Synthesis and Insect Growth Regulatory Activity of Alkoxy-Substituted Benzaldoxime Ethers

Article abstract of DOI:10.1021/jf970062h

Alkoxy-substituted benzaldoxime ethers, namely (i) 3-methoxy-4-ethoxybenzaldoxime N-O-alkyl ethers, (ii) 3,4-dimethoxybenzaldoxime N-O-alkyl ethers, and (iii) 3,4-methylenedioxybenzaldoxime N-O-alkyl ethers, have been synthesized and evaluated for their insect growth regulatory activity against fifth-instar nymphs of the desert locust Schistocerca gregaria F. When injected into insect hemolymph at the lowest dose level of 3 μg/nymph, 3,4-methylenedioxybenzaldoxime N-O-methyl ether and 3,4-methylenedioxybenzaldoxime N-O-isopropyl ether showed 40 and 50% growth deformities respectively. On topical application (at 20 μg/nymph) 3-methoxy-4-ethoxybenzaldoxime N-O-methyl ether inflicted 100% abnormalties in insect growth. Structure-activity relationship studies revealed that maximum activity was associated with compounds having three carbons in the oxime ether moiety.

Full text of DOI:10.1021/jf970062h

J. Agric. Food Chem. 1998, 46, 731−736
731
Syn th esis a n d In sect Gr ow th Regu la tor y Activity of
Alk oxy-Su bstitu ted Ben za ld oxim e Eth er s
†
‡
,†
H. Chowdhury, V. S. Saxena, and S. Walia*
Divisions of Agricultural Chemicals and Entomology, Indian Agricultural Research Institute,
New Delhi 110 012, India
Alkoxy-substituted benzaldoxime ethers, namely (i) 3-methoxy-4-ethoxybenzaldoxime N-O-alkyl
ethers, (ii) 3,4-dimethoxybenzaldoxime N-O-alkyl ethers, and (iii) 3,4-methylenedioxybenzaldoxime
N-O-alkyl ethers, have been synthesized and evaluated for their insect growth regulatory activity
against fifth-instar nymphs of the desert locust Schistocerca gregaria F. When injected into insect
hemolymph at the lowest dose level of 3 µg/nymph, 3,4-methylenedioxybenzaldoxime N-O-methyl
ether and 3,4-methylenedioxybenzaldoxime N-O-isopropyl ether showed 40 and 50% growth
deformities respectively. On topical application (at 20 µg/nymph) 3-methoxy-4-ethoxybenzaldoxime
N-O-methyl ether inflicted 100% abnormalties in insect growth. Structure-activity relationship
studies revealed that maximum activity was associated with compounds having three carbons in
the oxime ether moiety.
Keyw or d s: Insect growth regulators; oxime ethers; Schistocerca gregaria
Biosynthesis and release of insect growth hormones
such as brain hormones (BHs), juvenile hormones (J Hs),
and molting hormones (MHs) govern the growth, molt-
ing, and development of insects (Reynolds and Truman,
procured from S. D. Fine Chem Ltd., Mumbai, India, and used
without further purification. Piperonal was obtained from
Aldrich Chemical Co. The organic solvents used in chroma-
tography, crystallization, and organic syntheses were of re-
agent grade.
Ch r om a togr a p h y a n d Sp ectr oscop y. Thin-layer chro-
matography (TLC) was performed on silica gel G plates
preactivated at 100 °C. The plates were developed in hexane/
acetone (75:25) and visualized by either iodine vapors or
spraying with 2,4-dinitrophenylhydrazine solution. Silica gel
(60-120) mesh was used for column chromatography using
hexane and hexane/acetone gradient. Gas chromatographic
(GC) analyses were performed on a Hewlett-Packard model
1
1
980; Chippendale, 1977; Goodman, 1990; Ridiford,
994). Because of the regulatory functions of insect
juvenile hormones in insect embryogenesis, larval growth,
metamorphosis, reproduction, hibernation, migration,
and metabolism, compounds mimicking or antagonizing
the function of juvenile hormones are considered an
important group of third-generation insecticides. Being
generally environmentally benign and possessing rela-
tively selective mode of action, such compounds are
considered safer alternatives to conventional highly
persistent and toxic insecticides (Miyamoto et al., 1993).
Among the various groups of insect growth regulators
5
890A gas chromatograph equipped with a flame ionization
detector (FID) and fitted with a glass column packed with 3%
OV-225 on Chromosorb W.
1
The H NMR spectra were recorded on a Varian EM-360,
6
3
0-MHz instrument. Samples were dissolved in CDCl , and
(IGRs) having diverse structural features, interest in
tetramethylsilane (TMS) was used as an internal standard.
Chemical shifts are reported in δ values relative to TMS.
Infrared (IR) spectra were scanned on a Digilab infrared
spectrophotometer in either Nujol or KBr disk. The mass
spectra (MS) were recorded on a DS-90 mass spectrometer at
70 eV using electron impact ionization.
Elem en ta l An a lysis. C, H, and N analysis was done on a
Perkin-Elmer 2400 C H N elemental autoanalyzer by Dumas
total combustion process using acetonitrile as standard. The
observed values were within (0.5% of the theoretical values.
oxime ethers has grown considerably in recent years
because of their overall impact on the insect endocrine
system. Several oxime ethers have been synthesized
previously and evaluated for their IGR activity (Hayashi
et al., 1990, 1991a,b; Nakayama et al., 1985; Niwa et
al., 1988; Ohsumi et al., 1985), insecticidal activity (Bull
et al., 1980; Nanjyo et al., 1980), and insecticide
synergistic activity (Walia et al., 1985). In this paper
we report the synthesis, IGR activity, and structure-
activity relationships of three series of oxime ethers,
namely (i) 3-methoxy-4-ethoxybenzaldoxime N-O-
alkyl ethers, (ii) 3,4-dimethoxybenzaldoxime N-O-
alkyl ethers, and (iii) 3,4-methylenedioxybenzaldoxime
N-O-alkyl ethers against the desert locust Schisto-
cerca gregaria (Forsk).
Syn th esis of Su bstitu ted Ben za ld oxim es. Equimolar
quantities of hydroxylamine hydrochloride and substituted
benzaldehydes such as 3-methoxy-4-ethoxybenzaldehyde, 3,4-
dimethoxybenzaldehyde, and 3,4-methylenedioxybenzaldehyde
(
piperonal) were refluxed in ethanol for 3 h in the presence of
anhydrous potassium carbonate. After completion of the
reaction (TLC), inorganic salts (KCl and K CO ) were filtered
2
3
off and the solvent was removed by distillation under reduced
pressure to give a viscous mass which crystallized from ethanol
as white powder. 3-Methoxy-4-ethoxybenzaldehyde was pre-
pared by refluxing solution of vanillin and ethyl bromide in
dry acetone containing anhydrous potassium carbonate. These
MATERIALS AND METHODS
Ch em ica ls a n d Rea gen ts. Vanillin, veratraldehyde, alkyl
bromides, and acrylonitrile required for the study were
1
compounds were characterized by H NMR spectroscopy.
*
Author to whom correspondence should be addressed.
Division of Agricultural Chemicals.
Division of Entomology.
†
3-Methoxy-4-ethoxybenzaldoxime N-O-Alkyl Ethers.
A
‡
solution of 3-methoxy-4-ethoxybenzaldoxime (3.9 g; 0.02 mol)
S0021-8561(97)00062-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/14/1998

732 J. Agric. Food Chem., Vol. 46, No. 2, 1998
Chowdhury et al.
in dry acetone (200 mL) containing anhydrous potassium
carbonate (10 g) was refluxed with appropriate alkyl halide
5 mL) was added to the mixture in 1-mL portions. After
completion of the reaction (TLC), water (50 mL) was added
and the mixture neutralized with dilute hydrochloric acid (pH
7.0). The precipitated compound was filtered and crystallized
(0.025 M) for 10 h. After completion of the reaction (TLC),
the solid potassium carbonate was filtered out, water (200 mL)
added, and the reaction mixture neutralized with dilute HCl
from methanol as a brown solid: yield, 4.0 g, 80.64%; R
f
0.45;
CH
CN, J ) 6 Hz), 3.85(s, 3H,
CH , J ) 7 Hz), 4.35 (t, 2H,
CN, J ) 6 Hz), 6.75 (d, 1H, J ) 8 Hz), 6.98 (dd,
1H, J ) 8 and 1.5 Hz), 7.25 (d, 1H, J ) 1.5 Hz), 8.00 (s, 1H,
: C, 62.90; H, 6.45;
1
(pH 7.0). The aqueous layer was then extracted with ethyl
mp 83-84 °C; H NMR (CDCl
J ) 7 Hz), 3.78 (t, 2H, -OCH
-OCH ), 4.20 (q, 2H, Ar-OCH
-NOCH CH
3
) δ 1.40 (t, 3H, Ar-OCH
2
3
,
acetate (2 × 100 mL), and the combined extract was washed
with water and dried over anhydrous magnesium sulfate. The
solvent was then distilled off and the concentrated material
subjected to column chromatography over silica gel using
hexane/benzene (1:1) as eluent to furnish oxime ethers either
in crystalline form or as viscous liquid.
2
CH
2
3
2
3
2
2
-CHdN-). Anal. Calcd for C13
16 3 2
H O N
O, 19.35; N, 11.29. Found: C, 62.80; H, 6.50; O, 19.39; N,
11.30%.
3
-Methoxy-4-ethoxybenzaldoxime N-O-methyl ether (I):
1
yield 3.3 g (79%); R
f
0.66; H NMR (CDCl
, J ) 7 Hz), 3.8 (s, 3H, -OCH
), 4.0 (q, 2H, -OCH CH , J ) 7 Hz), 6.75 (d, 1H, J )
Hz), 6.93 (dd, 1H, J ) 8 and 1.5 Hz), 7.25 (d, 1H, J ) 1.5
N: C,
3.16; H, 7.18; O, 23.0; N, 6.70. Found: C, 63.0; H, 7.17; O,
3.10; N, 6.71.
3
) δ 1.4 (t, 3H,
3,4-Dimethoxybenzaldoxime N-O-methyl ether (VIII): yield
1
-
-
8
OCH
NOCH
2
CH
3
3
), 3.95 (s, 3H,
3.5 g (89.7%); R
(s, 2 × -OCH
7.02 (dd, 1H, J ) 8 and 1.5 Hz), 7.29 (d, 1H, J ) 2 Hz), 8.05
N: C, 61.54; H,
f
0.55; mp 50 °C; H NMR (CDCl
3
) δ 3.85, 3.88
3
2
3
3
), 3.93 (s, 3H, -NOCH
3
), 6.83 (d, 1H, J ) 8 Hz),
Hz), 8.0 (s, 1H, -CHdN-). Anal. Calcd for C11
H
15
O
3
13 3
(s, 1H, -CHdN-). Anal. Calcd for C10H O
6.67; O, 24.61; N, 7.18. Found: C, 61.14; H, 6.36; O, 25.01;
N, 7.49.
6
2
3
-Methoxy-4-ethoxybenzaldoxime N-O-ethyl ether (II): yield
3,4-Dimethoxybenzaldoxime N-O-ethyl ether (IX): yield 3.5
-
1
1
3
9
(
.7 g (83%); R
f
0.71; mp 42 °C; IR (ν Nujol, cm ) 720, 810,
g (83.7%); R
3H, OCH CH
2H, -OCH
f
0.60; mp 49-51 °C; H NMR (CDCl
3
) δ 1.30 (t,
), 4.27 (q,
, J ) 6 Hz), 6.85 (d, 1H, J ) 8 Hz), 7.13 (dd,
1
45, 1010, 1090, 1140, 1245, 1450, 1500, 1575 1600; H NMR
) δ 1.30 (t, 3H, -NOCH CH , J ) 7 Hz), 1.40 (t, 3H,
Ar-OCH CH , J ) 7 Hz), 3.85 (s, 3H, -OCH ), 4.15 (q, 2H,
NOCH CH , J ) 7 Hz), 4.20 (q, 2H, Ar-OCH CH , J ) 7
2
3
, J ) 6 Hz), 3.88, 3.90 (s, 2 × -OCH
3
CDCl
3
2
3
2
CH
3
2
3
3
1H, J ) 8 and 1.5 Hz), 7.35 (d, 1H, J ) 2 Hz), 8.10 (s, 1H,
-
2
3
2
3
15 3
-CHdN-). Anal. Calcd for C11H O
O, 22.96; N, 6.70. Found; C, 63.25; H, 7.04; O, 22.98; N, 6.71.
N: C, 63.15, H, 7.18;
Hz), 6.75 (d, 1H, J ) 8 Hz), 7.02 (dd, 1H, J ) 8 and 1.5 Hz),
+
7
1
1
.25 (d, 1H, J ) 1.5 Hz), 8.0 (s, 1H, -CHdN-); MS 223 (M ,
3,4-Dimethoxybenzaldoxime N-O-n-propyl ether (X): yield
1
00%), 209 (27.6%), 195 (58.6%), 178 (30%), 150 (46%), 134,
3.6 g (80.7%); R
CH CH
(s, 2 × -OCH
(s, 1 H, J ) 8 Hz), 6.98 (dd, 1H, J ) 8 and 1.5 Hz), 7.20 (s, 1H,
J ) 2 Hz), 7.93 (s, 1H, -CHdN-). Anal. Calcd for C12
N: C, 64.57; H, 7.62; O, 21.52; N, 6.28. Found: C, 63.9; H,
7.69; O, 21.92; N, 6.48.
3,4-Dimethoxybenzaldoxime N-O-isopropyl ether (XI): yield
f
0.64; H NMR (CDCl
3
) δ 0.98 (t, 3H, -OCH
CH CH ), 3.80, 3.78
CH , J ) 6 Hz), 6.73
2
-
24, 106, 79, 77. Anal. Calcd for C12
H
17
O
3
N: C, 64.57; H, 7.62;
2
3
, J ) 6 Hz), 1.70 (m, 2H, -OCH
2
2
3
O, 21.52; N, 6.28. Found: C, 64.63; H, 7.60; O, 21.51; N, 6.20%.
-Methoxy-4-ethoxybenzaldoxime N-O-n-propyl ether (III):
3
), 4.10 (t, 2H, -OCH CH
2
2
3
3
1
yield 3.9 g (82.3%); R
f
0.74; H NMR (CDCl
, J ) 7 Hz), 1.40 (t, 3H, Ar-OCH
Hz), 1.60 (m, 2H, -NOCH CH CH ), 3.76 (s, 3H, -OCH
CH CH , J ) 7 Hz), 4.15 (q, 2H, Ar-
, J ) 7 Hz), 6.75 (d, 1H, J ) 8 Hz), 6.97 (dd, 1H, J
3
) δ 0.95 (t, 3H,
CH , J )
),
17
H -
-
7
4
NOCH
2
CH
2
CH
3
2
3
O
3
2
2
3
3
.00 (t, 2H, -NOCH
2
2
3
-1
OCH
2
CH
3
3.4 g (76.2%); R
1160, 1280, 1500, 1600; H NMR (CDCl
(CH
, J ) 6 Hz], 3.80, 3.79 (s, 2 × OCH
3 2
-CH(CH ) ], 6.72 (d, 1H, J ) 8 Hz), 6.98 (dd, 1H, J ) 8 and
f
0.64; IR(ν Nujol, cm ) 1810, 975, 1200, 1050,
1
)
)
5
8 and 1.5 Hz), 7.25 (d, 1H, J )1.5 Hz), 7.93 (s, 1H, -CHdN-
. Anal. Calcd for C13 N: C, 65.8; H, 8.02; O, 20.25; N,
.91. Found; C, 65.70; H, 8.03; O, 20.26; N, 6.0.
-Methoxy-4-ethoxybenzaldoxime N-O-isopropyl ether (IV):
3
) δ 1.25 [d, 6H, -OCH-
), 4.40 [m, 1H,
H
19
O
3
3
)
2
3
3
1.5 Hz), 7.20 (s, 1H, J ) 2 Hz), 7.90 (s, 1H, -CHdN-); MS
223 (M , 100%), 181 (75%), 165 (57.5%), 150 (32.2%), 138
1
+
yield 4.1 g (86.5%); R
f
0.73; mp 49-50 °C; H NMR (CDCl
, J ) 6 Hz], 1.40 (t, 3H, Ar-OCH CH
), 4.0 (q, 2H -OCH CH , J ) 7
], 6.75 (d, 1H, J ) 8 Hz), 6.98
dd, 1H, J ) 8 and 1.5 Hz), 7.23 (d, 1H, J ) 1.5 Hz), 7.96 (s,
H, -CHdN-). Anal. Calcd for C13 N: C, 65.82; H, 8.02;
O, 20.25; N, 5.91. Found: C, 65.80; H, 8.03; O, 20.27; N, 5.89.
3
) δ
3
1
.26 [d, 6H, -CH(CH
3
)
2
2
,
17 3
(66.7%), 120, 107, 92, 79, 77. Anal. Calcd for C12H O N: C,
64.57; H, 7.62; O, 21.52; N, 6.28. Found: C, 64.78; H, 7.50;
O, 21.41; N, 6.29.
J ) 7 Hz), 3.80 (s, 3H, -OCH
3
2
3
Hz), 4.45 [m, 1H, -NOCH(CH
3 2
)
(
1
3,4-Dimethoxybenzaldoxime N-O-n-butyl ether (XII): yield
1
H
19
O
3
3.9 g (82.3%); R
CH
), 3.70, 3.75 (s, 2 × -OCH
f
0.65; H NMR (CDCl
3
) δ 0.95 [t, 3H,
-O(CH
2
)
3
3
, J ) 6 Hz], 1.25-1.90 (m, 4H, -OCH
2
CH
CH
2
CH
2
-
-
3
-Methoxy-4-ethoxybenzaldoxime N-O-n-butyl ether (V):
CH
CH
3
3
), 4.10 (t, 2H, -OCH
2
2
CH
2
-
1
yield 4.0 g (79.7%); R
f
0.75; IR (ν Nujol, cm ) 675, 840, 990,
3
, J ) 6 Hz), 6.70 (d 1H, J ) 8 Hz), 6.93 (dd, 1H, J ) 8 and
1
1
0
050 1235, 1265, 1460, 1500, 1575, 1600; H NMR (CDCl
.97 (t, 3H, -NOCH CH CH CH , J ) 7 Hz), 1.45 (t, 3H, -
CH , J ) 7 Hz), 1.2-1.9 [m, 4H, -NOCH (CH CH ],
.83 (s, 3H, -OCH ), 4.0 (t, 2H, NOCH CH CH CH , J ) 7
Hz), 4.15 (q, 2H, -ArOCH CH , J ) 7 Hz), 6.70 (d, 1H, J ) 8
Hz), 6.97 (dd, 1H, J ) 8 and 1.5 Hz), 7.20 (d, 1H, J ) 1.5 Hz),
3
) δ
1.5 Hz), 7.20 (d, 1H, J ) 2 Hz), 7.93 (s, 1H, -CHdN-). Anal.
2
2
2
3
Calcd for C13 N: C, 65.82; H, 8.02; O, 20.25; N, 5.90.
19 3
H O
ArOCH
2
3
2
2
)
2
3
Found: C, 65.53; H, 8,24; O, 20.21; N, 6.01.
3
3
2
2
2
3
3,4-Dimethoxybenzaldoxime N-O-pentyl ether (XIII): yield
1
2
3
4.4 g (87.6%); R
CH
], 3.78, 3.80 (s, 2 × -OCH
f
0.68; H NMR (CDCl
3
) δ 0.93 [t, 3H
-O(CH
2
)
4
3
, J ) 6 Hz], 1.20-1.88 [m, 6H, -OCH
2
(CH
2
)
)
3
-
-
+
7
(
1
8
.90 (s, 1H, -CHdN-); MS 251 (M , 100%), 220 (48%), 206
69%), 195 (45%), 192 (31%), 179 (89.6%), 167 (54%), 150 (93%),
24, 109, 79, 77. Anal. Calcd for C14
.37; O, 19.12; N, 5.58. Found: C, 66.94, H, 8.35; O, 19.13;
CH
CH
3
3
), 4.10 [t, 2H, -OCH
2
(CH
2
3
3
, J ) 6 Hz], 6.70(d, 1H, J ) 8 Hz), 6.98 (dd, 1H, J ) 8 and
H
21
O
3
N: C, 66.93; H,
1.5 Hz), 7.20 (d, 1H, J ) 2 Hz), 7.90 (s, 1H, -CHdN-). Anal.
Calcd for C14 N: C, 66.93; H, 8.37; O, 19.12; N, 5.58.
21 3
H O
N, 5.57.
Found: C, 66.91; H, 8.39; O, 19.13; N, 5.56.
3
-Methoxy-4-ethoxybenzaldoxime N-O-n-pentyl ether (VI):
3,4-Dimethoxybenzaldoxime N-O-cyanoethyl ether (XIV):
1
1
yield, 4.5 g (84.9%); R
f
0.77; mp 40 °C; H NMR (CDCl
CH , J ) 7 Hz], 1.40 (t, 3H, Ar-
, J ) 7 Hz), 1.20-1.90 [m, 6H, -NOCH (CH CH ],
.80 (s, 3H, -OCH ), 3.94 [t, 2H, -NOCH (CH CH , J ) 7
CH ), 6.70, (d, 1H, J ) 8 Hz), 6.91
dd, 1H, J ) 8 and 1.5 Hz), 7.20 (d, 1H, J ) 1.5 Hz), 7.93 (s,
3
) δ 0.93
yield 4.0 g (85.5%); R
(t, 2H, -OCH CH
2H, -OCH CH
f
0.35; mp 85 °C; H NMR (CDCl
3
) δ 3.78
[
t, 3H, -NOCH
2
(CH
2
)
3
3
2
2
CN, J ) 6 Hz), 3.90 (s, 2 × OCH
3
), 4.35 (t,
OCH CH
2
3
2
2
)
3
3
2
2
CN, J ) 6 Hz), 6.90 (d, 1H, J ) 8 Hz), 7.13
3
3
2
2
)
3
3
(dd, 1H, J ) 8 and 1.5 Hz), 7.30 (d, 1H, J ) 2 Hz), 8.10 (s, 1H,
+
Hz], 4.0 (q, 2H, Ar-OCH
2
3
-CHdN-); MS 234 (M , 100%), 219 (34.5%), 203 (31%), 181
(38%), 164 (75%), 137 (71.3%), 122, 107, 92, 79, 77. Anal. Calcd
(
1
H, -CHdN-). Anal. Calcd for C15
H
23
O
3
N: C, 67.92; H, 8.68;
14 3 2
for C12H O N : C, 61.53; H, 5.98; O, 20.51; N, 11.97. Found:
C, 61.90; H, 6.01; O, 20.20; N, 11.83.
O, 18.11; N, 5.28. Found: C, 67.90; H, 8.69; O, 18.12; N, 5.27.
- Methoxy-4-ethoxybenzaldoxime N-O-Cyanoethyl Ether
VII). A solution of 3-methoxy-4-ethoxybenzaldoxime (0.02 M,
.90 g) in dimethylformamide (10 mL) was stirred by a
3
3,4-Methylenedioxybenzaldoxime N-O-methyl ether (XV):
1
(
3
yield 2.9 g (76.7%); R
(s, 3H, -OCH
f
0.75; mp 37 °C; H NMR (CDCl
3
) δ 3.87
3
), 5.90 (s, 2H, -OCH O-), 6.75 (d, 1H, J ) 8
2
magnetic stirrer along with acrylonitrile (0.025 M, 1.35 g) at
ambient temperature. While stirring, sodium hydroxide (15%,
Hz), 6.99 (dd, 1H, J ) 8 and 1.5 Hz), 7.22 (d, 1H, J ) 2 Hz),
+
7.92 (s, 1H, -CHdN-); MS 179 (M 100%), 164 (6%) 148

Synthesis and IGR Activity of Alkoxybenzaldoxime Ethers
J. Agric. Food Chem., Vol. 46, No. 2, 1998 733
(
60%), 134 (46%), 121 (65.5%), 107, 91. Anal. Calcd for
N: C, 60.33; H, 5.03; O, 26.81; N, 7.82. Found: C,
0.40; H, 5.10; O, 26.40; N, 8.09.
,4-Methylenedioxybenzaldoxime N-O-ethyl ether (XVI):
9 9 3
C H O
6
3
1
yield, 3.3 g (85.5%); R
-
-
f
0.77; H NMR (CDCl
, J ) 6 Hz), 4.20 (q, 2H, -OCH CH
O-), 6.73 (d, 1H, J ) 8 Hz), 6.89 (dd, 1H, J ) 8 and
3
) δ 0.95 [t, 3H,
OCH
OCH
2
CH
3
2
3
), 5.90 (s, 2H,
2
1
.5 Hz), 7.20 (d, 1H, J ) 2 Hz), 7.90 (s,1H, -CHdN-). Anal.
N: C, 62.18; H, 5.70; O, 24.87; N, 7.25.
Found: C, 62.03; H, 5.81; O, 24.89; N, 7.26.
,4-Methylenedioxybenzaldoxime N-O-n-propyl ether (XVII):
Calcd for C10
11 3
H O
3
1
yield, 3.5 g (84.5%); R
OCH CH CH
t, 2H, -OCH CH
d, 1H, J ) 8 Hz), 6.93 (dd, 1H, J ) 8 and 1.5 Hz), 7.20 (d, 1H,
N:
f
0.79; H NMR (CDCl
, J ) 6 Hz), 1.70 (m, 2H, -OCH
CH , J ) 6 Hz), 5.90 (s, 2H, -OCH
3
) δ 0.95 (t, 3H,
CH CH ), 4.05
O-), 6.65
-
(
(
2
2
3
2
2
3
2
2
3
2
J ) 2 Hz), 7.86 (s, 1H, CHdN-). Anal. Calcd for C11
13 3
H O
C, 63.77; H, 6.28; O, 23.19; N, 6.76. Found: C, 63.80; H, 6.25;
O, 23.20; N, 6.74.
3
,4-Methylenedioxybenzaldoxime N-O-isopropyl ether
1
(
[
5
XVIII): yield, 3.6 g (87.0%); R
d, 6H, -OCH(CH , J ) 6 Hz], 4.40 [m, 1H, -OCH(CH
.92 (s, 2H, -OCH O-), 6.70 (d, 1H, J ) 8 Hz), 6.93 (dd, 1H,
J ) 8 and 1.5 Hz), 7.20 (d, 1H, J ) 2 Hz), 7.90 (s, 1H,
CHdN-); MS 207 (M , 100%), 165 (88.5%), 148 (62%), 138
63%), 122 (75%), 107, 91, 76. Anal. Calcd for C11 N: C,
3.77; H, 6.28; O, 23.19; N, 6.76. Found: C, 63.47; H, 6.29;
f
0.77; H NMR (CDCl
3
) δ 1.24
3
)
2
3 2
)
],
2
+
-
(
6
13 3
H O
O, 23.02; N, 7.21.
3
,4-Methylenedioxybenzaldoxime N-O-n-butyl ether (XIX):
1
yield, 3.8 g (86.0%); R
f
0.97; mp 42-43 °C; H NMR (CDCl
CH CH CH , J ) 6 Hz), 1.10-1.80 [m,
], 4.10 (t, 2H, -OCH CH CH CH , J ) 6
O-), 6.73 (d, 1H, J ) 8 Hz), 6.93 (dd,
H, J ) 8 and 1.5 Hz), 7.21 (d, 1H, J ) 2 Hz), 7.96 (s, 1H,
CHdN-). Anal. Calcd for C12 N: C, 65.82; H, 8.02;
O, 20.25; N, 5.90. Found: C, 66.02; H, 8.15; O, 20.15; N, 5.79.
,4-Methylenedioxybenzaldoxime N-O-n-pentyl ether (XX):
3
) δ
0
4
.95 (t, 3H, N-OCH
2
2
2
3
H, OCH (CH CH
2
2
)
2
3
2
2
2
3
Hz), 5.93 (s, 2H, -OCH
2
1
-
15 3
H O
3
1
yield 3.9 g (83.0%); R
OCH
OCH
f
0.98; H NMR (CDCl
, J ) 6 Hz), 1.20-1.80 [m, 6H,
,], 4.10 [t, 2H, -OCH (CH CH , J ) 6 Hz],
O-), 6.72 (d, 1H, J ) 8 Hz), 6.93 (dd, 1H,
3
) δ 0.91 (t, 3H,
-
2
CH
(CH
2
CH
2 2 3
CH CH
-
2
2
)
3
CH
3
2
2
)
3
3
5
.91 (s, 2H, -OCH
2
J ) 8 and 1.5 Hz), 7.20 (d, 1H, J ) 2 Hz), 7.90 (s, 1H,
CHdN-). Anal. Calcd for C13 N: C, 66.38; H, 7.23; O,
0.43; N, 5.96. Found: C, 66.32; H, 7.30; O, 20.41; N, 5.92.
,4-Methylenedioxybenzaldoxime N-O-cyanoethyl ether
-
2
17 3
H O
3
1
(
XXI): yield 3.7 g (85.0%); R
δ 2.72 (t, 2H, -OCH CH CN, J ) 6 Hz), 4.30 (t, 2H, -OCH
CH CN, J ) 6 Hz), 5.98 (s, 2H, -OCH
Hz), 6.93 (dd, 1H, J ) 8 and 1.5 Hz), 7.12 (d, 1H, J ) 2 Hz),
: C, 60.55;
f
0.30; mp 82 °C; H NMR (CDCl
3
)
-
2
2
2
F igu r e 1. Generic structures of substituted benzaldoxime
N-O-alkyl ethers.
2
2
O-), 6.71 (d, 1H, J )
8
7
.96 (s, 1H, -CHdN). Anal. Calcd for C11
10 3 2
H O N
H, 4.59; O, 22.01; N, 12.84. Found: C, 61.0; H, 4.48; O, 22.0;
N, 12.51.
control. An untreated control for each treatment was simul-
taneously maintained.
Similarly, 20 and 5 µg of the test compound in 5 µL of
acetone was topically applied on the ventral side of individual
hoppers by the same microapplicator. An equal number of
hoppers treated topically with only acetone (5 mL) served as
control. After treatment, insects were kept in glass jars (30
cm × 20 cm) with sufficient food (cabbage leaf) for daily
observation. Insects were kept at 30 ( 1 °C under 12-h dark
and 12-h light conditions.
Lip op h ilicity of Test Com p ou n d s. Lipophilicity of the
test compounds was determined by finding out the R
on reversed-phase TLC and then calculating the R
by using the equation R ) log(1/R
965). Silica gel plates, after activation for 2 h at 100 °C, were
f
values
M
values
M
f
- 1) (Boyce and Milborrow,
1
coated with paraffin in hexane (10:90). The paraffin-coated
plates were then spotted with the test compounds and devel-
oped in an acetone/water (60:40) solvent system. The spots
were visualized by spraying with 2,4-dinitrophenylhydrazine
reagent solution. R
values. The experiment was repeated thrice, and the mean
of three replicates was used for derivation of R values.
f M
values were measured to calculate R
RESULTS AND DISCUSSION
M
3-Methoxy-4-ethoxybenzaldoxime, 3,4-dimethoxybenz-
aldoxime, and 3,4-methylenedioxybenzaldoxime needed
for the preparation of oxime ethers were obtained by
reacting corresponding substituted benzaldehydes with
hydroxylamine hydrochloride. Their identities were
Bioa ssa y. A stock culture of S. gregaria (Forsk) (family,
Acarididae; order, Orthoptera) was maintained in the labora-
tory on cabbage and maize leaves (Mehrotra et al., 1966) at a
temperature ranging from 30 to 40 °C. Three concentrations
of oxime ethers (10, 5, and 3 µg in 5 µL of ethanol) were
injected through the intersegmental membrane into the abdo-
men of each nymph by a hypodermic syringe fitted to a
microapplicator (Burkard). The IGR activity of the test
compounds was compared with that of the standard reference
buprofezin (Applaud,) under similar test concentrations. An
equal number of hoppers injected with only ethanol served as
1
confirmed by H NMR spectra. The oximes are usually
a 1:1 mixture of cis and trans isomers and are insepa-
rable by conventional chromatographic techniques. The
oximes were then reacted with alkyl halides/acryloni-
trile to furnish oxime ethers, which were bioassayed as
mixtures of both isomers.

734 J. Agric. Food Chem., Vol. 46, No. 2, 1998
Chowdhury et al.
Ta ble 1. IGR Activity of Oxim e Eth er s on F ifth -In sta r Nym p h s of S. gr ega r ia Wh en In jected a t 10, 5, a n d 3 µg/Nym p h (n
)
10, R ) 2)
test
chemical
Rm
value
nymphs
dead (%)
nymph-adult
intermediates (%)
abnormal adults
(%)
total abnormality
(%)
normal adults
survived (%)
normal adults
dead (%)
I
II
III
IV
V
VI
-0.445
-0.292
-0.151
-0.140
-0.036
0.214
20a
20/10
30
20
20/10/0
20
20
20/10
20
10
20/40/20
20
60/30
20
30
60/50/40
20
40
20/60
30
30
20/40/60
60
20
40/20
20
20
20
40/10/20
20
VII
VIII
IX
X
XI
XII
XIII
XIV
XV
XVI
XVII
XVIII
XIX
XX
-0.632
-0.613
-0.463
-0.295
-0.313
-0.098
-0.074
-0.935
-0.309
-0.131
0.064
20
20
0/30
0/0/20
60/10/40
40/10/20
20
20
60
0/10
20/20/10
0/0/0
20/20/0
20
40/0
60/40/20
0/50/0
40/30
60/40/40
60/60/40
60/50/40
20
60/60
20/30/50
40/40/50
20/30/50
60
0/10/0
0/0/10
0/0/0
20/40/20
20
20
40
60
0/10/10
20/20/10
20/20
40/30/0
20/30/20
0/20
60/40/40
60/20/10
40/0
100/70/40
80/50/30
40/20
0/10/40
0/30/60
40/60
10/20/30
100
0/10/10
0/0/0
0/0
0.0
0.265
0.474
10/10/10
60/60/10
20/10/40
80/70/50
0/0/10
100
XXI
Applaud
control
-0.673
20
50/40/30
20
90/70/40
80
0/10/40
90
10/10/10
40/30/10
0/10/10
10
a
The first, second, and/or third value 00/00/00 denotes IGR inhibition at 10, 5, and 3 µg/nymph, respectively.
The oxime ethers were visualized on TLC plates (as
pink spots) by spraying with 2,4-dinitrophenylhydrazine
solution. Unlike aromatic carbonyl compounds, which
gave instant pink color, the pink spots of oxime ethers
on TLC plates emerged fully 15-20 min after the spray.
Injection into the Hemolymph. When 3-methoxy-4-
ethoxybenzaldoxime homologues (I-VII) were injected
into the insect hemolymph at the dose level of 10 µg/
nymph, N-O-ethyl (II) and N-O-butyl derivative (V)
exihibited 60% abnormal molts (Table 1). Among 3,4-
dimethoxybenzaldoxime derivatives, IX-XI also gave
the same, 60%, abnormalities. Similarly, 3,4-methyl-
enedioxybenzaldoxime homologues such as XV, XVI,
and XVIII gave 100, 80, and 80% abnormalities.
Nymphal mortality (up to 30%) was recorded for the
compounds of the first subseries (I-VII) as compared
to 10% in the standard buprofezin (Applaud) at the
injection dose of 10 µg/nymph. Except for I, III, and
IV, none of the test chemicals showed any mortality
among the newly emerged normal adults.
Of 21 compounds tested by injection at 10 µg, 10
compounds were selected for further bioassay at the
lower dose of 5 µg/nymph. The data revealed that with
the decrease in injection dose, IGR activity also de-
creased. The six most active compounds identified in
this screen included 3-methoxy-4-ethoxybenzaldoxime
N-O-butyl ether (V), 3,4-dimethoxybenzaldoxime
N-O-n-propyl ether (X), 3,4-dimethoxybenzaldoxime
N-O-isopropyl ether (XI), 3,4-methylenedioxybenzal-
doxime N-O-methyl ether (XV), 3,4-methylenedioxy-
benzaldoxime N-O-ethyl ether (XVI), and 3,4-meth-
ylenedioxybenzaldoxime N-O-isopropyl ether (XVIII),
which inflicted 50, 60, 50, 70, 50, and 70% abnormali-
ties, respectively, during ecdysis. At a still lower dose
of 3 µg, compound XVIII showed 50% inhibition. The
adult emergence at 5- and 3-µg dose levels ranged from
10 to 60% and from 30 to 60%, respectively. Nymphal
mortality up to 20% was recorded for almost all test
chemicals. The IGR activity of the most active test
compounds (XV and XVIII) was comparable to that of
buprofezin (Applaud), a commercial IGR which at the
lowest dose level of 3 µg/nymph recorded 40% adult
emergence and inflicted 50% total abnormality and 10%
nymphal and adult mortality.
1
The test compounds were characterized by H NMR
spectroscopy, elemental analysis, and, whenever neces-
sary, IR and MS spectroscopy. The generic formulas of
the sets of compounds (I-XXI) studied are shown in
Figure 1.
A diagnostic one-proton singlet at δ 7.9-8.0 (CHdN)
1
was conspicuous in the H NMR spectra of all the oxime
ethers. The IR spectra of the compounds (I-XXI)
showed characteristic absorption bands around 800
(
aromatic), 1500 (-CHdN, str), 1575 (C-C str, aro-
-
1
matic), and 1600 cm (N-O-R), which were charac-
teristic of these compounds. The mass spectrum of a
representative compound 3-methoxy-4-ethoxybenzal-
doxime N-O-ethyl ether (II) showed a molecular ion
peak at m/z 223 along with a fragment ion peak at m/z
1
95 (M _ CH2dCH2) due to cleavage with hydrogen
migration. The peaks at m/z 178 and 150 were tenta-
tively attributed to loss of the -OCH2CH3 moiety from
the m/z 223 and 195 fragments, respectively. The other
fragment ion peaks at m/z 134 and 124 may arise due
to the loss of CH4 and CN moieties. In all of the oxime
ethers, the molecular ion peak was also the base ion
peak.
IGR Activity of th e Test Ch em ica ls. The oxime
ethers (I-XXI) were screened for their IGR activity
against fifth-instar nymphs of S. gregaria. The test
compounds were either injected into the hemolymph of
2
-3-day-old fifth-instar nymphs at 10, 5, and 3 µg/insect
or applied topically at 20 and 5 µg/insect. The IGR
activity was computed on the basis of total abnormal
counts recorded due to nymph-adult intermediates and
abnormal adults during and after the last molt. Nymph-
adult intermediates included either nymphs with in-
complete ecdysis during the last molt or adults with
exuviae attached on the ventral side. Abnormal adults,
on the other hand, had highly deformed wings, crippled
legs, or slight to medium abnormal wings.
Topical Application. Among the three subseries,
N-O-alkyl derivatives of 3-methoxy-4-ethoxy benzal-
doxime (I-VI) were more active than those derived from

Synthesis and IGR Activity of Alkoxybenzaldoxime Ethers
J. Agric. Food Chem., Vol. 46, No. 2, 1998 735
Ta ble 2. IGR Activity of Oxim e Eth er s on F ifth -In sta r Nym p h s of S. gr ega r ia F . Wh en Ap p lied Top ica lly a t 20 a n d 5
µg/Nym p h (n ) 10, R ) 2)
nymph-adult
intermediates
(%)
test
chemical
nymphs
dead (%)
abnormal adults
(%)
total abnormality
(%)
normal adults survived
(%)
normal adults dead
(%)
I
II
III
IV
V
VI
VIII
IX
10 (10)a
50 (10)
30 (0)
20 (0)
30 (0)
30 (0)
10
90 (30)
40 (20)
50 (20)
40 (20)
50 (10)
30 (10)
10
100 (40)
90 (30)
80 (20)
60 (20)
80 (10)
60 (10)
20
- (60)
10 (70)
20 (80)
40 (80)
20 (90)
20 (90)
40
40
40
10
10
20
40
X
10
40
50
50
XI
60
60
30
10
XII
XIII
XV
XVI
XVII
XVIII
XIX
XX
control
10
40
50
10
40
40
60
40
30
50
50
10
50
50
60
40
30
50
30
90
50
50
40
60
70
20
10
10
90
10
a
Values in parentheses denote percent change at 5 µg/nymph.
3
,4-dimethoxybenzaldoxime and 3,4-methylenedioxy-
benzaldoxime (Table 2). At a higher dose level of 20
µg, the N-O-alkyl ethers of 3-methoxy-4-ethoxy ben-
zaldoxime exhibited 60-100% inhibition. The most
active compounds were N-O-methyl (I), N-O-ethyl
(II), N-O-n-propyl (III), and N-O-n-butyl (V) homo-
logues, which showed >80% inhibition at 20-µg dose
level. At the lower dose level, the IGR activity was
drastically reduced and the most active compound (I)
could bring about only 40% inhibition of insect growth.
The compounds belonging to the remaining two series
were moderately active at 20 µg, the most active being
3
,4-dimethoxybenzaldoxime N-O-isopropyl ether (XI),
which produced 60% total abnormality. To examine the
effect of a cyano group, three cyanoethyl derivatives
were prepared. The insect growth disruption activity
of these compounds was disappointing.
Lip op h ilicity a n d Str u ctu r e-Activity Rela tion -
sh ips. The relationship between lipophilicity (RM value),
alkyl chain length, and percent insect growth inhibition
is illustrated in Figure 2. Comparison of the data on
RM value and IGR activity (percent abnormality ex-
pressed in log value) of the test compounds when
administered by injection into insect hemolymph re-
vealed no correlation, however, when applied topically;
activity was weakly correlated to lipophilicity. In the
case of 3-methoxy-4-ethoxybenzaldoxime N-O-alkyl
ethers (I-VI), the lipophilicity increased linearly with
an increase in the number of carbon atoms in the side
chain, but there is a gradual fall in their IGR activity
at dose level of 5 µg (Figure 2). In the case of 3,4-
dimethoxybenzaldoxime N-O-alkyl ethers and 3,4-
methylenedioxybenzaldoxime N-O-alkyl ethers, IGR
activity first increased with increasing chain length up
to three carbon atoms, beyond which it started dimin-
ishing. Both series exhibited an optimum RM value
corresponding to the most potent compound. The weak
correlation with derivatives of 3,4-dimethoxybenzal-
doxime N-O-alkyl ethers and 3,4-methylenedioxybenz-
aldoxime N-O-alkyl ethers was noted, with isopropyl
substitution having consistently highest activity. The
fact that the isopropyl substituent confers greatest
activity, despite its irregularity with respect to RM,
F igu r e 2. Relationship between R
M
value, IGR activity, and
alkyl chain length of 3-methoxy-4-ethoxybenzaldoxime N-O-
alkyl ethers. [Percent inhibition is expressed as log value (the
data refer to topical application).]
suggests that steric parameters are also important for
imparting activity.
In earlier structure-activity relationship studies on
a variety of J H active compounds having functions such
as ethers, oxime ethers, esters, hydroxylamines, and
amines (Nakayama et al., 1985; Niwa et al., 1988;
Hayashi et al., 1990, 1991), the common structural
features responsible for conferring high J H activity had
been suggested to be the overall molecular dimension
and a position-specific functional effect. Since the oxime
ether group of compounds reported herein has some
resemblance to those oxime juvenoides reported earlier,
such molecules are expected to behave in a similar mode
of action (Hayashi et al., 1991b). It is hoped that a
variety of potentially useful juvenoides based on such
oxime ethers can be developed for pest control. Because
of their diminished lethal action and environmentally
benign nature, such compounds have gained of late
considerable importance.

736 J. Agric. Food Chem., Vol. 46, No. 2, 1998
Chowdhury et al.
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