Novel entry to aryl α-fluoromethyl ketones via sodium hydroxide-induced hydrolysis of fluorinated enol tosylates

Article abstract of DOI:10.1055/s-2001-16069

Abstract: 1-Aryl-substituted 2,3,3-trifluoro-1-propenyl p-toluene-sulfonate 1 was smoothly hydrolyzed in a mixed solvent of dimethyl sulfoxide-water (1:1) in the presence of sodium hydroxide at 80 °C to afford the corresponding aryl α-monofluoromethyl ketones 2 in fair to good yields.

Full text of DOI:10.1055/s-2001-16069

1308
LETTER
Novel Entry to Aryl -Fluoromethyl Ketones via Sodium Hydroxide-Induced
Hydrolysis of Fluorinated Enol Tosylates
Kazumasa Funabiki,* Yoshitaka Fukushima, Tomonori Sugiyama, Katsuyoshi Shibata, Masaki Matsui*
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
Fax+81-58-230-1893; E-mail: kfunabik@apchem.gifu-u.ac.jp
Received 4 June 2001
Table Synthesis of Aromatic Fluoromethyl Ketones 2
Abstract: 1-Aryl-substituted 2,3,3-trifluoro-1-propenyl p-toluene-
sulfonate 1 was smoothly hydrolyzed in a mixed solvent of dimeth-
yl sulfoxide-water (1:1) in the presence of sodium hydroxide at
80 °C to afford the corresponding aryl -monofluoromethyl ketones
2 in fair to good yields.
Key words: fluorine, ketones
Organofluorine compounds now play indispensable roles
in synthetic, agricultural, and medicinal chemistry due to
their unique physical and biological properties arising
from the fluorine atom.1 Among them, -polyfluorocarbo-
nyl compounds have occupied a central position in orga-
nofluorine chemistry,2 because they serve not only as
practically applicable building blocks for the efficient
and/or stereoselective preparation of fluorine-containing
complex molecules,3 but also potent reversible inhibitors
of a variety of proteases4 or esterases.5 In addition, there
are some interesting literature sources, in which fluoroke-
tones were also utilized as an oxidation promoter.6
Many methods for the synthesis of functionalized
-monocarbonyl compounds have appeared, and some of
aAll the reaction was performed with 1 (0.5 mmol) and NaOH (1.65
them require the use of toxic or expensive starting materi- mmol) in DMSO (1 mL) and H2O (1 mL) at 80 °C.
bYields of isolated products. Values in parentheses stand for recovery
als.7 Hence, the development of the methodologies for
simple and efficient preparation of such compounds has
still been desired.
of 1.
cCarried out at room temperature.
d2,2,3-Trifluoro-1-(4-methoxyphenyl)-1-propenyl p-chlorobenzene-
sulfonate in the place of 1a was used.
In this communication, we describe the sodium hydrox-
ide-mediated hydrolysis of fluorinated enol tosylates 1,8
which provides a new simple and convenient access to
aryl -fluoromethyl ketones.
Surprisingly, the reaction of 1a at elevated temperature
(80 °C) for 1 h did not give 2-fluoro-3-hydroxy-1-(4-
methoxyphenyl)-2-propen-1-one but 2-fluoro-1-(4-meth-
oxyphenyl)ethanone (2a) in 59% yield, together with a
small amount of 1a (11%) (Entry 2). Elongation of the re-
action time (5 h) provided the fluoroketone 2a in good
yield (77%) (Entry 3).10 Treatment of 1a with 2.2 equiv of
NaOH produced 2a in 40% yield, together with the re-
maining 1a (40%) (Entry 4). Either the use of an excess
amount (5.0 equiv) of NaOH (44%) (Entry 5) or a pro-
longed reaction time (24 h) (50%) (Entry 6) reduced the
yield of 2a, probably because of further condensation of
2a leading to complex mixtures. Among the bases exam-
ined, such as NaOH, t-BuOK, and Et3N, NaOH was the
most suitable base for the reaction (Entries 3, 7, and 8).
Et3N did not effect the expected reaction at all (Entry 8).
The use of DMSO or MeCN as the solvent led to the most
satisfactory results (Entries 3 and 9). The reaction of 1a in
When 2,3,3-trifluoro-1-(4-methoxyphenyl)-1-propenyl p-
toluenesulfonate (1a) was treated with 3.3 equiv of sodi-
um hydroxide (NaOH) in a mixed solvents of DMSO-wa-
ter (H2O) (1:1) at room temperature for 1 h, the reaction
did not proceed at all, and the tosylate 1a was recovered
in quantitative yield (Scheme 1, Table, Entry 1).9
O
F2HC
F
R1
Base
F
R1
Solvent-H2O (1:1)
80 °C
OTs
1
2
Scheme 1
Synlett 2001, No. 8, 1308–1310 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Entry to Aryl -Fluoromethyl Ketones
1309
A plausible mechanism for the reaction is described in
Scheme 2.
R1
R1
H
F2HC
NaOH
Thus, enol tosylates 1 may undergo hydrolytic cleavage of
O
F
DMSO-H2O (1:1)
80 °C
F
OTs
the enol oxygen-sulfur bond to generate
-difluoro-
-
F
1
unsaturated ketones, which simultaneously react with hy-
droxide ion to give the corresponding -fluoro- -hy-
droxy- -unsaturated ketones and/or its aldehyde-
tautomers.11 Hydroxide ion may then attack them, fol-
lowed by the elimination of formic acid and/or sodium
formate, producing the aryl -monofluoromethyl ketones
2.12
OH-
R1
R1
H
H
O
OH
HO
O
F
F
In short, the hydrolysis of 1-aryl-substituted enol tosylates
1 readily proceeded in a mixed solvent of DMSO-H2O
(1:1) in the presence of NaOH at 80 °C for 5 h to afford
the corresponding aryl -monofluoromethyl ketones 2 in
fair to good yields. The present reaction can serve as a
new alternative method for the synthesis of aryl -monof-
luoromethyl ketones 2, which are significant intermedi-
ates for the synthesis of fluorinated biologically active
compounds.
H2O
base
H2O
R1
base
H
R1
H
O
ONa
NaO
O
F
F
XOH
-XOH
Acknowledgement
R1
HO
XO
We would like to thank Professors H. Yamanaka and T. Ishihara as
well as Dr. T. Konno of the Kyoto Institute of Technology for the
HRMS measurements. We are also grateful to Dr. H. Muramatsu for
his valuable discussions.
O
F
X = Na or H
-HCO2X
References and Notes
(1) Hiyama, T., Ed. Organofluorine Compounds: Chemistry and
Applications; Springer: Berlin, 2000. Ramachandran, P. V.,
Ed. Asymmetric Fluoroorganic Chemistry: Synthesis,
Applications, and Future Directions; American Chemical
Society: Washington D. C., 1999. Ojima, I.; McCarthy, J. R.;
Welch, J. T., Eds. Biomedical Frontiers of Fluorine
Chemistry; American Chemical Society: Washington D. C.,
1996. Banks, R. E.; Smarts, B. E.; Tatlow, J. C.
O
F
R1
2
Scheme 2
benzene or hexane did not take place at all, a quantitative
amount of 1a being recovered (Entries 10 and 11). The
use of 2,3,3-trifluoro-1-(4-methoxyphenyl)-1-propenyl p-
chlorobenzenesulfonate (1b) slightly decreased the yield
of 2a (Entry 12).
Organofluorine Chemistry: Principles and Commercial
Applications; Plenum: New York, 1994.
(2 For a recent review on fluoromethyl ketones, see: Bégué, J.-
P.; Bonnet-Delpon, D. Tetrahedron 1991, 47, 3207.
(3) For recent reports, see: Kuroki, Y.; Sakamaki, Y.; Iseki, K.
Org. Lett. 2001, 3, 457. Zhuang, W.; Gathergood, N.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009.
Ohkoshi, M.; Yoshida, M.; Matsuyama, H.; Iyoda, M.
Tetrahedron Lett. 2001, 42, 33. Poupart, M. -A.; Faxal, G.;
Goulet, S.; Mar, L. T. J. Org. Chem. 1999, 64, 1356. Funabiki,
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(4) Chatterjee, S.; Ator, M. A.; Bozyczko-Coyne, D.; Josef, K.;
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E.; Mallya, S.; O’Kane, T. M.; McKenna, B. A.; Siman, R.;
Mallamo, J. P. J. Med. Chem. 1997, 40, 3820, and references
cited therein.
The results of the reaction of other tosylates 1 are also
summarized in the Table. Various aromatic- or hetero-
aromatic-substituted tosylates 1a, b, c, e, f, g, and i parti-
cipated well in the reaction to produce the corresponding
-monofluoromethyl ketones 2 in moderate to good yields
(Entries 3, 13, 14, 16, 17, 18 and 20). Not only 4-nitrophe-
nyl substituted enol tosylate 1d but 2-pyridyl substituted
1h provided the ketones 2d,h in only 28-30% yields,
along with a trace amount (3-5%) of 1 (Entries 15 and 19),
which could not be improved in spite of the reaction con-
ditions being varied. Unfortunately, the corresponding ke-
tone, produced from the hydrolysis of 2,2,3-trifluoro-1-
methyl-1-propenyl tosylate (1j; R1 = Me), was not ob-
tained, probably due to the difficulty of the isolation by its
low boiling point, high volatility, and/or the decomposi-
tion of the ketone.
(5) Cregge, R. J.; Durham, S. L.; Farr, R. A.; Gallion, S. L.; Hare,
C. M.; Hoffman, R. V.; Janusz, M. J.; Kim, H. O.; Koehl, J.
R.; Mehdi, S.; Metz, W. A.; Peet, N. P.; Pelton, J. T.;
Schreuder, H. A.; Sunder, S.; Tardif, C. J. Med. Chem. 1998,
41, 2461, and references cited therein.
(6) For a recent review, see: Denmark, S. E.; Wu, Z. Synlett 1999,
847.
Synlett 2001, No. 8, 1308–1310 ISSN 0936-5214 © Thieme Stuttgart · New York

1310
K. Funabiki et al.
LETTER
(7) For recent examples, see: Shibata, N.; Suzuki, E.; Takeuchi,
Y. J. Am. Chem. Soc. 2000, 122, 10728. Hintermann, L.;
Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359. Hara, S.;
Okamoto, S.; Nakahara, M.; Fukuhara, T.; Yoneda, N. Synlett
1999, 411. Poss, A. J.; Shia, G. A. Tetrahedron Lett. 1999, 40,
2673. Davis, F. A.; Zhou, P.; Murphy, C. K.; Sundarababu, G.;
Qi, H.; Han, W.; Przeslawski, R. M.; Chen, B.-C.; Carroll, P.
J. J. Org. Chem. 1998, 63, 2273. Davis, F. A.; Kasu, P. V. N.
Tetrahedron Lett. 1998, 39, 6135.
(8) For the synthetic utilizations of tosylates 1 toward various
fluorinated molecules, see: Funabiki, K.; Ohtsuki, T.;
Ishihara, T.; Yamanaka, H. J. Chem. Soc., Perkin Trans. 1
1998, 2413. Funabiki, K.; Fukushima, Y.; Inagaki, T.; Murata,
E.; Matsui, M.; Shibata, K. Tetrahedron Lett. 1998, 39, 1913.
Funabiki, K.; Suzuki, C.; Takamoto, S.; Matsui, M.; Shibata,
K. J. Chem. Soc., Perkin Trans. 1 1997, 2679. Funabiki, K.;
Kurita, T.; Matsui, M.; Shibata, K. Chem. Lett. 1997, 739.
Funabiki, K.; Ohtake, C.; Muramatsu, H.; Matsui, M.;
Shibata, K. Synlett 1996, 444. Funabiki, K.; Ohtsuki, T.;
Ishihara, T.; Yamanaka, H. Chem. Lett. 1996, 5. Funabiki, K.;
Ohtsuki, T.; Ishihara, T.; Yamanaka, H. Chem. Lett. 1995,
239. Funabiki, K.; Ohtsuki, T.; Ishihara, T.; Yamanaka, H.
Chem. Lett. 1994, 1705.
(10) Representative Experiment. To a solution of NaOH (1.65
mmol, 0.069 g) in H2O (1 mL) was slowly added a DMSO (1
mL) solution of the tosylate 1a (0.5 mmol, 0.186 g) at room
temperature. After being stirred at 80 °C for 5 h, the entire
mixture was quenched with cold brine (100 mL), followed by
extraction with ethyl acetate (30 mL x 3), drying over
anhydrous sodium sulfate, and concentration. The residue was
chromatographed on silica gel using chloroform as the eluent,
giving 2-fluoro-1-(4-methoxyphenyl)ethanone (2a) (0.065 g,
77%, Table 1, Entry 3). The data for 2a are as follows. Mp
79.3-79.8 °C (hexane); IR (CHCl3) 1697.6 (C=O) cm–1; 1H
NMR (CDCl3) 3.87 (s, 3H), 5.48 (d, J = 47.08 Hz, 2H), 6.95
and 7.87 (AB quartet, J = 8.66 Hz, 1H); 13C NMR (CDCl3)
55.41, 83.31 (d, J = 181.12 Hz), 114.00, 126.59, 130.07,
164.11, 191.79 (d, J = 14.89 Hz); 19F NMR (CDCl3) -152.38
(t, J = 47.08 Hz, 1F); MS m/z (rel intensity) 168 (M+; 18.7),
135 (100.0), 107 (12.4), 92 (13.0), 77 (16.7); HRMS Found:
m/z 168.0577. Calcd for C9H9FO: M, 168.0587.
(11) For the reaction of
-difluoro- -unsaturated carbonyl
compounds with various oxygen nucleophiles via the
addition-elmination process, see: Ichikawa, J.; Kobayashi, M.;
Yokota, N.; Noda, Y.; Minami, T. Tetrahedron 1994, 50,
11637.
(9) Under these conditions, 2,2,3-trifluro-1-propenyl p-tosylate
(R1 = H) is smoothly hydrolyzed to produce -fluoromalon-
aldehyde sodium salt. The result of the generation of -fluoro-
malonaldehyde sodium salt and its reaction with various
carboxylic acid chlorides leading to -acyloxy- -fluoroacryl-
aldehyde has been published. Funabiki, K.; Fukushima, Y.;
Matsui, M.; Shibata, K. J. Org. Chem. 2000, 65, 606.
(12) Gómez-Sánchez, A.; Hermosín, I.; Lassaletta, J.-M.; Maya, I.
Tetrahedron 1993, 49, 1237.
Article Identifier:
1437-2096,E;2001,0,08,1308,1310,ftx,en;Y10501ST.pdf
Synlett 2001, No. 8, 1308–1310 ISSN 0936-5214 © Thieme Stuttgart · New York