A convenient synthesis of 3- and 5-amino-1 H -pyrazoles via 3(5)-amino-4-(ethylsulfi nyl)-1 H -pyrazole desulfi nylation

Article abstract of DOI:10.1515/HC.2011.026

Syntheses of 5-amino-3-aryl- and 3-amino-5-aryl-1 H -pyrazoles from β -bromo- α -(ethylsulfanyl)cinnamonitrile are described. The β -bromo- α -(ethylsulfanyl)cinnamonitriles were oxidized with H₂O ₂ to the corresponding β -bromo- α -

Full text of DOI:10.1515/HC.2011.026

Heterocycl. Commun., Vol. 17(3-4), pp. 139–145, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.026
A convenient synthesis of 3- and 5-amino-1H-pyrazoles via
3(5)-amino-4-(ethylsulfinyl)-1H-pyrazole desulfinylation
Frédéric Lassagne1,*, Katia Snégaroff1, Thierry
Roisnel2, Ekhlass Nassar3 and Florence Mongin1
A β-bromo leaving group has been employed for the
syntheses of different aza-heterocycles (Pochat, 1980a,b,
1983) including pyrazoles (Pochat, 1979a,b) from β-bromo-
α-(ethylsulfanyl)cinnamonitriles but, to our knowledge,
β-bromo-α-(ethylsulfinyl)cinnamonitriles have never been
used for this purpose. In the present paper, we report the
results of our investigation into the synthetic potential of
β-bromo-α-(ethylsulfinyl)cinnamonitriles as precursors in
3(5)-aminopyrazole synthesis. Finally, some starting products
and fused pyrimidines that were synthesized were evaluated
for their bactericidal and cytotoxic activities.
1 Chimie et Photonique Moléculaires, UMR 6510 CNRS,
Bâtiment 10A, Case 1003, Université de Rennes 1,
Campus Scientifique de Beaulieu, F-35042 Rennes, France
2 Centre de Diffractométrie X, Sciences Chimiques de
Rennes, UMR 6226 CNRS, Bâtiment 10B, Université
de Rennes 1, Campus Scientifique de Beaulieu, F-35042
Rennes, France
3 Department of Chemistry, Faculty of Women for Arts,
Science and Education, Ain Shams University, Asma
Fahmy Street, Heliopolis (El-Margany), Cairo, Egypt
*Corresponding author
e-mail: frederic.lassagne@univ-rennes1.fr
Results and discussion
To our knowledge, no reaction has been described between
β-bromo-α-(ethylsulfinyl)cinnamonitriles 2 and hydrazine.
The phenyl-substituted aminopyrazoles 3 and 5 were obtained,
as outlined in Table 1, in two steps from the β-bromo-α-
(ethylsulfanyl)cinnamonitriles 1.
As previously described (Pochat, 1979b), compounds
1a–f were readily obtained as Z/E mixtures in two steps
from aromatic aldehydes and ethyl thioacetonitrile followed
by bromination. Several methods were reported to oxi-
dize sulfides to sulfoxides (Kaya et al., 1981; Hirano et al.,
1997; Mohanakrishnan and Ramesh, 2005). However, the
experiment showed that the β-bromo-α-(ethylsulfanyl)cinna-
monitriles 1 can be smoothly oxidized with hydrogen perox-
ide in acetic acid to produce the corresponding sulfoxides 2
as Z/E mixtures in good yields (Table 1, entries 1–6) without
epoxide formation.
Abstract
Syntheses of 5-amino-3-aryl- and 3-amino-5-aryl-1H-pyra-
zoles from β-bromo-α-(ethylsulfanyl)cinnamonitrile are
described. The β-bromo-α-(ethylsulfanyl)cinnamonitriles
were oxidized with H2O2 to the corresponding β-bromo-α-
(ethylsulfinyl)cinnamonitriles. Subsequent treatment of the
resulting sulfoxides with hydrazine hydrate or methylhy-
drazine followed by hydrochloric acid hydrolysis afforded
5-amino-3-aryl- and 3-amino-5-aryl-1H-pyrazoles, respec-
tively, in good yields.
Keywords: biological evaluation; desulfinylation; hydra-
zine; pyrazole; pyrazolo[1,5-a]pyrimidines; sulfoxide.
Compounds 2a–f were then treated with hydrazine or meth-
ylhydrazine in a protic solvent to afford the 5-amino-3-aryl-
and 3-amino-5-aryl-1H-pyrazoles 3 and 5 in good yields after
acidic hydrolysis (Table 1, entries 1–6). The use of methylhy-
drazine gave the 1-methyl-1H-pyrazoles 4 and 5 with high regi-
oselectivity (Table 1, entries 3–5), while phenylhydrazine did
not react under the same reaction conditions (Table 1, entries 1
and 2), a result probably due to unfavorable steric interactions.
In the case of methylhydrazine, the reaction proceeds exclu-
sively via initial attack of the methyl-substituted amino group to
afford an intermediate pyrazole sulfoxide 4 that is transformed
into aminopyrazole 5 after a subsequent C–S bond cleavage
using aqueous hydrochloric acid. In the case of hydrazine, it
proved impossible to isolate an intermediate sulfoxide, and the
aminopyrazole 3 was formed after acidic hydrolysis.
Introduction
Pyrazoles belong to the most representative five-membered
heterocyclic systems (Katritzky, 1985; Eicher et al., 2003).
Phenyl-substituted 3(5)-amino-1H-pyrazoles and their deriv-
atives exhibit high biological activities and are used as inter-
mediates in the synthesis of pyrazolo-fused heterocycles,
such as pyrazolo[1,5-a]pyrimidines (Fraley et al., 2002a,b;
Compton et al., 2004) and pyrazolopyridines (Straub and
Alonso-Alija, 2001).
Synthesis of 3(5)-aminopyrazoles has been extensively
investigated in the past, and the different studies were recently
reviewed (Anwar and Elnagdi, 2009). These scaffolds can be
obtained by reaction between hydrazine and 3-oxoalkane-
nitriles (Pask et al., 2006; Riyadh et al., 2008), arylalkyne-
nitriles (Rama Rao et al., 2006) or α,β-unsaturated nitriles
(Ege et al., 1982; Sadek et al., 1993; Nenaidenko et al., 2004;
Cai et al., 2006) as depicted in Scheme 1.
It has been reported that hydrazine undergoes a nucleo-
philic addition to a nitrile triple bond with the formation of an
intermediate hydrazide (Rama Rao et al., 2006). In the case of
the β-bromo-α-(ethylsulfinyl)cinnamonitriles 2, nucleophilic
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140 F. Lassagne et al.
O
as discussed above, could lead to compound 4. A subsequent
desulfinylation could provide compound 5.
CN
Ar
Product 4d was unambiguously identified by X-ray diffrac-
tion data of suitable crystals (Figure 1).
Finally, according to the procedure described in Rama Rao
et al. (2006), some of the aminopyrazoles 3 were treated with
hexafluoroacetylacetonetoaffordthecorresponding2-aryl-5,7-
bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidines 6 in yields
ranging from 70 to 86% (Scheme 4).
Ar
Ar
Y
CN
Ar
CN
N
NH2
N
H
Ar=Phenyl
Y=CCL3, OEt, NMe2, SMe, NHAryl
Pharmacology
Scheme 1 Retrosynthetic access to 3(5)-aminopyrazoles
Applying the agar plate diffusion technique (Bauer et al.,
1966), the 4d and 4e compounds synthesized were screened
in vitro for their bactericidal activity against Gram-positive
(Staphylococcus aureus) and Gram-negative bacteria
(Escherichia coli), and for their fungicidal activity against
Fusarium oxysporium and Aspergillus niger. Nevertheless,
none of the compounds proved active when compared with
cibrofloxacin and nystin, respectively (Table 2).
Compounds 2e, 4d, 4e, 6a, 6b and 6d were also tested
against a human liver carcinoma cell line (HEPG2), a
human breast carcinoma cell line (MCF7), and a human
cervix carcinoma cell line (HELA) (Table 3). Compound
2e was found to be highly active against all the three kinds
of carcinoma cell lines, with IC50 values below those of
the reference drug doxorubicin (IC50 is defined as the con-
centration that results in a 50% decrease in cell number as
compared with that of the control structures in the absence
of an inhibitor).
addition followed by elimination reaction also furnished the
cyclized products.
Although we have not established the mechanism of this
unexpected reaction experimentally, a putative mechanism
for the formation of compounds 3, 4 and 5 starting from com-
pound 2 is depicted in Scheme 2 and Scheme 3. It is suggested
that the addition of hydrazine to the isomers of compound 2
would lead to an equilibrated mixture of ene-hydrazines A
and hydrazones B, allowing free rotation around of the C3–
C4 bond (Pochat, 1979b). Hydrolysis of the sulfoxides C to
the phenyl-substituted 3(5)-aminopyrazoles 3 would occur
under acidic catalysis with elimination of ethylsulfinic acid
(Scheme 2).
Addition of methylhydrazine to isomeric mixture 2 would
give the intermediates D through two forms justifying the rota-
tion around the C3–C4 bond (Scheme 3). Then a cyclization,
Table 1 Synthesis of pyrazoles 3, 4 and 5 from β-bromo-α-(ethylsulfanyl)cinnamonitriles 1.
R3
1) H2NNH2
EtOH, reflux, 2 h
R2
R3
R1
R3
R1
2) H2O, HCl
55 °C, 1 h
R1
H2O2,
N
R2
R2
CH3CO2H
N
H
NH2
SEt
CN
S(O)Et
CN
3
CH2Cl2
45 °C, 5 h
Br
Br
R3
R3
R1
1
2
R2
R2
H2O, HCl
55 °C, 1 h
RNHNH2
S(O)Et
R1
R
EtOH, reflux, 2h
N
N
R
N
NH2
NH2
N
4
5
Entry
R1
R2
R3
R
2, Yielda,b
3, Yielda
4, Yielda
5, Yielda
1
2
3
4
5
6
H
H
H
H
H
OMe
H
H
H
H
H
Cl
tBu
Ph
Ph
Me
Me
Me
–
2a, 84%
2b, 85%
2c, 86%
2d, 90%
2e, 86%
2f, 80%
3a, 85%
3b, 89%
3c, 90%
3d, 86%
3e, 85%
3f, 88%
0%c
0%c
0%c
0%c
4c, 90%
4d, 86%
4e, 95%
–
5c, 90%
5d, 75%
5e, 70%
–
OMe
OCH2O
H
H
aYields after purification. bZ/E mixtures. cStarting material recovered.
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Synthesis of 3- and 5-amino-1H-pyrazoles 141
R
SOEt
N
R
N
SOEt
R
SOEt
NH NH
2
2
Br
C
N
HN
- HBr
NH
NH
N
2
2
2
A
B
H
H
SOEt
NH
O
H
H
N
SOEt
SOEt
NH
Cl
O
R
R
R
HCl
H O
2
2
NH
EtS
2
N
N
H
N
N
H
N
H
R
H
NH
2
N
N
C
H
H
O
EtS
O
NH
H
R
2
- EtSO H
2
H
R
N
NH
NH
2
NaOH
N
N
3
Scheme 2 Mechanistic hypothesis to explain the formation of compound 3.
spectrometer at 300 and 75 MHz, respectively, or on a Bruker AC-
500 spectrometer at 500 and 125 MHz, respectively. High-resolution
mass spectra (HRMS) measurements were performed at the Centre
Regional de Mesures Physiques de l’Ouest (CRMPO) in Rennes
using either a Waters Q-TOF 2 or a Bruker micrOTOF Q II instru-
ment. Elemental analyses were performed at the CRMPO using a
Thermo-Finnigan Flash EA 1112 CHNS analyzer. Hydrazine hy-
drate, methyl hydrazine and phenyl hydrazine were purchased from
Aldrich and used without further purification. (Ethylsulfanyl)ac-
etonitrile and the β-bromo-α-(ethylsulfanyl)cinnamonitriles 1 were
prepared according to a procedure described in Dijkstra and Backer
Conclusion
We have developed a mild, convenient and inexpensive
approach for the preparation of 3(5)-aminopyrazoles from
β-bromo-α-(ethylsulfinyl)cinnamonitriles 2 through a simple
protocol. In comparison, we have established the equivalence
between β-bromo-α-(ethylsulfinyl)cinnamonitriles and acet-
ylenic nitrile analogs, and shown that the precursors 2 were
good alternatives for the formation of 3(5)-aminopyrazoles
without use of potential toxic agents.
(1954; Pochat, 1979a,b).
Experimental
General
Typical procedure for the preparation of compounds
2a–f
Thirty-five per cent hydrogen peroxide (36.5 mmol) was added to a
stirred solution of starting compound 1 (33 mmol) with a mixture of
glacial acetic acid (20 ml) and dichloromethane (10 ml) at 40–50°C.
After five hours at the same temperature, the mixture was quenched
with excess 10% aqueous sodium carbonate, extracted with dichlo-
romethane, dried over Na2SO4 and concentrated. Diethyl ether was
Liquid chromatography separations were achieved on silica gel (230–
400 mesh). The eluent is given in the product description. Melting
points were measured using Kofler apparatus. The infrared spectra
were obtained using KBr pellets. The H and 13C nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker Avance III
1
O
R
SOEt
Br
SOEt
Br
SEt
3
4
R
S(O)Et
R
cyclization
R
MeNHNH2
- HBr
NH
C
N
C
N
Me
C
N
NH
NH
2
Br
C
N
Me
NH2
Me
1
NH2
NH2
2
D
H
SOEt
NH2
O
EtS
O
R
NH2
H2O/HCl
- EtSO2H
R
H
- H
H
R
N
N
NH2
N
N
Me
Me
N
N
4
5
Me
Scheme 3 Mechanistic hypothesis to explain the formation of compounds 4 and 5.
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142 F. Lassagne et al.
C19
C18
C16
C15
C17
C12
S1
02
C13
C13
C3
C11
25
CU
N7
N9
C10
N8
Figure 1 ORTEP diagram (30% probability) of compound 4d.
R
R
O
O
EtOH
+
NH
N
F C
3
CF
3
∆
N
N
N
N
H
2
CF
F C
3
3
3a (R=H)
6a: 75% yield
6b: 70% yield
6c: 86% yield
3b (R=Cl)
t
3c (R= Bu)
Scheme 4 Synthesis of pyrazolo[1,5-a]pyrimidine 6 from pyrazole 3.
added to the oily residue, and the resulting mixture was cooled over-
night. The solid was filtered off, yielding the sufficiently pure sulfox-
ide as a Z/E mixture.
NMR (75 MHz, CDCl3): δC 6.8, 7.4, 47.5, 48.8, 111.9, 112.3, 123.5,
125.1, 129.4, 130.5, 133.6, 134.2, 138.9, 139.2, 146.9, 148.2. HRMS
(ESI): analysis calculated for C11H9BrClNOSNa [(M+Na)+• ] 339.92.
Found 339.92.
3-Bromo-2-(ethylsulfinyl)-3-phenylacrylonitrile (2a) White sol-
id; yield 84%; mp 68–70°C; IR: ν (cm-1) 2217(s); 1H NMR (300 MHz,
CDCl3): δH 1.29 and 1.42 (2 t, 3H, J=7.5 Hz), 2.95 and 3.25 (m, 2H),
7.41 and 7.55 (m, 3H), 7.70 (m, 2H); 13C NMR (75 MHz, CDCl3): δC
6.9, 7.3, 47.3, 47.9, 112.0, 112.3, 122.8, 124.4, 128.8, 129.0, 129.1,
129.1, 132.3, 132.7, 135.1, 135.7, 148.5, 149.6. HRMS (ESI): analy-
sis calculated for C11H11BrNOS [(M+H)+• ] 283.97. Found 283.98.
3-Bromo-3-(4-tert-butylphenyl)-2-(ethylsulfinyl)acrylonitrile
(2c) White solid; yield 86%; mp 116–118°C; IR: ν (cm-1) 2212 (s);
1H NMR (300 MHz, CDCl3): δH 1.32 (s, 9H), 1.42 (t, 3H, J=7.5 Hz),
3.00 and 7.27 (m, 2H), 7.48 (dd, 2H, J=7.5 and 2.0 Hz), 7.68 (dd, 2H,
J=7.5 and 2.0 Hz); 13C NMR (75 MHz, CDCl3): δC 6.9, 31.0, 35.2, 47.3,
112.3, 121.4, 125.9, 129.1, 132.7, 148.9, 156.8. HRMS (ESI): analysis
calculated for C15H18BrNOSNa [(M+Na)+• ] 362.02. Found 362.02.
3-Bromo-3-(4-chlorophenyl)-2-(ethylsulfinyl)acrylonitrile
(2b) Yellow solid; yield 85%; mp 98–100°C; IR: ν (cm-1) 2217 (s).
1H NMR (300 MHz, CDCl3): δH 1.31 and 1.44 (2 t, 3H, J=7.5 Hz),
3.03 and 3.27 (m, 2H), 7.44–7.69 (dd, 4H, J=8.7 and 2.0 Hz); 13C
3-Bromo-2-(ethylsulfinyl)-3-(4-methoxyphenyl)acrylonitrile
(2d) White solid; yield 90%; mp 96–98°C; IR: ν (cm-1) 2212 (s);
1H NMR (300 MHz, CDCl3): δH 1.30 and 1.42 (2 t, 3H, J=7.5 Hz),
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Synthesis of 3- and 5-amino-1H-pyrazoles 143
Table 2 Bactericidal and fungicidal activity of compounds 4d and 4e, ciprofloxacin and nystin.
Entry
Compound
Staphylococcus aureus
Escherichia coli
Aspergillus niger
Fusarium oxysporium
1
2
3
4
4d
4e
20 (++)
21 (++)
++++
–
16 (++)
17 (++)
++++
–
20 (++)
21 (++)
–
20 (++)
20 (++)
–
ciprofloxacin
nystin
++++
++++
The diameters of zones of inhibition are given in mm. Stock solution: 5 µg in 1 ml of DMF; 1 ml of stock solution in each hole of each paper
disk. +: <15 mm; ++: 15–24 mm; +++: 25–34 mm; ++++: 35–44 mm, etc.
2.86 and 3.31 (m, 2H), 3.87 (s, 3H,), 6.95–7.76 (dd, 4H, J=9.0 and
2.0 Hz); 13C NMR (75 MHz, CDCl3): δC 6.9, 7.4, 47.3, 47.9, 55.6,
112.5, 114.1, 114.2, 119.8, 127.3, 127.7, 131.5, 131.7, 148.6, 150.1,
163.0, 163.2. HRMS (ESI): analysis calculated for C12H12BrNOSNa
[(M+Na)+• ] 335.97. Found 335.97.
sodium hydroxide until reaching pH 9 and cooled overnight. The
crude solid was rapidly purified either on a silica gel column or by
crystallization.
5-Amino-3-phenyl-1H-pyrazole (3a) White solid (eluent: AcOEt-
EtOH 99/1); yield 85%; mp 128–130°C (Rama et al., 2006, mp 126–
127°C); 1H NMR (500 MHz, CDCl3): δH 5.91 (s, 1H), 7.32 (td, 1H,
J=7.35 and 1.1 Hz), 7.38 (dd, 2H, J=7.35 and 1.3 Hz), 7.69 (dd, 2H,
J=7.15 and 1.1 Hz); 13C NMR (125 MHz, CDCl3): δC 90.3, 125.5,
128.3, 128.9, 130.4, 145.8, 154.3. HRMS (ESI): analysis calculated
for C9H10N3 [(M+H)+• ] 160.09. Found 160.09.
3-(1,3-Benzodioxol-5-yl)-3-bromo-2-(ethylsulfinyl)acrylonitrile
(2e) Yellow solid; yield 86%; mp 134–136°C; IR: ν (cm-1) 2202 (s);
1H NMR (300 MHz, CDCl3): δH 1.31 and 1.41 (2 t, 3H, J=7.5 Hz),
2.96 and 3.29 (m, 2H), 6.07 (s, 2H), 6.86 (d, 1H, J=8.3 Hz), 7.17 (d,
1H, J=1.9 Hz), 7.33 (dd, 1H, J=8.3 and 2.0 Hz); 13C NMR (75 MHz,
CDCl3): δC 6.9, 7.4, 47.3, 47.9, 102.4, 108.2, 108.4, 109.4, 109.5,
112.3, 120.8, 125.0, 125.2, 128.7, 129.3, 148.0, 148.2, 148.2, 149.4,
151.4, 151.6. HRMS (ESI): analysis calculated for C12H10BrNO3SNa
[(M+Na)+• ] 349.95. Found 349.95.
5-Amino-3-(4-chlorophenyl)-1H-pyrazole (3b) White solid (elu-
ent: AcOEt-EtOH 99/1); yield 89%, mp 172°C (Nenaidenko et al.,
2004, mp 172–173°C); 1H NMR (500 MHz, CDCl3): δH 5.92 (s, 1H),
7.40 (d, 2H, J=8.5 Hz), 7.50 (d, 2H, J=8.5 Hz); 13C NMR (125 MHz,
CDCl3): δC 29.6, 90.7, 126.6, 129.1, 134.2, 145.2, 154.0. HRMS (ESI):
analysis calculated for C9H9N3Cl [(M+H)+• ] 194.05. Found 194.05.
3-Bromo-2-(ethylsulfinyl)-3-(2-methoxyphenyl)acrylonitrile
(2f) White solid; yield 80%; mp 88–90°C; IR: ν (cm-1) 2213 (s); 1H
NMR (300 MHz, CDCl3): δH 1.29 and 1.44 (2 t, 3H, J=7.5 Hz), 3.04
and 3.27 (m, 2H), 3.86 and 3.91 (s, 3H), 6.82–7.07 (m, 2H), 7.33–7.56
(m, 2H); 13C NMR (75 MHz, CDCl3): δC 6.6, 7.2, 47.5, 55.7, 111.3,
111.7, 120.8, 125.4, 129.9, 133.3, 144.2, 155.8. HRMS (ESI): analysis
calculated for C12H12BrNOSNa [(M+Na)+• ] 335.97. Found 335.97.
5-Amino-3-(4-tert-butylphenyl)-1H-pyrazole (3c) White solid
(eluent: AcOEt-EtOH 99/1); yield 90%; mp 164–166°C; 1H NMR
(500MHz, CDCl3): δH 1.37 (s, 9H), 5.92 (s, 1H), 7.44 (d, 2H, J=8.5 Hz),
7.47 (d, 2H, J=8.5 Hz); 13C NMR (125 MHz, CDCl3): δC 31.2, 34.6,
90.6, 125.1, 125.8, 127.3, 145.3, 151.7, 155.0. HRMS (ESI): analysis
calculated for C13H18N3 [(M+H)+• ] 216.15. Found 216.15.
General procedure for the preparation of compounds
3a–f, 4c–e, 5c–e
5-Amino-3-(4-methoxyphenyl)-1H-pyrazole (3d) White solid
(eluent: AcOEt-EtOH 97/3); yield 86%; mp 144°C (Nenaidenko
et al., 2004, mp 141–143°C); 1H NMR (500 MHz, DMSO-d6):
δH 3.75 (s, 3H), 5.7 (s, 1H), 6.95 (d, 2H, J=8.8 Hz), 7.6 (d, 2H,
J=8.8 Hz); 13C NMR (125 MHz, DMSO-d6): δC 55.0, 87.0, 113.9,
124.5, 126.0, 144.2, 152.8, 158.5. HRMS (ESI): analysis calcu-
lated for C10H12N3O [(M+H)+• ] 190.10. Found 190.10.
Hydrazine hydrate or methylhydrazine (30 mmol) was added with
stirring to a suspension of compound 2 (10 mmol) in absolute etha-
nol (40 ml) cooled to –5°C. After 20 min at 19–20°C and 2 h under
reflux, the mixture was cooled, filtered and concentrated under re-
duced pressure, affording compound 4. The solid was dissolved
into 6N aqueous hydrochloric acid (5 ml) and heated at 50–60°C
for 1 h. After cooling, the mixture was basified using 6N aqueous
5-Amino-3-(1,3-benzodioxol-5-yl)-1H-pyrazole (3e) Gray solid
(eluent:AcOEt-EtOH 99/1); yield 85%; mp 158°C; 1H NMR (300 MHz,
DMSO-d6): δH 3.85 (s, 3H), 5.89 (s, 1H), 6.95 (t, 1H, J=7.5 Hz), 7.07
(d, 1H, J=8.4 Hz), 7.26 (t, 1H, J=7.2 Hz), 7.62 (m, 1H); 13C NMR
(75 MHz, DMSO-d6) δC (ppm): 55.3, 91.5, 111.7, 114.1, 120.4, 120.4,
127.0, 128.5, 138.7, 155.5. HRMS (ESI): analysis calculated for
C10H10N3O2 [(M+H)+• ] 204.08. Found 204.08.
Table 3 In vitro cytotoxic activity (IC50) of compounds 2e, 4d, 4e,
6a, 6b and 6c and doxorubicin against a human liver carcinoma cell
line (HEPG2), a human breast carcinoma cell line (MCF7) and a
human cervix carcinoma cell line (HELA).
Entry
Compound
HEPG2
(µg.ml-1)
MCF7
(µg.ml-1)
HeLa
(µg.ml-1)
1
2
3
4
5
6
7
2e
4d
4e
6a
6b
6c
0.48
2.92
3.62
1.58
1.20
1.66
0.60
0.63
–
–
1.05
1.43
2.80
0.70
0.59
–
–
1.92
1.62
2.27
0.85
5-Amino-3-(2-methoxyphenyl)-1H-pyrazole (3f) White solid
(eluent: AcOEt-EtOH 97/3); yield 88%; mp 94–96°C; 1H NMR
(300 MHz, DMSO-d6): δH 3.85 (s, 3H), 5.89 (s, 1H), 6.95 (t, 1H,
J=7.5 Hz), 7.07 (d, 1H, J=8.4 Hz), 7.26 (t, 1H, J=7.2 Hz), 7.62 (m,
1H); 13C NMR (75 MHz, DMSO-d6): δC 55.3, 91.5, 111.7, 114.1,
120.4, 120.4, 127.0, 128.5, 138.7, 155.5. HRMS (ESI): analysis cal-
culated for C10H12N3O [(M+H)+• ] 190.10. Found 190.10.
doxorubicin
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144 F. Lassagne et al.
3-Amino-5-(4-tert-butylphenyl)-4-(ethylsulfinyl)-1-methyl-1H-
pyrazole (4c) The compound was obtained after crystallization from
AcOEt-EtOH as a pale yellow solid; yield 90%; mp 186°C; 1H NMR
(300 MHz, DMSO-d6): δH 1.07 (t, 3H, J=7.5 Hz), 1.32 (s, 9H), 2.98–
3.17 (m, 2H), 3.51 (s, 3H), 5.09 (br s, 2H), 7.32 (d, 2H, J=8.7 Hz), 7.52
(d, 2H, J=8.7 Hz); 13C NMR (75 MHz, CDCl3): δC 7.9, 30.9, 34.4, 36.3,
45.5, 102.0, 124.7, 125.4, 129.4, 142.8, 151.8, 153.4. HRMS (ESI):
analysis calculated for C16H24N3OS [(M+H)+• ] 306.16. Found 306.16.
mixture was heated under reflux for 3 h. The solvent was removed
and the crude material was purified by crystallization.
2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidine
(6a) The compound was obtained after crystallization from AcOEt-
EtOH as yellow crystals; yield 75%; mp 132–134°C; 1H NMR
(300 MHz, CDCl3): δH 7.34 (s, 1H), 7.43 (s, 1H), 7.45–7.55 (m, 3H),
8.06 (m, 2H). 13C NMR (75 MHz, CDCl3) δC (ppm): 96.8, 101.8 (m),
119.0 (q, J=275 Hz), 120.2 (q, J=275 Hz), 127.0, 129.0, 130.1, 131.2,
136.2 (q, J=39 Hz), 145.5 (q, J=38 Hz), 159.2. Analysis calculated
for C14H7F6N3: C, 50.77; H, 2.13; N, 12.69%. Found C, 50.33; H,
2.04; N, 12.60%.
3-Amino-4-(ethylsulfinyl)-5-(4-methoxyphenyl)-1-methyl-1H-
pyrazole (4d) The compound was obtained after crystallization
from AcOEt-EtOH as a yellow solid; yield 86%; mp.174–176°C;
1H NMR (300 MHz, DMSO-d6): δH 1.05 (t, 3H, J=7.5 Hz), 2.94–
3.13 (m, 2H), 3.49 (s, 3H), 3.81 (s, 3H), 5.07 (s, 1H), 7.06 (d, 2H,
J=8.7 Hz), 7.34 (d, 2H, J=8.7 Hz); 13C NMR (75 MHz, DMSO-d6):
δC 7.8, 36.1, 45.6, 55.2, 101.9, 114.1, 119.7, 131.1, 142.8, 153.4,
159.9. HRMS (ESI): analysis calculated for C13H18N3O2S [(M+H)+• ]
279.10. Found 279.10.
2-(4-Chlorophenyl)-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]
pyrimidine (6b) The compound was obtained after crystalliza-
1
tion from EtOH as yellow crystals; yield 70%; mp 164–166°C; H
NMR (300 MHz, CDCl3): δH 3.31 (s, 1H), 7.43 (s, 1H), 7.46 (d, 2H,
J=8.7 Hz), 7.99 (d, 2H, J=8.7 Hz); 13C NMR (75 MHz, CDCl3): δC
96.8, 102.1 (m), 118.9 (q, J=275 Hz), 120.1 (q, J=275 Hz), 128.2,
129.2, 129.7, 135.2 (q, J=38 Hz), 145.8 (q, J=38 Hz), 136.2, 149.4,
158.1. Analysis calculated for C14H7ClF6N3: C, 45.99; H, 1.65; N,
11.49%. Found C, 45.70; H, 1.75; N, 11.23%.
3-Amino-5-(1,3-benzodioxol-5-yl)-4-(ethylsulfinyl)-1-methyl-
1H-pyrazole (4e) The compound was obtained after crystallization
from AcOEt-EtOH as a white solid; yield 95%; mp 170°C; 1H NMR
(300 MHz, DMSO-d6): δH 1.12 (t, 3H, J=6.0 Hz), 3.01–3.19 (m,
2H), 5.15 (br s, 2H), 6.17 (s, 2H), 6.93 (dd, 1H, J=9.0 and 3.0 Hz),
7.08–7.12 (m, 2H); 13C NMR (75 MHz, DMSO-d6): δC 7.9, 36.3,
45.6, 101.6, 102.1, 108.5, 109.9, 121.1, 124.1, 142.6, 147.4, 148.2,
153.5. HRMS (ESI): analysis calculated for C13H16N3O3S [(M+H)+• ]
294.09. Found 294.09.
2-(4-tert-Butylphenyl)-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]
pyrimidine (6c) The compound was purified by crystallization
from EtOH as yellow crystals, yield 86%, mp 116–118°C. 1H NMR
(300 MHz, CDCl3) δH (ppm): 7.32 (s, 1H), 7.41 (s, 1H), 7.54 (d, 2H,
J=8.7 Hz), 8.00 (d, 2H, J=8.7 Hz); 13C NMR (75 MHz, CDCl3): δC
31.4, 35.0, 96.8, 101.8 (m), 118.9 (q, J=275 Hz), 120.1 (q, J=275 Hz),
126.1, 127.0, 128.6, 135.3 (q, J=38 Hz), 145.6 (q, J=38 Hz), 149.6,
153.7, 159.6. Analysis calculated for C18H15F6N3: C, 55.82; H, 3.90;
N, 10.85%. Found C, 5.72; H, 3.67; N, 10.60%.
3-Amino-5-(4-tert-butylphenyl)-1-methyl-1H-pyrazole
(5c) White solid (eluent: AcOEt); yield 90%; mp 140°C; 1H NMR
(300 MHz, CDCl3): δH 1.35 (s, 9H), 3.70 (s, 9H), 5.66 (s, 1H), 7.32
(d, 2H, J=8.7 Hz), 7.45 (d, 2H, J=8.7 Hz); 13C NMR (75 MHz,
CDCl3): δC 31.2, 34.6, 36.6, 93.1, 125.5, 127.9, 128.2, 145.0, 151.4,
153.2. HRMS (ESI): analysis calculated for C14H20N3 [(M+H)+• ]
230.166. Found 230.17.
Crystallographic data for compound 4d
Crystals of 4d were obtained from a CH2Cl2 solution by slow evapo-
ration of the solvent. The sample was studied with graphite mono-
chromatized MoKα radiation (λ=0.71073 Å). X-ray diffraction data
were collected at T= T=100(2) K using APEXII, Bruker-AXS diffrac-
tometer. The structure was solved by direct methods using the SIR97
program (Altomare et al., 1999) and then refined with full-matrix least-
square methods based on F2 (SHELXL-97) (Sheldrick, 2008) with
the aid of the WINGX program (Farrugia, 1999). All non-hydrogen
atoms were refined with anisotropic atomic displacement parameters.
Nitrogen-linked hydrogen atoms were introduced in the structural
model through Fourier difference map analysis. Molecular diagrams
were generated by ORTEP-3, version 1.08 (Farrugia, 1997).
3-Amino-5-(4-methoxyphenyl)-1-methyl-1H-pyrazole
(5d) Pale yellow solid (eluent: AcOEt-EtOH 99/1); yield 75%; mp
1
130°C; H NMR (500 MHz, CDCl3): δH 3.68 (s, 3H), 3.86 (s, 3H),
5.64 (s, 1H), 6.98 (d, 2H, J=6.7 Hz), 7.33 (d, 2H, J=6.7 Hz); 13C
NMR (75 MHz, CDCl3): δC 36.6, 55.5, 93.0, 114.0, 114.2, 123.3,
129.9, 131.0, 144.9, 153.3, 159.7. HRMS (ESI): analysis calculated
for C11H14N3O [(M+H)+• ] 204.11. Found 204.11.
3-Amino-5-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazole
(5e) The compound was obtained after crystallization from
AcOEt as a pale yellow solid; yield 70%; mp 142–144°C; 1H NMR
(300 MHz, DMSO-d6): δH 3.55 (s, 3H), 5.49 (s, 2H), 6.06 (s, 2H),
6.89 (dd, 1H, J=9.0 and 1.8 Hz), 6.96–7.00 (m, 2H);13C NMR (75
MHz, DMSO-d6): δC 36.3, 92.2, 101.2, 108.4, 108.5, 121.9, 124.5,
143.0, 147.0, 147.4, 154.0. HRMS (ESI): analysis calculated for
C11H12N3O2 [(M+H)+• ] 218.09. Found 218.09.
Crystal data for 4d C 13H17N3O2S, M=279.36 g.mol-1, monoclinic,
P21/c, a=8.4546(9), b=18.0721(17), c=9.1047(9) Å, β=95.676(5)°,
V=1384.3(2) Å3, Z=4, d=1.34 g.cm-3, µ=0.236 mm-1. A final refine-
ment on F2 with 3088 unique intensities and 181 parameters con-
verged at ωR(F2)=0.11 (R(F)=0.05) for 2143 observed reflections
with I >2σ(I). Crystallographic data were deposited in CSD under
CCDC registration number 809709.
4.4. General procedure for the preparation of
the 2-aryl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]
pyrimidines 6 according to the procedure described in
Rama et al. (2006)
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Received May 16, 2011; accepted July 22, 2011
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