A novel and efficient methodology for the construction of quinazolines based on supported copper oxide nanoparticles

Article abstract of DOI:10.1039/c002454f

A series of quinazolines were synthesized from 2-aminobenzophenones and benzylic amines in good to excellent yields by employing a new heterogeneous catalyst based on the copper oxide nanoparticles supported on kaolin.

Full text of DOI:10.1039/c002454f

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A novel and efficient methodology for the construction of quinazolines
based on supported copper oxide nanoparticlesw
Jintang Zhang, Chenmin Yu, Sujing Wang, Changfeng Wan and Zhiyong Wang*
Received 4th February 2010, Accepted 25th May 2010
First published as an Advance Article on the web 24th June 2010
DOI: 10.1039/c002454f
A series of quinazolines were synthesized from 2-aminobenzo-
phenones and benzylic amines in good to excellent yields by
employing a new heterogeneous catalyst based on the copper
oxide nanoparticles supported on kaolin.
Initially, copper oxide nanoparticles (CuO NPs) on different
supports were prepared according to the literature, with
modification.9 The as-prepared supported copper oxide nano-
particles (SCONP) were characterized by XRD, ICP Atomic
Emission and TEM (Fig. 1 and ESIw). Afterwards, CuO NPs
and SCONPs were used as the catalysts for the synthesis of
quinazoline from 2-aminobenzophenone and benzylic amine
(Scheme 1). Among these SCONPs, CuO NPs supported on
kaolin (SCONP-3) gave the best result in a yield of 66%, as
shown in Fig. 2. Copper(II) salts, such as Cu(OAc)2ÁH2O, can
also catalyze this reaction, but the catalytic efficiency of these
salts is inferior to that of the CuO NPs supported on kaolin.
No desired product was observed in the absence of copper
catalyst. Neat kaolin cannot catalyze this reaction either.
The reaction conditions were then optimized further (Table
ESI-1 in ESIw). Other oxidants, such as 30% H2O2 solution in
Metal nanoparticles have emerged as catalysts for organic
synthesis and have been attracting more and more research
interest because of the advantages of semi-heterogeneous
catalysts.1 These advantages include the recovery and
recyclability of heterogeneous catalysts as well as the efficiency
and selectivity of homogeneous catalysts. Furthermore, the
character and activity of the supported metal nanoparticles could
be tuned by the characteristics of the support.2 Supported
palladium nanoparticles and gold nanoparticles have already
exhibited excellent catalytic activity in organic reactions such as
hydrogenation, oxidation and coupling reactions.1b,3 Compared
to common zero-valent metal nanoparticles, copper oxide nano-
particles (CuO NPs) are quite stable and cheap. Very recently,
copper oxide nanoparticles joined the catalyst family for organic
synthesis.4 However, the application of copper oxide nano-
particles for synthesis is in its infancy and quite limited.
water, m-CPBA, O2 and
a stoichiometric amount of
Cu(OAc)2ÁH2O, were examined in this reaction, but no
product was observed (ESIw). Different solvents had little
influence on this reaction. After optimizing the reaction
temperature, the ratio of benzylic amine to the ketone, the
dosage of tert-butyl hydroperoxide and the catalyst loading,
the yield was improved to 76% (ESIw). Besides, prolonging the
reaction time improved the reaction yield. An excellent yield of
95% was obtained after reaction for 12 h. Finally, the optimum
conditions were obtained, that is, 3.4 mol% of SCONP-3 as
catalyst, 1.5 equivalents of benzylic amine and 2.0 equivalents
of TBHP at 90 1C for 12 h.
With the optimum conditions in hand, the scope of the
2-aminobenzoketone derivatives was investigated (Table 1).
2-Aminobenzoketone and benzylic amine gave the product in
90% yield (3aa). Different substituents on the phenyl ring of
R2 affected the reaction slightly. For instance, when the
substituents were on the para position of this phenyl ring,
there was little influence regardless of the electronic effect of
the substituents (3ba, 3ca and 3da). However, when a methyl
group was on the ortho position of the phenyl ring of R2, the
reaction yield decreased to 71% (3ea). This indicated that the
steric effect of the substitution affected this reaction
Quinazoline and its derivatives are important compounds
not only in organic synthesis but also in medicinal chemistry.5
There are a number of well established methods to prepare
quinazolines, such as the Bischler cyclization, the reaction of
dicarbonyl compounds with diamines and reactions from
2-aminobenzonitriles or anthranilic acids as well as N-aryl-
benzamides and so on.6 Nevertheless, these methods generally
suffer from limitations of substrate generality, the availability
of starting materials, and sometimes multistep procedures or
harsh reaction conditions. Recently, Fu and Truong have
developed new methodologies for the synthesis of quinazoline
derivatives from 2-halo-phenylprecursors.7 These methods are
generally quite efficient with short synthetic routes. As a part
of our continuous efforts to develop the catalytic application
of metal nanoparticles,1e,4d,8 herein, we report our use of
supported copper oxide nanoparticles as an efficient catalyst
for the synthesis of quinazolines from 2-aminobenzoketones
and benzylic amines under mild conditions.
Hefei National Laboratory for Physical Sciences at Microscale,
CAS Key Laboratory of Soft Matter Chemistry and Department of
Chemistry, University of Science and Technology of China, Hefei,
230026, P. R. China. E-mail: zwang3@ustc.edu.cn;
Fax: (+86) 551-360-3185
w Electronic supplementary information (ESI) available: General
information, further optimizing for the reaction conditions, synthesis
of substrates, characterization data for the products and crystallo-
graphic data. CCDC 757569. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c002454f
Fig. 1 TEM of: A, kaolin; B, SCONP-3; C, SCONP-3 after its fourth
use.
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Table 1 The reaction of benzylic amine with different 2-aminobenzo-
ketonesa
Scheme 1 SCONP as the catalyst for the synthesis of quinazoline.
a10 mg of SCONP or 5 mol% CuO NPs or Cu(II) salts were used.
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
4-fluorophenyl
4-bromophenyl
p-tolyl
2,5-dimethylphenyl
mesityl
Et
n-Bu
hexadecyl
isopropyl
t-Bu
cyclopropyl
cyclopentyl
Ph
Ph
Ph
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
3oa
3pa
3qa
3ra
90
88
83
82
71
0b
84
95
78
90
89
90
74
73
85
93
63
45
9
10
11
12
13
14
15
16
17
18
6-Cl
6-Br
6,7-diMe
6-Cl
Fig. 2 Results of different catalysts for the synthesis of quinazoline.
Catalysts on different supporting materials: SCONP-1, Al2O3 in situ;
SCONP-2, diatomite; SCONP-3, kaolin; SCONP-4, Al2O3; SCONP-5,
activated carbon.
H
H
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), SCONP-3
(3.4 mol%) and TBHP (0.4 mmol) were heated at 90 1C for 12 h.
Isolated yields were given. The starting material was recovered.
b
remarkably. The occupation of the both ortho positions of the
phenyl ring of R2 resulted in a total failure of the reaction with
a recovery of starting materials (3fa). When R2 was changed to
alkyl groups, including straight chains with different lengths,
branched chains or cycloalkyls, good to excellent reaction
yields were still obtained (3ga, 3ha, 3ia, 3ja, 3ka, 3la and
3ma). It was noteworthy that unsaturated carbon-carbon
bonds can also survive the reaction, providing a yield of
73% (3na).
Table
2
The reaction of 2-aminobenzophenone with different
benzylic aminesa
When R2 is phenyl, the introduction of electron-withdrawing
groups on the aniline ring of 2-aminobenzophenone, such as
chloro- or bromo-, favored this reaction (3oa and 3pa) while a
methoxyl substituent resulted in a lower yield (3qa). Finally,
when the reaction substrate ketone was replaced with aldehyde,
that is R2 is hydrogen, only 45% of 3ra was obtained, which is
probably due to the self-condensation of the starting material.
Subsequently, the generality of benzylic amines was inves-
tigated (Table 2). Firstly, a methyl group was introduced to
the phenyl ring of benzylic amine and excellent yields were
obtained, regardless of the substitution position on the
benzylic ring (3ab, 3ac and 3ad). Similarly, methoxyl substitution
on the benzylic ring can give a yield of 88% (3ae). The
methylenedioxyl substitution on the benzylic ring led to a
lower yield (3af). Electron-withdrawing groups, such as bromo-,
fluoro- and trifluoromethyl-, favored the reaction, giving
quinazolines in excellent yields (3ag, 3ah and 3ai). When the
phenyl ring of benzylic amine was replaced with a naphthyl
group, a high yield was obtained (3aj). Moreover, hetero-
aromatic ring replacement of the phenyl ring can still provide a
moderate yield of 51% (3ak).
