Synthesis and herbicidal evaluation of novel 3-[(α-hydroxy- substituted)benzylidene]pyrrolidine-2,4-diones

Article abstract of DOI:10.1021/jf051510l

A series of 3-[(α-hydroxy-substituted) benzylidene]pyrrolidine-2,4- dione derivatives were synthesized as candidate herbicides by reacting different aroyl acetates with N-substituted glycine esters. The new compounds were identified by ¹H NMR spectroscopy and elemental analyses. Their herbicidal activities were evaluated. Some compounds exhibited excellent herbicidal activities at a dose of 187.5 g/ha. A suitable electron-donating substituent at the 2- and/or 4-position of the phenyl ring was essential for high herbicidal activity, a result that has not been reported before. It was also found that the title compound's structure-activity relationships were different from those of other similar kinds of earlier compounds, a result that may depend on the enol structure difference.

Full text of DOI:10.1021/jf051510l

9566 J. Agric. Food Chem. 2005, 53, 9566−9570
Synthesis and Herbicidal Evaluation of Novel
3-[(
r-Hydroxy-substituted)benzylidene]pyrrolidine-2,4-diones
YOUQUAN ZHU, XIAOMAO ZOU, FANGZHONG HU, CHANGSHENG YAO,
BIN LIU, AND HUAZHENG YANG*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
A series of 3-[(R-hydroxy-substituted) benzylidene]pyrrolidine-2,4-dione derivatives were synthesized
as candidate herbicides by reacting different aroyl acetates with N-substituted glycine esters. The
1
new compounds were identified by H NMR spectroscopy and elemental analyses. Their herbicidal
activities were evaluated. Some compounds exhibited excellent herbicidal activities at a dose of 187.5
g/ha. A suitable electron-donating substituent at the 2- and/or 4-position of the phenyl ring was essential
for high herbicidal activity, a result that has not been reported before. It was also found that the title
compound’s structure-activity relationships were different from those of other similar kinds of earlier
compounds, a result that may depend on the enol structure difference.
KEYWORDS: Herbicide; aroyl acetate; HPPD; electron-donating group; structure-activity relationship
(SAR)
INTRODUCTION
The inhibitors of 4-hydroxyphenylpyruvate dioxygenase
(HPPD, EC 1.13.11.27) constitute a new kind of herbicide (1).
Generally, potent herbicides of this kind must possess the
following structural features: (1) a di- or tricarbonyl methane
structure, with one of the carbonyl groups being a substituted
benzoyl group; (2) the compound must be able to enolize so
that the enolate is capable of inhibiting the HPPD enzyme by
competitive combination with Fe2+sthe reaction center of the
HPPD enzyme; (3) electron-withdrawing groups are preferred
at both the 2- and 4-positions of the phenyl ring (2-4). In our
previous work (5, 6), the natural product A (Figure 1), which
was inhibitory toward HPPD with an IC50 ) 18 µM (7), was
modified to B (Figure 1) by the replacement of acetyl with
substituted benzoyl, and the bioassay results showed that when
R1 was electron-donating, compound B possessed higher
herbicidal activities and made the monocotyledonous plants
Echinochloa crus-galli and Digitaria sanguinalis bleached. The
analysis of their crystals confirmed that their molecular struc-
tures adopted the enol form B1 (Figure 1) and their molecular
skeletons contained one enol hydrogen-bonded moiety, formed
from benzoyl CdO isomerization (8, 9). On the basis of the
action mode of the HPPD inhibitors, the above phenomena
revealed that an electron-donating group may not only be
favorable to the formation of the enol tautomer B1 but also
reinforce its combination with Fe2+sthe reaction center of
HPPDsthrough raising the enol-oxygen’s electron density. In
the meantime, it was also found that when R1 at the phenyl
ring was electron-donating and R2 at the nitrogen atom was
Figure 1. Chemical structures of A, B, and B1.
isopropyl, tert-butyl, or methyl, respectively, the N-isopropyl
compound’s herbicidal activity was the highest. To further
amplify the structure-activity relationship (SAR) between R1
of B1 and the resulting activity and to find valuable lead
compounds with high herbicidal activity, subsequent optimiza-
tion of B1 was focused on varying the electron-donating
capability of the substituent R1 while retaining the pyrrolidin-
2,4-dione heterocycle. In this paper, we described the synthesis
and herbicidal activities of some 3-[(R-hydroxy-substituted)-
benzylidene]pyrrolidine-2,4-dione derivatives.
MATERIALS AND METHODS
Synthetic Procedures. Proton NMR spectra were obtained at 300
MHz using a Bruker AC-P300 spectrometer in CDCl3 solution with
TMS as internal standard. Chemical shift values (δ) were given in parts
per million. Elemental analyses were determined on a Yanaca CHN
Corder MT-3 elemental analyzer. Melting points were taken on a
Thomas-Hoover melting-point apparatus and were uncorrected. Yields
were not optimized.
General Synthetic Procedure for D1-15 and E1-3. Solvents were
dried according to standard methods and distilled prior to use.
