Design, synthesis, and biological evaluation of novel pyrethrin derivatives containing 1,3,4-oxadiazole and thioether moieties as active insecticidal agents

Article abstract of DOI:10.1007/s11696-019-01012-4

To discover and develop novel active molecules, in this study, a series of novel pyrethrin derivatives containing 1,3,4-oxadiazole and thioether moieties were designed and synthesized. Bioassay results revealed that some of the target compounds possessed good insecticidal activities against Plutella xylostella (P. xylostella), Vegetable aphids (V. aphids), and Empoasca vitis (E. vitis), respectively, which were even better than those of the commercial insecticidal agents chlorpyrifos, beta cypermethrin, spinosad, and azadirachtin. The results favored our rational design intention and provide a new class of small-molecule inhibitors available for the development of active insecticidal agents targeting P. xylostella, V. aphids, and E. vitis.

Full text of DOI:10.1007/s11696-019-01012-4

Chemical Papers
https://doi.org/10.1007/s11696-019-01012-4
ORIGINAL PAPER
Design, synthesis, and biological evaluation of novel pyrethrin
derivatives containing 1,3,4‑oxadiazole and thioether moieties
as active insecticidal agents
Zaibo Yang1 · Pei Li1,2,3 · Yinju He1 · Jun Luo1 · Jing Zhou1 · Yinghong Wu1 · Liantao Chen1
Received: 25 July 2019 / Accepted: 26 November 2019
© Institute of Chemistry, Slovak Academy of Sciences 2019
Abstract
To discover and develop novel active molecules, in this study, a series of novel pyrethrin derivatives containing 1,3,4-oxa-
diazole and thioether moieties were designed and synthesized. Bioassay results revealed that some of the target compounds
possessed good insecticidal activities against Plutella xylostella (P. xylostella), Vegetable aphids (V. aphids), and Empoasca
vitis (E. vitis), respectively, which were even better than those of the commercial insecticidal agents chlorpyrifos, beta
cypermethrin, spinosad, and azadirachtin. The results favored our rational design intention and provide a new class of small-
molecule inhibitors available for the development of active insecticidal agents targeting P. xylostella, V. aphids, and E. vitis.
Keywords Pyrethrin · trans-Ethyl chrysanthemate · 1,3,4-Oxadiazole · Thioether · Insecticidal activity
Introduction
Shelton 1993). However, the application of traditional pes-
ticides is not efective, resulting in high residues or negative
impact on the environment. Therefore, fnding novel insec-
ticidal agents remains a daunting task in pesticide science.
The pyrethrum plants (Tanacetum cinerariifolium, family
Asteraceae) synthesize a class of compounds called pyre-
thrins, which serve as efcient insecticides and have been
used by people for pest control since ancient times since they
are harmless to people and most vertebrates (Casida 1973;
Casida and Quistad 1995; Katsuda 1999). However, early
varieties, such as natural pyrethroids, are easily decomposed
and inefective under light, and are only suitable for indoor
pest control. Many scientists have conducted long-term stud-
ies to fnd out the unstable parts of the molecular structure,
which are easily decomposed by light. In the early 1970s,
they made a breakthrough in the structural changes and syn-
thesized the frst photostable permethrin for pest control in
agriculture and forestry. Since then, there have been many
varieties of photostable pyrethrin insecticides, for example,
allethrin, permethrin, fenpropathrin, cypermethrin, deltame-
thrin, and lambda-cyhalothrin, which have the advantages of
good biodegradability, environmental friendliness and harm-
lessness to humans and livestock, were developed (Holan
and Reimund 1982; Poulter et al. 1977).
For years, crop damage from harmful pests (e.g., Plutella
xylostella (P. xylostella), Vegetable aphids (V. aphids), and
Empoasca vitis (E. vitis)) has become more common and
the continued application of traditional pesticides can often
lead to the development of more resistant pests, thus bring-
ing about enormous losses in crop production (Talekar and
Zaibo Yang and Pei Li contributed equally to this work.
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-019-01012-4) contains
supplementary material, which is available to authorized users.
* Zaibo Yang
yzb1976110@sohu.com
* Pei Li
pl19890627@126.com
1
School of Chemistry and Chemical Engineering, Qiannan
Normal University for Nationalities, Duyun 558000,
People’s Republic of China
2
Qiandongnan Engineering and Technology Research Center
for Comprehensive Utilization of National Medicine, Kaili
University, Kaili 556011, People’s Republic of China
1,3,4-Oxadiazole derivatives belong to an important
class of heterocyclic compounds and attracted more and
more attention in the development of pesticides (Suwiński
3
Qiandongnan Traditional Medicine Research &
Development Center, Kaili University, Kaili 556011,
People’s Republic of China
Vol.:(0123456789)
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Chemical Papers
and Szczepankiewicz 2008). In the past few years, lots of
1,3,4-oxadiazole derivatives with better bioactivity have
been developed by pesticide chemistry companies that
possessed good prospects for commercialization. Difer-
ent classes of oxadiazoles possess an extensive spectrum
of pharmacological activities such as antimalarial (Hutt
et al. 1970), anti-infammatory (Omar et al. 1996), anticon-
vulsant (Zarghi et al. 2005), analgesic (Husain and Ajmal
2009), antibacterial (Xu et al. 2012), antitumor (Luo et al.
2012), herbicidal (Zhang et al. 2016), and antifungal (Xu
et al. 2013; Liu et al. 2008; Yang et al. 2007) activities. In
addition, recent works have highlighted that the thioether
group is a highly efcient pharmacophore that is widely con-
cerned in the research of new pesticide creation. In the past
few years, great progress has been made in the synthesis of
thioether compounds, and the biological activity research
has found that compounds containing thioether group have a
wide range of biological activities, such as anti-cancer (Shen
et al. 2013; Yang et al. 2007), antibacterial (Bao et al. 2013;
Li et al. 2018), nematocidal (Li et al. 2018), and antivirus
(Long et al. 2008) activities. In the previous work, many of
1,3,4-oxadiazole derivatives containing a thioether group
were synthesized and bioassay results showed that the tar-
get compounds revealed good antifungal (Shi et al. 2019),
antibacterial (Li et al. 2018), antiviral (Gan et al. 2016),
nematicidal (Li et al. 2018; Chen et al. 2018), and insecti-
cidal (Guo et al. 2017) activities.
on a Bruker DRX-400 NMR spectrometer (Bruker, Rhein-
stetten, Germany) at room temperature using TMS as an
internal standard. Elemental analysis was carried out using
an Elemental Vario-III CHN analyzer (Elementar, Hanau,
German). Microwave experiments were carried out using a
CEM Discover Labmate microwave apparatus (300 W with
ChemDriver Software). Analytical TLC was performed on
silica gel GF254. Column chromatographic purifcation was
carried out using silica gel. All solvents were dried by stand-
ard methods in advance and distilled before use.
Synthesis of (1R,3R)‑2,2‑dimethyl‑3‑(2‑methyl‑
prop‑1‑en‑1‑yl)cyclopropane‑1‑carbohydrazide (2)
As shown in Scheme 1, intermediate 2 was prepared via
hydrazidation reaction according to the reported methods
(Xu et al. 2012; Li et al. 2018; Gan et al. 2016; Chen et al.
2018). A mixture of trans-ethyl chrysanthemate (100 mmol)
and hydrazine hydrate (300 mmol) was dissolved with 50 mL
of anhydrous ethanol in 250-mL reaction fask and reacted
at 100 °C for 18 h. The residue was dried and obtained after
recrystallization from ethanol to obtain intermediate 2. 1H
NMR (400 MHz, CDCl3, ppm) δ: 7.21 (s, 1H, –NH–), 4.88
(d, 1H, J=8.00 Hz, –C=CH–), 3.91 (s, 2H, –NH2), 2.09 (t,
1H, J=2.00 Hz, –CH–), 1.76 (d, 1H, J=2.00 Hz, –CH–),
1.24 (s, 3H, –CH3), 1.23 (s, 3H, –CH3), 1.11 (s, 3H, –CH3),
1.09 (s, 3H, –CH3); 13C NMR (100 MHz, CDCl3, ppm) δ:
172.6, 135.3, 121.3, 34.8, 30.8, 28.9, 25.9, 22.2, 20.3, 18.5.
To aid the development of highly active novel com-
pounds, as shown in Fig. 1, we aimed to introduce the
1,3,4-oxadiazole and thioether groups into the pyrethrin
structure to design and synthesize a series of novel pyre-
thrin derivatives containing 1,3,4-oxadiazole and thioether
moieties as active insecticidal agents.
Synthesis of 5‑((1R,3R)‑2,2‑dimethyl‑3‑(2‑meth‑
ylprop‑1‑en‑1‑yl)cyclopropyl)‑1,3,4‑oxadia‑
zole‑2‑thiol (3)
Intermediate 3 was prepared via cyclization reaction accord-
ing to the reported methods (Xu et al. 2012; Li et al. 2018;
Gan et al. 2016; Chen et al. 2018). A mixture of 100 mmol
intermediate 2 and 150 mmol KOH was dissolved in
150 mL of anhydrous ethanol in 500-mL reaction fask.
Then 300 mmol of CS2 was added dropwise to completely
dissolve the reaction mixture under stirring at room tem-
perature. Upon completion of addition, the reaction solution
was continuously stirred for 18 h at 72 °C. Then the solvent
was removed under reduced pressure, a certain amount of
water was added to terminate the reaction, and the obtained
mixture was adjusted to pH 4–5 with HCl. A large amount
Materials and methods
General information
The melting points of the products were determined on a
XT-4 binocular microscope (Beijing Tech Instrument Co.,
China) and were not corrected. The IR spectra were recorded
on a Bruker VECTOR 22 spectrometer (Bruker, Rhein-
stetten, Germany) in KBr disk. 1H NMR and 13C NMR (sol-
vent CDCl3 or DMSO-d6) spectral analyses were performed
Fig. 1 Design route of the target
compounds 7a–7s
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Chemical Papers
Scheme 1 Synthetic route of the target compounds 7a–7s
of solid was precipitated, followed by fltration. The residue
was dried and intermediate 3 was attained after recrystalliza-
tion with ethanol. 1H NMR (400 MHz, DMSO-d6, ppm) δ:
14.34 (s, 1H, –SH), 5.01 (d, 1H, J=8.00 Hz, –C=CH–), 1.99
(t, 1H, J=5.60 Hz, –CH–), 1.92 (d, 1H, J=5.20 Hz, –CH–),
1.70 (s, 3H, –CH3), 1.68 (s, 3H, –CH3), 1.16 (s, 3H, –CH3),
1.01 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, ppm)
δ: 177.9, 163.8, 135.6, 121.1, 30.8, 27.7, 26.3, 25.8, 21.4,
21.4, 18.7.
reaction (monitored by TLC), the mixture was concentrated
under vacuum, followed by fltration. The residue was dried
and intermediate 4 was obtained after recrystallization from
1
ethanol. H NMR (400 MHz, DMSO-d6, ppm) δ: 5.03 (d,
1H, J=6.40 Hz, –C=CH–), 4.18–4.11 (m, 4H, 2×–CH2–),
2.08 (t, 1H, J=4.40 Hz, –CH–), 2.01 (d, 1H, J=4.00 Hz,
–CH–), 1.71 (s, 3H, –CH3), 1.68 (s, 3H, –CH3), 1.17 (s, 3H,
–CH3), 1.15 (s, 3H, –CH3), 1.08 (s, 3H, –CH3); 13C NMR
(100 MHz, DMSO-d6, ppm) δ: 168.5, 135.7, 121.7, 62.3,
34.48, 31.8, 28.1, 26.7, 26.1, 24.4, 21.9, 19.0, 14.7.
Synthesis of ethyl 2‑((5‑((1R,3R)‑2,2‑di‑
methyl‑3‑(2‑methylprop‑1‑en‑1‑yl)
cyclopropyl)‑1,3,4‑oxadiazol‑2‑yl)thio)acetate (4)
Synthesis of 2‑((5‑((1R,3R)‑2,2‑dimethyl‑3‑(2‑meth‑
ylprop‑1‑en‑1‑yl)cyclopropyl)‑1,3,4‑oxadiazol‑2‑yl)
thio)acetohydrazide (5)
Intermediate 4 was prepared via thioetherifcation reaction
according to the reported methods (Xu et al. 2012; Li et al.
2018; Chen et al. 2018). A mixture of 100 mmol intermedi-
ate 3, 100 mmol anhydrous K2CO3 and 10 mmol KI was
dissolved with 150 mL of anhydrous ethanol in 500-mL
reaction fask. Then 150 mmol of ethyl 2-bromoacetate was
added dropwise to completely dissolve the reaction mixture
under stirring at room temperature. Upon completion of the
Intermediate 5 was prepared via hydrazidation reaction
according to the reported methods (Xu et al. 2012; Li et al.
2018; Gan et al. 2016; Chen et al. 2018). To a solution of
intermediate 4 (100 mmol) in anhydrous ethanol (50 mL),
300 mmol of 98% hydrazine hydrate was slowly added
at room temperature. Then the mixture further reacted at
100 °C for 10 h. The solvent was removed under reduced
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Chemical Papers
pressure, and the residue was washed with water and anhy-
drous ethanol. The obtained crude product was further
The physical characteristic data of intermediates 2–5 and
the target compounds 7a–7s are shown in Table 1, and the
IR, 1H NMR, 13C NMR, and elemental analysis data for all
target compounds 7a–7s are shown below.
1
recrystallized and dried, giving intermediate 5. H NMR
(400 MHz, CDCl3, ppm) δ: 8.26 (s, 1H, –NH–), 4.96 (d,
1H, J=8.80 Hz, –C=CH–), 3.92 (s, 2H, –NH2), 3.82 (s, 2H,
–CH2–), 2.18 (t, 1H, J=8.00 Hz, –CH–), 1.74 (s, 3H, –CH3),
1.73 (s, 3H, –CH3), 1.22 (s, 3H, –CH3), 1.19 (s, 3H, –CH3),
0.87 (d, 1H, J = 7.60 Hz, –CH–); 13C NMR (100 MHz,
CDCl3, ppm) δ: 168.7, 168.1, 163.2, 136.6, 120.3, 33.3,
32.1, 28.3, 27.2, 25.6, 21.5, 21.4, 18.6.
2-((4-Chlorobenzyl)thio)-5-(((5-((1R,3R)-2,2-dimethyl-3-
(2-methylprop-1-en-1-yl)cyclopropyl)-1,3,4-oxadiazol-2-yl)
1
thio)methyl)-1,3,4-oxadiazole (7a). H NMR (400 MHz,
DMSO-d6, ppm) δ: 7.46–7.36 (m, 4H, Ar–H), 5.03 (d, 1H,
J=8.00 Hz, –C=CH–), 4.76 (s, 2H, –SCH2–), 4.48 (s, 2H,
–SCH2–), 2.07 (t, 1H, J1= 2.00 Hz, J2= 5.60 Hz, –CH–),
2.00 (d, 1H, J=5.60 Hz, –CH–), 1.71 (s, 3H, –CH3), 1.68
Synthesis of 5‑(((5‑((1R,3R)‑2,2‑dimethyl‑3‑(2‑meth‑
ylprop‑1‑en‑1‑yl)cyclopropyl)‑1,3,4‑oxadiazol‑2‑yl)
thio)methyl)‑1,3,4‑oxadiazole‑2‑thiol (6)
(s, 3H, –CH3), 1.16 (s, 3H, –CH3), 1.04 (s, 3H, –CH3); 13
C
NMR (100 MHz, DMSO-d6, ppm) δ: 168.5, 165.0, 163.8,
161.0, 135.7, 133.4, 132.0, 128.5, 124.4, 121.3, 37.3, 31.7,
27.9, 26.5, 26.2, 25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1) ν:
3435.71, 3207.99, 3125.45, 3062.84, 2951.48, 2924.04,
2870.22, 1686.57, 1573.02, 1484.92, 1463.02, 1439.26,
1376.41, 1280.32, 1221.45, 1153.65, 1114.64, 1075.64,
1042.39, 1022.65, 955.02, 895.10, 852.51, 755.34, 714.29;
Anal. calcd for C21H23ClN4O2S2: C 54.47%, H 5.01%, N
12.10%, found: C 54.65%, H 5.27%, N 12.33%.
Intermediate 6 was prepared via cyclization reaction accord-
ing to the reported methods (Xu et al. 2012; Li et al. 2018;
Gan et al. 2016; Chen et al. 2018). A mixture of 100 mmol
intermediate 5 and 150 mmol KOH was dissolved in 150 mL
of anhydrous ethanol in 500-mL reaction flask. Then
300 mmol of CS2 was added dropwise to completely dis-
solve the reaction mixture under stirring at room tempera-
ture. Upon completion of addition, the reaction solution was
continuously stirred for 18 h at 72 °C. Subsequently, the sol-
vent was removed under reduced pressure; a certain amount
of water was added to end the reaction, and the resulting
mixture was adjusted to pH 4–5 with HCl. A large amount
of solid was precipitated, followed by fltration. The residue
was dried and intermediate 6 was obtained after recrystal-
lization from ethanol. 1H NMR (400 MHz, DMSO-d6, ppm)
δ: 14.58 (s, 1H, –SH), 5.03 (d, 1H, J=8.00 Hz, –C=CH–),
4.62 (s, 2H, –CH2–), 2.09 (d, 1H, J=5.20 Hz, –CH–), 2.00
(t, 1H, J=5.60 Hz, –CH–), 1.71 (s, 3H, –CH3), 1.68 (s, 3H,
–CH3), 1.17 (s, 3H, –CH3), 1.07 (s, 3H, –CH3); 13C NMR
(100 MHz, DMSO-d6, ppm) δ: 168.3, 167.9, 135.4, 121.5,
34.2, 31.6, 27.7, 26.5, 25.9, 21.7, 18.8, 14.5.
2-((4-Bromobenzyl)thio)-5-(((5-((1R,3R)-2,2-dimethyl-3-
(2-methylprop-1-en-1-yl)cyclopropyl)-1,3,4-oxadiazol-2-yl)
1
thio)methyl)-1,3,4-oxadiazole (7b). H NMR (400 MHz,
DMSO-d6, ppm) δ: 7.66 (dd, 1H, J1=1.20 Hz, J2=8.00 Hz,
Ar–H), 7.56 (dd, 1H, J1= 1.60 Hz, J2= 7.60 Hz, Ar–H),
7.36–7.32 (m, 1H, Ar–H), 7.28–7.24 (m, 1H, Ar–H), 5.02
(d, 1H, J=7.60 Hz, –C=CH–), 4.76 (s, 2H, –SCH2–), 4.55
(s, 2H, –SCH2–), 2.01 (t, 1H, J1= 6.00 Hz, J2= 8.00 Hz,
–CH–), 2.00 (d, 1H, J=5.60 Hz, –CH–), 1.70 (s, 3H, –CH3),
1.68 (s, 3H, –CH3), 1.16 (s, 3H, –CH3), 1.04 (s, 3H, –CH3);
13C NMR (100 MHz, DMSO-d6, ppm) δ: 168.5, 164.9,
164.1, 161.0, 137.8, 136.9, 135.4, 131.7, 121.3, 94.4, 35.7,
31.7, 27.9, 26.5, 26.1, 25.8, 21.6, 21.5, 18.8; IR (KBr,
cm−1) ν: 3566.53, 2969.90, 2951.68, 2925.95, 2880.26,
1748.28, 1731.01, 1680.80, 1659.98, 1643.26, 1621.68,
1573.51, 1327.02, 1253.34, 1152.45, 1116.62, 1070.57,
1012.08, 971.19, 803.86, 749.82, 721.40; Anal. calcd for
C21H23BrN4O2S2: C 49.70%, H 4.57%, N 11.04%; found: C
49.83%, H 4.69%, N 11.22%.
Synthesis of the target compounds 7a–7s
Target compounds 7a–7s were synthesized based on the
previously reported method (Xia et al. 2016). To a 50-mL
round-bottom fask ftted with a magnetic stirring bar, inter-
mediate 6 (1 mmol) and anhydrous ethanol (5 mL) were
added. Then the solution of RCH2Cl (1.2 mmol) in anhy-
drous ethanol (5 mL) was added dropwise to the above solu-
tion, which was sealed and placed in the synthetic reactor
and irradiated in microwave at 90 °C and 150 W for 15 min.
Upon completion of the reaction (monitored by TLC),
the mixture was concentrated under vacuum. The residue
was purifed by silica gel column chromatography (ethyl
acetate:petroleum ether=1:8).
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((4-iodobenzyl)thio)-1,3,4-oxadiazol-
2-yl)methyl)thio)-1,3,4-oxadiazole (7c). 1H NMR (400 MHz,
DMSO-d6, ppm) δ: 7.67 (d, 2H, J=8.40 Hz, Ar–H), 7.22 (d,
2H, J=8.00 Hz, Ar–H), 5.02 (d, 1H, J=8.00 Hz, –C=CH–),
4.74 (s, 2H, –SCH2–), 4.42 (s, 2H, –SCH2–), 2.06 (t, 1H,
J1=6.00 Hz, J2=7.60 Hz, –CH–), 2.00 (d, 1H, J=5.60 Hz,
–CH–), 1.70 (s, 3H, –CH3), 1.68 (s, 3H, –CH3), 1.16 (s, 3H,
–CH3), 1.02 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-
d6, ppm) δ: 168.5, 164.9, 164.1, 161.0, 137.8, 136.9, 131.7,
121.3, 94.4, 35.7, 31.7, 27.9, 26.5, 26.1, 25.8, 21.6, 21.5,
18.8; IR (KBr, cm−1) ν: 3648.26, 3566.52, 2951.28, 2924.76,
2874.06, 1680.99, 1573.49, 1483.67, 1399.41, 1377.89,
The structures of the target compounds 7a–7s were con-
frmed by IR, 1H NMR, 13C NMR, and elemental analysis.
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Table 1 Physical characteristics
data of intermediates 2–5 and
the target compounds 7a–7s
Compounds Molecular formula Form
Yield (%) Rf value mp (°C)
2
C10H18N2O
C11H16N2OS
C15H22N2O3S
C13H20N4O2S
Gray-white solid
White solid
Pale yellow liquid
White solid
83.2
83.4
86.1
93.0
0.10
0.20
0.55
0.10
0.20
0.45
0.45
0.45
0.45
0.46
0.45
0.45
0.45
0.44
0.44
0.45
0.45
0.45
0.45
0.44
0.43
0.45
0.45
0.42
126.7–127.5
104.6–105.3
–
3
4
5
158.9–159.3
6
C14H18N4O2S2
C21H23ClN4O2S2
C21H23BrN4O2S2
C21H23IN4O2S2
C21H23FN4O2S2
C21H23FN4O2S2
C21H23ClN4O2S2
C22H26N4O3S2
C21H24N4O2S2
C21H22Cl2N4O2S2
C21H22ClFN4O2S2
C21H23BrN4O2S2
C21H22F2N4O2S2
C21H23N5O4S2
C21H23N5O4S2
C22H23F3N4O2S2
C22H23F3N4O2S2
C22H26N4O3S2
C22H23F3N4O3S2
C19H21ClN4O2S3
Brown-yellow viscous liquid 85.0
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
Pale yellow liquid
78.9
80.6
80.7
80.9
82.6
81.7
83.9
81.6
82.3
79.8
82.4
83.8
84.6
85.1
82.9
82.7
83.7
81.9
82.1
1327.09, 1275.08, 1252.05, 1152.62, 1059.61, 1008.00,
970.19, 852.78, 831.78, 800.83, 751.58, 720.17; Anal. calcd
for C21H23IN4O2S2: C 45.49%, H 4.18%, N 10.10%; found:
C 45.61%, H 4.35%, N 10.22%.
(m, 2H, Ar–H), 7.14–7.09 (m, 1H, Ar–H), 5.02 (d, 1H,
J=8.00 Hz, –C=CH–), 4.74 (s, 2H, –SCH2–), 4.49 (s, 2H,
–SCH2–), 2.06 (t, 1H, J1= 5.60 Hz, J2= 8.00 Hz, –CH–),
2.00 (d, 1H, J=5.60 Hz, –CH–), 1.70 (s, 3H, –CH3), 1.68
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((2-fluorobenzyl)thio)-1,3,4-oxadi-
(s, 3H, –CH3), 1.16 (s, 3H, –CH3), 1.03 (s, 3H, –CH3); 13
C
NMR (100 MHz, DMSO-d6, ppm) δ: 168.5, 164.8, 164.2,
161.0, 139.9, 135.4, 131.0, 130.9, 125.6, 121.3, 116.1,
115.2, 115.0, 35.6, 31.7, 27.9, 26.5, 26.1, 25.8, 21.6, 21.5,
18.7; IR (KBr, cm−1) ν: 2952.33, 2926.37, 2878.52, 1673.14,
1616.99, 1574.33, 1487.15, 1448.06, 1378.47, 1326.66,
1259.20, 1151.69, 1074.52, 1013.73, 970.15, 945.88,
886.14, 768.57, 743.17; Anal. calcd for C21H23FN4O2S2: C
56.48%, H 5.19%, N 12.55%; found: C 56.65%, H 5.38%,
N 12.69%.
1
azol-2-yl)methyl)thio)-1,3,4-oxadiazole (7d). H NMR
(400 MHz, DMSO-d6, ppm) δ: 7.50–7.46 (m, 1H, Ar–H),
7.39–7.33 (m, 1H, Ar–H), 7.23–7.13 (m, 2H, Ar–H), 5.02 (d,
1H, J=8.00 Hz, –C=CH–), 4.75 (s, 2H, –SCH2–), 4.50 (s,
2H, –SCH2–), 2.07 (t, 1H, J1=6.00 Hz, J2=7.60 Hz, –CH–),
2.00 (d, 1H, J=5.60 Hz, –CH–), 1.70 (s, 3H, –CH3), 1.68
(s, 3H, –CH3), 1.16 (s, 3H, –CH3), 1.04 (s, 3H, –CH3);
13C NMR (100 MHz, DMSO-d6, ppm) δ: 168.5, 165.0,
163.8, 161.0, 135.4, 131.8, 130.7, 125.0, 123.8, 123.7,
121.3, 116.1, 115.9, 31.7, 30.2, 27.9, 26.5, 26.1, 25.8, 21.6,
21.5, 18.7; IR (KBr, cm−1) ν: 2951.87, 2926.12, 2875.23,
1617.68, 1574.08, 1490.99, 1478.16, 1378.65, 1234.21,
1152.61, 1095.62, 1014.51, 969.56, 758.91; Anal. calcd for
C21H23FN4O2S2: C 56.48%, H 5.19%, N 12.55%; found: C
56.61%, H 5.32%, N 12.64%.
2-((2-Chlorobenzyl)thio)-5-(((5-((1R,3R)-2,2-dimethyl-3-
(2-methylprop-1-en-1-yl)cyclopropyl)-1,3,4-oxadiazol-2-yl)
1
thio)methyl)-1,3,4-oxadiazole (7f). H NMR (400 MHz,
DMSO-d6, ppm) δ: 7.67 (dd, 1H, J1=1.20 Hz, J2=8.00 Hz,
Ar–H), 7.56 (dd, 1H, J1= 1.60 Hz, J2= 7.60 Hz, Ar–H),
7.36–7.32 (m, 1H, Ar–H), 7.28–7.24 (m, 1H, Ar–H), 5.02 (d,
1H, J=7.60 Hz, –C=CH–), 4.76 (s, 2H, –SCH2–), 4.55 (s,
2H, –SCH2–), 2.07 (t, 1H, J1=6.00 Hz, J2=8.00 Hz, –CH–),
2.01 (d, 1H, J=5.60 Hz, –CH–), 1.70 (s, 3H, –CH3), 1.68
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((3-fuorobenzyl)thio)-1,3,4-oxadiazol-
2-yl)methyl)thio)-1,3,4-oxadiazole (7e). 1H NMR (400 MHz,
DMSO-d6, ppm) δ: 7.39–7.33 (m, 1H, Ar–H), 7.29–7.25
(s, 3H, –CH3), 1.16 (s, 3H, –CH3), 1.04 (s, 3H, –CH3); 13
C
NMR (100 MHz, DMSO-d6, ppm) δ: 168.5, 165.0, 163.8,
1 3

Chemical Papers
161.0, 135.4, 134.1, 133.7, 132.0, 130.4, 127.9, 121.3, 34.6,
31.7, 27.9, 26.5, 25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1) ν:
2925.45, 2738.40, 1669.47, 1621.45, 1574.02, 1474.93,
1445.90, 1378.22, 1327.47, 1282.16, 1251.40, 1153.28,
1053.56, 1037.99, 1016.06, 969.19, 854.23, 761.34, 734.58;
Anal. calcd for C21H23ClN4O2S2: C 54.47%, H 5.01%, N
12.10%; found: C 54.63%, H 5.19%, N 12.27%.
ν: 2951.90, 2925.89, 2878.88, 1574.12, 1473.52, 1416.80,
1379.54, 1326.76, 1251.41, 1152.57, 1116.67, 1098.96,
1051.37, 1013.05, 970.43, 867.48, 848.09, 751.94, 733.04;
Anal. calcd for C21H22Cl2N4O2S2: C 50.70%, H 4.46%, N
11.26%; found: C 50.83%, H 4.59%, N 11.47%.
2-((2-Chloro-4-fuorobenzyl)thio)-5-(((5-((1R,3R)-2,2-
dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropyl)-1,3,4-
oxadiazol-2-yl)thio)methyl)-1,3,4-oxadiazole (7j). 1H NMR
(400 MHz, DMSO-d6, ppm) δ: 7.61 (q, 1H, Ar–H), 7.50 (dd,
1H, J1= 2.40 Hz, J2= 8.80 Hz, Ar–H), 7.22–7.17 (m, 1H,
Ar–H), 5.02 (d, 1H, J = 6.40 Hz, –C=CH–), 4.75 (s, 2H,
–SCH2–), 4.54 (s, 2H, –SCH2–), 2.06 (t, 1H, J1=5.60 Hz,
J2=8.00 Hz, –CH–), 2.00 (d, 1H, J=5.60 Hz, –CH–), 1.70
(s, 3H, –CH3), 1.68 (s, 3H, –CH3), 1.16 (s, 3H, –CH3), 1.04
(s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, ppm) δ:
168.5, 165.1, 163.7, 160.8, 135.4, 134.6, 133.4, 130.6,
121.3, 117.6, 117.3, 115.2, 115.0, 34.0, 31.7, 27.9, 26.5,
26.1, 25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1) ν: 2952.92,
2925.87, 2876.65, 1602.22, 1575.59, 1490.24, 1417.72,
1397.51, 1378.47, 1327.51, 1250.91, 1235.20, 1154.22,
1043.56, 1016.19, 969.64, 911.99, 857.67, 823.06, 752.55;
Anal. calcd for C21H22ClFN4O2S2: C 52.44%, H 4.61%, N
11.65%; found: C 52.59%, H 4.78%, N 11.74%.
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((3-methoxybenzyl)thio)-1,3,4-oxa-
1
diazol-2-yl)methyl)thio)-1,3,4-oxadiazole (7g). H NMR
(400 MHz, DMSO-d6, ppm) δ: 7.23 (t, 1H, J1 = 7.60 Hz,
J2 =8.00 Hz, Ar–H), 7.01–6.96 (m, 2H, Ar–H), 6.87–6.84
(m, 1H, Ar–H), 5.02 (d, 1H, J1 =8.00 Hz, –C=CH–), 4.75 (s,
2H, –SCH2–), 4.45 (s, 2H, –SCH2–), 3.73 (s, 3H, –OCH3),
2.07 (t, 1H, J1= 6.00 Hz, J2= 7.60 Hz, –CH–), 2.01 (d,
1H, J = 6.00 Hz, –CH–), 1.70 (s, 3H, –CH3), 1.68 (s, 3H,
–CH3), 1.16 (s, 3H, –CH3), 1.05 (s, 3H, –CH3); 13C NMR
(100 MHz, DMSO-d6, ppm) δ: 168.5, 164.8, 164.3, 161.0,
159.7, 138.2, 135.4, 130.1, 121.6, 121.3, 115.1, 113.8, 36.2,
31.7, 27.9, 26.5, 26.1, 25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1)
ν: 2928.18, 2836.09, 1600.44, 1574.71, 1487.99, 1475.30,
1378.18, 1322.32, 1297.46, 1268.98, 1152.23, 1046.13,
970.64, 871.48, 853.47, 783.92, 735.24; Anal. calcd for
C22H26N4O3S2: C 57.62%, H 5.71%, N 12.22%; found: C
57.79%, H 5.83%, N 12.47%.
2-((2-Bromobenzyl)thio)-5-(((5-((1R,3R)-2,2-dimethyl-3-
(2-methylprop-1-en-1-yl)cyclopropyl)-1,3,4-oxadiazol-2-yl)
1
2-(Benzylthio)-5-(((5-((1R,3R)-2,2-dimethyl-3-(2-meth-
ylprop-1-en-1-yl)cyclopropyl)-1,3,4-oxadiazol-2-yl)thio)
methyl)-1,3,4-oxadiazole (7h). 1H NMR (400 MHz, DMSO-
d6, ppm) δ: 7.40 (d, 2H, J=6.80 Hz, Ar–H), 7.34–7.27 (m,
3H, Ar–H), 5.02 (d, 1H, J=8.00 Hz, –C=CH–), 4.75 (s, 2H,
–SCH2–), 4.47 (s, 2H, –SCH2–), 2.07 (t, 1H, J1=5.60 Hz,
J2=7.60 Hz, –CH–), 2.01 (d, 1H, J=5.20 Hz, –CH–), 1.70
(s, 3H, –CH3), 1.68 (s, 3H, –CH3), 1.16 (s, 3H, –CH3), 1.04
(s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, ppm) δ:
168.5, 164.8, 164.3, 161.0, 136.8, 135.4, 129.4, 129.0,
128.2, 121.3, 31.7, 27.9, 26.5, 26.1, 25.8, 25.7, 21.6, 21.5,
18.7; IR (KBr, cm−1) ν: 2951.66, 2925.33, 2872.17, 2737.72,
1669.25, 1573.68, 1475.48, 1454.71, 1378.11, 1326.74,
1251.62, 1153.65, 1072.11, 1014.75, 968.69, 853.54,
766.49; Anal. calcd for C21H24N4O2S2: C 58.85%, H 5.64%,
N 13.07%; found: C 58.98%, H 5.81%, N 13.26%.
thio)methyl)-1,3,4-oxadiazole (7k). H NMR (400 MHz,
DMSO-d6, ppm) δ: 7.51 (dd, 2H, J1=2.00 Hz, J2=6.80 Hz,
Ar–H), 7.38 (d, 2H, J = 5.60 Hz, Ar–H), 5.02 (d, 1H,
J=8.00 Hz, –C=CH–), 4.75 (s, 2H, –SCH2–), 4.45 (s, 2H,
–SCH2–), 2.07 (t, 1H, J1=5.60 Hz, J2=8.00 Hz, –CH–), 2.00
(d, 1H, J=5.60 Hz, –CH–), 1.71 (s, 3H, –CH3), 1.68 (s, 3H,
–CH3), 1.16 (s, 3H, –CH3), 1.03 (s, 3H, –CH3); 13C NMR
(100 MHz, DMSO-d6, ppm) δ: 168.5, 165.0, 163.8, 161.0,
135.7, 135.4, 133.4, 132.0, 130.7, 128.5, 124.4, 121.3, 37.3,
31.7, 27.9, 26.5, 26.2, 25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1)
ν: 2924.88, 1572.73, 1475.15, 1441.87, 1378.02, 1327.17,
1280.47, 1249.87, 1153.55, 1045.65, 1026.65, 968.93,
854.36, 761.43, 729.81; Anal. calcd for C21H23BrN4O2S2:
C 49.70%, H 4.57%, N 11.04%; found: C 49.89%, H 4.68%,
N 11.24%.
2-((2,4-Difluorobenzyl)thio)-5-(((5-((1R,3R)-2,2-di-
methyl-3-(2-methylprop-1-en-1-yl)cyclopropyl)-1,3,4-
2-((2,4-Dichlorobenzyl)thio)-5-(((5-((1R,3R)-2,2-dime-
thyl-3-(2-methylprop-1-en-1-yl)cyclopropyl)-1,3,4-oxa-
1
oxadiazol-2-yl)thio)methyl)-1,3,4-oxadiazole (7l). H
1
diazol-2-yl)thio)methyl)-1,3,4-oxadiazole (7i). H NMR
NMR (400 MHz, DMSO-d6, ppm) δ: 7.58–7.52 (m, 1H,
Ar–H), 7.29–7.24 (m, 1H, Ar–H), 7.07–7.02 (m, 1H,
Ar–H), 5.02 (d, 1H, J = 8.00 Hz, –C=CH–), 4.75 (s, 2H,
–SCH2–), 4.48 (s, 2H, –SCH2–), 2.06 (t, 1H, J1= 5.60 Hz,
J2=8.00 Hz, –CH–), 2.00 (d, 1H, J=5.60 Hz, –CH–), 1.70
(s, 3H, –CH3), 1.67 (s, 3H, –CH3), 1.16 (s, 3H, –CH3),
1.03 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, ppm)
δ: 168.5, 165.0, 163.7, 161.0, 135.4, 133.1, 133.0, 133.0,
132.9, 121.3, 112.2, 112.0, 104.8, 104.6, 104.3, 31.7, 29.7,
27.9, 26.5, 26.1, 25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1) ν:
(400 MHz, DMSO-d6, ppm) δ: 7.66 (d, 1H, J = 2.00 Hz,
Ar–H), 7.57 (d, 1H, J=8.40 Hz, Ar–H), 7.39 (m, 1H, Ar–H),
5.02 (d, 1H, J=8.00 Hz, –C=CH–), 4.74 (s, 2H, –SCH2–),
4.53 (s, 2H, –SCH2–), 2.05 (t, 1H, J1=6.00 Hz, J2=7.60 Hz,
–CH–), 1.99 (d, 1H, J=5.20 Hz, –CH–), 1.70 (s, 3H, –CH3),
1.67 (s, 3H, –CH3), 1.15 (s, 3H, –CH3), 1.03 (s, 3H, –CH3);
13C NMR (100 MHz, DMSO-d6, ppm) δ: 168.5, 165.1,
163.6, 161.0, 135.4, 134.7, 133.4, 129.6, 128.0, 121.3, 34.0,
31.7, 27.9, 26.5, 26.1, 25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1)
1 3

Chemical Papers
2953.74, 2925.38, 1618.69, 1603.91, 1574.21, 1478.22,
1436.33, 1378.44, 1327.83, 1279.01, 1252.07, 1138.63,
1088.94, 1015.69, 968.20, 850.14, 819.19, 751.84, 731.97;
Anal. calcd for C21H22F2N4O2S2: C 54.29%, H 4.77%, N
12.06%; found: C 54.41%, H 4.85%, N 12.23%.
853.53, 769.12; Anal. calcd for C22H23F3N4O2S2: C 53.21%,
H 4.67%, N 11.28%; found: C 53.31%, H 4.76%, N 11.34%.
2-(2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropyl)-
5-(((5-((4-(trifluoromethyl)benzyl)thio)-1,3,4-oxadia-
1
zol-2-yl)methyl)thio)-1,3,4-oxadiazole (7p). H NMR
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((2-nitrobenzyl)thio)-1,3,4-oxadia-
(400 MHz, DMSO-d6, ppm) δ: 7.67 (q, 4H, Ar–H), 5.02 (d,
1H, J=8.00 Hz, –C=CH–), 4.74 (s, 2H, –SCH2–), 4.56 (s,
2H, –SCH2–), 2.06 (t, 1H, J1=5.60 Hz, J2=8.00 Hz, –CH–),
2.00 (d, 1H, J=6.00 Hz, –CH–), 1.70 (s, 3H, –CH3), 1.67
1
zol-2-yl)methyl)thio)-1,3,4-oxadiazole (7m). H NMR
(400 MHz, DMSO-d6, ppm) δ: 8.11 (d, 1H, J = 8.00 Hz,
Ar–H), 7.72 (d, 2H, J = 4.00 Hz, Ar–H), 7.63–7.59 (m,
1H, Ar–H), 5.02 (d, 1H, J = 8.00 Hz, –C=CH–), 4.75 (d,
4H, J = 5.60 Hz, 2 × –SCH2–), 2.06 (t, 1H, J1= 5.60 Hz,
J2=8.00 Hz, –CH–), 2.00 (d, 1H, J=5.60 Hz, –CH–), 1.70
(s, 3H, –CH3), 1.68 (s, 3H, –CH3), 1.15 (s, 3H, –CH3),
1.03 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, ppm)
δ: 168.5, 165.0, 164.1, 161.0, 148.1, 135.4, 134.7, 133.0,
132.4, 130.1, 125.8, 121.3, 34.0, 31.7, 27.9, 26.5, 26.1,
25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1) ν: 2925.47, 1609.93,
1574.43, 1525.20, 1477.17, 1446.98, 1341.84, 1311.63,
1253.38, 1152.38, 1074.17, 1015.35, 969.47, 857.04,
807.88, 788.77, 756.08; Anal. calcd for C21H23N5O4S2: C
53.26%, H 4.90%, N 14.79%; found: C 53.37%, H 4.99%,
N 14.83%.
(s, 3H, –CH3), 1.15 (s, 3H, –CH3), 1.02 (s, 3H, –CH3); 13
C
NMR (100 MHz, DMSO-d6, ppm) δ: 168.5, 164.9, 164.0,
161.0, 142.1, 135.4, 130.3, 129.1, 128.8, 128.6, 129.2,
125.9, 125.9, 121.3, 35.5, 31.6, 27.9, 26.5, 26.1, 25.8, 21.7,
21.5, 18.7; IR (KBr, cm−1) ν: 2926.74, 1618.03, 1574.20,
1477.86, 1418.38, 1378.74, 1324.36, 1165.28, 1127.04,
1067.05, 1019.07, 969.36, 850.06, 753.24; Anal. calcd for
C22H23F3N4O2S2: C 53.21%, H 4.67%, N 11.28%; found: C
53.32%, H 4.75%, N 11.33%.
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((4-methoxybenzyl)thio)-1,3,4-oxa-
1
diazol-2-yl)methyl)thio)-1,3,4-oxadiazole (7q). H NMR
(400 MHz, DMSO-d6, ppm) δ: 7.33 (d, 2H, J = 8.80 Hz,
Ar–H), 6.87 (d, 2H, J = 8.80 Hz, Ar–H), 5.02 (d, 1H,
J=8.00 Hz, –C=CH–), 4.75 (s, 2H, –SCH2–), 4.42 (s, 2H,
–SCH2–), 3.72 (s, 3H, –OCH3), 2.07 (t, 1H, J1= 5.60 Hz,
J2=8.00 Hz, –CH–), 2.00 (d, 1H, J=5.60 Hz, –CH–), 1.70
(s, 3H, –CH3), 1.68 (s, 3H, –CH3), 1.15 (s, 3H, –CH3), 1.04
(s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, ppm) δ:
168.6, 164.7, 164.4, 161.0, 159.3, 135.4, 130.8, 128.5,
121.3, 114.4, 55.5, 36.0, 31.6, 27.9, 26.5, 26.1, 25.8, 21.6,
21.5, 18.7; IR (KBr, cm−1) ν: 2929.32, 1610.35, 1574.35,
1513.62, 1474.91, 1378.20, 1319.89, 1303.22, 1246.74,
1153.81, 1033.17, 969.61, 835.98, 752.70; Anal. calcd for
C22H26N4O3S2: C 57.62%, H 5.71%, N 12.22%; found: C
57.73%, H 5.89%, N 12.33%.
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((4-nitrobenzyl)thio)-1,3,4-oxadiazol-
2-yl)methyl)thio)-1,3,4-oxadiazole (7n). 1H NMR (400 MHz,
DMSO-d6, ppm) δ: 8.19 (d, 2H, J=8.80 Hz, Ar–H), 7.71 (d,
2H, J=8.80 Hz, Ar–H), 5.01 (d, 1H, J=8.00 Hz, –C=CH–),
4.74 (s, 2H, –SCH2–), 4.61 (s, 2H, –SCH2–), 2.05 (t, 1H,
J1=5.60 Hz, J2=8.00 Hz, –CH–), 1.99 (d, 1H, J=5.60 Hz,
–CH–), 1.70 (s, 3H, –CH3), 1.67 (s, 3H, –CH3), 1.15 (s, 3H,
–CH3), 1.08 (s, 3H, –CH3); 13C NMR (100 MHz, DMSO-
d6, ppm) δ: 168.5, 165.0, 163.9, 161.0, 147.3, 145.2, 135.4,
130.8, 124.1, 121.3, 35.3, 31.6, 27.9, 26.5, 26.1, 25.8, 21.6,
21.5, 18.7; IR (KBr, cm−1) ν: 2925.41, 1668.89, 1600.31,
1573.95, 1522.03, 1478.50, 1378.08, 1345.92, 1253.14,
1153.44, 1110.93, 1015.72, 969.35, 893.17, 858.67, 801.75,
756.42; Anal. calcd for C21H23N5O4S2: C 53.26%, H 4.90%,
N 14.79%; found: C 53.39%, H 4.98%, N 14.84%.
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((4-(trifuoromethoxy)benzyl)thio)-1,3,4-
oxadiazol-2-yl)methyl)thio)-1,3,4-oxadiazole (7r). 1H NMR
(400 MHz, DMSO-d6, ppm) δ: 7.55 (d, 2H, J = 8.80 Hz,
Ar–H), 7.32 (d, 2H, J = 8.00 Hz, Ar–H), 5.02 (d, 1H,
J=8.00 Hz, –C=CH–), 4.74 (s, 2H, –SCH2–), 4.51 (s, 2H,
–SCH2–), 2.06 (t, 1H, J1=5.60 Hz, J2=7.60 Hz, –CH–), 2.00
(d, 1H, J=5.60 Hz, –CH–), 1.70 (s, 3H, –CH3), 1.67 (s, 3H,
–CH3), 1.15 (s, 3H, –CH3), 1.03 (s, 3H, –CH3); 13C NMR
(100 MHz, DMSO-d6, ppm) δ: 168.5, 164.9, 164.2, 161.0,
148.2, 136.7, 135.3, 131.4, 121.5, 121.3, 35.3, 31.6, 27.9,
26.5, 26.1, 25.8, 21.5, 21.5, 18.7; IR (KBr, cm−1) ν: 2927.02,
1574.39, 1508.63, 1477.28, 1379.16, 1260.68, 1221.26,
1196.82, 1164.00, 1019.58, 969.56, 921.84, 853.09, 751.06;
Anal. calcd for C22H23F3N4O3S2: C 51.55%, H 4.52%, N
10.93%; found: C 51.66%, H 4.59%, N 10.98%.
2-((1R,3R)-2,2-Dimethyl-3-(2-methylprop-1-en-1-yl)
cyclopropyl)-5-(((5-((2-(trifuoromethyl)benzyl)thio)-1,3,4-
1
oxadiazol-2-yl)methyl)thio)-1,3,4-oxadiazole (7o). H
NMR (400 MHz, DMSO-d6, ppm) δ: 7.78–7.55 (m, 1H,
Ar–H), 5.02 (d, 1H, J = 8.00 Hz, –C=CH–), 4.76 (s, 2H,
–SCH2–), 4.64 (s, 2H, –SCH2–), 2.06 (t, 1H, J1=5.60 Hz,
J2=8.00 Hz, –CH–), 2.00 (d, 1H, J=6.00 Hz, –CH–), 1.70
(s, 3H, –CH3), 1.67 (s, 3H, –CH3), 1.15 (s, 3H, –CH3), 1.04
(s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, ppm) δ:
168.5, 165.1, 163.7, 160.9, 135.5, 135.4, 134.5, 133.5,
132.4, 129.3, 127.7, 127.4, 126.8, 123.3, 121.3, 33.5, 31.7,
27.9, 26.5, 26.1, 25.8, 21.6, 21.5, 18.7; IR (KBr, cm−1) ν:
2926.17, 1606.81, 1573.96, 1477.83, 1451.62, 1378.71,
1315.75, 1151.78, 1119.90, 1059.78, 1036.93, 898.61,
2-(((5-Chlorothiophen-2-yl)methyl)thio)-5-(((5-
((1R,3R)-2,2-dimethyl-3-(2-methylprop-1-en-1-yl)
1 3

Chemical Papers
cyclopropyl)-1,3,4-oxadiazol-2-yl)thio)methyl)-1,3,4-oxadi-
azole (7s). 1H NMR (400 MHz, DMSO-d6, ppm) δ: 6.96 (d,
1H, J=3.60 Hz, thiophyl–H), 6.93 (d, 1H, J=4.00 Hz, thi-
ophyl–H), 5.02 (d, 1H, J=8.00 Hz, –C=CH–), 4.76 (s, 2H,
–SCH2–), 4.68 (s, 2H, –SCH2–), 2.07 (t, 1H, J1=6.00 Hz,
J2=8.00 Hz, –CH–), 2.00 (d, 1H, J=5.60 Hz, –CH–), 1.70
(s, 3H, –CH3), 1.68 (s, 3H, –CH3), 1.16 (s, 3H, –CH3), 1.04
(s, 3H, –CH3); 13C NMR (100 MHz, DMSO-d6, ppm) δ:
168.5, 165.0, 164.0, 161.0, 138.9, 135.4, 128.6, 128.4,
126.9, 121.3, 31.7, 31.4, 27.9, 26.5, 26.1, 25.8, 21.6, 21.5,
18.8; IR (KBr, cm−1) ν: 2971.43, 2925.47, 1621.69, 1573.10,
1476.76, 1447.48, 1405.46, 1377.82, 1330.90, 1249.89,
1229.18, 1153.24, 1062.45, 1015.46, 994.54, 969.13,
853.57, 798.32, 736.27; Anal. calcd for C19H21ClN4O2S3:
C 48.65%, H 4.51%, N 11.94%; found: C 48.73%, H 4.68%,
N 12.17%.
in the agar-coated Petri dish. Thirty larvae of third-instar V.
aphids were carefully transferred to the Petri dish, sealed
with a perforated fresh-keeping flm, and placed in the arti-
fcial climate chamber at 25 1 °C with a light–dark period
of 14:10 h and a relative humidity of 75%.
Insecticidal activity against E. vitis
Fresh the tender tea shoots (length 13 cm) were dipped in the
prepared solutions containing compounds 6 and 7a–7s for
10 s, dried in air, wrapped with wet cotton and paraflm, and
then packed in test tube (3×20 cm). Ten tender tea stems
were placed in each test tube and 30 larvae of second–third-
instar E. vitis were carefully transferred to the tube. Finally,
the opening of the tube was wrapped with gauze and
placed in the artifcial climate chamber at 25 1 °C with a
light–dark period of 14:10 h and a relative humidity of 75%.
Insecticidal biological assay
In this study, the insecticidal activities against P. xylostella,
V. aphids, and E. vitis were performed using previously
reported procedures (Cahill et al. 1995; Feng et al. 2010;
Sudoi 1998; Subaharan and Regupathy 2000; Wang et al.
2006; Zhao et al. 2010). All bioassays were performed on
test organisms reared in the lab and repeated at 25 1 °C
according to statistical requirements. Mortalities were cor-
rected using Abbott’s formula. Evaluations were based on a
percentage scale (0=no activity and 100=complete eradica-
tion). Commercial agents of chlorpyrifos, beta cypermethrin,
spinosad and azadirachtin were used as controls, and water
was used as blank control. Three replicates and at least fve
concentrations were performed for each experiment and the
mortalities were determined after 72 h.
Results and discussion
Chemical
In this study, the synthetic route of the target compounds
7a–7s is depicted in Scheme 1. The target compounds 7a–7s
were synthesized from trans-ethyl chrysanthemate 1 in six
steps including hydrazidation, cyclization, and thioetherif-
cation reactions according to the reported methods (Xu et al.
2012; Li et al. 2018; Gan et al. 2016; Chen et al. 2018; Xia
et al. 2016). As shown in Scheme 1, trans-ethyl chrysanthe-
mate 1 was reacted with 80% hydrazine hydrate in alcohol
at refux condition to obtain intermediate 2. Then a mixture
of intermediate 2, KOH and CS2 was reacted in a mixture
of ethanol and H2O at refux condition and acidifed with
HCl to produce intermediate 3. Intermediate 3 and ethyl bro-
moacetate were reacted in anhydrous ethanol at refux condi-
tion to produce intermediate 4. Intermediate 4 was reacted
with 80% hydrazine hydrate in alcohol at refux conditions
to produce intermediate 5. With that intermediate 5, KOH
and CS2 were reacted in a mixture of ethanol and H2O at
refux condition and acidifed with HCl to produce the key
intermediate 6. Finally, intermediate 6 and RCH2Cl were
reacted in anhydrous ethanol under microwave irradiation
at 90 °C with 150 W to obtain the target compounds 7a–7s,
and confrmed their structures by IR, 1H NMR, 13C NMR,
and elemental analysis.
Insecticidal activity against P. xylostella
Fresh cabbage discs (diameter 2 cm) were dipped into the
prepared solutions containing compounds 6 and 7a–7s for
10 s, dried in air and placed in a Petri dish (diameter 9 cm)
lined with flter paper. Thirty larvae of second-instar P.
xylostella were carefully transferred to the Petri dish, and
placed in the artifcial climate chamber at 25 1 °C with a
light–dark period of 14:10 h and a relative humidity of 75%.
Insecticidal activity against V. aphids
The agar was mixed with distilled water to form agar solu-
tion with 1.3% mass fraction, and 5 mL liquid agar was taken
in a micropipette and added into a culture dish 5 cm in diam-
eter and 2 cm in height. Then the liquid agar was cooled
and solidifed. Fresh cabbage discs (diameter 4 cm) were
dipped in the prepared solutions containing compounds 6
and 7a–7s for 10 s, dried in air and placed the back face up
The main characteristic of the 1H NMR spectra of the title
compounds was the presence of a low-frequency downfeld
singlet at δ 6.87–8.19 and δ 5.01–5.03 ppm, which indicated
the presence of phenyl and –C=CH– protons, respectively.
Two –SCH2– groups showed absorption peaks of 1H NMR
spectra at 4.74–4.76 and 4.42–4.68 ppm, respectively. Mean-
while, typical chemical shifts at 168.6–160.8 ppm in the 13C
1 3

Chemical Papers
Table 3 The LC50 values of the target compounds against P. xylos-
NMR spectra confrmed the presence of oxadiazole ring.
In addition, the IR spectra exhibited characteristic absorp-
tion near 1570 cm−1, which indicated the presence of C=N
vibrations. The absorptions near 2950, 2920, and 1680 cm−1
were attributed to the presence of –CH3, –CH2–, and C=C
groups, respectively.
tella
Compounds
y=ax+b
LC50 (mg/L)
r
6
y=0.43x+4.11
y=0.72x+4.21
y=0.86x+3.83
y=0.78x+3.79
y=0.82x+4.06
y=1.08x+4.06
y=0.89x+3.53
y=0.92x+3.17
y=0.73x+3.61
y=1.25x+3.91
y=1.34x+3.91
y=0.84x+3.55
y=1.23x+4.29
y=0.48x+4.17
y=0.85x+3.75
y=1.19x+4.30
y=1.02x+4.79
y=0.92x+3.17
y=1.05x+4.62
y=0.92x+4.90
y=1.07x+4.05
y=1.32x+3.53
y=1.27x+4.13
y=1.06x+3.93
124 3.2
12 0.9
23 1.3
36 2.3
14 1.4
0.99
0.98
0.97
0.98
0.99
0.98
0.98
0.98
0.98
0.98
0.98
0.99
0.97
0.99
0.98
0.98
0.99
0.98
0.97
0.99
0.98
0.98
0.99
0.96
7a
7b
7c
Biological evaluations
7d
7e
7 1.0
The results of the preliminary bioassays, as can be seen
from Table 2, showed that compounds 6 and 7a–7s
had moderate to good insecticidal activities against P.
xylostella, V. aphids, and E. vitis at the concentration
of 500 mg/L. Especially, compounds 7j, 7l, 7o, 7p, 7r,
and 7s displayed excellent insecticidal activities against
P. xylostella, V. aphids, and E. vitis at the concentration
of 500 mg/L, with the inhibitory activity value of 100%,
which was equal to the commercial agents of chlorpyri-
fos, beta cypermethrin, spinosad, and azadirachtin. Mean-
while, the 50% lethal concentration (LC50) values were
also determined and are presented in Tables 3, 4, and 5.
Table 3 shows that compounds 7l, 7p, 7r, and 7s revealed
7f
44 2.6
99 3.1
78 2.6
7g
7h
7i
7
6
0.9
0.9
7j
7k
52 2.1
0.4
7l
4
7m
53 2.7
30 2.6
7n
7o
4
2
0.5
0.4
7p
7q
99 3.1
7r
2
1
8
0.4
0.5
0.7
7s
Chlorpyrifos
Beta cypermethrin
Spinosad
Azadirachtin
Table 2 The insecticidal activities against P. xylostella, V. aphids, and
E. vitis of the target compounds at 500 mg/L
13 0.9
0.7
10 0.9
5
Compounds
Insecticidal activity (%)
P. xylostella
V. aphids
E. vitis
6
60 2.1
93 0.8
90 0.7
83 0.9
90 0.9
100 1.1
87 0.7
70 0.7
73 0.8
100 0.9
100 1.1
80 0.7
100 1.2
70 0.6
87 0.9
100 1.0
100 1.2
73 0.7
100 1.0
100 1.1
100 1.4
100 1.4
100 1.6
100 1.2
65 1.0
93 1.0
90 0.8
80 0.8
93 0.9
97 1.0
83 0.7
73 0.6
80 0.8
97 1.0
100 1.0
80 0.7
100 1.0
73 0.7
83 0.9
100 1.2
100 1.1
80 0.9
100 1.1
100 1.2
100 1.4
100 1.5
100 1.6
100 1.3
64 0.8
97 1.0
90 0.9
83 0.7
93 0.8
100 1.0
90 0.7
77 0.7
80 0.8
100 1.1
100 1.1
83 0.8
100 1.2
80 0.7
87 0.8
100 1.1
100 1.2
80 0.8
100 1.0
100 1.2
100 1.5
100 1.6
100 1.5
100 1.7
7a
better bioactivities against P. xylostella, with the LC50
values of 4, 2, 2, and 1 mg/L, respectively, which were
superior to those of the commercial insecticidal agents
chlorpyrifos (8 mg/L), beta cypermethrin (13 mg/L), spi-
nosad (5 mg/L) and azadirachtin (10 mg/L). Meanwhile,
Table 4 shows that compounds 7j, 7l, 7o, 7p, 7r, and 7s
revealed better bioactivities against V. aphids, with the
LC50 values of 5, 3, 3, 2, 2, and 1 mg/L, respectively, than
chlorpyrifos (11 mg/L), beta cypermethrin (8 mg/L), spi-
nosad (14 mg/L) and azadirachtin (18 mg/L). In addition,
Table 5 shows that compounds 7o, 7p, 7r, and 7s revealed
better bioactivities against V. aphids, with the LC50 val-
ues of 3, 1, 2, and 1 mg/L, respectively, than chlorpyrifos
(6 mg/L), beta cypermethrin (5 mg/L), spinosad (8 mg/L)
and azadirachtin (14 mg/L). Especially, compound 7s
revealed the best insecticidal activities against P. xylos-
tella, V. aphids, and E. vitis with the LC50 values of 1,
1, and 1 mg/L, respectively. These results indicated that
pyrethrin derivatives containing 1,3,4-oxadiazole and
thioether moieties could be developed as novel and prom-
ising insecticides.
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
Chlorpyrifos
Beta cypermethrin
Spinosad
Azadirachtin
1 3

Chemical Papers
Table 5 The LC50 values of the target compounds against E. vitis
Table 4 The LC50 values of the target compounds against V. aphids
Compounds
y=ax+b
LC50 (mg/L)
r
Compounds
y=ax+b
LC50 (mg/L)
r
6
y=0.49x+3.98
y=0.70x+4.17
y=0.90x+3.72
y=0.76x+3.82
y=0.73x+4.25
y=0.66x+4.38
y=0.95x+3.46
y=1.00x+2.94
y=1.26x+2.57
y=0.87x+4.16
y=1.21x+4.11
y=0.87x+3.48
y=1.01x+4.51
y=0.74x+3.69
y=0.70x+4.01
y=1.10x+4.43
y=0.96x+4.82
y=0.82x+3.38
y=0.94x+4.75
y=0.80x+4.91
y=1.95x+2.94
y=1.58x+3.54
y=1.84x+2.92
y=2.41x+1.96
124 2.0
15 1.0
26 2.3
35 2.2
11 1.0
0.99
0.97
0.98
0.99
0.99
0.99
0.99
0.99
0.99
0.98
0.99
0.99
0.99
0.98
0.99
0.99
0.99
0.97
0.98
0.99
0.98
0.97
0.99
0.98
6
y=0.48x+3.97
y=0.83x+4.21
y=0.69x+4.25
y=0.70x+4.01
y=0.53x+4.42
y=1.37x+3.85
y=1.15x+3.08
y=1.12x+2.68
y=1.06x+2.95
y=1.11x+4.10
y=1.12x+4.15
y=1.06x+3.11
y=0.99x+4.42
y=1.29x+2.63
y=0.93x+3.57
y=1.45x+4.28
y=0.92x+4.90
y=1.23x+2.65
y=1.25x+4.61
y=0.86x+4.97
y=1.15x+4.09
y=1.35x+4.10
y=1.58x+3.58
y=1.62x+3.13
147 3.1
9 0.9
12 1.1
26 2.2
12 1.4
0.98
0.96
0.96
0.99
0.99
0.98
0.99
0.98
0.98
0.96
0.99
0.99
0.99
0.98
0.98
0.97
0.99
0.97
0.97
0.97
0.98
0.98
0.99
0.98
7a
7a
7b
7b
7c
7c
7d
7d
7e
9
1.0
7e
7 0.8
7f
42 2.2
114 3.2
86 3.2
7f
47 2.2
118 3.4
85 2.9
7g
7g
7h
7h
7i
9
5
0.9
0.8
7i
6
6
0.6
0.5
7j
7j
7k
55 2.7
0.4
7k
60 2.2
0.5
7l
3
7l
4
7m
59 2.2
26 1.5
7m
70 3.0
35 2.5
7n
7n
7o
3
2
0.4
0.5
7o
3
1
0.5
0.4
7p
7p
7q
93 3.1
7q
82 3.0
7r
2
1
0.4
0.3
7r
2
1
6
5
8
0.3
0.3
0.8
0.6
0.7
7s
7s
Chlorpyrifos
Beta cypermethrin
Spinosad
Azadirachtin
11 1.1
1.0
Chlorpyrifos
Beta cypermethrin
Spinosad
Azadirachtin
8
14 1.1
18 1.2
14 1.1
Conclusions
In conclusion, 19 novel pyrethrin derivatives containing
1,3,4-oxadiazole and thioether moieties were designed and
synthesized. Bioassay results revealed that some of the target
compounds possessed better insecticidal activities against P.
xylostella, V. aphids, and E. vitis, respectively. To the best
of our knowledge, this is the frst report on the insecticidal
activities against P. xylostella, V. aphids, and E. vitis of this
series of pyrethrin derivatives containing 1,3,4-oxadiazole
and thioether moieties and the present work demonstrated
that series of pyrethrin derivatives containing 1,3,4-oxadia-
zole and thioether moieties can be used to develop potential
agrochemicals. Furthermore, according to the requirements
of pesticide registration in China, further feld studies on the
photostability, biological efcacies, crop safety, and toxici-
ties of compound 7s as insecticidal candidates will be per-
formed in our next work.
Structure–activity relationship analysis
As an extension of this approach, based on the insecticidal
activities of the title compounds against P. xylostella, V.
aphids, and E. vitis indicated in Tables 2, 3, 4, and 5, the pre-
liminary structure–activity relationship (SAR) was deduced.
First, the insecticidal activities against P. xylostella, V. aphids,
and E. vitis of the target compounds 7a–7s were better than
that of compound 6. Second, the type and position of the sub-
stituent group at the phenyl had an important efect on the
insecticidal activity of the target compounds; compared with
the same substituent group on phenyl, the insecticidal activi-
ties against P. xylostella, V. aphids, and E. vitis of the corre-
sponding compounds with the substituent group at 4-position
are higher than those of at 2-position in the order of 7a>7f,
7n>7m, and 7p>7o; the electron-withdrawing groups at
the phenyl could increase the insecticidal activities against P.
xylostella, V. aphids, and E. vitis of the corresponding com-
pounds in the order of 7e>7h>7g.
Acknowledgements This research was funded by the National Natural
Science Foundation of China (Grant no. 21466031), Youth Science and
Technology Talent Growth Program of Guizhou Province’s Depart-
ment of Education (Qian Jiaohe KY [2018] 350), Construction Project
of Engineering Research Center of Ethnic Medicinal Plant Resources
Development in Guizhou Universities and Colleges (Qian Jiaohe KY
1 3

Chemical Papers
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Qiannan Normal University for Nationalities Chemistry First-class
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Special Fund for Achievement Conversion of School and Enterprise
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