Synthesis and herbicidal evaluation of 3-N-substituted amino-6-benzyloxypyridazine derivatives

Article abstract of DOI:10.1002/jhet.1831

A variety of 3-N-substituted amino-6-benzyloxypyridazine derivatives were designed and synthesized in satisfactory yields. Their structures were confirmed by IR, ¹H-NMR, and elemental analysis; compound 5j was further determined by X-ray diffraction crystallography. Their herbicidal activities were evaluated through barnyard grass and rape cup tests in laboratory bioassays. Most of the title compounds 5 displayed moderate herbicidal activities against the dicotyledonous plant Brassica campestris L. The most active compounds in the laboratory were also evaluated in the greenhouse.

Full text of DOI:10.1002/jhet.1831

1
404
Synthesis and Herbicidal Evaluation of 3-N-Substituted Amino-6-
Vol 51
benzyloxypyridazine Derivatives
Min Zhang, * Fang-Zhong Hu, * Ting Zhao, Liu-Qing Yang, and Hua-Zheng Yang
a,b
a
c
b
a
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
b
c
School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, Jiangsu, People’s Republic of China
School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, Jiangsu, People’s Republic of China
*
E-mail: zhangminnk@163.com or fzhu@nankai.edu.cn
Received June 24, 2012
DOI 10.1002/jhet.1831
Published online 25 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
O
Cl
F
CH OH
2
R
1 2
NH POCl
NH
3
N
KF
N sulfolane
N
N
O
F NHR R
N
N
R
O
Cl
F
1
2
3
4
1
2
O
NR R
1
2
Where -NR R = (a) -N(CH
)
2
, (b) -N
,
(c)
-N
O
3
N
N
R
5
A variety of 3-N-substituted amino-6-benzyloxypyridazine derivatives were designed and synthesized in
1
satisfactory yields. Their structures were confirmed by IR, H-NMR, and elemental analysis; compound 5j
was further determined by X-ray diffraction crystallography. Their herbicidal activities were evaluated
through barnyard grass and rape cup tests in laboratory bioassays. Most of the title compounds 5 displayed
moderate herbicidal activities against the dicotyledonous plant Brassica campestris L. The most active
compounds in the laboratory were also evaluated in the greenhouse.
J. Heterocyclic Chem., 51, 1404 (2014).
INTRODUCTION
herbicidal activities. The herbicidal activities of the title com-
pounds were determined with B. campestris and E. crus-galli
as examples of annual dicotyledonous and monocotyledon-
ous plants, respectively, using reported laboratory meth-
ods [16,17]. In addition, some compounds were selected
for bioassay in the glasshouse on four weeds representa-
tive of monocotyledonous and dicotyledonous plants
Pyridazine compounds are significant in modern
agrochemical chemistry, for they exhibit wide biological
activities and are usually used as herbicides in plant protec-
tion [1–6]. Many pyridazine herbicides, such as credazine,
pyridate, and metflurazon (Fig. 1), have been commercialized.
In addition, phenoxypyridazines can be considered as
bioisosters of diphenyl ethers that have been developed as
herbicides for several decades [7], as nitrogen-containing
heterocyclic rings are the classic phenyl-ring equivalents
according to the bioisosterism [8,9]. For these reasons, we
have for a long time been interested in the synthesis of new
pyridazine derivatives of potential herbicidal value.
[16,17]. Through these tests, the herbicidal activities of the ti-
tle compounds can be evaluated comprehensively.
RESULTS AND DISCUSSION
Synthesis.
Maleic hydrazide (1) was prepared using
In our previous work, numerous phenoxypyridazines A
and benzyloxypyridazine derivatives B (Fig. 2) have been
synthesized as potential herbicides [9–15]. To our interest,
benzyloxypyridazine analogs also possess good inhibitory
activities against Brassica campestris L. and Echinochloa
crus-galli (L.) Beauv [13–15]. The new discoveries have led
us to synthesize a series of 3-substituted benzyloxypyridazine
analogs C (Fig. 2) [16], which showed excellent herbicidal
activity against B. campestris. With the objective of advancing
the earlier work, exploring the herbicidal activity of novel
compounds, and studying the relationship of structure and
herbicidal activity, 3-N-substituted amino-6-benzyloxypyridazine
derivatives 5 were designed and synthesized. In this article, the
synthesis of the title compounds is described, as well as their
maleic anhydride and hydrazine hydrate as the starting
materials in the presence of concentrated HCl in good yield.
1 was treated with freshly distilled phosphorus oxychloride
to generate intermediate 2. 3,6-Difluoropyridazine (3) was
achieved by the reaction of 2 and anhydrous potassium
fluoride in absolute sulfolane in 56.6% yield. Treatment of
compound 3 and the corresponding benzyl alcohol in the
presence of sodium hydroxide under reflux in acetonitrile
furnished the desired intermediate 4.
The title compounds 5 can be obtained by the reaction of
3-substituted benzyloxy-6-fluoropyridazine (4) and second-
ary amine in the presence of sodium hydroxide in refluxing
acetonitrile [11] or treatment of 3-substituted benzyloxy-6-
fluoropyridazine (4) in refluxing secondary amine or with
©
2014 HeteroCorporation

September 2014
Synthesis and Herbicidal Evaluation of 3-N-Substituted Amino-6-
benzyloxypyridazine Derivatives
1405
(H3C)2N
Cl
n-C8H17S
O
O
O
N
N
O
CH3
N
N
Cl
N
N
credazine
pyridate
metflurazon
Figure 1. Some commercialized herbicides of pyridazines.
H3C
N
(Table 2). Through these tests, we can comprehensively
evaluate the herbicidal activities of the title compounds.
As shown in Table 1, the title compounds showed herbi-
cidal activities to some extent in the rape root and barnyard
grass cup tests. Among the 20 compounds, compounds with
dimethylamino group at the 3-position of the pyridazine ring
have a higher level of herbicidal activities. For example,
compound 5d displayed 85.6% inhibition of rape root
growth at a dosage of 10 mg/L, and compound 5a possessed
R1
R2
N
C
O
n
N N
O
R3
n = 0, 1
CF3
A (n=0), B (n=1)
Figure 2. Chemical structures of A to C.
the solution of dimethylamine in absolute ethanol in a sealed
tube at 75–80 C, respectively [14]. We preferred the latter
method to prepare the target products 5 because it avoids the
hydrolysis of 4 and provides greater convenience for the next
purification (Scheme 1). All of the title compounds 5 were
8
9.8% inhibition of barnyard grass seedling growth at a
ꢀ
concentration of 100 mg/L, respectively. In addition, it is
worth noting that all the target compounds 5 exhibited a higher
inhibition rate for the dicotyledonous plant B. campestris than
that for the monocotyledonous plant E. crus-galli.
1
characterized by IR, H-NMR, and elemental analysis. To
From the biological assay results in Table 2, it was also
found that these compounds showed better selectivity to
dicotyledonous plants B. campestris and Amaranthus retro-
flexus. Nevertheless, some compounds with a larger rape root
inhibition value did not exhibit a higher herbicidal efficacy.
For example, compound 5d, the most active compound in
the laboratory tests, only can control 41.7% B. campestris
at the rate of 1500 g/ha in pre-emergence application, which
is less active than that of compound 4a (79.2%). As com-
pared with compounds 5c and 4a, which possess the same
group (3,5-dimethylbenzyloxy) at the 6-position of the pyri-
dazine ring and nearly equal rape root inhibition values
further elucidate the structure of products, a single crystal of
compound 5j was prepared, and its structure was determined
by X-ray diffraction (Fig. 3) [18].
Herbicidal activities.
The herbicidal activities of the
title products 5 were determined with B. campestris and
E. crus-galli as examples of annual dicotyledonous and
monocotyledonous plants, respectively, using reported
laboratory methods [16,17], and the results were listed in
Table 1. In addition, the herbicidal activities were also
bioassayed in the glasshouse on four species representative
of monocotyledonous and dicotyledonous plants [16,17]
Scheme 1. Synthesis of the title compound 5.
O
Cl
F
CH OH
2
R
NH POCl3
NH
N
KF
N sulfolane
N
N
O
Cl
F
1
2
3
1
2
1
2
O
F NHR R
O
NR R
N N
N N
-N
R
R
4
5
1
2
Where -NR R = (a) -N(CH3)2
-N
O
,
(b)
,
(c)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
406
M. Zhang, F.-Z. Hu, T. Zhao, L.-Q. Yang, and H.-Z. Yang
Vol 51
Figure 3. Molecular structure of compound 5j.
Table 1
CONCLUSION
Herbicidal activities of compounds 5a–5t (percent inhibition, %;
In summary, a series of 3-N-substituted amino-6-subtituted
benzyloxypyridazine derivatives were designed and
synthesized in satisfactory yields. The results of bioassays
indicated that some of these title compounds displayed
some herbicidal activities. It was found that a suitable
substituent at the 3-position of 6-benzyloxypyridazines
was essential for a good herbicidal activity.
concentration, mg/L).
Brassica campestris
Echinochloa crus-galli
Compound
1
0
100
10
100
a
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
4
a
53.0
37.1
63.9
85.6
59.9
31.4
67.8
46.9
25.7
8.6
43.0
30.3
21.4
11.2
66.3
17.9
13.4
0
93.7
90.1
93.1
94.0
83.1
60.6
96.4
77.4
35.3
13.2
65.6
49.8
29.4
38.8
97.2
23.1
27.2
31.6
22.2
7.8
8.7
21.4
0
14.0
5.0
1.2
0
19.4
0
0
0
0
0
0
0.2
0
1.7
9.9
13.4
0
89.8
69.7
35.8
30.5
14.7
31.8
32.5
34.5
0
a
b
a
c
a
d
a
e
f
EXPERIMENTAL
a
a
1
g
h
i
H-NMR spectra were recorded on a Bruker AC-P500
(300 MHz) (Rheinstetten, Germany) or a Varian Oxford AS400
(400 MHz) instrument (Palo Alto, CA, USA) at RT in CDCl3
with TMS as an internal standard. Melting points were determined
on an X-4 binocular microscope melting point apparatus (Beijing
Tech Instruments Co., Beijing, China) and are uncorrected. Elemen-
tal analysis was performed on a Yanaco MT-3CHN elemental anal-
ysis instrument (Kyoto, Japan). IR spectra were measured on a
Tensor 27 OPUS FTIR spectrometer (Bruker, Germany) as KBr pel-
lets with absorption given in reciprocal centimeter. X-ray diffraction
was carried out on a Rigaku Saturn 724 CCD diffractometer (Tokyo,
Japan). Analytical TLC was performed on silica gel GF254 (Qingdao
Haiyang Chemical Co., Qingdao, China). Reagents were purchased
either from J&K Scientific Co. Ltd. (Beijing, China) or Nanjing Tian
Zun Ze Zhong Chemical Co. Ltd (Nanjing, China) and were used
directly without further purification. All solvents were dried and
redistilled before use. Maleic hydrazide (1) was prepared by the
hydrazinolysis reaction of maleic anhydride with hydrazine hydrate
in the presence of concentrated HCl according to the reported syn-
j
0
k
l
61.5
11.4
27.7
30.6
73.9
0
18.1
17.9
17.7
4.2
m
n
a
o
p
q
r
s
11.8
0
68.9
t
b,c
a
92.4
0
89.5
a
These data had been reported in ref [14].
The data had been reported in ref [13].
The structure of compound 4a is
b
c
ꢀ
thetic protocols [10], yield 91.1%, mp 297–300 C. 3,6-Dichloropy-
ridazine (2) was prepared from 1 and freshly distilled phosphorus
ꢀ
oxychloride (POCl ) in 78.7% yield, mp 69–70 C according to
3
the reported procedure [20,21].
Synthesis of 3,6-difluoropyridazine (3) [11,13]. A solution
of 3,6-dichloropyridazine (11.20 g, 75.0 mmol) and anhydrous
potassium fluoride (34.00 g, 0.58 mol) dissolved in dry sulfolane
ꢀ
(
Table 1), it was also found that compound 5c displayed
(40 mL) was heated to 150 C with stirring for 1 h and then was
ꢀ
continued to heat slowly to 175–180 C for 12 h. The solution
was cooled below 100 C, filtered quickly, and washed with hot
sulfolane. The combined organic phase was distilled under
vacuum at about 0.35 kPa, and the eluent fraction of 44–45 C
weaker activities (Table 2). These results may be due to the
loss of dimethylamino moiety of benzyloxypyridazines in
the light [19]. Considering that compound 4a possessed
good herbicidal activity for B. campestris (79.2%) and A.
retroflexus (79.6%) in pre-emergence (Table 2), the choice
of a suitable substituent for the 3-position of 6-benzyloxy-
pyridazines will be our next research emphasis.
ꢀ
ꢀ
was collected. The product was obtained as a white solid in
ꢀ
5
6.6% yield, mp 54–55 C.
Synthesis of 3-substituted benzyloxy-6-fluoropyridazine (4)
[13]. A mixture of 3,6-difluoropyridazine (3) (0.25 g, 2.15 mmol),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2014
Synthesis and Herbicidal Evaluation of 3-N-Substituted Amino-6-
1407
benzyloxypyridazine Derivatives
Table 2
a
À1
Herbicidal activities of compounds (percent inhibition) in greenhouse test (rate = 1500 g ha ).
Brassica campestris Amaranthus retroflexus Echinochloa crus-galli
Digitaria sanguinalis
Compound
Pre
Post
Pre
Post
Pre
Post
Pre
Post
5
5
5
5
5
4
a
b
c
d
e
31.9
11.1
9.7
41.7
33.3
79.2
45.4
41.3
27.2
24.6
30.2
17.9
47.7
15.9
9.1
13.6
38.6
79.6
15.2
4.6
0
0
0
0
0
0
0
5.3
3.7
14.4
17.1
0
0
0
0
0
0
5.4
0
0
3.7
0
1.5
8.2
50.8
a
3.0
0
0
a
Pre, pre-emergence; Post, post-emergence.
substituted benzyl alcohol (2.03 mmol), sodium hydroxide (0.09 g,
.25 mmol), and acetonitrile (20 mL) was heated under reflux with
stirring. The reaction was monitored by TLC. Upon termination,
the solution was allowed to cool to RT and poured into cold
water (20 mL). The resulting precipitate was filtered, washed with
J= 9.6 Hz, 1H, pyridazine-H), 6.95 (d, J= 9.6 Hz, 1H, pyridazine-H),
7.25 (dd, J=2.1, 8.4Hz, 1H, ArH), 7.41 (d, J= 2.1 Hz, 1H, ArH),
7.51 (d, J= 8.4 Hz, 1H, ArH); IR (KBr) n: 3147, 1622, 1506, 1398,
2
À1
1289, 1101, 1029, 798 cm . Anal. Calcd for C H Cl N O: C,
13
13
2 3
52.37; H, 4.39; N, 14.09. Found: C, 52.31; H, 4.41; N, 13.91.
3-Dimethylamino-6-(4-bromobenzyloxy)pyridazine (5e). White
water, dried, and purified by recrystallization from petroleum ether
ꢀ
ꢀ
1
(
60–90 C) to give the product.
solid, mp 130–131 C, yield 93.8%; H-NMR (CDCl
3.10 (s, 6H, CH NCH ), 5.39 (s, 2H, CH O), 6.86 (d, J=9.6Hz,
1H, pyridazine-H), 6.92 (d, J= 9.6 Hz, 1H, pyridazine-H), 7.34
d, J= 8.4 Hz, 2H, ArH), 7.49 (d, J= 8.0 Hz, 2H, ArH); IR (KBr) n:
3
, 400 MHz) d:
General synthetic procedure for 5a–5e. Compounds 5a–5e
were synthesized as the literature described [14].
A mixture of corresponding 4 (1.5mmol) and 5 mL solution of
3
3
2
(
À1
3
140, 1629, 1398, 1289, 1101, 812 cm . Anal. Calcd for
dimethylamine in absolute ethanol (2.0mol/L) was added to a
ꢀ
C H BrN O: C, 50.67; H, 4.58; N, 13.64. Found: C, 50.51; H,
sealed tube and then was heated to 75–80 C for 8 h. The solvent
13 14
3
4.58; N, 13.42.
was removed under reduced pressure, and water (20mL) was added
to the residue. The solution was extracted three times with dichlor-
omethane (30 mL), and the extracts were washed with water and
General synthetic procedure for 5f–5t. Compounds 5f–5t
were synthesized as the literature described [14].
A solution of 4 (1.5 mmol) in dry morpholine or piperidine (20 mL)
was heated under reflux with stirring till the reaction was completed
(monitored by TLC). The solvent was removed under reduced
pressure, and the residue was added to water (20 mL). The crude
product was collected by filtration, washed with water, and then dried,
which was recrystallized from ethyl acetate : petroleum ether (1:4, v/v)
to afford the pure target compounds as a white or yellow solid.
3-(1-Piperidinyl)-6-benzyloxypyridazine (5f). White solid,
2 4
then dried over Na SO . The solvent was removed under reduced
pressure to give crude product 5a–5e, which was purified by flash
column chromatography on silica gel, using ethyl acetate: petro-
leum ether (1:4, v/v) as the eluent to afford the pure target product.
3
-Dimethylamino-6-(2-methoxybenzyloxy)pyridazine (5a). Pale
1
yellow oil, yield 82.1%; H-NMR (CDCl
3
, 300MHz) d: 3.11 (s, 6H,
CH NCH ), 3.84 (s, 3H, OCH ), 5.50 (s, 2H, CH O), 6.86–7.05
3
3
3
2
(m, 4H, pyridazine-H + ArH), 7.27–7.35 (m, 1H, ArH), 7.43–7.54
ꢀ
1
(
1
m, 1H, ArH); IR (KBr) n: 3133, 2880, 2836, 1607, 1549, 1492,
mp 103 C, yield 80.5%; H-NMR(CDCl
(m, 6H, (CH ), 3.49–3.54 (m, 4H, CH
CH O), 6.87 (d, J = 9.6 Hz, 1H, pyridazine-H), 7.04 (d, J = 9.9Hz,
, 300 MHz) d: 1.63–1.71
3
À1
427, 1398, 1289, 1246, 1116, 1029, 993, 942, 870, 827, 747 cm
.
2
)
3
2
NCH ), 5.45 (s, 2H,
2
Anal. Calcd for C H N O : C, 64.85; H, 6.61; N, 16.20. Found: C,
2
14 17 3 2
64.62; H, 6.51; N, 16.29.
1H, pyridazine-H), 7.32–7.42 (m, 3H, PhH), 7.45–7.51 (m, 2H,
3
-Dimethylamino-6-(2-methylbenzyloxy)pyridazine (5b). White
PhH); IR (KBr) n: 3063, 2937, 1620, 1439, 1299, 1253, 1119,
ꢀ
1
À1
solid, mp 80–82 C, yield 83.9%; H-NMR (CDCl
s, 3H, CH ), 3.11 (s, 6H, CH NCH ), 5.44 (s, 2H, CH
d, J = 9.6Hz, 1H, pyridazine-H), 6.93 (d, J = 9.6 Hz, 1H,
pyridazine-H), 7.19–7.31 (m, 3H, ArH), 7.44–7.49 (m, 1H, ArH);
IR (KBr) n: 3154, 3118, 1622, 1549, 1492, 1398, 1275, 1101,
3
, 400MHz) d: 2.37
1012, 917, 851, 727, 692 cm . Anal. Calcd for C16
H N O: C,
19 3
(
(
3
3
3
2
O), 6.87
71.35; H, 7.11; N, 15.60. Found: C, 71.38; H, 7.10; N, 15.45.
3-(1-Piperidinyl)-6-(2-methoxybenzyloxy)pyridazine
ꢀ
1
(5g). White solid, mp 67–68 C, yield 73.6%; H-NMR(CDCl
300 MHz) d: 1.63–1.71 (m, 6H, (CH ), 3.47–3.54 (m, 4H,
CH NCH ), 3.84 (s, 3H, OCH ), 5.51 (s, 2H, CH O), 6.87
3
,
2 3
)
À1
9
78, 805, 733 cm . Anal. Calcd for C14
17 3
H N O: C, 69.11; H,
2
2
3
2
7
.04; N, 17.27. Found: C, 69.19; H, 7.19; N, 17.28.
-Dimethylamino-6-(3,5-dimethylbenzyloxy)pyridazine
(d, J = 9.6 Hz, 1H, pyridazine-H), 6.89–7.00 (m, 2H, ArH),
7.02 (d, J = 9.9 Hz, 1H, pyridazine-H), 7.27–7.35 (m, 1H,
ArH), 7.44–7.50 (m, 1H, ArH); IR (KBr) n: 3140, 3017, 2930,
2858, 2814, 1593, 1492, 1441, 1398, 1296, 1246, 1173, 1116,
3
1
(5c). Pale yellow oil, yield 85.7%; H-NMR (CDCl
3
, 300MHz)
d: 2.33 (s, 6H, 2Â CH ), 3.11 (s, 6H, CH NCH ), 5.37 (s, 2H,
3
3
3
À1
CH O), 6.87 (d, J = 9.6 Hz, 1H, pyridazine-H), 6.92 (d, J = 9.6Hz,
1007, 913, 841, 740 cm . Anal. Calcd for C H N O : C,
2
17 21 3 2
1
H, pyridazine-H), 6.97 (s, 1H, ArH), 7.09 (s, 2H, ArH); IR (KBr)
68.20; H, 7.07; N, 14.04. Found: C, 67.95; H, 6.99; N, 14.15.
n: 3147, 3017, 1687, 1607, 1549, 1470, 1405, 1282, 1210, 1166,
3-(1-Piperidinyl)-6-(3,5-dimethylbenzyloxy)pyridazine
À1
ꢀ
1
1
108, 1029, 949, 841, 696cm . Anal. Calcd for C H N O: C,
(5h).
300 MHz) d: 1.63–1.72 (m, 6H, (CH ) ), 2.33 (s, 6H, 2 Â CH ),
Pale yellow solid, mp 52–53 C, 92.0%; H-NMR(CDCl ,
1
5
19
3
3
7
0.01; H, 7.44; N, 16.33. Found: C, 70.01; H, 7.49; N, 16.49.
-Dimethylamino-6-(2,4-dichlorobenzyloxy)pyridazine
2
3
3
3
3.47–3.55 (m, 4H, CH NCH ), 5.37 (s, 2H, CH O), 6.87
2 2 2
ꢀ
1
(5d). White solid, mp 117–118 C, yield 80.0%; H-NMR (CDCl
3
,
(d, J= 9.6 Hz, 1H, pyridazine-H), 6.97 (s, 1H, ArH), 7.02
(d, J = 9.6 Hz, 1H, pyridazine-H), 7.09 (s, 2H, ArH); IR (KBr)
3
00 MHz) d: 3.12 (s, 6H, CH NCH ), 5.52 (s, 2H, CH O), 6.90 (d,
3
3
2
Journal of Heterocyclic Chemistry
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M. Zhang, F.-Z. Hu, T. Zhao, L.-Q. Yang, and H.-Z. Yang
Vol 51
À1
n: 3140, 3031, 2923, 2858, 1607, 1441, 1398, 1289, 1253, 1217,
747 cm . Anal. Calcd for C H N O : C, 63.77; H, 6.36; N,
1
6 19 3 3
À1
1
123, 1022, 978, 906, 834, 696 cm . Anal. Calcd for
13.94. Found: C, 63.74; H, 6.41; N, 13.75.
C
7
18
H
23
N
3
O: C, 72.70; H, 7.80; N, 14.13. Found: C, 72.64; H,
.64; N, 14.31.
-(1-Piperidinyl)-6-(4-bromobenzyloxy)pyridazine (5i). White
3-(4-Morpholinyl)-6-(4-bromobenzyloxy)pyridazine (5p). White
ꢀ
1
solid, mp 165–166 C, yield 89.7%;
3
H-NMR(CDCl ,
3
300 MHz) d: 3.49 (t, J= 4.8 Hz, 4H, CH NCH ), 3.84 (t, J=4.8Hz,
2
2
ꢀ
1
solid, mp 132–133 C, yield 72.4%; H-NMR(CDCl
.63–1.74 (m, 6H, (CH ), 3.48–3.58 (m, 4H, CH
s, 2H, CH O), 6.87 (d, J= 9.6 Hz, 1H, pyridazine-H), 7.05
3
, 300 MHz) d:
4H, CH OCH ), 5.42 (s, 2H, CH O), 6.91 (d, J= 9.6 Hz, 1H,
2 2 2
1
(
2
)
3
2
NCH ), 5.43
2
pyridazine-H), 7.02 (d, J= 9.6 Hz, 1H, pyridazine-H), 7.35
(d, J= 8.4 Hz, 2H, ArH), 7.50 (d, J= 8.4 Hz, 2H, ArH); IR (KBr) n:
3140, 3017, 1629, 1542, 1398, 1289, 1239, 1108, 920, 870,
2
(d, J= 9.6 Hz, 1H, pyridazine-H), 7.36 (d, J= 8.4 Hz, 2H, ArH),
À1
7.51 (d, J= 8.4 Hz, 2H, ArH); IR (KBr) n: 3118, 1614, 1398, 1239,
834 cm . Anal. Calcd for C H BrN O : C, 51.44; H, 4.60; N,
15
16
3 2
À1
1101, 1007, 790 cm . Anal. Calcd for C16
3
H18BrN O: C, 55.18; H,
12.00. Found: C, 51.58; H, 4.51; N, 12.01.
5
.21; N, 12.07. Found: C, 54.95; H, 5.24; N, 11.97.
-(1-Piperidinyl)-6-(4-nitrobenzyloxy)pyridazine (5j). Yellow
3-(4-Morpholinyl)-6-(4-nitrobenzyloxy)pyridazine (5q). Yellow
ꢀ
1
3
solid, mp 197–199 C, yield 73.0%; H-NMR(CDCl , 300 MHz)
3
ꢀ
1
solid, mp 148–149 C, yield 80.0%; H-NMR(CDCl , 300 MHz) d:
d: 3.50 (t, J=4.8Hz, 4H, CH NCH ), 3.85 (t, J=4.8Hz, 4H,
3
2
2
1
(
(
.63–1.71 (m, 6H, (CH
s, 2H, CH O), 6.91 (d, J= 9.6 Hz, 1H, pyridazine-H), 7.06
d, J= 9.6 Hz, 1H, pyridazine-H), 7.62 (d, J= 8.7 Hz, 2H, ArH),
2
)
3
), 3.47–3.56 (m, 4H, CH
2
NCH
2
), 5.57
CH OCH ), 5.58 (s, 2H, CH O), 6.98 (d, J= 9.6 Hz, 1H, pyridazine-H),
2 2 2
2
7.06 (d, J= 9.6 Hz, 1H, pyridazine-H), 7.63 (d, J= 8.7 Hz, 2H, ArH),
8.23 (d, J= 8.7 Hz, 2H, ArH); IR (KBr) n: 3140, 3010, 2858, 1600,
À1
8.23 (d, J= 8.7 Hz, 2H, ArH); IR (KBr) n: 3125, 3017, 2937, 2858,
1506, 1398, 1340, 1296, 1246, 1108, 1029, 920, 834 cm . Anal. Calcd
À1
1600, 1520, 1405, 1347, 1296, 1239, 1108, 1043, 906, 827 cm
.
for C H N O : C, 56.96; H, 5.10; N, 17.71. Found: C, 56.75; H, 5.39;
15 16 4 4
Anal. Calcd for C16
C, 60.95; H, 5.60; N, 18.01.
-(1-Piperidinyl)-6-(2-fluorobenzyloxy)pyridazine (5k). White
H
18
N
4
O
3
: C, 61.13; H, 5.77; N, 17.82. Found:
N, 17.69.
3-(4-Morpholinyl)-6-(2-fluorobenzyloxy)pyridazine (5r). White
ꢀ
1
3
solid, mp 115–116 C, yield 82.6%; H-NMR(CDCl , 300 MHz) d:
3
ꢀ
1
solid, mp 64–65 C, yield 88.9%; H-NMR(CDCl , 300 MHz) d:
3.52 (t, J= 4.8 Hz, 4H, CH NCH ), 3.87 (t, J=4.8Hz, 4H,
3
2
2
1
.60–1.74 (m, 6H, (CH
2
)
3
), 3.45–3.58 (m, 4H, CH
2
NCH
2
), 5.53
2 2 2
CH OCH ), 5.56 (s, 2H, CH O), 6.94 (d, J= 9.6 Hz, 1H, pyridazine-
(
s, 2H, CH
2
O), 6.86 (d, J= 9.6 Hz, 1H, pyridazine-H),
H), 7.04 (d, J= 9.6 Hz, 1H, pyridazine-H), 7.07–7.21 (m, 2H, ArH),
7.30–7.39 (m, 1H, ArH), 7.50–7.58 (m, 1H, ArH); IR (KBr) n:
3133, 2981, 2858, 1614, 1448, 1398, 1296, 1246, 1217, 1108, 1029,
7
7
3
1
.04 (d, J= 9.9 Hz, 1H, pyridazine-H), 7.07–7.19 (m, 2H, ArH),
.27–7.37 (m, 1H, ArH), 7.48–7.56 (m, 1H, ArH); IR (KBr) n:
125, 2937, 2865, 2814, 1484, 1441, 1398, 1296, 1246, 1116,
007, 906, 834, 747 cm . Anal. Calcd for C16
À1
928, 834, 740 cm . Anal. Calcd for C H FN O : C, 62.27; H,
15
16
3 2
À1
3
H18FN O: C, 66.88;
5.57; N, 14.52. Found: C, 62.15; H, 5.62: N, 14.58.
3-(4-Morpholinyl)-6-(3-fluorobenzyloxy)pyridazine (5s). White
H, 6.31; N, 14.62. Found: C, 66.87; H, 6.31; N, 14.55.
-(1-Piperidinyl)-6-(3-fluorobenzyloxy)pyridazine (5l). White
solid, mp 80 C, yield 90.5%; H-NMR(CDCl
ꢀ
1
3
solid, mp 122–123 C, yield 84.8%; H-NMR(CDCl , 300 MHz)
3
ꢀ
1
3
, 300 MHz) d:
NCH ), 5.45
d: 3.50 (t, J=4.8Hz, 4H, CH NCH ), 3.85 (t, J=4.8Hz, 4H,
2
2
1
.58–1.72 (m, 6H, (CH ), 3.37–3.57 (m, 4H, CH
)
2 3
2
2
2 2 2
CH OCH ), 5.47 (s, 2H, CH O), 6.89–7.08 (m, 3H, pyridazine-
(
(
(
s, 2H, CH O), 6.88 (d, J = 9.6Hz, 1H, pyridazine-H), 6.95–7.09
m, 2H, pyridazine-H+ ArH), 7.14–7.25 (m, 2H, ArH), 7.28–7.38
H+ArH), 7.12–7.40 (m, 3H, ArH); IR (KBr) n: 3125, 2973, 2865,
2
1622, 1586, 1455, 1398, 1289, 1246, 1094, 1014, 928, 827, 776,
À1
m, 1H, ArH); IR (KBr) n: 3125, 2937, 2822, 1614, 1586, 1441,
675 cm . Anal. Calcd for C H FN O : C, 62.27; H, 5.57; N,
1
5
16
3 2
À1
1
398, 1296, 1246, 1130, 1014, 913, 834, 776, 747cm . Anal.
14.52. Found: C, 62.25; H, 5.41; N, 14.55.
Calcd for C16
6.85; H, 6.24; N, 14.72.
-(1-Piperidinyl)-6-(4-fluorobenzyloxy)pyridazine (5m). White
H
18FN
3
O: C, 66.88; H, 6.31; N, 14.62. Found: C,
3-(4-Morpholinyl)-6-(4-fluorobenzyloxy)pyridazine (5t). White
ꢀ
1
6
solid, mp 138–139 C, yield 76.7%; H-NMR(CDCl
d: 3.49 (t, J= 4.8 Hz, 4H, CH NCH ), 3.84 (t, J= 4.8 Hz, 4H,
CH OCH ), 5.42 (s, 2H, CH O), 6.91 (d, J= 9.6 Hz, 1H,
3
, 400 MHz)
3
2
2
ꢀ
1
solid, mp 111–112 C, yield 91.8%; H-NMR(CDCl
3
, 300MHz) d:
2
2
2
1
2
3
3
.60–1.74 (m, 6H, (CH ) ), 3.38–3.57 (m, 4H, CH NCH ), 5.42 (s,
pyridazine-H), 7.02 (d, J= 9.6 Hz, 1H, pyridazine-H), 7.03–7.09
(m, 2H, ArH), 7.41–7.47 (m, 2H, ArH); IR (KBr) n: 3140, 2973,
2
3
2
2
H, CH O), 6.85 (d, J= 9.9 Hz, 1H, pyridazine-H), 7.01–7.10 (m,
2
H, pyridazine-H + ArH), 7.40–7.49 (m, 2H, ArH); IR (KBr) n:
2872, 1614, 1520, 1448, 1398, 1296, 1239, 1108, 1022, 920,
À1
À1
140, 2930, 1607, 1434, 1390, 1210, 1108, 1007, 812 cm . Anal.
819 cm . Anal. Calcd for C15
H
16FN
3
O
2
: C, 62.27; H, 5.57; N,
Calcd for C H FN O: C, 66.88; H, 6.31; N, 14.62. Found: C,
14.52. Found: C, 62.29; H, 5.40; N, 14.58.
16
18
3
6
6.95; H, 6.21; N, 14.72.
Bioassays. The herbicidal activities of the title compounds
3
-(4-Morpholinyl)-6-benzyloxypyridazine (5n). White solid,
were evaluated using a previously reported procedure [16,17]. For
glasshouse tests, all the experiments were performed under natural
ꢀ
1
mp 135–136 C, yield 80.5%; H-NMR(CDCl , 300 MHz) d: 3.50
3
ꢀ
(t, J=4.80Hz, 4H, CH NCH ), 3.85 (t, J= 4.80 Hz, 4H, CH OCH ),
light conditions at 18–28 C. Additionally, adverse weather
2
2
2
2
5
.47 (s, 2H, CH
2
O), 6.92 (d, J= 9.6 Hz, 1H, pyridazine-H), 7.02
lighting was provided using sodium vapor lamps with a 12:12h
light: dark photoperiod. For all of the bioassay tests, each
treatment was repeated two times.
(d, J= 9.6 Hz, 1H, pyridazine-H), 7.30–7.49 (m, 5H, PhH); IR (KBr)
n: 3003, 2867, 1607, 1455, 1297, 1255, 1112, 1026, 930, 829, 730,
À1
690 cm . Anal. Calcd for C H N O : C, 66.40; H, 6.32; N, 15.49.
Treatment.
The emulsions of purified compounds were
15 17 3 2
Found: C, 66.23; H, 6.25; N, 15.55.
-(4-Morpholinyl)-6-(2-methoxybenzyloxy)pyridazine
prepared by dissolving them in 100mL of N,N-dimethylformamide
with the addition of a little Tween 20 and proper water. For
glasshouse tests, the emulsions were sprayed using a laboratory
belt sprayer at 750L/ha. The mixture of the same amount of
water, N,N-dimethylformamide, and Tween 20 was used as control.
Inhibition of the root growth of rape (B. campestris). Rape
seeds were soaked in distilled water for 4 h before being placed on a
filter paper in a 6-cm Petri plate, to which 2 mL of inhibitor solution
3
ꢀ
1
(
5o). White solid, mp 86–87 C, yield 69.8%; H-NMR(CDCl
3
,
3
00 MHz) d: 3.50 (t, J = 4.8 Hz, 4H, CH NCH ), 3.80–3.89
2
2
(
(
(
m, 7H, CH OCH +OCH ), 5.52 (s, 2H, CH O), 6.88–7.04
m, 4H, pyridazine-H+ ArH), 7.27–7.35 (m, 1H, ArH), 7.43–7.50
m, 1H, ArH); IR (KBr) n: 3133, 3024, 2973, 2843, 1600, 1557,
2 2 3 2
1
492, 1427, 1390, 1289, 1246, 1166, 1116, 1022, 920, 819,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2014
Synthesis and Herbicidal Evaluation of 3-N-Substituted Amino-6-
1409
benzyloxypyridazine Derivatives
had been added in advance. Usually, 15 seeds were used on each
plate. The plate was placed in a dark room and allowed to
[2] Komori, T. European Patent 947509, 1999; Chem Abstr 1999,
31, 243276.
[3] Krueger, B.-W.; Ullmann, A.; Hillebrand, S.; Mauler-Machnik,
A.; Wachendorff-Neumann, U. World Patent 2003024938, 2003; Chem
Abstr 2003, 138, 255241.
1
ꢀ
germinate for 65 h at 28(Æ1) C. The lengths of 10 rape roots
selected randomly from each plate were measured, and the means
were calculated. The percentage inhibition was used to describe
the control efficiency of these compounds. The herbicidal activity
is summarized in Table 1.
[4] Okada, I; Takizawa, E.; Fukuchi, T. Japan Patent 2002003479,
2
002; Chem Abstr 2002, 136, 53753.
[5] Patterson, D. R. European Patent 49971, 1982; Chem Abstr
Inhibition of the seedling growth of barnyard grass
E. crus-galli). Ten E. crus-galli seeds were placed into a 50-mL
1982, 97, 92301.
[
6] Heinisch, G.; Kopelent, F. H. Prog Med Chem 1992,
(
2
9, 141.
cup covered with a layer of glass beads and a piece of filter paper at
the bottom, to which 5 mL of inhibitor solution had been added in
advance. The cup was placed in a bright room, and the seeds were
[7] Hirai, K. In Peroxidizing Herbicides; Boger, P.; Wakabayashi,
K., Eds.; Springer-Verlag: Berlin Herdelberg, 1999, p 15‐70.
[
[
8] Patani, G. A.; Lavoie, E. J. Chem Rev 1996, 96, 3147.
9] Hu, F.-Z.; Zhang, G.-F.; Liu, B.; Zou, X.-M.; Zhu, Y.-Q.;
ꢀ
allowed to germinate for 65 h at 28(Æ1) C. The heights of the
aboveground parts of the seedlings in each cup were measured, and
the means were calculated. The percentage inhibition was used to
describe the control efficiency of the compounds. The herbicidal
activity is summarized in Table 1.
Yang, H.-Z. J Heterocycl Chem 2009, 46, 584.
[10] Ren, K.-T.; Song, H.-H.; Yang, X.-F.; Yang, H.-Z. Chem J
Chinese Univ 2000, 21, 1840 (in Chinese).
[
11] Yang, H.-Z.; Wang, X.; Hu, F.-Z.; Yang, X.-F. Chem J
Chinese Univ 2002, 23, 2261 (in Chinese).
12] Wang, Z.-P.; Hu, F.-Z.; Zou, X.-M.; Yang, X.-F.; Yang, H.-Z.
Chinese J Pesticide Sci 2004, 6, 15 (in Chinese).
13] Zhang, M.; Hu, F.-Z.; Zhu, Y.-Q.; Liu, B.; Zou, X.-M.; Yang,
Pre-emergence.
Sandy clay (100 g) in a plastic box
[
(
11 Â 7Â 7 cm) was wetted with water. Then, 15 germinated seeds of
the tested weeds were planted at a depth of 0.6 cm in the glasshouse,
and the soil was sprayed at a test compound concentration of 1500 g/ha.
Post-emergence. Seedlings (one leaf and one stem) of the
weeds were sprayed with the test compound at the same rate as
used for the pre-emergence test.
[
H.-Z. Chin J Org Chem 2007, 27, 749 (in Chinese).
[14] Hu, F.-Z.; Zhang, M; Zhu, Y.-Q.; Zou, X.-M.; Liu, B.; Yang,
H.-Z. Chin J Org Chem 2007, 27, 1530 (in Chinese).
[
15] Hu, F.-Z.; Zhang, G.-F.; Zou, X.-M.; Liu, B.; Zhu, Y.-Q.;
Yang, H.-Z. Chin J Org Chem 2008, 28, 1227 (in Chinese).
16] Xu, H.; Zhu, Y.-Q.; Zou, X.-M.; Liu, B.; Wang, Y.; Hu, F.-Z.;
Yang, H.-Z. Pest Manag Sci 2012, 68, 276.
17] Zhu, Y.-Q.; Zou, X.-M.; Hu, F.-Z; Yao, C.-S.; Liu, B.; Yang,
H.-Z. J Agric Food Chem 2005, 53, 9566.
18] The single-crystal growth was carried out in ethyl acetate:
For both methods, fresh weights were determined 24 days later,
and the percentage inhibition relative to the controls was calcu-
lated. The herbicidal activity is summarized in Table 2.
[
[
[
Acknowledgments. We are grateful for financial support by the
National Key Technology Research and Development Program
petroleum ether (1:4, v/v) at room temperature. X-ray crystallo-
graphic analysis was performed using a Rigaku Saturn 724 CCD area
diffractometer. Crystal data for 5j: C16
H
18
N
4
O
3
, crystal dimension
(
(
No. 2011BAE06B03-12), the Tianjin Natural Science Foundation
No. 11JCYBJC14200), and the Research Foundation of Jiangsu
0
.20 Â 0.20 Â 0.20 mm, monoclinic, space group P 21/c, a = 19.172
ꢀ
4) Å, b = 7.6293(15) Å, c = 10.967(2) Å, b = 103.83(3) , V = 1557.7
3 3
(
(
University (No. 09JDG064).
5) Å , Mr = 314.34, Z = 4, Dc = 1.422 g/cm , l = 0.71073 Å,
À1
m
wR
(Moka) = 0.128 mm
= 0.2434.
[19] Hancock, K. G.; Uriarte, A. K.; Dickinson, D. A. J Am Chem
1
, F(000) = 682, S = 1.155, R = 0.0832,
2
REFERENCES AND NOTES
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Wilkins, C. J Org Chem 1963, 28, 218.
1
[21] Coad, P.; Coad, R. A. J Org Chem 1963, 28, 1919.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet