An Efficient One-Pot, Four-Component Synthesis of Pyrazolo[3,4-b]pyridines Catalyzed by Tetrapropylammonium Bromide (TPAB) in Water

Article abstract of DOI:10.1071/CH17642

A novel and one-pot pseudo-four-component reaction between a series of arylglyoxals, malononitrile, 3-methyl-1-phenyl-1H-pyrazol-5-amine, and acetone in the presence of tetrapropylammonium bromide (TPAB) has been developed to synthesize a series of new substituted pyrazolo[3,4-b]pyridines, using water as an environmentally friendly solvent, in high to excellent yields.

Full text of DOI:10.1071/CH17642

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
https://doi.org/10.1071/CH17642
An Efficient One-Pot, Four-Component Synthesis
of Pyrazolo[3,4-b]pyridines Catalyzed by
Tetrapropylammonium Bromide (TPAB) in Water
A
A C
,
A
Mahnaz Ezzati, Jabbar Khalafy,
Rolf H. Prager
Ahmad Poursattar Marjani, and
B
A
Department of Organic Chemistry, Faculty of Chemistry, Urmia University,
Urmia 5756151818, Iran.
B
Department of Chemistry, Flinders University, GPO Box 2100, Adelaide, SA 5001,
Australia.
C
Corresponding author. Email: j.khalafi@urmia.ac.ir
A novel and one-pot pseudo-four-component reaction between a series of arylglyoxals, malononitrile, 3-methyl-1-phenyl-
1H-pyrazol-5-amine, and acetone in the presence of tetrapropylammonium bromide (TPAB) has been developed to
synthesize a series of new substituted pyrazolo[3,4-b]pyridines, using water as an environmentally friendly solvent, in
high to excellent yields.
Manuscript received: 15 December 2017.
Manuscript accepted: 15 April 2018.
Published online:
8 May 2018.
Introduction
zeolites of the ZSM type such as ZSM-5, and has many
applications in various catalytic processes.[25,26] TPAB is an
inexpensive, readily available catalyst and has inherent proper-
ties of environmental compatibility, operational simplicity, non-
corrosive nature, and ease of reusability.
As part of our ongoing efforts in the development of new
heterocyclic compounds with potential pharmacological and
biological activities using arylglyoxals,[27–34] herein we report a
one-pot four-component method for the synthesis of pyrazolo
[3,4-b]pyridines by reaction of arylglyoxal derivatives, malo-
nonitrile, and acetone with 5-aminopyrazoles in the presence of
TPAB in water (Scheme 1).
A multicomponent reaction (MCR) is a process in which three or
more easily accessible components are combined together to
produce a final product containing features of all components.[1]
Such multicomponent reactions in green solvents and using
green catalysts will be a powerful tool in organic synthesis.
Multicomponent reactions offer significant advantages over
conventional linear-type syntheses by allowing the production
of highly functionalized molecules with high atom efficiency
and minimized use of hazardous organic solvents.[2,3]
Among fused heterocyclic compounds, pyrazoles have spe-
cial importance because of their wide range of biological and
pharmaceutical activities. Pyrazolo[3,4-b]pyridine derivatives
are gaining importance in medicinal and organic chemistry.
They are used as antagonists of angiotensin II,[4] antileishmanial
drugs,[5] inhibitors of cyclin-dependent kinase (CDK),[6] inhi-
bitors of the adenosine receptor (AR),[7] and inhibitors of
Electrophorus electricus acetylcholinesterase,[8] and have
potent antitumour,[9] antibacterial,[9] antimicrobial,[10] antivi-
ral,[11] oncogenic Ras-inhibiting,[12] and cyclooxygenase-inhi-
biting activities.[13] Some examples are shown in Fig. 1.[14–18]
The synthesis of pyrazolopyridone derivatives has been
extensively explored in recent years,[19–24] but some of the
reported methodologies for the synthesis of these products are
associated with various difficulties such as prolonged reaction
times, low yields, harsh reaction conditions, use of expensive
reagents and catalysts, and tedious workup. Therefore, any
facile and highly efficient synthetic approach to pyrazolopyr-
idone derivatives is highly desirable.
Results and Discussion
According to our previous experience in one-pot three-
component reactions, from the reaction of arylglyoxals and
malononitrile with 3-methyl-1-phenyl-1H-pyrazol-5-amine in
acetone/water, we expected the formation of pyrazolo[3,4-b]
pyridines 4a–h, but interestingly, it was found that acetone had
acted as the fourth component to provide the pyrazolo[3,4-b]
pyridine derivatives 5a–g. In preliminary experiments, the one-
pot three-component reaction of 1a, 2, and 3 in water in the
presence of TPAB gave 4a, but only in mediocre yields. While
examining the efficacy of organic cosolvents, we found that
the use of acetone led to the formation not of 4 but 5. However,
when 4-nitrophenylglyoxal was used, 1-(5-amino-3-methyl-1-
phenyl-1H-pyrazol-4-yl)-2-(4-nitrophenyl)ethane-1,2-dione 6
was formed as the only product. In the absence of catalyst, low
product yields were observed, even after prolonged reaction
times (Scheme 2).
Tetrapropylammonium bromide (TPAB) is a phase-transfer
catalyst that has been used in the preparation of the high-silica
Journal compilation ꢀ CSIRO 2018
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B
M. Ezzati et al.
CH3
O
N
CN
N
N
N
O
N N
NH
N
H3C
O
5-HT6 receptor antagonist,
N
N
KiϽ1 nm
N
H3C
N
H
Binds the endogenous neurotransmitter
serotonin. Mediates excitatory
neurotransmission
N
CH3
Tracazolate
Ruxolitinib
Antianxiolytic, anticonvulsant,
sedative and muscle relaxant drug
Treatment of high-risk myelofibrosis
and polycythemia vera
CH3
CH3
O
O
H2N
HN
N
Br
N
N
N
F
N
N
N
N
N
F
HO
N
N
NC
Inhibitor of GSK-3
Neurodegenerative and psychiatric
disorder
Zaleplon
Sleep disorder sedative hypnotic
BAY 41-2272
sGC stimulator
Fig. 1. Examples of bioactive pyrazole-based pharmaceutical drugs.
Ar
CN
isolated product 6. A proposed pathway for the formation of this
compound is depicted in Scheme 4.
O
N
Me
NC
Me
Me
Me
O
TherecyclabilityofTPABwasalsoexaminedinthesynthesisof
5a. For that purpose, the recovered catalyst was recycled up to 4
times for the synthesis of 4-benzoyl-1-phenyl-3,6,6-trimethyl-
1,4,6,7-tetrahydro-5H-pyrazolo[3,4-b]pyridine-5,5-dicarbonitrile
without significant loss of its catalytic performance (Fig. 2).
The structures of products 5a–g were confirmed by their 1H
NMR, 13C NMR, Fourier-transform (FT)-IR, and mass spectral
data, and X-ray crystallography of 5e.
The structure of compound 6 was deduced from its 1H NMR,
13C NMR, FT-IR, and mass spectral data and X-ray crystallog-
raphy (Fig. 3).
N
H2N
Ar
ϩ Me2CO
ϩ CH2(CN)2 ϩ
N
N
N
H
OH
HO
Scheme 1. Retrosynthesis of substituted pyrazolo[3,4-b]pyridines.
The arylglyoxals 1a–h[35] and the 3-methyl-1-phenyl-1H-
pyrazole-5-amine 3[36] were prepared according to literature
methods. We found that reaction of arylglyoxals 1a–g with
malononitrile 2 and 3-methyl-1-phenyl-1H-pyrazol-5-amine 3,
in H2O/Me2CO at 408C and in the presence of TPAB afforded
pyrazolo[3,4-b]pyridines derivatives 5a–g by a one-pot four-
component reaction in good to excellent yields. The reaction
conditions were then applied with a range of different arylglyox-
als. The results with various arylgloxals and product yields are
summarized in Table 1.
In the 1H NMR spectra of products 5a–g, the characteristic
singlets at d 5.10–5.27 ppm were ascribed to the CH of the
tetrahydropyridine ring and were present in all new products.
The characteristic singlets at d 1.90–1.98, 1.79–1.80, and 1.58–
1.64 ppm were attributed to the 3-methyl and 6,6-dimethyl
groups respectively.
In the 13C NMR spectra of products 5a–g, signals located at
184.3–199.3 ppm were due to the carbonyl group.
Two possible pathways for the synthesis of the products 5a–g
are depicted in Scheme 3. The first step in alternative A involves
the Knoevenagel reaction of malononitrile with the arylglyoxals
to form an intermediate 7, followed by the Michael addition of
the pyrazole amine 3, leading to an intermediate, which com-
bines with acetone and then undergoes intramolecular cycliza-
tion to produce the final products 5a–g. The intermediate
product in this proposed mechanism, 7a, was synthesized, and
when it was reacted with malononitrile and 3 in the absence of
acetone, the outcome was a mixture of products that could not be
separated. The preferred pathway is shown in alternative B,
involving initial reaction of glyoxals with 3 to give the interme-
diate 8, which then undergoes Michael addition with malononi-
trile, followed by reaction with acetone and intramolecular
cyclization to 5.
The crystallographic data for structures 5e and 6 have been
deposited at the Cambridge Crystallographic Data Centre (entry
nos CCDC-1587573 and 1587574) and are available free of
charge on request to CCDC, 12 Union Road, Cambridge, UK
(Fax: þ44–1223–336033, email: deposit@ccdc.cam.ac.uk).
Conclusions
In conclusion, we have described a convenient one-pot four-
component reaction leading to the synthesis of pyrazolo[3,4-b]
pyridine derivatives using readily available precursors as start-
ing materials. Some important advantages of this method
include the use of an inexpensive and recoverable catalyst, short
reaction times, ease of separation, high yields, wide substrate
scope, and using water as an environmentally friendly solvent.
The new pyrazolo[3,4-b]pyridines may have useful biological
and medicinal properties.
The highly electrophilic 4-NO2 glyoxal reacts directly with 3
to give an intermediate that undergoes rapid oxidation to the

Four-Component Synthesis of Pyrazolo[3,4-b]pyridines
C
Ar
O
N
NC
H2N
Me
N
N
H
O
4a–h
Ar
1a–h
OH
Ar
HO
Me
N
O
CN
ϩ
NC
Me
Me
Ar ϭ C6H5, 4-ClC6H4, 4-FC6H4,
TPAB
NC
H2N
N
N
N
H
Me
N
CN
4-MeC6H4, 4-MeOC6H4,
3,4-(MeO)2C6H3,
H2O/Me2CO
2
5a–g
(65–98 %)
Ar
3-MeO-4-HOC6H3
3
O
Me
O
Ar ϭ 4-O2NC6H4
N
H2N
N
6 (46 %)
Scheme 2. Synthesis of pyrazolo[3,4-b]pyridines 5a–g and 6.
Experimental
for an appropriate time (45–90 min) as monitored by TLC
(CH2Cl2/n-hexane/MeOH 20 : 10 : 1). After completion of the
reaction, half of the solvent was evaporated and the precipitate
was filtered, washed with cold water, and recrystallized from
ethanol to give the desired products 5a–g in good to excellent
yields (65–98 %).
The chemicals used in this work were purchased from Acros
Organics or from Merck, and were used without purification.
Melting points were measured on a Philip Harris C4954718
apparatus. Infrared spectra were recorded on a Thermo-Nicolet
Nexus 670 FT-IR instrument using KBr discs. 1H and 13C NMR
spectra were recorded on a Bruker Avance AQS 300-MHz
spectrometer at 300 and 75.5 MHz respectively. Chemical shifts
were measured in CDCl3 or DMSO-d6 as solvents relative to
TMS as the internal standard. Mass spectra were recorded on a
Varian Matt 311 spectrometer and the relative abundance of
fragments is quoted in parentheses after the m/z values.
4-Benzoyl-1-phenyl-3,6,6-trimethyl-1,4,6,7-
tetrahydro-5H-pyrazolo[3,4-b]pyridine-5,5-
dicarbonitrile (5a)
White crystals, 98 %, mp 1718C. dH (300 MHz, CDCl3) 8.18
(dd, J1 7.2, J2 1.2, 2H, Ar), 7.75 (t, J 7.5, 1H, Ar), 7.67–7.56 (m,
4H, Ar), 7.48 (t, J 7.5, 2H, Ar), 7.34 (t, J 7.5, 1H, Ar), 5.17 (s, 1H,
CH), 4.05 (bs, 1H, NH, exchanged by D2O addition), 1.90 (s, 3H,
Me), 1.79 (s, 3H, Me), 1.61 (s, 3H, Me). dC (75.5 MHz, CDCl3)
194.7, 145.9, 141.0, 138.2, 136.7, 135.0, 129.5, 129.3, 129.0,
127.1, 122.6, 114.2, 112.4, 95.1, 59.9, 43.9, 42.8, 26.0, 23.1,
13.9. nmax (KBr)/cmꢀ1 3367, 3081, 2935, 2996, 2249, 1680,
1598, 1501, 1451, 1394, 1230, 1163, 1120, 763, 694. m/z 396
([Mþ þ 1], 21 %), 395 ([Mþ], 50), 330 (38), 302 (17), 291 (31),
290 (100), 250 (51), 249 (22), 105 (57), 77 (78), 51 (17). m/z
(high-resolution mass spectroscopy (HRMS) 395.1702 [M]þ;
calc. for C24H21N5O: 395.1746.
General Procedure for the Synthesis of
Tetrapropylammonium Bromide (TPAB)
A mixture of tripropylamine (1 mol) and propyl bromide
(1.5 mol) in DMF (100 mL) was stirred at 1108C for 15 h under an
N2 atmosphere. After completion of reaction, the reaction
mixture was cooled (ice-bath) and n-hexane/toluene (2: 1)
(200 mL) was added. The precipitate was filtered and washed
with n-hexane/toluene (3: 1) (40 mL) to give the desired
TPAB.[37]
Recovery of TPAB
4-(4-Chlorobenzoyl)-1-phenyl-3,6,6-trimethyl-1,4,6,7-
tetrahydro-5H-pyrazolo[3,4-b]pyridine-5,5-
dicarbonitrile (5b)
After filtration of products 5a–g and washing with water, the
filtrate was extracted with CHCl3 and the aqueous phase was
separated. The water was evaporated to give TPAB as white
crystals, which may be recrystallized from Et2O.
Yellow crystals, 65 %, mp 2118C. dH (300 MHz, CDCl3) 8.12
(d, J 7, 2H, Ar), 7.68–7.52 (m, 4H, Ar), 7.49 (t, J 7.5, 2H, Ar),
7.35 (t, J 7.5, 1H, Ar), 5.10 (s, 1H, CH), 4.03 (s, 1H, NH,
exchanged by D2O addition), 1.90 (s, 3H, Me), 1.80 (s, 3H, Me),
1.59 (s, 3H, Me). dC (75.5 MHz, DMSO-d6) 195.4, 147.2, 131.8,
130.2, 130.0, 129.8, 129.6, 128.8, 127.8, 124.4, 124.1, 122.6,
89.7, 54.7, 31.1, 28.3, 23.1, 14.3, 13.2. nmax (KBr)/cmꢀ1 3338,
2929, 2862, 2243, 1678, 1602, 1587, 1569, 1527, 1499, 1391,
1217, 1095, 1005, 919, 770, 701. m/z 431 ([Mþ þ 2], 14 %), 429
([Mþ], 38), 364 (30), 336 (13), 291 (30), 290 (100), 250 (48),
139 (31), 111 (22), 77 (36), 51 (13). m/z (HRMS) 429.1329
[M]þ; calc. for C24H20ClN5O: 429.1356.
General Procedure for the Synthesis of 4-Benzoyl-1-phenyl-
3,6,6-trimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-b]
pyridine-5,5-dicarbonitriles 5a–g
A mixture of arylglyoxal (1 mmol), malononitrile (1 mmol),
and TPAB (20 mol-%) in water (5 mL) was stirred in an
ice-bath. After formation of the intermediate 7 as pale
yellow needles (monitored by TLC, CH2Cl2/MeOH 20 : 1),
5-amino-1-phenyl-3-methylpyrazole (1 mmol) and acetone
(10 mL) were added. The reaction mixture was stirred at 408C

D
M. Ezzati et al.
Table 1. (Continued)
Table 1. The structure of products 5a–g synthesized via Scheme 2
Entry
Arylgloxal
Product
Mp [8C]
196
Yield [%]
45 (93A)
Entry
Arylgloxal
Product
Mp [8C]
Yield [%]
98
O2N
O2N
8
1
171
O
O
O
N
CN
O
NC
Me
Me
Me
N
Me
OH
HO
HO
O
OH
N
H
1h
1a
N
H2N
N
6
5a
Cl
Cl
2
3
4
211
169–170
210
65
76
94
O
AUsing 1h, 2, and 3 in 1 : 2 : 1 molar ratio.
O
N
CN
NC
Me
Me
Me
N
HO
OH
1b
N
H
4-(4-Fluorobenzoyl)-1-phenyl-3,6,6-trimethyl-1,4,6,7-
tetrahydro-5H-pyrazolo[3,4-b]pyridine-5,5-
dicarbonitrile (5c)
5b
White crystals, 76 %, mp 169–1708C. dH (300 MHz, CDCl3)
8.22 (dd, J1 5.1, J2 8.7, 2H, Ar), 7.61 (d, J 7.8 Hz, 2 H, Ar), 7.49
(t, J 7.2, 2H, Ar), 7.35 (t, J 7.2, 1H, Ar), 7.29 (t, J 8.4, 2H, Ar),
5.11 (s, 1H, CH), 4.04 (bs, 1H, NH, exchanged by D2O addition),
1.88 (s, 3H, Me), 1.80 (s, 3H, Me), 1.59 (s, 3H, Me). dC
(75.5 MHz, CDCl3) 193.0, 145.9, 141.0, 138.2, 131.9, 131.8,
129.5, 127.2, 122.6, 116.7, 116.5, 114.2, 95.0, 59.9, 44.0, 42.8,
26.0, 23.1, 13.9. nmax (KBr)/cmꢀ1 3339, 3074, 2989, 2931, 2245,
1682, 1597, 1528, 1499, 1458, 1391, 1242, 1216, 1159, 921,
858, 772, 670. m/z 414 ([Mþ þ 1], 17 %), 413 ([Mþ], 55), 348
(53), 320 (23), 291 (55), 290 (100), 250 (91), 249 (30), 200 (13),
123 (95), 95 (72), 77 (86), 51 (30). m/z (HRMS) 413.1630 [M]þ;
calc. for C24H20FN5O: 413.1652.
F
F
O
O
N
CN
NC
Me
Me
N
HO
OH
1c
N
H
Me
5c
Me
Me
O
O
N
CN
NC
Me
Me
N
HO
OH
1d
N
H
Me
1-Phenyl-3,6,6-trimethyl-4-(4-methylbenzoyl)-1,4,6,7-
tetrahydro-5H-pyrazolo[3,4-b]pyridine-5,5-
dicarbonitrile (5d)
5d
MeO
MeO
White crystals, 94 %, mp 2108C. dH (300 MHz, DMSO-d6)
8.21 (d, J 7.8, 2H, Ar), 7.68 (d, J 7.8, 2H, Ar), 7.60–7.35 (m, 4H,
Ar), 7.31 (t, J 7.2, 1H, Ar), 6.80 (bs, 1H, NH, exchanged by D2O
addition), 5.48 (s, 1H, CH), 2.45 (s, 3H, Me), 1.73 (s, 3H, Me),
1.65 (s, 3H, Me), 1.46 (s, 3H, Me). dC (75.5 MHz, DMSO-d6)
196.1, 146.3, 145.8, 142.7, 139.2, 134.5, 130.3, 129.8, 129.6,
122.1, 115.3, 113.4, 95.0, 60.2, 43.8, 43.1, 25.7, 23.6, 21.8, 13.9.
nmax (KBr)/cmꢀ1 3324, 3208, 2929, 2249, 1694, 1628, 1598,
1518, 1437, 1385, 1291, 1156, 1065, 825, 757, 687. m/z 409
([Mþ], 2 %), 386 (54), 385 (100), 369 (34), 368 (61), 367 (44),
353 (39), 294 (23), 276 (49), 222 (34), 180 (12), 119 (48), 91
(59), 77 (41), 65 (23), 51 (15). m/z (HRMS) 409.1938 [M]þ;
calc. for C25H23N5O: 409.1903.
5
197
89
O
O
CN
NC
Me
HO
OH
Me
Me
N
1e
N
H
N
5e
OMe
OMe
MeO
MeO
6
197–198
98
O
O
N
CN
NC
Me
Me
Me
HO
OH
1f
N
N
H
4-(4-Methoxybenzoyl)-1-phenyl-3,6,6-trimethyl-
1,4,6,7-tetrahydro-5H-pyrazolo[3,4-b]pyridine-5,5-
dicarbonitrile (5e)
5f
OMe
HO
OMe
HO
7
205
93
White crystals, 89 %, mp 1978C. dH (300 MHz, CDCl3) 8.17
(d, J 8.7, 2H, Ar), 7.61 (d, J 8.1, 2H, Ar), 7.48 (t, J 7.5, 2H, Ar),
7.34 (t, J 7.2, 1H, Ar), 7.07 (d, J 8.7, 2H, Ar), 5.11 (s, 1H, CH),
4.03 (bs, 1H, NH, exchanged by D2O addition), 3.94 (s, 3H,
OMe), 1.90 (s, 3H, Me), 1.79 (s, 3H, Me), 1.64 (s, 3H, Me). dC
(75.5 MHz, DMSO-d6) 199.3, 169.8, 150.5, 147.4, 137.0, 134.4,
134.1, 130.2, 127.3, 126.9, 119.7, 119.4, 99.8, 64.9, 61.0, 48.0,
33.0, 30.5, 28.4, 18.6. nmax (KBr)/cmꢀ1 3319, 2930, 2842, 2245,
1666, 1594, 1509, 1456, 1384, 1335, 1272, 1226, 1168, 1025,
O
O
CN
NC
Me
Me
Me
N
HO
OH
N
H
1g
N
5g
(continued)

Four-Component Synthesis of Pyrazolo[3,4-b]pyridines
E
Ar
O
O
Ar
CN
CN
3
Alt A:
ϩ
H
O
CN
Ar
Ar
CN
Ar
CN
H
O
N
O
N
O
N
NC
7
NC
NC
NC
Me
Me
Me
N
Me
Me
NC
Me
Me
2
1a–g
Acetone
N
N
N
H
H2N
N
Ar
O
Me
N
O
Ar
2
Alt B:
ϩ
3
5a–g
HN
N
O
H
1a–g
8
Scheme 3. Proposed pathways for the synthesis of pyrazolo[3,4-b]pyridine-5,5-dicarbonitriles 5a–g.
O
O
O2N
O2N
Me
N
Me
N
O
O
HO
H2N
Aerial oxidation
3
O2N
H2N
O
N
N
H
6
Scheme 4. Proposed pathway for the synthesis of 6.
1280, 1252, 1167, 1137, 1018, 878, 770, 700. m/z 457
([Mþ þ 2], 11 %), 456 ([Mþ þ 1], 46), 455 ([Mþ], 80), 290
(11), 166 (12), 165 (100), 77 (27), 51 (10). m/z (HRMS)
455.1921 [M]þ; calc. for C26H25N5O3: 455.1957.
98
97
95
93
100
80
60
40
20
0
4-(4-Hydroxy-3-methoxybenzoyl)-1-phenyl-3,6,6-
trimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[3,4-b]
pyridine-5,5-dicarbonitrile (5g)
White crystals, 93%, mp 2058C. dH (CDCl3, 300 MHz) 7.82–
7.68 (m, 2H, Ar), 7.61 (d, J 7.5, 2H, Ar), 7.48 (t, J 7.5, 2H, Ar),
7.34 (t, J 7.2, 1H, Ar), 7.05 (d, J 9, 1H, Ar), 6.52 (s, 1H, OH
exchanged by D2O addition), 5.11 (s, 1H, CH), 4.06 (s, 1H, NH
exchanged by D2O addition), 4.02 (s, 3H, OMe), 1.90(s, 3H, Me),
1.79 (s, 3H, Me), 1.58 (s, 3H, Me). dC (75.5 MHz, CDCl3) 192.5,
152.4, 147.5, 146.0, 141.0, 138.2, 129.5, 127.1, 124.6, 122.6,
114.3, 114.1, 112.6, 110.6, 95.5, 59.8, 56.2, 43.2, 43.0, 26.0, 23.2,
13.8. nmax (KBr)/cmꢀ1 3494, 3356, 3093, 2986, 2844, 2613,
2255, 1662, 1586, 1517, 1500, 1456, 1427, 1393, 1378, 1349,
1279, 1203, 1175, 1145, 1026, 883, 769, 699. m/z 442 ([Mþ þ 1],
38%), 441 ([Mþ], 100), 397 (13), 151 (8), 77 (24), 51 (9). m/z
(HRMS) 441.1839 [M]þ; calc. for C25H23N5O3: 441.1801.
1
2
3
4
Run number
Fig. 2. Reusability of TPAB for the synthesis of 5a.
919, 835, 764, 694, 595, 517. m/z 426 ([Mþ þ 1], 12 %), 425
([Mþ], 37), 360 (10), 332 (15), 290 (47), 250 (25), 135 (100),
106 (18), 92 (20), 77 (56), 51 (10). m/z (HRMS) 425.1874 [M]þ;
calc. for C25H23N5O2: 425.1852.
4-(3,4-Dimethoxybenzoyl)-1-phenyl-3,6,6-trimethyl-
1,4,6,7-tetrahydro-5H-pyrazolo[3,4-b]pyridine-5,5-
dicarbonitrile (5f)
1-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-(4-
nitrophenyl)ethane-1,2-dione (6)
White crystals, 98 %, mp 197–1988C. dH (300 MHz, CDCl3)
7.79 (d, J 8.4, 1H, Ar), 7.74 (s, 1H, Ar), 7.61 (d, J 7.8, 2H, Ar),
7.48 (t, J 7.8, 2H, Ar), 7.34 (t, J 7.2, 1H, Ar), 7.00 (d, J 8.4, 1H,
Ar), 5.12 (s, 1H, CH), 4.04 (bs, 1H, NH, exchanged by D2O
addition), 4.02 (s, 3H, OMe), 4.01 (s, 3H, OMe), 1.91 (s, 3H,
Me), 1.80 (s, 3H, Me), 1.59 (s, 3H, Me). dC (75.5 MHz, CDCl3)
184.3, 152.5, 146.1, 138.2, 129.5, 129.5, 129.5, 122.7, 122.6,
114.3, 114.2, 114.1, 110.7, 106.3, 95.5, 79.4, 60.0, 59.8, 56.2,
43.4, 43.3, 26.0, 23.2. nmax (KBr)/cmꢀ1 3623, 3368, 3093, 2943,
2984, 2943, 2842, 2248, 1663, 1590, 1575, 1501, 1458, 1352,
A mixture of p-nitrophenylglyoxal (1 mmol), malononitrile
(1 mmol), and TPAB (20 mol-%) in water (5 mL) was stirred in
an ice-bath. After formation of the intermediate 8 as an orange
precipitate, 3-methyl-1-phenyl-1H-pyrazol-5-amine (1 mmol)
in water or acetone or EtOH or acetonitrile/urea was added and
the reaction mixture was stirred at room temperature for an
appropriate time (monitored by TLC, CH2Cl2/n-hexane/MeOH
20 : 10 : 1). After completion of the reaction, the precipitate was
filtered, washed with water, and recrystallized from ethanol to
give the product 6.

F
M. Ezzati et al.
O4
C3
C1
C5
N4
C2
C3
N3
C16
C2
C6
C4
C1
C10
C9
N1
O1
C4
N1
N5
C20
C23
C17
C12
C13
O2
C11
O2
N2
C19
C15
C17
C7
C8
C15
C14
C5
C7
C24
C18
O1
C6
C25
C18
C10
C21
C22
C13
N2
N3
C14
C16
C8
C11
C12
O3
O5
N4
C9
5e
6
Fig. 3. Molecular single-crystal plots of 5e and 6.
Yellow crystals, 45 %, mp 1968C. dH (300 MHz, CDCl3) 8.38
A. Martinelli, C. Tintori, M. Botta, J. Med. Chem. 2005, 48, 7172.
doi:10.1021/JM050407K
(d, J 8.4, 2H, Ar), 8.23 (d, J 8.4, 2H, Ar), 7.65–7.40 (m, 5H, Ar),
6.20 (bs, 2H, NH2, exchanged by D2O addition), 2.10 (s, 3H,
Me). dC (75.5 MHz, DMSO-d6) 192.9, 186.1, 152.6, 151.4,
148.4, 137.4, 137.2, 131.5, 130.0, 128.4, 125.0, 124.4, 101.8,
14.5. nmax (KBr)/cmꢀ1 3339, 3263, 3170, 1681, 1632, 1609,
1597, 1546, 1521, 1495, 1350, 1320, 1222, 1092, 883, 849, 785,
762, 723, 717, 589. m/z 350 ([Mþ], 11 %), 201 (73), 200 (100),
157 (15), 131 (35), 104 (45), 91 (23), 77 (63), 66 (20), 51 (17).
m/z (HRMS) 350.1044 [M]þ; calc. for C18H14N4O4: 350.1015.
Repeating reaction with p-nitrophenylglyoxal (1 mmol),
malononitrile (2 mmol), TPAB (20 mol-%), and 3-methyl-1-
phenyl-1H-pyrazol-5-amine (1 mmol) gave the desired product
in 93 % yield.
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Supplementary Material
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1H and 13C NMR, FT-IR, and mass spectral data for compounds
5a–g and 6 are available on the Journal’s website.
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Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
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The authors are grateful to Urmia University for financial support.
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