Synthesis and biological activity of new (E)-α-(Methoxyimino) benzeneacetate derivatives containing a substituted pyrazole ring

Article abstract of DOI:10.1021/jf9026348

Strobilurins are one of the most important classes of agricultural fungicides. To discover new strobilurin analogues with high activity, a series of new strobilurin derivatives containing a substituted pyrazole in the side chain were synthesized and their biological activities were tested. The compounds were identified by ¹H nuclear magnetic resonance, infrared, and elemental analysis. The test results indicated that the compounds exhibited strong fungicidal activities against Pyricularia oryzae, Phytophthora infestans, Pseudoperonospora cubenssi, and Erysiphe graminis. The relationship between structure and biological activity is discussed in terms of the effects of the substituents on the pyrazole ring. The present work demonstrates that strobilurin analogues with a 3-(substituted phenyl)-1 H-pyrazol-5-oxy side chain can be used as possible lead compounds for the development of potential agrochemicals.

Full text of DOI:10.1021/jf9026348

2664 J. Agric. Food Chem. 2010, 58, 2664–2667
DOI:10.1021/jf9026348
Synthesis and Biological Activity of New
(E )-r-(Methoxyimino)benzeneacetate Derivatives
Containing a Substituted Pyrazole Ring†
§
M
IAO
L
I
,
§,# CHANG-LING
L
IU,*,§ J
I
-CHUN
Y
Z
ANG,§ JIN-B
O
Z
HANG,§ ZHI-NIAN
LI,
§
H
ONG
Z
HANG
,
AND
HENG-MING L #
I
§Agrochemical Discovery Department, Shenyang Research Institute of Chemical Industry, Shenyang
110021, China, and #State Key Laboratory of Elemento-Organic Chemistry, National Pesticides
Engineering Research Center, College of Chemistry, Nankai University, Tianjin 300071, China
Strobilurins are one of the most important classes of agricultural fungicides. To discover new
strobilurin analogues with high activity, a series of new strobilurin derivatives containing a
substituted pyrazole in the side chain were synthesized and their biological activities were tested.
The compounds were identified by 1H nuclear magnetic resonance, infrared, and elemental analysis.
The test results indicated that the compounds exhibited strong fungicidal activities against
Pyricularia oryzae, Phytophthora infestans, Pseudoperonospora cubensis, and Erysiphe graminis.
The relationship between structure and biological activity is discussed in terms of the effects of the
substituents on the pyrazole ring. The present work demonstrates that strobilurin analogues with a
3-(substituted phenyl)-1H-pyrazol-5-oxy side chain can be used as possible lead compounds for the
development of potential agrochemicals.
KEYWORDS: Strobilurin; pyrazole; fungicide
INTRODUCTION
The strobilurins are a class of fungicidal compounds modeled
after natural compounds isolated from several basidomycete
species that inhabit decaying plant material in woodland soils,
and they have, therefore, been applied to agricultural disinfec-
tants in many countries (1, 2). These compounds, which contain
the (E)-β-methoxyacrylate pharmacophore, act through inhibi-
tion of mitochondrial respiration by blocking electron transfer at
the ubiquinol oxidation center (Qo site) of the cytochrome bc1
complex (complex III) (3). The related methyl(E)-methoxyimino-
acetate pharmacophore (4) is represented in the synthetic strobi-
lurin kresoxim-methyl. Substituted pyrazole ring derivatives
exhibit a broad spectrum of biological activities such as anti-
microbial (5), herbicidal (6), antitumor (7), and antiinflamma-
tory (8) activities. For example, the fungicide pyraclostrobin
contains a 1H-pyrazol-3-oxy side chain and exhibits excellent
biological activity (2). Additionally, the strobilurin derivatives
containing both a β-methoxyacrylate and a substituted pyrazole
in the side chain display excellent fungicidal and acaricidal
activities (9). In this study we synthesized a series of strobilurin
analogues containing methyl (E)-methoxyiminoacetate and
N-methyl (E)-methoxyiminoacetamide with a 1H-pyrazol-5-oxy
side chain. We found that compounds 5i and 6l displayed
excellent fungicidal activity against Pseudoperonospora cubensis
MATERIALS AND METHODS
All starting materials and reagents were commercially available
and used withoutfurther purificationexceptasindicated. Melting
points were determined on a Buchi melting point apparatus and
are uncorrected. 1H NMR spectra were recorded with a Mercury
300 (Varian, 300 MHz) spectrometer with CDCl3 as the solvent
and TMS as the internal standard. Infrared spectra were mea-
sured with KBr disks using a PF-983G instrument (Perkin-
Elmer). Mass spectra were recorded using a JEOL JMS-700 mass
spectrometer.
