Synthesis and herbicidal activity of new pyrazole ketone derivatives

Article abstract of DOI:10.1080/10426507.2020.1828884

A series of pyrazole derivatives was designed according to prodrug strategy. These compounds were synthesized via eight steps and their structures were confirmed by ¹H NMR spectroscopy and MS. The preliminary herbicidal bioassay results indicated that the title pyrazole ketone compounds exhibited low herbicidal activity against six weeds at 150 g/ha, which is weaker than that of the commercial HPPD herbicide topramezone. The docking results showed that the binding mode of the key intermediate (3-(2-(2-fluorophenoxy)ethoxy)-2-methyl-4-(methylsulfonyl)phenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone is the same as the reported inhibitor DAS689 in the complex.

Full text of DOI:10.1080/10426507.2020.1828884

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Synthesis and herbicidal activity of new pyrazole
ketone derivatives
Qing Fu , Sheng-Jie Kang , Liang-Kun Zhong , Jie Chen , Cheng-Xia Tan , Jian-
Quan Weng , Tian-Ming Xu & Xing-Hai Liu
To cite this article: Qing Fu , Sheng-Jie Kang , Liang-Kun Zhong , Jie Chen , Cheng-Xia Tan ,
Jian-Quan Weng , Tian-Ming Xu & Xing-Hai Liu (2020): Synthesis and herbicidal activity of new
pyrazole ketone derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, DOI:
10.1080/10426507.2020.1828884
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2020.1828884
Synthesis and herbicidal activity of new pyrazole ketone derivatives
Qing Fua,b, Sheng-Jie Kanga,b, Liang-Kun Zhonga,b, Jie Chenc, Cheng-Xia Tana, Jian-Quan Wenga, Tian-Ming Xub,
and Xing-Hai Liua
b
aCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou, China; Zhejiang Base of National Southern Pesticide
c
Research Centre, Zhejiang Research Institute of Chemical Industry, Hangzhou, China; School of Forestry & Biotechnology, Zhejiang A & F
University, Hangzhou, China
ABSTRACT
ARTICLE HISTORY
Received 24 February 2020
Accepted 23 September 2020
A series of pyrazole derivatives was designed according to prodrug strategy. These compounds
were synthesized via eight steps and their structures were confirmed by 1H NMR spectroscopy
and MS. The preliminary herbicidal bioassay results indicated that the title pyrazole ketone com-
pounds exhibited low herbicidal activity against six weeds at 150g/ha, which is weaker than that
of the commercial HPPD herbicide topramezone. The docking results showed that the binding
mode of the key intermediate (3-(2-(2-fluorophenoxy)ethoxy)-2-methyl-4-(methylsulfonyl)phenyl)(5-
hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone is the same as the reported inhibitor DAS689 in
the complex.
KEYWORDS
Synthesis; pyrazole
derivatives; molecular
docking; herbicidal activity
GRAPHICAL ABSTRACT
[5]
Introduction
derivatives,[3,4] triketone derivatives
and isoxazole deriva-
tives.[6] Among them, triketone HPPD herbicides have been
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an ideal
herbicidal target[1] in green plants, because it catalyzes p-
hydroxyphenylpyruvic acid conversion to homogentisic acid
in plant photosynthesis.[2] Many different kinds of HPPD
widely used and studied.[7–12]
Prodrug strategy is an important method in drug design.
Among these commercial HPPD herbicides, isoxaflutole,
benzobicyclon, pyrazolynate, pyrazoxyfen and benzofenap
herbicides (Figure 1) have been discovered, such as pyrazole belonged to prodrug HPPD herbicides. Topramezone is a
CONTACT Xing-Hai Liu
xutianming@sinochem.com
Hangzhou, China.
xhliu@zjut.edu.cn
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China; Tian-Ming Xu
Zhejiang Base of National Southern Pesticide Research Centre, Zhejiang Research Institute of Chemical Industry,
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2020.1828884.
ß 2020 Taylor & Francis Group, LLC

2
Q. FU ET AL.
Figure 2. The design strategy of title compounds.
Among them, all the compounds showed no activity against
P. annua and P. fugax under post mergence conditions. For
the other monocotyledon weed A. aequalis, only compound
B5 exhibited moderate herbicidal activity (ꢀ40%). For the
weed C. serotinum, most of them exhibited certain activity,
only compound B5 (50%) and B8 (40%) possessed moderate
herbicidal activity. For the weed S. media, most of the com-
pounds displayed no herbicidal activity, except compound
B8 (50%). For the weed B. juncea, only compounds B2 and
B8 exhibited moderate herbicidal activity.
To study the binding mode of our intermediate and
AtHPPD complex(PDB code: 1TFZ) with pyrazole HPPD
inhibitor DAS869,[36] the molecular docking was carried out
by DS 2.5. As shown in Figure 3A and 3B, the binding site
of DAS869 and intermediate 9 in the active pocket of
AtHPPD are well matched. The intermediate 9 was noticed
to constitute a bidentate combination with the Fe2þ, form-
ing twisted square-pyramidal complex with a mainly five-
coordinate with the distances of 2.0 Å (Glu 373), 2.2 Å (His
205), 4.5 Å (OH of intermediate 9), 2.4 Å (Phe 360), 2.9 Å
(CO of intermediate 9). It was the same as the binding
mode of DAS869 in crystal of AtHPPD with the distances of
2.0 Å (Glu 373), 2.2 Å (His 205), 2.2 Å (OH of DAS869),
2.4 Å (Phe 360), 2.3 Å (CO of DAS869). In the complex,
there are two p-p stacking interactions between the DAS869
and Phe 360(4.5 Å), Phe 403(4.5 Å) respectively. But in our
intermediate 9, the p-p stacking interaction was not
observed. The molecular docking indicated that the p-p
stacking interaction may increase the herbicidal activity.
Figure 1. Representative some commercial HPPD herbicides.
good HPPD herbicide, which is used to control weeds in
maize fields.[13] As a part of our research in pesticides,[14–32]
many pyrazole compounds have been designed and synthe-
sized. Herein, topramezone was used as a lead compound;
the isoxazole ring of topramezone was opened and replaced
by a flexible chain, and the hydroxyl group on the pyrazole
ring was etherified or esterified. Ten pyrazole ketone deriva-
tives were synthesized. The preliminary herbicidal activity
indicated that the title compounds exhibited low herbicidal
activity against six weeds. The design strategy of title com-
pounds was shown in Figure 2.
Results and discussion
The synthetic procedure of title pyrazole ketone compounds
is illustrated in Scheme 1. For the key intermediate 4, the
thioether group was synthesized by using NaSCH3. The
reagent NaSCH3 is smelly and must be strictly used in a
fumehood. The solvent DMF must be anhydrous, otherwise
it may lead to hydrolysis of the ester group. Then the thio-
ether was oxidized by Na2WO4 to give CH3SO2 group.
Another key process is the synthesis of pyrazole aromatic
ketone. Several synthetic methods were reported.[33–35] The
common method is using pyrazole-5-ol and RCOCl as start-
ing materials, then rearranged to give a pyrazole aromatic
ketone under base conditions. The second method is using
methamiprid and pyrazole as starting materials, then hydro-
lyzed to give a pyrazole aromatic ketone. The most recent
method is that CO was inserted between ArX and pyrazole
under Pd catalyst. In this step, the key intermediate 9 was
prepared by using acetone cyanohydrin as the base at room
temperature.
Experimental
Instrument and materials
1H NMR spectra were recorded on a Bruker AV-600 instru-
ment using TMS as an internal standard and CDCl3 as the
solvent. LRMS were measured on a Thermo Finnigan LCQ
Advantage LC/mass detector instrument. All the reagents
are of analytical grade or freshly prepared before use. The
course of the reactions was monitored by TLC; analytical
TLC was performed on silica gel GF254. The Supplemental
Materials contains sample 1H NMR spectra for the products
B1–B8 (Figures S1–S8).
The structures of compounds B1~B8 were confirmed by
1
1H NMR and ESI-MS. In the H NMR spectra, three CH3
proton signals of on the pyrazole and benzene ring can be
found around at 2.20, 2.35 and 3.65 ppm respectively. The
final CH3 proton signals of SO2CH3 was observed around at
3.2 ppm. The mass spectra of pyrazol-4-one compounds
showed molecular ion peak and consistent with the corre-
sponding calculated values.
The postemergence herbicidal activities of compounds
B1ꢀB8 were tested against Poa annua (PA), Chenopodium
serotinum (CS), Alopecurus aequalis (AA), Polypogon fugax
(PF), Brassica juncea (BJ), Stellaria media (SM), at 150 g ai/
ha in a greenhouse, topramezone is used as positive control.
General procedure
The intermediate 1 and 2 were published in our previous
work.[4] The intermediates 3ꢀ8 were synthesized by using
the same method according to our previous work,[4] which
Most of them exhibited low herbicidal activities (Table S 1). changed the 4-Cl to 2-F on the phenyl ring.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 1. The synthetic route of title compounds.
Synthesis of intermediate 9
4-(3-(2-(2-Fluorophenoxy)ethoxy)-2-methyl-4-(methylsulfonyl)-
benzoyl)-1,3-dimethyl-1H-pyrazol-5-yl furan-2-carboxylate B2
The intermediate 8 was dissolved in CH3CN (100 mL), and
then acetone cyanohydrin (0.11 g, 0.0013 mol) and Et3N
(1.42 g, 0.014 mol) was added at room temperature. After
the mixture was stirred 6 h, the solvent was removed. The
residue was dissolved in H2O (65 mL), then acidified to pH
¼ 7 using HCl, and the organic layer was exacted with ethyl
acetate to give red brown liquid 9, yield 43%.
1
Waxy solid, yield 55%, H NMR (d, ppm): 2.30 (s, 3H, Ar-
CH3), 2.50 (s, 3H, pyrazole-CH3), 3.14 (s, 3H, -SO2CH3),
3.65 (s, 3H, pyrazole-CH3), 4.23-4.24 (m, 2H, -OCH2-),
4.36-4.37 (m, 2H, -OCH2-), 6.49-6.50 (m, 1H, oxole-H),
6.92-6.94 (m, 1H, Ar-H), 7.02-7.09 (m, 5H, Ar-H、 oxole-
H), 7.14 (d, 1H, J ¼ 7.9 Hz, Ar-H), 7.63 (br, 1H, oxole-H),
7.69 (d, 1H, J ¼ 7.9 Hz, Ar-H); ESI-MS: 556 [M þ H] þ. ESI-
HRMS: m/z [M þ H]þ calcd for [C27H25FN2O8S]: 557.1388,
found, 557.1390.
General synthetic procedure for final compounds B
To a solution of intermediate 9 (1 g, 0.0022 mol) in dry acet-
one (50 mL), RX (0.0022 mol) and K2CO3 (0.33 g,
0.0024 mol) was added dropwise at room temperature, and
then the mixture was refluxed for 5 h. The solution was
evaporated and the residue was purified by column chroma-
tography on silica gel with PE and EA as solvents to give
product B (1:1).
4-(3-(2-(2-Fluorophenoxy)ethoxy)-2-methyl-4-(methylsulfonyl)-
benzoyl)-1,3-dimethyl-1H-pyrazol-5-yl methanesulfonate B3
Waxy solid, yield 65%, H NMR (d, ppm): 1.97 (s, 3H, Ar-
1
CH3), 2.41 (s, 3H, pyrazole-CH3), 3.31 (s, 3H, -SO2CH3),
3.33 (s, 3H, -SO2CH3), 3.82 (s, 3H, pyrazole-CH3), 4.46-4.48
(m, 4H, -OCH2CH2O-), 6.92-6.96 (m, 1H, Ar-H), 7.01-7.09
(m, 3H, Ar-H), 7.23 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.92 (d, 1H,
J ¼ 8.0 Hz, Ar-H); ESI-MS: 540 [M þ H] þ. ESI-HRMS: m/z
1-((4-(3-(2-(2-Fluorophenoxy)ethoxy)-2-methyl-4-(methyl-
sulfonyl)benzoyl)-1,3-dimethyl-1H-pyrazol-5-yl)oxy)ethyl
methyl carbonate B1
[M þ H]þ
calcd
found, 541.1108.
for
[C23H25FN2O8S2]:
541.1109,
Waxy solid, yield 44%, 1H NMR (d, ppm): 1.47 (d, 3H,
J¼ 5.2 Hz, -CHCH3), 1.97 (s, 3H, Ar-CH3), 2.40 (s, 3H, pyra- 4-(3-(2-(2-Fluorophenoxy)ethoxy)-2-methyl-4-(methylsulfonyl)-
zole-CH3), 3.30 (s, 3H, -SO2CH3), 3.65 (s, 3H, pyrazole-CH3), benzoyl)-1,3-dimethyl-1H-pyrazol-5-yl methyl carbonate B4
1
Waxy solid, yield 48%, H NMR (d, ppm): 2.33 (s, 3H, Ar-
3.73 (s, 3H, -OCH3), 4.45-4.48 (m, 4H, -OCH2CH2O-), 6.24 (q,
1H, -CHCH3), 6.91-6.94 (m, 1H, Ar-H), 7.04-7.10 (m, 3H, Ar-
CH3), 2.35 (s, 3H, pyrazole-CH3), 3.30 (s, 3H, -SO2CH3),
H), 7.24 (d, 1H, J¼ 8.0 Hz, Ar-H), 7.92 (d, 1H, J ¼ 8.0 Hz, Ar- 3.65 (s, 3H, pyrazole-NCH3), 3.73 (s, 3H, -OCH3), 4.44-4.49
H); ESI-MS: 564 [M þ H] þ. ESI-HRMS: m/z [Mþ H]þ calcd (m, 4H, -OCH2CH2O-), 6.92-6.96 (m, 1H, Ar-H), 7.03-7.10
for [C26H29FN2O9S]: 565.1651, found, 565.1655.
(m, 3H, Ar-H), 7.14 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.89 (d, 1H,

4
Q. FU ET AL.
535 [M þ H] þ. ESI-HRMS: m/z [M þ H]þ calcd for
[C25H27FN2O8S]: 535.1545, found, 535.1550.
Greenhouse in vivo biological evaluation
The herbicidal activities of compounds B1~B8 against
monocotyledon weeds such as P. annua, A. aequalis, P.
fugax and dicotyldon weeds such as C. serotinum, S. media,
B. juncea were evaluated according to our previous
work.[37,38] Topramezone was used as positive control. The
herbicidal activities treated at three replicates are shown in
Table S1 (Supplemental Materials).
Figure 3. (A) binding mode of intermediate 9 with 1TFZ; (B) Crystal complex of
1TFZ with DAS869.
J¼ 8.0 Hz, Ar-H); ESI-MS: 520 [M þ H] þ. ESI-HRMS: m/z
[M þ H]þ calcd for [C24H25FN2O8S]: 521.1388, found, 521.1389.
Molecular docking
Benzyl (4-(3-(2-(2-fluorophenoxy)ethoxy)-2-methyl-4-(methyl-
sulfonyl)benzoyl)-1,3-dimethyl-1H-pyrazol-5-yl) carbonate B5
Waxy solid, yield 46%, H NMR (d, ppm): 2.29 (s, 3H, Ar-
The molecular docking was carried out by using Discovery
Studio 2.5 software according to the reported method.[39,40] The
reference reported that the prodrug pyrazoxyfen is metabolized
to active intermediate 5-hydroxypyrazole derivative in plants.[41]
In this paper, the intermediate (3-(2-(2-fluorophenoxy)ethoxy)-
2-methyl-4-(methylsulfonyl)phenyl)(5-hydroxy-1,3-dimethyl-
1H-pyrazol-4-yl)methanone 9 was selected as ligand to dock
into the AtHPPD structure. The structure of AtHPPD (PDB ID:
1TFZ) was downloaded from the protein data bank (PDB). The
The 3 D structure of intermediate 9 was constructed and opti-
mized according to the standard methods by using Discovery
Studio 2.5. Discovery Studio 2.5 was used to dock intermdiate 9
to the active site of AtHPPD. The protein crystal structure
AtHPPD was prepared by standard methods using Discovery
Studio 2.5. After molecular docking, the best binding modes
were selected by the docking energy as well as by comparison
with the cocrystal ligand. The force field used for protein and
intermediate 9 was CHARMm. After energy minimization,
PYMOL was used to analyze the binding modes.
1
CH3), 2.34 (s, 3H, pyrazole-CH3), 3.19 (s, 3H, -SO2CH3),
3.61 (s, 3H, pyrazole-CH3), 4.43-4.46 (m, 4H, -OCH2CH2O-
), 5.09 (s, 2H, Bn), 6.92-6.96 (m, 1H, Ar-H), 7.02-7.09 (m,
5H, Ar-H), 7.14 (d, 1H, J ¼ 8.0 Hz, Ar-H), 7.34-7.38 (m, 5H,
Ar-H), 7.87 (d, 1H, J ¼ 8.0 Hz, Ar-H); ESI-MS: 596 [M þ H]
þ. ESI-HRMS: m/z [M þ H]þ calcd for [C30H29FN2O8S]:
597.1701, found, 597.1703.
4-(3-(2-(2-Fluorophenoxy)ethoxy)-2-methyl-4-(methylsulfonyl)-
benzoyl)-1,3-dimethyl-1H-pyrazol-5-yl propyl carbonate B6
Waxy solid, yield 52%, 1H NMR (d, ppm): 0.92 (t, 3H,
-CH3), 1.67-1.68 (m, 2H, -CH2CH3), 2.28 (s, 3H, Ar-CH3),
2.35 (s, 3H, pyrazole-CH3), 3.29 (s, 3H, -SO2CH3), 3.65 (s,
3H, pyrazole-NCH3), 4.03-4.05 (m, 2H, -OCH2), 4.45-4.48 (m,
4H, -OCH2CH2O-), 6.92-6.96 (m, 1H, Ar-H), 7.01-7.09 (m, 3H,
Ar-H), 7.15 (d, 1H, J ¼ 7.9 Hz, Ar-H), 7.87 (d, 1H, J ¼ 7.9 Hz,
Ar-H); ESI-MS: 548 [M þ H] þ. ESI-HRMS: m/z [M þ H]þ
calcd for [C26H29FN2O8S]: 549.1701, found, 549.1700.
Conclusions
Sec-butyl (4-(3-(2-(2-fluorophenoxy)ethoxy)-2-methyl-4-(methyl-
sulfonyl)benzoyl)-1,3-dimethyl-1H-pyrazol-5-yl) carbonate B7
Waxy solid, yield 47%, 1H NMR (d, ppm): 0.90 (t, 3H,
-CH3), 1.26 (d, 3H, J ¼ 6.3 Hz, -CHCH3), 1.57-1.67 (m, 2H,
-CHCH2CH3), 2.21 (s, 3H, Ar-CH3), 2.35 (s, 3H, pyrazole-
CH3), 3.28 (s, 3H, -SO2CH3), 3.66 (s, 3H, pyrazole-NCH3),
4.45-4.47 (m, 4H, -OCH2CH2O-), 6.92-6.95 (m, 1H, Ar-H),
7.03-7.10 (m, 3H, Ar-H), 7.18 (d, 1H, J ¼ 8.0 Hz, Ar-H),
7.88 (d, 1H, J ¼ 8.0 Hz, Ar-H); ESI-MS: 562 [M þ H] þ. ESI-
HRMS: m/z [M þ H]þ calcd for [C27H31FN2O8S]: 563.1858,
found, 563.1860.
In summary, ten pyrazole ketone derivatives were designed
by using the prodrug method. The herbicidal activity indi-
cated that these compounds possessed low herbicidal activity
at 150 g/ha, compared with the positive control topramezone.
The molecular docking showed that the binding mode of the
key intermediate (3-(2-(2-fluorophenoxy)ethoxy)-2-methyl-4-
(methylsulfonyl)phenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-
4-yl)methanone is the same as the reported inhibitor
DAS689 in the complex. It provides a useful method for the
discovery of new HPPD herbicides.
Funding
Ethyl (4-(3-(2-(2-fluorophenoxy)ethoxy)-2-methyl-4-(methylsul-
fonyl)benzoyl)-1,3-dimethyl-1H-pyrazol-5-yl) carbonate B8
Waxy solid, yield 44%, 1H NMR (d, ppm): 1.28 (t, 3H,
-CH3), 2.31 (s, 3H, Ar-CH3), 2.35 (s, 3H, pyrazole-CH3),
3.29 (s, 3H, -SO2CH3), 3.65 (s, 3H, pyrazole-NCH3), 4.11 (q,
2H, -OCH2CH3), 4.46-4.49 (m, 4H, -OCH2CH2O-), 6.93-
6.95 (m, 1H, Ar-H), 7.03-7.11 (m, 4H, Ar-H), 7.15 (d, 1H,
J ¼ 7.9 Hz, Ar-H), 7.88 (d, 1H, J ¼ 7.9 Hz, Ar-H); ESI-MS:
This work was funded by Zhejiang Provincial Natural Science
Foundation of China (No. LY19C140002) and Research Fund of
Department of Education of Zhejiang Province (Y201941832).
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