Synthesis and Transformation of 4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-methylquinazoline: Spectral Characterization and Anti-cancer Properties of some Novel Quinazoline Derivatives

Article abstract of DOI:10.1002/jhet.3897

An efficient and simple method has been reported for the synthesis of 4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-methylquinazoline (2) as a key compound for further transformation to other novel 6,7-dimethoxy-2-methyl-4-substituted quinazolines. The structure of the synthesized compounds was characterized by spectroscopic methods. The pathway of some unprecedented reactions was proposed. (E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-3-(4-nitrophenyl)prop-2-en-1-one (11) exhibits high in vitro cytotoxicity on three cell lines, Hepatocellular carcinoma (Hep-G2), Human lung carcinoma (LU-1), and Human breast carcinoma (MCF-7) with IC₅₀ of 2.1, 11.6 and 2.2 μM, respectively.

Full text of DOI:10.1002/jhet.3897

Received: 3 March 2019
DOI: 10.1002/jhet.3897
Revised: 26 December 2019
Accepted: 27 December 2019
A R T I C L E
Synthesis and Transformation of 4-(1-Chloro-1-nitroethyl)-
6,7-dimethoxy-2-methylquinazoline: Spectral
Characterization and Anti-cancer Properties of some
Novel Quinazoline Derivatives
Duong Quoc Hoan1
Nguyen Huu Dinh1
| Le Thi Hoa2 | Trinh Thi Huan2
|
1Department of Chemistry, Hanoi
National University of Education, A4
Hall, 136 Xuanthuy, Caugiay, Hanoi,
Vietnam
2Department of Science, Hong Duc
University, Thanh Hoa, Vietnam
Abstract
An efficient and simple method has been reported for the synthesis of
4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-methylquinazoline (2) as a key com-
pound for further transformation to other novel 6,7-dimethoxy-2-methyl-
4-substituted quinazolines. The structure of the synthesized compounds was
characterized by spectroscopic methods. The pathway of some unprecedented
reactions was proposed. (E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-
3-(4-nitrophenyl)prop-2-en-1-one (11) exhibits high in vitro cytotoxicity on
three cell lines, Hepatocellular carcinoma (Hep-G2), Human lung carcinoma
(LU-1), and Human breast carcinoma (MCF-7) with IC50 of 2.1, 11.6 and
2.2 μM, respectively.
Correspondence
Nguyen Huu Dinh, Department of
Chemistry, Hanoi National University of
Education, A4 Hall, 136 Xuanthuy,
Caugiay, Hanoi, Vietnam.
Email: huudinhhnue@gmail.com
1 | INTRODUCTION
with substituent groups at 2-, 4- and 6-position could pro-
mote the anti-cancer and antimicrobial activities; iii)
Quinazolines, an important class of fused heterocyclic
compounds have attracted high attention in organic and
medicinal chemistry due to their significant and wide
range of biological activities. Quinazolines is considered
as an important starting material for the synthesis of vari-
ous physiological significance and pharmacological uti-
lized molecules. During the past several decades, interest
in synthesis and expanding the biological effects of
quinazoline and quinazolinone derivatives grew expo-
nentially, as indicated by the large number of publica-
tions reporting the syntheses and isolations of these
compounds from natural as well as their biological
applications[1–7] It could be seen from the reviews[1–6]
that: i) Traditional synthetic methods for quinazoline
derivatives still in general use; ii) Quinazoline derivatives
Many of approved drugs with quinazoline structure in
commercial availability are 4-aminoquinazoline deriva-
tives with two alkoxy, mainly two methoxy groups at 6-
and 7-position such as: Prazosin is a sympatholytic medi-
cation that is used to treat high blood pressure, anxiety,
and posttraumatic stress disorder; Doxazosin is a non-
selective alpha-1 adrenergic antagonist (alpha-blocker)
used in the therapy of hypertension and benign prostatic
hypertrophy; Terazosin is a selective alpha-1 antagonist
used for treatment of symptoms of an enlarged prostate;
Gefitinib is a drug used for certain breast, lung and other
cancers; Erlotinib (Tarceva) is a drug used to treat non-
small cell lung cancer, pancreatic cancer and several
other types of cancer; Alfuzosin is used to improve urina-
tion in men with benign prostatic hyperplasia.[6]
J Heterocyclic Chem. 2020;1–9.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
HOAN ET AL.
changeable group to expand our research as presented in
Scheme 1 (The numeration on presented structures is
specifically used for NMR analysis).
First of all, 4,5-dimethoxy-2-(3-methylfuroxan-4-yl)
phenylamine (Am) was prepared from methyleugenol
according to our manner.[10] Then, amide 1 was obtained
in 80% yield when a mixture of Am, Ac2O in ethanol was
refluxed for 3 hoursours. Next, in the reaction b,
DMF/POCl3 was used in order to convert amide 1 into
quinazoline 2 in 64% yield.
The IR, 1H, 13C and MS spectra of 1 and 2 (see Experi-
mental) are associated with their structures. For example,
In the ESI MS of 2, there is a pseudomolecular ion peak
at m/z 311.9/52% (M + H+) accompanied by a isotope
peak at m/z 314.0/20% (37Cl), and the base peak at m/z
265.9/100% (M + H+-NO2) accompanied by an isotope
peak at m/z 267.9/20% (37Cl). These correspond with the
presence of one Cl atom in molecule C13H14ClN3O4 of 2.
The proton and carbon signals of 2 were assigned by
using NOESY, HSQC and HMBC spectra. For example,
Some time ago, we focused our attention to several
natural arylolefins (eugenol, methyleugenol, safrole,
anethole) from vegetable essential oils that could act as
good substrates in order to prepare heterocyclic com-
pounds. For example, many poly-functionalized
quinolines were synthesized from eugenol with a conve-
nient route;[8,9] 4,5-dimethoxy-2-(3-methylfuroxan-4-yl)
phenylamine (Am), which was synthesized from meth-
yleugenol, acted as a key compound for preparation of
some series of imines, azo, 1,3-thiazolidin-4-ones and
indoles incorporating furoxan moiety.[10,11]
1
six singlets in H NMR spectrum of 2 were distinguished
using NOESY spectrum as in Figure 1.
Considering above mentions, we have decided to
design and synthesize a series of 6,7-dimethoxy-2-methyl-
4-substituted quinazolines and to investigate whether the
resulting compounds have useful anti-cancer activities.
2 | RESULTS AND DISCUSSION
As mentioned above and in literature,[12] our quinazoline
derivatives were designed on purpose in which substitu-
ents at 2,4,6 positions were set up to improve anti-cancer
activity; 6,7-dimethoxy-quinazoline was derived from
methyleugenol-a natural source; R substituent was a
FIGURE 1 NOESY spectrum of 2
SCHEME 1 Synthesis of
quinazoline 2

HOAN ET AL.
3
Singlet at 7.08 ppm gives rise to two cross peaks a and
It is known that DMF and POCl3 are ready to form in
situ formylating agent (Wilsmeier-Haack reagent), which
allows the formylation of electron-rich arenes.[13] This
brings up the question: how was the compound
1 converted into the quinazoline 2? In order to answer
this question, the reaction of 1 with POCl3 was also car-
ried out in two other manners than that described in the
Experimental to evaluate the role of DMF and HCl. In
the first manner, a mixture of 1 and POCl3 (without
DMF) was heated at 60ꢀC for 4 hoursours. In the second
b with two singlets of methyl protons at 2.64 ppm and
3.86 ppm, while singlet at 7.44 ppm has only one cross
peak c with singlet of methyl protons at 3.99 ppm. Thus,
singlet at 7.08 ppm is assigned to aromatic H5, singlet at
7.44 ppm - to aromatic H8; two methyl groups at
2.64 ppm and 3.86 ppm are assigned to H4b and H6a,
respectively; methyl group at 3.99 ppm is assigned to
H7a. Singlet of methyl group at 2.76 ppm does not have
any cross peak, so it belongs to H2a.
Because compound 2 is the product of unprecedented
reaction (b in Scheme 1), its single crystal X-ray diffrac-
tion was analyzed. The results (Figure 2) shown that
manner, a mixture of 1, DMF and concentrated
hydrochloric acid (without POCl3) was heated at 60ꢀC for
4 hours. The first try gave compound 2 in 62% yield only,
meanwhile, the Am was obtained in 72% yield due to
hydrolysis in the second manner. These results allow us
to explain the formation of 2 from 1 ignoring DMF and
HCl as Scheme 2.
2
crystallized in triclinic system and each
unit cell is occupied with a pair of enantiomers of 2 with
S-configuration C4a and R-configuration C04a.
The activation exerted by the nitro, chloro and hetaryl
groups renders an availability of the ethyl side chain of
2 for various chemical transformations as presented in
Scheme 3.
When compound 2 was reacted with AgNO3 in
MeOH (reaction c, Scheme 3), instead of substitution or
elimination products, compound 3 was obtained with the
yield of 52%. The IR absorption and MS data (see Experi-
mental) correspond with the formula of 3 in which six
proton singlets and twelve carbon signals of 3 were
assigned using NOESY and HMBC spectra. The forma-
tion of 3 can be explained as in Scheme 4.
Upon the treating 2 with KClO3/HCl solution, it was
oxidized to form compound 4 (reaction d, Scheme 3). All
obtained data from IR, MS, 1H, 13C and HMBC spectra of
4 (see Experimental, Table 2) are associated with its
structure.
Interestingly, upon refluxing quinazoline 2 and
NaOH in 95% ethanol (v/v) we obtained an indole deriva-
tive, compound 5 (reaction e, Scheme 3). Strong absorp-
tion band at 1671 cm−1 and weak absorption band at
FIGURE 2 Crystal packing of 2, showing a pair of
enantiomers
SCHEME 2 Explanation of the
formation of 2

4
HOAN ET AL.
SCHEME 3 Chemical
transformation of 2
SCHEME 4 Proposed explanation
of the formation of 3
TABLE 1 Cancer cytotoxicity evaluation on four cell lines, IC50 (μM)
Compd.
KB
Hep-G2
–
Lu
–
MCF-7
–
2
78.0
109.1
8.00
1.23
8.6
4
–
–
–
5
41.79
1.25
11.6
2.1
94.95
1.84
–
12.0
3.57
–
7
10
11
> 337
1.14
11.6
1.71
2.2
Ellipticine
1.14
1.70
TABLE 2 1H and 13C NMR signals of compounds 1–6, δ (ppm)
Comp.
1
2
3
4
5
6
H2a/H4b
H6a/H7a
H5/H8
2.00 s / 1.94 s
3.76 s / 3.79 s
7.06 s / 7.24 s
168.9/23.6/8.7
157.1 / 114.4
113.1 / 109.6
146.6 / 151.1
56.1 / 56.4
2.76 s / 2.64 s
3.86 s / 3.99 s
7.08 s / 7.44 s
160.4/29.7/25.5
157.3 / 103.9
100.3 / 107.3
150.0 / 156.0
55.7 / 56.4
2.60 s / 4.10 s
3.89 s / 3.93 s
7.29 s / 7.21s
161.2/25.1/54.4
165.4 / –
2.62 s / –
2.30 s / –
2.76 s / 2.74 s
3.90 s / 3.98 s
7.95 s / 7.34 s
161.0/25.6/27.9
155.4 / 202.5
106.1 / 102.8
150.7 / 156.0
55.7 / 56.2
3.90 s / 3.93s
7.46 s / 7.35s
156.6/18.2/−
158.6 / –
3.84 s / 3.87 s
7.39 s / 7.04 s
152.8/21.3/−
– / –
C2/C2a/C4b
C4/C4a
C5/C8
101.1 / 104.8
149.3 / 155.6
56.1 / 55.9
105.9 / 102.3
149.1 / 155.2
55.8 / 56.0
136.5 / 112.4
104.9 / 107.4
147.9 / 154.4
55.6 / 55.8
145.1 / 113.4
C6/C7
C6a/C7a
C9/C10
130.8 / 112.1
150.1 / 113.2
146.4 / 107.6
150.9 / 113.9

HOAN ET AL.
5
1637 cm−1 in IR spectrum of 5 indicate the presence of
conjugated N=C-C=O group. The remarkable difference
in NMR spectra of 5 in comparison with spectrum of 2 is
the decrease of one proton signal of methyl group, one
methyl carbon signal and one other carbon signal. Fur-
thermore, all signals in HMBC of 5 (Figure 3) are associ-
ated with its structure.
signal of C6 and C7, consequently the largest chemical
shift signal at 161.3 ppm should be assigned to carbonyl
carbon C3. The signal of C3 has stronger cross peaks
s with aromatic proton at 7.39 and weaker cross peak
t with aromatic proton at 7.03 ppm. Because three-bond
correlations are stronger than four-bond one, therefore
the signal at 7.39 ppm is assigned to H5 and the signal at
7.03 ppm is assigned to H8. Similarly, proton and carbon
signals of 5 were assigned.
It is known that quinazolines is destroyed when its
alkaline or acidic solution boiled. o-Aminobenzaldehyde,
ammonia, and formic acid are formed when quinazoline
is boiled with hydrochloric acid.[5] The formation of
5 from 2 can be explained as in Scheme 5.
In Figure 3 the cross peak r of methyl protons H2a
indicates that signal at 152.8 ppm belongs to C2. The
cross peaks m, p of two methoxy group (H6a, H7a) show
When the compound 2 was reacted with Na2S2O4 in
alkaline medium (reaction f in Scheme 3) the nitro group
was reduced to an amino group, atom Cl was replaced by
OH group followed by the releasing NH3 to afford methyl
ketone 6. The IR spectrum of 6 showed strong absorption
band at 1691 cm−1 attributed to C=O group. The ESI
+ MS spectrum of 6 displayed an intensive peak at m/z
246.9 (100%, [M + H]+) corresponding to the expected
molecular formula C13H14N2O3 (M = 246 au). Six proton
singlets and thirteen carbon signals of 6 (Table 2) were
assigned using its HMBC spectrum. The remarkable dif-
ference in 13C NMR spectrum of 6 in comparison with
spectrum of 2 is the absence of signal at 103.9 ppm (C4a
of 2) and the appearance of the signal at 202.5 ppm
assigned to carbonyl carbon (C4a of ketone 6). The con-
densation of
6
and phenylhydrazine to form
phenylhydrazone 7 (reaction g in Scheme 6) was a final
characterization for ketone 6.
FIGURE 3 A part of HMBC spectrum of 5
SCHEME 5 Explanation of the
formation of 5
SCHEME 6 Condensation
reactions of ketone 6

6
HOAN ET AL.
TABLE 3 1H and 13C NMR signals of compounds 7–12, δ (ppm), J (Hz)
Comp.
H2a
7
8
9
10
11
12
2.72 s
2.81 s
2.93 s
2.87 s
2.82 s
2.81 s
H4b
–
7.81 d, J 16
7.90 d, J 16
3.91 s / 4.00 s
7.84 s / 7.39 s
7.48/7.48 dJ 8
7.80/7.80 t, J 8
7.48 t, J 8/ –
161.0 / 25.6
156.1 / 191.7
123.6/145.8
106.2 / 102.6
150.7 / 157.1
55.7 / 56.1
7.85 d, J 16
7.87 d, J 16
4.04 s / 4.06 s
8.09 s / 7.31 s
7.66/7.66 d, J 9
6.95/6.95 d, J 9
−/ 3.87 s (MeO)
161.9 / 26.1
157.5 / 192.1
121.1 / 146.1
106.2 / 103.5
151.0 / 156.3
56.3 / 56.4
7.50 d, J 15
7.67 d, J 15
3.88 s / 3.98 s
7.74 s / 7.35 s
7.61/7.61 d, J 7
6.74/6.74 d, J 7
−/ 3.01 s (Me2N)
159.8 / 24.4
154.5 / 185.6
121.5 / 144.5
107.6 / 102.8
151.0 / 156.3
55.5 / 56.0
7.90 d, J 16
8.07 d, J 16
3.92 s / 3.99 s
7.89 s / 7.39 s
8.08/8.08 d, J 9
8.28/8.28 d, J 9
− / –
7.92 d, J 16
H4c
–
8.09 d, J 16
H6a/H7a
H5/H8
3.89 s / 3.97 s
7.29 s / 8.54 s
7.39/7.39 d, J 8
7.29/7.29 t, J 8
6.90 t, J 8 / –
160.0 / 24.6
144.7 / 151.0
13.3 / –
3.94 s / 4.01 s
7.95 s / 7.41 s
− / 8.05 d, J 8
8.13 d/7.85 t, J 8
7.74 t, J 8 / –
161.0 / 25.5
H12/H16
H13/H15
H14/H14a
C2/C2a
C4/C4a
C4b/C4c
C5/C8
161.1 / 25.6
156.2 / 191.5
142.6 / 127.3
106.3 / 102.6
150.9 / 156.3
55.8 / 56.2
155.9 / 191.3
140.2 / 127.6
106.2 / 102.5
150.9 / 156.3
55.7 / 56.2
106.1 / 102.7
155.6 / 159.4
55.6 / 56.1
149.9 / 114.8
141.6/120.9/−
129.1 / 129.1
113.6 / 113.6
C6/C7
C6a/C7a
C9/C10
C11/14/14a
C12/C16
C13/C15
150.3 / 114.6
134.2 / 131.1/−
129.1 / 129.1
128.9 / 128.9
149.8 / 115.8
127.6/162.1/55.5
130.8 / 130.8
114.5 / 114.5
146.8 / 115.7
124.0/148.1/40.1
130.8 / 130.8
110.9 / 110.9
150.5 / 114.7
140.7/148.4 / –
129.9 / 129.9
124.1 / 124.1
150.5 / 114.7
129.6/131.3 / –
148.6 / 129.2
124.8 / 134.0
Next, ketone 6 was subject for the crotonic condensa-
tion reaction to promote the side chain. Quinazolines are
stable in cold dilute acid and alkaline solutions, but it is
destroyed when these solutions are boiled,[5] therefore
the reaction of 6 with aromatic aldehydes (reaction h in
Scheme 6) was carried out in ethanol with 10%
hydrochloric acid as catalyst at room temperature. The
obtained products (8-12) are yellow solids melting at
about 200ꢀC (see Experimental).
3 | CONCLUSIONS
4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-methylquinazoli-
ne (2) was synthesized and used as a key compound
for further transformation to 4,6,7-trimethoxy-2-meth
ylquinazoline (3), 6,7-dimethoxy-2-methylquinazolin-4-ol
(4), 5,6-dimethoxy-2-methyl-3H-indol-3-one (5), 1-(6,7-dime
thoxy-2-methyl-quinazolin-4-yl)ethanone (6), 6,7-dimetho
xy-2-methyl-4-(1-[2-phenylhydrazono]ethyl)quinazoline (7),
(E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-3-phenylpro
p-2-en-1-one (8), (E)-1-(6,7-dimethoxy-2-methylquinazolin-
4-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (9), (E)-1-(6,7-
dimethoxy-2-methyl-quinazolin-4-yl)-3-(4-[dimethylamino]
phenyl)prop-2-en-1-one (10), (E)-1-(6,7-dimethoxy-2-meth
yl-quinazolin-4-yl)-3-(4-nitrophenyl)prop-2-en-1-one (11) and
(E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-3(2-nitrophe-
nyl)prop-2-en-1-one (12). Detailed NMR spectroscopic
investigations with all prepared compounds were performed.
The pathway of some unprecedented reactions was proposed.
Compound 11 exhibits high in vitro cytotoxicity on three cell
lines, Hepatocellular carcinoma (Hep-G2), Human lung carci-
noma (LU-1), and Human breast carcinoma (MCF-7) with
IC50 is 2.1, 11.6 and 2.2 μM respectively.
Two IR absorption bands at 1656-1691 and
1611-1615 cm−1 of 8-12 are associated with conjugated
α,β-unsaturated carbonyl system of Hr-CO-CH=CH-Ar.
Two doublets at 7.51-7.92 and 7.67-8.10 ppm with
J = 16 Hz (Table 3) confirm the presence of trans
-CH=CH- group in molecules of 8-12. By using HMBC
1
spectra all H NMR and 13C NMR signals of 8-12 were
assigned as listed in Table 3.
Compounds 2, 4, 5, 7, 10 and 11 were tested for cell
in vitro cytotoxicity on four cell lines Human epidermic
carcinoma (KB), Hepatocellular carcinoma (Hep-G2),
Human lung carcinoma (Lu), and Human breast carci-
noma (MCF-7). The cell in vitro cytotoxicity of examined
compounds, IC50 (μM), are listed in Table 1. The potency
of the anticancer effect of the tested compounds was
compared with ellipticine which was used as a standard
drug. All selected compounds exhibited quite good anti-
cancer activity with selectivity of one or some cancer cell
lines. Especially, compounds 7 and 11 performed IC50
values close to that of the standard drug on Hep-G2 and
MCF-7, ccompound 7 also inhibited well KB cell line,
Table 1.
3.1 | Experimental Section
3.1.1 | General
IR spectra were recorded on an IMPACK-410 NICOLET
spectrometer in KBr discs at 400-4000 cm−1. ESI mass

HOAN ET AL.
7
spectra were recorded using Agilent LC-MSD-Trap-SL
series 1100 spectrometer. NMR spectra were recorded on
a Bruker AVANCE 500 MHz spectrometer, in DMSOd6
with TMS as the internal standard, at 298-300 K. C, H,
and N were analyzed on a LECO CHNS model 932 ele-
mental analyser. The anticancer activities were tested at
the Experimental Biological Laboratory - Institute of
Chemistry of Natural Compounds (in Hanoi), according
to the described method;[14] IC50 values were calculated
based on OD values taken on an Elisa instrument at
515-540 nm.
grey precipitate was filtered out and the filtrate was left
at room temperature to give white crystals (3) in 122 mg
and 52% yield, mp 164-166ꢀC. IR (cm−1): 3045, 2976 (C-
1
H); 1611, 1560, 1512 (ring). H NMR and 13C NMR see
Table 2. ESI, +MS, m/z (au)/relative intensity (%):
235/100 (M + H+). Anal. Calcd for C12H14N2O3
(M 234.25): C, 61.53; H, 6.02; N, 11.96. Found: C,
61.23; H, 6.31; N, 12.14.
6,7-Dimethoxy-2-methylquinazolin-4-ol (4)
A solution of 2 (312 mg, 1 mmol) in hydrochloric acid 1:1
(5 mL) was heated at 50ꢀC and a solution of KClO3
(367 mg in 5 mL water) was slowly added during
30 minutes under stirring. The reaction mixture
was stirred for 1 hour at 50ꢀC. The precipitate was filtered
out, washed with water and recrystallized from 95% EtOH
to give white crystals (4) in 180 mg and 59% yield, mp
173-175ꢀC. IR (cm−1): 3452 (OH); 2985, 2922(C-H); 1611,
3.1.2 | Preparation
4-(2-acetamido-4,5-dimethoxyphenyl)-3-methyl-
1,2,5-oxadiazole-2-oxide (1)
A
solution of 4,5-dimethoxy-2-(3-methylfuroxan-4-yl)
1
phenylamine (Am, previously prepared in reference [10],
2.51 g, 10 mmol) in ethanol (200 mL) and acetic anhy-
dride (1 mL, 10.5 mmol) was refluxed for 3 hours. After
cooling down to room temperature, the precipitate was
filtered out and recrystallized from EtOH to give white
crystals (1) in 2.34 g and 80% yield, mp 171-172ꢀC. IR
(cm−1): 3261 (NH); 3044, 2952, 2836 (C-H); 1672 (C=O);
1618, 1531, 1487 (ring). 1H NMR and 13C NMR see
Tables 2. ESI, +MS, m/z (au)/relative intensity (%):
316/100 (M + Na+). Anal. Calcd for C13H15N3O5
(M 293.28): C, 53.24; H, 5.16; N, 14.33. Found: C,
52.98; H, 5.35; N, 14.65.
1468 (ring). H NMR and 13C NMR see Table 2. ESI, MS,
m/z (au)/relative intensity (%): +MS, 220.9/100 (M + H+);
-MS, 218.8/30 (M-H+), 203.8/100 (M-H+-Me). Anal. Calcd
for C11H12N2O3 (M 220.22): C, 59.99; H, 5.49; N, 12.72.
Found: C, 59.68; H, 5.24; N, 12.89.
5,6-Dimethoxy-2-methyl-3H-indol-3-one (5)
A mixture of 2 (312 mg, 1 mmol) in NaOH solution (1 g
in 10 mL of water) was refluxed for 6 hours. After cooling
down to room temperature, the precipitate was filtered
out and recrystallized from EtOH-H2O 1:1 by volume to
give yellow needle crystals (5) in 168 mg and 82% yield,
decomposed at 253-255ꢀC. IR (cm−1): 3021, 2999, 2896
(C-H); 1671 (C=O); 1637, 1613, 1505 (ring). 1H NMR and
13C NMR see Tables 2. Anal. Calcd for C11H11NO3
(M 205.21): C, 64.38; H, 5.40; N, 6.83. Found: C, 64.69; H,
5.15; N, 6.55.
4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-
2-methylquinazoline (2)
To a solution of POCl3 (8 mL) and DMF (4 mL) at 0-5ꢀC,
2 (1.85 g, 7 mmol) was slowly added and stirred. The
reaction mixture was heated at 60ꢀC and stirred for 4 h.
After cooling down to room temperature, 30 mL cool
water (0-5ꢀC) was added. The obtained mixture was
neutralised with 5 M NaOH solution. The precipitate was
filtered out and recrystallized from EtOH-H2O 1:1 by vol-
ume to give dark yellow needles (2) in 1.396 g (64%
yield), mp 167-168ꢀC. IR (cm−1): 3080, 2991, 2935 (C-H);
1613, 1565, 1500 (ring). 1H NMR and 13C NMR see
Table 2. ESI, +MS, m/z (au)/relative intensity (%):
[311.9/52, 314.0/20 (M + H+)]; [265.9/100, 267.9/38 (M
+ H+-NO2]. Anal. Calcd for C13H14ClN3O4 (M 311.07): C,
50.09; H, 4.53; N, 13.48. Found: C, 49.81; H,
4.75; N, 13.20.
1-(6,7-Dimethoxy-2-methylquinazolin-4-yl)ethanone (6)
Na2S2O4 (5.32 g) was dissolved in 0.75 M NaOH solution
(40 mL) to form first solution. A solution of 2 (1.56 g,
5 mmol) in ethanol (30 mL) was heated at 70ꢀC and the
first solution was slowly added during 1 hour under stir-
ring. The reaction mixture was stirred for additional
2 hours at 70ꢀC, and then ethanol was evaporated. After
cooling, ice (20 g) was added. The precipitate was filtered
out, washed with water and recrystallized from 95%
EtOH to give yellow crystals (6) in 763 mg and 62% yield,
mp 185-186ꢀC. IR (cm−1): 3130, 3020, 2924, 2830(C-H);
1
1691 (C=O); 1615, 1555, 1450 (ring). H NMR and 13C
NMR see Table 2. ESI, +MS, m/z (au)/relative intensity
(%): 246.9/100 (M + H+). Anal. Calcd for C13H14N2O3
(M 246.10): C, 63.40; H, 5.73; N, 11.38. Found: C,
63.09; H, 5.95; N, 11.57.
4,6,7-Trimethoxy-2-methylquinazoline (3)
A solution of AgNO3 (170 mg, 1 mmol) and 2 (312 mg,
1 mmol) in ethanol (25 mL) was refluxed for 3 h. The

8
HOAN ET AL.
1
6,7-dimethoxy-2-methyl-4-(1-[2-phenylhydrazono]ethyl)
quinazoline (7)
(-CO-CH=CH-); 1580, 1548, 1527 (ring). H NMR and
13C NMR see Table 3. Anal. Calcd for C22H23N3O3
(M 377.44): C, 70.01; H, 6.14; N, 11.13. Found: C,
69.72; H, 5.94; N, 11.41.
To a solution of 6 (246 mg, 1 mmol) in EtOH (15 mL) at
60ꢀC, a solution of C6H5NHNH2.HCl (145 mg, 1 mmol),
CH3COONa (82 mg, 1 mmol) in EtOH (10 mL) was
slowly added under stirring. The reaction mixture was
stirred for 5 hours at 60ꢀC and left at room temperature
to give an orange precipitate. The precipitate was filtered
out and recrystallized from 95% EtOH to afford orange
needles (7) in 235 mg (70% yield), mp 151-153ꢀC. IR
(cm−1): 3443, 3250 (NH); 2922, 2852 (C-H); 1601, 1543,
(E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-
3-(4-nitrophenyl)prop-2-en-1-one (11)
This compound was prepared starting from 2 (246 mg,
1 mmol) and 4-O2NPh-CHO (151 mg, 1 mmol) according
to the procedure for the preparation of 8. The yield was
258 mg (68%), yellow needles (11) mp 195-196ꢀC. IR
(cm−1): 3090, 2980, 2848 (C-H); 1674/1610 (-CO-
CH=CH-); 1599, 1552, 1523 (ring). 1H NMR and 13C
NMR see Table 3. Anal. Calcd for C20H17N3O5
(M 379.37): C, 63.32; H, 4.52; N, 11.08. Found: C,
63.61; H, 4.24; N, 11.31.
1
1451 (ring). H NMR and 13C NMR see Table 3. Anal.
Calcd for C19H20N4O2 (M 336.39): C, 67.84; H, 5.99; N,
16.66. Found: C, 67.52; H, 6.21; N, 16.35.
(E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-
3-phenylprop-2-en-1-one (8)
To a solution of 6 (246 mg, 1 mmol) in concentrated
hydrochloric acid (5 mL) and water (4 mL), a solution of
PhCHO (106 mg, 1 mmol) in EtOH (5 mL) was slowly
added under stirring. The reaction mixture was stirred
for 24 hours at room temperature. The obtained mixture
was neutralized with 10% NaOH solution. The precipitate
was filtered out and recrystallized from 95% EtOH to
afford yellow needles (8) in 248 mg (71% yield), mp
183-184ꢀC. IR (cm−1): 3093, 2922, 2852 (C-H); 1665/1615
(E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-
3-(2-nitrophenyl)prop-2-en-1-one (12)
This compound was prepared starting from 2 (246 mg,
1 mmol) and 2-O2NPh-CHO (151 mg, 1 mmol)
according to the procedure for the preparation of 8.
The yield was 216 mg (57%), yellow needles (12) mp
172-193ꢀC. IR (cm−1): 3070, 2923, 2851 (C-H);
1
1681/1615 (-CO-CH=CH-); 1555, 1506, 1450 (ring). H
NMR and 13C NMR see Table 3. Anal. Calcd for
C20H17N3O5 (M 379.37): C, 63.32; H, 4.52; N, 11.08.
Found: C, 63.59; H, 4.26; N, 11.37.
1
(-CO-CH=CH-); 1593, 1551, 1521 (ring). H NMR and
13C NMR see Table 3. Anal. Calcd for C20H18N2O3
(M 334.37): C, 71.84; H, 5.43; N, 8.38. Found: C, 72.04; H,
5.18; N, 8.06.
ORCID
Duong Quoc Hoan https://orcid.org/0000-0001-7540-
6142
Trinh Thi Huan https://orcid.org/0000-0002-4584-822X
Nguyen Huu Dinh https://orcid.org/0000-0001-9536-
5069
(E)-1-(6,7-dimethoxy-2-methylquinazolin-4-yl)-
3-(4-methoxyphenyl)prop-2-en-1-one (9)
The compound was prepared starting from 2 (246 mg,
1 mmol) and 4-MeOPh-CHO (136 mg, 1 mmol) according
to the procedure for the preparation of 8. The yield was
237 mg (65%), yellow needles (9) mp 187-189ꢀC. IR
(cm−1): 2966, 2923, 2850 (C-H); 1664/1617 (-CO-
CH=CH-); 1597, 1547, 1499 (ring). 1H NMR and 13C
NMR see Table 3. ESI, MS, m/z (au)/relative intensity
(%): +MS, 396.9/70 (M + MeOH+H+); -MS, 394.8/100
(M + MeOH-H+). Anal. Calcd for C21H20N2O4
(M 364.39): C, 69.22; H, 5.53; N, 7.69. Found: C, 69.54; H,
5.28; N, 7.86.
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178-180ꢀC. IR (cm−1): 3095, 2926, 2860 (C-H); 1658/1615

HOAN ET AL.
9
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How to cite this article: Hoan DQ, Hoa LT,
Huan TT, Dinh NH. Synthesis and Transformation
of 4-(1-Chloro-1-nitroethyl)-6,7-dimethoxy-2-
methylquinazoline: Spectral Characterization and
Anti-cancer Properties of some Novel Quinazoline
Derivatives. J Heterocyclic Chem. 2020;1–9. https://
doi.org/10.1002/jhet.3897