A convenient synthesis of quinazoline derivatives via cascade imino-Diels-Alder and oxidation reaction

Article abstract of DOI:10.1016/j.cclet.2010.03.003

Quinazoline derivatives were synthesized from a-iminoesters via a cascade imino-Diels-Alder and then oxidation reaction catalyzed with CuBr₂. This method provided a new strategy for preparing quinazoline derivatives which may be useful in the s

Full text of DOI:10.1016/j.cclet.2010.03.003

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 782–786
www.elsevier.com/locate/cclet
A convenient synthesis of quinazoline derivatives via
cascade imino-Diels-Alder and oxidation reaction
Xue Ming Chen a,b, Hui Wei a, Lu Yin a, Xing Shu Li a,
*
a School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, China
b National Technical Center, Shenzhen Neptunus Bioengineering Holdings Co., Ltd., Shenzhen 518057, China
Received 15 October 2009
Abstract
Quinazoline derivatives were synthesized from a-iminoesters via a cascade imino-Diels-Alder and then oxidation reaction
catalyzed with CuBr2. This method provided a new strategy for preparing quinazoline derivatives which may be useful in the
synthesis of heterocyclic intermediates.
# 2010 Xing Shu Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Quinazolines; a-Iminoesters; Imino-Diels-Alder reaction; CuBr2
Quinazoline derivatives are endowed with a large spectrum of biological activities, including remarkable anti-
inflammatory activity [1], anti-cancer [2], antiviral [3] and antitubercular activity [4]. For example, gefitinib (Iressa1)
and erlotinib hydrochloride (Tarceva1), which are potent inhibitors of epidermal growth factor receptor-tyrosine
kinase enzymes [5] with the structure of central quinazoline units, were approved by FDA for the treatment of non-
small-cell lung cancer [6]. Traditional preparations of quinazoline derivatives, including Niementowski synthesis [7],
Bischler synthesis [8], Riedel synthesis [9] and modified Duff synthesis [10], suffer from limited source of starting
material. From practical standpoints, it is desirable to develop new methods for the synthesis of these useful
compounds.
On the other hand, imino-Diels-Alder reaction [11] that involved coupling of imines with electron rich olefins has
emerged as a powerful tool for the synthesis of tetrahydroquinolines [12]. Cycloadditions of arylimines to dienophiles
including enolates, thioenolates, enamines, and dienes such as cyclopentadiene and cyclohexadiene are well
documented in literature (Scheme 1) [13]. Moreover, a-iminoesters have been used in synthetic organic chemistry for
many years [14], such as the preparation of amino acids [15,16] and their derivatives [17]. Recently, we have
synthesized a series of new compounds such as tetrasubstituted 3-alkynylpyrroles [18], b-amino esters [19], 1,4-
dihydropyridines [20], chiral tricarboxylate [21] and imidazolin-4-ones [22] by using a-iminoesters as starting
material. Herein, we disclose a convenient synthesis of quinazoline derivatives from a-iminoesters.
We chose aniline and ethyl glyoxalate as the substrates, and hypothesized those two molecules of a-iminoesters,
which were produced in situ by condensation of aniline and ethyl glyoxalate, could form quinazoline derivatives 2 via
* Corresponding author.
E-mail address: lixsh@mail.sysu.edu.cn (X.S. Li).
1001-8417/$ – see front matter # 2010 Xing Shu Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.003

X.M. Chen et al. / Chinese Chemical Letters 21 (2010) 782–786
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Scheme 1. Cycloadditions of arylimines to dienophiles.
Scheme 2. Strategy of imino-Diels-Alder reaction for the synthesis of quinazoline derivatives.
imino-Diels-Alder reaction [23,13d,e], originally described by Povarov et al. (Scheme 2). However, no other product
but aldimine was obtained when the reaction was carried out in toluene under refluxing for 24 h.
Efforts then were focused to find appropriate catalysts and reaction conditions to perform the proposed strategy. In
the preliminary study for finding effective catalyst, we chose Lewis acids, such as FeCl3, AlCl3, CuCl2, Cu(OAc)2,
AgNO3, Cu(OTf)2, CuBr2, ZnBr2, and Sc(OTf)3 as candidates for this screening test (Table 1).
It was interesting that quinazoline 3a, rather than 2, was obtained in 76% yield when CuBr2 was used as the catalyst.
Other catalysts were also tested for the reaction, AlCl3 and Cu(OTf)2 gave product 3a in 50% and 70% yields,
Table 1
Synthesis of quinazolines by various catalysts.a
.
Entry
Catalyst
Solvent
Yield (%)b
1
2
FeCl3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
DMF
ND
50
AlCl3
3
CuCl2
Trace
ND
ND
Trace
Trace
70
4
AgNO3
Cu(OAc)2
ZnBr2
5
6
7
Sc(OTf)3
Cu(OTf)2
CuBr2
8
9
76
10
11
CuBr2
72
CuBr2
Trace
a
Reaction conditions: amine (1.0 mmol), ethyl glyoxalate (1.2 mmol), and catalyst (0.1 mmol).
Isolated yield.
b

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X.M. Chen et al. / Chinese Chemical Letters 21 (2010) 782–786
Table 2
Synthesis of quinazoline derivatives via cascade Povarov-oxidation reaction.a
.
Entry
R
Product
Yield (%)b
1
2
p-CH3O
p-CH3
p-Cl
3a
3b
3c
3d
3e
3f
76
70
3
61
4
p-Br
55
5
m-CH3
m-Cl
63
6
51
7
m-CH3O
o-Cl
3h
3j
Polymer
Polymer
Polymer
Trace
8
9
o-CH3
H
3k
3i
10
a
Reaction conditions: amine (1.0 mmol), ethyl glyoxalate (1.2 mmol), and CuBr2 (0.1 mmol).
Isolated yield.
b
respectively. On the other hand, CuCl2, ZnBr2 and Sc(OTf)3 only gave trace quinazoline 3a in the same reaction
conditions. Other factors such as solvent and temperature were also studied with CuBr2 as the catalyst. Xylene
provided 72% yield but DMF and DMSO gave either low yield or byproducts. Very low yields were obtained when the
reactions were performed at a lower temperature.
In order to extend the scope of this reaction, other amines were tested at refluxing with toluene as the optimal
solvent. The results listed in Table 2 [24] indicated that aromatic amines with electron-donating group on the para-
position of the phenyl ring, such as methoxy, methyl, chloride or bromide group afforded corresponding quinazoline
derivatives with good yields from 55% to 76% (entries 1–4, Table 2). When the amine was meta-methyl or meta-
chloride aniline, the yield was also good (entries 5–6, Table 2). However, amines derived from meta-methoxy, ortho-
chloride and ortho-methyl aniline did not provide the desired products (entries 7–9, Table 2).
It was unexpected that amine 4, ethyl 2,2-bis(2-nitrophenylamino)acetate, rather than quinazoline derivative, was
isolated in 61% yield for o-nitroaniline (Scheme 3). The single-crystal of compound 4 was obtained and the structure
was characterized by X-ray diffraction analysis (Fig. 1).
We also carried out the reaction with the preformed a-iminoester 1 as the substrates at the same reaction conditions
as that of amines and ethyl glyoxalate (Table 3). The same products and yields indicated that a-iminoester is the sole
intermediate of the reaction.
In summary, we have developed a simple synthetic protocol for quinazoline derivatives via imino-Diels-Alder
reaction which occurred between two a-iminoesters. The use of simple and cheap materials and catalyst, as well as
mild reaction conditions make this strategy an alternative to these useful compounds. Further efforts on expanding the
scope of the cascade Povarov-oxidation reaction, reaction mechanism and the enantioselective synthesis of this class
of quinazoline derivatives are in progress.
Scheme 3. The reaction of o-nitroaniline and ethyl glyoxalate.

X.M. Chen et al. / Chinese Chemical Letters 21 (2010) 782–786
785
Fig. 1. ORTEP presentation of ethyl 2,2-bis(2-nitrophenylamino)acetate 4 at 50% probability (CCDC719014).
Table 3
Synthesis of quinazoline derivatives from imines.a
.
Entry
R
Product
Yield (%)b
1
2
3
4
5
6
p-CH3O
p-CH3
p-Cl
3a
3b
3c
3d
3e
3f
79
75
63
54
66
52
p-Br
m-CH3
m-Cl
a
Reaction conditions: imine (1.0 mmol), CuBr2 (0.1 mmol).
Isolated yield.
b
Acknowledgment
We thank the financial support from National Natural Science Foundation of China (No. 20972198).
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[24] General procedure for the synthesis of quinazoline derivatives: In a 10 mL round-bottomed flask, amine (1.0 mmol), ethyl glyoxalate
(1.2 mmol), CuBr2 (0.1 mmol) and toluene (15 mL) were added. The mixture was stirred for 5 days at refluxing. The reaction was monitored by
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yellow oil. 1H NMR (300 MHz, CDCl3): d 1.06 (t, 3H, J = 6.9 Hz), 1.23 (t, 3H, J = 6.9 Hz), 3.78 (s, 3H), 3.79 (s, 3H), 4.19 (m, 4H), 5.30 (s, 1H),
6.72 (d, 1H, J = 3.0 Hz), 6.85 (m, 3H), 7.05 (dd, 2H, J = 6.9 Hz, J = 2.4 Hz), 7.33 (d, 1H, J = 2.4 Hz). 13C NMR (75 MHz, CDCl3): d 14.16,
14.49, 55.90, 62.36, 64.18, 111.67, 114.73, 115.20, 121.41, 125.31, 127.45, 133.68, 136.85, 145.88, 158.25, 158.82, 162.63, 169.97. HRMS m/
z calcd. for C22H24N2O6 (M+): 412.1629, found: 412.1633.