LETTER
Efficient Synthesis of 4-Fluorocyclohexa-2,5-dienone Derivatives
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(5) Banks, R.E.; Mohialdin-Khaffaf, S.N.; Lal, S.G.; Sharif, I.;
Syvret, R.G. J. Chem. Soc., Chem. Commun. 1992, 595.
(6) a) Banks, R.E. J. Fluorine Chem. 1998, 87, 1; b) Stavber, S.;
Zupan, M.Tetrahedron Lett. 1996, 37, 3591; c) Umemoto, T.;
Nagayoshi, M. Bull. Chem. Soc. Jpn. 1996, 69, 2287.
(7) Gilicinski, A.G.; Pez, G.P.; Syvret, R.G.; Lal, G.S. J. Fluorine
Chem. 1992, 59, 157.
(8) a) Stavber, S.; Zupan, M. Tetrahedron Lett. 1993, 34, 4355;
b) Stavber, S.; Koir, I.; Zupan, M. J. Org. Chem. 1997, 62,
4916; c) Stavber, S.; Zupan, M. J. Chem. Soc., Chem.
Commun. 1994, 149; d) Stavber, S.; Koren, Z.; Zupan, M.
Synlett 1994, 265.
Encouraged by the above mentioned results, we applied
the reaction to a series of estrogen steroids (2j-o) and
found that estrone (2j) as well as its methyl ether deriva-
tive could be almost quantitatively converted to 10b-fluo-
ro-1,4-estradiene-3,17-dione (3j). 17a-Ethynylestradiol
(2l) and its methyl ether analogue were also converted to
10b-fluoro-3-oxo-1,4-estradien-17a-ethynyl-17b-ol (3l)
in very high yield, as well as b-estradiol (2k) to 10b-fluo-
ro-3-oxo-1,4-estradien-17b-ol (3k) and estriol (2o) to
10b-fluoro-3-oxo-1,4-estradien-16a,17b-diol18 (3o). In
all cases only trace amounts of aromatic ring fluorinated
products were detected in the crude reaction mixtures.
The opposite regioselectivity of fluorofunctionalisation of
estrogen steroids on the other hand was observed when N-
fluoro pyridinium salts were used as the fluorinating re-
agent, and only 2-fluoro- and 4-fluoro estrogen deriva-
tives were formed.19, 20
(9) a) Stavber, S.; Zupan, M. Synlett 1996, 693; b) Zupan, M.;
Iskra, J.; Stavber, S. Bull. Chem. Soc. Jpn. 1995, 68, 1655.
(10) SelectfluorTM F-TEDA-BF4 is produced and commercialised
by Air Products and Chemicals, Inc.
(11) AccufluorTM NFTh is produced and commercialised by
AlliedSignals, Inc. We are indebted to Dr. George Shia for
providing us with free samples of the reagent.
(12) The following reaction procedure is typical. To a solution of 5
mmol of substrate (entry 1-15 , Table) in MeCN (50 ml) 1.77
g (5 mmol) F-TEDA BF4 or 1.6 g (5 mmol) NFTh was added
and the reaction mixture stirred at room or elevated
The more or less efficient synthesis of 4-fluorocylohexa-
2,5-dienones was previously reported to have been carried
out using electrophilic fluorinating reagents (trifluorome-
thylhypofluorite CF3OF,21 perchloryl fluoride ClO3F,22 N-
fluoroperfluoroalkylsulfonylimides,23 fluorine24) or HF in
combination with oxidants25, 26 as the source of fluorine
atom. The use of these very reactive and toxic reagents re-
quires special laboratory equipment and stringent safety
precautions. The simple experimental protocol also ac-
ceptable to non-specialised organic laboratories, in addi-
tion to a high level of regioselectivity and efficiency of the
fluorination of a comprehensive range of phenols with F-
TEDA BF4 or NFTh as reagents are the advantages that
make the synthetic method presented a very convenient
procedure for the preparation of 4-fluorocyclohexa-2,5-
dienones. Mechanistic elucidation of these reactions in or-
der to formulate some general conclusions concerning the
reactions of N-fluoro reagents with phenols are in
progress, and will be the subject of a future publication.
temperature (Table) until KI starch paper showed the
consumption of the fluorinating reagent. The reaction solvent
was removed under reduced pressure and the crude reaction
mixture dissolved in CH2Cl2, insoluble material filtered off
and the solution, except in the case of steroids (entry 10-15),
washed with 10% aqueous KOH (50 ml) in order to remove
traces of starting material or unwanted ortho fluorinated
phenols. The organic layer was then washed with water, dried
over Na2SO4 and the solvent evaporated. The isolated crude
reaction mixtures were analysed by 1H (at 60 MHz, TMS as
standard) and 19F nmr (at 56.4 MHz, CCl3F as standard) and
TLC, and pure products were obtained after flash
chromatography over SiO2. The spectroscopic data for the
known compounds 3a,24 3f,25 3g,26 3h26 and 3j-n22 were in
agreement with the literature, while unknown products were
fully characterised as listed below.
(13) (±)3,4-Dimethyl-4-fluorocyclohexa-2,5-dienone (3c):
hygroscopic liquid compound; 1H NMR: d =1.60(d,J=21.6Hz,
3H), 2.1(s, 3H), 6.0(s, 1H), 6.1(d, J=10 Hz, 1H), 6.9(dd, J=10
Hz, J=7.5 Hz); 19F NMR: d = -153.8(dq, J=21.6 Hz, J=7.5
Hz); IR(neat): nCO = 1670 cm-1; MS: m/z: 140 (M+, 48%),
125(23), 112(48), 97(100), 91(25), 77(25); HRMS: calcd for
C8H9FO: 140.0637, found: 140.0633. anal.calcd for C8H9FO .
1/4H2O: C 66.42, H 6.62; found: C 66.42, H 6.47.
Acknowledgement
The authors are grateful to the Ministry of Science and Technology
of the Republic of Slovenia for financial support, and to T. Stipano-
viè and Prof. B. Stanovnik for elemental combustion analysis.
(14) 4-Fluoro-4-isopropylcyclohexa-2,5-dienone (3b):
hygroscopic liquid compound; 1H NMR : d = 1.05(d, J=9 Hz,
6H), 2.10(m, 1H), 6.20(d, J=12 Hz, 2H), 6.95(dd, J=12 Hz,
J=6 Hz, 2H); 19F NMR : d = -153.3(m); IR(neat): nCO = 1670
cm-1; MS: m/z: 154 (M+, 6%), 139(20), 112(100); HRMS:
calcd for C9H11FO 154.0794, found 154.0800; anal.calcd for
C9H11FO . 1/3H2O: C 67.48, H 7.34; found: C 67.56, H 7.15.
(15) (±)4-Fluoro-4-isopropyl-3-methylcyclohexa-2,5-dienone
(3d): hygroscopic liquid compound; 1H NMR: d = 0.7(d, J=10
Hz, 3H), 1.17(d, J=10 Hz, 3H), 2.0(s, 3H), 2.3(m, 1H), 6.13(s,
References and Notes
(1) a) Banks, R.E.; Smart, B.E.; Tatlow, J.C., eds. Organofluorine
Chemistry. Principles and Commercial Applications, Plenum
Press: New York 1994; b) Hudlicky, M.; Pavlath, A.E. eds.
Chemistry of Organic Fluorine Compounds II. A Critical
Review, ACS Monograph 187; ACS, Washington DC, 1995.
(2) a) Filler, R.; Kobayashi, Y.; Yagupolskii, L.M., eds.
Organofluorine Compounds in Medicinal Chemistry and
Biomedicinal Application, Elsevier: Amsterdam, 1993;
b) Resnati, G.; Soloshnok, V.A., eds. Fluoroorganic
Chemistry: Synthetic Challenges and Biomedicinal Rewards,
Tetrahedron Symposia-in-Print No. 58, Tetrahedron, 1996,
52, 1-330.
1H), 6.3(d, J=10 Hz, 1H), 6.93(dd, J=10 Hz, J=10Hz); 19
F
NMR: d = -160.0 (dd, J=10 Hz, J=10 Hz). IR(neat): nCO = 1680
cm-1. MS m/z: 168 (M+ , 2%), 153(1), 126 (100), 125(25),
97(10); HRMS: calcd for C10H13FO: 168.0950; found:
168.0953; anal. calcd. for C10H13FO . 1/2H2O: C 67.78, H
7.96; found: C 68.02, H 7.28.
(16) 4-fluoro-3,4,5-trimethylcyclohexa-2,5-dienone (3i):
hygroscopic liquid compound; 1H NMR: d = 1.44(d, J=21 Hz,
3H), 2.1(s, 6H), 5.97(s, 2H); 19F NMR: d = -160.5 (q, J=21
Hz); IR: nCO = 1678 cm-1; MS m/z: 154 (M+, 42%), 139(25),
(3) Baasner, B.; Hagemann, H.; Tatlow, J.C., eds. Methods of
Organic Chemistry (Houben-Weyl) Vol 10a: Organo-
Fluorine Compounds. Thieme: New York 1999.
(4) Lal, G.S.; Pez, G.P.; Syvret, R.G. Chem. Rev. 1996, 96, 1737.
Synlett 1999, No. 9, 1375–1378 ISSN 0936-5214 © Thieme Stuttgart · New York