Entry
R3
Product
Yield (%)
1
2
3
4
5
6
7
8
p-tolyl
m-tolyl
o-tolyl
4-methoxyphenyl
benzo[1,3]dioxol-5-yl
4-chlorophenyl
4-fluorophenyl
4-(trifluoromethyl)phenyl
naphthalene-1-yl
furan-2-yl
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
89
86
94
88
58
87
91
92
86
51
9
10
3aj
3ak
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), SCONP-3
(3.4 mol%) and TBHP (0.4 mmol) were heated at 90 1C for 12 h.
Isolated yields were given.
crystallographic analysis (Fig. 3). This definitely confirmed
the formation of the quinazoline ring.10
The recyclability of the catalyst was also investigated with a
model reaction of 2-aminobenzophenone with benzylic amine.
After each run the catalyst was centrifuged, washed with ethyl
acetate, dried under an infrared lamp and then used directly in
the next run. The results are listed in Table 3. When SCONP-3
was used for four times, the yields decreased from 90% to
More importantly, the single crystal of 3aa was obtained
and the corresponding structure was identified by X-ray
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Fig. 3 The structure of 3aa determined by X-ray crystallographic
analysis.
67%. The leaking of copper from kaolin may account for the
sluggishness of the catalyst. A measurable amount of copper
was detected in the mother liquid after centrifugation by ICP
Atomic Emission, and the TEM image of the catalyst after the
fourth run confirmed the leaking of copper oxide (Fig. 1).
Scheme 2 Postulated reaction pathway for the construction of
quinazoline.
Notes and references
a
Table 3 The recycling of the catalyst
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67
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a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), SCONP-3
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Isolated yields were given.
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The exact mechanism for the synthesis of quinazolines
catalyzed by CuO NPs is not clear at present. However, based
on the experimental results and previous literatures,11
a
postulated reaction pathway is proposed, as shown in
Scheme 2. Firstly, CuO NPs may activate 2-aminobenzophenone
to generate intermediate I. Meanwhile, benzylic amine can
attach to the surface of the CuO NPs to form intermediate II.
In the intermediate II, the distance between 2-amino-
benzophenone and benzylic amine may be shortened, facilitating
the attack of benzylic amine to 2-aminobenzophenone. After
attacked by benzylic amine, imine A is formed.12 A sub-
sequently undergoes an oxidation process and is stabilized
by CuO NPs (intermediate III). Intramolecular attack of the
amino-group to the imine cation results in intermediate B.
Further oxidation of intermediate B gives the quinazoline
product.
In conclusion, a new heterogeneous catalyst consisting of
CuO NPs supported on kaolin was prepared and a new
methodology for the synthesis of quinazolines was developed
in virtue of this new catalyst. A series of quinazoline derivatives
were synthesized from 2-aminobenzophenones and benzylic
amines under mild conditions in good to excellent yields. The
employment of a suitable supporting material can not only
increase the catalytic activity of CuO NPs but also facilitate
the separation between the catalyst and the product. Further
application of this heterogeneous catalyst to other reactions is
in progress in our laboratory.
8 Z. H. Zhang and Z. Y. Wang, J. Org. Chem., 2006, 71, 7485.
9 K. B. Zhou, R. P. Wang, B. Q. Xu and Y. D. Li, Nanotechnology,
2006, 17, 3939.
10 CCDC-757569 contains the supplementary crystallographic data
for this paper.
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(b) Z. P. Li and C. J. Li, J. Am. Chem. Soc., 2005, 127, 3672.
12 Compound A was also synthesized, and could be converted to 3aa
in quantative yield under the reaction conditions.
We are grateful to the Natural Science Foundation of China
(20932002, 20972144, 20628202, 20772188 and 90813008), the
support from the Chinese Academy of Sciences and the
Graduate Innovation Fund of USTC.
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This journal is The Royal Society of Chemistry 2010
5246 | Chem. Commun., 2010, 46, 5244–5246