Ecofriendly and efficient one-pot procedure for the synthesis of quinazoline derivatives catalyzed by an acidic ionic liquid under aerobic oxidation conditions

Article abstract of DOI:10.1080/00397910903395250

A three-component condensation reaction between 2-aminobenzophenone derivatives, formaldehyde or aromatic aldehydes, and ammonium acetate efficiently provides substituted quinazolines in a one-pot reaction in the presence of Bronsted acidic ionic liquid, 1-methylimidazolium triflouroacetate ([Hmim]TFA), in conjunction with aerobic oxidation. The ionic liquid was separated from the reaction mixture by simple extraction and was recycled three times without considerable loss in activity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903395250

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Ecofriendly and Efficient One-Pot
Procedure for the Synthesis of
Quinazoline Derivatives Catalyzed by
an Acidic Ionic Liquid Under Aerobic
Oxidation Conditions
Minoo Dabiri a , Peyman Salehi b & Mahboobeh Bahramnejad a
a Faculty of Science, Department of Chemistry , Shahid Beheshti
University , Tehran, Iran
b Department of Phytochemistry, Medicinal Plants and Drugs
Research Institute , Shahid Beheshti University , Tehran, Iran
Published online: 04 Oct 2010.
To cite this article: Minoo Dabiri , Peyman Salehi & Mahboobeh Bahramnejad (2010) Ecofriendly
and Efficient One-Pot Procedure for the Synthesis of Quinazoline Derivatives Catalyzed by an Acidic
Ionic Liquid Under Aerobic Oxidation Conditions, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 40:21, 3214-3225, DOI:
10.1080/00397910903395250
To link to this article: http://dx.doi.org/10.1080/00397910903395250
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Synthetic Communications1, 40: 3214–3225, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903395250
ECOFRIENDLY AND EFFICIENT ONE-POT PROCEDURE
FOR THE SYNTHESIS OF QUINAZOLINE DERIVATIVES
CATALYZED BY AN ACIDIC IONIC LIQUID UNDER
AEROBIC OXIDATION CONDITIONS
Minoo Dabiri,1 Peyman Salehi,2 and
Mahboobeh Bahramnejad1
1Faculty of Science, Department of Chemistry, Shahid Beheshti University,
Tehran, Iran
2Department of Phytochemistry, Medicinal Plants and Drugs Research
Institute, Shahid Beheshti University, Tehran, Iran
A
three-component condensation reaction between 2-aminobenzophenone derivatives,
formaldehyde or aromatic aldehydes, and ammonium acetate efficiently provides substituted
quinazolines in a one-pot reaction in the presence of Bro¨nsted acidic ionic liquid, 1-methyl-
imidazolium triflouroacetate ([Hmim]TFA), in conjunction with aerobic oxidation. The
ionic liquid was separated from the reaction mixture by simple extraction and was recycled
three times without considerable loss in activity.
Keywords: Aerobic oxidation; catalysis; heterocycles; multicomponent; quinazolines
INTRODUCTION
Multicomponent reactions are some of the most efficient methods for the
synthesis of organic molecules.[1] The strategy offers significant advantages over
classical step-by-step approaches, allowing the formation of several bonds and the
construction of complex molecular architectures from simple precursors in a single
synthetic operation without isolating the intermediates. Over the past decade, the
synthesis of heterocycles has become the cornerstone of synthetic organic chemistry.
This is because substituted heterocyclic compounds offer a high degree of structural
diversity and have proven to be broadly useful as therapeutic agents.[2]
Among the nitrogen-containing heterocycles, pyrimidines and quinazolines are
useful as fungicides and anticancer, anti-inflammatory, antimicrobial, and antihyper-
tensive agents.[3] In particular, they are potent and highly selective inhibitors of tyro-
sine kinase.[4] Also, a new series of quinazolines were discovered that function as CC
chemokine receptor-4 (CCR4) antagonists. Several CCR4 antagonists with potent
inhibitory activity have been reported in the literature (Fig. 1).[5]
Received July 12, 2009.
Address correspondence to Minoo Dabiri, Faculty of Science, Department of Chemistry, Shahid
Beheshi University, G. C., Evin, Tehran 983963113, Iran. E-mail: m-dabiri@sbu.ac.ir
3214

QUINAZOLINE DERIVATIVE SYNTHESIS
3215
Figure 1. Some 4-substituted quinazoline derivatives with CCR4 inhibitory activities.
