Design, synthesis, and bioactivity study of novel benzoylpyridazyl ureas

Article abstract of DOI:10.1021/jf900882c

A series of novel benzoylpyridazyl ureas were designed and synthesized from maleic anhydride and hydrazine monohydrate. These benzoylureas were identified by ¹H NMR spectroscopy and element analysis. The bioactivities of the new compounds were evaluated. These compounds exhibited larvicidal activities against oriental armyworm, and in particular, compound 13 displayed comparable activity to the commercial insecticide Hexaflumuron. Most of these compounds also had some larvicidal activities against mosquito. Interestingly, some compounds showed good plant growth regulatory activities.

Full text of DOI:10.1021/jf900882c

6356 J. Agric. Food Chem. 2009, 57, 6356–6361
DOI:10.1021/jf900882c
Design, Synthesis, and Bioactivity Study of Novel
Benzoylpyridazyl Ureas
R
ANFENG
SUN, YONGLIN
Z
HANG, FUCHUN
B
I
,
AND
Q
INGMIN
W
ANG*
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, People’s Republic of China
A series of novel benzoylpyridazyl ureas were designed and synthesized from maleic anhydride and
1
hydrazine monohydrate. These benzoylureas were identified by H NMR spectroscopy and element
analysis. The bioactivities of the new compounds were evaluated. These compounds exhibited
larvicidal activities against oriental armyworm, and in particular, compound 13 displayed comparable
activity to the commercial insecticide Hexaflumuron. Most of these compounds also had some
larvicidal activities against mosquito. Interestingly, some compounds showed good plant growth
regulatory activities.
KEYWORDS: Benzoylphenyl ureas (BPUs); benzoylurea; benzoylpyridazyl ureas; larvicidal activity;
plant growth regulating activities; insect growth regulator
400 spectrometer in CDCl3 solution with tetramethylsilane as the inter-
INTRODUCTION
nal standard. Chemical shift values (δ) are given in parts per million.
The control of insects is of vital importance to the feeding of an
ever-growing poplulation. It is well-known that insects at the
larval stage, such as those belonging to the order of Lepidoptera,
cause extensive damage to many crops (1). Benzoyl ureas repre-
sent a class of pesticide that act as insect growth regulators
(IGRs), which act on the larval stages of most insects by inhibiting
orblockingthesynthesis ofchitin, a vitalandalmost indestructible
part of the insect exoskeleton during the molting stage; therefore,
the failure to successfully cast off the old exoskeleton leads to the
eventual death of the larvae (2, 3). During the past decades,
benzoylureas have attracted considerable attention (4-11).
L-7063 and EL-494 (Figure 1) are two commercial products of
Eli Lilly Co., which contain pyrazinal groups. L-7063 displays
excellent larvicidal activities against the order of Lepidoptera and
shows good systemic activities (1). Aryloxyphenyl and (haloalk-
oxy)phenyl benzoylureas such as Flufenoxuron and Hexaflumur-
on (Figure 1) exhibited better larvicidal activities and had a
broader spectrum of control of insects than diflubenzuron. For
example, the larvicidal activity of Flufenoxuron against Tetrany-
chus cinnabarinus was >100 times higher than that of Difluben-
zuron (12,13). Bioisosterism is an effective way to design bioactive
compounds and used in the design of benzoylurea com-
pounds (14, 15). Building on these developments (Figure 1 and
bioisosterism, which is a method for selecting molecular groups for
drug design and lead-compound development, a series of novel
benzoylpyridazyl ureas (Figure 1) were designed and synthesized.
The bioactivities of the new compounds were evaluated.
Elemental analyses were determined on
a Yanaca CHN Corder
MT-3 elemental analyzer. The melting points were determined on an
X-4 binocular microscope melting point apparatus (Beijing Tech Instru-
ments Co., Beijing, China) and are uncorrected. Yields were not opti-
mized.
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 (16).
Synthesis of 1,2-Dihydropyridazine-3,6-dione (I-1). To a solution
of hydrazine monohydrate (6.0 g, 120 mmol) in water (50 mL) cooled with
an ice-water bath was slowly added concentrated hydrochloric acid
(9.6 g), and then maleic anhydride (9.8 g, 100 mmol) was added. Then
the mixture was heated under reflux for 3 h. When the mixture was cooled
to room temperature, a white solid was separated out from the reaction
solution, which was filtered and washed with water to obtain intermediate
I-1 (9.6 g, 86%): mp 301-302 °C [lit. 299-300 °C (17)].
Synthesis of 3,6-Dichloropyridazine (I-2). Phosphorus oxychloride
(40 mL) was added to compound I-1 (9.6 g, 85.7 mmol), and the mixture
was heated at 90 °C for 4 h. Then the excess phosphorus oxychloride was
removed under reduced pressure, and crushed ice (20 g) and water (20 mL)
were added; sodium bicarbonate was slowly added to the mixture until the
neutralization reaction was completed. The mixture was extracted by ethyl
acetate. The organic extract was dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to give a crude product, which was
purified by flash column chromatography on silica gel to give compound I-
2 (10.8 g, 85%) as a white solid: mp 68-69 °C; 1H NMR (400 MHz,
CDCl3) δ 7.50 (s, 2H).
Synthesis of 6-Chloropyridazin-3-amine (I-3). Ammonium was
bubbled into the anhydrous ethanol (100 mL) below -15 °C to make an
ammonia-saturated ethanol solution. This ammonia-saturated ethanol
solution (100 mL) was added to intermediate I-2 (13.6 g, 84.6 mmol) in
an autoclave, and the mixture was heated at 130 °C for 20 h under
sealed condition. Then the mixture was cooled to room temperature, and
the solvent was removed under reduced pressure to give a crude
product, which was dissolved in ethyl acetate. The ethyl acetate solution
was washed with saturated brine, dried over anhydrous sodium sulfate,
MATERIALS AND METHODS
Instruments. 1H NMR spectra were obtained at 300 MHz using a
Bruker AC-P300 spectrometerorat400 MHz using a Varian Mercury Plus
*Author to whom correspondence should be addressed [telephone
þ86-(0)22-23499842; fax þ86-(0)22-23499842; e-mail wang98h@263.
net or wangqm@nankai.edu.cn].
pubs.acs.org/JAFC
Published on Web 06/23/2009
© 2009 American Chemical Society

Article
J. Agric. Food Chem., Vol. 57, No. 14, 2009 6357
Figure 1. Commercial products of benzoylpyrizinyl ureas and benzoylphenyl ureas, designed benzoylpyridazyl ureas.
Table 1. Experimental Data of Compounds I-4b-I-4ma
a /, not tested.
filtered, and concentrated in vacuo to give compound I-3 (7.9 g, 67%) as a
colorless crystal: mp 229-231 °C; 1H NMR (300 MHz, CDCl3) δ 4.75 (br s,
2H, NH2), 6.75 (d, 3JHH=9.2 Hz, 1H, Ar-H), 7.22 (d, 3JHH=9.2 Hz, 1H,
Ar-H).
Synthesis of 6-(4-Chlorophenoxy)pyridazin-3-amine (I-4a). To a
mixture of sodium hydroxide (0.31 g, 7.8 mmol) and 4-chlorophenol
(1.00 g, 7.8 mmol) in water (10 mL) in the autoclave was added
intermediate I-3 (0.50 g, 3.9 mmol), and then the mixture was heated at
190 °C for 20 h under sealed condition. Then the mixture was cooled to
room temperature and extracted by ethyl acetate. The organic extract was
washed with saturated brine, dried over anhydrous sodium sulfate, and
filtered. The filtrate was concentrated in vacuo to give a crude product,

6358 J. Agric. Food Chem., Vol. 57, No. 14, 2009
Sun et al.
Table 2. Physical Properties and Elemental Analyses of Compounds 2-14
Table 3. 1H NMR (CDCl3) of Compounds 2-14
compd
δ
2
2.36 (s, 3H, ArCH3), 7.05 (t, 3JHH = 3JHF = 8.4 Hz, 2H, Ar-H), 7.08 (d, 3JHH = 8.5 Hz, 2H, Ar-H), 7.16 (d, 3JHH = 9.5 Hz, 1H, Ar-H), 7.21 (d, 3JHH = 8.4 Hz, 2H, Ar-H),
7.46-7.58 (m, 1H, Ar-H), 8.26 (br, 1H, CONHAr), 8.33 (d, 3JHH = 9.4 Hz, 1H, Ar-H), 11.11 (br, 1H, CONHCO)
3
3.82 (s, 3H, OCH3), 6.93 (d, 3JHH = 9.0 Hz, 2H, Ar-H), 7.05 (t, 3JHH = 3JHF = 8.4 Hz, 2H, Ar-H), 7.13 (d, 3JHH = 9.0 Hz, 2H, Ar-H), 7.16 (d, 3JHH = 9.5 Hz, 1H, Ar-H),
7.48-7.58 (m, 1H, Ar-H), 8.31 (d, 3JHH = 9.5 Hz, 1H, Ar-H), 8.35 (br, 1H, CONHAr), 11.11 (br, 1H, CONHCO)
7.06 (t, 3JHH = 3JHF = 8.6 Hz, 2H, Ar-H), 7.11 (d, 3JHH = 8.8 Hz, 2H, Ar-H), 7.21(d, 3JHH = 9.4 Hz, 1H, Ar-H), 7.48-7.58 (m, 1H, Ar-H), 7.53 (d, 3JHH = 8.6 Hz, 2H,
Ar-H), 8.31 (br, 1H, CONHAr), 8.37 (d, 3JHH = 9.4 Hz, 1H, Ar-H), 11.16 (br, 1H, CONHCO)
4
5
7.06 (t, 3JHH = 3JHF =8.4 Hz, 2H, Ar-H), 7.38(d, 3JHH = 9.5 Hz, 1H, Ar-H), 7.42 (s, 2H, Ar-H), 7.48-7.58 (m, 1H, Ar-H), 8.20 (br, 1H), 8.46 (d, 3JHH = 9.5 Hz, 1H, Ar-H,
CONHAr), 11.16 (br, 1H, CONHCO)
6
7.06 (t, 3JHH = 3JHF = 8.4 Hz, 2H, Ar-H), 7.29-7.32 (m, 3H, Ar-H), 7.45(d, 4JHH = 2.2 Hz, 1H, Ar-H), 7.50-7.58 (m, 1H, Ar-H), 8.16 (br, 1H, CONHAr), 8.43 (d, 3JHH
9.5 Hz, 1H, Ar-H), 11.14 (br, 1H, CONHCO).
=
7
7.05 (t, 3JHH = 3JHF = 8.4 Hz, 2H, Ar-H), 7.18-7.39 (m, 4H, Ar-H), 7.46-7.58 (m, 2H, Ar-H), 8.36 (d, 3JHH = 9.5 Hz, 1H, Ar-H), 8.45 (br, 1H, CONHAr), 11.14 (br, 1H,
CONHCO)
8
5.12 (s, 2H, OCH2Ar), 7.05 (t, 3JHH = 3JHF = 8.3 Hz, 2H, Ar-H), 7.06 (d, 3JHH = 9.6 Hz, 1H, Ar-H), 7.36 (d, 3JHH = 8.5 Hz, 2H, Ar-H), 7.44 (d, 3JHH = 8.5 Hz, 2H, Ar-H),
7.48-7.58 (m, 1H, Ar-H), 8.27 (d, 3JHH = 9.5 Hz, 1H, Ar-H), 8.28 (br, 1H, CONHAr), 11.13 (br, 1H, CONHCO)
1.45 (t, 3JHH = 7.0 Hz, 3H, CH3CH2), 4.56 (q, 3JHH = 7.0, 2H, CH3CH2O), 6.98 (d, 3JHH = 9.5 Hz, 1H, Ar-H), 7.04 (t, 3JHH = 3JHF = 8.3 Hz, 2H, Ar-H), 7.46-7.58 (m, 1H,
Ar-H), 8.19 (d, 3JHH = 9.5 Hz, 1H, Ar-H), 8.63 (br, 1H, CONHAr), 11.18 (br, 1H, CONHCO)
9
10
11
12
13
14
1.41 (d, 3JHH = 6.1 Hz, 6H, OCH(CH3)2), 5.47-5.49 (m, 1H, OCH(CH3)2), 6.92 (d, 3JHH = 9.5 Hz, 1H, Ar-H), 7.04 (t, 3JHH = 3JHF = 8.3 Hz, 2H, Ar-H), 7.46-7.56 (m, 1H,
Ar-H), 8.15 (d, 3JHH = 9.5 Hz, 1H, Ar-H), 8.70 (br, 1H, CONHAr), 11.15 (br, 1H, CONHCO)
1.44-1.54 (m, 5H, CH3CH2CH2CH2O), 1.72-1.79 (m, 2H, CH3CH2CH2CH2O), 3.32 (t, 3JHH = 7.4 Hz, 2H, CH3CH2CH2CH2O), 7.05 (t, 3JHH = 3JHF = 8.4 Hz, 2H, Ar-H),
7.32 (d, 3JHH = 9.4 Hz, 1H, Ar-H), 7.50-7.57 (m, 1H, Ar-H), 8.10 (d, 3JHH = 9.4 Hz, 1H, Ar-H), 8.36 (br, 1H, CONHAr), 11.15 (br, 1H, CONHCO)
7.04 (t, 3JHH = 3JHF = 8.4 Hz, 2H, Ar-H), 7.09 (d, 3JHH = 9.4 Hz, 1H, Ar-H), 7.41-7.46 (m, 3H, Ar-H), 7.47-7.54 (m, 1H, Ar-H), 7.57-7.63 (m, 2H, Ar-H), 8.10 (d,
3JHH = 8.4 Hz, 1H, Ar-H), 8.43 (br, 1H, CONHAr), 11.20 (br, 1H, CONHCO)
4.90 (q, 3JHF = 8.3 Hz, 2H, CF3CH2O), 7.04 (t, 3JHH = 3JHF = 8.5 Hz, 2H, Ar-H), 7.15 (d, J = 9.5 Hz, 1H, Ar-H), 7.50-7.57 (m, 1H, Ar-H), 8.32 (d, 3JHH = 9.5 Hz, 1H,
Ar-H), 8.53 (br, 1H, CONHAr), 11.18 (br, 1H, CONHCO)
2.65 (s, 3H, ArCH3), 7.05 (t, 3JHH = 3JHF = 8.6 Hz, 2H, Ar-H), 7.34 (d, 3JHH = 9.1 Hz, 1H, Ar-H), 7.47-7.57 (m, 1H, Ar-H), 8.24 (d, 3JHH = 9.1 Hz, 1H, Ar-H), 8.59 (br,
1H, CONHAr), 11.44 (br, 1H, CONHCO)

Article
J. Agric. Food Chem., Vol. 57, No. 14, 2009 6359
which was purified by flash column chromatography on silica gel to give
compound I-4a (0.39 g, 46%) as a white solid: mp 203-207 °C; 1H NMR
(300 MHz, CDCl3) δ 4.54 (br s, 2H, NH2), 6.85 (d, 3JHH=9.3 Hz, 1H, Ar-
H), 7.00 (d, 3JHH=9.3 Hz, 1H, Ar-H), 7.10 (d, 3JHH=8.9 Hz, 2H, Ph),
7.32 (d, 3JHH = 8.9 Hz, 2H, Ph).
Compounds I-4b-I-4m were prepared according to a method similar to
that of compound I-4a. When sodium alkoxide was used as a nucleophile,
the corresponding alkyl alcohol was used as the solvent. The experimental
data of compounds I-4b-I-4m are listed in Table 1.
Synthesis of Target Compound 1. A solution of 2,6-difluorobenzoyl
isocyanate (0.18 g, 1.0 mmol) in dichloromethane (5 mL) was added
dropwise to a solution of compound I-4a (0.22 g, 1.0 mmol) in dichloro-
methane (10 mL) at room temperature, and the mixture was allowed to
stand for 2 h. Then part of the solvent was removed in vacuo, and the
precipitated solid was filtered to give a white solid (0.22 g, 55%): mp 208-
210 °C; 1H NMR (300 MHz, CDCl3) δ 7.06 (t, 3JHH= 3JHF=8.4 Hz, 2H,
Ar-H), 7.16 (d, 3JHH=8.9 Hz, 2H, Ar-H), 7.22 (d, 3JHH=9.5 Hz, 1H,
Ar-H), 7.38 (d, 3JHH=8.9 Hz, 2H, Ar-H), 7.49-7.59 (m, 1H, Ar-H),
8.27 (br, 1H, CONHAr), 8.38 (d, 3JHH=9.5 Hz, 1H, Ar-H), 11.15 (br, 1H,
CONHCO). Anal. Calcd. for C18H11ClF2N4O3: C, 53.41; H, 2.47; N,
13.84. Found: C, 53.35; H, 2.89; N, 13.85.
Compounds 2-14 were prepared according to a method similar to
that of compound 1. The physical properties, elemental analyses of
title compounds 2-14, and their 1H NMR data are listed in Tables 2
and 3.
Figure 2. General synthetic procedure for compounds 1-13.
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 (18). Evaluations are based on a percentage scale of
0-100, in which 0=no activity and 100=total kill. The deviation of values
was (5%.
Figure 3. Synthetic procedure for compound 14.
Larvicidal Activity against Oriental Armyworm (Mythimna
separata). The larvicidal activities of compounds 1-14 against oriental
armyworm were evaluated by foliar application using the reported
procedure (19-21). 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 (the test compound was
resolved in acetone) 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 three
times. For comparative purposes, Hexaflumuron was tested under the
same condition.
in Figure 2. Then compound I-1 was treated with phosphorus
oxychloride to give intermediate I-2, which was reacted with
ammonia to yield compound I-3. The nucleophilic substitution of
intermediate I-3 produced compounds I-4a-I-4m, which were
combined with 2,6-difluorobenzoyl isocyanate to obtain the target
compounds 1-13. It was found that intermediate I-1 was not
obtained without hydrochloric acid, and the reaction temperature
had an important effect on the yield of compound I-3 because a lot
of black byproducts were produced if the reaction temperature
exceeded 95 °C. The nucleophilic aromatic substitution of inter-
mediate I-3 was accomplished in sealed condition because of the
difficulty of substituting the chloride atom on the pyridazine ring in
the presence of the amino group.
Larvicidal Activity against Mosquito (Culex pipiens pallens). The
larvicidal activity of compounds 1-10, 13, and 14 was evaluated against
mosquito according to the reported procedure (22). The test solutions were
prepared by dissolving the compound in acetone and adding distilled
water. Ten fourth-instar mosquito larvae were put into the 10 mL of the
test solution and left for 8 days. The results are expressed as percentage
mortality. For comparative purposes, Hexaflumuron was tested under the
same condition.
Compound 14 was obtained from the combination between
6-methylpyridazin-3-amine and 2,6-difluorobenzoyl isocyanate
as shown in Figure 3.
Plant Growth Regulatory Activity Assay. The plant growth
regulatory activities of compounds 1-7 and 14 were evaluated using
previously reported procedures (23-25). Seeds of cucumber were
incubated at 26 °C in the dark for 72 h, and 10 cotyledons were cut off.
N,N-Dimethylformamide solutions of the test compounds were prepared
at concentrations of 10 mg/L. The experiments were conducted in sterile
Petri dishes (6 cm diameter) lined with a sheet of filter paper. To each dish
was added 0.3 mL of the test solution, and the solvent was evaporated
before the addition of 3 mL of water, followed by the above cotyledons.
Assays were carried out at 26 °C in the dark in an incubator for 5 days. The
number of roots was counted, and the growth regulatory activities were
evaluated. Controls were performed under the same conditions, using only
water. Each treatment was performed in triplicate. Hexaflumuron was
tested under the same condition.
Biological Activity. Table 4 shows the larvicidal activities of
compounds 1-14 and Hexaflumuron against oriental armyworm
and mosquito. The results indicate that most of the compounds
1-14 exhibited larvicidal activities against oriental armyworm
and mosquito. One the whole, the larvicidal activities of the
alkyloxy-substituted benzoylpyridazyl ureas against oriental
armyworm were better than those of aryloxy-substituted com-
pounds. For example, compounds 9, 10, and 13 displayed higher
larvicidal activities against oriental armyworm than compounds
1-7. In particular, compound 13 had 80% mortality on oriental
armyworm at 10 mg L-1, which exhibited comparable activity
with commercial Hexaflumuron. Compound 4 exhibited best
larvicidal activities against mosquito in the tested compounds,
which had 90% mortality even at 1 mg L-1, but was not as
effective as Hexaflumuron, which showed 100% mortality at
0.25 mg L-1. The plant growth regulatory activities of com-
pounds 1-7 and 14 were evaluated, and their effects on the radi-
cle growth of cucumber are shown in Table 5. Interestingly,
RESULTS AND DISSCUSSION
Synthesis. 1,2-Dihydropyridazine-3,6-dione (I-1) was synthe-
sized from maleic anhydride and hydrazine monohydrate as shown

6360 J. Agric. Food Chem., Vol. 57, No. 14, 2009
Sun et al.
Table 4. Larvicidal Activities against Oriental Armyworm and Mosquito of Compounds 1-14 and Hexaflumurona
a *, Larivicidal activity was calculated according to the following equation: larvicidal activity (%) = numbers of dead insects ꢀ 100/numbers of total insects. /, not tested.
some compounds showed good stimulation of radicle growth of
cucumber, such as compounds 5 and 7, which, respectively, gave
130 and 105% promotion, whereas Hexaflumuron gave only
65% growth promotion.
In summary, a series of novel alkyloxy(thio)- or aryloxy-
substituted benzoylpyridazyl ureas were designed and synthe-
sized, and their structures were characterized by 1H NMR
and elemental analysis. The larvicidal activities against oriental
armyworm and mosquito and plant growth regulatory activities
of these benzoylpyridazyl ureas were evaluated. The results
indicate that most of the compounds 1-14 exhibited larvicidal
activities against oriental armyworm and mosquito. In particular,
compound 13 exhibited activity against oriental armyworm
comparable with that of the commercial Hexaflumuron. Inter-
estingly, some compounds showed good stimulation of radicle
growth of cucumber.

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J. Agric. Food Chem., Vol. 57, No. 14, 2009 6361
Table 5. Plant Growth Activities on the Radicle Growth of Cucumber
plant growth regulatory activities at 10 mg L-1 (%)
4-yl)-3-(2,6-difluorobenzoyl)urea derivatives. Chin. J. Org. Chem.
2006, 26 (8), 1120–1124.
compd
ranka
(12) Rigterink, R. H.; Sbiagia, R. J. Substituted N-aroyl N0-phenyl urea
compounds. EP 71279, 1983.
1
30
50
þ
þ
(13) Anderson, M. Pesticidal benzoylurea compounds. EP161019, 1985.
(14) Lima, L. M. A.; Barreiro, E. J. Bioisosterism: a useful strategy for
molecular modification and drug design. Curr. Med. Chem. 2005, 12
2
3
30
þ
4
50
þ
(1), 23–49.
5
130
65
þþ
þ
::
(15) Sun, R. F.; Lu, M. Y.; Chen, L.; Li, Q. S.; Song, H. B.; Bi, F. C.;
6
Huang, R. Q.; Wang, Q. M. Design, synthesis, bioactivity, and
structure-activity relationship (SAR) studies of novel benzoylphe-
nylureas containing oxime ether group. J. Agric. Food Chem. 2008,
56, 11376–11391.
7
105
-35
65
þþ
14
Hexaflumuron
-
þ
a
(16) Meazza, G.; Rama, F.; Bettarini, F. Synthesis and bioactivity of
some fluorine-containing benzoyl arylureas. Part I: Insecticidalacar-
icidal products in which the aryl group bears a trifluoromethyl-
substituted alkyl or alkenyl side chain. Pestic. Sci. 1992, 35, 137.
(17) Feuer, H.; White, E. H.; Wyman, J. E. The reactions of maleic
anhydride with hydrazine hydrate. J. Am. Chem. Soc. 1958, 80, 3790–
3792.
þþ, g100%; þ, g50%; -, <50%.
LITERATURE CITED
(1) Miesel, J. L. Novel 1-(mono-O-substituted benzoyl)-3-(substituted
pyrazinyl) ureas. U.S. Patent, 4293552, 1981.
(2) Oberlander, H.; Silhacek, D. L. New perspectives on the mode of
action of benzoylphenyl urea insecticides. In Insecticides with Novel
Modes of Action: Mechanism and Application, 1st ed.; Ishaaya, I.,
Degheele, D., Eds.; Springer-Verlag: Berlin, Germany, 1998; pp 92-105.
(3) Oberlander, H.; Silhacek, D. L. Mode of action of insect growth regulators
in Lepidopteran tissue culture. Pestic. Sci. 1998, 54, 300–302.
(4) Xu, X. Y.; Qian, X. H.; Li, Z.; Huang, Q. C.; Chen, G. Synthesis and
insecticidal activity of new substituted N-aryl-N0-benzoylthiourea
compounds. J. Fluorine Chem. 2003, 121, 51–54.
(5) Qian, X. H. Quantitative studies on structure-activity relationship of
sulfonylurea and benzoylphenylurea type pesticides and their sub-
stituents’ bioisosterism using synthons’ activity contribution.
J. Agric. Food Chem. 1999, 47, 4415–4418.
(6) Yang, X. L.; Wang, D. Q.; Chen, F. H.; Zhang, Z. N. The synthesis
and larvicidal activity of N-aroyl-N0-(5-aryl-2-furoyl)ureas. Pestic.
Sci. 1998, 52, 282–286.
(7) Li, X. H.; Ling, Y.; Yang, X. L. Synthesis of novel benzoyl ureas
containing thiadiazole and their insecticidal activity. Huaxue Tong-
bao 2003, 66 (5), 333–336.
(8) Kubato, S.; Shono, Y.; Matsunaga, T.; Tsunoda, K. Laboratory
evaluation of bistrifluron, a benzoylphenylurea compound, as a bait
toxicant against Coptotermes formosanus (Isoptera: Rhinotermiti-
dae). J. Econ. Entomol. 2006, 99, 1363–1368.
(9) Chen, L.; Ou, X. M.; Mao, C. H.; Shang, J.; Huang, R. Q.; Bi, F. C.;
Wang, Q. M. Synthesis and bioassay evaluation of 1-(4-substitutedi-
deneaminooxymethyl)-phenyl-3-(2,6-difluorobenzoyl)ureas. Bioorg. Med.
Chem. 2007, 3678–3683.
(10) Yoon, C.; Yang, J. O.; Kang, S. H.; Kim, G. H. Insecticidal
properties of bistrifluron against sycamore lace bug, Corythucha
ciliata (Hemiptera: Tingidae). J. Pestic. Sci. 2008, 33, 44–50.
(11) Wei, Z. Z; Pang, H. L.; Liu, A. P.; Cheng, H.; Lin, L. Z.; Liu, Y.; Hu,
C. H.; Yang, G. F. Synthesis and biological activity of 1-(pyrimidin-
(18) Abbott, W. S. A method of computing the effectiveness of an
insecticide. J. Econ. Entomol. 1925, 18, 265–267.
(19) Mao, C. H.; Wang, Q. H.; Huang, R. Q.; Bi, F. C.; Chen, L.; Liu, Y.
X.; Shang, J. Synthesis and insecticidal evaluation of novel N-oxalyl
derivatives of tebufenozide. J. Agric. Food Chem. 2004, 52, 6737–
6741.
(20) Hsu, A. C.; Murphy, R. A.; Aller, H. E.; Hamp, D. W.; Weinstein, B.
Insecticidal N0-substituted-N,N0-disubstitutedhydrazines. U.S. Pa-
tent 5117057, 1992.
(21) Luo, Y. P.; Yang, G. F. Discovery of a new insecticide lead by
optimizing
a target-diverse scaffold: tetrazolinone derivatives.
Bioorg. Med. Chem. 2007, 15, 1716–1724.
(22) Chen, L.; Huang, Z. Q.; Wang, Q. M.; Shang, J.; Huang, R. Q.; Bi, F.
C. Insecticidal benzoylphenylurea-S-carbamate: a new propesticide
with two effects of both benzoylphenylureas and carbamates. J.
Agric. Food Chem. 2007, 55, 2659–2663.
(23) Liu, Y. X.; Cai, B. L.; Li, Y. H.; Song, H. B.; Huang, R. Q.; Wang, Q.
M. Synthesis, crystal structure, and biological activities of 2-cya-
noacrylates containing furan or tetrahydrofuran moieties. J. Agric.
Food Chem. 2007, 55, 3011–3017.
(24) Einhellig, F. A.; Schan, M. K.; Rasmunsen, J. A. Synergistic effects
of four cinnamic acid compounds on grain sorghum. Plant Growth
Regul. 1983, 1, 251–258.
(25) Demuner, A. J.; Barbosa, L. C. A.; Veloso, D. P. New 8-oxabicyclo
[3.2.1]oct-6-en-3-one derivatives with plant growth regulatory activ-
ity. J. Agric. Food Chem. 1998, 46, 1173–1176.
Received March 15, 2009. Revised manuscript received May 13, 2009.
Accepted June 17, 2009. This work was supported by the National
Natural Science Foundation of China (20672064).