One-pot synthesis of 4-aminoquinazolines by hexamethyldisilazane-mediated reaction of quinazolin-4(3h)-ones with amines

Article abstract of DOI:10.1080/00397911.2010.519843

Hexamethyldisilazane-mediated reaction of quinazolin-4(3H)-ones with primary amines led to facile formation of 4-aminoquinazolines through tandem silylation and substitution in a single pot. Excellent yields of the products (83-97%) and environmental friendliness (avoiding the use of chlorination reagents) are the advantages of this method. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.519843

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One-Pot Synthesis of 4-
Aminoquinazolines by
Hexamethyldisilazane-Mediated Reaction
of Quinazolin-4(3H)-ones with Amines
Zhen-Lu Shen a , Xiao-Fei He a , Yi-Ming Hong a , Xin-Quan Hu a ,
Wei-Min Mo a , Bao-Xiang Hu a & Nan Sun a
a College of Chemical Engineering and Materials Science , Zhejiang
University of Technology , Hangzhou , China
Accepted author version posted online: 30 Jun 2011.Published
online: 09 Jun 2011.
To cite this article: Zhen-Lu Shen , Xiao-Fei He , Yi-Ming Hong , Xin-Quan Hu , Wei-Min Mo , Bao-
Xiang Hu & Nan Sun (2011) One-Pot Synthesis of 4-Aminoquinazolines by Hexamethyldisilazane-
Mediated Reaction of Quinazolin-4(3H)-ones with Amines, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:24, 3644-3653, DOI:
10.1080/00397911.2010.519843
To link to this article: http://dx.doi.org/10.1080/00397911.2010.519843
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Synthetic Communications1, 41: 3644–3653, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.519843
ONE-POT SYNTHESIS OF 4-AMINOQUINAZOLINES BY
HEXAMETHYLDISILAZANE-MEDIATED REACTION OF
QUINAZOLIN-4(3H)-ONES WITH AMINES
Zhen-Lu Shen, Xiao-Fei He, Yi-Ming Hong, Xin-Quan Hu,
Wei-Min Mo, Bao-Xiang Hu, and Nan Sun
College of Chemical Engineering and Materials Science, Zhejiang University
of Technology, Hangzhou, China
GRAPHICAL ABSTRACT
Abstract Hexamethyldisilazane-mediated reaction of quinazolin-4(3H)-ones with primary
amines led to facile formation of 4-aminoquinazolines through tandem silylation and substi-
tution in a single pot. Excellent yields of the products (83–97%) and environmental friend-
liness (avoiding the use of chlorination reagents) are the advantages of this method.
Keywords Amination; aminoquinazolines; hexamethyldisilazane; quinazolin-4(3H)-ones
INTRODUCTION
Heterocyclic compounds offer a high degree of structural diversity and have
proven to be broadly useful as therapeutic agents. Quinazoline derivatives are an
important class of nitrogen-containing heterocycles, which display a wide variety
of biological activities such as anticonvulsant,[1] antihypertensive, vasodilator,[2]
anti-inflammatory,[3] and antibiosis[4] activities and has been used as fibrinogen
receptor antagonists,[5] nanomolar Hedgehog antagonists,[6] and specific matrix
metalloproteinase-13 inhibitors.[7] Among the family of quinazolines, 4-aminoquina-
zolines have received particular interest because of their pharmacological
properties.[8–12] Gefitinib [ZD1839, Iressa, 4-(30-chloro-40-fluroanilino)-7-methoxy-6-
(3-morpholinopropoxy) quinazoline], derived from 4-aminoquinazolines, has
Received September 20, 2009.
Address correspondence to Zhen-Lu Shen or Wei-Min Mo, College of Chemical Engineering and
Materials Science, Zhejiang University of Technology, Hangzhou 310014, China. E-mail: zhenlushen@
zjut.edu.cn or mowm@zjut.edu.cn
3644

SYNTHESIS OF 4-AMINOQUINAZOLINES
3645
Scheme 1. One-pot synthesis of 4-aminoquinazolines mediated by HMDS.
already been approved by the U.S. Food and Drug Administration for the treatment
of advanced non-small-cell lung cancer (NSCLC).[13]
Generally, 4-aminoquinazolines are obtained through SNAr substitution of
4-chloroquinazolines with the appropriate amines, while 4-chloroquinazolines are
prepared from the corresponding quinazolin-4(3H)-ones via a chlorination reaction.
The chlorination reagents include SOCl2, POCl3, and PCl5, and the chlorination
reactions are often performed under harsh conditions.[8–14] However, several disad-
vantages exist in this method for the synthesis of 4-aminoquinazolines. These chlori-
nation reagents are not environmentally benign, and the chlorination conditions may
destroy sensitive functional groups in the molecules. In addition, many of 4-chloro-
quinazolines are moisture sensitive and will hydrolyze to quinazolin-4(3H)-ones. To
overcome these inherent problems, recently some efficient phosphonium reagents,
such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
(BOP), have been developed to active quinazolin-4(3H)-ones and successfully avoid
the chlorination step during the synthesis of 4-aminoquinazolin-4(3H)-ones.[15,16]
However, these reagents are usually very expensive, and most of them are toxic.
Herein, we report a hexamethyldisilazane (HMDS)–mediated, single-pot, facile syn-
thesis of 4-aminoquinazolines from quinazolin-4(3H)-ones and amines in excellent
yield (Scheme 1).
RESULTS AND DISCUSSION
It was reported that HMDS could in situ activate the hydroxyl group in
N-heterocycles via silylation to enable the substitution by primary amines.[17–20]
Quinazolin-4(3H)-ones 1, as the conventional tautomerizable heterocycle, possessed
=
the common interconvertible structural unit [ꢀC( O)ꢀNHꢀ] (lactam form) and
=
[ꢀC(ꢀOH) N-] (phenol form). We speculated that the silylation of the phenol form
could occurr in situ and the resulting reactive intermediate 2 could readily
undergo the substitution by primary amines to generate 4-aminoquinazolines 3
(Scheme 1).
After carefully optimizing the reaction conditions, we were pleased to find that
the amination of quinazolin-4(3H)-one 1a with benzylamine mediated by HMDS
could be completed in 2 h. The crude product was purified by column chromato-
graphy to afford product 3a with excellent yield (97%). Subsequently, to examine
the efficiency and applicability of this protocol, the reaction was extended to other
substituted quinazolin-4(3H)-ones and substituted primary amines. To our delight,

3646
Z.-L. SHEN ET AL.
these reactions proceeded smoothly to afford a series of 4-aminoquinazoline
derivatives 3 in excellent yields (Table 1, entries 2–15). Only reaction times showed
the effects of substituents to the activity. The strong electron-withdrawing nitro
group would efficiently active quinazoline structure, and the reaction time of amina-
tion of 1i with benzylamine could be shortened to 1.5 h (Table 1, entry 9). When
5-methyl-1H-pyrazol-3-amine was used as the amination reagent, complete conver-
sion of 1a could not be achieved though the reaction time was prolonged to 14 h
(Table 1, entry 15). The experimental results listed in Table 1 showed that the scope
of the reaction is quite broad in regard to the quinazolin-4(3H)-ones and primary
amines.
As a contrast, quinazolin-4(3H)-ones 1 were chlorinated with POCl3 to gener-
ate 4-chloroquinazolines. In most cases, the yields of the chlorination products were
in a range of 38% to 87% (1a 72%, 1c 87%, 1d 82%, 1f 80%, 1g 70%, 1h 41%, 1i 38%,
and 1j 85%). Though chlorination of 5-methylquinazolin-4(3H)-one 1b or
5-chloroquinazolin-4(3H)-one 1e has been reported,[21] the major products were
not the desired compounds when they were chlorinated under our reaction con-
ditions. The infrared (IR) spectra of chlorination product of 1e showed a peak at
1694 cmꢀ1, which might be attributed to a carbonyl group. Its spectral data are listed
as follows: 1H NMR (CDCl3), d 7.69–7.71 (m, 1H), 7.79–7.80 (m, 1H), 7.87–7.91 (m,
1H), 7.98–8.00 (m, 1H), 8.12–8.15 (t, 1H, J ¼ 8 Hz), 8.25–8.27 (m, 1H), 8.71 (s, 1H),
9.52 (s, 1H). 13C NMR (CDCl3), d 118.32, 119.41, 127.31, 127.89, 128.63, 130.48,
131.86, 132.95, 135.30, 135.39, 145.88, 150.08, 153.21, 154.61, 155.73, 158.46. HRMS
(ESI), m=z, 343.0152 [M þ Hþ]. Based on this information, we can conclude that its
molecular formula should be C16H8Cl2N4O and its structure was assigned in Fig. 1.
The chlorination product of 1b was also presented in Fig. 1. It is obvious that the
one-pot HMDS-mediated synthesis of 4-aminoquinazolines was more powerful than
the traditional synthetic method with a separate chlorination step of quinazolin-4(3-
H)-ones.
In conclusion, we have developed an efficient method for the synthesis of
4-aminoquinazolines by HMDS-mediated reaction of quinazolin-4(3H)-ones with
primary amines. Excellent yields of the products and environmental friendliness
are the advantages of this method.
EXPERIMENTAL
Melting points were measured using an XRL-1 melting-point instrument and
were uncorrected. Fourier transform (FT)–IR spectra were recorded on a Nicolet
instrument, Avetar 370. 1H NMR and 13C NMR spectra were obtained on a Bruker
Avance III (500 MHz) spectrometer. Dimethylsulfoxide (DMSO-d6) and CDCl3
were used as solvents with tetramethylsilane (TMS) as the internal standard.
High-resolution mass spectra (HRMS) were recorded on an Agilent 6210 LC=
TOF mass spectrometer. The reactions were monitored by thin-layer chromato-
graphy (TLC) associating with gas chromatography (GC) or high-performance
liquid chromatography (HPLC). Quinazolin-4(3H)-ones were synthesized from
anthranilic acids and amidines-acetate, and their structures were confirmed by mass
1
spectrometry (MS), H NMR, and 13C NMR. Other reagents were purchased from
suppliers and used without any further treatment.

SYNTHESIS OF 4-AMINOQUINAZOLINES
3647
Table 1. Synthesis of 4-aminoquinazolines by HMDS-mediated reaction of quinazolin-4(3H)-ones with
aminesa
Entry
1
Quinazolin-4(3H)-ones
Amines
Time (h)
Products
Yieldb (%)
2
97
2c
14
2
88
95
3
4
4.5
92
5
6
2
3
93
93
95
92
95
93
95
7
2
8
2
9
1.5
2.5
10
11d
12
1.5
2
96
(Continued )

3648
Z.-L. SHEN ET AL.
Table 1. Continued
Entry
Quinazolin-4(3H)-ones
Amines
Time (h)
Products
Yieldb (%)
13c
14
13
92
95
14
15c
14
83
aN(Quinazolin-4(3H)-one)=N(amine)=N(HMDS)=N[(NH4)2SO4] ¼ 1:1.4:1.4:0.1.
bYields refer to isolated pure products.
cN(Quinazolin-4(3H)-one)=N(amine)=N(HMDS)=N[(NH4)2SO4] ¼ 1:2:2:0.1.
dThe reaction was performed in a sealed vessel.
General Procedure for Synthesis of 4-Aminoquinazolines Mediated
by HMDS
Quinazolin-4(3H)-ones
1
(0.40 mmol), amines (0.56 mmol), HMDS
(0.56 mmol), and (NH4)2SO4 (0.04 mmol) were added to a 5-mL glass tube with mag-
netic stirring bar. Then the tube was placed in an oil bath, which was preheated to
125 ꢁC. The mixture was stirred for 1.5–16 h. After completion of the reaction, the
reaction mixture was allowed to cool to room temperature. Then it was diluted with
CH2Cl2 and purified through a column of silica gel to obtain the pure product 3. All
of the new compounds were characterized by IR, 1H NMR, 13C NMR, and HRMS.
Figure 1. Chlorination products of 1b and 1e.

SYNTHESIS OF 4-AMINOQUINAZOLINES
3649
General Procedure for the Chlorination of Quinazolin-4(3H)-ones
with POCl3
Quinazolin-4(3H)-ones 1 (8 mmol), 20 mL of POCl3, and 1 mL of diisopropy-
lethylamine were added to a 100-mL flask. After refluxing for 2.5 h, the reaction mix-
ture was concentrated in vacuo. The residue was dissolved in cold dichloromethane
and washed with cold 1 M HCl (100 mL ꢂ 2). After drying over MgSO4 and filtering,
K2CO3 was added to the organic layer to neutralize the residual acid. Then the
organic phase was concentrated, and the resulting residue was chromatographed
on silica gel to afford the desired product 4-chloroquinazolines.
Data
N-Benzylquinazolin-4-amine (3a).[22] White solid, mp 168–170 ꢁC. IR nmax
1
(KBr)=cmꢀ1 3228, 3060, 2966, 2935, 1619, 1575, 1541, 1495, 1415, 1340. H NMR
(CDCl3) d 8.71 (s, 1H), 7.86 (d, J ¼ 8.0 Hz,1H), 7.71–7.76 (m, 2H), 7.31–7.47(m,
6H), 6.07 (br, s, 1H), 4.88 (d, J ¼ 5.5 Hz, 2H). 13C NMR (CDCl3) d 159.35,
155.46, 149.50, 138.09, 132.77, 128.95, 128.69, 128.12, 127.89, 126.18, 120.57,
114.88, 45.43. MS (ESI) m=z 250.1 (M þ Hþ).
