Straightforward transformation of isoxazoles into pyrazoles: renewed and improved

Article abstract of DOI:10.1016/j.tet.2007.09.046

Isoxazoles bearing alkyl or carbamoyl groups were transformed into the corresponding pyrazoles in high yields by the treatment with hydrazine in methanol in the presence of a hydrogenation catalyst, e.g., Raney nickel, at ambient temperature. For the synthesis of N-substituted pyrazoles, hydrogenolysis of isoxazole followed by the treatment with substituted hydrazine was required. 3(5)-Aryl- or acylamido-substituted isoxazoles are less suitable for such transformations.

Full text of DOI:10.1016/j.tet.2007.09.046

Tetrahedron 63 (2007) 12195–12201
Straightforward transformation of isoxazoles into pyrazoles:
renewed and improved
a
Sergey I. Sviridov,a Andrei A. Vasil’evb, and Sergey V. Shorshnev
*
aChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russian Federation
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky pr. 47, 119991 Moscow, Russian Federation
Received 13 June 2007; revised 5 September 2007; accepted 20 September 2007
Available online 26 September 2007
Abstract—Isoxazoles bearing alkyl or carbamoyl groups were transformed into the corresponding pyrazoles in high yields by the treatment
with hydrazine in methanol in the presence of a hydrogenation catalyst, e.g., Raney nickel, at ambient temperature. For the synthesis of
N-substituted pyrazoles, hydrogenolysis of isoxazole followed by the treatment with substituted hydrazine was required. 3(5)-Aryl- or acyl-
amido-substituted isoxazoles are less suitable for such transformations.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
data,1–3 our finding stimulated us to investigate the possibil-
ities of isoxazole–pyrazole conversion and examine its scope
and limitations. In the present publication we report a simple
and efficient procedure for the preparation of pyrazoles from
certain isoxazoles by simply stirring them in methanol in the
presence of hydrazine and Raney nickel. Although both isox-
azoles and pyrazoles are generally obtained from the same
precursors, it should be noted that in some cases isoxazole
diversity can be greater, which is important for combina-
torial chemistry. For example, sufficient CH-acidity of the
alkyl group in position 5 of isoxazoles allows the prepara-
tion of coupling products of the corresponding (isoxazol-
5-yl)carbinyl anions with a variety of electrophiles.
The straightforward preparation of pyrazoles from the corre-
sponding isoxazoles with retention of the substitution pattern
by treating them with hydrazines is a rare and nearly forgot-
ten reaction. Approximately ten publications1–3 mostly from
the 1940 to 1950s were briefly reviewed in more recent
years,4 whereas this reaction is not mentioned at all in the
modern comprehensive multi-volume editions.5,6 Apparently,
this transformation has received little use because of modest
or even unreported yields and a strong substrate dependence,
which was difficult to systematize. Isoxazoles bearing elec-
tron-withdrawing nitro or carbonyl groups in position 4
could give pyrazoles upon heating with hydrazines in the
absence of catalysts.1 The effect of copper catalysis in the
case of isoxazole-3-carboxylic acids was stated.2 A two-step
protocol involving catalytic hydrogenolysis of the isoxazole
ring followed by hydrazine-assisted heterocyclization of
the acyclic intermediate was proposed based on extensive
investigations.3
2. Results and discussion
3,5-Dimethylisoxazole (1a) was chosen as a model com-
pound to search for conditions for its conversion into the
corresponding3,5-dimethylpyrazole(2a)(Scheme1, Table 1).
Simple storage of 1a in the presence of hydrazine in metha-
nol in the absence of a catalyst gave only traces of product 2a
(entry 1), whereas stirring of this mixture in the presence of
Raney nickel ultimately leads to its complete conversion into
pyrazole 2a (entries 2–4). The use of elevated temperature
(entry 5) allows acceleration of the process. Raney nickel
may be recycled (entry 6); however, once the reaction is
complete the catalyst should not be kept in contact with
the reaction components otherwise it loses its activity (entry
7). Active palladium on carbon (10%) showed satisfactory
results (entries 8 and 9), whereas less active 0.8% Pd/C
(entry 10) and Lindlar catalyst (entry 11) proved to be essen-
tially inactive. The catalysts Ni/SiO2 and Cu/Cr2O3 designed
With the aim of performing transformation of a complex
nitrobenzene derivative bearing a remote isoxazole fragment
into the corresponding aniline, we used standard hydrazine
reduction in boiling methanol in the presence of Raney
nickel. To our surprise, reduction of the nitro group was
accompanied by complete transformation of the isoxazole
residue into the pyrazole. Taking into account the available
Keywords: Isoxazoles; Pyrazoles; Heterocyclization; Hydrogenolysis;
Hydrogenation.
* Corresponding author. Tel.: +7 499 1358961; fax: +7 499 1355328;
e-mail: vasiliev@ioc.ac.ru
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.046

12196
S. I. Sviridov et al. / Tetrahedron 63 (2007) 12195–12201
Me
Me
Me
N2H4
a
NH2
NH2
N NH2
NH
OH
Me
Me
Me
Me
O
Me
A
B
C
N2H4
Ni
-NH3
Me
N
Me
H
O
1a
Me
NH
Me
b
NH
Me
N
Me
O
O
N
H
D
E
2a
Scheme 1.
Table 1. Influence of the nature of the catalyst on hydrazinolysis of
3,5-dimethylisoxazole
are usually unobservable, whereas carbons of substituents
at these positions resonate as broad weak signals.
Entry
Catalysta
Time, h
GLC composition, %
Isomeric N-benzoylamido-substituted isoxazoles 1f and 1g
did not give smoothly the expected pyrazoles 2f and 2g
(it should be noted that 2f and 2g are the tautomers of the
same compound). The complete conversion of 1f and 1g
afforded complex multi-component mixtures. In the case of
isomer 1f the corresponding pyrazole was obtained as an
inseparable mixture with benzamide (Table 2, entry 6),
whereas in case of isomer 1g the target pyrazole was gener-
ated only in trace amounts. This phenomenon may be ratio-
nalized by considering the structures of probable primary
hydrogenolysis products of these isoxazoles (Scheme 2),
which are imides and are prone to easily undergo fragmen-
tation in the presence of nucleophiles.
1a
2a
1
2
3
4
5
6
7
8
None
Ni (Ra)
Ni (Ra)
Ni (Ra)
24
1
4
w100
37
10
0
Traces
63
90
100
100
100
13
73
85
4
24
4b
24
24
5
24
24
24
24
24
24
Ni (Ra)
0
0
Ni (Ra) recycledc
Ni (Ra) recycledd
10% Pd/C
10% Pd/C
0.8% Pd/C
Lindlar catalyst
Ni/SiO2
87
27
15
94
95
98
94
100
9
10
11
12
13
14
5
2
6
Cu/Cr2O3
Ni(acac)2
—
a
Reaction conditions: 1 mmol 3,5-dimethylisoxazole, 2 mL MeOH,
0.2 mL N2H4$H2O, 50 mg catalyst,w20 ꢀC.
Under reflux (w64 ꢀC).
The first cycle continued for 24 h.
The first cycle continued for 10 days, when the reaction mixture turned
dark brown.
The unsubstituted amines corresponding to benzamides 1f
and 1g, namely, 3-amino-5-methyl- and 5-amino-3-methyl-
isoxazoles, remained unchanged on contact with hydrazine
in the presence of Raney nickel.
b
c
d
Under the same conditions, 3,5-diphenylisoxazole (1h) did
not give the target pyrazole 2h and the reaction stalled at the
known 3-amino-1,3-diphenylprop-2-en-1-one (3) (Scheme
3), whichconfirmsthegeneral pathway of the process in ques-
tion via amino enone intermediates (cf. Scheme 1). Amino
enone 3 did not further react with hydrazine even on pro-
longed reflux in methanol. Evidently, the two phenyl groups
in compound 3 are involved in conjugation with the amino
enone fragment, resulting in a decrease in its electrophilicity.
However, we succeeded in preparing pyrazole 2h from com-
pound 3 in 80% yield by replacing methanol with acetonitrile,
which is more favorable for nucleophilic addition.
for high-pressure and high-temperature hydrogenation did
not assist conversion of isoxazole 1a (entries 12 and 13).
Finally, Ni(acac)2 also did not catalyze the process (entry 14).
Apparently, the N2H4–Ni (Ra) system being the substitute
for H2–Ni causes hydrogenolysis of the N–O bond in isox-
azole 1a (Scheme 1, pathway a). This gives acyclic interme-
diate A, whose amino enone tautomer B belongs to a
well-known class of organic compounds. The reaction of
amino enone B with excess hydrazine produces hydrazone
C, whose heterocyclization affords ultimately pyrazole 2a.
It should be noted that d’Alcontres3 suggested the addition
of a hydrogen molecule at the heterocyclic C]N bond re-
sulting in isoxazoline derivative D (pathway b), which would
undergo ring opening to give imino ketone E. The latter is
the tautomer of amino enone B.
In contrast to isoxazole 1h, 5-methyl-3-phenyl-4-(N-phenyl-
carbamoyl)isoxazole (1i), when subjected to the above
two-step protocol, gave a complex mixture, in which the tar-
get 5-methyl-3-phenyl-4-(N-phenylcarbamoyl)pyrazole was
detected by HPLC–MS in only minor quantities. However,
we failed to isolate this product in the pure form because
of its low yield. It is worth noting that isoxazole 1i differs
from its analog 1e (see Table 2, entry 4) only by the presence
of the 3-positioned phenyl group instead of methyl.
The above-described method was applied to a variety of
functionalized isoxazoles 1b–f (Table 2, entries 1–5). In
most cases the corresponding pyrazoles 2b–e were obtained
in high yields. The procedure was in fact very simple: stir-
ring of isoxazole 1 with hydrazine hydrate in MeOH in the
presence of Raney nickel at ambient temperature for ca. 1
day gave essentially individual pyrazoles 2. Their isolation
presented no difficulties and was determined mainly by their
solubility in methanol. Pyrazoles 2b–e are characterized by
prototropic tautomerism, which is manifested in their 13C
NMR spectra: signals of 3- and 5-positioned carbon atoms
O
Ph
NHPh
N
Me
O
1i

S. I. Sviridov et al. / Tetrahedron 63 (2007) 12195–12201
Table 2. Yields of pyrazole derivatives derived from the corresponding isoxazolesa
12197
Entry
Starting isoxazole
Product
Yield,b
92
%
Me
Me
O
O
1
1b
1c
2b
2c
N
N
NHPh
N
H
NHPh
O
Me
Me
OH
OH
N
N
2
3
86
75
O
N
H
OMe
OMe
O
N
O
N
NHPh
NHPh
NHPh
1d
1e
2d
2e
Me
Me
N
H
O
O
O
Me
Me
NHPh
Me
4
82
N
Me
N
N
O
H
H
N
Ph
O
H
N
Ph
22
65
5
1f
2f¼2g
2g¼2f
N
Me
N
N
O
O
Me
Me
H
O
N
PhC(O)NH2
H
N
H
N
Ph
Ph
6
1g
Traces
O
NH
Me
O
N
a
Reaction conditions: N2H4$H2O, Ni(Ra), MeOH, 20 ꢀC, 24 h.
Yield of isolated products.
b
The use of methyl- or phenylhydrazine in a one-step proce-
dure did not give N-substituted pyrazoles, because these hy-
drazines do not form hydrogen in the presence of Raney
nickel. The slow addition of hydrazine hydrate to a metha-
nolic solution of isoxazole 1a and excess methylhydrazine
in the presence of Raney nickel afforded a mixture of
NH- and NMe-pyrazoles. Hence for the preparation of
N-substituted pyrazoles it seemed reasonable to apply the
d’Alcontres two-step protocol.3 In fact, hydrogenation of
isoxazoles (1 atm H2, MeOH, Raney Ni, 2–3 h)7 followed
by the treatment of the substance obtained with RNHNH2
gave the target products (Scheme 4). Sufficiently nucleo-
philic methylhydrazine did react with intermediate amino
enones in methanol at ambient temperature (synthesis of 4
and 40) or on heating (synthesis of 5). In the case of the
less nucleophilic phenylhydrazine heterocyclization did
not take place in methanol, so it appeared to be necessary
to use acetic acid as the solvent in this step (synthesis of 6).
H
N
H
N
Ph
Ph
N2H4
Ni
N2H4
Ni
1g
1f
When the starting isoxazole, e.g., 1e, bore identical substit-
uents at positions 3 and 5, this two-step protocol gave pyr-
azoles differing only in substituents at nitrogen, e.g., 5 or 6
(Scheme 4). In the case of a substrate (1c) with different
O
Me
O
O
NH2
Me
O
NH2
Scheme 2.
Ph
Ph
Ph
N2H4, Ni
MeOH,
N2H4
NH2
68%
N
Ph
N
Ph
Ph
MeCN,
N
H
O
O
80%
1h
3
2h
Scheme 3.

12198
S. I. Sviridov et al. / Tetrahedron 63 (2007) 12195–12201
Me
Me
OH
OH
H2, Ni
H2N
MeNHNH2
N
O
MeOH
O
MeOH, 20 °C
OMe
OMe
1c
11.0
13.3
Me
C
C
Me
nOe
OH
OH
N
Me
N
+
N
35.8
N
C
35.7
38.1
C
C
Me
OMe
43%
OMe
22%
35.7
C
nOe
4'
4
O
Me
NHPh
MeNHNH2
MeOH,
N
Me
74%
N
O
O
5
Me
Me
H2N
Me
NHPh
Me
H2, Ni
MeOH
NHPh
Me
O
N
O
Me
O
NHPh
Me
PhNHNH2
AcOH, 20
1e
N
°
C
N
6
80%
Ph
Scheme 4.
substituents, a w1:2 mixture of isomers 4 and 40 was
obtained. The isomers were separated by column chromato-
graphy. This may be attributed to the fact that methylhydra-
zine can add to both electrophilic sites of intermediate amino
enone, viz. the C]O and H2NC] carbon atoms. The struc-
tures of isomers 4 and 40 were unambiguously derived from
NOESY experiments. In addition, chemical shifts of the
exocyclic 3- and 5-positioned carbon atoms in 13C NMR
spectra were in pairs diagnostic: the negative g-effect of
the vicinal N-Me substituent caused a noticeable (2.2–
2.4 ppm) upfield shift of the corresponding carbon atom
(see Scheme 4).
2.50 ppm in DMSO-d6 for 1H NMR) or to signals of deuter-
ated solvent (dC 77.0 ppm in CDCl3 or 39.6 ppm in DMSO-
d6 for 13C NMR). IR spectra were recorded on Infralum
FT-801 (Russia) instrument. Elemental analyses were per-
formed at the Analytical Laboratory of the Nesmeyanov
Institute of Organoelement Compounds, Moscow. To moni-
tor the transformation of 1a/2a GC analysis was carried
out on a 25 m capillary column with SE-30 at 130 ꢀC.
TLC analyses were performed on Kieselgel 60 F254 alumi-
num sheets (Merck, 1.05554.0001). All starting materials
used for the synthesis of isoxazole derivatives 1b–i were
commercially available and used as purchased. All solvents
used in reactions and as eluents for column chromatography
were freshly distilled.
3. Conclusion
4.2. Preparation of isoxazole derivatives
In the conclusion, we have developed a simple and efficient
method for the conversion of isoxazoles into the correspond-
ing pyrazoles by treating them with hydrazine in methanol in
the presence of Raney nickel. Although this straightforward
method is restricted to certain types of substituents in the
heterocyclic ring, the target product can be prepared in spe-
cial cases with the use of a modified procedure. We believe
that our findings will promote wider use of pyrazoles in
various fields of organic and combinatorial chemistry.
4.2.1. N-Phenyl-2-(3-methylisoxazol-5-yl)acetamide (1b).
To a stirred suspension of 3-methylisoxazole-5-acetic acid
(353 mg, 2.5 mmol) in CH2Cl2 (5 mL), containing 1 drop
of DMF, oxalyl chloride (0.218 mL, 2.5 mmol) was added
dropwise at 20 ꢀC. After 1 h, gas evolution ceased and the
solid dissolved. The solution of acid chloride thus prepared
was added dropwise at 0–5 ꢀC to a stirred solution of aniline
(0.228 mL, 2.5 mmol) and triethylamine (0.7 mL,w5 mmol)
in CH2Cl2 (5 mL), and stirring was continued for additional
2 h. The reaction mixture was treated with 5% aqueous HCl
(10 mL), the organic layer was separated, and the aqueous
phase was extracted with CH2Cl2 (10 mL). The combined
extracts were washed with brine (20 mL), dried with
CaCl2, and concentrated in vacuo. The residue was triturated
with tetrachloromethane (2 mL), the solid was filtered off,
recrystallized from benzene (2 mL), and washed with hex-
ane (10 mL). Final drying in air gave 389 mg (72%) of the
title compound as a white solid, mp 122–123 ꢀC [Found:
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in CDCl3 or DMSO-
d6 at 400.13 MHz (1H) or 100.62 MHz (13C) on a DRX 400
Avance (Bruker) instrument. The chemical shifts were refer-
enced to residual protons (dH 7.27 ppm in CDCl3 or

S. I. Sviridov et al. / Tetrahedron 63 (2007) 12195–12201
12199
C, 66.69; H, 5.60; N, 12.99. C12H12N2O2 requires C, 66.65;
H, 5.59; N, 12.95%.]; nmax (Nujol) 3254, 3195, 3137, 1663,
1619, 1600, 1545, 1503 cmꢁ1; dH (400 MHz, DMSO-d6)
2.21 (3H, s, Me), 3.89 (2H, s, CH2), 6.26 (1H, s, ]CH),
7.06 (1H, t, J 7.8 Hz, ]CH), 7.32 (2H, t, J 7.8 Hz, ]CH),
7.58 (2H, d, J 7.8 Hz, ]CH), 10.25 (1H, br s, NH); dC
(100 MHz, DMSO-d6) 11.0 (Me), 34.7 (CH2), 104.0 (CH),
119.2 (CH), 123.6 (CH), 128.8 (CH), 138.9 (C), 159.6 (C),
165.3 (C), 166.7 (C).
(68%) of the title compound as the white solid, mp
164–166 ꢀC (lit.10 mp 164 ꢀC). dH (400 MHz, DMSO-d6)
2.42 (3H, s, Me), 6.75 (1H, s, ]CH), 7.52 (2H, t, J 7.6 Hz,
]CH), 7.61 (1H, t, J 7.1 Hz, ]CH), 8.01 (2H, d, J 7.6 Hz,
]CH), 11.27 (1H, br s, NH); dC (100 MHz, DMSO-d6)
12.2 (Me), 97.0 (CH), 128.1 (CH), 128.5 (CH), 132.3
(CH), 133.2 (C), 158.7 (C), 165.3 (C), 169.4 (C).
4.2.6. 5-Benzoylamido-3-methylisoxazole (1g). Com-
pound 1g was prepared analogously to amide 1f from 5-ami-
no-3-methylisoxazole in a yield of 54%, mp 144–146 ꢀC
(lit.11 mp 147 ꢀC). dH (400 MHz, DMSO-d6) 2.22 (3H, s,
Me), 6.33 (1H, s, ]CH), 7.54 (2H, t, J 7.4 Hz, ]CH),
7.64 (1H, t, J 7.4 Hz, ]CH), 8.01 (2H, d, J 8.1 Hz,
]CH), 11.90 (1H, br s, NH).
4.2.2. 1-(4-Methoxyphenyl)-2-(3-methylisoxazol-5-yl)-
ethan-1-ol (1c). To a stirred solution of diisopropylamine
(1.7 mL,w12 mmol) in THF (20 mL) at ꢁ78 ꢀC under argon
n-butyllithium (7.84 mL of 1.4 M solution in hexanes,
11 mmol) was added. After 10 min, 3,5-dimethylisoxazole
(1.07 g, 11 mmol) dissolved in THF (3 mL) was added,
and the mixture was stirred for an additional 30 min. 4-Me-
thoxybenzaldehyde (1.36 g, 10 mmol) dissolved in THF
(2 mL) was then added, and the mixture was allowed to
reach ambient temperature. After the usual work up and col-
umn chromatography (gradient 25/100% CH2Cl2 in light
petroleum) 1.87 g (80%) of the title compound was ob-
tained, pale yellow solid, mp 53–54 ꢀC. Rf (20% AcOEt/hex-
ane) 0.26; dH (400 MHz, CDCl3) 2.19 (3H, s, Me), 2.86 (1H,
d, J 3.7 Hz, OH), 3.03 (1H, A part of ABX system, J 15.0,
5.1 Hz, CH2), 3.14 (1H, B part of ABX system, J 15.0,
8.1 Hz, CH2), 3.77 (3H, s, OMe), 4.96 (1H, m, OCH), 5.81
(1H, s, ]CH), 6.85 (2H, d, J 8.8 Hz, ]CH), 7.24 (2H, d,
J 8.8 Hz, ]CH). Spectral characteristics were in a good
agreement with the earlier reported.8
4.2.7. 5-Methyl-3-phenyl-4-(N-phenylcarbamoyl)isox-
azole (1i). Compound 1i was prepared analogously to amide
1b, yield 45%, white solid, mp 198–200 ꢀC (lit.12 mp 193–
195.5 ꢀC) [Found: C, 73.11; H, 5.11; N, 10.03.
C17H14N2O2 requires C, 73.37; H, 5.07; N, 10.07%.]; nmax
(Nujol) 3275, 3248, 3192, 3128, 1650, 1594, 1530,
1504 cmꢁ1; dH (400 MHz, DMSO-d6) 2.59 (3H, s, Me),
7.12 (1H, t, J 7.6 Hz, ]CH), 7.35 (2H, t, J 7.6 Hz, ]CH),
7.50 (3H, m, ]CH), 7.63 (2H, d, J 7.6 Hz, ]CH), 7.71
(2H, m, ]CH), 10.42 (1H, br s, NH); dC (100 MHz,
DMSO-d6) 11.9 (Me), 113.4 (C), 119.8 (CH), 124.1 (CH),
127.8 (CH), 128.1 (C), 128.9 (CH), 130.1 (CH), 138.6 (C),
160.0 (C), 160.2 (C), 169.9 (C).
4.3. Straightforward conversion of isoxazoles
into pyrazoles (general procedure)
4.2.3. 5-Methyl-3-(N-phenylcarbamoyl)isoxazole (1d).
Compound 1d was prepared analogously to amide 1b in
a yield of 75%. White solid, mp 133–135 ꢀC (lit.9 mp
134 ꢀC); dH (400 MHz, DMSO-d6) 2.51 (3H, s, Me), 6.65
(1H, s, ]CH), 7.14 (1H, t, J 7.4 Hz, ]CH), 7.36 (2H, t, J
7.4 Hz, ]CH), 7.78 (2H, d, J 8.1 Hz, ]CH), 10.51 (1H,
br s, NH).
To a stirred solution/suspension of an isoxazole derivative
(1 mmol) in MeOH (2–4 mL depending on solubility) and
hydrazine hydrate (0.4–0.8 mL) Raney nickel (50–80 mg
of wet substance) was added, which resulted in evolution
of hydrogen bubbles. The mixture was stirred at ambient
temperature for ca. 1 day. Usually in several hours the start-
ing compound was completely consumed, when TLC analy-
sis showed the presence of several components (two of
which being the major products were characterized by
higher polarity than the starting isoxazole). Further aging
of the mixture finally led to the formation of mostly one
product. The nickel was removed by filtration and rinsed
on a filter with MeOH (caution: to avoid inflammation of
waste nickel it should be immediately covered with water
and carefully quenched with dilute HCl or H2SO4). The
filtrate was concentrated, and the product was isolated
by crystallization. If the product precipitated during the re-
action (e.g., compound 2e), 1–2 mL of silica gel and 5 mL
of toluene were added to the mixture, and the volatiles
were removed in vacuo. The pre-adsorbed material was
loaded on the top of a chromatography column packed
with silica gel, and the product was eluted with an appropri-
ate system of solvents (usually a gradient of MeOH in
CH2Cl2).
4.2.4. 3,5-Dimethyl-4-(N-phenylcarbamoyl)isoxazole
(1e). Compound 1e was prepared analogously to amide 1b,
yield 60%, white solid, mp 153–154 ꢀC [Found: C, 66.63;
H, 5.71; N, 12.80. C12H12N2O2 requires C, 66.65; H, 5.59;
N, 12.95%.]; nmax (Nujol) 3289, 3248, 3192, 3128, 1650,
1594, 1530, 1504 cmꢁ1; dH (400 MHz, DMSO-d6) 2.33
(3H, s, Me), 2.55 (3H, s, Me), 7.11 (1H, t, J 7.6 Hz,
]CH), 7.35 (2H, t, J 7.6 Hz, ]CH), 7.66 (2H, d, J
7.6 Hz, ]CH), 10.00 (1H, br s, NH); dC (100 MHz,
DMSO-d6) 10.5 (Me), 12.2 (Me), 113.7 (C), 120.0 (CH),
123.9 (CH), 128.7 (CH), 138.8 (C), 158.4 (C), 160.2 (C),
169.7 (C).
4.2.5. 3-Benzoylamido-5-methylisoxazole (1f). To a solu-
tion of 3-amino-5-methylisoxazole (587 mg, 6 mmol) in
pyridine (10 mL) benzoyl chloride (0.696 mL, 6 mmol)
and it was added dropwise over 2 h (TLC control). The reac-
tion mixture was carefully treated with excess cold 5% HCl
(pH¼1) and extracted with CH2Cl2 (2ꢂ20 mL). The com-
bined extracts were washed successively with 5% HCl,
NaCl, and NaHCO3 solutions (20 mL each), dried with
CaCl2 and concentrated. The residue was triturated with
benzene (2 mL), the solid was filtered off, washed
with benzene (5 mL), and dried in air to give 825 mg
4.3.1. 3,5-Dimethylpyrazole (2a). Compound 2a was ob-
tained from 3,5-dimethylisoxazole (see Table 1) using either
Raney nickel or other catalysts. The product and the authen-
tic sample of 2a showed the same retention time during GC
analysis and characteristic chemical shifts in 1H NMR

12200
S. I. Sviridov et al. / Tetrahedron 63 (2007) 12195–12201
spectrum; dH (400 MHz, DMSO-d6) 2.13 (s, 3H), 5.74
(s, 1H), 12.01 (br s, 1H).
J 7.3 Hz, ]CH), 10.6 (1H, br s, NH), 12.1 (1H, br s, NH)
was in good agreement with that reported earlier;14 dC
(100 MHz, DMSO-d6) 10.8 (broad low signal, Me), 96.6
(broad low signal, CH), 127.7 (CH), 128.3 (CH), 131.7
(CH), 138.2 (broad low signal, C), 164.4 (C), the rest of
the signals are missing; HPLC–MS (CI): MH+ 202. Benz-
amide: dH (400 MHz, DMSO-d6) 7.43 (1H, br s, NH2), 7.49
(3H, m, ]CH), 7.88 (2H, d, J 7.3 Hz, ]CH), 7.95 (1H, br
s, NH2); dC (100 MHz, DMSO-d6) 127.5 (CH), 128.2
(CH), 131.5 (CH), 134.3 (C), 168.0 (C); HPLC–MS (CI):
MH+ 122; these spectral data were similar to those of the
authentic sample.
4.3.2. N-Phenyl-2-(3-methylpyrazol-5-yl)acetamide (2b).
White solid, mp 164–166 ꢀC [Found: C, 66.71; H, 6.30; N,
19.43. C12H13N3O requires C, 66.96; H, 6.09; N,
19.52%.]; nmax (Nujol) 3293, 3267, 3184, 3124, 1676,
1614, 1598, 1540, 1503 cmꢁ1; dH (400 MHz, DMSO-d6)
2.17 (3H, s, Me), 3.57 (2H, s, CH2), 5.92 (1H, s, ]CH),
7.03 (1H, t, J 7.8 Hz, ]CH), 7.29 (2H, t, J 7.8 Hz, ]CH),
7.59 (2H, d, J 7.8 Hz, ]CH), 10.05 (1H, br s, NH), 12.21
(1H, br s, NH); dC (100 MHz, DMSO-d6) 10.6 (broad
weak signal, Me), 36.7 (broad weak signal, CH2), 103.5
(CH), 119.1 (CH), 123.2 (CH), 128.7 (CH), 139.3 (C),
168.4 (broad weak signal, C), the signals of the rest of the
carbon atoms are missing.
4.4. Two-step conversion of isoxazoles into pyrazoles
(representative examples)
4.4.1. 3,5-Diphenylpyrazole (2h). 3,5-Diphenylisoxazole
(1h) (22 mg, 0.1 mmol) and hydrazine hydrate (0.08 mL)
were stirred in MeOH (0.5 mL) in the presence of Raney
nickel (w20 mg). The reaction was slow, so the mixture
was heated to 60 ꢀC for 1 h, which led to complete conver-
sion of the starting material (TLC). The mixture was then
kept at ambient temperature for 3 days, which did not lead
to changes in its composition. Column chromatography
(CH2Cl2 as an eluent) gave 15 mg (68%) of 3-amino-1,3-di-
phenylprop-2-en-1-one (3) as a yellow oil. Rf (3% MeOH/
CH2Cl2) 0.66; dH (400 MHz, CDCl3) 5.51 (1H, br s, NH2),
6.16 (1H, s, ]CH), 7.48 (6H, m, ]CH), 7.65 (2H, d,
J 7.4 Hz, ]CH), 7.96 (2H, d, J 7.4 Hz, ]CH), 10.44 (1H,
br s, NH2); dC (100 MHz, CDCl3) 91.9 (CH), 126.3 (CH),
127.2 (CH), 128.3 (CH), 129.0 (CH), 130.7 (CH), 131.0
(CH), 137.6 (C), 140.3 (C), 162.9 (C), 190.2 (C); these spec-
tral data were in good agreement with that reported earlier.15
The amino enone (3) was dissolved in MeCN (0.5 mL), hy-
drazine hydrate (0.1 mL) was added, and the mixture was re-
fluxed for 4 h. The mixture was concentrated and subjected
to 1H NMR analysis, which showed the presence of 20% in-
termediate amino enone (3) and 80% 3,5-diphenylpyrazole
(2h), identical to the authentic sample.16 dH (400 MHz,
CDCl3) 6.84 (1H, s, ]CH), 7.31–7.42 (6H, m, ]CH),
7.73 (4H, br d, J 7.4 Hz, ]CH), 11.6 (1H, br s, NH).
4.3.3. 1-(4-Methoxyphenyl)-2-(3-methylpyrazol-5-yl)-
ethan-1-ol (2c). White solid, mp 107–109 ꢀC [Found: C,
67.38; H, 7.08; N, 12.00. C13H16N2O2 requires C, 67.22;
H, 6.94; N, 12.06%.]; nmax (Nujol) 3217, 3150, 3120,
1611, 1585, 1511 cmꢁ1; dH (400 MHz, DMSO-d6) 2.11
(3H, s, Me), 2.82 (2H, m, CH2), 3.72 (3H, s, OMe), 4.72
(1H, m, OCH), 5.16 (1H, br s, OH), 5.71 (1H, s, ]CH),
6.85 (2H, d, J 8.8 Hz, ]CH), 7.23 (2H, d, J 8.8 Hz,
]CH), 11.98 (1H, br s, NH); dC (100 MHz, DMSO-d6)
9.0–14.3 (broad weak signal, Me), 34.3–38.4 (broad weak
signal, CH2), 55.0 (Me), 71.9 (CH), 103.4 (CH), 113.3
(CH), 127.2 (CH), 137.7 (C), 158.2 (C), the signals of the
rest of the carbon atoms are missing.
4.3.4. 5-Methyl-3-(N-phenylcabamoyl)pyrazole (2d).
White solid, mp 167–168 ꢀC [Found: C, 65.71; H, 5.43; N,
20.68. C11H11N3O requires C, 65.66; H, 5.51; N,
20.88%.]; nmax (Nujol) 3377, 3373, 3189, 3124, 1674,
1657, 1597, 1579, 1542 cmꢁ1; dH (400 MHz, DMSO-d6)
2.29 (3H, s, Me), 6.50 (1H, s, ]CH), 7.06 (1H, t,
J 7.3 Hz, ]CH), 7.31 (2H, t, J 7.3 Hz, ]CH), 7.80 (2H,
d, J 7.3 Hz, ]CH), 9.88 (1H, br s, NH), 13.05 (1H, br s,
NH); dC (100 MHz, DMSO-d6) 10.4 (Me), 104.6 (CH),
120.1 (CH), 123.3 (CH), 128.6 (CH), 138.9 (C), 140.2 (C),
147.1 (C), 160.6 (C).
4.4.2. 1-(4-Methoxyphenyl)-2-(dimethylpyrazolyl)ethan-
1-ols 4 and 40. A mixture of 1-(4-methoxyphenyl)-2-(3-
methylisoxazol-5-yl)ethan-1-ol (1c) (466 mg, 2 mmol),
methanol (5 mL), and Raney nickel (0.1 g) was stirred under
hydrogen (1 atm) for 3 h. The mixture was filtered, methyl-
hydrazine (1 mL) was added, and the mixture was kept under
argon overnight. The volatiles were removed in vacuo and
the remainder was subjected to column chromatography
(gradient 0/2% MeOH in CH2Cl2 as an eluent) to give
107 mg (23%) of unreacted isoxazole derivative, 108 mg
(22%) of isomer 4 as the viscous oil, and 212 mg (43%) of
isomer 40 as the viscous oil, which solidified on standing.
1-(4-Methoxyphenyl)-2-(1,5-dimethylpyrazol-3-yl)ethan-
1-ol (4) [Found: C, 68.00; H, 7.28; N, 11.14. C14H18N2O2
requires C, 68.27; H, 7.37; N, 11.37%.]; Rf (5% MeOH/
CH2Cl2) 0.54; nmax (Nujol) 3323, 3242, 1613, 1586,
1548 cmꢁ1; dH (400 MHz, CDCl3) 2.23 (3H, s, Me), 2.50
(1H, br s, OH), 2.90 (2H, m, CH2), 3.73 (3H, s, NMe),
3.80 (3H, s, OMe), 4.90 (1H, m, OCH), 5.81 (1H, s,
]CH), 6.88 (2H, d, J 8.8 Hz, ]CH), 7.34 (2H, d, J
8.8 Hz, ]CH); dC (100 MHz, CDCl3) 11.0 (Me), 35.8
4.3.5. 3,5-Dimethyl-4-(N-phenylcabamoyl)pyrazole (2e).
White solid, mp 246–247 ꢀC (lit.13 mp 244–245 ꢀC) [Found:
C, 66.73; H, 6.01; N, 19.61. C12H13N3O requires C, 66.96;
H, 6.09; N, 19.52%.]; nmax (Nujol) 3329, 3152, 3095,
1643, 1597, 1525 cmꢁ1; dH (400 MHz, DMSO-d6) 2.33
(6H, s, Me), 7.04 (1H, t, J 7.8 Hz, ]CH), 7.30 (2H, t,
J 7.8 Hz, ]CH), 7.66 (2H, d, J 7.8 Hz, ]CH), 9.43 (1H,
br s, NH), 12.23 (1H, br s, NH); dC (100 MHz, DMSO-d6)
12.6 (broad low signal, Me), 114.0 (C), 119.6 (CH), 123.1
(CH), 128.6 (CH), 139.6 (C), 163.3 (C), the signals of the
rest of the carbon atoms are missing.
4.3.6. 3-Benzoylamido-5-methylpyrazole (2f). Compound
2f was obtained from 3-benzoylamido-5-methylisoxazole
(1f) (202 mg, 1 mmol) as an inseparable by column chroma-
tography mixture with benzamide (123 mg, 1:3 M ratio from
1H NMR), yields were calculated as 22 and 65%, respec-
tively; Rf (5% MeOH/CH2Cl2) 0.43. 3-Benzoylamido-5-
methylpyrazole (2f): dH (400 MHz, DMSO-d6) 2.23 (3H, s,
Me), 6.41 (1H, s, ]CH), 7.49 (3H, m, ]CH), 7.99 (2H, d,

S. I. Sviridov et al. / Tetrahedron 63 (2007) 12195–12201
12201
(Me), 38.1 (CH2), 55.2 (Me), 72.9 (CH), 104.8 (CH), 113.6
(CH), 127.0 (CH), 136.3 (C), 139.1 (C), 148.7 (C), 158.8 (C).
1-(4-Methoxyphenyl)-2-(1,3-dimethylpyrazol-5-yl)ethan-1-ol
(40) [Found: C, 68.29; H, 7.44; N, 11.21. C14H18N2O2 re-
quires C, 68.27; H, 7.37; N, 11.37%.]; Rf (5% MeOH/
74.21; H, 5.88; N, 14.42%.]; Rf (5% MeOH/CH2Cl2) 0.43;
nmax (Nujol) 3300, 1646, 1632, 1595, 1556, 1553 cmꢁ1; dH
(400 MHz, DMSO-d6) 2.37 (3H, s, Me), 2.41 (3H, s, Me),
7.07 (1H, t, J 7.8 Hz, ]CH), 7.34 (2H, t, J 7.8 Hz, ]CH),
7.41–7.62 (5H, m, Ph), 7.70 (2H, d, J 7.8 Hz, ]CH), 9.85
(1H, br s, NH); dC (100 MHz, DMSO-d6) 11.8 (Me), 13.0
(Me), 117.0 (C), 119.7 (CH), 123.4 (CH), 125.0 (CH),
128.1 (CH), 128.8 (CH), 129.4 (CH), 138.9 (C), 139.4 (C),
140.1 (C), 147.4 (C), 162.8 (C).
CH2Cl2) 0.47; nmax (Nujol) 3252, 1613, 1586, 1548 cmꢁ1
;
dH (400 MHz, CDCl3) 2.19 (3H, s, Me), 2.59 (1H, br s,
OH), 2.91 (1H, A part of ABX system, J 14.7, 5.9 Hz, CH2),
2.99 (1H, B part of ABX system, J 14.7, 7.4 Hz, CH2), 3.53
(3H, s, NMe), 3.80 (3H, s, OMe), 4.84 (1H, X part of ABX sys-
tem, J 7.4, 5.9 Hz, OCH), 5.84 (1H, s, ]CH), 6.86 (2H, d, J
8.8 Hz, ]CH), 7.22 (2H, d, J 8.8 Hz, ]CH); dC (100 MHz,
CDCl3) 13.3 (Me), 35.7 (two signals, Me and CH2), 55.2
(Me), 73.0 (CH), 105.1 (CH), 113.8 (CH), 126.8 (CH),
135.6 (C), 139.9 (C), 147.1 (C), 159.2 (C).
References and notes
1. (a) Musante, C. Gazz. Chim. Ital. 1942, 72, 537; (b) Musante,
C. Gazz. Chim. Ital. 1943, 73, 355; (c) Musante, C.; Stener,
A. Gazz. Chim. Ital. 1959, 89, 1579; (d) Fusco, R.; Zumin, S.
Gazz. Chim. Ital. 1946, 76, 223; (e) Gardner, T. S.; Smith,
F. A.; Wenis, E.; Lee, J. J. Org. Chem. 1956, 21, 530; (f)
Lemke, T. L.; Sawhney, K. N.; Lemke, B. K. J. Heterocycl.
Chem. 1982, 19, 363.
2. (a) Cusmano, C. Gazz. Chim. Ital. 1940, 70, 227; (b) Cusmano,
C. Gazz. Chim. Ital. 1940, 70, 237; (c) Cusmano, C. Gazz.
Chim. Ital. 1940, 70, 240.
3. d’Alcontres, G. S. Gazz. Chim. Ital. 1950, 80, 441.
4. Quilico, A. Five- and Six-membered Compounds with Nitrogen
and Oxygen; Wiley, R. H., Ed.; The chemistry of heterocyclic
compounds; Interscience: NewYork, NY, London, 1962; Vol.
17, pp 48–49.
5. (a) Elguero, J. Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, New
York, NY, 1984; Vol. 5, pp 167–303; (b) Lang, S. A.; Lin,
Y.-i. Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Oxford, New York, NY,
1984; Vol. 6, pp 1–130.
4.4.3. 1,3,5-Trimethyl-4-(N-phenylcabamoyl)pyrazole
(5). A solution of N-phenyl-3,5-dimethylisoxazole-4-carb-
oxamide (1e) (108 mg, 0.5 mmol) in MeOH (3 mL) was
hydrogenated (1 atm H2) in the presence of Raney nickel
(w80 mg) for 3 h (TLC showed the complete conversion of
the starting compound 1e). The catalyst was filtered off,
methylhydrazine (0.2 mL) was added to the filtrate, and
the mixture was refluxed for 12 h (at ambient temperature re-
action did not occur). Silica gel (1.5 mL) and toluene (5 mL)
were added and the volatiles were removed in vacuo to leave
a pre-adsorbed material, which was loaded on the top of
chromatography column packed with silica gel. Eluting
with gradient 0/1.5% MeOH in CH2Cl2 afforded 85 mg
(74%) of the title compound as a white solid, mp 161–
162 ꢀC (lit.12 mp 161–163 ꢀC) [Found: C, 67.97; H, 6.59;
N, 18.31. C13H15N3O requires C, 68.10; H, 6.59; N,
18.33%.]; Rf (5% MeOH/CH2Cl2) 0.35; nmax (Nujol) 3300,
3271, 3234, 1641, 1594, 1544, 1525 cmꢁ1; dH (400 MHz,
DMSO-d6) 2.27 (3H, s, Me), 2.36 (3H, s, Me), 3.69 (3H, s,
NMe), 7.05 (1H, t, J 7.3 Hz, ]CH), 7.31 (2H, t, J 8.3 Hz,
]CH), 7.67 (2H, d, J 8.3 Hz, ]CH), 9.58 (1H, br s, NH);
dC (100 MHz, DMSO-d6) 12.6 (Me), 12.9 (Me), 35.8
(Me), 115.1 (C), 119.7 (CH), 123.2 (CH), 128.7 (CH),
139.6 (C), 140.1 (C), 145.4 (C), 163.2 (C).
6. (a) Elguero, J. Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, New York, NY, 1996; Vol. 3, pp 1–75;
(b) Sutharchanadevi, M.; Murugan, R. Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, New York, NY,
1996; Vol. 3, pp 221–260.
7. Reductive Mo(CO)6-assisted ring opening of isoxazoles lead-
ing to amino enones, which were further transformed into pyr-
idine-4-ones and pyran-4-ones, was also reported: (a) Nitta, M.;
Higuchi, T. Heterocycles 1994, 38, 853; (b) Li, C.-S.; Lacasse,
E. Tetrahedron Lett. 2002, 43, 3565.
ꢀ˜
8. Fuentes, J. A.; Maestro, A.; Testera, A. M.; Banez, J. M.
Tetrahedron: Asymmetry 2000, 11, 2565.
9. Lepage, F.; Tombret, F.; Cuvier, G.; Marivain, A.; Gillardin,
J. M. Eur. J. Med. Chem. Chim. Ther. 1992, 27, 581.
10. Buscemi, S.; Frenna, V.; Vivona, N. Heterocycles 1991, 32,
1765.
11. Yamamoto, Y.; Azuma, Y. Heterocycles 1978, 9, 185.
12. (a) Quilico, A.; Panizzi, L. Gazz. Chim. Ital. 1938, 68, 411; (b)
Quilico, A.; Fusco, R. Gazz. Chim. Ital. 1937, 67, 589.
13. Huppatz, J.L. Patent DE 2701091, 1977; Chem. Abstr. 1977,
87, 147056.
14. Butler, D. E.; DeWald, H. A. J. Org. Chem. 1975, 40, 1353.
15. Seko, S.; Tani, N. Tetrahedron Lett. 1998, 39, 8117.
16. Kitajima, N.; Fujisawa, K.; Fujimoto, C.; Morooka, Y.;
Hashimoto, S.; Kitagawa, T.; Toriumi, K.; Tatsumi, K.;
Nakamura, A. J. Am. Chem. Soc. 1992, 114, 1277.
4.4.4. 3,5-Dimethyl-1-phenyl-4-(N-phenylcabamoyl)pyr-
azole (6). A solution of N-phenyl-3,5-dimethylisoxazole-
4-carboxamide (1e) (108 mg, 0.5 mmol) in MeOH (3 mL)
was hydrogenated (1 atm H2) in the presence of Raney
nickel (w80 mg) for 3 h (TLC showed complete conversion
of the starting compound 1e). The catalyst was filtered off
and the filtrate was concentrated. Glacial AcOH (2 mL)
was added to the residue followed by the addition of phenyl-
hydrazine (108 mg, 1.0 mmol), and the mixture was stirred
at ambient temperature for 3 h (TLC control). The mixture
was concentrated and the rest of AcOH was removed by
co-evaporating with xylene. The residue was dissolved in
a toluene/CH2Cl2 mixture, silica gel (w1.5 mL) was added,
and the volatiles were removed in vacuo to leave a pre-
adsorbed material, which was loaded on the top of chro-
matography column packed with silica gel. Eluting with
a gradient 0/1% MeOH in CH2Cl2 afforded 117 mg
(80%) of the yellow solid. Rinsing with toluene afforded
white crystals, mp 181–182 ꢀC (lit.12 mp 182–183 ꢀC)
[Found: C, 74.26; H, 5.84; N, 14.45. C18H17N3O requires C,