Synthesis of 3-aminoalkyl-2-arylaminoquiazolin-4(3H)-ones and 3,3′-disubstituted bis-2-arylaminoquinazolin-4(3H)-ones via reactions of 1-aryl-3-(2-ethoxycarbonylphenyl)carbodiimides with diamines

Article abstract of DOI:10.1002/jhet.5570450518

(Chemical Equation Presented) 1-Aryl-3-(2-ethoxycarbonylphenyl) carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aryl isocyanates, reacted with primary diamines in 1:1 and 2:1 molar ratio under mild conditions to give selecti

Full text of DOI:10.1002/jhet.5570450518

Sep-Oct 2008
1365
Synthesis of 3-Aminoalkyl-2-arylaminoquiazolin-4(3H)-ones and
3,3'-Disubstituted Bis-2-arylaminoquinazolin-4(3H)-ones via
Reactions of 1-Aryl-3-(2-ethoxycarbonylphenyl)carbodiimides with
Diamines
Xu-Hong Yang,a Ming-Hu Wu,*a Shao-Fa Sun,a Ming-Wu Ding,b Jia-Li Xiea
and Qing-Hua Xiac
a Department of Chemistry and Life Sciences, Xianning College, Xianning 437100, P. R. of China
E-mail: minghuwu@hotmail.com
b Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P. R. of China
c Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules,
College of Chemistry, Hubei University, Wuhan 430062, P. R. of China
Received January 14, 2008
O
O
O
N
COOEt
PPh3
R
1, ArNCO
RNH2
NHAr
N
N
N
+
2, H2NRNH2
N
N
N
NHAr NHAr
1
3
4
1-Aryl-3-(2-ethoxycarbonylphenyl)carbodiimides 2, obtained from aza-Wittig reactions of iminophos-
phorane 1 with aryl isocyanates, reacted with primary diamines in 1:1 and 2:1 molar ratio under mild
conditions to give selectively the regioisomers 3-aminoalkyl-2-arylaminoquinazolin-4(3H)-ones 3 and 3,3'-
disubstituted bis-2-arylaminoquinazolin-4(3H)-ones 4 in good yields, respectively. To fully characterize
the regioselectivity of aza-Wittig reactions of 1-aryl-3-(2-ethoxycarbonylphenyl)carbo-diimides with
primary diamines, crystals of 4e were obtained, and its structure was determined by X-ray crystallography.
J. Heterocyclic Chem., 45, 1365 (2008).
INTRODUCTION
intermediate [25]; (b) Usually, 4H-benzo[d][1,3]oxazin-4-
ones are valuable starting materials for the synthesis of
variety of 2,3-disubstituted quinazolin-4(3H)-ones [26];
(c) Initial synthesis of 3-substituted 2-thio-2,3-dihydro-
quinazolin-4(1H)-one from methoxyaniline or methyl-
anthranilate via thiourea intermediate followed by
hydrazinolysis or aminolysis affords 2,3-substituted
quinazolin-4(3H)-one [27]; (d) Recently, synthesis of
2,3-disubstituted quinazolin-4(3H)-ones via a one-pot,
three component reaction of isatoic anhydride and an
orthoester with ammonium acetate or a primary amine
catalyzed by silica sulfuric acid under solvent-free
conditions have been developed [28]. Unfortunately,
some of these reported methods suffer from drawbacks
like forcing conditions, long reaction times, unsatisfactory
yields, cumbersome product isolation procedures and
synthesis in multi-step synthetic programs.
The synthesis of quinazoline-4(3H)-one derivatives has
been the focus of great interest recently [1-4]. This is due,
in part, to the broad spectrum of their biological
properties. Some of these activities include antimicrobial
[5,6], anti-inflammatory [7,8], antifungal [9], anticancer
[10], antidiabetic [11], anticonvulsant [12], analgesic [13],
antibacterial [14], protein tyrosine kinase inhibitors [15],
EGFR inhibitors [16], PDGFR phosphorylation inhibitors
[17], CNS depressants [18], antitumor activity [19] and
AMPA receptor-antagonistic properties [20,21].
Furthermore, the heterocyclic core constitutes more than
40 alkaloids [22] isolated from natural products, and some
show interesting biological profiles such as antimalarial
[23] and diuretic [24] properties. The ranges of biological
activities, the extensive existence in nature products and
characteristic chemical structures have made synthetic
studies of quinazoline-4(3H)-one very attractive.
Keeping in view the potential biological activities of
2,3-disubstituted quinazolin-4(3H)-ones, many of them
have been synthesized. Over the past 20 years, the aza-
Wittig reactions of iminophosphoranes have attracted
increasing interest in view of their utility in the synthesis
of nitrogen-containing heterocyclic compounds [29].
Annelation of ring systems with N-heterocycles by means
of an aza-Wittig reaction has been widely utilized because
In accordance with the significance of quinazolin-
4(3H)-ones, numerous synthetic methods have been
developed for the construction of these kinds of fused
heterocycles: (a) The most common synthetic method to
2,3-substituted quinazolin-4(3H)-ones are based on the
acylation-cyclisation of anthranilic acid or its derivative
and proceed usually via an o-aminobenzamide

1366
X. H. Yang, M. H. Wu, S. F. Sun, M. W. Ding, J. L. Xie and Q. H. Xia
Vol 45
alkylamino group rather than arylamino one. This is
probably due to the geometry of intermediates 5 and 6
that are mainly in the E-form, which is suitable for the
alkylamino group to cyclize (Figure 1).
of the availability of functionalized iminophosphoranes.
However, the chemistry of tandem aza-Wittig reactions of
iminophosphorane with aryl isocyanates, and primary
diamines has received less attention. Although there are
numerous methods available for the synthesis of
quinazolinones and their derivatives, until now, no
general and simple approach to the synthesis of 3-
aminoalkyl-2-arylaminoquinazolin-4(3H)-one 3 and 3,3'-
disubstituted bis-2-arylaminoquinazolin-4(3H)-one 4.
EtOOC
NH
COOEt
NHRNH2
COOEt
NH
R
N
N
N
ArHN
NHAr
NHAr
6
5
Scheme 1
Figure 1
COOEt
PPh3
COOEt
ArNCO
H2NRNH2
O
O
O
N
N
N
C NAr
Ar
N
Ar
Ar
N
N
2
1
N
NHR
N
NHRNH
O
O
7
8
O
R
RNH2
N
N
+
N
Figure 2
N
N
NHAr NHAr
N
NHAr
The fact that base catalyst has no influence on the
reaction selectivity is perhaps attributed to the higher
nucleophilic activity of alkylamino group than the
arylamino one in the intermediates 5 and 6 for which
there would not be time for base catalyst to react with the
arylamino group followed by nucleophilic addition to the
carbonyl group to give the regioisomers 7 and 8
(Figure 2).
3
4
In connection with our ongoing heterocyclic synthesis
and drug discovery project [30], we have focused on the
synthesis of quinazolinones, thienopyrimidinones and
imidazaolinones by employing aza-Wittig reaction of ꢀ or
ꢁ-ethoxycarbonyl iminophosphorane with aromatic
isocyanate and subsequent reaction with various
nucleophiles under mild conditions. Herein, we wish to
report a fundamental approach to the synthesis of novel 3-
aminoalkyl-2-arylaminoquinazolin-4(3H)-one 3 and 3,3'-
disubstituted bis-2-arylaminoquinazolin-4(3H)-ones
4
(Scheme 1).
RESULTS AND DISCUSSION
Iminophosphorane 1, easily prepared from ethyl ꢁ-
aminobenzoate according to the method described in our
previous work [31], reacted with aromatic isocyanates to
give 1-aryl-3-(2-ethoxycarbonylphenyl) carbodiimides 2
without needing to remove the byproduct Ph3PO. 1-Aryl-
Figure 3. X-ray molecular structure of 4e.
3-(2-ethoxycarbonylphenyl) carbodiimides
2
were
allowed to react with primary diamines in 1:1 and 2:1
molar ratio, either in absent of or in the presence of
sodium ethoxide, to generate selectively the regioisomers
1
The structures of 3 and 4 are deduced from their H
NMR and IR data and/or X-ray analysis. For example,
the H NMR analysis in 3e shows the signals of NH at
1
3-aminoalkyl-2-arylaminoquinazolin-4(3H)-ones
3 and
3,3'-disubstituted bis-2-arylaminoquinazolin-4(3H)-ones 4
in same satisfactory yields, respectively. The results are
listed in Table 1.
The solitary formation of 3 and 4 can be rationalized in
terms of an initial nucleophilic addition in 1:1 and 2:1
molar ratio to give the guanidine intermediate 5 and 6
respectively, which cyclized to give 3 and 4 across the
11.02 ppm as a sharp absorption, NH2 at 1.84 ppm as
wide absorption, NCH2 at 4.29 ppm as triplet and CH2N at
3.29 ppm as triplet, which strongly suggests the existence
1
of NH and NCH2CH2NH2 groups in 3e. The H NMR
analyses in 4e shows signals of NCH2 at 4.28 ppm as
triplet, 3.92 ppm as triplet and 3.78 ppm as singlet, which
strongly suggests the existence of the NCH2CH2OCH2-

Sep-Oct 2008
3, 3'-Disubstituted Bis-2-arylaminoquinazolin-4(3H)-ones
1367
using TMS as internal standard. Mass spectra were recorded on a
Finnigan Trace mass spectrometer. Elemental analyses were
performed on a Perkin-Elmer CHN 2400 elementary analysis
instrument. X-ray data for 4e were collected using a Bruker Smart
Apex CCD area detector diffractometer and Mo-Ka radiation.
Synthesis of 3-Aminoalkyl-2-arylaminoquinazolin-4(3H)-
one 3; General Procedure. To a solution of iminophosphorane
1 (1.28 g, 3.0 mmol) in anhydrous THF (10 mL) was added
aromatic isocyanate (3 mmol) at room temperature. The reaction
mixture was left unstirred for 6-12 h at 0-5 °C to generate
carbodiimides 2, which were used directly without further
purification.
To a solution of primary diamines (3 mmol) in THF (10 mL)
was dropwise added above prepared solution of 2. After the
reaction mixture was stirred for 6–12h at room temperature, the
solvent was removed under reduced pressure and the residue
was recrystallized from CH2Cl2/CH3OH (1:1/v:v) to give 3-
aminoalkyl-2-arylaminoquinazolin-4(3H)-one 3.
Synthesis of 3,3'-Disubstituted Bis-2-arylaminoquinazolin-
4(3H)-one 4; General Procedure. To the solution of 2 prepared
above was added a solution of primary diamines (1.5 mmol) in
THF (10 mL). After the reaction mixture was stirred 6–12h at
room temperature, the solvent was removed under reduced
pressure and the residue was recrystallized from CH2Cl2/CH3OH
(1:1/v:v) to give 3, 3'-disubstituted bis-2-arylaminoquinazolin-
4(3H)-one 4.
3a: White crystals; mp 160–161 °C. IR (KBr): 3379 (N–H),
1665 (C=O), 1603 (C=N), 1345 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 11.12 (s, 1H, NH), 7.02–8.13 (m, 9H, Ar-H), 4.23
(t, 2H, J = 5.6 Hz, NCH2), 3.20 (m, 2H, CH2N), 1.79 (s, 2H,
NH2). MS: m/z (%) = 280.4 (25) [M+], 262.6 (20), 236.5 (100),
144.9 (29), 119.1 (22), 89.9 (51), 77.1 (84), 65.2 (25). Anal.
Calcd for C16H16N4O: C, 68.55; H, 5.75; N, 19.99. Found: C,
68.68; H, 5.73; N, 20.02.
CH2OCH2CH2N group in 4e. It should also be noted here
that NH signals or NH2 signals were only observed in the
1H NMR spectra of some of 3 and 4 whereas others
missed their NH signals or NH2 signals in 1H NMR
spectra. Such cases occur in of the analogous heterocycles
and other hetercycles bearing phenol moieties [32]. The
IR analysis of 3 and 4 all shows strange absorption bands
in the range of 1650–1686 cm-1 belonging to C=O
stretching vibration. The MS of 3 and 4 all show M+
peaks with low to moderate abundance. Moreover, the
structure of 3,3'-disubstituted bis-2-arylamino quinazolin-
4(3H)-one 4e was also confirmed by X-ray diffraction
analysis (Figure 3) [33].
Table 1
Preparation of 3-aminoalkyl-2-arylaminoquinazolin-4(3H)-one 3 and
3,3'-disubstituted bis-2-arylaminoquinazolin-4(3H)-ones 4a.
Time
(h)
Yield
(%)b
Entry
Ar
R
3a
3b
3c
3d
3e
4a
4b
4c
4d
Ph
Ph
-CH2CH2-
6
80
65
82
80
85
85
78
80
55
-CH2CH2CH2-
-CH2CH2-
8
4-Cl-Ph
Cl-Ph
4-F-Ph
Ph
6
-CH2CH(CH3)-
-CH2CH2-
10
6
-CH2CH2-
6
Ph
Ph
-CH2CH(CH3)-
-CH2CH2CH2-
-CH2CH2CH2CH2-
10
8
Ph
12
O
O
4e
4f
Ph
12
6
75
88
82
4-Cl-Ph
4-Cl-Ph
-CH2CH2-
4g
-CH2CH2CH2-
8
O
O
4h
4i
4-Cl-Ph
4-F-Ph
4-F-Ph
4-F-Ph
12
6
78
89
78
85
3b: White crystals; mp 143–145 °C. IR (KBr): 3366 (N–H),
1664 (C=O), 1609 (C=N), 1345 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 7.03–8.15 (m,9H, Ar–H), 4.30 (t, J = 4.1Hz, 2H,
NCH2), 2.84 (m, 2H, CH2N), 2.09 (m, 2H, CCH2C), 1.56 (s, 2H,
NH2). MS: m/z (%) = 294.0 (51) [M+], 276.1 (30), 250.0 (55),
235.6 (100), 220.6 (85), 201.8 (88), 144.9 (28), 118.9 (28), 92.9
(35), 76.6 (47), 64.9 (13). Anal. Calcd for C17H18N4O: C, 69.37;
H, 6.16; N, 19.03. Found: C, 69.17; H, 6.20; N, 19.08.
-CH2CH2-
4j
-CH2CH(CH3)-
-CH2CH2CH2-
10
8
4k
O
O
4l
4-F-Ph
12
80
aThe reaction was carried out according to general experimental
procedure. bIsolated yields based on iminophosphorane 1.
3c: White crystals; mp 151–153 °C. IR (KBr): 3384 (N–H),
1667 (C=O), 1602 (C=N), 1343 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 7.18–8.12 (m, 8H, Ar–H), 4.23 (t, J = 3.6 Hz, 2H,
NCH2), 3.23 (m, 2H, CH2N), 1.86 (s, 2H, NH2). MS: m/z (%) =
313.8 (18) [M+], 297.0 (40), 272.3 (100), 255.0 (17), 235.1 (8),
145.2 (14), 118.8 (14), 91.1 (13). Anal. Calcd for C16H15N4OCl:
C, 61.05; H, 4.80; N, 17.80. Found: C, 61.23; H, 4.80; N, 17.74.
3d: White crystals; mp 137–139 °C. IR (KBr): 3452 (N–H),
1666 (C=O), 1604 (C=N), 1344 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 7.14–7.98 (m, 8H, Ar–H), 4.38(d, J = 6.4 Hz, 2H,
NCH2), 2.34 (m, 1H, CH), 1.77 (d, J = 3.5 Hz 3H, CH3). MS:
m/z (%) = 327.3 (7) [M+], 309.6 (30), 297.7 (13), 269.7 (89),
254.4 (55), 235.2 (26), 220.3 (22), 143.6 (39), 118.8 (45), 92.6
(97), 75.8 (36), 62.3 (100). Anal. Calcd for C17H17N4OCl: C,
62.10; H, 5.21; N, 17.04. Found: C, 62.21; H, 5.21; N, 16.99.
3e: White crystals; mp 164–165 °C. IR (KBr): 3387 (N–H),
1666 (C=O), 1607 (C=N), 1346 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 11.02 (s, 1H, NH), 7.01–8.14 (m, 8H, Ar–H), 4.29
(t, J = 4.4 H, NCH2), 3.29 (m, 2H, CH2N), 1.84 (s, 2H, NH2).
MS: m/z (%) = 298.2 (29) [M+], 280.1 (37), 256.4 (100), 239.2
In conclusion, we have developed an efficient synthesis
of novel 3,3'-disubstituted bis-2-arylaminoquinazolin-
4(3H)-ones via a tandem aza-Wittig reaction of 1-aryl-3-
(2-ethoxycarbonylphenyl)carbodiimides with primary
diamines. Due to the mild reaction conditions, high
selectivity, good yields, easily accessible starting
materials and straightforward product isolation, we think
that this synthetic method discussed here provided us a
efficient approach to synthesize 3-aminoalkyl-2-aryl-
aminoquinazolin-4(3H)-ones and 3,3'-disubstituted bis-2-
arylaminoquinazolin-4(3H)-ones.
EXPERIMENTAL
Melting points were recorded on X-4 apparatus and are
uncorrected. IR spectra were recorded on a Perkin–Elmer
Spectrum One spectrophotometer using KBr optics. 1H NMR
spectra were recorded with a Varian mercury 400 spectrometer

1368
X. H. Yang, M. H. Wu, S. F. Sun, M. W. Ding, J. L. Xie and Q. H. Xia
Vol 45
(84), 183.9 (19), 144.9 (25), 109.0 (31), 89.9 (28), 75.1 (7).
Anal. Calcd for C16H15N4OF: C, 64.42; H, 5.07; N, 18.78.
Found: C, 64.50; H, 5.08; N, 18.73.
4i: White crystals; mp 235–237 °C. IR (KBr): 3207 (N–H),
1686 (C=O), 1612 (C=N), 1358 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 9.06 (s, 2H, NH), 6.81–8.18 (m, 16H, Ar–H), 4.53
(s, 4H, 2ꢀNCH2). MS: m/z (%) = 536.6 (25) [M+], 279.7 (100),
255.3 (95), 238.8 (17), 145.0 (10), 118.9 (18), 91.0 (14), 69.8
(6). Anal. Calcd for C30H22N6O2F2: C, 67.16; H, 4.13; N, 15.66.
Found: C, 67.33; H, 4.12; N, 15.70.
4j: White crystals; mp 215–217 °C. IR (KBr): 3345 (N–H),
1668 (C=O), 1608 (C=N), 1346 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 9.22 (s, 2H, NH), 6.75–8.13 (m, 16H, Ar–H), 4.78
(m, 1H, CH), 4.29 (d, J = 1.2 Hz, 2H, NCH2), 1.27 (d, J = 9.6
Hz, 3H, CH3 ). MS: m/z (%) = 550.2 (26) [M+], 389.1 (20),
294.0 (39), 279.9 (57), 255.5 (92), 238.7 (100), 200.0 (17),
144.8 (26), 118.8 (14), 89.5 (59), 74.1 (14), 62.9 (9). Anal.
Calcd for C31H24N6O2F2: C, 67.63; H, 4.39; N, 15.26. Found: C,
67.47; H, 4.40; N, 15.31.
4k: White crystals; mp 239–241 °C. IR (KBr): 3338 (N–H),
1668 (C=O), 1610 (C=N), 1348 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ =: 6.84–8.10 (m, 16H, Ar–H), 4.39 (t, J = 8.0 Hz, 4H,
2ꢀNCH2), 2.35 (m, 2H, CCH2C). MS: m/z (%) = 550.0 (25)
[M+], 389.4 (20), 294.2 (100), 281.6 (65), 253.3 (96), 239.6 (95),
119.4 (65), 91.6 (89), 77.0 (33), 63.7 (26). Anal. Calcd for
C31H24N6O2F2: C, 67.63; H, 4.39; N, 15.26. Found: C, 67.45; H,
4.39; N, 15.30.
4l: White crystals; mp 141–143 °C. IR (KBr): 3390 (N–H),
1665 (C=O), 1610 (C=N), 1345 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 6.85–8.12 (m, 16H, Ar–H), 4.25 (t, J = 4.4 Hz, 4H,
2ꢀNCH2), 3.90 (t, J = 4.4 Hz, 4H, 2ꢀCH2O), 3.80 (s, 4H,
OCH2CH2O). MS: m/z (%) = 624.8 (25) [M+], 298.5 (7), 280.1
(51), 256.2 (100), 239.0 (90), 213.0 (29), 145.1 (15), 120.1 (19),
89.7 (28), 74.9 (17). Anal. Calcd for C34H30N6O4F: C, 65.38; H,
4.84; N, 13.45. Found: C, 65.18; H, 4.85; N, 13.47.
4a: White crystals; mp 249–250 °C. IR(KBr): 3425 (N–H),
1664 (C=O), 1609 (C=N), 1343 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 8.97 (s, 2H, NH), 6.75–8.20 (m, 18H, Ar–H), 4.56
(s, 4H, 2ꢀNCH2CH2N). MS: m/z (%) = 500.3 (53) [M+], 262.0
(100), 238.4 (42), 221.0 (51), 165.7 (9), 144.9 (8), 118.9 (11),
89.6 (28), 76.9 (23), 62.8 (11). Anal. Calcd for C30H24N6O2: C,
71.99; H, 4.83; N, 16.79. Found: C, 72.07; H, 4.82; N, 16.81.
4b: White crystals; mp 160–162 °C. IR (KBr): 3442 (N–H), 1682
(C=O), 1607 (C=N), 1364 (C–N) cm-1. 1HNMR (400 MHz, CDCl3):
ꢀ = 9.23 (s, 2H, NH), 6.80–8.14 (m, 18H, Ar–H), 4.78 (m, 1H,
CHN), 4.36 (d, J = 13.2 Hz, 2H, CH2), 1.67 (d, J = 3.3 Hz, 3H,
CH3). MS: m/z (%) = 514 (31) [M+], 275 (100), 237 (79), 220 (23),
144 (6), 117 (14), 91 (16), 77 (17). Anal. Calcd for C31H26N6O2: C,
72.36; H, 5.09; N, 16.33. Found: C, 72.34; H, 5.11; N, 16.33.
4c: White crystals; mp 229–231 °C. IR (KBr): 3329 (N–H),
1650 (C=O), 1610 (C=N), 1345 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 8.67 (s, 2H, NH), 7.14–7.98 (m,18H, Ar–H), 4.41
(t, J = 7.2 Hz, 4H, 2ꢀNCH2), 2.12 (m, 2H, CCH2C). MS: m/z
(%) = 514 (63) [M+], 352 (27), 276 (80), 265 (54), 237 (100),
145 (13), 117 (18), 91 (14), 76 (7). Anal. Calcd for C31H26N6O2:
C, 72.36; H, 5.09; N, 16.33. Found: C, 72.26; H, 5.10; N, 16.37.
4d: White crystals; mp 194–196 °C. IR (KBr): 3343 (N–H),
1668 (C=O), 1608 (C=N), 1343 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 6.67–8.12 (m, 18H, Ar–H), 4.47 (t, J = 4.4 Hz, 4H,
NCH2), 2.03 (t, J = 3.6 Hz, 4H, CCH2CH2C). MS: m/z (%) =
528.2 (65) [M+], 366.9 (16), 278.2 (38), 235.9 (100), 90.0 (15),
77.2 (16), 65.2 (4). Anal. Calcd for C32H28N6O2: C, 72.71; H,
5.34; N, 15.90. Found: C, 72.85; H, 5.33; N, 15.94.
4e: White crystals; mp 132–133 °C. IR (KBr): 3349 (N–H),
1683 (C=O), 1608 (C=N), 1360 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 6.91–8.12 (18H, Ar–H), 4.28 (t, J = 4.4 Hz, 4H, N-
CH2), 3.92 (t, J = 4.0 Hz, 4H, 2ꢀCH2O), 3.78 (s, 4H,
OCH2CH2O). MS: m/z (%) = 588 (20) [M+], 352 (4), 297 (7),
238 (100), 221 (24), 145 (12), 118 (21), 77 (15), 64 (11). Anal.
Calcd for C34H32N6O4: C, 69.37; H, 5.48; N, 14.28. Found: C,
69.46; H, 5.49; N, 14.22.
Acknowledgement. The authors would like to thank
Open Fund of Ministry-of-Education Key Laboratory for the
Synthesis and Application of Organic Functional Molecules
(grant no. 2006-KL-013) and Natural Science Foundation of
Hubei Province (grant no.2006ABA334) for financial
support.
4f: White crystals; mp 240–242 °C. IR (KBr): 3327 (N–H),
1655 (C=O), 1605 (C=N), 1365 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 9.64 (s, 2H, NH), 6.59–7.77 (m, 16H, Ar–H), 4.68
(s, 4H, 2ꢀNCH2). MS: m/z (%) = 569.7 (24) [M+], 320.2 (92),
295.6 (83), 271.2 (100), 235.3 (21), 146.5 (35), 90.8 (20), 77.0
(9). Anal. Calcd for C30H22N6O2Cl2: C, 63.28; H, 3.89; N, 14.76.
Found: C, 63.37; H, 3.88; N, 14.80.
4g: White crystals; mp 225–227 °C. IR (KBr): 3399 (N–H),
1667 (C=O), 1613 (C=N), 1359 (C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 7.17–8.10 (m, 16H, Ar–H), 4.36 (t, J = 7.0 Hz, 4H,
2ꢀNCH2), 2.34 (m, 2H, CCH2C). MS: m/z (%) = 583.0 (27)
[M+], 420.2 (18), 346.5 (20), 297.4 (59), 270.4 (100), 254.7 (43),
235.3 (15), 144.6 (18), 120.0 (17), 91.9 (16). Anal. Calcd for
C31H24N6O2Cl2: C, 63.81; H, 4.15; N, 14.40. Found: C, 64.01; H,
4.14; N, 14.43.
4h: White crystals; mp 149–151 °C. IR (KBr): 3325 (N–H),
1681 (C=O), 1606 (C=N), 1339(C–N) cm-1. 1HNMR (400 MHz,
CDCl3): ꢀ = 7.08–8.20 (m, 16H, Ar–H), 4.25 (t, J = 4.4 Hz, 4H,
2ꢀNCH2), 3.90 (t, J = 4.5 Hz, 4H, 2ꢀCH2O), 3.80 (s, 4H,
OCH2CH2O). MS: m/z (%) = 657 (22) [M+], 353 (15), 296 (52),
271 (100), 236 (59), 221 (23), 146 (11), 118 (14), 91 (13), 76
(8). Anal. Calcd for C34H30N6O4Cl2: C, 62.10; H, 4.60; N, 12.78.
Found: C, 62.01; H, 4.61; N, 12.75.
REFERENCES AND NOTES
[1] Li, F.; Feng, Y.; Meng, Q.; Li, W.; Li, Z.; Wang, Q.; Tao, F.
Arkivoc. 2007, (i) 40.
[2] Carpintero, M.; Cifuentes, M.; Ferrito, R.; Haro R.; Toledo,
M. A. J. Comb. Chem. 2007, 9, 818.
[3] Witt, A.; Bergman, J. Tetrahedron. 2000, 56, 7245.
[4] Deepthi, K. S.; Reddy, P. S. N. Synthesis. 2002, 15, 2168.
[5] Pandeya, S. N.; Sriram, D.; Nath, G.; Clercq, E. De. Pharm.
Acta Helv. 1999, 74, 11.
[6] Shiba, S. A.; El-Khamry, A. A.; Shaban, M. E.; Atia, K. S.
Pharmazie. 1997, 52, 189.
[7] Santagati, N. A.; Bousquet, E.; Spadaro, A.; Ronsisvalle, G.
Farmaco. 1999, 54, 780.
[8] Bekhit, A. A. and Khalil, M. A. Farmaco. 1998, 53, 539.
[9] Bartroli, J.; Turmo, E.; Alguero, M.; Boncompte, E.; Vericat,
M. L.; Conte, L.; Ramis, J.; Merlos, M.; Garcia-Rafanell, J.; Forn, J. J.
Med. Chem. 1998, 41, 1869.
[10] Skelton, L.; Bavetsias, V.; Jackman, A. WO 0050417, 2000;
Chem. Abstr. 2000, 133, 207917q.
[11] Malamas, M. S.; Millen, J. J. Med. Chem. 1991, 34, 1492.
[12] Mannscherck, A.; Koller, H.; Stuhler, G.; Davis, M. A..;
Traber, J. Eur. J. Med. Chem. 1984, 19, 381.
[13] Fisnerova, L.; Brunova, B.; Kocfeldova, Z.; Tikalova, J.;

Sep-Oct 2008
3, 3'-Disubstituted Bis-2-arylaminoquinazolin-4(3H)-ones
1369
Maturova, E.; Grimova, J. Collect. Czech. Chem. Commun. 1991, 56,
2373.
[14] Kung, P.-P.; Casper, M. D.; Cook, K. L.; Wilson-Lingard, L.;
Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt, R.; Cook,
P. D.; Ecker, D. J. J. Med. Chem. 1999, 42, 4705.
[15] Palmer, B. D.; Trumpp-Kallmeyer, S.; Fry, D. W.; Nelson, J.
M.; Showalter, H. D. H.; Denney, W. A. J. Med. Chem. 1997, 40, 1519.
[16] Tsou, H.-R.; Mamuya, N.; Johnson, B. D.; Reich, M. F.;
Gruber, B. C.; Nilakantan, F. Ye, R.; Shen, R.; Discafani, C.; Deblanc,
R.; Davis, R.; Kohen, F. E.; Greenberger, L. M.; Wang, Y.-F.; Wissner,
A. J. Med. Chem. 2001, 44, 2719.
[17] Matsuno, K.; Chimura, M.; Nakajima, T.; Tahara, K.;
Fujiwara, S.; Kase, H.; Vishiki, J.; Giese, N. A.; Pandey, A.;
Scarborough, R. M.; Lokker, N. A.; Yu, J.-C.; Irie, J.; Tsukuda, E.; Ide,
S.-I.; Oda, S.; Nomoto,Y. J. Med. Chem. 2002, 45, 3057.
[18] Srivastava, B.; Shukla, J. S. Indian J. Chem., Sec. B. 1991,
30B, 332.
1977, 42, 656; Rastogi, V. K.; Parmar, S. S.; Singh, S. P.; Akers, T. K. J.
Heterocyl. Chem. 1978, 15, 497; Kornet, M. J.; Varia, T.; Beaven, W. J.
Heterocycl. Chem. 1983, 20, 1553; Parkanyi, C.; Yuan, H. L.;
Stromberg, B. H. E.; Evenzahav, A. J. Heterocycl. Chem. 1992, 29, 749.
[27] Alagarsamy V.; Murugesan, S. Chem. Pharm. Bull. 2007, 55,
76; Alagarsamy, V.; Murugesan, V.; Pavalarani, N.; Vasanthanathan, P.;
Revathi, R. Bio. Pharm. Bull. 2003, 26, 557.
[28] Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M.
Tetrahedron Lett. 2005, 46, 7051.
[29] Ding, M., Xu, S.; Zhao, J. J. Org. Chem. 2004, 69, 8366;
Yadav, J. S.; Srinivas, C. Tetrahedron. 2003, 59, 10325; Csampai, A.;
Turos, G.; Kudar, V.; Simon, K.; Oeynhausen, H.; Wamhoff, H.; Sohar,
P. Eur. J. Org. Chem. 2004, 4, 717.
[30] Zhao, J.; Xie, C.; Ding, M.; He, H. Chem. Lett. 2005, 7,
1022; Ding, M.; Yang, S.; Zhu. J. Synthesis. 2004, 1, 75; Li, H.; Xie, C.;
Ding, M.; Liu, Z.; Yang, G. Synlett. 2007, 14, 2280.
[31] Ding, M.; Zeng, G.; Wu, T. Synth. Commun. 2000, 30, 1599.
[32] Atzrodt, J.; Beckert, R.; Günther, W.; Görls, H. Eur. J. Org.
Chem. 2000, 8, 1661; Qian, X.; Xu, X.; Li, Z.; Li Z.; Song, G. J. Fluor.
Chem. 2004, 125, 1609; Su, N.; Bradshaw, J. S.; Zhang, X.; Song, H.;
Savage, P. B.; Xue, G.; Krakowiak, K. E.; Izatt, R. M. J. Org. Chem.
1999, 64, 885.
[33] The structure of 4e, which was recrystallized from MeOH,
was determined by single-crystal X-ray diffraction analysis. Data
collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker,
2001); data reduction: SAINT; program(s) used to solve structure:
SHELXS97 (Sheldrick, 1997); program(s) used to refine structure:
SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek,
2003). Crystal data: C34H32N6O4, M = 558.66, Monoclinic, P2 (1)/c, a
= 15.822(2) Å, b = 8.0024(7) Å, c = 23.7333(14) Å, ꢀ = 90°, ꢁ =
93.993(1) °, ꢂ = 90°, V = 2997.6(5) Å3, Z = 4, Dcalcd = 1.304 g/cm3,
13493 collected reflections, 6514 independent (Rint = 0.0617), R1 =
0.0564, wR2 = 0.1171. The crystal data has been deposited in the
Cambridge Crystallographic Data Centre as supplementary publication
No. CCDC 668066. Copies of the data can be obtained, free of charge,
via the internet (http://www.ccdc.cam. ac.uk/data_request /cif), by
e-mail (data_request@ccdc.cam.ac.uk), or by fax (+44-1223-336033).
[19] Felter, J.; Czuppo, T.; Hornyak, G.; Feller, A. Tetrahedron.
1991, 47, 9393.
[20] Welch, W. M.; Ewing, F. E.; Huang, J.; Menniti, F. S.;
Pagnozzi, M. J;. Kelly, K.; Seymour, P. A.; Guanowsky, V.; Guhan, S.;
Guinn, R. M.; Critchett, D.; Lazzaro, J.; Ganong, A. H.; Devries, K. M.;
Staigers, T. L.; Chenard, B. L. Bioorg. Med. Chem. Lett. 2001, 11, 177.
[21] Chenard, B. L.; Menniti, F. S.; Welch, W. M. Jr. EP 900568,
1999; Chem. Abstr. 1999, 130, 218317h.
[22] Katritzky A. R.; Rees, C. W. Comprehensive Heterocyclic
Chemistry, The Structure, Reaction, Synthesis and Uses of Heterocyclic
Compounds, Pergamon Press, New York, 1984; Vol. 3, Part 2B;
Pelletier, S. W. Alkaloids: Chemical and Biological Prospective; John
Wiley & Sons Ltd., New York, 1983; Vol. 1; Johne, S. Alkaloids. 1986,
29, 99.
[23] Abdel-Rahman, M. M.; Mangoura, S. A.; Ei-Bitar, H. I. Bull.
Pharm. Sci. 1990, 13, 137.
[24] He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397.
[25] Filachione, E. M.; Lengel J. H.; Fisher, C. H. J. Am. Chem.
Soc. 1944, 66, 494.
[26] Errede, L. A.; MeBrady, J. J.; Oien, H. T. J. Org. Chem.