Synthesis, crystal structure, and fungicidal activity of novel 1,5-Diaryl-1H-pyrazol-3-oxyacetate derivatives

Article abstract of DOI:10.1002/jhet.424

A series of ethyl 2-(1,5-diaryl-1H-pyrazol-3-yloxy)acetate derivatives (5a-5i) have been efficiently synthesized by the reaction of 1,5-diaryl-1H-pyrazol-3-ols (4a-4i) with ethyl 2-bromoacetate. The structures of the newly synthesized compounds were characterized by ¹H NMR spectra and elemental analysis, and the crystal structure of the compound ethyl 2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yloxy)acetate (5c) was determined by single crystal X-ray diffraction analysis. The compound 5c belongs to triclinic system with space group P(-1), a = 5.8170(12) A, b = 11.804(2) A, c = 12.783(2) A, α = 83.89(2)°, β = 89.24(3)°, γ = 89.73(3)°, Formula weight: 356.80, Triclinic V = 872.7(3) A³, D_c = 1.358 mg/m³, Z = 2, F (000) = 372. Bioassay results indicated that the compound ethyl 2-(5-(4-fluorophenyl)-1- phenyl-1H-pyrazol-3-yloxy)acetate (5d) exhibited moderate inhibitory activity against Gibberella zeae at the dosage of 10 μg/mL.

Full text of DOI:10.1002/jhet.424

July 2010
Synthesis, Crystal Structure, and Fungicidal Activity of Novel
1,5-Diaryl-1H-pyrazol-3-oxyacetate Derivatives
897
Yuanyuan Liu, Hong Shi, Yufeng Li, and Hongjun Zhu*
Department of Applied Chemistry, College of Science, Nanjing University of Technology, Nanjing
210009, People’s Republic of China
*E-mail: zhuhjnjut@hotmail.com
Received October 17, 2009
DOI 10.1002/jhet.424
Published online 17 June 2010 in Wiley InterScience (www.interscience.wiley.com).
A series of ethyl 2-(1,5-diaryl-1H-pyrazol-3-yloxy)acetate derivatives (5a–5i) have been efficiently
synthesized by the reaction of 1,5-diaryl-1H-pyrazol-3-ols (4a–4i) with ethyl 2-bromoacetate. The struc-
tures of the newly synthesized compounds were characterized by H NMR spectra and elemental analy-
1
sis, and the crystal structure of the compound ethyl 2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-
yloxy)acetate (5c) was determined by single crystal X-ray diffraction analysis. The compound 5c
˚
˚
belongs to triclinic system with space group P(-1), a ¼ 5.8170(12) A, b ¼ 11.804(2) A, c ¼ 12.783(2)
3
ꢀ
ꢀ
ꢀ
˚
˚
A, a ¼ 83.89(2) , b ¼ 89.24(3) , c ¼ 89.73(3) , Formula weight: 356.80, Triclinic V ¼ 872.7(3) A ,
Dc ¼ 1.358 mg/m3, Z ¼ 2, F (000) ¼ 372. Bioassay results indicated that the compound ethyl 2-(5-(4-
fluorophenyl)-1-phenyl-1H-pyrazol-3-yloxy)acetate (5d) exhibited moderate inhibitory activity against
Gibberella zeae at the dosage of 10 lg/mL.
J. Heterocyclic Chem., 47, 897 (2010).
INTRODUCTION
Then the reaction of arylpropiolic acids and their esters
with phenylhydrazine became one of the most popular
methods for the synthesis of 1,5-diaryl-1H-pyrazol-3-ols
[8–11]. In recent years, synthesis of 1,5-diaryl-1H-pyra-
zol-3-ols by the reactions of 4-arylidene-1-phenyl-3,5-
pyrazolidinediones with oxidizing agents has been
achieved [12]. However, very few representatives of
biologically active 1,5-diaryl-1H-pyrazol-3-oxyacetate
derivatives have hitherto been described in the literature.
3-Arylacrylic acids and their esters are convenient and
easily available starting materials or intermediates for the
synthesis of a wide variety of heterocyclic compounds
[13,14]. In our previous studies, we have successfully
improved the procedure for the synthesis of 1,5-diaryl-
1H-pyrazol-3-ols by the reaction of methyl 3-arylacry-
lates with arylhydrazines in high yields and have
reported some crystal structures [15–17]. In continuation
of our program directed toward the synthesis of
Biological studies of the pyrazole nucleus have been
shown to posses a variety of biological activities such as
fungicidal [1], insecticidal [2], herbicidal [3], and plant
growth regulatory activities [4]. Furthermore, several bi-
ological studies have also pointed out the value of alky-
loxyacetate [5] and aryloxyacetate [6] as biologically
active groups. These findings primarily focused on
incorporating alkyloxyacetate and aryloxyacetate groups
with 1H-pyrazole derivatives in the hope of obtaining
compounds of potential insecticidal, fungicidal, and her-
bicidal activities.
1,5-Diaryl-1H-pyrazol-3-ols, one important kind of
1H-pyrazole derivatives, have been developed for their
synthesis since the early twentieth century. The first syn-
thesis of 1,5-diaryl-1H-pyrazol-3-ol from a pyrazolidone
derivative was published by Japp and Maitland [7].
C
V
2010 HeteroCorporation

898
Y. Liu, H. Shi, Y. Li, and H. Zhu
Vol 47
Scheme 1
biologically active novel 1,5-diaryl-1H-pyrazol-3-oxy-
acetate derivatives, we report herein the synthesis and
fungicidal activity of a series of novel ethyl 2-(1,5-dia-
ryl-1H-pyrazol-3-yloxy)acetates (5a–5i), and the single
crystal structure of the compound ethyl 2-(5-(4-chloro-
Figure 1. The molecular structure of 5c. [Color figure can be viewed
in the online issue, which is available at www.interscience.wiley.com.]
phenyl)-1-phenyl-1H-pyrazol-3-yloxy)acetate (5c).
A
preliminary in vitro bioassay indicated that some of these
newly synthesized compounds displayed fungicidal
activity.
optimize the reaction conditions, different organic sol-
vents, such as ethanol and DMF were tested in the syn-
thesis of 1,5-diphenyl-1H-pyrazol-3-ol (4a). When the
conversion was carried out using iron (III) chloride in
refluxing ethanol, the yield was low and the separation
of the product from the iron (II) salts was tedious. How-
ever, the conversion in DMF gave good results. More-
over, the most satisfactory result was obtained when the
reaction was stirred in DMF at 80ꢀC for 2 h, and then at
30ꢀC for another 20 h. The crude solid 1,5-diaryl-1H-
pyrazol-3-ols (4a–4i) were recrystallized from ethanol.
The reactions of 1,5-diaryl-1H-pyrazol-3-ols (4a–4i)
with ethyl 2-bromoacetate were carried out in a molar
ratio 1:1.1 in acetone as solvent, and all the reactions
were monitored by thin-layer chromatography (TLC).
The most satisfactory results were obtained when the
reactions were performed under hot acetone for 3 h. The
crude residues were purified via flash chromatography to
give the pure products ethyl 2-(1,5-diaryl-1H-pyrazol-3-
yloxy)acetates (5a–5i) (Scheme 3).
RESULTS AND DISCUSSION
Methyl 3-arylacrylates (1) (Scheme 1) were prepared
by the reaction of 3-arylacrylic acids with methanol,
using p-toluenesulfonic acid as catalyst. Intermediates
arylhydrazines (2) (Scheme 2) were prepared according
to the reported methods from the substituted anilines
through diazotization reactions [18].
A previous report by Gaede and McDermott [19]
described that addition of methylhydrazine to a variety
of haloalkyl-substituted a,b-unsaturated ethers could
give 1,5-disubstituted-3-hydroxypyrazoles. Motivated by
this finding, in our procedure, methyl 3-arylacrylates (1)
were allowed to react with arylhydrazines (2) in boiling
n-butanol in the presence of sodium methoxide to afford
1,5-diarylpyrazolidin-3-ones (3a–3i) (Scheme 3) as sole
isolable products. No other pyrazoline type compounds
could be detected in the crude products. It was found
that the desired mode of initial Michael addition to
methyl 3-arylacrylates (1) could be achieved. The crude
solid 1,5-diarylpyrazolidin-3-ones (3a–3i) were recrys-
tallized from ethyl acetate.
A suitable crystal of ethyl 2-(5-(4-chlorophenyl)-1-
phenyl-1H-pyrazol-3-yloxy)acetate (5c) was obtained by
dissolving the compound in ethyl acetate and evaporat-
ing the solvent slowly at room temperature for about 10
days. Its solid-state structure was determined by single
crystal X-ray diffraction. Details of the structure deter-
mination and refinement are given in the experiment
section. The drawing of the molecular structure with the
The conversions from 1,5-diarylpyrazolidin-3-ones
(3a–3i) to 1,5-diaryl-1H-pyrazol-3-ols (4a–4i) (Scheme
3) were carried out in organic solvents, using oxygen as
oxidizing agent and iron (III) chloride as catalyst. To
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Synthesis, Crystal Structure, and Fungicidal Activity of Novel 1,5-Diaryl-
1H-pyrazol-3-oxyacetate Derivatives
899
Table 2
Crystal data and structure refinement for 5c.
Empirical formula
Formula weight
Temperature (K)
Wavelength
C
19H17ClN2O3
356.80
293
˚
0.71073 A
Crystal system
Space group
Triclinic
P-1
˚
a (A)
5.8170(12)
11.804(2)
12.783(2)
83.89(2)
89.24(3)
89.73(3)
872.7(3)
2
˚
b (A)
˚
c (A)
a (ꢀ)
b (ꢀ)
c (ꢀ)
Figure 2. A partial packing diagram of 5c. [Color figure can be
viewed in the online issue, which is available at www.interscience.
wiley.com.]
3
˚
V (A )
Z
Dcalc (mg/m3)
1.358
0.239
Absorption coefficient (mmꢂ1
F (000)
Crystal size (mm)
)
372
0.10 ꢁ 0.10 ꢁ 0.20
atom-numbering scheme and higher occupancy in the
three-dimensional packing arrangement is shown in Fig-
ures 1 and 2. Hydrogen bond is shown as a dashed line.
Atomic coordinates of nonhydrogen atoms (ꢁ10ꢂ4) and
their thermal parameters are summarized in Table 1.
The crystal data and structure refinement of 5c are listed
in Table 2.
y range, deg
1.6–25.3
3480
Reflections collected
Independent reflections
Date/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2s(I)]
R1
3140(Rint ¼ 0.084)
3140/0/220
1.009
0.0671
0.1483
wR2
Final R indices (all date)
R1
wR2
The compounds 5a–5i were screened for activity
against two fungi, namely Gibberella zeae and Rhizocto-
nia cerealis, at a concentration of 10 lg/mL according
to a reported method [20]. As the results in Table 3
0.1104
0.1778
none
Extinction correction
Table 1
Atomic coordinates of nonhydrogen atoms (ꢁ10ꢂ4
show, most of the compounds have weak fungicidal ac-
tivity. Among these compounds, only compound 5d, in
which X is F group in position 4 of the phenyl ring and
Y is H, exhibited moderate inhibitory activity against
G. zeae. This might imply that the introduction of the F
group to the phenyl ring of 1H-pyrazoles was important
for its fungicidal activity. In terms of X, the substituents
with electron-attracting groups on the phenyl rings seem
to have somewhat higher fungicidal activity. For exam-
ple, compounds 5c and 5d showed better activity than
)
and their thermal parameters.
x
y
z
U(eq)
Cl
O1
O2
O3
N1
N2
C1
C2
2885(2)
16,539(5)
12,920(7)
13,728(5)
12,700(6)
11,051(5)
18,381(9)
16,191(10)
14,764(8)
15,430(7)
12,367(7)
10,561(7)
9752(6)
58,718(10)
ꢂ2205(3)
ꢂ1840(3)
437(3)
6585(10)
8826(2)
9270(3)
8980(2)
7229(2)
6779(2)
8956(4)
9100(4)
8947(3)
8637(3)
8241(3)
8479(3)
7514(3)
7255(3)
7898(3)
7686(3)
6843(3)
6195(3)
6398(3)
5682(3)
5333(3)
4273(3)
3566(3)
3911(3)
4976(3)
743(4)
689(11)
1065(19)
728(11)
545(11)
509(11)
960
935(3)
1659(3)
ꢂ3992(5)
ꢂ3413(4)
ꢂ1527(4)
ꢂ319(4)
979(3)
1696(3)
2124(3)
3022(3)
3104(3)
3959(3)
4762(3)
4710(3)
3842(3)
1660(3)
1285(3)
1245(3)
1601(4)
1983(4)
2025(3)
870(2)
C3
C4
606(16)
648(17)
534(12)
550(14)
468(12)
498(12)
585(16)
585(16)
524(12)
575(12)
554(12)
465(12)
516(12)
573(14)
642(16)
662(17)
579(16)
Table 3
C5
C6
Antifungal activity of newly synthesized compounds (% inhibition).
C7
C8
10 lg/mL
8028(6)
6091(7)
C9
Compounds
X
Y
G. zeae R. cerealis
C10
C11
C12
C13
C14
C15
C16
C17
C18
C19
4502(7)
4829(7)
5a
5b
5c
5d
5e
5f
5g
5h
5i
H
4-CH3
4-Cl
H
H
H
H
H
H
21.29
0.00
18.44
7.79
6739(7)
8317(7)
39.20
53.09
20.06
30.25
15.53
24.27
9.06
17.15
0.97
0.97
10,695(6)
8648(6)
8322(7)
10,066(8)
12,104(8)
12,425(7)
4-F
3,4,5-OCH3H3
3-F
H
4-CH(CH3)2 13.89
4-CH(CH3)2 14.20
4-CH(CH3)2 13.89
4-OCH3
4-F
1.62
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

900
Y. Liu, H. Shi, Y. Li, and H. Zhu
Vol 47
Scheme 3
nol (9 mL). Then, methanol was removed by distillation, and
methyl 3-arylacrylate 1 (30 mmol) was added. The mixture was
refluxed for 40 min, after which arylhydrazine 2 (33 mmol)
was added. The mixture was refluxed for another 8 h and then
left to cool to room temperature. It was then acidified with ace-
tic acid (36%), allowed to stand and filtered. The solid was
recrystallized from ethyl acetate to give the compounds 3a–3i.
1,5-Diphenylpyrazolidin-3-one (3a). White crystal; mp
compounds 5a and 5b. Switching the substituent Y from
H to isopropyl has no effective impact on the inhibition
rates. Furthermore, compound 5d with the F group
in position 4 of the phenyl ring showed better activity
than 5f.
1
159–161ꢀC; yield, 85%. H NMR (CDCl3, 300 MHz, ppm): d
EXPERIMENTAL
2.52 (q, J ¼ 3.33, 16.8 Hz, 1H, CH), 3.28 (q, J ¼ 9.18, 16.8
Hz, 1H, CH), 4.93 (q, J ¼ 3.36, 9.17 Hz, 1H, CH), 7.02–7.43
(m, 10H, Ar-H); Anal. Calcd for C15H14N2O: C 75.61, H 5.92,
N 11.76; found C 75.69, H 5.89, N 11.72.
1-Phenyl-5-p-tolylpyrazolidin-3-one (3b). White crystal;
mp 145–146ꢀC; yield, 82%. 1H NMR (CDCl3, 300 MHz,
ppm): d 2.38 (s, 3H, CH3), 2.50 (q, J ¼ 3.45, 16.82 Hz, 1H,
CH), 3.26 (q, J ¼ 9.12, 16.77 Hz, 1H, CH), 4.89 (q, J ¼ 3.48,
9.08 Hz, 1H, CH), 7.01–7.38 (m, 9H, Ar-H), 8.49 (s, 1H, NH);
Anal. Calcd for C16H16N2O: C 76.16, H 6.39, N 11.10; found
C 76.25, H 6.37, N 11.15.
All reagents were of analytical reagent grade or were chemi-
cally pure. All solvents were dried by standard methods and
distilled before use. Reactions were monitored by TLC. Ana-
lytical TLC was performed on silica gel GF254. Flash column
chromatography was carried out using 200–300 mesh silica gel
at increased pressure. G. zeae and R. cerealis were obtained
from Jiangsu Research and Development Center for Pesticides,
China.
The melting points were measured on an X-4 microscope
electrothermal apparatus (Taike, China) and were uncorrected.
Elemental analyses were determined on a Vario EL III ele-
mental analyzer. The 1H NMR (solvent CDCl3 or DMSO-d6)
spectra was obtained on a Bruker AV 500 or AV 300 spec-
trometer at room temperature using tetramethylsilane as an in-
ternal standard. Chemical shift values (d) are given in parts
per million. X-ray intensity data were recorded on a Bruker
SMART 1000 CCD diffraction meter using graphite mono-
5-(4-Chlorophenyl)-1-phenylpyrazolidin-3-one (3c). White
1
crystal; mp 160–162ꢀC; yield, 80%. H NMR (DMSO-d6, 300
MHz, ppm): d 2.25 (q, J ¼ 2.79, 16.71 Hz, 1H, CH), 3.18 (q,
J ¼ 9.03,16.71 Hz, 1H, CH), 5.07 (q, J ¼ 2.67, 9.03 Hz, 1H,
CH), 6.94–7.58 (m, 9H, Ar-H), 10.45 (s, 1H, NH); Anal. Calcd
for C15H13ClN2O: C 66.06, H 4.80, N 10.27; found C 66.15,
H 4.79, N 10.23.
˚
5-(4-Fluorophenyl)-1-phenylpyrazolidin-3-one (3d). Yellow
crystal; mp 158–159ꢀC; yield, 78%. 1HNMR (CDCl3, 300
MHz, ppm): d 2.50 (q, J ¼ 2.82, 16.77 Hz, 1H, CH), 3.31 (q,
J ¼ 9.06, 16.71 Hz, 1H, CH), 4.95 (q, J ¼ 2.82, 9 Hz, 1H,
chromated Mo Ka radiation (k ¼ 0.71073) A.
The synthesis of 1,5-diarylpyrazolidin-3-ones (3a–3i). A
mixture of n-butanol (40 mL) and ethanolamine (60 mmol) was
added to a solution of sodium (36 mmol) in anhydrous metha-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2010
Synthesis, Crystal Structure, and Fungicidal Activity of Novel 1,5-Diaryl-
1H-pyrazol-3-oxyacetate Derivatives
901
CH), 7.04–7.44 (m, 9H, Ar-H); Anal. Calcd for C15H13FN2O:
C 70.30, H 5.11, N 10.93; found C 70.22, H 5.10, N 10.98.
1-Phenyl-5-(3,4,5-trimethoxyphenyl)pyrazolidin-3-one
(3e). White crystal; mp 157–159ꢀC; yield, 78%. 1H NMR
(CDCl3, 500 MHz, ppm): d 2.54 (q, J ¼ 3.88, 16.82 Hz, 1H,
CH), 3.28 (q, J ¼ 9.26, 16.82 Hz, 1H, CH), 3.86 (s, 9H,
OCH3), 4.85 (q, J ¼ 3.76, 9.21 Hz, 1H, CH), 6.70–7.32 (m,
7H, Ar-H), 8.45 (s, 1H, NH); Anal. Calcd for C18H20N2O4: C
65.84, H 6.14, N 8.53; found C 65.76, H 6.12, N 8.58.
5-(3-Fluorophenyl)-1-phenylpyrazolidin-3-one (3f). Yellow
crystal; mp 165–167ꢀC; yield, 75%. 1H NMR (CDCl3, 500
MHz, ppm): d 2.50 (d, 1H, CH), 3.30 (q, J ¼ 9.15, 16.85 Hz,
1H, CH), 4.98 (d, 1H, CH), 7.03–7.40 (m, 9H, Ar-H), 8.41 (s,
1H, NH); Anal. Calcd for C15H13FN2O: C 70.30, H 5.11, N
10.93; found C 70.23, H 5.10, N 10.96.
1-(4-Isopropylphenyl)-5-phenylpyrazolidin-3-one (3g). Yellow
crystal; mp 136–137ꢀC; yield, 78%. 1H NMR (CDCl3, 500
MHz, ppm): d 1.22 (d, J ¼ 6.85 Hz, 6H, CH3), 2.50 (q, J ¼
3.35, 16.75 Hz, 1H, CH), 2.86 (m, 1H, CH), 3.26 (q, J ¼
9.15,16.75 Hz, 1H, CH), 4.87 (q, J ¼ 3.35, 8.98 Hz, 1H, CH),
6.99–7.48 (m, 9H, Ar-H); Anal. Calcd for C18H20N2O: C
77.11, H 7.19, N 9.99; found C 77.05, H 7.21, N 9.94.
1-(4-Isopropylphenyl)-5-(4-methoxyphenyl)pyrazolidin-3-
one (3h). Yellow crystal; mp 143–145ꢀC; yield, 81%. 1H
NMR (CDCl3, 500 MHz, ppm): d 1.22 (d, J ¼ 6.90 Hz, 6H,
CH3), 2.55 (m, 1H, CH), 2.87 (m, 1H, CH), 3.21 (m, 1H, CH),
3.83 (s, 3H, OCH3), 4.82 (m, 1H, CH), 6.92–7.39 (m, 8H, Ar-
H); Anal. Calcd for C19H22N2O2: C 73.52, H 7.14, N 9.03;
found C 73.46, H 7.16, N 8.99.
5-(4-Fluorophenyl)-1-(4-isopropylphenyl)pyrazolidin-3-one
(3i). Yellow crystal; mp 126–127ꢀC; yield, 79%. 1H NMR
(CDCl3, 300 MHz, ppm): d 1.25 (d, J ¼ 6.87 Hz, 6H, CH3),
2.52 (q, J ¼ 3.78, 16.82 Hz, 1H, CH), 2.89 (m, 1H, CH), 3.33
(q, J ¼ 9.12, 16.8 Hz, 1H, CH), 4.87 (q, J ¼ 3.69, 9.14 Hz,
1H, CH), 6.94–7.19 (m, 8H, Ar-H); Anal. Calcd for
C18H19FN2O: C 72.46, H 6.42, N 9.39; found C 72.42, H
6.44, N 9.35.
1,5-Diaryl-1H-pyrazol-3-ols (4a–4i). Using oxygen as oxi-
dizing agent, compound 3a–3i (10 mmol) was dissolved in
DMF (40 mL) and mixed with FeCl3 (0.162 g, 1 mmol). The
mixture was heated to 80ꢀC and maintained at that temperature
for 2 h, and then stirred at 30ꢀC for another 20 h. The reaction
mixture was then poured into water (500 mL) with good stirring.
The precipitate which formed was filtered off, washed with
water and dried under reduced pressure. The crude product was
then recrystallized from ethanol to give the compounds 4a–4i.
1,5-Diphenyl-1H-pyrazol-3-ol (4a). White crystal; mp 258–
259ꢀC; yield, 81%. 1H NMR (DMSO-d6, 300 MHz, ppm): d
5.92 (s, 1H, CH), 7.14–7.33 (m, 10H, Ar-H), 10.36 (s, 1H,
OH); Anal. Calcd for C15H12N2O: C 76.25, H 5.12, N 11.86;
found C 75.32, H 5.09, N 11.82.
5-(4-Fluorophenyl)-1-phenyl-1H-pyrazol-3-ol (4d). White
crystal; mp 266–267ꢀC; yield, 81%. 1H NMR (CDCl3, 300
MHz, ppm): d 5.90 (s, 1H, CH), 6.98–7.33 (m, 9H, Ar-H),
11.35 (s, 1H, OH); Anal. Calcd for C15H11FN2O: C 70.86, H
4.36, N 11.02; found C 70.78, H 4.34, N 11.06.
1-Phenyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazol-3-ol
(4e). Brown crystal; mp 203–205ꢀC; yield, 85%. 1H NMR
(DMSO-d6, 500 MHz, ppm): d 3.62 (s, 9H, OCH3), 5.97 (s,
1H, CH), 6.46 (s, 2H, Ar-H), 7.21–7.39 (m, 5H, Ar-H), 10.09
(s, 1H, OH); Anal. Calcd for C18H18N2O4: C 66.25, H 5.56, N
8.58; found C 66.29, H 5.55, N 8.53.
5-(3-Fluorophenyl)-1-phenyl-1H-pyrazol-3-ol (4f). White
crystal; mp 274–275ꢀC; yield, 78%. 1H NMR (CDCl3, 300
MHz, ppm): d 6.45 (s, 1H, CH), 6.90–7.35 (m, 9H, Ar-H);
Anal. Calcd for C15H11FN2O: C 70.86, H 4.36, N 11.02; found
C 70.78, H 4.35, N 11.06.
1-(4-Isopropylphenyl)-5-phenyl-1H-pyrazol-3-ol (4g). Yellow
crystal; mp 203–205ꢀC; yield, 76%. 1H NMR (CDCl3, 500
MHz, ppm): d 1.24 (d, J ¼ 6.75 Hz, 6H, CH3), 2.90 (m, 1H,
CH), 5.90 (s, 1H, CH), 7.14–7.28 (m, 9H, Ar-H); Anal. Calcd
for C18H18N2O: C 77.67, H 6.52, N 10.06; found C 77.60, H
6.49, N 10.09.
1-(4-Isopropylphenyl)-5-(4-methoxyphenyl)-1H-pyrazol-3-
1
ol (4h). Yellow crystal; mp 193–194ꢀC; yield, 72%. H NMR
(CDCl3, 500 MHz, ppm): d 1.25 (d, J ¼ 7.00 Hz, 6H, CH3),
2.90 (m, 1H, CH), 3.80 (s, 3H, OCH3), 5.86 (s, 1H, CH),
6.80–7.26 (m, 8H, Ar-H); Anal. Calcd for C19H20N2O2: C
74.00, H 6.54, N 9.08; found C 73.94, H 6.53, N 9.12.
5-(4-Fluorophenyl)-1-(4-isopropylphenyl)-1H-pyrazol-3-ol
(4i). Yellow crystal; mp 225–227ꢀC; yield, 78%. 1H NMR
(CDCl3, 300 MHz, ppm): d 1.21 (d, J ¼ 6.96 Hz, 6H, CH3),
2.85 (m, 1H, CH), 6.34 (s, 1H, CH), 6.90–7.26 (m, 8H, Ar-H);
Anal. Calcd for C18H17FN2O: C 72.95, H 5.78, N 9.45; found
C 72.88, H 5.76, N 9.42.
Ethyl 2-(1,5-diaryl-1H-pyrazol-3-yloxy)acetates (5a–5i). To
a solution of 4a–4i (10 mmol) in acetone (30 mL) was added
potassium carbonate (2.07 g, 15 mmol). Then, the mixture was
refluxed and ethyl 2-bromoacetate (1.84 g, 11 mmol) was
added slowly. The mixture was refluxed and monitored by
TLC for about 3 h. The potassium carbonate was filtered off
and the solvent was evaporated under reduced pressure. After
the removal of the solvent, the residue was chromatographed
over silica gel (500 g) eluting with a mixture of ethyl acetate
and petroleum ether to gain the target compounds 5a–5i.
Ethyl 2-(1,5-diphenyl-1H-pyrazol-3-yloxy)acetate (5a). White
1
crystal; mp 79–80ꢀC; yield, 89%. H NMR (CDCl3, 300 MHz,
ppm): d 1.31 (t, J ¼ 7.17, 14.25 Hz, 3H, CH3), 4.28 (q, J ¼
7.17, 14.28 Hz, 2H, CH2), 4.88 (s, 2H, CH2), 6.04 (s, 1H,
CH), 7.20–7.27 (m, 10H, Ar-H); Anal. Calcd for C19H18N2O3:
C 70.79, H 5.63, N 8.69; found C 70.72, H 5.62, N 8.73.
Ethyl 2-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yloxy)acetate
(5b). White crystal; mp 106–107ꢀC; yield, 85%. 1H NMR
(CDCl3, 500 MHz, ppm): d 1.30 (t, J ¼ 7.15, 14.25 Hz, 3H,
CH3), 2.33 (s, 3H, CH3), 4.28 (q, J ¼ 7.15, 14.28 Hz, 2H,
CH2), 4.86 (s, 2H, CH2), 6.00 (s, 1H, CH), 7.09–7.29 (m, 9H,
Ar-H); Anal. Calcd for C20H20N2O3: C 71.41, H 5.99, N 8.33;
found C 71.34, H 5.97, N 8.28.
Ethyl 2-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-ylox-
y)acetate (5c). Yellow crystal; mp 51–52ꢀC; yield, 88%. 1H
NMR (CDCl3, 300 MHz, ppm): d 1.30 (t, J ¼ 7.20, 14.28 Hz,
3H, CH3), 4.28 (q, J ¼ 7.20, 14.19 Hz, 2H, CH2), 4.86 (s, 2H,
1-Phenyl-5-p-tolyl-1H-pyrazol-3-ol (4b). White crystal; mp
1
254–255ꢀC; yield, 84%. H NMR (CDCl3, 300 MHz, ppm): d
2.33 (s, 3H, CH3), 5.89 (s, 1H, CH), 7.09–7.36 (m, 9H, Ar-H);
Anal. Calcd for C16H14N2O: C 76.78, H 5.64, N 11.19; found
C 76.69, H 5.63, N 11.25.
5-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-3-ol (4c). White
crystal; mp 285–286ꢀC; yield, 82%. 1H NMR (CDCl3, 300
MHz, ppm): d 5.92 (s, 1H, CH), 7.13–7.46 (m, 9H, Ar-H);
Anal. Calcd for C15H11ClN2O: C 66.55, H 4.10, N 10.35;
found C 66.46, H 4.08, N 10.38.
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DOI 10.1002/jhet

902
Y. Liu, H. Shi, Y. Li, and H. Zhu
Vol 47
CH2), 6.03 (s, 1H, CH), 7.13–7.38 (m, 9H, Ar-H); Anal. Calcd
for C19H17ClN2O3: C 63.96, H 4.80, N 7.85; found C 63.88, H
4.82, N 7.82.
Ar-H); Anal. Calcd for C22H23FN2O3: C 69.09, H 6.06, N
7.33; found C 69.15, H 6.11, N 7.31.
Ethyl 2-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-ylox-
y)acetate (5d). White crystal; mp 76–77ꢀC; yield, 81%. 1H NMR
(CDCl3, 500 MHz, ppm): d 1.33 (t, J ¼ 7.15, 14.3 Hz, 3H, CH3),
4.31 (q, J ¼ 7.15, 14.2 Hz, 2H, CH2), 4.90 (s, 2H, CH2), 6.08 (s,
1H, CH), 7.01–7.28 (m, 9H, Ar-H); Anal. Calcd for C19H17FN2O3:
C 67.05, H 5.03, N 8.23; found C 67.14, H 5.04, N 8.19.
Ethyl 2-(1-phenyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrazol-
3-yloxy)acetate (5e). Yellow crystal; mp 75–76ꢀC; yield,
84%. 1H NMR (CDCl3, 500 MHz, ppm): d 1.21 (t, J ¼ 7,
14.2 Hz, 3H, CH3), 3.58 (s, 6H, OCH3), 3.65 (s, 3H, OCH3),
4.17 (q, J ¼ 7.2, 14.2 Hz, 2H, CH2), 4.83 (s, 2H, CH2), 6.26
(s, 1H, CH), 6.49 (s, 2H, Ar-H), 7.22–7.39 (m, 5H, Ar-H);
Anal. Calcd for C22H24N2O6: C 64.07, H 5.87, N 6.79; found
C 63.98, H 5.85, N 6.75.
Ethyl 2-(5-(3-fluorophenyl)-1-phenyl-1H-pyrazol-3-ylox-
y)acetate (5f). White crystal; mp 67–68ꢀC; yield, 81%. 1H
NMR (CDCl3, 500 MHz, ppm): d 1.30 (t, J ¼ 7.2, 14.25 Hz,
3H, CH3), 4.28 (q, J ¼ 7, 14.35 Hz, 2H, CH2), 4.87 (s, 2H,
CH2), 6.05 (s, 1H, CH), 6.91–7.27 (m, 9H, Ar-H); Anal. Calcd
for C19H17FN2O3: C 67.05, H 5.03, N 8.23; found C 67.14, H
5.04, N 8.20.
REFERENCES AND NOTES
[1] Vicentini, C. B.; Romagnoli, C.; Andreotti, E.; Mares, D.
J Agric Food Chem 2007, 55, 10331.
[2] Meegalla, S. K.; Doller, D.; Sha, D.; Soll, R.; Wisnewski,
N.; Silver, G. M.; Dhanoa, D. Bioorg Med Chem Lett 2004, 14, 4949.
[3] Morimoto, K.; Makino, K.; Yamamoto, S.; Sakata, G.
J Heterocycl Chem 1990, 27, 807.
[4] Sohn, E.; Handte, R.; Mildenberger, H.; Buerstell, H.;
Bauer, K.; Bieringer, H. Ger. Pat.3,633,840 (1988); Chem Abstr 1989,
110, 8202.
[5] Tohyama, Y.; Sanemitsu, Y. Eur. Pat.1,122,244 (2001);
Chem Abstr 2001, 135, 152820.
[6] Ono, R.; Nagaoka, M.; Yamada, O.; Tokumura, J. Jpn.
Pat.2,008,120,736 (2008); Chem Abstr 2008, 149, 10016.
[7] Japp, F. R.; Maitland, W. J Chem Soc Trans 1904, 85,
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[8] Al-Jallo, H. N. A. Tetrahedron Lett 1970, 11, 875.
[9] Al-Jallo, H.; Shandala, M.; Al-Hajjar, F.; Al-Jabour, N. J
Heterocycl Chem 1976, 13, 455.
[10] Baddar, F. G.; El-Newaihy, M. F.; Salem, M. R. J Chem
Soc 1969, 5, 836.
Ethyl 2-(1-(4-isopropylphenyl)-5-phenyl-1H-pyrazol-3-
yloxy)acetate (5g). Yellow crystal; mp 133–134ꢀC; yield,
[11] Selwood, D. L.; Brummell, D. G.; Budworth, J.; Burtin, G.
E.; Campbell, R. O.; Chana, S. S.; Charles, I. G.; Fernandez, P. A.;
Glen, R. C.; Goggin, M. C.; Hobbs, A. J.; Kling, M. R.; Liu, Q.;
Madge, D. J.; Millerais, S.; Powell, K. L.; Reynolds, K.; Spacey, G.
D.; Stables, J. N.; Tatlock, M. A.; Wheeler, K. A.; Wishart, G.; Woo,
C.-K. J Med Chem 2001, 44, 78.
1
88%. H NMR (CDCl3, 500 MHz, ppm): d 1.22 (d, J ¼ 6.85
Hz, 6H, CH3), 1.30 (t, J ¼ 7.15, 14.3 Hz, 3H, CH3), 2.87 (q, J
¼ 7, 13.8 Hz, 1H, CH), 4.28 (q, J ¼ 7.15, 14.15 Hz, 2H,
CH2), 4.87 (s, 2H, CH2), 6.02 (s, 1H, CH), 7.12–7.29 (m, 9H,
Ar-H); Anal. Calcd for C22H24N2O3: C 72.50, H 6.64, N 7.69;
found C 72.43, H 6.66, N 7.66.
[12] Metwally, S. A. M.; Mohamed, T. A.; Moustafa, O. S.; El-
Ossaily, Y. A. Chem Heterocycl Compd 2007, 43, 1131.
[13] Baumgartner, C.; Brandli, L.; Diederich, F. Heterocycles
2008, 76, 401.
Ethyl 2-(1-(4-isopropylphenyl)-5-(4-methoxyphenyl)-
1H-pyrazol-3-yloxy)-acetate (5h). Yellow crystal; mp
1
[14] Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S.;
Foces-Foces, C.; Llamas-Saiz, A. L.; Jagerovic, N.; Elguero, J. Tetra-
hedron 1999, 55, 10187.
127–128ꢀC; yield, 83%. H NMR (CDCl3, 500 MHz, ppm): d
1.22 (d, J ¼ 6.8 Hz, 6H, CH3), 1.30 (t, J ¼ 7.15, 14.25 Hz,
3H, CH3), 2.88 (t, J ¼ 6.8, 13.75 Hz, 1H, CH), 3.80 (s, 3H,
OCH3), 4.28 (q, J ¼ 7.15, 14.25 Hz, 2H, CH2), 4.86 (s, 2H,
CH2), 5.96 (s, 1H, CH), 6.81–7.26 (m, 8H, Ar-H); Anal. Calcd
for C23H26N2O4: C 70.03, H 6.64, N 7.10; found C 70.12, H
6.67, N 7.08.
[15] Liu, Y.-Y.; Wu, Z.-Y.; Shi, H.; Chu, Q.-Y.; Zhu, H.-J. Acta
Crystallogr Sect E 2008, 64, o2101.
[16] Liu, Y.-Y.; Shi, H.; Chu, Q.-Y.; Zhu, H.-J. Acta Crystallogr
Sect E 2008, 64, o1886.
[17] Sun, Y.-F.; Jia, H.-S.; Liu, S.; Zhu, H.-J. Acta Crystallogr
Sect E 2007, 63, o3397.
Ethyl 2-(5-(4-fluorophenyl)-1-(4-isopropylphenyl)-1H-pyr-
azol-3-yloxy)-acetate (5i). Yellow crystal; mp 81–82ꢀC; yield,
[18] Czeskis, B. A.; Wheeler, W. J. J Labelled Comp Radio-
pharm 2005, 48, 407.
1
89%. H NMR (CDCl3, 500 MHz, ppm): d 1.22 (d, J ¼ 6.75
Hz, 6H, CH3), 1.30 (t, J ¼ 7.2, 14.2 Hz, 3H, CH3), 2.88 (q, J
¼ 6.85, 13.8 Hz, 1H, CH), 4.15 (q, J ¼ 7.15, 14.18 Hz, 2H,
CH2), 4.83 (s, 2H, CH2), 6.19 (s, 1H, CH), 7.07–7.26 (m, 8H,
[19] Gaede, B. J.; McDermott, L. L. J Heterocycl Chem 1993, 30, 49.
[20] Ren, Q.-Y.; Cui, Z.-P.; He, H.-W.; Gu, Y.-C. J Fluor Chem
2007, 128, 1369.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet