Synthesis of substituted 3-phenyl-6H-pyrazolo[4,3-d]isoxazoles from corresponding 4-benzoyl-5-hydroxypyrazoles

Article abstract of DOI:10.1002/jhet.5570400216

Treatment of 1,(3)-(di)substituted 4-benzoyl-5-hydroxypyrazoles with phosphorus oxychloride affords the corresponding 4-benzoyl-5-chloropyrazoles. Reaction of the latter with hydroxylamine leads to oximes, which can be cyclized to novel 3-phenyl-6H-pyrazolo[4,3-d]isoxazoles by treatment with sodium hydride in dimethyl formamide. Detailed nmr spectroscopic studies (¹H, ¹³C) with all obtained compounds are presented.

Full text of DOI:10.1002/jhet.5570400216

Mar-Apr 2003
303
Synthesis of Substituted 3-Phenyl-6H-pyrazolo[4,3-d]isoxazoles
from Corresponding 4-Benzoyl-5-hydroxypyrazoles
*
Wolfgang Holzer and Katharina Hahn
Department of Pharmaceutical Chemistry, University of Vienna, Pharmaziezentrum, Althanstrasse 14,
A-1090 Vienna, Austria
Received December 25, 2002
Treatment of 1,(3)-(di)substituted 4-benzoyl-5-hydroxypyrazoles with phosphorus oxychloride affords
the corresponding 4-benzoyl-5-chloropyrazoles. Reaction of the latter with hydroxylamine leads to
oximes, which can be cyclized to novel 3-phenyl-6H-pyrazolo[4,3-d]isoxazoles by treatment with sodium
1
13
hydride in dimethyl formamide. Detailed nmr spectroscopic studies ( H, C) with all obtained
compounds are presented.
J. Heterocyclic Chem., 40, 303 (2003).
As some 1,2-benzisoxazole derivatives show interesting
the corresponding oxime 6e, but we could never observe
cyclization into the bicyclic system 3e (Scheme 4).
Another respresentative, namely 3,4-dimethyl-6-phenyl-
6H-pyrazolo[4,3-d]isoxazole has been mentioned in the
literature; again, neither a synthesis nor any data are given
[8]. To sum up, it is questionable if all these supposed
pyrazolo[4,3-d]isoxazoles really have been in the hands of
the authors.
Thus, to overcome the lack of data regarding 6H-pyra-
zolo[4,3-d]isoxazoles and in continuation to our previous
studies concerning the tautomerism, the synthetic and bio-
logical potential of pyrazolones (5-hydroxypyrazoles) [9-14]
we here report a synthetic route to the title compounds start-
ing from 1-substituted 4-benzoyl-5-hydroxypyrazoles.
pharmacological activities - the anticonvulsant and
antiepileptic drug Zonisamide may serve as an example [1]
- also some attention has been addressed to hetero-annu-
lated isoxazoles. However, only a few publications are
dealing with the synthesis of 6H-pyrazolo[4,3-d]isoxa-
zoles and a considerably small number of representatives
containing this core has been hitherto obtained. For the
synthesis of such systems one approach is based on pyra-
zole ring closure via reaction of 4-benzoyl-3-methyl-5-
hydroxyisoxazole (or the corresponding 5-chloro deriva-
tive) with hydrazine or phenylhydrazine [2], the other con-
sists in construction of the isoxazole ring starting from
appropriately substituted pyrazole derivatives. Thus, it is
claimed that a one-pot reaction of 5-chloro-3-methyl-1H-
pyrazole-4-carbaldehyde (or its 1-phenyl derivative, 5e in
Scheme 4) and hydroxylamine smoothly leads to
4-methyl-6H-pyrazolo[4,3-d]isoxazole or 4-methyl-6-
phenyl-6H-pyrazolo[4,3-d]isoxazole (3e in Scheme 4),
respectively [3-5]. However, these reports seem rather
mystic as neither experimental procedure nor spectro-
scopic data of the reaction products are provided [3-5].
Moreover, there is a considerable discrepancy concerning
the reported melting point for reaction product 3e (lit [5]
mp 95°, lit [3] mp 131°), the latter value being similar to
that given for 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carbaldehyde oxime (6e in Scheme 4) which has a mp of
134-136° [6] or 140-141° [7]. When we repeated one of
the mentioned reactions under the insinuated conditions,
i.e. treatment of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-
Synthesis.
For the synthesis of 1,2-benzisoxazoles one of the most
important methods consists in the dehydrating cyclization
of oximes derived from salicylaldehydes or alkyl (aryl)
2-hydroxyphenyl ketones [15]. For this purpose, amongst
conditions such as, for instance, heating the educts with
potassium hydroxide or sodium acetate in ethanol, treat-
ment with polyphosphoric acid, thionyl chloride/pyridine
or acetic anhydride/sulfuric acid [15] also the mild and
effective reaction system trichloroacetyl isocyanate/potas-
sium carbonate in dry tetrahydrofuran has been success-
fully applied, for instance for the cyclization of salicyl-
aldehyde oximes (Scheme 1) [16]. Similarly, 3-methyl-
isoxazolo[4,5-b]pyridine was conveniently prepared
applying this reaction system (Scheme 1) [17].
Scheme
1
4-carbaldehyde (5e) with hydroxylamine hydrochloride
and catalytic amounts of a base (sodium hydroxide or
piperidine) [5] in refluxing ethanol, we always obtained
However, attempted application of a similar synthetic con-
cept for the synthesis of 6H-pyrazolo[4,3-d]isoxazoles (3),
namely starting from 4-acetyl or 4-aroyl-5-hydroxypyrazoles

304
W. Holzer and K. Hahn
Vol. 40
Treatment of ketones 5 with hydroxylamine hydrochlo-
ride in ethanol/pyridine in the following gave the oximes
6. Compounds 6a and 6b were obtained as (E)/(Z)-mix-
tures with the (Z)-isomer predominating, 6c was isolated
(1) failed: Whereas under most of the above mentioned 'stan-
dard' conditions the corresponding oximes 2 did not react,
upon treatment with trichloroacetyl isocyanate/potassium
carbonate the educts were completely consumed.
Nevertheless, cyclization to bicyclic compounds 3 did not
occur. Instead, the formation of spiro compounds 4 was
observed (Scheme 2) [18]. This particular reaction behaviour
can be explained by the exclusive presence of 'oximes' 2 in
an enaminopyrazolone form (2a), which was unambiguously
confirmed by detailed NMR-spectroscopic investigations as
well as by X-ray structure analyses with compounds 2 and
their methylation products [19]. The complete absence of the
hydroxypyrazole form 2b obviously prevents cyclization to
6H-pyrazolo[4,3-d]isoxazoles 3.
1
13
as a single isomer to which according to H and C nmr
experiments (E)-configuration was assigned (see below).
Finally, treatment of oximes 6a-c with sodium hydride in
dimethyl formamide led to the target compounds 3a-c in
high yields. Whereas cyclization of 6b and 6c proceeded at
ambient temperature, with 6a heating to 60° was required.
In contrast, under such reaction conditions cyclization of
the aldehyde-derived oxime 6d into the corresponding
bicyclic compound 3d failed, only unreacted starting mate-
rial was isolated from the reaction mixture (Scheme 4).
Likewise, heating of aldoxime 6e in ethanol/NaOH or in
pyridine did not afford the corresponding ring closure
product 3e. A possible explanation for the failure of ring
closure with 6d and 6e is the exclusive presence of these
oximes in the 'wrong' (E)-configuration being not suitable
for isoxazole ring formation (see NMR-spectroscopic
investigations and Figure 1). It is well known that the con-
figuration of the starting oximes plays a crucial role in
such cyclization reactions [15,21,22]. Obviously, under the
applied reaction conditions with 6d and 6e isomerisation
to the corresponding (Z)-isomers does not occur, with only
the latter species being anticipated to be suitable for
cyclization into condensed systems 3.
Scheme 2
NMR-Spectroscopic Investigations.
Unambiguous assignment for all proton and carbon res-
onances was achieved on basis of NOE-difference [23] and
1D-TOCSY [24] experiments, fully H-coupled C nmr
spectra, APT [25], HMQC [26], 1D-HETCOR [27] and
long-range INEPT spectra with selective excitation
[28,29].
To overcome the above mentioned problems of
unwanted tautomerism the 5-hydroxypyrazoles (tautomer
to pyrazolones) 1 (R = Ph) were heated with phosphorus
oxychloride to smoothly afford the corresponding 4-ben-
zoyl-5-chloropyrazoles 5 (Scheme 3) [20].
1
13
3
Scheme 3
Scheme 4

Mar-Apr 2003
Synthesis of Substituted 3-Phenyl-6H-pyrazolo[4,3-d]isoxazoles
305
1
13
Discrimination between (Z)- and (E)-forms of oximes 6a
and 6b was carried out by comparison of the C nmr
2.49 ppm ( H in deuteriodimethyl sulfoxide), δ 77.0 ppm ( C in
13
13
deuteriochloroform), δ 39.5 ppm ( C in deuteriodimethyl sul-
foxide). Compounds 1b ((3-methyl-5-hydroxy-1-phenyl-1H-
pyrazol-4-yl)phenylmethanone = 4-benzoyl-3-methyl-1-phenyl-
5-pyrazolinone), 5d (5-chloro-1,3-dimethyl-1H-pyrazol-4-car-
baldehyde) and 5e (5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-
carbaldehyde) are commercially available.
chemical shifts of both isomers considering γ-effects.
Carbon atoms in γ-position (α to C=N) to a syn located
oxime oxygen atom suffer an upfield shift compared to the
γ-C-atoms in the anti-position due to steric compression
[30,31]. Thus, the signal of pyrazole C-4 in (Z)-6b (δ 111.6
ppm, syn-position to the oxime O-atom) is shifted 3.6 ppm
upfield compared to the corresponding pyrazole C-4 reso-
nance in (E)-6b (δ 115.2 ppm). Reversely, the signal of
C-phenyl C-1 in (Z)-6b (δ 134.9 ppm) is shifted to higher
frequencies compared to that in (E)-6b (δ 132.1 ppm)
(Figure 1). Oxime 6c, present as a single isomer in deuteri-
ochloroform solution, was assigned to have (E)-configura-
tion by comparison with the closely related pair (Z/E)-6b.
The stereochemistry in aldoximes 6d and 6e, which were
obtained as single isomers, was unequivocally determined
by NOE-difference experiments which revealed spatial
closeness of N=CH and NOH proton and thus (E)-configu-
ration [32]. This assignment is confirmed by the magni-
(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)phenylmethanone (5a).
A mixture of (1,3-dimethyl-5-hydroxy-1H-pyrazol-4-yl)-
phenylmethanone (1a) [34] (2.162 g, 10 mmoles) and phospho-
rus oxychloride (3.067 g, 20 mmoles) was heated to reflux for 2
hours. Then the mixture was poured onto ice-water (50 ml) and
neutralized with 40% aqueous sodium hydroxide. After extrac-
tion with ether (3×20 ml) the combined organic phases were
washed with water, dried (sodium sulfate) and evaporated under
reduced pressure to afford 2.018 g (86%) of an orange oil which
1
solidified on standing, lit. [35] mp 49-52°; H nmr (deuteriochlo-
roform): δ 7.72 (m, 2H, Ph H-2,6), 7.55 (m, 1H, Ph H-4), 7.44
13
(m, 2H, Ph H-3,5), 3.83 (s, 3H, N-Me), 2.28 (s, 3H, 3-Me);
C
nmr (deuteriochloroform): δ 190.0 (C=O), 150.2 (pyrazole C-3,
2
J(C-3,3-Me) = 6.9 Hz), 138.4 (Ph C-1), 132.6 (Ph C-4), 129.9
(pyrazole C-5), 129.2 (Ph C-2,6), 128.3 (Ph C-3,5), 116.8 (pyra-
13
1
tude of the one-bond C, H coupling constant of the
3
1
zole C-4, J(C4,3-Me) = 2.8 Hz), 36.1 (N-Me, J = 141.6 Hz),
1
1
1
N=CH moiety in 6d ( J = 162.9 Hz) and 6e ( J = 165.0
Hz), which is known to be strongly dependent from the
orientation of the nitrogens' lone-pair [33]. Thus, (Z)-con-
figuration should lead to a considerably larger coupling
constant in the range of 177 Hz [33].
13.9 (3-Me, J = 129.0 Hz).
(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)phenyl-
methanone (5b).
Compound 5b was prepared similiarly as described for the
synthesis of 5a starting from (3-methyl-5-hydroxy-1-phenyl-1H-
pyrazol-4-yl)phenylmethanone (1b) (2.783 g, 10 mmoles) and
phosphorus oxychloride (3.067 g, 20 mmoles). The obtained raw
product (2.929 g) was recrystallized from ethanol-water to afford
1
1.751 g (59%) of colorless needles , mp 87° (lit [36] mp 88°); H
nmr (deuteriochloroform): δ 7.83 (m, 2H, C-Ph H-2,6), 7.59 (m,
1H, C-Ph H-4), 7.56 (m, 2H, N-Ph H-2,6), 7.49 (m, 4H, C-Ph H-
3,5 and N-Ph H-3,5), 7.44 (m, 1H, N-Ph H-4), 2.37 (s, 3H, 3-
13
Me); C nmr (deuteriochloroform): δ 190.2 (C=O), 151.3 (pyra-
2
zole C-3, J(C-3, 3-Me ) = 6.9 Hz), 138.2 (C-Ph C-1), 137.5 (N-
Ph C-1), 132.8 (C-Ph C-4), 129.4 (C-Ph C-2,6), 129.2 (pyrazole
C-5), 129.1 (N-Ph C-3,5), 128.8 (N-Ph C-4), 128.4 (C-Ph C-3,5),
3
125.4 (N-Ph C-2,6), 118.3 (pyrazole C-4, J(C-4,3-Me) = 2.8
Hz), 14.0 (3-Me, J = 129.0 Hz).
1
Figure 1
(5-Chloro-1-phenyl-1H-pyrazol-4-yl)phenylmethanone (5c).
A mixture of (5-hydroxy-1-phenyl-1H-pyrazol-4-yl)phenyl-
methanone (1c) [37] (2.643 g, 10 mmoles) and phosphorus oxy-
chloride (3.067 g, 20 mmoles) was heated to reflux for 2 hours.
Then the mixture was poured onto ice-water (50 ml) and neutral-
ized with 40% aqueous sodium hydroxide. The aquous phase was
exhaustively extracted with ether and then with dichloromethane.
The combined etheral and dichloromethane phases were separately
washed with water, dried (sodium sulfate) and evaporated. The
combined residues were recrystallized from ethanol to afford 1.583
g (56%) of colorless crystals, mp 110°; ir (potassium bromide):
Figure 1. Discrimination between (Z)-6b and (E)-6b via
γ-effects regarding C nmr chemical shifts (in deuterio-
chloroform); determination of (E)-configuration in 6d and
6e via a strong NOE between N=CH and N-OH.
13
EXPERIMENTAL
Melting points were determined on a Reichert-Kofler hot-stage
microscope and are uncorrected. Mass spectra were obtained on a
Shimadzu QP 1000 instrument (EI, 70 eV), infrared spectra on a
Perkin-Elmer FTIR 1605 spectrophotometer. The nmr spectra
were obtained on a Varian UnityPlus 300 spectrometer (299.95
-1
1
1648 (C=O) cm ; H nmr (deuteriochloroform): δ 7.99 (s, 1H,
pyrazole H-3), 7.89 (m, 2H, C-Ph H-2,6), 7.61 (m, 1H, C-Ph H-4),
7.59 (m, 2H, N-Ph H-2,6), 7.54 (m, 2H, N-Ph H-3,5), 7.52 (m, 2H,
1
13
13
MHz for H, 75.43 MHz for C) at 28°. The centre of the solvent
signal was used as an internal standard which was related to
C-Ph H-3,5), 7.49 (m, 1H, N-Ph H-4); C nmr (deuteriochloro-
1
form): δ 188.0 (C=O), 142.9 (pyrazole C-3, J = 191.9 Hz), 138.3
1
tetramethylsilane with δ 7.26 ppm ( H in deuteriochloroform), δ
(C-Ph C-1), 137.4 (N-Ph C-1), 132.7 (C-Ph C-4), 131.1 (pyrazole

306
W. Holzer and K. Hahn
Vol. 40
C-5), 129.24 (N-Ph C-4), 129.2 (N-Ph C-3,5 and C-Ph C-2,6),
128.5 (C-Ph C-3,5), 125.5 (N-Ph C-2,6), 118.9 (pyrazole C-4,
C-3,5), 128.2 (N-Ph C-4), 127.1 (C-Ph C-2,6), 126.6 (pyrazole
3
C-5), 125.0 (N-Ph C-2,6), 111.6 (pyrazole C-4, J(C4,3-Me) =
2
+
1
J(C-4,H-3) = 9.9 Hz); ms: m/z (%) 284 (13), 283 (M , 6), 282
(32), 207 (29), 205 (100), 105 (17), 89 (10), 77 (87), 51 (40).
Anal. Calcd. for C H ClN O: C, 67.97; H, 3.92; N, 9.91.
3.3 Hz), 13.7 (3-Me, J = 128.6 Hz); (E)-isomer: δ 150.1
2
(C=NOH), 149.7 (pyrazole C-3, J(C-3,3-Me) = 6.9 Hz), 137.9
(N-Ph C-1), 132.1 (C-Ph C-1), 129.4 (C-Ph C-2,6 and C-Ph C-4),
128.9 (N-Ph C-3,5), 128.3 (N-Ph C-4), 128.1 (C-Ph C-3,5), 127.3
(pyrazole C-5), 125.2 (N-Ph C-2,6), 115.2 (pyrazole C-4,
16 11
2
Found: C, 67.89; H, 3.91; N, 9.81.
(E/Z)-(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)phenyl-
methanone Oxime (6a).
3
1
J(C4,3-Me) = 3.0 Hz), 13.5 (3-Me, J = 128.6 Hz); ms: m/z (%)
+
313 (13), 312 (M ,10), 311 (44), 294 (21), 276 (40), 216 (16),
204 (15), 198 (14), 194 (20), 192 (64), 157 (15), 104 (13), 102
(14), 91 (10), 77 (100), 51 (70), 50 (16).
A mixture of (5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)phenyl-
methanone (5a) (2.347 g, 10 mmoles), hydroxylamine hydrochlo-
ride (2.780 g, 40 mmoles), pyridine (2.4 ml) and ethanol (17 ml)
was heated to reflux for 5 hours. Then the mixture was poured
onto water (110 ml), the precipitated solid was collected by filtra-
tion, washed several times with water and dried to afford 2.222 g
Anal. Calcd. for C H ClN O: C, 65.49; H, 4.53; N, 13.48.
17 14
3
Found: C, 65.25; H, 4.47; N, 13.24.
(E)-(5-Chloro-1-phenyl-1H-pyrazol-4-yl)phenylmethanone
Oxime (6c).
1
(89%) of colorless crystals (ratio Z/E ~ 3.7:1 according to H
Compound 6c was prepared from (5-chloro-1-phenyl-1H-
pyrazol-4-yl)phenylmethanone (5c) (2.827 g, 10 mmoles) and
hydroxylamine hydrochloride (2.780 g, 40 mmoles) similarly as
described for the synthesis of 6b. Recrystallization of the whole
raw product from ethanol afforded 2.144 g (72%) of colorless
needles, mp 170-172°; ir (potassium bromide): 3250, 3203 (OH)
nmr). An analytical sample was obtained upon recrystallization
from ethanol, mp 188-190°; ir (potassium bromide): 3134, 2848
-1
1
(OH) cm ; H nmr (deuteriochloroform): (Z)-isomer: δ 9.94
(s, 1H, NOH), 7.52 (m, 2H, Ph H-2,6), 7.37 (m, 2H, Ph H-3,5),
7.36 (m, 1H, Ph H-4), 3.87 (s, 3H, N-Me), 2.14 (s, 3H, 3-Me); (E)-
isomer: δ 9.94 (s, 1H, NOH), 7.53 (m, 2H, Ph H-2,6), 7.41 (m, 3H,
-1
1
13
cm ; H nmr (deuteriochloroform) [38]: (E)-isomer: δ 8.82
Ph H-3,4,5), 3.80 (s, 3H, N-Me), 2.05 (s, 3H, 3-Me); C nmr
(s, 1H, NOH), 7.63 (s, 1H, pyrazole H-3), 7.57-7.44 (m, 10H,
(deuteriochloroform): (Z)-isomer: δ 149.6 (C=NOH), 148.0 (pyra-
13
2
Ph-H); C nmr (deuteriochloroform): (E)-isomer: δ 150.6
zole C-3, J(C-3,3-Me) = 6.8 Hz), 135.0 (Ph C-1), 129.5 (Ph C-4),
1
3
(C=NOH), 141.2 (pyrazole C-3, J = 191.4 Hz), 137.9 (N-Ph
128.5 (Ph C-3,5), 127.2 (pyrazole C-5, J(C5,NMe) = 2.8 Hz),
3
C-1), 131.9 (C-Ph C-1), 129.4 (C-Ph C-4), 129.0 (N-Ph C-3,5
and C-Ph C-2,6), 128.7 (N-Ph C-4), 128.3 (C-Ph C-3,5), 126.4
(pyrazole C-5), 125.4 (N-Ph C-2,6), 116.5 (pyrazole C-4,
127.0 (Ph C-2,6), 109.5 (pyrazole C-4, J(C4,3-Me) = 3.3 Hz),
1
1
36.1 (N-Me, J = 141.1 Hz), 13.6 (3-Me, J = 128.3 Hz); (E)-iso-
2
mer: δ 150.1 (C=NOH), 148.1 (pyrazole C-3, J(C-3,3-Me) = 6.8
2
+
J(C4,H3) = 9.0 Hz); ms: m/z (%) 299 (17), 298 (M , 11), 297
Hz), 132.3 (Ph C-1), 129.4 (Ph C-2,6), 129.3 (Ph C-4), 128.1 (Ph
3
(54), 180 (34), 178 (100), 102 (10), 77 (85), 51 (42).
C-3,5), 127.7 (pyrazole C-5, J(C5,NMe) = 2.8 Hz), 113.4 (pyra-
3
1
Anal. Calcd. for C H ClN O • 0.2 H O: C, 63.77; H, 4.15;
zole C-4, J(C4,3-Me) = 3.2 Hz), 36.0 (N-Me, J = 141.2 Hz),
16 12
3
2
1
+
13.4 (3-Me, J = 128.4 Hz); ms: m/z (%) 251 (14), 250 (M , 11),
249 (44), 232 (40), 214 (72), 156 (17), 154 (39), 142 (16), 136
(19), 132 (32), 130 (100), 129 (18), 95 (20), 77 (53), 51 (39).
N, 13.94. Found: C, 63.63; H, 4.04; N, 13.77.
(E)-5-Chloro-1,3-dimethyl-1H-pyrazol-4-carbaldehyde Oxime
(6d).
Anal. Calcd. for C H ClN O: C, 57.72; H, 4.84; N, 16.83.
12 12
3
A mixture of 5-chloro-1,3-dimethyl-1H-pyrazol-4-carbalde-
hyde (5d) (317 mg, 2 mmoles) and hydroxylamine hydrochloride
(167 mg, 2.4 mmoles) in methanol (3 ml) was slightly warmed
until the solution became clear. After stirring at room temperature
for 20 hours water (8 ml) was added and the mixture was left for
additional 3 hours. The precipitated solid was collected by filtra-
tion, washed with water and dried to afford 330 mg (95%) of col-
Found: C, 58.02; H, 4.72; N, 16.79.
(E/Z)-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)phenyl-
methanone Oxime (6b).
A mixture of (5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-
yl)phenylmethanone (5b) (2.968 g, 10 mmoles), hydroxylamine
hydrochloride (2.780 g, 40 mmoles), pyridine (2.4 ml) and
ethanol (20 ml) was heated to reflux for 4 hours and was then
stirred at room temperature overnight. The mixture was poured
onto water (150 ml) and was then extracted with
dichloromethane (3×40 ml). The combined organic phases were
washed several times with water (to remove traces of pyridine),
dried (sodium sulfate) and evaporated under reduced pressure to
afford 1.933 g (62%) of an almost colorless powder (ratio Z/E ~
1
orless needles, mp 163-165° (lit [39] mp 164-165°); H nmr
(deuteriodimethyl sulfoxide): δ 11.06 (s, 1H. NOH), 7.89 (s, 1H,
13
N=CH), 3.72 (s, 3H, N-Me), 2.24 (s, 3H, 3-Me); C nmr (deu-
2
teriodimethyl sulfoxide): δ 145.7 (pyrazole C-3, J(C3,3-Me) =
3
1
7.0 Hz, J(C3,N=CH) = 5.0 Hz), 140.0 (N=CH, J = 162.9 Hz,
3
J(N=CH,OH) = 9.8 Hz), 125.9 (pyrazole C-5), 109.4 (pyrazole
C-4, J(C4,N=CH) = 6.5 Hz, J(C4,3-Me) = 3.0 Hz), 35.8 (N-Me,
J = 141.4 Hz), 13.9 (3-Me, J = 128.1 Hz); ms: m/z (%) 175/173
(M , 31/100), 158/156 (20/63), 138 (76), 121 (49), 120 (70), 93
(76), 76 (37), 66 (67), 52 (37).
2
3
1
1
1
2:1 according to H nmr). An analytical sample was obtained
+
upon recrystallization from ethanol-water, mp 131°; ir (potas-
-1
1
sium bromide): 3218 (OH) cm ; H nmr (deuteriochloroform):
(Z)-isomer: δ 9.73 (s, 1H, NOH), 7.62 (N-Ph H-2,6), 7.58 (m, 2H,
C-Ph H-2,6), 7.52-7.38 (m, 6H, N-Ph H-3,4,5 and C-Ph H-3,4,5),
2.24 (s, 3H, 3-Me); (E)-isomer: δ 9.73 (s, 1H, NOH), 7.64-7.55
Anal. Calcd. for C H ClN O: C, 41.51; H, 4.64; N, 24.20.
6
8
3
Found: C, 41.47; H, 4.43; N, 23.98.
(E)-5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-carbaldehyde
Oxime (6e).
(m, 2H, N-Ph H-2,6), 7.60 (m, 2H, C-Ph H-2,6), 7.52-7.38 (m,
6H, N-Ph H-3,4,5 and C-Ph H-3,4,5), 2.16 (s, 3H, 3-Me);
13
C
nmr (deuteriochloroform): (Z)-isomer: δ 149.5 (C=NOH), 149.5
(pyrazole C-3, J(C-3,3-Me) = 6.9 Hz), 138.0 (N-Ph C-1), 134.9
(C-Ph C-1), 129.6 (C-Ph C-4), 128.9 (N-Ph C-3,5), 128.6 (C-Ph
A mixture of 5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-
carbaldehyde (5e) (221 mg, 1 mmole) and hydroxylamine
hydrochloride (114 mg, 1.64 mmoles) in ethanol (3 ml) was
2

Mar-Apr 2003
Synthesis of Substituted 3-Phenyl-6H-pyrazolo[4,3-d]isoxazoles
307
slightly warmed until the solution became clear. After stirring at
room temperature for 3 hours water (10 ml) and saturated sodium
bicarbonate solution (5 ml) was added, the precipitated solid was
collected by filtration, washed several times with water and dried
to afford 220 mg (93%) of a colorless powder, mp 138-140° (lit
carried out similarly as described for the synthesis of 3b. The
almost colorless solid obtained after work-up (209 mg, 80%) was
crystallized from ethanol to afford 138 mg (53%) of thin, color-
1
less needles, mp 160-161°; H nmr (deuteriochloroform): δ 7.94
(m, 2H, C-Ph H-2,6), 7.90 (m, 2H, N-Ph H-2,6), 7.79 (s, 1H, H-
4), 7.53 (m, 3H, C-Ph H-3,4,5), 7.52 (m, 2H, N-Ph H-3,5), 7.32
1
[6] mp 134-136°, lit [7] mp 140-141°]); H nmr (deuteriochloro-
13
form): δ 8.93 (s, 1H, NOH), 8.14 (s, 1H, N=CH), 7.58-7.36 (m,
(m, 1H, N-Ph H-4); C nmr (deuteriochloroform): δ 166.4 (C-
13
3
5H, Ph-H), 2.47 (s, 3H, 3-Me); C nmr (deuteriochloroform): δ
6a, J(C-6a,H-4) = 4.5 Hz), 154.8 (C-3), 137.3 (N-Ph C-1), 131.0
2
3
1
149.0 (pyrazole C-3, J(C3,3-Me) = 6.9 Hz, J(C3,N=CH) = 5.0
(C-Ph C-4), 129.7 (C-4, J(C-4,H-4) = 194.0 Hz), 129.6 (N-Ph C-
1
Hz), 142.3 (N=CH, J = 165.0 Hz), 137.6 (Ph C-1), 129.1 (Ph C-
3,5), 129.1 (C-Ph C-3,5), 127.6 (C-Ph C-1 and C-Ph C-2,6),
2
3,5), 128.6 (Ph C-4), 127.6 (pyrazole C-5), 125.0 (Ph C-2,6),
126.4 (N-Ph C-4), 117.5 (N-Ph C-2,6), 111.9 (C-3a, J (C-3a, H-
2
3
+
111.2 (pyrazole C-4, J(C4,N=CH) = 6.0 Hz, J(C4,3-Me) = 2.9
4) = 10.9 Hz); ms: m/z (%) 261 (M , 69), 260 (49), 128 (29), 105
1
Hz), 14.5 (3-Me, J = 128.8 Hz).
(50), 91 (29), 77 (100), 53 (20), 51 (46).
Anal. Calcd. for C H N O•0.2H O: C, 72.55; H, 4.34; N,
Anal. Calcd. for C H ClN O: C, 56.06; H, 4.28; N, 17.83.
16 11
3
2
11 10
3
15.86. Found: C, 72.78; H, 4.20; N, 15.75.
Found: C, 55.94; H, 4.51; N, 17.61.
4,6-Dimethyl-3-phenyl-6H-pyrazolo[4,3-d]isoxazole (3a).
REFERENCES AND NOTES
To sodium hydride (80% suspension in mineral oil, 35 mg,
1.17 mmoles) in dry dimethyl formamide (3 ml) was added a
solution of (5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)phenyl-
methanone oxime (6a) (250 mg, 1 mmol) in dry DMF (1 ml) via
a syringe and the mixture was stirred for 1.5 hours at 60°. Then it
was poured onto water (10 ml), the precipitated solid was col-
lected by filtration, washed with water and dried to afford 188 mg
(88%) of colorless crystals. An analytical sample was obtained
[1] A. Kleemann and J. Engel, Pharmaceutical Substances, 3rd
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(1995).
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Abstr., 125, 300885 (1996).
[12] W. Holzer, B. Plagens and K. Lorenz, Heterocycles, 45, 309
(1997).
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Plagens, M. Hitzler, E. Richter and G. Ecker, J. Med. Chem., 41, 4001
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[14] W. Holzer, K. Mereiter and B. Plagens, Heterocycles, 50, 799
(1999).
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Chemie, Vol E8a, E. Schaumann, ed, Thieme Verlag, Stuttgart - New
York, 1993, pp 226-348.
1
upon recrystallization from ethanol, mp 100°; H nmr (deuteri-
ochloroform): δ 7.84 (m, 2H, Ph H-2,6), 7.48 (m, 3H, Ph H-
13
3,4,5), 3.82 (s, 3H, N-Me), 2.46 (s, 3H, 4-Me); C nmr (deuteri-
3
ochloroform): δ 168.2 (C-6a), 155.9 (C-3, J(C-3,Ph H-2,6) = 4.5
2
Hz), 137.8 (C-4, J(C-4,4-Me) = 7.0 Hz), 130.5 (Ph C-4), 128.9
3
(Ph C-3,5), 128.2 (Ph C-1), 127.8 (Ph C-2,6), 108.6 (C-3a, J(C-
1
1
3a,4-Me) = 3.4 Hz), 34.8 (N-Me, J = 140.9 Hz), 14.8 (4-Me, J =
+
128.3 Hz); ms: m/z (%) 214 (26), 213 (M , 100), 212 (69), 149
(14), 142 (32), 105 (37), 77 (63), 70 (14), 67 (49), 51 (32).
Anal. Calcd. for C H N O: C, 67.59; H, 5.20; N, 19.71.
12 11
3
Found: C, 67.44; H, 5.03; N, 19.52.
3,6-Diphenyl-4-methyl-6H-pyrazolo[4,3-d]isoxazole (3b).
The synthesis of 3b starting from 5-chloro-3-methyl-1-phenyl-
1H-pyrazol-4-yl)phenylmethanone oxime (6b) (312 mg, 1 mmol)
was carried out similarly as described for the synthesis of 3a
except that the reaction was carried out at room temperature.
After work-up 242 mg (88%) of colorless crystals were obtained.
An analytical sample was obtained upon recrystallization from
1
diisopropyl ether, mp 141-143°; H nmr (deuteriochloroform): δ
7.90 (m, 2H, C-Ph H-2,6), 7.85 (m, 2H, N-Ph H-2,6), 7.53 (m,
1H, C-Ph H-4), 7.52 (m, 2H, C-Ph H-3,5), 7.50 (m, 2H, N-Ph H-
[16] G. Stokker, J. Org. Chem., 48, 2613 (1983).
[17] Y. Tagawa and Y. Goto, Heterocycles, 26, 2921 (1987).
[18] W. Holzer, R. M. Claramunt, M. Perez-Torralba, D. Guggi and
T. Brehmer, submitted; presented at the 8th Blue Danube Symposium on
Heterocyclic Chemistry, Bled (Slovenia), Sept. 2000, abstract PO30.
[19] W. Holzer, K. Hahn, T. Brehmer, R. M. Claramunt and M.
Perez-Torralba, Eur. J. Org. Chem., 1205 (2003); presented at the 16th
Scientific Meeting of the Austrian Pharmaceutical Society, Vienna
(Austria), Sept. 2001, Sci. Pharm., 69, Suppl. 1, 48 (2001).
13
3,5), 7.27 (m, 1H, N-Ph H-4), 2.59 (s, 3H, 4-Me); C nmr (deu-
3
teriochloroform): δ 166.8 (C-6a), 155.7 (C-3, J(C-3,Ph H-2,6) =
2
4.4 Hz), 139.5 (C-4, J(C-4,4-Me) = 7.0 Hz), 137.3 (N-Ph C-1),
130.7 (C-Ph C-4), 129.5 (N-Ph C-3,5), 129.1 (C-Ph C-3,5), 128.0
(C-Ph C-2,6), 127.9 (C-Ph C-1), 125.8 (N-Ph C-4), 117.1 (N-Ph
3
1
C-2,6), 110.8 (C-3a, J(C-3a,4-Me) = 3.3 Hz), 15.1 (4-Me, J =
+
128.6 Hz); ms: m/z (%) 276 (20), 275 (M , 79), 274 (22), 142
(17), 105 (59), 91 (58), 77 (100), 69 (27), 67 (45), 51 (52).
3
[20] With 4-acetyl-5-hydroxpyrazoles (1, R = Me) under similar
Anal. Calcd. for C H N O: C, 74.17; H, 4.76; N, 15.26.
17 13
3
reaction conditions the formation of undefined multi-component mix-
tures and polymerisation was observed.
Found: C, 74.16; H, 4.73; N, 15.09.
[21] S. A. Lang Jr. and Y.-i Lin, Isoxazoles and their Benzo
Derivatives, in Comprehensive Heterocyclic Chemistry, Vol 6, A. R.
Katritzky and C. W. Rees, eds, Pergamon Press, Oxford, 1984, p 115.
[22] K.-H. Wünsch and A. J. Boulton, Indoxazenes and Anthranils,
3,6-Diphenyl-6H-pyrazolo[4,3-d]isoxazole (3c).
The synthesis of 3c starting from 5-chloro-1-phenyl-1H-pyra-
zol-4-yl)phenylmethanone oxime (6c) (298 mg, 1 mmol) was

308
W. Holzer and K. Hahn
Vol. 40
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344 (1986).
[38] Compound 6c has a limited solubility in deuteriochloroform,
the solution containing only pure (E)-isomer. It is more soluble in deu-
teriodimethyl sulfoxide, however, this solution decomposes.
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