Synthesis and Acaricidal- and Insecticidal-Activity Evaluation of Novel Oxazolines Containing Sulfiliminyl Moieties and Their Derivatives

Article abstract of DOI:10.1021/acs.jafc.9b00657

Sulfimides and sulfoximines are highly relevant for medicinal chemistry and crop protection, as the resulting products can reveal interesting bioactivities. Herein, we report the design and synthesis of a series of novel 2,4-diphenyl-1,3-oxazolines containing sulfiliminyl and sulfoximinyl moieties. The acaricidal and insecticidal activities of the new compounds were evaluated and indicated that these compounds exhibited excellent acaricidal activities against spider mite larvae and eggs. The LC₅₀ values of 6a-7, 6b-3, 6b-4, 6c-2, and 6c-4 against spider mite larvae were about 4 to 6 times lower than that of the commercial insecticide etoxazole (0.0221 mg L^-1), and the LC₅₀ value of 6a-4 against spider mite eggs was 0.0006 mg L^-1, which was 10 times lower than that of etoxazole (0.0063 mg L^-1). At the same time, most of the compounds showed insecticidal activity though their structure-activity relationships that were different. Oxazolines containing an N-cyano sulfiliminyl moiety at the para position of the 4-phenyl group exhibited better insecticidal activities against cotton bollworm and corn borer than etoxazole, whereas the compounds containing groups derived from sulfiliminyl and sulfoximinyl had weak insecticidal activities. This research again proved that the substituent type at the para site of the 4-phenyl moiety has a decisive role on the biological activity and insecticidal spectrum.

Full text of DOI:10.1021/acs.jafc.9b00657

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Agricultural and Environmental Chemistry
Synthesis and Acaricidal/Insecticidal Activities Evaluation of
Novel Oxazolines Containing Sul#liminyl Moieties and Derivatives
Xiuling Yu, Yu Zhang, Yuxiu Liu, Yongqiang Li, and Qingmin Wang
J. Agric. Food Chem., Just Accepted Manuscript • Publication Date (Web): 24 Mar 2019
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Page 1 of 29
Journal of Agricultural and Food Chemistry
Synthesis and Acaricidal/Insecticidal Activities Evaluation of Novel
Oxazolines Containing Sulfiliminyl Moieties and Derivatives
Xiuling Yu1, Yu Zhang1, Yuxiu Liu1,* Yongqiang Li1 and Qingmin Wang1,2*
1 State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, College of Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
2Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071,
People’s Republic of China
* Corresponding authors. Tel: +86-(0)22-23503952; Fax: +86-(0)22-23503952; Qingmin Wang,
E-mail: wangqm@nankai.edu.cn Yuxiu Liu, E-mail: liuyuxiu@nankai.edu.cn
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ABSTRACT
Sulfimides and sulfoximines are highly relevant for medicinal chemistry and crop
protection, as the resulting products can reveal interesting bioactivities. Herein, we
report the design and synthesis of a series of novel 2,4-diphenyl-1,3-oxazolines
containing sulfiliminyl and sulfoximinyl moieties. The acaricidal and insecticidal
activities of the new compounds were evaluated and indicated that these compounds
exhibited excellent acaricidal activities against spider mite larvae and eggs. The LC50
values of 6a-7, 6b-3, 6b-4, 6c-2 and 6c-4 against larvae of spider mite were about 4 to
6 times lower than commercial insecticide etoxazole (0.0221 mg L-1), and the LC50
value of 6a-4 against eggs of spider mite was 0.0006 mg L-1, which was ten times
lower than etoxazole (0.0063 mg L-1). At the same time, most of the compounds
showed insecticidal activity though their structure-activity relationships were different.
Oxazolines containing N-cyano sulfiliminyl moiety at the para position of 4-phenyl
group exhibited better insecticidal activities against cotton bollworm and corn borer
than etoxazole, while the compounds containing groups derived from sulfiliminyl and
sulfoximinyl had weak insecticidal activities. This research again proved that the
substituent type at the para site of 4-phenyl moiety have a decisive role on its
biological activity and insecticidal spectrum.
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KEYWORDS: 2,4-diphenyl-1,3-oxazoline, etoxazole, sulfimides, sulfoximines
acaricidal/insecticidal activity, structure-activity relationship
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INTRODUCTION
Phytophagous mites are common pests on agricultural production. There are about
dozens of phytophagous mites in our country, including the most destructive
Tetranychus urticae (Koch), and Panonychus citri (Mcgregor); they mainly cause
damage to crops such as cottons, vegetables, fruit trees, tea trees and wheats. Mites
not only feed on plant juices, but also spread plant pathogens and viruses thus
resulting in huge decrease in agricultural production.1
Now, the application of acaricides is still one of the effective methods to prevent
and control agricultural spider mites. But the frequent use and misuse of acaricide
caused more and more resistance of the mites.2 In order to deal with the growing
insect resistance problem, low toxic, highly efficient and environment friendly
acaricides with unique structure and novel mechanism of action are still needed to
continuously introduce to the market, which also is a difficult task and huge challenge
for pesticide chemists.
Sulfimides (R1R2S=NR) and sulfoximines (R1R2S(O)=NR) are mono-aza analogues
of sulfoxides and sulfones, respectively. Sulfoximines have been applied with great
success in asymmetric synthesis,3 and more recently, much attention has been focused
on their bioactive profiles in crop protection and drug development.3-7 For example,
sulfoximines can be modified at the nitrogen atom, which allows improving the
solubility of the corresponding molecules.8,9 Sulfoxaflor (Figure 1) aroused our
interests in that it has a sulfoximine group linked to N-cyano and exhibited excellent
insecticidal activities.10 Sulfilimines, possessing a nitrogen substituent and a free
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electron pair at the sulfur atom, are intermediates in the sulfoximine synthesis and
have shown interesting insecticidal activities.6b,11 Furthermore, sulfilimines should
also be similar in properties to the corresponding sulfoximines but they have not been
extensively examined for use in agrochemical research, except that some sulfiliminyl
derivatives were reported to exhibit herbicidal properties.12 The sulfilimine moiety
was postulated to have a small hydrophilic core as well as a hydrogen bond acceptor
site, thus when it was introduced into compounds, the novel structures might bring us
unknown, interesting bioactivities.
Etoxazole (Figure 1) is the only commercial acaricides/insecticides belonging to the
chemical class of 2,4-diphenyl-1,3-oxazolines. The acaricidal and insecticidal
structure-activity relationships of etoxazole analogues showed that the substituent
type at the para site of 4-phenyl moiety has a decisive role on their biological
activities
and
insecticidal
spectrum.13,14
In
2015,
we
reported
2,4-diphenyl-1,3-oxazolines containing sulfur ether moiety which exhibited excellent
acaricidal activities.15 In consideration of the above viewpoints, a series of
2,4-diphenyl-1,3-oxazolines were designed by introducing the sulfiliminyl and
sulfoximinyl group into the para position of 4-phenyl moiety, and the synthesis are
shown in Figure 1. Their acaricidal/insecticidal activities were evaluated accordingly,
and the structure-activity relationships were discussed.
64 MATERIALS AND METHODS
65
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Instruments. Reaction progress was monitored by thin-layer chromatography on
silica gel GF254 with ultraviolet (UV) detection. Melting points were obtained using
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an X-4 binocular microscope melting point (mp) apparatus and are uncorrected.
1
Yields were not optimized. H-NMR spectra and 13C-NMR spectra were recorded
utilizing a Bruker AV400 spectrometer with CDCl3 as solvent and tetramethylsilane
as internal standard. Chemical shifts (δ) were given in parts per million (ppm).
High-resolution mass spectra (HRMS) data were obtained with a Fourier transform
ion cyclotron resonance mass spectrometry (FTICR-MS) spectrometer (ionspec, 7.0T).
InfraRed (IR) was conducted with a MAGNA-560 FTIR (Nicolet).
General Synthesis. The reagents were all analytically or chemically pure
purchased from commercial sources and were used as received. All anhydrous
solvents were dried and distilled by standard techniques just before use. All the
sulfides 5 were synthesized according to the method reported in our previous
publication.13 The synthetic route is given in Figure 2.
General Synthetic Procedure for the Target Compounds 6a, 6b, 6c, 6d,
80 and 6e (Figure 2).
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Synthesis
2-(2,6-difluorophenyl)-4-(4-((naphthalen-2-yl-N-cyanosulfilimidoyl)methyl)phenyl)-
4,5-dihydrooxazole mixture of
of
(6a-1).
A
2-(2,6-difluorophenyl)-4-(4-((naphthalen-2-ylthio)methyl)phenyl)-4,5-dihydrooxazole
(0.2 g, 0.46 mmol) and cyanamide (0.02 g, 0.51 mmol) in 20 mL of acetonitrile was
cooled below 0 °C. To this solution was added iodobenzene diacetate (0.15 g, 0.46
mmol) all at once. The reaction mixture was allowed to stir below 0 °C for 10 min
and slowly warmed to room temperature; the progress of the reaction was monitored
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by TLC. Excess oxidant was destroyed by adding 5 mL of 2.5% aqueous sodium
hydrogen sulfite, and then the solution was added dichloromethane and water. The
aqueous phase was separated and then extracted with dichloromethane twice. The
combined organic layer was washed with saturated brine, dried over anhydrous
sodium sulfate, and filtered. After the solvent was removed in vacuo, the residue was
purified by column chromatography on silica gel to give the target compound
6a-1.16-19
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96
Compounds 6a-2−6a-10 were prepared according to the method used for
compound 6a-1. The physical data in detail are included in the Supporting
Information.
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98
99
Synthesis
2-(2,6-difluorophenyl)-4-(4-(p-tolyl-N-trifluoroacetylsulfilimidoylmethyl)phenyl)-4,5
-dihydrooxazole (6b-2). To solution of
of
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a
2-(2,6-difluorophenyl)-4-(4-(p-tolyl-N-cyanosulfilimidoylmethyl)phenyl)-4,5-dihydro
oxazole (6a-2) (0.50 g, 1.15 mmol) in 20 mL dichloromethane, trifluoroacetic
anhydride (TFAA) (0.72 g, 3.44 mmol) was added dropwise at room temperature.
Then the reaction mixture was stirred continuously until the raw material disappeared
(monitored by TLC). The resulting mixture was washed with water, the organic phase
was separated, and the aqueous phase was extracted by dichloromethane (2 ×20 mL).
The combined organic layer was washed with saturated brine and dried with
anhydrous sodium sulfate, then filtered and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel and eluted with
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petroleum ether and ethyl acetate (v/v = 3:1) to give the target compound 6b-2.20
Compounds 6b-1, 6b-3−6b-7, 6b-9 were synthesized by a method similar to that
used for compound 6b-2. Their physical data are included in the Supporting
Information.
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Synthesis
of
2-(2,6-difluorophenyl)-4-(4-(p-tolyl-NH-sulfoximidoyl
(6c-2). solution of
methyl)phenyl)-4,5-dihydrooxazole
A
2-(2,6-difluorophenyl)-4-(4-(p-tolyl-N-trifluoroacetylsulfilimidoylmethyl)phenyl)-4,5
-dihydrooxazole (6b-2) (0.42 g, 0.83 mmol) in 20 mL ethanol was added
3-chloroperoxybenzoic acid (m-CPBA) at 0 °C. Potassium carbonate (0.34 g, 2.49
mmol) aqueous solution was added dropwise to the above mixture. The progress of
the reaction was monitored by TLC until the reaction was complete. The reaction
mixture was concentrated under reduced pressure. The resulting mixture was added
dichloromethane and water, the organic phase was separated, and the aqueous phase
was extracted by dichloromethane (2 ×20 mL). The combined organic layer was
washed with saturated brine, dried with anhydrous sodium sulfate, and then filtered.
The solvent was removed in vacuo, and the residue was purified by silica gel column
chromatography to give the target compound 6c-2.21
The synthesis procedure of 6c-1, 6c-4 and 6c-5 was similar to that of compound
6c-2. The physical data in detail are included in the Supporting Information.
Synthesis
of
2-(2,6-difluorophenyl)-4-(4-(N-cyanosulfoximidoyl
methyl)phenyl)-4,5-dihydrooxazole (6d). The synthesis procedure of compounds
6d-1−6d-5, 6d-8, 6d-9 was similar to that of compound 6c-2 using intermediate
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6a-1−6a-5, 6a-8, 6a-9, respectively, as materials. Their physical data are included in
the Supporting Information.
Synthesis
of
2-(2,6-difluorophenyl)-4-(4-(p-tolyl-N-carbamoylsulfoximidoyl
(6e-2). To solution of
methyl)phenyl)-4,5-dihydrooxazole
a
2-(2,6-difluorophenyl)-4-(4-(p-tolyl-N-cyanosulfoximidoylmethyl)phenyl)-4,5-dihydr
ooxazole (6d-2) (0.44 g, 0.97 mmol) in 20 mL dichloromethane, trifluoroacetic acid
(0.33 g, 2.91 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at
0 °C until the reactant disappeared (monitored by TLC). The resulting mixture was
washed with water. The organic phase was separated and then the aqueous phase was
extracted with dichloromethane twice. The combined organic layer was washed with
saturated brine, dried with anhydrous sodium sulfate, and then filtered. The solvent
was concentrated in vacuo, and the residue was purified by silica gel column
chromatography to give the target compound 6e-2.21
The synthesis procedure of 6e-1, 6e-3−6e-5 was similar to that of compound 6e–2.
The physical data in detail can be found in the Supporting Information.
Biological Assay. Detailed bioassay procedures for spider mites22-24 and various
insects25,26 were carried out according to the published literature and can also be
found in the Supporting Information. According to statistical requirements each
bioassay was repeated at least three times. The error of the experimments was 5%.
Assessments were made on a dead/alive basis, and mortality rates were corrected
using Abbott’s formula. Evaluation were based on a percentage scale of 0−100, where
0 equals no activity and 100 equals total kill. For comparative purpose, etoxazole was
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tested under the same conditions.
156 RESULT AND DISCUSSION
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Chemistry
Synthesis. A series of sulfides 5 were initially prepared according to the
previously reported literature in moderate yields. The treatment of the sulfides with
cyanamine as a nitrogen source and iodobenzene diacetate as an oxidant in
acetonitrile led efficiently to corresponding N-cyanosulfilimines 6a in considerable
yields. However, when there is a heterocyclic ring connected with the sulfur atom in 5,
most of the oxidation step could not occur; only one compound 6a-10 was obtained,
in which the sulfur atom was connected with a thiadiazole ring. It is worth mentioning
that these novel compounds are much stable, as they are easily handled and stored for
weeks at room temperature without degradation.
Then the N-cyanosulfilimidoyl group of 6a was derived to provide more diverse
groups. The replacement of cyano of the sulfiliminyl moiety with trifluoroacetyl
group could bring changes in physical, chemical, and biological properties of the
whole molecule.25-30 So firstly N-trifluoroacetyl sulfilimines 6b were synthesized by
treating 6a with trifluoroacetic anhydride (TFAA) at room temperature. But the
product 6b-8 was not obtained using this method. This is probably because the steric
hindrance of tertiary butyl is unfavorable factor for the synthesis.
Subsequently, we conducted the oxidation reaction of 6b. Surprisingly, the
oxidation of 6b with m-CPBA didn’t afford the desired N-trifluoroacetylsulfoximines,
but afforded sulfoximine compounds 6c. The compounds 6b bearing a 4-phenyl group
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at the sulfur atom all converted to the corresponding sulfoximines (6c-1, 6c-2, 6c-4
and 6c-5), while both compounds 6b-6 (bearing a 2-methoxylphenyl group) and 6b-7
(bearing a 2-bromophenyl group) were not oxidized under the synthetic procedure
because of the ortho steric hindrance.
Direct oxidation of 6a with m-CPBA could afford N-cyanosulfoximines 6d.
Interestingly, the oxidation of 6a-6 and 6a-7 gave the same compound:
4-(2-(2,6-difluorophenyl)-4,5-dihydrooxazol-4-yl)benzaldehyde; it was reported that
the oxidation at sulfur is hindered by the adjacent ortho substituent and the removal of
the NCN group occurs in an unusual reductive transformation.21 Finally,
N-cyanosulfoximines 6d were treated with trifluoroacetic acid (TFA) in
dichloromethane under an ice bath to produce N-acylaminosulfilimines 6e.
Structure. The novel structures of the target compounds have been identified by
1H NMR, 13C NMR and HRMS. Since there are four different groups connected with
sulfur atom in each of the structures, the two hydrogen atoms on the methylene linked
to sulfur atom are chemical non-equivalent atoms and therefore give different
1
chemical shift in H-NMR spectrum. Correspondingly, these compounds also exhibit
two sets of peaks in 13C-NMR spectrum.
Biological Activity and Structure-Activity Relationship. Activities
195 against Spider Mite (T. cinnabarinus) Eggs and Larvae. The acaricidal
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activities of the compounds 6a-6e and etoxazole (as control) against the eggs and
larvae of spider mite (T. cinnabarinus) were tested and the data are listed in Table 1.
Most oxazolines 6a (containing N-cyanosulfilimidoyl group) exhibited good to
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excellent ovicidal and larvicidal activities. Compounds 6a-1 (containing
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N-cyano-S-naphthylsulfilimidoyl
group),
6a-2-6a-5
(containing
N-cyano-S-(4-substituted phenyl)sulfilimidoyl group), and 6a-8 (containing
N-cyano-S-t-butylsulfilimidoyl group) showed comparable ovicidal activities to that
of
etoxazole.
Especially,
the
mortality
of
6a-4
(containing
a
N-cyano-S-(4-fluorophenyl)sulfilimidoyl group) was 86% at the concentration of 0.01
mg/L, but etoxazole showed only a mortality of 67% at the same concentration.
Further test showed the LC50 value of 6a-4 (0.0006 mg L-1) was about ten times lower
than etoxazole (0.0063 mg L-1) (Table 2). The ovicidal activities of compound 6a-7
(containing N-cyano-S-2-brominephenyl sulfilimidoyl) were much better than that of
compound 6a-6 (containing N-cyano-S-2-methoxylphenyl sulfilimidoyl), and both of
them had higher larvicidal activities than etoxazole.
Other oxazolines (6b-6e) derived from corresponding 6a also exhibited excellent
acaricidal activities, but with no obvious structure-activity relationships.
In N-trifluoroacetylsulfilimines 6b, the larvicidal activities of compounds 6b-3
(containing 4-chlorophenyl) on sulfur atom and 6b-4 (containing 4-flluorophenyl)
were much better than etoxazole, and 6b-2, 6b-5, 6b-7 and 6b-9 also displayed good
larvicidal activity. Meanwhile, the ovicidal activities of 6b-4 and 6b-7 (containing
2-brominephenyl) on sulfur atom were as good as etoxazole. The activities of
NH-sulfoximines 6c against mite eggs were not as good as etoxazole, but the
activities against mite larvae of compounds 6c-2 (containing 4-methylphenyl on sulfur
atom) and 6c-4 (containing 4-flluorophenyl) were higher than etoxazole.
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N-cyanosulfoximine 6d-4 containing 4-flluorophenyl on sulfur atom had good
activities against both mite eggs and larvae. The acaricidal activities of
N-carbamoyl-sulfoximines
6e-4
and
6e-5
were
pretty
good.
N-trifluoroacetylsulfilimine 6b-4, NH-sulfoximine 6c-4, N-cyanosulfoximine 6d-4,
and N-carbamoyl-sulfoximine 6e-4 containing 4-fluorophenyl all showed wonderful
acaricidal activities against mite both eggs and larvae, while 6b-5, 6c-5, 6d-5 and 6e-5
containing 4-brominephenyl exhibited better larvicidal activities but weaker ovicidal
activities. The LC50, LC90 values of compounds 6a-7, 6b-3, 6b-4, 6c-2 and 6c-4
against larvae of spider mite are given in Table 3. These compounds showed lower
concentrations than commercial etoxazole. LC50 of 6c-2 was 0.0039 mg L-1, much
lower than etoxazole (0.0221 mg L-1 ).
Insecticidal Activities against Lepidopteran Pests and Mosquito Larvae.
The insecticidal activities of the target compounds 6a−6e and etoxazole against
mosquito larvae and lepidopteran pests larvae (oriental armyworm, cotton bollworm
and corn borer) are listed in Tables 4 and 5. As shown in Tables, most compounds
exhibited more or less insecticidal activities at the preliminary screening
concentration. The inhibitory activities of 6b, 6c, 6d, 6e series were superior to 6a
series and etoxazole for mosquito larvae, but were weaker than 6a series compounds
and etoxazole for cotton bollworm and corn borer. Compounds 6c-1、6d-1、6e-1、6d-3
and 6c-4 exhibited excellent activities against mosquito larvae; among these
compounds, 6d-1 and 6e-1 showed a morality of 60% and 20% at 0.5 mg/L,
respectively; the moralities of 6d-3 and 6c-4 were 20% and 60% at 0.25 mg/L
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respectively; etoxazole gave a death rate of only 20% at 2 mg/L. Compounds 6a-4
and 6a-5 displayed 50% and 40% insecticidal activities against cotton bollworm, 40%
and 60% insecticidal activities against corn borer at the concentration of 100 mg/L,
but etoxazole only showed insecticidal activities of 40% and 35% against cotton
bollworm and corn borer respectively.
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In
summary,
by
introducing
N-cyanosulfiliminyl
moieties
into
2,4-diphenyl-1,3-oxazolines and further derivation steps, a series of novel oxazoline
derivatives with sulfilimine functional groups were designed and synthesized. Their
acaricidal activities against spider eggs and larvae, insecticidal activities against
oriental armyworm, cotton bollworm, corn borer and mosquito larvae were evaluated.
The bioassay results of N-cyano sulfilimine oxazolines indicated that compounds
6a-1−6a-10 exhibited good to excellent acaricidal activities, among them compound
6a-4 (containing a N-cyano-S-(4-fluorophenyl)sulfilimidoyl group) displayed highest
morality against eggs, the LC50 value (0.0006 mg L-1) was about ten times lower than
etoxazole (0.0063 mg L-1); the LC50 of the acaricidal activity against spider larvae of
compound 6a-7 (containing 2-brominephenyl on sulfur atom ) was 0.0056 mg L-1,
also much lower than etoxazole (0.0221 mg L-1); especially compounds 6a-5, 6a-6,
6a-7 gave outstanding acaricidal activities against both spider eggs and larvae. In 6b、
6c、6d、6e series, compounds 6b-3, 6b-4, 6c-2 and 6c-4 had much better larvicidal
activities than etoxazole; their LC50 values were 0.0058 mg L-1, 0.0055 mg L-1, 0.0039
mg L-1, 0.0041 mg L-1 respectively. The insecticidal activities of 6a series compounds
showed that the target compounds displayed excellent activities against cotton
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bollworm and corn borer, but the activities against oriental armyworm and mosquito
larvae were weak. 6b, 6c, 6d, 6e series compounds all showed wonderful insecticidal
activities against mosquito larvae. It was further concluded that the present research
indicated that the introduction of sulfiliminyl moieties into the
2,4-diphenyl-1,3-oxazolines maintained or improved biological activities. Some of the
target compounds might be potential candidates for further investigation.
ASSOCIATED CONTENT
Supporting Information. The physical data of target compounds 6a-1−6a-10,
6b-1−6b-7, 6b-9, 6c-1−6c-2, 6c-4−6c-5, 6d-1−6d-5, 6d-8−6d-9, 6e-1−6e-5 can be
found in Supporting Information. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
Phone: +86-(0)22-23503952. Fax: +86-(0)22-23503952. Qingmin Wang, E-mail:
wangqm@nankai.edu.cn; Yuxiu Liu, E-mail: liuyuxiu@nankai.edu.cn
Funding Sources
This work was supported by the National Key Research and Development Program of
China (No. 2016YFD0300708) and the National Natural Science Foundation of China
(21772102).
Notes
The authors declare no competing financial interest.
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Figure Captions
Figure 1 The Design of the Target Compounds.
Figure 2 General Synthetic Procedure for the Target Compounds 6a−6e. Reagent
and conditions: (a) PhI(OAc)2, NH2CN, CH3CN, 0 °C to rt, (b) (CF3CO)2O, CH2Cl2, 0
°C to rt, (c) m-CPBA, K2CO3, EtOH, 0 °C to rt, (d) CF3COOH, CH2Cl2, ice bath.
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Figure 1
CF3
R
NH
O
R
N
F
F
F
F
S
S
N
O
N
O
O
6b
6c
F
F
O
N
OC2H5
F
R
Etoxazole
N
S
R
N CN
F
S
F
O
N
CN
O
N
S
Thioether compounds
F
6a
H3C
N
O
CH3
F3C
Sulfoxaflor
R
N
NH2
R
N CN
F
F
F
S
S
N
O
N
O
O
O
O
6e
F
6d
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Figure 2
F
Cl
Br
F
H
N
F
O
F
Cl
F
H
Cl
ClCH2CH(OCH3)2
N
KBr,KBrO3,HCl
H
NH2
N
F
O
F
O
cH2SO4
0 0C-rt
AlCl3,dryCH2Cl2
0 0C-rt
CH2Cl2,H2
O
F
O
2
OCH3
1
3
4
R
S
thiophenol
or
mercaptan
N
R
S
NC
F3C
N
R
S
F
b
a
F
O
N
O
F
N
N
F
O
O
F
6a
6b
5
F
O
O
c
c
NC
H2N
N
S
N
S
NH
R
O
R
O
S R
F
d
F
F
N
N
N
O
O
O
F
F
6c
Br
6e
6d
F
F
Cl
CH3
6a R=
6a-4
6a-5
6a-3
6a-8
6a-1
6a-2
H3CO
Br
S
CH3
N
N
6a-6
6a-10
6a-7
6a-9
CH3
F
Br
Cl
6b
R=
6b-2
6b-1
6b-4
6b-3
6b-5
H3CO
Br
6b-6
6b-7
6b-9
Br
F
CH3
6c
R=
6c-1
6c-2
6c-4
6c-5
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Br
Cl
F
CH3
6d
R=
6d-1
6d-2
6d-3
6d-4
6d-5
F
F
O
N
6d-8
CHO
F
6d-9
6e-2
6d-6'
6d-7'
Br
Cl
CH3
6e
R=
6e-1
6e-3
6e-4
6e-5
Table 1 Acaricidal Activities of the Target Compounds against Spider Mite
comp activities (%) against eggs at concentration activities (%) against larvae at concentration
(mg L-1) (mg L-1)
d
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100 50
25 2.5
1
0.1 0.01 100
50
100 100 100 94
100 100 91 84
25
2.5
1
0.1 0.01
6a-1 100 100 100 100 91
83
72
79
52
61
51
88
64
89
67
72
48
76
52
69
88
65
21
50
—
55
66
69
54
27
63
59
61
74
77
74
49
53
79
47
70
66
6a-2 100 100 100 90
6a-3 100 100 100 96
83
88
100 100 100 95
100 100 100 83
6a-4 100 100 100 100 100 100 86
6a-5 100 100 100 100 100 89
6a-6 100 100 90 79 67 54
6a-7 100 100 100 100 100 90
50
0
100 100 100 100 81
100 100 100 100 96
48
56
0
100 100 100 100 100 81
6a-8 100 100 100 100 95
88
49
54
82
77
67
100 100 100 86
100 100 90 79
78
63
87
88
69
48
75
67
79
6a-9 100 92
81
73
79
67
66
6a-10 100 100 92
36
79
30
49
71
51
51
71
43
64
66
69
100 100 100 92
100 100 100 93
6b-1 100 100 100 100 93
6b-2 100 100 100 95 89
6b-3 100 100 100 100 93
100 100 100 100 86
100 100 100 100 100 84
100 100 100 100 100 81
6b-4 100 100 100 100 100 82
6b-5 100 100 93
85
76
77
62
61
100 100 100 100 96
100 100 91 84 75
86
69
78
84
62
6b-6 100 100 100 90
6b-7 100 100 100 100 100 85
100 100 100 100 91
100 100 100 100 92
6b-9 100 100 100 93
6c-1 100 100 100 92
6c-2 100 100 100 93
85
85
80
70
75
76
76
100 100 100 91
79
100 100 100 100 100 87
100 100 100 100 100 89
6c-4 100 100 100 100 87
6c-5 100 100 100 100 92
6d-1 100 100 100 100 93
87
88
49
71
63
61
17
100 100 100 100 96
81
61
44
55
50
31
100 100 100 92
78
61
71
6d-2 100 100 88
72
61
82
100
94
86
77
80
6d-3 100 100 100 91
64
76
56
62
39
30
59
48
63
79
100 100 92
63
77
79
75
72
76
72
76
76
82
58
72
59
68
60
61
60
68
54
70
6d-4 100 100 100 100 100 86
100 100 100 100 90
100 100 100 100 93
6d-5 100 100 100 100 89
6d-8 100 100 100 100 93
74
81
60
46
72
53
100 100 100 90
100 100 100 90
100 100 100 89
100 100 100 93
83
83
83
81
6d-9 100 100 100 87
6e-1 100 100 94 82
6e-2 100 100 100 95
6e-3 100 100 94 78
79
63
83
61
100 100 100 100 89
100 100 100 100 89
100 100 100 100 95
6e-4 100 100 100 100 100 85
6e-5 100 100 100 100 100 88
Etox-
100 100 100 100 100 84
67
100 100 100 100 85
67
49
azole
Table 2 LC50, LC90 Values of 6a-4 and Etoxazole against Eggs of Spider Mite
compd
y=ax + b
LC50(mg L-1)
LC90(mg L-1)
correlation
coefficient
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6a-4
Etoxazole
y=1.47x + 9.77
y=2.43x + 5.32
0.0006
0.0063
0.0043
0.0455
0.9655
0.9437
Table 3 LC50, LC90 Values of 6a-7, 6b-3, 6b-4, 6c-2, 6c-4, and Etoxazole against
Larvae of Spider Mite
compd
y=ax + b
LC50 (mg L-1)
LC90 (mg L-1)
correlation
coefficient
0.9466
0.9580
0.9447
0.9533
0.9606
0.9855
6a-7
6b-3
6b-4
6c-2
6c-4
Etoxazole
y=1.40x + 8.17
y=1.46x + 8.27
y=1.42x + 8.22
y=1.33x + 8.21
y=1.35x + 8.24
y=0.66x + 6.10
0.0056
0.0058
0.0055
0.0039
0.0041
0.0221
0.0452
0.0434
0.0434
0.0357
0.0358
1.8293
Table 4 Insecticidal Activity of the Target Compounds against Mosquito
activities (%) against mosquito at concentration (mg L-1)
10
5
2
1
0.5
0.25
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compd
6a-1
6a-2
6a-3
6a-4
6a-5
6a-6
6a-7
6a-8
6a-9
6a-10
6b-1
6c-1
6d-1
6e-1
6b-2
6c-2
6d-2
6e-2
6b-3
6d-3
6e-3
6b-4
6c-4
6d-4
6e-4
6b-5
6c-5
6d-5
6e-5
6b-6
6b-7
6d-8
6b-9
6d-9
30
—
100
—
—
—
—
—
—
—
—
—
100
100
100
—
—
—
60
—
100
0
—
40
—
—
—
—
—
—
—
—
—
20
100
100
—
—
—
75
50
100
—
—
100
—
—
0
—
—
—
—
—
—
—
—
—
—
—
—
100
100
—
—
—
—
—
100
—
—
100
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
60
20
—
—
—
—
—
100
—
—
100
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
20
100
45
10
30
5
70
25
5
15
40
100
100
100
65
20
50
50
50
100
100
20
—
—
100
60
—
100
—
20
—
—
—
—
—
20
100
—
60
—
—
—
—
—
—
—
—
—
—
—
—
100
100
50
100
50
—
—
—
—
—
—
—
—
20
100
20
40
30
50
60
100
Etoxazole 100
Table 5 Insecticidal Activities of the Target Compounds (Mortality, Percent)
compd
cotton bollworm
(600 mg L-1)
corn borer
(600 mg L-1)
oriental armyworm
(600 mg L-1)
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6a-1
6a-2
6a-3
6a-4
6a-5
6a-6
6a-7
6a-8
6a-9
6a-10
6b-1
6c-1
55
80
85
45
85
80
30
45
75
50
20
75
30
50
45
20
25
10
100/100a/50b
100/100a/40b
100/100a/40b
100/100a/60b
65
100/60a
60
100/80a
75
60
85
0
70
45
80
0
20
15
6d-1
6e-1
20
50
5
50
10
45
6b-2
6c-2
50
0
45
10
75
5
6d-2
6e-2
70
15
65
25
40
20
6b-3
6d-3
6e-3
0
15
0
5
20
10
20
25
50
6b-4
6c-4
30
35
15
45
5
70
6d-4
6e-4
10
5
25
10
20
20
6b-5
6c-5
0
0
5
0
20
5
6d-5
6e-5
0
5
15
10
30
20
6b-6
6b-7
6d-8
6b-9
6d-9
Etoxazole
0
15
0
25
25
10
15
0
35
10
5
15
5
50
20
100/100a/40b
100/100a/35b
100/100a/60b
a Activities at 200 mg L-1. b Activities at 100 mg L-1.
TOC graphic
Agrochemical Bioregulators
28
ACS Paragon Plus Environment

Page 29 of 29
Journal of Agricultural and Food Chemistry
R
NH
O
CF3
R
N
S
F
F
S
F
F
F
N
O
N
O
O
N
O
OC2H5
6c
F
6b
Etoxazole
R
N
CN
F
F
S
N
O
CN
N
S
6a
H3
N
C
O
CH3
R
N
O
NH2
R
N CN
F3
C
F
F
F
S
S
N
O
N
O
O
O
Sulfoxaflor
6e
F
6d
29
ACS Paragon Plus Environment