A green, efficient and recyclable Fe+3@K10 catalyst for the synthesis of bioactive pyrazolo[3,4-b]pyridin-6(7H)-ones under on water conditions

Article abstract of DOI:10.1016/j.molstruc.2013.07.060

An efficient regioselective one-pot three-component synthesis of 4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones and their bis-derivatives (Table 3 and Fig. 2) catalyzed by Fe⁺³-K10 montmorillonite (Fe⁺³@K10) under the Sharpless conditions ( On water contdiions) is described. This rapid method produced the products in short reaction times (10-15 min) and excellent yields (87-95%). The antibacterial activity of the synthesized products was examined. Some products showed promising activities.

Full text of DOI:10.1016/j.molstruc.2013.07.060

Accepted Manuscript
A green, efficient and recyclable Fe+3@K10 catalyst for the synthesis of bioac‐
tive pyrazolo[3,4-b]pyridin-6(7H)-ones under " on water" conditions
Manouchehr Mamaghani, Farhad Shirini, Nosrat O. Mahmoodi, Abbas Azimi-
Roshan, Hussein Hashemlou
PII:
S0022-2860(13)00679-0
DOI:
http://dx.doi.org/10.1016/j.molstruc.2013.07.060
MOLSTR 19938
Reference:
To appear in:
Journal of Molecular Structure
Please cite this article as: M. Mamaghani, F. Shirini, N.O. Mahmoodi, A. Azimi-Roshan, H. Hashemlou, A green,
efficient and recyclable Fe+3@K10 catalyst for the synthesis of bioactive pyrazolo[3,4-b]pyridin-6(7H)-ones under
" on water" conditions, Journal of Molecular Structure (2013), doi: http://dx.doi.org/10.1016/j.molstruc.
2013.07.060
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A green, efficient and recyclable Fe+3@K10 catalyst for the synthesis of
bioactive pyrazolo[3,4-b]pyridin-6(7H)-ones under "on water" conditions
Manouchehr Mamaghania*, Farhad Shirinia, Nosrat O. Mahmoodia, Abbas Azimi-Roshana and
Hussein Hashemloub
aDepartment of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914,
Rasht, Iran.
bDepartment of Chemistry, Payame Noor University, Tehran, Iran.
Abstract
An efficient regioselective one-pot three-component synthesis of 4-aryl-3-methyl-4,5-dihydro-
1H-pyrazolo[3,4-b]pyridin-6(7H)-ones and their bis-derivatives (Table 3 and Figure 2) catalyzed
by Fe+3-K10 montmorillonite (Fe+3@K10) under the Sharpless conditions (“On water”
contdiions) is described. This rapid method produced the products in short reaction times (10–15
min) and excellent yields (87–95%). The antibacterial activity of the synthesized products was
examined. Some products showed promising activities.
Keywords: Fe+3@K10, Three-component, Regioselective, Pyrazolopyridone, Antibacterial
activity.
1. Introduction
The need to reduce the amount of toxic waste and by-products arising from chemical
processes requires increasing emphasis on the use of less toxic and more environmentally
compatible materials in the design of new synthetic methods [1]. The use of water as a solvent
for organic transformations offers several “green chemistry” benefits [2]. The structure and
properties of water have been studied by scientists representing almost all fields of knowledge,
1

and new theoretical models continue to emerge. Water is known to enhance the rates and to
affect the selectivity of a wide variety of organic reactions [3].
On the other hand, fused heterocyclic systems having a partially reduced pyridine moiety
display a wide variety of applications in medicinal chemistry [4]. Medicinal chemistry often
relies on the synthesis of core chemical scaffolds, which can be further derivatised to improve
their biological activity or pharmacokinetic properties [5]. Hydropyridine annulated heterocycles
are found in a number of molecules possessing biological and/or pharmacological properties [6].
In particular pyrazolopyridine derivatives have received more and more attention in recent years.
Biological activities and pharmaceutical studies of this kind of products have been reported,
some of them have shown diverse bio-activities such as anti-viral agent [7], anxiolytic, inhibitors
of xanthine oxidases [8], antiviral and potential antimalarial agents [9], besides finding
applications as fluorescence standards and luminophores in organic light emitting diodes [10],
inhibitors, HIV reverse transcriptase inhibitors, inhibitors of cGMP degradation [11-12], potent
and selective inhibitors of A1 adenosine receptors, phosphodiesterase 4 (PDE4) inhibitors in
immune and inflammatory cells, glycogen synthase kinase-3 (GSK-3) inhibitors [13],
hypotensive, antibacterial, anti-inflammatory and antitumor properties [14]. In particular, the
structure-activity relationship (SAR) studies of 4-aminoaryl- pyrazolopyridinones (1), 7-alkyl-
1,5-bis-aryl-pyrazolopyridinones (2) as p38R inhibitors and 3-amino-1H-pyrazolo[4,3-
c]pyridine-4(5H)- one as kinase inhibitors (3) have been the subject of recent communications
(Figure 1) [5,15,16a].
<<Figure 1>>
The synthesis of pyrazolopyridone derivatives has been extensively explored in recent years [17-
25]. However, some of the reported methodologies for the synthesis of these products are
associated with several drawbacks such as prolonged reaction time, low yields, harsh reaction
conditions, use of expensive reagents and catalysts and tedious workup.
In the course of our current studies on the modification and use of heterogeneous solid acid
catalyst in organic transformations [26], we were motivated to search for a new and efficient
method for the synthesis of novel 4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-
6(7H)-ones and their bis-derivatives by using Fe+3@K10 under the conditions defined by
2

Sharpless and co-workers: when insoluble reactant(s) are stirred in aqueous emulsions or
suspensions without the addition of any organic co-solvents (“on water” conditions) [3,16b].
2. Experimental
2.1. Material and methods
Melting points were measured on an Electrothermal 9100 apparatus. FT-IR spectra were
1
13
determined on a Shimadzo FT-IR spectrometer. H NMR and C NMR spectra were recorded
on a 500 MHz Bruker DRX-500 in DMSO-d6 or CDCl3 as solvent and TMS as an internal
standard. Elemental analysis were done on a Carlo-Erba EA1110 CNNO-S analyzer 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.
2.2. Preparation of Fe+3-montmorillonite (Fe+3@K10) [ 27,28]
A total of 1% suspension of montmorillonite (K10) in a 1.5 mol/dm3 solution of FeCl3.6H2O was
stirred overnight. On settling, the supernatant solution was discarded and exchange process
repeated three times. The ion-exchanged material was filtered and washed free of chloride ion
(checked by 0.1M AgNO3) with deionised water and dried in air.
2.3. General procedure for the synthesis of (7a-s, 8a-h)
A solution of 5-amino-3-methyl-1H-pyrazole (1 mmol), 6,6-dimethyl-1,3,5-trioxane-2,4-dione (1
mmol), aryl aldehydes (1 mmol) (entry 8a-h, 0.5 mmol) and Fe+3@K10 (0.02 g) were reacted in
refluxing H2O (7 mL) in an oil bath for the required reaction times (Table 3, Figure 2). After
completion of the reaction, which was checked by TLC, the solvent was evaporated under
vacuum and the residue was purified by recrystallization from EtOH to furnish the desired
products (7a-s, 8a-h) (Table 3 and Figure 2).
2.3.1. 4-(furan-2-yl)-4,5-dihydro-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7d)
Yield 90%; Brown solid, mp >350 oC; FT-IR (KBr) (νmax/cm−1): 3170, 3150, 3037, 2975, 2920,
1650, 1510, 1250, 1040; 1H-NMR (CDCl3, 500 MHz): δH (ppm) 2.02 (s, 3H), 2.63 (dd, J = 15.9,
4.2 Hz, 1H), 2.79 (dd, J = 15.9, 7.0 Hz, 1H), 4.22 (t, J = 5.8 Hz, 1H), 5.98 (d, J = 2.5 Hz, 1H),
6.33 (s, 1H), 7.53 (s, 1H), 10.25 (s, 1H, NH), 11.81 (s, 1H, NH); Anal. Cald. for C11H11N3O2
(217.22): C, 60.82; H, 5.10; N, 19.34. Found: C, 60.65; H, 4.90; N, 19.15%.
2.3.2. 4,5-dihydro-3-methyl-4-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7e)
3

Light Yellow solid, mp >350 oC; FT-IR (KBr) (νmax/cm−1): 3200, 3160, 3120, 2950, 1650, 1620,
1510, 1330, 1100; 1H-NMR (DMSO-d6, 500 MHz): δH (ppm) 1.85 (s, 3H), 2.57 (dd, J = 16.0, 5.7
Hz, 1H), 2.87 (dd, J = 16.0, 7.2 Hz, 1H), 4.36 (t, J = 6.4 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 8.19
(d, J = 8.7 Hz, 2H), 10.39 (s, 1H, NH), 11.90 (s, 1H, NH); 13C-NMR (DMSO-d6, 125 MHz): δC
(ppm) 10.3, 34.6, 40.8, 101.6, 124.7, 129.2, 135.8, 147.2, 149.6, 152.6, 169.9; Anal. Cald. for
C13H12N4O3 (272.26): C, 57.35; H, 4.44; N, 20.58. Found: C, 57.12; H, 4.21; N, 20.75%.
2.3.3. 4,5-dihydro-3-methyl-4-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7f)
o
Yield 90%; White solid; mp 304-307 C; FT-IR (KBr) (νmax/cm−1): 3150, 3120, 3000, 2940,
1
2900, 1650, 1530, 1100; H-NMR (DMSO-d6, 500 MHz): δH (ppm) 1.82 (s, 3H), 2.55 (dd, J =
15.9, 5.9 Hz, 1H), 2.79 (dd, J = 15.9, 7.0 Hz, 1H), 4.14 (t, J = 6.4 Hz, 1H), 7.17 (dd, J = 8.2, 1.1
Hz, 2H), 7.21 (dt, J = 7.3, 1.1 Hz, 1H), 7.30 (t, J = 7.5 Hz, 2H), 10.28 (s, 1H, NH), 11.80 (s, 1H,
13
NH); C-NMR (DMSO-d6, 125 MHz): δC (ppm) 10.3, 34.9, 41.4, 102.8, 127.4, 127.8, 129.4,
135.4, 144.6, 149.6, 170.4; Anal. Cald. for C13H13N3O (227.26): C, 68.71; H, 5.77; N, 18.49.
Found: C, 68.50; H, 5.62; N, 18.32%.
2.3.4. 4-(4-chlorophenyl)-4,5-dihydro-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7g)
o
Yield 95%; White solid; mp 345-348 C; FT-IR (KBr) (νmax/cm−1): 3160, 3120, 3040, 2970,
1
2900, 1650, 1520, 1360, 1080, 1020; H-NMR (CDCl3, 500 MHz): δH (ppm) 1.84 (s, 3H), 2.53
(dd, J = 15.9, 5.9 Hz, 1H), 2.79 (dd, J = 15.9, 7.0 Hz, 1H), 4.17 (t, J = 6.4 Hz, 1H), 7.18 (d, J =
8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 10.32 (s, 1H, NH), 11.84 (s, 1H, NH); 13C-NMR (DMSO-
d6, 125 MHz): δC (ppm) 10.3, 34.2, 41.3, 102.3, 129.4, 129.7, 132.0, 135.6, 143.6, 149.6, 170.2;
Anal. Cald. for C13H12ClN3O (261.71): C, 59.66; H, 4.62; N, 16.06. Found: C, 59.75; H, 4.41;
N, 15.90%.
2.3.5. 4,5-dihydro-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7h)
o
Yield 90%; White solid; mp 311-312 C; FT-IR (KBr) (νmax/cm−1): 3180, 3160, 3050, 2950,
1
2900, 1655, 1610, 1510, 1090, 1030; H-NMR (DMSO-d6, 500 MHz): δH (ppm) 1.82 (s, 3H),
2.51 (dd, J = 15.8, 6.2 Hz, 1H), 2.73 (dd, J = 15.8, 6.9 Hz, 1H), 3.71 (s, 3H), 4.08 (t, J = 6.5 Hz,
1H), 6.86 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 10.25 (s, 1H, NH), 11.77 (s, 1H, NH);
13C-NMR (DMSO-d6, 125 MHz): δC (ppm) 10.3, 34.0, 41.7, 55.9, 103.1, 114.8, 128.8, 135.4,
4

136.5, 149.6, 158.8, 170.5; Anal. Cald. for C14H15N3O2 (257.29): C, 65.35; H, 5.88; N, 16.33.
Found: C, 65.10; H, 5.70; N, 16.48%.
2.3.6. 4-(2,4-dichlorophenyl)-4,5-dihydro-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7i)
o
Yield 94%; White solid; mp 233-234 C; FT-IR (KBr) (νmax/cm−1): 3200, 3160, 3140, 2900,
1650, 1620, 1080, 1050; 1H-NMR (CDCl3, 500 MHz): δH (ppm) 1.83 (s, 3H), 2.49 (dd, J = 16.0,
5.5 Hz, 1H), 2.86 (dd, J = 16.0, 7.4 Hz, 1H), 4.50 (t, J = 2.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H),
13
7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (d, 1H), 10.41 (s, 1H, NH), 11.94 (s, 1H, NH); C-NMR
(DMSO-d6, 125 MHz): δC (ppm) 10.2, 31.3, 39.5, 100.9, 128.7, 129.9, 130.8, 133.0, 133.9,
135.6, 140.3, 150.1, 169.6; Anal. Cald. for C13H11Cl2N3O (296.15): C, 52.72; H, 3.74; N, 14.19.
Found: C, 52.56; H, 3.58; N, 14.05%.
2.3.7. 4,5-dihydro-4-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7j)
o
Yield 94%; White solid; mp 233-234 C; FT-IR (KBr) (νmax/cm−1): 3110, 3040, 2980, 2920,
1640, 1520, 1380, 1080; 1H-NMR (CDCl3, 500 MHz): δH (ppm) 1.82 (s, 3H), 2.60 (dd, J = 15.8,
6.8 Hz, 1H), 2.71 (dd, J = 15.8, 6.8 Hz, 1H), 3.34 (s, 6H), 4.07 (t, J = 6.7 Hz, 1H), 6.63 (dd, J =
8.2, 2.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 10.25 (s, 1H, NH), 11.77 (s,
1H, NH); 13C-NMR (DMSO-d6, 125 MHz): δC (ppm) 10.34, 34.6, 41.7, 56.3, 56.4, 103.0, 111.9,
112.7, 119.6, 135.4, 136.9, 148.4, 149.6, 149.7, 170.6 (C=O); Anal. Cald. for C15H17N3O3
(287.31): C, 62.71; H, 5.96; N, 14.63. Found: C, 62.55; H, 6.10; N, 14.81%.
2.3.8. 4,5-dihydro-3-methyl-4-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7k)
o
Yield 90%; White solid; mp 303-305 C; FT-IR (KBr) (νmax/cm−1): 3180, 3160, 3040, 2980,
1
2900, 1655, 1600, 1570, 1530, 1080; H-NMR (DMSO-d6, 500 MHz): δH (ppm) 1.82 (s, 3H),
2.60 (d, J = 12.2 Hz, 1H), 2.82 (s, 1H), 4.36 (s, 1H), 7.32 (s, 1H), 7.54 (s, 1H), 8.43 (s, 2H),
13
10.38 (s, 1H, NH), 11.87 (s, 1H, NH); C-NMR (DMSO-d6, 125 MHz): δC (ppm) 10.3, 32.4,
41.0, 102.0, 124.6, 135.4, 135.6, 139.9, 148.8, 149.4, 149.6, 170.1 (C=O). Anal. Cald. for
C12H12N4O (228.25): C, 63.15; H, 5.30; N, 24.55. Found: C, 63.10; H, 5.20; N, 24.47%.
2.3.9. 4-(4-fluorophenyl)-4,5-dihydro-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7l)
5

o
Yield 90%; White solid; mp 304-307 C; FT-IR (KBr) (νmax/cm−1): 3180, 3120, 3040, 2980,
1
2910, 1645, 1615, 1530, 1505, 1230; H-NMR (DMSO-d6, 500 MHz): δH (ppm) 1.78 (s, 3H),
2.47 (dd, J = 15.9, 6.1 Hz, 1H), 2.74 (dd, J = 15.9, 6.4 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H), 7.10 (d,
J = 8.80 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 10.26 (s, 1H, NH), 11.78 (s, 1H, NH); Anal. Cald. for
C13H12FN3O (245.25): C, 63.66; H, 4.93; N, 17.13. Found: C, 63.50; H, 4.75; N, 17.00%.
2.3.10. 4,5-dihydro-4-(4-isopropylphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7m)
o
Yield 95%; White solid; mp 290-292 C; FT-IR (KBr) (νmax/cm−1): 3180, 3120, 3040, 2960,
1
1655, 1625, 1530, 1090; H-NMR (DMSO-d6, 500 MHz): δH (ppm) 1.16 (d, J = 6.02 Hz, 6H),
1.85 (s, 3H), 2.52 (d, J = 22.8 Hz, 1H), 2.79 (dd, J = 16.3, 6.48 Hz, 1H), 2.83 (m, 1H), 4.09 (s,
1H), 7.06 (d, J = 6.95 Hz, 2H), 7.15 (d, J = 6.8 Hz, 2H), 10.27 (s, 1H, NH), 11.79 (s, 1H, NH);
Anal. Cald. for C16H19N3O (269.34): C, 71.35; H, 7.11; N, 15.60. Found: C, 71.20; H, 6.95; N,
15.65%.
2.3.11. 4,5-dihydro-3-methyl-4-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7n)
o
Yield 90%; White solid; mp 307-309 C; FT-IR (KBr) (νmax/cm−1): 3145, 2992, 2894, 1652,
1523, 1189, 821; 1H-NMR (CDCl3, 500 MHz): δH (ppm) 1.85 (s, 3H), 2.54 (dd, J = 5.38 Hz, J =
15.98 Hz, 1H), 2.81(dd, J = 7.19 Hz, J = 16.00 Hz, 1H), 4.16 (t, J = 6.03 Hz, 1H), 7.14 (d, J =
5.90 Hz, 2H), 8.45 (t, J = 1.3 Hz, J = 5.95 Hz, 2H), 10.32 (s, 1H, NH), 11.85 (s, 1H, NH); 13C-
NMR (DMSO-d6, 100 MHz): δC (ppm) 9.9, 33.6, 40.6, 100.9, 122.8, 135.3, 149.2, 150.4, 152.9,
169.6 (C=O); Anal. Cald. for C12H12N4O (228.25): C, 63.15; H, 5.30; N, 24.55. Found: C, 63.20;
H, 5.25; N, 24.45%.
2.3.12. 4-(4-bromophenyl)-4,5-dihydro-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7o)
o
Yield 95%; White solid; mp 349-350 C; FT-IR (KBr) (νmax/cm−1): 3170, 3130, 3060, 3000,
2910, 1650, 1540, 1500, 1090; 1H-NMR (CDCl3, 500 MHz): δH (ppm) 1.80 (s, 3H), 2.48 (dd, J =
5.87 Hz, J = 15.91 Hz, 1H), 2.76 (dd, J = 7.09 Hz, J = 15.95 Hz, 1H), 4.12 (t, J = 6.32 Hz, 1H),
7.09 (t, J = 1.65 Hz, J = 8.45 Hz, 2H), 7.46 (m, 2H), 10.28 (s, 1H, NH), 11.80 (s, 1H, NH). 13C-
NMR (DMSO-d6, 100 MHz,): δC (ppm) 9.9, 33.8, 40.8, 101.9, 120.1, 129.7, 132.0, 135.2, 143.7,
149.2, 169.8 (C=O); Anal. Cald. for C13H12BrN3O (261.71): C, 51.00; H, 3.95; N, 13.72. Found:
C, 51.10; H, 3.90; N, 13.60%.
2.3.13. 4,5-dihydro-3-methyl-4-p-tolyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7p)
6

o
Yield 92%; White solid; mp 337-338 C; FT-IR (KBr) (νmax/cm−1): 3110, 3070, 2995, 2890,
1
1650, 1540, 1520, 1080; H-NMR (DMSO-d6, 400 MHz): δH (ppm) 1.83 (s, 3H), 2.27 (s, 3H),
2.54 (dd, J = 6.0 Hz, J = 15.2 Hz, 1H); 2.77 (dd, J = 6.8 Hz, J = 15.6 Hz, 1H); 4.10 (t, J = 6.4 Hz,
1H); 7.05 (d, J = 8.0 Hz, 2H); 7.12 (d, J = 8.0 Hz, 2H); 10.30 (s, 1H, NH); 11.81 (s, 1H, NH);
13C-NMR (DMSO-d6, 100 MHz): δC (ppm) 9.9, 21.1, 34.0, 41.2, 102.5, 127. 3, 129.6, 135.0,
136.0, 141.2, 149.2, 170.1 (C=O); Anal. Cald. for C14H15N3O (241.29): C, 69.69; H, 6.27; N,
17.41. Found: C, 69.85; H, 6.35; N, 17.35%.
2.3.14. 4,5-dihydro-4-(4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7q)
o
Yield 90%; White solid; mp 274-276 C; FT-IR (KBr) (νmax/cm−1): 3560, 3440, 3240, 3080,
1
2940, 2910, 1640, 1615, 1540, 1520, 1395, 1225; H-NMR (DMSO-d6, 500 MHz): δH (ppm)
1.82 (s, 3H), 2.48 (m, 1H), 2.72 (dd, J = 15.6, 6.6 Hz, 1H), 4.03 (t, J = 6.6 Hz, 1H), 6.69 (d, J =
8.2 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 9.28 (s, 1H, OH), 10.26 (s, 1H, NH), 11.78 (s, 1H, NH);
13C-NMR (DMSO-d6, 125 MHz): δC (ppm) 9.9, 33.7, 41.4, 103.0, 115.7, 128.4, 134.3, 135.0,
149.2, 156.4, 170.2 (C=O); Anal. Cald. for C13H13N3O2 (243.26): C, 64.19; H, 5.39; N, 17.27.
Found: C, 64.25; H, 5.47; N, 17.23%.
2.3.15. 4,5-dihydro-3-methyl-4-o-tolyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7r)
o
Yield 95%; White solid; mp 279-280 C; FT-IR (KBr) (νmax/cm−1): 3200, 3120, 3040, 2980,
1
2920, 1655, 1620, 1540, 1480, 1370, 1240, 1030, 815, 760; H-NMR (CDCl3, 500 MHz): δH
(ppm) 1.82 (s, 3H), 2.44 (dd, J = 16.1, 4.3 Hz, 1H), 2.74 (dd, J = 16.0, 7.4 Hz, 1H), 3.78 (s,
3H), 4.36 (dd, J = 7.4, 4.3 Hz, 1H), 6.77 (m, 2H), 6.95 (d, J = 8.11 Hz, 1H), 7.16 (dt, J = 8.52,
1.77 Hz, 1H), 10.19 (s, 1H, NH), 11.76 (s, 1H, NH); 13C-NMR (DMSO-d6, 125 MHz): δC (ppm)
9.8, 28.0, 40.6, 55.7, 101.5, 111.4, 120.8, 127.6, 128.3, 131.5, 134.9, 149.8, 156.7, 170.2 (C=O);
Anal. Cald. for C14H15N3O2 (257.29): C, 65.35; H, 5.87; N, 16.33. Found: C, 65.14; H, 5.70; N,
16.10%.
2.3.16. 4,5-dihydro-4-(2-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (7s)
o
Yield 95%; White solid; mp 303-305 C; FT-IR (KBr) (νmax/cm−1): 3350, 3105, 3030, 2960,
2880, 1655, 1595, 1520, 1460, 1390, 1245, 840, 75o; 1H-NMR (DMSO-d6, 500 MHz): δH (ppm)
1.88 (s, 3H), 2.55 (m, 1H), 2.72 (dd, J = 15.8, 7.3 Hz, 1H), 4.38 (dd, J = 7.3, 4.4 Hz, 1H), 6.68
(m, 2H), 6.83 (dd, J = 8.0, 0.8 Hz, 1H), 7.03 (m, 1H), 9.59 (s, 1H, OH), 10.23 (s, 1H, NH),
13
11.81 (s, 1H, NH); C-NMR (DMSO-d6, 125 MHz): δC (ppm) 9.8, 28.0, 40.60, 101.8, 115.6,
7

119.4, 127.7, 128.0, 129.8, 134.8, 149.8, 154.9, 170.4 (C=O); Anal. Cald. for C13H13N3O2
(243.29): C, 64.19; H, 5.39; N, 17.27. Found: C, 64.27; H, 5.20; N, 17.11%.
2.3.17. 4,5-dihydro-4-(4-(4,5,6,7-tetrahydro-3-methyl-6-oxo-1H-pyrazolo[3,4-b]pyridin-4-
yl)phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (8a)
Yield 93%; Light Yellow solid; mp >350 oC; FT-IR (νmax/cm−1): 3200, 3120, 3020, 2950, 2900,
1
1660, 1620, 1520, 1360, 1080; H NMR (CDCl3, 500 MHz): δH (ppm) 1.81 (s, 6H), 2.53 (m,
2H), 2.56 (dd, J = 16.7, 6.8 Hz, 2H), 4.10 (t, J = 6.3 Hz, 2H), 7.10 (s, 4H), 10.25 (s, 2H, NH),
11.79 (s, 2H, NH); 13C NMR 13C-NMR (DMSO-d6, 125 MHz): δC (ppm) 10.3, 34.4, 41.4, 102.8,
128.0, 135.5, 142.8, 149.5, 170.4 (C=O). Anal. Cald. for C20H20N6O2 (376.41): C, 63.82; H,
5.36; N, 22.33. Found: C, 63.78; H, 5.21; N, 22.15%.
2.3.18. 4,4'-(2,2'-(butane-1,4-diylbis(oxy))bis(2,1-phenylene))bis(3-methyl-4,5-dihydro-1H-
pyrazolo[3,4-b]pyridin-6(7H)-one) (8b)
o
Yield 95%; White solid; mp >350 C; FT-IR (KBr) (νmax/cm−1): 3215, 3080, 2940, 1660, 1615,
1
1600, 1535, 1365, 1240, 1060, 750; H-NMR (CDCl3, 500 MHz): δH (ppm) 1.78 (s, 6H), 1.88
(m, 4H), 2.50 (m, 2H), 2.70 (m, 2H), 4.05 (m, 4H), 4.37 (m, 2H), 6.73 (m, 2H), 6.78 (t, J = 7.36
13
Hz, 2H), 6.96 (d, J = 8.12 Hz, 2H), 7.13 (m, 2H), 10.18 (s, 2H, NH), 11.75 (s, 2H, NH); C-
NMR (DMSO-d6, 125 MHz): δC (ppm) 9.8, 26.1, 28.2, 28.3, 67.8, 101.4, 112.2, 120.7, 127.8,
128.3, 131.5, 134.9, 149.8, 156.1, 170.2 (C=O); Anal. Cald. for C30H32N6O4 (540.61): C, 66.65;
H, 5.97; N, 15.55. Found: C, 66.52; H, 5.85; N, 15.67%.
2.3.19. 4,4'-(2,2'-(hexane-1,6-diylbis(oxy))bis(2,1-phenylene))bis(3-methyl-4,5-dihydro-1H-
pyrazolo[3,4-b]pyridin-6(7H)-one) (8c)
o
Yield 92%; White solid; mp 259-260 C; FT-IR (KBr) (νmax/cm−1): 3240, 3040, 2930, 1650,
1620, 1600, 1520, 1440, 1360, 1240, 1050, 750; 1H-NMR (CDCl3, 500 MHz): δH (ppm) 1.45 (m,
4H), 1.74 (m, 4H), 1.78 (s, 6H), 2.50 (m, 2H), 2.70 (m, 2H), 3.98 (m, 4H), 4.36 (t, J = 5.91 Hz,
2H), 6.73 (m, 2H), 6.77 (t, J = 7.33 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 7.14 (m, 2H), 10.19 (s, 2H,
13
NH), 11.75 (s, 2H, NH); C-NMR (DMSO-d6, 125 MHz): δC (ppm) 9.8, 25.8, 28.3, 28.7, 29.1,
67.9, 101.4, 112.2, 120.7, 127.8, 128.3, 131.4, 134.9, 149.8, 156.2, 170.3 (C=O); Anal. Cald. for
C32H36N6O4 (568.67): C, 67.69; H, 6.38; N, 14.78. Found: C, 67.75; H, 6.31; N, 14.65%.
8

2.3.19. 4,4'-(4,4'-(hexane-1,6-diylbis(oxy))bis(3-methoxy-4,1-phenylene))bis(3-methyl-4,5-
dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) (8d)
o
Yield 95%; White solid; mp 219-220 C; FT-IR (KBr) (νmax/cm−1): 3170, 3120, 3060, 2940,
1
2900, 1655, 1615, 1520, 1370, 1260, 1230, 1040, 860, 800; H-NMR (CDCl3, 500 MHz): δH
(ppm) 1.41 (m, 4H), 1.66 (m, 4H), 1.78 (s, 6H), 2.54 (dd, J = 15.84, 6.7 Hz, 2H), 2.67 (dd, J =
15.84, 6.7 Hz, 2H), 3.66 (s, 6H), 3.86 (t, J = 6.44 Hz, 4H), 4.02 (t, J = 6.7 Hz, 2H), 6.56 (dd, J =
8.2, 1.90 Hz, 2H), 6.77 (d, J = 1.9 Hz, 2H), 6.81 (d, J = 8.2 Hz, 2H), 10.20 (s, 2H, NH), 11.73 (s,
2H, NH); 13C-NMR (DMSO-d6, 125 MHz): δC (ppm) 10.0, 25.8, 29.2, 34.2, 41.3, 56.0, 68.6,
102.7, 111.7, 113.5, 119.2, 135.0, 136.5, 147.3, 149.1, 149.5, 170.2 (C=O); Anal. Cald. for
C34H40N6O6 (628.72): C, 64.95; H, 6.41; N, 13.37. Found: C, 64.74; H, 6.67; N, 13.12%.
2.3.20. 4,4'-(2,2'-(1,4-phenylenebis(methylene))bis(oxy)bis(2,1-phenylene))bis(3-methyl-4,5-
dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) (8e)
o
Yield 90%; White solid; mp 204-205 C; FT-IR (KBr) (νmax/cm−1): 3215, 3040, 2970, 2920,
1660, 1620, 1600, 1530, 1380, 1240, 1040, 810, 740; 1H-NMR (DMSO-d6, 500 MHz): δH (ppm)
1.84 (s, 6H), 2.58 (d, J = 16.6 Hz, 2H), 2.81 (dd, J = 16.6, 6.2 Hz, 2H), 4.49 (s, br., 2H), 5.20 (s,
13
4H), 6.83 (m, 4H), 7.15 (m, 4H), 7.49 (s, 4H), 10.28 (s, 2H, NH), 11.86 (s, 2H, NH); C-NMR
(DMSO-d6, 125 MHz,): δC (ppm) 9.8, 19.0, 28.2, 56.5, 69.5, 101.4, 112.8, 121.1, 127.9, 128.0,
128.3, 131.8, 135.0, 137.2, 149.8, 155.7, 170.2 (C=O); Anal. Cald. for C34H32N6O4 (588.66): C,
69.37; H, 5.48; N, 14.28. Found: C, 69.20; H, 5.40; N, 14.13%.
2.3.21. 4,4'-(4,4'-(1,4-phenylenebis(methylene))bis(oxy)bis(4,1-phenylene))bis(3-methyl-4,5-
dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) (8f)
o
Yield 94%; White solid; mp 274-275 C; FT-IR (KBr) (νmax/cm−1): 3200, 3040, 2960, 2900,
1
1670, 1615, 1510, 1380, 1230, 1030, 840; H-NMR (DMSO-d6, 500 MHz): δH (ppm) 1.78 (s,
6H), 2.50 (m, 2H), 2.70 (dd, J = 15.8, 6.6 Hz, 2H), 4.04 (t, J = 6.6 Hz, 2H), 5.02 (s, 4H), 6.90
(d, J = 8.7 Hz, 4H), 7.03 (d, J = 8.7 Hz, 4H), 7.40 (s, 4H), 10.20 (s, 2H, NH), 11.73 (s, 2H, NH);
13C-NMR (DMSO-d6, 125 MHz): δC (ppm) 9.9, 33.6, 41.3, 69.4, 102.7, 115.3, 128.2, 128.4,
135.0, 136.4, 137.2, 149.1, 157.4, 170.1 (C=O); Anal. Cald. for C34H32N6O4 (588.66): C, 69.37;
H, 5.48; N, 14.28. Found: C, 69.45; H, 5.55; N, 14.30%.
2.3.22. 4,4'-(1,3-phenylene)bis(3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-one)
(8g)
9

o
Yield 90%; White solid; mp 379-380 C; FT-IR (KBr) (νmax/cm−1): 3200, 3040, 2980, 2920,
1660, 1615, 1520, 1370, 860, 800, 760, 700; 1H-NMR (CDCl3, 500 MHz): δH (ppm) 1.74 (s, 6H),
2.52 (m, 2H), 2.72 (dd, J = 15.9, 6.91 Hz, 2H), 4.07 (m, 2H), 6.97 (d, J = 7.5 Hz, 2H), 7.03 (s,
13
br., 1H), 7.20 (t, J = 7.5 Hz, 1H), 10.23 (s, 2H, NH), 11.73 (s, 2H, NH); C-NMR (DMSO-d6,
125 MHz): δC (ppm) 9.9, 34.5, 40.9, 102.3, 125.6, 126.4, 129.4, 135.1, 144.5, 149.1, 170.0
(C=O); Anal. Cald. for C20H20N6O2 (376.41): C, 63.82; H, 5.36; N, 22.33. Found: C, 63.70; H,
5.21; N, 22.16%.
2.3.23. 7-(3-methoxy-2-(6-(2-methoxy-6-(3-methyl-6-oxo-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-
b] pyridin-4-yl)phenoxy)hexyloxy)phenyl)-3-methyl-6,7-dihydro-1H-pyrazolo [4,3-b] pyridin-
5(4H)-one (8h)
o
Yield 87%; White solid; mp 269-270 C; FT-IR (KBr) (νmax/cm−1): 740, 790, 1060, 1080, 1210,
1
1270, 1360, 1440, 1520, 1585, 1620, 1655, 2930, 3035, 3130, 3210; H-NMR (DMSO-d6,
500MHz): δH (ppm) 1.50 (s, br. 4H), 1.73 (quint., J = 6.2 Hz, 4H), 1.80 (s, 6H), 2.47 (dd, J =
16.0, 6.6 Hz, 2H), 2.76 (dd, J = 16.0, 6.6 Hz, 2H), 3.78 (s, 6H), 3.94 (m, 4H), 4.46 (t, J = 6.6
Hz, 2H), 6.50 (dd, J = 7.6, 1.6 Hz, 2H), 6.90 (dd, J = 8.4, 1.6 Hz, 2H), 6.96 (t, J = 8.0 Hz, 2H),
10.31 (s, 2H, NH), 11.82 (s, 2H, NH); 13C-NMR (DMSO-d6, 125 MHz): δC (ppm) 9.8, 18.5, 25.8,
28.00, 30.2, 56.0, 73.0, 102.0, 111.6, 119.6, 124.3, 134.8, 137.3, 145.4, 149.6, 152.9, 170.0
(C=O); Anal. Cald. for C34H40N6O6 (628.72): C, 64.95; H, 6.41; N, 13.37. Found: C, 64.74; H,
6.35; N, 13.22%.
2.4. Determination of antimicrobial activity: A sterilized glass tube (5 mm diameter) was used
aseptically to make wells on plates. The antibacterial activity of compounds was assayed
biologically using the Agar well-diffusion method. A colony of each standard test organism was
sub-cultured in order to obtain fresh bacteria on the nutrient agar plates at 37°C for 18 h. To
preparations of suspensions of microorganisms (0.5 McFarland), one to two colonies from each
plate was dissolved in isotonic saline solution. Then Mueller-Hinton agar (Merck) plates were
prepared according to manufacturers’ instructions in order to evaluate the antibacterial activities
of compounds. The sterile Mueller-Hinton agar plates were inoculated with the bacteria. 0.01
gram of test samples was dissolved in 1 mL dimethyl sulfoxide (DMSO) to obtain a stock
solution. A concentration of 1 mg/ml or 100 µg/0.1mL of each sample was prepared. 0.1 mL of
prepared samples was dropped into each respective labeled well aseptically. The inoculated
plates were left on the table for 1 h to allow the each sample to diffuse into the agar. For
10

comparison, Gentamycin was used as a positive control and DMSO as a negative control. Test
organism growth may be affected by the inhibitory action of the test compound and so, a clear
zone around the disc appeared as an indication of the inhibition of the test organism growth. The
results of our tests were presented as the inhibition zones, given in millimeters (mm).
Measurements were obtained after 24 h for bacteria.
3. Results and discussion
Following our continued interest in the synthesis of heterocyclic compounds of biological
importance using eco-friendly methodologies [29-33], and prompted by the diverse biological
activities of pyrazolo[3,4-b]pyridinones, we envisioned our approach towards a regioselective
synthesis of novel derivatives of mono- and bispyrazolo[3,4-b]pyridin-6(7H)-one derivatives
(7a-s, 8a-h) by using Fe+3@K10 as an efficient and recyclable catalyst in one-pot three-
component reaction in refluxing H2O (Scheme 1). At the outset, in order to achieve optimal
reaction conditions for the synthesis of pyrazolo[3,4-b]pyridin-6(7H)-ones, the reaction of
equimolar amounts of 5-amino-3-methyl-1H-pyrazole (4), 6,6-dimethyl-1,3,5-trioxane-2,4-dione
(Meldrum's acid) (5) and 3-nitrobenzaldehyde (6a) in the presence of various amounts of readily
available Fe+3@K10 catalyst in different solvents was examined.
<<Scheme 1>>
Among the solvents tested the best yield and lowest reaction time was found when H2O was
employed in the presence of 0.02 g Fe+3-K10/1mmol substrate (Table 1). One reason for rate
acceleration in water may be explained by the classical hydrophobic effect. When non-polar
solutes (organic compounds) that are immiscible with water are dissolved/suspended in it, so
called clathrates are formed, which in turn, their coalescence into fewer, can increase the local
concentration of hydrophobic molecules and therefore the effective molarity of the reactants
[34].
To optimize the reaction condition, the effect of several acidic and basic catalysts (0.02
g/1mmol substrate ) on the efficiency of the reaction in aqueous medium was also examined by
using the synthesis of 7a as model reaction. This study revealed that Fe+3@K10 is the catalyst of
choice (Table 2). Therefore, preparation of all the mono- and bispyrazolo[3,4-b]pyridin-6(7H)-
ones described in this study were carried out under optimized conditions which furnished the
desired products (7a-s, 8a-h) (Scheme 1) in excellent yields (87–95%) and short reaction times
11

(10-15 min) (Table 3, Figure 2). Verification of the results presented in this study revealed that
aryl aldehydes containing both electron-releasing and electron-withdrawing substituent gave the
corresponding products in comparable yield and reaction time.
The catalyst, prepared by adapting the literature method [27,28] and was also recycled and
reused in the preparation of 7a as model compound in refluxing H2O. After each run the catalyst
was simply filtered, washed and activated at 120 oC. The result showed that after five successive
runs catalytic activity of the catalyst was remained without significant loss of activity (Table 4).
The structures of all new compounds were established by spectroscopic (FT-IR, 1H NMR, 13C
NMR) and elemental analyses and those of known products by comparison of their spectral data
and melting points with literature reports.
<<Table 1>>
<<Table 2>>
<<Figure 2>>
<<Table 3>>
<<Table 4>>
The in vitro antibacterial activities of compounds 7a-s and 8a-h were evaluated against gram-
positive and Gram-negative bacteria using the cultures of three different standard
microorganisms: Escherichia coli (E. coli) ATCC 25922 and Pseudomonas aeruginosa ATCC
27853 as gram-negative models, and Staphylococcus aureus (S. aureus) ATCC 29213 as a agram
positive model. The results of this study are presented in Table 5. As shown in the table,
compounds 7b-d, 7h, 7j-s and 8g exhibited good antibacterial activity against Pseudomonas
aeruginosa. Also the results indicate that compounds 7b-c, 7f-k, 7m-n, 7q-s, 8a-c and 8e have
moderate growth-inhibiting activity against Escherichia coli. Among these substances, 7b-d, 7g-
k, 7m-n, 7p-s, 8a, 8d and 8g show moderate growth inhibiting effects on Staphylococcus aureus.
<<Table 5>>
12

4. Conclusions
In summary, we have developed a simple one-pot three-component protocol for the synthesis of
mono- and bis-4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-ones (7a-s, 8a-h)
using Fe+3-K10 as an efficient solid acid catalyst in refluxing H2O. This new procedure offers
advantages such as reduced reaction time, mild reaction condition, higher yields and economic
viability of the catalyst. Simple process combined with easy of recovery and reuse of catalyst,
and employing water as solvent make this procedure economic, eco-friendly and a waste free
chemical process for the synthesis of pyrazolo[3,4-b]pyridin-6(7H)-ones and their bis-derivatives
and is amenable for iterative combinatorial library generation. Some of the compounds prepared
as part of this study exhibited good antibacterial activity against Pseudomonas aeruginosa.
Acknowledgment
Financial support from the Research Council of University of Guilan is sincerely
acknowledged. We also thank Dr. H. Kiyani.
References
1. M.I. Burguete, H. Erythropel, E. Garcia-Verdugo, S. Luis, V. Sans. Green. Chem. 10 (2008)
401-407.
2. M.C. Pirrung, K.D. Sarma, J. Am. Chem. Soc. 126 4(2004) 44-445.
3. A. Chanda, V.V. Fokin, Chem. Rev. 109 (2009) 725-748.
4. M.F.A. Adamo, E.F. Duffy, D. Donatib, P. Sarti-Fantonic, Tetrahedron 63 (2007) 2047-2052.
5. L.A. Smyth, T.P. Matthews, P.N. Horton, M.B. Hursthouse, I. Collins, Tetrahedron 66 (2010)
2843-2854.
6. S. Fadel, S. Hamri, Y. Hajbi, F. Suzenet, A. Hafid, E.M. Rakib, M. Khouili, M.D. Pujol, G.
Guillaumet, Arkivoc II (2011) 240-251.
7. A. Rahmati, Tetrahedron Lett. 51 (2010) 2967-2970.
8. X. Zhang, D. Li, X. Fan, X. Wang, X. Li, G. Qu, J. Wang, Mol. Divers. 14 (2010) 159-167.
9. J. Quiroga, J. Portilla, H. Serrano, R. Abonia, B. Insuasty, M. Noguerasb, J. Cobob,
Tetrahedron Lett. 48 (2007) 1987-1990.
13

10. K. Balamurugan, S. Perumal, J.C. Menendez, Tetrahedron 67 (2011) 3201-3208.
11. M. Nikpassand, M. Mamaghani, F. Shirini, K. Tabatabaeian, Ultrason. Sonochem. 17 (2010)
301-305.
12. C.L. Shi, D.Q. Shi, S.H. Kim, Z.B. Huang, S.J. Ji, M. Ji, Tetrahedron 64 (2008) 2425-2432.
13. A. Shaabani, M. Seyyedhamzeh, A. Maleki, M. Behnam, F. Rezazadeh, Tetrahedron Lett. 50
(2009) 2911-2913.
14. S. Paul, M. Gupta, R. Gupta, A. Loupyb, Tetrahedron Lett. 42 (2001) 3827-3829.
15. L.H. Pettus, R.P. Wurz, S. Xu, B. Herberich, B. Henkle, Q. Liu, H.J. McBride, S. Mu, M.H.
Plant, C.J. M. Saris, L. Sherman, L.M. Wong, S. Chmait, M.R. Lee, C. Mohr, F. Hsieh, A.S.
Tasker, J. Med. Chem. 53 (2010) 2973-2985.
16. (a) R.R. Milburn, O.R. Thiel, M. Achmatowicz, X. Wang, J. Zigterman, C. Bernard, J.T.
Colyer, E. DiVirgilio, R. Crockett, T.L. Correll, K. Nagapudi, K. Ranganathan, S.J. Hedley,
A. Allgeier, R.D. Larsen, Organic Process Research & Development 15 (2011) 31-43.
(b) S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless, Angew.
Chem., Int. Ed., 44 (2005) 3275-3279.
17. J. Quiroga, J. Trilleras, B. Insuasty, R. Abonia, M. Nogueras, J. Cobo, Tetrahedron Lett. 49
(2008) 2689–2691.
18. J. Quiroga, J. Trilleras, D. Pantoja, R. Abonia, B. Insuasty, M. Nogueras, J. Cobo,
Tetrahedron Lett. 51 (2010) 4717–4719.
19. R. Ghahremanzadeh, S. Ahadi, A. Bazgir, Tetrahedron Lett. 50 (2009): 7379–7381.
20. Z. Huang, Y. Hu, Y. Zhou, D. Shi, ACS Comb. Sci. 13 (2011) 45–49.
21. A. Kamal, P. Suresh, A. Mallareddy, B. Ashwini, K. Papagari, V. Reddy, P. Raju, J.R.
Tamboli, T.B. Shaik, N. Jain, S.V. Kalivendi, Bioorg. Med. Chem. 19 (2011) 2349–2358.
22. Z. Song-Lei, J. Shun-Jun, Z. Kai, L. Yu, Tetrahedron Lett. 49 (2008) 2578–2582.
23. S. Ahadi, R. Ghahremanzadeh, P. Mirzaei, A. Bazgir, Tetrahedron 65 (2009) 9316–9321.
24. A. Bazgir, M. Mohammadi-Khanaposhtani, A. Abolhasani-Soorki, Bioorg. Med. Chem. Lett.
18 (2008) 5800–5803.
25. R. Abonia, E. Rengifo, J. Quiroga, B. Insuasty, J. Cobob, M. Noguerasb, Tetrahedron 60
(2004) 8839–8843.
26. (a) F. Shirini, M. Mamaghani, S. V. Atghia, Appl. Clay Sci. 58 (2012) 67–72.
(b) F. Shirini, M. Mamaghani, S. V. Atghia, Catal. Commun. 12 (2011) 1088–1094.
14

27. P. Laszlo, A. Mathy, Helv. Chim. Acta. 70 (1987) 577-586.
28. M.P. Hart, D.R. Brown, J. Mol. Catal. A-Chem. 212 (2004) 315-321.
29. M. Mamaghani, A. Loghmanifar, M.R. Taati, Ultrason. Sonochem. 18 (2011) 45-48.
30. M. Nikpassand, M. Mamaghani, K. Tabatabaeian, M. Kupaei-Abiazi, Mol. Divers. 13 (2009)
389–393.
31. A. Azimi-Roshan, M. Mamaghani, N.O. Mahmoodi, F. Shirini, Chin. Chem. Lett. 23 (2012)
399-402.
32. M. Nikpassand, M. Mamaghani, K. Tabatabaeian, Molecules 14 (2009) 1468-1474.
33. M. Mamaghani, S. Dastmard, Ultrason. Sonochem. 16 (2009) 445–447.
34. M.C. Pirrung, K.D. Sarma, Tetrahedron 61 (2005) 11456-11472.
Figure Captions:
Figure 1. Amgen,s various p38α inhibitors (1,2) and a kinase inhibitor (3).
Scheme 1. Synthesis of mono- and bis-4-aryl -3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]
pyridin-6(7H)-ones.
Figure 2. Bispyrazolo[3,4-b]pyridin-6(7H)-ones (8a-h).
15

Figure 1: amgen,s various p38α inhibitors (1, 2) and a kinase inhibitor (3)
Cl
H
N
HN
H
N
R1
R2
N
O
N
N
N
O
HN
N
N
N
O
N
O
F
HN
R3
F
O
2
1
3
F
Scheme 1: Synthesis of mono- and bis-4-aryl -3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]
pyridin-6(7H)-ones
Ar
N
N
N
H
O
H
O
O
Fe+3-montmorillonite
7a-s
6
N
H2O, 100 oC
reflux
O
O
NH2
or
N
H
N
HN
5
O
4
HN
R
NH
O
H
O
6: ArCHO,
R
O
NH
H
8a-h
N
16

Figure 2. Novel Bispyrazolo[3,4-b]pyridin-6(7H)-ones (8a-h)
H
H
N
O
N
N
N
HN
O
O
HN
O(CH2)6O
NH
O
O
(CH2)n
O
OMe
MeO
NH
N
N
N
N
H
8b (n =1): 10 min, 95%
8c (n = 3): 12 min, 92%
8d: 10 min, 95%
H
H
H
H
N
O
H
N
N
N
O
N
N
O
O
O
NH
N
NH
N
O
N
H
N
H
8g (meta): 10 min, 90%
8a (para) [31]: 12 min, 93%
8e (ortho): 10 min, 90%
8f (para): 12 min, 94%
H
N
N
HN
O
OMe
O(CH2)6O
MeO
O
HN
N
NH
8h: 10 min, 87%
17

Table 1. Effect of various solvents in the synthesis of 7a.
Salvent
Time (min)
Yield (%)a
DMF
140
60
40
65
45
40
95
EtOH
CH2Cl2
1,4-dioxane
H2O
120
120
10
aIsolated yields.
Table 2. Effect of various catalysts in the synthesis of 7a in water.
Catalysta
L-proline
Time (min)
60
Yield (%)b
65
HOAc
100
120
140
80
40
35
40
55
NEt3
DABCO
p-TSA
K10 montmorillonite
Fe+3@K10
50
10
70
95
b
aAmount of catalyst 0.02 g/1 mmol substrate. Isolated yields.
18

Table 3. Synthesis of 4-aryl-3-methyl-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-one
derivatives 7a-s under optimized conditions.
Entry
7a
7b
7c
7d
7e
7f
Ar
MP (oC)
264-266 (265-267)c
301-303 (303-305)c
348-349 (347-349)c
> 350 (> 350)
> 350 (> 350)
304-307 (304-306)
345-348 (344-346)
311-312 (308-310)
> 350 (> 350)
233-234 (230-232)
303-305 (302-305)
304-307 (306-308)
290-292 (292-295)
307-309
Time (min)
Yield (%)a,b
3-O2NC6H4
2-thienyl
10
15
15
12
10
10
15
12
15
10
15
12
10
15
10
12
15
10
10
95
92
94
90
93
90
95
90
90
94
90
90
95
90
95
92
90
95
95
4-Me2NC6H4
2-Furyl
4-O2NC6H4
C6H5
7g
7h
7i
4-ClC6H4
4-MeOC6H4
2,4-Cl2C6H3
3,4-(MeO)2C6H3
pyridin-3-yl
4-FC6H4
7J
7k
7l
7m
7n
7o
7p
7q
7r
4-isopropyl
pyridin-4-yl
4-BrC6H4
349-350
4-MeC6H4
4-HOC6H4
2-MeOC6H4
2-HOC6H4
337-338
274-276
279-280
7s
303-305
a Isolated yields.b Identified by spectroscopic (FT- IR, 1H NMR,13C NMR) and elemental analyses. cMelting points
and spectroscopic data are consistent with reported values [31].
Table 4. Recyclability of Fe+3@K10 for synthesis of 7a in
19

refluxing H2O.
Entry
No. of recycling
Time (min) Yield (%)a
1
2
3
4
5
first
second
third
Fourth
fifth
10
10
10
10
10
95
93
91
91
87
aIsolated yields.
Table 5. Antimicrobial activity of the compounds (7a–s, 8a-h).
Antimicrobial activity (zone of inhibition in mm)
Conc. of compound in
DMSO µg/0.1mL
Entry
Compound
Pseudomonas
aeruginosa
Staphylococcus aureus
Escherichia .coli
1
2
3
4
5
6
7
8
9
100
100
100
100
100
100
100
100
100
_
_
9 (10)a
14 (12)a (13)b
15 (14)a (13)b
15(14)a (12)b
8
7a
7b
7c
7d
7e
7f
8 (10)a (9)b
9 (10)a (8)b
8
10 (10)a (8)b
8
9
_
_
9
_
8
10 (9)a
7
8 (10)a (9)b
15 (13)a (14)b
7
7g
7h
7i
8
7
10 (8)a
5 (6)a
10
100
9
10
12 (12)a (14)b
7j
11
12
13
14
15
16
17
18
19
20
21
22
23
24
100
100
100
100
100
100
100
100
100
100
100
100
100
100
10
9
14 (13)a (12)b
10 (8)a (9)b
11 (9)a (10)b
15 (13)a (114)b
10 (8)a (9)b
13 (10)a (11)b
14 (13)a (12)b
12 (11)a (10)b
16 (15)a (14)b
8
7k
7l
_
_
8 (7)a (9)b
8
7m
7n
7o
7p
7q
7r
7s
8
9 (10)a (9)b
_
_
10
_
11 (10)a (9)b
9 (8)a (10)b
8 (9)a
10
10 (9)a (11)b
11 (12)a (11)b
8
8
8a
8b
8c
8d
8e
_
9
10 (8)a
_
8 (10)a
_
8 (10)a
11
_
8
12 (11)a (9)b
8
20

25
26
27
28
29
100
100
100
100
100
_
8
_
_
9
8f
8g
14 (13)a (11)b
_
_
8
8h
23
----
22
-----
21
----
Gentamycin
DMSO
a Data of duplicated experiments.
b Data of triplicated experiments.
21

Graphical abstract
A green, efficient and recyclable Fe+3@K10 catalyst for the synthesis of
bioactive pyrazolo[3,4-b]pyridin-6(7H)-ones under "on water" conditions
Manouchehr Mamaghani*, Farhad Shirini, Nosrat O. Mahmoodi, Abbas Azimi-Roshan and
Hussein Hashemlou
Ar
N
N
N
O
H
O
O
H
Fe+3@K10
7a-s
6
N
H2O, 100 oC
reflux
O
O
or
NH2
N
H
N
HN
O
27 examples
5
4
O
O
HN
R
NH
6: ArCHO,
R
H
H
O
NH
8a-h
N
R:
,
O(CH2)6O
O
,
O
(CH2)n
OMe
MeO
n = 1, 3
OMe
,
O
O
O(CH2)6O
MeO
O
O
,
,
22

Highlights:
Novel bioactive pyrazolo[3,4-b]pyridin-6(7H)-ones and their bis-derivatives (27
examples) were synthesized.
An efficient procedure was designed using Fe+3-K10 montmorillonite (Fe+3@K10) as a
recyclable catalyst in H2O.
The procedure developed here is rapid, economic, eco-friendly and is amenable for
iterative combinatorial library generation.
23