Solvent free nucleophilic introduction of fluorine with [bmim][F]

Article abstract of DOI:10.1016/j.tetlet.2013.12.020

1-n-Butyl-3-methylimidazolium fluoride ([bmim][F]) proved very efficient fluorinated reagent for nucleophilic substitution over sulfonate esters and alkyl halides. Preparation of the ionic liquid as well as its use as the reagent has been performed to be the more eco-friendly as possible. No organic solvent is needed for the fluoride introduction, reaction times are reduced by using microwave as the heating source, and the ionic liquids carefully recycled. Furthermore, no special care has to be taken as the presence of water in [bmim][F] was not deleterious to the transformation yield.

Full text of DOI:10.1016/j.tetlet.2013.12.020

Tetrahedron Letters 55 (2014) 826–829
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent free nucleophilic introduction of fluorine with [bmim][F]
⇑
⇑
Sébastien Bouvet, Bruce Pégot , Jérome 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:
1-n-Butyl-3-methylimidazolium fluoride ([bmim][F]) proved very efficient fluorinated reagent for nucle-
ophilic substitution over sulfonate esters and alkyl halides. Preparation of the ionic liquid as well as its
use as the reagent has been performed to be the more eco-friendly as possible. No organic solvent is
needed for the fluoride introduction, reaction times are reduced by using microwave as the heating
source, and the ionic liquids carefully recycled. Furthermore, no special care has to be taken as the pres-
ence of water in [bmim][F] was not deleterious to the transformation yield.
Received 4 November 2013
Revised 29 November 2013
Accepted 6 December 2013
Available online 18 December 2013
Keywords:
Fluorination
Ó 2013 Elsevier Ltd. All rights reserved.
Ionic liquids
Nucleophilic substitution
Green chemistry
Microwaves
Introduction
anion.5 These molecules remain nevertheless somewhat hygro-
scopic and exhibit an enhanced basicity which sometimes causes
The increasing interest in fluorine chemistry stems from the
ability of this halogen to dramatically change the physical, chemi-
cal, and biological properties of many organic compounds. Its un-
ique properties such as its small size, high electronegativity,
conformational, and structural modifications account for this
side reactions such as elimination process.
Polar aprotic solvents (acetonitrile and dimethylformamide),
are frequently employed for nucleophilic displacement reactions.6
Recently, ionic liquids (ILs) have been proposed as a promising
alternative. Due to their very distinctive characteristics (e.g., good
solubility for many organic and inorganic compounds and recycla-
1
enthusiasm. Late and selective fluorination of organic molecules
7
has become a very important target in various fields of research
bility) these salts have been the subject of intense research as
pharmaceuticals, agrochemicals, materials,. . .).2 Apart from the
effective reaction solvents including nucleophilic substitution.
