An efficient synthesis of pyrazolo[3,4-b]pyridine derivatives in ionic liquid

Article abstract of DOI:10.1080/00397910903471796

A series of 3-methyl-1,4,6-triaryl-1H-pyrazolo[3,4-b]pyridines was synthesized via the reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine and,-unsaturated ketones in ionic liquid without any catalyst. This protocol has the advantages of easier work-up, milder reaction conditions, high yields and environmentally benign procedure. Copyright

Full text of DOI:10.1080/00397910903471796

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An Efficient Synthesis of Pyrazolo[3,4-
b]pyridine Derivatives in Ionic Liquid
Da-Qing Shi a , Yao Zhou b & Hai Liu a
a College of Chemistry, Chemical Engineering and Materials Science,
Key Laboratory of Organic Synthesis of Jiangsu Province, Soochow
University , Suzhou, P.R. China
b College of Chemistry and Chemical Engineering, Xuzhou Normal
University , Xuzhou, P.R. China
Published online: 09 Nov 2010.
To cite this article: Da-Qing Shi , Yao Zhou & Hai Liu (2010) An Efficient Synthesis of Pyrazolo[3,4-
b]pyridine Derivatives in Ionic Liquid, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:24, 3660-3668, DOI: 10.1080/00397910903471796
To link to this article: http://dx.doi.org/10.1080/00397910903471796
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Synthetic Communications1, 40: 3660–3668, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903471796
AN EFFICIENT SYNTHESIS OF PYRAZOLO[3,4-b]-
PYRIDINE DERIVATIVES IN IONIC LIQUID
Da-Qing Shi,1 Yao Zhou,2 and Hai Liu1
1College of Chemistry, Chemical Engineering and Materials Science, Key
Laboratory of Organic Synthesis of Jiangsu Province, Soochow University,
Suzhou, P.R. China
2College of Chemistry and Chemical Engineering, Xuzhou Normal University,
Xuzhou, P.R. China
A
series of 3-methyl-1,4,6-triaryl-1H-pyrazolo[3,4-b]pyridines was synthesized via
the reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine and a,b-unsaturated ketones in
ionic liquid without any catalyst. This protocol has the advantages of easier work-up, milder
reaction conditions, high yields and environmentally benign procedure.
Keywords: Ionic liquid; pyrazolo[3,4-b]pyridine; synthesis
INTRODUCTION
Pyrazole derivatives exhibit pharmacological activities such as hypotensive,
antibacterial, anti-inflammatory and antitumor properties.[1–4] In particular,
condensed pyrazoles are known for various biological activities, e.g., pyrazolo[3,4-
b]pyridines are useful for treatment of a wide variety of stress-related illnesses,
such as depression, Alzheimer’s disease, gastrointestinal disease, anorexia nervosa,
haemorrhaged stress, drug and alcohol withdrawal symptoms, drug addition and
infertility.[5] Pyrazolo[3,4-b]pyridine derivatives are generally prepared by reaction
of 5-aminopyrazole and substituted a,b-unsaturated nitriles in organic solvent (i.e.,
ethanol) using triethylamine as catalyst,[6–7] but most of them suffer from drawbacks
such as lower yields, and using organic solvent.
Room temperature ionic liquids, especially those based on 1-alkyl-3-
methylimidazolium cations, have shown great promise as an attractive alterative
to conventional organic solvents, and more attention has been currently focused
on organic reactions promoted by ionic liquids.[8] They are nonvolatile, recyclable,
nonexplosive, easily operable, and thermally robust.[9] There are many reports
concerning the applications of ionic liquid in organic reactions, such as
Friedel-Crafts reactions,[10] Diels-Alder reactions,[11] Heck reactions,[12] Pechmann
Received August 12, 2009.
Address correspondence to Da-Qing Shi, Department of Chemistry, College of Chemistry and
Chemical Engineering, Key Laboratory of Organic Synthesis of Jiangsu Province, Suzhou 215123,
China. E-mail: dqshi@suda.edu.cn
3660

SYNTHESIS OF PYRAZOLO[3,4-b]PYRIDINE
3661
Scheme 1. The synthetic route for the pyrazolo[3,4-b]pyridine derivatives 3.
condensations,[13] Biginelli reactions,[14] Beckmann rearrangements[15] and other
reactions.[16] As part of our current studies on the developments of new routes to
heterocyclic system in ionic liquid,[17] we herein described a facile synthesis of
pyrazolo[3,4-b]pyridine derivatives by the reaction of 3-methyl-1-phenyl-1H-
pyrazol-5-amine and a,b-unsaturated ketones in ionic liquid [bmim]Br without
any catalyst (Scheme 1).
Choosing an appropriate solvent is of crucial important for the successful
organic synthesis. To search for the optical solvent, the reaction of 3-methyl-1-
phenyl-1H-pyrazol-5-amine
1 and 1-(4-chlorophenyl)-3-(4-methylphenyl)prop-
2-en-1-one 2a was examined using different solvents, respectively. The results
are summarized in Table 1.
As can be seen from Table 1, the best result was obtained when the reaction
was carried out in [bmim]Br at 90 ꢀC (Table 1, entry 6). Indeed, the reaction using
[bmim]Br proceeded in higher yield and shorter reaction time than that using
another ionic liquids as reaction medium. [bmim]Br was chosen as the solvent for
all further reactions as it is environmentally friendly and the toxic organic reagents
can be avoided. Under these optimized reaction conditions, a series of pyrazolo[3,4-
b]pyridine derivatives 3 were synthesized. The results are summarized in Table 2.
As shown in Table 2, this protocol could be applied not only to the aromatic
rings of a,b-unsaturated ketones with electron-withdrawing groups (such as halide
and nitro groups), but also to a,b-unsaturated ketones with electron-donating
groups (such as alkyl and alkoxyl groups). Therefore, we concluded that the
Table 1. Solvent optimization for the synthesis of 3a
Reaction
temperature (ꢀC)
Reaction
time (h)
Isolated
yield (%)
Entry
Solvent
1
2
acetone
acetonitrile
ethanol
reflux
reflux
reflux
reflux
100
90
25
20
17
27
10
8.5
10
10
33
23
15
12
24
42
59
34
83
90
62
71
34
41
61
80
3
4
chloroform
DMF
5
6
[bmim]Br
[bmim]BF4
[bmim]PF6
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
7
90
90
8
9
r.t.
40
10
11
12
60
80

3662
D.-Q. SHI, Y. ZHOU, AND H. LIU
Table 2. The synthesis of 3 in ionic liquid [bmim]Br
Entry
Ar1
Ar2
Time (h)
Yield (%)
3a
3b
3c
3d
3e
3f
4-CH3C6H4
4-CH3C6H4
4-ClC6H4
4-ClC6H4
4-CH3OC6H4
4-CH3OC6H4
3-NO2C6H4
8.5
8
90
96
83
91
87
82
94
92
92
90
83
80
85
9
4-ClC6H4
4-BrC6H4
4-FC6H4
9
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
9.5
9
3g
3h
3i
3,4-Cl2C6H3
3,4-OCH2OC6H3
4-ClC6H4
9
8
4-ClC6H4
4-ClC6H4
8.5
8
3j
4-BrC6H4
4-BrC6H4
3k
3l
Naphthalen-2-yl
Naphthalen-2-yl
Naphthalen-2-yl
13
13
13
4-CH3C6H4
4-ClC6H4
3m
electronic nature of the substituents of aromatic rings of a,b-unsaturated ketones
has no significant effect on this reaction.
1
In this study, all the products 3 were characterized by mp, IR and H NMR
spectral data as well as HRMS analysis. The structure of 3j was further confirmed
by X-ray diffraction analysis. The molecular structure of 3j is shown in Figure 1.
Although the detailed mechanism of above reaction remains not to be fully
clarified, the formation of compounds 3 could be explained by a reaction sequence
presented in Scheme 2. We proposed that the reaction proceeded via a reaction
sequence of Michael addition, cyclization, dehydration and aromatization. First,
the Michael addition reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine 1 to a,b-
unsaturated ketones 2 give the intermediate product 4, which on intermolecular
cyclization and dehydration gave rise to 5. In the last step, the intermediate product
5 aromatized to product 3.
Figure 1. ORTEP diagram of 3j.

SYNTHESIS OF PYRAZOLO[3,4-b]PYRIDINE
3663
Scheme 2. The mechanistic pathway leading to the pyrazolo[3,4-b]pyridine.
In conclusion, we have developed an efficient synthesis of 3-methyl-1,4,6-
triaryl-1H-pyrazolo-[3,4-b]pyridines via the reaction of 3-methyl-1-phenyl-1H-
pyrazol-5-amine and a,b-unsaturated ketones in ionic liquid without any catalyst.
This protocol has the advantages of easier work-up, milder reaction conditions, high
yields and environmentally benign procedure.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected. IR
spectra were recorded on a Varian F-1000 spectrometer in KBr with absorptions
1
in cmꢁ1. H NMR was measured on a Varian-400 MHz spectrometer in DMSO-d6
with TMS as internal standard. High resolution mass spectra were obtained using
a time-of-flight mass spectrometry (TOF-MS) instrument.
General Procedure for the Preparation of 3-Methyl-1,4,6-triaryl-1H-
pyrazolo[3,4-b]pyridines (3)
A dry 50 mL flask was charged with 3-methyl-1-phenyl-1H-pyrazol-5-amine 1
(1 mmol), a,b-unsaturated ketones 2 (1 mmol), and ionic liquid [bmim]Br (2 mL).
The mixture was stirred at 90 ꢀC for 8–13 h to complete the reaction (monitored
by TLC), then 50 mL H2O was added. The solid was filtered off and washed with
water. The crude product was purified by recrystallization from ethanol to give 3.
SPECTRAL DATA
6-(4-Chlorophenyl)-3-methyl-1-phenyl-4-p-tolyl-1H-pyrazolo[3,4-
b]pyridine (3a)
Mp 155–157 ꢀC; 1H NMR (DMSO-d6) d: 2.27 (3H, s, CH3), 2.43 (3H, s, CH3),
7.30–7.40 (3H, m, ArH), 7.55–7.61 (6H, m, ArH), 7.75 (1H, s, ArH), 8.29 (2H, d,
J ¼ 8.4 Hz, ArH), 8.33 (2H, d, J ¼ 8.4 Hz, ArH); IR (KBr) n: 1595, 1577, 1555,
1513, 1472, 1385, 1345, 1309, 1149, 1093, 1052, 1015, 837, 819, 764, 730 cmꢁ1
HRMS calcd. for C26H2035ClN3, m=z: 409.1346 (Mþ); Found, m=z: 409.1345.
.

3664
D.-Q. SHI, Y. ZHOU, AND H. LIU
6-(4-Methoxyphenyl)-3-methyl-1-phenyl-4-p-tolyl-1H-pyrazolo[3,4-
b]pyridine (3b)
Mp 135–136 ꢀC; 1H NMR (DMSO-d6) d: 2.26 (3H, s, CH3), 2.24 (3H, s, CH3),
3.85 (3H, s, CH3O), 7.10 (2H, d, J ¼ 8.0 Hz, ArH), 7.34 (1H, t, J ¼ 7.2 Hz, ArH), 7.40
(2H, d, J ¼ 7.6 Hz, ArH), 7.55–7.62 (4H, m, ArH), 7.68 (1H, s, ArH), 8.25 (2H, d,
J ¼ 8.4 Hz, ArH), 8.38 (2H, d, J ¼ 8.0 Hz, ArH); IR (KBr) n: 1598, 1506, 1475,
1413, 1387, 1349, 1307, 1243, 1173, 1147, 1031, 824, 755, 691 cmꢁ1. HRMS calcd.
for C27H23N3O, m=z: 405.1841 (Mþ); Found, m=z: 405.1843.
