Switchable regioselection of C-H thiolation of indoles using different TMS counterions

Article abstract of DOI:10.1039/c9cc05652a

A switchable regioselectivity in C-H thiolation reaction by simply swapping the counteranions of TMS is reported here for the first time. An exclusive C3-H thiolation of indoles with sodium arylsulfinates was achieved in the presence of TMSCl as a promoter. In contrast, with the use of TMSOTf instead of TMSCl under otherwise identical conditions, a regiospecific C2-H thiolation of indoles was realized with the same set of substrates.

Full text of DOI:10.1039/c9cc05652a

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Ji, H. Li, J.
Zhang and Y. Wu, Chem. Commun., 2019, DOI: 10.1039/C9CC05652A.
Volume 54
This is an Accepted Manuscript, which has been through the
Number
January 2018
Pages 1-112
1
4
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/C9CC05652A
Graphical Abstract
Switchable regioselection of C-H thiolation of indoles using different TMS
counterions
Yuan-Zhao Ji, Hui-Jing Li, Jin-Yu Zhang, and Yan-Chao Wu
Ar
S
Ar
O
S
R1
TMSCl
R1
S
TMSOTf
R1
+
Ar
ONa
N
R2
N
R2
N
R2
switchable regioselectivity
metal-free and mild reaction conditions
without directing and blocking groups
Simply swapping the counteranions of TMS leads to a switchable regioselectivity in C2– and
C3–H thiolation of indoles.

Please do not adjust margins
ChemComm
Page 2 of 5
View Article Online
DOI: 10.1039/C9CC05652A
COMMUNICATION
Switchable regioselection of C-H thiolation of indoles using
different TMS counterions
Yuan-Zhao Ji, a Hui-Jing Li,*a,b Jin-Yu Zhang, a and Yan-Chao Wu*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A switchable regioselectivity in C–H thiolation reaction by simply assemble 2-thioindoles and 3-thioindoles with the same set of
swapping the counteranions of TMS is reported here for the first simple and readily accessible starting materials is still one of the
time. An exclusive C3–H thiolation of indoles with sodium most challenging tasks for synthetic chemists. It is worth noting
arylsulfinates was achieved in the presence of TMSCl as promoter. that sodium arylsulfinates are still not used for the C2–H
In contrast, with the use of TMSOTf instead of TMSCl under thiolation of indoles to date. However, sodium arylsulfinates are
otherwise identical conditions, a regiospecific C2–H thiolation of stable, odorless and easy-to-handle sulfur compounds, and thus
indoles was realized with the same set of substrates.
are the desirable sulfur sources for the construction of C–S
bonds.2c,15 In this context, we would like to report here a
regioselectivity-switchable C–H thiolation of indoles with
sodium arylsulfinates just by simply swapping the
counteranions of TMS (Scheme 1). Herein, indoles appeared to
serve the dual role of the substrates and reduction agents.
Reaction of 1-methyl-1H-indole (1a) with sodium 4-
methylbenzenesulfinate (2a) was used as a probe for evaluating
the reaction conditions, and the representative results (for
details, please see ESI, Tables S1–S2) are summarized in Table
1. The C–H thiolation of indole 1a with sodium arylsulfinate 2a
went smoothly in the presence of TMSOTf to afford exclusively
Because of the synthetic versatility of organosulfur compounds
in organic synthesis,1 C–H thiolation has become one of the
most important C–H functionalization transformations and
attracted considerable attention in the past decade.2 The C–H
thiolation of aromatic compounds with sulfur-based reagents
could be achieved in the presence of certain transition metals
such as palladium,3 copper,4 iron5 and others.6 Metal-free C–H
thiolation of arenes and heteroarenes has also been developed
with the use of thiols,7 sulfonyl hydrazides8 and sulfinate salts9
etc10 as the sulfenylating reagents. Usually, C–H thiolation of
indoles proceeds at the C3 position. In contrast, C2–H thiolation
of indoles is difficult, which has been accomplished by using
special strategies such as blocking the C3 position,11 introducing
a directing group at the N1 position,12 removing the proton at
the C2 position13, and using a N-(thio)succinimide/TFA reaction
system.14 Despite these advances, switchable reaction to
Table 1. Optimization of the reaction conditionsa
NaO
O
S
promoter
S
(4 equiv)
S
+
+
N
rt, CH2Cl2, 12h
N
N
1a
2a
3a
4a
Ar
X
OTf
=
Entry
Promoter
TMSOTf
TMSCl
Me2SiHCl
TMSCF3
Et3SiH
Ph3SiH
TfOH
p-TsOH
Yield 3a (%)b
80 (78c)
N.D.
Yield 4a (%)b
N.D.
R1
S
N
R2
1
2
3
4
5
6
7
8
O
S
X
TMS-
R1
+
83 (80c)
75
Ar
S
Ar
ONa
N
R2
X
Cl
=
N.D.
N.R.
N.R.
N.R.
60
N.D.
R1
N
N.R.
N.R.
N.R.
N.D.
R2
Scheme 1. Switchable C–H thiolation of indoles with sodium arylsulfinates.
48
a. School of Marine Science and Technology, Harbin Institute of Technology, Weihai
264209, P. R. China. E-mail: lihuijing@iccas.ac.cn
a General conditions: 1a (0.5 mmol), 2a (0.2 mmol), and promoter (0.8 mmol)
in CH2Cl2 (1.0 mL) at 25 °C for 12 h. The yield was determined by 1H NMR
b
b. Weihai Institute of Marine Biomedical Industrial Technology, Wendeng District,
Weihai 264400, P. R. China. E-mail: ycwu@iccas.ac.cn
spectroscopy using 0.2 mmol of CH2Br2 as a standard. c Isolated yield. N.D. = no
detection. N.R. = no reaction.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Please do not adjust margins

Please do not adjust margins
Page 3 of 5
ChemComm
COMMUNICATION
Journal Name
C2-thioindole 3a in a good yield (entry 1). However, a to afford C2-thioindoles 3j–q and 3s in moderate to excellent
View Article Online
DOI: 10.1039/C9CC05652A
regiospecific C–H thiolation reaction took place to give C3- yields. 2,3-Bis-thioindoles 5m–n and 5q–r were observed as the
thioindole 4a in 83% and 75% yields, respectively with the use reaction intermediates in some of the above C2-thiolation
of TMSCl and Me2SiHCl instead of TMSOTf (entries 2–3). With reactions. 2-naphthyl-, 1-naphthyl-, 2-thienyl- and methyl-
the use of other silica promoters such as TMSCF3, Et3SiH and substituted sodium sulfinates reacted smoothly with indole 1a
Ph3SiH, no reaction take place and the starting materials could to afford C2-thioindoles 3t–w in moderate to good yields.
be recovered (entries 4–6). Other promoters such as TfOH and
In the C3-H thiolation reaction (Scheme 2), indoles 1, with
p-TsOH could also execute this reaction but with lower substituent groups such as methoxy, halogen and methyl at
efficiencies (entries 7–8). Finally, the optimal C2–H thiolation their 2-, 4-, 5-, 6- and 7-positions, reacted smoothly with sodium
reaction conditions to obtain C2-thioindole 3a as follows: indole arylsulfinate 2a to give C3-thioindoles 4a–i in good to excellent
1a (2.5 equiv), sodium arylsulfinate 2a (1.0 equiv), and TMSOTf yields. Treatment of N-acetylindole with sodium arylsulfinate 2a
(4.0 equiv) in CH2Cl2 at 25 °C for 12 h and the optimal C3–H failed to give C3-thioindole 4j. Sodium arylsulfinates 2, with
thiolation reaction conditions to obtain C3-thioindole 4a as their aromatic rings bearing hydrogen atoms, electron-donating
follows: indole 1a (2.5 equiv), sodium arylsulfinate 2a (1.0 and electron-withdrawing groups, reacted well with indole 1a
equiv), and TMSCl (4.0 equiv) in CH2Cl2 at 25 °C for 12 h.
