Direct electrophilic trifluoromethylthiolation of N-benzyl indoles using AgSCF3

Article abstract of DOI:10.1016/j.tetlet.2016.05.086

A novel electrophilic trifluoromethylthiolation reaction system has been developed with AgSCF₃used directly as the SCF₃source, in the presence of KI/K₂S₂O₈/I₂. Various N-benzylindoles have been trifluoromethylthiolated successfully with this system, and the mechanism of investigation showed an electrophilic reagent was generated in situ.

Full text of DOI:10.1016/j.tetlet.2016.05.086

Accepted Manuscript
Direct Electrophilic Trifluoromethylthiolation of N-Benzyl Indoles Using
AgSCF3
Lan Ma, Xiu-Fen Cheng, Yan Li, Xi-Sheng Wang
PII:
S0040-4039(16)30619-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.086
TETL 47705
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 April 2016
20 May 2016
23 May 2016
Please cite this article as: Ma, L., Cheng, X-F., Li, Y., Wang, X-S., Direct Electrophilic Trifluoromethylthiolation
of N-Benzyl Indoles Using AgSCF , Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.086
3
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Tetrahedron Letters
Direct Electrophilic Trifluoromethylthiolation of N-Benzyl Indoles Using AgSCF3
a
a
a,
a,
Lan Ma , Xiu-Fen Cheng , Yan Li  and Xi-Sheng Wang 
a
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel electrophilic trifluoromethylthiolation reaction system has been developed with AgSCF
3
3 2 2 8 2
used directly as the SCF source, in the presence of KI/K S O /I . Various N-benzylindoles have
been trifluoromethylthiolated successfully with this system, and the mechanism investigation
showed an eletrophilic reagent was generated in situ.
Available online
Keywords:
Trifluoromethylthiolation
Indole
2
009 Elsevier Ltd. All rights reserved.
AgSCF
Electrophilic reaction
3
—
——


Corresponding author. e-mail: liyan08@ustc.edu.cn
Corresponding author. Tel.: +86-551-63606523; fax: +86-551-63606523; e-mail: xswang77@ustc.edu.cn

2
Tetrahedron
The selective introduction of fluorine-containing groups into
only with low yield (entries 10−11, see also Table S3 in the
supporting information). Increasing the amounts of KI to 2.0
equivalents led to a higher yield of 85% (entry 12). To our
organic molecules has attracted increasing interests and is
emerging as a new and valuable strategy in drug design and
screening, for the fluorinated compounds usually showed
unprecedented physical and chemical properties, such as
increasing hydrolytic stability and block metabolism, compared
with the parent molecules. Among all intriguing fluorine-
containing moieties, the trifluoromethylthio group (SCF
been widely used in pharmaceuticals, agrochemicals, and
material sciences owing to its strong electron-withdrawing effect
and high lipophilicity (π = 1.44).
3 3
interest, the replacement of AgSCF with CuSCF gave only 33%
yield of 2a, which clearly showed the importance of silver
species in this trifluoromethylthiolation system (entry 13).
1
Considering that I
oxidation of K
examined in place of KI/ K
trifluoromethylthiolated product 2a was obtained smoothly in
89% yield (entry 14). Notably, the addition of both I (2.5 equiv.)
and KI (1.5 equiv.) to AgSCF /K system could afford the
best isolated yield (82%, entry 18).
2
could be generated in situ through the
to KI, 1.25 equivalents of I has also been
, in which the desired
3
) has
2
S
2
O
8
2
2 2 8
S O
1,2
2
3
2 2 8
S O
Indole and its derivatives are important structural motifs in
various fields including materials, pharmaceuticals,
agrochemicals, and dyes. It was noted that fluorine-containing
indoles have emerged as biologically and medicinally beneficial
3
Table 1. Trifluoromethylthiolation of N-benzyl indole:
optimization of reaction conditions
a
4
compounds due to its various bioactive properties, and thus
considerable efforts have been devoted to developing new
methods to make such structure motifs. Based on the
development of electrophilic trifluoromethythiolating reagents in
the last few years, several newly-developed reagents have also
been used to realize the trifluoromethylthiolation of indoles. In
Entry
Oxidant
Additive (eq.)
-
Yield (%)
22
2012, Billard and Langlois reported the first example of Brønsted
1
2
3
4
5
6
7
8
2 2 8
K S O
acid-mediated trifluoromethylthiolation of indoles using the
5
PhI(OAc)2
NCS
-
6
electrophilic trifluoromethanesulfanylamide regent. Shibata and
co-workers developed the trifluoromethylthiolation of indoles
-
trace
60
with electrophilic-type trifluoromethanesulfonyl hypervalent
K
2
S
2
2
O
O
8
8
8
8
8
8
8
8
8
8
KI (1.5)
NaI (1.5)
TBAI (1.5)
NIS (1.5)
KCl (1.5)
KBr (1.5)
KI (1.5)
KI (1.5)
KI (2.0)
KI (2.0)
6
iodonium ylide catalyzed by copper(I) chloride. Shen group has
K
2
S
46
also trifluoromethylthiolated indoles successfully using their own
7
developed hypervalent iodine reagent. Most recently, Glorius
2
K S O
trace
trace
0
2
2
2
2
2
2
2
2
and
coworkers
reported
transition-metal-free
K
2
S
S
S
S
S
S
S
O
O
O
O
O
O
O
trifluoromethylthiolation of N-heteroarenes with the N-
8
(
trifluoromethylthio)phthalimide. Zhang group has also
K
2
developed new method using CF SO Na for direct
a
3
2
9
K
2
0
9
trifluoromethylthiolation of indoles. In view of our continuous
interests in trifluoromethylthiolation of organic molecules, we
c
1
0
K
2
20
d
envisioned that the stable and readily available AgSCF
3
can be
11
K
2
0
used as a trifluoromethylthiolating reagents on the combination
1
1
2
3
K
2
85 (78)
33
10
of suitable oxidant, which will avoid the preparation of
electrophilic reagents. Herein, we report a novel electrophilic
e
K
2
trifluoromethylthiolation system using AgSCF
3
as the SCF
3
14
I
I
2
2
(1.25)
(2.0)
89 (68)
53
source in presence of K /KI/I , with which a variety of N-
2
S
2
O
8
2
1
1
1
5
6
7
benzyl indoles were trifluoromethylthiolated at 3-position of
pyrrole ring.
K
2
S
2
S
2
S
2
O
O
O
8
8
8
KI (1.5)/I
KI (1.5)/I
KI (1.5)/I
2
2
2
(1.5)
(1.5)
(1.5)
90 (74)
86 (62)
98 (82)
K
2
In 2014, we have developed a practical and easy-handling
10
3
method to trigger F CS• radical with AgSCF
3
/K
2
2
S O
8
system,
18
K
2
which has now
trifluoromethylthiolation reactions by several groups. Herein,
we commenced our study with N-benzylindole (1a) as a model
substrate in the presence of AgSCF
been widely used
in various
a
Reaction conditions: 1a (0.1 mmol, 1.0 equiv.), AgSCF
3
(1.5 equiv.),
11
Oxidant (3.0 equiv.), Additive (1.5 equiv.), CH
3
CN (3 mL), 60 ˚C, 24 h.
b
GC yield. Isolated yield is displayed in parentheses.
MeOH was used as solvent.
c
3 2 2 8
(1.5 equiv.) and K S O (3.0
d
e
DMSO was used as solvent.
3
(1.5 equiv.) was used instead of AgSCF .
equiv.) in CH CN at 60˚C. To our delight, the desired
3
CuSCF
3
trifluoromethylthiolated product 2a was obtained successfully,
albeit with relatively low yield (22%, Table 1, entry 1). Not
With the optimized reaction conditions in hand, we next
surprisingly, the other oxidants, including PhI(OAc)
gave none of the desired product in this reaction system (entries
2
, and NCS
investigated the scope of N-benzyl indoles. As shown in Table 2,
a variety of N-benzyl indoles were trifluoromethylthiolated
smoothly at 3-position in moderate to good yields. Initially, the
examination of N-protecting groups indicated that benzyl group
(1a) and its derivatives (1m-1n) were still the optimal choice.
Next, the substituent effects of the aryl ring (1b-1l) were also
investigated. Not surprisingly, a series of N-benzyl indoles (1b-
1g) with electron-donating substituents, including Me and MeO,
afforded the desired products (2b-2g) in moderate to good yields,
no matter where such substituted groups were placed on the
phenyl ring. It seemed strange that no trifluoromethylthiolated
products were obtained when F, Cl, Br-containing indoles (1h-1l)
12
2
−3). As directed by Clark’s and Buchwald’s reports that
addition of KI or tetra-n-butylammonium iodide (TBAI) into
AgSCF in acetonitrile can release SCF moiety more easily via
the formation of intermediate [Ag(SCF )I] , we next investigated
3
3
-
3
different halide sources. To our excitement, KI and NaI enhanced
the yield dramatically to 60% and 46% (entries 4, 5), while no
product was observed with other iodides, bromides and chlorides
used as additives (entries 6−9, see also Table S2 in the supporting
information). To improve the yield further, a careful survey of
solvents was then performed. Unfortunately, the reaction was
almost quenched in most organic solvents except for MeOH, but
2
were used in condition B without the addition of I . Fortunately,

the corresponding trifluoromethylthiolated products 2 could be
obtained successfully when the additives were changed to KI (1.5
equiv.) and I (2.5 equiv.) (Condition A) or I only (Condition C).
2 2
when 1-benzyl-3-iodoindole 3 was subjected to the standard
conditions, which clearly indicated that iodoindole was not
involved in the reaction as a possible intermediate (Scheme 1).
Notably, conditions A and C were also suitable for the steric
hindrance substrate 1g. While the acid sensitive PMB (p-
methoxybenzyl) group could be well tolerated in this reaction
system (1n), indole with strong electron-withdrawing substituent
2
(NO , 1o) on the phenyl ring gave none of the desired product
under all three conditions. Comparing all conditions A, B and C,
condition A demonstrated the best functional groups tolerance
and gave the best results in almost all cases.
Scheme 1. Intermediate study.
a,b
Table 2. Scope of N-benzyl indoles
To get more details of the reaction process, we tracked
the reaction under the Condition A carefully using F NMR
spectroscopy. It was found that [Ag(SCF
was formed immediately, and the signal of [Ag(SCF
decreased gradually while F CSSCF (δ -46.8 ppm)
1
9
-
3
)I] (δ -16.3 ppm)
-
3
)I]
3
3
increased accordingly. The desired product 2a (δ -45.7 ppm)
was observed after 2 hours, and thus increased gradually
1
3
along with the reduction of F
exact role of F CSSCF , we next set out to perform a series
of controlled experiments. Under the standard conditions
3 3
CSSCF . To investigate the
3
3
1
9
without indole 1a
CSSCF could be detected after 5 hours. After filtration,
no reaction occurred with the subjection of 1a and K
2
Eq. 2, Scheme 2), but addition of KI and K or I only
,
F NMR monitoring showed only
F
3
3
2 2 8
S O
(
2
S
2
O
8
together with 1a afforded 2a in 21% and 53% yield,
respectively (Eq. 1 & 3). Meanwhile, stirring the mixture of
1
˚
.5 equiv. of AgSCF
C in 1 hour gave a large amount of F
was still I remaining to be detected by starch in the reaction
3
and 0.75 equiv. of I
2
in CH
3
CN at 60
3
CSSCF
3
, and there
2
system. It was found 2a was obtained with 73% GC yield
with the subjection of 1a (Eq. 4), which further confirmed
the active trifluoromethylthiolating reagent could be
generated in situ from F
3 3 2
CSSCF in presence of I (or KI/
2 2 8
K S O
).
Scheme 2. Controlled experiments.
On the base of all observations mentioned above and
previous reports, a possible mechanism is proposed (Scheme
3
). The oxidation of KI by K
generates ISCF after the following reaction with AgSCF
As an intermediate detected in all cases, F CSSCF is given
or reaction of AgSCF
and would regenerate active ISCF
2 2 8 2
S O affords I , which
3
3
.
a
Reaction conditions A: 1a (0.1 mmol, 1.0 equiv.), AgSCF
(3.0 equiv.), KI (1.5 equiv.), I (2.5 equiv.),CH CN (3 mL), 60˚C, 24
h. Reaction conditions B: 1a (0.1 mmol, 1.0 equiv.), AgSCF (1.5 equiv.),
(3.0 equiv.), KI (2.0 equiv.), CH CN (3 mL), 60˚C, 24 h. Reaction
conditions C: 1a (0.1 mmol, 1.0 equiv.), AgSCF (1.5 equiv.), I (1.25
3
(1.5 equiv.),
3
3
1
4
K
2
S
2
O
8
2
3
via disproportionation of ISCF
K
3
3
and
The
3
2
S
2
O
8
,
3
.
K
2
S
2
O
8
3
electrophilic attack of 3-position on pyrrole ring by ISCF
followed by hydrogen elimination, yields the desired
trifluoromethylthiolated indole 2a
3
,
3
2
b
equiv.), CH
3
CN (3 mL), 60˚C, 24 h. Isolated yield.
.
To understand the mechanism of this reaction, a series of
experiments were carried out. First, as directed by GC-MS
detection, 1-benzyl-3-iodoindole 3 has been observed in the
reaction mixture. However, no desired product 2a was obtained

4
Tetrahedron
Chem. 2011, 54, 2529. (g) Liang, T.; Neumann, C. N.; Ritter, T.
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5
(a) Acton J. J. III; Black, R. M.; Jones, A. B.; Moller, D. E.;
Colwell, L.; Doebber, T. W.; MacNaul, K. L.; Berger, J.; Wood,
H. B. Bioorg. Med. Chem. Lett. 2005, 15, 357. (b) Karali, N.;
Gürsoy, A.; Kandemirli, F.; Shvets, N.; Kaynak, F. B.; Özbey, S.;
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(a) Ferry, A.ꢀ Billard, T.ꢀ Bacꢁuꢂ, E.; Langlois, B. R. J. Fluorine
Chem. 2012, 134, 160. For trifluoromethylthiolation of other
substrates using the electrophilic trifluoromethanesulfanylamide
regent, see: (b) Alazet, S.; Zimmer, L.; Billard, T. J. Fluorine
Chem. 2015, 171, 78. (c) Glenadel, Q.; Alazet, S.; Billard, T. J.
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Scheme 3. Proposed mechanism.
In conclusion, we have developed a novel method for
electrophilic trifluoromethylthiolation of N-benzylindoles with
AgSCF
electrophilic trifluoromethylthiolating reagent was generated in
situ in the presence of KI/K /I . Further studies to
3 3
used directly as the SCF source, in which an
2 2 8 2
S O
understand the mechanism and application to modify more
complex molecules are still underway in our laboratory.
4
2
5
607;. (e) Luo, J.; Zhu, Z.-C.; Liu, Y.-N.; Zhao, X.-D. Org. Lett.
015, 17, 3620. (f) Jereb, M.; Dolenc, D. RSC Adv. 2015, 5,
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Acknowledgments
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(a) Yang, Y.-D.; Azuma, A.; Tokunaga, E.; Yamasaki, M.; Shiro,
M.; Shibata, N. J. Am. Chem. Soc. 2013, 135, 8782. (b) Huang, Z.-
Y.; Yang Y.-D.; Tokunaga, E.; Shibata, N. Org. Lett. 2015, 17,
We gratefully acknowledge the National Basic Research
Program of China (973 Program 2015CB856600), the
National Science Foundation of China (21522208,
1
094.
(a) Ma, B.-Q.; Shao, X.-X.; Shen, Q. J. Fluorine Chem. 2015, 171,
3. (b) Yang, T.; Lu, L.; Shen, Q.-L. Chem. Commun. 2015, 51,
21372209), the Chinese Academy of Sciences, China
7
Postdoctoral Science Foundation (2014M560513), and the
Fundamental Research Funds for the Central Universities
5479. (c) Shao, X.-X.; Xu, C.-F.; Lu, L.; Shen, Q.-L. Acc. Chem.
Res. 2015, 48, 1227.
Honeker, R.; Ernst, J. B.; Glorius, F. Chem. Eur. J. 2015, 21,
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1
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(WK2060190046) for financial support.
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5
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Direct Electrophilic
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Trifluoromethylthiolation of N-Benzyl
Indoles Using AgSCF
3
Lan Ma, Xiu-Fen Cheng, Yan Li,* and Xi-Sheng Wang*

6
Tetrahedron
Highlights
1
2
3
. AgSCF
3
/I /KI has been developed as a novel
2
electrophilic trifluoromethylthiolating system.
. Electrophilic trifluoromethylthiolation of N-
benzylindoles has been developed.
. Mechanistic studies indicate that ISCF
3
generated in situ played as the active SCF
reagent.
3