One-pot and efficient synthesis of 5-aminopyrazole-4-carbonitriles catalyzed by potassium phthalimide

Article abstract of DOI:10.3987/COM-16-13623

The potassium phthalimide (PPI) has been found to be an efficient, recyclable, inexpensive, commercially available, and easy to handle catalyst for the synthesis of 5-aminopyrazole-4-carbonitriles through the one-pot, three-component reaction of easily av

Full text of DOI:10.3987/COM-16-13623

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HETEROCYCLES, Vol. 94, No. 2, 2017
HETEROCYCLES, Vol. 94, No. 2, 2017, pp. 276 - 285. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 18th November, 2016, Accepted, 16th January, 2017, Published online, 27th January, 2017
DOI: 10.3987/COM-16-13623
ONE-POT
AND
EFFICIENT
SYNTHESIS
OF
BY
5-AMINOPYRAZOLE-4-CARBONITRILES
POTASSIUM PHTHALIMIDE
CATALYZED
Hamzeh Kiyani* and Maryam Bamdad
School of Chemistry, Damghan University, 36719-41167 Damghan, Iran; E-mail:
hkiyani@du.ac.ir
Abstract – The potassium phthalimide (PPI) has been found to be an efficient,
recyclable, inexpensive, commercially available, and easy to handle catalyst for the
synthesis of 5-aminopyrazole-4-carbonitriles through the one-pot, three-component
reaction of easily available starting reactants involving aldehydes, phenylhydrazine,
and malononitrile. This reaction was performed in a mixture of EtOH:H2O as a
green reaction media at 50 °C. The catalyst could be recovered easily from the
filtrate via evaporation of solvent and reused many times. The present eco-friendly
three-component cyclocondensation offers main benefits including, time-saving,
mild conditions, minimize the amount of waste, high atom efficiency, avoiding the
hazardous organic solvents or catalysts, and the ease of the work-up.
INTRODUCTION
Pyrazole and their derivatives are a class of nitrogen containing heterocyclic compounds that have much
more attention owing to their a broad spectrum of biological properties such as anticancer, antimicrobial,
anti-inflammatory, analgesic, neuroprotective, cytotoxic, antihypertensive, antiviral, anti-obesity,
antibacterial, antimycobacterial, antitubercular, antifungal, anticonvulsant, cardiovascular, antiglaucoma,
antihyperglycemic, antiparkinson, antioxidant, herbicidal, antipyretic, insecticide, fungicide, and protein
kinase inhibitor activities1 and have been used in the fields of pharmaceuticals and agrochemicals.
Polysubstituted pyrazoles have been employed as cosmetic colorings, UV stabilizers, ligands in
coordination chemistry, optical brighteners, photoinduced electron transfer systems, and in some
transition-metal cross-coupling reactions.2 They have also been used as an important building blocks and

HETEROCYCLES, Vol. 94, No. 2, 2017
277
structural motifs in the synthesis of natural products, biologically active molecules, and some heterocyclic
compounds.3 Furthermore, several reports showed that pyrazole-containing compounds had antimalarial
and antileishmanial activity.4 Aminopyrazoles, on the other hand, are increasingly being exploited as
multipurpose building blocks in synthetic organic chemistry for the synthesis of bioactive promising
organic molecules and drug candidates.5 Structures of some reported biologically active highly
functionalized pyrazole derivatives have shown in Figure 1.
Figure 1. Structures of some biologically active polysubstituted pyrazoles containing aminopyrazole units
There are several synthetic methods for the synthesis of polysubstituted pyrazoles under different
conditions and divers catalysts, such as ionic liquids,6 molecular iodine,7,8 piperidinium acetate,9
Cu(OAc)2,10 rhodium,11 ZnBr2,12 FeCl3,12 graphene oxide-TiO2 composite (GO–TiO2),13 Oxone,14
CuO/ZrO2,15 piperidine,16 eosin Y under atmospheric oxygen,17 1-methylimidazolium trinitromethanide
{[HMIM]C(NO2)3},18 cerium(IV) ammonium nitrate (CAN) in PEG-400,19 silica chloride,20 potassium
aluminum sulfate (Alum),21 ytterbium perfluorooctanoate [Yb(PFO)3],22 nano-TiO2,23 palladium and
copper,24 and CuBr-bpy.25 Furthermore, the use of ultrasound in PEG-400 and water medium is another
synthetic technique en route for smooth access to these important heterocyclic core units.26 The biological
and medicinal importance of these heterocycles encourages us to search for an efficient and commercially
available catalyst for their synthesis.
Potassium phthalimide (PPI) is readily available and cheap compound with weak basicity (pKa = 8.3 in
H2O) and is often used in the Gabriel synthesis reaction. It has also been found that PPI showed an
extremely high capacity for CO2 capture.27 We have recently discovered efficient approaches for the

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HETEROCYCLES, Vol. 94, No. 2, 2017
PPI-promoted some organic transformations.28 To date, there has been no article published in literature that
describes the use of PPI for the synthesis of polysubstituted pyrazoles. In this contribution, PPI has been
used for the green one-pot, three-component reaction (3CR) of various aldehydes (1a-s), phenylhydrazine
(2), and malononitrile (3) to synthesis of highly functionalized 5-aminopyrazole-4-carbonitriles (4a-s)
(Scheme 1).
Scheme 1. 3CR of aldehydes (1a-s) with phenylhydrazine (2), and malononitrile (3) to synthesis highly
functionalized 5-aminopyrazole-4-carbonitriles (4a-s) catalyzed by PPI
RESULTS AND DISCUSSION
Initial experiments were performed with benzaldehyde (1a), phenylhydrazine (2), and malononitrile (2a) in
order to optimize a variety of reaction parameters, such as temperature, solvent, and catalyst loading (Table
1).
Table
1.
Optimization
of
the
reaction
conditions
for
the
synthesis
of
5-amino-1,3-diphenyl-1H-pyrazole-4-carbonitrile (4a) via 3CR of benzaldehyde (1a), phenylhydrazine (2),
and malononitrile (3)
Entry Catalyst loading/mol%
Solvent
Temp./°C Time/min. Isolated yields/%
1
2
3
4
5a
6
7
8
5
5
5
10
15
15
15
15
EtOH:H2O (2:1)
EtOH:H2O (2:1)
EtOH:H2O (2:1)
EtOH:H2O (2:1)
25
30
50
50
90
50
25
10
5
85
80
70
15
30
45
60
95
85
86
88
EtOH:H2O (2:1) 50
EtOH:H2O (2:1)
EtOH:H2O (2:1)
EtOH:H2O (2:1)
25
30
40

HETEROCYCLES, Vol. 94, No. 2, 2017
279
9
15
15
20
15
15
15
15
15
15
15
-
EtOH:H2O (2:1)
EtOH:H2O (2:1)
EtOH:H2O (2:1)
H2O
EtOH
DCM
DMF
EtOAc
THF
-
60
70
50
50
50
50
50
50
50
50
50
4
2
5
5
5
5
5
5
94
90
98
74
91
83
50
85
75
10
15
10
11
12
13
14
15
16
17
18
19
5
15
240
EtOH:H2O (2:1)
a Optimized reaction conditions shown in bold.
Various amounts of PPI were tested in a mixture of EtOH:H2O (2:1) medium to promote the synthesis of
5-amino-1,3-diphenyl-1H-pyrazole-4-carbonitrile (4a) at different temperatures (Table 1, entries 1-11).
Among the catalytic quantities loaded and temperatures studied, 15 mol% PPI loading and 50 °C were
found to be the most effective (Table 1, entry 5). Reactions were next monitored in H2O, EtOH and other
different organic solvents such as dichloromethane (DCM), dimethylformamide (DMF), ethyl acetate
(EtOAc), and tetrahydrofuran (THF) in order to explore the best solvent (Table 1, entries 12-17). The use
any of these solvents, did not obtain better results than EtOH:H2O solvent. When the reaction was
conducted in the presence of optimum catalyst loading under solvent-free condition, only 10% of the
product was isolated (Table 1, entry 18). It was found that the low yield of the corresponding product (4a)
was obtained in the absence of catalyst (Table 1, entry 19). The model reaction was also investigated using
other bases, such as KOH, and K2CO3 and the results were not satisfactory.
After optimization of conditions for 5-aminopyrazole-4-carbonitriles synthesis and to examine the
generality of this method, a variety of aromatic aldehydes bearing electron-withdrawing and
electron-donating groups and heterocyclic aldehydes were reacted with phenylhydrazine (2) and
malononitrile (3) in presence of PPI under aqueous ethanol conditions at 50 °C (Table 2). The results
showed that the corresponding products (4a-s) were synthesized in 85-99% isolated yields in 2-10 min.
Moreover, the recyclability of the catalyst was explored for synthesis of 4a. After completion of the
reaction, the PPI catalyst was separated from the filtrate by removing of solvent, washed with small
amounts of ethanol and dried in the air. The remained catalyst was reused for four times and the
corresponding product was formed in 92%, 88%, 80%, and 70% isolated yields, respectively.

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HETEROCYCLES, Vol. 94, No. 2, 2017
Table 2. Potassium phthalimide (PPI) promoted 3C synthesis of highly functionalized pyrazoles
Mp (°C)
Reportedref.
Comp. no Structure of pyrazole derivatives
Time
(min)
Isolated
yields (%)
Found
5
95
161-162 159-1607
4a
2
99
117-119 118-1207
4b
2
2
98
94
107-109 106-1087
209-211 210-21115
4c
4d
3
85
104-106 105-1077
4e
4
3
4
4
4
90
98
97
94
95
167-168 164-1667
129-131 128-1307
164-166 163-16515
4f
4g
4h
4i
Oil
Oil7
119-120 120-12126
4j

HETEROCYCLES, Vol. 94, No. 2, 2017
281
9
90
120-121 120-1237
4k
10
4
90
88
220-222 221-22318
127-129 128-1307
4l
4m
5
9
8
4
98
89
91
96
Semi
solid
Semi solid7
4n
4o
4p
4q
161-163 160-16126
129-131 130-1327
160-162 159-16026
7
95
92
137-138 138-14026
223-225 224-22618
4r
4s
10
The probable reaction mechanism for this transformation is summarized in Scheme 2. The reaction occurs
through initial formation of nitrile intermediate 8 by the Knoevenagel condensation between the activated
aldehyde 6 and intermediate anion 5 from malononitrile (3) as a C-H acid followed by loss of water
molecules. This Knoevenagel reaction of the aldehydes and malononitrile has been reported to occur in the
presence of base.28, 29 Subsequently, Michael-type addition of the hydrazide anion 7 to the Michael acceptor
8, leads to intermediate 9 and then 10 that cyclizes to heterocyclic intermediate 11 via the intramolecular

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HETEROCYCLES, Vol. 94, No. 2, 2017
cyclization. A final dehydrogenation reaction, presumably by the oxygen in the air, leads to the
corresponding heterocyclic products (4a-s).
Scheme 2. Proposed reaction mechanism of the 3C synthesis 5-aminopyrazole-4-carbonitriles (4a-s)
In conclusion, this work describes an efficient, mild and PPI-catalyzed one-pot 3CR to rapidly access
diverse 5-aminopyrazole-4-carbonitriles using simple aldehydes, phenylhydrazine, and malononitrile as
starting materials. All reactions proceeded with high efficiency under simple conditions and gave
excellent yields avoiding time-consuming, costly synthesis, and tedious work-up, and purification of
products. This approach is easy to implement and was successfully carried out with satisfactory results in
a green solvent (EtOH:H2O).
EXPERIMENTAL
All chemicals, unless otherwise specified, were purchased from commercial sources and were used
without further purification, with the exception of liquid aldehydes, which were distilled before using.
The products were characterized by comparison of their physical data with those of known samples or by
their spectral data. Melting points were measured on a Buchi 510 melting point apparatus and are
1
13
uncorrected. H NMR and C NMR spectra were recorded on a Bruker AVANCE DRX spectrometer.
FT-IR spectra were recorded on a Perkin Elmer RXI spectrometer. The development of reactions was
monitored by thin layer chromatography (TLC) analysis on Merck pre-coated silica gel 60 F254 aluminum
sheets, visualized by UV light. Elemental microanalyses were performed on Elementar Vario EL III
analyzer at Damghan University, Damghan, Iran. All of the targeted products are reported in the literature
and are characterized by comparison of their spectral and physical data on the basis of literature
descriptions.

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General Procedure for the synthesis of 5-aminopyrazole-4-carbonitrile derivatives (4a-s) catalyzed
by PPI. The appropriate aldehyde (1 mmol), phenylhydrazine (2, 1 mmol), malononitrile (3, 1 mmol), and
PPI as a catalyst (15 mol%) was mixed in a mixture of EtOH:H2O (2:1). Then, the reaction mixture was
heated at 50 °C for the appropriate time (Table 2). After completion of the reaction as indicated by TLC
analysis, the reaction mixture was cooled to room temperature and poured into water. The precipitated
products were filtered off, washed with ice water and dried at room temperature. The crude products
(except 4i and 4n) were purified by recrystallization from EtOH. The filtrate containing the catalyst was
used as such for exploring the reusability of the catalyst. The catalyst is soluble in water while the
products are insoluble in water. Spectral data for 4a and 4j were as follows:
1
5-Amino-1,3-diphenyl-1H-pyrazole-4-carbonitrile (4a). H NMR (CDCl3, 500 MHz): 6.82 (t, J = 7.3
Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 7.28-7.36 (m, 3H), 7.42 (t, J = 7.7 Hz, 2H), 7.63 (s, 1H), 7.71 (d, J =
13
7.2 Hz, 2H), 7.73 (s, 1H); C NMR (CDCl3, 125 MHz): 112.9, 113.3, 120.7, 127.0, 128.9, 129.2, 129.8,
135.7, 137.8, 146.1, 150.4, 156.6; Anal. Calcd for C16H12N4: C, 73.83; H, 4.65; N, 21.52%. Found: C,
73.48; H, 4.86; N, 21.72%.
1
5-Amino-3-(4-hydroxy-3-methoxyphenyl)-1-phenyl-1H-pyrazole-4-carbonitrile (4j). H NMR (400
MHz, DMSO-d6): δ 3.93 (s, 3H), 6.86-6.94 (m, 2H), 7.06 (d, J = 7.1 Hz, 1H), 7.13 (d, J = 8.2 Hz, 2H),
13
7.30 (d, J = 7.4 Hz, 2H), 7.40 (s, 1H), 7.63 (s, 1H), 9.90 (s, 1H), 10.83 (s, 1H); C NMR (100 MHz,
DMSO-d6): δ 56.2, 113.6, 114.7, 118.8, 119.0, 119.5, 120.4, 131.7, 131.9, 132.9, 133.2, 138.6, 140.4,
150.7, 157.5; Anal. Calcd for C17H14N4O2: C, 66.66; H, 4.61; N, 18.29; Found: C, 66.61; H, 4.65; N,
18.26.
ACKNOWLEDGEMENT
The authors are grateful to the Research Council of Damghan University.
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