Discovery of novel 3-{[(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sulfonyl]methyl}benzo[d]isoxazole analogs as promising very long chain fatty acids inhibitors

Article abstract of DOI:10.1002/jhet.4162

Very long chain fatty acids (VLCFAs) are one of the most principal and promising targets for herbicides discovery. In order to explore and find novel VLCFAs inhibitors with higher herbicidal activity and improved crop safety, a variety of new 3-{[(5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sulfonyl]methyl}benzo[d]isoxazole derivatives were reasonably designed and synthesized. The results of greenhouse experiments indicated that several compounds exhibited good herbicidal activity against Digitaria sanguinalis, Echinochloa crus-galli, and Setaria faberii at rates of 150 g ai/ha. Compounds g4 and h1 displayed promising herbicidal activity against D sanguinalis and E crus-galli at rates of 75 g ai/ha, which is better than commercial pyroxasulfone and S-metolachlor. Moreover, compound h1 displayed higher activity against E crus-galli, D sanguinalis, and S faberii than pyroxasulfone and S-metolachlor even at a rate of 37.5 and 18.75 g ai/ha. Furthermore, both of the compounds g4 and h1 were much safer to these tested crops, especially to rice, wheat and rape, at the rate of 150 g ai/ha than pyroxasulfone. Therefore, h1 may act as a new lead structure for novel herbicides discovery.

Full text of DOI:10.1002/jhet.4162

Discovery of Novel 3 -(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl) sulfonyl) methyl)
benzo[d]isoxazole analogs as Promising Very long chain fatty acids Inhibitors
Jian Lin a,b*, Yitao Li a*, Xiaoyun Hu a, Weilin Chi a, Shuiming Zeng a, Junxing
Xu a
a Dongguan HEC Pesticides R&D Co., Ltd. Dongguan 523871, Guangdong, People’s Republic of
China.
b College of Chemistry Biology and Environmental Engineering, Xiangnan University, Chenzhou
423000, People’s Republic of China
*Jian Lin, Dongguan HEC Pesticides R&D Co., Ltd. Dongguan 523871, Guangdong, People’s
Republic of China. Tel +86-076985315888-5575. E-mail: linjian@hec.cn.
College of Chemistry Biology and Environmental Engineering, Xiangnan University, Chenzhou
423000, People’s Republic of China
*Li Yitao, Dongguan HEC Pesticides R&D Co., Ltd. Dongguan 523871, Guangdong, People’s
Republic of China. E-mail: liyitao@hec.cn
Abstract: Very long chain fatty acids (VLCFAs) are one of the most principal and promising targets for
herbicides discovery. In order to explore and find novel VLCFAs inhibitors with higher herbicidal
activity
and
improved
crop
safety,
a
variety
of
new
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sulfonyl)methyl)benzo[d]isoxazole
derivatives
were
reasonably designed and synthesized. The results of greenhouse experiments indicated that several
compounds exhibited good herbicidal activity against Digitaria sanguinalis, Echinochloa crus-galli
and Setaria faberii at rates of 150 g ai /ha. Compounds g4 and h1 displayed promising herbicidal
activity against D. sanguinalis and E. crus-galli at rates of 75 g ai/ha, which is better than commercial
pyroxasulfone and S-metolachlor. Moreover, compound h1 displayed higher activity against E.
crus-galli, D. sanguinalis and S. faberii than pyroxasulfone and S-metolachlor even at a rate of 37.5 g
ai/ha and 18.75 g ai/ha. Furthermore, both of the compounds g4 and h1 were much safer to these tested
crops, especially to rice, wheat and rape, at the rate of 150 g ai/ha than pyroxasulfone. Therefore, h1
may act as a new lead structure for novel herbicides discovery.
Keywords: Very long chain fatty acids, herbicidal activity, benzoisoxazole derivatives, heterocyclic
compounds.
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1 INTRODUCTION
Pyroxasulfone
was
mainly
used
for
In global agriculture, weeds control can
significantly avoid crop losses in many crop
protection strategies [1]. Thus, herbicides are
particularly important in weeds control and the
discovery of new environmentally friendly and
crop safety herbicides becomes imminent [2-4].
Very long chain fatty acids (VLCFAs) are
important components for plants, invertebrates
and vertebrates. In higher plants, VLCFAs are
involved in sphingolipids and phospholipids as
membrane components and signal molecules,
which can regulate cell size, division and
differentiation [5, 6]. They are also prerequisite
for the production of suberin and cuticular waxes,
which can protect plants from desiccation or
external aggressions [7-9]. Therefore, inhibiting
the synthesis of VLCFAs can effectively destroy
the cuticular waxes of the plant and reduce the
defense ability of the plant to achieve the
purpose of weeds control [10].
pre-emergence grass and broadleaf weeds
control at 125～250 g ai /ha in various crops
such as corn, soybean, cotton, peanut, wheat, etc
[26-28]. However, pyroxasulfone is less safe to
rice. The extended exposure of some VLCFAs
herbicides and improper use may lead to the
rapid development of herbicide-resistant
biotypes [29-31]. Therefore, it is still very
essential to find novel environmentally friendly
VLCFAs inhibitors with a unique structure.
Due to the broad spectrum and high
efficiency of heterocyclic compounds, it has
become the mainstream of pesticide discovery in
recent years [32,33]. More than 90% of the
world’s pesticide patents are about heterocyclic
compounds
[32-34].
Benzo-heterocyclic
compounds are an important branch of
heterocyclic compounds, and they occupy an
important position in the research and
development of pesticides and medicines [35,36].
There are many benzo five-membered
heterocyclic herbicides on the market, all of
which have good herbicidal activity, such as
fenoxaprop-p-ethyl and metamifop [37-39].
Benfuresate and ethofumesate are both
benzofuran ring herbicides that can control
annual or perennial grass weeds [40,41].
Benzoisoxazole, as an important biomedical
molecular skeleton, has extremely high
biological activity and pharmaceutical properties
and is abundantly applied in drugs [42,43]. In
agriculture, benzoisoxazole is mainly used in
fungicides as a molecular active fragment, and
The application of VLCFAs herbicides to
extirpate weeds in crop fields can be traced back
to the 1950s. With more than 60 years of
developments, a lot of different types of
VLCFAs inhibitors have been discovered [11].
They are mainly divided into Acetamides,
Chloroacetamides,
Oxyacetamides,
Tetrazolinones and others [12-14]. As an early
herbicide of chloroacetamide, acetochlor
occupies a large market, and metolachlor is the
same as acetochlor [15-19]. Subsequently,
Syngenta developed the optically active isomer
S- metolachlor [20-24]. In 2016, worldwide
sales of S- metolachlor reached $590 million,
making it the largest acetamide herbicide,
surpassing acetochlor. At present, with the
exposure of acetochlor and isopromethachlor
potential hazards to human and the forbiddance
of acetochlor in European Union, the herbicides
less
in
herbicides
[44].
Therefore,
promising
benzoisoxazole might be
a
pharmacophore moiety to integrate with a
five-membered ring pharmacophore of
pyroxasulfone. In this paper, we designed and
synthesized series of
containing
the
structural
type
of
a
3-sulfonylisooxazole, such as pyroxasulfone and
fenoxasulfone were commercialized by Japanese
companies in 2011 and 2014, respectively [25].
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sulfo
nyl)methyl)benzo[d]isoxazole compounds by
regarding pyroxasulfone as the lead compound
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to obtain novel molecules with better herbicidal
effects. S-metolachlor was used as a positive
control. In this paper, the synthesis of these
compounds, herbicidal activities against three
weeds and their structure-activity relationships
were reported in details.
in Scheme 2, Rc is diffirent substitutions.
Compound (n1) with Rc-C(=O)-Cl can undergo
nucleophilic substitution under a base condition
(i.e., K2CO3, TEA, Py, etc.) to give objective
compound (s).
2.2 Herbicidal activities
2 RESULTS AND DISCUSSION
The pre-emergence herbicidal activities of
these newly synthesized compounds f1, f2,
g1-g8, h1-h3, m1-m3, n1 and s1-s15 were tested
against D. sanguinalis, E. crus-galli and S.
faberii at rates of 150 g ai/ha in the greenhouse
2.1 Chemistry.
Synthesis of the target compounds were
revealed in Scheme 1 and 2, respectivly.
Synthetic route of target compound (g) and
compound (h) are shown in scheme 1, Rm, Rn, Rv
and Rw represent different substitutions.
Compound (a) can react with acetylchloride to
give compound (b); compound (b) can react with
experiments.
The
commercial
herbicide
pyroxasulfone and S-metolachlor were selected
as positive controls (table 1 and 2). The treated
weeds didn’t germinate, which demonstrated the
typical features of herbicides that inhibit
VLCFAs. Several compounds had good
herbicidal activity to three weeds at the
hydroxylamine hydrochloride under
a base
condition (i.e., sodium acetate, etc.) to give
compound (c); compound (c) can undergo
cyclization to give compound (d); compound (d)
can undergo bromination reaction to give
concentration of 150
g
ai/ha. Such as,
compounds g3, g4, g7, s14, h1 and h2 showed a
100% herbicidal activity against at least two
weeds in D. sanguinalis, E. crus-galli and S.
faberii at a concentration of 150 g ai/ha which is
compound
(e);
compound
(e)
with
5,5-dimethyl-4,5-dihydroisoxazol-3-yl
carbamimidothioate can undergo condensation
reaction to give compound (f); compound (f) can
further be oxidized to give objective compound
(g); objective compound (g) can react with
iodomethane to give objective compound (h).
Synthetic route of target compound(s) is shown
much
better
than
pyroxasulfone
and
S-metolachlor. Therefore, compounds with a
weed inhibition rate of 100% against at least two
weeds were selected for further herbicidal
testing.
Figure 1 Comparison of greenhouse pot experiment
Compounds g3, g4, g7, s14, h1 and h2
were choosed to detect herbicidal activity before
emergence against three species at lower
concentrations. As shown in table 3, compounds
g4 and h1 exhibited promising herbicide activity
against D. sanguinalis and E. crus-galli (Figure
1), with ≥80% inhibition at rates of 75 g ai/ha,
which is better than pyroxasulfone and
S-metolachlor. Moreover, compound g4 and h1
displayed excellent activity against E. crus-galli
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even at rates of 37.5 g ai/ha, which was better
than pyroxasulfone and S-metolachlor. The other
compounds, g3 and h2, had good activity against
E. crus-galli, but displayed poor activity against
D. sanguinalis and S. faberii at rates of 75 g
ai/ha. It can be concluded from table 1, 2 and 3
that the herbicide actidivity of compounds with
substituents Rm –F or –H and Rn –H or –F was
better than compounds with substituents on
benzoisoxazole is -Br. At the same time, most of
compounds s have poor herbicidal activity
against three weeds except s1, s4 and s14, which
indicated that substituent Rc on N was not
conducive to herbicidal activity except for ester
group. Finally, compounds g4 and h1 were
selected for further crop selectivity testing.
Table 1 Herbicidal activity of compounds under pre-emergence at 150 g ai ha−1
Compound
Rm
-H
-H
-H
-H
-H
-F
Rn
-F
Rw
-H
-F
Ra
-H
-H
-H
-H
-H
-H
-H
-H
-H
n
0
0
2
1
2
2
2
2
2
SF
0
EC
30
20
95
70
90
100
100
0
DS
0
f1
f2
-H
-F
0
0
g1
g2
g3
g4
g5
g6
g7
-H
-H
-F
80
20
100
100
90
40
100
90
70
100
100
80
0
-F
-H
-H
-Br
-H
-Cl
-H
-H
-Br
-H
-H
-H
-H
90
100
g8
h1
-H
-H
-Cl
-F
-H
-H
-H
1
2
90
100
100
90
-CH3
100
100
h2
-F
-H
-H
-H
-H
-Br
-H
-H
-CH3
-CH3
-H
2
2
2
2
2
2
100
0
100
0
90
0
h3
-NH2
-NO2
-H
-F
m1
m2
m3
n1
-F
0
0
30
0
-NO2
-Cl
-F
-H
40
0
0
-NO2
-NH2
-H
0
0
-H
0
0
0
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70
85
70
90
70
75
pyroxasulfone
960
g/L
S-Metolachlor
SF-Setaria faberii, EC-Echinochloa crus-galli, DS-Digitaria sanguinalis
Table 2 Herbicidal activity of compounds under pre-emergence at 150 g ai ha−1
Compound
s1
Rc
Ra
SF
EC
DS
-OC2H5
-H
90
90
80
0
s2
s3
-H
-H
0
0
-C(CH3)3
25
30
45
s4
s5
-OCH2CH=CH2
-H
-H
100
60
80
25
90
45
s6
s7
-H
-H
0
0
0
0
0
0
s8
s9
-H
20
80
30
80
15
80
-CH3
s10
s11
-H
-H
0
0
0
-CH2CH2Cl
20
30
15
s12
s13
s14
-(CH2)4CH3
-CH2Br
-H
-H
-H
25
15
50
30
40
25
-OCH(CH3)2
100
100
100
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s15
-H
45
60
70
pyroxasulfone
960 g/L
70
85
70
90
70
75
S-Metolachlor
SF-Setaria faberii, EC-Echinochloa crus-galli, DS-Digitaria sanguinalis
Table 3 Further herbicidal activity of six compounds under pre-emergence conditions at different
concentrations
Compound
Dosage g ai /ha
SF
EC
DS
g3
18.75
37.5
75
15
30
60
55
70
75
40
55
75
65
75
90
55
60
65
20
65
75
50
60
65
25
55
75
20
45
85
55
80
90
35
50
70
60
80
90
40
55
85
10
45
55
50
65
70
45
70
80
15
25
65
25
60
80
55
65
80
65
75
85
20
50
75
20
45
70
50
65
70
20
35
65
g4
18.75
37.5
75
g7
18.75
37.5
75
h1
18.75
37.5
75
h2
18.75
37.5
75
s14
18.75
37.5
75
Pyroxasulfone
18.75
37.5
75
960 g/L
18.75
37.5
75
S-Metolachlor
SF-Setaria faberii, EC-Echinochloa crus-galli, DS-Digitaria sanguinalis
2.3 Crop selectivity
600 g ai/ha (injury ≤10%). Compound g4
displayed high safety to soybean, cotton and
sunflower after pre-emergence application at a
dosage of 600 g ai/ha. However, the commercial
pyroxasulfone was safe only to soybean at
concentrations of 600 g ai/ha and 300 g ai/ha,
whereas compound h1 was quite safe to these
seven crops at a dosage of 300 g ai/ha (injury
≤10%). Moreover, the compound h1 show
Crop selectivity and safety is one of the
main difficulties in herbicides discovery. The
crop selectivity of h1, g4 and pyroxasulfone
were also tested at rates of 37.5, 75, 150, 300 and
600 g ai/ha, respectively (Table 4). Among
seven of the tested crops, soybean, cotton and
maize displayed high tolerance to compounds h1
by pre-emergence application even at rates of
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almost no harm to seven crops at a rate of 150 g
ai/ha, whereas the commercial pyroxasulfone
was found to show damage (injury >10%) to
most of tested crops at the same rate. These
results indicate that compound h1 might develop
as a promising and potential herbicidal for rice,
wheat and others fields.
Table 4 Crop selectivity (injury rating 0–100) of compounds h1 and g4 (pre-emergence 37.5, 75, 150,
300 and 600 g ai/ha)
Dosage
(g ai/ha)
37.5
75
sunflowe
Compound
h1
maize
soybean cotton
rape
wheat
rice
r
0
0
0
0
0
10
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
150
0
0
2
0
0
0
300
0
0
5
10
30
0
10
20
0
10
15
0
600
0
5
15
0
37.5
75
0
0
0
0
0
0
0
0
g4
150
0
0
2
10
30
50
0
10
30
50
0
0
300
10
30
0
0
8
5
600
3
15
25
45
50
75
90
10
5
37.5
75
15
25
40
55
85
0
20
30
40
50
20
40
70
90
15
25
50
60
Pyroxasulfone
150
10
50
80
300
600
internal reference. 13C NMR spectra were
recorded in CDCl3 or DMSO-d6 on the VARIAN
Mercury-Plus 400 or 600 spectrometer, and
chemical shifts (δ) are given in ppm relative to
the center line of a triplet at 77.0 ppm of CDCl3.
Multiplicities are indicated by the following
abbreviations: s, singlet; d, doublet; t, triplet; m,
multiplet; br, broad.
3 EXPERIMENTALS
3.1 Materials and methods
All reagents have been purchased commercially
1
and can be used without further purification. H
NMR spectra were recorded in CDCl3 or
DMSO-d6 on a VARIAN Mercury-Plus 400 or
600 spectrometer (varian Inc., Palo Alto,
California, USA) and TMS was regarded as the
3.2 Synthetic procedures
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Scheme 1. Synthetic route of compound (g) and compound (h). Rm, Rn and Rw represent different
substitutions.
Scheme 2. Synthetic route of compound (s). Rc is diffirent substitutions.
synthesis of 1-(4-fluoro-2-hydroxyphenyl)
ethanone
combined organic layers were concentrated in
vacuo to remove the solvent. Column
chromatography (eluent: petroleum ether/EtOAc
(v/v) = 10/1) was used to purify the residue to
give a brown solid (30.20 g), yeild: 70%.
In a three-neck flask, 3-Fluorophenol (31.36 g,
280 mmol) was added and stirred at 0 °C, then
acetyl chloride (24.22 g, 308 mmol) was added
slowly into the flask drop by drop. After
dropwise addition, the mixture was stirred at 25
°C for 2 hours, then heated to 130 °C, and
anhydrous aluminium trichloride (52.00 g, 389
mmol) was added slowly into the mixture. After
addition, stirring the mixture for 2 hours at 130
°C, then water (500 mL) to was added the
mixture. Ethyl acetate (300 mL) was used to
extract the mixture for three times, and the
synthesis of 1-(4-fluoro-2-hydroxyphenyl)
ethanone oxime
1-(4-Fluoro-2-hydroxyphenyl)ethanone (6.3 g,
41 mmol), hydroxylamine hydrochloride (5.70 g,
82 mmol) and anhydrous sodium acetate (7.73 g,
94 mmol) were added in anhydrous methanol
(60 mL). The mixture was refluxed in an oil-bath
at 70 °C for 4 hours, then the reaction was
stopped. Water (200 mL) was added to the
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mixture when it cooled to 25 °C. The resulting
mixture was stirred for 0.5 h, and then filtered.
The residue was washed with water (300 mL)
for three times to give a gray solid (6.60 g),
yield: 95%.
till the solid was dissolved. Hydroxyurea (15.2
g, 0.2 mol) was added to the solution and ethyl
3,3-dimethylacrylate (25.6 g, 0.2 mol) was
added drop by drop. After stirring the mixture
for 120 min at room temperature, it was filtered
and the filtrate was concentrated by rotary
evaporation in vacuo to remove the methanol.
Water (100 mL) was added into the residue and
the mixture was stirred until the residue was
dissolved completely at room temperature, then
the mixture was adjusted with concentrated HCl
(2 mol/L) to pH 2. Dichloromethane (60 mL)
was used to extract the mixture and the obtained
organic layer was concentrated by rotary
synthesis
of
6-fluoro-3-methylbenzo
[d]isoxazole
1-(4-Fluoro-2-hydroxyphenyl)ethanone oxime
(6.60 g, 39 mmol), acetic anhydride (28.00 g,
273 mmol) and anhydrous sodium acetate (7.40
g, 90 mmol) were mixed in DMF (100 mL). An
oil-bath was used to reflux the mixture for 12
hours at 136 °C, then the reaction was stopped.
Water (200 mL) was added to the mixture when
it cooled to 25 °C, then the mixture was stirred.
Ethyl acetate (300 mL) was used to extract the
mixture for three times. The combined organic
layers were concentrated in vacuo to remove the
solvent. Column chromatography (eluent:
petroleum ether/EtOAc (v/v) = 10/1) was used to
purify the residue to give a white solid (4.35 g),
yield: 74%.
evaporation
in
vacuo
to
remove
dichloromethane.
5,5-dimethylisoxazolidin-3-one as a white solid
(18 g) was obtained, yield: 78.3%.
To a 250 mL dried four-neck flask was added
dichloromethane
(100
mL),
phosphorus
oxychloride (24.5 g, 0.16 mol) and N,
N-dimethylformamide (3.7 g, 0.05 mol) under
nitrogen protection. Stir the mixture for 30
minutes at room temperature. The mixture of 5,
synthesis of 3-(bromomethyl)-6-fluorobenzo
[d]isoxazole
6-Fluoro-3-methylbenzo[d]isoxazole (2.10 g,
13.9 mmol) and NBS (7.42 g, 41.7 mmol) was
added in CCl4 (30 mL) and was heated to 75 °C
5-dimethylisoxazolidine-3-ketone
(12.1g,
0.1mol) and dichloromethane (30mL) was added
to the reaction flask drop by drop. After the
additon, stir the mixture until 2 hours later at
room temperature and the mixture was
concentrated by vacuum distillation to give
3-chloro-5,5-dimethyl-4,5-dihydroisoxazole as
light yellow liquid (12.8 g), yield: 95.5%.
under
nitrogen
protection,
then
azodiisobutyronitrile (0.92 g, 5.6 mmol) was
added to the mixture and stirred for 18 h. The
reaction was stopped, and the mixture was
filtered when it cooled to 25 °C. CCl4 (30 mL)
was used to wash the filtrate for three times, and
the organic layer was concentrated to remove
solvent in vacuo. Column chromatography
(eluent: petroleum ether/EtOAc (v/v) = 10/1)
was used to purify the residue to give a white
solid (1.10 g), yield: 34.4%.
synthesis
of
5,5-dimethyl-4,5-dihydroisoxazol-3-yl
carbamimidothioate hydrobromide
Thiourea (6 g, 79 mmol) was dissolved in
acetonitrile (65 mL) and hydrobromic acid
(48%, 10 mL) was added to the solution
dropwise. Then, stirr the mixture for 60 min at
room
synthesis
of
3-chloro-5,5-dimethyl-4,5
-dihydroisoxazole
To a 250 mL dried four-neck flask was added
anhydrous methanol (100 mL), then potassium
methoxide solid (21 g, 0.3 mol) was added
slowly into the flask, and the mixture was stirred
temperature.3-chloro-5,5-dimethyl-4,5-dihydrois
oxazole (12.6 g, 95 mmol) was added drop by
drop to the mixture, which was stirred overnight
at 40 °C. The solid was obtained by evaporating
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the solvent in the mixture under reduced
pressure and recrystallizing from ethyl acetate to
get a white crystaline (19.2 g), yield: 96.0%.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thi
o)methyl)-6-fluorobenzo[d]isoxazole
(compound f1)
white
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sulfo
nyl)methyl)-6-fluorobenzo[d]isoxazole (g1),
solid
product
(0.26
g):
yield: 73.3%; and a white solid product (50mg):
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sulfi
nyl)methyl)-6-fluorobenzo[d]isoxazole
(g2),
yield: 14.5%. The compounds of g3-g8 was
obtained according to this method.
3-(Bromomethyl)-6-fluorobenzo[d]isoxazole
(1.2
g,
5.2
mmol)
and
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
fonyl)methyl)-6-fluoro-5-nitrobenzo[d]isoxazo
e (commpound m1)
5,5-dimethyl-4,5-dihydroisoxazol-3-yl
carbamimidothioate hydrobromide (1.59 g, 6.3
mmol) was dissolved in acetonitrile (30 mL).
After stirring the mixture for 20 minutes,
potassium carbonate (2.88g, 21.0mmol) was
added to the mixture and stirred at 25 ℃ for 8
hours before stopping. To the reaction mixture
was added water (30 mL) with stirring. Ethyl
acetate (50 mL) was used to extract the mixture
for three times. To remove the solvent, the
organic layers were concentrated in vacuo.
Column chromatography (eluent: petroleum
ether/EtOAc (v/v) = 15/1) was used to purify the
residue to obtain brown liquid (1.04 g), yield:
71.2%. The compounds of f2 was obtained
according to this method.
To
thermometer
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
sulfonyl) methyl)-6-fluorobenzo[d]isoxazole
a
three-neck flask equipped with
was dissolved
(0.84 g, 2.7 mmol) in concentrated sulfuric acid
(98%, 10 mL). Stir the mixture at -5 ° C, then
slowly add concentrated nitric acid (63%, 0.42 g,
4.0 mmol) while the temperature of the mixture
was maintained below 0 °C. After addition, the
mixture was stirred below 15 °C for 4 h, then the
reaction was stopped. To the reaction mixture
was added ice-water (30 mL) with stirring, then
the mixture was filtered. Ice-water (20 mL) was
used to wash the solid for three times, then
column chromatography (eluent: petroleum
ether/EtOAc (v/v) = 4/1) was also used to purify
the residue to give a brown solid (0.3 g), yield:
31%. The compounds of m2 and m3 was
obtained according to this method.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
fonyl)methyl)-6-fluorobenzo[d]isoxazole
(compound
g1)
and
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
finyl)methyl) -6-fluorobenzo[d]isoxazole (g2)
3-(((5,5-Dimethyl-4,5-dihydroisoxazol-3-yl)thio
)methyl)-6-fluorobenzo[d]isoxazole (0.32 g, 1.1
mmol) and metachloroperbenzoic acid (0.46 g,
2.3 mmol) were dissolved in dichloromethane
(10 mL). The mixture was stirred for 4 hours
before stopping the reaction at 25 °C. Water (50
mL), saturated aqueous sodium sulphite (50 mL),
saturated brine (50 mL), saturated aqueous
sodium bicarbonate (50 mL) and saturated brine
(50 mL) were used to wash the mixture in turn.
Ethyl acetate (50 mL) was used to extract the
solution for three times. Rotary evaporation and
column chromatography (eluent: petroleum
ether/EtOAc (v/v) = 15/1) were used to get a
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
fonyl)methyl)-6-fluorobenzo[d]isoxazol
-5-amine (compound n1)
3-(((5,5-Dimethyl-4,5-dihydroisoxazol-3-yl)sulf
onyl)methyl)-6-fluoro-5-nitrobenzo[d]isoxazole
(0.26 g, 0.73 mmol), NH4Cl (0.078 g, 1.5 mmol)
and iron powder (0.16 g, 2.9 mmol) were
dissolved in a mixture of ethanol and water (
(v/v) = 3/1, 13 mL). Before stopping the
reaction, the mixture was refluxed for 8 hours at
85 °C. Celite pad and ethanol (30 mL) were used
to filter and wash the mixture respectively.
Rotary evaporation and column chromatography
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(eluent: petroleum ether/EtOAc (v/v) = 4/1)
were used to dry and purify the residue to obtain
a light yellow solid (0.088 g), yield: 36.8%.
sulfonyl)ethyl)-6-fluorobenzo[d]isoxazol-5-am
ine (compound h3)
3-(((5,5-Dimethyl-4,5-dihydroisoxazol-3-yl)sulf
onyl)methyl)-6-fluorobenzo[d]isoxazol-5-amine
(100 mg, 0.31 mmol) and K2CO3 (85.6 mg, 0.62
mmol) were put in DMF (10 mL). Iodomethane
(52 mg, 0.37 mmol) was added in the mixture
when it was stirred at 25 °C. Then, stirr the
mixture at 40 °C for 4 h befor stopping the
reaction. To the mixture was added water (20
mL), and ethyl acetate (30 mL) was used to
extract the resulting mixture for 3 times. The
solvent in combined organic layers was romoved
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thi
o)methyl)-7-fluorobenzo[d]isoxazole
(compound s1)
3-(((5,5-Dimethyl-4,5-dihydroisoxazol-3-yl)sulf
onyl)methyl)-6-fluorobenzo[d]isoxazol-5-amine
(100 mg, 0.31 mmol) and pyridine (48 mg, 0.62
mmol) were added in dichloromethane (10 mL).
Ethyl carbonochloridate (33.6 mg, 0.31 mmol)
was then put in the mixture and stirred at 25 °C
for 2 h. Water (20 mL) was added to the
mixtureand then extracted with ethyl acetate (30
mL) for three times. Rotary evaporation and
column chromatography (eluent: petroleum
ether/EtOAc (v/v) = 6/1) were used to remove
the solvent and purify the residue to give a light
yellow solid (68 mg), yield:55%. The
compounds of s2 - s15 was obtained according
to this method.
by
concentration
in
vacuo.
Column
chromatography (eluent: petroleum ether/EtOAc
(v/v) = 8/1) was used to purify the residue to
give a white solid (80 mg), yield: 77%.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thi
o)methyl)-6- fluorobenzo[d]isoxazole (f1)
1
Brown liquid (71.2%). H NMR (400 MHz,
CDCl3) δ 7.82 (dd, J = 8.7, 5.1 Hz, 1H), 7.26
(dd, J = 7.5, 2.5 Hz, 1H), 7.10 (td, J = 8.9, 2.0
Hz, 1H), 4.61 (s, 2H), 2.83 (s, 2H), 1.43 (s, 6H).
13C NMR (151 MHz, CDCl3) δ 165.25 (s),
164.16 (d, J = 13.7 Hz), 163.58 (s), 155.08 (s),
153.61 (s), 123.09 (d, J = 11.1 Hz), 117.16 (s),
113.17 (s), 113.00 (s), 97.44 (s), 97.26 (s), 85.49
(s), 49.88 (s), 26.84 (s), 24.54 (s). MS (ESI):
C13H13FN2O2S m/z 280.1 [M+H]+.
3-(1-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)s
ulfonyl)ethyl)-6-fluorobenzo[d]isoxazole
(compound h1)
3-(((5,5-Dimethyl-4,5-dihydroisoxazol-3-yl)sulf
onyl)methyl)-6-fluorobenzo[d]isoxazole (7.00 g,
22.4 mmol) and K2CO3 (6.20 g, 44.8 mmol)
were dissolved in N,N-dimethylformamide (100
mL). Iodomethane (3.82 g, 26.9 mmol) was
added to the reaction mixture at 25 °C and then
stirr the mixture at 40 °C for 8 hours. Saturated
brine (300 mL) and ethyl acetate (150 mL) were
used to wash and extract the mixture for three
times. The solvent in organic layer was removed
by rotary evaporation. Column chromatography
(eluent: petroleum ether/EtOAc (v/v) = 8/1) was
used to purify the residue to obtain a white solid:
3-(2-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
fonyl)propan-2-yl)-6-fluorobenzo[d]isoxazole
(1.3 g), yield: 17.1%. The compounds of h2 was
obtained according to this method.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)thi
o)methyl) -7-fluorobenzo[d]isoxazole (f2)
Brown liquid (52%). 1H NMR (400 MHz,
CDCl3) δ 7.65 – 7.59 (m, 1H), 7.32 – 7.27 (m,
2H), 4.63 (s, 2H), 2.84 (s, 2H), 1.43 (s, 6H). 13C
NMR (101 MHz, CDCl3) δ 155.42 (s), 153.47
(s), 151.35 (d, J = 13.2 Hz), 147.79 (s), 145.28
(s), 124.80 (d, J = 5.0 Hz), 117.44 (d, J = 4.7 Hz),
115.85 (d, J = 15.6 Hz), 85.49 (s), 49.85 (s),
26.80 (s), 24.57 (s). MS (ESI): C13H13FN2O2S
m/z 280.1 [M+H]+.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
3-(1-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
fonyl)methyl) -6-fluorobenzo[d]isoxazole (g1)
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White solid (73.3%). Melting points: 127.1～
127.6 °C. 1H NMR (600 MHz, CDCl3) δ 7.87
(dd, J = 8.8, 5.0 Hz, 1H), 7.32 (dd, J = 8.2, 2.0
Hz, 1H), 7.18 (td, J = 8.9, 2.0 Hz, 1H), 4.99 (s,
2H), 2.99 (s, 2H), 1.48 (s, 6H). 13C NMR (101
MHz, CDCl3) δ 165.90 (s), 164.63 (d, J = 13.8
Hz), 163.38 (s), 157.34 (s), 147.76 (s), 123.51
(d, J = 11.2 Hz), 117.31 (s), 114.13 (d, J = 25.4
Hz), 97.53 (d, J = 29.1 Hz), 90.95 (s), 51.04 (s),
44.22 (s), 27.03 (s). MS (ESI): C13H13FN2O4S
m/z 313.0 [M+H]+.
4.7 Hz), 121.46 (d, J = 11.0 Hz), 119.73 (d, J =
27.6 Hz) , 111.26 (d, J = 9.4 Hz), 107.21 (d, J =
25.1 Hz), 90.98 (s), 51.09 (s), 44.19 (s), 27.00
(s). MS (ESI): C13H13FN2O4S m/z 313.1
[M+H]+.
6-bromo-3-(((5,5-dimethyl-4,5-dihydroisoxazo
l-3-yl) sulfonyl)methyl)benzo[d]isoxazole (g5)
White solid (53.6%). Melting points: 126.0～
1
127.2 °C. H NMR (400 MHz, CDCl3): δ ppm
7.83 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.54 (d, J
= 8.5 Hz, 1H), 4.99 (s, 2H), 2.99 (s, 2H), 1.47 (s,
6H). 13C NMR (151 MHz, CDCl3) δ 160.82 (s),
159.46 (s), 146.80 (s), 127.37 (s), 124.65 (s),
124.45 (s), 119.29 (s), 111.14 (s), 88.23 (s),
48.66 (s), 38.26 (s), 27.71 (s). MS (ESI):
C13H13BrN2O4S m/z 372.9 [M+H]+.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
finyl)methyl) -6-fluorobenzo[d]isoxazole (g2)
White solid (14.5%). Melting points: 133.5～
134.1 °C. 1H NMR (400 MHz, CDCl3) δ 7.79
(dd, J = 8.7, 5.1 Hz, 1H), 7.30 (dd, J = 8.2, 1.8
Hz, 1H), 7.16 (td, J = 8.9, 1.9 Hz, 1H), 4.64 (dd,
J = 42.6, 13.6 Hz, 2H), 2.98 (dd, J = 79.2, 17.0
Hz, 2H), 1.45 (d, J = 12.8 Hz, 6H). 13C NMR
(151 MHz, CDCl3) δ 165.34 (s), 164.78 (d, J =
13.6 Hz), 163.66 (s), 156.63 (s), 151.35 (s),
130.90 (s), 123.94 (d, J = 11.0 Hz), 120.13 (s),
97.62 (d, J = 26.3 Hz), 62.07 (s), 45.02 (s),
30.47 (s), 27.04 (d, J = 14.9 Hz). MS (ESI):
C13H13FN2O3S m/z 297.0 [M+H]+.
7-bromo-3-(((5,5-dimethyl-4,5-dihydroisoxazo
l-3-yl) sulfonyl)methyl)benzo[d]isoxazole (g6)
White solid (67.9%). Melting points: 122.0～
1
123.0 °C. H NMR (400 MHz, CDCl3): δ ppm
7.84 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz,
1H), 7.29 (d, J = 7.8 Hz, 1H), 5.01 (s, 2H), 3.01
(s, 2H), 1.48 (s, 6H). 13C NMR (151 MHz,
CDCl3) δ 161.38 (s), 157.33 (s), 148.80 (s),
133.67 (s), 126.02 (s), 121.91 (s), 121.41 (s),
102.85 (s), 91.12 (s), 51.19 (s), 44.23 (s), 27.07
(s). MS (ESI): C13H13BrN2O4S m/z 372.9
[M+H]+.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
fonyl)methyl) -7-fluorobenzo[d]isoxazole (g3)
White solid (42.3%). Melting points:125.6 ～
126.6 °C. 1H NMR (400 MHz, CDCl3) δ 7.67 (d,
J = 5.9 Hz, 1H), 7.35 (d, J = 6.6 Hz, 2H), 5.01 (s,
2H), 3.00 (s, 2H), 1.49 (s, 6H). 13C NMR (151
MHz, CDCl3) δ 155.49 (s), 153.58 (s), 147.53
(s), 145.85 (s), 125.03 (d, J = 4.9 Hz), 117.75 (d,
J = 4.6 Hz), 116.09 (d, J = 15.6 Hz), 85.64 (s),
50.08 (s), 32.32 (s), 27.15 (s), 24.88 (s). MS
(ESI): C13H13FN2O4S m/z 313.0 [M+H]+.
6-chloro-3-(((5,5-dimethyl-4,5-dihydroisoxazo
l-3-yl) sulfonyl)methyl)benzo[d]isoxazole (g7)
White solid (55.0%). Melting points: 124.0～
1
125.6 °C. H NMR (400 MHz, CDCl3): δ ppm
7.82 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 1.2 Hz,
1H), 7.39 (dd, J = 8.5, 1.5 Hz, 1H), 5.00 (s, 2H),
2.99 (s, 2H), 1.47 (s, 6H). 13C NMR (151 MHz,
CDCl3) δ 164.14 (s), 157.30 (s), 147.83 (s),
137.61 (s), 125.82 (s), 122.97 (s), 119.49 (s),
110.59 (s), 91.03 (s), 51.00 (s), 44.18 (s), 27.05
(s). MS (ESI): C13H13ClN2O4S m/z 328.8
[M+H]+.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
fonyl)methyl) -5-fluorobenzo[d]isoxazole (g4)
White solid (50.3%). Melting points:122.5 ～
1
123.6 °C. H NMR (600 MHz, CDCl3) δ 7.57
(ddd, J = 9.9, 8.3, 3.1 Hz, 2H), 7.36 (td, J = 8.7,
2.2 Hz, 1H), 5.00 (s, 2H), 3.01 (s, 2H), 1.48 (s,
6H). 13C NMR (101 MHz, CDCl3) δ 160.82 (s),
160.59 (s), 158.40 (s), 157.39 (s), 148.09 (d, J =
6-chloro-3-(((5,5-dimethyl-4,5-dihydroisoxazo
l-3-yl) sulfinyl)methyl)benzo[d]isoxazole (g8)
White solid (37.9%). Melting points: 130.2～
1
131.6 °C. H NMR (400 MHz, CDCl3) : δ ppm
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7.75 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 1.2 Hz,
1H), 7.37 (dd, J = 8.5, 1.5 Hz, 1H), 4.65 (dd, J =
39.1, 13.6 Hz, 2H), 2.97 (dd, J = 80.2, 17.1 Hz,
2H), 1.44 (d, J = 12.9 Hz, 6H). 13C NMR (151
MHz, CDCl3) δ 163.92 (s), 161.59 (s), 149.71
(s), 137.56 (s), 125.59 (s), 122.78 (s), 119.95 (s),
110.60 (s), 88.37 (s), 48.78 (s), 43.00 (s), 27.20
(s), 26.98 (s). MS (ESI): C13H13ClN2O3S m/z
312.8 [M+H]+.
5.53 (q, J = 7.1 Hz, 1H), 5.38 (s, 2H), 2.98 (q, J
= 17.5 Hz, 2H), 1.83 (d, J = 7.1 Hz, 3H), 1.36 (d,
J = 10.0 Hz, 6H). 13C NMR (101 MHz,
DMSO-d6) δ 167.75 (s), 165.71 (d, J = 13.7 Hz),
163.28 (s), 156.75 (s), 152.91 (s), 124.72 (d, J =
11.1 Hz), 116.79 (s), 114.41 (s), 113.89 (s),
97.59 (d, J = 27.1 Hz), 90.79 (s), 57.90 (s),
45.15 (s), 26.99 (d, J = 8.9 Hz), 12.49 (s). MS
(ESI): C14H16FN3O4S m/z 342.1 [M+H]+.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
fonyl)methyl)-6-fluoro-5-nitrobenzo[d]isoxazo
le (m1)
3-(1-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)s
ulfonyl) ethyl)-6-fluorobenzo[d]isoxazole (h1)
White solid (17.1%). Melting points: 134.7～
1
135.1 °C. H NMR (600 MHz, CDCl3): δ ppm
Brown solid (31%). Melting points:141.1 ～
141.6 °C. 1H NMR (400 MHz, CDCl3) δ 8.73 (d,
J = 6.9 Hz, 1H), 7.55 (d, J = 9.5 Hz, 1H), 5.07 (s,
2H), 3.08 (s, 2H), 1.51 (s, 6H). 13C NMR (151
MHz, CDCl3) δ 158.35 (d, J = 13.0 Hz), 157.59
(s), 155.89 (s), 154.33 (s), 147.06 (s), 133.86 (d,
J = 15.3 Hz), 116.95 (s), 105.53 (d, J = 5.3 Hz),
97.47 (d, J = 24.8 Hz), 91.02(s), 51.34 (s), 44.46
(s), 27.06 (s). MS (ESI): C13H12FN3O6S m/z
358.1 [M+H]+.
7.92 (dd, J = 8.8, 5.1 Hz, 1H), 7.30 (dd, J = 8.2,
1.9 Hz, 1H), 7.16 (td, J = 8.9, 2.0 Hz, 1H), 5.08
(q, J = 7.2 Hz, 1H), 2.85 (dd, J = 53.8, 17.2 Hz,
2H), 2.04 (d, J = 7.3 Hz, 3H), 1.42 (d, J = 27.5
Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 165.75
(s), 164.72 (d, J = 13.7 Hz), 163.24 (s), 156.45
(s), 152.61 (s), 124.12 (d, J = 11.1 Hz), 116.59
(s), 114.11 (s), 113.85 (s), 97.49 (d, J = 26.9 Hz),
90.73 (s), 57.80 (s), 45.15 (s), 26.99 (d, J = 8.9
Hz), 12.39 (s). MS (ESI): C14H15FN2O4S m/z
327.1 [M+H]+.
7-bromo-3-(((5,5-dimethyl-4,5-dihydroisoxazo
l-3-yl)sulfonyl)methyl)-6-nitrobenzo[d]isoxazo
le (m2)
3-(1-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)s
ulfonyl) ethyl)-5-fluorobenzo[d]isoxazole (h2)
White solid (65.0%). Melting points: 129.1～
Yellow solid (43.6%). Melting points: 130.0～
131.2 °C.1H NMR (400 MHz, DMSO-d6): δ ppm
9.11 (d, J = 1.8 Hz, 1H), 8.79 (d, J = 1.8 Hz,
1H), 5.78 (s, 2H), 3.26 (s, 2H), 1.44 (s, 6H). 13C
NMR (151 MHz, DMSO-d6) δ 161.11 (s),
151.48 (s), 147.14 (s), 127.40 (s), 122.03 (s),
119.73 (s), 106.42 (s), 88.23 (s), 48.66 (s), 38.26
(s), 27.71 (s). MS (ESI): C13H12BrN3O6S m/z
419.9 [M+H]+.
1
129.3 °C. H NMR (600 MHz, CDCl3) δ ppm
7.59 (dd, J = 14.3, 5.4 Hz, 2H), 7.36 (t, J = 8.6
Hz, 1H), 5.08 (q, J = 7.0 Hz, 1H), 2.86 (dd, J =
50.7, 17.1 Hz, 2H), 2.04 (d, J = 7.1 Hz, 3H),
1.43 (d, J = 26.0 Hz, 6H). 13C NMR (101 MHz,
CDCl3) δ 160.69 (d, J = 7.2 Hz), 158.23 (s),
156.46 (s), 152.87 (d, J = 4.7 Hz), 120.69 (d, J =
11.0 Hz), 119.67 (d, J = 27.4 Hz), 111.24 (d, J =
9.3 Hz), 107.82 (d, J = 27.4 Hz), 90.70 (s), 57.84
(s), 45.11 (s), 27.00 (d, J = 9.0 Hz), 12.27 (s).
MS (ESI): C14H15FN2O4S m/z 327.1 [M+H]+.
3-(1-((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)s
ulfonyl)ethyl)-6-fluorobenzo[d]isoxazol-5-ami
ne (h3)
6-chloro-3-(((5,5-dimethyl-4,5-dihydroisoxazo
l-3-yl)sulfonyl)methyl)-5-nitrobenzo[d]isoxazo
le (m3)
Yellow solid (57.9%). Melting points: 135.9～
1
137.6 °C. H NMR (400 MHz, CDCl3): δ ppm
8.50 (s, 1H), 7.85 (s, 1H), 5.06 (s, 2H), 3.06 (s,
2H), 1.51 (s, 6H). 13C NMR (151 MHz, CDCl3)
δ 163.10 (s), 159.45 (s), 138.42 (s), 135.72 (s),
121.15 (s), 119.17 (s), 110.38 (s), 88.23 (s),
White solid (77%). Melting points:142.0～143.0
°C. 1H NMR (600 MHz, DMSO-d6): δ ppm 7.65
(d, J = 10.6 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H),
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48.66 (s), 38.26 (s), 27.71 (s). MS (ESI):
C13H12ClN3O6S m/z 373.9 [M+H]+.
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sul
fonyl)methyl)-6-fluorobenzo[d]isoxazol-5-ami
ne (n1)
144.37 – 127.22 (m), 144.37 – 123.22 (m),
122.57 (s), 117.71 (d, J = 19.1 Hz), 98.08 (s),
88.23 (s), 48.66 (s), 38.26 (s), 27.71 (s). MS
(ESI): C21H17F4N3O5S m/z 500.2 [M+H]+.
N-(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
sulfonyl)methyl)-6-fluorobenzo[d]isoxazol-5-y
l)pivalamide (s3)
Light
yellow
solid
(36.8%).
Melting
1
points:135.2～135.8 °C. H NMR (400 MHz,
CDCl3) δ 7.28 (d, J = 10.1 Hz, 1H), 7.15 (d, J =
8.2 Hz, 1H), 4.91 (s, 2H), 3.92 (s, 2H), 2.96 (s,
2H), 1.46 (s, 6H).
Light yellow solid (55.8%). Melting points:
138.9～140.8 °C. 1H NMR (400 MHz, CDCl3) δ
8.85 (d, J = 7.3 Hz, 1H), 7.69 (s, 1H), 7.39 (d, J
= 9.9 Hz, 1H), 4.98 (s, 2H), 3.04 (s, 2H), 1.50 (s,
6H), 1.35 (s, 9H). 13C NMR (151 MHz, CDCl3)
δ 159.75(d, J = 13.7 Hz), 157.42 (s), 156.14 (s),
154.48 (s), 148.11 (s), 125.03 (d, J = 12.0 Hz),
117.16 (s), 113.67 (s),97.18 (d, J = 25.3Hz),
90.84 (s), 50.63 (s), 44.15 (s), 40.06(s),27.53 (s)
,27.15 (s). MS (ESI): C18H22FN3O5S m/z 412.2
[M+H]+.
13C NMR (151 MHz, CDCl3) δ 158.05 (d, J =
13.0 Hz), 157.29 (s), 155.69 (s), 154.03 (s),
146.96 (s), 133.80 (d, J = 15.3 Hz), 116.92 (s),
105.13 (d, J = 5.3 Hz), 97.37 (d, J = 24.8 Hz),
91.01 (s), 51.32 (s), 44.44 (s), 27.04 (s). MS
(ESI): C13H14FN3O4S m/z 328.2 [M+H]+.
ethyl
(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)su
lfonyl)methyl)-6-fluorobenzo[d]isoxazol-5-yl)c
arbamate (s1)
allyl(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-
yl)sulfonyl)methyl)-6-fluorobenzo[d]isoxazol-
5-yl)carbamate (s4)
Light yellow solid (55%). Melting points: 145.1
1
～145.7 °C. H NMR (400 MHz, CDCl3) δ 8.59
Light yellow solid (65.2%). Melting points:
137.1～138.6 °C. 1H NMR (400 MHz, CDCl3) δ
8.60 (s, 1H), 7.38 (d, J = 9.9 Hz, 1H), 6.97 (s,
1H), 5.99 (ddd, J = 16.3, 11.0, 5.8 Hz, 1H), 5.40
(dd, J = 17.2, 1.3 Hz, 1H), 5.30 (dd, J = 10.4, 1.0
Hz, 1H), 4.99 (s, 2H), 4.72 (d, J = 5.8 Hz, 2H),
3.02 (s, 2H), 1.49 (s, 6H). 13C NMR (151 MHz,
CDCl3) δ 159.49 (d, J = 13.5 Hz), 155.15 (d, J =
678.2 Hz), 148.02 (s), 131.95 (s), 127.10 (s),
125.05 (d, J = 12.8 Hz), 121.53 (dd, J = 1060.2,
136.3 Hz), 97.40 (s), 97.23 (s), 90.84 (s), 66.50
(s), 50.75 (s), 44.16 (s), 27.08 (s). MS (ESI):
C17H18FN3O6S m/z 412.2 [M+H]+.
(s, 1H), 7.38 (d, J = 9.9 Hz, 1H), 6.90 (s, 1H),
4.99 (s, 2H), 4.29 (q, J = 7.0 Hz, 2H), 3.02 (s,
2H), 1.49 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ 158.07 (d, J = 13.0
Hz), 157.39 (s), 155.59 (s), 154.18 (s), 153.08
(s), 146.86 (s), 133.83 (d, J = 15.3 Hz), 116.96
(s), 105.16 (d, J = 5.3 Hz), 97.37 (d, J = 24.8
Hz), 91.01 (s), 61.04 (s) 51.32 (s), 44.44 (s),
27.04 (s), 22.04 (s). MS (ESI): C16H18FN3O6S
m/z 400.2 [M+H]+.
N-(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
sulfonyl)methyl)-6-fluorobenzo[d]isoxazol-5-y
l)-3-(trifluoromethyl)benzamide (s2)
N-(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
sulfonyl)methyl)-6-fluorobenzo[d]isoxazol-5-y
l)-4-fluorobenzamide (s5)
Light yellow solid (65%). Melting points: 160.7
～170.3 °C. 1H NMR (400 MHz, CDCl3) δ 8.98
(d, J = 7.0 Hz, 1H), 8.19 (s, 1H), 8.09 (d, J = 7.1
Hz, 2H), 7.87 (d, J = 7.1 Hz, 1H), 7.69 (t, J = 7.7
Hz, 1H), 7.47 (d, J = 9.9 Hz, 1H), 5.04 (s, 2H),
3.06 (s, 2H), 1.51 (s, 6H). 13C NMR (151 MHz,
CDCl3) δ 166.61 (s), 159.45 (s), 158.93 (s),
154.25 (s), 134.87 (s), 134.87 (s), 144.37 –
128.69 (m), 131.72 (dd, J = 434.3, 354.0 Hz),
Light yellow solid (53.6%). Melting points:
160.9 ～ 171.5 °C. 1H NMR (400 MHz,
DMSO-d6) δ 10.42 (s, 1H), 8.23 (d, J = 7.2 Hz,
1H), 8.10 (dd, J = 8.5, 5.6 Hz, 2H), 7.98 (d, J =
9.6 Hz, 1H), 7.40 (t, J = 8.7 Hz, 2H), 5.61 (s,
2H), 3.22 (s, 2H), 1.43 (s, 6H). 13C NMR (151
MHz, DMSO-d6) δ 165.90 (d, J = 204.6 Hz),
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181.00 – 159.37 (m), 181.00 – 143.22 (m),
131.45 (d, J = 33.8 Hz), 122.57 (s), 117.71 (d, J
= 19.1 Hz), 116.12 (s), 98.08 (s), 88.23 (s), 48.66
(s), 38.26 (s), 27.71 (s). MS (ESI):
C20H17F2N3O5S m/z 450.1 [M+H]+.
161.44(d, J = 14.6 Hz), 160.85 (s), 158.28 (s),
149.53(s), 139.07 (s), 132.76 (s), 130.26 (s),
128.74 (s), 123.95 (d, J = 15.5Hz), 121.33 (s),
117.60 (s), 98.63 (s), 98.45 (s), 91.43 (s), 49.86
(s),
44.49
(s),27.02(s).
MS
(ESI):
4-chloro-N-(3-(((5,5-dimethyl-4,5-dihydroisox
azol-3-yl)sulfonyl)methyl)-6-fluorobenzo[d]iso
xazol-5-yl)benzamide (s6)
C18H16FN3O5S2 m/z 438.0 [M+H]+.
N-(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
sulfonyl)methyl)-6-fluorobenzo[d]isoxazol-5-y
l)cyclopropanecarboxamide (s9)
Light yellow solid (44.6%). Melting points:
165.0～166.2 °C. 1H NMR (400 MHz, CDCl3) δ
8.97 (d, J = 7.0 Hz, 1H), 8.03 (d, J = 8.5 Hz,
1H), 7.86 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 24.8,
8.3 Hz, 4H), 5.03 (s, 2H), 3.05 (s, 2H), 1.51 (s,
6H). 13C NMR (151 MHz, CDCl3) δ 166.72 (s),
159.45 (s), 158.93 (s), 154.25 (s), 138.09 (s),
133.21 (s), 129.09 (s), 128.61 (s), 122.57 (s),
117.71 (d, J = 19.1 Hz), 98.08 (s), 88.23 (s),
48.66 (s), 38.26 (s), 27.71 (s). MS (ESI):
C20H17ClFN3O5S m/z 466.1 [M+H]+.
Light yellow solid (65.8%). Melting points:
1
148.0～148.7 °C. H NMR (400 MHz, CDCl3):
δ ppm (d, J = 7.1 Hz, 1H), 7.74 (s, 1H), 7.38 (d,
J = 9.9 Hz, 1H), 5.07 (q, J = 7.3 Hz, 1H), 2.89
(q, J = 17.1 Hz, 2H), 2.04 (d, J = 7.2 Hz, 3H),
1.45 (d, J = 13.8 Hz, 6H), 1.16 – 1.14 (m, 1H),
0.95 – 0.84 (m, 4H). 13C NMR (151 MHz,
CDCl3) δ 173.41 (s), 162.59 (s), 159.27 (d, J =
18.4 Hz), 120.86 (s), 117.96 (d, J = 11.2 Hz),
98.66 (s), 88.23 (s), 62.05 (s), 39.15 (s), 27.71
(s), 16.24 (s), 14.93 (s), 12.50 (s). MS (ESI):
C18H20FN3O5S m/z 396.1 [M+H]+.
4-bromo-N-(3-(((5,5-dimethyl-4,5-dihydroisox
azol-3-yl)sulfonyl)methyl)-6-fluorobenzo[d]iso
xazol-5-yl)benzamide (s7)
N-(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
sulfonyl)methyl)-6-fluorobenzo[d]isoxazol-5-y
l)adamantane-1-carboxamide (s10)
Light yellow solid (75.2%). Melting points:
1
158.1～159.2 °C. H NMR (400 MHz, CDCl3):
δ ppm 8.97 (d, J = 7.3 Hz, 1H), 8.05 (s, 1H),
7.79 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz,
2H), 7.45 (d, J = 12.9 Hz, 1H), 5.03 (s, 2H), 3.05
(s, 2H), 1.50 (s, 6H). 13C NMR (151 MHz,
CDCl3) δ 166.72 (s), 159.45 (s), 158.93 (s),
154.25 (s), 134.82 (s), 131.60 (s), 130.42 (s),
127.93 (s), 122.57 (s), 117.71 (d, J = 19.1 Hz),
98.08 (s), 88.23 (s), 48.66 (s), 38.26 (s), 27.71
(s). MS (ESI): C20H17BrFN3O5S m/z 510.0
[M+H]+.
Light yellow solid (48.8%). Melting points:
172.0 ～ 174.0 °C. 1H NMR (400 MHz,
DMSO-d6): δ ppm 9.25 (s, 1H), 8.08 (d, J = 7.1
Hz, 1H), 7.88 (d, J = 9.4 Hz, 1H), 5.57 (s, 2H),
3.21 (s, 2H), 2.03 (s, 3H), 1.94 (s, 6H), 1.72 (s,
6H), 1.43 (s, 6H). 13C NMR (151 MHz,
DMSO-d6) δ 176.96 (s), 161.19 (s), 159.84 (s),
158.29 (s), 158.16 (s), 149.41 (s), 124.86 (d,
J=15.6Hz), 121.06 (s),117.41 (s), 98.16 (d,
J=13.2Hz), 91.41 (s), 49.82 (s), 44.50 (s), 41.09
(s), 38.95 (s), 36.50 (s), 28.11 (s), 27.02 (s). MS
(ESI): C24H28FN3O5S m/z 490.1 [M+H]+.
N-(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
sulfonyl)methyl)-6-fluorobenzo[d]isoxazol-5-y
l)thiophene-2-carboxamide (s8)
3-chloro-N-(3-(((5,5-dimethyl-4,5-dihydroisox
azol-3-yl)sulfonyl)methyl)-6-fluorobenzo[d]iso
xazol-5-yl)propanamide (s11)
Light yellow solid (60.2%). Melting points:
149.0 ～ 150.6 °C. 1H NMR (400 MHz,
DMSO-d6) :δ ppm 10.42 (s, 1H), 8.20 (d, J = 7.2
Hz, 1H), 8.05 (d, J = 3.6 Hz, 1H), 7.98 (d, J =
9.6 Hz, 1H), 7.90 (d, J = 4.9 Hz, 1H), 7.29 –
7.23 (m, 1H), 5.61 (s, 2H), 3.22 (s, 2H), 1.43 (s,
Light yellow solid (56.3%). Melting points:
140.1 ～ 140.6 °C. 1H NMR (400 MHz,
DMSO-d6): δ ppm 10.08 (s, 1H), 8.49 (d, J = 7.3
Hz, 1H), 7.93 (d, J = 10.0 Hz, 1H), 5.59 (s, 2H),
3.91 (t, J = 6.0 Hz, 2H), 3.21 (s, 2H), 2.96 (t, J =
6H). 13C NMR (151 MHz, DMSO-d6)
δ
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6.0 Hz, 2H), 1.43 (s, 6H). 13C NMR (151 MHz,
DMSO-d6) δ 169.17(s), 160.30 (d, J = 13.7 Hz),
158.31 (s), 157.83 (s), 156.15 (s), 149.51 (s),
124.57 (d, J = 14.4Hz), 117.81 (s), 117.43
(s)98.29(d, J = 27.2Hz), 91.40 (s), 49.89 (s),
44.49 (s), 41.11 (s), 38.99 (s), 27.01 (s). MS
(ESI): C16H17ClFN3O5S m/z 418.1 [M+H]+.
N-(3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)
sulfonyl)methyl)-6-fluorobenzo[d]isoxazol-5-y
l)heptanamide (s12)
1H), 4.98 (s, 2H), 3.02 (s, 2H), 1.49 (s, 6H), 1.33
(d, J = 6.3 Hz, 6H). 13C NMR (151 MHz,
CDCl3) δ 169.67(s), 160.38 (d, J = 13.7 Hz),
158.39(s), 157.43 (s), 156.17 (s), 149.56 (s),
124.59 (d, J = 14.4Hz), 117.86 (s), 117.53
(s)98.39(d, J = 27.2Hz), 91.46 (s), 49.89 (s),
44.49 (s), 41.11 (s), 28.99 (s), 24.01 (s). MS
(ESI): C17H20FN3O6S m/z 414.0 [M+H]+.
6-chloro-N-(3-(((5,5-dimethyl-4,5-dihydroisox
azol-3-yl)sulfonyl)methyl)-6-fluorobenzo[d]iso
xazol-5-yl)nicotinamide (s15)
Light yellow solid (45.9%). Melting points:
135.0 ～ 136.6 °C. 1H NMR (400 MHz,
DMSO-d6) :δ ppm 9.84 (s, 1H), 8.42 (d, J = 7.2
Hz, 1H), 7.90 (d, J = 10.0 Hz, 1H), 5.57 (s, 2H),
3.21 (s, 2H), 2.41 (t, J = 7.1 Hz, 2H), 1.67 – 1.56
(m, 2H), 1.42 (s, 6H), 1.30 (m, 6H), 0.87 (t, J =
6.2 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ
172.37 (s), 160.26 (d, J = 13.1 Hz), 158.31 (s),
149.45 (s), 124.90 (d, J = 14.9 Hz),117.97 (s),
117.40 (s), 98.17 (d, J = 27.0 Hz), 91.54 (s),
49.90 (s), 44.50 (s), 36.08 (s), 31.51 (s), 28.74
(s), 27.00 (s), 25.54 (s), 22.48 (s), 14.40 (s). MS
(ESI): C20H26FN3O5S m/z 440.2 [M+H]+.
Light yellow solid (66.2%). Melting points:
160.1 ～ 160.6 °C. 1H NMR (400 MHz,
DMSO-d6): δ ppm 10.74 (s, 1H), 8.54 (dd, J =
13.0, 5.2 Hz, 2H), 8.11 (d, J = 7.4 Hz, 1H), 7.99
(d, J = 9.8 Hz, 1H), 7.59 (dd, J = 7.3, 4.9 Hz,
1H), 5.64 (s, 2H), 3.22 (s, 2H), 1.44 (s, 6H). 13C
NMR (151 MHz, DMSO-d6) δ164.82(s), 160.92
(d, J=13.5Hz), 158.31(s), 156.76(s), 151.19 (s),
149.63 (s),147.00 (s), 138.82 (s), 133.00 (s),
123.83 (d, J=13.9 Hz),123.65 (s), 118.92 (s),
117.56(s), 98.60 (d, J=25.9 Hz), 91.43 (s), 49.88
(s), 44.50 (s), 27.03 (s). MS (ESI):
C19H16ClFN4O5S m/z 467.0 [M+H]+.
2-bromo-N-(3-(((5,5-dimethyl-4,5-dihydroisox
azol-3-yl)sulfonyl)methyl)-6-fluorobenzo[d]iso
xazol-5-yl)acetamide (s13)
3.3 Herbicidal activities
The pre-emergence herbicidal activities of
3-(((5,5-dimethyl-4,5-dihydroisoxazol-3-yl)sulfo
Light yellow solid (75.3%). Melting points:
145.0 ～ 146.0 °C. 1H NMR (400 MHz,
DMSO-d6) δ 10.37 (s, 1H), 8.47 (t, J = 8.4 Hz,
1H), 7.96 (d, J = 10.0 Hz, 1H), 5.59 (s, 2H), 4.19
(s, 2H), 3.20 (s, 2H), 1.42 (s, 6H). 13C NMR
(151 MHz, DMSO-d6) δ 169.87(s), 160.70 (d, J
= 14.7 Hz), 158.37 (s), 157.87 (s), 156.45 (s),
149.56 (s), 124.57 (d, J = 14.4Hz), 117.81 (s),
117.48 (s)98.29(d, J = 27.2Hz), 91.48 (s), 49.89
(s), 44.49(s), 38.99 (s), 27.01 (s). MS (ESI):
C20H17BrFN3O5S m/z 448.0 [M+H]+.
nyl)methyl)benzo[d]isoxazole
against Setaria faberii(SF),
derivatives
Digitaria
sanguinalis(DS) and Echinochloa crus-galli(EC)
were tested according to methods reported
previously, the commercial VLCFAs inhibitor
S-metolachlor acted as a positive control. All the
experimental compounds were prepared into 1.0%
emulsified concentrates with DMF as solvent
and 1.0% Tween 80 as emulsifier. The
concentrate is then diluted with water to the
needed concentration and applied to potted
plants. These test targets were sown in a 7.5 cm
diameter flower pot filled with composite soil
(vegetable garden soil: seedling substrate, 1: 2, v
/ v), covered with 0.2 cm soil, and water was
added to keep the soil moist for 24 hours before
use. Each test compound was sprayed on the soil
Isopropyl(3-(((5,5-dimethyl-4,5-dihydroisoxaz
ol-3-yl)sulfonyl)methyl)-6-fluorobenzo[d]isoxa
zol-5-yl)carbamate (s14)
Light yellow solid (80.2%). Melting points:
1
133.0～135.0 °C. H NMR (400 MHz, CDCl3) :
δ ppm 8.60 (d, J = 6.7 Hz, 1H), 7.37 (d, J = 9.9
Hz, 1H), 6.85 (s, 1H), 5.07 (dt, J = 12.5, 6.2 Hz,
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surface by an automatic spray tower (model:
3WPSH-700E) at a dose of 150, 75, 37.5or
18.75 g ai / ha. After the soil surface liquid was
dried, it was placed in a greenhouse. The control
effect (%) of weeds was investigated and
evaluated after 25 days. The results of herbicidal
activities are shown in Table 1, 2 and 3.
SUPPORTING INFORMATION
The structural characterizations (1H NMR and
13C NMR) of synthesized compounds were
collected in Supporting Information.
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