Highly regioselective synthesis of novel 1,4'-bipyrazoles

Article abstract of DOI:10.1590/S0103-50532010000200008

Novel 1,4'-bipyrazoles were synthesized via highly regioselective cyclocondensation reactions of β-dimethylaminoenones with hydrazine monohydrate, tert-butylhydrazine hydrochloride, phenylhydrazine hydrochloride or carboxymethylhydrazine. X-ray diffractio

Full text of DOI:10.1590/S0103-50532010000200008

J. Braz. Chem. Soc., Vol. 21, No. 2, 240-247, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Highly Regioselective Synthesis of Novel 1,4’-Bipyrazoles
Marcos A. P. Martins,* Gabriela F. Fiss, Clarissa P. Frizzo, Fernanda A. Rosa,
Helio G. Bonacorso and Nilo Zanatta
aNúcleo de Química de Heterociclos, Departamento de Química,
Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil
Este trabalho descreve a síntese de 1,4’-bipirazóis inéditos pela da reação de ciclocondensação
de novas b-dimetilaminoenonas com as monoidrato de hidrazina, tert-butil hidrazina, fenil
hidrazina, carboximetilhidrazina. Os produtos foram obtidos com alta regiosseletividade em
rendimentos de bons a moderados (50-80%). A técnica de cristalografia de raios-X foi utilizada
para a elucidação da regiosseletividade da formação dos produtos. 1,4’-Bipirazolilisoxazóis
também foram descritos.
Novel 1,4’-bipyrazoles were synthesized via highly regioselective cyclocondensation reactions
of b-dimethylaminoenones with hydrazine monohydrate, tert-butylhydrazine hydrochloride,
phenylhydrazine hydrochloride or carboxymethylhydrazine. X-ray diffraction technique was
used in the elucidation of the regiochemistry of the b-dimethylaminoenaminones and of the
1,4’-bipyrazoles. 1,4’-Bipyrazolylisoxazoles were also reported.
Keywords: enaminones, bipyrazoles, heterocycles, cyclocondensation, regioselectivity
Introduction
of 2-pyrazolyl-3-dimethylamino acrylate and acrylonitrile
with hydrazine monohydrate and phenylhydrazine
hydrochloride under microwave irradiation conditions.14
Our research group has been dedicated to the development
of synthetic routes to heterocyclic compounds for around
twenty years.15 We have extensively explored the potential
of enones such as: 4-alkoxy-1,1,1-trihalo-3-alken-2-ones15
and enaminones16 as building blocks in cyclocondensation
reactions. Our results have shown that the obtainment
of heterocycles with high regioselectivity is generally
dependent on the structure of the building block and
sometimes it is dependent on the reaction conditions.
Now we are interested in finding an alternative route to
1,4’-bipyrazoles and 1,4’-bipyrazoylisoxazoles. In view
of the formation of new bonds C–C or C–N especially
in the 4-position of the pyrazolyl ring, herein we
reported our investigation in the regioselectivity of the
cyclocondensation reactions of b-dimethylaminoenones
with different 1,2-dinucleophiles such as hydrazine
monohydrate, tert-butylhydrazine hydrochloride,
phenylhydrazine hydrochloride, carboxymethylhydrazine
and hydroxylamine hydrochloride by a three-steps
procedure (alkylation, condensation and cyclocondensation
reactions, respectively) to obtain the respective azoles in
good yields. (Scheme 1).
Many heterocyclic compounds have interesting
biological activities. Pyrazoles and isoxazoles figure
prominently in this regard.1 The recent success of a pyrazole
COX-II inhibitor has further highlighted the importance
of these heterocycles in medicinal chemistry.2 The past
few years have also witnessed explosive developments
in combinatorial chemistry and solid-phase synthesis.
Currently, there is a particular interest in bipyrazoles
substituted in studies on intermolecular interactions with
the participation of pyrazoles and their derivatives.3-9 The
structure of pyrazole molecules, containing the fragment
RN–N(H)–, is favorable in the formation of various
hydrogen bonded complexes and associates in solid-cyclic
dimers, trimers and tetramers, linear chains and helices,
depending on the substituent.9-11 A literature survey turned
up a few reports on 1,4’-bipyrazole and isoxazole synthesis
and structure.12 The most promising method is a four-steps
synthesis via the cyclization of an a-oxo-a-(3,5-dimethyl-
1H-pyrazole-1-yl ketene dithioacetal with hydrazine
monohydrate or phenylhydrazine in refluxing ethanol.13
1,4’-Bipyrazoles have been also prepared by the reaction
*e-mail: mmartins@base.ufsm.br

Vol. 21, No. 2, 2010
Martins et al.
