Microwave assisted synthesis of novel 6,7,8-trimethoxy N-substituted-4- aminoquinazoline compounds

Article abstract of DOI:10.1002/jhet.5570450320

(Chemical Equation Presented) A fast, efficient and convenient reaction of 6,7,8-trimethoxy-4-chloroquinazoline and aryl (or benzyl) amines was achieved under microwave irradiation in isopropyl alcohol, providing a simple method for synthesis of novel 6,7,8-trimethoxy N-substituted-4-aminoquinazoline compounds in good yield in short time. The title compounds were evaluated for their in vitro anti-proliferative activities against PC3 cell by MTT method.

Full text of DOI:10.1002/jhet.5570450320

May-Jun 2008
759
Microwave Assisted Synthesis of Novel 6,7,8-Trimethoxy
N-Substituted-4-aminoquinazoline Compounds
Gang Liu,* Lin Sun, Chunping Liu, Chunnuan Ji, Quanwu Wen and Songmei Ma
School of Chemistry and Materials Science, Ludong University, Yantai 264025, P. R. of China
Received June 25, 2007
OMe
OMe
MeO
MeO
N
MeO
MeO
N
(i)
(HCl)n
N
N
Cl
NHR
R = aryl, benzyl
8
9
(i) aryl amines or benzyl amines, i-propanol, MW
A fast, efficient and convenient reaction of 6,7,8-trimethoxy-4-chloroquinazoline and aryl (or benzyl)
amines was achieved under microwave irradiation in isopropyl alcohol, providing a simple method for
synthesis of novel 6,7,8-trimethoxy N-substituted-4-aminoquinazoline compounds in good yield in short
time. The title compounds were evaluated for their in vitro anti-proliferative activities against PC3 cell by
MTT method.
J. Heterocyclic Chem., 45, 759 (2008).
chloroquinazoline and amines are refluxed at 80°C for
4-12 hours in isopropyl alcohol. This method, however,
involves long reaction times and complex handling and
gives low yields of products. In this paper, we wish to
report a rapid and convenient reaction using 6,7,8-
trimethoxy-4-chloroquinazoline and aryl (or benzyl)
amines for the synthesis of novel 6,7,8-trimethoxy N-
substituted-4-aminoquinazoline compounds under micro-
wave irradiation in short time in isopropyl alcohol
(Scheme 1). The new method requires short reaction
times, is very easy and mild and environmentally friendly.
To the best of our knowledge, this is the first report of the
rapid synthesis of novel 6,7,8-trimethoxy N-substituted-4-
INTRODUCTION
In recent years, quinazoline compounds have been
shown to possess biological activity in medicine and
pesticide. As part our ongoing research program on
heterocyclic compounds which may serve as leads for
designing novel antitumor agents regarding PD153035 [4-
(3-bromophenyl)amine-6,7-dimethoxyquinazoline] as the
leading compound, we were particularly interested in 4-
substituted quinazolines [1-3]. We considered the well
known activity of the quinazoline nucleus in
chemotherapy, where many of its substituted derivatives
are effective antitumor agents [4-7]. Furthermore, more
recent reported data has shown that a broad class of
quinazolines also act as potent and highly selective
inhibitors of epidermal growth factor receptor (EGFR) or
epidermal growth factor receptor tyrosine kinase (EGFR-
TK) [8-10]; members of this class are expected to have
great therapeutic potential in the treatment of malignant
and nonmalignant epithelial diseases [11,12]. In view of
these facts, and in order to study the influence of 4-
position and 8-position substituents on antitumor activity,
we have now prepared a series of novel 6,7,8-trimethoxy-
4-aryl(benzyl)aminoquinazolines starting from gallic acid
of natural materials, in the hope of discovering more
active ATP site inhibitors.
aminoquinazoline
irradiation.
compounds
under
microwave
RESULTS AND DISCUSSION
The reaction results with or without microwave
irradiation are shown in Table 1. It can be seen that the
presence of microwave irradiation both accelerated the
reactions and gave higher yields. The reaction time for
synthesis of compounds 9a-q was shortened from 360
minutes to only 10 minutes with the one-step microwave-
assisted procedure.
In order to optimize the reaction parameters, we
selected compound 9b for further study under different
conditions. These results are shown in Table 2. Without
microwave irradiation (Table 1) compound 9b could be
obtained in 47% after 360 minutes. When the reaction
was carried out under microwave irradiation at 80°C for 5
minutes, the yield of 9b was increased to 87%, and
increased further to 97% when the reaction time was
Microwave-assisted organic synthesis is a new and
rapidly expanding area of synthetic organic chemistry
[13-16]. This technique is based on the empirical
observation that some organic reactions proceed much
faster and with higher yields under microwave irradiation
compared to conventional heating. In the classical
synthesis of these compounds [17,18], a mixture of 4-

760
G. Liu, L. Sun, C.-P. Liu, C.-N. Ji, Q.-W. Wen and S.-M. Ma
Vol 45
Scheme 1
extended to 10 minutes (Table 2, entries 1 and 2).
However, no further improvement of the yield was noted
when the reaction time was prolonged to 15 minutes
(Table 2, entry 3). Consequently, we chose 10 minutes. as
the optimum reaction time (Table 2, entry 2). As for the
effect of the microwave power, it could be seen that when
it was increased from 40 to 60, 80 and 100 W, the yields
of 9b were 76%, 97%, 99%, and 97%, respectively (Table
2, entries 2 and 4-6). Hence, it’s better for the reaction to
be carried out at 60 W or higher power settings than at 40
W. No improvement was observed under irradiation when
the microwave power varied from 80 W to 100 W (Table
2, entries 5 and 6) and the yield even decreased a little, a
fact we attribute to the formation of byproducts. When the
reaction temperature was increased from 30°C to 50°C,
70°C or 80°C, 9b was obtained in 46%, 84%, 91% and
99% yields respectively (Table 2, entry 2 and entries 7-9).
The antitumor activities in vitro of these compounds
were evaluated against PC3 cell by MTT method. The
results for title compounds 9a-q and 8 are summarized in
Table 3. Unfortunately, most of the test compounds
exhibited less anticancer activity than the reference
standard drug PD153035. It can be found from Table 3
that compounds 9b (R=2-methoxydibenzofuran-3-yl), 9i
(R=3,4,5-trimethoxyphenyl), 9k (R=3-nitrophenyl), 9p
(R=(R)-α-methylbenzylphenyl), and 8 (4-chloro-6,7,8-
trimethoxyquinazoline) showed weak inhibitory activity
against PC3 cell. When 4-position in quinazoline ring was
substituted by different aryl moiety or benzyl moiety, the
compounds generally have potential anticancer
bioactivity, such as 9b, 9i, 9k and 9p with the inhibition
of 50.0, 35.0, 37.2 and 35.5% in the concentration of 10
µM against PC3 cell.
Reaction Route for Synthesis of 6,7,8-Trimethoxy N-Substituted-4-
aminoquinazoline Compounds 9a-q
OH
OMe
OMe
OMe
OMe
HO
OH
MeO
MeO
(ii)
(i)
(iii)
COOH
1
OMe
COOH
COOCH3
3
2
OMe
OMe
OMe
MeO
OMe
(iv)
MeO
OMe
MeO
(v)
(vi)
NO2
NO2
COOH
5
NH2
COOH
6
COOCH3
4
OMe
N
OMe
OMe
N
MeO
MeO
MeO
N
MeO
(vii)
NH
(viii)
(HCl)n
N
N
MeO
MeO
O
Cl
NHR
7
8
9
R = aryl, benzyl
Reagents and conditions: (i) (CH3O)2SO2 / NaOH, N2, reflux 3 hours,
then con. HCl pH=7; (ii) CH3OH / H2SO4, reflux 5 hours; (iii) fuming
HNO3 / CH3COOH, 30-40°C, 2 hours; (iv) 0.8 M NaOH / EtOH, 45-
50°C, 2 hours, then con. HCl pH=2-3; (v) SnCl2 / HCl, 80°C, 20
minutes, then the solid added 10% K2CO3 pH=9-10, then the filter
solution added CH3COOH pH=2-3; (vi) HCONH2, 130-140°C, 6 hours;
(vii) POCl3 / PhN(CH3)2, reflux 3 hours; (viii) aryl or benzyl amines, i-
propanol, MW, 80 W, 80°C, 10 minutes.
In summary, this work presents a new method of the
formation of novel 6,7,8-trimethoxy-4-aryl (benzyl)-
aminoquinazolines 9a-q under microwave irradiation and
offers several advantages: faster reaction rates and
excellent yields, while the classical method of formation
of
6,7,8-trimethoxy-4-aryl(benzyl)aminoquinazolines
involves long reaction times (6 hours). All compounds
Table 1
Yields and Reaction Conditions Used for the Microwave Assisted Synthesis of 9a-q
Microwave Method [a]
Classical Method [b]
Irradiation Time Yield [c]
Entry
Compound
R
n
Irradiation Time
Yield [c]
(%)
94
(minutes)
10
10
(minutes)
360
360
360
360
360
360
360
360
360
360
360
360
360
360
360
360
360
(%)
52
47
61
66
60
55
64
66
64
54
35
33
42
58
64
49
61
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
4-bromophenyl
2-methoxydibenzofuran-3-yl
3-chlorophenyl
2
2
1
1
1
0
0
1
1
1
1
1
2
2
0
0
0
99
93
95
85
87
89
91
90
87
84
83
92
98
86
81
84
10
10
10
10
10
10
10
10
10
10
10
10
10
10
3-bromophenyl
3-fluorophenyl
4-fluorophenyl
2-fluorophenyl
2-chloro-4-bromophenyl
3,4,5-trimethoxyphenyl
4-nitrophenyl
3-nitrophenyl
2-nitrophenyl
4-chlorophenyl
4-hydroxyphenyl
benzyl
(R)-α-methylbenzyl
(S)-α-methylbenzyl
10
[a] Reaction conditions: 8 (3.0 mmoles), aryl (or benzyl) amines (3.0 mmoles), i-propanol (30 mL), MW 80 W (80°C), 10 minutes.
[b] Reaction conditions: 8 (3.0 mmoles), aryl (or benzyl) amines (3.0 mmoles), i-propanol (30 mL), heated with oil-bath at reflux

May-Jun 2008
Microwave Assisted Synthesis of Novel 6,7,8-Trimethoxy
761
N-Substituted-4-aminoquinazoline Compounds
procedures [19-21]. Aryl amines and benzyl amines are
commercially available.
Table 2
Different Conditions Used for the Microwave Assisted Synthesis of 9b
Methyl 2-nitro-3,4,5-trimethoxybenzoate (4). A solution of
methyl 3,4,5-trimethoxybenzoate (2.0 g, 8.8 mmoles) in acetyl
hydrate (10 mL) at room temperature was carefully added
fuming nitric acid (2.5 mL) during 30 minutes with stirring.
After addition of acid, the solution was allowed to stir for 2
hours. The reaction mixture was then poured into ice water (60
mL). The solid obtained was collected by filtration, washed with
water, dried and recrystallized from ethanol-water (2:1, V/V) to
give 4 as pale yellow needles crystal; yield 25%; mp 62-63°C. ir
(potassium bromide): 3013, 2963, 2847, 1719, 1580, 1497,
Irradiation time
(minutes)
Power
(Watt)
60
60
60
Reaction
temperature (°C)
Yield [a]
(%)
87
Entry
1
2
3
4
5
6
7
8
9
5
80
80
80
80
80
80
30
50
70
10
15
10
10
10
10
10
10
97
97
40
80
76
99
100
80
80
97
46
84
1
1545, 1344, 1233, 1113, 866 cm-1. H nmr (DMSO-d6): δ 7.34
80
92
(s, 1H, PhH), 3.94-3.89 (3s, 9H, 3OCH3), 3.83 (s, 3H,
COOCH3). 13C nmr (DMSO-d6): δ 163.3, 154.7, 146.2, 145.5,
139.6, 117.7, 109.2, 63.1, 61.6, 57.1, 53.7. Anal. Calcd for
C11H13NO7 (271.2): C, 48.71; H, 4.83; N, 5.16. Found: C, 48.57;
H, 5.02; N, 4.91.
a Yields of isolated products. Each reaction was repeated three times
and the result was averaged.
Table 3
Inhibition Activity of 9a-q and 8 in the Concentration of 10 µM Against
PC3 Cancer Cell
2-Nitro-3,4,5-trimethoxybenzoic acid (5). A solution of
methyl 2-nitro-3,4,5-trimethoxybenzoate (14.0 g, 50 mmoles) in
0.8 M sodium hydroxide (120 mL, 100 mmoles) and 95%
ethanol (60 mL) at 45-50°C in water bath for 2 hours with
stirring. Then, the reaction mixture was cooled by ice-water and
concentrated hydrochloric acid was added dropwise with stirring
while maintaining the temperature at 20°C for the mixture pH 2-
3. The solid obtained was collected by filtration, washed with
water, dried and recrystallized from ethanol to give 5 as pale
yellow needles crystal; yield 92%; mp 160-161°C. ir (potassium
bromide): 3107, 2538, 2953, 2851, 1695, 1578, 1497, 1547,
Inhibition [a]
(%)
Inhibition [a]
(%)
Compound
Compound
9a
9b
9c
9d
9e
9f
19.5± 1.8*
50.0± 4.3*
26.7± 3.2**
22.2± 3.4**
16.3± 2.4*
16.6± 1.9*
18.1± 5.3**
11.5± 4.8**
35.0± 3.3*
34.5± 5.8**
9k
37.2± 1.4*
22.8± 3.0*
19.4± 5.5*
25.0± 6.1**
9.3± 3.1*
35.5± 4.1*
-7.44± 4.2*
71.3 ± 4.7**
87.5± 1.8**
9l
9m
9n
9o
9p
9g
9h
9i
9q
1
1341, 1246, 1117, 725 cm-1. H nmr (DMSO-d6): δ 7.32 (s, 1H,
8
PhH), 3.93-3.88 (3s, 9H, 3OCH3). 13C nmr (DMSO-d6): δ 164.1,
154.5, 145.8, 145.3, 139.8, 118.8, 109.3, 63.1, 61.5, 57.0. Anal.
Calcd for C10H11NO7 (257.2): C, 46.70; H, 4.31; N, 5.45. Found:
C, 46.77; H, 4.14; N, 5.32.
PD153035 [b]
9j
[a] Each value represents the mean ± SEM (n = 9). [b] the standard
compound was made of comparison for activity. Significance levels *p
< 0.1, **p < 0.05 as compared with the respective control.
2-Amino-3,4,5-trimethoxybenzoic acid (6). A mixture of
powder stannum (5.3 g, 45 mmoles) and concentrated
hydrochloric acid (18 mL) was stirred for 4-5 hours at room
temperature, then added 2-nitro-3,4,5-trimethoxy-benzoic acid
(2.6 g, 10 mmoles) to the solution. The reaction mixture was
carefully heated to 80°C, while maintaining the temperature for
20 minutes. Then, concentrated hydrochloric acid (5 mL) was
added into the reaction mixture, while maintaining the
temperature for 10 minutes. The reaction mixture was cooled by
ice-bath and stirred for 10 minutes. The precipitated complex
stannic double salt was collected by filtration, washed with few
concentrated hydrochloric acid. The white solid obtained was
stirred with portions of 10% potassium carbonate solution until
it dissolved with pH 9-10 and the mixture was alkaline,
whereupon a grayish precipitate appeared and was removed by
filter, washed with 10% potassium carbonate solution. The
solution was neutralized with acetyl hydrate to pH 2-3 while
maintaining the temperature blow 20°C. The white solid
obtained was collected by filtration, washed with water, dried
and recrystallized from ethanol-water (1:1, V:V) to give 6 as
white needles crystal; yield 62%; mp 126-128°C. ir (potassium
bromide): 3487, 3379, 3008, 1670, 1576, 1458, 1273, 1149, 744
9a-q were fully characterized by spectroscopic methods.
The title compounds 9a-q showed weak inhibitory
activity against PC3 cell.
EXPERIMENTAL
Melting points were determined on a XT-4 binocular
microscope mp apparatus and were not corrected. IR spectra
were recorded on a Bruker VECTOR22 spectrometer in
potassium bromide disks. The 1H nmr and 13C nmr spectra
(solvent DMSO-d6) were measured on a Varian-Inova 500 MHz
spectrometer at room temperature. Chemical shifts are reported
in ppm (δ) relative to TMS as an internal standard. D2O
exchange was used to confirm the assignment of the signals of
NH protons. Elemental analysis was performed by an Elementar
Vario-III CHN analyzer. Specific rotation was determined on a
WZZ-2A automatic polarimeter. Microwave reactions were
performed on a variable power Focused Microwave Synthesis,
DiscoverTM LabMate equipped with a high sensitivity IR sensor
for temperature control and measurement. Unless otherwise
indicated, all common reagents and solvents were used as
obtained from commercial supplies without further purification.
3,4,5-trimethoxybenzoic acid (2) and methyl 3,4,5-trimeth-
oxybenzoate (3) were prepared according to literature
1
cm-1. H nmr (DMSO-d6): δ 7.07 (s, 1H, PhH), 3.82-3.70 (3s,
9H, 3OCH3), 3.45 (s, 1H, NH). 13C nmr (DMSO-d6): δ 169.4,
147.6, 142.9, 141.6, 140.4, 1109.3, 104.5, 60.9, 60.6, 56.6. Anal.
Calcd for C10H13NO5 (227.2): C, 52.86; H, 5.77; N, 6.16. Found:
C, 52.74; H, 5.63; N, 6.02.

762
G. Liu, L. Sun, C.-P. Liu, C.-N. Ji, Q.-W. Wen and S.-M. Ma
Vol 45
DMSO-d6): δ 156.3, 154.0, 150.9, 148.9, 147.7, 145.3, 141.4,
127.7, 123.5, 123.3, 123.1, 121.3, 111.7, 111.4, 108.6, 103.6,
99.8, 62.0, 61.3, 56.9, 56.3. Anal. Calcd for C25H25N3O5·2HCl
(520.4): C, 57.70; H, 5.23; N, 8.07. Found: C, 57.60; H, 5.03; N,
8.16.
6,7,8-Trimethoxyquinazlin-4-one (7). A solution of 2-
amino-3,4,5-trimethoxybenzoic acid (1.1 g, 5 mmoles) and
excess of formamide (2 mL) was stirred for 5 hours at 130-
140°C. After the reaction was over, the suitable water was added
dropwise to the reaction mixture to resolve the excess of
formamide at 100°C. The gray solid obtained was collected by
filtration, washed with water, dried and recrystallized from
ethanol to give 7 as pale brown crystal; yield 25%; mp 220-
222°C. ir (potassium bromide): 3304, 3163, 3009, 1665, 1613,
1474, 1287, 1126, 798 cm-1. 1H nmr (DMSO-d6): δ 12.21 (s, 1H,
NH), 8.01 (s, 1H, quinazolone H-2), 7.35 (s, 1H, quinazolone H-
5), 3.95-3.88 (3s, 9H, 3OCH3). 13C nmr (DMSO-d6): δ 160.6,
152.7, 148.3, 147.7, 143.3, 139.0, 119.2, 101.7, 62.4, 61.4, 56.4.
Anal. Calcd for C11H12N2O4 (236.2): C, 55.93; H, 5.12; N, 11.86.
Found: C, 56.18; H, 5.18; N, 12.04.
4-(3-Chlorophenyl)amine-6,7,8-trimethoxyquinazoline hy-
drochloride (9c). This compound was obtained as pale yellow
solid; mp 172°C (dec.). ir (potassium bromide): 3013, 2947,
1
2847, 1628, 1487, 1288, 1126, 785 cm-1. H nmr (DMSO-d6): δ
11.43 (s, 1H, NH), 8.81 (s, 1H, quinazoline H-2), 8.10 (s, 1H,
quinazoline H-5), 7.90 (s, 1H, Ph-H-2), 7.71 (d, 1H, Ph-H-4, J =
9.15 Hz), 7.56-7.53 (m, 1H, Ph-H-5), 7.41 (d, 1H, Ph-H-6, J =
9.15 Hz), 4.05-4.02 (3s, 9H, 3OCH3). 13C nmr (DMSO-d6): δ
158.4, 153.9, 149.2, 147.6, 138.1, 132.8, 130.4, 126.2, 124.2,
123.0, 109.3, 99.8, 62.0, 61.2, 57.1. Anal. Calcd for
C17H16ClN3O3 ·HCl (382.2): C, 53.42; H, 4.48; N, 10.99. Found:
C, 53.50; H, 4.57; N, 10.74.
4-Chloro-6,7,8-trimethoxyquinazoline (8). A solution of
6,7,8-trimethoxyquinazolin-4-one (0.6 g, 2.5 mmoles) and four
drops N,N-dimethylaniline in phosphorus oxychloride (25 mL)
was heated at reflux for 3 hours. The phosphorus oxychloride
was removed by distillation at reduced pressure and the residue
was diluted with 20 mL chloroform and treated with 30 g ice-
water. To the mixture was added saturated potassium carbonate
with stirring until the mixture was pH 4-5. The organic layer
was separated and the residue was extracted twice with 40 mL
chloroform. The combined organic phases were dried
(anhydrous magnesium sulfate), filtered, evaporated under
reduced pressure, and recrystallized from petroleum ether (bp
60-90°C) to give 8 as pale gray solid; yield 63%; mp 101-103°C.
ir (potassium bromide): 3099, 2945, 2845, 1603, 1468, 1246,
4-(3-Bromophenyl)amine-6,7,8-trimethoxyquinazoline hy-
drochloride (9d). This compound was obtained as pale yellow
solid; mp 180°C (dec.). ir (potassium bromide) ν: 3011, 2945,
1
2849, 1626, 1487, 1286, 1126, 787 cm-1. H nmr (DMSO-d6): δ
11.62 (s, 1H, NH), 8.81 (s, 1H, quinazoline H-2), 8.20 (s, 1H,
quinazoline H-5), 8.03 (s, 1H, Ph H-2), 7.77 (d, 1H, Ph-H-4, J =
8.0 Hz), 7.54 (d, 1H, Ph-H-6, J = 8.0 Hz), 7.49-7.46 (t, 1H, Ph-
H-5, J = 4.0 Hz), 4.03-4.02 (3s, 9H, 3OCH3). 13C nmr (DMSO-
d6): δ 158.5, 154.0, 149.1, 147.7, 141.5, 138.8, 130.7, 129.1,
127.1, 123.6, 121.2, 109.3, 100.2, 62.1, 61.3, 57.2. Anal. Calcd
for C17H16BrN3O3·HCl (426.7): C, 47.85; H, 4.02; N, 9.85.
Found: C, 47.69; H, 4.25; N, 10.02.
4-(3-Fluorophenyl)amine-6,7,8-trimethoxyquinazoline hy-
drochloride (9e). This compound was obtained as pale yellow
solid; mp 232-234°C. ir (potassium bromide): 3419, 3013, 2951,
2853, 1628, 1489, 1288, 1134 cm-1. 1H nmr (DMSO-d6): δ 11.63
(s, 1H, NH), 8.81 (s, 1H, quinazoline H-2), 8.21 (s, 1H,
quinazoline H-5), 7.73 (d, 1H, Ph-H-4, J = 10.9 Hz), 7.73 (d,
1H, Ph-H-6, J = 8.0 Hz), 7.57-7.54 (m, 1H, Ph-H-5), 7.20 (t, 1H,
Ph-H-2, J = 4.0 Hz), 4.07-4.03 (3s, 9H, 3OCH3). 13C nmr
(DMSO-d6): δ 161.4, 159.0, 154.6, 149.7, 148.3, 131.0, 130.9,
121.1, 112.5, 112.3, 109.9, 100.7, 62.7, 61.9, 57.8. Anal. Calcd
for C17H16FN3O3·HCl (365.8): C, 55.82; H, 4.68; N, 11.49.
Found: C, 55.69; H, 4.72; N, 11.35.
4-(4-Fluorophenyl)amine-6,7,8-trimethoxyquinazoline (9f).
This compound was obtained as pale yellow solid; mp 184-
186°C. ir (potassium bromide): 3356, 3017, 2947, 2857, 1626,
1487, 1283, 1126, 789 cm-1. 1H nmr (DMSO-d6): δ 11.61 (s, 1H,
NH), 8.73 (s, 1H, quinazoline H-2), 8.17 (s, 1H, quinazoline H-
5), 7.74-7.71 (m, 2H, Ph-H-3,5), 7.38-7.34 (m, 2H, Ph-H-2,6),
4.05-4.02 (3s, 9H, 3OCH3). 13C nmr (DMSO-d6): δ 161.7, 159.8,
159.1, 154.5, 149.7, 148.1, 142.1, 133.3, 127.7, 127.6, 116.2,
116.1, 109.7, 100.7, 62.7, 61.8, 57.8. Anal. Calcd for
C17H16FN3O3 (329.3): C, 62.00; H, 4.90; N, 12.76. Found: C,
61.85; H, 4.88; N, 12.63.
4-(2-Fluorophenyl)amine-6,7,8-trimethoxyquinazoline (9g).
This compound was obtained as pale yellow solid; mp 194°C
(dec.). ir (potassium bromide): 3364, 2945, 2855, 1630, 1487,
1258, 1126, 1011, 760 cm-1. 1H nmr (DMSO-d6): δ 11.82 (s, 1H,
NH), 8.72 (s, 1H, quinazoline H-2), 8.23 (s, 1H, quinazoline H-
5), 7.56-7.36 (m, 4H, Ph-H-3,4,5,6), 4.06-4.03 (3s, 9H,
3OCH3). 13C nmr (DMSO-d6): δ 159.3, 157.8, 155.9, 153.9,
149.2, 147.7, 141.7, 129.3, 128.6, 116.3, 116.2, 108.9, 100.2,
62.0, 61.2, 57.1. Anal. calcd for C17H17ClFN3O3 (329.3): C,
55.82; H, 4.68; N, 11.49. Found: C, 55.66; H, 4.86; N, 11.31.
1
1136, 787 cm-1. H nmr (DMSO-d6): δ 8.93 (s, 1H, quinazoline
H-2), 7.29 (s, 1H, quinazoline H-5), 4.06-4.01 (3s, 9H, 3OCH3).
13C nmr (DMSO-d6): δ 158.9, 154.3, 150.9, 148.1, 146.3, 142.7,
120.1, 98.6, 62.2, 61.1, 56.3. Anal. Calcd for C11H11ClN2O3
(254.7): C, 51.88; H, 4.35; N, 11.00. Found: C, 52.02; H, 4.21;
N, 10.94.
4-(4-Bromophenyl)amine-6,7,8-trimethoxyquinazoline di-
hydrochloride (9a). A solution of 8 (0.71 g, 3.0 mmoles) and 4-
bromoamine (0.52 g, 3.0 mmoles) in isopropyl alcohol (30 mL)
was stirred for three minutes then the mixture was irradiated in
the microwave oven at 80 W for 10 minutes. Upon completion
of the reaction, as monitored by TLC, the solvent was removed
under reduced pressure and the residue was washed with water,
collected by filtration and purified by silicagel column
chromatography (petroleum ether-ethyl acetate, 5:1 v:v) to give
9a as pale yellow solid; yield 94%; mp170-173°C. ir (potassium
bromide): 3011, 2947, 2847, 1628, 1489, 1288, 1128, 804 cm-1.
1H nmr (DMSO-d6): δ 11.53 (s, 1H, NH), 8.76 (s, 1H,
quinazoline H-2), 8.14 (s, 1H, quinazoline H-5), 7.71 (s, 4H, Ph-
H), 4.05-4.02 (3s, 9H, 3OCH3). 13C nmr (DMSO-d6): δ 158.9,
154.5, 149.6, 148.2, 142.1, 136.5, 132.2, 127.3, 109.9, 100.6,
62.7, 61.9, 57.8. Anal. Calcd for C17H16BrN3O3·2HCl (463.1): C,
44.09; H, 3.92; N, 9.07. Found: C, 43.82; H, 4.18; N, 9.04.
4-(2-Methoxydibenzofuran-3-yl)amine-6,7,8-trimethox-
yquinazoline dihydrochloride (9b). This compound was
obtained as yellow solid; mp160-162°C. ir (potassium bromide):
1
3011, 2949, 2851, 1626, 1474, 1286, 1125, 764 cm-1. H nmr
(DMSO-d6): δ 11.45 (s, 1H, NH), 8.68 (s, 1H, quinazoline H-2),
8.22 (d, 1H, dibenzofurane H-5, J = 7.45 Hz), 8.09 (s, 1H,
quinazoline H-5), 8.03 (s, 1H, dibenzofurane H-1), 7.88 (s, 1H,
dibenzofura-ne H-4), 7.72 (d, 1H, dibenzofurane H-8, J = 7.45
Hz), 7.58-7.55 (m, 1H, dibenzofurane H-7), 7.47-7.45 (m, 1H,
dibenzofurane H-6), 4.04-3.93 (3s, 12H, 4OCH3). 13C nmr

May-Jun 2008
Microwave Assisted Synthesis of Novel 6,7,8-Trimethoxy
763
N-Substituted-4-aminoquinazoline Compounds
4-(2-Chloro-4-bromophenyl)amine-6,7,8-trimethoxyqui-
nazoline hydrochloride (9h). This compound was obtained as
white solid; mp 178°C (dec.). ir (potassium bromide): 3366,
3015, 2945, 2849, 1626, 1487, 1286, 1126 cm-1. 1H nmr
(DMSO-d6): δ 8.71 (s, 1H, quinazoline H-2), 8.04 (s, 1H,
quinazoline H-5), 8.00 (d, 1H, Ph-H-3, J = 2.3 Hz), 7.74 (d, 1H,
Ph-H-5, J = 8.6 Hz), 7.54 (d, 1H, Ph-H-6, J = 8.6 Hz), 4.03-4.02
(3s, 9H, 3OCH3). 13C nmr (DMSO-d6): δ 164.8, 159.8, 154.7,
154.4, 153.3, 147.2, 138.8, 137.7, 137.5, 136.6, 126.4, 114.1,
105.1, 104.9, 67.4, 66.7, 62.3. Anal. Calcd for
C17H15BrClN3O3·HCl (461.1): C, 44.28; H, 3.50; N, 9.11. Found:
C, 43.96; H, 3.76; N, 9.01.
4-(3,4,5-Trimethoxyphenyl)amine-6,7,8-trimethoxyqui-
nazoline hydrochloride (9i). This compound was obtained as
yellow solid; mp 195°C (dec.). ir (potassium bromide): 3419,
2947, 2839, 1634, 1456, 1285, 1130 cm-1. 1H nmr (DMSO-d6): δ
11.52 (s, 1H, NH), 8.75 (s, 1H, quinazoline H-2), 8.17 (s, 1H,
quinazoline H-5), 7.09 (s, 2H, Ph-H-1,6), 4.06-4.02 (3s, 9H,
3OCH3), 3.81 (s, 6H, Ph-3,5-2CH3), 3.71 (s, 3H, Ph-4-CH3). 13C
nmr (DMSO-d6): δ 159.0, 154.5, 153.3, 149.6, 148.1, 136.6,
132.8, 109.7, 103.5, 100.8, 62.7, 61.2, 60.7, 57.8, 56.6. Anal.
Calcd for C20H23N3O6·HCl (437.9): C, 54.86; H, 5.52; N, 9.60.
Found: C, 54.67; H, 5.61; N, 9.55.
(DMSO-d6): δ 11.57 (s, 1H, NH), 8.75 (s, 1H, quinazoline H-2),
8.23 (s, 1H, quinazoline H-5), 7.77 (d, 2H, Ph-3,5-H, J = 8.6
Hz), 7.57 (d, 2H, Ph-2,6-H, J = 8.6 Hz), 4.06-4.02 (3s, 9H,
3OCH3). 13C nmr (DMSO-d6): δ 158.4, 153.7, 149.3, 147.5,
135.8, 128.6, 126.4, 109.9, 100.2, 62.0, 61.2, 57.2. Anal. Calcd
for C17H16ClN3O3 ·2HCl (418.7): C, 48.77; H, 4.33; N, 10.04.
Found: C, 48.53; H, 4.63; N 9.97.
4-(4-Hydroxyphenyl)amine-6,7,8-triethoxyquinazoline di-
hydrochloride (9n). This compound was obtained as pale
yellow solid; mp 153°C (dec.). ir (potassium bromide): 3420,
1
3227, 3030, 2949, 2855, 1626, 1474, 1273, 1128 cm-1. H nmr
(DMSO-d6): δ 11.42 (s, 1H, NH), 9.75 (s, 1H, OH), 8.66 (s, 1H,
quinazoline H-2), 8.15 (s, 1H, quinazoline H-5), 7.43 (d, 2H, Ph-
3,5-H, J = 8.6 Hz), 6.87 (d, 2H, Ph-2,6-H, J = 8.6 Hz), 4.03-4.00
(3s, 9H, 3OCH3). 13C nmr (DMSO-d6): δ 158.3, 156.1, 153.7,
149.1, 147.3,141.6, 127.6, 126.3, 115.2, 109.1, 100.2, 61.9, 61.2,
57.1. Anal. Calcd for C17H17N3O4·2HCl (400.3): C, 51.01; H,
4.78; N, 10.50. Found: C, 51.24; H, 5.04; N, 10.52.
4-Benzylamine-6,7,8-trimethoxyquinazoline (9o). This
compound was obtained as white solid; mp 173-175°C. ir
(potassium bromide): 3235, 3001, 2938, 2832, 1614, 1454,
1
1283, 1128, 800 cm-1. H nmr (DMSO-d6): δ 8.60 (t, J=5.7 Hz,
1H, NH), 8.36 (s, 1H, quinazoline H-2), 7.54 (s, 1H, quinazoline
H-5), 7.37-7.31 (m, 4H, Ph-H-2,3,5,6), 7.23 (t, 1H, Ph-4-H, J =
7.45 Hz), 4.79 (d, 2H, CH2, J = 5.7 Hz), 3.97-3.87 (3s, 9H,
3OCH3). 13C nmr (DMSO-d6): δ 159.1, 153.1, 152.2, 147.6,
146.3, 140.9, 140.2, 128.8, 127.7, 127.3, 111.7, 98.5, 62.2, 61.4,
56.7, 42.1. Anal. Calcd for C18H19N3O3 (325.4): C, 66.45; H,
5.89; N, 12.91. Found: C, 66.56; H, 5.95; N, 12.93.
4-(4-Nitrophenyl)amine-6,7,8-trimethoxyquinazoline hy-
drochloride (9j). This compound was obtained as pale yellow
solid; mp 212°C (dec.). ir (potassium bromide): 3366, 3011,
1
2951, 2839, 1628, 1514, 1487, 1340, 1285, 1130 cm-1. H nmr
(DMSO-d6): δ 11.21 (s, 1H, NH), 8.82 (s, 1H, quinazoline H-2),
8.36 (d, 2H, Ph-3,5-H, J = 8.6 Hz), 8.15 (d, 2H, Ph-2,6-H, J =
8.6 Hz), 8.06 (s, 1H, quinazoline H-5), 4.06-4.02 (3s, 9H,
3OCH3). 13C nmr (DMSO-d6): δ 157.8, 153.6, 149.7, 147.4,
143.9, 124.4, 123.2, 110.5, 99.3, 62.0, 61.2, 56.9. Anal. Calcd
for C17H16N4O5·HCl (392.8): C, 51.98; H, 4.36; N, 14.26.
Found: C, 51.73; H, 4.52; N, 14.12.
(R)-4-(α-Methylbenzylphenyl)amine-6,7,8-trimethoxy-
quinazoline (9p). This compound was obtained as white solid;
mp 207-209°C; [α]D -213.0 (c 0.01, EtOH). ir (potassium
bromide): 3262, 3026, 2972, 2934, 2832, 1613, 1478, 1281,
22
1
1121, 702 cm-1. H nmr (DMSO-d6): δ 8.31 (s, 1H, quinazoline
4-(3-Nitrophenyl)amine-6,7,8-trimethoxyquinazoline hy-
drochloride (9k). This compound was obtained as pale yellow
solid; mp 204-206°C. ir (potassium bromide): 3419, 3015, 2947,
2843, 1632, 1469, 1485, 1346, 1284, 1121 cm-1. 1H nmr
(DMSO-d6): δ 11.84 (s, 1H, NH), 8.86 (s, 1H, quinazoline H-2),
8.72 (s, 1H, Ph-2-H), 8.29 (d, 1H, Ph-4-H, J = 9.15 Hz), 8.26 (s,
1H, quinazoline H-5), 8.18 (d, 1H, Ph-6-H, J = 9.7 Hz), 7.82-
7.79 (m, 1H, Ph-5-H), 4.08-4.03 (3s, 9H, 3OCH3). 13C nmr
(DMSO-d6): δ 159.1, 154.6, 149.8, 148.3, 142.3, 138.6, 131.2,
130.7, 121.3, 119.5, 110.1, 100.8, 62.7, 61.9, 57.9. Anal. Calcd
for C17H16N4O5 ·HCl (392.8): C, 51.98; H, 4.36; N, 14.26.
Found: C, 51.71; H, 4.55: N, 14.32.
4-(2-Nitrophenyl)amine-6,7,8-trimethoxyquinazoline hy-
drochloride (9l). This compound was obtained as white solid;
mp 210°C (dec.). ir (potassium bromide): 3019, 2945, 2845,
1624, 1458, 1489, 1356, 1286, 1130, 793 cm-1. 1H nmr (DMSO-
d6): δ 12.01 (s, 1H, NH), 8.66 (s, 1H, quinazoline H-2), 8.18 (s,
1H, quinazoline H-5), 8.17 (d, 1H, Ph-3-H, J = 7.45 Hz), 7.90 (t,
1H, Ph-4-H, J = 9.15 Hz), 7.77 (d, 1H, Ph-6-H, J = 7.45 Hz),
7.65 (t, 1H, Ph-5-H, J = 7.75 Hz), 4.06-4.02 (3s, 9H, 3OCH3).
13C nmr (DMSO-d6): δ 158.7, 153.9, 149.3, 147.8, 146.3, 144.8,
134.3, 128.9, 128.1, 125.2, 109.3, 99.9, 62.0, 61.2, 57.1. Anal.
Calcd for C17H16N4O5·HCl (392.8): C, 51.98; H, 4.36; N, 14.26.
Found: C, 52.18; H, 4.57; N, 14.29.
H-2), 8.22 (d, 1H, NH, J = 7.45 Hz), 7.64 (s, 1H, quinazoline H-
5), 7.42 (d, 2H, Ph-2,6-H, J = 7.45 Hz), 7.32 (t, 2H, Ph-3,5-H, J
= 7.45 Hz), 7.21 (t, 1H, Ph-4-H, J = 7.45 Hz), 5.62 (p, 1H, CH, J
= 7.45 Hz), 3.96-3.87 (3s, 9H, 3OCH3), 1.60 (d, 3H, CH3, J =
7.45 Hz). 13C nmr (DMSO-d6): δ 158.3, 153.0, 152.2, 147.6,
146.3, 145.4, 140.9, 128.8, 127.1, 126.6, 111.6, 98.7, 62.2, 61.4,
56.9, 49.6, 22.9. Anal. Calcd for C19H21N3O3 (339.4): C, 67.24;
H, 6.24; N, 12.38. Found: C, 67.31; H, 5.97; N, 12.23.
(S)-4-(α-Methylbenzylphenyl)amine-6,7,8-trimethoxy-
quinazoline (9q). This compound was obtained as white solid;
mp 205-206°C; [α]D +208.0 (c 0.01, EtOH). ir (potassium
bromide): 3242, 3028, 2972.3, 2936, 2832, 1613, 1478, 1312,
22
1
1130, 700 cm-1. H nmr (DMSO-d6): δ 8.31 (s, 1H, quinazoline
H-2), 8.22 (d, 1H, NH, J = 7.45 Hz), 7.64 (s, 1H, quinazoline H-
5), 7.42 (d, 2H, Ph-2,6-H, J = 7.45 Hz), 7.32 (t, 2H, Ph-3,5-H, J
= 7.45 Hz), 7.21 (t, 1H, Ph-4-H, J = 7.45 Hz), 5.62 (p, 1H, CH, J
= 7.45 Hz), 3.96-3.87 (3s, 9H, 3OCH3), 1.60 (d, 3H, CH3, J =
6.9 Hz). 13C nmr (DMSO-d6): δ 158.3, 153.0, 152.2, 147.6,
146.3, 145.4, 140.9, 128.8, 127.1, 126.6, 111.6, 98.7, 62.2, 61.4,
56.9, 49.6, 22.9. Anal. Calcd for C19H21N3O3 (339.4): C, 67.24;
H, 6.24; N, 12.38. Found: C, 67.43; H, 6.23; N, 12.37.
MTT Method. MTT assay against cancer cell proliferation
[22]. All tested compounds were dissolved in DMSO (1–100
µM solution) and subsequently diluted in the culture medium
before treatment of the cultured cells. Tested cells were plated in
96-well plates at a density 2×103 cells/well/100 µL of the proper
culture medium and treated with the compounds at 1–100 µM
for 72 hours. In parallel, the cells treated with 0.1% DMSO
4-(4-Chlorophenyl)amine-6,7,8-trimethoxyquinazoline di-
hydrochloride (9m). This compound was obtained as pale
yellow solid; mp 175°C (dec.). ir (potassium bromide): 3420,
1
3011, 2947, 2853, 1628, 1472, 1286, 1130, 806 cm-1. H nmr

764
G. Liu, L. Sun, C.-P. Liu, C.-N. Ji, Q.-W. Wen and S.-M. Ma
Vol 45
W.; Elliott, W. L.; Denny, W. A. J. Med. Chem. 2000, 43, 1380.
served as control. An MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazoliumbromide] assay (Roche Molecular Biochem-
icals, 1465-007) was performed 30 hours later according to the
instructions provided by Roche. This assay is based on the
cellular cleavage of MTT into formazan which is soluble in cell
culture medium. And the absorbance caused by formazan was
measured at 595 nm with a microplate reader (Bio-Rad, model
680), which is directly proportional to the number of living cells
in culture. Three types of cells were used in these assays, PC3
cell lines, provided by ATCC and cultivated in RPMI 1640 for
PC3 supplemented with 10% fetal bovine serum. Tissue culture
reagents were obtained from Gibco BRL.
[9] Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B.
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