Electrochemical fluorination using alkali-metal fluorides

Article abstract of DOI:10.1002/anie.201200438

Charged up: The selective electrochemical fluorination of organic compounds using the alkali-metal fluoride KF under very mild reaction conditions has been accomplished (see scheme). The long-standing problems of low solubility of metal fluorides in organic solvent and low nucleophilicity of fluoride ions for fluorination have been overcome by the use of of poly(ethylene glycol). Copyright

Full text of DOI:10.1002/anie.201200438

Angewandte
Chemie
DOI: 10.1002/anie.201200438
Synthetic Methods
Electrochemical Fluorination Using Alkali-Metal Fluorides**
Takahiro Sawamura, Kohta Takahashi, Shinsuke Inagi, and Toshio Fuchigami*
Electrochemical partial fluorination of organic compounds
has been established as a powerful tool for selective
fluorination under mild reaction conditions in the last two
decades.[1] Electrochemical fluorination has generally been
carried out in organic solvents containing HF salts such as
Et3N·nHF and Et4NF·nHF as both a supporting electrolyte
and fluorine source. The selective electrochemical fluorina-
tion of aromatic compounds and heteroatom compounds has
been achieved using these HF salts.[1] However, these salts are
costly and in particular, HF salts having a high HF content are
toxic and need to be handled carefully.
Inorganic fluoride salts such as alkali-metal fluorides
(MFs) are stable, easy to handle, and inexpensive. Therefore
Figure 1. Poly(ethylene glycol) having two terminal hydroxy groups
serves as a multifunctional additive for anodic fluorination using KF.
they are strong candidates for reagents in nucleophilic
fluorination as well as supporting electrolytes in chemical
and electrochemical fluorination. The challenge to overcome
problems such as poor solubility and low nucleophilicity of
MF in organic solvents is important.
We previously reported that poly(ethylene glycol) addi-
tives have a positive effect on anodic fluorination in ionic
liquid hydrogen fluorides (Et4NF·nHF).[4] To improve the
nucleophilicity of fluoride ions on anodic fluorination,
poly(ethylene glycol) [Mn ꢀ 200; PEG 200] having the ability
to coordinate a cation was introduced as an additive into the
reaction system in Et4NF·nHF. It was found that PEG 200
served as a good solvating agent for the ammonium cations
because of their coordination ability. Its stability for anodic
oxidation was also promising. According to a previous study,
we selected PEG 200 as a MF-solvating additive. To prove the
effect of poly(ethylene glycol) additives on the solubilization
of MF, we first examined the solubility of CsF and KF in
anhydrous MeCN in the presence of PEG 200 (0.3m) by using
neutralization titration techniques. The results are summar-
ized in Table 1. Although CsF and KF were hardly soluble in
MeCN without additives, the addition of PEG 200 improved
the solubility of CsF and KF up to 500 and 700 times,
respectively. Moreover, the linear sweep voltammograms of
KF only (Figure 2, trace a) and KF in the presence of 0.3m
PEG 200 (Figure 2, trace b) were measured in MeCN. For KF
only, no current was observed within the range of the applied
potential, that is, KF was hardly dissolved in MeCN, thus
making it difficult to provide sufficient ionic conductivity in
the MeCN solution. In sharp contrast, for KF in the presence
of PEG 200 an oxidation current for MeCN [over a range of
Phase-transfer catalysts such as crown ethers and quater-
nary ammonium or phosphonium salts are known to reduce
the Coulombic interactions of MFs and are commonly used.[2]
Recently, Kim and co-workers have demonstrated that either
tri- or tetraethylene glycol (terminal group: OH) could
dissociate MF into the fluoride anion and the metal cation
in aprotic polar solvents. As a result, nucleophilic fluorination
of organic compounds using potassium fluoride (KF) was
achieved in tri- and tetraethylene glycol.[3] However, this
method has a few drawbacks in that the reaction requires
a large amount of poly(ethylene glycol) solvent and harsh
reaction conditions such as high temperatures. In addition,
the substrates have to bear good leaving groups such as
tosylate and mesylate for the fluorination to proceed.
With this knowledge, we expected electrochemical fluo-
rination using MF as both the fluorine source and supporting
electrolyte in the presence of poly(ethylene glycol) as an
additive would proceed smoothly (Figure 1). Herein, we
report successful anodic fluorination in combination with an
electrochemical method using a poly(ethylene glycol)/MF
system where MF is either KF or CsF.
[*] Dr. T. Sawamura, K. Takahashi, Dr. S. Inagi, Prof. Dr. T. Fuchigami
Department of Electronic Chemistry, Tokyo Institute of Technology
Nagatsuta, Midori-ku, Yokohama 226-8502 (Japan)
E-mail: fuchi@echem.titech.ac.jp
Table 1: Solubility of MF in anhydrous MeCN with and without
a poly(ethylene glycol) additive.
Homepage: http://www.echem.titech.ac.jp/~fuchi/english-
top2.html
Entry
MF
Additive
Solubility in MeCN[a]
[**] This study was supported by a Grant-in-Aid for Scientific Research
(B) (No. 20350071). One of the authors (T.S.) also thanks the Japan
Society for the Promotion of Science (JSPS) for financial support of
his research fellowship.
1
2
3
4
CsF
CsF
KF
–
0.1 mm (15.2 mgLÀ1
)
)
PEG[b]
–
50 mm (7.6 gLÀ1
)
0.04 mm (2.3 mgLÀ1
28 mm (1.63 gLÀ1
KF
PEG[b]
)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200438.
[a] Determined by neutralizing titration techniques. [b] 0.3m PEG.
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using KF requires high reaction temperatures of up to at least
1008C.[3,5] Hence, the electrochemical method is of great
significance. In contrast, when we used [18]crown-6 ether and
poly(ethylene glycol)dimethyl ether [Mn ꢀ 250] as an additive,
for which a hydrogen-bonding effect with MF is not expected,
the fluorination proceeded in much lower yield than that
using PEG 200 (entries 6 and 7). These facts indicated that the
additive, PEG 200, worked not only to dissolve MF in MeCN,
but also to accelerate the anodic fluorination under very mild
reaction conditions. MeCN was found to be a better medium
than nitromethane (MeNO2) and dimethoxyethane (DME;
entries 4, 8, and 9).
Moreover, after electrolysis, the fluorinated product was
easily and solely extracted from the electrolytic solution with
n-hexane and the residual solution containing MF and PEG
could be reused for subsequent runs (Figure 3). As shown in
Figure 2. Linear sweep voltammograms of a) KF (0.04 mm) in MeCN
and b) KF (28 mm) in the presence of 0.3m PEG 200 in MeCN.
Recorded with a Pt disk working electrode (f=1.6 mm). The scan rate
was 100 mVsÀ1
.
2.0 V versus a saturated calomel electrode (SCE)] and
a reduction current for the H+ ion from PEG 200 could be
clearly observed. The result indicates that KF is dissolved in
the presence of PEG 200 in MeCN and serves as an ionic
carrier. With these results, the PEG/MF system appeared to
be applicable to electrochemical fluorination of organic
compounds.
We then investigated the anodic fluorination of triphenyl-
methane (1a) as a model substrate in the presence of MF and
PEG 200 in MeCN. As shown in Table 2, anodic fluorination
using CsF in the absence of additives at 408C provided
fluorinated product 2 in extremely low yield (entry 1),
whereas anodic fluorinations using CsF and PEG 200 pro-
ceeded efficiently at 208C and 408C to provide 2 in moderate
and excellent yields, respectively (entries 2 and 3). Surpris-
ingly, the use of the more inactive KF instead of CsF afforded
the similar results (entries 4 and 5). To the best of our
knowledge, other chemical nucleophilic partial fluorinations
Figure 3. Experimental schematic for anodic fluorination of 1a. Data
for the reusability of electrolytic solution containing KF and PEG.
Figure 3, the yield of 2 was kept at more than 80% upon the
reuse of the electrolytic solution containing KF and PEG
through the fourth run. The use of excess amounts of KF and
PEG relative to the substrate is suitable for repeat runs of the
fluorination. In addition, anodic passivation (formation of
nonconductive polymeric films on the anode) did not take
place at all during the electrolysis. This is in sharp contrast to
conventional anodic fluorination using amine HF salts, which
very often cause serious anode passivation.[1]
Table 2: Anodic fluorination of triphenylmethane using MF.[a]
This clearly suggests that the MF/PEG/MeCN electrolytic
system is recyclable for the selective fluorination of 1a.
Next, we investigated the anodic fluorodesulfurization of
phenyltriphenylmethylsulfide (1b) and dithioacetals 3 with
either CsF or KF in MeCN in the presence of 0.3m PEG 200.
Phenyltriphenylmethylsulfide (1b; Scheme 1) was also con-
Entry
MF (5 equiv)
Solvent
T [8C]
Yield [%][b]
1[c]
2
3
CsF
CsF
CsF
KF
KF
KF
KF
KF
KF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeNO2
DME
40
20
40
20
40
40
20
20
20
2
52
95 (85)[d]
4
5
47
91 (79)[d]
6[e]
7[f]
8
22
18
8
9
trace
[a] Used 0.3m PEG. [b] Determined by 19F NMR spectroscopy. [c] Run in
the absence of PEG. [d] Yield of isolated product is given within
parentheses. [e] Used 0.3m [18]crown-6 ether as an additive. [f] Used
0.3m poly(ethylene glycol)dimethyl ether [Mn ꢀ250] as an additive.
