Electrolytic partial fluorination of organic compounds. 30.1 Drastic improvement of anodic monofluorination of 2-substituted 1,3-oxathiolan-5- ones using the novel fluorine source Et4NF·4HF

Article abstract of DOI:10.1021/jo981437g

The highly regioselective anodic monofluorination of 2-substituted 1,3- oxathiolan-5-ones was successfully carried out using a novel supporting electrolyte, Et₄NF·4HF, while use of a conventional supporting electrolyte, Et₃N·3HF, resulted in no formation or extremely low yields of the fluorinated products.

Full text of DOI:10.1021/jo981437g

J . Org. Chem. 1999, 64, 133-137
133
Electr olytic P a r tia l F lu or in a tion of Or ga n ic Com p ou n d s. 30.1
Dr a stic Im p r ovem en t of An od ic Mon oflu or in a tion of 2-Su bstitu ted
1,3-Oxa th iola n -5-on es Usin g th e Novel F lu or in e Sou r ce Et4NF ‚4HF
Seiichiro Higashiya,† Satoru Narizuka,† Akinori Konno,†,§ Tomoko Maeda,†
Kunitaka Momota,‡ and Toshio Fuchigami*,†
Department of Electronic Chemistry, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku,
Yokohama 226-8502, J apan, and Department of Research and Development, Morita Chemical Industries
Co., Ltd., Higashi-mikuni, Yodogawa-ku, Osaka 532-0002, J apan.
Received J uly 22, 1998
The highly regioselective anodic monofluorination of 2-substituted 1,3-oxathiolan-5-ones was
successfully carried out using a novel supporting electrolyte, Et4NF‚4HF, while use of a conventional
supporting electrolyte, Et3N‚3HF, resulted in no formation or extremely low yields of the fluorinated
products.
Ta ble 1. In h ibitor y Activity of Hu m a n Typ e-II Secr etor y
P h osp h olip a se A2 by 2-Su bstitu ted 1,3-Oxa th iola n -5-on es
1 a n d Ma n oa lid e
In tr od u ction
The displacement of hydrogen atoms of organic com-
pounds by fluorine atoms sometimes significantly changes
their physical, chemical, biological, and pharmacological
properties.2-5 Recently, electrochemical oxidative fluori-
nation (anodic fluorination) has attracted much attention
as an ideal method for direct fluorination since it can be
performed in one step under safe and mild conditions.5-10
On the other hand, we recently found that 1,3-oxa-
thiolan-5-one derivatives 1 which have a heterocyclic O,S-
acetal ring system, possessed inhibitory activities toward
human type-II (nonpancreatic) secretory phospholipase
A2 (PLA2, EC 3.1.1.4)11 (Table 1). These activities were
comparable with the well-known PLA2 inhibitor, mano-
alide.12,13
substrate
1a
1b
1c
R
IC50/µg/mL
Et
n-Pr
i-Pr
1.9
0.9
0.9
m a n oa lid e
0.14-0.34
dins, or the platelet-activating factor.14 Therefore, the
PLA2 isozyme family plays crucial roles in regulating
diverse cellular responses, especially inflammation. At
the present time, to elucidate how these isozymes are
sharing the functions and to develop the biochemical,
medical, and pharmacological applications, the synthesis
and the development of these new compounds, which
strongly and selectively inhibit or enhance one of the
PLA2 isozymes, are strongly desired.15
PLA2 is an enzyme family which generates, for ex-
ample, a precursors of eicosanoids, such as prostaglan-
† Tokyo Institute of Technology.
‡ Morita Chemical Industries Co., Ltd.
§ Present address: Faculty of Engineering, Shizuoka University,
J ohoku, Hamamatsu, Shizuoka 432-8561, J apan.
(1) For part 29, see: Dawood, K. M.; Higashiya, S.; Hou, Y.;
Fuchigami, T. J . Fluorine Chem. In press.
(2) Biomedicinal Aspects of Fluorine Chemistry; Filler, R.; Koba-
yashi, Y., Eds.; Kodansha & Elsevier Biomedicinal: Tokyo, 1982.
(3) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chem-
istry; Wiley: New York, 1991.
(4) Selective Fluorination of Organic and Bioorganic Chemistry;
Welch, J . T., Ed.; American Chemical Society: Washington, DC, 1991.
(5) Silverster, M. J . Aldrichim. Acta 1991, 24, 31-38.
(6) Childs, W. V.; Christensen, L.; Klink, F. W.; Kolpin, C. F. In
Organic Electrochemistry, 3rd ed.; Lund, H., Baizer, M. M., Eds.;
Marcel Dekker: New York, 1991; Chapter 26, pp 1103-1127.
(7) Fuchigami, T. Rev. Heteroatom. Chem. 1994, 10, 155-172.
(8) Fuchigami, T.; Konno, A. J . Synth. Org. Chem. J pn. 1997, 55,
301-312.
(9) Fuchigami, T.; Nishiyama, S. DENKI KAGAKU (J . Electrochem.
Soc. J pn.) 1997, 65, 626-630.
(10) Electrochemistry in the Preparation of Fluorine and Its Com-
pounds; Childs, W. V., Fuchigami, T., Eds.; The Electrochemical
Society, Inc.: Pennington, 1997.
(11) Fuchigami, T.; Narizuka, S. Unpublished results. The inhibitory
activity was assayed with 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-
ethanolamine as a substrate, according to the method described by
Tojo et al. with a slight modification: Tojo, H.; Ono, T.; Okamoto, M.
Methods Enzymol. 1991, 197, 390.
On the basis of these facts, we tried to incorporate
fluorine atom into 1 in order to prepare more potent and
more selective inhibitors by means of partial anodic
fluorination.
Some examples of the partial anodic fluorination of
heterocyclic compounds have been reported,16-20 but the
yields and selectivity of the products were generally low
due to the low nucleophilicity of the fluoride ions and
passivation of the anodes.6 Therefore, it is important to
find excellent supporting electrolytes, fluoride salts,
(14) Murakami, M.; Nakatani, Y.; Atsumi, G.; Inoue, K.; Kudo, I.
Crit. Rev. Immunol. 1997, 17, 225-283.
(15) Glaser, K. B. Adv. Pharmacol. (San Diego) 1995, 6, 31-66.
(16) Gambaretto, J . R.; Napoli, M.; Franccaro, C.; Conk, L. J .
Fluorine Chem. 1982, 19, 427-436.
(17) Ballinger, J . R.; Teare, F. W.; Bowen, B. M.; Garnett, E. S.
Electrochim. Acta 1985, 30, 1075-1077.
(18) Makino, K.; Yoshioka, H. J . Fluorine Chem. 1988, 39, 435-
(12) J acobson, P. B.; Marshal, L. A.; Sung, A. Biochem. Pharmacol.
1990, 39, 1557-1564.
(13) Potts, B. C. M.; Faulkner, D. J . J . Nat. Prod. 1992, 55, 1701-
1717.
440.
(19) Meurs, J . H. H.; Eilenberg, W. Tetrahedron 1991, 47, 705-714.
(20) Sono, M.; Toyoda, N.; Shizuri, Y.; Tori, M. Tetrahedron Lett.
1994, 35, 9237-9238.
10.1021/jo981437g CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

134 J . Org. Chem., Vol. 64, No. 1, 1999
Higashiya et al.
Ta ble 2. Oxid a tion P ea k P oten tia ls (Ep ox) of
Sch em e 1
2-Su bstitu ted 1,3-Oxa th iola n -5-on es 1a
1
R
Epox/V vs SSCE
Ta ble 3. An od ic Mon oflu or in a tion of 2-Su bstitu ted
1,3-Oxa th iola n -5-on es 1
1a
1b
1c
1d
1e
Et
2.34
2.32
2.44
1.88
2.17
n-Pr
i-Pr
Ph
applied
supporting potential/ electricity/
yield/
%
cis/
b
1
electrolyte
1a Et3N‚3HF
1a Et4NF‚4HF 2.1
1b Et3N‚3HF
2.2-2.3c
1b Et4NF‚4HF 2.1
1c Et3N‚3HF
2.2c
1c Et4NF‚4HF 2.1
1d Et3N‚3HF
1.6c
1d Et4NF‚4HF 2.0
Va
2.3c
F mol-1
product
transb
p-CN-C6H4
3.4
2.6
3.6
2.2
2.2
2.4
4.0
2.3
3.4
3.2
2a
0
86
5.4
67
0
78
0
70
0
Pt electrodes; 0.1 M NaClO4/MeCN; sweep rate, 100 mv s-1
.
a
47:53
d
45:55
2b
2c
2d
2e
which have high nucleophilicity, and do not cause pas-
sivation in order to achieve efficient partial anodic
fluorination.
43:57
45:55
39:61
1e Et3N‚3HF
2.2c
Resu lts a n d Discu ssion
1e Et4NF‚4HF 2.0c
66
Oxidation P oten tials of 2-Su bstitu ted 1,3-Oxath io-
la n -5-on es. The oxidation potentials (anodic peak po-
tentials) of 2-substituted 1,3-oxathiolan-5-ones 1 were
measured by cyclic voltammetry, using a divided cell with
platinum electrodes in 0.1 M NaClO4/anhydrous aceto-
nitrile. These heterocycles exhibited irreversible anodic
waves. The first peak potentials, Epox, are summarized
in Table 2.
a
b
Versus Ag/Ag+ (0.01 M). Determined by 19F NMR spectra.
c Pulse electrolysis was employed. Not estimated due to the low
yield of 2b.
d
to complete the electrolytic reaction because of the
passivation, and this lead to the decomposition of the
products during the electrolysis.
We recently reported the dehydrofluorination of di-
fluorinated flavones by the free Et3N in Et3N‚3HF during
the anodic fluorination of flavones.21 We had confirmed
that this equilibratingly existing free Et3N28 was one of
the reasons for the low yields, because the free Et3N
caused the passivation of the anode. Therefore, we tried
to find another excellent supporting electrolyte/fluoride
source which did not cause the passivation.
Eventually, we found that a novel type of fluoride
supporting electrolyte, Et4NF‚4HF, drastically improved
the reaction. This electrolyte is one of the recently
developed new class as of fluoride supporting electrolytes
represented by R4NF‚mHF (R ) Me, Et, Pr; m > 3.5),
and one of the authors (K.M.) has achieved the partial
anodic fluorination of benzene, halobenzenes, and tri-
fluoromethylbenzene using these fluoride salts without
solvent.29-31 These fluoride salts are nonviscous liquids
and have a high electrolytic conductivity together with
a high electrochemical stability.29
We then used Et4NF‚4HF as a fluoride supporting
electrolyte and the anodic fluorination of 1 regioselec-
tively proceeded in high yields with good current efficien-
cies. In these cases, no passivation took place except for
1e. In the case of 1e, a slight passivation was observed;
therefore, the pulse electrolysis technique was used so
that the anodic potential was maintained at the oxidizing
potential for 45 s then at 0 V for 5 s. The electrolyzing
time was also significantly reduced (from ca. 12 h to 2-4
h). Although one of us (K.M.) used this electrolyte without
solvent for selective fluorination,29-31 we obtained much
better yields and current efficiencies by using the elec-
These heterocyclic compounds were oxidized at 1.9-
2.4 V vs a sodium saturated calomel electrode (SSCE).
The compounds which have aryl substituents such as Ph
ox
(1d ) or p-CN-C6H4 (1e) showed a lower Ep than 1a -c
which have alkyl substituents.
An od ic Mon oflu or in a tion of 2-Su bstitu ted 1,3-
Oxa th iola n -5-on es. In our previous studies on the
partial anodic fluorination of heteroatom compounds
including heterocycles, we found that Et3N‚3HF was a
suitable supporting electrolyte and fluorine source for the
selective anodic fluorination;7-9,21-27 consequently, we
initially used Et3N‚3HF. The anodic monofluorination of
1 was carried out at a platinum anode in an undivided
cell. However, we obtained the fluorinated products 2 in
negligible yields based on the 19F NMR measurements
in all cases, and no isolable product was formed, although
the starting materials 1 were completely consumed.
Severe passivation of the anode due to nonconductive film
formation on the anode was observed during the elec-
trolysis. To prevent the passivation to some extent, we
used the pulse electrolysis technique6 so that the anodic
potential was maintained at the oxidizing potential for
90 s then at 0 V for 10 s, but the yields were not improved
(Scheme 1 and Table 3).
The substrates 1 were almost stable in this electrolytic
solution, but the products 2 were not sufficiently stable
enough and gradually decomposed. It took a long time
(21) Hou, Y.; Higashiya, S.; Fuchigami, T. Synlett 1998, 973-973.
(22) Fuchigami, T.; Narizuka, S.; Konno, A. J . Org. Chem. 1992,
57, 3755-3757.
(23) Konno, A.; Naito, W.; Fuchigami, T. Tetrahedron Lett. 1992,
33, 7017-7020.
(24) Narizuka, S.; Konno, A.; Matsuyama, H.; Fuchigami, T. DENKI
KAGAKU (J . Electrochem. Soc. J pn.) 1993, 61, 868-869.
(25) Narizuka, S.; Fuchigami, T. J . Org. Chem. 1993, 58, 4200-
4201.
(26) Narizuka, S.; Fuchigami, T. Bioorg. Med. Chem. Lett. 1995, 5,
1293-1294.
(27) Fuchigami, T.; Narizuka, S.; Konno, A.; Momota, K. Electro-
chim. Acta 1998, 43, 1985-1989.
(28) Chen, S.-Q.; Hatakeyama, T.; Fukahara, T.; Hara, S.; Yoneda,
N. Electrochim. Acta 1997, 42, 1951-1960.
(29) Momota, K.; Morita, M.; Matsuda, Y. Electrochim. Acta 1993,
38, 1123-1130.
(30) Momota, K.; Kato, K.; Morita, M.; Matsuda, Y. Electrochim. Acta
1994, 40, 681-690.
(31) Momota, K.; Horio, H.; Kato, K.; Morita, M.; Matsuda, Y.
Electrochim. Acta 1995, 40, 233-240.

Partial Fluorination of Organic Compounds. 30
J . Org. Chem., Vol. 64, No. 1, 1999 135
F igu r e 1. Linear sweep voltammogram of 1: electrodes, Pt plates (2 × 3 cm2); solvent, CH3CN; sweep rate, 50 mV s-1; electrolytic
fluoride salt, (A) Et3N‚3HF (0.37 M), (B) Et4NF‚4HF (0.34 M); (a) without substrate; (b) with 1e (0.1 M); (c) with 1d (0.1 M); (d)
with 1c (0.1 M).
Sch em e 2
trolyte diluted with acetonitrile (in a 0.34 M solution)
compared with the use of the electrolyte without any
solvents.
We next investigated the properties of these two
electrolytic fluoride salts by measuring the linear sweep
voltammograms using these two electrolytic fluoride salts
with or without the substrate 1 (Figure 1).
While the conventional electrolytic system, Et3N‚3HF/
MeCN (Figure 1A, curve a) began to discharge around
1.5 V (2 V vs SSCE), presumably due to the free Et3N28
containing in Et3N‚3HF, the new electrolytic solution,
Et4NF‚4HF/MeCN (Figure 1B, curve a) was highly stable
against anodic oxidation up to ca. 2.5 V vs Ag/AgNO3 (3
V vs SSCE). Current densities with substrates were also
higher in the case of Et4NF‚4HF than that of Et3N‚3HF.
These observations explain the higher yields and current
efficiencies when Et4NF‚4HF is used.
We proposed that the anodic fluorination of 1 pro-
ceeded through the electrochemical-chemical-electro-
chemical-chemical (ECEC) mechanism described in
Scheme 2 as previously reported.8,9,32 Fluoride ions play
important roles in this reaction. Namely, fluoride ions
are not only a fluorine source but also react with the first
radical cation intermediate A at the sulfur atom and then
promote the second oxidation to the fluorosulfonium
cation intermediate B. From the viewpoint of the product
2, the fluorination regioselectively took place at the
4-position. Especially, in the case of 2-aryl-substituted
1,3-oxathiolan-5-ones, 1d and 1e, benzylic fluorination
was not observed at all, although in general anodic
benzylic substitution easily takes place. Even though the
cationic intermediate C′ seemed to be thermodynamically
more stable, fluorination proceeded through the less
stable intermediates C. This selectivity can be explained
in terms of the higher acidity and higher deprotonation
ability of the H4 proton compared to the H2 in the
intermediate B. The deprotonation ability of H4 is more
enhanced by the electron-withdrawing carbonyl group.
After this kinetically controlled deprotonation of H,4 the
next fluorination selectively takes place at the 4-position
via a Pummerer-type mechanism.33-35 Another possibility
is thermodynamically and stereochemically controlled
fluoride ion attack to the less hindered C4 carbon of
intermediate C, even though intermediate C′ seems to
be much more stable cation because the C2 cation
(33) Fuchigami, T.; Shimojo, M.; Konno, A.; Nakagawa, K. J . Org.
Chem. 1990, 55, 6074-6075.
(34) Fuchigami, T.; Konno, A.; Nakagawa, K.; Shimojo, M. J . Org.
Chem. 1994, 59, 5937-5941.
(32) Konno, A.; Nakagawa, K.; Fuchigami, T. J . Chem. Soc. Chem.
Commun. 1991, 1027-1029.
(35) Fuchigami, T.; Shimojo, M.; Konno, A. J . Org. Chem. 1995, 60,
3459-3464.

136 J . Org. Chem., Vol. 64, No. 1, 1999
Higashiya et al.
2-(4-Cya n op h en yl)-1,3-oxa th iola n -5-on e (1e). Almost the
same procedure for the synthesis of 1d 38 was employed. To
the solution of thioglycolic acid (4.61 g, 50 mmol) in benzene
(70 mL) was added 4-cyanobenzaldehyde (13.1 g, 0.1 mol), and
the resulting solution was refluxed overnight. The reaction
mixture was washed with 10% aqueous NaHCO3, and the
volatile materials were evaporated. The residue was distilled
in vacuo (110 °C/4 mmHg), and the distillate was recrystallized
from a small amount of EtOAc and hexane: yield ) 2.47 g
conjugated with oxygen and sulfur atoms, and an alkyl
or an aryl group. From these both effects, we concluded
that such a remarkable regioselectivity in these anodic
fluorination was achieved.
On the other hand, the cis/trans stereoselectivities for
the fluorination was low and showed a slight excess of
trans isomers.36 This is presumably due to the steric
hindrance with the substituent at the 2-position.
1
(24%). H NMR: δ 7.72 (d, J ) 8.3 Hz, 2H), 7.58 (d, J ) 8.3
Hz, 2H), 6.51 (s, 1H), 3.90 (d, J AB ) 16.5 Hz, 1H), 3.78 (d, J AB
) 16.5 Hz, 1H). Anal. Calcd for C10H7NO2S: C, 58.52; H, 3.44;
N, 6.82. Found: C, 58.55; H, 3.46; N, 6.60.
Con clu sion
Electr olytic P r oced u r es for F lu or in a tion . Electr olysis
Usin g Et3N‚3HF . Electrolysis was performed at a platinum
anode and cathode (3 × 4 cm2 each) in 0.37 M Et3N‚3HF/MeCN
(50 mL) containing 5 mmol of 1 using a cylindrical one-
compartment glass cell at ambient temperature under a
nitrogen atmosphere until the starting material was com-
pletely consumed (checked by TLC or GC-MS). To avoid
deposition of the polymerized products on the anode, pulse
electrolysis [applied potential (90 s)/0 V (10 s), see Table 3]
was performed.
Electr olysis Usin g Et4NF ‚4HF . Electrolysis was carried
out at a platinum anode and cathode (2 × 3 cm2) in 0.34 M
Et4NF‚4HF/MeCN (30 mL) containing 3 mmol of 1 using a
cylindrical one-compartment cell made of PFA or PTFE29 for
protection from the corrosive HF salt at ambient temperature
under a nitrogen atmosphere until the starting material was
completely consumed (checked by TLC or GC-MS). In the case
of 1e, to avoid deposition of the polymerized products on the
anode, pulse electrolysis [applied potential (45 s)/0 V (5 s), see
Table 3] was performed.
Ca lcu la tion of th e Yield s a n d th e cis/tr a n s Ra tios
Usin g 19F NMR. The electrolytic mixture was evaporated in
vacuo, and then a certain amount of monofluorobenzene as a
internal standard material was added for the integration. The
yields were calculated on the basis of the integral ratios
between the monofluorobenzene and each stereoisomer of 2.
Sep a r a tion a n d An a lysis of P r od u cts. The electrolytic
mixture was diluted with ether and washed with two portions
of H2O. The organic phase was dried over anhydrous Na2SO4
and evaporated. The residual material was purified using bulb-
to-bulb distillation (100-170 °C/4 mmHg) to give the fluori-
nated product 2. Product 2 was almost decomposed under
slightly basic and hydrous conditions or during column chro-
matography. We could not determine the isolated yields of 2
because 2 also began to decompose (seemed polymerizing)
liberating hydrogen fluoride immediately after the bulb-to-bulb
distillation at room temperature or even in freezer. Therefore,
we had to dilute the distillate immediately with CDCl3 to
measure NMR spectra. In the diluted solution, product 2 was
stable to some extent, finally decomposing at room tempera-
ture.
We have successfully carried out highly regioselective
anodic monofluorination of 1,3-oxathiolan-5-ones using
an Et4N‚4HF/MeCN electrolytic solution. This novel
electrolytic system provided high current efficiency and
did not cause severe passivation which has usually been
observed during partial anodic fluorination of organic
compounds. This successful electrolytic system using
Et4N‚4HF has a large potential which can be applicable
to other anodic fluorination including the difficult fluo-
rination, previously resulting in low yields or low current
efficiencies because of passivation or their high oxidation
potentials.
Exp er im en ta l Section
Gen er a l. Caution: Et3N‚3HF and Et4NF‚4HF are toxic; if
it comes in contact with skin, it causes a serious burn.
Therefore, proper safety precautions should be taken at all
times, and it is recommended that rubber gloves be used.
1H NMR and 19F NMR spectra were recorded at 270 and
254 MHz, respectively, in CDCl3 as a solvent. The chemical
shifts for 19F are given in δ ppm downfield from external
CF3COOH. Preparative electrolysis experiments were carried
out using a Potentiostat/Galvanostat HA-501, a Function
Generator HB-104, and a Coulomb/Amperehour meter HF-201
(Hokuto Denko, Ltd., products) with a reference electrode (0.01
M AgNO3, 0.1 M Et4NBF4 in CH3CN/Ag wire) for potentiostat
electrolysis.
Ma ter ia ls. The electrolytes, Et3N‚3HF and Et4NF‚4HF,
were kind gifts of Morita Chemical Industries Co., Ltd. (J apan)
and used for the electrolysis without further purification.
Et4NF‚4HF was also prepared by mixing Et4NF‚2HF and
anhydrous HF in a nitrogen atmosphere as described else-
where.37
The starting materials, 1,3-oxathiolan-5-ones 1a ,b,d , were
prepared from the condensation of thioglycolic acid with the
corresponding aldehydes according to the known procedure.38
2-Isop r op yl-1,3-oxa th iola n -5-on e (1c). Almost the same
procedure38 for the synthesis of 1a ,b was employed. To
isobutyraldehyde (7.21 g, 0.1 mol) was added thioglycolic acid
(9.21 g, 0.1 mol), and the resulting solution was stirred at room
temperature for 24 h. The volatile materials were evaporated,
and the residue was distilled in vacuo. The distillate was
washed with 10% aqueous NaHCO3 and redistilled in vacuo
(75 °C/3 mmHg) to give 5.76 g (39%) of the product 1c. 1H
NMR: δ 5.32 (d, J ) 6.6 Hz, 1H), 3.69 (d, J AB ) 16.7 Hz, 1H),
3.61 (d, J AB ) 16.7 HZ, 1H), 2.12 (oct, J ) 6.6 Hz, 1H), 1.06
(d, J ) 6.6 Hz, 3H), 1.01 (d, J ) 6.6 Hz, 3H). Anal. Calcd for
C6H10O2S: C, 49.29; H, 6.89. Found: C, 48.91; H, 6.78.
2-Eth yl-4-flu or o-1,3-oxa th iola n -5-on e (2a ): 1H NMR (cis
and trans mixture) δ 6.20, 6.20 (2d, J ) 5.4 and J ) 8.4 Hz,
1H), 5.72, 5.49 (dd and dt, J ) 11.6, 5.6 Hz and J ) 5.81, 6.52
Hz, 2H), 2.2-1.8 (m, 2H), 1.08 (t, J ) 7.43 Hz, 3H); 19F NMR
δ -65.51 (ddd, J ) 53.8, 8.9, 3.1 Hz, trans isomer), -74.49
(dd, J ) 55.8 Hz, J ) 5.0 Hz, cis isomer); MS for both of the
isomers m/e 150 (M+), 121, 106, 93; GC-HRMS calcd for C5H7-
FO2S m/e 150.0151, found 150.0135 (faster) and 150.0165
(slower).
4-F lu or o-2-n -p r op yl-1,3-oxa th iola n -5-on e (2b): 1H NMR
(cis and trans mixture) δ 6.18 (d, J ) 56.8 Hz, 1H), 5.75, 5.53
(dd and dt, J ) 12.2, 5.6 Hz and J ) 8.9, 6.8 Hz, 1H), 2.1 (m,
2H), 1.9 (m, 2H), 1.01, 0.99 (2t, J ) 7.3 Hz, 3H); 19F NMR δ
-67.60 (dd, J ) 56.5, 8.7 Hz, trans isomer), -74.80 (dd, J )
55.5, 5.3 Hz, cis isomer); MS m/e 164 (M+), 102, 101, 100, 88,
86; GC-HRMS calcd for C6H9FOS2 m/e 180.0078, found
180.0065.
(36) The cis/trans ratio of 2 was determined by the measurement
of 19F NMR of the crude 2. The trans isomer was established on the
basis of a large long-range coupling between the fluorine and the
hydrogen at the 2-position: Applications of Nuclear Magnetic Reso-
nance Spectroscopy in Organic Chemistry, 2nd ed.; J ackson, L. M.,
Sternhell, S., Eds.; Pergamon Press: Oxford, 1968; p 334.
(37) Momota, K.; Morita, M.; Matsuda, Y. Electrochim. Acta 1993,
38, 619-624.
2-Isop r op yl-4-flu or o-1,3-oxa th iola n -5-on e (2c): 1H NMR
(cis and trans mixture) δ 6.21, 6.19 (2d, J ) 57.4 and J ) 56.1
Hz, 1H), 5.57, 5.33 (t and dd J ) 6.44 Hz and J ) 9.74, 6.77
Hz, 1H), 2.14 (m, 1H), 1.1 (m, 6H); 19F NMR δ -67.44 (dd, J
(38) Satsumabayashi, S.; Irioka, S.; Kudo, H.; Tsujimoto, K.; Motoki,
S. Bull. Chem. Soc. J pn. 1972, 45, 913-915.

Partial Fluorination of Organic Compounds. 30
J . Org. Chem., Vol. 64, No. 1, 1999 137
) 57.7, 9.9 Hz, trans isomer), -74.40 (dd, J ) 55.8, 5.6 Hz,
cis isomer); MS m/e for both of the isomers 164 (M+), 121, 93,
73, 56; GC-HRMS calcd for C6H9FOS2 m/e 180.0078, found
180.0065.
4-F lu or o-2-p h en yl-1,3-oxa th iola n -5-on e (2d ): 1H NMR
(cis and trans mixture) δ 7.41 (brs, 5H), 6.65, 6.48 (2d, J )
5.28 and J ) 8.91 Hz, 1H), 6.32, 6.31 (2d J ) 55.4 Hz and J
) 56.4 Hz, 1H); 19F NMR δ -67.05 (dd, J ) 57.4, 9.0 Hz, trans
isomer), -75.62 (dd, J ) 55.8, 5.6 Hz, cis isomer); MS m/e for
both of the isomers 198 (M+), 154, 153, 121, 105, 77; GC-HRMS
calcd for C9H7FO2S m/e 198.0151, found 198.0146 (faster),
198.0157 (slower).
m/e 223 (M+), 132, 130, 102; GC-HRMS calcd for C10H6FNO2S
m/e 223.0103, found 223.0113 (faster), 223.0115 (slower).
Ack n ow led gm en t. We are grateful to the Mochida
Pharmaceutical Co., Ltd. for the measurement of the
PLA2 inhibitory activity. This work was financially
supported by a Grant-in Aid for Developmental Scien-
tific Research (no. 07555278) from The Ministry of
Education, Science, Sports and Culture J apan and
Novartis Foundation (J apan) for the Promotion of
Science.
Su p p or tin g In for m a tion Ava ila ble: 1H and 19F NMR
spectra for 2a -e (5 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
2-(4-Cya n op h en yl)-4-flu or o-1,3-oxa th iola n -5-on e (2e):
1H NMR (cis and trans mixture) δ 7.76, 7.74 (2d, J ) 8.6 Hz,
2H), 7.78, 7.74 (2d, J ) 8.6 Hz, 2H), 6.72, 6.57 (2d, J ) 5.6
and 7.9 Hz, 1H), 6.35, 6.34 (2d, J ) 54.8 and 56.4 Hz, 1H); 19
F
NMR δ -67.44 (dd, J ) 57.7, 9.9 Hz, trans isomer), -74.40
(dd, J ) 55.8, 5.6 Hz, cis isomer); MS for both of the isomers
J O981437G