Synthesis and herbicidal activities of sulfonylureas bearing 1,3,4-thiadiazole moiety

Article abstract of DOI:10.1002/jhet.1063

In this article, we report the synthesis and herbicidal activities of sulfonylureas bearing the 1,3,4-thiadiazole moiety. The target compounds were synthesized using 2-hydrazinocarbonyl benzenesulfonamide () and phenyl pyrimidinecarbamates as starting materials. The key intermediate, 2-(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)benzenesulfonamide (), was prepared from and CS₂ via a conventional method or an improved method. The improved method, in which sulfonamido group acts as a directing group for the cyclization reaction, is more concise and efficient. The structures of the target compounds were determined by IR, ¹H-NMR, ¹³C-NMR, MS, and elemental analysis. Their herbicidal activities were screened by Petri dish tests and pot tests. As the results, sulfonylureas and inhibited Brassica napus, Amaranthus retroflexus, and Echinochloa crusgalli at the 15 g/ha level, which is at the same level as azimsulfuron. Moreover, the safety tests showed that was safe to wheat at dosage of 60 g/ha and might develop further into a herbicide in wheat field.

Full text of DOI:10.1002/jhet.1063

February 2013
Synthesis and Herbicidal Activities of Sulfonylureas Bearing
1,3,4-Thiadiazole Moiety
E67
a
a
b
b
b
b
*
*
Xiang-Hai Song, Ning Ma, Jian-Guo Wang, Yong-Hong Li, Su-Hua Wang, and Zheng-Ming Li
aDepartment of Chemistry, School of Science, Tianjin University, Tianjin 300072
bState Key Laboratory of Elemento Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071
*
E-mail: mntju@tju.edu.cn or nkzml@vip.163.com
Received April 24, 2011
DOI 10.1002/jhet.1063
Published online 7 March 2013 in Wiley Online Library (wileyonlinelibrary.com).
In this article, we report the synthesis and herbicidal activities of sulfonylureas bearing the 1,3,4-thiadiazole
moiety. The target compounds 9a–l were synthesized using 2-hydrazinocarbonyl benzenesulfonamide (4) and
phenyl pyrimidinecarbamates as starting materials. The key intermediate, 2-(4,5-dihydro-5-thioxo-1,3,4-thiadia-
zol-2-yl)benzenesulfonamide (5), was prepared from 4 and CS2 via a conventional method or an improved method.
The improved method, in which sulfonamido group acts as a directing group for the cyclization reaction, is more
concise and efficient. The structures of the target compounds were determined by IR, 1H-NMR, 13C-NMR, MS,
and elemental analysis. Their herbicidal activities were screened by Petri dish tests and pot tests. As the results,
sulfonylureas 9h and 9j inhibited Brassica napus, Amaranthus retroflexus, and Echinochloa crusgalli at
the 15 g/ha level, which is at the same level as azimsulfuron. Moreover, the safety tests showed that 9j
was safe to wheat at dosage of 60 g/ha and might develop further into a herbicide in wheat field.
J. Heterocyclic Chem., 50, E67 (2013).
INTRODUCTION
Currently, azimsulfuron is the only commercialized SU
herbicide that bears a heterocycle on the aryl group at the
ortho position to the bridge (Scheme 1). Recently,
herbicidal SUs 1–3 have been reported to share structural
similarity to azimsulfuron [1c]. 1,3,4-Thiadiazole com-
pounds have already been used as herbicides. For exam-
ples, tebuthiuron is a broad-spectrum herbicide for
control of various classes of weeds, and fluthiacet-methyl
is served as a postemergence herbicide for control of
broad-leaved weeds (Scheme 1) [7a]. Other herbicidal
1,3,4-thiadiazole compounds were also reported recently
[7b]. Besides, some 1,3,4-oxadiazole compounds have
found their uses as herbicides in which dimefuron and
oxadiargyl are typical examples [7a]. In this article, we
aim to introduce a 1,3,4-thiadiazole or 1,3,4-oxazodiazole ring
to the ortho position on the aryl ring of SUs and investigate if
the herbicidal activities of this new type of compounds will be
changed.
Sulfonylureas (SUs) are a popular herbicide because of
their low dosage, low mammalian toxicity, high selectivity,
and benign environmental activity. Approximately, 30
different SU herbicides have been marketed since the
commercialization of chlorsulfuron in 1981 [1]. According
to structure–activity relationship proposed by Levitt, the
herbicidal SUs are composed of three distinct parts
(Scheme 1), and the heterocycle should contain a 4,6-
disubstituted pyrimidine or similarly substituted 1,3,5-
triazine [2]. To our delight, we found monosubstituted
pyrimidine SUs also presented the same level of herbicidal
activity as the 4,6-disubstituted pyrimidine SUs. Two of
the monosubstituted SUs, monosulfuron (MSu) and
monosulforon-ester (MSE), were developed as commercial
herbicides by Li and coworkers [3]. To investigate the
monosubstituted patterns, a variety of monosubstituted
pyrimidine SUs were synthesized and screened for
herbicidal activities [4]. Based on the results of the biological
screen, structure–activity relationships were proposed [5].
The crystal structures of MSu and MSE in complex with
acetohydroxyacid synthase (AHAS) were reported, which
helps to understand the mode of interaction for this class of
AHAS inhibitors [6].
