One-pot tandem synthesis of 2-arylquinazolines by a multicomponent cyclization reaction

Article abstract of DOI:10.3390/molecules181113860

A series of 2-arylquinazolines have been synthesized in moderate to excellent yields by one-pot tandem reaction of (2-aminophenyl)methanols, aldehydes and ceric ammonium nitrate (CAN). The utility of this transformation was demonstrated by its compatibility with a wide range of functional groups. Thus, the method represents a simple and practical procedure to access 2-arylquinazolines.

Full text of DOI:10.3390/molecules181113860

Molecules 2013, 18, 13860-13869; doi:10.3390/molecules181113860
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
One-Pot Tandem Synthesis of 2-Arylquinazolines by a
Multicomponent Cyclization Reaction
Leping Ye *, Lin Yu, Lijun Zhu and Xiaodong Xia
The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,
Wenzhou 325000, Zhejiang, China
* Author to whom correspondence should be addressed; E-Mail: yeleping@163.com;
Tel.: +86-577-8800-2124; Fax: +86-577-8883-2693.
Received: 8 October 2013; in revised form: 21 October 2013 / Accepted: 21 October 2013 /
Published: 8 November 2013
Abstract: A series of 2-arylquinazolines have been synthesized in moderate to excellent
yields by one-pot tandem reaction of (2-aminophenyl)methanols, aldehydes and ceric
ammonium nitrate (CAN). The utility of this transformation was demonstrated by its
compatibility with a wide range of functional groups. Thus, the method represents a simple
and practical procedure to access 2-arylquinazolines.
Keywords: quinazolines; multicomponent; cyclization reaction; one-pot tandem synthesis
1. Introduction
Quinazolines and derivatives thereof are ubiquitous structural motifs that frequently occur in a wide
variety of bioactive natural products such as prazosin [1], lapatinib [2], icotinib [3], etc. They possess a
wide range of biological and pharmacological activities, including antibacterial [4], anti-inflammatory [5],
antiplasmodial [6], antitumor [7], antimicrobial and antioxidant properties [8]. In addition, they have
also been used as photochemotherapeutic agents [9], DNA-gyrase, JAK2, PDE5, and EGFR tyrosine
kinase inhibitors [10] as well as CB2 receptor agonists [11]. Recently, Yang reported that substituted
quinazolines possess novel potent and selective FLT3 inhibitory and anti-acute myeloid leukemia
activities [12]. Consequently, in the past few years a number of synthetic methods to prepare these
compounds have been described. Fu and co-workers reported that copper-catalyzed cascade reactions
provide attractive and valuable routes for the construction of quinazoline derivatives via sequential
Ullmann-type coupling and intramolecular cyclization [13]. Walton reported a microwave-promoted

Molecules 2013, 18
13861
syntheses of quinazolines by the reaction of 2-(aminoaryl)alkanone O-phenyl oximes with
aldehydes [14]. Tandem reaction of 2-aminobenzophenones with benzylic amines followed by C–H
functionalization has also been reported [15–18]. Zhang reported a three-component synthesis of
quinazoline derivatives using a low melting sugar–urea–salt mixture as a solvent [19]. In 2012, Beifuss
and co-workers developed a copper-catalyzed coupling reaction of o-bromobenzylbromides and
benzamidines for the synthesis of quinazolines in an aqueous medium [20]. The condensation reactions
of 2-aminobenzylamines with aldehydes followed by subsequent oxidation with strong oxidants
(e.g., 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) [21], MnO2 [22], and NaClO [23]) provide a
conventional but simple method to synthesize quinazolines (Scheme 1(a)). However, these methods
are hampered by the need to use a stoichiometric amount of a nonrenewable oxidant and the yields
have not always been satisfactory. Recently, three improved methods have been reported for
constructing quinazolines: (i) copper-catalyzed aerobic oxidative cyclization reaction of
2-(aminomethyl)benzenamines with aldehydes [24]; (ii) aerobic oxidative cyclization reaction of
2-(aminomethyl)benzenamines with aldehydes by a cooperative catalytic system of platinum/iridium
alloyed nanoclusters and a dimeric catechol derivative [25]; (iii) iridium-catalyzed hydrogen transfer
reaction of 2-(aminomethyl)benzenamines with aldehydes using styrene as a hydrogen acceptor [26].
Scheme 1. Reaction of (2-aminophenyl)methanols with aldehydes under different conditions.
Previous work
OH
O
N
R
R
+
(a)
ArCHO
ArCHO
NH2
N
Ar
This work
CAN
OH
R
+
(b)
R
CuCl, BPy, TEMPO
KOH, CH3CN
NH2
N
Ar
Herein, we wish to report a new method for the synthesis of quinazolines by using a one-pot tandem
reaction of (2-aminophenyl)methanols, aldehydes and ceric ammonium nitrate (CAN) (Scheme 1(b)).
2. Results and Discussion
We began our study by examining the reaction between (2-aminophenyl)methanol (1a) and
benzaldehyde (2a) to obtain 2-phenyl-4H-benzo[d][1,3]oxazine (4a) and screen the optimal reaction
conditions. Surprisingly, a trace amount of unexpected 2-phenylquinazoline (3a) was detected by
GC/MS (EI) analysis during the process of performing the above condensation reaction in the presence
of ceric ammonium nitrate (CAN). To the best of our knowledge, the synthesis of quinazolines using a
one-pot tandem reaction of (2-aminophenyl)methanols, aldehydes and ceric ammonium nitrate has
never been investigated before. In the present study, this unexpected reaction was thoroughly
investigated. To realize the selective generation of 3a, we initially ran a series of trial experiments in

Molecules 2013, 18
13862
the presence of palladium catalysts by adjusting the reaction parameters. However, little-to-no
product 3a was detected. To our delight, after the catalyst was switched to a copper catalyst such as
CuOTf, the desired product 3a was isolated in 19% yield when the combination of KF and CH3CN was
employed (Table 1, entry 1). Encouraged by this promising result, we further adjusted reaction
parameters including copper catalysts, bases, and solvents.
Table 1. Optimization of the reaction conditions a.
OH
N
O
+
+
PhCHO
NH2
1a
N
Ph
N
Ph
2a
3a
4a
Entry
1
Cu sources
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuBr
Base
KF
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
THF
Yield (%) b
19
32
17
45
14
33
42
48
64
68
82
91
67
56
51
57
34
0
2
Li2CO3
CsOAc
K2CO3
K3PO4
t-BuOK
LiOH
NaOH
KOH
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CsOH
CuCl
Cu(OTf)2
Cu(OAc)2
CuBr2
CuCl2
CuO
none
CuCl
31
65
36
22
CuCl
CuCl
PhCl
CuCl
DMF
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), CAN (0.3 mmol), Cu source (10 mol%), 2,2'-bipyridine
(10 mol%), TEMPO (10 mol%), base (0.5 mmol), and solvent (2 mL), O2, 30 °C, 24 h then 60 °C for 24 h.
b Isolated yield of 3a.
Screening revealed that the use of CsOH or KOH as a base achieved the best results. Other bases,
including KF, Li2CO3, CsOAc, K2CO3, K3PO4, t-BuOK, LiOH, and NaOH, were less efficient
(Table 1, entries 2–10). Among the copper sources used (e.g., CuOTf, CuBr, CuCl, Cu(OTf)2,
Cu(OAc)2, CuBr2, CuCl2, and CuO), CuCl exhibited the highest catalytic reactivity (91% yield, Table 1,
entries 10–17). No reaction occurred when the procedure was carried out in the absence of copper
catalyst (Table 1, entry 18). Finally, we studied the solvent effect and found that CH3CN was superior

Molecules 2013, 18
13863
to toluene, THF, PhCl, and DMF (Table 1, entries 12, 19–22). In addition, the reaction failed to give
the desired product when the procedure was carried out under a N2 atmosphere.
With the optimized reaction conditions in hand, we next explored the substrate scope of
(2-aminophenyl)methanols 1 and aldehydes 2 for the one-pot tandem multicomponent cyclization
reaction (Table 2). First, the reaction of (2-aminophenyl)methanol (1a) with various aldehydes 2a−k in
the presence of CAN was investigated under the standard conditions. The results disclosed that a
variety of aldehydes are suitable substrates, and the cyclization reactions provide the corresponding
products in moderate to good yields (Table 2, entries 1−11).
Table 2. Substrate scope of (2-aminophenyl)methanols and aldehydes a.
OH
NH2
CAN
N
R
R
+
ArCHO
CuCl, BPy, TEMPO
CsOH, CH3CN
N
3
Ar
1
2
Entry
(2-Aminophenyl)methanols (1)
Aldehydes (2)
Product (3) Yield (%) b
OH
(2a)
CHO
(1a)
1
3a
3b
91
84
NH2
OH
(2b)
Me
CHO
(1a)
2
3
NH2
Me
OH
(2c)
(1a)
3c
66
CHO
NH2
OH
(2d)
CHO
MeO
F
(1a)
4
5
6
7
8
3d
3e
3f
82
93
86
84
71
NH2
OH
(2e)
CHO
(1a)
NH2
OH
(2f)
(2g)
(2h)
Cl
CHO
CHO
CHO
(1a)
NH2
OH
Br
(1a)
3g
3h
NH2
OH
F3C
(1a)
NH2
CHO
OH
(2i)
(1a)
9
3i
78
NH2
OH
(2j)
(2k)
(2a)
CHO
CHO
(1a)
10
11
12
3j
3k
3l
87
89
87
O
S
NH2
OH
(1a)
NH2
Me
OH
CHO
(1b)
NH2

Molecules 2013, 18
13864
Table 2. Cont.
Entry
(2-Aminophenyl)methanols (1)
Aldehydes (2)
Product (3) Yield (%) b
F
OH
(2a)
CHO
13
3m
81
(1c)
NH2
OH
Cl
(2a)
(2a)
CHO
CHO
14
3n
3o
80
67
(1d)
(1e)
NH2
OH
15
O2N
NH2
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), CAN (0.3 mmol), CuCl (10 mol%), 2,2'-bipyridine
(10 mol%), TEMPO (10 mol%), CsOH (0.5 mmol), and CH3CN (2 mL), O2, 30 °C, 24 h then 60 °C for 24 h.
b Isolated yield.
First, the mono-substituent positions at the aryl moiety of aldehydes were evaluated, and the results
demonstrated that steric effects of substituents had some effects on the reaction. For example, when the
cyclization reaction of 1a with para-, and ortho-methylbenzaldehyde was examined, 84% of 3b was
isolated, while the yield of 3c decreased to 66% (Table 2, entries 2–3). The electronic properties of the
substituents on the phenyl ring of the aldehydes also affected the yields of the reaction to some extent.
Generally, the aldehydes bearing an electron-withdrawing substituent (e.g., –F, –Cl and –Br, Table 2,
entries 5–7) afforded a slightly higher yield of cyclization products than those analogues bearing an
electron-donating substituent (e.g., –Me and –OMe, Table 2, entries 2–4). However, aldehydes bearing
a strong electron-withdrawing substituent (e.g.,–CF3) at the para position afforded a slightly lower
yield of product 3h (Table 2, entry 8). A moderate yield of 2-(naphthalen-2-yl)quinazoline (3i) was
observed using 1-naphthaldehyde (2i) as substrate (Table 2, entry 9). In addition, heterocyclic
aldehydes, such as 2-furylaldehyde (2j) and 2-thienylaldehyde (2k) could also be used as the
substrates, leading to the corresponding desired products 2-(furan-2-yl)quinazoline (3j) and
2-(thiophen-2-yl)quinazoline (3k) in 87% and 89% yields, respectively (Table 2, entries 10–11).
Subsequently, several (2-aminophenyl)methanols 1b–e, which bear different substituents at the aryl
moiety, were evaluated (Table 2, entries 12−15). The results showed that different functional groups,
including methyl, fluoro, chloro, and nitro, were well tolerated under the standard conditions. In
general, the (2-aminophenyl)methanols bearing an electron-donating substituent produced a slightly
higher yield of cyclization products than those analogues bearing an electron-withdrawing substituent.
For example, substrates 1b and 1e, bearing a methyl or nitro group, reacted with substrate 2a to give
the corresponding products 3l and 3o in 87% and 67% yields, respectively (Table 2, entries 12 and 15).
It is noteworthy that halogen-containing substrates 1c and 1d produced the desired products 3m and 3n
in 80% and 81% yields, respectively (Table 2, entries 13–14).
Two plausible reaction pathways for the formation of 2-arylquinazolines have been established and
are shown in Scheme 2. First, aerobic alcohol oxidation reaction of (2-aminophenyl)methanols 1
generates 2-aminobenzaldehydes 4. An imine intermediate III is formed from intermediate I or
intermediate II by two plausible reaction pathways, respectively. Then intramolecular cyclization of
intermediate III affords dihydroquinazolines IV. Aromatization of intermediate IV gives
2-arylquinazolines 3 as the desired products. However, the mechanism in detail on the formation of the
2-arylquinazolines remains unclear in current stage.

Molecules 2013, 18
13865
Scheme 2. Plausible reaction pathways.
CHO
R
ArCHO 2
CAN
path a
N
Ar
path a
CHO
NH2
I
OH
[O]
[O]
N
N
R
NH
Ar
R
R
R
R
NH2
path b
N
Ar
N
N
H
Ar
path b
ArCHO 2
4
1
NH
NH2
CAN
III
IV
3
R
II
3. Experimental
3.1. General
1
13
Melting points are uncorrected. H-NMR and C-NMR spectra were measured on a 500 MHz or
300 MHz spectrometer using DMSO-d6 or CDCl3 as the solvent with tetramethylsilane (TMS) as an
internal standard at room temperature. Chemical shifts are given n δ relative to TMS, and the coupling
constants J are given in hertz. High-resolution mass spectra were recorded on an ESI-Q-TOF mass
spectrometer. Other commercially obtained reagents were used without further purification.
All reactions under nitrogen atmosphere were conducted using standard Schlenk techniques. Column
chromatography was performed using EM silica gel 60 (300−400 mesh).
3.2. General Procedure for the Synthesis of 2-Arylquinazolins
To a Schlenk tube were added (2-aminophenyl)methanols 1 (0.2 mmol), aldehydes 2 (0.3 mmol),
CAN (0.3 mmol), CuCl (0.02 mmol), 2,2'-bipyridine (0.02 mmol), TEMPO (0.02 mmol), CsOH
(0.5 mmol), and CH3CN (2 mL). Next the tube was charged with O2 (1 atm), and was stirred
constantly at 30 °C for 24 h, then at 60 °C for 24 h. After the completion of the reaction, the reaction
mixture was cooled to room temperature, diluted with ethyl acetate, and washed with brine. After the
aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over anhydrous
MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography
(hexane/ethyl acetate) to afford the desired products 3.
2-Phenylquinazoline (3a) [24]. Pale yellow solid (91% yield), mp 98–99 °C (Lit. 97–98 °C); 1H-NMR
(DMSO-d6, 300 MHz): δ 9.70 (s, 1H), 8.55–8.59 (m, 2H), 8.17 (d, J = 8.1 Hz, 1H), 8.00–8.08 (m, 2H),
13
7.71–7.76 (m, 1H), 7.55–7.59 (m, 3H); C-NMR (DMSO-d6, 75 MHz): δ 161.3, 159.8, 149.8, 137.4,
134.8, 130.8, 128.7, 128.1, 127.9, 127.8, 123.3.
2-p-Tolylquinazoline (3b) [24]. Yellow solid (84% yield), mp 109–111 °C (Lit. 107–109 °C); 1H-NMR
(CDCl3, 500 MHz): δ 9.44 (s, 1H), 8.52 (d, J = 8.0 Hz, 2H), 8.07 (d, J = 8.0 Hz, 1H), 7.87–7.90 (m, 2H),
13
7.56–7.60 (m, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H); C-NMR (CDCl3, 125 MHz): δ 161.1,
160.4, 150.8, 140.8, 135.3, 134.0, 129.4, 128.52, 128.50, 127.1, 127.0, 123.5, 21.5.
2-o-Tolylquinazoline (3c) [25]. Colorless oil (66% yield); 1H-NMR (CDCl3, 500 MHz): δ 9.49 (s, 1H),
8.11 (d, J = 8.5 Hz, 1H), 7.89–7.95 (m, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.44

Molecules 2013, 18
13866
13
(t, J = 7.5 Hz, 1H), 7.05–7.11 (m, 2H), 3.87 (s, 3 H); C-NMR (CDCl3, 125 MHz): δ 162.4, 160.0,
157.7, 150.6, 134.0, 131.7, 130.8, 129.0, 128.5, 127.5, 127.0, 123.1, 120.7, 111.9, 56.0.
2-(4-Methoxyphenyl)quinazoline (3d) [24]. White solid (82% yield), mp 93–94 °C (Lit. 91–93 °C);
1H-NMR (CDCl3, 500 MHz): δ 9.40 (s, 1H), 8.57–8.59 (m, 2H), 8.03 (d, J = 8.9 Hz, 1H), 7.86
(t, J = 9.7 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H); 13C-NMR (CDCl3,
125 MHz): δ 161.9, 160.9, 160.4, 150.9, 134.0, 130.9 130.2, 128.4, 127.1, 126.8, 123.3, 114.0, 55.4.
2-(4-Fluorophenyl)quinazoline (3e) [24]. White solid (93% yield), mp 138–139 °C (Lit. 135–137 °C);
1H-NMR (CDCl3, 500 MHz): δ 9.42 (s, 1H), 8.61–8.64 (m, 2H), 8.06 (d, J = 8.5 Hz, 1H), 7.89
13
(t, J = 8.0 Hz, 2H), 7.60 (t, J = 7.0 Hz, 1H), 7.20 (t, J = 8.5 Hz, 2H); C-NMR (CDCl3, 125 MHz):
δ 165.6, 163.7, 160.5, 160.1, 150.7, 134.1, 130.7, 130.6, 128.5, 127.2, 127.1, 123.5, 115.6, 115.4.
2-(4-Chlorophenyl)-quinazoline (3f) [24]. White solid (86% yield), mp 135–137 °C (Lit. 133–135 °C);
1H-NMR (DMSO-d6, 500 MHz): δ 9.72 (s, 1H), 8.57 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.0 Hz, 1H),
13
8.04–8.08 (m, 2H), 7.75–7.78 (m, 1H ), 7.64 (d, J = 8.5 Hz, 2H); C-NMR (DMSO-d6, 125 MHz):
δ 161.5, 158.8, 149.8, 136.3, 135.8, 135.1, 129.9, 128.9, 127.93, 127.90, 123.4.
2-(4-Bromophenyl)quinazoline (3g) [23]. White solid (84% yield), mp 121–123 °C (Lit. 120–121 °C);
1H-NMR (CDCl3, 500 MHz): δ 9.43 (s, 1H), 8.50 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 9.0 Hz, 1H),
13
7.89–7.92 (m, 2H), 7.60–7.66 (m, 3H); C-NMR (CDCl3, 125 MHz): δ 160.5, 160.1, 150.7, 137.0,
134.2, 131.8, 130.2, 128.6, 127.4, 127.1, 125.4, 123.6.
2-(4-(Trifluoromethyl)phenyl)quinazoline (3h) [23]. White solid (71% yield), mp 144–146 °C (Lit. not
reported); 1H-NMR (DMSO-d6, 500 MHz): δ 9.76 (s, 1H), 8.75 (d, J = 8.5 Hz, 2H), 8.21 (d, J = 8.0 Hz,
1H), 8.06–8.12 (m, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.78–7.81 (m, 1H); 13C-NMR (DMSO-d6,
125 MHz): δ 161.6, 158.4, 149.7, 141.2, 135.1, 130.7, 150.5, 128.7, 128.4, 128.0, 127.9, 125.8, 125.7,
125.3, 123.6, 123.1.
2-(Naphthalene-1-yl)quinazoline (3i) [25]. white solid (78% yield), mp 121–123 °C (Lit. 120–121 °C);
1H-NMR (CDCl3, 500 MHz): δ 9.60 (s, 1H), 8.70 (d, J = 8.0 Hz, 1H), 8.17–8.19 (m, 2H), 7.93–8.03
13
(m, 4H), 7.70 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.52-7.58 (m, 2H); C-NMR (CDCl3,
125 MHz): δ 163.5, 160.4, 150.6, 136.3, 134.3, 134.2, 131.2, 130.4, 129.6, 128.7, 128.5, 127.7, 127.1,
126.8, 125.89, 125.87, 125.3, 123.1.
2-(Furan-2-yl)quinazoline (3j) [26]. Brown solid (87% yield), mp 132–134 °C (Lit. 131–132 °C);
1H-NMR (CDCl3, 500 MHz): δ 9.36 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.87–7.90 (m, 2H), 7.68 (s, 1H),
7.60 (t, J = 6.0 Hz, 1H), 7.44–7.45 (m, 1H), 6.60–6.61 (m, 1H); 13C-NMR (CDCl3, 125 MHz): δ 160.7,
154.1, 152.5, 150.4, 145.3, 134.5, 128.4, 127.2, 123.4, 114.1, 112.3.
2-(Thiophene-2-yl)quinazoline (3k) [13]. White solid (89% yield), mp 132–133 °C (Lit. 132–134 °C);
1H-NMR (CDCl3, 500 MHz): δ 9.34 (s, 1H), 8.14–8.15 (m, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.85–7.88
13
(m, 2H), 7.51–7.57 (m, 2H), 7.18–7.20 (m, 1H); C-NMR (CDCl3, 125 MHz): δ 160.5, 157.9, 150.6,
143.8, 134.3, 129.9, 129.2, 128.3, 128.2, 127.2, 127.0, 123.4.

Molecules 2013, 18
13867
6-Methyl-2-phenylquinazoline (3l) [27]. Pale yellow solid (87% yield), mp 131–132 °C (Lit.
130–132 °C); 1H-NMR (CDCl3, 500 MHz): δ 9.38 (s, 1H), 8.60 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz,
13
1H), 7.72–7.74 (m, 1H), 7.67 (s, 1H), 7.50–7.55 (m, 3H), 2.58 (s, 3H); C-NMR (CDCl3, 125 MHz):
δ 160.4, 159.7, 149.4, 138.2, 137.4, 136.4, 130.4, 128.6, 128.4, 128.3, 125.8, 123.6, 21.6.
6-Fluoro-2-phenylquinazoline (3m) [14]. White solid (81% yield), mp 121–122 °C (Lit. 120–121 °C);
1H-NMR (CDCl3, 500 MHz): δ 9.43 (s, 1H), 8.59–8.61 (m, 2H), 8.09–8.11 (m, 1H), 7.65–7.70 (m, 1H),
13
7.51–7.55 (m, 4H); C-NMR (CDCl3, 125 MHz): δ 161.4, 160.7, 159.8, 159.7, 159.4, 148.0, 128.2,
137.7, 131.4, 131.3, 130.7, 128.7, 128.5, 124.6, 124.4, 124.0, 123.9, 110.2, 110.0.
6-Chloro-2-phenylquinazoline (3n) [17]. Pale yellow solid (80% yield), mp 158–159 °C (Lit.
157–159 °C); 1H-NMR (CDCl3, 500 MHz): δ 9.38 (s, 1H), 8.59–8.61 (m, 2H), 8.02 (d, J = 9.0 Hz, 1H),
7.89 (d, J = 2.5 Hz, 1H), 7.81–7.83 (m, 1H), 7.51–7.55 (m, 3H); 13C-NMR (CDCl3, 125 MHz):
δ 161.3, 159.5, 149.2, 137.6, 135.0, 132.8, 130.9, 130.4, 128.7, 128.6, 125.8, 124.0.
7-Nitro-2-phenylquinazoline (3o). White solid (67% yield), mp 142–144 °C; IR (KBr) 2925, 1687,
1567, 1526, 1421, 1326, 1291, 927, 823, 740, 706, 686, 668 cm−1; 1H-NMR (CDCl3, 500 MHz): δ 9.62
(s, 1H), 8.97 (d, J = 2 Hz, 1H), 8.64–8.66 (m, 2H), 8.357–8.361 (m, 1H), 8.11 (d, J = 8.5 Hz, 1H),
13
7.56–7.58 (m, 3 H); C-NMR (CDCl3, 125 MHz): δ 162.9, 160.8, 151.2, 150.5, 136.9, 131.6, 129.0,
128.9, 128.8, 125.7, 124.9, 120.7. HRMS (ESI) m/z: [M+H]+ Calcd for C14H10N3O2 251.0695; Found:
251.0681.
4. Conclusions
In summary, we have successfully developed a new protocol for the copper-catalyzed cascade
reaction of (2-aminophenyl)methanols, aldehydes, and ceric ammonium nitrate to afford a series of
2-arylquinazolines in moderate to excellent yields. Further efforts to extend this catalytic system to the
preparation of other useful heterocyclic compounds are currently underway in our laboratories.
Acknowledgments
We thank the National Natural Science Foundation of China (No. 81102150), Traditional
Chinese Medicine Scientific Research Foundation of Zhejiang Province (No. 2010ZA091) and
Medicine and Health Science and Technology Projects of Zhejiang Province (No. 2012KYA133) for
financial support.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Antonello, A.; Hrelia, P.; Leonardi, A.; Marucci, G.; Rosini, M.; Tarozzi, A.; Tumiatti, V.;
Melchiorre, C. Design, synthesis, and biological evaluation of prazosin-related derivatives as
multipotent compounds. J. Med. Chem. 2005, 48, 28–31.

Molecules 2013, 18
13868
2. Oude Munnink, T.H.; de Vries, E.G.E.; Vedelaar, S.R.; Timmer-Bosscha, H.; Schröder, C.P.;
Brouwers, A.H.; Lub-de Hooge, M.N. Lapatinib and 17AAG reduce 89Zr-trastuzumab-F(ab’)2
uptake in SKBR3 tumor xenografts. Mol. Pharm. 2012, 9, 2995–3002.
3. Hu, S.-J.; Long, W.; Wang, F.; Li, Z.-Q. Methods of preparing icotinib and icotinib hydrochloride,
and intermediates thereof. WO Patent 2013064128, 2013.
4. Tiwari, R.; Chhabra, G. Evaluation of antibacterial activity of novel quinazoline derivatives.
Asian J. Chem. 2010, 22, 5981–5986.
5. Balakumar, C.; Lamba, P.; Kishore, D.P.; Narayana, B.L.; Rao, K.V.; Rajwinder, K.; Rao, A.R.;
Shireesha, B.; Narsaiah, B. Synthesis, anti-inflammatory evaluation and docking studies of some
new fluorinated fused quinazolines. Eur. J. Med. Chem. 2010, 45, 4904–4913.
6. Kabri, Y.; Azas, N.; Dumetre, A.; Hutter, S.; Laget, M.; Verhaeghe, P.; Gellis, A.; Vanelle, P.
Original quinazoline derivatives displaying antiplasmodial properties. Eur. J. Med. Chem. 2010,
45, 616–622.
7. Noolvi, M.N.; Patel, H.M.; Bhardwaj, V.; Chauhan, A. Synthesis and in vitro antitumor activity of
substituted quinazoline and quinoxaline derivatives: Search for anticancer agent. Eur. J. Med. Chem.
2011, 46, 2327–2346.
8. Kumar, A.; Sharma, P.; Kumari, P.; Lal Kalal, B. Exploration of antimicrobial and antioxidant
potential of newly synthesized 2,3-disubstituted quinazoline-4(3H)-ones. Bioorg. Med. Chem. Lett.
2011, 21, 4353–4357.
9. Barraja, P.; Caracausi, L.; Diana, P.; Montalbano, A.; Carbone, A.; Salvador, A.; Brun, P.;
Castagliuolo, I.; Tisi, S.; Dall’Acqua, F.; et al. Pyrrolo[3,2-h]quinazolines as photochemotherapeutic
agents. ChemMedChem 2011, 6, 1238–1248.
10. Yang, S.H.; Khadka, D.B.; Cho, S.H.; Ju, H.-K.; Lee, K.Y.; Han, H.J.; Lee, K-T.; Cho, W.-J.
Virtual screening and synthesis of quinazolines as novel JAK2 inhibitors. Bioorg. Med. Chem.
2011, 19, 968–977.
11. Saari, R.; Toermae, J.-C.; Nevalainen, T. Microwave-assisted synthesis of quinoline, isoquinoline,
quinoxaline and quinazoline derivatives as CB2 receptor agonists. Bioorg. Med. Chem. 2011, 19,
939–950.
12. Li, W.-W.; Wang, X.-Y.; Zheng, R.-L.; Yan, H.-X.; Cao, Z.-X.; Zhong, L.; Wang, Z.-R.; Ji, P.;
Yang, L.-L.; Wang, L.-J.; et al. Discovery of the novel potent and selective FLT3 inhibitor
1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and its
anti-acute myeloid leukemia (AML) activities in Vitro and in Vivo. J. Med. Chem. 2012, 55,
3852–3866.
13. Wang, C.; Li, S.; Liu, H.; Jiang, Y.; Fu, H. Copper-catalyzed synthesis of quinazoline derivatives
via ullmann-type coupling and aerobic oxidation. J. Org. Chem. 2010, 75, 7936–7938.
14. Portela-Cubillo, F.; Scott, J.S.; Walton, J.C. Microwave-promoted syntheses of quinazolines
and dihydroquinazolines from 2-aminoarylalkanone O-phenyl oximes. J. Org. Chem. 2009, 74,
4934–4942.
15. Han, B.; Wang, C.; Han, R.F.; Yu, W.; Duan, X.Y.; Fang, R.; Yang, X.L. Efficient
aerobic oxidative synthesis of 2-aryl quinazolines via benzyl C–H bond amination catalyzed by
4-hydroxy-TEMPO. Chem. Commun. 2011, 47, 7818–7820.

Molecules 2013, 18
13869
16. Karnakar, K.; Kumar, A.V.; Murthy, S.N.; Ramesh, K.; Nageswar, Y.V.D. Recyclable graphite
oxide promoted efficient synthesis of 2-phenyl quinazoline derivatives in the presence of TBHP
as an oxidant. Tetrahedron Lett. 2012, 53, 4613–4617.
17. Zhang, J.T.; Zhu, D.P.; Yu, C.M.; Wan, C.F.; Wang, Z.Y. A simple and efficient approach to the
synthesis of 2-phenylquinazolines via sp3 C–H functionalization. Org. Lett. 2010, 12, 2841–2843.
18. Zhang, J.T.; Yu, C.M.; Wang, S.J.; Wan, C.F.; Wang, Z.Y. A novel and efficient methodology for
the construction of quinazolines based on supported copper oxide nanoparticles. Chem. Commun.
2010, 46, 5244–5246.
19. Zhang, Z.-H.; Zhang, X.-N.; Mo, L.-P.; Li, Y.-X.; Ma, F.-P. Catalyst-free synthesis of
quinazoline derivatives using low melting sugar–urea–salt mixture as a solvent. Green Chem.
2012, 14, 1502–1506.
20. Malakar, C.C.; Baskakova, A.; Conrad, J.; Beifuss, U. Copper-catalyzed synthesis of quinazolines
in water starting from o-bromobenzylbromides and benzamidines. Chem. Eur. J. 2012, 18,
8882–8885.
21. Vanden Eynde, J.J.; Godin, J.; Mayence, A.; Maquestiau, A.; Anders, E. A new and convenient
method for the preparation of 2-substituted quinazolines. Synthesis 1993, 9, 867–869.
22. Peng, Y.; Zeng, Y.; Qiu, G. Cai, L.; Pike, V.W. A convenient one-pot procedure for the synthesis
of 2-arylquinazolines using active MnO2 as oxidant. J. Heterocycl. Chem. 2010, 47, 1240–1245.
23. Maheswari, C.U.; Kumar, G.S.; Venkateshwar, M.; Kumar, R.A.; Kantam, M.L.; Reddy, K.R.
Highly efficient one-pot synthesis of 2-substituted quinazolines and 4H-benzo[d][1,3]oxazines via
cross dehydrogenative coupling using sodium hypochlorite. Adv. Synth. Catal. 2010, 352, 341–346.
24. Han, B.; Yang, X.-L.; Wang, C.; Bai, Y.-W. Pan, T.-C.; Chen, X.; Yu, W. CuCl/DABCO/
4-HO-TEMPO-catalyzed aerobic oxidative synthesis of 2-substituted quinazolines and
4H-3,1-benzoxazines. J. Org. Chem. 2012, 77, 1136–1142.
25. Yuan, H.; Yoo, W.-J.; Miyamura, H.; Kobayashi, S. A cooperative catalytic system of
platinum/iridium alloyed nanoclusters and a dimeric catechol derivative: An efficient synthesis of
quinazolines through a sequential aerobic oxidative process. Adv. Synth. Catal. 2012, 354,
2899–2904.
26. Fang, J.; Zhou, J.; Fang, Z. Synthesis of 2-substituted quinazolines via iridium catalysis. RSC Adv.
2013, 3, 334–336.
27. Rossi, E.; Stradi, R. A new synthesis of quinazoline ring. Synthesis 1989, 1989, 214–215.
Sample Availability: Contact the authors.
© 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).