Compounds D1-15 were synthesized as the literature described (5,
6). Compounds E1-3 were synthesized as the literature described (5,
6, 10). All of them were identified by 1H NMR spectroscopy. The yields
of compounds D1-15 are listed in Table 1.
* Author to whom correspondence should be addressed [telephone +86-
(0)22-23503799; fax +86-22-23503627; e-mail nk_yanghz@126.com].
10.1021/jf051510l CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/29/2005

3-[(
R
-Hydroxy-substituted)benzylidene]pyrrolidine-2,4-diones
19
compd
J. Agric. Food Chem., Vol. 53, No. 24, 2005 9567
Table 1. Yields of Compounds D1
−
Table 2. Melting Points, Yields, and Elemental Analysis of Compounds
F1−36
compd
appearance
yield (%)
appearance
yield (%)
elemental analysis (%, calcd)
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
orange liquid
orange liquid
orange liquid
orange liquid
orange liquid
orange liquid
orange liquid
orange liquid
orange liquid
orange liquid
50
58
40
68
64.9
51
43
40
49
53
D11
D12
D13
D14
D15
D16
D17
D18
D19
orange liquid
orange liquid
orange liquid
white solid
orange liquid
orange liquid
orange liquid
orange liquid
orange liquid
30
43
43
45
66
82
87
89
82
yield
(%)
compd
mp (
°
C)
C
H
N
F1
F5
F6
F7
F8
F9
−4
see ref 6
146
178
134
147
141
−147
−179
−135
−149
−142
59.5
57.8
53
66.32 (66.42)
62.75 (62.94)
70.33 (70.31)
71.06 (71.05)
71.77 (71.73)
70.35 (70.31)
61.88 (61.88)
60.22 (60.11)
71.06 (71.05)
72.15 (72.35)
62.90 (62.94)
71.31 (71.20)
61.80 (61.88)
61.88 (61.88)
61.82 (61.88)
6.58 (6.62)
6.23 (6.27)
6.95 (7.01)
7.39 (7.37)
5.59 (5.67)
6.93 (7.01)
6.56 (6.63)
5.09 (5.04)
7.31 (7.37)
8.01 (7.99)
6.30 (6.27)
5.72 (5.68)
6.69 (6.63)
6.63 (6.63)
6.66 (6.63)
4.92 (4.84)
4.73 (4.59)
5.21 (5.12)
4.99 (4.77)
6.05 (6.06)
5.10 (5.12)
3.96 (4.01)
5.11 (5.01)
4.86 (4.87)
4.49 (4.44)
4.61 (4.59)
4.22 (4.15)
3.92 (4.01)
3.85 (4.01)
4.15 (4.01)
56.6
61.2
64.5
45.1
50.0
57.5
43.2
50.2
63.2
59.3
84.8
62.1
F10
F11
F12
F13
F14
F15
F16
F17
F18
F19
F20
F22
F23
F24
F25
F26
F27
F28
F29
F30
F31
F32
F33
F34
F35
F36
red liquid
97 98
orange liquid
−
General Synthetic Procedure for D16-19 (11). To a mixture of
NaH/oil dispersion (0.528 g, 50% NaH by weight, 0.264 g of NaH, 11
mmol), 12 mL of diethyl carbonate, and 15 mL of THF was added
dropwise a solution of 10 mmol of substituted acetophenone in THF.
The mixture was heated at reflux for 3 h. The reaction mixture was
poured into water, the pH was adjusted to 9, and the mixture was
extracted with methylene chloride. The solvent was removed, and the
residue was purified by flash silica gel chromatography using petroleum
ether (60-90 °C) and ethyl acetate as the eluent to yield D16-19. All
of the compounds were identified by 1H NMR spectroscopy. The yields
of compounds D16-19 are listed in Table 1.
General Synthetic Procedure for F1-36 (5, 6, 12). A mixture of
D (4.11 mmol) and E (4.30 mmol) in dry xylene (15 mL) was heated
at 125-130 °C with stirring for 20 h. The cooled solution was added
to methanolic CH3ONa, prepared from Na metal (0.10 g, 4.35 mmol)
and methanol (10 mL) at room temperature with stirring. After the
above mixture was stirred at room temperature for 48 h, water (30
mL) was added to the reaction mixture and the organic layer was
separated and extracted twice with water. The original water layer and
the extracts were combined and acidified to pH 2-3 with 2 N HCl
under cooling. The acidic solution was extracted three times with
chloroform (30 mL), and the extracts were washed with saturated brine
and then dried over Na2SO4. The solvent was removed under reduced
pressure to give crude product F, which was purified by flash column
chromatography on silica gel, using ethyl acetate-petroleum ether as
the eluant to afford the pure target product. The melting points, yields,
and elemental analyses of compounds F1-36 are listed in Table 2,
116
106
140
−117
−107
−141
orange liquid
orange liquid
orange liquid
orange liquid
see ref 6
−21
119−121
21
18
17
8.0
70.99 (71.01)
71.49 (71.73)
72.31 (72.35)
63.90 (63.93)
66.89 (66.88)
63.65 (63.36)
70.66 (70.83)
65.91 (65.92)
61.28 (61.25)
71.35 (71.56)
72.89 (72.82)
63.23 (63.36)
71.77 (71.63)
62.35 (62.24)
62.35 (62.24)
7.44 (7.37)
7.89 (7.69)
7.88 (7.99)
6.60 (6.63)
6.08 (5.96)
5.69 (5.65)
6.19 (6.32)
5.51 (5.53)
5.76 (5.74)
6.53 (6.71)
7.40 (7.40)
5.59 (5.65)
5.12 (5.11)
6.15 (6.09)
6.15 (6.09)
4.82 (4.87)
4.61 (4.65)
4.38 (4.44)
4.41 (4.39)
5.08 (4.88)
4.53 (4.62)
4.98 (5.16)
5.12 (5.13)
4.24 (4.20)
5.01 (4.91)
4.47 (4.47)
4.59 (4.65)
4.15 (4.18)
4.15 (4.09)
4.15 (4.09)
>141 decomp
135
174
161
152
−136
−176
−163
−154
61.6
58.9
70.9
61.0
96.8
57.9
52.7
66.5
63.5
87.5
68.2
84−86
133
123
112
−
−
−
135
124
113
96−97
brown liquid
orange liquid
orange liquid
orange liquid
calculated. The percentage inhibition was used to describe the control
efficiency of the compounds. The herbicidal activity is summarized in
Table 4.
Pre-emergence. Sandy clay (100 g) in a plastic box (11 × 7.5 × 6
cm) was wetted with water. Fifteen sprouting seeds of the weed under
test were planted in fine earth (0.6 cm depth) in the glasshouse and
sprayed with the test compound solution.
Postemergence. Seedlings (one leaf and one stem) of the weed were
sprayed with the test compounds at the same rate as used for the pre-
emergence test.
1
and their H NMR are listed in Table 3.
Bioassays. For comparative purposes, the herbicidal activities of the
title compounds (F1-36) and the triketone compound, sulcotrione [2-(2-
chloro-4-mesylbenzoyl)cyclohexane-1,3-dione], were evaluated using
a previously reported procedure (13).
Treatment. The emulsions of purified compounds were prepared by
dissolving them in 100 µL of N,N-dimethylformamide with the addition
of a little Tween 20 and proper water, and in glasshouse tests, it was
sprayed using a laboratory belt sprayer delivering a 750 L/ha spray
volume. There were two replicates for each treatment. The mixture of
the same amount of water, N,N-dimethylformamide, and Tween 20 was
used as control.
For both methods, the fresh weights were determined 15 days later,
and the percentage inhibition relative to the controls was calculated.
The herbicidal activity is summarized in Tables 5 and 6.
RESULTS AND DISCUSSION
Preparations. The synthesis of intermediate â-keto esters D
using two methods (5, 6, 11) has been reported (Schemes 1
and 2). Compounds D1-15 were synthesized by treating ethyl
acetoacetate with acid chloride followed by decomposition with
NH3‚H2O/NH4Cl. Because 2,4-dimethoxybenzoic acid and 2-/
3-/4-methoxyethoxymethoxybenzoic acid were not stable under
reflux with SOCl2 or reacted with (COCl)2 at room temperature
for the preparation of the corresponding benzoyl chloride of
D16-19, we adopted the reaction of substituted acetophenone
with diethyl carbonate in the presence of NaH.
Inhibition of the Root Growth of Rape (Brassica campestris L). Rape
seeds were soaked in distilled water for 4 h before being placed on a
filter paper in a 6-cm Petri plate, to which 2 mL of inhibitor solution
had been added in advance. Usually, 15 seeds were used on each plate.
The plate was placed in a dark room and allowed to germinate for 65
h at 28 ((1) °C. The lengths of 10 rape roots selected from each plate
were measured, and the means were calculated. The percentage
inhibition was used to describe the control efficiency of the compounds.
The herbicidal activity is summarized in Table 4.
Inhibition of the Seedling Growth of Barnyard Grass (Echinochloa
crus-galli L. BeauV). Ten E. crus-galli seeds were placed into a 50 mL
cup covered with a layer of glass beads and a piece of filter paper at
the bottom, to which 5 mL of inhibitor solution had been added in
advance. The cup was placed in a bright room, and the seeds were
allowed to germinate for 65 h at 28 ((1) °C. The heights of the above-
ground parts of the seedlings in each cup were measured and the means
Amino acid esters E1-3 were prepared conveniently from
2-bromoacetic acid ester and primary amines in dry ether
(Scheme 3) (10). E1 (R2 ) i-Pr ): yield, 40%; nd25 ) 1.4170.
E2 (R2 ) t-Bu ): yield, 65.4%; nd ) 1.4225. E3 (R2 )
25
cyclopropyl): yield, 87.4%; bp 94-96 °C/0.095 MPa; 1H NMR
3
δ 0.14-0.37 (m, 4H, CH2CH2), 1.05-1.23 (t, 3H, JHH ) 7

9568 J. Agric. Food Chem., Vol. 53, No. 24, 2005
Zhu et al.
Table 3. 1H NMR of Compounds F1
−36
compd
δ
F1
F5
−
4
see ref 6
1.21, 1.29 (d, 6H,3JHH
)
7 Hz, CH(CH3)2), 1.40
−
1.50 (t, 3H, 3JHH
)
7 Hz, CH2CH3), 3.72 (s, 2H, NCH2), 4.08
8.42 (d, 2H, 3JHH
8 Hz, Ph)
(OCH3)2), 4.35
4.70 (m, 1H, 3JHH
−
4.18
7 Hz, NCH),
7 Hz, NCH),
4.73
7 Hz, NCH),
(qd, 2H, 3JHH
)
7 Hz, CH2CH3), 6.91
1.19 (d, 6H,3JHH
7 Hz, CH2CH3), 3.66 (s, 2H, NCH2), 3.90 (s, 6H, Ar
6.79 6.97, 8.00 8.20 (m, 3H,Ph)
1.10 7 Hz, CH(CH3)2), 2.31 (s, 6H, Ar(CH3)2), 3.64 (s, 2H, NCH2), 4.37
1.27 (d, 6H, 3JHH
7.15 (s, 1H, Ph), 7.70 (s, 2H, Ph)
1.16 7 Hz, CH(CH3)2), 2.86
1.43 (m, 12H, 3JHH
(m, 1H, 3JHH 8.30 (m, 4H, 3JHH
7 Hz, NCH), 7.32 7.47, 8.08
1.13 7 Hz, CH(CH3)2), 1.28 (s, 9H, C(CH3)3), 3.65 (s, 2H, NCH2), 4.40
1.22 (d, 6H, 3JHH
7.34 8 Hz, Ph), 8.06 9 Hz, Ph)
7.49 (d, 2H, 3JHH 8.17 (d, 2H, 3JHH
1.10 7 Hz, CH(CH3)2), 2.29, 2.35 (s s, 6H, Ar(CH3)2), 3.61 (s, 2H, NCH2), 4.35
1.29 (d, 6H, 3JHH
(m, 1H, 3JHH
7 Hz, NCH), 6.92 7.28, 7.26 7.41 (m, 3H, Ph)
1.23
1.31 (d, 6H, 3JHH
7.87 (s, 2H, Ph)
1.27
1.29 (d, 6H, 3JHH
7.31
0.91
−
7.10 (d, 2H, 3JHH
)
9 Hz, Ph), 8.32
−
−
)
F6
F7
F8
F9
1.16−
)
−
)
−
−
−
)
− )
4.64 (m, 1H, 3JHH
−
)
−
3.13 (m, 1H, 3JHH
)
7 Hz, ArCH), 3.74 (s, 2H, NCH2), 4.44
−
)
−
−
) 9 Hz, Ph)
−
)
− )
4.62 (m, 1H, 3JHH
−
)
−
)
F10
F11
F12
F13
−
)
−
−4.62
)
−
−
−
)
)
7 Hz, CH(CH3)2), 3.74 (s, 2H, NCH2), 3.96 (s, 9H, Ar(OCH3)), 4.51
−
4.65 (m, 1H, 3JHH
)
7 Hz, NCH),
−
7 Hz, CH(CH3)2), 3.71 (s, 2H, NCH2), 4.01 (s, 9H, Ar(OCH3)), 4.50
−
4.74 (m, 1H, 3JHH
) 7 Hz, NCH),
−
7.62 (m, 4H, 3JHH
)
9 Hz, Ph)
7 Hz, CH2CH3), 1.22
8 Hz, CH2CH2CH3), 2.61
2.70 (t, 2H, 3JHH
7 Hz, NCH), 7.26 8 Hz, Ph), 8.13
7.33 (d, 2H, 3JHH
7 Hz, CH2CH3), 1.26, 1.24 (d, 6H, 3JHH
7 Hz, CH(CH3)2), 1.29
2.72 (t, 2H, 3JHH
8 Hz, ArCH2), 3.72 (s, 2H, NCH2), 4.52
7.33 (d, 2H, 3JHH 8.20 (d, 2H, 3JHH
8 Hz, Ph), 8.14 8 Hz, Ph)
7 Hz, CH(CH3)2), 3.64 (s, 2H, NCH2), 3.83, 3.86 (s s, 6H, Ar(OCH3)2), 4.49 4.64
7 Hz, NCH), 6.48 8 Hz, 1H, Ph)
6.60 (m, 2H, Ph), 7.48, 7.50 (d, 3JHH
1.22 (d, 6H, 3JHH 4.57 (m, 1H, 3JHH
7 Hz, CH(CH3)2), 3.63 (s, 2H, NCH2), 4.40 7 Hz, NCH), 6.93
1.24, 1.26 (d, 6H, 3JHH 3.58 (t, 2H, 3JHH
7 Hz, CH(CH3)2), 3.38 (s, 3H, OCH3), 3.50 5 Hz, CH3OCH2), 3.65 (s, 2H, NCH2),
3.85 (t, 2H, 3JHH 4.69 (m, 1H, 3JHH
5 Hz, CH3OCH2CH2), 4.43 7 Hz, NCH), 5.53 (s, 2H, ArOCH2),
7.58 (m, 4H, Ph)
7 Hz, CH(CH3)2), 3.38 (s, 3H, OCH3), 3.52
3.86 (t, 2H, 3JHH 4.65 (m, 1H, 3JHH
5 Hz, CH3OCH2CH2), 4.50
7.93 (m, 4H, Ph)
7 Hz, CH(CH3)2), 3.38 (s, 3H, OCH3), 3.52
5 Hz, CH3OCH2CH2), 4.50
4.65 (m, 1H, 3JHH
9 Hz, Ph), 8.30, 8.33 (d, 2H, 3JHH
9 Hz, Ph)
−
1.01 (t, 3H, 3JHH
)
−
1.27 (d, 6H, 3JHH
)
7 Hz, CH(CH3)2), 1.60
8 Hz, ArCH2), 3.710 (s, 2H, NCH2), 4.51
8.21 (d, 2H, 3JHH
8 Hz, Ph)
1.38 (m, 4H, CH2CH2CH2CH3),
4.64
−1.76
(m, 2H, 3JHH
)
)
−
)
−4.65
(m, 1H, 3JHH
−
)
−
)
F14
F15
0.85
1.57
(m, 1H, 3JHH
1.23, 1.25 (d, 6H, 3JHH
(m, 1H, 3JHH
1.07
−
0.94 (t, 3H, 3JHH
)
)
−
−
1.72 (m, 2H, CH2CH2CH2CH3), 2.63
−
)
−
)
7 Hz, NCH), 7.23
−
)
−
)
)
−
−
)
−
)
F16
F17
−
)
)
−
)
)
−7.95 (m, 9H, Ph)
−
3.77
6.91
−
−
)
−
)
F18
F19
1.24, 1.26 (d, 6H, 3JHH
)
−
3.58 (t, 2H, 3JHH
7 Hz, NCH), 5.35 (s, 2H, ArOCH2),
) 5 Hz, CH3OCH2), 3.72 (s, 2H, NCH2),
3.80
6.93
−
−
)
−
)
1.24, 1.26 (d, 6H, 3JHH
)
−
3.58 (t, 2H, 3JHH
7 Hz, NCH), 5.35 (s, 2H, ArOCH2), 7.11,
) 5 Hz, CH3OCH2), 3.72 (s, 2H, NCH2),
3.80
7.14 (d, 2H, 3JHH
see ref 6
1.51 (s, 9H, C(CH3)3), 2.38 (s, 6H, Ar(CH3)2), 3.82 (s, 2H, NCH2), 7.20 (s, 1H, Ph), 7.75 (s, 2H, Ph)
1.23 7 Hz, CH(CH3)2), 1.51 (s, 9H, C(CH3)3), 2.87 3.09 (m, 1H, ArCH), 3.83 (s, 2H, NCH2), 7.30
1.30 (d, 6H, 3JHH
(d, 2H, 3JHH 8.19 (d, 2H, 3JHH
9 Hz, Ph), 8.11 9 Hz, Ph)
1.35 (s, 9H, C(CH3)3), 1.51 (s, 9H, C(CH3)3), 3.83 (s, 2H, NCH2), 7.45
(d, 2H, 3JHH
9 Hz, Ph)
−
3.86 (t, 2H, 3JHH
)
−
)
)
)
F20
F22
F23
−
21
−
)
−
−7.37
)
−
)
F24
F25
F26
F27
F28
F29
−
7.54 (d, 2H, 3JHH
)
9 Hz, Ph), 8.12−8.20
)
1.51 (s, 9H, C(CH3)3), 3.84 (s, 2H, NCH2), 3.91
(m, 2H, Ph)
−
4.02 (d, 6H, Ar(OCH3)2), 6.94
−
7.04 (d, 1H, 3JHH
)
8 Hz, Ph), 8.05−8.20
0.78
(qd, 2H, 3JHH
0.77 0.98 (m, 4H, CH2CH2), 2.72
(d, 1H, 3JHH
9 Hz, Ph), 8.08
0.73 1.02 (m, 4H, CH2CH2), 2.38 (s, 6H, Ar(CH3)2), 2.73
7.77 (s, 2H, Ph)
0.64 1.03 (m, 4H, CH2CH2), 2.68
(d, 2H, 3JHH
9 Hz, Ph), 8.18
1.00 (m, 4H, CH2CH2), 2.73
1.02 (m, 7H, CH2CH2, CH2CH3), 1.59
2.90 (m, 1H, NCH), 3.72 (s, 2H, NCH2), 7.28
