Synthesis and herbicidal activity of lsoindoline-1,3-dione substituted benzoxazinone derivatives containing a carboxylic ester group

Article abstract of DOI:10.1021/jf901897f

A carboxylic ester group was introduced to three series of isoindolinedione substituted benzoxazinone derivatives. Some of these analogues exhibited good herbicidal activities, and the injury symptoms against weeds included leaf cupping, crinkling, bronzing, and necrosis, typical of protox inhibitor herbicides. Structurally, they were classified as Chemical Group A (4-carboxylic ester group-6-isoindolinyl-benzoxazinones), B (4-carboxylic ester group-7-isoindolinyl-benzoxazinones), and C (4-carboxylic ester group-6- tetrahydroisoindolinyl-benzoxazinones). All of the tested compounds were structurally confirmed by ¹H NMR, IR, mass spectroscopy, and elemental analysis. Preliminary bioassay data of these three classes of compounds showed that, in general, the order of the herbicidal effectiveness is C > A > B. Several of the lead compounds, for example, C10 (methyl 2-(6-(1,3-dioxo-4,5,6,7-tetrahydro-1 H-isoindol-2(3H)-yl)-7-fluoro-2-methyl-3- oxo-2H-benzo[b][1,4] oxazin-4(3H)-yl) propano-ate), C12 (ethyl 2-(6-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7 fluoro-2- methyl-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) propanoate), and C13 (ethyl 2-(6-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-2-methyl-3- oxo-2H-benzo-[>][1,4]oxazin-4(3H)-yl) butanoate), exhibited greater than 80% control at 75 g a.i./ha in both pre- and postemergence treatments against dicotyledonous weeds, such as Abutilon theophrastl Medic, Chenopodlum album L., and Amaranthus ascendens L., and monocotyledon weeds, such as Digitaria sangulnalls L., Echinochloa crus-galli L., and Setaria viridis L. On the basis of advanced screening tests and crop selectivity, compounds C10, C12, and C13 are safer to crops than flumioxazin. Compounds C10, C12, and C13 are potent to develop as pre-emergent herbicides used in peanut, soybean, maize, and cotton fields 2009 American Chemical Society.

Full text of DOI:10.1021/jf901897f

J. Agric. Food Chem. 2009, 57, 9585–9592 9585
DOI:10.1021/jf901897f
Synthesis and Herbicidal Activity of Isoindoline-1,3-dione
Substituted Benzoxazinone Derivatives Containing a
Carboxylic Ester Group
†
M
ING-ZHI
H
W
UANG,*,† FEI-XIAN
ANG,† XIAO-MING
L
O
UO,‡ HONG-B
O
M
O
,‡ Y
E
-GUO
R
EN
,
†
X
IAO-GUANG
U
,† MAN-XIANG
L
EI,† A
I
-PING
LIU,
†
‡
L
U
HUANG
,
AND
MAN-CAI
X
U
†National Engineering Research Center for Agrochemicals, Hunan Research Institute of Chemical
Industry, Changsha 410007, People’s Republic of China, and ‡Key Laboratory of Chemical Biology and
Traditional Chinese Medicine Research (Ministry of Education of China), Hunan Normal University,
Changsha 410081, People’s Republic of China
A carboxylic ester group was introduced to three series of isoindolinedione substituted benzox-
azinone derivatives. Some of these analogues exhibited good herbicidal activities, and the injury
symptoms against weeds included leaf cupping, crinkling, bronzing, and necrosis, typical of protox
inhibitor herbicides. Structurally, they were classified as Chemical Group A (4-carboxylic ester
group-6-isoindolinyl-benzoxazinones), B (4-carboxylic ester group-7-isoindolinyl-benzoxazinones),
and C (4-carboxylic ester group-6- tetrahydroisoindolinyl-benzoxazinones). All of the tested com-
pounds were structurally confirmed by 1H NMR, IR, mass spectroscopy, and elemental analysis.
Preliminary bioassay data of these three classes of compounds showed that, in general, the order of
the herbicidal effectiveness is C > A > B. Several of the lead compounds, for example, C10 (methyl
2-(6-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-2-methyl-3-oxo-2H-benzo[b][1,4] ox-
azin-4(3H)-yl) propano-ate), C12 (ethyl 2-(6-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-
fluoro-2- methyl-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl) propanoate), and C13 (ethyl 2-(6-(1,3-di-
oxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro-2-methyl-3-oxo-2H-benzo-[b][1,4]oxazin-4(3H)-yl)
butanoate), exhibited greater than 80% control at 75 g a.i./ha in both pre- and postemergence
treatments against dicotyledonous weeds, such as Abutilon theophrasti Medic, Chenopodium album L.,
and Amaranthus ascendens L., and monocotyledon weeds, such as Digitaria sanguinalis L.,
Echinochloa crus-galli L., and Setaria viridis L. On the basis of advanced screening tests and crop
selectivity, compounds C10, C12, and C13 are safer to crops than flumioxazin. Compounds C10, C12,
and C13 are potent to develop as pre-emergent herbicides used in peanut, soybean, maize, and
cotton fields.
KEYWORDS: Benzoxazinone; isoindoline-1; 3-dione substituted carboxylic ester derivatives; protox
inhibitor; synthesis; herbicidal activity
INTRODUCTION
triazolidinediones, thiazolidinones, triazolinones, thiadiazolines,
triazoles, tetrazolinones, trifluoromethyluracils, and other
6-membered cyclic imides were synthesized. The most optimal
heterocyclic ring is the tetrahydrophthalimides connected at the
6-position of the benzoxazinone system (8, 9). On the side of the
substituted benzoxazinone moiety, analogues with various sub-
stituents at C-2 and N-4 of the oxazinone ring and at positions of
C-5, C-6, C-7, and C-8 have been reported. The different
substituent combinations on the aromatic ring, including meth-
oxy, methoxycarbonyl, fluorine, chlorine, and trifluoromethyl,
were introduced at different positions. It has been recognized that
the optimal substituent is the fluorine at the 7-position (10).
However, the structural combination of the C-2 and N-4 of the
oxazine ring, a main element affecting the herbicidal activity of
benzoxazinones, has attracted the intense attention of many
Flumioxazin (1, 2) and thidiazimin (3) are commercial herbi-
cides with their mode of action classified as protoporphyrinogen
oxidase (protox) inhibitors. Protoporphyrinogen oxidase is an
enzyme in the chlorophyll biosynthetic pathway (4-7). Flumioxazin
and thidiazimin contain benzoxazinone as the core substructure.
These benzoxazinone-type herbicides contain a substituted-(2H)-
1,4-benzoxazin-3(4H)-one connected with a heterocyclic ring
group as a common structural feature (Figure 1). On the side
of heterocyclic ring moiety, a large number of heteroatom
derivatives, including tetrahydrophthalimides, tetraconimides,
oxazolinones, inmidazolidinediones, oxadiazolinones, pyrazoles,
*To whom correspondence should be addressed. Tel: (þ86)731-
85357883. Fax: (þ86)731-85959000. E-mail: huang-mz@163.com.
© 2009 American Chemical Society
Published on Web 09/22/2009
pubs.acs.org/JAFC

9586 J. Agric. Food Chem., Vol. 57, No. 20, 2009
Huang et al.
Figure 1. Chemical structure of flumioxazin, thidiazimin, B2055, B3015, 1, 2, and the key structure.
Scheme 1. Design Strategy for the Target Compounds
researchers. Most of the modification and optimization has been
focused on the substituents at the N-4 position of the oxazine
ring, ranging from propargyl, alkyl, halopropargyl, hydroxy,
and alkoxy to substituted amino, carboxy amine, and so
forth. (11-13).
the first time, targeted compounds in Chemical Groups A
(4-carboxylic ester group-6-isoindolinyl-benzoxazinones),
B
(4-carboxylic ester group-7-isoindolinyl-benzoxazinones), and C
(4-carboxylic ester group-6-tetrahydroisoindolinyl-benzoxazinones)
were designed on the principle of molecular diversity and synthe-
sized. Their structures were characterized by 1H NMR, IR, mass
spectroscopy, and elemental analysis. Their herbicidal activities
against monocotyledons and dicotyledons in pre- and postemer-
gence were determined.
In our previous work, we modified the structure of flumioxazin
and its iodo-analogue B2055 (14) by the replacement of the
tetrahydro-isoindolinedione moiety with isoindolinedione, which
resulted in the synthesis of analogues of N-4-substituted-benzox-
azinyl-isoindoline-1,3-dione 1 (15), as shown in Figure 1. Among
these analogues, the promising compound B3015 provided
>80% control at 75 g a.i. ha-1 in both pre- and post emergence
treatments against both dicotyledonous weeds such as A. theo-
phrasti Medic, C. album L., and A. ascendens L., and mono-
cotyledonous weeds such as D. sanguinalis L., E. crus-galli L., and
S. Viridis L. The IC50 values of B3015 for the postemergence
control of velvetleaf and crabgrass were comparable to those of
flumioxazin.
It was reported that compound 2 with N-4-acetamido sub-
stitution had also shown some promising herbicidal activities,
which were synthesized from the corresponding intermediates
with the N-4-carboxylic ester group by Kume’s research
group (16). To our surprise, however, the herbicidal activities of
these intermediates with N-4-carboxylic ester group have not
been reported. Since the carboxylic ester group is an essential
group contained many commercial herbicidal products, such as
fluazifop-butyl, haloxyfop-phenyl, cinidon-ethyl, chlorimuron-
ethyl, and pyraflufen-ethyl (17,18), an optimization program was
carried out by introducing the carboxylic ester group to the N-4
position of the oxazin ring of lead compounds flumioxazin and
B3015 with the hope that more novel compounds with promising
herbicidal activities may be achieved. As depicted in Scheme 1, for
MATERIALS AND METHODS
Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. The cross-linking degree of
1
the amino resin is 1%. H NMR spectra were obtained with a
Varian INOVA300 spectrometer using tetramethylsilane (TMS)
as internal standard and deuterochloroform or dimethyl-d6 sulf-
oxide as solvent. LC-mass spectra were recorded with an HP 1100
LC-MS using negative or positive ion scan mode. IR spectra were
recorded in potassium bromide disks with a PE System 2000
FTIR spectrophotometer. Elemental analyses were carried out
with a PE CHNS/O 2400 II elemental analyzer. Uncorrected
melting points were taken on a WRS-1 melting point apparatus.
Synthesis and Synthetic Methods. Target compounds in Chemical
Groups A and C, as shown in Scheme 2, were synthesized by the reaction
of phthalic anhydride 8 (4,5,6,7-tetrahydrophthalic anhydride 13) with
appropriate 2-(6-amino-7-fluoro-2-substituted-3-oxo-2H-benzo[b][1,4]-
oxazin-4(3H)-yl)-2-substituted acetate 7, which were prepared in three
steps from the intermediate 2-substituted benzoxazinone 3: (a) nitrating
benzoxazine derivatives with a HNO3-H2SO4 mixture; (b) N-carboxy
esterification of nitrobenzoxazine derivatives with appropriate 2-bromo-2-
substituted-carboxy esters 5; (c) and reduction of N-substituted nitroben-
zoxazinone derivatives 6 with iron powder as reducing reagent and acetic
acid as solvent. Target compounds in Chemical Group B were synthesized
by the reaction of (substituted) phthalic anhydride 8 with an appropriate

Article
J. Agric. Food Chem., Vol. 57, No. 20, 2009 9587
Scheme 2. General Synthetic Route for the Target Compounds in Chemical Group A and Chemical Group C
Scheme 3. General Synthetic Route for the Target Compounds in Chemical Group B
2-(6-fluoro-7-amino-2- substituted-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-
yl)-2-substituted-acetate 12. As shown in Scheme 3, compound 12 was
prepared using the same procedure as 7, but the starting substrates were
9 (14), which were obtained from 4-fluoro-2-nitrophenol.
All of the key intermediates, 7-fluoro-2-substituted-benzoxazinones 3,
7-fluoro-6-nitro-2-substituted-benzoxazinones 4, 6-fluoro-2-substituted-
benzoxazinones 9, and 6-fluoro-5-nitro-2-substituted-benzoxazinones 10,
were prepared according to the reported literature (14).
The synthetic procedure for the intermediates, compounds 11 and 12,
were prepared the aforementioned method.
General Synthetic Procedure for 2-(6-(1,3-Dioxo-isoindo-
lin-2-yl)-7-fluoro-2-substituted-3- oxo-2,3-dihydrobenzo[b][1,4]-
oxazin-4-yl)-2-substituted Acetate: Compunds in Chemical
Group A. A mixture of compound 7 (1.5 mmol) and (substituted)
phthalic anhydride 8 (1.8 mmol) in acetic acid (30 mL) was heated under
reflux for 4 h. After cooling to room temperature, the reaction mixture was
poured into ice water and extracted with ethyl acetate. The organic layer
was washed sequentially with water, saturated sodium bicarbonate
solutionc and brine, dried over anhydrous magnesium sulfate, and
concentrated in vacuo. The residue was purified by column chromatog-
raphy on silica gel using 6:1 petroleum ether (60-90 °C)/ethyl acetate
as eluent to yield the target compound in Chemical Group A as a yellow
solid.
General Synthetic Procedure for 2-(7-Fluoro-6-nitro-2-sub-
stituted-3-oxo-2H-benzo[b][1,4] oxazin-4(3H)-yl)-2-substituted
Acetate 6. Anhydrous potassium bicarbonate (6 mmol) was added to
a solution of 7-fluoro-6-nitro-2-substituted-benzoxazineone 4 (4 mmol)
in acetone. After stirring for 15 min at room temperature, a solution of
2-bromocarboxylic ester 5 (4 mmol) in acetone (20 mL) was added
dropwise to the reaction mixture, then was heated under reflux for 3 h.
After cooling to room temperature, the mixture was poured into ice water.
The solid residue was filtered, washed three times with water, and dried to
yield 2-(7-fluoro-6-nitro-2-substituted-3-oxo-2H-benzo[b] [1,4]oxazin-
4(3H)-yl)-2-substituted acetate 6 as solid with the yield of 62-83%.
General Synthetic Procedure for 2-(6-Amino-7-fluoro-2-sub-
stituted-3-oxo-2H-benzo[b][1,4] oxozin-4(3H)-yl)-2-substituted
Acetate 7. A solution of compound 6 in acetic acid (5 mL) was added
dropwise to a mixture of iron powder (10 mmol) and acetic acid (20 mL) at
60 °C and the mixture heated under reflux for 1 h. After cooling to room
temperature, the iron powder was filtered off, and the filtrate was poured
into water. The solid residue was filtered, washed three times with water, and
dried to yield 2-(6-amino-7-fluoro-2-substituted-3-oxo-2H-benzo[b][1,4]oxozin-
4(3H)-yl)-2-substituted-acetate 7 as a solid with a yield of 50-69%.
General Synthetic Procedure for 2-(7-(1,3-Dioxo-isoindo-
lin-2-yl)-6-fluoro-2-substituted-3-oxo-2,3-dihydro-benzo[b][1,4]-
oxazin-4-yl)-2-substituted Acetate: Compounds in Chemical
Group B. A mixture of compound 12 (1.5 mmol) and (substituted)
phthalic anhydride 8 (1.8 mmol) in acetic acid (30 mL) was heated
under reflux for 3.5 h. After cooling to room temperature, the reaction
mixture was poured into ice water and extracted with ethyl acetate. The
organic layer was washed sequentially with water, saturated sodium
bicarbonate solution and brine, dried over anhydrous magnesium sulfate,
and concentrated in vacuo. The residue was purified by column chroma-
tography on silica gel using 6:1 petroleum ether (60-90 °C)/ethyl
acetate as eluent to yield target compounds in Chemical Group B as white
solids.

9588 J. Agric. Food Chem., Vol. 57, No. 20, 2009
Huang et al.
Table 1. Chemical Structures, Physical Characteristics, Yields, Mass Spectrum, and Elemental Analysis Data of New Compounds in Groups A, B, and C
chemical structure
R3 R4
elemental analyses (%)
compd
R1
R2
Z
formula
m.p.(°C)
yield (%)
MS (m/z)
C(Calcd)
H(Calcd)
N(Calcd)
A1
A2
H
CH3
H
H
C19H13FN2O6
C20H15FN2O6
C20H15FN2O6
C20H13Cl2FN2O6
C21H16FN3O8
C21H15Cl2FN2O6
C22H19FN2O6
C21H17FN2O6
C20H14FN3O8
C20H15FN2O6
C21H17FN2O6
C21H15Cl2FN2O6
C19H17FN2O6
C20H19FN2O6
C21H21FN2O6
C20H19FN2O6
C21H21FN2O6
C22H23FN2O6
C26H23FN2O6
C23H25FN2O6
C20H19FN2O6
C21H21FN2O6
C21H21FN2O6
C22H23FN2O6
C23H25FN2O6
C27H25FN2O6
242-243
201-203
181-183
193 -194
184-186
163-164
179-181
172-174
181-182
260-261
218-219
167-168
172-174
187-189
159-160
116-118
204-206
164-166
150-151
147-150
166-167
128-130
132-134
167-169
127-128
168-171
78
75
72
52
71
65
53
60
51
53
66
60
64
70
58
61
67
58
56
71
72
69
65
73
68
57
385 [M þ H]
399 [M þ H]
397 [M - H]
465 [M - H]
456 [M - H]
479 [M - H]
425 [M - H]
411 [M - H]
442 [M - H]
397 [M - H]
411 [M - H]
479 [M - H]
389 [M þ H]
403 [M þ H]
415 [M - H]
403 [M þ H]
415 [M - H]
429 [M - H]
477 [M - H]
443 [M - H]
401 [M - H]
415 [M - H]
415 [M - H]
429 [M - H]
443 [M - H]
491 [M - H]
59.09 (59.38)
60.11 (60.30)
60.23 (60.30)
51.59 (51.41)
55.05 (55.15)
52.41 (52.41)
61.69 (61.97)
61.43 (61.16)
54.48 (54.18)
60.05 (60.30)
61.99 (61.97)
52.65 (52.41)
58.49 (58.76)
59.88 (59.70)
60.77 (60.57)
59.87 (59.70)
60.39 (60.57)
61.59 (61.39)
65.37 (65.27)
62.36 (62.15)
59.42 (59.70)
60.47 (60.57)
60.29 (60.57)
61.57 (61.39)
62.43 (62.15)
65.65 (65.85)
3.32 (3.41)
3.78 (3.80)
3.67 (3.80)
2.90 (2.80)
3.35 (3.53)
3.29 (3.14)
4.50 (4.49)
4.20 (4.16)
3.30 (3.18)
3.77 (3.80)
4.54 (4.49)
3.44 (3.14)
4.40 (4.41)
4.87 (4.76)
5.18 (5.08)
4.80 (4.76)
5.08 (5.08)
5.48 (5.39)
4.84 (4.85)
5.87 (5.67)
4.75 (4.76)
5.18 (5.08)
5.04 (5.08)
5.48 (5.39)
5.79 (5.67)
5.02 (5.12)
7.38 (7.29)
7.20 (7.03)
7.22 (7.03)
6.00 (6.00)
9.30 (9.19)
5.64 (5.82)
6.78 (6.57)
6.62 (6.79)
9.29 (9.48)
7.27 (7.03)
6.67.(6.57)
5.73 (5.82)
7.43 (7.21)
6.89 (6.96)
6.65 (6.73)
6.90 (6.96)
6.87 (6.73)
6.42 (6.51)
5.77 (5.85)
6.05 (6.30)
7.08 (6.96)
6.62 (6.73)
6.96 (6.73)
6.36 (6.51)
6.20 (6.30)
5.77 (5.69)
H
C2H5
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
A3
A4
H
CH3
H
H
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
5,6-2Cl
5-NO2
5,6-2Cl
5-CH3
5-CH3
5-NO2
A5
A6
H
CH3
CH3
CH3
H
H
A7
A8
H
H
A9
B1
H
H
H
H
B2
B3
H
H
5-CH3
5,6-2Cl
H
CH3
H
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
H
H
CH3
CH3
CH3
C2H5
H
H
H
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
H
CH3
C2H5
C6H5
CH3
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
C2H5
C2H5
C2H5
C2H5
CH3
C2H5
C6H5
General Synthetic Procedure for 2-(6-(1,3-Dioxo-4,5,6,7-
tetrahydro-1H-isoindol-2(3H)-yl)-7-fluoro2-substituted-3-oxo-
2,3-dihydro-benzo[b][1,4]oxazin-4-yl)-2-substituted Acetate:
Compounds in Chemical Group C. A mixture of compound 7
(1.5 mmol) and 4,5,6,7-tetrahydrophthalic anhydride 13 (1.8 mmol) in
acetic acid (30 mL) was heated under reflux for 3.5 h. After cooling to
room temperature, the reaction mixture was poured into ice water and
extracted with ethyl acetate. The organic layer was washed sequentially
with water, saturated sodium bicarbonate solution, and brine, dried over
anhydrous magnesium sulfate, and concentratedinvacuo. The residue was
purified by column chromatography on silica gel using 6:1 petroleum ether
(60-90 °C)/ethyl acetate as eluent to yield target compounds in Chemical
Group C as slight yellow solids.
treated at the 2-leaf stage, and monocotyledonous weeds were treated at
the 1-leaf stage. The pre- and postemergence application rates were 75 g of
ai/ha. Untreated seedlings were usedas the control group, while the solvent
(DMF)-treated seedlings were used as the solvent control group. Each
treatment was conducted in triplicate. After cultivation for 15 days, the
herbicidal activity on test weeds was evaluated by visually comparing the
weed growth inhibition of all test treatments with untreated controls,
calculated as the average of the triplicates, and rated on the basis of
percentage of weed growth inhibition using the following rating system:
þþ, >80%; þ, 50-80%; - <50%.
Determination of Advanced Herbicidal Activity. Six kinds of weeds
such as Abutilon theophrasti Medic (AT), Amaranthus spinosus L. (AS),
Chenopodium album L.(CA), Digitaria sanguinalis L. (DS), Echinochloa
crus-galli L. (EC), and Setaria viridis L. (SV) were used for the advanced
herbicidal screening test of compounds C10, C12, and C13. The bioassay
process was the same as the above-described method for determining the
preliminary herbicidal activity, but the treatment dosage was reduced to
7.5, 15, and 37.5 g a.i./ha. Each treatment was conducted in triplicate, and
the bioassay result was reported as the average of the percentage of weed
growth inhibition for the triplicates. The significance of differences of the
herbicidal activity for all treatments were subjected to statistical analysis
using Duncan’s multiple range test with P = 0.05.
Biological Activity (15) . Test compounds were formulated as 100 g/L
emulsified concentrates by using DMF as solvent and TW-80 as emulsi-
fication reagent. The stock solutions were diluted with water to the
required concentration and applied to pot-grown plants in a greenhouse.
The soil used was a clay soil, pH 6.5, 1.7% organic matter, 37.5% clay
particles, and CEC of 12.9 cmol/kg. The rate of application [grams of
active ingredient (ai) per hectare] was calculated by the total amount of
active ingredient in the formulation divided by the surface area of the pot.
Determination of Preliminary Herbicidal Activity against Dico-
tyledonous Weeds and Monocotyledonous Weeds. Plastic pots (9-cm
diameter) were filled with soil to a depth of 6 cm. Approximately 20 seeds
of Abutilon theophrasti Medic (AT), Chenopodium album L. (CA), Amar-
anthus ascendens L. (AA), Digitaria sanguinalis L. (DS), Echinochloa crus-
galli L. (EC), and Setaria viridis L. (SV) were sown in the soil at a depth of
5-mm and grown at 22-25 °C in a greenhouse. The diluted formulation
test solutions were applied to pre-emergence treatment 24 h after weeds
were sown. For the postemergence treatment, dicotyledonous weeds were
Determination of Crop Selectivity. The seeds of peanut (Arachis
hypogaea), rice (Oryza sativa L.), wheat (Triticum aestivum L.), maize (Zea
mays L.), cotton (Gossypium spp.), soybean (Glycine max), and rape
(Brassica campestris L.) were sown in plastic pots (9-cm diameter) filled
with soil to a depth of 6 cm and grown at 22-25 °C in the greenhouse. Test
compounds were applied at the dosage of 300, 150, 75, and 37.5 g a.i./ha at
the pre-emergence stage and at the dosage of 60, 30, 15, and 7.5 g a.i./ha for
the postemergence evaluation. Each treatment was conducted in triplicate.

Article
J. Agric. Food Chem., Vol. 57, No. 20, 2009 9589
After cultivation for 15 days, the crop selectivity was evaluated by visually
comparing the crop phytotoxicity of all test treatments with untreated
controls, calculated as the average of the triplicates, and rated on the basis
of percentage of crop growth inhibition using the following rating system:
þþ, >10% growth inhibition; þ, 1-10% growth inhibition; -, no
growth inhibition.
Second, compounds in Group C were more potent against
dicotyledonous weeds than monocotyledonous ones. All of the
tested 14 compounds in the Group C series had more than 80%
control at 75 g of ai/ha in postemergence treatment against
dicotyledonous weeds such as A. theophrasti Medic, C. album
L., and A. ascendens L. Among them, compounds C4, C5, C9,
C10, C11, C12, and C13 also exhibited more than 80% control in
pre-emergence treatment against dicotyledonous weeds such as
A. theophrasti Medic, C. album L., and A. ascendens L.
Third, compounds in Group C had some herbicidal activity
against monocotyledons, and the activity in postemergence
treatment was better than that in pre-emergence treatment.
Among all of the tested 14 compounds, C2, C5, C10, C12, and
C13 had more than 80% control at 75 g of ai/ha in postemergence
treatments against monocotyledonous weeds such as D. sangui-
nalis L., E. crus-galli L., and S. viridis L., while compound C7 had
more than 80% control against D. sanguinalis L. and S. viridis L.
Compounds C10, C12, C13, and C14 had same herbicidal
efficiency in pre-emergence treatments against monocotyledo-
nous weeds.
Fourth, several compounds in Group A showed herbicidal
activity against dicotyledonous weeds in postemergence treat-
ment. For example, compounds A1, A2, and A3 showed more
than 80% control against dicotyledonous weeds such as
A. theophrasti Medic, C. album L., and A. ascendens L., and
compound A7 showed more than 80% control against A. theo-
phrasti Medic.
Finally, comparable to flumioxazin and B3015, compounds
C10, C12, and C13 also possess more than 80% control at 75 g a.
i./ha in both pre- and postemergence treatments against both
dicotyledonous weeds and monocotyledonous weeds. It is
demonstrated that the introduction of the carboxylic ester to
the N-4 position of benzoxazinone can also enhance the herbici-
dal efficacy of benzoxazinones.
Preliminary Structure-Activity Relationship Study. Some
interesting structure-activity relationship may be drawn from
Tables 1 and 3. The substituted position of newly synthesized
carboxylic ester derivatives of isoindoline-1,3-dione-substituted
benzoxazine can sufficiently influence the herbicidal activity. For
example, when the substituted positionofisodoline-1,3-dione was
changed from the 6-position to 7-position, the resulting com-
pounds had almost no herbicidal activity.
Furthermore, from all 9 compounds of Group A, their herbi-
cidal activities were not influenced by the substituted group on the
ring of isoindoline. For example, activity was not increased when
a methyl, nitro, or chloro group was introduced onto the isoindo-
line ring.
Changing the substitution from isoindoline-1,3-dione to 1,3-
dioxo-4,5,6,7-tetrahydro-1H-isoindolin-2-yl significantly in-
creased the herbicidal activity. For example, the herbicidal
activity of compound C1, C2, or C4 was higher than that of
corresponding compound A1, A3, or A2, respectively.
The introduction of a methyl group on the 2-position of the
benzoxazine ring was propitioustoenhance the herbicidalactivity
in soil treatments. For example, compound C10, C12, or C13
against mono- and dicotyledons exhibited higher herbicidal
activities than compound C2, C5, or C6, respectively.
RESULTS AND DISCUSSION
Synthesis and Structure Characterization. Reduction Reaction.
The reduction of nitro to amines can be achieved by several
methods (19-22) including (a) reduced iron powder/acetic acid,
(b) high pressure hydrogen gas, (c) SnCl2/HCl, and (d) (NH4)2S/
Na2S. For the small scale reduction reaction to prepare inter-
mediates 7 or 12, we used the method of iron/acetic acid
conditions. Although the yield was not very high, its mild
condition (the reaction was generally completed within 40 min
at 55-65 °C reaction temperature) served well as a laboratory
method. For the larger scale preparation of compound 7 (>100 g),
however, we have used catalytic hydrogenation of compound 6 in
an autoclave. Although the reaction time is more than 5 h, the yield
can reach 90%.
Synthesis of Target Compounds in Chemical Groups A, B,
and C. The target compounds in Chemical Groups A, B, or C,
which were depicted in the last step reaction in Schemes 2 and 3
can be prepared by the condensation of compound 7 or 12 with a
20% molar excess of appropriate anhydride 8 or 13. After the
reaction was completed, the workup procedure was usually
undertaken in the following way: amino resin, an anhydride
scavenger, was added to the reaction mixture and was stirred at
80 °C for 6 h. The mixture was then cooled down to room
temperature, and the resin was filtered off. The filtrate was
poured into ice water and extracted with ethyl acetate several
times. The combined organic layer was washed sequentially with
water, saturated sodium bicarbonate, and brine. After drying
over anhydrous magnesium sulfate and filtration, the solution
was concentrated in vacuo to give a target product. However, the
results from the HPLC (using 1:4 methanol/purified water as flow
phase) indicated that the chemical purity was usually below 85%.
Further purification of the target compounds in Chemical Group
A, B, or C should be undertaken by column chromatography.
The procedure was not an economic and convenient method
to purify target compounds. Therefore column chromato-
graphy purification method has been adopted directly, while
more target compounds in Chemical Group A, B, or C were
synthesized.
Table 1 summarizes the chemical structures, physical char-
acteristics, yields, mass spectrum, and elemental analysis
data of three novel series of compounds in Chemical Groups
A, B, and C. 1H NMR data are listed in Table 2. All
compounds had characteristic IR absorbances at 1707-
1736 cm-1 (carbonyl in benzoxazinyl moiety), 1679-1705 cm-1
(carbonyl in isoindolin-1,3-dione moiety), and 1710-1769 cm-1
(carbonyl in N-substituted carboxylic ester moiety), respec-
tively.
Preliminary Herbicidal Activity. As shown in Table 3, several
compounds exhibited high herbicidal activity. The injury symp-
toms against weeds included leaf cupping, crinkling, bronzing,
and necrosis, typical of protox inhibitor herbicides (23, 24).
Several interesting characteristics of these target compounds may
be pointed out as follows.
The number of alkyl groups on the carboxyl carbon connected
to the N atom of the benzoxazine ring of the carboxylic ester
derivatives also influenced the herbicidal activity. If there was
only one methyl or ethyl group substituted on the carboxy
carbon, then it increased the herbicidal activity against the
monocotyledon. For example, except for compound C3, the
herbicidal activity of compound C2, C5, C10, or C12 against
monocotyledons was higher than that of compound C1, C4, C9,
First, among the three series of compounds, compounds in
Group C had greater herbicidal activity than compounds in
Groups A and B, and compounds in Group B had no detec-
table activity in the conditions tested, either in pre- or postemer-
gency.

9590 J. Agric. Food Chem., Vol. 57, No. 20, 2009
Huang et al.
Table 2. 1H NMR Data of the New Compounds in Chemical Groups A, B, and C
compd
1H NMR, δ(300 MHz,CDCl3, ppm)
A1 3.78 (s, 3H, OCH3), 4.65 (s, 2H, NCH2), 4.75(s, 2H, OCH2), 6.72 (d, 1H, J = 6.6 Hz, O-Ph-H), 6.97 (d, 1H, J = 9.9 Hz, O-Ph-H), 7.80-7.83 (m, 2H, Ar-H), 7.95-7.98
(m, 2H, Ar-H)
A2 1.27 (t, 3H, J = 7.2 Hz, CH3), 4.23 (q, 2H, J = 7.2 Hz, CH2), 4.64 (s,2H, NCH2), 4.75(s, 2H, OCH2), 6.73 (d, 1H, J = 6.6 Hz, OPh-H), 6.98 (d, 1H, J = 9.6 Hz, O-Ph-H),
7.81-7.84 (m, 2H, Ar-H), 7.96-7.99 (m, 2H, Ar-H)
A3 1.64 (d, 3H, J = 7.2 Hz, CHCH3), 3.76 (s, 3H, OCH3), 4.69 (q, 2H, J = 15 Hz, OCH2), 5.36 (q, 1H, J = 7.2 Hz, NCH), 6.78 (d, 1H, J = 6.6 Hz, Ar-H), 6.98 (d, 1H, J = 9.9 Hz,
Ar-H), 7.81-7.84 (m, 2H, Ar-H), 7.96-7.98 (m, 2H, Ar-H)
A4 1.26 (t, 3H, J = 6.9 Hz, CH2CH3), 4.24 (q, 2H, J = 6.9 Hz, CH2CH3), 4.63 (s, 2H, NCH2), 4.75 (s, 2H, OCH2), 6.70 (d, 1H, J = 6.9 Hz, O-Ph-H), 6.97 (d, 1H, J = 9.6 Hz,
O-Ph-H), 8.04 (s, 2H, Ar-H)
A5 1.22 (t, 3H, J = 7.2 Hz, CH2CH3), 1.63 (d, 3H, J = 7.2 Hz, CHCH3), 4.20-4.25(m, 2H, CH2CH3), 4.74 (q, 2H, J = 14.7 Hz, OCH2), 5.39 (q, 1H, J = 7.5 Hz, NCH), 6.81 (d, 1H,
J = 6.6 Hz, O-Ph-H), 7.01 (d, 1H, J = 9.6 Hz, O-Ph-H), 8.17 (d, 1H, J = 8.1 Hz, Ar-H), 8.71 (d, 1H, J = 8.1 Hz, Ar-H), 8.79 (s, 1H, Ar-H)
A6 1.21 (t, 3H, J = 7.2 Hz, CH2CH3), 1.63 (d, 3H, J = 7.2 Hz, CHCH3), 4.20-4.24(m, 2H, CH2CH3), 4.68 (q, 2H, J = 15 Hz, OCH2), 5.35 (q, 1H, J = 6.9 Hz, NCH), 6.78 (d, 1H,
J = 6.6 Hz, O-Ph-H), 6.98 (d, 1H, J = 9.6 Hz, O-Ph-H), 8.04 (s, 2H, Ar-H)
A7 1.21 (t, 3H, J = 7.2 Hz, CH2CH3), 1.63 (d, 3H, J = 7.2 Hz, CHCH3), 2.59 (s, 3H, Ph-CH3), 4.20-4.24(m, 2H, CH2CH3), 4.68 (q, 2H, J = 15 Hz, OCH2), 5.31 (q, 1H, J =
7.2 Hz, NCH), 6.80 (d, 1H, J = 6.6 Hz, O-Ph-H), 6.97 (d, 1H, J = 9.6 Hz, O-Ph-H), 7.61 (d, 1H, J = 7.8 Hz, Ar-H), 7.76 (s, 1H, Ar-H), 7.84 (d, 1H, J = 7.8 Hz, Ar-H)
A8 1.26 (t, 3H, J = 7.2 Hz, CH2CH3), 2.56 (s, 1H, CH3-Ph), 4.23 (q, 2H, J = 7.5 Hz, CH3CH2), 4.63 (s, 3H, OCH2), 4.73 (s, 2H, NCH2), 6.72 (d, 1H, J = 6.9 Hz, OPh-H), 6.95
(d, 1H, J = 9.6 Hz, OPh-H), 7.61 (d, 1H, J = 7.8 Hz, Ar-H), 7.76 (s, 1H, Ar-H), 7.83 (d, 1H, J = 7.8 Hz, Ar-H)
A9 1.27 (t, 3H, J = 7.2 Hz, CH2CH3), 4.23 (q, 2H, J = 7.2 Hz, CH3CH2), 4.63 (s, 3H, OCH2), 4.76 (s, 2H, NCH2), 6.73 (d, 1H, J = 6.9 Hz, OPh-H), 6.98 (d, 1H, J = 9.6 Hz,
OPh-H), 7.99-8.25 (m, 3H, Ar-H)
B1 1.32 (t, 3H, J = 7.2 Hz, CH3), 4.28 (q, 2H, J = 7.2 Hz, CH2), 4.64 (s,2H, NCH2), 4.73 (s, 2H, OCH2), 6.69 (d, 1H, J = 10.2 Hz, OPh-H), 7.04 (d, 1H, J = 6.6 Hz, O-Ph-H),
7.81-7.83 (m, 2H, Ar-H), 7.96-7.99 (m, 2H, Ar-H)
B2 1.32 (t, 3H, J = 7.2 Hz, CH3), 2.56 (s, 1H, CH3-Ph), 4.28 (q, 2H, J = 7.2 Hz, CH2), 4.63 (s,2H, NCH2), 4.72 (s, 2H, OCH2), 6.68 (d, 1H, J = 10.5 Hz, OPh-H), 7.03 (d, 1H, J =
6.9 Hz, O-Ph-H), 7.61-7.86 (m, 3H, Ar-H)
B3 1.24 (t, 3H, J = 7.2 Hz, CH2CH3), 1.65 (d, 3H, J = 7.2 Hz, CHCH3), 4.22-4.26(m, 2H, CH2CH3), 4.64-4.76 (q, 2H, OCH2), 5.37 (q, 1H, J = 6.9 Hz, NCH), 6.68 (d, 1H, J =
10.2 Hz, O-Ph-H), 7.03 (d, 1H, J = 6.6 Hz, O-Ph-H), 8.04 (s, 2H, Ar-H)
C1 1.81-1.85 (m, 4H, CH2CH2), 2.41-2.45 (m, 4H, 2*CH2), 3.77 (s, 3H, OCH3), 4.63 (s, 2H, NCH2), 4.72 (s, 2H, OCH2), 6.61 (d, 1H, J = 6.6 Hz, O-Ph-H), 6.91 (d, 1H, J =
9.9 Hz, O-Ph-H)
C2 1.62 (d, 3H, J = 7.2 Hz, CHCH3), 1.82-1.86 (m, 4H, CH2CH2), 2.42-2.46 (m, 4H, 2*CH2), 3.75 (s, 3H, OCH3), 4.68 (q, 2H, J = 15 Hz, OCH2), 5.36 (q, 1H, J = 7.2 Hz,
NCH), 6.65 (d, 1H, J = 6.6 Hz, O-Ph-H), 6.92 (d, 1H, J = 9.9 Hz, O-Ph-H)
C3 0.91 (t, 3H, J = 7.5 Hz, CH2CH3), 1.81-1.85 (m, 4 H, CH2CH2), 2.00-2.32 (d*m, 2H, -CH2-), 2.41-2.45 (m, 4H, 2*CH2), 3.74 (s, 3H, OCH3), 4.68(q, 2H, J = 15 Hz,
OCH2), 5.36 (q, 1H, J = 7.2 Hz, NCH), 6.67 (d, 1H, J = 6.6 Hz, O-Ph-H), 6.92 (d, 1H, J = 9.6 Hz, O-Ph-H)
C4 1.26 (t, 3H, J = 7.5 Hz, CH2CH3), 1.82-1.84 (m, 4H, CH2CH2), 2.42-2.43 (m, 4H, 2*CH2), 4.23(q, 2H, J = 6 Hz, CH2CH3), 4.61 (s, 2H, OCH2), 4.71 (s, 2H, NCH2), 6.61
(d, 1H, J = 6.9 Hz, O-Ph-H), 6.91(d, 1H, J = 9.9 Hz, O-Ph-H)
C5 1.22 (t, 3H, J = 7.5 Hz, CH2CH3), 1.63 (d, 3H, J = 7.2 Hz, CHCH3), 1.83-1.84 (m, 4H, CH2CH2), 2.40-2.48 (m, 4H, 2*CH2), 4.18-4.25 (m, 2H, CH2CH3), 4.70 (q, 2H, J =
15 Hz, OCH2), 5.29 (q, 1H, J =7.2 Hz, NCH), 6.68 (d, 1H, J = 6.9 Hz, O-Ph-H), 6.93 (d, 1 H, J = 9.9 Hz, O-Ph-H)
C6 0.91 (t, 3H, J = 7.5 Hz, CH2CH3), 1.20 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.81-1.85 (m, 4H, CH2CH2), 2.00-2.29 (d*m, 2H, -CH2-), 2.41-2.45 (m, 4H, 2*CH2), 4.16-4.25
(m, 2H, OCH2CH3), 4.68 (q, 2H, J = 15 Hz, OCH2), 5.31-5.36 (m, 1H, NCH), 6.70 (d, 1H, J = 6.6 Hz, O-Ph-H), 6.92 (d, 1H, J = 9.9 Hz, O-Ph-H)
C7 1.20 (t, 3H, J = 6.9 Hz, OCH2CH3), 1.77-1.81 (m, 4H, CH2CH2), 2.36-2.38 (m, 4H, 2*CH2), 4.21-4.33 (m, 2H, OCH2CH3), 4.76 (q, 2H, J = 15 Hz, OCH2), 6.41 (s, 1H,
NCH), 6.66 (d, 1H, J = 6.9 Hz, O-Ph-H), 6.91 (d, 1H, J = 9.9 Hz, O-Ph-H), 7.32-7.37 (m, 5H, Ph-H)
C8 1.31 (t, 3H, J = 6.9 Hz, OCH2CH3), 1.46 (s, 6H, C(CH3)2), 1.62 (d, 3H, J = 6.6 Hz, CHCH3), 1.83-1.84 (m, 4H, CH2CH2), 2.41-2.45 (m, 4H, 2*CH2), 4.12-4.21 (m, 2H,
OCH2CH3), 4.81-4.82 (m, 1H, CHCH3), 6.61 (d, 1H, J = 6.9 Hz, O-Ph-H), 6.91(d, 1H, J = 9.9 Hz, O-Ph-H)
C9 1.61 (d, 3H, J = 6.9 Hz, OCHCH3), 1.83-1.84 (m, 4H, CH2CH2), 2.41-2.45 (m, 4H, 2*CH2), 3.77 (s, 3H, OCH3), 464 (q, 2H, J = 15.6 Hz, NCH2), 4.74-4.76 (m, 1H,
OCHCH3), 6.58 (d, 1H, J = 6.3 Hz, O-Ph-H), 6.91 (d, 1H, J = 9.9 Hz, O-Ph-H)
C10 1.57 (d, 3H, J = 6.9 Hz, NCHCH3), 1.60 (d, 3H, J = 7.5 Hz, OCHCH3), 1.81-1.85 (m, 4H, CH2CH2), 2.42-2.46 (m, 4H, 2*CH2), 3.74 (s, 3H, OCH3), 4.73 (2*q, 1H, J =
6.9 Hz, OCHCH3), 4.74-4.76 (m, 1H, OCHCH3), 5.35-5.38 (m, 1H, NCH), 6.63 (d, 1H, J = 6.6 Hz, O-Ph-H), 6.91 (d, 1H, J = 9.9 Hz, O-Ph-H)
C11 1.25 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.60 (d, 3H, J = 6.9 Hz, OCHCH3), 1.81-1.85 (m, 4H, CH2CH2), 2.41-2.45 (m, 4H, 2*CH2), 4.23 (q, 2H, J = 7.2 Hz, OCH2CH3), 4.58
(q, 2H, J = 6.9 Hz, NCH2), 4.76 (q, 1H, J = 6.9 Hz, OCHCH3), 6.59 (d, 1H, J = 6.9 Hz, O-Ph-H), 6.90 (d, 1H, J = 9.9 Hz, O-Ph-H)
C12 1.20 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.53-1.61 (m, 6H, NCHCH3, OCHCH3), 1.82-1.85 (m, 4H, CH2CH2), 2.41-2.45 (m, 4H, 2*CH2), 4.16-4.25 (m, 2H, OCH2CH3),
4.68 (2*q, 1H, J = 6.9 Hz, OCHCH3), 5.32 (2*q, 1H, J = 7.2 Hz, NCHCH3), 6.66 (d, 1H, J = 6.9 Hz, O-Ph-H), 6.91 (d, 1H, J = 9.9 Hz, O-Ph-H)
C13 0.94 (t, 3H, J = 7.2 Hz, CHCH2CH3), 1.22 (t, 3H, J = 7.2 Hz, OCH2CH3), 1.60 (d, 3H, J = 6.9 Hz, OCHCH3), 1.82-1.86 (m, 4H, CH2CH2), 2.01-2.29 (d*m, 2H,
CHCH2CH3), 2.42-2.46 (m, 4H, 2*CH2), 4.17-4.26 (m, 2H, OCH2CH3), 4.68 (2*q, 1H, J = 6.9 Hz, OCHCH3), 5.32-5.36 (m, 1H, NCH), 6.69 (d, 1H, J = 6.6 Hz,
O-Ph-H), 6.91 (d, 1H, J = 9.9 Hz, O-Ph-H)
C14 1.19 (t, 3H, J = 6.9 Hz, OCH2CH3), 1.66 (d, 3H, J = 6.9 Hz, OCHCH3), 1.78-1.82 (m, 4H, CH2CH2), 2.35-2.39 (m, 4H, 2*CH2), 4.17-4.32 (m, 2H,OCH2CH3), 4.75-4.87
(m, 1H, OCHCH3), 6.47 (s, 1H, NCH), 6.60 (d, 1H, J = 6.9 Hz, O-Ph-H), 6.90 (d, 1H, J = 9.6 Hz, O-Ph-H), 7.30-7.39 (m, 5H, Ph-H)
or C11, respectively. However, when a compound contains two
substituents, the herbicidal activity decreased dramatically. As an
example, compound C8 exhibited much lower herbicidal activity
than compounds C10 and C12.
Advanced Screening Test and Crop Selectivity of Com-
pounds C10, C12, and C13. On the basis of the herbicidal
activity primary test, compounds C10, C12, and C13 show
promising activities comparable to those of flumioxazin. In order
to further assess the herbicidal activity of those compounds, C10,
C12, and C13 were selected as interesting leads for advanced
screening tests. As shown in Table 4, at the dosage of 7.5-37.5g a.
i./ha, all of the three compounds exhibited 100% control against
dicotyledon weeds such as Abutilon theophrasti Medic, Amar-
anthus spinosus L., and Chenopodium album L. in postemergence
treatment, and their herbicidal activity compared with that of
flumioxazin exhibited no significant differences at P = 0.05 on
the basis of a Duncan’s multiple range test (DMRT). However,
they did not have good activity to inhibit monocotyledon weeds
such as Digitaria sanguinalis L., Echinochloa crus-galli L., and
Setaria viridis L. As applied in pre-emergence, they also had more
than 90% control against docotyledon weeds such as Amaranthus
spinosus L. and Chenopodium album L. but less activity against
Abutilon theophrasti Medic. Only, at the dosage of 37.5 g a.i./ha,
compound C10 had 80% control against Echinochloa crus-galli L.
and Setaria viridis L.; compound C12 had 80% control against
Digitaria sanguinalis L.

Article
J. Agric. Food Chem., Vol. 57, No. 20, 2009 9591
postemergence activity (75 g a.i./ha)
Table 3. Preliminary Herbicidal Activity of New Compounds in Groups A, B, and C
pre-emergence activity (75 g a.i./ha)
compd
ATa
CA
AA
DS
EC
SV
AT
CA
AA
DS
EC
SV
b
A1
A2
þ
þ
þ
þ
þ
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
þþ
þþ
þþ
þ
þþ
þþ
þþ
þ
þþ
þþ
þþ
þ
-
-
-
-
-
-
þ
A3
A4
-
-
-
þ
þ
þ
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
A5
A6
þ
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
þ
-
-
A7
A8
þ
þþ
-
-
þ
þ
þ
A9
B1
-
-
þ
þ
þ
-
-
-
-
-
-
B2
B3
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
C1
C2
þ
þ
þ
-
-
-
-
-
-
-
-
-
-
-
-
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
þ
þ
þþ
-
þ
þ
þþ
þ
þþ
-
þþ
þ
C3
C4
-
-
þþ
þþ
þþ
þ
þþ
þþ
þ
þþ
þþ
þ
-
-
-
C5
C6
þ
-
þ
þþ
þþ
þþ
þ
þ
þ
þ
þ
þ
C7
C8
þþ
þþ
þ
þ
-
þ
þþ
þ
þ
þþ
þ
-
-
-
-
-
-
þ
C9
þþ
þþ
þþ
þþ
þþ
þ
þþ
þþ
þþ
þþ
þþ
þ
þþ
þþ
þþ
þþ
þþ
þ
-
-
þ
-
þ
C10
C11
C12
C13
C14
B3015
flumioxazin
þþ
þþ
þþ
þþ
-
þþ
þþ
-
-
-
-
-
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þ
þþ
þþ
-
þþ
þþ
þ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
þþ
a AT, Abutilon theophrasti Medic; CA, Chenopodium album L.; AA, Amaranthus ascendens L.; DS, Digitaria sanguinalis L.; EC,r Echinochloa crus-galli L.; SV, Setaria viridis L.
b Rating system for the growth inhibition percentage: þþ, >80%; þ, 80-50%; - for <50%.
Table 4. Biological Activity of Compounds C10, C12, and C13 against AT, AS, CA, DS, EC, and SV
postemergence activity (%)
pre-emergence activity (%)
compd
C10
dosage (g ai/ha)
ATa
AS
CA
DS
EC
SV
AT
AS
CA
DS
EC
0 f
SV
0 f
7.5
15
100 ab
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
10 h
20 g
60 d
20 g
30 g
50 e
40 f
10 e
30 d
50 c
10 e
30 d
50 c
0 f
10 g
50 d
80 b
20 f
50 e
60 d
70 c
0 h
100 a
100 a
100 a
90 c
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
100 a
0 e
10 d
50 b
0 e
10 e
80 a
0 f
10 e
80 a
0 f
37.5
7.5
15
C12
30 e
50 d
20 f
0 h
95 b
40 c
80 a
0 e
10 e
30 d
0 f
40 d
60 b
0 f
37.5
7.5
15
20 g
0 h
100 a
100 a
100 a
100 a
100 a
100 a
100 a
C13
50 e
70 c
80 b
90 a
95 a
0 f
30 e
70 c
80 b
90 a
95 a
40 f
70 c
50 e
80 b
100 a
0 e
0 e
0 f
0 f
37.5
7.5
15
50 c
50 c
70 b
80 a
0 f
0 f
flumioxazin
0 e
0 f
0 f
50 b
80 a
50 c
70 b
50 c
80 a
37.5
a AT, Abutilon theophrasti Medic; AS, Amaranthus spinosus L.; CA, Chenopodium album L.; DS, Digitaria sanguinalis L.; EC, Echinochloa crus-galli L.; SV, Setaria viridis L.
b Numbers in a longitudinal column followed by the same letter exhibited no significant differences at P = 0.05 based on Duncan’s multiple range test (DMRT).
C10, C12, and C13 were chosen for further evaluation of their
crop selectivity in comparison with that of flumioxazin. The
phytotoxicity to the seven crops are listed in Table 5. Surprisingly,
at the pre-emergence treatment, compounds C10, C12, and C13
are all safer to the crops than flumioxazin, and the safety ranking
among the three compounds are C13 > C12 > C10; at the dosage
of 37.5-300 g a.i./ha, all of the three compounds are safe to
peanuts and soybean, and C12 and C13 have no injury to maize
and cotton. Compound C10 is not safe to maize and cotton at the
dosage of 300 g a.i./ha, having more than 10% growth inhibition;
but all of the three compounds, being similar to flumioxazin, are
not good to rice, wheat, and rape. At the postemergent treatment,
compounds C10, C12, C13, and flumioxazin are not safe to all
tested crops. From all herbicidal test data, compounds C10, C12,
and C13 show development potential as a pre-emergent herbicide
in crops such as peanut, soybean, maize, and cotton.
In this article, we describe the synthesis and herbicidal activity
of three series of isoindoline-1,3-dione substituted benzoxazinone
derivatives containing a carboxylic ester group as a new class of
protox inhibitors. The preliminary structure-activity relation-
ships were also analyzed upon the basis of the preliminary
bioassay data. The advanced screening test and crop selectivity
data showed that compounds C10, C12, and C13 had promising
activities comparable to that of the lead compound flumioxazin.
All of the three compounds are much safer to crops than
flumioxazin. Compounds C10, C12, and C13 can be developed
as potential pre-emergent herbicides for use in peanut, soybean,
maize, and cotton fields.

9592 J. Agric. Food Chem., Vol. 57, No. 20, 2009
Huang et al.
Table 5. Phytotoxicity of Compounds C10, C12, C13, and Flumioxazin to
Crops (Pre-Emergence)
(11) Macı
´
as, F. A.; Marı
´
n, D.; Oliveros-Bastidas, A.; Chinchilla, D.;
Simonet, A. M.; Molinillo, J. M. G. Isolation and synthesis of
benzoxazinones and related compounds. J. Agric. Food Chem. 2006,
54, 991–1000.
cmpd
dosage (g ai/ha) PEA a SOY COT MAI WHE RIC RAP
b
(12) Macıas, F. A.; Marın, D.; Oliveros-Bastidas, A.; Castellano, D.;
´ ´
C10
37.5
75
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
þþ þþ
Simonet, A. M.; Molinillo, J. M. G. Structure-activity relationship
(SAR) studies of benzoxazinones, their degradation products and
analogues. Phytotoxicity on standard target species (STS). J. Agric.
Food Chem. 2005, 53, 538–548.
þþ þþ þþ
þþ þþ þþ
150
300
37.5
75
þþ þþ þþ þþ þþ
C12
C13
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
þ
þ
-
-
þþ þþ
þþ þþ
(13) Macıas, F. A.; Marın, D.; Oliveros-Bastidas, A.; Castellano, D.;
´ ´
Simonet, A. M.; Molinillo, J. M. G. Structure-activity (SAR) studies
of benzoxazinones, their degradation products, and analogues.
Phytotoxicity on problematic weeds Avena fatua L. and Lolium
rigidum Gaud. J. Agric. Food Chem. 2006, 54, 1040–1048.
(14) Hou, Z. K.; Ren, Y. G.; Huang, M. Z.; Lei, M. X.; Ou, X. M.; Zang,
K. B.; Wang, X. G.; Liu, A. P. Heterocyclic Substituted Benzo[b]-
[1,4]oxazine Derivatives and Their Bioactivity. CN 03118226.7,
2003.
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Hou, Z. K.; Liu, A. P.; Ou, X. M. Synthesis and herbicidal activity of
2-(7-fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)-isoin-
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150
300
37.5
75
þþ þþ þþ
þþ þþ þþ
-
-
-
-
-
þþ
þþ
150
300
þþ þþ
þþ þþ þþ
þþ þþ þþ
þþ þþ þþ
þþ þþ þþ
flumioxazin 37.5
75
-
þþ
150
300
þþ
þþ þþ þþ þþ þþ þþ
a PEA, peanut; SOY, soybean; COT, cotton; MAI, maize; WHE, wheat; RIC, rice;
RAP, rape. b Rating system for phytoxity: þþ, >10% growth inhibition; þ, 1-10%
growth inhibition; -, no growth inhibition.
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Received June 3, 2009. Revised manuscript received September 1, 2009.
Accepted September 3, 2009. We gratefully acknowledge the support
of this work by the National Natural Science Foundation of China
(Grant No. 20872033), Hunan Provincial Natural Science Foundation
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