Copper-catalyzed three-component one-pot synthesis of substituted 2-aryl-1,3-benzoselenazoles

Article abstract of DOI:10.1055/s-0034-1378934

A simple copper-catalyzed, one-pot synthesis of 2-aryl-1,3-benzoselenazole derivatives was developed using inexpensive, readily available 2-iodoanilines, selenium powder, and aromatic aldehydes as the starting materials. The mild reaction conditions and simple procedure without ligands and other additives make this methodology an alternative for preparing these potential selenium-containing compounds very conveniently.

Full text of DOI:10.1055/s-0034-1378934

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 215–220
letter
215
T. Su et al.
Letter
Synlett
Copper-Catalyzed Three-Component One-Pot Synthesis of Substi-
tuted 2-Aryl-1,3-benzoselenazoles
Tao Sua
Shishun Xiea
Bifu Lib
Jun Yana
Ling Huang*a
Xingshu Li*a
NH2
N
Cu (10 mol%), KOH
R1
R2
R2
R1
Se
+
+
O
DMSO, 120 °C , 36 h
Se
I
21 examples
up to 75% yield
a Institute of Drug Synthesis and Pharmaceutical Process, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
510006, P. R. of China
+
8
6
2
(
0
3
)
9
9
4
3
0
5
1
huangl72@mail.sysu.edu.cn
+
8
6
2
(
0
3
)
9
9
4
3
0
5
0
lixsh@mail.sysu.edu.cn
b College of Life Science and Technology, Southwest University for
Nationalities, Chengdu, 610041, P. R. of China
Received: 16.09.2014
Accepted after revision: 19.10.2014
Published online: 03.12.2014
nent synthesis gather the formation of several bonds in one
pot, without isolating the reaction intermediates, changing
the reaction conditions or supplementing other reagents.
Considering the potential importance of 2-aryl-substituted
benzoselenazoles, herein we report a novel, efficient, and
very simple one-pot strategy to achieve these compounds
with easily available ortho-halo anilines, benzaldehydes,
and selenium as starting materials catalyzed with copper.
DOI: 10.1055/s-0034-1378934; Art ID: st-2014-w0769-l
Abstract A simple copper-catalyzed, one-pot synthesis of 2-aryl-1,3-
benzoselenazole derivatives was developed using inexpensive, readily
available 2-iodoanilines, selenium powder, and aromatic aldehydes as
the starting materials. The mild reaction conditions and simple proce-
dure without ligands and other additives make this methodology an al-
ternative for preparing these potential selenium-containing compounds
very conveniently.
NH2
R1
Schneider's work
Key words multicomponent reactions, heterocycle, 2-aryl-1,3-ben-
Se
2
R2
zoselenazoles
Se0
O
Na2S2O5
n-BuLi, K3Fe(CN)6
Selenium-containing compounds have attracted much
attention as potential pharmaceuticals,1–11 synthetic inter-
mediates,12–15 and catalysts16,17 in organic synthesis during
the last decades. Among them, 2-aryl-substituted ben-
zoselenazoles are one of the important frameworks of sele-
catalysis, Se0,
N
R2
NH2
I
O
R2
R1
R1
Se
2-aryl-1,3-benzoselenazoles
this work: direct approach
nium-containing
heterocycles
because
of
their
pharmacologically and other applications.18–21 However,
there are limited reports on the preparation of this kind of
compounds despite their potential importance. In 2007,
Kambe and co-workers described the synthesis of 2-phe-
nyl-1,3-benzoselenazoles by copper iodide catalyzed cross-
coupling reaction and then with aryl Grignard reagent and
nickel dichloride.21 Very recently, Schneider reported the
synthesis of substituted 2-aryl-1,3-benzoselenazoles from
bis(2-aminophenyl)diselenides and arylaldehydes, using
Na2S2O5 as additive, where the starting material diselenide
was prepared by the reaction of 2-iodoaniline with n-BuLi,
and then, with elemental selenium and potassium ferrocya-
nide (Scheme 1).18
PhMgBr
NC
Seo, NuH
NiCl2
when Nu = SR
N
Nu
CuI (1 mol%)
X
Se
X = Br, I
Kambe's work
Scheme 1 Methods for the synthesis of 2-aryl-1,3-benzoselenazoles
We initiated our study by examining the three-compo-
nent cascade reaction using 2-iodoaniline, selenium pow-
der, and benzaldehyde in the presence of copper chloride
and potassium hydroxide at 120 °C in DMSO (Table 1, entry
2). Unfortunately, not any new compounds were observed
except of Schiff base formed from benzaldehyde and 2-io-
doaniline. Copper sulfate and copper bromide gave no
products under the same reaction conditions. Keeping on
Multicomponent reactions (MCR) represent an attrac-
tive and powerful strategy in diversity-oriented synthesis
of heterocycles.22–27 Compared with the classical step-by-
step reaction to give the target product, the multicompo-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 215–220

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T. Su et al.
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Synlett
Table 1 Screening Catalysts and Reaction Conditions for the Catalytic
to affect the reaction, a lower reaction temperature and
shorter reaction time induced the decrease of the yields
(Table 1, entries 17 and 18).
Three-Component Reactiona
I
N
catalyst, base
solvent
Further examination of this one-pot strategy’s substrate
scope under the optimized conditions revealed that the
strategy was widely applicable (Scheme 2). Expanding the
reaction to other 2-iodoanilines and aldehydes, different 2-
aryl-1,3-benzoselenazoles were obtained with moderated
to good yields. The yields of twelve products (3aa, 3ab, 3ac,
3ba, 3ca, 3da, 3ah, 3aj, 3al, 3an, 3aq, 3ar) were more than
60%. It is also indicated that steric hindrance of the substi-
tuted groups affects the reaction effectively. The para- and
meta-nitrobenzaldehyde reacted with aniline and selenium
to provide good yields of 3ab and 3ac (71% and 75% yields,
respectively), while no product was obtained from the reac-
tion of ortho-nitrobenzaldehyde under the same condi-
tions. The electronic effect is another important factor to
affect the reaction. Substituted 2-iodoanilines and alde-
hydes containing electron-withdrawing groups, such as ni-
tro and halogen, in aldehyde moiety seem favorable for the
yields (Scheme 2, 3ab, 3ac, 3aj, 3ai, 3al). On the contrary,
electron-donating groups on the aldehyde moiety gave rela-
tively lower yields (Scheme 2, 3ae–3ah, 3ak). Aromatic het-
erocyclic aldehydes, such as pyridinecarboxaldehydes 2n
and 2o, 2-thienaldehyde (2q), and 1-methylindole-2-car-
boxaldehyde (2r) were also suitable for the one-pot, three-
component reaction, which provide the corresponding
products in moderate to good yield (44–75%, 3an, 3ao, 3aq,
3ar).
O
Se
+
+
Se
NH2
1a
Entry
2a
3aa
Catalyst
–
Solvent
Base
Yield of 3aa
(%)b
1
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
KOH
–
2
CuCl2·2H2O
CuCl2·2H2Oc
CuSO4·5H2O
CuBr2
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
NaOH
KOH
KOH
KOH
KOH
–
3
–
4
–
5
–
6
CuI
53
52
41
59
36
72
68
27
61
67
–
7
CuIc
8
Cu(OAc)2
CuO
9
10
11
12
13
14
15
16
17d
18e
Cu2O
Cu (powder)
Cu(OTf)2
Cu (powder)
Cu (powder)
Cu (powder)
Cu (powder)
Cu (powder)
Cu (powder)
toluene
DMSO
DMSO
65
61
To investigate the reaction mechanism, we have ex-
plored the possible reaction pathway and intermediates
(Scheme 3). First, 2-iodoaniline reacted with benzaldehyde
in the presence of selenium powder only to produce Schiff
base 4 in good yield without copper (Scheme 3,A). On the
other hand, the reaction of 2-iodoaniline with selenium
powder in presence of copper gave bis(2-aminophe-
nyl)diselenide28 (5) in good yield (82%, Scheme 3,B). The pu-
rified intermediate 5 reacted with benzaldehyde in DMSO
to provide the target product 3aa and intermediate 6
(Scheme 3,C), which proceeded well in the absence of cata-
lyst. To further explore the detailed reaction process, GC–
MS was used to detect the proposed intermediates for this
reaction. The intermediate 5 and 6 were detected when the
reaction proceeded for 6–12 hours (see the Supporting In-
formation), which were converted into the target com-
pound 3aa in the absence of catalyst (Scheme 3,D, 72%
yield) with the prolonged reaction time of 36 hours. Anoth-
er control experiment (Scheme 3,E) was also carried out to
investigate the role of the copper catalyst in the reaction D,
and the result revealed that the copper has no effect on the
reaction.
a Reaction conditions: 2-iodoaniline (0.5 mmol), benzaldehyde (0.6 mmol),
selenium powder (1.5 mmol), KOH (1.0 mmol), catalysts (0.05 mmol),
120 °C, 36 h, under insert gas atmosphere.
b Isolated yield.
c 1,10-Phenanthroline was added.
d At 100 °C.
e For 24 h.
screening we found that copper(I) iodide as the catalyst
provide 53% yield of the product 2-phenyl-1,3-ben-
zoselenazole. These result inspired us to devote more emo-
tion to other copper resources, and the results are
summarized in Table 1. Among the different copper cata-
lysts tested, copper powder (Table 1, entry 11, 72% yield)
gave the best result, which was superior to that of CuI,
Cu(OAc)2 (41%), CuO (59%), Cu2O (36%), and Cu(OTf)2 (68%).
1,10-Phenanthroline ligand was tested for acceleration of
the reaction, but the results indicated no significant yields
improvement (Table 1, entry 6 vs. 7). Base and solvent
screening revealed that KOH was optimal and DMSO was
the most suitable (Table 1, entries 13–16). Interesting,
when the solvent changed to toluene (Table 1, entry 16),
not any product was obtained. This result reminds us that
the redox reaction may takes place as DMSO possesses oxi-
dation. Reaction temperature and time were other factors
Based on our observations and previous literature,18,28–31
a plausible mechanism is outlined in Scheme 4 with the
generation of 3aa32 as the example.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 215–220

