Design and synthesis of novel pyrethriods containing eugenol moiety

Article abstract of DOI:10.1007/s00044-011-9809-8

A novel series of pyrethriods was designed and synthesized by connecting various eugenol derivatives to either a chrysanthematic acid or 2-(4-chlorophenyl)-3-methylbutanoic acid. The insecticidal activity of target compounds has been evaluated by an immersion method on the fourth instar larvae of Culex pipens quinquefasciatus. The results revealed that the larvae were sensitive to synthesized compounds. Varying substituents in both acid moiety and eugenol group resulted in new compounds that exhibited different contact toxicity. Compound 3a showed the highest activity and is currently under further investigation.

Full text of DOI:10.1007/s00044-011-9809-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:2827–2830
DOI 10.1007/s00044-011-9809-8
ORIGINAL RESEARCH
Design and synthesis of novel pyrethriods containing
eugenol moiety
•
Xinlong Wang Meigui Yi Quanhai Du
•
•
•
Aimin Wu Rong Xiao
Received: 1 October 2009 / Accepted: 6 October 2011 / Published online: 30 October 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A novel series of pyrethriods was designed and
synthesized by connecting various eugenol derivatives to
either a chrysanthematic acid or 2-(4-chlorophenyl)-3-meth-
ylbutanoic acid. The insecticidal activity of target compounds
has been evaluated by an immersion method on the fourth
instar larvae of Culex pipens quinquefasciatus. The results
revealed that the larvae were sensitive to synthesized com-
pounds. Varying substituents in both acid moiety and eugenol
group resulted in new compounds that exhibited different
contact toxicity. Compound 3a showed the highest activity
and is currently under further investigation.
Two strategies can be used to develop novel pyrethriods.
One is to improve the efficacy of existing natural sub-
stances such as from allethrin to prallethrin, and the other is
to improve their stability to make them more photostable
just like resmethrin.
To address the insecticide resistance, there has been
mounting interest to combine the use of pyrethriods with
other substances in order to exploit the synergistic effects.
For example, it is well-established that piperonyl butoxide
(PBO) can be effectively used together with other synthetic
pyrethriods, due to its ability to inhibit the monooxygenases
as detoxifying enzymes. We noticed that molecules based on
eugenol are structurally similar to PBO (Fakoorziba et al.,
2009; Pap et al., 2001; Enan, 2001; Steven, 2001). Moreover,
eugenol itself is a repellent against mosquitoes, and its
derivatives have pronounced in medicinal properties, such as
antibacterial, fungicidal, antiviral, antioxidant, antitumor,
and anaesthetic (Mastelic et al., 2008; Ogata et al., 2005;
Chaieb et al., 2007; Park et al., 2000).
Keywords Pyrethriod Á Eugenol derivatives Á Synthesis Á
Synergy Á Insecticidal activity
Introduction
Insecticides with the structure of pyrethrins are neuropoi-
sons and broad-spectrum, which hold some promises in
vector control. They are highly toxic to target organisms,
biodegradable in nature, and less toxic to mammals (Fak-
oorziba et al., 2009; Sukumaran et al., 2005; Katsuda,
1999). However, due to the excessive use of pyrethriods
during the past 20 years, incidences in resistance to all
classes of existing insecticides have made vector control
more and more difficult. Therefore, there is an urgent need
to develop novel insecticides in order to combat resistance
(Tewary et al., 2006).
Here we report the synthesis of a novel class of com-
pounds which combine eugenol derivative to either a
chrysanthematic acid or 2-(4-chlorophenyl)-3-methylbuta-
noic acid moiety. We think that the combination of the two
moieties could result in functional synergy that leads to
target molecules with interesting insecticidal properties.
Since eugenol is widely available from natural sources, this
could make the synthesis of hybrid molecules economical.
Results and discussion
Chemistry
X. Wang Á M. Yi Á Q. Du Á A. Wu Á R. Xiao (&)
College of Chemical Engineering, Sichuan University,
Chengdu 610065, People’s Republic of China
e-mail: chem_xiao@163.com
The activities of target molecules depended on the synergy
between the eugenol with different substituents and the
123

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Med Chem Res (2012) 21:2827–2830
acidic moiety. In order to improve stability and minimize
oxidation of target molecules in the screening tests, the
eugenolic hydroxyl was protected by either an ethyl or an
acetyl group. The double bond was kept intact as it could
provide the product with antioxidant properties.
Table 1 Bioassay of contact activity against the 4th instar larvae of
Culex pipens quinquefasciatus
Timeb
1 (h)
4 (h)
12 (h)
24 (h)
Mortalitya
Comps
The synthetic route was outlined in Scheme 1.
Blank test
0
15
10
10
14
12
10
0
22
25
23
25
20
18
0
40
34
42
47
33
40
5
97
88
96
85
85
88
In the reaction processes, the conditions had a signifi-
cant influence on the selectivity. The main product and
reaction time would depend greatly on a correct solvent. In
the case of acetylation, the acetic anhydride was also used
as a solvent and the reaction was terminated shortly in
order to avoid acetylation toward the Friedel–Crafts reac-
tion. The subsequent radical brominations were carried out
in CCl4 to afford the desired bromides 2a and 2b. If a polar
solvent was used, the bromination would occur on the
benzene ring instead of the allylic position. During the
esterifications, the bromides 2a and 2b were added drop-
wise to the reaction media in order to avoid undesired
[1 ? 1] cyclization. Besides, a basic medium would benefit
the esterification more than an aroylation in side reaction.
3a
3b
4a
4b
Allethrin
Fenvalerate
a
Abbort’s formula was used to calculate percent corrected mortality
b
Contact time (h)
insecticidal activity over the O-acetylation (3b and 4b).
Indeed, the acetylation has led to a considerable loss of
activity (Tewary et al., 2006). This fact could be attributed
to the electron-donor of an alkyl.
Bioactivity
Experimental
The synthesized compounds (3a–4b) were tested against
the 4th instar larvae to evaluate their contact toxicities.
After a 24 h exposure, all compounds showed activities,
which varied according to the substituent on the eugenol
group as well as on acidic moiety. Table 1 showed the
results of contact toxicities.
General
Melting points were determined on a XSP-1 micro-melting
point apparatus. 1H NMR and 13C NMR spectra were
recorded on a Varian INOVA-400 spectrometer. Chemical
shifts were given with TMS as an internal reference. Ele-
mental analyses were carried out on a Carlo Erba 1106
analyzer. The results of these assays are shown in Tables 2
and 3.
The activity was showing in a decreasing order from 3a,
3b, 4a, to 4b. Compound 3a showed the highest contact
mortality after 24 h in the immersion test (Itoh et al.,
1986). The higher activity of 3a and 3b over 4a and 4b
could be attributed to higher volatility and permeability of
the chrysanthematic acid ester than the 2-(4-chlorophenyl)-
3-methylbutanoic acid ester. Also we noticed the O-ethy-
lation at the eugenol (3a and 4a) has resulted in higher
All reagents and solvents were of commercially
available unless otherwise stated. The fourth instar larvae
of Culex pipens quinquefasciatus were used for the test
insect.
O
O
CH3CH2Br
HO
or (CH3CO)2O
1a, 1b
RO
CCl4
NBS
O
O
OH
Cl
OH
Br
O
RO
O
O
Cl
OR
O
2a, 2b
OR
O
O
a, R=-C2H5
O
3a, 3b
4a, 4b
b, R=-COCH3
Scheme 1 Synthetic route of target molecules
123

Med Chem Res (2012) 21:2827–2830
Chemistry
2829
(1.30 g, yield 76%) was obtained and directly transferred
to the next step to avoid being hydrolyzed in air.
4-Allyl-2-methoxylphenetole (Haworth, 1936) 1a
3-Methoxyl-4-ethoxylphenyl-1-propenyl-3-yl-2,2-dimethyl-
3-(2-methylprop-1-enyl)cyclopropanecarboxylate 3a,
3-Methoxyl-4-ethoxylphenyl-1-propenyl-3-yl-2,2-dimethyl-
3-(2-methylprop-1-enyl)cyclopropanecarboxylate 3b
To a well-stirred solution of eugenol (5.41 g, 33 mmol),
C2H5OH (10 ml) and H2O (10 ml), 30% NaOH (3.1 ml)
was added dropwise at room temperature. Once the mixture
was warmed to 60°C, C2H5Br (7.30 g, 67 mmol) in ethanol
(10 ml) was added slowly. Then a stir was kept at 60°C for
20 h. After cooled and separated, the organic phase was
washed with H2O, 10% NaOH and H2O in turn. After dried
and concentrated, the resulting mixture was separated over
a silica column with the hexane/EtOAc (80/20, v/v). A
brown resinous semisolid 1a (5.8 g, yield 92%) was
obtained in M.p. 37–38°C.
A mixture of NaOH (0.96 g, 24 mmol) and 2,2-dimethyl-3-
(2-methylprop-1-enyl)cyclopropanecarboxylic acid (4.03 g,
24 mmol) in H2O (20 ml) was stirred at the room temper-
ature for 3 h. 2a (6.51 g, 24 mmol) or 2b (6.84 g,
24 mmol) in CCl4 (15 ml) was added dropwise and
refluxed for 15 h. The organic layer was extracted by ether,
washed with H2O, and then dried. After the solvent was
removed, the crude product was purified over a silica
column with THF/petroleum ether (1/20, v/v).
4-Allyl-2-methoxyphenyl acetate (Sato et al., 2007) 1b
3a: A yellow liquid was obtained (5.42 g, 63%).
3b: A yellow liquid was obtained (6.08 g, 68%).
A mixture of eugenol (0.98 g, 6 mmol), acetyl oxide
(2.04 g, 20 mmol) and CH3COOH (2 ml) was refluxed
1.5 h. Then it was cooled to the room temperature. A
mixture of H2O and ice was added under stirring. The
organic layer was separated and then was washed with
H2O, 10% NaOH and H2O in order. After dried and con-
centrated, the resulting mixture was separated over a silica
column with the hexane/EtOAc (80/20, v/v). A brown
resinous semisolid 1b (1.2 g, yield 97%) was obtained in
M.p. 30–31°C.
1-(4-Ethoxy-3-methoxyphenyl)allyl 2-(4-chlorophenyl)-3-
methylbutanoate 4a, 1-(4-Acetoxy-3-methoxyphenyl)allyl
2-(4-chlorophenyl)-3-methylbutanoate 4b
A mixture of 2-(4-chlorophenyl)-3-methylbutanoic acid
(5.10 g, 24 mmol) and NaOH (0.96 g, 24 mmol) in H2O
(20 ml) was stirred at a room temperature for 3 h. Then 2a
(6.51 g, 24 mmol) or 2b (6.84 g, 24 mmol) in CCl4
(15 ml) was added dropwise and refluxed for 15 h. The
organic layer was extracted by ether and washed with H2O,
then was dried. After the solvent was removed, the crude
product was purified over a silica column with THF/
petroleum ether (1/10, v/v).
4-(1-Bromoallyl)-1-ethoxy-2-methoxybenzene 2a,
4-(1-Bromoallyl)-2-methoxyphenyl acetate 2b
Being shone under a lamp (200 W), a mixture of 1a
(1.15 g, 6 mmol) or 1b (1.23 g, 6 mmol) and N-bromo-
succinimide (1.06 g, 9 mmol) in CCl4 (30 ml) was refluxed
for 25 h. After filtrated, the filtrate was evaporated to
dryness. The crude product 2a (1.31 g, yield 81%) or 2b
4a: White crystals were obtained (6.48 g, 67%), M.p.
142–143°C.
4b: White crystals were obtained (7.20 g, 72%), M.p.
150–151°C.
Table 2 Yields and characterization of target compounds
Compound Yielda
(%)
M.p.
(°C)
Formula
Elemental analysis
(%)b
Contact toxicity
C
H
The contact toxicity tests were conducted in the standard
immersion method (Itoh et al., 1986). These compounds
were diluted with acetone at a concentration of 0.025 mg/ml.
Tests were carried out by exposing the 20 early fourth instar
larvae to a mixture of H2O (200 ml) and the corresponding
solution of insecticide (1 ml) in a 250 ml glass beaker. The
dead and moribund larvae were recorded after 24 h of
exposure. The larvae were considered to be moribund if they
failed to flex their head to siphon, when stimulated. All the
tests were carried out at a room temperature of 25 2°C at a
relative humidity of 70 10% and 16:8 h (light:dark).
3a
3b
4a
4b
a
63
65
67
72
yel. lq. C22H30O4
73.45
8.51
(73.71)
71.21
(70.94)
142–143 C23H27ClO4 68.84
(68.56)
150–151 C23H25ClO5 66.40
(66.26)
(8.44)
7.83
(7.58)
6.80
(6.75)
5.83
(6.04)
yel. lq.
C22H28O5
Yield of isolated pure products
b
The data in parentheses are calculated values
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Med Chem Res (2012) 21:2827–2830
Table 3 Characterization of target compounds
Compound 1H NMR
13C NMR
UV (CH3OH)
kmax
3a
(CDCl3, 600 MHz) d: 1.133–1.301 (m, 7H, C(CH3)2, (CDCl3, 400 MHz) d: 14.89 (OCH2–CH3), 18.49,
203 nm (Abs
20.60 (2C, =C(CH3)2), 22.21, 25.57 (2C, C(CH3)2), 0.384), 238 nm
33.28 ((CH3)2C), 34.62 (=CH–CH), 54.08 (O=C– (0.140), 280 nm
O=C–CH), 1.455–1.482 (t, 3H, OCH2–CH3),
1.630–1.776 (m, 7H, CH–CH, =C(CH3)2),
3.418–3.472 (m, 1H, =CH2a), 3.707–3.774 (m,
1H, =CH2b), 3.900 (s, 3H, OCH3), 4.087–4.126
(quad, 2H, OCH2), 4.555–4.602 (m, 1H,
(CH3)2C=CH), 4.855–4.937 (m, 1H, Ph–CH),
6.118–6.164 (m, 1H, CH2=CH), 6.845–6.863 (d,
1H, Ph–H), 7.018–7.037 (d, 2H, Ph–H)
CH), 55.97 (OCH3), 64.25 (OCH2), 74.15 (Ph–CH), (0.070)
111.18, 111.87, 120.35, 135.24, 148.77, 169.69 (6C,
Ph), 117.84 (=CH2), 120.75 ((CH3)2C=CH), 127.60
((CH3)2C=), 135.93 (CH2=CH), 171.06 (C=O)
3b
(CDCl3, 600 MHz) d: 1.061–1.201 (m, 7H, C(CH3)2, (CDCl3, 400 MHz) d: 18.49, 20.60 (2C, =C(CH3)2), 210 nm (Abs
O=C–CH), 1.530–1.716 (m, 7H, CH–CH,
=C(CH3)2), 3.418–3.472 (m, 1H, =CH2a),
3.707–3.774 (m, 1H, =CH2b), 3.190 (s, 3H, O=C–
CH3), 3.890 (s, 3H, OCH3), 4.540–4.502 (m, 1H,
(CH3)2C=CH),4.955–5.137 (m, 1H, Ph–CH),
6.138–6.184 (m, 1H, CH2=CH), 6.675–6.893 (d,
1H, Ph–H), 6.728–6.897 (d, 2H, Ph–H)
22.21, 25.90 (2C, C(CH3)2), 33.34 ((CH3)2C), 34.63 1.600), 280 nm
(=CH–CH), 54.12 (O=C–CH), 55.98 (OCH3), 74.44 (0.150)
(Ph–CH), 111.18, 111.90, 120.41 (3C, Ph), 117.88
(=CH2), 120.39 ((CH3)2C=CH), 127.60 ((CH3)2C=),
135.29 (CH–Ph), 135.86 (CH2=CH), 148.74, 148.88
(2C, O–Ph), 169.72 (CH3–C=O), 171.06 (C=O)
4a
(CDCl3, 400 MHz) d: 0.722–0.749, 0.988–1.004 (dd, (CDCl3, 400 MHz) d: 14.78 (OCH2–CH3), 20.15,
232 nm (Abs
0.963), 275 nm
(0.544), 315 nm
(0.340)
6H, CH(CH3)2), 1.465–1.499 (t, 3H, CH2–CH3),
2.371–2.387 (m, 1H, (CH3)2CH),3.225–3.252 (d,
1H, O=C–CH), 3.343–3.391 (t, 1H, =CH2a),
3.625–3.652 (t, 1H, =CH2b), 3.820 (s, 3H, OCH3),
4.085–4.138 (quad, 2H, OCH2), 4.471–4.481 (m,
1H, OCH), 6.080–6.092 (s, 1H, =CH–),
21.46 (2C, CH(CH3)2), 31.73 ((CH3)2CH), 32.20
(OCH3), 53.47 (O=C–CH), 55.87 (OCH2), 59.54
(O–CH), 64.24, 74.79, 110.89, 120.33, 136.22,
148.84 (6C, O–Ph), 77.04 (=CH2), 127.03 (=CH),
111.79, 133.35 (2C, Cl–Ph), 128.73 (2C, Cl–Ph),
130.02 (2C, Cl–Ph), 171.73 (O=C)
6.823–6.843, 6.947–6.968 (dd, 2H, OPh–H), 6.905
(s, 1H, OAr–H), 7.248–7.329 (d, 4H, ClPh–H)
4b
(CDCl3, 400 MHz) d: 2.317 (s, 6H, CH(CH3)2), 3.861 (CDCl3, 400 MHz) d: 20.68 (2C, (CH3)2), 30.93
(s, 7H, (CH3)2CH, OCH3, O=C–CH3), 3.887–3.899 (O=C–CH3), 37.69 (2C, (CH3)2CH, OCH3), 53.48
205 nm (Abs
0.510), 283 nm
(0.078)
(d, 1H, ClPh–CH), 4.209–4.219 (d, 1H, =CH2a),
4.237–4.248 (d, 1H, =CH2b), 4.675–4.719 (m, 1H,
(2C, OPh–CH, ClPh–CH), 54.62 (2C, CH=CH2),
56.02 (3C, Cl–C, 2(CH–Ph)), 112.58, 120.68 (4C,
OPh–CH), 5.297 (s, 1H, =CH–), 5.319 (s, 1H, OPh– Cl–Ph), 122.84 (3C, O–Ph), 136.90, 140.25 (2C, O–
H), 7.008–7.045 (m, 6H, Ph–H) C), 151.05 (CH3–C=O), 168.68 (C=O)
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