An efficient synthesis of tetrahydropyrazolopyridine derivatives by a one-pot tandem multi-component reaction in a green media

Article abstract of DOI:10.3998/ark.5550190.p008.462

The synthesis of some tetrahydropyrazolopyridine derivatives has been described by a one-pot 2A + 2B + C + D four component reaction of a 1,3-dicarbonyl compound, an aldehyde, hydrazine and ammonium acetate in ethanol as a green media under catalyst-free condition. ARKAT-USA, Inc.

Full text of DOI:10.3998/ark.5550190.p008.462

General Papers
ARKIVOC 2014 (iv) 204-214
An efficient synthesis of tetrahydropyrazolopyridine derivatives by
a one-pot tandem multi-component reaction in a green media
Minoo Dabiri,a* Peyman Salehi,b* Majid Koohshari,a Zoleikha Hajizadeh,a and David Ian
MaGeec*
a Department of Chemistry, Faculty of Science, Shahid Beheshti University, G. C., Evin, Tehran
1983963113, Iran
b
Department of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid
Beheshti University, G. C., Evin, Tehran 1983963113, Iran
c Department of Chemistry, 30 Dineen Drive University of New Brunswick, Fredericton, New
Brunswick, Canada E3B 5A3
E-mail: m-dabiri@sbu.ac.ir, p-salehi@sbu.ac.ir, dmagee@unb.ca
DOI: http://dx.doi.org/10.3998/ark.5550190.0015.400
Abstract
The synthesis of some tetrahydropyrazolopyridine derivatives has been described by a one-pot
2A + 2B + C + D four component reaction of a 1,3-dicarbonyl compound, an aldehyde,
hydrazine and ammonium acetate in ethanol as a green media under catalyst-free condition.
Keywords: 1,4-Dihydropyridine, dipyrazolopyridine, multi-component reactions, green
chemistry
Introduction
Green chemistry is a doctrine that inspires chemists to design chemical procedures that minimize
the use and production of hazardous materials. In fact, the goal of green chemistry is to reduce
and prohibit the pollution of nature and ensure perpetual life on the earth.1-3
Multi-component reactions (MCRs) require the combination of at least three compounds to
generate a product, where all or most of the starting material atoms exist in the final product.4
The use of MCRs for the synthesis of complex molecules in one pot, is advantageous compared
to the classical routes that uses sequential synthesis. Owing to their usefulness for synthesizing
drug-like molecules and creating high structural diversity, MCRs play an important role in
combinatorial chemistry and industrial chemistry.5,6 Simple purification, atom economy,
convergent character, operational simplicity, elimination of overflow steps are other typical
advantages of these reactions.7
Since the first example of MCRs reported by Strecker, multi-component reactions have been
developed regularly and many useful MCRs such as Mannich, Passerini (three-component
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reactions) and Ugi (a four-component reaction) have been reported. The abundance of MCRs
decreases as the number of components increases and among them reaction using six or more
components are rare.8
Owing to their pharmacological and biological properties, 1,4-dihydropyridines (1,4-
DHPs) have garnered particular attention in both synthetic and medicinal research.7 1,4-
DHPs, as a class of calcium modulators, are extensively investigated for their
pharmacological activities as antioxidant, anti-tumor, anti-atherosclerosis, anti-diabetes, anti-
mutagenic, anti-vasodilator, neuromodulator, hepatoprotector, neuroprotector and memory
enhancer.9 The Hantzsch synthesis, one of the most famous multi-component reactions
involving an aldehyde, two equivalents of a β-ketoester and a nitrogen donor such as
ammonia or ammonium acetate, is most often used for the consturction of 1,4-
dihydropyridines.10 Several modifications have been devoloped to allow for the synthesis of
different 1,4-DHP derivatives.11
Pyrazoles exist in some compounds that are used as pharmaceuticals and agrochemicals.12
Also, fused pyrazoles have fungicidal,13 herbicidal,14 virucidal,15 and insecticidal16,17 activity and
have been used for the treatment of rheumatoid arthritis.16,18 On account of its variety of
biological activity, the chemistry of pyrazoles has attracted much attention and many methods
for their synthesis have been extended.19 Pyrazolopyridines and their derivatives have a wide
range of biological activities.20,21 For example, a number of pyrazolo[3,4-b]pyridines exhibit
biological activities, including anxiolytic (e.g., tracazolate), antiallergic and antiherpetic
properties.22 The research on organic light emitting diodes (OLEDs) has exploded and
progressed considerably in recent years. Dipyrazolopyridines are a new class of fluorescent
materials. Preliminary electroluminescence properties were reported in their polymer
systems.23,24
Scheme 1. Synthesis of tetrahydropyrazolopyridine 5.
The importance of green chemistry and also the existing attraction in the design and synthesis
of heterocyclic compounds through MCRs, motivated us to design a one-pot 2A + 2B + C + D
four component reaction for the synthesis of fused pyrazolo-1,4-dihydropyridines under green
reaction conditions. Although the synthesis of dipyrazolopyridines starting from pyrazole-
containing building blocks has already been reported,25-27 herein, we introduce the first example
of simultaneous assembly of all three heterocyclic rings from four acyclic building blocks. We
employed in situ preparation of the pyrazolone ring through the reaction between hydrazine and
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a β-dicarbonyl compound and subsequent reaction with aldehyde and ammonium acetate
(Scheme 1). We note that the in situ formation of pyrazolone as pronucleophiles in
multicomponent reactions has already been developed.28-30
Results and Discussion
Encouraged by the satisfactory results of our first attempts, the synthesis of the
tetrahydropyrazolopyridine 5b was selected for optimizing the reaction conditions. The optimal
reaction conditions for the reaction of 4-chlorobenzaldehyde, hydrazine hydrate, ethyl
acetoacetate and ammonium acetate were screened (Table 1) and ethanol was found to be the
best solvent for this reaction under reflux and catalyst-free condition.
Table 1. Optimization of reaction conditions for the synthesis of tetrahydropyrazolopyridine 5b
Solvent
EtOH
H2O/EtOH
[Hmim] TFA
H2O
Catalyst
Yield (%)
Time (h)
-
-
-
79
40
60
36
68
43
5
6
12
6
p-TSA
K2CO3
Piperidine
H2O
9
H2O
9
The efficiency of this multicomponent reaction was probed by employing a series of different
aldehydes and β-dicarbonyl compounds (Table 2). Aromatic aldehydes bearing electron-
withdrawing and electron-donating groups led to the formation of products 5a-5g in good yields
(65-76%). Also heteroaromatic aldehydes such as pyridine carboxaldehydes the use of aliphatic
aldehydes such as butyraldehyde led to products 5h (78%) and 5i (63%), respectively in good
yields, although the use of butyraldehyde gave the product 5j in a slightly lower yield (60%).
Isatin and acenaphthenquinone were used instead of the aldehyde in this reaction to produce
the related spiro-products (5k-5p). It became clear that as well as aldehydes, that activated
-diketones such as these also effectively participate in this reaction and give good yields (Table
3).
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We also used phenylhyrazines and its derivatives instead of hydrazine, and anilines instead of
ammonium acetate in this reaction but the desired products were not obtained in any
experiments. The products were characterized by NMR (1H and 13C), IR and HR-ESIMS
analysis. This protocol was shown to be facile, efficient, simple, and environmentally friendly.
Table 2. Synthesised products from aldehyde derivatives
Product
5a
R1
Me
Me
Me
Me
Me
Et
R2
Yield (%)
65
3-BrC6H4
4-ClC6H4
4-Tol
5b
5c
5d
5e
7624
7624
76
5-Br-2-(Pr-2-ynyloxy)C6H3
5-Me-2-(Pr-2-ynyloxy)C6H3
75
72
5f
Ph
5g
5h
5i
n-Pr
Me
Me
Me
4-ClC6H4
pyrid-2-yl
pyrid-3-yl
n-Pr
75
78
63
60
5j
A plausible mechanism for this multi-component process is presented in Scheme 2. The
mechanism most likely involves the initial nucleophilic attack of hydrazine on the β-ketoester
and subsequent cyclization to form the pyrazolone 6. In the next step, the reaction can be
continued via a Knoevenagel condensation followed by attack of the second pyrazolone ring that
leads to the formation of 7. Intermediate 7 has already been reported to be the final product of
the reaction of 1-phenyl-3-methyl-5-pyrazolone with an aldehyde.31,32 Finally, nucleophilic
attack of ammonia on intermediate 7 followed by intramolecular cyclization leads to compound
8 which can then tautomerize to form the final product 5.33
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Table 3. Synthesised products from isatin and acenaphthenquinone
Product
R1
Yielda (%)
or
5k
5l
Me
Me
Et
65
76
76
60
70
76
5m
5n
5o
Et
n-Pr
n-Pr
5p
Scheme 2. Plausible mechanism of the reaction.
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Conclusions
In summary, a facile procedure for the synthesis of 3,5-diaryl-4-(aryl/alkyl)-1,4,7,8-
tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine derivatives has been reported via a condensation
reaction of a 1,3-dicarbonyl compound, an aldehyde, hydrazine and ammonium acetate in
ethanol as a green media under catalyst-free conditions. The versatility of the reaction to allow
the formation of a variety of functionalities such as amido, hydroxyl and amino groups make
these compounds attractive candidates as precursors for drug discovery, combinatorial chemistry
and chemical biology. The simple performance, green and mild conditions, good yields and easy
purification of the products are among the advantages of this protocol.
Experimental Section
General. Melting points were measured on an Elecrtrothermal 9100 apparatus and are
uncorrected. HR-ESIMS spectra were acquired on a Bruker MicroTOF ESI-MS system. IR
1
spectra were recorded on a Shimadzu IR-470 spectrometer. H and 13C NMR spectra were
recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and 75.47 MHz,
1
13
respectively. H and C NMR spectra were obtained on solutions in DMSO-d6 using TMS as
internal standard. Elemental analyses were performed using a Heraeus CHN-O Rapid analyzer.
General procedure for the synthesis tetrahydropyrazolopyridine. A mixture of hydrazine
hydrate (2.0 mmol) and β-dicarbonyl compound (2.1 mmol) in EtOH (5 mL) was magnetically
stirred for 30 min at ca. 25 °C followed by addition of aldehyde (1.0 mmol) and ammonium
acetate (4.0 mmol). The reaction mixture was heated at reflux for 4-8 h and then cooled to ca. 25
°C and water (10 mL) was added and the resulting mixture was stirred for 30 min. The
precipitated product was filtered, washed with water and acetone then dried under vacuum. In
most cases no further purification was necessary.
4-(3-Bromophenyl)-3,5-dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine (5a).
1
Yield 65%, mp 245-247 °C; IR (KBr) (νmax/cm-1): 3331, 1604, 1468; H NMR (300.13 MHz,
DMSO-d6): δH 2.05 (s, 6H, 2CH3), 4.81 (s, 1H, CH), 7.09-7.16 (m, 2H, Ar-H), 7.18-7.25 (m, 2H,
13
Ar-H), 11.18-11.51 (br s, 3H, NH); C NMR (75.47 MHz, DMSO-d6): δC 10.7 (CH3), 32.9
(CH), 104.1 (C-8,12), 121.7, 127.1, 128.8, 130.4, 130.5 (5C, Ar), 140.2 (C-15,16), 146.7 (C-3),
161.4 (C-9,11); HR-MS (ESI) Calcd for C15H14BrN5 [M+NH4] 361.0771 found 361.0730.
4-(4-Chlorophenyl)-3,5-dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine (5b).
Yield 76%, mp 252-254 °C (lit.,24 254-256 °C); IR (KBr) (νmax/cm-1): 3165, 3100, 1603, 1526;
1H NMR (300.13 MHz, DMSO-d6): δH 2.01 (s, 6H, 2CH3), 4.80 (s, 1H, CH), 7.12 (br s, 2H, Ar-
13
H), 7.25 (br s, 2H, Ar-H), 11.35 (br s, 3H, NH); C NMR (75.47 MHz, DMSO-d6): δC 10.8
(CH3), 32.6 (CH), 104.3 (C-8,12), 128.1, 129.8, 130.5 (3C, Ar), 140.1 (C-15,16), 142.8 (C-3),
161.4 (C-9,11); HR-MS (ESI) Calcd for C15H14ClN5 [M+NH4] 317.1276 found 317.1217.
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3,5-Dimethyl-4-(4-methylphenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine (5c).
Yield 76%, mp 239-241°C (lit.,24 244-246 °C); IR (KBr) (νmax/cm-1): 3174, 3110, 1605, 1526; 1H
NMR (300.13 MHZ, DMSO-d6): δH 2.07 (s, 6H, 2CH3), 2.23 (s, 3H, CH3), 4.71 (s, 1H, CH),
13
7.00-7.04 (m, 4H, Ar-H), 11.06-11.71 (br s, 3H, NH); C NMR (75.47 MHz, DMSO-d6): δC
10.8 (CH3), 21.0 (CH3), 32.7 (CH), 104.8 (C-8,12), 127.8, 128.7, 129.3 (3C, Ar), 134.7 (C-
15,16), 140.7 (C-3), 161.4 (C-9,11); HR-MS (ESI) Calcd for C16H17N5 [M+NH4] 297.1822
found 297.1856.
4-[5-Bromo-2-(prop-2-ynyloxy)phenyl]-3,5-dimethyl-1,4,7,8-tetrahydrodipyrazolo[3,4-
b:4’3’-e]pyridine (5d). Yield 76%, mp 249-251 °C; IR (KBr) (νmax/cm-1): 3366, 3288, 1612; 1H
NMR (300.13 MHz, DMSO-d6): δH 2.07 (s, 6H, 2CH3), 3.58 (s, 1H, ( CH), 4.77 (s, 2H, CH2),
5.00 (s, 1H, CH), 6.89-6.93 (m, 1H, Ar-H), 7.25-7.31 (m, 1H, Ar-H), 7.67 (s, 1H, Ar-H), 11.58-
11.62 (br s, 3H, NH); 13C NMR (75.47 MHz, DMSO-d6): δC 10.4 (CH3), 27.0 (CH), 56.1 (CH2),
78.2 ( CH), 78.9 ( C), 103.2 (C-2,6), 112.4, 114.3, 129.1, 131.7 (4C, Ar), 135.1 (C-9,10),
140.0 (C-15), 153.2 (C-16), 161.3 (C-3,5); HR-MS (ESI) Calcd for C19H17BrN4O [M+2Na-2H]
417.0586 found 417.0538.
3,5-Dimethyl-4-[5-methyl-2-(prop-2-ynyloxy)phenyl]-1,4,7,8-tetrahydrodipyrazolo[3,4-
b:4’3’-e]pyridine (5e). Yield 75%, mp 249-251 °C; IR (KBr) (νmax/cm-1): 3366, 3284, 1606,
1490; 1H NMR (300.13 MHz, DMSO-d6): δH 2.08 (s, 6H, 2CH3), 2.15 (s, 3H, CH3), 3.52 (s, 1H,
CH), 4.70 (s, 2H, CH2), 5.05 (s, 1H, CH), 6.82-6.88 (m, 2H, Ar-H), 7.38 (s, 1H, Ar-H), 11.51
(br s, 3H, NH); 13C NMR (75.47 MHz, DMSO-d6): δC 11.0 (2CH3), 21.1, (CH3), 27.3 (CH), 56.4
(CH2), 78.3 ( CH), 80.1 ( C), 104.5 (C-2,6), 112.5, 127.3, 129.4, 130.4 (4C, Ar), 132.9 (C-
9,10), 140.6 (C-15), 152.4 (C-16), 162.0 (C-3,5); HR-MS (ESI) Calcd for C20H20N4O [M+NH4]
351.1926 found 351.1943.
3,5-Diethyl-4-phenyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine (5f).Yield 72%, mp
1
266-268 °C; IR (KBr) (νmax/cm-1): 3391, 1609, 1495; H NMR (300.13 MHz, DMSO-d6),
spectrum at 60 °C: δH 1.10 (t, 6H, J 7.2 Hz, 2CH3), 2.48-2.55 (m, 4H, 2CH2), 4.82 (s, 1H, CH),
13
7.11-7.20 (m, 5H, Ar-H), 11.20 (br s, 3H, NH); C NMR (75.47 MHz, DMSO-d6): δC 13.9
(2CH3), 18.5 (2CH2), 32.9 (CH), 103.9 (C-1,5), 125.8, 127.7, 128.1 (3C, Ar), 143.9 (C-9,10),
145.8 (C-13), 161.6 (C-2,4); HR-MS (ESI) Calcd for C17H19N5 [M+NH4] 311.1979 found
311.1973.
4-(4-Chlorophenyl)-3,5-dipropyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine (5g).