to afford C3-thioindoles 4k–t in good to excellent yields. 2-
With the optimized reaction conditions in hand, the substrate naphthyl-, 1-naphthyl-, 2-thienyl- and methyl- substituted
scope for the C2- and C3-H thiolation reactions was investigated sodium sulfinates reacted well with indole 1a to afford C3-
with a series of indoles and sodium arylsulfinates (Scheme 2). In thioindoles 4u–x in good yields.
the C2-H thiolation reaction (Scheme 2), indoles with electron-
To demonstrate the practicability of this reaction, 5-bromo-
donating and electron-withdrawing substituents at their 4-, 5-, 3-((3,4,5-trimethoxyphenyl)thio)-1H-indole (4y), a known lead
6- and 7-positions as well as N-substituted indoles were all anticancer compound,16 was synthesized from sodium 3,4,5-
suitable substrates, and the desired C2-thioindoles 3a–g and 3h trimethoxybenzenesulfinate and 5-bromo-1H-indole in 32%
were obtained in moderate to good yields. Treatment of N- yield under the standard C3-H thiolation conditions(Scheme 2).
acetylindole with sodium arylsulfinate 2a failed to give C2-
To understand the mechanism of C3–H thiolation, reaction of
1
thioindole 3i. Sodium arylsulfinates 2, with their aromatic rings indole 1a with sodium arylsulfinate 2a was monitored by H
bearing hydrogen atoms, electron-withdrawing and electron- NMR spectroscopy using CH2Br2 as an internal standard. During
donating groups, reacted smoothly with sodium arylsulfinate 2a the 12 h reaction process, three peaks including those for
sulfoxide 6a ( = 2.44 ppm), C3-thioindole 4a ( = 2.31 ppm) and
Ar
S
indole dimer 7a ( = 2.73 ppm) were observed (see ESI, Scheme
Ar
O
S
TMSCl
12 h, rt
TMSOTf
12 h, rt
R1
R1
S
R1
+
S1 and Table S3). The results indicated that sulfoxide 6a should
be a reaction intermediate in the synthesis of C3-thioindole 4a.
To gain more mechanistic information for the C3-H thiolation,
several control experiments were performed (Scheme 3). In the
presence of TMSCl, indole dimer 7a underwent tautomerization
to generate indole 1a. (Scheme 3a).17 Reaction of indole 1a with
p-toluenesulfinic acid (8a) conditions is complex under the
standard C3-H thiolation and the expected C3-thioindole was
not observed (Scheme 3b). Reaction of sulfoxide 6a with indole
1a (1 equiv) went smoothly under the standard C3-H thiolation
conditions to give C3-thioindole 4a in 70% yield (Scheme 3c),
confirming that sulfoxide 6a was a reaction intermediate in the
Ar
ONa
N
R2
N
R2
N
R2
4
1
2
3
C2-H Thiolation
R
S
R
R1
N
STol
S
N
R2
N
3t
3u
3v
: R = 2-naphthyl, 73%
: R = 1-naphthyl, 38%
: R = 2-thienyl , 15%
: R = Me, 31%
S
: R1 = H, R2 = Me, 78%
3a
3j
: R = H, 42%
: R1 = 4-Br, R2 = Me, 45%
: R1 = 5-Br, R2 = Me, 67%
: R1 = 5-OMe, R2 = Me, 53%
: R1 = 6-Cl, R2 = Me, 74%
3b
3c
3d
3e
3f
3k
: R = 4-F, 53%
3w
3l
: R = 4-Cl, 46%
3m
R
: R = 4-Br, 37%
3n
3o
3p
3q
: R = 4-CF3, 28%
R
: R1 = 6-F, R2 = Me, 73%
t
S
N
: R = 4- Bu, 87%
: R1 = 7-OMe, R2 = Me, 25%
: R1 = H, R2 = Bn, 75%
3g
: R = 4-OMe, 93%
: R = 3-Br, 26%
: R = 2-Cl, 0%
3h
3i
5m
: R = 4-Br, 14%
: R = 4-CF3, 22%
: R = 3-Br, 25%
: R = 2-Cl, 24%
: R1 = H, R2 = Ac, 0%
3r
5n
5q
5r
3s
: R = 2,4,6-Me, 11%
C3-H Thiolation
TMSCl (2 equiv)
N
STol
R
S
(a)
S
R
N
N
1a
7a
R1
N
R2
O
S
TMSCl (4 equiv)
CH2Cl2, rt, 12 h
N
N
1a
4a
, N.D.
+
(b)
(c)
Tol
OH
4u
4v
4w
4x
: R = 2-naphthyl, 87%
: R = 1-naphthyl, 87%
: R = 2-thienyl, 62%
: R = Me, 53%
: R1 = H, R2 = Me, 80%
8a
4a
4k
: R = H, 92%
: R1 = 4-Br, R2 = Me, 68%
: R1 = 5-Br, R2 = Me, 68%
: R1 = 5-OMe, R2 = Me, 78%
: R1 = 6-Cl, R2 = Me, 78%
O
4b
4c
4d
4e
4f
4l
: R = 4-F, 86%
Tol
S
4m
: R = 4-Cl, 86%
: R = 4-Br, 73%
: R = 4-CF3, 86%
TMSCl (4 equiv)
CH2Cl2, rt, 12 h
OMe
4n
4o
4p
4q
1a
4a,
70%
+
N
OMe
OMe
: R1 = 6-F, R2 = Me, 92%
: R1 = 7-OMe, R2 = Me, 74%
: R1 = 2-Me, R2 = Me, 96%
: R1 = H, R2 = Bn, 85%
: R1 = H, R2 = Ac, 0%
t
: R = 4- Bu, 95%
S
6a
Cl
Br
4g
: R = 4-OMe, 78%
: R = 3-Br, 92%
TMSCl (4 equiv)
CH2Cl2, rt, 12 h
4h
4i
4r
4s
2a
9a
4i
, 85%
+
+
(d)
(e)
N
4y
: 32%
N
N
Bn
H
: R = 2-Cl, 73%
Bn
a
anticancer16
1i
9a
, 26%
9a
, 92% recovered
4j
4t
: R = 2,4,6-Me, 84%
TMSCl (4 equiv)
CH2Cl2, rt, 12 h
Scheme 2. Substrate scopes. General conditions (for 3): 1a (0.5 mmol), 2a (0.2 mmol),
and TMSOTf (0.8 mmol) in CH2Cl2 (1.0 mL) at 25 °C for 12 h. General conditions (for 4):
1a (0.5 mmol), 2a (0.2 mmol), and TMSCl (0.8 mmol) in CH2Cl2 (1.0 mL) at 25 °C for 12 h.
2a
4i,
+
0%
+
Scheme 3. Control experiments for C3–H thiolation. a The yield was based on indole 1i.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

ChemComm
Please do not adjust margins
Page 4 of 5
Journal Name
COMMUNICATION
Scheme 5. Control experiments for the C2–H thiolation.
synthesis of C3-thioindole 4a. Treatment of sodium
arylsulfinate 2a with 1-benzyl-1H-indole (1i, 2.5 equiv) gave C3-
thioindole 4i in 85% yield, in which chlorinated indole 9a was
obtained in 26% yield (Scheme 3d). Treatment of 3-chloroindole
9a with sodium arylsulfinate 2a failed to give C3-thioindole 4i
and the starting material 9a was recovered in 92% yield
(Scheme 3e). 3-Chloroindole 9a displays relatively weaker
electron-donating ability in comparison with the corresponding
non-chlorinated indole, which might be a disadvantageous
factor for the reaction of 3-chloroindole 9a with sodium
arylsulfinate 2a.
Based on the above results and related reports in the
literature,18,19 a possible reaction mechanism for the C3-H
thiolation was illustrated in Scheme 4. TMSCl reacted with
sodium arylsulfinates 2 to form trimethylsilyl sulfinates 10.
Electrophilic substitution reaction of indoles 1 at the C-3
position with trimethylsilyl sulfinates 10 formed intermediates
11, which underwent in situ a TMSOH remove to generate
intermediates 12. Detachment of TMSCl from 12 afforded
sulfoxides 6. The reversible process could be terminated by
aqueous work-up with the consumption of one equivalent of
TMSCl. On the other hand, tautomerization of intermediates 12
formed intermediates 13. Nucleophilic substitution reaction of
intermediates 13 with indoles 1 to form sulfonium salts 14,
which underwent in situ an intramolecular nucleophilic
substitution reaction to afford C3-thioindoles 4 (Scheme 4). In
the latter process, intermediates 15 were also formed, which
underwent in situ a TMSOH remove to generate byproducts 9.
To gain more mechanistic information for the C2-H thiolation,
several control experiments were also performed (Scheme 5).
View Article Online
DOI: 10.1039/C9CC05652A
In the presence of TMSOTf, indole 1a underwent
tautomerization to form indole dimer 7a. (Scheme 5a).17
Treatment of C3-thioindole 4a with the 2.0 equivalents of
TMSOTf for 12 h, C2-thioindole 3a was gained in 70% yield
(Scheme 5b). This reaction afforded C2-thioindole 3a, 2,3-bis-
thioindole 5a and indole dimer 7a in 8%, 34% and 8% yields,
respectively under the identical conditions, albeit with a shorter
reaction time (i.e., 30 min versus 12 h), in which 15% amount of
C3-thioindole 4a was recovered (Scheme 5c). Treatment of 2,3-
bis-thioindole 5a with indole 1a (1.2 equiv) under the standard
C2-thiolation reaction conditions afforded C2-thioindole 3a in
72% yield, indicating that 2,3-bis-thioindole 5a should be a key
intermediate in the formation of C2-thioindole 3a (Scheme 5d).
Based on the above results and related reports in the
literature,14,20 a possible reaction mechanism for the C2-H
thiolation was shown in Scheme 6. Firstly, reaction of indoles 1
with sodium arylsulfinates 2 in the presence of TMSOTf formed
the C3-thioindole intermediates 4 via the simlar processes
shown in Scheme 4. Subsequently, electrophilic substitution
reaction of C3-thioindoles 4 at the C-3 position with TMSOTf
formed trace of indolenium intermediates 16 thanks to the
superior leaving ablility of a triflate anion compared to a
chloride anion. Indolenium intermediate 16 underwent an
aromatization reaction to generate trace of TfOSAr (18) and
compounds 17. The trace of TfOSAr chould be the key catalyst
for the conversion of C3-thioindoles 4 to C2-thioindoles 3. C3-
thiolation of C3-thioindoles 4 by TfOSAr (18) formed 3,3-bis-
sulfide indoleniums 19. The migration of one of the sulfide
groups to the C2 position, via the formation of the episulfonium
species 20, afforded 2,3-bisubstituted indoles 5. Electrophilic
substitution reaction of 2,3-bisubstituted indoles 5 at the C-3
position with TMSOTf formed indolenium intermediates 21,
which underwent an aromatization reaction to regenerate the
ClTMS
ClTMS
O
Ar
S
O
S
O
S
2 TMSCl
- NaCl
H
R1
NaO
Ar
TMSO
Ar
10
TMSO
N
R2
2
11
R1
N
R2
-TMSOH
1
R2
N
Ar
S
ClTMS
R1
O
TMSO
O
see Scheme 4
Ar
Interrupted
Pummerer
+
R1
Ar
Cl
R1
S
S
R1
R1
Ar
S
Cl
S
NaO
Ar
N
R2
N
R2
H
R1
2
1
4
N
N
TMSO
N
R2
R2
TMS
13 R2
12
TMS
Ar
N
14
R2
S
TMSOTf
R1
R1
+
TfOSAr
R1
- TMSCl
N
N
TfO
R2
R2
16
17
18
O
Ar
S
Ar
S
Ar
S
R1
R1
R1
N
N
R2
6
R2
Ar
N
R2
4
Cl
H
Cl
S
Ar
4
S
-TMSOH
R1
R1
R1
TfOSAr
TfO
N
R2
N
R2
N
TMSO
18
R2
15
9
19
Scheme 4. Proposed mechanism for the C3–H thiolation.
TMS
SAr
N
R2
SAr
R1
TMSOTf (2 equiv)
SAr
TfO
N
R2
TMS
R1
1a
4a
7a
3a
(a)
(b)
SAr
H
22
R1
SHAr
TMSOTf (2 equiv)
CH2Cl2, rt, 12 h
N
20
TfO
R2
, 70%
21
SAr
S
TMSOTf
TMSOTf (2 equiv)
CH2Cl2, rt, 30 min
R1
SAr
4a
5a
3a
, 8%
+
(c)
(d)
S
5a
N
R2
N
5
, 34%
TMS
H
4a,
7a,
8%
15%
+
R1
SAr
R1
SAr
TfO
TMSOTf (4 equiv)
CH2Cl2, rt, 12 h
-TMSOTf
N
R2
N
R2
1a
3a,
72%
+
3
23
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Page 5 of 5
ChemComm
COMMUNICATION
Journal Name
Scheme 6. Proposed mechanism for the C2–H thiolation.
c) A. Correa, M. Carril and C. Bolm, Angew. Chem. Int. Ed.
View Article Online
2008, 47, 2880.
DOI: 10.1039/C9CC05652A
6
7
For selected examples, see: a) D. Liu, H. X. Ma, P. Fang and T.
S. Mei, Angew. Chem. Int. Ed. 2019, 58, 5033; b) M. Arisawa,
T. Suzuki, T. Ishikawa and M. Yamaguchi, J. Am. Chem. Soc.
2008, 130, 12214; c) Y. C. Wong, T. T. Jayanth and C. H. Cheng,
Org. Lett. 2006, 8, 5613.
For selected examples, see: a) M. Chen, Y. Luo, C. Zhang, L.
Guo, Q. Wang and Y. Wu, Org. Chem. Front. 2019, 6, 116; b)
R. Ohkado, T. Ishikawa and H. Iida, Green Chem. 2018, 20, 984;
c) H. H. Wang, T. Shi, W. W. Gao, Y. Q. Wang, J. F. Li, Y. Jiang,
Y. S. Hou, C. Chen, X. Peng and Z. Wang, Chem. Asian J. 2017,
12, 2675.
For selected examples, see: a) Y. Yang, S. Zhang, L. Tang, Y. Hu,
Z. Zha and Z. Wang, Green Chem. 2016, 18, 2609; b) X. Zhao,
L. Zhang, T. Li, G. Liu, H. Wanga and K. Lu, Chem. Commun.
2014, 50, 13121; c) F. L. Yang and S. K. Tian, Angew. Chem. Int.
Ed. 2013, 52, 4929.
a) Z. Xu, G. Lu and C. Cai, Org. Biomol. Chem. 2017, 15, 2804;
b) R. Rahaman and P. Barman, Eur. J. Org. Chem. 2017, 6327;
c) Y. Lin, G. Lu, G. Wang and W. Yi, Adv. Synth. Catal. 2016,
358, 4100; d) C. R. Liu and L. H. Ding, Org. Biomol. Chem. 2015,
13, 2251; e) F. Xiao, H. Xie, S. Liu and G. J. Deng, Adv. Synth.
Catal. 2014, 356, 364; f) H. Rao, P. Wang, J. Wang, Z. Li, X. Suna
and S. Cao, RSC Adv. 2014, 4, 49165.
catalyst TfOSAr with the formation of 2-thioindole derivatives
22. The 2-thioindole derivatives 22 were protonated by
episulfonium species 20 to form 2-thioindole intermediates 23,
which underwent an aromatization reaction to afford C2-
thioindoles 3 with the release of TMSOTf (Scheme 6).
In summary, we have developed
switchable C-H thiolation reaction of indoles with sodium
arylsulfinates, which provided convenient and highly
a regioselectivity-
a
regioselective approach for the synthesis of both C2- and C3-
thioindoles. The reaction took place at room temperature under
metal-free reaction conditions, and displayed excellent
functional group compatibility. The essential roles of the TMS
reagents (TMSCl and TMSOTf) lies in their capacity to
significantly enhance both the reactivity and regioselectivity in
C2- and C3-H thiolation of indoles as well as the unexpected
finding that a simple swap of the counteranions of TMS from
triflate to chloride leads to a regioselective shift between C2-
and C3-H thiolation of indoles. The results underline the
potential importance of counteranions in tuning the
regioselectivity of the related reactions. Further mechanistic
investigations as well as applications of this method are in
progress.
8
9
10 For selected examples, see: a) L. H. Zou, J. Reball, J.
Mottweiler and C. Bolm, Chem. Commun. 2012, 48, 11307; b)
X. Yang, Y. Bao, Z. Dai, Q. Zhou, and F. Yang, Green Chem.
2018, 20, 3727; c) M. J. Böhm, C. Golz, I. Rüter and M.
Alcarazo, Chem. Eur. J. 2018, 24, 15026.
11 C. J. Nalbandian, E. M. Miller, S. T. Toenjes and J. L. Gustafson,
Chem. Commun. 2017, 53, 1494.
12 T. Gensch, F. J. R. Klauck and F. Glorius, Angew. Chem. Int. Ed.
2016, 55, 11287.
13 a) T. Fukuda, Y. Mine and M. Iwao, Tetrahedron 2001, 57, 975;
b) A. R. Katritzky, P. Lue and Y. X. Chen, J. Org. Chem. 1990,
55, 3688; c) M. G. Saulnier and G. W. Gribble, J. Org. Chem.
1982, 47, 757.
We thank the Natural Science Foundation of Shandong
Province (ZR2019MB009), the Key Research and Development
Program of Shandong Province (2019GSF108089), the National
Natural Science Foundation of China (21672046, 21372054),
and the Found from the Huancui District of Weihai City.
Conflicts of interest
There are no conflicts to declare.
14 T. Hostier, V. Ferey, G. Ricci, D. G. Pardoa and J. Cossy, Chem.
Commun. 2015, 51, 13898.
15 a) J. Zhu, W. Yang, X. Wang and L. Wu, Adv. Synth. Catal. 2018,
360, 386; b) H. Yue, C. Zhu and M. Rueping, Angew. Chem. Int.
Ed. 2018, 57, 1371; c) M. J. Cabrera-Afonso, Z. P. Lu, C. B. Kelly,
S. B. Lang, R. Dykstra, O. Gutierrez and G. A. Molander, Chem.
Sci. 2018, 9, 3186.
16 V. Giansanti, F. Piscitelli, T. Camboni, E. Prosper, G. L. Regina,
M. Parks, R. Silvestri and A. I. Scovassi, Oncol. Lett. 2010, 1,
109.
17 a) H. Yu and Z. Yu, Angew. Chem. Int. Ed. 2009, 48, 2929; b) R.