RESULTS AND DISCUSSION
Initially, condition (method A, Scheme 2) developed by
Baron and Wilson was used to prepare 2-(4,5-dihydro-5-
thioxo-1,3,4-thiadiazol-2-yl)benzenesulfonamide (5) from
© 2013 HeteroCorporation

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X.-H. Song, N. Ma, J.-G. Wang, Y.-H. Li, S.-H. Wang, and Z.-M. Li
Vol 50
Scheme 1
under reflux condition affords 5-aryl-1,3,4-oxadiazole-2-
thiones in 20–64% yield, whereas treating potassium ben-
zoyldithiocarbazates (obtained from reaction of benzoyl
hydrazines with CS2 and KOH in 95% ethanol at 0–5°C)
with sulfuric acid at 0–5°C furnishes 5-aryl-1,3,4-thiadia-
zole-2-thiones in 17–35% yield. Therefore, the sulfonamido
group acts as a directing group to induce the unexpected
product 5. This directing effect can be attributed to the in-
tramolecular H-bond between the carbonyl O atom and
the sulfonamide N-H in orthosulfonamido benzeneamide,
which were disclosed by both Woodward group and our
group [9]. It seems that the H-bond activates the carbonyl
group toward nucleophilic attack by the dithiocarboxy an-
ion and facilitates the formation of 1,3,4-thiadiazole
(Scheme 3).
SUs 9a, 9b, 9e, 9f, 9h, and 9j showed good activity in
the Petri dish herbicidal tests (Table 1). Tribenuron-methyl,
not azimsulfuron, was used as reference standard because
the former is a total herbicide with fairly high activity
(commonly used at dosage of 4–7.5 g/ha), whereas the lat-
ter is a selective compound for control of specified weeds
and grasses. The monosubstituted pyrimidine SUs 9c, 9d,
9k, and 9l showed lower activity than the disubstituted
SUs 9a, 9b, 9i, and 9j, respectively. Because of their high
herbicidal activity in the Petri dish screens, SUs 9b, 9f, 9h,
and 9j were screened further by pot tests (Table 2). SUs 9h
and 9j showed satisfactory inhibition to Brassica napus,
amaranthus retroflexus, and Echinochloa crusgalli at the
dosage of 15 g/ha. This activity fell into the same level as
that of azimsulfuron, which is normally used at dosage
of 20–25 g/ha. Notably, both 9h and 9j showed better inhi-
bition to E. crusgalli than tribenuron-methyl. Further
safety test uncovered that 9j is safe to wheat even at dosage
of 60 g/ha (Table 3).
In conclusion, a 1,3,4-thiadiazole ring was introduced to
the ortho position on the aryl ring of SUs, and a series of
new SUs possessing 1,3,4-thiadiazole ring were synthe-
sized using 2-hydrazinocarbonyl benzenesulfonamide and
phenyl pyrimidinecarbamates as starting materials. An im-
proved method, in which an ortho sulfonamide group acts
as a directing group, was proposed to prepare the key inter-
mediate, 2-(4,5-dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)
benzenesulfonamide. The herbicidal tests show that the in-
troduction of a 1,3,4-thiadizole group at the ortho position
of the bridge does not affect the activity of SU herbicide re-
markably. This modification may provide a new SU herbi-
cide with good inhibition to various weeds and grasses in
wheat field.
4 and CS2 [8]. However, in an attempt to prepare 2-(4,5-
dihydro-5-thioxo-1,3,4-oxadiazol-2-yl)benzenesulfonamide
(7) as described in the literature [8], we discovered an
alternate method (method B, Scheme 2). Comparing with
our initial condition (method A), method B provided a
higher yield of the final product which was pure enough
for next step. Purification of 5 was somewhat difficult,
although it was not required for purification in most cases.
It was surprising that the product of method B was 5 instead
of 7. According to the literature [8], treating substituted
benzoyl hydrazines with CS2 and KOH in 95% ethanol
EXPERIMENTAL
Melting points were determined using an X-4 apparatus and
are uncorrected. IR spectra were recorded on a Perkin-Elmer
1600 spectrophotometer. 1H-NMR and 13C-NMR (400 MHz
and 100 MHz, respectively) spectra were recorded on a Bruker
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February 2013 Synthesis and Herbicidal Activities of Sulfonylureas Bearing 1,3,4-Thiadiazole Moiety
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Scheme 2
AVANCE III 400 spectrometer in CDCl3 or DMSO-d6. Chemical
shifts are reported in ppm using TMS as internal standard. MS
(ESI) data were obtained on the Thermo Fisher LCQ Advantage
MAX apparatus. HRMS data were obtained on microOTOF-Q
II instrument. All reagents are commercially available without
further purification unless otherwise noted. 2-Hydrazinocarbonyl
benzenesulfonamide (4) was prepared as we described by Ma
and coworkers [9b]. Phenyl pyrimidinecarbamates (8) were pre-
pared as described in the literatures [10].
hundred milliliters of water was added. After the mixture was
stirred for 5 min, the undissolved solid was filtered off, and the
filtrate was acidified to pH = 2–3 with 20% HCl. The precipitate
was filtered, washed with water and dried. A total of 10.2 g of
yellow solid was obtained (63% yield, mp 197–198°C, dec.).
1H-NMR (DMSO-d6, ppm): 7.65 (s, 2H, SO2NH2), 7.70–7.82
(m, 3H, Ar-H), 8.05–8.07 (d, 1H, Ar-H), 14.81 (N-H).
HRMS (ESI): Found: m/z 295.9594 ([M+Na]+); Calcd for
C8H7N3NaO2S3: 295.9598. This crude product 5 was directly
carried on without further purification.
2-(4,5-Dihydro-5-thioxo-1,3,4-thiadiazol-2-yl)benzenesulfonamide
(5). Method A: 12.5 g (0.06 mol) 4 was added to a solution
of 4.79 g KOH (82%) in 150 mL 95% ethanol; the mixture
was cooled (0–5°C) with an ice bath and 7.2 mL carbon
disulfide was added dropwise. After carbon disulfide was
added, the bath was withdrawn, and the mixture was
stirred for 2 h. Then, the precipitate was filtered, washed
with 95% ethanol, and potassium 3-(2-sulfamoylbenzoyl)
2-(5-Methylthio-1,3,4-thiadiazol-2-yl)benzenesulfonamide
(6a). A total of 2.56 g (ca. 0.01 mol) crude 5, 0.82 g KOH (82%)
was added to 100 mL methanol, then 1.42 g (0.01 mol) methyl
iodide. The mixture was stirred for 4 h at room temperature. The
precipitate was filtered, washed with a 50% aqueous ethanol
solution, and dried under ambient conditions. A total of 2.30 g of
slightly yellow crystals was obtained (83% yield, mp 159–161°C,
1
dithiocarbazate was precipitated as
a
white (sometimes
dec.). IR (KBr, cm−1): 3286, 3180 (N-H), 1342, 1170 (S═O); H-
slightly yellow) solid. The solid was added to 90 mL H2SO4
in batches at 0–5°C. After stirred for 30 min at 0–5°C, the
solution was poured into 400 g crushed ice. The precipitate was
filtered, washed with cold water, and dried under ambient
conditions. A total of 6.2 g yellow solid was obtained (38%
yield, mp 194–197°C, dec.). This crude product 5 was used
directly into the next step without further purification.
Method B: 12.5 g (0.06 mol) 4 was added to a solution of 6.18
g KOH (82%) in 300 mL 95% ethanol, then 7.2 mL carbon disul-
fide was dropped in. The mixture was heated slowly to boiling
and refluxed for 5 h. The solvent was distilled in vacuo until the
volume of the residue solution was about 40 mL, and two
NMR (CDCl3, ppm): 2.86 (s, 3H, SCH3), 6.13 (s, 2H, SO2NH2),
7.59–7.68 (m, 3H, Ar-H), 8.26–8.28 (m, 1H, Ar-H); 13C-NMR
(CDCl3, ppm): 16.35, 126.58, 127.85, 131.14, 132.25, 132.84,
142.32, 164.83, 168.88; MS (ESI), m/z: 311 ([M+Na]+, 100%),
288 ([M+H]+, 55%).
2-(5-Ethylthio-1,3,4-thiadiazol-2-yl)benzenesulfonamide
(6b). Similarly, 6b was prepared with 5 and ethyl iodide in
ethanol as slightly yellow crystals with a yield of 79%, mp
117–118°C; IR (KBr, cm−1): 3295, 3181 (N-H), 1345, 1164
(S═O); 1H-NMR (CDCl3, ppm): 1.53 (t, 3H, J = 7.5Hz,
SCH2CH3), 3.42 (q, 2H, J = 7.5Hz, SCH2CH3), 6.12 (br, s,
2H, SO2NH2), 7.58–7.68 (m, 3H, Ar-H), 8.26–8.28 (m, 1H,
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X.-H. Song, N. Ma, J.-G. Wang, Y.-H. Li, S.-H. Wang, and Z.-M. Li
Vol 50
Scheme 3
diluted with 15 mL of water. After the solid was filtered off,
the filtrate was acidified to pH = 5–6 with 20% hydrochloride
acid. The precipitate was filtered and washed with water
(10 mL × 2). After dried under ambient conditions and
recrystallized with dichloromethane-acetone (1:1 v/v), 9a was
obtained as a white solid, yield 52%, mp 176–177°C (dec.);
IR (KBr, cm−1): 1698 (C═O), 1347, 1171 (S═O); 1H-NMR
(CDCl3, ppm): 2.52 (s, 6H, CH3), 2.79 (s, 3H, SCH3), 6.78
(s, 1H, Pyrim-H), 7.50 (s, 1H, CONH-Pyrim), 7.54–7.57
(m, 1H, Ar-H), 7.71–7.74 (m, 2H, Ar-H), 8.51–8.54 (m, 1H,
Ar-H), 13.04 (br, s, 1H, SO2NH); 13C-NMR (DMSO-d6, ppm):
16.67, 23.67, 115.22, 127.95, 131.47, 131.81, 133.46, 134.25,
138.37, 149.50, 156.73, 163.53, 168.17, 169.23; MS (ESI), m/z: 437
([M+H]+, 100%). Anal. Calcd. for C16H16N6O3S3: C, 44.02; H 3.69;
N, 19.25. Found: C, 43.86; H, 4.03; N, 19.12.
The following compounds 9b-l were synthesized similarly.
1-(2-(5-Methylthio-1,3,4-thiadiazol-2-yl)benzenesulfonamido)-
3-(4,6-dimethoxypyrimidin-2-yl)urea (9b). White solid, yield 54%,
m.p. 177–178°C (dec.); IR (KBr, cm−1): 1707 (C═O), 1358, 1168
Ar-H); 13C-NMR (CDCl3, ppm): 14.53, 28.76, 127.09, 129.24,
131.11, 132.62, 132.80, 141.59, 166.40, 168.26; MS (ESI),
m/z: 325 ([M+Na]+, 100%), 303 ([M+H]+, 73%).
1
(S═O); H-NMR (CDCl3, ppm): 2.78 (s, 3H, SCH3), 3.91 (s, 6H,
Methyl (5-(2-sulfamoylphenyl)-1,3,4-thiadiazol-2-ylthio)acetate
(6c). A total of 2.56 g (ca. 0.01 mol) crude 5 and 0.82 g KOH
(82%) was added to 100 mL methanol, then 1.53 g (0.01 mol)
methyl bromoacetate. The mixture was stirred for 6 h at room
temperature. The precipitate was filtered off, and the filtrate was
concentrated in vacuo. A viscous liquid was obtained. After 30 mL
water was added, a solid precipitated and was filtered, recrystallized
with an aqueous ethanol solution to provide slightly yellow crystals.
The yield was 75%, mp 77–79°C; IR (KBr, cm−1): 3318, 3234
OCH3), 5.81 (s, 1H, Pyrim-H), 7.26 (s, 1H, CONH-Pyrim),
7.53–7.56 (m, 1H, Ar-H), 7.73–7.77 (m, 2H, Ar-H), 8.51–8.54
(m, 1H, Ar-H), 12.47 (br, s, 1H, SO2NH); 13C-NMR (CDCl3,
ppm): 16.20, 54.86, 85.47, 128.43, 130.81, 132.65, 133.14,
133.57, 138.13, 148.82, 155.40, 163.96, 168.79, 171.61; MS,
m/z (ESI) 491 ([M+Na]+, 100%), 469 ([M+H]+, 76%). Anal.
Calcd. for C16H16N6O5S3: C, 41.02; H 3.44; N, 17.94. Found:
C, 41.10; H, 3.79; N, 17.70.
1-(2-(5-Methylthio-1,3,4-thiadiazol-2-yl)benzenesulfonamido)-
3-(4-methylpyrimidin-2-yl) urea (9c). Yellow solid, yield 50%, m.
p. 172–174°C (dec.); IR (KBr, cm−1): 1712 (C═O), 1359, 1169
1
(N-H), 1732 (C═O), 1338, 1168 (S═O); H-NMR (CDCl3, ppm):
3.83 (s, 3H, CH3), 4.23 (s, 2H, SCH2), 7.58–7.72 (m, 3H, Ar-H),
8.26–8.29(m, 1H Ar-H) ; 13C-NMR (CDCl3, ppm): 35.17, 53.14,
126.72, 129.16, 131.19, 132.55, 132.70, 141.52, 165.89, 167.11,
168.16; MS, ESI), m/z: 347 ([M+H]+, 100%), 369 ([M+Na]+, 86%).
1
(S═O); H-NMR (CDCl3, ppm): 2.63 (s, 3H, CH3), 2.79 (s, 3H,
SCH3), 6.91 (d, 1H, J = 5.1Hz, Pyrim-H5), 7.54–7.57 (m, 1H,
Ar-H), 7.72–7.75 (m, 2H, Ar-H), 8.50–8.56 (m, 2H, Ar-H,
Pyrim-H6), 8.95 (br, s, 1H, CONH-Pyrim), 12.85 (br, s, 1H,
SO2CONH); 13C-NMR (DMSO-d6, ppm): 16.14, 23.41,
115.35, 127.42, 130.94, 131.07, 132.92, 133.70, 137.88,
148.92, 156.31, 157.27, 162.95, 168.40, 168.79; MS (ESI), m/
z: 445 ([M+Na]+, 100%), 423 ([M+H]+, 32%). Anal. Calcd. for
C15H14N6O3S3: C, 42.64; H 3.34; N, 19.89. Found: C, 42.54;
H, 3.42; N, 19.78.
(1-(2-(5-Methylthio-1,3,4-thiadiazol-2-yl)benzenesulfonamido)-
3-(4-methoxypyrimidin-2-yl) urea (9d). White solid, yield
61%, m.p. 173–175°C (dec.); IR (KBr, cm−1): 1720 (C═O),
1356, 1164 (S═O); 1H-NMR (CDCl3, ppm): 2.78 (s, 3H,
SCH3), 3.97 (s, 3H, OCH3), 6.47 (d, 1H, J = 6.0Hz, Pyrim-H5),
7.54–7.57 (m, 1H, Ar-H), 7.72–7.76 (m, 2H, Ar-H), 8.35
(d, 1H, J = 6.0Hz, Pyrim-H6), 8.50–8.52 (m, 2H, Ar-H), 12.71
(br, s, 1H, SO2CONH); 13C-NMR (CDCl3, ppm): 16.25, 54.51,
103.22, 128.29, 130.69, 132.41, 132.58, 133.35, 138.22,
148.92, 156.24, 156.71, 163.78, 168.72, 170.30; MS (ESI), m/z:
461 ([M+Na]+, 100%), 439([M+H]+, 51%). Anal. Calcd. for
Ethyl (5-(2-sulfonamidophenyl)-1,3,4-thiadiazol-2-ylthio)
acetate (6d). 6d was prepared similarly with 5 and ethyl
bromoacetate in ethanol as slightly yellow crystals. The yield
was 70%, mp 87–89°C; IR (KBr, cm−1): 3305, 3214 (N-H),
1741 (C═O), 1343, 1168 (S═O); 1H-NMR (CDCl3, ppm): 1.33
(t, 3H, J = 7.2Hz, CO2CH2CH3), 4.22 (s, 2H, SCH2), 4.29
(q, 2H, J = 7.2Hz, CO2CH2CH3), 6.12 (br, s, 2H, SO2NH2),
7.58–7.71 (m, 3H, Ar-H), 8.26–8.29 (m, 1H, Ar-H); 13C-NMR
(CDCl3, ppm): 14.09, 35.45, 62.40, 126.71, 129.15, 131.18, 132.58,
132.72, 141.47, 166.00, 167.06, 167.68; MS (ESI), m/z: 382
([M+Na]+, 100%), 361 ([M+H]+, 79%).
1-(2-(5-Methylthio-1,3,4-thiadiazol-2-yl)benzenesulfonamido)-
3-(4,6-dimethylpyrimidin-2-yl)urea (9a). A total of 0.15 g DBU
(1,8-diazabicyclo[5.4.0]undec-11-ene) was dropped into a stirred
suspension of 0.27 g (1 mmol) 2-(5-methylthio-1,3,4-thiadiazol-2-yl)
benzenesulfonamide (6a) and 0.24 g (1 mmol) phenyl (4,6-
dimethylprimidin-2-yl)carbamate in 10 mL acetonitrile. The
mixture was stirred at room temperature for 2 h, and then
Table 1
Rape‐root growth method tests of the compounds 9a–l.
Dosage (μg/mL)
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
Tribenuron‐methyl
1
10
100
37.4
54.3
64.2
45.2
57.8
67.4
20.5
40.5
42.8
0
21.7
36.7
27.8
50.7
62.1
0
58.8
72.6
8.1
19.0
42.4
38.6
42.8
47.8
0
30.5
36.2
42.4
45.2
48.1
0
0
5.2
0
0
0
61.0
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February 2013 Synthesis and Herbicidal Activities of Sulfonylureas Bearing 1,3,4-Thiadiazole Moiety
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Table 2
Pot herbicidal tests of the compounds 9b, 9f, 9h, and 9j.
Brassica napus
Amaranthus retroflexus
Digitaria adscendens
Echinochloa crusgalli
Dosage
(g/ha)
S
F
S
F
S
F
S
F
9b
9f
9h
9j
A
3.75
7.5
15
16.0
27.5
63.2
68.8
71.7
60.3
76.2
93.8
94.9
55.2
77.3
87.5
96.0
68.3
64.9
79.0
100.0
1.6
30.2
32.5
39.2
39.9
26.4
42.9
47.4
100.0
39.5
50.9
82.8
87.7
34.6
38.7
39.2
86.5
0
0
0
0
21.1
8.9
15.5
21.6
0
0
11.4
61.8
4.7
3.5a
6.1a
22.6
32.2
38.7
67.4
3.6
25.2
56.2
72.2
26.8
53.8
68.5
71.5
23.9
37.8
66.1
72.8
32.0a
24.5
29.8
68.1
0
1.6
51.8
23.3
0
4.0
7.4
9.6
0
0
0
4.0
8.5
20.6
39.3
66.9
0
32.8a
31.7a
32.3a
30.7a
27.6a
38.1a
36.3a
23.9a
32.3a
32.1a
28.0a
26.7a
30.4a
29.3a
29.1a
17.7a
58.8a
5.8a
30
3.75
7.5
15
23.4
24.5
74.5
42.6
46.8
57.4
90.4
55.3
64.9
89.4
91.5
88.4
90.2
92.2
95.2
9.9
5.5
8.3
6.2a
19.9
34.9
33.3
66.6
93.3
98.3
11.0
60.0
100.0
100.0
69.4
80.6
83.3
88.9
16.9a
50.3a
41.6a
61.3a
63.7a
66.4a
29.7a
56.3a
63.4a
65.7a
30
39.4
35.0
75.6
80.4
84.6
16.9
54.3
77.6
83.8
35.1
39.6
46.2
48.1
3.75
7.5
15
14.0
15.0
40.5
61.3
0
16.0
51.1
65.4
30
3.75
7.5
15
0
41.5
40.4
24.0
35.6
40.4
48.1
30
3.75
7.5
15
30
A, tribenuron‐methyl; S, soil treatment; F, foliage spray.
aInhibition percentage calculated by the height of grass upon the soil surface; all the other data were calculated by the fresh weight of grass upon the soil
surface.
C15H14N6O4S3: C, 41.09; H 3.22; N, 19.17. Found: C, 40.90; H,
3.57; N, 19.01.
(s, 6H, CH3), 3.79 (s, 3H, CO2CH3), 4.15 (s, 2H, SCH2), 6.78 (s,
1H, Pyrim-H), 7.54–7.57 (m, 1H, Ar-H), 7.65 (s, 1H, CONH-
Pyrim), 7.72–7.75 (m, 2H, Ar-H), 8.51–8.54 (m, 1H, Ar-H),
13.07 (br, s, 1H, SO2NH); 13C-NMR (DMSO-d6, ppm): 23.13,
34.79, 52.57, 114.69, 127.25, 130.97, 131.34, 132.95, 133.71,
137.83, 149.00, 156.18, 164.02, 165.97, 167.63, 168.14; MS
(ESI), m/z: 517 ([M+Na]+, 100%), 495 ([M+H]+, 89%). Anal.
Calcd. for C18H18N6O5S3: C, 43.72; H 3.67; N, 16.99. Found: C,
43.33; H, 4.04; N, 17.12.
1-(2-(5-Ethylthio-1,3,4-thiadiazol-2-yl)benzenesulfonamido)-3-
(4,6-dimethylpyrimidin-2-yl) urea (9e). White solid, yield
57%, m.p. 152–154°C; IR (KBr, cm−1): 1699 (C═O), 1358,
1
1168 (S═O); H-NMR (CDCl3, ppm): 1.49 (t, 3H, J = 7.5Hz,
SCH2CH3), 2.53 (s, 6H, CH3), 3.33 (q, 2H, J = 7.5Hz,
SCH2CH3), 6.78 (s, 1H, Pyrim-H), 7.55–7.76 (m, 4H, Ar-H,
CONH-Pyrim), 8.50–8.54 (m, 1H, Ar-H), 13.03 (br, s, 1H,
SO2CONH); 13C-NMR (DMSO-d6, ppm): 14.30, 23.13, 28.14,
114.71, 127.39, 130.95, 131.26, 132.94, 133.72, 137.90,
148.94, 156.20, 163.20, 167.32, 167.62; MS (ESI), m/z: 451
([M+H]+, 100%), 473([M+Na]+, 62%). Anal. Calcd. for
C17H18N6O3S3: C, 45.32; H 4.03; N, 18.65. Found: C, 45.05;
H, 4.16; N, 18.55.
1-(2-(5-Methoxycarbonylmethylthio-1,3,4-thiadiazol-2-yl)
benzenesulfonamido)-3-(4,6-dimethoxypyrimidin-2-yl)urea
(9h). Yellow solid, yield 61%, m.p. 154–155°C; IR (KBr, cm−1):
1
1742, 1704 (C═O), 1363, 1168 (S═O); H-NMR (CDCl3, ppm):
3.81 (s, 3H, CO2CH3), 3.90 (s, 6H, OCH3), 4.16 (s, 2H, SCH2),
5.82 (s, 1H, Pyrim-H), 7.23 (s, 1H, CONH-Pyrim), 7.53–7.56
1-(2-(5-Ethylthio-1,3,4-thiadiazol-2-yl)benzenesulfonamido)-3-
(4,6-dimethoxypyrimidin-2-yl)urea (9f). White solid, yield 51%,
m.p. 160–162°C; IR (KBr, cm−1): 1706 (C═O), 1359, 1167
(S═O); 1H-NMR (CDCl3, ppm): 1.49 (t, 3H, J = 7.5Hz,
SCH2CH3), 3.34 (q, 2H, J = 7.5Hz, SCH2CH3), 3.91 (s, 6H,
OCH3), 5.80 (s, 1H, Pyrim-H), 7.23 (s, 1H, CONH-Pyrim),
7.54–7.56 (m, 1H, Ar-H), 7.72–7.77 (m, 2H, Ar-H), 8.51–8.54
(m, 1H, Ar-H), 12.49 (br, s, 1H, SO2NH); 13C-NMR (CDCl3,
ppm): 14.62, 28.52, 54.86, 85.46, 128.45, 130.77, 132.70, 133.17,
133.57, 138.07, 148.84, 155.39, 163.99, 168.11, 171.61; MS
(ESI), m/z: 505 ([M+Na]+, 100%), 483 ([M+H]+, 95%). Anal.
Calcd. for C17H18N6O5S3: C, 42.31; H 3.76; N, 17.42. Found: C,
42.35; H, 3.92; N, 17.54.
Table 3
Safety tests of 9h, 9j against wheat.
Soil treatment
Foliage spray
Dosage
(g/hm)
H
W
H
W
9h
9j
30
60
120
30
60
120
12.5
−4.0
−6.6
13.3
−15.2
1.3
6.4
6.5
−7.7
1.6
20.3
33.5
−0.4
9.1
16.5
5.1
25.7
9.3
14.9
15.0
15.4
20.7
27.9
6.9
1-(2-(5-Methoxycarbonylmethylthio-1,3,4-thiadiazol-2-yl)
benzenesulfonamido)-3-(4,6-dimethylpyrimidin-2-yl)urea (9g).
Yellow solid, yield 65%, m.p. 172–173°C; IR (KBr, cm−1): 1745,
H, inhibition percentage calculated by the height of plant upon the ground;
W, inhibition percentage calculated by the fresh weight of plant upon the
ground.
1
1695 (C═O), 1353, 1166 (S═O); H-NMR (CDCl3, ppm): 2.52
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E72
X.-H. Song, N. Ma, J.-G. Wang, Y.-H. Li, S.-H. Wang, and Z.-M. Li
Vol 50
(m, 1H, Ar-H), 7.73–7.78 (m, 2H, Ar-H), 8.52–8.55 (m, 1H, Ar-H),
12.52 (br, s, 1H, SO2NH); 13C-NMR (DMSO-d6, ppm): 34.68,
52.57, 54.46, 83.77, 127.24, 131.10, 131.65, 133.02, 133.94,
137.46, 148.51, 155.79, 163.96, 166.29, 168.19, 171.03; MS (ESI),
m/z: 549 ([M+Na]+, 100%), 527 ([M+H]+, 59%). Anal. Calcd.
for C18H18N6O7S3: C, 41.06; H 3.45; N, 15.96. Found: C, 41.08;
H, 3.67; N, 16.05.
The herbicidal activities of the compounds 9a–l were screened by
rape-root growth method in Petri dishes [11]. In brief, rape seeds were
soaked in distilled water for 4 h before being placed on a filter paper in
a 6-cm Petri dish, to which 2 mL of inhibitor solution had been added
in advance. Usually, 10 seeds were used on each plate. Duplicate was
tested for each trial. The plate was placed in a dark room and allowed
to germinate for 72 h at 28 ( 1)°C. The lengths of 10 rape roots were
measured and the means were calculated. The percentage inhibition
was calculated relative to controls using distilled water instead of the
inhibitor solution and listed in Table 1. Some compounds of high activ-
ities were selected to pot tests (Table 2). In brief, in plastic pots was
added definite weight of soil and water, then various weed seeds were
sown on the surface. Another batch of soil with water (foliage spray
test) or spray of inhibitor (soil treatment test) was added. The test pots
were kept in a green house under stable temperature and humidity, and
they were covered with transparent material before germination. Fixed
volume of water was sprayed in everyday to keep the continuous
growth of the weeds. Foliage treatment was carried out in the 1- to
2-leaf stage after emergence. The inhibition rate (Table 2) was calcu-
lated 20 days after the treatment by height and/or fresh weight of grass
upon the soil surface in comparison with the control sample (only us-
ing water). Similar to pot tests mentioned above, safety tests were car-
ried out by using wheat as the test crop instead of weeds and the results
were listed in Table 3.
1-(2-(5-Ethoxycarbonylmethylthio-1,3,4-thiadiazol-2-yl)
benzenesulfonamido)-3-(4,6-dimethylpyrimidin-2-yl)urea
(9i). Yellow solid, yield 57%, m.p. 179–180°C (dec.); IR
1
(KBr, cm−1): 1724 (C═O), 1363, 1165 (S═O); H-NMR (CDCl3,
ppm): 1.30 (t, 3H, J = 7.2Hz, CO2CH2CH3), 2.52 (s, 6H, CH3), 4.13
(s, 2H, SCH2), 4.25 (q, 2H, J = 7.2Hz, CO2CH2CH3), 6.78 (s, 1H,
Pyrim-H), 7.54–7.57 (m, 1H, Ar-H), 7.71–7.76 (m, 3H, Ar-H,
CONH-Pyrim), 8.50–8.53 (m, 1H, Ar-H), 13.07 (br, s, 1H, SO2NH);
13C-NMR (CDCl3, ppm): 14.21, 23.86, 35.58, 62.37, 115.33, 128.16,
130.87, 132.63, 132.81, 133.42, 138.32, 149.25, 156.20, 165.02,
165.60, 167.66, 168.55; MS (ESI), m/z: 531 ([M+Na]+, 100%), 509
([M+H]+, 96%). Anal. Calcd. for C19H20N6O5S3: C, 44.87; H 3.96;
N, 16.52. Found: C, 44.63; H, 4.30; N, 16.68.
1-(2-(5-Ethoxycarbonylmethylthio-1,3,4-thiadiazol-2-yl)
benzenesulfonamido)-3-(4,6-dimethoxypyrimidin-2-yl)urea (9j).
Yellow solid, yield 54%, m.p. 147–148°C; IR (KBr, cm−1): 1741,
1
1711 (C═O), 1357, 1166 (S═O); H-NMR (CDCl3, ppm): 1.31
(t, 3H, J = 7.2Hz, CO2CH2CH3), 3.91 (s, 6H, OCH3), 4.14 (s, 2H,
SCH2), 4.26 (q, 2H, J = 7.2Hz, CO2CH2CH3), 5.82 (s, 1H, Pyrim-
H), 7.22 (s, 1H, CONH-Pyrim), 7.53–7.56 (m, 1H, Ar-H), 7.73–7.76
(m, 2H, Ar-H), 8.52–8.55 (m, 1H, Ar-H), 12.50 (br, s, 1H, SO2NH);
13C-NMR (CDCl3, ppm): 13.88, 34.92, 54.48, 61.48, 83.78, 127.28,
131.11, 131.72, 133.02, 133.98, 137.41, 148.53, 155.80, 163.93,
166.36, 167.65, 171.02; MS (ESI), m/z: 541 ([M+H]+, 100%). Anal.
Calcd. for C19H20N6O7S3: C, 42.22; H 3.73; N, 15.55. Found: C,
41.92; H, 4.05; N, 15.78.
Acknowledgment. This work was supported by the National Basic
Research Program (2010CB126106) and the National Natural
Science Foundation of China (20802049).
REFERENCES AND NOTES
1-(2-(5-Ethoxycarbonylmethylthio-1,3,4-thiadiazol-2-yl)
benzenesulfonamido)-3-(4-methylpyrimidin-2-yl)urea (9k). Yellow
solid, yield 64%, m.p. 87–89°C (dec.); IR (KBr, cm−1): 1730, 1710
[1] For reviews, see: (a) Russell, M. H.; Saladini, J. L.; Lichtner,
F. Pestic Outlook 2002, 13, 166; (b) Duggleby, R. G.; McCourt, J. A.;
Guddat, L. W. Plant Physiol Biochem 2008, 46, 309; (c) Zhang, Y. B.
Mod Agrochem 2010, 9, 6.
1
(C═O), 1359, 1167 (S═O); H-NMR (CDCl3, ppm): 1.30 (t, 3H,
J = 7.2Hz, CO2CH2CH3), 2.62 (s, 3H, CH3), 4.14 (s, 2H, SCH2),
4.25 (q, 2H, J = 7.2Hz, CO2CH2CH3), 6.92 (d, 1H, J = 5.1Hz,
Pyrim-H5), 7.55–7.58 (m, 1H, Ar-H), 7.71–7.77 (m, 2H, Ar-H),
8.50–8.53 (m, 1H, Ar-H), 8.57 (s, 1H, J = 5.1Hz, Pyrim-H6),
8.80 (br, s, 1H, CONH-Pyrim), 12.89 (br, s, 1H, SO2NH);
13C-NMR (CDCl3, ppm): 14.09, 24.11, 35.46, 62.27, 115.51,
128.05, 130.78, 132.47, 132.57, 133.33, 138.27, 149.27,
156.37, 157.79, 164.86, 165.61, 167.56, 169.11; MS (ESI),
m/z: 517 ([M+Na]+, 100%), 495 ([M+H]+, 53%). Anal.
Calcd. for C18H18N6O5S3: C, 43.72; H 3.67; N, 16.99.
Found: C, 43.41; H, 3.83; N, 17.16.
[2] Levitt, G. In Synthesis and Chemistry of Agrochemicals II;
Baker, D. R., Fenyes, J. G., Moberg, W. K., Eds.; American Chemistry
Society: Washington DC, 1991; p16.
[3] Li, Z.-M.; Lai, C.-M. Chin J Org Chem 2001, 21, 810.
[4] (a) Ma, N.; Li, P.-F.; Li, Y.-H.; Li, Z.-M.; Wang, L.-X.; Wang,
S.-H. Chem J Chin Univ 2004, 25, 2259; (b) Ma, N.; Li, Z.-M.; Li, Y.-H.;
Hao, J.-J.; Fan, C.-W.; Wang, L.-X.; Wang, S.-H. Chin Appl Chem 2004,
21, 989; (c) Li, P.-F.; Ma, N.; Wang, B.-L.; Li, Z.-M.; Wang, S.-H.;
Li, Y.-H. Chem J Chin Univ 2005, 26, 1459.
[5] (a) Wang, J.-G.; Li, Z.-M.; Ma, N.; Wang, B.-L.; Jiang, L.;
Pang, S. S.; Lee, Y.-T.; Guddat, L. W.; Duggleby, R. G. J Comput Aided
Mol Des 2005, 19, 801; (b) Wang, J.-G.; Ma, N.; Wang, B.-L.; Wang,
S.-H.; Song, H.-B.; Li, Z.-M. Chin J Org Chem 2006, 26, 648.
[6] Wang, J.-G.; Lee, P. K.-M.; Dong, Y.-H.; Pang, S. S.;
Duggleby, R. G.; Li, Z.-M.; Guddat, L. W. FEBS J 2009, 276, 1282.
[7] (a) Tomlin, C. D. S. The Pesticide Manual, 12th ed.; British
Crop Protection Council: Surrey, UK, 2000; (b) Luo, Y.-P.; Yang, G.-F.
Bioorg Med Chem 2007, 15, 1716.
[8] Baron, M.; Wilson, C. V. J Org Chem 1958, 23, 1021.
[9] (a) Robinson, R. I.; Fryatt, R.; Wilson, C.; Woodward, S. Eur J
Org Chem 2006,4483; (b) Wang, S.-Y.; Guo, W.-C.; Ma, N. Acta Cryst
2007, E63, o3192.
1-(2-(5-Ethoxycarbonylmethylthio-1,3,4-thiadiazol-2-yl)
benzenesulfonamido)-3-(4-methoxypyrimidin-2-yl)urea (9l). Yellow
solid, yield 67%, m.p. 99–101°C (dec.); IR (KBr, cm−1): 1716
1
(C═O), 1358, 1163 (S═O); H-NMR (CDCl3, ppm): 1.31 (t, 3H,
J = 7.2Hz, CO2CH2CH3), 3.97 (s, 3H, OCH3), 4.14 (s, 2H,
SCH2), 4.26 (q, 2H, J = 7.2Hz, CO2CH2CH3), 6.51 (d, 1H,
J = 6.0Hz, Pyrim-H5), 7.55–7.58 (m, 1H, Ar-H), 7.72–7.77
(m, 2H, Ar-H), 8.34 (s, 1H, J = 6.0Hz, Pyrim-H6), 8.49–8.52
(m, 1H, Ar-H). 13C-NMR (CDCl3, ppm): 14.34, 35.54, 54.86,
62.56, 103.39, 128.21, 131.07, 132.66, 132.84, 133.65, 138.34,
149.39, 156.50, 164.99, 166.06, 167.88, 170.42; MS (ESI), m/z: 511
([M+H]+, 100%). Anal. Calcd. for C18H18N6O6S3: C, 42.35; H 3.55;
N, 16.46. Found: C, 42.32; H, 3.81; N, 16.24.
[10] (a) Ishida, Y.; Ohta, K.; Nakahama, T.; Yoshikawa, H. U.S.
Pat.5,017,212,1991; (b) Ma, N.; Fan, Z. J.; Wang, B. L.; Li, Y. H.;
Li, Z. M. Chin Chem Lett 2008, 19, 1268.
[11] Wang, J.-G.; Xiao, Y.-J.; Li, Y.-H.; Ma, Y.; Li, Z.-M. Bioorg
Med Chem 2007, 15, 374.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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