Synthesis and insecticidal activity of novel dihydropyrrole derivatives with N-sulfanyl, sulfinyl, and sulfonyl moieties

Article abstract of DOI:10.1016/S0968-0896(02)00476-5

This paper reports the synthesis and insecticidal activity of a new type of dihydropyrrole derivatives with sulfur moieties such as sulfanyl, sulfinyl, and sulfonyl groups at the 1-position. These derivatives exhibited high insecticidal potency against Nilaparvata lugens and Nephotettix cincticeps. Investigation of the structure-activity relationships revealed that the alkoxycarbonyloxy groups at the 4-position tended to increase the systemic insecticidal activity.

Full text of DOI:10.1016/S0968-0896(02)00476-5

Bioorganic & Medicinal Chemistry 11 (2003) 489–494
Synthesis and Insecticidal Activity of Novel Dihydropyrrole
Derivatives with N-Sulfanyl, Sulfinyl, and Sulfonyl Moieties
Mitsuru Ito,a,* Hideshi Okui,a Harumi Nakagawa,a Shigeru Mio,a Ayako Kinoshita,a
Takashi Obayashi,a Takako Miura,a Junko Nagai,a Shinji Yokoi,a Reiji Ichinose,b
Keiji Tanaka,a Seiichiro Kodama,c Toshiaki Iwasaki,d Takaaki Miyake,d
Miho Takashiod and Jun Iwabuchid
aAgroscience Research Laboratories, Sankyo Co., Ltd., 1041 Yasu, Yasu-cho, Yasu-gun, Shiga, 520-2342, Japan
bCrop Protection Department, Sankyo Co., Ltd., 7-12, Ginza 2-chome, Chuo-ku, Tokyo, 104-8113, Japan
cMarketing Department, Agrochemicals Division, Agro & Specialty Chemicals Group, Nippon Kayaku Co., Ltd.,
11-2, Fujimi 1-chome, Chiyoda-ku, Tokyo, 102-8172, Japan
dResearch & Development Laboratories, Agro & Specialty Chemicals Group, Nippon Kayaku Co., Ltd., 225-1,
Koshikiya, Ageo-city, Saitama, 362-0064, Japan
Received 9 August 2002; accepted 24 September 2002
Abstract—This paper reports the synthesis and insecticidal activity of a new type of dihydropyrrole derivatives with sulfur moieties
such as sulfanyl, sulfinyl, and sulfonyl groups at the 1-position. These derivatives exhibited high insecticidal potency against Nila-
parvata lugens and Nephotettix cincticeps. Investigation of the structure–activity relationships revealed that the alkoxycarbonyloxy
groups at the 4-position tended to increase the systemic insecticidal activity.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
would influence the insecticidal activity. The derived
compounds demonstrated significantly high insecticidal
activity against the sucking pests such as the brown
planthopper and green peach aphid (Myzus persicae). In
an investigation of the early structure–activity study, it
was revealed that small alkoxy and alkoxyalkoxyl
groups are more favorable than others. The affected
insects died before or during ecdysis without completing
molting. This symptom is unique for hemiptera pests,
and the mode of action appears to be entirely new. In
addition, the compounds had systemic property, being
absorbed from a plant’s roots and effectively transferred
to other parts of the plant such as young leaves. This
property is especially advantageous when combating the
above sucking pests, for a systemic insecticide can
spread all through a plant and kill any targeted insects
that feed on it.6
Hemiptera insects such as the brown rice planthopper
(Nilaparvata lugens) and green rice leafhopper (Nepho-
tettix cincticeps) are the sucking pests that cause serious
damage to rice plant in a paddy field.1,2 Once they
pierce a plant and suck its sap, often the plant is blighted,
or at the very least its market value is reduced. Although
several effective insecticides have been used to control
them,3,4 a new compound with a novel mode of action is
always hankered because those pests multiple so rapidly
that the chemical-resistant strains frequently emerge.5,6
In our previous study, we reported the synthesis and
insecticidal activity of a new series of N-oxydihy-
dropyrrole derivatives (1)7,8 that were designed based on
the insecticidal and acaricidal agents reported by Bayer’s
groups (Fig. 1).9À12 Our interest focused on how the
modification of the 1-position (–ORgroup in structure 1)
The above results prompted further exploration of the
related structures. It has often been observed that the
introduction of a sulfur atom to a biologically active agent
leads to interesting biological as well as physicochemical
features.13 Thus, we decided to replace the oxygen atom
*Corresponding author. Tel.: +81-77-586-1223; fax: +81-77-586-
2538; e-mail: mtitou@shina.sankyo.co.jp
0968-0896/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00476-5

490
M. Ito et al. / Bioorg. Med. Chem. 11 (2003) 489–494
On the other hand, the lead compounds (1) showed
some phytotoxicity against crops such as rice and
cucumber. Although the modification of the 1-position
could somewhat alleviate this damage as demonstrated
in the previous work,7 sufficient crop safety was still not
obtained. Therefore, it is another important objective to
seek the possibility of alleviating the phytotoxicity by
the modifications in the present work.
In this article we report the preparation of a new series of
dihydropyrrole derivatives (2) and their insecticidal activ-
ity against N. lugens and N. cincticeps. We also make a few
brief remarks on their phytotoxicity against rice plant.
Figure 1. Structures of the lead compound (1) and derivatives studied
in the present work (2).
Results and Discussion
Chemistry
in the structure (1) with a sulfur atom and designed a
structure (2). This dihydropyrrole skeleton (2) bearing
both a sulfur moiety and an enolated 1,3-dione system is
unique to our knowledge and has the potential to pro-
vide a novel mode of action as an insecticide.
Scheme 1 illustrates the synthetic routes used to prepare
the derivatives.
Scheme 1. Synthetic routes to novel dihydropyrrole derivatives with N-sulfanyl, sulfinyl, and sulfonyl moieties.

M. Ito et al. / Bioorg. Med. Chem. 11 (2003) 489–494
491
We developed a new facile method for the introduction of
sulfur moiety to the 1-position of the dihydropyrrole
ring.14 Ultrasound treatment of dihydropyrrole derivative
and N-sulfanyl phthalimides in the presence of base suc-
cessfully provided the desired N-sulfanylated products.
Alkylsulfanyl and phenylsulfnanyl moieties were readily
introduced to the 1-position, yielding corresponding
N-sulfanylated dihydropyrrole derivatives (2a–2g).
In order to modify the 4-position of the dihydropyrrole
ring, we initially tried to remove the 3,3-dimethylbutyr-
oyl group of 2a by treating the compound with several
bases or acids. This approach proved fruitless, as we
found that the conditions strong enough to hydrolyze
the acyl moiety also removed the ethylsulfanyl group.
Surmising that the methylcarbonate groups could be
selectively hydrolyzed in milder condition without affect-
ing the alkylsulfanyl group, we applied the above ultra-
sound method to the substrate 5 and successfully
obtained N-ethylsulfanylated intermediate (6).14 The
methylcarbonate group of 6 could be easily removed by
the treatment with potassium hydroxide in a methanol-
water solution at ambient temperature, thereby produ-
cing 1-ethylsulfanyl-4-hydroxy dihydropyrrole derivative
(7). The transformation of the hydroxyl group in 7 was
mainly a strategy for improving the systemic insecticidal
activity while maintaining the contact potency. We
chose carbonate groups for this purpose because they
seemed to have an appropriate balance of lipophilicity
and hydrophilicity, properties requisite for contact and
systemic activities, respectively. Then the hydroxyl
group of 7 was converted to a variety of alkyl carbonate
groups (2h–2q) by standard methods.
Table 1. Insecticidal activity and phytotoxicity of the N-sulfanyldi-
hydropyrrole derivativesa—effects of the 1-position
Compd R1
N. lugens
N. cincticeps
OSb
Systemic
Contact
Systemic
test 1 ppm test 1 ppm test 1 ppm test 1 ppm 100 ppm
Contact Spray test
2a
2b
2c
2d
2e
2f
Et
Pr
i-Pr
Bu
i-Bu
Ph
Bn
2
2
0
0
0
0
2
4
2
4
4
4
3
3
1
4
2
0
0
0
3
1
4
4
3
4
4
4
2
2
1
0
0
0
0
2g
aInsecticidal activity and phytotoxicity were each graded into 5 classes
from 0 to 4. See text.
bOS, Oryza sativa (rice).
Table 2. Insecticidal activity and phytotoxicity of the N-sulfanyldihydropyrrole derivativesa—effects of the 4-position
Compd
R3
N. lugens
N. cincticeps
OSb
Spray
Systemic test
1 ppm 0.1 ppm
Contact test
Systemic test
1 ppm 0.1 ppm
Contact test
1 ppm
0.1 pm
1 ppm
0.1 ppm
100 ppm
2a
2h
2i
t-BuCH2—
i-PrO—
t-BuCH2O—
2
4
2
0
2
0
4
4
4
2
3
0
2
4
0
0
1
0
4
4
4
1
4
0
2
4
4
2j
1
1
0
0
4
4
0
1
4
0
1
0
0
4
4
1
0
c
2k
—
2l
2m
(i-Pr)2CHO—
c-Hex-O—
0
4
—
1
0
2
0
2
1
4
1
0
1
4
0
3
0
4
2n
0
—
4
0
4
3
0
4
0
2o
2p
i-PrO-CH2CH2O—
4
4
1
2
4
4
2
1
4
4
1
0
4
4
1
0
4
4
2q
4
0
4
2
4
0
4
1
4
aInsecticidal activity and phytotoxicity were each graded into five classes from 0 to 4. See text.
bOS, Oryza sativa (rice).
cNot determined.

492
M. Ito et al. / Bioorg. Med. Chem. 11 (2003) 489–494
It was also interesting to note that the sulfur atom
in the structure (2n) could be further oxidized to
corresponding sulfoxide (2r) and sulfone (2s), respec-
tively, by treatment with 3-chloroperbenzoic acid
(mCPBA).
Unfortunately, derivatives with improved insecticidal
activity were also more phytotoxic.
Interestingly, when the sulfur atom was oxidized to the
corresponding sulfoxide (2r), a drastic loss of activity
was observed (Table 3). On the other hand, the sulfone
derivative (2s) seemed to maintain the activity of the ori-
ginal sulfanyl compound while exerting weaker phyto-
toxic effects against rice.
Biological evaluation
Table 1 shows the insecticidal activity of the N-sulfa-
nyldihydropyrrole derivatives with various alkylsulfanyl
and phenylsulfanyl groups at the 1-position in both
systemic and contact tests against N. lugens and
N. cincticeps, along with the results of an evaluation of
their phytotoxicity against rice. In these tests, the affec-
ted insects died before or during ecdysis without com-
pletion of molting. This symptom is unique for
hemiptera pests, and these compounds might possess a
novel mode of action. Although these derivatives tended
to demonstrate high contact activity against both pests,
almost all of them showed relatively poor control in
systemic tests. The only exception was 2b (R=Pr),
which exerted complete control of N. cincticeps at
1 ppm. In assessments of the phytotoxicity, several
compounds caused moderate damage to rice at
100 ppm.
Conclusion
In this developmental study on a potential new class of
insecticides, we designed and prepared a new series of
dihydropyrrole derivatives with sulfur moieties such as
sulfanyl, sulfinyl, and sulfonyl groups at the 1-position. In
our biological evaluation, all of the derivatives but the
sulfinyl type exhibited high insecticidal activity against N.
lugens and N. cincticeps, and the alkoxycarbonyloxy
groups at the 4-position of the dihydropyrrole ring tended
to improve the systemic insecticidal activity.
Experimental
Table 2 shows the results of biological assays of the
derivatives in which the substituents at the 4-position
were variously transformed to alkoxycarbonyloxy
groups in an effort to improve the systemic insecticidal
activity. In comparison with the acyl compound (2a),
several of the modified compounds (2h, 2o, 2p, and 2q)
exhibited clearly improved systemic activity against
both N. lugens and N. cincticeps with no change in
their contact activity. Compound (2m) exhibited
improved systemic and contact activities against N.
cincticeps while its contact efficacy against N. lugens
was decreased. The other compounds tended to exhi-
bit decreases in both systemic and contact activity.
All melting points (mp) are uncorrected. IRspectra
were measured on a Perkin–Elmer 1600 spectrometer.
1H NMRspectra were recorded at 200 MHz on a Var-
ian Gemini 200 spectrometer, or at 270 MHz on a JEOL
GX 270 spectrometer with tetramethylsilane as an
internal standard. Mass spectra (MS) and high-resolu-
tion mass spectra (HRMS) were obtained with a JEOL
JMS-D300 mass spectrometer and a VG Auto Spec M
mass spectrometer.
Synthetic preparation
Details on the preparation of compounds 2a–2g, and 6
are described in ref 14.
Table 3. Insecticidal activity and phytotoxicity of the N-sulfinyl- and
N-sulfonyldihydropyrrole derivativesa
1-Ethylsulfanyl-4-hydroxy-3-mesityl-5,5-dimethyl-1,5-di-
hidropyrrol-2-one (7). A 1.65 mL volume of 1 N NaOH
aq (1.65 mmol) was added to a stirred solution of 6
(0.59 g, 1.61 mmol) in ethanol (4 mL) at 0 ꢀC, and then
the reaction mixture was stirred at 0 ꢀC for 10 min and
at ambient temperature for 30 min. After adding 1 N
HCl aq to the reaction mixture to neutralize the solution
and extracting the water layer with EtOAc, the combined
organic layer was washed with brine, dried (MgSO4), and
concentrated under reduced pressure to a solid. Treatment
of this solid by silica gel column chromatography (EtOAc/
hexane, 1/4) yielded the title compound (7, 412.1 mg,
84%) as a colorless solid. Mp 142–145 ꢀC; 1H NMR
(CDCl3) d: 6.90 (2H, s), 6.80 (1H, br s), 2.83 (2H, q,
J=7.4Hz), 2.27 (3H, s), 2.11 (6H, s), 1.47 (6H, s), 1.25
(3H, t, J=7.4Hz); IR(KBr) cm À1: 2974, 1649, 1603, 1484,
1437, 1365, 1320, 1213, 1155, 1072, 1032; HRMS(EI)
calcd for C17H23NO2S 305.1450, found 305.1449.
Compd
n
N. lugens
N. cincticeps
OSb
Systemic
test
Contact
test
Systemic
test
Contact
test
Spray
1
0.1
1
0.1
1
0.1
1
0.1
100
ppm ppm ppm pm ppm ppm ppm ppm ppm
2n
2r
2s
0
1
2
3
0
4
0
—
0
4
0
4
0
—
0
0
0
1
—
—
0
4
0
3
0
—
0
4
3
1
c
aInsecticidal activity and phytotoxicity were each graded into five
classes from 0 to 4. See text.
2-Chloro-1,1-dimethylethyl 1-(ethylsulfanyl)-4-mesityl-
2,2-dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl carbonate
(2n). Triphosgene (130.0 mg, 0.44 mmol) and pyridine
bOS, Oryza sativa (rice).
cNot determined.

M. Ito et al. / Bioorg. Med. Chem. 11 (2003) 489–494
493
(0.12 mL, 1.48 mmol) were added to a stirred solution of
2-chloro-1,1-dimethylethyl alcohol (164.9mg, 1.34mmol)
in dichloromethane (CH2Cl2) at 0 ꢀC, and then the
reaction mixture was stirred at 0 ꢀC for 45 min. Next,
the mixture was added to a stirred solution of 7
(197.8 mg, 0.65 mmol) and triethylamine (Et3N;
0.185 mL, 1.3 mmol) in CH2Cl2 (2 mL) at 0 ꢀC, then
stirred at 0 ꢀC for another 1 h. After pouring the mix-
ture into water and extracting the mixture with EtOAc,
the combined organic layer was washed with brine,
dried (MgSO4), and concentrated under reduced pres-
sure to a solid. Treatment of this solid by silica gel
column chromatography (EtOAc/hexane, 1/4) yielded
1-(Ethylsulfanyl)-4-mesityl-2,2-dimethyl-5-methylene-
2,5-dihydro-1H-pyrrol-3-yl 1-isopropyl-2-methylpropyl
ꢀ
1
carbonate (2l). Yield: 57.8%; mp 89–90 C; H NMR
(CDCl3) d: 6.80 (2H,s), 4.14 (1H, t, J=6.2 Hz), 2.89
(2H, q, J=7.3 Hz), 2.21 (3H, s), 2.15 (6H, s), 1.89–1.72
(2H, m), 1.58 (6H, s), 1.28 (3H, t, J=7.3 Hz), 0.67 (12H,
dd, J=6.6, 3.7 Hz); IR(KBr) cm À1: 2972, 1774, 1708,
1687, 1612, 1463, 1309, 1296, 1218, 1130, 1094; HRMS(EI)
calcd for C25H37NO4S 447.2443, found 447.2443.
Cyclohexyl 1-(ethylsulfanyl)-4-mesityl-2,2-dimethyl-5-
oxo-2,5-dihydro-1H-pyrrol-3-yl carbonate (2m). Yield:
1
77.2%; colorless oil; H NMR(CDCl ) d: 6.85 (2H, s),
3
the title compound (2n, 249.4 mg, 85%) as a colorless
1
4.84–4.80 (1H, m), 2.88 (2H, q, J=7.3 Hz), 2.25 (3H, s),
2.15 (6H, s), 1.69–1.36 (8H, m), 1.28 (3H, t, J=7.3 Hz);
IR(KBr) cm À1: 2975, 1777, 1714, 1682, 1613, 1456,
1360, 1311, 1216, 1152, 1034; HRMS(EI) calcd for
C23H31NO4S 417.1974, found 417.1974.
solid. Colorless oil; H NMR(CDCl ) d: 6.84 (2H, s),
3
3.85 (2H, s), 3.21 (2H, s), 2.89 (5H, q, J=7.3 Hz), 2.24
(3H, s), 2.15 (6H, s), 1.56 (6H, s), 1.28 (6H, t,
J=7.3 Hz), 0.84 (9H, s); IR(KBr) cm À1: 2975, 1775,
1711, 1684, 1614, 1464, 1312, 1257, 1210, 1186, 1146;
HRMS(EI) calcd for C23H32ClNO4S 454.1741, found
454.1742.
1-(Ethylsulfanyl)-4-mesityl-2,2-dimethyl-5-oxo-2,5-dihy-
dro-1H-pyrrol-3-yl 2-isopropoxyethyl carbonate (2o).
1
Yield: 59.2%; colorless oil; H NMR(CDCl ) d: 6.85
3
Compounds 2h–2m and 2o–2q were synthesized by the
same procedure.
(2H, s), 4.11–4.06 (2H, m), 3.54–3.39 (3H, m), 2.88 (2H,
q, J=7.3 Hz), 2.25 (3H, s), 2.15 (6H, s), 1.50 (6H, s),
1.28 (3H, t, J=7.3 Hz), 1.11 (6H, d, J=6.2 Hz); IR
; HRMS(EI) calcd for C23H33NO5S
435.2079, found 435.2080.
1-(Ethylsulfanyl)-4-mesityl-2,2-dimethyl-5-oxo-2,5-dihy-
dro-1H-pyrrol-3-yl isopropyl carbonate (2h). Yield:
(KBr) cmÀ1
1
89.3%; colorless oil; H NMR(CDCl ) d: 6.84 (2H, s),
3
3.74 (2H, d, J=6.6 Hz), 2.89 (2H, q, J=7.3 Hz), 2.25
(3H, s), 2.15 (6H, s), 1.76 (1H, sep, J=6.6 Hz), 1.50 (6H,
s), 1.29 (3H, t, J=7.3 Hz), 0.77 (6H, d, J=6.6 Hz); IR
(KBr) cmÀ1: 2972, 1778, 1715, 1683, 1613, 1464, 1377,
1309, 1215, 1187, 1155, 1025; HRMS(EI) calcd for
C22H31NO4S 405.1974, found 405.1975.
1-(Ethylsulfanyl)-4-mesityl-2,2-dimethyl-5-oxo-2,5-dihy-
dro-1H-pyrrol-3-yl tetrahydrofuran-2-ylmethyl carbonate
1
(2p). Yield: 70.4%; colorless oil; H NMR(CDCl ) d:
3
6.85 (2H, s), 4.02–3.88 (3H, m), 3.80–3.70 (2H, m), 2.88
(2H, q, J=7.3 Hz), 2.25 (3H, s), 2.15 (6H, s), 1.89–1.60
(4H, m), 1.49 (6H, s), 1.27 (3H, t, J=7.3 Hz); IR(KBr)
cmÀ1: 2978, 1783, 1708, 1686, 1614, 1446, 1378, 1286,
1204, 1185, 1158, 1204; HRMS(EI) calcd for
C23H31NO5S 433.1923, found 433.1924.
1-(Ethylsulfanyl)-4-mesityl-2,2-dimethyl-5-oxo-2,5-dihy-
dro-1H-pyrrol-3-yl neopentyl carbonate (2i). Yield:
1
69.2%; colorless oil; H NMR(CDCl ) d: 6.83 (2H, s),
3
3.67 (2H, s), 2.89 (2H, q, J=7.3 Hz), 2.24 (3H, s), 2.15
(6H, s), 1.50 (6H, s), 1.28 (3H, t, J=7.3 Hz), 0.77 (9H,
s); IR(KBr) cm À1: 2973, 1776, 1710, 1683, 1613, 1455,
1310, 1217, 1184; HRMS(EI) calcd for C23H33NO4S
419.2130, found 419.2131.
1,1-Dimethyl-2-propynyl 1-(ethylsulfanyl)-4-mesityl-2,2-
carbonate
dimethyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl
1
(2q). Yield: 10.6%; colorless oil; H NMR(CDCl ) d:
3
6.83 (2H, s), 2.88 (2H, q, J=7.3 Hz), 2.43 (1H, s), 2.23
(3H, s), 2.15 (6H, s), 1.50 (6H, s), 1.42 (6H, s), 1.27 (3H,
t, J=7.3 Hz); IR(KBr) cm À1: 2925, 1775, 1710, 1470,
1451, 1373, 1300, 1226, 1199, 1183, 1104; HRMS(EI)
calcd for C23H29NO4S 415.1817, found 415.1819.
1,2-Dimethylpropyl 1-(ethylsulfanyl)-4-mesityl-2,2-dime-
thyl-5-oxo-2,5-dihydro-1H-pyrrol-3-yl carbonate (2j).
1
Yield: 71.6%; colorless oil; H NMR(CDCl ) d: 6.83
3
(2H, s), 4.23 (1H, m), 2.89 (2H, q, J=7.3Hz), 2.23 (3H, s),
2.15 (6H, s), 1.65–1.55 (1H, m), 1.50 (6H, s), 1.28 (3H, t,
J=7.3Hz), 0.97 (3H, d, J=6.6 Hz), 0.74 (6H, dd, J=7.0,
1.8 Hz); IR (KBr) cmÀ1: 2976, 1777, 1715, 1682, 1613,
1463, 1309, 1219, 1188, 1154, 1123, 1104; HRMS(EI)
calcd for C23H33NO4S 419.2130, found 419.2129.
3-Chloro-2,2-dimethylpropyl 1-(ethylsulfinyl)-4-mesityl-
2,2-dimethyl-5-oxo- 2,5-dihydro-1H-pyrrol-3-yl carbonate
(2r) and 3-chloro-2,2-dimethylpropyl 1-(ethylsulfonyl)-4-
mesityl-2,2-dimethyl-5-oxo- 2,5-dihydro-1H-pyrrol-3-yl
carbonate (2s). mCPBA (98.7 mg, ca. 0.57 mmol) was
added to a solution of 2n (110.0 mg, 0.24 mmol) in
1,2-dichloroethane (5 mL) at ambient temperature, and
then the mixture was stirred at the same temperature for
4 h. After pouring the reaction mixture into saturated
sodium bicarbonate aqueous solution and extracting
with EtOAc, the combined organic layer was washed
with brine, dried (Mg2SO4), and evaporated under
reduced pressure to an oil. Treatment of this oil by pre-
parative thin layer chromatography (EtOAc/hexane=1/
3) gave the title compounds, 2r (18.2 mg, 16%) and 2s
(90.0 mg, 77%), separately.
1-(Ethylsulfanyl)-4-mesityl-2,2-dimethyl-5-oxo-2,5-dihy-
dro-1H-pyrrol-3-yl 1,2,2-trimethylpropyl carbonate (2k).
1
Yield: 71.9%; colorless oil; H NMR(CDCl ) d: 6.82
3
(2H, s), 4.28 (1H, q, J=6.6 Hz), 2.89 (2H, q, J=7.3 Hz),
2.22 (3H, s), 2.15 (6H, s), 1.50 (6H, s), 1.28 (3H, t,
J=7.3 Hz), 0.94 (3H, d, J=6.6 Hz), 0.75 (9H, s); IR
(KBr) cmÀ1: 2979, 1771, 1709, 1678, 1612, 1459, 1367,
1310, 1214, 1190, 1156, 1077; HRMS(EI) calcd for
C24H35NO4S 433.2287, found 433.2286.

494
M. Ito et al. / Bioorg. Med. Chem. 11 (2003) 489–494
1
2r. Colorless oil; H NMR(CDCl ) d: 6.85 (2H, s),
taken of the numbers of live and dead insects 5 days after
insect release. Immobile insects were counted as dead.
3
4.18–4.00 (1H, m), 3.84 (2H, s), 3.60–3.42 (1H, m), 3.21
(2H, s), 2.24 (3H, s), 2.18 (3H, s), 2.15 (3H, s), 1.80 (3H,
s), 1.53 (3H, s), 1.29 (3H, t, J=7.7 Hz), 0.84 (9H, s); IR
(neat) cmÀ1: 2923, 1786, 1724, 1686, 1612, 1458, 1350,
1292, 1207, 1180, 1155, 1026; HRMS(EI) calcd for
C23H32NO5S 469.1703, found 469.1706.
Phytotoxicity evaluation. Compounds were formulated
as EC and sprayed in a post-emergence glasshouse test
for rice (Oryza sativa) seedlings at doses of 100 ppm.
Seven days after treatment, damage to the plants was
visually assessed by comparison with untreated plants
using a scale of 0 to 4: 0, <10% growth inhibition; 1,
11–30% growth inhibition; 2, 31–60% growth inhibi-
tion; 3, 61–90% growth inhibition; 4, >91% growth
inhibition.
1
2s. Colorless oil; H NMR(CDCl ) d: 6.86 (2H, s),
3
3.84 (2H, s), 3.61 (2H, q, J=7.3 Hz), 3.21 (2H, s), 2.25
(3H, s), 2.15 (6H, s), 1.80 (6H, s), 1.40 (3H, t,
J=7.3 Hz), 0.84 (6H, s); IR(neat) cm À1: 2934, 1782,
1692, 1458, 1375, 1211, 1040; HRMS(EI) calcd for
C23H32NO6S 485.1639, found 485.1640.
References and Notes
1. Dent, D. Insect Pest Management; CABI Publishing: Lon-
don, 2000.
Biological tests
2. Conway, G.; In The Doubly Green Revolution—Food for All
in the 21st Century; Penguin: London, 1997; p 205.
3. Holan, G.; Winkler, D. A. In Rational Approaches to
Structure, Activity, and Ecotoxicology of Agrochemicals; Dra-
ber, W., Fujita, T., Eds.; CRC: FL, 1992; p 123.
4. Baker, D.R.; Fenyes, J. G.; Lahm, G. P.; Selby, T. P.; Ste-
venson, T. M. In Synthesis and Chemistry of Agrochemicals VI
(ACS Symposium Series 800); Baker, D. R., Fenyes, J. G.,
Lahm, G. P., Selby, T. P., Stevenson, T. M., Eds.; American
Chemical Society (Oxford University Press): Washington, DC,
2002; p 219.
Insecticidal tests. Both systemic and contact tests were
conducted against N. lugens and N. cincticeps. Each
compound was formulated as an emulsifiable con-
centrate (EC) and then diluted with water containing a
surfactant (Gramin-S; 0.01% v/v) to give the active
ingredient (AI) concentration required to assess activity
levels. The activity ratings were expressed by a five-
point index (0, 1, 2, 3, and 4) corresponding to 0–29,
30–59, 60–89, 90–99, and 100% mortality.
5. Ishaaya, I.; Horowitz, A. R. In Insecticides with Novel
Modes of Action; Ishaaya, I., Degheele, D., Eds., Springer:
Berlin, 1998; p 1.
6. Cremlyn, R. J. In Agrochemicals; John Wiley & Sons: Chi-
chester, 1991; p 1.
7. Ito, M.; Okui, H.; Nakagawa, H.; Mio, S.; Kinoshita, A.;
Obayashi, T.; Miura, T.; Nagai, J.; Yokoi, S.; Ichinose, R.;
Tanaka, K.; Kodama, K.; Iwasaki, T.; Miyake, T.; Takashio,
M.; Iwabuchi, J. Biosci. Biotechnol. Biochem. 2002, 66, 2406.
8. Ito, M.; Okui, H.; Nakagawa, H.; Mio, S.; Iwasaki, T.;
Iwabuchi, J. Heterocycles 2002, 57, 881.
9. Fisher, R.; Bretshneider, T.; Krueger, W.; Bachmann, J.;
Erdeln, C.; Wachendorff-Neumann, U.; Stantel, H. J.; Luers-
sen, K.; Schmidt, R. R.; DE Patent 4216814, 1993; Chem.
Abstr. 1993, 119, 117088b.
Tests against N. lugens and N. cincticeps. Systemic test.
A 30 mL volume of the test solution was poured into a
conical test unit (4 cm diam. Â 15 cm high). Four rice
seedlings were positioned in the unit by a notched
sponge disk that sustained the stems and shielded the
solution from contact with insects. The rice seedlings
were allowed to absorb the compound from the solution
for 3 h in a growth chamber held at 25 ꢀC and 60%
relative humidity. Ten third-instar nymphs of N. lugens
or N. cincticeps were transferred into a test tube. The
test units were then held in the growth chamber under
long-day (16L/8D) conditions at 25 ꢀC and 60% relative
humidity. Duplicate experiments were performed.
Counts were taken of the numbers of live and dead
insects after 5 days of treatment. Immobile insects were
counted as dead.
10. Fischer, R.;, Dumas, J.; Bretschneider, T.; Erdelen, C.;
Wachendorff-Neumann, U.; DE Patent 4410420, 1995; Chem.
Abstr. 1996, 124, 29593k.
11. Fischer, R.; Dumas, J.; Bretschneider, T.; Erdelen, C.;
Wachendorff-Neumann, U.; Santel, H.-J.; Dollinger, M.;
Mencke, N.; Turberg, A.; DE Patent 19518962, 1996; Chem.
Abstr. 1996, 124, 231916g.
12. Krauskopf, B.; Luerssen, K.; Stantel, H.-J.; Schmidt, R.
R.; Wachendorff-Neumann, U.; Fisher, R.; Erdelen, C.; EP
Patent 456063, 1991; Chem. Abstr. 1992, 116, 106083 h.
13. Kudo, N.; Yoneda, T.; Sato, K.; Honma, T.; Sugai, S.
Chem. Pharm. Bull. 2000, 48, 509.
Contact test. Four rice stems were immersed in the
test solution for 20 s. After drying, the stems were
transferred into a glass tube (2 cm diam. Â 10 cm high)
containing a small amount of water. Ten third-instar
nymphs or adults of N. lugens or N. cincticeps were
released into the tube and kept there at 25 ꢀC and 60%
relative humidity under long-day (16L/8D) conditions.
Duplicate experiments were performed. Counts were
14. Ito, M.; Okui, H.; Nakagawa, H.; Mio, S.; Iwasaki, T.;
Iwabuchi, J. Heterocycles 2002, 57, 909.