Microwave-assisted synthesis of bipyrazolyls and pyrazolyl-substituted pyrimidines

Article abstract of DOI:10.1016/j.tet.2006.10.080

We describe the preparation of 1,4′-bipyrazolyls and 4-pyrazolylpyrimidines by the reaction of 2-pyrazolyl-3-dimethylamino acrylate and acrylonitrile with double nucleophilic reagents such as hydrazines, urea and guanidine. Reactions were performed under microwave irradiation in 5-60 min. This is a useful procedure for the preparation of valuable compounds with applications in medicinal and coordination chemistry.

Full text of DOI:10.1016/j.tet.2006.10.080

Tetrahedron 63 (2007) 748–753
Microwave-assisted synthesis of bipyrazolyls and pyrazolyl-
substituted pyrimidines
a
b
a
a
Antonio de la Hoz,a, Angel Dıaz, Jose Elguero, Agustın Jimenez, Andres Moreno,
*
ꢀ
ꢀ
ꢀ
ꢀ
Amparo Ruiz and Ana Sanchez-Migallon
ꢀ
a
a
ꢀ
ꢀ
aFacultad de Quꢀımicas, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain
b
´
Instituto de Quꢀımica Medica (C.S.I.C.), Juan de la Cierva, 3, E-28006 Madrid, Spain
Received 20 September 2006; revised 23 October 2006; accepted 29 October 2006
Available online 17 November 2006
Dedicated to Charles W. Rees, in memoriam
Abstract—We describe the preparation of 1,40-bipyrazolyls and 4-pyrazolylpyrimidines by the reaction of 2-pyrazolyl-3-dimethylamino
acrylate and acrylonitrile with double nucleophilic reagents such as hydrazines, urea and guanidine. Reactions were performed under micro-
wave irradiation in 5–60 min. This is a useful procedure for the preparation of valuable compounds with applications in medicinal and
coordination chemistry.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Microwave irradiation is a useful heating technique that is
able to improve many kinds of reactions10 and it has been
applied successfully in the preparation of heterocyclic
compounds.11–16
Pyrimidine derivatives form the basis of a large number
of pharmacological products, for example, as inhibitors of
HIV-1 integrase,1 anticancer drugs2 and protein kinase
inhibitors.3 The pharmacological properties of pyrazole de-
rivatives have also been reviewed recently.4,5 Pyrazolyl-
substituted pyrimidines show analgesic activity6 and have
been used in coordination chemistry as bitopic ligands.7
We have applied microwaves to heterocyclic chemistry,17,18
to cycloaddition reactions,19,20 in the study of the so-called
microwave effect21 and also for the preparation of hetero-
cyclic compounds with applications in coordination and
supramolecular chemistry.22
Bipyrazolyls show interesting properties in coordination
chemistry; for example, 4,40-bipyrazolyl compounds have
been used in the construction of coordination networks
and in self-assembly.8 Consequently, the preparation of
1,40-bipyrazolyl systems could form the basis for a new
kind of multi-site ligand and even for the synthesis of chains
of polypyrazoles.
In the work described here, we applied this methodology
for the preparation of 1,40-bipyrazolyls and 4-pyrazolyl-
substituted pyrimidines. Although many 4,40-bipyrazolyls
and pyrazolylpyrimidines have been described, those joined
through pyrazole position 4 are not common.
2. Results
3-(Dimethylamino)propenoates are starting materials for a
wide variety of heterocyclic compounds, particularly for
the construction of the pyrimidine ring.9 These compounds
are analogues of 1,3-dicarbonyl compounds and are more
stable than a-formyl acetates. They have been used for the
preparation of heterocyclic compounds by reaction with
double nucleophiles and with electrophiles. We therefore
chose these substrates for the preparation of our target
compounds. In this regard, 2-pyrazolyl-3-dimethylamino
acrylate and acrylonitrile were our starting materials.
2.1. Synthesis of precursors
We planned the synthesis of bipyrazolyls and pyrazolyl-
substituted pyrimidine bases by the reaction of 2-pyra-
zolyl-3-dimethylamino acrylate and acrylonitrile with
double nucleophiles.
The starting materials were prepared from pyrazolyl acrylate
and acrylonitrile by reaction with the Vilsmeier reagent23
(POCl3/DMF) at 80 ꢀC for 16 h. However, under these con-
ditions a complex mixture was obtained, with formylation in
* Corresponding author. Tel.: +34 926295411; fax: +34 926295318; e-mail:
antonio.hoz@uclm.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.080

A. de la Hoz et al. / Tetrahedron 63 (2007) 748–753
749
the activated 4-position of the pyrazole ring being the
main reaction. Also, decarboxylation has been previously
observed in the reaction of pyridinium acetic acid with
electrophiles,24 and in the Vielsmeir–Haack formylation
of 4-nitropyrazoles.25 In order to protect position 4, we
used 4-bromopyrazole as the starting material. Thus, ethyl
4-bromopyrazolyl acetate (2) and acetonitrile 3 were pre-
pared by alkylation of 4-bromopyrazole with ethyl bromo-
acetate and bromoacetonitrile in anhydrous THF using
sodium hydride as a base (Scheme 1). Reaction at room
temperature for 4 h afforded compounds 2 and 3 in 73%
and 94% yield, respectively.
The preparation of 4 was improved using Bredereck’s
reagent (tert-butoxy-bis-dimethylaminomethane).26 Irradia-
tion at 45 W (temp 120 ꢀC) for 45 min gave an excellent
yield (98%) of compound 4 as a single isomer (Z-isomer).
In this reaction, 1 mL/mmol of DMF was used to homoge-
nize the reaction mixture and to improve the absorption of
microwave irradiation. It is remarkable that conventional
heating for 6 h at 120 ꢀC is necessary to obtain similar
results.
The configuration of the double bond in 4 and 5 was deter-
mined by NOE experiments (Fig. 1). In compound 5, isomer
5E shows a 1% NOE on H5 (7.54) on irradiation at 7.04 (ole-
fin hydrogen) and a 4% NOE with the dimethylamino group
(3.18); isomer 5Z shows only a 4% NOE with the dimethyl-
amino group (2.70) on irradiation at 6.71 (olefin hydrogen).
In compound 4, a single isomer was obtained in which the
double bond has the Z-configuration. Irradiation at 7.52
again showed a 3% NOE with the dimethylamino group
(2.33 and 3.07).
Br
N
BrCH2CO2Et
N
NaH, THF
Br
CO2Et
2
N
N
H
Br
1
BrCH2CN
Br
Br
Br
NaH, THF
N
N
N
N
N
H
H
N
H
N
CH3
1%
4%
N
CH3
CN
3
H
N
N
CN
NC
CH3
EtO2C
CH3
N
H
Scheme 1.
H
H3C
CH3
4%
3%
5E
5Z
4Z
Formylation of 2 and 3 was performed under microwave
irradiation. Use of the Vilsmeier reagent gave a complex
mixture and, as a consequence, we used dimethyl form-
amide-diethyl acetal (DMF-DEA). Formylation of 2 was
performed by irradiation at 30 W for 15 min (temp 90 ꢀC)
using a 2-fold excess of DMF-DEA without addition of any
solvent. These conditions gave only a modest 10% yield of
2-(4-bromopyrazol-1-yl)-3-dimethylaminoacrylic acid ethyl
ester (4) (Scheme 2). The use of prolonged reaction times led
to a decrease in the yield due to decomposition of the final
product. However, in the case of compound 3, irradiation
at 30 W for 15 min (temp 90 ꢀC) afforded an excellent yield
(97%) of 2-(4-bromopyrazol-1-yl)-3-dimethylaminoacrylo-
nitrile (5) as a 32:68 mixture of Z and E isomers, respectively
(Scheme 3).
Figure 1.
2.2. Cyclization reactions
Reaction of the precursors described above with double nu-
cleophiles gave the desired compounds (Schemes 4 and 5).
Urea, thiourea and guanidine were used to obtain a wide
variety of pyrazolyl-substituted pyrimidines. For example,
uracil and thiouracil derivatives 7 and 6 were prepared by re-
action of 4 with urea and thiourea, respectively, and amino-
pyrimidines 9 and 10 were made by reaction of 5 with
thiourea and guanidine, respectively. Finally, the use of
hydrazine and phenylhydrazine gave bipyrazolyl derivatives
8, 11 and 12.
All reactions were performed under microwave irradiation
using a small quantity of solvent (1 mL/mmol) to homoge-
nize the reaction mixture (in most cases both reactants are
solids). When possible we used an apolar solvent like
mesitylene to ensure that the reagents and not the solvent
absorbed microwave radiation. However, with very polar
compounds the use of a polar solvent (ethanol) was neces-
sary to dissolve the reagents. Reaction times were in the
range of 20–60 min with mesitylene and 4–15 min with
the more polar ethanol.
Br
Br
ButOCH(NMe2)2, DMF
N
N
N
N
MW, 45 W, 45 min, 120 °C
Me2N
CO2Et
CO2Et
2
4
98%
Scheme 2.
Br
Br
Br
These conditions gave good yields of bipyrazolyls and pyr-
azolylpyrimidines and represents a general procedure for the
preparation of these heterocyclic systems.
DMF-DEA
N
N
N
+
N
N
3
N
MW, 30 W, 15 min, 90 ºC
Me2N
CN
CN
CN
97%
Me2N
In conclusion, we have described a new procedure for
the preparation of 4-pyrazolyl-substituted pyrimidines
and 1,40-bipyrazolyls starting from 2-pyrazolyl-3-dimethyl-
amino acrylate and acrylonitrile under microwave irradiation
5E
5Z
32%
68%
Scheme 3.

750
A. de la Hoz et al. / Tetrahedron 63 (2007) 748–753
Br
Br
H2N
H2N
H2N
H2N
Br
S
O
N
N
N
N
N
O
O
N
4
15 W, 60 min
Mesitylene
15 W, 20 min
Mesitylene
Me2N
HN
NH
HN
NH
CO2Et
O
7
S
6
1) NH2NH2 H2Ol
10 W, 3 min
Ethanol
58%
70%
2) HCl
Br
N
N
O
HCl
HN NH
8
92%
Scheme 4.
Br
Br
H2N
H2N
H2N
Br
NH
S
N
N
N
N
H2N
N
N
NH2
NH2
15 W, 20 min
Ethanol
15 W, 20 min
Mesitylene
Me2N
N
N
HN
N
CN
5
NH2
S
PhNHNH2 HCl
10 W, 15 min
Ethanol
NH2NH2 H2O
10 W, 4 min
Ethanol
10
9
38%
56%
Br
Br
N
N
N
N
NH2 HCl
NH2
N
N
HN
N
Ph
12
67%
11
69%
Scheme 5.
conditions. This result opens a new way to prepare valuable
compounds in medicinal chemistry, such as 4-pyrazolyl-
substituted pyrimidine bases, as well as systems of relevance
in coordination chemistry.
and, in the latter oven, controlled using a computer with
PACAM MPX-2 software.
3.1.1. 2-(4-Bromopyrazol-1-yl)acetic acid ethyl ester 2.
Sodium hydride (11 mmol, 0.27 g) was added to a suspen-
sion of 4-bromopyrazole 1 (10 mmol, 1.47 g) in dry THF
(20 mL) under argon. The mixture was stirred until the evo-
lution of hydrogen had finished. The mixture was cooled
to 0 ꢀC and a solution of bromoethyl acetate (10 mmol,
1.14 mL) in dry THF (20 mL) was added dropwise. The re-
action mixture was stirred at room temperature for 14 h. The
solvent was evaporated in vacuo and the residue extracted
with dichloromethane (3ꢁ10 mL), filtered and concentrated
to give an orange oil (1.71 g, 73%). The oil was distilled un-
der reduced pressure using Kugelrohr apparatus to afford
pure 2 as a colourless oil (0.804 g, 47%). Bp 183 ꢀC (oven
3. Experimental
3.1. General
Melting points were determined using a Gallenkamp melting
point apparatus and are uncorrected. NMR spectra were re-
corded on a Varian Unity 500 spectrometer with TMS as the
internal standard. IR spectra were obtained with Nicolet-550
FTIR and ThermoNicolet-IR-100 spectrophotometers. The
mass spectra were recorded on a VG AutoSpec apparatus
using electron impact at 70 eV and atmospheric pressure
chemical ionization (ApCI). Flash column chromatography
was performed on silica gel 60 (Merck, 230–400 mesh).
1
temperature)/10 mmHg. H NMR (CDCl3, ppm) d: 1.29 (t,
J¼7.32 Hz, 3H, CH3), 4.23 (q, J¼7.32 Hz, 2H, –CH2–O),
4.87 (s, 2H, N–CH2–), 7.51 (s, 2H, H3 and H5-pyrazole).
13C NMR (CDCl3, ppm) d: 14.03 (CH3), 53.46 (CH2),
62.03 (N–CH2), 94.05 (C–Br), 130.68 (C5-pyrazole), 140.62
(C3-pyrazole), 167.25 (C]O). IR (KBr) n (cmꢂ1): 3132,
2984, 1751, 1217. MS (APcI) m/z: 232.0 (M+).
Reactions under microwave irradiation were performed in
a CEM Discover or a modified PROLABO MAXIDIGEST
MX35. Temperature was measured with an IR pyrometer

A. de la Hoz et al. / Tetrahedron 63 (2007) 748–753
751
3.1.2. 2-(4-Bromopyrazol-1-yl)acetonitrile 3. Sodium hy-
dride (11 mmol, 0.27 g) was added to a suspension of 4-bro-
mopyrazole 1 (10 mmol, 1.47 g) in dry THF (20 mL) under
argon. The mixture was stirred until the evolution of hydro-
gen had finished. The mixture was cooled to 0 ꢀC and a solu-
tion of bromoacetonitrile (10 mmol, 0.7 mL) in dry THF
(20 mL) was added dropwise. The reaction mixture was
stirred at room temperature for 14 h. The solvent was evapo-
rated in vacuo and the residue was extracted with dichloro-
methane (3ꢁ10 mL). The organic extract was dried with
magnesium sulfate and the solvent evaporated in vacuo to
afford pure 3 as a white solid (1.76 g, 94%). Mp (hexane)
66.0–67.6 ꢀC. 1H NMR (CDCl3, ppm) d: 5.06 (s, 2H, CH2),
7.56 (s, 1H, H5-pyrazole), 7.59 (s, 1H, H3-pyrazole). 13C NMR
(CDCl3, ppm) d: 39.97 (CH2), 95.47 (C–Br), 113.22 (CN),
129.7 (C5-pyrazole), 141.95 (C3-pyrazole). IR (KBr) n (cmꢂ1):
3127, 2939, 1439, 1415. MS (APcI): m/z 185.0 (M+).
3-dimethylaminoacrylic acid ethyl ester 4 (1.0 mmol,
0.288 g), thiourea (10 mmol, 0.76 g) and anhydrous mesityl-
ene (1 mL) was introduced into a Pyrex flask and irradiated
at 15 W for 20 min. The product was purified by column
chromatography on silica gel (hexane/ethyl acetate 8:2) to
give a yellow solid. Yield: 0.192 g, 70%; mp 191–193 ꢀC
(decomposition). 1H NMR (DMSO-d6, ppm) d: 7.82 (s, 1H,
H3-pyrazole), 7.86 (s, 1H, H5-pyrazole), 8.36 (s, 1H, H6-pyrimidine),
12.8 (br s, 1H, NH), 13.1 (br s, 1H, NH). 13C NMR (DMSO-
d6, ppm) d: 93.46 (C–Br), 119.36 (C5-pyrimidine), 131.01
(C6-pyrimidine), 134.8 (C5-pyrazole), 140.63 (C3-pyrazole),
156.56 (C]O), 174.28 (C]S). IR (KBr) n (cmꢂ1): 3071,
1697, 1632, 1354. EIMS: m/z 271.9366 (M+).
3.1.6. 5-(4-Bromopyrazol-1-yl)-1H-pyrimidin-2,4-dione
7.
A mixture of 2-(4-bromopyrazol-1-yl)-3-dimethyl-
aminoacrylic acid ethyl ester 4 (1.0 mmol, 0.288 g), urea
(10 mmol, 0.6 g) and anhydrous mesitylene (1 mL) was
introduced into a Pyrex flask and irradiated at 15 W for
60 min. The product was purified by column chromato-
graphy on silica gel using ethyl acetate. A pale yellow solid
was obtained. Yield: 0.158 g, 58%; mp T>250 ꢀC (decompo-
sition). 1H NMR (DMSO-d6, ppm) d: 7.74 (s, 1H, H5-pyrazole),
7.91 (s, 1H, H6-pyrimidine), 8.21 (s, 1H, H3-pyrazole), 11.15
(br s, 1H, NH). 13C NMR (DMSO-d6, ppm) d: 92.85
(C–Br), 115.18 (C5-pyrimidine), 131.58 (C5-pyrazole), 140.08
(C3-pyrazole), 149.93 (C6-pyrimidine), 150.41 (C2]O), 159.75
(C4]O). IR (KBr) n (cmꢂ1): 3213, 3084, 1707. EIMS: m/z
255.9599 (M+).
3.1.3. 2-(4-Bromopyrazol-1-yl)-3-dimethylaminoacrylic
acid ethyl ester 4. A mixture of (4-bromopyrazol-1-yl)ace-
tic acid ethyl ester 2 (2.57 mmol, 0.60 g), tert-butyloxy-bis-
dimethylaminomethane (2.81 mmol, 0.58 mL) and DMF
(1 mL) was introduced into a Pyrex flask and irradiated at
45 W for 30 min. The crude product was distilled under
reduced pressure using Kugelrohr apparatus to give pure 4.
Yield: 0.728 g, 98%; bp 154 ꢀC (oven temperature)/
1
1.5 mbar. H NMR (CDCl3, ppm) d: 1.20 (t, J¼7.0 Hz,
3H, CH3–), 2.33 (br s, 3H, N–CH3), 3.07 (br s, 3H,
N–CH3), 4.13 (q, J¼7.0 Hz, 2H, O–CH2–), 7.44 (s, 1H, H3),
7.51 (s, 1H, H5-pyrazole), 7.57 (s, 1H, H3-pyrazole). 13C NMR
(CDCl3, ppm) d: 14.48 (–CH3), 36.35 (br s, N–CH3),
47.28 (br s, N–CH3), 60.13 (O–CH2), 93.48 (C–Br),
100.25 (C2), 134.69 (C3), 140.44 (C3-pyrazole), 146.83
(C5-pyrazole), 166.62 (C]O). IR (KBr) n (cmꢂ1): 3140,
3102, 1686, 1626. EIMS: m/z 287.0 (M+).
3.1.7. 4-Bromo-10,20-dihydro-[1,40]bipyrazolyl-30-one hy-
drochloride 8. A mixture of 2-(4-bromopyrazol-1-yl)-3-di-
methylaminoacrylic acid ethyl ester 4 (1.0 mmol, 0.288 g),
hydrazine monohydrate (2 mmol, 0.1 mL) and ethanol
(1 mL) was introduced into a Pyrex flask and was cooled
to ꢂ10 ꢀC. Hydrochloric acid (37%, 11 drops) was added.
The solution was allowed to warm up to room temperature
and the mixture was irradiated at 10 W for 3 min. The
solvent was evaporated in vacuo and dichloromethane
(15 mL) was added. The resulting precipitate was identified
as the pure product (0.145 g, 92%). Mp 233.7–235.0 ꢀC. 1H
NMR (DMSO-d6, ppm) d: 7.69 (s, 1H, H3-pyrazole), 7.84
0
3.1.4. (Z)- and (E)-2-(4-Bromopyrazol-1-yl)-3-dimethyl-
aminoacrylonitrile 5Z and 5E. A mixture of (4-bromopyr-
azol-1-yl)acetonitrile 3 (2.5 mmol, 0.47 g) and DMF-DEA
(5 mmol, 0.85 mL) was introduced into a Pyrex flask and ir-
radiated at 30 W for 15 min. The crude mixture was filtered
through silica gel (7 cmꢁ2 cm) using ethyl acetate. The
solvent was evaporated and the product distilled under re-
duced pressure using Kugelrohr apparatus to afford a 32:68
(s, 1H, H5 -pyrazolone), 8.09 (s, 1H, H5-pyrazole), 12.01 (sbroad
,
1H, NH). 13C NMR (DMSO-d6, ppm) d: 92.47 (C–Br),
1
0
0
mixture of 5Z and 5E, as determined by H NMR. Yield:
108.95 (C4 -pyrazolone), 123.45 (C5 -pyrazolone), 129.89
(C5-pyrazole), 139.55 (C3-pyrazole), 152.65 (C]O). IR (KBr)
n (cmꢂ1): 3146, 2966, 1569, 1494. EIMS: 226.9810
(M+).
0.585 g, 97%; bp 170 ꢀC (oven temperature)/4 mbar. IR
(neat) n (cmꢂ1): 3124, 2924, 2189,1642. EIMS: m/z 240.0
(M+).
1
Compound 5E: H NMR (CDCl3, ppm) d: 3.19 [s, 6H,
3.1.8. 4-Bromo-10-phenyl-10H-[1,40]bipyrazolyl-50-yl-
amine hydrochloride 12. A mixture of 2-(4-bromo-
pyrazol-1-yl)-3-dimethylaminoacrylonitrile 5 (1.0 mmol,
0.241 g), phenylhydrazine hydrochloride (2 mmol, 0.29 g)
and ethanol (1 mL) was introduced into a Pyrex flask and ir-
radiated at 10 W for 15 min. The product was purified by
column chromatography on silica gel (hexane/ethyl acetate
7:3). A red solid was obtained. Yield: 0.230 g, 67%; mp
N–(CH3)2], 7.04 (s, 1H, N–CH]C), 7.5 (s, 1H, H3-pyrazole),
7.54 (s, 1H, H5-pyrazole). 13C NMR (CDCl3, ppm) d: 42.50
(N–CH3), 82.59 (C2), 94.11 (C–Br), 117.6 (CN), 130.67
(C5-pyrazole), 140.79 (C3-pyrazole), 149.83 (C3).
1
Compound 5Z: H NMR (CDCl3, ppm) d: 2.71 (s, 6H,
N–(CH3)2), 6.72 (s, 1H, N–CH]C), 7.54 (s, 1H, H5-pyrazole),
7.58 (s, 1H, H3-pyrazole). 13C NMR (CDCl3, ppm) d: 81.17
(C2), 94.84 (C–Br), 119.58 (CN), 133.96 (C5-pyrazole),
141.58 (C3-pyrazole), 147.99 (C3).
1
135.5–136.1 ꢀC. H NMR (CDCl3, ppm) d: 4.71 (s, 2H,
NH2), 7.41 (t, J¼7.3 Hz, 1H, Hp-Ph), 7.52 (t, J¼7.8 Hz,
0
2H, Hm-Ph), 7.58–7.62 (m, 4H, Ho-Ph, H5 , H3), 7.71 (s, 1H,
H5). 13C NMR (CDCl3, ppm) d: 93.98 (C–Br), 108.51
0
(C4 ), 123.85 (Co-Ph), 127.99 (C5), 128.04 (Cp-Ph), 129.69
3.1.5. 5-(4-Bromopyrazol-1-yl)-2-thioxo-2,3-dihydro-1H-
pyrimidin-4-one 6. A mixture of 2-(4-bromopyrazol-1-yl)-
0
(Cm-Ph), 131.51 (C5 ), 137.99 (C3 ), 138.17 (Cipso-Ph),
0

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A. de la Hoz et al. / Tetrahedron 63 (2007) 748–753
140.12 (C3). IR (KBr) n (cmꢂ1): 3406, 3322, 1625, 1595.
EIMS: m/z 303.0117 (M+).
Acknowledgements
Financial support from the Spanish DGCyT (project
CTQ2004-01177/BQU) and Junta de Comunidades de
Castilla-La Mancha (projects PAI05-019 and PBI06-0020)
is gratefully acknowledged.
3.1.9. 5-(4-Bromopyrazol-1-yl)pyrimidine-2,4-diamine
10. Guanidine hydrochloride (2 mmol, 0.19 g) was dis-
solved in ethanol (3 mL) and a solution of sodium hydrox-
ide (2 mmol, 0.08 g) in ethanol (2 mL) was added dropwise
to give a basic pH. The resulting solution was filtered
to remove sodium chloride. The filtrate was mixed with
References and notes
2-(4-bromopyrazol-1-yl)-3-dimethylaminoacrylonitrile
5
(1.0 mmol, 0.241 g) and basic alumina (1 g). The mixture
was irradiated at 15 W for 20 min. The crude product
was extracted with chloroform and alumina was removed
by filtration. The filtrate was purified by column chromato-
graphy on silica gel using ethyl acetate. A pale yellow solid
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1
was obtained. Yield: 0.098 g, 38%; mp 127 ꢀC. H NMR
(CDCl3, ppm) d: 4.88 (br s, 2H, NH2), 5.68 (br s, 2H,
NH2), 7.66 (s, 1H, H3-pyrazole), 7.68 (s, 1H, H5-pyrazole),
7.93 (s, 1H, H6-pyrimidine). 13C NMR (CDCl3, ppm) d: 94.77
(C–Br), 109.76 (C5-pyrimidine), 129.57 (C5-pyrazole), 141.59
(C3-pyrazole), 150.20 (C6-pyrimidine), 157.86 (C4-pyrimidine),
161.64 (C2-pyrimidine). IR (KBr) n (cmꢂ1): 2923, 2853,
1464. EIMS: m/z 253.9911 (M+).
6. Miyashita, Y.; Seki, T.; Yotsui, Y.; Yamazaki, K.; Sano, M.;
Abe, H.; Sasaki, S. Chem. Pharm. Bull. 1982, 55, 1489–
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7. Elguero, J.; Guerrero, A.; Gomez de la Torre, F.; de la Hoz, A.;
Jalon, F. A.; Manzano, B. R.; Rodrıguez, A. New J. Chem.
3.1.10. 5-(4-Bromopyrazol-1-yl)-2-thioxo-2,3-dihydro-
1H-pyrimidine-4-amine 9. A mixture of 2-(4-bromo-
pyrazol-1-yl)-3-dimethylaminoacrylonitrile 5 (1.0 mmol,
0.241 g), thiourea (10 mmol, 0.76 g) and anhydrous mesityl-
ene (1 mL) was introduced into a Pyrex flask and irradiated
at 15 W for 20 min. Water (3 mL) was added and the result-
ing solid was filtered off. The solid was washed with hot
methanol (2ꢁ1 mL) to afford the pure product. Yield:
0.142 g, 56%; mp 256 ꢀC (decomposition). 1H NMR
(DMSO-d6, ppm) d: 7.19 (s, 1H, NH), 7.82 (s, 1H,
H6-pyrimidine), 7.86 (s, 1H, H3-pyrazole), 8.23 (br s, 1H, NH),
8.30 (s, 1H, H5-pyrazole), 12.51 (s, 1H, NH). 13C NMR
(DMSO-d6, ppm) d: 93.83 (C–Br), 111.92 (C5-pyrimidine),
132.01(C5-pyrazole), 138.83 (C6-pyrimidine), 141.67(C3-pyrazole),
157.10 (C4-pyrimidine), 178.84 (C]S). IR (KBr) n (cmꢂ1):
3368, 3232, 3127, 1650. EIMS: 270.9523 (M+).
ꢀ
ꢀ
2001, 25, 1050–1060.
8. (a) Bolgog, I.; Sieler, J.; Chernega, A. N.; Domasevitch, K. V.
Inorg. Chim. Acta 2002, 338, 69–77; (b) Boldog, I.; Rusanov,
E. B.; Chernega, A. N.; Sieler, J.; Domasevitch, K. V. Angew.
Chem., Int. Ed. 2001, 40, 3435–3438.
9. Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433–2480 and
references therein.
10. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284 and
references therein.
11. Romanova, N. N.; Kudan, P. V.; Gravis, A. G.; Bundel, Y. G.
Chem. Heterocycl. Compd. 2000, 36, 1130–1140.
12. Xu, Y.; Guo, Q.-X. Heterocycles 2004, 63, 903–974.
13. Ashry, E. S. H. E.; Kassem, A. ARKIVOC 2005, 1–16.
14. Ashry, E. S. H. E.; Ramadan, E.; Kassem, A. A.; Hagar, M. Adv.
Heterocycl. Chem. 2005, 88, 1–110.
15. Molteni, V.; Ellis, D. A. Curr. Org. Synth. 2005, 2, 333–
375.
16. Microwave-Assisted Synthesis of Heterocycles. In Topics
in Heterocyclic Chemistry; Van der Eycken, E., Kappe,
C. O., Eds.; Springer: Berlin, Heidelberg, New York, NY,
2006.
3.1.11. 4-Bromo-10H-[1,40]bipyrazolyl-30-ylamine 11.
A mixture of 2-(4-bromopyrazol-1-yl)-3-dimethylamino-
acrylonitrile 5 (1.0 mmol, 0.241 g), hydrazine monohydrate
(2 mmol, 0.1 g, 0.11 mL) and ethanol (1 mL) was intro-
duced into a Pyrex flask and was cooled to ꢂ10 ꢀC. Hydro-
chloric acid (37%, 11 drops) was added. The mixture was
allowed to warm up to room temperature and was irradiated
at 10 W for 4 min. The solvent was evaporated in vacuo and
the addition of dichloromethane (3 mL) gave the hydrochlo-
ride as a precipitate. The solid was filtered off and dissolved
in water (15 mL). The solution was neutralized with satu-
rated aqueous sodium hydrogen carbonate and extracted
with dichloromethane (4ꢁ5 mL). The organic extract was
dried over magnesium sulfate and the solvent was evapo-
rated under vacuum to afford a solid (0.158 g, 69%). Mp
152.4–154.9 ꢀC. 1H NMR (DMSO-d6, ppm) d: 4.5–6.5
ꢀ
17. Almena, I.; Carrillo, J. R.; de la Cruz, P.; Dıaz-Ortiz, A.; de la
Hoz, A.; Langa, F.; Prieto, P.; Sanchez-Migallon, A. Targets in
ꢀ
ꢀ
Heterocyclic Systems 1998, 2, 281–308.
ꢀ
18. de la Hoz, A.; Dıaz-Ortiz, A.; Mateo, M. C.; Moral, M.;
Elguero, J.; Foces-Foces, C.; Rodrıguez, M. L.; Sanchez-
ꢀ
ꢀ
ꢀ
Migallon, A. Tetrahedron 2006, 62, 5868–5874.
ꢀ
19. Dıaz-Ortiz, A.; Langa, F.; de la Hoz, A.; Moreno, A. Eur. J.
Org. Chem. 2000, 4, 3659–3673.
ꢀ
20. Dıaz-Ortiz, A.; de la Hoz, A.; Langa, F. Microwaves in
Cycloadditions. In Microwaves in Organic Synthesis; Loupy,
A., Ed.; Wiley: Weinheim, 2002; pp 295–343.
ꢀ
0
(br s, 2H, NH2), 7.79 (s, 1H, H3), 8.00 (s, 1H, H5 ), 8.34 (s,
21. Dıaz-Ortiz, A.; de la Hoz, A.; Moreno, A. Chem. Soc. Rev.
2005, 164–178.
1H, H5). 13C NMR (DMSO-d6, ppm) d: 93.11 (C–Br),
0
0
ꢀ ꢀ
22. Dıaz-Ortiz, A.; Elguero, J.; de la Hoz, A.; Jimenez, A.;
111.44 (C4 ), 125.27 (C5 ), 129.96 (C5), 139.98 (C3),
0
141.02 (C3 ). IR (KBr) n (cmꢂ1): 3476, 3346, 1598, 1537.
EIMS: 227.9640 (M+1).
Moreno, A.; Moreno, S.; Sanchez-Migallon, A. QSAR Comb.
Sci. 2005, 24, 649–659.
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