Regioselective multicomponent synthesis of fully substituted pyrazoles and bispyrazoles catalyzed by zinc triflate

Article abstract of DOI:10.1055/s-0030-1261202

A variety of fully substituted pyrazoles were easily prepared through a three-component condensation of aldehydes, arylhydrazines, and ethyl acetoacetate in the presence of catalytic amounts of zinc triflate [Zn(OTf) under solvent-free conditions. Selecti

Full text of DOI:10.1055/s-0030-1261202

2214
LETTER
Regioselective Multicomponent Synthesis of Fully Substituted Pyrazoles and
Bispyrazoles Catalyzed by Zinc Triflate
Synthesis of
F
h
ully Substitu
i
ted Pyr
r
azoles
a
i
n
yrazoles Safaei, Iraj Mohammadpoor-Baltork,* Ahmad Reza Khosropour,* Majid Moghadam, Shahram
Tangestaninejad, Valiollah Mirkhani
Catalysis Division, Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran
Fax +98(311)6689732; E-mail: imbaltork@sci.ui.ac.ir; E-mail: arkhosropour@sci.ui.ac.ir
Received 20 April 2011
ed pyrazoles.20 Consequently, it is still critically needed to
Abstract: A variety of fully substituted pyrazoles were easily pre-
pared through a three-component condensation of aldehydes, aryl-
hydrazines, and ethyl acetoacetate in the presence of catalytic
amounts of zinc triflate [Zn(OTf)2] under solvent-free conditions.
develop convenient and efficient methods for the synthe-
sis of fully substituted pyrazoles. Recently, the synthesis
of fully substituted pyrazoles has been reported via three-
Selective synthesis of symmetrical and unsymmetrical bispyrazoles component reactions catalyzed by Yb(PFO)3.21
from dialdehydes in high yields can be considered as a notable ad-
During the recent years, multicomponent reactions
vantage of this method.
(MCR) have received considerable attention because of
Key words: pyrazoles, aldehydes, arylhydrazines, zinc triflate, sol-
vent-free
Table 1 Optimization of the Reaction Conditions for Synthesis of
Pyrazole 4aa
O
Pyrazoles and their derivatives have received special at-
O
H
EtO
NHNH2
+
tention due to the wide range of useful biological activi-
ties and pharmacological properties, including antitumor,1
anti-inflammatory,2 antibacterial,3 and hypolipidemic
properties.4 N-Arylpyrazoles have also emerged as estro-
O
O
catalyst
OEt
N
N
+
gen receptor5 and HIV protease inhibitors.6 Known substi- Entry
Catalyst (mol%)
Ce(OTf)3 (2)
Cu(OTf)2 (2)
Bi(OTf)3 (2)
Bi(TFA)3 (2)
InCl3·4H2O (2)
ZrOCl2·8H2O (2)
ZnCl2 (2)
Time (min)
Yield (%)b
tuted pyrazole drugs are rimonabant (I) as an antiobesity
1
15
15
15
15
15
15
15
15
15
10 h
15
15
20
15
15
10
85
83
70
25
27
30
15
20
92
0
drug7 and lonazolac (II) as an anti-inflammatory drug8
(Figure 1). These heterocycles are also employed as
ligands for the transition-metal ions in coordination chem-
istry.9 Due to the importance of pyrazole derivatives, sev-
eral methods have been reported for the preparation of
these heterocycles. In the most common synthetic meth-
ods, pyrazoles are constructed by cyclization of 1,3- dike-
tones with hydrazines.10 However with unsymmetrical
1,3-dicarbonyl compounds, the formation of two regioiso-
meric pyrazoles with poor selectivity and also difficulty in
separation of these regioisomers are limitations of these
methods.11 Other methods have been employed including
reaction of hydrazines with a,b-unsaturated carbonyl
compounds12 or b-keto nitriles,13 reaction of hydrazones
with activated alkenes14 or alkynes,15 reaction of arylhy-
drazines with 3-butynol,16 coupling–cyclocondensation
sequence of acid chlorides, terminal alynes and hydra-
zines,17 palladium-catalyzed four-component coupling of
terminal alkynes, hydrazines, aryl halides, and carbon
monoxide or molybdenum hexacarbonyl,18 and 1,3-dipo-
lar cycloaddition of diazoalkanes with olefins or
alkynes.19
2
3
4
5
6
7
8
Zn(OAc)2 (2)
Zn(OTf)2 (2)
no catalyst
9
10
11c
12
13
14d
15
16
Zn(OTf)2 (2)
Zn(OTf)2 (3)
Zn(OTf)2 (2)
Zn(OTf)2 (2)
Zn(OTf)2 (1)
Zn(OTf)2 (2)
92
92
92
80
68
70
Although a wide range of procedures have been devised
for the synthesis of pyrazole derivatives, there are only a
few reports dealing with the preparation of fully substitut-
a Reaction conditions: aldehyde (1 mmol), phenylhydrazine (1 mmol),
ethyl acetoacetate (1.5 mmol), under solvent-free conditions at
120 °C.
b Isolated yield.
SYNLETT 2011, No. 15, pp 2214–2222
x
x
.x
x
.2
0
1
1
c Reaction was performed at 130 °C.
d Reaction was performed at 110 °C.
Advanced online publication: 30.08.2011
DOI: 10.1055/s-0030-1261202; Art ID: D12311ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Fully Substituted Pyrazoles and Bispyrazoles
2215
O
NHNH2
EtO
O
O
O
Zn(OTf)2 (2 mol%)
N
+
+
solvent-free, 120 °C
R
OEt
R
H
N
X
X
1
2
3
4
X
O
N
N
O
G
H
OEt
NHNH2
NHNH2
O
O
Zn(OTf)2 (4 mol%)
solvent-free, 120 °C
+
+
+
OEt
N
N
O
X
Y
Y
2
6
5
3
OEt
R = aryl, heteroaryl, alkyl
X = H, Cl, Me
G = 3-CHO, 4-CHO
Y = H, Me
Scheme 1 Synthesis of fully substituted pyrazoles and bispyrazoles catalyzed by Zn(OTf)2
It is noteworthy that in the absence of catalyst, the reac-
tion failed to give the desired product, even after long re-
action time (10 h, Table 1, entry 10). Then, the effect of
temperature, the amount of catalyst, and the reaction time
on the yield of the product were examined. Increasing ei-
ther the temperature or the amount of catalyst and/or pro-
longing the reaction time did not improve the yield
(Table 1, entries 11–13), while reducing these factors led
to a reduction in product yield (Table 1, entries 14–16).
Therefore, 1:1:1.5:0.02 molar ratios of benzaldehyde,
phenylhydrazine, ethyl acetoacetate, and Zn(OTf)2 at
120 °C under solvent-free conditions were found to be the
optimal conditions.
Cl
Cl
O
N
N
HN
O
OH
N
N
N
Cl
Cl
I
II
Figure 1 Structure of rimonabant (I) and lonazolac (II) – two pyra-
zole-based drugs
Under the optimized conditions, the aldehydes containing
electron-withdrawing and electron-donating groups in the
aromatic ring were reacted smoothly with arylhydrazines
and ethyl acetoacetate in the presence of 2 mol%
Zn(OTf)2 to afford the corresponding fully substituted
pyrazoles in high yields (Table 2, entries 1–8). The acid-
sensitive aldehyde such as thiophene-2-carbaldehyde
(Table 2, entry 9) and the aliphatic aldehyde such as hep-
tanal (Table 2, entry 10) were also reacted efficiently to
give the desired products in high yields. The reactions
were generally clean and no side products such as pyrazo-
lines were produced; in all cases, fully substituted pyra-
zoles were obtained as the sole products.24 Comparison of
the results obtained by this catalytic system with those re-
ported using Yb(PFO)3 catalyst21a show that in the pres-
ence Zn(OTf)2 the yields of the products are higher and
the reaction times are shorter. Also, only 2 mol%
Zn(OTf)2 is enough for successful reaction, whereas, re-
action in the presence of Yb(PFO)3 requires larger amount
(10 mol%) of the catalyst. Therefore, this catalytic system
can be used for novel and efficient three-component syn-
thesis of fully substituted pyrazoles.
their wide range of applications in synthetic chemistry for
the production of a broad spectrum of organic molecules.
These reactions offer significant advantages over conven-
tional bimolecular reactions, allowing the formation of
several bonds and the construction of complex molecules
from simple precursors in a single step without the need
for isolation of intermediates. The use of MCR under sol-
vent-free conditions provides even more benign process-
es.22
In continuation of our interest in the development of new
and efficient protocols for the preparation of heterocyclic
compounds,23 here, we would like to report a facile one-
pot synthesis of fully substituted pyrazoles and bispyra-
zoles from aldehydes, arylhydrazines, and ethyl acetoace-
tate catalyzed by Zn(OTf)2 under solvent-free conditions
at 120 °C (Scheme 1).
Initially, the reaction of benzaldehyde (1 mmol), phenyl-
hydrazine (1 mmol), and ethyl acetoacetate (1.5 mmol)
was carried out in the presence of different Lewis acids (2
mol%) at 120 °C under solvent-free conditions (Table 1,
entries 1–9). The results showed that Zn(OTf)2 was the
most effective catalyst in this reaction (Table 1, entry 9).
Synlett 2011, No. 15, 2214–2222 © Thieme Stuttgart · New York

2216
S. Safaei et al.
LETTER
a
Table 2 Synthesis of Fully Substituted Pyrazoles Catalyzed by Zn(OTf)2
Entry
1
Aldehyde 1
Arylhydrazine 2
Pyrazole 4
Time (min) Yield (%)b
N
O
N
NHNH2
15
15
15
92
93
90
H
O
EtO
4a
Cl
N
O
NHNH2
N
2
3
H
O
Cl
EtO
4b
4c
4d
Br
N
O
N
N
N
NHNH2
NHNH2
NHNH2
H
O
Br
EtO
N
OMe
O
4
5
6
10
75
75
90
84
88
H
O
MeO
EtO
N
CN
O
H
O
NC
EtO
N
4e
Me
CN
N
O
NHNH2
H
O
Me
NC
Cl
EtO
4f
Cl
O
N
N
NHNH2
7
8
20
15
87
91
H
O
N
EtO
4g
Cl
Me
O
NHNH2
N
Cl
H
Me
O
EtO
4h
Synlett 2011, No. 15, 2214–2222 © Thieme Stuttgart · New York

LETTER
Synthesis of Fully Substituted Pyrazoles and Bispyrazoles
2217
a
Table 2 Synthesis of Fully Substituted Pyrazoles Catalyzed by Zn(OTf)2 (continued)
Entry
9
Aldehyde 1
Arylhydrazine 2
Pyrazole 4
Time (min) Yield (%)b
S
N
N
O
NHNH2
S
15
15
84
83
O
H
EtO
4i
4j
N
N
NHNH2
O
10
O
H
EtO
a Reaction conditions: aldehyde 1 (1 mmol), arylhydrazine 2 (1 mmol), ethyl acetoacetate 3 (1.5 mmol), catalyst (2 mol%), under solvent-free
conditions at 120 °C.
b Isolated yield.
In order to further expand the scope of this new MCR and yl acetoacetate and therefore, such a synthesis can be con-
due to the extensive applications of bispyrazoles as sidered as a useful practical achievement in the
ligands in chemistry,25 the synthesis of fully substituted preparation of pyrazole derivatives.
bispyrazoles was also examined. As shown in Table 3, the
The structure of the products was identified by their IR,
reaction of dialdehydes such as terephthaldialdehyde and
MS, 1H NMR, and 13C NMR spectra and by their elemen-
isophthaldialdehyde with arylhydrazines and ethyl ace-
tal analysis. Furthermore, the structure of 7b was con-
toacetate in the presence of catalytic amounts of Zn(OTf)2
firmed by X-ray crystallographic analysis27 (CCDC
proceeded efficiently to furnish the corresponding sym-
817131, Figure 2).
metrical and unsymmetrical fully substituted bispyrazoles
in high yields.26 To the best of our knowledge, there is no
report on the synthesis of fully substituted bispyrazoles
through the MCR of dialdehydes, arylhydrazines, and eth-
Table 3 Synthesis of Fully Substituted Bispyrazoles Catalyzed by Zn(OTf)2
Entry Dialdehyde 5
Arylhydrazine 2
Arylhydrazine 6
Bispyrazole 7
Time Yield
(min) (%)a
EtO
Me
O
O
O
O
N
N
NHNH2
1b
–
25
25
89
90
H
N
N
O
Me
Me
Me
O
O
O
H
OEt
7a
Me
EtO
O
Me
N
NHNH2
NHNH2
N
2c
H
N
N
O
Me
H
OEt
7b
Cl
EtO
O
Me
N
NHNH2
NHNH2
N
3c
25
86
H
N
N
O
Cl
H
OEt
7c
Synlett 2011, No. 15, 2214–2222 © Thieme Stuttgart · New York

2218
S. Safaei et al.
LETTER
Table 3 Synthesis of Fully Substituted Bispyrazoles Catalyzed by Zn(OTf)2 (continued)
Entry Dialdehyde 5
Arylhydrazine 2
Arylhydrazine 6
Bispyrazole 7
Time Yield
(min) (%)a
EtO
Me
N
O
O
NHNH2
O
N
4b
–
25
80
N
H
H
Me
N
OEt
O
7d
Me
EtO
O
O
Me
NHNH2
NHNH2
5c
25
82
O
N
N
H
H
Cl
N
Me
Me
Cl
N
OEt
O
7e
a Isolated yield.
b Reaction conditions: dialdehyde 5 (1 mmol), arylhydrazine 2 (2 mmol), ethyl acetoacetate 3 (4 mmol), catalyst (4 mol%), under solvent-free
conditions at 120 °C.
c Reaction conditions: dialdehyde 5 (1 mmol), arylhydrazine 2 (1 mmol), arylhydrazine 6 (1 mmol), ethyl acetoacetate 3 (4 mmol), catalyst (4
mol%), under solvent-free conditions at 120 °C.
A plausible mechanism for this MCR is illustrated in sponding fully substituted pyrazole 4 as a desired product.
Scheme 2. First, Zn(OTf)2 catalyzes the keto–enol tau- To confirm the suggested mechanism, a radical scavenger
tomerization of ethyl acetoacetate and also activates the such as acrylamide was added to the reaction mixture. Un-
hydrazone to give 8 and 9, respectively. Then, cyclization der these conditions, no change in the yield of the product
of 8 with 9 gives the intermediate (5-hydroxypyrazoli- was observed. This shows that no radical species is
dine) 10, which upon dehydration affords the pyrazoline present in the reaction, which has been reported by Cao et
11. Finally, aromatization of 11 under ambient atmo- al. in the synthesis of fully substituted pyrazoles catalyzed
sphere in the presence of catalyst produces the corre- by Yb(PFO)3.21 Then the model reaction was performed
Figure 2 X-ray crystal structure of 7b
Synlett 2011, No. 15, 2214–2222 © Thieme Stuttgart · New York

LETTER
Synthesis of Fully Substituted Pyrazoles and Bispyrazoles
2219
(100.00) [M]+, 294.90 (83.93), 267.89 (76.03), 230.93 (60.73),
151.79 (87.23), 110.73 (100), 101.79 (82.32), 76.78 (85.93), 56.87
(80.27). Anal. Calcd for C19H17ClN2O2 (340.78): C, 66.96; H, 5.03;
N, 8.22. Found: C, 66.69; H, 5.10; N, 8.15.
under argon atmosphere, and the product yield was re-
duced considerably under these conditions. It is also note-
worthy that bubbling of the O2 gas into the reaction
mixture accelerated the reaction. These results show that
the presence of oxygen is essential and therefore, accord-
ing to the published results,28 the oxygen provided from
air in the presence of Zn(OTf)2 catalyst can act as oxidiz-
ing agent. All these observations showed that the pro-
posed mechanism is reasonable.
Ethyl 3-(4-Bromophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-
carboxylate (4c)21a
Mp 62–64 °C. IR (KBr): 3064, 2979, 1705, 1596, 1500, 1435, 1304,
1
1086, 835, 764 cm–1. H NMR (500 MHz, CDCl3): d = 1.26 (t,
J = 7.2 Hz, 3 H), 2.58 (s, 3 H), 4.27 (q, J = 7.2 Hz, 2 H), 7.46–7.51
(m, 5 H), 7.53 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H). MS:
m/z = 386.31 (100.00) [M + 2]+, 384.31 (100.00) [M]+, 338.83
(100.00), 311.85 (87.06), 230.94 (85.10), 117.82 (100), 76.33
(100), 50.82 (96.47).
(OTf)2
Zn
O
O
H
O
O
OEt
X
OEt
R
Ethyl 3-(4-Methoxyphenyl)-5-methyl-1-phenyl-1H-pyrazole-4-
carboxylate (4d)21a
3
Zn(OTf)2
X
8
..
O
NHNH2
N
Mp 84–85 °C. IR (KBr): 3064, 2967, 1707, 1607, 1504, 1249, 1151,
838, 699 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.26 (t, J = 7.1 Hz,
3 H), 2.57 (s, 3 H), 3.84 (s, 3 H), 4.26 (q, J = 7.1 Hz, 2 H), 6.94 (d,
J = 8.6 Hz, 2 H), 7.44–7.52 (m, 5 H), 7.64 (d, J = 8.6 Hz, 2 H). MS:
m/z = 338.07 (15.64) [M + 2]+, 336.01 (94.02) [M]+, 291.00
(83.27), 264.04 (42.23), 129.88 (47.41), 117.81 (95.62), 76.80
(100.00), 50.82 (83.27).
N
+
R
H
H
Zn(OTf)2
1
2
9
cyclization
X
X
X
Ethyl 3-(4-Cyanophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-
carboxylate (4e)
Mp 111–112 °C. IR (KBr): 3074, 2978, 2223, 1707, 1591, 1498,
1434, 1309, 1154, 1087, 850, 769 cm–1. 1H NMR (500 MHz,
CDCl3): d = 1.25 (t, J = 7.2 Hz, 3 H), 2.60 (s, 3 H), 4.27 (q, J = 7.2
Hz, 2 H), 7.46–7.56 (m, 5 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.83 (d,
J = 8.0 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 12.85, 14.16,
60.28, 110.73, 111.68, 118.98, 125.75, 129.02, 129.38, 130.22,
131.42, 137.87, 138.49, 145.33, 151.66, 163.60. MS: m/z = 333.05
(8.64) [M + 2]+, 331.03 (97.66) [M]+, 286.00 (93.13), 259.06
(53.76), 129.93 (32.24), 117.91 (66.82), 101.88 (28.62), 76.88
(100.00), 50.92 (80.37). Anal. Calcd for C20H17N3O2 (331.34): C,
N
N
N
HN
dehydration
HN
Zn(OTf)2, air
oxidation
N
OH
R
R
R
COOEt
COOEt
COOEt
11
4
10
Scheme 2 A plausible mechanism
In summary, we have demonstrated an efficient and novel 72.49; H, 5.17; N, 12.68. Found: C, 72.57; H, 5.14; N, 12.66.
multicomponent synthesis of fully substituted pyrazoles,
symmetrical and unsymmetrical bispyrazoles under sol-
vent-free conditions using Zn(OTf)2 as catalyst. Short re-
action times, high yields of products, convenient
procedure avoiding toxic organic solvents, and operation-
al simplicity are notable advantages of the present method
which makes it a useful and attractive process for the the
synthesis of pyrazole derivatives.
Ethyl 3-(4-Cyanophenyl)-5-methyl-1-p-tolyl-1H-pyrazole-4-
carboxylate (4f)
Mp 96–98 °C. IR (KBr): 3072, 2981, 2224, 1705, 1608, 1514, 1454,
1306, 1159, 824, 784 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.24
(t, J = 7.1 Hz, 3 H), 2.43 (s, 3 H), 2.56 (s, 3 H), 4.26 (q, J = 7.1 Hz,
2 H), 7.30–7.34 (m, 4 H), 7.67 (d, J = 8.2 Hz, 2 H), 7.82 (d, J = 8.2
Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 12.78, 14.15, 21.20,
60.25, 110.58, 111.76, 119.02, 125.62, 129.94, 130.23, 131.45,
136.07, 137.99, 139.22, 145.33, 151.58, 163.72. MS: m/z = 346.94
(16.91) [M + 2]+, 344.94 (100.00) [M]+, 299.94 (98.68), 272.98
(78.23), 131.94 (75.24), 101.89 (68.02), 90.92 (89.75), 76.92
(51.64), 64.96 (79.51). Anal. Calcd for C21H19N3O2 (345.36): C,
73.03; H, 5.54; N, 12.17. Found: C, 72.92; H, 5.60; N, 12.04.
Ethyl 5-Methyl-1,3-diphenyl-1H-pyrazole-4-carboxylate (4a)21a
Mp 100–102 °C. IR (KBr): 3069, 2983, 1710, 1596, 1501, 1310,
1146, 1089, 773, 700 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.22
(t, J = 7.2 Hz, 3 H), 2.60 (s, 3 H), 4.25 (q, J = 7.2 Hz, 2 H), 7.38–
7.42 (m, 3 H), 7.45–7.54 (m, 5 H), 7.67–7.69 (m, 2 H). MS:
m/z = 308.05 (10.71) [M + 2]+, 306.01 (89.39) [M]+, 260.99
(89.39), 234.01 (69.39), 129.90 (59.18), 117.86 (86.53), 76.81
(100.00), 50.83 (89.39).
Ethyl 3-(3-Chlorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-
carboxylate (4g)
Mp 78–80 °C. IR (KBr): 3067, 2980, 1703, 1595, 1500, 1436, 1310,
1154, 1094, 764, 686 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.25
(t, J = 7.1 Hz, 3 H), 2.56 (s, 3 H), 4.26 (q, J = 7.1 Hz, 2 H), 7.36–
7.31 (m, 2 H), 7.47 (d, J = 7.1 Hz, 1 H), 7.51–7.54 (m, 4 H), 7.57
(d, J = 7.1 Hz, 1 H), 7.70 (s, 1 H). 13C NMR (125 MHz, CDCl3):
d = 12.71, 14.05, 60.14, 110.65, 125.83, 127.74, 128.27, 128.85,
128.89, 129.32, 129.71, 133.49, 134.97, 138.70, 145.16, 152.14,
163.92. MS: m/z = 341.97 (26.99) [M + 2]+, 339.96 (100.00) [M]+,
294.94 (100.00), 267.98 (74.48), 130.02 (77.78), 118.00 (80.75),
110.93 (51.88), 77.00 (87.03), 51.04 (76.15). Anal. Calcd for
C19H17ClN2O2 (340.78): C, 66.96; H, 5.03; N, 8.22. Found: C,
66.52; H, 5.15; N, 8.08.
Ethyl 1-(4-Chlorophenyl)-5-methyl-3-phenyl-1H-pyrazole-4-
carboxylate (4b)
Mp 68–70 °C. IR (KBr): 3071, 2982, 1697, 1500, 1254, 1178, 1085,
835, 687 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.21 (t, J = 7.1 Hz,
3 H), 2.59 (s, 3 H), 4.24 (q, J = 7.1 Hz, 2 H), 7.38–7.43 (m, 3 H),
7.44 (d, J = 8.7 Hz, 2 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.64–7.67 (m, 2
H). 13C NMR (125 MHz, CDCl3): d = 12.73, 14.07, 60.08, 111.04,
127.01, 127.70, 128.35, 129.43, 129.46, 132.98, 134.57, 137.36,
144.78, 153.89, 164.04. MS: m/z = 341.90 (71.37) [M + 2]+, 339.95
Synlett 2011, No. 15, 2214–2222 © Thieme Stuttgart · New York

2220
S. Safaei et al.
LETTER
Ethyl 3-(3-Chlorophenyl)-5-methyl-1-p-tolyl-1H-pyrazole-4-
carboxylate (4h)
132.01 (16.43), 117.96 (22.02), 90.95 (43.81), 76.95 (53.33). Anal.
Calcd for C33H32N4O4 (548.63): C, 72.24; H, 5.88; N, 10.21. Found:
C, 71.98; H, 5.92; N, 10.09.
Mp 70–72 °C. IR (KBr): 3033, 2928, 1706, 1525, 1439, 1164, 1093,
1014, 834, 784, 710 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.25 (t,
J = 7.1 Hz, 3 H), 2.43 (s, 3 H), 2.57 (s, 3 H), 4.26 (q, J = 7.1 Hz, 2
H), 7.30–7.36 (m, 6 H), 7.57–7.69 (m, 1 H), 7.70 (s, 1 H). 13C NMR
(125 MHz, CDCl3): d = 12.69, 14.08, 21.20, 60.10, 110.42, 125.64,
127.76, 128.72, 128.88, 129.71, 129.87, 133.46, 135.05, 136.20,
138.96, 145.16, 151.97, 163.96. MS: m/z = 356.94 (79.22) [M +
2]+, 354.92 (100.00) [M]+, 309.01 (99.61), 282.90 (83.14), 131.90
(96.08), 110.83 (87.84), 90.88 (99.61), 64.90 (95.29). Anal. Calcd
for C20H19ClN2O2 (354.81): C, 67.70; H, 5.40; N, 7.89. Found: C,
67.41; H, 5.47; N, 7.79.
Ethyl 1-(4-Chlorophenyl)-3-{4-[4-(ethoxycarbonyl)-5-methyl-
1-phenyl-1H-pyrazol-3-yl]phenyl}-5-methyl-1H-pyrazole-4-
carboxylate (7c)
Mp 140 °C. IR (KBr): 3080, 2972, 1594, 1500, 1430, 1297, 1180,
1
1083, 837, 698 cm–1. H NMR (500 MHz, CDCl3): d = 1.21–1.25
(m, 6 H), 2.59 (s, 6 H), 4.23–4.28 (m, 4 H), 7.44–7.52 (m, 9 H), 7.71
(d, J = 8.4 Hz, 2 H), 7.74 (d, J = 8.4 Hz, 2 H). 13C NMR (125 MHz,
CDCl3): d = 12.67, 12.69, 14.17, 14.18, 60.04, 60.12, 110.83,
111.20, 125.87, 127.01, 128.67, 128.72, 128.82, 129.27, 129.47,
132.81, 133.18, 134.55, 137.41, 138.89, 144.91, 153.13, 153.45,
164.16, 164.30. MS: m/z = 570.32 (4.30) [M + 2]+, 568.30 (10.97)
[M]+, 477.18 (2.93), 424.20 (2.80), 191.11 (2.16), 151.98 (11.04),
129.98 (29.60), 117.96 (14.23), 110.94 (18.57), 90.94 (33.23),
76.94 (79.70), 55.01 (100.00). Anal. Calcd for C32H29ClN4O4
(569.09): C, 67.54; H, 5.14; N, 9.85. Found: C, 67.51; H, 5.17; N,
9.80.
Ethyl 5-Methyl-1-phenyl-3-(thiophen-2-yl)-1H-pyrazole-4-car-
boxylate (4i)
Mp 73–74 °C. IR (KBr): 3109, 2978, 1702, 1593, 1499, 1470, 1226,
1
1117, 777, 697 cm–1. H NMR (500 MHz, CDCl3): d = 1.37 (t,
J = 7.1 Hz, 3 H), 2.55 (s, 3 H), 4.35 (q, J = 7.1 Hz, 2 H), 7.09 (dd,
1J = 5.0 Hz, 2J = 3.7 Hz, 1 H), 7.33 (dd, 1J = 5.0 Hz, 2J = 1.0 Hz, 1
H), 7.53–7.46 (m, 5 H), 7.81 (dd, 1J = 3.7 Hz, 2J = 1.0 Hz, 1 H). 13
C
NMR (125 MHz, CDCl3): d = 13.00, 14.32, 60.25, 110.20, 125.96,
126.13, 127.00, 128.55, 128.80, 129.27, 134.47, 138.68, 145.00,
147.27, 163.97. MS: m/z = 315.91 (2.52) [M + 4]+, 313.90 (77.25)
[M + 2]+, 311.94 (100.00) [M]+, 266.92 (100.00), 239.90 (86.27),
148.81 (57.25), 133.82 (93.73), 117.89 (95.29), 76.87 (96.08),
50.92 (83.53). Anal. Calcd for C17H16SN2O2 (312.39): C, 65.36; H,
5.17; N, 8.97; S, 10.26. Found: C, 64.98; H, 5.24; N, 8.86; S, 10.54.
Diethyl 3,3¢-(1,3-Phenylene)-bis(5-methyl-1-phenyl-1H-pyra-
zole-4-carboxylate) (7d)
Oil. IR (neat): 3064, 2924, 1704, 1595, 1500, 1430, 1254, 1088,
1
1017, 766, 696 cm–1. H NMR (500 MHz, CDCl3): d = 1.17 (t,
J = 7.1 Hz, 6 H), 2.59 (s, 6 H), 4.22 (q, J = 7.1 Hz, 4 H), 7.41–7.52
(m, 11 H), 7.69 (d, J = 1.7 Hz, 1 H), 7.70 (d, J = 1.7 Hz, 1 H), 8.00
(s, 1 H). 13C NMR (125 MHz, CDCl3): d = 12.65, 14.00, 60.00,
110.72, 125.80, 126.81, 128.56, 129.16, 129.43, 130.60, 132.74,
138.93, 144.84, 153.33, 164.33. MS: m/z = 536.16 (11.66) [M +
2]+, 534.15 (100.00) [M]+, 442.01 (77.58), 390.05 (92.83), 230.27
(53.81), 117.96 (76.23), 76.95 (89.24). Anal. Calcd for C32H30N4O4
(534.61): C, 71.89; H, 5.66; N, 10.48. Found: C, 71.65; H, 5.60; N,
10.39.
Ethyl 3-Hexyl-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate
(4j)
Oil. IR (neat): 3052, 2928, 1705, 1597, 1547, 1449, 1250, 1099,
764, 695 cm–1. 1H NMR (500 MHz, CDCl3): d = 0.87–0.9 (m, 5 H),
1.26–1.42 (m, 7 H), 1.66–1.72 (m, 2 H), 2.52 (s, 3 H), 2.89 (t,
J = 7.7 Hz, 2 H), 4.33 (q, J = 7.1 Hz, 2 H), 7.39–7.50 (m, 5 H). 13
C
NMR (125 MHz, CDCl3): d = 12.66, 14.09, 14.41, 22.65, 28.49,
29.44, 29.46, 31.72, 59.71, 110.26, 125.74, 128.36, 129.18, 138.97,
144.52, 155.67, 164.54. MS: m/z = 316.09 (3.42) [M + 2]+, 314.08
(72.40) [M]+, 271.04 (60.40), 244.01 (91.60), 171.95 (100.00),
117.86 (83.60), 76.84 (94.00), 50.86 (50.00).
Ethyl 1-(4-Chlorophenyl)-3-{3-[4-(ethoxycarbonyl)-5-methyl-
1-p-tolyl-1H-pyrazol-3-yl]phenyl}-5-methyl-1H-pyrazole-4-
carboxylate (7e)
Mp 66–68 °C. IR (KBr): 3085, 2978, 1702, 1499, 1435, 1253, 1088,
1010, 831, 784, 701 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.15–
1.19 (m, 6 H), 2.42 (s, 3 H), 2.56 (s, 3 H), 2.58 (s, 3 H), 4.20 (q,
J = 7.1 Hz, 4 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.33 (d, J = 8.2 Hz, 2 H),
7.04–7.48 (m, 5 H), 7.66 (d, J = 7.7 Hz, 1 H), 7.70 (d, J = 7.7 Hz, 1
H), 7.97 (s, 1 H). 13C NMR (125 MHz, CDCl3): d = 12.64, 13.98,
14.01, 21.17, 59.96, 60.10, 110.47, 111.08, 125.61, 126.83, 126.93,
129.33, 129.40, 129.58, 129.75, 130.42, 130.52, 130.63, 132.48,
132.87, 134.48, 136.41, 137.39, 138.60, 144.85, 153.10, 153.61,
164.18, 164.34. MS: m/z = 584.16 (25.69) [M + 2]+, 582.13 (63.97)
[M]+, 491.08 (20.24), 438.09 (79.69), 319.99 (3.05), 263.99 (6.74),
244.10 (35.16), 151.98 (22.02), 110.96 (46.88), 91.00 (100.00).
Anal. Calcd for C33H31ClN4O4 (583.08): C, 67.98; H, 5.36; N, 9.61.
Found: C, 67.82; H, 5.30; N, 9.69.
Diethyl 3,3¢-(1,4-Phenylene)-bis(5-methyl-1-phenyl-1H-pyra-
zole-4-carboxylate) (7a)
Mp 160–162 °C. IR (KBr): 3089, 2975, 1702, 1594, 1499, 1441,
1
1153, 1086, 769 cm–1. H NMR (500 MHz, CDCl3): d = 1.23 (t,
J = 7.1 Hz, 6 H), 2.59 (s, 6 H), 4.26 (q, J = 7.1 Hz, 4 H), 7.43–7.52
(m, 10 H), 7.74 (s, 4 H). 13C NMR (125 MHz, CDCl3): d = 12.71,
14.20, 60.05, 110.82, 125.85, 128.67, 128.78, 129.27, 133.04,
138.88, 144.92, 153.17, 164.33. MS: m/z = 533.97 (3.63) [M]+,
388.95 (6.37), 300.65 (18.87), 284.85 (32.08), 230.68 (6.60),
129.24 (29.83), 76.77 (100.00). Anal. Calcd for C32H30N4O4
(534.61): C, 71.89; H, 5.66; N, 10.48. Found: C, 71.65; H, 5.65; N,
10.43.
Acknowledgment
Ethyl 3-{4-[4-(Ethoxycarbonyl)-5-methyl-1-p-tolyl-1H-pyrazol-
3-yl]phenyl}-5-methyl-1-phenyl-1H-pyrazole-4-carboxylate
(7b)
The authors are grateful to the Center of Excellence of Chemistry
and the Research Council of the University of Isfahan for financial
support of this work.
Mp 140–142 °C. IR (KBr): 3081, 2972, 1692, 1517, 1430, 1300,
1180, 1082, 849, 694 cm–1. 1H NMR (500 MHz, CDCl3): d = 1.23
(t, J = 7.0 Hz, 6 H), 2.43 (s, 3 H), 2.56 (s, 3 H), 2.59 (s, 3 H), 4.23–
4.27 (m, 4 H), 7.30 (d, J = 8.2 Hz, 2 H), 7.36 (d, J = 8.2 Hz, 2 H),
7.45–7.53 (m, 5 H), 7.73 (s, 4 H). 13C NMR (125 MHz, CDCl3):
d = 12.64, 12.67, 14.20, 21.18, 59.99, 60.03, 110.61, 110.84,
125.68, 125.86, 128.64, 128.75, 128.78, 129.26, 129.80, 132.98,
133.14, 136.42, 138.72, 138.92, 144.89, 153.00, 153.19, 164.34,
164.37. MS: m/z = 550.28 (10.24) [M + 2]+, 548.22 (100.00) [M]+,
503.20 (6.22), 457.12 (20.00), 404.15 (11.67), 237.10 (10.83),
References and Notes
(1) (a) Taylor, E. C.; Patel, H. H. Tetrahedron 1992, 48, 8089.
(b) Sondhi, S. M.; Singhal, N.; Verma, R. P.; Arora, S. K.;
Dastidar, S. G. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2001, 40, 113. (c) Banday, A. H.; Mir, B. P.;
Lone, I. H.; Suri, K. A.; Kumar, H. M. S. Steroids 2010, 75,
Synlett 2011, No. 15, 2214–2222 © Thieme Stuttgart · New York

LETTER
Synthesis of Fully Substituted Pyrazoles and Bispyrazoles
2221
805. (d) Lv, P. C.; Li, H. Q.; Sun, J.; Zhou, Y.; Zhu, H. L.
Mani, N. S. Org. Lett. 2008, 10, 1307.
Bioorg. Med. Chem. 2010, 18, 4606.
(15) (a) Bardakos, V.; Sucrow, W.; Fehlauer, A. Chem. Ber.
1975, 108, 2161. (b) Baumes, R.; Jacquier, R.; Tarrago, G.
Bull. Soc. Chim. Fr. 1976, 260.
(16) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Org. Lett.
2008, 10, 2377.
(17) Liu, H.-L.; Jiang, H.-F.; Zhang, M.; Yao, W.-J.; Zhu, Q.-H.;
Tang, Z. Tetrahedron Lett. 2008, 49, 3805.
(2) (a) Oezdemir, Z.; Kandilci, H. B.; Guemuesel, B.; Calis, U.;
Bilgin, A. A. Eur. J. Med. Chem. 2007, 373. (b) Nauduri,
D.; Reddy, G. B. Chem. Pharm. Bull. 1998, 46, 1254.
(c) Bekhit, A. A.; Fahmy, H. T. Y.; Rostom, S. A. F.; Bekhit,
A. E. D. A. Eur. J. Med. Chem. 2010, 6027.
(3) (a) Raman, N.; Kulandaisamy, A.; Jeyasubramanian, K.
Synth. React. Inorg. Met. 2002, 32, 1583. (b) Raman, N.;
Kulandaisamy, A.; Jeyasubramanian, K. Synth. React.
Inorg. Met. 2004, 34, 17. (c) Manikannan, R.; Venkatesan,
R.; Muthusubramanian, S.; Yogeeswari, P.; Sriram, D.
Bioorg. Med. Chem. Lett. 2010, 20, 6920.
(4) (a) Idrees, G. A.; Aly, O. M.; El-Din, A. A.; Abuo-Rahma,
G.; Radwan, M. F. Eur. J. Med. Chem. 2009, 3973.
(b) Palaska, E.; Sahin, G.; Kelicen, P.; Durlu, N. T.; Altinok,
G. Farmaco 2002, 57, 101.
(5) (a) Nilsson, S.; Kuiper, G.; Gustafsson, J. A. Trends
Endocrinol. Metab. 1998, 9, 387. (b) Stauffer, S. R.;
Katzenellenbogen, J. A. J. Comb. Chem. 2000, 2, 318.
(6) (a) Palazzino, G.; Cecchi, L.; Melani, F.; Colotta, V.;
Filacchioni, G.; Martini, C.; Lucacchini, A. J. Med. Chem.
1987, 30, 1737. (b) Thapa, D.; Lee, J. S.; Heo, S. W.; Lee, Y.
R.; Kang, K. W.; Kwak, M. K.; Choi, H. G.; Kim, J. A.;
Thapa, D. Eur. J. Pharmacology 2011, 650, 64.
(18) (a) Ahmed, M. S. M.; Kobayashi, K.; Mori, A. Org. Lett.
2005, 7, 4489. (b) Stonehouse, J. P.; Chekmarev, D. S.;
Ivanova, N. V.; Lang, S.; Pairaudeau, G.; Smith, N.; Stocks,
M. J.; Sviridov, S. I.; Utkina, L. M. Synlett 2008, 100.
(19) (a) Aggarwal, K. V.; Vicente, D. J.; Bonnert, V. R. J. Org.
Chem. 2003, 68, 5381. (b) Huisgen, R. Angew. Chem., Int.
Ed. Engl. 1963, 2, 565. (c) Cheung, K. M. J.; Reynisson, J.;
Donald, E. M. Tetrahedron Lett. 2010, 51, 5915.
(20) (a) Suen, Y. F.; Hope, H.; Nantz, M. H.; Haddadin, M. J.;
Kurth, M. J. J. Org. Chem. 2005, 70, 8468. (b) Neumann, J.
J.; Suri, M.; Glorius, F. Angew. Chem. Int. Ed. 2010, 49, 1.
(c) Gosselin, F.; O’Shea, P. D.; Webster, R. A.; Reamer, R.
A.; Tillyer, R. D.; Grabowski, E. J. J. Synlett 2006, 3267.
(21) (a) Shen, L.; Cao, S.; Liu, N.; Wu, J.; Zhu, L.; Qian, X.
Synlett 2008, 1341. (b) Shen, L.; Zhang, J.; Cao, S.; Yu, J.;
Liu, N.; Wu, J.; Qian, X. Synlett 2008, 3058.
(22) (a) Multicomponent Reactions; Zhu, J.; Bienayme, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Orru, R. V. A.; de Greef,
M. Synthesis 2003, 1471. (c) Dömling, A. Chem. Rev. 2006,
106, 17. (d) Weber, L.; Illgen, K.; Almstetter, M. Synlett
1999, 366. (e) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P.
G. Angew. Chem. Int. Ed. 2006, 45, 7134.
(23) (a) Mohammadpoor-Baltork, I.; Tangestaninejad, S.;
Moghadam, M.; Mirkhani, V.; Anvar, S.; Mirjafari, A.
Synlett 2010, 3104. (b) Mohammadpoor-Baltork, I.;
Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.;
Eskandari, Z. Ultrason. Sonochem. 2010, 17, 857.
(c) Mohammadpoor-Baltork, I.; Khosropour, A. R.; Hojati,
S. F. Catal. Commun. 2007, 8, 200. (d) Mohammadpoor-
Baltork, I.; Khosropour, A. R.; Hojati, S. F. Synlett 2005,
2747. (e) Mohammadpoor-Baltork, I.; Khosropour, A. R.;
Hojati, S. F. Catal. Commun. 2007, 8, 1865.
(7) Donohue, S. R.; Halldin, C.; Pike, V. W. Tetrahedron Lett.
2008, 49, 2789.
(8) Ismail, M. A. H.; Lehmann, J.; Abou El Ella, D. A.; Albohy,
A.; Abouzid, K. A. M. Med. Chem. Res. 2009, 18, 725.
(9) (a) Chen, C.; Jordan, R. F. J. Organomet. Chem. 2010, 695,
2543. (b) Mukherjee, A.; Sarkar, A. Tetrahedron Lett. 2005,
46, 15.
(10) (a) Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M. V.
J. Org. Chem. 2001, 66, 6787. (b) Wang, Z.; Qin, H. Green
Chem. 2004, 6, 90. (c) Polshettiwar, V.; Varma, R. S.
Tetrahedron Lett. 2008, 49, 397. (d) Xiong, W.; Chen, J. X.;
Liu, M. C.; Ding, J. C.; Wu, H. Y.; Su, W. K. J. Braz. Chem.
Soc. 2009, 20, 367. (e) Mikhaylichenko, S. N.; Patel, S. M.;
Dalili, S.; Chesnyuk, A. A.; Zaplishny, V. N. Tetrahedron
Lett. 2009, 50, 2505. (f) Polshettiwar, V.; Varma, R. S.
Tetrahedron 2010, 66, 1091.
(11) (a) Elguero, J. In Comprehensive Heterocyclic Chemistry II,
Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon Press: Oxford, 1996, 1. (b) Willy, B.; Müller, T.
J. J. Eur. J. Org. Chem. 2008, 4157. (c) Grotjahn, D. B.;
Van, S..; Combs, D.; Lev, D. A.; Schneider, C.; Rideout, M.;
Meyer, C.; Hernandez, G.; Mejorado, L. J. Org. Chem. 2002,
67, 9200. (d) Song, L.-P.; Zhu, S.-Z. J. Fluorine Chem.
2001, 111, 201. (e) Gosselin, F.; Oshea, P. D.; Webster, R.
A.; Reamer, R. A. Synlett 2006, 3267.
(12) (a) Safaei-Ghomi, J.; Bamoniri, A. H.; Soltanian-Telkabadi,
M. Chem. Heterocycl. Compd. 2006, 42, 892. (b)Katritzky,
A. R.; Wang, M.; Zhang, S.; Voronkov, M. V. J. Org. Chem.
2001, 66, 6787. (c) Huang, Y. R.; Katzenellenbogen, J. A.
Org. Lett. 2000, 2, 2833. (d) Landge, M. S.; Schmidt, A.;
Outerbridge, V.; Torok, B. Synlett 2007, 1600. (e) Pinto, D.
C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Elguero, J. Eur.
J. Org. Chem. 2003, 747.
(13) (a) Suryakiran, N.; Srikanth, R. T.; Asha, L. K.; Prabhakar,
P.; Venkateswarla, Y. J. Mol. Catal. A: Chem. 2006, 258,
371. (b) Dorsch, J. B.; Mcelvain, S. M. J. Am. Chem. Soc.
1932, 54, 2960. (c) Wang, G.; Liu, X.; Zhao, G.
(f) Khosropour, A. R.; Mohammadpoor-Baltork, I.;
Ghorbankhani, H. Catal. Commun. 2006, 7, 713.
(g) Khosropour, A. R.; Mohammadpoor-Baltork, I.;
Ghorbankhani, H. Tetrahedron Lett. 2006, 47, 3561.
(24) General Procedure for the Synthesis of Fully Substituted
Pyrazoles
A mixture of aldehyde 1 (1 mmol) and arylhydrazine 2 (1
mmol) was stirred for 20 min, then ethyl acetoacetate 3 (1.5
mmol) and Zn(OTf)2 (0.02 mmol) were added, and the
mixture was stirred at 120 °C for the appropriate time
according to Table 2. The progress of the reaction was
monitored by TLC (eluent: n-hexane–EtOAc, 10:1). After
completion of the reaction, the mixture was cooled to r.t.,
and the crude product was purified by chromatography on
silica gel (eluent: n-hexane–EtOAc, 10:1) or by
recrystallization from EtOH to afford the pure product.
(25) (a) Li, K.; Mohlala, M. S.; Segapelo, T. V.; Shumbula, P. M.;
Guzei, I. A.; Darkwa, J. Polyhedron 2008, 27, 1017.
(b) Boixassa, A.; Pons, J.; Ros, J.; Mathieu, R.; Lugan, N.
J. Organomet. Chem. 2003, 682, 233. (c) de León, A.; Pons,
J.; García-Antón, J.; Ros, J. Polyhedron 2010, 29, 2318.
(26) General Procedure for the Synthesis of Fully Substituted
Bispyrazoles
Tetrahedron: Asymmetry 2005, 16, 1873.
(14) (a) Le Fevre, G.; Hamelin, J. Tetrahedron 1980, 36, 887.
(b) Kobayashi, S.; Hirabayashi, R.; Shimizu, H.; Ishitani, H.;
Yamashita, Y. Tetrahedron Lett. 2003, 44, 3351. (c) Deng,
X.; Mani, N. S. Org. Lett. 2006, 8, 3505. (d) Deng, X.;
A mixture of dialdehyde 5 (1 mmol) and arylhydrazine 2 (2
mmol) was stirred for 20 min (for unsymmetrical
bispyrazoles, a mixture of dialdehyde 5 (1 mmol) and
arylhydrazine 2 (1 mmol) was stirred for 20 min, then
Synlett 2011, No. 15, 2214–2222 © Thieme Stuttgart · New York

2222
S. Safaei et al.
LETTER
arylhydrazine 6 (1 mmol) was added and stirred for further
20 min). Ethyl acetoacetate 3 (4 mmol) and Zn(OTf)2 (0.04
mmol) were added, and the mixture was heated at 120 °C for
the appropriate time (Table 3). The progress of the reaction
was monitored by TLC (eluent: n-hexane–EtOAc, 10:1).
After completion of the reaction, the mixture was cooled to
r.t., and the crude product was purified by chromatography
on silica gel (eluent: n-hexane–EtOAc, 10:1) or by
(27) CCDC 817131 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44 (1223)336033;
e-mail: deposit@ccdc.cam.ac.uk].
(28) Shah, J. N.; Shah, K. C. J. Org. Chem. 1978, 43, 1266.
recrystallization from EtOH to give the pure product.
Synlett 2011, No. 15, 2214–2222 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.