Synthesis and herbicidal activities of novel 3-N-substituted amino-6-methyl-4-(3-trifluoromethylphenyl)pyridazine derivatives

Article abstract of DOI:10.1021/jf800900h

4-(3-Trifluoromethylphenyl)pyridazine is a new series of compounds with bleaching and herbicidal activities. Starting from ethyl 2-(3- trifluoromethylphenyl)acetate, an important intermediate 7 was synthesized in five steps with a moderate total yield of

Full text of DOI:10.1021/jf800900h

J. Agric. Food Chem. 2008, 56, 6567–6572 6567
Synthesis and Herbicidal Activities of Novel
3-N-Substituted
Amino-6-methyl-4-(3-trifluoromethylphenyl)pyridazine
Derivatives
HAN XU,†,‡ XU-HONG HU,† XIAO-MAO ZOU,*,† BIN LIU,† YOU-QUAN ZHU,†
YONG WANG,§ FANG-ZHONG HU,† AND HUA-ZHENG YANG*,†
State Key Laboratory of Elemento-organic Chemistry, Research Institute of Elemento-organic
Chemistry, and Department of Biology, College of Life Sciences, Nankai University,
Tianjin 300071, China
4-(3-Trifluoromethylphenyl)pyridazine is a new series of compounds with bleaching and herbicidal
activities. Starting from ethyl 2-(3-trifluoromethylphenyl)acetate, an important intermediate 7 was
synthesized in five steps with a moderate total yield of 51.5% in a safe and practical way. Twenty-six
novel 3-N-substituted amino-6-methyl-4-(3-trifluoromethylphenyl)pyridazine derivatives were synthe-
sized and evaluated through a Spirodela polyrrhiza test and greenhouse test. Some compounds can
completely inhibit Chl at 1 µg/mL and exhibit equal or higher herbicidal activities with the commercial
bleaching herbicide diflufenican against dicotyledonous plants at a rate of 75 g/ha.
KEYWORDS: 3-Trifluoromethylphenyl; pyridazine; herbicidal activity; bleaching activity; synthesis
INTRODUCTION
ylamino group at the 5-position of the central ring, can control
annual grasses at 1-8 kg/ha (4). When the methylamino group
was replaced by an amino or methoxy group, the bleaching
activity was decreased (5). Another PDS inhibitor that is amino-
substituted is flurtamone; it possesses a methylamino group at
the central dihydrofuranone ring and controls annual broad grass
at 250-500 g/ha. For diphenylpyrimidines, modification of the
5-substituent from CH3 to CH3NH or to CH3CH2NH increased
the inhibitory properties considerably (6). We also noticed some
higher active PDS inhibitors such as diflufenican, used at
125-250 g/ha, in which the central heterocycle carried two
substituted phenyl rings.
Carotenoids are essential components for the assembly of the
photosynthetic apparatus of green plants. A lack of carotenoid
synthesis, which is inhibited by corresponding compounds, may
lead to typical bleaching symptoms in plants. Commercially
important bleaching herbicides are found among the phytoene
desaturase inhibitors (1, 2).
Typical and efficient bleaching compounds possess a central
five- or six-membered heterocycle carrying one or two substi-
tuted phenyl rings in which a 3-trifluoromethylphenyl group is
a common structure in all compounds (2). In our previous work
(3), it was indicated that 1 showed better bleaching and
herbicidal activities, with a Chl inhibition of >80% at 10 µg/
mL for most of compounds and that 1a,b controlled >80%
Digitaria adscendens at 300 g/ha (3). This series of compounds
fits quite well into the characteristics of an optimized inhibitor
of phytoene desaturase in which it has a 3-trifluoromethylphenyl
ring, a central heterocycle, and additional substituents (2).
In some series of PDS (phytoene desaturase) inhibitors, the
substituted amino group is important for activity. Norflurazon,
a PDS inhibitor having a central pyridazinone ring and meth-
* To whom correspondence should be addressed. Tel.: +86-22-
23503799; e-mail: (H.-Z.Y.) nk_yanghz@126.com or (X.-M.Z.)
zouxiaomao1111@sina.com.
With the previous options in mind and to find more highly
active compounds, compounds 1 were modified by the replace-
ment of pyridazinone with a pyridazine ring, and substituted
aryl amino or arylalkyl amino groups in the 3-position of the
pyridazine were introduced to give compounds 2. The bioassay
† State Key Laboratory of Elemento-organic Chemistry, Research
Institute of Elemento-organic Chemistry, Nankai University.
‡ Present address: National Engineering Research Center of Pesticides
(Tianjin), Nankai University, Tianjin 300071, China.
§ College of Life Sciences, Nankai University.
10.1021/jf800900h CCC: $40.75  2008 American Chemical Society
Published on Web 07/08/2008

6568 J. Agric. Food Chem., Vol. 56, No. 15, 2008
Scheme 1. Synthetic Route to Compound 8
Xu et al.
Scheme 2. Synthetic Route to the Title Compounds 2
Synthesis of Diethyl 2-Acetyl-3-(3-trifluoromethylphenyl)succi-
nate (5). A mixture of ethyl 2-bromo-2-(3-trifluoromethylphenyl)acetate
(16.5 g, 50 mmol), 3-oxo-butyric acid ethyl ester (6.5 g, 50 mmol),
and anhydrous potassium carbonate (7.6 g, 55 mmol) was dissolved in
100 mL of dry acetone and refluxed for 2 h. The resulting mixture was
cooled and concentrated in vacuo. Water (50 mL) was added and
extracted 3 times with dichloromethane (3 × 75 mL). The organic phase
was washed twice with saturated brine (2 × 50 mL) and concentrated
in vacuo. Crude diethyl 2-acetyl-3-(3-trifluoromethylphenyl)succinate
(5) was obtained without further purification and can be used in the
next step.
results showed that compounds 2 have a higher level of
bleaching and herbicidal activities than compounds 1 using a
S. polyrrhiza test and a greenhouse test. Some compounds can
completely inhibit chlorophyll (Chl) at 1 µg/mL and exhibit
equal or higher herbicidal activities with commercial bleaching
of the herbicide diflufenican against dicotyledonous plants at a
rate of 75 g/ha.
Synthesis of 6-Methyl-4-(3-trifluoromethylphenyl)-4,5-dihydro-
2H-pyridazin-3-one (6). To the crude product of diethyl 2-acetyl-3-
(3-trifluoromethylphenyl)succinate (5) was added a sodium hydroxide
solution (1 M, 100 mL), and then the resulting mixture was refluxed
for 2 h. After being cooled to room temperature, concentrated
hydrochloric acid was added dropwise until the pH was 1. The reaction
mixture was stirred at room temperature for 1 h and then extracted 3
times with dichloromethane (3 × 75 mL). The organic phase was dried
over magnesium sulfate. After the solvent was distilled off, the residue
was dissolved in 70 mL of ethanol, and 85% hydrazine hydrate (2.9 g,
50 mmol) was added dropwise. The mixture was refluxed for 3 h. After
being cooled, the mixture was slowly added to 250 mL of ice water in
which a light yellow solid was formed. The solid was filtered and dried
to give a yellow solid (7.13 g) in 55.7% yield. 1H NMR (400 MHz) δ:
2.09 (s, 3H, CH3), 2.72-2.87 (m, 2H, CH2), 3.73-3.77 (m, 1H, CH),
7.43 (d, JH ) 7.6 Hz, 1H, ArH), 7.48-7.51 (m, 2H, 2ArH), 7.57 (d, JH
) 8.0 Hz, 1H, ArH), 8.48 (s, 1H, NH).
Synthesis of 6-Methyl-4-(3-trifluoromethylphenyl)-2H-pyridazin-
3-one (7). Compound 6 (0.51 g, 2.0 mmol) was added to a mixture of
potassium carbonate powder (0.28 g, 2.0 mmol) and 30 mL of
anhydrous dimethyl sulfoxide. The reaction mixture was stirred at room
temperature for 24 h and then poured into 50 mL of water and
neutralized with 15% diluted hydrochloric acid until the pH was 7.
The mixture was extracted with ether (5 × 20 mL). The combined
organic layer was washed with saturated brine (2 × 50 mL), dried over
magnesium sulfate, and concentrated under a vacuum to give a white
solid (0.48 g) in 94.0% yield. 1H NMR (400 MHz) δ: 2.42 (s, 3H,
CH3), 7.32 (s, 1H, pyridazinone), 7.59 (t, JH ) 7.8 Hz, 1H, ArH), 7.69
(d, JH ) 7.6 Hz, 1H, ArH), 8.02 (s, 1H, ArH), 8.10 (d, JH ) 7.6 Hz,
1H, ArH), 11.77 (s, 1H, NH).
In a previous paper, the important intermediate 7 was
synthesized through 3-(trifluoromethylphenyl)magnesium bro-
mide, and the yield was low (38.6%) (3). Herein, we report a
new method for the preparation of intermediate 7 from ethyl
2-(3-trifluoromethylphenyl)acetate in five steps with a moderate
total yield of 51.5% (Scheme 1).
MATERIALS AND METHODS
Instruments. 1H NMR spectra were recorded in a deuterochloroform
solution with a Bruker AC-P500 (300 MHz) or an Oxford AS400 (400
MHz) instrument, using tetramethylsilane as an internal standard.
Elemental analyses were performed on a Yanaco MT-3CHN elemental
analyzer. Melting points were determined using a Thomas-Hoover
melting-point apparatus and were uncorrected. Yields were not
optimized (Schemes 1 and 2).
Synthesis of Ethyl 2-Bromo-2-(3-trifluoromethylphenyl)acetate
(4). A mixture of ethyl 2-(3-trifluoromethylphenyl)acetate (23.2 g, 0.100
mol) and N-bromosuccinimide (18.7 g, 0.105 mol) in 100 mL of dry
carbon tetrachloride was stirred at room temperature, and then a catalytic
amount of 48% hydrobromic acid was added. The mixture was stirred
at reflux until the orange color faded. The solid was filtered off, and
the filtrate was concentrated to give a colorless liquid (30.6 g) in 98.4%
yield. 1H NMR (300 MHz) δ: 1.30 (t, JH ) 7.2 Hz, 3H, CH3),
4.24-4.28 (m, 2H, CH2), 5.35 (s, 1H, CH), 7.51 (t, JH ) 7.6 Hz, 1H,
ArH), 7.62 (d, JH ) 7.8 Hz, 1H, ArH), 7.77 (d, JH ) 7.8 Hz, 1H,
ArH), 7.81 (s, 1H, ArH).
Synthesis of 3-Chloro-6-methyl-4-(3-trifluoromethylphenyl)py-
ridazine (8). Compound 7 (2.00 g, 7.9 mmol) was dissolved in 40 mL
of dry phosphorous oxychloride. The reaction mixture was refluxed

3-(Trifluoromethylphenyl)pyridazine Derivatives
J. Agric. Food Chem., Vol. 56, No. 15, 2008 6569
for 2 h, and then the excess phosphorous oxychloride was removed by
distillation. The residue was poured into ice water (200 mL) while being
stirred to give a white solid. The mixture was neutralized with 20%
sodium hydroxide until the pH was 7. The solid was collected by
filtration and dried in vacuo to give a white solid (2.10 g) in 98.0%
yield. mp 125-126 °C; 1H NMR (300 MHz) δ: 2.78 (s, 3H, CH3),
7.32 (s, 1H, ArH), 7.62-7.78 (m, 4H, 4ArH); Anal. calcd for
C12H8ClF3N2: C 52.86, H 2.96, N 10.27; found: C 52.82, H 3.03, N
10.04.
General Synthetic Procedures for Target Compounds 2a-j.
Compound 8 (0.5 mmol) and the corresponding 9 (2.5 mmol) were
mixed together and heated to 190 °C for 20 h in a sealed reactor (7).
After cooling to room temperature, the residue was purified on a silica
gel column eluted with petroleum ether (60-90 °C)/ethyl acetate (1:
1) to give 2a-j.
2H, CH2), 4.08-4.34 (b, 1H, NH), 6.88 (s, 1H, pyridazine), 7.12-7.26
(m, 5H, 5ArH), 7.39 (d, 1H, JH ) 7.8 Hz, ArH), 7.50-7.55 (m, 2H,
2ArH), 7.67 (d, 1H, JH ) 7.8 Hz, ArH); Anal calcd for C20H18F3N3: C
67.22, H 5.08, N 11.76; found: C 67.15, H 5.26, N 11.60.
Data for 2k: Yield, 54.5%; mp, 140-141 °C. 1H NMR (300 MHz)
δ: 2.66 (s, 3H, CH3), 6.28 (s, 1H, NH), 6.98-7.07 (m, 2H, 2ArH),
7.23-7.30 (m, 2H, 2ArH), 7.55-7.78 (m, 6H, 6ArH); Anal calcd for
C18H14F3N3: C 65.65, H 4.28, N 12.76; found: C 65.40, H 4.46, N
12.51.
1
Data for 2l: Yield, 70.6%; mp, 136-137 °C. H NMR (400 MHz)
δ: 2.07 (s, 3H, CH3), 2.65 (s, 3H, CH3), 6.20 (s, 1H, NH), 6.92-7.16
(m, 4H, 4ArH), 7.23-7.30 (m, 2H, 2ArH), 7.63-7.75 (m, 4H, 4ArH),
8.03 (d, 1H, JH ) 8.0 Hz, ArH); Anal calcd for C19H16F3N3: C 66.46,
H 4.70, N 12.24; found: C 66.40, H 4.68, N 12.10.
Data for 2m: Yield, 58.5%; mp, 118-119 °C. 1H NMR (300 MHz)
δ: 2.31 (s, 3H, CH3), 2.66 (s, 3H, CH3), 6.24 (s, 1H, NH), 6.82 (d, 1H,
JH ) 7.5 Hz, ArH), 7.06 (s, 1H, ArH), 7.16 (t, 1H, JH ) 7.8 Hz, ArH),
7.21 (d, 1H, JH ) 7.8 Hz, ArH), 7.64-7.77 (m, 4H, 4ArH); Anal calcd
for C19H16F3N3: C 66.46, H 4.70, N 12.24; found: C 66.50, H 4.43, N
12.20.
General Synthetic Procedures for Target Compounds 2k-z.
Compound 8 (0.5 mmol) and the corresponding 9 (2.5 mmol) were
mixed together and heated to 160 °C for 4 h in a sealed reactor. After
cooling to room temperature, the residue was purified on a silica gel
column eluted with petroleum ether (60-90 °C)/ethyl acetate (2:1) to
give 2k-z.
Data for 2n: Yield, 64.7%; mp, 147-148 °C. 1H NMR (300 MHz)
δ: 2.29 (s, 3H, CH3), 2.64 (s, 3H, CH3), 6.20 (s, 1H, NH), 7.04 (s, 1H,
Data for 2a: Yield, 58.3%; mp, 162-164 °C. 1H NMR (400 MHz)
δ: 2.59 (s, 3H, CH3), 4.51-4.62 (b, 1H, NH), 4.76 (d, 1H, JH ) 5.2
Hz, CH2), 6.94 (s, 1H, pyridazine), 7.26-7.36 (m, 5H, 5ArH),
7.61-7.70 (m, 4H, 4ArH); Anal calcd for C19H16F3N3: C 66.46, H 4.70,
N 12.24; found: C 66.29, H 5.00, N 12.40.
ArH), 7.09 (d, 2H, JH
2ArH), 7.64-7.77 (m, 4H, 4ArH); Anal calcd for C
H 4.70, N 12.24; found: C 66.20, H 4.85, N 11.97.
) 8.1 Hz, 2ArH), 7.45 (d, 2H, JH ) 8.4 Hz,
19H16F3N3: C 66.46,
Data for 2o: Yield, 55.6%; mp, 144-145 °C. 1H NMR (300 MHz)
δ: 2.05 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.64 (s, 3H, CH3), 6.09 (s,
1H, NH), 6.93-7.05 (m, 3H, 3ArH), 7.61-7.87 (m, 5H, 5ArH); Anal
calcd for C20H18F3N3: C 67.22, H 5.08, N 11.76; found: C 67.03, H
5.10, N 11.64.
Data for 2b: Yield, 67.2%; mp, 95-97 °C. 1H NMR (300 MHz) δ:
2.32 (s, 3H, CH3), 2.59 (s, 3H, CH3), 4.49-4.52 (b, 1H, NH), 4.71 (d,
1H, JH ) 5.4 Hz, CH2), 6.93 (s, 1H, pyridazine), 7.12 (d, 2H, JH ) 7.8
Hz, 2ArH), 7.25 (d, 2H, JH ) 8.1 Hz, 2ArH), 7.60-7.69 (m, 4H, 4ArH);
Anal calcd for C20H18F3N3: C 67.22, H 5.08, N 11.76; found: C 67.38,
H 4.94, N 11.60.
Data for 2p: Yield, 61.1%; mp, 156-157 °C. 1H NMR (300 MHz)
δ: 2.66 (s, 3H, CH3), 3.73 (s, 3H, CH3), 6.81-7.07 (m, 4H, 4ArH),
7.35 (s, 1H, NH), 7.69-7.83 (m, 4H, 4ArH), 8.82-8.86 (m, 1H, ArH);
Anal calcd for C19H16F3N3O: C 63.51, H 4.49, N 11.69; found: C 63.40,
H 4.40, N 11.85.
Data for 2c: Yield, 54.2%; mp, 83-85 °C. 1H NMR (300 MHz) δ:
2.61 (s, 3H, CH3), 3.80 (s, 3H, CH3), 4.42-4.53 (b, 1H, NH), 4.70 (d,
1H, JH ) 5.1 Hz, CH2), 6.85-6.88 (m, 2H, 2ArH), 6.95 (s, 1H,
pyridazine), 7.28-7.32 (m, 2H, 2ArH), 7.63-7.71 (m, 4H, 4ArH); Anal
calcd for C20H18F3N3O: C 64.34, H 4.86, N 11.25; found: C 64.17, H
4.98, N 11.09.
Data for 2q: Yield, 66.7%; mp, 136-137 °C. 1H NMR (300 MHz)
δ: 2.63 (s, 3H, CH3), 3.78 (s, 3H, CH3), 6.13 (s, 1H, NH), 6.83 (d, 2H,
JH ) 9.0 Hz, 2ArH), 7.03 (s, 1H, ArH), 7.45 (d, 2H, JH ) 9.0 Hz,
2ArH), 7.66-7.76 (m, 4H, 4ArH); Anal calcd for C19H16F3N3O: C
63.51, H 4.49, N 11.69; found: C 63.44, H 4.30, N 11.69.
Data for 2r: Yield, 57.1%; mp, 116-117 °C. 1H NMR (300 MHz)
δ: 2.68 (s, 3H, CH3), 6.67 (s, 1H, NH), 6.93-7.19 (m, 4H, 4ArH),
7.72-7.76 (m, 4H, 4ArH), 8.66-8.71 (m, 1H, ArH); Anal calcd for
C18H13F4N3: C 62.25, H 3.77, N 12.10; found: C 62.10, H 3.95, N
12.05.
Data for 2d: Yield, 64.9%; mp, 130-131 °C. 1H NMR (300 MHz)
δ: 2.58 (s, 3H, CH3), 4.64-4.82 (m, 3H, NH + CH2), 6.93-7.72 (m,
9H, 9ArH); Anal calcd for C19H15F4N3: C 63.16, H 4.18, N 11.63;
found: C 63.10, H 4.10, N 11.73.
Data for 2e: Yield, 72.2%; mp, 88-90 °C. 1H NMR (300 MHz) δ:
2.59 (s, 3H, CH3), 4.57-4.61 (b, 1H, NH), 4.72 (d, 1H, JH ) 5.7 Hz,
CH2), 6.95 (s, 1H, pyridazine), 7.28-7.32 (m, 4H, 4ArH), 7.62-7.73
(m, 4H, 4ArH); HRMS (ESI) for [C19H15ClF3N3 + 1]+, calcd: 378.0995;
found: 378.0997.
1
Data for 2s: Yield, 51.4%; mp, 163-164 °C. H NMR (300 MHz)
δ: 2.65 (s, 3H, CH3), 6.20 (s, 1H, NH), 6.95-7.06 (m, 3H, 3ArH),
7.49-7.54 (m, 2H, 2ArH), 7.68-7.79 (m, 4H, 4ArH); Anal calcd for
C18H13F4N3: C 62.25, H 3.77, N 12.10; found: C 62.19, H 3.71, N
12.34.
Data for 2f: Yield, 73.7%; mp, 99-101 °C. 1H NMR (300 MHz) δ:
2.58 (s, 3H, CH3), 4.82 (d, 1H, JH ) 5.7 Hz, CH2), 4.89-4.93 (b, 1H,
NH), 6.93 (s, 1H, pyridazine), 7.20-7.22 (m, 2H, 2ArH), 7.32-7.37
(m, 1H, ArH), 7.56-7.74 (m, 5H, 5ArH); Anal calcd for C19H15ClF3N3:
C 60.40, H 4.00, N 11.12; found: C 60.60, H 4.10, N 10.92.
Data for 2g: Yield, 83.3%; mp, 178-180 °C. 1H NMR (300 MHz)
δ: 1.54 (d, 3H, JH ) 5.4 Hz, CH3), 2.56 (s, 3H, CH3), 4.49-4.56 (b,
1H, NH), 5.45-5.55 (m, 1H, CH), 6.90 (s, 1H, pyridazine), 7.22-7.37
(m, 5H, 5ArH), 7.63-7.73 (m, 4H, 4ArH); Anal calcd for C20H18F3N3:
C 67.22, H 5.08, N 11.76; found: C 67.30, H 5.18, N 11.59.
Data for 2h: Yield, 68.4%; mp, 101-103 °C. 1H NMR (300 MHz)
δ: 1.51 (d, 3H, JH ) 6.9 Hz, CH3), 2.56 (s, 3H, CH3), 4.48-4.51 (b,
1H, NH), 5.40-5.47 (m, 1H, CH), 6.91-7.01 (m, 3H, 3ArH),
7.30-7.35 (m, 2H, 2ArH), 7.58-7.75 (m, 4H, 4ArH); Anal calcd for
C20H17F4N3: C 64.00, H 4.56, N 11.19; found: C 64.04, H 4.33, N
11.16.
Data for 2t: Yield, 58.3%; mp, 98-99 °C. 1H NMR (400 MHz) δ:
2.68 (s, 3H, CH3), 6.90-8.86 (m, 10H, 9ArH + NH); Anal calcd for
C18H13ClF3N3: C 59.43, H 3.60, N 11.55; found: C 59.40, H 3.76, N
11.39.
Data for 2u: Yield, 63.9%; mp, 139-140 °C. 1H NMR (300 MHz)
δ: 2.67 (s, 3H, CH3), 6.31 (s, 1H, NH), 6.95-7.41 (m, 4H, 4ArH),
7.68-7.79 (m, 5H, 5ArH); Anal calcd for C18H13ClF3N3: C 59.43, H
3.60, N 11.55; found: C 59.50, H 3.40, N 11.58.
Data for 2v: Yield, 52.8%; mp, 164-166 °C. 1H NMR (300 MHz)
δ: 2.66 (s, 3H, CH3), 6.27 (s, 1H, NH), 7.08 (s, 1H, ArH), 7.24 (d, 2H,
JH ) 9.0 Hz, 2ArH), 7.55 (d, 2H, JH ) 8.7 Hz, 2ArH), 7.68-7.80 (m,
4H, 4ArH); Anal calcd for C18H13ClF3N3: C 59.43, H 3.60, N 11.55;
found: C 59.20, H 3.50, N 11.54.
1
Data for 2i: Yield, 61.5%; mp, 118-120 °C. H NMR (300 MHz)
Data for 2w: Yield, 48.8%; mp, 147-148 °C. 1H NMR (300 MHz)
δ: 2.68 (s, 3H, CH3), 6.28 (s, 1H, NH), 7.10-7.14 (m, 3H, 3ArH),
7.46-7.50 (m, 1H, ArH), 7.68-7.82 (m, 5H, 5ArH); Anal calcd for
C18H13BrF3N3: C 52.96, H 3.21, N 10.29; found: C 52.71, H 3.26, N
10.31.
δ: 1.50 (d, 3H, JH ) 6.9 Hz, CH3), 2.55 (s, 3H, CH3), 4.42-4.51 (b,
1H, NH), 5.35-5.47 (m, 1H, CH), 6.91 (s, 1H, pyridazine), 7.24-7.31
(m, 4H, 4ArH), 7.54-7.76 (m, 4H, 4ArH); Anal calcd for
C20H17ClF3N3; C 61.31, H 4.37, N 10.72; found: C 61.08, H 4.20, N
10.48.
Data for 2x: Yield, 36.6%; mp, 175-176 °C. 1H NMR (300 MHz)
δ: 2.66 (s, 3H, CH3), 6.26 (s, 1H, NH), 7.08 (s, 1H, ArH), 7.39 (d, 2H,
JH ) 9.0 Hz, 2ArH), 7.51 (d, 2H, JH ) 9.0 Hz, 2ArH), 7.67-7.80 (m,
1
Data for 2j: Yield, 66.7%; mp, 124-126 °C. H NMR (300 MHz)
δ: 2.58 (s, 3H, CH3), 2.96 (t, 2H, JH ) 6.6 Hz, CH2), 3.78-3.84 (m,

6570 J. Agric. Food Chem., Vol. 56, No. 15, 2008
Xu et al.
4H, 4ArH); Anal calcd for C18H13BrF3N3: C 52.96, H 3.21, N 10.29;
found: C 52.70, H 3.45, N 10.05.
Table 1. Activities of Compounds against S. polyrrhiza
Data for 2y: Yield, 52.5%; mp, 113-114 °C. 1H NMR (300 MHz)
δ: 2.68 (s, 3H, CH3), 6.42 (s, 1H, NH), 7.12 (s, 1H, ArH), 7.25 (d, 1H,
JH ) 7.5 Hz, ArH), 7.39 (t, 1H, JH ) 8.1 Hz, ArH), 7.69-7.83 (m,
6H, 6ArH); Anal calcd for C19H13F6N3: C 57.44, H 3.30, N 10.58;
found: C 57.28, H 3.24, N 10.61.
Chl inhibition (%)
10 µg/mL 1 µg/mLa
compd
2a
n
R2
R1
1
1
1
1
1
1
1
1
1
2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
H
H
86
74
84
81
85
90
63
79
83
34
51
77
25
73
31
47
2b
2c
2d
2e
4-CH3
4-OCH3
2-F
4-Cl
2-Cl
H
4-F
4-Cl
H
H
H
H
H
Data for 2z: Yield, 56.1%; mp, 148-149 °C. 1H NMR (300 MHz)
δ: 2.67 (s, 3H, CH3), 6.29 (s, 1H, NH), 7.09 (s, 1H, ArH), 7.14 (d, 2H,
JH ) 8.4 Hz, 2ArH), 7.60 (d, 2H, JH ) 9.0 Hz, 2ArH), 7.68-7.80 (m,
4H, 4ArH); Anal calcd for C19H13F6N3O: C 55.21, H 3.17, N 10.17;
found: C 54.99, H 3.39, N 10.28.
Bioassays. The herbicidal activities of title compounds 2a-z and
reported compounds 1a,b were evaluated using a previously reported
procedure (3).
2f
H
2g
2h
2i
2j
2k
2L
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
CH3
CH3
CH3
H
23
15
100
100
83
100
96
100
100
65
100
95
69
62
100
100
100
82
100
87
100
59
100
65
H
2-CH3
3-CH3
4-CH3
2,4-(CH3)2
2-OCH3
4-OCH3
2-F
4-F
2-Cl
3-Cl
4-Cl
Inhibition of Growth and Chlorophyll Determination in S. polyrrhiza.
S. polyrrhiza was cultivated aseptically in a medium as described in
the literature (8). A N,N-dimethylformamide solution of the compound
to be tested was applied on a piece of filter paper as droplets. After
evaporation of solvent for 15 min, the filter paper was placed into an
Erlenmeyer flask with 15 mL of fresh medium. The flask was then
shaken for more than 10 min before 10 fronds were inoculated into
each flask. Cultures of fronds were performed at 23-26 °C with a 16 h
light to 8 h dark photoperiod and a light intensity of ca. 45 µE m-2
s-1. The test was terminated after 7 days of cultivation. The mixture
of the same amount of N,N-dimethylformamide and fresh medium was
used as a control. The changes in Chl content of fronds in each flask
were analyzed and recorded as a percentage of the control.
Chl was measured according to the method described in ref 9. Briefly,
Chl in plant materials was extracted with 96% ethanol overnight at 4
°C. After brief centrifugation, the supernatant was used to measure the
OD at 665 and 649 nm, respectively. The content of Chl in plant
material was finally calculated by the following formula: Chl content
) (6.10A665 + 20.04A649) × total volume of extract/FW (µg/g).
Glasshouse Tests. The emulsions of purified compounds were
prepared by being dissolved in 100 µL of N,N-dimethylformamide with
the addition of a small amount of Tween 20 and water. The mixture of
the same amount of water, N,N-dimethylformamide, and Tween 20 was
used as a control. The solutions of test compounds were sprayed using
a laboratory belt sprayer delivering a 750 L/ha spray volume.
Pre-emergence. Sandy clay (100 g) in a plastic box (11 cm × 7.5
cm × 6 cm) was wetted with water. Sprouting seeds (15) of the weed
under test were planted in fine earth (0.6 cm depth) in the glasshouse
and sprayed with the test compound solution at 750 g/ha.
72
82
100
100
100
100
100
100
100
63
100
83
100
90
3-Br
4-Br
3-CF3
4-OCF3
2y
2z
1a
R ) CO2C2H5
R ) n-C3H7
-
-
90
1b
diflufenican
94
a Error of these number is 2%. -: not tested.
K2CO3 to give 5, which can be used for the next step without
purification. Pyridazinone 6 was synthesized from 5 by hy-
drolysis, decarboxylation, and ring closure reactions with
hydrazine hydrate in 55.7% yield. Compound 7 was obtained
by the dehydrogenation of 6 with K2CO3/DMSO in 94.0% yield.
Compound 8 was synthesized by the reaction of 7 with
phosphorous oxychloride in high yield (98.0%). Compounds
2a-z were obtained by heating 8 with the corresponding amine
via a neat reaction. The title compounds were identified by 1H
NMR. The measured elemental analyses are also consistent with
the corresponding calculated values.
Postemergence. Seedlings (one leaf and one stem) of the weed were
sprayed with the test compound solution at 750, 600, 300, 150, or 75
g/ha. For both methods, the fresh weights of the aboveground portions
were determined 24 days later, and the percent inhibition relative to
the controls was calculated. There were two replicates for each
treatment.
Biological Assay. S. polyrrhiza (L.) Schleiden, which is the
largest duckweed (giant duckweed) in the Lemnaceae family,
frequently is used to determine the potential impacts of heavy
metals and other pollutants in environmental risk assessments.
It is a sensitive plant that could exhibit effects when treated in
low concentrations (17, 18). Herein, we used it to evaluate the
bleaching activities of the title compounds (Table 1). In addition,
the herbicidal activities also were bioassayed in the glasshouse
on four weeds representative of monocotyledonous and dicoty-
ledonous plants (Tables 2 and 4) (3, 19, 20). Through these
tests, we can comprehensively evaluate the bleaching and
herbicidal activities of the title compounds.
RESULTS AND DISCUSSION
Synthesis. In a previous paper (3), intermediate 7 was
synthesized through 3-(trifluoromethylphenyl)magnesium bro-
mide, and the yield was low (38.6%). Literature references
mentioning detonations of trifluoromethylphenyl Grignard re-
agents surfaced (10, 13). Pfizer scientists reported a violent
explosion of 3-(trifluoromethylphenyl)magnesium bromide,
resulting in extensive laboratory damage (14). Another report
mentioned the detonation of 4-(trifluoromethylphenyl)magne-
sium bromide resulting in destruction of a factory and loss of
life (15). The trifluoromethylphenyl moiety is frequently
encountered in pharmaceutical drug, catalysts, and synthetic
intermediates (16), so we need a safe and reliable preparation
of this valuable intermediate. In this paper, we explored another
way to synthesize intermediate 7. Starting with (3-trifluorom-
ethylphenyl)acetic acid ethyl ester 3, it can be converted easily
to 4 by bromization with 98.4% yield. Further reaction of 4
with acetylacetic ether could proceed readily in the presence of
In our previous work, novel 4-(3-trifluoromethylphenyl)py-
ridazinone derivatives were synthesized, and bioassay results
indicated that modification of the hydrogen atom at N2 in the
pyridazinone ring of 7 can increase the activities. Most of these
compounds can inhibit Chl biosynthesis at 10 µg/mL, and some
compounds control more than 80% D. adscendens at 300 g/ha
in pre-emergence applications (3). To find more high activity
compounds and further investigate the structure-activity rela-
tionship of the 3-position in the pyridazine ring, the title
compounds were synthesized by the replacement of pyridazinone

3-(Trifluoromethylphenyl)pyridazine Derivatives
J. Agric. Food Chem., Vol. 56, No. 15, 2008 6571
Table 2. Herbicidal Activities of Compounds (Percent Inhibition)a in
Greenhouse Test (750 g/ha)
Table 4. Herbicidal Activities of Compounds (Percent Inhibition)a in
Greenhouse (Postemergence Treatment)
Brassica
Amaranthus Echinochioa
retroflexus crus-galli
Digitaria
rate
B.
A.
rate
B.
A.
campestris
adscendens
compd (g/ha) campestris retroflexus compd (g/ha) campestris retroflexus
2k
2m
2n
2r
600
300
150
75
600
300
150
92b
84b
74b
66b
42b
30
61b
43b
41b
18
2s
2v
2y
600
300
150
75
600
300
150
75
600
300
150
75
93b
83b
58b
55b
90b
89b
87b
52b
88b
79b
72b
48b
98b
94b
88b
44b
64b
55b
43b
32
66b
60b
45b
42b
54b
42b
37b
32
compd
2a
2b
2c
2d
2e
2f
log Pb pre post pre post pre
post
pre post
5.55
6.04 16 20
5.42 14
5.71 24 49
0
30
4
31
2
8
3
36
10
1
16
16
33
0
81c
90c
0
27
2
0
8
0
0
10
15
26
7
64
0
23
54
8
78
22
0
9
3
10
14
13
4
43
0
0
18
44
44
33
7
52b
25
0
0
1
24
18
29
54
57
67
11
0
6.11
6.11
5.87 12
6.03 13
7
0
27
34
0
0
23
2g
2h
2i
43 12
28
600
300
150
59b
54b
39
59b
28
0
1
0
6.43
5.83
2
0
8
45
17
30
60c
38
64c
85c
0
27 11
13 27
15 43
10 11
29
2
25
11
28
17
2j
2k
2L
2m
2n
2o
2p
2q
2r
5.78 48 99c
600
300
150
75
96b
88b
67b
60b
75b
58b
48b
39b
diflufenican 600
100b
74b
70b
41b
6.27
7
86c
1
300
150
75
6.27 18 79c
6.27 82c 99c
6.76 10 22
8
0
0
7
6
17
7
0
18
11
0
5.66
5.66 13 44
9
6
4
55
0
19
10
12
0
0
54
0
30
27
100c
85c
41
38
100c
30
45
95c
26
0
5
0
2
2
0
0
0
15
0
0
46
82c
a Error of these numbers is 2%. b Leaves emerged after treatments were
completely white.
2
89
40
0
19
5
5.94 18 100c
21 15
2s
2t
5.94
6.34
6.34
8
9
3
88c
93c
63
23
24
7
0
0
0
0
0
0
0
gence applications against dicotyledonous plants B. campestris
and A. retroflexus. For example, 2v (Table 4) can control
(inhibition >80%) B. campestris at the rate of 150 g/ha in
postemergence applications, which is different from 1a and 1b
(3). Modification of the structure 1 to 2 increased the overall
lipophilicity of the molecule, which can be measured by log P
(21). Log P listed in Table 2 showed that compounds 2 have
larger values than 1a,b. This may result in the difference in
their activities and application times.
2u
2v
2w
2x
2y
2z
1ad
1bd
6.34 18 100c
6.61 14 17
6.61 26 36
0
0
13 14
26
0
35
6.71
7.31
2.81 87c 55
0
0
96c
50
8
21
0
0
5
35
100c 61
100c 13
100c 19
3
61
6
51
90c
28
5
diflufenican 4.99 71 98c
100c 94c
67 100c 83c
a Error of these numbers is 2%. b Calculated by ChemBioDraw Ultra 11.0.
c Leaves emerged after treatments were completely white. d Application rate 600
g/ha.
Among the 26 compounds, compounds with n ) 0 showed
better herbicidal activities than the others. For example, 2r, 2v,
and 2y can control (inhibition >95%) B. campestris and A.
retroflexus in postemergence treatment, and 2n exhibited good
herbicidal activities (inhibition >80%) against dicotyledonous
plants B. campestris and A. retroflexus both in postemergence
and in pre-emergence treatments. When n was 1 or 2, the
corresponding compounds’ herbicidal activities (such as 2a-i)
decreased remarkably. It is well-known that steric properties
are one of the factors affecting biological activities of com-
pounds. The tolerance of enzymes and receptors for the
bulkiness of substrates and drugs to which they are exposed is
a problem of great concern in biomedicinal/biochemical studies.
MR may be crude but provides useful measures of bulk (21).
As compared to 2k, with the introduction of F at the ortho
position, the activity increased, but bulkier substitutions (Table
3) (e.g., 2l, R2 ) 2-CH3; 2p, R2 ) 2-OCH3; and 2t, R2 ) 2-Cl)
decreased activity. When R2 is at the meta position, CH3 (2m)
and CF3 (2y) were better than other bulkier substitutions (e.g.,
2u, R2 ) 3-Cl and 2w, R2 ) 3-Br). At the para position, the
substituent can be bulkier, and 2n (R2 ) 4-CH3), 2s (R2 ) 4-F),
and 2v (R2 ) 4-Cl) exhibited better activity than 2x (R2 ) 4-Br)
and 2z (R2 ) 4-OCF3). These results indicate that the appropri-
ate bulkiness substituent at the right position is very important
for the herbicidal activity of the compounds. Footnote c in Table
2 indicates that leaves emerged after treatments were completely
white, which is the character of bleaching herbicide. As
compared to diflufenican, some of these compounds (e.g., 2r,
2s, 2v, and 2y) showed better selectivity to dicotyledonous plants
in postemergence treatment, and further study on their selective
application in crops is planned.
Table 3. MR Value of Substitutent
R2
H
F
Cl
Br
CH3
5.65
OCH3
7.87
CF3
OCF3
7.86
MR
1.03
0.92
6.03
8.88
5.02
with a pyridazine ring and the introduction of a substituted
amino group in the 3-position.
As shown in Table 1, some compounds showed excellent
bleaching activities; for example, 2j, 2k, 2m, 2q, 2r, 2s, 2u,
2w, and 2y can inhibit the synthesis of Chl completely (Chl
inhibition ) 100%) at 1 µg/mL, which is better than diflufeni-
can. At the same time, it can be seen that the target compounds
in which the amines are (un)substituted phenyl amines (n ) 0)
mostly showed a better bleaching activity than (un)substituted
benzyl amines (n ) 1) (e.g., Chl inhibition: 2k > 2a; 2n > 2b;
2q > 2c; 2r > 2d; 2v > 2e; and 2t > 2f at 10 or 1 µg/mL).
When the substituted amines are R-methylbenzyl amines, the
bleaching activity is much lower (e.g., Chl inhibition: 2a > 2g
and 2e > 2i at 10 or 1 µg/mL). The activity of 2j in which the
amine is phenethyl amine (n ) 2) is better than 2a. Within the
(un)substituted phenyl derivatives (2k-z), meta-substituted
compounds always displayed better bleaching activities. For
example, 2m, 2u, 2w, and 2y, which have meta substituents,
can completely inhibit the synthesis of Chl at 1 µg/mL.
From the biological assay results in Table 2, it was found
that compounds with (un)substituted phenyl amine in the
3-position of the pyridazine ring have a higher level of herbicidal
activities. As compared to 1 and 2, 1 showed better activities
in pre-emergence applications. However, from 2k-z, most of
the compounds exhibited more efficient activities in postemer-
From Tables 1 and 2, we notice that most compounds that
showed better herbicidal activities in greenhouse tests had equal
bleaching activities in the S. polyrrhiza test (e.g., 2k, 2m, 2n,

6572 J. Agric. Food Chem., Vol. 56, No. 15, 2008
Xu et al.
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2r, 2s, 2v, and 2y). Nevertheless, some compounds with a larger
Chl inhibition value did not exhibit a higher herbicidal efficacy
(e.g., 2j, 2q, 2u, and 2w). These results may be because different
plant species exhibited different sensitivities to the same
compound, and S. polyrrhiza is a sensitive plant, so it can detect
activities in low concentrations.
Target compounds that showed excellent herbicidal activities
against B. campestris and A. retroflexus also were bioassayed
at decreasing rates in postemergence (Table 4). Compounds
2k, 2r, 2s, 2v, and 2y exhibited equal or higher herbicidal
activities against B. campestris with diflufenican at a rate of 75
g/ha. Compounds 2r and 2v showed equal activities with
diflufenican against A. retroflexus at 75 g/ha. These results
indicate that changing the structure 1 by replacement of
pyridazinone with a pyridazine ring and introducing (un)sub-
stituted phenyl amino groups in the 3-position of the pyridazine
can enhance herbicidal activities.
In conclusion, we described here a practical and safe pro-
cedure for the preparation of intermediate 7 from ethyl 2-(3-
trifluoromethylphenyl)acetate in five steps with a moderate total
yield of 51.5%. Twenty-six novel 3-N-substituted amino-6-
methyl-4-(3-trifluoromethylphenyl)pyridazine derivatives were
synthesized. The results of bioassays showed that some of these
title compounds exhibited equal or higher herbicidal activities
against dicotyledonous plants B. campestris and A. retroflexus
in postemergence treatments with diflufenican at a rate of 75
g/ha. It was found that a suitable substituent amine at the
3-position of the pyridazine ring was essential for a high
herbicidal activity. All results in this paper will be very useful
for later research.
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