Highly selective electrochemical fluorination of dithioacetal derivatives bearing electron-withdrawing substituents at the position α to the sulfur atom using poly(HF) salts

Article abstract of DOI:10.3762/bjoc.11.12

Anodic fluorination of dithioacetals bearing electron-withdrawing ester, acetyl, amide, and nitrile groups at their α-positions was comparatively studied using various supporting poly(HF) salts like Et₃N·nHF (n = 3-5) and Et₄NF·nHF (

Full text of DOI:10.3762/bjoc.11.12

Highly selective electrochemical fluorination of dithioacetal
derivatives bearing electron-withdrawing substituents at
the position α to the sulfur atom using poly(HF) salts
Bin Yin, Shinsuke Inagi and Toshio Fuchigami*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 85–91.
Department of Electronic Chemistry, Tokyo Institute of Technology,
Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
doi:10.3762/bjoc.11.12
Received: 13 November 2014
Accepted: 08 January 2015
Published: 19 January 2015
Email:
Toshio Fuchigami* - fuchi@echem.titech.ac.jp
* Corresponding author
This article is part of the Thematic Series "Electrosynthesis".
Guest Editor: S. R. Waldvogel
Keywords:
anodic fluorination; anodic fluorodesulfurization; electrosynthesis;
fluorination product selectivity; poly(HF) salt
© 2015 Yin et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Anodic fluorination of dithioacetals bearing electron-withdrawing ester, acetyl, amide, and nitrile groups at their α-positions was
comparatively studied using various supporting poly(HF) salts like Et3N·nHF (n = 3–5) and Et4NF·nHF (n = 3–5). In the former
two cases, the corresponding α-fluorination products or fluorodesulfurization products were obtained selectively depending on
supporting poly(HF) salts used. In sharp contrast, in the latter two cases, fluorination product selectivity was strongly affected by
the electron-withdrawing ability of α-substituents: A dithioacetal bearing a relatively weak electron-withdrawing amide group
provided a fluorodesulfurization product selectively while a dithioacetal having a strongly electron-withdrawing nitrile group gave
the α-fluorination product predominantly regardless of the poly(HF) salts used.
Introduction
The introduction of fluorine atom(s) into organic molecules in mind, we have developed a selective electrochemical fluorin-
very often improves or enhances their desired characteristic ation using ionic liquid poly(HF) salts such as Et3N·nHF and
physical and biological properties hence organofluorine com- Et4NF·nHF (n = 3–5) as supporting electrolyte and fluorine
pounds are highly useful for medicinal, agrochemical, and ma- source [9-11], and we have systematically studied the anodic
terials science [1-6]. In order to prepare new fluorine com- fluorination of various heteroatom-containing compounds
pounds, selective fluorination of organic compounds is including heterocycles and macromolecules so far [12-20].
becoming significantly important. Although the selective fluo-
rination has been extensively studied, highly efficient and safe More than 20 years ago, we reported the first successful
fluorination methods are still demanded [7,8]. With these facts example of the electrochemical selective fluorination of
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Beilstein J. Org. Chem. 2015, 11, 85–91.
heteroatom-containing compounds such as α-(phenylthio)ester are summarized in Table 1. It was expected that the introduc-
and its analogues as shown in Scheme 1 [21,22]. Furthermore, tion of an additional phenylthio group to the α-position of the
anodic fluorodesulfurization of dithioacetals was achieved by sulfides would decrease their oxidation potentials. However,
direct and indirect anodic oxidation in the presence of the unexpectedly they are higher than those of the corresponding
poly(HF) salts [12-16,23-25] or alkali-metal fluorides like KF sulfides having a single phenylthio group. Although a detailed
and CsF with PEG 200 [17]. The anodic fluorination of a reason is not clear at present, the additional phenylthio group
dithioacetal derived from an aliphatic aldehyde provided the does not act as an electroauxiliary, but acts as an electron-with-
fluorodesulfurization product while a dithioacetal derived from drawing group. As shown in Table 1, the oxidation potentials of
an aromatic aldehyde provided the α-fluorination product sulfide 1g and dithioacetal 1h having a stronger electron-with-
(Scheme 2) [25]. These results suggest that the fluorinated prod- drawing cyano group (Taft σ* = +1.30) [29] are much higher
uct selectivity seems to be controlled by the easiness of the compared to those of 1a, 1b with an ester group (Taft
deprotonation of the cationic intermediate A. Namely, since the σ* = +0.69) [29] and 1c, 1d with an acetyl group (Taft
α-proton of the aromatic dithioacetal is more acidic compared to σ* = +0.60) [29], respectively. This indicates that the polar
that of an aliphatic dithioacetal, the deprotonation of the former effect, namely electron-withdrawing effect of a substituent
is faster than it is for the latter. Therefore, it can be stated that greatly affects the electron-transfer step from the substrate to
the product selectivity is controlled by the kinetic acidity of the the anode.
cationic intermediate A [26,27].
Table 1: First oxidation potentials,
of compounds 1.
Substrate
X
R (σ* value)a
(V vs SCE)b
1a
1b
1c
1d
1e
1f
H
COOEt (+ 0.69)
COOEt (+ 0.69)
COMe (+ 0.60)
COMe (+ 0.60)
CONEt2
1.60
1.73
1.59
1.63
1.60
1.64
1.85
2.04
Scheme 1: Anodic fluorination of sulfides having an electron-with-
drawing group.
SPh
H
SPh
H
With these facts in mind, we studied comparatively the anodic
fluorination of dithioacetal derivatives having various electron-
withdrawing groups at their α-positions using various poly(HF)
salts [28].
SPh
H
CONEt2
1g
1h
CN (+ 1.30)
CN (+ 1.30)
SPh
aFrom [29]. bSubstrate concentration: 5 mM; sweep rate: 100 mV/s;
working electrode: Pt disk (Ø = 1 mm).
Results and Discussion
Various α-substituted methyl phenyl sulfides, 1a, 1c, 1e, and
1g, and their α-phenylthio derivatives (dithioacetals) were At first, anodic fluorination of ethyl α,α-bis(phenylthio)acetate
prepared, and their oxidation potentials ( ) were measured (1b) [30,31] was carried out at platinum plate electrodes in an
by cyclic voltammetry in an anhydrous acetonitrile (MeCN) undivided cell using various solvents in the presence of
solution containing n-Bu4NBF4 (0.1 M) using a platinum disk Et3N·3HF as supporting salt and fluorine source. A constant
working electrode and a saturated calomel electrode (SCE) as current was passed until the starting material 1b was completely
the reference electrode. All compounds exhibited irreversible consumed (monitored by TLC). As shown in Table 2, the
multiple oxidation peaks and the first oxidation peak potentials anodic fluorination of 1b proceeded to give the corresponding
Scheme 2: Anodic fluorination of dithioacetals.
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Beilstein J. Org. Chem. 2015, 11, 85–91.
Table 2: Anodic fluorination of 1b in various solvents containing Et3N·3HFa.
Entry
Solvent
Charge passed (F/mol)
Yield (%)b,c
Total yield (%)
2b
3b
4b
1
MeCN
DME
3.0
5.0
2.5
2.2
–
74 (70)
74
9
9
5
7
–
0
0
4
1
–
83
83
82
81
–
2
3
CH2Cl2
MeNO2
MeCN
73
4
73
5d
–
aConstant current (8 mA/cm2) electrolysis was carried out in 0.3 M Et3N·3HF/solvent. bDetermined by 19F NMR. cIsolated yield given in parentheses.
dMechanical stirring was performed overnight at ambient temperature without electrolysis.
