Design, Synthesis and Herbicidal Activities of Tetrahydroisoindoline-1,3-dione Derivatives Containing Alkoxycarbonyl Substituted 2-Benzoxazolinone

Article abstract of DOI:10.1002/cjoc.201500046

Several different alkoxycarbonyl-substituted 2-benzoxazolinone moieties have been incorporated into a tetrahydroisoindoline-1,3-dione scaffold to provide 25 compounds (1a-1u and 2a-2d). The structures of these compounds were confirmed by ¹H and ¹³C NMR, HRMS and X-ray single-crystal diffraction. Some of these compounds (1g, 1h, 1j, 1k) exhibited excellent herbicidal activities against Abutilon theophrasti, Amaranthus retroflexus and Echinochloa crus-galli at a rate of 375 g AI·ha^-1. Among them, compounds 1h and 1j displayed the best post-emergence herbicidal effect against Abutilon theophrasti with ED₅₀ values of 1.8 and 5.3 g AI·ha^-1, respectively, which are superior to that of the commercial acifluorfen (44.3 g AI·ha^-1). Field trials demonstrated that compound 1h exhibited similar herbicidal activity to a high concentration atrazine, and found to be safer for maize than atrazine. The results of this study therefore show that compound 1h could potentially be used as a post-emergence herbicide for maize fields. Two series of tetrahydroisoindoline-1,3-diones containing an alkoxycarbonyl substituted 2-benzoxazolinone moiety were designed and synthesized. Compound 1h displayed excellent herbicidal effect against Abutilon theophrasti with ED₅₀ values of 1.8 g AI·ha^-1, and compound 1h could potentially be used as a new post-emergence herbicide for maize fields.

Full text of DOI:10.1002/cjoc.201500046

FULL PAPER
DOI: 10.1002/cjoc. 201500046
Design, Synthesis and Herbicidal Activities of Tetrahydroiso-
indoline-1,3-dione Derivatives Containing Alkoxycarbonyl
Substituted 2-Benzoxazolinone
a
a
a
a
b
,b
Hao Zhang, Kechang Liu, Ruiquan Liu, Qibo Li, Yongqiang Li, Qingmin Wang,*
,a
and Shangzhong Liu*
a
Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry,
b
Nankai University, Tianjin 300071, China
Several different alkoxycarbonyl-substituted 2-benzoxazolinone moieties have been incorporated into a tetrahy-
droisoindoline-1,3-dione scaffold to provide 25 compounds (1a–1u and 2a－2d). The structures of these com-
1
13
pounds were confirmed by H and C NMR, HRMS and X-ray single-crystal diffraction. Some of these compounds
1g, 1h, 1j, 1k) exhibited excellent herbicidal activities against Abutilon theophrasti, Amaranthus retroflexus and
(
−
1
Echinochloa crus-galli at a rate of 375 g AI•ha . Among them, compounds 1h and 1j displayed the best
post-emergence herbicidal effect against Abutilon theophrasti with ED50 values of 1.8 and 5.3 g AI•ha , respec-
tively, which are superior to that of the commercial acifluorfen (44.3 g AI•ha ). Field trials demonstrated that
compound 1h exhibited similar herbicidal activity to a high concentration atrazine, and found to be safer for maize
than atrazine. The results of this study therefore show that compound 1h could potentially be used as a
post-emergence herbicide for maize fields.
−
1
−
1
Keywords synthesis, tetrahydroisoindoline-1,3-dione, benzoxazolinone, protoporphyrinogen oxidase, herbicidal
activity
Introduction
last two decades, and resulted in several different het-
[9]
erocyclic compound families, including tetrahydro-
phthalimides, oxadiazolinones, triazolinones, thiadia-
zoles, pyrazoles and uracils. Phenyl heterocycles usually
possess a 2,4,5-trisubstituted phenyl group as a common
structural feature, which is required to obtain high her-
Chemical herbicides have been used successfully for
several decades to achieve convenient and economical
weed control in agricultural practices. Unfortunately,
however, the overuse of herbicides has inevitably re-
sulted in the evolution of herbicide-resistant weeds,
which represents a significant threat to the security and
[
1]
[10]
bicidal activity. Following on from the discovery and
development of new PPO inhibitors, a novel class of
benzoheterocycle herbicides was obtained when the
substituents at 4 and 5 positions of the characteristic
phenyl ring were linked together to yield a broad range
[
2]
stability of food supplies. According to the results of a
recent survey from the Herbicide Resistance Action
Committee, there are currently 404 unique cases (spe-
cies×site of action) throughout the world of herbicide
resistant weeds, however only six weed species have
been found to be resistant to protoporphyrinogen oxi-
dase (PPO, EC 1.3.3.4) inhibiting herbicides up to
[
11]
[5]
of benzoheterocycles,
zimidazole
including flumioxazin, ben-
[
12]
[13]
and benzothiazole derivatives
(Figure
1
). Flumioxazin, whose core scaffold is based on a tet-
rahydrophthalimide skeleton, exhibited a high level her-
bicidal activity towards annual broadleaf weeds at a
very low dosage. Despite its promising activity, there
are several limitations associated with the use of flumi-
oxazin. For example, flumioxazin can cause injury to
[
2,3]
2
014.
PPO-inhibiting herbicides, such as saflu-
[4]
[5]
fenacil and flumioxazin, could be used as part of a
multi-component approach for the management of re-
[6]
sistant biotypes,
such as glyphosate resistance
[7]
weeds, which has stimulated our interest in the dis-
maize, barley, wheat and rice, and can only be applied
[
8]
[14]
covery of novel PPO inhibitors.
as a pre-emergence herbicide.
With this in mind,
Research towards the development of novel phenyl
heterocycles as PPO inhibitors has intensified during the
there is therefore considerable interest in the design of
new tetrahydrophthalimide derivatives with both post-
*
E-mail: shangzho@cau.edu.cn, wangqm@nankai.edu.cn; Tel.: 0086-010-62731070; Fax: 0086-010-62731070
Received January 16, 2015; accepted March 3, 2015; published online XXXX, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500046 or from the author.
Chin. J. Chem. 2015, XX, 1—7
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Zhang et al.
FULL PAPER
emergence herbicidal activity and good crop safety
properties.
(HRMS) was recorded on an Agilent G1969A spec-
trometer (Agilent Technologies, Santa Clara, CA, USA).
X-ray diffraction was performed on a Rigaku MM007-
HF diffractometer (Rigaku, Tokyo, Japan) equipped
with a Saturn724＋ detector using graphite monochro-
mated Mo Kα radiation (λ＝0.71073 Å). The melting
points were obtained utilizing a Stuart melting point
apparatus (Bibby Scientific Limited, Staffordshire, UK)
and were uncorrected.
Benzoxazolinones are a group of secondary metabo-
lites found in cereals that play an important role in de-
[15]
fense of cereals against pests, diseases and weeds.
For example, 2-benzoxazolinone (BOA) and 6-methoxy-
-benzoxazolinone (MBOA) are well known allelo-
chemicals, which exhibit phytotoxicity against the ger-
2
[16]
mination and early growth of several plant species
(
Figure 1). BOA has also been studied for its herbicidal
[15,17]
General procedure for preparation of intermediates
potential.
It was envisaged that the incorporation of
1
0 and 11
a benzoxazolinone ring into a tetrahydrophthalimide
moiety could be used as promising strategy for the iden-
tification of novel herbicidal compounds. It is notewor-
thy that a large number of herbicidal compounds contain
an alkoxycarbonyl group, and it was therefore envis-
aged that the incorporation of an alkoxycarbonyl group
into the benzoxazolinone-substituted tetrahydrophthali-
mides described above would lead to enhanced levels of
lipophilicity, which would favor translocation. Based
on these considerations, we designed and synthesized a
series of N-(2-benzoxazolinone-5-yl)-4,5,6,7-tetrahydro-
isoindole-1,3-diones 1a－1u. For comparison, we also
synthesized the corresponding N-(2-benzoxazolinone-
Synthesis of 6-fluorobenzo[d]oxazol-2(3H)-one
(
4a) A solution of triphosgene (8.2 g, 27.5 mmol) in
THF (50 mL) was added in a dropwise manner to a so-
lution of compound 3a (10.0 g, 78.7 mmol) and pyridine
(12.5 g, 158.0 mmol) in THF (150 mL) at 5 ℃, and the
resulting mixture was stirred at this temperature for 30
min before being warmed to room temperature and
stirred for a further 3 h. The reaction was then evapo-
rated to dryness under vacuum to give a residue, which
was partitioned between a saturated aqueous solution of
[
18]
[
19]
3
NaHCO and ethyl acetate. The aqueous layer was col-
lected and extracted with ethyl acetate, and the com-
bined organic extracts were washed with brine and dried
6
-yl)-4,5,6,7-tetrahydroisoindole-1,3-dione compounds
2
a－2d. Herein, we have described the synthesis of
over MgSO . The solvent was then removed under vac-
4
these compounds and the subsequent evaluation of their
herbicidal activities.
uum to give the crude product, which was recrystallized
from a 1∶1 (V/V) mixture of petroleum ether and ethyl
acetate to give 4a as a yellow solid (8.4 g, yield 70%);
1
Experimental
m.p. 192.6－193.3 ℃; H NMR (300 MHz, DMSO-d
6
)
δ: 11.68 (s, 1H), 7.33 (dd, J＝8.6, 2.4 Hz, 1H), 7.14－
General
6
.93 (m, 2H).
All reagents were purchased from commercial sup-
Synthesis of 6-fluoro-5-nitrobenzo[d]oxazol-
1
pliers, and used directly without further purification. H
2(3H)-one (5a) HNO
added in dropwise manner to a solution of compound 4a
(10.0 g, 65.3 mmol) in 80% H SO (180 mL) at 0 ℃,
3
(60%, 8.9 g, 84.8 mmol) was
1
3
NMR and C NMR spectra were recorded in CDCl
3
or
DMSO-d on a Bruker DPX300 spectrometer (Bruker,
6
2
4
Fallanden, Switzerland), using tetramethylsilane as in-
ternal standard. High-resolution mass spectrometry
and the resulting mixture was stirred at 0 ℃ for 2 h.
The reaction mixture was then poured into a mixture of
F
O
F
O
N
N
F
O
O
N
3
F C
N
S
N
N
N
O
O
N
O
CF3
O
S
O
O
Flumioxazin
Benzothiazole
Benzimidazole
R
X
X
N
O
O
N
R
O
X
N
N
O
O
O
O
heterocycle
O
N
O
+
O
N
R
O
O
1
2
BOA:R = H
R
MBOA: R = OMe
O
O
N
H
Figure 1 Design strategy for compounds 1 and 2.
2
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Chin. J. Chem. 2015, XX, 1—7

Design, Synthesis and Herbicidal Activities of Tetrahydroisoindoline-1,3-dione Derivatives
ice and water (1800 mL), and the resulting solid was
the resulting mixture was heated at reflux for 12 h. The
filtered, rinsed with water, and dried to afford 5a as a
reaction was then cooled to ambient temperature and
slowly poured into a mixture of ice and water (400 mL).
The resulting solid was collected by filtration and
washed with water, then dried to afford 10a as a brown
brown solid (11.9 g, yield 92%); m.p. 179.7－181.1 ℃;
1
H NMR (300 MHz, DMSO-d
H), 7.75 (d, J＝4.4 Hz, 1H).
6
) δ: 12.22 (s, 1H), 7.78 (s,
1
1
solid (3.9 g, yield 72%); m.p. 207.0－208.3 ℃; H
Synthesis of 5-amino-6-fluorobenzo[d]oxazol-
(3H)-one (6a) Compound 5a (10.3 g, 52.2 mmol)
NMR (300 MHz, CDCl
9
4
3
) δ: 11.82 (s, 1H), 7.56 (d, J＝
.3 Hz, 1H), 7.17 (d, J＝6.5 Hz, 1H), 2.39－2.31 (m,
H), 1.79－1.70 (m, 4H).
Intermediates 10b, 11 were synthesized according to
2
and NH Cl (4.2 g) were added to a 1∶1 (V/V) mixture
4
of C H OH and H O (250 mL), and the resulting sus-
2
5
2
pension was heated at 60 ℃ until all of the solid mate-
rial had dissolved. Fe powder (8.7 g) was then added to
the reaction in a portionwise manner, and the resulting
mixture was heated at reflux for 3 h until the reaction
was complete. The hot mixture was then filtered imme-
diately, and the filtrate was concentrated under vacuum
and poured into cold water (500 mL). The resulting sol-
id was collected by filtration and washed with water,
the method described for 10a, and their characterization
data are given in the Supporting Information.
General procedure for preparation of the target
compounds 1 and 2
A halogenated carboxylate (3.0 mmol) was added to
a mixture of compound 10 (or 11) (2.5 mmol) and an-
hydrous K CO (2.5 mmol) in acetone (10 mL), and the
2 3
then dried to afford 6a as a black solid (5.9 g, yield
resulting mixture was heated at reflux for 3 h. The reac-
tion was then cooled to room temperature and filtered.
The resulting filtrate was then evaporated to dryness to
give a residue, which was purified by flash chromatog-
raphy over silica gel eluting with a 10∶1 (V/V) mixture
of petroleum ether and ethyl acetate to give the title
compounds 1a－1u and 2a－2d. The data for com-
pound 1h are shown below, and the data for other title
compounds are given in the Supporting Information.
1
6
7%); m.p. 189.4－191.0 ℃; H NMR (300 MHz,
DMSO-d ) δ: 11.26 (s, 1H), 7.13 (d, J＝10.5 Hz, 1H),
6
6
.51 (d, J＝8.0 Hz, 1H), 4.98 (s, 2H).
Synthesis of 2-(6-fluoro-2-oxo-2,3-dihydrobenzo-
[
(
d]oxazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3-
2H)-dione (10a) Compound 6a (3 g, 17.8 mmol) and
4
,5,6,7-tetrahydroisobenzofuran-1,3-dione (3.2 g, 21.3
mmol) were added to glacial acetic acid (80 mL), and
Scheme 1 Synthetic route for the construction of compounds 1a－1u and 2a－2d
X
X
X
X
ii
O
NO
2
NH2
i
O
iii
O
HO
O
N
H
O
N
O
N
H
H
2
H N
3
3
a X = F
b X = Cl
4aX = F
4b X = Cl
5a X = F
5b X = Cl
6a X = F
6b X = Cl
Cl
Cl
Cl
i
iii
NO2
HN
NH2
H
2
N
NO
2
HN
O
O
O
O
HO
7
8
9
X
N
X
N
O
O
O
O
6
O
v
O
N
H
N
R
iv
O
O
O
1
0aX = F
0b X = Cl
1a- 1n X = F
1o - 1u X = Cl
1
O
R
N
O
H
N
Cl
Cl
O
O
O
v
O
9
O
O
N
N
iv
O
O
1
1
2a - 2d
2 5 2
, 0 ℃; (iii) Fe, NH Cl, C H OH/H O, reflux; (iv) 4,5,6,7-tetra-
Reagents and conditions: (i) pyridine, triphosgene, THF, 5 ℃; (ii) HNO
/conc. H SO
3 2 4
4
hydroisobenzofuran-1,3-dione, HOAc, reflux; (v) RX, K CO , acetone, reflux.
2
3
Chin. J. Chem. 2014, XX, 1—7
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3

Zhang et al.
FULL PAPER
Ethyl 2-(5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-iso-
indol-2(3H)-yl)-6-fluoro-2-oxobenzo[d]oxazol-3(2H)-
in triplicate. After 15 d, the crop safety was determined
by visually comparing the injury caused by the test
treatments relative to the untreated controls.
yl)propanoate (1h) White solid; yield 68%; m.p.
1
1
11.8－112.4 ℃; H NMR (300 MHz, CDCl
3
) δ: 7.17
Field trials
(
d, J＝8.5 Hz, 1H, Ar-H), 6.87 (d, J＝6.1 Hz, 1H, Ar-H),
5
.04 (q, J＝7.4 Hz, 1H, CH), 4.27－4.19 (m, 2H,
), 2.49－2.38 (m, 4H, 2×CH ), 1.89－1.78 (m,
H, CH CH ), 1.72 (d, J＝7.4 Hz, 3H, CHCH ), 1.24 (t,
J＝7.1 Hz, 3H, CH ); C NMR (75 MHz, CDCl ) δ:
68.81, 154.09 (d, JC-F＝246.8 Hz), 153.60, 142.36 (d,
C-F＝13.0 Hz), 142.35, 125.89, 115.12 (d, JC-F＝15.5
Hz), 110.38, 100.21 (d, JC-F＝27.3 Hz), 62.28, 51.75＋,
1.16, 20.17, 14.81, 13.92; HRMS (ESI) m/z: [M＋H]
calcd for C20 : 403.1300; found 403.1304.
The field trials were carried out at Yangtze Univer-
sity, Jingzhou City (Hubei Province, South China). The
soil used in this study was a loam soil containing 1.48%
organic matter, and the pH of the soil was 7.4. The
maize variety Luoyu No. 8 was planted in the soil, and
the treated plots were arranged in a random block array
with four replicates. Compound 1h was formulated as a
10% emulsifiable concentrate, and the commercial her-
bicide 38% atrazine SC was used as a positive control.
The application rate for the post-emergence treatment
OCH
4
2
2
2
2
3
13
2
CH
3
3
1
J
2
H
2 6
20FN O
Greenhouse herbicidal activity
−1
was varied from 100 to 300 g AI•ha . The weed num-
The herbicidal activities of compounds 1a－1u and
a－2d were tested against monocotyledon weeds (i.e.,
bers were measured at regular intervals, and the final
fresh weights of the aerial portions of the weeds were
also measured. The percentage of inhibition relative to
the water-sprayed control group was calculated. The
control effects expressed as percentages were arcsine
transformed to homogenize any variance prior to analy-
sis, and those of the different spraying treatments were
examined using Duncan’s multiple range test.
2
Echinochloa crus-galli and Digitaria sanguinalis) and
broadleaf weeds (i.e., Abutilon theophrasti and Ama-
ranthus retroflexus) using a previously published pro-
[20]
cedure.
Acifluorfen was used as a positive control.
All of the test compounds were dissolved in 100 μL of
N,N-dimethylformamide (DMF) containing a couple of
drops of Tween 20, and the resulting solutions were
sprayed onto pot-grown plants. The rate of application
Results and Discussion
−1
(g AI•ha ) was calculated according to the total amount
of active ingredient in the formulation divided by the
surface area of the pot. Plastic pots with a diameter of 6
cm were filled with soil to a depth of 8 cm. Approxi-
mately 15 seeds of selected weeds were sown in the soil
at the depth of 1－3 cm and grown at 20－30 ℃ in a
greenhouse. The formulation solutions were applied for
pre-emergence treatment 24 h after the seeds had been
sown. For post-emergence treatment, the broadleaf
weeds were treated at the two-leaf stage, whereas the
monocotyledon weeds were treated at the one-leaf stage.
The pre- and post-emergence application rate was set at
Synthesis
As shown in Scheme 1, the target compounds 1a－
1
u were prepared via a five-step linear sequence starting
from either 2-amino-5-fluorophenol (3a) or 2-amino-5-
chlorophenol (3b). By performing the cyclization reac-
tion with BTC, compounds 3a and 3b were converted to
the corresponding 6-substituted-benzo[d]oxazol-2(3H)-
ones 4a and 4b, respectively. Subsequent nitration and
reduction reactions gave the corresponding 5-amino-6-
substituted benzo[d]oxazol-2(3H)-one intermediates 6a
and 6b, which were reacted with 4,5,6,7-tetrahydro-
isobenzofuran-1,3-dione to afford the 2-(2-oxo-2,3-di-
hydrobenzo[d]oxazol-5-yl)-4,5,6,7-tetrahydro-1H-iso-
indole-1,3(2H)-dione intermediates 10a and 10b in
moderate yields. Finally, intermediates 10a and 10b
were reacted with various alkylating agents to give the
target compounds 1a－1u in yields of 56%－80%. In-
termediate 11 was prepared from 2-amino-4-chloro-5-
nitrophenol. Compounds 2a－2d were prepared from
intermediate 11 in yields of 55%－76% according to the
alkylation procedure used for the preparation of com-
pounds 1a－1u.
−1
3
75 g AI•ha . A mixture containing the same amount
of water, DMF and Tween 20 was sprayed as the sol-
vent control. Each treatment was conducted in triplicate.
The fresh weights of the aerial parts of the plant were
measured 10 d after treatment, and the percentage inhi-
bition value was used to describe the control efficiency
of the compounds.
ED50 values of some compounds against Echinoch-
loa crus-galli and Abutilon theophrasti were calculated
with SPSS 17.0 software.
Crop selectivity
Halogenated alkylation reagents generally prefer to
react with nitrogen atoms through N-alkylation reaction
in the target compounds preparation. However, these
Conventional crops of rice, soybean, cotton, wheat
and maize were planted separately in plastic pots (di-
ameter 9 cm) filled with soil and grown in a greenhouse
at 20－25 ℃. After the plants had reached the 4-leaf
[21]
reagents can also react through O-alkylation reactions.
To further confirm the structures of the target com-
stage, the test compounds were applied at a dosage of
3
pounds, The crystal structure of 1h is shown in Figure
2, which unambiguously demonstrates that the target
00 or 150 g AI•ha− for the post-emergence evaluation
1
[22]
of the test compounds. Each experiment was conducted
compounds were N-alkylation products.
4
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© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2015, XX, 1—7

Design, Synthesis and Herbicidal Activities of Tetrahydroisoindoline-1,3-dione Derivatives
X
N
ester carbon and the core structure had a favorable ef-
fect on the inhibitory activity, as demonstrated by the
following trend in the activity of these compounds: 1j
O
N
O
N-Alkylation
O
R
(
(
CH
CH
2
CH
CO
2
CH
2
CO
2 2 5 2 2 2 2 5
C H ) ＞1i (CH CH CO C H ) ＞1c
O
2 5
C H ). However, compounds 1m and 1n,
10
2
2
which both had an unsaturated C＝C bond in their R
group, displayed decreased herbicidal activities com-
pared with their saturated analogues 1j and 1i. The in-
troduction of a methyl or ethyl group at the α-position
of the ester group generally led to a significant increase
in the herbicidal activities of the corresponding com-
pounds, as exemplified by the following trend in the
X
N
R
O
N
O
O-Alkylation
O
O
activities of these compounds: 1g (CH(CH
h (CH(CH )CO ), 1k (CH(C )CO
2 2 5
CO ), 1b (CH CO CH ), 1c (CH CO C H
3
)CO
C H
2 2 5
2
CH
)>>1a
). This
3
),
1
(
3
2
C
2
H
2
5
2
H
5
2
C
2
H
5
2
3
2
rule was also found to be applicable to the chlorinated
derivatives (i.e., 1q, 1r, 1t, 1u＞1o, 1p, 1s).
Table 1 Herbicidal activities (inhibition ratings of 0－100) of
−
1
compounds 1a－1u and 2a－2d at 375 g AI•ha
a
AT
AR
EC
DS
No.R
b
b
pre post pre post prepost pre post
Figure 2 Crystal structure of compound 1h.
1
a CO
2
2
C
2
H
5
0
82
0
86 0 10
0
0
0
0
0
10
15
5
Greenhouse herbicidal activity and structure-activity
relationships
1b CH
CO
2
CH
3
15 100 35 30 0 15
10 100 20 24 0 10
1
c CH CO C H
2 2 2 5
The herbicidal activities of compounds 1a－1u and
a－2d were evaluated against monocotyledon weeds
E. crus-galli and D. sanguinalis) and broadleaf weeds
A. theophrasti and A. retroflexus) in a greenhouse at
1d CH CO CH CH CH
3
0 100 20
10 100
0
0 15
5
2
2
2
2
2
(
(
1
1
1
1
e CH CO CH(CH )
0
15 0 10
10
0
2
2
3 2
f CH CO C(CH )
3 3
20 100 99 52 40 62 84
2
2
g CH(CH )CO CH
85 100 99 100 20 100 42 27
96 100 99 100 40 100 35 53
29 100 90 27 10 45 35 50
3
3
2
2
3
different rates. All of the compounds were initially
tested at a rate of 375 g AI•ha− for their pre-emergence
and post-emergence herbicidal activities. As shown in
Table 1, compounds 1a－1n (X＝F) generally dis-
played greater herbicidal activities than the correspond-
ing chlorine-containing compounds 1o－1u (X＝Cl).
Furthermore, compounds 2a－2d showed no detectable
activity in the pre- or post-emergence activity studies.
Compounds 1a－1u were found to be more potent to-
wards dicotyledon weeds than monocotyledons, and the
activities observed in the post-emergence treatment
group were generally better than those observed in the
pre-emergence treatment group. For example, most of
the compounds belonging to series 1 displayed 100%
control in the post-emergence treatment group against A.
theophrasti. Among them, compounds 1g, 1h, 1j and 1k
also exhibited 100% control against E. crus-galli and A.
retroflexus. Unfortunately, however, these compounds
displayed poor herbicidal activity against D. sanguinalis.
Taken together, these results indicated that the confor-
mation of the scaffold is critical to the activities of these
compounds. For example, compounds belonging to se-
ries 1 gave much higher levels of inhibitory activity
than the corresponding compounds belonging to series 2
bearing the same R group. Meanwhile, the structure of
R substituent also exerts a significant influence over the
herbicidal activities of the compounds belonging to se-
ries 1. The introduction of a longer chain between the
1
h CH(CH
CH
)CO
CO
2
C
2
H
5
1i CH
C
H
2
2
2
5
1j CH CH CH CO C H 100 100 100 100 0 99 49 51
2
2
2
2
2
5
1
1
1
1
k CH(C H )CO C H
100 100 100 100 60 100 28 24
3 3
0 25 20 87 25
2
5
2
2
5
l CH(C H )CO C(CH ) 20 100 80
2
5
2
m CH CHCHCO C H
0 100 53
0 100 50
0 20 50
0 10 20
0
0
0
0
0
0
0
0
0
0
0
0
30
40
0
2
2
2
5
n CH
2
C(CH
2
)CO
2
C
2
H
5
1o CH CO C H
5
0
0
0
5
0
0
0
0
0
0
0
0
0
2
2
2
1
p CH CO C(CH )
3 3
10
0 10
0
2
2
1
q CH(CH )CO CH
3
15 100 40
0
0
0
5
0
0
50
60
5
3
2
1
r CH(CH )CO C H
5
0 100
5
0
0
3
2
2
1
s CH CH CO C H
5
0
15
89
2
2
2
2
5
1t CH
2
CH
2
CH
2
CO
2
C
2
H
5
0 15
0
1u CH(C H )CO C H
15 100 39 10 0 15
0
2
5
2
2
5
2
2
2
2
a CH CO C H
5
0
0
5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
2
2
b CH CO C(CH )
3 3
0 10
0
2
2
c CH(CH )CO CH
3
0
0
0
0
3
2
d CH CH CH CO C H
5
5 15
0
2
2
2
2
2
acifluorfen
a
50 100 97 97 65 87 100 65
AT, Abutilon theophrasti; AR, Amaranthus retroflexus; EC,
b
Echinochloa crus-galli; DS, Digitaria sanguinalis. pre: pre-
emergence; post: post-emergence.
Compounds 1h and 1j that showed excellent levels
Chin. J. Chem. 2014, XX, 1—7
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Zhang et al.
FULL PAPER
of activity were chosen for further testing their ED50
values. As shown in Table 2, compound 1h exhibited
better herbicidal activity against A. theophrasti and E.
activity and crop selectivity in the greenhouse field test,
was evaluated further in a maize field trial. As shown in
Table 4, 10% of the EC of 1h showed good control ef-
fects against broadleaf weeds and some grass weeds at
−1
crus-galli (ED50 value of 1.8 and 48.4 g AI•ha , re-
spectively) than compound 1j (ED50 values of 5.3 and
−1
dosages in the range of 200－300 g AI•ha . The 7-day
−1
−1
7
4.2 g AI•ha , respectively). Notably, their activities
herbicidal effect (88% control) of 1h at 300 g AI•ha
was almost equal to that of atrazine (90% control) at
against A. theophrasti were found to be far superior to
−1
the commercial herbicide acifluorfen (ED50 value of
8
00 g AI•ha . Compound 1h was also found to be safer
−1
4
4.3 g AI•ha ). Furthermore, the results of the crop
for maize than atrazine (10% injury). 28 d after being
sprayed onto the plants, compound 1h still exhibited a
higher level of activity (91% control) towards the
weight of the weeds than atrazine (85% control). Most
notably, compound 1h showed a long lasting control
effect, and there was no significant difference between
the levels of control observed at 14 and 28 d.
safety test showed that compound 1h was safe for rice,
−1
wheat and maize at a dosage of 150 g AI•ha (Table 3),
whereas the same rate of flumioxazin led to damage in
all five of the crops tested in the current study. Even at
−1
an application rate of 300 g AI•ha , maize still exhib-
ited high tolerance towards compound 1h.
Table 2 ED50 values of compounds 1h, 1j and acifluorfen
a
Conclusions
(
post-emergence)
Two series of tetrahydroisoindoline-1,3-diones have
been designed and synthesized containing an alkoxy-
carbonyl substituted 2-benzoxazolinone moiety. The
results of greenhouse tests indicated that some of these
newly synthesized compounds exhibited excellent her-
bicidal activities against A. theophrasti, A. retroflexus
and E. crus-galli. Compound 1h was identified as the
most promising candidate of all of the compounds tested
because of its good post-emergence herbicidal activity
and excellent selectivity for maize. Further field trials
indicated that compound 1h possessed similar herbicidal
activity to atrazine, as well as a long duration of control
efficacy. These results therefore suggest that compound
Abutilon theophrasti
Echinochloa crus-galli
Compd.
y＝bx＋a
ED50
y＝bx＋a
ED50
1
h
j
y＝1.48x−0.38 1.8
y＝1.02x−0.74 5.3
y＝0.89x−1.50
y＝0.81x−1.52
48.4
74.2
1
b
acifluorfen y＝3.24x−5.34 44.3
/
a
−1 b
ED50, 50% effective dose, the unit is g AI•ha . /, not tested.
Table 3 Crop selectivities of compound 1h and flumioxazin
post-emergence)
(
a
Compd.
Dose Rice
White Maize Cotton Soybean
b
1h
150
00
＋
＋
−
−
＋＋ ＋＋
c
3
/
/
/
/
1
h could be a potential candidate for the development of
flumioxazin 150
＋＋ ＋＋ ＋＋ ＋＋ ＋＋
a new post-emergence herbicide for use in maize fields.
a
the unit is g AI•ha−1. b Rating system for injury: ＋＋, injury＞
0%; ＋, injury＝1%－10%; −, no injury. /: not tested.
c
Acknowledgement
1
This work was supported by the National Key Tech-
nologies R&D Program (No. 2011BAE06B03), and Na-
tional Natural Science Foundation of China (No.
21172256).
Table 4 Herbicidal effects of compound 1h in a maize field
(
Jingzhou, China)
Control effect of Control effect
weed number /% after 28 d /%
Maize
injury/%
b
b
a
Compd. Dose
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c
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Chin. J. Chem. 2014, XX, 1—7
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
7