4-(4-Chlorophenyl)-6-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine (3c)
Mp 134–136 ꢀC; 1H NMR (DMSO-d6) d: 2.24 (3H, s, CH3), 3.85 (3H, s,
CH3O), 7.09 (2H, d, J ¼ 8.4 Hz, ArH), 7.34 (1H, t, J ¼ 7.2 Hz, ArH), 7.57–7.65
(4H, m, ArH), 7.71 (3H, d, J ¼ 8.4 Hz, ArH), 8.24 (2H, d, J ¼ 8.4 Hz, ArH), 8.36
(2H, d, J ¼ 8.0 Hz, ArH); IR (KBr) v: 1600, 1575, 1559, 1505, 1490, 1387, 1351,
1243, 1185, 1145, 1088, 1053, 1028, 829, 756, 686 cmꢁ1. HRMS calcd. for
C26H2035ClN3O, m=z: 425.1295 (Mþ); Found, m=z: 425.1294.
4-(4-Chlorophenyl)-3-methyl-6-(3-nitrophenyl)-1-phenyl-1H-
pyrazolo[3,4-b]pyridine (3d)
Mp 194–196 ꢀC; 1H NMR (DMSO-d6) d: 2.28 (3H, s, CH3), 7.38 (1H, t,
J ¼ 7.2 Hz, ArH), 7.62 (2H, t, J ¼ 8.0 Hz, ArH), 7.68 (2H, d, J ¼ 8.0 Hz, ArH),
7.77 (2H, d, J ¼ 8.0 Hz, ArH), 7.85 (1H, t, J ¼ 8.0 Hz, ArH), 8.00 (1H, s, ArH),
8.32–8.36 (3H, m, ArH), 8.75 (1H, d, J ¼ 7.6 Hz, ArH), 9.06 (1H, s, ArH);
IR (KBr) v: 1596, 1577, 1554, 1526, 1503, 1344, 1290, 1246, 1154, 1145, 1092,
1014, 841, 761, 690 cmꢁ1. HRMS calcd. for C25H1735ClN4O2, m=z: 440.1040 (Mþ);
Found, m=z: 440.1053.
4-(4-Bromophenyl)-6-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine (3e)
Mp 138–140 ꢀC; 1H NMR (DMSO-d6) d: 2.26 (3H, s, CH3), 3.85 (3H, s,
CH3O), 7.10 (2H, d, J ¼ 8.0 Hz, ArH), 7.34 (1H, t, J ¼ 7.6 Hz, ArH), 7.58–7.66
(4H, m, ArH), 7.74 (1H, s, ArH), 7.79 (2H, d, J ¼ 7.6 Hz, ArH), 8.26 (2H, d,
J ¼ 8.4 Hz, ArH), 8.37 (2H, d, J ¼ 8.4 Hz, ArH); IR (KBr) v: 1598, 1574, 1555,
1506, 1474, 1414, 1350, 1239, 1253, 1173, 1035, 1011, 855, 825, 752 cmꢁ1. HRMS
calcd. for C26H2079BrN3O, m=z: 469.0790 (Mþ); Found, m=z: 469.0795.
4-(4-Fluorophenyl)-6-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine (3f)
Mp 131–132 ꢀC; 1H NMR (DMSO-d6) d: 2.25 (3H, s, CH3), 3.85 (3H, s,
CH3O), 7.10 (2H, d, J ¼ 8.8 Hz, ArH), 7.34 (1H, t, J ¼ 7.6 Hz, ArH), 7.42 (2H, t,
J ¼ 8.8 Hz, ArH), 7.60 (2H, t, J ¼ 8.0 Hz, ArH), 7.73–7.76 (3H, m, ArH), 8.26
(2H, d, J ¼ 8.4 Hz, ArH), 8.37 (2H, d, J ¼ 8.0 Hz, ArH); IR (KBr) v: 1598, 1565,

SYNTHESIS OF PYRAZOLO[3,4-b]PYRIDINE
3665
1510, 1476, 1416, 1350, 1308, 1241, 1173, 1158, 1032, 837, 756, 699 cmꢁ1. HRMS
calcd. for C26H20FN3O, m=z: 409.1590 (Mþ); Found, m=z: 409.1589.
4-(3,4-Dichlorophenyl)-6-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine (3g)
Mp 168–169 ꢀC; 1H NMR (DMSO-d6) d: 2.26 (3H, s, CH3), 3.85 (3H, s,
CH3O), 7.11 (2H, d, J ¼ 8.4 Hz, ArH), 7.35 (1H, t, J ¼ 7.6 Hz, ArH), 7.60 (2H, t,
J ¼ 7.2 Hz, ArH), 7.69 (1H, d, J ¼ 8.4 Hz, ArH), 7.80 (1H, s, ArH), 7.84 (1H, d, J ¼
8.4 Hz, ArH), 8.03 (1H, s, ArH), 8.27 (2H, d, J ¼ 8.4 Hz, ArH), 8.36 (2H, d,
J ¼ 8.4 Hz, ArH); IR (KBr) v: 1599, 1575, 1506, 1469, 1416, 1390, 1347, 1298,
1251, 1237, 1180, 1145, 1129, 1038, 833 cmꢁ1. HRMS calcd. for C26H1935Cl2N3O,
m=z: 459.0905 (Mþ); Found, m=z: 459.0900.
4-(3,4-Methylenedioxylphenyl)-6-(4-chlorophenyl)-3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]pyridine (3h)
Mp 162–164 ꢀC; 1H NMR (DMSO-d6) d: 2.34 (3H, s, CH3), 6.16 (2H, s,
OCH2O), 7.13 (1H, d, J ¼ 7.6 Hz, ArH), 7.18 (1H, d, J ¼ 8.0 Hz, ArH), 7.33–7.37
(2H, m, ArH), 7.58–7.62 (4H, m, ArH), 7.78 (1H, s, ArH), 8.31–8.35 (4H, m,
ArH); IR (KBr) v: 1592, 1560, 1505, 1473, 1443, 1385, 1247, 1227, 1094, 1037,
1010, 837, 809, 762, 693 cmꢁ1. HRMS calcd. for C26H1835ClN3O2, m=z: 439.1088
(Mþ); Found, m=z: 439.1091.
4,6-Bis(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-
b]pyridine (3i)
Mp 159–160 ꢀC; 1H NMR (DMSO-d6) d: 2.26 (3H, s, CH3), 7.35 (1H, t,
J ¼ 7.2 Hz, ArH), 7.58–7.62 (4H, m, ArH), 7.66 (2H, d, J ¼ 7.6 Hz, ArH), 7.73
(2H, d, J ¼ 7.2 Hz, ArH), 7.82 (1H, s, ArH), 8.30–8.34 (4H, m, ArH); IR (KBr) v:
1596, 1552, 1497, 1403, 1342, 1309, 1089, 1052, 858, 832, 766 cmꢁ1. HRMS calcd.
for C25H1735Cl2N3, m=z: 429.0800 (Mþ); Found, m=z: 429.0797.
4-(4-Bromophenyl)-6-(4-chlorophenyl)-3-methyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine (3j)
Mp 167–168 ꢀC; 1H NMR (DMSO-d6) d: 2.26 (3H, s, CH3), 7.35 (1H, t,
J ¼ 7.2 Hz, ArH), 7.57–7.61 (4H, m, ArH), 7.65 (2H, d, J ¼ 8.4 Hz, ArH), 7.74–7.75
(1H, m, ArH), 7.77–7.80 (2H, m, ArH), 8.28–8.34 (4H, m, ArH); IR (KBr) v: 1595,
1576, 1553, 1505, 1473, 1413, 1344, 1151, 1091, 1070, 1011, 856, 823, 756 cmꢁ1
HRMS calcd. for C25H1779Br35ClN3, m=z: 473.0294 (Mþ); Found, m=z: 473.0291.
.
4-(4-Bromophenyl)-3-methyl-6-(naphthalen-3-yl)-1-phenyl-1H-
pyrazolo[3,4-b]pyridine (3k)
Mp 158–159 ꢀC; 1H NMR (DMSO-d6) d: 2.28 (3H, s, CH3), 7.37 (1H, t,
J ¼ 7.6 Hz, ArH), 7.58–7.66 (4H, m, ArH), 7.70 (2H, d, J ¼ 7.6 Hz, ArH), 7.82

3666
D.-Q. SHI, Y. ZHOU, AND H. LIU
(2H, d, J ¼ 8.4 Hz, ArH), 7.97–8.01 (2H, m, ArH), 8.09 (2H, d, J ¼ 8.4 Hz, ArH),
8.40–8.48 (3H, m, ArH), 8.88 (1H, s, ArH); IR (KBr) v: 1597, 1577, 1549, 1503,
1487, 1418, 1159, 1070, 1011, 857, 830, 812, 753, 691 cmꢁ1. HRMS calcd. for
C29H2079BrN3, m=z: 489.0841 (Mþ); Found, m=z: 489.0840.
3-Methyl-6-(naphthalen-3-yl)-1-phenyl-4-p-tolyl-1H-pyrazolo[3,4-
b]pyridine (3l)
Mp 172–174 ꢀC; 1H NMR (DMSO-d6) d: 2.30 (3H, s, CH3), 2.46 (3H, s, CH3),
7.37 (1H, t, J ¼ 7.6 Hz, ArH), 7.43 (2H, d, J ¼ 8.0 Hz, ArH), 7.62–7.66 (6H, m, ArH),
7.98–8.00 (2H, m, ArH), 8.08–8.11 (2H, m, ArH), 8.41–8.49 (3H, m, ArH), 8.88 (1H,
s, ArH); IR (KBr) v: 1600, 1579, 1554, 1503, 1436, 1418, 1363, 1161, 1055, 814, 778,
751 cmꢁ1. HRMS calcd. for C30H23N3, m=z: 425.1892 (Mþ); Found, m=z: 425.1892.
4-(4-Chlorophenyl)-3-methyl-6-(naphthalen-3-yl)-1-phenyl-1H-
pyrazolo[3,4-b]pyridine (3m)
Mp 163–165 ꢀC; 1H NMR (DMSO-d6) d: 2.29 (3H, s, CH3), 7.38 (1H, t,
J ¼ 7.6 Hz, ArH), 7.59–7.70 (6H, m, ArH), 7.76–7.80 (2H, m, ArH), 7.99–8.02
(2H, m, ArH), 8.08–8.11 (2H, m, ArH), 8.40–8.43 (2H, m, ArH), 8.46–8.50 (1H,
m, ArH), 8.87–8.90 (1H, m, ArH); IR (KBr) v: 1598, 1578, 1558, 1506, 1491,
1412, 1197, 1147, 1089, 854, 834, 814, 756 743 cmꢁ1. HRMS calcd. for
C29H2035ClN3, m=z: 445.1346 (Mþ); Found, m=z: 445.1346.
Crystal Data for 3j
C25H17BrClN3; M ¼ 474.78, colorless block crystals, 0.60 ꢂ 0.30 ꢂ 0.20 mm,
˚
monoclinic, space group P21=c, a ¼ 15.023(3), b ¼ 6.6109(10), c ¼ 21.924(4) A,
3
b ¼ 102.019(4) , V ¼ 2129.7(6) A , Z ¼ 4, Dc ¼ 1.481 g cmꢁ3. F(000) ¼ 960,m(MoKa) ¼
ꢀ
˚
2.073 mmꢁ1. Intensity data were collected on Rigaku Mercury diffractometer with
˚
graphite monochromated MoKa radiation (k ¼ 0.71070 A) using x scan mode with
3.02ꢀ < h < 25.35ꢀ. 3786 unique reflections were measured and 3067 reflections
with I > 2r (I) were used in the refinement. The structure was solved by direct meth-
ods and expanded using Fourier techniques. The final cycle of full-matrix least
squares technique to R ¼ 0.1040 and wR ¼ 0.2767.
ACKNOWLEDGMENT
We are grateful to the Foundation of the Key Laboratory of Organic Synthesis
of Jiangsu Province for financial support.
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SYNTHESIS OF PYRAZOLO[3,4-b]PYRIDINE
3667
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