Oxidative Rearrangement of Isatins with Arylamines Using H2O2 as Oxidant: A Facile Synthesis of Quinazoline-2,4-diones and Evaluation of Their Antibacterial Activity

Article abstract of DOI:10.1002/cjoc.201700280

A green and highly efficient synthetic method for the synthesis of quinazoline-2,4-diones with hydrogen peroxide as the terminal oxidant has been developed. The reaction features the mild reaction conditions, broad substrate scope, metal-free catalysts, and sole byproduct water. A plausible mechanism for this process was proposed. Moreover, an antibacterial activity study was performed to evaluate the antimicrobial activities towards two Gram-negative bacterial strains (Escherichia coli, and Klebsiella pneumonia) and two Gram-positive bacterial strains (Staphylococcus epidermidis, and Staphylococcus aureus) using the Broth microdilution method.

Full text of DOI:10.1002/cjoc.201700280

FULL PAPER
DOI: 10.1002/cjoc.201700280
Oxidative Rearrangement of Isatins with Arylamines Using
H2O2 as Oxidant: A Facile Synthesis of Quinazoline-2,4-diones
and Evaluation of Their Antibacterial Activity
Guanghao Shi, Xinwei He, Yongjia Shang,* Cheng Yang, and Liwei Xiang
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Key Laboratory of Molecule-Based
Materials, College of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, China
A green and highly efficient synthetic method for the synthesis of quinazoline-2,4-diones with hydrogen perox-
ide as the terminal oxidant has been developed. The reaction features the mild reaction conditions, broad substrate
scope, metal-free catalysts, and sole byproduct water. A plausible mechanism for this process was proposed. More-
over, an antibacterial activity study was performed to evaluate the antimicrobial activities towards two
Gram-negative bacterial strains (Escherichia coli, and Klebsiella pneumonia) and two Gram-positive bacterial
strains (Staphylococcus epidermidis, and Staphylococcus aureus) using the Broth microdilution method.
Keywords antibacterial activity, hydrogen peroxide, isatins, quinazoline-2,4-diones, rearrangement
Introduction
monoxide as a source of carbonyl,[10] Wang et al. de-
veloped a green method of iodine-catalyzed reaction of
2-aminobenzamides and triethyl orthoformate or tri-
phosgene in ionic liquid,[11] Willis et al. reported tandem
palladium-catalyzed urea arylation-intramolecular ester
amidation sequence to a diverse range of functionalized
quinazolinedione products.[12] Bergman et al. and Finlay
et al. utilized hydrogen peroxide as oxidant for the
preparation of quinazolino[4,5-b] quinazoline-6,8-dione
and quinazolin-4-amine in the presence of NaOH.[13]
Therefore, the development of a simple, effective, mild
and economic method for the preparation of quinazoli-
nones is still highly desirable.
Aqueous 30% hydrogen peroxide has recently been
utilized as an attractive and environmentally benign ox-
idant in organic synthesis,[14] because 30% hydrogen
peroxide is inexpensive, easy to handle, safely stored
and low toxicity considerations.[15] Furthermore, aque-
ous 30% hydrogen peroxide was also considered to be
one of the most straightforward, clean, and versatile
oxidant[16] from both an environmental and economic
perspective because H2O2 has a high content of active
oxygen and generates water as the sole byproduct.[17] As
a part of our ongoing efforts to determine the synthesis
of heterocyclic compounds and evaluation of their anti-
bacterial activity,[18] herein, we report a green one-pot
pathway for synthesis of quinazoline-2,4-dione deriva-
tives with isatins and arylamines by using aqueous 30%
hydrogen peroxide as oxidant in good to excellent yields
(Scheme 1). In addition, assessment results against two
As an important class of nitrogen-containing heter-
ocycles, quinazolinone is one of the ubiquitous structur-
al motifs that occur in natural products and pharmaceu-
tically active molecules.[1] Among them, quinazo-
line-2,4-dione and its derivatives are important com-
pounds for their wide range of biological activities, such
as anti-inflammatory,[2] antihypertensive,[3] anticancer,[4]
antitumor,[5] and antibacterial activity.[6] During recent
decades, conventional synthetic routes, including the
reactions of acyl azides or amines with triphosgene,
o-aminobenzamides with phosgene, isatoic anhydride
with amines, anthranilic acids with ureas, and the reac-
tions of potassium cyanates, isocyanates, and anthranil-
ates with N-aryldithio carbamates, have been developed
for constructing the quinazoline-2,4-dione framwork.[7]
In view of the great value of quinazoline-2,4-diones and
their analogs, various new methodologies for their syn-
thesis have been developed. For example, Azizian et al.
reported rearrangement of 4-imino-(1H,4H)-3,1-ben-
zoxazine-2-ones with m-chloroperbenzoic acid as oxi-
dant,[8] Alper et al. utilized o-iodoanilines with hetero-
cumulenes (e.g. isocyanates, carbodiimides, and
ketenimines) to obtain various quinazoline-2,4-diones
by using a catalyst system comprising palladium ace-
tate-bidentate phosphine under carbon monoxide pres-
sure.[9] Recently, some new, efficient and practical
methods have been reported. Yu reported selenium-cat-
alyzed carbonylation of o-nitrobenzamides with carbon
*
E-mail: shyj@mail.ahnu.edu.cn; Tel.: 0086-0553-5910129; Fax: 0086-0553-5910126
Received April 24, 2017; accepted June 19, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201700280 or from the author.
Chin. J. Chem. 2017, XX, 1—9
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Shi et al.
FULL PAPER
Gram-negative bacterial strains (E. coli, and K. pneu-
monia) and two Gram-positive bacterial strains (S. epi-
dermidis, and S. aureus) indicated that several com-
pounds exhibit moderate antibacterial activity specifi-
cally for the multi-drug resistant strain, S. aureus, which
provided unusual leads for further optimization during
the drug discovery process.
Table 1 Optimization of reaction conditionsa
Br
O
NH2
O
HN
30 % aq H2O2 (3 equiv.)
base (1.2 equiv.), solvent
+
O
N
O
Br
HN
1a
2i
Scheme 1 Synthesis of quinazoline-2,4-dione derivatives via
the rearrangement oxidation of isatins and arylamines using
aqueous 30% hydrogen peroxide as oxidant
3i
Entry
1
Base
Solvent
DCM
THF
T/℃ Time/h Yieldb/%
R3
N
O
O
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
－
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
4
12
8
8
8
75
56
30% aq H2O2 (3 equiv.)
NaHCO3 (1.2 equiv.)
O
2
HN
O
HN
+ R3 NH2
3
Et2O
47
CH3OH, r.t., 8 h
R2
R2
2
4
DMF
80
R1
R1
1
5
Acetonitrile
MeOH
EtOH
75
3
6
92
7
69
Results and Discussion
8
H2O
28
We started by studying the tandem reaction of isatin
(1a), 4-bromoaniline (2i), KF and 30% aqueous H2O2 in
MeOH at room temperature for 8 h (Table 1, entry 13).
To our delight, the reaction afforded 3-phenylquinazo-
line-2,4(1H,3H)-dione (3i) in 50% yield. The reaction
was further carried out in various bases, solvents and
temperatures to improve the yield, the results were
summaried in Table 1. The yield of 3i could be in-
creased to 92% when NaHCO3 was used as base (Table
1, entry 6). When using other inorganic bases, such as
NaOH, Na2CO3, a lower yield was obtained (Table 1,
entries 14, 15). In comparison to inorganic base, a trace
product was detected by LC-MS when organic bases
were used, such as pyridine, Et3N, and DMAP (Table 1
entries 10－12). It was found that base was found to be
critical for the reaction, a trace yield of the product was
observed by LC-MS in the absence of base (Table 1,
entry 9). To determine the ideal solvent for the trans-
formation, we investigated the model reaction in di-
chlormethane (DCM, 75%), tetrahydrofuran (THF,
56%), Et2O (47%), dimethylformamide (DMF, 80%),
acetonitrile (75%), MeOH (92%), EtOH (69%), and
H2O (28%) (Table 1, entries 1－8). The desired product
3i was obtained in all the tested solvents, and the polar
solvent MeOH gave the best isolated yield (Table 1,
entry 6). The influences of reaction time and tempera-
ture were also investigated, but the results were negative
(Table 1, entries 16－20). Thus, NaHCO3 was consid-
ered to be the best base, MeOH was the best solvent and
the reaction time was 8 h at room temperature (Table 1,
entry 6).
9
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
trace
trace
trace
trace
50
10
11
12
13
14
15
16
17
18
19
20
Pyridine
DMAP
Et3N
KF
NaOH
23
Na2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
45
62
92
79
60
82
reflux
80
a Reaction conditions: isatin 1a (0.1 mmol), 4-bromine aniline 2i
(0.1 mmol) and hydrogen peroxide (0.03 mL, 30%), base (0.12
mmol) and solvent (1.5 mL). b Isolated yield.
observed that the electric nature of the substituent on the
benzene ring of arylamines affected the yields of the
products. As illustrated in Table 2, arylamines with
electorn-withdrawing groups (e.g. －F, －Cl, －Br)
(Table 2, entries 6－9) resulted in higher yields than
those with electron-donating groups (e.g. － CH3,
－CH2CH3, －CH(CH3)2) (Table 2, entries 2, 3, 11－
14). When arylamines with a strong electron-donating
group (－OCH3) or an iodine group were subjected to
this reaction, the yields of the desired products de-
creased to 29% and 32% (Table 2, entries 4, 10). For
arylamines with a strong electron-withdrawing group
(－NO2), the reaction hardly took place (Table 2, entry
15). Similarly, when other amines, such as aliphatic
amines, heteroarylamines (Table 2, entries 31－33), and
disubstituted arylamines, such as 2,6-dimethylaniline,
2-bromo-6-methylaniline (Table 2, entries 34, 35), were
used as substrates under standard reaction conditions, no
desired product was obtained. The structure of the
With the optimized conditions in hand, we investi-
gated the substrate scope of isatins and arylamines to
test the generality of this reaction, the results are sum-
marized in Table 2. It was found that a variety of aryla-
mines reacted smoothly with isatin 2a to give the de-
sired products in moderate to excellent yields. It was
2
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Chin. J. Chem. 2017, XX, 1—9

A Facile Synthesis of Quinazoline-2,4-diones
product 3i was conformed by X-ray crystallographic
analysis as shown in Figure 1.
After the examination of arylamines, isatins were
also investigated. Isatins with electron-withdrawing
groups (e.g. －F, －Cl, －Br) resulted in higher yields
than those with electron-donating groups (e.g. －CH3,
－CH2CH3) (Table 2, entries 16－18, 20, 21). When
isatins with a strong electron-donating group (－OCH3)
or an iodine group were subjected to this reaction, the
yield of the desired products decreased to 35% and 43%,
respectively (Table 2, entries 19, 22, 26, 30).
On the basis of the results described above and pre-
vious studies,[20] we propose a possible mechanism for
the rearrangement oxidation of isatin 1a and arylamine
Figure 1 X-ray crystal structure of product 3i.[19]
Table 2 Synthesis of quinazoline-2,4-diones via rearrangement oxidation of isatins and arylamines using hydrogen peroxide as an oxi-
danta
Entry
R1, R2
R3
Product
Yieldb/%
1
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1b (F, H)
C6H5 (2a)
3a
3b
3c
3d
3e
3f
71
72
71
29
27
90
90
89
89
32
71
65
64
60
trace
88
89
91
35
73
72
35
88
72
87
43
89
90
87
2
4-CH3C6H4 (2b)
4-CH3CH2C6H4 (2c)
4-CH3OC6H4 (2d)
3-CH3OC6H4 (2e)
4-FC6H4 (2f)
3
4
5
6
7
4-ClC6H4 (2g)
3g
3h
3i
8
3-ClC6H4 (2h)
9
4-BrC6H4 (2i)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
4-IC6H4 (2j)
3j
2-CH3C6H4 (2k)
2-CH3CH2C6H4 (2l)
3-CH3CH2C6H4 (2m)
2-(CH3)2CHC6H4 (2n)
4-NO2C6H4 (2o)
4-CH3C6H4 (2b)
4-CH3C6H4 (2b)
4-CH3C6H4 (2b)
4-CH3C6H4 (2b)
4-CH3C6H4 (2b)
4-CH3C6H4 (2b)
4-CH3C6H4 (2b)
4-CH3C6H4 (2b)
4-CH3C6H4 (2b)
C6H5 (2a)
3k
3l
3m
3n
－
3o
3p
3q
3r
3s
1c (Cl, H)
1d (Br, H)
1e (I, H)
1f (CH3, H)
1g (CH3CH2, H)
1h (OCH3, H)
1i (H, Cl)
1j (H, CH3)
1b (F, H)
3t
3u
3v
3w
3x
3y
3z
3aa
3ab
1e (I, H)
C6H5 (2a)
1c (Cl, H)
1g (CH3CH2, H)
1g (CH3CH2, H)
4-(CH3)2CHC6H4 (2p)
4-FC6H4 (2f)
4-ClC6H4 (2g)
Chin. J. Chem. 2017, XX, 1—9
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3

Shi et al.
FULL PAPER
Continued
Entry
R1, R2
R3
Product
Yieldb/%
30
31
32
33
34
35
1h (OCH3, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
1a (H, H)
4-CH3CH2C6H4 (2c)
n-Bu (2q)
3ac
－
－
－
－
－
38
trace
trace
trace
trace
trace
CH3CH2 (2r)
2-pyridyl (2s)
2,6-(CH3)2C6H3 (2t)
2-CH3-6-BrC6H3 (2u)
a Reaction conditions: isatins 1 (0.1 mmol), arylamines 2 (0.1 mmol) and hydrogen peroxide (0.03 mL, 30%), NaHCO3 (0.12 mmol) at
room temperature in MeOH (1.5 mL) for 8 h. b Isolated yields.
S. aureus strain which is resistant to most known antibi-
otics (levofloxacin MIC＝32 μg/mL).
2a as shown in Scheme 2. Initially, the intermediate A is
produced by the Knoevenagel condensation between
isatin 1a and arylamine 2a in the presence of NaHCO3.
Subsequently, the intermediate B was generated from
the intermediate A via the Baeyer-Villiger oxidation
with hydrogen peroxide. Then, the intermediate D was
afforded from the intramolecular nucleophilic addition
of the isocyanate carboxamide intermediate C, which
was formed by the rearrangement of intermeditate B.
Finally, by the stabilization of the intermediate D, the
final product 3a was afforded.
Scheme 2 Possible reaction mechanism for the formation of the
quinazoline-2,4-diones
Figure 2 The photos of antibacterial activities with the synthe-
sized compounds.
The quinazoline-2,4-dione skeleton is the core
structure of many pharmacological agents and natural
alkaloids. It was the substitutions on quinazoline-2,4-
dione ring functionality that had distinctive effect on the
potency of these compounds against the tested bacterial
strains. For instance compound 3t, with 5-CH2CH3 on
quinazoline-2,4-dione ring and with 4-CH3 substituent
on the phenyl ring of arylamine was found to be the
most active against S. epidermidis and good antibacteri-
al activity against S. aureus. Similarly, compounds 3p,
3q, 3r and 3z with halogen groups (Cl, Br, I) on
quinazoline-2,4-dione ring were found to have good
antibacterial activity against S. aureus. Inaddition,
compounds 3t, 3u with an electron-donating group on
quinazoline-2,4-dione ring were also found to have
moderate antibacterial activity against S. aureus.
In the present study, the antibacterial activities of the
synthesized compounds were screened against two
Gram-negative bacterial strains (E. coli, and K. pneu-
monia) and two Gram-positive bacterial strains (S. epi-
dermidis, and S. aureus) using the Broth microdilution
method. The results revealed that the synthesized com-
pounds exhibited antibacterial activity against both S.
epidermidis and S. aureus. The results are summarized
in Table 3 and Figure 2. Compared to the standard bac-
teria against S. epidermidis, compound 3t showed im-
proved activity. In addition, compounds 3p, 3q, 3r, 3t,
3u and 3z showed good antibacterial activity against the
Conclusions
In summary, we have developed a green and effi-
cient one-pot synthetic route to prepare quinazo-
line-2,4-diones from readily available isatins and aryla-
mines using hydrogen peroxide as an oxidant at room
temperature. This rearrangement oxidation provided a
facile method to the direct synthesis of quinazoline-2,4-
diones and exhibited good functional group tolerability,
obviating the need for oxidants and only environmen-
tally benign H2O was released. This reaction is interest-
4
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Chin. J. Chem. 2017, XX, 1—9

A Facile Synthesis of Quinazoline-2,4-diones
1
ing in keeping with the notion of green chemistry be-
cause of the use of hydrogen peroxide as the terminal
oxidant. The antibacterial activity of all compounds was
also evaluated for both Gram-negative and Gram-posi-
tive bacteria. Some of the testing compounds inhibited
the growth of the Staphylococcus aureus, which could
potentially solve the problem of multidrug resistance.
cording to standard techniques. The H and 13C NMR
data were recorded on 400 MHz NMR spectrometers,
unless otherwise specified. Chemical shifts (δ) in parts
per million are reported relative to the residual signals
of chloroform (δ 7.26 for H and 76.1 for 13C). Multi-
1
plicities are described as s (singlet), d (doublet), t (tri-
plet), q (quartet), or m (multiplet), and coupling con-
stants (J) are reported in hertz. HRMS analysis with a
quadrupole time-of-flight mass spectrometer yielded ion
mass/charge (m/z) ratios in atomic mass units. IR spec-
tra were measured as dry films (KBr), and peaks are
reported in terms of wave number (cm1).
Table 3 The MIC of all compounds against bacteria (µg/mL)
HPLC
S.
E.
S.
K.
Comp.
purity/% epidermidis coli aureus pneumoniae
3a
3b
97.95
96.19
100
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞64
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 64
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞64
General procedure for the synthesis of 1H-quinazo-
line-2,4-dione derivatives 3
3c
To a solution of isatin 1 (0.1 mmol) and aryamine 2
(0.1 mmol) in MeOH (1.5 mL), NaHCO3 (0.12 mmol)
and hydrogen peroxide (0.03 mL, 30%) were added and
the resulting mixture was stirred for 8 h at room tem-
perature. Upon the completion of this reaction (moni-
tored by TLC), the mixture was evaporated in vacuum,
diluted with CH2Cl2 (3×10 mL), and washed by brine.
Organic layers were combined, dried over Na2SO4, fil-
tered, and evaporated in a vacuum. The residue was pu-
rified by flash column chromatography on silica gel
(300－400 mesh) with CH2Cl2 and MeOH (20∶1, V/V)
as eluting solvent to give the desired products 3.
3d
100
3e
100
3f
98.06
100
3g
3h
100
3i
98.08
100
3j
3k
91.31
97.84
100
3l
3m
3n
3-Phenylquinazoline-2,4(1H,3H)-dione
(3a)[9]
99.78
100
1
White solid. m.p. 267－269 ℃; H NMR (400 MHz,
DMSO-d6) δ: 11.54 (s, 1H), 7.94 (t, J＝7.2 Hz, 1H),
7.72－7.67 (m, 1H), 7.50－7.40 (m, 3H), 7.33 (d, J＝
6.8 Hz, 2H), 7.24 (t, J＝7.6 Hz, 2H); 13C NMR (100
MHz, DMSO-d6) δ: 162.6, 150.6, 140.3, 136.2, 135.6,
129.5, 129.2, 128.5, 128.0, 122.9, 115.7, 114.8; IR (KBr)
ν: 3198, 3144, 1732, 1648, 1491, 1438, 1404, 1275,
1170, 758, 702, 692, 661, 577, 547 cm1; HRMS (ESI)
calcd for C14H11N2O2 ([M＋H]＋ ) 239.0821, found
239.0809.
3o
3p
98.05
100
3q
＞64 64
3r
100
＞128
＞128
64
＞128 64
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
64
3s
98.64
100
＞128 128
＞128 64
3t
3u
100
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
＞128
0.125
＞128 64
3v
98.91
100
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 ＞128
＞128 32
3w
3x
3-p-Tolylquinazoline-2,4(1H,3H)-dione
(3b)[9]
1
92.08
92.87
100
White solid. m.p. 265－267 ℃; H NMR (400 MHz,
DMSO-d6) δ: 7.94－7.92 (m, 1H), 7.71－7.67 (m, 1H),
7.28 (d, J＝8.4 Hz, 2H), 7.24 (d, J＝8.4 Hz, 2H), 7.19
－7.16 (m, 2H), 2.36 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ: 162.7, 150.7, 140.3, 137.91, 135.6, 133.5,
129.7, 129.2, 128.0, 122.9, 115.7, 114.8, 21.2; IR (KBr)
ν: 3200, 3144, 1731, 1650, 1604, 1513, 1492, 1440,
1405, 1275, 1168, 812, 759, 692, 651, 518 cm1; HRMS
(ESI) calcd for C15H13N2O2 ([M＋H]＋) 253.0977, found
253.0971.
3y
3z
3aa
3ab
3ac
levofloxacin
100
＞128 128
＞128 128
＞128 ＞128
0.002 32
100
97.16
Experimental
3-(4-Ethylphenyl)quinazoline-2,4(1H,3H)-dione
(3c) Yellow solid. m.p. 288－290 ℃; H NMR (400
1
Chemistry
Unless otherwise specified, all reagents and starting
materials were purchased from commercial sources and
used as received, and the solvents were purified and
dried by standard procedures. The chromatography sol-
vents were technical grade and distilled prior to use.
Flash chromatography was performed using 200－300
mesh silica gel with the indicated solvent system ac-
MHz, DMSO-d6) δ: 11.52 (s, 1H), 7.94 (d, J＝8.0 Hz,
1H), 7.71 (t, J＝7.2 Hz, 1H), 7.31 (d, J＝8.0 Hz, 2H),
7.23 (t, J＝8.4 Hz, 4H), 2.69 (m, 2H), 1.25 (t, J＝7.6 Hz,
3H); 13C NMR (100 MHz, DMSO-d6) δ: 162.7, 150.7,
144.1, 140.2, 135.6, 133.7, 129.3, 128.6, 128.0, 122.9,
115.6, 114.7, 28.3, 16.0; IR (KBr) ν: 3066, 2932, 1723,
1666, 1609, 1489, 1445, 1401, 1288, 1151, 870, 825,
Chin. J. Chem. 2017, XX, 1—9
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Shi et al.
FULL PAPER
755, 671, 508 cm1; HRMS (ESI) calcd for C16H15N2O2
H]＋) 273.0431, found 273.0423.
([M＋H]＋) 267.1134, found 267.1122.
3-(4-Methoxyphenyl)quinazoline-2,4(1H,3H)-di-
one (3d) White soild. m.p. 298－300 ℃. H NMR
3-(4-Bromophenyl)quinazoline-2,4(1H,3H)-dione
(3i)[9] White solid. m.p. 297－299 ℃; H NMR (400
1
1
MHz, DMSO-d6) δ: 9.74 (s, 1H), 7.95－7.93 (m, 1H),
7.72－7.67 (m, 3H), 7.33－7.31 (m, 2H), 7.25－7.21
(m, 2H); 13C NMR (100 MHz, DMSO-d6) δ: 162.5,
150.4, 140.2, 135.6, 135.5, 132.2, 131.8, 127.9, 122.9,
121.6, 115.7, 114.7; IR (KBr) ν: 3438, 3065, 2937, 1723,
1670, 1489, 1448, 1404, 1282, 1154, 1068, 1012, 820,
758, 728, 591 cm1; HRMS (ESI) calcd for
C14H10BrN2O2 ([M＋H]＋) 316.9926, found 316.9919.
3-(4-Iodophenyl)quinazoline-2,4(1H,3H)-dione (3j)
White solid. m.p. ＞ 300 ℃ . 1H NMR (400 MHz,
DMSO-d6) δ: 11.56 (s, 1H), 7.94 (d, J＝7.2 Hz, 1H),
7.85 (d, J＝7.2 Hz, 2H), 7.69 (d, J＝6.8 Hz, 1H), 7.23
(d, J＝7.2 Hz, 2H), 7.16 (d, J＝7.2 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) δ: 162.5, 150.4, 140.2, 138.2,
136.1, 135.7, 131.9, 128.0, 123.0, 115.7, 114.7, 94.7; IR
(KBr) ν: 3062, 2934, 1722, 1668, 1616, 1487, 1448,
1404, 1290, 1153, 1006, 871, 814, 757, 723, 582 cm1;
(400 MHz, DMSO-d6) δ: 11.64 (s, 1H), 7.95 (d, J＝7.6
Hz, 1H), 7.71 (t, J＝6.8 Hz, 1H), 7.32－7.22 (m, 4H),
7.03 (d, J＝8.0 Hz, 2H), 3.82 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ: 162.8, 159.2, 150.8, 140.3, 135.5,
130.4, 128.6, 127.9, 122.8, 115.7, 114.7, 114.4, 55.7; IR
(KBr) ν: 3439, 2938, 1720, 1660, 1513, 1490, 1447,
1405, 1249, 1175, 1030, 827, 760, 669, 539 cm1;
HRMS (ESI) calcd for C15H13N2O3 ([M ＋ H] ＋
)
269.0926, found 269.0924.
3-(3-Methoxyphenyl)quinazoline-2,4(1H,3H)-di-
one (3e)[9] White solid. m.p. 256－258 ℃; H NMR
1
(400 MHz, DMSO-d6) δ: 11.52 (s, 1H), 7.93－7.91 (m,
1H), 7.69 (t, J＝3.6 Hz, 1H), 7.38 (t, J＝6.4 Hz, 1H),
7.23－7.19 (m, 2H), 6.99－6.97 (m, 1H), 6.93 (t, J＝1.6
Hz, 1H), 6.88－6.86 (m, 1H), 3.75 (s, 3H); 13C NMR
(100 MHz, DMSO-d6) δ: 162.5, 160.1, 150.5, 140.2,
137.3, 135.6, 129.8, 128.1, 122.9, 121.7, 115.6, 115.3,
114.7, 114.2, 55.7; IR (KBr) ν: 3440, 3197, 3065, 3001,
1736, 1659, 1606, 1492, 1405, 1383, 1286, 1249, 1156,
1030, 825, 760, 696, 539 cm1; HRMS (ESI) calcd for
C15H13N2O3 ([M＋H]＋) 269.0926, found 269.0924.
3-(4-Fluorophenyl)quinazoline-2,4(1H,3H)-dione
HRMS (ESI) calcd for C14H10IN2O2 ([M ＋ H] ＋
)
364.9787, found 364.9775.
3-o-Tolylquinazoline-2,4(1H,3H)-dione
(3k)
1
White solid. m.p. 253－255 ℃; H NMR (400 MHz,
DMSO-d6) δ: 11.62 (s, 1H), 7.99 (d, J＝7.2 Hz, 1H),
7.73 (t, J＝7.2 Hz, 1H), 7.38－7.24 (m, 6H), 2.08 (s,
3H); 13C NMR (100 MHz, DMSO-d6) δ: 162.2, 150.1,
140.3, 136.1, 135.7, 135.3, 130.8, 129.6, 128.8, 128.0,
127.0, 123.0, 115.7, 114.5, 17.4; IR (KBr) ν: 3201, 3147,
2359, 1731, 1651, 1493, 1436, 1399, 1271, 1170, 877,
757, 717, 576 cm1; HRMS (ESI) calcd for
C15H13N2O2 ([M＋H]＋) 253.0977, found 253.0971.
3-(2-Ethylphenyl)quinazoline-2,4(1H,3H)-dione
1
(3f) White solid. m.p. 290－292 ℃; H NMR (400
MHz, DMSO-d6) δ: 11.55 (s, 1H), 7.94 (d, J＝7.6 Hz,
1H), 7.71 (t, J＝8.0 Hz, 1H), 7.41－7.37 (m, 2H), 7.33
(t, J＝8.8 Hz, 2H), 7.24 (t, J＝8.0 Hz, 2H); 13C NMR
1
(100 MHz, DMSO-d6) δ: 163.2 (d, JCF＝53.7 Hz),
1
160.8, 150.7, 140.2, 135.6, 132.4 (d, JCF＝3.9 Hz),
3
131.7 (d, JCF＝8.6 Hz), 128.0, 122.9, 116.2, 115.9 (d,
2JCF＝25.4 Hz), 114.7; IR (KBr) ν: 3201, 3145, 1732,
1647, 1508, 1441, 1402, 1276, 1237, 1170, 832, 692,
652, 507 cm1; HRMS (ESI) calcd for C14H10FN2O2
([M＋H]＋) 257.0726, found 257.0720.
(3l) White solid. m.p. 274－275 ℃; H NMR (400
1
MHz, DMSO-d6) δ: 11.63 (s, 1H), 7.99 (d, J＝7.6 Hz,
1H), 7.75 (t, J＝7.6 Hz, 1H), 7.41－7.24 (m, 6H), 2.42
－2.37 (m, 2H), 1.08 (t, J＝7.6 Hz, 3H); 13C NMR (100
MHz, DMSO-d6) δ: 162.5, 150.4, 141.4, 140.3, 135.7,
134.7, 129.7, 129.1, 129.0, 128.0, 127.0, 123.0, 115.7,
114.4, 23.9, 14.4; IR (KBr) ν: 3248, 3203, 2360, 1731,
1651, 1492, 1436, 1398, 1272, 1169, 879, 755, 662, 579
cm1; HRMS (ESI) calcd for C16H15N2O2 ([M＋H]＋)
267.1134, found 267.1122.
3-(4-Chlorophenyl)quinazoline-2,4(1H,3H)-dione
(3g)[9] White solid. m.p. 295－297 ℃; H NMR (400
1
MHz, DMSO-d6) δ: 11.57 (s, 1H), 7.94 (d, J＝7.6 Hz,
1H), 7.72－7.68 (m, 1H), 7.56 (d, J＝8.8 Hz, 2H), 7.39
(d, J＝8.8 Hz, 2H), 7.24 (t, J＝8.0 Hz, 2H); 13C NMR
(100 MHz, DMSO-d6) δ: 162.6, 150.5, 140.3, 135.7,
135.1, 133.2, 131.5, 129.3, 128.0, 123.0, 115.7, 114.7;
IR (KBr) ν: 3199, 3062, 1732, 1648, 1492, 1440, 1405,
1275, 1169, 1092, 1016, 820, 761, 739, 691, 603, 514
cm1; HRMS (ESI) calcd for C14H10ClN2O2 ([M＋H]＋)
273.0431, found 273.0423.
3-(3-Ethylphenyl)quinazoline-2,4(1H,3H)-dione
White solid. m.p. 289－291 ℃; H NMR (400 MHz,
1
DMSO-d6) δ: 11.52 (s, 1H), 7.93 (d, J＝6.8 Hz, 1H),
7.71－7.67 (m, 1H), 7.39 (t, J＝6.2 Hz, 1H), 7.26－
7.20 (m, 3H), 7.14 (s, 1H), 7.11 (d, J＝6.4 Hz, 1H), 2.66
－2.62 (m, 2H), 1.21 (t, J＝6.2 Hz, 3H); 13C NMR (100
MHz, DMSO-d6) δ: 150.6, 144.9, 140.2, 136.1, 135.6,
129.1, 128.6, 128.0, 127.9, 126.7, 122.9, 115.6, 114.7,
28.2, 15.7; IR (KBr) ν: 3250, 3201, 2365, 1736, 1657,
1492, 1436, 1390, 1255, 1160, 889, 755, 652, 573 cm1;
3-(3-Chlorophenyl)quinazoline-2,4(1H,3H)-dione
(3h) White solid. m.p. 283－285 ℃; H NMR (400
1
MHz, DMSO-d6) δ: 11.59 (s, 1H), 7.94 (d, J＝6.0 Hz,
1H), 7.71 (t, J＝5.8 Hz, 1H) 7.51 (d, J＝4.4 Hz, 3H),
7.34 (t, J＝6.4 Hz, 1H), 7.24 (t, J＝6.0 Hz, 2H); 13C
NMR (100 MHz, DMSO-d6) δ: 162.5, 150.5, 140.3,
137.7, 135.7, 133.3, 130.8, 129.8, 128.7, 128.6, 128.0,
123.0, 115.7, 114.8; IR (KBr) ν: 3240, 3199, 3145, 1735,
1725, 1604, 1491, 1441, 1405, 1275, 1166, 1091, 761,
603 cm1; HRMS (ESI) calcd for C14H10ClN2O2 ([M＋
HRMS (ESI) calcd for C16H15N2O2 ([M ＋ H] ＋
)
267.1134, found 267.1122.
3-(2-Isopropylphenyl)quinazoline-2,4(1H,3H)-di-
1
one (3n) White solid. m.p. 248－250 ℃; H NMR
(400 MHz, DMSO-d6) δ: 11.62 (s, 1H), 7.99 (d, J＝7.6
6
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© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—9

A Facile Synthesis of Quinazoline-2,4-diones
Hz, 1H), 7.75 (t, J＝7.6 Hz, 1H), 7.49－7.42 (m, 2H),
7.33－7.22 (m, 4H), 2.73－2.69 (m, 1H), 1.14 (d, J＝
6.8 Hz, 6H); 13C NMR (100 MHz, DMSO-d6) δ: 162.7,
150.5, 146.3,140.3, 135.7, 133.7, 129.5, 129.3, 128.1,
126.8, 126.5, 123.0, 115.7, 114.4, 28.3, 23.7; IR (KBr) ν:
3255, 2967, 1732, 1651, 1617, 1492, 1435, 1400, 1269,
1169, 753, 693, 662, 531 cm1; HRMS (ESI) calcd for
C17H17N2O2 ([M＋H]＋) 281.1290, found 281.1281.
6-Fluoro-3-p-tolylquinazoline-2,4(1H,3H)-dione
DMSO-d6) δ: 162.7, 150.6, 138.1, 137.8, 136.5, 133.6,
132.1, 129.7, 129.2, 127.4, 115.6, 114.5, 21.2, 20.7; IR
(KBr) ν: 3217, 2919, 1731, 1651, 1514, 1435, 1380,
1275, 1194, 821, 758, 654, 563, 512 cm1; HRMS (ESI)
calcd for C16H15N2O2 ([M ＋H]＋ ) 267.1134, found
267.1124.
6-Ethyl-3-p-tolylquinazoline-2,4(1H,3H)-dione (3t)
1
White solid. m.p. 248－250 ℃; H NMR (400 MHz,
DMSO-d6) δ: 11.45 (s, 1H), 7.77 (s, 1H), 7.59－7.56 (m,
1H), 7.28 (d, J＝8.4 Hz, 2H), 7.19 (m, J＝8.0 Hz, 3H),
2.70－2.64 (m, 2H), 2.38 (s, 3H), 1.22 (t, J＝7.6 Hz,
3H); 13C NMR (100 MHz, DMSO-d6) δ: 162.7, 150.7,
138.5, 138.3, 137.8, 135.6, 133.6, 129.7, 129.2, 126.3,
115.7, 114.6, 27.8, 21.2, 16.1; IR (KBr) ν: 3120, 2960,
1731, 1651, 1513, 1436, 1386, 1274, 1189, 839, 756,
656, 512 cm1; HRMS (ESI) calcd for C17H17N2O2 ([M
＋H]＋) 281.1290, found 281.1280.
1
(3o) White solid. m.p. 255－257 ℃; H NMR (400
MHz, DMSO-d6) δ: 11.56 (s, 1H), 7.64－7.59 (m, 2H),
7.28 (t, J＝7.6 Hz, 3H), 7.18 (d, J＝8.8 Hz, 2H), 2.36 (s,
3
3H); 13C NMR (100 MHz, DMSO-d6) δ: 162.0 (d, JCF
1
＝3.9 Hz), 159.0 (d, JCF＝238.5 Hz), 150.4, 138.0,
2
136.9, 133.4, 129.7, 129.1, 123.7 (d, JCF＝24.6 Hz),
118.0 (d, 3JCF＝8.2 Hz), 115.9 (d, 2JCF＝11.2 Hz), 113.1
(d, 2JCF＝23.3 Hz), 21.2; IR (KBr) ν: 3197, 1737, 1647,
1512, 1378, 1272, 1142, 903, 831, 773, 682, 654, 516
cm1; HRMS (ESI) calcd for C15H12FN2O2 ([M＋H]＋)
271.0883, found 271.0880.
6-Methoxy-3-p-tolylquinazoline-2,4(1H,3H)-dione
1
(3u) White solid. m.p. 241－243 ℃; H NMR (400
MHz, DMSO-d6) δ: 11.41 (s, 1H), 7.38－7.34 (m, 2H),
7.30 (d, J＝8.4 Hz, 2H), 7.21 (t, J＝8.4 Hz, 3H), 3.81 (s,
3H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ:
162.5, 155.1, 150.4, 137.8, 134.4, 133.7, 129.7, 129.6,
129.2, 124.4, 117.3, 115.2, 109.1, 56.0, 21.1; IR (KBr) ν:
3251, 2925, 1716, 1662, 1505, 1442, 1361, 1270, 1149,
1025, 827, 763, 683, 657, 567, 514 cm1; HRMS (ESI)
calcd for C16H15N2O3 ([M ＋H]＋ ) 283.1083, found
283.1072.
6-Chloro-3-p-tolylquinazoline-2,4(1H,3H)-dione
1
(3p) White solid. m.p. 291－293 ℃; H NMR (400
MHz, DMSO-d6) δ: 11.66 (s, 1H), 7.85 (d, J＝2.4 Hz,
1H), 7.75－7.72 (m, 1H), 7.28－7.23 (m, 3H), 7.19 (d,
J＝8.0 Hz, 2H), 2.36 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ: 161.7, 150.4, 139.0, 138.0, 135.3, 133.2,
129.7, 129.0, 126.8, 117.8, 116.1, 21.1; IR (KBr) ν:
3055, 1722, 1674, 1604, 1479, 1440, 1380, 1284, 1152,
830, 778, 729, 668, 533, 515 cm1; HRMS (ESI) calcd
8-Chloro-3-p-tolylquinazoline-2,4(1H,3H)-dione
＋
1
for C15H12ClN2O2 ([M ＋ H] ) 287.0587, found
(3v) White solid. m.p. 245－247 ℃; H NMR (400
287.0579.
MHz, DMSO-d6) δ: 11.06 (s, 1H), 7.94 (d, J＝7.6 Hz,
1H), 7.85 (d, J＝7.6 Hz, 1H), 7.29－7.19 (m, 5H), 2.37
(s, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 161.9,
150.4, 138.0, 137.1, 135.4, 133.3, 129.8, 129.0, 127.1,
123.5, 119.1, 116.9, 21.1; IR (KBr) ν: 3191, 2913, 1726,
1642, 1605, 1498, 1441, 1380, 1288, 1511, 920, 830,
776, 725, 667, 532, 512 cm1; HRMS (ESI) calcd for
C15H12ClN2O2 ([M＋H]＋) 287.0587, found 287.0584.
8-Methyl-3-p-tolylquinazoline-2,4(1H,3H)-dione
6-Bromo-3-p-tolylquinazoline-2,4(1H,3H)-dione
(3q) White solid. m.p. 267－269 ℃; H NMR (400
1
MHz, DMSO-d6) δ: 11.66 (s, 1H), 7.99 (d, J＝2.4 Hz,
1H), 7.87－7.84 (m, 1H), 7.28 (d, J＝8.0 Hz, 2H), 7.19
－7.17 (m, 3H), 2.37 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ: 161.6, 150.4, 139.4, 138.1, 138.0, 133.2,
129.8, 129.7, 129.0, 118.0, 116.6, 114.3, 21.1; IR (KBr)
ν: 3447, 3195, 1716, 1670, 1613, 1503, 1399, 1316,
1270, 1164, 1141, 1054, 882, 779, 669, 518 cm1;
HRMS (ESI) calcd for C15H12BrN2O2 ([M ＋ H] ＋ )
331.0082, found 331.0073.
6-Iodo-3-p-tolylquinazoline-2,4(1H,3H)-dione (3r)
White solid. m.p. ＞300 ℃; 1H NMR (400 MHz,
DMSO-d6) δ: 11.62 (s, 1H), 8.16 (d, J＝2.0 Hz, 1H),
7.99－7.97 (m, 1H), 7.28 (d, J＝8.0 Hz, 2H), 7.18 (d,
J＝8.0 Hz, 2H), 7.06 (d, J＝8.8 Hz, 1H), 2.37 (s, 3H);
13C NMR (100 MHz, DMSO-d6) δ: 161.5, 150.4, 143.5,
139.7, 137.9, 135.8, 133.2, 129.7, 129.0, 118.0, 116.9,
85.5, 21.1; IR (KBr) ν: 3246, 1716, 1670, 1609, 1514,
1490, 1427, 1366, 1270, 1159, 823, 759, 716, 656, 518
cm1; HRMS (ESI) calcd for C15H12IN2O2 ([M＋H]＋)
378.9943, found 378.9936.
1
(3w) Yellow solid. m.p. 282－284 ℃; H NMR (400
MHz, DMSO-d6) δ: 10.78 (s, 1H), 7.84 (d, J＝7.2 Hz,
1H), 7.55 (d, J＝7.2 Hz, 1H), 7.31 (d, J＝8.0 Hz, 2H),
7.22 (d, J＝8.4 Hz, 2H), 7.16 (t, J＝7.6 Hz, 1H), 2.43 (s,
3H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ:
162.7, 150.9, 138.5, 137.9, 136.5, 133.5, 129.7, 129.1,
125.81, 124.4, 122.6, 114.9, 21.1, 17.5; IR (KBr) ν:
3223, 3053, 1735, 1648, 1482, 1433, 1380, 1336, 1224,
1150, 835, 758, 709, 563, 515 cm1; HRMS (ESI) calcd
for C16H15N2O2 ([M＋H]＋) 267.1134, found 267.1125.
7-Fluoro-3-phenylquinazoline-2,4(1H,3H)-dione
1
(3x) White solid. m.p. 283－285 ℃; H NMR (400
MHz, DMSO-d6) δ: 11.41 (s, 1H), 7.71－7.57 (m, 2H),
7.49 (t, J＝6.8 Hz, 2H), 7.43 (t, J＝7.6 Hz, 1H), 7.31 (d,
J＝7.2 Hz, 2H), 7.25－7.18 (m, 1H); 13C NMR (100
6-Methyl-3-p-tolylquinazoline-2,4(1H,3H)-dione
(3s)[9] White solid. m.p. 285－287 ℃; H NMR (400
MHz, DMSO-d6) δ: 162.1 (d, JCF＝3.5 Hz), 158.8 (d,
1
3
MHz, DMSO-d6) δ: 11.42 (s, 1H), 7.73 (s, 1H), 7.52－
7.49 (m, 1H), 7.27 (d, J＝8.0 Hz, 2H), 7.17－7.12 (m,
3H), 2.36 (s, 3H), 2.34 (s, 3H); 13C NMR (100 MHz,
1JCF＝238.6 Hz), 150.7, 137.8, 136.2, 129.4, 129.2,
128.5, 123.6 (d, 2JCF＝24.7 Hz), 118.4 (d, 3JCF＝7.7 Hz),
3
2
115.8 (d, JCF＝8.2 Hz), 112.9 (d, JCF＝23.9 Hz); IR
Chin. J. Chem. 2017, XX, 1—9
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7

Shi et al.
FULL PAPER
(KBr) ν: 3077, 2924, 1731, 1669, 1490, 1441, 1379,
1287, 1135, 830, 774, 713, 674, 547 cm1; HRMS (ESI)
calcd for C14H10FN2O2 ([M＋H]＋ ) 257.0726, found
257.0717.
297.1239, found 297.1230.
Biological assays
The bacterial strain of Staphylococcus aureus (Iden-
tification number: WXI-004) was obtained from WuXi
AppTec (Shanghai) Co., Ltd. Other bacterial strains,
such as Staphylococcus epidermidis (Identification
number: ATCC 35984), Escherichia coli (Identification
number: ATCC 25922), and Klebsiella pneumoniae
(Identification number: ATCC BAA-1898), were ob-
tained from American Type Culture Collection (ATCC).
6-Iodo-3-phenylquinazoline-2,4(1H,3H)-dione (3y)
1
White solid. m.p. 289－291 ℃. H NMR (400 MHz,
DMSO-d6) δ: 11.66 (s, 1H), 8.16 (s, 1H), 8.01－7.98 (m,
1H), 7.50－7.42 (m, 3H), 7.32 (d, J＝7.2 Hz, 2H), 7.07
13
(d, J＝8.4 Hz, 1H); C NMR (100 MHz, DMSO-d6) δ:
161.4, 150.4, 143.6, 139.8, 135.9, 135.8, 129.4, 129.2,
128.6, 118.0, 116.9, 85.6; IR (KBr) ν: 3220, 1744, 1639
cm1; HRMS (ESI) calcd for C14H10IN2O2 ([M＋H]＋)
364.9787, found 364.9779.
Preparing compound testing plates
6-Chloro-3-(4-isopropylphenyl)quinazoline-2,4-
(1H,3H)-dione (3z) White solid. m.p. 260－262 ℃;
1H NMR (400 MHz, DMSO-d6) δ: 11.70 (s, 1H), 7.88
(d, J＝2.4 Hz, 1H), 7.78－7.76 (m, 1H), 7.38 (d, J＝8.4
Hz, 2H), 7.27－7.22 (m, 3H), 2.99－2.96 (m, 1H), 1.28
Testing compounds were balanced and transferred
into 1.5 mL sterile centrifuge tubes. Pure DMSO (Sigma
D5879-1L, 12.8 mg/mL) was used to dissolve the com-
pounds. This stock solution was made and used on the
day of testing. On the day of testing, 980μCAMHB
(Cation-adjusted Muller Hinton Broth, BD-212322) was
added into column 1 of a 96-deep well plate (Corn-
ing-3960) and rest of the wells were filled with 500 µL
CAMHB. An aliquot of 20 µL stock solution was added
into a well in column 1 and mixed by pipetting. Then,
500 µL of the solution from well 1 was transferred to
well 2, and mixed by pipetting, and 2-fold serial dilution
was performed so forth until well 11. The well 12 con-
tained only CAMHB. Aliquots of 100 µL solution were
replicating transferred into 4 U-bottom 96-well testing
plates (Corning-3788), one for each strain. The residue
solution was transferred to another 96-well testing plate
for observing compounds precipitation. This plate was
not inoculated with bacteria. For some stock solutions in
which the compounds were prepared in 6.4 mg/mL, the
volume was adjusted accordingly.
13
(d, J＝6.8 Hz, 6H); C NMR (100 MHz, DMSO-d6) δ:
161.7, 150.4, 148.7, 139.1, 135.4, 133.5, 129.1, 127.1,
126.8, 126.8, 117.8, 116.2, 33.6, 24.2; IR (KBr) ν: 3268,
2913, 1734, 1670, 1510, ,1459, 1380, 1197, 894, 778,
677, 583, 536 cm1; HRMS (ESI) calcd for
C17H16ClN2O2 ([M＋H]＋) 315.0900, found 315.0891.
6-Ethyl-3-(4-fluorophenyl)quinazoline-2,4(1H,
1
3H)-dione (3aa) White solid. m.p. 254－256 ℃; H
NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 7.75 (s,
1H), 7.57 (d, J＝6.8 Hz, 1H), 7.39－7.28 (m, 4H), 7.17
(d, J＝8.4 Hz, 1H), 2.69－2.62 (m, 2H), 1.18 (t, J＝7.6
Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ: 162.7,
1
160.7 (d, JCF＝242.8 Hz), 150.6, 138.5, 138.3, 135.6,
132.4 (d, 3JCF＝3.0 Hz), 131.6 (d, 3JCF＝9.2 Hz), 126.2,
2
116.1, 115.9 (d, JCF＝16.4 Hz), 114.5, 27.8, 16.0; IR
(KBr) ν: 3252, 2962, 1725, 1666, 1431, 1431, 1388,
1274, 1223, 1187, 1153, 837, 760, 657, 509 cm1;
HRMS (ESI) calcd for C16H14FN2O2 ([M ＋ H] ＋ )
285.1039, found 285.1030.
Preparing bacterial inoculum
A day prior to the testing, 80 ℃ bacterial glycerol
stocks were streaked onto MHAII (Muller Hinton II
Agar, BD-211438) plates. The plates were incubated at
37 ℃ for 20 h. On the day of testing, single colonies
were picked from the plate and suspended in 5 mL of
sterile saline. A turbidity meter (Siemens MicroScan
Turbidity Meter) was used to adjust the turbidity to 0.5
McFarland standard, which is equivalent to a bacterial
density of ~1.0×108 CFU/mL. The bacteria/saline sus-
pension was diluted another 100× in a CAMHB to 1.0
×106 CFU/mL. This was used as the inoculum.
3-(4-Chlorophenyl)-6-ethylquinazoline-2,4(1H,
3H)-dione (3ab) White solid. m.p. 265－267 ℃; H
1
NMR (400 MHz, DMSO-d6) δ: 7.75 (s, 1H), 7.55 (d,
J＝8.4 Hz, 3H), 7.36 (d, J＝8.4 Hz, 2H), 7.18 (d, J＝
8.0 Hz, 1H), 2.67-2.62 (m, 2H), 1.18 (t, J＝7.6 Hz, 3H);
13C NMR (100 MHz, DMSO-d6) δ: 162.7, 150.6, 138.8,
138.3, 135.5, 135.3, 133.0, 131.4, 129.2, 126.1, 116.1,
114.5, 27.8, 16.0; IR (KBr) ν: 3052, 2973, 1736, 1479,
1469, 1380, 1280, 1197, 1019, 920, 799, 677, 583, 515
cm1; HRMS (ESI) calcd for C16H14ClN2O2 ([M＋H]＋)
301.0744, found 301.0733.
3-(4-Ethylphenyl)-6-methoxyquinazoline-2,4(1H,
3H)-dione (3ac) White solid. m.p. 286－288 ℃; H
Minimum inhibitory concentration (MIC) test
1
An aliquot of 100 µL bacterial inoculum was trans-
ferred into each well of the compound testing plates.
Each testing plate was inoculated with a single strain to
prevent cross contamination. The final testing concen-
trations were 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125
and 0 µg/mL. The starting bacterial density was ~5×
105 CFU/mL. The testing plates were incubated at
37 ℃ for 20 h before the MICs were read.
NMR (400 MHz, DMSO-d6) δ: 11.56 (s, 1H), 7.37－
7.27 (m, 5H), 7.21 (d, J＝4.4 Hz, 2H), 3.81 (s, 3H),
2.71－2.66 (m, 2H), 1.26 (t, J＝7.6 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6) δ: 162.5, 155.0, 150.4, 143.9,
134.4, 133.8, 129.2, 128.5, 124.4, 117.4, 115.1, 108.9,
56.0, 28.2, 15.9; IR (KBr) ν: 3438, 2964, 1723, 1660,
1513, 1492, 1436, 1360, 1283, 1149, 1027, 761, 567
cm1; HRMS (ESI) calcd for C17H17N2O3 ([M＋H]＋)
8
www.cjc.wiley-vch.de
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—9

A Facile Synthesis of Quinazoline-2,4-diones
(e) Garin, J.; Melendez, E.; Merchan, F. L.; Tejero, T.; Villarroya, E.
Synthesis 1983, 406.
[8] Azizian, J.; Mehrdad, M.; Jadidi, K.; Sarrafi, Y. Tetrahedron Lett.
2000, 41, 5265.
[9] Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773.
[10] Wu, X.; Yu, Z. Tetrahedron Lett. 2010, 51, 1500.
[11] Wang, S.-L.; Yang, K.; Yao, C.-S.; Wang, X.-S. Synth. Commun.
2012, 42, 341.
Determining the MIC
After the 20 h incubation, the MICs were evaluated
by visual observation. Based on the CLSI-M7, the MIC
is defined as the minimum compound concentration that
completely or significantly inhibits the growth of bacte-
rium.
[12] Willis, M. C.; Snell, R. H.; Fletcher, A. J.; Woodward, R. L. Org.
Lett. 2006, 8, 5089.
Acknowledgement
[13] (a) Bergman, J.; Arewang, C.-J.; Svensson, P. H. J. Org. Chem. 2014,
79, 9065; (b) Finlay, H. J.; Johnson, J. A.; Lloyd, J. L.; Jiang, J.;
Neels, J.; Gunaga, P.; Banerjee, A.; Dhondi, N.; Chimalakonda, A.;
Mandlekar, S.; Conder, M. L.; Sale, H.; Xing, D.; Levesque, P.;
Wexler, R. R. ACS Med. Chem. Lett. 2016, 7, 831.
[14] (a) Huang, H.-M.; Li, Y.-J.; Ye, Q.; Yu, W.-B.; Han, L.; Jia, J.-H.;
Gao, J.-R. J. Org. Chem. 2014, 79, 1084; (b) Nobuta, T.; Tada, N.;
Fujiya, A.; Kariya, A.; Miura, T.; Itoh, A. Org. Lett. 2013, 15, 574; (c)
Bodtke, A.; Pfeiffer, W.-D.; Ahrens, N.; Langer, P. Tetrahedron 2005,
61, 10926; (d) Bai, G.; Lan, X.; Liu, X.; Liu, C.; Shi, L.; Chen, Q.;
Chen, G. Green Chem. 2014, 16, 3160; (e) Tachikawa, Y.; Nagasawa,
Y.; Furuhashi, S.; Cui, L.; Yamaguchi, E.; Tada, N.; Miurab, T.; Itoh,
A. RSC Adv. 2015, 5, 9591.
The work was partially supported by the National
Natural Science Foundation of China (No. 21172001,
21372008), the Natural Science Foundation of Educa-
tion Administration of Anhui Province (KJ2016A267),
the Special and Excellent Research Fund of Anhui
Normal University and the Doctoral Scientific Research
Foundation of Anhui Normal University (No.
2016XJJ110).
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(Zhao, X.)
Chin. J. Chem. 2017, XX, 1—9
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
9