Synthesis, crystal structure, and insecticidal activity of novel N-alkyloxyoxalyl derivatives of 2-arylpyrrole

Article abstract of DOI:10.1021/jf801311h

Two series of novel N-alkyloxyoxalyl derivatives of 2-arylpyrrole were synthesized, and their structures were characterized by ¹H NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays indicated that some of these title compounds exhibited excellent insecticidal activities, and their insecticidal activities against oriental armyworm, mosquito, and spider mite are comparable to those of the commercialized Chlorfenapyr.

Full text of DOI:10.1021/jf801311h

7326 J. Agric. Food Chem. 2008, 56, 7326–7332
Synthesis, Crystal Structure, and Insecticidal Activity
of Novel N-Alkyloxyoxalyl Derivatives of
2-Arylpyrrole
YU ZHAO,† CHUNHUI MAO,‡,† YONGQIANG LI,† PENGXIANG ZHANG,†
ZHIQIANG HUANG,† FUCHUN BI,† RUNQIU HUANG,† AND QINGMIN WANG*,†
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China, and Hunan Branch of National
Pesticide R&D South Center, Hunan Research Institute of Chemical Industry, Changsha 410007,
Hunan Province, People’s Republic of China
Two series of novel N-alkyloxyoxalyl derivatives of 2-arylpyrrole were synthesized, and their structures
were characterized by 1H NMR spectroscopy, elemental analysis, and single-crystal X-ray diffraction
analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays
indicated that some of these title compounds exhibited excellent insecticidal activities, and their
insecticidal activities against oriental armyworm, mosquito, and spider mite are comparable to those
of the commercialized Chlorfenapyr.
KEYWORDS: Arylpyrrole; Chlorfenapyr; N-alkyloxyoxalyl derivatives; insecticidal activity; oriental ar-
myworm; spider mite; mosquito
INTRODUCTION
In 1987, scientists from the American Cyanamid Co. isolated
and identified dioxapyrrolomycin (A) from a Streptomyces strain
and found that dioxapyrrolomycin exhibited moderate broad-
spectrum insecticidal and miticidal activities (1). At about the same
time, this pyrrole, A, was also reported by Meiji Seika Kaisha and
the SS Pharmaceutical Co. in Japan as an antibiotic (2, 3). However,
an oral LD50 to mice of dioxapyrrolomycin was 14 mg kg-1, which
did not make dioxapyrrolomycin a candidate for development, but
its structure was simple enough to warrant consideration as a takeoff
for synthetic modification. Then American Cyanamid found that
the compound B exhibited excellent activity against tobacco
budworm, two-spotted spider mite, and potato leafhopper. How-
ever, 2-arylpyrrole B was found to have high levels of phytotox-
icity. To circumvent this problem, American Cyanamid further
prepared its derivative C by introduction of an ethoxymethyl group
into the compound B by substituting the hydrogen on the nitrogen
atom and found that the compound C retained the high insecticidal
activity of the parent pyrrole B with none of the undesirable
phytotoxic properties (4). Compound C was the first to be
commercialized as an insecticide-miticide under the trade name
Chlorfenapyr and the IUPAC name 4-bromo-2-(4-chlorophenyl)
-1-ethoxymethyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (5, 6). It
is a pro-insecticide activated by the oxidative in vivo removal of
its N-ethoxymethyl group (7). Its resistance has been detected (8–11).
The activity spectrum of a pesticide is often determined by
the physical properties of the compound, and it is possible to
develop a compound of new style by attaching an appropriate
functional group to a present insecticide. Moreover, the physical
properties of an insecticidal compound may be manipulated to
obtain products with other selected types of activity by proper
selection of the derivative moiety (12). It was reported that
N-oxalyl derivatives of carbofuran containing a carboxylic acid
or ester substituent (D) displayed an insecticidal activity
comparable or superior to that of carbofuran. In our previous
work, the synthesis and insecticidal evaluation of novel N-oxalyl
derivatives of tebufenozide (E) was reported, and the results of
bioassay showed that they exhibit excellent larvicidal activity
(13).
Encouraged by these findings, we developed an idea that
the introduction of an oxalyl substituent into 2-arylpyrrole
B by substituting the hydrogen on the nitrogen atom could
improve biological properties and decrease resistance. There-
* Author to whom correspondence should be addressed [telephone +86-
(0)22-23499842; fax +86-(0)22-23499842; e-mail wang98h@263.net].
† Nankai University.
‡ Hunan Research Institute of Chemical Industry.
10.1021/jf801311h CCC: $40.75  2008 American Chemical Society
Published on Web 07/12/2008

Novel N-Alkyloxyoxalyl Derivatives of 2-Arylpyrrole
J. Agric. Food Chem., Vol. 56, No. 16, 2008 7327
Table 1. Melting Points, Yields, and Elemental Analyses of Compounds VIa-VIo
elemental analysis (%), calcd (found)
compd
R1
mp (°C)
98-99
yield (%)
C
H
N
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
VIi
VIj
VIk
VIl
VIm
VIn
VIo
methyl
ethyl
n-propyl
37.3
36.4
58.0
58.1
36.4
19.7
35.2
61.1
64.7
29.1
61.4
69.4
47.1
51.1
41.3
41.27 (41.49)
42.57 (42.37)
43.79 (43.88)
43.79 (44.00)
44.95 (44.90)
44.95 (44.79)
44.95 (45.09)
44.95 (44.72)
47.26 (47.25)
47.26 (47.28)
43.97 (43.75)
41.03 (40.94)
38.26 (38.21)
42.42 (42.30)
43.58 (43.31)
1.95 (2.08)
2.31 (2.18)
2.65 (2.61)
2.65 (2.45)
2.98 (3.07)
2.98 (2.94)
2.98 (3.03)
2.98 (2.90)
3.21 (3.30)
3.21 (3.29)
2.26 (2.45)
2.03 (2.17)
1.51 (1.77)
2.57 (2.41)
2.89 (2.72)
6.02 (5.91)
5.84 (5.74)
5.67 (5.51)
5.67 (5.65)
5.52 (5.40)
5.52 (5.68)
5.52 (5.41)
5.52 (5.97)
5.25 (5.20)
5.25 (4.99)
5.70 (5.51)
5.63 (5.42)
5.25 (5.27)
5.50 (5.41)
5.35 (5.45)
101-103
63-64
64-65
72-74
108-109
79-80
i-propyl
n-butyl
i-butyl
s-butyl
t-butyl
110-111
100-102
cyclopentylmethyl
cyclohexyl
propenyl
2-fluoroethyl
2,2,2-trifluoroethyl
2-methoxyethyl
2-ethoxyethyl
oil
258-260
84-86
200 (dec)
106-108
220 (dec)
Table 2. 1H NMR of Compounds VIa-VIo
compd
1H NMR (CDCl3) δ (ppm)
3
VIa
VIb
3.95 (s, 3H); 5.94 (s, 2H); 7.51 (dd, 4H, JHH ) 8.1 Hz)
3
3
1.40 (t, 3H, J ) 6.9 Hz); 4.40 (q, 2H, JHH ) 6.9 Hz); 5.93 (s, 2H); 7.51
HH
3
(dd, 4H, JHH ) 8.4 Hz)
3
VIc
VId
VIe
VIf
0.99 (t, 3H, JHH ) 7.4 Hz); 1.73-1.82 (m, 2H); 4.28 (t, 2H,3JHH ) 6.7 Hz);
3
3
5.92 (s, 2H); 7.45 (d, 2H, JHH ) 8.4 Hz); 7.54 (d, 2H, JHH ) 8.4 Hz)
3
1.37 (d, 6H, JHH ) 6.3 Hz); 5.13-5.23 (m, 1H); 5.91 (s, 2H); 7.45 (d, 2H,
3JHH ) 8.4 Hz); 7.54 (d, 2H, JHH ) 8.4 Hz)
3
3
0.97 (t, 3H, JHH ) 7.5 Hz); 1.39-1.48 (m, 2H); 1.69-1.79 (m, 2H); 4.33 (q,
3
3
2H, JHH ) 7.5 Hz); 5.93 (s, 2H); 7.51 (dd, 4H, JHH ) 8.4 Hz)
0.99 (d, 6H, JHH ) 6.7 Hz); 2.02-2.09 (m,1H); 4.11 (d, 2H, JHH ) 6.7 Hz);
5.93 (s, 2H); 7.49 (d, 2H, JHH ) 8.5 Hz); 7.55 (d, 2H, JHH ) 8.5 Hz)
0.94 (t, 3H, JHH ) 7.4 Hz); 1.34 (d, 3H, JHH ) 6.3 Hz); 1.64-1.76 (m, 2H);
3
3
3
3
3
3
VIg
3
4.98-5.07 (m, 1H); 5.92 (s, 2H); 7.49 (d, 2H, JHH ) 8.4 Hz); 7.51 (d, 2H,
3JHH ) 8.4 Hz)
3
VIh
VIi
1.57 (s, 9H); 5.90 (s, 2H); 7.51 (dd, 4H, JHH ) 8.4 Hz)
1.24∼1.27 (m, 2H); 1.55-1.62 (m, 4H); 1.77-1.80 (m, 2H); 2.25-2.34 (m,
3
3
1H); 4.21(d, 2H, JHH ) 7.2 Hz); 5.92 (s, 2H); 7.45 (d, 2H, JHH ) 8.5 Hz);
3
7.54 (d, 2H, JHH ) 8.5 Hz)
VIj
1.24-1.42 (m, 3H); 1.53-1.59 (m, 3H); 1.75-1.79 (m, 2H); 1.90-1.94 (m,
2H); 4.86-4.95 (m, 1H); 5.91 (s, 2H); 7.45 (d, 2H, JHH ) 8.5 Hz); 7.54 (d,
3
3
2H, JHH ) 8.5 Hz)
VIk
VIl
4.77-4.81 (m, 2H); 5.32-5.45 (m, 2H); 5.93-6.03 (m, 1H); 5.96 (s, 2H); 7.41
3
3
(d, 2H, JHH ) 8.5 Hz); 7.55 (d, 2H, JHH ) 8.5 Hz)
4.65 (dt, 2H, JHH ) 4.2 Hz,2JHF ) 80.1 Hz); 4.62 (q, 3H, JHH ) JHF ) 2.6
3
3
3
3
3
Hz); 5.95 (s, 2H); 7.46 (d, 2H, JHH ) 8.6 Hz); 7.56 (d, 2H, JHH ) 8.6 Hz)
4.67 (q, 2H, JHH ) 8.0 Hz); 5.97 (s, 2H); 7.44 (d, 2H, JHH ) 8.6 Hz); 7.56
3
3
VIm
VIn
VIo
3
(d, 2H, JHH ) 8.6 Hz)
3
3
3.41 (s, 3H); 3.69(t, 2H, JHH ) 4.56 Hz); 4.46 (t, 2H, JHH ) 4.67 Hz); 5.93
(s,2H); 7.45 (d, 2H, JHH ) 8.4 Hz); 7.54 (d, 2H, JHH ) 8.4 Hz)
1.21 (t, 3H, JHH ) 6.9 Hz); 3.54 (q, 2H, JHH ) 6.97 Hz); 3.72 (t, 2H, JHH
3
3
3
3
3
)
3
3
3.8 Hz); 4.45 (t, 2H, JHH ) 3.8 Hz); 5.92 (s, 2H); 7.45 (d, 2H, JHH ) 8.4
3
Hz); 7.54 (d, 2H, JHH ) 8.4 Hz)
solvents and liquid reagents were dried by standard methods in advance
and distilled before use. 4-Bromo-2-(4-chlorophenyl)-5-(trifluorom-
ethyl)pyrrole-3-carbonitrile(B)waspreparedaccordingtotheliterature(14–18).
N-(Hydroxymethyl)acetamide acetate (I) was obtained according to the
reported procedure (19). tert-Butyl potassium oxalate (Vh) was
synthesized according to the published procedure (20).
fore, in a search for new arylpyrrole insecticides with
improved profiles, we designed and synthesized two series
of novel N-alkyloxyoxalyl derivatives of 2-arylpyrrole as
shown in Schemes 4 and 6.
MATERIALS AND METHODS
Synthetic Procedure for 4-Bromo-1-(bromomethyl)-2-(4-chlo-
rophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (III). A slurry
of 4-bromo-2-(4-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile
(B) (17.47 g, 0.05 mol) and tetrahydrofuran (60 mL) was cooled to 10
°C and treated portionwise over 20 min with sodium hydride (2.2 g,
60% in oil, 0.055 mol). After 15 min of stirring, this solution was added
dropwise to a 50 °C solution of N-(hydroxymethyl)acetamide acetate
(I) (9.65 g, 0.074 mol) in tetrahydrofuran (40 mL). The reaction mixture
was refluxed for 4 h cooled to room temperature, diluted with water
1
Instruments. H NMR spectra were obtained at 300 MHz using a
Bruker AV300 spectrometer or at 400 MHz using a Varian Mercury
Plus400 spectrometer in CDCl3 solution with tetramethylsilane as the
internal standard. Chemical shift values (δ) are given in parts per
million. Elemental analyses were determined on a Yanaca CHN Corder
MT-3 elemental analyzer. The melting points were determined on an
X-4 binocular microscope melting point apparatus (Beijing Tech
Instruments Co., Beijing, China) and are uncorrected. Yields were not
optimized. The reagents were all analytically or chemically pure. All

7328 J. Agric. Food Chem., Vol. 56, No. 16, 2008
Zhao et al.
Table 3. Melting Points, Yields, and Elemental Analyses of Compounds IXa-IXl
elemental analysis (%), calcd (found)
H
compd
R2
n-propyl
i-propyl
n-butyl
s-butyl
t-butyl
propenyl
cyclohexyl
phenyl
o-methylphenyl
p- methylphenyl
o-chlorophenyl
p-chlorophenyl
mp(°C)
74-75
yield (%)
C
N
IXa
IXb
IXc
IXd
IXe
IXf
IXg
IXh
IXi
67.6
68.1
60.1
57.0
60.9
63.1
50.0
67.5
43.8
45.8
57.1
48.4
43.88 (43.62)
43.88 (43.95)
45.04 (45.05)
45.04 (45.27)
45.04 (45.03)
44.06 (13.94)
47.34 (47.21)
47.89 (47.80)
48.87 (48.62)
48.87 (48.98)
44.95 (44.73)
44.95 (44.72)
2.86 (2.82)
2.86 (2.98)
3.18 (3.18)
3.18 (3.11)
3.18 (3.28)
2.41 (2.40)
3.41 (3.47)
2.30 (2.46)
2.61 (2.48)
2.61 (2.68)
1.98 (2.04)
1.98 (1.99)
8.53 (8.36)
127-129
107-109
113-115
70-72
106-108
162-164
97-99
166-168
149-151
136-138
153-155
8.53 (8.40)
8.29 (8.14)
8.29 (7.92)
8.29 (8.32)
8.56 (8.45)
7.89 (7.86)
7.98 (7.76)
7.77 (7.80)
7.77 (7.64)
7.49 (7.59)
7.49 (7.53)
IXj
IXk
IXl
Table 4. 1H NMR of Compounds IXa- IXl
compd
1H NMR (CDCl3, δ)
3
IXa
0.97 (t, 3H, JHH ) 7.4 Hz); 1.55-1.65 (m, 2H); 3.24-3.36 (m, 2H); 5.91 (s,
3
3
2H); 7.10 (br, 1H); 7.48 (d, 2H, JHH ) 8.7 Hz); 7.54 (d, 2H, JHH ) 8.7 Hz)
3
IXb
IXc
1.24 (d, 6H, JHH ) 6.6 Hz); 4.06-4.16 (m, 1H); 5.91 (s, 2H); 6.72-6.80 (br,
3
3
1H); 7.49 (d, 2H, JHH ) 8.7 Hz); 7.55 (d, 2H, JHH ) 8.7 Hz)
3
0.94 (t, 3H, JHH ) 7.4 Hz); 1.34-1.39 (m, 2H); 1.52-1.57 (m, 2H);
3
3.32-3.37 (m, 2H); 5.90 (s, 2H); 6.95 (br, 1H); 7.48 (d, 2H, JHH ) 8.6 Hz);
3
7.53 (d, 2H, JHH ) 8.6 Hz)
3
3
IXd
0.93 (t, 3H, JHH ) 7.5 Hz); 1.21 (d, 3H, JHH ) 6.6 Hz); 1.50-1.57 (m, 2H);
3
3.88-3.97 (m, 1H); 5.92 (s, 2H); 6.73(br, 1H); 7.49 (d, 2H, JHH ) 8.7 Hz);
3
7.55 (d, 2H, JHH ) 8.7 Hz)
3
IXe
IXf
1.41 (s, 9H); 5.90 (s, 2H); 6.81 (br, 1H); 7.49 (d, 2H, JHH ) 8.7 Hz); 7.55 (d,
3
2H, JHH ) 8.7 Hz)
3.96-4.00 (m, 2H); 5.23-5.30 (m, 2H); 5.78-5.96 (m, 1H); 5.92 (s, 2H); 7.02
3
3
(br, 1H); 7.48 (d, 2H, JHH ) 8.5 Hz); 7.55 (d, 2H, JHH ) 8.5 Hz)
1.21-1.66 (m, 6H); 1.72-1.77 (m, 2H); 1.92-1.97 (m, 2H); 3.73-3.82 (m,
1H); 5.90 (s, 2H); 6.82 (br, 1H); 7.48 (d, 2H, JHH ) 8.4 Hz); 7.53 (d, 2H, JHH
IXg
3
3
) 8.4 Hz)
IXh
IXi
IXj
IXk
IXl
5.99 (s, 2H); 7.40-7.64 (m, 9H); 8.67 (s, 1H)
2.33 (s, 3H); 5.99 (s, 2H); 7.16-8.02 (m, 8H); 8.65 (s, 1H)
2.35 (s, 3H); 5.97 (s, 2H); 7.14-8.01 (m, 8H); 8.77 (s, 1H)
6.00 (s, 2H); 7.14-8.42 (m,8H); 9.33 (s, 1H)
5.98 (s, 2H); 7.35-8.76 (m, 8H); 8.68 (s, 1H)
Scheme 1. Synthetic Route of Compound III
sulfate, and concentrated in vacuo to obtain a solid. Recrystallization
from a mixture of ethyl acetate and heptane gave the desired compound
Scheme 2. General Synthetic Route of Compound V
1
III as a white solid (1.02 g, 80%): mp 136-138 °C; H NMR δ 5.61
3
(s, 2H), 7.49 (d, 2H, JHH ) 8.7 Hz), 7.54 (d, 2H,3JHH ) 8.7 Hz).
Anal. calcd. (%) for C13H6Br2ClF3N2: C, 35.29; H, 1.37; N, 6.33. Found
(%): C, 35.32; H, 1.54; N, 6.57.
General Synthetic Procedure for Alkyloxyloxalic Acid (V). The
appropriate alcohol (100 mmol) was added dropwise over 20 min to
an excess of oxalyl chloride (200 mmol) at 0 °C. When the addition
was complete, the mixture was allowed to warm to room temperature.
Excess oxalyl chloride was removed by vacuum distillation. Further
distillation afforded alkyloxyoxalyl chloride (IV). Then water (15 mL)
was added dropwise over 10 min to alkyloxyoxalyl chloride at 0 °C,
and the mixture was stirred at room temperature for 1.5 h. The reaction
mixture was diluted with ethyl ether (30 mL). The organic layer was
washed successively with brine (20 mL) and water (20 mL) and then
dried over anhydrous sodium sulfate. The solvent was evaporated to
give alkyloxyl oxalic acid (V) as colorless oil, which was directly used
for the next step without further purification.
(30 mL), and extracted with ethyl acetate (3 × 60 mL). The organic
extract was washed with water (2 × 40 mL), dried over anhydrous
magnesium sulfate, and concentrated in vacuo to give a solid. The solid
was purified by column chromatography on a silica gel using a mixture
of petroleum ether (60-90 °C) and ethyl acetate as the eluent to afford
compound II as a white crystal (8.00 g, 36%): mp 149-151 °C. Anal.
calcd (%) for C15H10BrClF3N3O: C, 42.83; H, 2.40; N, 9.99. Found
(%): C, 42.86; H, 2.41; N, 9.82.
A mixture of compound II (1.22 g, 2.90 mmol) and phosphoryl
tribromide (2.35 g, 8.2 mmol) was heated at reflux temperature for 30
min and then diluted with water and extracted with ethyl acetate (3 ×
20 mL). The combined organic extract were washed successively with
water (20 mL) and brine (20 mL), dried over anhydrous magnesium

Novel N-Alkyloxyoxalyl Derivatives of 2-Arylpyrrole
Scheme 3. Synthetic Route of Compound Vh
J. Agric. Food Chem., Vol. 56, No. 16, 2008 7329
aqueous sulfuric acid (5 mol L-1), and then saturated with sodium
chloride. The organic layer was dried over anhydrous sodium sulfate.
The solvent was evaporated to give alkylaminooxalic acid (VIII), which
was directly used for the next step without further purification.
General Synthetic Procedure for the Title Compounds IXa-IXl.
Alkylaminooxalic acid (VIII) (4.50 mmol) was added to a stirred
suspension of sodium hydroxide (0.18 g, 4.50 mmol) in dimethylfor-
mamide (10 mL) at room temperature. After 1 h of stirring, the solution
of compound III (0.40 g, 0.90 mmol) in dimethylformamide (3 mL)
was added dropwise. After 6 h of stirring at room temperature, the
reaction mixture was poured into ice water (15 mL) and extracted with
ethyl acetate (3 × 20 mL). The organic layer was washed successively
with water (3 × 20 mL) and brine (20 mL) and then dried over
anhydrous sodium sulfate. After removal of the solvent, the residue
was purified by recrystallization from a mixture of ethyl acetate and
petroleum ether (60-90 °C) to afford the title compounds IXa-IXl.
The melting points, yields, and elemental analyses of compounds
IXa-IXl are listed in Table 3. The 1H NMR data are listed in Table
4.
X-ray Diffraction. The crystal structure of compound VIi was
determined, and X-ray intensity data were recorded on a Bruker
SMART 1000 CCD diffraction meter using graphite monochromated
Mo KR radiation (λ )0.71073 Å). In the range of 1.64° e θ e 27.87°,
5386 independent reflections were obtained. All calculations were
refined anisotropically. All hydrogen atoms were located from a
difference Fourier map and were placed at calculated positions and
were included in the refinements in the riding mode with isotropic
thermal parameters.
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 (21).
Evaluations are 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 purpose, Chlorfenapyr was tested under the same conditions.
The insecticidal activity is summarized in Table 6.
Insecticidal ActiVity against Oriental Armyworm (Mythimna
separata). The insecticidal activities of the title compounds
VIa-VIo, and IXa-IXl and Chlorfenapyr were evaluated using
the reported procedure (22, 23). 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 with 10 fourth-instar oriental
armyworm larvae. Percentage mortalities were evaluated 2 days after
treatment. Each treatment was performed three times.
Scheme 4. General Synthetic Route of the Title Compound VI
Synthetic Procedure for tert-Butylpotassium Oxalate (Vh).
Methyl oxalyl chloride (5.0 g, 40.80 mmol) was added dropwise to a
mixture of anhydrous pyridine (5.06 g, 64.05 mmol), tert-butyl alcohol
(4.74 g, 64.05 mmol) and anhydrous ether (80 mL). The mixture was
stirred at room temperature for 1.5 h. Then the mixture was washed
successively with water (60 mL), saturated aqueous sodium hydrogen
carbonate solution (100 mL), and water (60 mL) and then dried over
anhydrous sodium sulfate. The solvent was evaporated to give tert-
butyl methyl oxalate as a colorless oil: 1H NMR (CDCl3) δ 1.56 (s,
9H), 3.87 (s, 3H).
Methyl tert-butyl oxalate (3.22 g, 20.10 mmol) was dissolved in a
mixture of acetonitrile (10 mL) and water (10 mL), followed by the
addition of potassium hydroxide (1.37 g, 82%, 20.1 mmol). The mixture
was stirred at room temperature for 2 h. The solvent was evaporated
to give tert-butyl potassium oxalate (Vh) (3.18 g) as a white solid,
which was directly used for the next step without further
purification.
General Synthetic Procedure for the Title Compounds VIa-VIo.
Alkyloxyloxalic acid (V) (4.50 mmol) was added to a stirred suspension
of sodium hydroxide (0.18 g, 4.50 mmol) in dimethylformamide (10 mL)
at room temperature. After 1 h of stirring, the solution of compound III
(0.40 g, 0.90 mmol) in dimethylformamide (3 mL) was added dropwise.
After 6 h of stirring at room temperature, the reaction mixture was poured
into ice water (15 mL) and extracted with ethyl acetate (3 × 20 mL). The
organic layer was washed successively with aqueous saturated sodium
hydrogen carbonate solution (20 mL) and water (3 × 20 mL) and brine
(20 mL) and then dried over anhydrous sodium sulfate. After removal of
the solvent, the residue was purified by recrystallization from a mixture
of ethyl acetate and petroleum ether (60-90 °C) to afford the title
compounds VIa-VIo. The melting points, yields, and elemental analyses
1
of compounds VIa-VIo are listed in Table 1. The H NMR data are
listed in Table 2.
General Synthetic Procedure for Alkylaminooxalic Acid (VIII).
A solution of ethyl oxalyl chloride (6.82 g, 0.05 mol) in dry toluene
(20 mL) was added to a mixture of appropriate amine (0.03 mol),
toluene (45 mL), and aqueous potassium carbonate (30 mL, 1 mol L-1
)
at 0-10 °C over 20 min. The layers were separated, and then aqueous
sodium hydroxide solution (36 mL, 1 mol L-1) was added to the organic
layer, and the mixture was heated to 40-45 °C for 30 min to hydrolyze
ester VII. The organic layer was discarded. Ethyl acetate was added to
the aqueous phase. The mixture was cooled to 10 °C, acidified with
Insecticidal ActiVity against Mosquito (Culex pipiens pallens).
The toxicities of the title compounds VIa-VIo and IXa-IXl and
Chlorfenapyr against mosquito were evaluated according to the
reported procedure (24–26). One milliliter of different concentrated
dilutions of each compound was added to 99 mL of water to got
different concentrations of tested solutions. Then 20 fourth-instar
mosquito larvae were put into 10 mL of the test solution and raised
for 2 days; the result was expressed by death percentage.
Insecticidal ActiVity against Spider Mite (Tetranychus cinnabarinus
BoisduVal). The insecticidal activities of the title compounds VIa-VIo
and IXa-IXl and Chlorfenapyr were evaluated using the reported
procedure (27, 28). Sieva bean plants (Phaseolus Vulgaris L.) with
primary leaves expanded to 10 cm were selected and cut back to one
plant per pot. A small piece was cut from a leaf taken from the main
colony and placed on each leaf of the test plants. This was done about
2 h before treatment to allow the mites to move to the test plant and to
lay eggs. The size of the piece was varied to obtain about 60-100
mites per leaf. At the time of the treatment, the piece of leaf used to
transfer the mites was removed and discarded. The mite-infested plants
Figure 1. Molecular structure of compound VIi.

7330 J. Agric. Food Chem., Vol. 56, No. 16, 2008
Scheme 5. General Synthetic Route of Compound VIII
Zhao et al.
Table 5. Selected Bond Lengths and Torsion Angles of Compound VIi
selected bond
length (Å)
selected bond
length (Å)
selected torsion angle
torsion angle (deg)
C(1)-C(2)
C(2)-C(3)
C(3)-C(4)
C(1)-C(5)
C(3)-C(6)
C(4)-C(7)
C(7)-C(8)
C(8)-C(9)
C(9)-C(10)
C(10)-C(11)
C(11)-C(12)
C(7)-C(12)
O(4)-C(15)
O(4)-C(16′′)
O(4)-C(16′)
1.364(5)
1.421(5)
1.381(5)
1.546(5)
1.425(5)
1.474(4)
1.385(4)
1.385(5)
1.383(5)
1.372(5)
1.383(5)
1.400(4)
1.321(4)
1.468(10)
1.469(8)
N(1)-C(4)
N(1)-C(1)
Br(1)-C(2)
Cl(1)-C(10)
F(1)-C(5)
F(2)-C(5)
F(3)-C(5)
O(1)-C(14)
O(1)-C(13)
O(2)-C(14)
O(3)-C(15)
N(1)-C(13)
N(2)-C(6)
O(4)-C(16)
1.382(4)
1.403(4)
1.854(4)
1.745(4)
1.291(4)
1.327(4)
1.329(4)
1.339(4)
1.441(4)
1.198(4)
1.198(4)
1.441(4)
1.147(4)
1.480(7)
C(4)-N(1)-C(1)-C(2)
C(13)-N(1)-C(1)-C(2)
C(4)-N(1)-C(1)-C(5)
C(13)-N(1)-C(1)-C(5)
N(1)-C(1)-C(2)-C(3)
C(5)-C(1)-C(2)-C(3)
N(1)-C(1)-C(2)-Br(1)
C(5)-C(1)-C(2)-Br(1)
C(1)-C(2)-C(3)-C(4)
Br(1)-C(2)-C(3)-C(4)
C(1)-C(2)-C(3)-C(6)
Br(1)-C(2)-C(3)-C(6)
C(2)-C(3)-C(4)-N(1)
C(6)-C(3)-C(4)-N(1)
C(2)-C(3)-C(4)-C(7)
1.3(4)
179.2(3)
-177.4(3)
0.5(5)
-0.2(4)
178.4(3)
-175.6(2)
3.0(5)
-0.9(4)
174.7(2)
-179.4(3)
-3.9(5)
1.7(4)
-179.8(3)
-172.9(3)
Scheme 6. General Synthetic Route of the Title Compound IX
Alkyloxyloxalic acid (V) was synthesized from alcohol and
oxalyl chloride as shown in Scheme 2. However, tert-buty-
loxyloxalic acid cannot be achieved using this method because
the boiling points of tert-butyloxyoxalyl chloride and oxalyl
chloride are so close that it is impossible to purify tert-
butyloxyoxalyl chloride by distillation. Hence, intermediate Vh
was synthesized according to the literature described in Scheme
3 (20).
The title compounds VIa-VIo were synthesized from inter-
mediates III and V as shown in Scheme 4. The key intermediate
III was reacted with alkyloxyloxalic acid (V) in dimethylformamide
using sodium hydroxide as alkali to yield N-oxalyl derivatives of
2-arylpyrrole VIa-VIo. The title compounds VIa-VIo could be
purified by recrystallization from a mixture of ethyl acetate and
petroleum ether. The melting points, yields, and elemental analyses
of compounds VIa-VIo are listed in Table 1. The 1H NMR data
are listed in Table 2.
were dipped in the test formulation for 3 s with agitation and set in the
hood to dry. Plants were kept for 2 days before the number of live and
dead adults was counted.
RESULTS AND DISCUSSION
Synthesis. 4-Bromo-1-(bromomethyl)-2-(4-chlorophenyl)-5-
(trifluoromethyl)pyrrole-3-carbonitrile (III) was synthesized as
shown in Scheme 1. 4-Bromo-2-(4-chlorophenyl)-5-(trifluo-
romethyl)pyrrole-3-carbonitrile (B) was prepared according to
the literature (14–18). N-(Hydroxymethyl)acetamide acetate (I)
was obtained according to the reported procedure (19). The
intermediate B was reacted with compound I in the presence
of sodium hydride to give compound II, and subsequent
treatment using phosphoryl tribromide as a bromination reagent
provided the key intermediate III.
Alkylaminooxalic acid (VIII) was synthesized as shown in
Scheme 5. Ethyl oxalyl chloride was reacted with appropriate
amine in the presence of potassium carbonate to obtain ester
VII, and subsequent hydrolysis using sodium hydroxide gave
intermediate VIII.
The title compounds IXa-IXl were synthesized from intermedi-
ates III and VIII as shown in Scheme 6. The key intermediate
III was reacted with alkylaminooxalic acid (VIII) in dimethylfor-
mamide using sodium hydroxide as alkali to yield N-oxalyl
derivatives of 2-arylpyrrole IXa-IXl. The title compounds
IXa-IXl could be purified by recrystallization from a mixture of
ethyl acetate and petroleum ether. The melting points, yields, and
elemental analyses of compounds IXa-IXl are listed in Table 3.
The 1H NMR data are listed in Table 4.
Crystal Structure Analysis. Compound VIi was recrystallized
from ethyl acetate/petroleum ether to give colorless crystal
suitable for X-ray single-crystal diffraction with the following
crystallographic parameters: a ) 28.617(4) Å, b ) 28.617(4)
Å, c ) 14.3516(18) Å, R ) 90°, ꢀ ) 90°, γ ) 120°, µ ) 1.990
mm-1, V )10178(2) Å3, Z ) 18, Dx ) 1.567 mg m-3, F (000)
) 4824, T ) 113(2) K, 1.64° e θ e 27.87°, and the final R
factor, R1 ) 0.0506, ωR2 ) 0.1294.
It could be seen from the X-ray single-crystal analysis that
Figure 2. Packing diagram of compound VIi.
the molecule consists of one benzene ring, one pyrrole ring,

Novel N-Alkyloxyoxalyl Derivatives of 2-Arylpyrrole
J. Agric. Food Chem., Vol. 56, No. 16, 2008 7331
Table 6. Insecticidal Activities of Compounds VIa-VIo and IXa-IXl against Oriental Armyworm, Mosquito, and Spider Mite
toxicities against oriental armyworm at toxicities against mosquito at toxicities against spider mite at
200 mg kg-1 100 mg kg-1 50 mg kg-1
compd
VIa
VIb
VIc
VId
VIe
VIf
VIg
VIh
VIi
VIj
VIk
VIl
VIm
VIn
VIo
IXa
IXb
IXc
IXd
IXe
IXf
IXg
IXh
IXi
IXj
IXk
IXl
20 mg kg-1
10 mg kg-1
5 mg kg-1
0.50 mg kg-1
0.25 mg kg-1
0.10 mg kg-1
100
100
100
100
100
100
100
100
100
100
100
100
70
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
15
80
100
70
100
100
100
10
30
20
30
10
10
20
20
25
20
0
30
20
15
20
0
10
10
30
20
100
0
100
100
100
100
10
20
100
100
0
0
100
100
90
90
10
10
100
100
100
100
100
100
100
100
100
100
100
100
100
90
100
100
30
20
20
80
100
0
20
80
80
30
20
100
90
84
100
100
100
92
95
95
83
92
94
90
100
100
80
100
48
95
0
87
90
100
30
10
96
76
99
93
46
92
89
86
79
100
100
100
100
90
30
100
100
20
0
100
40
96
71
100
100
90
51
92
97
100
100
10
100
0
100
84
93
Chlorfenapyr
0
and one cyclopentane ring. The benzene ring and the pyrrole
ring are connected through the C4 atom of the benzene ring
and the C7 atom of the pyrrole ring. The dihedral angel between
the plane of the benzene ring and the plane of the pyrrole ring
is about 66°. In addition, the cyclopentane ring exhibits a
disordered state (Figure 1). Selected bond lengths are listed in
Table 5. The bond lengths of C(1)sC(2) and C(3)sC(4) are
1.364(5) and 1.381(5) Å, respectively, which are longer than
normal CdC (1.34 Å). The bond length of C(2)sC(3) [1.421(5)
Å] is shorter than normal CsC (1.54 Å). The bond lengths of
C(4)sN(1) [1.382(4) Å] and C(1)sN(1) [1.403(4) Å] are shorter
than the normal CsN single bond (1.49 Å). The bond lengths
of C(14)sO(2) [1.198(4) Å] and C(15)sO(3) [1.198(4) Å] are
shorter than normal CdO (1.34 Å), and the bond lengths of
C(14)sO(1) [1.339(4) Å] and C(15)sO(4) [1.321(4) Å] are
shorter than normal single CsO (1.44 Å). The packing structure
of this compound is shown in Figure 2.
that some of the title compounds VIa-VIo and IXa-IXl
exhibited excellent activities against mosquito. For example,
the insecticidal activities of compounds VIl and IXi against
mosquito at 0.10 mg kg-1 were 100%, which is parallel to that
of the commercialized Chlorfenapyr.
Insecticidal ActiVities against Spider Mite (T. cinnabarinus
BoisduVal). The result of insecticidal activities given in Table
6 show that most of the title compounds VIa-VIo and IXa-IXl
exhibit excellent activities against spider mite. For example, the
insecticidal activities of the title compounds VIm and VIn were
equal to that of the commercilized Chlorfenapyr at 50 mg kg-1
.
In summary, two series of novel N-alkyloxyoxalyl derivatives
of 2-arylpyrrole were synthesized from 4-bromo-1-(bromom-
ethyl)-2-(4-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carboni-
trile, and their structures were characterized by 1H NMR
spectroscopy, elemental analysis, and single-crystal X-ray
diffraction analysis. The insecticidal activities of the new
compounds were evaluated. The results of bioassays indicated
that some of these title compounds exhibited excellent insec-
ticidal activities, and their insecticidal activities against oriental
armyworm, mosquito, and spider mite are comparable to that
of the commercial insecticide Chlorfenapyr.
Bioassay. Table 6 shows the insecticidal activities of the title
compounds VIa-VIo and IXa-IXl and that of contrast
compound Chlorfenapyr against oriental armyworm, mosquito,
and spider mite.
Insecticidal ActiVities against Oriental Armyworm (M. sepa-
rata Walker). The results of insecticidal activities given in Table
6 indicate that most of the title compounds VIa-VIo exhibit
excellent activity against oriental armyworm, which are good
compared to the commercialized Chlorfenapyr. For instance,
the insecticidal activities of the title compounds VIc, VIe, VIf,
and VIg were equal to that of Chlorfenapyr. Among R1 of the
title compounds VIa-VIo, a saturated short-chain alkyl group
is most prominent in increasing activity. From Table 6, we can
also find that the title compounds IXa-IXl exhibit lower
insecticidal activities against oriental armyworm than the title
compounds VIa-VIo.
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Received for review April 27, 2008. Revised manuscript received June
11, 2008. Accepted June 12, 2008. This work was supported by the
National Key Project for Basic Research (2003CB114400) and the
National Natural Science Foundation of China (20672064).
JF801311H