Synthesis, physicochemical properties, and biological activities of 4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfilimidoyl) anthranilic diamide

Article abstract of DOI:10.3390/molecules24193451

Novel anthranilic diamides with sulfilimidoyl and sulfoximidoyl functionalities were successfully prepared. Among newly-prepared organosulfur compounds, 3-bromo-1-(3-chloropyridin -2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)phenyl)-1H-pyrazole-5-

Full text of DOI:10.3390/molecules24193451

molecules
Communication
Synthesis, Physicochemical Properties, and Biological
Activities of 4-(S-Methyl-N-(2,2,2-
Trifluoroacetyl)Sulfilimidoyl) Anthranilic Diamide
Hwan Jung Lim 1, Won Hyung Lee 2 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; indium@krict.re.kr
Central Research Institute, Kyung Nong Co. Ltd., 34-14 Summeori-gil, Kyongju 38175, Kyongsangbuk-do,
Korea; whlee1@dongoh.co.kr
2
*
Correspondence: sjunpark@krict.re.kr; Tel.: +82-42-860-7175
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Paula Sério Branco, Filipa Siopa and Wim Dehaen
Received: 19 July 2019; Accepted: 19 September 2019; Published: 23 September 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Novel anthranilic diamides with sulfilimidoyl and sulfoximidoyl functionalities were
successfully prepared. Among newly-prepared organosulfur compounds, 3-bromo-1-(3-chloropyridin
-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)phenyl)-1H-pyrazole-5-carboxamide and
(S,E)-3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfinimidoyl)
-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide showed good levels of efficacy and a
strong correlation between insecticidal activities and physical properties, respectively. In particular,
available data indicated that the N-trifluoroacetyl sulfilimine moiety could be an appealing structural
scaffold for the discovery of a new crop-protecting agent.
Keywords: anthranilic diamide; sulfilimine; sulfoximine; insecticide
1. Introduction
After the discovery of sulfoxaflor by Dow AgroScience [
have received remarkable attention in crop protection. Consequently, a large number of studies
have examined the chemistry and mode of action of sulfoxaflor and sulfoximine insecticides [ ].
As shown in Figure 1, the interest in the sulfoximine moiety has led to the discovery of highly-active
1–3], compounds with sulfoximine moiety
4–8
sulfilimine-containing insecticides
sulfilimine-based anthranilic diamides
1
–
4
[
9
4
–
13]. For patent applications, researchers at BASF prepared
and reported that it is highly active in insects which are
resistant to ryanodine modulator insecticide [13]. Furthermore, various sulfoximine-containing
anthranilamides have been reported by researchers at Syngenta (Figure 1) [14 15]. In addition to
6
,
crop-protection applications, many research groups reported that sulfoximine could be a bioisostere of
sulfones and sulfonamides with enhanced absorption, distribution, metabolism, and excretion (ADME)
properties. These suggests that introducing a sulfur–nitrogen bond could be a promising approach
for the discovery of new biologically-active molecules [16
and sulfoximine-based compounds, synthetic methods and strategies have been widely investigated
by many research groups [23 27]. In particular, Bolm et al. reported facile and practical synthetic
–22]. For the preparation of sulfilimine-
–
approaches [28], which are applied in this study.
Molecules 2019, 24, 3451; doi:10.3390/molecules24193451
www.mdpi.com/journal/molecules

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Figure 1. Examples of alkyl sulfilimine- and sulfoximine-substituted insecticides [1–15].
Based on previous research and interest in sulfilimine and sulfoximine functionalities, we began
to identify these groups for the development of novel insecticides. Because alkyl sulfilimine- and
sulfoximine-substituted diamides have so far been reported in the literature (Figure 1), a more focused
exploration in our studies was sulfilimine and sulfoximine moieties directly substituted to the 4-position
on the anthranilamide ring (Figure 2). We hypothesized that better insecticidal activity could be
obtained by these small, lipophilic, electron-withdrawing substituents [1,29,30].
Figure 2. Previously-developed anthranilic diamide [31] and newly-designed insecticides in this study.
2. Results
In our previous study on a novel anthranilic diamide insecticide 7, we showed that the replacement
of N-methylcarbamoyl with O-methyl carbamate had a beneficial effect, resulting in high insecticidal
activity and low toxicity (Figure 2) [31]. Encouraged by these results, we have initially investigated the
synthesis of the sulfilimine- and sulfoximine-based diamide 15, 16 derivatives (Figure 2).
As shown in Scheme 1, the targeted compound 14 was successfully prepared using
commercially-available 3-fluoro-5-methylbenzoic acid
2-nitrobenzoic acid in good yield [29 32]. The nitrated product
aniline 11 by reaction sequence previously used [31 33 34]. Then, 2-amino-3-methyl-5-(methylthio)benzoic
acid 11 was coupled with 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid 13 12,14,33,34]
8.
Regio-selective nitration of
8 provided
9
,
9
was readily converted to thiomethylated
,
,
[
to give the desired benzoxazinone 12 in good yield [13]. After ring opening reaction of 12 with
methylamine [12,14,29,30,34], 4-methylthio anthranilamide 14 was readily obtained.

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Scheme 1. Reagents and conditions: (a) KNO3, H2SO4, RT, 1 h; (b) aqueous NaSMe (21 wt%), 150 ◦C, 18 h;
(c) Na2S2O4, THF/H2O (3:2), 60 ◦C, 0.5 h; (d) 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic
acid 13, MeSO2Cl, pyridine, CH3CN, RT, 13 h; (e) CH3NH2 (2.0 M in THF), THF, 60 ◦C, 5 h.
Next, the sulfur imination and oxidation of diamides 14 was explored (Table 1). Rhodium-catalyzed
imination of secondary amide-bearing sulfide 14 and sulfoxide 15b also provided the desired sulfilimine
15a and sulfoximine 16a, respectively (entries 1 and 2, Table 1) [28]. It is worth noting that this
metal-catalyzed imination of sulfide 14 led to a mixture of sulfilimine 15a and sulfoxide 15b (entry
1, Table 1). For the 4-sulfone group, an oxidation method using MonoPeroxyPhthalate hexahydrate
(MMPP·6H2O) easily provided the desired compound 16b (entry 3, Table 1).
Table 1. Synthesis of aryl organosulfur analogs of diamide insecticides
Substrates
Compd
Products
X
Reaction
Yield (%) b
Entry
Conditions a
Compd
Y
15a
15b
16a
16b
N-COCF3
••
••
O
29
22
43
93
Imination
14
1
O
N-COCF3
O
2
3
Imination
Oxidation
15b
14
O
a
Imination: H2NCOCF3, PhI(OAc)2, MgO, Rh2(OAc)2, CH2Cl2, 0 ◦C, 0.5 h; oxidation: MonoPeroxyPhthalate
b
hexahydrate (MMPP
compound; ••: 1 lone pair on sulfur.
·
6H2O), MeOH/CH2Cl2 (1:5), RT, overnight, after column chromatography; Compd:
For the practical test, newly-prepared compounds 14–16 were evaluated for their insecticidal
activities against the third instar larvae of Spodoptera litura according to the reported leaf-dip method [35].
In addition to sulfilimine 15a and sulfoximine 16a, all other synthetic compounds, that is, sulfide
14, sulfoxide 15b, and sulfone 16b, were also tested for their larvicidal activities (Table 2). Among
them, sulfide 14 and N-trifluoroacetyl sulfilimine 15a showed good activities with high inhibition
of feeding behaviors (eating area—14 and 15a: 5–10%, ref.: 0–5%, Table 2) (for images, please see
the Supplementary Materials). Highly sensitive and functional group specific insecticidal activities
were observed.

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Table 2. Insecticidal activities of sulfide- and N-trifluoroacetyl sulfilimine-based diamide 14 and 15a
against the third instar larvae of Spodoptera litura.
Diamides
Against the Third Instar Larvae of S. litura a
Larvicidal Activity (%) at Time
(h)
Eating Area
(%)
Entry
Compd
Functionality
72 h
96 h
96 h
1
2
3
4
5
14
sulfide
46.7
46.7
0
0
0
73.3
53.3
0
0
0
5–10
5–10
>30
>30
>30
15a
15b
16a
16b
N-trifluoroacetyl sulfilimine
sulfoxide
N-trifluoroacetyl sulfoximine
sulfone
a
Concentration of 14 and 15a was 50 ppm.
Because we believed that the physicochemical properties of newly-prepared diamides play
important roles in their insecticidal activities [14 36], the studies were extended to investigate the
bioavailability of organosulfur-based crop-protecting agents 14 15a 15b 16a, and 16b in terms of
,
,
,
,
plant systemic properties [14] and membrane permeability [36]. As references, their properties of
chlorantraniliprole and cyantraniliprole were also measured. Equilibrium solubility, log P, and parallel
artificial membrane permeability assay (PAMPA) values are reported in Figure 3 [37].
Figure 3. Physical properties of organosulfur-substituted anthranilic diamides 14–16 [38–40]: Open and
solid circles represent permeability (parallel artificial permeability assay, PAMPA) and solubility
(equilibrium), respectively; horizontal dash box describes similar permeability (PAMPA) with
chlorantraniliprole (dark yellow) and cyantraniliprole (violet); vertical dash box represents similar log
P with cyantraniliprole (violet).
Although poor water solubility was observed, sulfide 14 displayed relatively low log P and high
permeability value (black circle, Figure 3). According to the solubility and log P data, sulfoxide 15b
is believed to have hydrophilic properties (red circle, Figure 3) [41]. In the case of N-trifluoroacetyl
sulfilimine 15a and sulfoximine 16a, it seems that sulfilimine 15a is more bioavailable than sulfoximine
16a, especially considering its log P value (blue circle vs pink circle, Figure 3). In physicochemical
property tests on organosulfur-based anthranilic diamides, it has been proven that similar values (log
P and permeability) of sulfide 14 and N-trifluoroacetyl sulfilimine 15a to cyantraniliprole have resulted

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in promising insecticidal activities. It is worth noting that sulfilimine 15a has highly competitive water
solubility and permeability to cyantraniliprole, which should aid in plant uptake and translocation [29].
3. Material and Methods
General Information
Analytical thin layer chromatography (TLC) was performed on Kieselgel 60 F254 glass plates
precoated with a 0.2 mm thickness of silica gel. The TLC plates were visualized by shortwave (254 nm),
potassium permanganate, or ceric ammonium molybdate stain. Flash chromatography was carried
out with Kieselgel 60 (230 400 mesh) silica gel. Melting points: Barnstead/Electrothermal 9300,
−
measurements were performed in open glass capillaries. NMR spectra: Bruker AV 300MHz (1H-NMR:
300 MHz, 13C-NMR: 75 MHz), AV 500MHz (1H-NMR: 500 NHz, 13C-NMR: 125 MHz), AV2 500MHz
(19F-NMR: 470 MHz), the spectra were recorded in CDCl3 and DMSO-d6 using TMS as internal
1
standard and are reported in ppm. H-NMR data are reported as: (s = singlet, d = doublet, t = triplet
,
q = quartet, br = broad singlet, qui = quintet, oct = octet, m = multiplet; coupling constant(s) in Hz;
integration, proton assignment). High resolution mass spectra (HRMS): JEOL JMS-700. All solvents
were purified using a column filter solvent purification system before use unless otherwise indicated.
Reagents were purchased and used without further purification.
5-Fluoro-3-methyl-2-nitrobenzoic Acid (9)
To a solution of 3-fluoro-5-methylbenzoic acid (
8, 100 mg, 0.6488 mmol) in H2SO4 (0.8 mL) was
added potassium nitrate (72.16 mg, 0.7137 mmol) at 0 ◦C. After stirring at room temperature for 1 h,
the resulting solid was washed with H2O to give 5-fluoro-3-methyl-2-nitrobenzoic acid (
58%) as a white solid. Analytical data: lit [33].
9, 75.3 mg,
3-Methyl-5-(methylthio)-2-nitrobenzoic Acid (10)
To a solution of 5-fluoro-3-methyl-2-nitrobenzoic acid (
9
, 387.2 mg, 1.95 mmol) was add◦ed
◦
an aqueous sodium thiomethoxide (21%, 6.5 mL, 19.5 mmol) at 0 C. After stirring at 150 C
for 18 h, the reaction mixture was extracted with EtOAc. The organic layer was dried over
anhydrous MgSO4, filtered and evaporated. The resulting solid was washed with H2O to give
3-methyl-5-(methylthio)-2-nitrobenzoic acid (10, 325.5 mg, 74%). mp. 178 ◦C; 1H-NMR (300 MHz,
DMSO)
δ δ 165.4, 147.2,
7.54 (s, 1H), 7.41 (s, 1H), 2.54 (s, 3H), 2.23 (s, 3H); 13C-NMR (126 MHz, DMSO)
141.5, 130.2, 129.4, 128.8, 124.4, 16.5, 14.3.
2-Amino-3-methyl-5-(methylthio)benzoic acid (11)
To a solution of 3-methyl-5-(methylthio)-2-nitrobenzoic acid (17, 42.9 mg, 0.1888 mmo◦l) in THF
(3 mL) was added sodium hydrosulfite (75%, 219 mg, 0.9440 mmol) in H2O (2 mL) at 0 C. After
◦
stirring at 60 C for 0.5 h, the reaction mixture was extracted with EtOAc. The organic layer was
dried over anhydrous MgSO4, filtered, and evaporated. The resulting solid was washed with H2O
to give 2-amino-3-methyl-5-(methylthio)benzoic acid (11, quantitative). mp. 172 ◦C; 1H-NMR (300
MHz, DMSO)
δ 7.60 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 3.34 (br, 2H), 2.36 (s, 3H), 2.10 (s, 3H);
13C-NMR (126 MHz, DMSO) δ 169.4, 148.6, 135.9, 129.8, 124.5, 120.4, 109.7, 17.9, 17.3.
2-(3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-8-methyl-6-(methylthio)-4H-
benzo[d][1,3]oxazin-4-one (12)
To a solution of 3-bromo-1-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid (13, 432.5 mg,
1.4298 mmol) in dried acetonitrile (1 mL) was added pyridine (0.23 mL, 2.8596 mmol) and
methanesulfonyl chloride (0.16 mL, 2.1447 mmol) at 0 ◦C. After stirring at 0 ◦C for 30 min,
a solution of 2-amino-3-methyl-5-(methylthio)benzoic acid (11, 282.67 mg, 1.4298 mmol) in
dried acetonitrile and pyridine (0.35 mL, 4.2894 mmol) were added at 0 ◦C. After stirring at
room temperature for 13 h, the reaction mixture was extracted with EtOAc (200 mL). The
organic layer was dried over anhydrous MgSO4, filtered, and evaporated. The resulting
crude residue was purified by column chromatography on silica gel (EtOAc/n-Hexane, 1:1) to give
2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-8-methyl-6-(methylthio)-4H-benzo[d][1,3]oxazin-

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1
4-one (12, 481.4 mg, 73%). H-NMR (300 MHz, DMSO)
δ
8.62 (dd, J = 1.4 Hz, J = 4.7 Hz, 1H), 8.34 (dd,
J = 1.4 Hz, J = 8.1 Hz, 1H), 7.76 (dd, J = 4.7 Hz, J = 8.1 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 1.5
Hz, 1H), 7.47 (s, 1H), 2.54 (s, 3H), 1.71 (s, 3H); 13C-NMR (126 MHz, DMSO)
δ
157.7, 148.6, 147.7, 145.5,
140.5, 140.3, 139.9, 136.3, 135.8, 134.3, 128.5, 127.9, 127.3, 120.5, 117.8, 112.5, 15.8, 14.3.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)phenyl)-1H-
pyrazole-5-carboxamide (14)
To a solution of 2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-8-methyl-6-(methylthio)-4H-
benzo[d][1,3]oxazin-4-one (12, 400 mg, 0.862◦6 mmol) in THF (1.5 mL) was adde◦d methylamine solution
(2.0 M in THF, 1.4 mL, 2.8465 mmol) at 0 C. The mixture was stirred at 0 C for 5 h, the mixture
was extracted with EtOAc (200 mL). The organic layer was dried over anhydrous Na2SO4, filtered
and evaporated. The resulting crude residue was purified by column chromatography on silica gel
(CH2Cl2/MeOH, 20:1) to give 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-
(methylthio)phenyl)-1H-pyrazole-5-carboxamide (14, 263.4 mg, 62%). mp. 247 ◦C; LC/MS: Rt = 2.82
mins, m/z (ES-) = 494 (M + H for C19H17BrClN5O2S); IR (KBr):
1024, 958, 878, 861, 801, 794, 761 cm−1; 1H-NMR (300 MHz, CDCl3)
J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.17 (s, 1H), 7.05 (s, 2H), 6.26 (s, 1H), 2.92 (d, J = 3.1 Hz, 3H), 2.43 (s, 3H),
2.14 (s, 3H); 13C-NMR (126 MHz, DMSO)
167.0, 155.5, 148.3, 147.0, 139.5, 139.1, 136.8, 136.6, 134.6,
ν
1654, 1633, 1540, 1535, 1459, 1344, 1311,
δ
10.00 (s, 1H), 8.45 (s, 1H), 7.83 (d,
δ
129.3, 128.6, 127.7, 126.7, 126.5, 122.5, 110.4, 26.0, 17.7, 14.5; HRMS (EI) calcd for C19H17BrClN5O3S
494.9975, found 494.9949.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfinimidoyl)-
6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide (15a) and 3-bromo-1-(3-chloropyridin-2-yl)-
N-(2-methyl-6-(methylcarbamoyl)-4-(methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide (15b)
To a solution of 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)
phenyl)-1H-pyrazole-5-carboxamide (14, 50 mg, 0.1014 mmol) in dried CH2Cl2 (1 mL) was added
trifluoroacetamide (22.92 mg, 0.2028 mmol), magnesium oxide (16.35 mg, 0.4056 mmol), Rh◦odium(II)
acetate (2.2 mg, 0.005 mmol), and iodobenzene diacetate (49 mg, 0.1521 mmol) at 0 C. After
stirring at room temperature for 13 h, the reaction mixture was extracted with CH2Cl2 (100 mL).
The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated. The resulting
crude residue was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1) to give
3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfinimidoyl)-6-
(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide (15a, 17.9 mg, 29%) and 3-bromo-1-(3-
chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylsulfinyl)phenyl)-1H-pyrazole-5-
carboxamide (15b, 11.3 mg, 22%). 15a: mp. 199–200 ◦C; IR (KBr):
1266, 1183, 1145, 962, 801 cm−1; 1H-NMR (500 MHz, CDCl3)
10.70 (s, 1H), 8.43 (d, J = 4.6 Hz, 1H),
7.85 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.65 (s, 1H), 7.37 (dd, J = 4.7 Hz, J = 8.0 Hz, 1H), 7.14 (s, 1H), 6.93
(d, J = 4.7 Hz, 1H), 2.94 (d, J = 4.7 Hz, 3H), 2.86 (s, 3H), 2.24 (s, 3H); 13C-NMR (125 MHz, CDCl3)
ν 1635, 1535, 1465, 1413, 1354, 1302,
δ
δ
166.0, 164.6 (q, CF3CO, J = 33.4 Hz), 155.4, 148.2, 147.0, 139.2, 139.1, 138.2, 136.6, 135.5, 131.2, 130.3,
127.7, 126.8, 126.5, 124.6, 116.8 (q, CF3, J = 289.8 Hz), 110.8, 32.8, 26.0, 17.9; 19F NMR (470 MHz, CDCl3)
δ
-73.28 ppm; HRMS (EI) calcd for C21H17BrClF3N6O3S 603.9907, found 603.9898. 15b: mp. 155 ◦C; IR
(KBr):
CDCl3)
J = 1.7 Hz, 1H), 7.38 (dd, J = 4.7 Hz, J = 8.0 Hz, 2H), 7.09 (s, 1H), 6.70 (d, J = 4.7 Hz, 1H), 2.97 (d, J = 4.8
Hz, 3H), 2.67 (s, 3H), 2.27 (s, 3H); 13C-NMR (125 MHz, CDCl3)
168.3, 155.7, 149.0, 146.9, 143.0, 139.0,
ν
1654, 1636, 1533, 1459, 1355, 1344, 1297, 1241, 1041, 1024, 959, 797 cm−1; 1H NMR (500 MHz,
10.64 (s, 1H), 8.46 (dd, J = 1.5 Hz, J = 4.7 Hz, 1H), 7.85 (dd, J = 1.5 Hz, J = 8.0 Hz, 1H), 7.71 (d,
δ
δ
138.9, 137.7, 136.8, 130.2, 129.0, 128.3, 128.3, 125.8, 119.6, 111.0, 44.0, 26.9, 19.6; HRMS (EI) calcd for
C19H17BrClN5O3S 508.9924, found 508.9893.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl)
-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide (16a)
To a solution of 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-
(methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide (15b, 30 mg, 0.0587 mmol) in dried CH2Cl2 (1 mL)
was added trifluoroacetamide (13.28 mg, 0.1175 mmol), magnesium oxide (9.46 mg, 0.2348 mmol),

Molecules 2019, 24, 3451
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Rhodium(II) acetate (1.3 mg, 0.003 mmol), and iodobenzene diacetate (28.36 mg, 0.0881 mmol) at
0 ◦C. After stirring at room temperature for 12 h, the reaction mixture was extracted with CH2Cl2
( 2). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The resulting
×
crude residue was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1) to give
3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-(S-methyl-N-(2,2,2-trifluoroacetyl)sulfonimidoyl)-6-
(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide (16a, 15.7 mg, 43%). mp. 213.3 ◦C; IR (KBr):
ν
1678, 1640, 1545, 1468, 1411, 1367, 1315, 1239, 1177, 1151, 1111, 994, 963, 838 cm−1; 1H-NMR (300 MHz,
CDCl3) 10.79 (s, 1H), 8.46 (dd, J = 1.5 Hz, J = 4.7 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 1.5 Hz,
J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.39 (dd, J = 4.7 Hz, J = 8.0 Hz, 1H), 7.09 (s, 1H), 6.50 (s, 1H), 3.41 (s, 3H),
3.01 (d, J = 4.9 Hz, 3H), 2.32 (s, 3H); 13C-NMR (125 MHz, CDCl3)
167.5, 164.1 (CF3CO), 155.5, 148.8,
δ
δ
146.9, 140.5, 139.1, 138.8, 138.4, 133.4, 131.4, 130.1, 129.1, 128.4, 125.9, 123.5, 115.8 (q, CF3, J = 288.5 Hz),
111.3, 44.2, 27.1, 19.9; 19F NMR (471 MHz, CDCl3)
619.9856, found 619.9852.
δ -76.90 (s); HRMS (EI) calcd for C21H17BrClF3N6O4S
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylsulfonyl)phenyl)-
1H-pyrazole-5-carboxamide (16b)
To a solution of 3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylthio)
phenyl)-1H-pyrazole-5-carboxamide (14, 30 mg, 0.0609 mmol) in MeOH/CH2Cl2 (1:5, 1 mL) was
added magnesium bis(monoperoxyphthalate) hexahydrate (80%, 75.25 mg, 0.1217 mmol) at 0
◦C. After stirring at room temperature for 18 h, the reaction mixture was extracted with EtOAc
( 2). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The resulting
×
crude residue was purified by column chromatography on silica gel (EtOAc/n-Hexane, 3:1) to give
3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(methylcarbamoyl)-4-(methylsulfonyl)phenyl)-1H-
pyrazole-5-carboxamide (16b, 29.9 mg, 93%). mp. 122 ◦C; IR (KBr):
ν
1662, 1543, 1464, 1411, 1342, 1307,
10.54 (br, 1H), 8.50 (dd, J = 1.3 Hz, J = 4.7 Hz,
1H), 8.17 (dd, J = 1.3 Hz, J = 8.1 Hz, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.61 (dd, J = 4.7 Hz, J = 8.1 Hz, 1H),
7.41 (s, 1H), 3.22 (s, 3H), 2.69 (d, J = 4.5 Hz, 3H), 2.26 (s, 3H); 13C-NMR (126 MHz, DMSO)
166.2,
1141, 962, 796, 764 cm−1; 1H-NMR (300 MHz, DMSO)
δ
δ
155.5, 148.3, 147.2, 139.4, 139.2, 138.5, 137.8, 137.4, 134.6, 130.1, 127.9, 126.9, 126.7, 124.5, 110.9, 43.5, 26.2,
18.1; HRMS (EI) calcd for C19H17BrClN5O4S 524.9873, found 524.9844.
4. Conclusions
In summary, novel anthranilic diamides, in which organosulfur groups were substituted at
the 4-position on the phenyl ring, were prepared and tested for their insecticidal activities and
physical properties. For preparation of the target molecules, we expanded reported sulfur imination
procedures [28] to amide groups containing sulfide 14. Our results concerning the relationship between
insecticidal activities and physical properties showed that a better bioavailability profile (relatively
low log P and high permeability) results in efficacy of sulfide 14 and sulfilimine 15a (Table 2 and
Figure 3). Due to its higher water solubility, N-trifluoroacetyl sulfilimine 15a could be considered
the most promising candidate for discovery of a new diamide insecticide. Notably, these studies
have demonstrated that changing the substituents on sulfur atoms could lead to compounds with the
desired physicochemical property profiles. Among organosulfur groups, N-trifluoroacetyl sulfilimine
motif brings about desired properties such as solubility, lipophilicity, and permeability.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/19/3451/s1,
Figure S1: 1H, 13C, and 19F NMR of compounds
9
–
16, Figure S2: pH-metric log P of compounds 14–16, Table S1:
Larvicidal activity depend on time, Table S2: Picture of eating area.
Author Contributions: Methodology, H.J.L., W.H.L. and S.J.P.; investigation, H.J.L. and S.J.P.; analysis: H.J.L.,
W.H.L. and S.J.P.; writing—original draft preparation, S.J.P.; writing—review and editing, H.J.L. and S.J.P.
Funding: This work was fully supported by KRICT/ Kyung Nong Co. Ltd. co-research project (TS171-09R,
TS181-10R, TS191-06R, and KK1932-30). This research was funded by Ministry of Trade, Industry and Energy,
Republic of Korea, grant number 10052734 and 10077494.
Conflicts of Interest: The authors declare no conflict of interest.

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2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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