Therefore, the synthesis of quinazoline derivatives has attracted much atten-
tion recently. Introducing the chlorine atom at the 4-position in the quinazolinone
skeleton either by using POCl3 or thionyl chloride,[7] followed by its substitution
[6]
with various primary and secondary amines or with palladium-catalyzed intramol-
ecular reductive N-heterocyclization,[8] condensation reactions between amines and
carbonyl derivatives, and intramolecular cycloaddition approaches are common to
many of these synthetic methodologies.[9] Cross-coupling chemistry has recently
enabled the introduction of substituents on existing activated aza-heterocycles.[10]
Much effort also has been devoted to the development of the syntheses of these het-
erocycles by Chilin et al.[11] Ferrini and coworkers have recently reported a synthetic
approach to quinazolines by cyclization of acylamides in the presence of ammonium
formate under microwave irradiation.[12]
Although some of these methods provide useful strategies for the synthesis of
these compounds, they suffer from drawbacks such as multistep syntheses, poor
yields, and use of commercially nonviable reagents or expensive catalysts.[13]
Ionic liquids (ILs) have gained wide popularity in recent years. Interest in
ILs is brought about by their special properties such as no volatility, thermal
stability, no flammability, and the possibility of recycling and reuse.[14] At
present, the most extensively studied ILs are salts with imidazolium cations.
These ILs have received global attention in various fields of research such as
synthesis, catalysis, electrochemistry, and industrial applications.[15–20] Continuing
our interest in the progress of a highly expedient methodology for the synthesis of
outstanding chemicals and heterocyclic compounds of biological significance,[21–24]
in this article, we report an efficient and short route for the synthesis of the
quinazoline nucleus from 2-aminobenzophenone derivatives, aldehydes, and

3216
M. DABIRI, P. SALEHI, AND M. BAHRAMNEJAD
ammonium acetate in the presence of an acidic ionic liquid, 1-methylimidazolium
triflouroacetate ([Hmim]TFA).
RESULTS AND DISCUSSION
To develop an environmentally benign process for the synthesis of quinazoline
derivatives, we explored the use of different solvents and 0.1 mmol of various
Brønsted acids for 2 h. First, we carried out the reaction between 2-amino-5-
chloro-benzophenone, 4-methoxy-benzaldehyde, and ammonium acetate as a model
reaction (Scheme 1). From Table 1, it is evident that when the reaction was conduc-
ted at 80 ꢀC in the presence of 0.1 mmol (0.02 g) [Hmim]TFA without any solvent,
the desired product was obtained in 85% yield (Table 1, entry 10). In the absence
of a catalyst, the reaction did not yield any significant amount of the product after
2 h (Table 1, entry 11). In the period of our research, we encountered an important
point: in the absence of air blowing and under a nitrogen atmosphere, this reaction
did not proceed efficiently, and the reaction yielded only a trace after 2 h. Therefore,
air has a main role in the preparation of quinazoline derivatives. Also, there were
several reports based on aerobic oxidation conditions for the synthesis of various
heterocyclic compounds.[25] So, we next turned our attention to the formation
of the quinazoline ring systems in these optimal conditions for other substrates. A
variety of different substituted aromatic aldehydes and two different types of
2-aminobenzophenones were subjected to this reaction (Scheme 2, Table 2). A var-
iety of substituted aldehydes possessing a wide range of electron-donating and
Scheme 1. Optimization reaction.
Table 1. Optimization of the reaction conditions
Entry
Catalyst
Solvent
Temperature (ꢀC)
Yield (%)a
1
2
p-TSOH
p-TSOH
p-TSOH
p-TSOH
p-TSOH
p-TSOH
SSA
EtOH
MeOH
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80
17
Trace
Trace
Trace
Trace
10
3
4
CH3CN
PhMe
CH2Cl2
EtOH
EtOH
H2O
5
6
7
12
8
IL
IL
Trace
Trace
85
9
10
11
IL
—
—
—
80
Trace
aIsolated yield after 2 h.

QUINAZOLINE DERIVATIVE SYNTHESIS
3217
Scheme 2. Synthesis of quinazoline derivatives.
electron-withdrawing functional groups such as methoxy, hydroxy, bromo, chloro,
nitro, and fluoro afforded the corresponding products in good yields. Hetero-
aromatic aldehydes such as pyridine carbaldehyde derivatives produced the desired
products in excellent yields (Table 2, entries 9, 10, 19, and 20). Aliphatic aldehydes
were also examined. Among the aliphatic aldehydes, only formaldehyde reacted
smoothly to provide the corresponding quinazoline in excellent yield (Table 2,
entry 1). It seems that aliphatic aldehydes possessing an a-hydrogen atom undergo
aldol condensation under the reaction condition. In general, as indicated in
Table 2, in all cases the reactions proceeded efficiently with excellent yields within
2 h at 80 ꢀC under air blowing. The reactions were clean, and no side products could
be detected in the NMR spectra of the crude products.
Table 2. Synthesis of quinazolines by the reaction of 2-aminobenzophenones,
aldehydes, and ammonium acetate in the presence of [Hmim]TFA at 80 ꢀC
under aerobic oxidation conditions
Entry
X
R
Mp (ꢀC)
Yield (%)a
1
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
115
178
161
185
197
187
162
128
173
192
130
173
193
103
153
195
170
97
83
91
3-Br-C6H4
4-CH3O-C6H4
C6H5
3
85, 87, 82
80
87
4
5
2-OH-C6H4
4-Cl-C6H4
2,4-(Cl)2-C6H3
2-NO2-C6H4
3-Pyridyl
6
94
92
7
8
88
85
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4-Pyridyl
2-F-C6H4
90
95
3-F-C6H4
4-F-C6H4
92
90
3-Br-C6H4
4-CH3O-C6H4
4-NO2-C6H4
4-Cl-C6H4
2,4-(Cl)2-C6H3
3-Pyridyl
87
92
H
H
85
90
H
H
82
86
H
142
145
160
128
H
4-Pyridyl
3-F-C6H4
4-F-C6H4
85
85
H
H
90
aIsolated yield.

3218
M. DABIRI, P. SALEHI, AND M. BAHRAMNEJAD
Scheme 3. The plausible mechanism of the reaction.
Finally, to make this method more appropriate, we proved that the catalyst
([Hmim]TFA) could be reused for more cycles with almost consistent activity. For
this aim, the reaction in Scheme 1 was selected. After completion of the reaction,
water was added, and then the solid was isolated by filtration. The IL in water
was recovered easily by evaporation at 80 ꢀC under a vacuum. The recovered IL
was washed with diethyl ether. After heating at 80 ꢀC in a vacuum for another 1 h,
the IL was used in the following runs without considerable loss of its activity after
three runs (Table 2, entry 3).
The possible mechanism of the reaction of 2-aminobenzophenone derivatives 1,
aldehydes 2, and ammonium acetate 3 in the presence of [Hmim]TFA and air is shown
in Scheme 3. [Hmim]TFA acts as an acidic catalyst that promotes the three-
component condensation reaction and leads to the generation of 1,2-dihydroquinazo-
lines 4, which immediately undergo dehydration in conjunction with oxygen from the
air. At the end, quinazolines 5 are obtained in good to excellent yields.
EXPERIMENTAL
General
Melting points were measured on an Electrothermal 9100 apparatus and are
uncorrected. Infrared (IR) spectra were recorded on a Fourier transform (FT)–IR
10 MB BOMEM spectrometer. Mass spectra (MS) were documented on a
Finnigan-MAT8430 mass spectrometer operating at an ionization potential of
70 eV. The elemental analyses were performed with an Elementar Analysensysteme
1
GmbH Vario EL in CHNS mode. H and 13C NMR spectra were recorded on a
Bruker DRX-300 Avance spectrometer at 300.13 and 75.47 MHz. NMR spectra
were obtained on solutions in CDCl3 and DMSO-d6 using tetramethylsilane
(TMS) as internal standard. The chemicals used in this work were purchased from
Merck and Fluka chemical companies.
Typical Procedure for the Synthesis of 2-(3-Bromophenyl)-
6-chloro-4-phenylquinazoline (Table 2, Entry 2)
[Hmim]TFA (0.02 g, 0.1 mmol) was added at 80 ꢀC to a magnetically stirred
mixture of 5-chloro-2-aminobenzophenone (0.231 g, 1.0 mmol), 3-bromobenzalde-
hyde (0.185 g, 1.0 mmol), and ammonium acetate (0.07 g, 1.0 mmol), while air was
bubbled into the reaction mixture. After 2 h, water was added, and the mixture
was filtered. The residue was recrystallized from EtOH to afford the pure product
as a yellow powder (0.36 g, 91%): mp 178 ꢀC, IR (KBr) cmꢁ1: 1530, 1475, 1385,

QUINAZOLINE DERIVATIVE SYNTHESIS
3219
1
1070, 797. H NMR (300.13 MHz, CDCl3) d: 7.37–8.83 (10H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 122.34, 122.90, 125.84, 127.21, 128.82, 130.06, 130.10,
130.38, 130.89, 131.58, 133.06, 133.62, 134.72, 136.86, 139.83, 150.35, 158.95,
167.71. MS m=z: 395 (Mþ, 100), 359 (75), 177 (50), 75 (45), 51 (25). Anal. calcd.
for C20H12BrClN2: C, 60.71; H, 3.06; N, 7.08. Found: C, 60.54; H, 3.25; N, 7.25.
Compound Characterization Data
6-Chloro-4-phenylquinazoline (Table 2, Entry 1). White powder (0.19 g,
83%); mp 115 ꢀC. IR (KBr) cmꢁ1: 3029, 1691, 1534, 1480, 1362, 843, 696. 1H
NMR (300.13 MHz, CDCl3) d: 7.61–8.12 (6H, m, H-Ar), 9.39 (1H, s). 13C NMR
(75.47 MHz, CDCl3) d: 123.71, 125.83, 128.88, 129.85, 130.40, 130.69, 133.53,
134.73, 136.53, 149.62, 154.83, 167.66. MS m=z: 240 (Mþ, 70), 239 (100), 205 (95),
177 (25), 151 (20), 75 (35), 51 (30). Anal. calcd. for C14H9ClN2: C, 69.86; H, 3.77;
N, 11.64. Found: C, 69.60; H, 4.00; N, 11.87.
6-Chloro-2-(4-methoxyphenyl)-4-phenylquinazoline (Table 2, Entry 3). Light
yellow powder (0.30 g, 87%); mp 161 ꢀC, IR (KBr) cmꢁ1: 1607, 1527, 1249, 1023, 832,
1
700. H NMR (300.13 MHz, CDCl3) d: 3.91 (3H, s, OCH3), 7.03–8.66 (8H, m,
H-Ar). 13C NMR (75.47 MHz, CDCl3) d: 55.39, 113.91, 121.88, 125.77, 128.71,
130.01, 130.14, 130.35, 130.49, 130.65, 132.03, 134.38, 137.22, 150.58, 160.28,
161.97, 167.39. MS m=z: 346 (Mþ, 100), 345 (80), 311 (50), 77 (20), 51 (20). Anal.
calcd. for C21H15ClN2O: C, 72.73; H, 4.36; N, 8.08. Found: C, 72.58; H, 4.52;
N, 8.25.
6-Chloro-2,4-diphenylquinazoline (Table 2, Entry 4). Yellow powder
1
(0.25 g, 80%); mp 185 ꢀC, IR (KBr) cmꢁ1: 3044, 1531, 1474, 1170, 842, 687. H
NMR (300.13 MHz, CDCl3) d: 7.53–8.68 (9H, m, H-Ar). 13C NMR (75.47 MHz,
CDCl3) d: 122.19, 125.79, 128.59, 128.67, 128.76, 130.06, 130.23, 130.78, 130.88,
132.60, 134.51, 137.09, 137.77, 150.50, 160.47, 167.54. MS m=z: 316 (Mþ, 80), 315
(100), 281 (90), 177 (25), 77 (40), 51 (30). Anal. calcd. for C20H13ClN2: C, 75.83;
H, 4.14; N, 8.84. Found: C, 75.65; H, 4.34; N, 9.02.
2-(6-Chloro-4-phenylquinazoline-2-yl)phenol (Table 2, Entry 5). Yellow
powder (0.29 g, 87%); mp 197 ꢀC, IR (KBr) cmꢁ1: 3055, 1589, 1535, 1247, 841,
753. 1H NMR (300.13 MHz, CDCl3) d: 6.99–8.75 (10H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 117.94, 119.25, 121.66, 126.22, 128.99, 129.14, 130.88,
133.16, 133.66, 135.48, 137.12, 140.22, 145.43, 148.91, 151.69, 156.75, 160.97,
164.85. MS m=z: 332 (Mþ, 97), 331 (100), 279 (75), 166 (20), 119 (25), 65 (20). Anal.
calcd. for C20H13ClN2O: C, 72.18; H, 3.94; N, 8.42. Found: C, 72.00; H, 4.12;
N, 8.60.
6-Chloro-2-(4-chlorophenyl)-4-phenylquinazoline (Table 2, Entry 6). Light
yellow powder (0.33 g, 94%); mp 187 ꢀC, IR (KBr) cmꢁ1: 1529, 1386, 1081, 702.
1H NMR (300.13 MHz, CDCl3) d: 7.48–8.64 (8H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 122.19, 125.85, 128.79, 130.04, 130.38, 130.70, 132.89,
134.74, 136.11, 136.89, 137.05, 150.24, 159.37. MS m=z: 351 (Mþ, 70), 349 (100),
315 (90), 177 (40), 75 (45), 51 (20). Anal. calcd. for C20H12Cl2N2: C, 68.39; H,
3.44; N, 7.98. Found: C, 68.22; H, 3.62; N, 8.15.

3220
M. DABIRI, P. SALEHI, AND M. BAHRAMNEJAD
6-Chloro-2-(2,4-dichlorophenyl)-4-phenylquinazoline (Table 2, Entry 7).
Light yellow powder (0.35 g, 92%); mp 162 ꢀC, IR (KBr) cmꢁ1: 3429, 2926, 1555,
1
1519, 1382, 891, 696. H NMR (300.13 MHz, CDCl3) d: 7.39–8.17 (9H, m, H-Ar).
13C NMR (75.47 MHz, CDCl3) d: 121.92, 125.86, 127.26, 128.91, 130.09, 130.51,
130.76, 132.89, 133.81, 134.99, 135.86, 136.50, 149.96, 167.67. MS m=z: 385 (Mþ,
100), 349 (80), 100 (30), 75 (40), 51 (30). Anal. calcd. for C20H11Cl3N2: C, 62.28;
H, 2.87; N, 7.26. Found: C, 62.24; H, 2.93; N, 7.32.
6-Chloro-2-(2-nitrophenyl)-4-phenylquinazoline (Table 2, Entry 8).
Yellow powder (0.32 g, 88%); mp 128 ꢀC, IR (KBr) cmꢁ1: 3420, 1536, 1380, 772,
692. 1H NMR (300.13 MHz, CDCl3) d: 7.60–8.21 (10H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 122.14, 124.17, 125.95, 128.89, 130.14, 130.30, 130.56,
130.87, 131.76, 132.25, 133.42, 133.87, 134.99, 136.35, 150.19, 159.06, 167.69. MS
m=z: 361 (Mþ, 100), 326 (75), 280 (30), 279 (50), 177 (20), 77 (40), 51 (48). Anal.
calcd. for C20H12ClN3O2: C, 66.40; H, 3.34; N, 11.61. Found: C, 66.19; H, 3.54;
N, 11.80.
6-Chloro-4-phenyl-2-(pyridin-3-yl)quinazoline (Table 2, Entry 9). Yellow
1
powder (0.27 g, 85%); mp 173 ꢀC, IR (KBr) cmꢁ1: 3430, 2921, 1529, 1381, 693. H
NMR (300.13 MHz, CDCl3) d: 7.45–9.87 (10H, m, H-Ar). 13C NMR (75.47 MHz,
CDCl3) d: 122.44, 123.50, 125.89, 128.31, 128.85, 129.08, 130.05, 130.48, 130.90,
133.29, 133.45, 134.86, 136.73, 150.07, 150.36, 151.04, 158.51, 167.86. MS m=z:
317 (Mþ, 80), 316 (100), 282 (80), 75 (30), 51 (40). Anal. calcd. for C19H12ClN3:
C, 71.81; H, 3.81; N, 13.22. Found: C, 71.66; H, 3.95; N, 13.37.
6-Chloro-4-phenyl-2-(pyridin-4-yl)quinazoline (Table 2, Entry 10). Yellow
1
powder (0.28 g, 90%); mp 192 ꢀC, IR (KBr) cmꢁ1: 3435, 2911, 1529, 1384, 695. H
NMR (300.13 MHz, CDCl3) d: 7.63–8.82 (8H, m, H-Ar). 13C NMR (75.47 MHz,
CDCl3) d: 122.41, 122.77, 125.90, 128.87, 130.05, 130.54, 131.08, 133.85, 134.95,
136.64, 145.19, 150.28, 150.32, 158.28, 167.96. MS m=z: 317 (Mþ, 80), 316 (100),
282 (80), 75 (25), 51 (40). Anal. calcd. for C19H12ClN3: C, 71.81; H, 3.81; N,
13.22. Found: C, 71.73; H, 3.95; N, 13.34.
6-Chloro-2-(2-fluorophenyl)-4-phenylquinazoline (Table 2, Entry 11).
Yellow powder (0.31 g, 95%); mp 132 ꢀC, IR (KBr) cmꢁ1: 1617, 1527, 1379, 749,
691. 1H NMR (300.13 MHz, CDCl3) d: 7.25–8.24 (12H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 116.77, 117.08, 121.88, 124.22, 125.77, 128.84, 130.08,
130.37, 130.88, 131.71, 131.82, 132.18, 133.34, 134.76, 136.74, 150.20, 159.05,
160.01, 165.75, 167.72. MS m=z: 334 (Mþ, 70), 333 (100), 299 (95), 257 (20), 75
(60), 51 (35). Anal. calcd. for C20H12ClFN2: C, 71.75; H, 3.61; N, 8.37. Found: C,
71.56; H, 3.83; N, 8.56.
6-Chloro-2-(3-fluorophenyl)-4-phenylquinazoline (Table 2, Entry 12).
Yellow powder (0.30 g, 92%); mp 173 ꢀC, IR (KBr) cmꢁ1: 1589, 1534, 1381, 851.
1H NMR (300.13 MHz, CDCl3) d: 7.20–8.45 (12H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 115.25, 115.59, 117.47, 117.73, 122.29, 124.24, 125.79,
128.78, 129.95, 130.34, 130.87, 132.98, 134.65, 136.87, 140.17, 150.34, 159.18,
159.23, 167.59, 167.61. MS m=z: 334 (Mþ, 70), 333 (100), 299 (95), 257 (20),

QUINAZOLINE DERIVATIVE SYNTHESIS
3221
75 (60), 51 (35). Anal. calcd. for C20H12ClFN2: C, 71.75; H, 3.61; N, 8.37. Found: C,
71.63; H, 3.75; N, 8.51.
6-Chloro-2-(4-fluorophenyl)-4-phenylquinazoline (Table 2, Entry 13).
Yellow powder (0.30 g, 90%); mp 193 ꢀC, IR (KBr) cmꢁ1: 1597, 1537, 1380, 834.
1H NMR (300.13 MHz, CDCl3) d: 7.17–8.69 (10H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 115.38, 115.67, 122.06, 125.81, 128.77, 130.02, 130.29,
130.75, 130.80, 130.85, 132.62, 133.96, 134.60, 137.00, 150.44, 159.50, 166.43,
167.60. MS m=z: 334 (Mþ, 60), 333 (100), 299 (95), 257 (20), 75 (60), 51 (35). Anal.
calcd. for C20H12ClFN2: C, 71.75; H, 3.61; N, 8.37. Found: C, 71.62; H, 3.75; N, 8.51.
2-(3-Bromophenyl)-4-phenylquinazoline (Table 2, Entry 14). Yellow
powder (0.31 g, 87%); mp 103 ꢀC, IR (KBr) cmꢁ1: 1609, 1535, 1386, 774. 1H
NMR (300.13 MHz, DMSO-d6) d: 7.47–8.66 (13H, m, H-Ar). 13C NMR
(75.47 MHz, DMSO-d6) d: 121.66, 122.59, 127.31, 127.48, 128.75, 129.11, 129.22,
130.47, 130.66, 130.91, 131.38, 133.88, 135.00, 137.20, 140.21, 151.47, 157.85,
157.87, 168.59, 168.61. MS m=z: 361 (Mþ, 100), 279 (30), 177 (40), 76 (60), 50 (65).
Anal. calcd. for C20H13BrN2: C, 66.50; H, 3.63; N, 7.75. Found: C, 66.47; H, 3.80;
N, 7.93.
2-(4-Methoxyphenyl)-4-phenylquinazoline (Table 2, Entry 15). Yellow
powder (0.29 g, 92%); mp 153 ꢀC, IR (KBr) cmꢁ1: 3748, 1598, 1526, 1251, 1022,
1
771, 536. H NMR (300.13 MHz, CDCl3) d: 3.91 (3H, s, OCH3), 7.03–8.68 (9H,
m, H-Ar). 13C NMR (75.47 MHz, CDCl3) d: 55.39, 113.86, 121.40, 126.56, 127.03,
128.52, 128.88, 129.88, 130.17, 130.32, 130.86, 133.51, 137.76, 152.00, 160.03,
161.77, 168.22. MS m=z: 312 (Mþ, 95), 311 (100), 77 (20), 51 (20). Anal. calcd. for
C21H16N2O: C, 80.75; H, 5.16; N, 8.97. Found: C, 80.57; H, 5.32; N, 9.17.
2-(4-Nitrophenyl)-4-phenylquinazoline (Table 2, Entry 16). Yellow
powder (0.28 g, 85%); mp 195 ꢀC, IR (KBr) cmꢁ1: 1601, 1540, 1348, 1077, 839,
709. 1H NMR (300.13 MHz, CDCl3) d: 7.64–8.90 (9H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 121.97, 123.66, 127.15, 128.07, 128.68, 129.38, 129.44,
130.17, 130.26, 134.02, 137.23, 144.05, 149.13, 151.82, 157.94, 168.71. MS m=z:
327 (Mþ, 100), 326 (95), 280 (50), 75 (50), 51 (35). Anal. calcd. for C20H13N3O2:
C, 73.38; H, 4.00; N, 12.84. Found: C, 73.15; H, 4.21; N, 13.07.
2-(4-Chlorophenyl)-4-phenylquinazoline (Table 2, Entry 17). Light
yellow powder (0.28 g, 90%); mp 170 ꢀC, IR (KBr) cmꢁ1: 3067, 1534, 1334, 1085,
1
770, 699. H NMR (300.13 MHz, CDCl3) d: 7.49–8.68 (9H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 121.71, 127.08, 127.23, 128.59, 128.72, 129.10, 130.01,
130.17, 133.73, 136.69, 137.51, 151.89, 159.20, 168.45. MS m=z: 316 (Mþ, 80), 315
(100), 102 (20), 76 (23), 50 (23). Anal. calcd. for C20H13ClN2: C, 75.83; H, 4.14;
N, 8.84. Found: C, 75.63; H, 4.36; N, 9.04.
2-(2,4-Dichlorophenyl)-4-phenylquinazoline (Table 2, Entry 18). Yellow
powder (0.29 g, 82%); mp 97 ꢀC, IR (KBr) cmꢁ1: 3435, 2923, 1531, 1380, 780, 691.
1H NMR (300.13 MHz, CDCl3) d: 7.42–8.23 (10H, m, H-Ar). 13C NMR
(75.47 MHz, CDCl3) d: 121.40, 127.11, 127.21, 128.02, 128.69, 129.10, 130.19,
130.39, 132.84, 133.99, 134.03, 135.56, 136.90, 137.08, 151.53, 160.32, 168.42. MS

3222
M. DABIRI, P. SALEHI, AND M. BAHRAMNEJAD
m=z: 350 (Mþ, 60), 349 (100), 177 (25), 76 (30), 50 (25). Anal. calcd. for
C20H12Cl2N2: C, 68.39; H, 3.44; N, 7.98. Found: C, 68.26; H, 3.55; N, 8.11.
4-Phenyl-2-(pyridin-3-yl)quinazoline (Table 2, Entry 19). Yellow powder
1
(0.24 g, 86%); mp 142 ꢀC, IR (KBr) cmꢁ1: 1571, 1531, 1336, 767, 693. H NMR
(300.13 MHz, CDCl3) d: 7.28–9.91 (11H, m, H-Ar). 13C NMR (75.47 MHz, CDCl3)
d: 121.98, 123.64, 127.15, 127.70, 128.64, 129.22, 130.19, 133.94, 134.16, 136.66,
137.25, 149.50, 150.12, 151.84, 157.97, 168.70. MS m=z: 283 (Mþ, 70), 282 (100),
76 (25), 51 (25). Anal. calcd. for C19H13N3: C, 80.54; H, 4.62; N, 14.83. Found: C,
80.42; H, 4.81; N, 14.97.
4-Phenyl-2-(pyridin-4-yl)quinazoline (Table 2, Entry 20). Yellow powder
1
(0.24 g, 85%); mp 145 ꢀC, IR (KBr) cmꢁ1: 1600, 1528, 1386, 774, 693. H NMR
(300.13 MHz, CDCl3) d: 7.63–8.83 (9H, m, H-Ar). 13C NMR (75.47 MHz, CDCl3)
d: 122.32, 122.73, 127.17, 128.24, 128.68, 129.45, 130.19, 130.28, 134.05, 137.17,
146.41, 149.48, 151.79, 157.75, 168.83. MS m=z: 283 (Mþ, 70), 282 (100), 76 (25),
51 (25). Anal. calcd. for C19H13N3: C, 80.54; H, 4.62; N, 14.83. Found: C, 80.36;
H, 4.80; N, 15.08.
2-(3-Fluorophenyl)-4-phenylquinazoline (Table 2, Entry 21). Yellow
powder (0.25 g, 85%); mp 160 ꢀC, IR (KBr) cmꢁ1: 1589, 1537, 1334, 775. 1H
NMR (300.13 MHz, CDCl3) d: 7.21–8.53 (13H, m, H-Ar). 13C NMR (75.47 MHz,
CDCl3) d: 115.52, 117.32, 121.84, 124.30, 127.07, 127.38, 128.60, 129.19, 129.92,
130.03, 130.08, 130.21, 133.75, 137.47, 140.63, 151.86, 159.04, 161.64, 164.88,
168.47. MS m=z: 300 (Mþ, 100), 299 (90), 223 (20), 196 (25), 150 (20), 76 (40), 50
(35). Anal. calcd. for C20H13FN2: C, 79.98; H, 4.36; N, 9.33. Found: C, 79.80; H,
4.54; N, 9.53.
2-(4-Fluorophenyl)-4-phenylquinazoline (Table 2, Entry 22). Yellow
1
powder (0.27 g, 90%); mp 128 ꢀC, IR (KBr) cmꢁ1: 1600, 1544, 1334, 771, 697. H
NMR (300.13 MHz, CDCl3) d: 7.19–8.76 (13H, m, H-Ar). 13C NMR (75.47 MHz,
CDCl3) d: 115.32, 115.61, 120.45, 121.57, 127.09, 128.58, 128.70, 128.94, 130.05,
130.17, 130.76, 130.88, 133.74, 134.22, 137.54, 151.77, 154.15, 159.23, 168.53,
177.78. MS m=z: 300 (Mþ, 100), 299 (90), 223 (20), 150 (20), 76 (40), 50 (35). Anal.
calcd. for C20H13FN2: C, 79.98; H, 4.36; N, 9.33. Found: C, 79.76; H, 4.55; N, 9.56.
CONCLUSION
In conclusion, we have introduced a three-component condensation reaction
leading to quinazoline derivatives, which constitute an essential part of many natural
products and have antimicrobial, antitumor, or fungicidal activity, from simple and
readily available precursors employing [Hmim]TFA as an acidic IL and reusable
catalyst under aerobic oxidation conditions. To the best of our knowledge, this is
the first report on the synthesis of quinazolines starting from 2-aminobenzophe-
nones, aldehydes, and ammonium acetate. The simplicity, efficiency, excellent yields
of products, easy workup procedure, and avoidance of hazardous organic solvents
are among the advantages of this new method for the synthesis of different kinds
of quinazolines.

QUINAZOLINE DERIVATIVE SYNTHESIS
3223
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Research Council of
Shahid Beheshti University and the Catalyst Center of Excellence (CCE).
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