Synthesis and insecticidal activity of novel dihalopropene derivatives containing benzoxazole moiety: A structure-activity relationship study

Article abstract of DOI:10.1016/j.jfluchem.2013.09.003

Ten dichloropropene derivatives containing benzoxazole moiety were synthesized and bioassayed in order to determine their in vivo insecticidal activity. The structures of obtained compounds were identified by ¹H NMR, MS and elemental analyses. The bioassay results indicated that compound 2-(3-(2,6-dichloro-4-(3,3-dichloroallyloxy)phenoxy)propoxy)-5-(trifluoromethyl) benzo[d]oxazole (5i, R¹ is trifluoromethyl, R² is H and n is 3) had the optimal structure with best insecticidal activity against Spodoptera exigua (100%) at 1 mg/L concentration, highlighting the importance of trifluoromethyl group. The structure-activity relationship of the synthesized compounds was discussed as well.

Full text of DOI:10.1016/j.jfluchem.2013.09.003

Journal of Fluorine Chemistry 156 (2013) 120–123
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and insecticidal activity of novel dihalopropene
derivatives containing benzoxazole moiety: A structure–activity
relationship study
*
Aiying Guan, Yukun Qin, Junfeng Wang, Bin Li
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Co. Ltd., Shenyang 110021, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Ten dichloropropene derivatives containing benzoxazole moiety were synthesized and bioassayed in
order to determine their in vivo insecticidal activity. The structures of obtained compounds were
identified by 1H NMR, MS and elemental analyses. The bioassay results indicated that compound 2-(3-
(2,6-dichloro-4-(3,3-dichloroallyloxy)phenoxy)propoxy)-5-(trifluoromethyl)benzo[d]oxazole (5i, R1 is
trifluoromethyl, R2 is H and n is 3) had the optimal structure with best insecticidal activity against
Spodoptera exigua (100%) at 1 mg/L concentration, highlighting the importance of trifluoromethyl group.
The structure–activity relationship of the synthesized compounds was discussed as well.
ß 2013 Elsevier B.V. All rights reserved.
Received 26 June 2013
Received in revised form 30 August 2013
Accepted 2 September 2013
Available online 12 September 2013
Keywords:
Dihalopropene derivative
Benzoxazole
Active substructure combination
Insecticides
1. Introduction
compound. These two substructures were linked by different
length of methylene via oxygen atom. A successful example
Pyridalyl (Fig. 1),
a
novel dihalopropene insecticide was
incorporating benzoxazole with 3, 3-dichloroallyloxybenzene,
compound A (Fig. 1, discovered by FMC), had obtained with
100% control against Heliothis virescens at 10 ppm [11]. In addition,
it is well known that many fluorine-containing compounds exhibit
significant agricultural bioactivities owing to fluorine atom’s
unique properties, such as high thermal stability and lipophilicity
[12]. The trifluoromethyl (CF3) group considered a ‘pseudo-
halogen’, has often been found to impart unique biological activity
[13]. Therefore, in this study, a series of new dihalopropene analogs
with the substituents of H, Cl and CF3 was designed with increasing
order of electron withdrawing. These compounds were synthe-
sized and their structures were characterized by 1H NMR, MS and
elemental analyses. Their insecticidal screening was performed
and the excellent insecticidal activity against Spodoptera exigua at
1 mg/L of the compound 5i was discovered. The detailed synthesis,
insecticidal activities and structure–activity relationship of this
series of compounds were further discussed.
discovered and developed by Sumitomo Chemical Co., Ltd. and
commercialized in 2004. It exhibits excellent insecticidal activities
against various lepidopterous and thysanopterous pests on cotton
and vegetables, low toxicity to non-target pests and safety to
mammals [1,2]. Interestingly, it has been shown that pyridalyl is
highly efficient to a strain of P. xylostella, which has already
developed resistance to synthetic pyrethroids, organophosphates
and benzoylureas, probably due to the novel mode of actions of
pyridalyl [3–6]. As we know, currently, insect resistance to existing
pesticides has become a severe issue in the agrochemical field.
Therefore, the development of novel insecticides to fight against
this kind of resistance is becoming an intensive research topic. The
substructure of 3,3-dichloroallyloxybenzene of pyridalyl has been
recognized as pharmacophore in this series of insecticides.
Furthermore, benzoxazole derivatives with particular biologi-
cal activities are applied widely in the fields of agrochemicals and
pharmaceuticals [7], including herbicide metamifop (Fig. 1) [8].
Therefore, using strategies of active substructure combination [9]
and bioisosteric replacement [10] via organic synthesis route
(Scheme 1), we designed to replace original pyridine ring of
pyridalyl with benzoxazole ring using pyridalyl as the lead
2. Results and discussion
2.1. Synthesis
Starting from substituted 2-aminophenol (1), the (un)substi-
tuted 2-mercaptobenzoxazole was synthesized by cyclization with
carbon disulfide in the presence of potassium hydroxide (step a),
followed by chlorination reaction (step b) to afford the key
*
Corresponding author. Tel.: +86 2485869128; fax: +86 2485869337.
E-mail address: libin1@sinochem.com (B. Li).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.09.003

A. Guan et al. / Journal of Fluorine Chemistry 156 (2013) 120–123
121
O
O
C
O
Cl
H3C
O
Cl
Cl
CH3
N
C
N
O
O
Cl
N
O
F3C
O
O
O
Cl
Cl
H
F
F3C
N
Cl
O
Cl
Cl
metamifop
pyridalyl
compound A discovered by FMC
Fig. 1. Chemical structures of metamifop, pyridalyl and compound A.
R1
R2
R1
R2
NH2
OH
N
a
SH
O
2
1
b
Cl
Cl
Cl
3'
4
Cl
Cl
3
R1
R2
R1
R2
5
N
O
N
c
2
Cl
HO(CH2)nO
O
Cl
O
(CH2)nO
O
Cl
6
O
1
5'
7
Cl
3
4 (n=0, 2, 3, 4)
5
(n=0, 2, 3, 4)
Scheme 1. Reagents and conditions: (a) potassium hydroxide, CS2, EtOH/H2O; (b) SOCl2, DMF, toluene; (c) NaH/THF, room temperature.
intermediate (un)substituted 2-chlorobenzoxazole (3). The title
compounds (5) were prepared in 27–61% yield by reacting
compounds (3) with 3,3-dichloroallyloxyphenoxy intermediates
(4) [14] using sodium hydride as a base in tetrahydrofuran at room
temperature for 5 h (step c). The synthetic route is illustrated in
Scheme 1. The synthesized compounds are listed in Table 1, and
their structures were confirmed by 1H NMR, MS and elemental
analyses.
methylene significantly contributes to the insecticidal activity.
Generally, compounds (5a, 5b, 5e, 5i) with methylene linker of 3
carbon atoms exhibit higher insecticidal activities than com-
pounds with other linker lengths. Therefore, 3-carbon chain is the
optimal linker for enhancing the insecticidal activity. Secondly, the
electronic effect of R1 and R2 of benzoxazole ring plays an
important role on insecticidal activity. It is well known that
trifluoromethyl is a very strong electron withdrawing group. When
R1 is CF3 (5i), the insecticidal activity against S. exigua increased
greatly, compared with 5a in which R1 is hydrogen (100% versus
25% at 1 mg/L). Alterations of substituents at R2 exhibit the same
trend as R1 (5a versus 5b versus 5e). That is, when R2 is chlorine, a
moderate electron withdrawing group (5b), its activity is increased
compared to 5a (50% versus 25% at 1 mg/L). Again, when R2 is
trifluoromethyl (5e), a stronger electron withdrawing group than
chlorine, its activity was further increased to reach 88% at 1 mg/L,
2.2. Insecticidal activities
The insecticidal activities in vivo were evaluated using a
previously reported procedure [15]. The results of compounds 5a–
5j against Spodoptera exigua were also listed in Table 1. The levels
of insecticidal activities were reported in the range 0 (indicates no
mortality) to 100% (complete mortality).
As shown in Table 1, all of the synthesized compounds
exhibited insecticidal activities against S. exigua at 10 mg/L.
Compounds 5a, 5b, 5e, 5f, 5i and 5j exhibited 100% control at
10 mg/L while compounds 5e, 5i and 5j displayed better
insecticidal activity against S. exigua. In particular, compound 5i
showed excellent insecticidal activity with 100% control at 1 mg/L,
much higher than that of pyridalyl (50% control at 1 mg/L).
There is a very interesting relationship of structure and
activities among these compounds. First of all, linker length of
indicating a clear picture of the effect of substituents on
bioactivity: the stronger of electron withdrawing effect, the higher
of bioactivity. Finally, the position of substituent on benzoxazole
ring plays a critical role on the insecticidal activity as well. We see
higher insecticidal activity in compounds 5j, 5i and 5h with
trifluoromethyl group at 5-position as compared to compounds 5f,
5e and 5d with trifluoromethyl group at 6-position. Compound
5i with 5-position of CF3 at benzoxazole ring exhibited 100%
control at 1 mg/L against S. exigua, better than compound 5e (88%)
Table 1
Chemical structures, physical properties of compounds synthesized and their insecticidal activity against Spodoptera exigua (% control, mg/L).
Compd.
R1
R2
n
Appearance
mp (8C)
Yield (%)
Insecticidal activity against Spodoptera exigua
(% control at given concentration mg/L)
10
1
a
5a
H
H
3
Yellow oil
White s.
White s.
Yellow oil
Yellow oil
Yellow oil
White s.
Yellow oil
White s.
White s.
–
–
47
61
61
51
52
27
36
29
35
29
–
100
100
38
25
50
13
13
88
25
0
5b
H
Cl
3
0b
2
58–60
5c
H
CF3
CF3
CF3
CF3
H
79–81
5d
H
–
50
5e
H
3
–
100
100
25
5f
H
4
–
5g
CF3
CF3
CF3
CF3
–
0
63–65
–
5h
H
2
88
13
5i
H
3
46–47
49–50
–
100
100
100
100
88
5j
H
4
Pyridalyl
–
–
50
a
No data.
b
Linker is one oxygen atom.

122
A. Guan et al. / Journal of Fluorine Chemistry 156 (2013) 120–123
at 1 mg/L which CF3 is located at 6-position of benzoxazole ring.
Moreover, compound 5j with 5-position of trifluoromethyl group
showed higher insecticidal activity (88% control at 1 mg/L) than
compound 5f with 6-position of trifluoromethyl group (25%
control at 1 mg/L) when the linker has four repeated methylene
chain. Thus, we conclude that the compound with 5-positon strong
electron withdrawing group and 3 carbon linker has the best
insecticidal activity in this series of compounds. This SAR indicates
that electronic effect (electron withdrawing group) and spatial
effect (position of substituent at benzoxazole ring and linker length
of methylene group) work together to contribute the bioactivity.
2-chlorobenzoxazole as a yellow solid which was used in next
reaction without further purification. Finally, 60% of NaH
(1.0 mmol) was added into a solution of 3,3-dichloroallyloxyphe-
noxy intermediates (1.0 mmol) in THF (5 mL), after 2 h, (un)sub-
stituted 2-chloro-benzoxazole (1.0 mmol) was added, the reaction
mixture was stirred for another 5 h at room temperature. The
reaction mixture was poured into water and extracted with ethyl
acetate, the organic phase was washed with saturated sodium
bicarbonate, brine, dried over anhydrous magnesium sulfate,
concentrated and the residue was purified via silica gel column
chromatography to afford the title compounds.
4.1.1. Syntheses of 2-(3-(2,6-dichloro-4-(3,3-
3. Conclusions
dichloroallyloxy)phenoxy)propoxy)benzo[d]oxazole (5a)
Yield 47%, oil. 1H NMR (300 MHz, CDCl3):
d 7.49–7.52 (m, 1H, 6-
The present work demonstrates that dihalopropene derivatives
containing benzoxazole moiety with the presence of 5-trifluo-
methyl group in benzoxazole ring can be used as lead compounds
for developing novel insecticides. 5-Trifluomethyl group plays an
important role in enhancing the biological activity of target
compounds. Further synthesis and structure optimization studies
are in progress.
H), 7.34–7.37 (m, 1H, 5-H), 6.83–7.25 (m, 2H, 4, 7-2H), 6.83 (s, 2H,
30,50-2H), 6.10 (t, 1H, J = 6.3 Hz, CH2CH), 4.87 (t, 2H, J = 6.0 Hz,
CH2CH2CH2), 4.57 (d, 2H, J = 6.3 Hz, CHCH2), 4.15 (t, 2H, J = 6.0 Hz,
CH2CH2CH2), 2.34–2.42 (m, 2H, CH2CH2CH2). Anal. Calcd. for
19H15Cl4NO4: C, 49.27; H, 3.26; N, 3.02. Found: C, 49.37; H, 3.28;
N, 2.95.
C
4.1.2. Syntheses of 6-chloro-2-(3-(2,6-dichloro-4-(3,3-
dichloroallyloxy)phenoxy)propoxy)benzo[d]oxazole (5b)
Yield 61%, mp: 58–60 8C. 1H NMR (300 MHz, CDCl3):
7.41 (m, 2H, 5,7-2H), 7.21–7.25 (m, 1H, 4-H), 6.84 (s, 2H, 30,50-2H),
6.11 (t, 1H, J = 6.3 Hz, CH2CH), 4.87 (t, 2H, J = 6.3 Hz, CH2CH2CH2),
4.59 (d, 2H, J = 6.3 Hz, CHCH2), 4.15 (t, 2H, J = 5.7 Hz, CH2CH2CH2),
2.34–2.41 (m, 2H, CH2CH2CH2). Anal. Calcd. for C19H14Cl5NO4: C,
45.86; H, 2.84; N, 2.81. Found: C, 45.73; H, 3.91; N, 2.86.
4. Experimental
All starting materials and reagents were commercially available
and used without further purification otherwise stated. Melting
points were determined on a Bu¨chi melting point apparatus and
were uncorrected. 1H NMR spectra were recorded with a Mercury
300 (Varian, 300 MHz) spectrometer with deuterochloroform as
the solvent and tetramethylsilane (TMS) as the internal standard.
d 7.36–
Mass spectra were recorded using
a JEOL JMS-700 mass
spectrometer. Elemental analyses were determined on a Yanaco
MT-3CHN elemental analyzer. All materials for bioassays including
insects and 3,3-dichloroallyloxyphenoxy intermediates were
obtained from the Agrochemical Discovery Department of the
Shenyang Research Institute of the Chemical Industry.
4.1.3. Syntheses of 2-(2,6-dichloro-4-(3,3-dichloroallyloxy)phenoxy)-
6-(trifluoromethyl)benzo[d]oxazole (5c)
Yield 61%, mp: 79–81 8C. 1H NMR (300 MHz, CDCl3):
d 7.75 (s,
1H, 4-H), 7.58 (s, 2H, 5,7-2H), 6.99 (s, 2H, 30,50-2H), 6.15 (t, 1H,
J = 6.3 Hz, CH2CH), 4.66 (d, 2H, J = 6.3 Hz, CHCH2). Anal. Calcd. for
The preliminary insecticidal tests were performed as follows:
according to the solubility of testing compounds, the compounds
were dissolved in either acetone or dimethyl sulfoxide, and then
diluted with 0.1% aqueous solution of Tween 80 to form 50 mL
testing solution (the content of acetone or dimethyl sulfoxide in
the total solution was not more than 10%). The cabbage leaves were
made into plates of 1 cm diameter by punch. A testing solution
(0.5 mL) was sprayed by airbrush to both sides of every plate. 8
Third instar larvae were put into the petri-dishes after the leaf disk
air-dried and 3 replicates were set for each treatment. Then the
insects were maintained in observation room (24 8C, 60–70% R.H.).
The number of surviving insects was investigated and mortality
was calculated after 96 h.
C17H8Cl4F3NO3: C, 43.16; H, 1.70; N, 2.96. Found: C, 43.24; H, 1.76;
N, 2.85.
4.1.4. Syntheses of 2-(2-(2,6-dichloro-4-(3,3-
dichloroallyloxy)phenoxy)ethoxy)-6-
(trifluoromethyl)benzo[d]oxazole (5d)
Yield 51%, oil. 1H NMR (300 MHz, CDCl3):
d
7.65 (s, 1H, 4-H),
7.56 (s, 2H, 5,7-2H), 6.85 (s, 2H, 30,50-2H), 6.11 (t, 1H, J = 6.3 Hz,
CH2CH), 4.93–4.96 (m, 2H, CH2CH2), 4.59 (d, 2H, J = 6.3 Hz, CHCH2),
4.40–4.43 (m, 2H, CH2CH2). Anal. Calcd. for C19H12Cl4F3NO4: C,
44.13; H, 2.34; N, 2.71. Found: C, 43.03; H, 2.41; N, 2.76.
4.1.5. Syntheses of 2-(3-(2,6-dichloro-4-(3,3-
dichloroallyloxy)phenoxy)propoxy)-6-
(trifluoromethyl)benzo[d]oxazole (5e)
4.1. General procedure
Yield 52%, oil. 1H NMR (300 MHz, CDCl3):
d 7.62 (s, 1H, 4-H),
Potassium hydroxide (46 mmol), ethanol (25 mL) and water
(10 mL) were added to a dried round-bottomed flask sequentially,
followed by the dropwise addition of CS2 (25 mmol), after 15 min,
(un)substituted 2-aminophenol (23 mmol) was added, then the
resulting solution was heated to reflux for 4 h. The reaction
solution was acidified to pHꢀ4 with dilute hydrochloric acid and
then poured into water, extracted with ethyl acetate, the organic
phase was washed with brine, dried over anhydrous magnesium
sulfate, concentrated under reduced pressure and the residue was
purified via silica gel column chromatography to obtain the
intermediate the (un)substituted 2-mercaptobenzoxazole as a
yellow solid. Then, the (un)substituted 2-mercaptobenzoxazole
(5.5 mmol) was refluxed in SOCl2 (15 mL) for 2 h, excessive SOCl2
was removed under reduced pressure to give (un)substituted
7.55 (s, 2H, 5,7-2H), 6.84 (s, 2H, 30,50-2H), 6.11 (t, 1H, J = 6.3 Hz,
CH2CH), 4.92 (t, 2H, J = 6.3 Hz, CH2CH2CH2), 4.58 (d, 2H, J = 6.3 Hz,
CHCH2), 4.16 (t, 2H, J = 5.7 Hz, CH2CH2CH2), 2.37–2.41 (m, 2H,
CH2CH2CH2). Anal. Calcd. for C20H14Cl4F3NO4: C, 45.23; H, 2.66; N,
2.64. Found: C, 45.18; H, 2.59; N, 2.71.
4.1.6. Syntheses of 2-(4-(2,6-dichloro-4-(3,3-
dichloroallyloxy)phenoxy)butoxy)-6-
(trifluoromethyl)benzo[d]oxazole (5f)
Yield 27%, oil. 1H NMR (300 MHz, CDCl3):
d 7.62 (s, 1H, 4-H),
7.54 (s, 2H, 5,7-2H), 6.84 (s, 2H, 30,50-2H), 6.11 (t, 1H, J = 6.3 Hz,
CH2CH), 4.72 (t, 2H, J = 6.3 Hz, CH2CH2CH2CH2), 4.58 (d, 2H,
J = 6.3 Hz, CHCH2), 4.03 (t, 2H, J = 6.3 Hz, CH2CH2CH2CH2), 2.19–
2.36 (m, 2H, CH2CH2CH2CH2), 1.99–2.05 (m, 2H, CH2CH2CH2CH2).

A. Guan et al. / Journal of Fluorine Chemistry 156 (2013) 120–123
123
Anal. Calcd. for C21H16Cl4F3NO4: C, 46.27; H, 2.96; N, 2.57. Found:
Acknowledgments
C, 46.16; H, 2.91; N, 2.66.
The project was supported by the National Key Technology
Support Program during the 12th Five-Year Plan Period of China
(Grant No. 2011BAE06B00, 2011BAE06B01, 2011BAE06B02,
2011BAE06B03, 2011BAE06B05) and the National Key Basic Research
Program of China (973 Program) (Grant No. 2010CB126105 and
2012CB724501).
4.1.7. Syntheses of 2-(2,6-dichloro-4-(3,3-dichloroallyloxy)phenoxy)-
5-(trifluoromethyl)benzo[d]oxazole (5g)
Yield 36%, mp: 63–65 8C. 1H NMR (300 MHz, CDCl3):
d 7.82
(s, 1H, 7-H), 7.60 (s, 2H, 4,6-2H), 7.02 (s, 2H, 30,50-2H), 6.19 (t, 1H,
J = 6.3 Hz, CH2CH), 4.70 (d, 2H, J = 6.3 Hz, CHCH2). Anal. Calcd. for
C17H8Cl4F3NO3: C, 43.16; H, 1.70; N, 2.96. Found: C, 43.28; H, 1.63;
N, 3.01.
Appendix A. Supplementary data
4.1.8. Syntheses of 2-(2-(2,6-dichloro-4-(3,3-dichloroallyloxy)-
phenoxy)ethoxy)-5-(trifluoromethyl)benzo[d]oxazole (5h)
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.09.
003.
Yield 29%, oil. 1H NMR (300 MHz, CDCl3):
d 7.75 (s, 1H, 7-H),
7.48 (s, 2H, 4,6-2H), 6.85 (s, 2H, 30,50-2H), 6.11 (t, 1H, J = 6.3 Hz,
CH2CH), 4.92–4.95 (m, 2H, CH2CH2), 4.59 (d, 2H, J = 6.3 Hz, CHCH2),
4.40–4.43 (m, 2H, CH2CH2). Anal. Calcd. for C19H12Cl4F3NO4: C,
44.13; H, 2.34; N, 2.71. Found: C, 44.26; H, 2.23; N, 2.68.
References
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4.1.9. Syntheses of 2-(3-(2,6-dichloro-4-(3,3-dichloroallyloxy)-
phenoxy)propoxy)-5-(trifluoromethyl)benzo[d]oxazole (5i)
Yield 35%, mp: 46–47 8C. 1H NMR (300 MHz, CDCl3):
d 7.75 (s,
1H, 7-H), 7.42–7.46 (m, 2H, 4,6-2H), 6.84 (s, 2H, 30,50-2H), 6.11 (t,
1H, J = 6.3 Hz, CH2CH), 4.91 (t, 2H, J = 6.3 Hz, CH2CH2CH2), 4.58 (d,
2H, J = 6.3 Hz, CHCH2), 4.16 (t, 2H, J = 5.7 Hz, CH2CH2CH2), 2.35–
2.42 (m, 2H, CH2CH2CH2). Anal. Calcd. for C20H14Cl4F3NO4: C,
45.23; H, 2.66; N, 2.64. Found: C, 45.30; H, 2.68; N, 2.58. LC–MS
(m/z %): 532.5 [M+H]+.
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4.1.10. Syntheses of 2-(4-(2,6-dichloro-4-(3,3-dichloroallyloxy)-
phenoxy)butoxy)-5-(trifluoromethyl)benzo[d]oxazole (5j)
Yield 29%, mp: 49–50 8C. 1H NMR (300 MHz, CDCl3)
d 7.74 (s,
1H, 4-H), 7.44–7.46 (m, 2H, 5,7-2H), 6.85 (s, 2H, 30,50-2H), 6.11 (t,
1H, J = 6.3 Hz, CH2CH), 4.71 (t, 2H, J = 6.3 Hz, CH2CH2CH2CH2), 4.59
(d, 2H, J = 6.3 Hz, CHCH2), 4.04 (t, 2H, J = 6.0 Hz, CH2CH2CH2CH2),
2.13–2.30 (m, 2H, CH2CH2CH2CH2), 1.97–2.09 (m, 2H, CH2CH2CH2-
CH2). Anal. Calcd. for C21H16Cl4F3NO4: C, 46.27; H, 2.96; N, 2.57.
Found: C, 46.19; H, 3.06; N, 2.52.
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