Synthesis, crystal structure and biological activity of a novel anthranilic diamide insecticide containing allyl ether

Article abstract of DOI:10.1007/s11164-012-0820-6

In search of environmentally benign insecticides with high activity, low toxicity and low residue, a series of novel anthranilic diamides containing allyl ether were designed and synthesized. All the compounds were characterized by ¹H NMR spectroscopy, HRMS or elemental analysis. The single crystal structure of 18e was determined by X-ray diffraction. The insecticidal activities of the new compounds were evaluated. The results showed that some compounds exhibited excellent insecticidal activities against Lepidoptera pests. Among this series compounds, 18l showed 100 % larvicidal activity against Mythimna separate Walker and Plutella xylostella Linnaeus at the test concentration.

Full text of DOI:10.1007/s11164-012-0820-6

Res Chem Intermed
DOI 10.1007/s11164-012-0820-6
Synthesis, crystal structure and biological activity
of a novel anthranilic diamide insecticide containing
allyl ether
•
Yu Zhao Li-xia Xiong Li-ping Xu
•
•
•
•
•
•
Hongxue Wang Han Xu Hua-bin Li Jun Tong
Zheng-ming Li
Received: 19 July 2012 / Accepted: 12 September 2012
Ó Springer Science+Business Media Dordrecht 2012
Abstract In search of environmentally benign insecticides with high activity, low
toxicity and low residue, a series of novel anthranilic diamides containing allyl ether
were designed and synthesized. All the compounds were characterized by 1H NMR
spectroscopy, HRMS or elemental analysis. The single crystal structure of 18e was
determined by X-ray diffraction. The insecticidal activities of the new compounds
were evaluated. The results showed that some compounds exhibited excellent
insecticidal activities against Lepidoptera pests. Among this series compounds, 18l
showed 100 % larvicidal activity against Mythimna separate Walker and Plutella
xylostella Linnaeus at the test concentration.
Keywords Anthranilic diamide Á Ryanodine receptor Á Synthesis Á
Insecticidal activity
Introduction
Resistance has often been a problem or a potential problem for insecticides and is
one of the most important reasons why insecticides with a new mode of action have
been desired [1]. The ryanodine receptor (RyR) derives its name from the plant
metabolite ryanodine (A), a natural insecticide from Ryania speciosa, known to
modify calcium channels [2–5]. As ryanodine is a potent natural insecticide, it has
been conjectured that RyRs would provide an excellent target for insect control. The
phthalic dimides [6–8] from Nihon Nohyaku, and the anthranilic diamides [9–12]
Y. Zhao Á L. Xiong Á L. Xu Á H. Wang Á H. Xu Á H. Li Á J. Tong Á Z. Li (&)
State Key Laboratory of Elemento-Organic Chemistry, National Pesticidal Engineering
Centre (Tianjin), Nankai University, Tianjin 300071, China
e-mail: nkzml@vip.163.com
Y. Zhao
e-mail: zhyzhaoyu@yahoo.com.cn
123

Y. Zhao et al.
from Dupont, are the first synthetic classes of potent activators of insect RyRs.
The recent commercial introduction of RyR insecticides flubendiamide (B) and
chlorantraniliprole (C), is significant in the field of crop protection, and particularly
important in light of the ability of insects to rapidly develop resistance and the need
for safe and effective pesticides that act at new biochemical targets [13, 14].
Owing to their prominent insecticidal activity, unique modes of action and good
environmental profiles, anthranilic diamides and their chemical synthesis have recently
attracted considerable attention in the field of novel agricultural insecticides. There are
many reports in the literature on the modification of the anthranilic diamides [15–18], with
the most modification related to a variation of the substitution pattern in part of the aliphatic
amide moiety. Although less research has been devoted to the modification of the
anthraniloyl skeleton, it has been reported that the biological activity of such compounds
can be affected by changing the anthraniloyl skeleton to a large extent [19]. In continuation
of our research on biologically active heterocycles [20], a series of novel anthranilic
diamides containing allyl ether were designed and synthesized, and their insecticidal
activities were tested. The results showed that some compounds exhibited moderate
insecticidal activities against Mythimna separate Walker and Plutella xylostella Linnaeus.
Experimental
Materials and methods
1H NMR spectra were obtained at 400 MHz using a Bruker AV400 spectrometer or
Varian Mercury Plus400 spectrometer in CDCl3 solution with tetramethylsilane as
the internal standard. Chemical shift values (d) were given in ppm. Elemental
analyses were determined on a Yanaco CHN Corder MT-3 elemental analyzer. The
melting points were determined on an X-4 binocular microscope melting point
apparatus (Beijing Tech Instruments, Beijing, China) and were uncorrected. All
solvents and liquid reagents were dried by standard methods and distilled before
use.
General procedures
Chlorantraniliprole was prepared according to the route shown in Scheme 1. The
title compounds 18 were synthesized from compound 17 and the appropriate
intermediate 14 (obtained from the intermediate 13 and corresponding amine; see
Table 1) in dry tetrahydrofuran using triethylamine as base as shown in Scheme 2.
Synthetic procedure for 2-amino-3-methyl-benzoic acid (4)
Compound 4 was prepared according to the literature [13]. Chloralhydrate (8.1 g,
55 mmol, 1.1 equiv) and Na2SO4 (71.0 g, 0.5 mol, 10 equiv) were dissolved in
water (200 mL) in a three-neck 500-mL round-bottom flask. The solution was
stirred with a mechanical stirrer and heated to 40 °C until the mixture became clear.
123

Synthesis, crystal structure and biological activity of allyl ether
H
NH2
OH
N
H2SO4
O
2
NaOH, H2O2
Cl3CCH(OH)2
NH2OH.HCl
O
N
N
OH
NH2
H
O
O
1
3
4
NH2
NH2
NCS
SOCl2
THF, CH3NH2
H
O
N
H
Cl
Cl
CH3
O
O
5
6
Br
N
O
H2N
N
Cl
NH
8
NH
N
EtOOC
Diethyl maleate
POBr3
N
9
N2H4
EtOOC
Cl
Cl
N
Cl
Cl
N
N
7
10
Br
N
Br
N
H
Br
N
N
O
Me
Cl
H
N
(COCl)2, CH2Cl2
6
N
HOOC
K2S2O8, H2SO4
N
EtOOC
NaOH
MeOH
N
Cl
Cl
O
Cl
N
N
Me
N
Chlorantraniliprole
11
12
Scheme 1 General synthetic route of the chlorantraniliprole
Table 1 Melting points and
yields of the compounds
14a–14n
Compd.
R1
R2
R3
m.p. (°C)
119–121
Yield (%)
14a
14b
14c
14d
14e
14f
CH3
CH3
CH3
CH3
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
n-propyl
n-butyl
88.0
77.9
68.1
89.2
79.3
58.0
61.9
66.4
56.9
70.2
70.2
80.0
71.4
63.8
87–88
i-butyl
117–122
167–168
120–122
161–162
143–145
108–110
179–181
88–90
Cyclohexyl
n-propyl
i-propyl
H
14g
14h
14i
H
Cyclopropyl
n-butyl
H
H
Cyclohexyl
n-propyl
i-propyl
14j
CH3
CH3
CH3
CH3
CH3
14k
14l
H
137–139
118–120
161–163
157–159
H
Cyclopropyl
i-propyl
14m
14n
Br
Br
Cyclopropyl
A warm solution of the commercial o-toluidine 1 (5.4 g, 50 mmol) in water
(50 mL) and an aqueous solution of concentrated HCl (5.32 g, 4.5 mL, 52.5 mmol,
1.05 equiv.) was added, followed by a warm solution of hydroxylamine hydro-
chloride (10.4 g, 0.15 mol, 3.0 equiv.) in water (45 mL). The mixture was heated to
reflux under vigorous stirring, allowed to reflux for 10 min, and then cooled to room
123

Y. Zhao et al.
R1
R1
NH2
O
NH2
R3-NH2, SOCl2
ref.
H
H
N
R2
R2
R3
O
O
14 a-14 n
13
O
O
N
O
NH
NH
EtOOC
N
EtOOC
N
N
9
EtOOC
Cl
NaOH
K2S2O8
H2SO4
Cl
Br
Cl
N
N
N
16
15
O
H
O
N
O
R3
R2
H
N
14
N
N
N
HOOC
N
Cl
18 a-18 n
O
Cl
N
R1
N
17
Scheme 2 General synthetic route of the title compounds 18a–18n
temperature. The product precipitated out of solution, and after standing overnight,
the solid was collected and dried to obtain 2-hydroxyimino-N-o-tolyl-acetamide.
Sulfuric acid (60 mL) was heated in a three-neck 250-mL round-bottom flask to
60 °C and then removed. The dry 2-hydroxyimino-N-o-tolyl-acetamide (2) was added
in portions with stirring over 30 min so that the temperature did not exceed 70 °C. The
mixture was then heated to 80 °C for 20 min, then allowed to cool to room temperature.
The reaction mixture was poured over crushed ice (100 g) and left to stand for 1 h,
yielding a crude precipitate that was collected by suction filtration. The product was
washed with water (2 9 50 mL) and filtered to give crude 7-methyl-1H-indole-2,3-
dione, which was directly used for the next step without further purification.
To a stirred suspension of compound 3 in a 5 % aqueous sodium hydroxide solution
(150 mL) (this mixture was cooled to 0 °C) was added dropwise a 30 % aqueous
hydrogen peroxide solution (150 mL). The reaction mixture was stirred at 50 °C for
30 min and then allowed to reach room temperature. The filtered solution was acidified
to pH 4 with an aqueous 1 N hydrochloric acid solution, and a tan precipitate was
collected by filtration, washed thoroughly with cold water, and dried under vacuum to
afford 2-amino-3-methyl-benzoic acid (4). The overall yield of compound 4 was
25.6 %, m.p. 173–174 °C. 1H NMR (DMSO-d6, 400 MHz), d: 7.61 (d, J = 8.0 Hz, 1H,
Ph-H), 7.15 (d, J = 7.0 Hz, 1H, Ph-H), 6.50 (m, 1H, Ph-H), 2.09 (s, 3H, CH3).
Synthetic procedure for 2-amino-5-chloro-3-methyl-benzoic acid (5)
2-amino-5-chloro-3-methylbenzoic acid (5) was prepared according to the literature
[14]. To a solution of 2-amino-3-methylbenzoic acid (10 g, 66 mmol) in DMF
(40 mL) was added N-chlorosuccinimide (8.8 g, 66 mmol) and the reaction mixture
123

Synthesis, crystal structure and biological activity of allyl ether
was heated to 100 °C for 40 min. The reaction was cooled to room temperature and
let stand overnight. The reaction mixture was then slowly poured into ice-water
(150 mL) to precipitate a white solid. The solid was filtered and washed with water
(3 9 50 mL) and then taken up in ethyl acetate (600 mL). The ethyl acetate solution
was dried over magnesium sulfate, evaporated under reduced pressure and the
residual solid was washed with ether (3 9 30 mL) to afford intermediate 2-amino-
5-chloro-3-methylbenzoic acid (5): white solid, m.p. 196–197 °C (dec.) yield
76.0 %; 1H NMR (DMSO-d6, 400 MHz), d: 7.53 (s, 1H, Ph-H), 7.21 (s, 1H, Ph-H),
2.09 (s, 3H, CH3).
Synthesis of intermediates 2-amino-5-chloro-3,N-dimethyl-benzamide (6)
2-Amino-5-chloro-3,N-dimethyl-benzamide (6) was prepared according to the liter-
ature [15]. Into a 100-mL round-bottomed flask was placed 2-amino-5-chloro-3-
methylbenzoic acid (5) (3.7 g, 20 mmol) and then 50 mL of thionyl chloride was
added. The resulting mixture was refluxed for 3 h. The mixture was evaporated in
vacuo to dryness and then 60 mL of THF was added. To this solution was added
dropwise a solution 50 g of 25 % aqueous methylamine solution under an ice bath.
The resulting solution was allowed to stand at room temperature for 12 h and then
water (200 mL) was added. The yellow precipitate was collected by filtration and
1
dried to give 2.36 g (59.3 %) of compound 6, m.p. 130–132 °C. HNMR (CDCl3,
400 MHz) d: 7.16 (d, J = 2.2 Hz, 1H, Ph-H), 7.09 (d, J = 1.6 Hz, 1H, Ph-H), 6.01
(br, 1H, NH), 5.52 (br, 2H, NH2), 2.95 (d, J = 4.8 Hz, 3H, NHCH3), 2.13 (s, 3H,
CH3).
Synthetic procedure for (3-chloro-pyridin-2-yl)-hydrazine (8)
To a suspension of 2,3-dichloropyridine 7 (100.0 g, 0.676 mol) in anhydrous
ethanol (420 mL) was added 50 % hydrazine hydrate (280 mL, 2.884 mol). The
resulting mixture was refluxed for 36 h, and then cooled to room temperature. The
product precipitated out of solution, the white crystal was collected by filtration,
washed thoroughly with cold ethanol and dried to give white crystals (74.4 g,
1
76.8 %), m.p. 163–164 °C. H NMR (CDCl3, 300 MHz) d: 8.09 (d, J = 3.9 Hz,
1H, pyridyl-H); 7.47 (d, J = 8.1 Hz, 1H, pyridyl-H); 6.64 (dd, J1 = 3.9 Hz,
J2 = 8.1 Hz, 1H, pyridyl-H); 6.21 (s, 1H, NH); 3.97 (br. s, 2H, NH2).
Synthetic procedure for 2-(3-chloro-pyridin-2-yl)-5-oxo-pyrazolidine-3-
carboxylic acid ethyl ester (9)
To 200 mL of absolute ethanol in a 500-mL three-necked round-bottomed flask was
added 6.9 g (0.3 mol) of sodium cut in pieces of suitable size. When all the sodium
has reacted, the mixture was heated to reflux and (3-chloro-pyridin-2-yl)-hydrazine
(8) (39.82 g, 0.277 mol) was added. The mixture was refluxed for 10 min, then
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
123

Y. Zhao et al.
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 was stirred thoroughly. The solid was collected by filtration,
washed with aqueous ethanol (50 %, 3 9 50 mL) to give 2-(3-chloro-pyridin-
2-yl)-5-oxo-pyrazolidine-3-carboxylic acid ethyl ester (9) (36.6 g, 49.0 %), m.p.
132–134 °C. 1H NMR (DMSO-d6, 400 MHz) d: 10.18 (s, 1H, NH); 8.25 (d,
J = 4.8 Hz, 1H, pyridyl-H); 7.91 (d, J = 7.4 Hz, 1H, pyridyl-H); 7.18 (dd,
J1 = 4.8 Hz, J2 = 7.4 Hz, 1H, pyridyl-H); 4.81 (d, J = 9.8 Hz, 1H, CH); 4.17 (q,
J = 7.0 Hz, 2H, OCH2); 2.89 (dd, J1 = 9.8 Hz, J2 = 16.8 Hz, 1H, CH2–H); 2.34
(d, J = 16.8 Hz, 1H, CH2–H); 1.20 (t, J = 7.0 Hz, 3H, CH3).
5-Bromo-2-(3-chloro-pyridin-2-yl)-3,4-dihydro-2H-pyrazole-3-carboxylic acid
ethyl ester (10)
To a solution of 2-(3-chloro-pyridin-2-yl)-5-oxo-pyrazolidine-3-carboxylic acid
ethyl ester (9) (27 g, 0.1 mol) in acetonitrile (300 mL) was added phosphorous
oxybromide (34.4 g, 0.12 mmol). The reaction mixture was refluxed for 5 h, then
250 mL of solvent was removed by distillation. The concentrated reaction mixture
was slowly poured into saturated aq. Na2CO3 (250 mL) and was stirred vigorously
for 30 min. The resulting mixture was extracted with CH2Cl2 (2 9 250 mL), the
organic extract was separated, dried, filtered, concentrated and purified by silica gel
chromatography to afford 5-bromo-2-(3-chloro-pyridin-2-yl)-3,4-dihydro-2H-pyra-
1
zole-3-carboxylic acid ethyl ester (10) (31.0 g, 93.0 %), m.p. 59–60 °C. H NMR
(DMSO-d6, 400 MHz) d: 8.10 (d, J = 4.4 Hz, 1H, pyridyl-H); 7.83 (d, J = 7.7 Hz,
1H, pyridyl-H); 6.98 (dd, J1 = 4.4 Hz, J2 = 7.7 Hz, 1H, pyridyl-H); 5.17 (dd,
J1 = 8.7 Hz, J2 = 11.8 Hz, 1H, CH); 4.08 (q, J = 7.0 Hz, 2H, OCH2); 3.27 (dd,
J1 = 8.7 Hz, J2 = 17.6 Hz, 1H, CH2–H); 3.57 (dd, J1 = 11.8 Hz, J2 = 17.6 Hz,
1H, CH2–H); 1.12 (t, J = 7.0 Hz, 3H, CH3).
Synthetic procedure for 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-
carboxylic acid ethyl ester (11)
To a solution of 5-bromo-2-(3-chloro-pyridin-2-yl)-3,4-dihydro-2H-pyrazole-3-car-
boxylic acid ethyl ester (10) (17 g, 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 was refluxed for
4.5 h. After being cooled to 60 °C, the mixture was filtered to remove a fine filter
cake which was washed with acetonitrile (30 mL). The filtrate was concentrated to
100 mL, then was added slowly to water (250 mL) under stirring. The solid was
collected by filtration, washed with acetonitrile (3 9 30 mL), water (30 mL), and
then dried to give 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid
ethyl ester (11) (15.6 g, 92.7 %), m.p. 117–118 °C. 1H NMR (CDCl3, 300 M) d: 8.52
(d, J = 4.8 Hz, 1H, pyridyl-H); 7.92 (d, J = 8.1 Hz, 1H, pyridyl-H); 7.45 (dd,
J1 = 4.8 Hz, J2 = 8.1 Hz, 1H, pyridyl-H); 6.95 (s, 1H, pyrazolyl-H); 4.24 (q,
J = 7.2 Hz, 2H, CH2); 1.21 (t, J = 7.2 Hz, 3H, CH3).
123

Synthesis, crystal structure and biological activity of allyl ether
Synthetic procedure for 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-
carboxylic acid (12)
To a mixture of the ethyl 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-car-
boxylic acid ethyl ester (11) (15.6 g, 47.2 mmol) in methanol (120 mL) was added
aqueous sodium hydroxide solution (60 mL, 1 mol L-1). The solution was stirred at
room temperature for 6 h, then was concentrated in vacuo to about 50 mL. The
concentrated mixture was diluted with H2O (150 mL), and washed with ethyl
acetate (150 mL). The aqueous solution was acidified using concentrated hydro-
chloric acid to pH = 2. The solid was collected by filtration, washed with ether
(30 mL), and then dried to give 5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-
carboxylic acid (12) (12.75 g, 89.3 %), m.p. 197–200 °C. 1H NMR (CDCl3, 300 M)
d: 8.52 (dd, J1 = 1.5 Hz, J2 = 4.8 Hz, 1H, pyridyl-H); 7.94 (dd, J1 = 1.5 Hz,
J2 = 8.1 Hz, 1H, pyridyl-H); 7.48 (dd, 1H, J = 4.8, 8.1 Hz, pyridyl-H); 7.10 (s, 1H,
pyrazolyl-H).
Synthetic procedure for chlorantraniliprole
Chlorantraniliprole was prepared according to the literature [16, 17]. To a suspension
of N-pyridylpyrazole acid 12 (0.30 g, 1 mmol) in dichloromethane (20 mL) was
added oxalyl chloride (0.38 g, 3 mmol), followed by dimethylformamide (2 drops).
The solution was stirred at room temperature. After 6 h, the mixture was concentrated
in vacuo to obtain the crude acid chloride. The crude acid chloride in dichloromethane
(20 mL) was added slowly to a stirred solution of 2-amino-5-chloro-3,N-dimethyl-
benzamide (6) (0.24 g, 1.2 mmol) in dichloromethane (20 mL) in an ice bath. After
20 min, ethyl-diisopropyl-amine (0.13 g, 1 mmol) was added dropwise. The solution
was warmed to room temperature and stirred for 12 h. The solution was diluted with
CH2Cl2 (20 mL), and washed with 1 N aq. HCl solution (10 mL), saturated aq.
NaHCO3 (10 mL), and brine (10 mL). The organic extract was separated, dried,
filtered, and concentrated and purified by silica gel chromatography to afford the
chlorantraniliprole. (0.43 g, 89.3 %), m.p. 197–200 °C. 1H NMR (CDCl3, 400 M) d:
10.10 (br. s, 1H, NH); 8.46 (dd, J1 = 1.6 Hz, J2 = 4.8 Hz, 1H, pyridyl-H); 7.85 (dd,
J1 = 1.6 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 7.38 (dd, J1 = 4.8 Hz, J2 = 8.0 Hz, 1H,
pyridyl-H); 7.24 (d, J = 2.0 Hz, 1H, Ph-H); 7.21 (d, J = 2.0 Hz, 1H,Ph-H); 7.11 (s,
1H, pyrazolyl-H); 6.15–6.18 (m, 1H, NHCO); 2.95 (d, J = 4.9 Hz, 2H, NHCH3);
2.17 (s, 3H, CH3).
Synthetic procedure for 2-amino-5-chloro-3-methyl-N-propyl-benzamide (14a)
Compound 13 was synthesized according to the same method of compound 5. To a
100-mL round-bottomed flask was placed 2-amino-5-chloro-3-methylbenzoic acid
(5) (5.0 g, 27 mmol) and then 50 mL of thionyl chloride was added. The resulting
mixture was refluxed for 3 h. The mixture was evaporated in vacuo to dryness and
then 40 mL of THF was added. The solution was added slowly to a stirred solution
of propylamine (15.8 g, 270 mmol) in tetrahydrofuran (40 mL) in an ice bath. The
resulting solution was allowed to stir at room temperature for 12 h. Then, the
123

Y. Zhao et al.
solution was concentrated in vacuo and diluted with ethyl acetate (150 mL), and
washed with water (3 9 50 mL). The organic extract was separated, dried, filtered,
and concentrated and purified by silica gel chromatography to afford the desired
title compound 14a.
Compounds 14b–14n were prepared by similar method above using the
appropriate substrates. The melting points and yields of compounds 14a–14n are
1
listed in Table 1. The H NMR data are listed in Table 2.
Synthetic procedure for 2-(3-chloro-pyridin-2-yl)-5-oxo-2,5-dihydro-1H-
pyrazole-3- carboxylic acid ethyl ester (15)
To a solution of 2-(3-chloro-pyridin-2-yl)-5-oxo-pyrazolidine-3-carboxylic acid
ethyl ester (9) (10 g, 37 mmol) in acetonitrile (150 mL) was added sulfuric acid
(98 %, 7.2 g, 74 mmol). After being stirred for several minutes, the reaction
mixture was treated with K2S2O8 (15 g, 56 mmol) and was refluxed for 4.5 h. After
being cooled to 60 °C, the mixture was filtered to remove a fine filter cake which
was washed with acetonitrile (30 mL). The filtrate was concentrated and poured into
ice water (200 mL). The aqueous layer was extracted with dichloromethane (3
9 150 mL). The organic layer was washed with water (3 9 100 mL) and dried over
anhydrous sodium sulfate. Then, the ethyl acetate was concentrated. The residue
was purified by column chromatography over silica gel using petroleum ether
(60–90 °C) and ethyl acetate as the eluent to afford the 2-(3-chloro-pyridin-2-yl)-5-
oxo-2,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (15). (6.2 g, 62.4 %),
m.p. 136–138 °C. 1H NMR (CDCl3, 400 M) d: 9.35 (s, 1H, NH); 8.52 (d,
J = 4.4 Hz, 1H, pyridyl-H); 7.90 (d, J = 8.0 Hz, 1H, pyridyl-H); 7.43 (dd,
J1 = 4.4 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 6.36 (s, 1H, pyrazolyl-H); 4.19 (q, 2H,
J = 7.2 Hz, CH2); 1.19 (t, 3H, J = 7.2 Hz, CH3).
Synthetic procedure for ethyl 3-(allyloxy)-1-(3-chloropyridin-2-yl)-1H-
pyrazole-5-carboxylate (16)
The ester 16 was prepared according to the literature [7]. Compound 15 (2.0 g,
7.5 mmol) was dissolved in 30 mL of dry dimethylformamide, and potassium
carbonate (1.52 g, 11.0 mmol) was added. The mixture was heated to 40 °C. The
allyl bromide (1.08 g, 9 mmol) in dry dimethylformamide (5 mL) was added slowly
to the mixture. The solution was warmed at 100 °C and stirred for 3 h and poured
into ice water (50 mL). The aqueous layer was extracted with ethyl acetate
(3 9 40 mL). The organic layer was washed with water (3 9 40 mL) and dried
over anhydrous sodium sulfate. Then, the ethyl acetate was concentrated. The
residue was purified by column chromatography on a silica gel using petroleum
ether (60–90 °C) and ethyl acetate as the eluent to afford the ethyl 3-(allyloxy)-1-(3-
chloropyridin-2-yl)-1H-pyrazole-5-carboxylate (16). (2.11 g, 91 %), 1H NMR
(CDCl3, 400 M) d: 8.51 (dd, J1 = 1.6 Hz, J2 = 4.7 Hz, 1H, pyridyl-H); 7.90 (dd,
J1 = 1.6 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 7.41 (dd, 1H, J1 = 4.7 Hz, J2 = 8.0 Hz,
1H, pyridyl-H); 6.48 (s, 1H, pyrazolyl-H); 6.05–6.12 (m, 1H, CH=); 5.33–5.38 (m,
123

Synthesis, crystal structure and biological activity of allyl ether
Table 2 1H NMR of the compounds 14a–14n
Compd. 1H NMR d (ppm)
14a
(400 MHz, DMSO-d6), d: 8.37 (br, 1H, CONH); 7.41 (d, J = 1.8 Hz, 1H, Ph-H); 7.13 (d,
J = 1.8 Hz, 1H, Ph-H); 6.32 (s, 2H, PhNH2); 3.14–3.17 (m, 2H, NHCH2); 2.08 (s, 3H,
PhCH3); 1.50–1.52 (m, 2H, CH2CH3); 0.88 (t, J = 7.4 Hz, 3H, CH2CH3)
14b
(400 MHz, DMSO-d6), d: 8.34 (br, 1H, CONH); 7.41 (d, J = 1.8 Hz, 1H, Ph-H); 7.12 (d,
J = 1.8 Hz, 1H, Ph-H); 6.32 (s, 2H, PhNH2); 3.19–3.22 (m, 2H, NHCH2); 2.08 (s, 3H,
PhCH3); 1.45–1.52 (m, 2H, CH2); 1.29–1.36 (m, 2H, CH2CH3); 0.89 (t, J = 7.3 Hz, 3H,
CH2CH3)
14c
(400 MHz, DMSO-d6), d: 8.38 (br, 1H, CONH); 7.42 (d, J = 2.0 Hz, 1H, Ph-H); 7.14 (d,
J = 2.0 Hz, 1H, Ph-H); 6.29 (s, 2H, PhNH2); 3.01–3.03 (m, 2H, NHCH2); 2.08 (s, 3H,
PhCH3); 1.77–1.88 (m, 1H, CH(CH3)2); 0.88 (d, J = 6.6 Hz, 6H, CH(CH3)2)
14d
14e
(400 MHz, CDCl3), d: 7.05–7.14 (m, 2H, Ph-H); 5.81 (br, 1H, NH); 5.46 (br, 2H, NH2);
3.82–3.94 (m, 1H, cyclohexyl-H); 2.13 (s, 3H, CH3); 1.18–2.04 (m, 10H, cyclohexyl-H)
(400 MHz, DMSO-d6), d: 8.34–8.36 (m, 1H, CONH); 7.53 (d, J = 2.4 Hz, 1H, Ph-H); 7.15
(dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H, Ph-H); 6.70 (d, J = 8.7 Hz, 1H, Ph-H); 6.54 (s, 2H,
PhNH2); 3.13–3.16 (m, 2H, NHCH2); 1.46–1.53 (m, 2H, CH2CH3); 0.87 (t, J = 7.2 Hz, 3H,
CH2CH3)
14f
(400 MHz, DMSO-d6), d: 8.11–8.13 (m, 1H, CONH); 7.54 (d, J = 2.4 Hz, 1H, Ph-H); 7.15
(dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H, Ph-H); 6.70 (d, J = 8.8 Hz, 1H, Ph-H); 6.50 (s, 2H,
PhNH2); 4.01–4.09 (m, 1H, CH); 1.14 (d, J = 6.6 Hz, 6H, CH(CH3)2)
14g
(400 MHz, DMSO-d6), d: 8.35–8.37 (m,1H, CONH); 7.53 (d, J = 2.4 Hz, 1H, Ph-H); 7.20
(dd, J1 = 8.8 Hz, J2 = 4.8 Hz, 1H, Ph-H); 6.76 (d, J = 8.8 Hz, 1H, Ph-H); 6.61 (s, 2H,
PhNH2); 2.82–2.88 (m, 1H, cyclopropyl-H); 0.69–0.74 (m,2H, cyclopropyl-H); 0.58–0.62
(m, 2H, cyclopropyl-H)
14h
(400 MHz, DMSO-d6), d: 8.30–8.32 (m, 1H, CONH); 7.51 (d, J = 2.0 Hz, 1H, Ph-H); 7.15
(dd, J1 = 8.7 Hz, J2 = 2.0 Hz, 1H, Ph-H); 6.70 (d, J = 8.7 Hz, 1H, Ph-H); 6.53 (s, 2H,
PhNH2); 3.17–3.19 (m, 2H, NHCH2); 1.42–1.51 (m, 2H, CH2CH2); 1.26–1.35 (m, 2H,
CH2CH3); 0.89 (t, J = 7.2 Hz, 3H, CH2CH3)
14i
14j
(400 MHz, DMSO-d6), d: 8.10–8.12 (m, 1H, CONH); 7.52 (d, J = 2.0 Hz, 1H, Ph-H); 7.14
(dd, J1 = 8.7 Hz, J2 = 2.0 Hz, 1H, Ph-H); 6.69 (d, J = 8.7 Hz, 1H, Ph-H); 6.47 (s, 2H,
PhNH2); 3.67–3.70 (m, 1H, NHCH); 1.08–1.79 (m, 10H, cyclohexyl-H)
(400 MHz, DMSO-d6), d: 8.20–8.22 (m, 1H, CONH); 7.35 (d, J = 7.6 Hz, 1H, Ph-H); 7.06 (d,
J = 7.2 Hz, 1H, Ph-H); 6.45–6.49 (m,1H, Ph-H); 6.18 (s, 2H, PhNH2); 3.14–3.19 (m, 2H,
NHCH2); 2.07 (s, 3H, PhCH3); 1.46–1.55 (m, 2H, CH2CH3); 0.88 (t, J = 7.4 Hz, 3H,
CH2CH3)
14k
14l
(400 MHz, DMSO-d6), d: 8.19–8.21 (m, 1H, CONH); 7.33 (d, J = 7.6 Hz, 1H, Ph-H); 7.05 (d,
J = 7.0 Hz, 1H, Ph-H); 6.46–6.49 (m,1H, Ph-H); 6.11 (s, 2H, PhNH2); 4.22–4.30 (m, 1H,
CH); 2.18 (s, 3H, CH3); 1.25 (m, 6H, J = 6.6 Hz, CH(CH3)2)
(400 MHz, DMSO-d6), d: 8.18 (s, 1H, CONH); 7.30 (d, J = 7.6 Hz, 1H, Ph-H); 7.05 (d,
J = 6.8 Hz, 1H, Ph-H); 6.43–6.47 (m, 1H, Ph-H); 6.21 (s, 2H, PhNH2); 2.78–2.80 (m, 1H,
cyclopropyl-H); 2.07 (s,3H, PhCH3); 0.65–0.67 (m, 2H, CH2CH2, cyclopropyl-H); 0.53–0.55
(m, 2H, CH2CH2, cyclopropyl-H)
14m
14n
(400 MHz, CDCl3), d: 7.24-7.31 (m, 1H, Ar–H); 7.24-7.25 (m, 1H, Ar–H);5.87 (br, 1H, NH);
4.20-4.26 (m, 1H, CH); 2.19 (s, 3H, CH3); 1.26 (d, 6H, J = 6.4 Hz, CH3)
(400 MHz, CDCl3), d: 7.08–7.12 (m, 2H, Ph-H); 6.03 (br, 1H, NH); 5.43–5.64 (br, 2H, NH2);
2.68–2.72 (m, 1H, cyclopropyl-H); 2.02 (s, 3H, CH3); 0.71–0.76 (m, 2H, cyclopropyl-H);
0.46–0.50 (m, 2H, cyclopropyl-H)
123

Y. Zhao et al.
2H, =CH2); 4.78 (d, JHH = 5.5 Hz, 2H, CH2CH=); 4.22 (q, J = 7.2 Hz, 2H,
CH2CH3); 1.22 (t, J = 7.2 Hz, 3H, CH2CH3).
Synthetic procedure for 3-(allyloxy)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-
carboxylic acid (17)
To a mixture of the compound 16 (2.11 g, 7.5 mmol) in methanol (20 mL) was
added aqueous sodium hydroxide solution (10 mL, 1 mol L-1). The solution was
stirred at room temperature for 6 h, then was concentrated in vacuo to about 5 mL.
The concentrated mixture was diluted with H2O (40 mL), and washed with ethyl
acetate (20 mL). The aqueous solution was acidified using concentrated hydro-
chloric acid to pH = 2. The solid was collected by filtration, washed with ether
(10 mL), and then dried to give 3-(allyloxy)-1-(3-chloropyridin-2-yl)-1H-pyrazole-
1
5-carboxylic acid (17) (1.69 g, 73.3 %), m.p. 138–140 °C. H NMR (DMSO-d6,
400 M) d: 8.50 (dd, J1 = 1.5 Hz, J2 = 4.7 Hz, 1H, pyridyl-H); 7.90 (dd,
J1 = 1.5 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 7.40 (dd, J1 = 4.7 Hz, J2 = 8.0 Hz,
1H, pyridyl-H); 6.52 (s, 1H, pyrazolyl-H); 6.05–6.12 (m, 1H, CH=); 5.33–5.38 (m,
2H, =CH2); 4.76 (d, JHH = 5.6 Hz, 2H, CH2CH=).
Synthetic procedure for the title compounds 18a–18n
To a suspension of N-pyridylpyrazole acid 17 (1 mmol) in dichloromethane (20 mL)
was added oxalyl chloride (3 mmol) and dimethylformamide (2 drops). The solution
was stirred at ambient temperature for 4 h. Then, the mixture was concentrated in
vacuo to give the crude acid chloride. The crude acid chloride in tetrahydrofuran
(25 mL) was added slowly to a stirred solution of 14 (1.2 mmol) and triethylamine
(1.2 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at ambient
temperature for 8 h. Then, the solution was concentrated in vacuo and diluted with
CH2Cl2 (60 mL), and washed with 1 N aq. HCl solution (15 mL), saturated aq.
NaHCO3 (15 mL), and brine (15 mL). The organic extract was separated, dried,
filtered, and concentrated and purified by silica gel chromatography to afford the
desired title compound 18a–18n.
3-(allyloxy)-N-(4-chloro-2-methyl-6-(propylcarbamoyl)phenyl)-1-(3-chloropyri-
din-2-yl)-1H-pyrazole-5-carboxamide (18a): White crystal, yield, 58.3 %; m.p.
1
209–211 °C; H NMR (CDCl3, 400 M) d: 9.78 (s, 1H, CONH); 8.35–8.38 (m, 1H,
pyridyl-H); 7.73 (d, J = 7.8 Hz, 1H, pyridyl-H); 7.23 (dd, J1 = 4.0 Hz,
J2 = 7.8 Hz, 1H, pyridyl-H); 7.18 (s, 1H, Ph-H); 7.14 (s, 1H, Ph-H); 6.42 (s, 1H,
pyrazolyl-H); 6.01–6.04 (m, 1H, NHCH2); 5.94–5.99 (m, 1H, CH=); 5.19–5.35 (m,
2H, =CH2); 4.73 (d, JHH = 5.6 Hz, 2H, CH2CH=); 3.24–3.27 (m, 2H, CH2NH);
2.12(s, 3H, PhCH3); 1.51–1.54 (m, 2H, CH2CH3); 0.88 (t, J = 6.9 Hz, 3H,
CH2CH3); Anal. Calcd. for C23H23Cl2N5O3 (%): C, 56.57; H, 4.75; N, 14.34.
Found: C, 56.68; H, 4.78; N, 14.13.
3-(allyloxy)-N-(2-(butylcarbamoyl)-4-chloro-6-methylphenyl)-1-(3-chloropyridin-
2-yl)-1H-pyrazole-5-carboxamide (18b): White crystal, yield, 52.2 %; m.p.
1
183–185 °C; H NMR (CDCl3, 400 M) d: 9.81(s, 1H, CONH); 8.35–8.38 (m, 1H,
pyridyl-H); 7.73 (d, J = 7.5 Hz, 1H, pyridyl-H); 7.22–7.24 (m, 1H, pyridyl-H); 7.14
123

Synthesis, crystal structure and biological activity of allyl ether
(s, 1H, Ph-H); 7.10 (s, 1H, Ph-H); 6.46 (s, 1H, pyrazolyl-H); 6.07–6.12 (m, 1H,
NHCH2); 5.97–6.02 (m, 1H, CH=); 5.19–5.36 (m, 2H, =CH2); 4.72 (s, 2H,
CH2CH=); 3.25–3.28 (m, 2H, NHCH2); 2.10 (s, 3H, PhCH3); 1.42–1.45 (m, 2H,
CH2CH2); 1.26–1.28 (m, 2H, CH2CH2); 0.85 (t, J = 7.0 Hz, 3H, CH2CH3); The
value of HRMS [M?Na]? for C24H25Cl2N5O3:524.1227. Found: 524.1224
3-(allyloxy)-N-(4-chloro-2-(isobutylcarbamoyl)-6-methylphenyl)-1-(3-chloropyridin-
2-yl)-1H-pyrazole-5-carboxamide (18c): White crystal, yield, 58.2 %; m.p.
1
233–234 °C; H NMR (CDCl3, 400 M) d: 9.77 (s, 1H, CONH); 8.35–8.38 (m, 1H,
pyridyl-H); 7.74 (d, J = 7.5 Hz, 1H, pyridyl-H); 7.22–7.26 (m, 1H, pyridyl-H); 7.18 (s,
1H, Ph-H); 7.13 (d, 1H, Ph-H); 6.42 (s, 1H, pyrazolyl-H); 6.04–6.08 (m, 1H, NHCH2);
5.97–6.02 (m, 1H, CH=); 5.20–5.38 (m, 2H, =CH2); 4.73 (s, 2H, CH2CH=); 3.10–3.13
(m, 2H, NHCH2); 2.12 (s, 3H, PhCH3); 1.73–1.76 (m, 1H, CHCH2); 0.86 (d,
J = 6.2 Hz, 6H, (CH3)2); Anal. Calcd. for C24H25Cl2N5O3 (%): C, 57.38; H, 5.02; N,
13.94. Found: C, 57.46; H, 4.84; N, 13.85.
3-(allyloxy)-N-(4-chloro-2-(cyclohexylcarbamoyl)-6-methylphenyl)-1-(3-chlo-
ropyridin-2-yl)-1H-pyrazole-5-carboxamide (18d): White crystal, yield, 55.0 %;
1
m.p. 142–144 °C; H NMR (CDCl3, 400 M) d: 9.83 (s, 1H, CONH); 8.39 (d,
J = 4.7 Hz, 1H, pyridyl-H); 7.78 (d, J = 8.0 Hz, 1H, pyridyl-H); 7.28 (dd,
J1 = 4.7 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 7.18 (s, 1H, Ph-H); 7.13 (s, 1H, Ph-
H); 6.41 (s, 1H, pyrazolyl-H); 5.97–6.01 (m, 1H, NHCH); 5.86–5.93 (m, 1H,
CH=); 5.18–5.37 (m, 2H, =CH2); 4.71 (d, JHH = 5.6 Hz, 2H, CH2CH=);
3.68–3.71 (m, 1H, NHCH); 2.13 (s, 3H, PhCH3); 1.95–1.98 (m, 2H, CH2);
1.84–1.86 (m, 2H, CH2); 1.47–1.49 (m, 2H, CH2); 1.22–1.24 (m, 2H, CH2);
1.01–1.03 (m, 2H, CH2); The value of HRMS [M?Na]? for C26H27Cl2N5O3:
550.1383. Found: 550.1383.
3-(allyloxy)-N-(4-chloro-2-(propylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-1H-
pyrazole-5-carboxamide (18e): colourless oil, yield,61.7 %; 1H NMR (CDCl3,
400 M) d: 12.02 (s, 1H, CONH); 8.42 (dd, J1 = 1.5 Hz, J2 = 4.7 Hz, 1H, pyridyl-
H); 8.37–7.40 (m, 1H, Ph-H); 7.81 (dd, J1 = 1.5 Hz, J2 = 8.0 Hz, 1H, pyridyl-H);
7.26–7.36 (m, 3H, pyridyl-H, Ph-H); 6.45 (s, 1H, pyrazolyl-H); 6.15–6.18 (m, 1H,
NH); 6.00–6.09 (m, 1H, CH=); 5.20–5.35 (m, 2H, =CH2); 4.73 (d, JHH = 5.5 Hz, 2H,
CH2CH=); 3.33–3.36 (m, 2H, NHCH2); 1.59–1.61 (m, 2H, CH2CH2); 0.96 (t,
J = 7.4 Hz, 3H, CH2CH3); The value of HRMS [M?Na]? for C22H21Cl2N5O3:
496.0914. Found: 496.0917.
3-(allyloxy)-N-(4-chloro-2-(isopropylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-
1H-pyrazole-5-carboxamide (18f): White crystal, yield, 53.6 %; m.p. 188–190 °C; 1H
NMR (CDCl3, 400 M) d: 12.15 (s, 1H, CONH); 8.52 (dd, J1 = 1.5 Hz, J2 = 4.7 Hz,
1H, pyridyl-H); 8.46 (d, J = 9.0 Hz, 1H, Ph-H); 7.93 (dd, J1 = 1.5 Hz, J2 = 8.0 Hz,
1H, pyridyl-H); 7.33–7.45 (m, 3H, pyridyl-H, Ph-H); 6.53 (s, 1H, pyrazolyl-H);
6.10–6.13 (m, 1H, NH); 6.04–6.11 (m, 1H, CH=); 5.24–5.42 (m, 2H, =CH2); 4.80 (d,
JHH = 5.6 Hz, 2H, CH2CH=); 4.27–4.30 (m, 1H, NHCH); 1.31 (d, J = 6.6 Hz, 6H,
(CH3)2); Anal. Calcd. for C22H21Cl2N5O3 (%): C, 55.71; H, 4.46; N, 14.76. Found: C,
55.64; H, 4.55; N, 14.68.
3-(allyloxy)-N-(4-chloro-2-(cyclopropylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-
1H-pyrazole-5-carboxamide (18g): White crystal, yield, 47.9 %; m.p. 195–196 °C; 1H
NMR (CDCl3, 400 M) d: 12.05 (s, 1H, CONH); 8.42 (dd, J1 = 1.2 Hz, J2 = 4.7 Hz,
123

Y. Zhao et al.
1H, pyridyl-H); 8.38 (d, J = 9.0 Hz, 1H, Ph-H); 7.80 (dd, J1 = 1.2 Hz, J2 = 8.0 Hz,
1H, pyridyl-H); 7.24–7.34 (m, 3H, pyridyl-H, Ph-H); 6.48 (s, 1H, pyrazolyl-H);
6.23–6.25 (m, 1H, NH); 6.00–6.09 (m, 1H, CH=); 5.00–5.16 (m, 2H, =CH2); 4.72 (d,
JHH = 5.5 Hz, 2H, CH2CH=); 2.80–2.83(m, 1H, NHCH); 0.85–0.87(m, 2H, CH2CH2);
0.58–0.60 (m, 2H, CH2CH2); The value of HRMS [M?Na]? for C22H19Cl2N5O3:
494.0757. Found: 494.0758.
3-(allyloxy)-N-(2-(butylcarbamoyl)-4-chlorophenyl)-1-(3-chloropyridin-2-yl)-
1H-pyrazole-5-carboxamide (18h): White crystal, yield, 46.2 %; m.p.
196–198 °C; 1H NMR (CDCl3, 400 M) d: 12.03 (s, 1H, CONH); 8.40 (dd,
J1 = 1.5 Hz, J2 = 4.7 Hz, 1H, pyridyl-H); 8.36 (d, J = 9.0 Hz, 1H, Ph-H); 7.79
(dd, J1 = 1.5 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 7.24–7.39 (m, 3H, pyridyl-H, Ph-
H); 6.43 (s, 1H, pyrazolyl-H); 6.18–6.20 (m, 1H, NH); 5.95–6.04 (m, 1H, CH=);
5.14–5.37 (m, 2H, =CH2); 4.71 (d, JHH = 5.5 Hz, 2H, CH2CH=); 3.35–3.38 (m,
2H, NHCH2); 1.50–1.53 (m, 2H, CH2CH2); 1.32–1.34 (m, 2H, CH2CH2); 0.89 (t,
J = 7.2 Hz, 3H, CH2CH3); The value of HRMS [M?Na]? for C23H23Cl2N5O3:
510.1070. Found: 510.1066.
3-(allyloxy)-N-(4-chloro-2-(cyclohexylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-
1H-pyrazole-5-carboxamide (18i): White crystal, yield, 54.8 %; m.p. 145–147 °C; 1H
NMR (CDCl3, 400 M) d: 12.04 (s, 1H, CONH); 8.42 (dd, J1 = 1.4 Hz, J2 = 4.7 Hz,
1H, pyridyl-H); 8.39 (d, J = 9.0 Hz, 1H, Ph-H); 7.80 (dd, J1 = 1.4 Hz, J2 = 8.0 Hz,
1H, pyridyl-H); 7.26–7.34 (m, 3H, pyridyl-H, Ph-H); 6.45 (s, 1H, pyrazolyl-H);
6.02–6.04 (m, 1H, NH); 5.86–5.93 (m, 1H, CH=); 5.13–5.25 (m, 2H, =CH2); 4.73 (d,
JHH = 5.5 Hz, 2H, CH2CH=); 3.87–3.89 (m, 2H, CH2); 1.95–1.97 (m, 2H, CH2);
1.70–1.72 (m, 2H, CH2); 1.60–1.62 (m, 2H, CH2); 1.36–1.38 (m, 2H, CH2); 1.18–1.20
(m, 2H, CH2); The value of HRMS [M?Na]? for C25H25Cl2N5O3: 536.1227. Found:
536.1236.
3-(allyloxy)-1-(3-chloropyridin-2-yl)-N-(2-methyl-6-(propylcarbamoyl)phenyl)-1H-
1
pyrazole-5-carboxamide (18j): White crystal, yield, 49.6 %; m.p. 177–179 °C; H
NMR (CDCl3, 400 M) d: 9.96 (s, 1H, CONH); 8.38 (dd, J1 = 1.4 Hz, J2 = 4.7 Hz,
1H, pyridyl-H); 7.62 (dd, J1 = 1.4 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 7.15–7.26 (m,
3H, pyridyl-H, Ph-H); 7.06–7.08 (m, 1H, Ph-H); 6.41 (s, 1H, pyrazolyl-H); 6.08–6.10
(m, 1H, NHCH); 6.00–6.07 (m, 1H, CH=); 5.21–5.39 (m, 2H, =CH2); 4.73 (d,
JHH = 5.5 Hz, 2H, CH2CH=); 3.25–3.27 (m, 2H, CH2CH2); 2.15 (s, 3H,
PhCH3);1.50–1.52 (m, 2H, CH2CH2); 1.19 (t, J = 7.2 Hz, 3H, CH2CH3); Anal.
Calcd. for C23H24Cl2N5O3 (%): C, 60.86; H, 5.33; N, 15.43. Found: C, 60.62; H, 5.30;
N, 15.17.
3-(allyloxy)-1-(3-chloropyridin-2-yl)-N-(2-(isopropylcarbamoyl)-6-methylphenyl)-
1H-pyrazole-5-carboxamide (18k): White crystal, yield, 63.3 %; m.p. 158–160 °C;
1H NMR (CDCl3, 400 M) d: 9.97 (s, 1H, CONH); 8.38 (d, J = 4.4 Hz, 1H, pyridyl-
H); 7.74 (dd, J1 = 1.8 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 7.15–7.24 (m, 3H, pyridyl-
H, Ph-H); 7.04–7.06 (m, 1H, Ph-H); 6.43 (s, 1H, pyrazolyl-H); 6.01–6.06 (m, 1H,
CH=); 5.92–5.96 (m, 1H, NHCH); 5.21–5.38 (m, 2H, =CH2); 4.73 (d, JHH = 5.5 Hz,
2H, CH2CH=); 4.09–4.11 (m, 1H, CH); 2.26 (s, 3H, PhCH3); 1.12(d, J = 6.0 Hz, 6H,
(CH3)2); The value of HRMS [M?Na]? for C23H24ClN5O3: 476.1460. Found:
476.1462.
123

Synthesis, crystal structure and biological activity of allyl ether
3-(allyloxy)-1-(3-chloropyridin-2-yl)-N-(2-(cyclopropylcarbamoyl)-6-methylphenyl)-
1
1H-pyrazole-5-carboxamide (18l): White crystal, yield, 52.3 %; m.p. 183–185 °C; H
NMR (CDCl3, 400 M) d: 9.92 (s, 1H, CONH); 8.39 (d, J1 = 1.4 Hz, J2 = 4.7 Hz, 1H,
pyridyl-H); 7.74 (dd, J1 = 1.4 Hz, J2 = 8.0 Hz, 1H, pyridyl-H); 7.20–7.26 (m, 3H,
pyridyl-H, Ph-H); 7.05–7.10 (m, 1H, Ph-H); 6.42 (s, 1H, pyrazolyl-H); 6.14–6.16 (m,
1H, NH); 6.03–6.06 (m, 1H, CH=); 5.19–5.33 (m, 2H, =CH2); 4.73 (d, JHH = 5.5 Hz,
2H, CH2CH=); 2.74–2.76 (m, 1H, CH); 2.15 (s, 3H, PhCH3); 1,55–1.57 (m, 2H,
CH2CH2); 0.79–0.81 (m, 2H, CH2CH2); The value of HRMS [M?Na]? for
C23H22ClN5O3: 474.1303. Found: 474.1295.
3-(allyloxy)-N-(4-bromo-2-(isopropylcarbamoyl)-6-methylphenyl)-1-(3-chloropyri-
din-2-yl)-1H-pyrazole-5-carboxamide (18m): White crystal, yield, 55.8 %; m.p.
181–182 °C; 1H NMR (CDCl3, 400 M) d: 9.97 (s, 1H, CONH); 8.46 (dd,
J1 = 1.6 Hz, J2 = 4.8 Hz, 1H, pyridyl-H); 8.39 (dd, J1 = 1.6 Hz, J2 = 8.0 Hz,
1H, pyridyl-H); 7.38–7.40 (m, 1H, Ph-H); 7.31–7.35 (m, 2H, pyridyl-H, Ph-H); 6.56
(s, 1H, pyrazolyl-H); 6.05–6.14 (m, 1H, CH=); 5.94–5.96 (m, 1H, NH); 5.33–5.48 (m,
2H, =CH2); 4.81 (d, JHH = 5.5 Hz, 2H, CH2CH=); 4.16–4.18 (m, 1H, CH); 2.19 (s,
3H, PhCH3); 1.21 (d, J = 6.6 Hz, 6H, (CH3)2); The value of HRMS [M?Na]? for
C23H23BrClN5O3: 554.0565. Found: 554.0569.
N-(4-bromo-2-methyl-6-(propylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-3-meth-
oxy-1H-pyrazole-5-carboxamide (18n): White crystal, yield, 42.1 %; m.p.
235–236 °C; 1H NMR (CDCl3, 400 M) d: 9.91 (s, 1H, CONH); 8.46 (s, 1H,
pyridyl-H); 7.83 (d, J = 7.6 Hz, 1H, pyridyl-H); 7.32–7.37 (m, 3H, pyridyl-H, Ph-H);
6.64 (s, 1H, pyrazolyl-H); 6.38–6.40 (m, 1H, NH); 6.08–6.15 (m, 1H, CH=); 5.29–5.48
(m, 2H, =CH2); 4.82 (d, JHH = 3.7 Hz, 2H, CH2CH=); 2.78–2.81 (m, 1H, CH); 2.17
(s, 3H, PhCH3); 0.84–0.86 (m, 2H, CH2CH2); 0.55–0.58 (m, 2H, CH2CH2); The value
of HRMS [M?Na]? for C23H21BrClN5O3: 552.0409. Found: 552.0402.
Crystal structure
Compound 18e was recrystallized from ethyl acetate/petroleum ether to give a colorless
crystal suitable for X-ray single-crystal diffraction. The crystal with dimensions of
0.20 9 0.18 9 0.12 mm was mounted on a rigaku saturn diffractometer with a
˚
graphite-monochromated MoKa radiation (k = 0.71073 A) by using a Phi scan modes
at 113(2) K in the range of 2.36° B h B 25.01°. The crystals are Monoclinic, space
˚
˚
˚
group P2(1)/n with a = 8.0423(16) A, b = 17.238(3) A, c = 16.648(3) A, a = 90°,
3
˚
b = 97.77(3)°, c = 90°, V = 2,286.7(8) A , Z = 4, F(000) = 452, Dc = 1.378 g/
cm3, l = 0.32 cm-1. A total of 15,151 reflections were collected, of which 4,029 were
independent (Rint = 0.0468) and 2,826 were observed with I[2r(I). The calculations
were performed with SHELXS-97 program [21] 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 R1 = 0.068
and wR2 = 0.211 (w = 1/[r2(Fo2) ? (0.1265P)2] where P = (Fo2 ? 2F2c)/3), S = 1.05,
(D/r)max = 0.004, Dqmax = 0.69 and Dqmin = -0.37 e A-3. Atomic scattering factors
˚
and anomalous dispersion corrections were taken from International Table for X-Ray
Crystallography.
123

Y. Zhao et al.
Biological assay
All bioassays were performed on representative test organisms reared in the
laboratory. The bioassay was repeated at 25 1 °C according to statistical
requirements. Assessments were made on a dead/alive basis, and mortality rates
were corrected using Abbott’s formula. Evaluations are based on a percentage scale
of 0–100 in which 0 equals no activity and 100 equals total kill.
Insecticidal activity against oriental armyworm (Mythimna separata); The
insecticidal activities of the title compounds 18a–18n against oriental armyworm
were evaluated using the reported procedure [22]. The insecticidal activity against
oriental armyworm was tested by foliar application, individual corn leaves were
placed on moistened pieces of filter paper in Petri dishes. The leaves were then
sprayed with the test solution and allowed to dry. The dishes were infested 10
fourth-instar Oriental armyworm larvae. Percentage mortalities were evaluated
2 days after treatment. Each treatment was performed three times. For comparative
purposes, chlorantraniliprole was tested under the same conditions. The results were
summarized in Table 3.
Insecticidal activity against diamond-back moth (Plutella xylostella Linnaeus):
The insecticidal activities of the title compounds 18a–18n against diamondback
moth were evaluated using the leaf disc assay [23]. The leaf discs (5 9 3 cm) were
cut from fresh cabbage leaves and then dipped into the test solution for 15 s. After
air-drying, the treated leaf discs were placed individually into boxes (80 cm3), and
then the second-instar diamondback moth larvae were transferred to the Petri dish.
Table 3 Insecticidal activities against oriental armyworm of the title compounds 18a–18n and
chlorantraniliprole
Compd.
Larvicidal activity (%) at conc. (mg kg-1
)
200
100
50
25
10
5
2.5
1
18a
100
100
100
100
0
100
100
100
100
100
100
60
100
100
100
40
60
18b
18c
18d
60
18e
18f
100
0
50
18g
18h
0
18i
0
18j
100
100
100
100
100
100
100
100
100
100
100
100
20
100
100
100
100
100
18k
100
100
100
60
20
100
100
18l
100
100
100
100
40
20
18m
18n
Chlorantraniliprole
100
100
100
100
100
123

Synthesis, crystal structure and biological activity of allyl ether
Table 4 Insecticidal activities against diamond-back moth of the title compounds 18a–18n and
chlorantraniliprole
Compd.
Larvicidal activity (%) at conc. (mg kg-1
)
50
20
10
5
1
18a
100
100
100
100
100
100
0
100
100
100
100
100
100
100
100
40
100
0
40
0
18b
18c
18d
0
18f
100
60
0
0
0
18g
18h
18i
40
18j
100
100
100
100
100
100
100
100
100
100
100
100
100
0
0
18k
18l
100
100
100
100
100
100
100
100
50
0
18m
18n
0
Chlorantraniliprole
100
Three replicates (seven larvae per replicate) were carried out. The commercial
insecticide chlorantraniliprole was used as a standard. The results were summarized
in Table 4.
Results and discussion
Synthesis
In the present work, the synthesis of two series novel anthranilic diamide derivatives
as well as their insecticidal activities against three lepidopterous pests were studied.
The target allyl ether compounds 18a–18n were synthesized by a simple and
convenient four-step procedure starting from the key intermediate 2-(3-chloro-
pyridin-2-yl)-5-oxo-pyrazolidine-3-carboxylic acid ethyl ester (9). Compound 9 was
oxidized to give pyrazolone 15 in low yield. The compound 15 was reacted with allyl
bromide in dry dimethylformamide to yield ethyl 3-(allyloxy)-1-(3-chloropyridin-2-
yl)-1H-pyrazole-5-carboxylate (16). Then, compound 16 was hydrolyzed to give the
key intermediate 3-(allyloxy)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic
acid (17). The title compounds 18 were synthesized from compound 17 and the
appropriate intermediate 14 (obtained from the intermediate 13 and corresponding
amine—see Table 1) in dry tetrahydrofuran using triethylamine as base.
123

Y. Zhao et al.
Crystal structure analysis
The structure of compound 18e was further confirmed by single crystal X-ray
diffraction analysis (Figs. 1, 2). In the molecular structure of title compound, the
three ring (benzene ring, pyridine ring and pyrazole ring) are nearly vertically with h
angle of 83.2° (benzene ring vs. pyridine ring), 87.3° (pyrazole ring vs. pyridine),
respectively, but the pyrazole ring is planar with the benzene ring (12.3°). The
average bond lengths and bond angles of the phenyl ring [24–28], the pyrazole ring
[29], the pyridine ring [30], and the amide bond [31–35] are normal. The
intermolecular edge-to-face p–p stacking appears between the pyridine ring and
the phenyl ring in another adjacent molecule, in which the distance of H2O and the
˚
centroid of phenyl ring is 3.298 A. These interactions can help to further stabilize
the crystal structure. The title compound has an extensive network of hydrogen
bonding involving the two acceptor N atoms. In the bc plane, they are linked
together by N–HÁÁÁO hydrogen bonds, also the intramolecular N–HÁÁÁO hydrogen-
bonding sequence is repeated to form a ring.
Biological activity
Table 3 shows the insecticidal activities of the title compounds 18a–18n and
chlorantraniliprole against oriental armyworm. The results of insecticidal activities
given in Table 3 indicated that most of the title compounds exhibited excellent
activity against oriental armyworm. For instance, the insecticidal activities of
Fig. 1 Molecular structure of the compound 18e
123

Synthesis, crystal structure and biological activity of allyl ether
Fig. 2 Packing diagram of the compound 18e
compounds 18a, 18l and 18m against oriental armyworm at 5 mg kg-1 were 100 %.
Moreover, compounds 18l and 18m still exhibited good insecticidal activity against
oriental armyworm when the concentration was reduced to 2.5 mg kg-1
.
Table 4 shows the insecticidal activities of the title compounds 18a–18n and
chlorantraniliprole against diamond-back moth. The results indicate that the title
compounds have good insecticidal activities against diamond-back moth. For
instance, the insecticidal activities of compounds 18a, 18l, 18m and 18n against
diamond-back moth at 5 mg kg-1 were 100 %.
From Tables 3 and 4, we can see that the larvicidal activities of the title compounds
appeared to be strongly associated with the substituent R and its position on the
benzene. Methyl-substituted at ortho- and chloro-substituted at para is very important
for increasing activity. Further studies on structural optimization and structure–
activity relationships of these anthranilic diamide derivatives are in progress.
Acknowledgments This work was supported by the National Basic Research Program of China (No.
2010CB126106), the Fundamental Research Funds for the Central Universities for the financial support
(Grant BE018201) and the Specialized Research Fund for the Doctoral Program of Higher Education
(20110031120011).
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