1.40 (m, 4H, CH2CH2CH3), 1.57
2.88 (m, 1H, NCH), 3.72 (s, 2H, NCH2), 7.23
8.18 (d, 2H, 3JHH
8 Hz, Ph)
2.90 (m, 1H, NCH), 3.63 (s, 2H, NCH2), 3.81, 3.85 (s
7.53 (m, 1H, Ph)
−
0.97 (m, 4H, CH2CH2), 1.42
7 Hz, OCH2), 6.92
2.91 (m, 1H, NCH), 3.73 (s, 2H, NCH2), 3.94
8.21 (m, 2H, Ph)
−
1.51 (t, 3H, 3JHH
7.02 (d, 2H, 3JHH
)
7 Hz, CH2CH3), 2.78
−
−
2.89 (m, 1H, NCH), 3.72 (s, 2H, NCH2), 4.07
8.40 (d, 2H, 3JHH
9 Hz, Ph)
4.02 (d, 6H, Ar(OCH3)2), 6.91
−4.20
)
−
)
9 Hz, Ph), 8.32
)
−
−
−
−
−7.01
)
−
−2.91 (m, 1H, NCH), 3.72 (s, 2H, NCH2), 7.22 (s, 1H, Ph),
−
−
−
−
2.96 (m, 1H, NCH), 3.74 (s, 2H, NCH2), 3.90 (s, 3H, OCH3), 6.97
8.56 (d, 2H, 3JHH
8 Hz, Ph)
2.94 (m, 1H, NCH), 3.74 (s, 2H, NCH2), 3.94 (s, 9H, Ar(OCH3)3), 7.86 (s, 2H, Ph)
1.77 (m, 2H, 3JHH 2.71 (t, 2H, 3JHH
7 Hz, CH3CH2), 2.60 7 Hz, ArCH2),
7.30 (d, 2H, 3JHH 8.20 (d, 2H, 3JHH
8 Hz, Ph), 8.12 9 Hz, Ph)
1.70 (m, 2H, ArCH2CH2), 2.63 2.71
7.34
−7.00
)
)
F30
F31
0.78
0.70
−
−
−
)
−
)
2.80−
−
)
−
)
−
F32
F33
0.79
−
0.94 (m, 7H, CH2CH3, CH2CH2), 1.26
−
−
(t, 2H, 3JHH
)
7 Hz, ArCH2), 2.78
−
−
(d, 2H, 3JHH
)
9 Hz, Ph), 8.13
−
−
)
0.83
−0.91 (m, 4H, CH2CH2), 2.74
−s, 6H, Ar(OCH3)2), 6.45−6.61
(m, 2H, Ph), 7.45
+
F34
F35
0.62
0.68
−
0.91 (m, 4H, CH2CH2), 2.75
−
2.87 (m, 1H, NCH), 3.64 (s, 2H, NCH2), 6.94
2.90 (m, 1H, NCH), 3.37 (s, 3H, OCH3), 3.53
4 Hz, CH3OCH2CH2), 5.33 (s, 2H, ArOCH2), 7.24
2.88 (m, 1H, NCH), 3.37 (s, 3H, OCH3), 3.52
3.59 (t, 2H, 3JHH
3.86 (t, 2H, 3JHH
5 Hz, CH3OCH2CH2), 5.35 (s, 2H, ArOCH2), 7.11,
9 Hz, Ph)
−
−
7.93 (m, 9H, Ph)
−0.96 (m, 4H, CH2CH2), 2.74
−
3.59 (t, 2H, 3JHH
)
4 Hz, CH3OCH2),
7.91 (m, 4H, Ph)
) 4 Hz, CH3OCH2),
3.72 (s, 2H, NCH2), 3.80
0.69
3.70 (s, 2H, NCH2), 3.79
7.13 (d, 2H, 3JHH
−
3.87 (t, 2H, 3JHH
)
−
F36
−0.96 (m, 4H, CH2CH2), 2.74
−
−
−
)
)
8 Hz, Ph), 8.29, 8.32 (d, 2H, J
)
Hz, CH2CH3), 2.0-2.16 (m, 2H, NHCH), 3.31 (s, 2H, NCH2),
reaction of aroyl acetates with N-alkyl aminoacetates (12). We
preferred the latter method to prepare the target products B1
for its less toxic reagents and greater convenience. Intermediate
D was reacted with E in refluxing absolute xylene to give the
3
3.99-4.16 (qd, 2H, JHH ) 7 Hz, OCH2).
Compound F can be synthesized by acetylation of pyrrolidine-
2,4-dione followed by the aroyl group’s migration (14) or

3-[(
Table 4. Herbicidal Activity of Compounds (Percent Inhibition)
B. campestris root test E. crus-galli cup test
R
-Hydroxy-substituted)benzylidene]pyrrolidine-2,4-diones
J. Agric. Food Chem., Vol. 53, No. 24, 2005 9569
Scheme 1a
compd
10
µ
g/mL
100
µ
g/mL
10
µ
g/mL
100
µ
g/mL
F1a
F2a
F3a
F4a
F5
F6
F7
F8
F9
15
8
3
12
8
24
3
±
±
1.1
0.6
1.0
0.0
0.2
2.1
0.8
62
86
59
71
82
34
81
74
85
54
69
62
86
29
69
81
28
10
51
88
78
82
83
79
70
47
72
86
70
60
75
57
77
80
35
51
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
2.0
1.2
2.1
1.5
2.7
1.5
0.8
0.6
1.2
1.2
0.5
0.8
0.6
1.1
1.3
1.1
0.2
0.5
0.0
1.2
1.3
1.0
1.6
1.3
0.3
0.5
0.3
0.6
0.9
0.3
0.5
0.6
0.2
0.9
0.6
1.1
77
±
0.3
0.2
0.7
0.4
1.2
2.1
1.0
77
78
78
80
80
76
42
39
44
76
0
64
57
12
80
67
52
74
21
48
80
40
18
18
59
79
65
29
66
26
41
23
79
66
33
12
±
±
±
±
±
±
±
±
±
±
1.2
1.6
0.6
1.1
0.4
0.9
0.8
1.5
1.0
1.4
77
77
80
79
68
22
0
28
74
0
±
±
±
±
±
±
a Compounds D1 15: R1
− ) 2-CH3; 4-CH3; 2-CH3O; 4-CH3O; 3,4-(CH3O)2;
±
±
±
±
±
3,5-(CH3)2; 4-CH(CH3)2; 2,4-(CH3)2; 3,4,5-(CH3O)3; 4-C(CH3)3; 2,4,5-(CH3O)3;
4-n-Pr; 4-(CH2)4CH3; 4-C2H5O; 3-C6H5O.
Scheme 2a
0
0
±
±
1.1
0.8
F10
F11
F12
F13
F14
F15
F16
F17
F18
F19
F20
F21a
F22a
F23
F24
F25
F26
F27
F28
F29
F30
F31
F32
F33
F34
F35
F36
10
61
60
60
14
27
0
±
±
±
±
±
±
0.5
2.3
1.3
2.3
3.0
2.8
0
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
1.5
1.0
2.1
1.3
0.6
1.7
1.6
1.3
1.1
1.5
2.8
2.4
1.6
2.5
1.4
1.7
2.6
2.4
0.6
0.7
1.0
0.6
0.6
2.0
2.6
27
5.7
78
57
17
8
±
0.2
a Compounds D16 19: R1
− ) 2-MEMO (CH3OCH2CH2OCH2O); 3-MEMO;
4-MEMO; 2, 4-(CH3O)2.
±
±
±
±
0.4
0.7
1.5
0.5
Scheme 3a
7
0
±
1.1
19
14
5
41
75
64
58
0
69
70
35
45
0
±
±
±
±
±
±
±
2.0
2.8
1.0
0.5
1.5
1.2
2.3
0
36
79
1.0
10
4
0
78
0
0
62
4
8
5
±
±
±
±
±
1.3
0.6
0.3
0.5
0.6
− ) i-Pr; t-Bu; cyclopropyl.
a Compounds E1 3: R2
Scheme 4a
±
1.2
±
±
±
±
1.3
1.9
1.5
1.5
±
±
±
±
±
±
±
0.6
0.5
0.6
1.4
1.1
2.4
1.2
a Compounds F1 19: R1
− ) 2-CH3; 4-CH3; 2-CH3O; 4-CH3O; 4-C2H5O;
0
3,4-(CH3O)2; 3,5-(CH3)2; 4-CH(CH3)2; 4-C(CH3)3; 2,4-(CH3)2; 3,4,5-(CH3O)3;
2,4,5-(CH3O)3; 4-n-Pr; 4-(CH2)4CH3; 2,4-(CH3O)2; 3-C6H5O; 2-MEMO; 3-MEMO;
16
28
0
78
58
4
4-MEMO. R2
)
CH(CH3)2. Compounds F20
(CH3)2; 4-CH(CH3)2; 4-C(CH3)3; 3,4-(CH3O)2. R2
36: R1
4-C2H5O; 3,4-(CH3O)2; 3,5-(CH3)2; 4-CH3O; 3,4,5-(CH3O)3; 4-n-Pr;
4-(CH2)4CH3; 2,4-(CH3O)2; 3-C6H5O; 3-MEMO; 4-MEMO. R2
cyclo-C3H5.
−
25: R1
)
)
4-CH3; 4-CH3O; 3,5-
±
±
1.1
2.0
C(CH3)3. Compounds F26
−
19
0
)
)
a These compounds and their herbicidal activities had been reported in ref 6.
activities were tested, and the results listed in Table 4 show
that when the substituents at the 2- and/or 4-position were
smaller alkyl/alkoxy groups (such as methyl, methoxy, and
ethoxy), the corresponding molecules always had a higher
inhibition rate for E. crus-galli (compounds F1-6, 10, 15, 21,
26, and 33) at 10 µg/mL. It was also found that when the
5-position hydrogen at the phenyl ring of F15 was modified by
a methoxy group, the target molecule F12 had little inhibitory
effect on E. crus-galli, indicating that a meta-position group
(methyl or alkoxy) would not be essential for herbicidal activity.
Thus, some compounds with higher inhibition rates for E. crus-
galli were further bioassayed at a dosage of 1500 g/ha in the
target compounds F (Scheme 4). This reaction was assumed to
go through a nucleophilic addition/elimination reaction. During
this process, an intermediate amide’s formation and a cyclizative
condensation were involved. According to this, when the R2
substituent is bulky, the corresponding amide’s yield would be
lower (R2 ) t-Bu, Table 2), as a result of substituent steric
hindrance.
Structure-Activity Relationship. The phenyl ring was
substituted by different electron-donating groups R1, and the
related target products F were prepared. Their herbicidal
Table 5. Herbicidal Activity of Compounds (Percent Inhibition) (Rate
)
1500 g/ha)a
B. campestris A. retroflexus
E. crus-galli
D. sanguinalis
compd
pre
post
pre
post
pre
post
pre
post
F1
F2
F3
F4
0
24
0
0
0
20
0
21
6
0
0
44
20
21
6
0
16
0
0
0
0
0
±
±
±
±
1.5
50
11
16
11
0
13
0
23
0
±
±
±
±
1.1
0
0
0
0
0
0
9
0
13
0
84
77
93
98
100.0
71
0
93
100
0
81
±
±
±
±
±
±
0.3
76
±
±
±
±
±
±
0.7
−
−
−
−
98
−
0
−
42
11
57
0
−
±
1.1
0.4
2.1
1.0
2.0
1.0
0.6
0.6
1.0
0.3
0.0
1.2
67
87
75
19
66
0
66
0
3
1.2
0.5
1.3
2.0
1.3
−
−
−
0
−
0
−
6
0
0
10
F5
±
0.4
F10
F16
F21
F26
F27
F29
F34
±
2.2
±
2.3
±
±
0.5
0.8
±
±
0.6
1.5
±
±
2.0
1.7
±
±
0.8
0.0
±
±
±
1.2
1.0
1.6
±
±
±
1.8
1.0
2.8
±
±
1.5
1.3
0
0
0
0
9
±
0.6
0
15
0
3
±
1.0
±
2.0
0
a Post, postemergence; pre, pre-emergence;
−, not measured.

9570 J. Agric. Food Chem., Vol. 53, No. 24, 2005
Zhu et al.
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pre-emergence treatment
compd
F1
rate (g/ha)
E. crus-galli
D. sanguinalis
750
375
68
43
±
±
1.3
1.1
66
30
±
±
1.2
2.0
F2
F4
750
22
±
1.0
0
750
375
92
20
±
±
0.4
1.8
54
38
±
±
1.6
1.0
F5
750
375
187.5
93.75
98
94
52
8
±
±
±
±
0.4
0.6
1.5
2.0
96
94
84
22
±
±
±
±
0.4
0.6
0.7
1.1
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F15
750
375
187.5
93.75
100
100
93
±
±
±
±
0.0
0.0
0.3
1.8
93
77
68
0
±
±
±
0.1
0.4
1.7
34
F21
F26
750
375
73
0
±
1.1
58
8
±
±
1.0
2.0
750
375
187.5
99
13
0
±
±
0.2
2.0
77
33
18
±
±
±
0.3
1.6
2.1
F29
750
375
69
7
±
±
1.2
1.6
73
69
±
±
1.0
0.7
sulcotrione
750
375
187.5
93.75
100
100
93
±
±
±
±
0.0
0.0
1.4
2.0
100
100
100
100
±
±
±
±
0.0
0.0
0.0
0.0
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and dicotyledonous plants (Table 5).
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showed a much greater herbicidal activity in pre-emergence
treatment than in postemergence treatment, especially for
monocotyledonous plants E. crus-galli and D. sanguinalis. We
analyzed the SAR according to the bioassay data in the pre-
emergence treatment. When R2 was not changed, the herbicidal
activity rank for R1 was 2-CH3, 4-CH3 < 4-CH3, 4-CH3O <
4-C2H5O, 2,4-(CH3O)2; when R1 was fixed, such as a 4-methoxy
group, the herbicidal activity rank was cyclo-C3H5, t-Bu <
i-C3H7 for E. crus-galli.
At the rate of 187.5 g/ha (Table 6), compounds F5 and F15
exhibited good herbicidal activities in comparison with sulcot-
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D. sanguinalis bleached completely. Compared with the reported
compounds of this kind (15), both of them showed excellent
herbicidal activities. Compound F4 exhibited excellent herbi-
cidal activity at 1500 g/ha; however, its activity decreased
remarkably when the dose was reduced to 375 g/ha.
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In summary, we have demonstrated that when the substituents
at the benzene ring of 3-[(R-hydroxy-substituted)benzylidene]-
pyrrolidine-2,4-diones were electron-donating, especially at the
2- and/or 4-positions, these kinds of compounds presented
excellent herbicidal activities. The results of the bioactivities
of the new compounds against E. crus-galli and D. sanguinalis
showed that some of the new compounds are effective herbicides
compared to sulcotrione.
Received for review June 26, 2005. Revised manuscript received
September 11, 2005. Accepted September 13, 2005. This work was sup-
ported by the National Key Project for Basic Research (2003CB114400),
the National Natural Science Foundation of China (20572054), and the
Research Foundation for the Doctoral Program of Higher Education
(20020055022).
JF051510L