Synthesis, structure and insecticidal activities of some novel amides containing N-pyridylpyrazole moeities

Article abstract of DOI:10.3390/molecules170910414

In our search for environmentally benign insecticides with high activity, low toxicity and low residue, a novel series of amides containing N-pyridylpyrazole moieties were designed and synthesized. The structures of the title compounds were characterized and confirmed by ¹H-NMR and elemental analysis. Furthermore, the structure of compound 7l was determined by single crystal X-ray diffraction. The preliminary bioassay tests showed that some of them exhibited good insecticidal activities against Mythimna separata Walker, Plutella xylostella (Linnaeus, 1758) and Laphygma exigua Huebner.

Full text of DOI:10.3390/molecules170910414

Molecules 2012, 17, 10414-10428; doi:10.3390/molecules170910414
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis, Structure and Insecticidal Activities of Some Novel
Amides Containing N-Pyridylpyrazole Moeities
Wei-Li Dong 1,*, Jing-Ying Xu 2, Li-Xia Xiong 2 and Zheng-Ming Li 2
1
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and
Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
2
State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center,
Nankai University, Tianjin 300071, China; E-Mails: xujunying@mail.nankai.edu.cn (J.-Y.X.);
xionglixia@nankai.edu.cn (L.-X.X.); zml@nankai.edu.cn (Z.-M.L.)
* Author to whom correspondence should be addressed; E-Mail: wldong33@163.com;
Tel./Fax: +86-22-2354-2014.
Received: 1 August 2012; in revised form: 13 August 2012 / Accepted: 18 August 2012 /
Published: 31 August 2012
Abstract: In our search for environmentally benign insecticides with high activity, low
toxicity and low residue, a novel series of amides containing N-pyridylpyrazole moieties
were designed and synthesized. The structures of the title compounds were characterized
and confirmed by 1H-NMR and elemental analysis. Furthermore, the structure of compound 7l
was determined by single crystal X-ray diffraction. The preliminary bioassay tests showed
that some of them exhibited good insecticidal activities against Mythimna separata Walker,
Plutella xylostella (Linnaeus, 1758) and Laphygma exigua Hübner.
Keywords: amide; N-pyridylpyrazole; synthesis; crystal structure; insecticidal activity
1. Introduction
Development of crop-protection molecules with unique modes of action is necessary to combat
widespread insecticide resistance. Calcium channels, in particular, the ryanodine receptor (RyR)
represent an attractive biological target for insect control and thus offers excellent promise in
integrated pest management strategies [1]. Anthranilic diamides, discovered by DuPont, are a
promising novel class of insecticides which exhibit their action by binding to insect ryanodine
receptors (RyR) and activating the uncontrolled release of calcium stores [2–4]. Anthranilic diamide

Molecules 2012, 17
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insecticides are characterized by a three-part chemical structure as shown in Figure 1A, where (X) is
an anthraniloyl moiety, (Y) an aromatic acyl moiety and (Z) an aliphatic amide moiety. Notably,
anthranilic diamides containing an N-pyridylpyrazole in the second section (Y) showed significantly
better activity than other heterocyclic derivatives [5]. Work in this area has led to the discovery of
RynaxypyrTM (Figure 1B), a highly potent and selective activator of insect ryanodine receptors with
exceptional activity on a broad range of Lepidoptera, as the first new insecticide from this class [6].
Figure 1. Chemical structures of anthranilic diamide insecticides.
(A) General formula.
(B) RynaxypyrTM.
In our previous work, when the N-pyridylpyrazole ring was replaced with 1,2,3-thiadiazole [7] or
triazolopyrimidine [8] ones, the insecticidal activities were completely eliminated. In contrast, the
modification of insecticidal anthranilic diamides with an ester group [9] or sulfonamide [10]
substituting an amide group in the aliphatic amide moiety (Z) showed similar insecticidal activity,
though of a lesser degree. Thus, these results suggest that the N-pyridylpyrazole unit plays an
important role in the insecticidal activities of anthranilic diamides, but the aliphatic amide moiety (Z)
may not be essential to insecticidal activities.
Encouraged by these reports, we developed an idea to examine whether the modification of the
anthraniloyl skeleton by removing the aliphatic amide moiety (Z) could have an effect on potential
insecticidal activities. Enlightened by all of the descriptions above, to further explore the
comprehensive structure-activity relationships of the insecticidal activity, a series of novel amides
containing N-pyridylpyrazoles were synthesized, and their insecticidal activities against Mythimna separata
Walker, Culex pipiens pallens, Plutella xylostella (Linnaeus, 1758) and Laphygma exigua Hübner
were tested and are discussed in this publication.
2. Results and Discussion
2.1. Chemistry
The synthetic route to the title compounds 7a–s is shown in Scheme 1. The pyrazole carboxylic acid 6
is a key intermediate to the synthesis of target amides 7 containing N-pyridylpyrazoles. Various
synthetic routes have been reported for the synthesis of intermediate pyrazole-5-carboxylic acid 6 [11,12].
Considering the practical application of the synthetic method, an alternate route for the preparation of
pyrazole carboxylic acid 6 was developed. Reaction of 2,3-dichloropyridine (1) with hydrazine hydrate
at reflux using ethanol as solvent gave 3-chloro-2-hydrazinylpyridine (2). Condensation of diethyl
maleate with hydrazine 2 in the presence of sodium ethoxide afforded the pyrazolidinone 3.
Subsequent treatment of 3 with phosphorus oxybromide in acetonitrile afforded the pyrazoline 4.

Molecules 2012, 17
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A variety of reagents were explored for oxidation of 4 to the pyrazole 5. We first chose potassium
permanganate as oxidant, but pyrazole 5 was obtained in only 32% yield. Subsequently potassium
persulfate was used to give 5 in a good yield. The intermediate 6 could be prepared by hydrolysis of 5
with known methods. Finally, pyrazole carboxylic acid 6 was treated with oxalyl chloride at reflux to
give the corresponding acid chloride, which was then reacted with commercially available substituted
anilined to afford the title compounds 7a–s. The various amides 7a–s containing N-pyridylpyrazoles
prepared are listed in Table 1.
Scheme 1. The synthetic route to title compounds 7.
Reagents and conditions: (i) N2H4, EtOH; (ii) Diethyl maleate, NaOC2H5/C2H5OH; (iii) POBr3,
CH3CN; (iv) K2S2O8, H2SO4, CH3CN; (v) NaOH, MeOH; (vi) 1. CH2Cl2, oxalyl chloride, DMF 2.
ArNH2, CH2Cl2, (i-Pr)2EtN.
Table 1. List of N-pyridylpyrazole-containing amides 7a–s.
Br
R1
H
N
R2
R3
N
N
O
Cl
R5
N
R4
7a-s
R5
Compd.
7a
R1
H
R2
Cl
H
H
H
H
H
Cl
H
H
H
R3
H
R4
H
H
H
H
H
H
H
H
H
H
Compd.
7k
R1
CH3
Cl
R2
H
H
H
H
H
H
H
H
H
R3
H
R4
H
H
H
H
Cl
H
H
H
H
R5
NO2
H
H
H
7b
H
F
7l
NO2
NO2
Cl
7c
H
Cl
H
7m
7n
Br
H
7d
H
I
H
NO2
Cl
H
7e
H
NO2
OC2H5
F
H
7o
H
H
7f
H
H
7p
CH3
CH3
CH3
CH3
Cl
CH3
CH3
Cl
7g
H
H
7q
Br
7h
CH3
CH3
CH3
CH3
NO2
H
H
7r
NO2
Cl
7i
H
7s
NO2
7j
CH3

Molecules 2012, 17
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2.2. Crystal Structure
The structure of compound 7l was further confirmed by single crystal X-ray diffraction analysis
(Figures 2 and 3). In the molecular structure of title compound, the three ring (benzene ring, pyridine
ring and pyrazole ring) are nearly vertically with θ angle of 80.6° (benzene ring vs. pyridine ring),
76.8° (pyrazole ring vs. pyridine) respectively, but the pyrazole ring is planar with the benzene ring (7.8°).
Figure 2. The molecular structure of 7l.
Figure 3. The packing of the molecules in the crystal lattice of 7l.
The average bond lengths and bond angles of the phenyl ring [13–17], the pyrazole ring [18], pyridine
ring [19] and the amide bond [20–24] are normal. The intermolecular edge-to-face π-π stacking
appears between the pyridine ring and the phenyl ring in another adjacent molecule, in which the
distance of H13 and the centroid of phenyl ring is 3.725 Å. These interactions can help to further
stabilize the crystal structure. The title compound has an extensive network of hydrogen bonding

Molecules 2012, 17
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involving the two acceptor N atoms. In the bc plane, they are linked together by N-H···N hydrogen
bonds. This hydrogen-bonding sequence is repeated to form a ring.
2.3. Insecticidal Activities and Structure-Activity Relationship (SAR)
The insecticidal activities of all target compounds 7a–s were determined in vivo. The results are
summarized in Table 2. As shown, 7l showed the most potent insecticidal activity against oriental
armyworm (M. separata) in all the tested compounds, the death rate is 80% at 10 µg·mL−1.
Compounds 7c, 7i, 7p, 7q, 7i and 7r also exhibited significant insecticidal activity against oriental
armyworm, with death rates of more than 70% at 25 µg·mL−1.
Table 2. Insecticidal activity against Mythimna separata Walker and Culex pipiens pallens
of title compounds (mortality/%).
Mythimna separata Walker
µg·mL−1/death rate (%)
Culex pipiens pallens
µg·mL−1/death rate (%)
Compd.
200
0
100
50
25
10
5
2
a
7a
—
7b
100
100
100
100
100
100
100
100
100
100
100
100
10
100
100
100
90
100
100
50
50
70
0
10
100
20
30
—
—
40
—
50
80
40
40
10
30
30
—
20
100
7c
0
7d
7e
20
7f
0
7g
0
7h
70
0
7i
100
80
100
40
80
50
80
7j
7k
80
20
7l
100
100
100
30
100
0
7m
7n
7o
0
7p
100
100
100
100
100
100
100
100
100
100
100
100
80
100
70
20
30
30
7q
7r
7s
60
RynaxypyrTM
100
a Not tested.
Further, the Structure-Activity Relationships (SAR) for different substitutions on the phenyl ring
can be inferred from the results. Compound 7i with an electron-donating methyl group at R1 exhibited
similar insecticidal activity to that of compound 7l with an electron-withdrawing chlorine group at R1, but
the insecticidal activity decreased significantly when the chlorine atom was replaced with a bromine
atom at R1 (compound 7m). From these results, it appears that steric effects rather than electrostatic
effects have substantial effects on the insecticidal activity at the R1. This observation appears
consistent with the structure–activity of anthranilic diamides reported in the literature [25]. Among

Molecules 2012, 17
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compounds 7b–e, the electron-withdrawing group substituted analogues at R3 (compounds 7b–e) were
more active than the electron-donating group substituted analogue (compound 7f). Besides, the
electron-withdrawing halide substituted analogues at R3 (compounds 7p, 7q, 7s) exhibited more
insecticidal potency than unsubstituted analogs (compounds 7j, 7k). The electron-donating group
substitution (compound 7j) and electron-withdrawing group substitution (compound 7k) showed
similar levels of activity, and the presence of a chloro substituent at R5 (compound 7r) and
unsubstituted analog (compound 7i) exhibited similar insecticidal activity. This result indicates that
different substitutions at R5 did not exhibit significant influence on insecticidal activities. In addition,
the insecticidal activity decreased significantly when electron-withdrawing chloro substituent was
present at R2 and R4, such as 7a, 7g, 7o. As shown in Table 2, the title compounds displayed good
larvicidal activities against C. p. pallens, for example, the larvicidal activity of 7d was 100% at 2 µg·mL−1,
as compared with 100% mortality of RynaxypyrTM at the same concentration, but showed no clear
SAR trends.
Figure 4 shows the symptoms of larvae affected by the title compounds and commercial
RynaxypyrTM. Insects treated with the title compound 7l showed abnormal symptoms such as body
contraction, vomiting, feeding cessation, body thickening and shortening, which are similar to those
observed for larvae treated with commercial RynaxypyrTM. These results suggest that the title
compounds exhibit their activity by activating insect RyR.
Figure 4. Symptoms of forth-instar larvae of Mythimna separata Walker treated by leaf dipping.
(a)
(b)
(c)
(a) Untreated; (b) RynaxypyrTM at 10 µg·mL−1, 36 h after application; (c) 7l at 10 µg·mL−1, 36 h
after application.
For the compounds 7b, 7c, 7p, 7q, 7s, 7l, 7m, further bioassay was conducted against P. xylostella
and L. exigua. The results are summarized in Table 3. At a dose of 25 µg·mL−1, most of compounds
have good insecticidal activity against P. xylostella and L. exigua, which can be compared with that of
the control RynaxypyrTM. This result showed that the title compounds have insecticidal activity on a
broad spectrum of Lepidoptera.

Molecules 2012, 17
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Table 3. Insecticidal activity against Plutella xylostella (Linnaeus, 1758) and
Laphygma exigua Hübner of title compounds (mortality/%).
Plutella xylostella (Linnaeus, 1758)
Laphygma exigua Hübner
µg·mL−1/death rate (%)
Compd.
µg·mL−1/death rate (%)
200
100
100
100
78
100
98
98
98
72
100
72
89
—
0
50
25
88
97
90
200
95
100
100
100
100
86
50
92
25
96
7b
99
7c
100
100
100
91
100
100
78
100
100
65
7m
96
7l
0
7p
100
89
97
94
100
100
98
100
100
100
—
98
94
a
7q
0
—
89
93
7s
RynaxypyrTM
Ck
95
—
84
76
94
0
95
92
100
—
100
0
100
0
0
0
0
0
a Not tested.
3. Experimental
3.1. General
Melting points were determined on an X-4 binocular microscope melting point apparatus and were
uncorrected. 1H-NMR spectra were obtained on a Bruker AC-P500 spectrometer or Bruker Avance 400
spectrometer using tetramethylsilane (TMS) as an internal standard and CDCl3 or DMSO-d6 as solvents.
Elemental analyses were performed on a Vario EL elemental analyzer. High-resolution mass (HRMS)
were recorded on a 7.0-T (Ionspec, Irvine, CA, USA) Fourier transform ion cyclotron resonance
mass spectrometer. Crystallographic data of the compound 7l were collected on a Rigaku Saturn
diffractometer. All chemicals or reagents were purchased from standard commercial suppliers.
Petroleum ether refers to the fraction of bp 60–90 C.
3.2. Chemical Synthesis
3.2.1. 3-Chloro-2-hydrazinylpyridine (2)
50% Hydrazine hydrate (200 mL).was added to a suspension of 2,3-dichloropyridine (1, 73.5 g,
0.5 mol) in anhydrous ethanol (300 mL). The resulting mixture was refluxed for 36 h, and then cooled
to room temperature. A white crystalline product precipitated out of solution, which was collected by
filtration, washed thoroughly with cold ethanol and dried to give hydrazine 2 (49.6 g, 69.0%), m.p.
1
163–164 °C; H-NMR (CDCl3, 400 MHz) δ: 3.97 (br s, 2H, NH2), 6.21 (br s, 1H, NH), 6.64 (m, 1H,
pyridyl-H), 7.47 (d, J = 7.6 Hz, 1H, pyridyl-H), 8.09 (d, J = 4.9 Hz, 1H, pyridyl-H).
3.2.2. Ethyl 2-(3-Chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate (3)
To absolute ethanol (200 mL) in a 500 mL three-necked round-bottomed flask was added sodium
(6.9 g, 0.3 mol) cut into pieces of suitable size. After all the sodium had reacted, the mixture was
heated to reflux and 2 (39.82 g, 0.277 mol) was added. The mixture was refluxed for 10 min, then

Molecules 2012, 17
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diethyl maleate (51.65 g, 0.3 mol) was added dropwise. The resulting orange-red solution was held at
reflux for 30 min. After being cooled to 65 °C, the reaction mixture was treated with glacial acetic acid
(30 g, 0.51 mol). The mixture was diluted with water (30 mL). After removal of most of the solvent,
the residue was treated with water (300 mL). The slurry formed was dissolved in aqueous ethanol
(70%, 200 mL) and stirred thoroughly. The solid was collected by filtration, washed with aqueous
1
ethanol (50%, 50 mL × 3) to give pyrazolidinone 3 (36.6 g, 49.0%), m.p. 132–134 C; H-NMR
(DMSO-d6, 300 MHz) δ: 1.20 (t, J = 6.8 Hz, 3H, CH2CH3), 4.18 (q, J = 7.2 Hz, 2H, CH2CH3), 2.34 (d,
J = 16.8 Hz, 1H, CH2), 2.90 (q, J = 10.0 Hz, 1H, CH), 4.81 (d, J = 9.2 Hz, 1H, CH2), 7.18 (dd, J = 4.8,
7.6 Hz, 1H, pyridyl-H), 7.92 (d, J = 7.6 Hz, 1H, pyridyl-H), 8.25 (d, J = 4.0 Hz, 1H, pyridyl-H), 10.18
(br s, 1H, NH).
3.2.3. Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (4)
To a solution of 3 (0.1 mol) in acetonitrile (300 mL) was added phosphorus oxybromide (0.12 mmol).
The reaction mixture was refluxed for 5 h, then most of the solvent (ca. 250 mL) was removed by
distillation. The concentrated reaction mixture was slowly poured into saturated aq. Na2CO3 (250 mL)
and stirred vigorously for 30 min. The resulting mixture was extracted with CH2Cl2 (250 mL × 2), the
organic extract was separated, dried, filtered, concentrated and purified by silica gel chromatography
1
to afford intermediates 4. Yield 93.0%, m.p. 59–60 C; H-NMR (DMSO-d6, 400 MHz) δ: 1.12 (t,
J = 7.0 Hz, 3H, CH2CH3), 3.24–3.31 (m, 1H, CH2), 3.54–3.61 (m, 1H, CH2), 4.08 (q, J = 7.0 Hz, 2H,
CH2CH3), 5.14–5.19 (m, 1H, CH), 6.98 (dd, J = 4.8, 7.6 Hz, 1H, pyridyl-H), 7.83 (d, J = 7.7 Hz, 1H,
pyridyl-H), 8.10 (d, J = 4.4 Hz, 1H, pyridyl-H).
3.2.4. Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (5)
To a solution of 4 (51 mmol) in acetonitrile (250 mL) was added sulfuric acid (98%, 10 g, 102 mmol).
After being stirred for several minutes, the reaction mixture was treated with K2S2O8 (21 g, 76.5 mmol)
and refluxed for 4.5 h. After being cooled to 60 °C, the mixture was filtered, the filter cake was
washed with acetonitrile (30 mL). The filtrate was concentrated to 100 mL, then added slowly to water
(250 mL) under stirring. The solid was collected by filtration, washed with acetonitrile (25%, 30 mL × 3),
1
water (30 mL), and then dried to give intermediates 5. Yield 92.7%, m.p. 117–118 C; H-NMR
(CDCl3, 400 MHz) δ: 1.21 (t, J = 6.8 Hz, 3H, CH2CH3), 4.22 (q, J = 7.2 Hz, 2H, CH2CH3), 7.03 (s, 1H,
pyrazolyl-H), 7.44 (dd, J = 4.8, 8.4 Hz,1H, pyridyl-H), 7.91 (dd, J = 1.4, 8.0 Hz, 1H, pyridyl-H), 8.51
(dd, J = 1.4, 4.7 Hz, 1H, pyridyl-H).
3.2.5. 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (6)
A mixture of 5 (47.2 mmol), methanol (120 mL), H2O (60 mL) and NaOH (2.3 g, 56.6 mmol) was
stirred at room temperature for 6 h, then concentrated in vacuo to about 80 mL. The concentrated
mixture was diluted with H2O (150 mL), and washed with ethyl acetate (150 mL). The aqueous
solution was acidified using concentrated hydrochloric acid to pH 1.5. The solid was collected by
filtration, washed with water (30 mL), and then dried to give pyrazolecarboxylic acid 6. Yield 89.3%,

Molecules 2012, 17
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m.p. 197–200 C; 1H-NMR (CDCl3, 300 MHz) δ: 7.10 (s, 1H, pyrazolyl-H), 7.48 (dd, J = 4.8, 8.1 Hz,
1H, pyridyl-H), 7.94 (dd, J = 1.4, 8.0 Hz, 1H, pyridyl-H), 8.52 (dd, J = 1.4, 4.7 Hz, 1H, pyridyl-H).
3.2.6. General Procedure for the Synthesis of Compounds 7a–s
To a suspension of N-pyridylpyrazole acid 6 (1 mmol) in dichloromethane (20 mL) was added
oxalyl chloride (3 mmol), followed by dimethylformamide (2 drops). The solution was stirred at room
temperature. After 3 h the mixture was concentrated in vacuo to obtain the crude acid chloride. The
crude acid chloride in dichloromethane (10 mL) was added slowly to a stirred solution of substituted
aniline 1 (1.2 mmol) in dichloromethane (20 mL) in an ice bath. After 20 min, diisopropylethylamine
(1 mmol) was added dropwise. The solution was warmed to room temperature and stirred for 12 h,
then diluted with CH2Cl2 (20 mL), and washed with 1 mol·L−1 aq. HCl solution (20 mL), saturated aq.
NaHCO3 (20 mL), and brine (20 mL). The organic extract was separated, dried, filtered, concentrated
and purified by silica gel chromatography to afford the desired N-pyridylpyrazole-containing amides 7.
3-Bromo-N-(3-chlorophenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7a). Yield: 70.7%.
White solid, m.p. 154–156 °C; 1H-NMR (CDCl3, 400 MHz) δ: 6.87 (s, 1H, pyrazolyl-H), 7.10–7.14 (m,
3H, Ar-H), 7.44 (dd, J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.58–7.59 (m, 1H, Ar-H), 7.93 (dd, J = 1.6, 8.0 Hz,
1H, pyridyl-H), 8.26 (br. s, NH), 8.48 (dd, J = 1.6, 4.8 Hz, 1H, pyridyl-H); Elemental anal. (%), calcd.
for C15H9BrCl2N4O: C, 43.72; H, 2.20; N, 13.60; found: C, 43.56; H, 2.55; N, 13.30.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(4-fluorophenyl)-1H-pyrazole-5-carboxamide (7b). Yield: 86.4%.
White solid, m.p. 197–198 °C; 1H-NMR (CDCl3, 400 MHz) δ: 6.84 (s, 1H, pyrazolyl-H), 6.93–6.97 (m,
2H, Ar-H), 7.34–7.37 (m, 2H, Ar-H), 7.41 (dd, J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.91 (dd, J = 1.6, 8.0 Hz,
1H, pyridyl-H), 8.43–8.45 (m, 2H, pyridyl-H, NH); Elemental anal. (%), calcd. for C15H9BrClFN4O: C,
45.54; H, 2.29; N, 14.16; found: C, 45.65; H, 2.58; N, 13.90.
3-Bromo-N-(4-chlorophenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7c). Yield: 79.9%.
White solid, m.p. 179–180 °C; 1H-NMR (CDCl3, 400 MHz) δ: 6.87 (s, 1H, pyrazolyl-H), 6.23–6.26 (m,
2H, Ar-H), 7.37–7.40 (m, 2H, Ar-H), 7.43 (dd, J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.93 (dd, J = 1.6, 8.0 Hz,
1H, pyridyl-H), 8.27 (br. s, NH), 8.47 (dd, 1H, J = 1.6, 4.8 Hz, pyridyl-H); Elemental anal. (%), calcd.
for C15H9BrCl2N4O: C, 43.72; H, 2.20; N, 13.60; found: C, 43.82; H, 2.29; N, 13.53.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(4-iodophenyl)-1H-pyrazole-5-carboxamide (7d). Yield: 62.3%.
White solid, m.p. 198–201 °C; 1H-NMR (CDCl3, 400 MHz) δ: 6.87 (s, 1H, pyrazolyl-H), 7.21 (d, 2H,
J = 8.8 Hz, Ar-H), 7.45 (dd, J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.58 (d, 2H, J = 8.4 Hz, Ar-H), 7.94 (dd,
1H, J = 1.6, 8.0 Hz, pyridyl-H), 8.275 (br. s, NH), 8.48 (dd, 1H, J = 1.6, 4.8 Hz, pyridyl-H); Elemental
anal. (%), calcd. for C15H9BrClIN4O: C, 35.78; H, 1.80; N, 11.13; found: C, 36.14; H, 2.21; N, 10.82.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(4-nitrophenyl)-1H-pyrazole-5-carboxamide (7e). Yield: 64.5%.
White solid, m.p. 240–243 °C; 1H-NMR (CDCl3, 400 MHz) δ: 7.00 (s, 1H, pyrazolyl-H), 7.48 (dd,
J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.69–7.71 (m, 2H, Ar-H), 7.96 (d, 1H, J = 8.0 Hz, pyridyl-H), 8.19–8.21
(m, 2H, Ar-H), 8.51 (d, 1H, J = 4.8 Hz, pyridyl-H), 8.70 (br. s, NH); Elemental anal. (%), calcd. for
C15H9BrClN5O3: C, 42.63; H, 2.15; N, 16.57; found: C, 42.91; H, 2.48; N, 16.51.

Molecules 2012, 17
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3-Bromo-1-(3-chloropyridin-2-yl)-N-(4-ethoxyphenyl)-1H-pyrazole-5-carboxamide (7f). Yield: 90.9%.
White solid, m.p. 191–193 °C; 1H-NMR (CDCl3, 400 MHz) δ: 1.39 (t, 3H, J = 6.8 Hz, CH3), 3.98 (q, 2H,
J = 6.8 Hz, CH2), 6.79–6.81 (m, 2H, Ar-H), 6.84 (s, 1H, pyrazolyl-H), 7.31–7.33 (m, 2H, Ar-H), 7.41
(dd, J = 4.4, 8.0 Hz, 1H, pyridyl-H), 7.91 (dd, J = 1.6, 8.0 Hz, 1H, pyridyl-H), 8.15 (br. s, NH), 8.46 (dd,
1H, J = 1.6, 4.8 Hz, pyridyl-H); Elemental anal. (%), calcd. for C17H14BrClN4O2: C, 48.42; H, 3.35; N,
13.29; found: C, 48.66; H, 3.20; N, 12.91.
3-Bromo-N-(3-chloro-4-fluorophenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7g). Yield:
1
95.3%. White solid, m.p. 167–169 °C; H-NMR (CDCl3, 400 MHz) δ: 6.85 (s, 1H, pyrazolyl-H),
7.02–7.07 (m, 2H, Ar-H), 7.20–7.23 (m, 2H, Ar-H), 7.45 (dd, J = 4.8, 7.6 Hz, 1H, pyridyl-H), 7.63 (dd,
1H, J = 1.6, 5.6 Hz, pyridyl-H), 7.95 (d, 1H, J = 8.0 Hz, pyridyl-H), 8.35 (br. s, NH); Elemental anal.
(%), calcd. for C15H8BrCl2FN4O: C, 41.89; H, 1.87; N, 13.03; found: C, 41.63; H, 2.17; N, 12.74.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2,4-dimethylphenyl)-1H-pyrazole-5-carboxamide (7h). Yield:
69.1%. White solid, m.p. 168–170 °C; 1H-NMR (CDCl3, 400 MHz) δ: 2.20 (s, 3H, CH3), 2.27 (s, 3H,
CH3), 6.85 (s, 1H, pyrazolyl-H), 6.96–7.00 (m, 2H, Ar-H), 7.39 (dd, 1H, J = 4.8, 8.0 Hz, pyridyl-H),
7.46 (d, 1H, J = 8.0 Hz, Ar-H), 7.66 (br. s, 1H, NH), 7.87 (dd, 1H, J = 1.2, 8.0 Hz, pyridyl-H), 8.46
(dd, 1H, J = 1.6, 4.8 Hz, pyridyl-H; Elemental anal. (%), calcd. for C17H14BrClN4O: C, 50.33; H, 3.48;
N, 13.81; found: C, 50.63; H, 3.50; N, 13.75.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-nitrophenyl)-1H-pyrazole-5-carboxamide (7i). Yield:
1
62.3%. Yellow solid, m.p. 185–187 °C; H-NMR (DMSO-d6, 400 MHz) δ: 2.35 (s, 3H, CH3), 7.49 (s,
1H, Het-H), 7.61–7.67 (m, 2H, Ar-H), 8.06 (dd, J = 4.2 Hz, J = 4.4 Hz, 1H, Ar-H), 8.17 (d, J = 3.8 Hz,
1H, Py-H), 8.22 (d, J = 4.8 Hz, 1H, Py-H), 8.53 (dd, J = 4.5 Hz, J = 1.5 Hz, 1H, Py-H), 10.57(s, 1H,
NH); Elemental anal. (%), calcd. for C16H11BrClN5O3: C, 44.01; H, 2.54; N, 16.04; found: C, 44.23; H,
2.38; N, 15.89.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2,6-dimethylphenyl)-1H-pyrazole-5-carboxamide (7j). Yield:
1
49.5%. White solid, m.p. 216–219 °C; H-NMR (CDCl3, 400 MHz) δ: 2.21 (s, 6H, CH3), 6.93 (s, 1H,
pyrazolyl-H), 7.05–7.13 (m, 3H, Ar-H), 7.36–7.39 (m, 1H, pyridyl-H, 1H, NH), 7.87 (d, 1H, J = 6.8 Hz,
pyridyl-H), 8.46 (d, 1H, J = 1.6, 4.4 Hz, pyridyl-H); Elemental anal. (%), calcd. for C17H14BrClN4O:
C, 50.33; H, 3.48; N, 13.81; found: C, 50.03; H, 3.48; N, 13.81.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-nitrophenyl)-1H-pyrazole-5-carboxamide (7k). Yield:
1
64.3%. White solid, m.p. 143-145 °C; H-NMR (DMSO-d6, 400 MHz) δ: 2.27 (s, 3H, CH3), 7.39
(s, 1H, pyrazolyl-H), 7.45 (t, 1H, J = 7.6 Hz, Ar-H), 7.61 (dd, J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.65
(d, 1H, J = 7.6 Hz, Ar-H), 7.79 (d, 1H, J = 7.6 Hz, Ar-H), 8.18 (dd, J = 1.2, 8.0 Hz, 1H, pyridyl-H),
8.50 (dd, 1H, J = 1.2, 4.4 Hz, 1H, pyridyl-H), 10.63 (br. s, NH); Elemental anal. (%), calcd. for
C16H11BrClN5O3: C, 44.01; H, 2.54; N, 16.04; found: C, 44.25; H, 2.69; N, 15.85.
3-Bromo-N-(2-chloro-4-nitrophenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7l). Yield:
52.7%. White solid, m.p. 176–177 °C; 1H-NMR (CDCl3, 400 MHz) δ: 6.99 (s, 1H, pyrazolyl-H), 7.48
(dd, J = 4.8, 8.4 Hz, 1H, pyridyl-H), 7.96 (dd, J = 1.6, 8.4 Hz, 1H, pyridyl-H), 8.13 (dd, 1H, J = 2.4,

Molecules 2012, 17
10424
9.2 Hz, Ar-H), 8.34 (d, 1H, J = 2.4 Hz, Ar-H), 8.51 (dd, 1H, J = 1.2, 4.4 Hz, pyridyl-H), 8.55 (d, 1H,
J = 9.2 Hz, Ar-H), 8.62 (br. s, 1H, NH); Elemental anal. (%), calcd. for C15H8BrCl2N5O3: C, 39.42; H,
1.76; N, 15.32; found: C, 39.09; H, 2.01; N, 15.51.
3-Bromo-N-(2-bromo-4-nitrophenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7m). Yield:
46.0%. White solid, m.p. 176–178 °C; 1H-NMR (CDCl3, 400 MHz) δ: 6.99 (s, 1H, pyrazolyl-H), 7.48
(dd, J = 4.8, 8.4 Hz, 1H, pyridyl-H), 7.96 (dd, J = 1.6, 8.0 Hz, 1H, pyridyl-H), 8.16 (dd, 1H, J = 2.4,
9.2 Hz, Ar-H), 8.49–8.53 (m, 1H, pyridyl-H, 2H, Ar-H), 8.60 (br. s, 1H, NH); Elemental anal. (%),
calcd. for C15H8Br2ClN5O3: C, 35.92; H, 1.61; N, 13.96; found: C, 36.24; H, 1.73; N, 14.08.
3-Bromo-N-(2-nitro-4-chlorophenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7n). Yield:
55.5%. White solid, m.p. 193–194 °C; 1H-NMR (CDCl3, 400 MHz) δ: 7.02 (s, 1H, pyrazolyl-H), 7.46
(dd, J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.57 (dd, 1H, J = 2.8, 9.2 Hz, Ar-H), 7.94 (dd, J = 1.2, 8.0 Hz,
1H, pyridyl-H), 8.27 (d, 1H, J = 2.4 Hz, Ar-H), 8.51 (dd, 1H, J = 1.6, 4.8 Hz, pyridyl-H), 8.66 (d, 1H,
J = 9.2 Hz, Ar-H), 11.14 (br. s, 1H, NH); Elemental anal. (%), calcd. for C15H8BrCl2N5O3: C, 39.42; H,
1.76; N, 15.32; found: C, 39.76; H, 1.98; N, 15.80.
3-Bromo-1-(3-chloropyridin-2-yl)-N-(2,5-dichlorophenyl)-1H-pyrazole-5-carboxamide (7o). Yield:
1
74.0%. White solid, m.p. 190–192 °C; H-NMR (CDCl3, 400 MHz) δ: 6.94 (s, 1H, pyrazolyl-H),
7.06–7.08 (m, 1H, Ar-H), 7.31–7.36 (m, 1H, Ar-H), 7.45–7.48 (m, 1H, pyridyl-H), 7.94 (d, 1H, J = 8.0 Hz,
pyridyl-H), 8.35 (s, 1H, NH), 8.51 (d, 1H, J = 4.4 Hz, pyridyl-H); Elemental anal. (%), calcd. for
C15H8BrCl3N4O: C, 40.35; H, 1.81; N, 12.55; found: C, 40.28; H, 2.06; N, 12.32.
3-Bromo-N-(4-chloro-2,6-dimethylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7p).
1
Yield: 52.3%. White solid, m.p. 225–228 °C; H-NMR (CDCl3, 400 MHz) δ: 2.14 (s, 6H, CH3), 6.89
(s, 1H, pyrazolyl-H), 7.04 (s, 2H, Ar-H), 7.38 (dd, J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.45 (br. s, 1H,
NH), 7.87 (dd, 1H, J = 1.6, 8.0 Hz, pyridyl-H), 8.44 (dd, 1H, J = 1.6, 4.4 Hz, pyridyl-H); Elemental
anal. (%), calcd. for C17H13BrCl2N4O: C, 46.39; H, 2.98; N, 12.73; found: C, 46.18; H, 3.28; N, 12.17.
3-Bromo-N-(4-bromo-2,6-dimethylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7q).
1
Yield: 55.2%. White solid, m.p. 237–238 °C; H-NMR (CDCl3, 400 MHz) δ: 2.17 (s, 6H, CH3), 6.92
(s, 1H, pyrazolyl-H), 7.22 (s, 2H, Ar-H), 7.38 (dd, J = 4.8, 8.0 Hz, 1H, pyridyl-H), 7.41 (br. s, 1H,
NH), 7.86 (dd, 1H, J = 1.6, 8.0 Hz, pyridyl-H), 8.45 (dd, 1H, J = 1.6, 4.8 Hz, pyridyl-H); Elemental
anal. (%), calcd. for C17H13Br2ClN4O: C, 46.99; H, 3.55; N, 13.70; found: C, 46.78; H, 3.38; N, 13.78.
3-Bromo-N-(2-chloro-6-methyl-4-nitrophenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7r).
1
Yield: 53.2%. Yellow solid, m.p. 107–109 °C; H-NMR (DMSO-d6, 400 MHz) δ: 2.30 (s, 3H, CH3),
7.45 (s, 1H, pyrazolyl-H), 7.62 (dd, J = 4.4, 8.0 Hz, 1H, pyridyl-H), 8.18–8.23 (m, 2H, pyridyl-H, Ar-H),
7.80–7.82 (m, 1H, Ar-H), 8.34 (d, 1H, J = 2.4 Hz, Ar-H), 8.51 (dd, 1H, J = 1.2, 4.4 Hz, pyridyl-H),
10.79 (br. s, NH); Elemental anal. (%), calcd. for C16H10BrCl2N5O3: C, 40.79; H, 2.14; N, 14.87; found:
C, 40.58; H, 2.21; N, 14.89.

Molecules 2012, 17
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3-Bromo-N-(4-chloro-2-methyl-6-nitrophenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (7s).
1
Yield: 46.6%. White solid, m.p. 100–104 °C; H-NMR (DMSO-d6, 400 MHz) δ: 2.28 (s, 3H, CH3),
7.01 (s, 1H, pyrazolyl-H), 7.40 (dd, J = 4.8, 8.4 Hz, 1H, pyridyl-H), 7.51 (d, 1H, J = 2.4 Hz, Ar-H),
7.87–7.90 (m, 2H, pyridyl-H, Ar-H), 8.47 (dd, 1H, J = 1.6, 4.8 Hz, pyridyl-H), 9.05 (br. s, 1H, NH);
HRMS (ESI) m/z: 491.9233 (Calcd for C16H10BrCl2N5O3 [M+Na]+: 491.9236).
3.3. Crystal Structure Determination
The prism-shaped single crystal of the title compound was obtained by recrystallization from EtOH.
The crystal with dimensions of 0.20 mm × 0.16 mm × 0.12 mm was mounted on a rigaku saturn
diffractometer with a graphite-monochromated MoKα radiation (λ = 0.71073Å) by using a Phi scan
modes at 113(2) K in the range of 2.28 ≤ θ ≤ 25.02. The crystals are triclinic, space group P-1 with
a = 8.8252(18), b = 9.1389(18), c = 10.448(2) Å, α = 96.61(3), β = 91.95(3), γ = 99.49(3)°, V = 824.4(3)
Å3, Z = 2, F(000) = 452, Dc = 1.841g/cm3, μ = 0.285 cm−1. A total of 5604 reflections were collected,
of which 2884 were independent (Rint = 0.0345) and 2197 were observed with I > 2σ(I). The
calculations were performed with SHELXS-97 program [26] and the empirical absorption corrections
were applied to all intensity data. The non-hydrogen atoms were refined anisotropically. The hydrogen
atoms were determined with theoretical calculations and refined isotropically. The final full-matrix
least squares refinement gave:
2
R1 = 0.0345 and wR2 = 0.0785 (w = 1/[2(Fo ) + (0.0391P)2]
2
where P = (Fo + 2Fc2)/3, S = 1.07, (Δ/σ)max = 0.002, Δρmax = 0.46 and Δρmin = −0.65 e Å−3.
Atomic scattering factors and anomalous dispersion corrections were taken from International Table
for X-Ray Crystallography [27]. CCDC-893647 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge at http://www.ccdc.cam.ac.uk/conts/retrieving.html
or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk.
3.4. Biological Assay
All bioassays were performed on representative test organisms reared in the laboratory, which were
repeated at 25 ± 1 C according to statistical requirements. Assessments were made on a dead/alive
basis and evaluations are based on a percentage scale of 0–100 in which 0 = no activity and 100 = total kill.
3.4.1. Stomach Toxicity against Mythimna separata Walker
The leaf dipping assay method was used for M. separata tests [28,29], in which the corn leaves
were dipped into a test solution for 20 s and allowed to dry. The treated diet was placed into a 7 cm
diameter Petri dish, and 10 fourth-instar M. separata larvae were released into the dish. The symptoms
of affected larvae were observed at 24 h after the application, and percentage mortalities were
evaluated 72 h after treatment. For comparative purposes, RynaxypyrTM was tested under the same
conditions. Each treatment was performed three times.

Molecules 2012, 17
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3.4.2. Toxicity against Culex pipiens pallens
The immersion method assay was used for C. p. pallens tests [30], and concentrations of test
compounds were adjusted by serial dilution of a stock solution of the compounds in acetone. Each
compound in acetone was suspended in distilled water, 10 early fourth-instar larvae of C. p. pallens
were put into glass cups (125 mL) containing each test solution (100 mL). Larvicidal activity was
evaluated 72 h after treatment. For comparative purposes, RynaxypyrTM was tested under the same
conditions. Each treatment was performed three times.
3.4.3. Stomach Toxicity against Plutella xylostella (Linnaeus, 1758) and Laphygma exigua Hübner
The leaf dipping assay method was used for P. xylostella and L. exigua tests [31,32]. 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 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 second-instar P. xylostella larvae (third-instar L. exigua larvae). Percentage
mortalities were evaluated three days after treatment. Leaves treated with water and dimethylformamide
were provided as controls. For comparative purposes, RynaxypyrTM was tested under the same
conditions. Each treatment was performed three times.
4. Conclusions
In summary, a series of amides containing N-pyridylpyrazoles were synthesized and assessed for
their insecticidal activities in vivo, using RynaxypyrTM as reference control. Several of the synthesized
compounds exhibited significant insecticidal activity on a broad spectrum of Lepidoptera. Compared
with the anthranilic diamide insecticide RynaxypyrTM, the removal of the aliphatic amide moiety (Z)
from the anthraniloyl skeleton resulted in slightly decreased insecticidal efficacy. This implies that the
aliphatic amide moiety might not be the insecticidal pharmacophore. The present findings provided a
powerful complement to the SARs of amide insecticides, and warrant future investigation of the
mechanism of action of these analogues.
Acknowledgments
This work was supported financially by the National Natural Science Funds of China (grant No.
21102103), the China Postdoctoral Science Foundation (grant No. 2011M500532).
Conflict of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
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