Synthesis and insecticidal activities of novel anthranilic diamides containing modified N-pyridylpyrazoles

Article abstract of DOI:10.1021/jf102842r

In order to look for novel insecticides targeting the ryanodine receptor, four new series of anthranilic diamides containing modified N-pyridylpyrazoles were designed and synthesized. All of the compounds were characterized and confirmed by ¹H NMR, ¹³C NMR, and HRMS. The single crystal structure of 10c was determined by X-ray diffraction. Their insecticidal activities against oriental armyworm (Mythimna separata) and diamondback moth (Plutella xylostella) indicated that most of the compounds showed moderate to high activities at the tested concentration, while compound 19 showed comparable higher activity at the concentration of 0.125 mg/L. The preliminary structure-activity relationship (SAR) was discussed.

Full text of DOI:10.1021/jf102842r

J. Agric. Food Chem. 2010, 58, 12327–12336 12327
DOI:10.1021/jf102842r
Synthesis and Insecticidal Activities of Novel Anthranilic
Diamides Containing Modified N-Pyridylpyrazoles
Q
I
F
ENG, ZHI-L
I
L
IU, L
I-XIA
X
IONG, MING-ZHONG
HENG-MING
W
ANG, YONG-QIANG
L
I, AND
Z
L *
I
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China
In order to look for novel insecticides targeting the ryanodine receptor, four new series of anthranilic di-
amides containing modified N-pyridylpyrazoles were designed and synthesized. All of the compounds were
1
characterized and confirmed by H NMR, 13C NMR, and HRMS. The single crystal structure of 10c was
determined by X-ray diffraction. Their insecticidal activities against oriental armyworm (Mythimna separata)
and diamondback moth (Plutella xylostella) indicated that most of the compounds showed moderate to
high activities at the tested concentration, while compound 19 showed comparable higher activity at the
concentration of 0.125 mg/L. The preliminary structure-activity relationship (SAR) was discussed.
KEYWORDS: Anthranilic diamides; N-pyridylpyrazole; insecticidal activity
INTRODUCTION
two series of general structures D and E reported by Bayer AG
showed high larvicidal activity against Lepidopera (7) (9).
Consequently, the general structures F, G, H, and I were designed
through a bioisosterism approach (16). In this article, four novel
series of anthranilic diamides containing N-pyridylpyrazole were
synthesized as shown in Schemes 1-7. Their bioactivity against
orientalarmywormsand diamondback moths were tested accord-
ingly. The preliminary structure-activity relationships (SAR) were
also discussed.
In order to overcome resistance and ecobiological problems
associated with conventional insecticides, there was an urgent need
to discover novel potent insecticides with a new mode of action.
In the past decade, Dupont discovered the anthranilic diamides (1),
which originated from the insecticidal phthalic diamides and are
highly potent and selective activators of the insect ryanodine recep-
tor (2). The insect ryanodine receptor is a nonvoltage-gated cal-
cium channel and regulates the release of intracellular calcium
stores critical for muscle contraction (3). Until now, two repre-
sentive molecules, chlorantraniliprole (Rynaxypyr; DPX-E2Y45)
(Figure 1, A) and cyantraniliprole (Cyazypyr) (B) have been
marketed (4, 5). Both compounds show exceptional insecticidal
activity on a broad range of Lepidopera, Coleoptera, Diptera,
and Isoptera insects (2). In addition to larvicidal activity, chlor-
antraniliprole has been found to have significant ovicidal activity
among some Lepidoperan pests (6).
Since the discovery of anthranilic diamides, most modification
can be categorized into three substructures (C): the N-pyridylpyr-
azole moiety (a) (7-9), anthraniloyl moiety (b) (10-12), and
aliphatic amide moiety (c) (13-15). In previous work, most
modifications were related to parts b and c. The most successful
example is cyantraniliprole (Cyazypyr) (B) (10), which replaced
a cyano group of the 4-halo substituent of the former anthranilic
diamides. Improved plant mobility and increased spectrum has
been reported for this new compound (2). However, the pyrazole
heterocycle in the N-pyridylpyrazole moiety (a), which is a key
pharmacophore in this kind of compounds, was not much altered
in the previous patents, and most variation was focused on the
3-substituted position, with halogen and trifluoromethyl. Other
substitutes, such as alkoxy (8), oxime ether (7), and heteroaromatic
substituents (9) were reported in individual patents. In particular,
MATERIALS AND METHODS
Instruments. 1H NMR spectra were recorded at 400 MHz using a
Bruker AV 400 spectrometer (Bruker CO., Switzerland) in CDCl3 or
DMSO-d6 solution with tetramethylsilane as the internal standard, and
chemical shift values (δ) were given in ppm. High-resolution mass spectro-
metry (HRMS) data were obtained on a Varian QFT-ESI instrument.
Flash chromatography was performed with silica gel (200-300 mesh). The
melting points were determined on an X-4 binocular microscope melting
point apparatus (Beijing Tech Instruments Co., Beijing, China) and were
uncorrected. Yields were not optimized. Reagents were all analytically or
chemically pure. All solvents and liquid reagents were dried by standard
methods in advance and distilled before use. Chlorantraniliprole was used
as the control and synthesized according to the literature (17).
Ethyl-4-(2-furyl)-2,4-dioxobutanoate (3). Sodium (2.58 g, 112.0
mmol) was dissolved in 300 mL of anhydrous ethanol. To this ice-cooled
solution of sodium ethoxide, the orange red solution containing diethyl
oxalate (32.74 g, 224.0 mmol) and 2-acetylfurane (12.32 g, 111.9 mmol) in
50 mL of anhydrous ethanol was added dropwise with stirring. The
resulting mixture was stirred at room temperature, and a large amount of
solid powder was formed. The reaction was stirred for 2 h until the solution
became a gray solid. Then 2 mol/L hydrochloric acid was added until pH 2
was obtained. The mixture was poured into 200 mL of water, and a yellow
solid was precipitated. The resulting suspension was filtered, and the filter
cake was washed with 50 mL of water. After drying under infrared light,
16.30 g of ethyl-4-(2-furyl)-2,4-dioxobutanoate (3) was obtained as a
yellow solid powder; yield, 69.3%; mp 78-80 °C (literature: mp 88-
*To whom correspondence should be addressed. Tel: þ86-22-
23503732. Fax: þ86-22-23505948. E-mail: nkzml@vip.163.com.
1
89 °C) (18). H NMR (400 MHz, CDCl3): δ 14.50 (br s, 1H, OH), 7.69
© 2010 American Chemical Society
Published on Web 11/03/2010
pubs.acs.org/JAFC

12328 J. Agric. Food Chem., Vol. 58, No. 23, 2010
Feng et al.
Figure 1. Chemical structures of compounds A-I.
Scheme 1. Synthetic Route of Title Compounds 8a-h
Reagents and conditions: (a) EtOH, NaOEt; (b) AcOH, reflux; (c) KMnO4, acetone/H2O, reflux; (d) (COCl)2, DMF, CH2Cl2; (e) 7a-f, 7i-j, pyridine, CH2Cl2.
Scheme 2. Synthesis of Compounds 7a-k
(s, 1H, Ar-H), 7.35 (d, 1H, 3JHH = 3.6 Hz, Ar-H), 6.94 (s, 1H, CH), 6.62
and 3-chloro-2-hydrazinylpyridine (4) (23.25 g, 0.16 mol) were added to
350 mL of acetic acid. The resulting red solution was refluxed for 0.5 h. The
mixture was permitted to cool to room temperature and then poured into
300 g of ice water with stirring. A lot of red powder was precipitated. The
precipitate was filtered and washed with 100 mL of water. After drying under
3
3
3
(dd, 1H, JHH = 1.0 Hz, JHH = 3.4 Hz, Ar-H), 4.39 (q, 2H, JHH
=
7.2 Hz, CH2), 1.41 (t, 3H, 3JHH = 7.2 Hz, CH3).
Ethyl 1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-car-
boxylate (5). Ethyl-4-(2-furyl)-2,4-dioxobutanoate (3) (27.34 g, 0.13 mol)

Article
J. Agric. Food Chem., Vol. 58, No. 23, 2010 12329
Scheme 3. Synthetic Route of Title Compounds 11a-d
Reagents and Conditions: (a) NaOH, MeOH/H2O; (b) alcohol, cat. DMAP, DCC, CH2Cl2; (c) KMnO4, acetone/H2O, reflux; (d) (COCl)2, DMF, CH2Cl2; (e) 7a, pyridine, CH2Cl2.
Scheme 4. Synthetic Route of Title Compounds 13a-m
Reagents and conditions: (a) (COCl)2, DMF, CH2Cl2, then R3NH2; (b) KMnO4, KH2PO4, acetone/H2O, reflux; (c) (COCl)2, DMF, CH2Cl2; (d) 7a-g, pyridine, CH2Cl2.
Scheme 5. Synthetic Route of Title Compounds 16a-j
Reagents and conditions: (a) LiAlH4, THF, 0 °C; (b) acetyl chloride, pyridine, CH2Cl2; (c) KMnO4, acetone/H2O, reflux; (d) (COCl)2, DMF, CH2Cl2; (e) 7a-f, 7h-k, pyridine,
CH2Cl2.
infrared light, the red powder was dissolved in 100 mL of ethyl acetate, the
undissolved material was filtered, and the filtrate was concentrated in vacuo
to afford a brown powder, 35.11 g; yield, 85.0%; mp 116-117 °C. 1H
NMR (400 MHz, CDCl3): δ 8.56 (dd, 1H, 4JHH = 1.6 Hz, 3JHH = 4.8 Hz,
Ar-H), 7.94 (dd, 1H, JHH = 1.6 Hz, JHH = 8.4 Hz, Ar-H), 7.49
(dd, 1H, 3JHH =4.8Hz, 3JHH =8.4Hz, Ar-H), 7.34 (d, 1H, 3JHH =1.2Hz,
Ar-H), 7.20 (s, 1H, Ar-H), 6.34 (dd, 1H, 3JHH = 1.5 Hz, 3JHH = 3.0 Hz,
Ar-H), 5.99 (d, 1H, 3JHH = 3.2 Hz, Ar-H), 4.45 (q, 2H, 3JHH = 7.2 Hz,
CH2), 1.42 (t, 3H, 3JHH = 7.2 Hz, CH3).
and 1H NMR data of 7a-d, 7g, and 7i-k were consistent with the
literature (19) (20).
2-Amino-5-chloro-N-methoxy-3-methylbenzamide (7e). Yellow
solid, yield 65.0%, mp 134-136 °C. 1H NMR (400 MHz, CDCl3):
4
3
4
δ 8.63 (s, 1H, NHO), 7.15 (d, 1H, JHH = 2.4 Hz, Ar-H), 7.13 (s,
1H, Ar-H), 5.49 (s, 2H, NH2), 3.86 (s, 3H, OCH3), 2.14 (s, 3H,
Ar-CH3).
2-Amino-N-benzyl-5-chloro-3-methylbenzamide (7f). White solid,
yield 70.3%, mp 119-121 °C. 1H NMR (400 MHz, CDCl3): δ 7.39-7.26
General Synthetic Procedure for Compounds 7a-k. 2-Amino-
3-methylbenzamide derivatives 7a-k were synthesized in moderate yield
by the method reported by Dong et al. (Scheme 2) (19). The melting point
(m, 5H, Ph-H), 7.18 (d, 1H, 4JHH = 2.4 Hz, Ar-H), 7.11 (d, 1H, 4JHH
1.6 Hz, Ar-H), 6.26 (s, 1H, NH), 5.59 (s, 2H, NH2), 4.59 (d, 2H, 3JHH
5.6 Hz, CH2), 2.15 (s, 3H, Ar-CH3).
=
=

12330 J. Agric. Food Chem., Vol. 58, No. 23, 2010
Feng et al.
Scheme 6. Synthetic Route of Title Compounds 16k-p and 18
Reagents and conditions: (a) LiAlH4, THF, 0 °C; (b) acid chloride or acid anhydride, pyridine, CH2Cl2; (c) PCC, CH2Cl2.
Scheme 7. Synthetic Route of Title Compounds 21a-d
Reagents and conditions: (a) NaN3, acetone/H2O, room temperature; (b) H2, 10% Pd/C, MeOH, room temperature; (c) acid chloride or acid anhydride, pyridine, CH2Cl2.
2-Amino-N,3-dimethylbenzamide (7h). White solid, yield 50.1%, mp
115-117 °C. 1H NMR (400 MHz, CDCl3): δ 7.20 (d, 1H, 3JHH = 8.0 Hz,
Ar-H), 7.13 (d, 1H, 3JHH = 7.2 Hz, Ar-H), 6.59 (t, 1H, 3JHH = 7.6 Hz,
Ar-H), 6.06 (s, 1H, NH), 5.57 (s, 2H, NH2), 2.98 (d, 3H, 3JHH = 4.8 Hz,
NHCH3), 2.17 (s, 3H, Ar-CH3).
stirred at room temperature for 1 h and then evaporated, dissolved in ethyl
acetate (30 mL), and washed with 1 mol/L hydrochloric acid (2 ꢀ 30 mL)
and saturated sodium bicarbonate solution (2 ꢀ 30 mL). The organic layer
was dried and evaporated. Silica gel flash chromatography, eluting with
a gradient of petroleum ether/ethyl acetate (1:1 to 2:1), gave the title
compounds 8a-h.
General Synthetic Procedure for Compounds 8a-h. 1-(3-Cl-2-
Pyridinyl)-3-ethoxycarbonyl-1H-pyrazole-5-carboxylic Acid (6). To a mixture
of ethyl 1-(3-chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-carboxylate
(5) (6.35 g, 20.0 mmol) in 100 mL of acetone and 100 mL of water, KMnO4
(22.12 g, 0.140 mol) was added in small portions. During the addi-
tion, the temperature rose, and the mixture was refluxed without addi-
tional heating. When the addition was complete, the reaction was heated
and refluxed for 30 min. The resulting mixture was filtered and washed
with 50 mL of hot water. The filtrate was acidified with 2 mol/L HCl and
extracted with CH2Cl2 (3 ꢀ 50 mL). The extracts were dried with Na2SO4
and evaporated to give the crude product, which was further purified
with recrystallization (ethanol) to give the title compound as a yellow solid,
3.01 g; yield 50.1%, mp 234-236 °C. 1H NMR (400 MHz, CDCl3): δ 8.50
(dd, 1H, 4JHH = 1.4 Hz, 3JHH = 4.6 Hz, Ar-H), 7.92 (dd, 1H, 4JHH = 1.6
Hz, 3JHH = 8.0 Hz, Ar-H), 7.55 (s, 1H, Ar-H), 7.47 (dd, 1H, 3JHH = 4.6
Hz, 3JHH = 8.2 Hz, Ar-H), 4.45 (q, 2H, 3JHH = 7.2 Hz, CH2), 1.41 (t, 3H,
3JHH =7.2 Hz, CH3).
