An efficient regioselective sonochemical synthesis of novel 4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones

Article abstract of DOI:10.1016/j.cclet.2011.12.009

An efficient ultrasound-assisted preparation of a series of novel 4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones via the reaction of 5-amino-3-methyl-1H-pyrazole, Meldrum's acid and various arylaldehydes using one-pot three-component approach is described. This rapid method produced the products in short reaction times (3-4 min) and excellent yields (87-95%).

Full text of DOI:10.1016/j.cclet.2011.12.009

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 399–402
www.elsevier.com/locate/cclet
An efficient regioselective sonochemical synthesis of novel
4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones
*
Abbas Azimi Roshan, Manouchehr Mamaghani , Nosrat Ollah Mahmoodi, Farhad Shirini
Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran
Received 21 October 2011
Available online 3 March 2012
Abstract
An efficient ultrasound-assisted preparation of a series of novel 4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-
ones via the reaction of 5-amino-3-methyl-1H-pyrazole, Meldrum’s acid and various arylaldehydes using one-pot three-component
approach is described. This rapid method produced the products in short reaction times (3–4 min) and excellent yields (87–95%).
# 2011 Manouchehr Mamaghani. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Pyrazolo[3,4-b]pyridin-6(7H)-one; Meldrum’s acid; 5-Amino-3-methylpyrazole; One-pot; Ultrasonic irradiation; Three-component;
Regioselective
Multi-component reactions (MCRs) in which three or more reactants are brought together in a highly convergent
approach to rapidly build up molecular structure and complexity, high atom economy and environmentally benign
procedures, have occupied a prominent and advantageous position in pharmaceutical and synthetic chemistry [1,2].
On the other hand, pyrazole and its derivatives are key substructures in a large variety of compounds and pyrazole-
containing compounds have received considerable attention owing to their diverse biological activities and
pharmacological properties [3–6], some pyrazoles have been implemented as antileukemic [7], antitumor [8] and anti-
proliferative [9] agents. In addition combination of the pyrazole moiety with various heterocyclic ring systems have
been resulted in interesting biological and pharmacological properties [10–13]. In particular pyrazolopyridines have
attracted many interests in recent years as possible anti-viral agent [14,15], potent p38 kinase inhibitors [16], HIV
reverse transcriptase inhibitors [17], and inhibitors of cGMP degradation [18,19]. Some derivatives exhibit potential
antimalarial properties [20]. Others show intense fluorescence in the blue green region and have been considered for
applications as fluorescence standards and luminophores in organic light emitting diodes [21], bactericidal activity
[22], and also used as vasodilators [23] or evaluated for CCR1 antagonists and enzymatic inhibitory activities [24,25].
Therefore, extensive studies have been devoted to the synthesis and evaluation of activities of pyrazolopyridines [26].
However, most of these methods suffer from multi-step reactions, use of more expensive reagents, harsh reaction
conditions, long reaction times, low yields of products and low regioselectivity, therefore, development of an efficient
and versatile method is still required for the synthesis of pyrazolopyridines.
* Corresponding author.
E-mail addresses: m-chem41@guilan.ac.ir, mchem41@gmail.com (M. Mamaghani).
1001-8417/$ – see front matter # 2011 Manouchehr Mamaghani. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.12.009

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A.A. Roshan et al. / Chinese Chemical Letters 23 (2012) 399–402
Recently, the use of ultrasonic irradiation as clean, green and environmentally benign route to activate organic
reactions has attained greater value, compared to conventional heating. It has been used for a wide variety of organic
reactions, such as oxidations, reductions, cleavage of epoxides, multicomponent reactions, synthesis of ionic liquids
and N-heterocyclic compounds [27].
Our continued interests in heterocycles of potent medicinal values [27,28] and considering the great synthetic
potentiality of ultrasound induced organic reactions triggered us to explore the use of this methodology in the synthesis
of pyrazolopyridinones. In this report we have devised an efficient one-pot three-component reaction for the synthesis
of novel derivatives of pyrazolo[3,4-b]pyridin-6(7H)-ones (4a–n) from 5-amino-3-methyl-1H-pyrazole (1), 6,6-
dimethyl-1,3,5-trioxane-2,4-dione (Meldrum’s acid) (2) and aryl aldehydes (3a–n) under ultrasonic irradiation
(Scheme 1). Equimolar amounts of reactants 1, 2 and 3 (Table 1, entry n, 0.5 equiv.) in ethanol were placed into Pyrex-
glass open vessel and irradiated at 60 8C by ultrasound (45 kHz) to produce the desired pyrazolo[3,4-b]pyridin-6(7H)-
one derivatives (4a–n) in 3–4 min with excellent yields (87–95%) (Table 1). The reaction under conventional heating
using 4a and 4b as model compounds in refluxing ethanol, furnished the desired products in much longer reaction
times (120–140 min) and lower yields (45–50%) (Table 1). The structures of all the products were fully characterized
1
by spectroscopic (FT-IR, H NMR, 13C NMR) and elemental analyses.
The effect of several solvents (1,4-dioxane, CH3CN, DMF, EtOH, H2O) on the efficiency of the reaction was also
examined by using synthesis of 4a as model reaction. This study revealed that EtOH is the solvent of choice.
Interestingly this one-pot multicomponent approach also afforded an efficient protocol for the synthesis of bis-
pyrazolo[3,4-b]pyridin-6(7H)-one (Fig. 1) in high yield (90%) (Table 1).
Mechanistically the formation of the products (4a–n) can be visualized by initial Knoevenagel condensation of
arylaldehydes 3 and 6,6-dimethyl-1,3,5-trioxane-2,4-dione resulting in arylidene 5, followed by a Michael type
Ar
O
O
Ultrasound
EtOH, 60 oC
N
ArCHO
N
O
O
NH2
N
H
N
H
N
H
O
4a-n
3a-n
1
2
Ar: 3-NO2C6H4, 4-MeOC6H4, 4-Me2NC6H4, furan-2-yl, 4-NO2C6H4, C6H5, 4-ClC6H4, thiophen-2-yl,
2,4-Cl2C6H3, 3,4-(MeO)2C6H3, 4-FC6H4, 4-iPrC6H4, pyridin-3-yl, 1,4-phenylene
Scheme 1. Synthesis of 4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones 4a–n.
Table 1
Synthesis of 4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-one derivatives 4a–n.
Entry
Ar
MP (8C)
Time (min)
Yield (%)a,b
a
b
c
3-NO2C6H4
2-Thienyl
265–267
303–305
347–349
>350
3 (120)c
95 (50)c
95 (45)c
90
4 (140)c
4-Me2NC6H4
2-Furyl
3
4
4
3
3
3
3
3
3
4
4
d
e
87
4-NO2C6H4
C6H5
>350
95
f
304–306
344–346
308–310
230–232
306–308
292–295
302–305
>350
95
g
h
j
4-ClC6H4
95
4-MeOC6H4
3,4-(MeO)2C6H3
4-FC6H4
4-iPr C6H4
Pyridin-3-yl
1,4-phenylene
87
90
k
l
95
95
m
n
90
90
a
Isolated yields.
Identified by spectroscopic (FT-IR, 1H NMR, 13C NMR) and elemental analyses.
b
c
Classical method with heating in refluxing EtOH.

A.A. Roshan et al. / Chinese Chemical Letters 23 (2012) 399–402
401
N
HN
O
HN
NH
O
NH
N
Fig. 1. Synthesis of bis-pyrazolo[3,4-b]pyridin-6(7H)-one.
O
Ar
O
O
N
H
O
O
NH
2
- CH COCH
3
N
H
3
N
N
O
Ar
-CO
2
N
H
O
NH
N
H
H N
O
2
O
5
6
4
Scheme 2. Plausible mechanism of formation of 4a–n.
nucleophilic addition of C-4 of the pyrazole ring to the enone intermediate (5) and subsequent cyclodehydration to
furnish the desired compounds (Scheme 2).
A comparison of the results obtained under ultrasonic irradiations with those of conventional heating in refluxing
ethanol (Table 1) revealed that the reaction under ultrasonic irradiation proceeds in much lower reaction times and
excellent yields. The rate acceleration using ultrasonic irradiations may be due to cavitation phenomena, in which the
energy being transmitted more efficiently to the substrates [27a].
In summary, we have reported here a simple one-pot three component protocol under ultrasonic irradiation for the
synthesis of pyrazolo[3,4-b]pyridin-6(7H)-ones without catalyst in short reaction times (3–4 min) and excellent yields
(87–95%). The simplicity, easy workup, together with the use of inexpensive and environmentally friendly organic
solvent and clean source of energy are the notable features of this protocol. Moreover this method is also extendable to
the synthesis of bis-pyrazolo[3,4-b]pyridin-6(7H)-ones.
1. Experimental
Melting points were measured on an Electrothermal 9100 apparatus. For the ultrasound reactions, ultrasound
apparatus Astra 3D (9.5 L, 45 kHz frequency, input power with heating, 305 W, number of transducers, 2) from
TECNO-GAZ was used. FT-IR spectra were determined on a Shimadzo FT-IR spectrometer. 1H NMR and 13C NMR
spectra were recorded on a 500 MHz Bruker DRX-500 in DMSO as solvent and TMS as an internal standard.
Elemental analyses were done on a Carlo-Erba EA1110 CNNO-S analyser and agreed with the calculated values.
Chemicals were purchased from Merck and Aldrich. All solvents used were dried and distilled according to the
standard procedures.
A solution of 5-amino-3-methyl-1H-pyrazole (1 mmol), 6,6-dimethyl-1,3,5-trioxane-2,4-dione (1 mmol) and aryl
aldehydes (1 mmol) (Table 1, entry n, 0.5 mmol) were reacted in refluxing EtOH (7 mL) or placed into Pyrex glass
open vessel and irradiated in a water bath under silent condition by ultrasound (45 kHz) at 60 8C for the required
reaction times (Table 1). After completion of the reaction, which was checked by TLC the solvent was evaporated
under vacuum and the residue was purified by recrystallization from a mixture of EtOH and H2O to furnish the desired
products (4a–n) (Table 1).
4a: Yellow solid, 1H NMR (DMSO-d6): d 1.86 (s, 3H); 2.62 (dd, 1H); 2.89 (dd, 1H); 4.39 (t, 1H); 7.62 (t, 1H); 7.66
(d, 1H) 8.00 (s, 1H); 8.08 (dd, 1H); 10.40 (s, 1H, NH); 11.91 (s, 1H, NH). 13C NMR (DMSO-d6): d 10.3, 34.3, 41.0,
101.8, 122.4, 122.6, 131.1, 134.8, 135.8, 147.0, 148.9, 149.7, 169.9 (C O). FT-IR (KBr): n 3200, 3150 cmÀ1 (NH),

402
A.A. Roshan et al. / Chinese Chemical Letters 23 (2012) 399–402
1640 cmÀ1 (C O). Anal. Calcd. for C13H12N4O3 (272.26): C, 57.35; H, 4.44; N, 20.58%; Found: C, 57.15; H, 4.28 N,
20.41%.
4b: White solid, 1H NMR (DMSO-d6): d 2.02 (s, 3H); 2.64 (dd, 1H); 2.88 (dd, 1H,); 4.44 (dd, 1H,); 6.83 (d, 1H);
6.93 (dd, 1H); 7.32 (dd, 1H); 10.30 (s, 1H, NH); 11.86 (s, 1H, NH). 13C NMR (DMSO-d6): d 10.2, 30.0, 41.7, 103.3,
124.5, 125.1, 127.8, 135.6, 149.0, 149.1, 170.0 (C O). FT-IR (KBr): n 3160, 3100 cmÀ1 (NH), 1650 cmÀ1 (C O).
Anal. Calcd. for C11H11N3OS (233.29): C, 56.63; H, 4.75; N, 18.01%; Found: C, 56.30; H, 4.61; N, 17.85%.
4c: White solid, 1H NMR (DMSO-d6): d 1.83 (s, 3H), 2.49 (dd, 1H), 2.71 (dd, 1H), 2.83 (s, 6H), 4.0 (t, 1H), 6.65 (d,
2H), 6.97 (d, 2H), 10.22 (s, 1H, NH), 11.76 (s, 1H, NH); 13C NMR (DMSO-d6): d 10.3, 33.9, 41.9, 103.4, 113.5, 128.3,
132.0, 135.4, 149.6, 150.1, 170.7 (C O); FT-IR (KBr): 3180, 3160 cmÀ1 (NH), 1640 cmÀ1 (C O). Anal. Calcd. for
C15H18N4O (270.33): C, 66.65; H, 6.71; N, 20.72%; Found: C, 66.43; H, 6.51; N, 20.60%.
Acknowledgments
Financial support from the Research Council of University of Guilan is sincerely acknowledged. We also thank Dr.
H. Sobhi.
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