Oxidative desulfurization-fluorination reaction promoted by [bdmim][F] for the synthesis of difluorinated methyl ethers

Article abstract of DOI:10.1016/j.tetlet.2015.02.034

A new ionic liquid [bdmim][F] has been prepared and fully characterized. Its potential as a fluoride source for the desulfurization-fluorination process has been evaluated with success. The carbon-sulfur double bond of xanthates and thiocarbonates has bee

Full text of DOI:10.1016/j.tetlet.2015.02.034

Tetrahedron Letters 56 (2015) 1682–1686
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative desulfurization–fluorination reaction promoted
by [bdmim][F] for the synthesis of difluorinated methyl ethers
⇑
Sébastien Bouvet, Bruce Pégot, Patrick Diter, Jérôme Marrot, Emmanuel Magnier
Institut Lavoisier de Versailles (ILV), UMR CNRS 8180, Université de Versailles, St Quentin en Yvelines, 45 avenue des Etats-Unis, 78035 Versailles Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new ionic liquid [bdmim][F] has been prepared and fully characterized. Its potential as a fluoride source
for the desulfurization–fluorination process has been evaluated with success. The carbon–sulfur double
bond of xanthates and thiocarbonates has been difluorinated to give rise to small libraries of halogenated
ketals and thioketals.
Received 20 January 2015
Revised 5 February 2015
Accepted 10 February 2015
Available online 16 February 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Xanthate
Ionic liquids
Fluorine
Desulfurization
Introduction
and solvent, trifluoromethyl ethers C are obtained (Scheme 1).6
Whereas by using TBAH2F37 the difluoro(methylthio)methyl ethers
a
-Fluorinated methyl ethers are a highly important class of
B are isolated in moderate yields as the sole products.6a,b The com-
mon mechanism may be interpreted as a successive bromonium
formation with sulfur atoms followed by iterative nucleophilic
introduction of fluorine substituents.
emergent and promising moieties for various applications, par-
ticularly in materials, and in agrochemical and pharmaceutical
sciences.1 The perfluorination of the carbon adjacent to the oxygen
atom often results in an increased lipophilicity of the molecule as
well as a profound modification of the electronic and steric
parameters.2 These remarkable properties associated with a still
Recently, ionic liquids (ILs) have been proposed as promising
alternatives to many organic solvents. Due to their very distinctive
characteristics (e.g., good solubility for many organic and inorganic
compounds and recyclability),8 these salts rapidly proved to be
efficient solvents for various chemical transformations9 including
nucleophilic fluorination.10 Amine–(HF)n (Onium Poly-Hydrogen
Fluorides) are intrinsically also ionic liquids.11 They have been
used to alleviate the volatility and toxicity of neat anhydrous
HF and also as stable and useful substitutes for hydrogen fluoride
in fluorination of organic compounds.12 Nevertheless, their
availability, preparation, or in some case difficult handling, still
challenging preparation of
a-fluorinated ethers have stimulated
many synthetic works in recent years.3 Two approaches are at
the disposal of the chemist: the direct introduction of a perfluori-
nated methyl group starting from a hydroxyl group or the con-
struction of the perfluorinated ether moiety from a properly
designed organic function. These two methods are complementary
in terms of target molecules as well as their respective scope and
limitations. The second approach, which is also the seminal one,
is versatile as it allows the transformation of the same precursor
to either difluoromethyl- or trifluoromethyl ethers by simply tun-
ing the reaction parameters. Nevertheless, it often requires harsh
conditions or toxic reagents difficult to handle such as CCl4/HF,
SF4, SbF5, MoF6, BrF3, XeF2.4 In the early 90s Hiyama et al. devel-
oped a promising methodology, the oxidative desulfurization–
fluorination reaction. Indeed, by treatment of dithiocarbonates A
(xanthate esters) with 1,3-dibromo-5,5-dimethylhydantoin (DBH)
in hydrogen fluoride–pyridine (Olah’s reagent5) as both reagent
S
X
X
X
S
X
F
X
F
S
R
O
SMe
F
O
R
O
F
SMe
R
SMe
A
F
F
F
F
F
-SX2
X
F
-MeSX
R
OCF3
R
O
SMe
R
O
F
SMe
X
B
C
⇑
Corresponding author. Tel.: +33 1 39254466; fax: +33 1 39254452.
E-mail address: emmanuel.magnier@uvsq.fr (E. Magnier).
Scheme 1. Mechanism of the oxidative desulfurization–fluorination.
http://dx.doi.org/10.1016/j.tetlet.2015.02.034
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

S. Bouvet et al. / Tetrahedron Letters 56 (2015) 1682–1686
1683
remain as limitations. In this context, we assume that an ionic
liquid containing a single fluoride ion may be a solution to these
difficulties. We have indeed recently disclosed an easy access to
1-n-butyl-3-methylimidazolium fluoride [bmim][F] and showed
imidazole ring. The fluoride anion is spatially close to the hydrogen
attached to the C-4 of the imidazole ring. As expected, this is differ-
ent from the [bmim][F] case for which the fluoride anion formed a
hydrogen bond with the hydrogen at the C-2 position. This diagram
showed a close association of one molecule of water and one
molecule of methanol per anion which precluded the possibility
of convenient removal all these two compounds. We assume
furthermore that presence of water accounts for the stability of
our IL.10d
its potential as
a fluorinating agent for mild nucleophilic
substitutions.13
Results and discussion
Optimization of the oxidative desulfurization–fluorination pro-
cess started with S-methyl O-4-bromophenyl dithiocarbonate 3a
as model substrate on a 0.4 mmol scale (Table 1).
The N-bromosuccinimide (NBS) was firstly chosen as the
oxidizing agent. All the reagents were mixed at À30 °C without
As part of our program devoted to the use of fluorinated ionic
liquids, we were really intrigued by their use as a source of fluoride
in a desulfurization–fluorination process, instead of Olah’s reagent.
Herein, we report a practical synthesis of a new fluorinated ionic
liquid and its application as a fluoride source in an oxidative desul-
furization–fluorination reaction for the preparation of difluorinat-
ed ethers. The first tryouts were conducted with [bmim][F] as
both reagent and solvent and were quickly disappointing as the
IL proved incompatible with various oxidative reagents (DBH,
NBS, Br2, etc.). The mixing of the two partners resulted in a strong
exothermic phenomenon, fumes and complete degradation of the
IL. We assume that the acidic proton position C2 of the imidazole
ring is responsible for this unwanted side reaction. This position
is sensitive and can particularly be easily halogenated.14 To cir-
cumvent the problem, we focused our attention on the synthesis
of the unknown 1-n-butyl-2,3-dimethylimidazolium fluoride
([bdmim][F]). The synthesis was achieved in two steps (Scheme 2).
The precursor [bdmim][Cl] was prepared according to the lit-
erature via solvent-free N-alkylation of 1,2-dimethylimidazole
with 1-chlorobutane in closed vessels under monomode micro-
wave irradiation.15 The second step, the anion exchange of azolium
halides, was carried out with potassium fluoride in methanol as the
solvent.16 The desired IL was prepared on a multigram scale and
isolated in pure form without any purification steps and with an
almost quantitative yield.
Table 1
Perfluorination of S-methyl O-4-bromophenyl dithiocarbonate 3a
S
[bdmim][F]
F
F
N-halo imide
Br
O
S
Br
O
S
-30°C to rt, 3h
4a
3a
Entry BDMIMF N-Halo imide
Additive (equiv)
and/or solvent
Yielda (%)
(equiv)
(equiv)
1
2
3
4
5
6
7
8
5
NBS (6)
NBS (6)
NBS (6)
NBS (6)
NBS (9)
NBS (9)
NBS (9)
NBS (12)
DBH (9)
NIS (9)
/
/
14
20
19
17
31
24
10
10
10
10
10
20
10
10
10
10
10
KF(3)/MeOH (1 ml)
CsF(3)/MeOH (1 ml)
CH2Cl2 (4 ml)
CH2Cl2 (7 ml)
CH2Cl2 (4 ml)
CH2Cl2 (4 ml)
CH2Cl2 (4 ml)
CH2Cl2 (4 ml)
CH2Cl2 (4 ml)
22
45 (40)b
9
<5
<5
/
10
11
12
NCS (9)
Selectfluor (9) CH2Cl2 (4 ml)
/
The structure of [bdmim][F] was ascertained by X-ray analysis
(Fig. 1). This diagram revealed that the cationic parts of the IL are
a
Yield determined 19F NMR with 4-(chloro-difluoro-methoxy)-phenylamine as
internal reference.
b
Isolated yield.
associated by
p
-stacking with a distance of 3.405 Å between the
1.2 eq KF, MeOH
rt, 30 min
C4H9Cl, MW
N
N
N
N
N
N
150°C, 15 min
F
Cl
2
95%
1
91%
Scheme 2. Synthesis of [bdmim][F].
Figure 1. Molecular packing diagram of 1-butyl-2,3-dimethylimidazolium fluoride monohydrate.

1684
S. Bouvet et al. / Tetrahedron Letters 56 (2015) 1682–1686
any particular handling precautions and the reaction was then left
to stir at room temperature for 3 h. We were pleased to achieve, in
poor but very encouraging yields, the formation of difluoro deriva-
tive 4a. With 10 equiv of IL, the yield was slightly improved (entry
2). Addition of a supplementary source of fluoride, such as KF or
CsF dissolved in methanol, was not beneficial (entries 3 and 4).
The increase in the number of equivalents of NBS (to a maximum
of 12) allowed the isolation of 4a with an acceptable yield of 40%
(entries 5–8). The presence of a minimum amount of dichloro-
methane (4 ml) was added to simply avoid stirring problems. The
use of other N-halo imides proved inefficient, giving rise either to
complete degradation of the substrate (entries 9 and 10) or to no
conversion at all (entries 11 and 12).
Whatever the conditions employed, no trifluoromethyl ether
was even formed, only the difluoro(methylthio)methyl ethers
were. As a first conclusion, [bdmim][F] appears not as an equiva-
lent of HF–pyridine but more like an analogue of TBAH2F3, the lat-
ter being often prepared with HF. In this context, we were happy to
describe the fluorination of a xanthate with simple IL as a fluoride
source.
The previously optimized conditions (12 equiv of NBS, 10 equiv
of [bdmim][F]) were successfully applied to a wide range of sub-
strates to give rise to the corresponding difluoro(methylth-
io)methyl ethers 4a–f with correct yields for aromatic compounds
(entries 1–6) to low yields for aliphatic series (entries 7 and 8).
The compounds are nevertheless isolated in similar or better yields
compared to the literature. As the conversion was always almost
total, a careful investigation of the numerous side-products formed
during this process was conducted with xanthate 3b and enabled us
to isolate and characterize most of them (Scheme 3).
Despite the large excess of brominating agent, aromatic rings
did not suffer from ring halogenation even with an electron-donat-
ing group attached to the aromatic moiety. The undesired mole-
cules were presumably formed because of the presence of water
and methanol in the [bdmim][F]. The presence of S-methyl
O-4-biphenyl thiocarbonate 6, isolated with 10% yield can indeed
be explained by hydrolysis side reaction whereas carbonate 7
may result in the nucleophilic attack of methanol. More the
more surprisingly was the isolation of the 4-[difluoro(methy-
loxy)methoxy]biphenyl 5 in which the methylthio was substituted
by a methoxy group once again due to the presence of methanol in
the IL. This observation turned our attention to the possibility of
finding adequate conditions and/or substrates to improve the yield
of the formation of such rare difluorinated ketals.
Encouraged by these results, the scope and limitations of
the reactivity of [bdmim][F] were thus evaluated with a set of
xanthates (Table 2).17
Table 2
Only a few methods leading to the difluoromethylenedioxy
group (OCF2O) have been reported.18 Those types of compounds
have been prepared mainly by reacting various nucleophilic fluor-
ide reagents (e.g., BrF3, HF, AgF, Bu4NH2F3) with either dichlorodi-
oxomethylene derivatives or thiocarbonates. The synthesis of
asymmetrical aryl–alkyl difluoromethylenedioxy compounds
requires quite harsh conditions outlining the urgent need for a
more practical preparation. The O,O-aryl-methylthiocarbonates,
substrates for fluoro-desulfurization process, were prepared by
an adaptation of the described methods without further optimiza-
tion. These thiocarbonates were then engaged in reaction in the
presence of [bdmim][F] (10 equiv) and NBS (12 equiv), following
our previous protocol17 (Scheme 4). Compound 9a was chosen
for the first attempt because the ketal 10a was already described.
To our delight, we were able to isolate the pure molecule 10a albeit
in rather low yields in spite of a total conversion. We assume those
side reactions as partial hydrolysis may occur during the process.
Synthesis of difluoro(methylthio)methyl ethers 4 from xanthate 3
S
NBS (12 eq), [bdmim][F] (10 eq)
CH2Cl2 4 ml, 3h, -30°C -> rt
F
F
R
R
O
S
O
S
4 a-h
3 a-h
Entry
R
Product
Yielda (%)
1
2
3
4
5
6
7
8
(3a) 4-Br–C6H4–
(3b) 4-Ph–C6H4–
(3c) 4-Me–C6H4–
(3d) 4-MeO–C6H4–
(3e) 3-MeO2C–C6H4–
(3f) 4-IsoPr–C6H4–
(3g) Ph–(CH2)3–
4a
4b
4c
4d
4e
4f
45 (41)b
52 (43)b
40 (25)b
38 (27)b
43 (30)b
48 (36)b
36
4g
4h
(3h) C16H33
–
29
a
Yield determined 19F NMR with 4-(chloro-difluoro-methoxy)-phenylamine as
internal reference.
b
Isolated yield.
Ph
Ph
F
F
F
F
+
NBS (12 eq),
[bdmim][F] (10 eq)
O
S
Ph
O
O
S
5
12%
4b 43%
CH2Cl2 4 ml,
3h, -20°C to rt
O
S
Ph
Ph
3b
O
O
+
+
O
S
O
O
6
7
11%
10%
Scheme 3. Synthesis of 4-(difluoro(methylthio)methoxy) biphenyl 4b from xanthate 3b.
CSCl2
S
[bdmim][F] (10 eq)
S
NaOH 5%
MeOH
F
F
ROH
RO
OMe
CHCl3,
1h, 0°C
Et3N,
NBS (12 eq)
CH2Cl2, 5h, -30°C -> rt
RO
OMe
RO
Cl
1h, 0°C
(38%))a 24%
10a
8a
8b
9a
9b
68% R= 3-NO2-C6H4-
72% R = 4-MeO-C6H4-
67% yield
71% yield
10b (38%)a 29%
5
10d
(36%))a 24%
- (37%))a 33%
8c 50% R= 4-Ph-C6H4-
8d
8e
9c 30% yield
9d
9e
40% R= 2-Naphyl-CH2-
90% R= 4-Br-C6H4-
32% yield
73% yield
10e - (38%))a 15%
a Yield determined 19F NMR with 4-(chloro-difluoro-methoxy)-phenylamine as internal reference.
Scheme 4. Formation of asymmetric aryl–alkyl difluoromethylenedioxy derivatives.

S. Bouvet et al. / Tetrahedron Letters 56 (2015) 1682–1686
1685
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Because of the large excess of [bdmim][F] needed for the reac-
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core was lastly undertaken. After the completion of the fluorina-
tion process, the desired difluorinated compound was extracted
with diethyl ether. The resulting mixture of ILs was dissolved in
water and of 1.1 equiv of lithium bistriflimide was added. ILs were
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Conclusion
In conclusion, a new ionic liquid [bdmim][F] was prepared on a
multi gram scale and fully characterized. Its use as a nucleophilic
source of fluoride proved very efficient in the desulfurization–
fluorination process. Without any particular precaution, we were
able to achieve the difluorination of xanthates and thiocarbonates
without the use of HF–pyridine or TBAH2F3. This methodology only
employed stable and non-toxic reagents to achieve the preparation
of promising new compounds. Synthetic opportunities
offered both by these difluorinated ethers and by this IL are under
current development in our laboratory and will be reported in due
course.
Acknowledgments
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We thank the CNRS and the French Ministry of Research
and UVSQ for the PhD grant for S.B. We warmly acknowledge
François Metz (Rhodia-Solvay Company) for the gift of LiNTf2
and Loïc Pantaine for the improvement of the English
manuscript.
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potassium fluoride (2.5 g, 43.5 mmol, 1.5 equiv) in methanol (42 mL) was
added, at room temperature, in one portion to a solution of 1,2-dimethyl-3-(n-
butyl)imidazolium chloride (5.45 g, 29 mmol, 1 equiv) in methanol (38 mL).
After one hour stirring, the insoluble KCl was removed by filtration and washed
with methanol (50 mL). The liquid phase was concentrated under vacuum.
Dichloromethane (20 mL) was then added and the resulting precipitate was
removed by filtration. The solution was concentrated under vacuum to afford
the desired product as orange crystals (4.8 g, 28 mmol, 95% yield). Melting
point: 19–22 °C. 1H NMR (200 MHz, MeOD): d = 0.99 (t, 3J = 7.3 Hz, 3H), 1.40
(tq, 3J = 7.3 Hz, 2H), 1.81 (tt, 3J = 7.6 Hz, 3H), 2.65 (s, 3H), 3.84 (s, 3H), 4.18 (t,
3J = 7.4 Hz, 3H), 7.49–7.61 (m, 2H) ppm. 13C NMR (50 MHz, MeOD): d = 9.5,
13.9, 20.6, 32.8, 35.4, 49.2, 49.9, 122.2, 123.7, 145.9 ppm. 19F NMR (188 MHz,
MeOD): d = À151.0 ppm.
3. For reviews see (a) Leroux, F.; Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105,
827–856; (b) Leroux, F. R.; Manteau, B.; Vors, J.-P.; Pazenok, S. Beilstein J. Org.
Chem. 2008, 4. http://dx.doi.org/10.3762/bjoc.4.13; (c) Manteau, B.; Pazenok,
S.; Vors, J.-P.; Leroux, F. R. J. Fluorine Chem. 2010, 131, 140–158; (d) Liang, T.;
Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52, 8214–8264; (e) Hu, J.;
Zhang, W.; Wang, F. Chem. Commun. 2009, 7465–7478.
17. General procedure for preparation of
a-difluorinated ethers: At À30 °C, to a
solution of [bdmim][F] (689 mg, 4 mmol, 10 equiv) dissolve in
dichloromethane (2 mL) were successively added NBS (855 mg, 4.8 mmol,
4. For selected examples see: (a) Yarovenko, N. N.; Vasileva, A. S. J. Gen. Chem.
USSR 1958, 28, 2539; (b) Hoechst, A. G. Fab. Brevet Brit. 1957, 765527 (Chem.
Abstr. 1957, 51, 14803); (c) Feiring, A. E. J. Org. Chem. 1979, 44, 2907–2910; (d)
Sheppard, W. A. J. Org. Chem. 1964, 29, 1–11; (e) Mathey, F.; Bensoam, J.
12 equiv) then dropwise
a solution of xanthate (0.4 mmol, 1 equiv) in
dichloromethane (2 mL). The solution was stirred at room temperature for
3 h and the mixture was concentrated under vacuum to remove
dichloromethane. Diethyl ether (10 mL) was added and the mixture was

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S. Bouvet et al. / Tetrahedron Letters 56 (2015) 1682–1686
stirred for 10 min. The ether phase and the ionic liquid phase were separated.
18. (a) Saint-Jalmes, L. J. Fluorine Chem. 2006, 127, 85–90; (b) Guidotti, J.; Schanen,
V.; Tordeux, M.; Wakselman, C. J. Fluorine Chem. 2005, 126, 445–449; (c)
Kuroboshi, M.; Hiyama, T. Synlett 1994, 251–252; (d) Hagooly, Y.; Rozen, S. J.
Org. Chem. 2008, 73, 6780–6783; (e) Alles, H.-U.; Klauke, E.; Lauerer, D. Justus
Liebigs Ann. Chem. 1969, 730, 16–30.
This procedure was carried out six times in order to extract completely the
product. Organic phases were combined and concentrated under vacuum.
The crude mixture was purified by chromatography on silica gel to afford the
desired product.