According toknown methods, (10) substituted β-keto esters (2)
were prepared from substituted ketones (1) [substituted aceto-
phenones (1: R2 = H) and propiophenones (1: R2 = Me)] and
dimethyl carbonate. The ester (2) and methyl hydrazine were
dissolved in methanol, and the mixture was heated to reflux to
obtainthesubstituted5-hydroxy-1H-pyrazole(3). Thestrobilurin
analogues (5) were prepared by reacting the intermediate pyra-
zoles (3) with (E)-methyl 2-(2-(bromomethyl)phenyl)-2-meth-
oxyiminoacetate (4) under basic conditions. The pyrazole
derivatives (6) were prepared by reaction of the compounds
€
at the concentration of 6.25 mg L-1
.
†Part of the ECUST-Qian Pesticide Cluster.
*Author to whom correspondence should be addressed (telephone
þ86-24-85869078; fax þ86-24-85869137; e-mail liuchangling@
vip.163.com).
pubs.acs.org/JAFC
Published on Web 12/04/2009
© 2009 American Chemical Society

Article
J. Agric. Food Chem., Vol. 58, No. 5, 2010 2665
a
Scheme 1
a Reagents and conditions: (a) NaH/(CH3O)2CO in THF, reflux; (b) CH3NHNH2 in CH3OH, reflux; (c) NaH in DMF, 80°C; (d) CH3NH2 in THF, reflux.
(5) with aqueous methylamine in tetrahydrofuran (THF) as
shown in Scheme 1.
Biological Assay. Evaluations of biological activities of the reported
compounds were performed as previously described (11-13). Biological
data were reported as the range from 0 (indicates no control) to 100%
(complete control).
General Procedure for the Synthesis of Intermediate β-Keto
Esters (2). A suspension of 60% sodium hydride (0.10 mol, washed with
petroleum ether) in a mixture of dimethyl carbonate (0.05 mol) and 100
mL of tetrahydrofuran was heated to reflux for 0.5 h. A solution of the
substituted phenyl ketones (1) (0.05 mol) in 100 mL of tetrahydrofuran
was added dropwise over 0.5 h while refluxing continued. When the
reaction mixture became clear, it was refluxed for an additional 4-5 h.
Then, the mixture was cooled and acidified with 36.5% hydrochloric acid
and filtered. The filtrate was poured into a large amount of water,
extracted three times with ethyl acetate. The combined extracts were
washed with brine, dried, and concentrated under vacuum to obtain the
crude oily product.
RESULTS AND DISCUSSION
Synthetic Chemistry. According to procedures exemplified
above, strobilurin derivatives were synthesized mostly with good
overall yields of 60-75% (5) and 70-90% (6), as shown in
Tables 1 and 2 (for 3-substituted-phenyl-1-methyl-1H-pyrazol-5-
yloxy analogues, 5a-5h and 6a-6h) and in Tables 1 and 2 (for
3-substituted-phenyl-1,4-dimethyl-1H-pyrazol-5-yloxy ana-
logs, 5i-5r and 6i-6r). The synthesized compounds were char-
acterized by 1H NMR, IR, and elemental analyses. All spectral
and analytical data were consistent with the assigned structures.
The IR spectra of compounds showed C-H and CdO stretching
bands at 2920-2960 and 1700-1720 cm-1, respectively.
Fungicidal Activities. As indicated in Tables 1 and 2, many of
the synthesized compounds exhibit potent activity against Pyr-
icularia oryzae, Phytophthora infestans, P. cubensis, and Erysiphe
graminis. Methylpyrazolyloxy analogues (abbreviated as the Me
series, hereafter) seem to be slightly less potent than the corres-
ponding equivalent dimethylpyrazolyloxy analogues (abbre-
viated as the Me2 series). However, there are a few exceptions
such as the pair of 2,4-(CH3)2-Ph analogues (e and l). For both the
oximinoacetates 5 and the oxinoacetamides 6, under equivalent
dosage conditions of 25 or 400 mg L-1, most of the two series of
analogues show 100% inhibition against P. oryzae, P. infestans,
P. cubensis, and E. graminis. Therefore, the fungicidal activity was
measured at a lower dose range.
Because of the paucity of the dose-potency data, detailed
structure-activity discussion for the fungicidal activity is almost
impossible. There seems to be an optimal hydrophobicity and/or
a sterically acceptable limit of phenyl substituents (R1) as shown
for the mono and dimethyl phenyl substituents in compounds e, j,
k, l, and m in Tables 1 and 2. This structure-activity relationship
appears to apply for the activity against P. cubensis and
E. graminis. The most potent compounds at the lowest doses
are, in general, the most active against P. oryzae and P. infestans
as shown in Tables 1 and 2. Due to the lack of a wide range of
phenyl substituents, it is difficult to conclude if there is an
electron-withdrawing effect. For example, in the Me series of
Tables 1 and 2, 4-Cl-Ph (b) versus 4-CH3O-Ph (f) and 2-Cl-Ph
(h) versus 2-CH3O-Ph (g) provide substantially similar activities.
In the Me2 series of Table 1 4-Cl-Ph (i) is more active than
4-CH3O-Ph (p), whereas in Table 2 they are about equivalent in
activity. In this study, compounds 5i, 5j, 5l, 6l, and 6m of the Me2
series are the most active and possess a broader spectrum of
fungicidal activity than compounds of the Me series.
General Procedure for the Synthesis of Intermediate Pyrazoles
(3). Each of the β-keto esters (2) was dissolved in methanol and heated to
reflux. Methyl hydrazine was added dropwise to the reaction solution. The
process of the reaction was monitored by thin-layer chromatography
(TLC), and upon completion the reaction solution was evaporated under
vacuum and cooled. The filtered solid was washed with methanol, dried,
and used directly in the preparation of compounds 5.
Procedure for the Synthesis of Compound 5i. 3-(4-Chlorophenyl)-
1,4-dimethyl-1H-pyrazol-5-ol (10.10 mmol) was dissolved in 5 mL of
DMF, and 60% sodium hydride (19.00 mmol, washed with petroleum
ether) was added to the solution. The solution was stirred for 0.5 h, and
(E)-methyl 2-(2-(bromomethyl)phenyl)-2-methoxyiminoacetate (10.30
mmol) was added. The reaction mixture was heated to 80 °C and
monitored by TLC. At completion of the reaction (after 3 h), the mixture
was added to 50 mL of brine and extracted three timeswith 100 mL of ethyl
acetate. The combined organic extracts were dried and concentrated to
obtain the crude product. It was purified via silica gel column chroma-
tography, using a 1:4 (v/v) mixture of ethyl acetate and petroleum ether
(boiling range = 60-90 °C) as the eluting solution to obtain compound 5i
as viscous oil.
Procedure for the Synthesis of the Compounds 6. The compounds
5 (3.00 mmol) were dissolved in 5 mL of THF, and a slight excess of a
methylamine solution (25-30%) was added dropwise to the solution. The
mixture was refluxed for 1 h (the reaction was monitored by TLC) and
then concentrated. Water was added to the residue and extracted three
times with 50 mL of ethyl acetate, and the combined organic extracts were
dried and concentrated. The crude product was purified via silica gel
column chromatography to obtain the compounds 6.
Example data of 5i and 6l are shown as follows, whereas data for the
other compounds can be found in the Supporting Information.
Data for 5i: yield 75.3% of oil; IR (KBr) ν 2945 (s, C-H), 1730 (s,
CdO), 1490 (s, CdN), 1440 (s, CH3), 1310 (m, C-N), 1210 (s, C-O), 770,
700 (s, Ph-H) cm-1 1H NMR (300 MHz, CDCl3) δ 7.59-7.61
;
(m, 1H, Ph-6-H), 7.40-7.46 (m, 4H, 3-Ph-2,3,5,6-4H), 7.26-7.30 (m,
2H, Ph-3,5-2H), 7.19-7.21 (m, 1H, Ph-4-H), 5.15 (s, 2H, CH2), 4.05 (s,
3H, OCH3), 3.85 (s, 3H, CO2CH3), 3.61 (s, 3H, NCH3), 1.84 (s, 3H, Py-
CH3). Anal. Calcd: C, 61.75; H, 5.18; N, 9.82. Found: C, 61.54; H, 5.27; N,
10.03.
Data for 6l: yield 87.5% of a white solid; mp 163-165 °C; IR (KBr) ν
3240(s, NH), 2920 (s, C-H), 1660 (s, CdO), 1500 (s, CdN), 1400 (s, CH3),
1295(m, C-N), 1190 (s, C-O), 820, 750 (s, Ph-H) cm-1; 1H NMR (300
MHz, CDCl3) δ 7.59-7.61 (m, 1H, Ph-6-H), 7.39-7.41 (m, 2H, Ph-3,5-
2H), 7.20 (m, 1H, Ph-4-H), 7.04-7.08 (m, 3H, 3-Ph-3,5,6-3H), 6.76 (m,
1H, NH), 5.15 (s, 2H, CH2), 3.96 (s, 3H, OCH3), 3.41 (s, 3H, NCH3),
2.87-2.89 (d, J = 4.8 Hz, 3H, NHCH3), 2.37 (s, 3H, 2-CH3), 2.09 (s, 3H,
4-CH3), 1.70 (s, 3H, Py-4-CH3).
Insecticidal Activity. Some of the synthesized compounds
exhibit insecticidal and acaricidal activities. The compounds were
tested against Leucania venalba, Myzus persicae, Culex pipiens
pallens, and Tetranychus cinnabarinus at 600 mg L-1. Com-
pounds 5m and 6p exhibited 100% control against L. venalba,
whereas compounds 5a, 5d, 5e, 5m, 6b, 6d, 6g, and 6m exhibited
100% control against M. persicae. Compounds 5b and 6b

2666 J. Agric. Food Chem., Vol. 58, No. 5, 2010
Li et al.
Table 1. Fungicidal Activity of the Synthesized Compounds 5 (Percent Control)
pathogen
R2
P. oryzae
25 0.92
P. infestans
25 0.92
P. cubensis
E. graminis
compd
R1
mp (°C)
oil
yield
400
25
6.25
400
6.25
1.56
a
5a
5b
Ph
4-Cl-Ph
H
72.1
68.7
75.0
69.4
70.3
71.2
66.9
77.5
75.3
67.6
64.7
76.1
72.0
70.5
73.4
68.2
71.6
66.0
0
/
/
0
80
/
50
60
80
100
0
95
100
95
70
90
0
/
80
/
70
100
0
/
40
/
/
H
102-105
86-88
117-118
oil
80
100
100
100
0
5c
5d
4-C(CH3)3-Ph
3,4-(CH3)2-Ph
2,4-(CH3)2-Ph
4-CH3O-Ph
2-CH3O-Ph
2-Cl-Ph
H
80
50
0
100
100
100
100
0
/
/
H
98
40
90
50
/
/
100
100
100
100
100
100
100
100
100
100
100
70
30
/
5e
H
95
65
/
65
/
5f
5g
H
oil
/
98
10
/
H
oil
100
100
50
50
0
/
50
/
90
40
45
98
100
60
75
20
100
/
5h
5i
H
oil
100
100
100
100
100
100
100
0
0
80
30
100
60
75
100
80
70
/
/
75
4-Cl-Ph
4-CH3-Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
oil
/
100
100
100
100
60
80
/
100
95
100
/
100
100
100
100
40
5j
oil
50
/
5k
3,4-(CH3)2-Ph
2,4-(CH3)2-Ph
2,5-(CH3)2-Ph
4-C2H5-Ph
4-C(CH3)3-Ph
4-CH3O-Ph
4-C2H5O-Ph
4-CF3CH2O-Ph
130-132
oil
100
100
100
50
80
80
100
/
100
100
100
98
70
98
40
50
/
5l
5m
oil
5n
5o
oil
100
/
118-120
oil
50
/
40
5p
5q
100
100
100
100
100
80
50
80
/
100
100
50
50
50
/
100
100
80
55
40
0
15
/
100
100
100
100
100
85
30
50
15
60
100
98-100
oil
100
70
5r
azoxystrobin
kresoxim-methyl
/
/
100
/
100
/
100
35
95
0
100
100
/
/
a /, no data.
Table 2. Fungicidal Activity of the Synthesized Compounds 6 (Percent Control)
pathogen P. oryzae
R2 25 0.92
P. infestans
P. cubensis
E. graminis
compd
R1
mp (°C)
oil
yield
25
0.92
400
25
6.25
400
6.25
1.56
a
6a
6b
Ph
4-Cl-Ph
H
69.6
71.4
90.3
88.6
89.4
91.0
89.1
87.5
90.6
89.9
86.8
87.5
87.8
85.9
88.2
87.3
88.1
90.2
0
/
/
/
/
/
/
100
100
80
100
100
0
70
60
/
50
100
0
/
40
/
0
H
132-134
172-174
109-111
115-117
oil
0
100
100
100
100
100
0
6c
6d
4-C(CH3)3-Ph
3,4-(CH3)2-Ph
2,4-(CH3)2-Ph
4-CH3O-Ph
2-CH3O-Ph
2-Cl-Ph
H
50
50
50
80
0
100
100
100
100
0
50
80
100
0
/
/
H
100
100
98
100
100
30
85
70
/
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
0
40
30
/
6e
H
6f
6g
H
H
oil
/
75
10
/
100
90
45
55
85
40
55
65
0
6h
6i
H
oil
/
100
100
100
100
100
100
100
100
80
0
90
40
/
4-Cl-Ph
4-CH3-Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
oil
0
/
/
80
40
/
100
95
6j
oil
0
/
100
100
100
100
80
40
50
50
50
/
65
/
/
6k
3,4-(CH3)2-Ph
2,4-(CH3)2-Ph
2,5-(CH3)2-Ph
4-C2H5-Ph
4-C(CH3)3-Ph
4-CH3O-Ph
4-C2H5O-Ph
4-CF3CH2O-Ph
184-186
163-165
134-136
oil
100
100
100
100
100
100
100
80
80
50
100
0
100
100
100
50
100
100
100
/
40
100
50
/
100
100
40
6l
6m
6n
6o
100
0
90
0
oil
100
50
100
50
/
95
20
/
6p
6q
135-137
142-144
oil
98
85
55
/
100
100
100
100
100
75
70
40
60
100
100
100
/
98
20
6r
azoxystrobin
kresoxim-methyl
100
100
/
80
30
95
0
100
100
100
35
/
100
/
a /, no data.
exhibited 100% control against C. pipiens, and compounds 5d, 5q,
and 6d exhibited 100% control against T. cinnabarinus.
Because the bioactivity was measured in vivo, effects of
metabolism and/or biotransformation within the plant/fungus
may make some contribution to the apparent potency vari-
ations. The inference that the electron-withdrawing substituents
of the phenyl moiety seem to enhance the potency may be related
to the fact that they tend to retard mechanisms of oxidative
metabolism occurring on (or close to) the benzene ring (14).
Moreover, a higher electronic (negative) charge within the ring
system may facilitate oxidative metabolism as hydroxylation of the
benzene ring.
Conclusion. Strobilurin analogues synthesized by introducing
various substituted-phenyl groups (R1) into the 1H-pyrazol-5-
oxy ring of the designed skeletal lead, 5 and 6 were fungicidally
activeinplanta, against P. cubensis and E. graminis. Some of these
new strobilurins were more potent than the reference strobilurin
compounds azoxystrobin and kresoxim-methyl. Variations in the
in vivo potency may be affected by hydrophobic, steric, and
electronic effects of the phenyl substituents (R1) and can also be
additionally influenced by metabolic detoxification. All of these
combined factors result in complex structure-activity relation-
ships. Further analogue syntheses and structure optimization
studies are in progress.
Supporting Information Available: 1H NMR, IR, melting
point, and element analysis data for the target compounds. This
information is available free of charge via the Internet at http://
pubs.acs.org.
The fungicidal activity of two commercial fungicides, azox-
ystrobin and kresoxim-methyl, is shown in Tables 1 and 2. The
fungicidal activity of the compounds of this study is equal to or
slightly better than those of these two commercial standards.

Article
J. Agric. Food Chem., Vol. 58, No. 5, 2010 2667
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supported by the National Key Project for Basic Research
(2003CB114400), Chinese National Technology Support Project of
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