217
T. Su et al.
Letter
Synlett
NH2
N
Cu (10 mol%), KOH
DMSO, 120 °C, 36 h
R1
R2
Se
+
R2
+
R1
O
Se
I
1
2
3
NO2
N
N
N
NO2
Se
Se
Se
3aa, 72%
3ab, 75%
3ac, 71%
O2N
N
Cl
N
N
Se
Se
Se
Cl
3ad, 0%
3ba, 74%
3ca, 70%
N
N
N
OMe
Se
Se
Se
3af. 57%
F
3da, 71%
3ae, 51%
OMe
OMe
N
N
N
Cl
F
Se
Se
Se
3ah, 62%
3aj, 64%
3ai, 58%
O
N
N
N
NMe2
CN
NH
Se
Se
3al, 64%
Se
3am, 58%
3ak, 29%
N
N
N
N
N
Se
Se
Se
3an, 61%
3ao, 44%
3ap, 56%
OMe
N
N
F
N
OMe
Se
N
Se
S
Se
Me
3aq, 67%
3ar, 75%
3eg, 48%
OMe
OMe
N
Se
MeO
3fh, 52%
Scheme 2 Copper-catalyzed, three-component formation of 2-aryl-1,3-benzoselenazoles. Reaction was performed with 0.5 mmol of 1, 0.6 mmol of 2,
1.5 mmol of selenium powder, 1.0 mmol of KOH, and 0.05 mmol of Cu powder, in 1.5 mL of DMSO at 120 °C for 36 h. Isolated yields are reported.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 215–220

218
T. Su et al.
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Synlett
NH2
I
N
KOH
DMSO, 120 °C,10 h
O
+
Se
A
B
+
I
1a
1a
4 (90%)
NH2
I
NH2
Cu (10 mol%), KOH
DMSO, 120 °C, 5 h
+
Se
Se
2
5 (82%)
NH2
Se
N
N
Se
O
+
C
+
DMSO, 120 °C 12 h
Se
2
2
5
6
3aa (25%)
NH2
Se
N
O
O
D
E
+
Se
DMSO, 120 °C 36 h
2
3aa (72%)
5
5
NH2
Se
N
Cu (10 mol%)
+
DMSO, 120 °C 36 h
Se
2
3aa (70%)
Scheme 3 Investigation of the reaction pathway
The reaction of 2-iodoaniline with selenium in the pres-
ence of copper powder produces bis(2-aminophenyl)disele-
nide (5), which reacts with the benzaldehyde to form the
imine diselenide compound 6. Finally, the homolytic cleav-
age of the imine diselenide 6 generates a radical which cy-
clize to provide the target product 3aa. The generation
pathway of other 2-aryl-1,3-benzoselenazole is similar to
3aa.
ucation of China (20120171120045) and the Opening Project of
Guangdong Provincial Key Laboratory of New Drug Design and Evalu-
ation (2011A060901014) for financial support of this study.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378934.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
In conclusion, we have developed a simple one-pot mul-
ticomponent strategy for the synthesis of 2-aryl-1,3-ben-
zoselenazole derivatives using inexpensive, readily
available 2-iodoanilines, selenium powder, and aromatic al-
dehydes as the starting materials. The mild reaction condi-
tions, simple procedure without ligands and other
additives, and good chemical yields make this methodology
an alternative approach for preparing these potential sele-
nium-containing compounds very conveniently.
References and Notes
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We thank the Natural Science Foundation of China (No. 21302235,
20972198) and the Ph.D. Programs Foundation of the Ministry of Ed-
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Letter
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OH–
Se2–
2–
+
Se0
+
SeHO3
H2O
+
Se0
2–
Se2
NH2
Cu
I–
I
NH2
Cu
NH2
–
Se2
I
Cu
1
NH2
Se
NH2
O
-
Se2
2
5
NH2
Cu
I
N
N
Se
N
2
cyclization
6
Se
•
Se
3aa
Scheme 4 Plausible reaction mechanism for the formation of 2-phenyl-1,3-benzoselenazole (3aa)
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(32) Typical Procedure for the Synthesis of 2-Aryl-1,3-ben-
zoselenazole 3aa
To a solution of 2-iodoaniline (0.5 mmol) and benzaldehyde (0.6
mmol) in dry DMSO (1.5 mL), selenium powder (1.5 mmol), cat-
alyst (0.05 mmol), and KOH (1.0 mmol) were added, the reac-
tion mixture was stirred in
a sealed tube under argon
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atmosphere at 120 °C for 36 h. After the reaction was finished,
the mixture was cooled to r.t., diluted with sat. aq NH4Cl (15
mL), and extracted with EtOAc (3 × 10 mL). The organic layer
was dried over Na2SO4, and the solvent was removed under
reduced pressure. The residue was purified by silica gel column
chromatography to afford the corresponding product 3aa.
White solid; mp 116.2–117.1 °C. 1H NMR (400 MHz, CDCl3): δ =
8.12 (d, J = 8.0 Hz, 1 H), 8.06–7.98 (m, 2 H), 7.94 (d, J = 7.8 Hz, 1
H), 7.50–7.46 (m, 4 H), 7.31 (t, J = 7.5 Hz, 1 H). 13C NMR (101
MHz, CDCl3): δ = 172.47, 155.85, 138.33, 136.20, 131.03, 129.06,
128.01, 126.39, 125.26, 124.86, 124.82. HRMS: m/z [M + H]+
calcd for C13H10NSe: 259.9973; found: 259.9948.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 215–220

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