Synthesis and bioactivities of novel 1,3,4-oxadiazole derivatives containing 1,2,3-thiadiazole moiety

Article abstract of DOI:10.1080/10426507.2014.906424

Some novel 1,3,4-oxadiazole derivatives containing 1,2,3-thiadiazole were synthesized under microwave-assistant condition by multi-step reactions. The structures were characterized by ¹H NMR, MS, and elemental analyses. The target compounds were evaluated for their herbicidal activities against Brassica campestris and Echinochloa crusgalli, and the results indicated that some of the title compounds displayed good herbicidal activities.

Full text of DOI:10.1080/10426507.2014.906424

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Phosphorus, Sulfur, and Silicon and the Related
Elements
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Synthesis and bioactivities of novel 1,3,4-oxadiazole
derivatives containing 1,2,3-thiadiazole moiety
Guo-Xiang Sunac, Ming-Yan Yangb, Zhao-Hui Sunb, Hong-Ke Wub, Xing-Hai Liub & Yun-Yang
Weic
a School of Chemical and Biological Engineering, Yancheng Institute of Technology, Yancheng
224051,Jiangsu,China
b College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014,
China
c School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing
210094,China
Accepted author version posted online: 19 Jun 2014.
To cite this article: Guo-Xiang Sun, Ming-Yan Yang, Zhao-Hui Sun, Hong-Ke Wu, Xing-Hai Liu & Yun-Yang Wei (2014): Synthesis
and bioactivities of novel 1,3,4-oxadiazole derivatives containing 1,2,3-thiadiazole moiety, Phosphorus, Sulfur, and Silicon and
the Related Elements, DOI: 10.1080/10426507.2014.906424
To link to this article: http://dx.doi.org/10.1080/10426507.2014.906424
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Synthesis and bioactivities of novel 1,3,4-oxadiazole derivatives containing 1,2,3-thiadiazole
moiety
Guo-Xiang Sun a,c, Ming-Yan Yang b, Zhao-Hui Sun b, Hong-Ke Wub, Xing-Hai Liub,*,
Yun-Yang Weic
a
School of Chemical and Biological Engineering, Yancheng Institute of Technology, Yancheng
224051,Jiangsu,China
b College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014,
China
c School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing
210094,China
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Abstract: Some novel 1,3,4-oxadiazole derivatives containing 1,2,3-thiadiazole were synthesized
under microwave assistant condition by multi-step reactions. The structures were characterized
by 1H NMR, MS and elemental analyses. The target compounds were evaluated for their
herbicidal activities against Brassica campestris and Echinochloa crusgalli, and the results
indicated that some of the title compounds displayed good herbicidal activities.
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Keywords: 1,3,4-oxadiazole, 1,2,3-thiadiazole, Herbicidal activity, Microwave synthesis
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INTRODUCTION
In recent years, nitrogen-containing heterocyclic compounds had received considerable attention
due to their pharmacological and pesticidal importance [1-4], especially 1,3,4-oxadiazole and
1,2,3-thiadiazole. 1,3,4-Oxadiazole, and its derivatives, represent one of the most biologically
active classes of compounds with exhibited diversity in medicinal and agrochemical fields,
including anti-inflammatory activities [5], antibacterial activities[6], herbicidal activities[7],
insecticidal activities [8], antifungal activities [9]. Some compounds have been developed as
commercial fungicides or herbicides, such as Triadimefon, Triadimenol, Flusilazole and
Flupoxam. On the other hand, the 1,2,3-thiadiazole moiety has been claimed to have many
applications, because its derivatives exhibited wide spectrum biological properties, such as
antiviral [10], herbicidal [11, 12], antifungal activities [13]. There are many reports about each of the
two heterocycles, but the combination of 1,2,3-thiadiazole ring with 1,2,4-triazole ring in one
molecule is seldom reported both in chemistry and their biological activity studies.
In view of these facts mentioned above, and also as a part of our work [14] on the synthesis of
bioactive lead compounds, the title compounds were designed by introducing 1,2,3-thiadiazole
pharmacophore into 1,3,4-oxadiazole scaffold. Some novel 1,3,4-oxadiaiazole derivatives were
synthesized and characterized by 1H NMR, MS and elemental analysis. The herbicidal
activities of these compounds were tested in vivo.
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RESULTS AND DISCUSSION
The synthesis procedures for title compounds were shown in Scheme 1. The key
intermediate ethyl 4-methyl-1,2,3-thiadiazole-5-carboxylate was synthesized using the
Hurd-Mori method[16]. Then the intermediate 3 was reacted with 85% hydrazine hydrate to give
intermediate 4. The intermediate 4 was easily cyclized with CS2 to give intermediate 5 under
alkaline conditions, such as KOH. Furthermore intermediate 5 was reacted with
substituted benzyl chlorides to afford compounds 6 under microwave irradiation. The microwave
irradiation assisted synthesis and conventional methods were also employed in this experiment.
In the microwave irradiation reaction system, NaOH/DMF/H2O was added to the reaction
mixture. From the Table 1, the best microwave irradiation reaction condition is at 90 oC for 15
min. The yield of title compound is higher than that of the conventional method; also the
microwave reaction time is shorter.
All the proposed structures were fully confirmed by 1H NMR, MS, elemental analysis and
ESI-MS or HRMS. The signal peak of CH2 protons of the thioether adjacent to the oxadiazole
ring was observed at δ 4.51～4.65 ppm respectively. The chemical shifts around 3.0 ppm are the
CH3 of 4-methyl-1,2,3-thiadiazole group. The ESI-MS spectra showed that the m/z of molecular
ion, was in accorded with its molecular formula. The elemental analyses also confirmed this.
The herbicidal activity against Echinochloa crusgalli and Brassica campestris of the title
compounds was evaluated and the data were shown in Table S 1 (Supplemental materials). As
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can be seen from the data, all the compounds exhibited a good inhibition against Brassica
campestris at 100 µg·ml-1. Especially, compounds 6c and 6e displayed good herbicidal activity at
100 mg/mL with 75.3% and 71.9% inhibitory, respectively. Even at 10µg·ml-1, compound 6c still
exhibited moderate herbicidal activity (50.6%). All the other compounds showed moderate
herbicidal activity against Brassica campestris. But all these compounds showed weak herbicidal
activity against Echinochloa crusgalli, except compound 6i which exhibited moderate activity.
EXPERIMENTAL
Materials and Methods
All the reagents were of analytical grade. Melting points were determined using an X-4
apparatus and uncorrected. 1H NMR spectra were measured on a Bruker AC-P500 (300Hz)
instrument using TMS as an internal standard and CDCl3 as solvent. Elemental analyses were
performed on a Vario EL elemental analyzer.
Microwave assistant synthesis was carried out in a CEM Discover Focused Synthesizer.
Representative 1H NMR for products 6a, 6c and 6i are presented in the Supplemental Materials
(Figures S 1 – S 3)
Synthesis
Intermediate 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide 4 was synthesized
according to the literature [16]
.
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Carbonic acid diethyl ester (11.8 g, 0.1 mol) and hydrazine hydrate (5.6 mL, 0.095 mol, 85%)
were added into a 250 mL round-bottom flask equipped with a condenser. The reaction mixture
was heated to 50 oC and stirred for 20 min, and then cooled down to room temperature and
further stirred for 30 h. Water, ethanol, and excess carbonic acid diethyl ester were distilled off
under reduced pressure. After drying, a white crystal (2) (9.88 g) was obtained with a yield of
95%.
To a stirred solution of compound 2 (6.36 g, 0.06 mol) in ethanol (16.7 mL), a solution of ethyl
acetoacetate (7.8 g, 0.06 mol) in ethanol (3.7 mL) was added at room temperature. After stirring
for 6 h, then, the solvent was removed in vacuo and the crude product 3-ethoxy carbonyl
hydrazonoacetic acid ethyl ester was directly used in the next step without further purification.
3-Ethoxy carbonyl hydrazonoacetic acid ethyl ester (12.8 g, 0.06 mol) was dissolved in dry
dichloromethane (25 mL), and thionyl chloride (20 mL) was further added into the stirred
reaction mixture dropwisely at 0 oC for 1 h. Next, the reaction mixture was permitted to stand for
20 h at room temperature. The excess thionyl chloride and dichloromethane were distilled off,
and the remaining residue was subjected to fractional distillation under reduced pressure. A
slightly yellowish oil 3 (7.95 g) was obtained in yield of 77%.
A mixture of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid ethyl ester (1.72 g, 10 mmol) and
hydrazine hydrate (12 mmol) in 10 mL of methanol was stirred vigorously for 0.5 h at room
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temperature, the resulted mixture was then filtered, and the solid was washed with cold
methanol. After drying, the solid was recrystallized from methanol to give intermediate (4).
Preparation of 5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole-2-thiol (5)
A solution of 4-methyl-1,2,3-thiadiazole-5-carbohydrazide 4 (1.58 g, 10 mmol), potassium
hydroxide (0.56 g, 10 mmol) and ethanol (15 mL) was heated under reflux for 6 h. Methanol was
distilled off under reduced pressure and the yellow product was acidified with dilute
hydrochloric acid. The precipitate was filtered off, washed with water, dried and recrystallized
from ethanol to afford a white solid 1.4 g; yield 70%; mp147-148 ˚С. 1H NMR(400 MHz,
CDCl3) δ: 11.20(s, 1H, SH), 3.28 (s, 3H, CH3).
General procedure for thioether (6)
A CEM designed 10 mL pressure-rated vial was charged with DMF (15 mL), 5 (1.5 g, 5.1 mmol)
and K2CO3 (0.2 g, 5.6 mmol) and 2,4-dichlorobenzyl chloride (5.1 mmol). The mixture was
irradiated in a CEM Discover Focused Synthesizer (150 W, 90°C, 200 psi, 15 min). The mixture
was cooled to room temperature by passing compressed air through the microwave cavity for 2
min. It was poured into cold ice (40 mL) and the precipitate that formed with filtered. The crude
solid was recrystallized from EtOH to give the title compounds 6a. All the other compounds
were synthesized according the same procedure.
2-(2,4-dichlorobenzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole 6a: Yield 86%,
yield as white crystals; m.p. 85-86 ◦C;1H NMR (CDCl3, 400 MHz), :3.06(s, 3H, Het-Me),
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4.60(s, 2H, SCH2), 7.22(d, J=8.49Hz, 1H, ArH), 7.44(s, 1H, ArH), 7.61(d, J = 8.27 Hz, 1H,
ArH). MS (ESI), m/z: 360 (M+1). Elemental anal. (%), calculated: C, 40.12; H, 2.24; N, 15.60;
found: C, 39.88; H, 2.55; N,15.79.
2-(3-chlorobenzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole 6b: Yield 73.5%,
white crystal; m.p. 88-89◦C;1H NMR (CDCl3, 400 MHz), :3.06(s, 3H, Het-Me), 4.51(s, 2H,
SCH2), 7.30(s, 2H, ArH), 7.34-7.39(m, 1H, ArH), 7.47(s, 1H, ArH). MS (ESI), m/z: 326 (M+1).
Elemental anal. (%), calculated: C, 44.37; H, 2.79; N, 17.25; found: C, 44.67; H, 2.85; N,17.43.
2-(3-fluorobenzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole 6c: Yield 88%, white
crystal; m.p. 63-64◦C;1H NMR (CDCl3, 400 MHz), :3.06(s, 3H, Het-Me), 4.53(s, 2H, SCH2),
7.04(t, J=7.46Hz, 1H, ArH), 7.19(d, J=9.27Hz, 1H, ArH), 7.29-7.35(m, 2H, ArH). MS (ESI),
m/z: 309 (M+1). Elemental anal. (%), calculated: C, 46.74; H, 2.94; N, 18.17; found: C, 46.45;
H, 3.12; N, 18.44.
2-(2-chlorobenzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole 6d: Yield 83%, white
crystal; m.p. 98-99◦C;1H NMR (CDCl3, 400 MHz), :3.06(s, 3H, Het-Me), 4.65(s, 2H, SCH2),
7.26-7.30(m, 2H, ArH), 7.41(d, J=7.45Hz, 1H, ArH), 7.63(d, J=7.14Hz, 1H, ArH). MS (ESI),
m/z: 326 (M+1). Elemental anal. (%), calculated: C, 44.37; H, 2.79; N, 17.25; found: C, 44.64;
H, 2.99; N, 17.01.
2-(2-fluorobenzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole 6e: Yield 84%, white
crystal; m.p. 78-79◦C;1H NMR (CDCl3, 400 MHz), :3.06(s, 3H, Het-Me), 4.58(s, 2H, SCH2),
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7.07-7.14(m, 2H, ArH), 7.29-7.33(m, 1H, ArH), 7.55(t, J=8.20Hz, 1H, ArH). MS (ESI), m/z:
309 (M+1). Elemental anal. (%), calculated: C, 46.74; H, 2.94; N, 18.17; found: C, 46.88; H,
3.12; N, 18.43.
2-(4-methyl-1,2,3-thiadiazol-5-yl)-5-(2-methylbenzylthio)-1,3,4-oxadiazole 6f: Yield 90%, white
crystal; m.p. 79-80◦C;1H NMR (CDCl3, 400 MHz), :2.45(s, 3H, Ar-Me), 3.06(s, 3H, Het-Me),
4.59(s, 2H, SCH2), 7.8-7.23(m, 2H, ArH), 7.29-7.34(m, 1H, ArH), 7.42(d, J=6.11Hz, 1H, ArH).
MS (ESI), m/z: 305 (M+1). Elemental anal. (%), calculated: C, 51.30; H, 3.97; N, 18.41; found:
C, 51.55; H, 3.87; N, 18.49.
2-(4-fluorobenzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole 6g: Yield 87%, white
crystal; m.p. 84-85◦C;1H NMR (CDCl3, 400 MHz), :2.45(s, 3H, Ar-Me), 3.06(s, 3H, Het-Me),
4.52(s, 2H, SCH2), 7.06(t, J=8.55Hz, 2H, ArH), 7.46(d, J=5.76Hz, 2H, ArH). MS (ESI), m/z:
305 (M+1). Elemental anal. (%), calculated: C, 46.74; H, 2.94; N, 18.17; found: C, 46.88; H,
3.06; N, 17.99.
2-(benzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole 6h: Yield 90%, white crystal;
m.p. 72-73◦C;1H NMR (CDCl3, 400 MHz), :3.05(s, 3H, Het-Me), 4.55(s, 2H, SCH2),
7.30-7.37(m, 3H, ArH), 7.46(d, J=7.21Hz, 2H, ArH). MS (ESI), m/z: 291 (M+1). Elemental
anal. (%), calculated: C, 49.64; H, 3.47; N, 19.30; found: C, 50.01; H, 3.78; N, 19.12.
2-(4-methoxybenzylthio)-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-oxadiazole 6i: Yield 91%,
white crystal; m.p. 56-57◦C;1H NMR (CDCl3, 400 MHz), :3.05(s, 3H, Het-Me), 3.80(s, 3H,
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OMe), 4.52(s, 2H, SCH2), 6.87(d, J=8.41Hz, 2H, ArH), 7.41(d, J=8.46Hz, 2H, ArH). MS (ESI),
m/z: 321 (M+1). Elemental anal. (%), calculated: C, 48.73; H, 3.78; N, 17.49; found: C, 48.78;
H, 3.99; N, 17.54.
Herbicidal Activity Assay
The herbicidal activities were determined according the reference method[17]. Each sample was
repeated three times.
Acknowledgment
This work was supported financially by National Natural Science Foundation of China
(No.21002090), The Key Innovation Team of Science and Technology in Zhejiang Province
(2010R50018-06) and the National Key Technologies R&D Program (2011BAE06B03-01).
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O
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N
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i
ii
iii
NH2
HN
O
N
H
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1
2
N
N
S
N
N
v
iv
H
N
N
O
N
N
SH
S
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5
NH2
N
S
O
3
O
4
N
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vi
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R
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6
Scheme 1. Reagents and conditions: (i) NH2NH2 H2O, EtOH, reflux; (ii) ethyl 3-oxobutanoate, EtOH,
room temperature; (iii) SOCl2, room temperature (iv) NH2NH2 H2O, EtOH, reflux; (v) CS2, KOH, MeOH,
reflux,HCl; (vi) R2CH2Cl,NaOH, DMF, MW
Table 1 Comparison of yields of 6a through methods with orwithout microwave irradiation
No.
6a
6a
6a
6a
6a
Method
No-MW
No-MW
MW
MW
MW
Time
24h
4h
10min
15min
20min
Temperature/℃
Yield/%
78
84
74
86
r.t.
90
90
90
90
85
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