Lewis acid-promoted formation of benzoselenazole derivatives using SeO2as a selenium source

Article abstract of DOI:10.1039/d1ob01070k

A new one-pot method of using bothortho-inactivated anilines and acetophenones (or methylquinolines) which possess an active H in the α-position of ketones (or benzyl positions) as starting materials to make benzoselenazole derivatives has been developed, which uses SeO₂as a selenium agent. This method first establishes SeO₂as a source of selenium to form benzoselenazole derivatives, which enriches the synthesis method of benzoselenazole. This method has several advantages, including good yields, simple operation, and availability of raw materials. Furthermore, the reaction could be easily scaled and its practical value in organic synthesis is displayed.

Full text of DOI:10.1039/d1ob01070k

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Lewis acid-promoted formation of benzoselenazole
derivatives using SeO2 as a selenium source†
Minhui Hu *a and Yaokun Ren*b
Cite this: Org. Biomol. Chem., 2021,
19, 6692
A new one-pot method of using both ortho-inactivated anilines and acetophenones (or methylquinolines)
which possess an active H in the α-position of ketones (or benzyl positions) as starting materials to make
benzoselenazole derivatives has been developed, which uses SeO2 as a selenium agent. This method first
establishes SeO2 as a source of selenium to form benzoselenazole derivatives, which enriches the syn-
thesis method of benzoselenazole. This method has several advantages, including good yields, simple
operation, and availability of raw materials. Furthermore, the reaction could be easily scaled and its practi-
cal value in organic synthesis is displayed.
Received 2nd June 2021,
Accepted 2nd July 2021
DOI: 10.1039/d1ob01070k
rsc.li/obc
Many synthesis methods of benzoselenazole derivatives
have been reported, including photocatalysis,10 transition
Introduction
Selenium dioxide (SeO2) is often used as a mild oxidant for the metal catalysis,11 and so on. But almost all these methods
oxidation of the C–H bond on the α-position of carbonyl or directly or indirectly used ortho-activated 2-iodoaniline as a
allyl groups.1 In these Riley reactions, SeO2 only acts as an oxi- starting material, whereas other reaction partners are phenyl
dizing agent without introducing the selenium element into acetic acid/Se, benzyl chloride/Se,12 2-oxo-2-phenylacetic
the product structures. In addition, SeO2 can be also used as a acid,13 2-oxo-2-phenylacetaldehyde14 or Woollin’s reagent.15 In
selenium source to supply elemental selenium to make sel- 2020, Liang and co-workers16 reported that ortho-inactivated
enium-containing heterocycles. However, the reactions using aniline derivatives, selenium powder and aldehydes were cata-
SeO2 as both an oxidizing agent and a selenium source are lyzed by iodine to generate benzoselenazole derivatives
quite limited. On the other hand, selenium is a trace and (Scheme 1). Although other selenium sources have been used
important element that possesses different biological func- to achieve similar reactions, using SeO2 as a selenium agent is
tions in the human body,2 some organoseleniums even still an attractive method for preparing synthetic
possess anti-cancer,3 anti-immunity,4 anti-bacterial5 and anti- benzoselenazoles.
viral functions.6 Therefore, much effort has been expended to
Compared with previously reported methods, a new
develop new methods to make selenium-containing hetero- method is proposed for the one-step synthesis of benzoselena-
cycles or trying to introduce the Se element into the structures zole derivatives using anilines and acetophenones (methyl-
of some bioactive compounds or drugs. Among these quinolines) as starting materials. Here, SeO2 is employed not
methods, Se powder,7 RSeSeR, and KSeCN8 have often been only as an oxidant but also as a selenium source. In addition,
used as selenium sources.
the method also avoids using ortho-activated 2-iodoaniline to
Benzoselenazole is an important selenium-containing aro- make the benzoselenazole derivatives.
matic heterocycle, it is also a bioisostere of benzothiazole and
benzoxazole which are popular privileged moieties in some
marketed drugs and natural products.9 Therefore, synthetic
methods of generating benzoselenazole are highly valued, and
Results and discussion
are especially practical methods under mild conditions.
In order to screen the most suitable reaction conditions for
the reaction shown in Table 1, acetophenone, SeO2 and
p-methylaniline were used first as reactants (Table 1). Initially,
MgCl2 was chosen as catalyst, dissolved in DMSO, at 120 °C
under an air atmosphere for 12 h, and it was found that the
reaction gave two major products instead of one, product 3a
with a 40% yield and also 3a′ with a 37% yield (entry 1,
Table 1). When FeCl3 and ZnCl2 were used as catalysts, the
main product was 3a′ (entries 2 and 3). When using AlCl3 as a
aLaw School, Nanjing University, Hankou Road 22, Nanjing City, Jiangsu 210093,
China. E-mail: huminhui2015@163.com
bPharmacy School, Jiangsu University, Xuefu Road 301, Zhenjiang City, Jiangsu
212013, China. E-mail: ryk1517030@163.com
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1ob01070k
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a 46% yield of 3a′ (entry 5). Finally, using HCl as the acid cata-
lyst, 3a and 3a′ were not obtained (entry 6). From the previous
results it was decided that AlCl3 is the most suitable catalyst
for this reaction.
Then different solvents were screened for this reaction.
Using DMF, NMP, dioxane and CH3OH as the reaction solvent
at 120 °C gave 3a in yields of 52%, 60%, 43% and 13% (entries
7–10), respectively. This showed that NMP was a good solvent
to selectively make product 3a. Decreasing the temperature
from 120 °C to 100 °C in NMP led to a higher yield of 3a (entry
11), but continually decreasing the temperature led to a
reduction in the yield of 3a (entry 12). So, it was decided that
the most suitable reaction temperature is 100 °C. Increasing
the AlCl3 content of the reaction from 0.5 equivalent to 1.0
equivalent gave yields of 3a and 3a′ of 71% and 24% (entry 13),
respectively. Decreasing AlCl3 to 0.3 equivalents and 0.1
equivalents produced yields of 3a of 37% and 15% (entries 14
and 15), respectively. This result indicated that 0.5 equivalent
of AlCl3 gives the best outcomes for this reaction, so all the fol-
lowing reactions were carried out with 0.5 equivalent of AlCl3.
Without AlCl3 in the reaction, 3a′ with 56% yield is mainly gen-
erated (entry 16). When the reaction was carried out in a N2
atmosphere, the reaction gave a lower yield of 3a (entry 17).
After screening, the suitable conditions for making benzosele-
nazole derivatives were: acetophenone substrate (1.0 equiv.),
aniline (1.2 equiv.), SeO2 (1.2 equiv.), AlCl3 (0.5 equiv.) in anhy-
drous NMP solvent at 100 °C.
Scheme 1 Reported methods for synthesizing benzoselenazole
derivatives.
Table 1 Screening reactions of p-methylaniline with SeO2 and
acetophenonea,b
Under the selected optimum reaction condition (Table 1,
entry 11), the scope of the reaction was investigated by using
different substituted anilines and acetophenones to make ben-
zoselenazole derivatives (Table 2). Both the reactants have elec-
tron-donating and electron-withdrawing groups on their
structures.
Catalyst
(equiv.)
Temperature
(°C)
Yieldb (%)
3a/3a′
Entry
Solvent
When the substrates had either electron-donating (–Me,
–MeO) or electron-withdrawing (–Cl, –Br) substituents on the
aromatic ring, all the reactions proceeded well, giving 3a to 3j
in good yields. But the yields of the desired products (3k)
decreased when the aromatic ring had stronger electron-with-
drawing substituents (–NO2). Furthermore, the steric factor
has a negative influence on the reaction, for example, when
using o-methylacetophenone as the reactant, the reaction only
gave a yield of 57% for 3l. The reactivity of p-aminopyridine,
8-aminoquinoline and 2-fluoro-4-nitroaniline (3m–3o) was also
tested, and the yields of these reactions are not ideal due to
the reduction of the aniline analogs’ nucleophilicity.
Next, methylquinolines were chosen as substrates to test
the method. As a reactant, methylquinolines have similar pro-
perties to acetophenone (Table 3). In this study, 2-methyl-
quinoline and p-methylaniline were used as substrates, and
the best result (5a, 55% yield) was obtained at 120 °C, and
then other substrates were used to explore the scope of the
substrates. When using 2-methylquinoline as the reactant, the
conversion rate is high but the yield of the desired product is
1
2
3
4
5
6
7
8
MgCl2 (0.5)
FeCl3 (0.5)
ZnCl2 (0.5)
AlCl3 (0.5)
BF3·Et2O (0.5)
HCl (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (1.0)
AlCl3 (0.3)
AlCl3 (0.1)
—
120
120
120
120
120
120
120
120
120
120
100
80
100
100
100
100
100
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
40/37
15/67
10/75
48/32
35/46
0/0
52/34
60/27
43/47
13/38
70/21
63/24
71/24
37/40
15/52
7/56
NMP
9
Dioxane
CH3OH
NMP
NMP
NMP
NMP
NMP
NMP
NMP
10
11
12
13
14
15
16
17c
AlCl3 (0.5)
45/20
a Reaction conditions: acetophenone (0.5 mmol, 1.0 equiv.), p-methyl-
aniline (1.2 equiv.), SeO2 (1.2 equiv.), anhydrous solvent (0.5 mL), in
air. Reaction time 12 h, temperature refers to the oil bath temperature.
b Isolated yields are based on reactant 1a. c In an N2 atmosphere.
catalyst in DMSO, it generated a mixture of 3a and 3a′ with only about 50% (5a–5d) because the N on 2-methylquinoline
48% and 32% yields, respectively (entry 4). Using BF3·Et2O (0.5 may form hydrogen bonds with H2O. It was pleasing to note
equiv.) as a catalyst in DMSO generated a 35% yield of 3a and that when aniline at different substitution positions reacted
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Table 2 Synthesis
acetophenonesa,b
of
benzoselenazole
derivatives
using
Table 3 Synthesis
methylquinolinesa,b
of
benzoselenazole
derivatives
using
a The reactions were carried out as follows: 2-methylquinoline analogs
(0.5 mmol, 1.0 equiv.), aniline analogs (1.2 equiv.), SeO2 (1.2 equiv.),
anhydrous NMP (0.5 mL), AlCl3 (0.5 equiv.), in air, at 120 °C, 12 h.
b Isolated yields are based on reactant 4.
a The reactions were carried out as follows: acetophenone analogs
(0.5 mmol, 1.0 equiv.), aniline analogs (1.2 equiv.), SeO2 (1.2 equiv.),
anhydrous NMP (0.5 mL), AlCl3 (0.5 equiv.), In air, at 100 °C, 12 h.
b Isolated yields are based on reactant 1.
with 4-methylquinoline, good yields of products (5e–5i) were
obtained. However, when 4-aminopyridine was used, both
reactions failed to give the desired products (5j and 5k). And
using 2-methylpyridine instead of methylquinoline did not
give the target under standard conditions (5l).
Next the reaction substrates were explored further. Firstly,
using 2-phenylethanol or styrene oxide instead of acetophe-
none as a substrate, the reaction only gave 10% and 12% of 3a,
respectively. Secondly, using phenylacetone, ethylbenzene and
styrene as the reaction substrates, the desired product 3a was
not obtained. Indole was also used instead of p-methylaniline
as a partner for the reaction under standard conditions, but
the reaction did not proceed. Also, when acetone was used as
the reaction substrate, it led to very complicated reaction
results due to the decomposition of p-methylaniline
(Scheme 2).
In addition, a gram-level reaction (1.0 g) was carried out to
further demonstrate the practical use of this transformation
(Scheme 3), which provided the desired product 3a with a yield
of 67%. This was almost equivalent to the yield obtained in a
0.5 mmol scale reaction.
Scheme 2 Researches on the reactivity of other substrates. The reac-
tions were carried out as follows: 6, 7, 8, 9, 10, 11, 1a (0.5 mmol, 1.0
equiv.), aniline analogs (1.2 equiv.), SeO2 (1.2 equiv.), anhydrous NMP
(0.5 mL), AlCl3 (0.5 equiv.), in air, at 100 °C, 12 h.
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phenylglyoxal (Scheme 4a). Next, using AlCl3 as the catalyst,
the reaction generated an 87% yield of 3aa (Scheme 4b). When
the phenylglyoxal was reacted with SeO2 or Se powder under
standard conditions, only 3a′ was obtained in high yield
(Scheme 4c and 4d). Finally, the reaction of 3aa and p-methyl-
aniline did not give the final product 3a.
Scheme 3 Gram-scale reaction.
Based on the control experiments and the mechanism of
Riley oxidation,17 a plausible reaction mechanism is suggested and
shown in Scheme 5. Initially, the aryl ketone reacts with AlCl3 to
attack the SeO2 to form the intermediate A. Then the intermediate
A constitutes intermediate B. Under the attack of aniline, one
molecule of oxygen is removed from IVSe which gives IISe, which
forms intermediate C, D is produced after attack by the aniline
rich electrons’ ortho-position, and finally D is oxidized by air to
give product 3. Due to the hydrogen bond, intermediate C will also
be attacked by water and finally produce 3′under air conditions.
Conclusions
In summary, for the first time the synthesis of benzoselenazoles
from SeO2 is reported. Compared with the previous method,
this method simplifies the operation, shortens the synthesis
steps, and prefers more available raw materials for synthesis,
such as benzoselenazole derivatives which are also much more
inexpensive. Moreover, this method could easily be used to
perform gram-scale reactions, and this greatly enriches the syn-
thesis of selenium-containing heterocycles. Because organic
selenide is a very important compound and SeO2 is an excellent
source of selenium, our laboratory will continue to explore the
reaction of SeO2 as a source of selenium.
Scheme 4 Control experiment.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The acknowledgements come at the end of an article after the
conclusions and before the notes and references.
Notes and references
1 (a) C. Foley, A. Shaw and C. Hulme, Org. Lett., 2018, 20,
1275–1278; (b) M. N. Truc and L. Daesung, Org. Lett., 2001,
3, 3161–3163.
2 (a) D. Thavarajah, A. Vandenberg, G. N. Georeg and
I. J. Pickering, J. Agric. Food Chem., 2007, 55, 7337–7341;
(b) H. J. Reich and R. J. Hondal, ACS Chem. Biol., 2016, 11,
821–841; (c) E. N. Silva, F. Aureli, M. D’Amato, A. Raggi,
S. Cadore and F. Cubadda, J. Agric. Food Chem., 2017, 65,
3031–3068; (d) J. Gao, F. Yang, J. Che, Y. Han, Y. Wang,
N. Chen, D. W. Bak, S. Lai, X. Xie, E. Weerapana and
C. Wang, ACS Cent. Sci., 2018, 4, 960–970.
Scheme 5 Possible mechanism.
On the basis of a literature search, the following control
experiments were carried out (Scheme 4). Firstly, acetophe-
none was directly reacted with SeO2 to obtain a 52% yield of
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3 (a) T. Li, M. Smet, W. Dehaen and H. Xu, ACS Appl. Mater.
Interfaces, 2016, 8, 3609–3614; (b) T. Li, F. Li, W. Xiang,
Y. Yi, Y. Chen, L. Cheng, Z. Liu and H. Xu, ACS Appl. Mater.
Interfaces, 2016, 8, 22106–22112.
4 (a) S. Hao, J. Hu, S. Song, D. Huang, H. Xu, G. Qian, F. Gan
and K. Huang, J. Agric. Food Chem., 2016, 64, 1385–1393;
(b) F. Gan, X. Chen, S. F. Liao, C. Lv, F. Ren, G. Ye, C. Pan,
9 (a) S. H. Doan, K. D. Nguyen, T. T. Nguyen and
N. T. S. Phan, RSC Adv., 2017, 7, 1423–1431;
(b) A. B. Khemnar and B. M. Bhanage, RSC Adv., 2014, 4,
8939–8942; (c) B. Maleki, M. Baghayeri, S. M. Vahdat,
A. Mohammadzadeh and S. Akhoondi, RSC Adv., 2015, 5,
46545–46551; (d) X. Wang, D. Xu, C. Miao, Q. Zhang and
W. Sun, Org. Biomol. Chem., 2014, 12, 3108–3113.
D. Huang, J. Shi, X. Shi, H. Zhou and K. Huang, J. Agric. 10 Y. Liu, X. L. Chen, K. Sun, X. Y. Li, F. L. Zeng, X. C. Liu,
Food Chem., 2014, 62, 4502–4508; (c) C. Zhu, Q. Ling,
Z. Cai, Y. Wang, Y. Zhang, p. R. Hoffmann, W. Zheng,
L. B. Qu, Y. F. Zhao and B. Yu, Org. Lett., 2019, 21, 4019–
4024.
T. Zhou and Z. Huang, J. Agric. Food Chem., 2016, 64, 5060– 11 (a) T. Su, S. S. Xie, B. F. Li, J. Yun, L. Huang and X. S. Li,
5070.
Synlett, 2015, 26, 215–220; (b) T. Ramana and
T. Punniyamurthy, Eur. J. Org. Chem., 2011, 4756–4759.
12 R. Gu, X. Wang, Z. Yang and S. Q. Han, Tetrahedron Lett.,
2018, 59, 2835–2838.
5 D. Song, Y. Cheng, X. Li, F. Wang, Z. Lu, X. Xiao and
Y. Wang, ACS Appl. Mater. Interfaces, 2017, 9, 14724–14740.
6 (a) L. Sancineto, A. Mariotti, L. Bagnoli, F. Marini,
J. Desantis, N. Iraci, C. Santi, C. Pannecouque and 13 D. B. Lima, F. Penteado, M. M. Vieira, D. Alves, D. Perin,
O. Tabarrini, J. Med. Chem., 2015, 58, 9601–9614;
(b) V. Alexander, W. J. Choi, J. Chun, H. O. Kim, J. H. Jeon,
C. Santi and E. J. Lenardao, Eur. J. Org. Chem., 2017, 3830–
3836.
D. K. Tosh, H. W. Lee, G. Chandra, J. Choi and L. S. Jeong, 14 R. A. Balaguez, E. S. Betin, T. Barcellos, E. J. Lenardao,
Org. Lett., 2010, 10, 2242–2245.
7 (a) H. Liu, Y. Fang, S. –Y. Wang and S. –J. Ji, Org. Lett.,
D. Alves and R. F. Schumacher, New J. Chem., 2017, 41,
1483–1487.
2018, 20, 930–933; (b) C. D. Prasad, M. Sattar and 15 S. Redon, Y. Kabri, M. D. Crozet and P. Vanelle, Tetrahedron
S. Kumar, Org. Lett., 2017, 19, 774–777; (c) X. Gao, L. Tang, Lett., 2014, 55, 5052–5054.
L. Huang, Z. –S. Huang, Y. Ma and G. Wu, Org. Lett., 2019, 16 W. Chen, X. M. Zhu, F. Wang, Y. Yang, G. B. Deng and
21, 745–748; (d) M. Wang, Q. L. Fan and X. F. Jiang, Org. Y. Liang, J. Org. Chem., 2020, 85, 3349–3357.
Lett., 2016, 18, 5756–5759; (e) Y. M. Li, Y. H. Wang, 17 (a) B. M. Laloo, H. Mecadon, M. R. Rohman,
T. L. Yang, Z. Y. Lin and X. F. Jiang, Green Chem., 2021, 23,
2986–2991; (f) P. H. Ni, J. Tan, W. Q. Zhao, H. W. Huang
and G. J. Deng, Adv. Synth. Catal., 2019, 361, 5351–5356.
8 (a) P. Maity, D. Kundu, R. Roy and B. C. Ranu, Org. Lett.,
2014, 16, 4122–4125; (b) Y. Guan and S. D. Townsend, Org.
Lett., 2017, 19, 5252–5255; (c) P. Maity, B. Paroi and
B. C. Ranu, Org. Lett., 2017, 19, 5748–5751.
I.
Kharbangar,
I.
Kharkongor,
M.
Rajbangshi,
R. Nongkhlaw and B. Myrboh, J. Org. Chem., 2012, 77, 707–
712; (b) O. R. Shangpliang, B. Kshiar, K. Wanngiang,
I. D. Marpan, P. M. Lipon, B. M. Laloo and B. Myboh,
J. Org. Chem., 2018, 83, 5829–5835; (c) M. A. Lynn,
L. J. Carlson, H. Hwangbo, J. M. Tanski and L. A. Tyler,
J. Mol. Struct., 2012, 1011, 81–93.
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