Friedel-Crafts Cyclization of 1,1-Difluoroalk-1-enes: Synthesis of Benzene-Fused Cyclic Ketones via α-Fluorocarbocations

Abstract

1,1-Difluoroalk-1-enes bearing a phenyl group at the C-3, -4, or -5 position, readily obtained from 2,2,2-trifluoroethyl p-toluenesulfonate, are treated with FSO₃H·SbF₅ to undergo Friedel-Crafts cyclization in (CF₃)₂CHOH. The cyclization takes place via α-fluorocarbocations, followed by spontaneous hydrolysis of the C-F bond to afford bicyclic ketones including a five, six, or seven-membered ring in good yield.

Key words

Friedel-Crafts cyclization - difluoroalkene - bicyclic ketone - α-fluorocarbocation - fluoroalcohol solvent

References

• 1 Smart BE. In Organofluorine Chemistry, Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum Press; New York: 1994. 
• 2a Tian F. Battiste MA. Dolbier WR. Org. Lett.  1999,  1:  193 
• 2b McAllister M. Tidwell TT. Peterson MR. Csizmadia IG. J. Org. Chem.  1991,  56:  575 
• 2c Kispert LD. Pittman CU. Allison DL. Patterson TB. Gilbert CW. Hains CF. Prather J. J. Am. Chem. Soc.  1972,  94:  5979 
• 2d For a review on fluorinated carbocations, see: Allen AD. Tidwell TT. Advances in Carbocation Chemistry   Vol. 1:  Jai Press; Grennwich Conn.: 1989.  p.1 
• For reports where the effect of fluorine on carbocations was advantageously applied in organic synthesis, see:
• 3a Johnson WS. Daub GW. Lyle TA. Niwa M. J. Am. Chem. Soc.  1980,  102:  7800 
• 3b Johnson WS. Lyle TA. Daub GW. J. Org. Chem.  1982,  47:  161 
• 3c Fish PV. Johnson WS. Jones GS. Tham FS. Kullnig RK. J. Org. Chem.  1994,  59:  6150 ; and references cited therein
• 3d Morikawa T. Kumadaki I. Shiro M. Chem. Pharm. Bull.  1985,  33:  5144 
• For recent reports on the allylic rearrangement of fluoroallylalcohol derivatives, see:
• 4a Funabiki K. Sawa K. Shibata K. Matsui M. Synlett  2002,  1134 
• 4b Ichikawa J. Fujiwara M. Miyazaki S. Ikemoto M. Okauchi T. Minami T. Org. Lett.  2001,  3:  2345 ; and references cited therein
• 4c Yamazaki T. Hiraoka S. Sakamoto H. Kitazume T. Org. Lett.  2001,  3:  743 
• 5a Ichikawa J. Miyazaki S. Fujiwara M. Minami T. J. Org. Chem.  1995,  60:  2320 
• 5b Ichikawa J. Fujiwara M. Okauchi T. Minami T. Synlett  1998,  927 
• For reports on the Friedel-Crafts reaction of fluorinated allylic cations, see:
• 6a Gyenes F. Purrington ST. Liu Y.-S. J. Org. Chem.  1999,  64:  1366 
• 6b Kobayashi Y. Nagai T. Kumadaki I. Takahashi M. Yamauchi T. Chem. Pharm. Bull.  1984,  32:  4382 
• 7 Ichikawa J. J. Fluorine Chem.  2000,  105:  257 
• 8 For reports on the protonation of 1,1-difluoroethylene with FSO₃H·SbF₅ to give 1,1,1-trifluoroethane or 1,1-difluoro-ethyl fluorosulfonate, see: Olah GA. Mo YK. J. Org. Chem.  1972,  37:  1028 
• 9 Bégué JP. Bonnet-Delpon D. Crousse B. Synlett  2004,  18 
• For recent reports on the cationic reactions conducted in HFIP, see:
• 10a Ohwada A. Nara S. Sakamoto T. Kikugawa Y. J. Chem. Soc., Perkin Trans. 1  2001,  3064 
• 10b Bjurling E. Björkman A. Andersson C.-M. Organometallics  2001,  20:  990 
• 11a For reports on the synthesis of benzene-fused cyclic ketones, see: Gagnier SV. Larock RC. J. Am. Chem. Soc.  2003,  125:  4804 
• 11b See also: Cui D.-M. Zhang C. Kawamura M. Shimada S. Tetrahedron Lett.  2004,  1741 ; and references cited therein
• 11c For a review on the intramolecular aromatic Friedel-Crafts Reaction, see: Heaney H. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergamon Press; Oxford: 1991.  Chap. 3.3.
• For recent examples, see:
• 12a Vukics K. Fodor T. Fischer J. Fellegvári I. Lévai S. Org. Process Res. Dev.  2002,  6:  82 
• 12b Suh Y.-G. Shin D.-Y. Min K.-K. Hyun S.-S. Jung J.-K. Seo S.-Y. Chem. Commun.  2000,  1203 
• 12c Deshpande MN. Cain MH. Patel SR. Singam PR. Brown D. Gupta A. Barkalow J. Callen G. Patel K. Koops R. Chorghade M. Foote H. Pariza R. Org. Process Res. Dev.  1998,  2:  351 
• 12d Geen GR. Mann IS. Mullane MV. McKillop A. Tetrahedron  1998,  54:  9875 
• 12e Sugimoto H. Iimura Y. Yamanishi Y. Yamatsu K. J. Med. Chem.  1995,  38:  4821 
• 15 For discussions on the ability of halogens to stabilize carbocations, see: Christe KO. Zhang X. Bau R. Olah GA. Prakash GKS. Sheehy JA. J. Am. Chem. Soc.  2000,  122:  481 ; and references cited therein
• The spectroscopic data (¹H, ¹³C NMR and IR) of 2a,b,d are in agreement with the reported data:
• 16a Pouchert CJ. Behnke J. The Aldrich Library of ¹³ C and ¹ H FT NMR Spectra   Aldrich Chemical Company, Inc.; Milwaukee: 1992. 
• 16b Pouchert CJ. The Aldrich Library of Infrared Spectra 3rd ed.   Aldrich Chemical Company, Inc.; Milwaukee: 1981. 

13

The configuration of 1h was assigned by ¹H NMR measurement. The ¹H NMR spectrum for the major isomer of 1h exhibits a large geminal coupling constant (J _gem = 13.4 Hz) between the protons H_ax and H_eq at C-3. H_ax is coupled to the C-2 and C-4 protons with coupling constant values of 11.3 Hz and 4.6 Hz, which are consistent with typical axial-axial and axial-equatorial values, respectively. In the ¹H NMR spectrum of the minor isomer of 1h, two large axial-axial coupling constants are observed between the C-3 axial proton and the C-2 proton and between the C-3 axial proton and the C-4 proton (J ₃₂ = 14.0 Hz, J ₃₄ = 11.9 Hz). Moreover, the observed NOEs between the C-2 axial proton and the methyl proton of the major isomer and between the C-2 axial proton and the C-4 axial proton of the minor isomer support this assignment. Stereochemistry was assigned for 2g on the basis of the proton coupling constants in a similar manner.

14

Vinyl fluoride 14 (X = F) was not detected by ¹⁹F NMR measurement of the reaction mixture.