4-Functionally-substituted 3-heterylpyrazoles: XIX. 3-aryl-4-(5-isoxazolyl) pyrazoles

Article abstract of DOI:10.1007/s11178-008-2010-y

Oximes of 4-(4-pyrazolyl)-3-buten-2-onees obtained by successive reaction of 3-aryl-4-formylpyrazoles with acetone and hydroxylamine at the treatment with iodine suffered an oxidative cyclization yielding 3-aryl-4-(5-isoxazolyl) pyrazoles.

Full text of DOI:10.1007/s11178-008-2010-y

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 2, pp. 247−250. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © M.K. Bratenko, Yu.V. Kadel’nik, V.A. Chornous, M.V. Vovk, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44,
No. 2, pp. 256−258.
4-Functionally-Substituted 3-Heterylpyrazoles: XIX.*
3-Aryl-4-(5-Isoxazolyl)pyrazoles
M. K. Bratenkoa, Yu. V. Kadel’nika, V. A. Chornousa, and M. V. Vovkb
aBukovina State Medical University, Chernovtsy, Ukraine
bInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, 02094 Ukraine
e-mail: chornous@inbox.ru
Received April 10, 2007
Abstract—Oximes of 4-(4-pyrazolyl)-3-buten-2-onees obtained by successive reaction of 3-aryl-4-formylpyrazoles
with acetone and hydroxylamine at the treatment with iodine suffered an oxidative cyclization yielding 3-aryl-4-
(5-isoxazolyl)pyrazoles.
DOI: 10.1134/S1070428008020103
1
The designing of new types of polyheterocyclic
IIIa–IIIf. Analysis of H NMR spectra of α,β-vinyl
compounds alongside the refining of procedures for
preparation of these known substances is an urgent target
of the modern heterocyclic chemistry. Many among the
heterocyclic ensembles are both convenient models for
investigating the interaction of heterofragments and
structures with potential high biological activity. The
analysis of published data shows the high promise of
purposeful synthetic search in the series of heteryl-
substituted pyrazoles. In particular, pyrazole derivatives
already were formerly obtained containing in the position
4 oxazoline [2], dihydropyridine [3], pyrazoline [4, 5],
dihydropyrimidine [6], and benzopyran [7] fragments.
ketones Ia–If indicted that they existed exclusively in
the form of Ε-isomers. Yet their oximes formed as Ε,Z-
and Ε,Ε-isomers, the fact previously unknown for 4-aryl-
3-buten-2-ones [11–13]. This fact is proved by a double
set of signals from protons H5 of the pyrazole ring and
from groups CH3 and OH. Taking into account the data
of [11, 12] it is possible to assume reliably that in the
case in question prevailingly form Ε,Z-isomers more
stereochemically favorable for further cyclization: The
content of these isomers varies in the range 81–85%.
The preferable procedure for conversion of oximes IIIa–
IIIf into target 4-(5-isoxazolyl)pyrazoles IVa–IVf
Here we report on investigation results on the syn-
thesis of new pyrazole derivatives functionalized in the
position 4 with pharmacologically significant [8]
isoxazole ring. The information on similar compounds
is limited to [9, 10] where the building up of pyrazole or
isoxazole rings respectively occurs based on relatively
difficultly available isoxazolyl- or pyrazolyl-β-diketones.
The condensation of more accessible β-(1,3-diphenyl-
pyrazolyl)-α-ethyl vinyl ketone with hydroxylamine how-
ever provided only 4-(4,5-dihydroisoxazolyl)-1,5-
diphenylpyrazole [4].
CH3
CHO
Ar
O
Ar
Me2CO
_H2O
N
N
N
N
Ph
Ph
_
_
Ià Iå
IIà IIf
H3C
N
O
CH3
We found that β-(1,3-diphenylpyrazolyl)-α-ethyl vinyl
ketones Ia–If obtained by condensation of 3-aryl-4-
formylpyrazoles IIa–IIf with acetone in reaction with
hydroxylamine hydrochloride in boiling pyridine did not
form a 4,5-dihydroisoxazole ring but give stable oximes
Ar
Ar
N
I2
NH2OH
OH
N
N
N
N
Ph
Ph
_
_
IIIà IIIf
IVà IVf
Ar = Ph (a), 4-FC6H4 (b), 4-ClC6H4 (c), 4-MeC6H4 (d),
4-ΕtC6H4 (e), 4-MeOC6H4 (f).
* For communication XVIII, see [1].
247

BRATENKO et al.
248
1
cm–1: 1660 (C=O). H NMR spectrum, δ, ppm: 2.22 s
(3H, CH3), 2.27 C (3H, CH3), 6.74 d (1H, H2, J 16.2 Hz),
7.32–7.53 m (6H, 5Harom+H1), 7.63 d (2Harom, J 8.2 Hz),
7.92 d (2Harom, J 7.8 Hz), 9.16 s (1H, H5pyrazole). Found,
%: C 79.42; H 6.09; N 9.13. C20H18N2O. Calculated, %:
C 79.47; H 5.96; N 9.27.
proved to be the oxidative cyclization by means of iodine
[13]. The application of a system I2–KI–NaHCO3 in
boiling DMF made it possible to obtain compounds IVa–
IVf in 58–71% yields.
The structure of 4-isoxazolopyrazoles IV was
confirmed by 1H NMR spectra where along with typical
signals of aromatic and methyl substituents were
observed the singlet of proton H4 from the isoxazole ring
(6.19–6.29 ppm) and proton H5 of the pyrazole ring
(8.90–9.11 ppm).
4-[1-Phenyl-3-(4-ethyl)-4-pyrazolyl]-3-buten-2-
one (Ie). Yield 72%, mp 119–120°C. IR spectrum, cm–1:
1665 (C=O). H NMR spectrum, δ, ppm: 1.27 t (3H,
CH3, J 7.5 Hz), 2.27 s (3H, CH3), 2.70 q (2H, CH2,
J 7.5 Hz), 6.73 d (1H, H2, J 16.5 Hz), 7.27–7.54 m (8H,
7Harom+H1), 7.92 d (2Harom), 9.16 s (1H, H5pyrazole). Found,
%: C 80.04; H 6.29; N 8.95. C21H20N2O. Calculated, %:
C 79.75; H 6.33; N 8.86.
1
EXPERIMENTAL
IR spectra of compounds were recorded on
a spectrophotometer UR-20 from KΒr pellets. 1H NMR
spectra were registered on a spectrometer Varian-Gemini
(300 MHz) in (CD3)2SO, internal referece TMS.
4-[3-(4-Methoxyphenyl)-1-phenyl-4-pyrazolyl]-3-
buten-2-one (If). Yield 71%, mp 135–136°C. IR
spectrum, cm–1: 1660 (C=O). 1H NMR spectrum, δ, ppm:
2.26 s (3H, CH3), 3.84 C (3H, CH3O), 6.72 d (1H, H2,
J 16.2 Hz), 7.05 d (2Harom, J 8.8 Hz), 7.35–7.56 m (6H,
5Harom+H1), 7.91 d (2H, Harom, J 8.8 Hz), 9.12 s (1H,
H5pyrazole). Found, %: C 75.32; H 5.76; N 8.64.
C20H18N2O2. Calculated, %: C 75.47; H 5.66; N 8.81.
4-(4-Pyrazolyl)-3-buten-2-ones Ia–If. To a solution
of 40 mmol of aldehyde IIa–IIf in 50 ml of acetone was
added at stirring 5 ml of 10% water solution of NaOH,
the mixture was stirred at room temperature for 12 h,
then into the reaction mixture 200 ml of ice water was
poured. The separated precipitate was filtered off, washed
with dilute hydrochloric acid, dried, and recrystallized
from ethanol.
4-(4-Pyrazolyl)-3-buten-2-ones oximes IIIa–IIIf.
To a solution of 10 mmol of vinyl ketone Ia–If in 20 ml
of pyridine was added 1.39 g (20 mmol) of hydroxyl-
amine hydrochloride, and the mixture was boiled at reflux
for 3 h. On cooling to room temperature the reaction
mixture was poured into 100 ml of ice water, the
separated precipitate was filtered off, washed with 10%
hydrochloric acid, dried, and crystallized from ethanol.
4-(1,3-Diphenyl-4-pyrazolyl)-3-buten-2-one (Ia).
Yield 73%, mp 124–126°C. IR spectrum, cm–1: 1665
1
(C=O). H NMR spectrum, δ, ppm: 2.26 s (3H, CH3),
6.71 d (1H, H2, J 16.0 Hz), 7.05–7.64 m (11H, Harom+H1),
9.17 s (1H, H5pyrazole). Found, %: C 78.89; H 5.67; N
9.60. C19H16N2O. Calculated, %: C 79.16; H 5.56; N
9.72.
4-(1,3-Diphenyl-4-pyrazolyl)-3-buten-2-one oxime
(IIIa). Yield 83%, mp 150–152°C. IR spectrum, cm–1:
1630 (C=N), 3280 (OH). H NMR spectrum, δ, ppm:
1.95 s, 1.99 s (3H, CH3), 6.72 d (1H, =CHA, J 15.5 Hz),
6.79 d (1H, =CHΒ, J 15.5 Hz), 7.30–7.51 m (6Harom),
7.65 d (2Harom, J 6.9 Hz), 7.91 d (2Harom, J 7.1 Hz), 8.94 s,
9.01 s (1H, H5pyrazole), 10.08 s, 10.96 s (1H, OH). Found,
%: C 75.49; H 5.44; N 14.05. C17H17N3O. Calculated,
%: C 75.25; H 5.61; N 13.86.
1
4-[1-Phenyl-3-(4-fluorophenyl)-4-pyrazolyl]-3-
buten-2-one (Ib). Yield 81%, mp 142–143°C. IR
spectrum, cm–1: 1665 (C=O). 1H NMR spectrum, δ, ppm:
2.27 s (3H, CH3), 6.73 d (1H, H2, J 16.2 Hz), 7.29–
7.93 m (10H, 9Harom+H1), 9.16 s (1H, H5pyrazole). Found,
%: C 74.23; H 5.03; N 9.02. C19H15FN2O. Calculated,
%: C 74.51; H 4.90; N 9.15.
4-[1-Phenyl-3-(4-chlorophenyl)-4-pyrazolyl]-3-
buten-2-one (Ic). Yield 78%, mp 139–141°C. IR
spectrum, cm–1: 1670 (C=O). 1H NMR spectrum, δ, ppm:
2.28 s (3H, CH3), 6.73 d (1H, H2, J 16.2 Hz), 7.32–
7.56 m (6H, 5Harom+H1), 7.68 d (2H, Harom, J 8.4 Hz),
7.91 d (2Harom, J 8.2 Hz), 9.16 s (1H, H5pyrazole). Found,
%: C 70.48; H 4.61; N 8.57. C19H15ClN2O. Calculated,
%: C 70.70; H 4.65; N 8.68.
4-[1-Phenyl-3-(4-fluorophenyl)-4-pyrazolyl]-3-
buten-2-one oxime (IIIb). Yield 85%, mp 224–226°C.
IR spectrum, cm–1: 1625 (C=N), 3285 (OH). 1H NMR
spectrum, δ, ppm: 1.93 s, 1.98 s (3H, CH3), 6.70 d (1H,
=CHA, J 15.6 Hz), 6.77 d (1H, =CHΒ, J 15.6 Hz), 7.25–
7.90 m (9Harom), 8.92 s, 8.98 s (1H, H5pyrazole), 10.64 s,
10.78 s (1H, OH). Found, %: C 70.77; H 5.14; N 13.32.
C19H16FN3O. Calculated, %: C 71.03; H 4.98; N 13.08.
4-[3-(4-Tolyl)-1-phenyl-4-pyrazolyl]-3-buten-2-
4-[1-Phenyl-3-(4-chlorophenyl)-4-pyrazolyl]-3-
one (Id). Yield 76%, mp 140–142°C. IR spectrum,
buten-2-one oxime (IIIc). Yield 87%, mp 248–250°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

4-FUNCTIONALLY-SUBSTITUTED 3-HETERYLPYRAZOLES: XIX.
249
1
IR spectrum, cm–1: 1625 (C=N), 3290 (OH). H NMR
spectrum, δ, ppm: 1.95 s, 1.99 s (3H, CH3), 6.74 d (1H,
=CHA, J 15.6 Hz), 6.80 d (1H, =CHΒ, J 15.6 Hz), 7.29–
7.97 m (9Harom), 8.93 s, 9.01 s (1H, H5pyrazole), 10.68 s,
10.95 s (1H, OH). Found, %: C 67.82; H 4.85; N 12.59.
C19H16ClN3O. Calculated, %: C 67.56; H 4.74; N 12.44.
4-(3-Methyl-5-isoxazolyl)-1-phenyl-3-(4-fluoro-
phenyl)pyrazole (IVb). Yield 67%, mp 136–137°C.
1H NMR spectrum, δ, ppm: 2.25 s (3H, CH3), 6.29 s
(1H, H4isoxazole), 7.33–7.67 m (7Harom), 7.96 d (2Harom
,
J 7.9 Hz), 9.11 s (1H, Hp5yrazole). Found, %: C 71.40;
H 4.46; N 13.08. C19H14FN3O. Calculated, %: C 71.46;
H 4.42; N 13.16.
4-[3-(4-Tolylphenyl)-1-phenyl-4-pyrazolyl]-3-
buten-2-one oxime (IIId). Yield 78%, mp 223–225°C.
4-(3-Methyl-5-isoxazolyl)-1-phenyl-3-(4-chloro-
phenyl)pyrazole (IVc). Yield 63%, mp 135–136°C.
1H NMR spectrum, δ, ppm: 2.26 s (3H, CH3), 6.24 s
1
IR spectrum, cm–1: 1630 (C=N), 3280 (OH). H NMR
spectrum, δ, ppm: 1.94 s, 1.98 s (3H, CH3), 6.73 d (1H,
=CHA, J 15.5 Hz), 6.81 d (1H, =CHΒ, J 15.5 Hz), 7.31–
7.88 m (9Harom), 8.91 s, 8.99 s (1H, H5pyrazole), 10.72 s,
10.94 s (1H, OH). Found, %: C 75.79; H 6.05; N 13.29.
C20H19N3O. Calculated, %: C 75.71; H 5.99; N 13.25.
(1H, H4isoxazole), 7.36–7.66 m (7Harom), 7.95 d (2Harom
,
J8.0 Hz), 9.07 s (1H, H5pyrazole). Found, %: C 71.40; H 4.46;
N 13.08. C19H14ClN3O. Calculated, %: C 67.96; H 4.20;
N 12.51.
4-[1-Phenyl-3-(4-ethylphenyl)-4-pyrazolyl]-3-
4-(3-Methyl-5-isoxazolyl)-3-(4-tolylphenyl)-1-
phenylpyrazole (IVd). Yield 71%, mp 142–143°C.
1H NMR spectrum, δ, ppm: 2.24 s (3H, CH3), 2.40 s
(3H, CH3), 6.20 s (1H, H4isoxazole), 7.26–7.54 m (7Harom),
7.41 d (2Harom, J 7.2 Hz), 9.03 s (1H, H5pyrazole). Found,
%: C 76.23; H 5.35; N 13.38. C20H17N3O. Calculated,
%: C 76.17; H 5.43; N 13.32.
buten-2-one oxime (IIIe). Yield 81%, mp 175–176°C.
1
IR spectrum, cm–1: 1630(C=N), 3280 (OH). H NMR
spectrum, δ, ppm: 1.27 t (3H, CH3, J 7.5 Hz), 1.95 s,
1.99 s (3H, CH3), 2.68 d (2H, CH2, J 7.5 Hz), 6.77 d
(1H, =CHA, J 15.5 Hz), 6.84 d (1H, =CHΒ, J 15.5 Hz),
7.28–7.94 m (9Harom), 8.93 C, 9.01 s (1H, H5pyrazole), 10.69
s, 10.95 s (1H, OH). Found, %: C 70.77; H 5.14; N 13.32.
C19H16FN3O. Calculated, %: C 71.03; H 4.98; N 13.08.
4-(3-Methyl-5-isoxazolyl)-1-phenyl-3-(4-ethyl-
phenyl)pyrazole (IVe). Yield 58%, mp 139–140°C.
1H NMR spectrum, δ, ppm: 1.27 t (3H, CH3, J 7.5 Hz),
2.24 C (3H, CH3), 2.71 q (2H, CH2, J 7.5 Hz), 6.17 s
4-[3-(4-Methoxyphenyl)-1-phenyl-4-pyrazolyl]-3-
buten-2-one oxime (IIIf). Yield 77%, mp 192–194°C.
1
IR spectrum, cm–1: 1625 (C=N), 3275 (OH). H NMR
(1H, Hi4soxazole), 7.31–7.52 m (7Harom), 7.93 d (2Harom
,
J 7.0 Hz), 9.03 s (1H, H5pyrazole). Found, %: C 76.50; H 5.88;
N 12.70. C21H19N3O. Calculated, %: C 76.57; H 5.81;
N 12.76.
spectrum, δ, ppm: 1.95 s, 1.99 s (3H, CH3), 3.83 s (3H,
CH3O) 6.73 d (1H, =CHA, J 15.6 Hz), 6.80 d (1H, =CHΒ,
J 15.6 Hz), 7.02–7.94 m (9Harom), 8.88 s, 8.96 s (1H,
H5pyrazole), 10.64 s, 10.91 s (1H, OH). Found, %: C 71.79;
H 5.56; N 12.50. C20H19N3O2. Calculated, %: C 72.07;
H 5.71; N 12.61.
4-(3-Methyl-5-isoxazolyl)-3-(4-methoxyphenyl)-1-
phenylpyrazole (IVf). Yield 63%, mp 129–130°C.
1H NMR spectrum, δ, ppm: 2.24 s (3H, CH3), 3.83 C (3H,
CH3O), 6.16 s (1H, Hi4soxazole), 7.01 d (2Harom, J 6.9 Hz),
7.36–7.53 m (5Harom), 7.92 d (2Harom, J 6.9 Hz), 8.99 s
(1H, H5pyrazole). Found, %: C 72.40; H 5.27; N 12.63.
C20H17N3O2. Calculated, %: C 72.49; H 5.17; N 12.68.
3-Aryl-4-(5-isoxazolyl)pyrazoles IVa–IVf. To
a solution of 3.3 mmol of oxime IIIa–IIIf in 15 ml of
DMF was added a mixture of 0.85 g (3.3mmol) of iodine,
1.8 g (11 mmol) of potassium iodide, and 1 g (12 mmol)
of sodium hydrogen carbonate in 5 ml of water, and the
reaction mixture was boiled for 3 h. On cooling to room
temperature the reaction mixture was poured into
100 ml of 2% solution of sodium thiosulfate, the
separated precipitate was filtered off, washed with water,
and crystallized from acetic acid.
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1
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