Synthesis of 2-(2-Aminophenyl)-4-arylquinazoline Derivatives by

Reaction of 2-Aminoarylbenzimidamides with Isatoic Anhydride

Kamal M. El-Shaieba and Peter G. Jonesb
a
b

Chemistry Department, Faculty of Science, Minia University, El-Minia, Egypt

Institut fur Anorganische und Analytische Chemie, Technische Universitat Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany

Reprint requests to Dr. Kamal M. El-Shaieb. Fax: +2-086-2342601. E-mail: [email protected]

Z. Naturforsch. 2009, 64b, 945 951; received April 30, 2009
A series of 2-(2-aminophenyl)-4-arylquinazoline derivatives (5a j), with various 4-substituents,
have been synthesized by one-pot cyclization in 66 79 % yield by heating 2-aminoarylbenzimidamides 3a j with isatoic anhydride (4). The high yield and simplified workup procedure, in addition
to the neutral reaction conditions, are the main advantages of our approach. The structure of the
product 5e was further confirmed by single-crystal X-ray structure analysis.
Key words: Aminoarylbenzimidamides, Cycloaddition, Isatoic Anhydride, Quinazolines

Introduction
Quinazoline derivatives constitute an important
class of heterocyclic compounds; they form a large
number of products with a broad spectrum of biological activities, such as hypnotic, antibacterial, anticancer, analgesic, antiallergic, anticonvulsant, antimalarial, antidiabetic, and other effects [1 7]. For this
reason their synthesis has received considerable attention. Quinazoline derivatives can be prepared by heating isatoic anhydride with diamines [8] or by condensing 2-aminobenzimidamides with aldehydes [9, 10].
Recently, quinazoline derivatives have been obtained
by heating 2-aminobenzamides with aldehydes [11],
or by heating isatoic anhydride with azomethines [12]
or aldehydes in the presence of ammonium acetate
[13]. Heterocyclization of aminobenzimidamides with
isatoic anhydride, however, has been largely overlooked.
Results and Disccusion
2-Aminoarylbenzimidamides 3a j used in this
study were made in good yields by treatment of 2aminobenzonitrile (1) with aniline derivatives 2a i
in the presence of aluminum chloride as a catalyst
(Scheme 1) and were fully characterized by spectral
as well as X-ray structural analyses [14].
High yields of 2-aminoarylbenzimidamides 3a j
were obtained by using equimolar ratios of the reactants at 170 180 C [14]. Most of the known syn-

theses of quinazoline derivatives, such as those using various catalysts such as Yb(OTf)3 [15], NafionH [16], Bi(TFA)3 -FeCl3 [17], silica gel/FeCl3 [18],
La(NO3 )3 6H2 O [19], and KAl(SO4 )2 12H2O [20] require either reflux for several hours in a large volume of
solvent, or the use of an expensive catalyst. Continuing
our work on the synthesis of 2,4-disubstituted quinazoline derivatives, in this report we describe the reaction of 2-aminobenzimidamides 3a j with isatoic anhydride (4) as a simple approach for 2,4-disubstituted
quinazolines. We found that heating equimolar ratios
of 2-aminoarylbenzimidamides 3a j with isatoic anhydride (4) in absolute ethanol for 2 3 h yielded 2-(2aminophenyl)-4-arylquinazoline derivatives 5a j in
66 79 % yield (Scheme 2).
The formation of the products 5a j can be rationalized according to the pathway shown in Scheme 3.
With regard to the reaction mechanism, we propose
that the condensation reaction begins with a decarboxylation of 4 to the ortho-quinoid intermediate 6.
This iminoketene can subsequently be attacked by
3a j yielding intermediates 7, which could cyclize to
8 by loss of water. Two hydrogen shift processes would
finally lead to the formation of 5, the driving force being largely provided by rearomatization.
The structures of the products 5a j were fully characterized and elucidated on the basis of spectral and
analytical data. The structure of the selected example
5e was further confirmed by X-ray structural analysis,
as shown in Fig. 1. The bicyclic system is essentially

c 2009 Verlag der Zeitschrift fur Naturforschung, Tubingen http://znaturforsch.com

09320776 / 09 / 08000945 $ 06.00

946

K. M. El-Shaieb P. G. Jones Synthesis of 2-(2-Aminophenyl)-4-arylquinazoline Derivatives

a, R = R1 = R2 = H
b, R = R2 = H, R1 = CH3
c, R = R2 = H, R1 = Cl

d, R = R2 = H, R1 = Br
e, R1 = R2 = H, R = I
f, R1 = H, R = R2 = CH3

g, R1 = H, R = R2 = Cl
h, R = R1 = H, R2 = OCH3
i, R = R2 = H, R1 = OCH3

Scheme 1. Synthesis of 2-aminoarylbenzimidamides 3a j.

a, R = R1 = R2 = R3 = H
b, R = R3 = CH3 , R1 = R2 = H
c, R = R3 = Cl, R1 = R2 = H
d, R = R3 = H, R1 = R2 = Cl
e, R = R2 = CH3 , R1 = R3 = H

f, R = R1 = R3 = H, R2 = CH3
g, R = R1 = R3 = H, R2 = OCH3
h, R = R2 = R3 = H, R1 = OCH3
i, R = R1 = R3 = H, R2 = Cl
j, R = R1 = R3 = H, R2 = Br

Scheme 2. Reaction of 2-aminoarylbenzimidamides 3a j with isatoic anhydride (4).

and subtends angles of

planar (mean deviation 0.05 A)
13 and 63 to the rings C1116 and C2226, respectively. The near-coplanarity to C1116 is connected
with the intramolecular hydrogen bond N18 N1. The
other two NH functions form intermolecular hydrogen
bonds N18 N3 and N19 N1 , which serve to connect the molecules to layers parallel to the crystallographic yz plane.
The detailed spectral data are given in the Experimental Section, and only the salient features are discussed here.
The IR spectra of compounds 5a j show, besides
the absorption at = 1617 1605 cm1 corresponding
to the C=N group, three distinguishable absorptions in
the range = 3489 3211 cm1 related to both NH
and NH2 groups. The protons of these groups resonate
in the 1 H NMR spectrum at = 10.50 7.00 ppm.
Taking 5j as an example, its 1 H NMR spectrum ex-

hibits two doublets at = 7.89 and 7.66 ppm with coupling constants 8.90 Hz corresponding to the 1,4disubstituted aromatic moiety (H-19,23 and H-20,22);
8-H displays a doublet at = 8.29 ppm with J = 8.29
Hz, and the protons H-16,15,14,13 appear as multiplets at = 7.63 7.57, 7.17 7.11, 6.79 6.76, 6.64
6.58 ppm, respectively. The rest of the aromatic protons resonate in the 1 H NMR spectrum as one doublet of doublets at = 8.32 8.29 (J = 1.51, 8.06 Hz)
and one doublet at = 7.86 (J = 3.80 Hz) related
to 5-H and 6,7-H, respectively. The 13 C NMR spectrum exhibits twenty distinct resonances in agreement
with the quinazoline derivative 5j. Twelve of them are
secondary, and the rest are quaternary carbon atoms.
Two of the quaternary carbon atoms resonate at =
161.14 and 156.81 ppm characteristic for C-4 and
C-2, respectively; C-11 appears at = 113.12 ppm,
and the four secondary 1,4-disubstituted aromatic car-

K. M. El-Shaieb P. G. Jones Synthesis of 2-(2-Aminophenyl)-4-arylquinazoline Derivatives

947

Scheme 3. Rational pathway for the formation of the products 5a j.

bon atoms (C-20,22,19,23) resonate at = 131.31,

124.31 ppm. The IR, 1 H NMR and 13 C NMR spectra of
5i are similar to those of 5j (see Experimental Section).
Both mass spectra and elemental analyses confirm the
molecular formulae of the products 5a j.
Conclusion
New heterocyclic systems, which might possess
interesting biological properties, have been synthesized. Herein we report a simple and efficient onepot synthesis of 2-(2-aminophenyl)-N-arylquinazolin4-amine derivatives under mild conditions with good
yield. In all cases the reaction of two components
proceeded rapidly to afford the corresponding desired
products.
The structure of the selected example 5e was elucidated by single X-ray structural analysis. The mechanism of formation of the obtained products 5a j has
been rationalized.
Experimental Section
Starting materials
All reagents were purchased from Alfa Aesar, Fluka,
Acros, and Aldrich companies and were used without further
purification. 2-Aminoarylbenzimidamide derivatives 3a j
were prepared according to ref. [14]. Melting points were

measured in capillary tubes without corrections using a

Buchi 530 melting point apparatus. IR spectra were run as
KBr discs using a Bruker Tensor 27 instrument. The NMR
spectra were recorded on a Bruker AM 400 MHz spectrometer with TMS as internal standard; the coupling constants are
given in Hz. The mass spectra (EI, 70 eV) were performed
using a Finnigan MAT 8430 spectrometer.
Reactions of 2-aminoarylbenzimidamides 3a j with isatoic
anhydride (4)
General procedure
In a three-necked flask fitted with a reflux condenser a
solution of 0.25 mmol of 2-aminoarylbenzimidamides 3a j
in 15 mL of absolute ethanol was added dropwise under nitrogen to a solution of 0.25 mmol of isatoic anhydride (4)
in 20 mL of absolute ethanol at r. t. The reaction mixture
was heated under gentle reflux for 2 3 h. The progress of
the reaction was monitored by TLC, and after completion,
the mixture was cooled to r. t. The solvent was removed under reduced pressure, and the residue was purified by silica
gel chromatography using ethyl acetate / n-pentane (3 : 1) as
the eluent to give the desired products as off-white to yellow
solids in 66 79 % yield.
2-(2-Aminophenyl)-N-phenylquinazolin-4-amine (5a)
Colorless solid, 55 mg (70 %), m. p. 179 181 C.
IR (film): = 3489, 3354, 3263 (NH, NH2 ), 1676, 1611

948

K. M. El-Shaieb P. G. Jones Synthesis of 2-(2-Aminophenyl)-4-arylquinazoline Derivatives

(10), 92 (28), 77 (20). C20 H16 N4 (312.37): calcd. C 76.90,
H 5.16, N 17.94; found C 76.67, H 5.11, N 17.70.
2-(2-Aminophenyl)-N-(2,5-dimethylphenyl)quinazolin-4amine (5b)
Pale-yellow solid, 63 mg (74 %), m. p. 123 124 C. IR
(film): = 3459, 3369, 3292 (NH, NH2 ), 1682, 1612 (C=N),
1568, 1553 cm1 (C=C). 1 H NMR (400 MHz, CDCl3 ):
= 8.34 8.29 (dd, 1 H, J = 1.61, 8.05 Hz), 7.79 7.72 (m,
2 H), 7.64 7.57 (m, 1 H), 7.51 (br, s, 1 H, NH), 7.33 7.25
(m, 1 H), 7.19 7.03 (m, 2 H), 6.89 6.82 (m, 1 H), 6.65
6.57 (m, 3 H), 4.83 (br, s, 2 H, NH2 ), 2.24 (s, 3 H, CH3 ),
2.12 (s, 3 H, CH3 ). 13 C NMR (100 MHz, CDCl3 ): =
162.29 (C), 157.94 (C), 149.55 (C), 136.98 (C), 136.73 (C),
134.46, 133.24 (CH), 131.66 (2 CH), 130.96 (CH), 129.68
(CH), 128.93 (CH), 127.01 (CH), 126.47 (CH), 125.97 (CH),
121.22 (CH), 120.15 (C), 117.55 (C), 116.69 (CH), 113.50
(C), 21.52 (CH3 ), 18.81 (CH3 ). MS (EI, 70 eV): m/z
(%) = 340 (68) [M]+ , 324 (4) [MNH2 ]+ , 309 (18) [M
(CH3 +NH2 )]+ , 294 (10), 272 (20), 245 (12), 220 (16), 192
(16), 166 (12), 155 (34), 141 (8), 118 (16), 92 (20), 75 (12).
C22 H20 N4 (340.42): calcd. C 77.62, H 5.92, N 16.46; found
C 77.39, H 5.90, N 16.26.
2-(2-Aminophenyl)-N-(2,5-dichlorophenyl)quinazolin-4amine (5c)

Fig. 1. Crystal and molecular structure of compound 5e.

Above: ellipsoid representation (50 % level) of the molecular structure. Below: packing diagram showing the layers formed by hydrogen bonds of the type NH N (xylyl
groups are reduced to the ipso carbon atoms for clarity).
(C=N), 1570, 1513 cm1 (C=C). 1 H NMR (400 MHz,
[D6 ]DMSO): = 9.90 (s, 1 H, NH), 8.00 7.72 (m, 4 H),
7.62 7.56 (m, 1 H), 7.42 (s, 2 H, NH2 ), 7.31 7.05 (m,
3 H), 6.93 6.76 (m, 2 H), 6.71 6.53 (m, 3 H). 13 C NMR
(100 MHz, [D6 ]DMSO): = 167.33 (C-4), 157.01 (C-2),
151.25 (C-9), 149.96 (C-12), 139.16 (C-18), 134.37 (CH,
C-7), 133.84 (CH, C-20), 133.03 (CH, C-22), 130.50 (CH,
C-14), 128.44 (CH, C-5), 127.38 (CH, C-8), 126.07 (CH,
C-13), 125.34 (CH, C-19), 123.75 (CH, C-23), 122.90 (CH,
C-6), 122.57 (CH, C-21), 117.62 (C-10), 116.43 (CH, C-16),
114.62 (CH, C-15), 113.09 (C-11). MS (EI, 70 eV): m/z
(%) = 312 (80) [M]+ , 311 (100) [M1]+ , 294 (8) [M
NH3 ]+ , 270 (2), 237 (30) [MPh]+ , 220 (18) [MPhNH2 ]+ ,
194 (56), 178 (4), 166 (16), 156 (12), 139 (8), 119 (26), 102

Colorless solid, 66 mg (69 %), m. p. 243 245 C.

IR (film): = 3474, 3410, 3352 (NH, NH2 ), 1659, 1602
(C=N), 1572, 1513 cm1 (C=C). 1 H NMR (400 MHz,
[D6 ]DMSO): = 10.27 (s, 1 H, NH), 8.75 8.72 (dd, 1 H,
J = 0.98, 8.41 Hz, 8-H), 8.55 (d, 1 H, J = 7.46 Hz, 5-H),
8.25 8.22 (dd, 1 H, J = 1.61, 8.06 Hz, 6-H), 8.02 7.97 (m,
1 H, 7-H), 7.90 (d, 1 H, J = 2.55 Hz, 19-H), 7.73 (d, 1 H,
J = 8.65 Hz, 22-H), 7.53 7.49 (dd, 1 H, J = 2.54, 8.61 Hz,
21-H), 7.50 7.46 (m, 1 H, 16-H), 7.36 (m, 1 H, 14-H), 7.13
7.08 (m, 1 H, 15-H), 6.88 6.79 (m, 1 H, 13-H), 6.56 (s,
2 H, NH2 ). 13 C NMR (100 MHz, [D6 ]DMSO): = 167.74
(C-4), 159.97 (C-2), 150.23 (C-20), 148.25 (C-23), 140.15
(C-9), 137.04 (C-12), 132.60 (CH, C-7), 131.48 (CH, C-21),
131.07 (CH, C-22), 129.44 (CH, C-19), 128.07 (C-18),
127.62 (CH, C-14), 126.92 (CH, C-5), 123.00 (CH, C-8),
122.28 (CH, C-13), 119.90 (CH, C-6), 116.94 (CH, C-16),
115.19 (C-10), 114.99 (CH, C-15), 113.03 (C-11). MS (EI,
70 eV): m/z (%) = 384 (8) [M+4]+ , 382 (42) [M+2]+ , 380
(78) [M]+ , 364 (4) [MNH2 ]+ , 329 (10) [M(Cl+NH2 )]+ ,
294 (12), 272 (24), 245 (12), 220 (16), 192 (16), 166 (12),
155 (34), 141 (8), 118 (16), 92 (20), 75 (12). C20 H14 Cl2 N4
(381.26): calcd. C 63.01, H 3.70, Cl 18.60, N 14.70; found
C 62.82, H 3.63, Cl 18.34, N 14.53.
2-(2-Aminophenyl)-N-(3,4-dichlorophenyl)quinazolin-4amine (5d)
Colorless solid, 64 mg (67 %), m. p. 203 205 C. IR
(film): = 3340, 3367, 3208 (NH, NH2 ), 1667, 1610 (C=N),

K. M. El-Shaieb P. G. Jones Synthesis of 2-(2-Aminophenyl)-4-arylquinazoline Derivatives

1568, 1548, 1511 cm1 (C=C). 1 H NMR (400 MHz,
[D6 ]DMSO): = 9.97 (s, 1 H, NH), 8.51 (d, 1 H, J = 8.27 Hz,
19-H), 8.42 (d, 1 H, J = 2.40 Hz, 22-H), 8.34 8.29 (dd, 1 H,
J = 1.50, 8.10 Hz, 18-H), 7.87 7.83 (m, 2 H), 7.47 (br, s,
2 H, NH2 ), 7.23 7.14 (m, 2 H), 6.86 6.82 (m, 2 H), 6.64
6.56 (m, 2 H). 13 C NMR (100 MHz, [D6 ]DMSO): =
160.98 (C), 156.59 (C), 150.09 (C), 149.51 (C), 139.53 (C),
133.37 (CH), 131.08 (C), 130.68 (CH), 130.33 (CH), 130.25
(CH), 127.54 (CH), 125.71 (CH), 124.73 (C), 123.27 (CH),
122.84 (CH), 121.79 (CH), 117.33 (C), 116.54 (CH), 114.69
(CH), 113.66 (C). MS (EI, 70 eV): m/z (%) = 384 (10)
[M]+4 , 382 (52) [M]+2 , 380 (86) [M]+ , 364 (4) [MNH2 ]+ ,
330 (30) [M(Cl+NH2 )]+ , 294 (4), 261 (24), 245 (12), 220
(6), 192 (10), 166 (12), 155 (24), 141 (18), 118 (16), 92 (12),
75 (8). C20 H14 Cl2 N4 (381.26): calcd. C 63.01, H 3.70,
Cl 18.60, N 14.70; found C 62.78, H 3.67, Cl 18.39, N 14.46.
2-(2-Aminophenyl)-N-(2,4-dimethylphenyl)quinazolin-4amine (5e)
Pale-yellow solid, 65 mg (76 %), m. p. 155 157 C.
IR (film): = 3431, 3376, 3226 (NH, NH2 ), 1684, 1611
(C=N), 1574, 1504 cm1 (C=C). 1 H NMR (400 MHz,
[D6 ]DMSO): = 9.71 (s, 1 H, NH), 8.52 (d, 1 H, J = 8.09 Hz,
8-H), 8.22 (d, 1 H, J = 7.00 Hz, 5-H), 7.81 (d, 1 H, J =
3.71 Hz, 22-H), 7.77 7.73 (m, 1 H, 7-H), 7.57 7.49 (m,
1 H, 6-H), 7.33 (d, 1 H, J = 7.88 Hz, 19-H), 7.26 7.21 (m,
1 H, 20-H), 7.15 (d, 1 H, J = 7.73 Hz, 16-H), 7.10 (br, s,
2 H, NH2 ), 6.81 (d, 1 H, J = 8.47 Hz, 14-H), 6.75 6.70 (m,
1 H, 15-H), 6.60 6.46 (m, 1 H, 13-H), 2.35 (s, 3 H, CH3 ),
2.12 (s, 3 H, CH3 ). 13 C NMR (100 MHz, [D6 ]DMSO):
= 167.36 (C-4), 161.38 (C-2), 158.21 (C-9), 151.29 (C-12),
149.91 (C-18), 135.34 (C-10), 134.55 (C-23), 133.83 (CH,
C-7), 131.09 (CH, C-14), 130.66 (CH, C-5), 130.53 (CH,
C-8), 128.22 (CH, C-13), 127.26 (CH, C-6), 126.75 (C-21),
122.94 (CH, C-20), 117.77 (CH, C-19), 116.45 (CH, C-22),
114.62 (CH, C-16), 112.77 (CH, C-15), 108.93 (C-11), 20.60
(CH3 ), 17.88 (CH3 ). MS (EI, 70 eV): m/z (%) = 341 (30)
[M]+1 , 340 (100) [M]+ , 324 (8) [MNH2 ]+ , 309 (30) [M
(CH3 +NH2 )]+ , 294 (6), 272 (40), 245 (2), 220 (16), 192 (16),
166 (12), 155 (34), 141 (8), 118 (16), 92 (20), 75 (12).
C22 H20 N4 (340.42): calcd. C 77.62, H 5.92, N 16.46; found
C 77.41, H 5.87, N 16.28.
2-(2-Aminophenyl)-N-p-tolylquinazolin-4-amine (5f)
Colorless solid, 62 mg (76 %), m. p. 159 160 C. IR
(film): = 3357, 3287, 3211 (NH, NH2 ), 1608 (C=N),
1573, 1552, 1511 cm1 (C=C). 1 H NMR (400 MHz,
[D6 ]DMSO): = 9.77 (s, 1 H, NH), 8.51 (d, 1 H, J = 8.33 Hz,
8-H), 8.33 8.30 (dd, 1 H, J = 1.59, 8.07 Hz, 5-H), 7.87
7.81 (m, 2 H, 6,7-H), 7.73 (d, 2 H, J = 8.40 Hz, 20,22-H),
7.58 7.53 (m, 1 H, 16-H), 7.36 (br, s, 2 H, NH2 ), 7.26 (d,
2 H, J = 8.26 Hz, 19,23-H), 7.14 7.09 (m, 1 H, 14-H),

949

6.77 6.74 (dd, 1 H, J = 1.01, 8.17 Hz, 15-H), 6.61 6.54

(m, 1 H, 13-H), 2.35 (s, 3 H, CH3 ). 13 C NMR (100 MHz,
[D6 ]DMSO): = 161.30 (C-4), 157.05 (C-2), 150.01 (C-9),
149.51 (C-12), 136.56 (C-18), 133.06 (CH, C-7), 132.91
(CH, C-14), 130.87 (CH, C-5), 130.48 (CH, C-8), 128.97
(2 CH, C-20,22), 127.44 (CH, C-13), 125.36 (CH, C-6),
122.90 (CH, C-16), 122.69 (2 CH, C-19,23), 117.68 (C-21),
116.42 (C-10), 114.60 (CH, C-15), 113.11 (C-11), 20.57
(CH3 ). MS (EI, 70 eV): m/z (%) = 326 (100) [M]+ , 325
(86) [M1]+ , 309 (4) [MNH3 ]+ , 232 (8) [MPhNH2 ]+ ,
220 (12), 208 (48), 192 (16), 180 (8), 163 (16), 129 (4), 118
(16), 102 (4), 92 (16), 75 (12). C21 H18 N4 (326.39): calcd.
C 77.28, H 5.56, N 17.17; found C 77.02, H 5.51, N 16.94.
2-(2-Aminophenyl)-N-(4-methoxyphenyl)quinazolin-4amine (5g)
Brown solid, 60 mg (70 %), m. p. 131 133 C. IR
(film): = 3385, 3277, 3243 (NH, NH2 ), 1610 (C=N), 1559,
1535, 1505 cm1 (C=C). 1 H NMR (400 MHz, CDCl3 ):
= 7.92 7.86 (m, 2 H), 7.77 7.62 (m, 2 H), 7.49 7.42
(m, 1 H), 7.44 (br, s, 1 H, NH), 7.31 7.22 (m, 2 H), 7.01
6.93 (m, 1 H), 6.79 6.62 (m, 4 H), 5.71 (br, s, 2 H, NH2 ),
3.73 (s, 3 H, OCH3 ). 13 C NMR (100 MHz, CDCl3 ): =
162.03 (C-4), 151.75 (C-2), 150.39 (C-21), 147.15 (C-9),
140.43 (C-12), 139.52 (C-18), 134.65 (C-10), 133.93 (CH,
C-7), 131.19 (2 CH, C-19,23), 127.09 (CH, C-14), 126.40
(CH, C-5), 124.16 (CH, C-8), 122.27 (CH, C-13), 116.63
(2 CH, C-20,22), 116.19 (CH, C-6), 114.78 (CH, C-16),
114.14 (CH, C-15), 109.36 (C-11), 55.70 (OCH3 ). MS (EI,
70 eV): m/z (%) = 342 (62) [M]+ , 325 (4) [MNH3 ]+ , 294
(4) [M(NH2 +OCH3 )]+ , 251 (6) (MPhNH2 ]+ , 192 (10),
163 (8), 129 (4), 118 (16), 102 (4), 92 (16), 75 (12).
C21 H18 N4 O (342.39): calcd. C 73.67, H 5.30, N 16.36; found
C 77.43, H 5.23, N 16.12.
2-(2-Aminophenyl)-N-(3-methoxyphenyl)quinazolin-4amine (5h)
Pale-brown solid, 58 mg (68 %), m. p. 93 95 C. IR
(film): = 3378, 3287, 3253 (NH, NH2 ), 1615 (C=N), 1545,
1523, 1500 cm1 (C=C). 1 H NMR (400 MHz, CDCl3 ):
= 7.79 7.68 (m, 2 H), 7.66 7.60 (m, 2 H), 7.53 7.48
(m, 1 H), 7.47 (br, s, 1 H, NH), 7.31 7.22 (m, 2 H), 7.01
6.93 (m, 1 H), 6.79 6.62 (m, 4 H), 5.73 (br, s, 2 H, NH2 ),
3.79 (s, 3 H, OCH3 ). 13 C NMR (100 MHz, CDCl3 ): =
161.32 (C-4), 151.57 (C-2), 151.43 (C-21), 147.61 (C-9),
141.03 (C-12), 139.52 (C-18), 134.65 (C-10), 133.93 (CH,
C-7), 131.19 (2 CH, C-19,23), 127.09 (CH, C-14), 126.40
(CH, C-5), 124.16 (CH, C-8), 122.27 (CH, C-13), 116.63
(2 CH, C-20,22), 116.19 (CH, C-6), 114.78 (CH, C-16),
114.14 (CH, C-15), 109.36 (C-11), 55.89 (OCH3 ). MS (EI,
70 eV): m/z (%) = 342 (40) [M]+ , 326 (12) [MNH2 ]+ , 296
(4), 250 (8) [MPhNH2 ]+ , 220 (2), 208 (6), 192 (12), 182

950

K. M. El-Shaieb P. G. Jones Synthesis of 2-(2-Aminophenyl)-4-arylquinazoline Derivatives

(8), 160 (16), 129 (4), 118 (16), 102 (4), 92 (16), 75 (12).
C21 H18 N4 O (342.39): calcd. C 73.67, H 5.30, N 16.36; found
C 77.49, H 5.26, N 16.17.
2-(2-Aminophenyl)-N-(4-chlorophenyl)quinazolin-4-amine
(5i)
Colorless solid, 57 mg (66 %), m. p. 195 196 C. IR
(film): = 3352, 3270, 3211 (NH, NH2 ), 1607 (C=N),
1571, 1552, 1512 cm1 (C=C). 1 H NMR (400 MHz,
[D6 ]DMSO): = 9.93 (s, 1 H, NH), 8.53 (d, 1 H, J = 8.31 Hz,
8-H), 8.32 8.29 (dd, 1 H, J = 1.61, 8.08 Hz, 5-H), 7.93
(d, 2 H, J = 8.90 Hz, 20,22-H), 7.86 (d, 2 H, J = 3.65 Hz,
6,7-H), 7.62 7.57 (m, 1 H, 16-H), 7.51 (d, 2 H, J = 8.88 Hz,
19,23-H), 7.18 7.15 (m, 1 H, 14-H), 7.42 (s, 2 H, NH2 ),
6.80 6.76 (dd, 1 H, J = 1.06, 8.20 Hz, 15-H), 6.63 6.57 (m,
1 H, 13-H). 13 C NMR (100 MHz, [D6 ]DMSO): = 161.15
(C-4), 156.87 (C-2), 150.03 (C-9), 149.53 (C-12), 138.22
(C-18), 133.26 (CH, C-7), 130.97 (CH, C-14), 130.46 (CH,
C-5), 128.41 (2 CH, C-20,22), 127.50 (C-21), 127.34 (CH,
C-8), 125.56 (CH, C-13), 124.01 (2 CH, C-19,23), 122.93
(CH, C-6), 117.48 (C-10), 116.45 (CH, C-16), 114.73 (CH,
C-15), 113.09 (C-11). MS (EI, 70 eV): m/z (%) = 348 (40)
[M]+2 , 346 (100) [M]+ , 330 (2) [MNH2 ]+ , 254 (4) [M
PhNH2 ]+ , 237 (16), 228 (50), 22 (18), 201 (4), 192 (16), 166
(12), 155 (12), 141 (8), 118 (18), 111 (8), 92 (20), 75 (10).
C20 H15 ClN4 (346.81): calcd. C 69.26, H 4.36, Cl 10.22,
N 16.15; found C 69.03, H 4.33, Cl 9.97, N 15.92.
2-(2-Aminophenyl)-N-(4-bromophenyl)quinazolin-4-amine
(5j)
Colorless solid, 65 mg (67 %), m. p. 243 245 C. IR
(film): = 3353, 3275, 3211 (NH, NH2 ), 1607 (C=N),
1569, 1551, 1510 cm1 (C=C). 1 H NMR (400 MHz,
[D6 ]DMSO): = 9.91 (s, 1 H, NH), 8.52 (d, 1 H, J =
8.29 Hz, 8-H), 8.32 8.29 (dd, 1 H, J = 1.51, 8.06 Hz, 5-H),
7.89 (d, 2H, J = 8.90 Hz, 20,22-H), 7.86 (d, 2 H, J = 3.80 Hz,
6,7-H), 7.66 (d, 2 H, J = 8.87 Hz, 19,23-H), 7.63 7.57 (m,
1 H, 16-H), 7.43 (s, 2 H, NH2 ), 7.17 7.11 (m, 1 H, 14-H),
6.79 6.76 (dd, 1 H, J = 1.33, 8.18 Hz, 15-H), 6.64 6.58
(m, 1 H, 13-H). 13 C NMR (100 MHz, [D6 ]DMSO): =
[1] a) T. Herget, M. Freitag, M. Morbitzer, R. Kupfer,
T. Stamminger, Stamminger, M. Stamminger, Antimicrob. Agents & Chemother. 2004, 48, 4154 4162;
b) A. Rosowsky, J. B. Hynes, S. F. Queener, ibid. 1995,
39, 79 86.
[2] B. V. Brumas, M. M. L. Fiallo, G. Berthon, J. Inorg.
Biochem. 2006, 100, 362 373.
[3] S. Madapa, Z. Tusi, A. Mishra, K. Srivastava, S. K.
Pandey, R. Tripathi, S. K. Puri, S. Batra, Bioorg. &
Med. Chem. 2009, 17, 222 234.

161.14 (C-4), 156.81 (C-2), 150.03 (C-9), 149.52 (C-12),

138.66 (C-18), 133.27 (CH, C-7), 131.31 (2 CH, C-20,22),
130.98 (CH, C-14), 130.46 (CH, C-5), 127.50 (CH, C-8),
125.57 (CH-13), 124.31 (2 CH, C-19,23), 122.92 (CH, C-6),
117.46 (C-21), 116.45 (CH, C-16), 115.39 (C-10), 114.74
(CH, C-15), 113.12 (C-11). MS (EI, 70 eV): m/z (%) =
392 (90) [M]+2 , 390 (100) [M]+ , 374 (92) [MNH2 ]+ , 309
(30) [MHBr]+ , 294 (4) [MPhNH2 ]+ , 272 (40), 245 (2),
220 (16), 192 (16), 166 (12), 155 (34), 141 (8), 118 (16),
92 (20), 75 (12). C20 H15 BrN4 (391.26): calcd. C 61.39,
H 3.86, N 14.32; found C 61.23, H 3.81, N 14.14.
X-Ray structure determination of 5e
Crystal data: C22 H20 N4 , Mr = 340.42, monoclinic, P21 /c,
T = 173 C, a = 12.2795(3), b = 13.4766(3), c =
3 , Z = 4,
= 105.739(4) , V = 1778.22 A
11.1640(3) A,
= 0.6 mm1 ,
F(000) = 720, (CuK ) = 1.54184 A,
Dx = 1.272 g cm3 . Data collection: A colorless tablet, ca.
0.25 0.1 0.05 mm3 , was mounted in inert oil on a glass
fibre and transferred to the cold gas stream of an Oxford
Diffraction Nova Atlas diffractometer. Data were recorded
to 2 = 152 and were complete to 145 . Structure refinement: The structure was refined using S HELXL -97 [21]. NH
hydrogen atoms were refined freely; the methyl group at C26
was refined as an idealized rigid group and that at C27, rotationally disordered, as an idealized hexagon of half-occupied
hydrogen positions; other H were included using a riding
model. The final wR2 (all reflections) was 0.100 for 3681
intensities and 249 parameters, with R1 [I 2 (I)] = 0.036;
3 .
S = 1.08, max. = 0.22 e A
CCDC 726886 contains the supplementary crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data request/cif.
Acknowledgements
Kamal M. El-Shaieb thanks Prof. H. Hopf for the provision of laboratory facilities and valuable discussion, and the
Egyptian Government for a post-doctoral fellowship and financial support.
[4] a) S. Tamaoki, Y. Yamauchi, Y. Nakano, S. Sakano,
A. Asagarasu, M. Sato, J. Pharm. Exp. Ther. 2007, 322,
1315 1323; b) M. F. Pereira, R. Chevrot, E. Rosenfeld, V. Thiery, T. Besson, J. Enzym. Inhib. Med. Chem.
2007, 22, 577 583.
[5] a) M. F. Brana, J. M. Castellano, G. Keilhauer,
A. Machuca, Y. Martin, C. Redondo, E. Schlick,
N. Walker, Anti-Cancer Drug Des. 1994, 9, 527
538; b) P. Helissey, S. Cros, S. Giorgi-Renault, AntiCancer Drug Des. 1994, 9, 51 67; c) A. E. Wake-

K. M. El-Shaieb P. G. Jones Synthesis of 2-(2-Aminophenyl)-4-arylquinazoline Derivatives

[6]

[7]

[8]
[9]
[10]
[11]

ling, A. J. Barker, D. H. Davies, D. S. Brown, L. R.

Green, S. A. Cartlidge, J. R. Woodburn, Breast Cancer Res. & Treat. 1996, 38, 67 73; d) G. M. Chinigo,
M. Paige, S. Grindrod, E. Hamel, S. Dakshanamurthy,
M. Chruszcz, W. Minor, M. L. Brown, J. Med. Chem.
2008, 51, 4620 4631.
a) I. K. Kacker, S. H. Zaheer, J. Ind. Chem. Soc. 1951,
28, 344 346; b) J. F. Riou, P. Helissey, L. Grondard,
S. Giorg-Renault, Mol. Pharmacol. 1994, 40, 699
706; c) E. Ibrahim, A. M. Montgomerie, A. H. Sneddon, G. R. Proctor, B. Green, Eur. J. Med. Chem. 1988,
23, 183 188.
a) A.-L. Larroque, B. Peor, C. Williams, Y. Q. Fang,
Q. Qiu, Z. Rachid, B. J. Jean-Claude, Chem. Biol.
Drug. Des. 2008, 71, 374 379; b) S. A. Rocco; J. E.
Barbarini; R. Rittner Synthesis 2004, 3, 429 435.
E. C. Taylor, F. Yoneda, Angew. Chem. 1967, 79, 901
902, Angew. Chem., Int. Ed. Engl. 1967, 6, 878 879.
W. Szczepankiewicz, J. Suwinski, R. Bujok, Tetrahedron 2000, 56, 9343 9349.
K. M. El-Shaieb, H. Hopf, P. G. Jones, Arkivoc 2009, x,
146 160.
a) X. Cheng, S. Vellalath, R. Goddard, B. List, J. Am.
Chem. Soc. 2008, 130, 15786 15787; b) R. Z. Qiao,

[12]
[13]
[14]
[15]
[16]
[17]

[18]
[19]

[20]

[21]

951

B. L. Xu, Y. H. Wang, Chin. Chem. Lett. 2007, 18,

656 658.
E. Jacob, L. Mathew, B. Thomas, J. Chem. Sci. 2007,
119, 47 51.
J. Chen, D. Wu, F. He, M. Liu, H. Wu, J. Ding, W. Su,
Tetrahedron Lett. 2008, 49, 3814 3818.
K. M. El-Shaieb, H. Hopf, P. G. Jones, Z. Naturforsch.
2009, 64b, in press.
L. Wang, J. Xia, F. Qin, C. Qian, J. Sun, Synthesis 2003,
1241 1247.
V. B. Lingaiah, G. T. Ezikiel, V. G. Reddy, P. S. Rao,
Synlett. 2006, 2507 2509.
R. A. Khosropour, I. Mohammadpoor-Baltork,
H. Ghorbankhani, Tetrahedron Lett. 2006, 47,
3561 3564.
M. Adharvana Chari, D. Shobha, K. Mulkkanti, Catal.
Commun. 2006, 7, 787 790.
M. Narasimhulu, K. C. Mahesh, T. S. Reddy, K. Rajesh, Y. Venkateswarlu, Tetrahedron Lett. 2006, 47,
4381 4383.
M. Dabiri, P. Salehi, S. Otokesh, M. Baghbazadeh,
G. Kozehgary, A. A. Mohammadi, Tetrahedron Lett.
2005, 46, 6123 6126.
G. M. Sheldrick, Acta Cryst. 2008, A64, 112 122.