Synthesis of 2,3-dihydroquinazolin-4(1H)-ones via one-pot three-component reaction catalyzed by L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate (supported on silica gel) as novel and recoverable catalyst

Article abstract of DOI:10.1007/s13738-012-0074-7

A wide variety of 2,3-dihydroquinazolin- 4(1H)-ones has been prepared via one-pot three-component condensation of isatoic anhydride, aldehydes and primary amines or ammonium acetate in the presence of a catalytic amounts of L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate (supported on silica gel), as green, non-toxic and reusable catalyst, in water at 80 °C. Iranian Chemical Society 2012.

Full text of DOI:10.1007/s13738-012-0074-7

J IRAN CHEM SOC (2012) 9:607–613
DOI 10.1007/s13738-012-0074-7
ORIGINAL PAPER
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones via one-pot
three-component reaction catalyzed by L-pyrrolidine-2-carboxylic
acid-4-hydrogen sulfate (supported on silica gel) as novel
and recoverable catalyst
•
Arash Ghorbani-Choghamarani Parisa Zamani
Received: 29 September 2011 / Accepted: 14 December 2011 / Published online: 13 March 2012
Ó Iranian Chemical Society 2012
Abstract
A
wide variety of 2,3-dihydroquinazolin-
pharmacological and biological activities. In view of these
useful properties, a number of procedures have been
reported toward the synthesis of 2,3-dihydroquinazolin-
4(1H)-ones. These heterocyclic compounds have been
prepared mainly via condensation of amines and aldehydes
with isatoic anhydride or anthranilide in the presence of an
appropriate catalyzed [11–17]. Some of these procedures
are associated with several drawbacks such as harsh reac-
tion conditions, non-recoverability of the catalyst, tedious
work-up procedure, and low yields of products. In this
light, we decided to design a new procedure for the prep-
aration of 2,3-dihydroquinazolin-4(1H)-ones.
4(1H)-ones has been prepared via one-pot three-component
condensation of isatoic anhydride, aldehydes and primary
amines or ammonium acetate in the presence of a catalytic
amounts of L-pyrrolidine-2-carboxylic acid-4-hydrogen
sulfate (supported on silica gel), as green, non-toxic and
reusable catalyst, in water at 80 °C.
Keywords 2,3-Dihydroquinazolin-4(1H)-one Á Isatoic
anhydride Á L-Pyrrolidine-2-carboxylic acid-4-hydrogen
sulfate Á Multi-component reaction Á Catalysis
Introduction
Experimental
Within the repertoire of synthetic strategies available to
organic chemists, multi-component reactions (MCRs) are
mostly advantageous because they allow the creation of
several bonds in a single operation [1–4]. Also usage of
water addresses the several concerns of green chemistry
such as easy availability, safe handling, simple workups
and cost effective for small and bulk-scale process indus-
tries [5].
Chemicals were purchased from Fluka, Merck and Aldrich
chemical companies. The known products were charac-
terized by comparison of their spectral (1H NMR, and 13C
NMR) and physical data with those of authentic samples.
1
Unknown compounds were identified by their H and 13C
NMR spectra.
Compounds with biological activity are often derived
from heterocyclic structures [6]. Among them, quinazoli-
none derivatives have been found to possess a wide spec-
trum of pharmacological activities, e.g. as antibacterial [7],
antitumor [8], anticancer [9], and antifungal agents [10]. In
this light, 2,3-dihydroquinazolin-4(1H)-one derivatives are
an important class of quinazolinones, which exhibit
Preparation of supported L-pyrrolidine-2-carboxylic
acid-4-hydrogen sulfate on silica gel
A 100 mL suction flask containing L-hydroxyproline (5 g,
38.13 mmol) was equipped with a constant-pressure
dropping funnel containing chlorosulfonic acid (2.53 mL)
and gas inlet tube (the HCl created during the reaction was
trapped in water). Chlorosulfonic acid was added dropwise
over a period of 30 min at room temperature. The resulting
mixture was shaken for 30 min and kept at 50 °C for 5 h.
Then, silica gel (8.05 g) was added to the resulting gummy
product and shaken for 30 min. A white solid [supported
A. Ghorbani-Choghamarani (&) Á P. Zamani
Department of Chemistry, Faculty of Science,
Ilam University, P.O. Box 69315516, Ilam, Iran
e-mail: arashghch58@yahoo.com; a.ghorbani@mail.ilam.ac.ir
123

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J IRAN CHEM SOC (2012) 9:607–613
L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate on sil-
ica gel (50% w/w)] of 16.10 g was obtained.
6.69–6.63 (m, 2H), 5.88 (s, 1H), 3.90–3.84 (m, 1H),
2.80–2.73 (m, 1H), 1.58–1.51 (m, 1H), 1.49–1.44 (m, 1H),
1.23 (m, 6H), 0.86–0.83 (m, 3H) ppm; 13C NMR
(100 MHz, DMSO-D6): d = 162.6, 146.5, 140.7, 133.7,
133.4, 129.0, 128.5, 127.9, 117.7, 115.5, 114.8, 69.8, 45.0,
31.4, 27.9, 26.4, 22.5, 14.4 ppm.
L-Pyrrolidine-2-carboxylic acid-4-hydrogen sulfate
1H NMR (400 MHz, DMSO-D6): d = 9.70 (s, 1H), 8.74 (s,
1H), 4.40 (m, 1H), 4.36 (m, 1H), 3.31–3.33 (m, 1H),
3.00–3.10 (m, 1H), 2.15–2.20 (m, 1H), 2.00–2.06 (m, 1H),
ppm; 13C NMR (100 MHz, DMSO-D6): d = 170.1, 69.0,
58.2, 53.8, 37.5 ppm.
3-Hexyl-2-p-tolyl-2,3-dihydroquinazolin-4(1H)-one
(4g) 1H NMR (400 MHz, DMSO-D6): d = 7.64 (d, 1H,
J = 7.6 Hz), 7.29–7.14 (m, 6H), 6.67–6.62 (m, 2H), 5.80
(s, 1H), 3.88–3.83 (m, 1H), 2.76–2.69 (m, 1H), 2.26 (s,
3H), 1.57–1.50 (m, 1H), 1.48–1.41 (m, 1H), 1.27–1.23 (m,
6H), 0.86–0.83 (m, 3H) ppm; 13C NMR (100 MHz,
DMSO-D6): d = 162.7, 146.8, 138.7,138.1, 133.5, 129.5,
127.8, 126.6, 117.5, 115.5, 114.7, 70.4, 44.8, 31.4, 27.8,
26.5, 22.5, 21.1, 14.4 ppm.
General procedure for the synthesis
of 2,3-dihydroquinazolin-4(1H)-ones
Supported L-pyrrolidine-2-carboxylic acid-4-hydrogen sul-
fate on silica gel (0.42 g) was added to the mixture of isatoic
anhydride (1 mmol), primary amine (1.1 mmol) or ammo-
nium acetate (1.2 mmol) and aldehyde (1 mmol) in water
(5 mL). The mixture was heated at 80 °C for the appropriate
time (reaction progress was monitored by TLC). After
completion of the reaction, the white solid mixture was fil-
tered off and washed with water (4 9 20 mL). The resulting
mixture was dissolved in hot ethanol (25 mL) and filtered.
Then, the residue was concentrated and dried to obtain cor-
responding 2,3-dihydroquinazolin-4(1H)-one. To obtain high
pure 2,3-dihydroquinazolin-4(1H)-one, the crude product
was crystallized from water/ethanol mixture (1:1).
2-(4-Bromophenyl)-3-hexyl-2,3-dihydroquinazolin-4(1H)-
one (4h) 1H NMR (400 MHz, DMSO-D6): d = 7.66 (d,
1H, J = 8.0 Hz), 7.56 (d, 2H, J = 8.4 Hz), 7.39–7.38 (m,
1H), 7.29 (d, 2H, J = 8.4 Hz), 7.22–7.18 (m, 1H),
6.69–6.63 (m, 2H), 5.87 (s, 1H), 3.92–3.85 (m, 1H),
2.80–2.73 (m, 1H), 1.58–1.51 (m, 1H), 1.49–1.44 (m, 1H),
1.23 (m, 6H), 0.86–0.82 (m, 3H) ppm; 13C NMR
(100 MHz, DMSO-D6): d = 162.6, 146.5, 141.1, 133.7,
131.9, 128.8, 127.9, 122.0, 117.8, 115.5, 114.8, 69.8, 45.0,
31.4, 27.9, 26.4, 22.5, 14.4 ppm.
1
Selected H NMR and 13C NMR data
3-Hexyl-2-(4-methoxyphenyl)-2,3-dihydroquinazolin-
4(1H)-one (4i) 1H NMR (400 MHz, DMSO-D6):
d = 7.65 (d, 1H, J = 7.6 Hz), 7.29–7.17 (m, 4H), 6.91 (d,
2H, J = 8.4 Hz), 6.67–6.63 (m, 2H), 5.79 (s, 1H),
3.86–3.79 (m, 1H), 3.72 (s, 3H), 2.77–2.70 (m,
1H),1.55–1.49 (m, 1H), 1.47–1.42 (m, 1H), 1.25–1.23 (m,
6H), 0.86–0.83 (m, 3H) ppm; 13C NMR (100 MHz,
DMSO-D6): d = 162.7, 159.8, 146.8, 133.6, 133.5, 128.0,
127.8, 117.5, 115.5, 114.7, 114.3, 70.3, 55.6, 44.7, 31.4,
27.8, 26.5, 22.5, 14.4 ppm.
2-(4-Chlorophenyl)-3-hexyl-2,3-dihydroquinazolin-4(1H)-
one (4f) 1H NMR (400 MHz, DMSO-D6): d = 7.65 (d,
1H, J = 7.6 Hz), 7.44–7.34 (m, 5H), 7.23–7.18 (m, 1H),
HO
HO3SO
+ ClSO3H
COOH
COOH
+ HCl
N
H
N
H
2-(3,4-Dimethoxyphenyl)-3-hexyl-2,3-dihydroquinazolin-
4(1H)-one (4j) 1H NMR (400 MHz, DMSO-D6):
d = 7.66 (d, 1H, J = 7.6 Hz), 7.25–7.18 (m, 2H), 7.04 (m,
Scheme 1 Preparation of pyrrolidine-2-carboxylic acid-4-hydrogen
sulfate
Scheme 2 Synthesis of 2,3-
dihydroquinazolin-4(1H)-ones
O
HO3SO
O
/SiO
COOH
2
R1
R2
N
H
O
N
(Cat.)
+ R1NH2 + R2CHO
H2O, 80 °C
N
H
O
N
H
1
2
3
4
R1 = H, Alkyl or Aryl
R2 = Aryl
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J IRAN CHEM SOC (2012) 9:607–613
609
Table 1 Synthesis of 2,3-
dihydroquinazolin-4(1H)-one
derivatives via condensation of
isatoic anhydride, aldehydes and
primary amines or ammonium
acetate in the presence of a
catalytic amount of supported
L-pyrrolidine-2-carboxylic acid-
4-hydrogen sulfate on silica gel
at 80 °C in water
Yield
(%)a
Time
(min)
Ref.
Mp (°C) found
Mp (°C)
reported
O
H
N
N
H
O
H
N
N
H
Me
O
H
N
N
H
Br
O
H
N
N
H
OMe
O
C6H13
N
N
H
O
C6H13
N
N
H
Cl
O
C6H13
N
N
H
Me
O
C6H13
N
N
H
Br
O
C6H13
N
N
H
OMe
O
C6H13
N
N
H
OMe
OMe
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J IRAN CHEM SOC (2012) 9:607–613
Table 1 continued
Yield
(%)a
Time
(min)
Ref.
Mp (°C) found
Mp (°C)
reported
Me
O
N
N
H
Me
O
N
N
H
Cl
Me
O
N
N
H
F
Me
O
N
N
H
Me
CH(CH3
)
2
O
N
N
H
CH(CH3
)
2
O
N
N
H
Br
CH(CH3
)
2
O
N
N
H
OMe
OMe
CH(CH3
)
2
O
N
N
H
F
Molar ratio of reagents: isatoic
anhydride/aldehyde/amine/
catalyst for entries 1–5:
(1:1:1.2:0.42 g); for entries
6–21: (1:1:1.1:0.42 g)
CH(CH3
)
2
O
N
N
H
Me
a
Crude isolated yield
1H), 6.91–6.89 (m, 1H), 6.82–6.80 (m, 1H), 6.68–6.64 (m,
2H), 5.78 (s, 1H), 3.88–3.81 (m, 1H), 3.72 (s, 3H), 3.71 (s,
3H), 2.79–2.72 (m, 1H), 1.56–1.49 (m, 1H), 1.48–1.44 (m,
1H), 1.27–1.23 (m, 6H), 0.86–0.82 (m, 3H) ppm; 13C NMR
(100 MHz, DMSO-D6): d = 162.8, 149.3, 149.2, 146.9,
133.8, 133.5, 127.8, 118.8, 117.5, 115.6, 114.7, 111.8,
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J IRAN CHEM SOC (2012) 9:607–613
611
Scheme 3 Preparation of 2,3-
dihydroquinazolin-4(1H)-ones
in the absence of catalyst
O
NH2
CHO
O
O
N
(Without catalyst)
H2O, 80 °C, 6h
+
+
N
H
O
N
H
Cl
Cl
40 %
110.8, 70.5, 55.9, 55.8, 44.7, 31.4, 27.9, 26.5, 22.5,
14.4 ppm.
129.1 (d, 36 Hz), 128.4, 127.0, 126.6, 118.1, 115.9, 115.7
(d, 84 Hz), 115.3, 72.4, 33.4, 24.3 ppm.
2-(4-Fluorophenyl)-3-p-tolyl-2,3-dihydroquinazolin-
4(1H)-one (4m) 1H NMR (400 MHz, DMSO-D6):
d = 7.70 (d, 1H, J = 7.6 Hz), 7.57 (m, 1H), 7.40–7.11 (m,
Results and discussion
9H), 6.75–6.71 (m, 2H), 6.26 (s, 1H), 2.24 (s, 3H) ppm; 13
C
In continuation of our recent success in the introduction of
new catalysts for the organic functional group transfor-
mations [18–26], we became interested in preparation L-
pyrrolidine-2-carboxylic acid-4-hydrogen sulfate as an
efficient, non-toxic, and green catalyst. L-Pyrrolidine-2-
carboxylic acid-4-hydrogen sulfate was prepared by reac-
tion of L-hydroxyproline with chlorosulfonic acid at room
temperature (Scheme 1). Because of gummy properties of
this compound, it was supported on silica gel.
NMR (100 MHz, DMSO-D6): d = 162.7, 162.3 (d,
976 Hz), 147.0, 138.5, 137.4, 135.9, 134.2, 129.6, 129.3 (d,
36 Hz), 128.4, 126.9, 118.1, 115.8, 115.4 (d, 132 Hz), 73,
21.0 ppm.
2-(3,4-Dimethoxyphenyl)-3-(4-isopropylphenyl)-2,3-dihy-
(4q) HNMR
droquinazolin-4(1H)-one
(400 MHz,
DMSO-D6): d = 7.73 (d, 1H, J = 6.8 Hz), 7.58 (m, 1H),
7.29–7.22 (m, 5H), 7.00 (s, 1H), 6.89–6.84 (m, 2H),
6.77–6.70 (m, 2H), 6.18 (s, 1H), 2.87 (sep, 1H, J = 6.8),
1.19 (d, 6H, J = 6.8) ppm; 13C NMR (100 MHz, DMSO-
D6): d = 162.7, 149.1, 149.0, 147.0, 146.5, 139.2, 134.1,
133.5, 128.3, 126.9, 126.5, 119.1, 117.9, 116.0, 115.3,
111.5, 110.8, 72.9, 55.9, 55.8, 33.4, 24.3 ppm.
Therefore, supported L-pyrrolidine-2-carboxylic acid-4-
hydrogen sulfate on silica gel was used as an effective
catalyst for the one-pot three-component condensation of
different types of aldehydes, primary amines or ammonium
acetate and isatoic anhydride in water (as solvent) at 80 °C
(Scheme 2). The results for this transformation are sum-
marized in Table 1.
2-(4-Fluorophenyl)-3-(4-isopropylphenyl)-2,3-dihydroqui-
nazolin-4(1H)-one (4r) 1H NMR (400 MHz, DMSO-D6):
d = 7.74–7.72 (m, 1H), 7.65–7.64 (m, 1H), 7.44–7.40 (m,
2H), 7.30–7.12 (m, 7H), 6.77–6.71 (m, 2H), 6.28 (s, 1H),
2.87 (sep, 1H, J = 6.8), 1.19 (d, 6H, J = 6.8) ppm; 13C
NMR (100 MHz, DMSO-D6): d = 162.6, 162.3 (d,
972 Hz), 146.8, 146.7, 138.9, 137.6 (d, 12 Hz), 134.2,
2,3-Dihydroquinazolin-4(1H)-one compounds were eas-
ily prepared by mixing an aldehyde, isatoic anhydride, a
primary amine or ammonium acetate and supported L-pyr-
rolidine-2-carboxylic acid-4-hydrogen sulfate on silica gel
(10 mol %) in water, then stirring this suspension at 80 °C
for the appropriate time. After completion of the reaction,
the resulting solid precipitate was filtrated off and washed
HO3SO
Scheme 4 Recoverability of
the catalyst
CH(CH3)2
O
NH2
CHO
O
COOH
N
O
N
H
+
+
H2O, 80 °C, 35 min
N
H
O
N
H
CH(CH3)2
Run No.
Yield
1
2
3
4
5
6
98
92
90
89
89
91
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J IRAN CHEM SOC (2012) 9:607–613
Scheme 5 Mechanism of
synthesis of 2,3-
dihydroquinazolin-4(1H)-ones
HO3SO
O
/SiO
COOH
(Cat.)
OH
2
H
O
N
H
N
R1
O
O
O
H2N -R1
N
H
O
N
H
O
N
H
O
H
H
O
O
H
R1
N
R1
Cat
N
OH
-Co2
NH2
N
R2
H
R2
O
R1
R2
N
N
H
with water. The resulting solid mixture was dissolved in hot
ethanol and filtered off. Then, the ethanol was evaporated to
obtain corresponding 2,3-dihydroquinazolin-4(1H)-one.
Recrystallization of the crude product from water/ethanol
gave highly pure 2,3-dihydroquinazolin-4(1H)-one.
To investigate the role of catalyst for the preparation of
2,3-dihydroquinazolin-4(1H)-ones, isatoic anhydride was
reacted with 4-chlorobenzaldehyde and 4-iso-propylaniline
in the absence of supported L-pyrrolidine-2-carboxylic
acid-4-hydrogen sulfate on silica gel. As is evident from
Scheme 3, we observed that the corresponding 2,3-dihy-
droquinazolin-4(1H)-one was formed in only 40% yield
after 6 h.
important features provided by this procedure are the use of
L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate (sup-
ported on silica gel) as an effective, non-toxic, cost effec-
tive and recoverable catalyst. Eventually, the most
important feature of described protocol is the use of water
(as solvent), because water is the most abundant, cheapest
and eco-friendly solvent.
Acknowledgments Financial support to this work by the Ilam
University, Ilam, Iran is gratefully acknowledged.
References
Scheme 4 shows the reusability of the catalyst for the
preparation of 3-(4-isopropylphenyl)-2-phenyl-2,3-dihy-
droquinazolin-4(1H)-one. It was observed from the recycle
study that the efficiency of L-pyrrolidine-2-carboxylic acid-
4-hydrogen sulfate remained unchanged even after the 6th
recycle. It could be suggested that the catalyst was not
deactivated during the catalytic or separation processes.
Also, L-pyrrolidine-2-carboxylic acid-4-hydrogen sulfate
could be recovered almost completely.
1. M.B.M. Reddy, M.A. Pasha, Synth Commun. 41, 1875 (2011)
2. M. Guasconi, X.Y. Lu, A. Massarotti, A. Caldarelli, E. Ciraolo,
G.C. Tron, E. Hirsch, G. Sorba, T. Pirali, Org. Biomol. Chem. 9,
4144 (2011)
3. V.P. Mehta, S.G. Modha, E. Ruijter, K. Van Hecke, L. Van
Meervelt, C. Pannecouque, J. Balzarini, R.V.A. Orru, E.D. Eyc-
kent, J. Org. Chem. 76, 2828 (2011)
4. A.R. Kazemizadeh, A. Ramazani, J. Braz. Chem. Soc. 20, 309
(2009)
5. D. Kumar, N.M. Kumar, G. Patel, S. Gupta, R.S. Varma, Tetra-
hedron Lett. 52, 1983 (2011)
Suggested mechanism for this transformation has been
outlined in Scheme 5.
6. J. Chen, D. Wu, F. He, M. Liu, H. Wu, J. Ding, W. Su, Tetra-
hedron Lett. 49, 3814 (2008)
In conclusion, we have delineated a green, versatile and
facile procedure for the synthesis of 2,3-dihydroquinazolin-
4(1H)-one derivatives via one-pot three-component con-
densation of isatoic anhydride, aldehydes and primary
amines or ammonium acetate in water at 80 °C. The
7. N.B. Patel, J.C. Patel, Med. Chem. Res. 20, 511 (2011)
8. R.J. Abdel-Jalil, E. Al-Momani, L. Tahtamooni, H.J. Machulla,
W. Voelter, Lett. Org. Chem. 7, 360 (2010)
9. A. Kamal, E.V. Bharathi, J.S. Reddy, M.J. Ramaiah, D. Dastagiri,
M.K. Reddy, A. Viswanath, T.L. Reddy, T.B. Shaik, S.N.C.V.L.
Pushpavalli, M.P. Bhadra, Eur. J. Med. Chem. 46, 691 (2011)
123

J IRAN CHEM SOC (2012) 9:607–613
613
10. H. Wu, X.L. Xie, G. Liu, J. Comb. Chem. 12, 346 (2010)
11. L.Y. Zeng, C. Cai, J. Heterocycl. Chem. 47, 1035 (2010)
12. M. Baghbanzadeh, P. Salehi, M. Dabiri, G. Kozehgary, Synthesis
344 (2006)
21. A. Ghorbani-Choghamarani, M.A. Zolfigol, R. Ayazi-nasrabadi,
J. Braz. Chem. Soc. 21, 33 (2010)
22. A. Ghorbani-Choghamarani, J. Zeinivand, J. Iran. Chem. Soc. 7,
190 (2010)
13. Z.H. Zhang, H.Y. Lu, S.H. Yang, J.W. Gao, J. Comb. Chem. 12,
643 (2010)
23. A. Ghorbani-Choghamarani, N. Cheraghi-Fathabad, Chin.
J. Catal. 31, 1103 (2010)
14. S. Rostamizadeh, A.M. Amani, G.H. Mahdavinia, H. Sepehrian,
S. Ebrahimi, Synthesis 1356 (2010)
24. A. Ghorbani-Choghamarani, M.A. Zolfigol, T. Rastegar, Chin.
J. Catal. 30, 273 (2009)
15. O.I. El-Sabbagh, S.M. Ibrahim, M.M. Baraka, H. Kothayer, Arch.
Pharm. Chem. Life Sci. 343, 274 (2010)
16. Y.X. Zong, Y. Zhao, W.C. Luo, X.H. Yu, J.K. Wang, Y. Pan,
Chin. Chem. Lett. 21, 778 (2010)
17. J. Chen, W. Su, H. Wu, M. Liu, C. Jin, Green Chem. 9, 972
(2007)
18. A. Ghorbani-Choghamarani, M. Norouzi, Bull. Korean Chem.
Soc. 32, 1399 (2011)
25. A. Ghorbani-Choghamarani, M. Hajjami, H. Goudarziafshar, M.
Nikoorazm, S. Mallakpour, F. Sadeghizadeh, G. Azadi, Monatsh.
Chem. 140, 607 (2009)
26. A. Ghorbani-Choghamarani, P. Zamani, J. Iran. Chem. Soc. 8,
142 (2011)
27. A. Davoodnia, S. Allameh, S. Fakhari, N. Tavakoli-Hoseini,
Chin. Chem. Lett. 21, 550 (2010)
28. A. Ghorbani-Choghamarani, T. Taghipour, Lett. Org. Chem. 8,
470 (2011)
19. A. Ghorbani-Choghamarani, M. Norouzi, Chin. J. Catal. 32, 595
(2011)
20. A. Ghorbani-Choghamarani, M.A. Zolfigol, M. Hajjami, K.
Darvishi, L. Gholamnia, Collect. Czech. Chem. Commun. 75,
607 (2010)
123