Tin (IV) chloride-promoted one-pot synthesis of novel tacrine analogues

Article abstract of DOI:10.3390/molecules16021878

A facile synthesis of potential acetylcholinesterase (AChE) inhibitors, the tacrine analogues 3a-p, has been accomplished by direct cyclocondensation of 1-aryl-4- cyano-5-aminopyrazole with β-ketoesters using tin(IV) chloride as catalyst. The structures o

Full text of DOI:10.3390/molecules16021878

Molecules 2011, 16, 1878-1887; doi:10.3390/molecules16021878
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Tin (IV) Chloride-Promoted One-Pot Synthesis of Novel
Tacrine Analogues
Huanan Hu *, Liangfu Song, Qianqian Fang, Junjun Zheng, Zhiwei Meng and Yiting Luo
College of Pharmaceutical and Chemical Engineering, Taizhou University, Linhai 317000, China
* Author to whom correspondence should be addressed; E-Mail: hhn12192000@yahoo.com.cn;
Tel.: +86 576 89372982; Fax: +86 576 85137004.
Received: 5 January 2011; in revised form: 13 January 2011 / Accepted: 15 February 2011 /
Published: 22 February 2011
Abstract: A facile synthesis of potential acetylcholinesterase (AChE) inhibitors, the
tacrine analogues 3a-p, has been accomplished by direct cyclocondensation of 1-aryl-4-
cyano-5-aminopyrazole with β-ketoesters using tin(IV) chloride as catalyst. The structures
of all the compounds have been confirmed by IR, 1H- and 13C-NMR.
Keywords: Alzheimer’s disease; tacrine; tin(IV) chloride; cyclocondensation
1. Introduction
Alzheimer’s disease (AD), the most common form of dementia among the elderly, is a progressive,
degenerative disorder of the brain with a loss of memory and cognition [1]. Tacrine is a reversible
inhibitor of acetylcholinesterase (AChE) that was launched in 1993 as the first drug for the treatment
of AD [2]. The evaluation of the clinical effects of tacrine has shown efficacy in delaying the
deterioration of the symptoms of AD, but the poor selectivity of this drug for AChE has resulted in a
number of side effects, specially hepatotoxicity [3], and current research is focused on developing new
AChE inhibitors with improved activity and reduced adverse side effects, therefore novel tacrine
analogues have been reported [4-18].
Friedlander annulation is one of the simplest and most straightforward protocols for the preparation
of quinoline derivatives [19,20]. Although it has been known for more than a century, it is still a
hotspot of research. Herein, we report that the Friedlander annulation of 1-aryl-4-cyano-5-

Molecules 2011, 16
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aminopyrazole with β-ketoesters using SnCl4 as catalyst afforded the novel tacrine analogues 3a-p in
good yields.
2. Results and Discussion
The main synthetic approach to tacrine analogues is the cyclocondensation of o-aminonitrile
derivatives with ketones using anhydrous AlCl3 as catalyst, but that method gives low to moderate
yields [4-18]. Cabrera and co-workers [21] have reported that the synthesis of 4-aminoquinolines from
2-aminobenzonitrile and β-dicarbonyl compounds could be accomplished using Lewis acids as
catalysts. They found that SnCl4 was a very effective catalyst for the preparation of the target
compounds compared with other Lewis acids.
For the investigation of reaction conditions for cyclocondensation of 1-aryl-4-cyano-5-amino-
pyrazole with β-ketoesters, we chose the reaction of 1-phenyl-4-cyano-5-aminopyrazole (1a) with
methyl acetoacetate as a model reaction. Because the choice of the catalyst played a crucial role, we
initially studied the effect of several catalysts on the yields and found the use of anhydrous AlCl3,
ZnCl2 and TiCl4 to be much less effective and tacrine analogue 3a was obtained in less than 43% yield.
Moreover, none of the product desired 3a was obtained when we used CuCl and CuCl2 as catalysts.
However, when a mixture of 1-phenyl-4-cyano-5-aminopyrazole (1a) and methyl acetoacetate in
toluene was stirred under reflux in the presence of SnCl4, the reaction was complete within 3 h and
after work up, the product 3a was obtained in 78% yield (Table 1).
Scheme 1. Cyclocondensation of 4-cyano-5-aminopyrazoles and β-ketoesters.
O
R2
H2N
O
CN
NH2
N
N
N
SnCl4
N
N
CH3COCH2COOR2
toluene
R1
R1
1
2
3
Table 1. Effect of the catalyst on the yields. a
Entry
Catalyst
CuCl
CuCl2
AlCl3
ZnCl2
TiCl4
Time(h)
Yield(%)b
1
2
3
4
5
6
3
3
3
3
3
3
0
0
36
23
43
78
SnCl4
a
All reactions were carried out using 1a (10 mmol), methyl acetoacetate (10 mmol), catalyst (20
mmol) and toluene (20 mL), reflux for 3 h; b Isolated yields.
A profound solvent effect on the reaction was observed. We initially studied the effect on the
reaction of non-polar solvents, such as DCM, DCE, THF and toluene, in which SnCl4 is easily

Molecules 2011, 16
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dissolved. Then we went on to study the polar solvent DMF. The results are summarized in Table 2.
These results suggest that the solvent had a dramatic effect on the yields. Toluene was found to be the
best solvent.
Table 2. Effect of the solvent on the yields. a
Entry
Solvent
DCM
DCE
THF
Toluene
DMF
Time (h)
Yield (%)b
1
2
3
4
5
3
3
3
3
3
53
68
51
78
0
a
All reactions were carried out using 1a (10 mmol), methyl acetoacetate (10 mmol), SnCl4 (20
mmol) and solvent (20 mL), reflux for 3 h; b Isolated yields.
Under the optimized reaction conditions (SnCl4 as catalyst and anhydrous toluene as solvent, reflux
for 3 h), a series of reactions between 1-aryl-4-cyano-5-aminopyrazoles and β-ketoesters were tested
and a series of tacrine analogues 3 was thus prepared in good yields, regardless of the position of the
group R1 on the aromatic ring. The results were summarized in Table 3.
Table 3. Cyclocondensation of substituted o-aminobenzonitrile and β-ketoesters. a
Entry
1
R1
H
4-CH3
3-CH3
4-Cl
3-Cl
2-Cl
4-NO2
2,4-NO2
H
R2
Me
Me
Me
Me
Me
Me
Me
Me
Et
Product(3)
Yield(%)b
78
3a
3b
3c
3d
3e
3f
3g
3h
3i
2
3
4
5
6
7
8
9
75
70
74
72
65
62
58
76
10
11
12
13
14
15
16
4-CH3
3-CH3
4-Cl
3-Cl
2-Cl
Et
Et
Et
Et
Et
Et
Et
3j
3k
3l
3m
3n
3o
3p
74
71
75
73
64
60
57
4-NO2
2,4-NO2
a
All reactions were carried out using 1a (10 mmol), β-ketoesters (10 mmol), SnCl4
(20 mmol) and toluene (20 mL), reflux for 3 h; b Isolated yields.
The mechanism of formation of tacrine analogue 3 can be explained by Scheme 2. The attack of the
amino group of 1 onto the carbonyl carbon atom of 2 gave intermediate I, from which product 3 was
obtained through the Friedlander reaction.

Molecules 2011, 16
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Scheme 2. Proposed mechanism.
CN
..
CN
OH
CN
O
O
CH2COOR
N
N
CH2COOR
NH2
N
N
H
R
N
N
N
N
O
2
1
I
SnCl4
O
O
R
R
H2N
HN
:
SnCl4
N
C
H
N
O
O
COOR
..
N
N
N
N
N
N
N
N
H
3
3. Experimental
3.1. General
All melting points were determined on an XT-4A apparatus. TLC was performed using precoated
silica gel GF254 (0.25 mm), column chromatography was performed using silica gel (200–300 mesh).
The 1H- and 13C-NMR spectra were measured at 300 and 75 MHz, respectively, on a Bruker Advance
300 spectrometer at 25 °C, using TMS as internal standard. J-values are given in Hz. The IR spectra
were taken on a Bruker Vector 55 spectrometer. 1-Aryl-4-cyano-5-aminopyrazoles 1 were prepared
according to a reported procedure [22].
3.2. Typical procedure
1-Aryl-4-cyano-5-aminopyrazole 1 (10 mmol) and SnCl4 (2.3 mL, 20 mmol) were added to a stirred
solution of β-ketoester (10 mmol) in dry toluene (20 mL). The reaction mixture was stirred under
nitrogen at room temperature for 30 min and then heated under reflux for 3 h. The reaction mixture
was cooled and dispersed into water and titrated to pH 12–13 with a saturated aqueous solution of
Na2CO3. After filtration, the filtrate was extracted three times with ethyl acetate, the organic layers
were dried and evaporated at reduced pressure to give the solid product. The product was purified by
silica gel column chromatography to give 3a-p.
Methyl 4-amino-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3a). Colorless solid.
1
m.p. 125–126 °C. H-NMR (CDCl3) δ: 8.24 (d, J = 6.9 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H),
7.41–7.48 (m, 2H, Ar-H), 7.23–7.28 (m, 1H, Ar-H), 6.74 (br, 2H, -NH2), 3.90 (s, 3H, -OCH3), 2.80 (s,

Molecules 2011, 16
1882
13
3H, -CH3). C-NMR (CDCl3) δ: 169.9, 163.1, 151.8, 150.0, 138.7, 131.6, 128.8, 126.3, 121.6, 105.3,
101.2, 51.6, 28.1. MS-ESI (m/z, relative intensity, %): 285 (M++3) (3), 284 (M++2) (18), 283 (M++1)
(100). IR (KBr, cm−1) ν: 3,451, 3,330 (NH2), 3,111 (ArH), 2,976, 2,926 (CH3), 1,665 (C=O), 1,590,
1,495, 1,460 (C=N and aromatic ring skeleton vibration), 1,260 (O-CH3).
Methyl 4-amino-6-methyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3b). Colorless solid.
1
m.p. 167–168 °C. H-NMR (CDCl3) δ: 8.08 (d, J = 7.2 Hz, 2H, Ar-H), 8.05 (s, 1H, pyrazole H),
7.25–7.29 (m, 2H, Ar-H), 6.74 (br, 2H, -NH2), 3.91 (s, 3H, -OCH3), 2.80 (s, 3H, pyridine-CH3), 2.38
(s, 3H, benzene-CH3). 13C-NMR (CDCl3) δ: 169.2, 162.1, 151.9, 149.5, 136.3, 135.4, 130.6, 128.9,
121.0, 104.7, 100.5, 51.5, 27.9, 20.8. MS-ESI (m/z, relative intensity, %): 299 (M++3) (3), 298 (M++2)
(20), 297 (M++1) (100). IR (KBr, cm−1) ν: 3,452, 3,333 (NH2), 3,110 (ArH), 2,976, 2,925 (CH3), 1,660
(C=O), 1,590, 1,495, 1,460 (C=N and aromatic ring skeleton vibration), 1,246 (O-CH3).
Methyl 4-amino-6-methyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3c). Colorless solid.
1
m.p. 151–153 °C. H-NMR (CDCl3) δ: 8.07 (d, J = 7.6 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H),
7.33–7.39 (m, 1H, Ar-H), 7.11–7.16 (m, 1H, Ar-H), 6.72 (br, 2H, -NH2), 3.91 (s, 3H, -OCH3), 2.82 (s,
3H, pyridine-CH3), 2.40 (s, 3H, benzene-CH3). 13C-NMR (CDCl3) δ: 169.0, 162.1, 151.0, 149.5, 138.6,
131.4, 128.1, 126.2, 125.1, 121.5, 118.7, 104.9, 101.0, 51.8, 28.1, 21.0. MS-ESI (m/z, relative
intensity, %): 299 (M++3) (2), 298 (M++2) (22), 297 (M++1) (100). IR (KBr, cm−1) ν: 3,453, 3,332
(NH2), 3,112 (ArH), 2,978, 2,923 (CH3), 1,672 (C=O), 1,596, 1,497, 1,465 (C=N and aromatic ring
skeleton vibration), 1,260 (O-CH3).
Methyl
4-amino-1-(4-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate
(3d).
1
Colorless solid. m.p. 160–162 °C. H-NMR (CDCl3) δ: 8.26 (d, J = 7.2 Hz, 2H, Ar-H), 8.04 (s, 1H,
pyrazole H), 7.40–7.48 (m, 2H, Ar-H), 6.72 (br, 2H, -NH2), 3.91 (s, 3H, -OCH3), 2.81 (s, 3H, -CH3).
13C-NMR (CDCl3) δ: 168.8, 161.7, 151.2, 135.0, 131.7, 130.6, 127.9, 121.0, 118.2, 104.9, 100.4, 51.7,
28.0. MS-ESI (m/z, relative intensity, %): 320 (9), 319 (32), 317 (M++1) (100). IR (KBr, cm−1) ν:
3,451, 3,330 (NH2), 3,111 (ArH), 2,976, 2,926 (CH3), 1,665 (C=O), 1,592, 1,494, 1,458 (C=N and
aromatic ring skeleton vibration), 1,260 (O-CH3).
Methyl
4-amino-1-(3-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate
(3e).
1
Colorless solid. m.p. 127–128 °C. H-NMR (CDCl3) δ: 8.36–8.40 (m, 1H, Ar-H), 8.27–8.31 (m, 1H,
Ar-H), 8.05 (s, 1H, pyrazole H), 7.40–7.43 (m, 1H, Ar-H), 7.24–7.26 (m, 1H, Ar-H), 6.74 (br, 2H, -
NH2), 3.90 (s, 3H), 2.82 (s, 3H, -CH3). 13C-NMR (CDCl3) δ: 168.9, 161.7, 151.1, 132.7, 131.5, 130.6,
130.1, 129.6, 128.4, 125.6, 121.7, 120.8, 118.4, 51.7, 28.0. MS-ESI (m/z, relative intensity, %): 319
(7), 318 (33), 317 (M++1) (100). IR (KBr) ν: 3,453, 3,333 (NH2), 3,110 (ArH), 2,976, 2,924 (CH3),
1,668 (C=O), 1,592, 1,496, 1,461 (C=N and aromatic ring skeleton vibration), 1,258 (O-CH3).
Methyl 4-amino-1-(2-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3f). Color-
1
less solid. m.p. 154–155 °C. H-NMR (CDCl3) δ: 8.12 (s, 1H, Ar-H), 8.05 (s, 1H, pyrazole H),
7.55–7.58 (m, 1H, Ar-H), 7.39–7.42 (m, 2H, Ar-H), 6.74 (br, 2H, -NH2), 3.90 (s, 3H, -OCH3), 2.80 (s,
13
3H, -CH3). C-NMR (CDCl3) δ: 169.2, 162.8, 151.4, 151.3, 135.9, 131.7, 132.1, 130.5, 129.4, 129.1,

Molecules 2011, 16
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126.4, 103.1, 100.9, 51.6, 27.9. MS-ESI (m/z, relative intensity, %): 319 (8), 318 (33), 317 (M++1)
(100). IR (KBr, cm−1) ν: 3,451, 3,330 (NH2), 3,112 (ArH), 2,975, 2,923 (CH3), 1,665 (C=O), 1,591,
1,495, 1,458 (C=N and aromatic ring skeleton vibration), 1,262 (O-CH3).
Methyl
4-amino-6-methyl-1-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate
(3g).
1
Yellowish solid. m.p. 190–192 °C. H-NMR (DMSO) δ: 8.62–8.74 (m, 3H, Ar-H and pyrazole H),
8.37–8.40 (m, 2H, Ar-H), 7.84 (br, 2H, -NH2), 3.92 (s, 3H, -OCH3), 2.79 (s, 3H, -CH3). 13C-NMR
(DMSO) δ: 168.0, 161.4, 151.3, 150.9, 144.6, 136.6, 125.1, 119.8, 118.5, 105.0, 102.4, 51.8, 29.0. MS-
ESI (m/z, relative intensity, %): 330 (M++3) (3), 329 (M++2) (18), 328 (M++1) (100). IR (KBr,
cm−1) ν: 3,451, 3,330 (NH2), 3,111 (ArH), 2,976, 2,926 (CH3), 1,680 (C=O), 1,610, 1,543, 1,508 (C=N
and aromatic ring skeleton vibration), 1,272 (O-CH3).
Methyl
4-amino-1-(2,4-dinitrophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate
(3h).
Yellowish solid. m.p. 202–204 °C. 1H-NMR (DMSO) δ: 8.86 (s, 1H, Ar-H), 8.69-8.73 (m, 1H, Ar-H),
8.52 (s, 1H, pyrazole H), 8.41–8.45 (m, 1H, Ar-H), 7.76 (br, 2H, -NH2), 3.91 (s, 3H, -OCH3), 2.80 (s,
3H, -CH3). 13C-NMR (DMSO) δ: 167.8, 162.2, 151.4, 150.7, 137.4, 134.9, 128.6, 128.4, 126.3, 126.1,
126.0, 121.7, 119.5, 51.8, 28.2. MS-ESI (m/z, relative intensity, %): 375 (M++3) (5), 374 (M++2) (21),
373 (M++1) (100). IR (KBr, cm−1) ν: 3,453, 3,332 (NH2), 3,112 (ArH), 2,979, 2,933 (CH3), 1,679
(C=O), 1,612, 1,550, 1,515 (C=N and aromatic ring skeleton vibration), 1,277 (O-CH3).
Ethyl 4-amino-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3i). Colorless solid. m.p.
130–131 °C. 1H-NMR (CDCl3) δ: 8.25 (d, J = 7.8 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.46–7.50
(m, 2H, Ar-H), 7.25–7.31 (m, 1H, Ar-H), 6.76 (br, 2H), 4.39 (q, J = 7.2 Hz, 2H, -CH2CH3), 2.81 (s,
3H, -CH3), 1.42 (t, J = 7.2 Hz, 3H, -CH2CH3). 13C-NMR (CDCl3) δ: 169.2, 162.5, 151.4, 150.2, 139.4,
131.7, 128.9, 126.1, 121.4, 105.1, 101.5, 60.7, 28.4, 14.3. MS-ESI (m/z, relative intensity, %): 299
(M++3) (3), 298 (M++2) (19), 297 (M++1) (100). IR (KBr, cm−1) ν: 3,453, 3,333 (NH2), 3,110 (ArH),
2,976, 2,926 (CH2 and CH3), 1,665 (C=O), 1,592, 1,494, 1,460 (C=N and aromatic ring skeleton
vibration), 1,260 (O-CH3).
Ethyl 4-amino-6-methyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3j). Colorless solid. m.p.
173–174 °C. 1H-NMR (CDCl3) δ: 8.09 (d, J = 6.6 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.25–7.29
(m, 2H, Ar-H), 6.72 (br, 2H, -NH2), 4.40 (q, J = 7.2 Hz, 2H, -CH2CH3), 2.81 (s, 3H, pyridine-CH3),
2.39 (s, 3H, benzene-CH3), 1.43 (t, J = 7.2 Hz, 3H, -CH2CH3). 13C-NMR (CDCl3) δ: 168.9, 162.0,
151.0, 149.7, 136.5, 135.5, 130.9, 129.1, 121.1, 104.5, 100.9, 60.3, 28.0, 20.6, 13.9. MS-ESI (m/z,
relative intensity, %): 313 (M++3) (2.5), 312 (M++2) (22), 311 (M++1) (100). IR (KBr, cm−1) ν: 3,453,
3,335 (NH2), 3,112 (ArH), 2,977, 2,930 (CH2 and CH3), 1,658 (C=O), 1,590, 1,492, 1,460 (C=N and
aromatic ring skeleton vibration), 1,260 (O-CH3).
Ethyl 4-amino-6-methyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3k). Colorless solid.
m.p. 148–149 °C. 1H-NMR (CDCl3) δ: 8.08 (d, J = 8.7 Hz, 2H, Ar-H), 8.01 (s, 1H, pyrazole H), 7.38
(t, J = 7.8 Hz, 1H, Ar-H), 7.11 (d, J = 7.5 Hz, 1H, Ar-H), 6.72 (br, 2H, -NH2), 4.40 (q, J = 7.2 Hz, 2H,
-CH2CH3), 2.82 (s, 3H, pyridine-CH3), 2.45 (s, 3H, benzene-CH3), 1.43 (t, J = 7.2 Hz, 3H, -CH2CH3).

Molecules 2011, 16
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13C-NMR (CDCl3) δ: 168.8, 162.1, 150.9, 149.6, 138.5, 131.1, 128.3, 126.6, 125.6, 121.7, 118.3,
104.6, 101.1, 60.4, 28.0, 21.2, 13.9. MS-ESI (m/z, relative intensity, %): 313 (M++3) (2), 312 (M++2)
(20), 311 (M++1) (100). IR (KBr, cm−1) ν: 3,453, 3,336 (NH2), 3,111 (ArH), 2,976, 2,926 (CH2 and
CH3), 1,662 (C=O), 1,590, 1,494, 1,462 (C=N and aromatic ring skeleton vibration), 1,262 (O-CH3).
Ethyl 4-amino-1-(4-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3l). Colorless
solid. m.p. 143–144 °C. 1H-NMR (CDCl3) δ: 8.27 (d, J = 6.6 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H),
7.43–7.49 (m, 2H, Ar-H), 6.74 (br, 2H, -NH2), 4.40 (q, J = 7.2 Hz, 2H, -CH2CH3), 2.81 (s, 3H, -CH3),
1.43 (t, J = 7.2 Hz, 3H, -CH2CH3). 13C-NMR (CDCl3) δ: 168.9, 162.0, 151.0, 135.3, 131.6, 130.9,
128.1, 121.1, 118.5, 104.5, 100.9, 60.3, 28.0, 13.9. MS-ESI (m/z, relative intensity, %): 334 (8), 333
(33), 331 (M++1) (100). IR (KBr, cm−1) ν: 3,453, 3,338 (NH2), 3,113 (ArH), 2,973, 2,925 (CH2 and
CH3), 1,660 (C=O), 1,593, 1,457 (C=N and aromatic ring skeleton vibration), 1,260 (O-CH3).
Ethyl
4-amino-1-(3-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate
(3m).
1
Colorless solid. m.p. 105–106 °C. H-NMR (CDCl3) δ: 8.37–8.42 (m, 1H, Ar-H), 8.28–8.33 (m, 1H,
Ar-H), 8.04 (s, 1H, pyrazole H), 7.41–7.46 (m, 1H, Ar-H), 7.23–7.27 (m, 1H, Ar-H), 6.73 (br, 2H, -
NH2), 4.41 (q, J = 7.2 Hz, 2H, -CH2CH3), 2.83 (s, 3H, -CH3), 1.44 (t, J = 7.2 Hz, 3H, -CH2CH3). 13C-
NMR (CDCl3) δ: 168.7, 161.9, 150.9, 132.9, 131.6, 130.6, 130.2, 129.5, 128.6, 125.4, 121.8, 120.6,
118.5, 60.4, 27.9, 13.8. MS-ESI (m/z, relative intensity, %): 334 (6), 333 (31), 331 (M++1) (100). IR
(KBr, cm−1) ν: 3,453, 3,337 (NH2), 3,111 (ArH), 2,974, 2,928 (CH2 and CH3), 1,661 (C=O), 1,592,
1,490, 1,458 (C=N and aromatic ring skeleton vibration), 1,258 (O-CH3).
Ethyl 4-amino-1-(2-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3n). Colorless
1
solid. m.p. 164–165 °C. H-NMR (CDCl3) δ: 8.11 (s, 1H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.51–7.57
(m, 1H, Ar-H), 7.38–7.42 (m, 2H, Ar-H), 6.83 (br, 2H, -NH2), 4.40 (q, J = 7.2 Hz, 2H, -CH2CH3), 2.72
13
(s, 3H), 1.41 (t, J = 7.2 Hz, 3H, -CH2CH3). C-NMR (CDCl3) δ: 168.8, 162.5, 151.1, 150.9, 135.4,
131.9, 131.8, 130.2, 129.6, 129.4, 126.9, 103.4, 101.2, 60.3, 27.7, 13.9. MS-ESI (m/z, relative
intensity, %): 334 (5), 333 (32), 331 (M++1) (100). IR (KBr, cm−1) ν: 3,453, 3,338 (NH2), 3,112 (ArH),
2,973, 2,930 (CH2 and CH3), 1,660 (C=O), 1,590, 1,493, 1,457 (C=N and aromatic ring skeleton
vibration), 1,263 (O-CH3).
Ethyl 4-amino-6-methyl-1-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3o). Yellowish
solid. m.p. 197–199 °C. 1H-NMR (DMSO) δ: 8.62–8.74 (m, 3H, Ar-H and pyrazole H), 8.36–8.41 (m,
2H, Ar-H), 7.84 (br, 2H, -NH2), 4.32 (q, J = 7.2 Hz, 2H, -CH2CH3), 2.67 (s, 3H, -CH3), 1.33 (t,
J = 7.2 Hz, 3H, -CH2CH3). 13C-NMR (DMSO) δ: 167.8, 161.2, 151.0, 150.5, 144.4, 136.3, 124.9,
119.6, 118.9, 105.4, 102.6, 60.6, 29.3, 14.2. MS-ESI (m/z, relative intensity, %): 344 (M++3) (2.5), 343
(M++2) (18), 342 (M++1) (100). IR (KBr, cm−1) ν: 3,453, 3,333 (NH2), 3,112 (ArH), 2,978, 2,930 (CH2
andCH3), 1,678 (C=O), 1,616, 1,545, 1,512 (C=N and aromatic ring skeleton vibration), 1,275 (O-CH3).
Ethyl
4-amino-1-(2,4-dinitrophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate
(3p).
Yellowish solid. m.p. 205–206 °C. 1H-NMR (DMSO) δ: 8.86 (s, 1H, Ar-H), 8.69–8.73 (m, 1H, Ar-H),
8.52 (s, 1H, pyrazole H), 8.43 (d, J = 9.0 Hz, 1H, Ar-H), 7.74 (br, 2H, -NH2), 4.39 (q, J = 7.2 Hz, 2H, -

Molecules 2011, 16
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13
CH2CH3), 2.66 (s, 3H, -CH3), 1.39 (t, J = 7.2 Hz, 3H, -CH2CH3). C-NMR (DMSO) δ: 167.8, 162.2,
151.4, 150.7, 137.4, 134.9, 128.6, 128.4, 126.3, 126.1, 126.0, 121.7, 119.5, 60.2, 27.9, 14.0. MS-ESI
(m/z, relative intensity, %): 389 (M++3) (4), 388 (M++2) (19), 387 (M++1) (100). IR (KBr, cm−1) ν:
3,453, 3,331 (NH2), 3,113 (ArH), 2,979, 2,932 (CH2 and CH3), 1,680 (C=O), 1,617, 1,545, 1,512 (C=N
and aromatic ring skeleton vibration), 1,272 (O-CH3).
4. Conclusions
We have developed an efficient catalyst system using SnCl4 in anhydrous toluene for the reaction
between o-aminonitriles containing pyrazole moieties with β-ketoesters. A series of novel tacrine
analogues 3a-p has been thus synthesized and their spectroscopic characterization and structural
features have been presented.
Acknowledgements
We are grateful for financial support from Taizhou University (Project No. 2010PY21), and the
Undergraduate Scientific and Technological Innovation Project of Zhejiang Province, and the Nature
Science Foundation of China (Project No. 20905057).
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Sample Availability: Samples of compounds 3a-p are available from the authors.
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