An efficient one-step synthesis of 1H-pyrazolo[3,4-b]pyridines in basic ionic liquid [bmim]OH

Article abstract of DOI:10.2174/157017812803521144

Chain 1,3-dicarbonyl compounds were firstly used as starting material to react with 5-amino-3-methyl-1- phenylpyrazol and aromatic aldehydes to prepare 1H-pyrazolo[3,4-b]pyridines in basic ionic liquid [bmim]OH. The onestep three-component reaction is sim

Full text of DOI:10.2174/157017812803521144

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Letters in Organic Chemistry, 2012, 9, 671-676
671
An Efficient One-Step Synthesis of 1H-pyrazolo[3,4-b]pyridines in Basic
Ionic Liquid [bmim]OH
Ling-ling Zhaoa,c, Yu Wanb, Hai-ying Wanga,c, Chao Wanga, Xiao-xiao Zhanga, Shu-ying Huanga,
Gui-xiang Liua, Liang-feng Chena and Hui Wua,b*
aSchool of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou, 221116, P. R. China
bJiangsu Key Laboratory of Biotechnology on Medical Plant, Xuzhou, 221116, P. R. China
cJiangsu Key Laboratory of Green Synthesis of Functional Material, Xuzhou, 221116, P. R. China
Received March 02, 2012: Revised August 01, 2012: Accepted September 06, 2012
Abstract: Chain 1,3-dicarbonyl compounds were firstly used as starting material to react with 5-amino-3-methyl-1-
phenylpyrazol and aromatic aldehydes to prepare 1H-pyrazolo[3,4-b]pyridines in basic ionic liquid [bmim]OH. The one-
step three-component reaction is simple and efficient. Additionally, water was the only one by-product during the whole
process.
Keywords: Basic ionic liquid, pyrazolo[3,4-b]pyridines.
1. INTRODUCTION
Herein, we report a new method to access pyrazolo[3,4-
b]pyridines via an efficient one-step three-component reac-
tion of chain 1,3-dicarbonyl compounds, 5-amino-3-methyl-
1-phenylpyrazol and aromatic aldehydes in basic ionic liquid
[bmim]OH. Moreover, basic ionic liquids are rarely used as
solvent in organic reactions, so, we hope our efforts can pro-
vide some support to the synthesis of pyrazolopyridines and
give some supplements for the applied range of basic ionic
liquids (Scheme 1).
Pyrazolopyridine is an important fused heterocyclic
framework which has attracted significant attention because
of their biological activities for many years. They were used
as dopamine D3 receptor antagonist, [1] partial agonist, [1]
dopamine D4 antagonist, [2] adenosine A1 receptor antago-
nist, [3] TYK2 kinase and PDE10a inhibitors [4, 5]. Particu-
larly, pyrazolo[3,4-b]pyridines are useful for the treatment of
a wide variety of stress-related illnesses, such as depression,
Alzheimer's disease, gastrointestinal disease, anorexia ner-
vosa, hemorrhaged stress, drug and alcohol withdrawal
symptoms, drug addiction and infertility [6]. Recently, pyra-
zolopyridines were used as inhibitors of the kinase LRRK2
to treat cancer and neurodegenerative diseases [7]. There-
fore, their synthesis is very important in medicine and phar-
maceutics chemistry.
2. RESULTS AND DISCUSSION
Initially, the three-component reaction of p-
fluorobenzaldehyde (1a), 5-amino-3-methyl-1-phenylpyrazol
(2) and acetylacetone (3) was investigated to optimize the
reaction conditions. The results are summarized in Table 1.
As can be seen, when water was chosen as solvent, the yield
was 58% (Entry 1). But when DMF (Entry 2) and DMSO
(Entry 3) was taken as medium, there is no desired product.
Then, ethanol, [bpy]Br, [bpy]BF4, [bmim]Br and [bmim]BF4
(Entries 4-8) was tested. It was found that the solvent with
higher pKa could give the higher yield, which indicated that
this reaction is a nucleophilic one. So, basic ionic liquid
[bmim]OH (pH=9~10) was used to increased the yield (91%,
Entry 9). Subsequently, we found the optimum temperature
is 60 oC (Entries 10-12). Finally, the reaction time was inves-
tigated. The results shown in Table 1 indicated that the opti-
mum condition is to react in [bmim]OH under 60 oC for 6 h.
By far, there have been many approaches to synthesize
pyrazoles. In 1986, Nielsen [8] firstly obtained pyrazolo[3,4-
b]quinolines from aminopyrazole, cyclohexanone and aro-
matic amine with P4O10 as catalyst. Then, pyrazolo[3,4-
b]quinolines were prepared by several groups in succession
[8-10]. But most of them are associated with one or more of
the following drawbacks: unavailable raw material, lower
yields, higher temperatures, rigorous reaction conditions and
use of organic solvent.
Most of all, due to their lower reactivity than that of ring
1,3-dicarbonyl compounds, chain 1,3-dicarbonyl compounds
haven’t been employed as substrate until now to synthesize
pyrazolo[3,4-b]pyridines.
Under the optimal conditions, the reaction of a variety of
aromatic aldehydes with acetylacetone and 5-amino-3-
methyl-1-phenylpyrazol was investigated (Table 2). The
Product 5 (except 5j), was obtained with the yields ranging
from 78 to 89 %. We think the reason is the activity of acety-
*Address correspondence to this author at the School of Chemistry and
Chemical Engineering, Jiangsu Normal University, Xuzhou, 221116, P. R.
China; Tel: +86 (0) 51683500434; Fax: +86 (0) 51683500431;
E-mail: zllcpu@163.com
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

672 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Zhao et al.
Ar
N
O
R
O
O
N
N
[bmim]OH
60oC
H2N
ArCHO
+
N
+
N
R
5 (R=CH3)
6 (R=OC2H5)
3 (R=CH3)
4 (R=OC2H5)
1
2
OH
N
N
[bmim]OH =
Scheme 1. One-pot synthesis of pyrazolo[3,4-b]pyridines.
Table 1. Optimization of Reaction Conditions.
Entry
Solvent
T(oC)
Time (h)
Yield (%)
1
2
H2O
60
60
60
60
60
60
60
60
60
25
40
80
60
60
60
60
6
6
6
6
6
6
6
6
6
6
6
6
2
4
8
10
58
NPa
NP
53
DMF
3
DMSO
4
EtOH (95%)
[bpy] Brb
5
NP
35
6
[bpy]BF4
[bmim]Br
[bmim]BF4
[bmim]OH
[bmim]OH
[bmim]OH
[bmim]OH
[bmim]OH
[bmim]OH
[bmim]OH
[bmim]OH
7
NP
46
8
9
91
10
11
12
13
14
15
NP
46
90
43
69
92
16
90
a: No desired products;
N
b: [bpy] is
.
the advantages that all the reactants were added at the begin-
ning and the same reaction conditions were maintained
throughout, the features of this process include: (1) commer-
cial available starting material; (2) mild reaction conditions;
(3) good yields; (4) convenient procedure; (5) water was the
only one by-product.
lacetone is too low to react with 3,4,5-trimethoxybenz-
aldehyde (1j) which has high steric hindrance and low reac-
tivity. The results indicated that the electronic nature of sub-
stituted group has no obvious influence on the yield. Subse-
quently, another chain 1,3-dicarbonyl compound ethyl ace-
toacetate (4) was used as reagent to react with aromatic alde-
hydes (1) and 5-amino-3-methyl-1-phenylpyrazol (2), the
yields of 6 displayed a similar regulation with that of 5.
3. EXPERIMENTAL
General Information
In summary, low active chain 1,3-dicarbonyl compounds
were applied to synthesize 1H-pyrazolo[3,4-b]pyridines in
basic ionic liquid [bmim]OH simply and efficiently. Besides
All reagents were purchased from commercial sources
and used without purification. TLC analysis was performed

An Efficient One-Step Synthesis of 1H-Pyrazolo[3,4-b]pyridines
Letters in Organic Chemistry, 2012, Vol. 9, No. 9
673
Table 2. Synthesis of Compounds 5 and 6 in Ionic Liquid [bmim]OH.
Entry
1
Ar
Product
Time (h)
Yield (%)
mp (oC)
5a
6a
5b
6b
5c
6c
5d
6d
5e
6e
5f
84
82
83
83
79
85
81
83
78
73
80
65
85
81
87
88
88
86
-
167-168
213-214
144-146
237-238
147-149
209-210
113-114
122-123
192-193
136-138
149-150
137-138
250-251
123-124
161-162
218-219
133-135
214-215
-
4-FC6H4
6
2
3
4-ClC6H4
4-BrC6H4
6
7
4
2,4-Cl2C6H3
4-CNC6H4
7
5
7
6
3-NO2C6H4
12
6
6f
5g
6g
5h
6h
5i
7
4-MeC6H4
8
4-MeOC6H4
2,3-(MeO)2C6H3
3,4,5-(MeO)3C6H2
6
9
6
6i
5j
10
6
6j
83
116-118
with glass backed plates precoated with silica gel and exam-
ined under UV (254 nm). NMR spectra were measured in
DMSO-d6 or CDCl3 with Me4Si as the internal standards on
a Bruker Advance DPX-400 at room temperature. IR spectra
were recorded on Bruker FTIR spectrometer, absorbances
are reported in cm-1.
2.46 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 7.07 (d, J = 8.4 Hz,
2H, ArH), 7.29-7.31 (m, 3H, ArH), 7.52 (t, J = 8.4 Hz, 2H,
ArH), 8.20 (d, J = 8.0 Hz, 2H, ArH). 13C NMR (100 MHz,
CDCl3): ꢀ 13.2, 23.6, 32.2, 59.9, 114.1, 120.3, 121.7, 124.0,
125.6, 128.2, 129.1, 131.8, 138.9, 143.0, 145.5, 148.9, 152.2,
154.1, 204.3. HR-MS: cacld for C23H21N3O2 (M+H)+
372.1707, found 372.1704.
General Procedure for the Preparation of 1H-
pyrazolo[3,4-b]pyridines
1-(4-(4-fluorophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pridine-5-yl)ethanone (5a).
Aromatic aldehyde (1, 2 mmol), 5-amino-3-methyl-1-
phenylpyrazol (2, 2 mmol), acetylacetone (3, 2 mmol), and
[bmim]OH (2 mL) were added into a one-necked 50 mL
round bottom flask, the mixture was then heated in a 60 oC
oil bath. When the reaction was finished (monitored by
TLC), distilled water was poured into, the deposition was
then filtered and recrystallized with DMF to give 5.
o
1
Yellow crystal (DMF), mp 167-168 C; H NMR (400MHz,
CDCl3): ꢀ 2.06 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.68 (s, 3H, CH3),
7.23(t, 2H, J=8.0 Hz, ArH), 7.32(t, 1H, J=7.2 Hz, ArH), 7.37-
7.40(m, 2H, ArH), 7.54(t, 2H, J=8.0 Hz, ArH), 8.30(d, 2H, J=8.0
Hz, ArH). 13C NMR (100MHz, CDCl3): ꢀ 14.4, 23.4, 32.3,
112.4, 115.3, 115.6, 120.4, 125.7, 129.1, 131.4, 131.5, 131.7,
138.8, 140.6, 142.8, 149.2, 153.9, 204.9. HR-MS: cacld for
C22H18FN3O (M+Na)+ 382.1326, found 382.1293.
With the same procedure, ethyl acetoacetate (4, 2 mmol)
was allowed to take place of acetylacetone to give product 6.
1-(4-(4-chlorophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pridine-5-yl)ethanone (5b).
Yellow crystal (DMF), mp 144-146 oC; 1H NMR
(400MHz, DMSO): ꢀ 2.02 (s, 3H, CH3), 2.11 (s, 3H, CH3),
1-(4-(4-methoxyphenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-yl)ethanone (5h).
o
1
Yellow crystal (DMF), mp 161.2-161.6 C; H NMR
(400MHz, CDCl3): 1.98 (s, 3H, CH3), 2.01 (s, 3H, CH3),

674 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Zhao et al.
2.60 (s, 3H, CH3), 7.35 (t, 1H, J=7.6 Hz, ArH), 7.48(d, 2H,
J=8.4 Hz, ArH), 7.58(t, 2H, J=7.6 Hz, ArH), 7.64 (d, 2H,
J=8.0 Hz, ArH), 8.24 (d, 2H, J=8.4 Hz, ArH). 13C NMR
(100MHz, DMSO): ꢀ14.4, 23.4, 32.5, 112.2, 120.5, 125.8,
128.6, 129.2, 131.1, 133.1, 134.2, 138.8, 140.4, 142.8, 154.0,
173.1, 211.1. HR-MS: cacld for C22H18ClN3O (M+Na)+
398.1030, found 398.1007.
1-(3,6-dimethyl-1-phenyl-4-p-tolyl-1H-pyrazolo[3,4-
b]pyridine-5-yl)ethanone (5g).
Yellow crystal (DMF), mp 250-251 oC; 1H NMR
(400MHz, CDCl3): ꢀ 2.03 (s, 3H, CH3), 2.18 (s, 3H, CH3),
2.67 (s, 3H, CH3), 3.92 (s, 3H, CH3), 7.05 (d, 2H, J=8.4 Hz,
ArH), 7.32 (d, 3H, J=8.4 Hz, ArH), 7.54 (t, 2H, J=8.0 Hz,
ArH), 8.30 (d, 2H, J=8.0 Hz, ArH). 13C NMR (100MHz,
CDCl3): ꢀ 14.4, 23.4, 32.3, 112.4, 115.3, 115.6, 120.4, 125.7,
129.1, 131.4, 131.5, 131.7, 138.8, 142.8, 149.2, 153.9, 204.9.
HR-MS: cacld for C23H21N3O (M +Na)+ 378.1577, found
378.1561.
1-(4-(4-bromophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-yl)ethanone (5c).
Yellow crystal (DMF), mp 147-149 oC; 1H NMR
(400MHz, DMSO): ꢀ 2.02 (s, 3H, CH3), 2.11 (s, 3H, CH3),
2.60 (s, 3H, CH3), 7.35 (t, 1H, J=7.6 Hz, ArH), 7.41(d, 2H,
J=8.0 Hz, ArH), 7.57(t, 2H, J=8.4 Hz, ArH), 7.77 (d, 2H,
J=8.4 Hz, ArH), 8.24 (d, 2H, J=7.6 Hz, ArH). 13C NMR
(100MHz, DMSO): ꢀ 14.5, 23.4, 32.5, 112.7, 120.5, 122.8,
125.8, 129.2, 131.3, 131.4, 131.6, 133.4, 139.0, 140.4, 142.8,
154.0, 183.4, 204.8. HR-MS: cacld for C22H18BrN3O
(M+Na)+ 442.0531, found 442.0555.
1-(4-(2,3-dimethoxyphenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-yl)ethanone (5i).
Yellow crystal (DMF), mp 133-135 oC; 1H NMR
(400MHz, CDCl3): ꢀ 2.11 (s, 3H, CH3), 2.26 (s, 3H, CH3),
2.71 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 3.96 (s, 3H, OCH3),
6.81 (d, 1H, J=7.6 Hz, ArH), 7.07(d, 1H, J=8.0 Hz, ArH),
7.16(t, 1H, J=8.0 Hz, ArH), 7.31(d, 1H, J=7.2 Hz, ArH),
7.53 (t, 2H, J=7.6 Hz, ArH), 8.32 (d, 2H, J=8.0 Hz, ArH).
13C NMR (100MHz, CDCl3): ꢀ 13.2, 23.6, 32.2, 55.8, 59.9,
112.9, 114.1, 120.3, 121.7, 124.0, 125.6, 128.1, 129.1, 131.8,
138.4, 138.9, 143.0, 145.5, 148.9, 152.2, 154.1. HR-MS:
cacld for C24H23N3O3 (M +Na)+ 424.1632, found 424.1641.
1-(4-(2,4-dichlorophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-yl)ethanone (5d). ꢀ
Yellow crystal (DMF), mp 113-114 oC; 1H NMR
(400MHz, DMSO): ꢀ 1.97 (s, 3H, CH3), 2.27 (s, 3H, CH3),
2.65(s, 3H, CH3), 7.36 (t, 1H, J=7.6 Hz, ArH), 7.58(t, 2H,
J=8.0 Hz, ArH), 7.64(d, 1H, J=2.4 Hz, ArH), 7.70(dd, 1H,
J=8.4 Hz, ArH), 7.76 (d, 1H, J=8.8 Hz, ArH), 8.24 (d, 2H,
J=8.0 Hz, ArH). 13C NMR (100MHz, DMSO): ꢀ 13.0, 23.6,
32.0, 112.7, 116.1, 118.7, 120.5, 125.9, 129.2, 130.7, 131.0,
131.1, 132.0, 137.0, 138.7, 142.5, 149.1, 151.4, 154.7, 214.5.
HR-MS: cacld for C22H17Cl2N3O (M+H)+ 410.0821, found
410.0790.
Ethyl-4-(4-fluorophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pridine-5-carboxylate (6a).
White powder (DMF), mp 213-214 oC; 1H NMR
(400MHz, CDCl3): ꢀ 1.02 (t, 3H, CH3), 1.58 (s, 3H, CH3),
2.14 (s, 3H, CH3), 4.21 (q, 2H, CH2), 7.30 (t, 3H, J=8.0 Hz,
ArH), 7.46-7.57 (m, 4H, ArH), 8.42 (d, 2H, J=8.4 Hz, ArH).
13C NMR (100MHz, CDCl3): ꢀ 14.7, 15.0, 15.3, 62.5, 113.6,
115.3, 115.5, 120.3, 121.1, 125.2, 129.0, 130.2, 130.6, 130.7,
139.6, 140.2, 144.2, 150.5, 207.0. HR-MS: cacld for
C23H20FN3O2 (M+H)+ 390.1612, found 390.1611.
4-(5-acetyl-3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-
b]pyridine-4-yl)benzonitrile (5e).
Yellow crystal (DMF), mp 192-193 oC; 1H NMR
(400MHz, DMSO): ꢀ 1.97 (s, 3H, CH3), 2.14 (s, 3H, CH3),
2.62 (s, 3H, CH3), 7.35 (t, 1H, J=7.6 Hz, ArH), 7.58(t, 2H,
J=7.6 Hz, ArH), 7.68(d, 2H, J=8.0 Hz, ArH), 8.05 (d, 2H,
J=8.0 Hz, ArH), 8.24 (d, 2H, J=8.4 Hz, ArH). 13C NMR
(100MHz, DMSO): ꢀ 14.4, 23.5, 32.6, 103.4, 112.1, 118.4,
120.6, 125.9, 129.2, 130.3, 131.4, 132.3, 138.8, 139.1, 139.9,
142.7, 149.2, 154.1, 204.6. HR-MS: cacld for C23H18N4O
(M+H)+ 367.1553, found 367.1533.
Ethyl-4-(4-chlorophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxylate (6b).
Yellow crystal (DMF), mp 237-238 oC; 1H NMR
(400MHz, CDCl3): ꢀ 1.26 (t, 3H, CH3), 1.58 (s, 3H, CH3),
2.15 (s, 3H, CH3), 4.21 (q, 2H, CH2), 7.28-7.32 (m, 2H,
ArH), 7.43 (d, 1H, J=7.6 Hz, ArH), 7.51 (d, 2H, J=8.0 Hz,
ArH), 7.53 (d, 2H, J=8.0 Hz, ArH), 8.39 (d, 2H, J=8.0 Hz,
ArH). 13C NMR (100MHz, CDCl3): ꢀ 14.4, 23.4, 32.5, 69.0,
112.2, 120.5, 125.8, 128.6, 129.2, 131.1, 133.1, 134.2, 138.8,
140.4, 142.8, 154.0, 173.1. HR-MS: cacld for C23H20ClN3O2
(M+H)+ 406.1317, found 406.1316.
1-(3,6-dimethyl-4-(3-nitrophenyl)-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-yl)ethanone (5f).
Yellow crystal (DMF), mp 149-150 oC; 1H NMR
(400MHz, DMSO): ꢀ 1.98 (s, 3H, CH3), 2.01 (s, 3H, CH3),
2.53 (s, 3H, CH3), 7.06-7.54 (m, 5H, ArH), 7.58 (t, 1H,
J=8.0 Hz, ArH), 7.87 (d, 1H, J=7.6 Hz, ArH), 8.17 (d, 1H,
J=8.0 Hz, ArH), 8.42 (s, 1H, ArH). 13C NMR (100MHz,
DMSO): ꢀ 14.5, 23.4, 32.2, 113.8, 120.4, 125.7, 126.1, 127.1,
129.1, 130.6, 138.9, 141.7, 142.9, 149.3, 153.9, 158.7, 159.8,
174.9, 205.2. HR-MS: cacld for C22H18N4O3 (M+H)+
387.1452, found 387.1476.
Ethyl-4-(4-bromophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxylate (6c).
Yellow crystal (DMF), mp 209-210 oC; 1H NMR
(400MHz, CDCl3): ꢀ 1.02 (t, 3H, CH3), 1.57 (s, 3H, CH3),
2.14 (s, 3H, CH3), 4.09 (q, 2H, CH2), 7.30 (t, 2H, J=7.6 Hz,
ArH), 7.37 (d, 1H, J=8.0 Hz, ArH), 7.55 (t, 2H, J=7.6 Hz,
ArH), 7.72 (d, 2H, J=8.0 Hz, ArH), 8.39 (d, 2H, J=8.0 Hz,
ArH). 13C NMR (100MHz, CDCl3): ꢀ 14.3, 23.5, 32.6, 34.5,
112.4, 120.5, 125.6, 128.2, 129.2, 130.2, 131.3, 132.3, 138.0,

An Efficient One-Step Synthesis of 1H-Pyrazolo[3,4-b]pyridines
Letters in Organic Chemistry, 2012, Vol. 9, No. 9
675
139.1, 139.8, 142.6, 154.0, 204.6. HR-MS: cacld for
C23H20BrN3O2 (M+H)+ 450.0812, found 450.0811.
7.38 (d, 1H, J=8.0 Hz, ArH), 7.54 (t, 3H, J=7.6 Hz, ArH),
8.41 (d, 2H, J=8.4 Hz, ArH). 13C NMR (100MHz, CDCl3): ꢀ
13.0, 23.6, 32.0, 112.0, 120.5, 125.9, 129.2, 130.6, 131.0,
131.1, 131.2, 132.0, 134.8, 137.0, 138.7, 142.5, 149.0, 154.6,
203.7. HR-MS: cacld for C24H23N3O3 (M+H)+ 402.1812,
found 402.1812.
Ethyl-4-(2,4-dichlorophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxylate (6d).
o
1
Yellow crystal (DMF), mp 123 C; H NMR (400MHz,
CDCl3): ꢀ 1.01 (t, 3H, CH3), 2.06 (s, 3H, CH3), 2.81 (s, 3H,
CH3), 4.12 (q, 2H, CH2), 6.71 (d, 1H, J=8.0 Hz, ArH), 6.93
(d, 1H, J=8.8 Hz, ArH), 7.30 (t, 2H, J=8.0 Hz, ArH), 7.42-
7.54 (m, 2H, ArH), 8.27 (d, 2H, J=8.4 Hz, ArH). 13C NMR
(100MHz, CDCl3): ꢀ 13.5, 24.4, 61.3, 112.7, 121.1, 122.5,
125.9, 129.0, 130.0, 130.4, 131.7, 132.5, 136.4, 139.1, 140.0,
143.1, 149.9, 157.2, 167.5, 206.9. HR-MS: cacld for
C23H19Cl2N3O2 (M+H)+ 440.0927, found 440.0935.
Ethyl-4-(2,3-dimethoxyphenyl)-3,6-dimethyl-1-phenyl-
1H-pyrazolo[3,4-b]pyridine-5-carboxylate (6i).
White powder (DMF), mp 214-215 oC; 1H NMR
(400MHz, CDCl3): ꢀ 1.25 (t, 3H, CH3), 1.56 (s, 3H, CH3),
2.17 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 3.96(s, 3H, OCH3),
4.22 (q, 2H, CH2), 6.71 (d, 1H, J=8.0 Hz, ArH), 6.93 (d, 1H,
J=8.8 Hz, ArH), 7.05-7.21 (m, 2H, ArH), 7.31 (d, 1H, J=8.4
Hz, ArH), 7.51 (t, 2H, J=7.6 Hz, ArH), 8.25 (d, 2H, J=8.0
Hz, ArH). 13C NMR (100MHz, CDCl3): ꢀ 12.3, 13.5, 14.1,
55.8, 61.1, 96.3, 112.6, 112.8, 115.7, 118.7, 120.1, 121.2,
124.0, 124.3, 128.94, 129.0, 129.1, 145.8, 207.0. HR-MS:
cacld for C25H25N3O4 (M+H)+ 432.1918, found 432.1917.
Ethyl-4-(4-cyanophenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxylate (6e).
Yellow crystal (DMF), mp 136-138 oC; 1H NMR
(400MHz, CDCl3): ꢀ 1.35 (t, 3H, CH3), 2.57 (s, 3H, CH3),
2.79 (s, 3H, CH3), 4.30 (q, 2H, CH2), 7.31 (t, 2H, J=7.2 Hz,
ArH), 7.55(t, 3H, J=8.0Hz, ArH), 7.67(d, 1H, J=8.0 Hz,
ArH), 7.90 (d, 1H, J=8.0 Hz, ArH), 8.38 (d, 2H, J=7.6 Hz,
ArH). 13C NMR (100MHz, CDCl3): ꢀ 15.0, 15.6, 30.9, 112.8,
113.2, 113.3, 120.3, 125.4, 129.0, 129.8, 131.9, 138.4, 139.3,
139.4, 143.6, 150.3, 207.0. HR-MS: cacld for C24H20N4O2
(M+H)+ 397.1659, found 397.1673.
Ethyl-3,6-dimethyl-1-phenyl-4-(3,4,5-trimethoxyphenyl)-
1H-pyrazolo[3,4-b]pyridine-5-carboxylate (6j).
Yellow crystal (DMF), mp 116-118 oC; 1H NMR
(400MHz, DMSO): ꢀ 1.02 (t, 3H, CH3), 1.56 (s, 3H, CH3),
2.75 (s, 3H, CH3), 3.86 (s, 6H, OCH3), 3.93(s, 3H, OCH3),
4.10 (q, 2H, CH2), 6.60 (s, 2H, ArH), 7.52 (t, 3H, J=8.0 Hz,
ArH), 8.26 (d, 2H, J=8.0 Hz, ArH). 13C NMR (100MHz,
CDCl3): ꢀ13.8, 14.8, 23.8, 56.2, 61.1, 61.4, 106.2, 112.8,
113.2, 121.1, 123.7, 125.8, 129.0, 130.8, 138.2, 139.3, 143.3,
143.7, 152.9, 155.8, 168.8. HR-MS: cacld for C26H27N3O5
(M+H)+ 462.2023, found 462.2044.
Ethyl-3,6-dimethyl-4-(3-nitrophenyl)-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxylate (6f).
Yellow powder (DMF), mp 137-138 oC; 1H NMR
(400MHz, CDCl3): ꢀ 1.04 (t, 3H, J=7.2 Hz, CH3), 2.07 (s,
3H, CH3), 2.81 (s, 3H, CH3), 4.11 (q, 2H, CH2), 7.34 (t, 1H,
J=7.6 Hz, ArH), 7.55 (t, 2H, J=7.6 Hz, ArH), 7.70-7.77 (m,
2H, ArH), 8.29 (d, 2H, J=8.0 Hz, ArH), 8.33 (s, 1H, ArH),
8.39 (d, 1H, J=8.0 Hz, ArH). 13C NMR (100MHz, CDCl3): ꢀ
13.7, 15.1, 113.2, 113.3, 120.3, 123.5, 125.2, 129.0, 129.1,
130.5, 131.4, 133.2, 139.5, 144.1, 150.4, 207.0. HR-MS:
cacld for C23H20N4O4 (M+H)+ 417.1557, found 417.1557.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
We are grateful to the foundation of the “Priority Aca-
demic Program Development of Jiangsu Higher Education
Institutions”, “Qing Lan Project in Jiangsu Province”
(No.08QL001T), “Key Basic Research Project in Jiangsu
University” (No. 10KJA430050), the “Post-graduate Innova-
tion Project in Jiangsu Province” (No. CXZZ12_0979 No.
CXZZ11_0904) for financial support.
Ethyl-3,6-dimethyl-1-phenyl-4-p-tolyl-1H-pyrazolo[3,4-
b]pyridine-5-carboxylate (6g).
Yellow crystal (DMF), mp 123-124 oC; 1H NMR
(400MHz, CDCl3): ꢀ 0.98 (t, 3H, CH3), 2.08 (s, 3H, CH3),
2.44 (s, 3H, CH3), 2.74 (s, 3H, CH3), 4.07 (q, 2H, CH2), 7.30
(d, 2H, J=8.0 Hz, ArH), 7.24 (m, 2H, ArH), 7.51 (t, 3H,
J=8.0 Hz, ArH), 8.26 (d, 2H, J=8.0 Hz, ArH). 13C NMR
(100MHz, CDCl3): ꢀ 13.7, 14.7, 21.4, 23.9, 61.2, 113.1,
121.1, 123.9, 125.6, 128.6, 128.7, 129.0, 132.4, 138.5, 139.4,
143.5, 144.2, 150.0, 155.7, 168.8. HR-MS: cacld for
C24H23N3O2 (M+H)+ 386.1863, found 386.1889.
REFERENCES
[1]
Bettinetti, L.; Schlotter, K.; Hübner, H.; Gmeiner, P. Interactive
SAR studies: rational discovery of super-potent and highly selecti-
ve dopamine D3 receptor antagonists and partial agonists. J. Med.
Chem., 2002, 45(21), 4594-4597.
[2]
Löber, S.; Hübner, H.; Utz, W.; Gmeiner, P. Rationally based effi-
cacy tuning of selective dopamine D4 receptor ligands leading to
the complete antagonist 2-[4-(4-Chlorophenyl)piperazin-1-
ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213). J. Med. Chem.,
2001, 44(17), 2691-2694.
Ethyl-4-(4-methoxyphenyl)-3,6-dimethyl-1-phenyl-1H-
pyrazolo[3,4-b]pyridine-5-carboxylate (6h).
Yellow powder (DMF), mp 218-219 oC; 1H NMR
(400MHz, CDCl3): ꢀ 1.29 (t, 3H, CH3), 2.07 (s, 3H, CH3),
2.16 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.30 (q, 2H, CH2),
7.08 (d, 2H, J=8.4 Hz, ArH), 7.29 (d, 1H, J=7.6 Hz, ArH),
[3]
Kuroda, S.; Akahane, A.; Itani, H.; Nishimura, S.; Durkin, K.;
Tenda, Y.; Sakane, K. Novel adenosine A1 receptor antagonists.
Synthesis and structure-activity relationships of a novel series of 3-
(2-cyclohexenyl-3-oxo-2,3-dihydropyridazin-6-yl)-2-

676 Letters in Organic Chemistry, 2012, Vol. 9, No. 9
Zhao et al.
phenylpyrazolo[1,5-a]pyridines. Bioorg. Med. Chem., 2000, 8(1),
55-64.
rodegenerative diseases. Internation Patent WO 2012038743, Mar
29, 2012.
[4]
[5]
Blench, T.; Goodacre, S.; Lai, Y. J.; Liang, Y.; MacLeod, C.; Mag-
nuson, S.; Tsui, V.; Williams, K.; Zhang, B. R. Preparation of
pyrazolopyridines and their use as TYK2 kinase inhibitors. Interna-
tion Patent WO 2012066061, May 24, 2012.
Davenport, T.; Vile, J.; Pal, S. Pyrazolopyridine compounds as
PDE10a inhibitors. Internation Patent WO 2012019954, Feb 16,
2012.
[8]
Nielsen, S. V.; Pedersen, E. B. Phosphorus pentoxide in organic
synthesis. XXIX. Synthesis of 4-arylamino-5,6,7,8-tetrahydro-1H-
pyrazolo[3,4-b]quinolines and the corresponding N-Mannich bases.
Liebigs. Ann. Chem., 1986, 10, 1728-1735.
Narsaiah, B.; Sivaprasad, A.; Venkatarranam, R. V. A. A novel
synthesis of 3,4-disubstituted 1H-pyrazolo[3,4-b]quinolines. Synth.
Commun., 1991, 21(15-16), 1611-1617.
[9]
[6]
[7]
Chen, Y. L. Pyrazolo- and pyrrolopyridines useful as CRF antago-
nists. Internation Patent WO 9534563, Dec 21, 1995.
Chan, B.; Chen, H. F.; Estrada, A.; Shore, D.; Sweeney, Z.;
McIver, E. Pyrazolopyridines as inhibitors of the kinase LRRK2
and their preparation and use in the treatment of cancer and neu-
[10]
Lipson, V. V.; Karnozhitskaya, T. M.; Desenko, S. M.; Shishkina,
S. V.; Shishkin, O. E.; Musatov, V. I. Reactions of ꢀ-aminoazoles
with diethyl benzylidenemalonate. Russ. J. Org. Chem., 2007,
43(2), 249-255.