Design, synthesis and insecticidal activity of novel phenylurea derivatives

Article abstract of DOI:10.3390/molecules20035050

A series of novel phenylurea derivatives were designed and synthesized according to the method of active groups linkage and the principle of aromatic groups bioisosterism in this study. The structures of the novel phenylurea derivatives were confirmed bas

Full text of DOI:10.3390/molecules20035050

Molecules 2015, 20, 5050-5061; doi:10.3390/molecules20035050
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Design, Synthesis and Insecticidal Activity of Novel
Phenylurea Derivatives
Jialong Sun † and Yuanming Zhou †,*
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University,
Qingdao 266109, China; E-Mail: sunjialong6289@163.com
†
These authors contributed equally to this work.
* Author to whom correspondence should be addressed; E-Mail: zym7410@163.com;
Tel.: +86-532-8608-0147.
Academic Editor: Jean Jacques Vanden Eynde
Received: 28 February 2015 / Accepted: 17 March 2015 /Published: 19 March 2015
Abstract: A series of novel phenylurea derivatives were designed and synthesized
according to the method of active groups linkage and the principle of aromatic groups
bioisosterism in this study. The structures of the novel phenylurea derivatives were
1
confirmed based on ESI-MS, IR and H-NMR spectral data. All of the compounds were
evaluated for the insecticidal activity against the third instars larvae of Spodoptera exigua
Hiibner, Plutella xyllostella Linnaeus, Helicoverpa armigera Hubner and Pieris rapae
Linne respectively, at the concentration of 10 mg/L. The results showed that all of the
derivatives displayed strong insecticidal activity. Most of the compounds presented higher
insecticidal activity against S. exigua than the reference compounds tebufenozide,
chlorbenzuron and metaflumizone. Among the synthesized compounds, 3b, 3d, 3f, 4b and
4g displayed broad spectrum insecticidal activity.
Keywords: phenylurea; diacylhydrazine; metaflumizone; insecticidal activity; synthesis
1. Introduction
Benzoylphenyl ureas (BPUs), acting as insect growth regulators (IGRs) and affecting the larval
stages of most insects by blocking or inhibiting the synthesis of chitin, have been rapidly developed
since the first benzoylphenylurea, diflubenzuron, was commercialized in 1972 [1,2]. BPUs have

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attracted considerable attention for decades for their unique mode of action coupled with a high degree
of activity on target pests and low toxicity to non-target organisms [3,4]. More than 20 BPUs have
been developed as IGRs, such as chlorfluazuron, flufenoxuron, triflumuron and chlorbenzuron [5].
Diacylhydrazines have been another of the most important classes of insect growth regulators since
the discovery of the N-tert-butyl-N,N'-diacylhydrazines in the mid-1980s by Rohm and Haas Co. [6,7].
They affect the ecdysone receptor and lead to lethal premature molting. For their unique mode of
action with high insecticidal selectivity, lower toxicity to vertebrates and simple structure,
diacylhydrazines have attracted considerable attention [8,9]. Among nonsteroidal ecdysone agonists,
N-tert-butyl-N'-(4-ethylbenzoyl)-3,5-dimethylbenzoylhydrazine (tebufenozide) was the first introduced
to market [10,11]. At present, a series of diacylhydrazines, such as methoxyfenozide, halofenozide and
chromafenozide have already been widely applied as pesticides in the agrochemical field.
Metaflumizone, which was discovered by Nihon Nohyaku in the early 1990s, is a novel sodium
channel blocker insecticide. It belongs to the new class of semicarbazone insecticides and its structure
contains an acylhydrazone moiety. It provides good control of most of the economically important
lepidopterous pests and other orders pests including Siphonaptera, Diptera, Hymenoptera and
Coleoptera. Meanwhile, it presents low risk to non-target organisms as well as humans and the
environment. Moreover, insect strains which were resistant to the organophosphates, imidacloprid and
carbamates have not showed cross-resistance to metaflumizone. Therefore, metaflumizone has a great
potential in Integrated Pest Management(IPM) strategy and resistance management [12–14].
Aromatic diacylhydrazine moiet
O
Tebufenozide
N
N
H
O
O
the method of
O
H
N
R
active groups linkage
N
H
N
H
N
H
the principle of
aromatic groups bioisosterism
O
O
OCF3
Triflumuron
Cl
N
F
F
O
O
O
N
H
N
H
Cl
F
N
O
O
H
N
H
N
N
H
N
H
the method of
active groups linkage
N
R
N
H
CF3
CN
Flucycloxuron
F
O
the principle of
aromatic groups bioisosterism
Phenylurea moiet
F3CO
O
N
N
N
CF3
CN
H
H
Phenylurea derivatives
Metaflumizone
Aromatic acylhydrazone moity
Figure 1. Design of the skeleton of phenylurea derivatives.
An abundance of insects belonging to the order Lepidoptera, such as the diamondback moth
(Helicoverpa armigera Hubner), beet armyworm (Spodoptera exigua Hiibner), cabbage caterpillar
(Pieris rapae Linne) and cotton bollworm (Plutella xyllostella Linnaeus) etc., are among the most
damaging pests for crops all over the world. Because they cause enormous agricultural production

Molecules 2015, 20
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losses, various insecticides have been used to control Lepidoptera pests. These insecticides brought
great benefits, but they have caused negative effects such as toxicity to non-target organisms,
including mammals, and environmental pollution. Moreover insecticide resistance has strengthened
yearly [15]. Therefore, researchers have to develop novel, low toxicity, highly efficient, friendly
environmental insecticides.
In view on the facts above, we sought to incorporate a phenylurea unit with an aromatic
diacylhydrazine and acylhydrazone moiety, respectively, according to the method of active groups
linkage and the principle of aromatic groups bioisosterism (Figure 1), and eighteen such phenylurea
derivatives were then designed and synthesized (Scheme 1). Moreover the new compounds’
insecticidal activities against the third instars larvae of diamondback moth, beet armyworm, cabbage
caterpillar and cotton bollworm, were evaluated. We expected that by this approach the combination
of the critical components could further strengthen the biological activity of phenylurea derivatives.
O
O
O
H
H
N
H2N
H
N
H
N
O
Ar
NCO
NH2NH2 H2O
N
Ar
O
Ar
NH NH2
O
O
O
1a-1m
2a-2m
O
Cl
H
H
H
N
N
N
N
Ar
N
N
Cl
H
O
O
Cl
3a-3i
O
O
H
H
N
N
N
CN
Ar
N
H
O
CF3
CN
4a-4i
CF3
Ar-
Ar-
Ar-
Ar-
Cl
3g
3f
4a
4b
3a
3b
4f
Cl
F
F
F
F
F3C
4g
(F3C)2FC
CF3
F
4h
4i
4c
3h
3c
F
F
F
F
Br
3d
3e
3i
4d
4e
F
Cl
F3CO
F
Cl
Cl
Cl
Scheme 1. Synthesis of phenylurea derivatives.

Molecules 2015, 20
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2. Results and Discussion
2.1. Chemistry
As indicated in Scheme 1, eighteen phenylurea derivatives 3a–3i, 4a–4i were successfully synthesized.
The raw materials 3-aminobenzoic acid ethyl ester and a substituted phenyl isocyanate (Ar-NCO) were
dissolved in toluene and refluxed to give ethyl 3-(3-substituted phenylureido) benzoates 1a–1m. Then
with alcohol as solvent, 3-(3-substituted phenylureido)benzohydrazides 2a–2m were produced by the
reaction of compounds 1a–1m with hydrazine hydrate. Subsequently, compounds 2a–2m reacted with
2-chloronictinoyl chloride in tetrahydrofuran at room temperature to provide phenylurea derivatives,
N'-[3-(3-substituted phenylureido)benzoyl]-N-(2-chloro)nicotino-hydrazides 3a–3i. Meanwhile,
compounds 2a–2m also reacted with 2-(4-nitrilo)benzyl-1-(3-trifluoromethyl)phenyl ketones in
tetrahydrofuran at room temperature to give others phenylurea derivatives, N-substituted phenylureido
benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano) phenyl ethanone hydrazones 4a–4i. The structures of
all the phenylurea derivatives were confirmed by 1H-NMR, IR, ESI-MS and MP (Scheme 1).
2.2. Insecticidal Activities
As displayed in Table 1, all of the phenylurea derivatives 3a–3i, 4a–4i indicated strong insecticidal
activities against the third instars larval of beet armyworm at the concentration of 10 mg/L. Most of the
synthesized compounds showed higher insecticidal activity than the references chlorbenzuron,
tebufenozide and metaflumizone at the 72 h time point. Among the synthesized compounds, the
mortality of the compounds 3g, 3i, 4d and 4e exceeded 90% at 72 h. Moreover the mortality of
compound 4g reached 100%. Meanwhile the data of Table 1 shows that the mortality of the
compounds indicated a positive correlation with administration time.
Table 1. Insecticidal activities of the phenylurea derivatives against the third instars larval
of beet armyworm (Concentration of 10 mg/L).
Mortality (%)
48 h
Mortality (%)
48 h
Compound
Compound
24 h
72 h
83.33
87.50
83.33
87.50
87.50
87.50
95.83
83.33
91.67
41.67
75.00
24 h
25.00
12.50
20.83
50.00
41.67
41.67
45.83
16.67
20.83
12.50
72 h
87.50
75.00
79.17
91.67
95.83
87.50
100.0
79.17
83.33
45.83
3a
12.50
8.33
45.83
37.50
37.50
45.83
50.00
41.67
66.67
41.67
62.50
20.83
66.67
4a
41.67
3b
4b
37.50
3c
4.17
4c
45.83
3d
12.50
16.67
8.33
4d
70.83
3e
4e
75.00
3f
4f
66.67
3g
20.83
8.33
4g
75.00
3h
3i
4h
4i
37.50
16.67
4.17
45.83
Tebufenozide
Chlorbenzuron
16.67
Metaflumizone 37.50

Molecules 2015, 20
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The data in Table 2 showed the mortality of the phenylurea derivatives 3a–3i, 4a–4i against the
third instars larval of diamondback moth (P. xyllostella), cotton bollworm (H. armigera) and cabbage
worm (P. rapae) at the concentration of 10 mg/L after 72 h. The data presented that all the phenylurea
derivatives showed strong insecticidal activity against diamondback moth, cotton bollworm and
cabbage worm. Among the synthesized compounds, 3b, 3d, 3f, 4b and 4g displayed broad spectrum
insecticidal activity.
Table 2. Insecticidal activities of phenylurea derivatives (Concentration of 10 mg/L, 72 h).
Mortality(%)
Compound
P. xyllostella
87.50
91.67
87.50
91.67
91.67
95.83
83.33
83.33
95.83
79.17
91.67
83.33
79.17
75.00
87.50
91.67
91.67
83.33
83.33
87.50
66.67
H. armigera
91.67
95.83
91.67
95.83
87.50
91.67
83.33
87.50
83.33
87.50
95.83
79.17
87.50
87.50
91.67
95.83
87.50
79.17
83.33
79.17
37.50
P. rapae
91.67
95.83
91.67
95.83
95.83
95.83
100.0
91.67
100.0
91.67
95.83
87.50
100.0
100.0
87.50
100.0
87.50
87.50
87.50
83.33
75.00
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
Tebufenozide
Chlorbenzuron
Metaflumizone
3. Experimental Section
3.1. General Procedures
1H-NMR spectra were obtained at 500 MHz using an AM-500 spectrometer in DMSO-d6 solution
(Bruker, Karlsruhe, Germany). The melting points were determined on WRS-1A type melting point
apparatus (Shanghai, China) and uncorrected. IR spectra were measured on a Nicolet IR-200
spectrophotometer (Thermo Electron, Madison, WI, USA) using KBr disks. A Micromass Q-TOF
spectrometer (Waters Crop., Manchester, UK) was used to record HR-ESI-MS data. Pre-coated silica
gel plates were used for analytical thin layer chromatography (TLC) and spots were visualized with
UV (254 nm).Yields were not optimized.

Molecules 2015, 20
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3.2. General Procedure for the Preparation of 1a–1m
3-Aminobenzoic acid ethyl ester (50 mmol) was dissolved in toluene (30 mL).With ice-water bath
cooling, a substituted phenyl isocyanate (Ar-NCO) (50 mmol) dissolved in toluene (30 mL), was
added dropwise. With the water bath, the mixture was reacted at a temperature of 25 °C, for 5 h, and
then heated to reflux for 2 h. After cooling to room temperature, the reaction mixture was filtered
under vacuum and dried to produce ethyl 3-(3-substituted phenylureido)benzoates 1a–1m, in yields
ranging from 85% to 95%.
3.3. General Procedure for the Preparation of 2a–2m
Ethyl 3-(3-substituted phenylureido)benzoates 1a–1m (20 mmol) and 80% hydrazine hydrate
(100 mmol) were dissolved in ethanol (100 mL). The mixture was stirred and heated under reflux for
4 h. After cooling to room temperature, the reaction mixture was filtered under vacuum. The solid
residue was washed with ice-water (50 mL), to give 3-(3-substituted phenylureido)benzohydrazides
2a–2m in yields ranging from 80% to 95%.
3.4. General Procedure for the Preparation of 3a–3i
3-(3-Substituted phenylureido)benzohydrazides 2a–2m (4.42 mmol) was dissolved in dried
tetrahydrofuran (50 mL) in a 250 mL round bottom flask. With ice water bath cooling,
2-chloronictinoyl chloride (5.7 mmol) dissolved in dried tetrahydrofuran (50 mL), was added into the
flask dropwise. The mixture was reacted at room temperature for 17 h, then it was distilled under
reduced pressure to remove the tetrahydrofuran. The solid residue was recrystallized from DMF and
water (volume ratio, 1:1) to give the target compounds, N'-[3-(3-substituted phenylureido)benzoyl]-N-
(2-chloro)nicotinohydrazides 3a–3i, with yields ranging from 50% to 70%.
3.5. General Procedure for the Preparation of 4a–4i
3-(3-substituted phenylureido)benzohydrazides 2a–2m (2 mmol) and 2-(4-nitrilo)benzyl-1-(3-
trifluoromethyl)phenyl ketones (2 mmol) were dissolved in a mixture of methanol (15 mL) and
n-hexane (2 mL) in a 100 mL round bottom flask and heated to 60 °C with a water bath. After adding
three drops of trifluoroacetic acid, the mixture was stirred and reacted for 6 h. The reaction mixture
was filtered while hot and the solid obtained was washed with 15 mL methanol, then dried to give the
target compounds, N-(3-substituted phenylureido)benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)-phenyl
ethanone hydrazones 4a–4i, in yields ranging from 60% to 75%. All eighteen phenylurea derivatives
3a–3i, 4a–4i were novel and the physical and spectral data for these compounds are listed below.
N'-[3-(3-(2-Methyl)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide (3a): Yellow solid, yield
1
63.6%, m.p.203.0~203.9 °C. H-NMR (DMSO-d6) δ: 10.68, 10.60 (each s, H, -CONHNHCO-), 9.24 (s,
1H, NH), 8.55 (dd, J = 4.8, 1.8 Hz, 1H), 7.96–8.02 (overlap, 4H), 7.84 (d, J = 8.0 Hz, 1H), 7.68 (d,
J = 7.8 Hz, 1H), 7.58 (dd, J = 7.4, 4.9 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.19
(d, J = 7.4 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.4 Hz, 1H), 2.25 (s, 3H, -CH3). IR (KBr): ν
3281, 3148, 3027, 1643, 1588, 1561, 1455, 1334, 1295, 1244, 1182, 994, 752, 693 cm−1.

Molecules 2015, 20
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N'-[3-(3-(2-Fluoro)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide (3b): Gray white solid, yield
60.7%, decomposed before melting. HR-ESI-MS m/z: 428.0908 [M+H]+ (calcd. for C20H17ClFN5O3,
1
428.0926). H-NMR (DMSO-d6) δ: 10.64 (s, 2H, -CONHNHCO-), 9.29(s, 1H, NH), 8.62 (d,
J = 2.1 Hz, 1H), 8.55 (dd, J = 4.8, 1.8 Hz, 1H), 8.16 (dt, J = 8.2, 1.3 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H),
7.98 (dd, J = 7.6, 1.8 Hz, 1H), 7.67 (dd, J = 8.0, 1.8 Hz, 1H), 7.58 (dd, J = 7.5, 4.8 Hz, 1H), 7.55 (d,
J = 7.8 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.24 (ddd, J = 11.5, 8.2, 1.1 Hz, 1H), 7.15 (t, J = 7.7 Hz, 1H),
7.03 (ddt, J = 7.3, 5.2, 1.5 Hz, 1H). IR (KBr): ν 3566, 3394, 3297, 3211, 3078, 3011, 1647, 1588,
1561, 1491, 1451, 1405, 1299, 1252, 1193, 806, 752, 646 cm−1.
N'-[3-(3-(2,4-Difluoro)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide (3c): Gray white solid,
yield 58.3%, m.p. 184.2~185.9 °C. HR-ESI-MS m/z: 446.0808 [M+H]+ (calcd. for C20H15ClF2N5O3,
446.0826). 1H-NMR (DMSO-d6) δ: 10.68, 10.60 (each s, 1H, -CONHNHCO-), 9.21 (s, 1H, NH), 8.56
(d, J = 2.1 Hz, 1H), 8.55 (dd, J = 4.8, 1.9 Hz, 1H), 8.09 (dt, J = 9.2, 6.1 Hz, 1H), 7.98 (s, 1H), 7.95 (s,
1H), 7.66 (dd, J = 8.0, 1.3 Hz, 1H), 7.57 (dd, J = 7.5, 4.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.43 (t,
J = 7.9 Hz, 1H), 7.33 (ddd, J = 11.6, 8.9, 2.8 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H). IR (KBr): ν 3539, 3304,
3172, 3035, 1721, 1663, 1600, 1553, 1432, 1401, 1190, 1139, 1096, 845, 802, 740 cm−1.
N'-[3-(3-(3,4-Difluoro)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide (3d): Yellow solid, yield
52.5%, m.p. 214.9~215.2 °C. HR-ESI-MS m/z: 446.0829 [M+H]+ (calcd. for C20H15ClF2N5O3, 446.0826).
1H-NMR (DMSO-d6) δ: 10.67, 10.59 (each s, 1H, -CONHNHCO-), 8.97 (s, 2H, -NHCONH-), 8.55
(dd, J = 4.8, 1.8 Hz, 1H), 7.96–8.02 (overlap, 2H), 7.64–7.70 (overlap, 2H), 7.58 (dd, J = 7.5, 4.8 Hz,
1H), 7.55 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 10.4 Hz, 1H), 7.15 (m, 1H). IR
(KBr): ν 3344, 3249, 3091, 1685, 1648, 1561, 1515, 1490, 1436, 1403, 1208, 905, 860, 748, 673 cm−1.
N'-[3-(3-(3,4-Dichloro)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide (3e): Gray white solid,
yield 54.9%, m.p. 194.2~194.7 °C. HR-ESI-MS m/z: 478.0235 [M+H]+ (calcd. for C20H15Cl3N5O3,
478.0235). 1H-NMR (DMSO-d6) δ: 10.68, 10.60 (each s, 1H, -CONHNHCO-), 9.06, 9.02 (each s, 1H,
-NHCONH-), 8.55 (dd, J = 4.8, 1.9 Hz, 1H), 8.01 (s, 1H), 7.99 (dd, J = 7.5, 1.9 Hz, 1H), 7.91 (d,
J = 2.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 7.6, 4.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H) 7.53
(d, J = 8.8 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H). IR (KBr): ν 3277, 3236,
3093, 3010, 1653, 1581, 1536, 1473, 1401, 1378, 1292, 1223, 1132, 906, 808, 748 cm−1.
N'-[3-(3-(3,5-Dichloro)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide (3f): Gray white solid,
yield 65.6%, m.p. 223.6~224.5 °C. HR-ESI-MS m/z: 478.0235 [M+H]+ (calcd. for C20H15Cl3N5O3,
478.0235). 1H-NMR (DMSO-d6) δ: 10.68, 10.60 (each s, 1H, -CONHNHCO-), 9.12, 9.11 (each s, 1H,
-NHCONH-), 8.56 (dd, J = 4.8, 1.9 Hz, 1H), 8.01 (s, 1H), 7.99 (dd, J = 7.5, 1.8 Hz, 1H), 7.95 (s, 1H),
7.66 (d, J = 7.9 Hz, 1H), 7.54–7.60 (overlap, 3H), 7.45 (t, J = 7.9 Hz, 1H), 7.17 (t, J = 1.8 Hz, 1H). IR
(KBr): ν 3362, 3308, 3168, 1725, 1659, 1604, 1584,1538, 1484, 1392, 1304, 1281, 1246, 1195, 1100,
1063, 820, 739, 665 cm−1.
N'-[3-(3-(4-Ditrifluoromethylmethyl)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide (3g): white
1
powder, yield 62.4%, m.p. 196.76~198.1 °C. H-NMR (DMSO-d6) δ: 10.64 (s, 2H, -CONHNHCO-),
9.45 (s, 1H, NH), 8.55 (dd, J = 4.8, 1.8 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.22 (s, 1H), 8.02 (s, 1H),

Molecules 2015, 20
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7.99 (dd, J = 7.5, 1.8 Hz, 1H), 7.69 (dd, J = 7.9, 1.2 Hz, 1H), 7.58 (dd, J = 7.5, 4.8 Hz, 1H), 7.55 (d,
J = 7.8 Hz, 1H), 7.43–7.49 (overlap, 3H), 2.35 (s, 3H, -PhCH3). IR (KBr): ν 3254, 3005, 1662, 1613,
1584, 1533, 1401, 1306, 1272, 1218, 1178, 1135, 1106, 977, 888, 811, 754 cm−1.
N'-[3-(3-(2-Trifluoromethyl)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide (3h): Yellow solid,
yield 68.7%, m.p. 199.3~199.6 °C. HR-ESI-MS m/z: 478.0889 [M+H]+ (calcd. for C21H16ClF3N5O3,
478.0888). 1H-NMR (DMSO-d6) δ: 10.66, 10.62 (each s, 1H, -CONHNHCO-), 9.58 (s, 1H, NH), 8.55
(dd, J = 4.8, 1.2 Hz, 1H), 8.13 (s, 1H), 7.94–8.02 (m, overlap, 2H), 7.62–7.72 (m, overlap, 3H),
7.53–7.60 (m, overlap, 2H), 7.434 (t, J = 7.9 Hz, 1H), 7.30 (t, J = 7.5 Hz, 2H). IR (KBr): ν 3572, 3435,
3303, 3216, 3083, 3012, 1652, 1590, 1544, 1507, 1453, 1407, 1316, 1279, 1179, 1109, 1059, 1038,
905, 806, 764, 690, 648 cm−1.
N'-[3-(3-(4-Trifluoromethoxyl)phenyl)ureido]benzoyl-N-(2-chloro)nicotinohydrazide
(3i):
white
powder, yield 59.1%, m.p. 233.6~234.4 °C. HR-ESI-MS m/z: 494.0839 [M+H]+ (calcd. for
C21H16ClF3N5O4, 494.0837). 1H-NMR (DMSO-d6) δ: 10.67, 10.60 (s, 1H, -CONHNHCO-), 8.99, 8.97
(each s, 1H, -NHCONH-), 8.55 (dd, J = 4.8, 1.8 Hz, 1H), 7.97–8.02 (m, overlap, 2H), 7.94 (s, 1H),
7.67 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 7.9 Hz, 1H),
7.30 (d, J = 8.7 Hz, 2H). IR (KBr): ν 3373, 3299, 3182, 3033, 2929, 2855, 1723, 1660, 1611, 1590,
1507, 1478, 1399, 1279, 1154, 1096, 827, 744, 682, 636 cm−1.
N-[3-(3-(2-Methyl)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenylethanone
hydrazone (4a): White powder, yield 70.0%, m.p. 208.3~208.7 °C. HR-ESI-MS m/z: 556.195 [M+H]+
1
(calcd for C31H25F3N5O2, 556.1955). H-NMR (DMSO-d6) δ: 11.34 (s, 1H, PhCONH-), 9.24 (s,
1H, -NHCONH-), 8.17 (s, 1H), 8.07 (s, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.77
(d, J = 8.0 Hz, 2H), 7.73 (s, 1H), 7.55–7.70 (overlap, 2H), 7.38–7.45 (overlap, 3H), 7.34 (d, J = 7.7 Hz,
1H), 7.12–7.22 (overlap, 2H), 6.96 (t, J = 7.2 Hz, 1H), 4.60 (s, 2H, -CH2-), 2.24 (s, 3H, -CH3). IR
(KBr):ν 3336, 3307, 3216, 3050, 2958, 2229, 1652, 1590, 1548, 1486, 1432, 1349, 1258, 1171, 1117,
1080, 893, 764, 702, 644, 545 cm−1.
N-[3-(3-(2-Fluoro)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenylethanone
hydrazone (4b): White powder, yield 63.4%, m.p. 239.0~239.6 °C. HR-ESI-MS m/z: 560.1706
[M+H]+ (calcd for C30H22F3N5O2, 560.1704). 1H-NMR (DMSO-d6) δ: 11.34 (s, 1H, PhCONH-), 9.27,
8.59 (each s, 1H, -NHCONH-), 8.15 (t, J = 8.0 Hz, 2H), 8.07 (s, 1H), 7.92 (s, 1H), 7.77 (d, J = 8.2 Hz,
2H), 7.72 (s, 1H), 7.63 (s, 2H), 7.35–7.45 (m, overlap, 4H), 7.25 (dd, J = 10.7, 8.4 Hz, 1H), 7.15 (t,
J = 7.4 Hz, 1H), 7.01 (dd, J = 12.6, 6.2 Hz, 1H), 4.60 (s, 2H, -CH2-). IR (KBr): ν 3328, 3257, 3104,
2925, 2224, 1723, 1669, 1590, 1544, 1519, 1436, 1295, 1129, 1071, 752, 694, 553 cm−1.
N-[3-(3-(2,4-Difluoro)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenylethanone
hydrazone (4c): White powder, yield 67.5%, m.p. 243.6~243.7 °C. HR-ESI-MS m/z: 578.1612 [M+H]+
(calcd for C30H21F5N5O2, 578.1610).1H-NMR (DMSO-d6) δ: 11.33 (s, 1H, PhCONH-), 9.21, 8.54
(each s, 1H, -NHCONH-), 8.17 (s, 1H), 8.02–8.12 (overlap, 2H), 7.91 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H),
7.73 (s, 1H), 7.63 (s, 2H), 7.35–7.45 (overlap, 4H), 7.30 (m, 1H), 7.06 (t, J = 8.2 Hz, 1H), 4.60 (s, 2H,

Molecules 2015, 20
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-CH2-). IR (KBr): ν 3535, 3308, 3257, 3187,2577, 1678, 1565, 1397, 1186, 1131, 1096, 1064, 842,
744, 611 cm−1.
N-[3-(3-(3,4-Difluoro)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenylethanone
hydrazone (4d): White powder, yield 69.6%, m.p. 243.2~243.5 °C. HR-ESI-MS m/z: 578.1606
[M+H]+ (calcd for C30H21F5N5O2, 578.1610). 1H-NMR (DMSO-d6) δ: 11.32 (s, 1H, PhCONH-), 8.96,
8.94 (each s, 1H, -NHCONH-), 8.17 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.73
(s, 1H), 7.59–7.70 (m, overlap, 3H), 7.30–7.45 (m, overlap, 5H), 7.14 (d, J = 7.9 Hz, 1H), 4.60 (s, 2H,
-CH2-). IR (KBr): ν3336, 3316, 3258, 3101, 2226, 1718, 1663, 1593, 1550, 1510, 1432, 1209, 1131,
1072, 1022, 869, 689, 552 cm−1.
N-[3-(3-(3,4-Dichloro)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenylethanone
hydrazone (4e): White powder, yield 72.4%, m.p. 245.4~245.8 °C. HR-ESI-MS m/z: 610.1021 [M+H]+
(calcd. for C30H21Cl2F3N5O2, 610.1019).1H-NMR (DMSO-d6) δ: 11.33 (s, 1H, PhCONH-), 9.07, 9.05
(each s, 1H, -NHCONH-), 8.18 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.77 (d,
J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.64 (s, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.31–7.45 (m, overlap, 5H), 4.60
(s, 2H, -CH2-). IR (KBr): ν 3325, 3299, 3096, 3033, 2228, 1716, 1659, 1590, 1518, 1473, 1430, 1378,
1326, 1289, 1192, 1132, 1069, 854, 811, 745, 691, 545 cm−1.
N-[3-(3-(2,6-Dimethyl)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenyl ethanone
1
hydrazone (4f): White powder, yield 70.4%, m.p. 240.1~240.3 °C. H-NMR (DMSO-d6) δ: 11.31 (s,
1H, PhCONH-), 8.96 (s, 1H, -NHCONH-), 8.16 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.77 (s, 1H), 7.75
(s, 1H), 7.73 (s, 1H), 7.56–7.69 (overlap, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 7.9 Hz, 1H), 7.31
(d, J = 7.7 Hz, 1H), 7.05–7.11 (overlap, 3H), 4.58 (s, 2H, -CH2-), 2.20 (s, 6H, -CH3). IR (KBr): ν 3295,
3159, 3004, 2227, 1655, 1640, 1607,1595,,1487, 1342, 1307, 1266, 1241, 1176, 800, 770, 745 cm−1.
N-[3-(3-(3-Trifluoromethyl)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenyl
ethanone hydrazone (4g): White powder, yield 68.7%, m.p. 220.0~221.2 °C. HR-ESI-MS m/z:
1
610.1669 [M+H]+ (calcd. for C31H22F6N5O2, 610.1672). H-NMR (DMSO-d6) δ: 11.33 (s, 1H,
PhCONH-), 9.08, 9.01 (each s, 1H, -NHCONH-), 8.18 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.93 (s, 1H),
7.77 (d, J = 8.2 Hz, 2H), 7.73 (s, 1H), 7.61–7.70 (overlap, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.9 Hz,
1H), 7.35–7.45 (m, overlap, 4H), 7.32 (d, J = 7.6 Hz, 1H), 4.60 (s, 2H, -CH2-). IR (KBr): ν3336, 3261,
3207, 3093, 2225, 1717, 1663, 1596, 1553, 1514, 1491, 1444, 1330, 1295, 1252, 1197, 1154, 1115,
1068, 869, 795, 752, 693, 670, 552 cm−1.
N-[3-(3-(3-Fluoro)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenylethanone
hydrazone (4h): Yellow powder, yield 62.5%, m.p. 231.7~231.9 °C. HR-ESI-MS m/z: 560.1706
[M+H]+ (calcd. for C30H22F4N5O2, 560.1704). 1H-NMR (DMSO-d6) δ: 11.33 (s, 1H, PhCONH-), 8.94 (s,
2H, -NHCONH-), 8.17, 8.07, 7.91 (each s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.73, 7.65 (each s, 1H), 7.50
(d, J = 11.8 Hz, 1H), 7.35–7.45 (m, overlap, 4H), 7.31 (dd, J = 15.3, 7.9 Hz, 1H), 7.14 (d, J = 7.8 Hz), 6.79
(dt, J = 8.4, 1.9 Hz, 1H), 4.60 (s, 2H, -CH2-). IR (KBr): ν3340, 3311, 3257, 3145, 3100, 2224, 1714,
1664, 1511, 1490, 1436, 1308, 1196, 1071, 1017, 897, 872, 752, 690, 557 cm−1.

Molecules 2015, 20
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N-[3-(3-(3-Bromo)phenyl)ureido]benzoyl-1-(3-trifluoromethyl)phenyl-2-(4-cyano)phenyl
ethanone
hydrazone (4i): White powder, yield 61.8%, m.p. 232.4~232.8 °C. HR-ESI-MS m/z: 620.0906 [M+H]+
(calcd. for C30H22BrF3N5O2, 620.0903).1H-NMR (DMSO-d6) δ: 11.33 (s, 1H, PhCONH-), 8.97, 8.93 (each
s, 1H, -NHCONH-), 8.18, 8.07, 7.92 (each s, 1H), 7.86 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.74 (s, 1H), 7.64
(s, 2H), 7.39–7.44 (m, overlap, 3H), 7.37 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.25 (t, J = 8.0 Hz,
1H), 7.16 (d, J = 7.7 Hz, 1H), 4.60 (s, 2H, -CH2-). IR (KBr): ν3336, 3303, 3265, 3104, 2224, 1723,
1656, 1590, 1536, 1515, 1478, 1428, 1300, 1196, 1129, 1071, 1017, 993, 901, 856, 752, 694, 553 cm−1.
3.6. Bioassay for Insecticidal Activities
Wheat leaf discs (0.5 cm × 0.5 cm) were treated with 5 μL solutions made from 5 mg of test sample
dissolved in 500 mL of acetone. Tebufenozide, chlorbenzuron and metaflumizone were used as
positive controls and acetone was used as negative control. The third instars larvae of beet armyworm
were fed with the discs. Cohorts of 24 beet armyworms were treated each time and bioassays were
replicated three times. After 24 h, 48 h and 72 h, the numbers of knocked down larvae (symptoms: the
larvae were narcotized, the bodies were very soft and immobilized, and response disappeared
completely) were recorded respectively [16,17].
Bioassay for insecticidal activities against cotton bollworm, diamondback moth and cabbage worm
was performed according to the above method. The third instars larvae of cotton bollworm,
diamondback moth and cabbage worm were fed with the discs instead, respectively. The numbers of
knocked down larvae after 72 h were recorded. The experiments showed that the mortality of acetone
as negative controls was 0%.
4. Conclusions
In conclusion, eighteen phenylurea derivatives 3a–3i, 4a–4i have been designed and synthesized
according to the method of active groups linkage and the principle of aromatic groups bioisosterism.
The insecticidal activities of these novel phenylurea derivatives against the third instars larvae of
S. exigua, H. armigera, P. xyllostella and P. rapae were evaluated, at a concentration of 10 mg/L. The
bioassay results showed that all of the synthesized compounds displayed high insecticidal activity.
Most of them presented higher insecticidal activity against S. exigua than the reference compounds
tebufenozide, chlorbenzuron and metaflumizone. Among the synthesized compounds, 3b, 3d, 3f, 4b
and 4g displayed broad spectrum insecticidal activity. The results above have encouraged us to further
explore novel phenylurea derivatives as insecticidal agents and this will be reported in future work.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/03/5050/s1.
Acknowledgments
This work was supported by Wheat Innovation Team of Modern Agricultural Industry Technology
System of Shandong Province and High Level Talents Fund of Qingdao Agricultural University
(No. 6631110).

Molecules 2015, 20
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Author Contributions
Jialong Sun designed the research; Jialong Sun and Yuanming Zhou performed the research and
analyzed the data; Yuanming Zhou wrote the paper. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Zhang, J.; Tang, X.H.; Ishaaya, I.; Cao, S.; Wu, J.J.; Yu, J.L.; Li, H.; Qian, X.H. Synthesis and
insecticidal activity of heptafluoroisopropyl-containing benzoylphenylurea structures. J. Agric.
Food Chem.2010, 58, 2736–2740.
2. Oberlander, H.; Silhacek, D.L. Mode of action of insect growth regulators in lepidopteran tissue
culture. Pestic. Sci.1998, 54, 300–302.
3. Sun, R.F.; Zhang, Y.L.; Bi, F.C.; Wang, Q.M. Design, synthesis, and bioactivity study of novel
benzoylpyridazyl ureas. J. Agric. Food Chem.2009, 57, 6356–6361.
4. Sun, R.F.; Lu, M.Y.; Chen, L.; Li Q.S.; Song, H.B.; Bi, F.C.; Huang, R.Q.; Wang, Q.M. Design,
synthesis, bioactivity, and structure-activity relationship (SAR) studies of novel benzoylphenylureas
containing oxime ether group. J. Agric. Food Chem. 2008, 56, 11376–11391.
5. Sun, R.F.; Liu, Y.X.; Zhang, Y.L.; Xiong, L.X.; Wang, Q.M. Design and synthesis of
benzoylphenylureas with fluorinated substituents on the aniline ring as insect growth regulators.
J. Agric. Food Chem. 2011, 59, 2471–2477.
6. Wing, K.D. RH-5849, a nonsteroidal ecdysone agonist: Effects on adrosophila cell line. Science
1988, 241, 467–469.
7. Sun, R.F.; Zhang, Y.L.; Chen, L.; Li, Y.Q.; Li, Q.S.; Song, H.B.; Huang, R.Q.; Bi, F.C.; Wang, Q.M.
Design, synthesis, and insecticidal activities of new N-benzoyl-N'-phenyl-N'-sulfenylureas.
J. Agric. Food Chem.2009, 57, 3661–3668.
8. Zhao, P.L.; Li, J.; Yang, G.F. Synthesis and insecticidal activity of chromanone and chromone
analogues of diacylhydrazines. Bioorg. Med. Chem. 2007, 15, 1888–1895.
9. Sawada, Y.; Yanai, T.; Nakagawa, H.; Tsukamoto, Y.; Yokoi, S.; Yanagi, M.; Toya, T.; Sugizaki, H.;
Kato, Y.; Shirakura, H.; et al. Synthesis and insecticidal activity of benzoheterocyclic analogues
of N'-benzoyl-N-(tert-butyl) benzohydrazide: Part 1. Design of benzoheterocyclic analogues.
Pest Manag. Sci. 2003, 59, 25–35.
10. Dhadialla, T.S.; Jansson, R.K. Non-steroidal ecdysone agonists: new tools for IPM and insect
resistance management. Pestic. Sci.1999, 55, 357–359.
11. Wang, H.; Yang, Z.K.; Fan, Z.J.; Wu, Q.J.; Zhang, Y.J.; Mi, A.; Wang, S.X.; Zhang, Z.C.;
Song, H.B.; Liu, F. Synthesis and insecticidal activity of N-tert-butyl-N,N'-diacylhydrazines
containing 1,2,3-thiadiazoles. J. Agric. Food Chem. 2011, 59, 628–634.
12. Chatterjee N.S.; Gupta, S.; Varghese, E. Degradation of metaflumizone in soil: Impact of varying
moisture, light, temperature, atmospheric CO2 level, soil type and soil sterilization. Chemosphere
2013, 90, 729–736.

Molecules 2015, 20
5061
13. Salgado, V.L.; Hayashi, J.H. Metaflumizone is a novel sodium channel blocker insecticide.
Vet. Parasitol. 2007, 150, 182–189.
14. Hempel, K.; Hess, F.G.; Bogi, C.; Fabian, E.; Hellwig, J.; Fegert, I. Toxicological properties of
metaflumizone. Vet. Parasitol.2007, 150, 190–195.
15. Li, Y.Q.; Qin, Y.G.; Yang, N.; Sun, Y.F.; Yang, X.L.; Sun, R.F.; Wang, Q.M.; Ling, Y. Studies
on insecticidal activities and action mechanism of novel benzoylphenylurea candidate NK-17.
PLoS One 2013, 8, e66251.
16. Mao, C.H.; Wang, Q.M.; 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.
17. Zhang, J.W.; Hu, Z.; Li, S.K.; Wu, W.J. Synthesis and insecticidal activities of new
ester-derivatives of Celangulin-V. Int. J. Mol. Sci. 2011, 12, 9596–9604.
Sample Availability: Samples of the compounds 3a–3i, 4a–4i are available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/4.0/).