A tetra-: N -butylammonium iodide mediated reaction of indoles with Bunte salts: Efficient 3-sulfenylation of indoles under metal-free and oxidant-free conditions

Article abstract of DOI:10.1039/c6ob01528j

A highly efficient tetra-n-butylammonium iodide (TBAI) triggered procedure for 3-sulfenylation of indoles with Bunte salts is demonstrated. This protocol provides a simple strategy to prepare 3-alkylthioindoles and 3-arylthioindoles from the corresponding indoles under metal-free and oxidant-free conditions.

Full text of DOI:10.1039/c6ob01528j

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tetra-n-Butylammonium iodide mediated reaction of
indoles with Bunte salts: efficient 3-sulfenylation of
indoles under metal-free and oxidant-free conditions†
Cite this: DOI: 10.1039/x0xx00000x
Jian Li, Zhong-Jian Cai, Shun-Yi Wang* and Shun-Jun Ji*
Received 00th January 2015,
Accepted 00th January 2015
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly efficient tetra-n-butylammonium iodide (TBAI) reactions have the limitations such as expensive reagents, lower
triggered procedure for 3-sulfenylation of indoles with reaction yields, unpleasant odors, unstable to air, and difficult to
Bunte salts is demonstrated. This protocol provides a simple handle. Moreover, many of these sulfenylating agents can only
strategy to prepare 3-alkylthioindole and 3-arylthioindoles prepare aryl-sulfenylindoles.
from the corresponding indoles under metal-free and
Bunte salts has been developed and well applied in organic
oxidant-free conditions.
synthesis due to their easy preparation and stabilities without
unpleasant smell.17 In 2014, Senanayake’s group reported a new
Indole-containing organic molecules are important structural
method for the synthesis of sulfide by Bunte salts and Grignard
motifs in a variety of natural products and biologically active
reagent, avoiding the use of a thiol.18 Luo’s group have designed and
compounds.1 Indole thioethers are currently attracting
successfully developed an efficient catalytic method for the synthesis
considerable attention due to their therapeutic value, including
of 3-thioindoles.19 This protocol used iodine as the non-metallic
obesity, cancer 2 and allergies.3 For example, MCF-7
can be used as breast cancer inhibitor; 4 5-chloro-3-(phenylthio)-
-indole-2-carboxamide II (Figure 1) can be used as HIV
I (Figure 1)
catalyst, and employed DMSO as the oxidant and the solvent. Herein,
we report a TBAI promoted sulfenylation of indoles with Bunte salts.
This protocol provides a simple strategy to prepare 3-(benzylthio)-
1H-indole from the corresponding indoles under metal-free and
oxidant-free conditions.
1
H
inhibitor.5 Recently, many methodologies have been developed
for the 3-sulfenylation of indoles to prepare 3-sulfenylindoles.
Scheme 1 TBAI mediated reaction of indoles with Bunte salts.
. Fig. 1 Examples of thiolated indoles with biological actives.
Initially, we tried the reaction of indole 1a（0.5 mmol）with
sodium S-benzyl sulfothioate 2a (0.7 mmol) as the test substrates in
Sulfenylation agents such as disulfides,6 sulfonium salts,7
sulfenyl halides,8 N-thioimides,9 thiols,10 quinone mono-O, S-
acetals,11 p-toluenesulfonyl hydrazide,12 sulfinic acids,13 arylsulfonyl
o
the presence of TBAI (0.75 mmol) in DCE at 80 C. To our delight,
the reaction proceeded smoothly for 10 h to afford the expected 3-
(benzylthio)-1H-indole 3a in 72% yield (Table 1, entry 1). It should
be noted that no sulfenylation product was detected when iodine and
other catalysts such as NIS (N-Iodosuccinimide), NaI, PIDA
16
chlorides,14 p-tolylsulfinate15 and
α
-acylthiones have been applied
to the 3-sulfenylation of indoles. Nevertheless, most of these
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DOI: 10.1039/C6OB01528J
((Diacetoxyiodo) benzene) and CuI were added instead of TBAI Table 2 Reaction of different indoles with sodium S-benzyl
(Table 1, entries 2-6). Screening of solvents, showed that DCE was sulfothioate a, b
the best of choice. (Table 1 entries 7-13). Next, we explored the
influence of reaction temperature. Increasing the temperature from
room temperature to reflux temperature, the reflux temperature led to
the best result and 3a was obtained in 86% yield (Table 1, entries 14-
18). Therefore, the optimized reaction conditions were following:
indole (1a, 1 equiv.), Bunte salts (2a, 1.4 equiv.), TBAI (1.5 equiv.),
in DCE at reflux temperature for 10 h (Table 1, entry 18).
Table 1 Optimization of the reaction conditions a
Entry
1
2
Catalyst
TBAI
I2
Solvent
DCE
DCE
T (o C)
80
Yied b (%)
72
0
80
3
NIS
DCE
80
0
a General conditions : 1a (0.5 mmol), 2a (0.7 mmol), TBAI (0.75
mmol). b Isolated yield
4
5
6
NaI
PIDA
CuI
DCE
DCE
DCE
80
80
80
0
0
0
examined the reactivity of various aryl-Bunte salts, which showed
that aryl-Bunte salts bearing electron-withdrawing groups reacted
well with indoles in good yields (Table 3, 5g-h). It should be
mentioned that when a CF3 group was employed, the respective
product was obtained in high yield too (Table 3, 5i-j). Further
attention was turned to a 5 mmol scaled reaction. It was found that
when 5 mmol indole 1a was used to react with 7 mmol sodium S-2-
bromobenzyl sulfothioate 4k, the expected product 3-((2-
bromobenzyl)thio)-1H-indole 5k could be obtained in 47% yield.
Bunte salts without aromatic rings such as sodium S-(2-(tert-
butoxy)-2-oxoethyl) sulfothioate 4l and
7
8
9
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
H2O
80
80
80
80
80
80
80
r.t.
40
0
0
0
0
49
0
0
0
0
MeCN
EtOH
DMF
DMSO
Dioxane
CH2Cl2
DCE
DCE
DCE
DCE
DCE
10
11
12
13
14
15
16
17
18
60
80
reflux
36
72
86
a
General conditions: 1a (0.5 mmol), 2a (0.7 mmol), TBAI (0.75
mmol). b GC yield
Table 3. Reaction of 1H-indole with different Bunte salts a, b
With the optimized conditions in hand, we investigated the
substrate scope of indoles and the results were summarized in Table
2. It was gratifying to find that a variety of indoles with methyl
groups could react well with Bunte salts to give the desired products
(Table 2, 3b-f) in up to 94% yields. Indoles having electron-donating
groups such as 5-methoxy and 2-phenyl gave the respective
sulfenylated products (Table 2, 3g-h). Indole with electron-
withdrawing group such as bromo group also exhibited high
reactivity (Table 2, 3i).
Next, we evaluated the scope of Bunte salts. The benzyl Bunte
salts with ortho-, meta- and para-chloro groups on the aromatic
rings were tested, and all of them reacted smoothly with indoles,
yielding the desired 3-arylthioindoles with high efficiency (Table 3,
5a-c). Bunte salts possessing electron-withdrawing substituents
resulted in the respective products in 69-94% yields (Table 3, 5d-f).
Furthermore, we
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a General conditions : 1a (0.5 mmol), 2a (0.7 mmol), TBAI (0.75
Based on the above results and the literature reports, 6a, 13, 17, 21, 22
a
b
c
mmol). Isolated yield. 1a (5 mmol), 2a (7 mmol), TBAI (7.5 plausible mechanism was proposed in Scheme 5. Bunte salt 2 reacts
mmol).
with water (from Bunte salt and undried solvent) to give the thiol or
thiol anion 10 and bisulfate anion in the presence of TBAI.17, 21 I- is
further oxidized by bisulfate anion to furnish I2.13 Another Bunte salt
2 undergoes nucleophilic attack by 10 to give disulfide 11, 22 which
can be detected by GC-MS (For details, please see supporting
information). Disulfide 11 reacts with I2 to form an electrophilic
species RSI 12.6b, 13 Following the reaction of 12 with indole 1a and
deprotonation, the desired product 3 and I- are observed.6b
sodium S-(cyanomethyl) sulfothioate 4m also reacted with indoles
under optimized reaction conditions in DCE to produce the
corresponding 3-selenylated indoles in 50% and 85% yield (Table 3,
5l-m). Bunte salts with electron-donating groups such as sodium S-
(2-methylbenzyl) sulfurothioate (Table 3, 5n), sodium S-(4-
methylbenzyl) sulfurothioate (Table 3, 5o) and sodium S-(4-
methoxybenzyl) sulfurothioate (Table 3, 5p) with indole,
repectively. Unfortunately, no desired products were observed under
the identical contions.
Next, we treated the sodium S,S'-(1,4-phenylenebis(methylene))
disulfothioate 6 with 2 equiv indoles 1 under standard conditions, the
corresponding 1,4-bis(((1H-indol-3-yl)thio)methyl)benzene 7 was
also prepared in 20% yield (Scheme 2).
Scheme 5 proposed mechanism.
Scheme
2
Reaction of 1H-indole with sodium S,S'-(1,4-
In summary, we developed a highly efficient TBAI mediated 3-
sulfenylation of indoles with Bunte salts under metal-free and
oxidant conditions. This protocol provides a simple strategy for the
efficient synthesis of 3-alkylthioindoles and 3-arylthioindoles under
mild conditions.
phenylenebis(methylene)) disulfothioate.
Furthermore, the versatile synthetic utility of the 3-(benzylthio)-
1H-indolewas 5a was studied (Scheme 3). It should be noted that 3-
(benzylsulfonyl)-1H-indole 8 can be obtained in 96% yield through
the simple oxidation of 5a by m-CPBA.
Acknowledgements
We gratefully acknowledge the Natural Science Foundation of China
(21372174, 21542015, 21672157), PAPD, the Major Basic Research
Project of the Natural Science Foundation of the Jiangsu Higher
Education Institutions (No.16KJA150002), and Soochow University
for financial support, and State and Local Joint Engineering
Laboratory for Novel Functional Polymeric Materials.
Scheme 3 Oxidation of 3-(benzylthio)-1H-indole.
In order to extend the application of our reaction, we tried the
Pd-catalyzed intramolecular annulation reaction20 of 3-((2-
bromobenzyl)thio)-1H-indole 5l. To our delight, the C–H
functionalization product 11-dihydroisothiochromeno[4,3-b]indole 9
was delivered in 79% yield (Scheme 4).
Notes and references
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science & Collaborative
Innovation Center of Suzhou Nano Science and Technology, Soochow
University, Suzhou, 215123, P. R. China; Fax:+86-512-65880307;
Tel:+86-512-65880307;
shunjun@suda.edu.cn
E-mail:
shunyi@suda.edu.cn,
† Electronic Supplementary Information (ESI) available: For ESI or other
electronic format see: 10.1039/c000000x/
Scheme 4 Cyclization of 3-((2-bromobenzyl)thio)-1H-indole
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