Synthesis, crystal structure, and herbicidal activities of 2-cyanoacrylates containing 1,3,4-thiadiazole moieties

Article abstract of DOI:10.1002/cjoc.201190196

Three series of novel 2-cyanoacrylates 7a-7f, 9a-9f, 10a-10f containing 1,3,4-thiadiazole ring moieties were synthesized as herbicidal inhibitors of photosystem II (PS II) electron transportation. Their structures were clearly verified by 1H NMR, 13C NMR, elemental analysis (or HRMS analysis) and single-crystal X-ray diffraction analysis. Bioassay showed that a suitable group at the 3-position of acrylates was essential for high herbicidal activity. In particular, compound 7e showed the best herbicidal activities and gave 100% inhibitory activity against rape and amaranth pigweed at a dose of 1.5 kg/ha. Introduction of substituent with higher polarity such as sulfinyl or sulfonyl to the 5-position of 1,3,4-thiadiazole decreased herbicidal activities.

Full text of DOI:10.1002/cjoc.201190196

FULL PAPER
Synthesis, Crystal Structure, and Herbicidal Activities of
2-Cyanoacrylates Containing 1,3,4-Thiadiazole Moieties
Wang, Tingting(王婷婷)
Bing, Guifang(邴贵芳)
Yu, Haibo(于海波)
Miao, Wenke(苗文科)
Wu, Shanshan(吴姗姗)
Zhang, Xin(张欣)
Qin, Zhenfang(秦振芳)
Qin, Xue(秦雪)
Fang, Jianxin*(方建新)
State Key Laboratory of Elemento-organic Chemistry, Research Institute of Elemento-organic Chemistry,
Nankai University, Tianjin 300071, China
Three series of novel 2-cyanoacrylates 7a— 7f, 9a— 9f, 10a— 10f containing 1,3,4-thiadiazole ring moieties
were synthesized as herbicidal inhibitors of photosystem II (PS II) electron transportation. Their structures were
clearly verified by 1H NMR, 13C NMR, elemental analysis (or HRMS analysis) and single-crystal X-ray diffraction
analysis. Bioassay showed that a suitable group at the 3-position of acrylates was essential for high herbicidal activ-
ity. In particular, compound 7e showed the best herbicidal activities and gave 100% inhibitory activity against rape
and amaranth pigweed at a dose of 1.5 kg/ha. Introduction of substituent with higher polarity such as sulfinyl or
sulfonyl to the 5-position of 1,3,4-thiadiazole decreased herbicidal activities.
Keywords 2-cyanoacrylate, 1,3,4-thiadiazole, inhibitors of photosystem II electron transportation, herbicidal
activity, synthesis
Introduction
thetic electron transportation at a common binding do-
main on the 32 kDa polypeptide (D1 protein) of the PS
II reaction center. Among these cyanoacrylates, com-
pound B (Figure 1) exhibits high inhibitory activity of
the Hill reaction yet reported.4-6 Bayer AG reported
compound C (Figure 1), but little information was given
on its herbicidal activity.7 It has been reported that the
Herbicidal activity of cyanoacrylates has been the
subject of intense interest for the past decades.1-3 A de-
tailed study of compounds with general structure A
(Figure 1) revealed that cyanoacrylates are inhibitors of
photosystem II (PS II) electron transportation, which
inhibits the growth of weeds by disrupting photosyn-
Figure 1 Chemical structures of compounds A— H.
*
E-mail: fjx@nankai.edu.cn; Tel.: 0086-022-23505330; Fax: 0086-022-23503627
Received May 31, 2010; revised October 3, 2010; accepted January 26, 2011.
Project supported by the National Natural Science Foundation of China (NNSFC) (No. 20772068) and the National Key Project of Scientific and
Technical Supporting Programs Funded by Ministry of Science & Technology of China (No. 2006BAE01A01-5).
Chin. J. Chem. 2011, 29, 959— 967
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Wang et al.
FULL PAPER
D1 protein of PS II is the herbicide binding site, and the
benzyl group of cyanoacrylate fits into the hydrophobic
domain of the site maximizing van der Waals
ring-stacking interactions with aromatic amino acids
(Phe 211, Phe 255, Tyr 262) flanking this part of the
binding domain.4,8,9 However, the complete nature and
topography of this hydrophobic domain of the D1 pro-
tein are unknown. Since cyanoacrylates have not com-
mercialized as herbicides, so it has broad prospects for
development.
Varous N- or S-containing heterocyclic derivatives
always display broad-spectrum biological activities. In
previous work on the synthesis of 2-cyanoacrylates,
Wang et al.10,11 reported that some compounds D (Figure
1) modified by replacing phenyl with heterocycles (pyri-
dine or thiazole) showed higher herbicidal activity than
parent compounds B and C. Recently, Song et al.12,13 first
reported that cyanoacrylates derivatives E and F (Figure
1) also exhibited moderate to excellent antiviral activity
against tobacco mosaic virus (TMV) According to the
bioisosterism principles, compounds D, E and F were all
analogues of structures A, B and C.
In our previous work on the synthesis of cyanoacry-
lates we found that some compoumds with heterocycles
showed good herbicidal activities.14-17 For example, we
have reported that compound G could control more than
90% of rape and amaranth pigweed at a dose of 1.5
kg/ha17 and compound H could control 83.7% of ama-
ranth pigweed even at a dose of 0.3 kg/ha.16 At the same
time we noticed that compounds G and H were also
analogues of structures A, B and C which encouraged us
to introduce thiadiazole rings with different polarity
substitutents into 2-cyanoacrylates and further study the
relationship of structure-herbicidal activity.
hydrate (85%, 44.2 g, 0.75 mol) was added at the tem-
perature of about 20 ℃, then carbon disulfide (57.5 g,
0.75 mol) was added dropwise at the temperature of
about 9—10 ℃. After stirring at this temperature for 2
h, dimethyl sulfate (94.5 g, 0.75 mol) was added drop-
wise at the temperature of about 12—15 ℃, then keep
stirring at the same temperature for 1 h. After filtration,
the residue was washed with water then recrystallized
with dichloromethane to obtain a white solid (71.5 g,
78.0%), m.p. 78—80 ℃ (Lit.18 80—82 ℃).
Synthesis of (5-methylthio-1,3,4-thiadiazol-2-yl)-
methylchloride (3)
To a solution of 1 (61.1 g, 0.50 mol) in dioxane (100
mL) was added a solution of sodium acetate (53.0 g,
0.64 mol) in water (100 mL). The mixture was cooled to
－15 ℃, and chloroacetylchloride (57.0 g, 0.50 mol)
was then added dropwise. After stirring at 10 ℃ for 1 h,
the mixture was extracted with ethyl ether, dried over
MgSO4, and evaporated in vacuo to yield a light yellow
oil 2. Then it was dumped in solution of 10% sodium
bicarbonate to obtain a yellow solid. After filtration, the
residue was washed with water and then recrystallized
with methanol to obtain a light yellow solid (70.5 g,
78.0%), m.p. 71—73 ℃ (Lit.19 70—71 ℃).
Synthesis of (5-methylthio-1,3,4-thiadiazol-2-yl)-
methylamine (5)
To a solution of 3 (9.0 g, 0.05 mol) in N,N-
dimethylformamide was added potassium phthalimide
(4) (9.3 g, 0.05 mol) in a small portion. After the mix-
ture had been stirred at room temperature for 12 h, ice
water (30 mL) was added, and lots of precipitate ap-
peared. The precipitate was filtered with water to gave
the desired N-substituted phthalimide intermediate (14.4
g, 99.9%).
To a suspension of N-substituted phthalimide inter-
mediate (14.4 g, 0.05 mol) in ethanol (100 mL) was
added hydrazinehydrate (80%, 10.7 g, 0.17 mol). The
reaction mixture was refluxed for 3 h and then cooled.
The precipitated phthalylhydrazide was filtered and
washed with ethanol, and then the combined filtrate was
evaporated under reduced pressure to give crude 5 (oil,
7.2 g, 90.0%), which underwent the next reaction with-
out further purification.
Experimental
General procedure
The melting points of the products were determined
on an X-4 binocular microscope (Beijing Technology
Instrument Co, Beijing, China) and were not corrected.
1H NMR spectra were obtained at 300 MHz using a
Bruker AC-P 300 spectrometer and 400 MHz using a
Varian Mercury Plus 400 MHz spectrometer. Chemical
shift values (δ) were downfield from internal tetrame-
thylsilane. Elemental analyses were determined on a
Yanaco CHN Corder MT-3 elemental analyzer, and
HRMS data were obtained on an FTICR-MS spec-
trometer (Ionspec 7.0T). X-ray single-crystal diffraction
was recorded using a Bruker SMART-1000 spectrometer.
The reagents were all analytically or chemically pure.
All solvents and liquid reagent were dried in advance
and distilled before use. Compounds 6a—6f were syn-
thesized according to the reported methods.10,11
General synthetic procedures for target compounds
7a— 7f
A mixture of intermediates 6a—6f (4.8 mmol) and 5
(5 mmol) in ethanol (30 mL) was refluxed for 3 h and
then evaporated under reduced pressure to give crude
products. The products were purified by column chro-
matography on a silica gel to give pure target com-
pounds 7a—7f.
(Z)-Ethoxyethyl 2-cyano-3-methylthio-3-(5-methyl-
thio-1,3,4-thiadiazol-2-yl)methanaminoacrylate (7a)
Synthesis of compound 1
1
Yield 62.9%. m.p. 74—75 ℃; H NMR (CDCl3) δ:
To a solution of isopropanol (50 mL), water (60 mL)
and postassium hydroxide (51.3 g, 0.75 mol), hydrazine
10.48 (br, 1H, CH2NH), 5.15 (d, J＝6.2 Hz, 2H,
CH2NH), 4.31 (t, J＝5.0 Hz, 2H, OCH2), 3.70 (t, J＝5.0
Chin. J. Chem. 2011, 29, 959— 967
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Synthesis, Crystal Structure, and Herbicidal Activities of 2-Cyanoacrylates
1
Hz, 2H, CH2O), 3.57 (q, J＝7.6 Hz, 2H, OCH2CH3),
2.80 (s, 3H, CH3S-thiadiazole), 2.73 (s, 3H, CH3S), 1.21
(t, J＝7.0 Hz, 3H, OCH2CH3); 13C NMR (CDCl3) δ:
172.43, 168.59, 167.68, 164.91, 117.35, 67.98, 66.84,
64.42, 44.01, 18.58, 16.48, 15.15. Anal. calcd for
C13H18N4O3S3: C 41.69, H 4.84, N 14.96; found C 41.64,
H 4.80, N 14.90.
(Z)-Ethoxymethyl 2-cyano-3-methylthio-3-(5-me-
thylthio-1,3,4-thiadiazol-2-yl)methanaminoacrylate
(7b) Yield 59.1%. m.p. 89—90 ℃; 1H NMR (CDCl3) δ:
10.47 (br, 1H, CH2NH), 5.15 (d, J＝6.2 Hz, 2H, CH2NH),
4.32 (t, J＝4.8 Hz, 2H, OCH2), 3.66 (t, J＝4.8 Hz, 2H,
CH2O), 3.41 (s, 3H, CH3O), 2.80 (s, 3H, CH3S-
thiadiazole), 2.73 (s, 3H, CH3S); 13C NMR (CDCl3) δ:
172.48, 168.60, 167.64, 164.89, 117.40, 70.18, 64.16,
59.21, 44.03, 18.58, 16.49. Anal. calcd for C12H16N4O3S3:
C 39.98, H 4.47, N 15.54; found C 40.21, H 4.59, N
15.51.
(E)-Ethoxyethyl 2-cyano-3-ethyl-3-(5-methylthio-
1,3,4-thiadiazol-2-yl)methanaminoacrylate (7c) Yield
64.6%. m.p. 57—58 ℃; 1H NMR (CDCl3) δ: 10.36 (br,
1H, CH2NH), 4.90 (d, J＝6.4 Hz, 2H, CH2NH), 4.30 (q,
J＝5.0 Hz, 2H, OCH2), 3.69 (t, J＝4.9 Hz, 2H, CH2O),
3.57 (q, J＝7.0 Hz, 2H, OCH2CH3), 2.80 (s, 3H, CH3S-
thiadiazole), 2.70 (q, J＝7.6 Hz, 2H, CH3CH2C＝C),
1.28 (t, J＝7.7 Hz, 3H, OCH2CH3), 1.21 (t, J＝7.0 Hz,
3H, CH3CH2C＝C); 13C NMR (CDCl3) δ: 174.94,
168.87, 168.52, 165.02, 117.76, 73.23, 68.05, 66.83,
63.99, 42.32, 24.51, 16.49, 15.15, 12.22. Anal. calcd for
C14H20N4O3S2: C 47.17, H 5.66, N 15.72; found C 47.01,
H 5.52, N 15.58.
(E)-Ethoxymethyl 2-cyano-3-ethyl-3-(5-methylthio-
1,3,4-thiadiazol-2-yl)methanaminoacrylate (7d) Yield
62.7%. m.p. 71—72 ℃; 1H NMR (CDCl3) δ: 10.38 (br,
1H, CH2NH), 4.90 (d, J＝6.4 Hz, 2H, CH2NH), 4.31 (t,
J＝4.8 Hz, 2H, OCH2), 3.65 (t, J＝4.8 Hz, 2H, CH2O),
3.41 (s, 3H, CH3O), 2.81 (s, 3H, CH3S-thiadiazole), 2.70
(q, J＝7.7 Hz, 2H, CH3CH2C＝C), 1.28 (t, J＝7.6 Hz,
3H, CH3CH2C＝C); 13C NMR (CDCl3) δ: 174.97,
168.86, 168.48, 164.97, 117.81, 72.94, 70.25, 63.74,
59.21, 42.32, 24.52, 16.50, 12.21. Anal. calcd for
C13H18N4O3S2: C 45.60, H 5.30, N 16.36; found C 45.34,
H 5.18, N 16.14.
Yield 59.6%. m.p. 88—89 ℃; H NMR (CDCl3) δ:
10.75 (br, 1H, CH2NH), 4.97 (d, J＝6.3 Hz, 2H, CH2NH),
4.31 (t, J＝4.8 Hz, 2H, OCH2), 3.66 (t, J＝4.8 Hz, 2H,
CH2O), 3.41 (s, 3H, CH3O), 3.22 [m, 1H, (CH3)2CHC＝
C], 2.80 (s, 3H, CH3S-thiadiazole), 1.40 [d, J＝7.1 Hz,
6H, (CH3)2CHC＝C]; 13C NMR (CDCl3) δ: 179.0, 169.4,
168.7, 165.3, 118.1＋, 71.7, 70.3, 63.9, 59.2, 42.5, 30.3,
18.9, 16.5; MS (ESI ) m/z: 357.02 [M＋H]＋. Anal. calcd
for C14H20N4O3S2: C 47.17, H 5.66, N 15.72; found C
46.96, H 5.48, N 15.84.
General synthetic procedures for target compounds
9a— 9f
To a mixture of compounds 7a—7f (3 mol) in 20 mL
CH2Cl2 was added m-chloroperoxybenzoic acid
(m-CPBA) (3.1 mol) in portions at 0 ℃. After the mix-
ture was stirred at room temperature for 1 h, 6 mol/L
NaOH (aq.) was added to pH≈8. The organic layer was
separated and dried over MgSO4. The filtrate was
evaporated in vacuo and the products were purified by
column chromatography on a silica gel to give the cor-
responding pure target compounds 9a—9f.
(Z)-Ethoxyethyl 2-cyano-3-methylthio-3-(5-methyl-
sulfinyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
1
(9a) Yield 99.2%. oil. H NMR (CDCl3) δ: 10.57 (br,
1H, CH2NH), 5.28 (d, J＝6.3 Hz, 2H, CH2NH), 4.32 (t,
J＝5.0 Hz, 2H, OCH2), 3.71 (t, J＝5.0 Hz, 2H, CH2O),
3.58 (q, J＝7.0 Hz, 2H, OCH2CH3), 3.15 (s, 3H,
CH3S＝O), 2.75 (s, 3H, CH3S), 1.21 (t, J＝7.0 Hz, 3H,
OCH2CH3); 13C NMR (CDCl3) δ: 180.24, 172.43, 170.31,
167.22, 117.37,－67.84, 66.57, 64.27, 44－.25, 43.26, 18.55,
15.06; MS (ESI ) m/z: 388.96 [M—H] . Anal. calcd for
C13H18N4O4S3: C 39.98, H 4.65, N 14.35; found C 39.80,
H 4.40, N 14.23. HRMS (ESI) calcd for C13H18N4NaO4S3
(M＋Na)＋ 413.0382, found 413.0386.
(Z)-Ethoxymethyl 2-cyano-3-methylthio-3-(5-
methylsulfinyl-1,3,4-thiadiazol-2-yl)methanamino-
1
acrylate (9b) Yield 99.7%. oil. H NMR (CDCl3) δ:
10.56 (br, 1H, CH2NH), 5.29 (d, J＝6.3 Hz, 2H, CH2NH),
4.33 (t, J＝4.8 Hz, 2H, OCH2), 3.67 (t, J＝4.8 Hz, 2H,
CH2O), 3.41 (s, 3H, OCH3), 3.15 (s, 3H, CH3S＝O),
2.75 (s, 3H, CH3S); 13C NMR (CDCl3) δ: 180.75, 172.55,
170.08, 167.61, 117.11, 70.16, 64.27, 59.22, 44.13, 43.45,
18.64; HRMS (ESI) calcd for C12H16N4NaO4S3 (M＋Na)＋
399.0226, found 399.0221.
(E)-Ethoxyethyl 2-cyano-3-isopropyl-3-(5-methyl-
thio-1,3,4-thiadiazol-2-yl)methanaminoacrylate (7e)
1
(E)-Ethoxyethyl 2-cyano-3-ethyl-3-(5-methyl-
sulfinyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
Yield 62.6%. m.p. 70—71 ℃; H NMR (CDCl3) δ:
10.76 (br, 1H, CH2NH), 4.95 (d, J＝6.3 Hz, 2H,
CH2NH), 4.30 (t, J＝5.1 Hz, 2H, OCH2), 3.70 (t, J＝5.1
Hz, 2H, CH2O), 3.58 (q, J＝7.0 Hz, 2H, OCH2CH3),
3.18—3.25 [m, 1H, CH (CH3)2], 2.80 (s, 3H, CH3S-
thiadiazole), 1.40 [d, J＝7.1 Hz, 6H, CH (CH3)2], 1.21 (t,
J＝7.0 Hz, 3H, OCH2CH3); 13C NMR (CDCl3) δ:
178.93, 169.44, 168.73, 165.37, 118.11, 71.89, 68.05,
66.86, 64.11, 42.47, 30.25, 18.96, 16.48, 15.18. Anal.
calcd for C15H22N4O3S2: C 48.63, H 5.99, N 15.12;
found C 48.70, H 5.72, N 14.98.
1
(9c) Yield 95.7%. oil. H NMR (CDCl3) δ: 10.23 (br,
1H, CH2NH), 4.95 (d, J＝5.8 Hz, 2H, CH2NH), 4.03 (t,
J＝4.4 Hz, 2H, OCH2), 3.43 (t, J＝4.4 Hz, 2H, CH2O),
3.30 (q, J＝6.9 Hz, 2H, OCH2CH3), 2.92 (s, 3H, CH3S＝
O), 2.49 (q, J＝7.4 Hz, 2H, CH3CH2C＝C), 1.04 (t, J＝
7.4 Hz, 3H, CH3CH2C＝C), 0.93 (t, J＝7.0 Hz, 3H,
OCH2CH3); 13C NMR (CDCl3) δ: 180.55, 174.90, 170.12,
168.02, 117.94, 72.62, 67.89, 66.43, 63.73, 43.26, 42.46,
24.52, 15.02, 12.08; HRMS (ESI) calcd for C14H20N4Na-
O4S2 (M＋Na)＋ 395.0818, found 395.0813.
(E)-Ethoxymethyl 2-cyano-3-isopropyl-3-(5-methyl-
thio-1,3,4-thiadiazol-2-yl)methanaminoacrylate (7f)
(E)-Ethoxymethyl 2-cyano-3-ethyl-3-(5-methylsul-
Chin. J. Chem. 2011, 29, 959— 967
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finyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate (9d)
Yield 96.5%. oil. H NMR (CDCl3) δ: 10.46 (br, 1H,
methylsulfonyl-1,3,4-thiadiazol-2-yl)methanaminoa-
crylate (10b) Yield 82.1%. m.p. 78—80 ℃; 1H NMR
(CDCl3) δ: 10.57 (br, 1H, CH2NH), 5.29 (d, J＝6.3 Hz,
2H, CH2NH), 4.35 (t, J＝4.8 Hz, 2H, OCH2), 3.67 (t, J＝
4.8 Hz, 2H, CH2O), 3.49 (s, 3H, CH3SO2), 3.41 (s, 3H,
CH3O), 2.76 (s, 3H, CH3S); 13C NMR (CDCl3) δ:
172.49, 171.35, 170.11, 167.59, 116.89, 78.54, 70.15,
64.37, 59.21, 43.92, 43.02, 18.65. Anal. calcd for
C12H16N4O5S3: C 36.72, H 4.11, N 14.28; found C 36.71,
H 3.98, N 14.42.
(E)-Ethoxyethyl 2-cyano-3-ethyl-3-(5-methyl-
sulfonyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
(10c) Yield 83.0%. m.p. 88—89 ℃; 1H NMR (CDCl3)
δ: 10.44 (br, 1H, CH2NH), 5.16 (d, J＝6.5 Hz, 2H,
CH2NH), 4.27 (t, J＝4.8 Hz, 2H, OCH2), 3.68 (t, J＝4.8
Hz, 2H, CH2O), 3.55 (q, J＝7.0 Hz, 2H, OCH2CH3),
3.49 (s, 3H, CH3SO2), 2.71 (q, J ＝ 7.6 Hz, 2H,
CH3CH2C＝C), 1.29 (t, J＝7.6 Hz, 3H, CH3CH2C＝C),
1.18 (t, J＝7.0 Hz, 3H, OCH2CH3); 13C NMR (CDCl3) δ:
174.96, 171.76, 170.04, 168.15, 117.82, 73.21, 67.94,
66.59, 63.92, 43.12, 42.38, 24.59, 15.06, 12.17. Anal.
calcd for C14H20N4O5S2: C 43.29, H 5.19, N 14.42;
found C 43.16, H 5.36, N 14.63.
(E)-Ethoxymethyl 2-cyano-3-ethyl-3-(5-methyl-
sulfonyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
(10d) Yield 96.8%. m.p. 133—135 ℃; 1H NMR
(CDCl3) δ: 10.46 (br, 1H, CH2NH), 5.08 (d, J＝6.5 Hz,
2H, CH2NH), 4.31 (t, J＝4.8 Hz, 2H, OCH2), 3.65 (t,
J＝4.8 Hz, 2H, CH2O), 3.49 (s, 3H, CH3SO2), 3.40 (s,
3H, CH3O), 2.71 (q, J＝7.7 Hz, 2H, CH3CH2C＝C),
1.30 (t, J＝7.7 Hz, 3H, CH3CH2C＝C); 13C NMR
(CDCl3) δ: 174.78, 171.52, 170.25, 168.36, 117.42,
74.04, 70.22, 63.89, 59.17, 43.04, 42.35, 24.58, 12.27.
Anal. calcd for C13H18N4O5S2: C 41.70, H 4.85, N 14.96;
found C 41.69, H 4.77, N 14.81.
1
CH2NH), 5.03 (d, J＝6.5 Hz, 2H, CH2NH), 4.32 (t, J＝
4.8 Hz, 2H, OCH2), 3.66 (t, J＝4.8 Hz, 2H, CH2O), 3.41
(s, 3H, OCH3), 3.15 (s, 3H, CH3S＝O), 2.72 (q, J＝7.5
Hz, 2H, CH3CH2C ＝ C), 1.30 (t, J ＝ 7.6 Hz, 3H,
CH3CH2C＝C); 13C NMR (CDCl3) δ: 180.52, 175.00,
170.09, 168.01, 118.04, 72.41, 70.12, 63.50, 58.83,
43.25, 42.47, 24.55, 12.07; HRMS (ESI) calcd for
C13H18N4NaO4S2 (M＋Na)＋ 381.0664, found 381.0660.
(E)-Ethoxyethyl 2-cyano-3-isopropyl-3-(5-methyl-
sulfinyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
1
(9e) Yield 93.8%. oil. H NMR (CDCl3) δ: 10.86 (br,
1H, CH2NH), 5.08 (d, J＝6.4 Hz, 2H, CH2NH), 4.31 (t,
J＝4.8 Hz, 2H, OCH2), 3.71 (t, J＝5.0 Hz, 2H, CH2O),
3.58 (q, J＝7.0 Hz, 2H, OCH2CH3), 3.15 (s, 3H, CH3S＝
O), 3.19—3.24 [m, 1H, CH(CH3)2], 1.42 [d, J＝7.0 Hz,
CH(CH3)2], 1.21 (t, J＝7.0 Hz, 3H, OCH2CH3); 13C
NMR (CDCl3) δ: 180.96, 171.95, 170.50, 169.31, 117.97,
68.02, 66.87, 64.25, 64.20, 43.49, 19.01, 15.15; HRMS
(ESI) calcd for C15H22N4NaO4S2 (M＋Na)＋ 409.0975,
found 409.0976.
(E)-Ethoxymethyl 2-cyano-3-isopropyl-3-(5-methyl-
sulfinyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
1
(9f) Yield 97.7%. oil. H NMR (CDCl3) δ: 10.87 (br,
1H, CH2NH), 5.09 (dd, J＝6.5, 10.3 Hz, 2H, CH2NH),
4.33 (t, J＝4.8 Hz, 2H, OCH2), 3.67 (t, J＝4.8 Hz, 2H,
CH2O), 3.42 (s, 3H, OCH3), 3.18—3.24 [m, 1H, CH-
(CH3)2], 3.14 (s, 3H, CH3S＝O), 1.42 [d, J＝7.2 Hz,
CH(CH3)2]; 13C NMR (CDCl3) δ: 180.44, 171.96, 170.44,
169.06, 118.39, 70.18, 63.72, 59.00, 43.28, 38.78, 34.78,
19.24, 18.83; HRMS (ESI) calcd for C14H20N4NaO4S2
(M＋Na)＋ 395.0818, found 395.0814.
General synthetic procedures for target compounds
10a— 10f
(E)-Ethoxyethyl 2-cyano-3-isopropyl-3-(5-methyl-
sulfonyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
(10e) Yield 89.8%. m.p. 98—99 ℃; 1H NMR (CDCl3)
δ: 10.86 (br, 1H, CH2NH), 5.12 (d, J＝6.7 Hz, 2H,
CH2NH), 4.31 (t, J＝5.1 Hz, 2H, OCH2), 3.70 (t, J＝5.1
Hz, 2H, CH2O), 3.58 (q, J＝7.0 Hz, 2H, OCH2CH3),
3.49 (s, 3H, CH3SO2), 3.18—3.21 [m, 1H, CH(CH3)2],
1.43 [d J＝7.1 Hz, 6H, CH(CH3)2], 1.21 (t, J＝7.0 Hz,
3H, OCH2CH3); 13C NMR (CDCl3) δ: 178.66, 171.84,
170.20, 169.28, 117.64, 72.95, 67.98, 66.84, 64.29, 43.02,
42.49, 30.50, 19.07, 15.13; HRMS (ESI) calcd for
C15H22N4NaO5S2 (M＋Na)＋ 425.0924, found 425.0919.
(E)-Ethoxymethyl 2-cyano-3-isopropyl-3-(5-methyl-
sulfonyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
To a mixture of compounds 7a—7f (3 mol) in 4 mL
of AcOH and 2 mL of H2O was added KMnO4 (4.0 mol)
in portions at 0 ℃. After the mixture was stirred at
room temperature for 2 h, 3 mL of saturated NaHSO3
(aq.) was added. The mixture was extracted with CH2Cl2.
The organic layer was dried over MgSO4, filtered and
concentrated in vacuo. The products were purified by
column chromatography on a silica gel to give the cor-
responding pure target compounds 10a—10f.
(Z)-Ethoxyethyl 2-cyano-3-methylthio-3-(5-methyl-
sulfonyl-1,3,4-thiadiazol-2-yl)methanaminoacrylate
(10a) Yield 87.20%. m.p. 79—80 ℃; 1H NMR
(CDCl3) δ: 10.58 (br, 1H, CH2NH), 5.29 (d, J＝6.4 Hz,
2H, CH2NH), 4.33 (t, J＝5.0 Hz, 2H, OCH2), 3.71 (t, J＝
5.0 Hz, 2H, CH2O), 3.57 (q, J＝7.0 Hz, 2H, OCH2CH3),
3.49 (s, 3H, CH3SO2), 2.76 (s, 3H, CH3S), 1.22 (t, J＝
7.0 Hz, 3H, OCH2CH3); 13C NMR (CDCl3) δ: 172.52,
171.50, 169.97, 167.58, 117.00, 78.37, 67.91, 66.86,
64.59, 43.92, 43.03, 18.69, 15.15. Anal. calcd for
C13H18N4O5S3: C 38.41, H 4.46, N 13.78; found C 38.20,
H 4.67, N 13.61.
1
(10f) Yield 90.6%. m.p. 78—79 ℃; H NMR (CDCl3)
δ: 10.85 (br, 1H, CH2NH), 5.14 (d, J＝6.4 Hz, 2H,
CH2NH), 4.31 (t, J＝4.8 Hz, 2H, OCH2), 3.66 (t, J＝4.8
Hz, 2H, CH2O), 3.49 (s, 3H, CH3SO2), 3.41 (s, 3H,
CH3O), 3.19—3.23 [m, 1H, CH(CH3)2], 1.42 [d, J＝7.2
Hz, 6H, CH(CH3)2]; 13C NMR (CDCl3) δ: 178.75, 171.80,
170.18, 169.22, 117.74, 72.69, 70.21, 63.99, 59.18, 43.02,
42.47, 30.46, 19.03; HRMS (ESI) calcd for C14H20N4Na-
O5S2 (M＋Na)＋ 411.0767, found 411.0769.
(Z)-Ethoxymethyl 2-cyano-3-methylthio-3-(5-
962
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 959— 967

Synthesis, Crystal Structure, and Herbicidal Activities of 2-Cyanoacrylates
X-ray diffraction
ranth pigweed (Amaranthus retroflexus) and rape (Bras-
sica napus L.), and two monocotyledonous weeds, al-
falfa (Medicago sativa L.) and hairy crabgrass [Digi-
taria sanguinalis (L.) Scop.] were used to test the herbi-
cidal activities of the compounds. The seeds of amaranth
pigweed were reproduced outdoors and stored at room
temperature. Seeds of alfalfa and rape were bought from
the Institute of Crop, Tianjin Agriculture Science
Academy.
Culture method The seeds were planted in 6 cm
diameter paper boxes containing artificial mixed soil.
Before plant emerged, the boxes were covered with
plastic film to retain moisture. Plants were grown in
green house. Fresh weight of the above ground tissues
was measured 10 d after treatment. Inhibition percent-
age was used to describe control efficiency of the com-
pounds.
The crystal structure of compound 7b was deter-
mined, and X-ray intensity data were record on a Bruker
SMART 1000CCD diffraction meter using graphite
monochromated Mo Kα radation (λ＝0.71073 Å). In the
range of 1.96°≤θ≤25.02°, 3055 independent reflec-
tions were obtained. All calculations were refined anis-
tropically. All hydrogen atoms were located from a dif-
ference Fourier map and were placed at calculated posi-
tions and were included in the refinements in the riding
mode with istropic thermal parameters (Figures 2, 3 and
Table 1).
Treatment The dosage (activity ingredient) for
each compound corresponded to 1.5 kg/ha. Purified
compounds were dissoved in 100 µL of N,N-dimethyl-
formamide with the addition of a little Tween 20 and
then were sprayed using a laboratory belt sprayer deliv-
ering a 750 L/ha spray volume. Compounds were
sprayed immediately after seed planting (preemergence
treament) or after the expansion of the first true leaf
(postemergence treatment). The mixture of same amount
of water, N,N-dimethylformamide, and Tween 20 was
sprayed as the control. Each treatment was tripilcated.
The activity numbers represented the percent displaying
herbicidal damage as compared to the control. The error
of the experiments was 2%.
Figure 2 Molecular structure of 7b in the crystal.
Results and discussion
Chemistry
The key intermediate [5-(methylthio)-1,3,4-thiadia-
zol-2-yl]methanamine (5) was synthesized starting from
readily available dimethyl sulfate and carbon disulfide as
shown in Scheme 1. Dimethyl sulfate was reacted with
carbon disulfide and hydrazine hydrate in the presence of
potassium hydroxide to give thiohydrazide 1,18 which was
subsequently reacted with chloroacetylchloride at the
temperature below －5 ℃ to obtain N-acylation inter-
mediate 2. Compound 2 was cyclized in 10% sodium
bicarbonate to provide (5-methylthio-1,3,4-thiadiazol-2-
Figure 3 Packing diagram of crystal 7b.
Herbicidal activity bioassay
The herbicidal activities of compounds 7a—7f, 9a—
9f and 10a—10f were evaluated using a previously re-
ported procedure.7,20
Plant Material Two dicotyledonous weeds, ama-
Table 1 Selected bond lengths (Å) and torsion angles (°) of crystal 7b
N(2)— C(3) 1.320(5) N(3)-C(5)-C(7)-C(8)
N(3)— C(4) 1.503(4) N(3)-C(5)-C(7)-C(9)
S(1)— C(1)
S(2)— C(2)
S(3)— C(5)
O(1)— C(9)
O(2)— C(9)
O(3)— C(11)
N(1)— N(2)
N(1)— C(2)
1.831(5)
1.770(4)
1.799(4)
1.229(4)
1.376(4)
1.434(4)
1.409(4)
1.334(5)
－
172.9(3)
8.9(5)
N(4)— C(8)
C(3)— C(4)
C(5)— C(7)
C(7)— C(8)
C(7)— C(9)
C(10)— C(11)
1.150(4)
1.514(5)
1.431(4)
1.446(5)
1.490(5)
1.523(5)
C(5)-C(7)-C(9)-O(1)
C(5)-C(7)-C(9)-O(2)
C(8)-C(7)-C(9)-O(1)
C(8)-C(7)-C(9)-O(2)
C(6)-S(3)-C(5)-C(7)
C(6)-S(3)-C(5)-N(3)
－ 9.8(5)
169.1(3)
171.9(3)
－
9.2(4)
－
131.3(3)
51.9(3)
Chin. J. Chem. 2011, 29, 959— 967
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963

Wang et al.
FULL PAPER
yl)methylchloride 3 in a higher yield of 78.9% com-
pared to the reported yield of 44.0%.19 The reaction of 3
with potassium phthalimide 4 (prepared according to the
published procedure21) gave intermediate N-substituted
phthalimide which was subsequently refluxed with hy-
drazine in ethanol to afford the corresponding
[5-(methylthio)-1,3,4-thiadiazol-2-yl]methanamine 5 in
one pot.
Intermediates 2-cyano-3,3-dimethylthioacrylates 6a,
6b were achieved by treating corresponding esters 8 with
carbon disulfide and 2 mol of dimethyl sulfate in a one
pot reaction using potassium hydroxide as alkali in good
yield according to the reported methods (Scheme 2).11
Intermediate (Z ＋ E)-2-cyano-3-methoxyacrylates
6c—6f were synthesized by treating esters 8 with the
corresponding acid chloride followed by methylation
with diazomethane in good yield according to the re-
ported methods (Scheme 3).11
β-unsaturated double bond to form a transition state in
which the orientation of thiadiazolemethylamino and
ester carbonyl is cis because of the presence of an in-
tramolecular hydrogen bonding. The configuration of
target compounds was kept with the loss of a mole of
the methylthio group (or methoxy) and was confirmed
by the X-ray single-crystal structure of 7b, the X-ray
data confirmed the Z sterochemistry of 7b and demon-
strated the presence of a planar core stablized by an in-
tramolecular hydrogen bond between the ester carbonyl
oxygen and the thiadiazolemethylamino hydrogen atom.
To further investigate the influence of polarity on
herbicidal activity, two other series of 2-cyanoacrylates
(9a—9f and 10a—10f) with higher polarity such as
sulfinyl or sulfonyl at the 5-position of 1,3,4-thiadiazole
were synthesized by using different oxidation methods
(m-CPBA, KMnO4) as shown in Scheme 5 and Scheme
6, respectively. All these target compounds were con-
1
1
The target compounds (7a—7f) were synthesized by
the reaction of methylamine 5 and 2-cyanoacrylates
(6a—6f) with high yields. This reaction was assumed to
go through a nucleophilic addition and elimination reac-
tion (Scheme 4).11 The methylamine attached the α,
firmed by H NMR and elemental analysis. The H
NMR (CDCl3) spectra of these target compounds all
have peaks between δ 10.30—10.80, which are the
characteristic peaks of NH in these target compounds.
Scheme 1
Scheme 2
Scheme 3
964
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Chin. J. Chem. 2011, 29, 959— 967

Synthesis, Crystal Structure, and Herbicidal Activities of 2-Cyanoacrylates
Scheme 4
Scheme 5
Scheme 6
Crystal structure analysis
and 3). The result showed that most of the compounds
(7c, 7d—7e, 9a—9e, 10a, 10e) showed higher herbi-
cidal activities in postemergence treatment than in
preemergence treatment. And in postemergence treat-
ment, most of the compounds (7c, 7e—7f, 9a—9f, 10a,
10d—10e) showed greater herbicidal activities againat
dicotyledonous weeds (rape and amaranth pigweed)
than monocotyledon weeds (alfalfa and hairy crabgrass).
The structure-activity relationship according to herbi-
cidal activities of compounds 7a—7f against rape and
amaranth pigweed in postemergence treatment (Table 2)
showed that a suitable isopropyl group (7e, 7f) at the
3-position of acrylates was essential for high herbicidal
activity. Compound 7e which contains ethoxyethyl at
the 3-position showed 100% herbicidal activities against
dicotyledonous weeds (rape and amaranth pigweed) at
1.5 kg/ha. Compound 7f which contains ethoxymethyl
at the 3-position showed the same herbicidal activities
(98.0%) against dicotyledonous weed (rape). At the
rates of 0.6 and 0.3 kg/ha (Table 3), compound 7e still
exhibited excellent herbicidal activities, respectively.
Decreasing of herbicidal activities was observed
when methylthio of 1,3,4-thiadizole was replaced by
sulfinyl or sulfonyl (Table 2, compounds 9a—9f, 10a—
10f), suggesting that introduction of substituent with
higher polarity such as sulfinyl or sulfonyl to the
5-position of 1,3,4-thiadiazole decreased herbicidal ac-
tivities.
Compound 7b was recrystalized from ethyl acetate to
give colorless crystals suitable for X-ray single-crystal
diffraction with the following crystallographic parame-
ters: a＝7.972(9) Å, b＝14.171(16) Å, c＝15.293(17) Å,
－1
α＝90.00°, β＝90.00°, γ＝90.00°, µ＝0.445 mm , V＝
1728(3) Å3. There are four molecules in the unit cell and
the space group P21/c, z＝4, Dx＝1.386 mg/m3, F(000)
＝752, T＝294 (2) K, 1.96°≤θ≤25.02°; and the final R
factor, R1＝0.0485, wR2＝0.1211.
It could be seen from the X-ray single-crystal analy-
sis that amino and carbonyl are of the same side of the
vinyl, and there are intramolecular hydrogen bond be-
tween the nitrogen atom and oxygen of the carbonyl
(Figures 2, 3). The bond length of C(5)—C(7) (1.431 Å)
is longer than normal C＝C (1.34 Å), the bond lengths
of C(7)—C(8) (1.446 Å) and C(7)—C(9) (1.490 Å) are
shorter than normal C—C (1.54 Å), the bond length of
C(9)—O(1) (1.229 Å) is shorter than normal C＝O
(1.34 Å), the bond length of C(9)—O(2) (1.376 Å) is
shorter than normal C—O (1.44 Å) , the bond length of
C(5)—N(3) (1.349 Å) is shorter than normal C—N sin-
gle bond (1.49 Å), which suggest that the electron den-
sity is localized among N(3)-C(5)-C(7)-C(9)-O(1) and
O(2) (Table 1).
Herbicidal activities
Many papers have reported that cyanoacrylates con-
taining heterocycles such as furan, tetrahydrofuran, thi-
azole, pyridine showed good herbicidal avtivi-
ties.10,11,22,23 To further amplify the interaction of
cyanoacrylates with the lipophilic binding domain, we
introduced 1,3,4-thiadiazole to the cyanoacrylates, and
their herbicidal activities have been evaluated (Tables 2
Conclusions
In summary, three series of novel 2-cyanoacrylates
containing 1,3,4-thiadiazole moieties which were sub-
stituted in 5-position by different polarity substituents
Chin. J. Chem. 2011, 29, 959— 967
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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965

Wang et al.
FULL PAPER
Table 2 Herbicidal activities of target compounds 7a— 7f, 9a— 7f and 10a— 10f (1.5 kg/ha, percent inhibition/%)
Postemergency treatment
Amaranth pigweed Alfalfa Hairy crabgrass
Preemergency treatment
Rape Amaranth pigweed Alfalfa Hairy crabgrass
Compound
Rape
7a
7b
7c
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
66.2
25.7
100.0
0
15.0
0.7
0
0
49.1
20.0
86.6
98.0
0
0
0
0
7d
7e
0
40.0
5.0
0
0
0
0
100.0
66.2
26.7
16.8
8.9
24.8
18.8
0
0
0
5.0
0
7f
0.7
5.8
4.2
8.9
0
40.0
0
0
9a
12.1
14.1
23.7
6.3
5.0
5.0
10.0
0
10.0
5.0
5.0
0
0
9b
9c
0
0
0
0
0
10.0
5.0
10.0
33.3
0
9d
9e
0
0
15.2
26.3
20.0
0
9.7
0
5.0
5.0
0
2.7
23.0
0
0
5.0
0
9f
0
10a
10b
10c
10d
10e
10f
10.0
0
5.0
0
0
0
0
0
0
0
0
0
0
20.0
0
15.0
0
30.1
37.2
0
0
0
0
20.6
32.5
25.7
0
12.5
5.0
0
0
0
0
5.0
33.1
0
0
16.1
14.0
0
0
51.5
5.0
Table 3 High hebicidal activities of compounds 7e and 7f (percent inhibition/%)
Postemergency treatment
Amaranth pigweed
1
Compound
Dose/(g•ha－
)
Rape
95
600
300
600
300
100
73.1
77.9
0
7e
7f
74.2
43.2
20.1
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