A new method for the synthesis and herbicidal activity of 3-phenoxy-6-(1H-(substituted)pyrazol-1-yl) pyridazines

Article abstract of DOI:10.1002/jhet.120

(Chemical Equation Presented) A series of 3-substituted phenoxy-6-((substituted)1H-pyrazol-1-yl) pyridazines were synthesized from the condensation of various phenols and 3-chloro-6-(1H-pyrazol-1-yl) pyridazine 2 or 3-chloro-6-(5′-methyl-4-ethoxycarbonyl-

Full text of DOI:10.1002/jhet.120

584
A New Method for the Synthesis and Herbicidal Activity
of 3-Phenoxy-6-(1H-(substituted)pyrazol-1-yl) Pyridazines
Vol 46
Fang-Zhong Hu,* Gui-Feng Zhang, Bin Liu, Xiao-Mao Zou,*
You-Quan Zhu, and Hua-Zheng Yang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry,
Nankai University, Tianjin 300071, China
*E-mail: fzhu@nankai.edu.cn or Zouxiaomao1111@sina.com
Received December 23, 2008
DOI 10.1002/jhet.120
Published online 25 June 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of 3-substituted phenoxy-6-((substituted)1H-pyrazol-1-yl) pyridazines were synthesized from
the condensation of various phenols and 3-chloro-6-(1H-pyrazol-1-yl) pyridazine 2 or 3-chloro-6-(50-
methyl-4-ethoxycarbonyl-1H-pyrazol-1-yl) pyridazine 6 in N,N-dimethylformamide (DMF) at 120ꢀC
with K2CO3 as an acid receptor. The intermediates 2 or 6 were obtained from the cyclization of
3-chloro-6-hydrazinyl pyridazine 1 with 3-dimethylamino-acrylaldehyde or ethyl 2-((dimethylamino)
methylene)-3-oxobutanoate in n-butanol under reflux, respectively, and side products 3 or 7 were also
generated. All of the title compounds were confirmed by 1H NMR, infrared spectometry (IR) and
elemental analyses. Preliminary bioassay indicated that some of the title compounds showed high inhibitory
activity against Brassica campestris L. (B. campestris) and moderate inhibitory activity against Echinochloa
crusgalli. For example, the inhibition percentages of compound 4b and 4c against B. campestris were both
94% at 10 lg/mL.
J. Heterocyclic Chem., 46, 584 (2009).
INTRODUCTION
herbicides for several decades [2]. DPEs are one of the
important Protox inhibitors, and numerous diphenyl-
ether compounds have been developed as commercial
herbicides (Fig. 1), for example, nitrofen, chlomethoxy-
nil, bifenox, oxyfluorfen, acifluorfen, fluoroglycofen-
ethyl, fomesafen, and lactofen.
Protoporphyrinogen IX oxidase (Protox, EC 1.3.3.4)
is the key enzyme in chlorophyll biosynthesis pathways
in plants, which catalyzes the oxidative O2-dependent
aromatization of the colorless protoporphyrinogen IX to
the highly conjugated protoporphyrin IX. The phyto-
toxicity of Protox inhibitors is light dependent and
involves intracellular peroxidation caused by protopor-
phyrin IX, chlorophyll precursor, leading to accumula-
tion of protoporphyrin IX in plant mitochondria and
plant chloroplasts. Abnormal accumulated protopor-
phyrin IX in plant tissue is assumed to cause light-
induced formation of active oxygen, which induces
disruption of membranes, chlorophyll degradation, and
desiccation of plants in the light [1].
According to the commercialized Protox inhibitors,
DPEs, a pharmacophore of Protox, and its inhibitors
were established in our group [3], which indicated that
two phenyl rings in DPEs, connected by an oxygen
atom as a hydrogen-bonding acceptor, play important
roles in their herbicidal activity. In addition, it is
deduced from the Protox pharmacophore that a molecule
bearing three aromatic rings connected directly or by
oxygen atoms or nitrogen atoms maybe also shows good
inhibition against Protox.
So far, several structurally distinct classes of com-
pounds, cyclic imides, phenyltriazolinones, diphenyl
ethers (DPEs), etc, targeted at Protox, have been used as
Heterocyclic rings are the classic phenyl-ring equiva-
lents according to the bioisosterism [4], especially nitro-
gen-containing heterocyclic rings. So, it is reasonable to
C
V
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A New Method for the Synthesis and Herbicidal Activity of
3-Phenoxy-6-(1H-(substituted)pyrazol-1-yl) Pyridazines
585
Figure 3. 3-Aryloxy-6-fluoro pyridazines.
showed inhibitory activity against B. campestris and E.
crus-galli to some extent [14].
In continuation on our research program for the syn-
thesis of novel pyrazolyl-pyridazine derivatives and
study on the relationship of structure and herbicidal
activity, we design 3-substituted phenoxy-6-(1H-pyra-
zol-1-yl)pyridazines 4 and 3-substituted phenoxy-6-(50-
methyl-40-ethoxycarbonyl-1H-pyrazol-1-yl) pyridazines
8, which were synthesized from the condensation of var-
ious phenols and 3-chloro-6-(1H-pyrazol-1-yl) pyrida-
zine or 3-chloro-6-(50-methyl-40-ethoxycarbonyl-1H-pyr-
azol-1-yl) pyridazine in DMF at 120ꢀC using K2CO3 as
an acid acceptor(Scheme 1). All novel compounds were
Figure 1. Commercialized herbicides of diphenyl ethers.
1
use a heterocyclic ring to replace one of the phenyl
rings in DPEs. Pyridazine ring is an important moiety in
some pharmaceuticals and agrochemicals [5–7]. In our
previous work, we synthesized numerous 3-phenoxy-6-
dimethylamino pyridazines, and some of them showed
inhibitory activity against Brassica campestris L. (B.
campestris) and Echinochloacrus-galli (E. crus-galli)
(Fig. 2, X3 ¼ H, Cl, CF3, etc) [8]. However, after treat-
ment of above weeds using the synthesized phenoxy
pyridazines, B. campestris and E. crus-galli were desic-
cated but not killed completely. Ten days later after
‘‘desiccation,’’ these two weeds can grow again, which
may be attributed to the loss of dimethylamino moiety
of phenoxy-pyridazines in above weeds in the light [9].
To get new phenoxy pyridazines, which can be tolerated
in above two weeds, we synthesized 3-aryloxy-6-fluoro
pyridaiznes and found that they can inhibit the growth
of B. campestris and E. crus-galli to some extent (Fig.
3, X4 ¼ Cl, OMe, NO2, etc.) [10]. It was excited that
they can be well tolerated in these two weeds. Cur-
rently, pyrazole ring is an important moiety in the pesti-
cide researches [11–13]. We introduced pyrazole ring
into phenoxy pyridazines because pyrazol-yl moiety has
electron-withdrawing characteristic in pyrazolyl pyrida-
zines as nitro group in DPEs (Fig. 4). In addition, the
structures in Figure 4 almost meet the requirement of
the deducation from Protox pharmacophore. So, we syn-
characterized by H NMR, IR, and elemental analyses.
Preliminary bioassay indicated that some of the title
compounds showed high inhibitory activity against
B. campestris and moderate inhibitory activity against
E. crus-galli. Moreover, the title compounds are well
tolerated in above weeds during the bioassay procedure.
RESULTS AND DISCUSSION
Synthesis. The synthetic procedure of the title com-
pounds is shown in Scheme 1. The intermediate 2 was
achieved from the cyclization of starting materials 1 and
3-(dimethylamino)-acrylaldehyde. When this reaction
was carried out in anhydrous ethanol under reflux, side
product 3, rather than the desired compound 2, was
obtained in high yield. However, compound 1 was
treated with 3-(dimethylamino)acrylaldehyde in iso-pro-
panol or n-butanol under reflux to afford compound 2 in
20% and 80% yield, respectively. Steiner et al., [15]
Steel and Constable, [16] and Blake et al. [17] have pre-
viously obtained 2 in 53–74% yield by treatment of pyr-
azole and 3,6-dichloropyridazine in DMF with NaH as a
base. However, side product, 3,6-bis(1H-pyrazol-1-yl)
pyridazine, was not avoidable.
As such, treatment of starting materials 1 and ethyl
2-((dimethylamino)methylene)-3-oxobutanoate 5 under
reflux in n-butanol furnished the desired intermediate 6
thesized
3-aryloxy-6-(30,50-dimethyl-1H-pyrazol-1-yl)
pyridazines (Fig. 4, X5 ¼ Cl, Br, Me, etc.), which
Figure 4. Structure of 3-aryloxy-6-(30,50-dimethyl-1H-pyrazol-1-yl)
pyridazines.
Figure 2. 3-Aryloxy-6-substituted pyridazines.
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DOI 10.1002/jhet

586
F.-Z. Hu, G.-F. Zhang, B. Liu, X.-M. Zou, Y.-Q. Zhu, and H.-Z. Yang
Vol 46
Scheme 1. General procedure for the synthesis of the title compounds.
and side product 7 in the yields of 60% and 10%,
respectively. Compound 6 was first synthesized by
Bagrov [18] from the reaction of ethyl 2-(ethoxymethy-
lene)-3-oxobutanoate with 1.
from the cyclization of starting materials 1 and 5. 7 is
conformed by X-ray diffraction (Fig. 5) [19], indicating
that methyl group is at 5th position and ethoxycarbonyl
moiety is at 4th position in the pyrazole ring.
A proposed mechanism of the generation of 6 and 7
is shown in Scheme 2. First, the hydrazinyl group in
compound 1 attacks the carbon nucleus, which is linked
to the dimethylamino moiety, to generate intermediate 9
with elimination of dimethylamine. 9 proceeds the intra-
molecular cyclization to furnish intermediate 10, which
is dehydrated to give 6. 7 is obtained through the con-
densation of 6 and dimethylamine, which is produced
The title compounds 4 or 8 were obtained from the
treatment of intermediates 2 or 6 and substituted phenols
in DMF at 120ꢀC for several hours until 2 or 6 was con-
sumed completely as indicated by thin layer chromato-
graphy. After the reactions were over, the resulting
mixtures were poured into cold water, and crude solids
were filtrated, which were recrystallized with ethanol
and cyclohexane to give pure products. All of the title
Scheme 2. Proposed mechanisms for the generation of 6 and 7.
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A New Method for the Synthesis and Herbicidal Activity of
3-Phenoxy-6-(1H-(substituted)pyrazol-1-yl) Pyridazines
587
120ꢀC with K2CO3 as an acid receptor. The title com-
pounds were screened for herbicidal activity against B.
Campestris and E. crus-galli. Preliminary bioassay indi-
cated that some of title compounds show high inhibitory
activity against B. Campestris and moderate inhibitory
activity against E. crus-galli at 10 and 100 lg/mL,
respectively. Further study of structure-activity relation-
ship of modified 3-phenoxy 6-substituted pyrazolyl pyri-
dazines is now under investigation.
Figure 5. Crystal structure of compound 7.
1
compounds were confirmed by H NMR, IR, and ele-
mental analyses.
EXPERIMENTAL
Herbicidal activities. The title compounds were
screened for herbicidal activity against B. campestris
and E. crus-galli using a previously reported procedure
[20,21], and the data of herbicidal activity were listed in
Table 1. It was found that the title compounds are well
tolerated in two weeds during the bioassay procedure.
Most of compounds 8, containing a methyl group at 5th
position and an ethylcarbony moiety at 4th position in
pyrazole ring, have no or slight herbicidal activity
against B. Campestris and E. crus-galli. Compounds 4a–
d, which only have H-atoms at 4th and 5th positions in
pyrazole ring, showed high inhibitory activity against
B. Campestris and moderate inhibitory activity against
E. crus-galli. at the concentration of 100 and 10 lg/mL,
respectively. Compounds 4b (Rn ¼ 4-Cl) and 4c (Rn ¼
4-Me) both showed high inhibitory activity against
B. Campestris, which indicates that electron-donating
groups or weak electron-withdrawing groups at 4th posi-
tion in phenyl rings are favorable to the increase of her-
bicidal activity. However, compounds 4e (Rn ¼ 3-CF3)
and 4f (Rn ¼ 4-CH3OC(O)) have no herbicidal activity
against B. Campestris, indicating that strong electron-
withdrawing groups at 3rd or 4th positions in phenyl
rings are unfavorable to the enhancement of herbicidal
activity. When Rn ¼ 3,4-Cl2, inhibitory activity of com-
pound 4d against B. Campestris decreased slightly com-
pared with that of 4b, suggesting that introduction of
chlorine at 3rd position in phenyl ring be unfavorable to
the increase of herbicidal activity. Compound 4a with
chlorine atom at 3rd position in phenyl ring has lower
herbicidal activity against B. Campestris and E. crus-
galli than compound 4b with chlorine atom at 4th posi-
tion in phenyl ring.
1
General methods. H NMR spectra were recorded on a
Varian Mercury Plus 400 MHz spectrometer using CDCl3 or
DMSO-d6 as a solvent and chemical shift values (d) were
given in parts per million downfield of internal tetramethylsi-
lane. 13C NMR spectra were recorded on a Varian Mercury
Plus 400 MHz spectrometer (100 MHz) using CDCl3 as a sol-
vent, and chemical shift values (d) were reported in parts per
million relative to the residual chloroform (77.00 ppm) and
1
was obtained with H decoupling. IR spectra were recorded on
a MAGNA-560 FTIR (Nicolet Company) spectrometer using
KBr plates (thin film). The melting points were determined on
an X-4 binocular microscope melting point apparatus (Beijing
Tech Instruments Co., Beijing, China) and were not corrected.
Elemental analyses were performed on a Yanaca CHN Corder
MT-3 elemental analyzer. All anhydrous solvents were dried
and purified by standard techniques just before use. 3-Chloro-
6-hydrazinylpyridazine 1 was prepared according to the litera-
ture procedure [22], and 3-(dimethylamino)acrylaldehyde and
3-((dimethylamino) methylene)-1-ethoxy-pentane-2,4-dione
were both available commercially.
5
Synthesis of 3-chloro-6(1H-pyrazol-1-yl) pyridazine 2 and
3-dimethylamino-6(1H-pyrazol-1-yl) pyridazine 3. A mixture
of 3-(dimethylamino)acrylaldehyde (1.09 g, 11.00 mmol) and
3-chloro-6-hydrazinyl pyridazine 1 (1.45 g, 10.00 mmol) in
n-butanol(20mL) was refluxed for half an hour. When the
Table 1
Herbicidal activity against B. campestris and E. crus-galli of the title
compounds (inhibition percentage, %).
B. campestris E. crusgalli
100
10
100
10
Compounds
lg/mL lg/mL lg/mL lg/mL
4a
4b
4c
4d
4e
4f
8a
8b
8c
8d
8e
8f
3-ClC6H4
4-ClC6H4
4-CH3C6H4
62
97
97
83
0
54
94
94
79
0
0
65
84
26
0
0
42
40
19
0
3,4-Cl2C6H3
3-CF3C6H4
4-CH3OC(O) C6H4
4-CH3C6H4
3,5-(CH3)2C6H3
2-CH3OC(O)C6H4
4-ClC6H4
0
0
0
0
CONCLUSION
54
0
38
0
0
0
0
14
16
0
In conclusion, a series of 3-substituted phenoxy 6-
(substituted pyrazol-yl)pyridazines were obtained from
the condensation of various phenols and 3-chloro-6-(1H-
pyrazol-1-yl) pyridazine or 3-chloro-6-(50-methyl-4-
ethoxycarbonyl-1H-pyrazol-1-yl) pyridazine in DMF at
0
0
0
0
0
0
3-ClC6H4
3,4-Cl2C6H3
4-CH3OC(O) C6H4
34
0
0
0
9
0
0
0
0
0
0
0
8g
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F.-Z. Hu, G.-F. Zhang, B. Liu, X.-M. Zou, Y.-Q. Zhu, and H.-Z. Yang
Vol 46
starting materials were consumed completely as indicated by
thin layer chromatography, the reaction mixture was allowed
to cool to room temperature. After removal of the solution
under pressure, the resulting residue was subjected to flash
column chromatography on silica gel to give compound 2
(1.50 g) as a white crystal (eluent: petroleum ether: ethyl
acetate¼4:1 (V/V) in 80% yield, mp.143–144ꢀC (ref.: mp.
124–126ꢀC[15]). 1H NMR (CDCl3, 400 MHz), d: 6.54–6.56
(m, 1H, pyrazole-H), 7.63 (d, J ¼ 9.2 Hz, 1H, pyridazine-H),
7.81 (d, J ¼ 2.0 Hz, 1H, pyrazole-H), 8.22 (d, J ¼ 9.2 Hz,
1H, pyridazine-H), 8.73 (d, J ¼ 2.8 Hz, 1H, pyrazole-H); 13C
NMR (CDCl3, 100 MHz), d: 109.18, 119.92, 127.40, 130.43,
143.28, 153.62, 154.23; IR (KBr) m (cmꢁ1): 3129, 1635, 1575,
1523, 1448, 1402, 1143, 1016, 860, 765.
Side product 3-dimethylamino-6(1H-pyrazol-1-yl) pyridazine
3 was also obtained in 15% yield, mp. 147–149ꢀC. 1H NMR
(CDCl3, 400 MHz), d: 3.21 (s, 6H, NMe2), 6.47 (m, 1H, pyr-
azole-H), 7.00 (d, J¼9.6 Hz, 1H, pyridazine-H), 7.73 (d,
J¼2.0 Hz, 1H, pyrazole-H), 7.97 (d, J¼9.6 Hz, 1H, pyrida-
zine-H), 8.62 (d, J¼2.4 Hz, 1H, pyrazole-H). GC-MS(EI, m/
z(%)): 189.09 (Mþ, 40), 160.10(100). 13C NMR(CDCl3, 100
MHz), d: 38.38, 107.86, 119.40, 126.26, 141.48, 147.77,
159.08. Anal. calcd. for C9H11N5: C, 57.13; H, 5.86; N, 37.01;
found: C, 57.18; H, 5.72; N, 36.89.
General Procedure for the Synthesis of 3-aryloxy-6-(1H-
pyrazol-1-yl) pyridazine 4. A 25-mL three-necked round bot-
tom flask equipped with a thermometer, magnetic stir bar, and
a dropping addition funnel was charged sequentially with new
distilled DMF (7 mL), compounds 2 (2.00 mmol), substituted
phenols (2.00 mmol), anhydrous potassium carbonate 0.29 g
(2.10 mmol). The resulting mixture was heated at 120ꢀC. After
stirring for 12 h, the reaction mixture was allowed to cool to
room temperature, poured into 30 mL of ice water, and fil-
trated to give the crude product. The resulting precipitate was
washed with water (5 mL). The collected solid was dried over-
night under vacuum to give a white powder, which was recrys-
tallized from ethanol/cyclohexane (1/3: (V/V) to generate pure
compounds 4.
3-(3-chlorophenoxy)-6-(1H-pyrazol-1-yl)pyridazine(4a). White
solid, yield 86%, mp.130–131ꢀC. 1H NMR (DMSO-d6,
400 MHz) d: 6.51–6.52 (m, 1H, pyrazole-H), 7.15 (dd,
J1¼8.8Hz, J2¼2.0Hz, 1H, ArH), 7.22–7.29 (m, 2H, ArH), 7.35
(s, 1H, ArH), 7.37 (d, J ¼ 9.2 Hz, 1H, pyridazine-H), 7.77 (d,
J¼2.0Hz, 1H, pyrazole-H), 8.30 (d, J ¼ 9.2 Hz, 1H, pyrida-
zine-H), 8.40 (d, J¼2.4Hz, 1H, pyrazole-H). IR (KBr) m
(cmꢁ1): 3136, 3093, 3021, 1578, 1523, 1469, 1418, 1290,
1197, 1126, 1085, 1046, 1018, 909, 858, 768. Anal. calcd for
C13H9ClN4O: C, 57.26; H, 3.33; N, 20.55; found: C, 57.36; H,
3.21; N, 20.31.
d:2.37 (s, 3H, ArCH3), 6.50–6.51 (m, 1H, pyrazole-H), 7.11 (d,
J ¼ 8.4 Hz, 2H, ArH), 7.23 (d, J ¼ 8.0 Hz, 2H, ArH), 7.31 (d, J
¼ 9.6 Hz, 1H, pyridazine-H), 7.76 (d, J ¼ 2.0Hz, 1H, pyrazole-
H), 8.23 (d, J ¼ 9.2 Hz, 1H, pyridazine-H) 8.63 (d, J ¼ 2.0 Hz,
1H, pyrazole-H); IR (KBr) m (cmꢁ1): 3136, 3093, 3042, 1581,
1514, 1459, 1411, 1296, 1258, 1203, 1133, 1104, 1032, 1014,
931, 861, 762; Anal. calcd for C14H12N4O: C, 66.65; H, 4.79; N,
22.21; found: C, 66.78; H, 4.89; N, 22.45.
3-(3,4-dichlorophenoxy)-6-(1H-pyrazol-1-yl)pyridazine (4d).
1
White solid, yield 87%, mp.158–159ꢀC. H NMR (CDCl3, 400
MHz), d: 6.52–6.56 (m, 1H, pyrazole-H), 7.14 (dd, J1 ¼ 2.4
Hz, J2 ¼ 8.8 Hz, 1H, ArH), 7.37 (d, J ¼ 9.6 Hz, 1H, pyrida-
zine-H), 7.40 (d, J ¼ 2.8 Hz, 1H, ArH), 7.50 (d, J ¼ 8.8 Hz,
1H, ArH), 7.77 (d, J¼2.0Hz, 1H, pyrazole-H), 8.30 (d, J ¼
9.6 Hz, 1H, pyridazine-H), 8.63 (d, J ¼ 2.4 Hz, 1H, pyrazole-
H); IR (KBr) m (cmꢁ1): 3143, 3084, 3056, 3028, 1568, 1530,
1469, 1418, 1398, 1299, 1261, 1206, 1120, 1043, 1018, 918,
864, 810, 755; Anal. calcd. for C13H8Cl2N4O: C, 50.84; H,
2.63; N, 18.24; found: C, 50.62; H, 2.83; N, 18.34.
3-(3-trifluorophenoxy)-6-(1H-pyrazol-1-yl)pyridazine (4e).
White solid, yield 80%, mp. 160–161ꢀC. 1H NMR (CDCl3,
400 MHz) d: 6.51–6.53 (m, 1H, pyrazole-H), 7.40 (d, J ¼ 9.6
Hz, 1H, pyridazine-H), 7.46 (d, J ¼ 7.6 Hz, 1H, ArH), 7.51–
7.59 (m, 3H, ArH), 7.77(d, J¼2.0Hz, 1H, pyrazole-H), 7.82
(d, J ¼ 9.6 Hz, 1H, pyridazine-H), 8.63 (d, J ¼ 2.0 Hz, 1H,
pyrazole-H); IR (KBr) m (cmꢁ1): 3136, 3086, 3035, 1574,
1523, 1459, 1408, 1325, 1286, 1206, 1162, 1136, 1068, 1018,
909, 864 762; Anal. calcd. for C14H9F3N4O: C, 54.91; H,
2.96; N, 18.29; found: C, 54.98; H, 2.94; N, 18.29.
3-(4-methoxycarbonylphenoxy)-6-(1H-pyrazol-1-yl) pyridazine
(4f). White solid, yield 80%; mp. 187–188ꢀC. 1H NMR
(CDCl3, 400 MHz), d: 3.93 (s, 3H, COOCH3), 6.51–6.52 (m,
1H, pyrazole-H), 7.31 (d, J ¼ 8.0 Hz, 2H, ArH), 7.39 (d, J ¼
9.6 Hz, 1H, pyridazine-H), 7.77 (d, J ¼ 2.0 Hz, 1H, pyrazole-
H), 8.13 (d, J ¼ 8.0 Hz, 2H, ArH), 8.31 (d, J ¼ 9.6 Hz, 1H,
pyridazine-H), 8.64 (d, J ¼ 2.0 Hz, 1H, pyrazole-H); IR (KBr)
m (cmꢁ1): 3136, 3093, 3028, 2958, 1725, 1597, 1517, 1456,
1408, 1283, 1197, 1158, 1110, 1046, 1014, 931, 861, 774;
Anal. calcd. for C15H12N4O3: C, 60.78; H, 4.08; N, 18.91;
found: C, 60.78; H, 4.02; N, 18.92.
Synthesis of 3-chloro-6-(4-ethoxycarbonyl-5-methyl-1H-
pyrazol-1-yl)pyridazine 6 and 3-dimethylamin-6-(4-ethoxycar-
bonyl-5-methyl-1H-pyrazol-1-yl)pyridazine 7. A mixture of
ethyl 2-((dimethylamino)methylene)-3-oxobutanoate 5 (1.50 g,
8.10 mmol) and 3-chloro-6- hydrazinyl pyridazine 1(1.16 g,
8.00 mmol) in n-butanol (20mL) was refluxed. When the start-
ing materials were consumed completely as indicated by thin
layer chromatography, the workup of reaction mixture was the
same as that of compound 2 to give compound 6 (1.52 g) as a
1
3-(4-chlorophenoxy)-6-(1H-pyrazol-1-yl)pyridazine(4b). White
solid, yield 85%, m.p. 151–152ꢀC.1H NMR (CDCl3, 400
MHz) d: 6.51–6.52 (m, 1H, pyrazole-H), 7.19 (d, J ¼ 8.8 Hz,
2H, ArH), 7.35 (d, J ¼ 9.2 Hz, 1H, pyridazine-H), 7.40 (d,
J ¼ 8.8 Hz, 2H, ArH), 7.77 (d, J ¼ 2.0Hz, 1H, pyrazole-H),
8.28 (d, J ¼ 9.2 Hz, 1H, pyridazine-H), 8.63 (d, J ¼ 2.4 Hz,
1H, pyrazole-H); IR (KBr) m (cmꢁ1): 3150, 3006, 1571, 1530,
1498, 1459, 1408, 1299, 1254, 1200, 1171, 1136, 1043, 1008,
934, 838, 762; Anal. calcd for C13H9ClN4O: C, 57.26; H,
3.33; N, 20.55; found: C, 57.01; H, 3.48; N, 20.58.
white crystal in 60% yield, mp. 140–141ꢀC. H NMR (CDCl3,
400 MHz) d: 1.39 (t, J ¼ 7.2 Hz, 3H, CH2CH3), 3.05 (s, 3H,
pyrazole-CH3), 4.35 (q, J ¼ 7.2 Hz, 2H, CH2CH3), 7.69 (d, J
¼ 9.2 Hz, 1H, pyridazine-H), 8.10 (s, 1H, pyrazole-H), 8.14
(d, J ¼ 9.2 Hz, 1H, pyridazine-H); 13C NMR (CDCl3, 100
MHz), d: 13.73, 14.55, 60.53, 115.59, 124.14, 130.73, 143.91,
146.59, 155.38, 156.06, 163.31; LC-MS: 267 (Mþ, 100), 269
(33); IR (KBr) m (cmꢁ1): 3131, 1633, 1448, 1402, 1089, 1018,
860, 765. Anal. calcd. for C11H11ClN4O2: C, 49.54; H, 4.16;
N, 21.01; found: C, 49.28; H, 4.26; N, 20.98.
3-(4-methylphenoxy)-6-(1H-pyrazol-1-yl)pyridazine(4c). White
solid, yield 70%, mp. 131–132ꢀC.1H NMR (CDCl3, 400 MHz)
Side product 3-dimethylamin-6-(4-ethoxycarbonyl-5-methyl-
1H-pyrazol-1-yl) pyridazine 7 was also obtained in 10% yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
A New Method for the Synthesis and Herbicidal Activity of
3-Phenoxy-6-(1H-(substituted)pyrazol-1-yl) Pyridazines
589
1
mp. 102–104ꢀC. H NMR (CDCl3, 400 MHz) d: 1.38 (t, J ¼
7.2 Hz, 3H, CH2CH3), 2.92 (s, 3H, pyrazole-CH3), 3.24(s, 6H,
N(CH3)2), 4.33 (q, J ¼ 7.2 Hz, 2H, CH2CH3), 6.98((d, J ¼
10.0 Hz, 1H, pyridazine-H), 7.34 (d, J ¼ 9.6 Hz, 1H, pyrida-
zine-H), 8.04 (s, 1H, pyrazole-H). Anal. calcd. for
C13H17N5O2: C, 56.71; H, 6.22; N, 25.44; found: C, 56.77; H,
6.27; N, 25.41. Compound 7 was further confimred by X-ray
diffraction (Fig. 5).
H); IR (KBr) m (cmꢁ1): 3136, 3035, 1718, 1584, 1562, 1442,
1402, 1290, 1248, 1187, 1040, 1094, 854, 778; Anal. calcd.
for C17H15ClN4O3: C, 56.91; H, 4.21; N, 15.62; found: C,
57.32; H, 4.05; N, 15. 44.
3-(3,4-dichlorophenoxy)-6-(4-ethoxycarbonyl-5-methyl-1H-
pyrazol-1-yl) pyridazine(8f). White solid, yield 58%, mp.
145–146ꢀC. 1H NMR (CDCl3, 400 MHz) d: 1.38 (t, J ¼
7.2 Hz, 3H, CH2CH3), 2.97 (s, 3H, pyrazole-CH3), 4.34 (q,
J ¼ 7.2 Hz, 2H, CH2CH3), 7.14 (dd, J1 ¼ 8.8Hz, J2 ¼ 2.8Hz,
1H, ArH), 7.36–7.42 (m, 2H, ArHþ pyridazine-H), 7.52 (d,
J ¼ 8.8 Hz, 1H, ArH), 8.07 (s, 1H, pyrazole-H), 8.20 (d, J ¼
9.2 Hz, 1H, pyridazine-H); IR (KBr) m (cmꢁ1): 3114, 3021,
1718, 1552, 1443, 1402, 1296, 1246, 1187, 1094, 1037, 922,
890, 838, 771; Anal. calcd. for C17H14Cl2N4O3: C, 51.93; H,
3.59; N, 14.25; found: C, 52.11; H, 4.05; N, 14.03.
3-(4-methoxycarbonylphenoxy)-6-(4-ethoxycarbonyl-5-methyl-
1H-pyrazol-1-yl) pyridazine(8g). White solid, yield 52%, mp.
129–130ꢀC. 1H NMR (CDCl3, 400 MHz) d: 1.38 (t, J ¼ 7.2
Hz, 3H, CH2CH3), 2.96 (s, 3H, pyrazole-CH3), 3.94(s, 3H,
COOCH3), 4.33 (q, J ¼ 7.2 Hz, 2H, CH2CH3), 7.32(d, J ¼
8.8 Hz, 2H, ArH), 7.42 (d, J ¼ 9.6 Hz, 1H, pyridazine-H),
8.07 (s, 1H, pyrazole-H), 8.14 (d, J ¼ 8.8 Hz, 2H, ArH), 8.19
(d, J ¼ 9.6 Hz, 1H, pyridazine-H); IR (KBr) m (cmꢁ1): 3136,
3013, 2025, 1723, 1606, 1590, 1554, 1506, 1481, 1456, 1435,
1412, 1400, 1298, 1245, 1206, 1184, 1168, 1098, 1042, 1016,
935, 877, 771; Anal. calcd. for C19H18N4O5: C, 59.68; H,
4.74; N, 14.65; found: C, 59.64; H, 4.55; N, 14.45.
3-(4-methylphenoxy)-6-(4-ethoxycarbonyl-5-methyl-1H-
pyrazol-1-yl)pyridazine(8a). White solid, yield 41%, mp.
110–111ꢀC. 1H NMR (CDCl3, 400 MHz) d: 1.38 (t, J ¼
7.2 Hz, 3H, CH2CH3), 2.38 (s, 3H, ArACH3), 2.95 (s, 3H,
pyrazole-CH3), 4.33 (q, J ¼ 7.2 Hz, 2H, CH2CH3), 7.12 (d,
J ¼ 8.4 Hz, 2H, ArH), 7.25 (d, J ¼ 8.4 Hz, 2H, ArH), 7.34
(d, J ¼ 9.2 Hz, 1H, pyridazine-H), 8.06 (s, 1H, pyrazole-H),
8.11 (d, J ¼ 9.2 Hz, 1H, pyridazine-H); IR (KBr) m (cmꢁ1):
3114, 3035, 1710, 1545, 1446, 1402, 1302, 1251, 1184, 1085,
1018, 934, 880, 842, 771; Anal. calcd. for C18H18N4O3: C,
63.89; H, 5.36; N, 16.56; found: C, 63.92; H, 5.41; N 16.49.
3-(3,5-dimethylphenoxy)-6-(4-ethoxycarbonyl-5-methyl-1H-
pyrazol-1-yl) pyridazine(8b). White solid, yield 80%, mp.
119–120ꢀC. 1H NMR (CDCl3, 400 MHz) d: 1.38 (t, J ¼ 7.2
Hz, 3H, CH2CH3), 2.34 (s, 6H, ArA(CH3)2), 2.95 (s, 3H, pyr-
azole-CH3), 4.34 (q, J ¼ 7.2 Hz, 2H, CH2CH3), 6.83 (s, 2H,
ArH), 6.90 (s, 1H, ArH), 7.33 (d, J ¼ 9.6 Hz, 1H, pyridazine-
H), 8.06 (s, 1H, pyrazole-H), 8.10 (d, J ¼ 9.6 Hz, 1H, pyrida-
zine-H); IR (KBr)
m
(cmꢁ1):3114, 3035, 2985,
2934,1718,1619, 1555, 1443, 1402, 1296, 1251, 1184, 1133,
1094, 1034, 934, 835, 784; Anal. calcd. for C19H20N4O3: C,
64.76; H, 5.72; N, 15.90; found: C, 64.56; H, 6.00; N, 15.97.
3-(2-methoxycarbonylphenoxy)-6-(4-ethoxycarbonyl-5-methyl-
1H-pyrazol-1-yl) pyridazine(8c). White solid, yield 75%, mp.
130–131ꢀC. 1H NMR (CDCl3, 400 MHz) d: 1.38 (t, J ¼ 7.2
Hz, 3H, CH2CH3), 2.93 (s, 3H, pyrazole-CH3), 3.74 (s, 3H,
COOCH3), 4.33 (q, J ¼ 7.2 Hz, 2H, CH2CH3), 7.32 (d, J ¼
8.0 Hz, 1H, ArH), 7.37 (t, J ¼ 7.6 Hz, 1H, ArH), 7.45 (d, J ¼
9.6 Hz, 1H, pyridazine-H), 7.65 (t, J ¼ 7.6 Hz, 1H, ArH),
8.06 (s, 1H, pyrazole-H), 8.09 (d, J ¼ 7.6 Hz, 1H, ArH), 8.17
(d, J ¼ 9.6 Hz, 1H, pyridazine-H); IR (KBr) m (cmꢁ1): 3122,
2992, 1710, 1602, 1552, 1478, 1446, 1402, 1299, 1258, 1184,
1133, 1091, 1034, 931, 880, 835, 774; Anal. calcd. for
C19H18N4O5: C, 59.68; H, 4.74; N, 14.65; found: C, 59.70; H,
4.61; N, 14.69.
3-(4-chlorophenoxy)-6-(4-ethoxycarbonyl-5-methyl-1H-pyra-
zol-1-yl) pyridazine(8d). White solid, yield 80%, mp. 175–
176ꢀC. 1H NMR (CDCl3, 400 MHz) d: 1.38 (t, J ¼ 7.2 Hz,
3H, CH2CH3), 2.95 (s, 3H, pyrazole-CH3), 4.33 (q, J ¼ 7.2
Hz, 2H, CH2CH3), 7.19 (d, J ¼ 8.8 Hz, 2H, ArH), 7.38 (d,
J ¼ 9.6 Hz, 1H, pyridazine-H), 7.41 (d, J ¼ 8.8Hz, 2H, ArH),
8.06(s, 1H, pyrazole-H), 8.16 (d, J ¼ 9.6 Hz, 1H, pyridazine-
H); IR (KBr) m (cmꢁ1): 3134, 3012, 1716, 1578, 1552, 1443,
1402, 1285, 1254, 1168, 1041, 1087, 848, 772; Anal. calcd.
for C17H15ClN4O3: C, 56.91; H, 4.21; N, 15.62; found: C,
56.73; H, 4.34; N, 15.90.
3-(3-trifluorophenoxy)-6-(4-ethoxycarbonyl-5-methyl-1H-
pyrazol-1-yl) pyridazine(8h). White solid, yield 80%, mp.:
133–134ꢀC. 1H NMR (CDCl3, 400 MHz) d: 1.38 (t, J ¼ 7.2
Hz, 3H, CH2CH3), 2.96 (s, 3H, pyrazole-CH3), 4.34 (q, J ¼
7.2 Hz, 2H, CH2CH3), 7.43 (d, J ¼ 9.6 Hz, 1H, pyridazine-
H), 7.47 (d, J ¼ 8.0 Hz, 1H, ArH), 7.52 (s, 1H, ArH), 7.54 (d,
J ¼ 8.0 Hz, 1H, ArH), 7.58 (t, J ¼ 7.6 Hz, 1H, ArH), 8.08 (s,
1H, pyrazole-H), 8.20 (d, J ¼ 9.6 Hz, 1H, pyridazine-H); IR
(KBr) m (cmꢁ1): 3181, 3145, 3060, 2992, 2931,1718, 1648,
1581, 1554, 1474, 1444, 1380, 771, 691; Anal. calcd. for
C18H15F3N4O3: C, 55.10; H, 3.85; N, 14.28; found: C, 55.24;
H, 4.05; N, 14.39.
Herbicidal activity tests [20,21]. Inhibition of the root-
growth of rape (Brassica campestris L.). The compounds to
be tested are made into emulsions to aid dissolution. Rape
seeds are soaked in distilled water for 5 h before being placed
on a filter paper in a 6-cm Petri plate, to which 2 ml of inhibi-
tor solution had been added in advance. Usually, 15 seeds are
used on each plate. The plate is placed in a dark room and
allowed to germinate for 72 h at 28(ꢂ1)ꢀC. The lengths of 10
rape roots selected from each plate are measured and the
means are calculated. The inhibition percentage is calculated
relative to controls using distilled water instead of the inhibitor
solution. There were two replicates for each treatment. The
data of herbicidal activity are listed in Table 1.
Inhibition of the seedling growth of barnyard grass (Echi-
nochloa crusgalli (L.) Beauv.). The compounds to be eval-
uated are made into emulsions to aid dissolution. Ten baryard
grass seeds are placed into a 50-mL cup covered with a layer
of grass beads (diameter ¼ 0.5cm) and a piece of filter paper
at the bottom, to which 5 mL of inhibitor solution had been
added in advance. The cup is placed in a bright room, and the
seeds were allowed to germinate for 72 h at 28(ꢂ1)ꢀC. The
height of the above-ground parts of the seedlings in each cup
3-(3-chlorophenoxy)-6-(4-ethoxycarbonyl-5-methyl-1H-pyrazol-
1-yl) pyridazine(8e). White solid, yield 72%, mp. 130–131ꢀC.
1H NMR (DMSO-d6, 400 MHz) d: 1.38 (t, J ¼7.2 Hz, 3H,
CH2CH3), 2.97 (s, 3H, pyrazole-CH3), 4.34 (q, J ¼ 7.2 Hz,
2H, CH2CH3), 7.16(dd, J¼1.6Hz, 6.8Hz, 1H, ArH), 7.27–
7.30(m, 2H, ArH), 7.38–7.42 (m, 2H, pyridazine-H þ ArH),
8.07 (s, 1H, pyrazole-H), 8.18 (d, J ¼ 9.2 Hz, 1H, pyridazine-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

590
F.-Z. Hu, G.-F. Zhang, B. Liu, X.-M. Zou, Y.-Q. Zhu, and H.-Z. Yang
Vol 46
[9] Hancock, K. G.; Uriarte, A. K.; Dickinson, D. A. J Am
Chem Soc 1973, 95, 6980.
is measured and the means calculated. The inhibition percent-
age is calculated relative to controls using distilled water
instead of the inhibitor solution. There were two replicates for
each treatment. The data of herbicidal activity are listed in
Table 1.
[10] Wang, Z.-P.; Hu, F.-Z.; Zou, X.-M.; Yang, X.-F.; Yang,
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chenko, O. A. Tetrahedron Lett, 2008, 49, 3104, and the references
cited therein.
Acknowledgment. The authors thank the National Key Project
for Basic Research (No. 2003CB114400) and the National Natu-
ral Science Foundation of China (No. 20302004) for financial
support.
[12] Ren, X.-L.; Hu, F.-Z.; Zou, X.-M.; Yang, H.-Z. Pesticides
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet