Synthesis, insecticidal and acaricidal activities of novel 2-arylpyrroles

Article abstract of DOI:10.1007/s11426-012-4733-4

To search for novel 2-arylpyrroles with unique biological activities, a series of novel 2-arylpyrrole derivatives were designed and synthesized, and their structures were characterized by ¹H and ¹³C NMR spectroscopy, MS spectrometry, and elemental analysis. Their insecticidal activities against Lepidopteran pests (e.g. Mythimna separata) and acaricidal activities against mites (e.g. Tetranychus urticae) were evaluated. The results of bioassays indicate that some of these title compounds exhibited excellent insecticidal and acaricidal activities. For example, 4-bromo-1-((chloromethoxy) methyl)-2-(4-chloro phenyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (6a), 4-bromo-2-(4-chlorophenyl)-1-((2-fluoroethoxy)-methyl)-5-(trifluoromethyl) pyrrole-3-carbonitrile (6d) showed insecticidal activity against Mythimna separata and 4-bromo-2-(4-chlorophenyl)-1-((isopropoxymethoxy)methyl)-5- (trifluoro methyl)pyrrole-3-carbonitrile (7d) showed acaricidal activity against Tetranychus urticae. They were more effective than Chlorfenapyr, which has been the only commercialized member of a new class of chemicals of 2-arylpyrroles.

Full text of DOI:10.1007/s11426-012-4733-4

SCIENCE CHINA
Chemistry
January 2013 Vol.56 No.1: 117–123
doi: 10.1007/s11426-012-4733-4
• ARTICLES •
Synthesis, insecticidal and acaricidal activities of novel
2-arylpyrroles
LIU AiPing1,2*, TANG Ming1,3, YU ShuYing1,2, LIU XingPing1,2, WANG XiaoGuang1,2,
PEI Hui1,2, WU DaoXin1,3, HU Li1,2, OU XiaoMing1,2 & HUANG MingZhi1,2*
1National Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical Industry, Changsha 410014, China
2Hunan Province Key Laboratory for Agrochemicals, Changsha 410014, China
3School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha 410004, China
Received May 31, 2012; accepted July 3, 2012; published online September 5, 2012
To search for novel 2-arylpyrroles with unique biological activities, a series of novel 2-arylpyrrole derivatives were designed
1
and synthesized, and their structures were characterized by H and 13C NMR spectroscopy, MS spectrometry, and elemental
analysis. Their insecticidal activities against Lepidopteran pests (e.g. Mythimna separata) and acaricidal activities against
mites (e.g. Tetranychus urticae) were evaluated. The results of bioassays indicate that some of these title compounds exhibited
excellent insecticidal and acaricidal activities. For example, 4-bromo-1-((chloromethoxy)methyl)-2-(4-chloro phe-
nyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (6a), 4-bromo-2-(4-chlorophenyl)-1-((2-fluoroethoxy)-methyl)-5-(trifluorome-
thyl)pyrrole-3-carbonitrile (6d) showed insecticidal activity against Mythimna separata and 4-bromo-2-(4-chlorophenyl)-
1-((isopropoxymethoxy)methyl)-5-(trifluoro methyl)pyrrole-3-carbonitrile (7d) showed acaricidal activity against Tetranychus
urticae. They were more effective than Chlorfenapyr, which has been the only commercialized member of a new class of
chemicals of 2-arylpyrroles.
2-arylpyrroles, Chlorfenapyr, synthesis, insecticidal activity, acaricidal activity
mite, and potato leafhopper. However, 2-arylpyrrole (B)
was found to have high levels of phytotoxicity [2]. Further
optimization on the N-hydrogen of compound B has been
done. In 1988, by substituting the hydrogen on the nitrogen
atom with an ethoxymethyl group in compound B, Ameri-
can Cyanamid Company found compound C which was
developed and commercialized as an agricultural insecticide
in 2001 under the common name Chlorfenapyr [4-bromo-
2-(4-chlorophenyl)-1-ethoxymethyl-5-(trifluoromethyl)-1H-
pyrrole-3-carbonitrile] [3, 4]. As the only commercialized
member of a new class of chemicals, 2-arylpyrroles,
Chlorfenapyr is a pro-insecticide activated through oxida-
tive removal of the N-ethoxymethyl group by mixed func-
tion oxidases to form the compound B, which uncouples
oxidative phosphorylation at the mitochondria and results in
disruption of ATP production, cellular death, ultimately
organism mortality [5]. The acute oral LD50 of Chlorfenapyr
1 Introduction
Dioxapyrrolomycin (A, Figure 1), isolated from a Strepto-
myces strain by American Cyanamid Company in 1987,
was found to have moderate activity against a number of
insects and mites [1]. Although its acute oral LD50 to mice
was 14 mg/kg which was too high to become a candidate
for further development, its novel structure was simple
enough to warrant consideration as a take-off for synthetic
modifications. To solve the problem of high toxicity, most
of the modifications and optimizations have been focused
on the novel 2-arylpyrroles. American Cyanamid Company
also found that the compound B (Figure 1) exhibited excel-
lent activity against tobacco budworm, two-spotted spider
*Corresponding authors (email: aipliu@yahoo.com.cn; huang-mz@163.com)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

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Liu AP, et al. Sci China Chem January (2013) Vol.56 No.1
is 55 mg/kg to mice and 626 mg/kg to rats. It has been re-
ported that Chlorfenapyr can induce DNA damage in spleen,
liver, renal cells and peripheral blood lymphocytes in mice
[6, 7].
This paper reports the synthesis, insecticidal and acaricidal
activity of these novel 2-arylpyrrole derivatives.
2 Experimental
To search for novel 2-arylpyrroles with unique biological
activities and lower toxicity towards mammalian cells, a
series of optimization programs were carried out by replac-
ing the N-ethoxymethyl group of Chlorfenapyr with an
N-alkyloxyoxalyl, an N-ester or a N-bridged derivative
[8–10] based on the principle of prodrug [11]. In our previ-
ous work a series of novel sulfur-containing oxime-ethers
had shown remarkable insecticidal activity. The compound
D (Figure 1) showed better insecticidal activity than either
of the commercial insecticides Chlorfenapyr and Fen-
valerate. We also found another oxime-ethers compound E
(Figure 1), with acaricidal potency comparable to that of
commercial acaricides such as fluacrypyrim, tebufenpyrad
and chlorfenapyr [12–15].
Unless otherwise noted, reagents and solvents were used as
1
received from commercial suppliers. H NMR and 13C
NMR spectra were obtained with a Varian INOVA-300
spectrometer using tetramethylsilane (TMS) as the internal
standard and deuterochloroform (CDCl3) as the solvent.
Mass spectra (MS) were obtained with both Hewlett-
Packard 6890-5973 GC/MS and Agilent 1100 Series
LC/MSD. Elemental analyses were carried out with a PE
CHNS/O 2400 II elemental analyzer. Uncorrected melting
points were taken on a WRS-1A digital melting points ap-
paratus.
Encouraged by these reports, we developed an idea of in-
troducing a sulfur, oxygen and/or halogen-containing sub-
stituent into Chlorfenapyr by substituting the ethyl group to
improve biological properties and decrease DNA damage.
With this goal in mind, a series of novel 2-arylpyrrole de-
rivatives (6–10, Figure 2) were designed and synthesized.
2.1 Synthesis
The general synthetic schemes for representative com-
pounds (6a–6e, 7a–7i, 8a–8f, 9 and 10) are shown in Figure
2. All reactions were carried out under a protective atmos-
Figure 1 Design strategy for the target compounds.
Figure 2 Synthesis schemes of compounds 6a–6e, 7a–7i, 8a–8f, 9 and 10.

Liu AP, et al. Sci China Chem January (2013) Vol.56 No.1
119
phere of dry nitrogen or utilizing a calcium chloride tube.
Reaction yields were not optimized. Representative proce-
dures are given below. Every other compound was synthe-
sized in manners similar to representatives and every new
compound was identified and verified by 1H NMR, MS, and
elemental analyses.
4-Bromo-2-(4-chlorophenyl)-5-(trifluoromethyl)-1H-
pyrrole-3-carbonitrile (5) was prepared according to the
literature [16].
for C16H13BrClF3N2OS: C 42.36, H 2.89, N 6.17; found C
42.35, H 2.86, N 6.15.
Compounds 7a–7i, 8a–8b and 8d–8f could be synthe-
sized by the method similar to that described in the synthe-
sis of compound 8c.
4-Bromo-2-(4-chlorophenyl)-1-((2-(methylsulfinyl)ethoxy)
methyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (9) was
prepared as follows. A solution of compound 8c (93.50%,
1.51 g, 3.00 mmol), hydrogen peroxide (30 wt.%, 1.00g,
8.80 mmol), methanol (12 mL) and acetic acid (6 mL) was
stirred at room temperature for 5–6 h. The reaction mixture
was poured into ice-water and then extracted with ethyl
acetate. The combined ethyl acetate extracts were washed
with water, dried with anhydrous sodium sulfate, filtered
and the solvent was removed. Residue materials were sepa-
rated by silica-gel column chromatography using petroleum
ether + ethyl acetate (10:1 by volume) as the eluant to give
compound 9: 1.08 g (72.90%) of a pale yellow viscous liq-
uid; 1H NMR (CDCl3, 300 MHz) : 2.78 (s, 3H, CH3), 2.81
(t, J = 6.9 Hz, 2H, CH2), 3.78 (t, J = 6.9 Hz, 2H, CH2), 5.27
(s, 2H, CH2), 7.47–7.58 (m, 4H, Ph H); 13C NMR (CDCl3,
75 MHz) δ: 144.37, 137.51, 131.09, 129.81, 124.71, 121.72,
118.13, 113.13, 103.86, 99.40, 75.35, 61.36, 53.89, 39.17;
LC-MS (APCI, Pos) (m/z) Calcd. 468, found 468; Anal.
calcd for C16H13BrClF3N2O2S: C 40.91, H 2.79, N 5.96;
found C 40.94, H 2.76, N 5.99.