Scheme 1. Anodic fluorination of phenyltriphenylmethylsulfide using
the KF/PEG system.
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Table 4: Anodic fluorination of triphenylphosphine and triphenylanti-
mony using KF.[a]
verted into the corresponding fluorodesulfurization product 2
in quantitative yield by using KF at 408C. In the case of the
dithioacetals 3, we previously found that the anodic fluorina-
tion of 3 showed a selectivity dependence on electrolysis
method.[6,7] The direct anodic fluorination of 3 provided
difluorinated compounds as a major product,[6] while indirect
anodic fluorination using a bromine mediator provided
monofluorinated compound as a major product.[7] Interest-
ingly, we selectively obtained the corresponding mono-
fluorodesulfurization products 4 without formation of the
difluorinated product by the direct electrochemical fluorina-
tion of 3 in this system (Table 3). In entry 1, the anodic
Entry
Z
T [8C]
Yield [%][b]
1[c]
2
3
P
P
P
Sb
40
20
40
40
7: trace
7: 26
7: 74 (64)[d]
8: 52 (39)[d]
4
[a] Used 0.3m PEG. [b] Determined by 19F NMR spectroscopy. [c] In the
absence of PEG. [d] Yield of isolated product given within parentheses.
Table 3: Anodic fluorination of dithioacetals using MF.[a]
The anodic difluorination of thionoester 9 was also
investigated using this KF/PEG system (Scheme 2). The
reaction proceeded to give the difluorinated product 10 in
moderate yield, whereas the product was hardly obtained by
the conventional method using on HF salts.[4b]
Entry
X
MF (5 equiv)
T [8C]
Yield [%][b,c]
1[d]
2
3
4
5
6
7
8
9
H
H
H
H
Cl
Cl
Cl
Cl
Br
CsF
CsF
KF
20
20
20
40
20
40
20
40
40
trace
quant.
82
KF
quant. (89)[e]
75
CsF
CsF
KF
KF
KF
quant.
48
quant. (84)[e]
quant. (85)[e]
Scheme 2. Anodic difluorination of thionoester using the KF/PEG
system.
[a] Used 0.3m PEG. [b] Determined by 19F NMR spectroscopy.
[c] Difluorinated compound was not obtained. [d] Run in the absence of
PEG. [e] Yield of isolated product is given within parentheses.
In conclusion, we have developed a novel electrolytic
system for selective anodic fluorination of various organic
compounds using MF/PEG in MeCN. The PEG 200 additive
effectively enhanced the solubility of KF and CsF, and the
yield of the fluorinated products. This system has many
practical advantages and characteristics: a) it proceeds under
very mild reaction conditions (20–408C); b) it uses cheap and
safe MF and PEG; c) the MF plays roles as both the fluorine
source and the supporting electrolyte; d) the fluorinated
products can be easily separated from the electrolytic solution
containing MF and PEG; and e) the electrolytic solution is
electrochemically stabile and can be recycled. We expect to
develop this new methodology as a basic concept in electro-
organic synthesis. For example, we are currently conducting
the use of cheap and safe inorganic salts dissolved by PEG in
MeCN for a variety of electrolytic reactions. The scope and
limitations of the method are now under investigation.
fluorination of 3a using CsF in the absence of PEG 200 gave
a trace amount of the monofluorinated product because of the
low solubility of CsF. However, in the CsF/PEG system, the
fluorinated product 4a was obtained quantitatively at 208C
(entry 2). When we used KF as the fluorine source and
supporting electrolyte, the anodic fluorodesulfurization of 3a
proceeded effectively in 82% yield at 208C, and quantita-
tively at 408C (entries 3 and 4). Compounds 3b and 3c, in
which a chlorine or bromine substituent was introduced at the
para position of the benzene ring, also provided mono-
fluorodesulfurization products quantitatively using KF at
408C (entries 8 and 9). The MF/PEG-based anodic fluorina-
tion seems to be a promising method for smoothly converting
À
À
C S bonds into C F bonds.
In 1968, Kobayashi and his co-workers reported that
difluorotriphenylphosphine (7) had utility as a fluorinating
agent for alcohols.[8] We therefore applied this electrolytic
system to the anodic fluorine addition reaction of triphenyl-
phosphine (5) and triphenylantimony (6) in the presence of
KF and PEG 200 in MeCN (Table 4). As expected, corre-
sponding difluorinated products 7 and 8 were obtained in
good to moderate yields. Thus, the KF/PEG system in MeCN
was also applicable to the fluorine addition reaction of 5 and
6.
Received: January 17, 2012
Published online: March 14, 2012
Keywords: alkali metals · electrochemistry · fluorine ·
.
nucleophilic addition · synthetic methods
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