Eco-safe and expeditious approaches for synthesis of quinazoline and pyrimidine-2-amine derivatives using ionic liquids aided with ultrasound or microwave irradiation

Article abstract of DOI:10.1016/j.molliq.2014.09.018

Green approaches for efficient synthesis of quinazoline- and pyrimidine-2-amine derivatives were established based on the one-pot and three-component condensation of guanidine carbonate, cyclic ketones and aldehydes. These approaches involve the evaluation of the activity of several acidic ionic liquids (ILs) as organocatalysts under solvent-free medium in the microwave and as solvents and catalysts in the ultrasound irradiations. Reactions were evaluated for a number of substituted aldehydes and cyclic ketones on the basis of variation of parameters including type and amount of ILs, reaction temperature and time. Compared to the ultrasound method, the solvent-free procedure in the microwave was found to be more efficient in terms of both chemical yield and reaction time. Catalyst recyclability, simplicity, and time-saving aspects of the reaction suggests that these methods present real alternatives to conventional reaction protocols.

Full text of DOI:10.1016/j.molliq.2014.09.018

Journal of Molecular Liquids 199 (2014) 267–274
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Eco-safe and expeditious approaches for synthesis of quinazoline and
pyrimidine-2-amine derivatives using ionic liquids aided with
ultrasound or microwave irradiation
b
Masoumeh Zakeri a, , Mohamed M. Nasef
, Ebrahim Abouzari-Lotf
⁎
a,b,⁎⁎
a
Malaysia-Japan International Institute of Technology, International Campus, Universiti Teknologi Malaysia, 54100 Kuala Lumpur, Malaysia
Advanced Materials Research Group, Institute of Hydrogen Economy, Universiti Teknologi Malaysia, International Campus, Jalan Semarak, 54100 Kuala Lumpur, Malaysia
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 August 2014
Received in revised form 2 September 2014
Accepted 11 September 2014
Available online 16 September 2014
Green approaches for efficient synthesis of quinazoline- and pyrimidine-2-amine derivatives were established
based on the one-pot and three-component condensation of guanidine carbonate, cyclic ketones and aldehydes.
These approaches involve the evaluation of the activity of several acidic ionic liquids (ILs) as organocatalysts
under solvent-free medium in the microwave and as solvents and catalysts in the ultrasound irradiations. Reac-
tions were evaluated for a number of substituted aldehydes and cyclic ketones on the basis of variation of param-
eters including type and amount of ILs, reaction temperature and time. Compared to the ultrasound method, the
solvent-free procedure in the microwave was found to be more efficient in terms of both chemical yield and re-
action time. Catalyst recyclability, simplicity, and time-saving aspects of the reaction suggests that these methods
present real alternatives to conventional reaction protocols.
Keywords:
Microwave irradiation
Ultrasonic
Ionic liquid
Quinazoline
Pyrimidine
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
and low vapor pressure. Such properties lead to better catalysts and sol-
vents for a variety of reactions [15–19] including reactions involving
Because of the serious pollution problems, minimizing environmen-
tal risks and designing new eco-safe procedures are becoming an urgent
priority in chemistry. On the other hand, green chemistry and sustain-
ability are becoming increasingly important in organic synthesis [1–3].
One approach to increase the environmental benign of reactions is to
conduct them under solvent-free conditions. In this view, microwave
and ultrasonic irradiations, as eco-environmental technologies in
green chemistry, have become favored in organic chemistry [4–6].
Microwave- and ultrasound-assisted organic syntheses were proven
to be a valuable tool for the efficient synthesis of heterocyclic com-
pounds with biological activities [7–10]. It has been demonstrated that
the use of microwave or ultrasound irradiation, as safe heating sources,
can dramatically reduce the reaction time, increase the purity and yield
of the desired products, allow for closer control over the reaction condi-
tions, and can also be applied in solvent-free conditions [5,11,12].
Recently, there has been a considerable interest in the use of acidic
ILs due to their unique properties in organic reactions [13,14]. This is
due to their environmental compatibility, recyclability, thermal stability
bio-based chemicals [20–22]. Task-specific ILs have also been success-
fully employed as acid catalysts and solvents to perform multicompo-
nent reactions [23–25]. The combination of microwave or ultrasonic
irradiation as a heating source with ILs as catalysts and solvents, for or-
ganic synthetic transformation, opened a new area for investigations
during the past several years [5,11]. Through such combination, ILs
can absorb the irradiation very efficiently and transfer energy quickly
in a way that has potential to efficiently catalyze some reactions [11,26].
The quinazoline- and pyrimidine-2-amine structural sub-units are
contained in a growing number of both natural products and synthetic
compounds with biological properties. For example, Doxazosin mesy-
late, a quinazoline compound, is a α1-selective alpha blocker used to
treat high blood pressure (Fig. 1) [27]. These structural motifs have con-
sequently been extensively used as a drug like scaffold in medicinal
chemistry [28,29].
There are only a few protocols using cyclic aryl ketones for conden-
sation which produced quinazoline and pyrimidine derivatives. But
these methodologies suffer from some drawbacks like use of expensive
and/or toxic catalysts such as FeCl3 [30], pyrrolidinium tosylate [31] and
iodotrimethylsilane (Me3SiI) [32] and other limitations such as unsatis-
factory yields and incompatibility with certain functional groups.
Thus, the request remains for a practical and convenient method. Our
experience in using ILs as catalysts in the synthesis of heterocyclic com-
pounds [19,33–36] encouraged us to establish an efficient synthesis of
⁎
Corresponding author.
⁎⁎ Corresponding author at: Malaysia-Japan International Institute of Technology,
International Campus, Universiti Teknologi Malaysia, 54100 Kuala Lumpur, Malaysia.
E-mail addresses: ms.zakeri@gmail.com (M. Zakeri), mahmoudeithar@cheme.utm.my
(M.M. Nasef).
http://dx.doi.org/10.1016/j.molliq.2014.09.018
0167-7322/© 2014 Elsevier B.V. All rights reserved.

268
M. Zakeri et al. / Journal of Molecular Liquids 199 (2014) 267–274
N-methyl imidazole, pyridine, and 1,4-butane sultone were purchased
from Sigma-Aldrich Chemicals.
2.3. General procedure for preparation of quinazolin- and pyrimidine-2-
amine
2.3.1. In a microwave reactor
In a typical experimental run for the synthesis of 4f, a mixture of 4-
methyl cyclohexanon (2 mmol, 0.224 g), furfural (4 mmol, 0.384 g),
guanidine carbonate (2 mmol, 0.180 g) and [BSO3HPy]HSO4 (15 mol%)
was added to the 10 ml microwave reactor and the reactor was heated
to 120 °C and held for a certain time with the microwave irradiation.
After the reaction was completed as indicated by TLC, the mixture was
allowed to cool to room temperature. Water was then added to the reac-
tion mixture and the resulting solid was collected by filtration, washed
with water (2 × 10 ml) and then followed by drying under vacuum at
80 °C overnight. For further purification, the solid products were recrys-
tallized from ethanol. Similar procedure was followed for the synthesis
of all the products without any need for column chromatography.
Fig. 1. The structure of Doxazosin mesylate.
quinazoline- and pyrimidine-2-amine derivatives using a green proce-
dure. As shown in Scheme 1, various aromatic aldehydes and cyclic ke-
tone derivatives and guanidine carbonate were used as starting
materials. ILs were employed as catalysts with the aid of microwave
and also as solvents and catalysts in the ultrasonic irradiation. The cata-
lytic activities of ILs were evaluated and the relationship between the
catalytic activity and acidity was discussed. It was also found that the
[BSO3HPy]HSO4 was the most effective catalyst and solvent for these
syntheses. Additionally, this IL is a halogen-free, which might be more
eco-friendly and less expensive.
2.3.2. In an ultrasonic reactor
A mixture of 4-methyl cyclohexanon (2 mmol, 0.224 g), furfural
(4 mmol, 0.384 g), guanidine carbonate (2 mmol, 0.180 g) and
[BSO3HPy]HSO4 (1 g) was sonicated in a sonic bath with a frequency
of 25 kHz maintained at 50 °C (temp. of ultrasonic bath) for the appro-
priate period of time. After the reaction was completed as indicated by
TLC, the mixture was allowed to cool to room temperature. Water was
then added to the reaction mixture and the resulting solid was collected
by filtration, washed with water (3 × 20 ml) and then followed by dry-
ing under vacuum at 80 °C overnight. For further purification, the solid
products were recrystallized from ethanol.
2. Experimental
2.1. Materials and reagents
All common reagents and solvents were used as obtained from com-
mercial suppliers without further purification. Melting points were
measured using the capillary tube method with an electro thermal
9200 apparatus. IR spectra were recorded on a JASCO-FT-IR model
5300 spectrometer. 1H NMR and 13C NMR spectra were recorded on a
Bruker AQS AVANCE-500 spectrometer using TMS as an internal stan-
dard. Elemental analysis was performed using a Perkin Elmer 2004 (II)
CHN analyzer. Microwave experiments were conducted in a CEM Dis-
cover 1-300W system. Sonication was carried out with a microtip
probe (3 mm) connected to a 500 Watt Sonics Vibra-cell ultrasonic
processor.
2.4. Spectroscopic data for the new compounds
(E)-8-(4-fluorobenzylidene)-4-(4-fluorophenyl)-6-methyl-5,6,7,8-
tetrahydroquinazolin-2-amine (5e): IR (KBr): 3490, 3295, 3170, 2945,
1630, 1605, 1540, 1505, 1455, 1285, 1150, 875 cm−1 1H NMR
;
(500 MHz, DMSO-d6): δ 0.94–0.95 (3H, d, J = 6.0 Hz, CH3), 1.65–1.67
(1H, m, CH), 2.35–2.50 (3H, m, 3CH), 2.87–2.90 (1H, d, J = 16.1 Hz,
CH), 6.41 (2H, s, NH2), 7.25–7.31 (4H, m, ArH), 7.48–7.51 (2H, m,
ArH), 7.59–7.62 (2H, m, ArH), 8.03 (1H, s, CH) ppm; 13C NMR
(125 MHz, DMSO-d6): δ 22.2, 29.9, 35.0, 36.2, 115.8 (2J C–F = 21.5),
116.0, 116.3 (2J C–F = 21.2), 128.2, 131.8 (3J C–F = 8.2), 132.5
2.2. Preparation of ILs
For the present study, three Brønsted acidic ILs (cat. 1), (cat. 2) and
(cat. 3) were prepared according to the literature procedure [37–39].
The rest of the ILs (N95%) were obtained from Sigma-Aldrich Chemicals.
Scheme 1. Synthesis of quinazoline- and pyrimidine-2-amine derivatives with cyclic ketones, guanidine carbonate and different aldehydes.

M. Zakeri et al. / Journal of Molecular Liquids 199 (2014) 267–274
269
O
-
SO3H
HO3S
2HSO4
H3C
H3C
H3C
SO3H
-
N
HSO4
N
N
N
cat. 2:
cat. 1:
cat. 3:
[BSO3HMIM]HSO4
[DBSO3HDM]2HSO4
SO3H
SO3H
-
N
-
HSO4
N
CF3SO3
N
cat. 4:
N
[BSO3HPy]HSO4
[BSO3HMIM]CF3SO3
HSO4
-
H3C
N
N
Cl-
N
N
cat. 5:
[BMIM]Cl
[BMIM]Br
cat. 6:
[BMIM]HSO4
H3C
H3C
CH3COO-
Br-
N
N
N
N
cat. 7:
cat. 8:
[BMIM]Ac
H3C
-
BF4
N
cat. 9:
[BMIM]BF4
Fig. 2. Acidic ILs examined in this work.
(3J C–F = 8.0), 134.0 (4J C–F = 3.0), 135.2, 135.8 (4J C–F = 2.8),
160.5, 162.1 (1J C–F = 244.0), 162.0, 163.1 (1J C–F = 244.6),
166.3 ppm; Anal. Calcd for C22H19F2N3: C, 72.71; H, 5.27; N, 11.56.
Found: C, 72.50; H, 5.40; N, 11.47.
(500 MHz, CDCl3): δ 1.20–1.21 (3H, d, J = 6.5 Hz, CH3), 1.94–1.98
(1H, m, CH), 2.40–2.46 (1H, ddd, J = 16.2, J = 11.6 and J = 2.4 Hz,
CH), 2.52–2.57 (1H, dd, J = 16.0 and J = 10.4 Hz, CH), 3.10–3.15 (1H,
dd, J = 16.0 and J = 4.2 Hz, CH), 3.33–3.37 (1H, d, J = 16.0 Hz, CH),
5.04 (2H, s, NH2), 6.53–6.54 (1H, m, ArH), 6.60–6.62 (1H, m, ArH),
7.09–7.10 (1H, d, J = 3.2 Hz, ArH), 7.56 (1H, d, J = 1.4 Hz, ArH), 7.68
(1H, d, J = 1.2 Hz, ArH), 7.93 (1H, s, CH) ppm; 13C NMR (125 MHz,
DMSO-d6): δ 22.1, 28.9, 34.5, 35.7, 112.2, 112.3, 114.0, 115.3, 116.3,
118.3, 131.6, 131.7, 143.7, 144.9,151.8, 151.9, 153.8, 160.4 ppm; Anal.
Calcd for C18H17N3O3: C, 70.34; H, 5.58; N, 13.67. Found: C, 70.20;
H, 5.65; N, 13.79.
(E)-4-(furan-2-yl)-8-(furan-2-ylmethylene)-6-methyl-5,6,7,8-
tetrahydroquinazolin-2-amine (5f): IR (KBr): 3465, 3285, 3155,
2945, 1620, 1535, 1485, 1445, 1395, 1085, 815 cm−1 1H NMR
;
Table 1
Screening of different ILs for the synthesis of 4
(E)-4-(naphthalen-1-yl)-7-(naphthalen-1-ylmethylene)-6,7-
dihydro-5H-cyclopenta[d]pyrimidin-2-amine (5i): IR (KBr): 3475,
3375, 3065, 2930, 1605, 1580, 1535, 1440, 1295, 1170, 830 cm−1 1H
;
NMR (500 MHz, DMSO-d6): δ 2.74–2.77 (2H, dd, J = 6.5 and J =
8.5 Hz, CH2), 3.04–3.07 (2H, m, CH2), 7.52–7.63 (7H, m, ArH), 7.69–
7.71 (1H, d, J = 7.2 Hz, ArH), 7.86–7.88 (2H, t, J = 7.0 Hz, ArH), 7.92–
7.98 (3H, m, ArH), 8.31 (1H, s, CH), 8.33–8.35 (1H, m, ArH) ppm; 13C
NMR (125 MHz, DMSO-d6): δ 30.4, 31.6, 122.1, 122.9, 123.5, 124.0,
125.4, 126.0, 126.3, 126.4, 126.9, 128.3, 128.4, 128.7, 128.8, 131.3,
132.7, 132.0, 133.6, 134.2, 135.6, 138.7, 140.5, 160.5, 162.4, 166.5 ppm;
Anal. Calcd for C28H21N3: C, 84.18; H, 5.30; N, 10.52. Found: C, 84.30;
H, 5.45; N, 10.37.
Entry
Catalyst (mol%)
Time (min)
Isolated yield (%)
1
2
3
4
5
6
7
8
[BSO3HPy]HSO4 (5)
[BSO3HPy]HSO4 (10)
[BSO3HPy]HSO4 (15)
[BSO3HPy]HSO4 (20)
[DBDSO3HDM]2HSO4 (15)
[BSO3HMIM]HSO4 (15)
[BSO3HMIM]CF3SO3 (15)
[BMIM]Cl (15)
20
20
10
10
10
10
10
10
10
15
15
30
52
78
90
90
82
80
85
72
78
60
45
Trace
4-(4-Fluorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-amine (5k):
IR (KBr): 3485, 3300, 3175, 2930, 1625, 1550, 1505, 145015, 895 cm−1
;
1H NMR (500 MHz, DMSO-d6): δ 2.76 (4H, s, 4CH), 6.55 (2H, s, NH2),
7.27–7.33 (3H, m, ArH), 7.37–7.40 (2H, m, ArH), 7.62–7.65 (2H, m,
ArH), 8.18–8.20 (1H, dd, J = 1.3 and J = 7.2 Hz, ArH) ppm; 13C NMR
(125 MHz, DMSO-d6): δ 24.4, 28.4, 115.4 (2J C–F = 21.4), 115.7, 125.8,
127.5, 128.6, 131.2, 131.8 (3J C–F = 8.4), 133.8, 135.5 (4J C–F = 3.2),
9
[BMIM]HSO4 (15)
[BMIM]Br (15)
[BMIM]BF4 (15)
10
11
12
[BMIM]Ac (15)

270
M. Zakeri et al. / Journal of Molecular Liquids 199 (2014) 267–274
Table 2
[BSO3HMIM]HSO4 and [BSO3HMIM]CF3SO3 as catalysts, for 10 min
Solvent optimization for the synthesis of 4
under microwave irradiation, desired product 4f could be obtained in
isolated yields of 82%, 80% and 85%, respectively (Table 1, entries 5, 6
and 7). In this work, sulfonic acid ILs were found to effectively catalyze
the synthesis of tetraquinazoline-2-amine 4f as indicated from the ob-
tained superior results. When the reaction was carried out using
[BMIM]Cl, [BMIM]HSO4, [BMIM]Br, and [BMIM]BF4 as catalysts, the
products could be obtained in moderate to high yield of 72%, 78%, 60%,
and 45%, respectively (Table 1, entries 8, 9, 10 and 11). [BMIM]Ac did
not significantly increase the yield of the desired product (Table 1,
entry 12). However, when the model reaction was run in [BSO3HPy]
HSO4, the reaction was completed in 10 min and offered the desired
product with 90% isolated yield (Table 1, entry 3). To compare the
catalytic performance based on the acidity measurement, five ILs
with the same cations and different anions were selected. The relative
acidity of these ILs is as follows: [BMIM]HSO4 N [BMIM]Cl N [BMIM]
BF4 N [BMIM]Ac N [BMIM]Br [26]. However, no clear relationship
could be established between the catalytic performance and acidic
strength. The catalytic activities of the acidic ILs decreased in the
order of [BMIM]HSO4 N [BMIM]Cl N [BMIM]Br N [BMIM]BF4 N [BMIM]
Ac. While the most acidic ILs are the best performing, the reactivity of
the rest of the ILs does not follow the trend in their acidity. It can be sug-
gested, that not only the acidity of the ILs is influencing the reactions,
but also the nature of anions of ILs is having a significant effect on the
yield.
Entry
Solvent
Temperature (°C)
Time (min)
Isolated yield (%)
1
2
3
4
5
6
7
8
H2O
EtOH
MeCN
CHCl3
–
120
120
120
120
80
100
120
150
20
20
20
15
20
20
10
10
15
60
52
42
44
65
90
90
–
–
–
140.2, 160.8, 163.0, 163.2 (1J C–F = 244.4), 164.6 ppm; Anal. Calcd for
C18H14FN3: C, 74.21; H, 4.84; N, 14.42. Found: C, 74.33; H, 5.03; N, 14.27.
4-(Furan-2-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine (5l): IR
(KBr): 3320, 3200, 2925, 1640, 1580, 1540, 1490, 1460, 1215,
775 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 2.85–2.88 (2H, dd, J = 7.5
and J = 6.9 Hz, CH2), 3.05–3.08 (2H, dd, J = 7.7 and J = 6.7 Hz, CH2),
6.5 (2H, s, NH2), 6.69–6.70 (1H, m, ArH), 7.1 (1H, d, J = 3.3 Hz, ArH),
7.29–7.31 (1H, d, J = 7.2 Hz, ArH), 7.36–7.40 (2H, m, ArH), 7.92 (1H, s,
ArH), 8.15–8.17 (1H, d, J = 7.3 Hz, ArH) ppm; 13C NMR (125 MHz,
DMSO-d6): δ 23.5, 28.1, 112.73, 113.5, 114.3, 125.8, 127.5, 128.6, 131.2,
133.7, 140.1, 145.5, 153.0, 154.1, 161.3, 162.8 ppm; Anal. Calcd for
C16H13N3O: C, 72.86; H, 4.98; N, 15.96. Found: C, 72 .67; H, 5.06; N, 15.79.
When [BSO3HPy]HSO4 was used as a catalyst, the amount of catalyst
required for this reaction was evaluated (Table 1, entries 1–4). Only
15 mol% of IL was required to convert the substrate into the correspond-
ing product and higher amounts of the catalyst did not significantly in-
crease the yields (Table 1, entry 3). Reaction with 10 mol% of the catalyst
required a longer reaction time (Table 1, entry 2) while the reaction
with 5 mol% of [BSO3HPy]HSO4 produced only 52% yield of the product
after 20 min under microwave irradiation (Table 1, entry 1).
3. Results and discussion
Choosing an appropriate solvent has crucial importance for the suc-
cessful microwave-assisted synthesis. To search for the optimal solvent,
the model reaction was investigated in the presence of a catalytic
amount of [BSO3HPy]HSO4 using various solvents such as EtOH, H2O,
MeCN, and CHCl3 at 120 °C under microwave irradiation to determine
which one can give the best results. The results of these comparative ex-
periments are summarized in Table 2. Unfortunately, the obtained yield
using water as a solvent was too small because of the low solubility of
the reactants (Table 2, entry 1).
At the onset of our work, 9 ILs shown in Fig. 2 with unique ability in
catalyzing of multicomponent reactions were selected [37,38]. Reaction
of furfural 1g, guanidine carbonate 2 and 4-methyl cyclohexanon 3c
was selected as a model reaction.
It was observed that almost all of the investigated ILs were capable of
catalyzing the synthesis of desired quinazoline- and pyrimidine-2-
amine derivatives under the microwave at 120 °C except for [BMIM]
Ac. Optimization studies revealed that when the reaction was carried
out using sulfonic acid-bearing ILs such as [DBSO3HDM]2H2SO4,
The effect of temperature on this one-pot and multicomponent reac-
tions was also investigated. It was observed that there is a clear trend
Table 3
Optimization of reaction conditions
Entry
Catalyst (mol%)
Solvent
Temperature
Time (min)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
[BSO3HPy]HSO4 (15)
[BSO3HPy]HSO4 (15)
[BSO3HPy]HSO4 (15)
[BSO3HPy]HSO4 (15)
–
–
–
–
–
H2O
EtOH
MeCN
CHCl3
[BSO3HPy]HSO4
[BSO3HPy]HSO4
[BSO3HPy]HSO4
[BMIM]Cl
[BMIM]HSO4
30
30
30
30
30
40
50
50
50
120
120
120
120
40
40
40
60
60
nra
54
35
33
75
78
80
76
72
a
nr = no reaction.

M. Zakeri et al. / Journal of Molecular Liquids 199 (2014) 267–274
271
Table 4
Synthesis of quinazoline- and pyrimidine-2-amine derivatives 4.
Entry
Aldehydes/cyclic ketones
Products
Microwave
Time (min)
5
Ultrasound
Time (min)
45
M.p. (°C)
Found
Yield
85
Yield
80
Lit.
4a
1d/3b
210–212
210–212 [39]
4b
4c
1b/3b
1c/3b
5
7
90
85
40
50
78
74
224–227
211–213
224–226 [40]
210–212 [39]
4d
4e
1e/3b
1a/3c
7
7
83
80
45
50
75
75
224–227
224–226 [40]
211–213 [39]
213
4f
1 g/3c
10
90
40
80
200–203
–
4g
4h
1d/3a
1b/3a
7
8
80
75
50
45
73
75
248–249
167–168
256–258 [39]
165–167 [39]
4i
1f/3a
10
75
55
65
207–209
–
4j
1d/3e
1a/3e
10
8
85
80
50
55
72
67
182–183
192–193
182–183 [41]
4k
4l
1 g/3e
1d/3d
7
8
78
85
50
50
68
60
243–244
206–208
–
4m
206–208 [39]
toward in situ formation of the C\C bond at 120 °C. While decreasing
the reaction temperature from 120 °C to 100 and 80 °C significantly
slowed the reaction rate and led to slightly lower yield of the products
(Table 2, entries 5 and 6), increasing the reaction temperature to
150 °C didn't improve the reaction yield (Table 2, entry 8). On the
other hand, when the reaction was carried out in a solvent-free condi-
tion at 120 °C, a good yield was achieved and the results showed that,
‘no solvent’ under microwave irradiation is the ‘best solvent’ and this
complies with the green chemistry principles (Table 2, entry 7).
The combined results clearly indicate that microwave irradiation
plays an important role in the synthesis of desired products. These find-
ings confirm the establishment of an efficient and optimized green
approach for the preparation of quinazoline- and pyrimidine-2-amine
derivatives in excellent isolated yields through one-pot reaction involv-
ing 1:2:1 M ratios 4-methyl cyclohexanon, furfural and guanidine car-
bonate in the presence of 15 mol% [BSO3HPy]HSO4 under microwave
irradiation for 10 min at 120 °C.
The effect of the amount of catalyst, type of solvent, and reaction
temperature was also evaluated under ultrasonic condition. A number
of solvents were tried with a catalytic amount of [BSO3HPy]HSO4 to
find out a suitable reaction medium under ultrasonic irradiation. It
was found that the use of [BSO3HPy]HSO4 with a dual role of catalyst
and solvent at 50 °C reduced the reaction time dramatically (40 min)
and improved the product yield (80%) (Table 3, entry 7).

272
M. Zakeri et al. / Journal of Molecular Liquids 199 (2014) 267–274
Fig. 3. 1H NMR spectrum of 4f.
As shown in Table 4, the optimized protocol was then extended to
ultrasonic irradiations. In most cases, the reactions were conducted
cleanly. Aromatic aldehydes containing both electron donating (such
as alkoxy and methyl) and electron withdrawing (such as nitro and
halide) substituents were found to show no significant effect on the
the reaction of cyclic ketones and guanidine carbonate with different al-
dehydes and a series of quinazoline- and pyrimidine-2-amine deriva-
tives were synthesized with excellent yield under microwave and
Scheme 2. Plausible mechanism for the reaction of 4-methyl cyclohexanon and furfural with guanidine carbonate.

M. Zakeri et al. / Journal of Molecular Liquids 199 (2014) 267–274
273
Scheme 3. Recycling of the IL in the synthesis of 4f.
formation of the final product. Therefore, it was concluded that the elec-
tronic nature of the substituents does not affect this reaction. The prod-
ucts were easily isolated by dilution with water and filtration of the
precipitated product. However, they were subjected to further purifica-
tion by recrystallization and the reported yields are obtained after this
procedure.
most effective IL for the synthesis of these multicomponent reactions.
This catalyst can be reused for 4 times without significant loss in the cat-
alytic activity and change of chemical structure. Therefore, it is hoped
that these eco-efficient and green protocols be of great value for both
synthetic and medicinal chemistry for academic research and practical
applications.
The structure of these synthesized compounds was confirmed by el-
emental analysis, IR, mass, NMR spectroscopy and CHN. For instance,
the IR spectrum of 4f showed absorption bands at around 3465 and
3286 cm−1. This couples with broad band at around 1620 cm−1
Acknowledgments
Authors wish to acknowledge the financial support from Research
University (RU) fund (vot. #05H16) for Universiti Teknologi Malaysia
from The Malaysian Ministry of Higher Education (MOHE).
(\NH2) and stretching vibrations of the \NH2 at around 790 cm−1
.
The 1H NMR spectrum of 4f is presented in Fig. 3. The resonance signal
at a downfield region of 7.93 ppm is ascribed to the proton of vinylic
group. The area of integration for the protons is in accordance with
the assignment. In addition, separate signals for each protons of methy-
lene groups, due to the chiral center, are observed (c, d, e and f).
The formation of desired product can be explained by the sequence
of Knoevenagel condensation and Michael addition followed by cycliza-
tion and aromatization, as shown in Scheme 2 for 4f. A hydrogen bond
between the hydrogen atom of [BSO3HPy] and carbonyl groups of alde-
hyde and 4-methyl cyclohexanon could expedite the Knoevenagel con-
densation. [BSO3HPy]HSO4 first catalyzes the keto-enol tautomerization
of 4-methyl cyclohexanon and activates furfural to give the intermedi-
ate A via Knoevenagel condensation. Then, intermediate A is attacked
via Michael addition of guanidine carbonate to give the intermediate
B, followed by the cycloaddition of amine group to the carbonyl and fi-
nally, aromatization under air atmosphere affords 4f.
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