Synthesis and biological activity of ethyl 2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylate

Article abstract of DOI:10.1080/10426507.2017.1393423

A series of novel ethyl 2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylates I-1-6 were synthesized. The structures of all target compounds were characterized by ¹H NMR, ¹³C NMR, IR,MS and elemental analyses. Their fungicidal and herbicidal activities were evaluated. The results of preliminary bioassays show that the title compounds I-4 possess 20-50% inhibition against most of the tested plants at the dosage of 150 g ai/ha, while the title compounds I-1-5 possess 32-58% inhibition against FusaHum graminearum, Thanatephorus cucumeris, Botrytis cinereapers and Fusarium oxysporum in vitro at the concentration of 100 mg/L.

Full text of DOI:10.1080/10426507.2017.1393423

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis and Biological Activity of Ethyl 2-
(5-methyl-3-arylisoxazole-4-carboxamido)-4-
alkylthiazole-5-carboxylate
Wei Wang, Lie-Ping Wang, Min-Zhen Mao, Xiao-Guang Zhang, Xiao-Rui
Zheng, Xiao-Ying Huang, Chao Xue & Bin-Ke Ning
To cite this article: Wei Wang, Lie-Ping Wang, Min-Zhen Mao, Xiao-Guang Zhang, Xiao-Rui
Zheng, Xiao-Ying Huang, Chao Xue & Bin-Ke Ning (2017): Synthesis and Biological Activity of
Ethyl 2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylate, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2017.1393423
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1393423
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Date: 23 October 2017, At: 08:59

ACCEPTED MANUSCRIPT
Synthesis and Biological Activity of Ethyl
2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylate
*
Wei Wang , Lie-Ping Wang, Min-Zhen Mao, Xiao-Guang Zhang, Xiao-Rui Zheng,
*
Xiao-Ying Huang, Chao Xue, Bin-Ke Ning
State Key Laboratory of Fluorine & Nitrogen Chemicals, Xi’an Modern Chemistry Research
Institute, Xi’an, Shaanxi, P. R. China
E-mail:wangwei204@aliyun.com
Synthesis
and
Biological
Activity
of
Ethyl
2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylate
*
*
Wei Wang , Lie-Ping Wang , Min-Zhen Mao, Xiao-Guang Zhang, Xiao-Rui Zheng, Xiao-Ying
*
Huang, Chao Xue, Bin-Ke Ning
State Key Laboratory of Fluorine & Nitrogen Chemicals, Xi’an Modern Chemistry Research
Institute, Xi’an, Shaanxi, P. R. China
ABSTRACT:
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A
series
of
novel
ethyl
were
2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylates
I-1~6
1
13
synthesized. The structures of all target compounds were characterized by H NMR, C NMR,
IR, MS and elemental analyses. Their fungicidal and herbicidal activities were evaluated. The
results of preliminary bioassays show that the title compounds I-4 possess 20~50% inhibition
against most of the tested plants at the dosage of 150 g ai/ha, while the title compounds I-1~5
possess 32-58% inhibition against FusaHum graminearum, Thanatephorus cucumeris, Botrytis
cinereapers and Fusarium oxysporum in vitro at the concentration of 100 mg/L.
Supplemental materials are available for this article. Go to the publisher`s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Synthesis; Thiazole; Isoxazole; Herbicidal activity; Fungicidal activity
*Address correspondence to Bin-ke Ning or Wei Wang or Lie-ping Wang,
State Key Laboratory
of Fluorine & Nitrogen Chemicals, Xi’an Modern Chemistry Research Institute, Xi’an, Shaanxi,
P. R. China. E-mail: wangwei204@aliyun.com or wlpcxm@qq.com or bkning@126.com.
INTRODUCTION
Sulfur is an important element that is incorporated into some biomolecules. Compounds
containing sulfur have a wide range of bioactivities in agrochemical industries [1~2]. And a
2
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number of sulfur-containing products have been launched into the market during the past decade
[1~2]. In recent years, heterocyclic compounds had received considerable attention due to their
interesting and diverse biological properties[3~6]. Also, sulfur-containing heterocycles have
been under investigation for a long time because of their interesting ang diverse biological
properties. Among various biological heterocycles, sulfur-containing heterocycles as the main
source of lead molecules play an important role in pesticide chemistry and are often introduced
in the design of bioacitve compounds[7-10]. Thiazoles as sulfur-containing compounds play an
important role possessed various applications in the field of agrochemical products[2,10~13].
Some of these compounds have been developed as commercial fungicides[2], such as
Ethaboxam and Thifuzamide (Figure 1). On the other hand, isoxazole derivatives as
nitrogen-containing heterocyclic compounds which have attracted much attention for their good
bioactivity and are often introduced in the design of bioactive compounds[14~17]. However,
documents seldom reported the synthesis and biological activity of the heterocyclic compounds
containing both thiazole and isoxazole moieties in one molecule. Our motivation in this work is
to combine different heterocyclic moieties and evaluate their biological activity.
In crop protection and bioactive chemicals, acylamides have been reported to display a
variety of biological activities, such as herbicidal, fungicidal and insecticidal, etc[2, 12, 18~20].
As a part of our extensive research program to find novel bioactive heterocycles, a series of
novel sulfur-containing heterocycle derivatives were designed by introducing the isoxazole
3
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structural unit into the thiazole molecule. Here, we report the preparation of ethyl
2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylate and their fungicidal
and herbicidal activity were evaluated to discuss the structure-activity relationships.
RESULTS AND DISCUSSION
Synthesis
As shown in Scheme 1, the intermediates 2 were prepared by the reaction of thiourea with
ethyl 2-chloro-3-oxobutanoate or ethyl 2-chloro-4-methyl-3-oxopentanoate according to the
reported method [2], followed by reacting with 5-methyl-3-arylisoxazole-4-carbonyl chloride 7
(Scheme 2) in dichloromethane using triethylamine as a catalyst to afford title compounds I-1~6
in good yields. The structures of these newly synthesized compounds were confirmed by by 1H
NMR, 13C NMR, IR, MS and elemental analyses. The IR spectra of compound I-1 showed NH at
3218 cm-1 and C=O at 1665 cm-1. The aromatic protons of compound I-1 revealed the expected
multiplet near 7.41~7.52 ppm and the proton signal corresponding to NH displayed signal at 9.47
1
ppm and the integration curve accorded with the assigned structures in H NMR. All of the
nonequivalent carbon atoms of compound I-1 were identified in 13C NMR. The signals at
12.9~61.0, 111.4~160.3, 162.2 and 174.2 ppm belong to alkyl, aromatic carbons (C=N), C=O of
amide and ester, respectively. All spectral and analytical data were consistent with the assigned
structures. The IR spectra of the title compounds I-1~6 showed NH stretching bands at
3195~3230 cm-1, the stretching bands of two different C=O at 1660~1680 and 1715~1735 cm-1,
4
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1
respectively. In the H NMR spectra of the title compounds I-1~6, the proton signal
corresponding to NH displayed signals at 8.4~10.8 ppm. The EI mass spectra of the title
compounds I-1~6 revealed the existence of the molecular ion peaks, which were in good
accordance with the given structures of title compounds. The elemental analysis of all target
compounds are in good agreement with the theoretical data.
Biological Activities
Fungicidal Activity
The fungicidal activities of I-1~6 were evaluated at the concentration of 100 mg/L using
Chlorothalonil as a positive control. The four fungi FusaHum graminearum, Thanatephorus
cucumeris, Botrytis cinereapers and Fusarium oxysporum, belong to the group of field fungi and
were isolated from corresponding crops.
[Insert Scheme 1]
[Insert Scheme 2]
Insert [Scheme 3]
Herbicidal Activity
All of the title compounds were tested at 150 g ai/ha for post-emergence herbicide activity
against monocotyledonous weeds such as Echinochloa crusgalli, Digitaria sanguinalis and
Setaria viridis and dicotyledonous weeds such as Brassica juncea, Abutilon theophrasti and
Descurainia sophia using 2,4-D as a positive control.
Experimental details and the fungicidal activities (Table S 1) and herbicidal activities (Table
5
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S 2) are presented in the Supplemental Materials, together with sample 1H and 13C NMR spectra
for the products (Figures S 1-S 12).
CONCLUSIONS
In
conclusion,
a
series
of
novel
Ethyl
2-(5-methyl-3-arylisoxazole-4-carboxamido)-4-alkylthiazole-5-carboxylate I-1~6 were designed
and synthesized. The results of an in vitro bioassays showed the title compounds I-1~5 possessed
30~58% inhibition effect against all the tested fungi. In addition, the compounds I-2~4 also
exhibited 0~50% herbicidal activity at the dosage of 150 g ai/ha. These results indicated that the
title compounds I could be modified and used as lead compounds for further study.
EXPERIMENTAL
All the reagents were of analytical grade. Melting points were determined using an X-4
1
13
apparatus and uncorrected. H and C NMR spectra were measured on a Bruker AC-P400 (400
Hz) instrument using TMS as an internal standard and CDCl3 as solvent. MS spectra were
analyzed on a Finnigan TRACE spectrometer and API2000LC/MS. Elemental analyses were
performed by a Vario EL III elemental analyzer.
Synthesis of the Intermediate Ethyl 2-amino-4-alkylthiazole-5-carboxylate 2
The ethyl 2-amino-4-alkylthiazole-5-carboxylate 2 was synthesized by a standard method [2].
Synthesis of the Intermediate 5-methyl-3-arylisoxazole-4-carbonyl chloride 7
6
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The 5-methyl-3-arylisoxazole-4-carboxylic acid 6 was synthesized by a standard method [15].
Their melting point and yields (Table S 3) are presented in the Supplemental Materials. A
mixture containing 5-methyl-3-arylisoxazole-4-carboxylic acid 6 (4.0 mmol) and thionyl
chloride (3 mL) was added into a 25 mL flask and refluxed for 5-6 h. Excess thionyl chloride
was evaporated off under reduced pressure, and a light yellow oil 7a-d was obtained with a yield
of 85~90%.
General procedure for the Synthesis of the Title Compounds I-1~6.
A solution of 5-methyl-3-arylisoxazole-4-carbonyl chloride 7 (3.3 mmol) in dichloromethane
(15 mL) was added to a stirred mixture of 2 (3 mmol) and triethylamine (3.3 mmol) in
o
dichloromethane (20 mL) at 0~5 C. The resulting mixture was stirred for 3~5 h at room
o
temperature and then for 1~2 h at 40 C. The dichloromethane layer was washed with 0.1 M
hydrochloric acid, saturated sodium hydrogen carbonate solution, and brine, dried, and
concentrated. The residue was purified by column chromatography on silica gel and elution with
petroleum ether/acetone (4:1, v/v) to give the corresponding pure title compounds I-1~6 in
1
66~90% yields. Their structures were confirmed by IR, MS, elemental analysis, H and 13C
NMR spectral data. And the physicochemical properties and spectroscopic data for all of the title
compounds I-1~6 are as follows.
Ethyl 2-[5-methyl-3-(2-chlorophenyl)isoxazole-4-carboxamido]-4-methylthiazole
-5-carboxylate I-1:
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White solid; yield 69%; m.p. 129-131oC; IR (KBr)/cm-1: 3314, 3218, 3071, 2983, 2922, 1717,
1665, 1578, 1547, 1531, 1482, 1370, 1271, 1105, 807, 747; 1H NMR (CDCl3, 400MHz) δ1.35 (t,
3H, -CH2CH3, J=7.2Hz), 2.45 (s, 3H, -CH3), 2.78 (s, 3H, -CH3), 4.28~4.33 (dd, 2H, -CH2CH3,
J1=14.0Hz, J2=6.8Hz), 7.41~7.52 (m, 4H, H3,4,5,6-Ph), 9.47 (s,1H, NH); 13C NMR (100MHz,
CDCl3): δ12.9, 14.2, 16.2, 61.0, 111.4, 115.6, 126.4, 127.5, 130.1, 131.3, 131.6, 133.4, 151.2,
154.1, 158.7, 160.3, 162.2, 174.2; MS (EI) (m/z): 405 (M+); Anal. Calcd for C18H16ClN3O4S: C,
53.27; H, 3.97; N, 10.35; Found: C, 53.50; H, 4.29; N, 10.66.
Ethyl 2-[5-methyl-3-(3-chlorophenyl)isoxazole-4-carboxamido]-4-methylthiazole
-5-carboxylate I-2:
White solid; yield 75%; m.p. 135~137oC; IR (KBr)/cm-1: 3327, 3196, 3063, 2984, 2939, 1719,
1664, 1596, 1553, 1534, 1491, 1372, 1261, 1088, 811; 1H NMR (CDCl3, 400MHz) δ1.39 (t, 3H,
-CH2CH3, J=7.2Hz), 2.52 (s, 3H, -CH3), 2.73 (s, 3H, -CH3), 4.33~4.38 (q, 2H, -CH2CH3,
J=7.2Hz), 7.22~7.44 (m, 4H, H2,4,5,6-Ph), 10.77(s, 1H, NH); 13C NMR (100MHz, CDCl3): δ12.6,
14.3, 15.4, 61.2, 110.5, 114.4, 126.1, 128.3, 128.9, 129.3, 129.8, 134.6, 150.3, 158.8, 161.9,
162.8, 163.1, 175.6; MS (EI) (m/z): 405 (M+); Anal. Calcd for C18H16ClN3O4S: C, 53.27; H,
3.97; N, 10.35; Found: C, 53.39; H, 4.00; N, 10.75.
Ethyl 2-[5-methyl-3-(4-chlorophenyl)isoxazole-4-carboxamido]-4-methylthiazole
-5-carboxylate I-3:
8
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White solid; yield 77%; m.p. 136~138oC; IR (KBr)/cm-1: 3245, 3222, 3055, 2982, 2932, 1725,
1662, 1613, 1553, 1528, 1512, 1372, 1242, 1089, 815, 756; 1H NMR (CDCl3, 400MHz) δ1.39 (t,
3H, -CH2CH3, J=7.2Hz), 2.53 (s, 3H, -CH3), 2.74 (s, 3H, -CH3), 4.33~4.39 (dd, 2H, -CH2CH3,
13
J1=14.0Hz, J2=6.8Hz), 7.27~7.36 (m, 4H, H2,3,5,6-Ph), 9.58(s,1H, NH); C NMR (100MHz,
CDCl3): δ12.6, 14.4, 15.3, 61.2, 110.5, 114.7, 125.8, 128.8, 129.4, 135.6, 149.4, 159.1, 161.8,
162.9, 163.2, 175.6; MS (EI) (m/z): 405 (M+); Anal. Calcd for C18H16ClN3O4S: C, 53.27; H,
3.97; N, 10.35; Found: C, 53.41; H, 4.11; N, 10.49.
Ethyl2-[5-methyl-3-(2,4-dichlorophenyl)isoxazole-4-carboxamido]-4-methylthiaz-ole-5-carb
oxylate I-4:
White solid; yield 80%; m.p. 149-151oC; IR (KBr)/cm-1: 3234, 3236, 3088, 2982, 2909, 1726,
1659, 1539, 1533, 1509, 1508, 1370, 1232, 1091, 818, 746; 1H NMR (CDCl3, 400MHz) δ1.37 (t,
3H, -CH2CH3, J=7.2Hz), 2.51 (s, 3H, -CH3), 2.75 (s, 3H, -CH3), 4.30~4.36 (q, 2H, -CH2CH3,
J=7.2Hz), 7.29~7.45 (m, 4H, H3,5,6-Ph), 9.78(s,1H, NH); 13C NMR (100MHz, CDCl3): δ12.5,
14.3, 15.7, 61.2, 109.7, 111.9, 125.2, 127.8, 129.6, 131.9, 131.9, 134.2, 136.6, 136.6, 158.1,
161.9, 162.1, 174.3; MS (EI) (m/z): 439 (M+); Anal. Calcd for C18H15Cl2N3O4S: C, 49.10; H,
3.43; N, 9.54; Found: C, 49.51; H, 3.66; N, 9.85.
Ethyl 2-[5-methyl-3-(2,4-dichlorophenyl)isoxazole-4-carboxamido]-4-isopropylt-
hiazole-5-carboxylate I-5:
White solid; yield 73%; m.p. 156~157 oC; IR (KBr)/cm-1: 3266, 3223, 3060, 2929, 1722, 1684,
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1527, 1490, 1377, 1293, 1180, 801, 727; 1H NMR (CDCl3, 400MHz) δ1.16 (d, 6H, -CH(CH3)2,
J = 6.8 Hz), 1.34 (t, 3H, -CH2CH3, J = 7.2 Hz), 2.85 (s, 3H, -CH3), 3.87~3.94 (m, 1H,
-CH(CH3)2), 4.26~4.32 (dd, 2H, -CH2CH3, J1=14.0Hz, J2=6.8Hz), 7.48~7.60 (m, 3H, H3,5,6-Ph),
8.61 (s, 1H, NH); 13C NMR (100MHz, CDCl3): δ13.3, 14.3, 21.7, 28.4, 60.9, 110.8, 114.9, 125.0,
128.2, 130.4, 132.4, 134.6, 137.9, 157.8, 158.5, 158.7, 162.2, 165.7, 174.9; MS (EI) (m/z): 467
(M+); Anal. Calcd for C20H19Cl2N3O4S: C, 51.29; H, 4.09; N, 8.97; Found: C, 51.35; H, 4.11; N,
9.00.
Ethyl 2-[5-methyl-3-(2-nitrophenyl)isoxazole-4-carboxamido]-4-isopropylthiazole
-5-carboxylate I-6:
White solid; yield 59%; m.p. 112~114oC; IR (KBr)/cm-1: 3270, 3215, 3058, 2996, 1727, 1668,
1
1546, 1541, 1533, 1481, 1374, 1291, 1166, 757; H NMR (CDCl3, 400MHz) δ1.17 (d, 3H,
-CH(CH3)2, J=7.2Hz), 1.21 (d, 3H, -CH(CH3)2, J=6.8Hz), 1.32 (t, 3H, -CH2CH3, J=7.2Hz), 2.87
(s, 3H, -CH3), 3.87~3.95 (m, 1H, -CH(CH3)2), 4.25~4.30 (dd, 2H, -CH2CH3, J1=14.0Hz,
J2=6.8Hz), 7.60~8.28 (m, 4H, H3,4,5,6-Ph), 8.93 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): δ13.3,
14.2, 21.6, 28.1, 60.9, 111.4, 116.4, 120.4, 123.4, 124.8, 125.1, 131.5, 132.4, 133.9, 146.5, 148.5,
159.4, 162.1, 173.0;MS (EI) (m/z): 444 (M+); Anal. Calcd for C20H20N4O6S: C, 54.03; H, 4.54;
N, 12.61; Found: C, 54.28; H, 4.66; N, 13.00.
Acknowledgements.
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The present work was supported by Science and Technology Entire Innovation Project Plan
Foundation of Shaanxi Province (2016KTCL01-09).
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Br
CF3
H
N
H
N
S
N
N
O
S
HN
S
CF3
CN
O
O
Br
Ethaboxam
Thifuzamide
Figure 1. Chemical structures of Ethaboxam and Thifuzamide.
Scheme 1. Synthesis of Compounds 2.
R
O
O
O
O
N
a
b
OEt
H2N
R
OEt
R
OEt
S
O
Cl
1
2
R: Methyl or Isopropyl
Reagents and conditions: (a)SO2Cl2, CCl4, r.t.; (b) Thiourea, NaHCO3, THF, reflux;
Scheme 2. Synthesis of Compounds 7.
Cl
CHO
N OH
O
N OH
X
X
e
c
X
d
X
OEt
N
O
3
4
5
X
X
f
g
COOH
COCl
N
N
O
O
6
7
Reagents and conditions: (c) NH2OH.HCl, Na2CO3, r.t.; (d) N-Chlorosuccinimide, DMF, r.t.; (e)
Ethyl acetoacetate, Et3N, DCM, r.t.; (f)KOH, H2O, Ethanol, r.t.; (g)SOCl2, reflux ;
13
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Scheme 3. Synthesis of the Target Compounds I.
R
O
N
R
X
OEt
X
N
COCl
N
H
Et3N
DCM
S
OEt
+
H2N
O
N
S
N
O
O
O
2
I-1~6
7
I-1 R: Methyl; X: 2-Cl; I-2 R: Methyl; X: 3-Cl;
I-3 R: Methyl; X: 4-Cl; I-4 R: Methyl; X: 2,4-Cl2;
I-5 R: Isopropyl; X: 2,4-Cl2; I-6 R: Isopropyl; X: 2-NO2;
Biological Activity
Table S 1. Fungicidal Activities of the Target Compounds I
R
O
N
X
OEt
N
S
H
O
N
O
inhibition (%),in vitro ,100mg/L
R
X
Compd.
F.G.
40
45
52
57
58
10
73
T.C.
40
50
50
55
57
5
B.C.
37
F.O.
33
32
38
50
55
0
I-1
I-2
I-3
I-4
I-5
I-6
CH3
CH3
CH3
2-Cl
3-Cl
4-Cl
39
43
CH3 2,4-Cl2
i- pro 2,4-Cl2
i- pro 2-NO2
46
48
10
96
96
83
Chlorothalonil
F. G. for FusaHum graminearum; T. C. for Thanatephorus cucumeris；
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B.C. for Botrytis cinerea； F. O. for Fusarium oxysporum
Table S 2. Herbicidal Activities of the Target Compounds I (Percent inhibition)
R
O
N
X
OEt
N
S
H
O
N
O
Post-emergence, 150 gai/ha
R
X
Compd
E.C. D.S. S. V. B.J. A.T. D.E.
I-1
I-2
I-3
I-4
I-5
I-6
CH3
CH3
CH3
2-Cl
3-Cl
4-Cl
0
0
0
0
0
0
0
0
0
0
0
0
40
20
0
30 50
40
50
0
CH3 2,4-Cl2 20
30
0
20 40 40
i- pro 2,4-Cl2
i- pro 2-NO2
2,4-D
0
0
0
0
0
0
0
0
0
0
50
50
60 90 100 100
E.C. for Echinochloa crusgalli; D. S. for Digitaria sanguinalis； S. V. for Setaria viridis；
B. J. for Brassica juncea; A. T. for Abutilon theophrasti; D. E. for Descurainia sophia;
2,4-D for 2,4-Dichlorophenoxyacetic acid
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Fungicidal Activity
The fungicidal activity measurement method was adapted from the literature [12]. The
fungicidal activities of I-1~6 were evaluated at the concentration of 100 mg/L using
Chlorothalonil as a positive control. The four fungi FusaHum graminearum, Thanatephorus
cucumeris, Botrytis cinereapers and Fusarium oxysporum, belong to the group of field fungi and
were isolated from corresponding crops. As listed in Table S1, most of compounds display
32~58% inhibition effect against the above four fungi except the compound I-6 with 2-NO2
substitution on the benzene ring against all the target fungi with 0-10% inhibition effect in vitro
at the concentration of 100 mg/L. It can be found that the R and X groups with compounds seem
to have some impacts on the fungicidal activity. Interestingly, when he R group as methyl, the
2,4-Cl2 di-substitution on the benzene ring was the most promotive, followed by 4-Cl, 3-Cl and
2-Cl. Compound I-8 (R as isopropyl, X as 2,4-Cl2) exhibited much higher fungicidal activity
(48~58% inhibition effect) than the other compounds, indicating that isopropyl group introduced
to the parent structure was more beneficial for the improvement of fungicidal activity than the
methyl group.
Herbicidal Activity
The title compounds I-1~6 were tested against dicotyledonous weeds such as Echinochloa
crusgalli, Digitaria sanguinalis and Setaria viridis and dicotyledonous weeds such as Brassica
juncea, Abutilon theophrasti and Descurainia sophia at the doseage of 150 g ai/ha using 2,4-D as
a positive control according to the method described in the literature [2]. As shown by the data in
Table S 2, all compounds with R group as isopropyl were inactive against all of the tested weeds,
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whereas some of compounds with R group as methyl exhibited 0~50% inhibition such as
compounds I-2~4. For example compound I-2 exhibited 40% inhibition against Brassica juncea,
and compound I-3 exhibited 20% inhibition against monocotyledonous weeds Echinochloa
crusgalli and 30~50% inhibition against all of tested dicotyledonous weeds. It is worthwhile to
note that compound I-4 displayed 20~30% inhibition all of tested monocotyledonous weeds and
40~50% inhibition against all of tested dicotyledonous weeds. Our result showed that a
reasonable combination both X group on benzene and R group of compounds I had a very
important effect on herbicidal activity.
Table S 3. The yields and melting point of the intermediates 6
X
COOH
N
O
Compd
6-1
X
m.p.
yields
2-Cl
3-Cl
4-Cl
193~196 oC 95%
171~173 oC 97%
217~218 oC 95%
6-2
6-3
6-4
2,4-diCl 207~208 oC 93%
2-NO2 209~211 oC 90%
6-5
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Ethyl
2-[5-methyl-3-(2-chlorophenyl)isoxazole-4-carboxamido]-4-methylthiazole-5-carboxylate
I-1:
Figure S 1: The 1H NMR spectrum of compound I-1
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Figure S 2: The 13C NMR spectrum of compound I-1
Ethyl
2-[5-methyl-3-(3-chlorophenyl)isoxazole-4-carboxamido]-4-methylthiazole-5-carboxylate
I-2:
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Figure S 3: The 1H NMR spectrum of compound I-2
Figure S 4: The 13C NMR spectrum of compound I-2
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Ethyl
2-[5-methyl-3-(4-chlorophenyl)isoxazole-4-carboxamido]-4-methylthiazole-5-carboxylate
I-3:
Figure S 5: The 1H NMR spectrum of compound I-3
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Figure S 6: The 13C NMR spectrum of compound I-3
Ethyl
2-[5-methyl-3-(2,4-dichlorophenyl)isoxazole-4-carboxamido]-4-methylthiazole-5-carboxylat
e I-4:
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Figure S 7: The 1H NMR spectrum of compound I-4
Figure S 8: The 13C NMR spectrum of compound I-4
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Ethyl
2-[5-methyl-3-(2,4-dichlorophenyl)isoxazole-4-carboxamido]-4-isopropylthiazole-5-carboxy
late I-5:
Figure S 9: The 1H NMR spectrum of compound I-5
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Figure S 10: The 13C NMR spectrum of compound I-5
Ethyl
2-[5-methyl-3-(2-nitrophenyl)isoxazole-4-carboxamido]-4-isopropylthiazole-5-carboxylate
I-6:
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Figure S 11: The 1H NMR spectrum of compound I-6
Figure S 12: The 13C NMR spectrum of compound I-6
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