Byproduct promoted regioselective sulfenylation of indoles with sulfinic acids

Article abstract of DOI:10.1039/c4ob02575j

An unprecedented method to synthesise 3-sulfenylindoles is demonstrated via byproduct promoted sulfenylation of indoles with sulfinic acids in the absence of an external catalyst. The reaction selectively afforded structurally diverse indole thioethers in good to excellent yields in 1,2-dichloroethane at 80 °C. This journal is

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ARTICLE TYPE
Byproduct Promoted Regioselective Sulfenylation of Indoles with
Sulfinic Acids
a
a
Cong-Rong Liu,* Liang-Hui Ding
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
o
An unprecedented method to synthetise 3-sulfenylindoles is
iodide as additive in 1,2 - dichloroethane at 80 C. To our delight,
demonstrated via byproduct promoted sulfenylation of 50 TsOH was identified as the acid of choice, which promoted the
indoles with sulfinic acids in the absence of external catalyst.
The reaction selectively afforded structurally diverse indole
formation of 3-sulfenylindole 3a in 69% yield (Table 1, entry 1).
Nevertheless, the yield decreased dramatically when replacing
tetrabutylammonium iodide with sodium iodide or potassium
iodide (Table 1, entries 5 and 6). A number of common solvents
were examined, but no better yield was obtained. (Table 1, entries
7-15). A high yield was obtained when the loading of
Tetrabutylammonium iodide was increased to 1.2 equivalent
(Table 1, entriy 16). Further efforts to increase the yield of 3-
sulfenylindole 3a by increasing the loading of TsOH to 0.2
equivalent resulted in a higher yield 98% (Table 1, entriy 17).
1
0
thioethers in good to excellent yields in 1,2 - dichloroethane at
o
8
0 C.
5
5
The indole moiety is an important unit because of its presence in
many bioactive relevant molecules, such as colchicines,
combretastatin A-4, indolyl-3-glyoxamide D-24851 and 2-aryl-3-
1
1
2
2
3
3
4
4
5
0
5
0
5
0
5
arylcarbonylindole. Developing efficient synthetic approaches to
60
construct differently substituted indole derivatives is one of the
2
most exciting topics in organic synthesis. Among them, the
a
Table 1. Optimization of Reaction Conditions
direct carbon-hydrogen bond functionalization is
a more
H
convenient method for the formation of carbon-carbon and
H
N
N
3
additive, acid
carbon-heteroatom bonds on indole rings. In this regard, the
+
PhSO2H
o
solvent, 80 C
sulfenylation of indoles has been developed for the synthesis of
3
-sulfenylindoles, some of which are important drugs assessed in
SPh
several disease areas, including bacterial infection, cancer, HIV,
1a
2a
3a
4
obesity, heart diseases and allergies. Various sulfenylating
Entry Solvent
Additive (eq)
Acid(eq)
Yield(%)
69
5
agents such as sulfonium salts, quinone mono-O,S-acetals,
1
2
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
n-Bu NI (1.0) TsOH (0.1)
6
7
8
9
10
4
sulfonyl hydrazides, sulfinates, disulfides, sulfenyl halides,
1
1
12
13
n-Bu NI (1.0)
HCl (0.1)
47
N-thioimides,
thiols
and arylsulfonyl chlorides
were
4
smoothly coupled with indoles. However, many of these
sulfenylating agents are impractical due to the accessibility,
substrate compatibility, stability. Moreover, many reported
sulfenylation reactions of indoles frequently require catalysts,
harsh reaction conditions or excess sulfenylating agents.
Therefore, a new general and flexible approach for the
sulfenylation of indoles is still necessary.
3
n-Bu NI (1.0) TfOH (0.1)
63
4
4
n-Bu NI (1.0) H SO (0.1)
55
4
2
4
5
NaI (1.0)
TsOH (0.1)
TsOH (0.1)
23
6
KI (1.0)
11
7
n-Bu NI (1.0) TsOH (0.1)
27
4
8
MeNO2 n-Bu NI (1.0) TsOH (0.1)
14
4
Sulfinic acids are readily accessible and they have been
employed to form sulfones which have versatile applications in
9
Toluene n-Bu NI (1.0) TsOH (0.1)
38
4
1
4
medicinal chemistry. Moreover, sulfinic acids can be reduced to
disulfides ,which are conventional sulfenylating agents. So we
envisioned that sulfinic acids might serve as potential
sulfenylating agents to couple with indoles under certain reaction
conditions. To our knowledge, there are no examples describing
the sulfenylation of indoles using sulfinic acids as potential
sulfenylating agents. Herein we report an efficiend synthesis of 3-
sulfenylindoles via byproduct promoted sulfenylation of indoles
with sulfinic acids in the absence of external catalysts.
10
DMA
DMSO
DMF
n-Bu NI (1.0) TsOH (0.1)
43
4
1
1
1
2
n-Bu NI (1.0) TsOH (0.1)
40
4
n-Bu NI (1.0) TsOH (0.1)
43
4
13
Dioxane n-Bu NI (1.0) TsOH (0.1)
32
4
1
1
4
5
EtOH
n-Bu NI (1.0) TsOH (0.1)
30
4
H O
2
n-Bu NI (1.0) TsOH (0.1)
40
4
16
DCE
n-Bu
NI (1.2) TsOH (0.1)
87
4
To get the optimized reaction conditions, several Brønsted
acids (10 mol%) were examined in the model reaction of indole
1
7
DCE
n-Bu NI (1.2) TsOH (0.2)
98
4
1
a with benzenesulfinic acid 2a using tetrabutylammonium
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a
Reaction conditions: indole 1a (0.20 mmol), benzenesulfinic acid 2a
0.24 mmol), additive , acid, solvent (1.0 mL), 80 C (oil bath), 12 h.
4
5
6
7
8
9
2e (4-ClC H )
3n
3o
3p
3q
3r
90
89
88
94
84
96
80
70
77
o
b
6
4
(
Isolated yield.
2f (4-BrC H )
6 4
Encouraged by our preliminary findings, we investigated the
substrate scope for the sulfenylation of indoles with
benzenesulfinic acid (2a). Under the optimized reaction
number of indoles bearing either electron-
withdrawing groups (Cl, Br, NO , and CO Me) or electron-
donating groups (Me, Ph, and OMe) on the N-1, C-2, C-4, C-5 or
C-6 positions of the indole rings, were transformed into their
corresponding 3-phenylthioindoles in good to excellent yields
2g (4-IC H )
6 4
5
0
5
2h (4-MeC H )
6
4
conditions,
a
2i (4-MeOC H )
6 4
2
2
2j (2-naphthyl)
2k (Me)
3
s
1
0
3t
3u
3v
1
11
2l (CH ) CH
3
2
7
(
table 2). Lower yields was obtained when strong electron
1
2
2m CH Ph
2
withdrawing groups, like a carbomethoxy group or nitro group,
were present at the C-5 position in the indole (table 2, entries 8
and 9).
a
Reaction conditions: indole 1a (0.20 mmol), Sulfinic acid 2 (0.24 mmol),
o
1
30 n-Bu NI (0.24 mmol), TsOH (0.040 mmol), DCE (1.0 mL), 80 C (oil
4
b
bath), 12 h. Isolated yield.
Table 2. Regioselective Sulfenylation of Indoles with benzenesulfinic
a
Acid (2a)
donating groups were introduced into the sulfenylation product
by employing arylsulfinic acid bearing such groups on the
aromatic ring. Furthermore, alkylsulfinic acids also could
35 smoothly react with indole 1a to give the corresponding 3-
alkylthioindoles, and as expected, lower yieldes were given for
the sulfenylation of indoles with these less reactive sulfinic acids
H
H
N
N
n-Bu NI, TsOH
4
+
PhSO2H
R
R
o
DCE, 80 C
SPh
1
2a
3a-j
(
table 3, entries 10-12).
