Synthesis, fungicidal activity, structure-activity relationship and density functional theory studies of novel oxime ether derivatives containing 1-aryl-3-oxypyrazoles

Article abstract of DOI:10.3184/174751915X14424777344265

A series of 16 oxime ether derivatives containing 1-aryl-3-oxypyrazoles were synthesised, and the structure of one of them, (E)-methyl 2-(2-({(1-(4-chlorophenyl)-1H-pyrazol-3-yl)-oxy}methyl)phenyl)-2-(methoxyimino)acetate was determined by X-ray diffraction crystallography. Preliminary bioassays indicated that some of these compounds exhibited very good fungicidal activities against Rhizoctonia solani, especially the ester 2-(2-({(1-(4-chlorophenyl)-1H-pyrazol-3-yl)-oxy}methyl)phenyl)-2-(methoxyimino)acetate, which displayed greater activity than control compound pyraclostrobin at a dosage of 0.1 μg mL-1. The relationship between structure and fungicidal activity was discussed. Density functional theory studies of the 3-methyl heterocyclic ester and the 4-chorophenyl heterocyclic N-methylamide were carried out and the results discussed in terms of the wide difference in fungicidal activity shown by each compound.

Full text of DOI:10.3184/174751915X14424777344265

594 RESEARCH PAPER
VOL. 39 OCTOBER, 594–600
JOURNAL OF CHEMICAL RESEARCH 2015
Synthesis, fungicidal activity, structure–activity relationship and density
functional theory studies of novel oxime ether derivatives containing 1-aryl-3-
oxypyrazoles
Kunzhi Lva, Yuanyuan Liub*, Yi Lic, Guanghui Xuc, Xuechun Pana, Fangshi Lia, Kai Chena, Bin Huangb
and Yaping Yangb
aCollege of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing 211816, P. R. China
bDepartment of Chemical and Pharmaceutical Engineering, Southeast University ChengXian College, Nanjing 210088, P. R. China
cCollege of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, P. R. China
A series of 16 oxime ether derivatives containing 1-aryl-3-oxypyrazoles were synthesised, and the structure of one of them, (E)-methyl
2-(2-({(1-(4-chlorophenyl)-1H-pyrazol-3-yl)-oxy}methyl)phenyl)-2-(methoxyimino)acetate was determined by X-ray diffraction
crystallography. Preliminary bioassays indicated that some of these compounds exhibited very good fungicidal activities against
Rhizoctonia solani, especially the ester 2-(2-({(1-(4-chlorophenyl)-1H-pyrazol-3-yl)-oxy}methyl)phenyl)-2-(methoxyimino)acetate, which
-1
displayed greater activity than control compound pyraclostrobin at a dosage of 0.1 µg mL . The relationship between structure and
fungicidal activity was discussed. Density functional theory studies of the 3-methyl heterocyclic ester and the 4-chorophenyl heterocyclic
N-methylamide were carried out and the results discussed in terms of the wide difference in fungicidal activity shown by each compound.
Keywords: strobilurin analogues, oxime ether, 1-aryl-3-oxypyrazoles, X-ray crystal structure, fungicidal activities, density functional theory
1-3
Strobilurin fungicides
have attracted enormous attention
structures with enhanced biological activities. The fungicidal
activities against Rhizoctonia solani were evaluated and their
preliminary structure–activity relationships were discussed.
Furthermore, density functional theory (DFT) studies were carried
out and their relationship with biological activities was investigated.
because of their low toxicity toward mammalian cells, diverse
bioactivities, and exceptional broad-spectrum and high
activity.4-6 It has been demonstrated that the (E)-β-methyl
methoxyiminoacetate or isosteric (E)-β-methyl methoxyacrylate
group is the essential pharmacophore of Strobilurin fungicides.7
Linking the pharmacophore with a structurally diverse side chain
is an effective way of obtaining new strobilurin derivatives.8-12 For
example, previous researchers have synthesised new strobilurins
such as trifloxystrobin, metominostrobin and pyraclostrobin
through modification of the structure of methoxyacrylate.13,14
Asacontinuationofourresearchintofungicidalaryloxypyrazoles,
the oxime ether pharmacophore of strobilurins were introduced
into the 1-aryl-3-oxypyrazole structure of pyraclostrobin according
to the principle of active parts combination, and a series of new
aryloxypyrazole-based strobilurin analogues have been designed
and synthesised (Fig. 1).
Results and discussion
Intermediates 1a–h and 4 were synthesised using reported
pathways (Schemes 115 and 216 respectively). In a previous
study,16 we have prepared the 4-chorophenyl heterocyclic
ester 5c and the corresponding N-methyl amide 6c. Using
similar methods, we now report the synthesis of five more
X-phenyl heterocyclic esters 5a–b, d–h and five more X-phenyl
heterocyclic N-methyl amides 6a–b, d–h (Scheme 3). All the
1
new products were characterised by their H NMR and 13C
NMR spectra and by elemental analysis.
We now report the design and synthesis of a series of 16 novel
oxime ether derivatives containing 1-aryl-3-oxypyrazoles. The
single crystal of one of them, the 4-chorophenyl heterocyclic
ester 5c has been verified, which could help point the way to new
X-ray crystallography
The single X-ray crystallographic analysis of one of the title
compounds, the 4-chlorophenylheterocyclic-ester 5c showed
O
O
H
C
3
O
N
O
O
N
N
HN
H
OC
3
H
3CO
H
OC
3
N
l
C
H
3C
N
O
N
O
O
F
C
3
Pyraclostrobin
Trifloxystrobin
Metominostrobin
O
N
H
3CO
Y
Y=OMe, NHMe
N
X=H, 2-Me,4-Cl, 3-CF3-4-F,
3-CF3,3-Me, 4-OCF3,4-Br
N
O
X
Target products
Fig. 1 Design strategy for the target products.
* Correspondent. E-mail: liuyuanyuan1985419@163.com

JOURNAL OF CHEMICAL RESEARCH 2015 595
NH2
NHNH2
H l
H
N
N
NaNO2
SnCl2
Et
H
O
FeCl3
DMF
H
O
O
N
N
C
toluene
X
X
X
X
1a-h
a
b
c
d
e
f
g
h
:X=H
:X=2-Me
:X=4-Cl
:X=3-CF3-4-F
:X=3-CF3
:X=3-Me
:X=4-OCF3
:X=4-Br
Scheme 1
O
O
O
H
N
N
O
C
O
3
H
H
H
H
H
3CO
H
OC
3
O
3CO
OC
3
KMnO4
NaOH
MeOH
NB
S
H
H
C
C
C
3
3
3
Br
BP
O
MeONH2 HCl
3
2
4
Scheme 2
O
N
O
O
N
N
H
2CO3
H
3
3CO
OC
H
NH
H
3CO
C
H
+
H
3
3N
3CO
OC
N
N
K
MeNH2
X
MeOH
H
O
N
O
N
O
N
Br
X
acetone
X
1a-h
4
5a-h
6a-h
a
b
c
d
e
f
g
h
:X=4-Br
:X=H
:X=2-Me
:X=4-Cl
:X=3-CF3-4-F
:X=3-CF3
:X=3-Me
:X=4-OCF3
Scheme 3
Table
1
Crystallographic data and structure refinement for the
that it crystallises in the monoclinic space group P21/c. The
detailed crystal and structure refinement data for 5c are listed
in Table 1. Selected molecular structure parameters are listed
in Table 2. The lengths of two hydrogen bonds and relevant
dihedral angles are listed in Table 3. In the crystal structure
of 5c (Fig. 2), the bond length of C18–Cl is 1.741(4) Å,
representing a typical aryl–Cl bond, and the value is similar to
those [1.738(4) Å] reported for other related derivatives. 17 The
bond length of C12–O4 is 1.344(4) Å, which is longer than a
standard C=O double bond (1.229 Å), and is closer to a C–O
single bond. The bond angle of C12–C13–C14 (104.0(3)º)
is similar to the typical angle value of a five-membered ring
(108.0°). The dihedral angle between ring A (the bridge
benzene ring) and ring B (the terminal benzene ring) is 59.30º.
Rings A and B in 5c are twisted 57.67º and 5.80º, respectively,
from the plane of ring C (the pyrazole ring). The ester group
was twisted by 84.08º, 85.69º and 88.58º, from the planes of the
rings A, B and C, respectively. For the methanamide group, the
corresponding angles are 77.05 º, 86.08º and 88.13º, respectively.
The intramolecular C20–H20A···N3 H–bonds results in the
formation of a coplanar pseudo ring D [N(3)/N(2)/C(15)/
C(20)/H(20A)]. In the crystal of 5c, the existence of intra- and
intermolecular H-bonds appear to reinforce the crystal packing
(Fig. 3). These crystallographic data might provide the basis for
elucidating how structure relates to biological activity.
Fungicidal activity and structure–activity relationship: The
fungicidal activity of the title compounds and of commercial
pyraclostrobin against Rhizoctonia solani are listed in Table
4. All of the compounds were initially tested at dosages of 10,
1.0 and 0.1 µg mL-1, respectively. As can be seen in Table 4,
most compounds showed moderate to good control efficacy at
10 µg mL-1, especially 5c and 6c, with 100% antifungal activity.
From Table 4, we can see that at a concentration of 10 µg mL-1,
the 4-Cl and 3-CF3-4-F substituted compounds 5c–d and 6c–d
showed over 90% antifungal activities against Rhizoctonia
solani. When the concentration of the test compounds was
reduced to 0.1 µg mL-1, only 5c and 6c had 99 and 71%
inhibition rates. The general trend in antifungal activity was
4-chorophenyl heterocyclic ester 5c (Scheme 3)
5c
Empirical formula
CCDC number
Formula weight
Temperature [K]
Wavelength [Å]
Crystal system,
Space group
Unit cell dimensions
a/Å
C20H18ClN3O4
1421325
399.82
293(2)
0.71073
Monoclinic
P21/c
11.868(2)
7.693(15)
21.303(4)
90.00
b/Å
c/Å
α/º
β/º
γ/º
92.26(3)
90.00
1943.5(7)
4
1.366
0.228
832
0.30 × 0.20 × 0.10
1.72 to 25.41
0≤h≤14
0≤k≤9
–25≤l≤25
Volume/Å3
Z
ρ
calcd/g cm-3
µ/mm-1
F(000)
Crystal size/mm3
θ range/º for data collection
Index ranges
Reflections collected
3747
Independent reflections
Max. and min. transmission
Refinement method on F2
Data/restraints/parameters
Goodness-of-fit on F2
3564 [Rint = 0.0797]
0.9776/0.9347
Full-matrix least-squares
3564/2/253
1.006
R1=0.0712, wR2=0.1670
R1=0.1301, wR2=0.1946
0.522 and –0.305
Final R indices [I>2σ(I)]; R1,
R1, wR2 (all data)
Largest diff. peak and hole/e·Å-3

596 JOURNAL OF CHEMICAL RESEARCH 2015
Table 2 Selected molecular structure parameters of the 4-chorophenyl
heterocyclic ester 5c (Scheme 3)
Bond lengths/Å X-ray
Bond angles/º
C7–N1–O3
X-ray
C18–Cl
N1–C7
N1–O3
O1–C8
N2–N3
N2–C15
O2–C8
O2–C9
O3–C10
O4–C12
1.714(4)
111.7(3)
111.2(3)
118.9(3)
103.8(3)
110.8(3)
115.6(2)
113.8(3)
125.5(3)
104.0(3)
120.0(3)
1.278(5)
1.384(4)
1.220(4)
1.377(4)
1.421(4)
1.288(5)
1.455(5)
1.393(5)
1.344(4)
C14–N2–N3
N3–N2–C15
C12–N3–N2
N1–O3–C10
C12–O4–C11
N1–C7–C8
N1–C7–C6
C12–C13–C14
C19–C18–Cl
Table 3 Lengths of hydrogen bonds (Å), and relevant dihedral angles
(°), in the molecular structure of the 4-chorophenyl heterocyclic ester
5c (Scheme 3)
Comp.
D–H…A
C20–H20A…N3 0.9300
C19–H19A…O1a 0.9300
D–H
H…A
2.4200
2.4500
D…A
2.758(4)
3.325(5)
D–H…A
101.00
157.00
Fig. 2 ORTEP plot of the molecular structure of the 4-chorophenyl
heterocyclic ester 5c showing the atom-numbering scheme; 50%
probability thermal ellipsoids (Scheme 3).
5c
Symmetry codes: a1+x, y, z.
Fig. 3 A packing diagram of 4-chorophenyl heterocyclic ester 5c with intermolecular H-bonds (Scheme 3).
4-Cl group >3-CF3–4-F group >3-CF3 group >4-Br group
> Me group. For example, at a concentration of 10 µg mL-1,
compound 5c (X=4-Cl group), 5d (X = 3-CF3–4-F group), 5e
(X = 3-CF3 group), 5h (X = 4-Br group), 5f (X = 3-Me group)
exhibited 100, 91, 85, 64 and 54% activity against Rhizoctonia
solani, respectively. Similarly, this trend could also be found
in compounds 6a–h. This revealed that the introduction of
other electron-withdrawing substituents in X might contribute
to an antifungal activity increase against Rhizoctonia solani:
According to the different positions of a methyl group, the
sequence of fungicidal activity is o-substituted (5b and 6b) >
m-substituted (5f and 6f). With the introduction of the fluoro
group, the fungicidal activity showed improvement, as seen in
the comparison of 6d vs. 6e. In terms of the pharmacophore, the
compound with an oximino ester moiety (5c and 5e) had better
fungicidal activity than that with an oximino amide (6c and 6e)
when the substituent X had electron-withdrawing properties,
such as Cl and CF3 groups. The present work indicated that 5c
and 6c could be used as potential lead compounds for further
studies of novel fungicides.
DFT calculation: Based on frontier molecular orbital theory,
the HOMO and the LUMO are both important factors that

JOURNAL OF CHEMICAL RESEARCH 2015 597
affect the bioactivities of chemicals.18HOMO (highest occupied
molecular orbital) donates electrons first, whereas LUMO
(lowest unoccupied molecular orbital) accepts electrons first.19
Studying the frontier orbital energy might help in investigations
of active mechanisms. To elucidate the significant differences
in antifungal activity between compounds 5a to 5h and 6a to
6h, we calculated the frontier molecular orbital of the 3-methyl
heterocyclic ester 5f and the 4-chlorophenyl heterocyclic
N-methylamide 6c which have a wide difference in activity.
The HOMO and LUMO energies of 5f and 6c are listed in
Table 5, and the LUMO and HOMO maps of 5f and 6c are
shown in Fig. 4. The calculations showed similarities between
5f and 6c in the LUMO and HOMO maps. In the HOMO, the
electrons were mainly delocalised on the aromatic rings which
included the benzene ring and the pyrazole ring (including
O atom in the 3-position of pyrazole ring ). When electron
transitions take place, some electrons in the HOMO transform
into the LUMO.20 In the LUMO of 5f and 6c, the electrons were
similarly delocalised on the bridge benzene rings and oxime
ether moieties, which included oxime ester (5f) or oxime amide
moiety (6c). The different electron distributions among 5f and
6c might cause the large difference in antifungal activity.
Table 4 Fungicidal activity (% inhibition) against Rhizoctonia solani, at
three dosages, of a series of X-phenyl heterocyclic esters 5a–h and
X-phenyl heterocyclic N-methylamides 6a–h (Scheme 3)
Rhizoctonia solani
Comp
Y
X
-1
-1
-1
10 µg mL
1 µg mL 0.1 µg mL
5a
5b
5c
5d
5e
5f
5g
5h
6a
6b
6c
6d
6e
6f
6g
6h
H
2-CH3
4-Cl
3-CF3,4-F
3-CF3
3-CH3
4-OCF3
4-Br
H
2-CH3
4-Cl
3-CF3,4-F
3-CF3
3-CH3
4-OCF3
4-Br
61
59
100
91
85
54
59
64
60
59
100
98
67
57
59
63
62
53
50
100
75
81
50
52
58
53
51
95
91
48
49
52
53
39
47
46
99
48
48
45
44
48
46
47
71
50
36
50
49
48
36
OMe
NHMe
Pyraclostrobin
-
-
In the HOMO map of compound 6c, the amide group can
be seen. Through hydrophobic interactions, the amide group
can play an important role in insecticidal activity.21 Therefore,
the distribution of the frontier orbitals may be interrelated to
the hydrophobic interaction of the molecule with the target
receptor. As is shown in Fig. 4, 5f and 6c exhibited different
degrees of electron delocalisation in LUMO maps. The general
trend was 5f >6c with respect to electron delocalisation, which
demonstrated a negative relation with their antifungal activity.
Table 5 LUMO and HOMO energies and LUMO–HOMO (L–H) gaps
(in eV) of the 3-methyl heterocyclic ester 5f and the 4-chorophenyl
heterocyclic N-methylamide 6c (Scheme 3)
Compound
E(HOMO)
–0.203
–0.204
E(LUMO)
–0.036
–0.042
L–H gaps
0.167
5f
6c
0.162
HOMO(5f)
LUMO(5f)
HOMO(6c)
LUMO(6c)
Fig. 4 LUMO and HOMO maps for the 3-methyl heterocyclic ester 5f and the 4-chorophenyl heterocyclic N-methylamide 6c from DFT calculations
(Scheme3).The green parts represent positive molecular orbitals and the red parts represent negative molecular orbitals.

598 JOURNAL OF CHEMICAL RESEARCH 2015
Fig. 5 Electrostatic potential mapping on the electron density (isovalue = 0.02) for the 3-methyl heterocyclic ester 5f and the 4-chorophenyl heterocyclic
N-methylamide 6c from DFT calculations (Scheme 3).The blue areas indicate positive potential, and the red areas indicate negative potential.
95–98°C (MeOH); 1H NMR:δ 7.60 (d, J = 3.2 Hz, 1 H, CH), 7.44–7.19
As reported, the frontier molecular orbitals are situated on
(m, 8 H, ArH), 5.80(d, J = 3.2 Hz, 1 H, CH), 5.14 (s, 2H, CH2), 4.02
(s, 3H, OCH3), 3.82 (s, 3H, OCH3), 2.26 (s, 3H, CH3) ;13C NMR: δ
164.0, 150.3, 140.1, 139.6, 139.4, 129.7, 129.2, 128.1, 127.9, 126.3,
126.2, 118.7, 114.9, 93.8, 70.2, 63.1, 52.4,30.9, 21.5. Anal. calcd for
C21H21N3O4: C, 66.48; H, 5.58; N, 11.08; found: C, 66.42; H, 5.53; N,
11.13%.
(E)-Methyl 2-(2-({(1-(4-chlorophenyl)-1H-pyrazol-3-yl}oxy)methyl)
phenyl)-2-(methoxyimino)acetate (5c):White needles; yield 82%.
Melting point and spectral data can be found in our previous report.16
(E)-Methyl2-(2-({(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-
the main groups, the atoms of which can easily bind with the
receptor. 21 In addition, the orbital interaction may be affected
by the different degrees of delocalisation.22 Therefore, we
concluded that the high electron delocalisation of 5f in the
LUMO could potentially make the orbital interactions limited,
which might lead to a decrease in activity.
The molecular electrostatic potential (MEP) maps of
compound 5f and 6c were also calculated by DFT/B3LYP /6-
31G*. MEP reveals the charge properties and distributions of
the molecule. From Fig. 5, it is obvious that both the oxygen
and nitrogen atoms had the greatest negative charges. Thus, it
seems probable that these atoms interacted with the receptor or
acceptor.
pyrazol-3-yl}oxy)methyl)phenyl)-2-(methoxyimino)acetate
(5d):
White platelets; yield 80%; m.p. 106–108°C (MeOH); 1H NMR: δ 7.84
(d, J = 3.6 Hz, 1 H, CH), 7.32–7.22(m, 7H, ArH), 5.91 (d, J = 3.6 Hz,
1 H, CH), 5.20 (s, 2H, CH2), 4.06 (s, 3H, OCH3), 3.87 (s, 3H, OCH3);
13C NMR: δ 164.0, 163.0, 149.0, 136.0, 134.6, 129.5, 129.1, 128.2,
128.1, 127.6, 127.5, 122.2, 122.1, 117.6, 117.4, 116.1, 116.0, 94.8, 68.8,
63.4, 52.6. Anal. calcd for C21H17F4N3O4: C, 55.88; H, 3.80; N, 9.31;
found: C, 55.84; H, 3.83; N, 9.34%.
Experimental
All reagents were of analytical grades. Solvents were dried by standard
methods and distilled before use. Melting points were measured on
an X-4 microscope electrothermal apparatus (Taike, P.R.China) and
are uncorrected. NMR spectra were obtained on a Bruker AV-400
spectrometer (1H NMR at 400 Hz, 13C NMR at 100 Hz) in CDCl3 using
TMS as an internal standard. Chemical shifts (δ) are given in ppm and
coupling constants (J) in Hz. Elemental analyses were performed
on a Flash EA-1112 elemental analyser. Intermediates 1-aryl-1H-
(E)-Methyl2-(methoxyimino)-2-(2-({(1-(3-(trifluoromethyl)phenyl)-
1H-pyrazol-3-yl}oxy)methyl)phenyl)acetate (5e): White needles; yield
1
82%; m.p. 104–106°C (MeOH); H NMR:δ 7.88 (d, J = 3.6 Hz, 1 H,
CH), 7.77–7.22 (m, 8H, ArH), 5.91 (d, J = 3.6 Hz, 1 H, CH), 5.23 (s,
2H, CH2), 4.07 (s, 3H, OCH3), 3.87 (s, 3H, OCH3); 13C NMR: δ 164.0,
163.0, 149.1, 140.0, 134.7, 132.1, 131.7, 131.3, 129.6, 129.5, 129.0,
128.2, 128.1, 127.7, 127.6, 125.2. 121.6, 121.3, 121.2, 120.0, 114.2,
114.1, 114.0, 94.8, 68.8, 63.4, 52.6. calcd for C21H18F3N3O4: C, 58.20;
H, 4.19; N, 9.70; found: C, 58.17; H, 4.16; N, 9.75%.
(E)-Methyl 2-(methoxyimino)-2-(2-({(1-(m-tolyl)-1H-pyrazol-3-yl)
oxy}-methyl)phenyl)acetate (5f): White platelets; yield 84%; m.p.
69–79°C (EtOH); 1H NMR: δ 7.37 (d, J = 2.4 Hz, 1 H, CH), 7.35–6.91
(m, 8H, ArH), 5.74 (d, J = 2.4 Hz, 1 H, CH), 5.10 (s, 2H, CH2), 3.95 (s,
3H, OCH3), 3.74 (s, 3H, OCH3), 2.31 (s, 3H, CH3); 13C NMR: δ 164.0,
163.4, 149.5, 140.0, 135.3, 129.5, 129.2, 128.6, 128.4, 127.9, 127.8,
126.2, 118.7, 115.7, 93.8, 69.1, 63.8, 53.0, 50.7, 21.5. Anal. calcd for
C21H21N3O4: C, 66.48; H, 5.58; N, 11.08; found: C, 66.43; H, 5.54; N,
11.12%.
(E)-Methyl2-(methoxyimino)-2-(2-({(1-(4-(trifluoromethoxy)
phenyl)-1H-pyrazol-3-yl}oxy)methyl)phenyl)acetate (5g): White
platelets; yield 82%; m.p. 82–84°C (MeOH); 1H NMR: δ 7.49 (d,
J = 2.4 Hz, 1 H, CH), 7.37–7.11 (m, 8H, ArH), 5.77 (d, J = 2.4 Hz,
1 H, CH), 5.10 (s, 2H, CH2), 3.95 (s, 3H, OCH3), 3.75 (s, 3H, OCH3);
13C NMR: δ 164.2, 163.4, 149.5, 146.3, 138.7, 135.2, 129.8, 129.5, 128.6,
128.4, 128.0, 127.9, 122.1, 118.8, 94.7, 69.1, 63.8, 53.0. Anal. calcd for
C21H18F3N3O5: C, 56.13; H, 4.04; N, 9.35; found: C, 56.10; H, 4.07; N,
9.32%.
15
pyrazol-3-ols (1a–h) and (E)-methyl 2-(2-(bromomethyl)-phenyl)-2-
(methoxyimino)-acetate (4) 16 were prepared according to the reported
method, and the spectral data matched those previously reported. The
products 5a–h and 6a–h were synthesised according to the methods
reported in the literature, with some modification.16
Synthesis of 5a–h; general procedure
Intermediates 1a–h (1.0 mmol) were dissolved in acetone (30 mL), and
K2CO3 (2.5 mmol) and 4 (1.1 mmol) were added slowly. The reaction
mixture was heated to reflux for 5h and cooled to room temperature.
Then K2CO3 was filtered off and the solvent was evaporated under
reduced pressure. The crude product was purified using a silica-gel
column chromatography (petroleum ether/ ethyl acetate = 5:1) to afford
products 5a–h.
(E)-Methyl 2-(methoxyimino)-2-(2-({(1-phenyl-1H-pyrazol-3-yl)oxy}
methyl)phenyl)acetate (5a): White needles; yield 78%; m.p. 75–77°C
1
(MeOH); H NMR: δ 7.63 (d, J = 2.4 Hz, 1 H, CH), 7.55–7.10(m, 9
H, ArH), 5.77(d, J = 2.4 Hz, 1 H, CH), 5.12 (s, 2H, CH2), 3.97 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3) ;13C NMR:δ 164.0, 163.4, 149.5, 140.2,
135.3, 129.8, 129.5, 129.3, 128.5, 128.4, 127.9, 127.7, 125.3, 117.8,
94.0, 69.0, 63.8, 53.0. Anal. calcd for C20H19N3O4: C, 65.74; H, 5.24; N,
11.50; found: C, 65.77; H, 5.18; N, 11.56%.
(E)-Methyl
2-(methoxyimino)-2-(2-({(1-(o-tolyl)-1H-pyrazol-3-yl}
(E)-Methyl2-(2-({(1-(4-bromophenyl)-1H-pyrazol-3-yl)oxy)
methyl}phenyl)-2-(methoxyimino)acetate (5h): White needles; yield
oxy)methyl)phenyl)acetate (5b): White needles; yield 80%; m.p.

JOURNAL OF CHEMICAL RESEARCH 2015 599
1
82%; m.p. 105–107°C (MeOH); H NMR: δ 7.58 (d, J = 2.8Hz, 1 H,
J = 4.8 Hz, 3H, CH3); 13C NMR: δ 171.1, 164.3, 163.0, 151.1, 146.2,
146.2, 138.7, 135.4, 129.4, 128.7, 128.3, 127.9, 127.7, 122.1, 118.8, 94.7,
69.2, 63.2, 60.4, 26.2, 21.0, 14.2. Anal. calcd for C21H19F3N4O4: C,
56.25; H, 4.27; N, 12.49; found: C, 56.28; H, 4.25; N, 12.45%.
(E)-2-(2-({(1-(4-Bromophenyl)-1H-pyrazol-3-yl)oxy)methyl}
phenyl)-2-(methoxyimino)-N-methylacetamide (6h): Yellow platelets;
yield 86%; m.p. 96–98°C (MeOH); 1H NMR: δ 7.59 (d, J = 2.4Hz, 1 H,
CH), 7.51–7.15(m, 8H, ArH), 6.70 (s,1H, NH), 5.77(d, J = 2.4 Hz, 1 H,
CH), 5.08(s, 2H, CH2), 3.85 (s, 3H, OCH3), 2.80 (d, J = 4.8 Hz, 3H,
CH3); 13C NMR: δ 163. 2, 162.0, 150.1, 138.1, 134.3, 131.2, 128.3, 127.7,
127.3, 126.7, 126.6, 118.1, 117.1, 93.6, 68.2, 62.2, 25.2. Anal. calcd for
C20H19BrN4O3: C, 54.19; H, 4.32; N, 12.64; found: C, 54.15; H, 4.37; N,
12.68%.
X-ray diffraction crystallography: Suitable single crystal of the
4-chorophenyl heterocyclic ester 5c was evaporated in methanol slowly
at room temperature. The diffraction data were collected on a Nonius
CAD4 single crystal diffractometer with graphite-monochromated
MoKa radiation (λ = 0.71073 Å) by using a ω/2θ scan mode at 293 K.
All of the structures were solved by the direct method and refined by
the full-matrix least-squares procedure on F2 using the SHELXL-97
program.23, 24
Crystallographic data for the structural analysis of the title compound
have been deposited at the Cambridge Crystallographic Data Center,
12 Union Road, Cambridge CB2 1EZ, UK, fax: +44 1223 336033 or
E-mail: deposit@ccdc.cam.ac.uk. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/data_request/cif by quoting
the reference CCDC 1421326, which contains the supplementary
crystallographic data for the 4-chorophenyl heterocyclic ester 5c.
Fungicidal activity assays: The preventive activities of compounds
5a–h and 6a–h against Rhizoctonia solani were tested according to the
literature procedures.25, 26 The detailed method of test has been reported
by us.16 The results are listed in Table 4.
Theoretical calculation: On the basis of the above structure,
compounds 5f and 6c were selected as the initial structures, while
the DFT/B3LYP method with the 6-31G*basis set 27 in the Gaussian
09 package was used to optimise structures in accordance with
the minimum points on the potential energy surfaces. All of the
calculations were carried out on a personal computer.
CH), 7.53–7.12 (m, 8H, ArH), 5.77 (d, J = 2.8 Hz, 1 H, CH), 5.10 (s,
2H, CH2), 3.95 (s, 3H, OCH3), 3.75 (s, 3H, OCH3); 13C NMR: δ 163.1,
162.3, 148.4, 138.1, 134.1, 131.3, 128.8, 128.4, 127.5, 127.4, 126.9,
126.6, 118.1, 117.1, 93.6, 68.0, 62.8, 52.0. Anal. calcd for C20H18BrN3O4:
C, 54.07; H, 4.08; N, 9.46; found: C, 54.05; H, 4.05; N, 9.43%.
Synthesis of 6a–h; general procedure
The compound 5a–h (1.0 mmol) was dissolved in MeOH (50 mL), and
CH3NH2 in MeOH (30% w/w, 1 mL) was added slowly. The reaction
mixture was heated to reflux for 5h and cooled to room temperature.
The solvent was evaporated under reduced pressure, and the residue
was purified using silica-gel column chromatography (petroleum
ether/ ethyl acetate = 5:1) to afford 6a–h.
(E)-2-(Methoxyimino)-N-methyl-2-(2-({(1-phenyl-1H-pyrazol-3-yl)
oxy}methyl)phenyl)acetamide (6a): Yellow platelets; yield 82%; m.p.
105-107°C (EtOH); 1H NMR: δ 7.61 (d, J = 2.4 Hz, 1 H, CH), 7.52–7.08
(m, 9H, ArH), 6.70 (s,1H, NH), 5.76(d, J = 2.4 Hz, 1 H, CH), 5.10 (s,
2H, CH2), 3.85 (s, 3H, OCH3), 2.78 (d, J = 5.2 Hz, 3H, CH3);13C NMR:
δ 164.1, 163.1, 151.2, 140.1, 135.5, 129.4, 129.3, 128.7, 128.4, 127.8,
127.7, 125.3, 117.8, 94.0, 69.3, 63.3, 26.2. Anal. calcd for C20H20N4O3:
C, 65.92; H, 5.53; N, 15.38; found: C, 65.96; H, 5.57; N, 15.32%.
(E)-2-(Methoxyimino)-N-methyl-2-(2-({(1-(o-tolyl)-1H-pyrazol-
3-yl)oxy}methyl)phenyl)acetamide (6b): Yellow needles; yield 85%;
1
m.p. 101–103°C (MeOH); H NMR: δ 7.60 (d, J = 3.2 Hz, 1 H, CH),
7.42–7.21(m, 8 H, ArH), 6.79 (s,1H, NH), 5.82(d, J = 3.2 Hz, 1 H, CH),
5.14 (s, 2H, CH2), 3.93 (s, 3H, OCH3), 2.71 (d, J = 6.8 Hz, 3H, CH3),
2.17 (s, 3H, CH3) ;13C NMR: δ 163.8, 163.5, 151.8, 140.3, 136.1, 134.0,
132.2, 131.7, 129.7, 128.7, 128.4, 128.3, 128.0, 127.0, 126.1, 92.7, 69.4,
63.6, 26.4, 18.5. Anal. calcd for C21H22N4O3: C, 66.65; H, 5.86; N,
14.81; found: C, 66.62; H, 5.82; N, 14.85%.
(E)-2-(2-({(1-(4-Chlorophenyl)-1H-pyrazol-3-yl)oxy}methyl)
phenyl)-2-(methoxyimino)-N-methylacetamide (6c): Yellow needles
(87%); m.p. 95–97°C (MeOH). The spectral data could be found in our
previous reported.16
(E)-2-(2-({(1-(4-Fluoro-3-(trifluoromethyl)phenyl)-1H-pyrazol-3-
yl}oxy)methyl)phenyl)-2-(methoxyimino)-N-methylacetamide (6d):
Yellow needles; yield 80%; m.p. 85–87°C (EtOH); 1H NMR: δ 7.84 (d,
J = 3.6 Hz, 1 H, CH), 7.60–7.23(m, 7H, ArH), 6.76 (s,1H, NH), 5.91(d,
J = 3.6 Hz, 1 H, CH), 5.20 (s, 2H, CH2), 3.97 (s, 3H, OCH3), 2.93 (d, J =
6.8 Hz,3H, CH3); 13C NMR: δ 164.1, 162.5, 150.7, 134.8, 129.0, 128.3,
128.0, 127.4, 122.1, 122.0, 117.7, 117.4, 116.1, 116.0, 94.8, 68.9, 62.9,
60.0, 25.8, 20.7, 13.8. Anal. calcd for C21H18F4N4O3: C, 56.00; H, 4.03;
N, 12.44; found: C, 56.04; H, 4.05; N, 12.48%.
(E)-2-(Methoxyimino)-N-methyl-2-(2-({(1-(3-(trifluoromethyl)
phenyl)-1H-pyrazol-3-yl}oxy)methyl)phenyl)acetamide (6e): Yellow
platelets; yield 87%; m.p. 118–120°C (MeOH); 1H NMR: δ 7.40
(d, J = 2.8Hz, 1 H, CH), 7.36–7.13(m, 8H, ArH), 6.72 (s,1H, NH),
5.80(d, J = 2.8 Hz, 1 H, CH), 5.11 (s, 2H, CH2), 3.85(s, 3H, OCH3),
2.80 (d, J = 4.8Hz, 3H, CH3); 13C NMR: δ 164.5, 163.0, 151.1, 140.4,
135.3, 132.0, 131.7, 130.0, 129.4, 128.8, 128.4, 127.9, 127.8, 125.2,
121.6, 121.5. 120.4, 114.5, 114.4, 95.2, 69.3, 63.2, 26.2. Anal. calcd for
C21H19F3N4O3: C, 58.33; H, 4.43; N, 12.96; found: C, 58.36; H, 4.46; N,
12.93%.
Conclusions
In summary, a series of oxime ether derivatives containing
1-aryl-3-oxypyrazoles were designed and synthesised, and
their structures were characterised and confirmed. Preliminary
bioassays indicated that some of these compounds exhibited
good fungicidal activities against Rhizoctonia solani,
especially compounds 5c, which displayed 100, 100 and 99%
activity against Rhizoctonia solani, at 10, 1 and 0.1 µg mL-1,
respectively. The preliminary structure–activity relationship of
the title compounds indicated that compounds with electron-
withdrawing substituents in X might contribute to the antifungal
activities increase against Rhizoctonia solani. In addition,
through density functional theory studies, it seemed that the
high electron delocalisation of 5f in LUMO might possibly
make the orbital interactions limited, which might bring about
a decrease in activity.
(E)-2-(Methoxyimino)-N-methyl-2-(2-({(1-(m-tolyl)-1H-pyrazol-
3-yl)oxy}methyl)phenyl)acetamide (6f): Yellow needles (85%);
m.p. 106–108°C (EtOH); H NMR: δ 7.33 (d, J = 2.4 Hz, 1 H, CH),
1
7.31–7.13(m, 8H, ArH), 6.73 (s,1H, NH), 5.75(d, J = 2.4 Hz, 1 H, CH),
5.06 (s, 2H, CH2), 3.84 (s, 3H, OCH3), 2.62 (d, J = 5.2 Hz, 3H, CH3),
2.09 (s, 3H, CH3); 13C NMR: δ 163.5, 163.2, 151.4, 140.0, 135.8, 133.7,
131.9, 131.4, 129.4, 129.3, 128.4, 128.0, 127.9, 127.7, 126.6, 125.8,
92.4, 69.1, 63.2, 26.0, 18.2. Anal. calcd for C21H22N4O3: C, 66.65; H,
5.86; N, 14.81; found: C, 66.68; H, 5.82; N, 14.85%.
Electronic Supplementary Information
The H NMR and 13C NMR spectra of 5a–h and 6a–h can be
found in the electronic supplementary information available
through stl.publisher.ingentaconnect.com/content/stl/jcr/supp-
data
1
(E)-2-(Methoxyimino)-N-methyl-2-(2-(((1-(4-(trifluoromethoxy)
phenyl)-1H-pyrazol-3-yl)oxy)methyl)phenyl)acetamide (6g): Yellow
needles; yield 82%; m.p. 100–103°C (MeOH); H NMR: δ 7.60 (d,
J = 2.8 Hz, 1 H, CH), 7.51–6.73(m, 8H, ArH), 6.74 (s,1H, NH), 5.78(d,
J = 2.8 Hz, 1 H, CH), 5.10 (s, 2H, CH2), 3.85 (s, 3H, OCH3), 2.80 (d,
This work was financially supported by the Natural
Science Youth Foundation of Jiangsu Province, China
(BK20130749); The Project of the Twelfth Five Year Plan of
China (2012BAK17B09); The Project of Food Fast Detection
1

600 JOURNAL OF CHEMICAL RESEARCH 2015
12 W. Huang, P. L. Zhao, C. L. Liu, Q. Chen, Z. M. Liu and G. F. Yang, J.
Agric. Food Chem., 2007, 55, 3004.
13 S. Herms, K. Seehaus, H. Koehle and U. Conrath, Plant Physiol., 2002,
130, 120.
Technology of Jiangsu Province, China(BM2012026). We
thank the Jiangsu Pesticide Research Institute Co., Ltd for
testing the biological activities.
14 J.V. Mercader, C. S. Pantaleon, C. Agullo, A. A. Somovilla and A. A.
Fuentes, J. Agric. Food Chem., 2008, 56, 7682.
15 Y. Li, R.Liu, Z. Yan, X. Zhang and H. Zhu, Bull. Korean Chem. Soc., 2010,
31, 3341.
16 Y. Liu, Y. Li, N. Chen, K. Lv, C. Zhou, X. Xiong and F. Li, Molecules,
2014, 19, 8140.
17 Y. Liu, G. He, K. Chen, Y. Li and H. Zhu, J. Heterocycl. Chem., 2012, 49,
1370.
18 Y. L. Ma,; R.J. Zhou, X. Y. Zeng, Y.X. An, S. S. Qiu and L.J. Nie, J. Mol.
Struct., 2014, 1063, 226.
19 N. B. Sun, J.Q. Fu, J.Q. Weng, J.Z. Jin, C.X. Tan and X.H. Liu, Molecules,
2013 18, 12725.
20 X. H. Liu, W. G. Zhao, B. L. Wang and Z. M. Li, Res. Chem. Intermed,
2012, 38, 1999.
Received 28 August 2015; accepted 13 September 2015
Paper 1503565 doi: 10.3184/174751915X14424777344265
Published online: 2 October 2015
References
1
2
3
S. Herms, K. Seehaus, H. Koehle and U. Conrath, Plant Physiol., 2002,
130, 120.
J.V. Mercader, C. S. Pantaleon, C. Agullo, A. A. Somovilla and A. A.
Fuentes, J. Agric. Food Chem., 2008, 56, 7682.
B. Wolf, R. Benoit, H. Sauter, W. Grammenos, H. Wingert, T.
Kuekenhoehner and M. Hepp, German Patent 4042272, 1992; Chem.
Abstr., 1992, 117, 170986.
4
5
6
P.L. Zhao, C. L. Liu, W. Huang, Y. Z. Wang and G. F. Yang, J. Agric. Food
Chem., 2007, 55, 5697.
S. Tu, L.H. Xu, L.Y. Ye, X. Wang, Y. Sha and Z.Y. Xiao, J. Agric. Food
Chem., 2008, 56, 5247.
I. Hwang, J. Kim, H. Kim and S. Kyung, Bull. Kor. Chem. Soc., 2009, 30,
1475.
21 B. L.Wang, H. W.Zhu, Y. Ma, L. X. Xiong, Y. Q. Li, Y. Zhao, J. F. Zhang,
Y. W. Chen, S. Zhou and Z. M. Li, J. Agric. Food Chem., 2013, 61, 5483.
22 J.K. Cho and S. Shaik, J. Am. Chem. Soc., 1991, 113, 9890.
23 G. M.Sheldrick, SHELXL-97, Universität Göttingen, Göttingen
Germany,1997.
24 G. M. Sheldrick, Acta Crystallogr. Sect. A., 64, 2008, 112.
25 Y.Y. Liu, H. Shi, G. K. He, G. L. Song and H. J. Zhu, Helv. Chim. Acta.,
2012, 95, 1645.
7
8
G. Li and H. Yang, Chin. J. Chem., 2009, 27, 2055.
P.L. Zhao, W.H .Liu, Y. Z. Wang and G.F. Yang, J. Agric. Food Chem.,
2007, 55, 5697.
26 J. Wilamowski, E. Kulig, J.J. Sepiol and Z.J. Burgiel, Pest Manag. Sci.,
2001, 57, 625.
27 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman et al. Gaussian 09, Revision A. 02,Gaussian, Inc., Wallingford,
CT, USA, 2009.
9
I. H. Aspinall and P. A. Worthington, Pestic. Sci., 1999, 55, 197.
10 Y. Li, H. Q. Zhang, J. Liu, X. P. Yang and Z. J. Liu, J. Agric. Food Chem.,
2006, 54, 3636.
11 Y. Li, J. Liu, H. Q. Zhang, X. P. Yang and Z. J. Liu, Bioorg. Med. Chem.
Lett., 2006, 16, 2278.