Design, synthesis and biological activities of novel 1,2,3-thiadiazole derivatives containing oxime ether

Article abstract of DOI:10.3184/030823408X303998

A series of novel 2-methoxyimino-1,2,3-thiadiazole-5-acetamide derivatives were synthesised. Their structures were identified by means of elemental analysis, IR, ¹H NMR and MS spectra. The preliminary biological activity tests showed that some of the compounds snowed some fungicidal activity.

Full text of DOI:10.3184/030823408X303998

JOURNAL OF CHEMICAL RESEARCH 2008
MARCH, 145–147
Design, synthesis and biological activities of novel 1,2,3-thiadiazole
derivatives containing oxime ether
Wei-li Dong, Hong-wei Yao, Zheng-ming Li and Wei-guang Zhao*
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071 China
A series of novel 2-methoxyimino-1,2,3-thiadiazole-5-acetamide derivatives were synthesised. Their structures were
identified by means of elemental analysis, IR, 1H NMR and MS spectra. The preliminary biological activity tests
showed that some of the compounds showed some fungicidal activity.
Keywords: 1,2,3-thiadiazole, oxime ether, biological activity
In the investigation of new agrochemicals, we found 1,2,3-
thiadiazole derivatives, which had good biological and
pharmaceutical activities,1-3 had received only limited
attention, but commercial pesticides containing 1,2,3-
thiadiazole often possess simple structure and unique active
mechanism. For example, thidiazuron (TDZ),4 a cotton
defoliant, has been found to exhibit more significant plant
growth regulative activity than 6-benzyladenine (6-BA) and
zeatin. Benzothiadiazole (BTH)5 was the first commercial
plant activator. Tiadinil was an excellent plant activator6
(Fig. 1). Furthermore, 1,2,3-thiadiazolecarboxamides also
displayed good fungicidal activities.7,8 We herein became
interested in making 1,2,3-thiadiazoleacetamides, analogues
of three commercial pesticides.
In the previous paper, we had reported some 1,2,3-
thiadiazoleacetamides exhibited better anti-tobacco mosaic
virus (anti-TMV) activity, plant growth-regulating activity and
showed some anti-hepatitis B virus (anti-HBV) activity.9-12
Considering the oxime ethers are very important active
compounds, many of them are used as insecticide, fungicide,
herbicide and so on, and oxime ether group is often used in
new pesticide discovery because of their high biological
activites and their good environmental profiles.13 In order
to search for novel 1,2,3-thiadiazole derivatives which have
high activities, we report here our synthesise a series of novel
2-methoxyimino-1,2,3-thiadiazole-5-acetamides 6. Their
1
structures were confirmed by elemental analysis, IR, H
NMR and MS spectra. And we also synthesised commercial
Tiadinil. Fungicidal activities of these 1,2,3-thiadiazole
compounds synthesised were evaluated through disc paper
method. The results showed that these compounds exhibited
weak fungicidal activities.
Experimental
Instruments
Melting points were conducted on a Yanaco MP-500 micro melting-
point apparatus. 1H NMR spectra were recorded in CDCl3 as solvent
on Bruker AC-300 instrument using TMS as an internal standard.
Elemental analysis was performed on a Yanaco CHN Corder MF-3
automatic elemental analyser. Mass spectra were recorded with VG
ZAB-HS, 8kV, 1 mA using the Fast Atom Bombardment (FAB)
method. Microwave activation was carried out with LWMC-201.
Synthesis of diethyl 2-(1,2,3-thiadiazol-5-yl)malonate (2): The
starting material, 5-chloro-1,2,3-thiadiazole 1 was obtained by
synthesis.14 To 100 ml of absolute ethanol in a 250 ml three-necked
round-bottomed flask equipped with a reflux condenser bearing
a calcium chloride tube is added 1.38 g (60 mmol) of sodium
cut in pieces of suitable size. When all the sodium has reacted,
diethyl malonate (9.60 g, 60 mmol) was added dropwise at room
temperature and the mixture was stirred for 20 min, then 5-chloro-
N
H
N
O
N
N
Cl
S
N
N
N
S
N
H
N
H
S
O
S
O
TDZ
BTH
Tiadinil
Fig. 1 Structures of TDZ, BTH, Tiadinil.
N
N
N
N
N
N
CH2(COOEt)2
1, SeO2
LiBr, H 2O
microwave
CH(COOEt)2
.
Cl
S
2, NH2OCH3 HCl
EtONa
S
CH2COOEt
S
1
2
3
O
O
N
N
O
O
N
N
N
N
R
NH2
NaOH
EtOH
R
N
O
S
OH
S
S
DCC, THF
H
N
N
N
O
O
4
5
6a-h
Scheme 1 Synthesis routes of the derivatives of 1,2,3-thiadiazole (6a–6h). 6a R = 4-methylphenyl; 6b R = 3-chloro-4-
methylphenyl; 6c R = 3,4-dichlorophenyl; 6d R = 3-nitrophenyl; 6e R = 4-methylpyrimidin-2-yl; 6f R = 2,5-dichlorophenyl;
6g R = naphthalen-2-yl; 6h R = 3,4-dimethoxyphenethyl
* Correspondent. E-mail: zwg@nankai.edu.cn
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146 JOURNAL OF CHEMICAL RESEARCH 2008
1,2,3-thiadiazole 1 (6.63 g, 55 mmol) was slowly added, the mixture
was stirred at room temperature for 24 h. After removal of solvent,
the residue was treated with 200 ml water, acidified to ca pH = 4
with 6 mol/l HCl. The solution was extracted with ethyl acetate
(2 × 100 ml). The combined ethyl acetate extracts were washed with
water (2 × 50 ml), dried over anhydrous MgSO4 and evaporated in
vacuo. The residue was purified by silica-gel column eluted with
ethyl acetate/petroleum ether (volume ratio1:10) to obtain 2 (8.06 g,
60.0%) as a yellow liquid; 1H NMR (CDCl3, 300 MHz), δ: 1.26–1.31
(m, 6H, CH3), 4.25–4.31 (m, 4H, CH2), 4.15 (s, 1H, CH), 8.73 (s, 1H,
thiadiazole-H); Elemental anal. (%), calculated for C9H12N2O4S: C,
44.25; H, 4.95; N, 11.47; found: C, 43.99; H, 4.90; N, 11.29.
Synthesis of ethyl 2-(1,2,3-thiadiazol-5-yl)acetate (3): A mixture
of the malonate ester 2 (2.44 g, 10 mmol), lithium bromide (1.73 g,
20 mmol), tetrabutylammonium bromide (0.32 g, 1 mmol) and
5 ml water. The reaction mixture was heated for 30 min under MW
heating conditions with an irradiation power of 120 W. After being
cooled to room temperature, water (10 ml) was added, the mixture
was extracted with ethyl acetate (2 × 20 ml), dried over anhydrous
MgSO4 and evaporated in vacuo. The residue was purified by silica-
gel column eluted with ethyl acetate/petroleum ether (volume ratio
1:10) to obtain 3 (1.50 g, 87.1%) as a white solid; m.p. 32–34°C;
1H NMR (CDCl3, 300 MHz), δ: 1.31 (t, J = 7.2 Hz, 3H, CH3), 4.11 (s,
1H, CH), 4.25 (q, J = 7.2 Hz, 4H, CH2), 8.64 (s, 1H, thiadiazole-H);
Elemental anal. (%), calculated for C6H8N2O2S: C, 41.85; H, 4.68; N,
16.27; found: C, 41.56; H, 4.94; N, 16.35.
N-(3,4-Dichlorophenyl)-2-(methoxyimino)-2-(1,2,3-thiadiazol-5-
yl)acetamide (6c): The compound was obtained in 55.6% yield as a
1
white solid; m.p. 163–166°C; H NMR (CDCl3, 300 MHz), δ: 4.44
(s, 3H, CH3), 7.31–8.46 (m, 3H, Ph), 9.43 (br, 1H,NH), 9.91 (s, 1H,
thiadiazole-H); IR (KBr), ν/cm-1: 3429, 3329, 3132, 3104, 2951,
1690, 1604, 1589,1451, 1420, 1230. Elemental anal. (%), calculated
for C11H8Cl2N4O2S: C, 39.89; H, 2.43; N, 16.92; found: C, 39.78; H,
2.75; N, 16.51.
N-(3-Nitrophenyl)-2-(methoxyimino)-2-(1,2,3-thiadiazol-5-yl)
acetamide (6d): The compound was obtained in 56.0% yield as a
1
white solid; m.p. 208–214°C; H NMR (CDCl3, 300 MHz), δ: 4.46
(s, 3H, CH3), 7.57–8.514 (m, 4H, Ph), 9.99 (br, 1H, NH), 9.92 (s,
1H, thiadiazole-H); IR (KBr), ν/cm-1: 3430, 3227, 3106, 2987, 1732,
1609, 1584, 1550, 1453, 1349. Elemental anal. (%), calculated for
C11H9N5O4S: C, 43.00; H, 2.95; N, 22.79; found: C, 43.42; H, 3.21;
N, 22.58.
N-(4-Methylpyrimidin-2-yl)-2-(methoxyimino)-2-(1,2,3-thiadiazol-
5-yl)acetamide (6e): The compound was obtained in 54.0% yield
as a white solid; m.p. 129–133°C; 1H NMR (CDCl3, 300 MHz),
δ: 2.56 (s, 3H, CH3), 4.44 (s, 3H, OCH3), 6.99–8.60 (m, 2H, pyrimidin-
H), 9.48 (br, 1H, NH), 9.95 (s, 1H, thiadiazole-H); IR (KBr), ν/cm-1:
3409, 3231, 3194, 3020, 1714, 1605, 1558, 1524, 1400. Elemental
anal. (%), calculated for C10H10N6O2S: C, 43.16; H, 3.62; N, 30.20;
found: C, 43.45; H, 3.82; N, 29.93.
N-(2,5-Dichlorophenyl)-2-(methoxyimino)-2-(1,2,3-thiadiazol-5-yl)
acetamide (6f): The compound was obtained in 58.6% yield as a
1
Synthesis of ethyl 2-(methoxyimino)-2-(1,2,3-thiadiazol-5-
yl)acetate (4): A mixture of selenium dioxide (0.23 g, 11 mmol)
dissolved in 30 ml 1,4-dioxane and 0.5 ml H2O was heated under
reflux, then the solution of monoesters 3(1.9 g, 11 mmol) in 20 ml
1,4-dioxane was added dropwise. After the mixture was refluxed for
8 h, cooled, evaporated in vacuo to give the residue. Subsequently,
a solution of the residue, NaOH (0.47 g, 11.8 mol), and hydroxylamine
hydrochloride (0.99 g, 11.8 mol) in absolute ethanol (30 ml) was
heated under reflux for 3 h. After the mixture was cooled, evaporated
in vacuo to give the residue, the solid residue was purified by silica-
gel column eluted with ethyl acetate/petroleum ether (volume
ratio 1:3) to give compound 4 (1.32 g, 56.0%) as a yellow solid;
white solid; m.p. 182–185°C; H NMR (CDCl3, 300 MHz), δ: 4.38
(s, 3H, CH3), 7.03–8.51 (m, 3H, Ph), 9.43 (br, 1H,NH), 9.85 (s, 1H,
thiadiazole-H); IR (KBr), ν/cm-1: 3423, 3337, 3117, 3004, 2949,
1686, 1580, 1518, 1445, 1407. Elemental anal. (%), calculated for
C11H8Cl2N4O2S: C, 39.89; H, 2.43; N, 16.92; found: C, 39.65; H,
2.70; N, 17.22.
N-(Naphthalen-2-yl)-2-(methoxyimino)-2-(1,2,3-thiadiazol-5-yl)
acetamide (6g): The compound was obtained in 50.0% yield as a
1
white solid; m.p. 173–175°C; H NMR (CDCl3, 300 MHz), δ: 4.38
(s, 3H, CH3), 7.38–8.28 (m, 7H, naphthalene-H), 8.87 (br, 1H, NH),
9.87 (s, 1H, thiadiazole-H); IR (KBr), ν/cm-1: 3442, 3386, 3304,
3044, 2933, 1670, 1582, 1534, 1437, 1363. Elemental anal. (%),
calculated for C15H12N4O2S: C, 57.68; H, 3.87; N, 17.94; found: C,
57.36; H, 4.13; N, 18.18.
1
m.p. 44–46°C; H NMR (CDCl3, 300 MHz), δ: 1.44 (t, J = 6.9 Hz,
3H, CH3), 4.41 (s, 1H, CH), 4.42 (q, J = 6.9 Hz, 4H, CH2), 9.69 (s,
1H, thiadiazole—H); Elemental anal. (%), calculated for C7H9N3O3S:
C, 39.06; H, 4.21; N, 19.52; found: C, 38.86; H, 4.19; N, 19.49.
Synthesis of 2-(methoxyimino)-2-(1,2,3-thiadiazol-5-yl)acetic acid
(5): Aqueous NaOH (15%, 80 ml) was added to a solution of ester 4
(3.31 g, 15.4 mmol) in MeOH-tetrahydrofuran (40 ml, volume ratio
1:1). After the mixture had been stirred for 1 h at room temperature
the organic solvents were evaporated off, water was added, and the
solution was and acidified using dilute HCl to pH 1.5. The aqueous
solution was extracted with ethyl acetate (2 × 100 ml), dried over
anhydrous MgSO4 and evaporated in vacuo to give product 5 (2.7 g,
93%, yellow solid) as a yellow solid; m.p. 126–132°C; 1H NMR
(CDCl3, 300 MHz), δ: 4.463 (s, 1H, CH), 9.882 (s, 1H, thiadiazole-
H); Elemental anal. (%), calculated for C5H5N3O3S: C, 32.08; H,
2.69; N, 22.45; found: C, 31.79; H, 2.69; N, 22.00.
Synthesis of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(methoxyimino)-
1,2,3-thiadiazole-5-acetamide (6h):
A mixture of ethyl 2-
(methoxyimino)-2-(1,2,3-thiadiazol-5-ly)acetic acid, ethyl ester 4
(0.215 g 1 mmol) and 2-(3,4-dimethoxyphenyl)ethanamine (0.36 g,
2 mmol) was stirred at 120~140°C for 2 h, cooled, the solid residue
was purified by silica-gel column eluted with ethyl acetate/petroleum
ether (volume ratio 1:3) to give the amides 6h (0.21 g, 60%) as a
yellow solid; m.p. 126–132°C; 1H NMR (CDCl3, 300 MHz), δ: 2.86
(t, J = 7.2 Hz, 2H, CH2), 3.65 (q, J = 6.6 Hz, 2H, CH2), 3.88 (s,
3H, CH3), 3.88 (s, 3H, CH3), 4.28 (s, 3H, CH3), 6.76–6.85 (m, 3H,
Ph), 7.06 (br, 1H, NH), 9.82 (s, 1H, thiadiazole-H); IR (KBr), ν/cm-1:
3423, 3277, 3002, 2941, 2866, 2836, 1665, 1589, 1519, 1452, 1270,
1230. Elemental anal. (%), calculated for C15H18N4O4S: C, 51.42; H,
5.18; N, 15.99; found: C, 51.18; H, 5.27; N, 16.25.
General procedure for 2-(methoxyimino)-2-(1,2,3-thiadiazol-
5-yl)acetamide (6a–g): 2-(Methoxyimino)2-(-1,2,3-thiadiazol-5-
yl)acetic acid 5 (1.5 mmol), the amine (1.5 mmol), DCC (1.55 mmol),
and a catalytic amount of DMAP (0.15 mmol) were suspended in
anhydrous THF (20 ml). After the mixture was heated under reflux
for 12 h, the solvent was removed in vacuo, and the solid residue
was purified by silica-gel column eluted with ethyl acetate/petroleum
ether (volume ratio 1/3) to give the amides 6a–g.
2-(Methoxyimino)-2-(1,2,3-thiadiazol-5-yl)-N-(p-tolyl)acetamide
(6a): The compound was obtained in 54.3% yield as a white solid;
m.p. 125–127°C; 1H NMR (CDCl3, 300 MHz), δ: 2.86 (t, J = 7.2 Hz,
2H, CH2), 3.63–3.70 (q, J = 6.6 Hz, 2H, CH2), 3.88 (s, 3H, CH3),
3.88 (s, 3H, CH3), 4.28 (s, 3H, CH3), 6.76–6.85 (m, 3H, Ph), 7.06 (br,
1H,NH), 9.82 (s, 1H, thiadiazole-H); IR (KBr), ν/cm-1: 3458, 3236,
3037, 3002, 1735, 1602, 1583, 1450, 1364. Elemental anal. (%),
calculated for C12H12N4O2S: C, 52.16; H, 4.38; N, 21.27; found: C,
51.90; H, 4.50; N, 20.98.
N-(3-Chloro-4-methylphenyl)-2-(methoxyimino)-2-(1,2,3-
thiadiazol-5-yl)acetamide (6b): The compound was obtained in
69.8% yield as a white solid; m.p. 155–156°C; 1H NMR (CDCl3,
300 MHz), δ: 2.36 (s, 3H, CH3), 4.41(s, 3H, CH3), 7.23–7.73 (m, 3H,
Ph), 8.70 (br, 1H,NH), 9.89 (s, 1H, thiadiazole-H); IR (KBr), ν/cm-1:
3454, 3148, 3025, 2979, 1741, 1605, 1583, 1447, 1312. MS (ESI),
m/z: 310 (M -1). Elemental anal. (%), calculated for C12H11ClN4O2S:
C, 46.38; H, 3.57; N, 18.03; found: C, 46.15; H, 3.46; N, 18.29.
Synthesis of N-(3-chloro-4-methylphenyl)-2-(1,2,3-thiadiazol-5-yl)
carboxamide (Tiadinil)
Tiadinil obtained according to the literature.15
Results and discussion
Synthesis
In the step of removing a balkoxy carbonyl group from the malonic
16,17
ester 2, Krapcho’s method
was unsuitable, because the malonic
ester contains an 1,2,3-thiadiazole which is liable to decompound
in DMSO (>160°C), in order to avoid he use of DMSO at high
temperatures, we exploited the method of coupling microwave
irradiation and solvent-free PTC(NBu4Br),18 but considering
instability of 1,2,3-thiadiazole, in the reaction procedure, the water
as solvent added excessively to control reaction temperature, the
malonate ester 2 can easily be converted into the monoesters 3 by
dealkoxycarbonylation, the method has the advantage of comparative
and produces higher overall yields than the classical procedure which
involves saponification, decarboxylation and esterification.
Biological activities of compounds
The preliminary biological tests showed that both the title compound
and Tiadinil shows have little bactericidal activity against Gibberella
zeae, Alternaria solani, Cercosporsa arachidicola, Physalospora
piricola Nose, Phomaasparagi (Table 1), it may be that tiadinil is a
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JOURNAL OF CHEMICAL RESEARCH 2008 147
Table 1 Fungicidal activity of some compounds (50 μg/ml)
NO.
Inhibition rate/%
Gibberella
zeae
Alternaria
solani
Cercosporsa
arachidicola
Physalospora
piricola Nose
Phomaasparagi
6b
27.3
28.7
27.3
15.4
30.8
33.3
27.6
28.6
23.5
23.5
23.5
34.2
29.4
29.4
17.7
23.9
36.6
34.8
35.5
38.7
32.0
21.5
20.0
12.0
24.0
6e
6f
6h
Tiadinil
3
4
5
6
S.A. Bowles, A. Miller and M. Whittaker, WO 9 315 047, 1993.
H.R. Krueger, F. Arndt and R. Rush, DE 3 139 505, 1983.
W. Kunz, R. Schurter and T. Maetzke, Pestic. Sci., 1997, 50, 275.
K. Tsubata, O. Sanpei, K. Takagi, K. Umetani, T. Uchikurohane and
S. Tajima, WO 9 923 084, 1999.
Nihon Nohyaku Co., WO 9 629 871, 1996.
Z.F. Li, Z.R. Wu and F.Y. Luo, J. Agric. Food Chem., 2005, 53, 3872.
Z.M. Li, W.G. Zhao and Z. Yang, CN 1 346 827, 2002.
plant activator by inducing the plant defense mechanism against a
pathogen, but without direct antimicrobial activity. A further study of
their plant activator is underway.
We gratefully thank the China 973 Program (grant no.
2003CB114406) and the National Natural Science Foundation
of China (grant no. 20772069) for financial support of this
research.
7
8
9
10 W.G. Zhao, Z.M. Li and Y. Zhao J. Heterocyclic Chem., 2003, 40, 925.
11 W.G. Zhao, J.G. Wang, Z.M. Li and Z. Yang, Bioorg. Med. Chem. Lett.,
2006, 16, 6107.
12 W.L. Dong, H.W. Yao, F.L. Wang, L.L. Shen, Y.M. Qian, Z.M. Li and
W.G. Zhao, Chem. J. Chin. Univ.-Chin., 2007, 28, 1671.
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Received 30 January 2007; accepted 12 March 2008
Paper 08/5073
doi: 10.3184/030823408X303998
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