Solvent-free multicomponent synthesis of pyranopyrazoles: per-6-amino-β-cyclodextrin as a remarkable catalyst and host

Article abstract of DOI:10.1016/j.tetlet.2010.04.087

A simple, green and efficient protocol is developed with per-6-amino-β-cyclodextrin (per-6-ABCD) which acts simultaneously as a supramolecular host and as an efficient solid base catalyst for the solvent-free syntheses of various dihydropyrano[2,3-c]pyrazole derivatives involving a four-component reaction. This atom-economical protocol, reported for the first time with ketones also, includes a much milder procedure, does not involve any tedious work-up or purification, avoids hazardous reagents/byproducts and results in near quantitative yields. The catalyst can be reused at least six times without any change in its catalytic activity.

Full text of DOI:10.1016/j.tetlet.2010.04.087

Tetrahedron Letters 51 (2010) 3312–3316
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent-free multicomponent synthesis of pyranopyrazoles:
per-6-amino-b-cyclodextrin as a remarkable catalyst and host
*
Kuppusamy Kanagaraj, Kasi Pitchumani
School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, green and efficient protocol is developed with per-6-amino-b-cyclodextrin (per-6-ABCD) which
acts simultaneously as a supramolecular host and as an efficient solid base catalyst for the solvent-free
syntheses of various dihydropyrano[2,3-c]pyrazole derivatives involving a four-component reaction. This
atom-economical protocol, reported for the first time with ketones also, includes a much milder proce-
dure, does not involve any tedious work-up or purification, avoids hazardous reagents/byproducts and
results in near quantitative yields. The catalyst can be reused at least six times without any change in
its catalytic activity.
Received 5 March 2010
Revised 12 April 2010
Accepted 20 April 2010
Available online 24 April 2010
Keywords:
Per-6-ABCD catalysis
Multicomponent reaction
Pyranopyrazole
Ó 2010 Elsevier Ltd. All rights reserved.
Solvent-free conditions
1. Introduction
During the last few years, synthesis of dihydropyrano[2,3-c]
pyrazoles has received great interest.15–27 Otto16 has used a reaction
Organic syntheses oriented towards ‘Green Chemistry’ evoke
increasing interest in recent years1 resulting in new environmen-
tally benign procedures such as solvent-free syntheses, multicom-
ponent reactions and reusable heterogeneous catalysts to save
resources and energy. These organic reactions possess advantages
over traditional reactions in organic solvents. For example, sol-
vent-free, multicomponent reactions with reusable heterogeneous
catalysts reduce the consumption of environmentally unfriendly
solvents and utilize scaled-down reaction vessels. Recently, several
techniques for the efficient use of solvent-free reactions,2 reusable
heterogeneous catalyzed reactions3 and multicomponent reac-
tions3a,4 have been developed individually but when these three
wings of green chemistry can be combined, an excellent green
chemistry protocol is expected.5
sequence involving base-catalyzed cyclization of 4-aryliden-5-pyr-
azolone. Pyranopyrazole is also synthesized from the reaction be-
tween
3-methyl-1-phenylpyrazolin-5-one
and
tetracyano
ethylene.13 In addition, weak bases can also be used for this Mi-
chael-type cyclization.17,18 A three-component condensation19 be-
tween N-methylpiperidone, pyrazolin-5-one and malononitrile in
absolute ethanol and a two-component reaction20 involving pyran
derivatives and hydrazine hydrate to obtain pyranopyrazoles are
also reported. Other recent methods for the synthesis of 1,4-dihy-
dropyrano[2,3-c]pyrazoles include synthesis in aqueous media,21,22
use of piperidine as a base in water,23 N-methylmorpholine in
ethanol,24 microwave irradiation25 and also solvent-free condi-
tions.26,27a,b Herein, we report a facile, general and efficient method
to prepare 1,4-dihydropyrano[2,3-c]pyrazoles.
