Synthesis and insecticidal activities and SAR studies of novel benzoheterocyclic diacylhydrazine derivatives

Article abstract of DOI:10.1021/jf8036193

Two series of novel N′-tert-butyl-N′-substituted benzoyl-N-2,3-dihydrobenzofuran-5-carbohydrazide derivatives were synthesized, their activities and different insecticidal action modes for different Lepidopteral larvicidal assays were evaluated carefully. The results of larvicidal activities against oriental armyworm and mosquito indicate that different benzoheterocyclic analogues of diacylhydrazide have different structure-activity relationships according to the types and patterns of substitution on the benzene, and 3,5-dimethyl is the most efficient substituent for benzoheterocyclic diacylhydrazine. Among them, N′-tert-butyl-N′- (3,5-dimethylbenzoyl)-N-2,4-dimethyl-2,3-dihydrobenzofuran-5-carbo-hydrazide (li) stood out as the best compound with high activity. Compound li and N′-tert-butyl-N′-(3,5-dimethylbenzoyl)-N-5-chloro-6- chromanecarbohydrazide (F) have higher contact activities against diamond-back moth and stomach toxicities against cotton bollworm than ANS-118 and JS-118. Compound F has higher contact toxicity against beet armyworm than ANS-118 and JS-118. These results indicate that different heterocycles and substitutents on the benzene rings of benzoheterocyle moiety not only influence the larvicidal activities strongly but also are very sensitive to the insecticidal action modes for different Lepidopteran larvicidal insects.

Full text of DOI:10.1021/jf8036193

J. Agric. Food Chem. 2009, 57, 2447–2456 2447
Synthesis and Insecticidal Activities and SAR
Studies of Novel Benzoheterocyclic Diacylhydrazine
Derivatives
ZHIQIANG HUANG,† QUANMIN CUI,§ LIXIA XIONG,† ZIWEN WANG,†
KAIYUN WANG,§ QIQI ZHAO,† FUCHUN BI,† AND QINGMIN WANG*,†
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China, and College of Plant Protection,
Shandong Agriculture University, Tai’an 271018, People’s Republic of China
Two series of novel N′-tert-butyl-N′-substituted benzoyl-N-2,3-dihydrobenzofuran-5-carbohydrazide
derivatives were synthesized, their activities and different insecticidal action modes for different
Lepidopteral larvicidal assays were evaluated carefully. The results of larvicidal activities against
oriental armyworm and mosquito indicate that different benzoheterocyclic analogues of diacylhydrazide
have different structure-activity relationships according to the types and patterns of substitution on
the benzene, and 3,5-dimethyl is the most efficient substituent for benzoheterocyclic diacylhydrazine.
Among them, N′-tert-butyl-N′-(3,5-dimethylbenzoyl)-N-2,4-dimethyl-2,3-dihydrobenzofuran-5-carbo-
hydrazide (Ii) stood out as the best compound with high activity. Compound Ii and N′-tert-butyl-N′-
(3,5-dimethylbenzoyl)-N-5-chloro-6-chromanecarbohydrazide (F) have higher contact activities against
diamond-back moth and stomach toxicities against cotton bollworm than ANS-118 and JS-118.
Compound F has higher contact toxicity against beet armyworm than ANS-118 and JS-118. These
results indicate that different heterocycles and substitutents on the benzene rings of benzoheterocyle
moiety not only influence the larvicidal activities strongly but also are very sensitive to the insecticidal
action modes for different Lepidopteran larvicidal insects.
KEYWORDS: Benzofuran; diacylhydrazine; ANS-118; JS-118; stomach toxicity; contact toxicity; insec-
ticidal activity; insect growth regulator
INTRODUCTION
N-(tert-butyl)benzofurancarbohydrazide were reported. Among
them compounds C and D (Figure 1) and their analogues show
high activity to Lepidopteran insects such as Spodoptera litura,
Cnaphalocrocis medinalis Guenee, and Adoxophyes orana
N-tert-Butyl-N,N′-diacylhydrazines discovered by Rohm and
Haas Co. in the mid-1980s act as a new class of insect growth
regulators (IGR) (1, 2). Because of their high insecticidal
activities, especially in Lepidoptera, and low toxicity to non-
target organisms such as mammalians, birds, fishes, and so on,
diacylhydrazines have attracted considerable attention in recent
years (3-8). Among these active compounds, N-tert-butyl-N′-
4-ethylbenzoyl-N-3,5-dimethylbenzoylhydrazide (tebufenozide,
RH-5992, A, Figure 1) was the first to be commercialized as
a leptidopteran-specific insecticide under the trade names Mimic,
Confirm, and Romdan in several countries (9). ANS-118 (B,
Figure 1), a benzoheterocyclic analogue of N′-benzoyl-N-(tert-
butyl)benzohydrazide, which was 4 times more active than RH-
5992 against Spodoptera litura, was commercialized by Nippon
Kayaku Co. Ltd. and Sankyo Co. Ltd. (10, 11).
Recently, many benzoheterocyclic analogues of N′-benzoyl-
* Author to whom correspondence should be addressed (telephone
+86-(0)22-23499842; fax +86-(0)22-23499842; e-mail wang98h@
263.net.).
† Nankai University.
§ Shandong Agriculture University.
Figure 1. Chemical structures of compounds A-F.
10.1021/jf8036193 CCC: $40.75  2009 American Chemical Society
Published on Web 02/17/2009

2448 J. Agric. Food Chem., Vol. 57, No. 6, 2009
Scheme 1. General Synthetic Route for Compound I
Huang et al.
poured into ice-water. The mixture was extracted with petroleum ether
(60-90 °C, 3 × 100 mL). The organic layer was washed successively
with water (100 mL), saturated aqueous sodium bicarbonate (100 mL),
and brine (100 mL) and then dried over anhydrous sodium sulfate.
After removal of the solvent, the residue was distilled under reduced
pressure to give 2-tert-butyl-5-methylphenol (b) as a yellow liquid (9.88
g, 60%): bp 104-106 °C/2 mmHg [lit. (15) bp 224 °C]; 1H NMR
(CDCl3) δ 7.17 (d, 1H, JHH ) 7.9 Hz, Ph); 6.71 (d, 1H, JHH ) 7.9
Hz, Ph); 6.51 (s, 1H, Ph); 4.71 (s, 1H, PhOH); 2.28 (s, 3H, PhCH3);
1.41 (s, 9H, C(CH3)3).
Fischer von Roslerstamm (12). N′-Benzoyl-N-(tert-butyl)dihy-
drobenzofurancarbohydrazide analogues such as compound E
(Figure 1), which shows high activity to Lepidopteran insects
such as armyworm and diamond-back moth, also have been
reported. Compound E, named JS-118, has been developed by
the Jiangsu Institute of Agricultural Chemicals, People’s
Republic of China (13). Recently, we used bioisosterism to
design and synthesize a series of novel N′-tert-butyl-N′-
substituted benzoyl-N-5-chloro-6-chromanecarbohydrazide de-
rivatives and evaluated their larvicidal activites against oriental
armyworm. Among them, compound F (Figure 1) has the
highest activity (14).
It is interesting and disappointing that reports about the
relationships between the changes of different heterocycles and
substitutents on the benzene rings of benzoheterocyle moiety
with different Lepidopteran larvicidal insects’ activities, espe-
cially the insecticidal action modes in depth, are rare. Encour-
aged by these reports, we designed and synthesized two series
of novel N′-tert-butyl-N′-substituted benzoyl-N-2,3-dihydroben-
zofuran-5-carbohydrazide derivatives Ia-Il as shown in Scheme
1 and IIa-IIo as shown in Scheme 2.
3
3
Synthesis of 1-tert-Butyl-4-methyl-2-(prop-2-ynyloxy)benzene (c)
(11). 3-Bromoprop-1-yne (1.74 g, 14.5 mmol) was added to the stirred
mixture of compound b (2.05 g, 12.5 mmol), toluene (15 mL), 25.3%
aqueous sodium hydroxide (2.32 g, 14.7 mmol), and tetrabutylammo-
nium bromide (0.40 g, 1.24 mmol) in an ice bath. After stirring for 4 h
at 50-55 °C, the reaction mixture was cooled and diluted with ethyl
acetate (20 mL). The organic layer was washed successively with water
(2 × 20 mL) and brine (2 × 20 mL) and then dried over anhydrous
sodium sulfate. The solvent was evaporated to give 1-tert-butyl-4-
methyl-2-(prop-2-ynyloxy)benzene (c) as a yellow oil (1.53 g, 60%):
1H NMR (CDCl3) δ 7.17 (d, 1H, 3JHH ) 7.8 Hz, Ph); 6.76 (s, 1H, Ph);
3
6.75 (d, 1H, JHH ) 7.8 Hz, Ph); 4.71 (s, 2H, CH2); 2.48-2.49 (br,
1H, CH); 2.32 (s, 3H, PhCH3); 1.37 (s, 9H, C(CH3)3).
Synthesis of 7-tert-Butyl-2,4-dimethylbenzofuran (d). A mixture
of compound c (0.81 g, 4.0 mmol), cesium fluoride (0.08 g, 0.52 mmol),
and N,N-diethylaniline (7 mL) was refluxed for 3 h. After cooling to
room temperature, the reaction mixture was neutralized with hydro-
chloric acid (2 mol L-1) and then extracted with petroleum ether (60-90
°C, 3 × 10 mL). The organic layer was washed successively with water
(3 × 10 mL) and brine (10 mL) and then dried over anhydrous sodium
sulfate. After the solvent was removed under vacuum, and the residue
was distilled under reduced pressure to give 7-tert-butyl-2,4-dimeth-
ylbenzofuran (d) as a colorless oil (0.67 g, 83%): bp 80-81 °C/1
MATERIALS AND METHODS
1
Instruments. H NMR spectra were obtained at 300 MHz using a
Bruker AV300 spectrometer or at 400 MHz using a Varian Mercury
Plus400 spectrometer in CDCl3 solution with tetramethylsilane as the
internal standard. Chemical shift values (δ) are given in parts per
million. Elemental analyses were determined on a Yanaca CHN Corder
MT-3 elemental analyzer. HRMS was obtained on FTICR-MS (Ionspec
7.0T). The melting points were determined on an X-4 binocular
microscope melting point apparatus (Beijing Tech Instruments Co.,
Beijing, China) and are uncorrected. Yields were not optimized.
General Synthesis. All anhydrous solvents were dried and purified
by standard techniques just before use.
Synthesis of 2-tert-Butyl-5-methylphenol (b). Under stirring, urea
(6 g, 0.1 mol) and tert-butyl alcohol (7.4 g, 0.1 mol) were added to
75% H2SO4 (100 mL) slowly at 10-25 °C. After 2 h, 3-methylphenol
(a) (10.8 g, 0.1 mol) was added to the reaction mixture at 0-5 °C.
After stirring at room temperature for 3 h, the reaction mixture was
1
3
mmHg; H NMR (CDCl3) δ 6.91 (d, 1H, JHH ) 7.6 Hz, Ph); 6.85
3
(1H, d, JHH ) 7.6 Hz, Ph); 6.30 (s, 1H, CH); 2.38 (s, 3H, CCH3);
2.33 (s, 3H, PhCH3); 1.39 (s, 9H, C(CH3)3). Anal. Calcd for C14H18O
(%): C, 83.12; H, 8.97. Found: C, 83.11; H, 8.74.
Synthesis of 7-tert-Butyl-2,4-dimethyl-2,3-dihydrobenzofuran (e).
A mixture of compound d (10.00 g, 48.95 mmol), acetic acid (100
mL), and 10% palladium on activated carbon (2.00 g, 60% in water)
was vigorously stirred under 1 atm of hydrogen at room temperature

Novel Benzoheterocyclic Diacylhydrazine Derivatives
J. Agric. Food Chem., Vol. 57, No. 6, 2009 2449
Scheme 2. General Synthetic Route for Compound II
for 48 h. The reaction mixture was filtered and washed with petroleum
ether (60-90 °C, 3 × 50 mL). The filtrate was washed successively
with saturated aqueous sodium bicarbonate (2 × 50 mL), water (2 ×
50 mL), and brine (50 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under vacuum to give 7-tert-butyl-
2,4-dimethyl-2,3-dihydrobenzofuran (e) as a colorless oil (9.79 g, 97%):
1H NMR (CDCl3) δ 6.99 (d, 1H, 3JHH ) 7.9 Hz, Ph); 6.61 (d, 1H, 3JHH
aqueous layer was acidified with hydrochloric acid (1 mol L-1) and
extracted with dichloromethane (3 × 100 mL). The combined organic
layer was washed successively with water (100 mL) and brine (100
mL) and then dried over anhydrous sodium sulfate. The solvent was
removed under vacuum to give 2,4-dimethyl-2,3-dihydrobenzofuran-
5-carboxylic acid (g) as a white amorphous solid (2.33 g, 91%): mp
171-172 °C; 1H NMR (CDCl3) δ 12.81 (br, 1H, COOH); 7.98 (d, 1H,
3
) 7.9 Hz, Ph); 4.90-4.98 (m, 1H, OCH); 3.20-3.26 (m, 1H, CH2);
3JHH ) 8.4 Hz, Ph); 6.64 (d, 1H, JHH ) 8.4 Hz, Ph); 4.98-5.04 (m,
3
2.67-2.73 (m, 1H, CH2); 2.21 (s, 3H, PhCH3); 1.46 (d, 3H, JHH
)
1H, OCH); 3.29-3.35 (m, 1H, CH2); 2.76-2.77 (m, 1H, CH2), 2.53
3
6.2 Hz, CCH3); 1.36 (s, 9H, C(CH3)3).
(s, 3H, Ph); 1.49 (d, 3H, JHH ) 6.2 Hz, CCH3). Anal. Calcd for
C11H12O3 (%): C, 68.74; H, 6.29. Found: C, 68.52; H, 6.09.
Synthesis of 5-Acetyl-2,4-dimethyl-2,3-dihydrobenzofuran (f).
Acetyl chloride (3.02 g, 38.44 mmol) was added to a stirred suspension
of aluminum chloride (6.46 g, 48.9 mmol) in dichloromethane (140
mL) at -15 °C under N2. After 1 h of stirring, the solution of compound
e (7.14 g, 34.95 mmol) in dichloromethane (10 mL) was added
dropwise. After stirring for 2 h at room temperature, the reaction mixture
was poured into hydrochloric acid (0.5 mol L-1, 80 mL) and extracted
with dichloromethane (3 × 40 mL). The organic layer was washed
successively with saturated aqueous sodium bicarbonate (100 mL),
water (3 × 100 mL), and brine (100 mL) and then dried over anhydrous
sodium sulfate. After removal of the solvent, the residue was purified
by column chromatography on a silica gel using a mixture of petroleum
ether (60-90 °C) and ethyl acetate (v/v ) 10:1) as the eluent to give
5-acetyl-2,4-dimethyl-2,3-dihydrobenzofuran (f) as a colorless crystal
Synthesis of N′-tert-Butyl-N-2,4-dimethyl-2,3-dihydrobenzofuran-
5-carbohydrazide (i). A mixture of compound g (0.20 g, 1.04 mmol)
and thionyl chloride (5 mL) was refluxed for 2 h. After excess thionyl
chloride was removed under reduced pressure, the residue was dissolved
in dichloromethane (2 mL). The resulting solution was added dropwise
to a stirred mixture of tert-butylhydrazine hydrochloride (0.15 g, 1.25
mmol), sodium hydroxide (0.09 g, 2.29 mmol), dichloromethane (30
mL), and water (2 mL) at -15 °C. After overnight stirring at room
temperature, the organic layer was washed successively with water (3
× 15 mL) and brine (15 mL) and then dried over anhydrous sodium
sulfate. The solvent was removed under vacuum to give N′-tert-butyl-
N-2,4-dimethyl-2,3-dihydrobenzofuran-5-carbohydrazide (i) as a white
1
solid (0.25 g, 93%): mp 122-123 °C; H NMR (CDCl3) δ 7.21 (d,
(2.77 g, 42%): mp 35-36 °C; 1H NMR (CDCl3) δ 7.65 (d, 1H, 3JHH
)
1H, JHH ) 8.2 Hz, Ph); 6.58 (d, 1H, JHH ) 8.2 Hz, Ph); 4.90-5.54
(m, 1H, OCH); 3.24-3.30 (m, 1H, CH2); 2.71-2.77 (m, 1H, CH2);
2.34 (s, 3H, PhCH3); 1.47 (d, 3H, 3JHH ) 6.2 Hz, CCH3); 1.16 (s, 9H,
C(CH3)3). Anal. Calcd for C15H22N2O2 (%): C, 68.67; H, 8.45; N, 10.68.
Found: C, 68.78; H, 8.47; N, 10.50.
3
3
8.4 Hz, Ph); 6.61 (d, 1H, 3JHH ) 8.4 Hz, Ph); 4.92-4.98 (m, 1H, OCH);
3.21-3.27 (m, 1H, CH2); 2.70-2.74 (m, 1H, CH2); 2.43 (s, 3H,
3
OdCCH3); 2.40 (s, 3H, PhCH3); 1.43 (d, 3H, JHH ) 6.3 Hz, CCH3).
Anal. Calcd for C12H14O2 (%): C, 75.76; H, 7.42. Found: C, 75.50; H,
7.42.
Synthesis of 1-tert-Butyl-4-methyl-2-(2-methylallyloxy)benzene
(j). The solution compound b (10 g, 60.89 mmol) in N,N-dimethyl-
formamide (40 mL) was added dropwise to the mixture of sodium
hydride (3.46 g, 50% NaH, 72.11 mmol) and N,N-dimethylformamide
(80 mL) at 0 °C. After 1 h of stirring at room temperature, 3-chloro-
2-methylprop-1-ene (6.53 g, 72.11 mmol) was added dropwise to the
reaction mixture at room temperature. After 4 h of stirring, saturated
aqueous ammonium chloride (80 mL) was added to the reaction mixture.
Synthesis of 2,4-Dimethyl-2,3-dihydrobenzofuran-5-carboxylic
Acid (g). Bromine (6.38 g, 39.9 mmol) was added dropwise to a stirred
solution of sodium hydroxide (4.99 g, 119.7 mmol) in water (20 mL)
in an ice bath. After 30 min, compound f (2.53 g, 13.3 mmol) in 1,4-
dioxane (25 mL) was added with stirring, and the mixture was stirred
overnight at room temperature. Water (100 mL) was added to the
reaction mixture and extracted with diethyl ether (2 × 50 mL). The

2450 J. Agric. Food Chem., Vol. 57, No. 6, 2009
Huang et al.
The resulting mixture was extracted with ether (3 × 50 mL). The
organic layer was washed with brine (50 mL) and dried over anhydrous
sodium sulfate. After removal of the solvent, the residue was distilled
under reduced pressure to give 1-tert-butyl-4-methyl-2-(2-methylally-
loxy)benzene (j) as a colorless oil (11.32 g, 91%): bp 99-100 °C/2
mmHg; 1H NMR (CDCl3) δ 7.22 (d, 1H, 3JHH ) 7.7 Hz, Ph); 6.75 (d,
3JHH ) 8.4 Hz, Ph); 2.97 (s, 2H, CH2); 2.52 (s, 3H, CH3CdO); 2.43
(s, 3H, PhCH3); 1.49 (s, 6H, C(CH3)2). Anal. Calcd for C13H16O2 (%):
C, 76.44; H, 7.90. Found: C, 76.41; H, 7.89.
Synthesis of 2,2,4-Trimethyl-2,3-dihydrobenzofuran-5-carboxylic
Acid (o). The procedure is the same as for preparing 2,4-dimethyl-
2,3-dihydrobenzofuran-5-carboxylic acid (g). 5-Acetyl-2,2,4-trimethyl-
2,3-dihydrobenzofuran (n) (2.75 g, 13.46 mmol) was reacted with
bromine (7.11 g, 44.42 mmol) and sodium hydroxide (7.11 g, 177.67
mmol) in water (10 mL) and 1,4-dioxane (25 mL) to give 2,2,4-
trimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (o) as a white crystal
3
1H, JHH ) 7.9 Hz, Ph); 6.73 (s, 1H, Ph); 5.19 (s, 1H, CH2); 5.03 (s,
1H, CH2); 4.43 (s, 2H, OCH2); 2.34 (s, 3H, PhCH3); 1.92 (s, CH3);
1.43 (s, 9H, C(CH3)3). Anal. Calcd for C15H22O (%): C, 82.52; H, 10.16.
Found: C, 82.59; H, 10.08.
1
(2.69 g, 97%): mp 169-171 °C; H NMR (CDCl3) δ 12.45 (s, 1H,
Synthesis of 6-tert-Butyl-3-methyl-2-(2-methylallyl)phenol (k). A
mixture of compound j (9.04 g, 44.26 mmol) and N,N-diethylaniline
(50 mL) was refluxed for 36 h. After cooling to room temperature, the
COOH); 7.99 (d, 1H, 3JHH ) 8.5 Hz, Ph); 6.62 (d, 1H, 3JHH ) 8.4 Hz,
Ph); 3.00 (s, 2H, CH2); 2.52 (s, 3H, PhCH3); 1.51 (s, 6H, C(CH3)2).
Anal. Calcd for C12H14O3 (%): C, 69.88; H, 6.84. Found: C, 70.00; H,
6.90.
reaction mixture was neutralized with hydrochloric acid (2 mol L-1
)
and then extracted with petroleum ether (60-90 °C, 3 × 25 mL). The
combined organic layer was washed successively with water (25 mL)
and brine (25 mL) and then dried over anhydrous sodium sulfate. After
the solvent was removed under vacuum, the residue was purified by
column chromatography on a silica gel using petroleum ether (60-90
°C) as the eluent to give 6-tert-butyl-3-methyl-2-(2-methylallyl)phenol
(k) as a colorless oil (6.20 g, 69%): 1H NMR (CDCl3): δ 7.15 (d, 1H,
Synthesis of N′-tert-Butyl-N-2,2,4-trimethyl-2,3-dihydrobenzo-
furan-5-carbohydrazide (q). The procedure is the same as for
preparing N′-tert-butyl-N-2,4-dimethyl-2,3-dihydrobenzofuran-5-car-
bohydrazide (i). First, compound o (2.69 g, 13.04 mmol) was reacted
with thionyl chloride (10 mL) to give compound p. Then compound p
was reacted with tert-butylhydrazine hydrochloride (1.95 g, 15.65
mmol) and sodium hydroxide (1.13 g, 28.69 mmol) in dichloromethane
(110 mL) and water (20 mL) at -15 °C to give N′-tert-butyl-N-2,2,4-
trimethyl-2,3-dihydrobenzofuran-5-carbohydrazide (q) as a white crystal
(2.79 g, 78%): mp 117-118 °C; 1H NMR (CDCl3) δ 7.21 (d, 1H, 3JHH
3
3JHH ) 8.0 Hz, Ph); 6.80 (d, 1H, JHH ) 8.0 Hz, Ph); 5.35 (s, 1H,
PhOH); 4.99 (s, 1H, CdCH2); 4.84 (s, 1H, CdCH2); 3.45 (s, 2H, CH2);
2.33 (s, 3H, PhCH3); 1.86 (s, 3H, CH3); 1.46 (s, 9H, C(CH3)3). Anal.
Calcd for C15H22O (%): C, 82.52; H, 10.16. Found: C, 82.22; H, 10.24.
At the same time, 7-tert-butyl-2,2,4-trimethyl-2,3-dihydrobenzofuran
(l) (0.90 g) was obtained as byproduct.
3
) 8.2 Hz, Ph); 6.97 (br, 1H, NH); 6.56 (d, 1H, JHH ) 8.2 Hz, Ph);
4.93 (br, 1H, NH); 2.95 (s, 2H, CH2); 2.33 (s, 3H, PhCH3); 1.44 (s,
6H, C(CH3)2); 1.16 (s, 9H, C(CH3)3). Anal. Calcd for C16H24N2O2 (%):
C, 69.53; H, 8.75; N, 10.14. Found: C, 69.41; H, 8.51; N, 10.03.
General Synthetic Procedure for Target Compounds N′-tert-
Butyl-N′-substituted Benzoyl-N-2,3-dihydrobenzofuran-5-carbohy-
drazide (Ia-Il and IIa-IIo). A solution of substituted benzoyl chloride
(1.35 mmol) in dichloromethane (10 mL) was added dropwise to a
stirred mixture of N′-tert-butyl-N-2,3-dihydrobenzofuran-5-carbohy-
drazide (i or q, 1.35 mmol), triethylamine (0.16 g, 1.54 mmol), and
dichloromethane (10 mL) in an ice bath. After stirring of the reaction
mixture at room temperature overnight, dichloromethane (20 mL) was
added. The reaction mixture was washed successively with water (3 ×
20 mL) and brine (20 mL) and then dried over anhydrous sodium
sulfate. After evaporation of the solvent, the residue was purified by
recrystallization or column chromatography on silica gel to afford
compounds Ia-Il and IIa-IIo as colorless crystals. The physical
properties and elemental analyses of new compounds (Ia-Il and
Synthesis of 7-tert-Butyl-2,2,4-trimethyl-2,3-dihydrobenzofuran
(l). A mixture of compound k (8.00 g, 39.17 mmol) and sulfuric acid
(0.39 g, 3.92 mmol) was heated at 110 °C for 15 min. After the mixture
had cooled to room temperature, saturated aqueous sodium bicarbonate
(100 mL) was added. The resulting mixture was extracted with
petroleum ether (60-90 °C, 3 × 50 mL). The combined organic layer
was washed successively with water (2 × 50 mL) and brine (50 mL)
and then dried over anhydrous magnesium sulfate. The solvent was
removed under vacuum to give 7-tert-butyl-2,2,4-trimethyl-2,3-dihy-
1
drobenzofuran (l) as a yellow solid (6.44 g, 81%): mp 56-58 °C; H
NMR (CDCl3) δ 7.01 (d, 1H, 3JHH ) 7.7 Hz, Ph); 6.63 (d, 1H, 3JHH
)
7.8 Hz, Ph); 2.92 (s, 2H, CH2); 2.22 (s, 3H, PhCH3); 1.51 (s, 6H,
C(CH3)2); 1.37 (s, 9H, C(CH3)3). Anal. Calcd for C15H22O (%): C, 82.52;
H, 10.16. Found: C, 82.32; H, 10.05.
Synthesis of 5-Acetyl-7-tert-butyl-2,2,4-trimethyl-2,3-dihydroben-
zofuran (m). Acetyl chloride (1.85 g, 23.48 mmol) was added dropwise
to a stirred suspension of aluminum chloride (3.94 g, 29.88 mmol) in
dichloromethane (40 mL) at -15 °C under N2. After 1 h of stirring, a
solution of compound l (4.66 g, 21.34 mmol) in dichloromethane (10
mL) was added dropwise. After stirring for 0.5 h, the reaction mixture
was poured into ice-water (40 mL). The organic layer was washed
with water and then dried over anhydrous sodium sulfate. After removal
of the solvent, the residue was purified by column chromatography on
a silica gel using a mixture of petroleum ether (60-90 °C) and ethyl
acetate (v/v ) 30:1) as the eluent to give 5-acetyl-7-tert-butyl-2,2,4-
trimethyl-2,3-dihydrobenzofuran (m) as a colorless crystal (3.09 g,
1
IIa-IIo) are listed in Table 1, and their H NMR data are listed in
Table 2.
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 (16). Evaluations were based on a percentage scale of 0-100
in which 0 ) no activity and 100 ) total kill.
Stomach Toxicity against Oriental Armyworm (Mythimna sepa-
rate). The stomach toxicities of the title compounds Ia-Il and IIa-IIo
against oriental armyworm were evaluated by foliar application using
the reported procedure (17-20). 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, ANS-118 and JS-118 were tested under the same
conditions.
Toxicity against Mosquito (Culex pipiens pallens). The toxicities
of the title compounds Ia-Il and IIa-IIo against mosquito were
evaluated according to the reported procedure (21-23). One milliliter
of different concentrated dilutions of each compounds was added to
99 mL of water to obtain different concentrations of tested solution.
Then 20 fourth-instar mosquito larvaes were put into the solution.
Percentage mortalities were evaluated 7-10 days after treatment. For
comparative purposes, ANS-118 and JS-118 were tested under the same
conditions.
1
81%): mp 47-48 °C; H NMR (CDCl3) δ 7.57 (s, 1H, Ph); 2.94 (s,
2H, CH2); 2.55 (s, 3H, CH3CdO); 2.41 (s, 3H, PhCH3); 1.49 (s, 6H,
C(CH3)2); 1.37 (s, 9H, C(CH3)3). Anal. Calcd for C17H24O2 (%): C,
78.42; H, 9.29. Found: C, 78.21; H, 9.35.
Synthesis of 5-Acetyl-2,2,4-trimethyl-2,3-dihydrobenzofuran (n).
A solution of compound m (3.09 g, 11.87 mmol) in dichloromethane
(15 mL) was added dropwise to a mixture of aluminum chloride (4.70
g, 35.60 mmol) and dichloromethane (45 mL) at room temperature.
After stirring for 1 h at room temperature, the reaction mixture was
poured into hydrochloric acid (1 mol L-1, 20 mL). The organic layer
was washed successively with water (20 mL) and brine (20 mL) and
then dried over anhydrous sodium sulfate. After removal of the solvent,
the residue was recrystallized from a mixture of petroleum ether (60-90
°C) and ethyl acetate (v/v ) 30/1) to give 5-acetyl-2,2,4-trimethyl-
2,3-dihydrobenzofuran (n) as a white crystal (2.04 g, 84%): mp 49-51
°C; 1H NMR (CDCl3) δ 7.64 (d, 1H, 3JHH ) 8.4 Hz, Ph); 6.58 (d, 1H,

Novel Benzoheterocyclic Diacylhydrazine Derivatives
J. Agric. Food Chem., Vol. 57, No. 6, 2009 2451
Table 1. Physical Properties and Elemental Analyses of Compounds Ia-Il and IIa-IIo
elem anal. (%, calcd)
compd
R
mp (°C)
yield (%)
C
H
N
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Ii
Ij
Ik
H
175-177
108-109
251-252
262-263
196-197
202-203
218-219
211-212
136-138
134-136
120-121
164-166
194-196
239-240
256-258
238-239
184-185
210-211
230-232
235-236
169-170
199-200
207-208
177-179
222-223
121-123
181-182
99
65
13
31
47
72
99
76
98
12
59
91
95
73
27
80
67
99
80
99
47
87
64
99
18
88
69
71.95 (72.11)
64.09 (64.22)
64.07 (64.22)
64.29 (64.22)
65.72 (65.91)
65.81 (65.91)
65.75 (65.91)
72.40 (72.60)
72.93 (73.07)
7.15 (7.15)
6.07 (6.12)
5.98 (6.12)
5.99 (6.12)
6.45 (6.29)
6.33 (6.29)
6.32 (6.29)
7.49 (7.42)
7.51 (7.66)
479.1541(479.1537)a
5.76 (5.56)
5.51 (5.56)
7.20 (7.42)
6.48 (6.40)
6.61 (6.40)
6.19 (6.40)
6.43 (6.56)
6.45 (6.56)
6.64 (6.56)
7.11 (7.37)
7.23 (7.37)
7.22 (7.37)
7.52 (7.66)
7.82 (7.90)
5.68 (5.57)
5.70 (5.83)
6.00 (5.83)
7.85 (7.64)
10.22 (10.21)
10.48 (10.21)
10.29 (10.21)
6.96 (6.99)
6.85 (6.99)
7.09 (6.99)
7.47 (7.36)
6.97 (7.10)
2-NO2
3-NO2
4-NO2
2-Cl
3-Cl
4-Cl
3-Me
3,5-Me2
3,5-(NO2)2
3,5-Cl2
2,4-Cl2
H
2-NO2
3-NO2
4-NO2
2-Cl
3-Cl
4-Cl
2-OMe
3-OMe
4-OMe
3-Me
60.51 (60.70)
60.51 (60.70)
72.44 (72.60)
64.75 (64.93)
64.65 (64.93)
64.70 (64.93)
66.59 (66.58)
66.64 (66.58)
66.39 (66.58)
70.38 (70.22)
70.38 (70.22)
70.21 (70.22)
72.90 (73.07)
73.41 (73.50)
58.42 (58.72)
61.65 (61.47)
61.49 (61.47)
6.21 (6.43)
6.31 (6.43)
7.38 (7.36)
9.86 (9.88)
9.87 (9.88)
9.71 (9.88)
6.76 (6.75)
6.67 (6.75)
6.74 (6.75)
6.85 (6.82)
6.62 (6.82)
6.80 (6.82)
6.95 (7.10)
6.72 (6.86)
11.98 (11.91)
6.21 (6.23)
6.22 (6.23)
Il
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
IIm
IIn
IIo
3,5-Me2
3,5-(NO2)2
3,5-Cl2
2,4-Cl2
a The [M + Na]+ value of HRMS.
Stomach Toxicity against Beet Armyworm (Laphygma exigua
Hu¨bner). The stomach toxicities of the title compounds Ii and F and
the contrast compounds ANS-118 and JS-118 against beet armyworm
were tested by the leaf-dip method using the reported procedure (24, 25).
Leaf disks (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 disks were placed individually into boxes (80 cm3). Each
dried treated leaf disk was infested with five third-instar beet armyworm
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.
Contact Toxicity against Beet Armyworm (L. exigua Hu¨bner).
The contact toxicities of the title compounds Ii and F and the contrast
compounds ANS-118 and JS-118 against beet armyworm were tested
by a topical application method recommended by the FAO (25, 26).
The compounds were dissolved in acetone to test at various concentra-
tions. For each fourth-instar larva of beet armyworm, 1.0 µL of tested
dilution was applied on the thoracic tergite with an automatic
microapplicator (Robbins Scientific). After treatment, the insects were
then transferred to their standard rearing conditions. Mortalities were
calculated 48 and 72 h after treatment, and LC50 values were established.
Each treatment was performed three times and acetone alone served
as a control.
Contact Toxicity against Diamond-back Moth (Plutella xylostella
L.). The contact toxicities of the title compounds Ii and F and the
contrast compounds ANS-118 and JS-118 against diamond-back moth
were tested by using an insect-dip method (27, 28). The compounds
were dissolved in acetone and diluted with water to prepare five
concentrations. Each fourth-instar larva of diamond-back moth was
immersed in the above solution for 5 min. After treatment, the insects
were then transferred to their standard rearing conditions at 25 ( 1
°C. Mortalities were calculated 48 and 72 h after treatment, and LC50
values were established. Usually, 30 insects per dose were tested, and
each treatment was replicated three times; water alone served as a
control.
reported procedure (29). The compounds were dissolved in acetone to
test at 1000 mg L-1. Corn leaves were dipped into the test solution.
After air-drying, the treated leaf disks were placed individually into
boxes that had 24 holes. Each dried treated leaf disk was infested with
10 third-instar cotton bollworm larvae. Percentage mortalities were
evaluated 4 days after treatment.
Contact Toxicity against Cotton Bollworm (H. armigera (Hu¨b-
ner)). The contact toxicities of the title compounds Ii and F and the
contrast compounds ANS-118 and JS-118 against cotton bollworm were
tested by topical application method using the reported procedure (30, 31).
The compounds were dissolved in acetone to test at 1000 mg L-1. For
each third-instar larva of cotton bollworm, 0.5 µL of tested dilution
was applied on the thoracic tergite with a microapplicator (PB600-1).
After treatment, the insects were then transferred to their standard
rearing conditions. Percentage mortalities were evaluated 4 days after
treatment.
Stomach Toxicity against Corn Borer (Ostrinia nubilalis). The
stomach toxicities of the title compounds Ii and F and the contrast
compounds ANS-118 and JS-118 against corn borer were tested by
the leaf-dip method. Leaf disks (about 5 cm) were cut from fresh corn
leaves and then were dipped into the test solution for 3-5 s. After
air-drying, the treated leaf disks were placed individually into a glass-
surface vessel (7 cm). Each dried treated leaf disk was infested with
10 third-instar corn borer larvae. Percentage mortalities were evaluated
4 days after treatment. Leaves treated with acetone were provided as
controls. Each treatment was performed four times. LC50 and LC95
values were established.
RESULTS AND DISCUSSION
Synthesis. The title compounds Ia-Il were synthesized as
shown in Scheme 1. First, 3-methylphenol (a) was reacted with
urea and tert-butyl alcohol in 75% H2SO4 to give 2-tert-butyl-
5-methylphenol (b) as a initial intermediate for synthesis of the
title compounds Ia-Il and IIa-IIo (32). 1-tert-Butyl-4-methyl-
2-(prop-2-ynyloxy)benzene (c) was synthesized from compound
b according to the literature (11). Compound c was refluxed in
N,N-diethylaniline in the presence of cesium fluoride to give
Stomach Toxicities against Cotton Bollworm (HelicoWerpa ar-
migera (Hu¨bner)). The stomach toxicities of the title compounds Ii
and F and the contrast compounds ANS-118 and JS-118 against cotton
bollworm were tested according to the leaf-dip method using the

2452 J. Agric. Food Chem., Vol. 57, No. 6, 2009
Table 2. 1H NMR of Compounds Ia-Il and IIa-IIo
compd
Huang et al.
δ
3
3
Ia
Ib
Ic
Id
Ie
If
7.48 (s, 1H, NH); 7.45-7.46 (m, 2H, Ph); 7.29-7.35 (m, 3H, Ph); 6.47 (d, 1H, JHH ) 6.4 Hz, Ph); 6.38 (d, 1H, JHH ) 6.4 Hz, Ph);
3
4.88-4.95 (m, 1H, CH); 3.12-3.22 (m, 1H, CH2); 2.59-2.68 (m, 1H, CH2); 1.96 (s, 3H, PhCH3); 1.60 (s, 9H, C(CH3)3); 1.42 (d, 3H, JHH
) 6.2 Hz, CCH3)
8.11 (d, 1H, JHH ) 8.3 Hz, Ph); 7.63 (d, 1H, JHH ) 8.3 Hz, Ph); 7.60 (s, 1H, NH); 7.47-7.53 (m, 2H, Ph); 6.36 (d, 1H,3JHH ) 8.3 Hz,
3
3
Ph); 6.29 (d, 1H,3JHH ) 8.3 Hz, Ph); 4.88-4.94 (m, 1H, CH); 3.12-3.20 (m, 1H, CH2); 2.54-2.67 (m, 1H, CH2); 1.99 (s, 3H, PhCH3);
3
1.63 (s, 9H, C(CH3)3); 1.41 (d, 3H, JHH ) 5.8 Hz, CCH3)
3
3
3
8.28 (s, 1H, NH); 8.20 (s, 1H, Ph); 7.92 (d, 1H, JHH ) 7.6 Hz, Ph); 7.64 (d, 1H, JHH ) 7.7 Hz, Ph); 7.52 (q, 1H, JHH ) 7.9 Hz, Ph);
6.65 (d, 1H,3JHH ) 8.2 Hz, Ph); 6.40 (d, 1H, JHH ) 8.2 Hz, Ph); 4.89-4.95 (m, 1H, CH); 3.12-3.20 (m, 1H, CH2); 2.59-2.66 (m, 1H,
3
3
CH2); 1.91 (s, 3H, PhCH3); 1.62 (s, 9H, C(CH3)3); 1.42 (d, 3H, JHH ) 6.3 Hz, CCH3)
8.17 (d, 2H, JHH ) 8.1 Hz, Ph); 7.65 (d, 2H,3JHH ) 8.0 Hz, Ph); 7.49 (s, 1H, NH); 6.61 (d, 1H, JHH ) 8.2 Hz, Ph); 6.41 (d, 1H, JHH
8.2 Hz, Ph); 4.90-4.95 (m, 1H, CH); 3.14-3.20 (m, 1H, CH2); 2.61-2.67 (m, 1H, CH2); 1.94 (s, 3H, PhCH3); 1.61 (s, 9H, C(CH3)3);
)
3
3
3
3
1.42 (d, 3H, JHH ) 6.1 Hz, CCH3)
7.64 (s, 1H, NH); 7.48 (d, 1H, JHH ) 7.5 Hz, Ph); 7.34 (d, 1H,3JHH ) 7.5 Hz, Ph); 7.22-7.29 (m, 2H, Ph); 6.38 (d, 1H, JHH ) 8.3 Hz,
Ph); 6.32 (d, 1H, JHH ) 8.2 Hz, Ph); 4.89-4.94 (m, 1H, CH); 3.14-3.21 (m, 1H, CH2); 2.60-2.67 (m, 1H, CH2); 2.01 (s, 3H, PhCH3);
3
3
3
1.62 (s, 9H, C(CH3)3); 1.42 (t, 3H,3JHH ) 6.1 Hz, CCH3)
3
3
3
7.50 (s, 1H, NH); 7.46 (s, 1H, Ph); 7.36 (d, 1H, JHH ) 7.7 Hz, Ph); 7.32 (d, 1H, JHH ) 8.2 Hz, Ph); 7.22 (d, 1H, JHH ) 7.8 Hz, Ph);
6.60 (d, 1H, JHH ) 8.2 Hz, Ph); 6.42 (d, 1H, JHH ) 8.2 Hz, Ph); 4.90-4.95 (m, 1H, CH); 3.15-3.22 (m, 1H, CH2); 2.62-2.68 (m, 1H,
CH2); 1.98 (s, 3H, PhCH3); 1.59 (s, 9H, C(CH3)3); 1.42 (d, 3H, JHH ) 6.2 Hz, CCH3)
8.04 (s, 1H, NH); 7.45 (d, 2H, JHH ) 8.4 Hz, Ph); 7.30 (d, 2H, JHH ) 8.3 Hz, Ph); 6.62 (d, 1H, JHH ) 8.3 Hz, Ph); 6.45 (d, 1H, JHH
8.2 Hz, Ph); 4.90-4.98 (m, 1H, CH); 3.17-3.23 (m, 1H, CH2); 2.62-2.67 (m, 1H, CH2); 1.96 (s, 3H, PhCH3); 1.59 (s, 9H, C(CH3)3);
3
3
3
3
3
3
3
Ig
Ih
Ii
)
3
1.43 (d, 3H, JHH ) 6.2 Hz, CCH3)
7.37 (s, NH); 7.31 (s, 1H, Ph); 7.22-7.25 (m, 1H, Ph); 7.15-7.20 (m, 2H, Ph); 6.46 (d, 1H, JHH ) 8.1 Hz); 6.39 (d, 1H,3JHH ) 8.2 Hz);
4.89-4.96 (m, 1H, CH); 3.15-3.21 (m, 1H, CH2); 2.62-2.66 (m, 1H, CH2); 2.32 (s, 3H, PhCH3); 1.99 (s, 3H, PhCH3); 1.60 (s, 9H,
3
3
C(CH3)3); 1.42 (d, 3H, JHH ) 6.2 Hz, CCH3)
3
3
7.38 (s, 1H, NH); 7.06 (s, 2H, Ph); 6.96 (s, 1H, Ph); 6.47 (d, 1H, JHH ) 8.1 Hz, Ph); 6.38 (d, 1H, JHH ) 8.0 Hz, Ph); 4.89-4.95 (m, 1H,
CH); 3.14-3.20 (m, 1H, CH2); 2.61-2.67 (m, 1H, CH2); 2.26 (s, 6H, PhCH3); 2.01 (s, 3H, PhCH3); 1.59 (s, 9H, C(CH3)3); 1.42 (d, 3H,
3JHH ) 6.2 Hz, CCH3)
9.00 (s, 1H, NH); 8.70 (s, 2H, Ph); 7.72 (s, 1H, Ph); 6.82 (d, 1H, JHH ) 8.1 Hz, Ph); 6.44 (d, 1H, JHH ) 8.3 Hz, Ph); 4.91-4.97 (m, 1H,
CH); 3.12-3.21 (m, 1H, CH2); 2.59-2.67 (m, 1H, CH2); 1.92 (s, 3H, PhCH3); 1.63 (s, 9H, C(CH3)3); 1.42 (d, 3H, JHH ) 6.2 Hz, CCH3)
7.56 (s, 1H, NH); 7.35 (s, 2H, Ph); 7.32 (s, 1H, Ph); 6.75 (d, 1H, JHH ) 8.2 Hz, Ph); 6.46 (d, 1H, JHH ) 8.2 Hz, Ph); 4.92-4.97 (m, 1H,
CH); 3.17-3.24 (m, 1H, CH2); 2.64-2.70 (m, 1H, CH2); 2.03 (s, 3H, PhCH3); 1.58 (s, 9H, C(CH3)3); 1.44 (d, 3H, JHH ) 6.2 Hz, CCH3)
7.62 (s, NH); 7.45 (d, 1H, JHH ) 8.2 Hz, Ph); 7.36 (s, 1H, Ph); 7.23 (d, 1H, JHH ) 8.2 Hz); 6.46 (d, 1H, JHH ) 6.3 Hz, Ph); 6.38 (d,
1H, JHH ) 6.4 Hz, Ph); 4.91-4.99 (m, 1H, CH); 3.17-3.23 (m, 1H, CH2); 2.64-2.70 (m, 1H, CH2); 2.02 (s, 3H, PhCH3); 1.61 (s, 9H,
3
3
Ij
3
3
3
Ik
Il
3
3
3
3
3
3
C(CH3)3); 1.44 (d, 3H, JHH ) 6.2 Hz, CCH3)
3
3
3
IIa
IIb
7.49 (s, 1H, NH); 7.47 (d, 2H, JHH ) 6.0 Hz, Ph); 7.31-7.35 (m, 3H, Ph); 6.44 (d, 1H, JHH ) 8.2 Hz, Ph); 6.35 (d, 1H, JHH ) 8.2 Hz,
Ph); 2.85 (s, 2H, CH2); 1.95 (s, 3H, PhCH3); 1.60 (s, 9H, C(CH3)3); 1.43 (s, 3H, CH3); 1.42 (s, 3H, CH3)
8.12 (d, 1H, JHH ) 8.2 Hz, Ph); 7.64 (d, 1H, JHH ) 4.0 Hz, Ph); 7.62 (s, 1H, NH); 7.54-7.60 (m, 1H, Ph); 7.47-7.51 (m, 1H, Ph); 6.33
(d, 1H, JHH ) 8.3 Hz, Ph); 6.27 (d, 1H, JHH ) 8.3 Hz, Ph); 2.84 (s, 2H, CH2); 1.99 (s, 3H, PhCH3); 1.64 (s, 9H, C(CH3)3); 1.43 (s, 3H,
CCH3); 1.42 (s, 3H, CCH3)
3
3
3
3
3
3
3
IIc
8.31 (s, 1H, NH); 8.21 (d, 1H, JHH ) 8.3 Hz, Ph); 7.93 (d, 1H, JHH ) 8.2 Hz, Ph); 7.58 (s, 1H, Ph); 7.53 (q, 1H, JHH ) 8.0 Hz, Ph);
3 3
6.66 (d, 1H, JHH ) 8.2 Hz, Ph); 6.39 (d, 1H, JHH ) 8.3 Hz, Ph); 2.84 (s, 2H, CH2); 1.90 (s, 3H, PhCH3); 1.62 (s, 9H, C(CH3)3); 1.43 (s,
6H, C(CH3)2)
3
3
3
3
IId
IIe
8.18 (d, 2H, JHH ) 8.8 Hz, Ph); 7.67 (d, 2H, JHH ) 6.9 Hz, Ph); 7.48 (s, 1H, NH); 6.62 (d, 1H, JHH ) 8.2 Hz, Ph); 6.40 (d, 1H, JHH )
8.2 Hz, Ph); 2.85 (s, 2H, CH2); 1.93 (s, 3H, PhCH3); 1.61 (s, 9H, C(CH3)3); 1.43 (s, 6H, C(CH3)2)
7.64 (s, 1H, NH); 7.48 (d, 1H, JHH ) 7.5 Hz, Ph); 7.34 (d, 1H, JHH ) 7.6 Hz, Ph); 7.21-7.29 (m, 2H, Ph); 6.36 (d, 1H, JHH ) 8.2 Hz,
Ph); 6.31 (d, 1H, JHH ) 8.2 Hz, Ph); 2.85 (s, 2H, CH2); 2.00 (s, 3H, PhCH3); 1.62 (s, 9H, C(CH3)3); 1.43 (s, 3H, CCH3); 1.42 (s, 3H,
CCH3)
3
3
3
3
3
3
3
IIf
7.70 (s, 1H, NH); 7.43 (s, 1H, Ph); 7.34 (d, 1H, JHH ) 7.6 Hz, Ph); 7.30 (d, 1H, JHH ) 7.4 Hz, Ph); 7.22 (q, 1H, JHH ) 7.8 Hz, Ph);
3 3
6.59 (d, 1H, JHH ) 8.2 Hz, Ph); 6.37 (d, 1H, JHH ) 8.2 Hz, Ph); 2.85 (s, 2H, CH2); 1.96 (s, 3H, PhCH3); 1.57 (s, 9H, C(CH3)3); 1.43 (s,
6H, C(CH3)2)
3
3
3
3
IIg
IIh
7.50 (s, 1H, NH); 7.45 (d, 2H, JHH ) 8.4 Hz, Ph); 7.28 (d, 2H, JHH ) 8.4 Hz, Ph); 6.61 (d, 1H, JHH ) 8.2 Hz, Ph); 6.41 (d, 1H, JHH )
8.2 Hz, Ph); 2.87 (s, 2H, CH2); 1.94 (s, 3H, PhCH3); 1.58 (s, 9H, C(CH3)3); 1.44 (s, 6H, C(CH3)2)
7.87 (s, 1H, NH); 7.44 (d, 1H, JHH ) 7.4 Hz, Ph); 7.30 (q, 1H, JHH ) 7.7 Hz, Ph); 6.96 (q, 1H, JHH ) 7.5 Hz); 6.86 (d, 1H, JHH ) 8.3
Hz, Ph); 6.38 (d, 1H, JHH ) 8.4 Hz, Ph); 6.34 (d, 1H, JHH ) 8.3 Hz, Ph); 2.84 (s, 2H, CH2); 1.90 (s, 3H, PhCH3); 1.62 (s, 9H,
C(CH3)3); 1.43 (s, 6H, C(CH3)2)
3
3
3
3
3
3
3
3
3
IIi
7.33 (s, 1H, NH); 7.22 (q, 1H, JHH ) 7.8 Hz, Ph); 7.04 (s, 1H, Ph); 7.02 (d, 1H, JHH ) 7.6 Hz, Ph); 6.89 (d, 1H, JHH ) 8.1 Hz, Ph);
3 3
6.49 (d, 1H, JHH ) 8.2 Hz, Ph); 6.37 (d, 1H, JHH ) 8.2 Hz, Ph); 3.77 (s, 3H, OCH3); 2.85 (s, 2H, CH2); 1.99 (s, 3H, PhCH3); 1.59 (s,
9H, C(CH3)3); 1.43 (s, 6H, C(CH3)2)
3
3
3
3
IIj
7.52 (s, 1H, NH); 7.48 (d, 2H, JHH ) 8.7 Hz, Ph); 6.82 (d, 2H, JHH ) 8.7 Hz, Ph); 6.62 (d, 1H, JHH ) 8.2 Hz, Ph); 6.40 (d, 1H, JHH )
8.2 Hz, Ph); 3.78 (s, 3H, OCH3); 2.86 (s, 2H, CH2); 1.96 (s, 3H, PhCH3); 1.58 (s, 9H, C(CH3)3); 1.43 (s, 6H, C(CH3)2)
7.36 (s, 1H, NH); 7.31 (s, 1H, Ph); 7.13-7.23 (m, 3H, Ph); 6.46 (d, 1H, JHH ) 8.2 Hz, Ph); 6.36 (d, 1H, JHH ) 8.3 Hz, Ph); 2.85 (s, 2H,
CH2); 2.31 (s, 3H, PhCH3); 1.97 (s, 3H, PhCH3); 1.60 (s, 9H, C(CH3)3); 1.43 (s, 6H, C(CH3)2)
8.04 (s, 1H, NH); 7.00 (s, 2H, Ph); 6.92 (s, 1H, Ph); 6.46 (d, 1H, JHH ) 8.1 Hz, Ph); 6.28 (d, 1H, JHH ) 8.2 Hz, Ph); 2.82 (s, 2H, CH2);
2.19 (s, 6H, Ph(CH3)2); 1.95 (s, 3H, PhCH3); 1.53 (s, 9H, C(CH3)3); 1.41 (s, 6H, C(CH3)2)
9.00 (s, 1H, NH); 8.71 (s, 2H, Ph); 7.70 (s, 1H, Ph); 6.82 (d, 1H, JHH ) 8.1 Hz, Ph); 6.42 (d, 1H, JHH ) 8.2 Hz, Ph); 2.84 (s, 2H, CH2);
1.91 (s, 3H, PhCH3); 1.63 (s, 9H, C(CH3)3); 1.43 (s, 6H, C(CH3)2)
3
3
IIk
IIl
3
3
3
3
IIm
IIn
IIo
3
3
3
3
7.46 (s, 1H, NH); 7.37 (d, 2H, JHCl ) 1.9 Hz, Ph); 7.33 (d, 1H, JHCl ) 1.9 Hz, Ph); 6.77 (d, 1H, JHH ) 8.2 Hz, Ph); 6.45 (d, 1H, JHH
8.2 Hz, Ph); 2.88 (s, 2H, CH2); 2.02 (s, 3H, PhCH3); 1.58 (s, 9H, C(CH3)3); 1.45 (s, 3H, CH3); 1.44 (s, 3H, CH3)
7.63 (s, 1H, NH); 7.44 (d, 1H, JHH ) 8.1 Hz, Ph); 7.36 (s, 1H, Ph); 7.23 (d, 1H,3JHH ) 8.2 Hz, Ph); 6.50 (d, 1H, JHH ) 8.2 Hz, Ph);
)
3
3
3
6.42 (d, 1H, JHH ) 8.2 Hz, Ph); 2.87 (s, 2H, CH2); 2.00 (s, 3H, PhCH3); 1.60 (s, 9H, C(CH3)3); 1.44 (s, 6H, C(CH3)2)

Novel Benzoheterocyclic Diacylhydrazine Derivatives
J. Agric. Food Chem., Vol. 57, No. 6, 2009 2453
Table 3. Toxicities (Percent) against Oriental Armyworm and Mosquito of Compounds Ia-Il and IIa-IIo and Contrast Compounds ANS-118 and JS-118
stomach toxicities against oriental armyworm at toxicities against mosquito at
200 mg
kg-1
100 mg
kg-1
50 mg
kg-1
25 mg
kg-1
10 mg
kg-1
5 mg
kg-1
2.5 mg
kg-1
2 mg
kg-1
1 mg
kg-1
0.5 mg
kg-1
compd
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Ii
Ij
Ik
Il
IIa
IIb
IIc
IId
IIe
IIf
IIg
IIh
IIi
IIj
IIk
IIl
IIm
IIn
IIo
ANS-118
JS-118
100
100
20
100
100
0
90
60
80
20
0
0
0
30
20
40
30
60
0
0
20
10
0
20
20
0
0
0
60
0
100
100
100
100
100
20
100
100
40
50
10
10
60
80
90
0
100
60
100
100
40
100
100
100
100
100
0
100
100
10
0
100
80
100
100
100
40
30
90
100
100
0
10
0
100
95
10
10
0
15
80
0
20
0
0
80
30
80
0
10
20
50
0
30
20
20
0
20
0
10
10
30
0
10
10
0
100
100
0
90
90
90
0
10
0
50
40
30
20
70
10
60
20
40
10
50
70
30
30
50
100
100
10
10
10
0
0
0
0
10
10
0
30
0
90
100
0
0
0
0
0
10
20
0
30
90
0
20
10
0
20
20
0
10
0
10
10
60
90
100
100
0
10
100
100
0
100
100
100
100
100
100
100
100
80
95
80
100
10
50
7-tert-butyl-2,4-dimethylbenzofuran (d) as a new intermediate
according to the literature method (33); at the same time, 8-tert-
butyl-5-methyl-2H-chromene was obtained as byproduct. We
found that acetic acid is a better solvent than other protic
solvents such as methanol and ethanol when compound d was
reduced to 7-tert-butyl-2,4-dimethyl-2,3-dihydrobenzofuran (e);
this is due to the conjugation between furan and benzene to
induce greater double-bond stabilization. Compound e was
reacted with aluminum chloride in dichloromethane to provide
5-acetyl-2,4-dimethyl-2,3-dihydrolbenzofuran (f) in one step.
This method is easier than the literature method (11). Compound
f was treated with bromine and sodium hydroxide to give the
new intermediate 2,4-dimethyl-2,3-dihydrobenzofuran-5-car-
boxylic acid (g) in 91% yield. Subsequent chlorination with
thionyl chloride and further reaction with tert-butylhydrazine
hydrochloride provided the new intermediate N′-tert-butyl-N-
2,4-dimethyl-2,3-dihydrobenzofuran-5-carbohydrazide (i) in 93%
yield. Finally, compound i was reacted with substituted benzoyl
chlorides to give the title compounds Ia-Il.
The title compounds IIa-IIo were synthesized as shown in
Scheme 2. 2-tert-Butyl-5-methylphenol (b) was reacted with
3-chloro-2-methylprop-1-ene to give the new intermediate,
1-tert-butyl-4-methyl-2-(2-methylallyloxy)benzene (j) according
to the literature method (34). At first, we attempted to reflux
compound j in N,N-diethylaniline to yield 7-tert-butyl-2,2,4-
trimethyl-2,3-dihydrobenzofuran (l). However, we obtained
6-tert-butyl-3-methyl-2-(2-methylallyl)phenol (k) as a main
product, and compound l was obtained only as byproduct. Then,
according to the literature method (35), we heated k at 110 °C
for 15 min in the presence of sulfuric acid to give compound l
in good yield. These new intermediates m, n, o, q, and the title
compounds IIa-IIo, were synthesized according to the same
procedure as in Scheme 1.
The physical properties and elemental analyses of the title
compounds Ia-Il and IIa-IIo are listed in Table 1, and their
1H NMR data are listed in Table 2.
Bioassay. We have reported the larvicidal activity against
oriental armyworm of compound F (LC50 ) 2.25 mg L-1) (14).
To compare insecticidal spectrum and insecticidal level between
compound F and the commercialized compound ANS-118 and
further study influence of substitutents on the benzene rings of
benzoheterocyle moiety on insecticidal activity, we tested their
larvicidal activities against other lepidopteral insects as shown
below.
Stomach Toxicity against Oriental Armyworm (Mythimna
separata Walker). Table 3 shows the stomach toxicities of
the title compounds Ia-Il and IIa-IIo and contrast com-
pounds ANS-118 and JS-118 against oriental armyworm. The
results indicate that compounds Ia-Il exhibit higher stomach
toxicities against oriental armyworm than compounds
IIa-IIo. From Table 3, we can also see that the larvicidal
activities against oriental armyworm of the compounds Ia-Il
and IIa-IIo varied drastically, depending upon the types and
patterns of substitution on the benzene. Among monosub-
stitued derivatives, compared to nonsubstituted compound
(Ia and IIa), methoxy (IIi) or methyl (Ih, IIk) at meta is
most prominent in increasing activity, and nitro at meta (Ic,
IIc) or para (Id, IId) can drastically decrease activity.
Compared with nonsubstituted compound IIa, chloro sub-
stitued at meta (IIf) or para (IIg) can increase the activity,
but the activity of 3-chloro (If) or 4-chloro (Ig) derivatives
has no obvious improvement to nonsubstituted compound Ia.
Among multisubstituted compounds, 3,5-dimethyl (Ii) and
3,5-dichloro (Ik) derivatives are most prominent in increasing
activity, and 3,5-dinitro (Ij) derivative has lower activity than
nonsubstituted compound (Ia). However, compared with

2454 J. Agric. Food Chem., Vol. 57, No. 6, 2009
Huang et al.
Table 4. Stomach Toxicities (72 h) against Beet Armyworm of Compounds
Ii and F and Contrast Compounds ANS-118 and JS-118
Table 6. Contact Toxicities (48 and 72h) against Diamond-back Moth of
Compounds Ii and F and Contrast Compounds ANS-118 and JS-118
compd
Ii
y ) a + bx
LC50 (mg/L)
toxic ratio
compd
Ii
time (h)
48
y ) a + bx
LC50 (mg/L)
toxic ratio
y ) 3.5776 + 1.2906x
y ) 3.5251 + 1.9937x
y ) 3.6598 + 1.6786x
y ) 3.7029 + 1.8640x
12.7
5.5
6.3
5.0
1
y ) 2.0417 + 1.4133x
y ) 0.3993 + 2.2393x
y ) 1.0496 + 1.6649x
y ) 1.9568 + 1.1838x
123.9
113.4
235.9
372.2
3.0
3.3
1.6
1
F
2.3
2.0
2.5
F
ANS-118
JS-118
ANS-118
JS-118
Ii
F
72
y ) 2.2938 + 1.4166x
y ) 0.7782 + 2.2821x
y ) 3.1342 + 0.8929x
y ) 2.7788 + 0.8944x
81.4
70.8
122.9
304.4
3.7
4.3
2.5
1
Table 5. Contact Toxicities (48 and 72 h) against Beet Armyworm of
Compounds Ii and F and Contrast Compounds ANS-118 and JS-118
ANS-118
JS-118
compd
Ii
time (h)
48
y ) a + bx
LD50 (mg/L) toxic ratio
y ) 2.8008 + 0.9648x
y ) -0.1439 + 4.1538x
y ) 2.8928 + 1.4291x
y ) 3.3303 + 0.9406x
190.3
17.3
29.8
59.6
1
11
6.4
3.2
Table 7. Stomach Toxicities and Contact Toxicities against Cotton
Bollworm at 1000 mg L-1 of Compounds Ii and F and Contrast
Compounds ANS-118 and JS-118
F
ANS-118
JS-118
compd
Ii
stomach toxicities (%)
contact toxicities (%)
Ii
F
72
y ) 2.6114 + 1.3865x
y ) 2.4583 + 2.3763x
y ) 2.7896 + 1.8860x
y ) 2.8875 + 1.9192x
52.8
11.7
14.9
12.6
1
4.5
3.5
4.2
70
80
65
60
50
40
60
60
ANS-118
JS-118
F
ANS-118
JS-118
nonsubstituted compound (IIa), 3,5-dimethyl (IIl) and 2,4-
dichloro (IIo) derivatives are most prominent in increasing
activity and 3,5-dinitro (IIm) and 3,5-dichloro (IIn) deriva-
tives have no obvious effect on the activity. From the above
discussion, we conclude that different benzoheterocyclic
analogues of diacylhydrazide have different structure-activity
relationships according to diversification of substitution on
the benzene, and 3,5-dimethyl derivatives Ii and IIl have
higher activity than other componds Ia-Il and IIa-IIo,
respectively. Among them, compound Ii (80% mortality at
5 mg L-1) stood out as better than other compounds but is
lower than compounds ANS-118 and JS-118 against oriental
armyworm larvae.
Table 8. Stomach Toxicities (4 Days) against Corn Borer of Compounds Ii
and F and Contrast Compounds ANS-118 and JS-118
compd
Ii
y ) a + bx
LC50 (mg/L)
LC95 (mg/L)
y ) 1.8041 + 1.9885x
y ) 1.6757 + 1.9052x
y ) 2.6107 + 1.8818x
y ) 1.9605 + 2.1591x
40.48
55.57
18.61
25.57
271.89
405.65
139.25
147.78
F
ANS-118
JS-118
At 72 h after treatment, the contact activities of compounds Ii
and F were about 1.5 times that of ANS-118 and about 4 times
that of JS-118, respectively.
Stomach Toxicities and Contact Toxicities against Cotton
Bollworm (H. armigera (Hu¨bner)). Table 7 shows the stomach
toxicities of compounds Ii and F and ANS-118 and JS-118
against cotton bollworm. The results indicate that compounds
Ii and F have a little higher stomach activity than ANS-118
and JS-118. Contact activity of compounds Ii and F is a little
lower than those of ANS-118 and JS-118.
Stomach Toxicity against Corn Borer (O. nubilalis). Table
8 shows the stomach toxicities of compounds Ii and F and ANS-
118 and JS-118 against corn borer. LC50 is the median lethal
concentration, and LC95 is the 95% lethal concentration. The
values of LC50 and LC95 indicate that the toxicity of compound
Ii is higher than that of compound F, but the activities of
compounds Ii and F are lower than those of ANS-118 and JS-
118.
From Table 3, we know that compound Ii (95% mortality at
10 mg L-1) has higher activity against oriental armyworm than
compound IIl (90% mortality at 50 mg L-1) but has lower
activity than ANS-118 (100% mortality at 5 mg L-1) and JS-
118 (95% mortality at 2.5 mg L-1). The stomach toxicity (72
h) and contact toxicity (48 and 72 h) against beet armyworm
of compound Ii are obviously lower than that of ANS-118 and
JS-118 as shown in Tables 4 and 5, respectivly. However,
compound Ii has 2-3 times higer contact toxicity (48 and 72 h)
against diamond-back moth than ANS-118 and JS-118 as shown
in Table 6. All of these results indicate that different hetero-
cycles of benzoheterocyclic diacylhydrazide not only influence
the larvicidal activities strongly but also are very sensitive to
the insecticidal action modes for different Lepidopteran larvi-
cidal insects. The differentiation between compound F and ANS-
Toxicity against Mosquito (C. pipiens pallens). The title
compounds Ia-Il and IIa-IIo show moderate activities against
mosquito larvae as shown in Table 3. They show almost the
same disciplines of structure-activity relationship as mentioned
above for oriental armyworm larvae.
Stomach Toxicity against Beet Armyworm (L. exigua Hu¨bner).
Table 4 shows the stomach toxicities of compounds Ii and
F and ANS-118 and JS-118 against beet armyworm. LC50 is
the median lethal concentration. The results indicate that the
toxicity of compound Ii is lower than that of ANS-118 and
JS-118, but compound F has the same activity as ANS-118
and JS-118.
Contact Toxicity against Beet Armyworm (L. exigua Hu¨bner).
Table 5 shows the contact toxicities of compounds Ii and F
and ANS-118 and JS-118 against beet armyworm. LD50 is the
median lethal dose. The results indicate that the toxicity of
compound Ii is lower than that of ANS-118 and JS-118 at 48
and 72 h after teatment, but compound F has a higher contact
activity than compound ANS-118 (1.7 times at 48 h and 1.3
times at 72 h, respectively) and JS-118 (3.4 times at 48 h and
1.1 times at 72 h, respectively).
Contact Toxicities (48 and 72 h) against Diamond-back Moth
(P. xylostella L.). Table 6 shows the contact toxicities of
compounds Ii andF and ANS-118 and JS-118 against diamond-
back moth. The results indicate that compounds Ii and F have
higher activity than ANS-118 and JS-118. At 48 h after
treatment, the contact activities of compounds Ii and F were 2
times that of ANS-118 and 3 times that of JS-118, respectively.

Novel Benzoheterocyclic Diacylhydrazine Derivatives
J. Agric. Food Chem., Vol. 57, No. 6, 2009 2455
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(72 h) against beet armyworm as ANS-118 (Table 4) and
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Received for review November 20, 2008. Revised manuscript received
January 18, 2009. Accepted January 21, 2009.
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