Iodine-promoted direct thiolation (selenylation) of imidazole with disulfides (diselenide): A convenient and metal-free protocol for the synthesis of 2-arylthio(seleno)imidazole

Article abstract of DOI:10.1016/j.tet.2020.130951

A convenient and metal-free protocol for the synthesis of 2-arylthio(seleno)imidazoles from imidazoles and disulfides (diselenides) was developed through the direct thiolation (selenylation) of imidazoles promoted by 0.5 equiv. of iodine. This process is

Full text of DOI:10.1016/j.tet.2020.130951

Journal Pre-proof
Iodine-promoted direct thiolation (selenylation) of imidazole with disulfides
(diselenide): A convenient and metal-free protocol for the synthesis of 2-
arylthio(seleno)imidazole
Rongnan Yi, Sen Liu, Hongxia Gao, Zhiwu Liang, Xinhua Xu, Ningbo Li
PII:
S0040-4020(20)30041-7
https://doi.org/10.1016/j.tet.2020.130951
TET 130951
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 October 2019
Revised Date: 8 January 2020
Accepted Date: 10 January 2020
Please cite this article as: Yi R, Liu S, Gao H, Liang Z, Xu X, Li N, Iodine-promoted direct thiolation
(selenylation) of imidazole with disulfides (diselenide): A convenient and metal-free protocol for
the synthesis of 2-arylthio(seleno)imidazole, Tetrahedron (2020), doi: https://doi.org/10.1016/
j.tet.2020.130951.
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Metal-Free Protocol for Synthesis of 2-Arylthio(seleno)imidazole
Rongnan Yi,a Sen Liu,a Hongxiao Gao,a Zhiwu Liang,a,* Xinhua Xu,a,* and Ningbo Li,b,*
a State Key Laboratory of Chemo/Biosensing and Chemometrics College of Chemistry and Chemical Engineering Hunan University Changsha, Hunan, 410082, (P.
R. China) E-mail: zwliang@hnu.edu.cn; xhx1581@hnu.edu.cn.
b Basic Medical College, Shanxi Medical University, Taiyuan, 030001, (P.R. China) E-mail: ningboli@sxmu.edu.cn.

1
Tetrahedron
journal homepage: www.elsevier.com
Iodine-promoted direct thiolation (selenylation) of imidazole with disulfides (diselenide): a
convenient and metal-free protocol for the synthesis of 2-arylthio(seleno)imidazole
Rongnan Yi,a Sen Liu,a Hongxia Gao,a Zhiwu Liang*a, Xinhua Xu*a and Ningbo Li*b
a State Key Laboratory of Chemo/Biosensing and Chemometrics College of Chemistry and Chemical Engineering Hunan University Changsha,
Hunan, 410082, (P. R. China) E-mail: zwliang@hnu.edu.cn; xhx1581@hnu.edu.cn.
b Basic Medical College, Shanxi Medical University, Taiyuan, 030001, (P.R. China) E-mail: ningboli@sxmu.edu.cn.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient and metal-free protocol for the synthesis of 2-arylthio(seleno)imidazoles from
imidazoles and disulfides (diselenides) was developed through the direct thiolation
(selenylation) of imidazoles promoted by 0.5 equiv. of iodine. This process is scalable and
tolerates a wide spectrum of disulfides (diselenides) to deliver products in high yields.
Compared with previous methods, this protocol has the advantages of a simple operation, wide
functional group tolerance and good yields, providing an efficient route to 2-
arylthio(seleno)imidazoles, which are key structural scaffolds of many natural products.
Available online
Keywords:
Iodine-promoted thiolation(selenylation)
Imidazoles
Diaryldisulfides(diselenides)
2-arylthio(seleno)imidazoles
2009 Elsevier Ltd. All rights reserved
.
1. Introduction
However, some of these methods must be performed under
harsh conditions owing to the use of organometallic reagents
such as n-BuLi and C6H5ZnBr, which are highly sensitive to
water (Scheme 2a and 2b).14,15 In addition, the toxic and
odorous thiols or mercaptan (as starting reagents) must be used
in other methods (Scheme 2b-2d).16 Recently, Wu et al.
reported an effective method for the synthesis of 2-arylseleno-
1H-imidazole by the three-component coupling reaction of
electron-deficient heterocycles, Se powder and aryl iodides
catalyzed by copper chloride (Scheme 2e).13a Nevertheless, this
process requires a high temperature and nitrogen protection.
Furthermore, all of the abovementioned catalytic systems must
use metal catalysts.
Imidazole derivatives are common structural motifs in many
natural products and drugs,1-3 such as kealiiquinone,4 naamidine
A5 and clathridine A,6 which show anti-cancer activity. Some
intermediate for natural product7 can be synthesized by
imidazole derivatives. In addition, 48 aryl-1H-imidazole
compounds displayed similar in vitro growth inhibition in
cancer cells, and were found to be cytostatic in melanoma cell
line (Scheme 1).8 The aforesaid compounds and other
medicines possessing therapeutic potential can be synthesized
from imidazoles, especially 2-arylthio(seleno)-1H-imidazole
and its derivatives.9,10
Scheme 1. Bioactive molecules with the imidazole motif.
Because of the important application of 2-arylthio(seleno)-
1H-imidazole derivatives in the synthesis of many natural
products and medicinal agents,11 efforts are devoted toward
their generation.12 Various methods for the synthesis of 2-
arylthio(seleno)-1H-imidazole derivatives have been reported.13
Scheme 2. General methods for the synthesis of 2-
arylthio(seleno)imidazoles.
Up to now, a metal-free catalysis for the synthesis of 2-
arylthio(seleno)-1H-imidazole has not been reported. Therefore,

2
Tetrahedron
as an environment-friendly and less expensive methodology, yields were obtained (Table 1, entries 4, 12-17). No desired
the development of transition-metal-free systems for the product was observed without additives (Table 1, entry 18).
synthesis of 2-arylthio(seleno)-1H-imidazole derivatives, which
Lastly, we explored the influence of the additive amount for
sulfenylation. We found that 0.5 equiv. of iodine was enough to
are ubiquitous scaffolds,17 is highly desired. Diaryl
disulfides(diselenides), which are known to be air-stable, free promote the sulfenylation effectively by extending the reaction
of smell, and good electrophilic reagents with low toxicity, time to 16 hours (Table 1, entry 21). A lower yield of 82% was
have been used often in the arylthiolation and
arylselenylation.18 Iodine reagents have also been used in C-S
bond formation.19,20 As a part of our research program in the
synthesis of sulfur-containing compounds,21,22 we report an
iodine-mediated direct thiolation(selenylation) of imidazole
obtained when the oxidant amount was decreased to 0.3 equiv.
despite extending the reaction time to 20 hours (Table 1, entry
22). After extensive screening, we found that the sulfenylation
of 1-methylimidazole (1a) and diphenyl disulfide (2a) in
DMSO promoted by 0.5 equiv. of iodine in air provided the
with diaryl disulfides (diselenides) for synthesis of 2- desired product with an excellent yield of 92% within 16 hours.
arylthio(seleno)-1H-imidazole, which is in sharp contrast to the
transition-metal-catalyzed reactions (Scheme 2f).
To demonstrate the efficiency of the sulfenylation, we
explored the generality of our method by extending the optimal
conditions to various substituted imidazoles and diaryl
disulfides, and the results are summarized in Table 2.
2. Results and discussion
We used the thiolation of 1-methylimidazole (1a) with
diphenyl disulfide (2a) as a model reaction to optimize the
reaction parameters, and the results are summarized in Table 1.
Table 2. The sulfenylation of 1-alkyl-1
H
-imidazoles with
diaryl disulfides.a, b
N
N
I2 (0.5 equiv.)
DMSO, 120 oC,16 h
R2SSR2
SR2
N
N
Table 1. Optimization of the reaction conditions.a
R1
R1
1
2
3
N
N
N
N
N
N
O
N
N
N
N
N
I2 (equiv.)
S
S
S
S
HN
PhSSPh
SPh
Solvent, Temp., Time
N
Me
Me
Me
Me
Me
1a
Me
3a
2a
Me
OCH3
Additive (equiv.)
Temp. (oC)
Solvent
Time (h) Yield (%)b
3a, 92%
3b, 97%
Entry
3c, 93%
3d, 99%
1
2
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
32
53
77
88
83
37
24
35
47
69
60
80
DMSO
DMSO
DMSO
DMSO
12
12
12
12
12
12
12
12
12
12
N
N
S
N
N
N
N
S
S
S
3
4
100
120
130
150
120
120
120
120
N
N
Me
Me
Me
NO2
Me
5
DMSO
DMSO
Cl
6
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
NO2
3e, 90%
3f, 93%
3g, 72%
3h, 88%
Toluene
7
8
9
THF
MeCN
N
N
N
N
nBu
N
N
S
NO2
S
S
S
10
11
12
13
14
15
16
17
18
19
20
21
22
DMF
N
N
Me
nBu
nBu
1,4-dioxane
52
I2 (1.0)
120
120
12
12
NO2
TBHP (2.0)
DTBP (2.0)
BPO (2.0)
CuBr (2.0)
CuI (2.0)
NH4I (2.0)
none
I2 (0.5)
21
19
28
11
DMSO
DMSO
Cl
120
120
120
120
120
120
120
120
120
120
12
12
12
12
12
12
12
12
16
20
3i, 74%
3j, 96%
3k, 93%
3l, 89%
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
N
O
N
N
S
S
HN
S
24
N
N
N
nBu
N. D.c
N. D.c
84
nBu
nBu
NO2
Me
I2 (0.3)
I2 (0.5)
I2 (0.3)
76
92 (90)d
82
3o, 99%
3m, 82%
3n, 98%
N
N
N
S
N
S
S
a
Reaction conditions: 1-methyl-1H-imidazole (1a) (0.5 mmol),
N
N
diphenyl disulfide (2a) (0.25 mmol), iodine, solvent (2.0 mL), in
Me
air; b GC yields; c N.D. for not detected; d Isolated yields.
3r, trace
3p, 32%
3q, trace
Analyzing Table 1, we can see that the desired product 1-
methyl-2-(phenylthio)-1H-imidazole (3a) was obtained with a
a
Reaction conditions: 1-alkane-1H-imidazoles (1) (0.55 mmol),
diaryl disulfides (2) (0.25 mmol), iodine (0.125 mmol), DMSO
yield of 32% via the thiolation of 1-methylimidazole (1a) and
diphenyl disulfide (2a) in the presence of 1.0 equiv. of iodine
(I2) at 60 oC (Table 1, entry 1). We then explored the influence
of temperature on the reaction by varying the temperature from
(2.0 mL), 120 oC, 16 h, in air. b Isolated yields.
A variety of diaryl disulfides could efficiently undergo
sulfenylation to afford the corresponding products with good to
excellent yields (3a-3i, 72-99%). Electron-donating groups
(e.g., Me and OCH3) or electron-withdrawing groups (e.g., Cl
and NO2) on the benzene ring of the diaryl disulfides slightly
affected the sulfenylation, and provided the corresponding
products in good to excellent yields. Notably, this protocol is
also applicable to the diphenyl disulfide-containing amide
group, which gave the desired product 3d with a 99% yield.
When N-butyl-1H-imidazole reacted with diaryl disulfides, all
o
60 to 150 C (Table 1, entries 1-6), and the results showed that
o
120 C was the best temperature for giving the desired product
with a yield of 88% (Table 1, entry 4). The screening of
solvents (Table 1, entries 4 and 7-11) revealed that DMSO was
the best solvent (Table 1, entry 4, 88%), mainly because of its
excellent solubility to reactants and oxidability to the
sulfenylation. Other oxidants such as TBHP, DTBP, BPO,
CuBr, CuI and NH4I were also investigated, and low or poor

3
corresponding products were obtained in excellent yields
(
3j-3o
,
diphenyl disulfide (2a) with DMSO (Scheme 3b, Eq. 1) and
82-99%). The steric effect of N-iPr and N-tBu at the 1-position DMF (Scheme 3b, Eq. 2) under a nitrogen and oxygen
of 1-alkane-1H-imidazole was significant (3p and 3q, 32% and
trace amount). The yield of desired product 3r was obtained in
trace amounts when 1-methylbenzimidazole was treated with
diphenyl disulfide under standard conditions. However, alkyl
disulfides (such as dipropyl disulfide and diisobutyl disulfide)
plausibly failed to yield desirable products because they easily
formed ionic liquids.
atmosphere. The yield of the desired product (3a) indicates that
O2 may be involved in the oxidation process during the whole
sulfenylation. No reaction was observed when 1-
methylimidazole was replaced by 1,2-dimethylimidazole,
indicating the regioselectivity of this method (Scheme 3b, Eq.
3).
Encouraged by the successful synthesis of 2-
arylthioimidazole, we decided to expend this strategy to the
selenation of imidazoles under milder reaction conditions (100
oC, 8.0 h), and the results are summarized in Table 3.
Analyzing Table 3, we can see that electron-donating and
electron-withdrawing functional groups at the o- and p-
positions of the diaryl selenides slightly affected the selenation,
affording the corresponding products with excellent yields
(Table 3, 5a-5f, 93%-99%). When N-butyl-1H-imidazole
reacted with diaryl diselenides, all corresponding products were
obtained in excellent yields (5g-5j, 95-99%). The steric effect
of N-iPr and N-tBu at the 1-position of 1-alkane-1H-imidazole
was slightly less than that of the reaction with diphenyl
disulfide (5k and 5l, 78% and 55%).However, only a trace yield
was observed when an imidazole with a bulky substituent at N-
atom position was used as the substrate (5m). In addition, the
reaction can also be applied to 1-methylbenzimidazole, which
reacted with diaryldiselenides to afford the corresponding
products in the yields of 80-91% (5n-5p).
Scheme 3. (a) Larger-scale synthesis of 3a; (b) Control
experiments for mechanism study.
On the basis of the above experimental results and previous
work,21 a possible mechanism is depicted in Scheme 4. The first
step is the generation of PhSI via the reaction of iodine with
diphenyldisulfide at high temperature, which was detected by
GC-MS. Meanwhile, the blank reaction was performed to
verify the generation of PhSI (listed in SI). Then, the
replacement reaction of the intermediate PhSI with 1-
methylimidazole (1a) yielded the desired product (3a) and HI,
which was then converted to I2 via the oxidation of DMSO and
oxygen from air.
Table 3. The selenation of 1-alkane-1H-imidazoles with diaryl
diselenides.a,b
PhSSPh
2a
I2
DMS+H2O
Metal-Free
[O]
I
SPh
H
I
DMSO
N
N
N
N
Ph
S
3a
Me
1a
Me
Scheme 4. Proposed mechanism for sulfenylation
.
3. Conclusion
In summary, we have developed a metal-free and convenient
protocol for the synthesis of 2-arylthio(seleno)imidazoles via
the
sulfenylation(selenylation)
of
imidazoles
with
a
disulfides(diselenides) promoted by 0.5 equiv. of iodine. A
broad range of diaryldisulfides or diaryldiselenides were
tolerated, and all desired products could be obtained in good to
excellent yields, providing a convenient and general way to
synthesize 2-arylthio(seleno)imidazoles.
Reaction conditions: 1-alkane-1H-imidazoles (1) (0.55 mmol),
diaryl diselenides (2) (0.25 mmol), iodine (0.125 mmol), DMSO
(2.0 mL), 100 oC, 8.0 h, in air. b Isolated yields.
The sulfenylation can also be carried out on a larger scale
reaction. The desired product (3a) was obtained with a yield of
88% when 10 mmol of 1-methylimidazole (1a) was treated
with 4.5 mmol of diphenyl disulfide (2a) under the standard
conditions (Scheme 3a). To shed light on the mechanism of the
sulfenylation, 1-methylimidazole (1a) was treated with
4. Experimental Section
Unless noted, all reactions were conducted in Schlenk tubes
under an atmosphere of air using commercial solvents. Iodine,

4
Tetrahedron
1-methylimidazole, 1-butylimidazole, 1-methylbenzimidazole,
6.84 (m, 2H), 3.80 (s, 3H), 3.66 (s, 3H); 13C NMR (100 MHz,
diphenyl disulfide, 4,4’-dichlorodiphenyl disulfide, 4- CDCl3) δ 159.17, 139.75, 131.65, 129.79, 124.36, 123.36,
methylphenyl disulfide, bis(2-benzamidophenyl) disulfide,
dibenzyl disulfide, 4,4’-dinitrodiphenyl disulfide, 3,3-
dinitrodiphenyl disulfide, 2,2’-dinitrodiphenyl disulfide were
purchased from Energy company and used as received.
Diphenyl diselenide, di(4-methylphenyl) diselenide, di(4-
chlorophenyl) diselenide, dinaphthyl diselenide, dibenzyl
diselendide and di(2,6-dimethylphenyl) diselenide were
synthesized according to the previous work.23
114.93, 55.35, 33.82; MS (m/z): 221.0 (M+).
N-(2-((1-methyl-1H-imidazol-2-yl)thio)phenyl)benzamide (3d):
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 3/1, Rf = 0.4). The title compound was
1
obtained as a yellow solid (99%, 152.9 mg); H NMR (400
MHz, CDCl3) δ 11.00 (s, 1H), 8.30 (d, J = 4.0 Hz, 3H), 7.63 (d,
J = 8.0 Hz, 1H), 7.54-7.51 (m, 3H), 7.43 (t, J = 8.0 Hz, 1H),
7.10-7.05 (m, 2H), 6.95 (s, 1H), 3.76 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 166.07, 141.28, 139.57, 135.05, 134.67, 131.77,
130.70, 129.21, 128.50, 128.16, 124.67, 124.58, 123.34, 122.09,
33.95; HRMS (ESI): [M + H]+ calcd for [C17H15N3OS]:
309.0942, found: 309.0937.
4.1 Analytical methods
Thin-layer chromatography (TLC) analysis was carried out
using gel 60 F254 pre-coated plates. Visualization was
accomplished with UV lamp or I2 stain. Silica gel 300-400
mesh size was used for column chromatography using the
combination of ethyl acetate and hexane as an eluent. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded at
2-((4-chlorophenyl)thio)-1-methyl-1H-imidazole (3e): Isolated
by flash column chromatography (petroleum ether/ethyl acetate
= 2/1, Rf = 0.4). The title compound was obtained as a colorless
liquid (90%, 100.8 mg); 1H NMR (400 MHz, d6-DMSO) δ
7.24-7.20 (m, 3H), 7.12-7.08 (m, 3H),3.65 (s, 3H); 13C NMR
(100 MHz, d6-DMSO) δ 137.64, 133.14, 132.85, 130.15,
129.55, 129.44, 123.97, 33.92; HRMS (ESI): [M + H]+ calcd
for [C10H9ClN2S]: 224.0181, found: 224.0172.
400 MHz. Chemical shift were recorded in parts per million
1
(ppm, δ) relative to tetramethyl silane (δ 0.00).
HNMR
splitting patterns are designated as singlet (s), doublet (d),
double doublet (dd), triplet (t) or multiplet (m). Carbon nuclear
magnetic resonance (13C NMR) spectra were recorded at 100
2-(benzylthio)-1-methyl-1H-imidazole (3f)13c: Isolated by flash
column chromatography (petroleum ether/ethyl acetate = 1/1,
Rf = 0.6). The title compound was obtained as a yellow solid
1
MHz. H NMR and 13C NMR spectra were recorded using
residue solvent peaks as internal standards (CHCl3, δ = 7.26
1
1
1
ppm for H, δ = 77.0 ppm for 13C; DMSO, δ = 2.5 ppm for H,
δ = 39.5 ppm for 13C). Coupling constants are given in hertz.
Mass spectra (MS) were obtained using EI mass spectrometer.
(93%, 95.4 mg); H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m,
5H),6.67 (s, 1H), 6.57 (s, 1H), 5.25 (s, 2H), 3.01 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 162.87, 135.86, 128.87, 128.30,
128.15, 118.03, 116.36, 51.35, 35.27; MS (m/z): 205.1 (M+).
