Synthesis and biological activity of 4-(4,6-Disubstitutedpyrimidin-2-yloxy) phenoxy acetates

Article abstract of DOI:10.3390/molecules15021074

Ten novel 4-(4,6-dimethoxypyrimidin-2-yloxy)phenoxy acetates and 4-(4,6-dimethylpyrimidin-2-yloxy)phenoxy acetates were synthesized with hydroquinone, 2-methylsulfonyl-4,6-disubstituted-pyrimidine and chloroacetic ester as starting materials. The products

Full text of DOI:10.3390/molecules15021074

Molecules 2010, 15, 1074-1081; doi:10.3390/molecules15021074
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Biological activity of 4-(4,6-Disubstituted-
pyrimidin-2-yloxy)phenoxy Acetates
Lin Jiang 1,*, Hao Wang 1, Maorong Wang 1 and Xinhuan Teng 2
1
College of Chemistry and Material Science, Shandong Agricultural University, Taian 271018,
China; E-Mails: hw@sdau.edu.cn (H.W.), maorongwang@163.com (M.R.W.)
2
College of Plant Protection, Shandong Agricultural University, Taian 271018, China;
E-Mail: tengxinhuan_0505@163.com (X.H.T.)
* Author to whom correspondence should be addressed; E-mail: jiangl@sdau.edu.cn
Received: 14 January 2010; in revised form: 1 February 2010 / Accepted: 20 February 2010 /
Published: 23 February 2010
Abstract: Ten novel 4-(4,6-dimethoxypyrimidin-2-yloxy)phenoxy acetates and
4-(4,6-dimethylpyrimidin-2-yloxy)phenoxy acetates were synthesized with hydroquinone,
2-methylsulfonyl-4,6-disubstituted-pyrimidine and chloroacetic ester as starting materials.
1
The products were characterized by IR, H-NMR, MS spectra and elemental analyses.
Preliminary bioassay indicates that the target compounds possess high herbicidal activity
against monocotyledonous plants such as Digitaria sanguinalis L. at concentrations of
100 mg/L and 50 mg/L.
Keywords: pyrimidine; phenoxyacetate; synthesis; herbicidal activity
1. Introduction
Aryloxy-phenoxy propionates are an important class of herbicides due to their high efficiency,
broad spectrum, low toxicity and good selectivity. They act by blocking the biosynthesis of fatty acids
by inhibiting acetyl-coenzyme A carboxylase [1–3]. Since the first herbicide of this series, diclofop-
methyl, was synthesized in 1972, more than twenty aryloxy-phenoxy propionate herbicides such as
fluazifop-butyl, heloxyfop-methyl, quizalofop-ethyl and cyhalofop-butyl have been developed [4], and
are widely used to control gramineous weeds. In addition, some aryloxy-phenoxy acetates exhibit good
herbicidal activity. For example, two substituted pyrazolo[3,4-d] pyrimidin-4-yloxy phenoxy acetates

Molecules 2010, 15
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display considerable activities [5], with 100% inhibition against the root growth of Brassica napus L.
at a concentration of 100 mg/L, and 98.1% and 100% against the root growth of Echinochloa crusgalli
L. at the same concentration, respectively.
On the other hand, a lot of compounds containing 4,6-dimethoxypyrimidin-2-yl or
4,6-dimethylpyrimidin-2-yl moieties display excellent herbicidal activity. Most sulfonylurea
herbicides and all pyrimidinylbenzoate herbicides (two series of super-efficient herbicides) [6–10],
such as nicofulfuron, amidosulfuron, halopyrazosulfuron, ethoxysulfuron, pyriminobac-methyl and
pyriftalid, possess 4,6-dimethoxypyrimidin-2-yl groups, while sulfometuron-methyl, a kind of
sulfonylurea, contains a 4,6-dimethylpyrimidin-2-yl group, which suggests that the two disubstituted-
pyrimidin-2-yl groups possess high biological activity [11]. In order to seek efficient herbicidal
compounds, herein we introduced 4,6-dimethoxypyrimidin-2-yl or 4,6-dimethylpyrimidin-2-yl into
aryloxy-phenoxy acetates by the sub-structure link route, synthesizing ten novel 4-(4,6-
dimethoxypyrimidin-2-yloxy)phenoxy acetates and 4-(4,6-dimethylpyrimidin-2-yloxy)phenoxy
acetates.
2. Results and Discussion
2.1. Synthesis
There are two pathways (route A and route B, Scheme 1) in the synthesis of aryloxy-phenoxy
propionate herbicides [12]. In route A, hydroquinone reacts with 2-chloropropionates to yield 4-
hydroxyphenoxy propionates which react with aryl chlorides to give the target compounds. In route B,
hydroquinone firstly reacts with an aryl chloride to give a 4-hydroxyphenyl aryl ether which reacts
with 2-chloropropionates to give the target compound.
Scheme 1. Synthetic pathways of aryloxy-phenoxy propionates.
CH3
CH3
Ar Cl
OH
Cl CHCOOR
O
CHCOOR
HO
HO
A.
+
CH3
O
CHCOOR
Ar
O
CH3
Cl CHCOOR
Ar Cl
B.
Ar
O
OH
+ HO
OH
Considering the lower yield of 4-hydroxyphenoxy propionate in the reaction of hydroquinone with
2-chloropropionate in route A, we choose route B as the synthetic strategy in our work. Moreover, we
used 2-methylsulfonyl-4,6-disubstitutedpyrimidines instead of 2-chloro-4,6-disubstitutedpyrimidines
to produce 2-(4-hydroxyphenoxy)-4,6-disubstitutedpyrimidines 2a, 2b owing to their higher activity [13].
The reaction of hydroquinone with 2-methylsulfonyl-4,6-dimethoxylpyrimidine in tetrahydrofuran or
N,N-dimethylformamide at 70–80 ºC [14] gives 2a in very low yield and low purity. Hence, depending
on the preparation method of 2-(4-hydroxyphenoxy)-6-chlorobenzoxazole [15], we used sodium

Molecules 2010, 15
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hydroxide as a base, and benzyltriethylammonium chloride as a phase transfer catalyst, thus, refluxing
the hydroquinone with 2-methylsulfonyl-4,6-dimethoxylpyrimidine for 3.5 h with stirring in a mixed
solvent of toluene and water affords compound 2a with a satisfactory yield. The reaction of 2a (or 2b)
with the appropriate chloroacetates in acetonitrile in the presence of potassium carbonate gives
compounds 3a–3j (Scheme 2).
Scheme 2. Synthetic route of target compounds 3a–3j.
R1
R1
R1
N
N
N
N
NaOH
O
OH
SO2CH3
OH
HO
+
R1
1a, 1b
2a, 2b
R1
N
N
ClCH2COOR2
K2CO3
O
OCH2COOR2
R1
R1
3a - 3j
3
R2
3
f
R1
R2
a
b
c
OCH3 CH3
CH3 CH3
1a, 2a: R1 = OCH3
1b, 2b: R1 = CH3
OCH3 CH2CH3
g
CH3 CH2CH3
OCH3 CH2CH2CH3
h
i
CH3
CH3
CH2CH2CH3
CH(CH3)2
d
e
OCH3 CH(CH3)2
OCH3 CH2(CH2)2CH3
j
CH3 CH2(CH2)2CH3
Both spectral and elemental analyses data of the prepared compounds 3a–3j were all in agreement
with the suggested molecular structures (see Experimental). Their IR spectra exhibited absorption
bands assignable to C=O stretching vibrations and characteristic bands near υ 1208–1193 cm−1and
1
1084–1062 cm−1, corresponding to the C-O-C linkages. In addition, the H-NMR spectra of 3a–3j
showed characteristic singlet signals at δ 4.59–4.64, 3.82–3.83, and 2.39 ppm, assignable to the
methylene, methoxy and methyl protons, respectively, and singlet signals at δ 5.76 ppm or at δ 6.74–
6.75 ppm corresponding to the dimethoxy- or dimethylpyrimidine ring protons (5-H), in addition to the
expected aromatic protons appear as double doublet signals at 6.91–6.93 and 7.12–7.14 ppm, respectively.
2.2. Biological Activity
The herbicidal activities are summarized in Table 1. In all tested compounds, the rates of inhibition
of Brassica napus L. root growth are 15.9%–58.4%, 13.1%–36.4% and 9.2%–22.9% at concentrations
of 100 mg/L, 50 mg/L and 10 mg/L, respectively, which means that the synthesized compounds
display low herbicidal activities against this plant. However, the rates of inhibition of Digitaria
sanguinalis L. root growth are all 100% at a concentration of 100 mg/L, 95.2%–98.5% at 50 mg/L,
and 32.5%–44.7% at 10 mg/L. The results demonstrate that the target compounds exhibit excellent
herbicidal activities against this kind of weed at 100 mg/L and 50 mg/L, but their activities are not
satisfactory at a lower concentration (10 mg/L).

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Table 1. Herbicidal activities of compounds 3a–3j.
Inhibitory rate (%)
Compd.
Brassica napus L.
Echinochloa crusgalli L.
100 mg/L
50 mg/L
34.4
31.0
13.1
21.0
13.4
26.7
32.7
33.9
14.3
34.2
39.2
10 mg/L 100 mg/L 50 mg/L
10 mg/L
42.8
39.9
32.5
32.7
41.8
44.7
38.5
36.9
35.0
42.6
63.5
3a
39.8
41.1
15.9
25.1
28.3
44.7
58.4
54.5
26.4
50.2
51.2
22.9
13.4
10.1
14.6
9.5
100
100
100
100
100
100
100
100
100
100
100
98.5
96.2
95.2
96.5
96.9
97.3
98.4
97.5
95.1
97.6
95.3
3b
3c
3d
3e
3f
11.9
14.2
12.1
9.2
3g
3h
3i
3j
21.5
33.8
quizalofop-P-ethyl
3. Experimental
3.1. General
Melting points were measured on an X-5 microscopic melting-point apparatus and uncorrected. IR
1
spectra were recorded in KBr pellets on a Shimadzu IR-440 infrared spectrophotometer. H-NMR
spectra were registered on an Inova-600 spectrometer (in CDCl3 solvent, TMS as internal standard).
Mass spectra were recorded on an Agilent 1100 LC-MS spectrometer (APCI source). Elemental
analyses were performed with a Vario EL III Elemental Analyzer.
3.2. General method for the synthesis of 2-(4-hydroxyphenoxy)-4,6-disubstitutedpyrimidines 2a, 2b
To a solution of sodium hydroxide (1.20 g, 30.0 mmol) and benzyltriethylammonium chloride
(0.10 g, 0.4 mmol) in water (15 mL) were added hydroquinone (2.98 g, 27.0 mmol) and toluene (7
mL). The resulting mixture was heated to 60 ºC while stirring under nitrogen, then 2-methylsulfonyl-
4,6-disubstitutedpyrimidine 1a or 1b (18.0 mmol) in dichloromethane (8 mL) was added dropwise in 1
h. The reaction mixture was further refluxed with stirring for 3 h, then toluene and dichloromethane
were evaporated in a rotary evaporator. Sodium hydroxide (5%, 30 mL) was added to the residue, and
extracted with ethyl acetate (10 mL × 2). The aqueous layer was acidified with concentrated
hydrochloric acid to pH4–5. The precipitated solid was filtered off, washed with water, dried and
crystallized from a mixed solvent of ethanol and water (V:V = 1:2) to give 2a, 2b respectively.
2-(4-Hydroxyphenoxy)-4,6-dimethoxypyrimidine (2a): Yield: 86.5%; m.p. 120.1-121.8 ºC; 1H-NMR δ:
3.84 (s, 6H, CH3), 5.76 (s, 1H, Pyrim-H), 5.79 (s, 1H, OH), 6.82 (d, 2H, J = 8.4 Hz, Ph-H), 7.03 (d, 2H, J
= 8.4 Hz, Ph-H) ppm; IR (KBr): 3453, 1620, 1573, 1513, 1454, 812 cm−1; MS (APCI) m/z: 249.9 (M +
2H)+; Anal. for C12H12N2O4 (%): C 58.06, H 4.87, N 11.28; found C 58.31, H 4.74,
N 11.41.

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1
2-(4-Hydroxyphenoxy)-4,6-dimethylpyrimidine (2b): Yield: 90.6%, m.p. 195.8-197.2 ºC; H-NMR δ:
2.41 (s, 6H, CH3), 6.76 (s, 1H, Pyrim-H), 6.78 (d, 2H, J = 8.4 Hz, Ph-H), 6.98 (d, 2H,
J = 8.4 Hz, Ph-H), 7.45 (s, 1H, OH) ppm; IR (KBr): 3448, 1637, 1560, 1509, 1458, 820 cm−1; MS
(APCI) m/z: 218.0 (M + 2H)+; Anal. for C12H12N2O2 (%): C 66.65, H 6.66, N 12.95; found C 66.69, H
6.21, N 12.91.
3.3. General method for the preparation of 4-(4,6-disubstitutedpyrimidin-2-yloxy)phenoxy acetates
3a–3j
To a mixture of 2-(4-hydroxyphenoxy)-4,6-disubstitutedpyrimidine 2a or 2b (5.0 mmol) and
anhydrous potassium carbonate (0.97 g, 7.0 mmol) in acetonitrile (10 mL), was added the appropriate
chloroacetic ester (6.0 mmol) while stirring. The reaction mixture was refluxed with stirring for 7 h.
The solvent was removed in a rotary evaporator, then, the residue was poured into ice-water (20 mL),
and leave aside for 1 h to solidify. The solid so formed was filtered off, washed with ice-water, dried
and crystallized from a mixed solvent of petroleum ether and ethyl acetate (V: V = 5:1–2) to afford 3a–3j.
Methyl 4-( 4,6-dimethoxypyrimidin-2-yloxy)phenoxy acetate (3a): Yield: 81.2%; m.p. 77.5–79.0 ºC;
1H-NMR δ: 3.82 (s, 3H, COOCH3), 3.83 (s, 6H, Pyrim-OCH3), 4.64 (s, 2H, OCH2), 5.76 (s, 1H,
Pyrim-H), 6.92 (d, 2H, J = 9.0 Hz, Ph-H), 7.14 (d, 2H, J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1754, 1205,
1083, 820 cm−1; MS (APCI) m/z: 321.9 (M + 2H)+; Anal. for C15H16N2O6 (%): C 56.25, H 5.04, N
8.74; found C 56.51, H 4.99, N 8.79.
Ethyl 4-(4,6-dimethoxypyrimidin- 2-yloxy)phenoxy acetate (3b): Yield: 78.5%; m.p. 75.2–76.1 ºC;
1H-NMR δ: 1.30 (t, 3H, J = 7.2 Hz, CH2-CH3), 3.83 (s, 6H, Pyrim-OCH3), 4.28 (q, 2H,
J = 7.2 Hz, COOCH2), 4.62 (s, 2H, OCH2), 5.76 (s, 1H, Pyrim-H), 6.92 (d, 2H, J = 9.0 Hz, Ph-H), 7.14
(d, 2H, J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1758, 1205, 1068, 825 cm−1; MS (APCI) m/z: 335.9 (M +
2H)+; Anal. for C16H18N2O6 (%): C 57.48, H 5.43, N 8.38; found C 57.75, H 5.35, N 8.25.
Propyl 4-(4,6-dimeth oxypyrimidin-2-yloxy)phenoxy aceta te (3c): Yield: 75.6%; m.p. 82.8–84.3 ºC;
1H-NMR δ: 0.93 (t, 3H, J = 7.2 Hz, CH2-CH3), 1.69 (m, 2H, CH2-CH3), 3.83 (s, 6H, Pyrim-OCH3),
4.18 (t, J = 6.6 Hz, 2H, COOCH2), 4.63 (s, 2H, OCH2), 5.76 (s, 1H, Pyrim-H), 6.92 (d, 2H, J = 9.0 Hz,
Ph-H), 7.14 (d, 2H, J = 9.0 Hz, Ph-H) ppm; IR (KBr) 1759, 1206, 1066, 829 cm−1; MS (APCI) m/z:
350.0 (M + 2H)+; Anal. for C17H20N2O6 (%): C 58.61, H 5.79, N 8.04; found C 58.71,
H 5.72, N 8.05.
Isopropyl 4-(4,6-dimethoxypyrimidin-2-yloxy)phenoxy acetate (3d): Yield: 80.9%; m.p. 79.8–81.5 ºC;
1H-NMR δ: 1.28 (d, 6H, J = 6.6 Hz, CH-(CH3)2), 3.82 (s, 6H, Pyrim-OCH3), 4.59 (s, 2H, OCH2), 5.15
(m, 1H, COOCH), 5.76 (s, 1H, Pyrim-H), 6.91 (d, 2H, J = 9.0 Hz, Ph-H), 7.12 (d, 2H,
J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1760, 1213, 1062, 815 cm−1; MS (APCI) m/z: 349.9 (M + 2H)+;
Anal. for C17H20N2O6 (%): C 58.61, H 5.79, N 8.04; found C 58.65, H 5.71, N 8.02.
Butyl 4-( 4,6-dimethoxypyrimidin-2-yloxy)phenoxy acetate (3e): Yield: 71.3%; m.p. 70.1–71.3 ºC;
1H-NMR δ: 0.93 (t, 3H, J = 7.2 Hz, CH2-CH3), 1.36 (m, 2H, CH2-CH3), 1.64 (m, 2H,
CH2–C2H5), 3.83 (s, 6H, Pyrim-OCH3), 4.22 (t, 2H, J = 6.6 Hz, COOCH2), 4.63 (s, 2H, OCH2), 5.76 (s,

Molecules 2010, 15
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1H, Pyrim-H), 6.91 (d, 2H, J = 9.0 Hz, Ph-H), 7.14 (d, 2H, J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1763,
1208, 1082, 809 cm−1; MS (APCI) m/z: 363.9 (M + 2H)+; Anal. for C18H22N2O6 (%): C 59.66, H 6.12,
N 7.73; found C 59.49, H 6.08, N 7.77.
Methyl 4-(4,6- dimethylpyrimidin-2-yloxy)phenoxy acetate (3f): Yield: 80.1%; m.p. 114.5–116.0 ºC;
1H-NMR δ: 2.39 (s, 6H, Pyrim-CH3), 3.82 (s, 3H, COOCH3), 4.64 (s, 2H, OCH2), 6.75 (s, 1H, Pyrim-
H), 6.92 (d, 2H, J = 9.0 Hz, Ph-H), 7.13 (d, 2H, J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1753, 1200, 1082,
833 cm−1. MS (APCI) m/z: 289.9 (M + 2H)+; Anal. for C15H16N2O4 (%): C 62.53, H 5.59, N 9.71;
found C 62.86, H 5.55, N 9.70.
Ethyl 4-(4,6-dimethylpyrimid in-2-yloxy)phenoxy acetate (3g): Yield: 77.2%; m.p. 90.2–92.1 ºC;
1H-NMR δ: 1.31 (t, 3H, J = 7.2 Hz, CH2-CH3), 2.39 (s, 6H, Pyrim-CH3), 4.28 (q, 2H,
J = 7.2 Hz, COOCH2), 4.62 (s, 2H, OCH2), 6.74 (s, 1H, Pyrim-H), 6.92(d, 2H, J = 9.0 Hz, Ph-H),
7.13(d, 2H, J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1758, 1197, 1078, 845 cm−1; MS (APCI) m/z: 303.9 (M
+ 2H)+; Anal. for C16H18N2O4 (%): C 63.62, H 6.01, N 9.26; found C 64.03, H 5.98, N 9.33.
Propyl 4-( 4,6-dimethylpyrimidin-2-yloxy)phenoxy acetate (3h): Yield: 75.0%; m.p. 95.4–97.3 ºC;
1H-NMR δ: 0.93 (t, 3H, J = 7.2 Hz, CH2-CH3), 1.69 (m, 2H, CH2-CH3), 2.39 (s, 6H, Pyrim-CH3); 4.18
(t, J = 6.6 Hz, 2H, COOCH2), 4.64 (s, 2H, OCH2), 6.74 (s, 1H, Pyrim-H), 6.93 (d, 2H, J = 9.0 Hz, Ph-
H), 7.13(d, 2H, J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1760, 1198, 1078, 849 cm−1; MS (APCI) m/z: 317.9
(M + 2H)+; Anal. for C17H20N2O4 (%): C 64.54, H 6.37, N 8.85; found C 64.84, H 6.28, N 8.76.
Isopropyl 4-(4,6-dimethylpyrim idin-2-yloxy)phenoxy acetate (3i): Yield: 80.9%; m.p. 90.5–92.2 ºC;
1H-NMR δ: 1.28 (d, 6H, J = 6.6 Hz, CH-(CH3)2), 2.39 (s, 6H, Pyrim-CH3), 4.59 (s, 2H, OCH2), 5.15
(m, 1H, COOCH), 6.74 (s, 1H, Pyrim-H), 6.92 (d, 2H, J = 9.0 Hz, Ph-H), 7.12 (d, 2H,
J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1721, 1204, 1073, 854 cm−1; MS (APCI) m/z: 317.9 (M + 2H)+;
Anal. for C17H20N2O4 (%): C 64.54, H 6.37, N 8.85; found C 64.76, H 6.29, N 8.68.
Butyl 4-( 4,6-dimethylpyrimidin-2-yloxy)phenoxy acetate (3j): Yield: 71.3%; m.p. 34.2–36.0 ºC;
1H-NMR δ: 0.92 (t, 3H, J = 7.2 Hz, CH2-CH3), 1.37 (m, 2H, CH2-CH3), 1.65 (m, 2H,
CH2–C2H5), 2.39 (s, 6H, Pyrim-CH3), 4.22 (t, 2H, J = 6.6 Hz, COOCH2), 4.63 (s, 2H, OCH2), 6.74 (s,
1H, Pyrim-H), 6.92 (d, 2H, J = 9.0 Hz, Ph-H), 7.13(d, 2H, J = 9.0 Hz, Ph-H) ppm; IR (KBr): 1752,
1193, 1084, 830 cm−1. MS (APCI) m/z: 331.9 (M + 2H)+; Anal. for C18H22N2O4 (%): C 65.44, H 6.71,
N 8.48; found C 65.14, H 6.74, N 8.21.
3.4. Biological activity
The herbicidal activities of the target compounds were determined using Brassica napus L. and
Digitaria sanguinalis L. as samples of dicotyledonous and monocotyledonous plants, respectively [16,17].
Emulsions of the tested compounds were prepared by dissolving them in
N,N-dimethylformamide (100 μL) with the addition of Tween 20 (2 μL), and then diluting with
distilled water. The germinated seeds were placed on two filter papers in a 9-cm Petri plate, to which 5
mL of tested solution was added in advance. Usually, 15 seeds were used on each plate. The plates

Molecules 2010, 15
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were placed in a dark room and allowed to germinate for 65 h at 28 (±1) ºC. The lengths of 10 seed
roots selected from each plate were measured and the means were calculated. Moreover, quizalofop-P-
ethyl, a commercial aryloxy-phenoxy propionate herbicide and the emulsion which does not contain
tested compounds were used as control and blank respectively. For all of the bioassay tests, each
treatment was repeated three times. The inhibitory rate was calculated relative to the blank. The
bioassay results are shown in Table 1.
4. Conclusions
A new method of preparing 2-(4-hydroxyphenyloxy)-4,6-disustitutedpyrimidine has been
developed with the advantages of a shorter reaction time, fewer side-products and higher yields. Ten
novel 4-(4,6-dimethoxypyrimidin-2-yloxy)phenoxy acetate and 4-(4,6-dimethylpyrimidin-2-
1
yloxy)phenoxy acetate compounds have been synthesized, and characterized by IR, H-NMR, MS
spectra and elemental analyses. Preliminary bioassay indicates that the target compounds exhibit high
herbicidal activity against monocotyledonous plant such as Digitaria sanguinalis L. at concentrations
of 100 mg/L and 50 mg/L.
Acknowledgements
The authors are grateful to Prof. Wang Jin-Xin of Shandong Agricultural University for the
herbicidal activity tests.
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Sample Availability: Samples of the target compounds are available from the authors.
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