1
Yield 75%, mp 264 °C (decomp.); IR (KBr) (νmax/cm-1): 3352, 1602, 1520; H NMR (300.13
MHz, DMSO-d6): δH 0.86 (t, 6H, J 7.6 Hz, 2CH3), 1.42-1.57 (m, 4H, 2CH2), 2.48 (t, 4H, J 7.6
Hz, 2CH2), 4.79 (s, 1H, CH), 7.09 (d, 2H, J 8.4 Hz, Ar-H), 7.26 (d, 2H, J 8.8 Hz, Ar-H), 11.21-
13
11.74 (br s, 3H, NH); C NMR (75.47 MHz, DMSO-d6): δC 13.7 (2CH3), 22.1 (2CH2), 26.6
(2CH2), 32.1 (CH), 103.6 (C-1,5), 127.6, 129.2, 130.0 (3C, Ar), 140.1 (C-9,10), 142.5 (C-13),
161.1 (broad, C-2,4): HR-MS (ESI) Calcd for C19H22ClN5 [M+NH4] 373.1902 found 373.1943.
3,5-Dimethyl-4-(pyrid-2-yl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine (5h). Yield
1
78%, mp 218 °C (decomp.); IR (KBr) (νmax/cm-1): 3178, 3089, 1612, 1465; H NMR (300.13
MHz, DMSO-d6): δH 2.00 (s, 6H, 2CH3), 4.94 (s, 1H, CH), 7.15-7.29 (m, 2H, Ar-H), 7.60-7.67
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13
(m, 1H, Ar-H), 8.34-8.38 (m, 1H, Ar-H), 9.74 (br s, 3H, NH); C NMR (75.47 MHz, DMSO-
d6): δC 10.8 (2CH3), 36.6 (CH), 103.5 (C-8,12), 122.0, 122.9, 137.7 (3C, Ar), 140.2 (C-15,16),
148.1 (C-5), 160.7 (C-9,11), 162.4 (C-3); HR-MS (ESI) Calcd for C14H14N6 [2M+2Na] 578.2355
found 578.2304.
3,5-Dimethyl-4-(pyrid-3-yl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine (5i). Yield
1
63%, mp >270 °C; IR (KBr) (νmax/cm-1): 3313, 3197, 1604, 1481; H NMR (300.13 MHz,
DMSO-d6): δH 2.09 (s, 6H, 2CH3), 4.89 (s, 1H, CH), 7.22-7.26 (m, 1H, Ar-H), 7.50-7.54 (m, 1H,
Ar-H), 8.30-8.34 (m, 2H, Ar-H), 11.20-11.35 (br s, 3H, NH); 13C NMR (75.47 MHz, DMSO-d6):
δC 10.8 (2CH3), 31.1 (CH), 103.8 (C-8,12), 123.3, 135.5 (C-3), 139.1 (C-4), 140.1 (C-15,16),
147.0 (C-6), 149.5 (C-4), 161.4 (C-9,11); HR-MS (ESI) Calcd for C14H14N6 [2M-H+K]
569.2035 found 569.2069.
3,5-Dimethyl-4-propyl-1,4,7,8-tetrahydrodipyrazolo[3,4-b:4',3'-e]pyridine (5j). Yield 60%,
1
mp 262-264 °C; IR (KBr) (νmax/cm-1): 3367, 1621, 1494; H NMR (300.13 MHz, DMSO-d6),
spectrum at 60 °C: δH 0.81-0.85 (m, 3H, CH3), 1.08-1.12 (m, 2H, CH2), 1.78-1.84 (m, 2H, CH2),
13
2.06 (s, 6H, 2CH3), 2.40-2.52 (m, 1H, CH), 11.34 (s, 3H, NH), C NMR (75.47 MHz, DMSO-
d6): δC 10.1 (2CH3), 13.6 (CH3), 20.7 (2CH2), 27.7 (2CH3), 33.9 (CH), 105.3 (C-1,5), 138.7 (C-
7,12), 161.2 (C-2,4); HR-MS C12H17N5 (ESI) Calcd for [M+NH4] 249.1484 found 249.1486.
3,5-Dimethyl-7,8-dihydro-1H-spiro(dipyrazolo[3,4-b:4’,3’-e]pyridine-4,3’-indolin)-2’-one
(5k). Yield 55%, mp 242-244 °C; IR (KBr) (νmax/cm-1): 3423, 3251, 1718, 1616, 1519; 1H NMR
(300.13 MHz, DMSO-d6): δH 1.71 (s, 6H, 2CH3), 6.76-6.81 (m, 1H, Ar-H), 6.82-6.89 (m, 1H,
13
Ar-H), 7.07-7.18 (m, 2H, Ar-H), 9.81-11.20 (br s, 3H, NH), 10.55 (s, 1H, , NH); C NMR
(75.47 MHz, DMSO-d6): δC 11.7 (2CH3), 49.0 (spiro C), 99.4 (C-1, 5), 109.8, 121.5, 126.8,
128.0, 133.8 (5C, Ar), 137.4 (C-9, 10), 141.5 (C-N), 159.9 (C-2, 4), 181.7 (C=O); HR-MS
C16H14N6O (ESI) Calcd for [M+NH4] 324.1567 found 324.1510.
3',5'-Dimethyl-7',8'-dihydro-1'H,2H-spiro(acenaphthylene-1,4'-dipyrazolo[3,4-b:4',3'-
e]pyridin)-2-one (5l). Yield 40%, mp 232-235 °C; IR (KBr) (νmax/cm-1): 3269, 1722, 1604,
1517; 1H NMR (300.13 MHz, DMSO-d6): δH 1.78-1.82 (s, 6H, 2CH3), 7.42-7.70 (m, 1H, Ar-H),
7.52-7.63 (m, 1H, Ar-H), 7.71-7.88 (m, 3H, Ar-H), 8.10-8.30 (m, 1H, Ar-H), 8.86-11.24 (br m,
13
3H, NH); C NMR (75.47 MHz, DMSO-d6): δC 11.4 (2CH3), 52.7 (spiro C), 100.3 (C-13, 17),
121.3, 121.9, 123.1, 127.8, 128.5, 130.1, 131.1, 132.8, 137.4 (9C, Ar), 139.7 (C-20, 21), 143.4
(C, Ar), 158.9 (C-14, 16), 203.3 (C=O); HR-MS C20H15N5O (ESI) Calcd for [M+NH4] 359.1615
found 359.1639.
3,5-Diethyl-7,8-dihydro-1H-spiro(dipyrazolo[3,4-b:4’,3’-e]pyridine-4,3’-indolin)-2’-one
1
(5m). Yield 60%, mp 252-254 °C; IR (KBr) (νmax/cm-1): 3320, 1723, 1619, 1510; H NMR
(300.13 MHz, DMSO-d6): δH 0.70-0.82 (m, 6H, 2CH3), 2.06-2.09 (m, 4H, 2CH2), 6.80-6.85 (m,
1H, Ar-H), 6.85-6.88 (m, 1H, Ar-H), 7.11-7.20 (m, 2H, Ar-H), 9.06-11.24 (br s, 3H, NH), 10.67
13
(s, 1H, NH); C NMR (75.47 MHz, DMSO-d6): δc 14.1 (2CH3), 18.8 (2CH2), 49.4 (spiro C),
98.4 (C-1, 5), 109.9, 121.5, 126.4, 128.2, 133.6 (5C, Ar), 141.8 (C-9, 10), 142.9 (C-N), 159.8 (C-
2, 4), 182.3 (C=O); HR-MS C18H18N6O (ESI) Calcd for [M+NH4] 352.1880 found 352.1865.
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3',5'-Diethyl-7',8'-dihydro-1'H,2H-spiro(acenaphthylene-1,4'-dipyrazolo[3,4-b:4',3'-
e]pyridin)-2-one (5n). Yield 60%, mp 267-269 °C; IR (KBr) (νmax/cm-1): 3461, 3268, 1708,
1597, 1526; 1H NMR (300.13 MHz, DMSO-d6): δH 0.80-0.91 (m, 6H, 2CH3), 2.08-2.22 (m, 4H,
2CH2), 7.44 (d, 1H, J 6.8 Hz, Ar-H), 7.58-7.63 (m, 1H, Ar-H), 7.73-7.78 (m, 1H, Ar-H), 7.85-
13
7.90 (m, 2H, Ar-H), 8.21 (d, 1H, J 6.5 Hz, Ar-H), 8.91-11.37 (br m, 3H, NH); C NMR (75.47
MHz, DMSO-d6): δC 13.2 (2CH3), 18.5 (2CH2), 52.9 (spiro C), 99.5 (C-13, 17), 121.4, 121.8,
123.2, 127.9, 128.5, 130.0, 131.2, 132.7, 139.7 (9C, Ar), 143.0 (C-20, 21), 143.3 (C, Ar), 158.0
(C-14, 16), 203.2 (C=O); HR-MS (ESI) Calcd for C22H19N5O [M+NH4] 387.1928 found
387.1946.
3,5-Dipropyl-7,8-dihydro-1H-spiro(dipyrazolo[3,4-b:4’,3’-e]pyridine-4,3’-indolin)-2’-one
1
(5o). Yield 70%, mp 223-225 °C; IR (KBr) (νmax/cm-1): 3313, 1706, 1618, 1517; H NMR
(300.13 MHz, DMSO-d6): δH 0.62 (br s, 6H, 2CH3), 0.85-0.91 (m, 4H, 2CH2), 2.04-2.08 (m, 4H,
2CH2) 6.84-6.95 (m, 2H, Ar-H), 7.11-7.20 (m, 2H, Ar-H), 9.05-11.32 (br s, 3H, NH), 10.71 (s,
13
1H, NH); C NMR (75.47 MHz, DMSO-d6): δC 14.0 (2CH3), 22.9 (2CH2), 27.3 (2CH2), 49.4
(spiro C), 99, 109.9 (C-1, 5), 121.4, 126.1, 128.1, 132.9 (4C, Ar), 141.6 (C-9, 10), 160 (C-2, 4),
182.6 (C=O); HR-MS (ESI) Calcd for C20H22N6O [M+NH4] 380.2193 found 380.2181.
3',5'-Dipropyl-7',8'-dihydro-1'H,2H-spiro(acenaphthylene-1,4'-dipyrazolo[3,4-b:4',3'-
e]pyridine)-2-one (5p). Yield 76%, mp 284-286 °C; IR (KBr) (νmax/cm-1): 3283, 1682, 1596,
1
1523; H NMR (300.13 MHz, DMSO-d6), spectrum at 60 °C: δH 0.61 (t, 6H, J 7.5 Hz, 2CH3),
1.14-1.28 (m, 4H, 2CH2), 2.04 (t, 4H, J 7.5 Hz, 2CH2), 7.46 (d, 1H, J 6.7 Hz, Ar-H), 7.61-7.66
(m, 1H, Ar-H), 7.75-7.80 (m, 1H, Ar-H), 7.88-792 (m, 2H, Ar-H), 8.24 (d, 1H, J 8.0 Hz, Ar-H),
8.85-10.6 (br m, 3H, NH); 13C NMR (75.47 MHz, DMSO-d6): δC 13.7 (2CH3), 22.0 (2CH2), 27.2
(2CH2), 53.3 (spiro C), 99.4 (C-13, 17), 121.7, 121.9, 123.5, 128.0, 128.4, 130.1, 131.4, 132.4,
139.8 (9C, Ar), 141.8 (C-20, 21), 142.9 (C, Ar), 159.1 (C-14, 16), 203.8 (C=O); HR-MS (ESI)
Calcd for C24H23N5O [M+NH4] 415.2241 found 415.2200.
Acknowledgements
We gratefully acknowledge financial support from the Research Council of Shahid Beheshti
University and the University of New Brunswick.
References
1. Tejedor, D.; Garcia-Tellado, F. Chem. Soc. Rev. 2007, 36, 484-491.
http://dx.doi.org/10.1039/b608164a
2. Weber, L. Drug Discov. Today 2002, 7, 143-147.
http://dx.doi.org/10.1016/S1359-6446(01)02090-6
3. Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51-80.
Page 212
©ARKAT-USA, Inc

General Papers
ARKIVOC 2014 (iv) 204-214
http://dx.doi.org/10.2174/0929867033368600
4. Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168-3210.
http://dx.doi.org/10.1002/1521-3773(20000915)39:18<3168::AID-ANIE3168>3.0.CO;2-U
5. Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79-87.
6. Dabiri, M.; Salehi, P.; Bahramnejad, M.; Sherafat, F. J. Comb. Chem. 2010, 12, 638-642.
http://dx.doi.org/10.1021/cc100043z
7. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043-1052.
http://dx.doi.org/10.1016/S0223-5234(00)01189-2
8. Domling, A. Ugi, I. Angew. Chem. Intl. Ed. 1993, 32, 563-564.
9. Varache-Lembège, M.; Nuhrich, A.; Zemb, V.; Devaux, G.; Vacher, P.; Vacher, A. M.;
Dufy, B. Eur. J. Med. Chem. 1996, 31, 547-556.
http://dx.doi.org/10.1016/0223-5234(96)89551-1
10. Hantzsch, A. Ber. Dtsch. Chem. Ges. 1881, 14, 1637-1638.
http://dx.doi.org/10.1002/cber.18810140214
11. Ghosh, S.; Saikh, F.; Das, J.; Pramanik, A. K. Tetrahedron Lett. 2013, 54, 58-62.
http://dx.doi.org/10.1016/j.tetlet.2012.10.079
12. Acheson, R. M. An Introduction to the Chemistry of Heterocyclic Compounds, 2nd ed.;
Wiley: New York, 1967; p. 309.
13. Pulido, M. L.; Fenyes, J. G. Eur. Pat. Appl. 467,708, 1991; Chem. Abstr. 1992, 116,
146150J.
14. Ohyama H.; One, T., Terakawa, T. Eur. Pat. Appl 202,169, 1986; Chem. Abstr. 1987, 106,
33046t.
15. Zikan, V.; Radl, S.; Smejkal, F.; Zelena, D. Czech CS 233445, 1986; Chem. Abstr. 1987, 106,
138437q.
16. Harlin, W.; Linke, A.; Messer, E. Deut. Arch. Klin. Med. 1995, 201, 690-692; Chem. Abstr.
1956, 50, 11519c.
17. Roberts, D. A.; Hawkins, D.; Ross, W. Eur. Pat. Appl. 403,309, 1991; Chem. Abstr. 1991,
114, 185494c.
18. Pacousky, V.; Holecek, V. Casopis Lekaru Ceskych 1956, 95, 300-319; Chem. Abstr. 1956,
50, 7306c.
19. Hanefeld, U.; Rees, C. W.; White, A. J. P.; Williams, D. J. J. Chem. Soc., Perkin Trans. 1,
1996, 1545-1552.
http://dx.doi.org/10.1039/p19960001545
20. Yu, G.; Mason, H.; Wu, X.; Wang, J.; Chong, S.; Dorough, G.; Henwood, A.; Pongrac, R.;
Seliger, L.; He, B.; Normandin, D.; Adam, L.; Krupinski, J.; Macor, J. J. Med. Chem. 2001,
44, 1025-1027.
http://dx.doi.org/10.1021/jm0155042
21. Liu, C.; Li, Z.; Zhao, L.; Shen, L. Arkivoc, 2009, (ii), 258-268.
http://dx.doi.org/10.3998/ark.5550190.0010.224
22. Chen, Y. L. WO Pat. 9534563 A1, 1995; Chem. Abstr. 1995, 124, 232447.
Page 213
©ARKAT-USA, Inc

General Papers
ARKIVOC 2014 (iv) 204-214
23. Tao, Y. T.; Balasubramaniam, E.; Danel, A.; Tomasik, P. Appl. Phys. Lett. 2000, 77, 933-
935.
http://dx.doi.org/10.1063/1.1288811
24. Tao, Y. T.; Chuen, C. H.; Ko, C. W.; Peng, J. W. Chem. Mater. 2002, 14, 4256-4261.
http://dx.doi.org/10.1021/cm020284h
25. Sharma, C.; Sharma, S.; Sain, D.; Talesara, G.L. Indian J. Heterocycl. Chem. 2008, 18, 153-
156.
26. Zhao, K.; Lei, M.; Ma, L.; Hu, L. Monatsh. Chem. 2011, 142, 1169-1173.
http://dx.doi.org/10.1007/s00706-011-0565-8
27. Thakre, W.; Meshram, J. M. Indian J. Heterocycl. Chem. 2008, 18, 17-20.
28. Vasuki, G.; Kumaravel, K. Tetrahedron Lett. 2008, 49, 5636-5638.
http://dx.doi.org/10.1016/j.tetlet.2008.07.055
29. Litvinov, Y. M.; Shestopalov, A. A.; Rodinovskaya, L. A.; Shestopalov, A. M. J. Comb.
Chem. 2009, 11, 914-919.
http://dx.doi.org/10.1021/cc900076j
30. Kumaravel, K.; Vasuki, G. Green. Chem. 2009, 11, 1945-1947.
http://dx.doi.org/10.1039/b913838b
31. Sobhani, S.; Hasaninejad, A.-R.; Maleki, M. F.; Pakdin Parizi, Z. Synth. Commun. 2012, 42,
2245-2255.
http://dx.doi.org/10.1080/00397911.2011.555589
32. Hasaninejed, A.; Rasekhi Kazerooni, M.; Zare, A. ACS Sustainable Chem. Eng. 2013, 1,
679-684.
http://dx.doi.org/10.1021/sc400081c
33. Koohshari, M.; Dabiri, M.; Salehi, P. RSC Adv. 2014, 4, 10660-10671.
http://dx.doi.org/10.1039/c3ra47639a
Page 214
©ARKAT-USA, Inc