N-substituted 5-chloro-6-phenylpyridazin-3(2H)-ones: Synthesis, insecticidal activity against Plutella xylostella (L.) and SAR study

Article abstract of DOI:10.3390/molecules17089413

A series of N-substituted 5-chloro-6-phenylpyridazin-3(2H)-one derivatives were synthesized based on our previous work; all compounds were characterized by spectral data and tested for in vitro insecticidal activity against Plutella xylostella. The result

Full text of DOI:10.3390/molecules17089413

Molecules 2012, 17, 9413-9420; doi:10.3390/molecules17089413
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
N-Substituted 5-Chloro-6-phenylpyridazin-3(2H)-ones:
Synthesis, Insecticidal Activity Against Plutella xylostella (L.)
and SAR Study
Jian Wu *, Shenghong Kang, Qinkun Yuan, Lijun Luo, Juan Ma, Qingcai Shi and Song Yang
State Key Laboratory Breeding Base of Green Pesticides and Agricultural Bioengineering,
Key Laboratory of Green Pesticides and Agricultural Bioengineering, Ministry of Education,
Guizhou University, Guiyang 550025, China; E-Mails: concenhom0627@126.com (S.K.);
momo1989.ok@163.com (Q.Y.); luolijun01013610@163.com (L.L.); majuanmalong@163.com (J.M.);
shiqingcai1988@yahoo.com.cn (Q.S.); yangsdqj@126.com (S.Y.)
* Author to whom correspondence should be addressed; E-Mail: jianwu2691@yahoo.com.cn;
Tel./Fax: +86-851-8292-0900.
Received: 5 July 2012; in revised form: 27 July 2012 / Accepted: 30 July 2012 /
Published: 6 August 2012
Abstract: A series of N-substituted 5-chloro-6-phenylpyridazin-3(2H)-one derivatives
were synthesized based on our previous work; all compounds were characterized by
spectral data and tested for in vitro insecticidal activity against Plutella xylostella. The
results showed that the synthesized pyridazin-3(2H)-one compounds possessed good
insecticidal activities, especially the compounds 4b, 4d, and 4h which showed >90%
activity at 100 mg/L. The structure-activity relationships (SAR) for these compounds were
also discussed.
Keywords: pridazin-3(2H)-one; synthesis; insecticidal activity; SAR study; Plutella xylostella
1. Introduction
The diamondback moth (Plutella xylostella L.) is a serious pest insect in many parts of the World [1,2].
Serious yield losses to crucifers (such as cabbage, cauliflower, broccoli, brussels sprouts and turnip)
from the diamondback moth have become more common in recent years. Currently, insecticide
application is the primary method for controlling this pest [2,3], but particularly severe diamondback
moth resistance to insecticides has been resulting from the indiscriminate use of pesticides in many

Molecules 2012, 17
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tropical and subtropical countries [4–6] so controlling the diamondback moth has become more and more
difficult, and the development of novel insecticides for this insect has attracted more and more attention.
Pyridazinones, an important class of heterocyclic ring, have attracted more and more attention
due to their broad-spectrum biological activity as plant virucides [7,8], antitumor agents [9],
fungicides [10–12], insecticides [13,14], and herbicides [15–17]. In the insecticidal area, many
pyridazin-3(2H)-one derivatives with good insecticidal activity have been discovered and
commercialized, such as pyridaphenthion, pyidaben, NC-184, and NC-170 [18]. Moreover, some
compounds containing N-substituted 6-phenylpyridazin-3(2H)-one moieties (Figure 1, 1–3) were
reported, all of which showed excellent insecticidal activity against Spodoptera exigua (H.),
Heliothis virescens, Tetranychus urticae, et al. [19–21]. In our previous study, several N-substituted
6-phenylpyridazin-3(2H)-one derivatives 4 were reported, which showed fungicidal activity against
G. zeae, F. oxysporum and C. mandshurica to a certain extent [22]. However, in the process of
developing novel insecticidal molecules, we noted that these compounds 1–4 have as a common
structure (N-substituted 5-chloro-6-phenylpyridazin-3(2H)-one), see Figure 1). With this in mind, in an
effort to discover new scope of application for compounds 4, we sought to test their insecticidal
activity against Plutella xylostella (L.), and occasionally found that some of the pyridazin-3(2H)-one
derivatives [22] showed 100% insecticidal activity against Plutella xylostella at 100 mg/L. In the
current work, several new N-substituted 5-chloro-6-phenylpyridazin-3(2H)-one derivatives 4i–s were
synthesized based on our previous synthetic route (Scheme 1) [22], the insecticidal activity and
structure-activity relationship (SAR) for these compounds [including the compounds (4a–h) in
reference [22] against Plutella xylostella were evaluated and discussed, respectively.
Figure 1. The common cores of biologically active compounds 1 to 4.
2. Results and Discussion
2.1. Chemistry
The synthetic protocols of the title compounds was depicted in Scheme 1. Friedel-Crafts alkylation
of benzene with mucochloric acid leads to γ-phenyldichlorocrotonolactone (7), then 7 reacts in a
complex manner with hydrazine hydrate, with elimination of one atom of chlorine [23], to afford a
high yields of 5-chloro-6-phenylpyridazin-3(2H)-one (8). Compounds 4a–s were then obtained in
excellent yields by reaction of 8 with different halides based on our previous work [22]. The structures
of the synthesized compounds were confirmed by 1H-NMR, 13C-NMR, IR and elemental analysis. All
spectral and analytical data were consistent with the assigned structures.

Molecules 2012, 17
Scheme 1. Synthetic route to N-substituted 5-chloro-6-phenylpyridazin-3(2H)-ones 4a–s.
9415
2.2. Insecticidal Activity
As indicated in Table 1, many of the synthesized compounds exhibited weak to excellent
insecticidal activities against P. xylostella at 100 mg/L. Compounds 4b, 4d, 4h and 4t showed 100%,
93%, 97% and 84% activity at 100 mg/L, respectively. Compounds 4f, 4g and 4l showed moderate
activities against P. xylostella at 100 mg/L (50%, 60% and 62%, respectively). When the concentration
was 50 mg/L, compound 4b still showed 97% activity against P. xylostella, which was similar as that
of chlorpyrifos (97%), and compound 4s possessed 84% activity on P. xylosella. In addition,
compounds 4d and 4h also displayed >70% activity on P. xylostella at 50 mg/L. Moreover, when
the concentration was 25 mg/L, the insecticidal activities were decreased, although we noted that
compounds 4b, 4d, 4h and 4s still possessed insecticidal activity to a certain extent (21%, 20%, 20%
and 15%, respectively).
2.3. Structure-Activity Relationship (SAR) Study
The preliminary SAR analysis indicated that a big (in bulk) group with strong electronegativity at
the 2-postion on the benzene (in a –CH2R group) has a positive influence enhancing the insecticidal
activity of the synthesized compounds, that’s why the compounds 4b (–CH2R = 2-NO2-C6H4CH2-) and
4h (–CH2R = 2-CH3O-C6H4CH2-) showed higher activity than 4e (–CH2R = 2-F-C6H4CH2-) and 4m
(–CH2R = 2-CH3-C6H4CH2-), therefore, we can speculate that both the bulk and electronegativity of
the substituent group at the 2-position on benzene play important roles in the insecticidal activity
against P. xylostella. In addition, the position of the group on benzene also a key factor for the activity,
as we can see that compound 4b showed excellent activity, while compound 4c (–CH2R=
3-NO2-C6H4CH2-) and 4i (–CH2R=4-NO2-C6H4CH2-) showed little (or no) activity (4b > 4c > 4i); a
similar case can be found when the group was CH3O- (4h > 4j > 4k). Moreover, the introduction of
2-Cl-substituted pyridine and thiazole in group of –CH2R can also enhance insecticidal activity, e.g.,
compound 4b (–CH2R = 2-Cl-pyridine-CH2-) and 4t (–CH2R = 2-Cl-thiazole-CH2-) also displayed
good insecticidal activity against P. xylostella.

Molecules 2012, 17
Table 1. Insecticidal activity of the synthesized compounds against P. xylostella.
9416
Insecticidal activity (%) at a
concentration of (mg/L)
Comp.
100
20
100
25
93
13
50
45
97
10
45
60
62
20
15
14
21
43
31
84
0
50
/
97
0
76
/
13
0
70
0
13
30
33
0
/
/
0
10
0
60
0
97
100
25
/
21
/
20
/
0
/
20
/
0
13
0
/
/
/
/
/
/
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
15
0
67
100
Blank control
Chlorpyrifos
Avermectin
100
100
3. Experimental
3.1. Chemistry
Melting points were determined by using a XT-4 binocular microscope (Beijing Tech Instrument
Co., Beijing, China) and are uncorrected. 1H and 13C-NMR spectra were recorded on a JEOL ECX 500
NMR spectrometer operating at room temperature and 500 MHz using acetone-d6 or CDCl3 as solvent
and TMS as an internal standard. Infrared spectra were recorded by KBr using a Bruker VECTOR 22
spectrometer. Elemental analysis was performed using an Elemental Vario-III CHN analyzer. The
course of the reactions was monitored by TLC; analytical TLC was performed on silica gel GF254. All
reagents were of analytical grade or chemically pure. All anhydrous solvents were dried and purified
according to standard techniques just before use. All the intermediates and title compounds were
prepared according to the literature [22]. The properties for compounds 4a–h were reported in our
previous work [22]. The properties for 4i–s are listed as follows.
5-Chloro-2-(3-nitrobenzyl)-6-phenylpyridazin-3(2H)-one (4i): White solid; yield: 76%; m.p.: 79–80 °C;
1H-NMR (CDCl3) δ: 8.32 (s, 1H, Ph-H), 8.18, (J = 8.0 Hz, 1H, Ph-H), 7.81 (1H, J = 7.45 Hz, Ph-H),
7.47–7.56 (m, 6H, 6Ph-H), 7.15 (s, 1H, pyridazine-H), 5.43 (s, 2H, CH2); 13C-NMR (CDCl3) δ:

Molecules 2012, 17
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158.71, 148.49, 145.90, 140.21, 137.51, 135.12, 133.31, 129.82, 129.21, 129.02, 128.42, 123.83,
123.33, 54.61, 49.73; IR (KBr): ν 3058.0, 2951.0, 2834.1, 1673.6 cm−1; Anal. Calc. for C17H12ClN3O3:
C 59.75, H 3.54, N 12.30. Found: C 59.69, H 3.60, N 12.33.
5-Chloro-2-(4-methoxybenzyl)-6-phenylpyridazin-3(2H)-one (4j): White solid; yield: 78%; m.p.:
3
138–140 °C; 1H-NMR (CDCl3) δ: 8.22 (d, 3J = 8.6 Hz, 2H, 2Ph-H), 7.63 (d, J = 8.6 Hz, 2H, 2Ph-H)
7.43–7.52 (m, 5H, 5Ph-H), 7.12 (s, 1H, pyridazine-H), 5.43 (s, 2H, CH2), 3.85 (s, 3H, OCH3);
13C-NMR (CDCl3) δ: 158.72,148.44, 145.91, 141.22 133.53, 132.16, 133.33, 128.82, 127.28, 127.08,
126.43, 122.88, 122.33, 53.89, 49.74; IR (KBr): ν 3016.2, 2961.3, 1672.6 cm−1 Anal. Calc. for
C18H15ClN2O2: C 66.16, H 4.63, N 8.57. Found: C 66.19, H 4.60, N 8.61.
5-Chloro-2-(3-methoxybenzyl)-6-phenylpyridazin-3(2H)-one (4k): White solid; yield: 76%; m.p.:
1
83–85 °C; H-NMR (CDCl3) δ: 7.82 (s, 1H, Ph-H), 7.64, (d, J = 7.45 Hz, 1H, Ph-H), 7.53–7.55 (m,
2H, Ph-H), 7.45–7.47 (m, 2H, Ph-H), 7.41 (d, J = 7.45 Hz, 1H, Ph-H), 7.12 (d, 1H, pyridazine-H), 7.06
13
(t, J = 7.4 Hz, 1H, Ph-H), 5.27 (s, 2H, CH2), 3.82 (s, 3H, OCH3); C-NMR (acetone-d6) δ: 158.38,
157.32, 144.47, 139.10, 134.23, 129.32, 128.80, 128.46, 128.14, 124.60, 110.50, 55.12, 49.81; IR
(KBr): ν 3058.0, 2951.0, 2834.1, 1673.6 cm−1; Anal. Calc. for C18H15ClN2O2: C 66.16, H 4.63, N 8.57.
Found: C 66.21, H 4.58, N 8.58.
5-Chloro-2-(3-fluorobenzyl)-6-phenylpyridazin-3(2H)-one (4l): White solid; yield: 73%; m.p.:
82–84 °C; 1H-NMR (CDCl3) δ: 8.32 (t, J = 1.7 Hz, 1H, Ph-H), 8.18 (d, J = 8.6 Hz, 1H, Ph-H), 7.80 (d,
J = 7.45 Hz, 1H, Ph-H), 7.46–7.56 (m, 6H, 6Ph-H), 7.15 (s, 1H, pyridazine-H), 5.44 (s, 2H, CH2);
13C-NMR (CDCl3) δ: 157.75, 147.46, 144.95, 140.23, 136.53, 135.14, 133.23, 129.85, 129.72, 129.07,
128.45, 123.94, 123.33, 56.63; IR (KBr): ν 3058.5, 2955.3, 2835.5, 1675.6 cm−1; Anal. Calc. for
C17H12ClFN2O: C 64.87, H 3.84, N 8.90. Found: C 64.89, H 3.86, N 8.88.
5-Chloro-2-(2-methylbenzyl)-6-phenylpyridazin-3(2H)-one (4m): White solid; yield: 78%; m.p.:
1
78.6–79.8 °C; H-NMR (acetone-d6) δ: 7. 7.37–7.87 (m, 9H, Ph-H), 7.15 (s, 1H, pyridazine-H), 5.45
13
(s, 2H, CH2), 2.35 (s, 3H, CH3); C-NMR (acetone-d6) δ: 156.35, 154.41, 146.47, 137.01, 133.29,
128.28, 128.36, 127.85, 127.45, 127.16, 122.30, 120.31, 108.67, 52.03, 20.12; IR (KBr): ν 3041.0, 2956.0,
2834.4, 1674.6 cm−1; Anal. Calc. for C18H15ClN2O: C 69.57, H 4.86, N 9.01. Found: C 69.62, H 4.88,
N 8.98.
5-Chloro-2-(3-methylbenzyl)-6-phenylpyridazin-3(2H)-one (4n): White solid; yield: 78%; m.p.:
1
95.4–96.8 °C; H-NMR (acetone-d6) δ: 7.40–8.07 (m, 9H, Ph-H), 7.19 (s, 1H, pyridazine-H), 5.38 (s,
2H, CH2), 2.29 (s, 3H, CH3); 13C-NMR (acetone-d6) δ: 157.35, 154.45, 145.15, 136.61, 134.24, 128.56,
128.16, 127.55, 127.35, 127.13, 121.33, 120.33, 108.47, 52.83, 20.72; IR (KBr): ν 3045.1, 2955.6, 2837.6,
1665.6 cm−1; Anal. Calc. for C18H15ClN2O: C 69.57, H 4.86, N 9.01. Found: C 69.49, H 4.81, N 9.03.
5-Chloro-2-(4-methylbenzyl)-6-phenylpyridazin-3(2H)-one (4o): White solid; yield: 83%; m.p.:
99–101 °C; 1H-NMR (acetone-d6) δ: 7.93(d, 3J = 8.6 Hz, 2H, 2Ph-H), 7.43 (d, 3J = 8.6 Hz, 2H, 2Ph-H)
7.23–7.52 (m, 5H, 5Ph-H), 7.13 (s, 1H, pyridazine-H), 5.54 (s, 2H, CH2), 2.17 (s, 3H, CH3); 13C-NMR
(acetone-d6) δ: 158.36, 156.45, 144.16, 135.65, 134.27, 128.76, 128.56, 126.56, 126.35, 126.13,

Molecules 2012, 17
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120.33, 120.30, 108.77, 57.83, 19.02; IR (KBr): ν 3044.8, 2945.5, 2834.6, 1668.4 cm−1; Anal. Calc. for
C18H15ClN2O: C 69.57, H 4.86, N 9.01. Found: C 69.56, H 4.79, N 9.02.
5-Chloro-2-(3-chlorobenzyl)-6-phenylpyridazin-3(2H)-one (4p): Light yellow solid; yield: 83%; m.p.:
98–99 °C; 1H-NMR (acetone-d6) δ: 7.83 (s, 1H, Ph-H), 7.65 (d, J = 8.6 Hz, 1H, Ph-H), 7.45–7.56 (m,
13
5H, 5Ph-H), 7.43 (d, J = 8.6 Hz, 1H, Ph-H), 7.12 (s, 1H, pyridazine-H), 5.31 (s, 2H, CH2); C-NMR
(acetone-d6) δ: 158.53, 144.03, 137.84, 137.38, 133.54, 130.48, 129.73, 129.32, 129.05, 128.37,
128.31, 94.55, 54.63; IR (KBr): ν 3044.7, 3024.4, 1664.5 cm−1; Anal. Calc. for C17H12Cl2N2O: C 61.65,
H 3.65, N 8.46. Found: C 61.59, H 3.68, N 8.50.
2-(2-Bromobenzyl)-5-chloro-6-phenylpyridazin-3(2H)-one (4q): Light yellow solid; yield: 74%; m.p.:
79.5–81.2 °C; 1H-NMR (acetone-d6) δ: 8.08 (dd, J1 = 1.15, J2 = 8.55 Hz, 1H, Ph-H), 7.44–7.58 (m, 7H,
Ph-H), 7.19 (t, J=7.45 Hz, 1H, Ph-H), 7.17 (s, 1H, pyridazine-H), 5.77 (s, 2H, CH2); 13C-NMR
(acetone-d6) δ: 158.9, 148.70, 146.02, 140.31, 133.78, 133.23, 131.08, 129.81, 129.28, 129.24,
129.07, 128.91, 128.41, 125.41, 52.60; IR (KBr): ν 3054.7, 3024.6, 1674.5 cm−1; Anal. Calc. for
C17H12BrClN2O: C 54.35, H 3.22, N 7.46. Found: C 54.40, H 3.25, N 7.50.
5-Chloro-2-(4-chlorobenzyl)-6-phenylpyridazin-3(2H)-one (4r): White solid; yield: 86%; m.p.:
124–126 °C; 1H-NMR (CDCl3) δ: 7.66 (d, 3J = 8.6 Hz, 2H, 2Ph-H), 7.45–7.55 (m, 5H, 5Ph-H), 7.21 (d,
3J = 8.6 Hz, 2H, 2Ph-H), 7.11 (s, 1H, pyridazine-H), 5.28 (s, 2H, CH2); 13C-NMR (CDCl3) δ: 158.67,
145.61, 139.83, 137.90, 135.29, 133.55, 131.05, 129.69, 129.31, 128.80, 128.40, 94.19, 54.80; IR
(KBr): ν 3045.7, 3023.4, 1664.6 cm−1; Anal. Calc. for C17H12Cl2N2O: C 61.65, H 3.65, N 8.46. Found:
C 61.63, H 3.65, N 8.41.
5-Chloro-2-((2-chlorothiazol-5-yl)methyl)-6-phenylpyridazin-3(2H)-one (4s): Light yellow solid; yield:
1
78%; m.p.: 76–78 °C; H-NMR (acetone-d6) δ: 7.53–7.97 (m, 4H, Ph-H), 7.22 (s, 1H, Pyridazine-H),
6.72 (s, 1H, Thiazole-H), 5.25 (s, 2H, CH2); 13C-NMR (acetone-d6) δ: 156.37, 145.76, 137.67, 136.49,
135.78, 135.46, 127.95, 127.65, 127.32, 126.96, 126.63, 126.33, 125.53, 93.64, 53.35; IR (KBr): ν
3035.3, 3022.6, 1673.5 cm−1; Anal. Calc. for C14H9Cl2N3OS: C 49.72, H 2.68, N 12.42. Found: C 49.75,
H 2.64, N 12.38.
3.2. Insecticidal Bioassays
The insecticidal activities for the synthesized compounds against P. xylostella were evaluated using
previously reported procedures [24–26]. Fresh cabbage discs (diameter 2 cm) were dipped into the
prepared solutions containing compounds 4a to 4s for 10 s, dried in air and placed in a Petri dish
(diameter 9 cm) lined with filter paper. Ten larvae of second-instar P. xylostella were carefully transferred
to the Petri dish. Avermectin and chlorpyrifos were used as controls; three replicates were performed
for each experiment. Mortalities were determined after 72 h. The results were summarized in Table 1.
4. Conclusions
In the present study, a series of N-substituted 5-chloro-6-phenylpyridazin-3(2H)-one derivatives
were synthesized by employing mucochloric acid and benzene as the starting materials. The

Molecules 2012, 17
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13
synthesized compounds were characterized by spectral data (1H-NMR, C-NMR, IR) and elemental
analysis. The compounds were tested for insecticidal activity in vitro against P. xylostella. The results
showed that the synthesized pyridazin-3(2H)-one compounds possessed weak to good insecticidal
activities, especially the compounds 4b, 4d, and 4h which showed >90% activities at 100 mg/L. The
preliminary SAR analysis indicated that a big (in bulk) group with strong electronegativity at the
2-postion on the benzene ring (in a –CH2R group) had a positive influence enhancing the insecticidal
activity of the synthesized compounds; moreover, the introduction of a 2-Cl-substituted pyridine and
thiazole in the –CH2R group can also enhance the insecticidal activity. Further studies are currently
underway to optimize the structure to obtain better insecticidal activity in these N-substituted
pyridazin-3(2H)-one derivatives.
Acknowledgements
We are grateful to the National Natural Science Foundation of China (No. 21162004), the Special
Foundation of Governor for Outstanding talents in Guizhou (No.2011-38) and the Introduction of
Talent Research projects of Guizhou University (No. 2011-24) for their financial support.
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Sample Availability: Samples of all the intermediates and the title compounds 4a–s are available from
the authors.
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