Synthesis and insecticidal activities of novel N-sulfenyl-N′-tert- butyl-N,N′-diacylhydrazines. 2. N-substituted phenoxysulfenate derivatives

Article abstract of DOI:10.1021/jf800740z

A series of novel N-substituted phenoxysulfenyl-N′-tert-butyl-N, N′-diacylhydrazines were designed and synthesized as insect growth regulators via the key intermediates N-chlorosulfenyl-N′-tert-butyl-N, N′-diacylhydrazines. Compared to the parent compound

Full text of DOI:10.1021/jf800740z

5254 J. Agric. Food Chem. 2008, 56, 5254–5259
Synthesis and Insecticidal Activities of Novel
N-Sulfenyl-N′-tert-butyl-N,N′-diacylhydrazines. 2.
N-Substituted Phenoxysulfenate Derivatives
QIQI ZHAO,† JIAN SHANG,‡,† ZHIQIANG HUANG,† 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-substituted phenoxysulfenyl-N′-tert-butyl-N,N′-diacylhydrazines were designed
and synthesized as insect growth regulators via the key intermediates N-chlorosulfenyl-N′-tert-butyl-
N,N′-diacylhydrazines. Compared to the parent compounds, these N-substituted phenoxysulfenyl
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-(4-chlorophenoxy)sulfenyl-N′-tert-butyl-N-4-ethyl-
benzoyl-N′-3,5-dimethylbenzoylhydrazide (IIIi) as a field testing candidate has higher stomach
toxicities against oriental armyworm and tobacco cutworm than the corresponding parent compound
RH-5992. Furthermore, the compound IIIi exhibits higher contact activities against Asian corn borer,
tobacco cutworm, and cotton bollworm than RH-5992.
KEYWORDS: N-Sulfenate derivative; substituted phenoxysulfenyl; diacylhydrazine; RH-5992; stomach
toxicity; contact toxicity; insecticidal activity; insect growth regulator
INTRODUCTION
N-tert-Butyl-N,N′-diacylhydrazines, discovered by Rohm and
Haas Company, are a class of chemically and mechanistically
novel insect growth regulator which have been found to work
as nonsteroidal ecdysone agonists inducing, especially in
Lepidoptera, precocious molting, leading to death (1–5). Because
of the unique action mechanism, simple structure, low toxicity
to vertebrates, and high insecticidal selectivity, diacylhydrazines
have attracted considerable attention for decades (6–10). Among
these active compounds, N-tert-butyl-N,N′-dibenzoylhydrazine
(RH-5849, A) was the first to be thoroughly investigated with
regard to the insecticidal effects and the functional modes.
N-tert-Butyl-N′-4-ethylbenzoyl-N-3,5-dimethylbenzoyl hydrazide
(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 (11, 12).
N-tert-Butyl-N′-4-chlorobenzoyl-N-benzoyl hydrazide (ha-
lofenozide, RH-0345, C), developed by Rohm and Haas
Company and American Cyanamid Company, was found to bear
high activity against Coleopteran larvae and ova, though the
activity against Lepidoptera was lower than that of tebufenozide
(13). N-tert-Butyl-N′-3-methoxy-2-methylbenzoyl-N-3,5-di-
methylbenzoyl hydrazide (methoxyfenozide, RH-2485, D),
developed by Rohm and Haas Company, exhibited higher
* 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.
§ Shandong Agriculture University.
10.1021/jf800740z CCC: $40.75  2008 American Chemical Society
Published on Web 06/10/2008

Synthesis and Insecticidal Activities of Novel Diacylhydrazines
J. Agric. Food Chem., Vol. 56, No. 13, 2008 5255
Scheme 1. General Synthetic Route for Compound III
Table 1. Physical Properties and Elemental Analyses of the Compounds IIIa-y
elemental analysis (%, calcd)
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
H
4-Cl
4-Me
H
2-Br
4-Br
2-Cl
3-Cl
4-Cl
2,4-Cl2
2,4,6-Cl3
2-Me
H
H
H
H
H
H
85-86
14.9
42.9
33.3
83.9
62.6
82.0
64.2
46.6
85.0
62.3
16.2
26.2
40
72.4
48.4
28.2
39.5
48.0
70.9
78.0
64.7
72.3
43.1
74.3
62.2
68.66 (68.55)
63.49 (63.36)
68.96 (69.10)
70.77 (70.56)
60.42 (60.54)
60.62 (60.54)
65.71 (65.80)
65.70 (65.80)
65.70 (65.80)
61.44 (61.65)
57.84 (57.99)
70.83 (70.99)
70.86 (70.99)
70.82 (70.99)
71.22 (71.40)
68.55 (68.75)
68.71 (68.75)
68.74 (68.75)
67.49 (67.39)
67.59 (67.39)
67.25 (67.39)
73.64 (73.88)
64.98 (65.14)
64.04 (63.80)
58.86 (58.90)
5.84 (5.75)
5.20 (5.10)
5.93 (6.03)
6.51 (6.77)
5.49 (5.62)
5.72 (5.62)
6.31 (6.11)
6.12 (6.11)
6.17 (6.11)
5.58 (5.54)
5.23 (5.04)
7.07 (6.98)
7.03 (6.98)
6.79 (6.98)
7.20 (7.19)
6.69 (6.76)
6.71 (6.76)
6.54 (6.76)
6.28 (6.41)
6.25 (6.41)
6.60 (6.41)
6.69 (6.56)
5.97 (6.01)
6.07 (5.93)
4.62 (4.53)
6.91 (6.66)
6.42 (6.16)
6.49 (6.45)
5.74 (5.88)
5.09 (5.04)
5.13 (5.04)
5.65 (5.48)
5.65 (5.48)
5.53 (5.48)
5.14 (5.14)
5.01 (4.83)
5.91 (5.71)
5.89 (5.71)
5.94 (5.71)
5.53 (5.55)
5.57 (5.53)
5.51 (5.53)
5.80 (5.53)
5.33 (5.24)
5.21 (5.24)
5.39 (5.24)
5.05 (5.07)
5.21 (5.06)
5.69 (5.31)
5.75 (5.72)
121-123
145-146
75-77
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
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
H
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
4-Et
a
122-124
80-82
114-116
74-76
84-86
126-127
121-123
111-113
65-67
87-89
133-135
89-92
94-96
97-99
122-124
93-95
3-Me
4-Me
3,4-Me2
2-OMe
3-OMe
4-OMe
2-CO2Me
3-CO2Me
4-CO2Me
4-Ph
IIIs
IIIt
IIIu
IIIv
IIIw
IIIx
IIIy
104-106
132-134
72-74
62-64
140-142
4-Cl
4-Cl
4-Cl
3-OMe, 2-Me
Cl
a R1 is identical with the corresponding substituents of the parent compound (JS-118).
activity against Lepidoptera and wider insecticidal spectrum than
tebufenozide (14, 15). Both methoxyfenozide and halofenozide
were characterized with significant root systemic activity. It has
been reported that N′-benzoheterocyclecarbonyl-N-tert-butyl-
3,5-dimethylbenzohydrazide analogues showed high insecticidal
activities (16–18), 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, E) has been commercialized as insecticide under the trade
name Matric (19, 20), and N′-tert-butyl-N′-3,5-dimethylbenzoyl-
2,7-dimethyl-2,3-dihydrobenzofuran-6-carbohydrazide (JS-118,
F) has been developing by Jiangsu Institute of Agricultural
Chemicals, P. R. China (21, 22).
may be manipulated to obtain products with other selected types
of activity by proper selection of the derivatizing moiety (24–27).
For example, N-methoxysulfenyl-N′-tert-butyl-N-4-ethylben-
zoyl-N′-3,5-dimethylbenzoylhydrazide (G), the N-methoxy
sulfenate derivative of RH-5992, showed higher stomach and
contact activities than the parent compound RH-5992 (28).
However, the preceding diacylhydraines have low solubility
in water and limited solubility in common organic solvents.
Moreover, they have poor hydrophobicity and cuticular penetra-
tion; thus, they have low contact toxicity. These disadvantages
impede their field application (15, 23, 24).
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
It has been reported that phenyl group has better hydropho-
bicity than short-chain alkyl groups (29). Hence, we developed
an idea that the introduction of an substituted phenoxysulfenyl
substituent into N′-tert-butyl-N,N′-diacylhydrazines by substitut-
ing the hydrogen on the N′ atom could improve hydrophobicity
and biological properties. Herein, we are reporting the synthesis
and insecticidal activities of a series of novel N-substituted
phenoxysulfenyl-N′-tert-butyl-N,N′-diacylhydrazines (III) as
shown in Scheme 1.

5256 J. Agric. Food Chem., Vol. 56, No. 13, 2008
Table 2. 1H NMR of Compounds IIIa-y
compd
Zhao et al.
δ (ppm)
IIIa
IIIb
IIIc
IIId
7.44-6.77 (m, 15H, Ph), 1.66 (s, 9H, C(CH3)3)
7.42-6.57 (m, 14H, Ph), 1.67 (s, 9H, C(CH3)3)
7.47-6.60 (m, 14H, Ph), 2.26 (s, 3H, PhCH3), 1.66 (s, 9H, C(CH3)3)
3
7.12-6.77 (m, 12H, Ph), 2.63 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.21 (s, 6H,
3
Ph(CH3)2), 1.63 (s, 9H, C(CH3)3), 1.23 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3),
3
IIIe
IIIf
IIIg
IIIh
IIIi
7.50-6.79 (m, 11H, Ph), 2.66 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.24 (s, 6H,
3
Ph(CH3)2), 1.60 (s, 9H, C(CH3)3), 1.24 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
3
7.12-6.55 (m, 11H, Ph), 2.64 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.22 (s, 6H,
3
Ph(CH3)2), 1.66 (s, 9H, C(CH3)3), 1.22 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
3
7.31-6.77 (m, 11H, Ph), 2.64 (q, JHH ) 7.8 Hz, 2H, PhCH2CH3), 2.22 (s, 6H,
3
Ph(CH3)2), 1.61 (s, 9H, C(CH3)3), 1.22 (t, JHH ) 7.8 Hz, 3H, PhCH2CH3)
3
7.09-6.50 (m, 11H, Ph), 2.64 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.22 (s, 6H,
3
Ph(CH3)2), 1.66 (s, 9H, C(CH3)3), 1.22 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
3
7.00-6.60 (m, 11H, ph), 2.64 (q,
) 7.5 Hz, 2H, PhCH2CH3), 2.22 (s, 6H,
HH
3
Ph(CH3)2), 1.66 (s, 9H, C(CH3)3), 1.23 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3),,
3
IIIj
7.25-6.54 (m, 10H, Ph), 2.64 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.23 (s, 6H,
3
Ph(CH3)2), 1.64 (s, 9H, C(CH3)3), 1.24 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
7.04-6.68 (m, 9H, Ph), 2.49 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.25 (s, 6H,
3
IIIk
IIIl
3
Ph(CH3)2), 1.76 (s, 9H, C(CH3)3), 1.11 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
3
7.30-6.62 (m, 11H, Ph), 2.67 (q, JHH ) 7.8 Hz, 2H, PhCH2CH3), 2.14 (s, 9H,
3
Ph(CH3)2 and PhCH3), 1.63 (s, 9H, C(CH3)3), 1.25 (t, JHH )7.8 Hz, 3H,
PhCH2CH3)
3
IIIm
IIIn
IIIo
IIIp
IIIq
IIIr
7.09-6.60 (m, 11H, Ph), 2.63 (q, JHH )7.8 Hz, 2H, PhCH2CH3), 2.20 (s, 9H,
3
Ph(CH3)2 and PhCH3), 1.65 (s, 9H, C(CH3)3), 1.22 (t, JHH )7.8 Hz, 3H,
PhCH2CH3)
3
7.00-6.64 (m, 11H, Ph), 2.63 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.26 (s, 3H,
3
PhCH3), 2.21 (s, 6H, Ph(CH3)2), 1.64 (s, 9H, C(CH3)3), 1.23 (t, JHH ) 7.5 Hz,
3H, PhCH2CH3),
3
7.05-6.48 (m, 10H, Ph), 2.63 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3), 2.20 (s, 6H,
Ph(CH3)2), 2.16 (s, 3H, PhCH3), 2.09 (s, 3H, PhCH3), 1.66 (s, 9H, C(CH3)3),
3
1.22 (t, JHH ) 7.5 Hz, 3H, PhCH2CH3)
3
6.99-6.65 (m, 11H, Ph), 3.71 (s, 3H, OCH3), 2.56 (q, JHH ) 7.5 Hz, 2H,
3
PhCH2CH3), 2.25 (s, 6H, Ph(CH3)2), 1.65 (s, 9H, C(CH3)3), 1.18 (t, JHH )7.5
Hz, 3H, PhCH2CH3)
7.10-6.29 (m, 11H, Ph), 3.70 (s, 3H, OCH3), 2.63 (q, JHH ) 7.5 Hz, 2H,
3
3
PhCH2CH3), 2.21 (s, 6H, Ph(CH3)2), 1.65 (s, 9H, C(CH3)3), 1.22 (t, JHH ) 7.5
Hz, 3H, PhCH2CH3)
3
3
7.04-6.70 (m, 7H, Ph), 6.67 (d, JHH ) 9.0 Hz, 2H, Ph), 6.59 (d, JHH ) 9.0
3
Hz, 2H, Ph), 3.74 (s, 3H, OCH3), 2.62 (q, JHH ) 7.5 Hz, 2H, PhCH2CH3),
3
2.22 (s, 6H, Ph(CH3)2), 1.65 (s, 9H, C(CH3)3), 1.22 (t, JHH ) 7.5 Hz, 3H,
PhCH2CH3)
7.76-6.76 (m, 11H, Ph), 3.86 (s, 3H, OCH3), 2.62 (q, JHH ) 7.5 Hz, 2H,
PhCH2CH3), 2.21 (s, 6H, Ph(CH3)2), 1.62 (s, 9H, C(CH3)3), 1.22 (tt, JHH ) 7.5
Hz, 3H, PhCH2CH3)
7.76-6.56 (m, 11H, Ph), 3.91 (s, 3H, OCH3), 2.59 (q, JHH ) 7.5 Hz, 2H,
PhCH2CH3), 2.21 (s, 6H, Ph(CH3)2), 1.67 (s, 9H, C(CH3)3), 1.20 (t, JHH ) 7.5
Hz, 3H, PhCH2CH3)
7.88-6.62 (m, 11H, Ph), 3.90 (s, 3H, OCH3), 2.64 (q, JHH ) 7.5 Hz, 2H,
PhCH2CH3), 2.22 (s, 6H, Ph(CH3)2), 1.65 (s, 9H, C(CH3)3), 1.24 (t, JHH ) 7.5
Hz, 3H, PhCH2CH3)
7.54-7.27 (m, 7H, Ph), 7.07-6.70 (m, 9H, Ph), 2.61 (q, JHH ) 7.5 Hz, 2H,
PhCH2CH3), 2.22 (s, 6H, Ph(CH3)2), 1.68 (s, 9H, C(CH3)3), 1.19 (t, JHH ) 7.5
Hz, 3H, PhCH2CH3)
7.08-6.50 (m, 9H, Ph), 4.97-4.79 (m, 1H, PhOCH(CH3)CH2), 3.31-3.19 (m,
1H, PhOCH(CH3)CH2), 2.83-2.68 (m, 1H, PhOCH(CH3)CH2), 2.27 (s, 6H,
Ph(CH3)2), 1.69 (s, 9H, C(CH3)3), 1.59-1.41 (m, 6H, PhOCH(CH3)CH2 and
PhCH3)
3
IIIs
IIIt
3
3
3
3
IIIu
IIIv
IIIw
3
3
3
IIIx
IIIy
7.08-6.42 (m, 10H, Ph), 3.78 (s, 3H, OCH3), 2.28 (s, 6H, Ph(CH3)2), 1.70 (s,
9H, C(CH3)3), 1.51 (s, 3H, PhCH3)
7.45-7.27 (m, 5H, Ph), 7.16-7.00 (m, 4H, Ph), 6.72-6.49 (m, 3H, Ph), 1.66
(s, 9H, C(CH3)3)
MATERIALS AND METHODS
composition was 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 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-
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) are given in ppm. Elemental

Synthesis and Insecticidal Activities of Novel Diacylhydrazines
J. Agric. Food Chem., Vol. 56, No. 13, 2008 5257
Table 3. Stomach Toxicities against Oriental Armyworm of Compounds
IIIa-y and Parent Compounds
temperature. The reaction mixture was warmed to about 70 °C, and
stirring was continued for 2 h and 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 a mixture
of petroleum ether (60-90 °C) and ethyl acetate as the eluent to afford
the title compounds IIIa-y.
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 (31). 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-y and the
parent compounds I against oriental armyworm were evaluated by foliar
application using the reported procedure (24, 28, 32, 33). 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, JS-118, RH-2485, and RH-0345, were tested under the same
conditions.
larvicidal activity (%) at a concentration of
compd 50 mg kg-1 25 mg kg-1 10 mg kg-1 5 mg kg-1 2.5 mg kg-1
IIIa
IIIb
IIIc
IIId
100
100
100
100
100
100
80
0
0
10
100
100
90
100
100
95
90
100
90
90
100
95
100
70
90
100
100
100
90
100
100
100
100
30
/
95
100
100
70
70
30
50
80
80
90
40
50
60
70
30
10
80
50
80
60
80
100
90
90
100
0
IIIe
IIIf
IIIg
IIIh
IIIi
IIIj
IIIk
IIIl
IIIm
IIIn
IIIo
IIIp
IIIq
IIIr
IIIs
IIIt
IIIu
IIIv
IIIw
IIIx
IIIy
RH-5849
RH-5992
JS-118
RH-2485
RH-0345
Stomach Toxicity against Tobacco Cutworm (Spodoptera litura).
The stomach toxicities of the title compound IIIi and the corresponding
parent compound RH-5992 against tobacco cutworm were tested by
leaf-dip method using the reported procedure (28, 34, 35). 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 disk was infested with five third-instar tobacco cutworm larvae.
Percentage 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.
100
70
/
/
100
0
100
/
100
/
/
/
55
90
100
10
100
Table 4. Stomach Toxicities against Tobacco Cutworm of Compounds IIIi
and RH-5992
compd
IIIi
RH-5992
y ) a + bx
LC50 (mg/L)
toxic ratio
Contact Toxicity against Tobacco Cutworm (Spodoptera litura),
Asian Corn Borer (Ostrinia furnacalis), and Cotton Bollworm
(HelicoWerpa armigera). The contact toxicities of the title compound
IIIi 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 (35–37). 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). 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.
y ) 1.5640 + 3.6577x
y ) 3.5588 + 1.2691x
7.215
11.178
1.55
1
drazines (I) were synthesized by the literature method (3, 23). Sulfur
dichloride was prepared by the reaction of sulfur monochloride with
chlorine (30). Pyridine was distilled over sodium hydroxide pellets and
kept dry by storing over the same reagent.
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.
RESULTS AND DISCUSSION
Synthesis. N-Substituted phenoxysulfenyl-N′-tert-butyl-
N,N′-diacylhydrazines (IIIa-y) were synthesized as shown
in Scheme 1. N-Chlorosulfenyl-N′-tert-butyl-N,N′-diacylhy-
drazines (II) were prepared by the reaction of sulfur
dichloride with N′-tert-butyl-N,N′-diacylhydrazines (I) in the
presence of pyridine according to our previous work (28).
General Synthetic Procedure for the Target Compounds IIIa-y.
To a suspension of sodium hydride (8 mmol) in anhydrous xylene (20
mL) was added substituted phenol (7 mmol) in small portions at room
Table 5. Contact Toxicities against Asian Corn Borer, Tobacco Cutworm, and Cotton Bollworm of Compounds IIIi and RH-5992
IIIi RH-5992
y ) a + bx
LD50 (µg/g)
y ) a + bx
LD50 (µg/g)
toxic ratio
Asian corn borer
tobacco cutworm
cotton bollworm
y ) 2.0735 + 1.9932x
y ) 2.5178 + 1.7545x
y ) 2.1725 + 1.5087x
29.393
25.986
74.835
y ) 3.1305 + 1.0539x
y ) 1.5124 + 1.2813x
y ) 0.2223 + 1.5321x
59.414
527.12
1311.9
2.0
20.3
17.5

5258 J. Agric. Food Chem., Vol. 56, No. 13, 2008
Zhao et al.
The key intermediates II without further purification were
reacted with sodium substituted phenoxy to give the title
compounds IIIa-y. 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 hydrophobicities of the title compounds
III were obviously improved. The physical properties and
elemental analyses of the title compounds IIIa-y are listed
toxicities against oriental armyworm and tobacco cutworm than
the corresponding parent compound RH-5992. Furthermore,
compound IIIi exhibits higher contact activities against Asian
corn borer, tobacco cutworm, and cotton bollworm than that of
RH-5992.
LITERATURE CITED
(1) Wing, K. D. RH5849, anonsteroidal ecdysone agonist: effects on
a Drosophila cell line. Science (Washington, DC) 1988, 241, 467–
469.
(2) Wing, K. D.; Slawecki, R. A.; Carlson, G. R. RH5849, a
nonsteroidal ecdysone agonist effects on Lepidoptera. Science
(Washington, DC) 1988, 241, 470–472.
(3) Hsu, A. C.-T. 1,2-Diacyl-1-alkylhydrazines, a new class of insect
growth regulators. In Synthesis and Chemistry of Agrochemicals
II; Baker, B. R., Fenyes, J. G., Moberg, W. K. Eds.; ACS
Sympoisum Series 443; American Chemical Society: Washington,
DC, 1991; pp 478-490.
(4) Aller, H. E.; Ramsay, J. R. RH-5849: a novel insect growth
regulator with a new mode of action. Brighton Crop Prot. Conf.
Pests Dis. 1988, 2, 511–518.
(5) Dhadialla, T. S.; Carlson, G. R.; Le, D. P. New insecticides with
ecdysteroidal and juvenile hormone activity. Annu. ReV. Entomol.
1998, 43, 545–569.
(6) Qian, X. H. Molecular modeling study on the structure-activity
relationship of substituted dibenzoyl-1-tert-butylhydrazines and
their structural similarity to 20-hydroxyecdysone. J. Agric. Food
Chem. 1996, 44, 1538–1542.
(7) Cao, S.; Qian, X. H.; Song, G. H. N′-tert-Butyl-N′-aroyl-N-
(alkoxycarbonylmethyl)-N-aroylhydrazines, a novel nonsteroidal
ecdysone agonist: syntheses, insecticidal activity, conformational,
and crystal structure analysis. Can. J. Chem. 2001, 79, 272–278.
(8) Wang, Q. M.; Huang, R. Q.; Bi, F. C. Dithiobis(hydrazide)
compounds and its application. CN1271727, 2000.
(9) Mao, C. H.; Wang, Q. M.; Huang, R. Q.; Bi, F. C.; Wang, K. L.
Preparation of diacylhydrazide derivatives as insect growth
regulators. CN 1654464, 2005.
1
in Table 1, and their H NMR data are listed in Table 2.
Bioassay. Stomach Toxicity against Oriental Armyworm
(Mythimna separata). Table 3 shows the stomach toxicities of
N′-tert-butyl-N,N′-diacylhydrazines and their N-substituted phe-
noxysulfeny derivatives III against oriental armyworm. The
results indicate that the title compounds III have excellent
stomach toxicities against oriental armyworm, and some of the
title compounds III exhibit higher larvicidal activities than the
corresponding parent compounds. For example, the larvicidal
activities of IIIa and IIIb were 100% at 25 mg kg-1, whereas
the corresponding parent compound RH-5849 caused 70%
mortality at this concentration; the larvicidal activities of IIIg,
IIIh, IIIi, IIIp, IIIr, IIIt, IIIu, and IIIv at 2.5 mg kg-1 were
80%, 80%, 90%, 80%, 80%, 80%, 100%, and 90%, respectively,
as compared with 55% mortality of the corresponding parent
compound RH-5992 at the same concentration. In particular,
IIIi was sent for advanced testing.
Stomach Toxicity against Tobacco Cutworm (Spodoptera
litura). Table 4 shows the stomach toxicities of the field testing
candidate IIIi and the corresponding parent compound RH-
5992 against tobacco cutworm. The results indicated that the
stomach toxicity of IIIi against tobacco cutworm was 1.55-
fold as high as that of RH-5992 from the value of LC50.
The results of the stomach toxicities of the title compounds
III against oriental armyworm and tobacco cutworm implied
that the introduction of the N-substituted phenoxysulfenate was
essential for the larvacidal activity, and the changes in physical
properties might account for the improvement of larvicidal
activities.
(10) Zhao, P. L.; Li, J.; Yang, G. F. Synthesis and insecticidal activity
of chromanone and chromone analogues of diacylhydrazines.
Bioorg. Med. Chem. 2007, 15, 1888–1895.
(11) Dhadialla, T. S.; Jansson, R. K. Non-steroidal ecdysone agonists:
new tools for IPM and insect resistance management. Pestic. Sci.
1999, 55, 357–359.
Contact Toxicity against Tobacco Cutworm (Spodoptera
litura), Asian Corn Borer (Ostrinia furnacalis), and Cotton
Bollworm (HelicoVerpa armigera). Table 5 shows the contact
toxicities of the field testing candidate IIIi and the corresponding
parent compound RH-5992 against Asian corn borer, tobacco
cutworm, and cotton bollworm. The results indicated that IIIi
has higher contact activities than RH-5992, especially toward
tobacco cutworm and cotton bollworm, 20.3 times and 17.5
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.
(12) Heller, J. J.; Mattioda, H.; Klein, E.; Sagenmuller, A. Field
evalution of RH-5992 on lepidopterous pests in Europe. Brighton
Crop Prot. Conf. Pests Dis. 1992, 1, 59–66.
(13) Cowles, R. S.; Villani, M. G. Susceptibility of Japanese beetle,
Oriental beetle, and European chafer (Coleoptera: Scarabaeidae)
to halofenozide, an insect growth regulator. J. Econ. Entomol.
1996, 89, 1356–1365.
(14) Le, D. P.; Thirugnanam, M.; Lidert, Z.; Carlson, G. R.; Ryan,
J. B. RH-2485: a new selective insecticide for caterpillar control.
Brighton Crop Prot. Conf. Pests Dis. 1996, 481–486.
(15) Carlson, G. R.; Dhadialla, T. S.; Hunter, R.; Jansson, R. K.; Jany,
C. S.; Lidert, Z.; Slawecki, R. A. The chemical and biological
properties of methoxyfenozide, a new insecticidal ecdysteroid
agonist. Pest Manage. Sci. 2001, 57, 115–119.
In summary, a series of novel N-substituted phenoxysulfenyl-
N′-tert-butyl-N,N′-diacylhydrazines were designed and synthe-
sized as insect growth regulators from the key intermediate
N-chlorosulfenyl-N′-tert-butyl-N,N′-diacylhydrazines. Compared
to N′-tert-butyl-N,N′-diacylhydrazines, these N-substituted phe-
noxysulfenyl derivatives displayed better solubility and im-
proved hydrophobicities. The results of bioassays showed that
the title compounds possessed a combination of strong stomach
as well as contact poison properties higher than the correspond-
ing parent compounds. In particular, N-(4-chlorophenoxysulfe-
nyl)-N′-tert-butyl-N-4-ethylbenzoyl-N′-3,5-dimethylbenzoylhy-
drazide (IIIi), as a field testing candidate, has higher stomach
(16) Sawada, Y.; Yanai, T.; Nakagawa, H.; Tsukamoto, Y.; Yokoi,
S.; Yanagi, M.; Toya, T.; Sugizaki, H.; Kato, Y.; Shirakura, H.;
Watanabe, T.; Yajima, Y.; Kodama, S.; Masui, A. Synthesis and
insecticidal activity of benzoheterocyclic analogues of N′-benzoyl-
N-(tert-butyl)benzohydrazide: Part 1. Design of benzoheterocyclic
analogues. Pest Manage. Sci. 2003, 59, 25–35.
(17) Sawada, Y.; Yanai, T.; Nakagawa, H.; Tsukamoto, Y.; Yokoi,
S.; Yanagi, M.; Toya, T.; Sugizaki, H.; Kato, Y.; Shirakura, H.;
Watanabe, T.; Yajima, Y.; Kodama, S.; Masui, A. Synthesis and
insecticidal activity of benzoheterocyclic analogues of N′-benzoyl-
N-(tert-butyl)benzohydrazide: Part 2. Introduction of substituents
on the benzene rings of the benzoheterocycle moiety. Pest
Manage. Sci. 2003, 59, 36–48.

Synthesis and Insecticidal Activities of Novel Diacylhydrazines
J. Agric. Food Chem., Vol. 56, No. 13, 2008 5259
(18) Sawada, Y.; Yanai, T.; Nakagawa, H.; Tsukamoto, Y.; Tamagawa,
Y.; Yokoi, S.; Yanagi, M.; Toya, T.; Sugizaki, H.; Kato, Y.;
Shirakura, H.; Watanabe, T.; Yajima, Y.; Kodama, S.; Masui, A.
Synthesis and insecticidal activity of benzoheterocyclic analogues
of N′-benzoyl-N-(tert-butyl)benzohydrazide: Part 3. Modification
of N-tert-butylhydrazine moiety. Pest Manage. Sci. 2003, 59, 49–
57.
(19) Yanagi, M.; Sugizaki, H.; Toya, T.; Kato, Y.; Shirakura, H.;
Watanabe, T.; Yajima, Y.; Kodama, S.; Masui, A.; Yanai, T.;
Tsukamoto, Y.; Sawada, Y.; Yokoi, S. New hydrazine derivative
and pesticidal composition comprising said derivative as an
effective ingredient. EP 496342, 1992.
(28) Zhao, Q. Q.; Shang, J.; Liu, Y. X.; Wang, K. Y.; Bi, F. C.; Huang,
R. Q.; Wang, Q. M. Synthesis and Insecticidal Activities of Novel
N-Sulfenyl-N′-tert-butyl-N,N′-diacylhydrazines. 1. N-Alkox-
ysulfenate Derivatives. J. Agric. Food Chem. 2007, 55, 9614–
9619.
(29) Zhu, Y. P.; Ishihara, K.; Masuyama, A.; Nakatsuji, Y.; Okahara,
M. Preparation and properties of double-chain bis(quaternary
ammonium) compounds. Yukagaku 1993, 42 (3), 161–167.
(30) He, Z. R. Sulfur dichloride. Inorganic Preparation Chemistry
Handbook; Fuel Chemical Industry Press: 1972; p 224 (Chinese).
(31) Abbott, W. S. A method of computing the effectiveness of an
insecticide. J. Econ. Entomol. 1925, 18, 265–267.
(20) Yanagi, M.; Watanabe, T.; Masui, A. ANS-118: A novel
insecticide. Brighton Crop Prot. Conf. Pests Dis. 2000, 2, 27–
32.
(32) Hsu, A. C.; Murphy, R. A.; Aller, H. E.; Hamp, D. W.; Weinstein,
B. Insecticidal N′-substituted-N,N′-disubstitutedhydrazines. US
5117057, 1992.
(21) Zhang, X. N.; Li, Y. F.; Zhu, L. M.; Liu, L. Y.; Sha, X. Y.; Xu,
H.; Ma, H. J.; Wang, F. Y.; Ni, Y. P.; Guo, L. P. Preparation of
diacylhydrazines insecticides and their intermediates. CN 1313276,
2001.
(22) Xu, N. F.; Zhang, Y.; Zhang, X. N.; Ni, J. P.; Xiong, J. M.; Shen,
M. Manufacture of JS118 insecticide suspension agent. CN
1918986, 2007.
(23) Wang, Q. M.; Cheng, J. R.; Huang, R. Q. Synthesis and
insecticidal evaluation of novel N-(S-amino)sulfenylated deriva-
tives of diacylhydrazines. Pest Manage. Sci. 2002, 58, 1250–1253.
(24) Mao, C. H.; Wang, Q. H.; Huang, R. Q.; Bi, F. C.; Chen, L.; Liu,
Y. X.; Shang, J. Synthesis and insecticidal evaluation of novel
N-oxalyl derivatives of tebufenozide. J. Agric. Food Chem. 2004,
52, 6737–6741.
(25) Fukuto, T. R. Propesticides. In Pesticides Synthesis through
Rational Approaches; Magee, P. S. Eds.; American Chemical
Society: Washington, DC, 1984; pp 87-101.
(33) Luo, Y. P.; Yang, G. F. Discovery of a new insecticide lead by
optimizing a target-diverse scaffold: Tetrazolinone derivatives.
Bioorg. Med. Chem. 2007, 15, 1716–1724.
(34) Ma, H.; Wang, K. Y.; Xia, X. M.; Zhang, Y.; Guo, Q. L. The
toxity testing of five insecticides to different instar larvae of
Spodoptera exigua. Xiandai Nongyao 2006, 5, 44–46.
(35) Busvine, J. R. Recommended methods for measurement of pest
resistance to pesticides. In FAO Plant Production and Protection
Paper; Rome, Italy, 1980; No. 21, pp 3-13, 119-122.
(36) Wang, K. Y.; Jiang, X. Y.; Yi, M. J.; Chen, B. K. Studies on
resistance change and management strategy of Spodoptera exigua.
Nongyao 2001, 40 (6), 29–32.
(37) Chen, B. K.; Wang, K. Y.; Jiang, X. Y.; Yi, M. J. Toxicity of
insecticides to different generations or different instar of Spodoptera
exigua. Nongyaoxue Xuebao 2000, 2 (3), 91–93.
Received for review March 10, 2008. Revised manuscript received April
8, 2008. Accepted April 9, 2008. This work was supported by the
National Key Project for Basic Research (2003CB114400) and the
National Natural Science Foundation of China (20672064).
(26) Kawata, M.; Umetsu, N.; Fukuto, T. R. N-Alkoxy sulfenylcar-
bamates. US 4394383, 1983.
(27) Umetsu, N.; Nishioka, T.; Fukuto, T. R. Formation of Alkoxy-
sulfenyl Derivatives of Carbofuran by Acid-Catalyzed Alcoholysis
of Carbosulfan. J. Agric. Food Chem. 1984, 32, 765–768.
JF800740Z