Synthesis and properties of pentafluorosulfanyl group (Sf5)-containing meta-diamide insecticides

Article abstract of DOI:10.3390/molecules25235536

Herein, we describe novel pentafluorosulfanyl (SF₅) group-containing meta-diamide insecticides. For the facile preparation of the SF₅-based compounds 4a–d, practical synthetic methods were applied. Among newly synthesized compounds, 3-benzamido-N-(2,6-dimethyl-4-(pentafluoro-λ⁶-sulfanyl)phenyl)-2-fluorobenzamide 4d showed (i) a high insecticidal activity, (ii) an excellent selectivity to insects, and (iii) good levels of water solubility and log P values. In this study, we demonstrated that the pentafluorosulfanyl moiety could serve as an attractive functionality for the discovery of a new scope of crop-protecting agents.

Full text of DOI:10.3390/molecules25235536

molecules
Communication
Synthesis and Properties of Pentafluorosulfanyl
Group (SF5)-Containing Meta-Diamide Insecticides
Jae Gon Kim 1, On-Yu Kang 1,2, Sang Mee Kim 1, Guldana Issabayeva 1,3, In Seok Oh 1,4
,
Yaeji Lee 1,3, Won Hyung Lee 5, Hwan Jung Lim 1,3,* and Seong Jun Park 1,
*
1
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro,
Yuseong-gu, Daejeon 34114, Korea; jgkim@krict.re.kr (J.G.K.); dhdb0901@krict.re.kr (O.-Y.K.);
smk95@krict.re.kr (S.M.K.); guldana@krict.re.kr (G.I.); ois0821@krict.re.kr (I.S.O.); leeyj@krict.re.kr (Y.L.)
Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea
Department of Medicinal and Pharmaceutical Chemistry, University of Science & Technology,
Daejeon 34113, Korea
Department of Chemistry, Sogang University, Seoul 04107, Korea
Central Research Institute, Kyung Nong Co. Ltd., 34-14 Summeori-gil, Kyongju 38175, Korea;
whlee1@dongoh.co.kr
2
3
4
5
*
Correspondence: indium@krict.re.kr (H.J.L.); sjunpark@krict.re.kr (S.J.P.); Tel.: +82-42-860-7177 (H.J.L.);
+82-42-860-7175 (S.J.P.)
Academic Editors: György Szöllösi and Eva Frank
Received: 21 October 2020; Accepted: 23 November 2020; Published: 25 November 2020
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Herein, we describe novel pentafluorosulfanyl (SF5) group-containing meta-diamide
insecticides. For the facile preparation of the SF5-based compounds 4a , practical synthetic
methods were applied. Among newly synthesized compounds, 3-benzamido-N-(2,6-dimethyl-4-
(pentafluoro-
6-sulfanyl)phenyl)-2-fluorobenzamide 4d showed (i) a high insecticidal activity, (ii) an
–
d
λ
excellent selectivity to insects, and (iii) good levels of water solubility and log P values. In this study,
we demonstrated that the pentafluorosulfanyl moiety could serve as an attractive functionality for
the discovery of a new scope of crop-protecting agents.
Keywords: meta-diamide; pentafluorosulfanyl; insecticide; GABARs
1. Introduction
The introduction of a fluorine atom into a biologically active compound can have a significant
influence on its properties. One or more incorporated fluorine atoms can alter the electrostatic and
hydrogen bonding parameters of the molecule as well as its physicochemical and pharmacokinetic
properties [
in commercial pharmaceuticals and agrochemicals, include fluoroaromatic, trifluoromethyl (CF3),
trifluoromethoxy (OCF3), and trifluoromethlythio (SCF3) functionalities [ ]. Another fluorinated
1,2]. Currently, fluorine-containing substituents, which are commonly encountered
3,4
substituent that reflects the continuing development of a relatively new fluorinated building block
with distinct properties could be the pentafluorosulfanyl (SF5) group. The SF5 group is often called the
“super-trifluoromethyl group”, and aryl sulfanyl pentafluorides display high thermal and chemical
stability, electronegativity, and lipophilicity [5–7]. Due to its unique properties, the SF5 group has
widely been applied in drug discovery and crop protection research (Figure 1) [
organic pentafluorosulfanyl compound was described in 1950 [15].
8–14], since the first
Molecules 2020, 25, 5536; doi:10.3390/molecules25235536
www.mdpi.com/journal/molecules

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Figure 1. SF5-containing biologically active compounds [8–14].
