Design and synthesis of benzylpyrazolyl coumarin derivatives via a four-component reaction in water: Investigation of the weak interactions accumulating in the crystal structure of a signified compound

Article abstract of DOI:10.1039/c2gc36021g

A combinatorial library of benzylpyrazolyl coumarin derivatives have been synthesized by a green one-pot four-component reaction between aryl hydrazine/hydrazine hydrate (1), ethyl acetoacetate (2), aromatic aldehydes (3) and 4-hydroxycoumarin (4). Molecular scaffolds which assimilate bio-active 3-benzylsubstituted 4-hydroxycoumarins as well as a pyrazolone ring in a single nucleus may be worthwhile molecules from a biological point of view. The reactions were performed in water and employed glacial acetic acid as the right choice of catalyst, and was demonstrated to be the key for rendering the reaction possible and obtained good to excellent yields under reflux conditions within a short period of time. The crystal structures of (R/S)-benzylpyrazolyl coumarin, easily produced by a chromatography-free highly product-selective reaction, were explored by means of single crystal X-ray diffraction analysis and the main intra- and intermolecular interactions perceivable through crystal structure analysis. The presence of a strong intramolecular hydrogen bond was confirmed. In addition, the whole crystal structure consists of other intermolecular hydrogen bonds, such as CH...O and aromatic CH...π interactions between R- and S-molecules and CH...O, NH...O and aromatic CH...π interactions among only R-molecules and S-molecules in the asymmetric unit.

Full text of DOI:10.1039/c2gc36021g

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COMMUNICATION
Design and synthesis of benzylpyrazolyl coumarin derivatives via a four-
component reaction in water: investigation of the weak interactions
accumulating in the crystal structure of a signified compound†
Partha Pratim Ghosh, Gargi Pal, Sanjay Paul and Asish R. Das*
Received 3rd July 2012, Accepted 6th August 2012
DOI: 10.1039/c2gc36021g
functionalized compound libraries of medicinal motifs is an
attractive area of research in both academia and the pharma-
ceutical industry.2 Multi-component reactions (MCRs) in water
have been shown to be powerful tools in the search for develop-
ing libraries of medicinal scaffolds as well as for the require-
ments of green chemistry because of the cheap, easy availability
and relevant character.3
3-Substituted 4-hydroxycoumarin particularly 3-benzylsubsti-
tuted 4-hydroxycoumarin derivatives are of much importance
because they exist in many natural products. It is also established
that these compounds also exhibit a wide range of biological
activities due to its abundance in medicinal scaffolds namely
warfarin, phenprocoumon, coumatetralyl, carbochromen, broma-
dialone (Fig. 1a) offering antibacterial, anti-HIV,4 antiviral,5 anti-
coagulant,6 antioxidant7 and anticancer activities.8
A combinatorial library of benzylpyrazolyl coumarin deriva-
tives have been synthesized by a green one-pot four-com-
ponent reaction between aryl hydrazine/hydrazine hydrate
(1), ethyl acetoacetate (2), aromatic aldehydes (3) and
4-hydroxycoumarin (4). Molecular scaffolds which assimilate
bio-active 3-benzylsubstituted 4-hydroxycoumarins as well as
a pyrazolone ring in a single nucleus may be worthwhile
molecules from a biological point of view. The reactions were
performed in water and employed glacial acetic acid as the
right choice of catalyst, and was demonstrated to be the key
for rendering the reaction possible and obtained good to
excellent yields under reflux conditions within a short period
of time. The crystal structures of (R/S)-benzylpyrazolyl cou-
marin, easily produced by a chromatography-free highly
product-selective reaction, were explored by means of single
crystal X-ray diffraction analysis and the main intra- and
intermolecular interactions perceivable through crystal
structure analysis. The presence of a strong intramolecular
hydrogen bond was confirmed. In addition, the whole crystal
structure consists of other intermolecular hydrogen bonds,
such as CH⋯O and aromatic CH⋯π interactions between
R- and S-molecules and CH⋯O, NH⋯O and aromatic
CH⋯π interactions among only R-molecules and S-molecules
in the asymmetric unit.
Pyrazolones are also important structural cores in many drug
substances of medicinal fields. Heterocyclic nucleus containing
pyrazolones (viz. phenazone, propyphenazone, ampyrone and
metamizole) (Fig. 1b) are useful antipyretic and analgesic
drugs,9 whilst edaravone (MCI-186) has been used for treating
brain10 and myocardial ischemia.11 In addition, pyrazolones
possess kinase inhibitory properties, particularly of enzymes
which catalyze the phosphorylation of serine and threonine in
proteins, and is also used for treating diseases related to these
enzymes, such as rheumatoid arthritis, psoriasis, bone loss,
cancer and other proliferative diseases like antimicrobial, anti-
fungal,12 antimycobacterial,13 antibacterial,14 anti-inflamma-
tory,15
antitumor,16
gastric
secretion
stimulatory,17
Introduction
antidepressant,18 antifilarial activities19 and anti-tubercular
The task of achieving efficacy in all features of chemical con-
struction in the medicinal field is the design and synthesis of bio-
logically active molecules. Green chemistry can be recognized as
pioneering research, which widely reports intrinsic atom
economy, energy savings, waste reduction, easy work ups and
the avoidance of hazardous chemicals.1 The development of a
simple, eco-friendly reaction protocol for the synthesis of highly
activities.20
A molecular scaffold which assimilates 3-benzylsubstituted
coumarin as well as pyrazolone moieties might integrate proper-
ties of both, and the synergism of both the heterocyclic moieties
in a single nucleus may result in the formation of some worth-
while molecules from a biological point of view. It is surprising
that there is no compound possessing such a molecular skeleton
reported in the literature to date. We herein wish to report, for the
first time, a glacial acetic acid catalyzed four-component reaction
for the combinatorial synthesis of highly functionalized benzyl-
pyrazolyl coumarin frameworks in water medium under reflux
conditions (Scheme 1). The present work materializes as a part
of our ongoing research programme recently published on the
synthesis of various biologically active coumarin moieties.21
Department of Chemistry, University of Calcutta, Kolkata-700009,
India. E-mail: ardchem@caluniv.ac.in, ardas66@rediffmail.com;
Fax: (+91)3323519754; Tel: (+91)3323501014, (+91)9433120265
†Electronic supplementary information (ESI) available. CCDC reference
number 886519. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2gc36021g
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Fig. 1 (a) Some biologically active 3-substituted coumarin; (b) bio-active pyrazolone moieties.
Scheme 1 Green synthesis of benzylpyrazolyl coumarins.
a trace amount of the desired product (Table 1, entry 9). We then
applied glacial acetic acid (AcOH) (10 mol%) as catalyst in
water, eventually we achieved satisfaction because the reaction
proceeded well, affording the desired product in 94% yield
within 40 min (Table 1, entry 10). AcOH played a key and
amazing catalytic role in this particular MCR in comparison to
other organic acids applied, which can be attributed to its low
acidity, marked solvent character (towards polar organic sub-
strates and reagents), high tunability of solvent (water) polarity
and the created ambient conditions which optimized the reaction
purity, yield and speed for the reaction to proceed.
Taking glacial acetic acid (AcOH) as the right catalyst for the
experiment, we then concentrated our attention on designing and
also generalizing the favorable conditions for the reaction. We
firstly attempted some screening tests with glacial AcOH. The
quantity of the catalyst had a large effect on the formation of the
desired product. The use of 5 mol% glacial AcOH diminished
the quantity of the yield, whereas the yield of the product also
decreased when we used 15 mol% glacial AcOH (Table 1,
entries 11 and 12). Water (Table 1, entry 10) showed superiority
Result and discussion
To recognize the optimization of the reaction conditions, the
reaction was studied by employing a series of catalysts and sol-
vents as well as under solvent-free conditions with the hope to
maximize the product yield in short reaction times (Table 1).
Initially, phenyl hydrazine (1.0 mmol), ethyl acetoacetate
(1.0 mmol), 3-nitrobenzaldehyde (1.0 mmol) and 4-hydroxycou-
marin (1.0 mmol) were refluxed in the presence of H2O and
ethanol as the solvent without any catalyst, however, the reac-
tion, even after 24 h, failed to afford any product (Table 1,
entries 1 and 2). Then the reaction was carried out in water in
the presence of p-toluenesulphonic acid (PTSA) under reflux
conditions and the product was isolated in 26% yield (Table 1,
entry 3). The reactions were also restrained by using trifluoro-
acetic acid (TFA), trifluoro methanesulphonic acid (TfOH) and
formic acid as the catalyst (Table 1, entries 4, 5 and 6). Lewis
acid catalysts, such as Cu(OAc)2 and InCl3 were tested but did
not promote the reaction (Table 1, entries 7 and 8), while the use
of nano crystalline ZnO as a catalyst in aqueous media provided
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Table 1 Screening of catalyst and solvents and reaction conditions
Entry
Catalysts
Solvent
Condition
Time (h)
Yielda,b (%)
c
1
2
3
4
5
6
7
8
—
—
H2O
EtOH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
EtOH
CH3CN
CHCl3
—
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
110 °C
24
24
24
24
24
24
24
24
—
—
26
23
22
41
c
PTSA (10 mol%)
TFA (10 mol%)
TfOH (10 mol%)
HCOOH (10 mol%)
Cu(OAc)2 (10 mol%)
InCl3 (10 mol%)
Nano ZnO
Gl. AcOH (10 mol%)
Gl. AcOH (5 mol%)
Gl. AcOH (15 mol%)
Gl. AcOH (10 mol%)
Gl. AcOH (10 mol%)
Gl. AcOH (10 mol%)
Gl. AcOH (10 mol%)
c
—
c
—
Trace
94
9
24
10
11
12
13
14
15
16
40 min
40 min
40 min
40 min
40 min
40 min
40 min
77
84
68
32
37
46
a All reactions were carried out with phenyl hydrazine (1 mmol), ethyl acetoacetate (1 mmol), 3-nitrobenzaldehyde (1 mmol) and 4-hydroxycoumarin
(1 mmol). b Yield of isolated product. c Reaction failed to provide any product.
1
to the other solvents tested [ethanol (Table 1, entry 13), aceto-
nitrile (Table 1, entry 14) and chloroform (Table 1, entry 15)],
while under the solvent-free conditions (Table 1, entry 16) at
110 °C, AcOH failed to provide satisfactory outputs. Therefore
water was chosen as the solvent for this reaction as the
maximum yield (94%) was obtained under aqueous conditions.
Hence, these optimized conditions were applied for all exper-
iments: taking equimolar amounts of substituted hydrazine (1),
ethyl acetoacetate (2), aromatic aldehydes (3) and 4-hydroxy
coumarin (4) under reflux conditions in the presence of 10 mol%
glacial acetic acid in aqueous media (Scheme 1). Typically, a
mixture of substituted hydrazine (1.0 mmol), ethyl acetoacetate
(1.0 mmol), aromatic aldehydes (1.0 mmol), 4-hydroxycoumarin
(1.0 mmol) and 10 mol% glacial acetic acid in 3 ml water was
refluxed for 30–55 min, which afforded a library of benzylpyra-
zolyl coumarin (5) derivatives in good to excellent yields
(80–94%) (Table 2).
To study the scope and limitations of this protocol, we
employed a wide range of aromatic aldehydes. Phenyl hydrazine,
hydrazine hydrate and p-nitrophenylhydrazine are also applied
for developing the pyrazolone ring with ethyl acetoacetate to
access the corresponding benzylpyrazolyl coumarin derivatives.
The reaction proceeded smoothly and provided excellent yields
and tolerated unsubstituted benzaldehydes, and also electron-
withdrawing and electron-donating para-substituted benz-
aldehydes. The reactions were consistently carried out at the
1 mmol scale and no change of product yield was observed
when scaled up to the 10 mmol scale. From the context of green
chemistry, it was positive to find that the final products could be
isolated by filtration due to their lower solubility in the glacial
acetic acid–water mixture. Furthermore, their purity was too high
to require their preparation in an analytically pure form by single
recrystallization, thus avoiding extraction steps and chromato-
graphic separations. Therefore, we preferred water as the reaction
medium over unsafe organic solvents which decrease the chemi-
cal impurity, easy work-up procedure and produce large volumes
of waste from the discarded chromatographic static phases. The
structure of the final products were well characterized by using
spectral (IR, H, 13C NMR and HRMS) and elemental analysis
data (ESI†). The structural motif was fully established by single
X-ray crystallographic analysis of one signified compound 5d
(Fig. 2).22 Compound 5d (CCDC 886519†) crystallized in the
monoclinic P2(1)/n space group with two molecules in the
asymmetric unit, and formed a heterochiral dimer synthon by
intermolecular H-bonding, such as CH⋯O and aromatic CH⋯π
interactions between R- and S-molecules in the solid state
(Fig. 3). Weak interactions (such as CH⋯O, NH ⋯O and aro-
matic CH⋯π interactions) were also observed, extending the
structure into an infinite chain along the b-direction by R-mole-
cules (Fig. 4) only and for S-molecules (Fig. 5) in the unit cell.
Presumably, the four-component reaction seems to proceed
following the mechanistic pathway presented in Scheme 2.
Initially, aryl hydrazine/hydrazine hydrate is reacted with ethyl
acetoacetate to generate the pyrazolone ring (I). Additionally,
glacial acetic acid catalyzed the Knoevenagel reaction between
4-hydroxycoumarin and aromatic aldehyde to form the Knoeve-
nagel product (II). Subsequently, during the Michael addition
step, nucleophilic attack on (II) by the tautomeric form of pyra-
zolone (I) afforded the desired product (5) via intermediate (III).
Alternatively, there is another possible reaction pathway for the
reaction, via the formation of intermediate (IV) followed by reac-
tion with 4-hydroxycoumarin to afford 5. We tried to isolate
intermediate (IV) from the two-component reaction between pyr-
azolone (I) and m-nitrobenzaldehyde and the three-component
reaction of phenyl hydrazine, ethyl acetoacetate and m-nitro-
benzaldehyde in presence of glacial acetic acid in water, and found
that bis-pyrazolone (Fig. 7(ii))was formed. We also attempted a
reaction between 4-hydroxycoumarin and m-nitrobenzaldehyde,
where bis-coumarin (Fig. 7(i)) was formed instead of intermedi-
ate (II). These results revealed that intermediates (II) and (IV)
were both very reactive towards the subsequent reaction with
pyrazolone and 4-hydroxycoumarin respectively. Hence infor-
mation on the relative rates of formation, as well as further reac-
tions of (II) and (III) with pyrazolone or 4-hydroxycoumarin
respectively, could not be obtained and evaluated. Therefore,
information on whether the multicomponent reactions proceeded
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Table 2 Substrates scope for the synthesis of benzylpyrazolyl coumarins (5)
Entry
1
Hydrazines
Aldehydes
Product
Time (min)
30
Yielda (%)
93
2
35
92
3
40
94
4
45
92
5
40
93
6
45
93
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Table 2 (Contd.)
Entry
7
Hydrazines
Aldehydes
Product
Time (min)
45
Yielda (%)
90
8
50
89
9
55
88
10
11
12
45
50
55
86
83
80
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Table 2 (Contd.)
Entry
13
Hydrazines
Aldehydes
Product
Time (min)
35
Yielda (%)
91
14
15
30
40
90
90
a Yield of the isolated product.
Fig. 3 The intermolecular H-bonds in the asymmetric unit between
R- and S-molecules. All hydrogens, except those participating in
H-bonding have been omitted for clarity.
Fig. 2 ORTEP diagram of the single crystal of compound 5d: CCDC
886519.†
We can conclude that the reaction is very product-selective,
affording only benzylpyrazolyl coumarins (5), bis-coumarin, bis-
pyrazolone and their annulated products (Fig. 7) were not
observed at all in this reaction.
through intermediate (II) or (IV) could not be ascertained in the
current study.
It is pertinent to mention here that after completion of the
reaction, tautomerisation occurred in the pyrazolone ring of 5,
and it may exist in three tautomeric forms, viz. the CH, OH and
NH forms (Fig. 6) as reported23 previously, but we observed that
tautomerisation occurred only in the NH form, which was estab-
Conclusion
In conclusion, a highly product-selective and chromatography-
free four-component reaction protocol was developed in the pres-
ence of glacial acetic acid in water under mild reaction con-
ditions which afforded highly potent benzylpyrazolyl coumarin
1
lished through H NMR and the X-ray crystallographic study.
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Fig. 4 The intermolecular H-bonds among the R-molecules. All hydro-
gens, except those participating in the H-bonding have been omitted for
clarity. Symmetry codes: A 1.5 − x, −0.5 + y, 1.5 − z. B x, −1 + y, z.
C 1.5 + x, −1.5 + y, 1.5 − z.
Scheme 2 Plausible mechanism for the formation of benzylpyrazolyl
coumarins.
Fig. 7 Bis-coumarin (i), bis-pyrazolone (ii) and their annulated pro-
ducts (iii and iv)
Fig. 5 The intermolecular H-bonds among the S-molecules. All hydro-
gens, except those participating in the hydrogen bonds have been
omitted for clarity. Symmetry codes: A 0.5 − x, −0.5 + y, 1.5 − z B x,
1 + y, z, C 0.5 − x, 0.5 + y, 1.5 − z.
scaffolds in good to excellent yields. Several green chemistry
principles were included for the development of the combinator-
ial libraries: it is a one-pot multicomponent reaction offering
only ethanol and water as the byproducts. The one representative
molecular structure was investigated by means of X-ray diffrac-
tion analysis.
Fig. 6 Three tautomeric forms of benzylpyrazolyl coumarin.
Acknowledgements
We gratefully acknowledge the financial support from U.G.C.
and Calcutta University. P.P.G. and S.P thank U.G.C, New Delhi,
India for the grant of their Junior Research fellowship. G.P.
thanks CSIR, India for her Junior Research fellowship. Crystal-
lography was performed at the DST-FIST, India-funded Single
Crystal Diffractometer Facility at the Department of Chemistry,
University of Calcutta.
Experimental procedure
To a mixture of 10 mol% glacial acetic acid and 5 ml water,
hydrazine 1 (1 mmol), ethyl acetoacetate 2 (1 mmol), aromatic
aldehyde 3 (1 mmol) and 4-hydroxycoumarin 4 (1 mmol) were
added and heated to reflux. The resulting clear solution, that
gradually became turbid, was stirred for the stipulated time men-
tioned in Table 2. After completion of the reaction (indicated by
TLC), the free flowing solid was filtered and washed with water
(10 ml) to afford the desired products as pale yellow solids. The
product thus obtained was recrystallized from ethanol to get pure
compounds as white or pale yellow crystals. The isolated com-
pounds were well characterized by IR, 1H NMR, 13C NMR,
HRMS, elemental analysis and an X-ray crystallographic study.
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