Synthesis and herbicidal activity of 2-cyano-3-(2-fluoro-5-pyridyl) methylaminoacrylates

Article abstract of DOI:10.1016/j.jfluchem.2004.12.015

A series of 2-cyano-3-(2-fluoro-5-pyridyl)methylaminoacrylates were synthesized as herbicidal inhibitors of photosystem II (PSII) electron transport. 2-Fluoro-5-pyridinemethylamine was prepared from 2-amino-5- methylpyridine, subsequent reaction with 2-cyano-3,3-dimethylthioacrylates or 2-cyano-3-methoxyacrylates to yield these title compounds. All of these compounds were confirmed by ¹H NMR, IR, mass spectrum and elemental analyses. Their herbicidal activities were evaluated. All of the title compounds showed excellent herbicidal activities to amaranth pigweed and rape in post-emergence treatment. At the rate of 150 g/ha, one compound exhibited similar activity to Cl-analogue. The replacement of chlorine by fluorine group showed the same herbicidal activity.

Full text of DOI:10.1016/j.jfluchem.2004.12.015

Journal of Fluorine Chemistry 126 (2005) 345–348
www.elsevier.com/locate/fluor
Synthesis and herbicidal activity of
-cyano-3-(2-fluoro-5-pyridyl)methylaminoacrylates
2
*
Yuxiu Liu, Qiqi Zhao, Qingmin Wang , Heng Li, Runqiu Huang, Yonghong Li
State Key Laboratory of Elemento-organic Chemistry, Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, PR China
Received 28 October 2004; received in revised form 14 December 2004; accepted 15 December 2004
Available online 25 February 2005
Abstract
A series of 2-cyano-3-(2-fluoro-5-pyridyl)methylaminoacrylates were synthesized as herbicidal inhibitors of photosystem II (PSII)
electron transport. 2-Fluoro-5-pyridinemethylamine was prepared from 2-amino-5-methylpyridine, subsequent reaction with 2-cyano-3,3-
1
dimethylthioacrylates or 2-cyano-3-methoxyacrylates to yield these title compounds. All of these compounds were confirmed by H NMR,
IR, mass spectrum and elemental analyses. Their herbicidal activities were evaluated. All of the title compounds showed excellent herbicidal
activities to amaranth pigweed and rape in post-emergence treatment. At the rate of 150 g/ha, one compound exhibited similar activity to Cl-
analogue. The replacement of chlorine by fluorine group showed the same herbicidal activity.
#
2005 Elsevier B.V. All rights reserved.
Keywords: 2-Cyanoacrylates; 2-Fluoro-5-pyridylmethylamine; Herbicidal activity
1
. Introduction
[4–6]. Bayer AG reported compound C, but little information
was given on herbicidal activity [7]. In previous work [8,9] we
reported that D showed excellent herbicidal activity, control-
ling more than 95% of rape (Brassicanapus) at 1.5 kg/ha.
Many examples demonstrated that the introduction of
fluorine into certain pesticide molecular could improve its
bioactivity [10–14]. In this paper, structure D is modified by
replace of chlorine with fluorine atom, with the intention of
getting higher herbicidal activity. Here the synthesis and
herbicidal activities of these 2-cyano-3-(2-fluoro-5-pyri-
dyl)methylaminoacrylates are reported.
The herbicidal activity of cyanoacrylates has been the
subject of intense interest for past decades [1–3]. A detailed
study of compounds with general structure A revealed that
cyanoacrylatesareinhibitorsofphotosystemII(PSII)electron
transport, which inhibits the growth of weeds by disrupting
photosynthetic electron transport at a common binding
domain on the 32 kDa polypeptide of the PSII reaction center.
Among these cyanoacrylates, the compound B exhibits the
highest inhibitory activity of the Hill reaction yet reported
*
Corresponding author. Tel.: +86 22 23 504 229; fax: +86 22 23 503 438.
E-mail address: wang98h@263.net (Q. Wang).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.12.015

346
Y. Liu et al. / Journal of Fluorine Chemistry 126 (2005) 345–348
Scheme 1.
Scheme 2.
2
. Results and discussion
2.2. Biological activities
2
.1. Synthesis
The herbicidal activities of the compounds 8a–d were
evaluated using the previously reported procedure [9,22].
Their herbicidal activities are summarized in Tables 1 and 2.
All of the compounds 8a–d showed excellent herbicidal
activities to amaranth pigweed and rape in post-emergence
treatment. The compounds 8a–d had higher herbicidal
activity to alfalfa than Cl-analogue D in pre-emergence
treatment. At the rate of 150 g/ha, the compounds 8a–d still
2
-Fluoro-5-pyridylmethylamine (5) was prepared from 2-
amino-5-methylpyridine (1) (Scheme 1) [15]. Aminopyridine
was treated with fluoroboric acid and sodium nitrite to give
-fluoro-5-methylpyridine (2) with respect to Schiemann
reaction [16]. Bromination of 2 with N-bromosuccinimide in
refluxing carbon tetrachloride afforded 2-fluoro-5-bromo-
methylpyridine (3) by using benzoyl peroxide or azodiiso-
butyronitrile as irrigator [17,18]. After workup the reaction
solutionas described intheliterature, yellow oil was obtained.
1
2
1
GC-detection and H NMR showed this oil contained 2-
fluoro-5-bromomethylpyridine (67%), unreacted 2-fluoro-5-
methylpyridine (15%) and dibromide of 2-fluoro-5-methyl-
pyridine (18%). Since 2-fluoro-5-bromomethylpyridine (3) is
irritant to eyes and skin, 3 was not purified. Crude 3 was
treated with potassium phthalimide to afford N-(2-fluoro-5-
pyridylmethyl)phthalimide (4), which was then converted to
Scheme 3.
Table 1
Herbicidal activities of products 8a–d (1.5 kg/ha)
Post-emergence treatment
Pre-emergence treatment
2
-fluoro-5-pyridylmethylamine (5) by hydrazine cleavage
19–21].
Cyanoacrylates 7 were synthesized from ethoxyethyl 2-
cyanoacetate 6 according to the reporting method (Scheme
[
Alfalfa
Amaranth
pigweed
Rape
Alfalfa
Amaranth
pigweed
Rape
8a
98.7
73.6
78.7
100
100
100
100
100
100
100
100
100
52.8
61.8
70.7
72.0
75.0
92.8
92.8
94.6
73.8
63.1
73.2
97.0
8
8
8
b
c
d
2
) [9,22].
Intermediates 7 were reacted with 2-fluoro-5-pyridyl-
methylamine (5) in refluxing ethanol to give the target
compounds 8 (Scheme 3).
D
89.1
100
100
19.1
12.5
35.7

Y. Liu et al. / Journal of Fluorine Chemistry 126 (2005) 345–348
347
Table 2
peroxide (0.7 g) and carbon tetrachloride (200 mL) was
refluxed for 2 h. After cooling, the precipitate was filtered
and the filtrate was washed with water and dried. Finally, the
solvent was distilled off to give crude 2-fluoro-5-bromo-
Herbicidal activities of products 8 against rape (post-emergence treatment)
(150 g/ha)
8
8
8
8
a
b
c
61.5
61.9
63.9
88.1
90.9
1
methylpyridine (30.1 g, purity 67% analysis from GC. H
3
NMR (CDCl ) d 4.40 (s, 2H, CH ), 6.87 (dd, J = 8.1 Hz,
d
3
2
HH
3
D
JHF = 3.1 Hz, 1H, pyridine), 7.80–7.76 (m, 1H, pyridine),
.16 (s, 1H, pyridine).
8
gave a good herbicidal activity, especially 8d exhibited
similar activity to D. The replacement of chlorine by fluorine
3.3. Synthesis of N-(2-fluoro-5-pyridylmethyl)phthalimide
(4)
1
group showed the same herbicidal activity. When R = i-Pr,
the compounds 8d exhibited better activities than other
compounds 8a–c to rape, which indicated a suitable group at
the 3-position of acrylate was essential for high herbicidal
activity.
To a solution of crude 2-fluoro-5-bromomethylpyridine
(10.4 g, purity 67%, 0.037 mol) in N,N-dimethylformamide
(25 mL) was added potassium phthalimide (9.25 g,
0.05 mol) in a small portion. The mixture was stirred at
room temperature for 5 h, and then water (50 mL) was
added. The precipitate was collected by filtration and
washed with water. Recrystallization of the crude product
3
. Experimental
from ethanol gave white crystal in 59% yield (calculated on
1
All of the reactions were carried out under a nitrogen
2-fluoro-5-methylpyridine, 7.53 g) mp 157–159 8C.
H
NMR (CDCl ) d 4.85 (s, 2H, CH ), 6.89 (dd, J = 8.4 Hz,
3
3 2 HH
atmosphere with the exclusion of moisture. Proton NMR
spectra were obtained using a Bruker AC-P 300 spectro-
meter. Chemical shift values are given in ppm and downfield
from internal tetramethylsilane. Infrared spectra were
recorded on a Shimadzu-435 spectrometer. Elemental
analyses were determined on an MT-3 elemental analyzer.
Melting points were taken on a Thomas-Hoover melting
point apparatus and were uncorrected. Mass spectra were
recorded with HP 5988A spectrometer using the EI method.
3
JHF = 2.9 Hz, 1H, pyridine), 7.94–7.90 (m, 1H, pyridine),
8.34 (s, 1H, pyridine), 7.73–7.88 (m, 4H, benzene); Anal.
Calcd. for C H FN O : C, 65.62; H, 3.54; N, 10.93. Found:
2 2
1
4
9
C, 65.50; H, 3.46; N, 10.78.
3.4. Synthesis of 2-fluoro-5-pyridylmethylamine (5)
To a suspension of N-(2-fluoro-5-pyridylmethyl)phtha-
limide (10.2 g, 0.04 mol) in 95% ethanol (40 mL) was
added hydrazine hydrate (2.25 g, 0.04 mol). The reaction
mixture was refluxed for 5 h, and then cooled to 0 8C,
acidified to pH = 2–3 with 36% aqueous hydrochloric acid,
and refluxed again for 30 min. The precipitated N,N-
phthaloylhydrazine was filtered and washed with water,
and then the combined solution was alkalized to pH 12–13
with 25% sodium hydroxide and extracted with chloroform
(3 mL Â 20 mL). The combined organic layer was dried
over anhydrous magnesium sulfate, filtered and distilled
3
.1. Synthesis of 2-fluoro-5-methylpyridine (2)
-Amino-5-methylpyridine (70 g, 0.48 mol) was dis-
2
solved in 40% fluoroboric acid (290 mL) at À10 8C. Sodium
nitrite (46 g, 0.66 mol) was added slowly, in a small portion,
so as not to allow the temperature to rise above 0 8C. The
reaction mixture was stirred at 0 8C for 30 min and then
warmed to 50 8C for 30 min. Sodium carbonate was added to
make the solution alkaline. The mixture was steam distilled
until the distillate was no longer cloudy. The yellowish oil
that separated from the water layer was separated and the
water layer was extracted with ethyl ether (3 mL Â 50 mL).
The ether extracts and oil layer were combined, dried with
sodium sulfate and the solvent was removed in vacuo. The
remaining residue was distilled to give 2-fluoro-5-methyl-
under reduced pressure to give a colorless liquid in 44%
1
yield (2.21 g) bp 63–65 8C/75 Pa. H NMR (CDCl ) d 1.48
3
3
(s, 2H, NH ), 3.83 (s, 2H, CH N), 6.84 (dd, J = 8.2 Hz,
2
2
HH
3
JHF = 3.0 Hz, 1H, pyridine), 7.75–7.71 (m, 1H, pyridine),
8.08 (s, 1H, pyridine). n2 = 1.5131. IR (oil, cm ) 3371,
7
À1
D
3299, 1597, 1484, 1399, 1245, 826. EI-MS m/e (100%):
+
126.1 (M , 100).
pyridine as a colorless oil in 45% yield (32.4 g) having a
1
boiling point of 52–557 8C/2 mmHg. H NMR (CDCl ) d
3
3
.29 (s, 3H, CH ), 6.80 (dd, JHH = 8.3 Hz, J = 3.0 Hz,
2
3.5. Ethoxyethyl 2-cyanoacetate (6), 2-cyano-3,3-
dimethylthioacrylates (7a) and (Z + E)-2-cyano-3-
methoxyacrylates (7b–d)
3
HF
1H, pyridine), 7.56–7.54 (m, 1H, pyridine), 7.99 (s, 1H,
pyridine).
3
.2. Synthesis of 2-fluoro-5-bromomethylpyridine (3)
A mixture of 2-fluoro-5-methylpyridine (16.65 g, 0.15
mol), N-bromosuccinimide (26.7 g, 0.15 mol), benzoyl
Ethoxyethyl 2-cyanoacetate (6), 2-cyano-3,3-dimethy-
lthioacrylates (7a) and (Z + E)-2-cyano-3-methoxyacrylates
(7b–d) were synthesized according to the reporting method
[9,15].

348
Y. Liu et al. / Journal of Fluorine Chemistry 126 (2005) 345–348
3.6. General synthetic procedures for target
compounds 8a–d
3.6.4. Ethoxyethyl 2-cyano-3-isopropyl-3-(2-fluoro-5-
pyridyl)methylaminoacrylate (8d)
Ethoxyethyl 2-cyano-3-isopropyl-3-(2-fluoro-5-pyridyl)-
1
The mixture of intermediates 7 (5 mmol), 2-fluoro-5-
pyridylmethylamine (5) (6 mmol), and ethanol (12 mL) was
refluxed for 3 h, and then evaporated under reduced pressure
to give crude products 8. The product was purified by
vacuum column chromatography on silica gel using ethyl
acetate and petroleum ether as the eluent.
methylaminoacrylate (8d). Yield, 35%; mp, 95–97 8C. H
3
) d 1.13 (t, JHH = 6.9 Hz, 3H, CH
NMR (CDCl
3
), 1.33 (d,
3
3
J
(q, J = 6.9 Hz, 2H, OCH ), 3.62(t, J = 4.9 Hz, 2H,
= 7.5 Hz, 6H, C(CH ) ), 3.18–3.05 (m, 1H, CH), 3.50
3 2
HH
3
3
HH
2
HH
3
CH O), 4.21(t, JHH = 4.9 Hz, 2H, CO CH ), 4.56(d,
2
2
2
3
3
JHH = 6.1 Hz, 2H, CH N), 6.93 (dd, JHH = 8.2 Hz,
JHF = 3.2 Hz, 1H, pyridine), 7.62–7.67 (m, 1H, pyridine),
2
3
8
.09 (s, 1H, pyridine), 10.49 (s, 1H, NH); Anal. Calcd. for
: C, 60.88; H, 6.61; N, 12.53. Found: C, 60.69;
3.6.1. Ethoxyethyl 2-cyano-3-methylthio-3-(2-fluoro-5-
pyridyl)methylaminoacrylate (8a)
C H
H, 6.57; N, 12.48. IR (KBr, cm ) 3414, 3237, 2201,1671,
17
22FN
3
O
3
À1
+
1589, 1485, 1357, 1285, 1084. EI-MS m/e (%): 307 (M ,
32), 235 (30), 218 (42), 191 (34), 190 (23), 110 (100).
Ethoxyethyl 2-cyano-3-methylthio-3-(2-fluoro-5-pyri-
dyl)methylaminoacrylate (8a). Yield, 81%; mp, 54–55 8C.
1
3
H NMR (CDCl ) d 1.13 (t, J = 7.0 Hz, 3H, CH ), 2.62
3
HH
3
3
(
s, 3H, SCH ), 3.49 (q, J = 7.0 Hz, 3H, OCH ), 3.62 (t,
3 HH 2
3
3
JHH = 5.2 Hz, 2H, CH O), 4.22 (t, JHH = 5.2 Hz, 2H,
Acknowledgements
2
3
CO CH ), 4.73 (d, J = 5.2 Hz, 2H, CH N), 6.91 (dd,
2
2
HH
2
3 3
JHH = 8.4 Hz, J = 3.0 Hz, 1H, pyridine), 7.67–7.62 (m,
This work was supported by the National Key Project for
Basic Research (2003CB114400) and the National Natural
Science Foundation of China (20272030) and the Founda-
tion for the Author of National Excellent Doctoral
Dissertation of PR China (200255).
HF
1
H, pyridine), 8.09 (s, 1H, pyridine), 10.27 (s, 1H, NH);
Anal. Calcd. for C H FN O S: C, 53.08; H, 5.35; N,
1
5
18
3 3
1
2.38. Found: C, 53.11; H, 5.22; N, 12.20.
3.6.2. Ethoxyethyl 2-cyano-3-methyl-3-(2-fluoro-5-
pyridyl)methylaminoacrylate (8b)
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Ethoxyethyl 2-cyano-3-methyl-3-(2-fluoro-5-pyridyl)-
1
[
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2
HH
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3
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[
[
[
[
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1
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1
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3 3
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[
5
[
[
[
[
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3
.6.3. Ethoxyethyl 2-cyano-3-ethyl-3-(2-fluoro-5-
pyridyl)methylaminoacrylate (8c)
Ethoxyethyl 2-cyano-3-ethyl-3-(2-fluoro-5-pyridyl)-
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121 (2003) 51–54.
1
methylaminoacrylate (8c). Yield, 49%; mp, 64–65 8C. H
3
NMR (CDCl ) d 1.22 (t, J = 7.0 Hz, 3H, CH ), 1.30 (t,
[
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35 (3) (2004) 10–12 (in Chinese).
3
HH
3
3 3
JHH = 7.6 Hz, 3H, CH ), 2.68 (q, J = 7.1 Hz, 2H, CH ),
3
HH
2
[
[
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3
3
3
.58 (q, J = 7.0 Hz, 2H, OCH ), 3.71(t, J = 4.9 Hz,
HH 2 HH
3
2
H, CH O), 4.30 (t, J = 4.9 Hz, 2H, CO CH ), 4.59 (d,
2 HH 2 2
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3
JHH = 5.2 Hz, 2H, CH N), 7.02 (dd, JHH = 9.0 Hz,
2
3
JHF = 2.9 Hz, 1H, pyridine), 7.76–7.71 (m, 1H, pyridine),
[
[
[
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C H FN O : C, 59.80; H, 6.27; N, 13.08. Found: C, 59.66;
H, 6.38; N, 13.08.
1
6
20
3 3
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922.