A novel strategy to the synthesis of 4-anilinoquinazoline derivatives

Article abstract of DOI:10.1016/j.tet.2013.12.028

A novel approach to prepare 4-anilinoquinazoline derivatives based on the transformation of indoline-2,3-dione to formamidine was developed. The processes with this approach are simple, efficient, and environmentally friendly. The efficiency of this approach was evaluated by synthesizing 17 4-anilinoquinazolines and comparing the obtained yields with those achievable through conventional synthetic methods. It was the first time that compounds 8d, 8e, 8h, and 13b-f were synthesized. The characteristics of the IR and the UV spectra of these compounds and the effects of their substituents on the spectra were observed.

Full text of DOI:10.1016/j.tet.2013.12.028

Tetrahedron 70 (2014) 906e913
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel strategy to the synthesis of 4-anilinoquinazoline derivatives
*
Zheng Wang, Cuiling Wang, Yanni Sun, Ning Zhang, Zhulan Liu, Jianli Liu
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University,
Xi’an 710069, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 August 2013
Received in revised form 1 December 2013
Accepted 10 December 2013
Available online 19 December 2013
A novel approach to prepare 4-anilinoquinazoline derivatives based on the transformation of indoline-
2,3-dione to formamidine was developed. The processes with this approach are simple, efficient, and
environmentally friendly. The efficiency of this approach was evaluated by synthesizing 17 4-
anilinoquinazolines and comparing the obtained yields with those achievable through conventional
synthetic methods. It was the first time that compounds 8d, 8e, 8h, and 13bef were synthesized. The
characteristics of the IR and the UV spectra of these compounds and the effects of their substituents on
the spectra were observed.
Keywords:
A novel strategy
Synthesis
Ó 2013 Elsevier Ltd. All rights reserved.
4-Anilinoquinazoline
Derivatives
1. Introduction
HN
N
HN
N
Br
4-Anilinoquinazolines are a class of potentially high selective
anticancer agents for their strong ability to inhibit several receptor
tyrosine kinases,1 such as EGFR, NGFR, and VEGFR-2, which often
over-expresses or deregulates in many solid tumors. These small
molecules can competitively fit into the ATP binding pocket of
tyrosine kinase domain.2e4 Among 4-anilinoquinazolines,
PD153035 (1) was firstly reported as a selective specific EGFR ty-
rosine kinase inhibitor in 1994.5 Then more similar molecules
were reported and approved as anticancer drugs successively, such
as Erlotinib (2, Tarceva), Gefitinib (3, Iressa), and Canertinib (4)
(Fig. 1).
O
O
O
O
O
O
N
N
F
F
1
2
HN
Cl
HN
Cl
H
N
N
N
N
O
O
N
O
N
O
O
N
3
4
Despite the widespread utility of this class of compounds, the
reported synthetic methods often require multi-steps and harsh
conditions. The starting materials used in the reported methods are
mainly substituted benzaldehydes (Scheme 1). The yields of the
processes are not satisfactory.6e8 The key intermediate of the
synthetic routes is either substituted quinazolin-4(3H)-one or
substituted N0-(2-cyanophenyl)-N,N-dimethylformamidine. Two
common steps in these procedures are nitration and reduction. The
nitration process needs to proceed at low temperature (no higher
than 5 ꢀC) with a large amount of concentrated sulfuric acid.9 Thus
restrictive control is required in adding reagents into sulfuric acid
to keep the temperature under 5 ꢀC. Nevertheless, the yield of the
Fig. 1. Structures of tyrosine kinase inhibitors.
nitration is not satisfactory. Although there are several different
ways to reduce the nitro group, the disappointing yields and diffi-
cult purification steps discouraged many researchers.10,11 Hydro-
genation process is a good choice to reduce the nitro group,
however, the application of precious metal catalyst undoubtedly
increases the cost of the product.12 In addition, a complex setup is
necessary regarding safety when using hydrogen. Therefore, a safe,
efficient, environmentally friendly, and universal pathway to syn-
thesize 4-anilinoquinazolines is highly demanded. In this paper
a novel approach for fulfilling these requirements to prepare 4-
anilinoquinazolines is disclosed.
* Corresponding author. Tel.: þ86 (0)29 88302013; fax: þ86 (0)29 88303572;
e-mail address: jlliu@nwu.edu.cn (J. Liu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.028

Z. Wang et al. / Tetrahedron 70 (2014) 906e913
907
Table 1
R1
R2
CN
R1
R2
CN
R1
R2
CHO
Optimization of the reaction time and the ratio of 6 to POCl3
6/POCl3
Time
1 h
NH2
R
NO2
2 h
3 h
4 h
5 h
1:1
3%
10%
23%
26%
d
17%
35%
57%
d
20%
43%
88%
d
21%
40%
85%
d
1:1.2
1:1.5
1:1.8
1:2
10%
10%
d
HN
R1
R2
CN
N
R1
N
d
d
d
d
d
N
R2
N
‘dd’ Complex reaction mixture was obtained, and it was difficult to be purified.
compound 6 is 1.5 to 1 and reaction time is 4 h, compound 7 was
obtained with a high yield (88%) and a simple common work up
procedure.
After compound 7 was successfully obtained, 10 different
substituted 4-anilinoquinazolines were synthesized (Scheme 2). To
further evaluate our new approach, six different 5,6,7,8-substituted
4-anilinoquinazolines were synthesized (Schemes 3 and 4) with
two more steps comparing with Scheme 2. Different substituted
R1
R2
COOH
R1
R2
CHO
R1
R2
COOH
NO2
NH2
R
HN
N
O
N
R1
R2
R1
R2
N
NH
N OH
O
O
R1
R1
R1
,
a
Scheme 1. Current general synthetic approaches.
b
c
O
N
N
NH2
H
H
2. Result and discussion
R2
R2
10a-d
R2
11a-d
9a-d
F
Substituted benzaldehydes were used as starting material in
literature to synthesize 4-anilinoquinazolines. Both steps of nitra-
tion and reduction were needed to synthesize the key intermediate
formamidine or quinazolin-4(3H)-one. To avoid these steps, we
developed a new synthetic approach. Indole-2,3-dione (5, a cheap
industrial scale product) was chosen as starting material. It un-
derwent condensation with hydroxylamine hydrochloride followed
by heated in the solution of DMF and POCl3 to form compound 7.13
Finally, compound 7 reacted with substituted anilines to produce
the target compounds 8aej (Scheme 2).14,15 This route also avoided
synthesizing anthranilonitrile and using DMF/DMA.
HN
Cl
R1
CN
R1
e
d
N
N
N
N
R2
12a-d
R2
13a-d
13a:R1=NO2, R2=H; 13b:R1=F, R2=H;
13c:R1=CH3, R2=H; 13d:R1=H, R2=Cl;
Scheme 3. The synthesis of 13aed. Reagents and conditions: (a) HONH3Cl, Cl3CCHO,
Na2SO4, H2O, reflux, 1 h; (b) 95% of H2SO4, 65 ꢀC, 1 h; (c) HONH3Cl, H2O, CH3COONa,
reflux, 30 min; (d) POCl3, DMF, Na2CO3, H2O, 0 ꢀC to rt to 70 ꢀC, 4 h; (e) 3-chloro-4-
fluorobenzenamine, CH3COOH, reflux, 3 h.
N OH
O
O
CN
N
b
a
O
N OH
O
O
N
N
N
H
H
7
6
5
c
R3
R2
O
N
Cl
N
H
Cl
H
11e
Cl
a
10e
Cl
HN
N OH
O
O
Cl
NH2
R1
c
N
c
9e
O
N
N
H
N
8a-j
H
10f
11f
F
8a:R1=H,R2=H,R3=H; 8b:R1=H,R2=Cl,R3=F;
8c:R1=H,R2=H,R3=OH; 8d:R1=H,R2=MeO,R3=H;
8e:R1=F,R2=H,R3=H; 8f:R1=H,R2=H,R3=F;
8g:R1=Cl,R2=H,R3=H; 8h:R1=Cl,R2=H,R3=Cl;
8i:R1=H,R2=H,R3=Br; 8j:R1=H,R2=Br,R3=H;
HN
Cl
CN
d
e
N
N
F
Scheme 2. Synthesis of compound 8aej. Reagents and conditions: (a) HONH3Cl, H2O,
CH3COONa, reflux, 30 min, 98%; (b) POCl3, DMF, Na2CO3, H2O, 0 ꢀC to rt to 70 ꢀC, 4 h,
88%; (c) amine derivatives, CH3COOH, reflux, 3 h, 85e93%.
Cl
N
N
N
Cl
N
13e
12e
Cl
Cl HN
Cl
CN
N
e
d
The synthesis of the key intermediate 7 was reported in 2010
with a low yield and in-sufficient purification process. To enhance
product yield and facilitate the purification process, we in-
vestigated this reaction thoroughly. It was found that the main
factors influencing the yield and purity of compound 7 were the
reaction time and the ratio of compound 6 to POCl3. As shown in
Table 1, under the optimized conditions, ratio of POCl3 to
N
12f
13f
Scheme 4. The synthesis of 13e and 13f. Reagents and conditions: (a) HONH3Cl,
Cl3CCHO, Na2SO4, H2O, reflux, 1 h; (b) 95% of H2SO4, 65 ꢀC, 1 h; (c) HONH3Cl, H2O,
CH3COONa, reflux, 30 min; (d) POCl3, DMF, Na2CO3, H2O, 0 ꢀC to rt to 70 ꢀC, 4 h; (e) 3-
chloro-4-fluorobenzenamine, CH3COOH, reflux, 3 h.

908
Z. Wang et al. / Tetrahedron 70 (2014) 906e913
Table 2
Overall yields comparison
anilines (9aee) were used as starting materials to synthesize isatin
derivatives with the following two steps. Compounds 9aee firstly
reacted with chloral hydrate and hydroxylamine hydrochloride to
produce anilide derivatives. Then Beckmann rearrangement was
carried out in 95% of H2SO4 to form compounds 10aef.16 The rest
steps were similar to Scheme 2. The yields of anilide derivatives
were affected by the substituent groups of anilines used in the
process. Generally, aniline with electron-drawing group gives
a higher yield of aniline derivatives than that with electron-
donating group. More by-product produced by more active
amine. It was observed that the yield of 10c (60.7%) was lower than
the yield of other compound 10. In addition, the efficiency of the
new strategy was also practiced by synthesizing compound 5 with
the above procedure. A total yield of 77.8% was obtained.
Compounds
Literature
Isolated (%)
From 5
From aniline
8a
8b
8c
8d
8e
8f
8g
8h
8i
46.7%,7 79.2%,18 67%19
d
71%20
d
76.6
79.9
73.3
75.6
81.9
82.7
81.1
78.5
73.3
80.2
d
60
62.2
57
58.8
63.7
64.3
63.1
61.1
57
62.2
61.1
53.8
41.9
54.6
23.7
26.1
50.1
d
65.1%21
72.1%22
d
34.6%,7 78.2%18
8j
33.1%7
13a
13b
13c
13d
13e
13f
1
72.3%,11 59.8%23
d
d
It is well known that aromatic ring with ortho- and para-
directing group can form two products when an electrophilic
substitution occurs on benzene ring. It is approved in this work at
d
d
d
d
d
d
d
55%,24 40%25
d
Beckmann rearrangement step
b
(Scheme 4), when 3-
d
chlorobenzeneamine was used as starting material. Compounds
10e and 10f were formed and the ratio of 10e to 10f was approxi-
mately 1 to 1 by comparing the peak area of HPLC (The spectrum of
HPLC is in Supplementary data.). After the whole process, the target
compounds 13e and 13f were obtained with total yields of 23.7%
and 26.1%, respectively.
PD153035 (1), one of the star molecule in 4-anilinoquinazoline
family, is a selective specific EGFR tyrosine kinase inhibitor re-
ported in 1994 for the first time. To further evaluate the developed
strategy in this work, PD153035 (1) was synthesized through five
steps using 3,4-dimethoxybenzenamine (9f) as starting material.17
The yield of the anilide derivative obtained with 9f, which has two
electron-donating groups on the benzene ring, was lower than
other compounds at reflux condition. To increase the yield of the
intermediate, reaction temperature was lowered while the ratio of
material in the system was also adjusted. High yield (90%) of anilide
derivative was achieved at 70 ꢀC. Consequently, 50.1% total yield of
compound 1 was obtained (Scheme 5).
‘dd’ The synthetic yields were not reported.
13b, 13d, and 1 are in the range of 50e61%. The yield of 13c is lower
due to the electron-donating effect of the methyl groups on the
quinazoline ring. The yields of 13e and 13f are approximately half of
other products due to co-existence of two isomers of 10e and 10f in
the process.
Following the new approach, the key intermediates 7 and 12aeg
can be produced by simple, efficient, and environmentally friendly
processes. Purification process after each step can be done easily
due to the high yield of target compound in each step. Extraction or
column separation is not required. A simple precipitation process
by controlling pH is performed followed by filtration. The prepa-
ration of compounds 5 and 10aeg from aniline derivatives followed
the method reported in the literature.16 Compounds 10aeg, 5, and
hydroxylamine hydrochloride are dissolved in water and kept
refluxing for 30 min to produce the intermediates 11aeg and 6 with
yields in the range of 88e98%. This is a green reaction that no or-
ganic solvents are used. Once compounds 11aeg and 6 are ob-
tained, the key intermediates 12aeg and 7 can be synthesized
according to the conditions listed in Table 1. Finally, compounds 7
and 12aeg react with corresponding substituted anilines to pro-
duce target compounds 8aej, 13aef, and 1.
O
N OH
O
MeO
MeO
MeO
MeO
MeO
c
a, b
O
N
N
NH2
MeO
H
H
11g
10g
9f
Previous studies reported the NMR and mass spectra of com-
pounds of group 8 and compound 1 that were successfully syn-
thesized. With the new approach developed in this work,
compounds 8d, 8e, 8h, and 13bef were successfully synthesized for
the first time. Therefore, IR and UV spectra of these compounds
were investigated and the effects of the substituent groups on such
spectra were summarized. The common features of IR spectra of
this kind of compounds include a sharp absorption peak in
3100e3500 cmꢁ1 region generated from secondary amine and
a smaller absorption peak in 3000e3100 cmꢁ1 region rose from the
benzene. Another common absorption peak of this group com-
pounds is a single sharp peak in 1620e1700 cmꢁ1 region from vi-
bration of C]N bond.
The characteristics of IR spectra among the different compounds
in this group originates from the different substituent groups,
which have their own vibration frequencies, such as hydroxyl group
of 8c at 3240.25 cmꢁ1, methoxyl group of 8d and 1 at 1155.80 cmꢁ1
and 1151.27 cmꢁ1, nitro group of 13a at 1533.45 cmꢁ1, and methyl
group of 13c at 3041.11 cmꢁ1. The bonds with halogen atoms exhibit
specific absorption peaks and the substituent positions of halogen
on benzene ring also influence their bond vibration frequencies.
The common absorption peaks of 8aej in 735e770 cmꢁ1 region
represent the four successive hydrogens on the quinazoline ring.
The common absorption peaks in 800e900 cmꢁ1 of 13aec, which
HN
Br
MeO
MeO
CN
N
MeO
MeO
N
e
d
N
N
12g
1 (PD153035)
Scheme 5. The synthesis of PD153035 (1). Reagents and conditions: (a) HONH3Cl,
Cl3CCHO, Na2SO4, H2O, 70 ꢀC, 1 h; (b) 95% of H2SO4, 65 ꢀC, 2 h; (c) HONH3Cl, H2O,
CH3COONa, reflux, 30 min; (d) POCl3, DMF, Na2CO3, H2O, 0 ꢀC to rt to 70 ꢀC, 4 h; (e) 3-
bromobenzenamine, CH3COOH, reflux, 3 h.
In summary,17 different substituted 4-anilinoquinazolines were
synthesized successfully, of which compounds 8d, 8e, 8h, and
13aeg were firstly synthesized in public literature. To verify the
efficiency of our new approach, overall yields of the final products
from this work along with those obtained with different routes
reported in literature are listed in Table 2. It reveals that the overall
yields of final products obtained through three steps with starting
compound 5 are more than 70%, which are higher than those re-
ported in literature using anthranilonitrile or anthranilic acid as
starting material; The overall yields of the final products 8aej,
using aniline as starting material, are in the range of 57e64%, which
are comparable to the range reported in literature. The yields of 13a,

Z. Wang et al. / Tetrahedron 70 (2014) 906e913
909
(anilide derivative) was collected by filtration and dried, which
was used for next step without further purification.
all have a substituent at 6 positions, correspond to two successive
hydrogens and a single hydrogen on quinazoline rings. The feature
absorption peaks of 13e are similar to 13aec. The feature peaks of
13d and 13e are in 710e850 cmꢁ1, corresponding to three succes-
sive hydrogens on quinazoline rings.
(b) A 100 ml, three-necked, round-bottomed flask fitted with a ther-
mometer was charged with concentrated sulfuric acid (10 equiv).
After heating to 50 ꢀC with stirring, the dried product (1 equiv)
from the above step was added in over a period of 20 min. The
resulting solution was heated to 65 ꢀC and kept for 1 h and then
cooled down to room temperature with an ice bath. The pre-
cipitate was filtered out and dried to get the target compounds.
Two main common absorption peaks of those compounds in UV
spectra are presented in the regions of 210e220 nm and
320e340 nm. The other two peaks appear in the regions of
235e250 nm and 280e290 nm and the sizes of the peaks depend
on the position of the substituent groups. A substituent at ortho-
position on aniline ring of 8aej causes the peak in the region of
280e290 nm larger than other positions, while a substituent at
para-position results in the peak in the region of 235e250 nm lager.
When a substituent at meta-position, the peaks in the regions of
235e240 nm and 280e290 nm are so small that only two main
peaks in the regions of 210e220 nm and 320e330 nm are observed.
When a substituent on quinazoline rings of 13aeg, the UV feature
peaks are similar to that on aniline ring. The substituent at meta-
position causes the peak in the region of 280e290 nm smaller than
at other positions.
4.2.1. Indoline-2,3-dione (5). The dried product from the above step
(15.4 g, 0.095 mol) was added into concentrated sulfuric acid
(50 ml) in a period of 20 min at 50 ꢀC. Then the resulted mixture
was heated to 65 ꢀC and kept for 1 h. The mixture was poured into
ice water. The precipitate in the mixture was filtered out and dried.
Red crystal solid of 11.51 g was obtained with a yield of 77.8%. Mp
189e192 ꢀC; IR (KBr): 3192.19, 1728.52, 1616.46, 1461.23, 1401.93,
770.77 cmꢁ1; UVevis (CH3OH),
(400 MHz, CDCl3):
l
/nm: 210, 242, 297 nm; 1H NMR
d
11.09 (s, 1H), 7.13 (t, 1H), 7.42 (t, 1H), 7.76 (d,
1H), 7.83 (d, 1H); ESI-MS for C8H5NO2 [MþH]þ: calcd: 148.13,
found: 148.08. Anal. Calcd for C8H5NO2: C, 65.31; H, 3.43; N, 9.52.
Found: C, 65.27; H, 3.44; N, 9.53.
3. Conclusion
A novel synthetic approach to produce 4-anilinoquinazolines
with cheap starting material was developed. The processes with
this approach are simple, efficient, and environmental friendly.
Nitration and reduction steps are eliminated. No other organic
solvents were used in this approach except of DMF and CH3COOH.
Seventeen 4-anilinoquinazolines were successfully synthesized
and the overall yields of the target products were higher than the
corresponding ones with conventional routes reported in literature.
The synthesis of compounds 8e, 8d, 8h, 13bef and IR and UV
spectra of these compounds along with the effects of their sub-
stituent groups on the spectra were reported for the first time in
public literature.
4.2.2. 5-Nitroindoline-2,3-dione (10a). The dried product from the
above step (20.5 g, 0.098 mol) was added into concentrated sulfuric
acid (53 ml) in a period of 20 min at 50 ꢀC. Then the resulted mixture
was heated to 65 ꢀC and kept for 1 h. The mixturewas poured into ice
water. The precipitate in the mixture was filtered out and dried. Pale
yellow crystal solid of 14.74 g was obtained with a yield of 76.4%. Mp
254e257 ꢀC; IR (KBr): 3334.61, 3095.36, 1770.03, 1751.21, 1619.29,
1533.45,1470.52,1336.55, 903.33, 852.46 cmꢁ1; UVevis (CH3OH),
l/
nm: 210, 321 nm; 1H NMR (400 MHz, CDCl3):
d 10.74 (s, 1H), 8.25 (d,
1H), 7.97 (s, 1H), 7.69 (d, 1H); ESI-MS for C8H4N2O4 [MþH]þ: calcd:
193.13, found: 193.08. Anal. Calcd for C8H4N2O4: C, 50.01; H, 2.10; N,
14.58. Found: C, 50.05; H, 2.06; N, 14.56.
4. Experimental sections
4.1. General
4.2.3. 5-Fluoroindoline-2,3-dione (10b). The dried product from the
above step (17.1 g, 0.095 mol) was added into concentrated sulfuric
acid (50 ml) in a period of 20 min at 50 ꢀC. Then the resulted
mixture was heated to 65 ꢀC and kept for 1 h. The mixture was
poured into ice water. The precipitate in the mixture was filtered
out and dried. Red solid of 12.35 g was obtained with a yield of
74.4%. Mp 221e224 ꢀC; IR (KBr): 3446.51, 3068.88, 1738.77, 1724.51,
All chemicals and solvents were analytical grade and used
without further purification. Analytical TLC was performed on pre-
coated silica gel plates (HG/T2354-92). Melting points were de-
termined on an X-5 micro melting point apparatus and were un-
1620.63, 1488.17, 1141.15, 890.43, 847.51 cmꢁ1; UVevis (CH3OH),
l/
nm: 215, 249, 295 nm; 1H NMR (400 MHz, CDCl3):
d 10.91 (s, 1H),
corrected. The UV spectra were recorded on
a 2600UV/VIS
7.63 (d, 1H), 7.57 (s, 1H), 6.95 (d, 1H); ESI-MS for C8H4NO2F [MþH]þ:
calcd: 166.12, found: 166.08. Anal. Calcd for C8H4NO2F: C, 58.19; H,
2.44; N, 8.48. Found: C, 58.21; H, 2.39; N, 8.51.
spectrophotometer using methanol as blank. The IR spectra were
recorded on an FT-IR spectrometer (Spectrum Two); 1H NMR
spectra were recorded at 400 MHz on a Bruker Avance-400 MHz
spectrometer with TMS as an internal standard; chemical shifts
were given in parts per million (ppm) and coupling constants in
hertz (Hz). Mass spectra were performed on LTQ-XL with direct
sample injection; HRMS were performed on Agilent Technologies
6520B accurate-Mass Q-TOF LC/MS. Elemental analysis was per-
formed on a Vario EL III CHNOS analyzer.
4.2.4. 5-Methylindoline-2,3-dione (10c). The dried product from
the above step (14.1 g, 0.08 mol) was added into concentrated
sulfuric acid (43 ml) in a period of 20 min at 50 ꢀC. Then the
resulted mixture was heated to 65 ꢀC and kept for 1 h. The mixture
was poured into ice water. The precipitate in the mixture was fil-
tered out and dried. Red solid of 9.83 g was obtained with a yield of
60.7%. Mp 168e171 ꢀC; IR (KBr): 3458.06, 2996.94, 2923.95,
1747.00, 1716.05, 1628.01, 1604.41, 1492.00, 1437.81, 900.35,
4.2. General procedure for the synthesis of 5 and 10aeg
812.40 cmꢁ1; UVevis (CH3OH),
(400 MHz, CD3OD):
l
/nm: 216, 246, 300 nm; 1H NMR
(a) A 500 ml, three-necked, round-bottomed flask fitted with
a condenser and a thermometer was charged with chloral hy-
drate (16.50 g, 0.1 mol) and 220 ml of water. Then anhydrous
sodium sulfate (15.00 g), aniline derivative (0.1 mol), HCl so-
lution (5.2%, 70 ml), and hydroxylamine hydrochloride
(20.81 g, 0.3 mol, in 95 ml of water) were added in successively.
After being heated to reflux for 1 h, the reaction mixture was
cooled to room temperature. The intermediate compound
d
7.40 (d, J¼8.0 Hz, 1H), 7.36 (s, 1H), 6.82 (d,
J¼8.0 Hz, 1H), 2.30 (s, 3H); ESI-MS for C9H7NO2 [MþH]þ: calcd:
162.15, found: 162.08. Anal. Calcd for C9H7NO2: C, 67.06; H, 4.38; N,
8.69. Found: C, 67.12; H, 4.08; N, 8.59.
4.2.5. 7-Chloroindoline-2,3-dione (10d). The dried product from
the above step (18.5 g, 0.094 mol) was added into concentrated

910
Z. Wang et al. / Tetrahedron 70 (2014) 906e913
sulfuric acid (50 ml) in a period of 20 min at 50 ꢀC. Then the
resulted mixture was heated to 65 ꢀC and kept for 1 h. The mixture
was poured into ice water. The precipitate in the mixture was fil-
tered out and dried. Red solid of 14.17 g was obtained with a yield of
77.9%. Mp 152e154 ꢀC; IR (KBr): 3456.09, 3076.51, 1771.23, 1746.61,
1614.52, 1529.23, 1475.12, 1434.67, 768.5, 734.2 cmꢁ1; UVevis
evaporated under reduced pressure, giving the compound 10g
as red solid.
Red solid; 2.58 g, 73% yield. Mp 246e249 ꢀC; IR (KBr): 3432.93,
2946.11, 1767.8, 1743.78, 1621.81, 1496.42, 1467.08, 1198.89,
865.61 cmꢁ1; UVevis (CH3OH), /nm: 211, 267, 321 nm; 1H NMR
l
(CH3OH), l
/nm: 218, 245, 300 nm; 1H NMR (400 MHz, CD3OD):
(400 MHz, CD3OD):
d 7.08 (s, 1H), 6.55 (s, 1H), 3.94 (s, 3H), 3.79 (s,
3H); ESI-MS for C10H9NO4 [MþH]þ: calcd: 208.17, found: 208.08.
Anal. Calcd for C10H9NO4: C, 57.97; H, 4.37; N, 6.76. Found: C, 57.88;
H, 4.32; N, 6.59.
d
7.60 (d, J¼8.1 Hz, 1H), 7.50 (d, J¼7.4 Hz, 1H), 7.33e7.29 (m, 2H);
ESI-MS for C8H4NO2Cl [MþH]þ: calcd: 182.57, found: 182.08. Anal.
Calcd for C8H4NO2Cl: C, 52.91; H, 2.22; N, 7.71. Found: C, 52.83; H,
2.10; N, 7.81.
4.3. General procedure for the synthesis of compounds 6 and
11aeg
4.2.6. 6-Chloroindoline-2,3-dione (10e). The dried product from the
above step (16.2 g, 0.09 mol) was added into concentrated sulfuric
acid (48 ml) in a period of 20 min at 50 ꢀC. Then the resulted
mixture was heated to 65 ꢀC and kept for 1 h. The mixture was
poured into ice water. The precipitate in the mixture was filtered
out and dried. Crude red solid of 13.2 g was obtained. The crude
product (6.5 g) was purified by column chromatography over silica
gel (using petroleum ether/EtOAc¼8:1) to afford 10e as a red solid
2.91 g with a yield of 32.5%. Mp 238e241 ꢀC; IR (KBr): 3460.23,
3106.31, 1756.24, 1732.80, 1615.04, 1589.10, 1436.88, 875.8, 838.97,
4.3.1. 3-(Hydroxyimino)indolin-2-one (6). A mixture of compound
5 (10.00 g, 0.068 mol) and hydroxylamine hydrochloride (5.00 g,
0.072 mol) in water (100 ml) was heated to reflux for 30 min, then
sodium acetate (5 g) was added in and the solution was continued
to reflux for another 30 min. The mixture was cooled down to room
temperature. The solid was filtered out and dried to obtain a yellow
solid 6, which was pure enough for the next reaction; 10.81 g, 98%
yield. Mp 219e221 ꢀC.
602.13 cmꢁ1; UVevis (CH3OH),
(400 MHz, CD3OD):
l
/nm: 213, 251, 300 nm; 1H NMR
4.3.2. Compounds 11aeg. A mixture of compound 10aeg
(0.01 mol) and hydroxylamine hydrochloride (0.013 mol) in water
(20 ml) was heated to reflux for 30 min, then sodium acetate (1.5 g)
was added and the solution was continued to reflux for another
30 min. The mixture was cooled down to room temperature. The
solid was filtered out and dried for the next step. The obtained
yields were all in the range of 88% and 97%.
d
7.52 (d, J¼8.0 Hz, 1H), 7.11 (dd, J¼8.0, 1.4 Hz,
1H), 6.97 (d, J¼1.3 Hz, 1H); ESI-MS for C8H4NO2Cl [MþH]þ: calcd:
182.57, found: 182.08. Anal. Calcd for C8H4NO2Cl: C, 52.91; H, 2.22;
N, 7.71. Found: C, 52.80; H, 2.06; N, 7.79.
4.2.7. 4-Chloroindoline-2,3-dione (10f). The dried product from
the above step (16.2 g, 0.09 mol) was added into concentrated
sulfuric acid (48 ml) in a period of 20 min at 50 ꢀC. Then the
resulted mixture was heated to 65 ꢀC and kept for 1 h. The
mixture was poured into ice water. The precipitate in the mixture
was filtered out and dried. Crude red solid of 13.2 g was obtained.
The crude product (6.5 g) was purified by column chromatogra-
phy over silica gel (using petroleum ether/EtOAc¼8:1 and 6:1) to
afford 10f as a red solid 3.04 g with a yield of 34.6%. Mp
261e263 ꢀC; IR (KBr): 3456.21, 3177.04, 1739.98, 1723.19, 1609.78,
1587.28, 1470.69, 1439.48, 788.70, 674.95 cmꢁ1; UVevis (CH3OH),
4.4. General procedure for the synthesis of compounds 7 and
12aeg
4.4.1. 3-(2-Cyanophenyl)-1,1-dimethylurea (7). Compound 6 (5.02 g,
0.031 mol) was added in slowly to the mixture of POCl3 (4.3 ml,
0.046 mol) and DMF (20 ml) that was iced to 0 ꢀC. The resulting
mixture was stirred at room temperature for 10 min followed by
heated to 70 ꢀC for 4 h. The reaction mixture was cooled down and
poured into water (100 ml). The unsolvable substance was filtered
out. Then sodium carbonate solution (10%) was added into the so-
lution to adjust the pH to 7. Thirty minutes later, the precipitate was
filtered out and dried. Yellow solid 7 of 4.72 g was obtained with 88%
yield, which was pure enough for the next reaction. Mp 145e148 ꢀC.
l
/nm: 218, 243, 306 nm; 1H NMR (400 MHz, CD3OD):
d 7.51 (t,
J¼8.0 Hz, 1H), 7.05 (d, J¼8.2 Hz, 1H), 6.86 (d, J¼7.9 Hz, 1H); ESI-MS
for C8H4NO2Cl [MþH]þ: calcd: 182.57, found: 182.08. Anal. Calcd
for C8H4NO2Cl: C, 52.91; H, 2.22; N, 7.71. Found: C, 52.58; H, 2.16;
N, 7.72.
4.2.8. General procedure for 5,6-dimethoxyindoline-2,3-dione (10g).
(a) A 250 ml, three-necked, round-bottomed flask fitted with
a condenser and a thermometer was charged with chloral hy-
drate (3.2 g, 0.019 mol) and 100 ml of water. Then anhydrous
sodium sulfate (45.5 g), 3,4-dimethoxybenzenamine (2.62 g,
0.017 mol), HCl solution (5.2%, 30 ml), and hydroxylamine hy-
drochloride (3.9 g, 0.056 mol, in 20 ml of water) were added in
successively. After being heated to 70 ꢀC for 1 h, the reaction
mixture was cooled to room temperature. The intermediate
compound (anilide derivative) was collected by filtration and
dried, which was used for next step without further
purification.
(b) A 50 ml, three-necked, round-bottomed flask fitted with
a thermometer was charged with concentrated sulfuric acid
solution (9 ml). After heating to 50 ꢀC with stirring, the dried
product (3.6 g, 0.016 mol) from the above step was added in
over a period of 20 min. The resulting solution was heated to
65 ꢀC and kept for 1 h and then cooled down to room tem-
perature with an ice bath. The precipitate was filtered out and
the filtrate was extracted with ethyl acetate (40 mlꢂ3). The
organic phase was dried over anhydrous sodium sulfate and
4.4.2. Compounds 12aef. Compounds 11aef (1.0 equiv) was added
in slowly to the mixture of POCl3 (1.5 equiv) and DMF (8 ml) that
was iced to 0 ꢀC. The resulting mixture was stirred at room tem-
perature for 10 min and then heated to 70 ꢀC for 4 h. The reaction
mixture was cooled down and poured into water (50 ml). The un-
solvable substance was filtered out. Then sodium carbonate solu-
tion (10%) was added into the solution to adjust the pH to 7. Thirty
minutes later, the precipitate was filtered out and dried to result the
target compounds 12aef, respectively. The yields were all in the
range of 80% and 85%.
4.4.3. 3-(2-Cyano-4,5-dimethoxyphenyl)-1,1-dimethylurea
(12g). Compound 11g (2.0 g, 0.009 mol) was added in slowly to the
mixture of POCl3 (1.3 ml, 0.014 mol) and DMF (8 ml) that was iced
to 0 ꢀC. The resulting mixture was stirred at room temperature for
10 min and then heated to 70 ꢀC for 4 h. The reaction mixture was
cooled down and poured into water (50 ml). The unsolvable sub-
stance was filtered out. Then sodium carbonate solution (10%) was
added into the solution to adjust the pH to 7. The aqueous phase
was extracted with ethyl acetate (30 mlꢂ3) and then the organic
phase was extracted with water (50 mlꢂ3) to remove DMF. The

Z. Wang et al. / Tetrahedron 70 (2014) 906e913
911
solvents were removed in vacuo giving a brown liquid product
without further purification for the next step.
0.01 mol) with 2-fluorobenzenamine (1.11 g, 0.01 mol), as a white
solid of 2.28 g. Mp 167e170 ꢀC; IR (KBr): 3067.19, 1620.17, 1599.04,
1571.53, 1500.84, 1454.18, 1407.94, 771.00, 745.94 cmꢁ1; UVevis
4.5. General procedure for the synthesis of compounds 8aej,
13aef, and PD153035 (1)
(CH3OH), l
/nm: 215, 289, 320 nm; 1H NMR (400 MHz, CD3OD):
d
8.40 (s, 1H), 8.31 (d, J¼8.3 Hz, 1H), 7.84 (d, J¼7.1 Hz, 1H), 7.77 (d,
J¼8.3 Hz, 1H), 7.61 (dd, J¼14.0, 6.7 Hz, 2H), 7.29 (s, 1H), 7.25e7.20
(m, 2H), 5.45 (s, 1H); ESI-MS for C14H10N3F [MþH]þ: calcd: 240.24,
found: 240.08; HRMS for C14H10N3F [MþH]þ: calcd: 240.2478,
found: 240.0928. Anal. Calcd for C14H10N3F: C, 70.28; H, 4.21; N,
17.56. Found: C, 70.41; H, 4.12; N, 17.26.
A mixture of compound 7 (1.0 equiv), 12aeg (1.0 equiv), and
different derivatives of aniline (1.0 equiv) in acetic acid (15 equiv)
was heated to reflux for 3 h. The mixture was poured into the ice
water. Twenty minutes later, the precipitate was filtered out and
washed three times with water. The solid was dried to result in the
target compounds.
4.5.6. N-(4-Fluorophenyl)quinazolin-4-amine (8f). The title com-
pound was obtained in 95.8% yield, by condensing 7 (1.72 g,
0.01 mol) with 4-fluorobenzenamine (1.11 g, 0.01 mol), as a white
solid of 2.29 g. Mp 205e208 ꢀC; IR (KBr): 3059.51, 1623.16, 1572.80,
4.5.1. N-Phenylquinazolin-4-amine (8a). The title compound was
obtained in 89.7% yield, by condensing 7 (1.72 g, 0.01 mol) with
aniline (0.93 g, 0.01 mol), as a white solid of 1.98 g. Mp 251e253 ꢀC;
IR (KBr): 3294.98, 3060.70, 1664.21, 1599.51, 1556.40, 1500.16,
1530.73, 1495.57, 1420.66, 1397.73, 832.88, 818.32, 765.95 cmꢁ1
;
UVevis (CH3OH),
CD3OD):
l
/nm: 219, 235, 332 nm; 1H NMR (400 MHz,
1436.01, 756.96, 694.62 cmꢁ1; UVevis (CH3OH),
l
/nm: 207, 239,
d
8.51 (s, 1H), 8.38 (d, J¼8.3 Hz, 1H), 7.88 (t, J¼7.6 Hz, 1H),
329 nm; 1H NMR (400 MHz, CD3OD):
d
8.50 (s, 1H), 8.39 (d,
7.80 (d, J¼8.3 Hz, 1H), 7.76e7.71 (m, 3H), 7.65 (t, J¼7.6 Hz, 1H), 7.16
(t, J¼8.7 Hz, 2H); ESI-MS for C14H10N3F [MþH]þ: calcd: 240.24,
found: 240.08. Anal. Calcd for C14H10N3F: C, 70.28; H, 4.21; N, 17.56.
Found: C, 70.42; H, 4.15; N, 17.15.
J¼7.8 Hz, 1H), 7.89e7.84 (m, 1H), 7.79 (d, J¼7.9 Hz, 1H), 7.73 (s, 1H),
7.66e7.61 (m, 1H), 7.50 (s, 2H), 7.41 (s, 2H), 7.19 (d, J¼7.4 Hz, 1H);
ESI-MS for C14H11N3 [MþH]þ: calcd: 222.25, found: 222.08. Anal.
Calcd for C14H11N3: C, 75.99; H, 5.01; N, 18.99. Found: C, 75.68; H,
5.11; N, 18.45.
4.5.7. N-(2-Chlorophenyl)quinazolin-4-amine (8g). The title com-
pound was obtained in 94.1% yield, by condensing 7 (1.72 g,
0.01 mol) with 2-chlorobenzenamine (1.47 g, 0.01 mol), as a white
solid. 2.41 g, mp 114e117 ꢀC; IR (KBr): 3436.45, 3039.16, 1621.61,
1601.29, 1588.12, 1496.67, 1445.93, 749.35, 673.30 cmꢁ1; UVevis
4.5.2. N-(3-Chloro-4-fluorophenyl)quinazolin-4-amine (8b). The ti-
tle compound was obtained in 92.7% yield, by condensing 7 (1.72 g,
0.01 mol) with 3-chloro-4-fluorobenzenamine (1.47 g, 0.01 mol), as
a white solid of 2.53 g. Mp 225e227 ꢀC; IR (KBr): 3352.33, 3044.28,
1679.76, 1605.64, 1579.51, 1495.22, 1423.78, 1060.05, 872.70,
(CH3OH), l
/nm: 214, 288, 317 nm; 1H NMR (400 MHz, CD3OD):
d
8.42 (s, 1H), 8.35 (d, J¼8.3 Hz, 1H), 7.90 (t, J¼7.3 Hz, 1H), 7.81 (d,
813.54, 761.49, 678.39 cmꢁ1; UVevis (CH3OH),
l
/nm: 216, 243,
J¼8.2 Hz, 1H), 7.66 (t, J¼7.9 Hz, 3H), 7.56 (d, J¼7.9 Hz, 1H), 7.42 (t,
J¼7.1 Hz, 1H), 7.34 (t, J¼7.1 Hz, 1H); ESI-MS for C14H10N3Cl [MþH]þ:
calcd: 256.70, found: 256.08. Anal. Calcd for C14H10N3Cl: C, 65.76;
H, 3.94 N, 16.43. Found: C, 65.81; H, 3.84; N, 16.01.
329 nm; 1H NMR (400 MHz, CD3OD):
d
8.58 (s, 1H), 8.37 (d,
J¼8.3 Hz, 1H), 8.06 (dd, J¼6.7, 2.6 Hz, 1H), 7.88 (t, J¼7.6 Hz, 1H), 7.81
(d, J¼8.2 Hz, 1H), 7.81e7.59 (m, 3H), 7.27 (t, J¼9.0 Hz, 1H); ESI-MS
for C14H9N3ClF [MþH]þ: calcd: 274.69, found: 274.08. Anal. Calcd
for C14H9N3ClF: C, 61.43; H, 3.31; N, 15.35. Found: C, 61.86; H, 3.01;
N, 15.40.
4.5.8. N-(2,4-Dichlorophenyl)quinazolin-4-amine (8h). The title
compound was obtained in 91.1% yield, by condensing 7 (1.72 g,
0.01 mol) with 2,4-dichlorobenzenamine (1.62 g, 0.01 mol), as
a white solid of 2.65 g. Mp 225e228 ꢀC; IR (KBr): 3360.25, 3034.22,
1683.39, 1595.30, 1572.07, 1502.43, 1475.91, 873.77, 812.35, 763.62,
4.5.3. 4-(Quinazolin-4-ylamino)phenol (8c). The title compound
was obtained in 85.1% yield, by condensing 7 (1.72 g, 0.01 mol) with
4-aminophenol (1.09 g, 0.01 mol), as a brown solid of 2.01 g. Mp
217e219 ꢀC; IR (KBr): 3433.41, 3240.25, 3094.13, 1656.92, 1618.36,
1586.07, 1494.86, 1446.14, 1359.70, 1232.90, 818.41, 803.69,
677.32 cmꢁ1; UVevis (CH3OH),
l
/nm: 210, 244, 331 nm; 1H NMR
8.41 (s, 1H), 8.32 (d, J¼8.2 Hz, 1H), 7.84 (t,
(400 MHz, CD3OD):
d
J¼7.5 Hz, 1H), 7.75 (d, J¼8.2 Hz, 1H), 7.60 (t, J¼7.5 Hz, 1H), 7.44 (d,
J¼8.5 Hz, 3H), 6.85 (d, J¼8.5 Hz, 2H); ESI-MS for C14H9N3Cl2
[MþH]þ: calcd: 291.14, found: 291.08; HRMS for C14H9N3Cl2
[MþH]þ: calcd: 291.1469, found: 291.0266. Anal. Calcd for
773.79 cmꢁ1; UVevis (CH3OH),
(400 MHz, CD3OD):
J¼7.5 Hz, 1H), 7.75 (d, J¼8.2 Hz, 1H), 7.60 (t, J¼7.5 Hz, 1H), 7.44 (d,
J¼8.5 Hz, 3H), 6.85 (d, J¼8.5 Hz, 2H); ESI-MS for C14H11N3O
[MþH]þ: calcd: 238.25, found: 238.08. Anal. Calcd for C14H11N3O: C,
70.87; H, 4.67; N, 17.71. Found: C, 70.87; H, 4.39; N, 17.13.
l
/nm: 210, 244, 332 nm; 1H NMR
8.41 (s, 1H), 8.32 (d, J¼8.2 Hz, 1H), 7.84 (t,
d
C14H9N3Cl2: C, 57.95; H, 3.12; N, 14.48. Found: C, 57.45; H, 3.34; N,
14.31.
4.5.9. N-(4-Bromophenyl)quinazolin-4-amine (8i). The title com-
pound was obtained in 85.0% yield, by condensing 7 (1.72 g,
0.01 mol) with 4-bromobenzenamine (1.72 g, 0.01 mol), as a white
solid of 2.55 g. Mp 232e234 ꢀC; IR (KBr): 3298.71, 3058.55, 1621.16,
4.5.4. N-(3-Methoxyphenyl)quinazolin-4-amine
(8d). The
title
compound was obtained in 87.7% yield, by condensing 7 (1.72 g,
0.01 mol) with 3-methoxybenzenamine (1.23 g, 0.01 mol), as
a white solid of 2.20 g. Mp 153e158 ꢀC; IR (KBr): 3260.91, 3090.48,
2935.00, 2834.59, 1623.55, 1601.60, 1571.51, 1498.91, 1452.52,
1356.10, 1155.80, 1053.61, 875.75, 818.55, 771.51 cm-1;UVevis
1598.79, 1571.46, 1497.46, 1455.38, 809.61, 767.53, 499.65 cmꢁ1
;
UVevis (CH3OH),
CD3OD):
(d, J¼8.0 Hz, 1H), 7.77e7.74 (m, 2H), 7.64 (dd, J¼11.2, 4.1 Hz, 1H),
7.55e7.52 (m, 2H), 5.48 (s, 1H); ESI-MS for C14H10N3Br [MþH]þ:
calcd: 301.15, found: 301.08. Anal. Calcd for C14H10N3Br: C, 56.02; H,
3.35; N, 13.99. Found: C, 56.39; H, 3.02; N, 13.90.
l
/nm: 210, 238, 332 nm; 1H NMR (400 MHz,
8.55 (s, 1H), 8.38 (d, J¼8.1 Hz,1H), 7.90e7.85 (m,1H), 7.80
d
(CH3OH),
l
/nm: 216, 332 nm; 1H NMR (400 MHz, CD3OD):
d
8.44 (s,
1H), 8.30 (d, J¼8.2 Hz, 1H), 7.77 (d, J¼7.9 Hz, 1H), 7.70 (d, J¼8.1 Hz,
1H), 7.54 (t, J¼7.6 Hz, 1H), 7.36 (s, 1H), 7.22 (d, J¼6.4 Hz, 3H), 6.69
(dt, J¼6.4, 2.4 Hz, 1H), 3.74 (s, 3H); ESI-MS for C15H13N3O [MþH]þ:
calcd: 252.28, found: 252.08; HRMS for C15H13N3O [MþH]þ: calcd:
252.2833, found: 252.1126. Anal. Calcd for C15H13N3O: C, 71.69; H,
5.21; N, 16.72. Found: C, 71.97; H, 5.01; N, 16.61.
4.5.10. N-(3-Bromophenyl)quinazolin-4-amine (8j). The title com-
pound was obtained in 93.3% yield, by condensing 7 (1.72 g,
0.01 mol) with 3-bromobenzenamine (1.72 g, 0.01 mol), as a white
solid of 2.80 g. Mp 195e198 ꢀC; IR (KBr): 3284.28, 3113.63, 1621.95,
4.5.5. N-(2-Fluorophenyl)quinazolin-4-amine (8e). The title com-
pound was obtained in 95.1% yield, by condensing 7 (1.72 g,
1597.18, 1568.89, 1501.23, 1477.64, 862.22, 797.30, 587.41 cmꢁ1
;

912
Z. Wang et al. / Tetrahedron 70 (2014) 906e913
UVevis (CH3OH),
l
/nm: 213, 330 nm; 1H NMR (400 MHz, CD3OD):
(m, 1H), 7.68 (dd, J¼6.0, 2.5 Hz, 1H), 7.62 (d, J¼8.9 Hz, 1H), 7.27 (t,
d
8.60 (s, 1H), 8.40 (d, J¼8.3 Hz, 1H), 8.14 (s, 1H), 7.89 (t, J¼7.6 Hz,
J¼4.3 Hz, 1H); ESI-MS for C14H8N3Cl2F [MþH]þ: calcd: 309.13,
found: 309.08. Anal. Calcd for C14H8N3Cl2F: C, 54.57; H, 2.62; N,
13.64. Found: C, 54.55; H, 2.36; N, 13.69.
1H), 7.79 (dd, J¼16.4, 6.0 Hz, 2H), 7.65 (t, J¼7.6 Hz, 1H), 7.32 (d,
J¼5.5 Hz, 2H), 5.49 (s, 1H); ESI-MS for C14H10N3Br [MþH]þ: calcd:
301.15, found: 301.08. Anal. Calcd for C14H10N3Br: C, 56.02; H, 3.35;
N, 13.99. Found: C, 56.37; H, 3.06; N, 13.91.
4.5.16. 5-Chloro-N-(3-chloro-4-fluorophenyl)quinazolin-4-amine
(13f). The title compound was obtained in 92.1% yield, by con-
densing 12f (0.83 g, 0.004 mol) with 3-chloro-4-
fluorobenzenamine (0.58 g, 0.004 mol), as a white solid of 1.15 g.
Mp 168e172 ꢀC; IR (KBr): 3393.77, 3119.57, 1620.82, 1574.52,
1501.99, 1425.33, 1264.46, 880.81, 817.43, 797.48 cmꢁ1; UVevis
4.5.11. N-(3-Chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine
(13a). The title compound was obtained in 91.2% yield, by con-
densing 12a (2.17 g, 0.01 mol) with 3-chloro-4-fluorobenzenamine
(1.47 g, 0.01 mol), as a yellow solid of 2.90 g. Mp 279e281 ꢀC; IR
(KBr): 3307.68, 3096.44,1625.21, 1587.82, 1573.43,1595.99,1538.13,
(CH3OH), l d 8.54 (s,
/nm: 213, 281, 339; 1H NMR (400 MHz, CD3OD):
1435.48, 1340.91, 875.17, 848.54, 809.04 cmꢁ1; UVevis (CH3OH),
l/
1H), 8.05 (dd, J¼6.7, 2.6 Hz,1H), 7.76 (d, J¼2.2 Hz, 2H), 7.70e7.67 (m,
nm: 218, 240, 359; 1H NMR (400 MHz, CD3OD):
d
9.51 (d, J¼2.2 Hz,
1H), 7.62 (dd, J¼6.1, 4.1 Hz, 1H), 7.28 (t, J¼8.9 Hz, 2H); HRMS for
1H), 8.70 (s, 1H), 8.63 (dd, J¼9.2, 2.3 Hz, 1H), 8.09 (dd, J¼6.6, 2.5 Hz,
1H), 7.95 (d, J¼9.2 Hz, 1H), 7.74 (dd, J¼7.9, 3.8 Hz, 1H), 7.30 (t,
J¼8.9 Hz, 1H); ESI-MS for C14H8N4O2ClF [MþH]þ: calcd: 319.69,
found: 319.08. Anal. Calcd for C14H8N4O2ClF: C, 52.76; H, 2.53; N,
17.58. Found: C, 52.01; H, 2.61; N, 17.48.
C
14H8N3Cl2F [MþH]þ: calcd: 309.1373, found: 309.0173. Anal. Calcd
for C14H8N3Cl2F: C, 54.57; H, 2.62; N,13.64. Found: C, 54.63; H, 2.56;
N, 13.58.
4.5.17. PD153035 (1). The title compound was obtained in 90.2%
yield, by condensing 12g (the crude brown liquid) with 3-bromo-
benzenamine (1.54 g, 0.009 mol), as a white solid of 2.02 g. Mp
247e249 ꢀC; IR (KBr): 3350.23, 3007.13, 1690.02, 1598.99, 1579.96,
4.5.12. N-(3-Chloro-4-fluorophenyl)-6-fluoroquinazolin-4-amine
(13b). The title compound was obtained in 93.2% yield, by con-
densing 12b (1.90, 0.01 mol) with 3-chloro-4-fluorobenzenamine
(1.47 g, 0.01 mol), as a white solid of 2.71 g. Mp 225e228 ꢀC; IR
(KBr): 3303.48, 3035.25,1672.97, 1613.01, 1577.05, 1495.78, 1420.65,
1515.84, 1472.68, 878.37, 788.69, 550.12 cmꢁ1; UVevis (CH3OH),
l/
nm: 223, 251, 333; 1H NMR (400 MHz, CD3OD):
d 8.51 (s, 1H), 8.07
(s, 1H), 7.79 (s, 1H), 7.75e7.70 (m, 1H), 7.35e7.29 (m, 2H), 7.18 (s,
1H), 5.49 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H); HRMS for C16H14N3Br
[MþH]þ: calcd: 329.2066, found: 329.0051. Anal. Calcd for
1328.01, 887.64, 873.21, 844.79, 810.61 cmꢁ1; UVevis (CH3OH),
l/
nm: 213, 286, 337; 1H NMR (400 MHz, CD3OD):
d 8.58 (s, 1H), 8.16
(dd, J¼9.6, 2.7 Hz, 1H), 8.07 (dd, J¼6.7, 2.6 Hz, 1H), 7.87 (dd, J¼9.2,
5.3 Hz,1H), 7.72 (dd, J¼8.4, 2.8 Hz, 2H), 7.27 (t, J¼9.0 Hz,1H), 5.49 (s,
1H); HRMS for C14H8N3ClF2 [MþH]þ: calcd: 292.6830, found:
292.0446. Anal. Calcd for C14H8N3ClF2: C, 57.64; H, 2.76; N, 14.41.
Found: C, 57.55; H, 2.48; N, 14.56.
C16H14N3Br: C, 58.55; H, 4.29; N, 12.80. Found: C, 58.48; H, 4.19; N,
12.91.
Acknowledgements
The present work was supported by the Program for Changjiang
Scholars and Innovative Research Team in University (No. IRT1174),
the National Natural Science Foundation of China (No. 20872118,
30070905), the Key Lab Fund of Shaanxi Province of China (No.
2010JS097, 11JS090, 12JS110) and the Foundation of the Education
Department of Shaanxi Province (12JK1010).
4.5.13. N-(3-Chloro-4-fluorophenyl)-6-methylquinazolin-4-amine
(13c). The title compound was obtained in 88.9% yield, by con-
densing 12c (1.86 g, 0.01 mol) with 3-chloro-4-fluorobenzenamine
(1.47 g, 0.01 mol), as a yellow solid of 2.55 g. Mp 223e224 ꢀC; IR
(KBr): 3330.07, 3041.11, 1677.04, 1618.89, 1572.27, 1498.63, 1440.12,
1236.07, 880.78, 829.95, 657.94 cmꢁ1; UVevis (CH3OH),
l
/nm: 220,
289, 335; 1H NMR (400 MHz, CD3OD):
d
8.54 (s, 1H), 8.19 (s, 1H),
Supplementary data
8.05 (dd, J¼6.7, 2.6 Hz, 1H), 7.75e7.69 (m, 3H), 7.27 (t, J¼8.9 Hz, 1H),
2.58 (s, 3H); HRMS for C15H11N3ClF [MþH]þ: calcd: 288.7192,
found: 288.0694. Anal. Calcd for C15H11N3ClF: C, 62.62; H, 3.85; N,
14.60. Found: C, 62.25; H, 3.58; N, 14.63.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.12.028.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
4.5.14. 8-Chloro-N-(3-chloro-4-fluorophenyl)quinazolin-4-amine
(13d). The title compound was obtained in 90.1% yield, by con-
densing 12d (2.06 g, 0.01 mol) with 3-chloro-4-fluorobenzenamine
(1.47 g, 0.01 mol), as a white solid of 2.78 g. Mp 261e263 ꢀC; IR
(KBr): 3290.11, 3077.87, 1694.13, 1603.57, 1571.84, 1500.01, 1483.22,
References and notes
1. Wissner, A.; Fraser, H. L.; Ingalls, C. L. Bioorg. Med. Chem. 2007, 15, 3635e3648.
2. Deng, W.; Guo, Z. R.; Guo, Y. S. Bioorg. Med. Chem. Lett. 2006, 16, 469e472.
3. Carmi, C.; Galvani, E. Eur. J. Med. Chem. 2012, 55, 2251e2264.
4. Li, R. D.; Zhang, X.; Li, Q. Y. Bioorg. Med. Chem. Lett. 2011, 21, 3637e3640.
5. David, W. F.; Alan, J. K.; Amy, M. M. Science 1994, 265, 1093e1095.
6. Rewcastle, G. W.; Denny, W. A.; Showalter, H. D. H. Curr. Org. Chem. 2000, 4,
679e706.
7. Szczepankiewicz, W.; Suwinski, J.; Bujok, R. Tetrahedron 2000, 56, 9343e9349.
8. Marzaro, G.; Guiotto, A.; Pastorini, G. Tetrahedron 2010, 66, 962e968.
9. Kulkarni, A. A.; Kalyani, V. S.; Joshi, R. A.; Joshi, R. R. Org. Process Res. Dev. 2009,
13, 999e1002.
1279.80, 871.7, 835.27, 790.94, 720.57 cmꢁ1; UVevis (CH3OH),
l/
nm: 215, 291, 330; 1H NMR (400 MHz, CD3OD):
d 8.59 (s, 1H), 8.31
(s, 1H), 8.07 (d, J¼4.2 Hz, 1H), 7.94 (d, J¼7.1 Hz, 1H), 7.75e7.69 (m,
1H), 7.28 (t, J¼8.9 Hz, 2H), 5.49 (s, 1H); HRMS for C14H8N3Cl2F
[MþH]þ: calcd: 309.1373, found: 309.0174. Anal. Calcd for
C
14H8N3Cl2F: C, 54.57; H, 2.62; N, 13.64. Found: C, 54.36; H, 2.55; N,
13.70.
10. Madapa, S.; Tusi, A.; Srivastava, K. Bioorg. Med. Chem. 2009, 17, 222e234.
11. Marvania, B.; Lee, P. C.; Chaniyara, R. Bioorg. Med. Chem. 2011, 19, 1987e1998.
12. Paul, R.; Otto, S. Helv. Chim. Acta 1935, 181, 1229e1239.
13. Li, J. R.; Chen, X.; Shi, D. X.; Zhang, Q.; Wei, X.; Li, Y. CHN. Patent 101693675 A,
2010.
4.5.15. 7-Chloro-N-(3-chloro-4-fluorophenyl)quinazolin-4-amine
(13e). The title compound was obtained in 89.6% yield, by con-
densing 12e (0.83 g, 0.004 mol) with 3-chloro-4-fluoro
benzenamine (0.58 g, 0.004 mol), as a white solid of 1.08 g. Mp
198e201 ꢀC; IR (KBr): 3395.78, 3117.85, 1620.2, 1574.8, 1501.71,
14. Jung, F. H.; Pasquent, G.; Lohmann, J.-J. M.; Warin, N.; Renaud, F. J. Med. Chem.
2006, 49, 955e970.
1448.09, 1298.29, 876.22, 817.22, 701.25 cmꢁ1; UVevis (CH3OH),
l/
15. Chandregowda, V.; Rao, G. V.; Reddy, C. C. Org. Process Res. Dev. 2007, 11,
813e816.
16. Bursavich, M. G.; Gilbert, A. M.; Lombardi, S.; Georigiadis, K. E.; Flannery, C. R.;
Morris, E. A. Bioorg. Med. Chem. Lett. 2007, 17, 5630e5633.
nm: 215, 286, 334; 1H NMR (400 MHz, CD3OD):
(s, 1H), 8.36 (d, J¼8.9 Hz, 1H), 8.04 (dd, J¼6.5, 2.9 Hz, 1H), 7.79e7.76
d 8.58 (s, 1H), 8.54

Z. Wang et al. / Tetrahedron 70 (2014) 906e913
913
17. Campagna, F.; Catto, M.; Purgatorio, R.; Altomare, C. D.; Carotti, A.; Stradis, A. D.;
Palazzo, G. Eur. J. Med. Chem. 2011, 46, 275e284.
18. Saari, R.; Torma, J. C.; Nevalainen, T. Bioorg. Med. Chem. 2011, 19, 939e950.
19. Berger, M.; Albrecht, B.; Berces, A.; Ettmayer, P.; Neruda, W.; Woisetschlager, M.
J. Med. Chem. 2001, 44, 3031e3038.
22. Grigis, N. S.; Moeller, J.; Pedersen, E. B. Chem. Scr. 1986, 26, 617e621.
23. Fernandes, C.; Oliveira, C.; Gano, L.; Bourkoula, A.; Pirmettis, L.; Santos, I. Bioorg.
Med. Chem. 2007, 15, 3974e3980.
24. Giovanni, M.; Adriano, G.; Giovanni, P.; Adriana, C. Tetrahedron 2010, 4,
962e968.
20. Agrawal, V. K.; Sharma, S.; Iyer, R. N.; Chatterjee, R. K.; Sen, A. B. Indian J. Chem.,
25. Liu, L. T.; Yuan, T. T.; Liu, H. H.; Chen, S. F.; Wu, Y. T. Bioorg. Med. Chem. Lett. 2007,
17, 6373e6377.
Sect. B 1980, 19, 1084e1087.
21. Breza, N.; Pato, J.; Opfi, L.; Banhegyi, P. J. Recept. Signal. Transduct. Res. 2008, 28,
361e373.