A novel multi-component synthesis of 4-arylaminoquinazolines

Article abstract of DOI:10.1016/j.tetlet.2008.12.044

A new multi-component synthesis of 4-arylaminoquinazolines from the reaction of 2-aminobenzamide, orthoesters, and substituted anilines in the presence of catalytic amounts of Keggin-type heteropolyacids is reported. The effects of reaction conditions and

Full text of DOI:10.1016/j.tetlet.2008.12.044

Tetrahedron Letters 50 (2009) 943–945
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Tetrahedron Letters
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A novel multi-component synthesis of 4-arylaminoquinazolines
a
a
a
a
Majid M. Heravi a, , Samaheh Sadjadi , Negar Mokhtari Haj , Hossein A. Oskooie , Rahim. Hekmat Shoar ,
*
Fatemeh F. Bamoharram b
a Department of Chemistry, School of Science, Azzahra University, PO Box 1993891176, Tehran, Iran
b Department of Chemistry, Islamic Azad University—Mashhad Branch, Mashhad, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new multi-component synthesis of 4-arylaminoquinazolines from the reaction of 2-aminobenzamide,
orthoesters, and substituted anilines in the presence of catalytic amounts of Keggin-type heteropolyacids
is reported. The effects of reaction conditions and different heteropolyacids have been studied.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 25 September 2008
Revised 30 November 2008
Accepted 9 December 2008
Available online 16 December 2008
Keywords:
4-Arylaminoquinazoline
Recyclable catalyst
Heteropolyacid
Keggin
The development of methods using heteropolyacids (HPAs) as
catalysts for the synthesis of fine chemicals, such as flavors, pharma-
ceuticals, and in food industries, has gained attention in the last dec-
ade.1 Catalysts based on heteropolyacids have many advantages
over liquid-acid catalysts. They are not corrosive and are environ-
mentally benign and present fewer disposal problems. Solid hetero-
polyacids have attracted much attention in organic synthesis owing
to easy work-up procedures, easy filtration, and reduction of cost
and waste generation through reuse and recycling of the catalysts.2
Natural and synthetic compounds possessing the quinazoline
structural motif display a wide range of biological activities. Re-
cently, quinazolin-4(3H)-ones were prepared via cyclocondensation
of 2-aminobenzamides with orthoesters catalyzed by SiO2/H2SO4
under anhydrous and microwave conditions.3 In other work, quinaz-
olin-4(3H)-one and quinazolin-2,4-dione derivatives were obtained
under microwave irradiation.4
ever, the yields of these reactions do not usually10 exceed 50%.
4-Arylaminoquinazolines have also been produced by reactions
of 4(3H)-quinazolone with aromatic amine hydrochlorides in the
presence of phosphorus pentoxide and dimethylcyclohexyl-
amine.11 4-Phenylaminoquinazoline was obtained by desulfuriza-
tion of 4-phenylaminoquinazol-2-thione using Raney nickel W7.12
In addition to the reactions mentioned above, 4-arylaminoquinaz-
olines have been obtained by the reaction of 2-aminobenzonitrile and
various anilines in the presence of AlCl3, and by subsequent conden-
sation of the products with formic acid.13 The drawback of this meth-
od is that the synthesis of 2-amino-N-aryl-benzamidines is limited by
the substituents on the anilines.
In connection with our research using heteropolyacids in organ-
ic reactions,14–19 and expansion of our work on multi-component
syntheses,20 herein, we report a simple method for the preparation
of 4-arylaminoquinazolines in high yields from the reaction of 2-
aminobenzamide, orthoesters, and various substituted anilines in
the presence of catalytic amounts of Keggin-type heteropolyacids:
H6[PMo9V3O40], H5[PMo10V2O40], H4[PMo11VO40], and H3[PMo12
O40] (Scheme 1).
There has been renewed interest in 4-arylaminoquinazolines
connected with reports on the very high activity of 6,7-dime-
thoxy-4-(3-bromophenylamino)quinazoline (PD 153035) as
a
tyrosine kinase inhibitor.5 Analogues of PD 153035 with more
complex structures6 as well as simple derivatives of 4-phenylami-
noquinazoline without, for example, methoxy groups,7 also show
interesting biological activity. Despite their biological activities,
no recent progress on their syntheses has been made.
Thereaction conditions(solvent, reaction time, and catalysttype)
were studied to optimize this procedure. Theresults on thesynthesis
of 4-arylaminoquinazolines 1 from the reaction of 2-aminobenzam-
ide, orthoesters, and various anilines, using H6[PMo9V3O40], are
summarized in Table 1. Anilines with electron-donating groups gave
slightly better yields than anilines with electron-withdrawing
groups.
4-Arylaminoquinazolines can be obtained via reactions of 4-
halo- or 4-mercaptoquinazolines with aromatic amines;8,9 how-
In all the reactions, 3-quinazolin-4-one, 2, was obtained as a
byproduct in low yield (Scheme 1). To optimize the yield of the de-
* Corresponding author. Tel.: +98 21 88044040; fax: +98 21 88035187.
E-mail address: mmh1331@yahoo.com (M.M. Heravi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.044

944
M. M. Heravi et al. / Tetrahedron Letters 50 (2009) 943–945
R
O
H
N
O
N
NH2
NH2
+
Heteropolyacid
N
NH
+
CH(OR')3
+
solvent ,
NH2
reflux
N
R
1
2
Scheme 1.
Table 1
Table 3
Effect of varying the amounts of aniline on the yields of 4-phenylaminoquinazolines
Synthesis of various 4-arylaminoquinazolines
Entry
R
R0
Yield (%)a
Mp (°C)
Lit. mp (°C)13
Entry
Time (h)
(mmol)
Yielda (%)
Aniline
1
2
3
4
5
6
7
8
9
H
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
CH3
CH3
CH3
CH3
91
93
95
89
88
85
89
91
94
87
85
82
220
192
197
194
190
131
220
192
197
194
190
131
220–221
191–193
196.5–8
194–195
189–190
131–132
220–221
191–193
196.5–8
194–195
189–190
131–132
1
2
3
4
2.5
2.5
2
10
12
15
20
83
87
91
91
4-Me
3,4-DiMe
4-Cl
4-Br
2-Br
2
a
Yield refers to isolated products from the reaction of 2-aminobenzamide
(10 mmol), various amounts of aniline and HC(OC2H5)3 (10 mmol) in the presence
of H6[PMo9V3O40] (0.03 mmol) under refluxing conditions in CH3CN.
H
4-Me
3,4-DiMe
4-Cl
4-Br
2-Br
10
11
12
The effect of solvent on the synthesis of different 4-arylamino-
quinazolines was also studied. Of solvents including CH3CN, H2O,
CH2Cl2, CHCl3, and EtOH, CH3CN proved to be the best in terms
of yield, Table 4.
To study the effect of catalyst type, the synthesis of 4-benzyla-
minoquinazoline was selected as a model reaction and the effi-
ciency using four Keggin-type heteropolyacids (H6[PMo9V3O40],
H5[PMo10V2O40], H4[PMo11VO40], and H3[PMo12O40]) was studied.
The results are reported in Table 5 with the order of efficiency as
follows: H6[PMo9V3O40] > H5[PMo10V2O40] > H4[PMo11VO40] > H3
[PMo12O40].
CH3
a
Yield refers to isolated products from the reaction of 2-aminobenzamide
(10 mmol), substituted aniline (15 mmol), and HC(OR0)3 (10 mmol) in the presence
of H6[PMo9V3O40] (0.03 mmol) under reflux in CH3CN.
sired product, the effects of reaction time, amount of aniline and
solvent were investigated.
The effect of varying the reaction duration was studied for the
synthesis of 4-arylaminoquinazolines by reaction of 2-aminobenz-
amide, HC(OC2H5)3, and various anilines. The results are summa-
rized in Table 2, and the optimum reaction time was found to be
2 h.
The amount of aniline required for reaction and to reduce the
yield of 2 was investigated, and the results are summarized in Ta-
ble 3. As shown, the optimum amount of aniline was 15 mmol in
the presence of 10 mmol each of 2-aminobenzamide and
orthoester.
In conclusion, we have reported a new catalytic method for the
synthesis of 4-arylaminoquinazolines from reactions of 2-amino-
benzamide, orthoesters, and substituted anilines in the presence
Table 4
Effect of varying the solvent on the yield of 4-arylaminoquinazolines
Entry
R
Solvent
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
H
H
H
H
CH3CN
CH2Cl2
CHCl3
H2O
EtOH
CH3CN
CH2Cl2
CHCl3
H2O
2
91
87
85
83
82
93
90
88
87
85
2.5
2.5
2.5
2.5
2
2.5
2.5
2.5
2.5
Table 2
Synthesis of 4-arylaminoquinazolines by varying the reaction times
H
Entry
R
Time (h)
Yield (%) 1a
Yield (%) 2a
4-Me
4-Me
4-Me
4-Me
4-Me
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
H
H
0.5
1
2
0.5
1
2
0.5
1
2
0.5
1
2
0.5
1
2
0.5
1
2
80
88
91
80
89
93
86
91
95
75
82
89
75
80
88
73
80
85
20
12
9
20
11
7
14
9
5
25
18
11
25
20
12
27
20
15
EtOH
4-Me
4-Me
4-Me
3,4-DiMe
3,4-DiMe
3,4-DiMe
4-Cl
4-Cl
4-Cl
4-Br
4-Br
a
Yield refers to isolated products from the reaction of 2-aminobenzamide
(10 mmol), substituted aniline (15 mmol), and HC(OC2H5)3 (10 mmol) in the pres-
ence of H6[PMo9V3O40] (0.03 mmol) under refluxing conditions.
Table 5
Effect of various Keggin-typeheteropolyacids on the yields of 4-phenylaminoquinazolines
Entry
Catalyst
Time (h)
Yield (%)a
4-Br
2-Br
2-Br
2-Br
1
2
3
4
H6[PMo9V3O40
]
2
91
88
85
81
H5[PMo10V2O40
H4[PMo11VO40
H3[PMo12O40
]
2.5
2.5
3
]
]
a
a
Yield refers to isolated products from the reaction of 2-aminobenzamide
(10 mmol), substituted aniline (15 mmol), and HC(OC2H5)3 (10 mmol) in the pres-
ence of H6[PMo9V3O40] (0.03 mmol) under refluxing conditions in CH3CN.
Yield refers to isolated products from the reaction of 2-aminobenzamide
(10 mmol), substituted aniline (15 mmol), and HC(OC2H5)3 (10 mmol) in the pres-
ence of H6[PMo9V3O40] (0.03 mmol) under refluxing conditions in CH3CN.

M. M. Heravi et al. / Tetrahedron Letters 50 (2009) 943–945
945
Table 6
d6, d ppm): 9.10 (s, 1H, NH) 8.68 (s, 1H, CH@N), 7–7.5 (m, 5H), 7.6–
7.9 (m, 4H); FT-IR: 3329 (NH), 1604 (C@N); MS: m/z 221 [M+].
Quinazolin-4-yl-p-tolyl-amine(C15H13N3 ): Mp: 192 °C, 1H NMR
(300 MHz, DMSO-d, d ppm): 9.10 (s, 1H, NH), 2.33 (s, 3H, CH3)
8.68 (s, lH, CH@N), 7–7.32 (m, 4H), 7.59–7.9 (m, 4H); FT-IR: 3329
(NH), 1604 (C@N); MS: m/z 235 [M+].
A comparison of the efficiency of H6[PMo9V3O40] on the synthesis of 4-arylamino-
quinazolines over three runs
Entry
R
Time (min)/run
Second
Yield (%)a/run
Second
First
Third
First
Third
1
2
3
4
5
6
H
160
160
160
160
160
160
165
165
165
165
165
165
165
165
170
165
170
170
91
93
95
89
88
85
89
93
93
88
87
84
87
91
92
87
86
83
4-Me
3,4-DiMe
4-Cl
4-Br
2-Br
Acknowledgment
The authors are thankful to the Presidential office for partial
financial support of this project, No. 87066/26
a
Yield refers to isolated products from the reaction of 2-aminobenzamide
(10 mmol), substituted aniline (15 mmol), and HC(OC2H5)3 (10 mmol) in the pres-
ence of H6[PMo9V3O40] (0.03 mmol) under refluxing conditions in CH3CN.
References and notes
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of catalytic amounts of Keggin-type heteropolyacids as efficient,
reusable, and eco-friendly heterogeneous inorganic catalysts. The
advantages of this method are the easy work-up procedure and
high yields of products.
General procedure for the synthesis of 4-arylaminoquinazolines: To
a mixture of 2-aminobenzamide (10 mmol), orthoester (10 mmol),
and substituted aniline (15 mmol), a catalytic amount of hetero-
polyacid (0.03 mmol) was added and the resulting mixture was
heated at reflux in CH3CN (10 mL). The progress of the reaction
was monitored by TLC. On completion, the catalyst was filtered
off, the solvent was evaporated and the pure product was obtained
by column chromatography. All the products were identified by
comparison of their physical and spectroscopic data with those re-
ported for authentic samples.13,21
Recyclability of the catalyst: At the end of the reaction, the cata-
lyst could be recovered by filtration. The recycled catalyst was
washed with dichloromethane and used in a second run. To con-
firm that the catalyst was not soluble in the reaction solvent, the
filtered catalyst was weighed before reuse. The results indicated
that the catalysts were not soluble in the solvent, and the yields
of reactions using these catalysts over three runs indicated only a
slight loss of activity (Table 6).
17. Heravi, M. M.; Sadjadi, S.; Oskooie, H. A.; Hekmat Shoar, R.; Bamoharram, F. F.
Catal. Commun. 2008, 9, 504.
18. Heravi, M. M.; Sadjadi, S.; Hekmat Shoar, R.; Oskooie, H. A.; Bamoharram, F. F.
Molecules 2007, 12, 255.
19. Heravi, M. M.; Sadjadi, S.; Oskooie, H. A.; Hekmat Shoar, R.; Bamoharram, F. F.
Catal. Commun. 2008, 9, 470.
20. Heravi, M. M.; Baghernejad, B.; Oskooie, H. A.; Hekmat Shoar, R. Tetrahedron
Lett. 2008, 49, 6101.
Physical and spectral data for selectedcompounds: Phenyl-quinazo-
lin-4-yl-amine (C14H11N3): mp: 220 °C, 1H NMR (300 MHz, DMSO-
21. Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153.