Direct selenation of imidazoheterocycles and indoles with selenium powder in a copper-catalyzed three-component one-pot system

Article abstract of DOI:10.1016/j.tetlet.2018.05.046

An efficient and convenient Cu-catalyzed three-component reaction is described for the selenation of imidazoheterocycles/indoles with Se powder and aryl iodides. This procedure provides diverse 3-arylselenylimidazoheterocycles and 3-arylselenylindoles with good yields and functional group tolerance. Some of the products exhibited better or comparable antiproliferative activities compared with the positive control 5-fluorouracil against H1975, PC-9, HGC-27, EC-109, and MCF-7 cancer cell lines.

Full text of DOI:10.1016/j.tetlet.2018.05.046

Accepted Manuscript
Direct selenation of imidazoheterocycles and indoles with selenium powder in
a copper-catalyzed three-component one-pot system
Tao Guo, Zhe Dong, Panke Zhang, Weiqin Xing, Liping Li
PII:
S0040-4039(18)30660-9
https://doi.org/10.1016/j.tetlet.2018.05.046
TETL 49993
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
29 March 2018
16 May 2018
18 May 2018
Please cite this article as: Guo, T., Dong, Z., Zhang, P., Xing, W., Li, L., Direct selenation of imidazoheterocycles
and indoles with selenium powder in a copper-catalyzed three-component one-pot system, Tetrahedron Letters
(2018), doi: https://doi.org/10.1016/j.tetlet.2018.05.046
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Direct selenation of imidazoheterocycles and indoles
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Tao Guo, Zhe Dong, Panke Zhang, Weiqin Xing, Liping Li

1
Tetrahedron Letters
Direct selenation of imidazoheterocycles and indoles with selenium powder in a
copper-catalyzed three-component one-pot system
Tao Guoa*, Zhe Dongc, Panke Zhangb, Weiqin Xinga, Liping Lia*
a College of Chemistry, Chemical and Environmental Engineering, Henan University of Technology, Zhengzhou, Henan 450001, P. R. China
b
College of Chemistry and Molecular Engineering, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, P. R.China
c National Institute for Food and Drug Control, Beijing, 100050, PR China.
ARTICLE INFO
ABSTRACT
An efficient and convenient Cu-catalyzed three-component reaction is described for the
selenation of imidazoheterocycles/indoles with Se powder and aryl iodides. This procedure
provides diverse 3-arylselenylimidazoheterocycles and 3-arylselenylindoles with good yields
and functional group tolerance. Some of the products exhibited better or comparable
antiproliferative activities compared with the positive control 5-fluorouracil against H1975, PC-
9, HGC-27, EC-109, and MCF-7 cancer cell lines.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
selenation
2009 Elsevier Ltd. All rights reserved.
imidazoheterocycles
indoles
C-H activation
Se-containing compounds have attracted much interest of
organic and medicinal chemists over the past few years.1 They are
prevalent in diverse drug candidates and bioactive compounds with
wide and interesting pharmacological properties such as antitumor,2
nature of substituent at the 3-position of imidazo ring.10 Recently,
much attention has been paid to incorporate Se into
imidazoheterocycles
to
synthesize
valuable
3-
selanylimidazoheterocycles.11 For instance, Hajra group developed a
synthetic method for 3-phenylselenylimidazo[1,2-a]pyridines
through the phenylselenylation of imidazo[1,2-a]pyridines using
phenylselenium bromide (Scheme 1a).11a Braga and co-workers
reported the synthesis of 3-selenylimidazo[1,2-a]pyridine derivatives
by iodine-catalyzed selenation of imidazo[1,2-a]pyridines with
diselenides.11b Liu group reported a visible-light-mediated aerobic
selenation of imidazo[1,2-a]pyridines with diselenides using FIrPic
as the photocatalyst (Scheme 1b).11c Recently, the use of Se powder,
a stable, odorless, commercially available, and easily handled
reagent, as a cross-coupling partner to construct C−Se bonds has led
to the development of a more attractive and straightforward
alternative Se reagent/selenation reaction.12 The use of Se powder
also allows an efficient synthesis of organoselenium compounds in
terms of atom economy. To achieve a library of Se-containing
compounds for drug development, our group developed a Cu-
catalyzed selenation of imidazoheterocycles with Se powder and
coumarinyl triflates (Scheme 1c).13 In continuation of our interest in
the development and application of heterocycle derivatives in
medicinal chemistry,14 herein, we report a Cu(OAc)2-catalyzed
selenation of imidazoheterocycles and indoles with Se powder to
afford 3-selenylimidazoheterocycle and 3-selenylindole derivatives
in good yields (Scheme 1d).
antioxidant,3
anti-inflammatory,4
enzyme inhibitory,5
and
antibacterial activities.6 In addition, organoselenium compounds are
useful catalysts and crucial building blocks in organic synthesis.7
Furthermore, organoselenium derivatives have demonstrated great
utility as fluorescent probes in materials science and
optoelectronics.8 Therefore, it is still highly desirable to develop
practical and environment-friendly synthetic methods for the
introduction of stable, convenient, and economical Se reagents into
organic structures.
Fig. 1 Examples of biologically active organoselenides.
Imidazoheterocycles are widely found in medicinal agents (such
as alpidem, necopidem, miroprofen, saripidem, zolpidem, and
zolimidine) and considered as privileged scaffolds.9 Generally, the
pharmacological activities of imidazoheterocycles depend on the

2
Tetrahedron Letters
6
CuI
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K3PO4
Na2CO3
Cs2CO3
KOH
KOH
KOH
KOH
KOH
DMAc
1,4-dioxane
DMF
59
61
74
49
38
65
82
48
32
62
48
76
68
72
79
7
CuI
8
CuI
9
CuSO4
DMF
10
11
12
13
14
15
16c
17d
18e
19f
CuO
DMF
CuBr2
DMF
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
20g
DMF
a
Reaction conditions: 1a (0.25 mmol), Se (0.5 mmol), 2a (0.375 mmol), catalyst (20
mol%), ligand (20 mol%), base (0.5 mmol), solvent (1 mL) in air, and 12 h at 120 °C. b
c
d
Isolated yields. Without ligand. bpy (20 mol%) was used. e 4,5-Diazafluoren-9-one
Scheme 1. Representative methods for the selenation of imidazoheterocycles
(20 mol%) was used. f At 130 oC . g 20 h.
A model reaction of 2-phenylimidazo[1,2-a]-pyridine (1a),
iodobenzene (2a), and Se powder was carried out to optimize various
reaction parameters. The results are shown in Table 1. First, the
reaction was carried out using CuI as the catalyst in DMSO without
any additive. The desired product 3a was obtained in 26% yield,
indicating that this reaction proceeded under a neutral condition. The
addition of a base and ligand helped in improving the efficiency of
reaction. For example, the yield of the desired product 3a increased
when KOH and phen were added to 1a (entries 2 and 3). The effect
of solvents on the efficiency of reaction was investigated under
similar reaction conditions. Only a trace amount of product was
observed when xylenes was used as the solvent (entry 4). When
NMP was used, the reaction did not proceed at all (entry 5). DMAc
and 1,4-dioxane were also poor solvents for this reaction, producing
product 3a in 59% and 61% yields, respectively (entries 6 and 7).
Among the solvents examined, DMF was the most effective,
affording 3a in 74% yield (entry 8). The catalyst also played a
crucial role. The yields were unsatisfactory with CuSO4 and CuO;
CuBr2 provided 3a in 65% yield (entries 9–11). Cu(OAc)2 was the
most suitable catalyst, affording the desired product 3a in 82% yield
(entry 12). A screening of base was also conducted; however, when
KOH was substituted with other bases such as K3PO4, Na2CO3, or
Cs2CO3, inferior results were obtained (entries 13–15). To improve
the yield of reaction, the effect of ligand was evaluated. The product
yield dramatically decreased when a ligand was not used (entry 16).
When phen was replaced with other ligands such as bpy and 4,5-
diazafluoren-9-one, lower yields were obtained (entries 17 and 18).
Other factors such as reaction temperature and time were also
investigated, but no improvement was achieved (entries 19 and 20).
Therefore, the conditions of entry 12 were selected as the optimized
reaction conditions.
With the optimized reaction conditions in hand, the substrate
scope of Cu-catalyzed regioselective C-3 selenation of
imidazoheterocycles 1 with Se powder and aryl iodides was
investigated. The results are shown in Table 2; the reaction worked
well for diverse substituted imidazoheterocycles, affording the
corresponding 3-selenylimidazoheterocycle derivatives in 58–83%
yields. Halogens on the benzene ring of imidazo[1,2-a]-pyridines
were tolerated well; for example, 2-(4-fluorophenyl)imidazo[1,2-
a]pyridine, 2-(4-chlorophenyl)imidazo[1,2-a]pyridine, and 2-(3-
bromophenyl)imidazo[1,2-a]pyridine provided the desired products
in 71% (3b), 80% (3c), and 65% (3d) yields, respectively. The
presence of a strong electron-withdrawing substituent such as nitro at
the phenyl ring slightly decreased the yield of 3e. Notably, thienyl,
n-pentyl, and cyclopropyl-substituted imidazo[1,2-a]pyridines were
also tolerated in this catalytic system, leading to efficient synthesis of
desired products 3f–3h in 84%, 79%, and 83% yields, respectively.
The yields of products 3i–3k showed that both electron-donating and
-withdrawing functionalities on the pyridine ring of imidazo[1,2-
a]pyridine slightly affect the reaction efficiency. Moreover, this
protocol could be applied to other imidazoheterocycles such as
imidazo[2,1-b]thiazole, affording the selenation product 3l in 67%
yield. To further explore the generality of this reaction, diverse
aryl iodides were examined in the reaction with 2-
phenylimidazo[1,2-a]pyridine 1a. Generally, under the optimized
conditions, electron-donating and -withdrawing substituents were
well tolerated without any electronic effect in this transformation.
Functional groups such as Me, OMe, F, Cl, and Br were suitable for
this protocol, furnishing the corresponding products 3m–3r in 70–
81% yields.
Table 2. Selenation of imidazoheterocycles with aryl iodidesab
Table 1. Optimization of reaction conditions
Entrya
Catalyst
CuI
Base
--
Solvent
DMSO
DMSO
DMSO
Xylenes
NMP
Yieldb (%)
1c
2c
3
26
41
CuI
KOH
KOH
KOH
KOH
CuI
65
4
CuI
trace
NR
5
CuI

