Electrolytic partial fluorination of organic compounds. 31.1 Regioselective anodic fluorination of 2-quinolyl and 4-(7- trifluoromethyl)quinolyl sulfides and the factors affecting its optimization

Article abstract of DOI:10.1021/jo981476s

Electrochemical fluorination of 2-quinolyl and 4-(7- trifluoromethyl)quinolyl sulfides bearing an electron-withdrawing group at the position α to the sulfur atom was studied. Fluorination was successfully carried out using Et₄NF·nHF (n = 3, 4) and Et₃N·3HF as a supporting electrolyte and a fluoride ion source in dimethoxyethane in a divided cell to provide the corresponding α-fluorinated sulfides in good yields. A trifluoromethyl group positioned on the quinoline ring significantly enhanced anodic α-fluorination. 4-(Methylthio)-7-(trifluoromethyl)quinoline was also found to undergo anodic fluorination efficiently. Solvent effects of various donor numbers were also established.

Full text of DOI:10.1021/jo981476s

1
38
J . Org. Chem. 1999, 64, 138-143
Electr olytic P a r tia l F lu or in a tion of Or ga n ic Com p ou n d s. 31.1
Regioselective An od ic F lu or in a tion of 2-Qu in olyl a n d
-(7-Tr iflu or om eth yl)qu in olyl Su lfid es a n d th e F a ctor s Affectin g
Its Op tim iza tion
4
2
,†
Kamal M. Dawood and Toshio Fuchigami*
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku,
Yokohama 226-0027, J apan
Received J uly 27, 1998
Electrochemical fluorination of 2-quinolyl and 4-(7-trifluoromethyl)quinolyl sulfides bearing an
electron-withdrawing group at the position R to the sulfur atom was studied. Fluorination was
successfully carried out using Et
4
NF‚nHF (n ) 3, 4) and Et N‚3HF as a supporting electrolyte and
3
a fluoride ion source in dimethoxyethane in a divided cell to provide the corresponding R-fluorinated
sulfides in good yields. A trifluoromethyl group positioned on the quinoline ring significantly
enhanced anodic R-fluorination. 4-(Methylthio)-7-(trifluoromethyl)quinoline was also found to
undergo anodic fluorination efficiently. Solvent effects of various donor numbers were also
established.
In tr od u ction
Recently, the discovery of many potent clinically
mutagenic11 activities. Elsewhere, fluorinated organic
compounds have received much interest due to the
increased recognition of their biological importance.
12
important antitumor drugs having a quinoline moiety has
Therefore, from a structure-activity relationship (SAR)
viewpoint, the introduction of fluorine atom(s) into the
quinoline ring (or its side chain) may provide medicinals
and pharmaceuticals with increased or new functionality.
However, conventional chemical fluorination processes
are not easy to perform and often require hazardous
3
been reported. Also, a large number of quinoline deriva-
tives are involved in the manufacture of a wide variety
4
of medicinals and pharmaceuticals, including antibiotic,
5
6
7
antimalarial, antibacterial, antimicrobial, and anal-
8
gesic drugs. The quinoline derivatives also have been
shown to have important cytotoxic,9 genotoxic, and
10
13
reagents. On the other hand, it was reported that anodic
fluorination was a convenient method to accomplish this
objective.
In continuation of our current efforts directed toward
†
14
Fax: +81 45 924 5406. E-mail: fuchi@echem.titech.ac.jp.
(1) Part 30: Higashiya, S.; Narizuka, S.; Konno, A.; Maeda, T.;
Momota, K.; Fuchigami, T. J . Org Chem., in press.
exploring the regioselective anodic fluorination of organic
(
2) UNESCO Research Fellow (1997-1998), on leave from the
compounds,1
4b,15
we successfully carried out regioselective
Department of Chemistry, Faculty of Science, Cairo University, Cairo,
Egypt.
anodic R-fluorination of 2-pyridyl and 2-benzothiazolyl
(3) (a) Deady, L. W.; Kaye, A. J .; Finaly, G. J .; Baguley, B. C.; Denny,
sulfides having an electron-withdrawing group (EWG) at
W. A. J . Med. Chem. 1997, 40, 2040. (b) Scharping, C. E.; Duke, C. C.;
Holder, G. M.; Larden, D. Carcinogenesis 1993, 14, 1041. (c) Moron,
J .; Rautureau, M.; Huel, C.; Pierre, A.; Berthier, L. K.; Atassi, G.;
Bisagni, E.; Anti-Cancer Drug Des. 1993, 8, 399. (d) Yamato, M.;
Takeuchi, Y.; Chang, M. R.; Hashigaki, K. Chem. Pharm. Bull. 1992,
1
6,17
the position R to the sulfur atom in an undivided cell.
However, we failed to fluorinate related sulfides devoid
of an EWG. R-Fluoro sulfides serve as useful synthetic
1
8
4
0, 528. (e) Takeuchi, Y.; Chang, M. R.; Hashigaki, K.; Tashiro, T.;
Tsuruo, T.; Tsukagoshi, S.; Yamato, M. Chem. Pharm. Bull. 1992, 40,
481.
4) (a) Sieb, J . P. Neurology 1997, 48, 1121. (b) Deshpande, S. S.;
intermediates to medicinally active compounds. With
1
(
(11) (a) Saeki, K.; Takahashi, K.; Kawazoe, Y. Biol. Pharm. Bull.
1993, 16, 232. (b) Debnath, A. K.; Decompadre, R. L. L.; Hansch, C.
Mutat. Res. 1992, 280, 55.
Sheridan, R. E.; Alder, M. Toxicon 1997, 35, 433. (c) Gazit, A.; App,
H.; Mcmahon, G.; Chen, J .; Levitzki, A.; Bohmer, F. D. J . Med. Chem.
1
996, 39, 2170.
5) (a) Egan, T. J .; Ross, D. C.; Adams, P. A. S. Afr. J . Sci. 1996, 92,
1. (b) J ain, R.; J ain, S.; Gupta, R. C.; Anand, N.; Dutta, G. P.; Puri,
(12) (a) Biomedicinal Aspects of Fluorine Chemistry; Filler, R.,
Kobayashi, Y., Eds.; Kodansha & Elsevier Biomedical: Tokyo, 1982.
(b) Fluorine in Bioorganic Chemistry; Welch, J . T., Eswarakrishnan,
S., Eds.; Wiley: New York, 1991. (c) Welch, J . T. Tetrahedron 1987,
43, 3123. (d) Yoshioka, H.; Nakayama, C.; Matsuo, N. J . Synth. Org.
Chem. J pn. 1984, 42, 809.
(
1
S. K. Indian J . Chem. 1994, 33B, 251.
6) (a) Lee, J . K.; Lee, S. H.; Chang, S. J . Bull. Korean Chem. Soc.
992, 13, 571. (b) Abdalla, M. A.; Ahmed, A. H. N.; Elzohry, M. F.;
(
1
Omar, F. A. Collect. Czech. Chem. Commun. 1992, 57, 1547. (c) Chu,
D. T. W.; Lico, I. M.; Claiborne, A. K.; Faubl, H. Can. J . Chem. 1991,
(13) Chemistry of Organic Fluorine Compounds II; Huddlicky, M.,
Pavlath, A. E., Eds.; American Chemical Society: Washington, DC,
1995.
7
0, 1323. (d) Chu, D. T. W.; Claiborne, A. K.; Clement, J . J .; Plattner,
J . J . Can. J . Chem. 1991, 70, 1328. (e) Hagen, S. E.; Domagala, J . M.;
Heifetz, C. L.; J ohnson, J . J . Med. Chem. 1991, 34, 1155.
(14) (a) 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. (b) Fuchigami, T. Rev.
Heteroatom Chem. 1994, 10, 155.
(15) Electrochemistry in the Preparation of Fluorine and Its Com-
pounds; Childs, W. V., Fuchigami, T., Eds.; The Electrochemical
Society: Pinnington, NJ , 1997.
(7) (a) Fournet, A.; Ferreira, M. E.; Dearias, A. R.; Deortiz, S. T.;
Fuentes, S.; Nakayama, H.; Schinini, A.; Hocquemiller, R. Antimicrob.
Agents Chemother. 1996, 40, 2447. (b) Miethling, R.; Hecht, V.;
Deckwer, W. D. Biotechnol. Bioeng. 1993, 42, 589. (c) Ruger, A.;
Schwarz, G.; Lingens, F.; Biol. Chem. Hoppe-Seyler 1993, 374, 479.
(
8) Kidawi, M.; Negi, N. Monatsh. Chem. 1997, 128, 85.
(16) Erian, A. W.; Konno, A.; Fuchigami, T. J . Org. Chem. 1995,
60, 7654.
(9) Peczynskaczoch, W.; Pognan, F.; Kaczmarek, L.; Boratynski, J .
J . Med. Chem. 1994, 37, 3503.
10) Lavoie, E. J .; Defauw, J .; Fealy, M.; Way, B. M.; Mcqueen, C.
A. Carcinogenesis 1991, 12, 217.
(17) Hou, Y.; Higashiya, S.; Fuchigami, T. J . Org. Chem. 1997, 62,
9173.
(18) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737.
(
1
0.1021/jo981476s CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/09/1998

Partial Fluorination of Organic Compounds
J . Org. Chem., Vol. 64, No. 1, 1999 139
Sch em e 1
Ta ble 1. Oxid a tion P oten tia ls of Qu in olyl Su lfid es 3a -d
a n d 4a -d
sulfide
no.
EWG
Epox (V vs SSCE)a
3
3
3
3
4
4
4
a
b
c
d
a
b
c
COMe
COOEt
CN
1.92
2.04
2.14
1.82
1.70
1.76
1.91
1.65
H
COMe
COOEt
CN
these facts in mind, we have attempted the anodic
fluorination of various 2- and 4-quinolyl sulfides using
various supporting flouride salts and solvents in this
work.
4d
H
a
In 0.1 M Bu4BF4/MeCN. Anode: Pt plate. Sweep rate: 100
mV s-
1
.
Ta ble 2. An od ic F lu or in a tion of
-(7-Tr iflu or om eth yl)qu in olyl Aceton yl Su lfid e (3a )
a
4
Resu lts a n d Discu ssion
yield (%)b
supporting
electrolyte
charge passed
(F/mol)
Syn th esis of th e Qu in olyl Su lfid es 3a -d a n d 4a -
d . Reaction of the appropriate mercaptoquinoline 1 or 2
with R-chloroacetone, ethyl R-chloroacetate, and R-chlo-
run
1
solvent
5a
6a
c
c
Et4NF‚4HF
Et4NF‚3HF
DME
DME
DME
MeCN
CH2Cl2
DME
4
4
4
2.7
3.5
4
80 (52)
96 (78)
14
28
23
6
7
e
3
9
6
2
roacetonitrile in refluxing THF, in the presence of K
CO , provided 4- and 2-quinolyl sulfides 3a -c and 4a -
c, respectively, in high yields (Scheme 1). Compounds 1
and 2 were treated with Me SO in aqueous NaOH
2
-
3d
Et NF‚3HF
4
4
5
6
Et4NF‚3HF
Et4NF‚3HF
Et3N‚3HF
3
84
2
4
a
Constant current electrolysis (5 mA cm-2). Anode and cathode
solution at room temperature to provide the correspond-
ing methylthio derivatives 3d and 4d , respectively, in
excellent yields.
Oxid a tion P oten tia ls of Qu in olyl Su lfid es. The
oxidation potentials of quinolyl sulfides 3a -d and 4a -d
were measured using cyclic voltammetry. The anhydrous
2
were Pt plate (3 × 2 cm ). A divided H-type cell with an anion-
b
19
exchange membrane was used. Calculated on the basis of
F
NMR. c Isolated yield. d Using an undivided cell. e A considerable
amount of bis[4-(7-trifluoromethyl)quinolyl] disulfide [MS: m/e 456
(M+), 228 (M+/2)] was detected.
Sch em e 2
acetonitrile solution containing Bu
4
4
N‚BF (0.1 M), plati-
num electrodes, and a SSCE reference electrode were
used in this study. All sulfides showed irreversible
oxidation peaks in the cyclic voltamograms. Generally,
the 4-(7-trifluoromethyl)quinolyl sulfides 3a -d have 0.2-
0
2
.3 V higher oxidation potentials than the corresponding
-quinolyl sulfides 4a -d due to the strongly electron-
3
withdrawing CF group. The presence of the electron-
withdrawing groups at the position R to the sulfur atom
caused the oxidation potentials to increase in the ascend-
ing order H < COMe < COOEt < CN as shown in Table
ratio of 15:1 (Scheme 2). Ring fluorination did not occur
at all. The formation of 6a was confirmed by mass
+
+
+
1
.
3
spectroscopy, m/e 321 (M ), 278 (M - COCH ), 228 (M
+
19
An od ic F lu or in a tion of 4- a n d 2-Qu in olyl Su l-
- CF
2
COCH
3
), and 196 (M - SCF
2
COCH
3
), and
F
fid es, 3a -d a n d 4a -d . The anodic oxidation of 4-(7-
trifluoromethyl)quinolyl acetonyl sulfide (3a ) was exam-
ined in detail as it serves as a model for the related
quinolyl sulfides. Anodic oxidation of 3a was studied in
the presence of a variety of fluorine sources under various
electrolytic conditions. The results are summarized in
Table 2. From these results, it is clear that anodic
fluorination of 3a took place regioselectively at the
position R to the sulfur atom. The yield was extremely
NMR spectra, δ +13.64 (s, 3F) and -4.71 (s, 2F) ppm.
On the other hand, the yield and selectivity of R-fluori-
nated product 5a decreased sharply as shown in Table 2
(runs 3-5) when the electrolytic solvent and/or the cell
type were changed.
Previously, we demonstrated that acetonitrile was
1
6
suitable for anodic fluorination of 2-pyridyl sulfides;
however, it was not effective for anodic fluorination of
4-quinolyl sulfide 3a . The use of an undivided cell
resulted in the formation of large amounts of bis[4-(7-
trifluoromethyl)quinolyl] disulfide due to the 3a C-S
bond cleavage. This indicates that the reductive cleavage
of the 3a C-S bond took place at the cathode during
electrolysis. This is sharp contrast to the previously
reported successful anodic fluorination of 2-pyridyl ac-
etonyl sulfide in an undivided cell.16
high especially when an Et NF‚3HF supporting electro-
4
lyte in a DME electrolytic solvent was used under
constant current electrolysis in a divided H-type cell
fitted with an anion-exchange membrane. Regardless of
supporting electrolytes, the R-monofluorinated product
5
a was obtained in a high yield and a small amount of
R,R-difluorinated byproduct 6a was generated with a

1
40 J . Org. Chem., Vol. 64, No. 1, 1999
Dawood and Fuchigami
Ta ble 3. An od ic F lu or in a tion of
-(7-Tr iflu or om eth yl)qu in olyl Su lfid es Usin g DME a s a
Solven t
Ta ble 4. An od ic F lu or in a tion of 2-Qu in olyl Su lfid es
4
4a -ca
sulfide
EWG
yield (%)d
supporting charge passed
sulfide
EWG
yield (%)a
supporting
electrolyte
charge passed
(F/mol)
run no.
electrolyte
(F/mol)
7
8
9
no.
5
6
1
2
3
4
5
6
7
8
9
0
1
4a COMe
4a COMe
4a COMe
4a COMe
4a COMe
4b COOEt Et4NF‚4HF
4b COOEt Et4NF‚3HF
4b COOEt Et3N‚3HF
Et4NF‚4HF
Et4NF‚3HF
Et3N‚3HF
Et3N‚3HF
Et3N‚3HF
4
6
7
6
4
4
4
6
8
8
8
54
50
55
64
28
62
54
69
61
52
62
8
8
8
5
5
5
3
3
3
3
3
3
3
a
b
b
b
c
c
c
COMe
COOEt
COOEt
COOEt
CN
Et4NF‚3HF
Et4NF‚4HF
Et4NF‚3HF
Et3N‚3HF
Et4NF‚4HF
Et4NF‚3HF
Et3N‚3HF
4
96 (78)b
62
83
7
2.5
4.5
6
4
4
b
c
67
b
86 (74)
5
5
7
12
12
12
CN
CN
87 (81)b
77
6
4c CN
4c CN
4c CN
Et4NF‚4HF
Et4NF‚3HF
Et3N‚3HF
a
Calculated on the basis of 19F NMR. b Isolated yield.
1
1
Sch em e 3
a
Constant current electrolysis using DME as an electrolytic
solvent. b Pulse electrolysis [1.7 V (50 s)/0.0 V (10 s)] was applied
using DME as a solvent. Pulse electrolysis [1.7 V (50 s)/0.0 V
10 s)] was applied using MeCN as a solvent. Calculated on the
basis of F NMR.
c
d
(
1
9
Sch em e 5
Sch em e 4
Sch em e 6
Anodic fluorination of other 2-quinolyl sulfides 4b,c
was attempted in DME. Spectral data indicated that
Next, the anodic fluorination of the other 4-(7-trifluo-
romethyl)quinolyl sulfides 3b,c was carried out using
DME in a divided cell. As shown in Table 3, fluorination
took place selectively at the position R to the sulfur atom.
No R,R- difluorination was detected regardless of the
fluoride sources used in this work. As compared with 3a ,
compounds 3b,c have higher oxidation potentials; there-
fore, their corresponding R-fluorinated products 5b,c
should be more difficult to oxidize than 5a . This seems
to be one of the main reasons why 5b,c were not
susceptible to further oxidation leading to the R,R-
difluorosulfides 6b,c.
Et
3
N‚3HF and Et
4
4
NF‚4HF were more effective than Et -
NF‚3HF for selective fluorination giving only two fluori-
nated products. These two products were identified as
R-fluorinated and R,6-difluorinated sulfides 7b,c and
b,c, respectively (Scheme 4).19 The H- H COSY NMR
1
1
9
spectrum of 9c indicated that the ring fluorination took
place at the 6-position of the quinoline moiety. R,R-
Difluorination was not detected at all during fluorination
of sulfides 4b,c (Table 4).
Moreover, anodic fluorination of 4-(methylthio)-7-(tri-
fluoromethyl)quinoline (3d ) devoid of EWG using Et
HF/DME under constant current electrolysis resulted
in the formation of the isolable 4-((fluoromethyl)thio)-7-
trifluoromethyl)quinoline (10) (Scheme 5) selectively in
4
NF‚
These results suggested further exploration of anodic
fluorination of 2-quinolyl sulfides 4a -c which are devoid
of CF groups on the quinoline ring. Anodic fluorination
3
3
(
of sulfide 4a was performed using various fluoride salts
and solvents. Regardless of the electrolytic solutions,
R-monofluorinated product 7a was formed preferentially
a good yield along with a small amount (8%) of its ring-
fluorinated analogue. The position of the additional
fluorine atom in the latter product could not be deter-
mined exactly, although 19F NMR signals at δ +13.89 (s,
with byproducts including the ring fluorinated and R,R-
difluorinated products 8a and 9a (Scheme 4).19 However,
3
5
F), -40.19 (d, 1F, J ) 6.44 Hz), and 108.50 (t, 1F, J )
1.47 Hz) ppm were found and the mass spectrum
pulse-controlled potential electrolysis in Et
provided 7a in a better yield and eliminated the byprod-
ucts. In contrast, Et N‚3HF/MeCN gave much lower 7a
yield even when pulse electrolysis was used.
3
N‚3HF/DME
+
+
fragment of m/e 279 (M ) and 260 (M - F) were
identified.
3
Similar anodic oxidation of 2-(methylmercapto)quino-
(
19) Due to the extremely low yield of 8a and 9a ,b, their structures
3
line (4d ) with Et N‚3HF/DME under pulse electrolysis
1
9
+
19
were confirmed by MS and F NMR spectra. 8a : m/e 253 (M );
F
resulted in a reasonable R-fluorinated yield (product 11
in Scheme 6). Thus, 3d provided a much higher R-fluor-
inated yield compared with 4d . This is probably due to
the strong electron-withdrawing effect of the quinoline
+
19
NMR δ -9.45 (s). 9a : m/e 253 (M ); F NMR δ -45.47 (dd, 1F, J )
+
1
2
0.12, 9.19 Hz), -89.09 (dq, 1F, J ) 49.63, 3.68 Hz). 9b: m/e 283 (M ),
+ + +
38 (M+ - OEt), 210 (M - COOEt), 191 (M - FCOOEt), 178 (M
-
+
19
CHFCOOEt), 146 (M - SCHFCOOEt); F NMR δ -45.64 (dd, 1F, J
)
10.11, 9.19 Hz), -88.45 (d, 1F, J ) 50.56 Hz) ppm. The 6-position
ring CF
3
group. Recently, it has been reported that anodic
at the quinoline ring of 9a ,b seems to be fluorinated in addition to R
to the sulfur atom similarly to the case of 9c.
R-fluorination of alkyl phenyl sulfides could be markedly

Partial Fluorination of Organic Compounds
J . Org. Chem., Vol. 64, No. 1, 1999 141
Sch em e 7
Sch em e 8
F igu r e 1. Current-potential curves of the electrolytic solu-
Therefore, the electrochemical fluorination offers a safe
alternative to conventional chemical methods which can
be carried out under mild conditions.
In conclusion, we have successfully carried out selec-
tive fluorination of 2- and 4-quinolyl sulfides in DME
tions 0.5 M Et
3
N‚3HF/DME (20 mL) (A) and 0.5 Et N‚3HF/
3
MeCN (20 mL) (B) in the presence (2) and the absence (4) of
substrate 4a (1.0 mmol).
improved by a strongly electron-withdrawing group at
the benzene ring.20 Previously, we successfully carried
containing Et
3
N‚3HF and Et NF‚nHF (n ) 3, 4) using a
4
divided cell. Such electrolytic systems are widely ap-
plicable to selective fluorination of various heterocyclic
sulfides.
out anodic R-fluorination of methyl phenyl sulfide in
DME.21 However, we failed to fluorinate methyl 2-pyridyl
sulfide.16 Therefore, these successful anodic fluorinations
of 3d and 4d in DME are significant.
DME was found to be the most suitable electrolytic
solvent. From the I-E curves shown in Figure 1, it is
Exp er im en ta l Section
Ca u tion ! Et
3
4
N‚3HF was purchased from Aldrich, and Et -
clear that the addition of 4a , for example, to the Et
3
N‚
NF‚nHF (n ) 3, 4)24 was obtained from Morita Chemical
Industries Co. Ltd. They are toxic and skin contact can result
in a serious burn, so proper safety precautions should be taken
at all times. It is recommended to practice good laboratory
safety procedures including, using rubber gloves for hand
protection.25
3
HF/DME solution resulted in a much smaller cathodic
shift as compared with the case of Et N‚3HF/MeCN. This
3
suggested that acetonitrile should be a more suitable
electrolytic solvent than DME. However, the experimen-
tal results were the inverse. The superiority of DME may
be explained in terms of its ability to solvate the cationic
part of the fluoride salt in which a naked fluoride anion
is left for easy attack on the anodically generated cationic
intermediate. In support of this, DME has much higher
donor number (23.9) than acetonitrile (14). A possible
mechanism is outlined in Scheme 7.22
1H NMR, 19F NMR, and 13C NMR spectra were recorded at
270, 254, and 68 MHz, respectively, in CDCl
3
as a solvent. The
1
13
chemical shifts for H and C NMR are given in δ ppm
1
9
downfield from internal TMS, and those for F NMR are given
in δ ppm downfield from internal C
reference is -162.2 ppm].
6
F
6
3 6 6
[δ(CFCl ) of the C F
Syn th esis of Qu in olyl Su lfid es. Gen er a l P r oced u r e. An
R-chloro compound (20 mmol) was added to a stirred solution
of mercaptoquinoline 1 or 2 (20 mmol) in tetrahydrofuran (40
mL), in the presence of potassium carbonate (3.4 g, 25 mmol).
The mixture was refluxed for 30 min and then left to cool to
the room temperature. The inorganic salts were filtered off,
and the filtrate was evaporated under vacuum. The solid
product was recrystallized from methanol or ethanol to give
the corresponding quinolyl sulfides 3a -c and 4a -c, respec-
tively.
N-Fluoropyridinium salts are known to be powerful
fluorinating reagents.23 However, fluorination of 3a , as
a model compound, with N-fluoropyridinium salts in
dichloromethane even under reflux resulted in no forma-
tion of the expected fluorinated products (Scheme 8).
(
20) Baroux, P.; Tardirel, R.; Simonet, J . J . Electrochem. Soc. 1997,
44, 841.
21) Fuchigami, T.; Konno, A.; Nakagawa, K.; Shimojo, M. J . Org.
Chem. 1994, 59, 5937.
1
(
(
22) We have already proposed that the fluorination of sulfides
21
proceeds via a fluorosulfonium ion as a key intermediate.
(24) Momota, K.; Kato, K.; Morita, M.; Matsuda, Y. Electrochim. Acta
1994, 39, 41.
(23) (a) Umemoto, T.; Tomizawa, G. Bull. Chem. Soc. J pn. 1986,
5
9, 3625. (b) Umemoto, T.; Tomizawa, G. J . Org. Chem. 1995, 60, 6563.
(25) Peters, D.; Mietchen, R. J . Fluorine Chem. 1996, 79, 161.

1
42 J . Org. Chem., Vol. 64, No. 1, 1999
Dawood and Fuchigami
Compounds 3d and 4d were prepared according to the
mmol) was added. An H-type divided cell with an anion-
exchange membrane (IE-DF 34-5 TOSOH) under a nitrogen
atmosphere at ambient temperature was used. Constant
known synthetic procedure of 4d .26a
1
-[4-(7-(Tr iflu or om et h yl)q u in olyl)t h io]-2-p r op a n on e
1
-2
(
(
3a ): 92% yield, mp 126-127 °C; H NMR δ 2.37 (s, 3H), 3.96
current electrolysis (5 mA cm ) was applied until the starting
s, 2H), 7.24 (d, 1H, J ) 4.62 Hz), 7.74 (dd, 1H, J ) 8.91, 1.98
sulfide was almost consumed (as monitored by TLC). After
electrolysis, the electrolytic solution was purified by silica gel
column chromatography employing ethyl acetate to remove the
fluoride salts. The collected effluent was evaporated under
reduced pressure, and the residue was further purified by
passing it through a long silica gel column chromatograph
using hexane/ethyl acetate (5:1) as an eluent.
Pulse electrolysis procedure [applied potential (50 s)/0.0 V
(10 s)] was used instead of constant current electrolysis, when
necessary.
Hz), 8.26 (d, 1H, J ) 8.91 Hz), 8.38 (s, 1H), 8.79 (d, 1H, J )
1
9
+
+
4
.62 Hz); F NMR δ +13.73 (s); MS m/e 285 (M ), 242 (M
COCH ). Anal. Calcd for C13 NOS: C, 54.73; H, 3.53; N,
.91. Found: C, 54.68; H, 3.26; N, 4.62.
E t h yl r-[4-(7-(t r iflu or om et h yl)q u in olyl)t h io]a cet a t e
-
3
10 3
H F
4
1
(
7
3b): 83% yield, mp 48-49 °C; H NMR δ 1.28 (t, 3H, J )
.26 Hz), 3.90 (s, 2H), 4.24 (q, 2H, J ) 7.26 Hz), 7.37 (d, 1H,
J ) 4.62 Hz), 7.74 (dd, 1H, J ) 8.91, 1.32 Hz), 8.25 (d, 1H, J
1
9
)
8.91 Hz), 8.37 (s, 1H), 8.81 (d, 1H, J ) 4.62 Hz); F NMR
13
δ +13.71 (s); C NMR (DEPT) δ 13.98 (CH
3
), 33.75, 62.26
1-F lu or o-1-[4-(7-(tr iflu or om eth yl)qu in olyl)th io]-2-p r o-
1
(
1
2
CH
2
), 118.13, 122.17, 124.80, 127.85, 150.58 (CH), 121.71,
p a n on e (5a ): H NMR δ 2.29 (d, 3H, J ) 2.97 Hz), 6.28 (d,
+
25.70, 131.39, 131.87, 146.61, 168.14 (C); MS m/e 315 (M ),
42 (M - COOEt). Anal. Calcd for C14
H, 3.84; N, 4.44. Found: C, 53.40; H, 3.83; N, 4.12.
1H, J ) 52.79 Hz), 7.74 (d, 1H, J ) 4.62 Hz), 7.81 (dd, 1H, J
) 8.91, 1.98 Hz), 8.37 (d, 1H, J ) 8.91 Hz), 8.44 (s, 1H), 8.93
(d, 1H, J ) 4.62 Hz); 1 F NMR δ +13.69 (s, 3F), -82.84 (dq,
+
12 3 2
H F NO S: C, 53.33;
9
1F, J ) 52.40, 2.76 Hz); 13C NMR (DEPT) δ 26.02 (CH
), 97.92
r-[4-(7-(Tr iflu or om e t h yl)q u in olyl)t h io]a ce t on it r ile
3
1
(
(
1
3c): 90% yield, mp 180-181 °C; H NMR δ 3.88 (s, 2H), 7.50
(d, CHF, J ) 238 Hz), 123.13, 125.08, 125.84, 127.98, 150.87
d, 1H, J ) 4.62 Hz), 7.80 (dd, 1H, J ) 8.91, 1.65 Hz), 8.23 (d,
(CH), 121.56, 129.22, 132.01, 140.41, 147.29, 198.24 (C); MS
1
9
+
+
+
H, J ) 8.91 Hz), 8.45 (s, 1H), 8.96 (d, 1H, J ) 4.62 Hz);
F
m/e 303 (M ), 260 (M - COCH
3
), 241 (M - CH
); HRMS calcd for C13
303.0341, found m/e 303.0333. Anal. Calcd for C13
3
COF), 196
NOS m/e
NOS:
1
3
+
NMR δ +13.67 (s); C NMR (DEPT) δ 16.03 (CH
2
), 119.25,
(M - SCHFCOCH
3
9 4
H F
1
1
22.44, 125.19, 127.24, 151.36 (CH), 116.93, 120.80, 130.01,
9 4
H F
+
+
30.50, 143.56, 146.60 (C); MS m/e 268 (M ), 228 (M - CH
S: C, 53.73; H, 2.63; N, 10.44.
Found: C, 53.69; H, 2.35; N, 10.41.
-(Meth ylth io)-7-(tr iflu or om eth yl)qu in olin e (3d ): 90%
2
-
C, 51.49; H, 2.99; N, 4.62. Found: C, 51.80; H, 3.16; N, 4.54.
CN). Anal. Calcd for C12
H
7
F
3
N
2
Eth yl r-flu or o-r-[4-(7-(tr iflu or om eth yl)qu in olyl)th io]-
1
a ceta te (5b): H NMR δ 1.15 (t, 3H, J ) 7.26 Hz), 4.14 (q,
4
2H, J ) 7.26 Hz), 6.30 (d, 1H, J ) 51.47 Hz), 7.79 (m, 2H),
8.38 (s, 1H), 8.42 (d, 1H, J ) 5.61 Hz), 8.94 (d, 1H, J ) 4.62
1
yield, mp 79 °C; H NMR δ 2.65 (s, 3H), 7.21 (d, 1H, J ) 4.62
1
9
Hz), 7.73 (dd, 1H, J ) 8.91, 1.65 Hz), 8.21 (d, 1H, J ) 8.91
Hz); F NMR δ +13.74 (s, 3F), -82.63 (d, 1F, J ) 51.48 Hz);
13
1
9
Hz), 8.37 (s, 1H), 8.81 (d, 1H, J ) 4.62 Hz); F NMR δ +13.74
3 2
C NMR (DEPT) δ 4.17 (CH ), 63.36 (CH ), 92.88 (d, CHF, J
+
+
(
s); MS m/e 243 (M ), 228 (M - CH
3
). Anal. Calcd for C11
H
8
F
3
-
) 229.57 Hz), 123.41, 125.98, 126.79, 128.39, 151.37 (CH),
NS: C, 54.32; H, 3.31; N, 5.76. Found: C, 54.07; H, 3.03; N,
122.06, 130.05, 132.61, 140.52, 147.85, 164.95 (C); MS m/e 333
+
+
+
+
5
.82.
-(2-Qu in olylth io)-2-p r op a n on e (4a ):26b 93% yield, mp
(M ), 260 (M - COOEt), 241 (M - FCOOEt), 197 (M
-
1
SCHFCOOEt). Anal. Calcd for C H F NO S: C, 50.45; H,
14 11
4
2
1
3.33; N, 4.20. Found: C, 50.16; H, 3.21; N, 3.83.
5
)
1
(
(
1
3-54 °C; H NMR δ 2.42 (s, 3H), 4.12 (s, 2H), 7.26 (d, 1H, J
8.58 Hz), 7.43 (ddd, 1H, J ) 7.92, 7.26, 1.0 Hz), 7.64 (ddd,
H, J ) 8.25, 7.26, 1.32 Hz), 7.72 (d, 1H, J ) 8.25 Hz)), 7.87
r-F lu or o-r-[4-(7-(t r iflu or om e t h yl)q u in olyl)t h io]a c-
1
eton itr ile (5c): mp 88-89 °C; H NMR δ 6.43 (d, 1H, J )
1
3
d, 1H, J ) 7.92 Hz), 7.91 (d, 1H, J ) 8.58 Hz); C NMR
DEPT) δ 28.75 (CH ), 39.75 (CH ), 120.14, 125.32, 127.24,
27.49, 129.65, 135.58 (CH), 147.79, 156.84, 203.56 (C); MS
48.83 Hz), 7.87 (m, 2H), 8.43 (d, 1H, J ) 8.90 Hz), 8.51 (s,
1H), 9.06 (d, 1H, J ) 4.29 Hz); 19F NMR δ +13.66 (s, 3F),
3
2
+
+
-78.18 (d, 1F, J ) 48.72 Hz); MS m/e 286 (M ), 228 (M
CHFCN). Anal. Calcd for C12
9.79. Found: C, 50.64; H, 2.01; N, 9.67.
-
+
+
+
+
m/e 217 (M ), 202 (M - CH
SCH COCH ). Anal. Calcd for C12
N, 6.45. Found: C, 66.20; H, 4.79; N, 6.12.
3
), 174 (M - COCH
3
), 128 (M
-
6 4 2
H F N S: C, 50.35; H, 2.11; N,
2
3
H
11NOS: C, 66.33; H, 5.10;
1-F lu or o-1-(2-qu in olylth io)-2-p r op a n on e (7a ): mp 50 °C;
H NMR δ 2.52 (d, 3H, J ) 2.97 Hz), 7.15 (d, 1H, J ) 49.81
2
6c
1
Eth yl r-(2-qu in olylth io)a ceta te (4b): 86% yield, mp
1
Hz), 7.27 (d, 1H, J ) 8.58 Hz), 7.51 (ddd, 1H, J ) 7.92, 7.26,
1.0 Hz), 7.71 (ddd, 1H, J ) 8.25, 7.26, 1.0 Hz), 7.77 (d, 1H, J
) 7.92 Hz), 7.96 (d, 1H, J ) 8.25 Hz), 8.03 (d, 1H, J ) 8.58
Hz); 19F NMR δ -88.93 (dq, J ) 49.64, 2.76 Hz); C NMR
8
4
1
1
7
3
1
7-88 °C; H NMR δ 1.28 (t, 3H, J ) 7.26 Hz), 4.12 (s, 2H),
.23 (q, 2H, J ) 7.26 Hz), 7.24 (d, 1H, J ) 8.91 Hz), 7.41 (ddd,
H, J ) 7.92, 6.93, 1.32 Hz), 7.62 (ddd, 1H, J ) 8.25, 6.93,
.65 Hz), 7.70 (d, 1H, J ) 7.92 Hz)), 7.88 (d, 1H, J ) 8.25 Hz),
13
1
3
(DEPT) δ 26.15 (CH ), 95.49 (d, CHF, J ) 223.2 Hz), 120.23,
.90 (d, 1H, J ) 8.91 Hz); C NMR (DEPT) δ 14.17 (CH
2.40, 61.55 (CH ), 120.32, 125.42, 127.58, 127.94, 129.65,
35.63 (CH), 126.02, 148.07, 157.06, 169.70 (C); MS m/e 247
3
),
3
126.23, 127.48, 128.03, 130.15, 137.13 (CH), 126.56, 147.74,
2
+
+
+
153.06, 200.72 (C); MS m/e 235 (M ), 215 (M - HF), 192 (M
+
+
+
+
- COCH ), 173 (M
+
- CH COF), 128 (M - SCHFCOCH ).
Anal. Calcd for C H FNOS: C, 61.26; H, 4.28; N, 5.95.
+
(
M ), 202 (M - OEt), 173 (M - HCOOEt), 160 (M - CH
2
-
-
3
3
3
+
COOEt), 128 (M - SCH
NO
N, 5.34.
r-(2-Qu in olylth io)a ceton itr ile (4c): 96% yield, mp 69-
2
COOEt). Anal. Calcd for C13
H
13
12 10
S: C, 63.14; H, 5.30; N, 5.66. Found: C, 63.01; H, 5.07;
Found: C, 60.99; H, 4.44; N, 5.78.
2
Eth yl r-flu or o-r-(2-qu in olylth io)a ceta te (7b): 1H NMR
δ 1.32 (t, 3H, J ) 7.26 Hz), 4.34 (q, 2H, J ) 7.26 Hz), 7.22 (d,
1H, J ) 8.57 Hz), 7.44 (d, 1H, J ) 50.47 Hz), 7.45 (ddd, 1H, J
1
7
(
8
0 °C; H NMR δ 4.20 (s, 2H), 7.23 (d, 1H, J ) 8.57 Hz), 7.49
ddd, 1H, J ) 8.25, 7.92, 1.32 Hz), 7.69 (ddd, 1H, J ) 8.57,
.25, 1.32 Hz), 7.76 (d, 1H, J ) 7.92 Hz), 7.99 (d, 1H, J ) 8.57
Hz), 8.01 (d, 1H, J ) 8.25 Hz); C NMR (DEPT) δ 14.95 (CH
19.87, 126.09, 127.65, 128.19, 130.15, 136.46 (CH), 116.99,
)
8.25, 6.93, 1.32 Hz), 7.67 (ddd, 1H, J ) 8.25, 7.58, 1.32 Hz),
7
.71 (dd, 1H, J ) 8.25, 1.32 Hz)), 7.98 (dd, 1H, J ) 8.25, 1.0
1
9
1
3
Hz), 8.00 (d, 1H, J ) 8.57 Hz); F NMR δ -85.31 (d, J ) 50.56
Hz); 13C NMR (DEPT) δ 13.91 (CH
), 62.51 (CH ), 90.01 (d,
CHF, J ) 225.80 Hz), 120.30, 126.20, 127.55, 128.19, 130.10,
2
),
1
1
3
2
+
+
26.31, 148.01, 154.07 (C); MS m/e 200 (M ), 173 (M - HCN).
S: C, 65.98; H, 4.03; N, 13.99. Found:
1
36.80 (CH), 126.55, 147.78, 153.00, 166.50 (C); MS m/e 265
Anal. Calcd for C11
8 2
H N
+
+
+
+
(M ), 220 (M - OEt), 192 (M - COOEt), 173 (M
-
12
-
C, 66.04; H, 3.96; N, 14.05.
An od ic F lu or in a t ion of Qu in olyl Su lfid es. Typical
+
FCOOEt), 128 (M - SCHFCOOEt); HRMS calcd for C13
FNO
C H FNO S: C, 58.85; H, 4.56; N, 5.28. Found: C, 59.17; H,
H
2
S m/e 265.0573, found m/e 265.0568. Anal. Calcd for
anodic fluorination conditions are as follows: Electrolysis was
2
performed using platinum electrodes (3 × 2 cm ) in 0.5 M Et
4
-
13 12
2
4
.50; N, 5.36.
NF‚3HF/DME (20 mL) to which the appropriate sulfide (1
r-F lu or o-r-(2-qu in olylth io)a ceton itr ile (7c): mp 60 °C;
1
H NMR δ 7.22 (d, 1H, J ) 8.57 Hz), 7.53 (ddd, 1H, J ) 8.24,
(26) (a) Maslankiewicz, A. Pol. J . Chem. 1980, 54, 2096. (b) Brad-
7
1
.92, 1.32 Hz), 7.73 (ddd, 1H, J ) 8.58, 6.93, 1.32 Hz), 7.79 (d,
H, J ) 8.24 Hz), 7.89 (d, 1H, J ) 48.83 Hz), 7.99 (d, 1H, J )
sher, C. K.; Lohr, D. F., J r. J . Heterocycl. Chem. 1967, 4, 71. (c)
Martynovskii, A. A.; Brazhko, A. A.; Lushchinskaya, E. N. Farm. Zh.
Kiev) 1986, 62; Chem. Abstr. 1987, 106, 196233c.
1
9
(
8.57 Hz), 8.07 (d, 1H, J ) 8.58 Hz); F NMR δ -83.13 (d, J )

Partial Fluorination of Organic Compounds
J . Org. Chem., Vol. 64, No. 1, 1999 143
F). Anal. Calcd for C11 NS: C, 50.58; H, 2.70; N, 5.36.
4
1
C
C
8.72 Hz); MS m/e 218 (M ), 198 (M - HF), 191 (M+ - HCN),
+
+
SCH
2
7 4
H F
+
+
60 (M - CHFCN), 128 (M - SCHFCN); HRMS calcd for
Found: C, 50.26; H, 2.66; N, 5.37.
H
H
7
FN
FN
2
S m/e 218.0314, found 218.0321. Anal. Calcd for
2-((F lu or om eth yl)th io)qu in olin e (11): 1H NMR δ 6.33
(d, 2H, J ) 51.47 Hz), 7.30 (d, 1H, J ) 8.58 Hz), 7.48 (ddd,
1H, J ) 8.25, 7.93, 1.0 Hz), 7.69 (ddd, 1H, J ) 8.25, 6.93, 1.32
Hz), 7.76 (d, 1H, J ) 7.93 Hz), 8.01 (d, overlapped 2H, J )
11
11
7
2
S: C, 60.54; H, 3.23; N, 12.84. Found: C, 60.52; H,
3
.07; N, 12.84.
r,6-Diflu or o-r-(2-qu in olylth io)a ceton itr ile (9c): mp 82
1
19
13
°
C; H NMR δ 7.21 (d, 1H, J ) 8.25 Hz), 7.31 (d, 1H, J ) 8.91
8.58 Hz); F NMR δ -112.38 (t, J ) 51.47 Hz); C NMR
(DEPT) δ 82.77 (d, CH F, J ) 214.90 Hz), 120.70, 126.06,
127.62, 128.50, 130.03, 136.60 (CH), 126.60, 147.80, 153.00 (C);
Hz), 7.68 (dt, 1H, J ) 8.57, 7.92 Hz), 7.82 (d, 1H, J ) 8.57
2
Hz), 7.86 (d, 1H, J ) 49.50 Hz), 8.38 (d, 1H, J ) 8.91 Hz); 19
F
+
+
+
+
NMR δ -45.00 (dd, 1F, J ) 10.11, 9.19 Hz), -83.65 (d, 1F, J
MS m/e 193 (M ), 173 (M - HF), 160 (M - CH
2
F), 129 (M
+
+
+
)
-
48.72 Hz); MS m/e 236 (M ), 216 (M - HF), 190 (M - HF
- SCHF). Anal. Calcd for C10H FNS: C, 62.16; H, 4.17; N,
8
+
+
CN), 178 (M - CHFCN), 146 (M - SCHFCN); HRMS
7.25. Found: C, 62.17; H, 4.40; N, 6.95.
calcd for C11
H
6
F
2
N
2
S m/e 236.0220, found m/e 236.0208. Anal.
Ack n ow led gm en t. We thank Dr. S. Higashiya for
his useful suggestions and measurement of high-resolu-
tion mass spectra (HRMS). We are also grateful to Dr.
K. Momota of Morita Chemical Industries Co. Ltd. for
his generous gifts of Et4NF‚nHF (n ) 3, 4). K.M.D. is
deeply indebted to UNESCO and the J apanese Ministry
of Education, Science, and Culture (Monbusho) for
granting him a research fellowship (1997-1998).
Calcd for C11
H
6 2 2
F N S: C, 55.93; H, 2.56; N, 11.86. Found: C,
5
6.28; H, 2.66; N, 11.89.
-((F lu or om et h yl)t h io)-7-(t r iflu or om et h yl)q u in olin e
4
1
(
(
1
10): mp 107 °C; H NMR δ 5.96 (d, 2H, J ) 51.47 Hz), 7.68
d, 1H, J ) 4.62 Hz), 7.77 (dd, 1H, J ) 8.91, 1.65 Hz), 8.23 (d,
1
9
H, J ) 8.91 Hz), 8.42 (s, 1H), 8.90 (d, 1H, J ) 4.62 Hz);
F
1
3
NMR δ +13.74 (s, 3F), -110.25 (t, 1F, J ) 51.47 Hz); C NMR
DEPT) δ 84.88 (d, CH F, J ) 221 Hz), 120.54, 122.57, 125.19,
27.98, 150.94 (CH), 121.67, 125.69, 131.85, 144.71; 146.90 (C);
(
1
2
+
+
+
+
MS m/e 261 (M ), 242 (M - F), 228 (M - CH
2
F), 196 (M
-
J O981476S