Design, synthesis, and insecticidal evaluation of new benzoylureas containing amide and sulfonate groups based on the sulfonylurea receptor protein binding site for diflubenzuron and glibenclamide

Article abstract of DOI:10.1021/jf304468b

On the basis of the sulfonylurea receptor (SUR) protein binding site for diflubenzuron and glibenclamide, 15 new benzoylphenylureas containing amide and sulfonate groups were designed and synthesized. Their structures were characterized by ¹H n

Full text of DOI:10.1021/jf304468b

Article
pubs.acs.org/JAFC
Design, Synthesis, and Insecticidal Evaluation of New Benzoylureas
Containing Amide and Sulfonate Groups Based on the Sulfonylurea
Receptor Protein Binding Site for Diflubenzuron and Glibenclamide
Ranfeng Sun, Ziwen Wang, Yongqiang Li,* Lixia Xiong, Yuxiu Liu, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
ABSTRACT: On the basis of the sulfonylurea receptor (SUR) protein binding site for diflubenzuron and glibenclamide, 15 new
benzoylphenylureas containing amide and sulfonate groups were designed and synthesized. Their structures were characterized
1
by H nuclear magnetic resonance (NMR) and elemental analysis [or high-resolution mass spectrometry (HRMS)]. The
larvicidal activities of the new compounds against oriental armyworm and diamondback moth were evaluated. Compound II-3
showed nearly the same level of insecticidal activity against oriental armyworm as commercial insecticide flucycloxuron and, thus,
emerged as a new lead compound for the development of new benzoylurea insecticides.
KEYWORDS: Benzoylphenylureas, benzoylurea, amide, sulfonate, insecticidal activity, insect growth regulator
Bioisosterism is an effective way to design bioactive com-
pounds.12 A series of compounds A containing haloalkylsulfonyl
groups reported by Takeda Chemical Industries, Ltd. (TCI)
exhibited high insecticidal activity against pests of Lepidoptera.13
Consequently, compound II was designed according to
bioisosterism and analogue synthesis to improve the lipid
solubility and find new benzoylurea insecticides.
INTRODUCTION
■
Benzoylurea insecticides, which have been used for almost 40 years,
have been very useful in many integrated pest management (IPM)
programs because of their unique mode of action.1,2 The action
mechanism research of benzoylureas has been under way since
diflubenzuron (dimilin) was discovered in 1972.3 The initial study
results showed that incorporation of uridine diphosphate-N-
acetylglucosamine (UDP-NAGA) to chitin was clearly inhibited
in vivo or in situ (isolated integument incubated in a tissue culture
medium). However, all of the subsequent studies trying to prove
some action of benzoylureas on any part of the chitin synthesis
pathway in insects in cell-free systems (rather than in vivo and in
situ) failed.4−9 In addition, benzoylureas showed no inhibitory
actions on fungal systems in vivo as well as in cell-free systems,
which have roughly equivalent chitin synthesis pathways as insects.4
Therefore, the action mechanism of benzoylureas remained
unresolved.
Recently, Matsumura and co-workers reported that the
benzoylurea insecticide diflubenzuron acted on the same target
site on the sulfonylurea receptor (SUR) protein as a typical
sulfonylurea, glibenclamide, in Drosophila melanogaster and
Blattella germanica. Furthermore, such action by these chemicals
is the cause of their inhibitory effect on chitin synthesis.10,11 It is a
great discovery on the action mechanism research of benzoylurea
insecticides.
On the basis of the SUR protein binding site for diflu-
benzuron and glibenclamide, we found that both chemicals
have a urea fragment but glibenclamide has an amide fragment
by comparing the chemical structure of diflubenzuron to
glibenclamide (Figure 1). To find new chitin synthesis
inhibitors, compound I was designed and synthesized according
to combination principles. The results of bioevaluation showed
that compound I did not exhibit good insecticidal activities
against oriental armyworm and diamondback moth. Probably
because compound I cannot pass smoothly through the stomach
lining of the insect and reach the target site on the receptor
protein because of the strong polarity and poor lipid solubility.
