Synthesis and herbicidal activity of diphenyl ether derivatives containing unsaturated carboxylates

Article abstract of DOI:10.1021/jf2039444

A series of novel diphenyl ether derivatives containing unsaturated carboxylates were designed and synthesized. Their structures were identified by ¹H nuclear magnetic resonance and elemental analyses. The bioassays indicated that the compounds 5b and 5c exhibited good herbicidal activities against velvetleaf at a concentration of 30-40 g/hm². The relationship between structure and herbicidal activity was also discussed. Among unsaturated carboxylates group, butenoate is the most promising one. Amonst them, 4-ethoxy-4-oxobutenyl 5-(2-chloro-4-(trifluoromethyl)phenoxy)-2- nitrobenzoate 5b was identified as the most promising candidate due to its high protoporphyrinogen IX oxidase inhibition effect (pI₅₀ = 6.64) and good herbicidal activity against broadleaf weeds with selectivity to soybean and low toxicity to mammals.

Full text of DOI:10.1021/jf2039444

ARTICLE
pubs.acs.org/JAFC
Synthesis and Herbicidal Activity of Diphenyl Ether Derivatives
Containing Unsaturated Carboxylates
Haibo Yu, Huibin Yang, Dongliang Cui, Liang Lv, and Bin Li*
State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry Co. Ltd.,
Shenyang 110021, People's Republic of China
ABSTRACT: A series of novel diphenyl ether derivatives containing unsaturated carboxylates were designed and synthesized. Their
structures were identified by 1H nuclear magnetic resonance and elemental analyses. The bioassays indicated that the compounds 5b
and 5c exhibited good herbicidal activities against velvetleaf at a concentration of 30À40 g/hm2. The relationship between structure
and herbicidal activity was also discussed. Among unsaturated carboxylates group, butenoate is the most promising one. Amonst
them, 4-ethoxy-4-oxobutenyl 5-(2-chloro-4-(trifluoromethyl)phenoxy)-2-nitrobenzoate 5b was identified as the most promising
candidate due to its high protoporphyrinogen IX oxidase inhibition effect (pI50 = 6.64) and good herbicidal activity against broadleaf
weeds with selectivity to soybean and low toxicity to mammals.
KEYWORDS: Protoporphyrinogen oxidase, diphenyl ether, unsaturated carboxylate, synthesis, herbicide
’ INTRODUCTION
As the last common enzyme in the biosynthesis pathway
leading to heme and chlorophyll synthesis, protoporphyrinogen
IX oxidase (PPO) has been identified as one of the most
significant targets for several chemical families of herbicides such
as diphenyl ethers (DPEs) and N-phenyl phthalimides that have
Figure 1. Evolution of DPE herbicides.
been available in the commercial market for many years.1À7 The
protoporphyrinogen oxidase enzyme catalyzes the oxidation of
requirements for chemical groups at these positions.11 Position 9
protoporphyrinogen IX to protoporphyrin IX by molecular
oxygen. Inhibition of the PPO results in the accumulation of
enzyme product protoporphyrin IX. In the presence of light,
protoporphyrin IX generates large amounts of single oxygen,
which results in peroxidation of the usaturated bonds of fatty
acids found in membranes.8 The end result of this peroxidation
process is the loss of membrane integrity and leakage, pigment
breakdown, and necrosis of the leaf that results in the death of
plant.9
DPEs are the first group of commercial herbicides targeting
PPO, among which nitrofen (1a) (Figure 1) is the first product
that entered market in the early 1960s. Following the discovery of
herbicidal activity of nitrofen, intense research by several com-
panies resulted in a vast number of highly active and diverse
agrochemicals.10À15 Replacement of the aromatic 4-chloro group
with the lipophilic trifluoromethyl group, as is the case with
acifluorfen, resulted in a significant improvement in biological
activity; 2-chloro-4-(trifluoromethyl)benzene became the domi-
nant substitution pattern for the DPEs. Many 4-CF3-DPEs
incorporated alkoxycarbonyl, carbamoyl groups into the 3-posi-
tion of phenyl ring and have been found to show high activities
since the development of acifluorfen, as shown in Figure 2.
Among them, fluoroflycofen-ethyl, fomesafen, and lactofen have
been successfully commercialized (Figure 1). However, there are
some defects in DPEs such as high use rate and low selectivity
for crops.
should be substituted by electronegative groups to increase the
electrostatic interaction with Arg98.16,17 Position 9 should also
be occupied by bulky groups with hydrogen bond acceptor atoms
to form van der Waals and hydrogen bond interactions with the
surrounding residues. DPEs need somewhat lipophilic groups
that interact with lipophilic areas of the target. Substituents at
position 9 have an important effect not only on the activity but
also on the crop selectivity.11 In previous work, we added a
lipophilic group unsaturated carboxylate in the acifluorfen, and
compounds 2aÀ3 were synthesized (Figure 2), which showed
higher herbicidal activities against broadleaf weeds than acifluor-
fen (1e).18 Therefore, as a continuation of our research work on
the development of new DPEs with low use rate and high
selectivity for crops, we are very interested in the DPE derivatives
containing unsaturated carboxylates, as shown in Figure 3. Here-
in, we report the detailed synthesis and herbicidal activities of
series 3À5 and also the relationship between their structures and
herbicidal activity.
’ MATERIALS AND METHODS
Synthetic Procedures. Melting points were measured using a RY-
1 melting point apparatus (TaiKe Co.) and are uncorrected. 1H NMR
Received: July 3, 2011
Extensive studies of the 1-, 3-, 8-, 9-positions of the phenyl ring
of DPEs revealed very specific electronic, steric, and lipophilic
Accepted: September 29, 2011
Published: September 29, 2011
r
2011 American Chemical Society
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|

Journal of Agricultural and Food Chemistry
ARTICLE
Figure 3. Design of novel DPE compounds.
reduced pressure and afforded acyl chloride 7. The acyl chloride was
used directly without further purification. Then, to a stirred solution of
acetoacetate 8 (10 mmol) and Et3N (12 mmol) in dichloromethane was
added a solution of acyl chloride 7 in dichloromethane at 0 °C. The
reaction mixture was stirred for 2 h, and then, the solvent was removed
under reduced pressure, and the residue was purified by silica gel (65 g)
column chromatography (1:10 ethyl acetate/petroleum ether) to afford
the title compounds. The melting points, yields, and elemental analyses
Figure 2. Structural modifications of 4-CF3-DPEs: 3-alkoxycarbonyl
and 3-carbamoyl derivatives.
spectra were recorded on a Bruker-300 (Bruker Co.) spectrometer using
tetraamethylsilane as an internal reference. Chemical shift values (δ)
were given in ppm. Elemental analyses were performed on a Yanaco
Corder MT-3 (Yanaco Co. Ltd.) elemental analyzer. X-ray diffraction
analyses were measured on a Siemens P4 diffractometer. The solvents
were used directly without further purification.
General Synthetic Procedure for 3aÀk. To a solution of
substituted benzoic acid 6 (10 mmol) in dichloromethane (10 mL)
were added (13 mmol) oxalyl dichloride and two drops of N,N-
dimethylformamide in an iceÀwater bath. The reaction was stirred at
room temperature for 2 h, and then, the solvent was removed under
1
of compounds 3aÀk are listed in Table 1. The H NMR analyses of
compounds 3aÀk are listed in Table 2.
General Synthetic Procedure for 4aÀc. A mixture of substi-
tuted benzoic acid 6 (1 mmol), K2CO3 (1.2 mmol) and 2-(bromo-
methyl) acrylate 10 (1.1 mmol) was stirred in N,N-dimethylformamide
at 40 °C. The mixture was allowed to react at this temperature until the
starting material was consumed [monitored by thin-layer chromatogra-
phy (TLC)]. The mixture was poured into water. The aqueous layer was
extracted with EtOAc (2 Â 100 mL). The combined organic layers were
Table 1. Melting Points, Yields, and Elemental Analyses of Compounds 3aÀk
elemental analysis (%, calcd)
H
compd
X
R1
R2
R3
mp (°C)
yield (%)
C
N
3a
3b
3c
3d
3e
3f
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
Cl
CH3
CH3
CH3
CH3
CH3
CH3
CF3
H
CH3
98À99, white solid
98À100, white solid
yellow oil
65
68
66
63
66
70
69
50
51
63
60
49.69 (49.64)
50.71 (50.70)
49.08 (49.04)
52.69 (52.65)
51.92 (51.92)
51.71 (51.75)
45.50 (45.52)
50.71 (50.70)
52.65 (52.68)
51.87 (51.86)
52.90 (52.85)
2.83 (2.85)
3.22 (3.19)
3.13 (3.09)
3.82 (3.88)
3.11 (3.13)
3.51 (3.50)
2.29 (2.33)
3.17 (3.19)
3.82 (3.83)
3.29 (3.26)
3.63 (3.59)
3.09 (3.05)
2.99 (2.96)
2.87 (2.86)
2.83 (2.79)
2.88 (2.89)
2.87 (2.92)
2.65 (2.66)
3.01 (2.96)
2.79 (2.75)
H
CH3CH2
H
CH3OCH2CH2
(CH3)3C
CH2dCHÀCH2
CH3CH2
H
yellow oil
H
yellow oil
CH3
H
79À81, white solid
111À112, white solid
yellow oil
3g
3h
3i
CH3CH2
C2H5
n-C3H7
CH3
CH3
H
CH3
H
CH3CH2
yellow oil
3j
H
CH3CH2
yellow oil
3k
Cl
CH3
CH3CH2
yellow oil
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Journal of Agricultural and Food Chemistry
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1
Table 2. H NMR of Compounds 3aÀk
compd
δ (ppm)
3a 2.49 (s, 3H, CH3), 3.75 (s, 3H, OCH3), 5.87 (s, H, CH), 7.09 (dd, J = 2.4 and 6.3 Hz, 1H, ArÀH), 7.19 (d, J = 2.4 Hz, 1H, ArÀH), 7.28 (d, J = 8.7 Hz,
1H, ArÀH), 7.64 (dd, J = 2.1 and 6.6 Hz, 1H, ArÀH), 7.83 (d, J = 1.8 Hz, 1H, ArÀH), 8.11 (d, J = 8.7 Hz, 1H, ArÀH)
3b 1.29 (t, J = 7.2 Hz, 3H, CH3), 2.48 (s, 3H, CH3), 4.20 (q, J = 7.2 Hz, 2H, OCH2), 5.86 (s, 1H, CH), 7.10 (dd, J = 2.7 and 6.6 Hz, 1H, ArÀH), 7.19 (d, J =
2.4 Hz, 1H, ArÀH), 7.29 (d, J = 8.7 Hz, 1H, ArÀH), 7.64 (dd, J = 2.1 and 8.7 Hz, 1H, ArÀH), 7.83 (d, J = 2.4 Hz, 1H, ArÀH), 8.12 (d, J = 8.7 Hz, 1H, ArÀH)
3c 2.49 (s, 3H, CH3), 3.40 (s, 3H, CH3), 3.62 (t, J = 7.5 Hz, Hz, 2H, CH2), 4.30 (t, J = 7.5 Hz, 2H, CH2), 5.92 (s, 1H, CdCH), 7.09À7.19 (m, 2H, ArÀH),
7.28 (d, J = 8.4 Hz, 1H, ArÀH), 7.65 (d, J = 9 Hz, 1H, ArÀH), 7.84 (d, J = 1.8 Hz, 1H, ArÀH), 8.12 (d, J = 9 Hz, 1H, ArÀH)
3d 1.49 (s, 9H, CH3), 2.41 (s, 3H, CH3), 5.74 (s, 1H, CdCH), 7.11 (d, J = 8.7 Hz, 1H, ArÀH), 7.26 (d, J = 9 Hz, 1H, ArÀH), 7.55À7.56 (m, 2H, ArÀH),
7.57 (d, J = 8.4 Hz, 1H, ArÀH), 7.83 (d, J = 9 Hz, 1H, ArÀH)
3e 2.46 (s, 3H, CH3), 4.64À4.67 (m, 2H, CH2), 5.24À5.38 (m, 2H), 5.87À5.99 (m, 2H), 7.11 (dd, J = 1.5 and 6.6 Hz, 1H, ArÀH), 7.20 (d, 1H, J = 8.7 Hz,
ArÀH), 7.56À7.62 (m, 2H, ArÀH), 7.78 (dd, J = 1.8 and 8.4 Hz, 1H, ArÀH), 7.86 (dd, J = 1.5 and 6.6 Hz, 1H, ArÀH)
3f 1.32 (t, J = 7.2 Hz, 3H, CH3), 1.81 (s, 3H, CH3), 2.36 (s, 3H, CH3), 4.25 (q, J = 7.2 Hz 2H, CH2), 7.11 (dd, J = 1.5 and 6.9 Hz, 1H, ArÀH), 7.21 (d, J =
6.9 Hz, 1H, ArÀH), 7.57 (d, J = 8.4 Hz, 1H, ArÀH), 7.78 (d, J = 2.1 Hz, 1H, ArÀH), 7.96 (dd, J = 2.1 Hz, 1H, ArÀH), 7.94 (d, J = 1.5 and 6.9 Hz, 1H, ArÀH)
3g 1.25 (t, J = 7.5 Hz, 3H, CH3), 4.21 (q, J = 7.5 Hz, 2H, CH2), 6.48 (s, 1H, CH), 7.14 (dd, J = 3 and 6.6 Hz, 1H, ArÀH), 7.21 (d, J = 8.4 Hz, 1H, ArÀH),
7.56À7.61 (m, 2H, ArÀH), 7.78 (d, J = 2.1 Hz, 1H, ArÀH), 7.97 (d, J = 8.4 Hz, 1H, ArÀH)
3h 1.14 (t, J = 6.9 Hz, 3H, CH3), 2.92 (q, J = 6.9 Hz, 2H, CH2), 3.74 (s, 3H, CH3), 5.91 (s, 1H, CdCH), 7.09 (dd, J = 6.6 Hz, 1H, ArÀH), 7.22 (d, J = 2.4 Hz,
1H, ArÀH), 7.29 (d, J = 2.4 Hz, 1H, ArÀH), 7.63À7.81 (m, 2H, ArÀH), 8.11 (d, J = 8.1 Hz, 1H, ArÀH)
3i 0.98 (t, J = 7.2 Hz, 3H, CH3), 1.27 (t, J = 7.5 Hz, 3H, CH3), 1.59 (q, J = 7.5 Hz, 2H, CH2), 2.88 (q, J = 7.2 Hz, 2H, CH2), 4.20 (q, J = 7.5 Hz, 2H, CH2),
5.84 (s, 1H, CdCH), 7.11 (d, J = 8.7 Hz, 1H, ArÀH), 7.18 (d, J = 2.4 Hz, 1H, ArÀH), 7.56À7.62 (m, 2H, ArÀH), 7.84 (d, J = 2.4 Hz, 1H, ArÀH),
7.87 (d, J = 8.7 Hz, 1H, ArÀH)
3j 1.27 (t, J = 7.5 Hz, 3H, CH3) 2.47 (s, 3H, CH3), 4.19 (q, J = 7.5 Hz, 2H, CH2), 5.83 (s, 1H), 7.04À7.09 (m, 2H, ArÀH), 7.48À7.52 (m, 3H, ArÀH),
7.77 (d, J = 8.7 Hz, 1H, ArÀH)
3k 0.87 (t, J = 7.5 Hz, 3H, CH3), 1.53 (s, 3H, CH3), 2.39 (s, 3H, CH3), 4.22 (q, J = 7.5 Hz, 2H, CH2), 7.06 (d, J = 8.7 Hz, 1H, ArÀH) ,7.74À7.52
(m, 2H, ArÀH), 7.76 (d, J = 3 Hz, 1H, ArÀH), 7.98 (d, J = 8.4 Hz, 1H, ArÀH), 8.27 (d, J = 8.7 Hz, 1H, ArÀH)
washed with a solution of saturated NaHCO3 and NaCl and dried over
anhydrous magnesium sulfate. Then, the solvent was removed under
reduced pressure, and the residue was purified by silica gel (65 g) column
chromatography (1:20 ethyl acetate/petroleum ether) to afford the title
compounds. The apperance, yields, and elemental analyses of com-
pounds 4aÀc are listed in Table 4. The 1H NMR analyses of compounds
4aÀc are listed in Table 5.
allowed to germinate and grow for 14 days. Test plants were selected for
uniformity, size, and stage of development and then treated with the test
compound, returned to the greenhouse, and watered. The plants not
treated with the compound under evaluation were used as a control. The
compound to be evaluated was dissolved in acetone and sprayed using a
carrier volume equivalent to 187 L per hectare at 2000 to 30 g/hm2. Two
weeks after application of the test compounds, the state of the plants was
observed. Each species was evaluated on a scale of 0À100 in which 0
equals no activity and 100 equals total control. The average control of
the three plant species was calculated.
General Synthetic Procedure for 4dÀe. To a stirred solution
of α-(hydroxymethyl)acrylate 11 (10 mmol) and Et3N (12 mmol) in
dichloromethane was added a solution of acyl chloride 7 in dichloro-
methane at 0 °C. The reaction mixture was stirred for 2 h, and then, the
solvent was removed under reduced pressure, and the residue was
purified by silica gel (65 g) column chromatography (1:10 ethyl acetate/
petroleum ether) to afford the title compounds. The appearance, yields,
and elemental analyses of compounds 4dÀe are listed in Table 4. The
1H NMR analyses of compounds 4dÀe are listed in Table 5.
Inhibitory Activity in Vitro against PPO. The pI50 values
against PPO of compounds 5b and acifluorfen were assayed according
to the procedure reported.19À22
’ RESULTS AND DISCUSSION
General Synthetic Procedure for 5aÀh. To a stirring solution
of substituted benzoic acid 6 (1 mmol) and K2CO3 (1.2 mmol) in N,N-
dimethylformamide, 4-bromobutenates 12 (1.1 mmol) was added at
room temperature. The mixture was allowed to react at 40 °C until the
starting material was consumed (monitored by TLC). The mixture was
poured into water. The aqueous layer was extracted with EtOAc (2 Â
100 mL). The combined organic layers were washed with a solution of
saturated NaHCO3 and NaCl and dried over anhydrous magnesiumsulfate.
Then, the solvent was removed under reduced pressure, and the residue was
purified by silica gel (65 g) column chromatography (1:10 ethyl acetate/
petroleum ether) to afford the title compounds. The appearance, yields, and
elemental analyses of compounds 5aÀh are listed in Table 7. The 1H NMR
analyses of compounds 5aÀh are listed in Table 8.
Synthesis. Compounds 6 were synthesized as described by
the literature.23,24 The 3-benzoxy acrylate derivatives of 3aÀk
were prepared according to the Scheme 1.25,26 Acetoacetate was
reacted with acyl chloride 7 to give O-acylated products 3 and
C-acylated products 9. The solvent had a great effect on the
reaction procedure. The major product was the O-acylated one
in the polar aprotic solvent, such as DMF. However, the major
product was C-acylated one in the less polar aprotic solvent, such
as toluene. The structure of compound 3a was further conformed
by the X-ray diffraction (Figure 4). The compound 3a exists as
the E configuration.
(2-Bromomethyl)-acrylate derivatives of 10 were prepared
starting from diethyl malonate according to the literature's
procedures.27,28 Substituted benzoic acid was reacted with 10
giving 2-(benzoxy) alkyl acrylate 4aÀc (Scheme 2). The reaction
was carried out in a polar aprotic solvent like DMF at 40 °C using
potassium carbonate as the base. Aldehyde and acrylate were
Biological Assay. Barnyard (Echinochloa crusgalli), crabgrass
(Digitaria sanguinalis), foxtail (Setaria glauca), velvetleaf (Abutilon
theophrasti), common purslane (Portulaca oleracea), redroot amaranth
(Amaranthus retroflexus), dayflower (Commelina communis), and heartleaf
cocklebur (Xanthius strumarium) were used for the test. The seeds were
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Journal of Agricultural and Food Chemistry
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Table 3. Herbicidal Activities of Compounds 3aÀka
compd
Clog P
dosage (g/hm2)
BYG
CRB
VEL
3a
5.7
1000
200
40
80
50
15
60
40
10
80
30
20
45
30
5
95
80
5
100
75
25
100
85
10
100
100
98
75
50
30
40
0
3b
3c
3d
6.4
5.8
7.1
1000
200
40
98
90
80
75
35
30
40
15
5
1000
200
40
1000
200
40
3e
3f
6.6
6.7
1000
200
1000
200
40
25
5
35
5
25
15
10
35
0
55
50
20
50
0
100
35
0
3g
3h
3i
6.5
6.4
7.4
6.0
1000
200
1000
200
1000
200
1000
200
40
60
0
35
0
15
5
10
0
35
5
15
5
0
0
3j
95
20
0
25
20
10
30
25
0
100
90
50
100
90
5
3k
6.1
4.9
1000
200
40
25
20
0
acifluorfen
1000
200
40
90
50
20
10
0
100
95
50
0
a 0 equals no activity; 100 equals total control. BYG, barnyard (E. crusgalli); CRB, crabgrass (D. sanguinalis); and VEL, velvetleaf (Abutilon thophrasti).
CLog P was predicted by ChemBioDraw 11.0.
Table 4. Appearance, Yields, and Elemental Analyses of Compounds 4aÀe
elemental analysis (%, calcd)
compd
X
R1
R2
apperance
yield (%)
C
H
N
4a
4b
4c
4d
4e
Cl
H
CH3
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
75
81
80
76
83
50.77 (50.80)
51.87 (51.86)
52.84 (52.85)
52.88 (52.85)
51.70 (51.71)
2.95 (2.92)
3.27 (3.26)
3.64 (3.59)
3.63 (3.59)
3.56 (3.51)
Cl
H
CH2CH3
Cl
H
CH2CH2CH3
CH2CH3
Cl
CH3
CH3
NO2
CH2CH3
2.91 (2.87)
subjected to BaylisÀHillman reaction with DABCO as the
catalyst to give α-(hydroxymethyl)acrylate analogues 11.29 The
title compounds of 2-(benzoxy) alkyl acrylate 4dÀe were
prepared by the reaction of benzoyl chloride with BaylisÀ
Hillman adducts 11 in dichloromethane using Et3N as the acid
acceptor (Scheme 3).
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Journal of Agricultural and Food Chemistry
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1
Table 5. H NMR of Compounds 4aÀe
compd
δ (ppm)
4a 3.73 (s, 3H, OCH3), 4.81 (s, 2H, OCH2), 5.96 (s, 1H, CdCH), 6.37 (s, 1H, CdCH), 7.02À7.09 (m, 2H, ArÀH), 7.44À7.55 (m, 3H, ArÀH), 7.66
(d, J = 8.4 Hz, 1H, ArÀH)
4b 1.31 (t, J = 7.5 Hz, 3H, CH3), 4.24 (q, J = 7.5 Hz, 2H, OCH2), 5.06 (s, 2H, OCH2), 5.93 (s, 1H, CdCH), 6.44 (s, 1H, CdCH), 7.07 (dd, J = 2.4 and
9 Hz, 1H, ArÀH), 7.26 (d, J = 7.5 Hz, 1H, ArÀH), 7.17 (d, J = 3 Hz, 1H, ArÀH), 7.62 (d, J = 6.9 Hz, 1H, ArÀH), 7.83 (d, J = 2.1 Hz, 1H, ArÀH), 8.04
(d, J = 9 Hz, 1H, ArÀH)
4c 0.95À0.98 (m, 3H, CH3), 1.66À1.73 (m, 2H, CH2), 4.11À4.17 (m, 2H, CH2), 5.95 (s, 1H), 6.37 (s, 1H), 7.02À7.09 (m, 2H, ArÀH), 7.48À7.52
(m, 3H, ArÀH), 7.763 (d, J = 2.1 Hz, 1H, ArÀH)
4d 1.31 (t, J = 6.9 Hz, 3H, CH3), 1.50 (d, J = 6.3 Hz, 3H, CH3), 4.24 (q, J = 6.9 Hz, 2H, OCH2), 5.06 (q, J = 6.3 Hz, 1H, OH), 5.93 (s, 1H, C=CH), 6.44
(s, 1H, CdCH), 7.07 (dd, J = 2.1 and 9 Hz, 1H, ArÀH), 7.26 (d, J = 7.5 Hz, 1H, ArÀH), 7.15 (d, J = 3 Hz, 1H, ArÀH), 7.62 (d, J = 6.9, 1H, ArÀH), 7.82
(d, J = 2.1 Hz, 1H, ArÀH), 8.04 (d, J = 9 Hz,1H, ArÀH)
4e 1.31 (t, J = 6.9 Hz, 3H, CH3), 1.53 (d, J = 6.3 Hz, 3H, CH3), 4.24 (q, J = 6.9 Hz, 2H, OCH2), 5.05 (q, J = 6.3 Hz, 1H, OH), 5.94 (s, 1H, C=CH), 6.36
(s, 1H, CdCH), 7.07 (dd, J = 3 and 8.7 Hz, 1H, ArÀH), 7.15 (d, J = 3 Hz, 1H, ArÀH), 7.26 (d, J = 9 Hz, 1H, ArÀH), 7.62 (d, J = 9 Hz, 1H, ArÀH), 7.81
(d, J = 1.8 Hz, 1H, ArÀH), 8.04 (d, J = 9 Hz, 1H, ArÀH)
Table 6. Herbicidal Activities of Compounds 4aÀe
compd
Clog P
dosage (g/hm2)
BYG
CRB
VEL
4a
6.1
1000
200
40
75
15
5
30
25
10
95
70
40
35
30
10
40
35
0
100
98
10
4b
6.6
7.1
6.9
6.3
4.9
1000
200
40
90
20
10
75
10
5
100
100
30
4c
1000
200
40
100
100
20
4d
1000
200
40
95
20
0
100
75
5
4e
1000
200
40
30
20
10
90
50
20
90
70
25
10
0
100
50
5
acifluorfen
1000
200
40
100
95
0
50
Table 7. Appearance, Yields, and Elemental Analyses of Compounds 5aÀh
elemental analysis (%, calcd)
H
compd
X
R1
R2
appearance
yield (%)
C
N
5a
5b
5c
5d
5e
5f
NO2
NO2
NO2
NO2
NO2
NO2
NO2
Cl
H
CH3
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
yellow oil
85
80
80
79
80
70
67
70
49.69 (49.64)
50.71 (50.70)
51.76 (51.71)
51.68 (51.71)
52.69 (52.65)
51.88 (51.92)
51.68 (51.71)
51.87 (51.86)
2.86 (2.85)
3.21 (3.19)
3.54 (3.51)
3.56 (3.51)
3.86 (3.82)
3.15 (3.11)
3.56 (3.51)
3.30 (3.26)
3.04 (3.05)
2.93 (2.96)
2.85 (2.87)
2.90 (2.87)
2.75 (2.79)
2.85 (2.88)
2.90 (2.87)
H
CH2CH3
H
CH2CH2CH3
CH(CH3)CH3
CH2CH2CH2CH3
CH2CHdCH2
CH2CH3
H
H
H
5g
5h
CH3
H
CH2CH3
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1
Table 8. H NMR of Compounds 5aÀh
compd
δ (ppm)
5a 3.74 (s, 3H, OCH3), 4.98 (q, J = 4.8 Hz, 2H, OCH2), 6.06 (d, J = 15.6 Hz, 1H, CHd), 6.94À7.02 (m, 1H, dCH), 7.09 (dd, J = 2.7 and 8.7 Hz, 1H,
ArÀH), 7.16 (d, J = 3 Hz, 1H, ArÀH), 7.27 (d, J = 8.4 Hz, 1H, ArÀH), 7.63 (dd, J = 1.8 and 8.4 Hz, 1H, ArÀH), 7.82 (d, J = 2.1 Hz, 1H, ArÀH),
8.07 (d, J = 8.7 Hz, 1H, ArÀH)
5b 1.29 (t, J = 7.5 Hz, 3H, CH3), 4.21 (q, J = 7.5 Hz, 2H, OCH2), 4.98 (q, J = 4.8 Hz, 2H, OCH2), 6.06 (d, J = 15.6 Hz, 1H, CHd), 6.93À7.01 (m, 1H,
dCH), 7.09 (dd, J = 3 and 8.7 Hz, 1H, ArÀH), 7.16 (d, J = 3 Hz, 1H, ArÀH), 7.27 (d, J = 8.7 Hz, 1H, ArÀH), 7.63 (d, J = 8.4 Hz, 1H, ArÀH), 7.82
(d, J = 2.4 Hz, 1H, ArÀH), 8.07 (d, J = 8.7 Hz, 1H, ArÀH)
5c 0.96 (t, J = 7.2 Hz, 3H, CH3), 1.60À1.72 (m, 2H, CH2) 4.12À4.18 (m, 2H, OCH2), 4.98 (q, J = 4.8 Hz, 2H, OCH2), 6.06 (d, J = 15.6 Hz, 1H, CHd),
6.92À7.01 (m, 1H, dCH), 7.08 (dd, J = 3 and 8.7 Hz, 1H, ArÀH), 7.16 (d, J = 3 Hz, 1H, ArÀH), 7.26 (d, J = 8.7 Hz, 1H, ArÀH), 7.62 (d, J = 8.4 Hz,
1H, ArÀH), 7.82 (d, J = 2.4 Hz, 1H, ArÀH), 8.06 (d, J = 8.7 Hz, 1H, ArÀH)
5d 1.26À1.28 (m, 6H, CH3), 4.98 (q, J = 4.8 Hz, 2H, OCH2), 5.06À5.09 (m, 1H, CH), 6.03 (d, J = 15.6 Hz, 1H, CHd), 6.92À6.97 (m, 1H, dCH), 7.09
(dd, J = 3 and 9 Hz, 1H, ArÀH), 7.16 (d, J = 2.7 Hz, 1H, ArÀH), 7.27 (dd, J = 2.4 and 6 Hz, 1H, ArÀH), 7.62 (d, J = 9 Hz, 1H, ArÀH), 7.82
(d, J = 2.1 Hz, 1H, ArÀH), 8.07 (d, J = 8.7 Hz, 1H, ArÀH)
5e 0.96 (t, J = 7.2 Hz, 3H, CH3), 1.362À1.54 (m, 2H, CH2), 1.60À1.67 (m, 2H CH2), 4.15 (q, J = 7.2 Hz, 2H, OCH2), 4.98 (q, J = 4.8 Hz, 2H, OCH2),
6.03 (d, J = 15.6 Hz, CHd), 6.97À6.93 (m,1H, dCH), 6.99 (dd, J = 2.4 and 6 Hz, 1H, ArÀH), 7.10 (d, J = 3 Hz, 1H, ArÀH), 7.27 (dd, J = 2.4 and
6 Hz, 1H, ArÀH), 7.63 (d, J = 9 Hz, 1H, ArÀH) 7.83 (d, J = 2.1 Hz, 1H, ArÀH), 8.06 (d, J = 8.7 Hz, 1H, ArÀH)
5f 4.66À4.69 (m, 1H, OCH2), 5.01À5.12 (m, 1H, OCH2), 5.30À5.82 (m, 2H, CdCH2), 5.91À5.98 (m, 1H, CHd), 6.11 (d, J = 15.6 Hz, 1H, CHd),
7.01À7.06 (m, 1H, dCH), 7.09 (dd, J = 3 and 8.7 Hz, 1H, ArÀH), 7.16 (d, J = 2.4 Hz, 1H, ArÀH), 7.28 (d, J = 8.1 Hz, 1H, ArÀH), 7.63 (dd, J = 2.1 and
6.3 Hz, 1H, ArÀH), 7.82 (d, J = 1.8 Hz, 1H, ArÀH), 8.07 (d, J = 9.0 Hz, 1H, ArÀH)
5g 1.29 (t, J = 7.5 Hz, 3H, CH3), 2.18 (s, 3H, CH3), 4.16 (q, J = 7.5 Hz, 2H, OCH2), 5.47 (s, 2H, OCH2), 5.83 (s, 1H, CdCH), 7.08 (dd, J = 3 and 6 Hz,
1H, ArÀH), 7.16 (d, J = 3 Hz, 1H, ArÀH), 7.27 (d, J = 7.2 Hz, 1H, ArÀH), 7.63 (dd, J = 1.8 and 6.6 Hz, 1H, ArÀH), 7.82 (d, J = 1.8 Hz, 1H, ArÀH), 8.03
(d, J = 9.0 Hz, 1H, ArÀH)
5h 1.30 (t, J = 6.9 Hz, 3H, CH3), 4.22 (q, J = 6.9 Hz, 2H, CH2), 4.99 (q, J = 4.8 Hz, 2H, CH2), 6.14 (d, J = 15.6 Hz, 1H, CdCH), 6.99À7.11 (m, 3H),
7.27À7.52 (m, 3H, ArÀH), 7.77 (d, J = 2.4 Hz, H, ArÀH)
Scheme 1a
a Reagents and conditions: (a) Oxalyl dichloride/CH2Cl2, DMF(cat). (b) Et3N, dichloromethane.
Figure 4. Crystal structure of compound 3a.
4-Bromobutenates 12 can be prepared from butenates via a halgena-
ted reaction with NBS. The title compounds 4-benzoxyÀbutenates
5aÀh were synthesized via intermediate 6 as shown in Scheme 4.
StructureÀActivity Relationship. The results of herbicidal
activities are listed in Tables 3, 6, and 9. In general, these com-
pounds exhibited higher herbicidal activities against broadleaf
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Scheme 2a
a Reagents and conditions: (a) KHCO3, H2O. (b) HBr (40%). (c) Alcohol/toulene, H2SO4(cat). (d) K2CO3, DMF.
Scheme 3a
Scheme 4a
a Reagents and conditions: (a) NBS/AIBN (cat), CCl4. (b) K2CO3,
DMF.
a Reagents and conditions: (a) DABCO, 1,4-dioxane. (b) Et3N, CH2Cl2.
Table 9. Herbicidal Activities of Compound 5aÀh
Table 10. Herbicidal Spectrum of Compound 5b and
Acifluorfena
compd
Clog P
dosage (g/hm2)
BYG
CRB
VEL
5b
acifluorfen
(400 g/hm2)
5a
5.5
480
120
30
80
60
10
70
50
40
70
40
10
80
60
30
40
20
10
60
30
35
20
5
90
80
20
90
80
60
90
80
70
90
85
80
85
80
70
55
25
20
10
10
70
30
20
10
0
100
95
species
(40 g/hm2)
barnyard grass (E. crusgalli, BYG)
crabgrass (D. sanguinalis, CRB)
foxtail (S. glauca, FOX)
C
B
C
A
A
A
C
B
C
B
C
B
A
A
C
C
30
5b
5c
5d
5e
6.0
6.4
6.5
7.1
480
120
30
100
99
velvetleaf (A. theophrasti, VEL)
common purslane (P. oleracea, CMP)
redroot amaranth (A. retroflexus, RDA)
dayflower (C. communis, DAY)
heartleaf cocklebur (X. strumarium, HLC)
95
480
120
30
100
100
95
480
120
30
100
95
a A equals 95À100% control, B equals 70À95%control, and C equals
below 70% control.
80
480
120
30
95
which showed higher herbicidal activities as compared to the
commercialized compound acifluorfen.
90
90
From the biological assay results in Table 3, compound 3c was
found to be the most active. A summary of results is outlined in
Figure 5 against velvetleaf. We first focused our attention on the
influence of substituent R3 to the herbicidal activity. Compounds
with methoxyethyl group (3c) exhibited higher herbicidal activ-
ity than that with methyl (3a) and ethyl (3b), while the
compounds with t-butyl (3d) and allyl (3e) groups were less
active. The structureÀactivity relationships for the substituents
R1 and R2 were also investigated. Elongation of the alkyl group at
R1 reduced the activity. Compounds with hydrogen atom at R2
gave a better herbicidal activity than methyl group. Replacement
of the nitro group (3b) by chlorine atom (3j) caused a slight
increase in activity.
5f
6.3
6.5
2000
1000
1000
200
40
100
80
5g
100
100
90
5h
6.7
4.9
1000
200
40
85
45
15
90
50
10
100
100
98
acifluorfen
1000
200
40
100
95
0
55
Table 6 shows herbicidal activities of compounds, and a
summary of results is outlined in Figure 6 against velvetleaf.
These data showed that efficacy was strongly influenced by the
weeds than grass in postemergent application. Some compounds
showed good herbicidal activities such as compounds 5b and 5c,
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Journal of Agricultural and Food Chemistry
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Table 12. Herbicidal Activities in Field Tests of 5ba
compd dosage (g/hm2) BYG CRB HLC VEL DAY soybean wheat
5b
25
100
100
400
0
55
25
80
5
60
10
40
98 100
80 85
65
35
95
60
5
10
5
10
25
0
acifluorfen
55 100 100 100
10
15
a 0 equals no activity; 100 equals total control. BYG, barnyard
(E. crusgalli); CRB, crabgrass (D. sanguinalis); HLC, heartleaf cocklebur
(X. strumarium); VEL, velvetleaf (A. thophrasti); and DAY, dayflower
(C. communis).
Figure 5. StructureÀactivity relationships for 3-benzoxy acrylate deri-
vatives 3 against velvetleaf.
Table 13. Acute Toxicity
acute toxicity test
species
rat
results
oral LD50 (mg kgÀ1
)
2330 (male)
2330 (female)
>2150 (male)
>2150 (female)
nonirritating
dermal
rat
skin irritation
eye irritation
skin sensitization
Ames
rabbit
rabbit
minimally irritating
nonsensitizing
negative
guinea pig
Figure 6. StructureÀactivity relationships for 2-(benzoxy) alkyl acry-
late derivatives 4 against velvetleaf.
(5b) and propyl group (5c) exhibited higher herbicidal activities
than those with isopryl (5d) and methyl (5a) groups. Introduc-
tion of an allyl group (5f) caused a significant decrease in the
activity. Replacement of the nitro group (5b) by chlorine atom
gave 5h, which was as active as 5b.
Lipophilicity as Clog P was predicted by ChemBioDraw 11.0
as shown in Tables 3, 6, and 9. There are some extent correlations
between herbicidal activity and lipophilicity. The appropriate
lipophilicity is essential for the herbicidal activity; the Clog P of title
compounds with potent herbicidal activity was between 5.8 and 6.1.
If the Clog P is too small or too big, the efficiency is lower.
Deeply Studies of Compound 5b. Compound 5b was the
most interesting compound in our primary screening. It was
further evaluted for inhibitory activity against PPO, herbicidal
spectrum, crop selectivity, field performance, and acute toxicity.
Inhibitory activity against PPO results showed that compound
5b exhibited stronger inhibition than acifluorfen in vitro. The
pI50 values against PPO of compound 5b and acifluorfen were
6.64 and 4.51, respectively. Compound 5b's PPO inhibitory
activity correlated well with its herbicidal activities.
The herbicidal spectrum results showed that compound 5b
exhibited higher herbicidal activities against broadleaf weeds than
grass as shown in Table 10. Compound 5b showed good
herbicidal activities against velvetleaf, common purslane, and
redroot amaranth at 40 g/hm2. As shown in Table 11, compound
5b exhibits good herbicidal activity on broadleaf weeds with
selectivity for soybean, and the selectivity index for soybean is 3.2,
which is commensurate to acifluorfen (3.4).
Figure 7. StructureÀactivity relationships for 4-benzoxy-butenoate
derivatives 5 against velvetleaf.
Table 11. Crop Selectivity (Postemergence)
g/hm2
compd
LD90 for velvetleaf LD10 for soybean crop selectivity index
5b
acifluorfen
19.4
63.0
3.2
3.4
137.4
461.8
group R1, while the hydrogen atom (4a) is better than methyl
group (4d) for R1. Compounds with methyl and ethyl groups at
R2 exhibited an equal activity. Replacement of the nitro group
(4e) by chlorine atom (4d) caused an obvious increase in
activity.
From the biological assay results in Table 9, compounds 5b
and 5c exhibited higher herbicidal activities, while 5f was
obviously less active than 5b. A summary of results is outlined
in Figure 7 against velvetleaf. A compound with a hydrogen atom
(5a) on R1 shows a higher activity than that with a methyl group
(5h). The effect at R2 on the herbicidal activity was investigated
with the compounds 5aÀf. Compounds with an ethyl group
Compound 5b was primary field tested in soybeans and wheat.
As shown in Table 12, postemergence field application of 5b at
100 g/hm2 demonstrated good broadleaf weed control, with
soybean tolerance, but low selectivity to wheat. Compound 5b
showed good herbicidal activities against velvetleaf, common
purslane, and redroot amaranth at 100 g/hm2, while acifluorfen
achieving the same efficacy at 400 g/hm2. Soybean plants
eventually outgrew initial injury at 7 days after application.
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As shown in Table 13, the acute toxicity results show that
compound 5b's acute toxicity to mammals is low.
ones and N-phenyl-1H-pyrrol-2-ones as protoporphyrinogen oxidase
inhibitors. Bioorg. Med. Chem. 2010, 18, 7948–7956.
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structure-activity relationship for cyclic imide derivatives of protopor-
phyrinogen oxidase inhibitors: a study of quantum chemical descriptors
from density functional theory. J. Chem. Inf. Comput. Sci. 2004,
44, 2099–2105.
(14) Jiang, L. L.; Tan, Y.; Zhu, X. L.; Wang, Z. F.; Zuo, Y.; Xi, Z.; Yang,
G. F. Design, synthesis, and 3D-QSAR analysis of novel 1,3,4-oxadiazol-
2(3H)-ones as protoporphyrinogen oxidase inhibitors. J. Agric. Food Chem.
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(15) Jiang, L. L.; Zuo, Y.; Wang, Z. F.; Tan, Y.; Wu, Q. Y.; Xi, Z.;
Yang, G. F. Design and syntheses of novel N-(benzothiazol-5-yl)-
4,5,6,7-tetrahydro-1H-isoindole- 1,3(2H)-dione and N-(benzothiazol-
5-yl)isoindoline-1,3-dione as potent protoporphyrinogen oxidase inhi-
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(16) Hao, G. F.; Tian, Y.; Yu, N. X.; Yang, G. F. StructureÀactivity
relationships of diphenyl-ether as protoporphyrinogen oxidase inhibi-
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Des. 2011, 25, 213–222.
In conclusion, a series of novel DPE derivatives were designed
and synthesized containing unsaturated carboxylates, and some
title compounds exhibited good herbicidal activities against
velvetleaf. Among unsaturated carboxylates group, butenate is
the most promising one. Compound 5b was identified as the
most promising candidate due to its high PPO inhibition effect
(pI50 = 6.64) and good herbicidal activity against broadleaf weeds
with selectivity for soybean and low toxicity to mammals and thus
is worth further study.
’ AUTHOR INFORMATION
Corresponding Author
*Tel: +86-24-85869218. Fax: +86-24-85869137. E-mail: libin1@
sinochem.com.
Funding Sources
(17) Hao, G. F.; Zhu, X. L.; Ji, F. Q.; Zhang, L.; Yang, G. F.; Zhan,
C. G. Understanding the mechanism of grug resistance due to a codon
deletion in protoporphyrinogen oxidase through computational model-
ing. J. Phys. Chem. 2009, 113, 4865–4875.
(18) Li, B.; Xu, J. D.; Xu, L. H.; Zhang, Z. J. Herbicides of benzoyloxy
unsaturated carboxylate type. C.N. Patent 1325624, 2001.
(19) Lee, H.; Duke, M. V.; Duke, S. O. Cellular localization of
protoporphyrinogen-oxidizing activities of etiolated barley (Hordeum
Vulgare L.) leaves. Plant Physiol. 1993, 102, 881–889.
This work was financially supported by the Key Projects in the
National Science & Technology Pillar Program during the 12th
Five-Year Plan Period (Grant No. 2011BAE06B03-03) and
National Key Basic Research Program (973 Program) (Grant
No. 2010CB735601).
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