3
a Reaction conditions: 4 (0.25 mmol), Se (0.5 mmol), 2 (0.375 mmol), Cu(OAc)2 (20
b
mol%), phen (20 mol%), KOH (0.5 mmol), NMP (1 mL) in air, and 12 h at 120 °C.
Isolated yields.
The in vitro antiproliferative activities of some compounds were
evaluated on five human cancer cell lines: H1975 (lung carcinoma),
PC-9 (lung carcinoma), HGC-27 (gastric carcinoma), EC-109
(esophageal carcinoma), and MCF-7 (breast carcinoma) by MTT
assay using a positive control 5-fluorouracil commonly used in the
clinical treatment of cancer. The biological results are shown in
Table 1. Most of these compounds exhibited comparable
antiproliferative activities with the positive control 5-fluorouracil.
Especially, compounds 3b, 3r, and 5d showed more potent
antiproliferative activities on PC-9, MCF-7, and H1975 cell lines,
respectively. These results show that our approach in designing
novel antiproliferative agents based on the framework of 3-
selenylimidazoheterocycles and 3-selenylindoles is good.
a Reaction conditions: 1 (0.25 mmol), Se (0.5 mmol), 2 (0.375 mmol), Cu(OAc)2 (20
b
mol%), phen (20 mol%), KOH (0.5 mmol), DMF (1 mL) in air, and 12 h at 120 °C.
Isolated yields.
After exploring the versatility and diversity of this Cu-catalyzed
C–Se bond formation via C–H bond activation, its application for the
selenation of other compounds was explored. The reactions of
indoles with Se powder and aryl iodides under the same reaction
conditions were examined. Fortunately, the selenation reaction of
indoles worked well, affording the desired 3-selenylindoles 5a–5j in
66–84% yields. These results indicate a broad substrate scope of our
selenation method that could be well applied to both N-H indole and
N-substituted indoles compared with the previous protocols.1f
Table 4. In vitro antiproliferative activity of products on H1975 (lung), PC-9 (lung),
HGC-27 (stomach), EC-109 (esophageal), MCF-7 (breast) cancer cell lines.
IC50 (μM)
compound
H1975
PC-9
HGC-27
EC-109
MCF-7
46.77±1.67
>80
6.35±0.80
>80
52.73±1.72
>80
43.19±1.63
>80
21.10±1.32
>80
3b
Table 3. Selenation of indoles with aryl iodidesab
3f
>80
>80
>80
16.57±1.21
>80
>80
3i
>80
>80
>80
>80
3k
43.22±1.63
14.60±1.16
30.90±1.49
23.16±1.36
37.30±1.57
3.74±0.57
40.65±1.60
24.09±1.38
43.31±1.63
26.56±1.42
26.88±1.43
49.97±1.70
>80
35.12±1.59
11.05±1.04
45.47±1.65
20.99±1.32
>80
32.59±1.51
13.12±1.12
25.49±1.41
8.47±0.92
72.75±1.86
8.10±0.91
21.74±1.34
22.45±1.35
6.49±0.81
62.93±1.80
17.19±1.24
54.47±1.74
9.34 ±0.97
>80
3m
3n
3o
3r
>80
5c
29.31±1.47
>80
6.87±0.83
39.41±1.59
24.26±1.38
6.04±0.78
12.27±1.09
84.23±1.93
32.02±1.51
13.78±1.13
5d
5e
5g
>80
47.96±1.68
5-fluorouracil
To elucidate the mechanism of this reaction, several control
experiments were carried out as shown in Scheme 2. In the presence

4
Tetrahedron Letters
of radical scavenger 2,6-di-tert-butyl-4-methylphenol (BHT; 2.0
equiv), 3a was obtained in 78% yield, indicating that radical
intermediates are not involved in the coupling reaction. Treatment of
iodobenzene with Se powder under the standard reaction conditions
provided diphenyl diselenide 6 in 92% yield. Subsequently, the
combination of diphenyl diselenide 6 and 1a at 120 C in DMF
produced 3a in 80% yield, indicating that diselenide could be a
possible reaction intermediate. Based on these results and those of
previous studies,15 a tentative mechanism for the Cu(OAc)2-
catalyzed selenation is shown in Scheme 3. Initially, the reaction of
iodobenzene with Se generates intermediate A that probably exists in
equilibrium with diselenide 6. Then, 6 reacts with LCu(I)I, affording
a Cu(III)-tetracoordinated square planar sulfate B.16 Subsequent
attack at the C3 position of imidazoheterocycle generates
intermediate C. Rearomatization via C–H bond cleavage and
reductive elimination of C afford the product 3, LCuI, and the
selenol, which is oxidized to the diselenide, thus completing the
catalytic cycle.
of Grain (No. 24400042), the Colleges and Universities Key
Research Program Foundation of Henan Province (No. 17A150006),
the Science and Technology Foundation of Henan Province (No.
172102310621, 182102210091) and the Fundamental Research
Funds for the Henan Provincial Colleges and Universities in the
Henan University of Technology (No. 2015QNJH08) is greatly
appreciated. The authors are also thankful to Xingzhen Li, Henan
University of Technology, for her assistance in the NMR analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at
References and notes
1
(a) Mugesh G, Mont WW, Sies H, Chem. Rev. 2001; 101: 2125-2080;
(b) Nogueira CW, Zeni G, Rocha JBT, Chem. Rev. 2004; 104: 6255-
6286; (c) Ostrovidov S, Franck P, Joseph D, et al. J. Med. Chem. 2000;
43: 1762-1769; (d) Mondal S, Manna D, Mugesh G, Angew. Chem., Int.
Ed. 2015; 54: 9298-9302; (e) Sancineton L, Mariotti A, Bagnoli L, et al.
J. Med. Chem. 2015; 58: 9601-9614; (f) Luo D, Wu G, Yang H, et al. J.
Org. Chem. 2016; 81: 4485-4493; (g) Manjare ST, Kim Y, Churchill
DG, Acc. Chem. Res. 2014; 47: 2985-2998;
2
3
Guan Q, Han CM, Zuo DY, et al. Eur. J. Med. Chem. 2014; 87: 306–
315.
Savegnago L, Vieira AI, Seus N, et al. Tetrahedron Lett. 2013; 54: 40-
44
4
5
Parnham MJ, Sies H, Biochem Pharmacol. 2013; 86: 1248-1253
Engman L, Stern D, Frisell H, et al. Bioorg. Med. Chem. 1995; 3: 1255-
1262
6
7
Li X, Liu Y, Wu J, et al. Thermochim Acta. 2001; 375: 109-113
(a) Ando T, Kwon TS, Kitagawa A, et al. Macromol. Chem. Phys. 1996;
197: 2803-2010; (b) Khanna PK, Das BK, Mater. Lett. 2004; 58: 1030-
1034; (c) Santoro S, Santi C, Sabatini M, et al. Adv. Synth. Catal. 2008;
350: 2281-2884; (d) Freudendahl DM, Santoro S, Shahzad SA, et al.
Angew. Chem. Int. Ed. 2009; 48: 8409-8411
Scheme 2. Control experiments
8
9
(a) Rampon DS, Rodembusch FS, Schneider JMFM, et al. J. Mater.
Chem. 2010; 20: 715-722; (b) Samb I, Bell J, Toullec PY, et al. Org.
Lett. 2011; 13: 1182-1185; (c) Goswami S, Hazra A, Chakrabarty R, et
al. Org. Lett. 2009; 11: 4350-4353; (d) Tang B, Xing Y, Li P, et al. J.
Am. Chem. Soc. 2007; 129: 11666-11667
(a) Bagdi AK, Santa S, Monir K, et al. Chem. Commun. 2015; 51:
1555–1575; (b) Cai D, Byth KF, Shapiro GI, Cancer Res. 2006; 66:
435–444; (c) Byth KF, Geh C, Forder CL, et al. Mol. Cancer Ther.
2006; 5: 655–664; (d) Enguehard-Gueiffier C, Gueiffier A, Mini-Rev.
Med. Chem. 2007; 7: 888-899; (e) Barradas JS, Errea MI, D’Accorso
NB, et al. Eur. J. Med. Chem. 2010; 46: 259-264; (f) Juspin T, Laget M,
Terme T, et al. Eur. J. Med. Chem. 2010; 45: 840-845; (g) Hamdouchi
C, Blas J, Prado M, et al. J. Med. Chem. 1999; 42: 50-59; (h) Lhassani
M, Chavignon O, Chezal J, et al. Eur. J. Med. Chem. 1999; 34: 271-274;
(i) Ali A, Cablewski T, Francis CL, et al. Bioorg. Med. Chem. Lett.
2011; 21: 4160-4163.
10 (a) Li Z, Hong J, Zhou X, Tetrahedron. 2011; 67: 3690-3697; (b)
Hiebel M, Berteina-Raboin S, Green Chem. 2015; 17: 937–944; (c) Gao
Z, Zhu X, Zhang R, RSC Adv. 2014; 4: 19891–19895; (d) Bagdi AK,
Mitra S, Ghosh M, et al. Org. Biomol. Chem. 2015; 13: 3314–3320; (e)
Ji X, Zhou S, Chen F, et al. Synthesis. 2015; 47: 659–671; (f) Ravi C,
Mohan DC, Adimurthy S, Org. Biomol. Chem. 2016; 14: 2282–2290; (g)
Ding Y, Xie P, Zhu W, et al. RSC Adv. 2016; 85: 81932-81935
11 (a) Jana S, Chakraborty A, Mondal S, et al. RSC Adv. 2015; 5: 77534-
77537; (b) Rafique J, Saba S, Rosário AR, et al. Chem. Eur. J. 2016; 22:
11854-11862; (c) Zhang Q, Ban Y, Yuan P, et al. Green Chem. 2017;
19: 5559-5563; (d) Redon S, Kosso ARO, Broggi J, et al. Tetrahedron
Lett. 2017; 58: 2771-2773; (e) Lim Z, Hong J, Zhou X, Tetrahedron.
2011; 67: 3690-3697; (f) Rafique J, Saba S, Franco MS, et al. Chem.
Eur. J. 2018; 24: 4173-4180
Scheme 3. Proposed mechanism.
A practical and efficient approach was developed for the Cu-
catalyzed selenation of imidazoheterocycles and indoles with Se
powder to afford diverse 3-selenylimidazoheterocycles and 3-
selenylindoles in good yields. This protocol has a broad substrate
scope and offers a simple coupling approach for the direct formation
of C–Se bonds using Se powder as the coupling partner, making it
attractive for the efficient synthesis of organoselenium compounds.
Importantly, the method can be added to the current pharmaceutical
chemistry tool box, as some of the obtained compounds exhibited
good antitumor activities.
12 Gao C, Wu G, Min L, et al. J. Org. Chem. 2017; 82: 250-255
13 Guo T, Wei X, Wang H, et al. Org. Biomol. Chem. 2017; 15: 9455-9464
14 (a) Guo T, Wei X, Synlett. 2017; 28: 2499-2504; (b) Guo T, Synthetic
Commun. 2017; 47: 2053-2061
15 (a) Stein AL, Alves D, Rocha JT, et al. Org. Lett. 2008; 10: 4983-4986;
(b) Guo T, Wang H, Synlett. 2017; 28: 1845-1851; (c) Fujiwara S,
Asanuma Y, Shin-ike T, et al. J. Org. Chem. 2007; 72: 8087-8090; (d)
Chakrabarty S, Choudhary S, Doshi A, et al. Adv. Synth. Catal. 2014;
356: 2135-2196; (e) Chen H, Peng W, Lee Y, et al. Organometallics
2013; 32: 5514-5522
Acknowledgments
Financial support from the National Natural Science Foundation
of China (41471253), the Open Project of the Grain&Corn
Engineering Technology Research Center in the State Administration

5
16 Paul S, Shrestha R, Edison TNJI, et al. Adv. Synth. Catal. 2016; 358:
3050-3056
Highlights
Cu-catalyzed selenation of imidazoheterocycles and
indoles
A
range of 3-selenylimidazoheterocycles/3-
selenylindoles are provided.
This methodology offers a facile approach for
direct C–Se bond formation.