MATERIALS AND METHODS
■
Instruments. 1H nuclear magnetic resonance (NMR) spectra were
obtained at 300 MHz using a Bruker AC-P300 spectrometer or at 400
MHz using a Varian Mercury Plus 400 spectrometer in CDCl3 or
DMSO-d6 solution with tetramethylsilane as the internal standard.
Chemical shift values (δ) were given in parts per million (ppm).
Elemental analyses were determined on a Yanaco CHN Corder MT-3
elemental analyzer. High-resolution mass spectrometry (HRMS) data
were obtained on a Fourier transform ion cyclotron resonance mass
spectrometry (FTICR−MS) instrument (Ionspec7.0T). The melting
points were determined on a X-4 binocular microscope melting point
apparatus (Beijing Tech Instruments Co., Beijing, China) and were
uncorrected. Yields were not optimized.
General Synthesis. The reagents were all analytically or
chemically pure. All anhydrous solvents were dried and purified by
standard techniques prior to use. 2,6-Difluorobenzoyl isocyanate was
prepared according to the literature method.14
General Synthetic Procedure for Target Compounds I-1−I-7
(Scheme 1). Synthesis of N-tert-Butyl-4-nitrobenzamide (I-1a). 4-
Nitrobenzoic acid (1.48 g, 8.9 mmol) was added to thionyl chloride
(30.0 g) and refluxed for 3 h. Then, excess thionyl chloride was
removed under vacuum, and anhydrous dichloromethane (20 mL) was
added. After the mixture was cooled to 0 °C, 2-methylpropan-2-amine
(0.78 g, 10.7 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloro-
methane (10 mL) were added dropwise. The reaction stood at room
temperature for 6 h. Then, the mixture was successively washed with 5%
Received: October 20, 2012
Revised: December 24, 2012
Accepted: December 24, 2012
Published: January 10, 2013
© 2013 American Chemical Society
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Figure 1. Design of compounds I and II.
Scheme 1. General Synthetic Procedure for Target Compounds I-1−I-7
aqueous HCl solution and saturated salt solution. The organic layer was
dried over anhydrous magnesium sulfate and filtered, and the filtrate was
concentrated under reduced pressure to give a crude product. The product
was purified by recrystallization from ethyl acetate and petroleum ether
(60−90 °C) to give compound I-1a (1.05 g, 53.0%) as a white solid.
melting point (mp) = 161−163 °C. 1H NMR (400 MHz, CDCl3) δ: 8.27
(d, 2H, J = 8.6 Hz, Ar−H), 7.87 (d, 2H, J = 8.7 Hz, Ar−H), 5.97 (brs, 1H,
NH(CH3)3), 1.49 (s, 9H, NH(CH3)3).
Synthesis of 4-Amino-N-tert-butylbenzamide (I-1b). Compound
I-1a (1.02 g, 4.6 mmol) was dissolved in ethyl acetate (35 mL), and
10% Pd/C (0.20 g, 53% moisture) was added. Hydrogen was bubbled
at room temperature through the reaction solution for 9 h. Then, the
mixture was filtered, and the filtrate was concentrated under reduced
pressure to give compound I-1b as a colorless liquid without further
purification in a nearly quantitative yield. 1H NMR (400 MHz,
CDCl3) δ: 7.56 (d, 2H, J = 8.4 Hz, Ar−H), 6.65 (d, 2H, J = 8.4 Hz,
Ar−H), 7.31 (d, 2H, J = 8.7 Hz, Ar−H), 5.82 (brs, 1H, NH(CH3)3),
3.94 (brs, 2H, NH2), 1.45 (s, 9H, NH(CH3)3).
Synthesis of N-(4-(tert-Butylcarbamoyl)phenylcarbamoyl)-2,6-
difluorobenzamide (Target Compound I-1). A solution of 2,6-
difluorobenzoyl isocyanate (0.84 g, 4.6 mmol) in dichloromethane
(20 mL) was added dropwise to a solution of I-1b (0.88 g, 4.6 mmol)
in dichloromethane (30 mL) at room temperature. The reaction
mixture was stirred at room temperature for 10 h. Then, the mixture
was filtered, and the crude product was purified by recrystallization
from ethyl acetate and petroleum ether (60−90 °C) to give compound I-1
(1.60 g, 93.0%) as a white solid. mp = 199−201 °C. 1H NMR (400 MHz,
DMSO-d6) δ: 10.61 (s, 1H, CONHCO), 9.21 (brs, 1H, CONHAr), 7.69
(d, 2H, J = 8.4 Hz, Ar−H), 7.52−7.60 (m, 3H, Ar−H), 7.06 (t, 2H, J = 8.3
Hz, Ar−H), 5.91 (s, 1H, NH(CH3)3), 1.48 (s, 9H, NH(CH3)3). Anal.
Calcd for C19H19F2N3O3: C, 60.79; H, 5.10; N, 11.19. Found: C, 60.61; H,
4.98; N, 10.98.
Compounds I-2a−I-7a, I-2b−I-7b, and I-2−I-7 were prepared
using the similar method for compounds I-1a, I-1b, and I-1,
respectively. The physical properties and 1H NMR data of compounds
I-2a−I-7a and I-2b−I-7b are listed in Table 2.
Data for N-(4-(Diisopropylcarbamoyl)phenylcarbamoyl)-2,6-difluor-
obenzamide (Target Compound I-2). White solid. Yield = 98.6%. mp =
193−196 °C. 1H NMR (400 MHz, CDCl3) δ: 10.52 (brs, 1H,
CONHCO), 9.47 (brs, 1H, CONHAr), 7.47−7.58 (m, 3H, Ar−H), 7.27
(d, J = 8.8 Hz, 2H, Ar−H), 7.06 (t, J = 8.4 Hz, 2H, Ar−H), 3.48−3.90
(m, 2H, 2(CH(CH3)2)), 1.23−1.45 (m, 12H, 2(CH(CH3)2)). Anal.
Calcd for C21H23F2N3O3: C, 62.52; H, 5.75; N, 10.42. Found: C, 62.31;
H, 5.86; N, 10.36.
Data for N-(4-((4-Chlorophenyl)(methyl)carbamoyl)-
phenylcarbamoyl)-2,6-difluoro-benzamide (Target Compound I-3).
1
White solid. Yield = 59.7%. mp = 194−196 °C. H NMR (400 MHz,
DMSO-d6) δ: 11.45 (brs, 1H, CONHCO), 10.20 (brs, 1H,
CONHAr), 7.58 - 7.66 (m, 1H, Ar−H), 7.45 (d, J = 8.4 Hz, 2H,
Ar−H), 7.34 (t, J = 8.7 Hz, 2H, Ar−H), 7.19−7.27 (m, 6H, Ar−H),
3.35 (s, 3H, CH3). Anal. Calcd for C22H16ClF2N3O3: C, 59.54; H,
3.63; N, 9.47. Found: C, 59.41; H, 3.65; N, 9.32.
Data for N-(4-(4-Chlorophenylcarbamoyl)phenylcarbamoyl)-2,6-
difluorobenzamide (Target Compound I-4). White solid. Yield =
76.7%. mp > 300 °C. 1H NMR (400 MHz, DMSO-d6) δ: 11.52 (brs, 1H,
CONHCO), 10.38 (brs, 1H, CONHAr), 10.30 (s, 1H, ArCONHAr), 7.94
(d, 2H, J = 8.2 Hz, Ar−H), 7.79 (d, J = 8.1 Hz, 2H, Ar−H), 7.71 (d, J =
8.0 Hz, 2H, Ar−H), 7.59−7.66 (m, 1H, Ar−H), 7.39 (d, J = 8.7 Hz, 2H,
Ar−H), 7.25 (t, J = 8.3 Hz, 2H, Ar−H). Anal. Calcd for C21H14ClF2N3O3:
C, 58.68; H, 3.28; N, 9.78. Found: C, 58.65; H, 3.35; N, 9.77.
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Table 1. Larvicidal Activities against Oriental Armyworm
and Diamondback Moth of Compounds I-1−I-7, II-1−II-8,
and Flucycloxuron
Table 2. Physical Properties and H NMR Data of
Compounds I-2a−I-7a and I-2b−I-7b
CONHCO), 8.78 (brs, 1H, CONHAr), 7.74 (d, J = 7.9 Hz, 2H, Ar−
H), 7.52−7.60 (m, 3H, Ar−H), 7.06 (t, 2H, J = 8.8 Hz, Ar−H), 6.07
(brs, 1H, NHCH2), 3.42 (q, J = 6.2 Hz, 2H, NHCH2CH2), 1.58−1.65
(m, 2H, CH2CH2CH2), 1.38−1.47 (m, 2H, CH2CH2CH3), 0.97
(t, 3H, J = 7.2 Hz, CH2CH2CH3). Anal. Calcd for C19H19F2N3O3: C,
60.79; H, 5.10; N, 10.12. Found: C, 60.71; H, 5.10; N, 10.90.
Data for 2,6-Difluoro-N-(4-(morpholine-4-carbonyl)-
phenylcarbamoyl)benzamide (Target Compound I-6). White solid.
a
C, concentration; P, larvicidal activity.
Data for N-(4-(Butylcarbamoyl)phenylcarbamoyl)-2,6-difluoro-
benzamide (Target Compound I-5). White solid. Yield = 92.6%.
mp = 171−173 °C. H NMR (400 MHz, CDCl3) δ: 10.59 (brs, 1H,
1
Yield = 93.0%. mp = 198−200 °C. H NMR (400 MHz, CDCl3)
δ: 10.57 (brs, 1H, CONHCO), 9.04 (brs, 1H, CONHAr), 7.51−7.57
1
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Scheme 2. General Synthetic Procedure for Target Compounds II-1−II-8
(m, 3H, Ar−H), 7.40 (d, J = 8.0 Hz, 2H, Ar−H), 7.06 (t, J = 8.8 Hz,
2H, Ar−H), 3.36−3.61 (m, 8H, (CH2)4). Anal. Calcd for
C19H17F2N3O4: C, 58.61; H, 4.40; N, 10.79. Found: C, 58.51; H,
4.65; N, 10.42.
Data for N-(4-(4-tert-Butylbenzylcarbamoyl)phenylcarbamoyl)-
2,6-difluoro-benzamide (Target Compound I-7). White solid. Yield =
86.7%. mp = 204−206 °C. 1H NMR (400 MHz, CDCl3) δ: 10.62 (brs,
1H, CONHCO), 9.12 (brs, 1H, CONHAr), 7.76 (d, J = 8.0 Hz, 2H,
Ar−H), 7.51−7.57 (m, 3H, Ar−H), 7.40 (d, J = 7.6 Hz, 2H, Ar−H),
7.31 (d, J = 7.7 Hz, 2H, Ar−H), 7.05 (t, 2H, J = 8.8 Hz, Ar−H), 6.33
(s, 1H, NHCH2), 4.62 (d, J = 4.8 Hz, 2H, CONHCH2), 1.33 (s, 9H,
C(CH3)3). Anal. Calcd for C26H25F2N3O3: C, 67.09; H, 5.41; N, 9.03.
Found: C, 67.05; H, 5.31; N, 9.18.
Data for 2-Isopropyl-5-methylcyclohexyl 4-(3-(2,6-
Difluorobenzoyl)ureido)benzenesulfonate (Target Compound II-2).
White solid. Yield = 81.6%. mp > 300 °C. 1H NMR (400 MHz,
CDCl3) δ: 10.77 (brs, 1H, CONHCO), 8.99 (brs, 1H, CONHAr),
7.87 (d, J = 8.3 Hz, 2H, Ar−H), 7.68 (d, J = 8.3 Hz, 2H, Ar−H),
7.53−7.61 (m, 1H, Ar−H), 7.07 (t, J = 8.7 Hz, 2H, Ar−H), 4.30 (td,
J = 10.8, 4.5 Hz, 1H, OCH), 2.15 (d, J = 12.0 Hz, 1H), 1.84−1.95 (m,
1H), 1.64−1.69 (m, 2H), 1.36−1.47 (m, 2H), 1.20 (m, 1H), 0.79−
1.04 (m, 8H), 0.56 (d, J = 6.9 Hz, 3H). Anal. Calcd for
C24H28F2N2O5S: C, 58.29; H, 5.71; N, 5.66. Found: C, 58.19; H,
5.79; N, 5.78.
Data for 2,2,2-Trifluoroethyl 4-(3-(2,6-Difluorobenzoyl)ureido)-
benzenesulfonate (Target Compound II-3). White solid. Yield =
1
90.7%. mp = 182−184 °C. H NMR (400 MHz, DMSO-d6) δ: 11.56
General Synthetic Procedure for Target Compounds II-1−II-
8 (Scheme 2). Synthesis of 4-Chlorophenyl 4-Nitrobenzenesulfo-
nate (II-1a). 4-Nitrobenzene-1-sulfonyl chloride (1.33 g, 6.0 mmol)
and 4-chlorophenol (0.73 g, 6.0 mmol) were dissolved in dichloro-
methane (30 mL). Then, triethylamine (0.73 g, 7.2 mmol) and N,
N-dimethylpyridin-4-amine (DMAP, 0.07 g) in dichloromethane
(10 mL) were added dropwise at room temperature. The mixture
was stirred for 10 h and then successively washed with 5% aqueous
HCl solution and saturated salt solution. The organic layer was dried
over anhydrous magnesium sulfate and filtered, and the filtrate was
concentrated under reduced pressure to give crude product. The
product was purified by recrystallization from ethyl acetate and
petroleum ether (60−90 °C) to give compound II-1a (1.57 g, 83.5%)
as a yellow solid. mp = 123−125 °C. 1H NMR (400 MHz, CDCl3) δ:
8.39 (d, J = 8.5 Hz, 2H, Ar−H), 8.04 (d, J = 8.5 Hz, 2H, Ar−H), 7.30
(d, J = 8.6 Hz, 2H, Ar−H), 6.95 (d, J = 8.6 Hz, 2H, Ar−H).
Synthesis of 4-Chlorophenyl 4-Aminobenzenesulfonate (II-1b).
Compound II-1a (1.57 g, 5.0 mmol) was dissolved in ethyl acetate
(40 mL), and 10% Pd/C (0.20 g, 53% moisture) was added. Then,
hydrogen was bubbled at room temperature through the reaction for 8
h. Then, the mixture was filtered, and the filtrate was concentrated
under reduced pressure to give compound II-1b as a white solid
without further purification in 95.8% yield. 1H NMR (400 MHz,
CDCl3) δ: 7.54 (d, J = 8.6 Hz, 2H, Ar−H), 7.24 (d, J = 8.8 Hz, 2H,
Ar−H), 6.92 (d, J = 8.7 Hz, 2H, Ar−H), 6.64 (d, J = 8.6 Hz, 2H, Ar−
H), 4.27 (brs, 2H, NH2).
(brs, 1H, CONHCO), 10.51 (brs, 1H, CONHAr), 7.96 (d, J = 8.3 Hz,
2H, Ar−H), 7.90 (d, J = 8.6 Hz, 2H, Ar−H), 7.60−7.68 (m, 1H, Ar−
H), 7.27 (t, J = 8.4 Hz, 2H, Ar−H), 4.88 (q, J = 8.6 Hz, 2H,
OCH2CF3). Anal. Calcd for C16H11F5N2O5S: C, 43.84; H, 2.53; N,
6.39. Found: C, 43.64; H, 2.73; N, 6.41.
Data for 2-Fluoroethyl 4-(3-(2,6-Difluorobenzoyl)ureido)-
benzenesulfonate (Target Compound II-4). White solid. Yield =
1
71.4%. mp = 213−215 °C. H NMR (400 MHz, DMSO-d6) δ: 11.55
(brs, 1H, CONHCO), 10.50 (brs, 1H, CONHAr), 7.87−7.92 (m, 4H,
Ar−H), 7.61−7.68 (m, 1H, Ar−H), 7.27 (t, J = 8.2 Hz, 2H, Ar−H),
4.66 (t, J = 3.7 Hz, 1H, CH2F), 4.54 (t, J = 3.7 Hz, 1H, CH2F), 4.33 (t,
J = 3.8 Hz, 1H, OCH2), 4.26 (t, J = 3.8 Hz, 1H, OCH2). HRMS (ESI)
m/z calcd for C16H13F3N2O5S (M + Na)+, 425.0398; found, 425.0390.
Data for 2-Chloroethyl 4-(3-(2,6-Difluorobenzoyl)ureido)-
benzenesulfonate (Target Compound II-5). White solid. Yield =
84.4%. mp = 206−209 °C. 1H NMR (400 MHz, CDCl3) δ: 10.81 (brs,
1H, CONHCO), 8.74 (brs, 1H, CONHAr), 7.90 (d, J = 8.2 Hz, 2H,
Ar−H), 7.74 (d, J = 8.3 Hz, 2H, Ar−H), 7.52−7.61 (m, 1H, Ar−H),
7.08 (t, J = 8.7 Hz, 2H, Ar−H), 4.27 (t, J = 5.7 Hz, 2H, OCH2CH2Cl),
3.68 (t, J = 5.6 Hz, 2H, OCH2CH2Cl). Anal. Calcd for
C16H13ClF2N2O5S: C, 45.89; H, 3.13; N, 6.69. Found: C, 45.74; H,
3.49; N, 6.72.
Data for 1,1,1,3,3,3-Hexafluoropropan-2-yl 4-(3-(2,6-
Difluorobenzoyl)ureido)benzenesulfonate (Target Compound II-6).
1
White solid. Yield = 90.7%. mp = 197−199 °C. H NMR (400 MHz,
Synthesis of 4-Chlorophenyl 4-(3-(2,6-Difluorobenzoyl)ureido)-
benzenesulfonate (Target Compound II-1). A solution of 2,6-difluoro-
benzoyl isocyanate (0.84 g, 4.6 mmol) in dichloromethane (20 mL)
was added dropwise to a solution of compound II-1b (1.30 g, 4.3 mmol)
in dichloromethane (30 mL) at room temperature. The reaction mixture
was stirred at room temperature for 12 h. Then, the mixture was filtered,
and the crude product was purified by recrystallization from ethyl acetate
to give compound II-1 (1.75 g, 81.4%) as a white solid. mp = 207−214
DMSO-d6) δ: 11.61 (brs, 1H, CONHCO), 10.60 (brs, 1H,
CONHAr), 8.05 (d, J = 8.8 Hz, 2H, Ar−H), 7.96 (d, J = 8.8 Hz,
2H, Ar−H), 7.62−7.69 (m, 1H, Ar−H), 7.28 (t, J = 8.3 Hz, 2H, Ar−
H), 6.78−6.85 (m, 1H, OCH(CF3)2). Anal. Calcd for C17H10F8N2O5S:
C, 40.33; H, 1.99; N, 5.53. Found: C, 40.36; H, 1.99; N, 5.53.
Data for 4-Chlorobutyl 4-(3-(2,6-Difluorobenzoyl)ureido)-
benzenesulfonate (Target Compound II-7). White solid. Yield =
68.2%. mp = 175−177 °C. 1H NMR (400 MHz, CDCl3) δ: 10.79 (brs,
1H, CONHCO), 8.82 (brs, 1H, CONHAr), 7.87 (d, J = 8.5 Hz, 2H,
Ar−H), 7.72 (d, J = 8.5 Hz, 2H, Ar−H), 7.54−7.61 (m, 1H, Ar−H),
7.08 (t, J = 8.6 Hz, 2H, Ar−H), 4.10 (s, 2H, CH2Cl), 3.53 (s, 2H,
OCH2), 1.84 (s, 4H, OCH2CH2CH2CH2Cl). Anal. Calcd for
C18H17ClF2N2O5S: C, 48.38; H, 3.83; N, 6.27. Found: C, 48.11; H,
3.95; N, 6.24.
1
°C. H NMR (400 MHz, DMSO-d6) δ: 11.56 (brs, 1H, CONHCO),
10.51 (brs, 1H, CONHAr), 7.90 (d, J = 8.6 Hz, 2H, Ar−H), 7.78 (d, J =
8.7 Hz, 2H, Ar−H), 7.60−7.68 (m, 1H, Ar−H), 7.47 (d, J = 8.6 Hz, 2H,
Ar−H), 7.26 (t, J = 8.3 Hz, 2H, Ar−H), 7.06 (d, J = 8.6 Hz, 2H, Ar−H).
Anal. Calcd for C20H13ClF2N2O5S: C, 51.46; H, 2.81; N, 6.00. Found: C,
51.33; H, 2.81; N, 6.00.
Compounds II-2a−II-8a, II-2b−II-8b, and I-2−I-8 were prepared
using the similar method for compounds II-1a, II-1b, and II-1. The
physical properties and 1H NMR data of compounds II-2a−II-8a and
II-2b−II-8b are listed in Table 3.
Data for Pentyl 4-(3-(2,6-Difluorobenzoyl)ureido)-
benzenesulfonate (Target Compound II-8). White solid. Yield =
87.9%. mp = 173−175 °C. 1H NMR (400 MHz, CDCl3) δ: 10.79 (brs,
1H, CONHCO), 9.07 (brs, 1H, CONHAr), 7.86 (d, J = 8.6 Hz, 2H,
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100, in which 0 = no activity and 100 = total kill. The standard
deviations of the tested biological values were 5%. LC50 values were
calculated by probit analysis.16
Table 3. Physical Properties and H NMR Data of
Compounds II-2a−II-8a and II-2b−II-8b
Larvicidal Activities against Oriental Armyworm (Mythimna
separata). The larvicidal activities of the target compounds I-1−I-7
and II-1−II-8 against oriental armyworm were evaluated by foliar
application using the reported procedure.17 For the foliar armyworm
tests, individual corn leaves were placed on moistened pieces of filter
paper in Petri dishes. The leaves were then sprayed with the test
solution and allowed to dry. The dishes were infested with 10 fourth-
instar oriental armyworm larvae. Percentage mortalities were evaluated
4 days after treatment. Each treatment was performed 3 times. The
biological data in Table 1 were the average value of the three tested
values. For comparative purposes, flucycloxuron was tested under the
same conditions.
Larvicidal Activities against Diamondback Moth (Plutella
xylostella). The larvicidal activities of the target compounds I-1−I-7
and II-1−II-8 against diamondback moth were evaluated by the
reported procedure.18 Compounds I-1−I-7 and II-1−II-8 were
prepared to different concentrations by dissolving compounds I-1−I-
7 and II-1−II-8 in dimethylformamide (DMF) and adding distilled
water. Leaf discs (5 × 3 cm) were cut from fresh cabbage leaves and
then were dipped into the test solution for 3 s. After air-drying, the
treated leaf discs were placed individually into vertical tubes and the
discs were infested with 10 s-instar diamondback moth larvae.
Percentage mortalities were evaluated 4 days after treatment. The
biological data in Table 1 were the average value of the three tested
values. For comparative purposes, flucycloxuron was tested under the
same conditions.
RESULTS AND DISCUSSION
■
Synthesis. The target compounds I-1−I-7 were synthesized
from 4-nitrobenzoic acid, as shown in Scheme 1. 4-Nitro-
benzoyl chloride was produced from 4-nitrobenzoic acid and
thionyl chloride, and subsequent reaction with a primary or
secondary amine yielded compounds I-1a−I-7a. Further
reduction using hydrogen with 10% Pd/C as a catalyst
provided compounds I-1b−I-7b, which were combined with
2,6-difluorobenzoyl isocyanate to afford compounds I-1−I-7.
The target compounds II-1−II-8 were synthesized from 4-
nitrobenzene-1-sulfonyl chloride, as shown in Scheme 2.
Compounds II-1a−II-8a were produced from 4-nitroben-
zene-1-sulfonyl chloride and different alcohol or phenol, and
further reduction using hydrogen with 10% Pd/C as a catalyst
provided compounds II-1b−II-8b, which were combined with
2,6-difluorobenzoyl isocyanate to afford compounds II-1−II-8.
Bioassay. Table 1 shows the larvicidal activities of the target
compounds I-1−I-7, II-1−II-8, and flucycloxuron against oriental
armyworm and diamondback moth. The results indicated that
benzoylureas containing amide groups did not have good larvicidal
activities against oriental armyworm and diamondback moth,
except compound I-1, which had 100% mortality against oriental
armyworm at 100 mg L−1. However, benzoylureas containing
sulfonate groups exhibited much better larvicidal activities against
oriental armyworm and diamondback moth than benzoylureas
containing amide groups. In particular, compound II-3 had 100%
mortality on oriental armyworm at 10 mg L−1 and 90% mortality
on diamondback moth at 5 mg L−1, which exhibited comparable
activity to commercial insecticide flucycloxuron. When R was 2−5
C straight-chain haloalkyl groups in the structure of compound II,
new benzoylureas exhibited better larvicidal activities against
oriental armyworm. For example, compounds II-3, II-4, and II-7
had 100% mortality at 100 mg L−1, whereas compounds II-1, II-2,
and II-6 with branched alkyl or aryl groups showed no larvicidal
activities at 200 mg L−1. Interestingly, among the sulfonates II,
compound II-3 with a 2,2,2-trifluoroethyl group exhibited the best
Ar−H), 7.69 (d, J = 8.6 Hz, 2H, Ar−H), 7.54−7.61 (m, 1H, Ar−H),
7.08 (t, J = 8.6 Hz, 2H, Ar−H), 4.04 (t, J = 6.5 Hz, 2H, OCH2CH2),
1.66 (t, J = 6.7 Hz, 2H, OCH2CH2CH2), 1.22−1.37 (m, 4H,
CH2CH2CH2CH3), 0.86 (t, J = 6.7 Hz, 3H, CH2CH3). Anal. Calcd for
C19H20F2N2O5S: C, 53.51; H, 4.73; N, 6.57. Found: C, 53.41; H, 4.86;
N, 6.61.
Biological Assay. All bioassays were performed on representative
test organisms reared in the laboratory. The bioassay was repeated at
25
1 °C according to statistical requirements. Assessments were
made on a dead/alive basis, and mortality rates were corrected using
Abbott’s formula.15 Evaluations are based on a percentage scale of 0−
521
dx.doi.org/10.1021/jf304468b | J. Agric. Food Chem. 2013, 61, 517−522

Journal of Agricultural and Food Chemistry
Article
(12) Lima, L. M. A.; Barreiro, E. J. Bioisosterism: A useful strategy for
molecular modification and drug design. Curr. Med. Chem. 2005, 12
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larvicidal activities against oriental armyworm and diamondback
moth; therefore, 2,2,2-trifluoroethyl group, which is proposed to
interact with the target protein of tested insects, did play an
important role in the insecticidal activity of benzoylureas
containing sulfonate groups.
In summary, a series of new benzoylureas containing amide
and the sulfonate groups were designed and synthesized. The
results of the bioassay showed that benzoylureas containing
sulfonate groups exhibited considerable larvicidal activities
against oriental armyworm and diamondback moth, especially
compound II-3, displaying comparable activity to commercial
insecticide flucycloxuron; thereby, compound II-3 could be
used as a lead compound for chemical modifications to find
more active benzoylurea insecticides.
(13) Hiroshi, N.; Yasuo, S. Benzoylureas, their production and use.
U.S. Patent 4,843,100, 1989.
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activity of 3′-benzoylurea derivatives of 6-phenyl-2,3,5,6-tetrahydro-
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U.S. Patent 5,117,057, 1992.
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AUTHOR INFORMATION
■
Corresponding Author
*Telephone/Fax: +86-22-23503952. E-mail: wang98h@263.net
and wangqm@nankai.edu.cn.
Funding
This work was supported by the National Key Project for Basic
Research (2010CB126106) and the National Natural Science
Foundation of China (21132003 and 21102077). We thank
China Agricultural University for the supply of some of the
chemical reagents and the National Key Technology Research
and Development Program (2012BAK25B03-3).
Notes
The authors declare no competing financial interest.
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