α-fluoro product 2b in a good yield regardless of the solvent (Table 2, entry 5). Therefor electrolysis is necessary for the
used. Thus, it was found that the solvents did not affect the fluorination to take place.
yield of 2b in contrast to the current efficiency. When the reac-
tion was performed in DME as the solvent, anodic decomposi- Among the solvents tested for electrolysis, we decided to use
tion of DME took place simultaneously with the anodic fluorin- MeCN for further studies on the anodic fluorination based on a
ation of 1b, which resulted in low current efficiency. In all good current efficiency and the formation of only one
cases, fluorodesulfurization product 3b [22] was detected in byproduct.
considerable yield. When CH2Cl2 and MeNO2 were used, a
small amount of ethyl α,α-difluoro-α-(phenylthio)acetate (4b) Next, anodic fluorination of 1b was carried out in MeCN using
[22] was also detected (Table 2, entries 3 and 4). As a blank various poly(HF) salts until the substrate was completely
test, the electrolytic solution of 1b was mechanically stirred consumed and the results are shown in Figure 1. As mentioned
without electrolysis overnight and 1b was mostly recovered earlier, the anodic fluorination of 1b using Et3N·3HF provided
Figure 1: Dependency of fluorinated product selectivity on a series of fluoride salts (a) Et3N·nHF (n = 3–5) and (b) Et4NF·nHF (n = 3–5).
87

Beilstein J. Org. Chem. 2015, 11, 85–91.
α-fluorinated product 2b selectively in good yield along with a fluorination of N,N-diethyl-α,α-bis(phenylthio)acetamide (1f)
small amount of fluorodesulfurization product 3b. In contrast, with Et3N·3HF required a large excess amount of electricity to
the fluorodesulfurization reaction was significantly promoted consume the starting substrate 1f, and fluorodesulfurization
with increasing HF content of the poly(HF) salts; especially the took place exclusively to provide the corresponding mono- and
use of Et3N·5HF gave predominantly the fluorodesulfurization difluorinated products 3f and 4f [22,34] with the same ratio in
product 3b in 85% yield (Figure 1a). Previously, we obtained rather low yields (Table 3, entry 5). The longer electrolysis
3b in 75% yield by constant potential anodic oxidation of ethyl caused the formation of complicated products. This result is
α-(phenylthio)acetate in a similar electrolytic solution [22]. A quite different from the case of 1b and 1d (Table 2, entry 1 and
comparable dependency of product selectivity on supporting Table 3, entry 1). Such different anodic behavior may be attrib-
poly(HF) salts was also observed in a series of Et4NF·nHF utable to different pKa values of the α-proton of the substrates.
(n = 3–5) although the product yields are moderate (Figure 1b). It is known that the acidity of the α-proton of N,N-diethylace-
toamide is 4 to 5 times lower than that of acetone and ethyl
According to these results, we carried out the anodic fluorin- acetate [35]. Therefore, the acidity of the α-proton of 1f having
ation of other dithioacetals bearing different electron-with- an amide group would be much lower compared to that of 1b
drawing substituents such as acetyl, amide, and cyano groups and 1d having an ester and acetyl group, respectively. Thus, it is
under similar conditions. The results are summarized in reasonable that no deprotonation of the cationic intermediate of
Table 3. In the case of α,α-bis(phenylthio)acetone (1d) [32], the 1f took place. Moreover, when a higher HF content poly(HF)
use of Et3N·3HF and Et4NF·3HF resulted in predominant salt like Et3N·5HF was used, fluorodesulfurization product 3f
α-fluorination to provide the corresponding monofluorinated was exclusively formed in good yield. This tendency is quite
product 2d in good to moderate yields (Table 3, entries 1 and similar to the result of anodic fluorination of 1b and 1d
3). On the contrary, when higher HF content salts such as (Figure 1a and Table 3, entries 2 and 4). Thus, it was found that
Et3N·5HF and Et4NF·5HF were used, fluorodesulfurization due to the low acidity of the α-proton of 1f, fluorodesulfuriza-
product 3d [22] was obtained almost exclusively in moderate or tion took place prior to α-fluorination even in the presence of
good yield (Table 3, entries 2 and 4). Regardless of poly(HF) Et3N·3HF containing the free base Et3N. In sharp contrast to
salts, difluorinated product 4d [33] was always formed due to these cases, α,α-bis(phenylthio)acetonitrile (1h) [36] bearing a
the further oxidation of products 2d and 3d. In contrast, anodic strongly electron-withdrawing cyano group underwent α-fluo-
Table 3: Anodic fluorination of dithioacetal derivative 1 in acetonitrilea.
Entry
R
Supporting electrolyte
Charge passed (F/mol)
Yield (%)b,c
2
3
4
1
COMe (1d)
COMe (1d)
COMe (1d)
COMe (1d)
CONEt2 (1f)
CONEt2 (1f)
CN (1h)
Et3N·3HF
Et3N·5HF
Et4NF·3HF
Et4NF·5HF
Et3N·3HF
Et3N·5HF
Et3N·3HF
Et3N·4HF
Et3N·5HF
Et4NF·3HF
Et4NF·4HF
Et4NF·5HF
3.0
2.5
2.7
2.5
5.0
3.0
3.0
2.8
2.5
2.7
2.5
2.5
80 (66)
–
5
2
–
63
3
3
60
6
–
10
1
4
78 (70)
5
0
18
17
1
6
0
72 (63)
7
98 (87)
98
90
94
95
93
0
0
0
0
0
0
0
8
CN (1h)
0
9
CN (1h)
0
10
11
12
CN (1h)
0
CN (1h)
0
CN (1h)
0
aConstant current (8 mA/cm2) electrolysis was carried out using 0.3 M supporting fluoride salt. bDetermined by 19F NMR. cIsolated yields are given in
parentheses.
88

Beilstein J. Org. Chem. 2015, 11, 85–91.
rination exclusively to produce α-fluorinated product 2h in ization occurs to provide the corresponding difluorinated prod-
excellent yields regardless of the poly(HF) salts (Table 3, ucts 4b and 4d, respectively. On the other hand, the desulfuriz-
entries 7–12). In case of 1h, no difluoro product was formed at ation of intermediate D followed by reaction with fluoride
all, which is probably due to a much higher oxidation potential provides the corresponding fluorodesulfurization products 3b,
of 2h compared to that of the starting substrate 1h. In support of 3d, and 3f.
this, we have already shown that introduction of one fluorine
atom to the α-position of α-(phenylthio)acetonitrile increased When high HF content salts like Et3N·5HF and Et4NF·nHF
the oxidation potential by 0.36 V [22].
(n = 4, 5) are used, the higher concentration of HF in the elec-
trolytic solution would increase the amount of D rather than E
A plausible mechanism for the anodic fluorination of dithio- in an equilibrium between them as shown in Scheme 4. Namely,
acetals 1b, 1d, and 1f is shown in Scheme 3. The fluorination the deprotonation of D would be retarded due to high concentra-
reaction is initiated by electron transfer from a sulfur atom of tion of protons in the solution, and consequently the C–S bond
the substrate to generate the corresponding radical cation B, cleavage seems to take place more favorably than a deprotona-
which traps a fluoride ion to afford radical C. This is followed tion. A similar effect on the suppression of defluorination of
by a further oxidation to give cationic intermediate D. In the CF3-enolate anion in the presence of a large amount of fluoride
cases of 1b and 1d having electron-withdrawing ester and ions has been reported [38].
acetyl groups, the α-protons are acidic enough and can be
cleaved by either base, free Et3N (from Et3N·3HF) [37] or fluo- On the other hand, it is known that the acidity of α-protons of
ride ions (from Et4NF·3HF). The resulting cation E reacts with acetoamides is much lower compared to that of acetate and
a fluoride ion to form 2b and 2d. Further anodic fluorodesulfur- acetone as mentioned. Therefore, it is understandable that the
Scheme 3: Plausible reaction mechanism for anodic fluorination of 1b, 1d, and 1f.
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Beilstein J. Org. Chem. 2015, 11, 85–91.
Acknowledgements
We gratefully acknowledge Morita Chemical Industries Co.,
Ltd for supplying triethylamine poly(hydrogen fluoride)
[Et3N·nHF (n = 3–5)] and tetraethylammonium fluoride
poly(hydrogen fluoride) [Et4NF·nHF (n = 3–5)] that were used
as supporting salt fluorine source. We also thank technical staffs
working at Center for Advanced Materials Analysis
(Suzukakedai Campus) of Tokyo Institute of Technology for
analyzing new compounds. One of the authors (Y. B.) acknowl-
edges Ministry of Education, Culture, Sports, Science & Tech-
nology of Japan for awarding national scholarship to conduct
this research.
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