Living Edition
| Editors: Jinbo Hu, Teruo Umemoto

N-Fluoropyridinium Salt Electrophilic Fluorination for Preparing Alkyl Fluorides

Living reference work entry

Latest version View entry history

DOI: https://doi.org/10.1007/978-981-10-1855-8_21-2


Fluorinated organic compounds have increasingly attracted much interest from chemists particularly in the fields of pharmaceuticals, agrochemicals, and specialty chemicals such as liquid crystals, because the fluorine atom often greatly changes the chemical and physical properties of the parent compounds owing to the characteristic features of fluorine such as the highest electronegativity (4.0), the smallest van der Waals radius (1.35 Å) next to hydrogen atom, and strong C–F bond (116 kcal/mol), which markedly differ from other halogens.

In the mid-1980s, N-fluoropyridinium salts (Fig. 1a), so-called Umemoto’s reagents, were developed as the first thermally stable, non-hygroscopic, easy-to-handle, and reactive electrophilic fluorinating reagents by Umemoto and his co-workers [1]. It was a breakthrough that the reagents made it possible to fluorinate a wide range of nucleophilic substrates using the standard glassware reactors without any special techniques. Before that,...
This is a preview of subscription content, log in to check access.


  1. 1.
    (a) T. Umemoto and K. Tomita, (1986), N-FLUOROPYRIDINIUM TRIFLATE AND ITS ANALOGS, THE FIRST STABLE 1:1 SALTS OF PYRIDINE NUCLEUS AND HALOGEN ATOM; Tetrahedron Lett. 27, 3271–3274. (b) T. Umemoto, K. Kawada, and K. Tomita, (1986), N-FLUOROPYRIDONIUM TRIFLATE AND ITS DERIVATIVES: USEFUL FLUORINATING AGENTS; Tetrahedron Lett. 27, 4465–4468. (c) T. Umemoto, S. Fukami, G. Tomizawa, K. Harasawa, K. Kawada, and K. Tomita, (1990), Power- and structure-variable fluorinating agents. The N-fluoropyridinium salt system; J. Am. Chem. Soc. 112, 8563–8575.Google Scholar
  2. 2.
    B. J. Magerlein, J. E. Pike, R. W. Jackson, G. E. Vandenberg, and F. Kagan, (1964), Reaction of Perchloryl Fluoride with Derivatives of Methyl 3,11-Diketo-4,17(20)-cis-pregnadien-21-oate. Synthesis of 4-Fluoro-and 6-Fluorohydrocortisone Acetate; J. Org. Chem. 29, 2982-2986.CrossRefGoogle Scholar
  3. 3.
    (a) R. C. Kennedy, and G. H. Cady, (1973), Reaction of carbonyl fluoride with fluorine in the presence of various fluorides as catalysts; J. Fluorine Chem. 3, 41–54. (b) D. Alker, D. H. R. Barton, R. H. Hesse, J. Lister-James, R. E. Markwell, M. M. Pechet, S. Rozen, T. Takeshita, H. T. Toh, (1980); Nouv. J. Chem. 4, 239.Google Scholar
  4. 4.
    (a) O. Lerman, Y. Tor, and S. Rozen, (1981), Acetyl hypofluorite as a taming carrier of elemental fluorine for novel electrophilic fluorination of activated aromatic rings; J. Org. Chem. 46, 4629–4631. (b) O. Lerman, Y. Tor, D. Hebel, and S. Rozen, (1984), A novel electrophilic fluorination of activated aromatic rings using acetyl hypofluorite, suitable also for introducing fluorine-18 into benzene; J. Org. Chem. 49, 806–813.Google Scholar
  5. 5.
    (a) L. V. Streng, and A. G. Streng, (1965), Formation of Xenon Difluoride from Xenon and Oxygen Difluoride or Fluorine in Pyrex Glass at Room Temperature; Inorg. Chem. 4, 1370–1371. (b) S. P. Anand, L. A. Quaterman, H. H. Hyman, K. G. Migliorese, and R. Filler, (1975), Direct ring fluorination of aryl oxygen compounds with xenon difluoride; J. Org. Chem. 40, 807–809. (c) M. Zupan, and A. Pollak, (1977), Fluorination with xenon difluoride. Stereochemistry of fluorine addition to phenyl-substituted olefins; J. Org. Chem. 42, 1559–1562.Google Scholar
  6. 6.
    W. E. Barnette, (1984), N-Fluoro-N-alkylsulfonamides: Useful Reagents for the Fluorination of Carbanions; J. Am. Chem. Soc. 106, 452-454.CrossRefGoogle Scholar
  7. 7.
    (a) S. T. Purrington, and W. A. Jones, (1983), 1-Fluoro-2-pyridone: a useful fluorinating reagent; J. Org. Chem., 48, 761–762. (b) S. T. Purrington, and W. A. Jones, (1984), Selective Fluorinations with 1-fluoro-2-pyridone; J. Fluorine Chem., 26, 43–46.Google Scholar
  8. 8.
    T. Umemoto, and G. Tomizawa, (1995), Highly Selective Fluorinating Agents: a Counteranion N-Fluoropyridinium Salt System; J. Org. Chem. 60, 6563-6570.CrossRefGoogle Scholar
  9. 9.
