Design, synthesis and insecticidal activity of novel analogues of flubendiamide containing alkoxyhexafluoroisopropyl groups

Article abstract of DOI:10.1039/d0ra07121h

Flubendiamide has received considerable attention in the agriculture field due to its novel mode of action and excellent insecticidal activity. However, the high cost and toxicity to aquatic invertebrates associated with flubendiamide limit its agronomic utility. On the basis of the structure of the lead compound, flubendiamide, we designed and synthesized a series of novel analogues of flubendiamide bearing a alkoxyhexafluoroisopropyl moiety using 2-methyl-4-(2-alkoxyhexafluoroisopropyl) anilines as the key intermediates. Their insecticidal activities against the oriental armyworm (Mythimna separataWalker) were evaluated. The results indicated that most of the target compounds exhibited high insecticidal activities. Specifically, compound8hshowed the best insecticidal activity against the armyworm and its insecticidal activity reached 70% at 0.156 mg L^?1. The LC₅₀value of compound8h(0.0512 mg L^?1) is nearly the same as the corresponding commercial product flubendiamide (0.0412 mg L^?1). Furthermore, the acute toxicity test showed that the 48 h LC₅₀values of compound8hand flubendiamide againstDaphnia magnaStraus were 0.0066 and 0.0021 mg L^?1, respectively. The toxicity of compound8his obviously lower than flubendiamide.

Full text of DOI:10.1039/d0ra07121h

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Design, synthesis and insecticidal activity of novel
analogues of flubendiamide containing
alkoxyhexafluoroisopropyl groups†
Cite this: RSC Adv., 2020, 10, 34486
Xianghu Zhao,‡ Sixue Xu,‡ Chuan Liu, Jingjing He, Chunmei Li, Yupian Deng
*
and Song Cao
Flubendiamide has received considerable attention in the agriculture field due to its novel mode of action
and excellent insecticidal activity. However, the high cost and toxicity to aquatic invertebrates associated
with flubendiamide limit its agronomic utility. On the basis of the structure of the lead compound,
flubendiamide, we designed and synthesized a series of novel analogues of flubendiamide bearing
a alkoxyhexafluoroisopropyl moiety using 2-methyl-4-(2-alkoxyhexafluoroisopropyl) anilines as the key
intermediates. Their insecticidal activities against the oriental armyworm (Mythimna separata Walker)
were evaluated. The results indicated that most of the target compounds exhibited high insecticidal
activities. Specifically, compound 8h showed the best insecticidal activity against the armyworm and its
insecticidal activity reached 70% at 0.156 mg Lꢀ1. The LC50 value of compound 8h (0.0512 mg Lꢀ1) is
nearly the same as the corresponding commercial product flubendiamide (0.0412 mg Lꢀ1). Furthermore,
the acute toxicity test showed that the 48 h LC50 values of compound 8h and flubendiamide against
Daphnia magna Straus were 0.0066 and 0.0021 mg Lꢀ1, respectively. The toxicity of compound 8h is
obviously lower than flubendiamide.
Received 19th August 2020
Accepted 10th September 2020
DOI: 10.1039/d0ra07121h
rsc.li/rsc-advances
diverse novel ubendiamide analogues have been discov-
ered.13–16 It has been demonstrated that the hepta-
Introduction
uoroisopropyl group in the aromatic amine moiety (part C) is
essential for high insecticidal activity and remarkably broadens
the insecticidal spectrum.17 However, the use of expensive
starting material (heptauoroisopropyl iodide) and the poor
stability and operational inconvenience of this reagent greatly
restrict the widespread applications of ubendiamide in crop
protection.18 The high cost of heptauoroisopropyl iodide likely
drives researchers to search other alternative polyuorinated
substrates. For example, in 2010, Zhu et al. synthesized a series
of phthalic acid diamides bearing the CF3 group at meta posi-
tion on the aniline ring.19 In 2014, the group of Zheng-ming Li
modied the structure of ubendiamide by replacing hepta-
uoroisopropyl group with different uorinated functionalities
in the aromatic amine moiety.20 Some of these novel u-
bendiamide derivatives exhibited high insecticidal activities.
Tohnishi et al. indicated that incorporation of uoroalkoxy
group at the 4-position of the aromatic amine moiety could
improve insecticidal activity.21 In addition, like hepta-
uoroisopropyl group, the hexauorocarbinol moiety
(–C(CF3)2OH) is also an attractive pharmacophore that is oen
included in medicines or bioactive compounds (e.g. Fig. 1,
compound I).22–25
Flubendiamide, a new generation of synthetic insecticide, has
attracted continuing interest in recent years because of its
unique insecticide mode of action, high activity against a broad
spectrum of lepidopterous insects and low acute toxicity to
mammals.1,2 It directly activates the insect ryanodine receptors
(RyRs), which causes permanent muscle contraction, paralysis
and eventually results in the death of the insect.3,4 Since the rst
commercial Ca2+ channel modulator, ubendiamide, was
launched in 2007 by Nihon Nohyaku and Bayer CropScience,
there have been many reports on the synthesis and bioassay of
ubendiamide.5–7
Flubendiamide oen serves as an ideal lead compound for
developing a new and selective ryanodine receptor activator.8,9
Generally, the structure of ubendiamide is composed of three
parts as shown in Fig. 1: (A) the phthaloyl moiety, (B) the
aliphatic amine moiety and (C) the aromatic amine moiety.10–12
Therefore, extensive efforts have been focused on the modi-
cation of these three moieties and a variety of structurally
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China
University of Science and Technology (ECUST), Shanghai 200237, China. E-mail:
scao@ecust.edu.cn
Inspired by the structure of ubendiamide and compound I,
in 2012, we synthesized a series of novel analogues of u-
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra07121h
bendiamide containing
a
hexauoro-2-hydroxypropan-2-yl
‡ These authors have equally contributed to this article.
34486 | RSC Adv., 2020, 10, 34486–34492
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Fig. 2 (a) Modification of the tert-butyl group of Bosentan with the
polyfluorinated isopropyl groups. (b) The dihedral angles of different
polyfluorinated isopropyl benzenes.
the conformation of polyuorinated substituents on the benzene
ring were observed.30
On the basis of the above consideration and preliminary
results of bioassay, we envisioned that the introduction of
hexauoro-2-alkoxyprop-2-yl group to the aromatic amine
moiety of ubendiamide might retain or improve the activity of
parent compound. In this paper, we designed and synthesized
a series of novel analogues of ubendiamide bearing alkox-
yhexauoroisopropyl moiety (Fig. 1, 8a–q). Their insecticidal
activities of the target compounds against oriental armyworm
and the acute toxicity of 8h against Daphnia magna Straus were
also evaluated.
Fig. 1 Design strategy for novel flubendiamide derivatives containing
alkoxyhexafluoroisopropyl group 8a–q.
moiety (Fig. 1, compound II).26 Compound II has some signi-
cant advantages over its leading compound, ubendiamide,
due to the use of cheap, stable and commercially available
starting material, CF3COCF3$H2O. However, compound II such
as 8r (R ¼ 2-CH3) (Fig. 1) exhibited worse activity than u-
bendiamide. Therefore, the requirements to develop novel
analogues of ubendiamide with low cost, low aquatic species
toxicity and excellent insecticidal activity are highly desirable.
In our initial experiments, three polyuorinated groups (Rf)
were introduced into the aromatic amine moiety of ubendia-
mide to replace heptauoroisopropyl group (Fig. 1, 8a0–c0).
Preliminary results indicated that analogue of ubendiamide
bearing uoroalkoxy group 8c0 possessed high insecticidal
activity, implying that the introduction of uoroalkoxy group
might be favorable for retaining insecticidal activity. In addi-
tion, pyubumide is a novel acaricide with remarkable activity
against spider mites. The structural feature of pyubumide is
that it contains a methoxy-substituted hexauoroisopropyl
group on the aromatic amine moiety (Fig. 1, pyubumide).27
Another bioactive compound bearing 2-uoroalkoxy-
hexauoroisopropyl group is Sevourane, a widely used inha-
lational anesthetic agent (Fig. 1, Sevourane).28
Results and discussion
The synthetic routes of the intermediates 20, 3a0–c0 and 3a–q and
compounds 8a0–c0 and 8a–q are outlined in Schemes 1–4,
Scheme 1 Synthesis of fluorine-containing anilines 3a0–c0.
In 2016, Cruciani et al. replaced the tert-butyl group of
bosentan with heptauoroisopropyl, hexauoro-2- hydroxyprop-
2-yl and hexauoro-2-methoxyprop-2-yl group, respectively
(Fig. 2a).29 These uorinated analogues of bosentan exhibited an
improved metabolic stability towards certain specic cyto-
chromes. More recently, aer carefully analysis of three X-ray
crystal structures of polyuorinated isopropyl benzenes
(Fig. 2b, compounds X1, X2 and X3), Maiensch et al. found that
the dihedral angles of X1 (C]C/C–F), X2 (C]C/C–OH), and X3
(C]C/C–OCH3) were slightly different. The subtle differences in
Scheme
2 Synthesis of novel anilines containing hexafluoro-2-
alkoxyprop-2-yl group 3a–q.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 34486–34492 | 34487

View Article Online
RSC Advances
Paper
Table
2
Insecticidal activities against oriental armyworm of
compounds 8a–r and flubendiamide (Flu)a
Insecticidal activity (%) at different concentration (mg Lꢀ1
)
Compds
100
50
10
5
2.5
1.25
0.625
0.156
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
100
100
70
20
73
100
100
100
100
100
100
100
100
100
10
100
100
57
100
100
40
80
87
0
67
77
57
73
50
40
0
0
60
50
100
90
100
100
70
100
100
87
10
90
83
100
97
50
90
90
83
47
100
100
100
100
100
100
100
100
90
87
80
90
90
13
90
90
80
20
83
77
87
83
73
70
85
80
40
23
70
60
Scheme 3 Two reported and our methods for the synthesis of 4-
(hexafluoro-2-alkoxypropan-2-yl)anilines.
87
87
77
83
60
73
60
17
30
respectively. These intermediates and title compounds were
readily synthesized according to the reported methods.26,31–33 In
some case, slight modications of these reaction conditions
67
were necessary in order to obtain satisfying yields (see ESI† for 8p
10
30
100
100
8q
details).
8r
100
100
100
100
80
97
80
93
67
90
30
85
0
70
The highly efficient synthesis of the key intermediates 3a–q
Flu
was one of the key steps in the total synthesis of these novel
a
Note that blank cells mean not tested.
analogues of ubendiamide (Scheme 2). A survey of the litera-
ture revealed that only a few methods were used to synthesize
the analogues of intermediates 3a–q (Scheme 3, methods A and
B).34–36 However, these methods suffer from the use of expensive
starting material (heptauoroisopropyl iodide) and/or the
lengthy protection and deprotection of amido group.
(Scheme 2). Some crude O-alkylation products 3a–q could be
used for the next step without additional purication (see ESI†
for details). The structures of 3a, 3a1 and 3a2 were determined
by the 1H NMR spectra and GC-MS, or 1H NMR spectra of their
corresponding pure compounds reported in the literature.34–36
The insecticidal activities of compounds 8a0–c0, 8a–r and
ubendiamide (as a control) against oriental armyworm were
listed in Tables 1 and 2.
As shown in Table 1, analogues of ubendiamide having
uoroalkoxy group 8c0 showed higher activity than other
compounds (8a0 and 8b0). These preliminary bioassay results
suggested that the incorporation of uoroalkoxy group into the
aromatic amine moiety (part C) could provide useful clue for
further structural optimization for the discovery of novel
analogues of ubendiamide.
Subsequently, seventeen novel analogues of ubendiamide
containing alkoxyhexauoroisopropyl group 8a–q were
designed and synthesized. Their bioassay results of seventeen
novel analogues of ubendiamide containing alkoxyhexa-
uoroisopropyl group 8a–q and 8r are summarized in Table 2.
Most of the alkoxyhexauoroisopropyl-containing compounds
displayed good to excellent larvicidal activities. The bioactivities
of compounds 8a–q were signicantly affected by the electronic
nature and the steric properties of the alkyl group (R) attached
to the oxygen atom. Generally, the larvicidal activities decreased
with an increase in the size of the substituent R in the
C(CF3)2OR moiety. The steric bulk of substituents was detri-
mental for activity (for example, 8a versus 8p and 8q). The target
compounds bearing short-chain alkyl group such as methyl (8a)
showed better larvicidal activities than that of compound
bearing long-chain alkyl group (8c and 8d). It was observed that
To access the above-mentioned intermediates in a conve-
nient and efficient manner, we tried to alkylate intermediates 2
with various alkyl halides (RX) directly. However, the chemo-
selective alkylation of intermediates 2 remains a challenge due
to the presence of two possible highly reactive sites (NH2 and
OH groups),37 which leads to the formation of different prod-
ucts (Scheme 3, 3a, 3a1 and 3a2, RX]CH3I). Aer careful
screening of bases, solvents, and reaction temperatures, we
found that the chemoselective alkylation of hydroxyl group in
intermediate 2 could proceed smoothly in the presence of 1.2
equiv. of CH3I and 1.5 equiv. of Cs2CO3 using DMF as the
ꢁ
solvent at 25 C for 0.5 h and afforded the desired O-alkylated
product 3a in excellent yields. Only trace amounts of N-alkylated
product 3a1 and double alkylated product 3a2 were detected.
Subsequently, compound 2 was alkylated with a variety of alkyl
halides RX under the optimized experimental conditions to
afford O-alkylated products 3a–q in high yields and high purity
Table
1 Insecticidal activities against oriental armyworm of
compounds 8a0–c0 and flubendiamide (Flu)
Insecticidal activity (%) at concentration (mg Lꢀ1
)
Compds
400
200
100
10
8a'
8b'
8c'
Flu
47
7
90
100
100
3
0
0
43
97
100
100
100
20
70
100
34488 | RSC Adv., 2020, 10, 34486–34492
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 3 LC50 values of compounds 8a–c, 8e–n, 8r and flubendiamide (Flu) at 72 h against oriental armyworm
Compds
Regression equation
LC50 (mg Lꢀ1
)
95% condence interval of LC50 (mg Lꢀ1
)
r
8a
8b
8c
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8r
y ¼ 0.91177x + 5.1361
y ¼ 1.4626x + 5.1970
y ¼ 0.7456x + 3.9798
y ¼ 0.5605x + 4.4081
y ¼ 1.0690x + 5.7120
y ¼ 1.7053x + 5.7005
y ¼ 1.0188x + 6.3151
y ¼ 0.9241x + 5.9809
y ¼ 2.667x + 2.9565
y ¼ 0.8938x + 6.0201
y ¼ 1.9854x + 5.6844
y ¼ 1.1781x + 5.5729
y ¼ 1.604x + 3.7044
y ¼ 2.2959x + 5.0371
y ¼ 0.8931x + 6.2370
0.7092
0.7334
23.3582
11.3793
0.2158
0.3884
0.0512
0.0868
5.8372
0.0722
0.4521
0.3264
6.4223
0.9635
0.0412
0.4376–1.1492
0.5419–0.9925
14.2972–38.1618
4.5377–28.5361
0.1426–0.3265
0.3126–0.4825
0.0168–0.1560
0.0428–0.1760
5.1008–6.6797
0.0315–0.1657
0.3770–0.5423
0.2357–0.4520
5.2645–7.8353
0.8172–1.1359
0.0146–0.1160
0.9839
0.9457
0.9864
0.9475
0.9752
0.9804
0.9760
0.9743
0.9785
0.9802
0.9839
0.9392
0.9832
0.9729
0.9996
Flu
Table 4 Insecticidal activities of compound 8h and chlorantraniliprole (CAP) against four insectsa
Insecticidal activity (%) at different concentration (mg Lꢀ1
)
Diamondback
moth
Oriental armyworm
Tea geometrid
Cabbage buttery
Concentration
(mg Lꢀ1
)
8h
CAP
8h
CAP
8h
CAP
8h
CAP
100
20
4
0.8
0.16
100
100
100
90
100
100
100
100
80
100
90
50
30
0
100
90
60
30
0
100
90
50
100
90
70
87
60
50
40
0
100
90
70
50
0
30
60
70
a
Note that blank cells mean not tested.
the introduction of appropriate small substituents with aniline moiety might have a benecial effect on the insecticidal
terminal halide atoms or unsaturated groups into the (2- activity of the title compounds.
hydroxyhexauoroisopropyl) aniline moiety oen had a positive
Furthermore, the LC50 values of compounds 8a–c, 8e–n, 8r as
effect on insecticidal activity. For example, compound 8g (R] well as ubendiamide against oriental armyworm were calcu-
CH2Cl) and compound 8h (R]CH2CN) exhibited 23% and 70% lated and summarized in Table 3. Compounds 8d and 8o–q
larvicidal activity against oriental armyworm at 0.156 mg Lꢀ1
,
were excluded from the regression analysis because these
respectively. Especially, compound 8h showed nearly the same compounds did not give acceptable LC50 values. As shown in
larvicidal activity as ubendiamide on armyworm. Further- Table 3, compounds 8f, 8i and 8k exhibited excellent insecti-
more, compound 8i (R]CH2CH]CH2), compound 8j (R] cidal activity against armyworm, with the LC50 values of 0.2158,
CH2C(CH3)]CH2), compound 8k (R]CF3C]CH2), compound 0.0868, and 0.0722 mg Lꢀ1, respectively. In particular, the LC50
8l (R]CH2C^CH) and compound 8m (R]CH2C^CH) also value of compound 8h was 0.0512 mg Lꢀ1, which was near that
had good insecticidal activities due to the presence of unsatu- of ubendiamide (0.0412 mg Lꢀ1).
rated carbon–carbon bonds in alkyl group. Interestingly,
replacement of a cyclopropylmethyl group (8f) by an oxiran-2-
ylmethyl group (8e) or an acetamide group (8n) by an acetate
group (8o) resulted in a remarkable decrease in activity. These
Table 5 Acute toxicity of compound 8h and flubendiamide (Flu) to
two compounds (8e and 8o) exhibited weak insecticidal activi-
ties against oriental armyworm at a test concentration of
5 mg Lꢀ1 (10% or 47%, respectively). Delightfully, the insecti-
cidal activities of compounds 8f–i and 8k–m exhibited appar-
ently higher larvicidal activities than compound 8r, previously
reported by our group (Scheme 1), suggesting that the intro-
duction of alkyl group into the (2-hydroxyhexauoroisopropyl)
Daphnia magna
Acute toxicity (%) at different concentration (mg Lꢀ1
)
Compds 0.175 0.0875 0.04375 0.02188 0.01092 0.00546 0.00273
8h
Flu
97
97
95
95
79
81
66
76
61
70
44
67
39
58
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 34486–34492 | 34489

View Article Online
RSC Advances
Paper
Table 6 LC50 and LC90 values of compound 8h and flubendiamide (Flu) against Daphnia magna
Compds
8h
Toxicity equation
LC50a (mg Lꢀ1
)
LC90a (mg Lꢀ1
)
rb
y ¼ 1.1899x + 7.5975
y ¼ 0.8523x + 7.2910
0.0066 (0.0035–
0.0099)
0.0021 (0.0004–
0.0046)
0.0784 (0.0512–
0.1495)
0.0654 (0.0369–
0.1765)
0.97
0.96
Flu
a
b
Values are given with 95% condence intervals. Correlation coefficient.
Scheme 4 The synthesis of new flubendiamide derivatives 8a0–c0 and 8a–q.
To get a better understanding of the insecticidal activity of chemoselective alkylation of 2-methyl-4-hexauoroisopropanol
synthesized compounds, the best bioactive compound 8h and aniline. The bioassay results indicated that some compounds
commercial insecticide chlorantraniliprole (CAP) were selected displayed high insecticidal activities against oriental armyworm
to further evaluate the activities against oriental armyworm, tea (Mythimna separata Walker) in comparison with ubendiamide.
geometrid, cabbage buttery and diamondback moths (Table Particularly, the insecticidal activity of compound 8h against
4). The results of the preliminary bioassays indicated that armyworm was as high as 70% at 0.156 mg Lꢀ1, the same as that
compound 8h displayed good to high insecticidal activities of control ubendiamide (0.156 mg Lꢀ1, 70%). The LC50 values
against these four insects. The larvicidal activity of compound of 8h and ubendiamide were 0.0512 and 0.0412 mg Lꢀ1
8h was comparable to that of chlorantraniliprole. respectively. Furthermore, compound 8h also exhibited strong
,
Recently, it was reported that ubendiamide was restricted insecticidal activities against tea geometrid, cabbage buttery
or banned in certain countries due to its toxicity to aquatic and diamondback moths, which is comparable to commercial
invertebrates.38,39 Consequently, the acute toxicity tests of chlorantraniliprole. In addition, the acute toxicity test showed
compound 8h and ubendiamide to Daphnia magna were that the 48 h LC50 value of compound 8h against Daphnia magna
carried out. Daphnia magna were exposed to different concen- Straus was 0.0066 mg Lꢀ1, whereas the LC50 value of u-
trations of compound 8h and ubendiamide aer 48 h. The bendiamide was 0.0021 mg Lꢀ1. The modication resulted in an
LC50 values of compound 8h and ubendiamide against obvious decrease in toxicity. The preliminary structure–activity
Daphnia magna were 0.0066 and 0.0021 mg Lꢀ1, respectively relationship of the title compounds revealed that the intro-
(Tables 5 and 6). The toxicity of compound 8h is lower than that duction of small, electron-poor substituent or unsaturated
of ubendiamide. It implied that the replacement of secondary group into the (2-hydroxyhexauoroisopropyl) aniline moiety
C–F bond in ubendiamide by C–OR moiety might lead to may be favorable for retaining high insecticidal activity. The
a decrease in the acute toxicity for Daphnia magna, whereas this ndings obtained in these studies provided useful guidance for
modication in the aromatic amine moiety could retain or the design of novel analogues of ubendiamide bearing poly-
improve insecticidal activity.
uorinated group. Further modication of ubendiamide and
eld trials of compound 8h are currently underway.
Conclusions
Experimental
General information
In summary, we designed and synthesized a variety of struc-
turally diverse analogues of ubendiamide containing alkox-
yhexauoroisopropyl group. The key intermediates, 2-methyl-4- All reagents were of analytic grade and obtained from
(2-alkoxyhexauoroisopropyl) anilines (3a–q), were synthesized commercial suppliers and used without further purication.
in good to excellent yields by the straightforward Reactions were monitored by GC-MS or thin-layer
34490 | RSC Adv., 2020, 10, 34486–34492
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
chromatography (TLC) on silica gel 60 GF254 with ultraviolet ubendiamide was tested under the same conditions. The
detection. Melting points were measured in an open capillary larvicidal activities of 8a0–c0, 8a–r and ubendiamide against
¨
using Buchi melting point B-540 apparatus and are uncor- oriental armyworm are listed in Tables 1 and 2. In addition, the
rected. 1H and 13C NMR spectra were recorded on a Bruker AM- LC50 values of compounds 8a–c, 8e–n, 8r and ubendiamide
400 spectrometer (400 MHz and 100 MHz, respectively) using (Flu) against oriental armyworm as shown in Table 3.
TMS as the internal standard. CDCl3 and DMSO-d6 were used as
Larvicidal activity against armyworm and other three insects.
NMR solvent. The 19F NMR spectra were recorded on a Bruker The larvicidal activity of the typical compound 8h and chlor-
AM-400 spectrometer (376 MHz) using CF3CO2H as external antraniliprole against oriental armyworm (Mythimna separata
standard. Gas chromatography-mass spectra (GC-MS) were Walker), tea geometrid (Ectropis oblique hypulina Wehrli),
recorded on HP 5973 MSD with 6890 GC. High resolution mass cabbage buttery (Pieris rapae L.) and diamondback moths
spectra (HRMS) were recorded under electron impact condi- (Plutella xylostella Linnaeus) were evaluated according to the
tions using a MicroMass GCT CA 055 instrument.
leaf-dip method using the literature procedures (Table 4).13,41–43
The acute toxicity test of compound 8h and ubendiamide to
Daphnia magna Straus were also performed according the re-
ported method with some modications.44–46 The results were
summarized in Tables 5 and 6.
Procedures for the synthesis of compounds in Scheme 4
Intermediates 4, 5 and 6 were prepared according to the liter-
ature procedures with some modication.26,33 General proce-
dure for the synthesis of target compounds 8a0–c0 and 8a–q. To
a solution of 6 (1.87 g, 5 mmol) in acetonitrile (25 mL) was
added substituted anilines 3a0–c0 or 3a–q (5.5 mmol) and tri-
uoroacetic acid (28.5 g, 0.25 mmol). The mixture was then
stirred for 3 h. The progress of the reaction was monitored by
TLC. When the reaction was complete, without further puri-
cation, the intermediate 7a0–c0 or 7a–q (5 mmol) was allowed to
react with the solution of m-chloroperoxybenzoic acid (1.90 g, 11
mmol) in acetonitrile (25 mL). The solution was stirred for
another 3 h at room temperature until the reaction was
complete. Then the solution was concentrated under reduced
pressure and the residue was dissolved in dichloromethane (10
mL). The organic layer was washed by water and dried over
anhydrous MgSO4. The CH2Cl2 was removed under reduced
pressure, and the residue was puried by silica gel column
chromatograph (eluent: petroleum ether (60–90 ꢁC)/ethyl
acetate ¼ 3/2, v/v) to afford compounds 8a0–c0 and 8a–q. The
physical characteristics, yields, 1H NMR, 13CNMR, 19F NMR and
HRMS (ESI) data of the target compounds can be found in ESI.†
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We are grateful for nancial support from the National Key
Research and Development Program of China (No.
2017YFD0200505).
Notes and references
1 H. Hamaguchi and T. Hirooka, in Modern Crop Protection
€
Compounds, ed. W. Kramer and U. Schirmer, Wiley-VCH
Verlag, Weinheim, Germany, 2nd edn, 2007, vol. 3, p. 1121.
2 P. L. George, C. Daniel and D. B. James, Bioorg. Med. Chem.,
2009, 17, 4127.
3 K. Kato, S. Kiyonaka, Y. Sawaguchi, M. Tohnishi,
H. Takeshima and Y. Mori, Biochemistry, 2009, 48, 10342.
4 S. Z. Qi and J. E. Casida, Pestic. Biochem. Physiol., 2013, 107,
321.
Biological assays
All bioassays were performed on representative test organisms
reared in the laboratory. The bioassay was repeated at 25 ꢂ 1 ꢁC
according to statistical requirements. Assessments were made
on a dead/alive basis, and mortality rates were corrected using
Abbott's formula. Evaluations are based on a percentage scale of
0–100 in which 0 ¼ no activity and 100 ¼ total kill.
¨
5 U. Ebbinghaus-Kintscher, P. Lummen, K. Raming, T. Masaki
and N. Yasokawa, Panzenschutz-Nachr. Bayer, 2007, 60, 117.
6 K. Tsubata, M. Tohnishi, H. Kodama and A. Seo,
Panzenschutz-Nachr. Bayer, 2007, 60, 105.
7 M. L. Feng, Y. F. Li, H. J. Zhu, J. P. Ni, B. B. Xi and L. Zhao,
Pest Manage. Sci., 2012, 68, 986.
8 Y. T. Xie, S. Zhou, Y. X. Li, M. Chen, B. Wang, L. Xiong,
N. Yang and Z. M. Li, Chin. J. Chem., 2018, 36, 129.
9 Y. B. Chen, Y. X. Xiao, X. S. Shao, X. Y. Xu and Z. Li, Chin. J.
Chem., 2014, 32, 592.
Larvicidal activity against oriental armyworm (Mythimna
separata Walker). The larvicidal activity of compounds 8a0–c0
and 8a–r (8r, Fig. 1, R ¼ 2-CH3) against oriental armyworm was
tested according to the leaf-dip method using the literature
procedures.40,41 In leaf-dip bioassay, leaf disks (about 5 cm) were
cut from fresh corn leaves and dipped in insecticide solutions 10 S. Zhou, T. Yan, S. Zhou, X. W. Hua, L. X. Xiong and Z. M. Li,
for 5 s, and then air-dried on lter paper. Leaf disks dipped in Chin. J. Chem., 2014, 32, 567.
water were used as controls. Aer drying, the treated leaf disks 11 S. Zhou, Z. H. Jia, L. X. Xiong, T. Yan and Z. M. Li, J. Agric.
were placed on a bed of agar in a small Petri dish (7 cm in Food Chem., 2014, 62, 6269.
diameter). Each dried treated leaf disk was infested with 10 12 H. Hamaguchi and T. Hirooka, in Modern Crop Protection
€
third-instar oriental armyworm larvae. Percentage mortalities
were assessed 3 days later. Each treatment was performed three
times. To compare their activities, the commercial
Compounds, ed. W. Kramer, U. Schirmer, P. Jeschke and M.
Witschel, Wiley, Weinheim, Germany, 2nd edn, 2012; vol.
3, p. 1396.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 34486–34492 | 34491

View Article Online
RSC Advances
Paper
13 M. Liu, Y. Wang, Y. L. Cui, S. Z. Liu and C. H. Rui, J. Agric.
Food Chem., 2010, 58, 6858.
14 C. Gnamm, A. Jeanguenat, A. C. Dutton, C. Grimm,
D. P. Kloer and A. J. Crossthwaite, Bioorg. Med. Chem. Lett.,
2012, 22, 3800.
protection—new discoveries originating from the unique
heptauoroisopropyl group, in Fluorine in Life Sciences:
Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals,
Elsevier Academic Press, 2019, ch. 17, pp. 607–629, DOI:
10.1016/B978-0-12-812733-9.00017-9.
15 S. Zhou, X. Meng, R. Jin, Y. Ma, Y. Zhao and Z. M. Li, Mol. 31 B. H. Lipshutz, R. Moser and K. R. Voigtritter, Isr. J. Chem.,
Diversity, 2017, 21, 915. 2010, 50, 691.
16 S. Zhou, Y. C. Gu, M. Liu, B. L. Wang, L. X. Xiong, N. Yang 32 R. Masciadri, M. Kamer and N. Nock, Eur. J. Org. Chem.,
and Z. M. Li, J. Agric. Food Chem., 2014, 62, 11054. 2003, 4286.
17 M. Tohnishi, T. Nishimatsu, K. Motoba, T. Hirooka and 33 M. Tohnishi, H. Nakao, T. Furuya, T. Hirooka and
A. Seo, J. Pestic. Sci., 2010, 35, 490. T. Nishimatsu, J. Pestic. Sci., 2005, 30, 354.
18 M. Onishi, A. Yoshiura, E. Kohno and K. Tsubata, EP 34 R. Bakthavatchalam, WO 2010138879 A1, 2010.
1006102 B1, 2000.
19 M. L. Feng, Y. F. Li, H. J. Zhu, L. Zhao, B. B. Xi and J. P. Ni, J.
Agric. Food Chem., 2010, 58, 10999.
35 S. M. Masoud, A. K. Mailyan, V. Dorcet, T. Roisnel,
P. H. Dixneuf, C. Bruneau and S. N. Osipov,
Organometallics, 2015, 34, 2305.
20 Y. W. Chen, Y. X. Li, L. Pan, J. B. Liu, N. Yang, H. B. Song and 36 T. Furuya, A. Suwa, M. Nakano, S. Fujioka, N. Yasokawa and
Z. M. Li, Bioorg. Med. Chem., 2014, 22, 6366. K. Machiya, J. Pestic. Sci., 2015, 40, 38.
21 T. Masaki, N. Yasokawa, S. Fujioka, M. Tohnishi and 37 B. Grimm, C. Risko, J. D. Azoulay, J. Bredas and G. C. Bazan,
T. Hirooka, J. Pestic. Sci., 2009, 34, 37. Chem. Sci., 2013, 4, 1807.
22 Y. J. Wang, N. Kumar, P. Nuhant, M. D. Cameron and 38 B. Erickson, Chem. Eng. News, 2016, 94(10), 18.
P. R. Griffin, ACS Chem. Biol., 2010, 5, 1029. 39 Bee, Chem. Eng. News, 2016, 94(7), 20.
23 L. Li, J. W. Liu, L. S. Zhu, S. Cutler, H. Hasegawa, B. Shan and 40 S. C. Chen, Y. Zhang, Y. X. Liu and Q. M. Wang, J. Agric. Food
J. C. Medina, Bioorg. Med. Chem. Lett., 2006, 16, 1638. Chem., 2019, 67, 13544.
24 R. Narlawar, K. Baumann, C. Czech and B. Schmidt, Bioorg. 41 J. Zhang, X. H. Tang, I. Ishaaya, S. Cao, J. J. Wu, J. L. Yu, H. Li
Med. Chem. Lett., 2007, 17, 5428. and X. H. Qian, J. Agric. Food Chem., 2010, 58, 2736.
25 L. T. Kong, J. Wang, X. C. Fu, Y. Zhong, T. Luo and J. H. Liu, 42 C. J. Cui, Y. Q. Yang, T. Y. Zhao, H. M. Cai, X. C. Wan and
Carbon, 2010, 48, 1262. R. Y. Hou, Molecules, 2019, 24, 4518.
26 M. X. Wu, W. W. Zhao, G. Y. Jin, Q. C. Huang and S. Cao, 43 E. E. Mansour, G. Zhang, F. Y. Mi, Y. M. Wang and A. Kargbo,
Chin. J. Chem., 2012, 30, 1310. Pestic. Biochem. Physiol., 2012, 102, 237.
27 T. Furuya, K. Machiya, S. Fujioka, M. Nakano and 44 F. Cui, T. Chai, L. Qian and C. J. Wang, Chemosphere, 2017,
I. K. nagaki, J. Pestic. Sci., 2017, 42, 132. 169, 107.
28 K. Ramakrishna, C. Behme, R. M. Schure and C. Bieniarz, 45 Y. H. Liu, R. X. Guo, S. K. Tang, F. Y. Zhu, Z. Y. Yan and
Org. Process Res. Dev., 2000, 4, 581. J. Q. Chen, Chemosphere, 2018, 195, 542.
29 S. Lepri, L. Goracci, A. Valeri and G. Cruciani, Eur. J. Med. 46 V. Lavtizar, R. Helmus, S. A. E. Kools, D. Dolenc,
´
Chem., 2016, 121, 658.
30 M. E. Qacemi, S. Rendine, P. Maiensch, G. Haufe and
F. R. Leroux, Recent applications of uorine in crop
S. L. Waaijers and M. H. S. Kraak, Environ. Sci. Technol.,
2015, 49, 3922.
34492 | RSC Adv., 2020, 10, 34486–34492
This journal is © The Royal Society of Chemistry 2020