Design and synthesis of benzoylphenylureas with fluorinated substituents on the aniline ring as insect growth regulators

Article abstract of DOI:10.1021/jf104578j

Enormous numbers of synthetic fluorine-containing compounds have been widely used in a variety of fields, especially in drug and pesticide design. To find novel insect growth regulators, a series of benzoylphenylureas with fluorinated substituents were de

Full text of DOI:10.1021/jf104578j

ARTICLE
pubs.acs.org/JAFC
Design and Synthesis of Benzoylphenylureas with Fluorinated
Substituents on the Aniline Ring as Insect Growth Regulators
Ranfeng Sun, Yuxiu Liu, Yonglin Zhang, Lixia Xiong, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, People’s Republic of China
ABSTRACT: Enormous numbers of synthetic fluorine-containing compounds have been widely used in a variety of fields,
especially in drug and pesticide design. To find novel insect growth regulators, a series of benzoylphenylureas with fluorinated
substituents were designed and synthesized. The results of larvicidal activities of those novel fluoro-substituted benzoylphenylureas
against oriental armyworm and mosquito revealed that most compounds exhibited excellent activities. It is worth mentioning that
compounds 3 and 6 exhibited higher activities against oriental armyworm and mosquito than commercial Hexaflumuron. It can be
further seen that the insecticidal activities would increase significantly by introducing fluorinated substituents into the structure of
the designed benzoylphenylureas.
KEYWORDS: benzoylphenylureas (BPUs), structure-activity relationship, larvicidal activity, insect growth regulator
’ INTRODUCTION
activities and minor structural changes at the anilide moiety could
discover novel insecticides as insect growth regulators (Figure 1).
Recently, Cao et al. have designed and synthesized a series of
novel benzoylphenylurea derivatives (compound 1) by introdu-
cing a heptafluoroisopropyl group into the structure of benzoyl-
phenylurea (Figure 2). They found that compound 2 had better
solubility than chlorfluazuron and exhibited similar efficacy
comparable with that of hexaflumuron against diamondback
moth.19 In view of the above statement, introducing fluorinated
substituents into the structure of benzoylphenylureas would
improve the insecticidal activities and solubility. To find novel
benzoylurea derivatives, compounds 3-8 were designed and
synthesized by introducing fluorinated substituents into the
structure of benzoylphenylureas according to substructure link-
ing (Figure 3). Then the larvicidal activities of these novel fluoro-
substituted benzoylphenylureas 3-8 against oriental armyworm
(Mythimna separata) and mosquito (Culex pipiens pallens) were
evaluated.
Food production capacity is faced with an ever-growing
number of challenges. Some 20-40% of the world’s potential
crop production is already lost annually because of the effects of
weeds, pests, and diseases (according to the Food and Agricul-
ture Organization of the United Nations or FAO). These crop
losses would be doubled if existing pesticide uses were aban-
doned, significantly raising food prices.1 The use of pesticides
brings numerous benefits and makes a significant contribution to
the lifestyles we have come to expect, but pollution and the
emergence of pesticide resistance push researchers to develop
novel pesticides. The extraordinary potential of fluorine-contain-
ing molecules in medicinal chemistry and chemical biology has
been recognized. The special nature of fluorine (mimic effect,
block effect, steric effect, and inductive effect) imparts a variety of
properties to certain pesticides, including enhanced binding
interactions, metabolic stability, changes in physical properties,
and selective reactivities.2-4 It is reported that 30-40% of
commercial pesticides contain fluorine atoms.5
Insect growth regulators (IGRs), which interrupt or inhibit the
life cycle of pests, are low-toxicity pesticides and widely used in
integrated pest management (IPM). Benzoylphenylureas (BPUs)
are a familiar type of IGRs, which have attracted considerable
attention for decades because of their unique mode of action and
low toxicity to nontarget organisms (including many beneficial
arthropods).6-10 More than 20 benzoylphenylureas have been
developed as IGRs since Dimilin (diflubenzuron) was introduced
to the market in 1972. Most of the commercial BPUs contain
fluorine atoms because QSAR studies of BPUs showed that ben-
zoylurea derivatives with a 2,6-difluoro substitution in the benzoyl
moiety exhibited much higher larvicidal activity than other
substitutions.11,12 The substituent changes of aniline ring have been
the focus of research on benzoylurea insecticides.13-18 Structural
comparison of commercial benzoylphenylureas revealed that fluori-
nated substituents at an anilide moiety could increase the insecticidal
’ MATERIALS AND METHODS
Instruments. 1H 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 solution with tetramethylsilane as the
internal standard. Chemical shift values (δ) were given in parts per
million (δ). 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
Instruments Co., Beijing, China) and were uncorrected. Yields were not
optimized.
Received: November 30, 2010
Revised:
January 26, 2011
Accepted: January 31, 2011
Published: March 02, 2011
r
2011 American Chemical Society
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Figure 1. Structures of commercial benzoylphenylureas as insect growth regulators.
over anhydrous magnesium sulfate and filtered. The filtrate was con-
centrated under reduced pressure to give compound 3b as a brown oil
(1.02 g, 29.0%): 1H NMR (400 M, CDCl3) δ 5.30 (br s, 1H, Ar-OH),
6.03 (tt, 3JHF =3.4Hz, 2JHF = 53.0 Hz, 1H, CF2CF2H), 6.84(s, 2H, Ar-H).
Synthesis of 1,3-Dichloro-5-(4-nitrophenoxy)-2-(1,1,2,2-
tetrafluoroethoxy)benzene (3c). Compound 3b (0.30 g, 1.08
mmol) and NaOH (0.043 g, 1.08 mmol) were dissolved in DMF (8 mL)
and toluene (10 mL), and the mixture was heated to remove mois-
ture by distillation as an azeotrope with toluene. Then 1-chloro-4-
nitrobenzene (0.16 g, 1.02 mmol) was added and refluxed for 7 h. When
the reaction was complete, DMF was removed and saturated brine water
(5 mL) was added. The mixture was extracted by ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate and filtered.
The filtrate was concentrated under reduced pressure to give a crude
product, which was purified by flash column chromatography on silica
gel using a mixture of petroleum ether (60-90 °C) and ethyl acetate
(v/v = 20:1) as the eluent to obtain compound 3c (0.20 g, 49.0%) as a
Figure 2. Structures of benzoylphenylureas containing a heptafluo-
roisopropyl group.
yellow solid: mp 81-82 °C; 1H NMR (400 M, CDCl3) δ 6.06 (tt, 3JHF
=
3.3 Hz, 2JHF = 52.9 Hz, 1H, CF2CF2H), 7.10 (s, 2H, Ar-H), 7.12 (d,
3JHH = 9.2 Hz, 2H, Ar-H), 8.28 (d, 3JHH = 9.2 Hz, 2H, Ar-H).
Synthesis of 4-(3,5-Dichloro-4-(1,1,2,2-tetrafluoroethox-
General Synthesis. The reagents were all analytically or chemi-
cally pure. All anhydrous solvents were dried and purified by standard
techniques prior to use. 2,6-Difluorobenzoyl isocyanate was prepared
according to the method of the literature.20
y)phenoxy)aniline (3d). To a solution of CuCl2 2H2O (0.04 g,
3
0.23 mmol) in 1.2% hydrochloric acid (10 mL) was added zinc powder;
the solution was removed until bubbles no longer appeared. Then the
Zn-Cu couple was washed with distilled water one time and directly
used in the next step.
Synthesis of 3,5-Dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenol (3b). To a mixture of water (70 mL) and concentrated sul-
furic acid (98%, 15 mL) was added dropwise 3,5-dichloro-4-(1,1,2,2-
tetrafluoroethoxy)aniline (3a, 3.5 g, 12.59 mmol) at 75-80 °C. When
3a was dissolved completely, the mixture was cooled to 0 °C, and a
solution of NaNO2 (0.96 g, 13.91 mmol) in water (5 mL) was slowly
dropwise added at this temperature. Then the reaction stood at 0 °C for
0.5 h and at 25 °C for another 0.5 h. After the mixture was slowly added
to a solution of CuSO4 (10.0 g, 62.89 mmol) in water (150 mL) at
boiling point, the solution was distilled until no oil was produced. The
fraction was extracted by ethyl acetate, and the organic layer was dried
Freshly prepared Zn-Cu couple was added to a mixture of com-
pound 3c (0.19 g, 0.48 mmol) in diethyl ether (15 mL) and saturated
aqueous NH4Cl (15 mL) and then stirred for 5 h at room temperature.