1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-carboxy-
lic Acid (9). Compound (5) (23.13 g, 72.8 mmol) was added to a mixture
of 100 mL of methanol and 50mL of water and NaOH (3.50 g, 87.4 mmol).
The resulting red solution was stirred at room temperature for 6 h, then
most of the solvent was evaporated. The concentrated mixture was diluted
with 100 mL water and washed with ethyl acetate (30 mL ꢀ 3). The
aqueous layer was acidified with 2 mol/L hydrochloric acid to pH 2. The
yellow precipitate was collected by filtration, washed with water (30 mL),
and then dried to give pyrazolecarboxylic acid (9), 16.01 g; yield 75.9%, mp
104-106 °C. 1H NMR (400 MHz, CDCl3): δ 8.58 (dd, 1H, 4JHH = 1.6 Hz,
4
3JHH = 4.8 Hz, Ar-H), 7.97 (dd, 1H, JHH = 1.4 Hz, 3JHH = 8.0 Hz,
Ar-H), 7.52 (dd, 1H, 3JHH = 4.8 Hz, 3JHH = 8.0 Hz, Ar-H), 7.35 (d, 1H,
3JHH = 1.2 Hz, Ar-H), 7.26 (s, 1H, Ar-H), 6.35 (dd, 1H, 3JHH = 1.6 Hz,
3JHH = 3.6 Hz, Ar-H), 6.03 (d, 1H, 3JHH = 3.2 Hz, Ar-H).
General Synthetic Procedure for 1-(3-Cl-2-Pyridinyl)-5-(2-furyl)-
1H-pyrazole-3-carboxylic Acid Ester 10a-d. DCC (1.1 mmol) was
added to a yellow solution of compound 9 (1.0 mmol), alkyl alcohol
(2.0 mmol), and DMAP (0.1 mmol) in 20 mL of dichloromethane. After
4 h, the reaction was complete, then the mixture was filtered, and the
filtrate was evaporated. The residue was applied to column chromatog-
raphy by eluting with petroleum ether/ethyl acetate (3:1) to give title
compounds 10a-d.
Carboxylic acid (6) (1.0 mmol) and oxalyl chloride (2.0 mmol) were
added to 20 mL of CH2Cl2, followed by one drop of DMF. The mixture
was stirred for 1 h at room temperature. Then the solvent was evaporated and
dissolved with 10 mL of THF. The solution was added dropwise to an ice-
cold solution of 2-amino-3-methylbenzamide derivatives (7a-f, 7i-j)
(1.0 mmol) and pyridine (1.1 mmol) in 10 mL of THF. The reaction was

Article
J. Agric. Food Chem., Vol. 58, No. 23, 2010 12331
Butyl 1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-car-
Ar-H), 7.95 (dd, 1H, 4JHH = 1.6 Hz, 3JHH = 8.0 Hz, Ar-H), 7.51 (dd, 1H,
3JHH =4.8Hz, 3JHH = 8.0Hz, Ar-H), 7.31 (d, 1H, 4JHH =1.6Hz, Ar-H),
7.15 (s, 1H, Ar-H), 6.81 (s, 1H, CONH), 6.34 (dd, 1H, 3JHH = 1.8 Hz,
3JHH = 3.4 Hz, Ar-H), 6.03 (d, 1H, 3JHH = 3.6 Hz, Ar-H), 1.46 (s, 9H,
C(CH3)3).
boxylate (10a). Yield 86.5%, white solid, mp 66-68 °C. 1H NMR
(400 MHz, CDCl3): δ 8.56 (d, 1H, 3JHH = 4.4 Hz, Ar-H), 7.93 (d, 1H,
3JHH = 8.0 Hz, Ar-H), 7.51-7.48 (m, 1H, Ar-H), 7.34 (s, 1H, Ar-H),
3
7.19 (s, 1H, Ar-H), 6.64 (d, 1H, JHH = 1.6 Hz, Ar-H), 5.99 (s, 1H,
Ar-H), 4.39 (t, 2H, 3JHH = 6.8 Hz, OCH2), 1.82-1.74 (m, 2H, OCH2CH2),
1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-N-phenyl-1H-pyrazole-
3-carboxamide (12e). Yield 87.6%, yellow solid, mp 179-181 °C.
1H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H, CONH), 8.62 (d, 1H, 3JHH
= 4.4 Hz, Ar-H), 7.99 (d, 1H, 3JHH = 8.0 Hz, Ar-H), 7.68 (d, 2H, 3JHH
= 7.6 Hz, Ar-H), 7.54 (dd, 1H, 3JHH = 4.8 Hz, 3JHH = 8.0 Hz, Ar-H),
7.37-7.33 (m, 3H, Ar-H), 7.29 (s, 1H, Ar-H), 7.12 (t, 1H, 3JHH = 7.4 Hz,
Ar-H), 6.36 (d, 1H, 3JHH = 1.2 Hz, Ar-H), 6.08 (d, 1H, 3JHH = 3.2 Hz,
Ar-H).
3
1.51-1.41 (m, 2H, CH2CH2CH3), 0.96 (t, 3H, JHH =7.4 Hz,
CH2CH2CH3).
Isopropyl 1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-
carboxylate (10b). Yield 83.5%, white solid, mp 120-121 °C. 1H NMR
3
(400 MHz, CDCl3): δ 8.56 (d, 1H, JHH = 4.4 Hz, Ar-H), 7.93
3
3
3
(d, 1H, JHH = 8.0 Hz, Ar-H), 7.49 (dd, 1H, JHH = 5.0 Hz, JHH
=
7.8 Hz, Ar-H), 7.34 (s, 1H, Ar-H), 7.19 (s, 1H, Ar-H), 6.33 (s, 1H,
Ar-H), 5.98 (d, 1H, 3JHH = 2.8, Ar-H), 5.37-5.31 (m, 1H, OCH), 1.40
(dd, 6H, 3JHH = 6.0 Hz, CH(CH3) 2).
1-(3-Chloropyridin-2-yl)-N-cyclohexyl-5-(furan-2-yl)-1H-pyra-
zole-3-carboxamide (12f). Yield 92.0%, yellow solid, mp 160-162 °C.
3
Benzyl 1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-car-
boxylate (10c). Yield 80.1%, white solid, mp 107-109 °C. 1H NMR
(400 MHz, CDCl3): δ 8.55 (d, 1H, 3JHH = 4.0 Hz, Ar-H), 7.93 (d, 1H,
1H NMR (400 MHz, CDCl3): δ 8.59 (d, 1H, JHH = 4.8 Hz, Ar-H),
3
3
7.95 (d, 1H, JHH = 8.4 Hz, Ar-H), 7.50 (dd, 1H, JHH = 4.8 Hz,
3JHH = 8.0 Hz, Ar-H), 7.30 (s, 1H, Ar-H), 7.19 (s, 1H, Ar-H),
3JHH
=
8.0 Hz, Ar-H), 7.49-7.47 (m, 3H, Ar-H), 7.39-7.33
6.81 (d, 1H, JHH = 7.6 Hz, CONH), 6.33 (dd, 1H, JHH = 1.8, JHH
3
3
3
3
3
3
(m, 4H, Ar-H), 7.20 (s, 1H, Ar-H), 6.33 (d, 1H, JHH = 1.6, Ar-H),
= 3.4 Hz, Ar-H), 6.04 (d, 1H, JHH = 2.8, JHH = 7.6 Hz, Ar-H),
4.00-3.92 (m, 1H, NHCH), 2.04-2.00 (m, 2H, cyclohexyl), 1.76-1.61
(m, 3H, cyclohexyl), 1.44-1.35 (m, 2H, cyclohexyl), 1.27-1.18 (m, 3H,
cyclohexyl).
5.97 (d, 1H, 3JHH = 2.8 Hz, Ar-H), 5.43 (s, 2H, OCH2).
Cyclohexyl 1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-
3-carboxylate (10d). Yield 83.0%, white solid, mp 133-134 °C. 1H
3
NMR (400 MHz, CDCl3): δ 8.56 (d, 1H, JHH = 4.0 Hz, Ar-H), 7.93
N-Butyl-1-(3-chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-3-
carboxamide (12g). Yield 91.2%, white solid, mp 101-103 °C. 1H NMR
(d, 1H, 3JHH =7.8Hz, Ar-H), 7.49 (dd, 1H, 3JHH =4.8Hz, 3JHH =7.6Hz,
Ar-H), 7.34 (s, 1H, Ar-H), 7.18 (s, 1H, Ar-H), 6.33 (d, 1H, 3JHH =1.2Hz,
Ar-H), 5.98 (s, 1H, Ar-H), 5.10-5.05 (m, 1H, OCH), 2.04-2.01(m, 2H,
cyclohexyl), 1.82-1.79 (m, 2H, cyclohexyl), 1.64-1.56 (m, 3H, cyclohexyl),
1.46-1.37 (m, 2H, cyclohexyl),1.30-1.25 (m, 1H, cyclohexyl).
4
3
(400 MHz, CDCl3): δ 8.58 (dd, 1H, JHH = 1.4 Hz, JHH = 4.6 Hz,
4
3
Ar-H), 7.95 (dd, 1H, JHH = 1.6 Hz, JHH = 8.0 Hz, Ar-H), 7.50
(dd, 1H, 3JHH =4.8Hz, 3JHH =8.0Hz, Ar-H), 7.31 (d, 1H, 3JHH =1.6Hz,
Ar-H), 7.19 (s, 1H, Ar-H), 6.92 (br s, 1H, CONH), 6.34 (dd, 1H, 3JHH
=
General Synthetic Procedure for Compounds 11a-d. Compounds
11a-d were prepared from corresponding pyrazolecarboxylic acid ester
10a-d by the procedure reported for compound 8. The overall yield was
based on ester 10a-d.
1.8 Hz, 3JHH = 3.4 Hz, Ar-H), 6.05 (s, 1H, 3JHH = 3.2 Hz, Ar-H), 3.43
3
(q, 2H, JHH = 6.8 Hz, NHCH2), 1.61-1.54 (m, 2H, CH2CH2CH2),
1.44-1.35 (m, 2H, CH2CH2CH3), 0.93 (t, 3H, 3JHH = 7.4 Hz, CH3).
General Synthetic Procedure for Compounds 13a-m. To a mixture of
compound 12 (10.0 mmol) and KH2PO4 (50.0 mmol) in 30 mL of acetone
and 30 mL of water, KMnO4 (50.0 mmol) was added in two portions. The
mixture was then refluxed for 0.5 h and filtered. The filter cake was washed
with 50 mL of hot water. The filtrate was acidified with 2 mol/L HCl and
extracted with CH2Cl2 (3 ꢀ 25 mL). The extracts were dried with Na2SO4
and evaporated. The crude pyrazolecarboxylic acid was obtained as a
yellow powder (2.50 g), which was used directly in the next step without
further purification.
General Synthetic Procedure for Compounds 12a-g. To a suspen-
sion of 1-(3-Cl-2-pyridinyl)-5-(2-furyl)-1H-pyrazole-3-carboxylic acid
(9) (1.50 g, 5.2 mmol) in 25 mL of dichloromethane was added oxalyl chlo-
ride (7.8 mmol) and a drop of dimethylformamide. After stirring for 3 h, the
solution became red and clear, then the solvent was evaporated. The resulting
acyl chloride was dissolved in 20 mL of THF and added dropwise to a 0 °C
solution of alkyl amine or aniline (15.6 mmol) in 30 mL of THF. The reaction
was complete after 1 h of stirring at room temperature. Then most of the sol-
vent was evaporated, and 40 mL of 1 mol/L hydrochloric acid solution was
added to the residue. The mixture was extracted with ethyl acetate; the
extracts were washed with 1 mol/L hydrochloric acid solution, saturated
sodium bicarbonate solution, and brine. The ethyl acetate solution was dried
with Na2SO4 and evaporated to give the title compounds 12a-g.
1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-N-methyl-1H-pyrazole-
3-carboxamide (12a). Yield 85.6%, yellow solid, mp 175-177 °C. 1H
NMR (400 MHz, CDCl3): δ 8.59 (d, 1H, 3JHH = 4.4, Ar-H), 7.96 (d, 1H,
Oxalyl chloride (1.5 mmol) was added to a mixture of the crude pyr-
azolecarboxylic acid (1.0 mmol) in 15 mL of dichloromethane, followed by a
drop of dimethylformamide. The mixture was stirred at room temperature
for 1 h, and the solvent was evaporated. The residue was dissolved in 15 mL of
dichloromethane, and the solution was added dropwise to an ice-cold solu-
tion of 2-amino-3-methylbenzamide derivatives (7a-g) (1.0 mmol) and
pyridine (1.0 mmol) in 20 mL of dichloromethane. After 2 h, the reaction
was complete, and 30 mL of dichloromethane was added. The solutionwas
washed with 1 mol/L hydrochloric acid solution, saturated sodium bicarbo-
nate solution, and brine. The dichloromethane solution was dried and
evaporated, and the residue was applied to a flash column chromatography
by eluting with petroleum ether/ethyl acetate (1:2) to give title compounds
13a-m. The overall yield was the based on 12a-g.
3
3
3JHH = 8.0 Hz, Ar-H), 7.51 (dd, 1H, JHH = 4.6 Hz, JHH = 7.8 Hz,
Ar-H), 7.32 (s, 1H, Ar-H), 7.20 (s, 1H, Ar-H), 6.93 (s, 1H, CONH), 6.34
(s, 1H, Ar-H), 6.05 (d, 1H, 3JHH = 3.2 Hz, Ar-H), 2.98 (d, 1H, 3JHH
5.2, CH3).
=
N-Benzyl-1-(3-chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazole-
3-carboxamide (12b). Yield 89.0%, yellow solid, mp 162-164 °C. 1H
(1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazol-3-yl)methanol
(14). To a 0 °C solution of ethyl 1-(3-chloropyridin-2-yl)-5-(furan-2-yl)-
1H-pyrazole-3-carboxylate (5) (3.0 mmol) in 30 mL of THF, LiAlH4
(6.0 mmol) was added in small portions. The reaction was mentained at 0 °C
and monitored with TLC. After 0.5 h, the reaction was complete, and the
mixture was poured into 100 g of ice-water. The yellow suspension was
acidified with 1 mol/L hydrochloric acid solution until pH 7 was obtained.
The aqueous layer was extracted with ethyl acetate, and the extracts were
washed with brine, dried over Na2SO4, and evaporated. The residue was
subjected to flash chromatography on silica gel with petroleum ether/ethyl
acetate (1:1) to give the title compound as a white solid. Yield 60.3%, mp
138-139 °C. 1H NMR (400 MHz, CDCl3): δ 8.55 (dd, 1H, 4JHH = 1.4 Hz,
3
NMR (400 MHz, CDCl3): δ 8.56 (d, 1H, JHH = 3.6 Hz, Ar-H), 7.94
(d, 1H, 3JHH =8.0Hz, Ar-H), 7.49 (dd, 1H, 3JHH = 4.4Hz, 3JHH =8.0Hz,
Ar-H), 7.36-7.23 (m, 8H, Ar-H, CONH), 7.15 (s, 1H, Ar-H), 6.80 (s, 1H,
CONH), 6.34 (d, 1H, 3JHH = 1.6 Hz, Ar-H), 6.05 (d, 1H, 3JHH = 3.2 Hz,
Ar-H), 4.63 (d, 2H, 3JHH = 6.0 Hz, CH2).
1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-N-isopropyl-1H-pyra-
zole-3-carboxamide (12c). Yield 88.7%, yellow solid, mp 110-111 °C.
1H NMR (400 MHz, CDCl3): δ8.60 (dd, 1H, 4JHH= 1.4Hz, 3JHH = 4.6 Hz,
4
3
Ar-H), 7.94 (dd, 1H, JHH = 1.2 Hz, JHH = 8.0 Hz, Ar-H), 7.51
(dd, 1H, 3JHH =4.8Hz, 3JHH =8.0Hz, Ar-H), 7.31 (d, 1H, 3JHH =1.6Hz,
Ar-H), 7.19 (s, 1H, Ar-H), 6.77 (d, 1H, 3JHH = 8.0 Hz, CONH), 6.34
(dd, 1H, 3JHH =1.6Hz, 3JHH =3.4Hz, Ar-H), 6.04 (d, 1H, 3JHH =3.6Hz,
Ar-H), 4.34-4.23 (m, 1H, CH), 1.24 (d, 6H, 3JHH = 6.8 Hz, CH(CH3)2).
N-tert-Butyl-1-(3-chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyra-
zole-3-carboxamide (12d). Yield 93.1%, yellow solid, mp 152-154 °C.
1H NMR (400 MHz, CDCl3):δ8.59 (dd, 1H, 4JHH =1.4Hz, 3JHH =4.4Hz,
4
3
3JHH = 4.6 Hz, Ar-H), 7.92 (dd, 1H, JHH = 1.4 Hz, JHH = 8.2 Hz,
Ar-H), 7.44 (dd, 1H, 3JHH = 4.6 Hz, 3JHH = 8.2 Hz, Ar-H), 7.32 (d, 1H,
3JHH = 1.2 Hz, Ar-H), 6.71 (s, 1H, Ar-H), 6.32 (dd, 1H, 3JHH = 1.8 Hz,
3
3JHH = 3.4 Hz, Ar-H), 5.98 (s, JHH = 3.6 Hz, Ar-H), 4.80 (s, 2H,
Ar-CH2), 2.20 (br s, 1H, OH).

12332 J. Agric. Food Chem., Vol. 58, No. 23, 2010
Feng et al.
(1-(3-Chloropyridin-2-yl)-5-(furan-2-yl)-1H-pyrazol-3-yl)methyl
Acetate (15). A solution of acetyl chloride (1.5 mmol) in 10 mL of dichlor-
omethane was added dropwise to an ice-cold solution of (1-(3-chloropyr-
idin-2-yl)-5-(furan-2-yl)-1H-pyrazol-3-yl)methanol (14) (1.5 mmol) and
triethylamine (1.5 mmol) in 20 mL of dichloromethane. The resulting mixture
was warmed to room temperature and monitored with TLC. The reaction
was then quenched with water, and the aqueous layer was extracted with
dichloromethane (2 ꢀ 20 mL). The combined extracts were washed with 1
mol/L hydrochloric acid solution, dried over anhydrous sodium sulfate,
and concentrated to give the title compound 15 as a yellow oil. Yield
87.6%. 1H NMR (400 MHz, CDCl3): δ 8.56 (dd, 1H, 4JHH = 2.2 Hz, 3JHH
= 6.2 Hz, Ar-H), 7.93 (dd, 1H, 4JHH = 2.0 Hz, 3JHH = 10.8 Hz, Ar-H),
7.46 (dd, 1H, 3JHH = 6.2 Hz, 3JHH = 10.6 Hz, Ar-H), 7.32 (d, 1H, 3JHH
= 2.0 Hz, Ar-H), 6.74 (s, 1H, Ar-H), 6.33 (dd, 1H, 3JHH = 2.6 Hz, 3JHH
= 4.6 Hz, Ar-H), 5.22 (s, 2H, Ar-CH2), 2.14 (s, 3H, CH3)
N-(2-(Methylcarbamoyl)-4-chloro-6-methylphenyl)-3-(azido-
methyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (19). To
a solution of compound 16k (0.5 mmol) in acetone (10 mL) and water
(10 mL) at room temperature, sodium azide (1.5 mmol) was added in one
portion. The resulting mixture was stirred at room temperature for 20 h.
Additional water (30 mL) was added, and a lot of white solid was pre-
cipitated. The mixture was filtered, washed with water, and dried to afford
the title compound as a white solid; yield 85.0%, mp 151-153 °C. 1H
NMR (400 MHz, CDCl3): δ 10.02 (s, 1H, CONHAr), 8.47 (dd, 1H, 4JHH
= 1.6 Hz, 3JHH = 4.8 Hz, Ar-H), 7.86 (dd, 1H, 4JHH = 1.6 Hz, 3JHH
=
8.0 Hz, Ar-H), 7.38 (dd, 3JHH = 4.8 Hz, 3JHH = 8.0 Hz, Ar-H), 7.23
(s, 1H, Ar-H), 7.21 (s, 1H, Ar-H), 7.13 (s, 1H, Ar-H), 6.24 (s, 1H,
NHCH3), 4.52 (s, 2H, Ar-CH2), 2.93 (d, 3H, 3JHH = 4.8 Hz, NHCH3),
2.19 (s, 3H, Ar-CH3). 13C NMR(100 MHz, CDCl3): δ 168.5, 157.2, 149.6,
148.9, 146.8, 138.9, 138.6, 138.4, 132.9, 132.4, 132.0, 131.8, 129.1, 125.6,
124.4, 107.5, 47.8, 26.9, 18.9. HRMS calcd for C19H1635Cl2N8O2Na ([M þ
Na] þ), 481.0661; found, 481.0666; calcd for C19H1635Cl37ClN8O2Na
([M þ Na] þ), 483.0634; found, 483.0637; calcd for C19H1637Cl2N8O2Na
([M þ Na] þ), 485.0609; found, 485.0612.
General Synthetic Procedure for Compounds 16a-j. The title
compounds were prepared from compound 15 by the procedure described
for compounds 13a-m with 7a-f and 7h-k substituted for 7a-g. The overall
yield was based on that of compound 15.
N-(2-(Methylcarbamoyl)-4-chloro-6-methylphenyl)-1-(3-chloro-
pyridin-2-yl)-3-(hydroxymethyl)-1H-pyrazole-5-carboxamide (17).
To a solution of compound 8a (1.0 mmol) in 20 mL of THF at 0 °C was
added lithium aluminum hydride (2.0 mmol) in small portions. After stirring
for 0.5 h at 0 °C, the mixture was poured into 100 mL of ice-water, then
acidified with 1 mol/L HCl. The aqueous layer was extracted with ethyl ace-
tate (2 ꢀ 30 mL). The extracts were combined, washed with brine, dried
overanhydrous sodium sulfate, and evaporated. The residue was subjected
to flash chromatography on silica gel with ethyl acetate to give the title
N-(2-(Methylcarbamoyl)-4-chloro-6-methylphenyl)-3-(amino-
methyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (20).
A
mixture of compound 19 (2.3 mmol) and 10% Pd/C (0.10 g) in methanol
(20 mL) was stirred under H2 at room temperature for 4 h, then filtered.
The resulting solution was evaporated to give the crude product. It was
further purified by recrystallization with the mixture solvent of ethyl
acetate/petroleum ether (1:1) to give the title compound as a white solid;
yield 90.3%, mp 139-141 °C. 1H NMR (400 MHz, CDCl3): δ 9.96 (br s,
1H, CONHAr), 8.45 (dd, 1H, 4JHH = 1.4 Hz, 3JHH = 4.8 Hz, Ar-H), 7.83
1
compound 17 as a white solid; yield 85.0%, mp 131-133 °C. H NMR
(dd, 1H, 4JHH = 1.6 Hz, 3JHH = 8.0 Hz, Ar-H), 7.35 (dd, 1H, 3JHH
=
(400 MHz, CDCl3): δ 10.12 (s, 1H, CONHAr), 8.41 (d, 1H, 3JHH = 4.4 Hz,
Ar-H), 7.82 (d, 1H, 3JHH = 8.0 Hz, Ar-H), 7.35 (dd, 1H, 3JHH = 4.8 Hz,
3JHH = 8.0Hz, Ar-H), 7.29 (s, 1H, Ar-H), 6.99 (s, 1H, Ar-H), 6.97 (s, 1H,
Ar-H), 6.53 (s, 1H, NHCH3), 4.79 (s, 2H, Ar-CH2), 3.99 (br s, 1H, OH),
4.8 Hz, 3JHH = 8.0 Hz, Ar-H), 7.17 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H),
7.06 (s, 1H, Ar-H), 6.35 (s, 1H, NHCH3), 4.03 (s, 2H, CH2NH2), 2.90
3
(d, 3H, JHH = 4.8, NHCH3), 2.14 (s, 3H, Ar-CH3). 13C NMR
(100 MHz, CDCl3): δ 168.5, 157.2, 149.6, 148.9, 146.8, 138.9, 138.6,
138.4, 132.9, 132.4, 132.0, 131.8, 129.1, 125.6, 124.4, 107.5, 47.8, 26.9,
18.9. HRMS calcd for C19H1835Cl2N6O3Na ([M þ Na] þ), 433.0935;
found, 433.0941; calcd for C19H1835Cl37ClN6O3Na ([M þ Na] þ), 435.0905;
found, 435.0913; calcd for C19H1837Cl2N6O3Na ([M þ Na] þ), 437.0878;
found, 437.0886.
General Synthetic Procedurefor Compounds 21a-d. Toa solution
of compound 20 (0.4 mmol) in 15 mL of THF at 0 °C was added
triethylamine (0.4 mmol), then acid chloride or acid anhydride (0.4 mmol)
in 10 mL of THF was added dropwise. The resulting mixture was stirred at
room temperature for 2 h. Cold 1 mol/L HCl (30 mL) was added to quench
the reaction, and the mixture was stirred for an additional 10 min. A lot of
white solid was precipated, then the mixture was filtered, washed with
1 mol/L HCl, and dried to give the crude residue, which was further
purified by recrystallization with the mixture solvent of ethyl acetate/
petroleum ether (2:1) to give the title compounds 21a-d.
Biological Assay. Insecticidal activities against oriental armyworms
(Mythimna separata) and diamondback moths (Plutella xylostella) were
performed on test organisms reared in a greenhouse. The bioassay was
replicated at 25 ( 1 °C according to statistical requirements. Assessments
were made on a dead/alive basis, and mortality rates were corrected applying
Abbott’s formula (21). Evaluation was based on a percentage scale of
0-100, where 0 equals no activity, and 100 equals total kill. Error of the
experiments was 5%. For comparative purposes, chlorantraniliprole was
tested as control under the same conditions. The insecticidal activity is
summarized in Tables 1, 2, and 3.
Larvicidal Activity against Oriental Armyworms. The insecticidal
activities of compounds 8a-h, 11a-d, 13a-m, 17, 16a-p, 19, 20, and 21a-d
and chlorantraniliprole were evaluated using the reported procedure (17).
The insecticidal activity against oriental armyworms was tested by foliar
application; individual corn (Tangyu 10, Zea mays L.) 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 with 10
fourth-instar oriental armyworm larvae. Percentage mortalities were evalu-
ated 2 days after treatment. Each treatment was replicated three times.
Larvicidal Activity against Diamondback Moths. The larvicidal
activity of compounds 13c-d, 16a-d, 16h, 19, and 21c and the control
chlorantraniliprole was tested by the leafdip method. At first, a
solution of each test sample in DMF (AR, purchased from Alfa
3
2.82 (d, 3H, JHH = 4.0 Hz, NHCH3), 2.01 (s, 3H, Ar-CH3). 13C NMR
(100 MHz, CDCl3): δ 168.9, 157.9, 155.2, 150.0, 146.6, 138.7, 137.7, 136.9,
133.7, 131.6, 130.4, 129.2, 125.4, 125.0, 124.9, 108.1, 58.5, 27.0, 17.9. HRMS
calcd for C19H1735Cl2N5O3Na ([M þ Na] þ), 456.0595; found, 456.0601;
calcd for C19H1735Cl37ClN5O3Na ([M þ Na] þ), 458.0566; found, 458.0572;
calcd for C19H1737Cl2N5O3Na ([M þ Na] þ), 460.0555; found, 460.0547.
General Synthetic Procedure for Compounds 16k-p. To a solu-
tionof compound 17 (0.50 mmol) in20 mL of dichloromethane at 0 °C was
added triethylamine (0.50 mmol), then acid chloride or acid anhydride
(0.50 mmol) was added dropwise. The resulting mixture was allowed to warm
to room temperature and monitored with TLC. Then 20 mL of water was
added to quench the reaction followed by extracting the aqueous layer with
dichloromethane (2 ꢀ 20 mL). The combined extracts were sequentially
washed with 1 mol/L HCl, saturated sodium bicarbonate solution, and brine.
The resulting solution was dried and evaporated to give the crude residue,
which was further purified by flash chromatography on silica gel with
petroleum/ethyl acetate (1:3) to afford the title compounds 16k-p.
N-(2-(Methylcarbamoyl)-4-chloro-6-methylphenyl)-1-(3-chloro-
pyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxamide (18). A solution
of compound 17 (0.3 mmol) in 20 mL of dichloromethane was added in one
portion to the suspension of PCC (pyridinium chlorochromate, 0.6 mmol) in
20 mL of dichloromethane. The mixture was stirred for 1.5 h at room
temperature, and 20 mL of ether was added, then the mixture was stirred for
an additional 0.5 h. The resulting black suspension was filtered, and the
insoluble residue was washed with ether whereupon it became a black gran-
ular solid. The combined organic solution was passed through a short pad of
silica gel, and the colorless solution was evaporated to afford the title com-
pound as a white solid; yield 83.1%, mp 184-187 °C. 1H NMR (400 MHz,
CDCl3): δ 10.26 (s, 1H, CHO), 10.11 (s, 1H, CONHAr), 8.50 (d, 1H, 3JHH
=
4.4 Hz, Ar-H), 7.91 (d, 1H, 3JHH = 8.0 Hz, Ar-H), 7.67 (s, 1H, Ar-H),
7.44 (dd, 1H, 3JHH = 4.6 Hz, 3JHH = 7.8 Hz, Ar-H), 7.20 (s, 1H, Ar-H),
7.18 (s, 1H, Ar-H), 6.24 (d, 1H, 3JHH = 3.6 Hz, CONHCH3), 2.96 (d, 3H,
3JHH = 4.4 Hz, NHCH3), 2.19 (s, 3H, Ar-CH3). 13C NMR (100 MHz,
CDCl3): δ 186.0, 168.4, 156.9, 151.8, 149.3, 147.0 (2C), 139.0 (2C), 138.6,
132.8, 132.3, 131.4, 128.9, 126.1, 124.5, 107.2, 26.9, 18.7. HRMS calcd for
C19H1535Cl2N5O3Na ([M þ Na] þ), 454.0447; found, 454.0444; calcd for
C19H1535Cl37ClN5O3Na ([M þ Na] þ), 456.0428; found, 456.0416; calcd for
C19H1537Cl2N5O3Na ([M þ Na] þ), 458.0433; found, 458.0391.

Article
J. Agric. Food Chem., Vol. 58, No. 23, 2010 12333
Table 1. Insecticidal Activities of Compounds 8a-h, 11a-d, 13a-m, 16a-p, 17, 18, 19, 20, and 21a-d and Chlorantraniliprole against Oriental Armyworms
larvicidal activity (%) at a concentration of (mg/L)
comp.
8a
R1
R2
X
R
200
100
50
20
10
5
2.5
CH3
Cl
Cl
Cl
Cl
Cl
Cl
H
COO
COO
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
(CH2)3CH3
CH(CH3)2
PhCH2
cyclohexyl
CH3
80
8b
CH(CH3)2
C(CH3)3
cyclopropyl
OCH3
PhCH2
CH(CH3)2
(CH2)2CH3
CH3
70
8c
8d
COO
COO
100
100
50
100
100
70
80
8e
COO
COO
8f
8g
20
COO
COO
100
100
80
100
100
60
60
8h
H
11a
11b
11c
11d
13a
13b
13c
13d
13e
13f
13g
13h
13i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
COO
COO
CH3
CH3
80
COO
COO
100
100
100
100
100
100
0
40
CH3
CH3
40
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CONH
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CH2O
CHO
60
CH(CH3)2
C(CH3)3
cyclopropyl
OCH3
PhCH2
(CH2)3CH3
CH3
CH3
CH3
60
100
100
100
100
100
100
100
20
40
CH3
CH3
CH3
CH3
100
100
100
100
100
100
0
60
20
PhCH2
CH(CH3)2
C(CH3)3
Ph
100
100
100
100
100
100
100
100
20
60
40
0
CH3
CH3
13j
13k
13l
CH3
CH3
cyclohexyl
(CH2)3CH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
SO2CH3
Tosyl
13m
16a
16b
16c
16d
16e
16f
16g
16h
16i
CH3
CH3
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
20
100
100
100
100
100
0
100
100
100
100
100
20
100
100
100
100
0
CH(CH3)2
C(CH3)3
cyclopropyl
OCH3
PhCH2
CH3
20
100
0
20
100
60
100
40
CH(CH3)2
cyclopropyl
(CH2)2CH3
CH3
H
100
100
100
100
100
100
100
100
100
100
40
100
100
100
100
100
100
100
100
100
100
100
40
40
40
80
20
60
40
40
60
0
H
16j
H
16k
16l
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH3
CH3
16m
16 n
16o
16p
17
COCF3
CO(CH2)3Cl
acetoxy acetyl
COPh
CH3
CH3
CH3
CH3
H
18
CH3
CH3
19
CH2N3
CH2NH
CH2NH
CH2NH
CH2NH
CH2NH
100
100
100
100
100
100
0
100
100
40
20
CH3
CH3
H
21a
21b
21c
21d
controla
COCH3
SO2CH3
COCF3
COPh
100
100
100
20
100
60
CH3
CH3
100
100
100
100
100
40
CH3
100
100
100
100
a Chlorantraniliprole.
Aesar) at a concentration of 200 mg/L was prepared and then diluted
to the required concentration with water (distilled). Leaf disks (6 cm ꢀ
2 cm) were cut from fresh cabbage leaves and then were sprayed with
the test solution for 3 s and allowed to dry. The resulting leaf disks
were placed individually into glass tubes. Each disk was infested with
seven second-instar diamondback moth larvae. Percentage mortalities
were evaluated 2 days after treatment. Each treatment was performed
three times.
RESULTS AND DISCUSSION
Synthesis. The syntheses of compounds 8a-h and 11a-d are
shown in Schemes 1 and 3. Ethyl-4-(2-furyl)-2,4-dioxobutanoate

12334 J. Agric. Food Chem., Vol. 58, No. 23, 2010
Feng et al.
Table 2. Insecticidal Activities of Compounds 13c-d, 16a-d, 16h, 19, and
21c and Chlorantraniliprole against Diamondback Moths
larvicidal activity (%) at a concentration of (mg/L)
comp.
20
10
5
2.5
1
0.5
85
0.25
30
0.125
0
13c
13d
16a
16b
16c
16d
16h
19
100
50
100
0
100
100
100
100
100
100
100
100
100
100
100
90
70
45
60
95
90
0
100
100
100
60
95
0
100
100
0
70
60
50
40
25
0
0
100
100
100
100
100
100
100
100
100
100
80
100
40
75
0
45
21c
controla
100
100
100
100
a Chlorantraniliprole.
Figure 2. Molecular structure of compound 10c.
Table 3. LC50 Values of Compound 19 and Chlorantraniliprole against
Diamondback Moths
acylated with different acylating agents to give the title com-
pounds 16k-p. In addition, the formyl product 18 was obtained
by the oxidation of compound 17 with PCC as an oxidant (25).
The title compounds 21a-d were synthesized from compound
16k as shown inScheme 6. The mesyl group ofcompound 16k was
displaced with sodium azide (26), followed by catalytic hydro-
genation to provide the primary amine 20. Compound 20 was
allowed to couple with various acid chlorides or anhydride to
afford the final products 21a-d.
comp.
y = a þ bx
LC50 (mg/L)
R
19
chlorantraniliprole
y = 10.91 þ 4.63x
y = 13.75 þ 3.61x
0.05
0.0038
0.94
0.93
(3) was synthesized according to the reported method with minor
improvements (18). The pure product was easily obtained after
filtration instead of extraction and distillation as the literature
described. Then compound 3 was condensed with 3-chloro-
2-hydrazinylpyridine (4) to regioselectively give compound 5. The
furan moiety was oxidized with potassium permanganate to afford
the corresponding carboxylic acid (6) (22). Compound 6 was con-
verted to the acyl chloride by treatment with oxalyl chloride and
coupled with 2-amino-3-methylbenzamide derivatives (7a-f, 7i-j)
in the presence of pyridine in THF to afford the title compounds
8a-h. Saponification of the pyrazole ester (5) afforded com-
pound 9, which was coupled with acohol to afford corresponding
esters (10a-d) (23). Oxidation of the furan moiety, acid chloride
formation, and subsequent coupling to 2-amino-3, N-methyl-
benzamide (7a) afforded the title compounds 11a-d.
The synthesis of compounds 13a-m is shown in Scheme 4.
Carboxylic acid (9) was treated with oxalyl chloride and then
coupled with excessive amine to provide amides 12a-g. At first,
the furan moiety was oxidized with potassium permanganate
directly by the same procedure shown in Scheme 1, but it failed to
give the carboxylic acid. It was found that the oxidation of this
kind of compounds needs a small portion of sodium dihydrogen
phosphate (5%) (24). We propose that the main reason is that the
reactant was decomposed under the basic conditions because of
the oxidation of potassium permanganate. After examing reac-
tion conditions, the carboxylic acid was obtained with potassium
permanganateand potassiumdihydrogenphosphate (both were 5
equivalents). Then the carboxylic acid was coupled with 2-amino-
3-methylbenzamide derivatives (7a-g) to provide the title
compounds 13a-m.
Structure of Compound 10c. Benzyl 1-(3-chloropyridin-2-yl)-
5-(furan-2-yl)-1H-pyrazole-3-carboxylate (10c) was confirmed by
1H NMR and the melting point. Santos Fustero et al. reported
that two N-arylpyrazole isomers were formed by the condensa-
tion of aryl hydrazines and 1,3-diketones in different reaction
conditions (27). In order to verify the regioselectivity in the
pyrazole (compound 5) formation, compound 10c, the derivative
of compound 5, was recrystallized from a mixture of ethyl acetate
and petroleum ether (60-90 °C) to give a colorless crystal for
X-ray single-crystal diffraction. It could be seen from the X-ray
single-crystal figure (Figure 2) that the pyrazole formation was
regioselective, and two conformers were found due to the different
dihedral angle between the furan ring and the pyrazole ring (28).
Structure-Activity Relationship (SAR). Larvicidal Activities
against Oriental Armyworms. The larvicidal activity against
oriental armyworms is summarized in Table 1. In general, most
of the compounds showed moderate potency against oriental
armyworms. In order to examine different substituents in the
3-substituted position of pyrazole, four kinds of bioisosterism
groups (Figure 1, F-I) were introduced. When R1 and R2 were
fixed as CH3 and Cl, respectively, compounds 21c, 16a, 13i, and
11c-d showed comparable higher activity in each series, and the
sequence was 21c > 16a > 13i > 11c-d. Furthermore, different
substituents in each series had different effects on the activity. On
the one hand, different amide groups had great impact on the
activity in the G and I series. For example, compound 21c showed
much higher activity than compound 21d; while compound 13i
showed 60% activity at the concentration of 20 mg/L, its ana-
logue 13l showed no activity even at the concentration of 200 mg/L.
On the other hand, different ester groups had little effect on
insecticidal activity. For example, in the H series, 16a and 16k-p
had similar activity at the concentration of 20 mg/L. The main
reason was probably due to the metabolic degradation of ester
groups in the insect. The ester hydrolysis productions of the H
series were compound 17; therefore, they had similar activity.
However, the ester hydrolysis productions of the F series were
carboxylic acids; therefore, their activity was comparably low,
which was consistent with the results obtained before (17).
The title compounds 16a-p and 18 were prepared as shown in
Schemes 5 and 6. In order to find the SAR, two different synthetic
pathways were used. First, acetate compounds 16a-j were
synthesized from intermediate 5. Compound 5 was reduced with
lithium aluminum hydride to provide alcohol 14, which in turn
underwent acetylation to give compound 15 in high yield. Then
the title compounds 16a-j were obtained by a procedure similar
to that shown in Scheme 1. Second, compounds 16k-p were
synthesized from compound 8a. It was found that 8a can be
regioselectively reduced with lithium aluminum hydride to pro-
vide alcohol 17 with high yield. Then, the alcohol 17 was easily

Article
J. Agric. Food Chem., Vol. 58, No. 23, 2010 12335
Surprisingly, replacement of the mesylate ester with the azide
(19) indicated an increase of the activity, while the oxidation
product 18 of compound 17 showed somewhat less activity.
Different substitutions in the aliphatic amide moiety were
introduced to investigate their influence on the insecticidal
activity. The bioactivity of compounds 13a-m, where X and R
were fixed as CONHCH3, indicated the sequence C (CH3)3 >
cyclopropyl > CH (CH3)2 > PhCH2 > CH3 > OCH3 in the
aliphatic amide moiety, while compounds 16a-f showed a similar
trend. The methyl amides, which showed the highest toxicity in
previous SARs (4), did not show the greater levels of insecticidal
activity this time. On the contrary, the t-butyl amides (8c, 13c, and
16c) tended to show greater levels of insecticidal activity than
other substituents, and the second were the cyclopropyl amides
(8d, 13d, and 16d). Furthermore, the methoxy amides (8e, 13e,
and 16e) showed very low activity, which did not correlate to the
results obtained before (29). In addition, the chloro-substituted
compounds in the H series (compounds 16a-p) showed better
activity than the corresponding nonchloro compounds, such as
compounds 16a and 16g, 16b and 16h, and 16d and 16i.
Larvicidal Activities against Diamondback Moths. Table 2
shows the insecticidal activity of compounds 13c-d, 16a-d, 16h,
19, and 21c against diamondback moth. The acitivity of 19 was
45% at 0.125 mg/mL, higher than that of the other listed com-
pounds. But its LC50 was 0.05 mg/mL, still lower than that of
chlorantraniliprole (0.0038 mg/mL, Table 3). It was also observed
that the t-butyl amides (13c and 16c) showed higher activity than
their anologues. The acitivity of compounds 16a-d and 16 h,
where X and R were fixed as CH2O and COCH3, respectively,
indicated the trend C(CH3)3 > cyclopropyl > CH(CH3)2 > CH3
(R2 = Cl) > CH3 (R2 = H). Surprisingly, the compound 13d,
which had favorable activity against oriental armyworms (100%
at 20 mg/mL), shows relatively lower activity against diamond-
back moths (50% at 20 mg/mL). In addition, compound 21c
showed a 40% death rate at 0.5 mg/mL.
In summary, four novel series of anthranilic diamides containing
modified N-pyridylpyrazoles were synthesized, and their struc-
tures were characterized and confirmed by 1H NMR, 13C
NMR, and HRMS. The single crystal structure of 10c confirmed
the regioselectivity in the pyrazole formation. The larvicidal
activities against oriental armyworms and diamondback moths
of these anthranilic diamides were evaluated. The results of the
larvicidal activities indicated that most compounds exhibited favor-
able larvicidal activities against oriental armyworms and diamond-
back moths. The preliminary structure-activity relationship of the
title compounds indicated that the improvement of insecticidal
activity required a reasonable combination of both substitu-
ents in the pyrazole ring and the aliphatic amide moiety.
The azide compound 19 showed the highest activity in the list
compounds, and t-butyl amides tended to show greater levels
of insecticidal activity than other amides in the aliphatic amide
moiety.
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Supporting Information Available: 1H NMR, 13C NMR,
HRMS, and melting point data for compounds 8a-h, 11a-d,
13a-m, 16a-p, and 21a-d. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Received for review July 20, 2010. Revised manuscript received October
20, 2010. Accepted October 21, 2010. We gratefully acknowledge the
financial support of this work by the National Natural Science Foundation of
China (project number NNSFC 20872069) and National Basic Research
Program of China (2010CB126106)