Ca(II)-catalyzed, one-pot four component synthesis of functionally embellished benzylpyrazolyl coumarins in water

Article abstract of DOI:10.1016/j.tetlet.2015.06.049

A facile one-pot, four-component synthesis of biologically important benzylpyrazolyl coumarins in water has been demonstrated using environmentally benign Ca(II) as the catalyst. Participation of aliphatic aldehydes has been described for the first time. Short reaction times, high yields and chromatography free isolation of the products, usage of eco-friendly catalyst and solvent are the key features of this method.

Full text of DOI:10.1016/j.tetlet.2015.06.049

Accepted Manuscript
Ca(II)-catalyzed, one-pot four component synthesis of functionally embellished
benzylpyrazolyl coumarins in water
Srinivasarao Yaragorla, Abhishek Pareek, Ravikrishna Dada
PII:
S0040-4039(15)01055-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.049
TETL 46441
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 June 2015
15 June 2015
17 June 2015
Please cite this article as: Yaragorla, S., Pareek, A., Dada, R., Ca(II)-catalyzed, one-pot four component synthesis
of functionally embellished benzylpyrazolyl coumarins in water, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.06.049
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Graphical Abstract
Ca(II)-catalysed one-pot, four component synthesis of
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functionally embellished benzylpyrazolyl coumarins in water
Srinivasarao Yaragorla,* Abhishek Pareek and Ravikrishna Dada

1
Tetrahedron Letters
journal hom epage: www.elsevier.com
Ca(II)-catalyzed, one-pot four component synthesis of functionally embellished
benzylpyrazolyl coumarins in water
Srinivasarao Yaragorla,∗ Abhishek Pareek and Ravikrishna Dada
aDepartment of Chemistry, Central University of Rajasthan, Bandarsindri, NH-8, Ajmer-distt., Rajasthan, 305817, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile one-pot, four-component synthesis of biologically important benzylpyrazolyl coumarins
in water has been demonstrated using environmentally benign Ca(II) as the catalyst.
Participation of aliphatic aldehydes has been described for the first time. Short reaction times,
high yields and chromatography free isolation of the products, usage of eco-friendly catalyst and
solvent are the key features of this method.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Benzylpyrazolylcoumarins
Ca(II) catalysis
Multicomponent reactions
Green synthesis
Heterocyclic compounds
One-pot reaction
In the last two decades, enormous thrust and exploration
towards the green chemistry practices has been taking place.
Chemists, being more sensible to the society and human
wellbeing, come up with various environmentally benign organic
transformations, with minimization of chemical waste, atom
economy, energy savings, easy work ups, alternative catalysts
and procedures, chromatography free isolation of the products.1-3.
Multicomponent reactions are one of the major contributions to
the green chemistry, in which several cascade one-pot
transformations takes place in the same pot to yield the final
product without isolating any intermediate.4 Use of universal
solvent (water) as an alternative to many of the organic solvents
is a very good practice,5 due to water being environmentally
benign natural product, high abundance, being economical, high
polarity and reactivity through hydrogen bonding interactions.
3-substituted coumarins, especially benzylcoumarins belongs
to a broad class of biologically active heterocyclic compounds.
They were also found in many of the natural products. For
example as showed in the figure 1, warfarin, phenprocumene and
coumatetralyl showed antibacterial, anti-HIV, antiviral,
anticoagulant activities.6 Similarly, pyrazolones are another
important heterocyclic compounds (Figure 1, first row) with a
broad spectrum of biological activities. To list a few phenazone,
propphenazone and ampyrone (Figure 1, second row) are well
known antipyretic and antianalgesic drugs. Pyrazolones are
generally known for anti-fungal, antimycobacterial, antibacterial,
anti-inflammatory, antitumor, antidepressant and anti-tuberculat
activities.7
In view of their biological activities and structural features, a
new hybrid molecule (benzylpyrazolylcoumarins) has been
designed by combining 3-benzylcoumarins and pyrazolones for
the improved activity.8-10 Till date there are only three reports
available on the synthesis of these benzylpyrazolylcoumarins.8-10
The first report describes the usage of glacial acetic acid in water
under reflux conditions,8 second one is ZrO2 nanoparticles
catalyzed synthesis9 and the last one is ZnO nanoparticles as the
catalyst.10 Owing to the wide natural abundance, stability,
inexpensive and non-toxic natures alkaline earth metal catalysts
(especially calcium salts bearing a hard conjugate base such as
triflate ion) have been demonstrated as an alternative to transition
———
∗ Corresponding author. Tel.: +91-463-238535; fax: +91-463-238722; e-mail: Srinivasarao@curaj.ac.in

2
Tetrahedron
metal and lanthanide based catalysts.11 In continuation our
conjugate manner. But when the Ca2+ is present in the reaction, it
chelates with the carbonyl oxygen and enhance the
electrophilicity of carbonyl carbon and thus facilitates the
Michael addition by 4-hydroxycoumarin (5E) to form the final
product 5. Alternatively, this reaction may also proceed via path-
B, where 4-hydroxycoumarin and benzaldehyde can react to give
a Knoevenagel adduct 5C. In the next step pyrazolone 5A and
Knoevenagel adduct 5C will undergo Ca-catalyzed Michael
addition (as depicted in 5E) to form the final product 5. However
during this procedure 5C may also react with 4-hydroxycoumarin
(1,4-addition) to yield biscoumarin methane (6)
interest in exploring the environmentally benign Ca(II) as the
green catalyst for the synthesis of several biologically important
heterocyclic compounds,12 here in we report a facile one-pot
multicomponent reaction for the synthesis of various
benzylpyrazolyl coumarins in water.
Table 1. Optimization of reaction conditions for the cascade
Knoevenagel condensation and Michael addition for the
synthesis of benzylpyrazolyl coumarins.12
We commenced our synthesis with the stoichiometric amounts
of all four reactants (4-hydroxycoumarin, ethylacetoacetate,
phenylhydrazine and benzaldehyde) in presence of 5 mol%
Ca(OTf)2 in water under reflux at 100 oC. After completion of the
reaction (4 h, monitored by TLC), we could isolate 40% of the
expected benzylpyrazolyl coumarin 5a along with 48% of benzyl
biscoumarin 6a (Scheme 1). In order to circumvent this undesired
product (6a), we conducted several experiments and isolated the
intermediates 5A, 5B and 5C (Scheme 2), based on the isolated
intermediates (also literature reports),8,9 we propose that there
could be two reaction pathways existing for the formation of 4-
((4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)methyl)-5-methyl-
2-phenyl-1H-pyrazol-3(2H)-one 5 (benzylpyrazolyl coumarin).
.
Entry
Ca(OTf) Bu4NPF Solvent
Tim
Temp
Yielda
2, mol%
6, mol%
e (h) (oC)
1
2
5
5
0
5
5
0
0
0
5
5
5
H2O
H2O
-
4
4
100
65
80
100
100
100
100
100
100
100
100
3
5
6
50
4
0
H2O
-
5
traceb
tracec
83
5
0
8
6
10
10
10
10
H2O
H2O
EtOH
H2O+Et
OH
4
7d
8
3.5
4
92
90
O
OH
Ph
9
3.5
92
H
OEt
+
N
+
H2N
R
O
10
11
10
10
5
5
H2O
H2O
16
12
min
5
rt
110,m
w
78
90
H3C
Ph
O
O
O
1
2
4
3
Knoevenagel
H2O
H2O
O
O
12
13
14
15
10
10
10
10
5
5
5
5
CH3CN
THF
90
40
45
70
40
O
O
Ph
OH
N
1, H2O
5
80
O
Ph
Toluene
CH2Cl2
5
110
55
O
5A
H3C
R
O
O
6
N
O
O
5C
a.Isolated Yields after filtration; b.trace amount of product and
1,4-addition
c
>90% of biscoumarin compound was observed; . trace amount of
Knoevenagel
R
product and 20% of biscoumarin was observed; d.optimum
conditions
R
Path-A
Path-B
N
HO
+
+Ca
O
N
N
O
N
5B
Ca2+
CH3
Ph
Scheme
biscoumarinmethane 6 could be avoided if the reaction proceeds
2
evidences
that
the
formation
of
CH3
Ph
O
II
O
1,4-addition
via path-A, based upon this hypothesis we modified our
procedure.12
5E
R
experimental
stoichiometric
amounts
of
O
N
N
+Ca
phenylhydrazine, ethylacetoacetate and benzaldehyde were
refluxed in water using 5 mol% of Ca(OTf)2 for 1 h (formation of
Knoevenagel product was observed by TLC), then 4-
hydroxycoumarin was added and the reflux was continued for 2
more hours and we were glad to notice the formation of
benzylpyrazolyl coumarin alone in 65% yield. Our next target
was to increase the yield of the product for which we conducted
several experiments using different conditions as shown in Table
1. Entry 4, 5 (Table 1) evidences the importance and necessity of
the catalyst to accelerate the reaction. Entry 2, tells that the yield
of the product increases when additive (Bu4NPF6) is added. It is
also observed that the protic solvents enhance the product
formation (Entries 7-11 versus 12-15). Over all, entry 7 shows
the optimum condition for the green synthesis of benzylpyrazolyl
OH Ph
OH
O
CH3
Ph
N
R
O
O
O
O
NH
CH3
5D
5
benzylpyrazolyl coumarins
Scheme 2
. plausible mechanism for the synthesis of benzylpyrazolylcoumarins
As shown in the scheme 2, first ethylacetoacetate and
phenylhydrazine will react to give the pyrazolone 5A, which will
undergo knoevenagel condensation with aldehydes to give the
adduct 5B. Owing to the presence of nitrogen atom next to the
carbonyl carbon in the 5B, nucleophile cannot add to it via a 1,4-

3
coumarin 5a in 92% (use of 10 mol% of Ca(II), 5 mol% of
additive, reflux in water for 3.5 h).
m-bromo benzaldehyde, p-chloro and p-bromo benzaldehydes
have been successfully participated in the multicomponent
synthesis and produced corresponding benzylpyrazolyl
coumarins 5b (88%), 5c (85%), 5g (78%) and 5h (78%)
respectively. Similarly, benzaldehydes with electron donating
groups like p-methyl, p-methoxy and m-methoxy groups also
reacted under the similar conditions to yield corresponding
benzylpyrazolyl coumarins 5d (91%), 5e (83%), 5i (84%) in
good yields. p-Nitrobenzaldehyde and m-nitrobenzaldehydes
(with electron withdrawing groups) gave the benzylpyrazolyl
coumarins 5f (90%) and 5n (88%). Encouraged by the
participation of diversely substituted aryl aldehydes, we extended
our methodology to check the participation of substituted
pyridine aldehydes, thiophenaldehyde and found all these were
equally participating to yield the products in good to excellent
yields (entries 5j, 5k, 5m, Table 2). To check the utility of
aliphatic aldehydes (so far no example of aliphatic aldehyde
participation is reported), we commenced with the reaction of 4-
hydroxycoumarin, ethylacetoacetate, phenyl hydrazine with
isovaleraldehyde and glad to isolate the product 5o in 90% yield
after 8 h. Encouraged by this result we extended this protocol to
other aliphatic aldehydes, isobutyraldehyde, butyraldehyde,
propanaldehyde and formaldehyde with 4-nitrophenyl hydrazine
and isolated the corresponding pyrazolyl coumarins 5p, 5q, 5r,
5s and 5t in good to excellent yields (Table 2). It is important to
notice that in case of aromatic aldehydes reaction completes in 3-
5 h, whereas in case of aliphatic aldehydes it is taking 7-10 h.
Table 2. Substrate scope in the Ca(II) catalysed one-pot 4-
component synthesis of benzylpyrazolylcoumarin derivatives.12
It is surprising to notice that entry 4 in Table 1, illustrates the
catalyst free synthesis of biscoumarin methanes in water with
high yields. When we looked into the literature reports for the
synthesis of biscoumarin methanes, we noticed that due to the
broad biological array of these compounds several methods were
reported using various catalytic systems.14 But no report was
there in which water mediated catalyst free synthesis of
biscoumarins under conventional heating. Although Gong et al.,
has reported the similar synthesis of biscoumarins under
microwave irradiation,14 but no example with aliphatic aldehyde
has been reported by them. Hence we are also reporting herewith
the catalyst free synthesis of biscoumarin methanes in water
under conventional heating. Not only aromatic aldehydes (with
variety of electronic and steric functionalities), aliphatic
aldehydes
like
acetaldehyde,
formaldehyde
and
isobutyraldehydes (6m, 6n, 6o, Scheme 3) have been taking part
in the reaction to produce high yielding biscoumarin methanes as
shown in Scheme 3
Scheme 3 Catalyst-free synthesis of biscoumarin metanes in
water under conventional heating
List of biscoumarins prepared (Scheme 3): 6a. R = Ph, 95%;
6b. R = Ph (4-NO2), 93%; 6c. R = Ph (4-Br), 93%; 6d. R = Ph (4-
Cl), 94%; 6e. R = Ph (4-OMe), 82%; 6f. R = Ph (4-OH), 88%;
6g. R = Ph (3,4,5-trimethoxy), 79%; 6h. R = Ph (3-OH, 4-OMe),
80%; 6i. R = Ph (2-OH), 92%; 6j. R = Ph (3-OMe), 91%; 6k. R =
Ph (2-Cl), 88%; 6l. R = Ph (3-Br), 81%; 6m. R = CH3, 65%; 6n.
R = CH2, 68%, 6o. R=isobutyl, 86%.
Isolated yields after filtration, all reactants are taken in
stoichiometric amounts
After successful mechanistic studies and optimization of
reaction conditions, we extended our methodology to utilize
various aldehydes in the Ca(II) catalyzed four component
synthesis of banzylpyrazolyl coumarins in water (Table 2).
Halogen substituted aryl aldehydes like o-chloro benzaldehyde,
All compounds were fully characterized by 1H NMR, 13C
NMR, Mass, IR and melting point data.12

4
Tetrahedron
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In summary, a facile one-pot multicomponent approach for
the synthesis of array of biologically important
benzylpyrazolylcoumarins has been described using
environmentally benign catalyst (Ca2+) and solvent (water).
Participation of aliphatic aldehydes has been described for the
first time. This reaction endures a variety of aromatic aldehydes
bearing electron withdrawing and donating groups, aliphatic
aldehydes and hydrazines as the reacting partners. Owing to its
simple reaction, work-up and isolation procedures, short reaction
times and high yields we believe that this methodology will be
amenable over the existing methods.
Acknowledgments
Two of the authors AP and RD thank Central University of
Rajasthan and CSIR for the fellowships respectively. SY thank
DST for the financial support under Fast Track Young Scientist
Scheme.
Indian
J.
Chem.,
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B: Org. Chem. Incl. Med. Chem., 1993, 32, 858–861. (m)
Gunasekaran, P.; Perumal, S.; Yogeeswari, P.; Sriram, D. Eur. J.
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13. General Experimental Procedure: a mixture of aryl aldehyde (1.0
equiv), phenyl hydrazine (1.0 equiv.) and ethyl acetoacetate (1.3
equiv.), Ca(OTf)2 (10 mol%) and additive Bu4NPF6 (5 mol%)
were weighed into a round bottom flask and refluxed in water at
100 oC for 1.5-2 h (monitored by TLC), then 4-hydroxycoumarin
(1.0 equiv.) was added to the above reaction and reflux was
continued for 1-1.5 h (monitored by TLC). After completion of
the reaction, cold water was added to the reaction mixture and
filtered through a Buchner flask washed 2-3 times with cold water
and the obtained solid was dried to get the final product. If
necessary the obtained solid was recrystallized with hot ethanol.
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