Synthesis and insecticidal activities of novel N-sulfenyl-N′-tert- butyl-N,N′-diacylhydrazines. 1. N-alkoxysulfenate derivatives

Article abstract of DOI:10.1021/jf072390f

A series of novel N-alkoxysulfenyl-N′-tert-butyl-N,N′- diacylhydrazines were designed and synthesized as insect growth regulators by the key intermediates N-chlorosulfenyl-N′-tert-butyl-N,N′- diacylhydrazines, which were prepared for the first time. Compa

Full text of DOI:10.1021/jf072390f

9614 J. Agric. Food Chem. 2007, 55, 9614–9619
Synthesis and Insecticidal Activities of Novel
N-Sulfenyl-N′-tert-butyl-N,N′-diacylhydrazines. 1.
N-Alkoxysulfenate Derivatives
QIQI ZHAO,† JIAN SHANG,†,‡ YUXIU LIU,† KAIYUN WANG,§ 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, Chemistry and Biologic College,
Yantai University, Yantai 264005, People’s Republic of China, and College of Plant Protection,
Shandong Agriculture University, Tai’an 271018, People’s Republic of China
A series of novel N-alkoxysulfenyl-N′-tert-butyl-N,N′-diacylhydrazines were designed and synthesized
as insect growth regulators by the key intermediates N-chlorosulfenyl-N′-tert-butyl-N,N′-diacylhydra-
zines, which were prepared for the first time. Compared to N′-tert-butyl-N,N′-diacylhydrazines, these
N-alkoxysulfenyl derivatives displayed better solubility and improved hydrophobicities. The insecticidal
activities of the new compounds were evaluated. The results of bioassays showed that the title
compounds possessed a combination of strong stomach as well as contact poison property higher
than the corresponding parent compounds. In particular, N-methoxysufenyl-N′-tert-butyl-N-4-
ethylbenzoyl-N′-3,5-dimethylbenzoylhydrazide (IIIf) as a field testing candidate has higher stomach
toxicities against oriental armyworm and beet armyworm than the corresponding parent compound
RH-5992. Furthermore, the compound IIIf exhibits higher contact activities against oriental armyworm,
Asian corn borer, tobacco cutworm, and cotton bollworm than RH-5992. The sulfenyl substituent
was essential for high larvacidal activity.
KEYWORDS: N-Sulfenate derivative; diacylhydrazine; RH-5992; stomach toxicity, contact toxicity;
insecticidal activity; insect growth regulator
INTRODUCTION
drazide analogues showed high insecticidal activities (13–15),
of which ANS-118 and JS-118 represent successful examples.
N′-tert-Butyl-N′-3,5-dimethylbenzoyl-N-5-methyl-6-chromane-
carbohydrazide (Chromafenozide; ANS-118, C) has been com-
mercialized as an insecticide under the trade name Matric (16, 17),
and N′-tert-butyl-N′-(3,5-dimethylbenzoyl)-2,7-dimethyl-2,3-
dihydrobenzofuran-6-carbohydrazide (JS-118, D) has been
developing by the Jiangsu Institute of Agricultural Chemicals,
P. R. China (18, 19).
Synthetic N-tert-butyl-N,N′-diacylhydrazines, discovered by
Rohm and Haas Company in the mid-1980s, are a promising
class of chemically and mechanistically novel insect control
agents which have been found to work as nonsteroidal ecdysone
agonists inducing, especially in Lepidoptera, precocious molting,
leading to death (1–5). Among these compounds, N-tert-butyl-
N,N′-dibenzoylhydrazine (RH-5849, A) was the first to be
thoroughly investigated with regard to insecticidal effects and
functional modes. N-tert-Butyl-N′-4-ethylbenzoyl-N-3,5-di-
methylbenzoylhydrazide (tebufenozide; RH-5992, B) was the
first to be commercialized as a leptidopteran-specific insecticide
under the trade names Mimic, Confirm, and Romdan in several
countries (6, 7). Because of the unique action mechanism, simple
structure, low toxicity to vertebrates, and high insecticidal
selectivity, diacylhydrazines have attracted considerable attention
for decades (8–12). Recently, it has been reported that N′-
benzoheterocyclecarbonyl-N-tert-butyl-3,5-dimethylbenzohy-
* To whom correspondence should be addressed. Telephone: +86-
(0)22-23499842. Fax: +86-(0)22-23499842. E-mail: wang98h@263.net.
† Nankai University.
‡ Yantai University.
However, the preceding diacylhydraines have low solubility
in water and limited solubility in common organic solvents.
§ Shandong Agriculture University.
10.1021/jf072390f CCC: $37.00
2007 American Chemical Society
Published on Web 10/18/2007

N-Sulfenyl-N′-tert-butyl-N,N′-diacylhydrazines
J. Agric. Food Chem., Vol. 55, No. 23, 2007 9615
Scheme 1. General Synthetic Route for Compound III
Table 1. Physical Properties and Elemental Analyses of the Compounds IIIa–u
elem anal. (%, calc)
compd
R
R1
R2
mp (°C)
yield (%)
C
H
N
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
IIIq
IIIr
methyl
ethyl
n-propyl
i-propyl
t-butyl
methyl
ethyl
n-propyl
i-propyl
n-butyl
i-butyl
t-butyl
n-pentyl
t-pentyl
benzyl
2-phenethyl
2-fluoroethyl
2,2,2-trifluoroethyl
2-methoxyethyl
2-ethoxyethyl
methyl
H
H
H
H
H
H
H
H
122–125
oil
oil
83–85
126–128
74–76
83–85
oil
29.6
19.5
70.0
18.5
45.3
56.6
77.0
53.8
72.2
29.7
50.7
76.6
40.7
49.8
36.0
43.7
61.2
56.7
46.3
56.6
37.0
63.38 (63.66)
64.53 (64.49)
65.20 (65.26)
65.41 (65.26)
66.07 (65.97)
66.51 (66.64)
67.17 (67.26)
67.77 (67.84)
67.88 (67.84)
68.20 (68.39)
6.13 (6.19)
6.34 (6.49)
6.54 (6.78)
6.95 (6.78)
6.93 (7.05)
7.24 (7.29)
7.57 (7.53)
7.45 (7.74)
7.72 (7.74)
7.90 (7.82)
7.61 (7.52)
7.47 (7.25)
7.46 (7.25)
7.26 (6.99)
6.77 (6.76)
6.71 (6.54)
6.40 (6.33)
6.49 (6.33)
5.99 (6.13)
H
H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
b
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
91–93
oil
oil
7.80 (7.95)
479.2343 (479.2339)a
7.93 (7.95)
8.11 (8.14)
123–125
43–45
94–96
75–76
90–92
96–98
86–88
77–79
oil
68.42 (68.39)
68.85 (68.90)
68.72 (68.90)
70.90 (70.99)
71.61 (71.40)
64.40 (64.55)
59.70 (59.74)
65.31 (65.47)
6.20 (6.13)
5.85 (5.95)
6.01 (5.95)
5.69 (5.71)
5.58 (5.55)
6.30 (6.27)
5.96 (5.81)
6.18 (6.11)
8.11 (8.14)
7.09 (6.98)
7.07 (7.19)
7.07 (7.00)
6.01 (6.06)
7.38 (7.47)
IIIs
IIIt
IIIu
495.2292 (495.2288)a
7.04 (7.06)
60–62
65.79 (65.76)
5.95 (6.14)
a The value of HRMS. b R1 is identical to the corresponding substituents of the parent compound (JS-118).
MATERIALS AND METHODS
Moreover, they have poor hydrophilicity and cuticular penetra-
tion; thus, they have low contact toxicity. These disadvantages
impede their field application (20–22).
Instruments. The title compounds were synthesized under a nitrogen
atmosphere. 1H 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) were given in ppm. Elemental
analyses were determined on a Yanaca CHN Corder MT-3 elemental
analyzer. HRMS data was obtained on a FTICR-MS instrument (Ionspec
7.0T). 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.
General Synthesis. All anhydrous solvents were dried and purified
by standard techniques just before use. N′-tert-Butyl-N,N′-diacylhy-
drazines (I) were synthesized by the literature method (3, 21). Sulfur
dichloride was prepared by the reaction of sulfur monochloride with
chlorine (26). Pyridine was distilled over sodium hydroxide pellets and
kept dry by storing over the same reagent.
The activity spectrum of a pesticide is often determined by
the physical properties of the compound, and it is possible to
develop a new insecticide with improved biological properties
by attaching an appropriate functional group to an 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 derivatizing moiety (22, 23).
For example, the N-methoxysulfenyl derivative (F) of carbofuran
displayed an insecticidal activity comparable to that of carbo-
furan (E) with a much lower mammalian toxicity (24, 25).
Encouraged by these reports, we developed an idea that the
General Synthetic Procedure for II. To a magnetically stirred and
cooled (-20 °C) solution of sulfur dichloride (0.83 g, 8 mmol) in
dichloromethane (15 mL) was added dropwise a solution of pyridine
(0.63 g, 8 mmol) in dichloromethane (5 mL). After addition was
complete, the reaction mixture was stirred below -15 °C for 15 min.
Then, a solution of N′-tert-butyl-N,N′-diacylhydrazines (I) (7 mmol)
in dichloromethane (5 mL) was added, and the resulting mixture was
stirred at room temperature for 4 h. The solvent was removed in vacuo
to afford a viscous residue, and then petroleum ether (60–90 °C (20
mL) was added. The mixture was stirred at -10 °C for 15 min and
then filtered to remove the pyridinium chloride. The filtrate was directly
used for the next step without further purification.
introduction of an alkoxysulfenyl substituent into N′-tert-butyl-
N,N′-diacylhydrazines by substituting the hydrogen on the N′
atom could improve biological properties and suffer shortcom-
ings. Therefore, in a search for new insect growth regulators
with improved profiles, we designed and synthesized a series
of novel N-alkoxysulfenyl-N′-tert-butyl-N,N′-diacylhydrazines
(III) as shown in Scheme 1.

9616 J. Agric. Food Chem., Vol. 55, No. 23, 2007
Table 2. 1H NMR of Compounds IIIa–u
compd
Zhao et al.
δ (ppm)
IIIa
IIIb
7.42–6.87 (m, 10H, Ph), 3.27 (s, 3H, OCH3), 1.67 (s, 9H, C(CH3)3)
7.45–6.78 (m, 10H, Ph), 3.48 (m, 1H, CH2), 3.15 (m, 1H, CH2), 1.60 (s, 9H, C(CH3)3), 0.84 (t, JHH ) 7.6 Hz, 3H,
CH2CH3)
3
IIIc
IIId
7.41–6.84 (m, 10H, Ph), 3.45 (m, 1H, OCH2), 3.07 (m, 1H, OCH2), 1.67 (d, 9H, C(CH3)3), 1.26 (m, 2H, CH2CH3), 0.66
(m, 3H, CH2CH3)
3
6.77–7.44 (m, 10H, Ph), 3.44–3.36 (m, 1H, CH), 1.68 (s, 9H, C(CH3)3), 1.04 (d, 3H, JHH ) 6.0 Hz, CH(CH3)2), 0.63
3
(d, 3H, JHH ) 6.0 Hz, CH(CH3)2)
7.49–6.73 (m, 10H, Ph), 0.90 (s, 9H, OC(CH3)3), 1.68 (s, 9H, NC(CH3)3)
IIIe
IIIf
3
7.26–6.85 (m, 7H, Ph), 3.31 (s, 3H, OCH3), 2.63 (q, JHH ) 7.6 Hz, 2H, PhCH2CH3), 2.24 (s, 6H, Ph(CH3)2), 1.65 (s,
3
9H, C(CH3)3), 1.20 (t, JHH ) 7.6 Hz, 3H, PhCH2CH3)
3
IIIg
IIIh
IIIi
7.26–6.83 (m, 7H, Ph), 3.65–3.54 (m, 1H, OCH2), 3.34–3.24 (m, 1H, OCH2), 2.62 (q, 2H, JHH ) 7.6 Hz, PhCH2CH3),
3
3
2.24 (s, 6H, PH(CH3)2), 1.65 (s, 9H, C(CH3)3), 1.20 (t, JHH ) 7.6 Hz, 3H, PhCH2CH3), 0.92 (t, JHH ) 7.0 Hz, 3H,
OCH2CH3)
7.26–6.83 (m, 7H, Ph), 3.54–3.44 (m, 1H, OCH2), 3.19–3.09 (m, 1H, OCH2), 2.62 (q, JHH ) 7.6 Hz, 2H, PhCH2CH3),
3
3
2.24 (s, 6H, Ph(CH3)2), 1.65 (s, 9H, C(CH3)3), 1.33–1.22 (m, 2H, CH2CH2CH3), 1.20 (t, 3H, JHH ) 7.6 Hz,
3
PhCH2CH3), 0.67 (t, 3H, JHH ) 7.2 Hz, CH2CH2CH3)
3
7.26–6.79 (m, 7H, Ph), 3.52–3.40 (m, 1H, CH), 2.63 (q, JHH ) 7.6 Hz, 2H, PhCH2CH3), 2.24 (s, 6H, Ph(CH3)2), 1.66
3
3
3
(s, 9H, C(CH3)3), 1.18 (t, JHH ) 7.6 Hz, 3H, PhCH2CH3), 1.04 (d, JHH ) 6.0 Hz, 3H, CH(CH3)2), 0.65 (d, JHH
6.0 Hz, 3H, CH(CH3)2)
)
3
IIIj
7.25–6.83 (m, 7H, Ph), 3.58–3.47 (m, 1H, OCH2), 3.21–3.10 (m, 1H, OCH2), 2.63 (q, JHH ) 7.6 Hz, 2H, PhCH2CH3),
2.24 (s, 6H, PH(CH3)2), 1.65 (s, 9H, C(CH3)3), 1.28–1.18 (m, 5H, PhCH2CH3 and CH2CH2CH2CH3), 1.15–1.02 (m,
3
2H, CH2CH2CH2CH3), 0.74 (t, JHH ) 7.2 Hz, 3H, CH2(CH2)2CH3)
3
3
IIIk
7.08 (d, JHH ) 8.1 Hz, 2H, Ph), 6.99 (s, 3H, Ph), 6.86 (d, JHH ) 8.1 Hz, 2H, Ph), 3.34–3.23 (m, 1H, OCH2),
3
2.99–2.89 (m, 1H, OCH2), 2.63 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.25 (s, 6H, Ph(CH3)2), 1.66 (s, 9H, C(CH3)3),
3
3
1.53–1.42 (m, 1H, CH2CH(CH3)2), 1.20 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3), 0.69 (d, JHH ) 6.6 Hz, 3H,
3
CH2CH(CH3)2), 0.62 (d, JHH ) 6.6 Hz, 3H, CH2CH(CH3)2)
3
IIIl
7.26–6.74 (m, 7H, Ph), 2.62 (q, JHH ) 7.6 Hz, 2H, PhCH2CH3), 2.19 (s, 6H, Ph(CH3)2), 1.67 (s, 9H, NC(CH3)3), 1.20
(t, 3H, PhCH2CH3), 0.91 (s, 9H, OC(CH3)3)
3
3
IIIm
7.08 (d, JHH ) 8.1 Hz, 2H, Ph), 6.99 (s, 3H, Ph), 6.84 (d, JHH ) 8.1 Hz, 2H, Ph), 3.59–3.46 (m, 1H, OCH2),
3
3.22–3.10 (m, 1H, OCH2), 2.63 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.25 (s, 6H, Ph(CH3)), 1.66 (s, 9H, C(CH3)3),
3
1.34–0.96 (m, 9H, PhCH2CH3 and CH2(CH2)3CH3), 0.80 (t, JHH ) 7.2 Hz, 3H, CH2(CH2)3CH3)
3
IIIn
IIIo
7.10–6.67 (m, 7H, Ph), 2.63 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.20 (s, 6H, Ph(CH3)3), 1.67 (s, 9H, C(CH3)3),
1.31–1.10 (m, 5H, PhCH2CH3 and C(CH3)2CH2CH3), 0.86 (s, 3H, C(CH3)2CH2CH3), 0.78 (s, 3H, C(CH3)2CH2CH3),
3
0.70 (t, JHH ) 7.5 Hz, 3H, C(CH3)2CH2CH3)
3
2
7.28–7.19 (m, 3H, Ph), 7.12 (d, JHH ) 8.1 Hz, 2H, Ph), 6.99 (s, 3H, Ph), 6.94–6.81 (m, 4H, Ph), 4.58 (d, JHH
)
2
3
11.4 Hz, 1H, OCH2), 4.09 (d, JHH ) 11.4 Hz, 1H, OCH2), 2.66 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.22 (s, 6H,
3
Ph(CH3)2), 1.69 (s, 9H, C(CH3)3), 1.24 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
7.24–6.79 (m, 12H, Ph), 3.80–3.67 (m, 1H, OCH2), 3.44–3.32 (m, 1H, OCH2), 2.70–2.52 (m, 4H, PhCH2CH3 and
IIIp
IIIq
3
OCH2CH2), 2.24 (s, 6H, Ph(CH3)3), 1.60 (s, 9H, C(CH3)3), 1.20 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
3
2
3
2
7.15–6.80 (m, 7H, Ph), 4.27 (t, JHH ) 4.2 Hz, JHF ) 47.4 Hz, 1H, FCH2), 4.12 (t, JHH ) 4.2 Hz, JHF ) 47.4 Hz,
3
1H, FCH2), 3.80–3.61 (m, 1H, OCH2), 3.47–3.27 (m, 1H, OCH2), 2.64 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.25 (s,
6H, Ph(CH3)2), 1.66 (s, 9H, C(CH3)3), 1.21 (t, J ) 7.5 Hz, 3H, PhCH2CH3)
3
IIIr
7.18–6.84 (m, 7H, Ph), 3.79–3.60 (m, 1H, OCH2), 3.44–3.26 (m, 1H, OCH2), 2.65 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3),
3
2.26 (s, 6H, Ph(CH3)2), 1.64 (s, 9H, C(CH3)3), 1.21 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
3
3
IIIs
7.09 (d, JHH ) 8.1 Hz, 2H, Ph), 6.99 (s, 3H, Ph), 6.85 (d, JHH ) 7.8 Hz, 2H, Ph), 3.71–3.60 (m, 1H, SOCH2),
3
3
3.34–3.24 (m, 1H, SOCH2), 3.21 (s, 3H, OCH3), 3.19 (t, JHH ) 4.8 Hz, 2H, CH3OCH2), 2.63 (q, JHH ) 7.5 Hz, 2H,
3
PhCH2CH3), 2.25 (s, 6H, Ph(CH3)2), 1.66 (s, 9H, C(CH3)3), 1.20 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
3
3
IIIt
7.08 (d, JHH ) 8.1 Hz, 2H, Ph), 6.99 (s, 3H, Ph), 6.86 (d, JHH ) 8.1 Hz, 2H, Ph), 3.72–3.61 (m, 1H, SOCH2),
3
3
3.39–3.27 (m, 3H, SOCH2 and OCH2CH3), 3.23 (t, JHH ) 7.5 Hz, 2H, SOCH2CH2), 2.63 (q, JHH ) 7.5 Hz, 2H,
3
3
PhCH2CH3), 2.24 (s, 6H, Ph(CH3)2), 1.66 (s, 9H, C(CH3)3), 1.20 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3), 1.10 (t, JHH
6.9 Hz, 3H, OCH2CH3)
7.11–6.70 (m, 5H, Ph), 4.95–4.81 (m, 1H, PhOCH(CH3)CH2), 3.32–3.21 (m, 4H, OCH3 and PhCH2), 2.81–2.72 (m, 1H,
)
IIIu
3
PhCH2), 2.26 (s, 6H, Ph(CH3)2), 1.66 (s, 9H, C(CH3)3), 1.57 (s, 3H, PhCH3), 1.42 (d, JHH ) 6.4 Hz, 3H,
PhOCH(CH3)CH2)
General Synthetic Procedure for the Target Compounds IIIa–u.
To a suspension of sodium hydride (8 mmol) in anhydrous xylene (20
mL) was added dropwise alcohol at room temperature. The reaction
mixture was warmed to about 70 °C, stirring was continued for 2 h,
and the mixture was then cooled to -10 °C. The above filtrate of
N-chlorosulfenyl diacylhydrazine (II) was added dropwise, the resulting
mixture was stirred at room temperature for 4 h and filtered, and the
filtrate was concentrated under reduced pressure. The residue was
purified by column chromatography on a silica gel using petroleum
ether (60–90 °C) and ethyl acetate as the eluent to afford the title
compounds IIIa–u.
on a dead/alive basis, and mortality rates were corrected using Abbott’s
formula (27). Evaluations are based on a percentage scale of 0–100 in
which 0 ) no activity and 100 ) total kill.
Stomach Toxicity against Oriental Armyworm (Mythimna sepa-
rata). The stomach toxicities of the title compounds IIIa–u and the
parent compounds I against Oriental armyworm were evaluated by foliar
application using the reported procedure (22, 28, 29). For the foliar
armyworm tests, 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 4 days after treatment. Each treatment was performed three
times. For comparative purposes, the parent compounds, RH-5849, RH-
5992, and JS-118, were tested under the same conditions.
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

N-Sulfenyl-N′-tert-butyl-N,N′-diacylhydrazines
J. Agric. Food Chem., Vol. 55, No. 23, 2007 9617
Table 3. Stomach Toxicities against Oriental Armyworm of Compounds
IIIa–u and Parent Compounds
were tested by topical application using the reported procedure (31, 32).
The compounds were dissolved in acetone to test at varying concentra-
tions. For each fourth-instar larva of Oriental armyworm, 0.306 µL of
tested dilution was applied on the thoracic tergite with a platinum loop.
After treatment, the insects were then transferred to their standard
rearing conditions. Mortalities were calculated 96 h after treatment,
and LD50 and LD90 values were established. Each treatment was
performed three times. Acetone alone served as a control, and RH-
5992 was used as a positive control sample.
larvicidal activity (%) at conc (mg kg-1
)
compd
IIIa
IIIb
100
100
50
25
10
5
2.5
100
85
100
0
0
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
90
100
100
50
10
10
10
100
100
100
100
100
100
100
100
100
100
100
100
Contact Toxicity against Tobacco Cutworm (Spodoptera litura),
Asian Corn Borer (Ostrinia furnacalis), and Cotton Bollworm
(HelicoWerpa armigera). The contact toxicities of the title compound
IIIf and the corresponding parent compound RH-5992 against tobacco
cutworm, Asian corn borer, and cotton bollworm were tested by topical
application using the reported procedure (31, 33, 34). The compounds
were dissolved in acetone to prepare five to seven concentrations. For
each fourth-instar larva, 1 µL of tested dilution was applied on the
thoracic tergite with an automatic microapplicator (Robbins Scientific,
America). Acetone alone served as a control, and RH-5992 was used
as a positive control sample. Usually, 40 insects per dose were tested,
and each treatment was replicated four times. After treatment, the insects
were returned to their standard rearing conditions. Mortalities were
calculated 48 h after treatment, and LD50 values (the median lethal
dose) were established.
100
100
90
100
100
100
70
100
80
90
90
100
70
80
50
90
80
60
100
70
70
50
70
90
70
90
80
100
100
100
100
IIIj
IIIk
IIIl
100
100
100
IIIm
IIIn
IIIo
IIIp
IIIq
IIIr
IIIs
IIIt
100
100
90
100
IIIu
RH-5849
RH-5992
JS-118
100
70
0
100
95
100
55
90
RESULTS AND DISCUSSION
Synthesis. N-Alkoxysulfenyl-N′-tert-butyl-N,N′-diacylhydra-
zines IIIa–u were synthesized as shown in Scheme 1. N-Chlo-
rosulfenyl-N′-tert-butyl-N,N′-diacylhydrazines (II) were pre-
pared for the first time by the reaction of sulfur dichloride with
N′-tert-butyl-N,N′-diacylhydrazines (I) in the presence of py-
ridine. The key intermediates II without further purification were
reacted with sodium alkoxy to give the title compounds IIIa–u.
We found that the title compounds III have better solubility
than the parent compound I in organic solvents such as
methylene dichloride, chloroform, toluene, xylene, petroleum
ether, etc., which should make them easier to apply in the field.
Moreover, compared to the parent compounds I, the hydropho-
bicities of the title compounds III were obviously improved.
The physical properties and elemental analyses of the title
Table 4. Stomach Toxicities against Beet Armyworm of Compounds IIIf
and RH-5992
toxic ratio
LC50 (mg/L) LC90 (mg/L) LC50 LC90
compd
IIIf
RH-5992
y ) a + bx
y ) 3.6670 + 0.9614x
y ) 3.3604 + 0.8534x
24.354
83.420
524.29
2648.6
3.4 5.1
1
1
Table 5. Contact Toxicities against Oriental Armyworm of Compounds IIIf
and RH-5992
toxic ratio
LD50
LD90
1
compounds IIIa–u are listed in Table 1, and their H NMR
compd (µg per larva) (µg per larva)
y ) a + bx
LD50 LD90
data are listed in Table 2.
IIIf
RH-5992
0.0195
0.0275
0.0479
0.0739
y ) -0.899 + 3.271x 141 154
y ) -0.813 + 2.976x 100 100
Bioassay. Stomach Toxicity against Oriental Armyworm
(Mythimna separata). Table 3 shows the stomach toxicities of
N′-tert-butyl-N,N′-diacylhydrazines and their N-alkoxysulfeny
derivatives III against oriental armyworm. The results indicate
that the title compounds III have excellent stomach toxicities
against oriental armyworm and that some of the title compounds
III exhibit higher larvicidal activities than the corresponding
parent compounds. For example, the larvicidal activities of IIIa,
IIId, and IIIe were 100% at 25 mg kg-1, whereas the
corresponding parent compound RH-5849 caused 70% mortality
at this concentration; and the larvicidal activities of IIIf, IIIh,
IIIj, IIIk, IIIm, IIIr, and IIIt at 2.5 mg kg-1 were 100%, 80%,
90%, 80%, 100%, 90%, and 90%, respectively, as compared
with 55% mortality of the corresponding parent compound RH-
5992 at the same concentration. In particular, IIIf stood out as
the best and was sent for advanced field testing. We found that
Stomach Toxicity against Beet Armyworm (Spodoptera exigua).
The stomach toxicities of the title compound IIIf and the corresponding
parent compound RH-5992 against beet armyworm were tested by the
leaf-dip method using the reported procedure (30, 31). Leaf discs (5
cm × 3 cm) were cut from fresh cabbage leaves and then were dipped
into the test solution for 3 s. After air-drying, the treated leaf discs
were placed individually into boxes (80 cm3). Each dried treated leaf
disc was infested with five third-instar beet armyworm larvae. Percent-
age mortalities were evaluated 3 days after treatment. Leaves treated
with water and acetone were provided as controls. Each treatment was
performed three times. For comparative purposes, the parent compound,
RH-5992, was tested under the same conditions.
Contact Toxicity against Oriental Armyworm (Mythimna sepa-
rata). The contact toxicities of the title compound IIIf and the
corresponding parent compound RH-5992 against Oriental armyworm
Table 6. Contact Toxicities against Asian Corn Borer, Tobacco Cutworm, and Cotton Bollworm of Compounds IIIf and RH-5992
IIIf
RH-5992
y ) a + bx
y ) a + bx
LD50(ug/g)
LD50(ug/g)
toxic ratio
Asian corn borer
tobacco cutworm
cotton bollworm
y ) 1.6368 + 2.0348x
y ) 2.4481 + 2.1164x
y ) -1.8340 + 3.6571x
44.961
16.061
73.907
y ) 3.1305 + 1.0539x
y ) 1.5124 + 1.2813x
y ) 0.2223 + 1.5321x
59.414
527.12
1311.9
1.6
32.8
17.8

9618 J. Agric. Food Chem., Vol. 55, No. 23, 2007
Zhao et al.
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Watanabe, T.; Yajima, Y.; Kodama, S.; Masui, A. Synthesis and
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Watanabe, T.; Yajima, Y.; Kodama, S.; Masui, A. Synthesis and
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Shirakura, H.; Watanabe, T.; Yajima, Y.; Kodama, S.; Masui, A.
Synthesis and insecticidal activity of benzoheterocyclic analogues
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compound IIIf is highly active in the field, comparable to the
case in laboratory tests, which will be the subject of a subsequent
publication.
Stomach Toxicity against Beet Armyworm (Spodoptera ex-
igua). Table 4 shows the stomach toxicities of the field testing
candidate IIIf and the corresponding parent compound RH-
5992 against beet armyworm. LC50 is the median lethal
concentration, and LC90 is the lethal concentration at 90%. The
results indicated that the stomach toxicity of IIIf against beet
armyworm was 3.4-fold higher than that of RH-5992 from the
value of LC50 and 5.1-fold higher from the value of LC90.
The results of the stomach toxicities of the title compounds
III against oriental armyworm and beet armyworm implied that
the introduction of the N-alkoxysulfenate was essential for the
larvacidal activity, and the changes in physical properties might
account for the improvement of larvicidal activities.
Contact Toxicity against Oriental Armyworm (Mythimna
separata). Table 5 shows the contact toxicities of the field
testing candidate IIIf and the corresponding parent compound
RH-5992 against oriental armyworm. The results indicated that
IIIf has higher contact activity than RH-5992.
Contact Toxicity against Tobacco Cutworm (Spodoptera
litura), Asian Corn Borer (Ostrinia furnacalis), and Cotton
Bollworm (HelicoVerpa armigera). Table 6 shows the contact
toxicities of the field testing candidate IIIf and the corresponding
parent compound RH-5992 against Asian corn borer, tobacco
cutworm, and cotton bollworm. The results indicated that IIIf
has higher contact activities than RH-5992, especially toward
tobacco cutworm and cotton bollworm, 32.8 times and 17.8
times, respectively. This could be explained by the marked
changes of the physical properties, particularly the decrease of
the polarity and the increase of the lipophilicity, both of which
lead to the enhancement of cuticular penetration and body
assimilation.
In summary, a series of novel N-alkoxysulfenyl-N′-tert-butyl-
N,N′-dyacylhydrazines were designed and synthesized as insect
growth regulators from the key intermediates N-chlorosulfenyl-
N′-tert-butyl-N,N′-diacylhydrazines, which were prepared for the
first time. Compared to N′-tert-butyl-N,N′-diacylhydrazines,
these N-alkoxysulfeny derivatives displayed better solubility and
improved hydrophobicities. The results of bioassays showed that
the title compounds possessed a combination of strong stomach
as well as contact poison properties higher than those of the
corresponding parent compounds. In particular, N-methoxysufe-
nyl-N′-tert-butyl-N-4-ethylbenzoyl-N′-3,5-dimethylbenzoylhy-
drazide (IIIf) as a field testing candidate has higher stomach
toxicities against oriental armyworm and beet armyworm than
the corresponding parent compound RH-5992. Furthermore, the
compound IIIf exhibits higher contact activities against oriental
armyworm, Asian corn borer, tobacco cutworm, and cotton
bollworm than RH-5992. The sulfenyl substituent was essential
for highlarvacidal activity.
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H.; Ma, H. J.; Wang, F. Y.; Ni, Y. P.; Guo, L. P. Preparation of
diacylhydrazines insecticides and their intermediates. CN 1313276,
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Received for review August 8, 2007. Revised manuscript received
September 21, 2007. Accepted September 21, 2007. This work was sup-
portedbytheNationalKeyProjectforBasicResearch(2003CB114400),
the National Natural Science Foundation of China (20672064 and
20421202), the Program for New Century Excellent Talents in
University (NCET-04-0228), and the Foundation for the Author of
National Excellent Doctoral Dissertation of P. R. China (200255).
JF072390F