Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-substituted isoxazoles

Article abstract of DOI:10.1016/j.tet.2018.09.015

A novel effective method is reported for the preparation of 1-amino-1H-pyrazole-4-carboxylic acid derivatives by Fe(II)-catalyzed rearrangement of isoxazoles having (2,4-dinitrophenylhydrazono)methyl substituent at C4. The reaction proceeds smoothly for both E and Z isomers of 4-(hydrazonomethyl)isoxazoles, and this means it is not necessary to separate mixtures of E/Z-isomers of the hydrazones prepared by reaction of 5-methoxy/pirrolidino-4-carbonylisoxazoles and 2,4-dinitrophenylhydrazine. The rearrangement proceeds via the formation of an aziridine intermediate which can be isolated in certain cases. The 2-nitro group in the synthesized 1-[(2,4-dinitrophenyl)amino]-1H-pyrazole-4-carboxylic esters can be selectively reduced in two steps via acylation of the amino group followed by hydrogenation-deacylation using H₂-Pd/C.

Full text of DOI:10.1016/j.tet.2018.09.015

Tetrahedron xxx (2018) 1e11
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Tetrahedron
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Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of
4-hydrazonomethyl-substituted isoxazoles
Ekaterina E. Galenko, Viktor K. Ivanov, Mikhail S. Novikov, Andrey A. Zolotarev,
Alexander F. Khlebnikov*
Saint Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya Nab., St. Petersburg, 199034, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel effective method is reported for the preparation of 1-amino-1H-pyrazole-4-carboxylic acid de-
rivatives by Fe(II)-catalyzed rearrangement of isoxazoles having (2,4-dinitrophenylhydrazono)methyl
substituent at C4. The reaction proceeds smoothly for both E and Z isomers of 4-(hydrazonomethyl)
isoxazoles, and this means it is not necessary to separate mixtures of E/Z-isomers of the hydrazones
prepared by reaction of 5-methoxy/pirrolidino-4-carbonylisoxazoles and 2,4-dinitrophenylhydrazine.
The rearrangement proceeds via the formation of an aziridine intermediate which can be isolated in
certain cases. The 2-nitro group in the synthesized 1-[(2,4-dinitrophenyl)amino]-1H-pyrazole-4-
carboxylic esters can be selectively reduced in two steps via acylation of the amino group followed by
hydrogenation-deacylation using H2-Pd/C.
Received 30 July 2018
Received in revised form
4 September 2018
Accepted 5 September 2018
Available online xxx
Keywords:
N-aminopyrazole
Hydrazone
© 2018 Elsevier Ltd. All rights reserved.
Isoxazole
Rearrangement
Fe-catalysis
1. Introduction
Earlier we found that isoxazoles containing a C]C unsaturated
moiety in the C4 position rearrange to the corresponding 1H-pyr-
Many medicines, including the best-selling drugs, are de-
rivatives of heterocycles from the list of privileged structures of
medical chemistry [1]. Pyrazole is one such privileged structure [2].
N-aminopyrazole derivatives in particular exhibit antiprotozoal
activity [3,4] and are patented as agents for the treatment of
depression [5,6] and heart failure [6]. N-Aminopyrazoles are also
used as intermediates in the production of a variety of nitrogen-
containing heterocycles [7]. The main method for the preparation
of N-aminopyrazoles is the electrophilic amination of a pyrazole
nitrogen. Recyclizations of hydrazinyl-substituted isoxazoles, het-
erocyclization with the participation of azides and reduction of
nitro derivatives are less often used [7]. The thermal rearrangement
of isoxazol-5-ylhydrazines gives 1-aminopyrazolin-5-ones [8].
Photochemical rearrangement of isoxazolopyridines [9] and iso-
xazolopyridazines [10], containing a hydrazinyl substituent in the
azine ring, yields N-aminopyrazole derivatives fused to the corre-
sponding azine ring in low yields. Catalytic transformation of iso-
xazoles into to N-aminopyrazole derivatives is to the best of our
knowledge unknown [7,11].
role derivatives under Fe(II)-catalysis [12]. Thus 4-vinylisoxazoles
are precursors of substituted pyrroles [12a], whereas 4-
arylisoxazoles give substituted indoles [12b] (Scheme 1). We hy-
pothesized that a replacement of the C]C moiety, which partici-
pates in the 1,5-cyclization of transient species during
rearrangement of 4-vinylisoxazoles, by another unsaturated frag-
ment such as RNHN ¼ C would lead to the corresponding N-ami-
nopyrazoles as products of the cyclization (Scheme 1).
2. Results and discussion
To check this hypothesis we tried to synthesize some hydra-
zones of 4-carbonyl-5-methoxyisoxazoles 1, which were prepared
according to modified published procedures by acylation of the
corresponding 3-substituted isoxazol-5(4H)-ones 2, followed by
methylation of the resulting 4-acyl-5-hydroxyisoxazoles 3 with
diazomethane (Scheme 2).
Unexpectedly, it was found that the corresponding hydrazones
were not formed by the reactions of 4-carbonylisoxazoles 1 with
hydrazine, phenylhydrazine and tosylhydrazine. Only the reaction
of 2,4-dinitrophenylhydrazine (DNPH) with isoxazoles 1 gave
hydrazones 4, either as the E-isomer or as a mixture of E/Z-isomers,
usually in good yields (Table 1). The E/Z-isomers were separated by
* Corresponding author.
E-mail address: a.khlebnikov@spbu.ru (A.F. Khlebnikov).
https://doi.org/10.1016/j.tet.2018.09.015
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
substituted isoxazoles, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.09.015

2
E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
E and Z isomers of hydrazones 4 does not occur by boiling their
solutions in acetonitrile or methanol. This would mean that a bar-
rier for the isomerization is too high for it to occur under these
conditions. Quantum-chemical calculations at the B3LYP/6-
31Gþ(d,p) level of the E and Z isomers of hydrazones 4a-e and of
the transition states of their Z/E-isomerization were performed to
evaluate the corresponding energy barriers. The barriers for the
transformation of the Z-hydrazones 4a-e to the corresponding E-
isomers are in the region of 35e37 kcal molꢀ1 and for the back
transformation are in the region of 34e37 kcal molꢀ1. The calcu-
lated barriers are high enough to prevent isomerization at the
temperatures used in this study. It is noteworthy that in the case
when only the E isomer (4a, b, d) was formed in the reaction of
DNPH with 4-carbonylisoxazoles 1a, b, d the corresponding Z iso-
mer according to the calculation is thermodynamically more stable.
The ratio of isomers is, therefore, defined by the reaction kinetics.
Next, we studied the reactivity of hydrazones 4a-h towards
FeCl2, including the effect of stereochemistry. The rearrangement of
the hydrazone of isoxazolecarbaldehyde E-4a proceeds easily
already at rt to give pyrazole 5a in 94% yield after 2 d (Table 2, entry
1). Changing the R2 substituent from H to Et has no influence on the
time of rearrangement (Table 2, entry 2), whereas introduction of a
nitro group into the phenyl moiety (R1) makes the reaction a little
slower, E- and Z-isomers react identically (Table 2, entry 3e5).
Isomer Z-4e rearranges much faster than isomer E-4e at rt, but at
70 ꢁC both the individual isomers as well as a mixture of isomers
gives 5e in 77%e92% yield only after 1 d (Table 2, entry 7e9). Steric
congestion in compound 4f with two Ph-substituents makes the
rearrangement at rt slower. The reaction of isomer Z-4f was also
accompanied by formation of some unidentified products. The
isomer E-4f under these conditions afforded azirine 6, which
Scheme 1. The routes of Fe(II)-catalyzed transformations of izoxazoles with unsatu-
rated substituent in the C4 position.
chromatography and their structures were established by standard
spectroscopic methods. The stereochemistry of the isomers of
hydrazones 4a-e,g,h were elucidated by 2D-NOESY 1H NMR spec-
troscopy, whereas XRD-analysis was used for hydrazone Z-4f
(Fig. 1).
Special experiments have shown that the interconversion of the
Scheme 2. Synthesis of starting 4-carbonyl-5-methoxyisoxazoles 1.
Table 1
Hydrazones of 4-carbonylisoxazoles.
entry
R1
R2
X
Yield of 4,a
%
Z/E ratio,b
%
Z, TSZ/E, E; MeOHc
Z, TSZ/E, E; MeCNc
1
2
3
4
5
6
7
8
Ph
Ph
H
Et
Et
Et
MeO
MeO
MeO
MeO
MeO
MeO
MeO
(CH2)4N
a, 91
b, 84
c, 83
d, 59
e, 66
f, 85
g, 67
h, 85
0/100
0/100
26/74
0/100
46/54
65/35
57/43
0/100
0.0, 35.4, 1.7
0.0, 36.7, 1.0
0.0, 37.0, 0.4
0.0, 36.8, 1.5
0.0, 35.7, 0.0
0.0, 35.4, 1.8
0.0, 36.7, 1.1
0.0, 37.0, 0.3
0.0, 36.8, 1.5
0.0, 35.8, 0.3
4-NO2C6H4
thien-2-yl
Me
Ph
4-MeC6H4
Ph
Ph
Ph
3-ClC6H4
H
a
Isolated yield.
b
c
According to 1H NMR analysis.
Relative Gibbs free energies of Z, E isomers 4 and transition states of their Z/E-isomerization computed at the DFT B3LYP/6-31 þ G(d,p) level (kcal molꢀ1, 298 K, PCM model
for MeOH and MeCN).
Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
substituted isoxazoles, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.09.015

E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
3
aminopyrazole E; (f) cleavage of the catalyst to give the final
product, N-aminopyrazole 5.
Although the 2,4-dinitrophenylamino moiety presents in com-
pounds with various bioactivity [14] we tried reducing one of the
NO2-groups of pyrazoles 5 to a more versatile amino group, which
could be useful for the synthesis of other substituted 1-(aryla-
mino)-1H-pyrazoles. Attempts to reduce directly the nitro groups
in these compounds were unsuccessful. Treatment of 5a, f with
hydrogen in the presence of Pd/C or Adams’ catalyst led to the
hydrogenolysis of the exocyclic N-N bond, affording methyl pyr-
azole-4-carboxylates 7a, b in high yields (Scheme 5).
The above mentioned problem was solved using protecting
group strategy. Acylation of 5b with p-toluoyl chloride in the
presence of Et3N afforded the N-protected aminopyrazole 8 in good
yield (Scheme 6). Hydrogenation of 8 with H2 on Pd/C led to a se-
lective reduction of the 2-nitro group to an amino group accom-
panied by the removal of the protecting group, giving target
aminopyrazole 9 in 88% yield.
3. Conclusion
An effective method is developed for the preparation of 1-
amino-1H-pyrazole-4-carboxylic acid derivatives
5 by Fe(II)-
catalyzed rearrangement of isoxazoles 4 having a hydrazono-
methyl substituent at C4. The rearrangement of the 4-(hydrazo-
nomethyl)-5-methoxyisoxazoles 4 in MeCN proceeds at rt for
2e25 d or for 1 d at 70 ꢁC affording 1-(2,4-dinitrophenylamino)-
1H-pyrazole-4-carboxylates 5 in high yields. The reaction proceeds
smoothly for both E and Z isomers of 4-(hydrazonomethyl)iso-
xazoles 4, and this means it is not necessary to separate mixtures of
E/Z-isomers of the hydrazones prepared by reaction of 5-methoxy/
pirrolidino-4-carbonylisoxazoles and 2,4-dinitrophenylhydrazine.
The interconversion of the E and Z isomers of hydrazones 4 does not
occur in acetonitrile or methanol at 65e82 ꢁC because of the high
barrier for the Z/E-isomerization, which according to calculations at
Fig. 1. Molecular structure of compound Z-4f.
further under Fe(II)-catalysis completely converted to pyrazole 5f
(Scheme 3). This suggests that the corresponding azirines are in-
termediates of the isoxazole 4 e pyrazole 5 rearrangement [11c],
although the transformation of E-4f is the only case where the
azirine intermediate was able to be isolated. The rearrangement
rate is significantly slowed down when the 5-MeO-group of
the B3LYP/6-31Gþ(d,p) level are in the region of 34e37 kcal molꢀ1
.
Changing the MeO substituent at C5 of the isoxazole 4 for a 5-
pyrrolidino substituent significantly slows down the reaction rate.
The rearrangement proceeds via the formation of an aziridine in-
termediate which can be isolated in one case. The 2-nitro group of
hydrazone
4 is replaced by a 5-pyrrolidino-substituent. For
instance, it was necessary to heat a solution of hydrazone 4h in
acetonitrile at 70 ꢁC for 3 days for complete conversion (Table 2,
entry 16). This is consistent with the previously observed retarding
of the opening of isoxazole ring under Fe(II)-catalysis conditions
when the methoxy-substituent at the 5-position was replaced by
the N-heterocycle [13]. The structures of aminopyrazoles 5a-h were
elucidated by standard spectroscopic methods and additionally the
structure of compound 5b was determined by XRD-analysis (Fig. 2).
An analysis of the results in Table 2 shows that there is no sense
in separating the mixtures of E/Z-isomers of the starting hydra-
zones of 4-carbonylisoxazoles before the preparation of N-amino-
pyrazoles by Fe(II)-catalyzed rearrangement.
the
synthesized
1-(2,4-dinitrophenylamino)-1H-pyrazole-4-
carboxylic esters 5 can be selectively reduced via acylation of the
amino group followed by hydrogenation-deacylation using H2-Pd/
C. The reduction of the N-nonacylated pyrazoles under these con-
ditions leads to hydrogenolysis of the exocyclic N-N bond, affording
the corresponding 1-unsubstituted pyrazoles with high yields.
4. Experimental section
4.1. General information and methods
On the basis of the obtained results and previous calculations
[12a,13], we propose the plausible reaction pathway shown in
Melting points were determined on a capillary melting point
apparatus Stuart® SMP30.1H (400 MHz) and 13C (100 MHz) NMR
spectra were recorded in CDCl3 or DMSO‑d6 with Bruker AVANCE III
Scheme
4 for the Fe(II)-catalyzed domino rearrangement of
hydrazonomethyl-substituted isoxazoles 4 to N-aminopyrazoles.
The mechanism involves the following steps: (a) the formation of
the isoxazole Fe-complex A, (b) opening of the isoxazole ring of A
via N-O bond cleavage to form the Fe-nitrene complex B having the
inappropriate configuration for 1,5-cyclization; (c) the recyclization
of complex B into the Fe-azirine complex C, which, according to the
calculation results [12a,13], should occur via a low activation bar-
rier; (d) low energy conformational transformation in C followed by
the opening of the three-membered ring leading to the Fe-nitrene
complex D with a configuration providing the possibility of 1,5-
cyclization, (e) 1,5-cyclization giving the Fe complex of N-
400 spectrometer. Chemical shifts (
million downfield from tetramethylsilane (TMS
d
) are reported in parts per
d
0.00). 1H NMR
spectra were calibrated according to the residual peak of CHCl3
(7.26 ppm), DMSO‑d6 (2.50 ppm). 13C{1H} and 13C DEPT-135 were
calibrated according to the peak of CDCl3 (77.00 ppm), DMSO‑d6
(39.51 ppm). Mass spectra were recorded on a Bruker maXis HRMS-
ESI-QTOF, electrospray ionization. Thin-layer chromatography
(TLC) was conducted on aluminum sheets with 0.2 mm silica gel
(fluorescent indicator, Macherey-Nagel) and Macherey-Nagel Silica
60M was used for column chromatography. Suitable single-crystals
of Z-4f and 5b were measured at Agilent Technologies SuperNova
Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
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E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
Table 2
Synthesis of aminopyrazoles 5.
entry
isoxazole
yielda of 5 at 20 ꢁC, %; time, d
yielda of 5 at 70 ꢁC, %; time, d
1
2
3
4
5
6
E-4a
94; 2
78; 2
83; 3
91; 3
88; 3
85; 2
e
e
e
e
e
E-4b
Z-4c
E-4c
Z/E-4c (26/74)
E-4d
e
7
8
9
Z-4e
E-4e
Z/E-4e (46/54)
83; 4
90; 20
77; 1
92; 1
83; 1
e
10
11
12
Z-4f
E-4f
Z/E-4f (65/35)
23; 6
96; 25
90; 1
67; 1
79; 1
e
13
14
Z-4g
E-4g
78; 6
95; 1
99; 1
e
e
e
15
16
Z/E-4g (57/43)
E-4h
94; 1
80; 3
a
Isolated yield.
diffractometer at a temperature of 100 K using monochromated
CuK radiation. Using Olex 2 [15], the structures were solved with
the ShelXT [16] structure solution program using Intrinsic Phasing
and refined with the ShelXL [16] refinement package using Least
Squares minimization. The crystallographic data and some
parameters of refinement are placed in Tables S1eS12 in the Sup-
plementary data. Crystallographic data for structures Z-4f and 5b
have been deposited with the Cambridge Crystallographic Data
Centre (CCDC, 1840301, 1840302). Compounds 1a [17], 1h [12a], 3d
[18] and 3e [19] were prepared by the reported procedures.
a
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E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
5
Scheme 3. Isomerization of isoxazole E-4f.
Scheme 4. Plausible reaction mechanism for the isomerization of isoxazoles 4 to N-
aminopyrazoles 5.
HCl added until pH 1e2 and extracted with DCM. The DCM solution
was washed with water and the product extracted with saturated
aq. Na2CO3. The aq. solution was acidified with conc. HCl until pH
1e2 and the precipitate formed was filtered off, washed with water
and dried in air to give analytically pure compound 3.
Fig. 2. Molecular structure of compound 5b.
4.2. Calculation details
4.3.1. 1-(5-Hydroxy-3-phenylisoxazol-4-yl)propan-1-one (3a)
Compound 3a (2.61 g, 60%) was prepared from 3-
phenylisoxazol-5(4H)-one 2a (3.22 g, 20 mmol), propionic anhy-
dride (3.25 g, 25 mmol), DMAP (5.50 g, 45 mmol) in benzene
(100 mL). Yellowish solid, mp 81e83 ꢁC (water). Rf (10% MeOH in
All calculations were performed by using the Gaussian 16 suite
of quantum chemical programmes [20] at Resource Centre “Com-
puter Centre of Saint Petersburg State University”. Geometry opti-
mizations of molecules were performed with the B3LYP density
functional method [21] and 6-31þG(d,p) basis set using PCM sol-
vent model [22]. Stationary points on the respective potential-
energy surfaces were characterized at the same level of theory by
evaluating the corresponding Hessian indices. Careful verification
of the unique imaginary frequency for the transition state was
carried out to check whether the frequency indeed pertains to the
desired reaction coordinate.
chloroform) 0.31.1H NMR (CDCl3, 400 MHz):
d
1.10 (t, J ¼ 7.5 Hz, 3H),
2.40 (q, J ¼ 7.5 Hz, 2H), 7.46e7.54 (m, 5H), 11.91 (br.s, 1H). 13C NMR
(CDCl3, 100 MHz): d 9.9 (CH3), 27.5 (CH2), 96.9 (C), 128.5 (CH), 128.8
(CH), 130.6 (CH), 161.4 (C), 176.7 (C), 188.7 (C). HRMS (ESI) m/z:
218.0812 calcd. for C12H12NOþ3 [MþH]þ, found 218.0820.
4.3.2. 1-(5-Hydroxy-3-(4-nitrophenyl)isoxazol-4-yl)propan-1-one
(3b)
4.3. General procedure for the preparation of 4-acyl-5-hydroxy-3-
R1-isoxazoles 3
Compound 3b (1.56 g, 50%) was prepared from 3-(4-
nitrophenyl)isoxazol-5(4H)-one 2b (2.47 g, 12 mmol), propionic
anhydride (2.34 g, 18 mmol), DMAP (3.30 g, 27 mmol) in benzene
(50 mL). Yellowish solid, mp 121e123 ꢁC (dec., water). Rf (10%
Compounds 3 were prepared according to a modified published
procedure [18]. A mixture of isoxazolone 2 (1.0 mmol), an acylating
agent (1.2e1.5 mmol) and DMAP (2.2e2.3 mmol) was refluxed in
benzene (3e6 mL) for 6 h. The reaction mixture was cooled, 5% aq.
MeOH in chloroform) 0.23.1H NMR (DMSO‑d6, 400 MHz):
d
0.94 (t,
J ¼ 7.5 Hz, 3H), 2.68 (q, J ¼ 7.5 Hz, 2H), 5.10 (br. s, 1H), 7.80 (d,
Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
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6
E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
Scheme 5. Hydrogenolysis of the N-N bond in N-aminopyrazoles 5b, f.
Scheme 6. Selective reduction of compound 8.
J ¼ 8.7 Hz, 2H), 8.19 (d, J ¼ 8.7 Hz, 2H). 13C NMR (DMSO‑d6,
of diazomethane was quenched with acetic acid and the solvents
were removed in vacuum. A solution of the residue in DCM was
filtered through a pad of silica, eluting with light petroleum ether/
EtOAc (3:1) to give, after evaporation of the solvents, washing of the
precipitate with pentane and drying on air, analytically pure com-
pound 1.
100 MHz):
d 9.3 (CH3), 30.9 (CH2), 90.0 (C), 122.4 (CH), 130.0 (CH),
139.6 (C), 147.2 (C), 161.3 (C), 175.1 (C), 191.9 (C). HRMS (ESI) m/z:
263.0662 calcd. for C12H11N2Oþ5 [MþH]þ, found 263.0669.
4.3.3. 1-(5-Hydroxy-3-(thiophen-2-yl)isoxazol-4-yl)propan-1-one
(3c)
Compound 3c (0.806 g, 40%) was prepared from 3-(thiophen-2-
yl)isoxazol-5(4H)-one 2c (1.50 g, 9 mmol), propionic anhydride
(1.76 g, 14 mmol), DMAP (2.47 g, 20 mmol) in benzene (50 mL).
Yellow solid, mp 131e133 ꢁC (dec., water). Rf (10% MeOH in chlo-
4.4.1. 1-(5-Methoxy-3-phenylisoxazol-4-yl)propan-1-one (1b)
Compound 1b (662 mg, 77%) was prepared from isoxazole 3a
(800 mg, 3.7 mmol) in THF (8 mL), NMU (952 mg, 9.3 mmol) in
ether (30 mL) and KOH (2.07 g, 37 mmol) in water (3 mL). Colorless
solid, mp 120e122 ꢁC (petroleum ether/EtOAc). Rf (25% EtOAc in
roform) 0.21.1H NMR (CDCl3, 400 MHz):
d
1.21 (t, J ¼ 7.5 Hz, 3H),
2.62 (q, J ¼ 7.5 Hz, 2H), 7.18e7.20 (m, 1H), 7.35 (d, J ¼ 3.1 Hz, 1H),
petroleum ether) 0.33.1H NMR (CDCl3, 400 MHz):
d
1.08 (t,
J ¼ 7.3 Hz, 3H), 2.71 (q, J ¼ 7.3 Hz, 2H), 4.31 (s, 3H), 7.41e7.49 (m,
3H), 7.59e7.62 (m, 2H). 13C NMR (CDCl3, 100 MHz):
7.6 (CH3), 34.9
7.56 (d, J ¼ 4.9 Hz, 1H), 12.92 (br. s, 1H). 13C NMR (CDCl3, 100 MHz):
d
10.0 (CH3), 27.5 (CH2), 97.0 (C), 127.8 (CH), 128.2 (C), 129.3 (CH),
d
129.9 (CH), 155.7 (C), 176.8 (C), 188.7 (C). HRMS (ESI) m/z: 246.0195
(CH2), 58.7 (CH3), 95.9 (C), 128.0 (CH), 128.8 (C), 129.2 (CH), 130.0
(CH), 165.3 (C), 173.0 (C), 193.1 (C). HRMS (ESI) m/z: 254.0788 calcd.
for C13H13NaNOþ3 [MþNa]þ, found 254.0794.
calcd. for C10H9NNaO3Sþ [MþNa]þ, found 246.0200.
4.3.4. (3-Chlorophenyl)(5-hydroxy-3-(p-tolyl)isoxazol-4-yl)
methanone (3f)
4.4.2. 1-(5-Methoxy-3-(4-nitrophenyl)isoxazol-4-yl)propan-1-one
(1c)
Compound 3f (1.97 g, 71%) was prepared from 3-(p-tolyl)iso-
xazol-5(4H)-one 2d (1.54 g, 8.8 mmol), 3-chlorobenzoyl chloride
(2.32 g, 13.2 mmol), DMAP (2.42 g, 19.8 mmol) in benzene (50 mL).
Orange solid, mp 162e164 ꢁC (water). Rf (10% MeOH in chloroform)
Compound 1c (362 mg, 35%) was prepared from isoxazole 3b
(1.00 g, 3.8 mmol) in THF (25 mL), NMU (979 mg, 9.5 mmol) in ether
(40 mL) and KOH (2.13 g, 38 mmol) in water (3.2 mL). Yellowish
solid, mp 137e138 ꢁC (light petroleum ether/EtOAc). Rf (25% EtOAc
0.32.1H NMR (DMSO‑d6, 400 MHz):
d. 2.31 (s, 3H), 6.12 (br. s, 1H),
7.12 (d, J ¼ 7.9 Hz, 2H), 7.30e7.34 (m, 1H), 7.36 (d, J ¼ 7.9 Hz, 2H),
in petroleum ether) 0.21.1H NMR (CDCl3, 400 MHz):
d 1.10 (t,
7.40e7.7.43 (m, 1H), 7.46e7.50 (m, 2H), 13C NMR (DMSO‑d6,
J ¼ 7.3 Hz, 3H), 2.78 (q, J ¼ 7.3 Hz, 2H), 4.36 (s, 3H), 7.81 (d,
100 MHz):
d 20.9 (CH3), 127.2 (CH), 127.3 (C), 128.0 (C), 128.1 (CH),
J ¼ 8.8 Hz, 2H), 8.28 (d, J ¼ 8.8 Hz, 2H). 13C NMR (CDCl3, 100 MHz):
128.3 (CH), 128.4 (CH), 129.2 (CH), 129.6 (CH), 138.0 (C), 142.4 (C),
d 7.4 (CH3), 34.9 (CH2), 59.1 (CH3), 95.9 (C), 123.1 (CH), 130.5 (CH),
163.5 (C), 173.9 (C), 185.2 (C). HRMS (ESI) m/z: 314.0578 calcd. for
C
135.2 (C), 148.7 (C), 163.7 (C), 173.3 (C), 192.9 (C). HRMS (ESI) m/z:
17H13ClNOþ3 [MþH]þ, found 314.0585.
277.0817 calcd. for C13H13N2Oþ5 [MþH]þ, found 277.0813.
4.4. General procedure for the preparation of 4-acyl-5-methoxy-3-
4.4.3. 1-(5-Methoxy-3-(thiophen-2-yl)isoxazol-4-yl)propan-1-one
(1d)
R1-isoxazoles 1b-g
Compound 1d (462 mg, 60%) was prepared from isoxazole 3c
(717 mg, 3.2 mmol) in THF (12 mL), NMU (864 mg, 8.4 mmol) in
ether (19 mL) and KOH (5.80 g, 103 mmol) in water (8.4 mL).
Yellowish solid, mp 98e99 ꢁC (light petroleum ether/EtOAc). Rf
(25% EtOAc in petroleum ether) 0.35.1H NMR (CDCl3, 400 MHz):
4-Acyl-5-methoxy-3-substituted isoxazoles 1 were prepared
according to a slightly modified published procedure [12a]. To a
suspension or solution of 4-acyl-5-hydroxyisoxazole 3 (1 mmol) in
THF (5 mL) a solution of diazomethane, prepared from N-nitroso-N-
methylurea (NMU) (2.5 mmol), 40% aq KOH (25 mmol) and ether
(10 mL), was slowly added under stirring and ice-cooling. The re-
action mixture was stirred for 1 h at room temperature, the excess
d
1.14 (t, J ¼ 7.2 Hz, 3H), 2.79 (q, J ¼ 7.2 Hz, 2H), 4.31 (s, 3H), 7.11e7.13
(m, 1H), 7.44 (d, J ¼ 5.0 Hz, 1H), 8.07 (d, J ¼ 3.6 Hz, 1H). 13C NMR
(CDCl3, 100 MHz):
d 7.7 (CH3), 35.0 (CH2), 58.8 (CH3), 95.7 (CH),
Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
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E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
7
127.4 (CH), 128.6 (CH), 128.9 (C), 131.7 (CH), 159.2 (C), 173.4 (C),
193.4 (C). HRMS (ESI) m/z: 238.0532 calcd. for C11H12NO3Sþ
[MþH]þ, found 238.0530.
HRMS (ESI) m/z: 406.0769 calcd. for C17H13NaN5Oþ6 [MþNa]þ, found
406.0781.
4.5.2. (E)-4-(1-(2-(2,4-Dinitrophenyl)hydrazono)propyl)-5-
methoxy-3-phenylisoxazole (4b)
Compound 4b (310 mg, 84%) was prepared from isoxazole 1b
(208 mg, 0.9 mmol) and DNPH (200 mg, 1.0 mmol) in MeOH (7 mL).
Red solid, mp 140e142 ꢁC (MeOH). Rf (toluene) 0.17.1H NMR
4.4.4. (5-Methoxy-3-methylisoxazol-4-yl)(phenyl)methanone (1e)
Compound 1e (1.085 g, 78%) was prepared from isoxazole 3d
(1.35 g, 6.7 mmol) in THF (28 mL), NMU (1.703 g, 16.5 mmol) in
ether (40 mL) and KOH (3.75 g, 67 mmol) in water (5.6 mL).
Yellowish solid, mp 57e59 ꢁC (light petroleum ether/EtOAc) (lit
[22]. 63e64 ꢁC). Rf (25% EtOAc in petroleum ether) 0.32.1H NMR
(DMSO‑d6, 400 MHz):
d
1.18 (t, J ¼ 7.6 Hz, 3H), 2.71 (q, J ¼ 7.6 Hz,
2H), 4.28 (s, 3H), 6.62 (d, J ¼ 9.6 Hz, 1H), 7.49e7.55 (m, 4H),
(CDCl3, 400 MHz):
7.52e7.57 (m, 1H), 7.69e7.71 (m, 2H). 13C NMR (CDCl3, 100 MHz):
12.5 (CH3), 58.4 (CH3), 95.4 (C), 128.1 (CH), 128.7 (CH), 132.4 (CH),
d 2.40 (s, 3H), 4.08 (s, 3H), 7.42e7.46 (m, 2H),
7.57e7.61 (m, 1H), 7.98 (dd, J ¼ 9.6, 2.6 Hz, 1H), 8.79 (d, J ¼ 2.6 Hz,
1H), 11.03 (s, 1H). 13C NMR (DMSO‑d6, 100 MHz):
d 9.2 (CH3), 21.2
d
(CH2), 59.2 (CH3), 91.7 (C), 115.7 (CH), 122.8 (CH), 128.4 (CH), 128.6
(CH), 129.1 (CH), 129.35 (C), 129.42 (CH), 130.2 (C), 137.0 (C), 144.1
(C), 150.2 (C), 163.9 (C), 170.2 (C). HRMS (ESI) m/z: 434.1071 calcd.
for C19H17NaN5O6þ [MþNa]þ, found 434.1065.
138.4 (C), 164.0 (C), 171.5 (C), 188.1 (C). HRMS (ESI) m/z: 218.0812
calcd. for C12H12NOþ3 [MþH]þ, found 218.0819.
4.4.5. 1-(5-Methoxy-3-phenylisoxazol-4-yl)(phenyl)methanone
(1f)
4.5.3. (E/Z)-4-(1-(2-(2,4-Dinitrophenyl)hydrozono)propyl)-5-
methoxy-3-(4-nitrophenyl)isoxazole (4c)
Compound 1f (1.41 g, 67%) was prepared from isoxazole 3e
(2.00 g, 7.5 mmol) in THF (20 mL), NMU (1.93 g, 19 mmol) in ether
(20 mL) and KOH (4.20 g, 75 mmol) in water (6.3 mL). Colorless
solid, mp 129e130 ꢁC (light petroleum ether/EtOAc). Rf (25% EtOAc
Compound 4c (417 mg, 83%) was prepared from isoxazole 1c
(304 mg, 1.1 mmol) and DNPH (218 mg, 1.1 mmol) in MeOH (9 mL).
Orange solid, mp 182e184 ꢁC (MeOH), Z/E ratio, 0.35:1 (1H NMR). A
mixture of isomers (329 mg) was separated to give (Z)-isomer
76 mg (1st fraction) and (E)-isomer 205 mg (2nd fraction).
(Z)-4-(1-(2-(2,4-Dinitrophenyl)hydrozono)propyl)-5-methoxy-3-
(4-nitrophenyl)isoxazole (Z-4c) Yellow solid, mp 174e176 ꢁC
in petroleum ether) 0.31.1H NMR (CDCl3, 400 MHz):
d
4.19 (s, 3H),
7.29e7.39 (m, 5H), 7.46e7.52 (m, 3H), 7.71e7.73 (m, 2H). 13C NMR
(CDCl3, 100 MHz): 58.6 (CH3), 98.8 (C), 128.1 (CH), 128.3 (CH),
d
128.5 (C), 128.6 (CH), 129.3 (CH), 130.0 (CH), 132.8 (CH), 137.8 (C),
165.3 (C), 172.3 (C), 187.7 (C). HRMS (ESI) m/z: 280.0968 calcd. for
(toluene). Rf (toluene) 0.19.1H NMR (DMSO‑d6, 400 MHz):
d 1.16 (t,
C
17H14NaNOþ3 [MþH]þ, found 280.0979.
J ¼ 7.4 Hz, 3H), 2.56 (q, J ¼ 7.4 Hz, 2H), 4.25 (s, 3H), 7.74e7.78 (m,
2H), 7.86 (d, J ¼ 9.6 Hz, 1H), 8.25e8.28 (m, 2H), 8.36 (dd, J ¼ 9.6,
2.5 Hz, 1H), 8.76 (d, J ¼ 2.5 Hz, 1H), 10.79 (s, 1H). 13C NMR (DMSO‑d6,
4.4.6. (3-Chlorophenyl)(5-methoxy-3-(p-tolyl)isoxazol-4-yl)
methanone (1g)
100 MHz):
d 8.9 (CH3), 21.1 (CH2), 59.3 (CH3), 91.9 (C), 115.1 (CH),
Compound 1g (286 mg, 27%) was prepared from isoxazole 3f
(1.00 g, 3.2 mmol) in THF (35 mL), NMU (0.824 g, 8 mmol) in ether
(70 mL) and KOH (1.79 g, 32 mmol) in water (2.7 mL). Orange solid,
mp 106e107 ꢁC (light petroleum ether/EtOAc). Rf (25% EtOAc in
122.6 (CH), 123.4 (CH), 129.1 (CH), 129.4 (C), 129.8 (CH), 136.2 (C),
137.1 (C), 143.9 (C), 148.1 (C), 149.8 (C), 162.1 (C), 170.3 (C). HRMS
(ESI) m/z: 455.0957 calcd. for C19H15N6Oꢀ8 [M-H]-, found 455.0936.
(E)-4-(1-(2-(2,4-Dinitrophenyl)hydrozono)propyl)-5-methoxy-3-
(4-nitrophenyl)isoxazole (E-4c) Orange solid, mp 192e194 ꢁC
petroleum ether) 0.22.1H NMR (CDCl3, 400 MHz):
d 2.34 (s, 3H), 4.19
(s, 3H), 7.14 (d, J ¼ 8.0 Hz, 2H), 7.28e7.30 (m, 1H), 7.39 (d, J ¼ 8.0 Hz,
(toluene)). Rf (toluene) 0.09.1H NMR (DMSO‑d6, 400 MHz):
d 1.22 (t,
2H), 7.43e7.46 (m, 1H), 7.56e7.58 (m, 1H), 7.67e7.68 (m, 1H). 13C
J ¼ 7.6 Hz, 3H), 2.76 (q, J ¼ 7.6 Hz, 2H), 4.31 (s, 3H), 6.71 (d,
J ¼ 9.6 Hz, 1H), 7.84 (d, J ¼ 8.7 Hz, 2H), 8.01 (dd, J ¼ 9.6, 2.5 Hz, 1H),
8.34 (d, J ¼ 8.7 Hz, 2H), 8.81 (d, J ¼ 2.5 Hz, 1H), 11.03 (s, 1H). 13C NMR
NMR (CDCl3, 100 MHz):
d 21.4 (CH3), 58.7 (CH3), 94.5 (C), 125.3 (C),
127.3 (CH),128.5 (CH),129.1 (CH), 129.3 (CH),129.4 (CH),132.5 (CH),
134.3 (C), 139.5 (C), 140.3 (C), 165.2 (C), 172.4 (C), 186.2 (C). HRMS
(DMSO‑d6, 100 MHz):
d 10.3 (CH3), 29.8 (CH2), 59.2 (CH3), 85.8 (C),
(ESI) m/z: 328.0735 calcd. for
328.0747.
C
18H15ClNOþ3 [MþH]þ, found
115.9 (CH), 122.4 (CH), 123.9 (CH), 128.1 (CH), 129.3 (C), 129.7 (CH),
134.0 (C), 137.2 (C), 143.7 (C), 148.4 (C), 149.1 (C), 160.6 (C), 169.5
(C).). HRMS (ESI) m/z: 455.0957 calcd. for C19H15N6Oꢀ8 [M-H]-, found
455.0936.
4.5. General procedure for the preparation hydrazones 4
2,4-Dinitrophenylhydrazone of 4-acyl-5-methoxy-3-
4.5.4. (E)-4-(1-(2-(2,4-dinitrophenyl)hydrazineylidene)propyl)-5-
methoxy-3-(thiophen-2-yl)isoxazole (2d)
Compound 2d (248 mg, 59%) was prepared from isoxazole 1d
(237 mg, 1.0 mmol) and DNPH (198 mg, 1.0 mmol) in MeOH (4 mL).
Red solid, mp 158e159 ꢁC (MeOH). Rf (toluene) 0.20.13C NMR
substituted isoxazoles 4 were prepared according to a modified
published procedure [23]. A mixture of 4-acylisoxazol 1 (1 mmol),
DNPH (1e1.2 mmol) and 1 drop of conc. HCl in MeOH (5e10 mL)
was refluxed for 15 min. Reaction mixture was cooled, precipitate
formed was filtered off, washed with cold MeOH and dried to give
analytically pure compound. If appropriate (E/Z)-isomers were
separated by column chromatography on silica (eluent toluene).
(DMSO‑d6,100 MHz):
d
1.16 (t, J ¼ 7.6 Hz, 3H), 2.74 (q, J ¼ 7.6 Hz,1H),
7.20 (dd, J ¼ 5.0, 3.6 Hz, 1H), 7.38 (d, J ¼ 9.6 Hz, 1H), 7.51 (dd, J ¼ 3.6,
1.0, 1H), 7.77 (dd, J ¼ 5.0, 1.0 Hz, 1H), 8.24 (dd, J ¼ 9.6, 2.5 Hz, 1H),
8.84 (d, J ¼ 2.5 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO‑d6, 100 MHz):
4.5.1. (E)-4-((2-(2,4-Dinitrophenyl)hydrazono)methyl)-5-methoxy-
3-phenylisoxazole (4a)
Compound 4a (349 mg, 91%) was prepared from isoxazole 1a
(204 mg, 1.0 mmol) and DNPH (198 mg, 1.02 mmol) in MeOH
(5 mL). Orange solid, mp 155e156 ꢁC (MeOH). Rf (toluene) 0.10.1H
d 8.9 (CH3), 22.0 (CH2), 59.0 (CH3), 91.5 (C), 115.7 (CH), 122.5 (CH),
127.3 (CH), 128.5 (CH), 128.9 (CH), 129.1 (C), 129.47 (CH), 129.54 (C),
137.3 (C), 144.1 (C), 150.0 (C), 157.6 (C), 170.1 (C). HRMS (ESI) m/z:
416.0670 calcd. for C17H14N5O6Sꢀ [M-H]-, found 416.0645.
NMR (CDCl3, 400 MHz):
(m, 2H), 7.88 (s, 1H), 8.20 (dd, J ¼ 9.6, 2.5 Hz, 1H), 9.09 (d, J ¼ 2.5 Hz,
1H), 11.10 (s, 1H). 13C NMR (DMSO‑d6, 100 MHz):
59.1 (CH3), 89.4
(C), 116.3 (CH), 122.9 (CH), 128.4 (C), 128.63 (CH), 128.65 (CH), 129.3
(CH), 130.2 (CH), 136.5 (C), 139.8 (CH), 144.2 (C), 163.0 (C), 171.0 (C).
d
4.34 (s, 3H), 7.51e7.60 (m, 4H), 7.67e7.70
4.5.5. (E/Z)-((2-(2,4-Dinitrophenyl)hydrazono)(phenyl)methyl)-5-
methoxy-3-methylisoxazole (4e)
Compound 4e (579 mg, 66%) was prepared from isoxazole 1e
(308 mg, 2.4 mmol) and DNPH (436 mg, 2.2 mmol) in MeOH
(10 mL). Orange solid, Z/E ratio, 0.85:1 (1H NMR). A mixture of
d
Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
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8
E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
isomers (350 mg) was separated to give (Z)-isomer 129 mg (1st
fraction) and (E)-isomer 169 mg (2nd fraction).
2.5 Hz, 1H), 8.81 (d, J ¼ 2.5 Hz, 1H), 11.12 (s, 1H). 13C NMR (DMSO‑d6,
100 MHz):
d 20.5 (CH3), 58.9 (CH3), 82.1 (C), 116.7 (CH), 122.4 (CH),
(Z)-4-((2-(2,4-Dinitrophenyl)hydrazono)(phenyl)methyl)-5-
125.7 (CH), 126.0 (CH), 126.3 (CH), 129.2 (CH), 129.8 (CH), 130.4
(CH), 130.5 (C), 137.4 (C), 138.2 (C), 140.1 (C), 142.0 (C), 143.2 (C),
162.4 (C), 169.9 (C). HRMS (ESI) m/z: 506.0873 calcd. for
methoxy-3-methylisoxazole (Z-4e) Orange solid, mp 180e182 ꢁC
(toluene). Rf (toluene) 0.19.1H NMR (CDCl3, 400 MHz):
d 1.95 (s, 3H),
4.21 (s, 3H), 7.43e7.49 (m, 3H), 7.68e7.71 (m, 2H), 8.18 (d, J ¼ 9.5 Hz,
C
24H17ClN5Oꢀ6 [M-H]-, found 506.0849.
1H), 8.38 (dd, J ¼ 9.5, 2.5 Hz, 1H), 9.14 (d, J ¼ 2.5 Hz, 1H), 11.31 (s,
(E)-4-((3-Chlorophenyl)(2-(2,4-dinitrophenyl)hydrazono)
1H). 13C NMR (CDCl3, 100 MHz):
d
12.0 (CH3), 58.5 (CH3), 84.6 (C),
methyl)-5-methoxy-3-(p-tolyl)isoxazole (E-4g). Orange solid, mp
116.9 (CH), 123.4 (CH), 127.6 (CH), 128.8 (CH), 129.8 (C), 130.0 (CH),
130.6 (CH), 135.9 (C), 138.4 (C), 138.4 (C), 144.3 (C), 144.4 (C), 161.9
(C), 169.5 (C). HRMS (ESI) m/z: 420.0915 calcd. for C18H15NaN5O6þ
[MþNa]þ, found 420.0931.
166e168 ꢁC (toluene). Rf (toluene) 0.19.1H NMR (DMSO‑d6,
400 MHz):
d
2.36 (s, 3H), 4.06 (s, 3H), 7.11 (d, J ¼ 9.5 Hz, 1H), 7.25 (d,
J ¼ 8.0 Hz, 2H), 7.42 (d, J ¼ 8.0 Hz, 2H), 7.49e7.51 (m, 1H), 7.54e7.59
(m, 2H), 7.64 (m, 1H), 8.13 (dd, J ¼ 9.5, 2.5 Hz,1H), 8.75 (d, J ¼ 2.5 Hz,
(E)-4-((2-(2,4-Dinitrophenyl)hydrazono)(phenyl)methyl)-5-
methoxy-3-methylisoxazole (E-4e) Red solid, mp 176e177 ꢁC
1H), 11.14 (s, 1H). 13C NMR (DMSO‑d6, 100 MHz):
d 20.6 (CH3), 58.8
(CH3), 91.8 (C), 115.8 (CH), 122.4 (CH), 129.3 (C), 126.5 (CH), 127.7
(CH), 128.2 (CH), 128.6 (CH), 129.1 (CH), 129.9 (CH), 131.0 (CH), 132.7
(C), 134.0 (C), 137.3 (C), 138.9 (C), 143.7 (C), 163.6 (C), 170.6 (C).
HRMS (ESI) m/z: 506.0873 calcd. for C24H17ClN5Oꢀ6 [M-H]-, found
506.0848.
(toluene). Rf (toluene) 0.09.1H NMR (CDCl3, 400 MHz):
d 2.42 (s,
3H), 3.93 (s, 3H), 7.32e7.34 (m, 2H), 7.58e7.61 (m, 3H), 7.94 (d,
J ¼ 9.6 Hz, 1H), 8.34 (dd, J ¼ 9.6, 2.5 Hz, 1H), 9.06 (d, J ¼ 2.5 Hz, 1H),
11.27 (s, 1H). 13C NMR (CDCl3, 100 MHz):
d 13.9 (CH3), 58.1 (CH3),
92.3 (C), 116.1 (CH), 123.5 (CH), 127.4 (CH), 129.2 (C), 129.8 (CH),
130.0 (CH), 130.6 (CH), 131.4 (C), 137.7 (C), 144.4 (C), 149.0 (C), 161.5
(C), 170.8 (C). HRMS (ESI) m/z: 420.0915 calcd. for C18H15NaN5O6þ
[MþNa]þ, found 420.0926.
4.5.8. (E)-4-((2-(2,4-Dinitrophenyl)hydrazono)methyl)-3-phenyl-
5-(pyrrolidin-1-yl)isoxazole (4h)
Compound 4h (360 mg, 85%) was prepared from isoxazole 1h
(242 mg, 1.0 mmol) and DNPH (200 mg, 1.02 mmol) in MeOH
(8 mL). Dark brown solid, mp 211e212 ꢁC (dec., MeOH). Rf (toluene)
4.5.6. (E/Z)-4-((2-(2,4-Dinitrophenyl)hydrazono)(phenyl)methyl)-
5-methoxy-3-phenylisoxazole (4f)
0.06.1H NMR (DMSO‑d6, 400 MHz):
d 2.02e2.05 (m, 4H), 3.67e3.70
Compound 4f (421 mg, 85%) was prepared from isoxazole 1f
(300 mg, 1.1 mmol) and DNPH (218 mg, 1.1 mmol) in MeOH (8 mL).
Orange solid, mp 198e200 ꢁC (MeOH), Z/E ratio, 1:0.55 (1H NMR). A
mixture of isomers (348 mg) was separated to give (Z)-isomer
221 mg (1st fraction) and (E)-isomer 116 mg (2nd fraction).
(Z)-4-((2-(2,4-Dinitrophenyl)hydrazono)(phenyl)methyl)-5-
methoxy-3-phenylisoxazole (Z-4f) Yellow solid, mp 168e170 ꢁC
(m, 4H), 6.93 (d, J ¼ 9.7 Hz, 1H), 7.54e7.59 (m, 5H), 7.98 (dd, J ¼ 9.7,
2.6 Hz, 1H), 8.64 (s, 1H), 8.78 (d, J ¼ 2.6 Hz, 1H), 11.42 (s, 1H). 13C
NMR (DMSO‑d6, 100 MHz):
d 24.6 (CH2), 48.7 (CH2), 88.4 (C), 116.2
(CH), 122.7 (CH), 128.0 (CH), 128.0 (C), 128.4 (CH), 128.6 (CH), 128.9
(CH), 130.1 (C), 135.7 (C), 141.8 (CH), 143.8 (C), 162.5 (C), 165.9 (C).
HRMS (ESI) m/z: 445.1231 calcd. for C20H18NaN6Oþ5 [MþNa]þ, found
445.1247.
(toluene). Rf (toluene) 0.28.1H NMR (CDCl3, 400 MHz):
d 4.21 (s,
3H), 7.21e7.30 (m, 3H), 7.36e7.42 (m, 3H), 7.47e7.50 (m, 2H),
7.75e7.78 (m, 2H), 8.10 (d, J ¼ 9.5 Hz, 1H), 8.33 (dd, J ¼ 9.5, 2.5 Hz,
1H), 9.06 (d, J ¼ 2.5 Hz, H), 11.34 (s, 1H). 13C NMR (CDCl3, 100 MHz):
4.6. Synthesis of N-aminopyrazoles 5 by Fe(II)-catalyzed
isomerization of hydrazones of 4-carbonylisoxazoles 4
d
58.7 (CH3), 83.0 (C), 116.7 (CH), 123.4 (CH), 127.0 (CH), 127.4 (CH),
A mixture of hydrazone 4 (1 mmol) and FeCl2$4H2O (0.1 mmol)
in dry MeCN (5 mL) was stirred at room temperature (procedure A)
or at 70 ꢁC (procedure B) till the completion of the reaction
(monitoring by TLC). The solvent was evaporated in vacuo, the
residue was dissolved in DCM and purified by column chroma-
tography (DCM/MeOH 1:0e100:1). After the evaporation of the
solvents the precipitate was washed with pentane and dried on air
to give analytically pure compound 5.
128.1 (C), 128.76 (CH), 128.79 (CH), 129.8 (C), 129.9 (CH), 130.5 (CH),
130.6 (CH), 135.6 (C), 138.4 (C), 144.2 (C), 144.7 (C), 163.4 (C), 170.1
(C). HRMS (ESI) m/z: 482.1071 calcd. for C23H17NaN5Oþ6 [MþNa]þ,
482.1088.
(E)-4-((2-(2,4-Dinitrophenyl)hydrazono)(phenyl)methyl)-5-
methoxy-3-phenylisoxazole (E-4f) Orange solid, mp 180e182 ꢁC
(toluene). Rf (toluene) 0.16.1H NMR (CDCl3, 400 MHz):
d 4.02 (s, 3H),
6.96 (d, J ¼ 9.6 Hz, 1H), 7.35e7.57 (m, 10H), 8.00 (dd, J ¼ 9.6, 2.5 Hz,
1H), 8.97 (d, J ¼ 2.5 Hz, 1H),11.32 (s, 1H). 13C NMR (CDCl3, 100 MHz):
4.6.1. Methyl 1-((2,4-dinitrophenyl)amino)-3-phenyl-1H-pyrazole-
4-carboxylate (5a)
d
58.4 (CH3), 92.3 (C), 116.5 (CH), 123.2 (CH), 127.6 (CH), 128.4 (CH),
128.8 (CH), 129.2 (C), 129.4 (CH), 129.5 (CH), 129.7 (CH), 130.1 (C),
130.6 (CH), 131.1 (C), 137.9 (C), 144.4 (C), 146.6 (C), 164.6 (C), 171.0
(C). HRMS (ESI) m/z: 482.1071 calcd. for C23H17NaN5O6 [MþNa]þ,
found 482.1069.
Compound 5a (104 mg, 94%) was prepared from hydrazone 4a
(111 mg, 0.29 mmol) and FeCl2$4H2O (6 mg, 0.03 mmol) in MeCN
(7 mL) according to procedure A for 2 days. Yellow solid, mp
86e87 ꢁC (DCM). Rf (DCM) 0.30.1H NMR (CDCl3, 400 MHz):
d 3.86 (s,
3H), 6.55 (d, J ¼ 9.3 Hz, 1H), 7.42e7.43 (m, 3H), 7.76e7.78 (m, 2H),
4.5.7. (E/Z)-4-((3-Chlorophenyl)(2-(2,4-dinitrophenyl)hydrazono)
methyl)-5-methoxy-3-(p-tolyl)isoxazole (4g)
8.18 (s, 1H), 8.30 (dd, J ¼ 9.3, 2.4 Hz, 1H), 9.16 (d, J ¼ 2.4 Hz, 1H),
10.55 (s, 1H). 13C NMR (CDCl3, 100 MHz):
d 51.8 (CH3), 112.5 (C),
Compound 4g (180 mg, 67%) was prepared from isoxazole 1g
(173 mg, 0.53 mmol) and DNPH (105 mg, 0.53 mmol) in MeOH
(4 mL). Orange solid, mp 195e196 ꢁC (MeOH), Z/E ratio, 1:0.75 (1H
NMR). A mixture of isomers (170 mg) was separated to give (Z)-
isomer 87 mg (1st fraction) and (E)-isomer 71 mg (2nd fraction).
(Z)-4-((3-Chlorophenyl)(2-(2,4-dinitrophenyl)hydrazono)
115.6 (CH), 122.9 (CH), 128.1 (CH), 129.1 (CH), 129.3 (CH), 130.5 (CH),
130.7 (C), 132.2 (C), 136.4 (CH), 140.6 (C), 146.8 (C), 153.4 (C), 162.3
(C). HRMS (ESI) m/z: 384.0939 calcd. for C17H14N5Oþ6 [MþH]þ,
found 384.0937.
4.6.2. Methyl 1-((2,4-dinitrophenyl)amino)-5-ethyl-3-phenyl-1H-
pyrazole-4-carboxylate (5b)
methyl)-5-methoxy-3-(p-tolyl)isoxazole (Z-4g). Orange solid, mp
171e173 ꢁC (toluene). Rf (toluene) 0.31.1H NMR (DMSO‑d6,
Compound 5b (38 mg, 78%) was prepared from hydrazone 4b
(49 mg, 0.12 mmol) and FeCl2$4H2O (3 mg, 0.015) in MeCN (2 mL)
according to procedure A for 2 days. Colorless solid, mp 199e200 ꢁC
400 MHz):
d
2.20 (s, 3H), 4.17 (s, 3H), 7.14 (d, J ¼ 8.0 Hz, 2H), 7.31 (d,
J ¼ 8.0 Hz, 2H), 7.40e7.44 (m, 1H), 7.46e7.49 (m, 1H), 7.65e7.67 (m,
1H), 7.84e7.85 (m, 1H), 8.16 (d, J ¼ 9.5 Hz, 1H), 8.43 (dd, J ¼ 9.5,
(DCM). Rf (DCM) 0.25.1H NMR (CDCl3, 400 MHz):
d
1.25 (t, J ¼ 7.5 Hz,
Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
substituted isoxazoles, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.09.015

E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
9
3H), 3.01 (q, J ¼ 7.5 Hz, 2H), 3.80 (s, 3H), 6.49 (d, J ¼ 9.3 Hz, 1H),
[MþH]þ, found 398.1106.
7.40e7.42 (m, 3H), 7.59e7.63 (m, 2H), 8.33 (dd, J ¼ 9.3, 2.6 Hz, 1H),
9.19 (d, J ¼ 2.6 Hz, 1H), 10.35 (s, 1H). 13C NMR (CDCl3, 100 MHz):
4.6.6. Methyl 1-((2,4-dinitrophenyl)amino)-3,5-diphenyl-1H-
pyrazole-4-carboxylate (5f)
d
13.6 (CH3), 18.6 (CH2), 51.5 (CH3), 108.9 (C), 115.7 (CH), 123.1 (CH),
128.0 (CH), 129.0 (CH), 129.1 (CH), 130.5 (CH), 131.8 (C), 132.5 (C),
140.6 (C), 147.1 (C), 151.5 (C), 153.2 (C), 163.4 (C). HRMS (ESI) m/z:
434.1071 calcd. for C19H17N5NaOþ6 [MþNa]þ, found 434.1085.
Compound 5f (12 mg, 23%) was prepared from hydrazone Z-4f
(62 mg, 0.14 mmol) and FeCl2$4H2O (3 mg, 0.015 mmol) in MeCN
(4 mL) according to procedure A for 6 days.
Compound 5f (83 mg, 90%) was prepared from hydrazone Z-4f
(92 mg, 0.2 mmol) and FeCl2$4H2O (4 mg, 0.02 mmol) in MeCN
(4 mL) according to procedure B for 1 day.
4.6.3. Methyl 1-((2,4-dinitrophenyl)amino)-5-ethyl-3-(4-
nitrophenyl)-1H-pyrazole-4-carboxylate (5c)
Compound 5c (25 mg, 83%) was prepared from hydrazone Z-4c
(30 mg, 0.073 mmol) and FeCl2$4H2O (2 mg, 0.01 mmol) in MeCN
(4 mL) according to procedure A for 3 days.
Compound 5f (27 mg, 96%) was prepared from hydrazone E-4f
(28 mg, 0.061 mmol) and FeCl2$4H2O (2 mg, 0.01 mmol) in MeCN
(4 mL) according to procedure A for 25 days.
Compound 5c (64 mg, 91%) was prepared from hydrazone E-4c
(70 mg, 0.17 mmol) and FeCl2$4H2O (4 mg, 0.02 mmol) in MeCN
(5 mL) according to procedure A for 3 days.
Compound 5f (34 mg, 67%) was prepared from hydrazone E-4f
(51 mg, 0.10 mmol) and FeCl2$4H2O (2 mg, 0.01 mmol) in MeCN
(4 mL) according to procedure B for 1 day.
Compound 5c (61 mg, 88%) was prepared from a mixture (26/
74) hydrazones E/Z-4c (69 mg, 0.15 mmol) and FeCl2$4H2O (4 mg,
0.02 mmol) in MeCN (8 mL) according to procedure A for 3 days.
Light yellow solid, mp 223e224 ꢁC (DCM). Rf (DCM) 0.25.1H
Compound 5f (92 mg, 79%) was prepared from a mixture (65/
35) hydrazones E/Z-4f (116 mg, 0.252 mmol) and FeCl2$4H2O (5 mg,
0.03 mmol) in MeCN (8 mL) according to procedure B for 1 day.
Yellowish solid, mp 159e161 ꢁC (DCM). Rf (DCM) 0.12.1H NMR
NMR (DMSO‑d6, 400 MHz):
d
1.14 (t, J ¼ 7.5 Hz, 3H), 2.91 (q,
(CDCl3, 400 MHz):
d
3.64 (s, 3H), 6.59 (d, J ¼ 9.3 Hz, 1H), 7.37e7.46
J ¼ 7.5 Hz, 2H), 3.76 (s, 3H), 6.50 (d, J ¼ 9.4 Hz, 1H), 7.88e7.92 (m,
2H), 8.27e8.31 (m, 2H), 8.35 (dd, J ¼ 9.4, 2.6 Hz, 1H), 8.92 (d,
(m, 8H), 7.70e7.72 (m, 2H), 8.31 (dd, J ¼ 9.3, 2.4 Hz, 1H), 9.08 (d,
J ¼ 2.4 Hz,1H),10.43 (s,1H). 13C NMR (CDCl3,100 MHz):
d 51.7 (CH3),
J ¼ 2.6 Hz, 1H), 11.68 (s, 1H). 13C NMR (DMSO‑d6, 100 MHz):
d
13.0
110.9 (C), 115.5 (CH), 123.0 (CH), 126.6 (C), 128.2 (CH), 128.5 (CH),
128.9 (CH), 129.2 (CH), 129.4 (CH), 130.3 (CH), 130.5 (CH), 131.3 (C),
131.9 (C), 140.3 (C), 146.9 (C), 147.6 (C), 152.2 (C), 163.3 (C). HRMS
(ESI) m/z: 460.1252 calcd. for C23H18N5O6 [MþH]þ, found 460.1266.
(CH3), 18.1 (CH2), 51.5 (CH3), 108.3 (C), 115.6 (CH), 122.7 (CH), 123.0
(CH), 130.3 (CH), 130.5 (CH), 131.8 (C), 138.6 (C), 138.9 (C), 146.3 (C),
147.3 (C), 149.0 (C), 151.4 (C), 162.6 (C). HRMS (ESI) m/z: 455.0957
calcd. for C19H15N6Oꢀ8 [M-H]-, found 455.0931.
4.6.7. (E)-Methyl 2-((2-(2,4-dinitrophenyl)hydrazono)(phenyl)
4.6.4. Methyl 1-((2,4-dinitrophenyl)amino)-5-ethyl-3-(thiophen-2-
yl)-1H-pyrazole-4-carboxylate (5d)
methyl)-3-phenyl-2H-azirine-2-carboxylate (6)
A
mixture of hydrazone E-4f (40 mg, 0.087 mmol) and
Compound 5d (177 mg, 85%) was prepared from hydrazone 4d
(208 mg, 0.50 mmol) and FeCl2$4H2O (10 mg, 0.05 mmol) in MeCN
(10 mL) according to procedure A for 2 days. Yellow solid, mp
FeCl2$4H2O (2 mg, 0.01 mmol) in MeCN (4 mL) was stirred at room
temperature for 4 d. The reaction mixture was filtered through
silica (eluent DCM/MeOH 100:1) to give 39 mg of the mixture of
azirine 6 and pyrazole 5f in the 0.55:1 ratio (according to 1H NMR)
The part of this mixture (13 mg) was separated by chromatography
(eluent toluene) affording pyrazole 5f (7 mg) and azirine 6 (5 mg).
Azirine 6: orange solid, mp 163e164 ꢁC (toluene). Rf (toluene)
94e95 ꢁC (DCM). Rf (DCM) 0.47.1H NMR (CDCl3, 400 MHz):
d 1.22 (t,
J ¼ 7.5 Hz, 3H), 2.96 (q, J ¼ 7.5 Hz, 2H), 3.91 (s, 3H), 6.47 (d,
J ¼ 9.3 Hz, 1H), 7.09 (dd, J ¼ 5.1, 3.7 Hz, 1H), 7.36 (dd, J ¼ 5.1, 1.2 Hz,
1H), 7.80 (dd, J ¼ 3.7,1.2 Hz,1H), 8.30 (dd, J ¼ 9.3, 2.6 Hz,1H), 9.17 (d,
J ¼ 2.6 Hz, 1H), 10.33 (s, 1H). 13C NMR (CDCl3, 100 MHz):
d
13.5
0.16.1H NMR (CDCl3, 400 MHz):
d 3.64 (s, 3H), 7.54e7.71 (m, 8H),
(CH3), 18.8 (CH2), 51.6 (CH3), 108.3 (C), 115.7 (CH), 123.1 (CH), 127.1
(CH), 127.3 (CH), 129.2 (CH), 130.5 (CH), 132.4 (C), 133.0 (C), 140.5
(C), 146.86 (C), 146.94 (C), 151.7 (C), 163.2 (C). HRMS (ESI) m/z:
416.0670 calcd. for C17H14N5O6Sꢀ [M-H]-, found 416.0644.
7.74e7.78 (m, 1H), 8.09e8.12 (m, 2H), 8.13 (dd, J ¼ 9.7, 2.5 Hz, 1H),
9.01 (d, J ¼ 2.5 Hz, 1H), 11.43 (s, 1H). 13C NMR (CDCl3, 100 MHz):
d
43.1 (C), 52.8 (CH3), 116.3 (CH), 122.0 (C), 123.2 (CH), 127.4 (CH),
129.5 (CH), 129.81 (CH), 129.85 (CH), 130.8 (CH), 130.9 (CH), 131.2
(C), 134.4 (CH), 138.4 (C), 144.4 (C), 153.8 (C), 159.9 (C), 169.8 (C).
HRMS (ESI) m/z: 482.1071 calcd. for C23H17N5NaOþ6 [MþNa]þ, found
482.1091.
4.6.5. Methyl 1-((2,4-dinitrophenyl)amino)-3-methyl-5-phenyl-
1H-pyrazole-4-carboxylate (5e)
Compound 5e (68 mg, 77%) was prepared from hydrazone Z-4e
(88 mg, 0.22 mmol) and FeCl2$4H2O (5 mg, 0.025 mmol) in MeCN
(6 mL) according to procedure B for 1 day.
4.6.8. Methyl 5-(3-chlorophenyl)-1-((2,4-dinitrophenyl)amino)-3-
(p-tolyl)-1H-pyrazole-4-carboxylate (5g)
Compound 5e (45 mg, 90%) was prepared from hydrazone E-4e
(50 mg, 0.13 mmol) and FeCl2$4H2O (3 mg, 0.015 mmol) in MeCN
(6 mL) according to procedure A for 20 days.
Compound 5g (31 mg, 78%) was prepared from hydrazone Z-4g
(40 mg, 0.079 mmol) and FeCl2$4H2O (2 mg, 0.01 mmol) in MeCN
(4 mL) according to procedure A for 6 days.
Compound 5e (115 mg, 92%) was prepared from hydrazone E-4e
(106 mg, 0.27 mmol) and FeCl2$4H2O (6 mg, 0.03 mmol) in MeCN
(5 mL) according to procedure B for 1 day.
Compound 5g (19 mg, 95%) was prepared from hydrazone Z-4g
(20 mg, 0.04 mmol) and FeCl2$4H2O (1 mg, 0.005 mmol) in MeCN
(4 mL) according to procedure B for 1 day.
Compound 5e (57 mg, 83%) was prepared from a mixture (46/
54) hydrazones E/Z-4e (69 mg, 0.17 mmol) and FeCl2$4H2O (4 mg,
0.02 mmol) in MeCN (8 mL) according to procedure B for 1 day.
Light yellow solid, mp 166e167 ꢁC (DCM). Rf (DCM) 0.20.1H NMR
Compound 5g (40 mg, 100%) was prepared from hydrazone Z-4g
(40 mg, 0.079 mmol) and FeCl2$4H2O (2 mg, 0.01 mmol) in MeCN
(4 mL) according to procedure B for 1 day.
Compound 5g (34 mg, 94%) was prepared from a mixture (57/
43) hydrazones E/Z-4g (36 mg, 0.073 mmol) and FeCl2$4H2O (2 mg,
0.01 mmol) in MeCN (3 mL) according to procedure B for 1 day.
Yellowish solid, mp 143e145 ꢁC (DCM). Rf (DCM) 0.46.1H NMR
(CDCl3, 400 MHz):
7.32e7.42 (m, 5H), 8.29 (dd, J ¼ 9.3, 2.5 Hz, 1H), 9.07 (d, J ¼ 2.5 Hz,
1H), 10.28 (s, 1H). 13C NMR (CDCl3, 100 MHz):
14.3 (CH3), 51.3
d
2.57 (s, 3H), 3.72 (s, 3H), 6.47 (d, J ¼ 9.3 Hz, 1H),
d
(CH3), 110.8 (C), 115.4 (CH), 123.0 (CH), 126.8 (C), 128.3 (CH), 129.4
(CH), 130.1 (CH), 130.4 (CH), 131.8 (C), 140.2 (C), 147.0 (C), 147.8 (C),
151.3 (C), 163.3 (C). HRMS (ESI) m/z: 398.1095 calcd. for C18H16N5O6þ
(CDCl3, 400 MHz):
7.25e7.30 (m, 3H), 7.33e7.37 (m, 1H), 7.42e7.43 (m, 1H), 7.58 (d,
J ¼ 8.1 Hz, 2H), 8.32 (dd, J ¼ 9.3, 2.5 Hz, 1H), 9.10 (d, J ¼ 2.5 Hz, 1H),
d
2.41 (s, 3H), 3.66 (s, 3H), 6.56 (d, J ¼ 9.3 Hz, 1H),
Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
substituted isoxazoles, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.09.015

10
E.E. Galenko et al. / Tetrahedron xxx (2018) 1e11
10.41 (s, 1H). 13C NMR (CDCl3, 100 MHz):
d
21.4 (CH3), 51.8 (CH3),
The solvent was evaporated to give analytically pure compound 8
(304 mg, 76%). Yellow solid, mp 92e93 ꢁC (DCM). Rf (DCM) 0.49.1H
111.1 (C), 115.5 (CH),123.1 (CH), 127.5 (CH),128.2 (C),128.4 (C),128.8
(CH),129.0 (CH),129.6 (CH),129.8 (CH),130.4 (CH),130.5 (CH),132.2
(C), 134.5 (C), 139.4 (C), 140.5 (C), 146.0 (C), 146.9 (C), 152.8 (C), 163.1
(C). HRMS (ESI) m/z: 508.1018 calcd. for C24H19ClN5Oþ6 [MþH]þ,
found 508.1031.
NMR (CDCl3, 400 MHz):
d
0.97 (t, J ¼ 7.4 Hz, 3H), 2.35 (s, 3H),
3.13e3.23 (m, 2H), 3.76 (s, 3H), 7.15 (d, J ¼ 8.0 Hz, 2H), 7.35e7.43 (m,
8H), 8.43 (dd, J ¼ 9.0, 2.5 Hz, 1H), 8.91 (d, J ¼ 2.5 Hz, 1H). 13C NMR
(CDCl3, 100 MHz):
d 12.9 (CH3), 18.8 (CH2), 21.6 (CH3), 51.5 (CH3),
109.9 (C), 121.2 (CH), 124.9 (CH), 127.9 (CH), 127.9 (CH), 128.4 (CH),
128.6 (C), 129.0 (CH), 129.18 (CH), 129.24 (CH), 130.6 (C), 131.4 (C),
139.1 (C), 143.2 (C), 145.6 (C), 151.4 (C), 152.8 (C), 163.1 (C). HRMS
(ESI) m/z: 552.14590 calcd. for C27H23N5NaOþ7 [MþNa]þ, found
552.1487.
4.6.9. (1-((2,4-Dinitrophenyl)amino)-3-phenyl-1H-pyrazol-4-
yl)(pyrrolidin-1-yl)methanone (5h)
Compound 5h (86 mg, 80%) was prepared from hydrazone 4h
(107 mg, 0.25 mmol) and FeCl2$4H2O (5 mg, 0.025 mmol) in MeCN
(8 mL) according to procedure B for 3 day. Yellow solid, mp
225e226 ꢁC (DCM). Rf (2% MeOH in DCM) 0.39.1H NMR (CDCl3,
4.7.4. Methyl 1-((2-amino-4-nitrophenyl)amino)-5-ethyl-3-
phenyl-1H-pyrazole-4-carboxylate) (9)
400 MHz):
d 1.70e1.76 (m, 2H), 1.83e1.90 (m, 2H), 3.05e3.08 (m,
2H), 3.62e3.65 (m, 2H), 6.61 (d, J ¼ 9.3 Hz, 1H), 7.37e7.43 (m, 3H),
Formic acid (44 mg, 0.95 mmol) in MeCN (0.5 mL) was added to
a mixture of pyrazole 8 (100 mg, 0.19 mmol), NEt3 (81.4 mg,
0.80 mmol) and catalyst (10%Pd/C, 6 mg) in MeCN (2.5 mL) under
stirring at ꢀ15 ꢁC. The mixture was stirred at room temperature for
0.5 h and refluxed for 3 h, then neutralized by saturated solution of
NaHCO3, extracted with DCM, dried over Na2SO4, filtered off and
the solvents were evaporated. The residue was purified by column
chromatography on silica (eluent DCM/MeOH 1:0 e 100:1). The
solvent was evaporated to give analytically pure compound 9,
(63 mg, 88%). Orange solid, mp 81e82 ꢁC (DCM). Rf (2% MeOH in
7.67e7.70 (m, 2H), 7.83 (s, 1H), 8.30 (dd, J ¼ 9.3, 2.4 Hz, 1H), 9.17 (d,
J ¼ 2.5 Hz, 1H), 10.57 (s, 1H). 13C NMR (CDCl3, 100 MHz):
d 24.4
(CH2), 25.8 (CH2), 46.0 (CH2), 48.3 (CH2), 115.9 (CH), 117.7 (C), 122.9
(CH), 126.9 (CH), 128.9 (CH), 129.2 (CH), 130.5 (CH), 131.42 (C),
131.44 (CH), 132.0 (C), 140.3 (C), 147.1 (C), 149.1 (C), 163.0 (C). HRMS
(ESI) m/z: 445.1231 calcd. for C20H18N6NaOþ5 [MþH]þ, found
445.1244.
4.7. Hydrogenation of N-aminopyrazoles
DCM) 0.35.1H NMR (CDCl3, 400 MHz):
d
1.16 (t, J ¼ 7.5 Hz, 3H), 2.96
4.7.1. Methyl 5-ethyl-3-phenyl-1H-pyrazole-4-carboxylate/3-ethyl-
5-phenyl-1H-pyrazole-4-carboxylate (7a)
(q, J ¼ 7.5 Hz, 2H), 3.69 (br.s., 2H), 3.77 (s, 3H), 6.13 (d, J ¼ 8.8 Hz,
1H), 7.40e7.41 (m, 3H), 7.53e7.54 (m, 1H), 7.59e7.62 (m, 3H), 7.91
Hydrogen was passed through a stirred suspension of N-ami-
nopyrazole 5b (22 mg, 0.05 mmol) and Adams’ catalyst (1.2 mg) in
MeOH (6 mL) at rt until consumption of the starting materials (TLC
monitoring). The reaction mixture was evaporated and the residue
was passed through pad of silica (DCM/MeOH 50:1). The solvent
was evaporated to give analytically pure compound 7a (11 mg, 92%)
as yellowish oil. Rf (2% MeOH in DCM) 0.34.1H NMR (CDCl3,
(s, 1H). 13C NMR (CDCl3, 100 MHz):
d 13.4 (CH3), 18.6 (CH2), 51.3
(CH3), 108.0 (C), 112.2 (CH), 113.1 (CH), 116.5 (CH), 127.9 (CH), 128.8
(CH), 129.2 (CH), 132.2 (C), 134.0 (C), 140.6 (C), 143.1 (C), 151.2 (C),
152.3 (C), 163.7 (C). HRMS (ESI) m/z: 404.1329 calcd. for
C
19H19N5NaOþ4 [MþNa]þ, found 404.1338.
Acknowledgements
400 MHz):
7.39e7.40 (m, 3H), 7.54e7.56 (m, 2H), 11.20 (br. s, 1H). 13C NMR
(CDCl3, 100 MHz): 13.0 (CH3), 20.4 (CH2), 50.9 (CH3), 107.9 (C),
128.0 (CH),128.7 (CH),129.2 (CH),129.2 (C),131.7 (br. s, C),164.4 (C).
HRMS (ESI) m/z: 231.1128 calcd. for C13H15N2O2 [MþH]þ, found
231.1138.
d
1.23 (t, J ¼ 7.5 Hz, 3H), 2.84e2.90 (m, 2H), 3.72 (s, 3H),
We gratefully acknowledge the financial support of the Russian
Science Foundation (Grant no. 16-13-10036). This research was
carried out using the resources of the Research Centre for X-ray
Diffraction Studies, the Centre for Magnetic Resonance, the Com-
puter Centre, the Centre for Chemical Analysis and Materials of St.
Petersburg State University.
d
4.7.2. Methyl 3,5-diphenyl-1H-pyrazole-4-carboxylate (7b)
Hydrogen was passed through a stirred suspension of N-ami-
nopyrazole 5f (104 mg, 0.23 mmol) and catalyst (10% Pd/C, 11 mg)
in MeOH (9 mL) at rt until consumption of the starting materials
(TLC monitoring). The reaction mixture was evaporated and the
residue was passed through pad of silica (DCM/MeOH 50:1). The
solvent was evaporated to give analytically pure compound 7b
(61 mg, 97%) as yellowish solid, mp 176e177 ꢁC (DCM/MeOH) (lit
mp. 180e181ꢁС (C6H5/MeOH) [24]. Rf (2% MeOH in DCM) 0.42.1H
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.09.015.
References
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3.63 (s, 3H), 7.37e7.41 (m, 6H), 7.55e7.57
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279.1126.
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4.7.3. Methyl 1-(N-(2,4-dinitrophenyl)-4-methylbenzamido)-5-
ethyl-3-phenyl-1H-pyrazole-4-carboxylate (8)
A solution of 4-methylbenzoyl chloride (154 mg, 1.00 mmol) in
DCM (10 mL) was added in one portion to a mixture of N-amino-
pyrazole 5b (317 mg, 0.77 mmol) and NEt3 (0.16 mL, 1.16 mmol) in
DCM (20 mL) under stirring and cooling with ice-bath. The mixture
was stirred at 0 ꢁC for 0.5 h and then at rt overnight. The precipitate
formed was filtered off and the solvent was evaporated. The residue
was purified by column chromatography on silica (eluent DCM).
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substituted isoxazoles, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.09.015

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Please cite this article in press as: E.E. Galenko, et al., Synthesis of N-aminopyrazoles by Fe(II)-catalyzed rearrangement of 4-hydrazonomethyl-
substituted isoxazoles, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.09.015