Electrolytic Partial Fluorination of Organic Compounds. 23.1 Regioselective Anodic Difluorination of Sulfides Using Novel Fluorine Source Et4NF·4HF

Full text of DOI:10.1021/jo971248i

J . Org. Chem. 1997, 62, 8579-8581
8579
Ta ble 1. Effect of Su p p or tin g Electr olytes on An od ic
Diflu or in a tion of Eth yl r-(P h en ylth io)Aceta te
Electr olytic P a r tia l F lu or in a tion of
Or ga n ic Com p ou n d s. 23.1 Regioselective
An od ic Diflu or in a tion of Su lfid es Usin g
Novel F lu or in e Sou r ce Et4NF ‚4HF
product
yield %
anodic
charge
passed
F/mol
supporting
electrolyte
potential,
run
V vs Ag/Ag+
2a
3a
1
2
3
4
5
Et3N‚3HFa
2.2
20.7
4.0
4.0
2.0
3.4
4
11
4
0
0
52
6
52
0
Akinori Konno2 and Toshio Fuchigami*
Et4NF‚4HFb
Et4NF‚4HF
1.4-2.0
1.6-1.9
c
Department of Electronic Chemistry, Tokyo Institute of
Technology, Nagatsuta, Midori-ku, Yokohama 226, J apan
Bu4NF‚3H2O
PhCH2NMe3‚HF2
2.4
0
a
b
Starting material is a monofluoro derivative 2a . No solvent;
Et4NF‚4HF (30 mL). c Constant current (10 mA/cm2) electrolysis.
Received J uly 9, 1997
In tr od u ction
Sch em e 1
Selective fluorination of organic molecules has at-
tracted much interest because a number of partially
fluorinated organic molecules are reported to show
unique chemical and physical properties and, in some
cases, biological activities.3-7 Among them, difluorom-
ethylene compounds attract interest because the struc-
ture is isopolar and isosteric with an ether oxygen which
is contained in many biologically active compounds.3 The
difluoromethylene group is prepared from the corre-
sponding compound using various reagents such as
molybdenum hexafluoride,8 selenium tetrafluoride,9 sul-
fur tetrafluoride,10 and (dimethylamido)sulfur trifluoride
(DAST).11 However, these reagents are highly toxic and
their use requires severe reaction conditions. Recently,
oxidative fluorodesulfurization of dithioacetals such as
1,3-dithiolanes was successfully conducted using chemi-
cal oxidants12-14 or electrochemical oxidation15,16 in the
presence of fluoride ion. Even in these methods, a large
amount of hazardous oxidant is required for the reac-
tions12-14 or the structure of starting dithioacetal is
limited.15,16 Recently, we successfully conducted highly
regioselective anodic monofluorinations of organo chal-
cogen compounds in acetonitrile using Et3N‚3HF as a
fluorine source and a supporting electrolyte.17 We also
attempted direct difluorination of these compounds.
Difluorination occurred regioselectively, but current ef-
ficiencies were extremely low due to competitive oxidation
of Et3N‚3HF and a monofluorinated product.17 Recently,
Momota et al. reported the anodic fluorination of benzene
using a novel molten salt Et4NF‚4HF as a fluorine source
and a solvent.18 Even benzene, which has high oxidation
potential (> 2.0 V vs SCE), can be fluorinated anodically
in Et4NF‚4HF. This result prompted us to conduct direct
anodic difluorination of sulfides using Et4NF‚4HF as a
fluorine source.
Resu lts a n d Discu ssion
Anodic difluorination of ethyl R-(phenylthio)acetate
(1a ) was investigated under several conditions as shown
in Table 1. As we reported previously,17 under con-
ventional anodic monofluorination conditions (0.37 M
Et3N‚3HF in acetonitrile), a large excess amount of
electricity (20.7 F/mol) was required in order to complete
the fluorination despite using monofluorinated sulfide 2a
as a starting material (run 1).
Next, anodic difluorination of 1a was conducted using
Et4NF‚4HF as a fluorine source and a solvent (same
conditions as the anodic fluorination of benzene18) (run
2). The starting sulfide and monofluorinated product
were almost consumed (GC-mass analysis) after 4 F/mol
of charge, theoretical amount for difluorination, was
passed. This result suggested that the current efficiency
should be improved by using Et4NF‚4HF compared to the
case of using Et3N‚3HF (run 1) as a fluorine source.
However, the yield of the desired difluorinated product
3a was very low (6%). The 19F NMR spectrum of the
crude product was complicated and indicated that the
nonregioselective polyfluorination occurred, i.e., fluorina-
tion at the aromatic ring as well as at the R-position to
the sulfur atom. The detection of diphenyl disulfide and
its oxidation products by GC-mass analysis, suggested
that oxidative cleavage of a carbon-sulfur bond also
occurred. From these results, it is considered that
fluorinating ability of Et4NF‚4HF is too high to fluorinate
1a regioselectively in the conditions of run 2.
(1) Part 22: Hou, Y.; Higashiya, S.; Fuchigami, T. J . Org. Chem.,
in press.
(2) Present address: Faculty of Engineering, Shizuoka University.
(3) Biomedicinal Aspects of Fluorine Chemistry; Filler, R., Koba-
yashi, Y., Eds.; Kodansha & Elsevier Biomedical: Tokyo, 1982.
(4) Welch, J . T. Tetrahedron 1987, 43, 3123.
(5) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chem-
istry; Wiley: New York, 1991.
(6) Yoshioka, H.; Nakayama, C.; Matsuo, N. J . Synth. Org. Chem.
J pn. 1984, 42, 809.
(7) Narizuka, S.; Fuchigami, T. Bioorg. Med. Chem. Lett. 1995, 5,
1293.
(8) Mathey, F.; Bensoam, J . Tetrahedron 1975, 31, 391.
(9) Olah, G. A.; Nojima, M.; Kerekes, I. J . Am. Chem. Soc. 1974,
96, 925.
(10) Boswell, G. A., Ripka, W. C.; Schribner, R. M.; Tullock, C. W.
Org. React. 1974, 21, 1.
(11) Middleton, W. H. J . Org. Chem. 1975, 40, 574.
(12) Sondej, S. C.; Katzenellenbogen, J . A. J . Org. Chem. 1986, 51,
3508.
To conduct anodic difluorination under milder condi-
tions, acetonitrile was added as a solvent. Anodic diflu-
orination of 1a in 0.2 M Et4NF‚4HF/CH3CN proceeded
smoothly without passivation of the anode to give a
satisfactory result (run 3). It is notable that the current
efficiency increased five times. The yield of difluorinated
(13) Kuroboshi, M.; Hiyama, T. Synlett. 1991, 909.
(14) Motherwell, W. B.; Wilkinson, J . A. Synlett. 1991, 191.
(15) Yoshiyama, T.; Fuchigami, T. Chem. Lett. 1992, 1995.
(16) Fuchigami, T.; Fujita, T. J . Org. Chem. 1994, 59, 7190.
(17) (a) Fuchigami, T.; Shimojo, M.; Konno, A.; Nakagawa, K. J . Org.
Chem. 1990, 55, 6074. (b) Fuchigami, T.; Shimojo, M.; Konno, A. J .
Org. Chem. 1995, 60, 3459 and references therein.
(18) Momota, K.; Morita, M.; Matsuda, Y. Electrochim. Acta 1993,
38, 1123.
S0022-3263(97)01248-6 CCC: $14.00 © 1997 American Chemical Society

8580 J . Org. Chem., Vol. 62, No. 24, 1997
Notes
Sch em e 2
was observed in the fluorination of benzyl R-(phenylthio)-
acetate (1b) (run 2). It is remarkable that anodic
difluorination proceeded with such a high regioselectivity
despite higher anodic potential required for difluorination
compared to monofluorination. Phosphonate derivative
1c was also difluorinated in fairly good yield, and the
difluorinated product 3c should be a promising building
block for biologically interested difluoromethylenephos-
phonates20 (run 3). The yield of difluorinated product
from cyano derivative 1d was rather low (run 4). Anodic
difluorination of aliphatic sulfide 1e also occurred as
efficiently as phenyl sulfides (run 5). It is noteworthy
that these fluorinations could all be conducted in an
undivided cell because reduction of protons of hydrogen
fluoride took place at the cathode predominantly, and
fluorinated products were not reduced under these condi-
tions.
In conclusion, direct anodic difluorination of sulfides
having electron-withdrawing groups at R to the sulfur
atom was successfully carried out with high current
efficiencies and in reasonable yields using a novel molten
salt Et4NF‚4HF as a supporting electrolyte and a fluorine
source in acetonitrile. Furthermore, biologically interest-
ing difluoromethylenephosphonate could be obtained
directly from nonfluorinated methylenephosphonate in
good yield by this method.
F igu r e 1. Current-potential curves: 0.37 M Et3N‚3HF/MeCN
(∆), 0.1 M PhSCHFCOOEt in 0.37 M Et3N‚3HF/MeCN (O),
0.2 M Et4NF‚4HF/MeCN (2).
Ta ble 2. An od ic Diflu or in a tion of Su lfid es Bea r in g
Electr on -With d r a w in g Su bstitu en ts
product
yield, %
anodic
charge
passed,
sulfide
potential,
run no.
R
EWG
V vs Ag/Ag+ F/mol
2a
3a
1
2
3
4
5
1a Ph
1b Ph
1c Ph
1d Ph
COOEt
COOBn
PO(OEt)2
CN
1.6-1.9
1.5-1.9
1.8-2.1
1.8-2.0
1.9-2.3
4.0
4.0
4.0
4.0
4.6
4
2
0
52
52
50
30 30
53
1e C7H15 COOEt
2
product 3a was reasonable considering the lack of ef-
ficient methods for direct difluorination of a methylene
group. Anodic fluorination using other fluorine sources
and supporting electrolytes were not effective as shown
in Table 1 (runs 4 and 5). In these cases, electrolysis
gave a complex mixture containing oxygenated products
detected by GC-mass analysis, and fluorinated products
were not detected by 19F NMR at all. The best yield and
current efficiency of 3a were obtained using Et4NF‚4HF
as a supporting electrolyte and acetonitrile as a solvent.
This improvement by using Et4NF‚4HF instead of
Et3N‚3HF is well explained by considering current-
potential relationships of electrolytes (Figure 1). As
anodic potential was increased, the oxidation of Et3N‚3HF
started around 1.2 V vs Ag/Ag+ at which potential
monofluorinated sulfide 2a is oxidized considerably. On
the other hand, Et4NF‚4HF is almost stable even at the
potential of 2.0 V vs Ag/Ag+. Figure 1 clearly shows that
the current efficiency of anodic difluorination increases
markedly when oxidation potentials of supporting elec-
trolytes are high enough. Thus, in the electrolyte con-
taining Et4NF‚4HF, anodic oxidation of monofluorinated
product took place preferably.
It is also notable that, in this anodic difluorination, the
addition of acetonitrile as a solvent resulted in improve-
ment of the yield of the desired difluorinated product.
This is sharp contrast to the case of anodic fluorination
of benzene: i.e., the addition of acetonitrile resulted in
decrease of both the yield and the current efficiency of
fluorination.19
The results of anodic difluorinations of several sulfides
having electron-withdrawing groups were summarized
in Table 2. In all cases, anodic difluorination takes place
R to the sulfur atom regioselectively. For example,
neither aromatic fluorination nor benzylic fluorination
Exp er im en ta l Section
Caution: Et4NF‚4HF is toxic, and contact with skin causes
serious burns. Et3N‚3HF is much less aggressive. However,
proper safety precautions should be taken at all times. It is
therefore recommended to refer to an authoritative paper21 for
treatment of HF and related compounds.
1H NMR and 19F NMR spectra were recorded at 270 or 90
MHz using CDCl3 as a solvent. The chemical shifts for 1H and
19F NMR are given in δ (ppm) downfield from internal Me4Si
and from external CF3COOH, respectively. High-resolution
mass spectra were obtained with a Hitachi M-80B GC-mass
spectrometer. Cyclic voltammetric and preparative electrolysis
experiments were carried out using a Hokutodenko HA-501
Potentiostat/Galvanostat equipped with a Hokutodenko HF-201
digital coulometer.
An od ic Diflu or in a tion of Su lfid es. Typical anodic diflu-
orination conditions are as follows. Electrolysis was conducted
with a platinum anode and cathode [6 cm2 (2 × 3 cm)] in 0.2 M
Et4NF‚4HF/CH3CN (30 mL) containing 3.0 mmol of sulfides
using a cylindrical undivided cell made of PFA resin at ambient
temperature. After the starting sulfide and monofluorinated
intermediate were almost consumed (monitored by silica gel TLC
and GC-mass spectra), the electrolysis solution was passed
through a short column of silica gel (CH2Cl2) to yield an almost
pure difluorinated product.
Eth yl r,r-d iflu or o-r-(p h en ylth io)a ceta te (3a ): 1H NMR
δ 1.25 (t, 3H, J ) 7.0 Hz), 4.22 (q, 2H, J ) 7.0 Hz), 7.0-7.8 (m,
5H); 19F NMR δ -3.3 (s); IR 3010, 1785, 1480, 1450, 1380, 1300,
1135, 1120, 1075, 1025, 980, 760, 695 cm-1; MS m/e 232 (M+),
159 (M+ - COOEt), 109 (PhS+), 77 (Ph+). Anal. Calcd for
C
10H10F2O2S: C, 51.72; H, 4.34. Found: C, 51.75; H, 4.51.
(20) Blades, K.; Cockerill, G. S.; Easterfield, H. J .; Lequeux, T. P.;
Percy, J . M. J . Chem. Soc., Chem. Commun. 1996, 1615.
(21) Peters, D.; Miethchen, R. J . Fluorine Chem. 1996, 79, 161.
(19) Momota, K.; Morita, M.; Matsuda, Y. Electrochim. Acta 1993,
38, 619.

Notes
J . Org. Chem., Vol. 62, No. 24, 1997 8581
Ben zyl r,r-d iflu or o-r-(p h en ylth io)a ceta te (3b): 1H NMR
Hz), 4.36 (q, 2H, J ) 7.2 Hz); 19F NMR δ -3.3 (s); IR 2932, 2862,
1771, 1468, 1373, 1296, 1102, 1017, 986, 723 cm-1; MS m/e 254
(M+), 181 (M+ - COOEt), 131 (C7H15S+), 97 (C7H13+); calcd for
C11H20F2O2S m/e 254.1152, found 254.1146.
δ 5.21 (s, 2H), 7.2-7.5 (m, 8H), 7.5-7.6 (m, 2H); 19F NMR δ
-3.3 (s); IR 3065, 3040, 2960, 1765, 1500, 1475, 1455, 1445, 1285,
1105, 990, 750, 690 cm-1; MS m/e 294 (M+), 159 (M+
-
COOCH2Ph), 109 (PhS+), 91 (PhCH2+), 77 (Ph+); calcd for
C
15H12F2O2S m/e 294.0526, found 294.0518.
Dieth yl r,r-d iflu or o-r-(p h en ylth io)m eth ylp h osp h on a te
Ack n ow led gm en t. We are grateful to Dr. Kunitaka
Momota of Morita Chemical Industries Co. Ltd. for his
generous gift of Et4NF‚4HF.
(3c): 1H NMR δ 1.38 (t, 6H, J ) 7.1 Hz), 4.30 (m, 4H), 7.4-7.5
(m, 3H), 7.6-7.7 (m, 2H); 19F NMR δ -6.7 (d, 1F, J ) 145 Hz),
-7.1 (d, 1F, J ) 145 Hz); IR 3080, 2960, 1275, 1117, 1036, 912,
750 cm-1; MS m/e 296 (M+), 214 (PhPO(OEt)2), 159 (M+ - PO-
(OEt)2), 109 (PhS+), 77 (Ph+); calcd for C11H15F2O3PS m/e
296.0447, found 296.0464.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR one-dimen-
sional spectra for compounds 3b-e (4 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.
r,r-d iflu or o-r-(p h en ylth io)a ceton itr ile (3d ): 1H NMR δ
7.3-7.8 (m); 19F NMR δ 8.6 (s); IR 3065, 2930, 2190, 1462, 1446,
1135, 940, 752, 700 cm-1; MS m/e 185 (M+), 109 (PhS+), 77 (Ph+);
calcd for C8H5F2NS m/e 185.0111, found 185.0117.
Eth yl r,r-d iflu or o-r-(h ep tylth io)a ceta te (3e): 1H NMR
δ 0.89 (t, 3H, J ) 5.7 Hz), 1.2-1.9 (m, 12H), 2.87 (t, 2H, J ) 7.0
J O971248I