N-Benzyl-5-methylquinazolin-4-amine (3b). Pale yellow oil. IR nmax
1
(KBr)=cmꢀ1 3498, 3060, 3029, 2924, 2872, 1578, 1524, 1349. H NMR (CDCl3) d
8.61 (s, 1H), 7.71 (d, J ¼ 8.0 Hz, 1H), 7.55–7.58 (m, 1H), 7.31–7.43 (m, 5H), 7.20
(d, J ¼ 7.0 Hz, 1H), 6.35 (br, s, 1H), 4.85 (d, J ¼ 5.0 Hz, 2H), 2.84 (s, 1H). 13C
NMR (CDCl3) d 160.72, 154.60, 151.45, 138.18, 132.75, 131.87, 129.18, 128.93,
127.80, 127.72, 127.04, 115.45, 46.02, 24.32. HRMS (ESI) m=z 250.1332 (M þ Hþ),
calcd. for C16H15N3 þ Hþ ¼ 250.1339.
N-Benzyl-6-methylquinazolin-4-amine
(3c).[23] White
solid,
mp
182–184 ꢁC. IR nmax (KBr)=cmꢀ1 3275, 1584, 1538, 1420, 1352, 1314. H NMR
(CDCl3) d 8.67 (s, 1H), 7.77 (d, J ¼ 8.5 Hz, 1H), 7.56–7.58 (m, 1H), 7.46 (s, 1H),
7.33–7.43 (m, 5H), 5.93 (br, s, 1H), 4.87 (d, J ¼ 5.5 Hz, 2H), 2.49 (s, 3H). 13C
NMR (CDCl3) d 159.00, 154.70, 147.79, 138.29, 136.15, 134.58, 128.89, 128.38,
128.10, 127.79, 119.75, 114.73, 45.39, 21.69. MS (ESI) m=z 250.1 (M þ Hþ).
1
N-Benzyl-8-methylquinazolin-4-amine (3d). White solid, mp 156–158 ꢁC.
IR nmax (KBr)=cmꢀ1 3250, 3126, 2935, 1585, 1531, 1492, 1417, 1357, 1329. 1H
NMR (CDCl3) d 8.78 (s, 1H), 7.60 (d, J ¼ 7.0 Hz, 1H), 7.54 (d, J ¼ 8.0 Hz, 1H),
7.32–7.42 (m, 6H), 5.96 (br, s, 1H), 4.87 (d, J ¼ 5.5 Hz, 2H), 2.71 (s, 3H). 13C
NMR (CDCl3) d 159.67, 154.43, 148.47, 138.22, 136.85, 132.93, 128.90, 128.04,
127.80, 125.59, 118.14, 114.59, 45.47, 17.98. HRMS (ESI) m=z 250.1353 (M þ Hþ),
calcd. for C16H15N3 þ Hþ ¼ 250.1339.
N-Benzyl-5-chloroquinazolin-4-amine (3e). White solid, mp 60–62 ꢁC. IR
1
nmax (KBr)=cmꢀ1 3430, 3059, 3026, 2925, 1606, 1577, 1533, 1484, 1401, 1341. H
NMR (CDCl3) d 8.61 (s, 1H), 8.04 (br, s, 1H), 7.75–7.76 (m, 1H), 7.57 (t, J ¼ 8.0 Hz,
1H), 7.30–7.43 (m, 6H), 4.86 (d, J ¼ 5.0 Hz, 2H). 13C NMR (CDCl3) d 158.87,
155.39, 152.22, 137.81, 131.89, 128.84, 128.45, 128.17, 128.07, 127.72, 127.64,

3650
Z.-L. SHEN ET AL.
113.14, 45.82. HRMS (ESI) m=z 270.0793 (M þ Hþ), calcd. for
C15H12ClN3 þ Hþ ¼ 270.0793.
N-Benzyl-6-chloroquinazolin-4-amine (3f). White solid, mp 170–172 ꢁC.
IR nmax (KBr)=cmꢀ1 3232, 3101, 3072, 2964, 1572, 1542, 1493, 1418, 1340, 1324.
1H NMR (CDCl3) d 8.69 (s, 1H), 7.81(d, J ¼ 9.5 Hz, 1H), 7.66–7.68 (m, 2H),
7.32–7.42 (m, 5H), 5.91 (br, s, 1H), 4.86 (d, J ¼ 5.5 Hz, 2H). 13C NMR (CDCl3) d
158.53, 155.61, 148.09, 137.77, 133.40, 131.52, 130.34, 128.94, 128.11, 127.94,
120.11, 115.56, 45.50. HRMS (ESI) m=z 270.0793 (M þ Hþ), calcd. for
C15H12ClN3 þ Hþ ¼ 270.0792.
N-Benzyl-7-chloroquinazolin-4-amine (3g). White solid, mp 180–181 ꢁC.
IR nmax (KBr)=cmꢀ1 3444, 3217, 3101, 3028, 2964, 1609, 1570, 1540, 1446, 1338.
1H NMR (CDCl3) d 8.68 (s, 1H), 7.84 (d, J ¼ 2.0 Hz, 1H), 7.65 (d, J ¼ 9.0 Hz,
1H), 7.31–7.40 (m, 6H), 6.07 (br, s, 1H), 4.86 (d, J ¼ 5.5 Hz, 2H). 13C NMR (CDCl3)
d 159.19, 156.41, 150.40, 138.78, 137.80, 128.92, 128.09, 127.92, 127.72, 126.87,
122.17, 113.23, 45.45. MS (ESI) m=z 270.1 (M þ Hþ).
N-Benzyl-7-fluoroquinazolin-4-amine (3h). White solid, mp 202–203 ꢁC.
IR nmax (KBr)=cmꢀ1 3240, 3074, 3030, 2935, 1627, 1579, 1544, 1458, 1340. 1H
NMR (CDCl3) d 8.68 (s, 1H), 7.72–7.75 (m, 1H), 7.48–7.50 (m, 1H), 7.31–7.42 (m,
5H), 7.18–7.22 (m, 1H), 6.02 (br, s, 1H), 4.87 (d, J ¼ 5.0 Hz, 2H). 13C NMR
(DMSO-d6) d 164.38 (d, J ¼ 401.98 Hz), 159.21, 156.20, 151.21 (d, J ¼ 20.2 Hz),
139.24, 128.31, 127.23, 126.81, 125.94 (d, J ¼ 16.16 Hz), 115.04 (d, J ¼ 38.38 Hz),
112.04, 111.41 (d, J ¼ 32.32 Hz), 43.56. HRMS (ESI) m=z 254.1096 (M þ Hþ), calcd.
for C15H12FN3 þ Hþ ¼ 254.1088.
N-Benzyl-6-nitroquinazolin-4-amine (3i).[24] Yellow solid, mp 226–228 ꢁC.
IR nmax (KBr)=cmꢀ1 3234, 3084, 3028, 2929, 1625, 1585, 1495, 1446, 1328.1H NMR
(CDCl3) d 8.81 (s, 1H), 8.71 (d, J ¼ 2.0 Hz, 1H), 8.50–8.53 (m, 1H), 7.96 (d,
J ¼ 9.5 Hz, 1H), 7.37–7.45 (m, 5H), 6.28 (br, s, 1H), 4.92(d, J ¼ 5.5 Hz, 2H). 13C
NMR (DMSO-d6) d 160.23, 158.23, 152.82, 144.06, 138.62, 129.13, 128.35, 127.49,
126.99, 126.32, 120.61, 114.04, 43.90. MS (ESI) m=z 281.1 (M þ Hþ).
N-Benzyl-2-methylquinazolin-4-amine
(3j).[25] White
solid,
mp
180–184 ꢁC. IR nmax (KBr)=cmꢀ1 3427, 3219, 3115, 1575, 1539, 1386, 1353. 1H
NMR (CDCl3) d 7.79 (d, J ¼ 8.5 Hz, 1H), 7.65–7.70 (m, 2H), 7.30–7.42 (m, 6H),
5.94 (br, s, 1H), 4.88 (d, J ¼ 5.5 Hz, 2H), 2.67 (s, 3H). 13C NMR (CDCl3) d
164.45, 159.26, 150.02, 138.47, 132.56, 128.79, 128.17, 127.76, 127.69, 125.11,
120.44, 112.87, 45.24, 26.61. MS (ESI) m=z 250.1 (M þ Hþ).
N-Butylquinazolin-4-amine (3k).[15] Yellow solid, mp 107–110 ꢁC. IR nmax
(KBr)=cmꢀ1 3258, 3129, 2959, 2922, 2855, 1619, 1578, 1543, 1470, 1422, 1348,
1
1324. H NMR (CDCl3) d 8.67 (s, 1H), 7.84 (d, J ¼ 8.5 Hz, 1H), 7.68–7.76 (m,
2H), 7.46–7.49 (m, 1H), 5.67 (br, s, 1H), 3.65–3.69 (m, 2H), 1.72–1.75 (m, 2H),
1.47–1.51 (m, 2H), 1.00 (t, J ¼ 7.5 Hz, 3H). 13C NMR (CDCl3) d 159.54, 155.52,
149.42, 132.53, 128.64, 125.94, 120.46, 115.00, 41.19, 31.48, 20.27, 13.89. MS (ESI)
m=z 202.1 (M þ Hþ).

SYNTHESIS OF 4-AMINOQUINAZOLINES
3651
N-Octylquinazolin-4-amine (3l). Yellow solid, mp 60–62 ꢁC. IR nmax (KBr)=
cmꢀ1 3221, 2956, 2927, 2854, 1581, 1542, 1498, 1356, 1326. 1H NMR (CDCl3) d 8.67
(s, 1H), 7.84 (d, J ¼ 8.5 Hz, 1H), 7.71–7.74 (m, 2H), 7.44–7.47 (m, 1H), 5.90 (br, s,
1H), 3.64–3.68 (m, 2H), 1.72–1.75 (m, 2H), 1.26–1.45 (m, 10H), 0.88 (t, J ¼ 7.0 Hz,
3H). 13C NMR (CDCl3) d 159.54, 155.36, 149.15, 132.54, 128.44, 125.95, 120.47,
114.93, 41.49, 31.80, 29.38, 29.33, 29.22, 27.07, 22.63, 14.06. MS (ESI) m=z 258.2
(M þ Hþ).
N-Cyclohexylquinazolin-4-amine (3m).[16] White solid, mp 138–140 ꢁC. IR
nmax (KBr)=cmꢀ1 3450, 3235, 3058, 2932, 2854, 1617, 1579, 1535, 1497, 1426, 1362,
1
1323. H NMR (CDCl3) d 8.65 (s, 1H), 7.83 (d, J ¼ 8.5 Hz, 1H), 7.68–7.74 (m, 2H),
7.44–7.47 (m, 1H), 5.61 (d, J ¼ 7.0 Hz, 1H), 4.24–4.30 (m, 1H), 2.14–2.17 (m, 2H),
1.79–1.83 (m, 2H), 1.69–1.73 (m, 1H), 1.46–1.55 (m, 2H), 1.25–1.35 (m, 3H). 13C
NMR (CDCl3) d 158.67, 155.47, 149.38, 132.43, 128.48, 125.79, 120.42, 114.92,
49.65, 33.06, 25.66, 24.94. MS (ESI) m=z 227.6 (M þ Hþ).
N-(1-Phenylethyl)quinazolin-4-amine
(3n).[26] White
solid,
mp
106–108 ꢁC. IR nmax (KBr)=cmꢀ1 3250, 3059, 2980, 1619, 1575, 1531, 1419, 1358,
1
1318. H NMR (CDCl3) d 8.66 (s, 1H), 7.84 (d, J ¼ 8.0 Hz, 1H), 7.71–7.75 (m,
2H), 7.44–7.46 (m, 3H), 7.30–7.38 (m, 2H), 7.27–7.29 (m, 1H), 6.01 (d, J ¼ 7.0 Hz,
1H), 5.62–5.68 (m, 1H), 1.69 (d, J ¼ 6.5 Hz, 3H). 13C NMR (CDCl3) d 158.64,
155.43, 149.44, 143.24, 132.61, 128.83, 128.59, 127.57, 126.35, 126.02, 120.52,
114.87, 50.18, 21.78. MS (ESI) m=z 250.1 (M þ Hþ).
N-(5-Methyl-1H-pyrazol-3-yl)quinazolin-4-amine (3o).[27] White solid, mp
279–280 ꢁC. IR nmax (KBr)=cmꢀ1 3271, 3177, 3072, 2928, 2868, 1625, 1599, 1550,
1483, 1403, 1320. 1H NMR (DMSO-d6) d 12.18 (br, s, 1H), 10.31 (br, s, 1H),
8.58–8.61 (m, 2H), 7.74–7.83 (m, 2H), 7.56 (t, J ¼ 7.5 Hz, 1H), 6.58 (br, s, 1H),
2.27 (m, 3H). 13C NMR (DMSO-d6) d 157.47, 155.00, 149.84, 147.67, 139.16,
133.25, 128.00, 126.57, 123.69, 115.49, 98.47, 11.45. HRMS (ESI) m=z 226.1083
(M þ Hþ), calcd. for C12H12N5 þ Hþ ¼ 226.1087.
ACKNOWLEGMENTS
The authors are grateful to the financial support of the National Natural
Science Foundation of China (NSFC, 20876149) and the Zhejiang Provincial
Natural Science Foundation of China (Y4090517).
REFERENCES
1. Hori, M.; Iemura, R.; Hara, H.; Ozaki, A.; Sukamoto, T.; Ohtaka, H. Novel 4-phenoxy-2-
(1-piperazinyl)quinazolines as potent anticonvulsive and antihypoxic agents. Chem.
Pharm. Bull. 1990, 38, 681.
2. Havera, H. J.; Vidrio, H. J. Derivatives of 1,3-disubstituted 2,4(1H,3H)-quinazolinediones
as possible peripheral vasodilators or antihypertensive agents. J. Med. Chem. 1979, 22,
1548.
3. Chao, Q.; Deng, L.; Shih, H.; Leoni, L. M.; Genini, D.; Carson, D. A.; Cottam,
H. B. Substituted isoquinolines and quinazolines as potential antiinflammatory

3652
Z.-L. SHEN ET AL.
agents: Synthesis and biological evaluation of inhibitors of tumor necrosis factor a. J.
Med. Chem. 1999, 42, 3860.
4. Kung, P. P.; Casper, M. D.; Cook, K. L.; Wilson-Lingardo, L.; Risen, L. M.; Vickers, T.
A.; Ranken, R.; Blyn, L. B.; Wyatt, J. R.; Cook, P. D.; Ecker, D. J. Structure–activity
relationships of novel 2-substituted quinazoline antibacterial agents. J. Med. Chem.
1999, 42, 4705.
5. Liverton, N. J.; Armstrong, D. J.; Claremon, D. A.; Remy, D. C.; Bardwin, J. J.; Lynch,
R. J.; Zhang, G.; Gould, R. J. Nonpeptide glycoprotein IIb=IIIa inhibitors: Substituted
quinazolinediones and quinazolinones as potent fibrinogen receptor antagonists. Bioorg.
Med. Chem. Lett. 1998, 8, 483.
6. Brunton, S. A.; Stibbard, J. H. A.; Rubin, L. L.; Kruse, L. I.; Guicherit, O. M.; Boyd, E. A.;
Price, S. Potent inhibitors of the hedgehog signaling pathway. J. Med. Chem. 2008, 51, 1108.
7. Li, J. J.; Nahra, J.; Johnson, A. R.; Bunker, A.; O’Brien, P.; Yue, W. S.; Ortwine, D. F.;
Man, C. F.; Baragi, V.; Kilgore, K.; Dyer, R. D.; Han, H. K. Quinazolinones and
pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13
inhibitors for the treatment of osteoarthritis. J. Med. Chem. 2008, 51, 835.
8. Liu, L. T.; Yuan, T. T.; Liu, H. H.; Chena, S. F.; Wub, Y. T. Synthesis and biological
evaluation of substituted 6-alkynyl-4-anilinoquinazoline derivatives as potent EGFR
inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 6373.
9. Mortlock, A. A.; Foote, K. M.; Heron, N. M.; Jung, F. H.; Pasquet, G.; Lohmann, J. J.
M.; Warin, N.; Renaud, F.; De Savi, C.; Roberts, N. J.; Johnson, T.; Dousson, C. B.; Hill,
G. B.; Perkins, D.; Hatter, G.; Wilkinson, R. W.; Wedge, S. R.; Heaton, S. P.; Odedra, R.;
Keen, N. J.; Crafter, C.; Brown, E.; Thompson, K.; Brightwell, S.; Khatri, L.; Brady, M.
C.; Kearney, S.; McKillop, D.; Rhead, S.; Parry, T.; Green, S. Discovery, synthesis, and
in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of Aurora B
kinase. J. Med. Chem. 2007, 50, 2213.
10. Rewcastle, G. W.; Palmer, B. D.; Bridges, A. J.; Showalter, H. D. H.; Sun, L.; Nelson, J.;
McMichael, A.; Kraker, A. J.; Fry, D. W.; Denny, W. A. Tyrosine kinase inhibitors, 9:
Synthesis and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors
of the tyrosine kinase activity of the epidermal growth factor receptor. J. Med. Chem.
1996, 39, 918.
11. Barlaam, B.; Ballard, P.; Bradbury, R. H.; Ducray, R.; Germain, H.; Hickinson, D. M.;
Hudson, K.; Kettle, J. G.; Klinowska, T.; Magnien, F.; Ogilvie, D. J.; Olivier, A.; Pearson,
S. E.; Scott, J. S.; Suleman, A.; Trigwell, C. B.; Vautier, M.; Whittaker, R. D.; Wood, R.
A new series of neutral 5-substituted 4-anilinoquinazolines as potent, orally active inhibi-
tors of erbB2 receptor tyrosine kinase. Bioorg. Med. Chem. Lett. 2008, 18, 674.
12. Luth, A.; Lowe, W. Syntheses of 4-(indole-3-yl)quinazolinese—A new class of epidermal
growth factor receptor tyrosine kinase inhibitors. Eur. J. Med. Chem. 2008, 43, 1478.
13. Barker, A. J.; Gibson, K. H.; Grundy, W.; Godfrey, A. A.; Barlow, J. J.; Healy, M. P.;
Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Scarlett, L.; Henthorn, L.; Richards, L.
Studies leading to the identification of ZD1839 (IressaTM): An orally active, selective
epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment
of cancer. Bioorg. Med. Chem. Lett. 2001, 11, 1911.
14. Zhang, Y. D.; Xu, C. L.; Houghten, R. A.; Yu, Y. P. Scaffold approach for solid-phase
synthesis of 2,3-disubstituted 8-arylamino-3H-imidazo[4,5-g]quinazolines. J. Comb.
Chem. 2007, 9, 9.
15. Wan, Z. K.; Wacharasindhu, S.; Binnun, E.; Mansour, T. An efficient direct amination of
cyclic amides and cyclic ureas. Org. Lett. 2006, 8, 2425.
16. Wan, Z. K.; Wacharasindhu, S.; Levins, C. G.; Lin, M.; Tabei, K.; Mansour, T. S. The
scope and mechanism of phosphonium-mediated SNAr reactions in heterocyclic amides
and ureas. J. Org. Chem. 2007, 72, 10194.

SYNTHESIS OF 4-AMINOQUINAZOLINES
3653
17. Singer, R. A.; Dore, M. Practical amination of nitropyridones by silylation. Org. Process
Res. Dev. 2008, 12, 1261.
18. Vorbruggen, H. Simple amination of aromatic hydroxy-nitrogen heterocycles. Angew.
Chem., Int. Ed. Engl. 1972, 11, 305.
19. Vorbruggen, H.; Krolikiewicz, K. Amination, III: Trimethylsilanol as leaving group, V:
Silylation–amination of hydroxy N-heterocycles. Chem. Ber. 1984, 117, 1523.
20. Nishikawa, S.; Kumazawa, Z.; Kashimura, N.; Maki, S. Nishikimi, Y. Sythesis and cyto-
kinin activity of 4- and 2,4-substituted pyrido[3,4-d]pyrimidines. Agric. Biol Chem. 1986,
50, 495.
21. Mitidieri-Costanza, A.; Sleiter, G. The reaction of 5-methyl-4-phenoxyquinazoline with
piperidine in isooctane: Further evidence for steric inhibition of bifunctional catalysis.
J. Prakt. Chem. 1985, 327, 865.
22. Gulevskaya, A. V.; Maes, B. U. W.; Meyers, C.; Herrebout, W. A.; van der Veken, B. J.
C–N bond formation by the oxidative alkylamination of azines: Comparison of
AgPy2MnO4 versus KMnO4 as oxidant. Eur. J. Org. Chem. 2006, 5305.
23. Breza, N.; Pato, J.; Orfi, L.; Hegymegi-Barakonyi, B.; Banhegyi, P.; Varkondi, E.;
Borbely, G.; Petak, I.; Keri, G. Synthesis and characterization of novel quinazoline type
inhibitors for mutant and wild-type EGFR and RICK kinases. J. Recept. Sig. Transd.
2008, 28, 361.
24. Hou, T. J.; Zhu, L. L.; Chen, L. R.; Xu, X. J. Mapping the binding site of a large set of
quinazoline type EGF-R inhibitors using molecular field analyses and molecular docking
studies. J. Chem. Inf. Comput. Sci. 2003, 43, 273.
25. Kurteva, V. B.; Zlatanova, V. N.; Dimitrov, V. D. Solvent-free synthesis of a series of
differently N-substituted 4-amino-2-methylquinazolines under microwave irradiation.
Arkivoc 2006, 1, 46.
26. Lee, Y. B.; Ahn, C. H. Quinazoline derivatives and therapeutic use thereof. U.S. Patent
Appl. 0187231, 2007.
27. Shen, Z. L.; Hong, Y. M.; He, X. F.; Mo, W. M.; Hu, B. X.; Sun, N.; Hu, X. Q. Switching
the chemoselectivity in the amination of 4-chloroquinazolines with aminopyrazoles. Org.
Lett. 2010, 12, 552.