Synthesis and Biological Activity of Anthranilic Diamide Derivatives Incorporating 1,3,4-oxadiazole or Nitrogen-containing Saturated Heterocyclic Moieties

Article abstract of DOI:10.1002/jhet.2724

A series of novel anthranilic diamide derivatives incorporating 1,3,4-oxadiazole or nitrogen-containing saturated heterocyclic moieties were synthesized, characterized, and evaluated for bacteriostatic activity against three phytopathogenic bacteria Xanthomonas oryzae pv. Oryzae (Xoo), Xanthomonas axonopodis pv. Citri (Xac), Ralstonia solanacearum (R. solanacearum). The preliminary biological results indicated that most compounds exhibit bacteriostatic activity against three phytopathogenic bacteria. Among these compounds, compounds 6g, 6f, and 6i displayed better antibacterial activity. In the test with concentration of 200 μg/mL, antibacterial activity of compound 6i and 6j was 96%. In particular, the bacteriostatic activity displayed by compound 6h against Xoo is similar to the one displayed by commercial drug bismerthiazol.

Full text of DOI:10.1002/jhet.2724

Month 2016
Synthesis and Biological Activity of Anthranilic Diamide Derivatives
Incorporating 1,3,4-oxadiazole or Nitrogen-containing Saturated
Heterocyclic Moieties
*
Wen-Juan Zhou, Li Zhang, Wei Xiao, He-Ju Chen, Wen-Neng Wu, and Gui-Ping Ouyang
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green
Pesticide and Agricultural Bioengineering, Ministry of Education, Center for Research and Development of Fine
Chemicals, Guizhou University, Guiyang 550025, People’s Republic of China
*
E-mail: oygp710@163.com
Received March 20, 2016
DOI 10.1002/jhet.2724
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel anthranilic diamide derivatives incorporating 1,3,4-oxadiazole or nitrogen-containing
saturated heterocyclic moieties were synthesized, characterized, and evaluated for bacteriostatic activity
against three phytopathogenic bacteria Xanthomonas oryzae pv. Oryzae (Xoo), Xanthomonas axonopodis
pv. Citri (Xac), Ralstonia solanacearum (R. solanacearum). The preliminary biological results indicated that
most compounds exhibit bacteriostatic activity against three phytopathogenic bacteria. Among these com-
pounds, compounds 6g, 6f, and 6i displayed better antibacterial activity. In the test with concentration of
200 μg/mL, antibacterial activity of compound 6i and 6j was 96%. In particular, the bacteriostatic activity
displayed by compound 6h against Xoo is similar to the one displayed by commercial drug bismerthiazol.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
herbicidal [19]. Moreover, 1,3,4-oxadiazole scaffold is an
important pharmacophore in agricultural science, and com-
pounds bearing this moiety often display antifungal [20],
herbicidal [21], antimicrobial [22,23], and insecticidal
[24,25] activities. Functional fragments or skeletons play a
crucial role in biologically active chemicals, and modifica-
tions in the functional groups could improve or change the
biological activity of parent compounds [26]. In accordance
with the principle of combination of active groups, the target
compound changing pyridine pyrazole ring part of
chlorantraniliprole introduced saturated heterocyclic moie-
ties containing 1,3,4-oxadiazole or nitrogen, for the purpose
of obtaining compounds high antibacterial activity. With this
in mind, two series of novel anthranilic diamide derivatives
were designed and synthesized in this paper by incorporating
1,3,4-oxadiazole or nitrogen-containing saturated heterocy-
clic moieties to increase biological activity [27].
Synthetic pesticides have been playing a pivotal role in
controlling pests and pathogens in the current agricultural
system. To overcome resistance and eco-biological problems
associated with conventional pesticides, there is an urgent
need to discover novel potent pesticides with new modes of
action and ecofriendly properties such as easy degradability
to nontoxic residues, harmlessness to human beings, and
benefits in protecting crop [1]. In recent years, DuPont has
discovered chlorantraniliprole, which exhibits exceptional
broad spectrum activity, high potency, and low mammalian
toxicity [2]. Because of their unique mode of action and good
environmental profiles, anthranilic diamides and their chem-
ical synthesis have recently attracted considerable attention
in the field of novel synthetic pesticides [3]. Since the discov-
ery of anthranilic diamides, most modification can be catego-
rized into three substructures: the N-pyridylpyrazole moiety
[4,5], benzene ring moiety [6,7], and aliphatic amide moiety
[8,9]. Antimicrobial activity of anthranilic diamides was
reported most of the time [10]. Heterocyclic containing nitro-
gen has better activity, including insecticidal [11–14],
antimicrobial [15,16], antiviral [17], antifungal [18], and
RESULTS AND DISCUSSION
Chemistry.
The detailed synthetic route for the
preparation of 5-chloro-2-(2-((5-substitute)-1,3,4-oxadiazol-
© 2016 Wiley Periodicals, Inc.

W.-J. Zhou, L. Zhang, W. Xiao, H.-J. Chen, W.-N. Wu, and G.-P. Ouyang
Vol 000
1
2-yl)thio)acetamido)-N, 3-dimethylbenzamide anthranilic
diamide derivatives, and 5-chloro-2-(2-substitute acetamido)-
N,3-dimethylbenzamide anthranilic diamide derivatives is
summarized in Schemes 1 and 2. Starting from substituted
benzoic acid, the key intermediate 5-R-phenyl-1,3,4-
oxadiazole-2-thiol was synthesized in three steps including
esterification, hydrazidation, and cyclization [27,28].
Subsequently, the 5-R-phenyl-1,3,4-oxadiazole-2-thiol (4)
and heterocyclic containing nitrogen were converted into
their corresponding anthranilic diamide derivatives (5a–6j)
by thioetherification with 5-chloro-2-(2-chloroacetamido)-
N,3-dimethylbenzamide in the presence of catalyst
potassium hydroxide. The physical characteristics, IR, H
NMR, 13C NMR, and elemental analysis data for all the
synthesized compounds are reported in the article.
Bacteriostatic Activity. To evaluate of the bacteriostatic
activity of anthranilic diamide derivatives incorporating
1,3,4-oxadiazole or nitrogen-containing saturated heterocyclic
moieties (5a–6j), anthranilic diamide derivatives were
tested for in vitro antibacterial activity against three
phytopathogenic bacteria (Xoo, Xac, and R. solanacearum)
by the turbidimeter test, with the commercial drug
bismerthiazol as the control. The bacteriostatic activity
results of all target compounds are listed in Table 1.
Scheme 1. Synthetic route to compounds 5a–5k.
Scheme 2. Synthetic route to compounds 6a–6g.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Anthranilic Diamide Derivatives with Antibacterial Activities
Table 1
Antibacterial activity data of synthesized compounds (100 and 200 μg/mL).
Inhibit (%)
Xoo
Xac
R. solanacearum
Compound
R
200 μg/mL
100 μg/mL
200 μg/mL
100 μg/mL
200 μg/mL
100 μg/mL
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-Cl
4-F
H
2-Cl
4-OCH3
Pyridine
2-Cl-5-Cl
4-NO2
49 3.1
34 2.6
38 2.8
56 1.8
60 2.6
41 1.5
38 2.3
71 1.5
36 2.0
52 1.2
57 1.4
63 1.7
47 2.8
40 1.6
35 2.1
54 2.9
42 1.6
96 2.8
100 3.4
96 1.8
27 3.0
100
28 3.5
19 1.8
24 2.6
37 2.6
41 3.5
27 1.8
20 1.9
57 2.5
24 3.4
31 1.2
32 2.2
38 2.4
34 2.7
34 3.4
15 2.0
30 4.0
24 2.1
65 1.2
100 1.2
49 3.7
11 1.8
100
57 2.4
59 2.0
46 2.1
38 2.2
61 2.9
59 3.3
32 3.2
62 1.3
24 2.5
30 1.9
45 2.3
46 1.3
47 2.8
53 2.9
43 1.1
63 2.0
80 1.5
68 1.9
97 2.1
85 2.8
48 3.0
100
36 1.4
37 1.2
28 3.1
24 3.7
38 2.3
39 2.8
23 2.2
37 2.4
13 3.1
15 3.4
26 3.0
27 2.0
24 1.6
29 1.3
26 2.5
40 1.9
55 1.6
46 2.7
74 2.0
58 1.4
25 2.4
100
50 2.1
54 1.6
41 1.4
32 1.3
57 1.1
47 1.5
28 1.7
57 2.1
26 1.0
25 1.8
38 1.2
55 3.1
51 2.1
41 1.8
28 1.2
69 1.3
84 1.9
88 2.5
89 0.9
73 2.0
45 1.4
100
33 1.3
36 2.0
25 2.2
17 1.6
32 0.7
28 0.9
19 1.8
31 2.5
18 1.6
10 1.5
19 1.4
28 2.9
25 3.0
22 1.3
19 2.7
45 1.4
58 1.2
57 1.1
67 1.7
55 1.2
21 1.6
100
2-OH
5j
4-Cl-benzyl
4-F-benzyl
Morpholine
Piperazine
N-methylpiperazine
Piperidine
Cyclopropylamine
Imidazole
Pyrrole
Cyclohexylamine
Cyclopentylamine
Piperidone hydrochloride
Bismerthiazo
5k
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
The results showed that most of the compounds exhib-
ited antibacterial activity against three phytopathogenic
bacteria (Xoo, Xac, and R. solanacearum) at 100 and
200μg/mL. Furthermore, some of the compounds showed
prominent activity against Xoo compared with Xac and R.
solanacearum. Especially, compounds 6g, 6f, and 6i
displayed the better antibacterial activity. In the test with
concentration of 200 μg/mL, antibacterial activity of com-
pound 6i and 6j was 96%. Moreover, the bacteriostatic ac-
tivity displayed by compounds 6h against Xoo is similar to
the one displayed by commercial drug bismerthiazol.
introduction of water-soluble group to improve solubility,
the bacteriostatic activity of novel anthranilic diamide deriva-
tives incorporating 1,3,4-oxadiazole or nitrogen-containing
saturated heterocyclic moieties was worthy of further study.
EXPERIMENTAL
General procedure. The melting points of the products
were determined on an XT-4 binocular microscope
(Beijing Tech Instrument Co., Beijing, China) and were
not corrected. The IR spectra were recorded on a Bruker
VECTOR 22 spectrometer (Billerica, MA, USA) using
1
CONCLUSIONS
KBr disks. H and 13C NMR was performed in a CDCl3
or DMSO-d6 solvent on a JEOL-ECX 500 NMR
spectrometer (Akishima, Tokyo, Japan) operating at 500
and 125 MHz at room temperature with TMS as the
internal standard. Elemental analysis was performed on
an Elementar Vario-IIICHN analyzer (Hanau, Hessia,
Germany). Mass spectral was conducted on an Agilent
5973 organic mass spectrometer (Santa Clara, CA, USA).
Analytical TLC was performed on silica gel GF254.
Chemical shifts were given in ppm (δ) and J values in
Hz, and the signals were designated as follows: s, singlet;
d, doublet; m, multiplet. All reagents were of analytical
reagent grade or chemically pure. All solvents were dried,
deoxygenated, and redistilled prior to use.
In summary, we have synthesized a series of anthranilic
diamide derivatives incorporating 1,3,4-oxadiazole or
nitrogen-containing saturated heterocyclic moieties. The title
compounds were evaluated for their bacteriostatic activity
against three phytopathogenic bacteria (Xoo, Xac, and R.
solanacearum) by the turbidimeter test in vitro. The prelimi-
nary biological results indicated that most compounds exhibit
bacteriostatic activity against three phytopathogenic bacteria
but bacteriostatic activity was not very good. The reason of
bad bacteriostatic activity was poor solubility. Furthermore,
most of title compounds showed prominent activity against
Xoo compared with Xac and R. solanacearum. By the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W.-J. Zhou, L. Zhang, W. Xiao, H.-J. Chen, W.-N. Wu, and G.-P. Ouyang
Vol 000
General procedure for synthesis of 5-chloro-2-(2-
chloroacetamido)-N,3-dimethylbenzamide (1). To a solution
5-Chloro-2-(2-((5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)thio)
acetamido)-N,3-dimethylbenzamide (5b).
White solid; mp
205–207°C; yield 86%; IR (KBr): v 3292, 1679, 1634,
1506, 1470, 1227, 1164, 852, 732 cmÀ1 1H NMR
of
2-amino-5-chloro-N,3-dimethylbenzamide
19.8g
(0.10M) and trimethylamine 15.2g (0.15M) in 50-mL
dichloromethane was added 16.8 g (0.15 M) chloroacetyl
chloride in 30-mL dichloromethane at room temperature for
0.6h. Then the reaction mixture was continuously stirred at
room temperature for another 3h and monitored by TLC
(the eluent of V(ethyl acetate) :V(petroleum ether) =3:1). After the
reaction was over, the mixture was concentrated under
reduced pressure, and the residual was filtered, washed
with 30mL of 10% diluted hydrochloric acid, 35mL of
saturated sodium bicarbonate solution, 30mL of water, and
30mL of petroleum ether successively, and then dried to
obtain 19.6-g intermediate 5-chloro-2-(2-chloroacetamido)-
N,3-dimethylbenzamide as white solid with yield of 73%,
mp 159–161°C.
General procedure for synthesis of 4-chlorobenzoateethyl (2)
to 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol (4). Compounds
2, 3, and 4 were synthesized, as shown in Scheme 1,
based on previously described methods by following
literature [28,29]. Using substituted benzoic acid as the
starting material, compounds 2, 3, and 4 were synthesized
in three steps including esterification, hydrazidation, and
cyclization.
;
(DMSO-d6, 500MHz): δ 2.16 (s, 3H, CH3), 2.62 (s, 3H,
CH3), 4.28 (s, 2H, CH2), 7.31 (s, 1H, Ar–H), 7.43
(d, J =8.60 Hz, 2H, 3,5-di-Ph-H), 7.45 (s, 1H, Ar–H),
8.06 (d, J= 5.70Hz, 2H, 2,6-di-Ph-H), 8.24 (s, 1H, NH),
9.99 (s, 1H, NH); 13C NMR (DMSO-d6, 125 MHz): δ
166.8, 165.6, 165.0, 163.8, 163.6, 138.8, 135.8, 132.9,
131.7, 130.8, 129.7, 125.8, 120.3, 117.3, 117.1, 36.2, 26.6,
18.4; MS (ESI) m/z: 435.1 ([M+H]+); Anal. Calcd for
C19H16ClFN4O3S: C 52.48, H 3.71, N 12.88; found C
52.87, H 3.95, N 13.17.
5-Chloro-N,3-dimethyl-2-(2-((5-phenyl-1,3,4-oxadiazol-2-yl)
thio)acetamido)benzamide (5c). White solid; mp 199–201°C;
yield 86%; IR (KBr): v 3281, 2974, 1680, 1635, 1473,
1322, 863, 776, 704cmÀ1 1H NMR (DMSO-d6,
;
500 MHz): δ 2.15 (s, 3H, CH3), 2.71 (s, 3H, CH3), 4.30
(s, 2H, CH2), 7.32 (t, J =7.45 Hz, 1H, 4-Ph-H), 7.44
(s, 1H, Ar–H), 7.59 (s, 1H, Ar–H), 7.61 (t, J=7.45Hz, 2H,
3,5-di-Ph-H), 7.98 (d, J=6.85Hz, 2H, 2,6-di-Ph-H), 8.25
(s, 1H, NH), 10.01 (s, 1H, NH); 13C NMR (DMSO-d6,
125 MHz): δ 166.8, 165.6, 163.8, 138.8, 135.8, 132.9,
132.6, 131.7, 130.8, 130.0, 127.0, 125.8, 123.5, 36.3,
26.6, 18.4; MS (ESI) m/z: 435.1 ([M+H]+); Anal. Calcd
for C19H17ClN4O3S: C 54.74, H 4.11, N 13.44; found C
54.95, H 4.27, N 13.73.
General procedure for synthesis of 5-chloro-2-(2-((5-(4-
chlorophenyl)-1,3,4-oxadiazol-2yl)thio)acetamido)-N,3-dimethyl
benzamide (5a).
To a 50-mL, three-necked, round-
bottomed flask equipped with a magnetic stirrer were
added 5-(4-chlorophenyl)-1,3,4-oxadiazole-2-thiol 2.54g
(0.012 M), potassium hydroxide 0.67g (0.012M), and
20-mL ethanol. The mixture, which was added 5-chloro-
2-(2-chloroacetamido)-N,3-dimethylbenzamide, was heated
to 70°C, and the reaction was continued for 1 h. After the
reaction mixture was stirred and heated to reflux four 5 h,
and monitored by TLC (the eluent of V(ethyl acetate) :V
(dichloromethane) =4:1) until the reaction was over, the mixture
was concentrated under reduced pressure and added 50-mL
water until white solid appeared, dried over anhydrous
magnesium sulfate, and recrystallized with ethanol to obtain
3.56-g white solid.
5-Chloro-2-(2-((5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)
acetamido)-N,3-dimethylbenzamide (5d).
White solid; mp
180–182°C; yield 83%; IR (KBr): v 3272, 1671, 1630,
1473, 1319, 1205, 1034, 766, 729cmÀ1; 1H NMR (DMSO-
d6, 500MHz): δ 2.10 (s, 3H, CH3), 2.60 (s, 3H, CH3), 4.25
(s, 2H, CH2), 7.28 (t, J= 7.56 Hz, 1H, 4-Ph-H), 7.41 (t,
J=6.53Hz, 1H, 5-Ph-H), 7.51 (d, J=7.34 Hz, 1H, 3-Ph-H),
7.59 (s, 1H, Ar–H), 7.67 (d, J=7.28Hz, 1H, 6-Ph-H), 7.95
(s, 1H, Ar–H), 8.19 (s, 1H, NH), 9.95 (s, 1H, NH)); 13C
NMR (DMSO-d6, 125 MHz): δ 166.8, 165.6, 165.0, 164.2,
163.2, 156.6, 138.9, 135.8, 133.9, 131.7, 130.8, 129.4,
125.8, 120.2, 117.6, 109.9, 36.3, 26.6, 18.4; MS (ESI) m/z:
451.0 ([M+H]+); Anal. Calcd for C19H16Cl2N4O3S: C
50.56, H 3.57, N 12.41; found C 50.95, H 3.86, N 12.60.
5-Chloro-2-(2-((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)
5-Chloro-2-(2-((5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl)thio)
acetamido)-N,3-dimethylbenzamide (5a).
White solid; mp
198–200°C; yield 80%; IR (KBr): v 3273, 1667, 1635,
1475, 1318, 1188, 864, 843, 726cmÀ1 1H NMR
thio)acetamido)-N,3-dimethylbenzamide (5e).
White solid;
;
mp 207–209°C; yield 85%; IR (KBr): v 3448, 2919,
1672, 1605, 1465, 1339, 1255, 1176, 881, 843, 796,
741 cmÀ1; 1H NMR (DMSO-d6, 500MHz): δ 2.09 (s, 3H,
CH3), 2.60 (s, 3H, CH3), 3.80 (s, 3H, CH3), 4.22 (s, 2H,
CH2), 7.10 (d, J= 8.60 Hz, 2H, 3,5-di-Ph-H),7.28 (s, 1H,
Ar–H), 7.40 (s, 1H, Ar–H), 7.89 (d, J =8.60 Hz, 2H,
2,6-di-Ph-H), 8.20 (s, 1H, NH), 9.95 (s, 1H, NH); 13C
NMR (DMSO-d6, 125 MHz): δ 166.8, 165.7, 165.6,
162.6, 138.8, 135.7, 132.9, 131.7, 130.8, 129.5, 128.8,
125.8, 115.9, 115.4, 56.1, 36.2, 26.6, 18.4; MS (ESI) m/z:
(DMSO-d6, 500 MHz): δ 2.09 (s, 3H, CH3), 2.59 (s, 3H,
CH3), 4.24 (s, 2H, CH2), 7.27 (s, 1H, Ar–H), 7.40 (s, 1H,
Ar–H), 7.64 (d, J= 8.60 Hz, 2H, 3,5-di-Ph-H), 7.97
(d, J=8.05Hz, 2H, 2,6-di-Ph-H), 8.19 (s, 1H, NH), 9.94 (s,
1H, NH); 13C NMR (DMSO-d6, 125 MHz): δ 166.9, 166.8,
165.5, 163.7, 138.9, 135.9, 133.8, 132.8, 132.5, 131.7,
131.4, 130.8, 129.2, 125.8, 36.2, 30.5, 26.6, 18.4; MS (ESI)
m/z: 451.1 ([M+H]+); Anal. Calcd for C19H16Cl2N4O3S: C
50.56, H 3.57, N 12.41; found C 50.91, H 3.83, N 12.77.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Anthranilic Diamide Derivatives with Antibacterial Activities
447.2 ([M+H]+); Anal. Calcd for C20H19ClN4O4S: C 53.75,
H 4.29, N 12.54; found C 53.91, H 4.57, N 12.76
C19H17ClN4O4S: C 52.72, H 3.96, N 12.94; found C
52.88, H 4.21, N 13.09.
5-Chloro-N,3-dimethyl-2-(2-((5-(pyridin-2-yl)-1,3,4-oxadiazol-
5-Chloro-2-(2-((5-(4-chlorobenzyl)-1,3,4-oxadiazol-2-yl)thio)
2-yl)thio)acetamido)benzamide (5f).
