Synthesis, herbicidal activities, and 3D-QSAR of 2-cyanoacrylates containing aromatic methylamine moieties

Article abstract of DOI:10.1021/jf072851x

A series of novel 2-cyanoacrylates containing different aromatic rings were synthesized, and their structures were characterized by ¹H NMR, elemental analysis, and single-crystal X-ray diffraction analysis. Their herbicidal activities against four weeds and inhibition of photosynthetic electron transport against isolated chloroplasts (the Hill reaction) were evaluated. Both in vivo and in vitro data showed that the compounds containing benzene, pyridine, and thiazole moieties gave higher activities than those containing pyrimidine, pyridazine, furan, and tetrahedronfuran moieties. To further explore the comprehensive structure-activity relationship on the basis of in vitro data, comparative molecular field analysis (CoMFA) was performed, and the results showed that a bulky and electronegative group around the para-position of the aromatic rings would have the potential for higher activity, which offered important structural insights into designing highly active compounds prior to the next synthesis.

Full text of DOI:10.1021/jf072851x

204 J. Agric. Food Chem. 2008, 56, 204–212
Synthesis, Herbicidal Activities, and 3D-QSAR of
2-Cyanoacrylates Containing Aromatic Methylamine
Moieties
YU-XIU LIU,†,§,4 DENG-GUO WEI,§,4 YE-RONG ZHU,#,4 SHAO-HUA LIU,†
YONG-LIN ZHANG,† QI-QI ZHAO,† BAO-LI CAI,† YONG-HONG LI,†
HAI-BIN SONG,† YING LIU,*,§ YONG WANG,*,# RUN-QIU HUANG,† AND
QING-MIN WANG*,†
State Key Laboratory of Elemento-Organic Chemistry, Tianjin Key Laboratory of Pesticide Science,
Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China; State Key
Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and
Molecular Engineering, Peking University, Beijing 100871, China; and College of Life Sciences,
Nankai University, Tianjin 300071, China
A series of novel 2-cyanoacrylates containing different aromatic rings were synthesized, and their
structures were characterized by 1H NMR, elemental analysis, and single-crystal X-ray diffraction
analysis. Their herbicidal activities against four weeds and inhibition of photosynthetic electron transport
against isolated chloroplasts (the Hill reaction) were evaluated. Both in vivo and in vitro data showed
that the compounds containing benzene, pyridine, and thiazole moieties gave higher activities than
those containing pyrimidine, pyridazine, furan, and tetrahedronfuran moieties. To further explore the
comprehensive structure–activity relationship on the basis of in vitro data, comparative molecular
field analysis (CoMFA) was performed, and the results showed that a bulky and electronegative group
around the para-position of the aromatic rings would have the potential for higher activity, which
offered important structural insights into designing highly active compounds prior to the next synthesis.
KEYWORDS: Herbicides; photosynthetic electron transport inhibitors; 2-cyanoacrylates; aromatic rings;
CoMFA
INTRODUCTION
herterocycles were carried out by us to develop better potential
herbicides (6–10). To study the structure–activity relationship,
a series of cyanoacrylates containing phenyl, pyridyl, thiazole,
pyridazine, and pyrimidine groups were synthesized and tested
for their herbicidal activity. The Hill reaction was conducted to
test their electron transport inhibitory ability, and the analysis of
the relationships between the structure and the in vitro activity was
performed by comparative molecular field analysis (CoMFA) (11).
Herein we report the new developments.
2-Cyanoacrylates are inhibitors of photosystem II (PSII)
electron transport, which inhibits the growth of weeds by
disrupting photosynthetic electron transport at the PSII reaction
center. Among these cyanoacrylates, the compound I-1 (Table
1) has been reported to exhibit high inhibitory activity of the
Hill reaction (1–3). The reported QSAR analysis has focused
on 2-cyanoacrylates containing phenyl or benzyl (4). In our
previous paper (5), compound I-2 (Table 1) showed good
herbicidal activity, and pyridyl compound I-3 showed better
herbicidal activity. Furthermore, it has been validated that
2-cyanoacrylates with an ethoxyethyl group at the ester moiety
have much higher activity than those with any other alkyl group.
Thus, some studies on ethoxyethyl cyanoacrylates containing
MATERIALS AND METHODS
Instruments. The melting points of the products were determined
on an X-4 binocular microscope (Beijing Tech Instrument Co., Beijing,
China) and were not corrected. 1H NMR spectra were obtained at 300
MHz using a Bruker AC-P 300 spectrometer. Chemical shift values
(δ) are given in parts per million downfield from the internal standard
tetramethylsilane. Elemental analyses were determined on a Yanaca
CHN Corder MT-3 elemental analyzer. MS was obtained at high
resolution, ESI-FTICR-MS (Ionspec 7.0T).
Synthetic Procedures. 4-Chloro-5-methylbenzene (IVa) and 2-chloro-
5-chloromethylpyridine (Vb) were commercial reagents. Compounds
IIIa, IIIb and IIIc (5), 2-bromo-5-methylpyridine (IVc) (12) and
2-bromo-5-methylthiozole (IVf) (13), 3-chloro-6-methylpyridazine
* Authors to whom correspondence should be addressed [(Wang)
telehone +86-(0)22-23499842, fax +86-(0)22-23499842, e-mail
wang98h@263.net; (Liu) telephone 86-10-62767284, fax 86-10-
62751725, e-mail liuying@pku.edu.cn].
† State Key Laboratory of Elemento-Organic Chemistry.
§ State Key Laboratory for Structural Chemistry of Unstable and
Stable Species.
# Nankai University.
4 Three authors contributed equally to this work.
10.1021/jf072851x CCC: $40.75
2008 American Chemical Society
Published on Web 12/04/2007

2-Cyanoacrylates
J. Agric. Food Chem., Vol. 56, No. 1, 2008 205
Table 1. Title Compounds Ia
Data for VIb: yield, 93.3%; mp, 137–139 °C; 1H NMR (CDCl3), δ
4.83 (s, 2H), 7.28 (d, 3JHH ) 8.4 Hz, 1H), 7.72–7.77 (m, 3H), 7.84–7.88
4
(m, 2H), 8.49 (d, JHH ) 2.4 Hz, 1H).
Data for VIc: yield, 90.5%; mp, 139–141 °C; 1H NMR (CDCl3), δ
4.81 (s, 2H), 7.44 (d, 3JHH ) 7.6 Hz, 1H), 7.63–7.66 (m, 1H), 7.72–7.75
(m, 2H), 7.85–7.87 (m, 2H), 8.48 (s, 1H). Anal. Calcd for C14H9BrN2O2
(%): C, 53.02; H, 2.86; N, 8.83. Found: C, 52.95; H, 2.70; N, 8.60.
Data for VIf: yield, 78.0%; mp, 93–95 °C; 1H NMR (CDCl3), δ
4.98 (s, 2H), 7.61 (s, 1H), 7.61–7.76 (m, 2H), 7.85–7.88 (m, 2H).
Data for VIk: yield, 79.0%; mp, 202–203 °C; 1H NMR (CDCl3), δ
5.20 (s, 2H), 7.48 (s, 2H), 7.73–7.81 (m, 2H), 7.86–7.95 (m, 2H).
Data for VIn: yield, 27.9% (from IVn); mp, 182–183 °C; 1H NMR
(CDCl3), δ 4.84 (s, 2H), 7.79–7.73 (m, 2H), 7.91–7.85 (m, 2H), 8.75
(s, 2H).
Synthetic Procedure for VIo. To a solution of sodium methoxide
(9 mmol) in methanol (20 mL) phthalimide (VIn) (3 mmol) was added
N-(2-chloro-5-pyrimidylmethyl), and the resulting mixture was refluxed
for 50 min. After the most of the solvent had been removed in vacuo,
the residue was neutralized to pH 7–8 with 1 mol/L hydrochloride acid.
The resulting pastelike mixture was filtered and successively washed
with water (3 mL) and ethanol (3 mL) to give N-(2-methoxy-5-
pyrimidylmethyl)phthalimide (VIo) as a white solid: yield, 77.5%; mp,
202–203 °C; 1H NMR (CDCl3), δ 3.99 (s, 3H), 4.78 (s, 2H), 7.76–7.70
(m, 2H), 7.89–7.83 (m, 2H), 8.64 (s, 2H). Anal. Calcd for C14H11N3O3:
C, 62.45; H, 4.12; N, 15.61. Found: C, 62.44; H, 3.89; N, 15.41.
Synthetic Procedure for VIp. Compound VIp was prepared from
VIn according to the same method as for VIo, which underwent the
next reaction without further purification.
General Synthetic Procedures for IIa, IIb, IIc, IIf, IIk, IIo, and
IIp. To a suspension of N-substituted phthalimide VI (0.04 mol) in
ethanol (40 mL) was added hydrazine hydrate (0.5 mL). The reaction
mixture was refluxed for 5 h and then cooled. The precipitated phthalyl
hydrazide was filtered and washed with ethanol, and then the combined
filtrate was condensed under reduced pressure to give crude II, which
underwent the next reaction without further purification.
1
Data for IIa: crude yield, 91.2%; H NMR (CDCl3), δ 1.45 (br s,
2H), 3.83 (s, 2H), 7.22–7.30 (m, 4H).
1
Data for IIb: crude yield, 91.2%; H NMR (CDCl3), δ 1.51 (br s,
3
3
2H), 4.57 (s, 2H), 7.35 (d, JHH ) 8.4 Hz, 1H), 7.71 (dd, JHH ) 8.4
4
4
Hz, JHH ) 2.4 Hz, 1H), 8.40 (d, JHH ) 2.4 Hz, 1H).
1
Data for IIc: crude yield, 87.4%; H NMR (CDCl3), δ 1.44 (br s,
3
2H), 3.86 (s, 2H), 7.46 (d, JHH ) 8.1 Hz, 1H), 7.55–7.59 (m, 1H),
4
8.33 (d, JHH ) 2.1 Hz, 1H).
1
Data for IIf: crude yield, 98.0%; H NMR (CDCl3), δ 1.63 (br s,
2H), 4.05 (s, 2H), 7.39 (s, 1H).
Data for IIk: crude yield, 93.0%; mp, 97–98 °C; 1H NMR (CDCl3),
3
δ 1.60 (br s, 2H), 4.13 (s, 2H), 7.42 (d, JHH ) 9.0 Hz, 1H), 7.49 (d,
3JHH ) 9.0 Hz, 1H).
Data for IIo: crude yield, 100%; 1H NMR (CDCl3), δ 1.77 (br s,
2H), 3.87 (s, 2H), 4.00 (s, 3H), 8.51 (s, 2H).
1
Data for IIp: crude yield, 100%; H NMR (CDCl3), δ 1.89 (br s,
2H), 1.43 (t, 3JHH ) 7.2 Hz, 3H), 3.84 (s, 2H), 4.41 (q, 3JHH ) 7.2 Hz,
a * Compounds I-1 to I-3 were not first synthesized, but a different procedure
was used in this paper. ** The synthetic procedures of compounds I-10 (7) and
I-31 to I-34 (10) were reported in the cited references.
2H), 8.47 (s, 2H).
General Synthetic Procedures for IIe, IIg, IIh, IIi, IIj, and IIl.
To corresponding alcohol (10 mL) was added metal sodium (5 mmol).
After the sodium disappeared, compound IIc, IIf, or IIk was added,
and the mixture was refluxed for 6-24 h monitored by TLC. Then the
solvent was evaporated, and the residue was dissolved in methylene
dichloride (10 mL) and washed with water. The organic layer was dried
and condensed to give corresponding II.
(IVk) (14) and 2-chloro-5-methylpyrimidine (IVn) (15), and 6-chlo-
ropyridine-3-carboxamide (VII) (9) were prepared according to pub-
lished procedures. Bromomethyl or chloromethyl compounds V were
synthesized from corresponding IV and NBS or NCS (16).
General Synthetic Procedures for VIa, VIb, VIc, VIf, VIk, and
VIn. To a solution of V (0.05 mol) in N,N-dimethylformamide (20
mL) was added potassium phthalimide (0.05 mol) in a small portion.
After the mixture had been stirred at room temperature for 5 h, water
(50 mL) was added, and lots of precipitate appeared. The crude product
was collected by filtration and washed with water. After recrystallization
from ethanol, a white crystal was obtained.
Data for VIa: yield, 91.0%; mp, 124–125 °C; 1H NMR (CDCl3), δ
4.85 (s, 2H), 7.29 (d, 3JHH ) 8.7 Hz, 2H), 7.38 (d, 3JHH ) 8.7 Hz, 2H),
7.70–7.73 (m, 2H), 7.83–7.86 (m, 2H).
1
Data for IIe: crude yield, 78.8%; H NMR (CDCl3), δ 1.48 (br s,
3
2H), 3.84 (s, 2H), 4.75 (q, JHF ) 8.1 Hz, 2H), 6.83–6.87 (m, 1H),
3
4
7.64 (d, JHH ) 8.4 Hz, 1H), 8.07 (d, JHH ) 2.4 Hz, 1H).
Data for IIg: crude yield, 58.9%; 1H NMR (CDCl3), δ 1.42 (t, 3JHH
3
) 7.2 Hz, 3H), 1.60 (br s, 2H), 3.91 (s, 2H), 4.42 (q, JHH ) 7.2 Hz,
2H), 6.90 (s, 1H).
Data for IIh: crude yield, 70.0%; 1H NMR (CDCl3), δ 1.02 (t, 3JHH
) 7.2 Hz, 3H), 1.64 (br s, 2H), 1.76–1.88 (m, 2H), 3.91 (s, 2H), 4.31
3
(t, JHH ) 6.6 Hz, 2H), 6.90 (s, 1H).

206 J. Agric. Food Chem., Vol. 56, No. 1, 2008
Liu et al.
Data for IIi: crude yield, 98.0%; 1H NMR (CDCl3), δ 1.21 (d, 3JHH
) 6.3 Hz, 6H), 1.65 (br s, 2H), 3.90 (s, 2H), 5.06–5.18 (m, 1H), 6.90
(s, 1H).
2H, CO2CH2), 4.54 (d, 3JHH ) 6.0 Hz, 2H, NCH2), 7.44–7.55 (m, 2H,
4
Py), 8.31 (d, JHH ) 2.1 Hz, 1H, Py), 10.18 (s, 1H, NH). Anal. Calcd
for C16H20BrN3O3 (%): C, 50.27; H, 5.27; N, 10.99. Found: C, 50.29;
H, 5.23; N, 10.95.
1
Data for IIj: crude yield, 90.0%; H NMR (CDCl3), δ 1.69 (br s,
3
1
2H), 3.93 (s, 2H), 4.78 (q, JHF ) 8.1 Hz, 2H), 6.92 (s, 1H).
Data for I-6: yield, 75.0%; mp, 121–122 °C; H NMR (CDCl3), δ
1.21 (t, 3JHH ) 6.9 Hz, 3H, CH3), 1.39 (d, 3JHH ) 7.2 Hz, 6H, C(CH3)2),
Data for IIl: crude yield, 60.0%; 1H NMR (CDCl3), δ 1.45 (t, 3JHH
3
3
3.10–3.19 (m, 1H, CH), 3.58 (q, JHH ) 6.9 Hz, 2H, OCH2), 3.69 (t,
) 6.9 Hz, 3H), 1.72 (br s, 2H), 4.07 (s, 2H), 4.56 (q, JHH ) 7.0 Hz,
3JHH ) 5.1 Hz, 2H, OCH2), 4.28 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.60
3
3
2H), 6.92 (d, JHH ) 9.0 Hz, 1H), 7.37 (d, JHH ) 9.0 Hz, 1H).
Synthetic Procedure for IIm. A mixture of (6-chloropyridazin-3-
yl)methylamine (IIk) (0.45 g, 3.1 mmol) and morpholine (10 mL) was
refluxed for 1 h. Then the excessive morpholine was evaporated, and
the residue was dissolved in methylene dichloride (10 mL) and washed
with water. The organic layer was dried and condensed to give crude
IIm as brown oil.
(d, 3JHH ) 6.0 Hz, 2H, NCH2), 7.45–7.55 (m, 2H, Py), 8.31 (d, 4JHH
)
2.4 Hz, 1H, Py), 10.57 (s, 1H, NH). Anal. Calcd for C17H22BrN3O3
(%): C, 51.52; H, 5.60; N, 10.60. Found: C, 51.46; H, 5.61; N, 10.50.
Data for I-7: yield, 52.7%; mp, 95–97 °C; 1H NMR (CDCl3), δ
3
1.22 (t, JHH ) 6.9 Hz, 3H, CH3), 2.71 (s, 3H, SCH3), 3.11 (s, 6H,
N(CH3)2), 3.58 (q, 3JHH ) 6.9 Hz, 2H, OCH2), 3.70 (t, 3JHH ) 5.4 Hz,
2H, OCH2), 4.29 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.63 (d, 3JHH ) 5.7
1
Data for IIm: crude yield, 72.0%; H NMR (CDCl3), δ 1.70 (br s,
3
2H), 3.71–3.84 (m, 4H), 3.97 (s, 2H), 4.48–4.58 (m, 4H), 6.84 (d, 3JHH
Hz, 2H, NCH2), 6.53 (d, JHH ) 9.0 Hz, 1H, Py), 7.35–7.39 (m, 1H,
4
3
Py), 8.10 (d, JHH ) 2.1 Hz, 1H, Py), 10.19 (s, 1H, NH). Anal. Calcd
) 9.3 Hz, 1H), 7.20 (d, JHH ) 9.3 Hz, 1H).
for C17H24N4O3S (%): C, 56.02; H, 6.64; N, 15.37. Found: C, 56.27;
H, 6.52; N, 15.27.
Synthetic Procedure for VIII. A mixture of 6-chloropyrimidine-
3-carboxamide (VII) (1.74 g, 11.1 mmol), diethylamine (2.67 mL),
and DMF (7 mL) was heated to 130 °C for 6 h. Then the mixture was
cooled and poured into water. 6-(Dimethylamino)pyrimidine-3-car-
boxamide (VIII) was filtered as a white solid: yield, 34.2%; mp,
231–232 °C; 1H NMR (DMSO-d6), δ 3.18 (s, 6H), 6.63 (d, 3JHH ) 9.0
Hz, 1H), 7.07 (br s, 1H), 7.71 (br s, 1H), 7.91–7.95 (m, 1H), 8.60 (d,
4JHH ) 1.8 Hz, 1H). Anal. Calcd for C8H11N3O (%): C, 58.17; H, 6.71;
N, 25.44. Found: C, 58.29; H, 6.59; N, 25.24.
Data for I-8: yield, 44.0%; mp, 73–74 °C; 1H NMR (CDCl3), δ
1.20 (t, 3JHH ) 7.2 Hz, 3H, CH3), 1.41 (d, 3JHH ) 7.2 Hz, 6H, C(CH3)2),
3
3.00 (s, 6H, N(CH3)2), 3.20–3.29 (m, 1H, CH), 3.57 (q, JHH ) 7.2
3
3
Hz, 2H, OCH2), 3.68 (t, JHH ) 5.1 Hz, 2H, OCH2), 4.25 (t, JHH
)
3
5.4 Hz, 2H, CO2CH2), 4.45 (d, JHH ) 5.7 Hz, 2H, NCH2), 6.52 (d,
3JHH ) 8.7 Hz, 1H, Py), 7.33–7.36 (m, 1H, Py), 8.06 (d, JHH ) 2.1
4
Hz, 1H, Py), 10.45 (s, 1H, NH). Anal. Calcd for C19H28N4O3 (%): C,
63.31; H, 7.83; N, 15.54. Found: C, 63.21; H, 7.71; N, 15.78.
Data for I-9: yield, 94.0%; mp, 54–56 °C; 1H NMR (CDCl3), δ
Synthetic Procedure for IId. To a suspension of LiAlH4 (1.5 g, 40
mmol) in anhydrous tetrahydrofuran (50 mL) was added 6-(dimethy-
lamino)pyrimidine-3-carboxamide (VIII) (1.36 g, 8.2 mmol) at 0 °C.
The reaction mixture was then stirred at room temperature for 4 h. To
the mixture was carefully added aqueous sodium hydroxide to
decompose excessive LiAlH4, and the inorganic salt was filtered. The
filtrate was diluted with water and extracted with chloroform. The
organic layer was dried and concentrated in vacuo to give crude IId
(1.02 g) as oil: crude yield, 89.0%; 1H NMR (CDCl3), δ 1.60 (br s,
2H), 3.08 (s, 6H), 3.73 (s, 2H), 6.51 (d, 3JHH ) 8.7 Hz, 1H), 7.44 (dd,
1.21 (t, 3JHH ) 6.9 Hz, 3H, CH3), 2.70 (s, 3H, SCH3), 3.57 (q, 3JHH
)
3
3
7.8 Hz, 2H, OCH2), 3.69 (t, JHH ) 4.8 Hz, 2H, OCH2), 4.29 (t, JHH
) 5.4 Hz, 2H, CO2CH2), 4.72–4.80 (m, 4H, CF3CH2, NCH2), 6.89 (d,
4
3JHH ) 8.4 Hz, 1H, Py), 7.54–7.58 (m, 1H, Py), 8.07 (d, JHH ) 2.4
Hz, 1H, Py), 10.29 (s, 1H, NH). Anal. Calcd for C17H20F3N3O4S (%):
C, 48.68; H, 4.81; N, 10.02. Found: C, 48.70; H, 4.96; N, 9.95.
Data for I-11: yield, 98.0%; mp, 79–81 °C; 1H NMR (CDCl3), δ
1.21 (t, 3JHH ) 6.9 Hz, 3H, CH3), 2.73 (s, 3H, SCH3), 3.57 (q, 3JHH
)
4
4
3JHH ) 8.7 Hz, JHH ) 2.4 Hz, 1H), 8.02 (d, JHH ) 2.4 Hz, 1H).
General Synthetic Procedures for the Title Compounds I. A
mixture of IIIa (or IIIb or IIIc) (5 mmol) and crude II (6 mmol) and
ethanol (20 mL) was refluxed for 1–3 h (monitored by TLC) and then
evaporated under reduced pressure to give crude product. The product
was purified by vacuum column chromatography on a silica gel.
3
3
6.9 Hz, 2H, OCH2), 3.69 (t, JHH ) 5.1 Hz, 2H, OCH2), 4.30 (t, JHH
) 5.1 Hz, 2H, CO2CH2), 4.91 (d, 3JHH ) 7.2 Hz, 2H, NCH2), 7.48 (s,
1H, thiazole), 10.31 (s, 1H, NH). Anal. Calcd for C13H16BrN3O3S2 (%):
C, 38.43; H, 3.97; N, 10.34. Found: C, 38.19; H, 3.96; N, 10.31.
Data for I-12: yield, 80.0%; mp, 76–78 °C; 1H NMR (CDCl3), δ
1.21 (t, 3JHH ) 6.9 Hz, 3H, CH3), 1.43 (d, 3JHH ) 6.9 Hz, 6H, C(CH3)2),
1
3
Data for I-1: yield, 91.1%; mp, 118–120 °C; H NMR (CDCl3), δ
3.14–3.21 (m, 1H, CH), 3.58 (q, JHH ) 6.9 Hz, 2H, OCH2), 3.69 (t,
1.21 (t, 3JHH ) 6.8 Hz, 3H, CH3), 1.36 (d, 3JHH ) 6.8 Hz, 6H, C(CH3)2),
3JHH ) 5.1 Hz, 2H, CH2O), 4.29 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.74
3
3
3.02–3.20 (m, 1H, CH), 3.57 (q, JHH ) 7.2 Hz, 2H, OCH2), 3.69 (t,
(d, JHH ) 6.0 Hz, 2H, NCH2), 7.47 (s, 1H, thiazole), 10.54 (s, 1H,
3JHH ) 5.2 Hz, 2H, OCH2), 4.28 (t, 3JHH ) 5.2 Hz, 2H, CO2CH2), 4.57
NH). Anal. Calcd for C15H20BrN3O3S (%): C, 44.78; H, 5.01; N, 10.44.
Found: C, 44.50; H, 5.03; N, 10.28.
3
3
(d, JHH ) 5.6 Hz, 2H, NCH2), 7.18 (d, JHH ) 8.4 Hz, 2H, Ph), 7.35
3
1
(d, JHH ) 8.4 Hz, 2H, Ph), 10.56 (s, 1H, NH).
Data for I-13: yield, 87.5%; yellow oil; H NMR (CDCl3), δ 1.21
Data for I-2: yield, 95.0%; mp, 72–73 °C; 1H NMR (CDCl3), δ
(t, 3JHH ) 6.9 Hz, 3H, CH3), 1.43 (t, 3JHH ) 7.2 Hz, 3H, CH3), 2.72 (s,
1.20 (t, 3JHH ) 6.8 Hz, 3H, CH3), 2.66 (s, 3H, SCH3), 3.56 (q, 3JHH
)
3
3
3H, SCH3), 3.57 (q, JHH ) 6.9 Hz, 2H, OCH2), 3.69 (t, JHH ) 5.1
3
3
Hz, 2H, CH2O), 4.29 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.44 (q, 3JHH
7.2 Hz, 2H, OCH2), 4.78 (d, JHH ) 6.0 Hz, 2H, NCH2), 7.02 (s, 1H,
thiazole), 10.21 (s, 1H, NH). HRMS, m/z 394.0864. Calcd for
C15H21N3O4S2 + Na: 394.0866.
)
6.8 Hz, 2H, OCH2), 3.69 (t, JHH ) 5.2 Hz, 2H, OCH2), 4.29 (t, JHH
) 4.8 Hz, 2H, CO2CH2), 4.74 (d, 3JHH ) 5.6 Hz, 2H, NCH2), 7.17 (d,
3JHH ) 8.4 Hz, 2H, Ph), 7.34 (d, 3JHH ) 8.4 Hz, 2H, Ph), 10.33 (s, 1H,
NH).
3
Data for I-3: yield, 90.0%; mp, 69–70 °C; 1H NMR (CDCl3), δ
1
Data for I-14: yield, 56.3; yellow oil; H NMR (CDCl3), δ 1.02 (t,
1.21 (t, 3JHH ) 7.2 Hz, 3H, CH3), 2.69 (s, 3H, SCH3), 3.57 (q, 3JHH
)
3JHH ) 6.9 Hz, 3H, CH3), 1.21 (t, JHH ) 7.0 Hz, 3H, CH3), 1.43 (d,
3
3
3
3JHH ) 6.9 Hz, 6H, C(CH3)2), 3.18–3.27 (m, 1H, CH), 3.57 (q, 3JHH
)
6.9 Hz, 2H, OCH2), 3.69 (t, JHH ) 5.1 Hz, 2H, OCH2), 4.30 (t, JHH
) 5.1 Hz, 2H, CO2CH2), 4.78 (d, 3JHH ) 6.0 Hz, 2H, NCH2), 7.36 (d,
3
3
6.9 Hz, 2H, OCH2), 3.69 (t, JHH ) 5.1 Hz, 2H, OCH2), 4.29 (t, JHH
) 5.1 Hz, 2H, CO2CH2), 4.44 (q, 3JHH ) 7.0 Hz, 2H, OCH2), 4.78 (d,
3JHH ) 6.0 Hz, 2H, NCH2), 7.02 (s, 1H, thiazole), 10.21 (s, 1H, NH).
HRMS, m/z 390.1457. Calcd for C17H25N3O4S + Na: 390.1458.
3JHH ) 8.4 Hz, 1H, Py), 7.55 (dd, JHH ) 8.4 Hz, JHH )2.4 Hz, 1H,
3
4
4
Py), 8.33 (d, JHH ) 2.4 Hz, 1H, Py), 10.35 (s, 1H, NH).
Data for I-4: yield, 60.0%; mp, 79–80 °C; 1H NMR (CDCl3), δ
1.21 (t, 3JHH ) 6.8 Hz, 3H, CH3), 2.69 (s, 3H, SCH3), 3.57 (q, 3JHH
)
Data for I-15: yield, 85.0%; yellow oil; H NMR (CDCl3), δ 1.02
1
3
3
6.8 Hz, 2H, OCH2), 3.70 (t, JHH ) 4.8 Hz, 2H, OCH2), 4.30 (t, JHH
) 5.1 Hz, 2H, CO2CH2), 4.76 (d, 3JHH ) 6.3 Hz, 2H, NCH2), 7.43–7.53
(m, 2H, Py), 8.31 (d, 4JHH ) 2.4 Hz, 1H, Py), 10.34 (s, H, NH). Anal.
Calcd for C15H18BrN3O3S (%): C, 45.01; H, 4.53; N, 10.50. Found: C,
44.96; H, 4.57; N, 10.41.
(t, 3JHH ) 6.9 Hz, 3H, CH3), 1.21 (t, 3JHH ) 6.9 Hz, 3H, CH3), 1.76–1.88
3
(m, 2H, CCH2C), 2.72 (s, 3H, SCH3), 3.57 (q, JHH ) 6.9 Hz, 2H,
OCH2), 3.69 (t, 3JHH ) 5.1 Hz, 2H, OCH2), 4.27–4.36 (m, 4H, OCH2,
3
CO2CH2), 4.78 (d, JHH ) 6.0 Hz, 2H, NCH2), 7.01 (s, 1H, thiazole),
10.21 (s, 1H, NH). HRMS, m/z 408.1018. Calcd for C16H23N3O4S2 +
Data for I-5: yield, 90.1%; mp, 77–79 °C; 1H NMR (CDCl3), δ
Na: 408.1022.
3
3
1
1.21 (t, JHH ) 6.9 Hz, 3H, CH3), 1.28 (t, JHH ) 7.8 Hz, 3H, CH3),
Data for I-16: yield, 70.0%; yellow oil; H NMR (CDCl3), δ 1.02
(t, JHH ) 6.9 Hz, 3H, CH3), 1.21 (t, JHH ) 7.2 Hz, 3H, CH3), 1.43
(d, 3JHH ) 6.9 Hz, 6H, C(CH3)2), 1.76–1.88 (m, 2H, CCH2C), 3.18–3.27
3
3
3
3
2.64 (q, JHH ) 7.8 Hz, 2H, CH2CdC), 3.57 (q, JHH ) 6.9 Hz, 2H,
3
3
OCH2), 3.69 (t, JHH ) 5.4 Hz, 2H, OCH2), 4.28 (t, JHH ) 5.1 Hz,

2-Cyanoacrylates
J. Agric. Food Chem., Vol. 56, No. 1, 2008 207
Chart 1. Framework of Molecular Structures
Scheme 1
Scheme 2
3
3
(m, 1H, CH), 3.58 (q, JHH ) 6.9 Hz, 2H, OCH2), 3.69 (t, JHH ) 5.1
Hz, 2H, OCH2), 4.27 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.34 (t, 3JHH
7.2 Hz, 2H, OCH2), 4.61 (d, JHH ) 6.0 Hz, 2H, NCH2), 7.00 (s, 1H,
thiazole), 10.43 (s, 1H, NH). HRMS, m/z 404.1612. Calcd for
C18H27N3O4S + Na: 404.1614.
Data for I-17: yield, 89.0%; yellow oil; H NMR (CDCl3), δ 1.21
(t, JHH ) 6.9 Hz, 3H, CH3), 1.40 (d, JHH ) 7.2 Hz, 6H, C(CH3)2),
2.72 (s, 3H, SCH3), 3.57 (q, JHH ) 6.9 Hz, 2H, OCH2), 3.68 (t, JHH
) 5.1 Hz, 2H, OCH2), 4.29 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.77 (d,
3JHH ) 6.0 Hz, 2H, NCH2), 5.12–5.20 (m, 1H, CHO), 7.00 (s, 1H,
thiazole), 10.20 (s, 1H, NH). HRMS, m/z 408.1023. Calcd for
C16H23N3O4S2 + Na: 408.1022.
)
3
1
3
3
3
3
1
Data for I-18: yield, 67.0%; yellow oil; H NMR (CDCl3), δ 1.21
(t, 3JHH ) 6.9 Hz, 3H, CH3), 1.39–1.44 (m, 12H, C(CH3)2, OC(CH3)2),
3
3.18–3.27 (m, 1H, CH), 3.58 (q, JHH ) 6.9 Hz, 2H, OCH2), 3.69 (t,
3JHH ) 5.1 Hz, 2H, CH2O), 4.27 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.60
(d, 3JHH ) 6.0 Hz, 2H, NCH2), 5.12–5.20 (m, 1H, CHO), 6.99 (s, 1H,
thiazole), 10.42 (s, 1H, NH). HRMS, m/z 404.1613. Calcd for
C18H27N3O4S + Na: 404.1614.
1
Data for I-19: yield, 90.6%; yellow oil; H NMR (CDCl3), δ 1.20
(t, JHH ) 6.9 Hz, 3H, CH3), 2.73 (s, 3H, SCH3), 3.57 (q, JHH ) 6.9
Hz, 2H, OCH2), 3.69 (t, JHH ) 5.1 Hz, 2H, CH2O), 4.27 (t, JHH
3
3
3
3
)
5.1 Hz, 2H, CO2CH2), 4.75–4.83 (m, 4H, NCH2, CF3CH2O), 7.04 (s,
1H, thiazole), 10.24 (s, 1H, NH). HRMS, m/z 448.0580. Calcd for
C15H18F3N3O4S2 + Na: 448.0583.
Data for I-20: yield 92.1%; yellow oil; 1H NMR (CDCl3), δ 1.21 (t,
3
3JHH ) 6.9 Hz, 3H, CH3), 1.43 (d, JHH ) 7.2 Hz, 6H, C(CH3)2),
3
3.17–3.27 (m, 1H, CH), 3.58 (q, JHH ) 6.9 Hz, 2H, OCH2), 3.69 (t,
3JHH ) 5.1 Hz, 2H, OCH2), 4.28 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.63
3
3
(d, JHH ) 6.0 Hz, 2H, NCH2), 4.80 (q, JHF ) 8.1 Hz, 2H, CF3CH2),
7.03 (s, 1H, thiazole), 10.46 (s, 1H, NH). HRMS, m/z 444.1170. Calcd
for C17H22F3N3O4S + Na: 444.1175.
Data for I-21: yield, 69.0%; mp, 103–104 °C; 1H NMR (CDCl3), δ
1.21 (t, 3JHH ) 7.0 Hz, 3H, CH3), 2.71 (s, 3H, SCH3), 3.58 (q, 3JHH
)
3
3
7.0 Hz, 2H, OCH2), 3.71 (t, JHH ) 5.1 Hz, 2H, OCH2), 4.32 (t, JHH
) 5.1 Hz, 2H, CO2CH2), 5.12 (d, 3JHH ) 6.0 Hz, 2H, NCH2), 7.39 (d,
3JHH ) 9.0 Hz, 1H, pyridazine), 7.56 (d, 3JHH ) 9.0 Hz, 1H, pyridazine),
10.64 (s, 1H, NH). Anal. Calcd for C14H17ClN4O3S (%): C, 47.12; H,
4.80; N, 15.70. Found: C, 47.13; H, 4.86; N, 15.89.
Data for I-22: yield, 68.0%; mp, 116–117 °C; 1H NMR (CDCl3), δ
1.20 (t, 3JHH ) 7.0 Hz, 2H, CH3), 1.36 (d, 3JHH ) 7.2 Hz, 6H, C(CH3)2),
3.20 (m, 1H, CH), 3.57 (q, 3JHH ) 6.8 Hz, 2H, OCH2), 3.70 (t, 3JHH
)
for C18H26N4O4 (%): C, 59.65; H, 7.23; N, 15.46. Found: C, 59.80; H,
7.40; N, 15.21.
3
4.8 Hz, 2H, OCH2), 4.30 (t, JHH ) 4.8 Hz, 2H, CO2CH2), 4.94 (d,
3
3JHH ) 6.0 Hz, 2H, NCH2), 7.44 (d, JHH ) 8.8 Hz, 1H, pyridazine),
1
Data for I-25: yield, 43.0%; yellow oil; H NMR (CDCl3), δ 1.21
3
7.59 (d, JHH ) 8.8 Hz, 1H, pyridazine), 10.88 (s, 1H, NH). Anal.
3
3
(t, JHH ) 6.9 Hz, 3H, CH3), 2.70 (s, 3H, SCH3), 3.57 (q, JHH ) 7.0
Calculated for C16H21ClN4O3 (%): C, 54.47; H, 6.00; N, 15.88. Found:
C, 54.63; H, 6.12; N, 16.06.
Data for I-23: yield, 58.0%; mp, 72–73 °C; 1H NMR (CDCl3), δ
Hz, 2H, OCH2), 3.64 (t, 3JHH ) 4.9 Hz, 4H, N(CH2)2), 3.69 (t, 3JHH
)
3
5.1 Hz, 2H, OCH2), 3.85 (t, JHH ) 4.8 Hz, 4H, O(CH2)2), 4.30 (t,
3JHH ) 5.1 Hz, 2H, CO2CH2), 4.96 (d, JHH ) 5.7 Hz, 2H, NCH2),
3
3
3
3
3
1.21 (t, JHH ) 6.9 Hz, 3H, CH3), 1.45 (t, JHH ) 7.0 Hz, 3H, CH3),
6.90 (d, JHH ) 9.0 Hz, 1H, pyridazine), 7.17 (d, JHH ) 9.0 Hz, 1H,
pyridazine), 10.57 (s, 1H, NH). Anal. Calcd for C18H25N5O4S (%): C,
53.06; H, 6.18; N, 17.19. Found: C, 52.51; H, 6.82; N, 17.37.
3
3
2.70 (s, 3H, SCH3), 3.57 (q, JHH ) 6.9 Hz, 2H, OCH2), 3.70 (t, JHH
) 5.2 Hz, 2H, OCH2), 4.31 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.59 (q,
3JHH ) 7.1 Hz, 2H, OCH2), 4.50 (d, JHH ) 6.0 Hz, 2H, NCH2), 6.97
3
1
Data for I-26: yield, 31.0%; yellow oil; H NMR (CDCl3), δ 1.21
3
3
3
3
(d, JHH ) 9.0 Hz, 1H, pyridazine), 7.28 (d, JHH ) 9.0 Hz, 1H,
pyridazine), 10.64 (s, 1H, NH). Anal. Calcd for C16H22N4O4S (%): C,
52.44; H, 6.05; N, 15.29. Found: C, 52.23; H, 5.87; N, 14.83.
(t, JHH ) 7.0 Hz, 3H, CH3), 1.37 (d, JHH ) 7.2 Hz, 6H, C(CH3)2),
3.29 (m, 1H, CH), 3.58 (q, 3JHH ) 7.0 Hz, 2H, OCH2), 3.64 (t, 3JHH
)
3
4.9 Hz, 4H, N(CH2)2), 3.70 (t, JHH ) 5.2 Hz, 2H, OCH2), 3.85 (t,
1
3
Data for I-24: yield, 44.0%; yellow oil; H NMR (CDCl3), δ 1.21
3JHH ) 4.8 Hz, 4H, O(CH2)2), 4.29 (t, JHH ) 5.2 Hz, 2H, CO2CH2),
3
3
3
3
(t, JHH ) 7.0 Hz, 3H, CH3), 1.37 (d, JHH ) 7.2 Hz, 6H, C(CH3)2),
4.78 (d, JHH ) 5.7 Hz, 2H, NCH2), 6.92 (d, JHH ) 9.3 Hz, 1H,
pyridazine), 7.20 (d, JHH ) 9.3 Hz, 1H, pyridazine), 10.78 (s, 1H,
3
3
3
1.45 (t, JHH ) 7.2 Hz, 3H, CH3), 3.26 (m, 1H, CH), 3.58 (q, JHH
)
3
3
7.0 Hz, 2H, OCH2), 3.70 (t, JHH ) 5.1 Hz, 2H, OCH2), 4.30 (t, JHH
NH). Anal. Calcd for C20H29N5O4 (%): C, 59.54; H, 7.24; N, 17.36.
Found: C, 59.14; H, 7.43; N, 17.30.
) 5.1 Hz, 2H, CO2CH2), 4.59 (q, 3JHH ) 7.2 Hz, 2H, OCH2), 4.82 (d,
3JHH ) 6.0 Hz, 2H, NCH2), 6.99 (d, JHH ) 9.0 Hz, 1H, pyridazine),
Data for I-27: yield, 68.0%; mp, 75–76 °C; 1H NMR (CDCl3), δ
3
7.31 (d, 3JHH ) 9.0 Hz, 1H, pyridazine), 10.85 (s, 1H, NH). Anal. Calcd
1.21 (t, 3JHH ) 7.2 Hz, 3H, CH3), 2.72 (s, 3H, SCH3), 3.57 (q, 3JHH
)

208 J. Agric. Food Chem., Vol. 56, No. 1, 2008
Liu et al.
Table 2. Herbicidal Activities of Compounds I (1.5 kg/ha, Percent
Inhibition)
Scheme 3
postemergence treatment
amaranth hairy
compd rape pigweed alfalfa crabgrass rape pigweed alfalfa crabgrass
preemergence treatment
amaranth hairy
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
100
100
100
100
100
100
100
100
100
100
100
100
100
100
97.8
80.9
100
68.9
12.9
41.3
59.9
77.8
32.1
51.6
58.3
54.2
37.1
26.8
30.8
62.6
41.4
57.3
48.7
53.6
43.4
60.9
53.3
27.8
31.4
24.2
50.7
32.8
15.2
45.1
26.0
74.0
40.8
23.4
60.5
41.3
13.2
46.4
4.4
40.5
59.4
13.7
91.9
21.6
48.6
13.5
75.7
0
67.6
29.7
18.9
43.2
37.8
27.0
27.0
40.5
0
0
1.5
12.0
28.8
0
0
27.9
0
15.7
8.2
1.7
14.8
5.4
17.6
0
4.5
1.7
1.7
0
12.9
24.8
18.6
0
18.8
16.8
28.7
52.5
0
28.7
8.9
3.0
44.6
0
0
6.9
14.8
6.9
8.9
34.6
0
10.9
0
31.2 24.9
89.9 68.9
60.0 23.9
95.2 71.9
42.4 68.7
45.6 37.4
88.0 29.3
3
7.2 Hz, 2H, OCH2), 4.05 (s, 3H, OCH3), 3.69 (t, JHH ) 5.1 Hz, 2H,
OCH2), 4.30 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.73 (d, 3JHH ) 5.7 Hz,
2H, NCH2), 8.48 (s, 2H, pyrimidine), 10.32 (s, 1H, NH). Anal. Calcd
for C15H20N4O4S (%): C, 51.12; H, 5.72; N, 15.90. Found: C, 51.19;
H, 5.44; N, 15.70.
100
100
88.0
100
10.0
45.6 70.3
36.0 28.7
48.0 82.2
51.2 23.3
51.2 48.7
Data for I-28: yield, 43.2%; mp, 52–54 °C; 1H NMR (CDCl3), δ
I-10 100
I-11 100
I-12 100
I-13 100
I-14 100
I-15 100
I-16 100
I-17 100
I-18 100
I-19 100
I-20 100
3
3
1.21 (t, JHH ) 7.2 Hz, 3H, CH3), 1.31 (t, JHH ) 7.8 Hz, 3H, CH3),
2.69 (q, 3JHH ) 7.8 Hz, 2H, CCH2), 3.57 (q, 3JHH ) 7.2 Hz, 2H, OCH2),
100
100
100
100
100
100
100
98.7
100
21.8
91.6
32.9
70.2
24.0
19.1
15.5
20.7
3.4
3
3
3.68 (t, JHH ) 5.1 Hz, 2H, OCH2), 4.04 (s, 3H, OCH3), 4.28 (t, JHH
) 5.1 Hz, 2H, CO2CH2), 4.51 (d, 3JHH ) 5.7 Hz, 2H, NCH2), 8.47 (s,
2H, pyrimidine), 10.10 (s, 1H, NH). Anal. Calcd for C16H22N4O4 (%):
C, 57.47; H, 6.63; N, 16.76. Found: C, 57.31; H, 6.75; N, 16.63.
Data for I-29: yield, 82.6%; mp, 108–110 °C; 1H NMR (CDCl3), δ
1.21 (t, 3JHH ) 7.2 Hz, 3H, CH3), 1.43 (d, 3JHH ) 6.9 Hz, 6H, C(CH3)2),
49.6
52.8
54.4 26.0
0
9.8
60.8 51.4 100
47.2 65.4
95.2 71.9
28.8 12.5
48.0 59.5
43.2
3
3.57 (q, JHH ) 7.2 Hz, 2H, OCH2), 3.18–3.22 (m, 1H, CH), 3.69 (t,
51.0
43.2
27.0
56.8
54.0
13.5
5.4
58.1
34.6
22.2
15.9
9.5
3JHH ) 5.1 Hz, 2H, OCH2), 4.04 (s, 3H, OCH3), 4.27 (t, JHH ) 5.1
3
I-21
I-22 100
I-23
I-24 100
81.0
0
4.5
0
3
Hz, 2H, CO2CH2), 4.56 (d, JHH ) 5.4 Hz, 2H, NCH2), 8.47 (s, 2H,
64.6
0.8
0
pyrimidine), 10.49 (s, 1H, NH). Anal. Calcd for C17H24N4O4 (%): C,
58.61; H, 6.94; N, 16.08. Found: C, 58.58; H, 6.91; N, 15.97.
Data for I-30: yield, 64.6%; mp, 90–92 °C; 1H NMR (CDCl3), δ
57.6 44.9
2.4 10.9
13.6 49.8
2.2 42.4
2.2 51.5
52.2
8.7
0
0
26.7
6.9
I-25
I-26
I-27
I-28
I-29
I-30
18.1
10.1
2.6
42.8
29.4
57.1
31.1
21.8
20.3
2.3
10.5
3
3
85.4
28.8
63.7
19.4
16.1
22.8
26.0
36.0
46.2
12.5
35.7
40.0
0
1.21 (t, JHH ) 7.2 Hz, 3H, CH3), 1.44 (t, JHH ) 7.2 Hz, 3H, CH3),
3
3
2.72 (s, 3H, SCH3), 3.57 (q, JHH ) 7.2 Hz, 2H, OCH2), 3.69 (t, JHH
) 7.2 Hz, 2H, OCH2), 4.29 (t, 3JHH ) 5.1 Hz, 2H, CO2CH2), 4.44 (q,
0
0
0
80.0
0
0
3JHH ) 7.2 Hz, 2H, OCH2), 4.72 (d, JHH ) 5.7 Hz, 2H, NCH2), 8.45
3
26.4
37.8
I-31a 47.5
(s, 2H, pyrimidine), 10.30 (s, 1H, NH). Anal. Calcd for C16H22N4O4S
(%): C, 52.44; H, 6.05; N, 15.29. Found: C, 52.32; H, 6.04; N,
15.21.
I-32a 97.2 100
100
57.6
0
3.2
12.6
22.1
I-33a 88.2
I-34a 51.9
37.8
27.4
33.6
Crystal Structure Determination. The crystal structure of the
compound I-11 was determined, and X-ray intensity data were recorded
on a Bruker SMART 1000 CCD diffraction meter using graphite
monochromated Mo KR radiation (λ ) 0.71073 Å). In the range of
2.05° e θ e 26.36°, 2312 independent reflections were obtained. All
calculations were refined anisotropically. All hydrogen atoms were
located from a difference Fourier map and were placed at calculated
positions and were included in the refinements in the riding mode with
isotropic thermal parameters. Final R and Rw values were 0.0387 and
0.0786, respectively {ω ) 1/[σ2 (F) + 99.0000 F2]}, and S )
1.024.
Biological Tests. In ViVo Herbicidal ActiVity. Two dicotyledon crops,
rape (Brassica napus L.) and amaranth pigweed (Amaranthus retrof-
lexus), and two monocotyledon crops, alfalfa (Medicago satiVa L.) and
hairy crabgrass (Digitaria sanguinalis L. Scop.), were used to test the
herbicidal activities of compounds I-1 to I-30 using a previously
reported procedure (10).
a The data of I-31 to I-34 were taken from published work (10).
In Vitro Measurement of the Hill Reaction. Hill reaction activity
was measured as terms of photoreduction of 2,6-dichlorophenol-
indophenol (DCPIP) mainly as described by Holt and French (17).
Preparation of functional chloroplasts and the Hill reaction system were
modified suitably.
Chloroplasts were isolated from fresh spinach (Spinacea oleracea
L.) leaves. Plant material was homogenized in ice-cold extraction buffer
(pH 7.8) containing 0.4 M sucrose, 10 mM NaCl, and 50 mM Tris-
HCl. The homogenate was filtered through surgical gauze, and the
filtrate was then centrifuged at 4 °C for 3 min at 120g. The supernatant
was collected and recentrifuged for 5 min at 1000g. Pelleted chloroplasts
were finally resuspended in the same buffer, and the chloroplast
suspension was kept on ice and away from bright light before Hill
reaction measurement.
The rate of photosynthetic electron transport was measured by
following light-driven DCPIP reduction. Chloroplast suspension was
appropriately diluted before use. The Hill reaction mixture (3 mL)
contained the following components: 2.5 mL of reacting buffer (350
mM NaCl, 10 mM Tris-HC1, pH 7.8), 0.35 mL of 0.3 mM DCPIP,
and 0.15 mL of chloroplast suspension. The assay was initiated by
exposure to light (360 µmol m-2 s-1) for 2 min, and the rate of DCPIP
reduction was measured against an exact blank at 620 nm. The effect
of compounds upon the Hill reaction was evaluated in parallel assays
in which the compounds were added to the reaction mixture to
concentrations ranging from 0.01 mg/L to 0.3 mg/mL. Each dose had
at least triplicate samples. The concentrations causing 50% inhibition
(IC50) of in vitro activity were estimated utilizing the linear regression
equation of activity values plotted against the logarithm of inhibitor
concentration.
Figure 1. Crystal of compound I-11. Hydrogen atoms except H2A are
omitted for clarity.

2-Cyanoacrylates
J. Agric. Food Chem., Vol. 56, No. 1, 2008 209
Table 3. Herbicidal Activities of Compounds I (Percent Inhibition)
postemergence treatment
postemergence treatment
compd
dose (kg/ha)
rape
amaranth pigweed
hairy crabgrass
compd
dose (kg/ha)
375
rape
45.4
amaranth pigweed
43.5
hairy crabgrass
I-1
750
375
150
75
100
100
87.7
40.9
100
92.3
78.2
54.5
I-12
750
375
150
75
100
100
62.9
35.3
74.2
56.9
I-2
I-3
I-4
I-5
750
375
150
75
100
100
6.6
0
100
95.2
26.7
17.8
I-13
I-14
I-15
I-16
750
375
93.1
77.3
80.9
70.3
750
375
150
75
100
100
73.8
55.7
100
750
375
100
94.0
63.6
36.8
92.3
73.3
48.0
750
375
98.5
92.5
66.5
42.6
750
375
150
75
100
100
58.4
40.0
100
83.7
750
375
150
75
100
100
57.1
22.3
65.6
48.3
750
375
150
75
96.4
94.6
44.8
8.0
100
100
83.3
74.0
82.8
69.4
I-17
I-18
750
375
79.1
71.9
61.7
40.7
750
375
150
75
100
100
57.1
37.1
63.6
63.6
I-6
I-7
I-8
750
375
100
89.0
84.7
42.6
750
375
91.4
44.1
56.9
39.7
I-19
I-20
750
375
150
75
100
100
56.0
40.9
73.2
63.6
750
375
150
75
100
100
56.7
41.9
78.0
49.3
96.4
85.7
750
375
150
75
100
100
83.3
50.9
100
100
94.6
11.3
8.0
91.4
98.0
76.7
I-9
750
375
100
100
85.0
61.0
15.1
0
I-10
750
375
150
75
100
100
69.4
63.8
100
62.7
I-22
750
375
94.8
95.7
70.3
33.0
I-32a
750
375
70.2
65.0
100
100
67.9
32.1
I-11
750
82.7
72.2
a The data of I-32 were taken from published work (10).
All of the compounds were dissolved in N,N-methylformamide and
then diluted with water, as desired. Controls received similar amounts
of solvent.
were scaled by the CoMFA-STD method in SYBYL. The electrostatic
fields were ignored at the lattice points with maximal steric interactions.
A partial least-squares (PLS) approach was used to derive the 3D-
QSAR, in which the CoMFA descriptors were used as independent
variables, and pIC50 values were used as dependent variables. The cross-
validation with the leave-one-out (LOO) option and the SAMPLS
program, rather than column filtering, was carried out to obtain the
optimal number of components to be used in the final analysis. After
the optimal number of components was determined, a non-cross-
validated analysis was performed without column filtering. The
modeling capability (goodness of fit) was judged by the correlation
coefficient squared, r2, and the prediction capability (goodness of
prediction) was indicated by the cross-validated r2 (q2).
Structure–Activity Relationships. Data Sets for 3D-QSAR Analysis.
Molecular modeling was performed using SYBYL 6.91 software
(Tripos, Inc.). The structures and biological activities of the 29
compounds used to derive the CoMFA analyses model are listed in
Table 4. The crystal structure of compound I-11 was used as a template
to build the other molecular structures. Each structure was fully
geometry-optimized using a conjugate gradient procedure based on the
TRIPOS force field and Gasteiger and Hückel charges. Because these
compounds share a common skeleton, four atoms marked with an
asterisk (shown in Chart 1) were used for rms-fitting onto the
corresponding atoms of the template structure.
CoMFA Descriptors. CoMFA steric and electrostatic interaction
fields were calculated at each lattice intersection on a regularly spaced
grid of 2.0 Å. The grid pattern was generated automatically by the
SYBYL/CoMFA routine, and an sp3 carbon atom with a van der Waals
radius of 1.52 Å and a +1.0 charge was used as the probe to calculate
the steric (Lennard-Jones 6–12 potential) field energies and electrostatic
(Coulombic potential) fields with a distance-dependent dielectric at each
lattice point. Values of the steric and electrostatic fields were truncated
at 30.0 kcal/mol. The CoMFA steric and electrostatic fields generated
RESULTS AND DISCUSSION
Synthesis. The title compounds I were synthesized from
arylmethylamine II and alkyoxy- or methylthio-substituted
cyanoacrylate III with good yields (Scheme 1; Table 1).
Halo-substituted arylmethylamines IIa, IIb, IIc, IIf, and IIk
were prepared by starting from haloaryl methane IV. IV was
reacted with NBS or NCS in the presence of AIBN and afforded

210 J. Agric. Food Chem., Vol. 56, No. 1, 2008
Table 4. Experimental and Predicted Activities of Compounds I
pIC50
Liu et al.
88.64°; that is, they are nearly perpendicular to each other. The
structure was used as the template for studying the 3D-QSAR
analysis.
compd
obsd IC50 (ppm)
obsd
calcda
res
Herbicidal Activity Bioassay. Herbicidal activities of com-
pounds I-1 to I-34 are listed in Table 2. In postemergence
treatment, most of the compounds showed higher herbicidal
activities compared to preemergence treatment, and the com-
pounds exhibited higher herbicidal activities against dicotyledon
weeds (rape and amaranth pigweed) than against monocotyledon
weeds (alfalfa and hairy crabgrass). Benzene-containing com-
pounds (I-1, I-2), pyridine-containing compounds (I-3 to I-9),
and thiazole-containing compounds (I-10 to I-20) gave obvi-
ously higher activities than pyridazine (I-21 to I-26), pyrimidine
(I-27 to I-30), and tetrahydronfuran and furan (I-31 to I-34)
analogues.
I-1
I-2
I-3
I-4
I-5
I-6
I-7
I-8
0.043
0.026
0.167
0.084
0.335
0.099
0.292
0.086
0.048
0.161
0.102
0.107
0.115
0.223
0.05
7.37
7.59
6.78
7.08
6.47
7.00
6.53
7.07
7.32
6.79
6.99
6.97
6.94
6.65
7.30
7.10
7.15
7.12
7.26
7.13
5.40
5.37
5.04
5.42
5.97
4.68
5.16
4.38
5.18
7.04
7.45
7.10
6.83
6.48
7.13
6.33
7.12
7.33
6.75
6.66
6.82
6.81
6.75
7.53
6.90
7.46
6.98
7.32
7.32
5.59
5.21
4.98
5.44
5.71
4.98
5.20
4.30
5.67
0.33
0.14
-0.32
0.25
-0.01
-0.13
0.20
-0.05
-0.01
0.04
0.33
0.15
0.13
-0.10
-0.23
0.20
-0.31
0.14
-0.06
-0.19
-0.19
0.16
0.06
-0.02
0.26
-0.30
-0.04
0.08
I-9
I-10
I-11
I-12
I-13
I-14
I-15
I-16
I-17
I-18
I-19
I-20
I-21
I-22
I-23
I-27
I-30
I-31
I-32
I-33
I-34
Their herbicidal activities at a lower dose revealed the
influence of substituent on their reactivity (Table 3). 3-Isopro-
pylacrylate compounds I-1, I-8, I-12, I-16, and I-20 exhibited
higher activities than 3-methylthio analogues I-2, I-7, I-11, I-15,
and I-19, which indicated the group at this position played an
important role. I-3, I-4, and I-19, although having a 3-methylthio
group, gave relatively high reactivity, which showed that a
suitable substituent on the aromatic ring also imposed a large
effect.
0.08
0.07
0.076
0.055
0.074
3.99
4.3
12.29
3.79
1.45
27.92
6.874
41.4
Inhibitory Activities (in Vitro Activity) on Hill Reaction.
The abilities of selected I compounds were evaluated as
inhibitors of the photosynthetic electron transport by detecting
their inhibiting effects on the Hill reaction. Photosynthetically
active thylakoid membranes were used and isolated from spinach
(S. oleracea L.) leaves. Observed IC50 data are listed in Table
4. Compounds I-1 and I-2 bearing a 4-chlorobenzyl group
exhibited higher inhibitory activities than those bearing other
aromatic compounds. Pyridine-containing compounds I-3 to I-9
and thiazole-containing compounds I-10 to I-20 showed a little
lower activity than I-1 and I-2, but much higher activity than
other compounds. Substituents on aromatic ring showed obvious
roles in activity. For example, compounds containing an alkoxy
group at the pyridine or thiazole ring exhibited different
inhibitory activities from halo-substituted analogues. R2 did play
an important role, but it was different from their in vivo data.
From Table 4, the activities of most compounds bearing a
methylthio group are a little higher than those of compounds
bearing isopropyl.
6.6
-0.49
a Calculated using the CoMFA model.
chloromethyl or bromomethyl compounds V, and then their
reaction with potassium phthalimide gave N-substituted phthal-
imides VI. VI was refluxed with hydrazine to afford the
corresponding methylamine II. Alkoxy-substituted arylmethy-
lamines IIe, IIg, IIh, IIi, IIj, and IIl were prepared from chloro-
arylmethylamine IIc, IIf, or IIk with sodium alkoxide in alcohol
solvent. However, IIo and IIp were obtained from correspond-
ing phthalimides VIo and VIp, which were synthesized by
refluxing VIn with sodium methoxide and ethoxide, respectively
(Scheme 2).
(6-Morpholinopyridazin-3-yl)methanamine IIm was prepared
from (6-chloropyridazin-3-yl)methanamine IIk with morpholine.
5-(Aminomethyl)-N,N-dimethylpyridin-2-amine IId was pre-
pared by the reduction of N,N-dimethylpyridine-5-carboxamide
VIII, which was obtained from 2-chloropyridine-5-carboxamide
VII (Scheme 3).
Most of the intermediates were determined by 1H NMR, and
all new title compounds were characterized with 1H NMR and
elemental analysis (or HRMS).
Structure–Activity Relationships. To further explore the
influence of aromatic rings and their substitutions on the
activity, the analysis of the relationships between the structure
and the in vitro activity was performed by CoMFA, which
correlates the molecular interaction field differences with
differences in the dependent target property. The cross-
validation with LOO option and the SAMPLS program were
used to determine the optimal number of components in
CoMFA 3D-QSAR analyses, and then a non-cross-validated
analysis was performed without column filtering. A model
with q2 (cross-validated r2) ) 0.565 and r2 (non-cross-
validated r2) ) 0.949, four components, was attained
according to the definitions in SYBYL. The observed and
calculated activity values are in Table 4. The models
exhibited a good predictability on these compounds. 3D
coefficient contour plots can view the field effect on the target
property; they are helpful to identify important regions
changing in the steric, electrostatic fields, and they may also
help to identify the possible interaction sites. The compound
I-9 was illustrated to explain the field contributions of
different properties obtained from the CoMFA analyses. The
Crystal Structure Analysis. Compound I-11 was recrystal-
lized from ethyl acetate/petroleum ether to give a colorless
crystal suitable for X-ray single-crystal diffraction with the
following crystallographic parameters: a ) 7.5899(16) Å, b )
21.892(5) Å, c ) 9.352(2) Å, R ) 90.00°, ꢀ ) 106.485(4)°, γ
) 90.00°, µ ) 0.092, V ) 1490.1(6) Å3. The crystal is
monoclinic, and in one unit there are four molecules arranged
in a pattern of central symmetry.
It can be seen from Figure 1 that amino and carbonyl are on
the same side of the vinyl, and there exists an intramolecular
hydrogen bond between the nitrogen atom and the oxygen of
the carbonyl. Due to the hydrogen bond, the atoms H2A-N2-
C5-C7-C9-O1 are close to planar. This plane and the plane of
the thiazole ring (S1-C1-N1-C2-C3) have a dihedral angle of

2-Cyanoacrylates
J. Agric. Food Chem., Vol. 56, No. 1, 2008 211
example, I-9 and I-20, which possess electronegative sub-
stituents on the aromatic ring and have high activity.
In summary, a series of novel 2-cyanoacrylates containing
different aromatic rings were synthesized from arylmethylamine
and alkyoxy- or methylthio-substituted cyanoacrylate with good
1
yields, and their structures were characterized by H NMR,
elemental analysis, and single-crystal X-ray diffraction analysis.
Their herbicidal activities against four weeds and inhibiting
photosynthetic electron transport against isolated chloroplasts
(the Hill reaction) were evaluated. In vivo data showed that
most of the compounds showed greater herbicidal activities in
postemergence treatment than in preemergence treatment. In
postemergence treatment, most of the compounds exhibited
higher herbicidal activities against dicotyledon weeds (rape and
amaranth pigweed) than against monocotyledon weeds (alfalfa
and hairy crabgrass). Both in vivo and in vitro data showed
that the compounds containing benzene, pyridine, and thiazole
moieties gave higher activities than those containing pyrimidine,
pyridazine, furan, and tetrahedronfuran moieties. 3D-QSAR
analysis based on in vitro data showed that a bulky and
electronegative group around the para-position of the aromatic
rings would have the potency to increase the activity, and further
study is underway.
Figure 2. Steric maps from the CoMFA model. Compound I-9 is shown
inside the field. Sterically favored areas (contribution level of 80%) are
represented by green polyhedra. Sterically disfavored areas (contribution
level of 20%) are represented by yellow polyhedra.
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Received for review September 26, 2007. Revised manuscript received
November 14, 2007. Accepted November 14, 2007. This work was
supportedbytheNationalKeyProjectforBasicResearch(2003CB114400),
National Key Project of Scientific and Technical Supporting Programs
(2006BAE01A01-5), and the National Natural Science Foundation of
China (20421202) and Program for New Century Excellent Talents in
University (NCET-04-0228).
JF072851X