One of the main challenges in medicinal chemistry is the design
and synthesis of biologically active molecules.6 Dihydropyr-
ano[2,3-c]pyrazoles play an essential role as biologically active com-
pounds and represent an interesting template for medicinal
chemistry. Many of these compounds are known for their antimicro-
bial,7 insecticidal8 and anti-inflammatory activities.9 Furthermore
dihydropyrano[2,3-c]pyrazoles show molluscicidal activity10,11
and are identified as a screening kit for Chk1 kinase inhibitor.12 They
also find applications as pharmaceutical ingredients and biodegrad-
able agrochemicals.13–15
Cyclodextrins (CDs), obtained from enzymatic degradation of
starch are cyclic oligosaccharides which catalyze a wide range of
chemical and photochemical reactions through the formation of a
reversible host–guest complex via non-covalent interactions.28,29
Modification of CDs improves their properties and enhances their
capability for complexation with guest molecules resulting in sig-
nificant increase in their applications in catalysis.30 Amino-CDs
are homogeneous CD derivatives modified by persubstitution at
the primary face with amino pendant groups and this manifests
combined hydrophobic and electrostatic binding of guest mole-
cules relative to native CDs. They are also employed as biomimetic
catalysts in Kemp elimination,30a deprotonation30b and chiral rec-
ognition processes.30c In our group, per-6-amino-b-cyclodextrin
(per-6-ABCD) is used extensively as a supramolecular chiral host
* Corresponding author. Tel.: +91 452 2456614; fax: +91 452 2459181.
E-mail addresses: pit12399@yahoo.com, profpitlab@yahoo.co.in (K. Pitchumani).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.087

K. Kanagaraj, K. Pitchumani / Tetrahedron Letters 51 (2010) 3312–3316
3313
Table 1
Table 3
Optimization of reaction conditionsa for the synthesis of pyranopyrazole from 4-
nitrobenzaldehyde
Synthesis of pyranopyrazoles33 with various substituted ketonesa
R
O
R
O
R
R'
N
R
R'
O
per-6-ABCD
Mixing, RT
6
C
N
NH2
H
O
CN
Conditions
+
C
H2N
+
NH2
3
NH
CN
+
H2N
+
1
4
O
O
1
NH
N
CN
O
NH2
2
4
O
O
N
CN
O
NH2
7
2
R = p-NO2-C6H4-
Entry
Ketone
Yield (%)
R0
Entry
Catalyst
Medium
Time (h)
Yield (%)
R
1
2
3
4
5
6
7
8
9
b-CD
Water
—
—
—
—
DMF
DMSO
—
—
—
24
10
10
10
10
24
24
1 min
1 min
1 min
1 min
Nil
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
C6H5–
C6H5–
p-Br–C6H4–
p-Cl–C6H4–
o-Cl–C6H4–
p-NH2–C6H4–
o-NH2–C6H4–
p-OH–C6H4–
o-OH–C6H4–
p-OCH3–C6H4–
p-CH3–C6H4–
20-Naphthyl–
10-Naphthyl–
5-Bromothiophene–
5-Chlorothiophene–
1-Piperazine–
2-Pyrrole–
4-Pyridine–
C6H5–
CH3–
CH3–CH2–CH2–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
CH3–
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–
C6H5–CH@CH–
C6H5–CH@CH–
(OCH3)2CH–CH2–
>99
99
Triethylamine
Diethylamine
Methylamineb
Piperidine
Per-6-ABCD
Per-6-ABCD
Per-6-ABCD
Per-6-ABCD
Per-6-ABCD
Mono-6-ABCD
40.5
56.2
61.2
68.1
58.2
61.6
>99
>99
>99
>99
>99
>99
>99
99
>99
99
>99
99
>99
>99
98
>99
>99
99
>99
>99
>99
99
>99c
98.0d
51.0
10
11
—
a
Reactions were performed on a 1 mmol scale of all reactants in solvent-free
conditions at room temperature.
b
40% solution of methylamine in water.
0.008 mmol per-6-ABCD as catalyst.
0.0001 mmol per-6-ABCD as catalyst.
c
d
and as a base catalyst for Cu-catalyzed N-arylation31 and for Mi-
chael addition of nitromethane to chalcones.32 In the present work,
we have utilized per-6-ABCD as an excellent supramolecular host
for the synthesis of pyranopyrazole derivatives,33 in an efficient
and ecofriendly four-component reaction protocol under solvent-
free conditions at room temperature. It is also interesting to note
that the catalyst can be recovered and reused several times.
p-Cl–C6H4–
p-NH2–C6H4–
o-NH2–C6H4–
p-OCH3–C6H4–
p-CH3–C6H4–
p-Br–C6H4–
98
96
94
62
p-OCH3–C6H4–
CH3–
a
Reactions were performed on a 1 mmol scale of all reactants with 0.008 mmol
per-6-ABCD in solvent-free conditions for 1 min at room temperature.
2. Results and discussion
Hydrazine hydrate, ethyl acetoacetate, 4-nitrobenzaldehyde
and malononitrile are taken as model substrates to optimize reac-
tion conditions and the results are discussed in Table 1. When b-CD
is used as a catalyst in aqueous medium, at room temperature,
there is no reaction (entry 1). The reaction is also studied using
conventional bases such as triethylamine (entry 2), diethylamine
(entry 3), methylamine (entry 4) and piperidine (entry 5) as a cat-
alyst in solvent-free conditions (entries 2–5). In all cases the yield
of the product is limited and also its separation from the reaction
mixture is difficult. When per-6-ABCD is used as a catalyst for this
reaction in DMF and DMSO, similar yields are obtained (entries 6
and 7). However, to our surprise, when the catalyst is mixed with
the reactants under solvent-free conditions, 100% yield is obtained
(entry 8) within one minute. Even with catalytic amount of per-6-
ABCD (0.008 mmol), successive addition of hydrazine hydrate,
ethyl acetoacetate, aldehyde/ketone and malononitrile has re-
Table 2
Synthesis of pyranopyrazoles33 with various substituted aldehydesa
R
O
R
N
H
O
per-6-ABCD
Mixing, RT
C
3
NH2
CN
+
H2N
+
NH
1
O
O
4
N
CN
O
NH2
2
6
Entry
R in aldehyde
Yield (%)
Entry
R in aldehyde
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5–
>99
>99
>99
>99
>99
99
14
15
16
17
18
19
20
21
22
23
24
25
26
p-OCH3–C6H4–
m-OCH3–C6H4–
p-CH3–C6H4–
p-i-Pr-C6H4–
C6H5–CH@CH–
CH3–CH@CH–
m-CH3–C6H4–
20-Furanyl–
20-Thiophenyl–
40-Pyridinyl–
Cyclohexyl–
CH3–
99
1-Pyrenyl–
p-NO2–C6H4–
m-NO2–C6H4–
p-Cl–C6H4–
m-Cl–C6H4–
o-Cl–C6H4–
m, p-Cl2–C6H3–
p-F–C6H4–
p-Br–C6H4–
>99
>99
>99
98
97
99
>99
>99
>99
>99
60
Table 4
Reusability of per-6-ABCD as a catalyst in the synthesis of pyranopyrazoles from p-
NO2–C6H5–CHOa
99
Runb
First
100
Second
100
Third
100
Fourth
99.9
Fifth
99.8
Sixth
99.7
>99
>99
>99
>99
99
Yield (%)
a
Reactions were performed on a 1 mmol scale of all reactants in solvent-free
p-OH–C6H4–
o-OH–C6H4–
p-NMe2–C6H4–
conditions for 1 min at room temperature.
b
After completion of the reaction, 1 ml of ethanol was added to the reaction
>99
H–
Trace
mixture and the precipitated per-6-ABCD was removed by filtration, washed with
distilled ethanol (1 ml) for three times, dried in vacuum and reused. The products
were obtained by evaporating the combined ethanol portions.
a
Reactions were performed on a 1 mmol scale of all reactants with 0.008 mmol
per-6-ABCD in solvent-free conditions for 1 min at room temperature.

3314
K. Kanagaraj, K. Pitchumani / Tetrahedron Letters 51 (2010) 3312–3316
sulted in quantitative yield of pyranopyrazoles under solvent-free
conditions (entry 9). Even here the reaction is very fast and gets
completed within 1 min. The result is similar even with
0.0001 mmol of catalyst (entry 10). The product is obtained not
only in excellent yield (100%) but also in excellent purity. Atom
economy is also very good in this reaction with only ethanol as
the side product. As the product is pure, there is no need for further
purification. When mono-6-amino-b-CD, prepared as per reported
procedure,35 is used as the catalyst, the reaction proceeds with
reduced yield and this highlights a more significant role for per-
6-ABCD catalyst. This study thus demonstrates the efficiency of
per-6-ABCD as an excellent supramolecular host as well as a reus-
able base catalyst with high turnover number.
This easy and clean protocol for the synthesis of functionalized
pyranopyrazoles is extended to various substituted aldehydes and
ketones and the observed results are presented in Tables 2 and 3.
The catalyst is also found to be reusable (Table 4). After completion
of the reaction, per-6-ABCD is filtered, washed with ethanol for
N
C
CN
HN
+
N
O
NH2
CN
O
H
Cage
Escape
1
Tautomerization
NH2
H2N
NH2 H2N
H
CN
CN
CN
N
H
H
O
N
O
H
NH
H
N
NH2
NH2
H3
H2N
N
NH3
N
H2
H2
Knoevenagel
Condensation
2
Cyclization
5
CN
CN
C
N
N
C
O
H
HO
H
N
N
H
H
H
NH2
N
N
N
H2
N
H2
H2
N
H2
NH3
H2
Dehydration
3
4
CN
Michael Addition
H2N
NH2
N
+
C
HN
Ethyl Acetoacetate
N
O
H
H
N
NH2
N
N
H2
H2
H3
N
HN
CN
O
CN
Ylidenemalononitrile (I)
Pyrazolone (II)
Scheme 1. Proposed mechanism for per-6-ABCD-catalyzed synthesis of pyranopyrazoles.

K. Kanagaraj, K. Pitchumani / Tetrahedron Letters 51 (2010) 3312–3316
3315
Table 5
three times, dried in vacuum and reused. Upto six runs, there is no
Control experimentsa in the synthesis of pyranopyrazoles from p-NO2–C6H5–CHO
change in the catalytic efficiency.
Perusal of literature23 shows that a tandem sequence of base-
catalyzed reactions is proposed to account for the formation of pyr-
anopyrazoles. The first step involves formation of pyrazolone by
the reaction between hydrazine and ethyl acetoacetate. In the sec-
ond step, ylidenemalononitrile is formed by Knoevenagel conden-
sation between malononitrile and aldehyde. In the third step,
Michael addition of pyrazolone to ylidenemalononitrile takes place
followed by cyclization and tautomerization to give the
pyranopyrazoles.
To account for the very efficient catalysis by per-6-ABCD, of this
tandem reaction, wherein base-catalyzed reactions are involved, it
is proposed that per-6-ABCD with its seven free primary amino
groups acting synergistically behaves as an efficient supramolecu-
lar host and base catalyst (Scheme 1). In the first step, the alde-
hyde/ketone binds to the CD cavity. Abstraction of a proton from
malononitrile by per-6-ABCD catalyzes its Knoevenagel condensa-
tion with the carbonyl group to give the ylidenemalononitrile (I).
The cooperative enzyme-like binding of these intermediates
which ensure their tighter fit into the cavity facilitates further reac-
tions, namely Michael addition of pyrazolone (II) to ylidenemalon-
onitrile (by abstraction of a proton from pyrazolone), cyclization
and tautomerization. It is also likely that the formation of ylidene-
malononitrile (I) and pyrazolone (II) may take place outside the
per-6-ABCD cavity and then they can go into the cyclodextrin cav-
ity. The proposed mechanism is also supported by observations of
peaks in UV corresponding to intermediates ylidenemalononitrile
(I) and pyrazolone (II) when the reaction is carried out in DMF
(see Supplementary data, Fig. S1). Binding constants for intermedi-
ates I, II and the product are also evaluated and found to be 1283,
1310 and 984 Mꢀ1, respectively. Hydrogen bonding interaction
with the secondary hydroxyl groups of per-6-ABCD (Scheme 1)
may also contribute to the faster reactivity.
Entry
Catalyst
Medium
Time
(h)
Yield
(%)
1
2
3
4
5
6
7
8
9
Ethylenediamine (1:4)b
Water
—
Water
—
DMF
—
DMF
—
DMF
—
DMF
—
24
24
24
24
24
24
24
24
24
24
24
24
Nil
Nil
Nil
Nil
2.6
—
—
—
5
—
Ethylenediamine (1:4)b
Ethylenediamine + b-CD (1:4)b
Ethylenediamine + b-CD (1:4)b
Per-6-ABCD + adamantanec (1:1)b
Per-6-ABCD + adamantanec (1:1)b
Per-6-ABCD + adamantanolc (1:1)b
Per-6-ABCD + adamantanolc (1:1)b
Mono-6-ABCD + adamantanec (1:1)b
Mono-6-ABCD + adamantanec (1:1)b
Mono-6-ABCD + adamantanolc (1:1)b
Mono-6-ABCD + adamantanolc (1:1)b
10
11
12
6
—
a
Reactions are performed on a 1 mmol scale of all reactants with per-6-ABCD in
solvent/solvent-free conditions at room temperature.
b
Ratio of substrate:catalyst.
1:1 complex formed by freeze-drying method.
c
Table 6
Free energy changes in the reactants, intermediates formed during the reaction and
the product (both without and inside per-6-ABCD cavity)a
Steps in Scheme 1
D
E (kcal/mol)
Inside CD cavityb
Without CD
1
2
3
4
24.3431
42.7437
68.8782
47.6696
57.5345
55.2510
296.4201
ꢀ24.5743
ꢀ25.0356
ꢀ85.4123
ꢀ80.1566
ꢀ38.3200
ꢀ32.2009
ꢀ285.6997
5
Final product
Total
DE
a
Error limit 0.0001 kcal/mol.
b
D
E can be calculated from
D
EComplex
ꢀ
D
EHost
ꢀ
DEGuest.
To ensure that the reaction involves inclusion of all the reac-
tants inside the CD cavity which looks essential for the catalytic
activity of per-6-ABCD (the enzyme-like cooperative binding of
all reactants and their closer proximity to the catalytic amino
groups which are suitably oriented and are acting synergistically
thus ensuring faster reactivity), the following control experiments
are carried out (Table 5). With ethylenediamine (4 equiv, com-
pared to 4-nitrobenzaldehyde) as the base catalyst, the reactants
are stirred for 24 h in water in the absence of b-CD (entry 1). The
experiment is also carried out in solid phase (entry 2). The
above-described experiment is repeated with equimolar amount
of b-CD, both in solution and in solid phase (entries 3 and 4). In
all the cases, the bisimine of 4-nitrobenzaldehyde with ethylenedi-
amine is obtained as the only product.
Per-6-ABCD is treated with equimolar amount of adamantane,
which forms an inclusion complex (binding constant for adaman-
tane/per-6-ABCD inclusion complex is found to be 1824 Mꢀ1 in
the present study). Then the reaction is carried out with this ada-
mantane included per-6-ABCD, in DMF at 24 h (entry 5) and also
in solvent-free conditions (entry 6). Control experiments (entries
7 and 8) are also carried out with adamantanol included per-6-
ABCD (binding constant 2248 Mꢀ1) and also with adamantane/ada-
mantanol included mono-6-ABCD (entries 9–12). Absence of any
reaction in all the cases confirms that inclusion into per-6-ABCD
cavity is essential for catalytic activity.
The proposed mechanism (Scheme 1) also finds strong support
from energy minimization studies. Molecular modelling and
energy minimization calculations are performed using Insight II/
Discover program in IRIX system. First, the energy change of the
reactants and intermediates in the absence and presence of
per-6-ABCD is calculated. The energy minimization studies are car-
ried out using different mode of inclusion of substrates in per-6-
ABCD cavity (see Supplementary data, Figs. S2–S7).
The data, given in Table 6, indicate that when the reaction takes
place without per-6-ABCD, the
(1–5) proposed in Scheme 1. The
D
D
E increases for the various steps
E for the overall heat of product
formation is 296.4201 kcal/mol. On the other hand, when the reac-
tion takes place inside the per-6-ABCD cavity, very significant de-
crease in
E is even more significant for steps 3 and 4 (which involve mul-
ticomponent reactions). After the formation of the final pyranopy-
razole, E increases resulting in expulsion of the same from the
per-6-ABCD cavity and the reaction cycle goes on. The E for the
DE is noticed for steps 1–5 in Scheme 1. This change in
D
D
D
overall heat of product formation is ꢀ285.6997 kcal/mol.
3. Conclusion
To summarize, a simple, faster, clean, green and atom-econom-
ical solvent-free protocol with high turnover is established for the
one-pot synthesis of pyranopyrazoles in excellent yields and purity
(without any tedious work-up or purification). Reaction conditions
are very simple for substituted aldehydes and ketones (reported
extensively for the first time) also react through this tandem reac-
tion. Ethanol is the only product eliminated during the reaction.
Only very small amount of this reusable catalyst is used, which is
Only ꢁ5% to 6% of pyranopyrazole is formed in DMF. In solvent-
free conditions, no product formation is observed. In our view,
these control experiments strongly suggest that inclusion is essen-
tial to promote the reaction. In addition, the enhanced reactivity
observed in the present study is also attributed to the synergistic
effect of all the seven amino groups present in proximity which
ensures enzyme-like reactivity and catalysis.

3316
K. Kanagaraj, K. Pitchumani / Tetrahedron Letters 51 (2010) 3312–3316
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Supplementary data
Supplementary data (complete experimental procedures are
provided, including 1H, 13C and HRMS (ESI) spectra, of all com-
pounds) associated with this article can be found, in the online ver-
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33. General procedure for the synthesis of the pyranopyrazoles.
Hydrazine hydrate (0.1 g, 2 mmol), ethyl acetoacetate (0.26 g, 2 mmol), 4-
nitrobenzaldehyde (0.30 g, 2 mmol) and malononitrile (0.13 g, 2 mmol) were
added successively to per-6-ABCD34 (0.01 g, 0.008 mmol). The reaction mixture
was ground for 1 min at room temperature. After completion of the reaction,
1 ml of distilled ethanol was added to the reaction mixture. The precipitated
per-6-ABCD was removed by filtration, washed with distilled ethanol (1 ml) for
three times, dried in vacuum and reused. The products were obtained by
evaporating the combined ethanol portions. The products were characterized
by 1H, 13C-NMR and mass spectral techniques (see Supplementary data).
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