L. Hinman and E. R. Shull, J. Org. Chem. 1961, 26, 2339.
18 a) Y. Z. Ji, J. Y. Zhang, H. J. Li, C. Han, Y. K. Yang and Y. C. Wu,
Org. Biomol. Chem. 2019, 17, 4789; b) W. Shi, T. Miao, Y. Li,
P. Li and L. Wang, Org. Lett. 2018, 20, 4416; c) T. Miao, P. Li,
Y. Zhang and L. Wang, Org. Lett. 2015, 17, 832.
19 a) D. L. Chen, Y. Sun, M. Chen, X. Li, L. Zhang, X. Huang, Y. Bai,
F. Luo and B. Peng, Org. Lett. 2019, 21, 3986; b) M. Šiaučiulis,
S. Sapmaz, A. P. Pulis and D. J. Procter, Chem. Sci. 2018, 9, 754;
c) H. Kawashima, T. Yanagi, C. C. Wu, K. Nogi and H. Yorimitsu,
Org. Lett. 2017, 19, 455; d) J. A. Fernández-Salas, A. P. Pulis
and D. J. Procter, Chem. Commun. 2016, 52, 12364; e) L. H. S.
Smith, S. C. Coote, H. F. Sneddon and D. J. Procter, Angew.
Chem. Int. Ed. 2010, 49, 5832.
Notes and references
1
a) H. A. Lin, K. Kato, Y. Segawa, L. T. Scott and K. Itami, Chem.
Sci. 2019, 10, 2326; b) S. Conroy, N. Kindon, B. Kellam and M.
J. Stocks, J. Med. Chem. 2016, 59, 9981.
2
For reviews, see: a) S. Liang, S. Shaaban, N. W. Liu, K. Hofman
and G. Manolikakes, Adv. Organomet. Chem. 2018, 69, 135; b)
C. F. Lee, R. S. Basha and S. S. Badsara, Top. Curr. Chem. 2018.
376, 25; c) D. Q. Dong, S. H. Hao, D, S, Yang, L. X. Li and Z. L.
Wang, Eur. J. Org. Chem. 2017, 6576; d) C. Shen, P. Zhang, Q.
Sun, S. Bai, T. S. A. Hor and X. Liu, Chem. Soc. Rev. 2015, 44,
291; e) C. F. Lee, Y. C. Liu and S. S. Badsara, Chem. Asian J.
2014, 9, 706; f) I. P. Beletskaya and V. P. Ananikov, Chem. Rev.
2011, 111, 1596.
3
4
5
For selected examples, see: a) S. Vásquez-Céspedes, A. Ferry,
L. Candish and F. Glorius, Angew. Chem. Int. Ed. 2015, 54,
5772; b) J. Mao, T. Jia, G. Frensch and P. J. Walsh, Org. Lett.
2014, 16, 5304; c) M. A. Fernández-Rodríguez, Q. Shen and J.
F. Hartwig, J. Am. Chem. Soc. 2006, 128, 2180.
For selected examples, see: a) Z. Qiao, N. Ge and X. Jiang,
Chem. Commun. 2015, 51, 10295; b) C. Uyeda, Y. Tan, G. C. Fu
and J. C. Peters, J. Am. Chem. Soc. 2013, 135, 9548; c) C. K.
Chen, Y. W. Chen, C. H. Lin, H. P. Lin and C. F. Lee, Chem.
Commun. 2010, 46, 282.
20 a) P. Hamel, J. Org. Chem. 2002, 67, 2854; b) P. Hamel, Y.
Girard and J. G. Atkinson, J. Org. Chem. 1992, 57, 2694; c) P.
Hamel, Y. Girard and J. G. Atkinson, J. Chem. Soc., Chem.
Commun. 1989, 63.
For selected examples, see: a) B. X. Du, Z. J. Quan, Y. X. Da, Z.
Zhang and X. C. Wang, Adv. Synth. Catal. 2015, 357, 1270; b)
J. R. Wu, C. H. Lin and C. F. Lee, Chem. Commun. 2009, 4450;
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins