Scalable Synthesis of S-Fluoromethyl Benzenesulfonothioate

Article abstract of DOI:10.1021/acs.oprd.0c00101

A general and practical method for the preparation of S-fluoromethyl benzenesulfonothioate on a 500 g scale in two steps from readily available CH2FCl, sulfur, and sodium benzenesulfinate is reported. The reaction was found to be rather sensitive to water and temperature. Furthermore, the main side product of the reaction was identified to be S-phenyl benzenesulfonothioate.

Full text of DOI:10.1021/acs.oprd.0c00101

Subscriber access provided by BIU Pharmacie | Faculté de Pharmacie, Université Paris V
Full Paper
Scalable Synthesis of S-(Fluoromethyl)benezenesulfonothioate
Qunchao Zhao, Ruichao Yao, Wenbo Chen, Long Lu, and Qilong Shen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00101 • Publication Date (Web): 21 Apr 2020
Downloaded from pubs.acs.org on April 21, 2020
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Scalable Synthesis of S-(Fluoromethyl)benezenesulfonothioate
†
‡
‡
†,
†,
Qunchao Zhao, Ruichao Yao, Wenbo Chen, Long Lu, * Qilong Shen *
†Key Laboratory of Organofluorine Chemistry, Center for Excellence in
Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
200032, People’s Republic of China
‡
Shanghai Key Laboratory of Materials Protection and Advanced Materials in
Electric Power, Shanghai University of Electric Power, 2588 Changyang Road,
Shanghai, 200090, People’s Republic of China
lulong@mail.sioc.ac.cn; shenql@mail.sioc.ac.cn
SO SNa
2
SO SCH F
2
2
980 g
495 g, 48%
CH FCl
2
22.5 mol
o
DMF, 80 C, 18 h
Abstract. A general and practical method for the preparation of
S-(fluoromethyl)benezenesulfonothioate on 500 gram-scale in two steps from
easily available CH FCl, sufur and sodium benzenesulfinate was reported. In
2
addition, it was found that the reaction was rather sensitive to water and
temperature. Furthermore, the main side product of the reaction was identified
to be S-(phenyl)benezenesulfonothioate.
Keywords fluorine, fluoroalkyl, monofluoromethylthio, electrophile
INTRODUCTION
Over the last three decades, the magic effect of fluorine has been widely
recognized by pharmaceutical and agrochemical industries, and site-specific
incorporation of a fluorine or a fluoroalkyl group on the target molecule has
1
now become a routine practice in new drug discovery. Among many
fluoroalkyl groups, the fluoroalkylthio groups including trifluoromethylthio group
ACS Paragon Plus Environment

Organic Process Research & Development
Page 2 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
(
-SCF ), difluoromethylthio group (-SCF H) and monofluoromethylthio group
3
2
(
-SCH F) have received special attention, mainly due to their ability in
2
fine-tuning the drug molecule’s pharmacokimetic and pharmacodynamic
properties. While a variety of efficient methods for the introduction of the
trifluoromethylthio and difluoromethylthio groups have been reported in the
past ten years, methods for the incorporation of monofluoromethylthio group
were limited.4-8 Notably, two drugs Fluticasone which is a steroid to treat nasal
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sympotoms, and Fluticasone propionate that is used for long-term
management of asthma contain the monofluoromethylthio group.9
Figure 1. Drugs containing a monofluoromethylthio group.
In 2017, our group reported the first shelf-stable electrophilic
monofluoromethylthiolating reagent S-(fluoromethyl) benezenesulfonothioate
4
(PhSO SCH F) that allowed for the introduction of the monofluoromethylthio
2
2
group into the target molecules highly efficiently for the very first time. For
example, in the presence of 5.0 mol% of CuSO4,
S-(fluoromethyl)benezenesulfonothioate reacted with various arylboronic acids
in methanol at ambient temperature to give monofluoromethylthiolated arenes
in high yields. In addition, a silver-catalyzed monofluorothio-sulfonylative
difunctionalized of unactivated alkenes was developed for the construction of
3
C(sp )-SCH F bond. In addition, both our and Wang’s groups discovered that
2
in the presence of radical initiator, reaction of an aldehyde with PhSO SCH F
2
2
occurred smoothly to give monofluoromethylthioesters in good to excellent
yields.5-6 These studies suggest that S-(fluoromethyl) benezenesulfonothioate
(
PhSO SCH F) is a highly reactive electrophilic monofluoromethylthiolating
2 2
reagent with a broad application potential. In our original work,
S-(fluoromethyl) benezenesulfonothioate were synthesized by the reaction of
ACS Paragon Plus Environment

Page 3 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
sodium benzenesulfonothioate with CH FCl, a cheap commercially available
2
material, on 6.1 g scale. Nevertheless, our initial attempts to scale up the
reaction to 1.0 mol scale resulted in significantly reduced yields, high yielding
formation of several by-products, and poor reproducibility. To ensure its future
applications, we have now investigated the reaction in detail to identify the key
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
factors
S-(fluoromethyl)benezenesulfonothioate. Herein, we report
procedure for the two-step preparation of
for
the
scale-up
preparation
of
a
reliable
S-(fluoromethyl)
benezenesulfonothioate on 500 g scale from easily available materials
CH FCl, sufur and sodium benzenesulfinate.
2
Figure 2. (A) PhSO SCH F as an electrophilic monofluoromethylthiolating
2
2
reagent for efficient introduction of fluoromethylthio group; (B) Hundred
gram-scale preparation of PhSO SCH F.
2
2
RESULTS AND DISCUSSION
Kilogram-scale preparation of sodium benzenesulfonothioate. The start
material sodium benzenesulfonothioate was prepared according to a slightly
modified reported procedure by reaction of sodium benzenesulfinate and sulfur
in pyridine at room temperature. Using 1.1 equiv. of sodium benzenesulfinate
ACS Paragon Plus Environment

Organic Process Research & Development
Page 4 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
to allow the sulfur for fully conversion is crucial to make sure that the resulting
sodium benzenesulfonothioate is free of sulfur contamination since sulfur is
rather difficult to be removed from the product. It was later found that the yield
of S-(fluoromethyl)benezenesulfonothioate in the subsequent reaction of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
sodium benzenesulfonothioate with CH FCl would decrease significantly if
2
sodium benzenesulfonothioate contaminated with trace amount of sulfur. The
complete consumption of sulfur in the reaction mixture can be easily
determined through careful observation of the color of the reaction mixture.
Once the color of the reaction changed from pale yellow to milky white, the
sulfur in the reaction mixture was sufficiently reacted, which typically required
24 h. Under these conditions, a reaction of 6.0 mol was conducted with a
mechanical stirrer and sodium benzenesulfonothioate was obtained by
filtration and subsequent wash with dichloromethane, as a white solid in 92%
yield.
Figure 3. Kilogram-scale preparation of sodium benzenesulfonothioate.
Optimization of the conditions for reaction of PhSO SNa with CH FCl.
2
2
With enough amount of PhSO SNa in hand, we then began to optimize the
2
reaction of PhSO SNa with CH FCl on 0.2 mol scale. Our initial efforts were to
2
2
attempt the reaction under the previously reported standard conditions using
ACS Paragon Plus Environment

Page 5 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
o
DMF as the solvent at 80 C for 12 h. Surprisingly, the formation of
S-(fluoromethyl)benezenesulfonothioate was minimal as determined by 19F
NMR spectroscopy when commercially available reagent grade DMF was
used as the solvent. We suspected that a small amount of water and/or air in
unpurified DMF might have a deteriorating effect on the reaction. We then tried
to remove the water and air in DMF simply by passage DMF over two columns
of activated molecular sieves, followed by bubbling a nitrogen gas for 15 min.
Notable, reaction using purified DMF as the solvent occurred smoothly after 12
h to give S-(fluoromethyl)benezenesulfonothioate in 46% isolated yield after
normal workup (Scheme 1, entry 1). Next, we investigated the effect of the
reaction time on the conversion and yield of the product. It was found that the
yield of the reaction could be increased to 56% when the reaction time was
extended to 18 h, while the yield could not be further improved even if the
reaction was allowed to be stirred for 36 h (Scheme 1, entries 2-3). We further
investigated whether the temperature of the reaction will have a significant
effect on the conversion of the reaction. It turned out that the temperature was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
crucial
for
the
high
yielding
formation
of
o
S-(fluoromethyl)benezenesulfonothioate. Reaction conducted at 60 C was
o
sluggish to give S-(fluoromethyl)benezenesulfonothioate after 18 h at 80 C in
2
5% yield (Scheme 1, entry 4). To facilitate the reaction, we attempted to
o
increase the reaction temperature to 100 C. Surprisingly, under these
conditions, the formation of S-(fluoromethyl)benezenesulfonothioate was not
formed. Instead,
a
side product S-(phenyl)benezenesulfonothioate
(
PhSO SPh) was isolated in 61% yield (Scheme 1, entry 5). Having
2
determined the appropriate reaction temperature, we then evaluated whether
switching to other polar solvents such as DMAc and DMSO could further
improve the yield of the reaction. It was found that reaction in DMAc under
otherwise identical conditions gave slightly lower yield, while reaction in DMSO
gave product in much lower yield (Scheme 1, entries 6-7).
Initially, we speculated that the small amount of water and/or air in
ACS Paragon Plus Environment

Organic Process Research & Development
Page 6 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
unpurified DMF might have a deteriorating effect on the reaction. To verify
whether our assumption is right, we conducted two control experiments. In the
first control experiment, the standard reaction was conducted in the presence
of 1.0 equivalent of H O. Not surprisingly, the formation of
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
S-(fluoromethyl)benezenesulfonothioate was not found while the formation of
side product PhSO SPh was generated in 53% yield, as determined by 19F
2
NMR spectroscopy (Scheme 1, entry 8). In the second control experiment, the
reaction was conducted in an open flask and it was found that the yield of the
reaction was decreased to 37% (Scheme 1, entry 9). These experiments
clearly suggest that it is the moisture not the air that has the significant
deteriorating effect for the formation of S-(fluoromethyl)benezene
sulfonothioate in the reaction.
Scheme 1. Optimization of the conditions for reaction of PhSO SNa with
2
a,b
CH FCl.
2
a
Reaction conditions: PhSO SNa 1 (39.8 g, 0.200 mol), CH FCl 2 (61.2 g,
2
2
b
0
.900 mol), solvent (200 mL). Isolated yields; H O (3.6 g, 0.20 mol) was
2
c
added; The reaction was conducted under air.
Proposed mechanism for the formation of side product PhSO SPh. The
2
formation of a side product PhSO SPh was not observed in a small scale
2
reaction and the mechanism for the formation of this unexpected compound is
intriguing. Nevertheless, we proposed a mechanism for the formation of
ACS Paragon Plus Environment

Page 7 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
PhSO SPh, as shown in Figure 4. Initially, attack of CH CFCl by PhSO SNa
2
2
2
either through nucleophilic substitution or a single-electron-transfer (SET)
process generates the desired product PhSO SCH F. At high temperature,
2
2
PhSO SNa will further nucleophilically attack PhSO SCH F to generate
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
intermediate PhSO SCH SSO Ph, which is unstable and undergoes Smiles
2
2
2
rearrangement to give side product PhSO SPh. At low temperature, this side
2
reaction is kinetically unfavorable since fluorine is not a good leaving group for
S 2-type reaction. Therefore, the formation of this side product at low
N
temperature is minimal. However, in the presence of water, fluorine becomes a
good leaving group because of the formation of the hydrogen bond between
the fluorine and the hydrogen of H O. Consequently, the nucleophilic
2
substitution of the fluorine by PhSO SNa was accelerated and results in the
2
formation of side product PhSO SPh through subsequent Smiles
2
rearrangement.
Figure 4. Proposed mechanism for the formation of side product PhSO SPh.
2
Preparation of S-(fluoromethyl) benezenesulfonothioate on 5.0 mol scale.
During the optimization of the conditions, we identified that the key factors
affecting the conversion and yield of the reaction, which should be paid special
attention during the amplification process, were water, reaction temperature
and air. As we mentioned earlier, a small amount of water in DMF was
removed by passing DMF through two columns with molecular sieves before
using. At the same time, it was found that sodium benzenesulfonothioate is
ACS Paragon Plus Environment

Organic Process Research & Development
Page 8 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
hydroscopic and should be kept in a desiccator after it was synthesized. More
importantly, we found that the reaction temperature should be well-controlled
o
that the temperature of the oil bath was maintained at 80 C, while the internal
o
temperature of the reaction was about 77 C. In addition, the air in the reaction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
must be exhausted by bubbling dry nitrogen for at least 15 min and the
airtightness of the reaction vessel should be maintained during the reaction to
prevent air from penetrating. Close observation of the reaction mixture
disclosed that the reaction mixture gradually became cloudy due to the
formation of NaCl, and the color changed from colorless to yellow. Finally, the
reaction was conducted on a scale of 5.0 mol to give the corresponding
product in 495 g (48% yield) as a light yellow oil after normal workup and
vacuum distillation.
Figure 5. Preparation of S-(fluoromethyl) benezenesulfonothioate on 5.0 mol
scale.
CONCLUSION
In summary, a simple and operable method for the preparation of
electrophilic
monofluoromethylthiolating
reagent
S-(fluoromethyl)benezenesulfonothioate PhSO SCH F has been developed
2
2
using commercially available and inexpensive starting materials from CH FCl,
2
sufur and sodium benzenesulfinate in two steps on a scale of 5.0 mol. It is
ACS Paragon Plus Environment

Page 9 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
found that water and temperature have significant effects on scale up
preparation of the reagent, which led to the formation of by-product PhSO SPh.
2
We believe that development of such a scalable procedure for the preparation
of S-(fluoromethyl)benezenesulfonothioate is beneficial for its broad
applications for the synthesis of monofluoromethylthiolated target molecules,
and subsequently accelerating new drug discovery.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
General procedure for the synthesis of S-(fluoromethyl)benezene
sulfonothioate. PhSO Na (1.08 kg, 6.60 mol) and sulfur (192 g, 6.00 mol)
2
were weighted into a 10.0 L round bottom flask with a mechanical stirrer.
Pyridine (5.0 L) was then added and the mixture was stirred at room
temperature for 24 h. The mixture was filtered and the residue was washed
with dichloromethane for three times. PhSO SNa (1083 g, 92% yield) was
2
obtained as a white solid and used without further purification.
In a 10.0 L three-neck round bottom flask with a magnetic stirring bar and
two reflux condensers, anhydrous DMF (3.0 L) was added under an
atmosphere of argon. The solvent was stirred in an ice-water bath, then
CH FCl gas was bubbled into the solution for a period of 1.5 h (22.5 mol,
2
determined by 19F NMR spectroscopy using PhCF as an internal standard).
3
PhSO SNa (980 g, 5.00 mol) was dissolved in DMF (2.0 L) and slowly add to
2
the flask under argon. (Caution: DMF should be dried with molecular sieve
before used and the device must be well airtight). The reaction mixture was
o
stirred at 80 C for 18 h. (Caution: The pressure of the reaction vessel
increased and it is necessary to ventilate the device several times). The
mixture was then cooled to room temperature and H O (50.0 L) was added
2
slowly. The mixture was extracted with Et O (5.0 L × 2). The organic phase
2
was combined, dried over anhydrous Mg SO and concentrated under
2
4
vacuum. The residue was purified by vacuum distillation (oil bath temperature:
45 oC, distillate temperature: 110 oC, 1.0 Pa) to give the
1
S-(fluoromethyl)benzene sulfonothioate (495 g, 48% yield) as a light yellow oil.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 10 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
H NMR (400 MHz, CDCl ) δ 7.95 (d, J = 7.9 Hz, 2 H), 7.66 (t, J = 7.4 Hz, 1 H),
3
19
7
.56 (t, J = 7.6 Hz, 2 H), 6.01 (d, J = 50.7 Hz, 2 H); F NMR (376 MHz, CDCl )
3
δ -186.38 (t, J = 50.7 Hz); 13C NMR (101 MHz, CDCl ) δ 145.53, 134.12,
3
1
1
2
29.43, 126.91, 87.09 (d, J = 225.6 Hz) ppm. IR (KBr): v = 3066, 1448, 1336,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-1
147, 999 cm . MS (EI): 77 (100), 141, 206. HRMS (EI): Calcd for C H FS O :
7
7
2
2
05.9872, Found: 205.9868.
Isolation of the side product S-(phenyl)benezenesulfonothioate. The
general procedure in the presence of 1.0 equivalent of water led to the
formation of S-(phenyl)benezenesulfonothioate as the major product, which
1
was obtained after normal workup. H NMR (400 MHz, CDCl ) δ 7.60-7.52 (m,
3
13
3
H), 7.49-7.44 (m, 1 H), 7.44-7.37 (m, 2 H), 7.37-7.28 (m, 4 H); C NMR (101
MHz, CDCl ) δ 142.75, 136.49, 133.61, 131.38, 129.38, 128.74, 127.66,
3
-1
1
27.44 ppm. IR (KBr): v = 3063, 1474, 1326, 1145, 1077, 750 cm . MS (ESI):
+
+
2
73.0 [M+Na] . HRMS (ESI) for C H O NaS [M+Na] Calcd: 273.0014;
12 10 2 2
Found: 273.0017.
Acknowledgements
The authors gratefully acknowledge the financial support from National Natural
Science Foundation of China (21625206, 21632009, 21421002).
Supporting information.
1H, 19F and 13C NMR spectra of PhSO SCH F, H and 13C NMR spectra of
1
2
2
PhSO SPh. The Supporting Information is available free of charge on the ACS
2
Publications website.
Reference
1
. (a) Wong, D. T.; Perry, K. W.; Bymaster, F. P. The Discovery of Fluoxetine
Hydrochloride (Prozac). Nat. Rev. Drug Discovery 2005, 4, 764−774; (b)
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal
Chemistry. Chem. Soc. Rev. 2008, 37, 320−330; (c) Hagmann, W. K.
The Many Roles for Fluorine in Medicinal Chemistry. J. Med. Chem., 2008,
ACS Paragon Plus Environment

Page 11 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
5
1, 4359−4369; (d) Meanwell, N. A. Synopsis of Some Recent Tactical
Application of Bioisosteres in Drug Design. J. Med. Chem. 2011, 54,
529−2591; (e) Meanwell, N. A. Fluorine and Fluorinated Motifs in the
Design and Application of Bioisosteres for Drug Design. J. Med. Chem.
011, 61, 5822−5880; (f) Vitaku, E.; Smith, D. T.; Njardarson, J. T.
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
Analysis of the Structural Diversity, Substitution Patterns, and Frequency
of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J.
Med. Chem. 2014, 57, 10257−10274; (g) Zhou, Y.; Wang, J.; Gu, Z.;
Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next
Generation of Fluorine-Containing Pharmaceuticals, Compounds
Currently in Phase II–III Clinical Trials of Major Pharmaceutical Companies:
New Structural Trends and Therapeutic Areas. Chem. Rev. 2016, 116,
422−518.
2
. Selected recent reviews for trifluoromethylthiolating methods: (a) Landelle,
G.; Panossian, A.; Leroux, F. R. Trifluoromethyl Ethers and -Thioethers a
Tolls for Medicinal Chemistry and Drug Discovery, Curr. Top. in Med.
Chem. 2014, 14, 941-951; (b) Shao, X.-X.; Xu, C.-F.; Lu, L.; Shen, Q.
Shelf-Stable Electrophilic Reagents for Trifluoromethylthiolation, Acc.
Chem. Res. 2015, 48, 1227−1236; (c) Xu, X.-H.; Matsuzaki, K.; Shibata, N.
Synthetic Methods for Compounds Having CF −S Units on Carbon by
3
Trifluoromethylation, Trifluoromethylthiolation, Triflylation, and Related
Reactions, Chem. Rev. 2015, 115, 731−764; (d) Chachignon, H.; Cahard,
D. State-of-the-Art in Electrophilic Trifluoromethylthiolation Reagents, Chin.
J. Chem. 2016, 34, 445−454; (e) Zhang, P.-P.; Lu, L.; Shen, Q. Recent
Progress on Direct Trifluoromethylthiolating Reagents and Methods, Acta
Chimica Sinica 2017, 75, 744−769.
3
. Selected recent reviews and methods for difluoromethylthiolation: (a)
Xiong, H.-Y.; Pannecoucke, X.; Besset, T. Recent Advances in the
Synthesis of SCF H- and SCF FG Containing Molecules, Chem. Eur. J.
2
2
2016, 22, 16734-16749; (b) Xiao, X.; Zheng, Z.-T.; Li, T.; Zheng, J.-L.; Tao,
ACS Paragon Plus Environment

Organic Process Research & Development
Page 12 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
T.; Chen, L.-M.; Gu, J.-Y.; Yao, X.; Lin, J.-H.; Xiao, J.-C. Recent Advances
in Difluoromethylthiolation, Synthesis 2020, 52, 197-207; (c) Zhu, D.; Gu,
Y.; Lu, L.; Shen, Q. N-Difluoromethylthiophthalimide: A Shelf-Stable,
Electrophilic Reagent for Difluoromethylthiolation. J. Am. Chem. Soc. 2015,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
137, 10547–10533; (d) Wu, J.; Gu, Y.; Leng, X.; Shen, Q.
Copper-Promoted Sandmeyer Difluoromethylthiolation of Aryl and
Heteroaryl Diazonium Salts. Angew. Chem. Int. Ed. 2015, 54, 7648–7652;
(
e) Ismalaj, E.; Le Bars, D.; Billard, T. Direct Electrophilic
Benzenesulfonyl)Difluoromethylthiolation with a Shelf-Stable Reagent.
(
Angew. Chem. Int. Ed. 2016, 55, 4790–4793; (f) Arimori, S.; Matsubara, O.;
Takada, M.; Shiro, M.; Shibata, N. Difluoromethane-sulfonyl hypervalent
iodonium ylides for electrophilic difluoromethylthiolation reactions under
copper catalysis. R. Soc. Open Sci. 2016, 3, 160102; (g) Xiong, H.-Y.;
Bayle, A.; Pannecoucke, X.; Besset, T. An Electrophilic Reagent for the
Direct Introduction of the SCF PO(OEt) Group to Molecules. Angew.
2
2
Chem. Int. Ed. 2016, 55, 13490–13494; (h) Huang, Z.; Matsubara, O.; Jia,
S.; Tokunaga, E.; Shibata, N. Difluoromethylthiolation of Phenols and
Related Compounds with a HF CSO Na/Ph PCl/Me SiCl System. Org.
2
2
2
3
Lett. 2017, 19, 934–937; (i) Yan, Q.; Jiang, L.; Yi, W.; Liu, Q.; Zhang, W.
Metal-Free Difluoromethylthiolation, Trifluoromethylthiolation, and
Perfluoroalkylthiolation with Sodium Difluoromethanesulfinate, Sodium
Trifluoromethanesulfinate or Sodium Perfluoroalkanesulfinate. Adv. Synth.
Catal. 2017, 359, 2471–2480; (j) Zhao, X.; Wei, A.; Li, T.; Su, Z.; Chen, J.;
Lu, K. Transition-metal free direct difluoromethylthiolation of electron-rich
aromatics with difluoromethanesulfonyl chloride. Org. Chem. Front. 2017,
4, 232–235; (k) Zhang, H.; Wan, X.-L.; Shen, Q. Asymmetric
Difluoromethylthiolation of Carbon Nucleophiles with Optically Pure
Difluoromethylthiolating Reagents Derived from Camphorsultam, Chin. J.
Chem. 2019, 37, 1041-1050.
ACS Paragon Plus Environment

Page 13 of 14
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
4
5
6
. Zhao, Q.-C.; Lu, L.; Shen, Q. Direct Monofluoromethylthiolation with
S-(Fluoromethyl) Benzenesulfonothioate, Angew. Chem. Int. Ed. 2017, 56,
11575-11578.
. Guo, S.-H.; Wang, M.-Y.; Pan, G.-F.; Zhu, X.-Q.; Gao, Y.-R.; Wang, Y.-Q.
Synthesis of Monofluoromethylthioesters from Aldehydes, Adv. Synth.
Catal. 2018, 360, 1861–1869.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
. Xu, B.; Li, D.-Z.; Lu, L.; Wang, D.-C.; Hu, Y.-H.; Shen, Q. Radical
fluoroalkylthiolation of aldehydes with PhSO SR (R = CF , C F , CF H or
2
f
f
3
2
5
2
CH F): a general protocol for the preparation of fluoroalkylthioesters, Org.
2
Chem. Front. 2018, 5, 2163-2166.
7. Liu, F.-M.; Jiang, L.-Q.; Qiu, H.-Y.; Yi, W.-B. Bunte Salt CH FSSO Na: An
2
3
Efficient and Odorless Reagent for Monofluoromethylthiolation, Org. Lett.
018, 20, 6270-6273.
2
8
. Senatore, R.; Malik, M.; Spreitzer, M.; Holzer, W.; Pace V. Direct and
Chemoselective Electrophilic Monofluoromethylation of Heteroatoms (O-,
S-, N-, P-, Se-) with Fluoroiodomethane, Org. Lett. 2020, 22, 1345-1349.
9. Howland, W. C. Fluticasone propionate: topical or systemic effects? Clin.
Exp. Allergy 1996, 26, 18-22.
ACS Paragon Plus Environment

Organic Process Research & Development
Page 14 of 14
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment