Synthesis of novel quinazolinone derivatives with methyl (E)-2-(3-methoxy)acrylate moiety

Article abstract of DOI:10.14233/ajchem.2013.13405

A new series of quinazolinone derivatives with methyl (E)-2-(3-methoxy) acrylate moiety have been designed and synthesized. All target compounds had been identified by ¹H NMR spectrum, IR spectrum and HR-MS (high resolution mass spectrum). Three target compounds (10a, 10e, 10h) were chosen to preliminarily test the antibacterial activities, the results showed that all three target compounds exhibited antibacterial activities against three bacterial strains (Proteobacteria, Salmonella, Colibacillus).

Full text of DOI:10.14233/ajchem.2013.13405

Asian Journal of Chemistry; Vol. 25, No. 2 (2013), 1039-1042
http://dx.doi.org/10.14233/ajchem.2013.13405
Synthesis of Novel Quinazolinone Derivatives with Methyl (E)-2-(3-methoxy)acrylate Moiety
1
2
1
2
1,*
KUI-KUI DONG , HUA-HONG ZHOU , A-RONG GUO , TIAN CHEN and YU-LIANG WANG
1Faculty of Chemistry, Sichuan University, Chengdu 610065, P.R. China
2Department of Pathogenic Biology, School of Biomedical Science, Chengdu Medical College, Chengdu 610083, P.R. China
*Corresponding author: Tel: +86 153781 95811, E-mail: chemwang2008@163.com; allendkk@163.com
(Received: 7 January 2012;
Accepted: 30 August 2012)
AJC-12039
A new series of quinazolinone derivatives with methyl (E)-2-(3-methoxy)acrylate moiety have been designed and synthesized. All target
compounds had been identified by 1H NMR spectrum, IR spectrum and HR-MS (high resolution mass spectrum). Three target compounds
(10a, 10e, 10h) were chosen to preliminarily test the antibacterial activities, the results showed that all three target compounds exhibited
antibacterial activities against three bacterial strains (Proteobacteria, Salmonella, Colibacillus).
Key Words: Quinazolinone derivatives, Methyl (E)-2-(3-methoxy)acrylate, Synthesis, Identification, Antibacterial activity.
INTRODUCTION
EXPERIMENTAL
Quinazoline derivatives (Fig. 1) are recognized as a class
of important heterocycles for their pharmacological properties,
such as antifungal, antibacterial and anticoccidial activities.
Fenazaquin(I), was successfully developed by Dow-Elanco
company as a kind of high efficient acaricides1. Fluquinconazole
(II), a triazole microbicide with quinazoline structure commer-
cialized by Schering2, can prevent and cure powdery mildew,
apple scab in a concentration of 2.5-15 g/L. Compound(III)
showed antibacterial activity against Staphylococcus aureus
in a very low concentration3, compounds (IV)4, (V)5 and (VI)6
also showed potent antimicrobial activities. In 1967
halofuginone (VII) (commercial name Stenorol) was designed
and synthesized based on the structure of febrifugine7.
Halofuginone is a broad-spectrum anticoccidial medicine with
low toxicity and no cross-resistance8. Compared to other
anticoccidial drugs, halofuginone has a higher anticoccidial
activity when administered to chickens.
Starting materials were either commercially available or
prepared as the method reported in the literature 9,14. Melting
points were determined with XRC-1 melting point apparatus
without corrected. Analytical TLC was performed on silica
gel GF254, and spots were visualized with ultraviolet (UV) light.
IR spectra were recorded on a Perkin-Elemer 16PC-FT spectro-
meter. Mass spectra (MS) were recorded with Agilent 6210
(DOF-MAS) spectrometer (Agilent Inc., Santa Clara, CA,
USA) using the electrospray ionization (ESI) method. 1H NMR
spectra were run on aVarian INVOA-400 spectrometer. Chemical
shift values (δ) are given in ppm and were downfield from
internal tetramethylsilane. The reagents were all analytically
or chemically pure.All solvents (except DMSO in the synthesis
of compounds 10a-h) and liquid reagents were used without
further purification.
2-[2-(6-Chloro-pyrimidin-4-yloxy)phenyl]-3-methoxy-
acrylic acid (5) was prepared according to the literature14 with
little modification. In the synthesis of 2-[2-(6-chloro-pyrimidin
-4-yloxy)-phenyl]-3-methoxy-acrylic acid methyl ester (4),
sodium methoxide was freshly prepared by sodium and methanol,
because sodium methoxide placed for a long time would reduce
the yield. And 5 was purified by column chromatography.
6,8-Substituted-3H-quinazolin-4-one (9a-h) were
synthesized according to the literature9.
In previous publications, several series of compounds
(VIII)9, (IX)10 and (X)11 exhibited anticoccidial activity against
Eimeria tenella in the chicken's diet with a dose of 9 or 18
mg/Kg. And a series of compounds (XI)12 displayed potent
antibacterial activity against Staphylococcus aureusATCC26112
and Staphylococcus aureus SC. These studies have encouraged
a continuing search for new varieties of compounds with novel
modes of bioactivity. In this article, a new series of quinazoline
derivatives (10a-h) with methyl (E)-2-(3-methoxy)acrylate
moiety have been used in the synthesis of several agricultural
fungicides13 were designed and prepared.
Synthesis of 6,8-substituted-3-methoxy-2-{2-[6-(4-oxo-
4H-quinazolin-3-yl)-pyrimidin-4-yloxy]phenyl}acrylic acid
methyl ester (10a-h): A solution of 0.84 g 5 (0.0026 mol) in 5
mL DMSO was added dropwise to a mixture of 9a-h (0.0031

1040 Dong et al.
Asian J. Chem.
O
N
Cl
Cl
O
N
N
H
Cl
N
F
H
N
N
N
N
O
I
N
Cl
N
III
II
CH3
O
O
N
O
N
O
N
N
CH
N
Br
N
N
Cl
N
N
N
Cl
O
F
Br
Cl
F
IV
V
VI
O
O
HO
O
N
O
R1
R1
Cl
Br
N
N
N
H
N
O
O
O
O
N
N
R2
R2
IX
VII
VIII
O
O
N
Me
OH
S
O
HN
O
R1
R1
N
N
Me
Me
O
O
Me
N
R2
R2
O
XI
X
Fig. 1. Quinazolinones derivaties and methyl (E)-2-(3-methoxy)acrylate derivaties
mol), 0.35 g KI, 0.075 g (0.0031 mol) NaH and 15 mL DMSO
under stirring at 75 ºC. After 10 h the mixture was cooled to
room temperature and then 40 mL water and 20 mL ethyl
acetate was added. The organic layer was separated, washed
with 40 mL water, dried over anhydrous Na2SO4 and concen-
trated under reduced pressure to give a crude product, which
was chromatographed on a silica gel column using petroleum
ether-ethyl acetate (2:1 v/v) as the mobile phase to give 10a-h
(Scheme-I).
850, 806, 768; HR-MS (+ESI): Calcd. for C23H18N4O5Cl
[M+H]+: 465.0966, Found: 465.0953.
2-{2-[6-(6,8-Dichloro-4-oxo-4H-quinazolin-3-yl)-
pyrimidin-4-yloxy]phenyl}-3-methoxy-acrylic acid methyl
ester (10b): Light yellow solid; yield: 25.78 %; m.p.: 168-
170 ºC; 1H NMR (400 MHz; d1-CDCl3; TMS): δ (ppm): 9.00
(1H, s, Quina-H), 8.78 (1H, s, Py-H), 8.41 (1H, d, J = 2Hz,
Ar-H), 8.03 (1H, d, J = 2.4Hz, Ar-H), 7.63 (1H, s, CH), 7.48
(1H, s, Py-H), 7.23-7.45 (4H, m, Ar-H), 3.76 (3H, s, CH3),
3.62 (3H, s, CH3); IR (KBr, νmax, cm-1): 3431, 2961, 2926,
2855, 1699, 1617, 1578, 1455, 1407, 1323, 1260, 1098, 1026,
902, 869, 804, 702; HR-MS (+ESI): Calcd. for C23H17N4O5Cl2
[M+H]+: 499.0576, Found: 499.0555.
2-{2-[6-(8-Chloro-4-oxo-4H-quinazolin-3-yl)-pyrimidin-
4-yloxy]phenyl}-3-methoxy-acrylic acid methyl ester (10a):
Light yellow solid; yield: 31.03 %; m.p.: 165-167 ºC; 1H NMR
(400 MHz; d1-CDCl3; TMS): δ (ppm): 9.00 (1H, s, Quina-H),
8.78 (1H, s, Py-H), 8.29 (1H, d, J = 7.6Hz, Ar-H), 7.91 (1H,d,
J = 7.6 Hz, Ar-H), 7.66 (1H, s, CH), 7.56 (1H, m, Ar-H), 7.49
(1H, s, Py-H), 7.31-7.43 (4H, m, Ar-H), 3.75 (3H, s, CH3),
3.63 (3H, s, CH3); IR (KBr, νmax, cm-1): 3420, 3109, 2960,
2838, 1704, 1627, 1445, 1386, 1260, 1213, 1102, 1044, 900,
2-{2-[6-(6-Chloro-4-oxo-4H-quinazolin-3-yl)-pyrimidin-
4-yloxy]phenyl}-3-methoxy-acrylic acid methyl ester (10c):
White solid; yield: 32.59 %; m.p.: 166-168 ºC; 1H NMR (400
MHz; d1-CDCl3; TMS): δ (ppm): 8.88 (1H, s, Quina-H), 8.78
(1H, s, Py-H), 8.33 (1H, d, J = 1.6Hz, Ar-H), 7.76 (1H, dd, J1

Vol. 25, No. 2 (2013)
Synthesis of Novel Quinazolinone Derivatives with Methyl (E)-2-(3-methoxy)acrylate Moiety 1041
N
N
CHOCH
3
COOH
HO
Cl
O
OH
O
O
O
O
O
O
O
O
O
O
1
2
3
4
5
R
R
1
R
R
1
1
1
NH
N
2
NO2
CH3
NO2
KMnO4
TBAB
H2
HCONH2
NH
R
Pd/C
2
R2
COOH
R2
R2
COOH
O
6a-h
7a-h
8a-h
9a-h
N
N
O
O
O
R
2
N
O
N
O
R
1
10a-h
6a-10a: R1 = Cl, R2 = H; 6b-10b: R1 = Cl, R2 = Cl; 6c-10c: R1 = H, R2 = Cl; 6d-10d: R1 = H, R2 = F;
6e-10e: R1 = Br, R2 = Br; 6f-10f: R1 = H, R2 = H; 6g-10g: R1 = H, R2 = I; 6h-10h: R1 = Cl, R2 = Br
Scheme-I: Synthetic route of compound 10a-h
= 8.8 Hz, J2 = 2 Hz, Ar-H), 7.72 (1H, d, J = 8.4 Hz, Ar-H), 7.65
(1H, s, CH), 7.49 (1H, s, Py-H), 7.24-7.45 (4H, m, Ar-H), 3.76
(3H, s, CH3), 3.63 (3H, s, CH3); IR (KBr, νmax, cm-1): 3434,
3068, 2945, 2848, 1697, 1623,1574, 1446,1381, 1251, 1205,
1127, 832, 769; HR-MS (+ESI): Calcd. for C23H18N4O5Cl
[M+H]+: 465.0966, Found: 465.0955.
m, Ar-H), 3.75 (3H, s, CH3), 3.63 (3H, s, CH3); IR (KBr, νmax
,
cm-1): 3433, 2960, 2924, 2852, 1699, 1628, 1562, 1449, 1391,
1325, 1260, 1211, 1131, 1056, 900, 859, 781, 699; HR-MS
(+ESI): Calcd. for C23H19N4O5 [M+H]+: 431.1355, Found:
431.1341.
2-{2-[6-(6-Iodo-4-oxo-4H-quinazolin-3-yl)-pyrimidin-
4-yloxy]phenyl}-3-methoxy-acrylic acid methyl ester (10g):
Light yellow solid; yield: 34.25 %; m.p.: 181-183 ºC; 1H NMR
(400 MHz; d1-CDCl3; TMS): δ (ppm): 8.89 (1H, s, Quina-H),
8.77 (1H, s, Py-H), 8.70 (1H, d, J = 2 Hz, Ar-H), 8.08 (1H,
dd, J1 = 8.8 Hz, J2 = 2 Hz, Ar-H), 7.63 (1H, s, CH), 7.51(1H, s,
Py-H), 7.48 (1H, d, J = 5.2 Hz, Ar-H), 7.23-7.44 (4H, m, Ar-
H), 3.75 (3H, s, CH3), 3.62 (3H, s, CH3); IR (KBr, νmax, cm-1):
3431, 2961, 2923, 2852, 1700, 1629, 1565, 1453, 1383, 1294,
1259, 1204, 1100, 1026, 902, 803, 728; HR-MS (+ESI): Calcd.
for C23H18N4O5I [M+H]+: 557.0322, Found: 557.0301.
2-{2-[6-(6-Bromo-8-chloro-4-oxo-4H-quinazolin-3-yl)-
pyrimidin-4-yloxy]phenyl}-3-methoxy-acrylic acid methyl
ester (10h): Gray solid; yield: 33.21 %; m.p.: 228-230 ºC; 1H
NMR (400 MHz; d1-CDCl3; TMS): δ (ppm): 8.98 (1H, s,
Quina-H), 8.78 (1H, s, Py-H), 8.25 (1H, d, J = 2.4 Hz, Ar-H),
7.88 (1H, d, J = 2.4 Hz, Ar-H), 7.63 (1H, s, CH), 7.49 (1H, s,
Py-H), 7.23-7.45 (4H, m, Ar-H), 3.76 (3H, s, CH3), 3.62 (3H,
s, CH3); IR (KBr, νmax, cm-1): 3435, 2926, 2855, 1703, 1628,
1565, 1462, 1379, 1260, 1098, 1027, 865, 804, 721; HR-MS
(+ESI): Calcd for C23H17N4O5BrCl [M+H]+: 543.0071,
545.0050 (isotope:), Found: 543.0061, 545.0037 (isotope).
Biological assay: The antibacterial activities of three
target compounds were tested via agar-well diffusion method
in vitro. Target compounds (1000 µg) were dissolved with
ethanol (1 mL) and diluted to 20 µg/mL with ethanol,A 50 µL
solution of each compound was injected into the correspond-
ing well in the Luria Bertani (LB) culture medium, which was
covered with bacteria suspension in advance, and the plates
were incubated at 37 ºC for 24 h. The results of average diame-
ters of the bacteriostatic circle were listed in Table-1.
2-{2-[6-(6-Fluoro-4-oxo-4H-quinazolin-3-yl)-pyrimidin-
4-yloxy]phenyl}-3-methoxy-acrylic acid methyl ester (10d):
Light yellow solid; yield: 36.60 %; m.p.: 152-154 ºC; 1H NMR
(400 MHz; d1-CDCl3; TMS): δ (ppm): 8.85 (1H, s, Quina-H),
8.78 (1H, s, Py-H), 8.00 (1H, m, Ar-H), 7.79 (1H, dd, J1 =
8.8 Hz, J2 = 4.8Hz, Ar-H), 7.66 (1H, s, CH), 7.54 (1H, m, Ar-H),
7.49 (1H, s, Py-H), 7.24-7.45 (4H, m,Ar-H), 3.76 (3H, s, CH3),
3.63 (3H, s, CH3); IR (KBr, νmax, cm-1): 3033, 2949, 1699,
1624, 1486, 1444, 1561, 1332, 1258, 1200, 1131, 1103, 1064, 990,
901, 838, 766, 720; HR-MS (+ESI): Calcd. for C23H18N4O5F
[M+H]+: 449.1261, Found: 449.1256.
2-{2-[6-(6,8-Dibromo-4-oxo-4H-quinazolin-3-yl)-
pyrimidin-4-yloxy]phenyl}-3-methoxy-acrylic acid methyl
ester (10e): Light yellow solid; yield: 29.92 %; m.p.: 182-
184 ºC; 1H NMR (400 MHz; d1-CDCl3; TMS): δ (ppm): 9.00
(1H, s, Quina-H), 8.77 (1H, s, Py-H), 8.46 (1H, d, J = 2 Hz,
Ar-H), 8.20 (1H, d, J = 2 Hz, Ar-H), 7.62 (1H, s, CH), 7.48
(1H, s, Py-H), 7.23-7.44 (4H, m, Ar-H), 3.75(3H, s, CH3),
3.63 (3H, s, CH3); IR (KBr, νmax, cm-1): 3438, 3068, 2924,
2852, 1702, 1629, 1563, 1444, 1381, 1258, 1208, 1129, 902, 802,
665, 465; HR-MS (+ESI): Calcd for C23H17N4O5Br2 [M+H]+:
586.9566, 588.9545, 590.9525 (isotope:), Found: 586.9554,
588.9537, 590.9520 (isotope).
3-Methoxy-2-{2-[6-(4-oxo-4H-quinazolin-3-yl)-
pyrimidin-4-yloxy]phenyl}acrylic acid methyl ester (10f):
Light yellow solid; yield: 33.95 %; m.p.: 112-114 ºC; 1H NMR
(400 MHz; d1-CDCl3; TMS): δ (p.p.m.): 8.95 (1H, s, Quina-
H), 8.77 (1H, s, Py-H), 8.37 (1H, d, J = 8 Hz, Ar-H), 7.83
(1H, m, Ar-H), 7.78 (1H, d, J = 7.2Hz, Ar-H), 7.67 (1H, s,
CH), 7.57 (1H, m, Ar-H), 7.49 (1H, s, Py-H), 7.24-7.45 (4H,

1042 Dong et al.
Asian J. Chem.
TABLE-1
In vitro ANTIBACTERIAL ACTIVITYOF 10a, 10e AND 10 h
AT THE CONCENTRATION 20.0 µg/mL
observed at 7.42-8.70 ppm assigned to C-H protons from
position 5 and position 8, when 10a-h was substituted at position
8 (example 10a), a multiplet and two doublets were observed
at 7.56-8.29 ppm, when 10a-h was substituted at both position
6 and position 8, two doublets were observed at 8.03-8.46
ppm, when there was no substitution (10f), two doublets and
two multiplets were observed at 7.57-8.37 ppm. The structural
assignments of compounds 10a-h were also supported by its
IR spectrum, Example for 10c, the C-Cl exhibited strong
absorption at 1127 cm-1, and the C=CH group exhibited absorp-
tion at 3068 cm-1, other groups aslo had the corresponding
absorption peaks. The high resolution mass spectrometer of
compounds 10a-h showed that all the errors between the
calculated value and measured value of molecular mass were
less than 0.0021.
Diameter of inhibition zone (mm)
Compound
Proteobacteria
Salmonella
Colibacillus
11
13
14
7
10
14
9
11
9
10a
10e
10h
Ethanola
10
7
7
aNegative control: ethanol; diameter of the well in each plate: 6 mm
RESULTS AND DISCUSSION
In the synthesis of intermediate 4, the temperature and
the quality of sodium methoxide influenced the yeild signifi-
cantly. The mixture of intermediate 3 in THF should be added
dropwise to a mixture of sodium methoxide and methanol
while the temperature was lower than 5 ºC. Additionally, the
sodium methoxide should be freshly prepared by sodium and
methanol.
Biological activity: The results of antibacterial activities
showed that all three target compounds (10a, 10e, 10h) exhi-
bited antibacterial activities against three bacterial strains
(Proteobacteria, Salmonella, Colibacillus) at the concentration
20.0 µg/mL.
In the synthesis of intermediate 9a-h, methanamide was
used as both solvent and reactant. Through screening, the
optimum ratio of 8a-h :methanamide was 1:5.
Conclusion
In summary, a series of novel quinazolinone derivatives
with a methyl-(E)-2-(3-methoxy)acrylate group had been designed
and synthesized and characterized by spectroscopy. Three target
compounds were chosen to simply test the antibacterial activi-
ties, the results showed that all three target compounds (10a, 10e,
10h) exhibited antibacterial activities against three bacterial
strains (Proteobacteria, Salmonella, Colibacillus) at the concen-
tration 20.0 µg/mL.
The acidity of intermediate 9a-h is so weak that K2CO3
and NaOH could not work to form the related sodium salt.
Finally, NaH was chosen because hydrogen, the only by-product
of this reaction, could escaped and the reaction system became
simple.According to the literature16, the methyl-(E)-2-(3-methoxy)-
acrylate group was unstable in alkaline environment, so the
alkalinity of reaction system should be maintained at a low
level. Intermediate 5 was added afer intermediate 9a-h and
NaH had been stirred together for 2 h, this could ensure inter-
mediate 9a-h and NaH had been adequately reacted and pro-
vided a low alkalinity.
ACKNOWLEDGEMENTS
The author appreciated the financial support from the
National Science Foundation of China (No. 21072135) and
Chengdu Medical College for the antibacterial activity test
(cx 20100037).
The amount of intermediate 5 was excessive to improve
the yeild. The optimum ratio of intermediate 9a-h: NaH: in-
termediate 5 was set at 1:1.25:1.25.
Temperature was another important influencing factor.
The synthetic reaction of 10a-h ran slowly at room tempe-
rature.An increase in temperature could speed up the process,
75-78 ºC was identified as the best condition.
REFERENCES
1. J.M. Huang, Chem. J. Chin. Univ., 8, 1216 (2000).
2. P.R. Russell, Pesticides, 27, 33 (1988).
3. S. Jantova, S. Stankovsk and K. Spirakova, Biologica Bratislava, 59,
741 (2004).
Among the commonly polar aprotic solvents, DMSO was
the best solvent. When DMF was used as solvent, NaH reacted
slowly with DMF at 75-78 ºC, which consumed the NaH, thus
decreased the yield, anhydrous DMSO could meet the reaction
condition well.
4. Y. Zhou, D. Murphy, Z. Sun and V. Greogr, Tetrahedron Lett., 45, 8049
(2004).
5. P. Panneerselvam, B.A. Rather, D.R.S. Reddy and N.R. Kumar, Eur. J.
Med. Chem., 44, 2328 (2009).
6. P.M. Chandrika, T.Yakaiah, A.R.R. Rao, B. Narsaiah, N. Chakra Reddy,
V. Sridhar and J.V. Rao, Eur. J. Med. Chem., 43, 846 (2008).
7. W.P. Emanuel, U.S. Patent 3320124 (1967).
8. C.C. Norton and D.R. Wise, The Veter. Rec., 109, 554 (1981).
9. J.H. You, C.W. Ye, Y.B. Weng, X.H. Mo and Y.L. Wang, Arkivoc, 1
(2008).
Products 10a-h were all new compounds and their
1
structrures were deduced from spectral datas. The H NMR
spectrum of compounds 10a-h all displayed two singlets at
3.62-3.76 ppm for two CH3 groups and a multiplet at 7.23-
7.45 ppm for 4 H protons on benzene ring, two singlets at
about 7.49 and 8.48 ppm for 2 H protons on pyrimidine ring,
a singlet at about 7.63 ppm from a C=CH proton and a singlet
at about 9.00 ppm from a N=CH proton. The difference was
present in benzene ring of quinazolinone: when 10a-h was
substituted at position 6 (example 10c), a signal was observed
at 7.76 ppm (dd, J1 = 8.8 Hz, J2 = 2 Hz) assigned to a C-H proton
from position 7, another two doublets or two multiplets were
10. Y.Y. Zhang and G.M. Chen, Lett. Drug Design Discov., 7, 471 (2010).
11. C.W. Ye and J.H. You, Pesticide Biochem. Physiol., 97, 194 (2010).
12. Y.-P. Yao and F.-Y. Dai, J. Chem. Res., 4 (2011).
13. W.A. Battaglin, M.W. Sandstrom, K.M. Kuivila, D.W. Kolpin and M.T.
Meyer, Water Air Soil Pollut., 218, 307 (2011).
14. J. Dong, D.-H. Liao, J.-S. Lou and H.-J. Pi, Fine Chem. Intermed., Vol.
37, No. 2.