As a part of our ongoing efforts to discover new eco-friendly insecticides [16
–
18], we are particularly
interested in small molecules containing the fluorine atom. One of the outstanding representatives of
this category is broflanilide, which is known as an efficient broad-spectrum meta-diamide insecticide
containing a high number of fluorine atoms [19
,20]. Taking into account the suggested potential
bioisosteric relationship between the SF5 and CF3 substituents [2,5
], we proposed the novel design
of the SF5-containing meta-diamide insecticide 4d (Figure 2). In order to examine the influence of
SF5 moiety on the properties of the meta-diamide 4d (R1 = H, R2 and R3 = CH3) and investigate
the significance of the effect caused by the replacement of the CF(CF3)2 group to SF5 functionality,
the known meta-diamide insecticide BPB1 (R1 = H, R2 and R3 = CH3) was selected for this study
(Figure 2). According to the previous studies on the development of meta-diamide-based insecticides,
it was discovered that the insecticide BPB3 (R1 = CH3) can be metabolized to its active form, BPB1
(R1 = H), which in its turn demonstrates insecticidal activity by acting on the target RDL GABARs
gene subunit and inhibiting its expression [19,20].
Figure 2. SF5-containing meta-diamide insecticides in this study.
2. Results
The synthetic route shown in Scheme 1 was successfully applied for the preparation of the para-SF5
substituted aniline derivatives, 1b–d. The synthesis was initiated by the bromination of a commercially
available aniline, 1a using N-bromosuccinimide (NBS), which led to the formation of mono- and
di-bromo anilines 1a0 and 1a”, respectively. The molecules, 1a0 and 1a” were subsequently methylated
by the Pd-catalyzed cross-coupling to give the corresponding anilines, 1b and 1d in 64% and 75%
yields, respectively. Finally, 2-methyl-aniline 1b was further reacted with NBS in DMF to produce
2-methyl-6-bromo-aniline 1c with excellent yield [21].

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Scheme 1. Reagents and conditions: (a) for 1a0: N-bromosuccinimide (1.1 eq), DMF, rt, 2 h; for 1a”
:
NBS (2.5 eq), DMF, rt, 2 h; (b) from 1a0 to 1b: CH3B(OH)2 (2.0 eq), Pd(dppf)2Cl2, Cs2CO3, 1,4-dioxane,
reflux, 12 h; from 1a” to 1d: CH3B(OH)2 (4.0 eq), Pd(dppf)2Cl2, Cs2CO3, 1,4-dioxane, reflux, 12 h; (c)
from 1b to 1c: N-bromosuccinimide (1.5 eq), DMF, rt, 2 h.
The target compounds with the incorporated SF5 group were successfully prepared starting
from 2-fluoro-3-nitrobenzoic acid, which is commercially available and can be readily converted into
the corresponding aniline 2 [22]. Benzoylation of
excellent yield [23]. Then, SF5-containing compounds 4a
of benzoic acid 3 with 4-SF5-anilines 1a–d (Scheme 2) [24].
2
provided 3-benzamido-2-fluorobenzoic acid
3 in
–d
were easily prepared by the condensation
Scheme 2. Reagents and conditions: (a) Benzoyl chloride, NaOH, H2O, rt, 6 h; (b) SOCl2, reflux, 1 h; (c)
4-SF5-anilines 1a–d, NaHCO3, Acetone/H2O, reflux, 2 h.
The synthesized SF5-containing derivatives 4a
ppm concentration against the 3rd instar larvae of Plutella xylostella using the leaf-dip method [16
–
d
were examined for their insecticidal activities at 10
18 25].
–
,
Among them, the compounds 4c and 4d showed excellent activities with high inhibition of feeding
behaviors (entry 3 and 4, Table 1). Interestingly, 2,6-dimethyl-substituted compound 4d, SF5-containing
meta-diamide BPB1, displayed an excellent potency with eating area—0~5%. According to the data
in Table 1, it is reasonable to believe that the SF5 group can be considered as an important part of
the toxophore.
The target site specificities of newly prepared SF5-based meta-diamide insecticide 4d should
differ in insect and mammalian GABA and glycine receptors. In this regard, the cell-based antagonist
activities of the meta-diamide 4d against the human GABAAR and glycine receptor (GlyR) A1 were
investigated. According to the results obtained from previous studies, the mammalian GABAAR
α
1
β
3
γ
2 and the human glycine receptor (GlyR) A1 were selected for this study [19
Table 2, the estimated IC50 values of SF5-containing meta-diamide 4d and broflanilide against GABAAR
and GlyR were more than 30 M. This discovery implies that SF5-containing meta-diamide 4d has
much higher selectivity toward targeted insects.
,26,27]. As shown in
µ

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Table 1. Insecticidal activities of SF5-containing meta-diamide insecticides 4a
larvae of Plutella xylostella.
–d against the 3rd instar
Against the 3rd Instar Larvae of
Plutella xylostella at 10 ppm
SF5-Containing Meta-Diamide Insecticides
Entry
Larvicidal Activity (%)
at Time (h)
Eating
Area (%)
R1
R2
R3
Compound
X
72 h
96 h
96 h
1
2
3
4
5
4a
4b
4c
H
H
H
H
H
H
Br
CH3
Br
H
SF5
SF5
SF5
28
7
90
83
100
36
7
90
87
100
>30
>30
5~10
0~5
CH3
CH3
CH3
CF3
4d
SF5
Broflanilide CH3
CF(CF3)2
0~5
Table 2. Summary of the antagonist activities of SF5-containing meta-diamide insecticide 4d according
to ion channel cell-based ionflux assays of wild-type GABAARs and GlyRs.
Estimated IC50 (µM)
Entry
Receptor
SF5-Containing
Broflanilide
Meta-Diamide 4d
1
2
GABAAR α1β3γ2
>30
>30
>30
>30
GlyRA1
There are a number of studies for confirming the existence of the strong relationship between
insecticidal activity and bioavailability of the potential insecticides [18 28]. In this context,
,
SF5-containing compound 4d, which showed the highest potency, was further investigated in its
physicochemical properties, including LogP and solubility. As a reference, properties of broflanilide
were also measured. For lipophilicity, most commonly referred to as LogP [29], replacing the
heptafluoroisopropyl group with the SF5 moiety resulted in similar LogP values in broflanilide and the
meta-diamide 4d (entry 1, Table 3). In addition, both the molecules meta-diamide 4d and broflanilide
showed high levels of kinetic solubility [30].
Generally, the presence of fluoroaromatics and perfluoroalkanes increases the lipophilicity values
of the molecules in comparison to the parental hydrocarbon bonds [31–35]. In addition to that,
regarding its structural differences, the SF5 group possesses superior properties over other available
fluorine-containing functionalities. Taking into consideration that lipophilicity plays a key role in
transport processes [36], this result could be an important finding to discover new functionalities for
application in the development of crop protecting agents.

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Table 3. Physical properties of SF5-containing meta-diamide insecticide 4d.
Entry
Compound
4d
R1
R2
R3
CH3
Br
X
LogP a,b
4.68
Solubility c,d (Kinetic)
313.3 ± 1.3 µM
(153.0 ± 0.6 µg/mL)
>500 µM
1
2
H
CH3
CF3
SF5
Broflanilide CH3
CF(CF3)2
4.22
(331.6 µg/mL)
a
b
c
Using ACD/Labs T3 method (pH—metric); for graphs, please see the supporting information; Method for
determination of kinetic solubility: nephelometry; d DMSO-stock solution 5% in water [18].
3. Material and Methods
3.1. General Information
Melting points: Barnstead/Electrothermal 9300—measurements were performed in open glass
capillaries. NMR spectra: Bruker AV 300 MHz (Bruker corporation, Billerica, MA, USA)(1H-NMR:
300 MHz, 13C-NMR: 75 MHz), AV 400 MHz (1H-NMR: 400 MHz, 13C-NMR: 100 MHz), AV 500 MHz
(1H-NMR: 500 MHz, 13C-NMR: 125 MHz), and AV2 500 MHz (19F-NMR: 470 MHz); the spectra were
recorded in CDCl3 and DMSO-d6 using tetramethylsilane (TMS) as the internal standard and are
reported in ppm. 1H-NMR data are reported as follows: (s—singlet; d—doublet; t—triplet; q—quartet;
dd—doublet of doublet; m—multiplet; coupling constant(s) J are given in Hz; integration, proton
assignment). High-resolution mass spectra (HRMS): JEOL JMS-700.
2-Methyl-4-(pentafluorothio)aniline (1b) [37,38]. A mixture of 2-bromo-4-(pentafluorothio)aniline (500 mg,
3.223 mmol), methylboronic acid (2.0 eq., 6.446 mmol), Pd(dppf)Cl2.DCM (0.1 eq., 0.322 mmol),
and Cs2CO3 (3.0 eq., 9.669 mmol) in 1,4-dioxane (8.6 mL) was stirred at 105 ◦C for 5 h. The reaction
mixture was diluted with EtOAc and washed with aq. NaHCO3. The organic layer was dried over
Na2SO4 and concentrated. The residue was purified by flash column chromatography on a silica gel
(hexane:EtOAc = 15:1) to give the desired product 1b as a yellow solid (481 mg, 64%).
2-bromo-6-methyl-4-(pentafluorothio)aniline (1c). To a solution of 2-methyl-4-(pentafluorothio)aniline
(350 mg, 1.5 mmol) in DMF (15 mL), NBS (1.03 eq., 1.545 mmol) was added. The reaction mixture was
stirred at RT for 2 h, quenched with water, and extracted with EtOAc (10 mL). The organic layer was
dried over NaSO4, filtered, and concentrated. The residue was purified by column chromatography
on a silica gel (hexane:EtOAc = 20:1) to give the desired product 1c as a red solid (459 mg, 98%). mp
64~65 ◦C; 1H-NMR (500 MHz, CDCl3)
(s, 3H); 13C-NMR (100 MHz, CDCl3)
CDCl3) 86.46 (p, 1F, JSF–SF4 = 150.3 Hz, SF), 64.90 (d, 4F, JSF4–SF = 150.2 Hz, SF4); HRMS (EI) calcd. for
δ
7.71 (d, J = 2.5 Hz, 1H), 7.40 (d, J = 2.5 Hz, 1H), 4.42 (s, 2H), 2.25
δ
146.0, 144.7, 129.2, 127.9, 122.8, 107.8, 19.4; 19F-NMR (470 MHz,
δ
C7H7BrF5NS 310.9403, found 310.9409 (see Supplementary Materials).
2,6-dimethyl-4-(pentafluorothio)aniline (1d). A mixture of 2-bromo-6-methyl-4-(pentafluorothio)aniline
(200 mg, 0.64 mmol), methylboronic acid (2.0 eq., 1.28 mmol), Pd(dppf)Cl2.DCM (0.1 eq., 0.064 mmol),
and Cs2CO3 (3.0 eq., 1.92 mmol) in 1,4-dioxane (1.7 mL) was stirred at 105 ◦C for 5 h. The mixture was
diluted in EtOAc, washed with aq. NaHCO3, dried over Na2SO4, and concentrated. The residue was
purified by flash column chromatography on a silica gel (hexane:EtOAc = 15:1) to give the desired
product 1d as a brown solid (119 mg, 75%). mp 205~206 ◦C; 1H-NMR (300 MHz, CDCl3)
3.90 (s, 2H), 2.20 (s, 6H); 13C-NMR (100 MHz, CDCl3)
145.2, 144.1, 128.0, 126.5, 121.8, 120.7, 18.0;
δ 7.34 (s, 2H),
δ

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19F-NMR (470 MHz, CDCl3)
δ
87.32 (p, 1F, JSF–SF4 = 149.9 Hz, SF), 64.88 (d, 4F, JSF4–SF = 149.8 Hz, SF4);
HRMS (EI) calcd. for C8H10F5NS 247.0454, found 247.0451 (see Supplementary Materials).
3-benzamido-2-fluorobenzoic acid ( ). To 2-fluoro-3-nitro-benzoic acid (2 g, 10.8 mmol) in 44 mL of
3
tetrahydrofuran, 20% palladium hydroxide on carbon (148 mg, 1.05 mmol) was added. The reaction
was stirred under hydrogen for 2 h. The reaction mixture was filtered through a short pad of celite
and the solution was evaporated (without a purification) to give the desired compound
color solid (1.64 g, 98%). mp 257~258 ◦C; 1H-NMR (300 MHz, DMSO-d6)
13.32 (s, 1H), 10.22 (s, 1H),
8.02–7.95 (m, 2H), 7.86–7.79 (m, 1H), 7.76–7.69 (m, 1H), 7.66– 7.59 (m, 1H), 7.58–7.51 (m, 2H), 7.31 (t,
3 as an ivory
δ
J = 7.8 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6)
δ 165.5, 164.8, 133.7, 131.9, 131.1, 128.5, 128.5, 128.3,
127.8, 126.9, 123.8, 123.8; 19F-NMR (470 MHz, CDCl3) δ −119.6; HRMS (EI) calcd. for C14H10FNO3
259.0645, found 259.0638 (see Supplementary Materials).
3.2. General Method for the Synthesis of 4a–d
A mixture of 3-benzamido-2-fluorobenzoic acid
3 (50 mg, 0.193 mmol) and SOCl2 (3.0 eq.,
0.579 mmol) was refluxed for 2 h. The solution of aniline (0.9 eq., 0.174 mmol) and NaHCO3 (2.7 eq.,
0.52 mmol) in acetone/water (0.4 mL/0.04 mL) was added in the reaction mixture. The reaction mixture
was refluxed for 1 h, quenched with water, and extracted with EtOAc (10 mL). The organic layer was
dried over NaSO4, filtered, and concentrated. The residue was purified by column chromatography on
a silica gel (hexane:EtOAc = 10:1) to give the desired product.
3-Benzamido-2-fluoro-N-(4-(pentafluorothio)phenyl)benzamide (4a). This follows the general method.
The residue was purified by column chromatography on a silica gel (Hexane:EtOAc = 10:1) to give the
desired diamide 4a as a white solid (55.3 mg, 78% yield). mp 193~194 ◦C; 1H-NMR (500 MHz, CDCl3)
δ
8.63–8.57 (m, 1H), 8.44 (d, J = 12.4 Hz, 1H), 8.09 (s, 1H), 7.94–7.88 (m, 2H), 7.85–7.80 (m, 1H), 7.78 (s,
4H), 7.65–7.60 (m, 1H), 7.57–7.52 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3)
165.6,
161.3, 140.2, 133.9, 132.6, 129.1, 127.2, 127.1,127.0, 126.8, 126.4, 126.3, 125.5, 125.4, 121.3, 121.2, 119.6;
19F-NMR (470 MHz, CDCl3)
84.83 (quin, 1F, JSF–SF4, J = 150.3 Hz, SF), 63.41 (d, 4F, JSF4–SF, J = 149.8 Hz,
SF4), 131.28– 131.40 (m, 1F); HRMS (EI) calcd. for C20H14F6N2O2S 460.0680, found 460.0680 (see
δ
δ
−
−
Supplementary Materials).
3-benzamido-2-fluoro-N-(2-methyl-4-(pentafluorothio)phenyl)benzamide (4b). This follows the general
method. The residue was purified by column chromatography on a silica gel (Hexane:EtOAc = 10:1) to
give the desired diamide 4b as a white solid (54.3 mg, 73% yield). mp 189~190 ◦C; 1H-NMR (500 MHz,
CDCl3)
1H), 7.64–7.60 (m, 2H), 7.56–7.52 (m, 2H), 7.38 (t, J = 8.0 Hz, 1H), 2.42 (s, 3H); 13C-NMR (100 MHz,
CDCl3) 165.6, 160.9, 152.2, 149.8, 138.6, 134.0, 132.6, 129.0, 127.9, 127.6, 127.1, 126.9, 126.8, 126.72,
126.70, 126.46, 126.44, 125.49, 125.46, 125.0, 121.3, 121.1, 121.0, 18.0; 19F-NMR (470 MHz, CDCl3)
85.10
(t, 1F, JSF–SF4, J = 150.2 Hz, SF), 63.42 (d, 4F, JSF4–SF, J = 149.9 Hz, SF4), 132.30 (s, 1F); HRMS (EI) calcd.
for C21H16F6N2O2S 474.0837, found 474.0837 (see Supplementary Materials).
δ 8.64–8.59 (m, 1H), 8.42–8.34 (m, 2H), 8.11 (s, 1H), 7.94–7.87 (m, 3H), 7.67 (dd, J = 9.0, 2.7 Hz,
δ
δ
−
3-benzamido-N-(2-bromo-6-methyl-4-(pentafluorothio)phenyl)-2-fluorobenzamide (4c). This follows the
general method. The residue was purified by column chromatography on a silica gel
(Hexane:EtOAc = 10:1) to give the desired diamide 4c as a brown solid (51.2 mg, 54% yield). mp
209~210 ◦C; 1H-NMR (500 MHz, CDCl3)
8.69–8.63 (m, 1H), 8.17–8.07 (m, 2H), 7.94–7.89 (m, 3H),
7.89–7.83 (m, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.64–7.59 (m, 1H), 7.56–7.52 (m, 2H), 7.40–7.35 (m, 1H), 2.43
(s, 3H); 13C-NMR (100 MHz, CDCl3)
165.6, 161.0, 152.4, 149.9, 138.9, 137.0, 134.0, 132.6, 129.1, 128.0,
127.6, 127.2, 127.1, 127.0, 126.5, 126.3, 125.4, 125.3, 121.4, 120.5, 120.4, 20.0; 19F-NMR (470 MHz, CDCl3)
82.97 (quin, 1F, JSF–SF4, J = 150.5 Hz, SF), 63.35 (d, 4F, JSF4–SF, J = 150.0 Hz, SF4), 130.98 (s, 1F); HRMS
δ
δ
δ
−
(EI) calcd. for C21H15BrF6N2O2S 551.9942, found 551.9954 (see Supplementary Materials).
3-benzamido-N-(2,6-dimethyl-4-(pentafluorothio)phenyl)-2-fluorobenzamide (4d). This follows the general
method. The residue was purified by column chromatography on a silica gel (Hexane:EtOAc = 10:1) to

Molecules 2020, 25, 5536
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give the desired diamide 4d as a white solid (52.7 mg, 70% yield). mp 205~206 ◦C; 1H-NMR (500 MHz,
CDCl3) 8.60 (t, J = 7.9 Hz, 1H), 8.13 (s, 1H), 7.93–7.90 (m, 2H), 7.85–7.80 (m, 2H), 7.64–7.59 (m, 1H),
7.56–7.51 (m, 4H), 7.36 (t, J = 8.0 Hz, 1H), 2.36 (s, 6H); 13C-NMR (100 MHz, CDCl3)
165.6, 161.4, 161.3,
136.5, 136.4, 133.9, 132.5, 129.0, 127.1, 126.9, 126.8, 126.4, 126.4, 126.1, 126.15, 125.8, 125.8, 125.7, 125.3,
125.2, 18.9; 19F-NMR (470 MHz, CDCl3)
84.69 (quin, 1F, JSF–SF4, J = 150.3, SF), 63.09 (d, 4F, JSF4–SF
J = 149.7 Hz, SF4), 131.55 (s, 1F); HRMS (EI) calcd. for C22H18F6N2O2S 488.0993, found 488.0988 (see
δ
δ
δ
,
−
Supplementary Materials).
4. Conclusions
In summary, starting from the known meta-diamide BPB1 containing a heptafluoroisopropyl
group and its isosteric replacement with pentafluorosulfanyl moiety (-SF5) led to the meta-diamide
insecticide 4d, a compound with good potency, high selectivity toward insects, and a similar level of
lipophilicity with broflanilide. For the preparation of SF5-containing meta-diamide insecticides 4a–d
an efficient synthetic route was established. This study has demonstrated that the pentafluorosulfanyl
group (-SF5) could be an appealing structural scaffold for the discovery of a new crop-protecting agent.
,
Supplementary Materials: The following are available online: 1H, 13C and 19F NMR spectroscopy of compound
1c.; 1H, 13C and 19F NMR spectroscopy of compound 1d.; 1H, 13C and 19F NMR spectroscopy of compound 3.;
1H, 13C and 19F NMR spectroscopy of compound 4a.; 1H, 13C and 19F NMR spectroscopy of compound 4b.; 1H,
13C and 19F NMR spectroscopy of compound 4c.; 1H, 13C and 19F NMR spectroscopy of compound 4d.; Table
S1 and S2: Larvicidal activity against Plutella xylostella (4c and 4d); Figure S1: pH-metric Log P of compounds
4d (KI-03066); Figure S2: pH-metric Log P of Broflanilide and Figure S3. Ion Channels assay of 4d (KI-03066)
and Broflanilide.
Author Contributions: Methodology, J.G.K., H.J.L. and S.J.P.; investigation, W.H.L., H.J.L. and S.J.P.; analysis,
J.G.K., O.-Y.K., S.M.K., G.I., I.S.O., Y.L., W.H.L., H.J.L. and S.J.P.; writing—original draft preparation, H.J.L. and
S.J.P.; writing—review and editing, O.-Y.K., S.M.K., G.I., I.S.O., Y.L., H.J.L. and S.J.P. All authors have read and
agreed to the published version of the manuscript.
Funding: This work was fully supported by KRICT/Kyung Nong Co. Ltd. co-research project (TS191-06R,
TS201-18R, and SI2031-40). This research was funded by the Ministry of Trade, Industry and Energy, Republic
of Korea, grant number 10077494. This research was also supported by the Bio and Medical Technology
Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT)
(No. 2019M3E5D506617712).
Conflicts of Interest: The authors declare no conflict of interest.
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