1-methyl-2-((4-nitrophenyl)thio)-1H-imidazole (3g): Isolated
by flash column chromatography (petroleum ether/ethyl acetate
= 2/1, Rf = 0.5). The title compound was obtained as a yellow
solid (72%, 84.6 mg); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J
= 8.0 Hz, 2H), 7.21 (s, 1H), 7.12 (s, 1H), 7.01 (d, J = 7.6Hz,
2H), 3.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.00,
145.25, 135.11, 131.07, 126.51, 124.73, 124.32, 33.96; HRMS
(ESI): [M + H]+ calcd for [C10H9N3O2S]: 235.0421, found:
235.0415.
4.2 Experimental Procedure for 3a and characterization data
of 3a-3p
Typical procedure for the synthesis of 1-Methyl-2-
(phenylthio)-1H-imidazole 3a: 1-methyl-1H-imidazole 1a (45.2
mg, 0.55 mmol) was added drowpwise to a solution of
diphenyldisulfane 2a (54.6 mg, 0.25 mmol) and I2 (31.7 mg,
0.125 mmol) in 2.0 mL of DMSO. Then the mixture was stirred
at 120 oC for 16 hours. Then the reaction mixture was
evaporated in vacuum, and the desired product 3a was obtained
by silica gel column chromatography using ethyl
acetate/hexane as an eluent in the yield of 92% (87.4 mg).
1-methyl-2-((3-nitrophenyl)thio)-1H-imidazole
(3h)13c
:
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 3/1, Rf = 0.3). The title compound was
1
1-methyl-2-(phenylthio)-1H-imidazole (3a)16: Isolated by flash
column chromatography (petroleum ether/ethyl acetate = 2/1,
Rf = 0.4). The title compound was obtained as a colorless liquid
obtained as a yellow solid (88%, 103.9 mg); H NMR (400
MHz, CDCl3) δ 8.10 (d, J = 8.8 Hz, 2H), 7.28 (s, 1H), 7.20 (s,
1H), 7.13 (d, J = 8.4 Hz, 2H), 3.70 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 145.95, 145.37, 135.06, 131.14, 126.43, 124.75,
124.31, 33.95; MS (m/z): 236.1 (M+).
1
(92%, 87.4 mg); H NMR (400 MHz, CDCl3) δ 7.25-7.21 (m,
2H), 7.16-7.11 (m, 4H), 7.06 (s, 1H), 3.61 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 137.95, 134.92, 130.14, 129.26, 127.92,
126.56, 123.92, 33.87; MS (m/z): 191.0 (M+).
1-methyl-2-((2-nitrophenyl)thio)-1H-imidazole (3i): Isolated
by flash column chromatography (petroleum ether/ethyl acetate
= 3/1, Rf = 0.4). The title compound was obtained as a yellow
solid (74%, 87.0 mg); 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J
= 8.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.32-7.27 (m, 2H), 7.21
(s, 1H), 6.59 (d, J = 8.4 Hz, 1H), 3.68 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 145.04, 136.82, 136.38, 134.15, 131.26, 127.73,
126.09, 126.00, 124.73, 33.93; HRMS (ESI): [M + H]+ calcd
for [C10H9N3O2S]: 235.0421, found: 235.0415.
1-methyl-2-(p-tolylthio)-1H-imidazole (3b)1c: Isolated by flash
column chromatography (petroleum ether/ethyl acetate = 3/1,
Rf = 0.3). The title compound was obtained as a colorless liquid
1
(97%, 99.3 mg); H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H),
7.39 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H),
3.53 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
140.79, 137.89, 136.15, 132.65, 129.98, 126.89, 31.56, 20.91;
MS (m/z): 205.1 (M+).
1-butyl-2-(phenylthio)-1H-imidazole (3j): Isolated by flash
column chromatography (petroleum ether/ethyl acetate = 2/1,
Rf = 0.5). The title compound was obtained as a colorless liquid
2-((4-methoxyphenyl)thio)-1-methyl-1H-imidazole
(3c):17c
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 1/1, Rf = 0.4). The title compound was
1
(96%, 111.5 mg); H NMR (400 MHz, CDCl3) δ 7.28-7.19 (m,
1
6H), 7.09 (s, 1H), 4.00 (t, J = 7.2 Hz, 2H), 1.65-1.58 (m, 2H),
obtained as a yellow oil (93%, 102.1 mg); H NMR (400 MHz,
1.30-1.21 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (100
CDCl3) δ 7.31-7.28 (m, 2H), 7.15 (s, 1H), 7.03 (s, 1H), 6.86-

5
MHz, CDCl3) δ 129.77, 129.26, 128.47, 126.83, 122.34, 99.99,
125.97, 47.10, 23.75; HRMS (ESI): [M + H]+ calcd for
46.99, 32.81, 19.66, 13.50; HRMS (ESI): [M + H]+ calcd for [C12H14N2S]: 218.0884, found: 218.0881.
[C13H16N2S]: 232.1040, found: 232.1032.
1-butyl-2-((4-chlorophenyl)thio)-1H-imidazole (3k)24: Isolated
by flash column chromatography (petroleum ether/ethyl acetate
= 3/1, Rf = 0.3). The title compound was obtained as a colorless
liquid (93%, 123.8 mg); 1H NMR (400 MHz, CDCl3) δ 7.72 (s,
1H), 7.41 (s, 1H), 7.21-7.13 (m, 4H), 3.95-3.93 (m, 2H), 1.61-
1.58 (m, 2H), 1.27-1.24 (m, 2H), 0.87-0.84 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 140.40, 139.38, 132.89, 130.41, 130.11,
129.47, 113.94, 45.94, 32.99, 19.66, 13.46; HRMS (ESI): [M +
H]+ calcd for [C13H15ClN2S]: 266.0650, found: 266.0643.
4.3 Experimental Procedure for 5a and characterization data
of 5a-5p
Typical procedure for the synthesis of 1-Methyl-2-
(phenylseleno)-1H-imidazole 3a: 1-methyl-1H-imidazole 1a
(45.2 mg, 0.55 mmol) was added drowpwise to a solution of
diphenyl diselenide 4a (78.1 mg, 0.25 mmol) and I2 (31.7 mg,
0.125 mmol) in 2.0 mL of DMSO. Then the mixture was stirred
at 100 oC for 8 hours. Then the reaction mixture was evaporated
in vacuum, and the desired product 5a was obtained by silica
gel column chromatography using ethyl acetate/hexane as an
eluent in the yield of 95% (113.1 mg).
1-butyl-2-((3-nitrophenyl)thio)-1H-imidazole (3l): Isolated by
flash column chromatography (petroleum ether/ethyl acetate =
2/1, Rf = 0.4). The title compound was obtained as a yellow
1
1-methyl-2-(phenylselanyl)-1H-imidazole (5a): Isolated by
flash column chromatography (petroleum ether/ethyl acetate =
2/1, Rf = 0.5). The title compound was obtained as a white solid
solid (89%, 123.4 mg); H NMR (400 MHz, CDCl3) δ 8.02-
8.00 (m, 1H), 7.97 (s, 1H), 7.44-7.43 (m, 2H), 7.27 (s, 1H),
7.18 (s, 1H), 4.04 (t, J = 7.2Hz, 2H), 1.70-1.63 (m, 2H), 1.31-
1.22 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 148.62, 138.55, 135.26, 133.00, 131.10, 129.93,
123.12, 121.92, 121.26, 47.03, 33.00, 19.63, 13.49; HRMS
(ESI): [M + H]+ calcd for [C13H15N3O2S]: 277.0891, found:
277.0886.
1
(95%, 113.1 mg); H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H),
7.40 (s, 1H), 7.23-7.13 (m, 5H), 3.58 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 140.92, 139.00, 131.52, 129.47, 129.23, 126.76,
32.75; HRMS (ESI): [M + H]+ calcd for [C10H10N2Se]:
238.0015, found: 238.0007.
1-methyl-2-(p-tolylselanyl)-1H-imidazole (5b): Isolated by
flash column chromatography (petroleum ether/ethyl acetate =
3/1, Rf = 0.4). The title compound was obtained as a white solid
1-butyl-2-((4-nitrophenyl)thio)-1H-imidazole (3m): Isolated by
flash column chromatography (petroleum ether/ethyl acetate =
3/1, Rf = 0.3). The title compound was obtained as a yellow
1
1
(98%, 123.6 mg); H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H),
solid (82%, 113.5 mg); H NMR (400 MHz, CDCl3) δ 8.09 (d,
7.37 (s, 1H), 7.12 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 7.2 Hz, 2H),
3.57 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
140.75, 138.73, 136.83, 130.24, 129.71, 127.54, 115.39, 32.72,
20.97; HRMS (ESI): [M + H]+ calcd for [C11H12N2Se]:
252.0172, found: 252.0166.
J = 8.0 Hz, 2H), 7.30 (s, 1H), 7.20-7.15 (m, 3H), 4.01 (t, J = 7.2
Hz, 2H), 1.71-1.63 (m, 2H), 1.31-1.22 (m, 2H), 0.87 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 145.96, 145.69,
134.46, 131.28, 126.47, 124.23, 123.31, 47.07, 33.01, 19.62,
13.48; HRMS (ESI): [M + H]+ calcd for [C13H15N3O2S]:
277.0891, found: 277.0886.
2-((2,6-dimethylphenyl)selanyl)-1-methyl-1H-imidazole (5c):
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 2/1, Rf = 0.5). The title compound was
obtained as a white solid (98%, 129.8 mg); 1H NMR (400 MHz,
CDCl3) δ 7.53 (s, 1H), 7.16-7.05 (m, 4H), 3.46 (s, 3H), 2.52 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 142.32, 139.82, 136.63,
130.28, 128.77, 128.32, 32.76, 24.07; MS (m/z): HRMS (ESI):
[M + H]+ calcd for [C12H14N2Se]: 266.0328, found: 266.0321.
1-butyl-2-(p-tolylthio)-1H-imidazole (3n): Isolated by flash
column chromatography (petroleum ether/ethyl acetate = 2/1,
Rf = 0.5). The title compound was obtained as a colorless liquid
1
(98%, 120.3 mg); H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H),
7.15-7.13 (m, 2H), 7.10-7.06 (m, 3H), 3.99 (t, J = 7.6 Hz, 2H),
2.29 (s, 3H), 1.65-1.58 (m, 2H), 1.30-1.21 (m, 2H), 0.87 (t, J =
7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 138.37, 137.01,
130.78, 130.00, 129.68, 129.12, 122.11, 46.90, 32.82, 20.99,
19.68, 13.52; HRMS (ESI): [M + H]+ calcd for [C14H18N2S]:
246.1197, found: 246.1194.
1-methyl-2-(naphthalen-1-ylselanyl)-1H-imidazole
(5d):
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 2/1, Rf = 0.4). The title compound was
1
obtained as a colorless liquid (99%, 142.1 mg); H NMR (400
N-(2-((1-butyl-1H-imidazol-2-yl)thio)phenyl)benzamide (3o):
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 1/1, Rf = 0.6). The title compound was
MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz,
1H), 7.76-7.72 (m, 2H), 7.61-7.49 (m, 3H), 7.30-7.26 (m, 1H),
7.14-7.13 (m, 1H), 3.56 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
141.06, 139.18, 134.05, 132.34, 130.34, 128.74, 127.87, 127.60,
126.75, 126.47, 126.13, 125.49, 32.82; HRMS (ESI): [M + H]+
calcd for [C14H12N2Se]: 288.0172, found: 288.0167.
1
obtained as a colorless liquid (99%, 173.1 mg); H NMR (400
MHz, CDCl3) δ 11.19 (s, 1H), 8.31-8.26 (m, 3H), 7.60 (d, J =
7.6 Hz, 1H), 7.56-7.50 (m, 3H), 7.43 (t, J = 7.6 Hz, 1H), 7.11-
7.08 (m, 2H), 6.97 (s, 1H), 4.12 (t, J = 7.6 Hz, 2H), 1.74-1.67
(m, 2H), 1.37-1.31 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.16, 141.39, 139.37, 134.96, 134.68,
131.72, 130.73, 128.90, 128.46, 128.19, 125.13, 124.73, 122.68,
121.79, 46.99, 33.12, 19.77, 13.60; HRMS (ESI): [M + H]+
calcd for [C20H21N3OS]: 351.1411, found: 351.1405.
2-(benzylselanyl)-1-methyl-1H-imidazole (5e)13c: Isolated by
flash column chromatography (petroleum ether/ethyl acetate =
3/1, Rf = 0.4). The title compound was obtained as a yellow
1
solid (96%, 121.4 mg); H NMR (400 MHz, CDCl3) δ 7.35 (s,
5H), 6.85 (s, 1H), 6.73 (s, 1H), 5.35 (s, 2H), 3.75 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 135.44, 128.95, 128.47, 128.36,
120.11, 118.50, 53.38, 37.31; MS (m/z): 253.0 (M+).
1-isopropyl-2-(phenylthio)-1H-imidazole (3p): Isolated by
flash column chromatography (petroleum ether/ethyl acetate =
1/1, Rf = 0.4). The title compound was obtained as a yellow oil
2-((4-chlorophenyl)selanyl)-1-methyl-1H-imidazole
(5f):
1
(32%, 34.6 mg); H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H),
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 2/1, Rf = 0.5). The title compound was
7.41 (s, 1H), 7.24-7.21 (m, 2H), 7.16-7.12 (m, 1H), 7.05-7.03
(m, 2H), 4.57-4.50 (m, 1H), 1.36 (d, J = 6.8Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 138.34, 137.39, 137.01, 129.11, 126.21,
1
obtained as a brown solid (93%, 126.1 mg); H NMR (400

6
Tetrahedron
MHz, CDCl3) δ 7.64 (s, 1H), 7.33 (s, 1H), 7.13-7.04 (m, 3H), 30.56; HRMS (ESI): [M + H]+ calcd for [C14H18N2Se]:
3.51 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.11, 139.20,
132.97, 131.75, 130.56, 129.70, 129.59, 129.11, 32.75; HRMS
(ESI): [M + H]+ calcd for [C10H9ClN2Se]: 271.9625, found:
271.9617.
280.0485, found: 280.0482.
1-methyl-2-(phenylselanyl)-1H-benzo[d]imidazole
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 2/1, Rf = 0.5). The title compound was
(5n):
1
1-butyl-2-(phenylselanyl)-1H-imidazole (5g): Isolated by flash
column chromatography (petroleum ether/ethyl acetate = 1/1,
Rf = 0.6). The title compound was obtained as a colorless liquid
obtained as a brown liquid (88%, 126.6 mg); H NMR (400
MHz, CDCl3) δ 7.79 (d, J = 7.2 Hz, 1H), 7.49-7.48 (m, 2H),
7.34-7.26 (m, 6H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
143.90, 143.54, 136.42, 132.31, 129.71, 128.32, 127.98, 123.35,
1
(97%, 135.7 mg); H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H),
7.40 (s, 1H), 7.20-7.14 (m, 5H), 3.93 (t, J = 7.2 Hz, 2H), 1.61- 122.47, 119.81, 109.59, 31.86; HRMS (ESI): [M + H]+ calcd
1.54 (m, 2H), 1.27-1.18 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H); 13C for [C14H12N2Se]: 288.0172, found: 288.0164.
NMR (100 MHz, CDCl3) δ 140.16, 139.06, 131.85, 129.38,
2-((4-chlorophenyl)selanyl)-1-methyl-1H-benzo[d]imidazole
(5o): Isolated by flash column chromatography (petroleum
129.21, 126.75, 45.97, 32.97, 19.66, 13.46; HRMS (ESI): [M +
H]+ calcd for [C13H16N2Se]: 280.0485, found: 280.0479.
ether/ethyl acetate = 3/1, Rf = 0.4). The title compound was
1
1-butyl-2-((4-chlorophenyl)selanyl)-1H-imidazole
(5h):
obtained as a colorless liquid (80%, 128.5 mg); H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 7.6 Hz,
2H), 7.31-7.23 (m, 5H), 3.75 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 143.71, 143.50, 136.45, 134.35, 133.67, 129.86,
126.40, 123.42, 122.50, 119.89, 109.58, 31.79; HRMS (ESI):
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 2/1, Rf = 0.4). The title compound was
1
obtained as a colorless liquid (95%, 148.7 mg); H NMR (400
MHz, CDCl3) δ 7.72 (s, 1H), 7.41 (s, 1H), 7.21-7.13 (m, 4H),
3.95-3.93 (m, 2H), 1.62-1.58 (m, 2H), 1.27-1.24 (m, 2H), 0.87- [M + H]+ calcd for [C14H11ClN2Se]: 321.9782, found: 321.9776.
0.84 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 140.40, 139.38,
1-methyl-2-(p-tolylselanyl)-1H-benzo[d]imidazole
(5p):
132.89, 130.41, 130.11, 129.47, 113.94, 45.94, 32.99, 19.66,
13.46; HRMS (ESI): [M + H]+ calcd for [C13H15ClN2Se]:
314.0095, found: 314.0087.
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 2/1, Rf = 0.5). The title compound was
1
obtained as a colorless liquid (91%, 137.1 mg); H NMR (400
1-butyl-2-(naphthalen-1-ylselanyl)-1H-imidazole
(5i):
MHz, CDCl3) δ 7.83-7.80 (m, 1H), 7.48-7.45 (m, 2H), 7.36-
Isolated by flash column chromatography (petroleum
ether/ethyl acetate = 2/1, Rf = 0.5). The title compound was
obtained as a white solid (99%, 162.6 mg); 1H NMR (400 MHz,
CDCl3) δ 8.21 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H),
7.73-7.70 (m, 2H), 7.60-7.51 (m, 2H), 7.47 (s, 1H), 7.28-7.24
(m, 1H), 7.15-7.13 (m, 1H), 3.90 (t, J = 7.2 Hz, 2H), 1.57-1.48
(m, 2H), 1.21-1.11 (m, 2H), 0.75 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 140.44, 139.53, 134.00, 132.32, 130.82,
7.29 (m, 3H), 7.12-7.10 (m, 2H), 3.78 (s, 3H), 2.33 (s, 3H); 13
C
NMR (100 MHz, CDCl3) δ 144.39, 138.45, 136.26, 133.04,
130.56, 123.94, 123.35, 122.59, 119.52, 109.55, 31.89, 21.16;
HRMS (ESI): [M + H]+ calcd for [C15H14N2Se]: 302.0328,
found: 302.0321.
Acknowledgements
128.71, 127.85, 127.47, 126.67, 126.39, 126.07, 125.45, 45.99, The authors thank the National Natural Science
32.98, 19.65, 13.42; HRMS (ESI): [M + H]+ calcd for Foundation of China (21802093, 21536003) for financial
[C17H18N2Se]: 330.0641, found: 330.0635.
support. We thank Rosalie Tran, PhD, from Liwen Bianji,
Edanz Editing China (www.liwenbianji.cn/ac), for editing
the English text of a draft of this manuscript.
1-butyl-2-(p-tolylselanyl)-1H-imidazole (5j): Isolated by flash
column chromatography (petroleum ether/ethyl acetate = 3/1,
Rf = 0.4). The title compound was obtained as a yellow liquid
1
References and notes
(99%, 150.0 mg); H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H),
7.39 (s, 1H), 7.13-7.06 (m, 4H), 3.95 (m, 2H), 2.30 (s, 3H),
1.60 (m, 2H), 1.25-1.24 (m, 2H), 0.85 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 140.03, 138.85, 136.77, 130.13, 129.61, 127.90,
114.80, 45.91, 32.98, 20.96, 19.68, 13.47; HRMS (ESI): [M +
H]+ calcd for [C14H18N2Se]: 294.0641, found: 294.0634.
1
2
3
4
(a) D. I. Shah, M. Sharma, Y. Bansal, G. Bansal, M. Singh, Eur. J.
Med. Chem. 2008, 43, 1808-1812. (b) R. Rossi, G. Angelici, G.
Casotti, C. Manzini and M. Lessi, Adv. Synth. Catal. 2019, 361,
2737-2803. (c) D. Kong, T. Huang, M. Wu and Q. Lin, Org. Biomol.
Chem. 2019, 17, 830-834.
,
,
,
(a) I. Kawasaki, M. Yamashita and S. Ohta, J. Chem. Soc., Chem.
Commun., 1994, 2085-2086. (b) I. Kawasaki, M. Yamashita and S.
1-isopropyl-2-(phenylselanyl)-1H-imidazole (5k): Isolated by
flash column chromatography (petroleum ether/ethyl acetate =
2/1, Rf = 0.4). The title compound was obtained as a yellow
liquid (78%, 103.3 mg); 1H NMR (400 MHz, CDCl3) δ 7.78 (s,
1H), 7.39 (s, 1H), 7.23-7.16 (m, 5H), 4.64-4.53 (m, 1H), 1.34
(d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 138.90,
137.24, 132.07, 130.27, 129.34, 129.03, 126.65, 48.21,
23.82; HRMS (ESI): [M + H]+ calcd for [C14H18N2Se]:
266.0328, found: 266.0322.
1-(tert-butyl)-2-(phenylselanyl)-1H-imidazole (5l): Isolated by
flash column chromatography (petroleum ether/ethyl acetate =
1/1, Rf = 0.5). The title compound was obtained as a yellow
liquid (55%, 76.5 mg); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J
= 1.2 Hz, 1H), 7.44-7.42 (m, 2H), 7.32-7.31 (m, 1H), 7.26-7.17
(m, 3H), 1.61 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 136.02,
132.90, 130.17, 129.01, 126.24, 125.21, 123.09, 55.59,
Ohta, Chem. Pharm. Bull.
Shen, J. Wang, H. Zhang, H.-Y. Zhao, M. Xin, Y.-X. Cao, Y. Li,
S.-Q. Zhang, Bioorg. Med. Chem. 2018, 26, 2173-2185.
(a) I. Kawasaki, H. Katsuma, Y. Nakayama, M. Yamashita and S.
Ohta, Heterocycles 1998, 48, 1887-1901. (b) Q. Liang, Y. Zhang,
M. Zeng, L. Guan, Y. Xiao and F. Xiao, Toxicol. Res. 2018, 7,
521-528. (c) B. Shi, Z. Zhu, Y.-S. Zhu, D. Zhou, J. Wang, P. Zhou
and H. Jing, Org. Biomol. Chem. 2016, 14, 2978-2984.
(a) I. Kawasaki, N. Taguchi, T. Yamamoto, M. Yamashita and S.
Ohta, Tetrahedron Lett. 1995, 36, 8251-8254. (b) I. Kawasaki, N.
Taguchi, T. Yamamoto, M. Yamashita and S. Ohta, Chem. Pharm.
Bull. 1997, 45, 1393-1398.
S. Ohta, N. Tsuno, S. Nakamura, N. Taguchi, M. Yamashita, I.
Kawasaki and M. Fujieda, Heterocycles 2000, 53, 1939-1955.
, 1996, 44, 1831-1837. (c) Y.-Y. Hei, Y.
,
,
,
,
,
,
5
6
,
S. Ohta, N. Tsuno, K. Maeda, S. Nakamura, N. Taguchi, M.
Fujieda, K. Futamura, T. Yoshida, M. Yamashita and I. Kawasaki,
Tetrahedron Lett.
S. Ohta, T. Yamamoto, I. Kawasaki, M. Yamashita, Y. Nagashima,
and T. Yoshikawa, Chem. Pharm. Bull. 1994, 42, 821-825.
, 2000, 41, 4623-4627.
7
,

7
8
9
V. Mathieu, E. Berge, J. Ceusters, T. Konopka, A. Cops, C.
Bruyere, C. Pirker, W. Berger, T. Trieu-Van, D. Serteyn, R. Kiss
18 (a) N.-B. Li, J. Yao, L. -X. Wang, J.-C. Wei, W. Liu, W. -Q. Liu,
X.-H. Xu, Z.-W. Liang, Inorg. Chem. Commun., 2018, 98, 99-104.
(b) S.-S. Wu, C.-T. Feng, D Hu, Y.-K. Huang, Z. Li, Z.-G. Luo, and
and R. Robiette, J. Med. Chem., 2013, 56, 6626-6637.
(a) S. Tsuji, K. L. Rinehart, S. P. Gunasekera, Y. Kashman, S. S.
S.-T. Ma, Org. Biomol. Chem., 2017, 15, 1680-1685. (c) D. Yang,
Cross, M. S. Lui, S. A. Pomponi and M. C. Diaz, J. Org. Chem.
1988, 53, 5446-5453. (b) S. Sakemi and H. H. Sun, J. Org. Chem.
1991, 56, 4304-4307.
,
,
K. Yan, W. Wei, J. Zhao, M. Zhang, X. Sheng, G. Li, S. Lu, and H.
Wang, J. Org. Chem., 2015, 80, 6083-6092. (d) L.-X. Wang, N.-B.
Li, H.-J. Wang, W. Liu, H.-P. Diao, X.-H. Xu, Chin. J. Org. Chem.,
2019, 39, 1802-1807. (e) C. Xia, Z. Wei, Y. Yang, W. Yu, H. Liao,
C. Shen, and P. Zhang, Chem. Asian J., 2016, 11, 360-366.
10 (a) X. Lei, Y. Wang, E. Fan and Z. Sun, Org. Lett.
1487. (b) D. J. Faulkner, Nat. Prod. Rep. 1992, 9, 323-364. (c) K.
Bartik, J. C. Breakman, D. Daloze, C. Stoller, J. Huysecom, G.
Vandevyver and R. Ottinger, Can. J. Chem. 1987, 65, 2118-2121.
11 (a) S. Nakamura, N. Tsuno, M. Yamashita, I. Kawasaki, S. Ohta
and Y. Ohishi, J. Chem. Soc., Perkin Trans. 1 2001, 429-436. (b) S.
Ohta, T. Yamamoto, I. Kawasaki, M. Yamashita, H. Katsuma, R.
, 2019, 21, 1484-
,
19 (a) C.-R. Liu, L.-H. Ding, Org. Biomol. Chem.
2254. (b) S. Sharma and A. Sharma, Org. Biomol. Chem.
4384-4405. (c) L. Bettanin, S. Saba, C. V. Doerner, M. S. Franco,
,
2015, 13, 2251-
,
,
2019, 17,
,
M. Godoi, J. Rafique, A. L. Braga, Tetrahedron, 2018, 74, 3971-
3980.
Nasako, K. Kobayashi and K. Ogawa, Chem. Pharm. Bull.
40, 2681-2685. (c) J. R. Lewis, Nat. Prod. Rep. 1992, 9, 81-101.
12 (a) B. Lin, C.-H. Lim and G. M. Miyake, J. Am. Chem. Soc. 2017
,
1992
,
20 (a) S.-Q. Chen, Q.-M. Wang, P.-C. Xu, S.-P. Ge, P. Zhong and X.-
H. Zhang, Phosphorus & Sulfur & the Related Elements 2016, 191,
100-103. (b) S. Zhang, P. Qian, M. Zhang, M. Hu, and J. Cheng, J.
Org. Chem. 2010, 75, 6732-6735. (c) D. Yang, P. Sun, W. Wei, L.
Meng, L. He, B. Fang, W. Jiang, and H. Wang, Org. Chem. Front.
2016, 3, 1457-1461. (d) W.-H. Bao, C. Wu, J.-T. Wang, W. Xia, P.
Chen, Z. Tang, X. Xu and W.-M. He, Org. Biomol. Chem. 2018
16, 8403-8407. (e) W.-H. Bao, M. He, J.-T. Wang, X. Peng, M.
,
,
,
,
139, 13616-13619. (b) C. Dai, Z.-Q. Xu, F. Huang, Z.-K. Yu and
Y.-F. Gao, J. Org. Chem. 2012, 77, 4414-4419.
13 (a) D. Hu, M. Liu, H. Wu, W. Gao and G. Wu, Org. Chem. Front.
2018, 5, 1352-1355. (b) Z.-S. Gu, W.-X. Chen and L.-X. Shao, J.
Org. Chem. 2014, 79, 5806-5811. (c) G. Roy and G. Mugesh, J.
Am. Chem. Soc., 2005, 127, 15207-15217. (d) J.-R. Huang, Q.-R.
Zhang, C.-H. Qu, X.-H. Sun, L. Dong and Y.-C. Chen, Org. Lett.
,
,
,
,
,
,
,
Sung, Z. Tang, S. Jiang, Z. Cao, W.-M. He, J. Org. Chem., 2019,
84, 6065-6071.
,
2013, 15, 1878-1881. (e) J. A. Jablonowski, K. S. Ly, M.
Bogenstaetter, C. A. Dvorak, J. D. Boggs, L. K. Dvorak, B. Lord, K.
L. Miller, C. Mazur, S. J. Wilson, T. W. Lovenberg, N. I.
21 (a) L.-Y. Xie, S. Peng, J.-X. Tan, R.-X. Sun, X. Yu, N.-N. Dai, Z.-L.
Tang, X. Xu, and W.-M. He, ACS Sustainable Chem. Eng. 2018, 6,
16976-16981. (b) W.-H. Bao, Z. Wang, X. Tang, Y.-F. Zhang, J.-X.
Tan, Q. Zhu, Z. Cao, Y.-W. Lin and W.-M. He, Chin. Chem. Lett.
,
Carruthers, Bioorg. Med. Chem. Lett.
14 (a) N. J. Curtis and R. S. Brown, J. Org. Chem.
4040. (b) B. T. Phillips, D. A. Claremon, S. L. Varga, Synthesis
1990, 9, 761-763. (c) G. Chauviere, B. Bouteille, B. Enanga, C.
,
2009, 19, 903-907.
,
,
1980, 45, 4038-
2019, DOI: 10.1016/j.cclet.2019.06.052. (c) C. Chen, P. Niu, Z.
Shen, and M. Li, J. Electrochem. Soc., 2018, 165, 67-74. (d) W. Ge
,
and Y. Wei, Green Chem.
Bao, Y. Song, J. Qu, B. Wang, Tetrahedron
22 (a) J. Chen, Z. Tang, R. Qiu, Y. He, X. Wang, N. Li, H. Yi, C.-T
Au, S.-F Yin, and X. Xu, Org. Lett. 2015, 17, 2162-2165. (b) N. Li,
,
2012, 14, 2066-2070. (e) H. Zhang, X.
Albuquerque, S. L. Croft, M. Dumas and J. Perie, J. Med. Chem.
2003, 46, 427-440.
,
,
2015, 71, 8885-8891.
15 I. M. Yonova, C. A. Osborne, N. S. Morrissette and E. R. Jarvo, J.
Org. Chem. 2014, 79, 1947-1953.
16 A.-X. Zhou, X.-Y. Liu, Y. Ke, S.-C. Zhao and Y.-M. Liang, Org.
Biomol. Chem. 2011, 9, 5456-5462.
17 (a) B. Y.-H. Tan, Y.-C. Teo, Tetrahedron
H.-L. Kao, C.-K. Chen, Y.-J. Wang and C.-F. Lee, Eur. J. Org.
Chem. 2011, 9, 1776-1781. (c) C.-K. Chen, Y.-W. Chen, C.-H. Lin, 23 D. Singh, A. M. Deobald, L. R. S. Camargo, G. Tabarelli, O. E. D.
H.-P. Lin, C.-F. Lee, Chem. Commun. 2010, 46, 282-284. (d) A. Rodrigues, A. L. Braga, Org. Lett. 2010, 12, 3288-3291.
24 N. W. Gilman, W. Y. Chen, Inc., 4973599 USA, 1990
,
,
J. Yao, L. Wang, J. Wei, W. Liu, W. Liu, X. Xu, Z. Liang, Inorg.
Chem. Commun., 2018, 98, 99-104. (c) X. Wang, R. Qiu, C. Yan, V.
,
P. Reddy, L. Zhu, X. Xu, S.-F Yin, Org. Lett.
(d) L. Wang, N. Li, H. Wang, W. Liu, H. Diao, X. Xu, Chin. J. Org.
Chem. 2019, 39, 1802-1807.
, 2015, 17, 1970-1973.
,
2016, 72, 6646-6653. (b)
,
,
,
,
Correa, M. Carril and C. Bolm, Angew. Chem. Int. Ed., 2008, 47,
.
2880-2883.

Highlights
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A convenient and metal-free protocol for the synthesis of 2-arylthio(seleno)imidazoles.
This process is scalable and tolerates a wide spectrum of disulfides (diselenides).
This method showed considerable advantages such as simple operation, wide functional group
tolerance and good yields.
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A plausible mechanistic approach has also been proposed.

Oct. 7, 2019
Dear Editor,
No conflict of interest exists in the submission of this manuscript, and the manuscript
is approved by all authors for publication. I would like to declare on behalf of my
co-authors that the work described is original and has not been published previously, and
not under consideration for publication elsewhere, in whole or in part. All the authors listed
have approved the contents of the manuscript.
Sincerely yours,
Xinhua Xu
Professor of State Key Laboratory of Chemo/Biosensing and Chemometrics
College of Chemistry and Chemical Engineering
Hunan University, Changsha 410082, P. R. China
E-mail: xhx1581@hnu.edu.cn