Aluminum hydrogen sulfate as a green catalyst for the solvent-free synthesis of pyrazolopyridines

Article abstract of DOI:10.1134/S1070363215050308

Aluminum hydrogen sulfate turned out to be a mild, convenient, and efficient reagent for the conversion of substituted benzyl alcohols into pyrazolopyridines via condensation with 3-methyl-1H-pyrazole-5-amine and CH acid (malononitrile or indan-1,3-dione)

Full text of DOI:10.1134/S1070363215050308

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 5, pp. 1179–1183. © Pleiades Publishing, Ltd., 2015.
Aluminum Hydrogen Sulfate as a Green Catalyst
for the Solvent-Free Synthesis of Pyrazolopyridines1
M. Nikpassanda and L. Zare Fekrib
a Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, Iran
e-mail: nikpassand@iaurasht.ac.ir
b Department of Chemistry, Payame Noor University, PO Box 19395-3697 Tehran, Iran
Received April 12, 2015
Abstract—Aluminum hydrogen sulfate turned out to be a mild, convenient, and efficient reagent for the
conversion of substituted benzyl alcohols into pyrazolopyridines via condensation with 3-methyl-1H-pyrazole-
5-amine and CH acid (malononitrile or indan-1,3-dione) at room temperature under solvent-free conditions
with high yield, high purity, and short reaction time.
Keywords: pyrazolopyridine, solvent free, aluminum hydrogen sulfate, green catalyst
DOI: 10.1134/S1070363215050308
The use of solid acids in organic reactions is
important since solid acids have many advantages such
as simplicity in handling, decreased reactor and plant
corrosion problems, and more environmentally safe
disposal. On the other hand, any reduction in the
amount of liquid acid is required for economic and
environmental protection. Among solid acids, Al
(HSO4)3 is a useful alternative to nitric acid as oxidant.
The pyrazolopyridine ring system represents the core
skeleton of a number of pharmaceutically important
heterocyclic compounds possessing a broad range of
biological activity, in particular potent cyclin kinase 1
(CDK1) inhibitors [1], HIV reverse transcriptase
inhibitors [2], CCR1 antagonists [3], protein kinase
inhibitors [4], inhibitors of cGMP degradation [5],
xanthine oxidase inhibitors [6], and antiviral [7],
antimalarial [8], vasodilator [9], antimicrobial [10],
anti-inflammatory [11], anxiolytic [12], hypoglycemic
[13], and antitumor agents [14].
of our knowledge, there has been no report on the
synthesis of pyrazolopyridine based on alcohols.
With the catalyst in hand (see Experimental), we
moved to study the effect of the catalyst amount on the
model reaction of 4-nitrobenzyl alcohol (Ia) with
malononitrile (II) and 3-methyl-1H-pyrazol-5-amine
(IV). No reaction occurred in the absence of Al(HSO4)3
even after extending the reaction time, whereas 10 mol %
of Al(HSO4)3 was sufficient to push the reaction
forward; lower or higher amount of the catalyst did not
improve the yield of pyrazolopyridine Va. The effect
of various solvents on the transformation of Ia into Va
in the presence of Al(HSO4)3 (10 mol %) was studied.
Acetonitrile, n-hexane, ethanol, chloroform, and
acetone, as well as solvent- free conditions, were tested
Table 1. Yields of pyrazolopyridine Va in the condensation
of 4-nitrobenzyl alcohol (Ia) with malononitrile (II) and
aminopyrazole IV in different solvents and under solvent-
free conditions at room temperature
In continuation of our ongoing studies on the
synthesis of heterocyclic and pharmaceutical compounds
using mild and practical protocols [15–18], herein we
report our experimental results on the synthesis of Al
(HSO4)3 and its application as a green oxidizing
catalyst for the synthesis of pyrazolopyridines from
different substituted benzyl alcohols, malononitrile or
indan-1,3-dione, and 3-methyl-1H-pyrazol-5-amine
under solvent-free condition (Scheme 1). To the best
Solvent
Acetonitrile
n-Hexane
Ethanol
Time, min
Yield, %
57
5
10
5
Traces
78
Chloroform
Acetone
5
64
5
37
1 The text was submitted by the authors in English.
No solvent
4
97
1179

1180
NIKPASSAND, ZARE FEKRI
Scheme 1.
N
NH
Me
Me
Al(HSO4)3
no solvent
OH
N
+
+
R
NC
CN
N
NH2
R
N
H
NH2
NC
Ia–If
II
IV
Va–Vf
NH
N
O
Al(HSO4)3
no solvent
N
Me
1a–1f +
+ IV
O
R
O
III
VIa–VIf
N
NH
Me
Al(HSO4)3
4 min
OH
N
+ II + III + IV
O2N
NH2
O2N
NC
Va (96%)
Ia
I, V, VI, R = 4-O2N (a), 3-O2N (b), 2-O2N (c), 4-Cl (d), 4-Br (e), 3-Br (f).
Scheme 2.
N
NH
Me
Al(HSO4)3
4 min
OH
N
+ II + III + IV
O2N
NH2
O2N
NC
Va (96%)
Ia
at room temperature. The results are summarized in
Table 1.
thesis of pyrazolopyridines from different CH acids.
The results showed that Al(HSO4)3 is able to dis-
criminate between various CH acids including indan-
1,3-dione and malononitrile. The reaction of Ia with
equimolar amounts of CH acids II and III and pyrazole
IV (1 mmol each) in the presence of Al(HSO4)3 gave
96% of Va, while no condensation product derived
from indandione III was formed (Scheme 2).
Thus the best results are attained using 0.1 mmol of
Al(HSO4)3 per mmole of the other components under
solvent-free conditions. To investigate the scope of this
synthesis, different substituted benzyl alcohols Ia–If
were reacted with malononitrile (II) or indanedione
(III) and 3-methyl-1H-pyrazol-5-amine (IV) in the
presence of 10 mol % of Al(HSO4)3 in the absence of a
solvent at room temperature. The results are listed in
Table 2. The reaction proceeded smoothly yielding 91–
98% of pyrazolopyridines Va–Vf or VIa–VIf.
In continuation of our study, other catalysts such as
β-cyclodextrin, ceric ammonium nitrate, ceric ammo-
nium sulfate, tetrabutylammonium hydrogen sulfide,
urea–hydrogen peroxide, and copper(II) chloride
(0.1 mmol) were used in the synthesis of pyrazolopyridine
VIa in comparison to aluminum hydrogen sulfate. As
Following these results, we further investigated the
potential of Al(HSO4)3 for the chemoselective syn-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015

ALUMINUM HYDROGEN SULFATE AS A GREEN CATALYST
Table 2. Synthesis of pyrazolopyridines V and VI from benzyl alcohols using Al(HSO4)3
Benzyl
1181
mp, ºC
observed reported
R
CH acid
Product
Time, min
Yield,a, b
%
alcohol
Ia
Ia
Ib
Ib
Ic
Ic
Id
Id
Ie
Ie
If
4-O2N
4-O2N
3-O2N
3-O2N
2-O2N
2-O2N
4-Cl
II
III
II
Va
VIa
Vb
4
97
96
91
94
98
98
94
96
93
95
96
94
308–310
234–235
286–287
267–268
288–290
302–303
269–271
271–273
276–278
302–303
265–266
267–268
310–312
5
–
3
285–287
III
II
VIb
Vc
4
–
3
4
290–292
III
II
VIc
Vd
–
Instant
Instant
Instant
3
268–270
4-Cl
III
II
VId
Ve
–
4-Br
278–280
4-Br
III
II
VIe
V f
VIf
–
–
–
3-Br
3
If
3-Br
III
Instant
a
The products were identified by comparison of their IR and NMR spectra and physical properties with those of authentic samples
[19, 20]. b Isolated yield.
Table 3. Synthesis of pyrazolopyridine VIa in the presence of different catalysts
Catalyst
β-Cyclodextrin
Reaction conditions
100°C
Time, min
Yield, %
89
15
10
15
10
20
15
10
05
Ceric ammonium nitrate
Ceric ammonium sulfate
Tetrabutylammonium hydrogen sulfide
Urea–hydrogen peroxide
Copper chloride
100°C
85
100°C
91
100°C
85
100°C
91
100°C
76
Al(HSO4)3
100°C
92
Al(HSO4)3
Solvent free
96
follows from the data in Table 3, Al(HSO4)3 ensured
higher yield and shorter reaction time.
1H and 125 MHz for 13C) in DMSO-d6 or CDCl3 using
TMS as internal standard. Chemicals were purchased
from Merck and Fluka. All solvents used were dried
and distilled according to standard procedures. All
yields refer to the isolated products.
EXPERIMENTAL
The melting points were measured on an
Electrothermal 9100 apparatus. The IR spectra were
determined on a Shimadzu IR-470 spectrometer. The
1H NMR and 13C NMR spectra were recorded on a
Bruker Avance DRX-500 spectrometer (500 MHz for
General procedure for the preparation of
aluminum hydrogen sulfate. A 500-mL suction flask
was equipped with a constant pressure dropping funnel
and a gas outlet connected to a vacuum system through
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015

1182
NIKPASSAND, ZARE FEKRI
an absorbing solution (water) and an alkali trap. The
flask was charged with 66.7 g (0.5 mol) of anhydrous
aluminum chloride, and 147.1 g (1.5 mol) of con-
centrated sulfuric acid was added dropwise over a
period of 40 min at room temperature. Gaseous
hydrogen chloride evolved immediately. When the
addition of H2SO4 was complete, the mixture was
shaken for 30 min while removing the residual HCl by
suction. A white solid material was thus obtained.
Yield 158.5 g.
130.12, 131.10, 131.56, 131.99, 135.62, 135.78, 137.35,
139.74, 147.21, 148.52, 150.13, 158.76, 190.54. Found,
%: C 67.21; H 3.67; N 15.65. C20H12N4O3. Calculated,
%: C 67.41; H 3.39; N 15.72.
3-Methyl-4-(3-nitrophenyl)indeno[1,2-b]pyrazolo-
[4,3-e]pyridin-5(1H)-one (VIc). mp 302–303°C. IR
spectrum (KBr), ν, cm–1: 1535, 1581, 1639, 1682,
1
3086, 3124. H NMR spectrum (CDCl3), δ, ppm: 1.78
s (3H), 5.59 s (1H), 7.21 d (1H, J = 7.2 Hz), 7.28 t
(2H, J = 7.7 Hz), 7.30–7.49 m (2H), 7.49–7.76 m (1H),
7.69 d (1H, J = 7.2 Hz), 7.76 t (1H, J = 7.2 Hz), 11.23
s (1H). 13C NMR spectrum (CDCl3), δC, ppm: 10.98,
103.25, 104.75, 120.21, 122.40, 124.98, 127.62,
130.19, 131.46, 131.97, 132.06, 133.87, 136.22, 138.85,
143.48, 148.22, 149.98, 157.12, 189.26. Found, %: C
67.61; H 3.43; N 15.49. C20H12N4O3. Calculated, %: C
67.41; H 3.39; N 15.72.
General procedure for the preparation of
pyrazolopyridines Va–Vf and VIa–VIf. A mixture of
1 mmol of substituted benzyl alcohol Ia–If, 1 mmol of
malononitrile (II) or indan-1,3-dione (III), 1 mmol of
3-methyl-1H-pyrazol-5-amine (IV) and 0.1 mmol of
Al(HSO4)3 was stirred at room temperature until the
reaction was complete according to the TLC data
(EtOAc–petroleum ether, 1 : 4; see Table 2). The
mixture was diluted with 10 mL of acetone and
filtered, the filtrate was evaporated under reduced
pressure, and the resulting crude material was purified
by recrystallization from ethyl acetate. The newly
synthesized compounds were characterized by IR and
NMR spectra, and the others were identified by
comparison of their IR and physical properties with
those of authentic samples [19, 20].
4-(4-Chlorophenyl)-3-methylindeno[1,2-b]pyrazolo-
[4,3-e]pyridin-5(1H)-one (VId). mp 271–273°C. IR
spectrum (KBr), ν, cm–1: 1072, 1493, 1547, 1628,
1
1687, 3029, 3152, 3329. H NMR spectrum (CDCl3),
δ, ppm: 1.89 s (3H), 7.19 d (1H, J = 7.2 Hz), 7.26 d
(2H, J = 8.2 Hz), 7.35 d (2H, J = 8.2 Hz), 7.24 t (1H,
J = 76 Hz), 7.35 t (1H, J = 7.7 Hz), 7.65 t (1H, J =
7.1 Hz), 11.12 s (1H). 13C NMR spectrum (CDCl3), δC,
ppm: 10.37, 104.78, 105.87, 119.76, 121.38, 128.90,
130.14, 130.84, 131.87, 131.99, 132.04, 135.70, 137.32,
145.43, 147.87, 157.34, 190.02. Found, %: C 69.28; H
4.01; N 12.21. C20H14ClN3O. Calculated, %: C 69.47; H
3.50; N 12.15.
3-Methyl-4-(4-nitrophenyl)indeno[1,2-b]pyra-
zolo[4,3-e]pyridin-5(1H)-one (VIa). mp 234–235°C ,
IR spectrum (KBr), ν, cm–1: 1537, 1570, 1625, 1678,
1
3154, 3325. H NMR spectrum (CDCl3), δ, ppm: 1.77
s (3H), 7.21 d (1H, J = 7.2 Hz), 7.29 t (1H, J = 7.4 Hz),
7.40 t (1H, J = 7.5 Hz), 7.72 d (2H, J = 8.5 Hz), 7.76 d
(1H, J = 7.1 Hz), 8.12 d (2H, J = 8.2 Hz), 11.13 s
(1H).13C NMR spectrum (CDCl3), δC, ppm: 10.87,
103.14, 105.03, 120.21, 120.67, 125.68, 129.55, 131.12,
131.60, 133.35, 135.93, 137.09, 137.35, 146.99, 147.64,
154.03, 158.08, 190.23. Found, %: C 67.20; H 3.50; N
15.79. C20H12N4O3. Calculated, %: C 67.41; H 3.39; N
15.72.
4-(4-Bromophenyl)-3-methylindeno[1,2-b]pyra-
zolo[4,3-e]pyridin-5(1H)-one (VIe). mp 312–313°C.
IR spectrum (KBr), ν, cm–1: 1021, 1490, 1555, 1626,
1
1677, 3056, 3150, 3312. H NMR spectrum (CDCl3),
δ, ppm: 1.80 s (3H), 7.15 d (1H, J = 7.2 Hz), 7.25 d
(2H, J = 8.4 Hz), 7.29 d (2H, J = 8.2 Hz), 7.34 t (1H,
J = 7.8 Hz), 7.46 t (1H, J = 7.4 Hz), 7.65 d (1H, J =
7.2 Hz), 11.00 s (1H). 13C NMR spectrum (CDCl3), δC,
ppm: 10.97, 103.78, 105.52, 119.47, 120.21, 128.67,
130.34, 130.77, 130.94, 131.67 131.96, 135.42, 137.68,
145.93, 147.63, 157.23, 190.32. Found, %: C 69.78; H
3.75; N 10.51. C20H14BrN3O. Calculated, %: C 61.56;
H 3.10; N 10.77.
3-Methyl-4-(3-nitrophenyl)indeno[1,2-b]pyrazolo-
[4,3-e]pyridin-5(1H)-one (VIb). mp 286–287°C. IR
spectrum (KBr), ν, cm–1: 1466, 1546, 1569, 1690,
3067, 3125, 3345. 1H NMR spectrum (CDCl3), δ, ppm:
1.78 s (3H), 7.24 d (1H, J = 7.2 Hz), 7.30 t (1H, J =
7.2 Hz), 7.38 t (1H, J = 7.4 Hz), 7.58 t (1H, J =
7.8 Hz), 7.72 d (1H, J = 7.4 Hz), 7.78 (1H, J = 7.8 Hz),
7.92 d.d (1H, J = 8.1, 1.8 Hz), 8.09 s (1H), 11.07 s
(1H). 13C NMR spectrum (CDCl3), δC, ppm: 11.76,
102.87, 104.76, 120.41, 120.98, 121.87, 122.04,
4-(3-Bromophenyl)-3-methylindeno[1,2-b]pyra-
zolo[4,3-e]pyridin-5(1H)-one (VIf). mp 267–268°C.
IR spectrum (KBr), ν, cm–1: 1348, 1557, 1586, 1627,
1677, 3163, 3359. 1H NMR spectrum (CDCl3), δ, ppm:
1.77 s (3H), 6.67–7.00 m (2H), 7.09–7.13 m (1H), 7.30
t (1H, J = 7.5 Hz), 7.42 d (1H, J = 7.3 Hz), 7.56 d (1H,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015

ALUMINUM HYDROGEN SULFATE AS A GREEN CATALYST
1183
Int. Appl. no. WO 2004009589.
6. Hafez, A.A., Awad, I., and Ahmed, R., Collect. Czech.
Chem. Commun., 1993, vol. 58, p. 1198.
7. Trucker, T.J., Sisko, J.T., Tynebor, R.M., Williams, T.M.,
Felock, P.J., Flynn, J.A., Lai, M.T., Liang, Y.,
McGaughey, G., Liu, M., Miller, M., Moyer, G.,
Munshi, V., Poehnelt, R.P., Prasad, S., Reid, J.C.,
Sanchez, R., Torrent, M., Vacca, J.P., Wan, B.L., and
Yan, Y., J. Med. Chem., 2008, vol. 51, p. 6503.
J = 7.2 Hz), 7.79 d (1H, J = 8.2 Hz), 7.80 s (1H), 10.89
s (1H). 13C NMR spectrum (CDCl3), δC, ppm: 11.99,
105.88, 108.12, 123.14, 124.14, 124.56, 127.57,
129.65, 131.07, 131.39, 132.65, 132.26, 133.92, 136.71,
136.98, 137.85, 138.92, 141.00, 145.61, 192.61. Found,
%: C 61.32; H 3.69; N 10.78. C20H14BrN3O.
Calculated, %: C 61.56; H 3.10; N 10.77.
6-Amino-4-(3-bromophenyl)-3-methyl-1H-pyra-
zolo[3,4-b]pyridine-5-carbonitrile (Vf). mp 265–266°C.
IR spectrum (KBr), ν, cm–1: 3346, 3267, 3100, 2937,
8. Stein, R.G., Biel, J.H., and Singh, T., J. Med. Chem.,
1970, vol. 13, p. 153.
1
2256, 1600, 1504, 1558, 1375. H NMR spectrum
9. Straub, A., Benet-Buckoltz, J., Frode, R., Kem, A.,
Kohlsdorfer, C.M., Schmitt, P., Schwarz, T., Siefert, H.M.,
and Stasch, J.P., Bioorg. Med. Chem., 2002, vol. 10,
p. 1711.
(CDCl3), δ, ppm: 2.11 s (3H), 6.93 d (1H, J = 7.5 Hz),
7.64 d (1H, J = 8.0 Hz), 8.01–8.05 m (2H), 8.79 s (1H)
13
9.19 s (1H), 10.5 s (1H). C NMR spectrum (CDCl3),
10. de Mello, H., Echevarria, A., Bemardino, A.M., Canto-
Cavalheiro, M., and Leon, L.L., J. Med. Chem., 2004,
vol. 47, p. 5427.
11. Ochiai, H., Ishida, A., Ohtani, T., Kusumi, K.,
Kishikawa, K., Yamamoto, S., Takeda, H., Obata, T.,
Makai, H., and Toda, M., Bioorg. Med. Chem., 2004,
vol. 12, p. 4089.
δC, ppm: 10.87, 103.19, 105.23, 120.29, 125.48, 129.88,
131.84, 131.60, 133.43, 137.95, 146.39, 147.35, 155.03,
168.08. Found, %: C 51.10; H 3.00; N 21.45.
C14H10BrN5. Calculated, %: C 51.24; H 3.07; N 21.34.
ACKNOWLEDGMENTS
12. Bare, T.M., Mclaren, C.D., Campbell, J.B., Firor, J.W.,
Resch, J.F., Walters, C.P., Salama, A.I., Meiners, B.A.,
and Patel, J.B., J. Med. Chem., 1989, vol. 32, p. 2561.
The authors are grateful to the Research Council of
Rasht Branch, Islamic Azad University, for the partial
support of this study.
13. Hoehn, H., Polacek, I., and Schulze, E., J. Med. Chem.,
1973, vol. 16, p. 1340.
14. Chu, I. and Lynch, B.M., J. Med. Chem., 1975, vol. 18,
REFERENCES
p. 161.
1. Huang, S., Lin, R., Yu, Y., Connolly, P.J., Chiu, G., Li, S.,
Emanuel, S.L., and Middleton, A., Bioorg. Med. Chem.
Lett., 2007, vol. 17, p. 1243.
15. Zare, L. and Nikpassand, M., Chin. Chem. Lett., 2011,
vol. 22, p. 531.
16. Nikpassand, M., Zare, L., and Saberi, M., Monatsh.
Chem., 2012, vol. 143, p. 289.
17. Nikpassand, M., Zare, L., and Shafaati, T., Chin. J.
Chem., 2012, vol. 30, p. 604.
2. Saggar, S.A., Sisko, J.T., Tucker, T.J., Tynebor, R.M.,
Su, D.S., and Anthony, N.J., US Patent Appl. Publ.
no. 2007021442.
3. Zhang, P., Pennell, A.M.K., Wright, J.J.K., Chen, W.,
Leleti, M.R., Li, Y., Li, L., and Xu, Y., PCT Int. Appl.
Publ. no. WO 2007002293.
18. Nikpassand, M., Zare Fekri, L., Gharib, M., and Marvi, M.,
Lett. Org. Chem., 2012, vol. 9, p. 745.
19. Zare, L., Mahmoodi, N.O., Yahyazadeh, A., and
4. Chiu, G., Li, S., Connelly, P.J., Middleton, S.A.,
Emanuel, S.L., Huang, S., Lin, R., Lu, Y., PCT Int.
Appl. Publ. no. WO 2006130673.
5. Feurer, A., Luithle, J., Wirtz, S., Koenig, G., Stasch, J.,
Stahl, E., Schreiber, R., Wunder, F., and Lang, D., PCT
Mamaghani, M., Synth. Commun., 2012, vol. 41, p. 2323.
20. Nikpassand, M., Mamaghani, M, Shirini, F., and
Tabatabaeian, K.A., Ultrason. Sonochem., 2010, vol. 17,
p. 301.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 5 2015