Ionic liquids as new media for electrophilic trifluoromethylation reactions

Article abstract of DOI:10.1016/j.jfluchem.2011.03.004

The electrophilic trifluoromethylation of aniline with a range of trifluoromethyl sulfonium salts has been studied in ionic liquids as solvent. The best ionic liquid for this reaction was identified after extensive scrutiny of the influence of the cation's nature (imidazolium or pyridinium salts), the effect of the alkyl side chain length of the cation, as well as that of the counter anion. Recycling experiments have demonstrated that the purification protocol was greatly simplified over conventional reactions performed in DMF and that the solvent could be reused five times without significant loss of activity.

Full text of DOI:10.1016/j.jfluchem.2011.03.004

Journal of Fluorine Chemistry 134 (2012) 156–159
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Ionic liquids as new media for electrophilic trifluoromethylation reactions
*
´
´
´
Bruce Pegot, Yohan Mace, Celine Urban, Patrick Diter, Jean-Claude Blazejewski, Emmanuel Magnier
Institut Lavoisier de Versailles (ILV), UMR CNRS 8180, Universite´ de Versailles, 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:
The electrophilic trifluoromethylation of aniline with a range of trifluoromethyl sulfonium salts has been
studied in ionic liquids as solvent. The best ionic liquid for this reaction was identified after extensive
scrutiny of the influence of the cation’s nature (imidazolium or pyridinium salts), the effect of the alkyl
side chain length of the cation, as well as that of the counter anion. Recycling experiments have
demonstrated that the purification protocol was greatly simplified over conventional reactions
performed in DMF and that the solvent could be reused five times without significant loss of activity.
ß 2011 Elsevier B.V. All rights reserved.
Received 13 January 2011
Received in revised form 3 March 2011
Accepted 4 March 2011
Available online 15 March 2011
Keywords:
Fluorine
Sulfur heterocycles
Electrophilic trifluoromethylation
Ionic liquids
Research thematic of our group
trifluoromethyl sulfoniums salts (Shreeve) [2], dibenzothiophe-
nium salts (Umemoto) [3], benzothiophenium salts (Shibata) [4]
The ILV Fluorine group at Versailles is mainly involved in the
following research topics:
and a sulfoximine derivative (Shibata) [5]. Recently, the group of
Togni succeeded in the preparation of very efficient hypervalent
iodine(III)–CF3 reagents [6]. Lastly, Umemoto described trifluor-
omethyl oxonium salts as powerful electrophilic reagents [7].
Our contribution in this field concerns the great improvement of
the preparation of two types of reagents. We indeed unlocked the
access to a trifluoromethyl sulfoximine precursor of Shibata’s
reagent, thanks to a new and high yielding procedure, which avoids
the use of hazardous compounds and conditions [8]. We also
proposed a one pot and benchmark procedure, which allowed the
easy homemade preparation of biaryl and dibenzothiophenium
sulfonium salts [9]. Our group also studied the scope of the
sulfonium salts based reagents with a mechanistic study showing
thatthe radicalpathway appears tobethepredominant route forthe
trifluoromethylation with such reagents [10]. All these studies shed
some light on the advantages and drawbacks of sulfonium salts. In
particular, their use suffers from two drawbacks: poor solubility in
non-polar solvent and the release of a sulfur aromatic core able to
compete with the nucleophilic species to be trifluoromethylated.
This core and resulting trifluoromethylated derivatives are some-
times not easily removed during the final purification step.
Over the past decade, ionic liquids (ILs) have been the subject of
intense research as effective reaction media for a wide range of
organic reactions and other applications in chemistry [11]. ILs are
defined by the combination of organic cations and appropriate
anions with melting points close to room temperature [12]. They
exhibit negligible vapor pressure and are usually poorly miscible
with non-polar organic solvents. As a consequence reaction
products are more easily extracted and the ionic liquid can be
recycled [13].
-
Synergy between fluorine and sulfur with emphasis to straight-
forward one pot synthesis of perfluoroalkyl sulfonium salts,
sulfilimines and sulfoximines. Preparation of electrophilic
perfluoroalkylating reagents (or precursors thereof) as well as
synthesis and physico-chemical properties studies of electron
withdrawing groups.
New and emergent fluorinated substituent: trifluoromethoxy
aliphatic compounds.
Use of new media for green chemistry: fluorous solvents for
catalysis, ionic liquids for the improvement of fluorination
reactions.
Fluorinated analogues of compounds of therapeutic interest:
estradiol, fulvestrantTM, and tamoxifenTM involved in breast
cancers regulation.
Preparation of fluorinated ligands for porous solids: fluorinated
MOFs (coll. Porous solids group in Versailles, MIL materials).
-
-
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More details as well as references at: http://www.ilv.uvsq.fr/
research/Echo/Fluor/fluor.html.
1. Introduction
Since the pioneering work of Yagulpolskii early published in
1984 [1], various sulfur based electrophilic trifluoromethylating
reagents have been described. Their structures rely upon biaryl
* Corresponding author. Tel.: +33 1 39 25 44 66; fax: +33 1 39 25 44 52.
E-mail address: magnier@chimie.uvsq.fr (E. Magnier).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.03.004

B. Pe´got et al. / Journal of Fluorine Chemistry 134 (2012) 156–159
157
For all these reasons, we expected ILs as a green answer to the
two drawbacks, previously mentioned concerning the electrophilic
trifluoromethylation with sulfonium salts. On one hand, they
should be able to solvate the polar ionic sulfonium salts insuring
better solubility, on the other hand they may improve the
purification step. To verify these hypotheses, we describe in this
article a study devoted to the choice of the best ionic liquid for the
purpose of trifluoromethylation, recycling experiences and the
scope of this new reaction media.
in ILs. Two of the most common family of these polar solvents have
been used for this study, pyridinium salts and imidazolium salts,
both with different side chains and varying anions (Table 1). All
these ILs have been prepared according to the literature [16]. The
reactions were performed at 80 8C, for 6 h, in a closed vessel to
avoid evaporation of aniline. Yields and the ratio of ortho/para
trifluoromethylaniline were determined by 19F NMR and are
reported in Table 1.
The influence of four anions was checked with three different
imidÀazolium cations (entries 1–3). Good yields were obtained with
À
NTf2 and BF4 whereas a small drop (10% yield) was observed
2. Results and discussion
with TfOÀ or BrÀ as anions. The substitution of the acidic proton in
position 2 of the imidazolium ring allowed a slight increase of the
yields (entry 2 vs 1 and 3 vs 4). On the other hand, increased length
of the alkyl chain on imidazolium ring is deleterious to the yield
(entries 1, 4 and 5 and entry 2 vs 3). This phenomenon could be
attributed to an enhanced viscosity of the ILs (according to the
literature) [12c] leading to a more sluggish and difficult to stir
reaction media. Lastly, a pyridinium core as cation is not beneficial
to the yield (entry 6). All these results also showed that ILs have no
effect on the ortho/para ratio, whatever the nature of the cation or
the anion employed.
The use of 1,2-dimethyl-3-butylimidazolium tetrafluoroborate
(bdmimBF4) 7 as solvent gave the same yield than with DMF and
appeared as the best ionic liquid for the present purpose. An
alternative to DMF as solvent for electrophilic trifluoromethylating
reaction has thus been found, reaching our first goal. Next studies
were then devoted to the recycling of the ionic liquid and to the
improvement of the purification step.
2.1. Trifluoromethylation reaction in ionic liquids
The trifluoromethylation of aniline in the presence of S-
(trifluoromethyl)dibenzothiophenium-3-sulfonate 1 was chosen
as model reaction (Scheme 1). The choice of this trifluoromethyla-
tion reagent was motivated by the simplified purification protocol
claimed by Umemoto et al. [14]. Under classical conditions the
resulting ionic species 5 was easily separated from the trifluor-
omethylated anilines by washing with water. We first repeated this
reaction in order to possess a standard forfurtheryield comparisons.
Under carefully anhydrous conditions, and in the presence of
distilled DMF as solvent, two isomers 3 and 4 (65/35) were obtained
in 77% yield (determined by NMR with internal references [15]).
This yield is slightly better than the one described by Umemoto.
We assume that this result can be explained by the only significant
difference between the two works: a higher concentration was
used in our case, to be in accordance with the reactions developed
Scheme 1. Trifluoromethylation of aniline in DMF.
Table 1
Evaluation of the trifluoromethylating activity of S-(trifluoromethyl)dibenzothiophenium-3-sulfonate 1 in different ILs at 80 8C for 6 h.
Entry
Ionic liquid
Counteranions and yields% (o/p ratio)a
TfOÀ
BrÀ
À
À
NTf2
BF4
1
71 (61/39)
67 (62/38)
59 (57/43)
61 (57/43)
2
3
4
5
75 (61/39)
68 (59/41)
60 (61/39)
57 (61/39)
58 (55/45)
69 (60/40)
65 (58/42)
65 (57/43)
68 (64/36)
58 (58/42)
58 (55/45)
–
–
–
–
–
–
–
–
–
6
a
Yields and ratios were determined by 19F NMR with internal references.

158
B. Pe´got et al. / Journal of Fluorine Chemistry 134 (2012) 156–159
2.3. Scope of the sulfonium salt
Umemoto’s reagent 12 and sulfonium salts 13–15 prepared in
our group [9b] have been tested on the model reaction with the
readily available bmimBF4 6 as solvent. All the salts proved
perfectly soluble in the ionic liquid. The results are reported in
Table 2.
Once again, during this study, no influence of the nature of the
sulfonium salt on the isomeric ratio has been noticed. As expected,
Umemoto’s reagent (Table 2, entry 2) revealed a trifluoromethy-
lating power equivalent to the sulfonium 1 (entry 1). The presence
of bulky electron-donating methyl groups affects the yield of
trifluoromethylated compound (entries 3 and 4) [17]. However, as
expected, an additional nitro group is beneficial and gave the best
yield (85%; entry 5). This is in accordance with the proposed
enhanced reactivity of electron-poor sulfonium salts. Furthermore,
we were very pleased to notice that with sulfonium salt 15, the
byproduct (2,4-dimethyl-10-nitro-dibenzothiophene) released
during the transformation precipitated in the IL. While allowing
the selective extraction of trifluoroanilines 3 and 4, as in the case of
Umemoto’s sulfonated sulfonium salt 1, the salt 15 gave a better
yield.
Fig. 1. Recycling experiments of the liquid ionic 7.
2.2. Recycling
After cooling, a simple extraction of the crude mixture with
diethyl ether afforded products 3 and 4 accompanied by traces of
unreacted aniline 2 (easily removed by washing with a slightly
acidic aqueous solution) [9b]. More importantly, at the end of the
reaction, the unwanted sulfur aromatic part dibenzothiophene-3-
sulfonate, precipitated as an ammonium sulfonate salt 5 in the IL.
This compound can be removed by simple filtration, but this
operation can be omitted. Indeed, the ionic liquid, still containing
byproduct 5, can be reused five times without loss of efficiency
(Fig. 1). The very small increase of the yield is simply explained by
the presence of unreacted sulfonium salts 1, still present in the
bdmimBF4. The slight decrease of the yield depicted in run 6 is due
to the accumulation of the side product 5 entailing stirring
problems. At this stage, simple filtration did not permit to retrieve
the yields obtained during the first five runs. Further purification of
the ionic liquid by column chromatography on silica gel could be
necessary.
3. Conclusion
We have shown that the trifluoromethylation reaction with
sulfonium salts could effectively be performed with various
sulfoniums in ILs in place of the toxic DMF solvent. ILs gave yields
that are, at least, as good as the yields obtained under classical
condition while providing an easier isolation of the trifluoro-
methylated target. Hydrophobic ILs with short alkyl chain should
be privileged for this reaction. Furthermore, for at least one
example, ILs could be recycled and reused without any purification
for five runs, allowing a greener chemistry. Lastly, easily prepared
reagent 15 providing the highest yield without any cumbersome
work-up may prove the choice reagent for electrophilic trifluor-
omethylations.
Table 2
Evaluation of the trifluoromethylating activity of the sulfonium salts in bmimBF4
for 6 h at 80 8C.
Further developments of these new reaction conditions are
under study in our laboratory.
Entry
1
Sulfonium salts
Yields% (o/p)a
71 (61/39)
4. Experimental
4.1. General
Each reaction was carried out under an argon atmosphere in
freshly distilled solvent, unless otherwise noted. DMF was distilled
from calcium hydride. NMR spectra were recorded on a Bruker AC
200 spectrometer. For 19F (282 MHz) NMR spectra, the reference
was internal CFCl3 (0 ppm).
2
3
4
70 (59/41)
53 (61/39)
61 (57/43)
85 (60/40)
4.2. General procedure for trifluoromethylation of aniline in DMF
Under an argon atmosphere, trifluoromethylsulfonium salt
(0.44 mmol) was added to a stirred solution of aniline (0.88 mmol,
80
mL) in dry DMF (0.5 mL). The mixture was stirred for 6 h at
80 8C. At the end of the reaction, the solution was cooled and 2 mL
of CDCl3 were added. Then 35 mg of trifluoromethoxybenzene
were introduced as internal reference for 19F NMR yield
determination. The yield and the ratio of ortho and para isomers
were determined by integration of the signals of the CF3 [15].
5
4.3. General procedure for trifluoromethylation of aniline in ILs
Under an argon atmosphere, trifluoromethylsulfonium salt
(0.44 mmol) was added to ILs (0.4 mL) then aniline (0.88 mmol,
80 mL) was added to the mixture and stirred for 6 h at 80 8C. The
a
Yields and ratio were determined by 19F NMR with internal references.

B. Pe´got et al. / Journal of Fluorine Chemistry 134 (2012) 156–159
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159
reaction solution was then extracted with ether (3 Â 10 mL). The
organic layer was concentrated and 2 mL of CDCl3 was added. Then
35 mg of trifluoromethoxybenzene were introduced as internal
reference for 19F NMR yield determination. The yield and the ratio
of ortho and para isomers were determined by integration of the
signals of the CF3.
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