When the reaction was complete (monitored by TLC), the organic layer
was washed successively with saturated sodium carbonate solution and
saturated brine. The organic layer was dried over anhydrous magnesium
sulfate and filtered. The solvent was removed to give a crude product,
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Figure 3. Design of novel fluoro-substituted benzoylphenylureas 3-8.
which was purified by flash column chromatography on silica gel using a
mixture of petroleum ether (60-90 °C) and ethyl acetate (v/v = 3:1) as
the eluent to give compound 3d as a brown oil (0.16 g, 91.0%): 1H NMR
6.96 (d, 4JHH = 2.6 Hz, 1H, Ar-H), 7.55 (dd, 4JHH = 2.6 Hz, 3JHH = 8.7
Hz, 1H, Ar-H),7.85 (d, 3JHH = 8.7 Hz, 1H, Ar-H).
Synthesis of 3-Chloro-4-(3,5-dichloro-4-(1,1,2,2-tetrafluo-
roethoxy)phenoxy)aniline (4d). Compound 4d was obtained as a
pale yellow viscous liquid (yield, 98.5%) by following the same pro-
cedure as for compound 3d: 1H NMR (300 M, CDCl3) δ 3.76 (br s, 2H,
Ar-NH2), 6.03 (tt, 3JHF = 3.4 Hz, 2JHF = 52.9 Hz, 1H, CF2CF2H), 6.60
(dd, 4JHH = 2.6 Hz, 3JHH = 8.6 Hz, 1H, Ar-H), 6.79 (d, 4JHH = 2.6 Hz,
1H, Ar-H), 6.86 (s, 2H, Ar-H), 6.93 (d, 3JHH = 8.6 Hz, 1H, Ar-H).
Synthesis of N-(3-Chloro-4-(3,5-dichloro-4-(1,1,2,2-tetra-
fluoroethoxy)phenoxy)phenylcarbamoyl)-2,6-difluoroben-
zamide (4). Target compound 4 was obtained as a white solid (yield,
89.2%, mp 185-187 °C) by following the same procedure as for com-
pound 3: 1H NMR (400 M, CDCl3) δ 6.05 (tt, 3JHF = 3.3 Hz, 2JHF = 52.8
Hz, 1H, CF2CF2H), 6.91 (s, 2H, Ar-H), 7.05-7.11 (m, 3H, Ar-H),
7.36 (dd, 4JHH = 2.5 Hz, 3JHH = 8.7 Hz, 1H, Ar-H), 7.49-7.57 (m, 1H,
Ar-H), 7.84 (d, 4JHH = 2.5 Hz, 1H, Ar-H), 9.13 (br s, 1H, CONHAr),
10.60 (br s, 1H, ArCONHCO). Anal. Calcd for C22H11Cl3F6N2O4: C,
44.96; H, 1.89; N, 4.77. Found: C, 45.08; H, 1.97; N, 4.89.
3
(400 M, CDCl3) δ 3.70 (br s, 2H, Ar-NH2), 6.02 (tt, JHF = 3.3 Hz,
2JHF = 52.9 Hz, 1H, CF2CF2H), 6.70 (d, 3JHH = 8.7 Hz, 2H, Ar-H), 6.86
(d, 3JHH = 8.7 Hz, 2H, Ar-H), 6.89 (s, 2H, Ar-H).
Synthesis of N-(4-(3,5-Dichloro-4-(1,1,2,2-tetrafluoroeth-
oxy)phenoxy)phenylcarbamoyl)-2,6-difluorobenzamide (3).
A solution of 2,6-difluorobenzoyl isocyanates (0.08 g, 0.44 mmol) in
dry dichloromethane (5 mL) was added dropwise to a solution of compound
3d (0.16 g, 0.43 mmol) in dry dichloromethane (10 mL) at room temperature.
The reaction stood for 2 h, and the solvent was evaporated off under reduced
pressure. Then the product was purified by recrystallization from a mixture of
ethyl acetate and petroleum ether (60-90 °C) (v/v = 2:1), giving target
compound 3as a white solid (0.16 g, 89.4%): mp 199-201 °C; 1H NMR(400
M, CDCl3) δ 6.04 (tt, 3JHF = 3.3 Hz, 2JHF = 52.9 Hz, 1H, CF2CF2H), 6.96 (s,
2H, Ar-H), 7.01-7.10 (m, 4H, Ar-H), 7.49-7.60 (m, 3H, Ar-H), 8.57(br s,
1H, CONHAr), 10.45 (br s, 1H, ArCONHCO). Anal. Calcd for
C22H12Cl2F6N2O4: C, 47.76; H, 2.19; N, 5.06. Found: C, 47.60; H, 2.17; N, 4.91.
Synthesis of 1,3-Dichloro-5-(2-chloro-4-nitrophenoxy)-
2-(1,1,2,2-tetrafluoroethoxy)benzene (4c). Intermediate 4c
was obtained as a yellow viscous liquid (yield, 87.0%) by following the
same procedure as for compound 3c: 1H NMR (300 M, CDCl3) δ 6.03
(tt, 3JHF = 3.4 Hz, 2JHF = 52.9 Hz, 1H, CF2CF2H), 6.86 (s, 2H, Ar-H),
Synthesis of 1,3-Dichloro-5-(4-nitrobenzyloxy)-2-(1,1,2,2-
tetrafluoroethoxy)benzene (5c). Intermediate 3b (0.35 g, 1.25
mmol) and NaOH (0.05 g, 1.25 mmol) were dissolved in ethanol (5 mL),
and the ethanol was removed under reduced pressure. Then the solid
was dissolved in DMF (10 mL) and 1-(bromomethyl)-4-nitrobenzene
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Scheme 1. General Synthetic Route for Compounds 3 and 4a
a Reagents and conditions: (a) NaNO2, H2SO4; CuSO4; (b) 1-chloro-4-nitrobenzene for compound 3c, 1,2-dichloro-4-nitrobenzene for compound 4c,
NaOH, DMF/toluene, reflux, 7 h; (c) Zn/Cu/NH4Cl, Et2O, 25 °C; (d) 2,6-difluorobenzoyl isocyanates, CH2Cl2, 25 °C.
Scheme 2. Synthetic Route for Compound 5a
a Reagents and conditions: (a) 1-(bromomethyl)-4-nitrobenzene, NaOH, DMF, 25 °C, 1 h; (b) Zn/Cu/NH4Cl, Et2O, 25 °C; (c) 2,6-difluorobenzoyl
isocyanates, CH2Cl2, 25 °C.
(0.27 g, 1.25 mmol) was added to the solution. The mixture was stirred
for 1 h, and the solvent was evaporated off under reduced pressure.
Afterward, saturated brine water (10 mL) was added, and the mixture
was extracted by ethyl acetate. The organic layer was dried over anhy-
drous magnesium sulfate and filtered. The filtrate was concentrated
under reduced pressure to give a crude product, which was purified by
recrystallization from a mixture of ethyl acetate and petroleum ether to
give compound 5c as a pale yellow solid (0.44 g, 85.3%): mp 117-
118 °C; 1H NMR (400 M, CDCl3) δ 5.15 (s, 2H, Ar-CH2O), 6.04 (tt,
3JHF = 3.4 Hz, 2JHF = 53.0 Hz, 1H, CF2CF2H), 7.00 (s, 2H, Ar-H), 7.58
(d, 3JHH = 8.7 Hz, 2H, Ar-H), 8.28 (d, 3JHH = 8.7 Hz, 2H, Ar-H).
Synthesis of4-((3,5-Dichloro-4-(1,1,2,2-tetrafluoroethoxy)-
phenoxy)methyl)aniline (5d). Compound 5d was obtained as a pale
yellow viscous liquid (yield, 98.5%) by following the same procedure as for
compound 3d: 1H NMR (400 M, CDCl3) δ 3.75 (br s2, 2H, CF2CF2H),
8.23 (br s, 1H, CONHAr), 10.45 (br s, 1H, ArCONHCO). Anal. Calcd for
C23H14-
Cl2F6N2O4: C, 48.70; H, 2.49; N, 4.94. Found: C, 48.53; H, 2.57; N, 4.85.
Synthesis of 1-(1,1,1,3,3,3-Hexafluoropropan-2-yloxy)-4-
nitrobenzene (6c) 21. To a solution of 1,1,1,3,3,3-hexafluoro-2-
propanol (0.50 g, 2.98 mmol) and N(Bu)4F 3H2O (1.53 g, 4.85 mmol)
3
in DMF (45 mL) was added 1,4-dinitrobenzene (0.17 g, 1.01 mmol),
and the mixture was stirred for 24 h at room temperature. Then 1.2%
hydrochloric acid (30 mL) was added, and the mixture was extracted by
diethyl ether. The organic layer was dried over anhydrous magnesium
sulfate and filtered. The filtrate was concentrated under reduced pres-
sure to give a crude product, which was purified by flash column chro-
matography on silica gel using a mixture of petroleum ether (60-90 °C)
and ethyl acetate (v/v = 10:1) as the eluent to give compound 6c as a
1
pale yellow solid (0.10 g, 34.5%): mp 52-53 °C; H NMR (400 M,
3
2
4.88 (s, 2H, Ar-CH2O), 6.02 (tt, JHF = 3.4 Hz, JHF = 53.0 Hz, 1H,
CF2CF2H), 6.69 (d, 3JHH = 8.3 Hz, 2H, Ar-H), 6.96 (s, 2H, Ar-H), 7.17
(d, 3JHH = 8.3 Hz, 2H, Ar-H).
CDCl3) δ 4.92-5.00 (m, 1H, OCH(CF3)2), 7.19 (d, 3JHH = 9.2 Hz, 2H,
Ar-H), 8.29 (d, 3JHH = 9.2 Hz, 2H, Ar-H).
Synthesis of 4-(1,1,1,3,3,3-Hexafluoropropan-2-yloxy)-
aniline (6d). Compound 6d was obtained as a pale yellow oil (yie-
Synthesis of N-(4-((3,5-Dichloro-4-(1,1,2,2-tetrafluoroeth-
oxy)phenoxy)methyl)phenylcarbamoyl)-2,6-difluoroben-
zamide (5). Target compound 5 was obtained as a white solid (yield,
72.5%, mp 211-212 °C) by following the same procedure as for
1
ld, 89.0%) by following the same procedure as for compound 3d: H
NMR (400 M, CDCl3) δ 3.59 (br s, 2H, Ar-NH2), 4.52-4.61 (m, 1H,
OCH(CF3)2), 6.30 (d, 3JHH = 8.8 Hz, 2H, Ar-H), 6.90 (d, 3JHH = 8.8
Hz, 2H, Ar-H).
Synthesis of 2,6-Difluoro-N-(4-(1,1,1,3,3,3-hexafluoropro-
pan-2-yloxy)phenylcarbamoyl)benzamide (6). Target compound
6 was obtained as a white solid (yield, 67.2%, mp 197-198 °C) by following
1
compound 3: H NMR (400 M, CDCl3) δ 5.00 (s, 2H, Ar-CH2O),
6.03 (tt, 3JHF = 3.3 Hz, 2JHF = 53.0 Hz, 1H, CF2CF2H), 6.98 (s, 2H, Ar-
H), 7.06 (t, 3JHH = 3JHF = 8.7 Hz, 2H, Ar-H), 7.37 (d, 3JHH = 8.4 Hz,
2H, Ar-H), 7.49-7.57 (m, 1H, Ar-H), 7.59 (d, 3JHH = 8.4 Hz, 2H, Ar-H),
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Scheme 3. Synthetic Route for Compound 6a
a Reagents and conditions: (a) tetra-n-butylammoniumfluoridetrihydrate (TBAF), DMF, 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), 25 °C, 24 h; (b)
Zn/Cu/NH4Cl, Et2O, 25 °C; (c) 2,6-difluorobenzoyl isocyanates, CH2Cl2, 25 °C.
the same procedure as for compound 3: 1HNMR(400M, CDCl3) δ4.71-
4.77(m, 1H, OCH(CF3)2), 7.04-7.09 (m, 4H, Ar-H), 7.50-7.56 (m, 3H,
Ar-H), 8.18 (br s, 1H, CONHAr), 10.39 (br s, 1H, ArCONHCO). Anal.
Calcd for C17H10F8N2O3: C, 46.17; H, 2.28; N, 6.33. Found: C, 46.07; H,
2.33; N, 6.33.
Scheme 4. Synthetic Route for Compound 7a
Synthesis of 1-((1,1,1,3,3,3-Hexafluoropropan-2-yloxy)-
methyl)-4-nitrobenzene (7c). Metal sodium (0.09 g, 3.91 mmol)
was added to 1 1,1,1,3,3,3-hexafluoro-2-propanol (5 mL), and then
DMF (5 mL) and 1-(bromomethyl)-4-nitrobenzene (0.43 g, 1.99 mmol)
were added and refluxed for 2 h. The solvent was removed, and water
(10 mL) was added. Afterward, the mixture was extracted by ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate and filtered.
The filtrate was concentrated under reduced pressure to give compound 7c
a Reagents and conditions: (a) 1,1,1,3,3,3-hexafluoropropan-2-ol
(HFIP), Na, DMF, 25 °C, 24 h; (b) Zn/Cu/NH4Cl, Et2O, 25 °C; (c)
2,6-difluorobenzoyl isocyanates, CH2Cl2, 25 °C.
1
as a brown oil (yield, 98.8%): H NMR (400 M, CDCl3) δ 4.15-4.23
(m, 1H, OCH(CF3)2), 4.99 (s, 2H, ArCH2O), 7.54 (d, 3JHH = 8.7 Hz, 2H,
Ar-H), 8.26 (d, 3JHH = 8.7 Hz, 2H, Ar-H).
Synthesis of 4-(3,3-Dichloroallyloxy)aniline (8d). Compound
8d was obtained as a yellow viscous liquid (yield, 99.5%) by following the
same procedure as for compound 3d: 1H NMR (400 M, CDCl3) δ 4.35
(br s, 2H, Ar-NH2), 4.57 (d, 3JHH = 6.1 Hz, 2H, OCH2CHCCl2), 6.14
(t, 3JHH = 6.1 Hz, 1H, OCH2CHCCl2), 6.64(d, 3JHH = 8.7 Hz, 2H, Ar-H),
6.73 (d, 3JHH = 8.7 Hz, 2H, Ar-H).
Synthesis of 4-((1,1,1,3,3,3-Hexafluoropropan-2-yloxy)-
methyl)aniline (7d). Compound 7d was obtained as a yellow oil
(yield, 90.0%) by following the same procedure as for compound 3d: 1H
NMR (400 M, CDCl3) δ 3.75 (br s, 2H), 4.04-4.12 (m, 1H, OCH-
(CF3)2), 4.74 (s, 2H, ArCH2O), 6.68 (d, 3JHH = 8.2 Hz, 2H, Ar-H),
7.14 (d, 3JHH = 8.2 Hz, 2H, Ar-H).
Synthesis of N-(4-(3,3-Dichloroallyloxy)phenylcarbamo-
yl)-2,6-difluorobenzamide (8). Target compound 8 was obtained
as a white solid (yield, 80.2%, mp 187-188 °C) by following the same
Synthesis of 2,6-Difluoro-N-(4-((1,1,1,3,3,3-hexafluoro-
propan-2-yloxy)methyl)phenylcarbamoyl)benzamide (7). Target
compound 7 was obtained as a white solid (yield, 27.6%, mp 174-175 °C)
1
1
procedure as for compound 3: H NMR (400 M, CDCl3) δ 4.66 (d,
by following the same procedure as for compound 3: H NMR (400 M,
3
3JHH = 6.2 Hz, 2H, OCH2CHCCl2), 6.16 (t, JHH = 6.2 Hz, 1H,
CDCl3) δ 4.07-4.16 (m, 1H, OCH(CF3)2), 4.84 (s, 2H, ArCH2O), 7.06 (t,
3JHH = 3JHF = 8.4 Hz, 2H, Ar-H), 7.34 (d, 3JHH = 8.4 Hz, 2H, Ar-H), 7.49-
7.57 (m, 1H, Ar-H), 7.57 (d, 3JHH = 8.4 Hz, 2H, Ar-H), 8.54 (br s, 1H,
CONHAr), 10.49 (br s, 1H, ArCONHCO). Anal. Calcd for C18H12F8N2O3:
C, 47.38; H, 2.65; N, 6.14. Found: C, 46.90; H, 3.09; N, 6.23.
3
3
OCH2CHCCl2), 6.85 (d, JHH = 9.0 Hz, 2H, Ar-H), 7.04 (t, JHH
=
3JHF = 8.3 Hz, 2H, Ar-H), 7.41 (d, 3JHH = 9.0 Hz, 2H, Ar-H), 7.47-
7.57 (m, 1H, Ar-H), 9.01 (br s, 1H, CONHAr), 10.29 (br s, 1H,
ArCONHCO). Anal. Calcd for C17H12Cl2F2N2O3: C, 50.89; H, 3.01;
N, 6.98. Found: C, 51.03; H, 3.04; N, 7.03.
Synthesis of 1-(3,3-Dichloroallyloxy)-4-nitrobenzene
(8c). 4-Nitrophenol (0.28 g, 2.01 mmol) and NaOH (0.08 g, 2.00
mmol) were dissolved in ethanol (10 mL), and the ethanol was removed
under reduced pressure. Then the solid was dissolved in DMF (10 mL),
and 1,1,3-trichloroprop-1-ene (0.50 g, 3.45 mmol) was added to the
solution. The mixture was heated to 70 °C and stirred for 2 h at this
temperature. Then the solvent was evaporated off under reduced pres-
sure, and saturated brine water (10 mL) was added. Afterward, the
mixture was extracted by ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate and filtered. The filtrate was concentrated
under reduced pressure to give a crude product, which was purified by
flash column chromatography on silica gel using a mixture of petroleum
ether (60-90 °C) and ethyl acetate (v/v = 8:1) as the eluent to give
compound 6c as a pale yellow solid (0.29 g, 58.5%): mp 55-56 °C; 1H
NMR (400 M, CDCl3) δ 4.74 (d, 3JHH = 6.3, 2H, OCH2CHCCl2), 6.15
(t, 3JHH = 6.3, 1H, OCH2CHCCl2), 6.93 (d, 3JHH = 9.2 Hz, 2H, Ar-H),
8.21 (d, 3JHH = 9.2 Hz, 2H, Ar-H).
Biological Assay. All bioassays were performed on representative
test organisms reared in the laboratory. The bioassay was carried out in
standard conditions (temperature, 25 ( 1 °C; humidity, 60-80%; light
cycle, L/D = 16:8). Assessments were made on a dead/alive basis, and
mortality rates were corrected using Abbott’s formula.22 Evaluations are
based on a percentage scale of 0-100 in which 0 = no activity and 100 =
total kill. The relative standard deviations of the test biological values
were (5%.
Larvicidal Activity against Oriental armyworm. The larvi-
cidal activities of the target compounds 3-8 against oriental army-
worm were evaluated by foliar application using the reported proce-
dure.23 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
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Journal of Agricultural and Food Chemistry
ARTICLE
Scheme 5. Synthetic Route for Compound 8a
a Reagents and conditions: (a) NaOH, DMF, 70 °C, 2 h; (b) Zn/Cu/NH4Cl, Et2O, 25 °C; (c) 2,6-difluorobenzoyl isocyanates, CH2Cl2, 25 °C.
treatment was performed three times. For comparative purposes,
compound 2 and Hexaflumuron were tested under the same con-
ditions.
Table 1. Larvicidal Activities against Oriental Armyworm
and Mosquito of Compounds 2-8 and Hexaflumuron
Larvicidal Activity against Mosquito. The larvicidal activities
of the target compounds 3-8 against mosquito were evaluated by
using the reported procedure.24 The compounds 3-8 were prepared
to different concentrations by dissolving 3-8 in acetone and adding
distilled water. Then 20 fourth-instar mosquito larvae were put into
10 mL of the test solution and raised for 8 days. The results were
expressed by death percentage. For comparative purposes, compound
2 and Hexaflumuron were tested under the same conditions.
toxicity against oriental
armyworm
toxicity against
mosquito
concn
concn
compd
(mg L-1
)
activity (%)
(mg L-1
)
activity (%)
3
2.5
1.0
100
0
0.005
100
50
0.0025
4
5
6
7
8
50
25
10
100
90
0.025
0.01
100
80
’ RESULTS AND DISCUSSION
60
0.005
30
Synthesis. Diazotization and hydrolysis of fluorine-contain-
ing intermediate 3a gave 3,5-dichloro-4-(1,1,2,2-tetrafluoroeth-
oxy)phenol (3b) in 34% yield (Scheme 1). Then nucleophilic
substitution of 1-chloro-4-nitrobenzene, 1,2-dichloro-4-nitro-
benzene, or 1-(bromomethyl)-4-nitrobenzene with intermediate
3b gave intermediates 3c, 4c, and 5c, respectively (Schemes 1
and 2).25 However, commonly used methods of reduction of
aromatic nitro group to amino (Fe/HCl, Fe/AcOH, SnCl2/
AcOH, Na2S, N2H4/Pd-C) were not suitable for the synthesis
of intermediate 5d from 5c, which was decomposed in these
conditions. After continuous attempts, intermediate 5d was
obtained in excellent yield using a Zn/Cu couple for the reduc-
tion of the nitro-aromatics 5c in saturated aqueous NH4Cl-
Et2O solution according to the literature.26 Afterward, inter-
mediate 5d was combined with 2,6-difluorobenzoyl isocyanate to
afford target compound 5 (see Scheme 2) . Intermediates 3d and
4d were obtained according to the same method used to obtain
intermediate 5d and then were combined with 2,6-difluoro-
benzoyl isocyanate to afford target compounds 3 and 4 (see
Scheme 1) . Target compounds 6-8 were synthesized (see
Schemes 3, 4, and 5, respectively) using methodologies similar to
those employed for the preparation of compound 5.
Biological Assay. Larvicidal Activities against Oriental Army-
worm and Mosquito. The larvicidal activities of novel fluoro-
substituted benzoylphenylureas 3-8, Cao's compound 2, and
commercial Hexaflumuron against oriental armyworm and mos-
quito were evaluated. The results (seen in Table 1) indicate that
most compounds have excellent larvicidal activities against oriental
armyworm and mosquito, and it was found that phenoxyl or alkoxyl
benzoylphenylureas exhibited better larvicidal activities than phe-
noxymethyl or alkoxymethyl benzoylphenylureas, respectively,. For
example, compound 3 has 100% morality at a concentration of
2.5 mg L-1, whereas compound 5 has only 10% morality at a
concentration of 5 mg L-1. Furthermore, compounds 3 and 6,
25
10
5
100
40
2
0
10
5
90
80
0
0.1
0.05
0.025
100
80
2.5
1.0
70
200
100
50
40
10
0
0.25
0.1
100
80
0.05
30
200
100
50
90
80
60
0.1
0.05
0.025
100
70
60
Hexaflumuron
10
80
0.25
100
2
5
100
90
0
0.01
0.005
0.0025
100
90
2.5
1.0
80
which are different types of BPUs, exhibited higher activity than
commercial Hexaflumuron. In particular, compound 3 displayed
larvicidal activities against oriental armyworm and mosquito similar
to thost of compound 2, which was reported by Cao et al.19 At the
same time, compound 4 exhibited lower activity than compound 3
with a 3-chlorine substituent at the aniline ring of compound 3.
In summary, a group of benzoylphenylureas with fluorinated
substituents at the anilide moiety were designed and synthesized,
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Journal of Agricultural and Food Chemistry
ARTICLE
1
and their structures were characterized by H NMR and ele-
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mental analysis. The larvicidal activities against oriental army-
worm and mosquito of these novel fluoro-substituted benzoyl-
phenylureas were evaluated. The result shows that most com-
pounds exhibited excellent larvicidal activities against oriental
armyworm and mosquito. Surprisingly, compounds 3 and 6
exhibited higher activities against oriental armyworm and mos-
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the insecticidal activities would increase significantly by the
introduction of fluorinated substituents into the structure of
the designed benzoylphenylureas.
’ AUTHOR INFORMATION
Corresponding Author
*Phone: þ86-(0)22-23499842. Fax: þ86-(0)22-23499842. E-mail:
wang98h@263.net or wangqm@nankai.edu.cn.
Funding Sources
This work was supported by the National Key Project for Basic
Research (2010CB126106) and the National Natural Science
Foundation of China (21072109).
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