Facile preparation of 2-arylbenzoselenazoles from three components reactions: 2-Chloronitrobenzene, Se, and arylacetic acids

Article abstract of DOI:10.1016/j.tetlet.2019.151393

A selenium-mediated decarboxylative cyclization of 2-chloronitrobenzene and arylacetic acids to prepare 2-arylbenzoselenazoles has been established under metal-free condition. The reactions proceeded in moderate to good yields with good functional toleran

Full text of DOI:10.1016/j.tetlet.2019.151393

Journal Pre-proofs
Facile Preparation of 2-Arylbenzoselenazoles from Three Components Reac-
tions: 2-Chloronitrobenzene, Se, and Arylacetic acids
Haifeng Gan, Douglas R. Macfarane
PII:
S0040-4039(19)31184-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151393
TETL 151393
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
13 October 2019
6 November 2019
11 November 2019
Please cite this article as: Gan, H., Macfarane, D.R., Facile Preparation of 2-Arylbenzoselenazoles from Three
Components Reactions: 2-Chloronitrobenzene, Se, and Arylacetic acids, Tetrahedron Letters (2019), doi: https://
doi.org/10.1016/j.tetlet.2019.151393
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Tetrahedron Letters
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Facile Preparation of 2-Arylbenzoselenazoles from Three Components Reactions: 2-
Chloronitrobenzene, Se, and Arylacetic acids
Haifeng Gan a, , Douglas R. Macfaraneb
a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211800, P. R. Of China
b School of Chemistry, Faculty of Science, Monash University, Clayton campus, Clayton, Victoria, 3800, Australia
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +86-25-5813-9970; fax: +86-25-5813-9971; e-mail: ganhaifeng@njtech.edu.cn
Article history:
Received
Received in revised form
Accepted
A selenium-mediated decarboxylative cyclization of 2-chloronitrobenzene and arylacetic acids
to prepare 2-arylbenzoselenazoles has been established under metal-free condition. The
reactions proceeded in moderate to good yields with good functional tolerance and gram-scale
application.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Benzoselenazoles
Arylacetic acid
Cyclization
Selenium powder
Selenium-containing compounds are important in that they
have been widely used in new materials,1 organic intermediates,2
and pharmaceuticals.3 2-Arylbenzoselenazoles are useful as
building blocks for the synthesis of bioactive molecules.3b,4 To
date, related synthetic methods include the condensation
reactions of bis(2-aminophenyl)diselenides with aldehydes,
carboxylic acids, α-keto acids, etc. under oxidative conditions
(Scheme 1, eq 1),4c,5 MW-assisted-intramolecular cyclization of
2-haloanilides (Scheme 1, eq 2),6 Se-mediated cyclization of 2-
iodoanilines with aldehydes, arylmethyl chlorides, arylacetic
acids, etc. under transition-metal-catalyzed or oxidative
conditions (Scheme 1, eq 3).5a,7 2-Halonitrobenzene has been
used extensively to synthesize benzothiazoles these years,8
however, literature employing it as a substrate to prepare
benzoselenazole has not been reported yet. Furthermore, Jiang et
al. reported a transition-metal-free diarylannulated sulfide and
selenide construction via radical/anion-mediated sulfur-iodine
and selenium-iodine exchange recently.9 Inspired by that and on
the basis of our publications in sulfur mediated reactions,8d,10 we
envisaged that o-chloronitrobenzene could undergo cyclization
with arylacetic acids in the presence of selenium powder under
metal-free conditions to afford important 2-aryl benzoselenazole
derivatives (Scheme 1, eq 4).
Scheme 1. Recent strategy for the synthesis of benzoselenazoles
in Na2CO3, NaHCO3 and Cs2CO3 (Table 1, entries 2-4). Besides,
N-methylmorpholine (NMM), triethylamine (TEA), pyridine and
Previous work
NH2
N
condensation
(1)
R1
R2
R2-Y
+
Se
Se
Se
NH2
Y = CHO, COOH
COCOOH, etc.
H
N
R2
Wollins' reagent
TEA, MW
N
R1
R1
(2)
(3)
O
R1
R2
Y
Se
Y = Halogen
NH2
I
condensation
N
+
Se
R2-Y
+
R1
R2
Se
metal or oxidant
Y = CHO, CH2Cl
CH2COOH, etc.
This work
NO2
NMP
N
COOH
+ Se
(4)
R1
+
R1
R2
R2
Se
Cl
3-picoline could not provide better results (Table 1, entries 5-
8).Then we used N-methylpiperidine (NMP) as base and found
that the isolated yield could be improved to 82% (Table 1, entry
9). Enhancing the reaction temperature to 140 oC or reducing it to
We began our investigation by conducting the reaction of 2-
chloronitrobenzene (1a), phenylacetic acid (2a), selenium
powder and K2CO3 (3.0 equiv.) in DMSO (2 mL) at 130 oC under
argon atmosphere. We could get the target product 3aa in 73%
isolated yield (Table 1, entry 1) and less products were obtained
o
120 C restrained the reaction yields (Table 1, entries 10-11). F-
urthermore, changing the equivalent of NMP, selenium powder
and 2a could not improve the reactions (Table 1, entries 12-17).
Conducting the reaction under air inhibited the result too (Table 1,
entry 18).

2
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Facile Preparation of 2-Arylbenzoselenazoles from
Three Components Reactions: 2-Chloronitrobenzene,
Se, and Arylacetic Acids
Haifeng Gan*, Douglas R. Macfarlane
NMP, 130 oC
Cl
R2
Se
N
R1
R1
COOH
+
Se
+
R2
O2N
1) metal free
2) easliy available SM
30 examples
up to 82%

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Facile Preparation of 2-Arylbenzoselenazoles from Three Components Reactions: 2-
Chloronitrobenzene, Se, and Arylacetic acids
Haifeng Gan a, , Douglas R. Macfaraneb
a College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211800, P. R. Of China
b School of Chemistry, Faculty of Science, Monash University, Clayton campus, Clayton, Victoria, 3800, Australia
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +86-25-5813-9970; fax: +86-25-5813-9971; e-mail: ganhaifeng@njtech.edu.cn
Article history:
Received
A selenium-mediated decarboxylative cyclization of 2-chloronitrobenzene and arylacetic acids
to prepare 2-arylbenzoselenazoles has been established under metal-free condition. The
Received in revised form
Accepted
reactions proceeded in moderate to good yields with good functional tolerance and gram-scale
application.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Benzoselenazoles
Arylacetic acid
Cyclization
Selenium powder
Selenium-containing compounds are important in that they
have been widely used in new materials,1 organic intermediates,2
and pharmaceuticals.3 2-Arylbenzoselenazoles are useful as
building blocks for the synthesis of bioactive molecules.3b,4 To
date, related synthetic methods include the condensation
reactions of bis(2-aminophenyl)diselenides with aldehydes,
carboxylic acids, α-keto acids, etc. under oxidative conditions
(Scheme 1, eq 1),4c,5 MW-assisted-intramolecular cyclization of
2-haloanilides (Scheme 1, eq 2),6 Se-mediated cyclization of 2-
iodoanilines with aldehydes, arylmethyl chlorides, arylacetic
acids, etc. under transition-metal-catalyzed or oxidative
conditions (Scheme 1, eq 3).5a,7 2-Halonitrobenzene has been
used extensively to synthesize benzothiazoles these years,8
however, literature employing it as a substrate to prepare
benzoselenazole has not been reported yet. Furthermore, Jiang et
al. reported a transition-metal-free diarylannulated sulfide and
selenide construction via radical/anion-mediated sulfur-iodine
and selenium-iodine exchange recently.9 Inspired by that and on
the basis of our publications in sulfur mediated reactions,8d,10 we
envisaged that o-chloronitrobenzene could undergo cyclization
with arylacetic acids in the presence of selenium powder under
metal-free conditions to afford important 2-aryl benzoselenazole
derivatives (Scheme 1, eq 4).
Scheme 1. Recent strategy for the synthesis of benzoselenazoles
in Na2CO3, NaHCO3 and Cs2CO3 (Table 1, entries 2-4). Besides,
N-methylmorpholine (NMM), triethylamine (TEA), pyridine and
Previous work
NH2
N
condensation
(1)
R1
R2
R2-Y
+
Se
Se
Se
NH2
Y = CHO, COOH
COCOOH, etc.
H
N
R2
Wollins' reagent
TEA, MW
N
R1
R1
(2)
(3)
O
R1
R2
Y
Se
Y = Halogen
NH2
I
condensation
N
+
Se
R2-Y
+
R1
R2
Se
metal or oxidant
Y = CHO, CH2Cl
CH2COOH, etc.
This work
NO2
NMP
N
COOH
+ Se
(4)
R1
+
R1
R2
R2
Se
Cl
3-picoline could not provide better results (Table 1, entries 5-
8).Then we used N-methylpiperidine (NMP) as base and found
that the isolated yield could be improved to 82% (Table 1, entry
9). Enhancing the reaction temperature to 140 oC or reducing it to
We began our investigation by conducting the reaction of 2-
chloronitrobenzene (1a), phenylacetic acid (2a), selenium
powder and K2CO3 (3.0 equiv.) in DMSO (2 mL) at 130 oC under
argon atmosphere. We could get the target product 3aa in 73%
isolated yield (Table 1, entry 1) and less products were obtained
o
120 C restrained the reaction yields (Table 1, entries 10-11). F-
urthermore, changing the equivalent of NMP, selenium powder
and 2a could not improve the reactions (Table 1, entries 12-17).
Conducting the reaction under air inhibited the result too (Table 1,
entry 18).
Table 1. Optimization of reaction conditionsa
Cl
Se
Conditions
+
+
Ph COOH
Se
N
3aa
NO2
2a
1a

2
Tetrahedron Letters
Entry
1
Base
Additive
Temperature oC
130
Yield % b
73
K2CO3
DMSO
2
Na2CO3
DMSO
130
42
3
NaHCO3
DMSO
130
trace
38
4
Cs2CO3
DMSO
130
5
N-methylmorpholine
Triethylamine
Pyridine
-
-
-
-
-
-
-
-
-
-
-
-
-
-
130
trace
55
6
130
7
130
trace
trace
82
8
3-Picoline
130
9
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
130
10
11
12c
13d
14e
15f
16g
17h
18i
140
80
120
74
130
83
130
36
130
82
130
69
130
81
130
74
130
68
a Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), Selenium (1.5 mmol), base (3.0 equiv.), 130 oC, 24 h under argon atmosphere.
b Isolated yield.
c NMP (4.0 mmol). d NMP (2.0 mmol). e Selenium (2.0 mmol). f Selenium (1.0 mmol). g 2a (2.0 mmol). h 2a (1.2 mmol). i Under air.
NMP = N-methylpiperidine.
With optimal reaction conditions gained, we began to
investigate the scope of substituted arylacetic acids 2 (Table 2).
Se
Cl
Se
N
COOH
A lot of substituents (including hydroxy) were tolerated in the
reaction and provided desired products in 42-82% yields. In
general, there are little effect on yields between the meta-position
substituents on aromatic rings of phenylacetic acids (3al-3aj, 3al-
3an) and their para-position substituted counterparts (3ab-3af).
Besides, 1-naphthylacetic acid and heteroaromatic acetic acids
accomplished the transformation smoothly, and offered the
desired products 3ao-3ar in good isolated yields. Furthermore,
disubstituted phenylacetic acids gave their desired product 3as-
3au in 54-72% yields.
+
R1
NMP, 130 oC
R1
NO2
3
1
2
Se
N
Se
N
3aa
, 82%
Se
N
OMe
3ac
, 67%
3ab
, 63%
Se
N
Se
N
Se
N
Cl
Br
F
3af
, 70%
1.10 g, 5 mmol of
3ae
, 75%
3ad
, 73%
1a
Se
N
Se
N
3ag
, 70%
Se
In addition, a gram-scale experiment was also carried out. 3af
could still be gained in 5 mmol scale in 70% isolated yield (1.10
g).
CF3
N
, 68%
3ai
, 71%
3ah
Se
N
Se
N
Se
N
Then we began to explore the scope of substituted o-
halonitrobenzenes 1b–j under optimal conditions to test the
applicability (Table 3). A variety of substituents accomplished
the reaction and provided desired products in 47-79% yields.
Methyl substituted chloronitrobenzene gave the desired products
3ba and 3ca in yields of 56% and 74%, respectively. Halogens
substituted chloronitrobenzene 1e-1g provided 3ea-3ga in good
yields. Azabenzoselenazoles 3ia and 3ja were prepared in
slightly inferior yields (35-41%). It was important that 3ia, which
could be obtained in a single step from commercially available
starting materials 1ea scaffold, was previously found to have
potentially antioxidant and anticholinesterasic activities.11
OMe
Cl
F
OH
Br
3aj
, 69%
3ak
, 42%
3al
, 65%
Se
N
Se
N
Se
N
3am
, 74%
3ao
3an
3aq
, 67%
, 69%
Se
Se
Se
N
N
N
N
N
S
, 73%
3ap
, 76%
3ar
, 68%
Cl
Cl
OMe
OMe
Se
N
Se
N
Se
N
OMe
OMe
3as
, 54%
3au
, 57%
3at
, 72%
To further clarify the reaction mechanism, several control
experiments were conducted. To explain if the reaction is radial
pathway, TEMPO or BHT was added under standard conditions
and gave the desired product 3aa in 54% or 61% isolated yields,
Table 2. Substrate scope of arylacetic acid 2a,b
a
Conditions: 1a (1.0 mmol), 2a-2u (1.5 mmol), Selenium (1.5 mmol), NMP
(3.0 equiv.), 130 oC, 24 h under argon atmosphere.

3
b Isolated yield.
Table 3. Substrate scope of 2-halonitrobenzene 1a,b
respectively (Scheme 2, eq 1), which could almost remove
radical mechanism. Moreover, treatment of 2-chloroaniline, 2a
and selenium powder under standard condition did not get 3aa
(Scheme 2, eq 2).
Cl
N
OH
1a
O
Ph
N-methyl
piperidine
O
O
2a
CO2
I
Se
Se
N
3
Cl
COOH
+
R2
R2
NMP, 130 oC
Se
NO2
H2O
Ph
2
1
Se
N
Se
N
Se
Cl
Hydrogen transfer
Cyclization
Se
Se
N
MeO
3ca
, 74%
3da
, 47%
3ba
, 56%
N
N
O
3aa
Se
N
Se
Se
II
N
N
F
Cl
Br
c
3ea
, 66%
3fa
, 79%
3ga, 72%
Scheme 3. Proposal mechanism
N
Se
Se
N
Se
N
3ja
, 35%
1H NMR and 13C NMR data and spectra of the products are
available. Supplementary data associated with this article can be
found, in the online version, at doi:
N
N
F3C
3ia
, 41%
3ha
, 70%
a
Conditions: 1b-1j (1.0 mmol), 2a (1.5 mmol), Selenium (1.5 mmol), NMP
(3.0 equiv.), 130 oC, 24 h under argon atmosphere.
References and notes
b Isolated yield.
1.
2.
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c 2-Bromo-5-chloronitrobenzene was used as starting material.
standard
conditions
Cl
Se
N
(1)
(2)
+
+
+
Ph COOH
Se
NO2
3aa
2a
1a
54% for TEMPO (2 equiv.)
61% for BHT (2 equiv.)
standard
conditions
Cl
Se
N
3aa
+
Ph COOH
Se
NH2
2a
(0%)
1a
2a
(1.5 mmol), Se (1.5 mmol), NMP (3 mmol)
Standard conditions:
(1 mmol),
130 oC, 24 h under argon atmosphere
Scheme 2. Controlled experiments
3.
(a) Nogueira, C. W.; Zeni, G.; Rocha, J. B. T. Chem. Rev. 2004,
104, 6255-6285; (b) Sarma, B. K.; Mugesh, G. J. Am. Chem. Soc.
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J. Med. Chem. 2015, 58, 3329-3339.
According to above experiments and previous literature,8d,10
plausible mechanism for the formation of 3 is presented (Scheme
3). In the presence of base NMP, 2a can undergo
decarboxylation8d,10b,12 and then attack at the NO2 group of the
substrate 1a followed by dehydration affords II via I. The
intermediate II can experience reduction and cyclization to afford
the desired product 3aa. Related data are showed in supporting
information.
Conclusions
4.
5.
(a) Bhabak, K. P.; Mugesh, G. Chem. Eur. J. 2007, 13, 4594-
4601; (b) Viglianisi, C.; Simone, L.; Menichetti, S. Adv. Synth.
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P. H. Tetrahedron 2013, 69, 1316-1321; (d) Sundaram, G. S. M.;
Dhavale, D. D.; Prior, J. L.; Yan, P.; Cirrito, J. R.; Rath, N. P.;
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Sci. Rep. 2016, 6, 35636-35648.
(a) Radatz, C. S.; Rampon, D. S.; Balaguez, R. A.; Alves, D.;
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D. B.; Penteado, F.; Vieira, M. M.; Alves, D.; Perin, G.; Santi, C.;
Lenardão, E. J. Eur. J. Org. Chem. 2017, 3830-3836; (c)
Balaguez, R. A.; Krüger, R.; Radatz, C. S.; Rampon, D. S.;
Lenardão, E. J.; Schneider, P. H.; Alves, D. Tetrahedron Lett.
2015, 56, 2735-2740.
In summary, a novel metal-free decarboxylative cyclization of
2-chloronitrobenzene, arylacetic acids and selenium powder to
synthesize 2-arylbenzoselenazoles has been disclosed. A variety
of functional groups were tolerated. The reactions proceeded in
moderate to good yields, and gram-scale is realized. This
methodology provides an alternative route for the efficient
synthesis of 2-arylbenzoselenazole derivatives. The exploration
of reaction mechanism and extension to other substrate is
currently underway in depth.
Acknowledgments
6.
7.
Redon, S.; Kabri, Y.; Crozet, M. D.; Vanelle, P. Tetrahedron Lett.
2014, 55, 5052-5054.
(a) Su, T.; Xie, S.; Li, B.; Yan, J.; Huang, L.; Li, X. Synlett 2015,
26, 215-220; (b) Gu, R.; Wang, X.; Yang, Z.; Han, S. Tetrahedron
Lett. 2018, 59, 2835-2838.
We are grateful to the National High Technology Research
and Development Program of China (No. 2013AA031901) for
the financial support.
8.
(a) Liu, J.; Gui, Q.; Yang, Z.; Tan, Z.; Guo, R.; Shi, J.-C. Synthesis
2013, 45, 943-951; (b) Nguyen, T. B.; Ermolenko, L.; Retailleau,
Supporting information

4
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P.; Al-Mourabit, A. Angew. Chem. Int. Ed. 2014, 53, 13808-
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Click here to remove instruction text...
10. (a) Gan, H. ChemistrySelect, 2019, 4, 8598-8601; (b) Gan, H.;
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2-Halonitrobenzene has not been employed to prepare 2-arylbenzoselenazole yet. Besides, the
development of metal-free protocols is highly urgent. In this article, a variety of functional groups were
tolerated. Disubstituted arylacetic acids were also suitable substrates. The reactions proceeded in moderate
to good yields, and gram-scale is accomplished.
Dear editor,
I am Haifeng Gan, Ph.D, in Nanjing Tech University. My research areas involve organic synthetic
methodology of heterocycle compounds, total synthesis of natural products, etc. I declare that I have no
conflicts interests.
Haifeng Gan
Table 1. Optimization of reaction conditionsa
Cl
Se
Conditions
+
+
Ph COOH
Se
N
3aa
NO2
2a
1a
Entry
Base
Additive
Temperature oC
Yield % b
73
1
2
3
4
5
6
7
K2CO3
DMSO
130
130
130
130
130
130
130
Na2CO3
DMSO
42
NaHCO3
DMSO
trace
38
Cs2CO3
DMSO
N-methylmorpholine
Triethylamine
Pyridine
-
-
-
trace
55
trace

5
8
3-Picoline
-
-
-
-
-
-
-
-
-
-
-
130
130
140
120
130
130
130
130
130
130
130
trace
82
80
74
83
36
82
69
81
74
68
9
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
N-methylpiperidine
10
11
12c
13d
14e
15f
16g
17h
18i
a Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), Selenium (1.5 mmol), base (3.0 equiv.), 130 oC, 24 h under argon atmosphere.
b Isolated yield.
c NMP (4.0 mmol). d NMP (2.0 mmol). e Selenium (2.0 mmol). f Selenium (1.0 mmol). g 2a (2.0 mmol). h 2a (1.2 mmol). i Under air.
NMP = N-methylpiperidine.