Friedel-Crafts trifluoromethylthiolation of electron-rich (hetero)arenes with trifluoromethylthio-saccharin in 2,2,2-trifluoroethanol (TFE)

Article abstract of DOI:10.1016/j.cclet.2019.07.060

A promoter-free Friedel-Crafts trifluoromethylthiolation of electron-rich arenes and heteroarenes with N-trifluoromethylthiosaccharin 5 using 2,2,2-trifluoroethanol (TFE) as the solvent was described. The reactions were conducted at 40 °C and a variety of

Full text of DOI:10.1016/j.cclet.2019.07.060

Accepted Manuscript
Title: Friedel-Crafts trifluoromethylthiolation of electron-rich
(hetero)arenes with trifluoromethylthio-saccharin in
2
,2,2-trifluoroethanol (TFE)
Authors: Shiyao Lu, Wenbo Chen, Qilong Shen
PII:
DOI:
Reference:
S1001-8417(19)30465-6
https://doi.org/10.1016/j.cclet.2019.07.060
CCLET 5143
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
11 April 2019
14 July 2019
29 July 2019
Please cite this article as: Lu S, Chen W, Shen Q, Friedel-Crafts
trifluoromethylthiolation of electron-rich (hetero)arenes with trifluoromethylthio-
saccharin in 2,2,2-trifluoroethanol (TFE), Chinese Chemical Letters (2019),
https://doi.org/10.1016/j.cclet.2019.07.060
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Communication
Friedel-Crafts trifluoromethylthiolation of electron-rich (hetero)arenes with
trifluoromethylthio-saccharin in 2,2,2-trifluoroethanol (TFE)
a
a,
b,*
Shiyao Lu , Wenbo Chen , Qilong Shen
a
Shanghai Key Laboratory of Materials Protection and Advanced Materials in Electric Power, Shanghai University of Electric Power, Shanghai 200090, China
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese
b
Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
Graphical abstract
A
promoter-free Friedel-Crafts trifluoromethylthiolation of electron-rich arenes and heteroarenes with N-
trifluoromethylthiosaccharin 5 using 2,2,2-trifluoroethanol (TFE) as the solvent was described.
ABSTRACT
A promoter-free Friedel-Crafts trifluoromethylthiolation of electron-rich arenes and heteroarenes with N-trifluoromethylthiosaccharin 5
using 2,2,2-trifluoroethanol (TFE) as the solvent was described. The reactions were conducted at room temperature and a variety of
common functional groups were compatible.
Keywords:
Fluorine
Trifluoromethylthio
Friedel-Crafts
Arene
Trifluoroethanol
Owing to its high lipophilicity (Hansch’s hydrophobicity
parameter for SCF :π = 1.44) and strong electron-withdrawing
property, the trifluoromethylthio group (CF S-) is generally
the last ten years, numerous elegant trifluoromethylthiolating
methods have been reported that were able to directly introduce
the trifluoromethylthio group into small molecules under mild
conditions [4-10].
Among these methods, Friedel-Crafts type of direct
trifluoromethylthiolation of an arene with an electrophilic
trifluoromethylthiolating reagent represents a straightforward
method for the preparation of trifluoromethylthiolated arenes.
The first such reaction was reported by Sheppard in 1964 where
3
3
regarded by the medicinal chemists as one of the privileged
druggable domains in improving the drug molecule’s
pharmacokinetic properties such as the cell membrane
permeability [1-3]. Consequently, the development of efficient
methods for the incorporation of the trifluoromethylthio group
into the target molecule has attracted great recent interests. Over
—
——

Corresponding authors.
E-mail addresses: shenql@mail.sioc.ac.cn (Q. Shen); wenbochen@shiep.edu.cn (W. Chen)

3
trifluoromethanesulfenyl chloride (CF SCl) was allowed to react
with variety of phenols to give the corresponding
a
trifluoromethylthiolated phenol derivatives in high yields [11].
Yet, the high toxicity of trifluoromethanesulfenyl chloride
limited its practical applications (Scheme 1, Eq. 1) [12]. Fifty
years later, Glorius and coworkers reported that, in the presence
of
10.0
equiv.
of
NaCl,
reactions
or
of
N-
N-
trifluoromethylthiophthalimide
4
trifluoromethylthiosaccharin 5 with a variety of electron-rich
arenes occurred smoothly to give the corresponding
trifluoromethylthiolated products in good yields [13,14]. It was
proposed that trifluoromethanesulfenyl chloride, which is the
reactive species that reacted with the substrates is generated in
situ by mixing reagents 4 or 5 with NaCl at high temperature
(Scheme 1, Eq. 2). Alternatively, reactions of an electrophilic
trifluoromethylthiolating reagent with an arene, in the presence
of a strong Brøsted acid or Lewis acid-a common Friedel-Crafts
promoter have been reported (Scheme 1, Eq. 3) [15-21]. For
example, Billard, Langlois and their coworkers described that
trifluoromethanesulfanylamide, readily synthesized from
diethylaminosulfur trifluoride (DAST) reacted with indoles in the
presence of p-TsOH [15]. Likewise, Lu and Shen reported that
the high yielding reactions of trifluoromethanesulfenate with
indoles in the presence of TfOH [18]. Very recently, several
groups reported that in the presence of a phosphorus reductant,
3 2 3 2
CF SO Na, CF SO Cl or their derivatives underwent an in situ
reduction to generate an electrophilic trifluoromethylsulfinate
species that reacted with indoles, followed by further reduction
to give the corresponding trifluoromethylthiolated indole
derivatives (Scheme 1, Eq. 5) [22-30]. Nevertheless, these
approaches typically use moisture or air sensitive phosphorus
reductant, which greatly hampers their broad applications.
Scheme 1. Friedel-Crafts-type trifluoromethylthiolation of arenes.
In 2014, we discovered that N-trifluoromethylthiosaccharin 5
was a highly reactive electrophilic trifluoromethylthiolating
reagent that reacted with various electron-rich arenes when
3 3 3
Me SiCl or CF SO H was used a promoter (Scheme 1, Eq. 4)
[
20]. Later on, we reported that Friedel-Crafts-type of
trifluoromethylthiolation of electron-rich arenes in DMF could
take place even in the absence of Brøsted acid or Lewis acid
promoter
when
a
highly
reactive
electrophilic
trifluoromethylthiolating reagent N-trifluoromethylthiodibenzene
sulfonimide 6 (Scheme 1) [21]. Because N-trifluoromethylthio
dibenzenesulfonimide 6 is moisture-sensitive and difficult in
handling while N-trifluoromethylthiosaccharin 5 is not sensitive
to moisture, we wonder whether analogous promoter-free
Friedel-Crafts-type of trifluoromethylthiolation with N-
trifluoromethylthiosaccharin 5 could be developed.
It has been previously observed that promoter-free Friedel-
Crafts alkylation and acylation often occurred smoothly when
hexafluoro-2-propanol (HFIP) was used as a solvent, because of
HFIP’s unique properties including high ionizing power, low
nucleophilicity, mild acidity and more importantly, strong
hydrogen bond donating ability [31-35]. We thus envisaged
whether hydrogen bond between the oxygen of N-
trifluoromethylthiosaccharin and hydrogen of HFIP could be
established to activate N-trifluoromethylthiosaccharin for
Friedel-Crafts trifluoromethylthiolation. Herein, we report the
realization of such a reaction using HFIP’s cheaper homologue
2
,2,2-trifluoroethanol (TFE).
We began our investigation by choosing the reaction of 6-
fluoroindole with reagent 5 as a model reaction to optimize the

reaction conditions. As shown in Table 1, reaction of 6-
methoxy groups reacted successfully to give the corresponding
fluoroindole with 1.5 equiv. of reagent 5 occurred after 12 h at
products 7s and 7t in 89% and 96% yields, while reaction of
anisole did not react at all when it is heated at 60 C for 12 h
o
o
4
0 C in 49%-81% yield when the reaction was conducted in
solvents such as CH
2
Cl
2
, THF, DMF or CH
3
CN, while reaction
(Scheme 2, 7s-t). Thus, the scope of the reaction is limited to
strongly activated heteroarenes and arenes. Nevertheless,
because of the mild conditions, various common functional
groups such as halides including fluoride (7a), chloride (7c and
7n), bromide (7d and 7p) and iodide (7m), nitro (7e), cyano (7f),
enolizable ketone (7k) and ester (7o and 7l) were compatible.
Overall, the current method represents a complementary method
in HFIP or TFE gave the corresponding product in 93% and 94%
yields, respectively (Table 1, entries 1-6). Next, the effect of the
amount of reagent 5 was studied. Decreasing the amount of the
reagent 5 led to significantly decreasing the yield of the product
(
Table 1, entries 7 and 8). Finally, we studied the effect of
reaction temperature. It was found that the yield decreased when
the reaction was conducted at ambient temperature, while no
for
Brøsted
acid
or
Lewis
acid-promoted
significant change in yields when the reaction was conducted at
trifluoromethylthiolation of arenes with reagent 5.
o
5
0-60 C.
Table 1
Optimization
trifluoromethylthiolation of indole with reagent 5.
of
conditions
for
Friedel-Crafts
a
o
b
Entry
Solvent
Equiv. of 5
Temp ( C)
Yield (%)
1
2
3
4
5
6
7
8
9
CH Cl
THF
DMF
2
2
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.0
40
40
40
40
40
40
40
40
rt
69
49
68
81
93
94
76
46
80
88
88
CH
(CF CH
CF
CF
CF
CF
CF
CF
3
CN
2
3
)
3
2
OH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
OH
OH
OH
OH
OH
OH
3
3
3
1.5
1.5
1.5
1
1
0
1
3
50
60
3
a
Reaction conditions: 6-fluoroindole (0.1 mmol), reagent 5 (01-0.15
mmol) in 1.5 mL of CF CH OH at the temperature for 12 h;
3
2
b
19
Yields were determined by F NMR analysis of the crude reaction
mixture with an internal standard.
Under the optimized conditions (Table 1, entry 6), we next
investigated the generality of the substrates. In general, reactions
of electron-rich heteroarenes such as indoles, pyrroles or 1H-
o
indazole with reagent 5 occurred smoothly after 12 h at 40 C
occurred
smoothly
to
give
the
corresponding
trifluoromethylthiolated products in 68%-99% yields.
Specifically, indoles with both electron-donating group and
electron-withdrawing group reacted with reagent 5 under the
optimized conditions to give the trifluoromethylthiolated
products in high yields. For example, reaction of 6-nitroindole
with reagent 5 gave compound 7e in 93% yield, while reaction of
6
-methoxyindole with reagent 5 generated the corresponding
Scheme 2. Scope for Friedel-Crafts trifluoromethylthiolation of
product 7h in 99% yields (Scheme 2, 7e and 7h). Reactions of
pyrroles with electron-withdrawing group such as enolizable
ketone or ester group occurred in 91% and 73% yields,
respective (Scheme 2, 7k and 7l). In addition, N-arylated
pyrroles also reacted successfully with reagent 5 to give the
desired trifluoromethylthiolated products in 68%-81% yields
indole with reagent 5 in TFE. Reaction conditions: arene (0.5 mmol),
o
reagent 5 (0.75 mmol) in 1.5 mL of CF
3
CH
2
OH at 40 C for 12 h;
Isolated yields.
Mechanistically, 2,2,2-trifluoroethanol (TFE) might play two
roles in Friedel-Crafts trifluoromethylthiolation of indole with
reagent 5. As we expected previously, TFE may act as a
hydrogen bond donor to activate reagent 5 which weakens the N-
(Scheme 2, 7m-p). Furthermore, 1H-indazole also reacted with
reagent 5 to give 3-((trifluoromethyl)thio)-1H-indazole in 70%
yield (Scheme 2, 7i). In addition, reaction of thiophenes with
SCF
Alternative, TFE may react with reagent 5 to give intermediate
CF CH O-SCF 8 which then is activated by TFE to react with
3
bond of reagent 5 and consequently, facilitates the reaction.
electron-rich
substituents
reacted
with
N-
3
2
3
trifluoromethylthiosaccharin to give the corresponding products
in 40% and 85% yields, respectively (Scheme 2, 7q and 7r).
However, reactions of thiophenes with electron-withdrawing
groups, benzothiophene or benzofuran occurred in less than 5%
arene. To probe whether intermediate 8 could be generated, we
studied the reaction of reagent 5 in TFE. Interestingly, no new
1
9
fluorine signal was observed as monitored by F NMR
spectroscopy. Therefore, we suggest that it is the hydrogen bond
between TFE and reagent 5 that facilitates the Friedel-Crafts
trifluoromethylthiolation of electron-rich arenes.
o
yield even if the reactions were heated at 60 C. Next, we further
studied the reactions of electron-rich arenes with reagent 5 under
the optimized conditions. Reactions of arenes with two or three

[
[
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In summary, we developed a promoter-free Friedel-Crafts
trifluoromethylthiolation of electron-rich arenes and heteroarenes
7
with
N-trifluoromethylthiosaccharin
5
using
2,2,2-
12] CF
3
SCl was reported to have an L(ct)50 of between 440 and 880 ppm
trifluoroethanol (TFE) as the solvent. The reactions were
conducted at room temperature and a variety of common
functional groups were compatible. Reactions of reagent 5 with
other nucleophiles in TFE are undergoing currently in our
laboratory.
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[
[
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