In particular, they have been shown to be efficient promoters for
8
9,10
(
recent transition metal catalyzed mediated fluorinations, two main
methods for the nucleophilic introduction of this halogen are cur-
1
1
nucleophilic fluorination. In 2002, Chi et al. reported the synthe-
sis of fluoroalkanes from alkyl mesylates or alkyl halides using KF
3
rently used. The first, is a fluorodeoxygenation, carried out on sub-
1
2
strates
bearing
hydroxyl
or
carbonyl
groups,
using
in various ILs. The use of 1-n-butyl-3-methylimidazolium salt
([bmim][X]) helped to reduce reaction time as well as the amount
of byproduct. One of the main drawbacks of this methodology is
the occurrence of side reactions which result in the degradation
diethylaminosulfur trifluoride (DAST) or improved analogues. The
second approach is the nucleophilic displacement of a leaving
group by the fluoride ion. This seminal strategy which employs
cheap and readily available alkali metal fluorides suffers however
from two major drawbacks due to the intrinsic properties of the re-
agents: a limited solubility in organic solvent and a strongly tamed
nucleophilicity due to the close solvatation of fluoride, emphasized
by its high hygroscopic properties. As a consequence, the proce-
dure described in initial publications required hazardous and harsh
1
3
of the ILs. The enhanced basicity of metal fluorides can lead to
Hoffman elimination on side chains of the cationic part of the sys-
tem. This phenomenon then required the design of more elabo-
rated ILs in order to preserve their integrity and their recycling
1
4
properties. An important breakthrough was recently reported
1
5
by Chae and co-workers This group showed that ILs can be used
as both solvents and reagents for the synthesis of primary and
secondary organohalides starting from sulfonate esters. Under
the reported conditions, the anionic moiety of [bmim][X] (X = Cl,
Br, I, OAc, SCN) reacted as nucleophilic entities. Surprisingly, this
methodology has not been extended to the key introduction of a
fluorine atom. This is probably due to the poor accessibility of
[bmim][F]. Contrary to conventional synthesis of ionic liquids,
[bmim][F] cannot be obtained readily by simple quaternization of
4
reagents or disadvantageous reaction conditions. In order to avoid
the problem of a solvated fluoride ion, phase transfer type protocol
and reagents (e.g., crown ether, tetraalkylammonium fluoride,
anhydrous tetrabutylammonium...) have been successfully
proposed to enhance the nucleophilic character of the fluoride
⇑
Corresponding authors. Tel.: +33 1 39254466; fax: +33 1 39254452.
E-mail address: Emmanuel.MAGNIER@chimie.uvsq.fr (E. Magnier).
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.020

S. Bouvet et al. / Tetrahedron Letters 55 (2014) 826–829
827
C4H9Cl, MW
50°C, 15 min
1.2eq KF, MeOH
rt, 30 min
properties of ionic liquids allow them to absorb microwaves very
efficiently, they are highly suitable for the microwave assisted or-
N
N
N
N
N N
1
2
0
Cl
yield = 91%
F
ganic synthesis. The second step, the anion exchange of azolium
halides, was carried out with potassium fluoride. The choice of KF
was clearly motivated by the low price of this compound, com-
pared to AgF or CsF. The anion metathesis was carried out at room
temperature, with methanol as the solvent and using a slight ex-
yield = 95%
Scheme 1. Synthesis of [bmim][F].
2
1
N-alkylimidazoles with alkyl fluoride, because of the strong C–F
bond. This particular IL was identified for the first time as a decom-
position product during the eating of the ionic liquid 1-butyl-3-
methylimidazolium hexafluorophosphate.16 Only two synthetic
methods have been since described. They both proceed according
to a two-step protocol: the classical preparation of N-alkylimidaz-
oles [bmim][Cl]or[I] is followed by an anion exchange either with
the help of a resin or by anion metathesis conducted with expen-
sive AgF. We were intrigued by a single example which described
the use of KF in substoichiometric ratio for the in situ formation of
cess (1.2 equiv) of KF. No special precautions had to be taken
for the transformation. Methanol was used without further purifi-
cation and the potassium fluoride was not dried prior to its intro-
duction into the reaction mixture.
The fluorinated IL was isolated in a good yield of 95% and its
purity, as well as the anion exchange, was carefully verified
through various analytic methods. Close examination of NMR spec-
tra revealed, in addition to a slight shifting of all the signals, the
intriguing disappearance of the peak of the hydrogen located in po-
sition C(2) that is between the two nitrogens. We assume that this
phenomenon can be explained by a hydrogen bond with the fluo-
rine anion. This hypothesis as well as the structure of synthesized
1
7
1
8
[
bmim][F]. The resulting crude IL was reacted directly with n-octyl
p-toluenesulfonate to give rise to n-octyl fluoride, as revealed by
gas chromatography analysis.1
8b
[
bmim][F] was ascertained by X-ray analysis (Fig. 1).22 This dia-
This result not only reinforces the great potential of [bmim][F]
as a fluorinating agent but also highlights the need for a reliable
method of preparation. This is the topic of this present paper. Here-
in, we report a cheap synthesis of [bmim][F], its application as a
nucleophilic fluorinating reagent and finally its recyclability. We
have tried to solve most of the reactivity problems mentioned in
the introduction. In particular, the opportunity to get a fine balance
between reactivity and stability of our reagent was carefully
examined.
gram revealed that the cations are associated by an overlapping
of the alkyl tails. The fluoride and the hydrogen attached to C-2
of the imidazolium ring are closed together (1.96 Å) which con-
firms the existence of a hydrogen bond between them. Impor-
tantly, this diagram showed the presence of one molecule of
water per anion. This fact accounts for the stability of our IL but
fortunately is not deleterious for the reactivity of our compound
as depicted in the following study.
The nucleophilic fluorination of 3-phenylpropyl p-tolenesulfo-
nate was investigated as model reaction (Table 1). During this
study no particular handling precautions were required.
Results and discussion
To our delight, the fluorination occurred in a good yield of 66%
in only 10 min, when 3-phenylpropyl p-toluenesulfonate was stir-
red with 2 equiv of [bmim][F] at 80 °C (entry 1). Increasing the tem-
perature had no influence on the yield whereas the use of 3 equiv of
fluorinated agent resulted in a slight increase of the yield to 77%
(entries 2 and 3). In order to find the best compromise between
In order to access the target molecule, the precursor [bmim][Cl]
was prepared according to the literature via solvent-free N-alkyl-
ation of 1-methylimidazole with 1-chlorobutane in closed vessels
under monomode microwave irradiation, as well as all the reac-
tions described in this Letter (Scheme 1).19 Since the dielectric
Figure 1. Molecular packing diagram of 1-butyl-3-methylimidazolium fluoride monohydrate.

8
28
S. Bouvet et al. / Tetrahedron Letters 55 (2014) 826–829
Table 1
R1
F
Fluorination of 3-phenylpropyl p-toluenesulfonate with [bmim][F]
R2
F
N
N
3eq [BMIM][F]
OTs
F
R1
Separation
MW
R2 LG
MW
Entry
Time (min)
Temperature (°C)
BMIMF (equiv)
Yielda (%)
[
BMIM][F]
1.1eq LiNTf2 [BMIM][NTf2]
+
H O,rt, 60 min
1
2
3
3
4
5
10
10
10
30
30
80
100
80
80
80
2
2
3
1
2
3
5
66
66
77
49
2
[
BMIM][LG]
yield = 92% from
starting [BMIM][F]
Scheme 2. Recycling of the IL.
84
30
360
80
80
95 (85)b
83
c
6
a
b
c
Yield determined 19F NMR with internal reference.
Isolated yield.
Reaction conducted under conventional heating.
halide, acceptable yields were obtained with sulfonates, providing
an increase of the temperature and the reaction time (entries 15–
1
7). It is important to point out that the yield matches with the
conversion for these last transformations. No elimination products
were observed. This could be explained by the F–H hydrogen bond
which insured the inherent nucleophilicity and reduced the basi-
city of the fluoride anion.
As part of our eco-friendly process, the recycling of the cationic
core of our reagent was undertaken (Scheme 2).
