An efficient and practical synthesis of benzazolo[2,1-b]quinazolinones and triazolo[2,1-b]quinazolinones catalyzed by nano-sized NS-C4(DABCO-SO3H)2)·4Cl

Article abstract of DOI:10.1007/s13738-017-1164-3

In this study, 4,4′-(butane-1,4-diyl)bis(1-sulfo-1,4-diazabicyclo[2.2.2]octane-1,4-diium)tetrachloride (NS-C₄(DABCO-SO₃H)₂)·4Cl is used as a nano-sized Br?nsted acid catalyst for the efficient and preferment synthesis of b

Full text of DOI:10.1007/s13738-017-1164-3

J IRAN CHEM SOC
DOI 10.1007/s13738-017-1164-3
ORIGINAL PAPER
An efcient and practical synthesis of benzazolo[2,1‑b]
quinazolinones and triazolo[2,1‑b]quinazolinones catalyzed
by nano‑sized NS‑C4(DABCO‑SO3H)2)·4Cl
Omid Goli‑Jolodar1 · Farhad Shirini1
Received: 8 September 2016 / Accepted: 5 July 2017
© Iranian Chemical Society 2017
Abstract In this study, 4,4′-(butane-1,4-diyl)bis(1-sulfo-
1,4-diazabicyclo[2.2.2]octane-1,4-diium)tetrachloride (NS-
C4(DABCO-SO3H)2)·4Cl is used as a nano-sized Brönsted
acid catalyst for the efcient and preferment synthesis of
benzazolo[2,1-b]quinazolinones and triazolo[2,1-b]quina-
zolinones derivatives. This protocol has many advantages
including mild reaction conditions, acceptable reaction
times, high yields and easy work-up of the products and
reusability of the catalyst.
Among heterocyclic compounds, quinazolines have a broad
scope of pharmacological and biological activities such
as anticancer [3], antitumor [4], antidiabetics [5], anti-
infammatory [6], antihypertensive [7], antihistamines [8],
antiviral [9], antimicrobial [10], antineoplastic [11], anal-
gesic and anti-HIV [12] activities. Employing as a propyl
hydroxylase inhibitor [13] and potent immunosuppressive
agents [14] are other applications of these compounds.
Some antifungal medications are adequate examples which
possess quinazolines motif in their structures (Fig. 1).
Benzazolo[2,1-b]quinazolinones and triazolo[2,1-b]
quinazolinones are important derivatives of quinazolines.
They are commonly synthesized from the condensation
of substituted aldehydes with 2-aminobenzimidazole or
3-amino-1,2,4-triazole as amine sources, and β-diketone.
For this purpose, a variety of conditions and catalysts have
been used [15–35]. Although these methods are useful,
they have some disadvantages such as harsh reaction
conditions, long reaction times, low yields of products,
need excess amounts of the catalyst, use of toxic solvents
and non-recoverable of the catalyst. Hence, there are still
needs for introducing easy, efcient and mild procedures to
overcome these problems.
Keywords Nano-catalyst · Multi-component reactions ·
Solvent-free conditions · Benzazolo[2,1-b]quinazolinones ·
Triazolo[2,1-b]quinazolinones
Introduction
Nowadays, designing and formulation of fast and facile
organic reactions, which target products can be easily
separated and purifed in high yields, are signifcant
purposes in current drug discovery. From this point of
view, multi-component reactions (MCRs) are playing
a key role in combinatorial chemistry. In MCRs, target
compounds are synthesized with greater efciency and
atom economy because in these reactions the structurally
complex products are generated in a single step by several
reactants [1, 2].
Experimental
General
Heterocyclic compounds have various biological activi-
ties which are essential and needed for everyday life.
The chemical materials and solvents were purchased from
Merck, Fluka and Sigma-Aldrich chemical companies.
The purity determinations of reaction monitoring were
accompanied by TLC on silicagel polygram SILG/UV 254
plates. The products were characterized by comparison of
their physical constants such as melting point, use of FT-IR
* Farhad Shirini
shirini@guilan.ac.ir
1
Department of Chemistry, College of Science, University
of Guilan, Rasht 41335, Islamic Republic of Iran
Vol.:(0123456789)
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J IRAN CHEM SOC
Fig. 1 Some antifungal medications possessing the quinazolines nucleus
1
and/or NMR spectroscopy. The FT-IR spectra were run
on a VERTEX 70 Bruker company (Germany) using KBr
disk. The 1H NMR and 13C NMR were run on a 400-MHz
Bruker Avance in DMSO-d6 using TMS as an internal
standard. The melting points of all products were defned
using an Electrothermal 9100 apparatus. The MS were
measured on an Agilent Technology (HP) manufacturer
company under 70 eV conditions.
MS: m/z = 311 (M+); HNMR (400 MHz, DMSO-d6): δ
(ppm) 1.88–1.99 (m, 2H, CH2), 2.17–2.27 (m, 2H, CH2),
2.64–2.67 (m, 2H, CH2), 6.98 (s, 1H, CH), 7.30 (d, 1H,
J = 1.2 Hz), 7.49 (dt, 1H, J1 = 7.6 Hz, J2 = 0.8 Hz), 7.61
(dt, 1H, J1 = 7.6 Hz, J2 = 1.2 Hz), 7.73 (s, 1H, CH), 7.86
(dd, 1H, J1 = 8 Hz, J2 = 1.2 Hz), 11.32 (s, 1H, NH);
13CNMR (100 MHz, DMSO-d6): δ (ppm) 21.1, 26.8, 36.4,
53.4, 106.19, 124.4, 129.4, 129.8, 133.8, 135.3, 147.2,
149.0, 150.8, 153.7, 193.9.
General procedure for the synthesis of benzazolo[2,1‑b]
quinazolinones and triazolo[2,1‑b]quinazolinones
derivatives
9-(4-Bromophenyl)-5,6,7,9-tetrahydro-[1,2,4]
triazolo[5,1-b]quinazolin-8(4H)-one (Table 2, entry
32): White powder; M.p. = 306–308 °C; IR (KBr, cm−1)
νmax: 3429, 3129, 2883, 1648, 1578, 1478, 1411, 1362;
1
A mixture of the requested benzylic aldehyde (1 mmol),
2-aminobenzimidazole or 3-amino-1,2,4-triazole (1 mmol),
β-diketone (1 mmol) and NS-C4(DABCO-SO3H)2·4Cl
(20 mg, 10 mol %) was heated at 90 °C under solvent-free
conditions. The progress of the reaction was monitored
by TLC (n-hexane: EtOAc, 70:30). After completion of
the reaction, the reaction mixture was cooled to room
temperature and 3 mL of water was added to it. The
catalyst was dissolved in water and fltered for separation of
the crude product. The separated product was washed twice
with water (2 × 5 mL), and the crude product was purifed
by recrystallization in ethanol.
MS: m/z = 344 (M+); HNMR (400 MHz, DMSO-d6): δ
(ppm) 1.89–2.01 (m, 2H, CH2), 2.22–2.34 (m, 2H, CH2),
2.61–2.71 (m, 2H, CH2), 6.23 (s, 1H, CH), 7.18 (d, 2H,
J = 8.4 Hz), 7.49 (d, 2H, J = 8.4), 7.71 (s, 1H, CH), 11.21
(s, 1H, NH);); 13CNMR (100 MHz, DMSO-d6): δ (ppm)
21.1, 26.8, 36.7, 44.4, 57.7, 106.6, 121.3, 129.7, 131.6,
141.3, 147.1, 150.6, 153.2, 193.8.
Results and discussion
Very recently and in continuation of our continuous
research program on the development of new catalysts for
the promotion of the organic transformations [37–41], we
have reported the preparation of nano-sized 4,4′-(butane-
1,4-diyl)bis(1-sulfo-1,4-diazabicyclo[2.2.2]octane-1,4-di-
ium) chloride ([NS-C4(DABCO-SO3H)2)]·4Cl) and its
Spectral data of new compounds are presented below:
9-(2-Nitrophenyl)-5,6,7,9-tetrahydro-[1,2,4]
triazolo[5,1-b]quinazolin-8(4H)-one (Table 2, entry
30): White powder; M.p. = 300–304 °C; IR (KBr, cm−1)
νmax: 3444, 3213, 2910, 1643, 1569, 1471, 1410, 1357;
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J IRAN CHEM SOC
application for the synthesis of polyhydroquinoline deriva-
tives via Hantzsch condensation (Fig. 2) [36].
Herein and in continuation of these studies, we
wish to report the applicability of this nano-catalyst
in the promotion of the synthesis of benzazolo[2,1-b]
quinazolinones
derivatives.
and
triazolo[2,1-b]quinazolinones
At frst, we focused our attention on the synthesis of
benzazolo[2,1-b]quinazolinones. For optimization of the
Fig. 2 Structure of NS-C4(DABCO-SO3H)2·4Cl
Table 1 Optimization of the
reaction conditions catalyzed by
NS-C4(DABCO-SO3H)2·4Cl
Entry
Catalyst (mg)
Solvent (mL)
Temperature (°C)
Time (min.)
Yield (%)a
1
2
3
4
5
6
7
8
30
30
30
30
30
20
15
10
20
25
20
20
CH3CN (3)
n-Hexane (3)
EtOH (3)
Refux
Refux
Refux
Refux
100
100
100
100
90
90
80
120
120
120
120
15
10
25
35
10
10
60
40
35
85
Trace
95
95
93
92
94
H2O (3)
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
9
10
11
12
93
65
92
120
10
aIsolated yields
Scheme 1 Synthesis of benzazolo[2,1-b]quinazolinones derivatives catalyzed by NS-C4(DABCO-SO3H)2·4Cl
Scheme 2 Synthesis of triazolo[2,1-b]quinazolinones derivatives catalyzed by NS-C4(DABCO-SO3H)2·4Cl
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Table 2 Synthesis of benzimidazoquinazolinone and triazoloquinazolinone derivatives using C4(DABCO-SO3H)2┬╖4Cl as the catalyst
M.p. (°C)
Reported [Ref.].
Time
(min.)
Yield
(%)a
Entry
Aldehyde
Product
Found
1
13
22
30
92
89
88
>300
368 [19]
>300 [20]
>300 [20]
2
>300
>300
3
4
5
6
15
20
16
92
93
95
>300
>300
>300
>300 [20]
>300 [20]
>300 [20]
7
10
94
>300
393 [19]
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Table 2 continued
M.p. (°C)
Reported [Ref.].
Time
Yield
(%)a
Entry
Aldehyde
Product
(min.)
Found
>300
8
25
95
389 [19]
9
10
94
>300
335 [19]
10
15
22
95
93
340-342
340-342 [34]
11
>300
344-346 [34]
12
35
30
92
91
>300
347-349 [34]
13
280-282
281–283 [35]
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Table 2 continued
M.p. (°C)
Reported [Ref.].
Time
(min.)
Yield
(%)a
Entry
Aldehyde
Product
Found
14
15
16
15
25
35
92
93
92
263-265
263–266 [35]
210–213 [35]
296–298 [35]
208-210
297-299
17
18
19
13
25
20
93
88
93
296-298
254-256
>300
297–300 [35]
256–258 [35]
300–302 [35]
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Table 2 continued
M.p. (°C)
Reported [Ref.].
Time
Yield
(%)a
Entry
20
Aldehyde
Product
(min.)
Found
20
28
25
95
92
92
248-250
248-250 [16]
>300 [20]
21
22
>300
291-292
290-292 [28]
23
24
30
30
93
91
>300
>300 [20]
265-266
266-269 [24]
25
26
18
30
94
92
301-303
222-224
303–305 [25]
222-224 [16]
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Table 2 continued
M.p. (°C)
Reported [Ref.].
Time
(min.)
Yield
(%)a
Entry
Aldehyde
Product
Found
27
20
35
91
92
285-286
284-285 [16]
287-290 [24]
28
286-288
29
30
25
35
95
84
>300
>300 [20]
300-304
New
31
32
30
20
91
94
>300
>300 [20]
306-308
New
33
35
92
306-308
>300 [20]
a
Isolated yields
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Scheme 3 Proposed mecha-
nism for the synthesis of
benzimidazoquinazolinone and
triazoloquinazolinone deriva-
tives in the presence of NS-
C4(DABCO-SO3H)2·4Cl
reaction conditions, the condensation of 4-chlorobenzal-
dehyde with 2-aminobenzimidazole and dimedone in the
presence of NS-C4 (DABCO-SO3H)2·4Cl was selected as
a model reaction, and various conditions including difer-
ent amounts of the catalyst, temperatures and solvent were
examined (Table 1). After careful studies, the optimal reac-
tion conditions were selected as shown in Scheme 1. Also
3-amino-1,2,4-triazole was another amine source which
could be successfully produced the corresponding products
under this optimized reaction condition (Scheme 2).
of the method, we have extended it to the three-compo-
nent condensation of various substituted benzaldehydes,
diferent type of β-diketones (dimedone, cyclohexanedi-
one and ethyl acetoacetate) and/or 2-aminobenzimida-
zole or 3-amino-1,2,4-triazole (Table 2). It was observed
that a wide range of aromatic aldehydes containing elec-
tron-withdrawing as well as electron-donating groups
such as Cl, CH3, OCH3, NO2 and CN in the ortho, meta
and para positions of the benzene ring were easily con-
verted to their corresponding benzimidazoquinazolinone
and/or triazoloquinazolinone in short reaction times with
good to excellent isolated yields. It is interesting to note
After optimization of the reaction conditions and in
order to establish the efectiveness and the acceptability
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J IRAN CHEM SOC
Fig. 3 Reusability of the
catalyst
Table 3 Compared performance of various catalysts with NS-C4(DABCO-SO3H)2·4Cl in the synthesis of quinazolinone derivatives
Entry
1
Compound
Catalyst (mol %)
– (–)
Conditions
Time (min.)
90
Yield (%)a
References
[18]
EtOH/refux
64
2
3
4
5
6
7
8
9
– (–)
Solvent free/110 °C
CH3CN/refux
CH3CN/80 °C
CH3CN/refux
EtOH/40 °C
CH3CN/40–50 °C
Acetic acid/60 °C
Solvent free/100 °C
DMF/refux
420
15
15
10
90
25
20
13
30
85
96
94
84
90
95
94
92
76
[20]
[24]
[25]
[28]
[29]
[30]
[31]
This work
[16]
H6P2W18O62·H2O (1)
Sulfamic acid (0.005)
Iodine (10)
Fe3O4@chitosan (2 mg)
p-TSA (15)
– (–)
C4(DABCO-SO3H)2·4Cl (10)
– (–)
10
11
12
13
14
15
16
17
18
– (–)
Solvent free/110 °C
CH3CN/refux
CH3CN/80 °C
Solvent free/100 °C
CH3CN/refux
CH3CN/40–50 °C
Acetic acid/60 °C
Solvent free/100 °C
240
30
30
20
10
30
25
20
93
95
95
93
81
96
95
95
[20]
[24]
[25]
[27]
[28]
[30]
[31]
This work
H6P2W18O62·H2O (1)
Sulfamic acid (0.005)
[Bmim]Br (0.1)
Iodine (10)
p-TSA (15)
– (–)
C4(DABCO-SO3H)2·4Cl (10)
a
Isolated yields
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J IRAN CHEM SOC
that 2-naphthaldehyde and fuorene-2-carbaldehyde as
polycyclic aromatic aldehydes also provided the desired
products in very good yields (Table 2, entries 11–12,
28). It should be mentioned that because of the forma-
tion of a mixture of unidentifed products the method is
not useful for the synthesis of the same products from
aliphatic aldehydes.
superior to other reported procedures in terms of the reac-
tion times and yields. Simple experimental procedure and
use of a reusable catalyst with lower loading are other
advantages of this method. Furthermore, this process avoids
problems associated with organic solvents and liquid acids
used, which makes it a useful and attractive strategy in view
of economic and environmental advantages.
The proposed mechanism for the synthesis of benzi-
midazoquinazolinone and triazoloquinazolinone deriva-
tives in the presence of NS-C4(DABCO-SO3H)2·4Cl as
a promoter is shown in Scheme 3. On the basis of this
Acknowledgements We are thankful to the University of Guilan
Research Council for the partial support of this work.
mechanism,
NS-C4(DABCO-SO3H)2·4Cl
catalyzes
the reaction through: (a) the activation of the carbonyl
groups for the nucleophilic attack of β-diketones, (b)
dehydration of the intermediate (I), (c) acceleration of
the nucleophilic attack of the amine group on (II) and
(III) and (d) dehydration of (IV).
References
1. J. Zhu, H. Bienayme, Multicomponent Reactions, 1st edn.
(Wiley-VCH, Weinheim, 2005)
2. N. Isambert, M.M.S. Duque, J. Plaquevent, Y. Genisson, J. Rod-
riguez, T. Constantieux, Chem. Soc. Rev. 40, 1347 (2011)
3. M.J. Hour, L.J. Huang, S.C. Kuo, Y. Xia, K. Bastow, Y. Nakani-
shi, E. Hamel, K.H. Lee, J. Med. Chem. 43, 4479 (2000)
4. Y. Xia, Z.Y. Yang, M.J. Hour, S.C. Kuo, P. Xia, K.F. Bastow,
Y. Nakanishi, P. Namboothiri, T. Hackle, E. Hamel, K.H. Lee,
Bioorg. Med. Chem. Lett. 11, 1193 (2001)
The reusability of catalyst is worthwhile and eco-
friendly. For this purpose, we chose the synthesis of
12-(4-chlorophenyl)-3,3-dimethyl-3,4,5,12-tetrahy-
drobenzo[4,5]imidazo[2,1-b]
quinazolin-1(2H)-one
(Table 2, entry 17) as a model reaction to investigate the
reusability of NS-C4(DABCO-SO3H)2·4Cl under the opti-
mized reaction conditions. After completion of the reac-
tion, the solid product was washed with water to separate
the catalyst (catalyst is soluble in water). Then, the fl-
trate was evaporated under vacuum up to 100 °C and the
obtained catalyst was washed with diethyl ether, dried and
reused for the same reaction. The recycled catalyst was
reused at least for 5 runs without considerable loss of its
activity. The obtained results are demonstrated in Fig. 3.
To highlight the merits of our newly developed pro-
cedures, we have compared our results obtained for the
synthesis of 3,3-dimethyl-12-phenyl-3,4,5,12-tetrahy-
5. F. Kato, H. Kimura, M. Omatsu, K. Yamamoto, R. Miyamoto,
European Patent Application, WO 02/040485 (2002)
6. B. McMaster, Anti-Infammatory Compositions and Methods of
Use, WO Patent 03105857, December 24 (2003)
7. V. Alagarsamy, U.S. Pathak, Bioorg. Med. Chem. 51, 3457
(2007)
8. V. Alagarsamy, Pharmazie 59, 753 (2004)
9. S. Shigeta, S. Mori, M. Baba, M. Hosoya, N. Mochizuki, T.
Chiba, E. De Clercq, Antivir. Chem. Chemother. 3, 171 (1992)
10. Z.M. Nofal, H.H. Fahmy, H.S. Mohamed, Arch. Pharm. Res. 25,
28 (2002)
11. A. Hafez, A.A. Monem, Arch. Pharm. Res. 30, 678 (2007)
12. V. Alagarsamy, R. Revathi, S. Meena, K.V. Ramaseshu, S.
Rajasekaran, C.E. De, Indian J. Pharm. Sci. 66, 459 (2004)
13. D. Chai, D. M. Fitch, Propyl Hydroxylase Inhibitors, WO Patent
09039322 A1, March (2009)
drobenzo[4,5]imidazo
[2,1-b]quinazolin-1(2H)-one
14. W.H.W. Lunn, R.W. Harper, R.L. Stone, J. Med. Chem. 14, 1069
(1971)
(Table 2, entry 1) and 6,6-dimethyl-9-phenyl-5,6,7,9-
tetrahydro-[1,2,4]triazolo[5,1-b]quinazolin-8 (4H)-one
(Table 2, entry 20) using NS-C4(DABCO-SO3H)2·4Cl as
the catalyst with other reported results for the same trans-
formations (Table 3). The results showed that the newly
expanded method avoids some of the disadvantages afli-
ated by the other procedures such as longer reaction time,
large excesses of reagents, use of organic solvents and/or
toxic reagents and low yields of the products.
15. V.V. Lipson, S.M. Desenko, S.V. Shishkina, M.G. Shirobokova,
S.V. Shishkin, V.D. Orlov, Chem. Heterocycl. Compd. 39, 1041
(2003)
16. V.V. Lipson, S.M. Desenko, M.G. Shirobokova, V.V. Borodina,
Chem. Heterocycl. Compd. 39, 1213 (2003)
17. V.V. Lipson, S.M. Desenko, V.V. Borodina, M.G. Shirobokova,
Russ. J. Org. Chem. 41, 114 (2005)
18. O.V. Fedorova, M.S. Zhidovinova, G.L. Rusinov, I.G. Ovchin-
nikova, Russ. Chem. Bull. 52, 1768 (2003)
19. B. Insuasty, A. Salcedo, J. Quiroga, R. Abonia, M. Nogueras, J.
Cobo, S. Salido, Heterocycl. Commun. 10, 399 (2004)
20. A. Shaabani, E. Farhangi, A. Rahmati, Comb. Chem. High
Throughput Screen. 9, 771 (2006)
Conclusions
21. A.E. Mourad, A.A. Aly, H.H. Farag, E.A. Beshr, Beilstein J.
Org. Chem. 3, 11 (2007)
22. Q. Shao, Sh Tu, Ch. Li, L. Cao, D. Zhou, Q. Wang, B. Jiang, Y.
Zhang, W. Hao, J. Heterocycl. Chem. 45, 411 (2008)
23. G. Krishnamurthy, K.V. Jagannath, J. Chem. Sci. 125, 807
(2013)
In the conclusion of this study, we have introduced NS-
C4(DABCO-SO3H)2·4Cl as a highly powerful nano-cata-
lyst for the simple and efcient synthesis of benzimidazo-
quinazolinone and triazoloquinazolinone derivatives. The
obtained results show that this method is convincingly
24. M.M. Heravi, L. Ranjbar, F. Derikvand, B. Alimadadi, H.A.
Oskooie, F.F. Bamoharram, Mol. Divers. 12, 181 (2008)
1 3

J IRAN CHEM SOC
25. M.M. Heravi, F. Derikvand, L. Ranjbar, Synth. Commun. 40,
677 (2010)
34. O. Goli-Jolodar, F. Shirini, J. Iran, Chem. Soc. 13, 1077 (2016)
35. M. Abedini, F. Shirini, M. Mousapour, O. Goli-Jolodar, Res.
Chem. Intermed. (2016). doi:10.1007/s11164-016-2456-4
36. O. Goli-Jolodar, F. Shirini, M. Seddighi, RSC Adv. 6, 26026
(2016)
26. K. Kumari, D.S. Raghuvanshi, K.N. Singh, Org. Prep. Proced.
Int. 44, 460 (2012)
27. A. Shabani, E. Farhangi, Sh Shabani, Iran. J. Chem. Chem. Eng.
32, 3–10 (2013)
37. F. Shirini, O. Goli Jolodar, J. Mol. Catal. A Chem. 356, 61
(2012)
28. R.G. Puligoundla, S.H. Karnakanti, R. Bantu, N. Kommu, S.B.
Kondra, L. Nagarapu, Tetrahedron Lett. 54, 2480 (2013)
29. A. Maleki, M. Aghaei, N. Ghamari, Chem. Lett. 44, 259 (2015)
30. M.R. Mousavi, M.T. Maghsoodlou, Monatsh. Chem. 145, 1967
(2014)
38. F. Shirini, M. Mamaghani, M. Seddighi, Catal. Commun. 36, 31
(2013)
39. F. Shirini, NGh Khaligh, J. Mol. Liq. 177, 386 (2013)
40. F. Shirini, NGh Khaligh, S. Akbari-Dadamahaleh, J. Mol. Catal.
A Chem. 365, 15 (2012)
31. M.R. Mousavi, M.T. Maghsoodlou, N. Hazeri, S.M. Habibi-
Khorassani, J. Iran. Chem. Soc. 12, 1419 (2015)
32. M.R. Mousavi, M.T. Maghsoodlou, J. Iran. Chem. Soc. 12, 743
(2015)
41. F. Shirini, P.N. Moghadam, S. Moayediab, M. Seddighi, RSC
Adv. 4, 38581 (2014)
33. G.M. Ziarani, A. Badiei, Z. Aslani, N. Lashgari, Arab. J. Chem.
8, 54 (2015)
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