Synthesis and herbicidal activity of 2-cyano-3-substituted-pyridinemethylaminoacrylates

Article abstract of DOI:10.1021/jf034067s

Two series of 2-cyano-3-substituted-pyridinemethylaminoacrylates, namely 12 new (Z)-2-cyano-3-methylthio-3-substituted-pyridinemethaneaminoacrylates and 10 new (Z)-2-cyano-3-alkyl-3-substituted-pyridinemethaneaminoacrylates, were synthesized as herbicidal inhibitors of photosystem II (PSII) electron transport. All of these compounds were confirmed by ¹H NMR, elemental, IR, and mass spectrum analyses. Their herbicidal activities were evaluated. Some compounds exhibited excellent herbicidal activities, even at a dose of 75 g/ha. A suitable substituent at the 2-position of the pyridine ring and the well-fit group at the 3-position of acrylate were essential for high herbicidal activity. 2-Cyanoacrylates containing a substituted pyridine ring provide higher herbicidal activities than parent compounds containing phenyl. These PSII inhibitor herbicides are safe to corn, which is a major crop in China.

Full text of DOI:10.1021/jf034067s

5030 J. Agric. Food Chem. 2003, 51, 5030−5035
Synthesis and Herbicidal Activity of
2-Cyano-3-substituted-pyridinemethylaminoacrylates
QINGMIN WANG, HUIKAI SUN, HUANYAN CAO, MURU CHENG, AND
RUNQIU HUANG*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
Two series of 2-cyano-3-substituted-pyridinemethylaminoacrylates, namely 12 new (Z)-2-cyano-3-
methylthio-3-substituted-pyridinemethaneaminoacrylates and 10 new (Z)-2-cyano-3-alkyl-3-substituted-
pyridinemethaneaminoacrylates, were synthesized as herbicidal inhibitors of photosystem II (PSII)
1
electron transport. All of these compounds were confirmed by H NMR, elemental, IR, and mass
spectrum analyses. Their herbicidal activities were evaluated. Some compounds exhibited excellent
herbicidal activities, even at a dose of 75 g/ha. A suitable substituent at the 2-position of the pyridine
ring and the well-fit group at the 3-position of acrylate were essential for high herbicidal activity.
2-Cyanoacrylates containing a substituted pyridine ring provide higher herbicidal activities than parent
compounds containing phenyl. These PSII inhibitor herbicides are safe to corn, which is a major
crop in China.
KEYWORDS: 2-Cyanoacrylates; substituted pyridinemethaneamino; herbicidal activity; inhibitors of PSII
electron transport
INTRODUCTION
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 cyanoacrylates
are inhibitors of photosystem II (PSII) electron transport, which
inhibits the growth of weeds by disrupting photosynthetic
electron transport at a common binding domain on the 32 kD
polypeptide of the PSII reaction center. Among these cyano-
acrylates, the compund B exhibits the highest inhibitory activity
of the Hill reaction yet reported (4-6). Bayer AG reported
compound C, but little information was given on herbicidal
activity (7). It has been reported that the D1 protein of PSII 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, and Tyr 262) flanking this part of the binding
domain (8-10). However, the complete nature and topography
of this hydrophobic domain of the D1 protein are unknown,
and cyanoacrylates have not commercialized as herbicides
because of their high dose rates.
2-cyanoacrylates and further study the relationship of structure-
herbicidal activity. We are reporting the synthesis of two series
of new 2-cyanoacrylates by the replacement of the phenyl-
methylamino with substituted pyridine methylamino and testing
of them for herbicidal activity.
MATERIALS AND METHODS
Synthetic Procedures. All reactions were carried out under a
nitrogen atmosphere with the exclusion of moisture. Proton NMR
spectra were obtained at 200 MHz using a Bruker AC-P 200
spectrometer. Chemical shift values (δ) 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.
Column chromatographic purification was carried out by using silica
gel.
In our previous work on the synthesis of D, we reported that
D (11, 12) showed some insecticidal activity and excellent
herbicidal activity, controlling more than 90% of rape (Brassica
napus) at 150 g/ha. At the same time, we noticed that the
compound D was also one analogue of structure A, which
encouraged us to introduce substituted pyridine heterocycles into
Structure Determination. A colorless crystal of approximate
dimensions of 0.15 mm × 0.20 mm × 0.25 mm of the target compound
7e was mounted on a glass fiber in a random orientation. The
* To whom correspondence should be addressed. Tel: +86(0)22-
23502673. Fax: +86(0)22-23503438. E-mail: wang98h@263.net.
10.1021/jf034067s CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/17/2003

2-Cyano-3-substituted-pyridinemethylaminoacrylates
J. Agric. Food Chem., Vol. 51, No. 17, 2003 5031
preliminary examination and data collection were performed on an
ENRAF-NONIUS CAD-4 diffractometer with Mo KR radiation (λ )
0.71073 Å) using the ω/2θ scan technique at 25 ( 2 °C. A total of
3200 independent reflections were collected in the range of 1.58° e
θ e 25.03°, of which 2168 reflections with I g 3σ(I) were considered
to be observed. The multiscan absorption correction was applied. The
correction for Lp factors was made by the SADABS program. Final R
and Rw values are 0.0516 and 0.1594, respectively (ω ) 1/(σ2(F) +
99.0000F2)), and S )1.024, (∆/σ)max ) 0.001, ∆Fmax ) 0.368e/Å3, and
∆Fmin ) -0.318e/Å3. All calculations were performed on a PDP11/44
and Pentium MMX/166 computer using the SDP PLUS program
system.
General Synthetic Procedure for 2-Alkoxy-5-pyridinemethane-
amines (2a-d). To absolute alcohol (30 mL) cooled with an ice water
bath was added metal sodium (1.12 g, 49 mmol). After the sodium
disappeared, 2-chloro-5-pyridinemethaneamine (1; 2.5 g, 17.5 mmol)
was added, and then, the solution was heated under reflux for 16-48
h. Excessive alcohol was evaporated in a vacuum. Water was then added
to the residue, and the products were extracted with chloroform. The
combined organic layer was dried over anhydrous sodium sulfate.
Thereafter, the drying agent was removed by filtration and the solvent
was evaporated in a vacuum to afford 2a-d, which were used directly
without further purification.
General Synthetic Prodedure for 3a-d. (Z + E)-2-Cyano-3-
methoxyacrylates (3a,b). To a mixture of ethoxylethyl 2-cyanoacetate
(3.93 g, 0.025 mol), triethylamine (5.05 g, 0.05 mol), magnesium
chloride (2.37 g, 0.025 mol), and anhydrous acetonitrile (25 mL) was
added acid chloride (0.025 mol) under an ice salt bath. The reaction
was continued for 5 h, and the solvent was evaporated. To the residue
was added 5 N aqueous hydrochloric acid solution (20 mL) and ether
(50 mL). The organic layer was separated, dried over anhydrous
magnesium sulfate, filtered, and distilled under reduced pressure to give
a colorless liquid (without further purification).
The gas of diazomethane (0.013 mol) synthesized from 1.32 g of
R-nitroso-R-methylurea according to the reported method (13) was
dissolved in a solution of ethoxylethyl 2-propionyl-2-cyanoacetate (1.07
g, 0.005 mol) in anhydrous ether (10 mL). The reaction mixture was
stirred for 12 h. Evaporation of the solvent afforded a yellow oil
(without further purification).
vacuum, and ethyl acetate (100 mL) was added to the residue. The
solid was filtered, and the filtrate was washed with water and dried
over anhydrous magnesium sulfate. The solvent was evaporated in a
vacuum, and the residual liquid was distilled to afford the corresponding
esters.
General Synthetic Procedures for 2-Cyano-3,3-dimethylthio-
acrylates (5a-g). Compound 4 (20 mmol) was added dropwise to a
mixture of potassium hydroxide powder (2.24 g, 40 mmol) and
anhydrous acetonitrile (30 mL) at 5 °C. The mixture was stirred for
0.5 h, and then, a solution of carbon disulfide (1.50 g, 20 mmol) in
anhydrous acetonitrile (5 mL) was added over about 10 min. The
reaction mixture was stirred for 3 h at room temperature. After the
solution was cooled to 4 °C, dimethyl sulfate (5.04 g, 40 mmol) was
added. The reaction mixture was stirred at room temperature for 4 h.
The solvent was evaporated 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 with anhydrous magnesium
sulfate. Ethyl acetate was evaporated to afford corresponding 5a-g.
General Synthetic Procedure for Target Compounds 6a-l. The
mixture of intermediate 5 (5 mmol), substituted pyridinemethaneamine
2 (6 mmol), and ethanol (12 mL) was refluxed for 3 h and then
evaporated under reduced pressure to give crude product. The product
was purified by vacuum column chromatography on a silica gel.
1
Data for 6a. Yield, 77.3%; mp, 74-75 °C. H NMR (CDCl3): δ
2.67 (s, 3H, SCH3), 4.64 (d, 2H, CO2CH2), 4.76 (d, 2H, CH2N), 5.32
(q, 2H, CdCH2), 5.98 (m, 1H, CHdC), 7.34-8.32 (m, 3H, C5H3N),
10.4 (w, 1H, NH). Anal. found: C, 51.73; H, 4.34; N, 12.92. Calcd
for C14H14ClN3O2S: C, 51.93; H, 4.36; N, 12.98.
Data for 6b. Yield, 81.5%; mp, 53.5-55 °C. 1H NMR (CDCl3): δ
1.30 (t, 3H, CH3), 3.22 (q, 2H, SCH2), 4.64 (d, 2H, CO2CH2), 4.78 (d,
2H, CH2N), 5.32 (q, 2H, CdCH2), 5.98 (m, 1H, CHdC), 7.31-8.32
(m, 1H, CHdC), 10.4 (w, 1H, NH). Anal. found: C, 52.97; H, 4.62;
N, 12.18. Calcd for C15H16ClN3O2S: C, 53.33; H, 4.78; N, 12.44.
Data for 6c. Yield, 74.3%. 1H NMR (CDCl3): δ 1.99 (m, 4H, CH2),
2.66 (s, 3H, SCH3), 3.82 (m, 3H, OCH, OCH2), 4.16 (d, 2H, CO2-
CH2), 4.76 (d, 2H, CH2N), 7.34-8.32 (m, 3H, C5H3N), 10.4 (w, 1H,
NH). Anal. found: C, 51.98; H, 5.21; N, 11.56. Calcd for C16H18-
ClN3O3S: C, 52.24; H, 4.93; N, 11.43.
1
Data for 6d. Yield, 80.3%; mp, 92-93 °C. H NMR (CDCl3): δ
(Z + E)-2-Cyano-3-alkoxyacrylates (3c,d). The mixture of ethox-
ylethyl 2-cyanoacetate (8.0 g, 48.4 mmol), triethyl orthoacetate or
orthoformate (61.6 mmol), and acetic acid (0.15 g, 2.5 mmol) was
heated under reflux for 2.5 h. The solvent was evaporated under reduced
pressure to afford a yellow oil, which was purified by column
chromatography using a silica gel. A colorless liquid was obtained.
General Synthetic Procedure for Esters 4a-d. A mixture of
cyanoacetic acid (25.5 g, 23.8 mmol), alkanol (31.5 mmol), sodium
bisulfate monohydrate (0.7 g, 5.1 mmol), and toluene (15 mL) was
placed in a flask equipped with a Dean Stark trap carrying a reflux
condenser at its upper end and then heated under reflux. The reaction
was not stopped until no more water was collected in appreciable
amounts in the water separator. The mixture was filtered, and the
filtration was washed with 10% sodium dicarbonate and brine, dried
over anhydrous sodium sulfate, and distilled under reduced pressure
to afford the corresponding esters.
Synthesis of Amide 4e. To the solution of cyanoacetic acid (8.51
g, 0.1 mol) in anhydrous ether (100 mL), phosphorus pentachloride
(20.9 g, 0.1 mol) was added gradually. After the addition was
completed, the reaction was continued for 0.5 h. The ether and
phosphorus oxychloride were evaporated under vacuum, and the residue
was cooled for immediate use in the following step.
Dry morpholine (17.4 g, 0.2 mol) was placed in a flask containing
anhydrous ether (100 mL). The acid chloride was added dropwise to
the stirred solution cooled on an ice bath. The reaction mixture was
stirred gently at room temperature for 3 h and filtered. The solvent
was evaporated in a vacuum, and the residual solid was recrystallized
from ethanol to give pure product.
2.63 (s, 3H, SCH3), 3.59-3.72 (m, 8H, 2OCH2, 2NCH2), 4.70 (d, 2H,
CH2N), 7.31-8.30 (m, 3H, C5H3N), 10.9 (w, 1H, NH). Anal. found:
C, 50.88; H, 4.75; N, 15.63. Calcd for C15H17ClN4O2S: C, 51.08; H,
4.86; N, 15.89.
Data for 6e. Yield, 66.1%; mp, 109-110 °C. 1H NMR (CDCl3): δ
2.71 (s, 3H, SCH3), 3.75 (s, 3H, CO2CH3), 4.67 (s, 2H, CO2CH2CO2),
4.75 (d, 2H, CH2N), 7.34-8.33 (m, 3H, C5H3N), 10.3 (w, 1H, NH).
Anal. found: C, 46.98; H, 3.77; N, 11.72. Calcd for C16H18ClN3O3S:
C, 47.26; H, 3.97; N, 11.81.
1
Data for 6f. Yield, 49.6%; mp, 87-89 °C. H NMR (CDCl3): δ
1.46 (t, 3H, CH3), 2.71 (s, 3H, SCH3), 4.20 (q, 2H, CO2CH2), 4.65 (s,
2H, CO2CH2CO2), 4.75 (d, 2H, CH2N), 7.31-8.30 (m, 3H, C5H3N),
10.2 (w, 1H, NH). Anal. found: C, 48.82; H, 4.30; N, 11.26. Calcd
for C17H20ClN3O3S: C, 48.71; H, 4.33; N, 11.37.
Data for 6g. Yield, 78.6%; mp, 66-67.5 °C. 1H NMR (CDCl3): δ
1.18 (t, 3H, CH2CH3), 2.67 (s, 3H, SCH3), 3.53 (q, 2H, OCH2), 3.66
(t, 2H, CH2O), 3.93 (s, 3H, OCH3), 4.25 (t, 2H, CO2CH2), 4.68 (d, 2H,
CH2N), 6.74-8.07 (m, 3H, C5H3N), 10.2 (w, 1H, NH). Anal. found:
C, 54.54; H, 5.77; N, 11.71. Calcd for C16H21N3O4S: C, 54.70; H,
6.03; N, 11.97.
Data for 6h. Yield, 73.3%; mp, 63.5-65 °C. 1H NMR (CDCl3): δ
1.11-1.37 (m, 6H, 2CH3), 2.63 (s, 3H, SCH3), 3.49-3.65 (m, 4H,
OCH2, CH2O), 4.20-4.32 (m, 4H, PrOCH2, CO2CH2), 4.63 (d, 2H,
CH2N), 6.66-8.02 (m, 3H, C5H3N), 10.2 (w, 1H, NH). Anal. found:
C, 55.72; H, 6.49; N, 11.73. Calcd for C17H23N3O4S: C, 55.89; H,
6.35; N, 11.51.
Data for 6i. Yield, 91.3%; yellow liquid. 1H NMR (CDCl3): δ 0.96
(t, 3H, C2H4CH3), 1.14 (t, 3H, CH2CH3), 1.74 (m, 2H, CH2CH2CH3),
2.63 (s, 3H, SCH3), 3.50 (q, 2H, OCH2), 3.63 (t, 2H, CH2O), 4.16-
4.24 (m, 4H, PrOCH2, CO2CH2), 4.64 (d, 2H, CH2N), 6.72-8.02 (m,
3H, C5H3N), 10.2 (s, 1H, NH). Anal. found: C, 56.82; H, 6.59; N,
11.07. Calcd for C18H25N3O4S: C, 56.96; H, 6.65; N, 11.07.
General Synthetic Procedure for Esters 4f,g. A mixture of sodium
cyanoacetate (8.50 g, 80 mmol) and an equivalent amount of ethyl
2-bromide acetate (80 mmol) in N,N-dimethylformamide (100 mL) was
heated to 90 °C for 4 h. N,N-Dimethylformamide was evaporated in a

5032 J. Agric. Food Chem., Vol. 51, No. 17, 2003
Wang et al.
Data for 6j. Yield, 82.3%; yellow liquid. 1H NMR (CDCl3): δ 2.66
(s, 3H, SCH3), 3.37 (s, 3H, OCH3), 3.62 (t, 2H, CH2O), 4.30 (t, 2H,
CO2CH2), 5.04 (d, 2H, CH2N), 7.32-8.63 (m, 4H, C5H4N), 10.7 (w,
1H, NH). Anal. found: C, 54.44; H, 5.58; N, 13.44. Calcd for
C14H17N3O3S: C, 54.71; H, 5.58; N, 13.68.
a
Scheme 1
a Compounds 2a−d:
R
) CH O, CH CH O, CH CH CH O, and
1
3
3
2
3
2
2
1
Data for 6k. Yield, 74.6%; mp, 70-71 °C. H NMR (CDCl3): δ
CH CH CH CH O.
3
2
2
2
2.76 (s, 3H, SCH3), 3.65 (t, 2H, CH2O), 4.04 (s, 3H, OCH3), 4.28 (t,
2H, CO2CH2), 4.66 (d, 2H, CH2N), 7.32-8.42 (m, 3H, C5H3N), 10.7
(w, 1H, NH). Anal. found: C, 53.41; H, 5.74; N, 12.58. Calcd for
C15H19N3O4S: C, 53.41; H, 5.68; N, 12.46.
a
Scheme 2
1
Data for 6l. Yield, 70.7%; mp, 83-84 °C. H NMR (CDCl3): δ
1.37 (t, 3H, CH3), 2.67 (s, 3H, SCH3), 3.38 (s, 3H, OCH3), 3.61 (t, 2H,
CH2O), 4.30 (m, 4H, OCH2), 4.67 (d, 2H, CH2N), 6.70-8.11 (m, 3H,
C5H3N), 10.2 (w, 1H, NH). Anal. found: C, 54.79; H, 6.11; N, 12.23.
Calcd for C16H21N3O4S: C, 54.67; H, 6.03; N, 11.97.
General Synthetic Procedure for Target Compounds 7a-j. The
mixture of intermediate 3 (6 mmol), substituted pyridinemethaneamine
2 (6 mmol), and ethanol (15 mL) was heated under reflux for 2 h. The
solvent was evaporated under reduced pressure to afford crude product.
The product was purified by recrystalliztion or vacuum column
chromatography on a silica gel.
2
a Compounds 3a,b: R ) CH CH and (CH ) CH.
3
2
3 2
1H, NH). Anal. found: C, 54.27; H, 5.13; N, 13.58. Calcd for
C14H16N3O3Cl: C, 54.28; H, 5.22; N, 13.57.
Data for 7i. Yield, 88.6%; mp, 82-84 °C. H NMR (CDCl3): δ
1
1.17 (t, 3H, CH2CH3), 2.30 (s, 3H, dCH3), 3.58 (q, 2H, OCH2), 3.65
(t, 2H, CH2O), 3.93 (s, 3H, PrOCH3), 4.24 (t, 2H, CO2CH2), 4.44 (d,
2H, CH2N), 6.74-8.05 (m, 3H, C5H3N), 10.1 (s, 1H, NH). Anal.
found: C, 60.04; H, 6.39; N, 13.31. Calcd for C16H21N3O4: C, 60.16;
H, 6.64; N, 13.16.
Data for 7j. Yield, 91.3%; yellow liquid. 1H NMR (CDCl3): δ 0.97
(t, 3H, C2H4CH3), 1.14 (t, 3H, CH2CH3), 2.28 (s, 3H, dCH3), 1.74 (m,
2H, CH2CH2CH3), 3.50 (q, 2H, OCH2), 3.60 (t, 2H, CH2O), 4.17-
4.24 (m, 4H, PrOCH2, CO2CH2), 4.41 (d, 2H, CH2N), 6.75-8.00 (m,
3H, C5H3N), 10.1 (s, 1H, NH). Anal. found: C, 62.27; H, 7.38; N,
12.23. Calcd for C18H25N3O4: C, 62.22; H, 7.27; N, 12.10.
Biological Assay. The herbicidal activities of the compounds 6a-l
and 7a-j and the reported compounds B and C were evaluated using
a previously reported procedure (7, 14).
Plant Material. The three broadleaf species used to test the herbicidal
activity of compounds were alfalfa (Medicago satiVa L.), rape (B.
napus), and amaranth pigweed (Amaranthus retroflexus). Seeds of A.
retroflexus 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. Seeds were planted in 6 cm diameter plastic boxes
containing artificial mixed soil. Before plant emergence, the boxes were
covered with plastic film to keep moist. Plants were grown in the green
house. Fresh weight of the above ground tissues was measured 10 days
after treatment. The inhibition percent was used to describe the control
efficiency of the compounds.
Data for 7a. Yield, 82.3%; mp, 92-93 °C. IR (KBr, cm-1): 3379,
1661, 1270, 1106, 1590, 1491, 1459, 2198, 1259, 1055. 1H NMR
(CDCl3): δ 1.18 (t, 3H, CH2CH3), 1.37 (d, 6H, C(CH3)2), 3.20 (m,
1H, CH), 3.54 (q, 2H, OCH2), 3.66 (t, 2H, CH2O), 3.93 (s, 3H,
PrOCH3), 4.24 (t, 2H, CO2CH2), 4.51 (d, 2H, CH2N), 6.74-8.05 (m,
3H, C5H3N), 10.6 (s, 1H, NH). EI MS: m/z (%) 347 (M+, 8.5), 122
(100). Anal. found: C, 62.27; H, 7.11; N, 12.15. Calcd for
C18H25N3O4: C, 62.27; H, 7.20; N, 12.10.
1
Data for 7b. Yield, 86.7%; mp, 47-49 °C. H NMR (CDCl3): δ
1.20 (t, 3H, OCH2CH3), 1.36-1.43 (m, 9H, C(CH3)2, PrOCH2), 3.15
(m, 1H, CH), 3.60 (q, 2H, OCH2), 3.68 (t, 2H, CH2O), 4.26 (t, 2H,
CO2CH2), 4.35 (q, 2H, PrOCH2), 4.52 (d, 2H, CH2N), 6.74-8.07 (m,
3H, C5H3N), 10.6 (s, 1H, NH). Anal. found: C, 63.17; H, 7.69; N,
11.74. Calcd for C19H27N3O4: C, 63.12; H, 7.54; N, 11.63.
1
Data for 7c. Yield, 85.7%; mp, 55-56 °C. H NMR (CDCl3): δ
1.00 (t, 3H, C2H4CH3), 1.17 (t, 3H, OCH2CH3), 1.37 (d, 6H, C(CH3)2),
1.78 (m, 2H, CH2CH2CH3), 3.15 (m, 1H, CH), 3.54 (q, 2H, OCH2),
3.65 (t, 2H, CH2O), 4.20-4.27 (m, 4H, PrOCH2, CO2CH2), 4.49 (d,
2H, CH2N), 6.73-8.04 (m, 3H, C5H3N), 10.5 (s, 1H, NH). Anal.
found: C, 63.69; H, 7.87; N, 11.18. Calcd for C20H29N3O4: C, 63.96;
H, 7.80; N, 11.19.
1
Data for 7d. Yield, 83.2%; yellow liquid. H NMR (CDCl3): δ
0.92 (t, 3H, C2H4CH3), 1.14 (t, 3H, CH2CH3), 1.34 (d, 6H, C(CH3)2),
1.42 (m, 2H, CH2C2H4), 1.78 (m, 2H, CH2C2H5), 3.15 (m, 1H, CH),
3.51 (q, 2H, OCH2), 3.62 (t, 2H, CH2O), 4.17-4.24 (m, 4H, PrOCH2,
CO2CH2), 4.47 (d, 2H, CH2N), 6.69-8.05 (m, 3H, C5H3N), 10.4 (s,
1H, NH). Anal. found: C, 64.77; H, 7.90; N, 11.06. Calcd for
C21H31N3O4: C, 64.77; H, 7.96; N, 10.79.
Treatment. The dosage (activity ingredient) for each compound was
1.5 kg/ha. Purified compounds were dissolved in 100 µL of N,N-
dimethylformamide with the addition of a little Tween 20 and were
then sprayed using a laboratory belt sprayer delivering a 750 L/ha spray
volume. The mixture of the same amount of water, N,N-dimethylform-
amide, and Tween 20 was sprayed as control.
Data for 7e. Yield, 90.3%; mp, 111-112 °C. 1H NMR (CDCl3): δ
1.17 (t, 3H, CH3), 1.33 (d, 6H, C(CH3)2), 3.13 (m, 1H, CH), 3.54 (q,
2H, OCH2), 3.67 (t, 2H, CH2O), 4.24 (t, 2H, CO2CH2), 4.59 (d, 2H,
CH2N), 7.24-8.30 (m, 3H, C5H3N), 10.6 (s, 1H, NH). Anal. found:
C, 57.83; H, 6.27; N, 11.77. Calcd for C17H22N3O3Cl: C, 58.04; H,
6.31; N, 11.95.
Preemergence Treatment. Compounds were sprayed immediately
after seed plantings. There were two replicates for each treatment.
Postemergence Treatment. Compounds were sprayed after the first
true leaf expanded.
RESULTS AND DISCUSSION
1
Data for 7f. Yield, 83.1%; mp, 78-79 °C. H NMR (CDCl3): δ
1.13-1.27 (m, 6H, 2CH3), 2.60 (q, 2H, CH3), 3.54 (q, 2H, OCH2),
3.64 (t, 2H, CH2O), 4.22 (t, 2H, CO2CH2), 4.53 (d, 2H, CH2N), 7.30-
8.30 (m, 3H, C5H3N), 10.2 (w, 1H, NH). Anal. found: C, 56.82; H,
5.64; N, 12.44. Calcd for C16H20N3O3Cl: C, 56.88; H, 5.92; N, 12.44.
Synthesis. The intermediate 2-chloro-5-pyridinemethane-
amine (1) was prepared readily from 2-chloro-5-chlorometh-
ylpyridine according to Cheng et al. (15). The substitution
reaction of 1 by sodium alkoxide under reflux afforded 2-alkoxy-
5-pyridinemethaneamine (2) in good yield (Scheme 1). When
R1 was propoxy or butoxy, the reaction was completed
quantitatively.
The synthesis of intermediate (Z + E)-2-cyano-3-alkoxy-
acrylates 3 using two methods (16, 17) has been reported
(Schemes 2 and 3). Compounds 3a,b were synthesized by
treating ester 4 with acid chloride followed by methylation with
diazomethane in good yields. As for the preparation of 3c,d,
we adopted the reaction of ester 4 with triethyl orthoacetate or
1
Data for 7g. Yield, 80.7%; mp, 85-86 °C. H NMR (CDCl3): δ
1.20 (t, 3H, CH3), 2.31 (s, 3H, dCCH3), 3.56 (q, 2H, OCH2), 3.60 (t,
2H, CH2O), 4.28 (t, 2H, CO2CH2), 4.55 (d, 2H, CH2N), 7.26-8.33
(m, 3H, C5H3N), 10.3 (s, 1H, NH). Anal. found: C, 55.55; H, 5.41; N,
12.95. Calcd for C15H18N3O3Cl: C, 55.61; H, 5.62; N, 12.99. IR (KBr,
cm-1): 1671, 1274, 1102, 1599, 1562, 1457, 2198, 3381, 810, 772. EI
MS: m/z (%) 323 (M+, 10.5), 126 (100).
Data for 7h. Yellow liquid. 1H NMR (CDCl3): δ 1.18 (t, 3H, CH3),
3.53 (q, 2H, OCH2), 3.67 (t, 2H, CH2O), 4.28 (t, 2H, CO2CH2), 4.50
(d, 2H, CH2N), 7.90 (s, 1H, dCH), 7.34-8.32 (m, 3H, C5H3N), 9.2 (s,

2-Cyano-3-substituted-pyridinemethylaminoacrylates
J. Agric. Food Chem., Vol. 51, No. 17, 2003 5033
a
Scheme 3
Table 1. Herbicidal Activities of Products 6f and C against Alfalfa
rate
herbicidal
correlation
ED
50
ED
90
(g/ha) activity (%) coefficient (r)
y ) a + bx
(g/ha) (g/ha)
6f 150.00
98.1
95.3
88.9
80.6
87.0
80.6
76.9
59.3
2
a Compounds 3c,d: R ) H and CH .
75.00
37.50
18.75
150.00
75.00
37.50
18.75
0.99
0.97
y ) 5.72 + 1.33x 4.35
39.3
3
Scheme 4
C
y ) 5.22 + 0.96x 8.85 193.95
the loss of a mole of the methylthio group (or methoxy) and
was confirmed by the X-ray single-crystal structure of 7e; the
X-ray data confirmed the Z sterochemistry of 7e and demon-
strated the presence of a planar core stablized by an intramo-
lecular hydrogen bond between the ester carbonyl oxygen and
the pyridinemethylamino hydrogen atom (19). All of these target
Scheme 5
1
compounds were confirmed by H NMR, elemental, IR, and
mass spectrum analyses.
Structure-Activity Relationship. In our previous work, the
cyanoacrylate structure modified by the replacement of phenyl
with ferrocenyl showed higher herbicidal activities than the
parent compound (14). Introduction of ferrocenyl into cyano-
acrylate increased the overall lipophilicity of the molecule.
To further amplify the interaction of these cyanoacrylates with
the lipophilic binding domain, phenyl was replaced by pyridine
heterocycles in 2-cyanoacrylates, and (Z)-ethoxyethyl 2-cyano-
3-methylthio-3-(4-chlorophenyl)methaneaminoacrylate (C) and
(Z)-ethoxyethyl 2-cyano-3-methylthio-3-(2-chloro-5-pyridyl)-
methaneaminoacrylate (6f) were prepared for comparison of
herbicidal activity. This comparison (Table 1) clearly showed
a significant enhanced activity, with compound 6f having a
higher level of herbicidal activity than compound C. Moreover,
by comparing the herbicidal activity of (Z)-ethoxyethyl 2-cyano-
3-isopropyl-3-(2-chloro-5-pyridyl)methaneaminoacrylate (7e)
and (Z)-ethoxyethyl 2-cyano-3-isopropyl-3-(4-chlorophenyl)-
methaneaminoacrylate (B) (Table 2), we found that the
introduction of pyridine to 2-cyanoacrylate increased the
herbicidal activity. These results were in agreement with the
above two compounds 6f and C. Thus, subsequent optimization
of cyanoacrylate focused on varying the nature of the substitents
R1, R2, and R3 while retaining the pyridine heterocycle.
a
Scheme 6
a Compounds 7a−d: R ) CH O, C H O, CH CH CH O, and CH CH -
1
3
2
5
3
1
2
2
3
2
2
2
CH CH O; R ) (CH ) CH. Compounds 7e−h: R ) Cl; R ) (CH ) CH,
2
2
3 2
3 2
1
2
C H , CH , and H. Compounds 7i,j: R ) CH O and CH CH CH O; R )
2
5
3
3
3
2
2
CH .
3
Scheme 7
triethyl orthoformate in the presence of acetic acid. It was
reported that acetic acid should be added in three separate
aliquots, but we found that a better yield was achieved by adding
acetic acid at once at 160 °C.
Esters 4 were prepared conveniently from cyanoacetic acid
and primary alcohols in the presence of a catalytic amount of
sodium bisulfate monohydrate (18). Intermediate 2-cyano-3,3-
dimethylthioacrylates 5 were achieved by treating corresponding
esters 4 with carbon disulfide and 2 mol of dimethyl sulfate in
a one pot reaction using potassium hydroxide as alkali in good
yield (76-92%) (Scheme 4).
Intermediates 3 or 5 were reacted with substituted pyr-
idinemethanamine 1 or 2 in refluxing absolute ethanol to give
the target compounds 6 or 7 in good yields (Schemes 5 and 6).
This reaction was assumed to go through a nucleophilic addition
and elimination reaction (Scheme 7). The amine attached the
R,â-unsaturated double bond to form a transition state in which
the orientation of pyridinemethylamino and ester carbonyl is
cis because of the presence of an intramolecular hydrogen
bonding. The configuration of target compounds was kept with
From the biological assay results in Table 2, which sum-
marized the herbicidal activity of the target compounds, most
of the compounds synthesized showed a greater herbicidal
activity in postemergence treatment than in preemergence
treatment except 7a,e,g; so, we herein analyzed the structure-
activity relationship according to the data of biological assay
in the postemergence treatment.
Compound 6j with the H-atom at the 2-position of the
pyridine ring had little inhibitory effect on weed development
as compared with compound 6k with methoxy at the 2-position,
indicating that a suitable group (chlorine or alkoxy) at the
2-position would be essential for herbicidal activity. The

5034 J. Agric. Food Chem., Vol. 51, No. 17, 2003
Wang et al.
Table 2. Herbicidal Activities of Products 6a−l and 7a−j (1.5 kg/ha)
In conclusion, we have demonstrated that 2-cyanoacrylates
containing substituted pyridine ring presented excellent herbi-
cidal activity and their structure-activity relationships were
studied. Some compounds exhibited excellent herbicidal activi-
ties, even at a dose of 75 g/ha. It was found that the suitable
substituent at the 2-position of the pyridine ring and the well-
fit group at the 3-position of acrylate were essential for high
herbicidal activity. These PSII inhibitor herbicides are safe for
corn, which is a major crop in China, at the rate of 750 g/ha.
Table 3. Herbicidal Activities of Products 6a,c,d,f and 7e−g
postemergence treatment
compd
rate (g/ha)
alfalfa
amaranth pigweed
rape
6a
1500
300
75
1500
300
75
1500
300
75
1500
300
75
1500
300
75
1500
300
75
100.0
56.1
15.9
64.0
52.3
41.9
75.0
9.7
100.0
61.6
22.2
98.8
88.4
79.1
100.0
25.0
0
100.0
96.2
52.3
100.0
93.0
72.1
100.0
100.0
88.4
100.0
18.3
91.7
82.7
33.3
100.0
97.3
94.7
99.4
0
6c
6d
6f
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0
0
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76.2
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36.3
75.6
45.3
14.0
83.7
62.8
45.3
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0
100.0
100.0
36.8
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94.1
100.0
14.6
7e
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75
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2-Cyano-3-substituted-pyridinemethylaminoacrylates
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