White solid; mp
206–208°C; yield 89%; IR (KBr): v 3276, 1669, 1609, 1527,
1466, 1206, 882, 794, 742 cmÀ1 1H NMR (DMSO-d6,
acetamido)-N,3-dimethylbenzamide (5j).
White solid; mp
177–179°C; yield 88%; IR (KBr): v 3286, 1667, 1637,
1522, 1491, 1175, 1091, 964, 776 cmÀ1 1H NMR
;
;
500MHz): δ 2.39 (s, 3H, CH3), 3.61 (s, 3H, CH3), 4.98
(s, 2H, CH2), 7.60 (t, J=5.32Hz, 1H, 4-Py-H), 7.70
(t, J=4.21Hz, 1H, 5-Py-H), 7.86 (s, 1H, Ar–H), 8.03
(s, 1H, Ar–H), 8.10 (d, J=5.35Hz, 1H, 3-Py-H), 8.73
(d, J=5.78Hz, 1H, 6-Py-H); 13C NMR (DMSO-d6,
125MHz): δ 171.8, 166.8, 165.5, 164.9, 150.8, 149.5,
143.0, 138.5, 135.8, 131.7, 130.8, 126.9, 125.8, 123.3,
122.6, 36.3, 26.9, 17.4; MS (ESI) m/z: 418.1 ([M+H]+);
Anal. Calcd for C18H16ClN5O3S: C 51.74, H 3.86, N
16.76; found C 52.01, H 4.02, N 17.13.
(DMSO-d6, 500MHz): δ 2.07 (s, 3H, CH3), 2.62 (s, 3H,
CH3), 4.14 (s, 2H, benzyl-H), 4.25 (s, 2H, CH2), 7.28–7.39
(m, 6H, Ph-H), 8.19 (s, 1H, NH), 9.92 (s, 1H, NH), 13C
NMR (DMSO-d6, 125MHz): δ 166.9, 166.8, 165.5, 163.7,
138.9, 135.9, 133.8, 132.8, 132.5, 131.7, 131.4, 130.8,
129.2, 125.8, 36.2, 30.5, 26.6, 18.4; MS (ESI) m/z: 465.1
([M+H]+); Anal. Calcd for C20H18Cl2N4O3S: C 51.62, H
3.90, N 12.04; found C 51.96, H 4.12, N 12.37.
5-Chloro-2-(2-((5-(4-fluorobenzyl)-1,3,4-oxadiazol-2-yl)thio)
acetamido)-N,3-dimethylbenzamide (5k). White solid; mp
166–168°C; yield 88%: IR (KBr): v 3286, 1669, 1636,
5-Chloro-2-(2-((5-(2,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl)
thio)acetamido)-N,3-dimethylbenzamide (5g). White solid;
mp 200–202°C; yield 88%; IR (KBr): v 3280, 1671,
1510, 1485, 1226, 1176, 967, 782 cmÀ1
;
1H NMR
(DMSO-d6, 500MHz): δ 2.07 (s, 3H, CH3), 2.62 (s, 3H,
CH3), 4.14 (s, 2H, benzyl-H), 4.25 (s, 2H, CH2), 7.28–7.39
(m, 6H, Ph-H), 8.19 (s, 1H, NH), 9.92 (s, 1H, NH), 13C
NMR (DMSO-d6, 125MHz): δ 166.9, 166.8, 165.5, 163.7,
138.9, 135.9, 133.8, 132.8, 132.5, 131.7, 131.4, 130.8,
129.2, 125.8, 36.2, 30.5, 26.6, 18.4; MS (ESI) m/z: 449.1
([M+H]+); Anal. Calcd for C20H18ClFN4O3S: C 53.51, H
4.04, N 12.48; found C 53.80, H 4.32, N 12.65.
1
1600, 1464, 1374, 884, 741 cmÀ1; H NMR (DMSO-d6,
500 MHz): δ 2.43 (s, 3H, CH3), 2.64 (s, 3H, CH3), 5.01
(s, 2H, CH2), 7.56 (s, 1H, Ar–H), 7.64 (s, 1H, 3-Ph-H),
7.74 (d, J = 8.60 Hz, 1H, 5-Ph-H), 7.90 (s, 1H, Ar–H),
8.00 (d, J = 8.60 Hz, 1H, 6-Ph-H); 13C NMR (DMSO-d6,
125 MHz): δ 168.2, 162.1, 151.8, 144.1, 138.3, 137.6,
134.8, 132.2, 129.2, 124.4, 123.7, 121.7, 119.5, 62.9,
61.9, 53.5, 53.2, 30.6, 17.2; MS (ESI) m/z: 484.1 ([M
+H]+); Anal. Calcd for C19H15Cl3N4O3S: C 46.98, H
3.11, N 11.53; found C 47.20, H 3.29, N 11.86.
General procedure for synthesis of 5-chloro-2-(2-
morpholinoacetamido)-N,3-dimethyl benzamide (6a). To a
50-mL, three-necked, round-bottomed flask equipped with
5-Chloro-N,3-dimethyl-2-(2-((5-(4-nitrophenyl)-1,3,4-oxadiazol-
a
magnetic stirrer were added 5-chloro-2-(2-
2-yl)thio)acetamido)benzamide (5h).
White solid; mp
chloroacetamido)-N,3-dimethylbenzamide 2.74g (0.01M),
morpholine 1.22g (0.015M), KI 0.57 g(0.0035M), and 10-
mL DMF; the mixture was heated to 70°C, and the
reaction was continued for 10h and monitored by TLC (the
eluent of V(ethyl acetate) :V(dichloromethane) =4:1) until the
reaction was over. The mixture was concentrated under
reduced pressure and added 50-mL water until white solid
appeared, dried over anhydrous magnesium sulfate, and
recrystallized with ethanol to obtain 2.12-g white solid.
5-Chloro-2-(2-morpholinoacetamido)-N,3-dimethyl benzamide
(6a). White solid; mp 197–199°C; yield 65%; IR (KBr): v
3281, 2958, 2812, 1673, 1647, 1580, 1560, 1494, 1318,
210–212°C; yield 85%; IR (KBr): v 3391, 1669, 1602, 1521,
1464, 1343, 883, 853, 797, 741 cmÀ1; 1H NMR (DMSO-d6,
500 MHz): δ 2.24 (s, 3H, CH3), 2.66 (s, 3H, CH3), 3.62
(s, 2H, CH2), 7.54 (s, 1H, Ar–H), 7.63 (s, 1H, Ar–H), 8.01
(d, J= 8.55Hz, 2H, 3,5-di-Ph-H), 8.29 (d, J=8.60Hz, 2H,
2,6-di-Ph-H), 13C NMR (DMSO-d6, 125MHz): δ 166.8,
165.6, 165.0, 163.8, 138.8, 135.8, 132.9, 131.7, 130.8,
129.7, 125.8, 117.3, 117.1, 36.2, 26.6, 18.4; MS (ESI) m/z:
462.1 ([M+H]+); Anal. Calcd for C19H16ClN5O5S: C
49.41, H 3.49, N 15.16; found C 49.64, H 3.60, N 15.34.
5-Chloro-2-(2-((5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)thio)
1
acetamido)-N,3-dimethylbenzamide (5i).
White solid; mp
1115, 1012, 868, 744cmÀ1; H NMR (CDCl3, 500 MHz):
221–223°C; yield 87%; IR (KBr): v 3271, 1669, 1628,
δ 2.58 (s, 3H, CH3), 2.60 (t, J= 4.50 Hz, 4H, morpholine-H),
3.72 (s, 2H, CH2), 3.76 (t, J=4. Hz, 4H, morpholine-H),
3.79 (s, 3H, CH3), 7.50 (s, 1H, Ar–H), 8.05 (s, 1H, Ar–H);
13C NMR (CDCl3, MHz): δ 162.2, 151.7, 144.1, 138.3,
134.8, 132.1, 123.6, 121.8, 67.0, 63.3, 53.5, 30.6, 17.2; MS
(ESI) m/z: 325.1 ([M+H]+); Anal. Calcd for C15H20ClN3O3:
C 55.30, H 6.19, N 12.90; found C 55.52, H 6.57, N 13.02.
5-Chloro-2-(2-(piperazin-1-yl)acetamido)-N,3-dimethyl benzamide
(6b). White solid; mp 157–159°C; yield 84%; IR (KBr): v
3264, 2940, 2832, 1666, 1648, 1495, 1318, 1132, 1020, 869,
1
1489, 1476, 1247, 877, 749 cmÀ1; H NMR (DMSO-d6,
500MHz): δ 2.15 (s, 3H, CH3), 2.65 (s, 3H, CH3), 4.27
(s, 2H, CH2), 6.99 (d, J=7.45Hz, 1H, 3-Ph-H), 7.06
(t, J=8.0Hz, 1H, 5-Ph-H), 7.32 (s, 1H, Ar–H), 7.41 (s, 1H,
OH), 7.45 (s, 1H, Ar–H), 7.76 (t, J=7.40Hz, 1H, 4-Ph-H),
8.24 (d, J=4.0Hz, 1H, 6-Ph-H), 9.99 (s, 1H, NH), 10.27
(s, 1H, NH), 13C NMR (DMSO-d6, 125MHz): δ 166.8,
165.6, 165.0, 163.2, 156.6, 138.9, 135.8, 133.9, 131.7,
130.8, 129.4, 128.3, 125.8, 120.2, 117.6, 110.0, 36.3, 26.6,
18.4; MS (ESI) m/z: 433.1 ([M+H]+); Anal. Calcd for
1
826, 744 cmÀ1; H NMR (CDCl3, 500MHz): δ 1.78 (s, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W.-J. Zhou, L. Zhang, W. Xiao, H.-J. Chen, W.-N. Wu, and G.-P. Ouyang
Vol 000
NH), 2.21 (s, 3H, CH3), 2.56 (t, J= 4.85 Hz, 4H, piperazine-H),
2.80 (d, J=4.6Hz, 3H, CH3), 3.00(t, J=4.87Hz, 4H,
piperazine-H), 3. 12 (s, 2H, CH2), 7.26 (s, 1H, Ar–H), 7.27
(s, 1H, Ar–H), 9.78 (s, 1H, NH); 13C NMR (CDCl3,
125MHz): δ 170.1, 167.7, 138.0, 133.9, 132.2, 131.9, 131.6,
125.0, 62.5, 55.0, 46.2, 26.5, 19.0; MS (ESI) m/z: 325.1 ([M
+H]+); Anal. Calcd for C15H21ClN4O2: C 55.47, H 6.52 N
17.25; found C 55.83, H 6.71 N 17.38.
121.4, 48.7, 29.8, 16.4; MS (ESI) m/z: 307.1 ([M+H]+);
Anal. Calcd for C14H15ClN4O2: C 54.82, H 4.93, N
18.26; found C 54.47, H 4.67, N 18.52.
5-Chloro-N,3-dimethyl-2-(2-(pyrrolidin-1-yl)acetamido)
benzamide (6g). White solid; mp 123–125°C; yield 81%;
IR (KBr): v 3423, 2966, 2796, 1678, 1603, 1460, 1339,
1
878, 797, 746 cmÀ1; H NMR (DMSO-d6, 500MHz): δ
1.67–1.69 (m, 4H, 3,4-dipyrrole-H), 2.47 (s, 3H, CH3),
2.53 (t, J = 5.75Hz, 4H, 2,5-dipyrrole-H), 2.62 (s, 3H,
CH3), 3.73 (s, 2H, CH2), 7.68 (s, 1H, Ar–H), 7.85 (s, 1H,
Ar–H); 13C NMR (DMSO-d6, 125MHz): δ 161.4, 154.9,
144.6, 138.8, 134.7, 130.9, 123.1, 121.7, 60.3, 53.8,
30.7, 23.8, 17.2; MS (ESI) m/z: 310.2 ([M+H]+); Anal.
Calcd for C15H20ClN3O2: C 58.16, H 6.51, N 13.56;
found C 58.50, H 6.73, N 13.94.
5-Chloro-2-(2-(4-methylpiperazin-1-yl)acetamido)-N,3-dimethyl
benzamide (6c). Yellow solid; mp 136–138°C; yield 83%;
IR (KBr): v 3329, 2942, 1692, 1643, 1484, 1331, 1292,
1
1167, 1011, 878, 839, 770, 743 cmÀ1; H NMR (CDCl3,
500 MHz):
δ
2.26 (s, 3H, CH3), 2.39 (s, 3H,
methylpiperazine-H), 2.56 (s, 8H, methylpiperazine-H), 3.
60 (s, 2H, CH2), 3.72 (s, 3H, CH3), 7.46 (s, 1H, Ar–H),
8.02 (s, 1H, Ar–H); 13C NMR (CDCl3, 125MHz): δ 162.2,
152.2, 150.1, 144.1, 138.3, 134.7, 132.0, 123.6, 121.7,
62.9, 55.1, 53.1, 46.1, 30.6, 17.2; MS (ESI) m/z: 339.1 ([M
+H]+); Anal. Calcd for C16H23ClN4O2: C 56.72, H 6.84, N
16.54; found C 56.95, H 7.13, N 16.90.
5-Chloro-2-(2-(cyclohexylamino)acetamido)-N,3-dimethyl
benzamide (6h). White solid; mp 72–73°C; yield 78%; IR
(KBr): v 3433, 2924, 2851, 1669, 1602, 1465, 1340, 873, 794,
1
759 cmÀ1; H NMR (DMSO-d6, 500MHz): δ 1.09–1.89
(m, 6H, 3,4,5-tr-cyclohexane-H), 1.52 (s, 1H, NH), 1.65–1.86
(m, 4H, 2,6-dicyclohexane-H), 2.53 (s, 3H, CH3), 3.72–3.75
(m, 1H, 1-cyclohexane-H), 3.85 (s, 2H, CH2), 7.68 (s, 1H,
Ar–H), 7.83 (s, 1H, Ar–H); 13C NMR (DMSO-d6,
125 MHz): δ 166.1, 161.5, 149.2, 143.2, 139.4, 135.3,
127.8, 126.2, 61.2, 54.8, 45.0, 34.6, 31.1, 29.7, 21.9;
MS (ESI) m/z: 338.3 ([M+H]+); Anal. Calcd for
C17H24ClN3O2: C 60.44, H 7.16, N 12.44; found C 60.60,
H 7.38, N 12.61.
5-Chloro-2-(2-(piperidin-1-yl)acetamido)-N,3-dimethylbenzamide
(6d). White solid; mp 208–210°C; yield 85%; IR (KBr): v
3305, 2934, 1667, 1556, 1486, 1316, 1159, 1127, 878, 797,
1
745cmÀ1; H NMR (DMSO-d6, 500MHz): δ 1.36–1.57
(m, 6H, 3,4,5-tr-piperidine-H), 2.11 (s, 3H, CH3), 2.38
(d, J=5.72Hz, 4H, 2,6-dipiperidine-H), 2.66 (s, 3H, CH3),
2.95 (s, 2H, CH2), 7.29 (s, 1H, Ar–H), 7.39 (s, 1H, Ar–H),
8.41 (s, 1H, NH), 9.72 (s, 1H, NH); 13C NMR (DMSO-d6,
125 MHz): δ 169.1, 167.2, 138.4, 134.7, 133.2, 131.8,
130.1, 125.3, 63.0, 55.0, 26.5, 26.1, 23.9, 19.0; MS
(ESI) m/z: 324.1 ([M+H]+); Anal. Calcd for C16H22ClN3O2:
C 59.35, H 6.85, N 12.98; found C 59.47, H 7.11, N
13.32.
5-Chloro-2-(2-(cyclopentylamino)acetamido)-N,3-dimethyl
benzamide (6i). White solid; mp 79–81°C; yield 85%; IR
(KBr): v 3425, 2958, 1680, 1664, 1601, 1464, 1341, 874,
797, 741, 713cmÀ1 1H NMR (DMSO-d6, 500 MHz):
;
δ 1.33–1.44 (m, 4H, 3,4-dicyclopentane-H), 1.60–1.70
(m, 4H, 2,5-dicyclopentane-H), 2.32 (s, 1H, NH), 2.46
(s, 3H, CH3), 3.09–3.93 (m, 1H, 1-cyclopentane-H), 3.54
(s, 3H, CH3), 3,82 (s, 3H, CH2), 7.68 (s, 1H, Ar–H), 7.83
(s, 1H, Ar–H); 13C NMR (DMSO-d6, 125MHz): δ 161.3,
156.4, 144.5, 138.5, 134.7, 130.6, 123.1, 121.4, 59.7, 51.7,
33.1, 30.0, 24.0, 17.1; MS (ESI) m/z: 325.1 ([M+H]+);
Anal. Calcd for C16H22ClN3O2: C 59.35, H 6.85, N 12.98;
found C 59.09, H 6.66, N 13.15.
5-Chloro-2-(2-(cyclopropylamino)acetamido)-N,3-dimethyl
benzamide (6e). White solid; mp 175–177°C; yield 86%;
IR (KBr): v 3292, 1667, 16,376.6, 1513, 132, 1228, 1207,
1
1010, 871, 725 cmÀ1; H NMR (DMSO-d6, 500 MHz): δ
0.34–0.35 (m, 4H, 2,3-di-cy-H), 2.14 (s, 3H, CH3), 2.18
(s, 1H, NH), 2.71 (s, 3H, CH3), 2.53 (s, 2H, CH2), 7.32
(s, 1H, Ar–H), 7.43 (s, 1H, Ar–H), 8.37 (s, 1H, NH); 13C
NMR (DMSO-d6, 125MHz): δ 171.2, 167.2, 138.4,
135.0, 133.5, 131.7, 130.1, 125.5, 53.0, 31.2, 26.6, 19.0,
6.6; MS (ESI) m/z: 296.1 ([M+H]+); Anal. Calcd for
C14H18ClN3O2: C 56.85, H 6.13, N 14.21; found C
56.59, H 6.42, N 14.54.
5-Chloro-N,3-dimethyl-2-(2-(4-oxopiperidin-1-yl)acetamido)
benzamide (6j). White solid; mp 82–84°C; yield 86%; IR
(KBr): v 3442, 2975, 1682, 1598, 1464, 1338, 1099,
1
900.0, 798, 745, 715 cmÀ1; H NMR (CDCl3, 500 MHz):
2-(2-(1H-imidazol-1-yl)acetamido)-5-chloro-N,3-dimethyl
benzamide (6f). White solid; mp 174–176°C; yield 86%;
IR (KBr): v 3361, 3132, 1684, 1611, 1462, 1331,1244,
δ 1.26 (t, J = 5.62 Hz, 4H, 3,5-dipiperidine-H), 2.57
(s, 3H, CH3), 3.63 (t, J=5.72Hz, 4H, 2,6-dipiperidine-H),
3.70 (s, 3H, CH3), 4.61 (s, 2H, CH2), 7.52 (s, 1H,
Ar–H), 8.08 (s, 1H, Ar–H); 13C NMR (CDCl3,
125MHz): δ 162.0, 151.8, 144.1, 138.5, 134.8, 133.1,
132.4, 123.6, 121.9, 77.4, 72.5, 30.7, 17.2, 15.2; MS
(ESI) m/z: 338.3 ([M+H]+); Anal. Calcd for
C16H20ClN3O3: C 56.89, H 5.97, N 12.44; found C 56.63,
H 5.62, N 12.81.
1077, 882, 796, 739 cmÀ1
;
1H NMR (DMSO-d6,
500MHz): δ 2.19 (s, 3H, CH3), 2.52 (s, 3H, CH3), 5.49
(s, 2H, CH2), 6.93 (s, 1H, 2-imidazole-H), 7.16 (s, 1H,
Ar–H), 7.63 (d, J= 8.0 Hz, 2H, 4,5-imidazole-H), 7.83
(s, 1H, Ar–H); 13C NMR (DMSO-d6, 125MHz): δ 161.0,
153.3, 144.2, 139.1, 138.6, 134.8, 131.0, 128.4, 123.1,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Anthranilic Diamide Derivatives with Antibacterial Activities
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Bacteriostatic Bioassay against Three Phytopathogenic
Bacteria (Xoo, Xac, and R. solanacearum). According to
the mycelium growth inhibition method, anthranilic
diamide derivatives were tested for in vitro antibacterial
activity against three phytopathogenic bacteria (Xoo, Xac,
and R. solanacearum) by the turbidimeter test [30].
Dimethylsulfoxide in sterile distilled water served as a
blank control, with the commercial drug bismerthiazol as
the control. The three phytopathogenic bacteria (Xoo,
Xac, and R. solanacearum) of 40μL were respectively
added to 4 mL of solvent M (10.0 g of glucose, 5.0 g of
peptone, 1.0 g of yeast, 3.0 g of beef extract, and
1000 mL of distilled water; pH =7.0) containing the test
compounds and positive controls. The inoculated test
tubes were incubated at 28 1°C and continuously
shaken at 180 rpm for 24–48 h. The growth of the
cultures was monitored on a microplate reader by
measuring the optical density at 595nm (OD595) given by
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3979.
[9] Mao, M. Z.; Li, Y. X.; Zhou, Y. Y. Agric Food Chem 2014,
62, 1536.
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[13] Zhao, P. L.; Wang, F.; Zhang, M. Z.; Liu, Z. M.; Huang, W.;
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turbiditycorrected values = ODbacterial wilt À ODno
,
bacterial wilt
and then the inhibition rate I was calculated by I (%) =
(Ctur À Ttur)/Ctur ×100. Ctur is the corrected turbidity
values of bacterial growth on untreated M (blank control),
and Ttur is the corrected turbidity values of bacterial
growth on treated M.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet