Design, Synthesis, and Acaricidal Activities of Novel Pyrazole Acrylonitrile Compounds

Article abstract of DOI:10.1002/jhet.2682

Using cyenopyrafen as the lead compound, a series of novel pyrazole acrylonitrile compounds were designed and synthesized via the reaction of butylphenylacetonitrile with the corresponding (substituted pyrazol-5-yl) methanone of pyrethroid alcohols in the presence of potassium tert-butoxide. These compounds showed prominent acaricidal activity against Tetranchus urticae. In particular, IIf, IIh, IIo, and IIp displayed excellent activities, which the median lethal concentrations were all lower 0.4 mg/L. In addition, the structure-activity relationship for the target compounds was discussed.

Full text of DOI:10.1002/jhet.2682

Month 2016
Design, Synthesis, and Acaricidal Activities of Novel Pyrazole
Acrylonitrile Compounds
Danling Huang,a,b Mingzhi Huang,b Aiping Liu,b Xingping Liu,b Weidong Liu,b Xiaoyang Chen,b Hansong Xue,b,c
b
a
b
*
*
Jiong Sun, Dulin Yin, and Xiaoguang Wang
aNational & Local Joint Engineering Laboratory for New Petro-chemical Materials and Fine Utilization of Resources,
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education of China),
College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha 410081, Hunan Province,
People’s Republic of China
bHunan Branch of National Pesticide R&D South Center, Hunan Research Institute of Chemical Industry,
Changsha 410007, Hunan Province, People’s Republic of China
cCollege of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan Province, People’s Republic of China
*
E-mail: dulinyin@126.com; xxggWang@163.com
Additional Supporting Information may be found in the online version of this article.
Received January 28, 2016
DOI 10.1002/jhet.2682
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Using cyenopyrafen as the lead compound, a series of novel pyrazole acrylonitrile compounds were
designed and synthesized via the reaction of butylphenylacetonitrile with the corresponding (substituted
pyrazol-5-yl) methanone of pyrethroid alcohols in the presence of potassium tert-butoxide. These com-
pounds showed prominent acaricidal activity against Tetranchus urticae. In particular, IIf, IIh, IIo, and
IIp displayed excellent activities, which the median lethal concentrations were all lower 0.4 mg/L. In addi-
tion, the structure-activity relationship for the target compounds was discussed.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
fenpyroximate [4,5], fipronil [6], and pyraclostrobin [7], are
all commercialization, which are widely used as herbicide,
insecticide, and fungicide. Moreover, more and more novel
pyrazole derivatives have been discovered to be excellent
pesticide [8–10]. Acrylonitrile compounds have attracted at-
tention because of the novel structure, high activity, low tox-
icity on mammals and fish, and no cross-resistance to
existing insecticides. One of the best known acrylonitrile
derivatives is cyenopyrafen (compound I in Fig. 1), which
integrates the advantages of pyrazole compounds and acrylo-
nitrile compounds and possesses high safety level on benefi-
cial insects and high acaricidal activity [11]. Cyenopyrafen
displays excellent bioactive to controlling spider mites
(Tetranychus, Oligonychus, and Panonychus) during all life
Plant diseases pose threat to crop production and limit the
development of agriculture worldwide. Pesticides applications
in the recent agricultural system have effectively controlled
many plant diseases; however, increasing resistances to cur-
rent pesticides demands the development of new pesticides
with excellent bioactivities [1,2]. Two novel classes of com-
pounds, pyrazole compounds and acrylonitrile compounds,
have become increasingly popular in the search of new
pesticides. Pyrazole compounds are known for high biological
activity, low toxicity, broad-spectrum, and structural changes.
Numerous pyrazole derivatives have been developed as pesti-
cides up to now. Among these compounds, fluazolate [3],
© 2016 Wiley Periodicals, Inc.

D. Huang, M. Huang, A. Liu, X. Liu, W. Liu, X. Chen, H. Xue, J. Sun, D. Yin, and X. Wang
Vol 000
Figure 1. Molecular designs of compounds I to II.
stages, although some Tetranchus urticae strains might
prossess cross-resistance [12].
respectively. Intermediate 5 was not purified and next
reaction was carried out, yielding target compounds of E
and Z form. These are readily separable by column chro-
matography on silica gel. For unambiguous structure
Motivated by the aforementioned findings, we considered
of using cyenopyrafen as a lead compound to design and
synthesize several novel pesticides (Fig. 1), with the inhibi-
tion of microbial mitochondrial respiration as their primary
mechanism of action [13,14]. Here are reported the design
and syntheses of a series of 25 unreported cyenopyrafen de-
rivatives (II) by using pro-drug theory, analogue synthesis,
and sub-structure theory. As shown in Figure 1, moiety A
was substituted to another six groups that were isosteres each
other. Meanwhile, R2, R3, and R4 of moiety B were optimized
as well. To search for novel cyenopyrafen analogues with
unique biological activities, a synthetic screening program
was carried out around commercialized I and II. Besides,
based on structural features of the commercialized
cyenopyrafen, which exhibit remarkable acaricidal activities,
the group of R1, R2, R3, and R4 of II was modified in order to
study their structure–activity relationship.
1
elucidation, we analyze H NMR spectroscopy of IIa–y.
According to the literature [11], the phenyl group of E iso-
mer gives resonance frequencies above 7.40 ppm, whereas
the corresponding signals of Z form were found below
7.35 ppm.
Acaricidal activities.
In primary screening, all the
compounds were active except IIj and IIy with over 95%
mortality against T. urticae at 500mg/L. All the
compounds were screening at 12.5 mg/L further, and the
result was shown in Table 1. Parts of the compounds
with high acaricidal activities were singled out to
calculate the regression equation, and the median lethal
concentration (LC50) value for these compounds was
shown in Table 2. It was revealed that most of II
exhibited high acaricidal activities against T. urticae. In
particular, IIf, IIh, IIo, and IIp display excellent
activities, which the LC50 was all lower 0.4mg/L.
Moreover, to our amazement, when IIe was mixed with
the equal amount of IIf, the LC50 was decreased to
0.358 mg/L, and the acaricidal activity of this isomer-
mixture was higher than that of each of them. To our
delight, we achieved some compounds (IIf, IIh, IIo, IIp,
and mixture of IIe and IIf) to defend T. urticae
efficiently, which the acaricidal activities were similar to
commercialized cyenopyrafen.
RESULTS AND DISCUSSION
Synthesis.
A series of novel pyrazole acrylonitrile
derivatives IIa–y were designed and synthesized (Table 1).
Their syntheses were summarized in Schemes 1 and 2; there
were two routes to synthesize the key intermediate 5
(Scheme 2). Although route 1 was simpler than route 2,
route 2 was used to synthesize intermediate 5 because we
found that the yields of route 2 were higher than that of route
1. The structures of target IIa–y were determined by 1H NMR.
Intermediate 5 undergo route 1 or route 2, yielding a
mixture of the two isomeric products E and Z form,
Structure–activity relationships.
The activities of the
compounds IIa–y depended on the R1, R3, and R4
moiety. As we can see in Table 2, R1 has an important
effect on the activity: kept R2, R3, and R4 as CH3, when
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Pyrazole Acrylonitrile
Table 1
Acaricidal activities of the I and IIa–y against Tetranchus urticae at the test concentration of 12.5 mg/L.
No.
Z/E isomer
R1
R2
R3
R4
Test concentration (12.5 mg/L)
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
IIm
IIn
IIo
IIp
IIq
IIr
IIs
Z
E
E
E
Z
E
E
Z
E
E
Z
E
Z
E
E
E
Z
E
E
Z
E
E
E
E
E
Z
E
A1
A1
A4
A2
A5
A5
A6
A3
A1
A2
A5
A5
A6
A6
A3
A1
A3
A1
A5
A6
A6
A6
A1
A2
A3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
Cl
Cl
H
H
H
H
H
100
100
100
100
100
100
86.22
100
72.23
64.82
98.3
98.41
99.14
100
96.05
94.39
95.54
99.59
No test
100
90.03
93.33
100
IIt
IIu
IIv
IIw
IIx
IIy
I(Z)
I(E)
Cl
Cl
Cl
Cl
CH3
CH3
100
55.60
tertiary butyl
tertiary butyl
CH3
CH3
Scheme 1. Synthetic pathway to compound 3a–c.
R1 = 1-chloro-tert-butyl(A3), the compound (IIh) showed
the highest activity; R1 = cyclopentane-yl(A5), the
compound (IIf) had good activity; R1 = substituent-
sulfane-yl, the compound (IIa–d) showed moderate
activity. In general, for the synthesized compounds, the
activity order for R1 is 1-chloro-tert-butyl(A3) >
cyclopentane-yl(A5). >substituent-sulfane-yl(A1, A2 or
A4). Both R3 and R4 also affect the activity considerably:
for the same R1 (e.g., R1 = ethyl(methyl)sulfane-3-yl),
when R3 = CH3 and R4 = Cl, the activity of the compound
(IIp) was better than that of another substituent
compound (IIa, IIr, and IIw).
It seems that the cis-trans isomers of compounds affect
insecticidal activities unregularly. But we were surprised
to find that the acaricidal activities of E/Z isomer mixture
were higher than that of either E isomer or Z isomer existed
individually, when this pair of E/Z isomer was mixed
equally. For instance, when IIe was mixed with the equal
amount of IIf, the LC50 was decreased to 0.358mg/L that
was lower both 0.414 mg/L of IIe and 0.364mg/L of IIf.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Huang, M. Huang, A. Liu, X. Liu, W. Liu, X. Chen, H. Xue, J. Sun, D. Yin, and X. Wang
Vol 000
Scheme 2. Synthetic pathway to compound IIa–y.
important effect on the activity, and activity order for R1 is
1-chloro-tert-butyl(A3)> cyclopentane-yl(A5). >substituent-
sulfane-yl(A1, A2 or A4).
Table 2
Median lethal concentration (LC50) of the target compounds against
Tetranchus urticae.
Compound
Regression equation
Correlation LC50 (mg/L)
EXPERIMENTAL
IIa
IId
IIe
IIf
IIh
IIm
IIn
IIo
IIp
IIq
IIr
IIt
IIu
IIv
IIw
IIx
IIe/IIf
(1:1)
I (Z)
I (E)
Y = 4.9113 + 2.5860x
Y = 4.6840 + 2.1718x
Y = 5.8415 + 2.1995x
Y = 5.8096 + 1.8420x
Y = 6.1553 + 2.2927x
Y = 5.0499 + 2.7971x
Y = 5.0887 + 2.7174x
Y = 6.0704 + 2.1887x
Y = 6.8171 + 3.5426x
Y = 5.1560 + 2.6318x
Y = 4.5261 + 2.0691x
Y = 5.4509 + 1.6726x
Y = 4.2751 + 1.8975x
Y = 4.9503 + 1.8083x
Y = 4.6833 + 2.1541x
Y = 4.5779 + 2.2126x
Y = 5.9581 + 2.1481x
0.9697
0.9846
0.9760
0.9527
0.9703
0.9322
0.9873
0.9821
0.9635
0.9636
0.9555
0.9846
0.9857
0.9829
0.9818
0.9805
0.9875
1.08
1.40
0.414
0.364
0.313
0.960
0.928
0.324
0.307
0.872
1.69
0.538
2.41
1.07
1.40
1.55
Materials and methods.
Melting points (m.p.) were
measured on a WPS-1B melting-point apparatus (made in
Shanghai Physical Optics Instrument Plant, Shanghai,
China) and are uncorrected; 1H NMR spectra were
recorded in CDCl3 with a Varian INOVA-300, using
TMS as internal standard; infrared spectra were acquired
on a PE System 2000 FT-IR spectrophotometer using
KBr discs; high resolution mass spectra were acquired
using a Agilent 5973-6890 gas chromatography-mass
spectrometer (GC-MS) and a Agilent 1100 series liquid
chromatography-mass spectrometer (LC-MS). Column
chromatography was performed using 200–300mesh
silica gel. The solvents and reagents were used as
received or were dried prior to use as needed.
0.358
Y = 6.8386 + 2.7374x
Y = 6.8438 + 3.2561x
0.9710
0.9759
0.213
0.272
Synthetic chemistry details
Synthesis of ethyl 2,4-dioxovalerate 1.
In 300mL of
anhydrous ethanol was dissolved sodium ethylate
(0.45 mol) with stirred below À10°C. Then the mixture
solution of acetone (0.35mol) and diethyl oxalate
(0.37 mol) was added slowly, and keep the reaction
temperature below À5°C for 3 h. The mixture was poured
into ice water. After using HCl (1 mol/L) to keep pH
around 4, the aqueous phase was extracted with ethyl
acetate (EA). The organic layer was washed twice with
water and dried over Na2SO4, filtered, and concentrated
under reduced pressure, 48.70 g (88% yeild, 96% purity);
yellow liquid was obtained.
Further studies on the biological activity and structure–
activity relationships of this series of compounds are in
progress.
CONCLUSION
In summary, a series of novel pyrazole acrylonitrile de-
rivatives were synthesized, and their acaricidal activities
were evaluated. The results of bioassays indicated that
most of these title compounds exhibit higher acaricidal ac-
tivities. In particulate, IIe, IIf, IIh, IIo, and IIp displayed
excellent activities, which the median lethal concentration
is 0.364 mg/L, 0.313 mg/L, 0.324mg/L, and 0.307 mg/L.
Structure–activity relationships indicated that R1 has an
Synthesis of ethyl 3-methyl-1H-pyrazole-5-carboxylate
2.
In 300 mL of anhydrous ethanol was dissolved 1
(0.3 mol) with stirred below À5°C. Then hydrazine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Pyrazole Acrylonitrile
hydrate (0.375mol) was added slowly, and the solution
was stirred below 0°C for 1h. The solvent was removed
under reduced pressure, and the aqueous phase was
extracted with EA. The organic layer was washed twice
with water and dried over Na2SO4, filtered, and
concentrated under reduced pressure, 42.50g (92% yeild,
90% purity); yellow solid was obtained, m.p. 80–82°C.
Synthesis of ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate
3a. In 120mL of N,N-dimethylformamide (DMF) was
dissolved 2 (10 g, 0.065 mol) and dimethyl sulfate
(9.83g,0.078mol), and the solution was stirred at 60°C
for 3 h. The progress of the reaction was monitored by
thin layer chromatograph (TLC). After complete
disappearance of the starting material, the solution was
extracted with EA. The organic layer was washed twice
with water and dried over Na2SO4, filtered, and
concentrated under reduced pressure, 10.28 g (90% yeild,
85% purity); brown liquid was obtained.
0.022mol), ethylene glycol monomethylether (2mL), n-
heptane (50mL), and 3 (, 0.022mol) were mixed sufficiently
for 0.5h. After 1h under reflux, 30% sodium methylate
solutions (6.20 g, 0.03mol) were added dropwise. Keep
reflux for 5h, and then the reaction solution was poured into
ice water, and the mixture was extracted with EA to remove
organic impurity. The aqueous phase was used HCl (1mol/L)
to keep weak acidity. Then the solutions were extracted
with EA again. The organic layer was washed twice with
water and dried over Na2SO4, filtered, and concentrated
under reduced pressure; brown liquid was obtained
(76–83% yeild).
Synthesis of substituted pyrazol carboxylic acid 6. Compound
3 (0.05 mol) was added to a stirred mixture of NaOH (6.0 g,
0.15 mol) and water (100 mL). After 4 h under 80°C, the
mixture was poured into ice water and adjusts the pH to
acidic. Then 10% HCl was slowly add to the solutions
until precipitate large amount of solids. Filtered and the
solids was dried, yield 70–79%.
Synthesis of ethyl 1,3-dimethyl-4-chlorine-1H-pyrazole-5-
Synthesis of substituted pyrazol acyl chloride 7. Compound
6 (0.04mol) and thionyl chloride (9.5g, 0.08mol) were
successively added to 100 mL 1,2-dichloroethane. After 4 h
under reflux, the solvent was removed under reduced
pressure; 7 was obtained, yield 78–89%.
carboxylate 3b.
SO2Cl2 (8.04 g, 0.06mol) was slowly
added to a stirred mixture of 3a (10 g, 0.06mol) and
ClCH2CH2Cl (50 mL) in ice bath. Then the solution was
stirred under reflux for 2 h. The solvent was removed
under reduced pressure, and the mixture was poured into
NaCl solution. Then the aqueous phase was extracted
with EA. The organic layer was washed twice with water
and dried over Na2SO4, filtered, and concentrated under
reduced pressure, 10.8g (95% yeild, 94% purity); brown
liquid was obtained.
Synthesis of ethyl 1,3-dimethyl-4-chloromethyl-1H-pyrazole-
5-carboxylate 4. Paraformaldehyde (3.6g, 0.12mol), 1,4-
dioxane (100mL), and 3a (10g, 0.06mol) were
successively added to a stirred mixture of H2SO4 (0.6 g,
0.006 mol) and concentrated hydrochloric acid (12 g,
12mol). After 5h under reflux, the solvent was removed
under reduced pressure, and the mixture was poured into ice
water. Then the aqueous phase was extracted with EA. The
organic layer was washed twice with water and dried over
Na2SO4, filtered, and concentrated under reduced pressure,
9.07 g (70% yeild, 80% purity); yellow solid was obtained.
Synthesis of ethyl 1,3,4-trimethyl-1H-pyrazole-5-carboxylate
Synthesis of (1H-pyrazol-1-yl) (substituted pyrazol-5-yl)
methanone 8.
Compound 7 (0.08mol) and thionyl
chloride (9.5 g, 0.08 mol) were successively added to
100 mL dichloromethane under room temperature for 2h.
Then the mixture was poured into water; the solutions
were extracted with dichloromethane and dried over
Na2SO4, filtered, and concentrated under reduced
pressure; 8 was obtained, yield 91–95%.
Synthesis of 2-(4-(tert-butyl)phenyl)-3-hydroxy-3-(substituted
pyrazol-5-yl)acrylonitrile
5
(route 2).
Compound 8
(0.024 mol), 2-(4-(tert-butyl) phenyl) acetonitrile (4.20 g,
0.024 mol), and 30mL tetrahydrofuran (THF) were mixed
homogeneously in ice bath for 10 min. Then potassium
tert-butoxide (0.026 mol) was slowly added to the
mixture under 5°C, and the mixture was stirred at room
temperature. The progress of the reaction was monitored
by TLC. After complete disappearance of the starting
material, the reaction solution was poured into ice water,
and the mixture was extracted with EA to remove
organic impurity. The aqueous phase was used HCl
(1 mol/L) to keep weak acidity. Then the solutions were
extracted with EA again. The organic layer was washed
twice with water and dried over Na2SO4, filtered, and
concentrated under reduced pressure; 5 was obtained,
yield 76–80%.
3c.
The 5% Pd/C catalyst (0.54g) and 4 (10.8 g,
0.05 mol) were, respectively, added to a stirred mixture
of ethanol (50 mL) and water (mL), which were carried
out in hydrogen atmosphere at room temperature for 6 h.
After filtered the catalyst, the mixture solutions were
poured into water, and then the aqueous phase was
extracted with EA. The organic layer was washed with
water and dried over Na2SO4, filtered, and concentrated
under reduced pressure, 9.07 g (80% yeild, 90% purity);
brown liquid was obtained.
Synthesis of 2-(4-(tert-butyl) phenyl)-3-hydroxy-3-(substituted
pyrazol-5-yl) acrylonitrile IIa–y. Compound 5 (0.005mol),
THF (30mL), and triethylamine (0.005mol) were mixed
homogeneously in ice bath for 10min. Then substituted
acyl chloride (0.01mol) was added to the mixture dropwise
Synthesis of 2-(4-(tert-butyl) phenyl)-3-hydroxy-3-(substituted
pyrazol- 5-yl) acrylonitrile 5 (route 1).
literature [11], the butylphenylacetonitrile (3.80 g,
According to the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Huang, M. Huang, A. Liu, X. Liu, W. Liu, X. Chen, H. Xue, J. Sun, D. Yin, and X. Wang
Vol 000
and, keep the reaction temperature below 5°C for 4h. The
reaction solution was poured into ice water, and the
mixture was extracted with EA. The organic layer was
washed twice with water and dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel, using
petroleum ether and EA (30:1v/v) as the eluent, to obtain
IIa–y white, yellow, or brown oil.
IIg: yield, 25%. yellow oil. 1H NMR (CDCl3,
300 MHz): 1.345 (s, 9H, 3CH3), 1.850–1.929 (m, 2H,
CH2), 2.106 (s, 3H, CH3), 2.221 (s, 3H, CH3), 3.689–
3.805 (m, 2H, CH2), 3.821–3.878 (m, 2H, CH2), 3.888
(s, 3H, CH3), 5.133–5.139 (m, 1H, CH), 7.466 (d,
J = 8.7 Hz, 2H, Ph H), 7.576–7.605 (m, 2H, Ph H). purity,
97% (HPLC). GC-MS M+ = 423. Anal. calcd for
C24H29N3O4: C, 68.06; H, 6.90; N, 9.92. Found: C,
68.36; H, 6.90; N, 9.92.
IIa: yield, 27%. yellow oil. 1H NMR (CDCl3,
300MHz): 1.269 (s, 9H, 3CH3), 1.546 (d, J =6.9Hz, 3H,
CH3), 1.904 (s, 3H, CH3), 2.063 (s, 3H, CH3), 2.163 (s,
3H, CH3), 3.458 (s, 3H, CH3), 3.528 (q, J =7.2 Hz, H,
CH), 7.045 (d, J= 9.0 Hz, 2H, Ph H), 7.291 (d, J= 8.4 Hz,
2H, Ph H). purity, 95% (high-performance liquid chroma-
tography, HPLC); GC-MS M+ = 411. Anal. calcd for
C23H29N3O2S: C, 67.12; H, 7.10; N, 10.21. Found: C,
67.10; H, 7.20; N, 10.25.
IIh: yield, 28%. white oil. 1H NMR (CDCl3, 300 MHz):
1.228 (s, 6H, 2CH3), 1.336 (s, 9H, 3CH3), 2.102 (s, 3H,
CH3), 2.205 (s, 3H, CH3), 3.514 (s, 2H, CH2), 3.913 (s,
3H, CH3), 7.263–7.497 (m, 4H, Ph H). purity, 96%
(HPLC).
GC-MS
M+ = 427.
Anal.
calcd
for
C24H30ClN3O2: C, 67.36; H, 7.07; N, 9.82. Found: C,
67.39; H, 7.27; N, 9.81.
IIi: yield, 21%. yellow oil. 1H NMR (CDCl3, 300 MHz):
1.334 (s, 9H, 3CH3), 1.370 (d, J= 6.9 Hz, 3H, CH3), 1.874
(s, 3H, CH3), 2.289 (s, 3H, CH3), 3.341 (q, J =7.2 Hz, 1H,
CH), 3.996 (s, 3H, CH3), 6.453 (d, J= 0.6 Hz, 1H, pyrazole
H), 7.435 (d, J= 8.7 Hz, 2H, Ph H), 7.528–7.557 (m, 2H,
Ph H). purity, 95% (HPLC). GC-MS M+ = 397. Anal. calcd
for C22H27N3O2S: C, 66.47; H, 6.85; N, 10.57. Found: C,
66.39; H, 6.79; N, 10.65.
IIb: yield, 25%. brown oil. 1H NMR (CDCl3,
300MHz): 1.340 (s, 9H, 3CH3), 1.394 (d, J =7.2Hz, 3H,
CH3), 1.849 (s, 3H, CH3), 2.123 (s, 3H, CH3), 2.219 (s,
3H, CH3), 3.359 (q, J= 7.2 Hz, 1H, CH), 3.934 (s, 3H,
CH3), 7.446–7.476 (m, 2H, Ph H), 7.567 (d, J= 8.7 Hz,
2H, Ph H). purity, 97% (HPLC). GC-MS M+ = 411. Anal.
calcd for C23H29N3O2S: C, 67.12; H, 7.10; N, 10.21.
Found: C,67.07; H, 7.33; N, 10.15.
IIc: yield, 25%. brown oil. 1H NMR (CDCl3, 300MHz):
1.340 (s, 9H, 3CH3), 1.975 (s, 3H, CH3), 2.112 (s, 3H,
CH3), 2.201 (s, 3H, CH3), 3.223 (s, 2H, CH2), 3.907 (s,
3H, CH3), 7.451 (d, J= 8.7 Hz, 2H, Ph H), 7.559 (d,
J =8.7Hz, 2H, Ph H). purity, 93% (HPLC). GC-MS
M+ = 397. Anal. calcd for C22H27N3O2S: C, 66.47; H,
6.85; N, 10.57. Found: C, 66.50; H, 6.86; N, 10.50.
IId: yield, 25%. yellow oil. 1H NMR (CDCl3,
300MHz): 1.220 (s, 6H, 2CH3), 1.388 (s, 9H, 3CH3),
1.974 (s, 3H, CH3), 2.107 (s, 3H, CH3), 2.201 (s, 3H,
CH3), 2.644 (s, 2H, CH2), 3.971 (s, 3H, CH3), 7.439–
7.541 (m, 4H, Ph H). purity, 96% (HPLC). GC-MS
M+ = 439. Anal. calcd for C25H33N3O2S: C, 68.30; H,
7.57; N, 9.56. Found: C, 68.67; H, 7.47; N, 9.43.
IIj: yield, 25%. yellow oil. 1H NMR (CDCl3, 300 MHz):
1.209 (s, 6H, CH3), 1.332 (s, 9H, CH3), 2.007 (s, 3H,
CH3), 2.285 (s, 3H, CH3), 2.647 (s, 2H, CH2), 4.000 (s,
3H, CH3), 6.353 (s, 1H, pyrazole H), 7.429–7.515 (m,
4H, Ph H). purity, 97% (HPLC). GC-MS M+ =425. Anal.
calcd for C24H31N3O2S: C, 67.73; H, 7.34; N, 9.87. Found:
C, 67.80; H, 7.30; N, 9.94.
IIk: yield, 32%. yellow oil. 1H NMR (CDCl3, 300MHz):
1.281 (s, 9H, CH3), 1.601–1.677 (m, 2H, CH2), 1.701–1.898
(m, 6H, CH2), 2.273 (s, 3H, CH3), 3.267 (s, 3H, CH3),
5.059–5.141 (m, 1H, CH), 6.282 (s, 1H, pyrazole H),
7.078 (d, J = 8.7Hz, 2H, Ph H), 7.315 (d, J = 9.0Hz, 2H,
Ph H). purity, 95% (HPLC). LC-MS Pos [M+1]+ =408.
Anal. calcd for C24H29N3O3: C, 70.74; H, 7.17; N, 10.31.
Found: C, 70.82; H, 7.19; N, 10.30.
IIe: yield, 24%. yellow oil. 1H NMR (CDCl3,
300MHz): 1.275 (s, 9H, CH3), 1.594–1.854 (m,
8H,4CH2), 1.867 (s, 3H, CH3), 2.180 (s, 3H, CH3), 3.427
(s, 3H, CH3), 5.106–5.124 (m, 1H, CH), 7.047–7.083 (m,
2H, Ph H), 7.285–7.322 (m, 2H, Ph H). purity, 97%
(HPLC). LC-MS Pos [M + 1]+ = 422. Anal. calcd for
C25H31N3O3: C, 71.23; H, 7.41; N, 9.97. Found: C,
71.19; H, 7.40; N, 9.99.
IIf: yield, 31%. yellow oil. 1H NMR (CDCl3, 300MHz):
1.344 (s, 9H, CH3), 1.598–1.646 (m, 8H, 4CH2), 2.107 (s,
3H, CH3), 2.219 (s, 3H, CH3), 3.884 (s, 3H, CH3), 5.099–
5.112 (m, 1H, CH), 7.456–7.485 (m, 2H, Ph H), 7.574–
7.603 (m, 2H, Ph H). purity, 95% (HPLC). LC-MS Pos
[M + 1]+ = 422. Anal. calcd for C25H31N3O3: C, 71.23; H,
7.41; N, 9.97. Found: C, 71.23; H, 7.41; N, 9.97.
IIl: yield, 33%. yellow oil. 1H NMR (CDCl3, 300 MHz):
1.338 (s, 9H, CH3), 1.546–1.809 (m, 8H, 4CH2), 2.301 (s,
3H, CH3), 3.949 (s, 3H, CH3), 4.992–5.030 (m, 1H, CH),
6.562 (d, J= 0.6 Hz, 1H, pyrazole H), 7.445 (d, J =9.0 Hz,
2H, Ph H), 7.528–7.572 (m, 2H, Ph H). purity, 92%
(HPLC). LC-MS Pos [M+ 1]+ = 408. Anal. calcd for
C24H29N3O3: C, 70.74; H, 7.17; N, 10.31. Found: C,
70.76; H, 7.11; N, 10.36.
IIm: yield, 26%. yellow oil. 1H NMR (CDCl3,
300 MHz): 1.284 (s, 9H, CH3), 2.044–2.138 (m, 1H,
CH2), 2.154–2.250 (m, 1H, CH2), 2.275 (s, 3H, CH3),
3.267 (s, 3H, CH3), 3.864–3.894 (m, 2H, CH2), 3.912–
3.960 (m, 2H, CH2), 5.233–5.239 (m, 1H, CH), 6.291 (d,
J = 0.6 Hz, 1H, pyrazole H), 7.081 (d, J= 8.7 Hz, 2H, Ph
H), 7.332–7.351 (m, 2H, Ph H). purity, 93% (HPLC).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Pyrazole Acrylonitrile
LC-MS Pos [M +1]+ =410. Anal. calcd for C23H27N3O4:
C, 67.46; H, 6.65; N, 10.26. Found: C, 67.50; H, 6.72;
N, 10.22.
CH3), 2.153–2.204 (m, 2H, CH2), 2.280 (s, 3H, CH3),
3.609 (q, J= 7.2 Hz, 2H, CH2), 3.868–3.895 (m, 2H,
CH2), 3.916–3.966 (m, 2H, CH2), 5.233–5.241 (m, 1H,
CH), 6.234 (s, 1H, pyrazole H), 7.084 (dd, J= 6.6,
2.1 Hz, 2H, Ph H), 7.311 (dd, J= 6.6, 1.8 Hz, 2H, Ph H).
purity, 95% (HPLC). LC-MS Pos [M + 1]+ = 424. Anal.
calcd for C24H29N3O4: C, 68.06; H, 6.90. Found: C,
68.11; H, 6.91; N, 9.85.
IIu: yield, 29%. yellow oil. 1H NMR (CDCl3,
300 MHz): 1.340 (s, 9H, CH3), 1.463 (t, J = 7.2Hz, 3H,
CH3), 1.855–2.145 (m, 2H, CH2),2.313 (s, 3H, CH3),
3.709–3.819 (m, 2H, CH2), 3.832–3.869 (m, 2H, CH2),
4.178 (q, J =7.2 Hz, 2H, CH2), 5.137 (d, J= 1.5Hz, 1H,
CH2), 6.547 (s, 1H, pyrazole H), 7.454–7.568 (m, 4H, Ph
H). purity, 95% (HPLC). LC-MS Pos [M + 1]+ = 424. Anal.
calcd for C24H29N3O4: C, 68.06; H, 6.90; N, 9.92. Found:
C, 68.07; H, 6.88; N, 9.86.
IIv: yield, 30%. yellow oil. 1H NMR (CDCl3,
300 MHz): 1.348 (s, 9H, CH3), 1.462 (t, J = 6.9Hz, 3H,
CH3) 2.093–2.205 (m, 2H, CH2), 2.289 (s, 3H, CH3),
3.754–3.945 (m, 4H, 2CH2), 4.167 (q, J= 7.2Hz, 2H,
CH2), 5.153–5.189 (m, 1H, CH), 7.480–7.515 (m, 2H, Ph
H), 7.608 (dd, J =6.6, 2.1 Hz, 2H, Ph H). purity, 98%
(HPLC). LC-MS Pos [M+ 1]+ = 458. Anal. calcd for
C24H28ClN3O4: C, 62.95; H, 6.16; N, 9.18. Found: C,
63.01; H, 6.17; N, 9.15.
IIn: yield, 26%. yellow oil. 1H NMR (CDCl3,
300MHz): 1.341 (s, 9H, CH3), 1.852–1.919 (m, 1H,
1/2CH2), 2.080–2.160 (m, 1H, 1/2CH2), 2.301 (s, 3H,
CH3), 3.671–3.818 (m, 2H, CH2), 3.832–3.910 (m, 2H,
CH2), 3.954 (s, 3H, CH3), 5.135–5.159 (m, 1H, CH),
6.548 (d, J =0.3 Hz, 1H, pyrazole H), 7.458–7.570 (m,
4H, Ph H). purity, 96% (HPLC). LC-MS Pos [M
+ 1]+ = 410. Anal. calcd for C23H27N3O4: C, 67.46; H,
6.65; N, 10.26. Found: C, 67.54; H, 6.59; N, 10.18.
IIo: yield, 26%. yellow oil. 1H NMR (CDCl3 300MHz):
1.293 (s, 6H, 2CH3), 1.341 (s, 9H, 3CH3), 2.256 (s, 3H,
CH3), 3.574 (s, 2H, CH2), 4.001 (s, 3H, CH3), 7.457 (d,
J =8.7Hz, 2H, Ph H), 7.542 (d, J= 9.0 Hz, 2H, Ph H). pu-
rity, 97% (HPLC). GC-MS M+ = 447. Anal. calcd for
C23H27Cl2N3O2: C, 61.61; H, 6.07; N, 9.37. Found: C,
61.59; H, 6.12; N, 9.38.
IIp: yield, 25%. yellow oil. 1H NMR (CDCl3,
300MHz): 1.343 (s, 9H, 3CH3), 1.428 (d, J =7.2Hz, 3H,
CH3), 1.940 (s, 3H, CH3), 2.262 (s, 3H, CH3), 3.386 (q,
J =7.2Hz, 1H, CH), 3.987 (s, 3H, CH3), 7.459 (d,
J =9.0Hz, 2H, Ph H), 7.623 (d, J= 9.0 Hz, 2H, Ph H). pu-
rity, 96% (HPLC). GC-MS M+ = 431. Anal. calcd for
C22H26ClN3O2S: C, 61.17; H, 6.07; N, 9.73. Found: C,
61.27; H, 6.12; N, 9.71.
IIw: yield, 22%. yellow oil. 1H NMR (CDCl3,
300 MHz): 1.341 (s, 9H, CH3), 1.418 (d, J = 6.9Hz, 3H,
CH3), 1.494 (t, J = 7.2 Hz, 3H, CH3), 1.918 (s, 3H, CH3),
2.278 (s, 3H, CH3), 3.400 (q, J= 7.5 Hz, 1H, CH), 4.218
(q, J = 7.5 Hz, 2H, CH2), 7.455 (dd, J= 6.9, 2.4 Hz, 2H,
Ph H), 7.618 (dd, J =6.6, 1.8 Hz, 2H, Ph H). purity, 97%
IIq: yield, 23%. yellow oil. 1H NMR (CDCl3,
300MHz): 1.218 (s, 6H, CH3), 1.331 (s, 9H, CH3), 1.525
(t, J= 7.2Hz, 3H, CH3), 2.302 (s, 3H, CH3), 3.509 (s, 2H,
CH2), 4.243 (q, J= 7.5 Hz, 2H, CH2), 6.335 (d, J= 0.6 Hz,
1H, pyrazole H), 7.455 (d, J = 1.8 Hz, 4H, Ph H). purity,
94% (HPLC). GC-MS M+ = 427. Anal. calcd for
C24H30ClN3O2: C, 67.36; H, 7.07; N, 9.82. Found: C,
67.38; H, 7.11; N, 9.77.
(HPLC).
GC-MS
M+ = 445.
Anal.
calcd
for
C23H28ClN3O2S: C, 61.94; H, 6.33; N, 9.42. Found: C,
61.98; H, 6.35; N, 9.34.
IIr: yield, 25%. brown oil. 1H NMR (CDCl3, 300MHz):
1.334 (s, 9H, CH3), 1.366 (d, J=6.9Hz, 3H, CH3), 1.497
(t, J=7.5Hz, 3H, CH3), 1.856 (s, 3H, CH3), 2.306 (s, 3H,
CH3), 3.308 (q, J=7.2Hz, 1H, CH), 4.227 (q, J=7.2Hz,
2H, CH2), 6.447 (s, 1H, pyrazole H), 7.425–7.468 (m, 2H,
Ph H), 7.523–7.566 (m, 2H, Ph H). purity, 96% (HPLC).
GC-MS M+ =411. Anal. calcd for C23H29N3O2S: C, 67.12;
H, 7.10; N, 10.21. Found: C, 67.08; H, 7.18; N, 10.1.
IIs: yield, 25%. yellow oil. 1H NMR (CDCl3,
300MHz): 1.031 (t, J= 7.2 Hz, 3H, CH3), 1.275 (s, 9H,
CH3), 1.598–1.662 (m, 2H, CH2), 1.747–1.904 (m, 6H,
CH2), 2.279 (s, 3H, CH3), 3.597 (q, J = 7.5 Hz, 2H, CH2),
5.116–5.150 (m, 1H, CH), 6.222 (s, 1H, pyrazole H),
7.073–7.117 (m, 2H, Ph H), 7.298–7.342 (m, 2H, Ph H).
purity, 95% (HPLC). GC-MS M+ =421. Anal. calcd for
C25H31N3O3: C, 68.06; H, 6.90; N, 9.92. Found: C,
68.00; H, 6.93; N, 9.94.
IIx: yield, 27%. yellow oil. 1H NMR (CDCl3,
300 MHz): 1.255 (s, 6H, CH3), 1.340 (s, 9H, CH3), 1.526
(t, J =7.2 Hz, 3H,CH3), 2.008 (s, 3H, CH3), 2.271 (s, 3H,
CH3), 2.682 (s, 2H, CH2), 4.228 (q, J= 7.2 Hz, 2H, CH2),
7.451 (dd, J =6.6, 1.8 Hz, 2H, Ph H), 7.562–7.591 (m,
2H, Ph H).purity, 94% (HPLC). GC-MS M+ =473. Anal.
calcd for C25H32ClN3O2S: C, 63.34; H, 6.80; N, 8.86.
Found: C, 63.30; H, 6.85; N, 8.88.
IIy: yield, 28%. yellow oil. 1H NMR (CDCl3,
300 MHz): 1.235–1.262 (m, 3H, CH3), 1.287 (s, 6H,
CH3), 1.340 (s, 9H, CH3), 2.635 (q, J= 7.8 Hz, 2H, CH2),
3.560 (s, 2H, CH2), 4.007 (s, 3H, CH3), 7.453 (d,
J = 8.7 Hz, 2H, Ph H), 7.537 (d, J =8.7 Hz, 2H, Ph H). pu-
rity, 96% (HPLC). GC-MS M+ = 461. Anal. calcd for
C24H29ClN3O2: C, 62.34; H, 6.32; N, 9.09. Found: C,
62.29; H, 6.35; N, 9.11.
Biological assay. Biological assay was carried out in
the Laboratory of Biological Activities Test, Hunan
Research Institute of Chemical Industry, Changsha,
IIt: yield, 27%. yellow oil. 1H NMR (CDCl3,
300MHz):1.030 (t, J =7.2 Hz, 3H,CH3), 1.277 (s, 9H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Huang, M. Huang, A. Liu, X. Liu, W. Liu, X. Chen, H. Xue, J. Sun, D. Yin, and X. Wang
Vol 000
REFERENCES AND NOTES
People’s Republic of China. The biological evaluation of
IIa–y was undertaken according to the mortality rate.
Insecticidal activities
[1] Gisi, U.; Sierotzki, H. Eur J Plant Pathol 2008, 122, 157.
[2] Feng, J. T.; Wang, H.; Ren, S. X.; He, J.; Liu, Y.; Zhang, X. J
Agric Food Chem 2012, 60, 3817.
[3] Paul, C. J.; Cameron, H. B.; Harold W. R. WO, 9602515.
1996.
[4] Swanson, M. B.; Ivancic, W. A.; Saxena, A. M.; Allton, J. D.;
O’Brien, G. K.; Suzuki, T.; Nishizawa, H.; Nokata, M. J Agric Food
Chem 1995, 43, 513.
[5] Motoba, K.; Nishizawa, H.; Suzuki, T.; Hamaguchi,
H.; Uchida, M.; Funayama, S. Pestic Biochem Physiol 2000,
67, 73.
Test insects.
Stock colonies of Mythimna separata,
Aphis fabae, and T. urticae were reared in a conditioned
room maintained at 25 ( 1) °C, 60 ( 5)% relative
humidity, and 14:10 h light : dark photoperiod.
Test compounds. Stock solutions of each test compound
were prepared in acetone at a concentration of 1.0g /L, and
then diluted to the required test concentrations with water
containing TritonX-100 (0.1mL/L).
[6] Philipp, W. R.; Markus, B.; Hilmar, F. J Agric Food Chem
2011, 59, 4365.
Biological activity against Tetranchus urticae [15]. Fifty
larvae of T. urticae were transferred to three horse bean
seedlings, and, 24 h later, the horse bean seedlings with
acarids were dipped in the test solutions for 5–10s, and
then allowed to dry with filter paper, transferred to a
beaker (100 mL) containing water (10 mL) and kept at
25°C. Each assay contained three replications. Mortality
was assessed 24 h after the treatment. A number of live
and dead insects were recorded. The test was run three
times, and results were averaged. The dose–response data
were analyzed by probit analysis [16], and the activities
were evaluated as LC50 values (95% CL).
[7] Fulcher, J. M.; Wayment, D. G.; White Jr., P. M.; Webber III,
C. L. J Agric Food Chem 2014, 62, 2141.
[8] Wang, B. L.; Wu, J.; Liu, Q. X.; Li, Y. H.; Song, H. B.; Li, Z.
M. Phosphorus Sulfur Silicon Relat Elem 2015, 190, 66.
[9] Wang, B. L.; Zhang, L. Y.; Zhan, Y. Z.; Zhang, Y.;
Zhang, X.; Wang, L. Z.; Li, Z. M. J Fluorine Chem 2016,
184, 36.
[10] Wang, B. L.; Zhu, H. W.; Ma, Y.; Xiong, L. X.; Li, Q. Y.;
Zhao, Y.; Zhang, J. F.; Chen, Y. W.; Zhou, S.; Li, Z. M. J Agric Food
Chem 2013, 61, 5483.
[11] Yu, H. B.; Xu, M.; Cheng, Y.; Wu, H. F.; Luo, Y. M.; Li, B.
ARKIVOC 2012, (vi), 26.
[12] Khalighi, M.; Tirry, L.; Van Leeuwen, T. Pest Manag Sci
2014, 70, 365.
[13] Nakahira, K. J Pestic Sci 2011, 36, 511.
[14] Hayashi, N.; Sasama, Y.; Takahashi, N.; Ikemi, N. Pest Manag
Sci 2013, 69, 1080.
[15] Liu, A. P.; Wang, X. G.; Chen, C.; Pei, H. Pest Manag Sci
2009, 65, 229.
[16] Finney, J. (Ed) Probit Analysis, 3rd ed.; Cambridge University
Press: Cambridge, UK, 1971.
Acknowledgments. This work was supported by National Natural
Science Foundation of China (No. 21272062) and the National
Science & Technology Pillar Program,China (No. 2011BAE06B03).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet