Synthesis and insecticidal activities of novel analogues of flubendiamide containing a hexafluoroisopropanol moiety

Article abstract of DOI:10.1002/cjoc.201200215

Ten novel analogues of flubendiamide containing a hexafluoroisopropanol moiety were designed and synthesized. Their insecticidal activities against armyworm (Pseudaletia separata Walker) were examined and compared with the commercial product flubendiamide. Compound 7b showed nearly the same insecticidal activity as flubendiamide against armyworm.

Full text of DOI:10.1002/cjoc.201200215

FULL PAPER
DOI: 10.1002/cjoc.201200215
Synthesis and Insecticidal Activities of Novel Analogues of
Flubendiamide Containing a Hexafluoroisopropanol Moiety†
Wu, Mingxi(吴明熹)
Zhao, Wenwen(赵雯雯)
Jin, Guanyi(金观毅)
Huang, Qingchun(黄青春)
Cao, Song*(曹松)
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Tech-
nology, Shanghai 200237, China
Ten novel analogues of flubendiamide containing a hexafluoroisopropanol moiety were designed and synthe-
sized. Their insecticidal activities against armyworm (Pseudaletia separata Walker) were examined and compared
with the commercial product flubendiamide. Compound 7b showed nearly the same insecticidal activity as fluben-
diamide against armyworm.
Keywords hexafluoroisopropanol moiety, flubendiamide, synthesis, insecticidal activities
Introduction
Since the first commercial phthalic diamide, fluben-
diamide, was widely used in the world in 2007, there
have been numerous reports and researches on the opti-
mization of flubendiamide.[4] These studies have fo-
cused on the modification of the phthaloyl moiety, the
heptafluoroisopropyl group in the anilide moiety, and
the sulfonylalkyl group in the aliphatic amide moiety.[5]
Although flubendiamide exhibits excellent activities
against various insects, the use of expensive starting
material (heptafluoroisopropyl iodide) and the difficult
handling and storing of this reagent have posed a few
problems for their further development. Furthermore,
the method of the synthesis of the key intermediates,
heptafluoroisopropyl anilines, is protected by patents.
Thus, it is highly desirable to replace heptafluoroiso-
propyl group by other fluorine-containing groups.[6]
It is well-known that the incorporation of fluorine-
containing group to alter the chemical, physical, and
biological properties of the parent compounds has found
many applications in pharmaceutical chemistry, materi-
als and agricultural industries.[7] Different fluorine-
containing groups surely have different effects on the
molecules. Hexafluoroisopropanol moiety attracts much
attention in materials chemistry due to its dissolution
behavior, anti-swelling property, and high contrast.[8]
However, only a few examples of the synthesis and
bioassay of hexafluoroisopropanol unit-containing
compounds have been reported.[9] For example, com-
pound I is a synthetic agonist for the orphan nuclear
receptors RORα and RORγ.[10] It was found that in
compound II, the hexafluorocarbinol moiety is essential
for activation of the LXRα receptor.[11]
Ryanodine is an ester of the alcohol (ryanodol) (Fig-
ure 1, left), a poisonous alkaloid derived from the South
American plant known as Ryania speciosa (Flacour-
tiaceae). It was originally used as an insecticide. Ry-
anodine can disrupt calcium channels of insects, modify
the calcium storage of muscles and cause uncontrollable
muscle spasms.[1] However, attempts to develop Ryano-
dine as a commercial insecticide have not proven suc-
cessful. The cost and mammalian toxicity associated
with Ryanodine limit their agricultural use. Moreover,
no commercial synthetic routes of Ryanodine or its de-
rivatives have been found so far. In 2007, Bayer Crop-
Science and Nihon Nohyaku launched flubendiamide
(Figure 1, right), a new insecticide with a novel mode of
action for controlling lepidopterous pests.[2] It disrupts
the proper muscle function in insects and therefore is
considered as the first synthetic classes of potent acti-
vators of insect ryanodine receptors.[3]
CH3
O
S
CH3
O
I
HN
CH3
O
OH
OH
HO
O
OH
O
OH
OH
O
H
N
HN
O
CF3
H3C
F
CF3
Figure 1 Structure of Ryanodine (left) and flubendiamide
(right).
*
E-mail: scao@ecust.edu.cn; Tel.: 0086-021-64253452; Fax: 0086-021-64252603
Received March 3, 2012; accepted March 27, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200215 or from the author.
Dedicated to Professor Jun Zhou on the occasion of his 80th birthday.
†
1310
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1310—1314

Synthesis and Insecticidal Activities of Novel Analogues of Flubendiamide
corded under electron impact conditions using a Mi-
croMass GCT CA 055 instrument.
F3C
OH
O
O
CF3
O
CF3
OH
S
F3C
Synthesis of compounds 1 and 2
N
HN
3-Iodophthalic anhydride (1) and 1,1-dimethyl-2-
methylthioethylamine (2) were synthesized according to
the methods reported in the literature with some modi-
fication.[12]
CF3
CF3
II
I
Figure 2 Structure of hexafluoroisopropanol unit-containing
bioactive compounds I and II.
Synthesis
of
3-(1,1-dimethyl-2-methylthioethyl-
In this paper, a hexafluoroisopropanol group was in-
troduced into the structure of the phthalic diamide by
using hexafluoroacetone trihydrate as the fluorinating
reagent. Ten hexafluoroisopropanol unit-containing
flubendiamide analogues were synthesized. Their insec-
ticidal activities against armyworm (Pseudaletia sepa-
rata Walker) were evaluated (Scheme 1, 7a—7j)
imino)-4-iodo-3H-isobenzofuran-1-one (3)
The intermediate 3 was synthesized by the reaction
of 3-iodophthalic anhydride (1) with 1,1-dimethyl-
2-methylthioethylamine (2) in acetonitrile, followed by
cyclization by trifluoroacetic anhydride in acetoni-
trile.[13] Compound 3 was identified by GC-MS.
Synthesis of 2-(4-aminoaryl)-1,1,1,3,3,3-hexafluoro-
propan-2-ol (5a—5j)
Scheme 1 Synthetic pathway of (2-hydroxy)hexafluoroiso-
propyl-containing flubendiamide analogues 7a—7j
A solution of hexafluoroacetone trihydrate (2.42 g,
11 mmol) and p-toluenesulfonic acid (0.1 g, 0.6 mmol)
in 5 mL of xylene was added to substituted anilines 4a
—4j (10 mmol) at 90 ℃. The mixture was then stirred
at 130 ℃ for about 12 h (monitored by TLC or
GC/MS). After the completion of reaction, the solution
was cooled to room temperature and the solid precipi-
tate was filtered, washed by petroleum ether.[14] The
crude products 5a—5j were obtained (Eq. 1).
S
I
O
H2N
2
(CF3CO)2O
Toluene
O
CH3CN
O
R1
1
CF3
OH
CF3
H2N
I
R2
N
S
5a 5j
O
CH3CN
R1
H3C
SO3H
O
3
.
.
CF3COCF3 3H2O
H2N
+
CH3
O
Xylene, reflux
S
O
H3C
HN
R2
4a 4j
S
CH3
H3C
HN
OH
Cl
O
I
O
CH3
I
R1
CH3
O
CF3
OH
O
O
(1)
H2N
CH3CN
O
R2
HN
CF3
R2
R2
5a 5j
HN
CF3
OH
CF3
OH
R1
F3C
7j
R1
F3C
General procedure for the synthesis of the target
compounds, hexafluoroisopropanol unit-containing
flubendiamide analogues, 7a—7j
7a
6a 6j
To a solution of 3 (3.75 g, 10 mmol) in acetonitrile
(50 mL) was added 2-(4-aminoaryl)-1,1,1,3,3,3-hexa-
fluoropropan-2-ol 5a—5j (11 mmol) and trifluoroacetic
acid (0.5 mmol). The mixture was then stirred for 3 h.
The progress of the reaction was monitored by TLC.
When the reaction was complete, without further puri-
fication, the intermediate 6a—6j was allowed to react
with the solution of m-chloroperoxybenzoic acid (22
mmol) in acetonitrile (50 mL). The solution was stirred
for another 3 h at room temperature until the reaction
was complete. Then the solution was concentrated under
reduced pressure and the residue was dissolved in di-
chloromethane (10 mL). The organic layer was washed
by water and dried over anhydrous magnesium sulfate.
The CH2Cl2 was removed under reduced pressure, and
Experimental
All reagents were of analytic grade and obtained
from commercial suppliers and used without further
purification. Melting points were measured in an open
capillary using Büchi melting point B-540 apparatus
and are uncorrected. H and 13C NMR spectra were re-
1
corded on a Bruker AM-400 spectrometer (400 MHz
and 100 MHz, respectively) using TMS as the internal
standard. DMSO-d6 was used as NMR solvent for all
cases. The 19F NMR spectra were recorded on a Bruker
AM-400 spectrometer (376 MHz) using CF3CO2H as
external standard. Gas chromatography-mass spectra
(GC-MS) were recorded on HP 5973 MSD with 6890
GC. High resolution mass spectra (HRMS) were re-
Chin. J. Chem. 2012, 30, 1310—1314
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1311

Wu et al.
FULL PAPER
the residue was purified by silica gel column chromato-
graph (petroleum ether/ethyl acetate＝1∶1, volume
ratio) to afford the target compounds 7a—7j.
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2-fluorophenyl]-1,2-benzenedicarboxamide
1
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
(7e) White solid, m.p. 78.1—84.3 ℃, yield 70%; H
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
NMR δ: 1.52 (s, 6H, 2CH3), 2.95 (s, 3H, CH3), 3.36 (s,
2H, CH2), 7.25—7.29 (m, 1H, ArH), 7.53—7.55 (m, 2H,
ArH), 7.68—7.70 (m, 1H, ArH), 8.02—8.09 (m, 2H,
ArH), 8.38 (s, 1H, NH), 8.94 (s, 1H, OH), 10.12 (s, 1H,
NH); 19F NMR δ: －121.60—－121.55 (m, 1F, ArF),
－74.07 (s, 6F, 2CF3); 13C NMR δ: 14.5, 26.5, 43.6,
52.9, 60.2, 95.8, 123.5, 124.6, 124.7, 128.0, 128.1,
128.2, 128.5, 128.6, 130.6, 135.8, 141.5, 141.7, 166.1,
168.1. HRMS (EI) calcd for C22H20F7IN2O5Na [M＋
Na]＋ 706.9924, found 706.9925.
ethyl)phenyl]-1,2-benzenedicarboxamide
(7a)
White solid, m.p.152.0—153.7 ℃, yield 70%; 1H NMR
δ: 1.53 (s, 6H, 2CH3), 2.94 (s, 3H, CH3), 3.63 (s, 2H,
CH2), 7.25—7.29 (m, 1H, ArH), 7.65—7.67 (m, 3H,
ArH), 7.81—7.83 (m, 2H, ArH), 8.01—8.03 (m, 1H,
ArH), 8.31 (s, 1H, NH), 8.62 (s, 1H, OH), 10.37 (s, 1H,
NH); 19F NMR δ: －74.09—－74.07 (m, 6F, 2CF3);
13C NMR δ: 27.1, 43.7, 52.9, 53.4, 58.7, 61.2, 95.8,
119.8, 125.9, 127.7, 127.9, 130.6, 136.7, 141.0, 141.2,
141.8, 166.1, 168.0. HRMS (EI) calcd for C22H21F6IN2-
O5SNa [M＋Na]＋ 689.0018, found 689.0022.
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2-chlorophenyl]-1,2-benzenedicarboxamide
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2-methylphenyl]-1,2-benzenedicarboxamide
(7b) White solid, m.p. 232.2—234.9 ℃, yield 80%;
1H NMR δ: 1.53 (s, 6H, 2CH3), 2.32 (s, 3H, CH3), 2.94
(s, 3H, CH3), 3.64 (s, 2H, CH2), 7.25—7.29 (m, 1H,
ArH), 7.50—7.55 (m, 2H, ArH), 7.67—7.72 (m, 2H,
ArH), 8.00—8.02 (m, 1H, ArH), 8.38 (s, 1H, NH), 8.66
(s, 1H, OH), 9.69 (s, 1H, NH); 19F NMR δ: －73.89 (s,
6F, 2CF3); 13C NMR δ: 14.5, 18.6, 21.2, 26.6, 43.6, 52.9,
60.2, 61.3, 95.9, 125.1, 127.8, 127.9, 129.3, 130.6,
132.6, 136.6, 138.3, 141.2, 141.8, 166.0, 168.2. HRMS
(EI) calcd for C23H23F6IN2O5Sna [M＋Na]＋ 703.0174,
found 703.0173.
1
(7f) White solid, m.p. 84.8—91.4 ℃, yield 70%; H
NMR δ: 1.52 (s, 6H, 2CH3), 2.96 (s, 3H, CH3), 3.65 (s,
2H, CH2), 7.25—7.30 (m, 2H, ArH), 7.37—7.41 (m, 1H,
ArH), 7.53—7.55 (m, 1H, ArH), 7.80—7.82 (m, 1H,
ArH), 8.02—8.04 (m, 1H, ArH), 8.42 (s, 1H, NH), 9.13
(s, 1H, OH), 9.70 (s, 1H, NH); 19F NMR δ: －74.09 (s,
6F, 2CF3); 13C NMR δ: 27.1, 43.7, 53.5, 58.8, 61.2, 96.0,
126.4, 127.3, 127.4, 127.9, 128.1, 130.1, 130.7, 135.2,
136.0, 141.5, 141.8, 156.2, 156.5, 168.2. HRMS (EI)
calcd for C22H21ClF6IN2O5S [M＋H]＋ 700.9809, found
700.9805.
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2-ethylphenyl]-1,2-benzenedicarboxamide (7g)
White solid, m.p. 103.7—106.4 ℃, yield 71%; 1H
NMR δ: 1.18 (t, J＝7.4 Hz, 3H, CH3), 1.55 (s, 6H,
2CH3), 2.96 (q, J＝7.4 Hz, 2H, CH2), 2.96 (s, 3H, CH3),
3.66 (s, 2H, CH2), 7.26—7.30 (m, 1H, ArH), 7.52—
7.54 (m, 1H, ArH), 7.59—7.64 (m, 2H, ArH), 7.69—
7.71 (m, 1H, ArH), 8.01—8.03 (m, 1H, ArH), 8.36 (s,
1H, NH), 8.71 (s, 1H, OH), 9.74 (s, 1H, NH); 19F NMR
δ: －74.12 (s, 6F, 2CF3); 13C NMR δ: 27.1, 28.0, 43.7,
53.5, 57.8, 58.9, 59.3, 89.9, 111.6, 114.5, 117.3, 120.2,
123.0, 131.8, 135.7, 145.7, 155.8, 156.2, 156.5, 156.9,
167.5, 167.9. HRMS (EI) calcd for C24H25F6IN2O5SNa
[M＋Na]＋ 717.0331, found 717.0337.
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2,3-dimethylphenyl]-1,2-benzenedicarbox-
amide (7c) White solid, m.p. 197.1—201.9 ℃, yield
78%; 1H NMR δ: 1.58 (s, 6H, 2CH3), 2.13 (s, 3H, CH3),
2.30 (s, 3H, CH3), 2.50 (s, 3H, CH3), 3.36 (s, 2H, CH2),
7.23—7.34 (m, 3H, ArH), 7.84—7.85 (m, 1H, ArH),
8.01—8.03 (m, 1H, ArH), 8.56 (s, 1H, NH), 9.09 (s, 1H,
OH), 9.58 (s, 1H, NH); 19F NMR δ: －73.74 (s, 3F,
CF3), －70.84 (s, 3F, CF3); 13C NMR δ: 14.5, 16.2, 20.7,
26.5, 27.2, 43.7, 53.0, 60.2, 61.4, 96.6, 125.3, 128.0,
128.2, 130.6, 135.7, 136.2, 137.8, 140.4, 141.6, 142.5,
164.2, 168.7. HRMS (EI) calcd for C24H25F6IN2O5SNa
[M＋Na]＋ 717.0331, found 717.0336.
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2-isopropylphenyl]-1,2-benzenedicarboxamide
(7h) White solid, m.p. 104.5—107.1 ℃, yield 76%;
1H NMR δ 1.18 (d, J＝6.8 Hz, 6H, 2CH3), 1.56 (s, 6H,
2CH3), 1.84 (s, 1H, CH), 2.96 (s, 3H, CH3), 3.66 (s, 2H,
CH2), 7.26—7.30 (m, 1H, ArH), 7.52 (s, 2H, ArH), 7.65
(s, 1H, ArH), 7.70—7.72 (m, 1H, ArH), 8.01—8.03 (m,
1H, ArH), 8.36 (s, 1H, NH), 8.70 (s, 1H, OH), 9.77 (s,
1H, NH); 19F NMR δ: －73.87 (s, 6F, 2CF3); 13C NMR
δ: 23.7, 26.7, 27.7, 43.7, 52.9, 61.5, 96.1, 124.8, 124.9,
127.3, 127.7, 129.1, 130.6, 136.5, 136.9, 141.2, 142.1,
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2,6-dimethylphenyl]-1,2-benzenedicarbox-
amide (7d) White solid, m.p. 200.1—202.5 ℃, yield
1
77%; H NMR δ: 1.57 (s, 6H, 2CH3), 2.30 (s, 6H,
2CH3), 3.02 (s, 3H, CH3), 3.69 (s, 2H, CH2), 7.27—7.31
(m, 1H, ArH), 7.41 (s, 2H, ArH), 7.76—7.78 (m, 1H,
ArH), 8.01—8.03 (m, 1H, ArH), 8.41 (s, 1H, NH), 8.67
(s, 1H, OH), 9.81 (s, 1H, NH); 19F NMR δ: －73.74 (s,
6F, 2CF3); 13C NMR δ: 18.9, 26.7, 27.2, 43.6, 52.8, 61.6,
96.4, 126.5, 127.7, 127.7, 129.4, 130.5, 136.5, 136.6,
137.1, 141.3, 142.5, 165.5, 168.2. HRMS (EI) calcd for
144.1, 165.2, 166.5, 168.1, 170.9. HRMS (EI) calcd for
＋
＋
C24H25F6IN2O5SNa [M ＋ Na]
717.0331, found
C25H27F6IN2O5SNa [M ＋ Na]
731.0487, found
717.0320.
731.0488.
1312
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1310—1314

Synthesis and Insecticidal Activities of Novel Analogues of Flubendiamide
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2-bromophenyl]-1,2-benzenedicarboxamide
(7i) White solid, m.p. 105.8—108.2 ℃, yield 75%;
1H NMR δ: 1.55 (s, 6H, 2CH3), 2.96 (s, 3H, CH3), 3.68
(s, 2H, CH2), 7.29—7.33 (m, 1H, ArH), 7.74—7.76 (m,
2H, ArH), 7.95—7.98 (m, 2H, ArH), 8.05—8.07 (m, 1H,
ArH), 8.47 (s, 1H, NH), 9.03 (s, 1H, OH), 9.80 (s, 1H,
NH); 19F NMR δ: －74.02 (s, 6F, CF3); 13C NMR δ:
26.2, 43.2, 52.5, 59.8, 60.7, 95.6, 117.4, 126.0, 126.8,
127.4, 129.2, 130.3, 131.1, 135.3, 138.0, 141.2, 141.4,
165.4, 167.6, 170.3. HRMS (EI) calcd for C22H21BrF6I-
N2O5S [M＋H]＋ 744.9304, found 744.9453.
ciently. This is due to the steric effect of the substituent
attached at the meta position relative to the amino
group.
The synthesis of 7b from the intermediate 3 was
served as the model reaction to investigate the effect of
solvent on the yields of 7a—7j. According to litera-
ture,[9b] toluene, dichloromethane, acetonitrile, and ethyl
acetate were frequently used as reaction solvents to
prepare 7a—7j, but after many trials, it was found that
acetonitrile is a more suitable solvent for both the ami-
nation of 3 and oxidation of 6a—7j because of its low
toxicity and simple workup.
The yield was also significantly affected by the
amount of m-chloroperoxybenzoic acid. The results of
experiments indicated that when the molar ratio of 3 to
m-chloroperoxybenzoic acid was 1∶2.2, the oxidation
of 6a—6j could be carried out successfully and gave the
expected compounds in moderate yields. A further in-
crease in the amount of m-chloroperoxybenzoic acid
showed no substantial improvement in the yield,
whereas the yield was reduced if the ratio is less than 2.
Under these optimized reaction conditions, a series
of hexafluoroisopropanol unit-containing flubendiamide
analogues 7a—7j were synthesized by the reaction of
hexafluoroisopropanol unit-containing anilies 5a—5j
with 3, followed by cyclization by trifluoroacetic anhy-
dride in acetonitrile.
N2-[1,1-Dimethyl-2-(methylsulfonyl)ethyl]-3-iodo-
N1-[4-(1-hydroxy-1-trifluoromethyl-2,2,2-trifluoro-
ethyl)-2,3-difluorophenyl]-1,2-benzenedicarbox-
amide (7j) White solid, m.p. 133.1—135.4 ℃, yield
69%; 1H NMR δ: 1.52 (s, 6H, 2CH3), 2.98 (s, 3H, CH3),
3.71 (s, 2H, CH2), 7.26—7.32 (m, 3H, ArH), 7.64—
7.66 (m, 1H, ArH), 8.07—8.09 (m, 1H, ArH), 8.82 (s,
1H, NH), 9.25 (s, 1H, OH), 10.36 (s, 1H, NH); 19F
NMR δ: －134.37 (d, J＝19.9 Hz, 1F, ArF), －131.98
(d, J＝22.2 Hz, 1F, ArF), －73.32 (s, 6F, 2CF3); 13C
NMR δ: 27.1, 43.4, 53.2, 58.9, 94.9, 126.2, 127.2, 127.8,
127.9, 128.4, 128.5, 128.6, 128.7, 129.3, 130.9, 131.1,
136.5, 141.8, 166.0, 168.9. HRMS (EI) calcd for
＋
C22H19F8IN2O5SNa [M ＋ Na]
724.9829, found
724.9836.
Table 1 Insecticidal activity against oriental armyworm of
compounds 7a—7j
Results and Discussion
Concentration/
(mg•L )
Compd. R1, R2
Insecticidal activity/%
－
1
In our previous paper, we successfully introduced a
heptafluoroisopropyl group into the structure of the
benzoylphenylurea by using 2-iodoheptafluopropane as
the fluorinating reagent.[15] Some of heptafluoroisopro-
pyl-containing benzoylphenylurea exhibited excellent
insecticidal activity. However, heptafluoroisopropyl
iodide is not a good starting material with regard to
handling and price.
7a
7b
H, H
500
5
50
100
100
80
2-methyl, H
2.5
0.6
7c
7d
7e
7f
2,3-dimethyl 100
2,6-dimethyl 100
10
50
Hexafluoroacetone trihydrate, a cheap, stable and
commercially available fluorinated building block, is
widely used in organic synthesis and materials indus-
try.[16] The 1,1,1,3,3,3-hexafluoro-2-hydroxy-propan-
2-yl group could be conveniently introduced by a
Friedel-Crafts type of reaction between an aniline and
hexafluoroacetone hydrate in the presence of an acid, as
shown in Scheme 2. When electron-donating group such
as methyl, ethyl and methoxy was substituted at the
ortho position to the amino group, the reaction pro-
ceeded smoothly. The substituted aniline having chlo-
rine, boromine and fluorine atom on the aromatic moi-
ety is unfavourable for the reaction and afforded
2-amino aryl hexafluoroisoropanols in relatively low
yields. The position of the substituent on the aniline
derivatives played an important role in this reaction.
When the meta position of the amino group was substi-
tuted by other substituent, no matter whether it is an
electron-withdrawing group or an electron-donating
group, the Friedel-Crafts reaction can not proceed effi-
2-fluoro, H
2-chloro, H
2-ethyl, H
10
50
10
50
7g
7h
7i
500
50
2-isopropyl, H 500
100
30
2-bromo, H
2,3-difluoro
500
500
0.6
7j
48
flubendiamide a
100
a The flubendiamide was synthesized by our laboratory according
to the literature. The purity is determined by m.p. and 1H NMR
(＞95%).
The insecticidal activities of the title compounds 7a
—7j against armyworm were evaluated according to the
literature procedures.[17] To compare their activities, the
commercial product flubendiamide was tested under the
same conditions. The insecticidal activity of 7a—7j
against armyworm is summarized in Table 1. It was
found that the position and kind of substituent group
Chin. J. Chem. 2012, 30, 1310—1314
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1313

Wu et al.
FULL PAPER
attached to the aniline ring has a profound influence on
the activity of the hexafluoroisopropanol unit-contain-
ing flubendiamide analogues 7a—7j. Among the ten
compounds tested, some of them exhibited good insec-
ticidal activities (7e and 7f). Compound 7b is the most
active compound, its insecticidal activity against army-
worm at 0.6 mg/L is 80%, which is slightly weaker than
the corresponding flubendiamide. The only difference in
structure between 7b and flubendiamide is that hepta-
fluoroisopropyl group in the anilide moiety is replaced
with 2-hydroxy hexafluoroisopropyl group.
In addition, the insecticidal activities of compound 7b
against other insects were also evaluated (Table 2). Bio-
assays were conducted according to the method described
by Wang.[18] The results indicated that compound 7b ex-
hibited high activities against all test insects.
China (863 Program, No. 2011AA10A204).
References
[1] Lahm, G. P.; Cordova, D.; Barry, J. D. Bioorg. Med. Chem. 2009, 17,
4127.
[2] Nauen, R. Pest Manag. Sci. 2006, 62, 690.
[3] (a) Tohnishi, M.; Nishimatsu, T.; Motoba, K.; Hirooka, T.; Seo, A. J.
Pestic. Sci. 2010, 35, 490; (b) Masaki, T.; Yasokawa, N.; Fujioka, S.;
Motoba, K.; Tohnishi, M.; Hirooka, T. J. Pestic. Sci. 2009, 34, 37.
[4] Tsubata, K.; Tonishi, M.; Kodama, H.; Seo, A. Pflanzenschutz-
Nachrichten Bayer 2007, 2, 105.
[5] (a) Fischer, R.; Funke, C.; Malsam, O.; Löesel, P.; Görgens, U.;
Arnold, C.; Tohnishi, M.; Yamaguchi, M.; Harayama, H.; Fujioka, S.
WO 2006024412, 2006 [Chem. Abstr. 2006, 144, 292428]; (b) Wada,
K.; Murata, T.; Shibuya, K.; Shimojo, E. WO 2006133823, 2006
[Chem. Abstr. 2006, 146, 62469].
[6] (a) Onishi, M.; Yoshiura, A.; Kohno, E.; Tsubata, K. EP 1380568,
2004 [Chem. Abstr. 2004, 140, 93779]; (b) Kando, Y.; Kajiwara, T.;
Tanimoto, T. JP 2005272304, 2005 [Chem. Abstr. 2005, 143,
367084]; (c) Feng, M. L.; Li, Y. F.; Zhu, H. J.; Zhao, L.; Xi, B. B.;
Ni, J. P. J. Agric. Food Chem. 2010, 58, 10999.
[7] (a) Jeschke, P. ChemBioChem 2004, 5, 570; (b) Purser, S.; Moore, P.
R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320; (c)
Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (d)
Wang, J.; Liu, H. Chin. J. Org. Chem. 2011, 31, 1785.
[8] (a) Narizuka, S.; Hagiwara, Y.; Nagamori, M.; Yamanaka, K. US
20090030173, 2009 [Chem. Abstr. 2009, 150, 192068]; (b) Yama-
naka, K.; Henderson, C.; Romeo, M.; Maeda, K. WO 2008069813,
2008 [Chem. Abstr. 2008, 149, 54812].
[9] (a) Annegrit, B.; Karl, K.; Koenig, A. H. DE 2839462, 1980 [Chem.
Abstr. 1980, 93, 114172]; (b) Tohnishi, M.; Nakao, H.; Kohno, E.;
Nishida, T.; Furuya, T.; Shimizu, T.; Seo, A.; Sakata, K.; Fujioka, S.;
Kanno, H. EP1006107, 2000 [Chem. Abstr. 2000, 133, 17278].
[10] Narlawar, R.; Baumann, K.; Czech, C.; Schmidt, B. Bioorg. Med.
Chem. Lett. 2007, 17, 5428.
[11] (a) Li, L. P.; Liu, J. W.; Zhu, L. S.; Cutler, S.; Hasegawa, H.; Shan,
B.; Medina, J. C. Bioorg. Med. Chem. Lett. 2006, 16, 1638; (b)
Wang, Y. J.; Kumar, N.; Nuhant, P.; Cameron, M. D.; Istrate, M. A.;
Roush, W. R.; Griffin, P. R.; Burris, T. P. ACS Chem. Biol. 2010, 5,
1029.
Table 2 The insecticidal activities of compound 7b against
other insects
Concentration/
(mg•L )
Insect
Insecticidal activity/%
－
1
1
100
80
Mosquito
(Culex pipiens pallens)
0.5
100
50
25
10
100
30
Cotton bollworm
(Helicoverpa armigera)
100
60
Asiatic Corn Borer
(Ostrinia furnacalis)
Diamondback moth
(Plutella xyllostella)
12.5
100
50
90
80
80
50
Beet armyworm
(Spodoptera exigua)
25
25
Tobacco cutworm
(Spodoptera litura)
12.5
In summary, on the basis of commercial insecticides
flubendiamide, a series of novel analogues of flubendi-
amide containing a hexafluoroisopropanol moiety were
synthesized via the key intermediate, 4-[(2-hydroxy)-
hexafluoroisopropyl] aniline. Their insecticidal activi-
ties against armyworm were evaluated. Compound 7b
exhibited nearly the same insecticidal activity as the
corresponding commercial product flubendiamide
against armyworm and had broad spectrum of activity
against several other insects.
[12] (a) Machiya, K.; Seo, A. JP 2000080058, 2000 [Chem. Abstr. 2000,
132, 194190]; (b) Abe, N.; Takagi, K.; Tsubata, K. JP 2001335571,
2001 [Chem. Abstr. 2001, 136, 5894]; (c) Sanpei, O.; Tsubata, K.
WO 20010123350, 2001 [Chem. Abstr. 2001, 134, 266031].
[13] Tohnishi, M.; Nakao, H.; Furuya, T.; Seo, A.; Kodama, H.; Tsubata,
K.; Fujioka, S.; Kodama, H.; Hirooka, T.; Nishimatsu, T. J. Pestic.
Sci. 2005, 30, 354.
[14] Masciadri, R.; Kamer, M.; Nock, N. Eur. J. Org. Chem. 2003, 21,
4286.
[15] Zhang, J.; Tang, X. H.; Ishaaya, I.; Cao, S.; Wu, J. J.; Yu, J. L.; Li,
H.; Qian, X. H. J. Agric. Food Chem. 2010, 58, 2736.
[16] (a) Chkanikov, N. D.; Sviridov, V. D.; Zelenin, A. E.; Galakhov, M.
V.; Kolomiets, A. F.; Fokin, A. V. Russ. Chem. Bull. 1990, 39, 323;
(b) Kong, L. T.; Wang, J.; Fu, X. C.; Zhong, Y.; Meng, F. L.; Luo,
T.; Liu, J. H. Carbon 2010, 48, 1262.
[17] (a) Sun, R. F.; Li, Y. Q.; Xiong, L. X.; Liu, Y. X.; Wang, Q. M. J.
Agric. Food Chem. 2011, 59, 4851; (b) 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. J. Agric. Food Chem. 2009, 57, 3661.
[18] (a) Song, H. J.; Liu, Y. X.; Xiong, L. X.; Li, Y. Q.; Yang, N.; Wang,
Q. M. J. Agric. Food Chem. 2012, 60, 1470; (b) Liu, Z. H.; Lei, Q.;
Li, Y. Q.; Xiong, L. X.; Song, H. B.; Wang, Q. M. J. Agric. Food
Chem. 2011, 59, 12543.
Acknowledgements
We are grateful for financial supports from the Na-
tional Natural Science Foundation of China (No.
21072057), the National Basic Research Program of
China (973 Program, No. 2010CB126101), the Key
Project in the National Science & Technology Pillar
Program of China in the twelfth five-year plan period
(No. 2011BAE06B01-15), and the National High
Technology Research and Development Program of
(Cheng, F.)
1314
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1310—1314