Synthesis and Herbicidal Activity of (Z)-Ethoxyethyl 2-Cyano-3-(2-methylthio-5-pyridylmethylamino)acrylates

Article abstract of DOI:10.1002/hc.10214

2-Methylthio-5-pyridinemethylene amine was prepared from 2-chloro-5-methylpyridine. Ethoxyethyl 2-cyano-3,3-dimethylthioacrylate was prepared from ethoxyethyl cyanoacetate, carbon disulfide, and dimethyl sulfate in 86.2% yield. Its reaction with 2-methylthio-5-pyridinemethylene amine yielded (Z)-ethoxyethyl 2-cyano-3-methylthio-3-(2-methylthio-5-pyridylmethylamino)acrylate. Ethoxyethyl (Z+E)-2-cyano-3-ethoxyacrylate was synthesized from ethoxyethyl 2-cyanoacetate and triethyl orthoacetate in 90.7% yield, and its reaction with 2-methylthio-5-pyridinemethylene amine yielded (Z)-ethoxyethyl 2-cyano-3-methyl-3-(2-methylthio-5-pyridylmethylamino)acrylate. The structures of all of the products were confirmed by ¹H NMR, elemental analysis, IR, and mass spectroscopy. The herbicidal activities of the products were evaluated, and the results of bioassay showed that (Z)-ethoxyethyl 2-cyano-3-methyl-3-(2-methylthio-5-pyridylmethylamino) acrylate exhibits good herbicidal activity on rape (Brassica napus) at a dose of 1.5 kg/ha.

Full text of DOI:10.1002/hc.10214

Heteroatom Chemistry
Volume 15, Number 1, 2004
S
ynthesis and Herbicidal Activity of
(
Z )-Ethoxyethyl 2-Cyano-3-(2-methylthio-
5-pyridylmethylamino)acrylates
Qing Min Wang, Hui Kai Sun, and Run Qiu Huang
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
Received 18 May 2003
INTRODUCTION
ABSTRACT: 2-Methylthio-5-pyridinemethylene
amine was prepared from 2-chloro-5-methylpyridine.
Ethoxyethyl 2-cyano-3,3-dimethylthioacrylate was
prepared from ethoxyethyl cyanoacetate, carbon
disulfide, and dimethyl sulfate in 86.2% yield. Its re-
action with 2-methylthio-5-pyridinemethylene amine
yielded (Z)-ethoxyethyl 2-cyano-3-methylthio-3-(2-
methylthio-5-pyridylmethylamino)acrylate. Ethoxy-
ethyl (Z+E)-2-cyano-3-ethoxyacrylate was synthesized
from ethoxyethyl 2-cyanoacetate and triethyl or-
thoacetate in 90.7% yield, and its reaction with 2-
methylthio-5-pyridinemethylene amine yielded (Z)-
ethoxyethyl 2-cyano-3-methyl-3-(2-methylthio-5-pyri-
dylmethylamino)acrylate. The structures of all of
Cyanoacrylates have been the subject of intense in-
terest for past decades as one kind of herbicides that
disrupt photosynthetic electron transportation at
a common binding domain on the 32 kD polypeptide
of the photosystem II (PSII) reaction center [1–3]
Among these cyanoacrylates, (Z)-ethoxyethyl 2-
cyano-3-(4-chloro-phenyl)methylamino-3-isopropyl-
acrylate (CPNPE) exhibits the highest Hill inhibitory
activity yet reported [4–6].
In our previous work about synthesis of (Z)-ethyl
2-cyano-3-methylthio-3-(2-chloro-5-pyridylmethyla-
mino)acrylate as one kind of pesticides, we found
that this compound showed some insecticidal ac-
tivity and excellent herbicidal activity [7–8], which
could kill more than 90% of rape (Brassica napus)
even at 150 g/ha and had a promising future to be
developed. At the same time, we noticed that this
compound was one analogue of cyanoacrylate that
encouraged us to introduce 2-methylthio-5-pyridine
heterocycle into 2-cyanoacrylate. So we synthesized
a series of new (Z)-ethoxyethyl 2-cyano-3-(2-methyl-
thio-5-pyridylmethylamino)acrylates and hoped to
screen compounds with higher herbicidal activity.
1
the products were confirmed by H NMR, ele-
mental analysis, IR, and mass spectroscopy. The
herbicidal activities of the products were eval-
uated, and the results of bioassay showed that
(
Z)-ethoxyethyl 2-cyano-3-methyl-3-(2-methylthio-5-
pyridylmethylamino)acrylate exhibits good herbicidal
activity on rape (Brassica napus) at a dose of 1.5 kg/ha.
ꢀ
7
C
2003 Wiley Periodicals, Inc. Heteroatom Chem 15:67–
0, 2004; Published online in Wiley InterScience
(
www.interscience.wiley.com). DOI 10.1002/hc.10214
RESULTS AND DISCUSSION
Correspondence to: Run Qiu Huang; e-mail: wang98h@263.net.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20272030.
c 2003 Wiley Periodicals, Inc.
2-Methylthio-5-pyridinemethylene amine (6) was
prepared from 2-chloro-5-methylpyridine as shown
in Scheme 1. 2-Chloro-5-methylpyridine was treated
with potassium permanganate to give 2-chloro-5-
ꢀ
6
7

6
8 Wang, Sun, and Huang
H
N
KMnO4
Cl
CH3
Cl
Cl
CO H
CH2
CH3S
CH3S
H
O
C
2
CH3S
N
N
6
+ 8
N
9
1
2 4 2 5
OC H OC H
S
O
SOCl2
NH3.H2O
CN
H2NCNH2
CNH2
N
O
2
SCHEME 3
+
N H2
-
NaOH CH3CO2H
Cl C
S
CNH2
N
3
NH2
O
O
presence of an intramolecular hydrogen bonding.
The configuration of target compounds was kept
with loss of a mole of methylthio group (or ethoxy
as shown in Scheme 4) and was confirmed by the
X-ray single crystal structure of a similar compound
synthesized by our research group [9].
CH3I
HS
CNH2
CH3S
N
CNH2
N
4
5
LiAlH4
CH3S
CH2NH2
6
N
Ethoxyethyl (Z + E)-2-cyano-3-ethoxyacrylate
SCHEME 1
(
11) was synthesized from ethoxyethyl 2-cyanoace-
tate (10) and triethyl orthoacetate in 90.7% yield.
Its reaction with 6 yielded (Z)-ethoxyethyl 2-cyano-
pyridinecarboxylic acid (1), and subsequent reaction
with thionyl chloride and aqueous ammonia yielded
3
-methyl-3-(2-methylthio-5-pyridylmethylamino)-
acrylate (12) as shown in Scheme 4. The structures
2-chloro-5-pyridinecarboxamide (2) in overall 86.2%
1
of all of the products were confirmed by H NMR,
yield. Compound 2 was reacted with thiourea to ob-
tain S-(5-carbamyl-2-pyridyl)thiouronium chloride
elemental analysis, IR, and mass spectroscopy.
(3), and further hydrolysis provided 2-mercapto-
5
-pyridinecarboxamide (4). Compound 4 was re-
BIOLOGICAL ACTIVITY
acted with iodomethane to give 2-methylthio-5-
pyridinecarboxamide (5), and its reduction with
lithium aluminum hydride yielded 2-methylthio-5-
pyridinemethanamine (6).
The herbicidal activities of the title compounds 9
and 12 and the reported compound CPNPE were
evaluated using a previously reported procedure [10,
11]. Dosage for each compound is 1.5 kg/ha. Pu-
rified compounds were dissolved in 100 ꢂl N,N-
dimethylformamide with the addition of a little
Tween 20, and then were sprayed using a labora-
tory belt sprayer delivering at 750 l/ha spray-volume.
Compounds were sprayed when the first leave was
expanding. The results of biological assay are given
in Table 1.
Ethoxyethyl 2-cyano-3,3-dimethylthioacrylate
(
8) was prepared from ethoxyethyl cyanoac-
etate, carbon disulfide, and dimethyl sulfate in
6.2% yield. Its reaction with 6 yielded (Z)-
ethoxyethyl 2-cyano-3-methylthio-3-(2-methylthio-
-pyridylmethylamino)acrylate (9) as shown in
8
5
Scheme 2. This reaction was assumed to go through
a nucleophilic addition and elimination reaction
as shown in Scheme 3. The amine attached to the
The results of biological assay given in Table 1
show that the title compound 12 exhibited good her-
bicidal activity on rape (Brassica napus) at a dose of
1.5 kg/ha.
ꢀ
,ꢁ-unsaturated double bond to form a transition
state in which the orientation of pyridinemethy-
lamino and ester carbonyl is the cis because of the
O
O
AcOH
NCCH2COC2H4OC2H5
+
3 2 5 3
CH C(OC H )
NCCH2C OC2H4OC2H5
+
CS2
+
3 2 4
(CH ) SO
1
0
7
O
C
O
6
C2H5O
CH3
OC2H4OC2H5
KOH
CH3S
CH3S
COC2H4OC2H5
6
CH3CN
8
CN
CN
11
H
O
H
O
CH3S
CH2N
COC2H4OC2H5
CH S
CH2N
2 4 2 5
COC H OC H
3
N
N
CH3S
CN
9
CH3
CN
12
SCHEME 2
SCHEME 4

Synthesis and Herbicidal Activity of (Z )-Ethoxyethyl 2-Cyano-3-(2-methylthio-5-pyridylmethylamino)acrylates 69
TABLE 1 Herbicidal Activities of the Title Compounds 9 and
drofuran (30 ml) was added lithium aluminum hy-
dride (0.24 g, 7.3 mmol). Then the mixture was
heated under reflux for 12 h and cooled. Cool water
1
2, and the Reported Compound CPNPE (1.5 kg/ha)
Postemergency Treatment
(1.0 g) was added to the solution carefully. The mix-
Alfalfa
Amaranth Pigweed
Rape
ture was stirred for another 30 min and solvent was
evaporated under reduced pressured. The residue
was used for further operations without purification.
9
1
56.5
0
28.1
14.3
39.6
93.9
29
98.4
96.5
2
CPNPE
2-Cyano-3,3-dimethylthioacrylate (8)
EXPERIMENTAL
To a mixture of potassium hydroxide powder (2.24 g,
4
5
0 mmol) and anhydrous acetonitrile (30 ml) under
C was added dropwise compound 7 (20 mmol). The
All reactions were carried out under a nitrogen at-
mosphere with the exclusion of moisture. Proton
NMR spectra were obtained at 200 MHz using a
Bruker AC-P 200 spectrometer. Chemical shift values
◦
mixture was stirred for 0.5 h and then a solution of
carbon disulfide (1.50 g, 20 mmol) in anhydrous ace-
tonitrile (5 ml) was added over about 10 min. The
reaction mixture was stirred for 3 h at room temper-
(δ) are given in ppm. Infrared spectra were recorded
on a Shimadzu-435 spectrometer. Elemental analy-
ses were determined on an MT-3 elemental analyzer.
Melting points were taken on a Thomas–Hoover
melting point apparatus and are uncorrected. Mass
spectra were recorded with HP 5988A spectrometer
using the EI method. Column chromatographic pu-
rification was carried out by using silica gel.
◦
ature. After the solution was cooled to 4 C, dimethyl
sulfate (5.04 g, 40 mmol) was added and the reac-
tion was over in 4 h. The solvent was removed off
under reduced pressure and then water (25 ml) and
ethyl acetate (50 ml) were added to the residue. The
organic layer was separated and dried by anhydrous
magnesium sulfate. Ethyl acetate was evaporated to
◦
afford corresponding 8. Yield: 86.2%, m.p. 32–34 C.
2-Chloro-5-pyridinecarboxylic Acid (1)
A mixture of potassium permanganate (36.42 g,
(
Z)-Ethoxyethyl 2-Cyano-3-methylthio-3-(2-
methylthio-5-pyridylmethylamino)acrylate
9)
2
5
30.5 mmol), distilled water (350 ml), and 2-chloro-
-methylpyridine (12.0 g, 94.1 mmol) was stirred and
(
refluxed for 5 h. Then the solid was filtered off and
the filtrate was concentrated under vaccum to 50 ml.
Aqueous hydrochloric acid (15 ml) was added to give
a white solid (9.04 g). The solid was then recrystal-
A mixture of intermediates 8 (5 mmol), 6 (6 mmol),
and ethanol (12 ml) was refluxed for 3 h and con-
centrated under reduced pressure to give a crude
product. The product was purified by vacuum col-
umn chromatography on a silica gel to obtain yellow
liquid. Yield: 18.2% (yield from 5). H NMR (CDCl
lized to obtain a colorless crystalline solid 1. Yield:
◦
6
0.1%, m.p. 188–190 C.
1
3
)
2
-Chloro-5-pyridinecarboxamide (2)
δ 1.13 (t, 3H, C CH
3
), 2.50 (s, 3H, Py SCH
3
), 2.60 (s,
3
4
H, CSCH
.21 (t, 2H, CO
N), 10.2 (s, 1H, NH). Anal. Found: C,
2.29; H, 5.71; N, 11.46. Calcd for C16 : C,
3
), 3.49 (q, 2H, OCH
2
), 3.61 (t, 2H, CH O),
2
A mixture of 1 (8.31 g, 52.8 mmol) and distilled
thionyl chloride (9.42 g) was refluxed for 15 h, and
evaporated in vacuo to dryness. The residue was dis-
solved in toluene (30 ml) and added to aqueous am-
monia (50 ml). Then the reaction mixture was stirred
at room temperature for 8 h and filtered to give a
white solid. The solid was then recrystallized from
2
CH
2
), 4.65 (d, 2H, CH N), 7.14–8.30
2
(m, 3H, C
5
H
3
5
5
1
H
21
N
3
O
3
S
2
−
1
2.34; H, 5.77; N, 11.44. IR (KBr, cm ): 3446, 2200,
653, 1593, 1566, 1468, 1275, 1251, 1118, 1052. EI
+
MS: m/z (%) 295 (M , 3.7), 138 (100).
distilled water to obtain a colourless crystalline solid
◦
2
(7.15 g). Yield: 86.2%, m.p. 211–213 C (lit. ref. [12],
(
Z + E)-2-Cyano-3-ethoxyacrylate 11
A mixture of ethoxyethyl 2-cyanoacetate (10) (8.0 g,
8.4 mmol), triethyl orthoacetate (61.6 mmol), and
◦
m.p. = 211 C).
Intermediates 3–5 were synthesized according to
the reported procedure [12].
4
acetic acid (0.15 g, 2.5 mmol) was heated under re-
flux for 2.5 h and the solvent was then removed off
under reduced pressure to afford a yellow oil, which
was purified by column chromatography using a sil-
ica gel. Colorless liquid was obtained. Yield: 90.7%.
2
-Methylthio-5-pyridinemethanamine (6)
To a suspension of 2-methylthio-5-pyridinecarbo-
xamide (5) (0.4 g, 2.4 mmol) and anhydrous tetrahy-

7
0 Wang, Sun, and Huang
(
(
Z)-Ethoxyethyl 2-Cyano-3-methyl-3-
2-methylthio-5-pyridylmethylamino)-
[2] McFadden, H. G.; Craig, D. C.; Huppatz, J. L.;
Phillips, J. N. Naturforsch 1991, 46C, 93–
8.
3] McFadden, H. G.; Phillips, J. N. Z Naturforsch 1990,
5C, 196–202.
4] Phillips, J. N.; Banham, W. K. Z Naturforsch 1993,
8C, 132–135.
5] Huppatz, J. L. Weed Sci 1996, 44, 743–748.
Z
9
acrylate (12)
[
[
[
4
A mixture of intermediates 11 (6 mmol), 6 (6 mmol),
and ethanol (15 ml) was heated under reflux for 2 h.
The solvent was removed under reduced pressure
to afford a crude product. The product was purified
by vacuum column chromatography on a silica gel
4
[6] Phillips, J. N.; Huppatz, J. L. Z Naturforsch 1987, 42C,
684–689.
[
7] Zhao, Y.; Liu, X.; Huang, R.; Cheng, M.;
to give a yellow liquid. Yield: 20.6% (yield from 5).
Li, Z. Nongyao xue Xuebao 1999, 1, 93–
1
H NMR (CDCl
CCH ), 2.52 (s, 3H, Py SCH
.63 (t, 2H, CH O), 4.22 (t, 2H, CO
CH N), 7.18–8.31 (m, 3H, C N), 10.1 (s, 1H, NH).
Anal. Found: C, 57.30; H, 6.14; N, 12.47. Calcd for
S: C, 57.28; H, 6.32; N, 12.53.
3
) δ 1.15 (t, 3H, C CH
), 3.51 (q, 2H, OCH
CH ), 4.45 (d, 2H,
3
), 2.27 (s, 3H,
9
5(Ch).
3
3
2
),
[
8] Liu, X.; Huang, R.; Cheng, M.; Zhao, Y.; Li, Z. Chem
J Chin Univ 1999, 20(19), 1404.
3
2
2
2
H
3
[9] Cao, H.; Li, Z.; Sun, H.; Wang, Q.; Huang, R. Chin J
Struct Chem 2002, 21(3), 241–244.
10] (a) Kluth, J.; Santel, H. J.; Schmidt, R. R. Eur US
Patent 4 832 733, 1989 (Bayer AG); (b) Kluth, J.;
Santel, H. J.; Schmidt, R. R. Eur Patent 0 241 826,
2
5
[
[
C
16
H
21
N
3
O
3
1
987 (Bayer AG).
11] Sun, H.; Wang, Q.; Huang, R.; Li, H.; Li, Y. J
Organomet Chem 2002, 655, 182.
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