Sodium hydroxide-promoted reaction of 1-substituted 2,3,3-trifluoroprop-1-enyl toluene-p-sulfonates with alcohols. First efficient and convenient access to α-fluoro-β,β-dialkoxy ketones

Article abstract of DOI:10.1039/a705495e

2,3,3-Trifluoro-1-aryl- or -1-alkyl-prop-1-enyl toluene-p-sulfonates 1, readily available from 2,2,3,3-tetrafluoropropanol, react smoothly with alcohols in the presence of sodium hydroxide at ambient temperature for 1 h to afford the corresponding α-fluor

Full text of DOI:10.1039/a705495e

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Sodium hydroxide-promoted reaction of 1-substituted 2,3,3-trifluoro-
prop-1-enyl toluene-p-sulfonates with alcohols. First efficient
and convenient access to á-fluoro-â,â-dialkoxy ketones
Kazumasa Funabiki,*,† Chisato Suzuki, Seizi Takamoto, Masaki Matsui and
Katsuyoshi Shibata
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-11,
Japan
Table 1 Synthesis of α-fluoro-β,β-dialkoxyketones 2
2,3,3-Trifluoro-1-aryl- or -1-alkyl-prop-1-enyl toluene-p-
sulfonates 1, readily available from 2,2,3,3-tetrafluoro-
propanol, react smoothly with alcohols in the presence
of sodium hydroxide at ambient temperature for 1 h to
afford the corresponding á-fluoro-â,â-dialkoxy ketones 2
in good to excellent yields.
Yield a
(%) of 2
Entry Tosylate R1
R2OH
Product
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1d
1e
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
m-MeOC6H4
p-NO2C6H4
p-EtOCOC6H4
Me
MeOH
EtOH
PrOH
PriOH
MeOH
MeOH
EtOH
MeOH
2a
2b
2c
2d
2e
2f
86
78
77
Trace
95
87
82
65
There has been considerable interest in fluorinated compounds,
which often confer unique biological and physical properties.
Fluorinated aldehydes,1 ketones2 and acetals3 are among the
most important and versatile intermediates for various fluorine-
containing molecules. Fluorinated ketones have also been used
as hydrolytic enzyme inhibitors.4 Although it is of great signifi-
cance to develop effective and facile methods for the synthesis
of these compounds, little is known about the preparation of
fluorinated molecules bearing both ketone and acetal moieties,5
and the methods that have been used previously have some
serious disadvantages, such as variable yields of products,
difficulties in accessibility or handling of the reagent because
of toxicity, and low applicability of the reaction.
In our continuing studies on the chemistry and synthetic
utilization of fluorinated enol toluene-p-sulfonates (tosylates),6
we have found that a 1-substituted fluorinated enol tosylate
smoothly reacted with alkoxide via the cleavage of the enol
oxygen–sulfur bond leading to α-fluoro-β,β-dialkoxy ketones.
This communication describes a new reaction of 1-substituted
enol tosylate 1 with alcohols in the presence of sodium hydrox-
ide, which offers a novel, promising and efficient method for
the synthesis of α-fluoro-β,β-dialkoxy ketones 2 in good to
excellent yields.
2g
2h
a
Isolated yields.
69–85% yields. Tetrahydrofuran and toluene as solvent gave
2a in 77% and 68% yields, respectively. Table 1 summarizes the
results of the reaction of 1 with various alcohols in the presence
of NaOH.
Ethanol (EtOH) and propan-1-ol (PrOH) also gave good
results in this reaction to provide the corresponding α-fluoro-
β,β-dialkoxy ketones 2 in good to excellent yields (entries 2 and
3). The reaction of propan-2-ol (PriOH) was extremely slug-
gish, providing only a trace amount of product 2d, and the
starting tosylate 1a was recovered in 81% yield (entry 4). The
recovery of 1a could be attributed to the undesirable cleavage
of the enol sulfur–oxygen bond by the bulky isopropoxide ion.
Other enol tosylates 1b–e reacted smoothly with MeOH or
EtOH in the presence of 2.2 equiv. of NaOH under the same
conditions to afford the products 2e–h (entries 5, 6, 7 and 8).
It should be noted that alkyl tosylates were obtained in simi-
lar yields to the α-fluoro-β,β-dialkoxy ketones 2 in all cases.
Although exact elucidation of the reaction mechanism awaits
further investigation, the reaction seems to occur via the cleav-
age of the enol oxygen–sulfur bond with alkoxide followed by
elimination of a fluoride ion to generate α,β-difluoro-α,β-
unsaturated ketones, which are simultaneously attacked by
alcohol or alkoxide to give α-fluoro-β,β-dialkoxy ketones 2.7
In summary, the reaction of 1-substituted enol tosylate 1
with alcohols in the presence of NaOH efficiently proceeds to
give the α-fluoro-β,β-dialkoxy ketone 2, which is difficult to
prepare by other methods.
R2O
R2O
O
HF2C
F
R1
NaOH
R1
MeCN–R2OH (1:1), rt, 1 h
OTs
F
1
2
Scheme 1
Treatment of 1a (R1 = p-MeOC6H4) with 1.1 equiv. of
sodium hydroxide (NaOH) in a mixed solvent of acetonitrile
(MeCN)–methanol (MeOH) (1:1) at ambient temperature for 3
h gave the α-fluoro-β,β-dialkoxy ketone 2a in 40% yield and the
starting tosylate 1a was recovered in 47% yield. The use of 2.2
equiv. of NaOH was found to provide an 86% yield of the
product 2a, together with methyl tosylate in 73% yield (Table 1,
entry 1). Triethylamine and tetrabutylammonium fluoride were
undesirable for the reaction, whereas n-butyllithium, sodium
hydride, potassium tert-butoxide efficiently provided 2a in
Experimental
Preparation of 2-fluoro-3,3-dimethoxy-1-(4-methoxyphenyl)-
propan-1-one 2a
To a methanol (2 ml) solution of NaOH (88 mg, 2.2 mmol) was
added dropwise to an acetonitrile (2 ml) solution of the tosylate
1a (370 mg, 0.99 mmol) at 0 ЊC. After being stirred at room
temperature for 1 h under an argon atmosphere, the reaction
mixture was quenched with cold brine (30 ml), followed by
† E-Mail: kfunabik@apchem.gifu-u.ac.jp
J. Chem. Soc., Perkin Trans. 1, 1997
2679

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3 For synthetic applications of fluorinated acetals, see: T.-P. Loh and
extraction with diethyl ether (30 ml × 3), drying over Na2SO4
and concentration under vacuum. Column chromatography of
the residual oil on silica gel using 1,2-dichloroethane as an elu-
ent afforded analytically pure 2a (206 mg, 86%) as a colourless
oil, νmax(neat)/cmϪ1 1682 (CO); δH (400 MHz; CDCl3; Me4Si;
J/Hz) 3.41 (3H, s, CH3), 3.52 (3H, s, CH3), 3.89 (3H, s, CH3),
4.74 [1H, dd, J 9.76 and 5.37, (CH3O)2CH], 5.47 (1H, dd, J
49.03 and 5.37, CFH ), 6.95 and 8.01 (4H, AB q, J 9.03); δF (376
MHz; CDCl3; ext. CF3COOH; J/Hz) Ϫ119.14 (1F, dd,
J 49.03 and 9.76); m/z (EI) 242.0948 (Mϩ, 1.5%, C12H15FO4
requires 242.0955), 222 (3), 205 (6), 135 (100), 107 (8), 96 (3), 75
(77), 64 (5).
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Acknowledgements
We thank Professors H. Yamanaka and T. Ishihara of Kyoto
Institute of Technology for HRMS measurements. We are
grateful to Dr H. Muramatsu for valuable discussions.
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Paper 7/05495E
Received 29th July 1997
Accepted 1st August 1997
2680
J. Chem. Soc., Perkin Trans. 1, 1997