2, 3.1 Hz, 1 H), 3.76 (s, 3 H), 1.06 (s, 9 H). ¹⁹F NMR (282 MHz, CDCl₃): –187.2, –188.5. ¹³C NMR (75 MHz, CDCl₃): δ = 170.2, 167.9 (d, J_{C –F} = 20.4 Hz), 135.5, 135.0, 132.7, 130.9 (d, J_{C –F} = 18.5 Hz), 130.0, 127.9, 119.5 (d, J_{C –F} = 11.9 Hz), 90.7 (d, J_{C –F} = 187.4 Hz), 64.0, 53.8, 52.6, 26.7, 19.3. HRMS (ESI+): m/z [M + H]⁺ calcd for C₂₄H₃₁FNO₄Si: 444.2006; found: 444.2000.
• 16 Methyl (2S)-3-{[tert-Butyl(diphenyl)silyl]oxy}-2-{[(3E)-2-fluorooctadec-3-enoyl]amino}propanoate (5f); Typical Procedure In a flask, allylic fluoride 4f (223 mg 0.5 mmol, 1 equiv) was dissolved in anhyd CH₂Cl₂ (5 mL). Hexadec-1-ene (168 mg 0.75 mmol, 1.5 equiv) and HG(II) catalyst (22 mg, 7 mol%) were added, and the mixture was stirred at r.t. for 24 h. The solution was concentrated under vacuum, and the crude product was purified by column chromatography [silica gel, cyclohexane–EtOAc (8:2)] to give a light brown colored oil; yield: 170 mg (53%). IR (neat): 3442, 2924, 2854, 1751, 1692, 1518 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.62 (m, 4 H), 7.42 (m, 6 H), 6.05 (m, 1 H), 5.65 (m, 1 H), 5.27 and 5.19 (t, J = 7.0 Hz, 48.7 Hz, 1 H), 4.71 (m, 1 H), 4.16 (m, 1 H), 3.91 (m, 1 H), 3.78 (s, 3 H), 2.12 (m, 2 H), 1.50–1.21 (m, 24 H), 1.06 (s, 9 H), 0.90 (t, J = 6.23 Hz, 3 H). ¹⁹F NMR (282 MHz, CDCl₃): –177.58, –177.79, –178.03, –179.19. ¹³C NMR (75 MHz, CDCl₃): δ (major diastereomer) = 170.3, 168.7 (d, J_{C –F} = 21.8 Hz), 139.6 (d, J_{C –F} = 11.2 Hz), 135.6, 134.9, 132.8, 132.7, 130.0, 127.9, 122.7 (d, J_{C –F} = 18.3 Hz), 122.6 (d, J_{C –F} = 18.3 Hz), 91.2 (d, J_{C –F} = 183.7 Hz), 64.2, 52.8, 52.6, 32.4, 32.0, 29.8, 29.7, 29.5, 29.3, 29.2, 28.6, 26.8, 26.7, 22.8, 19.3, 14.2. HRMS (ESI+): m/z [M + Na]⁺ Calcd for C₃₈H₅₈NO₄FSiNa: 662.4017; found: 662.4024.