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

Article abstract of DOI:10.1007/s13738-012-0176-2

A novel series of amides containing N-pyridylpyrazole were designed and synthesized. All of the compounds were characterized and confirmed by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The single crystal structure of 9d was determined by X-ray diffraction. The bioassay tests showed that the title compounds exhibited good insecticidal activities against Mythimna separata Walker, diamondback moth and Laphygma exigua Huebner.

Full text of DOI:10.1007/s13738-012-0176-2

J IRAN CHEM SOC (2013) 10:429–437
DOI 10.1007/s13738-012-0176-2
ORIGINAL PAPER
Synthesis, structure and insecticidal activity of some novel amides
containing N-pyridylpyrazole
•
•
•
Wei-Li Dong Jun-Ying Xu Li-Xia Xiong
Zheng-Ming Li
Received: 16 May 2012 / Accepted: 3 October 2012 / Published online: 19 October 2012
Ó Iranian Chemical Society 2012
Abstract A novel series of amides containing N-pyr-
idylpyrazole were designed and synthesized. All of the
insecticidals, phthalic acid diamides and anthranilic diam-
ides have been discovered with exceptional insecticidal
activity on a range of Lepidoptera, which exhibit their
action by binding to RyR and activating the uncontrolled
release of calcium stores [2–4]. Since then diamides have
been the focus of synthesis activities within the agro-
chemical industry. Anthranilic diamides and their chemis-
try have recently attracted considerable attention to the
field of novel agricultural insecticides, owing to their
prominent insecticidal activity, unique modes of action and
good environmental profiles [5–9].
1
compounds were characterized and confirmed by IR, H
NMR, 13C NMR, MS and elemental analysis. The single
crystal structure of 9d was determined by X-ray diffraction.
The bioassay tests showed that the title compounds
exhibited good insecticidal activities against Mythimna
separata Walker, diamondback moth and Laphygma exigua
Hu¨bner.
Keywords Amide Á N-pyridylpyrazole Á Synthesis Á
Crystal structure Á Insecticidal activity
Anthranilic diamide insecticide is characterized by a
three-part chemical structure as shown in Fig. 1a: (X) an
anthraniloyl moiety, (Y) an aromatic acyl moiety and
(Z) an aliphatic amide moiety. Notably, anthranilic diam-
ides contain N-pyridylpyrazole in the second section
(Y) showed significantly better activity than other hetero-
cyclic derivatives [10, 11]. Work in this area has led to the
discovery of RynaxypyrTM, a highly potent and selective
activator of insect RyR with exceptional activity on a broad
range of Lepidoptera, as the first new insecticide from this
class (Fig. 1b) [12]. In our previous work, when the N-
pyridylpyrazole ring was replaced with 1,2,3-thiadiazole
[13] or triazolopyrimidine [14], the insecticidal activities
were eliminated, and when the modification of insecticidal
anthranilic diamides with an ester group substituting an
amide group in the aliphatic amide moiety, the insecticidal
activities decreased markedly [15]. Thus, these results
suggest that N-pyridylpyrazole (Y) and aliphatic amide
(Z) in anthranilic diamides play an important role in its
insecticidal activities. Suramin (Fig. 2), a polysulphonated
naphtylurea contains diamide structures which is similar
with anthranilic diamide insecticides, was a RyR modu-
lating agent [16]. However, unlike anthranilic diamides, the
diamide structure in Suramin was not ortho-position but
Introduction
Due to the capability of insects to rapidly develop resis-
tance, the discovery of agents that act on new biochemical
targets is an important tool for effective pest management.
Calcium channels, in particular, the ryanodine receptors
(RyR) represent an attractive biological target for insect
control and thus offer excellent promise in integrated pest
management strategies [1]. Recently, two new classes of
W.-L. Dong (&)
Tianjin Key Laboratory on Technologies Enabling Development
of Clinical Therapeutics and Diagnostics (Theranostics), School
of Pharmacy, Tianjin Medical University, Tianjin 300070, China
e-mail: wldong33@163.com
J.-Y. Xu Á L.-X. Xiong Á Z.-M. Li
State Key Laboratory of Elemento-Organic Chemistry,
National Pesticide Engineering Research Center (Tianjin),
Nankai University, Tianjin 300071, China
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J IRAN CHEM SOC (2013) 10:429–437
Enlightened by all of the descriptions above, to further
explore the comprehensive structure–activity relationships
about the insecticidal activity, a series of novel meta-dia-
mide and para-diamide analog containing N-pyridylpyraz-
ole were designed and synthesized as shown in Schemes 1
and 2.
(a) General formula
(b) RynaxypyrTM
Experimental
Fig. 1 Chemical structures of anthranilic diamide insecticides
Instruments
meta-position. Encouraged by these reports, we developed
an idea that the replacement of the ortho-diamide structure
of RynaxypyrTM with a meta-diamide or a para-diamide
could obtain novel analog with high insecticidal activities.
Melting points were determined on an X-4 binocular
microscope melting point apparatus (Beijing Tech Instru-
ments Co., Beijing, China) and were uncorrected. 1H NMR
Fig. 2 Suramin, a RyR
modulating agent
Scheme 1 Synthetic pathway
to amides containing
N-pyridylpyrazole derivatives
5a–5c. Reagents and conditions:
(i) N-chlorosuccinimide (NCS),
DMF; (ii) SOCl2, i-PrNH2; (iii)
CH2Cl2, oxalyl chloride, DMF
Scheme 2 Synthetic pathway
to amides containing
N-pyridylpyrazole derivatives
9a–9i. Reagents and conditions:
(i) N-Chlorosuccinimide (NCS),
DMF/N-bromosuccinimide
(NBS), DMF; (ii) SOCl2,
R2NH2; (iii) CH2Cl2, oxalyl
chloride, DMF
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3-amino-N-isopropyl-4-methoxybenzamide 3b
spectra were obtained on Bruker AC-P500 spectrometer
(300 MHz; Bruker, Fallanden, Switzerland) and Bruker
Avance 400 spectrometer (400 MHz; Bruker) using tet-
ramethylsilane (TMS) as an internal standard. 13C NMR
spectra were obtained on Bruker Avance 400 spectrome-
ter (100 MHz) with TMS as an internal standard. Ele-
mental analyses were performed on a Vario EL elemental
analyzer (Elementar, Hanau, Germany). IR spectra were
obtained on a Bruker Vector 27 FT-IR spectrometer
(Bruker, Ettlingen, Germany). Mass spectra were recor-
ded on a Thermo Finnigan LCQ Advantage LC/mass
detector instrument. All chemicals or reagents were pur-
chased from standard commercial suppliers: petroleum
ether, bp 60–90 °C.
The compound was obtained in 72.1 % yield as a white
solid; m.p. 94–96 °C; 1H NMR (400 MHz, CDCl3) d: 1.22
(d, 6H, J = 6.4 Hz, CH(CH3)2), 3.87 (s, 3H, OCH3),
4.20–4.28 (m, 1H, CH(CH3)2), 5.87 (br. s, 1H, NH), 6.74
(d, 1H, J = 8.3 Hz, Ar–H), 7.06 (dd, 1H, J = 2.1, 8.0 Hz,
Ar–H), 7.15 (d, 1H, J = 2.4 Hz, Ar–H).
5-amino-2-chloro-N-isopropyl-4-methylbenzamide 3c
The compound was obtained in 56.5 % yield as a white solid;
m.p.160–165 °C; 1HNMR(400 MHz,CDCl3)d:1.25(d, 6H,
J = 6.8 Hz, CH(CH3)2), 2.21 (s, 3H, CH3), 4.15 (br. s, 2H,
NH), 4.24–4.33 (m, 1H, CH(CH3)2), 5.71(br. s, 1H, NH), 6.83
(d, 1H, J = 7.6 Hz, Ar–H), 6.98 (d, 1H, J = 8.0 Hz, Ar–H).
Synthesis of compounds
General method for preparing title compounds 5a–5c
Synthesis of 5-amino-2-chloro-4-methylbenzoic acid 2
Oxalyl chloride (3 mmol) and DMF (2 drop) was added to a
solution of 3-halo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxylic acid 4 (1 mmol) in 20 ml of CH2Cl2. The mixture
was stirred at room temperature for 3 h. Then the solvent was
evaporated to give the crude acyl chloride. To an ice-water
bath cooled solution of 2 (1.2 mmol) in CH2Cl2 (20 ml), acyl
chloride and diisopropylethylamine (1 mmol) were added
dropwise, then further stirring for 12 h at room temperature.
Subsequently, the mixture was added another 20 ml CH2Cl2,
then washed by HCl, NaHCO3, NaCl, dried over Na2SO4,
and evaporated. The residue was purified by chromatography
on a silica gel using petroleum ether and ethyl acetate as the
eluent to afford the compounds 5a–5c.
To a solution of 1 (3.02 g, 20 mmol) in DMF (30 ml) was
added the NCS (2.8 g, 21 mmol) and the mixture was
stirred for 1 h at 100 °C, cooled to room temperature, left
to stand overnight, and then slowly poured into ice-water
(100 ml) to precipitate a white solid. The solid was filtered
and dried to obtain the synthesis of 5-amino-2-chloro-4-
methylbenzoic acid 2 (2.51 g, 34 %), m.p. 162–163 °C; 1H
NMR (400 MHz, DMSO-d6) d: 3.76 (s, 3H, CH3), 6.63 (br.
s, 2H, NH2), 7.20–7.25 (m, 1H, Ar–H), 7.66–7.68 (m, 1H,
Ar–H).
General method for preparing intermediates 3a–3c
3-chloro-1-(3-chloropyridin-2-yl)-N-(5-
(isopropylcarbamoyl)-2-methylphenyl)-1H-pyrazole-5-
carboxamide 5a
To the substituted benzoic acid 2 (10 mmol) was added
thionyl chloride (30 mmol) and the mixture was refluxed
for 3 h to give acid chloride. A solution of isopropylamine
(20 mmol) in THF (20 ml) was dropwised and this mixture
was vigorously stirred at room temperature for overnight.
Subsequently, the reaction mixture was diluted with water
and extracted several times with ethyl acetate. The com-
bined organic phases were dried over MgSO4 and evapo-
rated. The residue was purified by chromatography on a
silica gel using petroleum ether and ethyl acetate as the
eluent to afford the compounds 3a–3c.
The compound was obtained in 82.5 % yield as a white
solid; m.p. 128–132 °C; IR mmax(KBr), cm-1: 3,343
(NH), 3,258 (NH), 1,680 (C=O), 1,636 (C=O); H NMR
1
(400 MHz, CDCl3) d: 1.17 (d, 6H, J = 6.8 Hz,
CH(CH3)2), 2.28 (s, 3H, CH3), 4.15–4.23 (m, 1H,
CH(CH3)2), 5.90 (d, 1H, J = 8.4 Hz, NH), 6.92 (s, 1H,
pyrazolyl-H), 7.21 (d, 1H, J = 8.0 Hz, Ar–H), 7.39 (dd,
1H, J = 4.8, 8.4 Hz, pyridyl—H), 7.51 (dd, 1H, J = 1.6,
8.0 Hz, Ar–H), 7.60 (s, 1H, Ar–H), 7.90 (dd, 1H, J = 1.6,
8.4 Hz, pyridyl-H), 8.39 (dd, 1H, J = 1.2, 4.4 Hz, pyridyl-
H), 8.55 (br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6)
d: 164.69, 155.32, 148.30, 147.17, 139.32, 138.93, 138.54,
136.05, 134.84, 128.74, 128.51, 127.80, 126.90, 126.68,
122.87, 110.66, 40.21, 26.29, 18.51. ESI–MS (m/z): 433.74
(M ? H)?. Elemental analysis for C20H19Cl2N5O2: found
C 55.31, H 4.60, N 15.94; calcd. C 55.57, H 4.43, N 16.20.
3-amino-N-isopropyl-4-methylbenzamide 3a
The compound was obtained in 86.5 % yield as a white
1
solid; m.p. 122–123 °C; H NMR (400 MHz, CDCl3) d:
1.23 (d, 6H, J = 6.8 Hz, CH(CH3)2), 2.19 (s, 3H, CH3),
3.71 (br. s, 2H, NH), 4.21–4.30 (m, 1H, CH(CH3)2), 5.87
(br. s, 1H, NH), 6.96-7.07 (m, 2H, Ar–H), 7.13 (d, 1H,
J = 1.6 Hz, Ar–H).
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3-bromo-1-(3-chloropyridin-2-yl)-N-(5-
(isopropylcarbamoyl)-2-methoxyphenyl)-1H-pyrazole-5-
carboxamide 5b
7.55 (s, 1H, Ar–H), 7.77 (s, 1H, Ar–H), 12.37 (br. s, 1H,
COOH).
4-amino-3-bromo-5-methylbenzoic acid 7b
The compound was obtained in 79.6 % yield as a white
solid; m.p. 202–203 °C; IR mmax(KBr), cm-1: 3,341 (NH),
3,266 (NH), 1,676 (C=O), 1,635 (C=O), 1,142 (C–O–C);
1H NMR (400 MHz, CDCl3) d: 1.20 (d, 6H, J = 6.8 Hz,
CH(CH3)2), 3.97 (s, 3H, OCH3), 4.18–4.27 (m, 1H,
CH(CH3)2), 5.87 (d, 1H, J = 7.6 Hz, NH), 6.90 (s, 1H,
pyrazolyl-H), 6.95 (d, 1H, J = 8.4 Hz, Ar–H), 7.45 (dd,
1H, J = 4.8, 8.0 Hz, pyridyl-H), 7.71 (d, 1H, J = 8.0 Hz,
Ar–H), 7.93 (d, 1H, J = 8.0 Hz, pyridyl-H), 8.43 (br.s, 1H,
NH), 8.49 (s, 1H, Ar–H), 8.51 (d, 1H, J = 4.4 Hz, pyridyl-
H). 13C NMR (100 MHz, DMSO-d6) d: 164.32, 155.48,
154.39, 148.35, 147.13, 139.36, 139.30, 133.92, 127.92,
126.80, 126.71, 126.31, 125.04, 124.49, 110.92, 110.65,
55.99, 40.92, 22.34. ESI–MS (m/z): 494.10 (M ? H)?.
Elemental analysis for C20H19BrClN5O3 found C 48.45, H
4.17, N 14.19; calcd. C 48.75, H 3.89, N 14.21.
The compound was obtained in 78.3 % yield as a white solid;
m.p. [230 °C (decomposition); 1H NMR (400 MHz, DMSO-
d6) d: 2.14 (s, 3H, CH3), 5.80 (s, 2H, NH2), 7.50 (s, 1H, Ar–H),
7.60 (s, 1H, Ar–H), 12.34 (br. s, 1H, COOH).
General method for preparing intermediates 8a–8i
To 4-amino-3-halo-5-methylbenzoic acid 7 (10 mmol) was
added thionyl chloride (30 mmol) and the mixture was
refluxed for 3 h to give acid chloride. A solution of iso-
propylamine (20 mmol) in THF (20 ml) was dropwised
and this mixture was vigorously stirred at room tempera-
ture for overnight. Subsequently, the reaction mixture was
diluted with water and extracted several times with ethyl
acetate. The combined organic phases were dried over
MgSO4 and evaporated. The residue was purified by
chromatography on a silica gel using petroleum ether and
ethyl acetate as the eluent to afford the compounds 8a–8i.
3-bromo-N-(4-chloro-5-(isopropylcarbamoyl)-2-
methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamide 5c
4-amino-N-3-dimethylbenzamide 8a
The compound was obtained in 45.3 % yield as a white
solid; m.p. 144–147 °C; IR mmax(KBr), cm-1: 3,336 (NH),
3,243 (NH), 1,675 (C = O), 1,633 (C = O); 1H NMR
(400 MHz, CDCl3) d: 1.27 (d, 6H, J = 6.8 Hz,
CH(CH3)2), 2.16 (s, 3H, CH3), 4.25–4.33 (m, 1H,
CH(CH3)2), 5.81 (d, 1H, J = 7.6 Hz, NH), 7.21 (d, 1H,
J = 8.0 Hz, Ar–H), 6.92 (s, 1H, pyrazolyl-H), 7.39 (dd,
1H, J = 4.8, 8.4 Hz, pyridyl—H), 7.51 (dd, 1H, J = 1.6,
8.0 Hz, Ar–H), 7.60 (s, 1H, Ar–H), 7.90 (dd, 1H, J = 1.6,
8.4 Hz, pyridyl—H), 8.39 (dd, 1H, J = 1.2, 4.4 Hz, pyri-
dyl-H), 8.55 (br.s, 1H, NH). 13C NMR (100 MHz, CDCl3)
d: 166.20, 155.41, 148.35, 145.78, 139.50, 137.73, 137.68,
133.05, 131.67, 128.34, 128.19, 127.84, 127.12, 125.67,
The compound was obtained in 58.9 % yield as a yellow
oil; 1H NMR (400 MHz, CDCl3) d: 2.16 (s, 3H, CH3), 2.95
(d, 3H, J = 4.8 Hz, NHCH3), 5.87 (br. s, 2H, NH), 6.20
(br. s, 1H, NH), 6.62 (d, 1H, J = 8.4 Hz, Ar–H), 7.43 (d,
1H, J = 8.0 Hz, Ar–H), 7.50 (s, 1H, Ar–H).
4-amino-N-isopropyl-3-methylbenzamide 8b
The compound was obtained in 86.7 % yield as a white solid;
1
m.p. 146–147 °C; H NMR (300 MHz, CDCl3) d: 1.16 (d,
6H, J = 6.6 Hz, CH(CH3)2), 2.11 (s, 3H, CH3), 3.83 (br. s,
2H, NH), 4.13–4.25 (m, 1H, CH(CH3)2), 5.73 (br. s, 1H,
NH), 6.57 (d, 1H, J = 8.1 Hz, Ar–H), 7.37 (dd, 1H, J = 2.1,
8.4 Hz, Ar–H), 7.43 (d, 1H, J = 1.5 Hz, Ar–H).
124.55, 110.34, 41.78, 21.39, 17.80. ESI–MS (m/z): 510.21
(M-H). Elemental analysis for C20H19BrClN5O3: found C
¯
47.25, H 3.29, N 13.58; calcd. C 46.99, H 3.55, N 13.70.
4-amino-3-chloro-N-5-dimethylbenzamide 8c
4-amino-3-halo-5-methylbenzoic acid 7a and 7b
The compound was obtained in 83.5 % yield as a white
solid; m.p. 222–224 °C; 1H NMR (400 MHz, DMSO-d6) d:
2.13 (s, 3H, CH3), 2.68 (d, 3H, J = 4.4 Hz, NHCH3), 5.52
(s, 2H, NH2), 7.44 (s, 1H, Ar–H), 7.58 (s, 1H, Ar–H), 8.09
(br, 1H, NHCH3).
The intermediate 7 was synthesized according to the
methods described in synthesis of 5-amino-2-chloro-4-
methylbenzoic acid 2.
4-amino-3-chloro-5-methylbenzoic acid 7a
4-amino-3-chloro-N-isopropyl-5-methylbenzamide 8d
The compound was obtained in 69.6 % yield as a white
solid; m.p. [ 197 °C (decomposition); 1H NMR (400
MHz, DMSO-d6) d: 2.18 (s, 3H, CH3), 5.75 (s, 2H, NH2),
The compound was obtained in 94.7 % yield as a white
1
solid; m.p. 194–195 °C; H NMR (400 MHz, CDCl3) d:
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433
1.24 (d, 6H, J = 6.4 Hz, CH(CH3)2), 2.22 (s, 3H, CH3),
4.20–4.30 (m, 1H, CH(CH3)2), 4.30 (br. s, 2H, NH), 5.76
(br. s, 1H, NH), 7.41 (s, 1H, Ar–H), 7.56 (d, 1H,
J = 1.6 Hz, Ar–H).
(20 ml), acyl chloride and diisopropylethylamine (1 mmol)
were added dropwise, then further stirring for 12 h at room
temperature. Subsequently, the mixture was added another
20 ml CH2Cl2, then washed by HCl, NaHCO3, NaCl, dried
over Na2SO4, and evaporated. The residue was purified by
chromatography on a silica gel using petroleum ether and
ethyl acetate as the eluent to afford the compounds 9a–9i.
4-amino-N-butyl-3-chloro-5-methylbenzamide 8e
The compound was obtained in 72.2 % yield as a white solid;
1
m.p. 120–121 °C; H NMR (400 MHz, CDCl3) d: 0.88 (t,
3-bromo-1-(3-chloropyridin-2-yl)-N-(2-methyl-4-
(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide
9a
3H, J = 7.2 Hz, CH2CH3), 1.27–1.38 (m, 2H, CH2CH3),
1.47–1.55 (m, 2H, CH2CH2CH3), 2.15 (s, 3H, CH3), 3.34 (q,
2H, J = 7.2 Hz, NHCH2CH2), 3.64 (br, 2H, NH), 5.88 (br.s,
1H, NH), 7.34 (s, 1H, Ar–H), 7.50 (s, 1H, Ar–H).
The compound was obtained in 68.2 % yield as a white
solid; m.p. 112–115 °C; IR mmax(KBr), cm-1: 3,300 (NH),
3,155 (NH), 1,660 (C=O), 1,642 (C=O); 1H NMR
(400 MHz, CDCl3) d: 2.28 (s, 3H, CH3), 2.98 (d, 3H,
NHCH3), 6.11 (br, 1H, NHCH3), 6.97 (s, 1H, pyrazolyl-H),
7.40–7.45 (m, 2H, pyridyl-H, Ar–H), 7.60 (s, 1H, Ar–H),
7.77 (d, 1H, J = 8.4 Hz, Ar–H), 7.91 (dd, 1H, J = 1.6,
8.0 Hz, pyridyl-H), 8.01 (br.s, 1H, NH), 8.47 (dd, 1H,
J = 1.6, 4.8 Hz, pyridyl-H). 13C NMR (100 MHz, CDCl3)
d: 164.73, 155.47, 148.42, 147.30, 139.53, 138.92, 138.52,
136.22, 134.54, 129.76, 128.49, 127.98, 126.30, 126.01,
123.89, 110.57, 26.28, 18.27. ESI–MS (m/z): 484.27 (M?
Cl)-. Elemental analysis for C18H15BrClN5O2: found C
47.96, H 3.21, N 15.87; calcd. C 48.18, H 3.37, N 15.61.
4-amino-N-tert-butyl-3-chloro-5-methylbenzamide 8f
The compound was obtained in 65.3 % yield as a white
1
solid; m.p. 130–131 °C; H NMR (400 MHz, CDCl3) d:
1.38 (s, 9H, C(CH3)3), 2.16 (s, 3H, CH3), 4.04 (br. s, 2H,
NH), 5.75 (br. s, 1H, NH), 7.30 (d, 1H, J = 0.8 Hz, Ar–H),
7.45 (d, 1H, J = 2.0 Hz, Ar–H).
4-amino-3-chloro-N-cyclohexyl-5-methylbenzamide 8g
The compound was obtained in 91.3 % yield as a white solid;
m.p. 213–215 °C; 1H NMR (400 MHz, CDCl3) d: 1.19–2.04
(m, 10H, cyclohexyl-H), 2.24 (s, 3H, CH3), 3.92–3.99 (m,
1H, cyclohexyl-H), 4.31 (br, 2H, NH2), 5.80 (d, 1H,
J = 6.4 Hz, NH), 7.43 (s, 1H, Ar–H), 7.57 (s, 1H, Ar–H).
3-bromo-1-(3-chloropyridin-2-yl)-N-(4-
(isopropylcarbamoyl)-2-methylphenyl)-1H-pyrazole-5-
carboxamide 9b
4-amino-N-benzyl-3-chloro-5-methylbenzamide 8 h
The compound was obtained in 66.0 % yield as a white solid;
m.p. 230–232 °C; IR mmax(KBr), cm-1: 3,335 (NH), 3,200
(NH), 1,680 (C=O), 1,632 (C=O); H NMR (400 MHz,
The compound was obtained in 69.5 % yield as a white
1
solid; m.p. 121–124 °C; H NMR (400 MHz, CDCl3) d:
1
2.14 (s, 3H, CH3), 4.00 (br, 2H, NH2), 4.53 (d, 2H,
J = 5.2 Hz, CH2), 6.24 (br, 1H, NH), 7.19–7.30 (m, 5H,
Ar–H), 7.37 (s, 1H, Ar–H), 7.54 (s, 1H, Ar–H).
CDCl3) d: 1.25 (d, 6H, J = 6.4 Hz, CH(CH3)2), 2.24 (s, 3H,
CH3), 4.21changed to n dash4.29 (m, 1H, CH(CH3)2), 5.89
(d, 1H, J = 7.2 Hz, NH), 7.05 (s, 1H, pyrazolyl-H),
7.37–7.43 (m, 2H, pyridyl-H, Ar–H), 7.52 (s, 1H, Ar–H),
7.65 (d, 1H, J = 8.4 Hz, Ar–H), 7.89 (d, 1H, J = 8.0 Hz,
pyridyl-H), 8.25 (br.s, 1H, NH), 8.47 (d, 1H, J = 4.4 Hz,
pyridyl-H). 13C NMR (100 MHz, CDCl3) d: 164.82, 155.46,
148.42, 147.27, 139.42, 138.70, 138.47, 136.12, 134.31,
129.55, 128.47, 127.97, 126.25, 125.96, 123.72, 110.63,
42.09, 22.83, 18.24. ESI–MS (m/z): 511.90 (M? Cl-). Ele-
mental analysis for C20H19BrClN5O2: found C50.70, H 3.84,
N 14.38; calcd. C 50.39, H 4.02, N 14.69.
4-amino-3-bromo-N-5-dimethylbenzamide 8i
The compound was obtained in 91.8 % yield as a white solid;
m.p. 220–225 °C; 1H NMR (400 MHz, DMSO-d6) d: 2.17 (s,
3H, CH3), 2.72 (d, 3H, J = 4.4 Hz, NHCH3), 5.47 (s, 2H, NH2),
7.50 (s, 1H, Ar–H), 7.77 (s, 1H, Ar–H), 8.12 (br, 1H, NH).
General method for preparing title compounds 9a-9i
Oxalyl chloride (3 mmol) and DMF (2 drop) was added to a
solution of 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-
5-carboxylic acid 4b (1 mmol) in 20 ml of CH2Cl2. The
mixture was stirred at room temperature for 3 h. Then the
solvent was evaporated to afford the crude acyl chloride. To
an ice-water bath cooled solution of 8 (1.2 mmol) in CH2Cl2
3-bromo-N-(2-chloro-6-methyl-4-
(methylcarbamoyl)phenyl)-1-
(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide 9c
The compound was obtained in 67.0 % yield as a white
solid; m.p. 227–230 °C; IR mmax(KBr), cm-1: 3,348 (NH),
123

434
J IRAN CHEM SOC (2013) 10:429–437
3,224 (NH), 1,677 (C=O), 1,632 (C=O); 1H NMR
(400 MHz, CDCl3) d: 2.19 (s, 3H, CH3), 2.99 (d, 3H,
J = 3.6 Hz, NHCH3), 6.19 (br, 1H, NHCH3), 7.19 (s, 1H,
pyrazolyl-H), 7.32 (s, 1H, Ar–H), 7.37 (dd, 1H, J = 4.8,
8.0 Hz, pyridyl-H), 7.44 (s, 1H, Ar–H), 7.85 (d, 1H,
J = 7.6 Hz, pyridyl-H), 8.36 (br.s, 1H, NH), 8.46 (d, 1H,
J = 4.0 Hz, pyridyl-H). 13C NMR (100 MHz, DMSO-d6)
d: 164.81, 155.41, 148.30, 147.18, 139.33, 138.87, 138.44,
134.53, 134.51, 132.02, 127.90, 127.81, 126.93, 126.69,
125.62, 110.71, 26.30, 18.27. ESI–MS (m/z): 517.97 (M ?
Cl-). Elemental analysis for C18H14BrCl2N5O2: found C
44.46, H 2.77, N 14.19; calcd. C 44.75, H 2.92, N 14.47.
Elemental analysis for C21H20BrCl2N5O2: found C 47.90,
H 4.01, N 13.24; calcd. C 48.02, H 3.84, N 13.33.
3-bromo-N-(4-(tert-butylcarbamoyl)-2-chloro-6-
methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamide 9f
The compound was obtained in 77.1 % yield as a white
solid; m.p. 207–210 °C; IR mmax(KBr), cm-1: 3,434 (NH),
3,246 (NH), 1,688 (C=O), 1,650 (C=O); 1H NMR
(400 MHz, DMSO-d6) d: 1.36 (s, 9H, C(CH3)3), 2.22 (s,
3H, CH3), 7.43 (s, 1H, pyrazolyl-H), 7.62 (dd, 1H, J = 4.8,
8.4 Hz, pyridyl-H), 7.68 (s, 1H, Ar–H), 7.78 (s, 1H, Ar–H),
7.88 (br.s, 1H, NH), 8.19 (dd, 1H, J = 1.2, 8.0 Hz, pyridyl-
H), 8.51 (dd, 1H, J = 1.6, 4.8 Hz, pyridyl-H), 10.52 (br.s,
1H, NH). 13C NMR (100 MHz, DMSO-d6) d: 164.42,
155.39, 148.31, 147.17, 139.32, 138.93, 138.15, 135.79,
134.24, 131.75, 128.11, 127.79, 126.92, 126.67, 125.87,
110.68, 51.03, 28.46, 18.18. ESI–MS (m/z): 525.96 (M?
H?). Elemental analysis for C21H20BrCl2N5O2: found C
47.89, H 3.97, N 13.01; calcd. C 48.02, H 3.84, N 13.33.
3-bromo-N-(2-chloro-4-(isopropylcarbamoyl)-6-
methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamide 9d
The compound was obtained in 82.4 % yield as a white
solid; m.p. 157–160 °C; IR mmax(KBr), cm-1: 3,338 (NH),
3,220 (NH), 1,677 (C=O), 1,632 (C=O); 1H NMR
(400 MHz, DMSO-d6) d: 1.16 (d, 6H, J = 6.4 Hz,
CH(CH3)2), 2.21 (s, 3H, CH3), 4.00-4.04 (m, 1H,
CH(CH3)2), 7.41 (s, 1H, pyrazolyl-H), 7.62 (dd, 1H,
J = 4.8, 8.0 Hz, pyridyl-H), 7.72 (d, 1H, J = 1.2 Hz, Ar–
H), 7.82 (s, 1H, Ar–H), 8.18 (dd, 1H, J = 1.6, 8.0 Hz,
pyridyl-H), 8.32 (d, 1H, J = 7.6 Hz, NHCH3), 8.51 (dd,
3-bromo-N-(2-chloro-4-(cyclohexylcarbamoyl)-6-
methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamide 9g
The compound was obtained in 70.9 % yield as a white
solid; m.p. 175–178 °C; IR mmax(KBr), cm-1: 3,340 (NH),
3,194 (NH), 1,678 (C=O), 1,638 (C=O); 1H NMR
(400 MHz, DMSO-d6) d: 1.10–1.81 (m, 10H, cyclohexyl—
H), 2.22 (s, 3H, CH3), 3.73 (br, 1H, CH), 7.43 (s, 1H,
pyrazolyl-H), 7.62 (dd, 1H, J = 4.8, 8.0 Hz, pyridyl-H),
7.73 (s, 1H, Ar–H), 7.82 (s, 1H, Ar–H), 8.19 (d, 1H,
J = 7.2 Hz, pyridyl-H), 8.30 (d, 1H, J = 8.0 Hz, NH),
8.51 (d, 1H, J = 4.4 Hz, pyridyl-H), 10.54 (br.s, 1H, NH).
13C NMR (100 MHz, DMSO-d6) d: 163.48, 155.39,
148.30, 147.17, 139.32, 138.90, 138.32, 134.81, 134.45,
131.89, 128.07, 127.79, 126.92, 126.68, 125.76, 110.70,
48.54, 32.33, 25.24, 24.89, 18.21. ESI–MS (m/z): 551.96
(M ? H)?. Elemental analysis for C23H22BrCl2N5O2:
found C 49.97, H 4.03, N 12.34; calcd. C 50.11, H 4.02, N
12.70.
1H, J = 1.6, 4.8 Hz, pyridyl-H), 10.54 (br.s, 1H, NH). 13
C
NMR (100 MHz, DMSO-d6) d: 163.50, 155.40, 148.31,
147.18, 139.32, 138.90, 138.33, 134.78, 134.46, 131.92,
128.04, 127.80, 126.93, 126.68, 125.74, 110.71, 41.23,
22.23, 18.22. ESI–MS (m/z): 512.09 (M ? H)?. Elemental
analysis for C20H18BrCl2N5O2: found C 46.90, H 3.67, N
13.76; calcd. C 46.99, H 3.55, N 13.70.
3-bromo-N-(4-(butylcarbamoyl)-2-chloro-6-
methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamide 9e
The compound was obtained in 46.2 % yield as a white
solid; m.p. 232–234 °C; IR mmax(KBr), cm-1: 3,340 (NH),
3,123 (NH), 1,681 (C=O), 1,632 (C=O); 1H NMR
(400 MHz, DMSO-d6) d: 0.89 (t, 3H, J = 7.2 Hz,
CH2CH3), 1.27–1.36 (m, 2H, CH2CH3), 1.45–1.53 (m, 2H,
CH2CH2CH3), 2.22 (s, 3H, CH3), 3.24 (q, 2H, J = 6.4 Hz,
NHCH2CH2), 7.43 (s, 1H, pyrazolyl-H), 7.63 (dd, 1H,
J = 4.4, 8.0 Hz, pyridyl-H), 7.72 (s, 1H, Ar–H), 7.81 (s,
1H, Ar–H), 8.19 (d, 1H, J = 8.0 Hz, pyridyl-H), 8.51–8.54
(m, 1H, pyridyl-H,1H, NH), 10.54 (br.s, 1H, NH). 13C
NMR (100 MHz, DMSO-d6) d: 164.25, 155.41, 148.30,
147.19, 139.34, 138.87, 138.40, 134.67, 134.50, 131.97,
127.98, 127.80, 126.94, 126.71, 125.67, 110.71, 31.08,
19.62, 18.26, 13.71. ESI–MS (m/z): 559.87 (M? Cl-).
N-(4-(benzylcarbamoyl)-2-chloro-6-methylphenyl)-3-
bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxamide 9h
The compound was obtained in 42.3 % yield as a white
solid; m.p. 247–250 °C; IR mmax(KBr), cm-1: 3,306 (NH),
3,213 (NH), 1,671 (C=O), 1,641 (C=O); 1H NMR
(400 MHz, DMSO-d6) d: 2.23 (s, 3H, CH3), 4.46 (d, 2H,
J = 6.0 Hz, CH2), 7.22-7.35 (m, 5H, Ar–H), 7.44 (s, 1H,
pyrazolyl-H), 7.62 (dd, 1H, J = 4.8, 8.4 Hz, pyridyl-H),
123

J IRAN CHEM SOC (2013) 10:429–437
435
7.79 (s, 1H, Ar–H), 7.88 (s, 1H, Ar–H), 8.19 (dd, 1H,
J = 1.2, 8.0 Hz, pyridyl-H), 8.52 (dd, 1H, J = 1.6, 4.8 Hz,
pyridyl-H), 9.15 (t, 1H, J = 6.0 Hz, NH), 10.57 (br.s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6) d: 164.41, 155.40,
148.28, 147.18, 139.33, 139.27, 138.85, 138.50, 134.73,
134.28, 132.05, 128.29. 128.09, 127.79, 127.26, 126.93,
126.82, 126.70, 125.79, 110.70, 42.75, 18.25. ESI–MS
(m/z): 560.83 (M? H?). Elemental analysis for C24H18Br
Cl2N5O2: found C51.28, H 3.53, N 12.19; calcd. C 51.51, H
3.24, N 12.52.
purposes, RynaxypyrTM was tested under the same condi-
tions. All treatments were replicated three times.
Results and discussion
Synthesis
The synthesis procedures for title compounds 5a–5c were
shown in Scheme 1. The intermediate 5-amino-2-c4hloro-
4-methylbenzoic acid 2 was prepared by halogenation of
commercially available 3-amino-4-methylbenzoic acid 1b
with N-chlorosuccinimide [17]. Compound 2 was aminated
with appropriate amines to give intermediates 3 [18]. The
acid intermediate pyrazole carboxylic acids 4, which were
previously synthesized [19], were treated with oxalyl
chloride at reflux to give acid chloride, which was then
reacted with 3 to afford the title compounds 5a–5c. The
title compounds 9a–9i were synthesized in a similar
method as described for the synthesis compounds 5a–5c, as
shown in Scheme 2.
3-bromo-N-(2-bromo-6-methyl-4-
(methylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-
pyrazole-5-carboxamide 9i
The compound was obtained in 56.7 % yield as a white
solid; m.p. 238–240 °C; IR mmax(KBr), cm-1: 3,331 (NH),
3,121 (NH), 1,665 (C=O), 1,632 (C=O); 1H NMR
(400 MHz, DMSO-d6) d: 2.23 (s, 3H, CH3), 2.76 (d, 3H,
J = 4.4 Hz, NHCH3), 7.43 (s, 1H, pyrazolyl-H), 7.62 (dd,
1H, J = 4.8, 8.0 Hz, pyridyl-H), 7.75 (s, 1H, Ar–H), 7.95
(s, 1H, Ar–H), 8.19 (dd, 1H, J = 1.6, 8.0 Hz, pyridyl-H),
8.51 (dd, 1H, J = 1.2, 4.8 Hz, pyridyl-H), 8.55 (br, 1H,
NHCH3), 10.55 (br.s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) d: 164.08, 155.45, 148.37, 147.20, 139.87,
138.98, 138.34, 134.83, 134.75, 132.05, 128.17, 127.90,
127.03, 126.79, 125.93, 110.72, 26.27, 18.23. ESI–MS
(m/z): 527.84 (M ? H)?. Elemental analysis for
C18H14Br2ClN5O2: found C 41.09, H 2.63, N 13.00; calcd.
C 40.98, H 2.67, N 13.27.
Crystal structure
The structure of compound 9d was further confirmed by
single crystal X-ray diffraction analysis (Fig. 3). Com-
pound 9d consists of pyrazole ring, pyridine ring, benzene
ring and a molecule of ethyl acetate according to X-ray
single-crystal structure determination. All the C–N dis-
tances are typically for a single bond in the range of
˚
1.321–1.463 A. The C=O distance is 1.230(4), 1.238(4)
Biological assay
˚
and 1.216(4) A, which are typically for a double bond. In
the molecular structure of title compound, the three rings
(benzene ring, pyridine ring and pyrazole ring) are nearly
vertically with h angle of 94.9°(benzene ring vs. pyridine
ring), 105.8° (pyrazole ring vs. pyridine), 62.5°(pyrazole
All bioassays were performed on representative test
organisms reared in the laboratory, which were repeated at
25 1 °C according to the statistical requirements. The
detailed procedure was described as follows. The leaf
dipping assay method was used for oriental armyworm
(Mythimna separata Walker) tests, in which the corn leaves
were dipped into a test solution for 20 s and allowed to dry.
The treated diet was placed in a 7 cm diameter Petri dish,
and 10 fourth-instar oriental armyworm larvae were
released into the Petri dish. The symptoms of affected
larvae were observed at 24 h after the application, and
percentage mortalities were evaluated 72 h after treatment.
The immersion method assay was used for Culex pipiens
pallens tests, and concentrations of test compounds were
adjusted by serial dilution of a stock solution of the com-
pounds in acetone. Each compound in acetone was sus-
pended in distilled water, 10 early fourth-instar larvae of
Culex pipiens pallens were put into glass cups (125 ml)
containing each test solution (100 ml). Larvicidal activity
was evaluated 72 h after treatment. For comparative
Fig. 3 Crystal structure of 9d
123

436
J IRAN CHEM SOC (2013) 10:429–437
R1 chloro-substituted or bromin-substituted amides (9c, 9d
and 9i) displayed more potent insecticidal activities than
the corresponding non-substituted analog (9a and 9b). For
example, compound 9c exhibited excellent activity against
Oriental Armyworm at 10 lgÁml-1, even at 5 lgÁml-1. In
addition, the methyl substitution at R2 was more favored
than isopropyl group due to the significant higher potencies
observed in R2 methyl substituted amines (9a and 9c) than
the corresponding isopropyl substituted analog (9b and
9d), but the insecticidal activity disappeared when the R2
was substituted with t-butyl or cyclohexyl group (9f and
9 g). Besides, the R2 benzyl substituted amine (9 h) also
displayed potent insecticidal activity against Oriental
Armyworm. As shown in Table 1, no significant larvicidal
activities were found of these compounds against Culex
pipiens pallens.
Table 1 Insecticidal activities data of title compounds (mortality/%)
Compd.
Mythimna separata Walker
lg ml-1/death rate (%)
Culex pipiens
pallens
lg ml-1/death
rate (%)
2
200 100 50
25
10
5
5a
0
0
0
0
5b
5c
30
50
0
9a
100 100
30
60
20
9b
10
10
0
9c
100 100 100 100 100 40
100 70 60
9d
9e
100 100 100
60
30
10
30
10
50
9f
0
0
9g
Figure 4 shows the symptoms of larvae affected by the
title compounds and commercial RynaxypyrTM. Insects
treated with the title compound 9c showed abnormal
symptoms such as body contraction, vomiting, feeding
cessation, body thickening and shortening, which are
similar to the larvae treated with commercial Rynaxy-
pyrTM. These results suggest that the title compounds
exhibit their activity by activating insect RyR.
9h
100 100 100 100 100
100 100 100 100 100
0
0
9i
RynaxypyrTM
100 100
ring vs. benzene ring), respectively. The average bond
lengths and bond angles of the phenyl ring [20–24], the
pyrazole ring [25, 26], pyridine ring [27, 28] and the amide
bond [29–32] are normal.
For the compound 9a, 9b, 9c, 9d, 9h, 9i, further
bioassay was conducted against diamondback moth and
Laphygma exigua Hu¨bner. The results are summarized in
Table 2. At a dose of 25 lg ml-1, all these compounds
have good insecticidal activity against diamondback moth
and Laphygma exigua Hu¨bner, which can be compared
Insecticidal activities and structure–activity relationship
(SAR)
The insecticidal activities of these synthesized amides
containing N-pyridylpyrazole were determined in vivo. The
results are summarized in Table 1. All these meta-substi-
tuted diamines (5a–5c) did not display obvious insecticidal
activities against Lepidoptera insect [Oriental Armyworm
(Mythimna separata Walker)]. The death rates are 0 at
200 lgÁml-1 except compound 5c with 30 %. Compared
with compounds 5a–5c, the para-substituted diamines (9a–
9i) displayed better insecticidal activities against Oriental
Armyworm, and some structure–activity relationships for
R1 and R2 variation can be observed from the results. The
with that of the control RynaxypyrTM
.
In summary, a series of amides containing N-pyr-
idylpyrazole were synthesized and assessed for their
insecticidal activities. Several synthesized compounds
exhibited significant insecticidal activity against Oriental
Armyworm, and these compounds also show good insec-
ticidal activity against diamondback moth and Laphygma
exigua Hu¨bner. The SAR study reveals that substitutions
R1 and R2 in para-diamide analog containing N-pyr-
idylpyrazole are important for the insecticidal activity,
Fig. 4 Symptoms of fourth-instar larvae of Mythimna separata Walker treated by leaf dipping. (a) Untreated; (b) RynaxypyrTM at 10 lgÁml-1
,
36 h after application; (c) 9c at 10 lgÁml-1, 36 h after application
123

J IRAN CHEM SOC (2013) 10:429–437
437
5. A.L. Knight, L. Flexner, Pest Manag. Sci. 63, 180 (2007)
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Table 2 Insecticidal activities data of title compounds (mortality/%)
Compd.
Diamondback moth
lg ml-1/death rate (%) lg ml-1/death rate (%)
200 100 50 25 200 100 50 25
Laphygma exigua Hu¨bner
8. Q. Feng, Z.L. Liu, L.X. Xiong, M.Z. Wang, Y.Q. Li, Z.M. Li,
J. Agric. Food Chem. 58, 12327 (2010)
9. G.P. Lahm, D. Cordova, J.D. Barry, Bioorg. Med. Chem. 17,
4127 (2009)
9a
100 100 100 100 100 100 100 100
9b
100 100
98
92 100 100 100
96
97
91
–
10. G.P. Lahm, T.P. Selby, J.H. Freudenberger, T.M. Stevenson,
B.J. Myers, G. Seburyamo, B.K. Smith, L. Flexner, C.E.
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12. G.P. Lahm, T.M. Stevenson, T.P. Selby, J.H. Freudenberger,
D. Cordova, L. Flexner, C.A. Bellin, C.M. Dubas, B.K. Smith,
K.A. Hughes, J.G. Hollingshaus, C.E. Clark, E.A. Benner, Bio-
org. Med. Chem. Lett. 17, 6274 (2007)
9c
100 100 100 100 100 100 100
9d
100 100 100 100 100 100
a
100 100 100 100
95
–
9h
–
–
9i
100 100 100 100 100 100 100 100
100 100 100 100
RynaxypyrTM
–
–
–
–
a
Not tested
13. W.L. Dong, J.Y. Xu, X.H. Liu, Z.M. Li, B.J. Li, Y.X. Shi, Chem.
J. Chinese U. 29, 1990 (2008)
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18. Z.L. Zhou, S.M. Kher, S.X. Cai, E.R. Whittemore, S.A. Espitia,
J.E. Hawkinson, M. Tran, R.M. Woodward, E. Weberb, J.F.W.
Keana, Bioorg. Med. Chem. 11, 1769 (2003)
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20. H.J. Liu, J.Q. Weng, C.X. Tan, X.H. Liu, Acta Cryst. E67, o1940
(2011)
compound 9c, with the chlorine substitution at R1 and the
methyl substitution at R2, showed the most potence
insecticidal activity against Oriental Armyworm. It was
also revealed that not only ortho-diamide compounds
(anthranilic diamides) showed prominent insecticidal
activity but also para-diamide analog showed excellent
insecticidal activity, and exhibited their activity by acti-
vating insect RyR. The studies described herein provided a
powerful complement to the SARs of diamide insecticides,
and provided useful information for further investigation of
the mechanism of action.
21. X.H. Liu, L. Pan, C.X. Tan, J.Q. Weng, B.L. Wang, Z.M. Li,
Pestic. Biochem. Physiol. 101, 143 (2011)
22. X.H. Liu, L. Pan, J.Q. Weng, C.X. Tan, Li, Y.H., B.L. Wang,
Z.M. Li. Mol. Divers. 16, 251 (2012)
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).
23. C.X. Tan, J.Q. Weng, Z.X. Liu, X.H. Liu, W.G. Zhao, Phos-
phorus Sulfur Silicon Relat. Elem. 187, 990 (2011)
24. X.H. Liu, C.X. Tan, J.Q. Weng, H.J. Liu, Acta Cryst. E68, o493
(2012)
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