Synthesis and fungicidal activity against Rhizoctonia solani of 2-alkyl (alkylthio)-5-pyrazolyl-1,3,4-oxadiazoles (thiadiazoles)

Article abstract of DOI:10.1021/jf991065s

Some series of 2-alkyl (alkythio)-5-((4-chloro)-3-ethyl-1-methyl-1H-pyrazole-5-yl)-1,3,4-oxadiazoles (thiadiazoles) were prepared as potential fungicides. Their fungicidal activity was evaluated against rice sheath blight, which is a major disease of rice in China. Structure-activity relationships for the screened compounds were evaluated and discussed. It was found that 5-(4-chloro-3-ethyl-1-methyl-1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-thione has the higher fungicidal activity.

Full text of DOI:10.1021/jf991065s

5312
J. Agric. Food Chem. 2000, 48, 5312−5315
Syn th esis a n d F u n gicid a l Activity a ga in st Rh izocton ia sola n i of
2-Alk yl (Alk ylth io)-5-p yr a zolyl-1,3,4-oxa d ia zoles (Th ia d ia zoles)
Hansong Chen, Zhengming Li,* and Yufeng Han
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, People’s Republic of China
Some series of 2-alkyl (alkythio)-5-((4-chloro)-3-ethyl-1-methyl-1H-pyrazole-5-yl)-1,3,4-oxadiazoles
(thiadiazoles) were prepared as potential fungicides. Their fungicidal activity was evaluated against
rice sheath blight, which is a major disease of rice in China. Structure-activity relationships for
the screened compounds were evaluated and discussed. It was found that 5-(4-chloro-3-ethyl-1-
methyl-1H-pyrazole-5-yl)-1,3,4-thiadiazole-2-thione has the higher fungicidal activity.
Keyw or d s: Pyrazolyl-1,3,4-oxadiazole; pyrazoly1-1,3,4-thiadiazole; fungicide; rice sheath blight;
Rhizoctonia solani
1. INTRODUCTION
1H). Analysis found: C, 46.03; H, 4.64; N, 26.26. Calcd. for
C8H10N4OS: C, 45.70; H, 4.79; N, 26.65.
It is well-known that the study of pyrazole derivatives
is significant in pesticide chemistry. Among the pyrazole
derivatives some compounds are broadly used as insec-
ticides, herbicides and fungicides, such as fripronil
(MB46030) (Colliot et al., 1992), tebufenpyrad (Okada
et al., 1988), pyrazosulfuron-ethyl (NC-311) (Nissan
Chemical Industries, Ltd. 1982), and so on.
However, a survey of the literature revealed that
linked biheterocyclic compounds containing pyrazole to
possess biological activity are seldom reported. 1,3,4-
Oxadiazole, 1,3,4-thiadiazole derivatives all being fun-
gicidal (Ashour et al., 1994; Funatsukuri and Ueda,
1966), if they are linked to pyrazole ring respec-
tively, the biheterocydic compounds obtained could have
better fungicidal activity. As part of our program aimed
at developing a new class of agrochemicals we synthe-
sized the title compounds and studied their fungicidal
activity.
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-methylthio-
1,3,4-oxadiazole (3a ). A mixture of compound 2a (0.61 g, 2.5
mmol), 1N aqueous sodium hydroxide solution (2.5 mL, 2.5
mmol), and tetrabutylammonium bromide (0.1 g) was stirred
for several minutes, and then methyl iodide (0.35 g, 2.5 mmol)
and toluene (20 mL) were added. After the mixture was stirred
for 24 h at room temperature, the organic layer was separated
and dried over magnesium sulfate. The solvent was removed
in vacuo, and the residue was subjected to silica gel column
chromatography to give 0.5 g of 3a as a white powder. Yield,
1
77%; mp, 85-86 °C. H NMR (CDCl3) δ: 1.25 (t, 3H), 2.66 (q,
2H), 2.77 (s, 3H), 4.16 (s, 3H). Analysis found: C, 41.81; H,
4.32; N, 21.53. Calcd. for C9H11ClN4OS: C, 45.78; H, 4.25; N,
21.65.
Compounds 3b-3l were prepared in the same method as
3a by using the corresponding alkyl halide instead of methyl
iodide.
5-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-2-propylthio-
1,3,4-oxadiazole (3b). Yield, 80%; mp, 37-38 °C. 1H NMR
(CDCl3) δ: 1.05 (t, 3H), 1.24 (t, 3H), 1.86 (m, 2H), 2.64 (q, 2H),
3.27 (t, 2H), 4.15 (s, 3H). Analysis found: C, 45.99; H, 5.16;
N, 19.58. Calcd. for C11H15ClN4OS: C, 46.07; H, 5.27; N, 19.54.
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-(2-methyl-
2. MATERIALS AND METHODS
1
2.1. Syn th etic p r oced u r es. All melting points were de-
termined with Yanaco MP-300 micro melting points apparatus,
and the values are uncorrected. 1H NMR spectra were recorded
on a Bruker AC-P200 spectrometer, using tetramethylsilane
(TMS) as an internal reference and CDCl3 or CD3COCD3 as
the solvent. Elemental analyses were performed on a Yanaco
CHN CORDER MT-3 instrument.
5-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-1,3,4-oxadia-
zole-2-thione (2a ). To a solution of compound 1a (2.35 g, 12.5
mmol) in ethanol (50 mL) at 0 °C were added carbon disulfide
(3.8 g, 50 mmol) and potassium hydroxide (0.86 g, 12.5 mmol).
After addition, the mixture was refluxed for 7 h. The solvent
was evaporated. The residue was dissolved in water and
acidified with dilute hydrochloric acid. The precipitate was
filtered and recrystallized from ethanol to give 2.4 g(yield 70%)
of 2a as a white solid. Yield, 70%; mp, 199 °C (d). 1H NMR
(CDCl3) δ: 1.28 (t, 3H), 2.68 (q, 2H), 4.12 (s, 3H), 11.39 (s,
1H). Analysis found: C, 39.63; H, 3.78; N, 23.20. Calcd. for
C8H9ClN4OS: C, 39.26; H, 3.71; N, 22.90.
propylthio)-1,3,4-oxadiazole (3c). Yield, 17%; an oil. H NMR
(CDCl3) δ: 1.03 (t, 6H), 1.21 (t, 3H), 2.08 (m, 1H), 2.62 (q, 2H),
3.15 (d, 2H), 4.13 (s, 3H). Analysis found: C, 47.83; H, 5.54;
N, 18.48. Calcd. for C12H17ClN4OS: C, 47.91; H, 5.70; N, 18.63.
2-Amylthio-5-(4-chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-
1
1,3,4-oxadiazole (3d ). Yield, 79%; an oil. H NMR (CDCl3) δ:
0.87 (t, 3H), 1.20 (t, 3H), 1.36 (m, 4H), 1.86 (m, 2H), 2.61 (q,
2H), 3.23 (t, 2H), 4.12 (s, 3H). Analysis found: C, 49.31; H,
5.92; N, 17.57. Calcd. for C13H19ClN4OS: C, 49.60; H, 6.08; N,
17.80.
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-heptylthio-
1,3,4-oxadiazole (3e). Yield, 73%; an oil. 1H NMR (CDCl3) δ:
0.84 (t, 3H), 1.08-1.46 (m, 11H), 1.81 (m, 2H), 2.63 (q, 2H),
3.25 (t, 2H), 4.14 (s, 3H). Analysis found: C, 52.68; H, 6.74;
N, 16.18. Calcd. for C15H23ClN4OS: C, 52.54; H, 6.76; N, 16.34.
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-octylthio-
1,3,4-oxadiazole (3f). Yield, 76%; mp, <30 °C. 1H NMR (CDCl3)
δ: 0.85 (t, 3H), 1.20-1.49 (m, 13H), 1.87 (m, 2H), 2.63 (q,
2H), 3.26 (t, 2H), 4.15 (s, 3H). Analysis found: C, 53.52; H,
6.96; N, 15.38. Calcd. for C16H25ClN4OS: C, 53.84; H, 7.06; N,
15.70.
5-(3-Ethyl-1-methyl-1H-pyrazole-5-y1)-1,3,4-oxadiazole-2-
thione (2b). Compound 2b was prepared by the same method
1
as 2a . Yield, 76%; mp, 199-200 °C. H NMR (CD3COCD3) δ:
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-(1-ethoxy-
1.69 (t, 3H), 3.09 (q, 2H), 4.53 (s, 3H), 7.19 (s, 1H), 13.80 (s,
carbonylethylthio)-1,3,4-oxadiazole (3g). Yield, 87%; an oil. 1H
10.1021/jf991065s CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

Synthesis and Fungicidal Activity of Thiadiazoles
J. Agric. Food Chem., Vol. 48, No. 11, 2000 5313
NMR (CDCl3) δ: 1.22 (m, 6H), 1.69 (d, 3H), 2.64 (q, 2H), 4.12
(s, 3H), 4.20 (q, 2H), 4.45 (q,1H). Analysis found: C, 45.20; H,
4.78; N, 15.96. Calcd. for C13H17ClNO3S: C, 45.28; H, 4.97; N,
16.25.
NMR (CDCl3) δ: 1.25 (t, 3H), 2.68 (q, 2H), 4.23 (s, 3H).
Analysis found: C, 38.81; H, 2.68; N, 20.14. Calcd. for C9H8-
ClF3N4O: C, 38.52; H, 2.87; N, 19.96.
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-2-ethyl-1,3,4-
1
2-(3-Ethyl-1-methyl-1H-pyrazole-5-y1)-5-methylthio-1,3,4-
oxadiazole (6c). Yield, 57%; mp, 62-63 °C. H NMR (CDCl3)
1
oxadiazole (3h ). Yield, 77%; mp, 68-69 °C. H NMR (CDCl3)
δ: 1.24 (t, 3H), 1.42 (t, 3H), 2.65 (q, 2H), 2.96 (q, 2H), 4.17 (s,
δ: 1.21 (t, 3H), 2.62 (q, 2H), 2.72 (s, 3H), 4.16 (s, 3H), 6.55 (s,
1H). Analysis found: C, 48.30; H, 5.28; N, 24.93. Calcd. for
C9H12N4OS: C, 48.20; H, 5.39; N, 24.98.
3H). Analysis found: C, 49.94; H, 5.50; N, 23.36. Calcd. for
C
10H13ClN4O: C, 49.90; H, 5.44; N, 23.28.
2-Butyl-5-(4-chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-1,3,4-
1
2-(3-Ethyl-1-methyl-1H-pyrazole-5-y1)-5-ethylthio-1,3,4-oxa-
diazole (3i). Yield, 73%; mp, 34-35 °C. 1H NMR (CDCl3) δ:
1.21 (t, 3H), 1.47 (t, 3H), 2.63 (q, 2H), 3.26 (q, 2H), 4.16 (s,
3H), 6.55 (s, 1H). Analysis found: C, 50.35; H, 5.93; N, 23.17.
Calcd. for C10H14N4OS: C, 50.40; H, 5.92; N, 23.51.
oxadiazole (6d ). Yield, 64%; mp, 43-44 °C. H NMR (CDCl3)
δ: 0.95 (t, 3H), 1.23 (t, 3H), 1.46 (m, 2H), 1.83 (m, 2H), 2.64
(q, 2H), 2.91 (t, 2H), 4.16 (s, 3H). Analysis found: C, 53.34; H,
6.13; N, 20.82. Calcd. for C12H17ClN4O: C, 53.63; H, 6.38; N,
20.85.
2-(3-Ethyl-1-methyl-1H-pyrazole-5-y1)-5-propylthio-1,3,4-
oxadiazole (3j). Yield, 80%; an oil. 1H NMR (CDCl3) δ: 1.02
(t, 3H), 1.21 (t, 3H), 1.84 (m, 2H), 2.62 (q, 2H), 3.22 (t, 2H),
4.16 (s, 3H), 6.54 (s, 1H). Analysis found: C, 52.20; H, 6.19;
N, 22.47. Calcd. for C11H16N4OS: C, 52.36; H, 6.39; N, 22.20.
2-Amylthio-5-(3-ethyl-1-methyl-1H-pyrazole-5-y1)-1,3,4-oxa-
diazole (3k). Yield, 71%; an oil. 1H NMR (CDCl3) δ: 0.89 (t,
3H), 1.22 (t, 3H), 1.38 (m, 4H), 1.79 (m, 2H), 2.64 (q, 2H), 3.25
(t, 2H), 4.17 (s, 3H), 8.56 (s, 1H). Analysis found: C, 55.49; H,
6.96; N, 20.08. Calcd. for C13H20N4OS: C, 55.69; H, 7.19; N,
20.08.
2-(3-Ethyl-1-methyl-1H-pyrazole-5-y1)-5-(1-ethoxycarbonyl-
ethylthio)-1,3,4-oxadiazole (3l). Yield, 84%; an oil. 1H NMR
(CDCl3) δ: 1.16 (m, 6H), 1.64 (d, 3H), 2.5 (q, 2H), 4.16 (s, 3H),
4.19 (q, 2H), 4.38 (q, 1H), 6.52 (s, 1H). Analysis found: C,
49.96; H, 5.62; N, 17.84. Calcd. for C13H18NO3S: C, 50.03; H,
5.84; N, 18.05.
5-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-1,3,4-oxadia-
zole-2-one (4). To a solution of compound 3b (0.59 g, 2.2 mmol)
in formic acid (98%, 15 mL) were added 30% hydrogen peroxide
(1.0 g, 8.8 mmol, 1.1 mL) and water (1 mL). The mixture was
stirred for 24 h at room temperature. The solvent was removed
in vacuo, and the solid obtained was washed with water then
recrystallized from ethanol to give 0.45 g of 4 as a white solid.
Yield, 75%; mp, 175-176 °C. 1H NMR (CDCl3) δ: 1.25 (t, 3H),
2.66 (q, 2H), 4.07 (s, 3H), 9.75 (s, 1H). IR: 1780 cm-1. Analysis
found: C, 41.70; H, 4.16; N, 24.20. Calcd. for C8H9ClN4O2: C,
42.03; H, 3.97; N, 24.50.
Potassium 3-(4-chloro-3-ethyl-1-methyl-1H-pyrazole-5-car-
bonyl)dithiocarbazate (7). A solution of potassium hydroxide
(2.06 g, 0.03mol), absolute ethanol (50 mL), and 1a (6.10 g,
0.03 mL) was treated to the addition of carbon disulfide
(3.43 g, 0.06 mol). The mixture was diluted with absolute
ethanol (70 mL) and stirred for 16 h. It was then diluted with
dry ether (100 mL) and vacuum-dried at 65 °C. This salt,
prepared as described above, was obtained in nearly quantita-
tive yield and was used in the next reaction without further
purification.
5-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-1,3,4-thiadi-
azole-2-thione (8). Potassium dithiocarbazate 7 (8.5 g, 27 mmol)
was added in portions to concentrated H2SO4 (35 mL) at 0 °C
over 40 min. The mixture was stirred for 1 h at room
temperature and poured over crushed ice and allowed to stand
overnight. The separated solid was dissolved in dilute aqueous
sodium hydroxide. The insoluble solid was filtered and the
filtrate was acidified with dilute hydrochloric acid. The solid
obtained was washed with water, dried, and recrystallized
from ethanol to give 4.5 g of 8 as a light green solid. Yield,
1
64%; mp, 182-183 °C. H NMR (CD3COCD3) δ: 1.20 (t, 3H),
2.59 (q, 2H), 3.21 (s, 1H), 4.06 (s, 3H). Analysis found: C, 37.00;
H, 3.21; N, 21.88. Calcd. for C8H9ClN4S2: C, 36.85; H, 3.48;
N, 21.49.
5-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-2-methylthio-
1,3,4-thiadiazole (9a ). A mixture of compound 8 (0.52 g, 2
mmol), 1N aqueous sodium hydroxide solution (2 mL, 2 mmol),
and tetrabutylammonium bromide (0.1 g) was stirred for
several minutes, and then methyl iodide (0.29 g, 2 mmol) and
toluene (20 mL) were added. After stirring for 24 h at room
temperature, the organic layer was separated and dried over
magnesium sulfate. The solvent was removed in vacuo and
the residue was subjected to silica gel column chromatography
to give 0.42 g of 9a as a white powder. Yield, 83%; mp, 106-
5-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-3-methyl-
1,3,4-oxadiazole-2-one (5). To a solution of compound 4 (0.40
g, 1.7 mmol) in THF (15 mL) was added 1N aqueous sodium
hydroxide (1.7 mL, 1.7 mmol). The mixture was stirred for
several minutes and then methyl iodide (0.5 mL) was added.
After stirring for 5 h at room temperature, the solvent was
concentrated under reduced pressure. The residue was dis-
solved in chloroform (20 mL), washed with water two times
(20 × 2), and then dried over magnesium sulfate. The solvent
was removed in vacuo, and the residue was subjected to silica
gel column chromatography to give 0.3 g of 5 as a white
powder. Yield, 73%; mp, 114-115 °C. 1H NMR (CDCl3) δ: 1.22
1
107 °C. H NMR (CDCl3) δ: 1.25 (t, 3H), 2.65 (q, 2H), 2.63 (s,
3H), 4.22 (s, 3H). Analysis found: C, 39.18; H, 4.03; N, 20.15.
Calcd. for C9H11ClN4S2: C, 39.34; H, 4.04; N, 20.39.
Compounds 9b-9e were prepared in the same method as
9a by using the corresponding alkyl halide instead of methyl
iodide.
(t, 3H), 2.61 (q, 2H), 3.50 (s, 3H), 4.01 (s, 3H). IR: 1784 cm-1
.
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-ethylthio-
1,3,4-thiadiazole (9b). Yield, 85%; mp, 93-94 °C. 1H NMR
(CDCl3) δ: 1.25 (t, 3H), 1.49 (t, 3H), 2.65 (q, 2H), 3.39 (q, 2H),
4.23 (s, 3H). Analysis found: C, 41.53; H, 4.52; N, 19.26. Calcd.
for C10H13ClN4S2: C, 41.59; H, 4.54; N, 19.40.
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-propylthio-
1,3,4-thiadiazole (9c). Yield, 71%; mp, 59-60 °C. 1H NMR
(CDCl3) δ: 1.05 (t, 3H), 1.24 (t, 3H), 1.83 (m, 2H), 2.65 (q, 2H),
3.34 (t, 2H), 4.22 (s, 3H). Analysis found: C, 43.70; H, 4.91;
N, 18.27. Calcd. for C11H15ClN4S2: C, 43.60; H, 4.99; N, 18.50.
2-Allylthio-5-(4-chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-
1,3,4-thiadiazole (9d ). Yield, 83%; mp, 66-67 °C. 1H NMR
(CDCl3) δ: 1.25 (t, 3H), 2.67 (q, 2H), 3.99 (d, 2H), 4.23 (s, 3H),
5.28 (s × 4, 2H), 5.99 (m, 1H). Analysis found: C, 43.77; H,
4.23; N, 18.41. Calcd. for C11H13ClN4S2: C, 43.92; H, 4.36; N,
18.62.
Analysis found: C, 44.40; H, 4.75; N, 22.93. Calcd. for C9H11
ClN4O2: C, 44.55; H, 4.57; N, 23.09.
-
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-chloromethyl-
1,3,4-oxadiazole (6a ). To a solution of 1a (0.72 g, 3.5 mmol) in
POCl3 (7 mL) was added dry chloroacetic acid (0.33 g, 3.5
mmol). The mixture was heated under reflux for 7 h. The
excess POCl3 was removed under reduced pressure, and the
residue was poured into ice water and allowed to stand
overnight. The solid obtained was washed with dilute aqueous
sodium hydroxide and water respectively, dried, and purified
by silica gel column chromatography to give 0.52 g of 6a as a
1
white solid. Yield, 56%; mp, 100-101 °C. H NMR (CDCl3) δ:
1.25 (t, 3H), 2.67 (q, 2H), 4.20 (s, 3H), 4.79 (s, 2H). Analysis
found: C, 41.53; H, 3.65; N, 21.44. Calcd. for C9H10Cl2N4O:
C, 41.40; H, 3.86; N, 21.46.
Compounds 6b-6d were prepared in the same method as
6a using the corresponding aliphatic acid instead of chloro-
acetic acid.
2-Amylthio-5-(4-chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-
1,3,4-thiadiazole (9e). Yield, 83%; mp, 54-55 °C. 1H NMR
(CDCl3) δ: 0.92 (t, 3H), 1.25 (t, 3H), 1.38 (m, 4H), 1.82 (m,
2H), 2.65 (q, 2H), 3.34 (t, 2H), 4.22 (s, 3H). Analysis found:
2-(4-Chloro-3-ethyl-1-methyl-1H-pyrazole-5-y1)-5-trifluoro-
methyl-1,3,4-oxadiazole (6b). Yield, 71%; mp, 52-53 °C. 1H

5314 J. Agric. Food Chem., Vol. 48, No. 11, 2000
Chen et al.
Sch em e 1
Sch em e 2
Sch em e 4
Sch em e 3
Ta ble 1. F u n gicid a l Scr een in g Resu lts of Com p ou n d s 2,
3, 4, a n d 5
C, 47.47; H, 5.72; N, 16.82. Calcd. for C13H19ClN4S2: C, 47.19;
H, 5.79; N, 16.93.
2.2 Biologica l a ssa y. Most of compounds were tested for
control of rice sheath blight pathogen, Rhizoctonia solani, on
rice seedlings at the fifth-leaf stage. The compounds were
formulated in water and DMF (5 + 1 by volume) (containing
2.5 g liter-1 Tween 80) to 500- and 100-mg-liter-1 solutions
which were applied to the rice seedlings as foliar sprays using
a hand-held spray gun. The next day the seedlings were
inoculated with the chaff medium within Rhizoctonia solani
(the causal fungus of the rice sheath blight). Then the plants
were immediately placed in a temperature- and humidity-con-
trolled chamber at 28 °C for 4 days. After treatment, percent-
age of disease control in the treated seedlings was compared
to that of seedlings with a treatment in the absence of the
experimental compounds, and fungicidal activity was esti-
mated. Four replicates were included in the evaluation. For
comparative purposes, the commercial fungicide Carbendazim
was tested under the same conditions as the title compounds.
inhibition of
rice sheath blighta
compd.
X
R
500 ppm
100 ppm
2a
2b
3a
3b
3d
3e
3f
3g
3h
3i
3j
3k
3l
4
Cl
H
H
H
1
2
4
4
3
2
2
0
4
4
3
2
1
0
1
5
0
1
3
2
1
2
2
0
2
2
1
0
0
0
0
5
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
CH3
n-C3H7
n-C5H11
n-C7H15
n-C8H17
CH(CH3)CO2Et
CH3
C2H5
n-C3H7
n-C5H11
CH(CH3)CO2Et
5
carbendazim
3. RESULTS AND DISCUSSION
a
On a scale of 0-5, where 0 ) 0-24% control; 1 ) 25-49%
control; 2 ) 50-69% control; 3 ) 70-89% control; 4 ) 90-99%
control, and 5 ) complete control.
3.1 Syn th esis. In our previous paper, we reported
the synthesis of 5-pyrazole formic acid hydrazide (1) (Li
et al., 1997). 5-pyrazolyl-1,3,4-oxadiazole-2-thione com-
pounds (2) were obtained via compounds 1 reacted with
carbon disulfide and potassium hydroxide in refluxing
ethanol; then alkylation of 2 afforded 2-alkylthio-5-
pyrazolyl-1,3,4-oxadiazoles (3) (Scheme 1).
concentrated sulfuric acid to afford 5-pyrazolyl-1,3,4-
thiadiazole-2-thiones (8), which, when followed by alky-
lation, gave compounds 9.
Oxidation of 3b by hydrogen peroxide gave 4 instead
of the corresponding compound 2-ethysulfonyl-5-pyra-
zolyl-1,3,4-oxadiazole. A strong oxidant is the cause of
the result. Compound 4 exists in “one” form, which was
confirmed by its infrared spectra. A strong absorption
was observed in the region of 1780 cm-1, which is
indicative of a carbonyl group.
Alkylation of 4 by methyl iodide yielded 5, and
infrared spectra confirmed its structure as well. A
methyl group is linked to the N atom at the 3-position
of the 1,3,4-oxadiazole ring instead of the O-atom of the
2-position. This result is different from the methylation
of compound 2. The theory of hard soft acid base can
explain this phenomenon. The S atom of 2 is a soft base,
the N atom is a medium base, and the C atom of 4 is a
hard acid. Methyl iodide as soft acid preferred to S
rather than N when it reacted with 2. But when it
reacted with 4, it preferred N to O.
Oxidation of 2-ethylthio-5-pyrazolyl-1,3,4-oxadiazole
by hydrogen peroxide in formic acid afforded 5-pyra-
zolyl-1,3,4-oxadiazole-2-one (4), which was alkylated by
methyl iodide to give 3-methyl-5-pyrazolyl-1,3,4-oxa-
diazole (5) (Scheme 2).
The chemical literature records several synthetic
routes leading to the formation of 3,5-disubstituted-
1,3,4-oxadiazole (Yang and Hua, 1996). In this paper,
2-alkyl-5-pyrazolyl-1,3,4-oxadiazoles were synthesized
from compound 1a and aliphatic acid via a one-pot
synthetic method in the presence of phosphorus oxy-
chloride (Scheme 3).
The synthesis of 2-alkylthio-5-pyrazolyl-1,3,4-thia-
diazoles (9) is outlined in Scheme 4. 5-pyrazole hy-
drazide (1a ) reacted with carbon disulfide in ethanolic
potassium hydroxide at room temperature to yield the
potassium 1-(4-chloro-3-ethyl-1-ethyl-1H-pyrazole-5-car-
bonyl) dithiocarbazates (7), which were cyclized in

Synthesis and Fungicidal Activity of Thiadiazoles
J. Agric. Food Chem., Vol. 48, No. 11, 2000 5315
Ta ble 2. F u n gicid a l Scr een in g Resu lts of Com p ou n d s 6
Removal of the sulfur atom, by replacement of the
alkylthio group with an alkyl group, resulted in some
decrease in activity. A sulfur atom at the 2-position of
1,3,4-oxadiazole is necessary for fungicidal activity to
occur.
inhibition of
rice sheath blighta
The idea of bioisosterism is one of the most successful
techniques of bioactive compound design (Lipinski,
1986). The substitution of oxygen for sulfur in the
heterocyclic ring represents an example of an approach
that is commonly known as bioisosterim. The 1,3,4-
thiadiazole ring is a bioisosteric analogue of the 1,3,4-
oxadiazole. The bioassay indicated that replacing O for
S appears to retain fungicidal activity. As with com-
pounds 3, the activity of compounds 9 was found to
increase with decreasing size of the alkyl group R at
the 3-position of the 1,3,4-thiadiazole. Compound 8 has
the same activity as compounds 9, which is different
from compounds 2 and 3.
compd.
R1
500 ppm
100 ppm
6a
6b
6c
6d
CH2Cl
CF3
C2H5
4
3
3
3
2
1
1
1
n-C4H9
a
On a scale of 0-5, where 0 ) 0-24% control; 1 ) 25-49%
control; 2 ) 50-69% control; 3 ) 70-89% control; 4 ) 90-99%
control, and 5 ) complete control.
Ta ble 3. F u n gicid a l Scr een in g Resu lts of Com p ou n d s 8
a n d 9
inhibition of
rice sheath blighta
LITERATURE CITED
compd.
R
500 ppm
100 ppm
Ashour F. A.; El-Hawash S. A. M.; Mahran, M. A.; et al.
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8
H
CH3
C2H5
n-C3H7
CH2CHdCH2
n-C5H11
5
4
4
3
2
3
4
4
4
3
1
1
9a
9b
9c
9d
9e
a
On a scale of 0-5, where 0 ) 0-24% control; 1 ) 25-49%
control; 2 ) 50-69% control; 3 ) 70-89% control; 4 ) 90-99%
control, and 5 ) complete control.
Lipinski, C. A. Bioisosterism in drug design. Annu. Rep. Med.
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3.2. St r u ct u r e-Act ivit y R ela t ion sh ip (SAR ).
Tables 1-3 summarize the fungicidal screening results
of the study compounds. The results indicated that
compounds 3 had significant potency against Rhizocto-
nia solani, and compounds 2 had hardly any inhibi-
tion against R.solani, that is to say, the activity of
compounds that were substituted by alkylthio at the
2-position of the 1,3,4-oxadiazole ring was higher than
the activity of those compounds that were substi-
tuted by mercapto. The activity was found to fall off
with increasing size of the alkyl group (R). The pre-
ferred substituent for R was found to be methyl. Loss
of biological activity was observed if the chloride
atom at the 4-position of the pyrazole ring was substi-
tuted by hydrogen. Oxidation of the sulfide group of
compound 3 to 2-one analogue 5 almost eliminated the
activity.
Yang, J .; Hua, W.. Review: Synthesis of 2,5-substituted-1,3,4-
oxadizole derivatives. Chemistry 1996, 9, 18.
Received for review September 27, 1999. Revised manuscript
received May 7, 2000. Accepted May 7, 2000. This project was
supported by the National Natural Science Foundation of
China (project no. 29832050).
J F991065S