A new version of Umemoto's reagents: A three-step one-pot preparation of 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium triflate

Article abstract of DOI:10.1016/j.jfluchem.2019.109347

A new one-pot method was developed for the practical preparation of powerful electrophilic trifluoromethylating agent, 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium triflate 2. This method comprised of three steps; (1) in situ generation of trifluoromethanesulfinyl trifluoroacetate 7, (2) treatment of 3,3′,4,4′-tetrafluorobiphenyl with 7 in the presence of trifluoromethanesulfonic acid and trifluoroacetic anhydride, and (3) treatment of the resulting mixture with hydrogen peroxide. By means of this effective three-step one-pot method, 2 was prepared in a good isolated yield by simple water-washing method. It is thus expected that easy access to 2 may lead to its wider or new applications to many areas, because tetrafluoro reagent 2 is much more powerful than 2,8-difluoro-S-(trifluoromethyl)dibenzothiophenium triflate 1.

Full text of DOI:10.1016/j.jfluchem.2019.109347

Accepted Manuscript
Title: A new version of Umemoto’s reagents: A three-step
one-pot preparation of
2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium
triflate [1]
Authors: Teruo Umemoto, Xiaocong Zhou, Yuanqiang Li
PII:
DOI:
Article Number:
S0022-1139(19)30156-3
https://doi.org/10.1016/j.jfluchem.2019.109347
109347
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FLUOR 109347
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10 July 2019
12 July 2019
Please cite this article as: Umemoto T, Zhou X, Li Y, A new version of
Umemoto’s reagents: A three-step one-pot preparation of 2,3,7,8-tetrafluoro-S-
(trifluoromethyl)dibenzothiopheniumtriflate[1], JournalofFluorineChemistry(2019),
https://doi.org/10.1016/j.jfluchem.2019.109347
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A new version of Umemoto’s reagents: A three-step one-pot preparation of 2,3,7,8-
tetrafluoro-S-(trifluoromethyl)dibenzothiophenium triflate [1]
Teruo Umemoto*, Xiaocong Zhou, and Yuanqiang Li
Zhejiang Raybow Pharmaceutical Co., Ltd., Hangzhou Lab.
Building No. 9, Medicine Port Town, East Hangzhou Economic and Technical Development
Zone, Hangzhou, Zhejiang, 310018, China
*Corresponding author. E-mail address: teruoumemoto@comcast.net
GRAPHICAL ABSTRACT
HIGHLIGHTS



・A three-step one-pot method was developed for the practical preparation of powerful
electrophilic trifluoromethylating agent, 2,3,7,8-tetrafluoro-S-
(trifluoromethyl)dibenzothiophenium triflate 2.
・The one-pot method comprised of (step 1) in situ generation of CF3S(O)OCOCF3, (step 2) its
reaction with 3,3’,4,4’-tetrafluorobiphenyl in the presence of trifluoromethanesulfonic acid and
trifluoroacetic anhydride, and (step 3) treatment with hydrogen peroxide.
・The CF3S by-product formed in step 2 was completely converted to the final product 2 in the
step 3.


・The powerful reagent 2 was easily isolated in a good yield by simple water-washing method.
・The reaction mechanism including the formation of the CF3S by-product was proposed.

ABSTRACT:
A new one-pot method was developed for the practical preparation of powerful electrophilic
trifluoromethylating agent, 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium triflate
2. This method comprised of three steps; (1) in situ generation of trifluoromethanesulfinyl
trifluoroacetate 7, (2) treatment of 3,3’,4,4’-tetrafluorobiphenyl with 7 in the presence of
trifluoromethanesulfonic acid and trifluoroacetic anhydride, and (3) treatment of the resulting
mixture with hydrogen peroxide. By means of this effective three-step one-pot method, 2 was
prepared in a good isolated yield by simple water-washing method. It is thus expected that easy
access to 2 may lead to its wider or new applications to many areas, because tetrafluoro
reagent 2 is much more powerful than 2,8-difluoro-S-(trifluoromethyl)dibenzothiophenium
triflate 1.
KEYWORDS: Umemoto’s reagent, 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium
salt, a three-step one-pot preparation, tetrafluorobiphenyl, trifluoromethanesulfinate
1. Introduction
Since it has unique properties such as high stability and lipophilicity [2], the trifluoromethyl
group is nowadays a widely attractive functional group, in particular, in pharmaceutical and
agrochemical fields [3]. Therefore, how to effectively introduce the trifluoromethyl group into
an organic molecule is a very active research target. The development of useful
trifluoromethylating agents has been made for a long time to solve the problem [4]. Among
them, electrophilic trifluoromethylating agents have occupied an important position in the
research and application [5]. We recently developed a new version of Umemoto’s reagents, 2,8-
difluoro- and 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium triflates 1 and 2 as
practically useful electrophilic trifluoromethylating agents that are powerful, thermally stable,
one-pot preparable, and recyclable [5r]. At first, the new reagents 1 and 2 were synthesized
from 3,3’-difluoro- and 3,3’,4,4’-tetrafluorobiphenyls 3 and 4, respectively, by modified
Magnier’s one-pot method [6] using sodium trifluoromethanesulfinate 5 and
trifluoromethanesulfonic anhydride (triflic anhydride, Tf2O) in nitromethane solvent. However,
for the case of 3, this method gave an 82:18 mixture of 1 and isomeric 2,6-difluoro triflate 1’ as
shown in Scheme 1.
Scheme 1. Modified Magnier’s one-pot treatment of 3,3’-difluorobiphenyl 3

As an economical and industrially applicable method, we succeeded in the development of a
new one-pot method which used cheap trifluoromethanesulfonic acid (triflic acid, TfOH) and
trifluoroacetic anhydride in place of expensive triflic anhydride and excluded the use of
potentially explosive nitromethane as the solvent [5r]. This two-step one-pot method provided
1 as a sole isomeric product in a good isolated yield (Scheme 2, see [7]) and made it possible to
produce 100 kg per batch of 1 in our factory [8].
Scheme 2. A two-step one-pot method for the preparation of 1 using TfOH and (CF3CO)2O in
place of Tf2O
However, this method was not useful for the preparation of Umemoto’s reagent 2, because the
yield was very low and a significant amount of a by-product was formed.
Reagent 2 with four fluorine atoms on the benzene rings was shown to be much more powerful
than 1 with two fluorine atoms [5r]. Because of the higher power of 2 [9], it may be expected
that 2 has wider or new applications to many areas. Therefore, an effective and industrially
applicable method for the production of 2 is highly desired. In this paper, we report a new
three-step one-pot method suitable for the practical production of the powerful tetrafluoro
Umemoto’s reagent 2.
2. Results and Discussion

The two-step one-pot method suitable for difluoro Umemoto’s reagent 1 was applied to the
preparation of more powerful tetrafluoro reagent 2. However, the reaction temperature for the
trifluoromethanesulfinylation of 3,3’,4,4’-tetrafluorobiphenyl 4 in step 2 was required to be
high (> r.t.) because of lower reactivity of 4 than 3,3’-difluorobiphenyl 3, the reaction of which
smoothly occurred at low temperature (< 0 oC). As a result, a large amount of a by-product was
formed as shown in Scheme 3. 19F NMR of the reaction mixture clearly showed a significant
amount of the formation of the by-product in addition to 2 (Figure 1). The by-product was
tentatively assigned as 3,3’,4,4’-tetrafluoro-6-(trifluoromethylthio)biphenyl 6 by the NMR
analysis and the reaction progress details discussed below. The 19F NMR (with 1H decoupling)
showed a singlet of -42.71 ppm and a set of four doublets with a F-F coupling constant of 22.5
Hz at -132.89, -134.82, -139.03, and -139.50 ppm. The former singlet could easily be assigned as
CF3S fluorine atoms of 6 and the latter four doublets as four different fluorine atoms on the
biphenyl ring of 6. The ratio of 2/6 changed depending on the reaction conditions. However,
despite all of our efforts, attempts to get rid of the formation of 6 failed.
Scheme 3. Attempt for the preparation of 2 from 3,3’,4,4’-tetrafluorobiphenyl 4 by the same
method as 1
Fig. 1. 19F NMR of the reaction mixture from the reaction of 4 with CF3SO2Na/(CF3CO)2O/TfOH

At this point, it is useful to discuss the difference in reaction between two cases of
difluorobiphenyl 3 and tetrafluorobiphenyl 4. There was nearly no formation of the
corresponding by-product in the former case [10], while a large amount of by-product 6 was
formed in the latter case. It could be explained clearly by the proposed mechanism as shown in
Scheme 4.
Scheme 4. Proposed reaction mechanism for the reactions of 3 and 4 with
CF3SO2Na/(CF3CO)2O/TfOH

As discussed in our previous paper [5r], intermediate 7 was formed in step 1. In step 2, 7
reacted with 4 at more than room temperature in the presence of TfOH to give 9, which then
underwent cyclization under the reaction conditions to give the final product 2. However, 7
caused an ester-exchange reaction at more than room temperature to give 10 and
trifluoroacetic anhydride, and 10 could undergo inner disproportionation reaction or
rearrangement to give 11, which then reacted with 4 to form the trifluoromethanethiolated by-
product 6. Yi et al. reported similar trifluoromethanethiolation of arenes by the reaction of
CF3SO2Na with Tf2O in which 11 was proposed as a reactive species formed by
disproportionation of two CF3S(O)OTf molecules (2CF3S(O)OTf -> 11 + Tf2O) [11]. On the other
hand, the corresponding by-product was scarcely formed in the case of 3,3’-difluorobiphenyl 3,
because the trifluoromethanesulfinylation of 3 with 7 in step 2 easily occurred at the low
temperature (< 0 oC) to give 8, which cyclized at more than room temperature to give 1.
Therefore, the strong trifluoromethanethiolating agent 11 could not be generated in the case of
3.
Scheme 5. Design of the improved method for the preparation of tetrafluoro reagent 2

Since we failed in all attempts to get rid of the formation of 6, we designed to follow the one-
pot process with the oxidation step (step 3, Scheme 5). We expected that, in step 3, the by-
product 6 could be oxidized to the CF3S(O)-intermediate 9, which was then cyclized to the final
product 2 by action of the existing triflic acid and trifluoroacetic anhydride (Scheme 6).
Scheme 6. Oxidation and cyclization reactions expected in step 3.
As a preliminary examination, we used m-chloroperbenzoic acid as an oxidizer and confirmed
the conversion of the by-product 6 to the final product 2. Finally, we chose 35% hydrogen
peroxide as the oxidizer that is cheap and does not leave any solid residue from it after the
reaction. In step 3, the actual oxidizer would be trifluoroperacetic acid (CF3COOOH), because
H2O2 could immediately react with existing (CF3CO)2O to form CF3COOOH.
Scheme 7. A three-step one-pot method for the preparation of powerful Umemoto’s reagent 2
The reaction conditions for each step and the ratios of the reactants were determined by
repeated experiments, as shown in Scheme 7. For 1 equiv. of CF3SO2Na 5, (CF3CO)2O (4.7
equiv.) and CF3COOH (1.2 equiv.) in step 1, tetrafluorobiphenyl 4 (0.56 equiv.) and TfOH (2.2
equiv.) in step 2, and aqueous 35% H2O2 solution (H2O2, 0.22 equiv.) in step 3 were used. The
amount (0.56 equiv.) of tetrafluorobiphenyl 4 was chosen so that all of 4 was consumed in
these reactions. The amount (0.22 equiv.) of H2O2 was chosen as a minimum amount to
consume the by-product 6. By these conditions, the desired product 2 was formed in a high

yield and easily isolated in a good yield by the water-washing method as seen in Scheme 7 (see
Experiment section).
The large amount (4.7 equiv.) of trifluoroacetic anhydride used in step 1 contained not only the
amount necessary for the reaction with CF3SO2Na in step 1 and for the cyclization in step 2, but
also for the reactions with H2O2 and H2O in aqueous 35% H2O2 solution, followed by the
cyclization reaction giving 2, in step 3. Trifluoroacetic anhydride also served as a solvent, in
particular in step 1. Since all the reactions of Scheme 7 were very sensitive to moisture, they
had to be completely dried. Trifluoroacetic anhydride was able to completely get rid of
moisture (water) in the reactor by the reaction of (CF3CO)2O + H2O -> 2CF3COOH, which also
served as a solvent. This was a very advantageous point to prepare 2 without special care in
highly humid climate areas like east China.
Figures 2 and 3 showed the 19F NMR of the reaction mixture after step 2 and step 3,
respectively. For this case, the former NMR showed that a 4:1 mixture of 2 and 6 was formed
and a very small amount of the starting material 4 remained intact at this moment. The latter
NMR showed that 6 was clearly converted to the final product 2 after the oxidation step 3.
Interestingly, it seemed that some of the starting material 4 was converted to 2 in step 3
because 4 was almost completely consumed after step 3. Thus, product 2 was found to be
formed in a high yield (89%) by the 19F NMR analysis of the reaction mixture using
benzotrifluoride as an internal reference and 2 was easily isolated in a good yield (72%) by the
water-washing method (see a typical procedure in the experimental section).
Fig. 2. 19F NMR of the reaction mixture after step 2
*
*

Fig. 3. 19F NMR of the reaction mixture after step 3
4. Conclusion
The problem in the preparation of powerful 2,3,7,8-tetrafluoro-S-
(trifluoromethyl)dibenzothiophenium triflate 2 was the significant formation of the by-product
6 due to the low reactivity of 3,3’,4,4’-tetrafluorobiphenyl. The practical three-step one-pot
method developed here by us clearly dissolved the problem and led to the high yield
production of the powerful reagent 2. Since the tetrafluoro reagent 2 is much more powerful
than difluoro reagent 1, it is thus expected that the easy access to 2 could advance wider or
new applications of 2 to many areas.
5. Experimental
General information. 19F and 1H NMR spectra were measured on 400 and 376 MHz
spectrometers, respectively. DMSO-d6 was used as a solvent unless otherwise noted and 19F
chemical shifts were given as  in ppm downfield from CFCl3.
Materials. CF3SO2Na was dried at 80 oC for several hours by a vacuum pump. Other
commercially available compounds, CF3COOH, (CF3CO)2O, and TfOH, were used without further
purification. 3,3’,4,4’-Tetrafluorobiphenyl 4 of high purity was easily prepared in a high yield by

the homo-coupling reaction of 3,4-difluoroiodobenzene with copper powder using a small
amount of N-methylpyrrolidinone [see ref. 12]. This method was useful at lab scale. Previously,
4 was prepared by the homo-coupling reaction of 3,4-difluorophenylmagnesium bromide with
air, catalyzed by MnCl2.2LiCl [5r]. However, as the purity of the product was not high, a
purification process such as distillation was needed.
A three-step one-pot procedure for the preparation of 2,3,7,8-tetrafluoro-S-
(trifluoromethyl)dibenzothiophenium triflate 2; a typical procedure.
(Step 1) In a 250 mL three-necked glassware flask equipped with a dropping funnel, a
condenser, a calcium chloride-drying tube, a thermometer, and a magnetic stirrer, were placed
12.5 g (80.1 mmol) of dry sodium trifluoromethanesulfinate 5. Into the flask, 52 mL (654 mmol)
of trifluoroacetic anhydride was dropwise added for 10 min and then 7.4 mL (97 mmol) of
trifluoroacetic acid was dropwise added for 10 min with stirring under water bath cooling [13].
The reaction mixture was stirred overnight (19 hr) at room temperature [14]. (Step 2) To the
reaction mixture, 10.0 g (44.2 mmol) of 3,3’,4,4’-tetrafluorobiphenyl 4 was added by one-
portion at room temperature and then 15.5 mL (176 mmol) of triflic acid was dropwise added
for 12 min with stirring under water bath cooling. After the reaction mixture was stirred at
room temperature for 7 h, the mixture was stirred on an oil bath at 35 oC for 15 h and then at
45 oC for 24 h. The mixture was cooled to room temperature. (Step 3) To the reaction mixture,
a mixture of 1.72 g of aqueous 35% H2O2 solution and 8 mL of CF3COOH was dropwise added
for 30 min with stirring under water bath cooling. After the reaction mixture was stirred at
room temperature for 2 h, the reaction mixture was stirred on an oil bath at 45 oC for 20 h and
cooled to room temperature. 19F NMR analysis of the reaction mixture using benzotrifluoride as
an internal standard showed that 2,3,7,8-tetrafluoro-S-(trifluoromethyl)dibenzothiophenium
triflate 2 was produced in 89% yield based on the starting material 4. The reaction mixture was
evaporated under reduced pressure. To the residue, 25 mL of toluene was added and toluene
was evaporated under reduced pressure. This process (addition and evaporation of 25 mL of
toluene) was repeated additionally two times. To the residue, 80 mL of water and 80 mL of
toluene were added and the mixture was vigorously stirred for 1 h at room temperature and
then for 1 h on an ice bath. The resulting precipitates were collected by filtration and washed
with cold water (20 mL x 2) and then with toluene (25 mL x 3), giving 15.04 g (72%) of the
product 2 after drying. If necessary, further purification could be made by recrystallization from
CH3CN-tBuOMe at room temperature [15]. The spectral data of the product agreed with those
of the authentic sample: 19F NMR (with 1H decoupling)  -51.49 (3F, s, CF3S), -77.83 (3F, s,
CF3SO3), -124.90 (2F, d, J = 21.5 Hz, 2,8-F), -129.49 ppm (2F, d, J = 21.5 Hz, 3,7-F); 1H NMR  8.75
(m, 2H), 8.85 ppm (m, 2H).
Acknowledgment
We thank Mr. Xinyi He for his technical contribution.

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[7] In a 1 L glassware flask equipped with a dropping funnel, a condenser, a thermometer, a
drying tube (CaCl2), and a magnetic stirrer, were put 120 g (769 mmol) of CF3SO2Na, and then
57 mL (745 mmol) of CF3COOH was added on an ice bath. Trifluoroacetic anhydride (320 ml,
483 g, 2.3 mol) was dropwise added for about 15 min on an ice bath and the resulting mixture
was stirred for 1 h on an ice bath. After 121.9 g (640 mmol) of 3,3’-difluorobiphenyl 3 was
added, the mixture was cooled to -25 oC and 230 g (1.53 mol) of TfOH was dropwise added for
3.5 h so that the temperature of the mixture was kept at -25 oC or less. After the addition, the
reaction mixture was stirred overnight (17 h) at -25 oC and then the mixture was stirred for 1 h
on an ice bath, for 1 h at room temperature, and then for 8 h on an oil bath at 45 oC. The
reaction mixture was evaporated under reduced pressure. The resulting residue was mixed with
300 mL of ethanol and the mixture was evaporated under reduced pressure. Again, the
resulting mixture was mixed with 300 mL of ethanol and the mixture was evaporated under
reduced pressure. To the resulting residue, 300 mL of toluene and 300 mL of water were added
and the mixture was stirred overnight. The resulting precipitates were collected by filtration
and washed with water (100 mL x 3) and toluene (100 mL x 3), giving 214.7 g (77%) of 2,8-
difluoro-S-(trifluoromethyl)dibenzothiophenium triflate 1 after drying (6 h at 75 oC).
[8] T. Umemoto, 23rd Winter Fluorine Conference held at Clearwater Beach, FL, U.S.A. on
January 15-20, 2017, Abstract No. WFC 60.
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Chem. 2013, 155, 124-131. (b) Li, M.; Xue, X.-S.; Guo, J.; Wang, Y.; Cheng, J.-P. J. Org. Chem.
2016, 81, 3119-3126.
[10] Three very small singlets at -43.36 ppm (0.03), -43.27 (0.04), and -42.93 (0.01) [the figure in
parentheses is a relative intensity to product 1 (1)] were observed in the range in which the
peak of SCF3 might appear. However, they could not be assigned because of very small amount.
[11] Liu, J.; Zhao, X.; Jiang, L.; Yi, W. Adv. Syn. & Cat. 2018, 360, 4012-4016.
[12] 3,3’,4,4’-Tetrafluorobiphenyl 4 was easily prepared by the following method: In a glassware
flask, were put 85.7 g (357 mmol) of 3,4-difluoroiodobenzene, 43.2 g (680 mmol) of copper
powder, and 86 g of N-methylpyrrolidinone (NMP). The mixture was stirred under nitrogen
atmosphere on an oil bath at 190 oC for 5 h. After cooling to room temperature, the reaction
mixture was mixed with 300 mL of tert-butyl methyl ether and filtered in order to remove
copper and its salt. The filtrate was washed with water (300 mL x 3) and then with saturated
aqueous sodium chloride solution (300 mL x 1), and dried with magnesium sulfate and filtered.
The filtrate was evaporated and the resulting residue was column-chromatographed using
hexane as an eluent to give a white solid (35 g, 87% yield) of product 4. The spectral data
agreed with those of the authentic sample: 19F NMR (CDCl3) (with 1H decoupling)  -136.88 (d, J
= 21 Hz, 2F), -139.64 ppm (d, J = 21 Hz, 2F); 1H NMR (CDCl3) 7.25 (m, 4H), 7.34 ppm (m, 2H).

[13] Note: If the stirring is difficult because of solidifying, an additional amount (7.4 mL) of
trifluoroacetic acid may be added.
[14] Note: This process (stirring overnight at room temperature) may be replaced by stirring for
3.5 hours at 35 oC.
[15] For the recrystallization, tBuOCH3 was added to a solution of 2 in the minimum amount of
acetonitrile at room temperature.