    T. Umemoto, M. Nagayoshi, K. Adachi, and G. Tomizawa, (1998), Synthesis, Properties, and Reactivity of N,N′-Difluorobipyridinium and Related Salts and Their Applications as Reactive and Easy-To-Handle Electrophilic Fluorinating Agents with High Effective Fluorine Content; J. Org. Chem. 63, 3379-3385.CrossRefGoogle Scholar
  10. 10.
    T. Umemoto, K. Harasawa, G. Tomizawa, K. Kawada, and K. Tomita, (1991), Synthesis and Properties of N-Fluoropyridinium Salts; Bull. Chem. Soc. Jpn., 64, 1081-1092.CrossRefGoogle Scholar
  11. 11.
    T. Umemoto, K. Tomita, and K. Kawada, (1993), N-FLUOROPYRIDINIUM TRIFLATE: AN ELECTROPHILIC FLUORINATING AGENT; Organic Syntheses, Coll. 8, 286-295.Google Scholar
  12. 12.
    Caution: The very dilute 2% F2/N2 was used for the method D with trimethylsilyl triflate. With 5% or more F2/N2 gas, a violent gas-phase reaction of the resulting volatile trimethylsilyl fluoride with F2 happened. When dimethylphenylsilyl triflate which formed non-volatile dimethylphenylsilyl fluoride was used, the method was conducted safely.Google Scholar
  13. 13.
    T. Umemoto, T. Tomizawa, (1996), Japan Kokai Tokkyo Koho, 1996-73434.Google Scholar
  14. 14.
    S. Fukami, K. Nukui, and K. Kawada, (1997), Japan Kokai Tokkyo Koho. 1997-255657.Google Scholar
  15. 15.
    A. J. Poss, M. Van Der Puy, D. Nalewajek, G. A. Shia, W. J. Wagner, and R. L. Frenette, J. Org. Chem. 1991, 56, 5962-5964.CrossRefGoogle Scholar
  16. 16.
    R. E. Banks, S. N. Mohialdin-Khaffaf, G. Sankar Lal, I. Sharif, and R. G. Syvret, J. Chem. Soc., Chem. Commun., 1992, 595–596.Google Scholar
  17. 17.
    M. Ihara, N. Taniguchi, T. Kai, K. Satoh, and K. Fukumoto, (1992), Enantioselective construction of quaternary stereogenic centers possessing a fluorine atom; J. Chem. Soc., Perkin Trans 1, 221–227.Google Scholar
  18. 18.
    C. Baudequin, J-F. Loubassou, J-C. Plaquevent, and D. Cahard, (2003), Enantioselective electrophilic fluorination: a study of the fluorine-transfer from achiral N-F reagents to chinchone alkaloids; J. Fluorine Chem., 122, 189-193.CrossRefGoogle Scholar
  19. 19.
    Jun-An. Ma, and D. Cahard, (2004), Screening of chiral catalysts for enantioselective electrophilic fluorination of β-ketoesters; J. Fluorine Chem., 125, 1357-1361.CrossRefGoogle Scholar
  20. 20.
    S. Suzuki, H. Furuno, Y. Yokoyama, and J. Inanaga, (2006), Asymmetric fluorination of β-keto esters catalyzed by chiral rare earth perfluorinated organophosphates; Tetrahedron-Asymmetry, 17, 504-507.CrossRefGoogle Scholar
  21. 21.
    T. Umemoto, and G. Tomizawa, (1986), α-Fluorination of Sulfides with N-Fluoropyridinium Triflates; Bull. Chem. Soc. Jpn., 59, 3625-3629CrossRefGoogle Scholar
  22. 22.
    S. Takeda, Y. Kaneko, H. Eto, M. Tokizawa, S. Sato, K. Yoshida, S. Namiki, and M. Ogawa, (2000), α,α-gem-Difluorination of α-(Alkylthio)acetophenone Derivatives with N-Fluoropyridinium Salts; Chem. Pharm. Bull., 48, 1097-1100.CrossRefGoogle Scholar
  23. 23.
    M. Okada, Y. Nakamura, H. Horikawa, T. Inoue, and T. Taguchi, (1997), Fluoro-lactonization of 4-alkenoic acid derivatives with N-fluoropentachloropyridinium triflate; J. Fluorine Chem. 82, 157-161.CrossRefGoogle Scholar
  24. 24.
    N. Shibata, T. Tarui, Y. Doi, and K. L. Kirk, (2001), Synthesis of Fluorogypsetin and Fluorobrevianamide E by a Novel Fluorination-Cyclization of cyclo-L-Trp-L-AAs; Angew. Chem. Int. Ed. 40, 4461-4463.CrossRefGoogle Scholar
  25. 25.
    T. Fujiwara, T. Seki, T. Yakura, and Y. Takeuchi, (2014), Useful procedures for fluorocyclization of tryptamine and tryptopho derivatives to 3a-fluoropyrrolo[2,3-b]indoles and 3a-fluorofuro[2,3-b]indoles; J. Fluorine Chem., 165, 7-13.CrossRefGoogle Scholar
  26. 26.
    J. R. Wolstenhulme, J. Rosenqvist, O. Lozano, J. Ilupeju, N. Wurz, K. M. Engle, G. W. Pidgeon, P. R. Moore, G. Sandford, and V. Gouverneur, (2013), Asymmetric Electrophilic Fluorocyclization with Carbon Nucleophiles; Angew. Chem. Int. Ed. 52, 9796-9800.CrossRefGoogle Scholar
  27. 27.
    P. Y. Toullec, I. Devillers, R. Frantz, and A. Togni, (2004), Relative Electrophilic Fluorinating Power as Assayed by Competitive Catalytic Halogenation Reactions; Helv. Chim. Acta., 87, 2706-2708.CrossRefGoogle Scholar

Authors and Affiliations

  1. 1.Life Sciences DivisionMitsubishi CorporationTokyoJapan