241
Results and Discussion
In the last step, the b-dimethylaminoenones
were converted to 1,4’-bipyrazoles by treatment
with hydrazine monohydrate, tert-butylhydrazine
hydrochloride, phenylhydrazine hydrochloride and
carboxymethylhydrazine.Whentheb-dimethylaminoenones
3a-b reacted with hydrazine monohydrate in ethanol at room
temperature for 5 h, the corresponding 1,4’-bipyrazoles 4a
(in 71% yield) and 4b (in 80% yield) were obtained; and
when reacted with tert-butylhydrazine hydrochloride
or phenylhydrazine hydrochloride in ethanol at 60 °C
for 5 h, 1,4’-bipyrazoles 5a-b and 6a-b were obtained,
respectively. After an initial screen of solvents and
reaction temperatures, the 1,4’-bipyrazole 7a was
synthesized by the cyclocondensation reaction of the
b-dimethylaminoenone 3a with carboxymethylhydrazine
The first step involves the synthesis of 2-(3,5-dimethyl-
1H-1-pyrazolyl)acetophenone 2a in (71% yield) and
3-(3,5-dimethyl-1H-1-pyrazolyl)acetophenone 2b
(in 75% yield) through the alkylation reactions of
3,5-dimethyl-1H-pyrazole with 2-bromoacetophenone
1a and 2-bromopropiophenone 1b, respectively, under
reflux of anhydrous acetone containing potassium
carbonate for 5 h.17 The second step consists of the
condensation reactions of these compounds with 1.2
equivalents of neat N,N-dimethylformamide dimethylacetal
(DMFDMA) under reflux for 10 h. After removal of the
excess reagent, 3-dimethylamino-2-(3,5-dimethyl-1H-1-
pyrazolyl)-1-phenyl-2-propen-1-one 3a (in 92% yield) and
3-dimethylamino-2-(3,5-dimethyl-1H-1-pyrazolylmethyl)-
1-phenyl-2-propen-1-one 3b (in 98% yield) were obtained.
Although carbanions resulting from proton
abstraction from N-alkylpyrazoles might also be
stabilized by the electron-attracting inductive effect of
the ring nitrogen, the reactivity of such a species towards
N,N-dimethylformamide dimethylacetal was demonstrated.
•
and the use of one equivalent of BF3 OEt2 in anhydrous
MeOH under reflux for 10 h in 72% yield. On the other
hand, the reaction of the b-dimethylaminoenone 3b with
carboxymethylhydrazine using these conditions did not
give the expected 1,4’-bipyrazole 7b. Our preparative
results are summarized in Scheme 1 and Table 1.
K2CO3,
acetone,
Me
Me
1
O
The structure of the compounds was determined by H
reflux, 5 h
NMR and 13C NMR spectroscopy, MS espectrometry,
and HRMS analysis. Moreover, X-ray crystallography
data confirmed the structure of compound 3b.By carrying
out a single crystal X-ray analysis, E-configutation of the
products was unequivocaly determined, showing that a
single isomer was obtained (Figure 1).
X
N
+ Ph
N
n
1a-b
Me
Me
N
H
N
71-75%
O
n
Ph
2a-b
Me
Me
DMFDMA,
hydrazine, EtOH
reflux, 60°C, 5 h
reflux, 10 h
N
Me
N
92-98%
N
O
NMe2
Me
50-80%
N
n-1
H
n-1
N
Ph
Ph
Z
3a-b
4a-b,5a-b
6a-b,7a-b
Z = NH, N-tert-Bu, N-Ph, N(C(O)OMe
Scheme 1.
Table 1. Reaction conditions to synthesis of the 1,4’-bipyrazoles 4-7
Conditions
Z
NH
n
1
2
1
2
1
2
1
2
Product Yield (%)a
•
NH2NH2 H2O,
4a
4b
5a
5b
6a
6b
7a
7b
71
80
50
66
64
67
72
EtOH, rt, 5 h
NH
t
NtBu
NtBu
NPh
•
BuNHNH2 HCl,
EtOH, 60 °C, 5 h
•
PhNHNH2 HCl,
EtOH, 60 °C, 5 h
NPh
NH2NHCO2Me,
NCO2Me
b
•
BF3 OEt2, MeOH, reflux, 10 h NCO2Me
_
a Yield of isolated products; b Product was not identified.
Figure 1. ORTEP of the compound 3b.

242
Highly Regioselective Synthesis of Novel 1,4’-Bipyrazoles
J. Braz. Chem. Soc.
Me
NH2OH.HCl,
EtOH,
Me
60 °C, 5 h
N
N
N
Me
O
Me
Ph
61%
N
NMe2
Ph
H
O N
3a
8a
NH2OH.HCl,
EtOH,
60 °C, 5 h
Me
Me
N
N
N
Me
Me
50%
N
O
NMe2
H
N
Ph
Ph
O
3b
8b
Scheme 2.
Me
Me
Et3N,
O
toluene,
reflux, 5 h
Cl
N
+ Me
N
Me
Me
67%
N
N
2c
N
1c
H
O
Me
Me
NH2NH2,
EtOH,
r.t., 5 h
Me
DMFDMA,
toluene
reflux, 48 h
N
N
Me
Me
Me
94%
71%
Figure 2. ORTEP of the compound 5b.
N
O
NMe2
The highly regioselective cyclocondensation reactions
of the b-dimethylaminoenones 3a-b with different
hydrazines gave 1,5-regioisomer rather than the potential
1,3-regioisomer. Moreover, the regiochemistry of the
compound 5b was unequivocally determined by single
crystal X-ray diffraction data,18 confirming the formation
of the 1,5-regioisomer as a single product (Figure 2).
Thus, the b-dimethylaminoenones 3a-b reacted
with different hydrazines to afford, in each case,
only one of the two possible regioisomers. Similarly,
when the b-dimethylaminoenone 3a reacted with
hydroxylamine hydrochloride in ethanol at 60 °C for
5 h, the 1,5-regioisomer of the 1,4’-bipyrazoylisoxazole
(8a) was obtained with high regioselectivity in 61%
yield. When the b-dimethylaminoenone 3b reacted with
hydroxylamine hydrochloride in ethanol at 60 °C for
5 h, the 1,5-regioisomer of the 1,4’-bipyrazoylisoxazole
(8b) was obtained in 50% yield. Therefore, we can
say that the cyclocondensation reactions of the
b-dimethylaminoenones 3a and 3b with hydroxylamine
hydrochloride in these conditions are highly regioselective
in both cases. Our preparative results are summarized in
Scheme 2.
Me
H
HN N
3c
4c
Scheme 3.
reflux of anhydrous toluene for 5 h in 67% yield. Then
the compound 2c condensed with 1.2 equivalents of
neat DMFDMA under reflux of toluene for 48 h. After
removal of the excess reagent, the 4-dimethylamino-3-
(3,5-dimethyl-1H-1-pyrazolyl)-3-buten-2-one 3c was
obtained in 94% yield.Although the condensation reaction
with two equivalents of DMFDMA may in theory lead to
a mixture of 3c and 3c’(Figure 3), in our experiment only
1
3c was formed. The H NMR spectra of 3c revealed the
presence of a singlet corresponding to methyl at d 2.25,
and the absence of the two olefinic doublets, which
would be observed in the H NMR spectra of 3c’. The
b-dimethylaminoenone 3c was used as starting material
for the synthesis of the 1,4’-bipyrazole 4c through the
cyclocondensation reaction with hydrazine monohydrate
in ethanol at room temperature for 5 h resulting in the
product with 71% yield.
1
Me
The same synthetic route was repeated via the synthesis
of (3,5-dimethyl-1H-1-pyrazolyl)acetone 2c (Scheme 3).
Thus, the compound 2c was synthesized by the
alkylation reaction of 3,5-dimethyl-1H-pyrazole with
chloroacetone 1c in the presence of triethylamine under
N
Me
N
Me2N
NMe2
O
Figure 3. Theoretical product from dicondensantion.

Vol. 21, No. 2, 2010
Martins et al.
243
Conclusions
CDCl3/TMS, 25 °C) d 10.9 (Me), 13.4 (Me), 55.2 (CH2),
105.8, 140.4, 148.2 (1H-1-pyrazolyl), 128.0, 128.8, 129.6,
133.1 (Ph), 192.7 (CO) ppm; MS (EI, 70 eV) m/z 214 (M+,
5%), 199 (2), 185 (100); HRMS (ESI+) m/z [M + H]+ calc.
for C13H14N2O: 215.1184; found: 215.1185.
The b-dimethylaminoenones 3a-c were synthesized via
highy regioselective condensation reactions. A convenient
syntheticrouteto1,4’-biazoles,containingavarietyofneutral,
electron-donating and electron-withdrawing substituents, by
a simple procedure from the b-dimethylaminoenones 3a-c is
now available. Studies on the syntheses of other heterocyclic
rings from 3a-c are in progress.
3-(3,5-Dimethyl-1H-1-pyrazolyl)propiofenona (2b)
1
mp 59-62 °C (from hexane); H NMR (400 MHz,
CDCl3/TMS, 25 °C) d 2.19 (s, 3 H, Me), 2.29 (s, 3 H, Me),
3.56 (t, JH,H = 6.8 Hz, 2 H, CH2), 4.37 (t, JH,H = 6.8 Hz, 2
H, CH2), 5.74 (s, 1 H, CH), 7.44 (t, JH,H = 8.4 Hz, 2 H, Ph),
7.55 (t, JH,H = 7.4 Hz, 1 H, Ph), 7.93 (d, JH,H = 7.1 Hz, 2 H,
Ph) ppm; 13C NMR (50 MHz, CDCl3/TMS, 25 °C) d 10.9
(Me), 13.3 (Me), 38.6 (CH2), 42.8 (CH2), 104.6, 139.1,
147.5, (1H-1-pyrazolyl), 127.9, 128.4, 133.2, 136.2 (Ph),
197.6 (CO) ppm; MS (EI, 70 eV) m/z 228 (M+, 14%), 123
(100); HRMS (ESI+) m/z [M + H]+ calc. for C14H16N2O:
229.1341; found: 229.1343.
Experimental
Unless otherwise indicated, all common reagents and
solvents were used as obtained from commercial suppliers
without further purification. The indicated solvents were
dried and purified according to recommended procedures.19
The1Hand13CNMRspectrawereacquiredonaBrukerDPX
200 or Bruker DPX 400 spectrometer (1H at 200.13 MHz
or 400.13 MHz and 13C at 50.32 MHz or 100.61 MHz,
respectively), in 5 mm tube, and CDCl3 was used as
solvent, containing TMS as internal standard at 298 K
(digital resolution of 0.01 ppm). The mass spectra were
registered in a HP 5973 MSD connected to a HP 6890 GC
and interfaced by a Pentium PC. The GC was equipped with
a split-splitless injector, autosampler, cross-linked to a HP-5
capillary column (30 m, 0.32 mm of internal diameter), and
helium as carrier gas. The high-resolution mass spectrum
were obtained from a MicroTOF Ic Bruker Daltonics
(Instituto de Química, Universidade de São Paulo, Brazil).
The melting points were measure using a Microquímica
MQAPF 301. The melting points were not corrected.
Procedure for synthesis of 2c
A mixture of chloroacetone 1c (10 mmol), 3,5-dimethyl-
1H-pirazole (10 mmol) and triethylamine (10 mmol) was
stirred at reflux temperature of anhydrous toluene (3 mL) for
5 h. Then the mixture was extracted with dichloromethane
(10mL)andwashedwithwater(3×10mL).Theorganiclayer
wasdriedwithanhydrousmagnesiumsulfate, filtered, andthe
solvent was evaporated under reduced pressure. The product
2c was purified by recrystallization in hexane as solvent.
(3,5-Dimethyl-1H-1-pyrazolyl)acetone 2c
mp 49-51 °C (from hexane) (lit.20 67-68 °C);1H NMR
(200 MHz, CDCl3/TMS, 25 °C) d 2.10 (s, 3 H, Me), 2.16
(s, 3 H, Me), 2.22 (s, 3 H, Me), 4.76 (s, 2 H, CH2), 5.89 (s,
1 H, CH) ppm; 13C NMR (50 MHz, CDCl3/TMS, 25 °C) d
10.9 (Me), 13.4 (Me), 26.8 (Me), 58.3 (CH2), 105.9, 139.8,
148.4 (1H-1-pyrazolyl), 203.0 (CO) ppm; MS (EI, 70 eV)
m/z 152 (M+, 49%), 137 (1), 109 (100); HRMS (ESI+) m/z
[M + H]+ calc. for C8H12N2O: 153.1028; found: 153.1023.
General procedure for synthesis of 2a-b
A mixture of 2-bromoacetophenone 1a or
3-bromopropiophenone 1b (20 mmol), 3,5-dimethyl-1H-
pirazole (20 mmol) and potassium carbonate (20 mmol)
was stirred at reflux temperature of anhydrous acetone
(20 mL) for 5 h. Then the mixture was filtered, extracted
with dichloromethane (20 mL) and washed with water
(3 × 20 mL). The organic layer was dried with anhydrous
magnesium sulfate, filtered, and the solvent was evaporated
under reduced pressure. The products 2a-b were purified
by recrystallization in hexane as solvent.
General procedure for synthesis of b-dimethylaminoenones
3a-b
2-(3,5-Dimethyl-1H-1-pyrazolyl)acetophenone 2a
or 3-(3,5-dimethyl-1H-1-pyrazolyl)propiophenone 2b
(10 mmol) was stirred at reflux temperature of DMFDMA
(12 mmol) for 10 h. Then the mixture was submitted at
reduced pressure for 1 h. The product 3a was purified
by filtration in a column chromatographic silica gel with
dichloromethane as an eluent, and the product 3b was
purified by recrystallization in ethyl acetate as solvent.
2-(3,5-Dimethyl-1H-1-pyrazolyl)acetophenone (2a)
mp 76-79 °C (from hexane) (lit.17 90-91 °C); 1H NMR
(400 MHz, CDCl3/TMS, 25 °C) d 2.15 (s, 3 H, Me), 2.23
(s, 3 H, Me), 5.45 (s, 2 H, CH2), 5.90 (s, 1 H, CH), 7.49
(t, JH,H = 7.7 Hz, 2 H, Ph), 7.61 (t, JH,H = 7.1 Hz, 1 H, Ph),
7.97 (d, JH,H = 7.4 Hz, 2 H, Ph) ppm; 13C NMR (100 MHz,

244
Highly Regioselective Synthesis of Novel 1,4’-Bipyrazoles
J. Braz. Chem. Soc.
(Z)-3-Dimethylamino-2-(3,5-dimethyl-1H-1-pyrazolyl)-1-
phenyl-2-propen-1-one (3a)
General Procedure for synthesis of 1,4’-bipyrazoles 4a-c
Oil; 1H NMR (200 MHz, CDCl3/TMS, 25 °C) d 1.94
(s, 3 H, Me), 2.26 (s, 3 H, Me), 2.35 (s, 3 H, NMe), 3.11
(s, 3 H, NMe), 5.79 (s, 1 H, CH), 7.22-7.35 (m, 3 H, Ph),
7.41-4.46 (m, 2 H, Ph), 7.61 (s, 1 H, CH) ppm; 13C NMR
(50 MHz, CDCl3/TMS, 25 °C) d 11.3 (Me), 13.7 (Me),
36.4 (NMe2), 105.4, 143.3, 148.3 (1H-1-pyrazolyl), 106.9
(C2), 109.9 (CH), 127.8, 127.9, 129.9, 139.7 (Ph), 190.3
(CO) ppm; MS (EI, 70 eV) m/z 269 (M+, 7%), 268 (8),
239 (40), 188 (100); HRMS (ESI+) m/z [M + H]+ calc. for
C16H19N3O: 270.1606; found: 270.1614.
A mixture of b-dimethylaminoenone 3a, 3b or 3c
(1 mmol), hydrazine monohydrate (1.2 mmol) and ethanol
(1 mmol) was stirred at room temperature for 5 h. Then the
mixture was extracted with dichloromethane (3 mL) and
washed with water (3 × 3 mL). The organic layer was dried
with anhydrous magnesium sulfate, filtered, and the solvent
was evaporated under reduced pressure. The products 4a-c
were purified by filtration in a column chromatographic
silica gel with dichloromethane as an eluent.
3,5-Dimethyl-5’-phenyl-1H-1,4’-bipyrazole (4a)
(E)-3-Dimethylamino-2-(3,5-dimethyl-1H-1-
Oil; 1H NMR (200 MHz, CDCl3/TMS, 25 °C) d 1.88 (s,
3 H, Me), 2.31 (s, 3 H, Me), 5.95 (s, 1 H, CH), 7.25-7.35
(m, 6 H, Ph and NH), 7.67 (s, 1 H, CH) ppm; C NMR
pyrazolylmethyl)-1-phenyl-2-propen-1-one (3b)
1
13
mp 115-118 °C (from ethyl acetate); H NMR
(200 MHz, CDCl3/TMS, 25 °C) d 2.19 (s, 3 H, Me), 2.39
(s, 3 H, Me), 3.23 (s, 6 H, NMe2), 5.12 (s, 2 H, CH2), 5.73
(s, 1 H, CH), 7.13 (s, 1 H, CH), 7.32-7.37 (m, 3 H, Ph),
7.41-7.45 (m, 2 H, Ph) ppm; 13C NMR (50 MHz, CDCl3/
TMS, 25 °C) d 11.2 (Me), 13.6 (Me), 41.7 (CH2), 43.8
(NMe2), 104.4, 141.3, 146.6 (1H-1-pyrazolyl), 105.3 (C2),
127.7, 128.2, 129.3, 139.8 (Ph), 157.2 (CH), 195.8 (CO)
ppm; MS (EI, 70 eV) m/z 283 (M+, 7%), 268 (8), 239
(40), 188 (100); HRMS (ESI+) m/z [M + Na]+ calc. for
C17H21N3ONa: 306.1583; found: 306.1585.
(100 MHz, CDCl3/TMS, 25 °C) d 11.1 (Me), 13.4 (Me),
105.8, 125.7, 128.2, 128.6, 128.6, 129.7, 132.3, 141.9,
143.2, 149.2 (2 × 1H-1-pyrazolyl and Ph) ppm; MS (EI,
70 eV) m/z 238 (M+, 49%), 223 (100); HRMS (ESI+) m/z
[M + H]+ calc. for C14H14N4: 239.1296; found: 239.1292.
1-(3,5-Dimethyl-1H-1-pyrazolyl)-1-(5-phenyl-1H-4-
pyrazolyl)methane (4b)
Oil; 1H NMR (200 MHz, CDCl3/TMS, 25 °C) d 1.97 (s,
3 H, Me), 2.19 (s, 3 H, Me), 5.14 (s, 2 H, CH2), 5.76 (s, 1 H,
CH), 7.14 (br s, 1 H, NH), 7.26-7.34 (m, 4 H, Ph and CH),
7.41-7.46 (m, 2 H, Ph) ppm;13C NMR (100 MHz, CDCl3/
TMS, 25 °C) d 10.7 (Me), 13.3 (Me), 43.5 (CH2), 105.2,
114.6, 127.8, 127.9, 128.1, 128.5, 131.4, 133.7, 138.8,
147.4 (2 ´ 1H-1-pyrazolyl and Ph) ppm; MS (EI, 70 eV)
m/z 252 (M+, 41%), 223 (1), 157 (100); HRMS (ESI+) m/z
[M + H]+ calc. for C15H16N4: 253.1453; found: 253.1455.
Experimental procedure for synthesis of b-dimethyl-
aminoenone 3c
A mixture of (3,5-dimethyl-1H-1-pyrazolyl)acetone
2c (3 mmol) and DMFDMA (3.6 mmol) was stirred at
reflux temperature of anhydrous toluene (1 mL) for 48 h.
Then the mixture was submitted at reduced pressure for
1 h. The product 3c was purified by filtration in a column
chromatographic silica gel with dichloromethane as an
eluent.
3,5-Dimethyl-5’-methyl-1H-1,4’-bipyrazole (4c)
Oil; 1H NMR (400 MHz, CDCl3/TMS, 25 °C) d 2.12 (s,
3 H, Me), 2.15 (s, 3 H, Me), 2.28 (s, 3 H, Me), 5.95 (s, 1 H,
CH), 7.55 (s, 1 H, CH) ppm; 13C NMR (100 MHz, CDCl3/
TMS, 25 °C) d 9.6 (Me), 11.3 (Me), 13.4 (Me), 105.3,
105.3, 141.4, 141.4, 148.9, 148.9 (2 × 1H-1-pyrazolyl)
ppm; MS (EI, 70 eV) m/z 176 (M+, 100%), 161 (6), 148
(8), 134 (24), 81 (15), 66 (12); HRMS (ESI+) m/z [M + H]+
calc. for C9H12N4: 177.1140; found: 177.1137.
(Z)-4-Dimethylamino-3-(3,5-dimethyl-1H-1-pyrazolyl)-3-
buten-2-one (3c)
Oil; 1H NMR (200 MHz, CDCl3/TMS, 25 °C) d 1.78
(s, 3 H, Me), 2.10 (s, 3 H, Me), 2.25 (s, 3 H, Me), 2.29 (s,
3 H, NMe), 3.11 (s, 3 H, NMe), 5.91 (s, 1 H, CH), 7.65
(s, 1 H, CH) ppm; 13C NMR (100 MHz, CDCl3/TMS,
25 °C) d 11.4 (Me), 13.6 (Me), 24.5 (Me), 36.2 (NMe),
47.3 (NMe), 105.2, 142.9, 148.8 (1H-1-pyrazolyl), 105.4
(C3), 109.3 (CH), 189.6 (CO) ppm; MS (EI, 70 eV) m/z
207 (M+, 53%), 192 (100), 164 (31), 135 (16); HRMS
(ESI+) m/z [M + H]+ calc. for C11H17N3O: 208.1450;
found: 208.1432.
General procedure for synthesis of 1,4’-biazoles 5a-b,
6a-b and 8a-b
Amixtureof b-dimethylaminoenone 3aor3b(1mmol),
tert-butylhydrazine hydrochloride, phenylhydrazine
hydrochloride or hydroxylamine hydrochloride (1.2 mmol)
and ethanol was stirred at 60 °C for 5 h. Then the mixture

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Martins et al.
245
was extracted with dichloromethane (3 mL) and washed
with water (3 × 3 mL). The organic layer was dried with
anhydrous magnesium sulfate, filtered, and the solvent
was evaporated under reduced pressure. The oil products
were purified by filtration in a column chromatographic
silica gel with dichloromethane as an eluent, and the
product 5b was purified by recrystallization in hexane
as solvent.
H, CH, 7.16-7.26 (m, 7 H, Ph), 7.35-7.38 (m, 3 H, Ph), 7.59
(s, 1 H, CH) ppm; 13C NMR (50 MHz, CDCl3/TMS, 25 °C)
d 10.7 (Me), 13.1 (Me), 43.1 (CH2), 105.5, 117.1, 119.7,
124.6, 127.1, 128.6, 128.7, 128.7, 128.7, 128.8, 129.4,
129.6, 129.9, 140.1 (2 × 1H-1-pyrazolyl and 2 × Ph) ppm;
MS (EI, 70 eV) m/z 328 (M+, 14%), 233 (100), 219 (3);
HRMS (ESI+) m/z [M + H]+ calc. for C21H20N4: 329.1766;
found: 329.1769.
1’-(tert-Butyl)-3,5-dimethyl-5’-phenyl-1H-1,4’-bipyrazole
4-(3,5-Dimethyl-1H-1-pyrazolyl)-5-phenylisoxazole (8a)
Oil; 1H NMR (200 MHz, CDCl3/TMS, 25 °C) d 1.92
(s, 3 H, Me), 2.31 (s, 3 H, Me), 5.99 (s, 1 H, CH),
7.32-7.35 (m, 3 H, Ph), 7.40 (m, 2 H, Ph), 8.74 (s, 1 H,
CH) ppm; 13C NMR (50 MHz, CDCl3/TMS, 25 °C) d 11.1
(Me), 13.5 (Me), 106.8, 126.1, 126.8, 127.2, 128.9, 129.1,
130.3, 150.5, 156.4, 158.2 (2 × 1H-1-pyrazolyl and Ph)
ppm; MS (EI, 70 eV) m/z 239 (M+, 100%), 210 (46), 144
(44); HRMS (ESI+) m/z [M + H]+ calc. for C14H13N3O:
240.1137; found: 240.1137.
(5a)
1
Oil; H NMR (400 MHz, CDCl3/TMS, 25 °C) d
1.48 (s, 9 H, tBu), 2.14 (s, 3 H, Me), 2.24 (s, 3 H,
Me), 5.52 (s, 1 H, CH), 7.31 (m, 5 H, Ph), 7.62 (s, 1 H,
CH) ppm; 13C NMR (100 MHz, CDCl3/TMS, 25 °C) d
10.9 (Me), 13.3 (Me), 30.9, 68.7 (tBu), 105.9, 127.8,
128.1, 128.3, 128.9, 129.9, 130.7, 133.1, 133.9, 148.3
(2 × 1H-1-pyrazolyl and Ph) ppm; MS (EI, 70 eV) m/z
294 (M+, 100%), 279 (2), 237 (29), 223 (83), 209 (6),
143 (6); HRMS (ESI+) m/z [M + H]+ calc. for C18H22N4:
295.1922; found: 295.1920.
1-(3,5-Dimethyl-1H-1-pyrazolyl)-1-(5-phenyl-4-
isoxazolyl)methane (8b)
1-[1-(tert-Butyl)-5-phenyl-1H-4-pyrazolyl]-1-(3,5-
Oil; 1H NMR (400 MHz, CDCl3/TMS, 25 °C) d 2.05
(s, 3 H, Me), 2.21 (s, 3 H, Me), 5.19 (s, 1 H, CH), 5.82
(s, 2 H, CH2), 7.49-7.52 (m, 3 H, Ph), 7.67-7.69 (m, 2 H,
Ph), 7.96 (s, 1 H, CH) ppm; 13C NMR (50 MHz, CDCl3/
TMS, 25 °C) d 10.8 (Me), 13.3 (Me), 42.2 (CH2), 105.9,
111.6, 125.7, 127.1, 129.0, 130.2, 138.9, 148.1, 151.1,
164.5 (1H-1-pyrazolyl, Ph and isoxazolyl) ppm; MS (EI,
70 eV) m/z 253 (M+, 100%), 238 (8), 224 (17), 158 (37);
HRMS (ESI+) m/z [M + H]+ calc. for C15H15N3O: 254.1293;
found: 254.1296.
dimethyl-1H-1-pyrazolyl)methane (5b)
1
mp 101-104 °C (from hexane); H NMR (400 MHz,
CDCl3/TMS, 25 °C) d 1.41 (s, 9 H, tBu), 1.85 (s, 3 H,
Me), 2.17 (s, 3 H, Me), 4.70 (s, 2 H, CH2), 5.67 (s, 1 H,
CH), 7.23-7.25 (m, 2 H, Ph), 7.38 (s, 1 H, CH), 7.39-7.42
(m, 3 H, Ph) ppm; 13C NMR (100 MHz, CDCl3/TMS, 25
°C) d 10.7 (Me), 13.4 (Me), 30.9, 61.2 (tBu), 43.0 (CH2),
104.8, 117.9, 128.1, 128.4, 128.7, 130.9, 132.4, 136.3,
138.5, 147.1 (2 × 1H-1-pyrazolyl and Ph) ppm; MS (EI,
70 eV) m/z 308 (M+, 14%), 293 (1), 251 (11), 213 (19),
157 (100); HRMS (ESI+) m/z [M + H]+ calc. for C19H24N4:
309.2079; found: 309.2078.
Experimental procedure for synthesis of 1,4’-bipyrazole 7a
A mixture of b-dimethylaminoenone 3a (1 mmol),
.
1’,5’-Diphenyl-3,5-dimethyl-1H-1,4’-bipyrazole (6a)
Oil; 1H NMR (400 MHz, CDCl3/TMS, 25 °C) d 1.79 (s,
3 H, Me), 2.28 (s, 3 H, Me), 5.84 (s, 1 H, CH), 6.99-7.02 (m,
2 H, Ph), 7.19-7.24 (m, 3 H, Ph), 7.30-7.33 (m, 5 H, Ph),
7.88 (s, 1 H, CH) ppm; 13C NMR (100 MHz, CDCl3/TMS,
25 °C) d 11.1 (Me), 13.6 (Me), 105.5, 122.1, 127.7, 127.8,
128.5, 128.7, 128.9, 129.0, 125.2, 138.2, 138.7, 141.5,
149.1, 139.8 (2 × 1H-1-pyrazolyl and 2 × Ph) ppm; MS (EI,
70 eV) m/z 314 (M+, 100%), 285 (1); HRMS (ESI+) m/z
[M + H]+ calc. for C20H18N4: 315.1609; found: 315.1609.
carboxymethylhydrazine (1.2 mmol) and BF3 OEt2
(1.2 mmol) was stirred at reflux temperature of methanol
(1 mL) for 10 h. Then the mixture was extracted with
dichloromethane (3 mL) and washed with water (3 × mL).
The organic layer was dried with anhydrous magnesium
sulfate, filtered, and the solvent was evaporated under
reduced pressure. The product 7a was purified by
filtration in a column chromatographic silica gel with
dichloromethane as an eluent.
3,5-Dimethyl-5’-phenyl-1’-methylcarboxyl-1H-1,4’-
bipyrazole (7a)
Oil; 1H NMR (400 MHz, CDCl3/TMS, 25 °C) d 2.07 (s,
3 H, Me), 2.21 (s, 3 H, Me), 3.85 (s, 1 H, OMe), 5.14 (s,
1 H, CH), 7.33 (s, 1 H, CH), 7.37-7.39 (m, 5 H, Ph) ppm;
1-(3,5-Dimethyl-1H-1-pyrazolyl)-1-(1,5-diphenyl-1H-4-
pyrazolyl)methane (6b)
Oil; 1H NMR (200 MHz, CDCl3/TMS, 25 °C) d 1.95 (s,
3 H, Me), 2.23 (s, 3 H, Me), 5.06 (s, 2 H, CH2), 5.76 (s, 1

246
Highly Regioselective Synthesis of Novel 1,4’-Bipyrazoles
J. Braz. Chem. Soc.
13C NMR (100 MHz, CDCl3/TMS, 25 °C) d 11.1 (Me),
13.2 (Me), 55.3 (OMe), 105.7, 126.4, 126.9, 128.0, 128.6,
128.6, 128.8, 129.4, 133.9, 148.4, (2 × 1H-1-pyrazolyl and
Ph), 155.3 (CO) ppm; MS (EI, 70 eV) m/z 296 (M+, 25%),
281 (100), 265 (1), 237 (3); HRMS (ESI+) m/z [M + Na]+
calc. for C16H16N4O2Na: 319.1171; found: 319.1172.
10. Elguero, J.; Cano, F. H.; Foces-Foces, C.; Llamas-Saiz, A. L.;
Limbach, H.- H.;Aguilar-Parrilla, F.; Claramunt, R. M.; López,
C.; J. Heterocycl. Chem. 1994, 31, 695.
11. Llamas-Saiz,A. L.; Foces-Foces, C.; Elguero, J.; J. Mol. Struct.
1994, 319, 231.
12. Sellier, N.; J. Heterocycl. Chem. 1999, 36, 1291; Shironina,
T. M.; Igidov, N. M.; Koz’minykh, E. N.; Kon’shina, L. O.;
Kasatkina,Yu. S.; Koz’minykh,V. O.; Russ. J. Org. Chem. 2001,
37, 1555;Vicente,V.; Fruchier,A.; Elguero, J.; ARKIVOC 2004,
iii, 5; Bouabdallah, I.; Touzani, R.; Zidane, I.; Ramdani, A.;
Radi, S.; ARKIVOC 2006, xiv, 46; Bakavoli, M.; Feizyzadeh,
B.; Rahimizadeh, M.; Tetrahedron Lett. 2006, 47, 8965;
13. Chen, H. S.; Li, Z. M.; Wang, Z. W.; Chin. Chem. Lett. 1999,
10, 643.
Acknowledgments
The autors thank the Conselho Nacional de
Desenvolvimento Científico e Tecnológico em Pesquisa
(CNPq/PADCT), Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior (CAPES) and Fundação de
Amparo à Pesquisa do Estado do Rio Grande do Sul
(FAPERGS) for financial support. The fellowships from
CNPq, CAPES and FAPERGS are also acknowledged.
14. Hoz, A. de la; Díaz, A.; Elguero, J.; Jiménez, A.; Moreno,
A.; Ruiz, A.; Sánches-Migallón, A.; Tetrahedron 2007, 63,
748.
References
15. Martins M. A. P.; Frizzo, C. P.; Moreira, D. N.; Zanatta, N.;
Bonacorso H. G.; Chem. Rev. 2008, 108, 2015 and references
therein; Martins, M.A. P.; Cunico, W.; Pereira, C. M. P; Flores,
A. F. C.; Bonacorso H. G.; Zanatta, N.; Curr. Org. Synth. 2004,
1, 391 and references therein; Bonacorso, H. G.; Lopes, I. S.;
Wastowski, A. D.; Zanatta, N.; Martins, M. A. P.; J. Fluorine
Chem. 2003, 120, 29; Flores,A. F. C.; Brondani, S.; Zanatta, N.;
Rosa, A.; Martins, M. A. P.; Tetrahedron Lett. 2002, 43, 8701;
Flores, A. F. C.; Zanatta, N.; Rosa, A.; Brondani, S.; Martins,
M. A. P.; Tetrahedron Lett. 2002, 43, 5005.
1. For example, there are 2292 pyrazoles and 906 isoxazoles in
the MDL Drug Report (MDDR-3D, 99.2), representing 3.0% of
entries. They are 1.6% of entries in Comprehensive Medicinal
Chemistry (CMC-3D 99.1). Both databases are from MDL
Information Systems.
2. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha,
J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.;Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S.
A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen,
A. W.; Zhang, Y. Y.; Isakson, P. C.; J. Med. Chem. 1997, 40,
1347.
16. Martins, M. A. P.; Cunico, W.; Scapin, E.; Emmerich, D. J.;
Fiss, G. F.; Rosa, F. A.; Bonacorso, H. G.; Zanatta, N.; Flores,
A. F .C.; Lett. Org. Chem. 2006, 3, 358; Zanatta, N.; Flores, D.
C.; Amaral, S. S.; Bonacorso, H. G.; Martins, M. A. P.; Flores,
A. F. C.; Synlett 2005, 3079; Martins, M. A. P.; Pereira, C. M.
P.; Cunico, W.; Moura, S.; Rosa, F. A.; Peres, R. L.; Machado,
P.; Zanatta, N.; Bonacorso, H. G.; Ultrason. Sonochem. 2006,
13, 364; Martins, M. A. P.; Cunico, W.; Brondani, S. Peres,
R. L.; Zimmermann, N.; Rosa, F. A.; Fiss, G. F.; Zanatta,
N.; Bonacorso, H. G.; Synthesis 2006, 9, 1485; Rosa, F. A.;
Machado, P.; Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P.;
J. Heterocyclic. Chem. 2008, 45, 879; F. A. Rosa, Machado,
P.; Rossatto, M.; Vargas, P. S.; Fernandes, T. S.; Bonacorso,
H. G.; Zanatta, N.; Martins, M. A. P.; Synlett 2008, 1673;
Rosa, F. A.; Machado, P.; Fiss, G. F.; Vargas, P. S.; Bonacorso,
H. G.; Zanatta, N.; Martins, M. A. P.; Synthesis 2008,
3639.
3. Smith, J.A. S.;Wehrle, B.;Aguilar-Parrilla, F.; Limbach, H.-H.;
Foces-Foces, M. C.; Cano, F. H.; Elguero, J.; Baldy,A.; Pierrot,
M.; Khurshid, M. M. T.; Larcombe-McDouall, J. B.; J. Am.
Chem. Soc. 1989, 111, 7304.
4. Foces-Foces, C.; Echevarria, A.; Jagerovich, N.; Alkorta, I.;
Elguero, J.; Langer, U.; Klein, O.; Minguet-Bonvehi, M.;
Limbach, H. -H.; J. Am. Chem. Soc. 2001,123, 7898.
5. Bertolasi,V.; Gilli, P.; Ferretti,V.; Gilli, G.; Fernandez-Castaño,
C.; Acta Crystallogr. Sect. B 1999, 55, 985.
6. De Paz, J. L. G.; Elguero, J.; Foces-Foces, C.; Llamas-Saiz, A.
L.; Aguilar-Parrilla, F.; Klein, O.; Limbach, H. -H.; J. Chem.
Soc., Perkin Trans. 1997, 2, 101.
7. Foces-Foces, C.; Hager, O.; Jagerovic, N.; Jimeno, M.L.;
Elguero, J.; Chem. Eur. J. 1997, 3,121.
17. Solomons, T. W. J.; Fowler, F. W.; Calderazzo, J.; J. Am. Chem.
Soc. 1965, 87, 528.
8. Claramunt, R. M.; Maria, M. D. S.; Forfar, I.; Aguilar-Parrilla,
F.; Minguet-Bonvehi, M.; Klein, O.; Limbach, H. -H.; Foces-
Foces, C.; Llamas-Saiz,A.L.; Elguero, J.; J. Chem. Soc., Perkin
Trans. 1997, 2, 1867.
18. Crystallographic data for the structural analysis of the
compounds 3b and 5b, reported in this paper, have been
deposited with the Cambridge Crystallographic Data Center
(CCDC) under the numbers 680984 and 680985, respectively.
Copies of the information may be obtained, free of charge, from
9. Claramunt, R. M.; Sanz, D.; López, C.; Jiménez, J. A.; Magn.
Res. Chem. 1997, 35,35.

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Martins et al.
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The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ,
20. Mohamed, M. H.; Abdel-Khalik, M. M.; Elnagdi, M. H.;
UK (Fax: + 44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk,
or www: http://ccdc.cam.ac.uk).
J. Heterocycl. Chem. 2001, 38, 685.
19. Perrin, D. D.; Armarego, W. L. F.; Purification of Laboratory
Chemicals, Pergamon: Oxford, 1998.
Received: March 27, 2009
Web Release Date: November 12, 2009