An efficient one-pot solvent-free synthesis of 2,3-dihydroquinazoline-4(1H) -ones via Al/Al2O3 nanoparticles

Article abstract of DOI:10.1002/jhet.506

An efficient one-pot, solvent-free method is reported for the synthesis of 2-phenyl-2,3-dihydroquinazoline-4(1H)-one as well as its o-Cl, o-OMe, m-Br, m-NO₂, p-OH, p-NO₂, p-CN, p-PhCH₂O, p-Cl, p-F, p-Br, p-Me, and o,m-dich

Full text of DOI:10.1002/jhet.506

November 2010
An Efficient One-Pot Solvent-Free Synthesis of
2,3-Dihydroquinazoline-4(1H)-ones via Al/Al2O3 Nanoparticles
1421
M. Z. Kassaee,a* Shahnaz Rostamizadeh,b Nasrin Shadjou,b Elahe Motamedi,a
and Maryam Esmaeelzadehb
aDepartment of Chemistry, Tarbiat Modares University, Tehran, Iran
bDepartment of Chemistry, K. N. Toosi University of Technology, Tehran, Iran
*E-mail: kassaeem@modares.ac.ir
Received January 1, 2010
DOI 10.1002/jhet.506
Published online 30 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
An efficient one-pot, solvent-free method is reported for the synthesis of 2-phenyl-2,3-dihydroquina-
zoline-4(1H)-one as well as its o-Cl, o-OMe, m-Br, m-NO2, p-OH, p-NO2, p-CN, p-PhCH2O, p-Cl, p-F,
p-Br, p-Me, and o,m-dichloro derivatives, using our ‘‘as-prepared’’ arc discharge fabricated Al/Al2O3
nanoparticles. Compared with our previous report and other known methods, this route gives higher
yields with shorter reaction times, whereas its green catalyst appears recyclable at least four times-with
minor decrease in its catalytic activity, under mild conditions.
J. Heterocyclic Chem., 47, 1421 (2010).
INTRODUCTION
Al/Al2O3 nanocatalyst with a high-surface/volume ratio
in, a three-component one-step synthesis of 2,3-dihydro-
quinazolin-4(1H)-ones (Scheme 1).
Dihydroquinazolinones and their derivatives are im-
portant heterocyclic compounds, which influence numer-
ous cellular processes. They are analgesic, diuretic, and
vasodilating agents, displaying a broad range of biologi-
cal, medicinal, and pharmacological properties [1–10].
Also, they are constituents of antitumor, antibiotic, anti-
defibrillatory, antipyretic, antihypertonic, antihistamine,
and antidepressant drugs. In addition, these compounds
can easily be oxidized to their quinazolin-4(3H)-one
analogues [11], which also include important pharmaco-
logically active compounds [12]. Several routes, includ-
ing our recent method, using iodine as the catalyst, have
been reported for the synthesis of 2,3-dihydroquinazoli-
nones [13–19]. Yet, development of a green, simple, ef-
ficient, and general method for the synthesis of these
widely used organic compounds, from readily available
reagents, remains one of the major challenges in organic
synthesis. In this manuscript, we have made use of the
novel, recently reported metal and metal oxide nanopar-
ticles, which exhibit high-surface/volume ratio, quantum
size, and quanta tunnel effects [20–23]. We think our
new procedure is cleaner and more environment friendly
than our previous one, where we used the relatively
toxic iodine catalyst [19]. Specifically, we employ small
amounts of novel, recyclable, nontoxic, and inexpensive
RESULTS AND DISCUSSION
After demonstrating the impact of media and current
on the arc fabrication of Al nanoparticles [24], we won-
dered if we could substitute Al/Al2O3 nanoparticles for
iodine in the preparation of 2,3-disubstituted quinazolin-
4(3H)-ones through multicomponent reactions, which
we had already reported [19]. The reason was our
immense desire to adopt rather green and economical
reaction conditions, since the vapor of iodine was toxic
at high-temperatures, and to remove the excess iodine
we had to use saturated Na2S2O3. Also the previous cat-
alyst was not reusable.
The scanning electron microscopy (SEM) images
showed spherical arc fabricated Al/Al2O3 NPs with a
size range of 30 – 40 nm (Fig. 1).
The X-ray diffraction (XRD) pattern confirmed the
formation of Al/Al2O3 NPs with similar average grain
size range estimated via Scherer’s equation [25], using
the maximum peak (111) was used (Fig. 2). At a scan-
ning speed of 2ꢀ/min from 20ꢀ to 80ꢀ (2y), the XRD
pattern showed five peaks, which were characteristic of
C
V
2010 HeteroCorporation

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M. Z. Kassaee, S. Rostamizadeh, N. Shadjou, E. Motamedi, and M. Esmaeelzadeh
Vol 47
Scheme 1. Three-component one-step synthesis of 2,3 dihydroquinazolin-4(1H)-ones.
aluminum (2y ¼ 38.56ꢀ; 44.84ꢀ; 65.25ꢀ; 78.33ꢀ, and
82.59ꢀ), corresponding to Miller indices (111), (200),
(220), (311), and (111), revealing the formation of face-
centered cubic (fcc) Al NPs. Besides, it illustrated the
lines (110), (104), and (220) at 2y ¼ 45.93ꢀ; 66.98ꢀ;
85.09ꢀ, respectively, for c-Al2O3.
Catalytic amounts of this as-prepared Al/Al2O3 NPs
was added to a well-stirred mixture of isatoic anhydride
(1), an aromatic aldehyde (3, either with electron-donat-
ing or electron-withdrawing groups), and ammonium ac-
etate. It gave the corresponding 2,3-dihydroquinazolin-
4(1H)-ones (5a – o) in 65 – 98% yields, at 115ꢀC, under
solvent-free conditions (Table 1).
0.00, 0.06, 0.012, 0.036, and 0.048 g against isatoic an-
hydride (0.163 g, 1.0 mmol), ammonium acetate, and 4-
chlorobenzaldehyde (0.14 g, 1.0 mmol), under solvent-
free condition, at 115ꢀC (Table 2).
The best results were obtained using 0.036 g of cata-
lyst (yield ¼ 94%). Increasing the amount of catalyst
higher than 0.048 g did not affect the reaction time and
yield. The absence of the catalyst required considerably
higher reaction time giving the lowest yield (75%).
To check the reusability of our catalyst, the prepared
Al/Al2O3 NPs (0.036 g) was stirred for 2 min with isa-
toic anhydride (0.163 g, 1 mmol), aromatic aldehyde
(0.14 g, 1 mmol), and ammonium acetate, at room tem-
perature. Then the mixture was heated in a paraffin bath
at 115ꢀC, for different periods of time (Table 1). After
completion of the reaction excess ammonium acetate
was washed away by water (5 mL). Subsequently, the
hydroquinazolinone products were extracted by ethanol
(50 mL). The solid residue was our catalyst, which was
dried and reused for at least four cycles (Fig. 3).
Reactions were completed under smooth conditions
within 8 – 30 min, and the products were isolated by a
simple workup procedure. Thus an easy and rather green
method for the synthesis of a novel class of the quinazo-
linone family was found. However, no simple relation-
ship was observed between the electronic properties of
the aryl groups and the corresponding quinazolinone
products. Specifically, the amount of the catalyst (Al/
Al2O3 NPs) for this condensation reaction was probed at
The question is how this catalyst works? Evidently,
the Al/Al2O3 NPs function as a good Lewis acid, which
attracts and activates the carbonyl and imine groups
involved and provides a surface on which the reactions
Figure 1. The SEM image of the as-prepared Al/Al2O3 nanoparticles.
Figure 2. The XRD pattern of the as-prepared Al/Al2O3 nanoparticles.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010 An Efficient One-Pot Solvent-free Synthesis of 2,3-Dihydroquinazoline-4(1H)-ones
via Al/Al2O3 Nanoparticles
1423
Table 1
The reaction time and the % yield of hydroquinazolin product.
Product
Ar
Time (min)
Yield (%)a
M.P (ꢀC) Found
M.P (ꢀC) Reported
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-OHC6H4
4-NO2C6H4
4-CNC6H4
4-PhCH2AOAC6H4
4-ClC6H4
8
8
91
78
75
98
94
89
80
79
82
95
90
80
88
92
65
285 – 287
300 – 302
350 – 351
238 – 240
207 – 208
279 – 280
195 – 197
230 – 231
173 – 175
229 – 230
232 – 233
183 – 184
225 – 226
228 – 230
180 – 182
278 – 280 [19]
310 – 312 [19]
350 – 351 [19]
238 – 240 [19]
207 – 208 [19]
279 – 280 [19]
195 – 197 [19]
230 – 231 [19]
173 – 175 [19]
229 – 230 [19]
232 – 233 [19]
183 – 184 [19]
225 – 226 [19]
229 – 231 [19]
180 – 182 [19]
15
15
15
30
10
12
10
15
5
4-FC6H4
4-BrC6H4
2-ClC6H4
2-OMeC6H4
3-BrC6H4
2,3-Cl2C6H3
4-MeOC6H4
C6H5
5j
5k
5l
8
5m
5n
5o
15
15
30
4-MeC6H4
3-NO2C6H4
a Isolated yield.
occur sequentially leading to the desired products
(Scheme 2).
rification of the products. The starting materials are also
inexpensive and commercially available.
Specifically, decarboxylation of 1 occurs through its
condensation with ammonium acetate in the presence of
Al/Al2O3 NPs, affording antranylamide intermediate 2,
which reacts with the aromatic aldehyde 3 and gives the
imine intermediate 4 that cyclizes to yield the corre-
sponding hydroquinazolinone 5.
EXPERIMENTAL
General remarks. Melting points were recorded on a Buchi
B-540 apparatus. IR spectra were recorded on an ABB Bomem
Model FTLA200-100 instrument. 1H and 13C NMR spectra
were measured on a Bruker DRX-300 spectrometer, at 300
and 75 MHz, using TMS as an internal standard. Chemical
shifts (d) were reported relative to TMS, and coupling con-
stants (J) were reported in hertz (Hz). Mass spectra were
recorded on a Shimadzu QP 1100 EX mass spectrometer with
70-eV ionization potential. Elemental analyses of new com-
pounds were performed using a Vario EL III 0 Serial
No.11024054 instrument. The particle shape and morphology
were characterized by SEM of a Holland Philips XL30 micro-
scope with an accelerating voltage of 20 kV. A Holland
CONCLUSION
We have employed Al/Al2O3 NPs as an effective cat-
alyst in the one-pot multicomponent synthesis of 2,3-
dihydroquinazolin-4(1H)-ones. This catalyst is highly ef-
ficient, easily available, economical, operationally sim-
ple, and requires mild reaction conditions. Also the
products were formed in excellent yields with short
reaction times. This method offers several advantages,
such as omitting toxic solvents or catalyst, very simple
workups, and needs no chromatographic method for pu-
Table 2
The reaction time and the yield of hydroquinazolin product as a
function of the amount of the employed catalyst (Al/Al2O3 NPs).
Amount of
Catalyst (g)
Temperature
(ꢀC)
Reaction
Time (min)
Yield
(%)a
Entry
1
2
3
4
5
6
0.000
0.006
0.012
0.024
0.036
0.048
115
115
115
115
115
115
55
30
25
20
15
15
75
81
82
84
94
95
a Isolated yield
Figure 3. Catalytic recyclability of Al/Al2O3 NPs.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1424
M. Z. Kassaee, S. Rostamizadeh, N. Shadjou, E. Motamedi, and M. Esmaeelzadeh
Vol 47
3245, 3350 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d ¼ 6.66 (t,
Scheme 2. A provisional mechanism for the synthesis of dihydroquina-
zoline in the presence of Al/Al2O3 NPs.
1H, J ¼ 6.0 Hz, CH), 6.77 (d, 1H, J ¼ 6.0 Hz, CH), 7.26 (d,
t, J1 ¼ 1.2 Hz, J2 ¼ 9.0 Hz, 1H, CH), 7.33 (s, 1H, NH), 7.59
(d, 1H, J ¼ 9.0 Hz, CH), 7.69 (t, J ¼ 6.0 Hz, 1H, CH), 7.83
(m, 1H, CH), 7.92 (d, 1H, J ¼ 9.0 Hz, CH), 8.19 (d, 1H, J ¼
6.0 Hz, 8.34 (s, 1H, CH), 8.54 (s, 1H, NH); 13C NMR
(75MHz, DMSO-d6): d ¼ 65.1, 114.6, 114.9, 117.5, 121.6,
122.7, 123.3, 125.9, 127.4, 131.3, 133.4, 133.6, 134.7, 144.3,
144.3, 147.3, 147.7, 163.3; MS (EI): m/e ¼ 269 (Mþ), 221,
147, 120, 92, 65, 39.
Acknowledgments. Authors gratefully acknowledge Research
Council of K. N. Toosi University of Technology and Tarbiat
Modares University for partial financial support of this work.
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stirred for 2 min with isatoic anhydride (0.163 g, 1 mmol), ar-
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3169 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d ¼ 5.84 (s, 1H,
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7.87 (m, 1H, CH), 8.02 (d, J ¼ 6.0 Hz, 2H, CH), 8.16 (d, J ¼
6.0 Hz, 1H, CH), 8.32 (d, J ¼ 6.0 Hz, 2H, CH), 12.7 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): d ¼ 65.5, 113.6, 118.3,
121.2, 125.9, 127.2, 127.7, 128.6, 132.5, 134.7, 136.9, 150.9,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet