Zn(Proline)2-catalyzed Knoevenagel condensation under solventfree/aqueous conditions and biological evaluation of products

Article abstract of DOI:10.1007/s00044-010-9376-4

A novel approach was adopted for the synthesis of series of Knoevenagel condensation products from 5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde with different cyclic active methylene compounds, using water soluble and recyclable Zn(Proline)₂ as a Lewis acid catalyst both under solvent-free condition and using water as a reaction medium in good yields. In each conversion, the catalyst was successfully recovered and recycled without significant loss in yield and selectivity. The compounds were screened for their antimicrobial activity. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9376-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:1438–1444
DOI 10.1007/s00044-010-9376-4
ORIGINAL RESEARCH
Zn(Proline)2-catalyzed Knoevenagel condensation under solvent-
free/aqueous conditions and biological evaluation of products
•
Zeba N. Siddiqui T. N. Mohammed Musthafa
•
•
Shagufta Praveen Farheen Farooq
Received: 22 February 2010 / Accepted: 26 May 2010 / Published online: 17 June 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A novel approach was adopted for the synthe-
sis of series of Knoevenagel condensation products from
5-chloro-3-methyl-1-phenylpyrazole-4-carboxaldehyde with
different cyclic active methylene compounds, using water
soluble and recyclable Zn(Proline)2 as a Lewis acid catalyst
both under solvent-free condition and using water as a reac-
tion medium in good yields. In each conversion, the catalyst
was successfully recovered and recycled without significant
loss in yield and selectivity. The compounds were screened
for their antimicrobial activity.
organic reactions are nowadays a well-established green
protocol for the synthesis of various heterocycles. The
shorter reaction time, experimental simplicity, selectivity,
and easy reaction work up have given clear indication on
the potentialities of this technique over conventional
heating (Kappe and Dallinger, 2009; Caddick, 1995; Var-
ma, 1999; Galema, 1997). Nowadays, water has emerged
as an ecofriendly solvent for the reaction medium because
of its easy availability, noninflammablity, nontoxicity, and
negligible cost (Li, 2005).
Knoevenagel condensation is one of the most well-
known reaction for the C–C bond formation in organic
synthesis (Tietze and Beifuss, 1991). This reaction has
been widely used for the synthesis of several intermediates
which are useful in perfumes, cosmetics, and bioactive
compounds (Meuly and Othmer, 1979; Xing and Zhu,
2004). The Knoevenagel condensation products also have
widespread applications including inhibition of antipho-
sphorylation of EGF-receptor and antiproliferative activity
(Vijender et al., 2008). Because of the importance from
pharmacological, industrial, and synthetic point of view,
several methods have been reported for this reaction, which
includes homogeneous condition catalyzed by base such as
a piperidine, ethylenediamine, or corresponding ammo-
nium salts like DMAP, organocatalysts such as glycine,
L-proline, and alanine (Wada and Suzuki, 2003, Zhang
et al., 2009), natural and synthetic phosphates (Sebti et al.,
2002), resins (Simpson et al., 1999), montmorillonite KSF
(Bigi et al., 1999), molecular iodine, ionic liquid (Ren and
Cai, 2007; Tahmassebi et al., 2009), Lewis acid (Lu et al.,
2004; Peng and Song, 2003), etc. Unfortunately, many of
these methods have some drawbacks such as use of
expensive, stoichiometric amount of reactants, low yields,
extended time, tedious procedure, etc. Thus, the need for
the development of an alternative route to construct
Keywords 5-Chloro-3-methyl-1-phenylpyrazole-
4-carboxaldehyde Á Zn(Proline)2 Á Knoevenagel
condensation Á Microwave irradiation Á Antibacterial
activity Á Antifungal activity
Introduction
Developing a simple, ecofriendly reaction protocol for the
synthesis of compound libraries of medicinal scaffolds is
an attractive area of research in both academic and phar-
maceutical R&D (Kanizsai et al., 2007). Hence, the chal-
lenge for sustainable environment calls for the use of clean
procedures, which can avoid the use of harmful solvents.
The chemists are, therefore, more interested in seeking new
processes involving solvent-free reactions which are
devoid of pollution with low cost and simplicity in pro-
cessing (Tanaka and Toda, 2000). Microwave-assisted
Z. N. Siddiqui (&) Á T. N. M. Musthafa Á S. Praveen Á
F. Farooq
Department of Chemistry, Aligarh Muslim University,
Aligarh 202002, India
e-mail: siddiqui_zeba@yahoo.co.in
123

Med Chem Res (2011) 20:1438–1444
1439
substituted electrophilic alkenes by reducing time from
hours to minutes at ambient temperature is in demand. As a
part of our ongoing research program aimed at developing
new catalysts and subsequent application for various
organic transformations, we report herein the recently
explored Zn(proline)2 complex as an efficient catalyst in
Knoevenagel condensation reaction. Ever since the explo-
ration of water soluble Zn(proline)2 complex by Darbre’s
group (Darbre and Machuqueiro, 2003), only few reports
have so far appeared employing Zn(proline)2 as a Lewis
acid catalyst for different organic reactions (Kofoed et al.,
2004; Sivamurugan et al., 2006; Kofoed et al., 2005;
Ruben et al., 2005; Kofoed et al., 2006). Thus, there is a lot
of scope to further explore the catalyst for its application in
forming various heterocyclic rings. To the best of our
knowledge, Zn(proline)2 has not been used as a catalyst for
Knoevenagel condensation reaction. This prompted us to
test the catalytic activity of the viable catalyst for this
reaction employing heteroaldehyde with various cyclic
active methylene compounds both under solvent-free
Scheme 1 Synthesis of
products 3a–i
H
O
Z
H3C
O
O
Zn(Proline)2
O
HO
2h-i
H3C
N
Cl
N
Z
1
Ph
N
O
N
Ph
O
Zn(Proline)2
2a-g
H
3h-i
H3C
Het
h; Z=
i; Z=
CH=C-CH3
N
Cl
N
Ph
3a-g
CH3
O
O
O
O
O
O
N
N
NH
NH
NH
O
O
S
Het=
NH
CH3
2d
2c
2b
O
2a
O
OH
O
O
S
Ph
N
N
O
CH3
CH3
N
H
O
O
O
CH3
O
O
2g
2e
H3C
2f
2h
OH
O
O
2i
123

1440
Med Chem Res (2011) 20:1438–1444
condition using microwave irradiation and using water as
an ecofriendly reaction medium.
Table 2 Recycling data of Zn(proline)2 complex for the Knoevena-
gel condensation of 5-chloro-3-methyl-1-phenyl-4-carboxaldehyde
with 1,3-indanedione
Catalyst recycle Conventional method
(aqueous medium)
Microwave irradiation
Results and discussion
Time (h) Yield (%) Time (min) Yield (%)
Chemistry
I
1
1
1
1
85
85
85
82
7
7
7
7
90
90
90
87
II
The Zn(proline)2 catalyst is easily preparable, stable,
inexpensive, and recyclable. The soluble nature of the cat-
alyst facilitates the separation of products from the catalyst.
The used catalyst can be recycled and used for the next
reaction without any further purification. We carried out
first the reaction of 5-chloro-3-methyl-1-phenylpyrazole-4-
carboxaldehyde 1 with various cyclic active methylene
compounds 2a–i in conventional method using ethanol as a
solvent in acidic/basic medium (Scheme 1). The reactions
took longer period of time for completion (3–12 h) with
lower yields. Then, we studied the efficacy of the Zn(pro-
line)2 complex by carrying reactions in green solvent,
water. The reactions were completed within 1–2 h, and the
products obtained were in good yield (81–89%). Further,
the catalytic activity of the complex was tested under sol-
vent-free condition employing microwave irradiation. To
our pleasant surprise, the reactions were completed in much
shorter period of time (5–9 min) in excellent yields (90–
95%) (Table 1).
III
IV
catalyst was recovered by separation of aqueous and
organic phases. The catalyst present in the aqueous med-
ium was used for the subsequent cycle. The same proce-
dure was applied for all recycling studies. The results
(Table 2) revealed that catalyst exhibited good catalytic
activity up to three cycles. The scope of the reaction was
further investigated with different cyclic-active methylene
compounds with viable catalyst, and the results obtained
were satisfactory. The reaction of heteroaldehyde with
triacetic acid lactone 2h and 4-hydroxycoumarin 2i did not
give the expected Knoevenagel condensation products;
instead, it afforded pyrazolo pyrones 3h and 3i as reported
earlier (Siddiqui and Asad, 2009) in a very short period of
time (Table 1).
All the products obtained were recrystallized from suit-
able solvents, and characterized by spectroscopic data. The
IR spectrum of 3a showed sharp and strong absorption band
at 1689 cm-1 for carbonyl group. The proton nuclear mag-
netic resonance spectroscopy (1H NMR) exhibited a sharp
singlet at d 2.40 for methyl group of pyrazole moiety. Nine
aromatic protons appeared as multiplet in the aromatic region
The reaction of 5-chloro-3-methyl-1-phenylpyrazole-4-
carboxaldehyde 1 with indane-1,3-dione 2a in the presence
of Zn(proline)2 in water as well as in microwave irradiation
was taken as model reaction for recycling studies. After
completion of reaction in specified time, the crude product
obtained was extracted by dichloromethane, and the
Table 1 Zn(proline)2 complex-catalyzed Knoevenagel condensation
Entry
Producta
Thermal heating in aqueous medium
Microwave irradiationc
Time
Time
Yield (%)
Yield (%)d
a
b
c
d
e
f
3ab
3b
3c
1 h
85
87
89
87
84
81
86
84
83
7 min
5 min
6 min
6 min
9 min
9 min
5 min
6 min
6 min
90
93
95
94
91
91
94
92
92
45 min
45 min
1 h
3d
3eb
3fb
3g
3h
3i
1.5 h
2 h
g
h
i
45 min
1 h
1 h
a
The products were confirmed by elemental analysis, spectral data and compared with reported literature (Fang et al., 2005; Latif et al., 1995)
b
c
d
New compounds
Microwave equipment multimode with full power was used
All yields refer to isolated products
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Med Chem Res (2011) 20:1438–1444
1441
Scheme 2 Proposed
mechanism for the Zn(proline)2
complex catalyzed Knoevenagel
condensation
NH
O
NH
O
O
Zn2+
Zn2+
O
O
O
NH
C6H5
N
N
C6H5
Cl
H3C
N
N
1
H
Cl
O
NH
O
H3C
Zn2+
H
C
N
O
Zn2+
O
O
C6H5
O
C6H5
N
N
N
N
Cl
H3C
O
Cl
H H
C
N
H3C
OH
Zn2+
H
C
O
N
O
HO
Zn2+
O
O
HO
O
-H2O
-
Zn(L-Pro)2
O
2a-g
H3C
O
N
N
C6H5
O
3a-g
Cl
d 7.45–8.04. The olefinic proton was discernible as a singlet
at d 7.80. Further confirmation of the structure was provided
by mass spectrometry which showed M? at m/z 349.
The proposed mechanism for the Zn(proline)2-catalyzed
synthesis of Knoevenagel products can be visualized as
given in Scheme 2.
Escherichia coli K12 and Salmonella typhimurium MTCC
98, also in vitro for antifungal activity against three fungal
strains Candida albicans IOA-109, Aspergillus niger (lab-
oratory isolate), and Aspergillus fumigatus (laboratory
isolate). The results are summarized in Table 3. The com-
pounds 3b, 3c, 3d, and 3f exhibited good activity against
Gram-positive bacteria Staphylococcus aureus, Bacillus
subtilis, and Gram-negative Salmonella typhimurium. The
other compounds were moderately active against both
Gram-positive and Gram-negative bacteria. Antifungal
screening showed that the compounds had moderate-to-
good activity against Candida albicans, while having lesser
activity against Aspergillus niger and Aspergillus fumigatus.
Biology
All the synthesized compounds were screened in vitro for
antibacterial activity against an assortment of two Gram-
positive bacteria, Staphylococcus aureus SA 22 and Bacillus
subtilis MTCC 121, and two Gram-negative bacteria,
123

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Med Chem Res (2011) 20:1438–1444
Table 3 In vitro antibacterial and antifungal activity of compounds 3a–g
Compounds
Diameter of inhibition zone in mm at 100 lg/ml
Gram-positive
Gram-negative
Fungal species
S. aureus
B. subtilis
E. coli
S. typhimurium
C. albicans
A. niger
A. fumigatus
3a
12
17
20
12
14
19
–
8
17
15
15
15
8
15
12
14
17
–
12
–
8
10
–
3b
19
16
8
–
3c
11
16
15
14
–
8
11
–
3d
–
3e
–
–
–
3f
15
12
24
–
–
–
–
–
3g
8
12
20
–
10
–
11
–
Chloram-phenicol
Nystatin
DMSO
26
–
25
–
–
20
–
18
–
18
–
–
–
–
–
– No activity detected
Conclusion
microwave irradiation were carried out in an unmodified
domestic microwave oven (National, Model NN-S557WF,
1.3 KW, 2450 MHz).
In brief, we developed an efficient procedure for the
synthesis of substituted alkenes through Knoevenagel
condensation from various cyclic-active methylene com-
pounds and heteroaromatic aldehyde using stable, inex-
pensive, easily preparable, and recyclable Zn(proline)2
complex in green solvent ‘‘water’’ and under solvent-free
condition. The present protocol is devoid of pollution and
involves mild reaction condition, and simple operational
and experimental procedure. The antibacterial and anti-
fungal screenings of the compounds reveal that some
substituted alkenes were strongly active against tested
organisms.
Thermal heating in aqueous medium
A mixture of 5-chloro-3-methyl-1-phenylpyrazole-4-car-
boxaldehyde 1 (1.00 mmol), active methylene compounds
2a–i (1.00 mmol), and Zn(proline)2 (0.30 mmol) was dis-
solved in minimum volume of methanol, and water (7 ml)
was added. The reaction mixture was then refluxed in a
heating mantle for specified time (Table 1) and cooled to
room temperature. The crude product was extracted with
dichloromethane, dried over anhydrous Na2SO4, and con-
centrated to furnish crude product, which was then
recrystallized from ethanol–chloroform mixture (6:4). The
catalyst was recovered by simple separation of aqueous and
organic phases. The catalyst present in the aqueous layer
was used for the subsequent cycle.
Experimental
Melting points were taken in Riechert Thermover instru-
ment and are uncorrected. The IR spectra were recorded on
1
Perkin Elmer spectrometer in KBr. H-NMR spectra on a
Microwave irradiation
Bruker DRX-300 and Bruker Avance 400 Spectrometer
using tetra methyl silane (TMS) as an internal standard.
Mass spectra were obtained on a Jeol-SX-120 (FAB) and
Micromass Quattro II (ESI). The microanalytical data were
collected on Elementar vario EL III elemental analyzer.
The Zn(proline)2 catalyst (Sivamurugan et al., 2004) and
the compound 1 (Pawar and Patil, 1994) were synthesized
as per reported procedures. Other chemicals were of
commercial grade and used without further purification.
The purity of all compounds was checked by TLC on glass
plates coated with silica gel (E-Merck G254). The plates
were run in chloroform–methanol (3:1) mixture and were
visualized by iodine vapors. All the experiments under
A mixture of 5-chloro-3-methyl-1-phenypyrazole-4-car-
boxaldehyde 1 (1.00 mmol) and active methylene com-
pounds 2a–i (1.00 mmol) was mixed with Zn(proline)2
(0.30 mmol) and grounded well using a mortar and pestle.
The mixture was then taken in an open Pyrex beaker and
subjected to microwave irradiation (multimode, full power).
The progress of reaction was monitored by TLC and, on
completion, the reaction mixture was slurred in water,
extracted with dichloromethane, dried over anhydrous
Na2SO4, and concentrated. The crude product as obtained
was recrystallized from ethanol–chloroform mixture (6:4).
The catalyst was recovered by simple separation of aqueous
123

Med Chem Res (2011) 20:1438–1444
1443
5-(5-Chloro-3-methyl-1-phenylpyrazol-4-yl)methylene-2,
2-dimethyl-1,3-dioxane-4,6-dione (3f)
and organic phases. The catalyst present in the aqueous
layer was used for the subsequent cycle.
m.p: 240–242°C. %CHN found. (Calcd) for C17H15N2
O4Cl: C, 58.94 (58.90); H, 4.35 (4.32); N, 8.03 (8.07). IR
(KBr, cm-1): 1725 (C=O). 1H NMR (CDCl3, 300 MHz): d
1.59 (s, 6H, 2 CH3), 2.52 (s, 3H, CH3), 7.00–7.73 (m, 6H,
Ar–H ? CH=C). FAB-MS: (%) m/z 347 (M?, 90).
2-(5-Chloro-3-methyl-1-phenylpyrazol-4-yl)methylene-1,
3-indanedione (3a)
m.p: 199–202°C. %CHN found. (Calcd) for C20H13
N2O2Cl: C, 68.96 (68.89); H, 3.77 (3.72); N, 8.08 (8.03).
IR (KBr, cm-1): 1689 (C=O). 1H NMR (CDCl3,
400 MHz): d 2.40 (s, 3H, CH3), 7.45–8.04 (m, 9H, Ar–H),
7.80 (s, 1H, –CH=C). FAB-MS: (%) m/z 349 (M?, 100).
4-(5-Chloro-3-methyl-1-phenylpyrazol-4-yl)methylene-3-
methyl-1-phenylpyrazol-5-one (3h)
m.p: 186–188°C. %CHN found. (Calcd) for C21H17N4OCl:
C, 66.92 (66.96); H, 4.49 (4.51); N, 14.83 (14.86). IR (KBr,
5-(5-Chloro-3-methyl-1-phenylpyrazol-4-yl)methylene-
2,4,6-pyrimidinetrione (3b)
cm-1): 1730 (C=O). H NMR (CDCl3, 400 MHz): d 2.41
(s, 6H, 2CH3), 4.93 (s, 1H, –CH=C), 7.23–7.76 (m, 10H,
1
m.p:[300°C. %CHN found. (Calcd) for C15H11N4O3Cl: C,
54.56 (54.49); H, 3.36 (3.32); N, 16.87 (16.94). IR (KBr,
cm-1): 1679 (C=O), 3195 (NH). 1H NMR (DMSO-d6,
300 MHz): d 2.29 (s, 3H, CH3), 7.31–7.82 (m, 5H, Ar–H),
8.12 (s, 1H, –CH=C), 11.05 (s, 1H, NH), 11.36 (s, 1H,
NH). ESI-MS: m/z 330.20 (M?).
Ar–H). FAB-MS: (%) m/z 376 (M?, 100).
Biological activity
Antibacterial studies
All the synthesized compounds were dissolved to prepare a
stock solution of 1 mg/ml using DMSO. The antibacterial
activity of test compounds and standard chloramphenicol
was done by filter paper disk method (Bauer et al., 1966).
Media with DMSO was set up as control. All cultures were
routinely maintained on NA (nutrient agar) and incubated
at 37°C for overnight. The culture was centrifuged at
1000 rpm, and pellets were resuspended and diluted in
sterile NSS to obtain viable count 105 cfu/ml. Approxi-
mately, 0.1 ml of diluted bacterial culture suspension was
spread with the help of spreader on NA plates uniformly.
Sterile 8-mm disks (Hi-media Pvt Ltd) were impregnated
with the test compounds. Antibiotic disk, chloramphenicol
(30 lg/disc Hi-Media), was used as control. The disk was
placed on to the plate. Each plate had one control disk
impregnated with the solvent. The plates were then incu-
bated for 24 h at 37°C, and the resulting zones of inhibition
(in mm) were measured.
5-(5-Chloro-3-methyl-1-phenylpyrazol-4-yl)methylene-1,
3-dimethyl-2,4,6-pyrimidinetrione (3c)
m.p: 208–210°C. %CHN found. (Calcd) for C17H15N4O3
Cl: C, 56.99 (56.93); H, 4.16 (4.18); N, 15.56 (15.61). IR
(KBr, cm-1): 1664 (C=O). 1H NMR (CDCl3, 400 MHz): d
2.43 (s, 3H, CH3), 3.42 (s, 3H, N–CH3), 3.45 (s, 3H, N–
CH3), 7.32–7.84 (m, 5H, Ar–H), 8.48 (s, 1H, –CH=C).
FAB- MS: (%) m/z 358 (M?, 90).
5-(5-Chloro-3-methyl-1-phenylpyrazol-4-yl)methylene-2-
mercapto-4,6-pyrimidinedione (3d)
m.p: [300°C. %CHN found. (Calcd) for C15H11N4O2SCl:
C, 51.99 (51.97); H, 3.13 (3.17); N, 16.07 (16.15). IR (KBr,
1
cm-1): 1007 (C=S), 1674 (C=O), 3124 (NH). H NMR
(DMSO-d6, 300 MHz): d 2.32 (s, 3H, CH3), 7.34–7.84 (m,
5H, Ar–H), 8.22 (s, 1H, –CH=C), 11.12 (s, 1H, NH), 11.43
(s, 1H, NH). ESI-MS: m/z 346.15(M?).
Antifungal studies
The synthesized compounds were dissolved in DMSO.
Media with DMSO was set up as control. All cultures were
routinely maintained on SDA and incubated at 28°C. Spore
formation of filamentous fungi was prepared from 7-day-
old culture in sterile normal solution (8% NaCl) and
approximately diluted to obtain 105 cfu/ml. The inoculum
of non-sporing fungi, Candida albicans were performed by
growing the culture in SD broth at 37°C for overnight. The
culture was centrifuged at 1000 rpm, and pellets were
resuspended and diluted in sterile NSS to obtain viable
2-(5-Chloro-3-methyl-1-phenylpyrazol-4-yl)methylene-1,
4-benzothiazine-3-one (3e)
m.p: 114–116°C (dec). %CHN found. (Calcd) for
C19H14N3OSCl: C, 62.08 (62.06); H, 3.83 (3.80); N, 11.39
(11.42). IR (KBr, cm-1): 1653 (C=O), 3185 (NH). 1H NMR
(CDCl3, 400 MHz): d 2.33 (s, 3H, CH3) 7.12–8.02 (m, 10H,
Ar–H ? CH=C), 9.61 (br s, 1H, NH). FAB-MS: (%) m/z 368
(M?, 70).
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Med Chem Res (2011) 20:1438–1444
count 105 cfu/ml. Approximately, 0.1 ml of diluted fungal
culture suspension was spread with the help of spreader on
SDA plates uniformly. Sterile 8-mm disks (Hi-media Pvt
Ltd) were impregnated with the test compounds. Antibiotic
disk, nystatin (30 lg/disk Hi-Media) was used as control.
The disk was placed on to the plate. Each plate had one
control disk impregnated with the solvent. The plates were
incubated at 28°C for filamentous fungi for 72 h or more,
while for Candida albicans, plates were incubated at 37°C
18–48 h. Antifungal activity was determined by measuring
the diameters of the inhibition zone.
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Acknowledgments Financial assistance in the form of major
research project [F.No. 37-15/2009 (SR)] from UGC, New Delhi, is
gratefully acknowledged. The authors would also like to thank SAIF,
CDRI, Lucknow, and SAIF, Panjab University, Chandigarh for
spectral data, and Dr. Iqbal Ahmad, Department of agricultural
microbiology, Aligarh Muslim University, Aligarh for biological
screening.
Sebti S, Smahi A, Solhy A (2002) Natural phosphate doped with
potassium fluoride and modified with sodium nitrate: efficient
catalyst for the Knoevenagel condensation. Tetrahedron Lett 43:
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