Selective synthesis of 3-Selanylindoles from Indoles and Diselenides using IK/mCPBA system

Article abstract of DOI:10.1002/aoc.3864

In the presence of a catalytic amount of KI combined with oxidant mCPBA, a convenient catalytic procedure is developed for the preparation of 3-selanylindoles from indoles and diselenides. In this protocol, KI is first oxidized by mCPBA into hypoiodous acid, which reacts with diselenide to cleave Se-Se bond. The in situ generated active electrophilic selenium species then reacts with indole, affording 3-selanylindole via an electrophilic substitution mechanism. This catalytic selenation of indoles has mild reaction conditions and is a simple procedure, which extends the synthetic application of KI in organic synthesis.

Full text of DOI:10.1002/aoc.3864

Received: 14 February 2017
DOI: 10.1002/aoc.3864
Revised: 17 March 2017
Accepted: 2 April 2017
F U L L PA P E R
Selective synthesis of 3‐Selanylindoles from Indoles and
Diselenides using IK/mCPBA system
Hongjie Li | Xiaolong Wang | Jie Yan
College of Chemical Engineering, Zhejiang
University of Technology, Hangzhou
310032, China
In the presence of a catalytic amount of KI combined with oxidant mCPBA, a con-
venient catalytic procedure is developed for the preparation of 3‐selanylindoles from
indoles and diselenides. In this protocol, KI is first oxidized by mCPBA into
hypoiodous acid, which reacts with diselenide to cleave Se‐Se bond. The in situ gen-
erated active electrophilic selenium species then reacts with indole, affording
3‐selanylindole via an electrophilic substitution mechanism. This catalytic
selenation of indoles has mild reaction conditions and is a simple procedure, which
extends the synthetic application of KI in organic synthesis.
Correspondence
Jie Yan, College of Chemical Engineering,
Zhejiang University of Technology,
Hangzhou 310032, P. R. of China.
Email: jieyan87@zjut.edu.cn
KEYWORDS
3‐Selanylindole, catalysis, diselenide, electrophilic substitution, KI
1 | INTRODUCTION
diselenides and oxidant trichloroisocyanuric acid (TCCA)
or ammonium persulfate was another method.[29,30] More
The indole nucleus is ubiquitous in a wide range of natural
products, pharmaceuticals and fine chemicals, and conse-
quently, much attention has been paid to the synthesis of
substituted indoles.[1–9] 3‐Selanylindoles is a significant
class of indole compounds due to they are bioactive[10–12]
and potentially useful as valuable synthetic intermedi-
ates.[13–18] There are some methods for synthesis of
3‐selanylindoles, besides the electrophilic cyclization of
2‐alkynylanilines,[19–21] the main route for obtaining them
is the use of easily available indole as starting material.
Recently, using Cu‐catalysts to improve the selenation of
indoles has become the important methodology for the prep-
aration of 3‐selanylindoles.[22–26] Wu and co‐workers
reported the CuO‐catalyzed three‐component reaction using
selenium powder as selenium source.[22] Under ultrasonic
(US) irradiation, the selenation of indoles with diselenides
catalyzed by CuI was also described.[23] On the other hand,
using metal‐like behavior of molecular iodine as catalyst,
under microwave (MW) irradiation this protocol can pro-
mote the direct reaction of indoles with diselenides.[27,28]
In addition, catalyst free selenation of indoles with
recently, Braga's group demonstrated a green procedure for
affording 3‐selanylindoles, they fount that only adding a cat-
alytic amount of K2CO3 in ethanol, the reaction of indoles
with diselenides proceeded efficiently and gave the products
in good yields by a radical pathway.[31] The similar proto-
cols in ionic liquids had been also investigated before.[32,33]
These above methods, despite being versatile process, the
synthesis of 3‐selenylindoles and study on their potential
bioactivity have not been extensively explored compared
with the analogous 3‐thioindoles.
We have been interesting in oxidation and
functionalization of organic compounds using hypervalent
iodine reagents. In our recent research, we found that some
inorganic iodides or molecular iodine can replace hypervalent
iodine reagents to promote some similar reactions.[34–37]
Based on this, we investigated the novel procedure for synthe-
sis of 3‐selenylindoles. Herein, we wish to report an efficient
selenation of indoles with diphenyl diselenide catalyzed by
KI in the presence of m‐chloroperbenzoic acid (mCPBA). To
the best of our knowledge, this method has not been reported
before.
Appl Organometal Chem. 2017;e3864.
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https://doi.org/10.1002/aoc.3864

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LI ET AL.
stirred at r. t. for 24 h. Upon completion, the reaction
was quenched by addition of sat. aq. Na2S2O3 (2 mL),
sat. aq. Na2CO3 (8 ml) and H2O (5 ml), respectively.
The mixture was extracted with CH2Cl2 (3 × 5 ml) and
the combined organic phase was dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure.
The residue was then purified on a silica gel plate (5:1
petroleum ether‐ethyl acetate) to furnish products 3.
2 | EXPERIMENTAL
2.1 | A typical procedure for the preparation
of 3‐selenylindoles
Indoles 1 (0.2 mmol), diselenides 2 (0.11 mmol), KI
(0.04 mmol) and mCPBA (0.24 mmol) were added succes-
sively to MeOH (2 ml). The suspension was vigorously
TABLE 1 Optimization of the selenation of indole (1a) with diselenide (2a) for synthesis of 3a
Entry
(PhSe)2 (equiv)
KI (equiv)
mCPBA (equiv)
Solvent
Time (h)
Yield (%)a
1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.2
2.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.2
0.2
1.2
CH3OH
CH3CN
CH2Cl2
CH2ClCH2Cl
EtOH
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
6
81
94
72
66
57
84
88
0
2
1.2
3
0.2
1.2
4
0.2
1.2
5
0.2
1.2
6
0.2
1.2
EtOAc
7
0.2
1.2
THF
8
0.2
1.2
DMF
9
0.2
1.2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
83
92
92
68
94
92
81
88
74
24
42
90
90
90
63
86
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
0.2
1.2
0.2
1.2
0.1
1.2
0.5
1.2
1.0
1.2
NaI (0.2)
NH4I (0.2)
Et4NI (0.2)
0.2
1.2
1.2
1.2
0.1
0.2
0.3
0.2
0.5
0.2
1.0
0.2
1.5
0.2
TBHP (1.2)
0.2
KHSO5 (1.2)
0.2
‐
‐
1.2
1.2
1.2
1.2
1.2
0
0.2
75
81
84
72
0.2
12
18
36
0.2
0.2
aIsolated yields.

LI ET AL.
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TABLE 2 Synthesis of 3‐selanylindoles 3
Entry
Indoles 1
Diselenides 2
R2 = Ph, 2a
3‐Selanylindoles 3
Yield (%)a
1
R1 = H, 1a
94
2
3
R1 = 1‐Me, 1b
R1 = 2‐Me, 1c
2a
2a
82
46
4
5
R1 = 3‐Me, 1d
R1 = 4‐Me, 1e
2a
2a
25b
91
6
7
R1 = 7‐Me, 1f
R1 = 5‐Me, 1 g
2a
2a
82
87
8
9
R1 = 5‐MeO, 1 h
R1 = 5‐F, 1i
2a
2a
70
54
10
11
R1 = 5‐Br, 1j
2a
2a
72
R1 = 5‐NO2, 1 k
‐
12
13
14
1a
1 g
1i
R2 = PhCH2, 2b
85
78
43
2b
2b
(Continues)

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LI ET AL.
TABLE 2 (Continued)
Entry
Indoles 1
Diselenides 2
3‐Selanylindoles 3
Yield (%)a
15
1j
2b
79
aIsolate yield.
b2‐Selanylindole 3d was obtained.
compared with KI (entries 2, 15–17). Following, the suitable
amount of oxidant mCPBA was examined, and with 1.2
equiv. of it, the best yield of 94% was reached (entries 2,
18–22). Other oxidants, such as TBHP and KHSO5 were
active in the reaction in place of mCPBA, normally gave
moderate to good yields (entries 23 and 24). As the control
experiment, 3a was not determined in the absence of mCPBA
or KI (entries 25 and 26). Finally, the reaction time was also
optimized and the results showed that in 24 hours the reaction
was completed (entries 2, 27–30).
With these optimized conditions in hands, a detailed
study was performed with different indoles and diselenides,
showing the generality of this method (Table 2). First, the
effect of methyl group on the indole nucleus was evaluated
through the reaction of various methyl lindoles from 1b to
1 g with 2a. It is obvious that most methyl indoles reacted
with 2a smoothly, resulting in the corresponding
3‐selanylindoles 3b, 3e, 3f and 3 g in good to excellent yields
(Table 2, entries 2, 5–7). 2‐Methylindole 1c also can react
with 2a; however, a low yield was obtained for 3c due to
the steric effect of neighbor methyl group (entry 3). Another
methyl indole 1d reacted with 2a difficultly and slowly, a
3 | RESULTS AND DISCUSSION
Initially, we utilized indole (1a) and diphenyl diselenide (2a)
as model substrates to investigate the reaction for the prepara-
tion of 3‐selenylindoles in the presence of IK/mCPBA system
at room temperature. It was found that on simple stirring of
the mixture of 1.0 equiv. of 1a, 1.1 equiv. of 2a and 1.2 equiv.
of mCPBA with 0.2 equiv of KI in MeOH for 24 h at room
temperature in air, the expected product, 3‐(phenylselanyl)‐
1H–indole 3a was obtained in 81% yield (Table 1, entry 1).
Then, the selenation of 1.0 equiv of 1a with 2a catalyzed
by KI combined with mCPBA at room temperature was opti-
mized. Several solvents were first evaluated, in which 3a was
obtained in the yields ranging from 57%–94% and MeCN had
the best effect (entries 1–7); while using DMF as solvent, 3a
was not detected (entry 8). With MeCN as the suitable sol-
vent, the optimized amount of 2a was investigated, and 1.1
equiv. proved to be the best choice (entries 2, 9–11). As for
catalyst KI, 0.2 equiv. of it was determined as the optimized
amount (entries 2, 12–14). Similar to KI, other iodine‐con-
taining catalysts such as NaI, NH4I and Et4NI, all can pro-
mote the reaction and resulted in the somewhat low yields
SCHEME 1 Proposed mechanism for the selenation of indole catalysed by KI

LI ET AL.
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much poor yield of 25% was determined for 2‐selanylindole
3d, meaning this protocol is not suitable for preparation of
2‐selanylindole (entry 4). The electronic character of both
electron‐donating and electron–withdrawing substituents on
the indole nucleus was also checked from several
5‐substituented indoles, which usually had no significant
influence on their reactivity (entries 7–10). However, when
5‐nitroindole 1 k was treated under the same conditions, the
desired product 3 k was not obtained (entry 11). Next, the
scope of diselenide was examined. Dibenzyl diselenide 2b,
similar to 2a, an aliphatic diselenide was also effective in
the reaction, affording the corresponding products 3 l‐3o in
43–85% yields (entries 12–15). As can be seen in Table 2,
except 1d and 1 k, all indoles provided the corresponding
products were 3‐selanylindoles, which indicates this catalytic
selenation has a high regioselectivity.
Based on the above results and control experiments, a
plausible mechanism is depicted in Scheme 1 for the catalytic
selenation of indoles. KI is first oxidized by mCPBA into
hypoiodous acid A, which reacts smoothly with diselenide
2 to form the active intermediate B, followed by a rapid of
Se‐Se bond cleavage.[34,38] The in situ generated active elec-
trophilic selenium species then reacts with indole in an elec-
trophilic substitution mechanism to form the unstable
intermediate C, and after removing a proton the desired prod-
uct 3‐selanylindole 3 is obtained with regioselectivity. In the
cycle, another active unstable intermediate ArSeI[39,40] can
further transfer a second equivalent of electrophilic selenium
to indole.
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How to cite this article: Li H, Wang X, Yan J.
Selective synthesis of 3‐Selanylindoles from Indoles
and Diselenides using IK/mCPBA system. Appl
Organometal Chem. 2017;e3864. https://doi.org/
10.1002/aoc.3864
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