Synthesis and bioactivity of sulfide derivatives containing 1,3,4-oxadiazole and pyridine

Article abstract of DOI:10.3906/kim-1901-45

A series of novel sulfide derivatives containing 1,3,4-oxadiazole and pyridine were synthesized, characterized, and tested for their antibacterial activity against tobacco bacterial wilt and rice bacterial blight and for insecticidal activity toward diamondback moth. The results showed that some compounds had good insecticidal and bactericidal activity, e.g., the activities of compounds 6e and 6g–6j toward tobacco bacterial wilt were much better than those of commercial thiodiazole-copper, and some of the synthesized compounds possessed good insecticidal activity against Plutella xylostella. Compounds 6d, 6h, 6j, 6l, 6p, 6r, and 6p displayed over 93% activity at 500 mg L^{? 1}.

Full text of DOI:10.3906/kim-1901-45

Turk J Chem
Turkish Journal of Chemistry
(2019) 43: 1075 – 1085
© TÜBİTAK
http://journals.tubitak.gov.tr/chem/
doi:10.3906/kim-1901-45
Research Article
Synthesis and bioactivity of sulfide derivatives containing 1,3,4-oxadiazole and
pyridine
Gang YU,, Shunhong CHEN,, Feng HE,, Dexia LUO,, Yu ZHANG,, Jian WU∗,
Key Laboratory of Green Pesticides and Agricultural Bioengineering, Ministry of Education, Guizhou University,
Huaxi District, Guiyang, P.R. China
Received: 22.01.2019
•
Accepted/Published Online: 13.05.2019
•
Final Version: 06.08.2019
Abstract: A series of novel sulfide derivatives containing 1,3,4-oxadiazole and pyridine were synthesized, characterized,
and tested for their antibacterial activity against tobacco bacterial wilt and rice bacterial blight and for insecticidal
activity toward diamondback moth. The results showed that some compounds had good insecticidal and bactericidal
activity, e.g., the activities of compounds 6e and 6g–6j toward tobacco bacterial wilt were much better than those
of commercial thiodiazole-copper, and some of the synthesized compounds possessed good insecticidal activity against
Plutella xylostella. Compounds 6d, 6h, 6j, 6l, 6p, 6r, and 6p displayed over 93% activity at 500 mg L−1
.
Key words: Sulfide derivative, 1,3,4-oxadiazole, pyridine, synthesis, antibacterial activity, insecticidal activity
1. Introduction
Bacterial disease in crops is extremely difficult to prevent due to the lack of effective antibacterial agents.
The threats from bacterial diseases in crops are still a big challenge for humans. For example, Xanthomonas
1
oryzae pv. oryzae (Xoo) is one of the most seriously harmful bacterial diseases in rice. The infection caused
2
by this disease may result in blighting of leaves and more than 10% yield loss of rice. Currently, only a
few measurements are available for bacterial diseases, including chemical and biological methods and the
use of resistant cultivars and lines, among which bismerthiazol and thiodiazole-copper are the main chemical
antimicrobial agents. However, their efficacy is not ideal. Therefore, the development of new antibacterial
agents against harmful bacterial diseases in crops remains a daunting task in pesticide science.
Derivatives of sulfides, which are an important class of bioactive compounds with a wide spectrum of
activities, have attracted more attention in the preparation of pesticides in recent years. They are employed
3
4,5
6
7,8
9
10
as antiinflammatory, anticancer,
agents.
anti-HIV-1, insecticidal,
herbicidal, fungicidal, and antibacterial
11−16
Some compounds with good antibacterial activity against Xoo and Xanthomonas oryzae pv. oryzae
(Xoc) have been reported by our group.
13−16
1,3,4-Oxadiazole, an important heterocycle, possesses a broad spectrum of biological and pharmaceutical
17−20
21−24
activities,
which have attracted growing attention because of their good herbicidal, insecticidal,
and antibacterial activity.
25−29
13−16,30,31
antifungal,
Some of the 1,3,4-oxadiazole derivatives (such as the
compounds in the Figure) were treated as pesticide candidates. In 2014, a series of 1,3,4-oxadiazole derivatives
with sulfone substructures were reported by Li et al., and many of the compounds showed excellent activity
∗Correspondence: wujian2691@126.com
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This work is licensed under a Creative Commons Attribution 4.0 International License.

YU et al./Turk J Chem
14
against the plant pathogenic bacteria Xoo and Xoc. More recently, Wang et al. reported a variety of 1-aryl-
4-hydroxy-1H -pyrrol-2(5H)-one derivatives bearing 1,3,4-oxadiazole moiety by placing the 1-aryl-4-hydroxy-
1H -pyrrol-2(5H)-one at the 2-position of 1,3,4-oxadiazole through a sulfide linkage. Some of the synthesized
compounds showed excellent antibacterial activity against plant pathogenic bacteria including Xoo, Ralstonia
15
solanacearum, and Xanthomonas axonopodis pv. citri. Moreover, as an important pyridine derivative, the
scaffold of 3-methyl-4-(2,2,2-trifluoroethoxy)pyridine has also received close attention due to the fluorine atoms
in its structure. Many compounds with this substructure showed good activity for both pharmaceutical and
7,32−37
agrochemical applications.
Figure. Pesticide candidates containing 1,3,4-oxadiazole.
Encouraged by the information above, and in continuation of works on sulfide derivatives and interesting
7,8
sulfides,
a series of new sulfide derivatives containing both 1,3,4-oxadiazole and pyridine moieties was designed
and synthesized by introducing 3-methyl-4-(2,2,2-trifluoroethoxy)pyridine into the 2-position of 1,3,4-oxadiazole
via a sulfide linkage. The antibacterial and insecticidal activities of these target compounds were evaluated and
the results indicated that some of the synthesized compounds showed good bioactivity.
2. Results and discussion
2.1. Synthesis
The synthetic route of the sulfide derivatives is drawn in the Scheme. First, substituted ethyl benzoate (2)
was prepared by treatment of substituted benzoic acid with ethanol in the presence of concentrated sulfuric
acid, which further reacted with hydrazine hydrate (80%) in good yield to get substituted benzoyl hydrazine
in excellent yield. Substituted 5-phenyl-1,3,4-oxadiazole-2-thiol (4) was synthesized via ring-closure reaction of
14,15
substituted benzoyl hydrazine 3 with CS2 in the presence of NaOH.
Subsequently, thioetherification of
substituted 5-phenyl-1,3,4-oxadiazole-2-thiol was carried out by treatment of 4 with 2-(chloromethyl)-3-methyl-
4-(2,2,2-trifluoroethoxy)pyridine hydrochloride in the presence of K2 CO3 in excellent yield as described in our
7,8
previous work.
1
Take compound 6g as an example. It can be seen from the H NMR spectrum of compound 6g that
at δ 8.36 ppm is H adjacent to the N atom on the pyridine ring, and it is coupled by the H atom in the meta
position, split into a doublet, with coupling constant J = 5.7 Hz. The H in the N position of the pyridine ring
appears at δ 8.36 ppm. Due to the H coupling of the ortho position, it is divided into double peaks, and the
coupling constant is 1J = 5.7 Hz. At δ 7.87 ppm is H on the benzene ring and it is bimodal with a coupling
2
constant of J = 2.2 Hz. Both δ 7.37 ppm and δ 7.35 ppm are H on the benzene ring. Due to the coupling of
H atoms with each other, they are split into d peaks with a coupling constant of 3J = 2.2 Hz. At δ 6.69 ppm
is H on the pyridine ring. Due to the ortho-H coupling, the split is divided into double peaks, and the coupling
4
constant is J = 5.6 Hz; δ 4.76 ppm is a single peak, which is -CH2 -, and -CH2 - connected to CF3 is affected
1076

YU et al./Turk J Chem
2
2
2
5
5
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1+
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1+ꢅ1+ꢅ +ꢅ2
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2+
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ꢅ
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Scheme. The synthesis of target sulfide derivatives containing 1, 3, 4-oxadiazole and pyridine.
by 3 couplings of F atoms, split into quadruple peaks, with coupling constant JF −H = 7.8 Hz. It appears at δ
13
4.41 ppm. In the C NMR spectrum (for example, compound 6d), due to the presence of CF3 , the C atom
is also split into a quartet, and C in the -CF3 group appears at δ 122.98 ppm. In the vicinity, the coupling
1
constant is JC−F = J = 277.9 Hz, and the C linked to the -CF3 group is also split into a quartet, with δ
2
65.52 ppm coupling constant JC−F = 36.3 Hz.
2.2. Antibacterial activity
2.3. Inhibitory activity of compounds against rice bacterial blight
Using bismerthiazol as a positive control, the inhibitory activities of the synthesized compounds against Xoo
were evaluated by turbidity method at concentrations of 100 mg L−1 and 50 mg L−1 . The results in Table 1
indicate that compounds 6a, 6j, 6k, 6l, 6n, 6q, and 6u possess potential bacteriostatic activity against Xoo,
with inhibition rates of 60.7%, 58.4%, 52.2%, 56.8%, 53.8%, 59.2%, and 64.2%, respectively. The antibacterial
activity of compound 6u was equivalent to the positive control, bismerthiazol (66.0%). When the concentration
was 50 mg L−1 , the activities of 6h, 6j, 6n, 6o, and 6t were 43.8%, 36.2%, 33.1%, 34.8%, and 41.3%,
respectively. Compounds 6h, 6j, and 6t showed slightly higher activity than that of bismerthiazol (33.3%).
2.3.1. Inhibitory activity of compounds against tobacco bacterial wilt
The bacteriostatic activity against tobacco bacterial wilt (Ralstonia solanacearum) as listed in Table 2 indicated
that some of synthesized compounds show good bacteriostatic activity against Ralstonia solanacearum. Com-
pounds 6e, 6g, 6h, 6i, 6j, and 6r showed 60% activity at 100 mg L−1 , and the inhibition rates of the other
compounds were as high as 73.8%, which was much higher than that of thiodiazole-copper (31.5%). When the
concentration was 50 mg L−1 , most of the synthesized compounds displayed better inhibition rates than that
of thiodiazole-copper, whereby the inhibition rate of compound 6v was as high as 59.0%.
1077

YU et al./Turk J Chem
Table 1. Inhibition of target compounds against Xanthomonas oryzae pv. oryzae.
Concentration
Concentration
Compound
Compound
100 mg L−1 50 mg L−1
100 mg L−1 50 mg L−1
6a
6b
6c
6d
6e
6f
6g
6h
6i
60.7
28.0
1.6
17.9
27.9
0.6
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
25.5
53.8
43.8
30.4
59.2
26.3
34.6
45.7
64.2
26.0
21.0
1.7
33.1
34.8
3.6
16.8
8.1
0
0
22.1
25.1
24.6
49.2
10.1
58.4
52.2
56.8
18.1
10.3
22.5
43.8
10.9
36.2
30.6
44.1
6.4
41.3
22.8
0
18.0
33.2
6j
6k
6l
Bismerthiazol 66.0
Table 2. Inhibitory effects of target compounds on Ralstonia solanacearum.
Concentration
Concentration
Compound
Compound
100 mg L−1 50 mg L−1
100 mg L−1 50 mg L−1
6a
6b
6c
6d
6e
6f
6g
6h
6i
53.6
0
23.2
0
73.8
0
66.5
65.8
67.5
60.3
30.3
9.3
33.3
0
13.8
0
58.6
0
50.3
41.4
53.0
43.6
0
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
23.6
52.3
53.1
36.8
38.6
67.9
33.1
39.3
57.0
66.1
63.1
22.2
47.5
51.2
28.5
30.3
53.0
30.9
24.3
40.3
59.0
55.2
9.4
6j
6k
6l
0
Thiodiazole-copper 31.5
2.4. Insecticidal activity
The bioassay results against Plutella xylostella are presented in Table 3. Some of the compounds possessed
weak to good bioactivities. For instance, compounds 6d, 6f, 6h, 6i, 6j, 6l, 6p, 6r, and 6p displayed activities
of over 93% at 500 mg L−1 . When the concentration was 200 mg L−1 , the activities of compounds 6h, 6j,
and 6l were still over 85%, and most of the compounds (6d, 6f, 6i, 6q, 6t, etc.) showed moderate activity.
However, the activities were sharply decreased when the concentration was 100 mg L−1 . Preliminary structure-
activity relationship analysis indicated that the insecticidal activity can be enhanced by introducing groups
of trifluoromethyl (6h, 6i, 6t) in the benzene ring, while the introduction of ethyl (6b) or iodine (6c) could
1078

YU et al./Turk J Chem
sharply decrease the insecticidal activities. However, the quantitative structure-activity relationship is not very
clear. Further studies are currently underway to establish a definite structure-activity relationship.
Table 3. Insecticidal activity of title compounds against P. xylostella.
Concentrations, mg L−1
Concentrations, mg L−1
Comp.
Comp.
500
250
32%
0%
100
0
/
/
500
250
34%
0%
100
12%
/
6a
6b
6c
6d
6e
6f
6g
6h
6i
57%
27%
17%
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
56%
23%
54%
97%
84%
97%
20%
87%
87%
97%
56%
0%
26%
46%
50%
62%
0%
72%
54%
68%
18%
0%
100% 77% 20%
13%
12%
23%
0%
23%
10%
23%
0%
53%
93%
23%
22% 13%
75% 23%
0%
/
100% 87% 27%
90% 53% 15%
100% 87% 24%
6j
6k
6l
37%
93%
16% 0%
85% 13%
Chlorantraniliprole 100% 100% 100%
2.5. Conclusions
In this article, 23 novel pyridine-containing 1,3,4-oxadiazole sulfide derivatives were designed and synthesized.
The bacteriostatic activities against tobacco bacterial wilt (Ralstonia solanacearum) and rice bacterial blight
(Xoo) were tested using the turbidity method. The results indicated that the synthesized compounds showed
good antibacterial activities against tobacco bacterial wilt and rice bacterial blight. The results of insecticidal
activity indicated that some of the synthesized compounds showed good insecticidal activities; for instance,
compounds 6d, 6h, 6j, 6l, 6p, 6r, and 6p displayed over 93% activity at 500 mg L−1 . The sulfide derivatives
containing 1,3,4-oxadiazole and pyridine could be considered as lead structures for the discovery of novel pesticide
molecules. Further studies for structural optimization and bioactivity testing are underway in our laboratory.
3. Experimental
3.1. Materials
All reactants and starting materials were purchased from Accela ChemBio Co., Ltd. (Shanghai, China). The
1
NMR spectra were recorded on a JEOL ECX500 NMR spectrometer (JEOL Ltd., Tokyo, Japan) with H NMR
13
19
1
at 500 MHz, C NMR at 125 MHz, and F NMR at 471 MHz operating at room temperature. The H NMR
chemical shifts were measured relative to CDCl3 as the internal reference (CDCl3 : δ = 7.26 ppm, DMSO-d6:
13
δ = 2.50 ppm). The C NMR chemical shifts were given using CDCl3 as the internal standard (CDCl3 : δ
= 77.2 ppm, DMSO-d6: δ = 39.5 ppm). High-resolution mass spectra (HR-MS) were recorded on an Orbitrap
LC–MS instrument (Q-Exative, Thermo Scientific, USA). Melting points were determined with X-4 and are
uncorrected. The process of the reaction was monitored by TLC.
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YU et al./Turk J Chem
3.2. Preparation of the intermediate
14,15
Intermediate 4 (5-substituted-1,3,4-oxadiazole-2-thiol) was prepared using previously reported protocols.
3.3. General synthetic procedures for compounds 6a–6w
A mixture of substituted phenyl-1,3,4-oxadiazole-2-thiol (4) (0.2 g, 1 mmol), 2-(chloromethyl)-3-methyl-4-(2,2,2-
trifluoroethoxy)pyridine (5) (1.1 mmol), and K2 CO3 (0.5 mmol) in acetonitrile was stirred under reflux and the
reaction was monitored with TLC. After completion of the reaction, the mixture was concentrated in vacuum
and the residue was poured into 20 mL of water, filtered, and dried to obtain the target compounds.
2-(3,5-Dichlorophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole
1
(6a): White solid; yield, 88.6%; mp 148–149◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.5 Hz, 1H),
7.90 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.68 (d, J = 5.5 Hz, 1H), 4.76 (s, 2H), 4.41
13
(q,J = 7.7 Hz, 2H), 2.33 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.53, 163.45, 161.69, 154.32, 148.19,
138.10, 133.92, 131.68, 131.27, 127.68, 123.06 (q,J = 263.9 Hz), 121.56, 121.37, 105.91, 65.53 (q, J = 36.7 Hz),
19
37.38, 10.76; F NMR (471 MHz, chloroform-D) δ –73.64; HR-MS (ESI): Calculated for C17 H12 O2 N3 Cl2 F3 S
+
[M+H] : 450.00418, found: 450.00521.
2-(4-Ethylphenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6b):
1
White solid; yield, 80.9%; mp 181–182 ◦ C; H NMR (500 MHz, Chloroform-D) δ 8.35 (d, J = 5.6 Hz, 1H),
7.92 (d, J = 7.2 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 5.6 Hz, 1H), 4.74 (s, 2H), 4.40 (q, J = 7.8 Hz,
13
2H), 2.71 (q, J = 7.6 Hz, 2H), 2.34 (s, 3H), 1.26 (t, J = 7.7, 6.4 Hz, 3H); C NMR (126 MHz, chloroform-D) δ
166.11, 164.13, 161.68, 154.63, 148.50, 148.19, 128.64, 126.88, 121.43, 121.17, 122.98 (q, J = 277.0 Hz), 105.85,
19
65.52 (q, J = 36.5 Hz), 37.34, 29.16, 15.31, 10.78. F NMR (471 MHz, chloroform-D) δ –73.67; HR-MS (ESI):
+
Calculated for C19 H18 O2 N3 F3 S[M+H] : 410.11446, found: 410.11340.
2-(3-Iodophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6c):
1
White solid; yield, 69.5%; mp 140–141 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 7.9 Hz, 1H),
8.35 (s, 1H), 7.95 (m, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.69 (d, J = 5.7 Hz, 1H), 4.75
13
(s, 2H), 4.41 (q, J = 7.8 Hz, 2H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.11, 164.41, 161.71,
154.39, 148.17, 140.59, 135.39, 130.73, 125.89, 125.55, 122.97 (q,J = 277.6 Hz), 121.42, 105.91, 94.37, 65.53
19
(q,J = 36.4 Hz), 37.41, 10.79; F NMR (471 MHz, chloroform-D) δ –73.66; HR-MS (ESI): Calculated for
+
C17 H13 O2 N3 F3 SI [M+H] : 507.97980, found: 507.97888.
2-(((3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-5-phenyl-1,3,4-oxadiazole (6d): White
1
solid; yield, 86.3%; mp 160–161 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.6 Hz, 1H), 8.02 (m,
13
2H), 7.54 (m, 3H), 6.68 (d,J = 5.6 Hz, 1H), 4.75 (s, 2H), 4.40 (q, J = 7.8 Hz, 2H), 2.34 (s, 3H); C NMR
(126 MHz, chloroform-D) δ 165.93, 164.56, 161.68, 154.53, 148.18, 131.73, 129.12, 126.80, 123.74, 122.98 (q,J =
19
277.9 Hz), 121.40, 105.87, 65.52 (q,J = 36.3 Hz), 37.36, 10.77; F NMR (471 MHz, chloroform-D) δ –73.66;
+
HR-MS (ESI): Calculated for C17 H14 O2 N3 F3 S [M+H] : 382.08316, found: 382.08209.
2-(4-Fluorophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6e):
1
White solid; yield, 65.2%; mp 101–102 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.30 (d, J = 4.0 Hz, 1H),
7.25 (d, J = 3.7 Hz, 2H), 7.07 (m, 2H), 6.66 (d, J = 4.0 Hz, 1H), 4.65 (s, 2H), 4.39 (q, J = 7.7, 4.0 Hz, 2H),
13
2.28 (s, 3H); C NMR (126 MHz, chloroform-D) δ 166.30, 165.09, 162.30 (d, J = 246.3 Hz), 161.66, 154.42,
148.12, 130.55 (d, J = 8.1 Hz), 129.43, 122.97 (q, J = 278.0 Hz), 121.32, 115.89 (d, J = 21.7 Hz), 105.85, 65.50
1080

YU et al./Turk J Chem
19
(q,J = 36.4 Hz), 31.17, 10.70; F NMR (471 MHz, chloroform-D) δ –73.68, –114.68; HR-MS (ESI): Calculated
+
for C17 H13 O2 N3 F4 S [M+H] : 400.07374, found: 400.07446.
2-(4-Iodophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6f):
1
White solid; yield, 53.0%; mp 172–173 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (s, 1H), 7.84 (d, J = 8.6
13
Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 6.69 (s, 1H), 4.75 (s, 2H), 4.41 (q, J = 7.8 Hz, 2H), 2.34 (s, 3H); C NMR
(126 MHz, chloroform-D) δ 165.35, 164.94, 161.73, 154.37, 148.13, 138.41, 128.13, 122.76 (q, J = 277.3 Hz),
19
106.36 (s), 105.90 (s), 98.57 (s), 65.53 (q, J = 36.6 Hz), 45.32, 37.33, 10.79; F NMR (471 MHz, chloroform-D)
+
δ –73.62; HR-MS(ESI): Calculated for C17 H13 O2 N3 F3 SI [M+H] : 507.97980, found: 507.97903.
2-(5-Chloro-2-methylphenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxa-
1
diazole (6g): White solid; yield, 59.3%; mp 129–130 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.36 (d,J = 5.7
Hz, 1H), 7.87 (d, J = 2.2 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 6.69 (d, J = 5.6 Hz, 1H),
13
4.76 (s, 2H), 4.41 (q, J = 7.8 Hz, 2H), 2.66 (s, 2H), 2.34 (s, 2H); C NMR (126 MHz, chloroform-D) δ 165.01,
164.66, 161.70, 154.46, 148.21, 136.82, 133.18, 132.00, 131.09, 128.47, 124.17, 121.38, 105.91, 65.53 (q,J = 36.5
19
Hz), 37.39, 29.80, 21.71, 10.77; F NMR (471 MHz, chloroform-D) δ –73.66; HR-MS (ESI): Calculated for
+
C18 H15 ClF3 N3 O2 S [M+H] : 430.05984, found: 430.05884.
2-(2-Trifluoromethyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole
1
(6h): White solid; yield, 99.1%; mp 124–125 ◦ C; H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J = 5.5 Hz, 1H),
8.02 (d, J = 7.4 Hz, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.90–7.83 (m, 2H), 7.09 (d, J = 5.5 Hz, 1H), 4.89 (q,
13
J = 8.5 Hz, 2H), 4.78 (s, 2H), 2.19 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 165.75, 163.53, 161.13, 161.13,
154.30, 148.19, 133.80, 133.06, 132.41, 127.78, 127.73, 122.75 (q, J = 39.2 Hz), 121.76, 120.20, 107.68, 65.53 (q,
19
J = 36.5 Hz), 37.64, 10.58; F NMR (471 MHz, chloroform-D) δ –59.82, –73.65; HR-MS (ESI): Calculated for
+
C18 H13 O2 N3 F6 S [M+H] : 450.07054, found: 450.06937.
2-(4-Trifluoromethyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole
1
(6i): White solid; yield 82.6%; mp 152–153 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.6 Hz, 1H),
8.14 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 6.69 (d, J = 5.6 Hz, 1H), 4.77 (s, 1H), 4.41 (q, J = 7.8 Hz,
13
2H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.63, 164.72, 161.70, 154.29, 148.19, 133.31 (q, J =
33.2 Hz), 127.10, 126.21, 126.18, 124.40 (q, J = 82.9 Hz), 122.98 (q, J = 105.8 Hz), 121.38, 105.92, 65.53 (q, J
19
= 36.5 Hz), 37.43, 10.78; F NMR (471 MHz, chloroform-D) δ –62.95, –73.66; HR-MS (ESI): Calculated for
+
C18 H13 O2 N3 F6 S [M+H] : 450.07054, found: 450.06949.
2-(2,4-Dimethylphenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole
1
(6j): White solid; yield, 86.3%; mp 145–146 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 4.2 Hz, 1H),
7.77 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.11 (d, J = 7.9 Hz, 1H), 6.67 (d,J = 4.3 Hz, 1H), 4.75 (s, 2H), 4.40 (q,
13
J = 7.8 Hz, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ 166.32, 163.77,
161.67, 154.64, 148.19, 141.66, 138.25, 132.56, 128.84, 126.99, 122.99 (q,J = 278.0 Hz), 121.39, 120.02, 105.85,
19
65.52 (q, J = 36.3 Hz), 37.30, 22.10, 21.49, 10.76; F NMR (471 MHz, chloroform-D) δ –73.64; HR-MS (ESI):
+
Calculated for C19 H18 O2 N3 F3 S [M+H] : 410.11446, found: 410.11359.
N ,N -Dimethyl-3-(5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazol-2-yl)
1
aniline (6k): White solid; yield, 78.5%; mp 150–151 ◦ C; H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 5.6
Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.16 (s, 1H), 7.08 (d,J = 5.7 Hz, 1H), 6.92 (d,
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13
J = 8.4 Hz, 1H), 4.88 (dd,J = 16.4, 8.7 Hz, 2H), 4.74 (s, 2H), 2.93 (s, 6H), 2.20 (s, 3H); C NMR (126 MHz,
DMSO-d6) δ 166.33, 164.07, 161.62, 154.70, 151.06, 148.24, 130.51, 124.12 (s), 123.73 (dd, J = 272.1, 151.7
19
Hz), 120.27, 116.14, 114.35, 109.43, 107.61, 65.18 (q, J = 25.2 Hz), 40.46, 37.56, 10.67; F NMR (471 MHz,
+
DMSO-d6) δ -72.60; HR-MS (ESI): Calculated for C19 H19 O2 N4 F6 S [M+H] : 425.12536, found: 425.12442.
2-(3-Chlorophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6l):
1
White solid; yield, 74.2%; mp 116–117◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.5 Hz, 1H), 8.00
(s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 8.7 Hz, 1H), 6.68 (d, J = 5.3 Hz,
13
1H), 4.76 (s, 2H), 4.40 (d, J = 7.8 Hz, 2H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.16, 164.76,
161.69, 154.39, 148.19, 135.27, 131.76, 130.49, 126.77, 125.35, 124.87, 122.97 (q, J = 277.0 Hz), 121.38, 105.90,
19
65.53 (d, J = 36.3 Hz), 37.43, 10.78; F NMR (471 MHz, chloroform-D) δ –73.66; HR-MS (ESI): Calculated
+
for C17 H13 O2 N3 F3 SCl [M+H] : 416.04419, found: 416.04327.
2-(3-Bromophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6m):
1
White solid; yield, 67.3%; mp 120– 21 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.36 (d, J = 5.7 Hz, 1H),
8.16 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.37 (t,J = 7.9 Hz, 1H), 6.69 (d, J = 5.6 Hz,
13
1H), 4.76 (s, 2H), 4.41 (q,J = 7.8 Hz, 2H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ 164.62, 164.37,
161.69, 154.36, 148.20, 134.70, 130.73, 129.63, 125.53, 125.33, 123.06, 122.98 (q,J = 277.6 Hz), 121.39, 105.89,
19
65.50 (q, J = 36.7 Hz), 37.42, 10.78; F NMR (471 MHz, chloroform-D) δ –73.65; HR-MS (ESI): Calculated
+
for C17 H13 O2 N3 F3 SBr [M+H] : 459.99367, found: 459.99292.
2-(3-Chloro-4-methylphenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxa-
1
diazole (6n): White solid; yield, 61.2%; mp 158–159 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.6
Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.80 (dd, J = 7.9, 1.7 Hz, 1H), 7.35 (d,J = 8.0 Hz, 1H), 6.68 (d,J = 5.6 Hz,
13
1H), 4.74 (s, 2H), 4.41 (q, J = 7.8 Hz, 2H), 2.43 (s, 3H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ
164.91, 164.73, 161.68, 154.46, 148.19, 140.22, 135.28, 131.66, 127.20, 124.89, 122.98 (q, J = 277.8 Hz), 122.82,
19
121.40, 65.52 (q,J = 36.6 Hz), 37.41, 20.41, 10.78; F NMR (471 MHz, chloroform-D) δ –73.66; HR-MS (ESI):
+
Calculated for C18 H15 O2 N3 F3 SCl [M+H] : 430.05984, found: 430.05899.
2-(4-Chloro-3-fluorophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadi-
1
azole (6o): White solid; yield, 83.2%; mp 158–160 ◦ C; H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 5.7 Hz,
1H), 7.97 (d, J = 9.6 Hz, 1H), 7.81 (d, J = 1.8 Hz, 2H), 7.09 (d, J = 5.7 Hz, 1H), 4.89 (q, J = 8.3 Hz, 2H), 4.78
13
(s, 2H), 2.21 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 165.27, 161.64, 157.00, 154.45, 148.22, 132.58, 124.26
(d, J = 3.9 Hz), 123.92, 122.97 (q, J = 278.0 Hz), 120.28, 120.00, 115.43, 115.24, 107.68, 65.36 (dd, J = 28.0,
19
14.9 Hz), 37.68, 10.67; F NMR (471 MHz, chloroform-D) δ –73.66, –112.81; HR-MS (ESI): Calculated for
+
C17 H12 O2 N3 F4 SCl [M+H] : 434.03476, found: 434.03384.
2-(((3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-5-(m-tolyl)-1,3,4-oxadiazole (6p): White
1
solid; yield, 85.6%; mp 140–141 ◦ C; H NMR (500 MHz, DMSO-d6) δ 8.27 (d, J = 5.4 Hz, 1H), 7.76 (s, 1H),
7.74 (d, J = 7.7 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 5.6 Hz, 1H), 4.89 (q,J
13
= 8.6 Hz, 2H), 4.76 (s, 2H), 2.37 (s, 3H), 2.21 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 165.75, 164.33, 161.64,
154.63, 148.23, 139.50, 133.21, 129.89, 127.22, 124.12, 122.97 (q, J = 278.0 Hz), 123.52, 120.30, 107.65, 65.52
19
(q, J = 36.2 Hz), 37.66, 21.34, 10.67; F NMR (471 MHz, chloroform-D) δ –73.66; HR-MS (ESI): Calculated
+
for C18 H16 O2 N3 F3 S [M+H] : 396.09881, found: 396.09805.
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2-(4-Bromophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6q):
1
White solid; yield, 78.4%; mp 183–184 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.7 Hz, 1H),
7.88 (d, J = 8.6 Hz, 2H), 7.63 (d,J = 8.6 Hz, 2H), 6.68 (d, J = 5.7 Hz, 1H), 4.75 (s, 2H), 4.41 (q, J = 7.8 Hz,
13
2H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.20, 164.94, 161.69, 154.40, 148.18, 132.48, 128.20,
19
126.41, 122.97 (q,J = 278.0 Hz), 122.64, 121.39, 105.89, 65.52 (q, J = 36.7 Hz), 37.39, 10.78; F NMR (471
+
MHz, chloroform-D) δ –73.66; HR-MS(ESI): Calculated for C17 H13 O2 N3 F3 SBr [M+H] : 459.99367, found:
459.99292.
2-(4-Bromo-2-fluorophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadi-
1
azole (6r): White solid; yield, 60.8%; mp 171–172 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.34 (d, J = 5.6
Hz, 1H), 7.88 (t,J = 8.0 Hz, 1H), 7.45 (s, 1H), 7.43 (d, J = 0.8 Hz, 1H), 6.68 (d, J = 5.6 Hz, 1H), 4.76 (s,
13
2H), 4.41 (q, J = 7.4 Hz, 2H), 2.33 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.46, 161.96 (d, J = 5.4
Hz), 161.69, 159.51 (d, J = 263.5 Hz), 154.34, 148.18, 130.35, 128.31, 126.66 (d,J = 8.9 Hz), 122.97 (q, J =
277.6 Hz), 121.40, 120.83 (d, J = 23.9 Hz), 111.42 (d, J = 12.1 Hz), 105.90, 65.52 (q,J = 36.1 Hz), 37.35, 10.76;
19
F NMR (471 MHz, chloroform-D) δ –73.66, –106.98; HR-MS (ESI): Calculated for C17 H12 O2 N3 F4 SBr
+
[M+H] : 477.98425, found: 477.98325.
2-(2-Fluorophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6s):
1
White solid; yield, 85.3%; mp 124–125 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d,J = 5.6 Hz, 1H), 8.11
– 7.88 (m, 1H), 7.52 (dddd, J = 8.6, 7.1, 5.1, 1.8 Hz, 1H), 7.28 (dt, J = 8.0, 4.1 Hz, 1H), 7.25–7.21 (m, 1H), 6.68
13
(d, J = 5.7 Hz, 1H), 4.76 (s, 2H), 4.41 (q, J = 7.8 Hz, 2H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D)
δ 165.12, 162.62 (d, J = 5.9 Hz), 161.69, 159.95 (d, J = 258.5 Hz), 154.49, 148.20, 133.49 (d, J = 8.3 Hz),
129.63, 124.71 (d, J = 3.4 Hz), 122.98 (q, J = 277.6 Hz), 121.42, 117.07 (d, J = 20.7 Hz), 112.29 (d, J = 11.6
19
Hz), 105.87, 65.52 (q, J = 72.6, 36.2 Hz), 37.33, 10.76; F NMR (471 MHz, chloroform-D) δ –73.68, –109.53;
+
HR-MS(ESI): Calculated for C17 H13 O2 N3 F4 S [M+H] : 400.07374, found: 400.07281.
2-(((3-Methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-5-(3-(trifluorom-ethyl)phenyl)-1,3,4-oxa-
1
diazole (6t): White solid; yield, 88.6%; mp 125–126 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.34 (dd,J = 5.5,
2.9 Hz, 1H), 7.99 (t, J = 6.6 Hz, 1H), 7.57–7.41 (m, 2H), 7.38–7.08 (m, 1H), 6.68 (dd, J = 5.4, 2.9 Hz, 1H), 4.75
13
(s, 2H), 4.41 (q, J = 7.8 Hz, 2H), 2.33 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.11, 162.63, 160.97,
158.91, 154.43, 148.19, 132.16 (q, J = 314.8 Hz), 129.61, 124.70, 123.69 (q, J = 173.1 Hz), 122.75 (q, J = 31.0
19
Hz), 121.40, 116.98, 112.20, 105.89, 65.50 (q, J = 36.5 Hz), 37.31, 10.75; F NMR (471 MHz, chloroform-D) δ
+
–73.68, –109.55; HR-MS (ESI): Calculated for C18 H13 O2 N3 F6 S [M+H] : 450.07054, found: 450.06949.
2-(4-Chlorophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadiazole (6u):
1
White solid; yield, 73.9%; mp 185–186 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.6 Hz, 1H), 7.95
(d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 5.7 Hz, 1H), 4.75 (s, 2H), 4.41 (q, J = 7.8 Hz,
13
2H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.10, 164.89, 161.68, 154.40, 148.18, 137.99, 129.52,
19
128.07, 122.97 (q, J = 277.7 Hz), 122.21, 121.38, 105.89, 65.52 (q, J = 36.7 Hz), 37.40, 10.78; F NMR (471
+
MHz, chloroform-D) δ –73.68; HR-MS (ESI): Calculated for C17 H13 O2 N3 F3 SCl [M+H] : 416.04419, found:
416.04306.
2-(5-Bromo-2-chlorophenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)thio)-1,3,4-oxadi-
1
azole (6v): White solid; yield, 87.8%; mp 140–141◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.6
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YU et al./Turk J Chem
Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.6, 2.2 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 5.7
13
Hz, 1H), 4.76 (s, 2H), 4.41 (q, J = 7.8 Hz, 2H), 2.34 (s, 3H); C NMR (126 MHz, chloroform-D) δ 165.77,
162.95, 161.69, 154.30, 148.20, 135.24, 133.44, 132.75, 132.07, 124.54, 122.97 (q, J = 278.0 Hz), 121.38, 120.69,
19
105.93, 65.53 (q, J = 72.5, 36.3 Hz), 37.41, 10.77; F NMR (471 MHz, chloroform-D) δ –73.67; HR-MS (ESI):
+
Calculated for C17 H12 BrClF3 N3 O2 S [M+H] : 494.95470, found: 494.95361.
2-(2-Methoxyphenyl)-5-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridine-2-yl)methyl)thio)-1,3,4-oxadi-
1
azole (6w): White solid; yield, 79.4%; mp 124–125 ◦ C; H NMR (500 MHz, chloroform-D) δ 8.35 (d, J = 5.6
Hz, 1H), 7.87 (dd,J = 7.7, 1.7 Hz, 1H), 7.48 (ddd, J = 8.4, 7.5, 1.7 Hz, 1H), 7.05 (td, J = 7.6, 1.0 Hz, 2H), 7.04
(d, J = 8.4 Hz, 1H), 6.67 (d,J = 5.7 Hz, 1H), 4.75 (s, 2H), 4.40 (q, J = 7.8 Hz, 2H), 3.94 (s, 3H), 2.34 (s, 3H);
13
C NMR (126 MHz, chloroform-D) δ 164.61, 164.14, 161.67, 157.85, 154.74, 148.19, 133.09, 130.38, 122.99 (q,J
19
= 278.2 Hz), 121.46, 120.78, 112.91, 111.98, 105.81, 65.51 (q, J = 36.4 Hz), 56.06, 37.24, 10.77; F NMR (471
MHz, chloroform-D) δ –73.68; HR-MS (ESI): Calculated for C18 H16 F3 N3 O3 S [M+H] : 412.09372, found:
+
412.09296.
3.4. Biological assays
3.4.1. Antibacterial activity
14
The turbidity method was used to carry out biological activity tests. When rice bacterial blight was de-
termined, leaf cumin was used as the control agent. When the tobacco bacterial wilt bacteria were used,
thiodiazole-copper was used as the control agent and warm water was used as the blank control. Three paral-
lels, using the following formulas, were used to calculate the bacterial inhibition rate:
Corrected OD value = OD value of bacteria-containing medium – OD value of sterile medium
Inhibition rate = (OD value of corrected control medium broth – corrected OD value of toxic medium)
/ corrected OD value of control medium broth × 100%
3.4.2. Insecticidal activity
7,8
Previously reported protocols
were used to test the insecticidal activities against Plutella xylostella. Fresh
cabbage discs (diameter of 2 cm) were dipped in the prepared solutions containing the synthesized compounds
for 10 s, dried in air, and placed in a petri dish lined with filter paper. Ten larvae of the second instar of Plutella
xylostella were carefully transferred to the petri dishes. Chlorantraniliprole was used as a positive control; three
replicates were performed for each experiment. Mortality was calculated after 72 h. Evaluations of mortality
were calculated on a percentage scale (0 = no activity and 100 = complete eradication) at 5% intervals.
Acknowledgments
Financial assistance from the National Natural Science Foundation of China (No. 21562012, 21762012), and
the Science and Technology Planning Project of Guizhou Province (No. [2017]1402, [2017]5788) is appreciated.
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