Expeditious synthesis of functionalized tricyclic 4-spiro pyrano[2,3-c]pyrazoles in aqueous medium using dodecylbenzenesulphonic acid as a Br?nsted acid-surfactant-combined catalyst

Article abstract of DOI:10.1039/c5nj01728a

An efficient, three-component, one-pot synthesis of highly functionalized tricyclic 4-spiro pyrano[2,3-c]pyrazoles incorporating medicinally privileged heterocyclic moieties has been developed, which also involves the tandem Knoevenagel/Michael addition reaction followed by dehydrative cyclization of pyrazolone derivatives, cyclic 1,3-diketones and cyclic ketones, catalyzed by dodecylbenzenesulphonic acid (DBSA) as a Br?nsted acid-surfactant-combined catalyst in aqueous medium. The catalyst is found to be highly competent in accelerating this reaction that results in a considerable short reaction time, alleviating the need for high thermal energy. Wide substrate scope, high to excellent product yield, operational simplicity, absence of any hazardous organic solvent, mild reaction conditions, a simple work up procedure and easily available starting materials are the salient features of this protocol.

Full text of DOI:10.1039/c5nj01728a

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DOI: 10.1039/C5NJ01728A
Journal Name
ARTICLE
Expeditious synthesis of functionalized tricyclic 4-spiro
pyrano[2,3-c]pyrazoles in aqueous medium using
dodecylbenzenesulphonic acid as a Brønsted acid-surfactant-
combined catalyst
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Prasun Mukherjee, Sanjay Paul, Asish R. Das*
www.rsc.org/
An efficient, three-component, one-pot synthesis of highly functionalized tricyclic 4-spiro pyrano[2,3-c]pyrazoles,
incorporating medicinally privileged heterocyclic moieties, has been developed that involves the tandem
Knoevenagel/Michael addition reaction followed by dehydrative cyclization of pyrazolone derivatives, cyclic 1,3-diketones
and cyclic ketones, catalyzed by dodecylbenzenesulphonic acid (DBSA) as a Brønsted acid-surfactant-combined catalyst in
aqueous media. The catalyst has found to be highly competent in accelerating this reaction that results in a considerable
short reaction time, alleviating the need of high thermal energy. Wide substrate scope, high to excellent product yield,
operational simplicity, absence of any hazardous organic solvent, mild reaction condition, simple work up procedure and
easily available starting materials are the salient features of this protocol.
because it might possess the properties of all moieties. Several
methodology have been developed in order to construct
diversified pyran molecular scaffolds and its spiro analogues,
Introduction
Combination of diverse pharmacophores into
molecular scaffold has revealed as a key strategy in design and
synthesis of new drugs. Accordingly development of synthetic
protocols able to furnish molecular diversity and complexity
from easily available and inexpensive starting materials has
become one of the main goals for organic chemists. The knack
of rapid introduction and expansion of molecular diversity by
assembling three or more different reactants in a single
a single
employing suitable active methylene compounds with various
6
1
aldehydes and ketones. Pyrazolone derivatives have been
recognized as significant active methylene compounds since
pyrazolone scaffold occurs in many drugs and synthetic
products (e.g., phenazone, propyphenazone, ampyrone and
metamizole) (Fig. 1a) which exhibit numerous biological
7
activities. In addition, pyrazole is a potent heterocycle which
plays an important role in pharmaceutical and agrochemical
chemical transformation makes multicomponent reactions
8
2
industries. On the other hand ninhydrin as well as isatin
(
MCRs) a powerful tool to achieve this goal. Over the past
derivatives are major starting materials to form spiro
functionality in different molecules since indan-1,3-dione
moiety can be found as the core structure of medicinal scaffolds
decades, several MCRs have been developed in order to
synthesize pyran molecular scaffold and its spiro analogue
since these classes of heterocyclic compounds are the key
structural motif of various natural products possessing wide
9
10
which displays hypolipidemic and anti-inflammatory
3
activities. Moreover, many natural products (e.g., Uncarine,
Isomitraphylline, Mitraphylline, Rynchophylline) (Fig. 1b)
have the skeletal structure of oxindole and some synthetic
compounds having oxindole unit possess several potent
range of biological activities. In addition, spirocyclic
compounds are valuable precursors for the easy access of
several cyclic molecules as they can undergo various
rearrangement reactions due to the steric strain at quaternary
1
1
4
bioactivities.
However, methods in order to synthesize polycyclic 4-spiro
carbon atom.
The biological activity of a diversified spiro pyran molecular
scaffold is greatly influenced due to the presence of other
potent heterocyclic moieties within the same molecule.
Presence of multiple bioactive heterocyclic fragments in a
single entity may increase the pharmacological activities
1
2
pyrano[2,3-c]pyrazoles are still limited.
Although,
5
heterocycles with tricyclic pyran moieties have been
acknowledged for their potent bioactivity as inhibitor of
1
3
14
acetylcholinesterase, γ-secretase, anti-angiogenic activity
1
5
against human umbilical vein endothelial cells. In this
context, it should be interesting to construct a diversified
tricyclic spiropyran scaffold, possessing pyrazole, pyran and
spiro functionality in single molecular entity, by utilizing a mild
and environmentally benign protocol.
§
*
Department of Chemistry, University of Calcutta, Kolkata-700009, India
Corresponding author. Tel.: +913323501014, +919433120265; fax:
+
913323519754;
E-mail address: ardchem@caluniv.ac.in, ardas66@rediffmail.com (A R Das).
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Journal Name
Result and discussion
Reaction conditions
In order to construct functionalized pyran structural motif
several protocols can be found in literature where one of the
active methylene compound is always acyclic. However
reactions where active methylene compounds are both cyclic,
generally require harsh reaction conditions. In the course of
our studies, we were interested to utilize the surfactant as well
as the Bronsted acid property of DBSA in exploration of a
milder reaction protocol to afford tricyclic 4-spiro pyrano[2,3-
c]pyrazoles. To begin with, hydrazine hydrate, ethyl
acetoacetate, ninhydrin and dimedone were chosen as the
model substrates for the proposed reaction. Initially hydrazine
hydrate (1 mmol) and ethyl acetoacetate (1 mmol) were reacted
in presence of DBSA (10 mol%) in water (3 ml) for 5 min then
to it ninhydrin (1 mmol) and dimedone (1 mmol) were added
View Article Online
DOI: 10.1039/C5NJ01728A
MCRs in aqueous media have always greeted as water is eco-
1
6
friendly and in particular it has unique physical and chemical
properties which may extend certain reactivity and selectivity
normally unattainable by other commonly used organic
2
2
1
7
solvents. However, one major drawback of using water as a
solvent is slower reaction rate of organic reactions due to the
2
3
1
8
poor solubility of most organic substrates in water medium.
To overcome this problem surfactants are frequently used, as
they can solubilize organic molecules or form colloidal
dispersion with them by forming micelles in aqueous medium
NaO
3
S
NH
2
N
N
N
N
N
O
N
O
O
O
N
O
N
N
N
N
Phenazone
Propyphenazone
Edaravone
Ampyrone
Metamizole Sodium
o
subsequently and the reaction mixture was heated to 100 C.
a
The complete conversion of the starting materials was observed
within 3 h as indicated by TLC (50% ethyl acetate in petroleum
ether) and the product was isolated as a pale yellow solid in
80% yield (Table 1, entry 1). The structure of the product
H
H
H
H
N
H
O
N
O
N
N
O
H
O
O
H
O
O
H
O
H
H
O
H
O
HN
N
OMe
N
O
O
OMe
H
N
H
OMe
1
spiropyran (6a) was characterized by spectroscopic analysis ( H
1
3
Uncarine
Rynchophyline
Isomitraphylline
Mitraphylline
NMR,
C NMR, IR). In addition, the single X-ray
crystallographic analysis of the product also confirmed the
identity of the desired tricyclic spiropyran structural motif
b
(
Figure 2a).
Fig. 1 (a) Some biologically active pyrazolone compounds, (b) Some natural products
Based on this promising result, we have then investigated the
effect on product yield by changing various experimental
parameters in order to optimize the reaction conditions. The
yield of the product was increased to 96% when the reaction
containing oxindole moiety
1
9
thereby diminishing the need of an organic co-solvent. In
recent years Brønsted acid-surfactant-combined catalyst
BASC), such as dodecylbenzenesulphonic acid (DBSA), has
o
was performed at 90 C temperature (Table 1, entry 2). Use of
(
o
2
0 mol% of DBSA at 90 C did not afford any further increase
been found to be effective to catalyze various types of organic
2
0
in the product yield, while use of 5 mol% of DBSA results in a
reactions in water medium. The unique feature of BASC is, it
can not only supply proton as an acid to activate the reactants
but also solubilizes them by forming micelle or form a stable
colloidal dispersion with them as a surfactant, resulting in an
overall enhancement of the reaction rate.
decrease in the product yield (Table 1, entries 3 and 4). When
o
1
0 mol% of DBSA was employed at 80 C the product was
obtained in 55% yield (Table 1, entry 5). Curiously, when the
reaction was performed in absence of any catalyst either in
aqueous or organic solvent medium, no product was obtained
even after allowing the reaction to proceed for a prolonged time
(Table 1, entries 6-8), thereby indicating the essence of a
catalyst for this typical reaction. In search of a more able
reaction condition, the reaction was further carried out in
presence of different catalysts. Various acid catalysts like acetic
acid (AcOH), p-toluenesulfonic acid (PTSA), (d,l)-
camphorsulphonic acid (d,l-CSA), and a polymer supported
In view of these important points and continuing our efforts on
the development of new MCRs involving green
2
1
methodologies, herein we wish to report an efficient, one-pot,
three component process for the synthesis of functionalized
tricyclic 4-spiro pyrano[2,3-c]pyrazoles from the reaction
between pyrazolone derivatives, cyclic 1,3-dicarbonyls and
cyclic ketones (ninhydrin, isatin and 9,10-phenanthroquinone)
o
in water medium at 90 C in presence of DBSA as a Brønsted
acid catalyst PEG-SO H were employed in aqueous medium as
3
acid- surfactant-combined catalyst (scheme 1).
well as in organic solvent. AcOH, PEG-SO H and PTSA were
3
failed to generate any considerable amount of product in
aqueous medium (Table 1, entries 9-11). (d,l)-CSA was found
to be inefficient catalyst for this reaction in ethanol, water and
O
O
O
+
O
DBSA 10 mol%
3ml
O
O
3
4
PEG-H O medium (Table 1, entries 12-14). The most efficient
RNHNH
1
+
2
O
N
2
N
90 o
OEt
H
2
O
N
C
N
O
catalytic system was found to be the DBSA-water combination
for this three-component reaction and the optimized reaction
2
R
R
1
1
o
condition thus obtained carrying out the reaction at 90 C using
Scheme 1: Synthesis of tricyclic spiropyran derivatives
10 mol% of DBSA as the catalyst in 3 ml of water (Table 1,
entry 2).
2
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Table 1 Optimization of reaction conditions
water medium afforded the pyrazolone derivaVtieiwveAsrticlwe Ohnilcinhe
DOI: 10.1039/C5NJ01728A
O
O
precipitated from the reaction medium, but after the addition of
O
O
O+
cyclic ketones and cyclic-1,3-dicarbonyls to the same medium
O
O
O
Catalyst
O
O
o
+
followed by heating the reaction mixture at 90 C, the initially
NH2NH2..H2O
O
N
N
OEt Solvent
N
H
Temperature
N
O
developed turbidity of the reaction mixture became a colloidal
dispersion as expected and ultimately get solubilized by
forming micelle in aqueous medium or forming colloidal
dispersion with them. From Table 2 it can be seen that the yield
of the product is excellent in case of unsubstituted pyrazolone.
Introduction of aromatic substituent on hydrazine part resulted
in decrease of the product yield which may be due to the
decrease in solubility of the initially formed pyrazolone
derivatives in DBSA-water medium. In case of 9,10-
phenanthraquinone, the desired 4-spiro pyrano[2,3-c]pyrazoles
are obtained when the pyrazolone was unsubstituted. The
completion of the reaction was monitored by TLC (50% ethyl
acetate in petroleum ether). Crystallization of the crude product
afforded the pure desired product while column
chromatography of the crude product was performed in some
cases.
H
a,b
Entry
Catalysts
Solvent Condition Time (h) Yield (%)
o
1
2
3
4
5
6
7
8
9
DBSA (10 mol%)
H
H
H
H
H
H
2
2
2
2
2
2
O
O
O
O
O
O
100 C
3
3
80
96
94
70
55
_c
_c
_c
10
20
15
25
o
DBSA (10 mol%)
90 C
o
DBSA (20 mol%)
90 C
3
o
DBSA (5 mol%)
90 C
6
o
DBSA (10 mol%)
80 C
8
-
reflux
24
24
24
18
8
o
-
Peg-400 100 C
The structures of the products were fully characterized by
1
13
spectral analysis ( HNMR, CNMR, IR and HRMS). The
structural motif of the compounds was fully established by
means of single X-ray crystallographic analysis of the
-
EtOH
reflux
reflux
AcOH (0.5 ml)
H
2
H
2
H
2
O
O
O
compounds 6a, 6f, 6i, 7h and 8c (Fig. 2).
o
1
0
1
2
PEG-SO
3
H
100 C
o
1
1
PTSA (10 mol%)
100 C
24
15
(d,l)-CSA (10
EtOH
reflux
reflux
mol%)
1
1
3
4
(d,l)-CSA (10
H
2
O
18
8
30
50
mol%)
o
(a) Ortep diagram of single crystal of compound 6a CCDC: 1031973
(d,l)-CSA (10
H
2
O-
PEG-400
2:1)
100 C
mol%)
(
a
all reactions are carried out with hydrazine hydrate (1 mmol), ethylacetoacetate
b
(1 mmol), ninhydrin (1 mmol) and dimedone (1 mmol); yield of isolated product;
c
the reaction failed to afford the desired product.
Substrate scope
With this optimized condition in hand, we then investigated the
scope and limitation of this reaction. Dimedone, cyclohexan-
1,3-dione and cyclopentan-1,3-dione were employed
successfully as the cyclic 1,3-dicarbonyls. A good range of
hydrazine derivatives were reacted with ethyl acetoacetate to
generate the corresponding pyrazolone derivatives in-situ. The
protocol was found to be facile to produce a library of tricyclic
(
b) Ortep diagram of single crystal of compound 6f CCDC:1031971
indeno-4-spiro pyrano[2,3-c]pyrazoles (6a-6j
) in good to
excellent yields (Table 2). When isatin, 5-bromoisatin and 9,10-
phenanthraquinone were employed in place of ninhydrin the
reaction proceeded with the same efficiency and corresponding
4-spiro pyrano[2,3-c]pyrazoles (7a-7l and 8a-8c) are obtained
in good to excellent yields (Table 2). Careful observation of the
reaction indicates that initially the reaction between ethyl
acetoacetate and hydrazine derivatives in presence of DBSA in
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ARTICLE
Journal Name
cyclohexan-1,3-dione and isatin, where tetraketoVnieew A(rFticilge.On3libne)
(
c) Ortep diagram of single crystal of compound 6i CCDC:1031972
DOI: 10.1039/C5NJ01728A
was formed instead of intermediate
that intermediates II and
V. These results revealed
V
were both very reactive towards the
subsequent reaction with pyrazolone and cyclohexan-1,3-dione
respectively. Hence information on the relative rates of
formation, as well as further reactions of II and
V with
cyclohexan-1,3-dione or pyrazolone respectively, could not be
obtained and evaluated. Therefore, information on whether the
multicomponent reactions proceeded through intermediate II or
V
could not be established in the current study.
We have taken the optical image of the reaction mixture (Fig.
), that clearly shows the formation of micelle promoted by
4
DBSA. The formation of micellar medium is attributed to the
surfactant property of DBSA which make the reaction to occur
inside the hydrophobhic interior and force the water molecules,
produced as by products in several steps, to exit from the
micelle. The rate of this three component reaction thereby
highly assisted by the formation of the micellar medium.
(
d) Ortep diagram of single crystal of compound 7h CCDC: 1039374
H
O
O
O
N
O
R
1
-
H O
2
R
1
H
-EtOH
HO
O
Et
OEt
N
N
N
N
2
N
DBSA
in water
R
1
H
2
N
R
1
H
(I)
(Ia)
N
H
1
-H O
2
H
3
DBSA
O
O
in water
OH
Intramolecular
dehydrative
cyclisation
O
4a
O
O
O
(
e) Ortep diagram of single crystal of compound 8c CCDC 1410076
Fig. 2: Ortep diagrams of compounds 6a, 6f, 6i, 7h and 8c
4
R
1
N
N
N
N
N
R
1
OHO
III)
DBSA
in water
DBSA
in water
N
1
O
R
(
(IV)
(II)
Reaction mechanism
-H
2
O
Intramolecular
DBSA
in water
dehydrative
cyclisation
R
N
2
4
1
Based on the above results, a plausible reaction mechanism
HO
N
for this multicomponent reaction is depicted in scheme 2.
Initially hydrazine derivative ( ) reacted with ethyl acetoacetate
) to form pyrazolone derivative ( ) in presence of DBSA in
OH
a
(I)
1
O
(
2
I
O
4a
O
water. Pyrazolone derivative can exist in tautomeric
equilibrium with its enol form (Ia) which being inherently
nucleophilic then undergoes Knoevenagel condensation with
N H
N
DBSA
in water
-H O
2
DBSA
in water
O
O
III)
O
O
R
1
(
3
(
V)
the cyclic ketone (3) (activated by getting proton from DBSA)
to form the intermediate II. The intermediate II is an α,β-
unsaturated ketone and further activation of it by proton causes
a rapid reaction between II and the tautomeric form of the
cyclic 1,3-dicarbonyls 4a and results the formation of the
intermediate III which then undergoes dehydrative cyclization
facilitated by DBSA to generate the desired spiropyran product
Scheme 2. A plausible reaction mechanism for the formation of tricyclic spiropyran
compounds
NH
NH
O
O
OOH
(
IV). If initially 4a undergoes Knoevenagel condensation with
then the intermediate should be formed that should undergo
Michael addition reaction with Ia to form III III then follows
the dehydrative cyclization pathway in order to generate the
product IV
We have tried to isolate intermediate II from the two-
component reaction between pyrazolone ( ) and isatin in
presence of DBSA in water, and found that bis-pyrazolone (Fig.
3
V
N
N
HN
NH
.
O
O
b
O
OH
a
.
Fig. 3:(a) bis-pyrazolone (b) tetraketone
I
3a) was formed. We also attempted a reaction between
4
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Journal Name
ARTICLE
a
Table 2 Substrate scope for the synthesis of tricyclic 4-spiro pyrano[2,3-c]pyrazoles 6, 7 and 8 (reaction time and yields of pure isolated products).
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
O
N
O
N
O
N
O
H
O
2
N
NC
6
a, 3 h, 96%
6b, 7 h, 87%
6c, 9 h, 82%
6d, 8 h, 86%
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
N
O
O
N
O
N
H
O
O
2
N
NC
6
f, 7 h, 88%
6g, 8 h, 83%
6h, 8 h, 87%
6
e, 3 h, 95%
NH
NH
Br
O
O
Br
O
O
O
O
O
O
O
O
N
N
N
N
N
O
N
H
N
O
O
N
O
H
O
2
N
7
b, 7 h, 86%
6
i, 3 h, 94%
6
j, 9 h, 78%
7a, 3 h, 93%
NH
NH
O
NH
NH
Br
O
O
O
Br
Br
Br
O
O
O
O
N
N
N
N
N
O
N
N
N
O
O
O
H
O
2
N
O N
7f, 9 h, 78%
2
7
d, 3 h, 94%
7
e, 7 h, 84%
7
c, 8 h, 80%
NH
NH
NH
NH
O
O
O
O
O
O
O
O
N
N
N
N
N
O
N
N
O
N
O
O
H
H
O
2
N
7
h, 7 h, 88%
7
g, 3 h, 94%
7i, 8 h, 82%
7j, 3 h, 92%
NH
O
NH
O
O
O
O
O
O
O
N
N
N
N
O
O
N
N
N
O
N
H
O
H
O
2
N
7
k, 8 h, 86%
8
a, 5 h, 78%
8b, 5 h, 75%
7
l, 9 h, 79%
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DOI: 10.1039/C5NJ01728A
O
O
N
N
O
H
8
c, 6 h, 76%
a
Reaction conditions: ethyl acetoacetate (1 mmol), hydrazines (1 mmol), cyclic ketones (1 mmol) and cyclic 1,3-diketones (1 mmol) were reacted in
o
presence of 10 mol% DBSA and 3 ml of water at 90 C.
Acknowledgment
We gratefully acknowledge the financial support from U.G.C.
and University of Calcutta. P. M. thanks U.G.C, New Delhi,
India for the grant of his Junior Research fellowship.
Crystallography was performed at the DST-FIST, India-funded
Single Crystal Diffractometer Facility at the Department of
Chemistry, University of Calcutta.
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Fig. 4: Optical micrograph of the reaction mixture
Conclusion
In summary, dodecylbenzenesulphonic acid has been
successfully used in the present study as an efficient Brønsted-
acid surfactant combined catalyst for the synthesis of a series of
tricyclic 4-spiro pyrano[2,3-c]pyrazole through one pot three-
component reaction employing pyrazolone derivatives, cyclic
ketones and cyclic 1,3-dicarbonyls in an aqueous medium at
ambient temperature. This synthetic methodology is found to be
mild, operationally simple, economical and environmentally
benign and affords the target products in good yields.
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New Journal of Chemistry
Page 8 of 8
View Article Online
DOI: 10.1039/C5NJ01728A
An eco-friendly multicomponent strategy has been developed to access a single tricyclic molecular
scaffold possessing pyran, pyrazole and spiro functionalities.