Novel and efficient synthesis of pyrazolo]3,4-b]pyridin-6-ones or their hydrogenated derivatives through one-pot reaction in ionic liquid

Article abstract of DOI:10.3987/COM-08-11561

Pyrazolo[3,4-b]pyridin-6-ones or their hydrogenated derivatives were obtained selectively and conveniently through one-pot reaction of aldehyde, ethyl cyanoacetate and 5-amino-3-methyl-1-phenylpyrazole in [bmim][BF₄] with or without ferric chlo

Full text of DOI:10.3987/COM-08-11561

HETEROCYCLES, Vol. 78, No. 4, 2009
923
HETEROCYCLES, Vol. 78, No. 4, 2009, pp. 923 - 936. © The Japan Institute of Heterocyclic Chemistry
Received, 27th September, 2008, Accepted, 25th November, 2008, Published online, 27th November, 2008
DOI: 10.3987/COM-08-11561
NOVEL AND EFFICIENT SYNTHESIS OF
PYRAZOLO[3,4-b]PYRIDIN-6-ONES OR THEIR HYDROGENATED
DERIVATIVES THROUGH ONE-POT REACTION IN IONIC LIQUID
Xin-Ying Zhang,* Xiao-Yan Li, Xue-Sen Fan,* Xia Wang, Gui-Rong Qu, and
Jian-Ji Wang
School of Chemistry and Environmental Sciences, Henan Key Laboratory for
Environmental Pollution Control, Henan Normal University, Xinxiang, Henan
453007, P. R. China. E-mail: xyzh518@sohu.com; xuesen.fan@yahoo.com
Abstract – Pyrazolo[3,4-b]pyridin-6-ones or their hydrogenated derivatives were
obtained selectively and conveniently through one-pot reaction of aldehyde, ethyl
cyanoacetate and 5-amino-3-methyl-1-phenylpyrazole in [bmim][BF4] with or
without ferric chloride at different temperatures. Advantages of this novel method
include high yield, mild conditions, simple procedure and good selectivity. In
addition, the ionic liquid used can be easily recovered and effectively reused.
INTRODUCTION
The development of efficient chemical process for the preparation of new biologically active molecules
constitutes a major challenge for chemists in organic synthesis. Part of this challenge is to develop novel
methods for the preparation of nitrogen-containing heterocyclic compounds, like pyrazolo-pyridine
derivatives, due to the fact that many of this kind of compounds possess various interesting biological
activities. Particularly, pyrazolo[3,4-b]pyridines possess wide-ranging biological activities such as
phychotropic,1 cytotoxic,2 antiviral,3 antifungal4 and antichagasic activities.5 They are also potent
inhibitors of glycogen synthase kinase-3 (GSK-3)6 and clcin-dependent kinase-1 (CDK-1).7 Recently,
novel pyrazolo[3,4-b]pyridin-6-ones as a subunit of pyrazolo[3,4-b]pyridine were designed and
synthesized by Falcó et al to be screened as potential hypnotic drugs.8
Due to their importance, many methods have been reported for the construction of
pyrazolo[3,4-b]pyridine derivatives including pyrazolo[3,4-b]pyridin-6-ones.9-14 However, with the
reported methods, multi-step preparative procedures were usually needed, and a combination of several
additives and catalysts was usually employed, or volatile solvents were used for the reaction to complete.
Thus, development of new methods capable of inducing simple and efficient preparation of
pyrazolo[3,4-b]pyridin-6-ones would be of interest to synthetic chemists.

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HETEROCYCLES, Vol. 78, No. 4, 2009
On the other hand, the development of environmentally friendly catalysts and solvents for organic
chemistry is an area of considerable importance. In the last few years rt ionic liquids (RTILs), especially
those based on 1,3-dialkylimidazolium cations, have been recognized as a possible environmentally
benign alternative to chemical volatile solvents because, in contrast with the conventional organic
solvents, they are non-volatile, recyclable, non-explosive, easy to handle, and thermally robust.15 RTILs
as a kind of ion solvent combine the advantages of both traditional molecular solvents and melt salts and
have been widely used in catalytic and non-catalytic reactions.16 Their high polarity and the ability to
solubilize both inorganic and organic compounds can result in enhanced rates of chemical processes and
can provide higher selectivity compared to conventional solvents. Moreover, ionic liquids are simple and
inexpensive to prepare and easy to recycle and their properties can be fine-tuned by changing the anion or
the alkyl group attached to cation. Accordingly they are emerging as novel replacements for volatile
organic solvents in organic synthesis. Recently, how to use ILs to promote the selectivity of various
organic reactions and to dramatically influence the outcome of chemical reactions has also attracted much
attention.17
As a continuation of our research in developing novel and efficient methodologies for the synthesis of
biologically important heterocyclic compounds by using ionic liquids as both reaction medium and
promoter,18 we would like to report our study on the one-pot reaction of aldehyde, ethyl cyanoacetate and
5-amino-3-methyl-1-phenylpyrazole in an ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate
([bmim][BF4]) with or without ferric chloride. From this reaction, pyrazolo[3,4-b]pyridin-6-ones or their
hydrogenated derivatives were obtained efficiently and selectively under different reaction conditions.
RESULTS AND DISCUSSION
Firstly, 4-nitrobenzilidene ethyl cyanoacetate (1a, Scheme 1), previously prepared from 4-nitrobenzalde-
hyde and ethyl cyanoacetate, was treated with 5-amino-3-methyl-1-phenylpyrazole (2) in [bmim][BF4].
After being stirred at rt for several hours, it gave pale yellow solids, which were collected by suction and
1
submitted to identification. H NMR, g-COSY and mass spectra analysis showed that the product
obtained so far is 3a (mixture of two isomers) instead of the desired 4a (Scheme 1).
To get 4a, higher reaction temperature was tried. It was observed that when 1a and 2 was stirred in
[bmim][BF4] at 80 °C, a new product was formed along with 3a. The mixture was let to be stirred at
80 °C until no change of the ratio of the two products was observed (based on TLC analysis). Subsequent
1
handling of the reaction mixture gave 3a and another solid, which was identified through H NMR and
MS as 4a, with yield of 45% and 35% respectively (Scheme 1).
Different temperature conditions and reaction period were then tried to improve the yield of 4a. But
higher reaction temperature and longer reaction time did not result in significant improvement with regard

HETEROCYCLES, Vol. 78, No. 4, 2009
925
NO2
Me
CN
O
[bmim]BF4
N
rt
N
H
N
Ph
Me
CO2Et
3a
O2N
C
C
+
N
H
NH2
NO2
NO2
N
CN
Ph
2
[bmim]BF4
80oC
1a
CN
O
Me
CN Me
+
N
N
O
N
H
N
H
N
N
Ph
Ph
3a
4a
Scheme 1
to the selectivity and yield of 4a.
Based on the above results, it is reasonable to suggest that in the above procedures 3a was firstly formed
through the condensation of 1a and 2, and part of 3a could be oxidized by air to give 4a at elevated
temperature. However, as an oxidant, air is not strong enough to give a complete transformation and as a
result, a mixture of 3a and 4a was obtained. It is therefore considered that an added oxidant would be able
to push the oxidation procedure to go further. Bearing in mind that FeCl3·6H2O has successfully acted as
a mild oxidant in many occasions,19 it was then recruited and used in the above reaction (Scheme 2). The
results were listed in Table 1.
NO2
NO2
Me
CN
O
Me
CN Me
CO2Et
[bmim]BF4
80oC
O2N
C
C
+
+
N
N
N
H
O
N
H
N
H
NH2
N
N
N
CN
Ph
Ph
Ph
2
3a
4a
1a
Fe3+
Fe2+
O2
Scheme 2
It turned out that with FeCl3·6H2O the reaction was improved remarkably with regard to the selectivity
and yield of 4a (Table 1, Entries 1-5). Firstly, 1 equivalent of FeCl3·6H2O was tried, and the reaction of
1a and 2 gave 4a exclusively with a yield of 81% after the mixture being stirred at 80 °C for 8 h (Table 1,
Entry 5). With the amount of FeCl3·6H2O less than 1 equivalent, to our surprise, not only could 4a be
obtained, but with better yield. For example, in the presence of 50 mol% or 20 mol% of FeCl3·6H2O, 4a

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HETEROCYCLES, Vol. 78, No. 4, 2009
was obtained with yield of 90% or 95% respectively (Table 1, Entries 4 and 3). However, amount less
than 20 mol% resulted in decrease in the yield of 4a (Table 1, Entry 2).
Table 1. Effect of additives on the preparation of 4aa
Amountof Catalyst
Reaction Yield
Time (h) (%)
Entry
Catalyst
Products
(mmol)
0
1
2
3
4
5
6
7
8
9
None
3a+4a
3a+4a
4a
12
8
45(3a)+35(4a)
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
Fe (NO3)3·9 H2O
Fe2(SO4)3·X H2O
CeCl3·7H2O
ZnCl2
0.1
0.2
0.5
1
12(3a)+71(4a)
8
95
4a
8
90
4a
8
81
0.2
0.2
0.2
0.2
4a
8
91
4a
8
90
3a+4a
3a+4a
12
12
80(3a)+5(4a)
70(3a)+10(4a)
a Reaction conditions: 1 mL [bmim][BF4], 1 mmol 1a, 1 mmol 2, 80℃.
It is postulated that in the presence of FeCl3·6H2O, 3a was oxidized to 4a by Fe(III) and the in situ formed
Fe(II) could be simultaneously oxidized back to Fe(III) by air to act as oxidant again. It is why catalytic
amount of FeCl3·6H2O is enough to give a complete transformation.
Furthermore, several other kinds of metallic salt were also tried and the results were included in Table 1.
It turned out that in addition to FeCl3·6H2O, presence of other two ferric(III) salts, Fe2(SO4)3·XH2O (20
mol%) or Fe(NO3)3·9H2O (20 mol%), also led to highly selective formation of 4a (Table 1, Entries 6, 7).
On the other hand, in the presence of CeCl3·7H2O or ZnCl2, the selectivity for 4a is even lower compared
with reactions without any additives (Table 1, Entries 8, 9).
As the art of performing efficient chemical transformation involving three or more components in one pot
represents a fundamental target of the modern organic synthesis, further efforts were then made to
investigate the possibility of preparing 4a directly from the corresponding aldehyde (5a), ethyl
cyanoacetate (6) and 2 in one pot. Thus, 5a, 6 and 2 were added to 1 mL of [bmim][BF4] and the mixture
was stirred at 80 °C in the presence of FeCl3·6H2O (Scheme 3). After being stirred for several hours,
however, it gave a mixture of two new compounds indicated by TLC analysis. A careful separation and
structural analysis of the mixture demonstrated that the products obtained were 7 and 8, the condensation
products of 5a and 2. From these results, it is obvious that with the coexistence of 5a, 6 and 2, it is more
favorable for 5a to react with 2 to give 7 and 8 instead of reacting with 6 and 2 to give 4a. This is
probably due to the stronger nucleophilic reactivity of 2 toward aldehyde than that of 6.

HETEROCYCLES, Vol. 78, No. 4, 2009
927
NO2
NO2
CHO
Me
Me
Me
FeCl3. 6H2O
Me
CN
Me
+
+
N
+
NH2
0
N
CO2Et
[bmim]BF
4
80 C,
N
N
N
N
N
N
N
N
N
NO2
Ph
NH2 H2N
Ph
Ph
Ph
Ph
5a
6
2
7
8
Scheme 3
To get the desired product 4a in one pot, an alternative manipulation in terms of the substrates addition
sequence was tried. Thus, 5a and 6 were firstly added to 1 mL of [bmim][BF4]. The mixture was stirred at
80 °C until the disappearance of 5a. Then, 2 and FeCl3·6H2O (20 mol %) was added and the mixture was
stirred at the same temperature. The following reaction went smoothly to give a solid product. It was
collected by suction and identified as 4a in almost quantitive yield of 96%.
In the next stage, the scope and generality of this one-pot procedure (Scheme 4) were studied and the
results were listed in Table 2. It turned out that various aryl aldehydes or heterocyclic aldehydes reacted
smoothly with 6 and 2 to give 4 in high yields. In addition, aryl aldehydes with group(s) on the
ortho-position gave relatively lower yields of 4, probably due to steric effect.
R
Me
CN
O
o
(1) [bmim]BF ,
80 C
CN
4
R-CHO
+
N
.
N
N
CO2Et
(2)
FeCl3 6H2O
2
,
H
Ph
5
6
4
Scheme 4
With the above products in hand, the MS and NMR-based structures of 4 were further confirmed by
X-ray crystallographic analysis of 4g (Figure 1).20
Figure 1 The molecular structure of 4g
Bearing in mind that hydrogenated pyrazolo[3,4-b]pyridin-6-ones like compound 3 have been found with
good biological activity such as GSK-3 inhibitors 21 and have the potential to be used as novel building
blocks to construct new nitrogen-containing molecules, our further effort is aimed at the development of
an efficient, mild and reliable protocol to prepare this class of compound (Scheme 5). Based on the results

928
HETEROCYCLES, Vol. 78, No. 4, 2009
Table 2. Preparation of pyrazolo[3,4-b]-pyridin-6-ones (4) in [bmim][BF4]
Reaction
Time (h)
10
Yield
(%)
96
91
94
90
92
93
90
93
93
91
88
89
87
85
91
90
Entry
R
Product
1
p-NO2C6H4
C6H5
4a
4b
4c
4d
4e
4f
2
10
3
p-ClC6H4
p-MeC6H4
p-BrC6H4
p-FC6H4
10
4
10
5
10
6
10
7
p-MeOC6H4
m-NO2C6H4
m-ClC6H4
m-BrC6H4
m-MeC6H4
o-NO2C6H4
o-FC6H4
4g
4h
4i
10
8
10
9
10
10
11
12
13
14
15
16
4j
10
4k
4l
11
11
4m
4n
4o
4p
11
o-ClC6H4
4-pyridyl
3-pyridyl
11
10
10
obtained so far, a procedure elaborately designed for the preparation of 3 via a three-component reaction
version was investigated. Thus, 5a and 6 were firstly added to 1 mL of [bmim][BF4]. The mixture was
stirred at 80 °C until the disappearance of 5a. Upon cooling to rt, 2 was added to the system and the
mixture was stirred at rt. The following reaction went smoothly and afforded 3a with a yield of 90%.
Further study with various aldehyde substrates showed that this procedure is quite general and reliable in
that all the aldehyde substrates studied reacted with 6 and 2 smoothly and gave 3 with good yields. The
results were listed in Table 3.
R
Me
CN
O
o
(1) [bmim]BF ,
80 C
CN
CO2Et
6
4
R-CHO +
N
N
(2)
rt
N
2,
H
Ph
5
3
Scheme 5
As mentioned earlier, one of the goals in the usage of ionic liquids is to identify the additional advantages
they have over conventional organic solvents besides a greener nature. Thus, several volatile organic

HETEROCYCLES, Vol. 78, No. 4, 2009
929
Table 3. Preparation of hydrogenated pyrazolo[3,4-b]pyridin-6-ones (3) in [bmim][BF4]
Reaction
Entry
R
Product
Yield (%)
Time (h)
1
2
3
4
5
6
7
p-NO2C6H4
C6H5
3a
3b
3c
3d
3e
3f
8
90
84
87
85
86
86
85
9
p-ClC6H4
p-BrC6H4
p-MeC6H4
m-ClC6H4
m-MeC6H4
9
9
10
9
3g
9
solvents such as MeOH, EtOH and toluene were chosen as solvent for the preparation of 3a from 1a and
2 (Scheme 1). The results (Table 4) showed that of the solvents studied, [bmim][BF4] gave the best result
in terms of both reaction time and product yield. With MeOH, EtOH or toluene as the reaction medium,
the reaction underwent much slower and resulted in much lower yields.
Table 4. Preparation of 3a in different solvents*
Yield
Solvent
Temperature (°C)
Product Reaction Time
(%)
90
65
65
70
[bmim][BF4] rt
3a
3a
3a
3a
8h
MeOH
EtOH
rt
rt
rt
36h
40h
3d
toluene
* Reaction conditions: 1 mmol of 1a and 2 respectively, 1 mL of IL or 4 mL of VOCs.
On the other hand, one important feature of ionic liquids as reaction medium is the possibility of its
recovery and reuse. Our study showed that the reuse of [bmim][BF4] is feasible in all the above
procedures. At completion of the above reactions, corresponding products were isolated by suction. The
ionic liquid phase was then concentrated and dried under reduced pressure for reuse. No remarkable
decrease in the efficiency of the reused ionic liquid was observed after 5 rounds.
As a conclusion, we have demonstrated that one-pot three-component reaction of aldehydes, ethyl
cyanoacetate and 5-amino-3-methyl-1-phenylpyrazole could be smoothly carried out in [bmim][BF4].
Through this reaction, pyrazolo[3,4-b]pyridin-6-ones or its hydrogenated derivatives were obtained
effectively and selectively with or without FeCl3·6H2O at different reaction temperatures. The notable
features of the procedures presented here are good selectivity, high efficiency, mild conditions, cleaner
reaction profiles, simple operation process together with convenient and efficient recovery and reuse of
the reaction medium.

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HETEROCYCLES, Vol. 78, No. 4, 2009
EXPERIMENTAL
1
Melting points were measured by a Kofler micromelting point apparatus and were uncorrected. H and
13C NMR spectra were determined on a Bruker AC 400 spectrometer as DMSO-d6 or CDCl3 solutions.
Chemical shifts (δ) were expressed in ppm downfield from the internal standard tetramethylsilane and
coupling constants J were given in Hz. Mass spectra were recorded on a Bruke Esquire 3000 mass
spectrometer. Elemental analyses were performed on an EA-1110 instrument.
General procedure for the preparation of 4-aryl-4,5,6,7-tetrahydro-3-methyl-6-oxo-1-phenyl-
1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (3)
To 1 mL of [bmim][BF4] were added aldehyde (5, 1 mmol) and ethyl cyanoacetate (6, 1 mmol). The
mixture was stirred at 80 °C until the disappearance of 5. Upon cooling to rt, 5-amino-3-methyl-1-
phenylpyrazole (2, 1 mmol) was added and the mixture was stirred at rt for a certain period of time to
complete the reaction (monitored by TLC). Upon completion, 2 mL of 50% EtOH in water was added.
The solid precipitated was collected by suction and rinsed with water and cold EtOH, and then dried to
give 3 with high purity. The ionic liquid layer was dried at 100 °C under reduced pressure to recover the
ionic liquid.
1
3a. Pale yellow solid; H NMR (DMSO-d6): 1.44 (s, 1.28H, CH3); 1.99 (s, 1.72H, CH3); 4.84 (d, J = 12
Hz, 0.43H, CH); 4.86 (d, J = 7.2 Hz, 0.57H, CH); 4.96 (d, J = 12 Hz, 0.43H, CH); 5.20 (d, J = 7.2 Hz,
13
0.57H, CH); 7.35-8.32 (m, 9H, Ar-H); 11.34 (br s, 0.43H, NH); 11.40 (br s, 0.57H, NH); C NMR
(DMSO-d6): 11.6, 12.6, 36.6, 41.9, 43.0, 100.9, 101.9, 116.0, 116.3, 123.1, 123.2, 124.1, 124.2, 127.3,
127.4, 129.0, 129.4, 130.1, 137.6, 137.7, 137.9, 145.0, 145.2, 146.4, 146.5, 147.3, 147.4, 163.1; MS
(ESI): m/z 396 (M+ +Na); Anal. Calcd for C20H15N5O3: C 64.34, H 4.05, N 18.76; Found: C 64.44, H 4.04,
N 18.69.
3b. White solid; 1H NMR (DMSO-d6): 1.41 (s, 1.31H, CH3); 1.99 (s, 1.69H, CH3); 4.56 (d, J = 12.0 Hz,
0.44H, CH); 4.58 (d, J = 6.8 Hz, 0.56H, CH); 4.85 (d, J = 12.0 Hz, 0.44H, CH); 5.07 (d, J = 6.8 Hz,
13
0.56H, CH); 7.18-7.52 (m, 10H, Ar-H); 11.24 (br s, 1H, NH); C NMR (DMSO-d6): 11.7, 12.4, 37.2,
42.4, 43.4, 102.1, 103.3, 116.2, 116.8, 122.9, 123.0, 127.2, 127.3, 127.5, 127.9, 128.1, 128.5, 128.9, 129.4,
137.6, 137.8, 137.9, 138.9, 139.0, 145.0, 145.1, 163.6; MS (ESI): m/z 351 (M+ +Na); Anal. Calcd for
C20H16N4O: C 73.15, H 4.91, N 17.06; Found: C 73.06, H 4.95, N 17.15.
1
3c. White solid; H NMR (DMSO-d6): 1.45 (s, 1H, CH3); 1.98 (s, 2H, CH3); 4.62 (d, J = 12 Hz, 0.34H,
CH); 4.64 (d, J = 7.2 Hz, 0.66H, CH); 4.86 (d, J = 12 Hz, 0.34H, CH); 5.09 (d, J = 7.2 Hz, 0.66H, CH);
7.18-7.49 (m, 9H, Ar-H); 11.28 (br s, 1H, NH); 13C NMR (DMSO-d6): 11.6, 12.5, 36.5, 42.3, 43.3, 101.7,
102.7, 116.2, 116.5, 123.0, 123.1, 127.2, 127.3, 129.0, 129.3, 129.4, 130.5, 132.6, 132.7, 137.5, 137.6,
137.8, 137.9, 145.1, 163.3, 163.4; MS (ESI): m/z 385, 387 (M+ +Na); Anal. Calcd for C20H15ClN4O: C

HETEROCYCLES, Vol. 78, No. 4, 2009
931
66.21, H 4.17, N 15.44; Found: C 66.29, H 4.15, N 15.38.
1
3d. White solid; H NMR (DMSO-d6): 1.47 (s, 1.28H, CH3); 2.01 (s, 1.72H, CH3); 4.63 (d, J = 12 Hz,
0.43H, CH); 4.65 (d, J = 7.2 Hz, 0.57H, CH); 4.89 (d, J = 12 Hz, 0.43H, CH); 5.12 (d, J = 7.2 Hz, 0.57H,
CH); 7.13-7.67 (m, 9H, Ar-H); 11.32 (br s, 1H, NH); 13C NMR (DMSO-d6): 12.0, 12.9, 36.8, 42.6, 43.6,
102.0, 103.0, 116.6, 116.9, 121.6, 123.3, 123.4, 127.6, 127.7, 129.7, 130.1, 131.2, 132.3, 137.9, 138.0,
138.1, 138.5, 138.6, 145.4, 163.7, 163.8; MS (ESI): m/z 429, 431 (M+ +Na); Anal. Calcd for
C20H15BrN4O: C 58.98, H 3.71, N 13.76; Found: C 58.89, H 3.72, N 13.81.
1
3e. Pale yellow solid; H NMR (DMSO-d6): 1.43 (s, 1.80H, CH3); 1.98 (s, 1.20H, CH3); 2.24 (s, 1.20H,
CH3); 2.31 (s, 1.80H, CH3); 4.50 (d, J = 12 Hz, 0.60H, CH); 4.52 (d, J = 6.8 Hz, 0.40H, CH); 4.79 (d, J =
12 Hz, 0.60H, CH); 5.03 (d, J = 6.8 Hz, 0.40H, CH); 7.03-7.49 (m, 9H, Ar-H); 11.19 (br s, 0.6H, NH);
11.21 (br s, 0.4H, NH); 13C NMR (DMSO-d6): 11.7, 12.5, 20.7, 20.8, 37.0, 42.6, 43.5, 102.2, 103.4, 116.3,
116.7, 122.9, 123.0, 127.1, 127.2, 127.4, 128.4, 129.3, 129.5, 135.6, 135.9, 137.2, 137.3, 137.4, 137.6,
137.7, 137.8, 145.0, 145.3, 163.6, 163.7; MS (ESI): m/z 365 (M+ +Na); Anal. Calcd for C21H18N4O: C
73.67, H 5.30, N 16.36; Found: C 73.59, H 5.31, N 16.40.
1
3f. White solid; H NMR (CDCl3): 1.79 (s, 1.91H, CH3); 2.14 (s, 1.09H, CH3); 3.94 (d, J = 10.4 Hz,
0.63H, CH); 4.34 (d, J = 6.8 Hz, 0.37H, CH); 4.45 (d, J = 6.8 Hz, 0.37H, CH); 4.46 (d, J = 10.4 Hz,
0.63H, CH); 7.15-7.57 (m, 9H, Ar-H); 8.19 (br s, 0.63H, NH); 8.33 (br s, 0.37H, NH); 13C NMR (CDCl3):
12.1, 12.9, 38.5, 41.3, 42.8, 44.3, 99.6, 101.2, 114.0, 114.7, 122.9, 123.1, 126.0, 126.3, 127.6, 127.9,
128.5, 128.6, 129.0, 129.1, 130.1, 130.5, 130.8, 135.1, 135.4, 135.8, 136.6, 136.7, 138.6, 139.7, 146.2,
146.8, 161.5; MS (ESI): m/z 385, 387 (M+ +Na); Anal. Calcd for C20H15ClN4O: C 66.21, H 4.17, N 15.44;
Found: C 66.30, H 4.17, N 15.39.
3g. White solid; 1H NMR (CDCl3): 1.57 (s, 2.44H, CH3); 1.78 (s, 0.56H, CH3); 2.35 (s, 2.44H, CH3); 2.39
(s, 0.56H, CH3); 3.97 (d, J = 10.0 Hz, 0.19H, CH); 4.32 (d, J = 6.8 Hz, 0.81H, CH); 4.42-4.44 (m, 1H,
CH); 7.02-7.53 (m, 9H, Ar-H); 8.02 (br s, 0.19H, NH); 8.13 (br s, 0.81H, NH); 13C NMR (CDCl3): 12.1,
13.0, 21.5, 38.9, 41.5, 43.1, 102.2, 114.2, 122.9, 123.1, 124.6, 124.9, 128.2, 128.3, 128.4, 129.1, 129.3,
129.5, 130.1, 135.8, 136.6, 136.9, 138.9, 146.3, 162.0; MS (ESI): m/z 365 (M+ +Na); Anal. Calcd for
C21H18N4O: C 73.67, H 5.30, N 16.36; Found: C 73.57, H 5.32, N 16.42.
General procedure for the preparation of 4-aryl-5-cyano-3-methyl-1-phenyl-7H-pyrazolo[3,4-b]-
pyridin-6-one (4)
To 1 mL of [bmim][BF4] were added aldehyde (5, 1 mmol) and ethyl cyanoacetate (6, 1 mmol). The
mixture was stirred at 80 °C until the disappearance of 5. Then, 5-amino-3-methyl-1-phenylpyrazole (2, 1
mmol) and FeCl3·6H2O (0.2 mmol) were added and the mixture was continued to be stirred at the same
temperature for a certain period of time to complete the reaction (monitored by TLC). Upon completion,

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HETEROCYCLES, Vol. 78, No. 4, 2009
the mixture was cooled to rt and 2 mL of 50% EtOH in water was added. The solid precipitated was
collected by suction and rinsed with water and cold EtOH, and then dried to give 4 with high purity. The
ionic liquid layer containing Fe (III) was dried at 100 °C under reduced pressure to recover the ionic
liquid and the oxidant.
4a. Pale yellow solid; mp 290-292 °C (Lit., 11 308 °C); 1H NMR (DMSO-d6): 1.91 (s, 3H, CH3); 7.35 (t, J
= 7.6 Hz, 1H, Ar-H); 7.53 (t, J = 8.0 Hz, 2H, Ar-H); 7.89 (d, J = 8.4 Hz, 2H, Ar-H); 8.05 (d, J = 8.0 Hz,
13
2H, Ar-H); 8.42 (d, J = 8.4 Hz, 2H, Ar-H); 13.28 (br s, 1H, NH); C NMR (DMSO-d6) : 14.4, 88.5,
109.2, 115.4, 121.5, 123.7, 126.7, 129.3, 130.5, 138.2, 140.0, 143.8, 148.5, 151.3, 163.8; MS (ESI): m/z
394 (M+ +Na).
1
4b. White solid; mp 173-175 °C (Lit., 11 183 °C); H NMR (CDCl3): 1.54 (s, 3H, CH3); 5.41 (br s, 1H,
NH); 7.29 (t, J = 7.6 Hz, 1H, Ar-H); 7.44-7.55 (m, 7H, Ar-H); 8.10 (d, J = 8.8 Hz, 2H, Ar-H); 13C NMR
(CDCl3): 14.2, 94.2, 106.5, 118.7, 121.8, 125.0, 127.8, 128.0, 128.2, 128.6, 135.1, 139.2, 143.8, 152.3,
152.5, 169.9; MS (ESI): m/z 349 (M+ +Na).
4c. White solid; mp 275-277 °C (Lit., 11 278 °C); 1H NMR (DMSO-d6): 1.93 (s, 3H, CH3); 7.33 (t, J = 7.2
Hz, 1H, Ar-H); 7.52 (t, J = 8.0 Hz, 2H, Ar-H); 7.59 (d, J = 8.4 Hz, 2H, Ar-H); 7.65 (d, J = 8.4 Hz, 2H,
13
Ar-H); 8.04 (d, J = 7.6 Hz, 2H, Ar-H); 13.15 (br s, 1H, NH); C NMR (DMSO-d6): 14.4, 91.4, 109.5,
115.6, 121.4, 126.6, 128.7, 129.2, 130.7, 132.5, 134.9, 138.2, 144.0, 149.1, 152.5, 163.8; MS (ESI): m/z
383, 385 (M+ +Na).
4d. Pale yellow solid; mp 298-300 °C; 1H NMR (DMSO-d6): 1.93 (s, 3H, CH3); 2.40 (s, 3H, CH3); 7.33 (t,
J = 7.2 Hz, 1H, Ar-H); 7.38 (d, J = 8.0 Hz, 2H, Ar-H); 7.43 (d, J = 8.0 Hz, 2H, Ar-H); 7.52 (t, J = 8.0 Hz,
2H, Ar-H); 8.05 (d, J = 7.6 Hz, 2H, Ar-H); 13.05 (br s, 1H, NH); 13C NMR (DMSO-d6): 14.5, 21.1, 109.6,
115.9, 121.4, 126.5, 128.7, 129.1, 129.2, 130.7, 138.3, 139.6, 144.1, 154.1, 163.9; MS (ESI): m/z 363 (M+
+Na); Anal. Calcd for C21H16N4O: C 74.10, H 4.74, N 16.46; Found: C 74.18, H 4.68, N 16.41.
4e. Pale yellow solid; mp 281-283 °C; 1H NMR (DMSO-d6) : 1.93 (s, 3H, CH3); 7.33 (t, J = 7.2 Hz, 1H,
Ar-H); 7.50-7.53 (m, 4H, Ar-H); 7.79 (d, J = 8.4 Hz, 2H, Ar-H); 8.05 (d, J = 8.0 Hz, 2H, Ar-H); 13.15 (br
13
s, 1H, NH); C NMR (DMSO-d6): 14.4, 91.3, 109.4, 115.7, 121.4, 123.6, 126.6, 129.2, 130.9, 131.6,
132.8, 138.2, 144.0, 149.1, 152.5, 163.8; MS (ESI): m/z 427, 429 (M+ +Na); Anal. Calcd for
C20H13BrN4O: C 59.30, H 3.23, N 13.80; Found: C 59.21, H 3.30, N 13.85.
1
4f. Pale yellow solid; mp 243-245 °C; H NMR (DMSO-d6): 1.94 (s, 3H, CH3); 7.34 (t, J = 7.6 Hz, 1H,
Ar-H); 7.42 (t, J = 8.8 Hz, 2H, Ar-H); 7.53 (t, J = 8.0 Hz, 2H, Ar-H); 7.62-7.65 (m, 2H, Ar-H); 8.05 (d, J
13
= 8.0 Hz, 2H, Ar-H); C NMR (DMSO-d6): 14.4, 91.6, 109.7, 115.6, 115.7, 115.8, 121.5, 126.6, 129.2,
130.0, 131.2, 131.3, 138.3, 144.0, 152.9, 161.8, 163.8, 164.3; MS (ESI): m/z 367 (M+ +Na); Anal. Calcd
for C20H13FN4O: C 69.76, H 3.81, N 16.27; Found: C 69.80, H 3.75, N 16.21.

HETEROCYCLES, Vol. 78, No. 4, 2009
933
1
4g. White solid; mp 295-297 °C (Lit., 11 320 °C); H NMR (DMSO-d6): 2.00 (s, 3H, CH3); 3.86 (s, 3H,
OCH3); 7.14 (d, J = 8.4 Hz, 2H, Ar-H); 7.36 (t, J = 7.2 Hz, 1H, Ar-H); 7.51-7.57 (m, 4H, Ar-H); 8.08 (d,
J = 7.6 Hz, 2H, Ar-H); 13.02 (br s, 1H, NH); 13C NMR (DMSO-d6): 17.2, 58.0, 93.9, 112.3, 116.5, 118.5,
124.0, 128.2, 129.1, 131.8, 133.0, 140.9, 146.7, 151.6, 156.5, 163.1, 166.5; MS (ESI): m/z 379 (M+ +Na).
1
4h. Yellow solid; mp 300-302 °C; H NMR (DMSO-d6): 1.90 (s, 3H, CH3); 7.34 (t, J = 7.2 Hz, 1H,
Ar-H); 7.53 (t, J = 7.6 Hz, 2H, Ar-H); 7.90 (t, J = 7.6 Hz, 1H, Ar-H); 8.05-8.06 (m, 3H, Ar-H); 8.43-8.47
(m, 2H, Ar-H); 13.25 (br s, 1H, NH); 13C NMR (DMSO-d6): 14.4, 91.5, 109.6, 115.5, 121.4, 123.7, 124.8,
126.6, 129.3, 130.5, 135.1, 135.4, 138.2, 143.8, 147.7, 149.2, 151.0, 163.8; MS (ESI): m/z 394 (M+ +Na);
Anal. Calcd for C20H13N5O3: C 64.69, H 3.53, N 18.86; Found: C 64.75, H 3.48, N 18.89.
4i. White solid; mp 252-254 °C; 1H NMR (DMSO-d6): 1.95 (s, 3H, CH3); 7.36 (t, J = 7.6 Hz, 1H, Ar-H);
7.53-7.57 (m, 3H, Ar-H); 7.63 (t, J = 7.6 Hz, 1H, Ar-H); 7.68 (d, J = 8.0 Hz, 1H, Ar-H); 7.73 (s, 1H,
13
Ar-H); 8.07 (d, J = 7.6 Hz, 2H, Ar-H); 13.21 (br s, 1H, NH); C NMR (DMSO-d6) : 14.7, 91.7, 109.9,
116.0, 121.7, 126.9, 128.0, 128.9, 129.6, 130.3, 130.9, 133.6, 135.9, 138.6, 144.3, 149.5, 152.4, 164.2;
MS (ESI): m/z 383, 385 (M+ +Na); Anal. Calcd for C20H13ClN4O: C 66.58, H 3.63, N 15.53; Found: C
66.66, H 3.55, N 15.54.
1
4j. Pale yellow solid; mp >360 °C; H NMR (DMSO-d6): 1.71 (s, 3H, CH3); 7.09 (t, J = 7.6 Hz, 1H,
Ar-H); 7.35-7.45 (m, 4H, Ar-H); 7.58 (s, 1H, Ar-H); 7.65 (d, J = 8.0 Hz, 1H, Ar-H); 8.23 (d, J = 8.0 Hz,
13
2H, Ar-H); C NMR (DMSO-d6): 14.8, 95.5, 104.1, 119.9, 120.3, 121.7, 124.2, 128.1, 129.0, 130.8,
131.4, 131.9, 138.7, 140.6, 143.1, 149.4, 155.1, 170.0; MS (ESI): m/z 427, 429 (M+ +Na); Anal. Calcd for
C20H13BrN4O: C 59.28, H 3.23, N 13.83; Found: C 59.35, H 3.16, N 13.84.
1
4k. Pale yellow solid; mp 264-266 °C; H NMR (DMSO-d6): 1.94 (s, 3H, CH3); 2.41 (s, 3H, CH3);
7.34-7.37 (m, 3H, Ar-H); 7.41 (d, J = 7.6 Hz, 1H, Ar-H); 7.48 (t, J = 7.6 Hz, 1H, Ar-H); 7.55 (t, J = 8.0
Hz, 2H, Ar-H); 8.08 (d, J = 7.6 Hz, 2H, Ar-H); 13.09 (br s, 1H, NH); 13C NMR (DMSO-d6): 14.7, 21.4,
109.9, 116.2, 121.8, 126.1, 126.9, 128.8, 129.5, 129.6, 130.9, 133.9, 138.3, 138.6, 144.5, 154.4, 164.2;
MS (ESI): m/z 363 (M+ +Na); Anal. Calcd for C21H16N4O: C 74.10, H 4.74, N 16.46; Found: C 74.16 H
4.69, N 16.41.
1
4l. Pale yellow solid; mp 276-278°C; H NMR (DMSO-d6): 1.83 (s, 3H, CH3); 7.37 (t, J = 7.6 Hz, 1H,
Ar-H); 7.56 (t, J = 8.0 Hz, 2H, Ar-H); 7.77 (d, J = 7.2 Hz, 1H, Ar-H); 7.93 (t, J = 8.0 Hz, 1H, Ar-H); 8.02
(t, J = 8.0 Hz, 1H, Ar-H); 8.08 (d, J = 8.0 Hz, 2H, Ar-H); 8.40 (d, J = 7.6 Hz, 1H, Ar-H); 13.35 (br s, 1H,
13
NH); C NMR (DMSO-d6): 13.5, 91.5, 109.6, 115.4, 121.9, 125.7, 127.1, 128.7, 129.7, 131.8, 132.2,
135.2, 138.5, 143.9, 147.4, 149.5, 150.8, 164.0; MS (ESI): m/z 394 (M+ +Na); Anal. Calcd for
C20H13N5O3: C 64.69, H 3.53, N 18.86; Found: C 64.75, H 3.50, N 18.83.
4m. Pale yellow solid; mp 290-292 °C; 1H NMR (DMSO-d6): 1.94 (s, 3H, CH3); 7.34 (t, J = 7.6 Hz, 1H,
Ar-H); 7.41-7.70 (m, 6H, Ar-H); 8.05 (d, J = 7.6 Hz, 2H, Ar-H); 13.28 (br s, 1H, NH); 13C NMR

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HETEROCYCLES, Vol. 78, No. 4, 2009
(DMSO-d6): 13.3, 92.2, 109.7, 115.3, 116.0, 116.2, 121.0, 121.2, 121.6, 125.0, 126.7, 129.2, 131.1, 132.7,
132.8, 138.2, 143.8, 147.4, 149.1, 157.2, 159.7, 163.8; MS (ESI): m/z 367 (M+ +Na); Anal. Calcd for
C20H13FN4O: C 69.76, H 3.81, N 16.27; Found: C 69.70, H 3.85, N 16.35.
4n. Pale yellow solid; mp 285-287 °C; 1H NMR (DMSO-d6): 1.85 (s, 3H, CH3); 7.34 (t, J = 7.6 Hz, 1H,
Ar-H); 7.51-7.64 (m, 5H, Ar-H); 7.72 (d, J = 8.0 Hz, 1H, Ar-H); 8.06 (d, J = 8.0 Hz, 2H, Ar-H); 13.31 (br
13
s, 1H, NH); C NMR (DMSO-d6): 13.0, 91.9, 109.6, 115.1, 121.5, 126.7, 127.8, 129.3, 129.7, 130.5,
131.3, 131.9, 132.6, 138.2, 143.8, 149.1, 150.6, 163.8; MS (ESI): m/z 383, 385 (M+ +Na); Anal. Calcd for
C20H13ClN4O: C 66.58, H 3.63, N 15.53; Found: C 66.49, H 3.65, N 15.46.
4o. White solid; mp 329-331 °C; 1H NMR (DMSO-d6): 1.94 (s, 3H, CH3); 7.37 (t, J = 7.6 Hz, 1H, Ar-H);
7.55 (t, J = 7.6 Hz, 2H, Ar-H); 7.63 (d, J = 4.8 Hz, 2H, C5H4N); 8.07 (d, J = 8.0 Hz, 2H, Ar-H); 8.83 (d, J
13
= 4.8 Hz, 2H, C5H4N); 13.26 (br s, 1H, NH); C NMR (DMSO-d6): 14.6, 91.4, 109.3, 115.7, 121.9,
123.7, 127.0, 129.6, 138.5, 141.9, 144.1, 149.5, 150.4, 151.2, 164.1; MS (ESI): m/z 350 (M+ +Na); Anal.
Calcd for C19H13N5O: C 69.71, H 4.00, N 21.39; Found: C 69.59, H 4.03, N 21.44.
4p. White solid; mp 310-312 °C; 1H NMR (DMSO-d6): 1.96 (s, 3H, CH3); 7.37 (t, J = 7.6 Hz, 1H, Ar-H);
7.56 (t, J = 7.6 Hz, 2H, Ar-H); 7.64-7.67 (m, 1H, Ar-H); 8.07-8.09 (m, 3H, Ar-H); 8.80-8.81 (m, 2H,
Ar-H); 13.24 (br s, 1H, NH); 13C NMR (DMSO-d6): 14.8, 92.1, 110.1, 115.9, 121.9, 123.9, 127.0, 129.6,
130.2, 137.0, 138.6, 144.3, 149.1, 149.5, 150.7, 151.4, 164.2; MS (ESI): m/z 350 (M+ +Na); Anal. Calcd
for C19H13N5O: C 69.71, H 4.00, N 21.39; Found: C 69.62, H 4.05, N 21.34.
1
7. Yellow solid; mp 196-197 °C; H NMR (CDCl3): 2.15 (s, 6H, CH3); 3.61 (s, 4H, NH2); 5.34 (s, 1H,
13
CH); 7.35-7.38 (m, 2H, Ar-H); 7.47-7.59 (m, 10H, Ar-H); 8.25 (d, J = 8.0 Hz, 2H, Ar-H); C NMR
(CDCl3): 12.2, 35.8, 100.2, 123.7, 127.1, 128.9, 129.2, 137.9, 142.0, 146.4, 147.6, 148.9; MS (ESI): m/z
502 (M+ +Na).
8. Yellow solid; mp 273-274 °C (Lit., 22 270-272 °C); 1H NMR (CDCl3): 2.13 (s, 6H, CH3); 7.32-7.36 (m,
2H, Ar-H); 7.56-7.60 (m, 4H, Ar-H); 7.75 (d, J = 7.2 Hz, 2H, Ar-H); 8.42 (d, J = 7.2 Hz, 4H, Ar-H); 8.50
(d, J = 7.6 Hz, 2H, Ar-H); 13C NMR (CDCl3): 14.6, 112.5, 120.0, 123.0, 125.1, 128.6, 129.7, 137.6, 139.0,
140.8, 143.1, 148.1, 150.0; MS (ESI): m/z 483 (M+ +Na).
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China (No.20772025), the Program for
Science & Technology Innovation Talents in Universities of Henan Province (No. 2008HASTIT006) and
the Natural Science Foundation of Department of Education of Henan Province (No. 2008A150013).
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