Optimization and Gram-Scale Preparation of S-Trifluoromethyl Sulfoximines and Sulfilimino Iminiums, Powerful Reagents for the Late Stage Introduction of the CF3 Group

Article abstract of DOI:10.1021/acs.oprd.9b00403

S-Trifluoromethyl sulfoximines and S-trifluoromethyl sulfilimino iminiums are important reagents for the electrophilic or radical late-stage introduction of the CF₃ group. We disclose in this article a reappraisal of our previous methodologies

Full text of DOI:10.1021/acs.oprd.9b00403

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Full Paper
Optimization and Gram-scale Preparation of S-Trifluoromethyl-
Sulfoximines and Sulfilimino iminiums, Powerful
Reagents for the Late Stage Introduction of the CF3 Group
Anne-Laure Barthelemy, Victor Certal, Guillaume Dagousset, Elsa Anselmi, Luc Bertin, Laurence
Fabien, Bruno Salgues, Philippe Courtes, Christian Poma, Youssef Elahmad, and Emmanuel Magnier
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00403 • Publication Date (Web): 28 Oct 2019
Downloaded from pubs.acs.org on October 28, 2019
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Optimization and Gram-scale Preparation of S-
Trifluoromethyl- Sulfoximines and Sulfilimino
iminiums, Powerful Reagents for the Late Stage
Introduction of the CF3 Group
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Anne-Laure Barthelemy,1 Victor Certal,2 Guillaume Dagousset,1 Elsa Anselmi,1 Luc
Bertin,2 Laurence Fabien,2 Bruno Salgues,2 Philippe Courtes,2 Christian Poma,2
Youssef El-Ahmad*2 and Emmanuel Magnier*1
1) Institut Lavoisier de Versailles (ILV), UMR CNRS 8180, Université de Versailles, St
Quentin en Yvelines, 45 av. des Etats-Unis, 78035 Versailles Cedex, France.
2) SANOFI, Centre de Recherche de Vitry/Alfortville, 13, quai Jules Guesde – BP 14 –
94403 Vitry-sur-Seine Cedex France.
emmanuel.magnier@uvsq.fr
ORCID :
Anne-Laure Barthelemy : orcid.org/0000-0003-2789-676X
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Guillaume Dagousset: orcid.org/0000-0001-8720-3828
Elsa Anselmi : orcid.org/0000-0003-2996-2775
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Emmanuel Magnier : orcid.org/0000-0003-3392-3971
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TOC Graphic
Multigram synthesis of sulfoximine 4 and sulfilimino iminium 5
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ABSTRACT: S-trifluoromethyl sulfoximine and S-trifluoromethyl sulfilimino iminiums are
important reagents for the electrophilic or radical late-stage introduction of the CF3 group.
We disclose in this article a reappraisal of our previous methodologies and their
adaptation to a large scale. More than 30 g of the key sulfoximine 4 and 40 g of S-
trifluoromethyl sulfilimino iminium 5 are prepared without purification. DSC
measurements have been performed on both the crude mixture and the isolated
compounds in order to insure a safe process. The cost of the synthesis is also detailed
and discussed.
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KEYWORDS: Trifluoromethyl, Sulfoximines, Sulfilimino iminiums, Sulfilimines, DSC
measurements.
INTRODUCTION
The introduction of a fluorine atom or perfluoroalkylated moieties into an organic
compound can lead to profound changes in its physical, chemical or biological properties
due to the peculiar intrinsic properties of the fluorine atom.1 Indeed, fluorine exhibits a
high electronegativity (4.0 on the Pauling scale), a small atomic radius (1.47 Å) and
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induces a strong C-F bond (about 116 kcal/mol). This is the reason why nowadays about
20% of pharmaceuticals and 50% of agrochemical compounds contain at least one
fluorine atom.2 However, the number of natural organic compounds containing a
fluorinated moiety is quite limited.3 This implies that access to organofluorine compounds
is essentially based on the development of practical fluorination or fluoroalkylation
reactions, and always requires new methodologies. The toolbox that chemists now
possess contains more and more fluorinating and perfluoroalkylating reagents which are
stable, selective and easy to handle. Among them, the electrophilic reagents of Umemoto
and Togni (Figure 1) have probably been the most popular.4 In addition, a third class of
compounds in this family, the fluorinated sulfoximines, should not be omitted and have
received increasing attention in the last decade.5 Indeed, these aza-analogs of sulfones
are fluoroalkylating reagents with flexible reactivity, via nucleophilic, electrophilic or
radical pathways. The Shibata reagent is the most known member of this family, but in
our laboratory, we have also discovered other types of sulfoximine-based reagents as
well as a very peculiar structure, a sulfilimino iminium, which has successfully been used
for the efficient production of the trifluoromethyl radical.6
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N
TfO
BF4
F3C
I
O
F3C
I
O
N
S
O N
S
O N Tf
S
O
CF3
CF3
CF3
S+
TfO-
F3C
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Umemoto reagent
Togni reagents
Shibata reagent
sulfoximine
sulfilimino iminium
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Figure 1: Electrophilic or radical perfluoroalkylating reagents
The synthesis of NH S-perfluoroalkylated sulfoximines was quite cumbersome, using
harsh and dangerous conditions, until our group described, in 2009, a three-step
methodology for the preparation of such compounds.7 A slight adaptation of the reaction
conditions allowed access to sulfilimino iminiums.
Consequently, because of the increasing use of sulfoximines as reagents, large-scale
production appeared to be essential. We describe in this article a gram-scale, divergent
synthesis of sulfoximine and sulfilimino iminium. Each step of our previous methodologies
has been reconsidered and improved. Differential Scanning Calorimetry (DSC)
measurements of both the reaction mixtures and the isolated molecules are described in
order to ensure the maximum safety of the process. Total costs of the synthesis are also
discussed.
RESULTS AND DISCUSSION
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The synthesis of these reagents starts from the phenyl trifluoromethyl sulfoxide 1, which
is treated with acetonitrile in the presence of triflic anhydride, leading, via a Ritter-type
reaction, to a putative bis-triflate intermediate 2 (Scheme 1). This intermediate, stable at
-15°C, can further evolve by two different pathways: i) hydrolysis of the reaction gives the
N-acetylated intermediate sulfilimine 3, which can be smoothly oxidized by KMnO4 and
deprotected in the presence of 6M HCl to obtain the trifluoromethylated sulfoximine 4; ii)
addition of a secondary amine to intermediate 2 directly leads to the sulfilimino iminium
5.
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Scheme 1: Synthetic scheme of the preparation of trifluoromethyl- sulfoximines and
sulfilimino iminiums
O
1. KMnO4
MeCN/H2O
TfO
OTf
O
S
Tf2O
H2O
N
O
H
N
N
S
2. HCl 6M
MeCN/H2O
CF3
Ph
N
MeC
CF3
Ph
S
S
CF3
CF3
Ph
Ph
4
1
2
3
Sulfoximine
Me
TfO-
Me
N
Me2NH
N
S
CF3
Ph
5
Sulfilimino iminium
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Synthesis of the phenyl trifluoromethyl sulfoxide 1.
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The phenyl trifluoromethyl sulfoxide 1 is commercially available but quite expensive (at
least 78 € per gram). However, compound 1 can be easily prepared following our
previously described one-pot procedure starting from sodium trifluoromethanesulfinate
(Langlois reagent) and benzene.8 A reappraisal of our protocol is presented herein
(Scheme 2). The production of compound 1 has been scaled up to 78 g without major
issues and with a good yield of 73% (Table 1, entry 3) after purification by distillation.
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Scheme 2: Synthesis of the sulfoxide 1
O
CF3SO2Na
S
CF3
TfOH (6.7 eq)
RT, 19h
(1.75 eq)
1
This reaction occurs without solvent which causes two major issues: elevation of the
temperature of the reaction and difficulty in stirring the reaction mixture. It is noteworthy
that the addition of trifluoromethanesulfonic acid to sodium trifluoromethanesulfinate
leads to a pasty mixture and to a rapid increase in temperature that can rise to 80°C. On
a 10 g scale (Table 1, entry 1), magnetic stirring gives a reasonably homogeneous mixture
and the exothermic phenomenon is not problematic. With larger quantities of reagents
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(Table 1, entries 2-3), mechanical stirring is required to obtain good dispersion and a
homogeneous medium. Otherwise, the formation of aggregates proves deleterious to the
yield. The triflic acid should be added portion wise (at least by thirds) to minimize
temperature elevation. An additional cold-water bath is required to maintain the
temperature of the reaction mixture (controlled by a thermometer) below 50°C. After 19
hours of stirring at room temperature, the reaction is poured onto ice (10 g of ice for 1 g
of sodium trifluoromethanesulfinate) to control the exothermicity of the quenching.
Table 1: Multigram synthesis of phenyl trifluoromethyl sulfoxide 1
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CF3SO2N
Entry
1
Benzene
10 mL
TfOH
35 mL
Sulfoxide
7.6 g
Yield
61 %
68 %
73 %
a
10 g
2a
50 mL
50 g
90 g
176 mL
315 mL
41.9 g
78.1 g
3a
90 mL
a Use of a mechanical stirrer
The thermal stability of this compound was explored by DSC analysis (Figure 2). The
phenyl trifluoromethyl sulfoxide 1 exhibits good thermal stability with decomposition from
205°C, proving the safety of the previously described reaction conditions and purification.
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Figure 2: DSC analysis of the phenyl trifluoromethyl sulfoxide 1
It is important to underline that purification of the sulfoxide 1 is not necessary for the
next steps.
Synthesis of the intermediary sulfilimine 3.
The second step is a Ritter-type reaction between the sulfoxide 1 and acetonitrile in the
presence of trifluoromethanesulfonic anhydride. The procedure described by our group
in 20097a has been adapted to a larger scale using acetonitrile as reagent and solvent,
increasing its quantity from 1.5 to 11 equivalents.
Scheme 3: Synthesis of the intermediary sulfilimine 3
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1. Tf2O (1.5 eq),
MeCN (11 eq),
-15°C, 18h, Ar
NAc
S
O
S
CF3
CF3
2. H2O
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3
1
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It should be noticed that a low temperature (-15°C) is necessary to control the first step
and to obtain an optimal formation of the intermediate sulfilimine 3. This experimental
observation was supported by DSC analysis of the reaction media just after the addition
of trifluoromethanesulfonic anhydride and also after full conversion of the sulfoxide 1. The
DSC analysis of the reaction medium after the dropwise addition of
trifluoromethanesulfonic anhydride (Tf2O) shows an endothermic peak at 20°C followed
by an exothermic peak from 55°C, revealing the instability of the reaction medium (Figure
3). Moreover, after full conversion of sulfoxide 1, it was shown that the medium is quite
unstable with an exothermic peak starting at 15°C (Figure 4). Therefore, the temperature
of the reaction should be maintained under -15°C to preserve an acceptable thermal
stability. For this purpose, the reaction can be simply stored in a freezer for 18 hours, as
the absence of stirring does not negatively impact the yield of the transformation.
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Figure 3: DSC analysis of the reaction medium after the addition of Tf2O
Figure 4: DSC analysis at full conversion of sulfoxide 1
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It should be underlined that there is an interaction between triflic anhydride Tf2O and
acetonitrile (Figure 5), regardless of the number of equivalents, with a thermal
phenomenon, which contributes to the one of the reaction (Figure 4).
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Figure 5: DSC analysis of the interaction between Tf2O and acetonitrile (Tf2O/MeCN =
1/2 v/v)
In our initial publication,7a water was directly added to the reaction mixture. On a larger
scale and in order to control the exothermicity of the reaction quench, it is necessary to
pour the crude mixture onto ice (10 g of ice for 1 g of sulfoxide 1). The pure N-acetylated
sulfilimine 3 shows a DSC profile with a decomposition starting from an onset temperature
of 145°C (Figure 6), far from the process temperature.
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Figure 6: DSC analysis of the N-acetylated sulfilimine 3
Synthesis of the trifluoromethyl sulfoximine 4.
The sulfilimine 3 is then smoothly oxidized in the presence of potassium permanganate
in dilute medium and the obtained acetylated sulfoximine 4’ is deprotected with
hydrochloric acid to give the sulfoximine 4.
Scheme 4: Synthesis of the sulfoximine 4
NAc
O
NH
O
NAc
KMnO4 (1 eq),
MeCN/H2O
HCl 6M (3 eq),
MeCN
S
S
S
CF3
CF3
CF3
RT, 24h
RT, 18h
3
4'
4
On a large scale, an excellent overall yield is obtained for the production of 33 g of
sulfoximine 4 (Table 2, entry 3). The scale up can be achieved without major issues. To
facilitate the oxidation step on scale-up, potassium permanganate was slowly added as
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a solid to the solution of intermediate sulfilimine 3 in water and acetonitrile. It is important
to note that no intermediate purification is required and the final product was simply
filtered through a pad of silica. Pleasingly, we noticed a substantial improvement in the
yield on increasing the scale of the reaction.
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Table 2: Multigram synthesis of phenyl trifluoromethyl sulfoximine 4
Entry Sulfoxide
Tf2O
6.5 mL
26 mL
MeCN
15 mL
60 mL
KMnO4
HCl 6M
Sulfoximine
2.7 g
Yield
50 %
66 %
76 %
1
2
3
5 g
4.07 g
8.4 mL
20 g
40 g
16.28 g 33.6 mL
14.3 g
52 mL 120 mL 32.56 g 67.2 mL
32.8 g
Both steps were analyzed by DSC. The oxidation medium exhibits an exothermic peak
from 125°C, revealing a good thermal stability of the mixture (Figure 7) under the reaction
conditions.
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Figure 7: DSC analysis of the oxidation reaction medium
The hydrolysis of the intermediate N-protected sulfoximine 4’ medium also possesses a
good thermal stability with an exothermic peak starting at 225°C (Figure 8). A slight
exothermic decomposition appears from 115°C but presents no notable risk under the
reaction conditions.
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Figure 8: DSC analysis of the hydrolysis reaction medium
The DSC profile of the isolated products were also explored. It is noteworthy that both
compounds 4’ and 4 exhibit an autocatalytic behavior (sharp peak) with an important
exothermic peak. Indeed, the N-acetylated sulfoximine 4’ decomposes with an energy
exceeding 600 J/g from 265°C (Figure 9).
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Figure 9: DSC analysis of the intermediate 4'
Similarly, the sulfoximine 4 decomposes with an exceptionally strong exothermic peak
with an energy exceeding 896 J/g from 270°C (Figure 10) after an endothermic peak at
48°C corresponding to the melting point of the compound.
Figure 10: DSC analysis of the sulfoximine 4
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Synthesis of the phenyl trifluoromethyl sulfilimino iminium 5.
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In the same way as the synthesis of the sulfoximine 4, the synthesis of the sulfilimino
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iminium 5 starts from the trifluoromethyl sulfoxide 1, and the first step is a Ritter-type
reaction between the sulfoxide 1 and acetonitrile in the presence of triflic anhydride. The
major difference is the quench reagent. This time, the addition of dimethylamine delivers
the desired sulfilimino iminium 5 (Scheme 5).
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Scheme 5: Synthesis of the sulfilimino iminium 5
N
TfO-
O
S
1. Tf2O (1.5 eq),
MeCN (1.5 eq)
-15°C, 18h, Ar
N
S
CF3
CF3
2. Me2NH (2.6 eq, 2M in THF)
-15°C to RT, 18h, Ar
1
5
In our previous protocol,7b the dimethylamine was added in pure form. The use of a
commercial solution of dimethylamine in THF (2M) is more convenient and was added
dropwise at -15°C (Table 3, entry 1). At the end of the addition, the temperature of the
reaction was allowed to rise slowly to room temperature. During the scale-up of the
reaction conditions, we realized that the introduction of 4 equivalents of dimethylamine
led to a very dilute reaction medium, and we assumed that fewer equivalents could afford
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the desired product with a similar yield. When 2.6 equivalents of dimethylamine in THF
are introduced, the desired sulfilimino iminium 5 is obtained with a good yield of 76 %
(Table 3, entry 2), similar to the yield with 4 equivalents (Table 3, entry 1).
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Table 3: Multigram synthesis of sulfilimino iminium 5
Me2NH
in THF
Compound
Entry
Sulfoxide
2.0 g
Tf2O
MeCN
Yield
71 %
76 %
64 %
1
2
3
2.6 mL
5.8 mL
20.6 mL/ 4 eq
3.0 g
24.3 g
40.5 g
15.0 g
30.0 g
19.5 mL 43.6 mL 100.0 mL/ 2.6 eq
39.1 mL 87.1 mL 200.9 mL/ 2.6 eq
The production of sulfilimino iminium 5 has been scaled up to 40 g with a good yield of
64 % (Table 3, entry 3). From a practical point of view, the purification of compound 5 by
chromatography on silica is quite cumbersome, using a lot of solvent and time. Changing
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the purification method quickly became essential during the scale-up of the synthesis.
Sulfilimino iminium 5 is insoluble in diethyl ether. Therefore, compound 5 can be placed
on a pad of Celite® (10 g of Celite® per gram of sulfoxide), impurities are removed by
washing the Celite® with diethyl ether and the desired product is then recovered by
washing the celite® with dichloromethane. If some impurities remain, the obtained solid
can be washed again with diethyl ether. It is important to mention that the use of a newly
opened bottle of high quality trifluoromethanesulfonic anhydride is crucial for the success
of the reaction.
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The thermal stability of sulfilimino iminium 5 has also been explored by DSC analysis
(Figure 11). After an endothermic phenomenon corresponding to the melting of 5 around
64°C, an exothermic peak is observed from 120°C with an energy at 412 J/g revealing its
good thermal stability under the process temperature.
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Figure 11: DSC analysis of sulfilimino iminium 4
Financial estimation for reagent production.
We have been able to produce 78 g of sulfoxide 1, 33 g of sulfoximine 4 and 40.5 g of
sufilimino iminium 5. We decided to determine the cost of the production of such batches.
To estimate the cost, the reagents, the solvents used for reactions and extraction, and
the solvents, Celite® or silica used for purifications have been taken into account (Tables
4, 5 and 6) but the cost of manpower has been overlooked.
Table 4: Financial estimation for the synthesis of sulfoxide 1
Reagent
Benzene
Chemicals costa
Quantity Cost (€)
50 mL 2.08
20.79 € / 500 mL
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£ 83.00 / 100 g
CF3SO2Na
TfOH
50 g
47.00b
176 mL 57.87
300 mL 0.49
193.98 € / 1 kg = 590 mL
8.10 € / 5 L
Dichloromethane
(Extraction)
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Total cost for the production of 42 g of sulfoxide 1
Total cost for the production of 1 g of sulfoxide 1
107.43
2.56 (2.91 $)
b
a Negotiated prices with chemical suppliers. b Exchange rate on 01/21/19, 13:15 UTC.
Table 5: Financial estimation for the production of sulfoximine 4
Reagent
Chemicals costa
Quantity
Cost (€)
Sulfoxide 1
2.56 € / 1 g
40 g
102.4
£ 270.0 / 1 kg = 596
mL
Tf2O
52 mL
26.61b
119 + 344
mL
Acetonitrile
KMnO4
13.70 € / 2.5 L
59.90 € / 500 g
5.57 € / 2,5 L
2.54
3.90
0.07
1.62
2.36
3.51
0.8
32.55 g
33.6 mL
1 L
HCl 37 %
Dichloromethane (Extraction) 8.10 € / 5 L
Silica (Purification) 11.80 € / 1 kg
Petroleum ether (Purification) 8.35 € / 5 L
200 g
2.1 L
Ethyl acetate (Purification)
10.0 € / 5 L
0.4 L
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Total cost for the production of 33 g of sulfoximine 4
Total cost for the production of 1 g of sulfoximine 4
142.93
4.33 (4.91 $)
b
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a Negotiated prices with chemical suppliers. b Exchange rate on 01/21/19, 13:15 UTC.
Table 6: Financial estimation for the production of sulfilimino iminium 5
Reagent
Chemicals costa
Quantity Cost (€)
30 g 76.8
Sulfoxide 1
2.56 € / 1 g
£ 270.0 / 1 kg = 596
mL
Tf2O
39.1 mL 20.05b
87.1 mL 0.48
Acetonitrile
Me2NH in THF (2M)
13.70 € / 2.5 L
74.00 € / 500 mL
200.9
mL
29.7
Dichloromethane (Extraction) 8.10 € / 5 L
360 mL 0.58
Celite® (Purification)
399.00 € / 25 kg
21.40 € / 5 L
300 g
0.6 L
0.6 L
4.79
Diethyl ether (Purification)
2.57
Dichloromethane (Purification) 8.10 € / 5 L
0.97
Total cost for the production of 40.5 g of sulfilimino iminium 5
Total cost for the production of 1 g of sulfilimino iminium 5
135.94
3.36 (3.81 $)
b
a Negotiated prices with chemical suppliers. b Exchange rate on 01/21/19, 13:15 UTC.
Globally, the cost per gram of these reagents is highly reasonable.
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CONCLUSION
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The production of sulfoxide 1, sulfoximine 4 and sulfilimino iminium 5 has been
optimized and performed on a multi-gram scale. DSC analyses, performed on only a few
milligrams of substance, allowed us to investigate the thermal stabilities of the
intermediates and final species. It is noteworthy that we are confident that these quantities
do not represent an upper limit, and that larger quantities could be obtained in good yields
with such optimized conditions. Moreover, the overall costs of these reagents are highly
reasonable. These efficient conditions clearly pave the way to easy syntheses of such
reagents in any laboratory for further applications, and should contribute to the
popularization of their use.
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EXPERIMENTAL SECTION
Synthesis of the ((trifluoromethyl)sulfinyl)benzene 1
A dry 1 L, three-necked, round-bottomed flask equipped with a thermometer and a
mechanical stirrer was charged with sodium trifluoromethanesulfinate (90 g, 0.58 mol)
and dried under vacuum for 24 hours prior to use. The flask is placed in a cold-water bath
and trifluoromethanesulfonic acid (315 mL, 3.56 mol) is added, under argon, in three
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portions with vigorous stirring (around 100 mL each), in order to keep the temperature
under 50°C. After the addition, the reaction is stirred for 20-30 minutes until the
temperature decreases to room temperature. Then, benzene (90 mL, 1.01 mol) is added
in one portion and the solution is stirred at room temperature for 19 h under an inert
atmosphere. The reaction is quenched by pouring the reaction medium on ice (900 g),
extracted with dichloromethane (3 x 100 mL), and washed with a saturated solution of
NaHCO3 (3 x 60 mL). The organic phase is dried over MgSO4, filtered and concentrated
under reduced pressure. The product is purified by distillation under reduced pressure
(78 - 80°C at 15 mmHg) to afford 1 (78.1 g, 73%, colorless oil).
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1H NMR (300 MHz, CDCl3) δ (ppm): 7.76 (d, J = 7.4 Hz, 2H), 7.70 – 7.49 (m, 3H). C
13
NMR (75 MHz, CDCl3) δ (ppm): 135.6 (q, J = 1.72 Hz), 133.6, 129.61, 125.9, 124.7 (q, J
= 335 Hz, CF3). 19F NMR (282 MHz, CDCl3) δ (ppm): -75.0 (s, 3F).
Imino(phenyl)(trifluoromethyl)-λ6-sulfanone 4
In a dry 500 mL two-necked round-bottomed flask equipped with a dropping-funnel and
a thermometer, a solution of phenyl trifluoromethyl sulfoxide 1 (40 g, 206.0 mmol) in dry
acetonitrile (120 mL, 2.28 mol) is cooled to -15°C under argon. Tf2O (52 mL, 309.1 mmol)
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is introduced into the dropping-funnel and added dropwise to the solution, keeping the
temperature around -15°C. The solution is then left at -15°C for 18 h under argon in a
freezer. The reaction is quenched by pouring the reaction media on ice (400 g), extracted
with dichloromethane (3 x 80 mL), and washed with a saturated solution of NaHCO3 (3 x
40 mL). The organic phase is dried over MgSO4, filtered and concentrated under reduced
pressure.
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To a solution of this crude product in acetonitrile (160 mL) and water (40 mL) is added
KMnO4 (32.56 g, 206.0 mmol) portion wise. The reaction is stirred at room temperature
for 18 hours, diluted with H2O (150 mL) and a saturated solution of Na2S2O4 is added until
complete discoloration of the solution. The product is extracted with dichloromethane (3
x 70 mL), and the organic phase is dried over MgSO4, filtered and concentrated under
reduced pressure.
The crude product is dissolved in acetonitrile (184 mL) and HCl 6M (67.2 mL) is added.
The reaction is stirred at room temperature for 18h. Then, water (100 mL) is added and
the organic phase is extracted with dichloromethane (3 x 50 mL), washed with a solution
of saturated NaHCO3 (3 x 20 mL), dried over MgSO4, filtered and concentrated under
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reduced pressure. The product is filtered on silica (200 g) using petroleum ether/ethyl
acetate 8/2 as eluent to afford the desired sulfoximine 4 (32.8 g, 76 %, white solid).
1H NMR (300 MHz, CDCl3) δ (ppm): 8.15 (d, J = 7.5 Hz, 2H), 7.84 – 7.72 (m, 1H), 7.63
(dd, J = 8.5, 7.1 Hz, 2H), 3.53 (s, br s, 1H). 13C NMR (75 MHz, CDCl3) δ (ppm): 135.6,
131.6, 130.7, 129.6, 121.0 (q, J = 333 Hz, CF3). 19F NMR (282 MHz, CDCl3) δ (ppm): -
70.3 (s, 3F).
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(Z)-N-methyl-N-(1-((phenyl(trifluoromethyl)-λ4-sulfanylidene)amino)ethylidene)methane-
minium 5
In a dry 500 mL two-necked round-bottomed flask equipped with a dropping-funnel and
a thermometer, under argon, a solution of phenyl trifluoromethyl sulfoxide 1 (30 g, 154.5
mmol) in dry acetonitrile (87.1 mL, 1.67 mol) is cooled to -15°C. Tf2O (39.1 mL, 232.4
mmol) is added dropwise, keeping the temperature around -15°C. The solution is then
left at -15°C for 18 h under argon in a freezer. A solution of Me2NH (2M in THF, 200.9
mL, 401.8 mmol) is added dropwise to the reaction, keeping the temperature at around -
15°C, under an inert atmosphere. Then, the reaction mixture is allowed to warm to room
temperature slowly. The reaction is stirred at room temperature for 18h, under an inert
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atmosphere. The reaction is quenched by addition of 100 mL of water and the product is
extracted with dichloromethane (3 x 120 mL). The organic phase is dried over MgSO4,
filtered and concentrated under reduced pressure. The crude residue is placed on Celite®
(300 g) and the solid is washed three times with diethyl ether to remove impurities. Then,
the deposit is washed three times with dichloromethane to recover the desired product 5
(40.5 g, 64 %, brownish solid).
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1H NMR (300 MHz, CDCl3) δ (ppm): 8.07 (d, J = 7.9 Hz, 2H), 7.89 – 7.75 (m, 1H), 7.70
(dd, J = 8.3, 6.8 Hz, 2H), 3.39 (s, 3H), 3.35 (s, 3H), 2.67 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ (ppm): 174.2, 135.9, 130.8, 129.2, 124.7, 123.3 (q, J = 127 Hz, CF3), 120.7 (q,
J = 320, CF3), 41.7, 40.0, 19.5. 19F NMR (282 MHz, CDCl3) δ (ppm): -67.4 (s, 3F), -79.0
(s, 3F, OTf).
Experimental conditions for DSC: DSC analysis were performed in a gold-plated closed
crucible high pressure 40 µL Mettler, under air, applying a heating rate of 5 K/min in the
range 0 K to 400 K/min.
Supporting Information
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NMR Spectra of the compounds 1, 4 and 5 are provided.
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Author Contributions
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The manuscript was written through contributions of all authors. All authors have given
approval to the final version of the manuscript.
ACKNOWLEDGMENT
We thank the CNRS and French Ministry of Research for their financial support. We also
acknowledge Dr. Karen Wright for the careful reading and improvement of the English,
Dr. F. Metz from Solvay-Rhodia Lyon for the gift of chemicals and the French Fluorine
Network for its support.
REFERENCES
(1) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, 2nd,
Completely Revised and Enlarged Edition; Wiley: New-York, 2013. (b) Müller, K.; Faeh, C.;
Diederich, F.; Fluorine in pharmaceuticals: looking beyond intuition, Science 2007, 317, 1881-
1886. (c) Bioorganic and Medicinal Chemistry of Fluorine (Eds.: Bégué, J.-P.; Bonnet-Delpon,
D.), Wiley, Hoboken, 2008. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. ; Fluorine
in medicinal chemistry, Chem. Soc. Rev. 2008, 37, 320-330. (e) Wang, J.; Sanchez-Rosello, M.;
Acena, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H.; Fluorine
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