Synthesis of pyranopyrazoles using isonicotinic acid as a dual and biological organocatalyst

Article abstract of DOI:10.1039/c3ra45289a

In this study, a green, simple and efficient method for the preparation of 6-amino-4-(4-methoxyphenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c] pyrazoles by means of a one-pot four component condensation reaction of aryl aldehydes, ethyl acetoacetate, malononitrile and hydrazine hydrate is reported. The reaction utilizes isonicotinic acid as a dual and biological organocatalyst at 85 °C under solvent-free conditions.

Full text of DOI:10.1039/c3ra45289a

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Synthesis of pyranopyrazoles using isonicotinic acid as a
dual and biological organocatalyst†
Cite this: RSC Adv., 2013, 3, 25681
a
a
b
*
*
Mohammad Ali Zolfigol, Mahsa Tavasoli, Ahmad Reza Moosavi-Zare,
Parvin Moosavi,a Hendrik Gerhardus Kruger,c Morteza Shirid and Vahid Khakyzadeha
Received 22nd September 2013
Accepted 15th October 2013
DOI: 10.1039/c3ra45289a
www.rsc.org/advances
In this study, a green, simple and efficient method for the prepara- particularly from a green chemistry point of view.12 Unlike
tion of 6-amino-4-(4-methoxyphenyl)-5-cyano-3-methyl-1-phenyl- conventional catalysis, these organocatalysts are advantageous
1,4-dihydropyrano[2,3-c]pyrazoles by means of
a one-pot four in many ways such as high stability, availability of the catalyst,
component condensation reaction of aryl aldehydes, ethyl acetoa- metal free nature, reduced toxicity, simple reaction conditions
cetate, malononitrile and hydrazine hydrate is reported. The reaction and it can promote a chemical reaction through different acti-
utilizes isonicotinic acid as a dual and biological organocatalyst at vation modes.13
85 ꢀC under solvent-free conditions.
Solvent-free reactions were demonstrated to be an efficient
technique for various organic transformations instead of using
harmful organic solvents. Solvent-free conditions oen lead to a
remarkable decrease in reaction times, increased yields and
easier workup; it also satises green chemistry protocols, and
may enhance the regioselectivity and stereoselectivity of
reactions.14–18
Some catalysts have been used to promote this reaction such
as imidazole,8 g-alumina and KF alumina,9b silicotungstic
acid,9c L-proline,9d MgO.9e However, some of them suffer from
the drawbacks. Therefore, it is highly desirable to develop effi-
cient and cost-effective catalysts and methods for the synthesis
of these valuable compounds.
In this research, we report our results on the efficient and
solvent-free synthesis of 6-amino-4-(4-methoxyphenyl)-5-cyano-
3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles via the
one-pot four component condensation of aryl aldehydes, ethyl
acetoacetate, malononitrile and hydrazine hydrate using iso-
nicotinic acid as a dual and biological organocatalyst under
solvent-free (SF) condition (Scheme 1).
Pyranopyrazoles are fused heterocyclic compounds, which are
important because of their biological properties such as fungi-
cidal,1 bactericidal,2 vasodilatory activities3 and they act as
anticancer agents.4 They also nd application as pharmaceu-
tical ingredients and biodegradable agrochemicals.5 Moreover,
pyrano[2,3-c]pyrazoles also act as potential insecticidal6 and
molluscicidal agents.7,8 Consequently, considerable attention
has been paid to the development of new procedures for the
preparation of these compounds.8
Multi-component reactions (MCRs) play an important role in
combinatorial chemistry because of the ability to synthesize
target compounds with greater efficiency and atom economy by
generating structural complexity in a single step from three or
more reactants. Moreover, MCRs offer the advantage of
simplicity and synthetic efficiency over conventional chemical
reactions.9–11
Development of organocatalytic processes in which the
reactions are catalyzed by organic molecules has become an
area of tremendous importance in current organic synthesis
aFaculty of Chemistry, Bu-Ali Sina University, Hamedan, 6517838683, Iran. E-mail:
mzolgol@yahoo.com
bDepartment of Chemistry, University of Sayyed Jamaleddin Asadabadi, Asadabad,
6541835583, Iran. E-mail: moosavizare@yahoo.com; Fax: +98 8118257407
cCatalysis and Peptide Research Unit, School of Health Science, University of KwaZulu-
Natal, Durban 4001, South Africa
dDepartment of Chemistry, College of Science, Alzahra University, Vanak 1993893973,
Tehran, Iran
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra45289a
Scheme
1
The preparation of pyranopyrazoles using isonicotinic acid as
catalyst.
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Table 1 Effect of different amounts of the catalyst and temperature on the
reaction of hydrazine hydrate (2.2 mmol) ethyl acetoacetate (2 mmol), malono-
nitrile (2 mmol) and benzaldehyde (2 mmol) in the absence of solvent
In order to optimize the reaction conditions, we chose the
model reaction of hydrazine hydrate (2.2 mmol) ethyl acetoa-
cetate (2 mmol), malononitrile (2 mmol) and benzaldehyde
(2 mmol). This reaction was studied in the presence of different
amounts of isonicotinic acid at temperatures ranging between
60 and 120 ꢀC under solvent-free conditions (Table 1). The
reaction was most efficient with 10 mol% of the catalyst at
85 ꢀC, and it gave the desired product in high yield within a
short reaction time (Table 1, entry 2). The reaction was also
examined at 85 ꢀC without catalyst under solvent-free condi-
tions in which the reaction did not proceed signicantly even
aer long reaction times (Table 1, entry 5).
Also the model reaction was tested in the presence of
10 mol% of picolinic acid in comparison with isonicotinic acid.
The corresponded product was obtained with 90% of yield in
20 minutes at 85 ꢀC. Although, aer 10 minutes of the reaction
time; the yield was 81%. This observation indicated that iso-
nicotinic acid was more successful than picolinic acid as cata-
lyst in this reaction. It should be noted that the products of this
reaction are isolated as a racemic mixture.
Mol%
of catalyst
Entry
Temp. [ꢀC]
Time [min]
Yielda [%]
1
2
3
4
5
6
7
8
9
10
10
10
10
—
1
5
10
15
60
85
100
120
85
85
85
85
85
25
10
10
10
90
30
30
10
10
75
90
90
90
30
25
65
90
90
a
Isolated yield.
Table 2 The reaction of hydrazine hydrate (2.2 mmol) ethyl acetoacetate
(2 mmol), malononitrile (2 mmol) and benzaldehyde (2 mmol) using isonicotinic
acid in different solvents
In the next step, the model reaction, was examined in several
solvents using 10 mol% of isonicotinic acid under reux
conditions. The results are depicted in Table 2. It is clear that
the addition of solvent was not efficient, and afforded the
product in low yields. Increasing the reaction times did not
improve the yields.
Entry
Solvent
Time (min)
Yielda (%)
1
2
3
4
5
EtOH
30
30
30
30
30
70
50
45
60
60
CH3CN
CHCl3
CH2Cl2
Acetone
Aer optimization of the reaction conditions, we wanted to
explore the efficacy of isonicotinic acid in the synthesis of a
a
Isolated yield.
Table 3 Preparation of pyranopyrazoles using isonicotinic acid as catalyst at 85 ꢀC (ref. 23)a
a
Isolated yield was reported for all of compounds. b The product was produced by the reaction of hydrazine hydrate (4.4 mmol) ethyl acetoacetate
(4 mmol), malononitrile (4 mmol) and terephthaldehyde (2 mmol) in the absence of solvent. c In this temperature the product was decomposed.
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Scheme 3 Another mechanism for the synthesis of 6-amino-4-(4-methoxy-
phenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles.
dihydropyrano[2,3-c]pyrazole-5-carbonitrile) (15) in 74% yield
within 60 min (Table 3, entry 14). Thus, the catalyst was general
and highly efficient.
In a plausible mechanism, initially, ethyl acetoacetate is
activated by isonicotinic acid and hydrazine attacks to the
carbonyl group of the activated ethyl acetoacetate. Then, loss of
H2O, and intramolecular nucleophilic attack by another NH2
group of hydrazine to the next carbonyl group of ethyl acetoace-
tate affords 5-methyl-2,4-dihydro-pyrazol-3-one (intermediate I)
and removesEtOH. In the next step, the aromatic aldehyde which
is activated by isonicotinic acid and malononitrile aer rear-
Scheme 2 Plausiblemechanism for the synthesis of 6-amino-4-(4-methoxy-
phenyl)-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles.
series of 6-amino-4-(4-methoxyphenyl)-5-cyano-3-methyl-1- rangement in II form, attacks to the carbonyl group of the acti-
phenyl-1,4-dihydropyrano[2,3-c]pyrazoles. This was achieved by vated aldehyde, removes H2O and affords intermediate III.
using aliphatic aldehydes, various aromatic aldehydes Finally, addition of I to III in the presence of isonicotinic acid
(including aldehydes with electron-releasing substituents, follows by intramolecular nucleophilic attack, can give the
electron withdrawing substituents and halogens on the expected pyranopyrazole as shown in Scheme 2.
aromatic ring) as well as hetero aromatic aldehydes in the
In this reaction condition, another mechanism can be dis-
reaction with hydrazine hydrate or phenyl hydrazine, ethyl cussed. Due to use of isonicotinic acid as a dual catalyst, it is
acetoacetate and malononitrile to give the corresponding plausible that ethyl acetoacetate or malononitrile abstracted one
products in high yields and in short reaction times. The results acidic hydrogen in the presence of catalyst and attacks to aryl
are summarized in Table 3. These results indicate that the aldehyde. Then the presented product was reacted to other
corresponding products were produced in high yields and short substrates to give the main products (Scheme 3). For this
reaction times.
purpose, we studied the reaction of two different substrates at 85
In another investigation, the condensation of tereph- ꢀC using isonicotinic acid in a separate test in comparison with
thaldehyde, malononitrile, ethyl acetoacetate and (4-nitro- other substrates. Aer that the reaction was completed, we
phenyl)hydrazine hydrate using isonicotinic acid was studied. investigated the reaction of two other substrates with the rst
Interestingly, the condensation of hydrazine hydrate (4.4 mmol) test. The results are summarized in Table 4. Although in all of
ethyl acetoacetate (4 mmol), malononitrile (4 mmol) and tests, the main product was produced, but the reaction between
ꢀ
terephthaldehyde (2 mmol) at 85 C under solvent-free condit- hydrazine hydrate and ethyl acetoacetate is faster than others. In
ions, afforded 4,40-(1,4-phenylene)bis(6-amino-3-methyl-2,4- other hands, the reaction time of the product is near to entry 1.
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Table 4 The study on the reaction between two different substrates to give product
Entry
1
Paths of reactions
2
3
Table 5 The reaction of hydrazine hydrate (2.2 mmol) ethyl acetoacetate
(2 mmol), malononitrile (2 mmol) and benzaldehyde (2 mmol) in the presence of
reused isonicotinic acid (10 mol%) as catalyst at 85 ꢀC under solvent-free
conditions
This work was supported by the Research Affairs Office of Bu-
Ali Sina University (Grant number 32-1716 entitled development
of chemical methods, reagents and molecules), and Center of
Excellence in Development of Chemical Method (CEDCM),
Hamedan, I. R. Iran.
Entry
Cycle
Time [min]
Yielda [%]
1
2
3
4
1st run
10
12
16
17
90
85
81
79
2
st run
3st run
4st run
Notes and references
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Isolated yield.
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Then the rst mechanism (Scheme 2) is more acceptable than
the second mechanism (Scheme 3).
In another study, recyclability of the catalyst was examined
upon the condensation of hydrazine hydrate (2.2 mmol) ethyl
acetoacetate (2 mmol), malononitrile (2 mmol) and benzalde-
hyde (2 mmol). Aer completion the reaction, the catalyst was
extracted by water and separated from the reaction mixture.
Water was removed and the recovered catalyst used for another
reaction. We observed that the catalytic activity of the catalyst
was restored within the limits of the experimental errors for
four successive runs (Table 5).
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Conclusions
In summary, we have reported the synthesis of 6-amino-4-(4-
methoxyphenyl)-5-cyano-3-methyl-1-phenyl-1,4- dihydropyr-
ano[2,3-c]pyrazoles using isonicotinic acid as a dual, bio-
logical and reusable organocatalyst in a green media. The
promising points for the presented methodology are effi-
ciency, generality, high yield, relatively short reaction time,
low cost, cleaner reaction prole, ease of product isolation,
simplicity, and nally compliance with the green chemistry
protocols.
25684 | RSC Adv., 2013, 3, 25681–25685
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2
(2.5 mmol) and isonicotinic acid (0.2 mmol) (0.0246 g,
10 mol%) was added to a test tube, and stirred at 85 C.
ꢀ
Aer the completion of the reaction, as monitored by
TLC, the reaction mixture was cooled to room
temperature. Water was added to the reaction mixture to
dissolve the catalyst and the aqueous layer was separated
from the reaction mixture. Water was removed and the
recovered catalyst was reused for up to four times
without any signicant changes in the yield and the
reaction time. Aerward the solid residue (crude
product) was triturated by a mixture of ethanol and water
(9/1) to give the pure product.
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Bull. Korean Chem. Soc., 2011, 32, 3963.
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