After the completion of the fluorination process, the desired
compound was extracted with pentane. The resulting crude solu-
tion was then a mixture of unreacted [bmim][F] and [bmim][X]
Table 2
Fluorination reaction on various substrates with [bmim][F]
Entry
Substrate
Time (min)
Temperature (°C)
Yielda (%)
1
2
3
4
5
6
7
8
9
C
C
C
C
C
C
C
C
C
6
H
6
H
8
H
8
H
6
H
8
H
8
H
6
H
6
H
5
O(CH
(CH
2
)
2
OTs
30
30
30
30
30
30
60
30
30
30
30
30
30
180
60
75
120
80
80
80
80
80
80
80
80
80
80
80
80
80
120
100
100
100
78
85
73
76
64
52
60
70
68
70
73
74
34
n.r
43
46
14
5
2
)
3
OMs
17OTs
17OMs
(CH
17Br
17
5
2
)
3
Br
(
X = Cl, Br, I, OMs, OTs). The composition of the anionic part was re-
I
lated to the substrate engaged in reaction. This chemical diversity
precluded the full regeneration of [bmim][F]. Regarding the case of
tosyl or mesyl anion, the reaction is unfavorable due to hard/soft
5
CH
CH
2
Br
2
Cl
5
10
11
12
13
14
15
16
17
(4-Me)C
(4-MeO)C
6
H
4
CH
CH
Br
CH
2
Br
2
5
2
metathesis consideration. To address this limitation, LiNTf rap-
6
H
CH
4
2
Cl
(4-F)C
(4-NO
6
H
4
2
idly appeared as the best candidate to insure a total conversion to-
ward a unique and useful known IL. The mixture of ILs was
dissolved in water and after addition of 1.1 equiv of lithium salt,
2
)C
CN
13CH(OTs)CH
13CH(OMs)CH
13CH(Br)CH
6
H
4
2
Br
C
C
C
C
6
H
6
H
6
H
6
H
5
CH
2
3
[
[
bmim][F] and [bmim][X] were both fully converted into
bmim][NTf ] which formed a lower phase during the reaction.
] was
recovered in a yield of up to 92%. This IL could be used later on
3
2
3
After the separation of the two phases, pure [bmim][NTf
2
a
Yield determined 19F NMR with internal reference.
8
b,7m
as reaction media for other organic syntheses.
the conversion and the number of equivalents of reagent engaged,
the reaction time was raised. Thirty minutes of microwave irradia-
tion was enough to obtain a complete conversion and to deliver the
Conclusion
We have shown that 1-n-butyl-3-methylimidazolium fluoride
could be easily synthetized using cheap potassium fluoride
without any special care. We have demonstrated its potential as
a fluorinating agent to provide soft nucleophilic substitution. No
solvent, special precautions or complex or hazardous additional
reagents are necessary for this transformation. The use of micro-
wave irradiation allows a short reaction time avoiding as a conse-
quence the formation of byproducts like the competitive
elimination product. The resulting mixture of ILs is entirely
recycled in a very green and easy way. Further developments of
this new reagent and other applications are under study in our
laboratory.
1
-fluoro-3-phenyl propane in a good isolated yield, (85%, entry 5).
As a comparison, with conventional heating, 6 h were needed with
5
equiv of ILs to obtain a comparable yield (entry 6).
Encouraged by these results, we attempted the fluorination
reaction on various substrates with different leaving groups in or-
der to evaluate the scope and limitations of [bmim][F] (Table 2).
The previously optimized conditions (30 min at 80 °C under micro-
wave irradiation) were successfully applied to a wide range of sub-
2
3
strates.
Primary aryl- and alkyl-sulfonate (tosyl and mesyl)
groups were displaced with a good yield to give rise to the desired
molecules (entries 1–4). If the leaving group is a halogen (Br or I),
the yields were slightly lower but still reasonable (entries 5–7) for
alkyl chains but remain high when they are on benzylic position.
Benzyl bromides and also chlorides were easily substituted by
Acknowledgments
[
bmim][F] (entries 8–13). The functionalization of the aromatic
Sébastien Bouvet thanks the French Ministry of Research for
PhD grant. We warmly acknowledge François Metz (Rhodia-Solvay
company) for the gift of LiNTf , F. Bourdreux and E. Galmiche-Loire
2
for NMR and ESI-MS analyses, Adeline Le Pape for technical sup-
port and Lucy Cooper for improvement of the English manuscript.
part, even by a fluorine atom, was not detrimental to the yield, ex-
cept for the nitro group. Unfortunately, a cyano group proved unre-
active. No displacement of this moiety has been observed and the
starting material is totally recovered even after three hours at ele-
vated temperatures. This result is not surprising, as a cyano group
is a poorer leaving group compared to sulfonate according to pre-
viously reported example.24
References and notes
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(38 mL) was added in one portion a solution of potassium fluoride (2.5 g,
43.5 mmol, 1.5 equiv) in methanol (42 mL). After one hour at room
temperature, the insoluble potassium chloride was removed by filtration and
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7
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reduced pressure to afford the desired product as a yellow waxy solid (95%,
4.3 g, 28 mmol). 19F NMR (CDCl
, 188 MHz) (ppm) d: À123.0 (1F, s); H NMR
1
3
3
(CDCl , 200 MHz) (ppm) d: 0.82 (t, J = 6 Hz, 3H), 1.28 (sextuplet, J = 6 Hz, 2H),
1.76 (quintuplet, J = 6 Hz, 2H), 3.94 (s, 3H), 4.15 (t, J = 6 Hz, 2H), 7.49–7.34 (m,
2H,); 13C NMR (D
135.8.
2
O, 75 MHz) (ppm) d: 12.6, 18.7, 31.2, 35.6, 48.8, 122.2, 123.4,
22. Crystal data: C
8
H
17FN
2
O, M
w
= 176.24, orthorhombic, space group P2
b = 10.4370(6) Å, c = 11.3144(5) Å,
= 0.09 mm ; 13878 reflections measured at 200 K;
independent reflections: 1670 [1432 Fo > 4 (Fo)]; data were collected up to a
max value of 60° (100% coverage). Number of variables: 119; R = 0.036,
1 1 1
2 2 ;
dimensions:
V = 997.68(9) Å ; Z = 4;
a = 8.4486(5) Å,
3
À1
l
r
2H
1
À3
2
009, 3, 321–327; (m) Hallett, J. P.; Welton, T. Chem. Rev. 2011, 111, 3508–
2
wR = 0.094, S = 1.06; highest residual electron density 0.13 e Å .
3
576.
23. General procedure for fluorination: The starting substrate (0.5 mmol) and 1-n-
butyl-3-methyl imidazolium fluoride (1.5 mmol, 3 equiv) were stirred for
30 min at 80 °C under microwave irradiation. The mixture was cooled to room
temperature and the fluorinated compound was extracted with diethyl ether
(3 Â 5 mL). Organic1 layers were mixed and concentrated under reduced
8
9
.
.
(a) Rogers, R. D.; Seddon, K. R. Ionic Liquids Industrial Applications to Green
Chemistry; ACS Symposium Series, 2001. 818; (b) Wasserscheid, P.; Welton, T.
Ionic Liquids in Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2008; (c) Rogers, R.
D.; Seddon, K. R. Ionic Liquids as Green Solvents; Progress and Prospects; Oxdord
University: USA, Washington, 2003.
9
pressure. For NMR F determination, chlorodifluoroanisole (88 mg, 0.5 mL)
(a) Wheeler, C.; West, K. N.; Liotta, C. L.; Eckert, C. A. Chem. Commun. 2001,
6
was introduced as internal reference in 0.75 mL of acetone-d . The product
8
(
87–888; (b) Lourenço, N. M. T.; Afonso, C. A. M. Tetrahedron 2003, 789–794;
c) Brinchi, L.; Germani, R.; Savelli, G. Tetrahedron Lett. 2003, 44, 2027–2029; (d)
Judeh, Z. M. A.; Shen, H.-Y.; Chi, B. C.; Feng, L.-C.; Selvatoshi, S. Tetrahedron Lett.
002, 43, 9381–9384.
could also be purified by chromatography on silica gel to afford the desired
product.
24. Stelzer, U.; Effenberger, F. Tetrahedron: Asymmetry 1993, 4, 161–163.
25. Pearson, R. G. Chemical Hardness; Wiley-VCH: Weinheim, 1997.
2