Entry
1 (R)
3
Yield (%)b
During these reactions, we observed that the colors of mixtures
4
0
were purple (Table 1,2 and 3), So we speculated that there was
iodine produced. To gain insight into the reaction mechanism,
four control experiments were set up under various reaction
conditions. No reaction occurred upon treatment of indole 1a
with benzenesulfinic acid 2a in the absence of
tetrabutylammonium iodide (Scheme 1, a). Under the optimized
reaction conditions, benzensulfinic acid was reduced into
diphenyldisulfane 4a in 96% yield, while iodide ion was oxidized
into iodine (scheme 1, b). In the presence of 1.2 equivalents
1
2
3
4
5
6
7
8
9
1a ( H)
1b (1-Me)
1c (2-Me)
1d (2-Ph)
1e (4-Br)
1f (5-Br)
3a
3b
3c
3d
3e
3f
98
99
87
93
95
98
90
86
70
97
45
1g (5-OMe)
3g
iodine, indole 1a smoothly reacted with diphenyldisulfane 4a to
1h (5-CO Me)
3h
3i
2
H
N
TsOH
1i (5-NO2)
PhSO H
+
2
No reaction
a
o
DCE, 80 C
1
0
1j (6-Cl)
3j
a
Reaction conditions: indole 1 (0.20 mmol), benzenesulfinic acid 2a
(0.24 mmol), n-Bu NI (0.24 mmol), TsOH (0.040 mmol), DCE (1.0 mL),
0 C (oil bath), 12 h. Isolated yield.
1a
2a
2
0
4
o
b
n-Bu NI, TsOH
8
4
PhSO2H
PhS SPh + I2
b
o
DCE, 80 C, 12h
Next, we examined the reactivity of various sulfinic acids
2a
4a : (96%)
toward indole (1a) (Table 3). A range of arylsulfinic acids
smoothly reacted with indole 1a to give the corresponding 3-
arylthioindoles in good to excellent yields (table 3, entries 1-9). It
is noteworthy that both electon-withdrawing and electron-
H
N
H
I2
N
2
5
+
+
PhS SPh
c
o
DCE, 80 C, 12h
a
SPh
Table 3. Regioselective Sulfenylation of Indole (1a) with Sulfinic Acids
1a
4a
3a : 99%
H
N
H
N
H
N
n-Bu NI, TsOH
4
n-Bu4NI, TsOH
+
RSO2H
o
PhS SPh
No reaction
d
DCE, 80 C
o
DCE, 80 C, 12h
SR
1
a
4a
50
1
a
2
3k-v
Entry
2 (R)
2b (3-O NC H )
3
Yield (%)
Scheme 1 Control Experiments
1
2
3
3k
92
96
83
2
6
4
give the corresponding 3-phenylthioindole 3a in 99% yield
scheme 1, c). No reaction occurred upon treatment of indole 1a
2c (4-O NC H )
3l
2
6
4
(
2d (4-FC H )
3m
55 with diphenyldisulfane 4a in the optimized reaction conditions
6
4
2
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(
Scheme 1, d).
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4
5
5
6
5
0
5
0
On the basis of the above experimental results and previous
[
9]
relevant mechanistic studies, we proposed the reaction pathway
depicted in Scheme 2. Initially, diphenyldisulfane (4) is generated
from sulfinic acid 2 in the presence of TsOH and n-Bu NI. Then
4
1
2
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reacts with I to give the sulfenyl iodide 5, which is attacked by
2
to give thioether 3 and HI. HI react with 2 to give 4 and
regenerate iodine to promoted the reaction continually.
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4
I2
1
R SO H
R1S SR1
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n-Bu NI, TsOH
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I2
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H
N
R2
1
R SI
SR1
65
3
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NH
R2
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6
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Scheme 2 Proposed Reaction Pathway
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Conclusions
2
In summary, we have developed an unprecedented method to
synthesise 3-arylthioindoles and 3-alkylthioindoles from indoles
and sulfinic acids. In the presence of 10 mol% TsOH and 1.2
75
80
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structurally diverse indole thioethers in good to excellent yields.
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2
transformation.
1
0
8
9
9
5
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Acknowledgement
1
688.
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21202154), Nanjing
Institute of Technology Scientific Research Foundation for
Introducing Talents (No. YKJ201329, YKJ201326), Nanjing
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Notes and references
a
School of Environment Engineering, Nanjing Institute of
Technology, 1 Hongjingdadao, Nanjing, Jiangsu 211167, China
Fax: 86-025-86118974; E-mail: congrong@njit.edu.cn
3
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† Electronic Supplementary Information (ESI) available: [spectral data 100
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