POCl3-Promoted Trifluoromethylthiolation-Based Vicinal Bifunctionalization of Indoles with CF3SO2Na

Article abstract of DOI:10.1002/ejoc.201800249

An efficient trifluoromethylthiolation-based vicinal bifunctionalization of indoles with sodium trifluoromethanesulfinate in the presence of phosphorus oxychloride were achieved to introduce a chlorine atom into the 2-position under transition-metal-free

Full text of DOI:10.1002/ejoc.201800249

A Journal of
Accepted Article
Title: POCl3-Promoted Trifluoromethylthiolation-based Vicinal
Bifunctionalization of Indoles with CF3SO2Na
Authors: Jin-Tao Liu, Dong-Wei Sun, Xu Jiang, Min Jiang, and Yun Lin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800249
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800249
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201800249
SHORT COMMUNICATION
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
POCl -Promoted Trifluoromethylthiolation-based Vicinal Bifunctionalization of
3
Indoles with CF SO Na
3
2
[a]
[b]
[a]
[b]
[a]
Dong-Wei Sun, Xu Jiang, Min Jiang, Yun Lin and Jin-Tao Liu*
Keywords: trifluoromethylthiolation, indole, bifunctionalization, perfluoromethylthiolation, sodium trifluoromethanesulfinate
An efficient trifluoromethylthiolation-based vicinal 2-position under transition-metal-free and mild conditions. The
bifunctionalization of indoles with sodium protocol could also extend to other sodium
trifluoromethanesulfinate in the presence of phosphorus perfluoroalkanesulfinates or phosphorus oxybromide. The
oxychloride were achieved to introduce a chlorine atom into the
possible pathway was proposed based on the experimental
results.
Therefore, it's greatly necessary to explore the cheap and
readily accessible trifluoromethylthiolating reagents. For this
purpose, CF SO -based trifluoromethylthiolating reagents have
Introduction
3
2
The importance of organofluorine compounds, especially in the
aroused great interest of organic and medicinal chemists in the
[
1]
area of material and life sciences, has recently attracted
increasing attention since fluorine or fluoroalkyl groups in
organic molecules can change their physical and biochemical
[10]
range of trifluoromethylthiolation reaction. In 2009, the group
of Magnier isolated a small quantity of trifluoromethylthiolation
product in the preparation of Umemoto reagent using CF SO K
[
2]
3
2
properties.
One of the fluorine-containing groups,
[11]
and biphenyl derivatives. In addition, trifluoromethanesulfonyl
hypervalent iodonium ylide was used for copper-catalyzed
trifluoromethylthio (CF S), has led to a resurgence of interest in
organofluorine chemistry due to its electron-withdrawing effect
and good lipophilicity.
3
trifluoromethylthiolation reaction reported by the group of
[
3]
[12]
Shibata, and afforded the desired CF S-substituted products.
3
In recent years, numerous methods involving transition metal
catalysis or transition-metal-free conditions for the introduction of
trifluoromethylthio group into aromatic compounds have been
Recently, various methods have emerged involving the
combination of trifluoromethanesulfonyl chloride (CF SO Cl)
3
2
[13]
and different phosphorus reagent, such as CF
3
SO
2
3
Cl/PMe ,
[
4]
developed.
In early times, more reactive and practical
SCl) was used as
[14]
[15]
CF
As we all know, sodium trifluoromethanesulfinate (CF
Langlois reagent) is a cheap and easily available commercial
3 2 2 3 2 3
SO Cl/(EtO) P(O)H, and CF SO Cl/PPh .
trifluoromethanesulfenyl chloride (CF
3
2
SO Na,
[
5]
3
electrophilic trifluoromethylthiolating reagents, but its corrosive
and toxic properties limited its use. Although shelf-stable and
easy-to-handle CF S-N or CF S-O based electrophilic
chemical. In 2015, Li, Zhang et al reported
a
direct
with
And
3
3
6]
2
[
trifluoromethylthiolation
of
C(sp )-H
bonds
trifluoromethylthiolating reagents
and a series of highly
[
16]
CF SO Na/(EtO) P(O)H system catalyzed by CuCl.
3
2
2
efficient nucleophilic trifluoromethylthiolating reagents (such as
[
7]
[8]
[9]
transition-metal-free fluoroalkylthiolation reaction was achieved
AgSCF3, Me NSCF
and CuSCF3 ) were established and
efficiency in range of
4
3
[
17]
using the similar reagent system very recently. Meanwhile, Cai
and coworkers also developed a direct trifluoromethylthiolation
demonstrated
high
a
trifluoromethylthiolation reaction in the past decades, the
preparation of these reagents required multiple steps before the
reaction, and expensive reagents could be required.
of indole derivatives with CF SO Na/PPh system, but an
3
2
3
+
additional X source such as N-chlorophthalimide was essential
[
18]
for this reaction.
simultaneously reported a selective trifluoromethylthiolation and
trifluoromethylsulfinylation of indoles with sodium
trifluoromethanesulfinate promoted by different phosphorus
Recently, Lu's group and our group have
[
[
a]
D.-W. Sun, Dr. M. Jiang, Prof. Dr. J.-T. Liu*
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of
Science
[
19]
reagent under transition-metal-free conditions. However, above
methods are trifluoromethylthiolation-based
monofunctionalization of indoles. So far, there is no report about
the bifunctionalization of indoles with sodium
trifluoromethanesulfinate. With our continuing to study the
CF SO Na/[P] system, we surprisingly found that 2-chloro-3-
3
45 Lingling Road, Shanghai 200032 (China)
E-mail: jtliu@sioc.ac.cn
Homepage: http://liujintao.sioc.ac.cn
b] X, Jiang, Dr. Y. Lin
Jiangsu Key Laboratory of Biofunctional Materials
College of Chemistry and Materials Science, Nanjing Normal
University
3
2
((trifluoromethyl)thio)-indole derivatives as bifunctionalization
products could be obtained. Herein, the results are reported in this
paper.
1
Wenyuan Road, Nanjing 210023 (China)
Homepage: http://www.njnu.edu.cn/
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Results and Discussion
Submitted to the European Journal of Organic Chemistry
1
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European Journal of Organic Chemistry
10.1002/ejoc.201800249
In our previous research, when indole (1a) was treated with 1.2
to 12 hours, compound 2a and 2-chloro-3-((trifluoromethyl)thio)-
1H-indole (4a) were obtained in 27% and 20% yield, respectively,
and the yield of 3a reduced to 38% (entry 2). Inspired by this
result, we commenced searching for a suitable condition to
equivalent of sodium trifluoromethanesulfinate (CF SO Na) and
3
2
1
.0 equivalent of phosphorus oxychloride in N, N-dimethyl
1
9
formide (DMF) at room temperature in 0.5 hour, F NMR
monitoring indicated that trifluoromethylsulfinylation product (3a) improve the yield of bifunctionalization product (4a). Through
was obtained in 89% yield along with trace amount of
trifluoromethylthiolated compound (2a) (Table 1, entry 1). But
interestingly enough, if we continued to extend the reaction time
investigating the ratio of the reactants, we found that the
increasing the amount of phosphorus oxychloride or sodium
trifluoromethanesulfinate was benefitful for bifunctionalization
Table 1: Optimization of conditions for the bifunctionalization reaction of 1a with CF
3
SO
2
Na.
a
o
b
b
b
entry
[Cl]
1a:CF
3
SO
2
Na:[Cl]
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
temp/ C
Rt
Rt
Rt
rt
time/h
0.5
12
12
12
12
12
12
12
12
12
12
3
2a/%
trace
27
3a/%
89
4a/%
0
1
2
3
4
5
6
7
8
9
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
POCl
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1:1.2:1
1:1.2:1
38
20
32
43
47
66
44
21
37
54
53
78
51
65
57
NR
62
NR
70
42
35
1:1.2:1.5
1:1.2:2
1:1.2:2.5
1:1.2:3
1:1.2:3.5
1:1.5:1
1:1.5:1.5
1:1.5:2
1:1.5:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.2:3
1:1.5:3
32
12
27
trace
trace
trace
trace
29
rt
21
rt
22
rt
16
rt
19
rt
25
15
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
1
rt
24
20
rt
trace
trace
23
trace
trace
trace
trace
14
50
80
50
50
50
50
50
50
50
50
3
CH
3
CN
3
20
THF
3
18
1.4-Dioxane
Toluene
DMSO
DMA
3
NR
13
NR
3
trace
NR
3
NR
11
3
trace
trace
trace
(COCl)
2
DMF
3
38
SOCl
2
DMF
3
40
a) Reaction conditions: 1a (0.4 mmol), CF
3
SO
2
Na (0.48-0.6 mmol), [Cl] (0.4-1.4 mmol), solvent (1.0 mL). b)
1
9
Determined by F NMR using PhCF
3
as internal standard.
reaction (entries 3-11). The yield of 4a was improved to 66% and
2% yield of 2a was still observed by employing a 1:1.2:3 ratio of
indole/CF SO Na/POCl (entry 6). Subsequently, we tested the
(DMA), were not suitable for this reaction (entries 14−19). We also
attempted to examine the effect of different chlorination reagents.
2
3
2
3
When POCl
3
was replaced by oxalyl chloride [(COCl)
2
] or thionyl
effect of the reaction temperature, when the reaction was employed
at 50 C, a higher yield (78%) was obtained and reaction time
chloride (SOCl
2
), the yield of 4a was decreased to 42% and 35%,
o
respectively, and a large amount of 2a were produced (entries 20-
could be shorten to 3 hours (entry 12). Further increasing the
reaction temperature did not improve the yield of 4a (entry 13).
Other solvents, such as acetonitrile, tetrahydrofuran (THF), 1,4-
dioxane, toluene, dimethyl sulfoxide (DMSO) and dimethylamide
21). Therefore, the optimal reaction conditions were set to 1.2
o
equivalent of CF SO Na, 3.0 equivalent of POCl in DMF at 50 C.
3
2
3
With the optimized conditions in hand, we explored the substrate
scope of the POCl -promoted bifunctionalization reaction. Both
3
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2
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European Journal of Organic Chemistry
10.1002/ejoc.201800249
electron-rich and electron-deficient indoles were evaluated and the
results are summarized in Scheme 1. The electronic property of the
indoles had light effect on the reaction. Indoles 1b-1d bearing
methyl
(trifluoromethyl)thio)-1H-indole derivatives 4b-4d in higher
yields. Chlorine substituted indole could also react with CF SO Na,
or
methoxy-substitution
produced
2-chloro-3-
(
3
2
but only 58% yield of 4e was obtained. The reaction of nitro-
substituent indole (1f) under standard conditions was also
investigated. Unfortunately, no product was observed and all of
indole was recovered. It is worth mentioning that the reaction of N-
methyl, N-ethyl and N-benzyl indoles proceeded well and afforded
the expected products (4g-4i) in moderate to good yields. In
addition, we have also extended this protocol to sodium
perfluoroalkanesulfinates (R SO Na), such as ClCF CF SO Na, n-
Scheme 2. The transformation of 4a.
f
2
2
2
2
C F SO Na
and
n-C F SO Na.
Gratefully,
4
9
2
6
13
2
The bifunctionalization products 4 obtained in Scheme 1
allowed modification of the trifluoromethylated compounds due to
the existence of chloro and bromo substitutions. To demonstrate
their synthetic potentials, 4a was reacted with phenylboronic acid
and E-styrylboronic acid in the presence of 5 mol% Pd(PPh ) Cl
perfluoromethylthiolation-based bifunctionalization took place
smoothly to give expected products (4j-4l) in moderate yields. In
order to further expend the scope of this reaction, phosphorus
oxybromide (POBr ) was also tried instead of phosphorus
oxychloride as phosphorous reagent, and 2-bromo-3-
3
3
2
2
as catalyst gave their Suzuki coupling products 5a and 5b in 91%
and 86% isolated yields, respectively (Scheme 2).
(
(trifluoromethyl)thio)-indole
derivatives
(4m-4o)
were
successfully isolated although yields were low, while acetonitrile
was used as solvent.
To explore the reaction mechanism of the transformation,
trifluoromethylsulfinylation compound 3a was employed with 2.0
equivalent of POCl3 at 50 C in DMF, trifluoromethylthiolated
a
Scheme 1. The bifunctionalization reaction of indoles and R
f
SO
2
Na
o
compound 2a and bifunctionalization products 4a were obtained in
1
6% and 78% yields, respectively (Scheme 3). Therefore, it is
indicated that bifunctionalization products 4a could be tranformed
from 3a.
Scheme 3. Reaction of 3a with POCl
3
[
19,20]
In light of literature reports and our experimental results,
a
plausible mechanism for this reaction was proposed in Scheme 4.
Initially, trifluoromethylsulfinylation of indole with sodium
trifluoromethanesulfinate in the presence of phosphorus
oxychloride rapidly takes place to give compound 3a, which could
continue to react with another phosphorus oxychloride to form the
intermediate A. Decomposition of intermediate A afford the
trifluoromethylthiolation product 2a (path A). At the same time,
-
intermediate A also could be attacked by chlorine anion (Cl ) to
produce intermediate B. Subsequent loss of
a proton in
intermediate B gives bifunctionalization product 4a (path B).
According to the reaction result in Scheme 3, both path A and path
B exist as completing reactions in the transformation and Path B
takes place dominantly to produce bifunctionalization product 2-
chloro-3-((trifluoromethyl)thio)-indole 4a as major product.
a) Reaction conditions: 1 (0.4 mmol), R
POBr (1.2 mmol), DMF (1 mL) under N
Reaction was carried out in CH CN.
f
SO
2
Na (0.48 mmol), POCl
at 50 C, isolated yields. b)
3
or
o
3
2
3
Submitted to the European Journal of Organic Chemistry
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European Journal of Organic Chemistry
10.1002/ejoc.201800249
_
___________
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In conclusion, we have demonstrated an efficient method for the
trifluoromethylthiolation-based vicinal bifunctionalization of
indoles with cheap and easily available reagents sodium
trifluoromethanesulfinate in the presence of phosphorus
oxychloride or phosphorus oxybromide, which affords another
functional group (chloro or bromo) for further transformation. This
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to perfluoromethylthiolation-based bifunctionalization reaction
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General procedure for trifluoromethylthiolation-based vicinal
bifunctionalization reaction: To a solution of indole 1a (0.4 mmol) and
CF SO Na (0.48 mmol) in DMF (1.0 mL) was added POCl (1.2 mmol).
3 2 3
The mixture was stirred at 50 ℃ for 3 hours. After the completion of the
reaction, the mixture was quenched with water. The resulting mixture
was extracted with EtOAc three times and the organic layers were
4
combined, dried over MgSO and concentrated. The resulting crude
product was purified by column chromatography on silica gel to give the
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General procedure for the Suzuki coupling reaction of 4a: To a
solution of 2-chloro-3-((trifluoromethyl)thio)-1H-indole 4a (0.4 mmol),
Pd(PPh
:v =2:1, 3 mL) was added NEt
00℃ for 10h. After the completion of the reaction, the reaction mixture
3
)
2
Cl
2
(0.05 equiv) and PhB(OH)
2
(1.5 equiv) in 1.4-dioxane/H2O
(
v
1
2
3
(3.0 equiv), The mixture was stirred at
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was cooled to room temperature and filtered by diatomaceous earth. The
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organic layers were combined, dried over MgSO and concentrated. The
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Submitted to the European Journal of Organic Chemistry
4
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European Journal of Organic Chemistry
10.1002/ejoc.201800249
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637.
Received: ((will be filled in by the editorial staff))
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Submitted to the European Journal of Organic Chemistry
5
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European Journal of Organic Chemistry
10.1002/ejoc.201800249
Entry for the Table of Contents
FULL PAPER
Bifunctionalization
Trifluoromethylthiolation
Dong-Wei Sun, Xu Jiang, Min Jiang, Yun
Lin and Jin-Tao Liu*
Page No. – Page No.
Direct trifluoromethylthiolation-based vicinal bifunctionalization of indoles with sodium
trifluoromethanesulfinate in the presence of phosphorus oxychloride were achieved, which
affords another functional group (chloro or bromo) for further transformation.
3
POCl -Promoted
Trifluoromethylthiolation-based
Vicinal Bifunctionalization of Indoles
3 2
with CF SO Na
Trifluoromethylthiolation, Indole, Bifunctionalization, Perfluoromethylthiolation, Sodium trifluoromethanesulfinate
Submitted to the European Journal of Organic Chemistry
6
This article is protected by copyright. All rights reserved.