Design, synthesis and insecticidal activity of novel phenylpyrazoles containing a 2,2,2-trichloro-1-alkoxyethyl moiety

Article abstract of DOI:10.1021/jf1001793

A series of novel phenylpyrazoles containing a 2,2,2-trichloro-1- alkoxyethyl moiety were designed and synthesized via the key intermediate 5-trichloroethylideneimino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl) -4-alkylsulfenylpyrazole (5). The addition reaction of the imine 5 was closely related with the nature of the alcohol. The target compounds were confirmed by ¹H NMR and elemental analysis. The results of bioassays indicated that the target compounds possessed excellent activities against a broad spectrum of insects such as bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens) and diamondback moth (Plutella xylostella). Especially, the foliar contact activity against bean aphid of compound 7h at 2.5 mg kg ^-1 was 89%, the larvacidal activity against mosquito of compound 6c at 2.5 μg kg^-1 was 100%, the activity against diamondback moth of compound 7a at 5 mg kg^-1 was 87%, and all of these activities were much higher than the contrast ethiprole. The results of insecticidal activities showed that the two pairs of enantiomers 7d-1 and 7d-2 gave activities without distinctive difference, and it was the similar situation for 7e-1 and 7e-2. Interestingly, the target compounds exhibited high selectivity between diamondback moth and oriental armyworm, both of which are of the order Lepidoptera. The 2,2,2-trichloro-1-alkoxyethyl moiety was essential for high insecticidal activities.

Full text of DOI:10.1021/jf1001793

4992 J. Agric. Food Chem. 2010, 58, 4992–4998
DOI:10.1021/jf1001793
Design, Synthesis and Insecticidal Activity
of Novel Phenylpyrazoles Containing a
2,2,2-Trichloro-1-alkoxyethyl Moiety
Q
IQI
Z
HAO, YONGQIANG
L
I, LIXIA
X
IONG
,
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 phenylpyrazoles containing a 2,2,2-trichloro-1-alkoxyethyl moiety were designed and
synthesized via the key intermediate 5-trichloroethylideneimino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-
phenyl)-4-alkylsulfenylpyrazole (5). The addition reaction of the imine 5 was closely related with the
1
nature of the alcohol. The target compounds were confirmed by H NMR and elemental analysis. The
results of bioassays indicated that the target compounds possessed excellent activities against a broad
spectrum of insects such as bean aphid (Aphis craccivora), mosquito (Culex pipiens pallens) and
diamondback moth (Plutella xylostella). Especially, the foliar contact activity against bean aphid of
compound 7h at 2.5 mg kg-1 was 89%, the larvacidal activity against mosquito of compound 6c at
2.5 μg kg-1 was 100%, the activity against diamondback moth of compound 7a at 5 mg kg-1 was 87%,
and all of these activities were much higher than the contrast ethiprole. The results of insecticidal
activities showed that the two pairs of enantiomers 7d-1 and 7d-2 gave activities without distinctive
difference, and it was the similar situation for 7e-1 and 7e-2. Interestingly, the target compounds exhibited
high selectivity between diamondback moth and oriental armyworm, both of which are of the order
Lepidoptera. The 2,2,2-trichloro-1-alkoxyethyl moiety was essential for high insecticidal activities.
KEYWORDS: Phenylpyrazole; GABA receptor; 2,2,2-trichloro-1-alkoxyethyl; insecticidal activity;
broad spectrum
INTRODUCTION
A trivial change in structure of a pesticide would lead to great
changes in properties and activities. According to refs 13, 14, a
2,2,2-trichloro-1-methoxyethyl group had been introduced to
organophosphorus pesticide (G) (Figure 3) so as to change the
toxicological properties and enhance the selectivity.
Herein a series of novel phenylpyrazoles containing a 2,2,2-
trichloro-1-alkoxyethyl moiety (H) (Figure 3) were designed and
synthesized, and their insecticidal activities against bean aphid
(Aphis craccivora), mosquito (Culex pipiens pallens), diamondback
moth (Plutella xylostella) and oriental armyworm (Mythimna
separata) were tested and discussed.
Synthetic 1-phenylpyrazoles such as fipronil (A) and ethiprole
(B) (Figure 1) belong to an important kind of insecticide, and the
toxicity of 1-phenylpyrazoles to insects and mammals is attribu-
table to their action at the GABA receptor as noncompetitive
blockers of the GABA-gated chloride channel (1-4). A was once
one of the most important insecticides for control of soil insects
on corn (5) and fleas on cats and dogs (6). Ethiprole B is a new
1-phenylpyrazole insecticide effective against a broad spectrum of
chewing and sucking insects with pronounced plant systemic
activity (7) as well as stored grain insect pests (8).
Besides fipronil and ethiprole, vaniliprole (C) (9), acetoprole
(D) (10), pyrafluprole (E) (11) and pyriprole (F) (12) (Figure 2) are
among the 1-phenylpyrazole insecticides. In common, there
are an electron-withdrawing group (cyano or acetyl), a sulfenyl
(or sulfinyl) group, and an amino (or substituted amino) on the
3-position, 4-position and 5-position of the pyrazole ring, respec-
tively. It is noticed that vaniliprole, pyrafluprole and pyriprole
could be prepared by reaction of the corresponding 5-amino
compound with the proper aromatic aldehyde, and a subsequent
reduction of the resulting imine intermediate is needed for
pyrafluprole and pyriprole (11, 12).
MATERIALS AND METHODS
Instruments. 1H NMR spectra were obtained at 300 MHz using a
Bruker AV300 spectrometer or at 400 MHz using a Varian Mercury
Plus400 spectrometer in CDCl3 or DMSO-d6 solution with tetramethylsi-
lane as the internal standard. Chemical shift values (δ) are given in ppm.
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 are uncorrected. Yields were not optimized.
General Synthesis. All anhydrous solvents as well as sulfur chloride
were dried and purified by standard techniques just before use. Chloral
was prepared from chloral hydrate by dehydration with concentrated
sulfuric acid (15). The synthetic route is given in Scheme 1.
*To whom correspondence should be addressed. Tel: þ86-(0)22-
23499842. Fax: þ86-(0)22-23499842. E-mail: wang98h@263.net, wangqm@
nankai.edu.cn.
Synthesis of 5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-
phenyl)pyrazole (2). Concentrated sulfuric acid (2.8 mL) was added
pubs.acs.org/JAFC
Published on Web 03/29/2010
© 2010 American Chemical Society

Article
J. Agric. Food Chem., Vol. 58, No. 8, 2010 4993
dropwise a solution of sulfur chloride (4.19 g, 31 mmol) in dichloro-
methane (20 mL). Then the mixture was stirred overnight at room
temperature, and the yellow slurry was filtered and the cake was washed
with dichloromethane to afford disulfide 3 as a yellow solid (20.1 g, 95%).
Mp >300 °C. 1H NMR (DMSO-d6): δ 7.97 (s, 4H, Ph), 6.68 (s, 4H, NH2).
General Synthesis of 5-Amino-3-cyano-1-(2,6-dichloro-4-trifluo-
romethylphenyl)-4-alkylsulfenylpyrazole (4). To a solution of disul-
fide 3 (5.64 g, 8 mmol) in dimethylformamide (130 mL) was added alkyl
halide (18 mmol), and then potassium hydrogen phosphate (4.53 g,
26 mmol) in water (60 mL) was added, followed by addition of sodium
dithionite (4.48 g, 26 mmol) in portions. The mixture was stirred for 4 h at
room temperature, and then water (200 mL) and ethyl acetate (100 mL)
were added. After separation, the water phase was again extracted by ethyl
acetate (2 ꢀ 80 mL). The combined organic phase was washed with water
(2ꢀ100 mL) and brine (2ꢀ100 mL) successively, dried over sodium sul-
fate, and concentrated to give 4 as a white solid. The alkylating reagents
were iodomethane and ethyl bromide for 4a and 4b, respectively.
Data for 5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-
phenyl)-4-methylsulfenylpyrazole (4a). Yield: 92%. Mp 173-175 °C.
1H NMR (CDCl3): δ 7.78 (s, 2H, Ph), 4.14 (s, 2H, NH2), 2.34 (s, 3H, CH3).
Data for 5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethyl-
phenyl)-4-ethylsulfenylpyrazole (4b). Yield: 89%. Mp 152-154 °C. 1H
NMR (CDCl3): δ 7.79 (s, 2H, Ph), 4.14 (s, 2H, NH2), 2.17 (q, 3JHH = 7.2
Hz, 2H, CH2), 1.26 (t, 3JHH = 7.2 Hz, 3H, CH3).
Figure 1. Chemical structures of fipronil (A) and ethiprole (B).
General Synthesis of 5-Trichloroethylideneimino-3-cyano-1-(2,6-
dichloro-4-trifluoromethylphenyl)-4-alkylsulfenylpyrazole(5). A mix-
ture of 4 (11 mmol) and chloral (35 g, 240 mmol) was refluxed in the
˚
presence of molecular sieves (4 A, 1 g) for 36 h, and then most of the chloral
was removed by distillation. The residue was purified by column chroma-
tography on a silica gel using petroleum ether (60-90 °C) and dichlor-
omethane as the eluent to afford 5 as a slight yellow solid.
Data for 5-Trichloroethylideneimino-3-cyano-1-(2,6-dichloro-4-
trifluoromethylphenyl)-4-methylsulfenylpyrazole(5a).Yield:44%. Mp:
113-115 °C. 1H NMR (CDCl3): δ 8.82 (s, 1H, CHdN), 7.74 (s, 2H, Ph),
2.58 (s, 3H, CH3). Anal. Calcd for C14H6Cl5F3N4S (%): C, 33.86; H, 1.22;
N, 11.28. Found: C, 33.99; H, 1.21; N, 11.12.
Data for 5-Trichloroethylideneimino-3-cyano-1-(2,6-dichloro-4-
trifluoromethylphenyl)-4-ethylsulfenylpyrazole (5b). Yield: 53%.
Mp: 112-114 °C. 1H NMR (CDCl3): δ 9.00 (s, 1H, CHdN), 7.75 (s,
2H, Ph), 2.95 (q, 3JHH = 7.2 Hz, 2H, CH2), 1.28 (t, 3JHH = 7.2 Hz, 3H,
CH3). Anal. Calcd for C15H8Cl5F3N4S (%): C, 35.29; H, 1.58; N, 10.97.
Found: C, 35.21; H, 1.59; N, 10.97.
Figure 2. Chemical structures of vaniliprole (C), acetoprole (D), pyra-
fluprole (E) and pyriprole (F).
General Synthesis of 5-(2,2,2-Trichloro-1-alkoxylethylamino)-3-
cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-alkylsulfenylpyr-
azole (6). The solution of imine 5 (2 mmol) in an alcohol (10 mL) was
heated at a certain temperature for several hours, and monitored by TLC.
After the imine 5 disappeared, the alcohol was removed in vacuo. The
residue was purified by column chromatography on a silica gel using
petroleum ether (60-90 °C) and ethyl acetate as the eluent to afford the
target compound 6 as a white solid. The physical properties and elemental
analysis of compounds 6a-6j are listed in Table 1, and their 1H NMR data
are listed in Table 2.
General Synthesis of 5-(2,2,2-Trichloro-1-alkoxylethylamino)-3-
cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-alkylsulfinylpyr-
azole (7). To a solution of 6 (1 mmol) in dichloromethane (15 mL) was
added trifluoroacetic acid (1 mL), and then the reaction mixture was
cooled to 10 °C. Hydrogen peroxide (0.23 mL of 30%, w/w, 2 mmol) was
added dropwise at 12-15 °C, and the mixture was kept at this temperature
for 3 h. Then sodium bisulfite (1.04 g, 10 mmol) was added in portions, and
the mixture was stirred for 1 h at room temperature. Water (15 mL) was
then added, and the aqueous phase was extracted with dichloromethane
(2 ꢀ 15 mL). The combined organic layer was washed with water (15 mL)
and brine (15 mL), dried over sodium sulfate, and concentrated. The
residue was purified by column chromatography on a silica gel using
petroleum ether (60-90 °C) and ethyl acetate as the eluent to afford the
sulfinyl compound 7 as a white solid. The physical properties and
elemental analysis of compounds 7a-7j are listed in Table 1, and their
1H NMR data are listed in Table 2.
Figure 3. Chemical structures of compound G and the title compounds H.
dropwise to sodium nitrite (0.76 g, 11 mmol) placed in a round-bottom
flask with mechanical stirring, and the reaction mixture was stirred for
15 min before acetic acid (2.5 mL) was added. After the mixture had cooled
to room temperature, 2,6-dichloro-4-trifluoromethylaniline (1, 2.12 g,
9.2 mmol) dissolved in acetic acid (10 mL) was slowly added. The mixture
was then heated at 55-60 °C for 40 min and poured into a solution of ethyl
2,3-dicyanopropionate (1.4 g, 9.2 mmol) in acetic acid (6 mL) and water
(10 mL) at 5 °C. After the mixture was stirred for 2 h at room temperature,
water and dichloromethane were added and the aqueous layer was
extracted twice with dichloromethane. The combined organic layer was
vigorously stirred with ammonium hydroxide (30%, 80 mL) overnight at
room temperature. The separated organic layer was then washed with
water (2 ꢀ 30 mL) and 1 M hydrochloric acid (25 mL), dried over sodium
sulfate, filtered, and concentrated. The crude oil was crystallized from
dichloromethane and petroleum ether (60-90 °C) to give 2 as a slight
yellow solid (2.12 g, 72%). Mp: 142-143 °C. 1H NMR (CDCl3): δ 7.78
(s, 2H, Ph), 6.05 (s, 1H, pyrazole), 3.81 (s, 2H, NH2).
Synthesis of Bis(5-amino-3-cyano-1-(2,6-dichloro-4-trifluoro-
methylphenyl)pyrazol-4-yl) Disulfide (3). To a cooled (-15 °C) solu-
tion of 2 (18.6 g, 60 mmol) in dichloromethane (150 mL) was added
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

4994 J. Agric. Food Chem., Vol. 58, No. 8, 2010
Zhao et al.
Scheme 1. General Synthetic Route for Compounds 6a-6j and 7a-7j
Table 1. Physical Properties and Elemental Analyses of Compounds 6a-6j and 7a-7j
elemental anal. (%) (calcd)
compd
R1
R2
mp (°C)
yield (%)
C
H
N
6a
6b
6c
6d
6e
6f
Me
Me
Me
Me
Me
Et
Me
Et
91-92
127-128
147-149
129-131
142-144
123-124
137-139
119-121
147-149
123-125
110-112
98-100
158-160
150-152
141-143
151-153
133-135
147-149
133-134
49-51
99
99
96
40
54
99
99
99
42
59
87
83
79
82a
34.19 (34.09)
35.44 (35.42)
36.51 (36.68)
34.09 (34.28)
33.38 (33.30)
35.41 (35.42)
36.71 (36.68)
37.67 (37.88)
35.40 (35.53)
34.09 (34.54)
33.28 (33.08)
34.57 (34.40)
35.45 (35.66)
33.12 (33.33)
33.18 (33.33)
32.56 (32.40)
32.49 (32.40)
34.32 (34.40)
35.90 (35.66)
36.81 (36.85)
33.93 (34.57)
33.53 (33.63)
2.05 (1.91)
2.19 (2.23)
2.59 (2.54)
2.10 (1.98)
1.92 (1.92)
2.39 (2.23)
2.59 (2.54)
2.95 (2.83)
2.32 (2.28)
2.29 (2.22)
2.00 (1.85)
2.24 (2.17)
2.41 (2.46)
2.05 (1.92)
2.15 (1.92)
1.98 (1.87)
1.95 (1.87)
2.28 (2.17)
2.65 (2.46)
2.78 (2.75)
2.68 (2.22)
2.23 (2.16)
10.61 (10.60)
10.43 (10.33)
10.00 (10.07)
9.79 (9.99)
9.72 (9.71)
10.39 (10.33)
10.08 (10.07)
9.76 (9.82)
9.95 (9.75)
9.55 (9.48)
10.37 (10.29)
10.09 (10.03)
9.79 (9.78)
9.67 (9.72)
9.75 (9.72)
9.26 (9.45)
9.30 (9.45)
10.07 (10.03)
9.54 (9.78)
9.80 (9.55)
9.42 (9.49)
9.10 (9.23)
n-Pr
FCH2CH2
ClCH2CH2
Me
6g
6h
6i
Et
Et
n-Pr
Et
Et
FCH2CH2
ClCH2CH2
Me
6j
Et
7a
7b
7c
7d-1
7d-2
7e-1
7e-2
7f
Me
Me
Me
Me
Me
Me
Me
Et
Et
n-Pr
FCH2CH2
FCH2CH2
ClCH2CH2
ClCH2CH2
Me
67b
89
97
73
64
72
7g
7h
7i
Et
Et
n-Pr
Et
Et
FCH2CH2
ClCH2CH2
67-69
52-54
7j
Et
a The overall yield of 7d-1 and 7d-2. Compounds 7d-1 and 7d-2 were two pairs of enantiomers, and the ratio of 7d-1 to 7d-2 was about 1:1.3. b The overall yield of 7e-1 and 7e-
2. Compounds 7e-1 and 7e-2 were two pairs of enantiomers, and the ratio of 7e-1 to 7e-2 was about 1:1.5.
dead/alive basis and mortality rates were corrected using Abbott’s
formula (16). Evaluations are based on a percentage scale of 0-100 in
which 0 = no activity and 100 = total kill.
Foliar Contact Activity against Bean Aphid (Aphis craccivora).
The foliar contact activities of compounds 6a-6j, 7a-7j and ethiprole
against bean aphid were tested according to a reported proce-
dure (17-19). Stock solutions of each test sample was prepared in
dimethylformamide at a concentration of 200 mg L-1 and then diluted
to the required concentration with water containing TW-20. Tender shoots
of soybean with 60 insects of each species were dipped in the diluted

Article
J. Agric. Food Chem., Vol. 58, No. 8, 2010 4995
Table 2. 1H NMR of Compounds 6a-6j and 7a-7j
compd
δ (ppm)
6a
6b
7.80 (s, 2H, Ph), 5.69 (d, 3JHH = 10.8 Hz, 1H, CH), 4.45 (d, 3JHH = 10.8 Hz, 1H, NH), 3.53 (s, 3H, OCH3), 2.45 (s, 3H, SCH3)
7.81 (s, 1H, Ph), 7.80 (s, 1H, Ph), 5.78 (d, 3JHH = 10.8 Hz, 1H, CH), 4.44 (d, 3JHH = 10.8 Hz, 1H, NH),
3.87-3.63 (m, 2H, OCH2), 2.45 (s, 3H, SCH3), 1.23 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3)
6c
6d
6e
6f
7.80 (s, 2H, Ph), 5.75 (d, 3JHH = 10.8 Hz, 1H, CH), 4.45 (d, 3JHH = 10.8 Hz, 1H, NH), 3.74-3.63 (m, 1H, OCH2), 3.57-3.47
(m, 1H, OCH2), 2.44 (s, 3H, SCH3), 1.65-1.55 (m, 2H, OCH2CH2CH3), 0.91 (t, 3H, 3JHH = 7.6 Hz, OCH2CH2CH3)
7.80 (s, 2H, Ph), 5.92 (d, 3JHH = 10.8 Hz, 1H, CH), 4.61 (t, 3JHH = 3.6 Hz, 1H, FCH2), 4.57-4.44 (m, 3H, FCH2 and NH),
4.08-3.85 (m, 2H, OCH2), 2.45 (s, 3H, SCH3)
7.81 (s, 2H, Ph), 5.92 (d, 3JHH = 10.8 Hz, 1H, CH), 4.51 (d, 3JHH = 10.8 Hz, 1H, NH), 4.04-3.89 (m, 2H, OCH2),
3.62 (t, 3JHH = 5.6 Hz, 2H, ClCH2), 2.46 (s, 3H, SCH3)
7.81 (s, 2H, Ph), 5.58 (d, 3JHH = 10.8 Hz, 1H, CH), 4.49 (d, 3JHH = 10.8 Hz, 1H, NH), 3.52 (s, 3H, OCH3), 2.93-2.79
(m, 2H, CH2), 1.34 (t, 3JHH = 7.2 Hz, 3H, SCH2CH3)
6g
6h
7.81 (s, 1H, Ph), 7.80 (s, 1H, Ph), 5.64 (d, 3JHH = 10.8 Hz, 1H, CH), 4.48 (d, 3JHH = 10.8 Hz, 1H, NH), 3.84-3.75 (m, 1H, OCH2),
3.73-3.64 (m, 1H, OCH2), 2.93-2.77 (m, 2H, SCH2), 1.33 (t, 3JHH = 7.2 Hz, 3H, SCH2CH3), 1.22 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3)
7.81 (s, 1H, Ph), 7.80 (s, 1H, Ph), 5.60 (d, 3JHH = 10.8 Hz, 1H, CH), 4.51 (d, 3JHH = 10.8 Hz, 1H, NH), 3.71-3.64 (m, 1H, OCH2),
3.54-3.47 (m, 1H, OCH2), 2.90-2.79 (m, 2H, SCH2), 1.62-1.54 (m, 2H, OCH2CH2CH3), 1.33 (t, 3JHH = 7.6 Hz, 3H, SCH2CH3),
0.90 (t, 3H, 3JHH = 7.6 Hz, OCH2CH2CH3)
6i
6j
7.83 (s, 1H, Ph), 7.82 (s, 1H, Ph), 5.81 (d, 3JHH = 10.8 Hz, 1H, CH), 4.61 (t, 3JHH = 4.0 Hz, 2JHF = 47.6 Hz, 1H, FCH2), 4.56 (d, 3JHH = 10.8 Hz, 1H, NH),
4.49 (t, 3JHH = 4.0 Hz, 2JHF = 47.6 Hz, 1H, FCH2), 4.07-3.87 (m, 2H, OCH2), 2.95-2.80 (m, 2H, SCH2), 1.34 (t, 3H, 3JHH = 7.6 Hz, SCH2CH3)
7.82 (s, 1H, Ph), 7.81 (s, 1H, Ph), 5.80 (d, 3JHH = 10.8 Hz, 1H, CH), 4.54 (d, 3JHH = 10.8 Hz, 1H, NH), 4.03-3.88 (m, 2H, OCH2), 3.61 (t, 3JHH = 6.0 Hz,
ClCH2), 2.93-2.80 (m, 2H, SCH2), 1.34 (t, 3JHH = 7.2 Hz, SCH2CH3)
7a
7b
7.85 (s, 1H, Ph), 7.82 (s, 1H, Ph), 6.31 (d, 3JHH = 10.8 Hz, 1H, CH), 4.59 (d, 3JHH = 10.8 Hz, 1H, NH), 3.33 (s, 3H, OCH3), 3.14 (s, 3H, SCH3)
7.84 (s, 1H, Ph), 7.81 (s, 1H, Ph), 6.17 (d, 3JHH = 10.8 Hz, 1H, CH), 4.71 (d, 3JHH = 10.8 Hz, 1H, NH), 3.77-3.64 (m, 1H, O CH2), 3.40-3.29
(m, 2H, OCH2), 3.15 (s, 3H, SCH3), 1.12 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3)
7c
7.85 (s, 1H, Ph), 7.81 (s, 1H, Ph), 6.24 (d, 3JHH = 10.8 Hz, 1H, CH), 4.71 (d, 3JHH = 10.8 Hz, 1H, NH), 3.62-3.52 (m, 1H, OCH2), 3.19-3.08
(m, 4H, OCH2 and SCH3), 1.53-1.44 (m, 2H, OCH2CH2CH3), 0.86 (t, 3H, 3JHH = 7.6 Hz, OCH2CH2CH3)
7.84 (s, 1H, Ph), 7.81 (s, 1H, Ph), 5.89 (d, 3JHH = 11.2 Hz, 1H, CH), 5.06 (d, 3JHH = 11.2 Hz, 1H, NH), 4.62-4.51 (m, 1H, FCH2),
4.50-4.38 (m, 1H, FCH2), 4.03-3.96 (m, 1H, OCH2), 3.95-3.87 (m, 1H, OCH2), 3.16 (s, 3H, SCH3)
7d-1
7d-2
7e-1
7e-2
7f
7.84 (s, 1H, Ph), 7.81 (s, 1H, Ph), 6.30 (d, 3JHH = 11.2 Hz, 1H, CH), 4.84 (d, 3JHH = 11.2 Hz, 1H, NH), 4.60-4.32 (m, 2H, FCH2),
3.95-3.63 (m, 2H, OCH2), 3.15 (s, 3H, SCH3)
7.85 (s, 1H, Ph), 7.82 (s, 1H, Ph), 5.91 (d, 3JHH = 10.8 Hz, 1H, CH), 5.10 (d, 3JHH = 10.8 Hz, 1H, NH), 3.90 (t, 3JHH = 6.0 Hz, 2H, OCH2),
3.57 (t, 2H, 3JHH = 6.0 Hz, ClCH2), 3.17 (s, 3H, SCH3)
7.82 (s, 2H, Ph), 6.30 (d, 3JHH = 11.2 Hz, 1H, CH), 4.84 (d, 3JHH = 11.2 Hz, 1H, NH), 4.60-4.32 (m, 2H, FCH2), 3.95-3.63 (m, 2H,
OCH2), 3.15 (s, 3H, SCH3)
The product was isolated as a mixture of two pairs of enantiomers in a ratio of 1.1:1. For major enantiomers: 7.83 (s, 2H, Ph), 6.58 (d, 3JHH = 11.2 Hz,
1H, CH), 4.55 (d, 3JHH = 11.2 Hz, 1H, NH), 3.37 (s, 3H, OCH3), 3.36-3.24 (m, 2H, CH2), 1.40 (t, 3JHH = 7.2 Hz, 3H, SCH2CH3).
For minor enantiomers: 7.83 (s, 2H, Ph), 6.15 (d, 3JHH = 11.2 Hz, 1H, CH), 4.73 (d, 3JHH = 11.2 Hz, 1H, NH), 3.43 (s, 3H, OCH3),
3.36-3.24 (m, 2H, SCH2), 1.40 (t, 3H, 3JHH = 7.2 Hz, SCH2CH3)
7g
7h
The product was isolated as a mixture of two pairs of enantiomers in a ratio of 1.8:1. For major enantiomers: 7.83 (s, 2H, Ph), 6.42
(d, 3JHH = 11.2 Hz, 1H, CH), 4.65 (d, 3JHH = 11.2 Hz, 1H, NH), 3.78-3.66 (m, 1H, OCH2), 3.45-3.23 (m, 3H, OCH2 and SCH2),
1.40 (t, 3JHH = 7.2 Hz, 3H, SCH2CH3), 1.14 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3). For minor enantiomers: 7.83 (s, 2H, Ph), 6.11 (d, 3JHH = 11.2 Hz,
1H, CH), 4.79 (d, 3JHH = 11.2 Hz, 1H, NH), 3.78-3.66 (m, 1H, OCH2), 3.61-3.53 (m, 1H, OCH2), 3.45-3.23 (m, 2H, SCH2),
1.39 (t, 3JHH = 7.2 Hz, 3H, SCH2CH3), 1.14 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3)
The product was isolated as a mixture of two pairs of enantiomers in a ratio of 1.1:1. For major enantiomers: 7.83 (s, 2H, Ph), 6.47 (d, 3JHH = 11.2 Hz,
1H, CH), 4.60 (d, 3JHH = 11.2 Hz, 1H, NH), 3.65-3.53 (m, 1H, OCH2), 3.40-3.24 (m, 2H, SCH2), 3.24-3.23 (m, 1H, OCH2), 1.55-1.46 (m, 2H,
OCH2CH2CH3), 1.40 (t, 3JHH = 7.2 Hz, 3H, SCH2CH3), 0.87 (t, 3JHH = 7.2 Hz, 3H, OCH2CH2CH3). For minor enantiomers: 7.82 (s, 2H, Ph),
6.22 (d, 3JHH = 11.2 Hz, 1H, CH), 4.74 (d, 3JHH = 11.2 Hz, 1H, NH), 3.65-3.53 (m, 1H, OCH2), 3.40-3.24 (m, 3H, SCH2 and OCH2),
1.55-1.46 (m, 2H, OCH2CH2CH3), 1.39 (t, 3JHH = 7.2 Hz, 3H, SCH2CH3), 0.86 (t, 3JHH = 7.2 Hz, 3H, OCH2CH2CH3)
The product was isolated as a mixture of two pairs of enantiomers in a ratio of 1.1:1. For major enantiomers: 7.83 (s, 2H, Ph), 6.56 (d, 3JHH = 11.2 Hz,
1H, CH), 4.79 (d, 3JHH = 11.2 Hz, 1H, NH), 4.61-4.36 (m, 2H, FCH2), 4.00-3.70 (m, 2H, OCH2), 3.42-3.24 (m, 2H, SCH2), 1.41 (t, 3JHH = 7.2 Hz,
3H, OCH2CH3). For minor enantiomers: 7.84 (s, 2H, Ph), 6.14 (d, 3JHH = 11.2 Hz, 1H, CH), 5.05 (d, 3JHH = 11.2 Hz, 1H, NH), 4.61-4.36 (m, 2H, FCH2),
4.00-3.70 (m, 2H, OCH2), 3.42-3.24 (m, 2H, SCH2), 1.41 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3)
7i
7j
The product was isolated as a mixture of two pairs of enantiomers in a ratio of 1.2:1. For major enantiomers: 7.86 (s, 2H, Ph), 6.61 (d, 3JHH = 11.2 Hz,
1H, CH), 4.75 (d, 3JHH = 11.2 Hz, 1H, NH), 3.95-3.86 (m, 1H, OCH2), 3.71-3.65 (m, 1H, OCH2), 3.59-3.54 (m, 2H, ClCH2), 3.39-3.25
(m, 2H, SCH2),1.42 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3). For minor enantiomers: 7.84 (s, 2H, Ph), 6.14 (d, 3JHH = 11.2 Hz, 1H, CH), 5.08
(d, 3JHH = 11.2 Hz, 1H, NH), 3.95-3.86 (m, 1H, OCH2), 3.82-3.77 (m, 1H, OCH2), 3.59-3.54 (m, 2H, ClCH2), 3.39-3.25 (m, 2H, SCH2),
1.41 (t, 3JHH = 7.2 Hz, 3H, OCH2CH3)
solutions of the chemicals for 5 s, then the superfluous liquor was removed,
and they were kept in the conditioned room for normal cultivation. The
mortality was evaluated by the number of live larvae in the treated bottles
relative to that in the untreated controls after 24 h. Controls were
performed under the same conditions. Each test was performed in
triplicate.
Toxicity against Mosquito (Culex pipiens pallens). The toxicities
of the target compounds 6a-6j and 7a-7j against mosquito were
evaluated according to the reported procedure (18, 20). One milliliter of
different concentrated dilutions of each compound was added to 99 mL of
water to obtain different concentrations of tested solution. Then 20 fourth-
instar mosquito larvae were put into the solution. Percentage mortalities
were evaluated 1 day after treatment. For comparative purposes, ethiprole
was tested under the same conditions, and each test was performs three
times.
Stomach Toxicity against Diamondback Moth (Plutella xylo-
stella). The stomach toxicities of the target compounds 6a-6j, 7a-7j and
the contrast ethiprole against diamondback moth were tested by the leaf-
dip method using the reported procedure (21, 22). A stock solution of
each test sample was prepared in dimethylformamide at a concentration of
200 mg L-1 and then diluted to the required concentration with water
containing TW-20. Leaf disks (6 cm ꢀ 2 cm) were cut from fresh cabbage

4996 J. Agric. Food Chem., Vol. 58, No. 8, 2010
Zhao et al.
leaves and then were dipped into the test solution for 3 s. After air-drying,
the treated leaf disks were placed individually into glass tubes. Each dried
treated leaf disk was infested with seven third-instar diamondback moth
larvae. Percentage mortalities were evaluated 3 days after treatment.
Leaves treated with water and dimethylformamide were provided as
controls. Each treatment was performed three times.
Stomach Toxicity against Oriental Armyworm (Mythimna sepa-
rata). The stomach toxicities of the target compounds 6a-6j, 7a-7j
and the contrast ethiprole against oriental armyworm were evaluated
by foliar application using the reported procedure (23, 24). For the
foliar armyworm tests, individual corn leaves were placed on mois-
tened 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 3 days after treatment. Each treatment was performed three
times.
RESULTS AND DISCUSSION
Synthesis. The target compounds 6a-6j and 7a-7j were pre-
pared from 2,6-dichloro-4-trifluoromethylaniline (1) as shown in
Scheme 1. Compound 1 was converted to 5-amino-3-cyano-
1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (2) according
to the reported method with a little modification (4), and further
treatment with sulfur chloride provided bis(5-amino-3-cyano-
1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazol-4-yl) disulfide
(3). The cleavage of disulfide 3 by alkylation assisted with an
alkali and a reducing reagent afforded the sulfenyl compound 4 in
high yield (25). Then the key intermediate 5-trichloroethylidene-
imino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-alkyl-
sulfenylpyrazole (5) was synthesized by reaction of 4 with chloral
Figure 4. Stereoisomers of 7d. The mixture of enantioners SSCS and
SRCR was noted as pair I, and the mixture of SSCR and SRCS was noted as
pair II. Then 7d-1 was one of the two pairs, and 7d-2 was the other pair.
It was a similar situation for 7e-1 and 7e-2.
Table 3. Foliar Contact Activities against Bean Aphid of Compounds 6a-6j,
7a-7j and Ethiprole
larvicidal activity (%) at concn (mg kg-1
)
˚
in the presence of molecular sieves (4 A). The imine 5 was reacted
with the proper alcohol to afford 5-(2,2,2-trichloro-1-alkoxyl-
ethylamino)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-
4-alkylsulfenylpyrazole (6), which was converted to the sulfinyl
compound 7 by hydrogen peroxide and trifluoroacetic acid.
The addition reaction of imine 5 was closely related with the
nature of the alcohol. When the alcohol was methanol or ethanol,
the reaction was completed under reflux in 2 h, while propanol
needed 5 h, and all of them gave high yields. As for 2-fluoroetha-
nol or 2-chloroethanol, the reaction was carried out at about
80 °C for more than 10 h with relatively low yield, while a higher
temperature or reflux could decompose the imine 5 markedly. In
addition, other nucleophilic reagent such as 2-propanol, 2,2,2-
trifluoethanol, 1-propanethiol and acetic acid were also tried but
failed to give addition products under similar conditions.
compd R1
R2
200
100
50
25
10
5
2.5
0
6a
6b
Me Me
Me Et
Me n-Pr
100
100
100
100
100
100
100
100
90
100
56
94
43
89
0
43
0
6c
6d
90
43
21
0
0
0
Me FCH2CH2 100
Me ClCH2CH2 100
100
100
80
74
62
28
69
6e
98
73
62
6f
6g
Et Me
Et Et
Et n-Pr
93
90
95
62
0
86
75
35
0
6h
6i
90
85
53
0
Et FCH2CH2 100
Et ClCH2CH2 100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
29
11
0
0
6j
100
100
100
100
100
100
100
100
96
51
7a
7b
Me Me
Me Et
Me n-Pr
100
100
100
100
85
88
63
91
72
70
61
68
76
81
100
73
0
0
0
7c
100
100
100
96
0
7d-1
7d-2
7e-1
7e-2
7f
Me FCH2CH2 100
Me FCH2CH2 100
Me ClCH2CH2 100
Me ClCH2CH2 100
43
46
0
It was noticed that compound 7 has two chiral centers each on
the sulfur and carbon atoms, and there were two pairs of
enantiomers theoretically. It was very interesting that only one
pair was obtained for 7a-7c, while both of the two pairs were
generated and separated for 7d (noted as 7d-1 and 7d-2, Figure 4)
and 7e (noted as7e-1 and 7e-2). But as for 7f-7j, onlya mixture of
two pairs of enantiomers was obtained because of the high
100
87
0
Et Me
Et Et
Et n-Pr
100
100
100
0
7g
7h
100
100
100
100
100
100
100
100
48
0
89
43
7i
Et FCH2CH2 100
Et ClCH2CH2 100
100
7j
ethiprole
1
similarity of Rf. But the corresponding H NMR spectra, espe-
31
0
cially the CH and NH of 7f-7j, were different for the two pairs,
and could also explain their ratio (Table 2).
same concentration. In particular, the activities of 7a, 7c, 7g and
7h were 88%, 91%, 81% and 100% at 5 mg kg-1, respectively,
while ethiprole caused no detectable mortality at this concentra-
tion. It was especially mentioned that the activity of 7h was still
89% at 2.5 mg kg-1. It was observed that the n-Pr group of R2
played a negative role in 6 but a positive role in 7, and most of the
sulfinyl compounds 7a-7j were more potent than the corre-
sponding sulfenyl compounds 6a-6j. The LC50 values in Table 4
showed that the foliar contact activities of 7a, 7c and 7h were 4.2-,
4.3-, and 7.9-fold as high as that of ethiprole, respectively.
Moreover, the activities of compounds 7d-1 and 7e-1 were very
Bioassays. Foliar Contact Activity against Bean Aphid (Aphis
craccivora). Table 3 showed the foliar contact activities of the
target compounds 6a-6j, 7a-7j and the contrast ethiprole
against bean aphid. The results indicate that the target com-
pounds have excellent foliar contact activities against bean
aphid, and some of them exhibited much higher activities than
ethiprole. For example, the activities of 6a, 7a, 7b, 7c, 7d-1, 7d-2,
7e-1, 7e-2, 7f, 7g, 7h and 7i were 89%, 100%, 85%, 100%, 100%,
100%, 96%, 100%, 87%, 100%, 100% and 100% at 10 mg kg-1
respectively, whereas ethiprole caused only 31% mortality at the
,

Article
J. Agric. Food Chem., Vol. 58, No. 8, 2010 4997
Table 4. LC50 Values of Compounds 7a, 7c, 7h and Ethiprole of Foliar
Contact Toxicities against Bean Aphid
Table 6. Larvacidal Activities against Diamondback Moth of Compounds
6a-6j, 7a-7j and Ethiprole
larvicidal activity (%) at concn (mg kg-1
)
compd
y = a þ bx
LC50a (mg kg-1
)
toxic ratio
compd R1
R2
200
100
50
25
10
5
2.5
7a
y = -2.3051 þ 5.0099x
y = -2.1989 þ 4.9845x
y = -0.7833 þ 4.5433x
y = -7.9808 þ 7.4646x
2.8848
2.7616
1.4873
11.7263
4.2
4.3
7.9
1
7c
7h
6a
6b
Me Me
Me Et
Me n-Pr
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
36
100
84
86
68
0
76
43
25
0
ethiprole
6c
6d
17
a LC50 is the median lethal concentration.
Me FCH2CH2 100
Me ClCH2CH2 100
100
100
94
100
100
34
89
100
0
81
87
34
62
6e
6f
6g
Et Me
Et Et
Et n-Pr
100
100
100
Table 5. Larvacidal Activities against Mosquito of Compounds 6a-6j, 7a-7j
and Ethiprole
96
44
18
17
29
27
91
85
71
77
76
81
79
0
6h
6i
89
58
larvicidal activity (%) at concn (μg kg-1
)
Et FCH2CH2 100
Et ClCH2CH2 100
100
88
100
43
0
0
compd R1
R2
100
50
25
10
5
2.5
6j
7a
7b
Me Me
Me Et
Me n-Pr
100
100
100
100
100
100
100
100
100
100
86
100
100
100
92
88
63
30
56
54
60
56
34
0
6a
6b
Me Me
Me Et
Me n-Pr
100
100
100
100
100
100
100
100
100
100
100
100
100
100
50
100
100
100
100
100
100
100
100
100
100
100
100
100
40
100
100
100
70
80
7c
0
6c
6d
100
7d-1
7d-2
7e-1
7e-2
7f
Me FCH2CH2 100
Me FCH2CH2 100
Me ClCH2CH2 100
Me ClCH2CH2 100
0
Me FCH2CH2
89
0
6e
Me ClCH2CH2 100
100
100
100
100
100
100
20
100
0
100
100
31
0
6f
6g
Et Me
Et Et
100
100
100
100
30
60
0
Et Me
Et Et
Et n-Pr
100
100
100
6h
6i
Et n-Pr
Et FCH2CH2
50
0
7g
7h
100
100
91
100
87
72
44
30
32
23
29
27
0
0
0
6j
Et ClCH2CH2 100
100
7i
Et FCH2CH2 100
Et ClCH2CH2 100
100
46
7a
7b
Me Me
Me Et
Me n-Pr
100
100
100
20
7j
ethiprole
100
100
46
0
100
100
30
50
69
0
7c
than 80% at 5 mg kg-1, while the activity of ethiprole was less
than 70% at 25 mg kg-1. Moreover, a small change in structure of
the target compounds could lead to a remarkable change of
activity. The activity of 6c was only 36% at 50 mg kg-1, whereas
the activity of 6e was 87% at 5 mg kg-1. The activity of 7a was
88% at 5 mg kg-1, much higher than the activity of 7f, which was
86% at 50 mg kg-1. Both of the structural changes from 6c to 6e
and from 7a to 7f only involved replacement of one substituent at
the pyrazole ring, so the 2,2,2-trichloro-1-alkoxyethyl moiety as
well as the R1 group was quite critical for the activity against
diamondback moth.
Stomach Toxicity against Oriental Armyworm (Mythimna
separata). Most of the target compounds and ethiprole showed
no detectable activity, for example, the activities against oriental
armyworm of 6i, 7c and ethiprole were 20%, 40% and 0 at 200 mg
kg-1, respectively. These data formed a sharp contrast to the
activities against diamondback moth, which was also of the order
Lepidoptera. The results indicated that the action passway or
metabolism of the target compounds probably varied for differ-
ent pest species.
In summary, a series of novel phenylpyrazole containing a
2,2,2-trichloro-1-alkoxyethyl moeity were designed and synthe-
sized via the key intermediate 5-trichloroethylideneimino-3-cya-
no-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-alkylsulfenylpyra-
zole (5). The addition reaction of the imine 5 was attempted and
discussed, and it was closely related with the nature of the
nucleophilic reagent. The results of bioassays indicated that the
target compounds possessed excellent activities against a broad
spectrum of insects such as bean aphid, mosquito and diamond-
back moth, even much higher than the contrast ethiprole. In
particular, the foliar contact activity against bean aphid of
compound 7h at 2.5 mg kg-1 was 89%, the larvacidal activity
against mosquito of compound 6c at 2.5 μg kg-1 was 100%, the
larvacidal activity against diamondback moth of compound 7a at
5 mg kg-1 was 87%, and all of these activities were much higher
than the contrast ethiprole. The bioactivity against bean aphid
and diamondback moth also showed that the two pairs of
enantiomers 7d-1 and 7d-2 gave activities without distinctive
7d-1
7d-2
7e-1
7e-2
7f
Me FCH2CH2
Me FCH2CH2
Me ClCH2CH2 100
50
40
Me ClCH2CH2
Et Me
Et Et
50
100
100
100
100
100
100
100
20
0
40
0
7g
7h
Et n-Pr
Et FCH2CH2
7i
7j
ethiprole
Et ClCH2CH2 100
100
0
100
50
close to those of their corresponding isomers 7d-2 and 7e-2.
Compounds 7f-7j were different from ethiprole at the 5-position
of the pyrazole ring, but most of them exhibited higher activities
than ethiprole. Thus, the R1 group, sulfinyl group and 2,2,2-
trichloro-1-alkoxyethyl group were important for the activity
against bean aphid.
Toxicity against Mosquito (Culex pipiens pallens). Table 5
showed the larvacidal activities of the target compounds 6a-6j,
7a-7j and the contrast ethiprole against mosquito. Generally, the
sulfenyl compounds 6a-6j were more potent than the sulfinyl
compounds 7a-7j. The activities of 6a, 6b, 6c, 6f and 6j were
100% at 5 μg kg-1, while the activities of the compounds 7a-7j as
well as ethiprole were not higher than 50% at 25 μg kg-1
.
Moreover, the substituents of the target compounds were also
important for the activities against mosquito. For instance, the
difference between the structures of compounds 6c and 6d was
only the replacement of an n-propyl group by a 2-fluoroethyl
group, but the activity of 6c was 100% at 2.5 μg kg-1, whereas the
activity of 6d was only 40% at 10 μg kg-1
.
Stomach Toxicity against Diamondback Moth (Plutella
xylostella). Table 6 showed the larvacidal activities of the target
compounds 6a-6j, 7a-7j and the contrast ethiprole against
diamondback moth. Overall, the activities of the target com-
pounds were higher when the R1 group was fixed as methyl than
as ethyl. The results indicated that some of the target compounds
exhibited excellent activities, much higher than ethiprole. For
example, the activities of 6a, 6d, 6e, 7a and 7b were at least 85% at
10 mg kg-1, and the activities of 6d, 6e and 7a were still higher

4998 J. Agric. Food Chem., Vol. 58, No. 8, 2010
Zhao et al.
difference, and it was a similar situation for 7e-1 and 7e-2 against
bean aphid and diamondback moth. Moreover, the target
compounds exhibited high selectivity between diamondback
moth and oriental armyworm, both of which are of the order
Lepidoptera. The results of insecticidal activities also suggested
that the structural requirement varied for different insect species,
for instance, compound 6c exhibited high activity against mos-
quito but relatively low activity against bean aphid and diamond-
back moth. The 2,2,2-trichloro-1-alkoxyethyl moiety was essen-
tial for high insecticidal activities.
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Received for review January 16, 2010. Revised manuscript received
March 13, 2010. Accepted March 19, 2010. We gratefully acknowledge
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