One-pot regioselective synthesis of novel oximino ester-containing 1-aryl-4-chloro-3-oxypyrazoles as potential fungicides

Article abstract of DOI:10.1002/hlca.201300407

A novel, functional-group-tolerant, and highly regioselective one-pot synthesis of six 4-chloro-1-aryl-3-oxypyrazoles, 8a-8f, containing an oximino ester moiety has been developed. Their structures were characterized by ¹H- and ¹³C-N

Full text of DOI:10.1002/hlca.201300407

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One-Pot Regioselective Synthesis of Novel Oximino Ester-Containing 1-Aryl-
4-chloro-3-oxypyrazoles as Potential Fungicides
by Yi Li*a), Yuan-Yuan Liu*b), Nan-Qing Chenc), Kun-Zhi Lꢀc), Xiao-Hui Xionga), and Jie Lib)
a) College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, P. R. China
(phone/fax: þ 86-25-58139432; e-mail: liynj2012@njtech.edu.cn)
b) Department of Chemical and Pharmaceutical Engineering, Southeast University ChengXian College,
Nanjing 210088, P. R. China (phone/fax: þ 86-25-83588933; e-mail: liuyuanyuan1985419@163.com)
c) Department of Applied Chemistry, College of Science, Nanjing Tech University, Nanjing 211816, P. R.
China
A novel, functional-group-tolerant, and highly regioselective one-pot synthesis of six 4-chloro-1-aryl-
3-oxypyrazoles, 8a – 8f, containing an oximino ester moiety has been developed. Their structures were
characterized by 1H- and 13C-NMR, IR, MS, and elemental analyses. The regioselectivity of the reaction
was also determined by single-crystal X-ray diffraction analysis of product 8d. The reaction pathway,
proposed with the aid of DFT calculations, likely proceeds via a DMF-catalyzed mechanism, which
involves an electrophilic attack by SOCl2 and two nucleophilic substitutions by benzyl bromide (BnBr)
and Clꢀ, respectively, as the key steps. A preliminary in vitro bioassay indicated that most compounds
exhibited good fungicidal activities against Sclerotinia sclerotiorum and Gibberella zeae. Especially, 8d
and 8e displayed higher or similar fungicidal activities compared with pyraclostrobin at the concentration
of 10 mg/ml.
Introduction. – Since the discovery of the strobilurin fungicide azoxystrobin (1) by
Syngenta scientists in 1992 (Fig. 1) [1], this novel fungicide class, developed from
natural fungicidal strobilurin A, oudemansin A, and myxothiazol A, has occupied an
important position in agrochemical market due to its lower mammalian toxicity, broad
spectrum, and higher fungicidal activity [2 – 6]. Pyraclostrobin (2), kresoxim-methyl
(3), and trifloxystrobin (4, Fig. 1), three representatives in the strobilurin family
containing methoxy carbamate or oximino ester moieties, play significant roles [7 – 10].
Generally, the chemical structure of strobilurin fungicides can be characterized by three
parts: i) a methyl (E)-2-(methoxyimino)acetate or isosteric methyl (E)-2-methoxy-
acrylate moiety as pharmacophore, ii) an aromatic bridge, and iii) a side chain. Analysis
of the mode of action revealed that these strobilurins inhibited the mitochondrial
respiration by binding their pharmacophore to the ubiquinol-oxidation center (Qo site)
of cytochrome bc1ꢀenzyme complex of a fungus where electron transfer took place
[11][12]. Therefore, researchers have mainly focused on keeping the pharmacophore
but changing the side chain, and some new strobilurins have been commercialized [13 –
15]. To prevent the resistance of pathogens to chemicals and develop more efficient
fungicides, we have also devoted considerable efforts. Bioactive (alkyl)oxy acetate,
thiazolidine-2-thione, and O-acetylated glucopyranosyl or benzoyl moieties were
introduced into the 1-aryl-3-methoxy-1H-pyrazole structure of pyraclostrobin (2) to
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Fig. 1. Representative strobilurin fungicides and 4-chloro-3-oxypyrazoles
replace its methoxycarbamate pharmacophore, which could not be synthesized in an
environmentally friendly way, and several novel 1,5-diaryl-3-oxypyrazoles with good
fungicidal activity were reported [16 – 19].
On the other hand, since the preparation of compound 5 (Fig. 1) in 1969 for the
control of susceptible and resistant pasture mosquitoes [20], the 4-chloro-3-oxy-
pyrazoles have attracted enormous attention due to their diverse biological features
such as antimicrobial (e.g., 6) and herbicidal (e.g., 7) activities [21][22]. Introduction of
Cl-atom can indeed led to a better fungicidal efficacy and plant systemicity. In
continuation of our program toward the preparation of fungicidal 1-aryl-3-oxypyrazole
derivatives, the oximino ester pharmacophores of 3 and 4, as well as Cl were introduced
into the 1-aryl-3-oxypyrazole structure of 2 according to the principles of active parts
combination, and novel 1-aryl-3-(arylmethoxy)-4-chloropyrazoles 8 were designed
(Fig. 2).
Herein, we report a novel, highly regioselective, and functional-group-tolerant
method to prepare six oximino ester-containing 4-chloro-1-aryl-3-(arylmethoxy)pyr-
azoles 8a – 8f in one step from readily accessible 1-aryl-1H-pyrazol-3-ols. The
regioselectivity of the reaction was established by single-crystal X-ray diffraction
analysis of 8d. The reaction mechanism was also proposed with the help of DFT
calculations. A preliminary in vitro bioassay indicated that most compounds displayed
good fungicidal activity against Sclerotinia sclerotiorum and Gibberella zeae, especially

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Fig. 2. Design strategy for the target compound 8
8d and 8e, which showed a higher or similar activity as compared with pyraclostrobin at
a concentration of 10 mg/ml.
Results and Discussion. – Synthesis. Recently, we have reported details of the DMF-
catalyzed 4-chlorination of 1-aryl-1H-pyrazol-3-ols [23]. Therefore, the reaction
sequence depicted in Scheme 1 was first proposed for the synthesis of the target
product 8a. In the presence of a catalytic amount of DMF, 1-phenyl-1H-pyrazol-3-ol
(Ia) was heated to reflux in SOCl2, and 4-chlorinated product IIa was isolated in 80%
yield, with high regioselectivity for monochlorination at C(4). Then, 82% yield of 8a
was obtained by the reaction of IIa with bromobenzyl derivative III in the presence of
K2CO3 in boiling acetone. Although 8a was prepared by this approach, it required two
time-consuming, purification processes via column chromatography, and the total yield
was only 65.6%. To address this problem, a one-pot synthesis (Table 1) was proposed.
However, since compound III contains many functional groups, such as alkoxy, ester,
imino, and aryl groups, i.e., both electron-donating and -withdrawing groups, the
regioselective formation of the 4-chlorinated product 8a seemed not so easy to
accomplish.

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Scheme 1. Synthesis of Target Product 8a
Unexpectedly, a better yield, i.e., 80% (Table 1, Entry 1), of 8a was obtained by the
one-pot reaction of Ia, III, K2CO3, and SOCl2 in boiling CHCl3 by using DMF (10 mol-
%) as catalyst. HPLC Analysis of the reaction mixture indicated that this reaction was
completed within 6 h without the formation of other chlorinated products. However,
Table 1. One-Pot Synthesis of the Target Product 8aa)
Entry
DMF [equiv.]
Solvent
Temp.
Time [h]
Yield of isolated 8a [%]
1
2
3
4
5
6
7
8
9
0.1
0.15
–
0.1
0.1
0.1
0.1
0.1
0.1
CHCl3
CHCl3
CHCl3
CH2Cl2
CCl4
Acetone
MeCN
CHCl3
–
reflux
reflux
reflux
reflux
reflux
reflux
reflux
r.t.
6
6
6
6
6
6
6
6
6
80
80
32
38
42
45
50
15
40
reflux
a) The reaction was carried out with Ia (1.0 mmol), III (1.05 mmol), K2CO3 (1.5 mmol), SOCl2
(5.0 mmol), and DMF (0 – 0.15 mmol) in a solvent and monitored by HPLC.

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the yield was not improved by increasing the amount of DMF, and this reaction turned
out to proceed with lower yield when using CH2Cl2, CCl4, acetone or MeCN instead of
CHCl3 as solvent (38 – 50%; Table 1, Entries 4 – 7). Furthermore, the reaction did not
run well at room temperature (15%; Table 1, Entry 8) or without DMF or solvent (32 –
40%; Table 1, Entries 3 and 9).
Similar results were obtained starting from 1-aryl-1H-pyrazol-3-ols Ib and Ic with
electron-donating Me and CF3O groups, and Id – If with electron-withdrawing F, Cl, or
CF3 groups at various positions of the 1-phenyl ring, giving yields of 75 and 76%
(Table 2, Entries 1 and 2) and 80 – 83% (Table 2, Entries 3 – 5) yield of 8b and 8c and
8d – 8f, respectively. All these examples revealed this one-pot synthesis to be a versatile
method with a good functional-group tolerance. The regioselectivity of the reaction and
the structures of the products 8 were unequivocally determined by NMR spectroscopy
and single-crystal X-ray diffraction analysis of 8d (Fig. 3).
Table 2. One-Pot Synthesis of the Target Products 8b – 8f a)
Entry
Substrate
X
Yield [%] (isolated product)
1
2
3
4
5
Ib
Ic
Id
Ie
If
m-Me
p-CF3O
p-Cl
m-CF3
m-CF3-p-F
76 (8b)
75 (8c)
82 (8d)
83 (8e)
80 (8f)
a) The reaction was carried out with Ib – If (1.0 mmol), III (1.05 mmol), K2CO3 (1.5 mmol), SOCl2
(5.0 mmol), and DMF (0.1 mmol) in boiling CHCl3 and monitored by HPLC.
Structures. Compound 8d crystallizes in the monoclinic space group P21/n. The
detailed crystal and structure refinement data for 8d are compiled in Table 4 in the
Exper. Part. In the crystal structure of 8d (Fig. 3), the bond length of C(3)ꢀCl(2) is
1.736(4) ꢂ, representing a typical arylꢀCl bond length, and the value is similar to those
(1.738(4) ꢂ) reported for other related derivatives [23]. The bridge benzene ring A
(C(11) – C(16)) and the terminal benzene ring B (C(1) – C(6)) are connected to the
pyrazole ring C, twisted by 77.208 and 20.938, respectively, whereas they form a dihedral
angle of 56.488. The ester and methoxyimino groups are almost coplanar, twisted by
60.988 and 59.528, 9.088, and 5.738, 19.948, and 19.528, respectively, from the planes of
the rings A, B, and C. The intramolecular CꢀH ··· O and CꢀH ··· N H-bonds result in the

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Fig. 3. X-Ray crystal structure of 8d
formation of three non-planar pseudo-rings D (N(2)/C(9)/O(1)/C(10)/H(10B)), E
(N(3)/C(17)/C(16)/C(11)/C(10)/H(10B)), and (O(4)/N(3)/C(17)/C(16)/C(11)/
F
C(10)/H(10B)) of envelope conformations, with O(1), N(3), and O(4) atoms displaced
by 0.415, 0.951, and 1.988 ꢂ, respectively, from the plane of the other ring atoms. In the
crystal, the molecules form intermolecular CꢀH ··· O H-bonds (Fig. 4) and CꢀH ··· p
stacking interactions (Fig. 5), one is between the MeO H-atom and the center of ring B
(C(20)ꢀH(20B) ··· Cg(1)), and the others from a phenyl H-atom to the center of ring A
(C(2)ꢀH(2B) ··· Cg(2) and C(4)ꢀH(4A) ··· Cg(2)).
In conclusion, 1-aryl-1H-pyrazol-3-ols I containing aryl and OH groups, with
electron-donating and -withdrawing groups, as well as bromobenzyl compound III
containing alkoxy, ester, imino, halogen, and phenyl groups, were all compatible with
this one-pot reaction, and the procedure led to the regioselective formation of the 4-
chlorinated products 8 in good yields. Significantly, this method does not involve
tedious steps of protection and deprotection of functional groups.
Reaction Mechanism. The following results were also obtained in studies to
elucidate the mechanism of this one-pot reaction: 1) with a catalytic amount of DMF, a
higher yield of 8a (80%) was obtained than without DMF; 2) the nucleophilic
substitution with elimination of HBr occurred between the OH group of Ia and
bromobenzyl derivation III; 3) to determine whether the SOCl2ꢀDMF complex SD

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Fig. 4. A packing diagram of 8d
was the chlorinating species (Scheme 2), SD was prepared [24] and allowed to react
with Ia, III, and K2CO3 in boiling CHCl3. However, only a trace of product 8a was
detected by HPLC. Therefore, it seems most likely that Ia reacts with SOCl2 and III
first, and then the reaction with the catalyst DMF occurs; 4) the 4-chlorination likely
proceeds via nucleophilic attack by Clꢀ, because SOCl2 is normally a source of Clꢀ, and
Scheme 2. Reaction of Ia, III, and K2CO3 with SOCl2ꢀDMF complex SD in boiling CHCl3

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Fig. 5. Intermolecular CꢀH ··· p interactions of 8d
the intermediacy of Clꢀ is feasible; 5) elemental sulfur was isolated during the column
chromatographic purification of 8a.
We propose a catalytic mechanism for the formation of 8a from Ia and III, which
was also illustrated with the aid of density-functional theory (DFT) calculations
(Scheme 3). The calculations were carried out in the ground-state (in vacuo) with
Gaussian 09 software by using B3LYP/6-31G* method [25 – 28]. As can be seen from
the NBO (natural bond orbital) charges of Ia, the initial electrophilic attack of SOCl2
occurs at the more electron-rich C(4) atom (ꢀ0.413; C(5) ꢀ 0.024). Meanwhile, the
nucleophilic substitution of the negatively charged O-atom (ꢀ0.602) to III occurs
competitively, releasing one molecule of HBr and generating an active intermediate A
[29][30]. This step involves a concerted sulfonylation/alkylation. Subsequently, an
intermediate B is formed via complexation of A with DMF, and Clꢀ takes part in the

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nucleophilic substitution of the SO-DMF group. Then, product 8a is formed via
extrusion of SO and regeneration of DMF. The longer CꢀS bond in B (1.79 ꢂ) than in
A (1.75 ꢂ) makes the bond rupture more easy when the nucleophilic substitution takes
place. In this reaction, K2CO3 is an acid-binding agent, and the catalyst DMF acts an
electron-withdrawing group to improve the reaction rate and, additionally, as a leaving
group upon protonation. Sulfur monoxide (SO) has been suggested as a product in
other redox reactions of SOCl2, but detection of SO has not been possible due to its
ready disproportionation to SO2 and elemental sulfur [31 – 34]. Indeed, elemental
sulfur was isolated, which indicated the possible involvement of SO in the reaction.
With the help of DFT calculations, the probability and position of this chlorination
on the pyrazole ring can be proposed. Related studies on the introduction of Cl or other
halogen atoms to other heterocycles, such as isoxazole, isothiazole, imidazole, and
thiazole, should also be calculated first, and then achieved. These works are underway
in our laboratory and will be reported in due course.
Fungicidal Activity Studies. Compounds 8a – 8f were screened for bioactivity
against two fungi, Sclerotinia sclerotiorum and Gibberella zeae, at a dosage of 10 mg/ml
each. As can be seen from Table 3, most compounds have moderate fungicidal
activities, except 8d (X ¼ p-Cl; 100%, 81%) with excellent inhibitory activity and 8e
(X ¼ m-CF3; 86%, 74%) with a level similar to that of pyraclostrobin. The products
containing substituent X with electron-withdrawing properties, such as F (i.e., 8f; 78%,
67%), Cl (i.e., 8d; 100%, 81%), and CF3 (i.e., 8e, 86%, 74%; and i.e., 8f, 78%, 67%)
groups showed higher activities than those with electron-donating Me (i.e., 8b, 61%,
46%) and CF3O (i.e., 8c, 63%, 50%) groups. However, switching X from Cl to the
strong electron-withdrawing F or CF3 groups without full consideration of the
electronic effects had negative impact on the inhibition rates, as seen in the comparison
of compounds 8d vs. 8e and 8f. This might imply that Cl could balance the HLB
(hydrophilic-lipophilic balance) value and increase the systemic of molecule within
plant. Moreover, classical intramolecular (CꢀH ··· O, CꢀH ··· N) and intermolecular
(CꢀH ··· O) H-bonds (Figs. 3 and 4, resp.) formed in the crystal of 8d seem to have an
impact on improving the hydrophilicity of molecule. The present work indicated that 8d
and 8e could be used as potential lead compounds for further studies of novel
fungicides. The enhancement of bioactivity requires a reasonable design of molecules,
Table 3. Antifungal Activity of the Tested Compounds (10 mg/ml)
Compounds
X
Inhibition [%]a)
S. sclerotiorum
G. zeae
8a
8b
8c
8d
8e
8f
H
65
61
63
100
86
78
51
46
50
81
74
67
71
m-Me
p-CF3O
p-Cl
m-CF3
m-CF3, p-F
–
Pyraclostrobin
96
a) 0, No activity, and 100, total kill.

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such as full consideration of H-bonds and electronic effects of substituents,
combination of heterocycle and pharmacophore, and introduction of halogen such as
Cl to balance the HLB value of molecule and enhance the plant systemicity.
Conclusions. – In summary, we have developed a simple and efficient method to
prepare six novel oximino ester-containing 4-chloro-1-aryl-3-oxypyrazoles, 8a – 8f, in
one step from readily accessible 1-aryl-1H-pyrazol-3-ols, Ia – If, bromobenzyl com-
pound III, and SOCl2. The DMF-catalyzed reaction mechanism proposed on the basis
of DFT calculations involves an electrophilic attack by SOCl2, and two nucleophilic
substitutions by III and Clꢀ, respectively, as the key steps. Good functionality tolerance
and high regioselectivity for monochlorination at C(4) render this method useful for
the synthesis of these 4-chloro-3-oxypyrazole strobilurins. The fungicidal activities of
8a – 8f were tested in vitro against Sclerotinia sclerotiorum and Gibberella zeae, and 8d
displayed a higher fungicidal activity, whereas 8e exhibited a similar level, as compared
with pyraclostrobin. This implies that full consideration of the electronic effects, and
introduction of halogen such as Cl to balance the HLB value and enhance the plant
systemicity are important for improving their fungicidal activities. Further introduction
of halogen to the pyrazole ring or other heterocycles, and the investigation of
bioactivities are underway in our laboratory and will be reported in due course.
This work was jointly supported by the Natural Science Foundation for Young Scholars of Jiangsu
Province of China (Grant No. BK20130749) and the Youth Foundation of Southeast University
ChengXian College (Grant No. 7303600001).
Experimental Part
General. All reagents used were of anal. grade, and solvents were dried by standard methods and
distilled before use [35]. Compounds Ia – If [36] and III [12] were prepared according to the published
procedures. TLC: Precoated silica-gel plates (Merck silica gel 60 F254); detection by UV light. M.p.: X-4
Microscope electrothermal apparatus; uncorrected. IR Spectra: Nicolet 380 FT-IR spectrophotometer.
1H- and 13C-NMR spectra: Bruker spectrometer, at 400 and 100 MHz, resp.; in CDCl3 or (D6)DMSO;
chemical shifts d in ppm rel. to TMS as internal standard, and coupling constants J in Hz. MS: Agilent
1100 Series LC/MSD Trap SL. Elemental analyses: Vario EL III elemental analyzer.
General Procedure for the Synthesis of Methyl (2E)-2-(2-{[(1-Aryl-4-chloro-1H-pyrazol-3-yl)oxy]-
methyl}phenyl)-2-(methoxyimino)acetate 8a – 8f [40]. To a soln. of 1-aryl-1H-pyrazol-3-ol (Ia – If;
1.0 mmol) and methyl (2E)-2-(2-[bromomethyl)phenyl]-2-(methoxyimino)acetate (III; 0.3 g, 1.05 mmol)
in CHCl3 (20 ml) was added K2CO3 (0.21 g, 1.5 mmol). Then, SOCl2 (5 ml) and a cat. amount of DMF
(0.1 mmol) were added. The mixture was heated to reflux for 6 h (reaction monitored by HPLC), and
then K2CO3 was filtered off. The solvent was evaporated under reduced pressure. The residue was
dispersed in H2O (200 ml) and extracted with AcOEt (3 ꢁ 15 ml). The org. phase was separated, dried
(Na2SO4), and then concentrated to dryness. It was then purified by flash column chromatography (CC;
silica gel; AcOEt/petroleum ether (PE) 1:12 (v/v)) to afford target product 8a – 8f.
Methyl (2E)-2-(2-{[(4-Chloro-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenyl)2-(methoxyimino)ace-
tate (8a). Yield: 0.32 g (80%). White solid. M.p. 104 – 1058. IR (KBr): 3147, 2949, 2895, 1734, 1598,
1557, 1511, 1463, 1438, 1406, 1356, 1323, 1223, 1122, 1063, 1012, 984, 947, 895, 862, 795, 756, 684. 1H-NMR
(400 MHz, CDCl3): 7.73 (s, CH); 7.63 – 7.19 (m, 9 arom. H); 5.25 (s, CH2); 4.04 (s, MeO); 3.84 (s, MeO).
13C-NMR (100 MHz, CDCl3): 163.3; 158.9; 149.4; 139.7; 134.8; 130.1; 129.5; 129.4; 128.9; 128.5; 128.1;
125.7; 125.6; 117.6; 98.3; 69.5; 63.9; 53.1. ESI-MS: 400.11 ([M þ H]þ), 422.09 ([M þ Na]þ). Anal. calc. for
C20H18ClN3O4 (399.83): C 60.08, H 4.54, N 10.51; found C 59.83, H 4.58, N 10.57.
Methyl (2E)-2-[2-({[4-Chloro-1-(3-methylphenyl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]-2-(meth-
oxyimino)acetate (8b). Yield: 0.31 g (76%). White solid. M.p. 108 – 1098. IR (KBr): 3133, 2946, 2820,

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1719, 1583, 1548, 1490, 1442, 1407, 1375, 1352, 1325, 1254, 1218, 1114, 1067, 1018, 952, 871, 823, 786, 728,
690. 1H-NMR (400 MHz, CDCl3): 7.69 (s, CH); 7.62 – 7.20 (m, 8 arom. H); 5.23 (s, CH2); 4.04 (s, MeO);
3.84 (s, MeO); 2.42 (s, Me). 13C-NMR (100 MHz, CDCl3): 162.3; 159.0; 149.4; 138.2; 137.4; 134.7; 131.3;
130.1; 129.8; 129.5; 128.9; 128.5; 128.1; 125.6; 119.8; 116.1; 98.6; 69.5; 63.9; 53.1; 20.4. ESI-MS: 414.11
([M þ H]þ), 436.09 ([M þ Na]þ). Anal. calc. for C21H20ClN3O4 (413.85): C 60.95, H 4.87, N 10.15; found
C 60.74, H 4.82, N 10.21.
Methyl (2E)-2-{2-[({4-Chloro-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-3-yl}oxy)methyl]phenyl}-
2-(methoxyimino)acetate (8c). Yield: 0.36 g (75%). White solid. M.p. 149 – 1508. IR (KBr): 3144, 2946,
1722, 1607, 1558, 1507, 1441, 1393, 1370, 1298, 1261, 1208, 1146, 1115, 1063, 1017, 957, 842, 808, 759, 728,
685. 1H-NMR (400 MHz, CDCl3): 7.71 (s, CH); 7.62 – 7.21 (m, 8 arom. H); 5.24 (s, CH2); 4.04 (s, MeO);
3.84 (s, MeO). 13C-NMR (100 MHz, CDCl3): 163.3; 159.2; 149.4; 146.6; 146.6; 138.2; 134.7; 130.1; 129.5;
128.9; 128.5; 128.2; 125.7; 122.2; 118.6; 99.0; 69.6; 63.9; 53.0. ESI-MS: 484.09 ([M þ H]þ), 506.06 ([M þ
Na]þ). Anal. calc. for C21H17ClF3N3O5 (483.82): C 52.13, H 3.54, N 8.68; found C 52.35, H 3.60, N 8.61.
Methyl (2E)-2-[2-({[4-Chloro-1-(4-chlorophenyl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]-2-(meth-
oxyimino)acetate (8d). Yield: 0.36 g (82%). White solid. M.p. 147 – 1488. IR (KBr): 3140; 2940; 1721;
1594; 1547; 1495; 1437; 1355; 1327; 1253; 1217; 1114; 1063; 1016; 959; 829; 785; 723; 689. 1H-NMR
(400 MHz, CDCl3): 7.68 (s, CH); 7.61 – 7.20 (m, 8 arom. H); 5.23 (s, CH2); 4.03 (s, MeO); 3.84 (s, MeO).
13C-NMR (100 MHz, CDCl3): 163.3; 159.0; 149.4; 138.2; 134.7; 131.0; 130.1; 129.5; 128.9; 128.5; 128.2;
125.6; 118.6; 98.8; 69.5; 63.9; 53.1. ESI-MS: 434.07 ([M þ H]þ), 456.05 ([M þ Na]þ). Anal. calc. for
C20H17Cl2N3O4 (434.27): C 55.31, H 3.95, N 9.68; found C 55.52, H 3.91, N 9.62.
Methyl (2E)-2-{2-[({4-Chloro-1-[3-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}oxy)methyl]phenyl}-
2-(methoxyimino)acetate (8e). Yield: 0.39 g (83%). White solid. M.p. 119 – 1208. IR (KBr): 3140,
2946, 1730, 1598, 1562, 1518, 1458, 1406, 1358, 1328, 1306, 1226, 1169, 1122, 1067, 1014, 948, 889, 794, 758,
692. 1H-NMR (400 MHz, CDCl3): 7.81 (s, CH); 7.79 – 7.21 (m, 8 arom. H); 5.26 (s, CH2); 4.05 (s, MeO);
3.85 (s, MeO). 13C-NMR (100 MHz, CDCl3): 163.3; 159.3; 149.4; 140.0; 134.5; 130.2; 130.1; 129.5; 129.0;
128.5; 128.2; 125.6; 122.1; 122.0; 120.1; 114.3; 99.6; 69.7; 63.9; 53.1. ESI-MS: 468.10 ([M þ H]þ), 490.08
([M þ Na]þ). Anal. calc. for C21H17ClF3N3O4 (467.83): C 53.91, H 3.66, N 8.98; found C 54.12, H 3.60, N
8.92.
Methyl (2E)-2-{2-[({4-Chloro-1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-pyrazol-3-yl}oxy)methyl]-
phenyl}-2-(methoxyimino)acetate (8f). Yield: 0.39 g (80%). White solid. M.p. 101 – 1028. IR (KBr): 3140,
2946, 1734, 1602, 1563, 1518, 1459, 1407, 1372, 1359, 1330, 1308, 1226, 1173, 1122, 1068, 1017, 952, 843, 792,
1
753, 696. H-NMR (400 MHz, CDCl3): 7.76 (s, CH); 7.75 – 7.24 (m, 7 arom. H); 5.60 (s, CH2); 4.01 (s,
MeO); 3.89 (s, MeO). 13C-NMR (100 MHz, CDCl3): 163.1; 162.8; 149.0; 147.8; 139.7; 130.6; 130.4; 130.2;
129.9; 129.6; 128.7; 128.4; 127.4; 125.7; 63.9; 53.1; 30.9. ESI-MS: 486.09 ([M þ H]þ), 508.07 ([M þ Na]þ).
Anal. calc. for C21H16ClF4N3O4 (485.82): C 51.92, H 3.32, N 8.65; found C 51.71, H 3.37, N 8.72.
Fungicidal Assays. The fungicidal activities of compounds 8a – 8f against fungi Sclerotinia
sclerotiorum and Gibberella zeae were evaluated as described in [17][37]. The compounds to be tested
were dissolved in acetone and added to a sterile agarized Czapek-Dox medium at 458. In preliminary
screenings, compounds were used in a concentration of 10 mg/ml. The control sample contained only
1 equiv. of acetone. The media were poured onto 8-cm Petri dishes (10 ml for each dish) and, after 2 d,
inoculated with 5-mm PDA (potato dextrose agar) discs with overgrown mycelium. In the case of
Sclerotinia sclerotiorum, the medium was inoculated by a prick of laboratory needle containing fungus
spores. The Petri dishes were incubated at r.t. in the dark. After 4 d, the diameters of the inoculation of
the cultures were measured. The percentage inhibition of fungal growth was determined by comparison
between the development of fungi colonies on media containing compounds and on the control. Three
replicates of each test were carried out.
X-Ray Crystallography. Suitable crystals of 8d were obtained by slow evaporation of EtOH soln. at
r.t. Further details of the data collection are compiled in Table 4. Crystal data1) were collected on a
Nonius CAD-4 diffractometer by using MoKa (0.71073 ꢂ) radiation. The structures were solved by direct
methods using SHELXS-97 and refined by full-matrix least-squares on F2 for all data using SHELXL-97
1
)
CCDC-949755 (8d) contains the supplementary crystallographic data for this article. These data can
be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 97 (2014)
1281
Table 4. Crystallographic Data for Compound 8d
Empirical formula
CCDC No.
Formula weight
Temp. [K]
Wavelength [ꢂ]
Crystal system
Space group
Unit cell dimensions:
a [ꢂ]
C20H17Cl2N3O4
949755
434.27
293(2)
0.71073
Monoclinic
P21/n
11.516(2)
16.498(3)
12.093(2)
90.00
b [ꢂ]
c [ꢂ]
a [8]
b [8]
g [8]
118.28(3)
90.00
Volume [ꢂ3]
Z
2023.3(7)
4
1.426
0.353
896
1calc. [g cmꢀ3
]
m [mmꢀ1
F(000)
]
Crystal size [mm3]
0.10 ꢁ 0.20 ꢁ 0.30
2.01 to 25.36
0 ꢂ h ꢂ 13,
q Range [8] for data collection
Index ranges
0 ꢂ k ꢂ 19,
ꢀ 14 ꢂ l ꢂ 12
Reflections collected
3899
Independent reflections
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
3709 (Rint ¼ 0.0921)
0.9656/0.9015
3709/0/262
1.006
Final R indices [I > 2s(I)]; R1, wR2
R1, wR2 (all data)
0.0627, 0.1601
0.1026, 0.1799
0.224 and ꢀ 0.351
Largest diff. peak and hole [e · ꢂꢀ3
]
[38][39]. All non-H-atoms were refined anisotropically, and the H-atoms were added at calculated
positions. The isotropic temp. factors were fixed to 1.2 times (1.5 times for Me group) the equivalent
isotropic displacement parameters of the C-atom the H-atom is attached to.
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Received November 16, 2013