Nano-Fe3O4 encapsulated-silica particles bearing sulfonic acid groups as a magnetically separable catalyst for green and efficient synthesis of functionalized pyrimido[4,5-b]quinolines and indeno fused pyrido[2,3-d]pyrimidines in water

Article abstract of DOI:10.1016/j.cclet.2013.02.018

The magnetic nanoparticles supported silica sulfuric acid was used as an efficient catalyst for the synthesis of pyrimido[4,5-b]quinolines and indeno fused pyrido[2,3-d]pyrimidines in water. The desired products were obtained in excellent yields. Fe₃O₄@SiO₂-SO₃H was readily recovered using an external magnet and could be reused several times without significant loss of reactivity.

Full text of DOI:10.1016/j.cclet.2013.02.018

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CCLET-2484; No. of Pages 3
Chinese Chemical Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Nano-Fe3O4 encapsulated-silica particles bearing sulfonic acid groups as a
magnetically separable catalyst for green and efficient synthesis of functionalized
pyrimido[4,5-b]quinolines and indeno fused pyrido[2,3-d]pyrimidines in water
*
Firouzeh Nemati , Raheleh Saeedirad
Department of Chemistry, Semnan University, Semnan 35131-19111, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
The magnetic nanoparticles supported silica sulfuric acid was used as an efficient catalyst for the
synthesis of pyrimido[4,5-b]quinolines and indeno fused pyrido[2,3-d]pyrimidines in water. The desired
products were obtained in excellent yields. Fe3O4@SiO2–SO3H was readily recovered using an external
magnet and could be reused several times without significant loss of reactivity.
ß 2013 Firouzeh Nemati. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Received 11 December 2012
Received in revised form 26 January 2013
Accepted 31 January 2013
Available online xxx
Keywords:
Magnetic nanoparticles
Pyrimido[4,5-b]quinolines
Indeno fused pyrido[2,3-d]pyrimidines
Green solvent
1. Introduction
pyrido[2,3-d]pyrimidines have also been identified as a new class
of fibroblast growth factor receptor (FGFR3) tyrosine kinase
Multi-component coupling reactions (MCRs) have proved a
highly valuable synthetic tool for building diverse and complex
molecular structures through C–C and C-heteroatom bond
formation. These types of reactions are especially attractive
because of their atom economy, operational simplicity, reduction
in the number of workup, extraction and purification processes
and hence minimize waste generation. Recently this strategy has
been used effectively in the synthesis of many biologically active
substrates and natural products [1]. The usefulness of multi-
component reactions is significantly expanded if they are
conducted with green procedures.
inhibitors [7].
Supported magnetic metal nanoparticles have emerged as a
new class of nano catalysts [8]. Because of their high surface area,
they generally exhibit higher catalytic activity than conventional
heterogeneous acid catalysts. Recently, sulfonic acid-functional-
ized silica-coated nano-Fe3O4 particles (Fe3O4@SiO2–SO3H) have
been prepared in our laboratory as an efficient acid catalyst. It
could be readily separated from the media using a simple external
magnet and reused several times [9]. The process is more effective
than filtration and centrifugation in preventing loss of the solid
catalyst.
Quinolines are valuable heterocyclic compounds due to their
various biological and pharmaceutical activities [2]. These
compounds have shown wide applications as key structural motifs
in a large number of bioactive drugs such as Quinine, Chloroquine,
Luotonine-A and Camptothecin [3]. Organic compounds contain-
ing pyrimidine scaffolds are of growing interest due to their
biological potencies such as AbI kinase inhibitor [4], tyrosine
phosphatase inhibitor [5], antiviral and calcium channel
antagonist activities [6]. Moreover, appropriately functionalized
2. Experimental
General procedure for the synthesis compounds 6 and 8: A mixture
of 6-amino-1,3-dimethyl uracil (1.0 mmol), benzaldehyde
(1.0 mmol), 1,3-diketone (1.0 mmol) and Fe3O4@SiO2–SO3H
(0.02 g) in distilled H2O (1 mL) was stirred for appropriate time
at 70 8C. Upon completion of the reaction (monitored by TLC), the
reaction mixture was allowed to cool to room temperature. The
catalyst was separated from the solid crude product using an
external magnet. The obtained solid was then filtered and the
crude product collected and crystallized from EtOH to afford the
pure product in 81%–95% yields.
* Corresponding author.
E-mail address: fnemati@semnan.ac.ir (F. Nemati).
1001-8417/$ – see front matter ß 2013 Firouzeh Nemati. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.02.018
Please cite this article in press as: F. Nemati, R. Saeedirad, Nano-Fe3O4 encapsulated-silica particles bearing sulfonic acid groups as a
magnetically separable catalyst for green and efficient synthesis of functionalized pyrimido[4,5-b]quinolines and indeno fused
pyrido[2,3-d]pyrimidines in water, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.02.018

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CCLET-2484; No. of Pages 3
2
F. Nemati, R. Saeedirad / Chinese Chemical Letters xxx (2013) xxx–xxx
Data For 6c: IR (KBr, cmꢀ1): ymax 3410, 1666, 1612; 1H NMR
(400 MHz, CDCl3): 1.26 (s, 3H), 1.28 (s, 3H), 2.26 (d, 1H,
J = 16.4 Hz), 2.31 (d, 1H, J = 16.8 Hz), 2.44 (d, 1H, J = 16.4 Hz), 2.50
(d, 1H, J = 16.8 Hz), 3.29 (s, 3H), 3.59 (s, 3H), 5.12 (s, 1H), 7.44–7.11
(m, 4H), 9.12 (s, 1H); 13C NMR (100 MHz, CDCl3):
d 18.4, 27.2, 27.3,
Table 1
Optimization of reaction condition and comparison of the efficiency of Fe3O4@SiO2-
SO3H with other catalyst for the synthesis of 8,9-dihydro-1,3,8,8-tetramethyl-5-(4-
chlorophenyl)pyrimido[4,5-b]quinoline- 2,4,6(1H,3H,5H,7H,10H)-trione (6g).
d
Entry
Catalyst
Catalyst
loading
condition
Time
Yield (%)
(min)
28.8, 29.2, 32.6, 32.8, 41.6, 50.2, 122.6, 123.3, 125.2, 126.3, 127.4,
129.65, 129.69, 130.5, 161.0, 203.2. Anal. Calcd. for C21H22N3O3Br:
C 58.07, H 5.08, 9.68 N; found: C 57.99, H 5.01, N 9.75.
1
2
3
4
5
6
7
8
p-TsOH
20 mol%
20 mol%
2 mL
H2O/90 8C
H2O/reflux
95 8C
H2O/70 8C
EtOH/reflux
CH3CN/reflux
H2O/70 8C
H2O/70 8C
150
60
89 [11]
91 [12]
90 [13]
92
InCl3
[bmim]Bra
210
25
6e: IR (KBr, cmꢀ1):
y
max 3409, 1697, 1596; 1H NMR (400 MHz,
Fe3O4@SiO2–SO3H
Fe3O4@SiO2–SO3H
Fe3O4@SiO2–SO3H
Nano-Fe3O4
Fe3O4@SiO2
20 mg
20 mg
20 mg
20 mg
20 mg
CDCl3): 1.14 (s, 3H), 1.27 (s, 3H), 2.21 (d, 1H, J = 16.4 Hz), 2.34 (d,
d
100
100
25
86
51
1H, J = 16.8 Hz), 2.56 (d, 1H, J = 16.4 Hz), 3.3 (s, 3H), 3.55 (s, 3H),
5.65 (s, 1H), 7.43–7.50 (m, 4H), 8.052 (s, 1 H), 12.62 (s, 1H); 13C
70
25
49
NMR (100 MHz, CDCl3):
d 18.4, 27.2, 27.3, 28.8, 29.2, 32.1, 32.6,
a
1-n-Buthyl-3-methylimidazolium bromide.
42.5, 51.0, 121.6, 124.7, 125.2, 126.3, 127.4, 129.65, 129.69, 135.4,
161.1, 203.0. Anal. Calcd. for C21H22N4O5: C 61.46, H 5.36, N 13.65;
found: C 61.55, H 5.29, N 13.74.
of yields. The proficient catalytic activity of Fe3O4@SiO2–SO3H was
related to the –SO3H groups of the catalyst, which could provide
efficient acidic sites. Various solvents were also screened to test the
efficiency of the catalyst in different reaction media (Table 1, entries
4–6). Product yields were found to be improved in water. It is
noteworthy to mention that quantity of the catalyst plays an
essential role in the formation of the desired product. The best result
was obtained by using 0.02 g catalyst at 70 8C in aqueous medium
(Table1, entry 4). The startingmaterialswerecompletelyconsumed.
Furthermore, the easy recovery of the catalyst and simple workup in
water follow principles of ‘‘green chemistry’’.
6j: IR (KBr, cmꢀ1): max 3402, 1697; 1H NMR (400 MHz, CDCl3):
n
d
2.33 (s, 3H), 3.34 (s, 6H), 3.52 (s, 6H), 5.64 (s, 1H), 7.06 (d, 2H,
J = 8.0 Hz), 7.12 (d, 2H, J = 8.0 Hz), 14.54 (s, 1H); 13C NMR
(100 MHz, CDCl3): 28.7, 28.8, 29.6, 128.7, 129.9, 134.3, 135.0,
d
135.6, 150.4, 151.1, 159.5, 160.5. Anal. Calcd. for C20H22N4O5: C
60.30, H 5.52, N 14.07; found: C 60.21, H 5.45, N 14.15.
8a: IR (KBr, cmꢀ1): nmax 1720, 1666, 1566, 1496; 1H NMR
(300 MHz, CDCl3):
7.56 (d, 2H, J = 7.4 Hz), 7.66–7.84 (m, 2H), 8.47–8.52 (m, 2H); 13C
NMR (100 MHz, CDCl3): 30.1, 37.5, 113.0, 118.6, 119.5, 125.7,
d 3.37 (s, 3H), 3.94 (s, 3H), 7.41–7.52 (m, 3H),
d
128.0, 128.1, 129.8, 130.3, 131.6, 132.5, 151.7, 158.4, 160.3, 170.2,
172.5, 185.5. Anal. Calcd. for C20H22N4O5: C 71.54, H 4.06, N 11.38;
found: C 71.46, H 3.95, N 11.26.
The advantages and limitations of this methodology were
investigated by reacting 6-amino-1,3-dimethyl uracil and dime-
done with various substituent benzaldehydes to give functional-
ized pyrimido[4,5-b]quinolines (Table 2, entries 1–9). Irrespective
of the presence of an electron withdrawing or releasing substitu-
ent, the reaction proceeded fairly well and afforded the desired
products in good yields. Similarly, scope of the reaction was also
extended by reacting other 1,3-diketones such as 1,3-indanedione,
1,3-dimethylbarbituric acid and ethyl acetoacetate (Table 2,
entries 10–14). As the results in Table 2 appended, Fe3O4@SiO2–
SO3H proved to be a useful nanomagnetic heterogeneous acid
catalyst for green synthesis of functionalized pyrimido[4,5-b]
quinolines and indeno fused pyrido[2,3-d]pyrimidines in excellent
yields.
The possible mechanism is postulated in Scheme 2. The
Knoevenagel condensation and Michael addition produce inter-
mediates A and B respectively. Subsequently, annulation, dehydra-
tion and aromatization on intermediate B yield the final product.
Fe3O4@SiO2–SO3H was simply recovered with an external
magnet, washed with chloroform several times and dried at 60 8C
for 1 h. The recovered catalyst successfully catalyzed synthesis of
6g three consecutive times without a significant drop in product
3. Results and discussion
In continuation of effort to employ environmentally benign
reaction media [10], we have attempted to develop catalytic
application of Fe3O4@SiO2–SO3H for clean synthesis of structurally
diverse functionalized pyrimido[4,5-b]quinolines and indeno
fused pyrido[2,3-d]pyrimidines via one-pot condensation of 6-
amino-1,3-dimethyl uracil, 1,3-dicarbonyl compounds and aro-
matic aldehydes in water (Scheme 1).
The efficiency of Fe3O4@SiO2–SO3H as a catalyst for the
synthesis of the model compound 8,9-dihydro-1,3,8,8-tetra-
methyl-5-(4-chlorophenyl)pyrimido[4,5-b]quinoline-2,4,6(1H,3H,
5H,7H,10H)-trione (6g) was compared with that of other catalysts
reported in the literature (Table 1). It is clear from this Table that
Fe3O4@SiO2–SO3H has proved to be the more efficient catalyst for
thesynthesisofquinolines. The modelreactionwasperformed using
nano-Fe3O4 and Fe3O4@SiO2 (Table 1, entries 7 and 8). As shown in
Table 1, the Fe3O4@SiO2–SO3H can act as a suitable catalyst in terms
O
Ar
O
Me
O
N
3, 4 or 5
N
N
H
O
Me
Me
Me
N
N
O
Nano-Fe3O4@SiO2-SO3H
70 o C/ H2O
Ar-CHO +
6a-l
Ar
H2N
O
O
O
1
2
Me
N
7
O
O
O
O
O
N
Me
N
Me
Me
O
O
N
N
8a-b
EtO
O
O
4
5
3
Scheme 1. Synthesis of pyrimido[4,5-b]quinolines and indeno fused pyrido[2,3-d]pyrimidines.
Please cite this article in press as: F. Nemati, R. Saeedirad, Nano-Fe3O4 encapsulated-silica particles bearing sulfonic acid groups as a
magnetically separable catalyst for green and efficient synthesis of functionalized pyrimido[4,5-b]quinolines and indeno fused
pyrido[2,3-d]pyrimidines in water, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.02.018

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CCLET-2484; No. of Pages 3
F. Nemati, R. Saeedirad / Chinese Chemical Letters xxx (2013) xxx–xxx
3
Table 2
Synthesis of pyrimido[4,5-b]quinolines and indeno fused pyrido[2,3-d]pyrimidines using Fe3O4@SiO2–SO3H in water.
Entry
Ar-CHO
Diketone
Product
Time (min)
Yield (%)
Mp (Lit.)8C
1
2
C6H5
Dimedone
6a
6b
6c
6d
6e
6f
30
40
35
25
30
35
25
30
35
20
30
35
30
25
92
86
90
92
90
81
92
89
87
95
92
87
90
94
268–270(268)[14]
>300 (>300)[13]
280–282
4-OMe-C6H4
3-Br-C6H4
4-NO2-C6H4
3-NO2-C6H4
2-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
2-Thiophen
4-Me-C6H4
C6H5
Dimedone
3
Dimedone
4
Dimedone
223–225(222–224)[12]
220–223
5
Dimedone
6
Dimedone
>300 (>300)[13]
289–292(291)[14]
234–236
7
Dimedone
6g
6h
6i
8
Dimedone
9
Dimedone
295–297(296–298)[12]
238–240
10
11
12
13
14
Dimethylbarbituric acid
Ethyl acetoacetate
Ethyl acetoacetate
1,3-Indanedione
1,3-Indanedione
6j
6k
6l
298–299
4-OMe-C6H4
C6H5
267–269
8a
8b
>300
4-NO2-C6H4
258–260(252-254)[12]
O
Me
O
N
H
O
O
Ar
O
H
OH
O
OH
H2N
N
Me
N
CH
H
Me
Ar
H
Cyclization
C
N
O
N
Michael addition
Knoevenagel condensation
Ar
NH
O
O
Me
B
A
O
Ar
O
O
Ar
O
Ar
N
O
O
Me
N
Me
O
[O]
Me
O
Dehydration
N
O
N
N
H
Aromatization
N
N
H
OH
N
Me
Me
Me
Scheme 2. Plausible mechanism.
[5] K.C. Thakkar, S.J. Berthel, A.W.H. Cheung, et al., US Applications, Patent No.
20070021445.
[6] X.S. Wang, Z.S. Zeng, D.Q. Shi, X.Y. Wei, Z.M. Zong, KF-Alumina catalyzed one-pot
synthesis of pyrido[2,3-d]pyrimidine derivatives, Synth. Commun. 34 (2004)
4331–4338.
[7] L. Le Corre, A.L. Girard, J. Aubertin, et al., Synthesis and biological evaluation of a
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nanocatalyst for the one-pot multicomponent synthesis of diazepines, Tetrahe-
dron 68 (2012) 7827–7833.
yields. The yields for the three runs were found to be 92%, 88% and
81%, respectively.
4. Conclusion
In conclusion, we have developed an efficient and eco-friendly
method for one pot synthesis of pyrimido[4,5-b]quinolines and
indeno fused pyrido[2,3-d]pyrimidines using nano-Fe3O4@SiO2–
SO3H as the catalyst in water under mild conditions. The catalyst is
completely magnetically recoverable and the efficiency of the
catalyst remains unaltered after three cycles. These advantages
make this methodology attractive for large-scale synthesis.
[9] F. Nemati, M.M. Heravi, R. Saeedirad, Nano-Fe3O4 encapsulated-silica particles
bearing sulfonic acid groups as
a magnetically separable catalyst for
highly efficient Knoevenagel condensation and Michael addition reactions
of aromatic aldehydes with 1,3-cyclic diketones, Chin. J. Catal. 33 (2012)
1825–1831.
[10] (a) F. Nemati, A. Elhampour, Cellulose sulphuric acid as a biodegradable catalyst
for conversion of aryl amines into azides at room temperature under mild
conditions, J. Chem. Sci. 124 (2012) 889–892;
Acknowledgment
(b) F. Nemati, H. Kiani, A green and highly efficient protocol for catalyst-free
Knoevenagel condensation and Michael addition of aromatic aldehydes with 1,3-
cyclic diketones in PEG-400, Chin. J. Chem. 29 (2011) 2407–2410;
(c) F. Nemati, M. Arghan, A. Amoozadeh, Efficient, solvent-free method for the one-
pot condensation of b-naphthol, aromatic aldehydes and cyclic 1,3-dicarbonyl
compounds catalyzed by silica sulfuric acid, Synth. Commun. 42 (2012) 33–39;
(d) F. Nemati, H. Kiani, Zn(NO3)2ꢁ6H2O/2, 4,6-trichloro-1,3,5-triazine (TCT) a mild
and selective system for nitration of phenols, Chin. Chem. Lett. 21 (2010) 403–406.
[11] G.K. Verma, K. Raghuvanshi, R. Kumar, M.S. Singh, An efficient one-pot three-
component synthesis of functionalized pyrimido[4,5-b]quinolines and indeno
fused pyrido[2,3-d]pyrimidines in water, Tetrahedron Lett. 53 (2012) 399–402.
[12] M.J. Khurana, A. Chaudhary, B. Nand, A. Lumb, Aqua mediated indium(III) chloride
catalyzed synthesis of fused pyrimidines and pyrazoles, Tetrahedron Lett. 53
(2012) 3018–3022.
[13] D.Q. Shi, S.N. Ni, F. Yang, et al., An efficient synthesis of pyrimido[4,5-b]quinoline
and indeno[20,10:5,6]pyrido[2,3-d]pyrimidine derivatives via multicomponent
reactions in ionic liquid, J. Heterocyclic Chem. 45 (2008) 693–702.
[14] M.H. Mosslemin, M.R. Nateghi, Rapid and efficient synthesis of fused heterocyclic
pyrimidines under ultrasonic irradiation, Ultrason. Sonochem. 17 (2010)
162–167.
We thank the Department of Chemistry and the office of gifted
students at Semnan University for their financial support.
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Please cite this article in press as: F. Nemati, R. Saeedirad, Nano-Fe3O4 encapsulated-silica particles bearing sulfonic acid groups as a
magnetically separable catalyst for green and efficient synthesis of functionalized pyrimido[4,5-b]quinolines and indeno fused
pyrido[2,3-d]pyrimidines in water, Chin. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.cclet.2013.02.018