4-Bromo-1-((2-chloroethoxy)methyl)-2-(4-chlorophenyl)-
5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile (6b) was pre-
pared as follows. A solution of compound 5 (7.10 g, 0.02
mol) in tetrahydrofuran (8 mL) was added dropwise over 15
min to a slurry of sodium hydride (0.96 g, 60 wt.%, 0.024
mol) and THF (20 mL) at 0–5 °C. The mixture was stirred
at the same temperature for 0.5 h before a solution of
1-chloro-2-(chloromethoxy)ethane (3.1 g, 0.024 mol) in
THF (5 mL) was added dropwise, and the mixture was
stirred at room temperature for 45 h. The reaction mixture
was cooled to room temperature, poured into ice-water and
then extracted with ethyl acetate. The combined ethyl ace-
tate extracts were washed with water, dried with anhydrous
sodium sulfate, filtered and the solvent was removed. Resi-
due materials were recrystallized from petroleum
ether+ethyl acetate (10:1 by volume) to give compound 6b:
1
5.80 g (60.70%) of a white solid: m.p. 104.4–106.1 °C; H
Compound 10 could be synthesized by the method simi-
lar to that described in the synthesis of compound 9 at re-
fluxed temperature with hydrogen peroxide (30 wt%, 1.0 g,
16 mmol).
Structures of compounds 6–10 were supported by spec-
troscopic data shown below.
NMR (CDCl3, 300 MHz) : 3.57 (t, J = 5.7 Hz, 2H, CH2),
3.66 (t, J = 5.7 Hz, 2H, CH2), 5.26 (s, 2H, CH2), 7.54 (s, 4H,
Ph H); 13C NMR (CDCl3, 75 MHz) δ: 144.41, 137.37,
131.21, 129.65, 124.79, 121.71, 118.13, 113.25, 103.73,
99.26, 75.37, 69.11, 42.28; MS (70 eV) m/z: Calcd. 440,
found 440; Anal. calcd for C15H10BrCl2F3N2O: C 40.75, H
2.28, N 6.34; found C 40.82, H 2.25, N 6.30.
4-Bromo-1-((chloromethoxy)methyl)-2-(4-chlorophenyl)-
5-(trifluoromethyl)pyrrole-3-carbonitrile (6a). White solid,
Compounds 6a, 6c–6e could be synthesized by the
method similar to that described in the synthesis of 6b.
4-Bromo-2-(4-chlorophenyl)-1-((2-(methylthio)ethoxy)
methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (8c) was
prepared as follows. A solution of compound 6b (94.00%,
4.71 g, 0.01 mol) and sodium methyl mercaptide (20 wt%,
7.0 g, 0.02 mol) in ethanol (20 mL) was stirred at 50–60 °C
for 3–4 h. The reaction mixture was cooled to room temper-
ature, poured into ice-water and then extracted with ethyl
acetate. The combined ethyl acetate extracts were washed
with water, dried with anhydrous sodium sulfate, filtered
and the solvent was removed. Residue materials were sepa-
rated by silica-gel column chromatography using petroleum
ether + ethyl acetate (30:1 by volume) as the eluant to give
compound 8c: 2.78 g (57.10%) of a white solid: m.p.
1
m.p. 82.8–84.4 °C; H NMR (CDCl3, 300 MHz) : 5.40 (s,
4H, 2CH2), 7.48–7.57 (m, 4H, Ph H); MS (70 eV) m/z:
Calcd. 426, found 426; Anal. calcd for C14H8BrCl2F3N2O: C
39.28, H 1.88, N 6.54; found C 39.15, H 1.91, N 6.44.
4-Bromo-1-((2-chloroethoxy)methyl)-2-(4-chlorophenyl)-
5-(trifluoromethyl)pyrrole-3-carbonitrile (6b). White solid,
m.p. 104.4–106.1 °C; 1H NMR (CDCl3, 300 MHz) : 3.57 (t,
J = 5.7 Hz, 2H, CH2), 3.66 (t, J = 5.7 Hz, 2H, CH2), 5.26 (s,
2H, CH2), 7.54 (s, 4H, Ph H); 13C NMR (CDCl3, 75 MHz)
: 144.41, 137.37, 131.21, 129.65, 124.79, 121.71, 118.13,
113.25, 103.73, 99.26, 75.37, 69.11, 42.28; MS (70 eV) m/z:
Calcd. 440, found 440; Anal. calcd for C15H10BrCl2F3N2O:
C 40.75, H 2.28, N 6.34; found C 40.82, H 2.25, N 6.30.
4-Bromo-1-((3-chloropropoxy)methyl)-2-(4-chlorophenyl)-
5-(trifluoromethyl)pyrrole-3-carbonitrile (6c). viscous liquid,
1H NMR (CDCl3, 300 MHz) : 1.952.03 (m, 2H, CH2),
3.48 (t, J = 5.7 Hz, 2H, CH2), 3.58 (t, J = 6.3 Hz, 2H, CH2),
5.21 (s, 2H, CH2), 7.46–7.57 (m, 4H, Ph H);MS (70 eV) m/z:
Calcd. 454, found 454; Anal. calcd for C15H10BrCl2F3N2O: C
42.14, H 2.65, N 6.14; found C 42.12, H 2.62, N 6.12.
1
66.067.8 °C. H NMR (CDCl3, 300 MHz) : 2.10 (s, 3H,
CH3), 2.61 (t, J = 6.3 Hz, 2H, CH2), 3.52 (t, J = 6.3 Hz, 2H,
CH2), 5.23 (s, 2H, CH2), 7.53 (s, 4H, Ph H); 13C NMR
(CDCl3, 75 MHz) : 144.41, 137.37, 131.24, 129.52, 124.79,
121.71, 118.13, 113.25, 103.73, 99.26, 75.85, 69.17, 42.27,
15.07; MS (70 eV) m/z: Calcd. 452, found 452; Anal. calcd

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Liu AP, et al. Sci China Chem January (2013) Vol.56 No.1
4-Bromo-2-(4-chlorophenyl)-1-((2-fluoroethoxy)-methyl)-
7.45–7.54 (m, 4H, Ph H); MS (70 eV) m/z: Calcd. 448,
found 448; Anal. calcd for C17H13BrClF3N2O2: C 45.41, H
2.91, N 6.23; found C 45.25, H 2.97, N 6.25.
5-(trifluoromethyl)pyrrole-3-carbonitrile (6d). White solid,
1
m.p. 86.6–88.8 °C; H NMR (CDCl3, 300 MHz) : 3.60 (t,
4-Bromo-2-(4-chlorophenyl)-1-((prop-2-yn-1-yloxy)
methoxy)methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (7f).
White solid, m.p. 139.3–140.7 °C; H NMR (CDCl3, 300
MHz) : 2.42 (s, 1H, CH), 4.11 (s, 2H, CH2), 4.73 (s, 2H,
CH2), 5.33 (s, 2H, CH2), 7.46–7.55 (m, 4H, Ph H); MS (70
eV) m/z: Calcd. 446, found 446; Anal. calcd for
C17H11BrClF3N2O2: C 45.61, H 2.48, N 6.26; found C 45.64,
H 2.56, N 6.15.
J = 4.2 Hz, 2H, CH2), 4.43 (t, J = 4.2 Hz, 2H, CH2), 5.27 (s,
2H, CH2), 7.49–7.55 (m, 4H, Ph H); MS (70 eV) m/z: Calcd.
424, found 424; Anal. calcd for C15H10BrClF4N2O: C 42.33,
H 2.37, N 6.58; found C 42.42, H 2.33, N 6.52.
1
4-Bromo-1-((2-bromoethoxy)methyl)-2-(4-chlorophenyl)-
5-(trifluoromethyl)pyrrole-3-carbonitrile (6e). White solid,
1
m.p. 91.7–94.2 °C; H NMR (CDCl3, 300 MHz) : 3.40 (t,
J = 5.7 Hz, 2H, CH2), 3.73 (t, J = 5.7 Hz, 2H, CH2), 5.26 (s,
2H, CH2), 7.49–7.55 (m, 4H, Ph H); 13C NMR (CDCl3, 75
MHz) δ: 144.41, 137.40, 131.12, 129.68, 124.77, 121.71,
118.12, 113.25, 103.74, 99.25, 75.18, 68.94, 29.31; MS (70
eV) m/z: Calcd. 484, found 484; Anal. calcd for
C15H10Br2ClF3N2O: C 37.03, H 2.07, N 5.76; found C 37.07,
H 2.11, N 5.72.
4-Bromo-2-(4-chlorophenyl)-1-((methoxymethoxy)methyl)-
5-(trifluoromethyl)pyrrole-3-carbonitrile (7a). White solid;
1H NMR (CDCl3, 300 MHz) : 3.29 (s, 3H, CH3), 4.60 (s,
2H, CH2), 5.29 (s, 2H, CH2), 7.50–7.52 (m, 4H, Ph H); MS
(70 eV) m/z: Calcd. 422, found 422; Anal. calcd for
C15H11BrClF3N2O2: C 42.53, H 2.62, N 6.61; found C 42.54,
H 2.50, N 6.67.
4-Bromo-2-(4-chlorophenyl)-1-((ethoxymethoxy)methyl)-
5-(trifluoromethyl)pyrrole-3-carbonitrile (7b). White solid,
m.p. 115.8–116.8 °C; 1H NMR (CDCl3, 300 MHz) : 1.08–
1.13 (t, J = 7.2 Hz, 3H, CH3), 3.46 (q, J = 7.0 Hz, 2H, CH2),
4.63 (s, 2H, CH2), 5.31 (s, 2H, CH2), 7.477.55 (m, 4H, Ph
H); 13C NMR (CDCl3, 75 MHz) : 144.48, 137.29, 131.26,
129.51, 125.04, 121.76, 118.18, 113.31, 103.68, 99.28,
93.60, 73.24, 64.28, 14.79; MS (70 eV) m/z: Calcd. 436,
found 436; Anal. calcd for C16H13BrClF3N2O2: C 43.91, H
2.99, N 6.40; found C 43.95, H 3.03, N 6.25.
4-Bromo-2-(4-chlorophenyl)-1-((propoxymethoxy)methyl)-
5-(trifluoromethyl)pyrrole-3-carbonitrile (7c). White solid,
m.p. 109.7–111.2 °C; 1H NMR (CDCl3, 300 MHz) δ: 0.83 (t,
J = 6.6 Hz, 3H, CH3), 1.43 (m, 2H, CH2), 3.36 (t, J = 7.5
Hz, 2H, CH2), 4.62 (s, 2H, CH2), 5.31 (s, 2H, CH2),
7.46–7.55 (m, 4H, Ph H); MS (70 eV) m/z: Calcd. 450,
found 450; Anal. calcd for C17H15BrClF3N2O2: C 45.21, H
3.35, N 6.20; found C 45.33, H 3.33, N 6.18.
4-Bromo-2-(4-chlorophenyl)-1-((2-methoxyethoxy)
methyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (7g). White
1
solid, m.p. 102.1–103.7 °C; H NMR (CDCl3, 300 MHz)
: 3.31 (s, 3H, CH3), 3.49–3.50 (m, 2H, CH2), 3.51–3.52 (m,
2H, CH2), 5.26 (s, 2H, CH2), 7.52 (s, 4H, Ph H); MS (70 eV)
m/z: Calcd. 436, found 436; Anal. calcd for
C16H13BrClF3N2O2: C 43.91, H 2.99, N 6.40; found C 43.90,
H 2.96, N 6.51.
1-((2-(Allyloxy)ethoxy)methyl-4-bromo-2-(4-chlorophenyl)-
5-(trifluoromethyl)pyrrole-3-carbonitrile (7h). White solid,
1
m.p. 77.3–80.2 °C; H NMR (CDCl3, 300 MHz) : 3.52–
3.58 (m, 4H, CH2CH2), 3.93 (d, J = 8.4 Hz, 2H, CH2), 5.17
(s, 2H, CH2), 5.25 (s, 2H, CH2), 5.78–5.88 (m, 1H, CH),
7.52–7.56 (m, 4H, Ph H); 13C NMR (CDCl3, 75 MHz) δ:
144.34, 137.11, 134.84, 131.21, 129.60, 125.03, 121.70,
118.12, 117.30, 113.36, 103.38, 98.92, 75.83, 72.13, 69.06,
68.33; MS (70 eV) m/z: Calcd. 462, found 462; Anal. calcd
for C18H15BrClF3N2O2: C 46.63, H 3.26, N 6.04; found C
46.69, H 3.43, N 6.09.
4-Bromo-2-(4-chlorophenyl)-1-((2-(prop-2-yn-1-yl)oxy)
ethoxy)methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (7i).
White solid, m.p. 78.1–80.6 °C; 1H NMR (CDCl3, 300 MHz)
δ: 2.08 (s, 1H, CH), 3.56–3.65 (m, 4H, CH2CH2), 4.12 (s,
2H, CH2), 5.26 (s, 2H, CH2), 7.53 (s, 4H, Ph H); 13C NMR
(CDCl3, 75 MHz) δ: 144.39, 137.17, 131.26, 129.55, 125.05,
121.75, 118.17, 113.39, 103.52, 98.83, 78.99, 75.83, 74.90,
68.82, 68.18, 58.39; MS (70 eV) m/z: Calcd. 460, found 460;
Anal. calcd for C18H13BrClF3N2O2: C 46.83, H 2.84, N 6.07;
found C 46.83, H 2.93, N 6.00.
4-Bromo-2-(4-chlorophenyl)-1-((methylthio)methoxy)
methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (8a). Yel-
low solid, m.p. 145.9–146.7 °C; 1H NMR (CDCl3, 300 MHz)
δ: 2.09 (s, 3H, CH3), 4.55 (s, 2H, CH2), 5.35 (s, 2H, CH2),
7.46–7.56 (m, 4H, Ph H); MS (70 eV) m/z: Calcd. 438,
found 438; Anal. calcd for C15H11BrClF3N2OS: C 40.98, H
2.52, N 6.37; found C 40.85, H 2.61, N 6.34.
4-Bromo-2-(4-chlorophenyl)-1-((isopropoxymethoxy)
methyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (7d). White
solid, m.p. 74.976.9 °C; 1H NMR (CDCl3, 300 MHz) : 1.04
(d, J = 9.3 Hz, 6H, 2CH3), 3.72–3.78 (m, 1H, CH), 4.64 (s,
2H, CH2), 5.32 (s, 2H, CH2), 7.46–7.54 (m, 4H, Ph H); MS
(70 eV) m/z: Calcd. 450, found 450; Anal. calcd for
C17H15BrClF3N2O2: C 45.21, H 3.35, N 6.20; found C 45.09,
H 3.30, N 6.29.
4-Bromo-2-(4-chlorophenyl)-1-((ethylthio)methoxy)
methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (8b). White
1
solid, m.p. 97.6–98.8 °C; H NMR (CDCl3, 300 MHz) δ:
1-((2-Allyloxy)methoxy)methyl-4-bromo-2-(4-chlorophe-
nyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (7e). White
solid, m.p. 116.0–118.1 °C; 1H NMR (CDCl3, 300 MHz) :
3.95 (d, J = 5.7 Hz, 2H, CH2), 4.65 (s, 2H, CH2), 5.15–5.18
(m, 2H, CH2), 5.33 (s, 2H, CH2), 5.70–5.83 (m, 1H, CH),
1.20 (t, J = 7.2 Hz, 3H, CH3), 2.49 (q, J = 7.2 Hz, 2H, CH2),
4.58 (s, 2H, CH2), 5.35 (s, 2H, CH2), 7.44–7.55 (m, 4H, Ph
H); 13C NMR (CDCl3, 75 MHz) δ: 144.49, 137.45, 131.19,
129.62, 124.90, 121.71, 118.13, 113.24, 103.80, 99.27,
72.80, 71.14, 24.89, 14.49; MS (70 eV) m/z: Calcd. 452,

Liu AP, et al. Sci China Chem January (2013) Vol.56 No.1
121
found 452; Anal. calcd for C16H13BrClF3N2OS: C 42.36, H
C 39.57, H 2.70, N 5.77; found C 39.50, H 2.62, N 5.73.
2.89, N 6.17; found C 42.50, H 2.89, N 6.20.
4-Bromo-2-(4-chlorophenyl)-1-((2-(methylthio)ethoxy)
methyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (8c). White
solid, m.p. 66.0–67.8 °C; H NMR (CDCl3, 300 MHz)
2.2 Biological assay
1
Test insects
δ: 2.10 (s, 3H, CH3), 2.61 (t, J = 6.3 Hz, 2H, CH2), 3.52 (t, J =
6.3 Hz, 2H, CH2), 5.23 (s, 2H, CH2), 7.53 (s, 4H, Ph H); 13C
NMR (CDCl3, 75 MHz) δ: 144.41, 137.37, 131.24, 129.52,
124.79, 121.71, 118.13, 113.25, 103.73, 99.26, 75.85, 69.17,
42.27, 15.07; MS (70 eV) m/z: Calcd. 452, found 452; Anal.
calcd for C16H13BrClF3N2OS: C 42.36, H 2.89, N 6.17;
found C 42.35, H 2.86, N 6.15.
The entire set of the test insects were reared in a condi-
tioned room maintained at 25 (±1) °C, 65 (±5) % relative
humidity and 14:10 h light: dark photoperiod.
Test compounds
Stock solutions of each test compound were prepared in
DMF at a concentration of 1.0 g/L, and then diluted to the
required test concentrations with water containing Triton
X-100 (0.1 ml/L).
4-Bromo-2-(4-chlorophenyl)-1-(2-(ethylthio)ethoxy)
methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (8d). White
1
solid, m.p. 63.0–64.1 °C; H NMR (CDCl3, 300 MHz) δ:
1.21 (t, J = 6.3 Hz, 3H, CH3), 2.49 (q, J = 7.4 Hz, 2H, CH2),
2.64 (t, J = 6.6 Hz, 2H, CH2), 3.51 (t, J = 6.6 Hz, 2H, CH2),
5.23 (s, 2H, CH2), 7.53 (s, 4H, Ph H); MS (70 eV) m/z:
Calcd. 466, found 466; Anal. calcd for C17H15BrClF3N2OS:
C 43.65, H 3.23, N 5.99; found C 43.58, H 3.32, N 6.03.
4-Bromo-2-(4-chlorophenyl)-1-((2-(propylthio)ethoxy)
methyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (8e). White
solid; 1H NMR (CDCl3, 300 MHz) δ: 0.95 (t, J = 7.2 Hz, 3H,
CH3), 1.54–1.62 (m, 2H, CH2), 2.45 (t, J = 7.2 Hz, 2H,
CH2), 2.62 (t, J = 6.6 Hz, 2H, CH2), 3.50 (t, J = 6.6 Hz, 2H,
CH2), 5.23 (s, 2H, CH2), 7.53 (s, 4H, Ph H); MS (70 eV) m/z:
Calcd. 480, found 480; Anal. calcd for C17H15BrClF3N2OS:
C 44.88, H 3.56, N 5.81; found C 44.79, H 3.55, N 5.75.
4-Bromo-2-(4-chlorophenyl)-1-(2-(isopropylthio)ethoxy)
methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (8f). White
Test methods
(i) Insecticidal activity against Lepidopteran pest–Mythimna
separate [12].
The insecticidal activity against Mythimna separata of
the title compounds 6–10 and Chlorfenapyr were evaluated
using the following procedure. Ten third-instar Mythimna
separata and five pieces of corn fragments were placed in a
Petri dish, and sprayed with test solutions using a Potter
sprayer. After air-drying, they were kept in a room for nor-
mal cultivation. After 24 h, the numbers of live and dead
insects were recorded. Control groups were tested with the
solvent (DMF) only. Each assay contained three replications,
and results were averaged. Data were subjected to probit
analysis and the death rate of each tested compound was
calculated. Evaluations were based on a percentage scale of
0100, where 0 equals no activity and 100 equals total kill,
and the median lethal concentration (LC50) value of some
compounds was also calculated.
1
solid, m.p. 46.5–48.2 °C; H NMR (CDCl3, 300 MHz) δ:
1.23 (d, J = 6.6 Hz, 6H, 2CH3), 2.64 (t, J = 6.6 Hz, 2H,
CH2), 2.91–2.98 (m, 1H, CH), 3.50 (t, J = 6.6 Hz, 2H, CH2),
5.22 (s, 2H, CH2), 7.53 (s, 4H, Ph H); MS (70 eV) m/z:
Calcd. 480, found 480; Anal. calcd for C17H15BrClF3N2OS:
C 44.88, H 3.56, N 5.81; found C 44.87, H 3.66, N 5.84.
4-Bromo-2-(4-chlorophenyl)-1-(2-(methylsulfinyl)ethoxy)
methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (9). Vis-
(ii) Acaricidal activity against mite–Tetranychus urticae
[13, 14].
The acaricidal activity against Tetranychus urticae of the
title compounds 6–10 and Chlorfenapyr was evaluated us-
ing the following procedure. Fifty adults of Tetranychus
urticae were transferred to three horse bean seedlings. After
24 h, the horse bean seedlings with acarids were dipped in
the test solutions for 5–10 s, and then allowed to dry with
filter paper. After drying they were transferred to a beaker
(100 mL) containing water (10 mL) and kept at 25 °C. Each
assay contained three replications. Mortality was assessed
24 h after the treatment. Control groups were tested with the
solvent (DMF) only. Evaluations were based on a percent-
age scale of 0–100, where 0 equals no activity and 100
equals total kill.
1
cous liquid; H NMR (CDCl3, 300 MHz) δ: 2.78 (s, 3H,
CH3), 2.81 (t, J = 6.9 Hz, 2H, CH2), 3.78 (t, J = 6.9 Hz, 2H,
CH2), 5.27 (s, 2H, CH2), 7.47–7.58 (m, 4H, Ph H); 13C
NMR (CDCl3, 75 MHz) δ: 144.37, 137.51, 131.09, 129.81,
124.71, 121.72, 118.13, 113.13, 103.86, 99.40, 75.35, 61.36,
53.89, 39.17; LC-MS(APCI, Pos) m/z: Calcd. 468, found
468; Anal. calcd for C16H13BrClF3N2O2S: C 40.91, H 2.79,
N 5.96; found C 40.94, H 2.76, N 5.99.
4-Bromo-2-(4-chlorophenyl)-1-((2-(methylsulfonyl)ethoxy)
methyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (10). Vis-
cous liquid; 1H NMR (CDCl3, 300 MHz) δ: 2.90 (s, 3H, CH3),
3.18 (t, J = 5.4 Hz, 2H, CH2), 3.75 (t, J = 5.4 Hz, 2H, CH2),
5.30 (s, 2H, CH2), 7.44–7.59 (m, 4H, Ph H); 13C NMR
(CDCl3, 75 MHz) δ: 144.30, 137.56, 131.09, 129.85, 124.60,
121.68, 118.10, 112.99, 104.10, 99.57, 75.40, 62.59, 54.28,
42.92; LC-MS(APCI, Pos) m/z: Calcd. 468, found 468;
Calcd. 484, found 484; Anal. calcd for C16H13BrClF3N2O3S:
3 Results and discussion
3.1 Synthesis
The synthesis scheme is shown in Figure 2. Table 1 sum-
marizes the chemical structures of all the title compounds

122
Liu AP, et al. Sci China Chem January (2013) Vol.56 No.1
Table 1 Chemical structures, insecticidal and acaricidal activities of the target compounds (T)
Chemical structure
R
Mythimna separate
1000 mg/L 100 mg/L 10 mg/L LC50 mg/L
Tetranychus urticae
Compd.
n
1
2
3
2
2
1
1
1
1
1
1
2
2
2
1
1
2
2
2
2
2
2
500 mg/L
100
100
19.20
100
95.7
95.0
100
100
100
100
83.3
0
100 mg/L
100
10 mg/L
100
LC50 mg/L
1.27
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
7f
Cl
100
100
75
100
100
26.47
14.17
25.45
Cl
10.53
100
94.05
no test
79.58
0
2.62
Cl
no test
100
no test
no test
15.80
no test
96.55
0
>500
1.18
F
100
100
no test
100
100
100
100
100
NT
13.51
Br
100
0
no test
no test
23.95
>100
no test
0.86
OCH3
no test
100
no test
no test
100
no test
98.44
36.90
100
OCH2CH3
OCH2CH2CH3
OCH(CH3)2
OCH2CH＝CH2
OCH2C≡CH
OCH3
16.12
100
0
no test
no test
no test
no test
no test
no test
no test
>100
100
11.65
0.31
100
0
100
45
0
100
68.57
no test
no test
no test
no test
no test
no test
0
5.19
100
0
no test
0
no test
no test
no test
no test
no test
no test
3.70
>100
>500
≈500
>500
>500
>500
>500
>500
>500
>500
>500
>500
0.36
7g
7h
7i
no test
100
OCH2CH＝CH2
OCH2C≡CH
SCH3
100
NT
58.1
0
no test
no test
100
no test
no test
0
8a
8b
8c
8d
8e
8f
0
0
SCH2CH3
SCH3
100
100
100
64.58
100
90.45
90.91
100
no test
38.46
0
100
3.45
0
37.95
0
SCH2CH3
SCH2CH2CH3
SCH(CH3)2
SOCH3
100
no test
no test
no test
no test
no test
21.72
no test
no test
no test
no test
no test
100
no test
no test
no test
no test
no test
97.06
no test
100
no test
0
0
9.50
0
9
85.91
100
0
10
SO2CH3
0
0
Chlorfenapyr
100
16.22
100
6–10. The observed molecular mass for each compound was
as expected in MS analysis, H NMR data for each com-
(25.45 mg/L), 6d (15.80 mg/L), 7b ( 23.95 mg/L) and the
acaricidal potency (LC50) against mite–Tetranychus urticae
of compounds 7b (0.86 mg/L), 7d (0.31 mg/L) are compa-
rable to that of Chlorfenapyr ( 21.72 mg/L and 0.36 mg/L).
1
pound of formulas 6–10 and 13C NMR data for 6b, 6d, 7b,
7h–7i, 8b–8c, 9 and 10 are listed. Compounds 6 and 8–10
were prepared in >50% yield, but compounds 7 were syn-
thesized with a <50% yield by the procedure shown in Fig.
2 because of the nucleophilicity of the sulfur is stronger
than that of oxygen. The yields can be improved by chang-
ing the starting materials 6 (X = Cl) to 6 (X = Br) in the
synthesis of 7.
3.3 Apparent structure activity relationship
The activity of the synthesized 2-arylpyrrole derivatives
(Figure 1) depended on both n and the substituent R. n and
R have important effects on the activities.
For the same n (e.g. n = 1), when R = halo (e.g. Cl) or
saturated C2–C3 alkoxy (e.g. OCH2CH3, OCH2CH2CH3,
OCH(CH3)2), the compounds (e.g. 6b, 6d, 7b, 7d) showed
the highest activity; when R was changed from halo or
alkoxy to alkylthio and alkylsulfinyl or alkylsulfonyl, the
activities decreased (e.g. 9 ≈ 10 < 8d < 6b < 7b). The aca-
ricidal activities decreased abruptly when R was changed
from halo or alkoxy to alkylthio and alkylsulfinyl or alkyl-
sulfonyl (e.g. 8~9 << 7 ≈ 6).
For the same R (e.g. R = Cl), when n = 1, the compound
(e.g. 6a) showed the highest activity. With the increase of n,
the activity became lower and lower (e.g. 6c < 6b < 6a).
In general, for the synthesized compounds (Figure 1):
Activity order of n is: 1 ≈ 2 > 3
3.2 Insecticidal and acaricidal activities
Table 1 shows the insecticidal and acaricidal activities of
the synthesized 2-arylpyrrole derivatives. The activities of
Chlorfenapyr, the only commercialized member of a new
class of chemicals of 2-arylpyrrols, are also shown in Table
1.
As shown in Table 1, most of the synthesized
2-arylpyrrole derivatives 6–10 exhibit remarkable insecti-
cidal and/or acaricidal activities. Some compounds show
high insecticidal and/or acaricidal activities. For example,
the insecticidal potency (LC50) against Lepidopteran pest–
Mythimna separate of compounds 6a (14.17 mg/L), 6b

Liu AP, et al. Sci China Chem January (2013) Vol.56 No.1
123
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3
4
5
4 Conclusions
A series of novel 2-arylpyrrole derivatives were designed
and synthesized; their insecticidal and acaricidal activities
were evaluated against Lepidopteran pests (e.g. Mythimna
separata) and Mites (e.g. Tetranychus urticae). The results
showed that most compounds exhibited remarkable activity
against Mythimna separate and Tetranychus urticae and the
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Compound 6b has demonstrated low acute toxicity to
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results were observed in the Ames, chromosomal aberration
test, mutation assay, and mouse bone marrow micronucleus
assay; while compounds 6d [21.5 (male), 14.7 (female)
mg/kg] and 7b [178 (male), 147 (female) mg/kg] have high
acute toxicity to mammals.
6
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This work was supported by the National Basic Research Program of China
(973 Program, 2010CB126104), National Twelfth-five Key Project of China
(2011BAE06B01–03), National Natural Science Foundation of China
(21272062), the Hunan Provincial Natural Science Foundation (11JJ2006,
11JJ3022 and 10JJ3053) and Science Plan of Hunan Province (2010FJ2003).
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