Rapid cesium fluoride-catalyzed Knoevenagel condensation for the synthesis of highly functionalized 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives

Article abstract of DOI:10.1007/s00706-015-1424-9

Abstract A rapid, convenient, and environmentally friendly protocol was developed for the synthesis of functionalized 4,4′-(arylmethylene)bis(1H-pyrazol-5-ols) via a tandem Knoevenagel-Michael reaction by condensing pyrazolone with readily available diffe

Full text of DOI:10.1007/s00706-015-1424-9

Monatsh Chem
DOI 10.1007/s00706-015-1424-9
ORIGINAL PAPER
Rapid cesium fluoride-catalyzed Knoevenagel condensation
for the synthesis of highly functionalized 4,40-
(arylmethylene)bis(1H-pyrazol-5-ol) derivatives
•
Khalid Mohammed Khan Munira Taj Muhammad
•
•
Imran Khan Shahnaz Perveen Wolfgang Voelter
•
Received: 26 December 2014 / Accepted: 12 January 2015
Ó Springer-Verlag Wien 2015
Abstract A rapid, convenient, and environmentally
friendly protocol was developed for the synthesis of
functionalized 4,40-(arylmethylene)bis(1H-pyrazol-5-ols)
via a tandem Knoevenagel–Michael reaction by condens-
ing pyrazolone with readily available differently
substituted aldehydes and catalyzed by cesium fluoride at
room temperature.
Introduction
In synthetic organic chemistry carbon–carbon bond for-
mations provide a base for building molecular skeletons
[1]. Due to its fundamental importance in organic chem-
istry laboratories throughout the world are trying to
develop new methodologies for carbon–carbon bond for-
mation which are environmentally friendly, rapid, easy to
workup, and afford excellent yields [2]. The Knoevenagel
condensation is one of the most frequently used organic
reactions for carbon–carbon bond formations [3] and,
therefore, plays an important role in the synthesis of bio-
logically active compounds [4]. Pyrazolones and their
derivatives belong to an important biologically active class
of nitrogen-containing heterocycles [5]. 4,40-(Phenylmeth-
ylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) (1, Fig. 1)
is applied due to its anti-inflammatory, antipyretic, anti-
bacterial, and anti-depressant activities [6]. A literature
survey reveals that a different set of synthetic approaches
was used for pyrazolone syntheses using a variety of
reaction conditions [7]. Synthesis of pyrazolones was car-
ried out by utilizing the cerium ammonium nitrate as
catalyst in the presence of water [8] as well as the use of
ionic salts as a catalyst in organic synthesis is attracting
great attention to synthetic chemists. Wang et al. [9] pub-
lished a synthesis of pyrazoles in water in the presence of
catalytic amounts of sodium dodecyl sulfate requiring a
reaction time of 1 hour and high temperature. However,
most of the methods suffer from harsh reaction conditions,
moderate yields, long reaction times, and tedious workup
procedures.
Graphical abstract
Keywords Tandem Knoevenagel–Michael reaction ꢀ
Pyrazalones ꢀ Cesium fluoride
K. M. Khan (&) ꢀ M. T. Muhammad ꢀ I. Khan
H. E. J. Research Institute of Chemistry, International Centre for
Chemical and Biological Sciences, University of Karachi,
Karachi 75270, Pakistan
e-mail: khalid.khan@iccs.edu; hassaan2@super.net.pk
S. Perveen
PCSIR Laboratories Complex, Shahrah-e-Dr. Salimuzzaman
Siddiqui, Karachi 75280, Pakistan
Previously reported reactions with fluoride and halide
ions are documented like polymers of increased molecular
mass formed by nucleophilic substitution [10], and elimi-
nation reactions [11]. Fluoride ions increase the
W. Voelter
¨
Interfakultares Institut fur Biochemie, Universitat Tubingen,
Hoppe-Seyler-Str. 4, Tu
¨
¨
¨
¨bingen 72076, Germany
123

K. M. Khan et al.
nucleophilicity of certain compounds which contain acidic
protons [12], promote aromatic polysulfide synthesis from
their respective aromatic thiols [13], provide an alternative
route for the synthesis of esters from organic acids [14], or
catalyze chemo- and regioselective SN2 type ring opening
of epoxides with thiols [15]. In view of our previous reports
on CsF as a solid base [16–22] and its strong affinity for
active hydrogens prompted us to explore its utility to
promote tandem Knoevenagel–Michael reactions of pyr-
azolone with different aldehydes and we present here an
expeditious, practical, and high yielding method for the
synthesis of functionalized 4,40-(arylmethylene)bis(1H-
pyrazol-5-ol).
We subjected benzaldehydes with electron-donating and
withdrawing groups for this method and found that the latter
benzaldehydes furnished excellent yields (Table 1) provid-
ing an easy access and excellent yields to functionalized 4,40-
(arylmethylene)bis(1H-pyrazol-5-ols) in short reaction time,
under mild reaction conditions, and simple workup. All
synthesized compounds were characterized by 1H, 13C NMR,
and FAB-MS. All the compounds gave satisfactory CHN
analysis and the experimental percentage of carbon and
hydrogen atoms was found in good agreement with the cal-
culated values. The 1H NMR spectra were run in deuterated
dimethyl sulfoxide at 300 MHz which gave a broadband for
OH present in enol form of pyrazolone. A characteristic
proton signal for the bispyrazolones is a singlet around 2 ppm
for 6 protons of 2 methyls of pyrazolone. A sharp singlet for a
single proton around 5 ppm is characteristic for the benzylic
proton. As these compounds are not stable enough EI mass
spectrometry, FAB was applied giving the desired [M-1]?
peak. The broadband decoupled 13C NMR spectrum of the
bispyrazole of 2-ethoxybenzaldehyde showed twenty-nine
carbons, while the DEPT spectrum identified fifteen methine,
one methylene, and three methyls along with ten quaternary
carbons.
Results and discussion
In a CsF-catalyzed tandem Knoevenagel–Michael reaction,
CsF probably plays two important roles, first it increases
the electrophilicity of the carbonyl carbon of the aldehyde,
and secondly the fluoride counter ion works as a base
generating the enolate of pyrazolone. Consequently, for-
mation of a carbon–carbon double bond by condensation
with the aldehydes forms an intermediate 1,4-Michael type
substrate serving for a 1,4-attack by the second fluoride-
generated enolate of the pyrazolone resulting in the for-
mation of the target bispyrazoles. Scheme 1 shows the
general chemical reaction and Fig. 2 the proposed
mechanism.
Conclusions
In conclusion, we have successfully developed a new, fast,
and eco-benign method for the synthesis of highly func-
tionalized 4,40-(arylmethylene)bis(1H-pyrazol-5-ols) 1–15
which broadens the scope of the Knoevenagel–Michael
reaction. Cesium fluoride is proved to be an excellent base
for promoting the reaction to the targeted products.
Experimental
All aldehydes and other starting materials were used as
received from the supplier. Nuclear magnetic resonance
spectra were recorded on Bruker 300 MHz and 500 MHz
Fig. 1 4,40-(Phenylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-
ol) (1)
Scheme 1
123

Rapid cesium fluoride-catalyzed Knoevenagel condensation
Fig. 2 A plausible mechanism for the synthesis of functionalized 4,40-(arylmethylene)bis(1H-pyrazol-5-ols)
Table 1 Functionalized 4,40-(arylmethylene)bis(1H-pyrazol-5-ols) 1-15 (Scheme 1)
Comp.
R
Yield/%
M.p./°C
Lit. m.p./°C
1
C6H5-
94
91
93
90
95
93
97
94
91
88
86
95
90
90
95
170–173
235–238
224–227
275–278
236–238
203–205
205–210
212–214
229–231
150–152
175–178
252–256
202–205
220–225
181–185
170–172 [23]
–
2
2-EtO-C6H4-
2-NO2-C6H4-
2,3,4-(MeO)3-C6H2-
2-Cl-C6H4-
3
221–223 [24]
–
4
5
235–237 [23]
202–204 [23]
201–203 [23]
215–217 [23]
225–227 [23]
151–153 [23]
227–229 [25]
185–188 [25]
195–197 [23]
–
6
4-Me-C6H4-
4-MeS-C6H4-
4-Cl-C6H4-
7
8
9
4-NO2-C6H4-
3-NO2-C6H4-
2,4-Cl2-C6H3-
4-EtO-C6H4-
3,4-(MeO)2-C6H3-
4-Pyridinyl
10
11
12
13
14
15
4-MeO-C6H4-
173–175 [24]
General procedure for the synthesis of functionalized
4,40-(arylmethylene)bis(1H-pyrazol-5-ols) 1–15
spectrometers and mass spectra were recorded at JEOL JMS-
HX110 mass spectrometer using FABMS-H. Elemental
analyses (C, H, N) were obtained on a Carlo Erba Stru-
mentazione-Mod-1106 and found to agree favorably with the
calculatedvalues. Thin layerchromatography was carried out
on aluminum plates pre-coated with silica gel (Kieselgel 60,
E. Merck, Darmstadt, Germany). UV light at 254 and 365 nm
was used for chromatograms visualization.
In a typical reaction, a catalytic amount of CsF (5 mol%)
was added to the solution of an aromatic aldehyde (1.0
equiv) in 10 cm3 de-ionized water at room temperature
slowly and gradually 0.49 g pyarazolone (2.0 equiv) was
added and the reaction mixture was swirled for 5–10 min.
123

K. M. Khan et al.
122.8 (C-4), 120.3 (C-70, C-110, C-700, C-1100), 102.9 (C-2),
The product formation was monitored by TLC analysis and
resulting precipitates were washed with distilled water to
give the pure products in excellent yields.
32.9 (C-7), 11.7 (2 Me) ppm; FAB-MS: m/z = 436.
Acknowledgments The authors are grateful to the Organization for
Prohibition of Chemical Weapons (OPCW), The Netherlands (Project
No. L/ICA/ICB/173681/12) for financial support and DAAD (Deut-
scher Akademischer Austauschdienst), Bonn, Germany, for granting a
fellowship to Prof. Dr. Khalid Mohammed Khan.
4,40-[(2-Ethoxyphenyl)methylene]bis(3-methyl-1-phenyl-
1H-pyrazol-5-ol) (2, C29H28N4O3)
Yield: 91 %; m.p.: 235–238 °C; 1H NMR (DMSO-d6):
d = 14.63 (broad OH, 1H), 7.71 (d, 4H, J = 7.8 Hz, H-20,
H-60, H-200, H-600), 7.43 (t, 4H, J = 7.5 Hz, H-30, H-50,
H-300, H-500), 7.22 (m, 3H), 6.91 (d, 1H, J = 8.1 Hz), 6.85
(t, 1H, J = 7.2 Hz), 5.20 (s, 1H), 4.09 (q, 2H, J = 6.9 Hz),
2.25 (s, 6H), 1.38 (t, 3H, J = 6.9 Hz) ppm; 13C NMR
(DMSO-d6): d = 154.8 (C-3, C-30), 146.0 (C-40, C-400),
137.8 (C-50, C-500), 131.5 (C-60, C-600), 128.8 (C-90, C-900),
128.7 (C-70, C-110, C-700, C-1100), 127.0 (C-6), 125.0 (C-5),
120.3 (C-80, C-100, C-800, C-1000), 119.8 (C-4), 111.4 (C-3),
104 (C-2), 63.2 (OCH2), 27.14 (C-7), 14.8 (Me), 11.9 (Me)
ppm; FAB-MS: m/z = 479.
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phenyl-1H-pyrazol-5-ol) (4, C30H30N4O5)
Yield: 90 %; m.p.: 275–278 °C; 1H NMR (DMSO-d6):
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