Synthesis of pyrazolopyridine 3-carboxylates by Friedlander condensation

Article abstract of DOI:10.1002/jhet.294

(Chemical Equation Presented) A series of 1,3,6-trisubstituted and 1,3,5,6-tetrasubstituted pyrazolo [3,4-b] pyridines 5 have been synthesized by series of reactions on 1-phenyl-3-carboxylate pyrazolone to obtain o-aminoaldehyde, which undergo facile condensation with various a-methylene ketones, nitriles, and esters, furnish fused pyridine derivative in good yield.

Full text of DOI:10.1002/jhet.294

March 2010
Synthesis of Pyrazolopyridine 3-Carboxylates by Friedlander
Condensation
287
Raghunath B. Toche,* Dinesh C. Bhavsar, Muddassar A. Kazi,
Sandeep M. Bagul, and Madhukar N. Jachak
Post Graduate Department of Chemistry, K. R. T. Art, B. H. Commerce and A. M. Science
College, Nashik 422 002, India
*E-mail: raghunath toche@rediffmail.com
Received June 30, 2009
DOI 10.1002/jhet.294
Published online 22 February 2010 in Wiley InterScience (www.interscience.wiley.com).
A series of 1,3,6-trisubstituted and 1,3,5,6-tetrasubstituted pyrazolo [3,4-b] pyridines 5 have been syn-
thesized by series of reactions on 1-phenyl-3-carboxylate pyrazolone to obtain o-aminoaldehyde, which
undergo facile condensation with various a-methylene ketones, nitriles, and esters, furnish fused pyri-
dine derivative in good yield.
J. Heterocyclic Chem., 47, 287 (2010).
INTRODUCTION
is prepared by esterification of ethyl 4,5-dihydro-5-oxo-
1-phenyl-1H-carboxylicacid [17].
Pyrazolo[3,4-b]pyridines as aza-analogues of inda-
zoles are attractive targets in organic synthesis because
of their significant biological activities, such as hypogly-
cemic [1], psychotropic [2], cytotoxic [3], antiviral [4],
fungicidal [5], antiasthmatic [6], antiallergic [7], antitu-
mor [8], and antibacterial [9]. These compounds were
also used in coronary of neurodegenerative diseases
[10,11]. A number of pyrazolo[3,4-b]pyridines display
interesting anxiolytic activity (e.g., tracazolate), which
are potentially biologically active compounds as new
inhibitors of xantine oxidases [12]. They have proved to
be active against gram-positive and gram-negative bac-
teria [13] and also as compounds for inhibition of cho-
lesterol formation [14].
o-Aminoaldehyde 4, the key starting compound, was
obtained by series of reactions including Vilsmeir-Haack
formylation of 1 to furnish o-chloroaldehyde 2, which
on SN2 displacement of chloride (Clꢀ) by azide (AN3)
yield 3 in 68% yield. Compound 3 on reductions with
sodium dithionate Na2S2O4 yields two products o-ami-
noaldehyde 4 in 80% and triazine-5-carboxylate 5 in
20%. The formation of compound 5 can be rationalized
by condensation of carbonyl with electronegative nitro-
gen of azide.
Compounds 4 and 5 were separated on column and
were characterized by spectroscopic and analytical
methods (Scheme 1), e.g., IR spectra of 4 and 5 both
showed ester carbonyl stretching at 1760 cmꢀ1, whereas
only 4 showed doublet at 3451 and 3347 cmꢀ1 for NH2
and 2712 and 1716 cmꢀ1for CHO groups. The peaks
due to NH2 and CHO are absent in IR spectra of 5. The
1H-NMR of 4 and 5 also help lot to distinguish between
4 and 5. The NH2 and CHO protons were observed at d
5.91 and 10.26 in compound 4 and both of these signals
o-Aminoaldehydes are the key intermediates for the
synthesis of various biologically active heterocycles,
e.g., [15,16]. The Friedlander condensation of o-amino-
aldehyde with ketones furnished required tri/tetra cyclic
pyrazolo[3,4-b]pyridine. The required starting compound
i.e., ethyl 4,5-dihydro-5-oxo-1-phenyl-1H-carboxylate 1
C
V
2010 HeteroCorporation

288
R. B. Toche, D. C. Bhavsar, M. A. Kazi, S. M. Bagul, and M. N. Jachak
Vol 47
Scheme 1
are absent in 5. While compound 5 showed a sharp
singlet at d 8.31 for C4H. The elemental analyses were
also in agreement with the proposed structures of 4
and 5.
The novel Friedlander condensation of o-aminoalde-
hyde 4 with a-methylene ketones, nitriles, and esters
containing active methylene groups was carried out in
the presence of piperidine offered fused pyridines in
good yields. Thus, the condensation of aromatic methyl
ketones 6 and 4 under ethanol reflux furnishes 7 in 60–
65% yields. The cyclic ketones 8 on condensation with
4 yield tricyclic pyridines 9 in 60–65% yield.
Similarly, o-aminoaldehyde 4 on condensation with
dimedone or cyclohexane 1,2-dione 10 offered 11 in
60% yield. Compound 11 is a-methylene ketones func-
tionality, which has potential to generate new hetero-
cycles (Scheme 2). All the obtained compounds were
well characterized by IR, 1H-, 13C-NMR, and mass
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Synthesis of Pyrazolopyridine 3-Carboxylates by Friedlander Condensation
289
CHO). Anal. Cacld. for C13H11N5O3: C, 54.74; H, 3.89; N,
24.55. Found: C, 54.67; H, 3.78; N, 24.38. m/z (70 eV): 285.
General procedure for the synthesis of ethyl-5-amino-4-
formyl-4,5-dihydro-1-phenyl-1H-pyrazole-3-carboxylate (4)
and ethyl-7-phenyl-7H-pyrazolo[3,4-d][1,2,3]triazene-5-car-
boxylate (5). A mixture of ethyl-5-azido-4-formyl-4,5-dihy-
dro-1-phenyl-1H-pyrazole-3-carboxylate (25 g, 0.089 mol) and
sodium dithionate (0.1 mol, 17.4 g) in ethanol (275 mL) was
refluxed for 3 h (TLC check, toluene/acetone, 8:2). The mix-
ture was then poured into ice-cold water (800 mL). The pre-
cipitated solid was filtered by suction, washed with water, and
dried. The obtained solid was separated by column chromatog-
raphy using silica 60–120 mesh powder and eluting with tolu-
ene/acetone as 9:1. mp. 183–184ꢁC, yield 18.44 g (80%), pale-
yellow-color needles (ethanol) IR: 3451m, 3347m, 2712s,
spectroscopy given in the Experimental section. In all
above reaction, the ester group remains intact in the
product. The reactions reported here provide a versatile
method for synthesis of various substituted 3-ethycar-
boxy pyrazolo[3,4-b]pyridines. We have extended Fried-
lander condensation using nitriles and esters having re-
active methylene group to generate libraries of new het-
erocycles having multifunctional groups. Reactions with
reactive methylene such as aroylacetonitrile 12 and
malanonitrile 14 with 4 furnished 6-aryl 5-cyanopyra-
zloyridines 13 and 6-amino-5-cyanopyrazloyridines 15
in 60–65% yield. Another multifunctional heterocycle
17 was obtained by condensation of diethylmalonate
1
1
1716m, 1677s, 1597w cmꢀ1. H-NMR (CDCl3): d 1.41 (t, J ¼
with o-aminopyrazole 4 (Scheme 2). The IR, H-NMR,
13C-NMR, Mass, and elemental analysis confirm all
structures of these synthesized compounds.
7.2 Hz, 3H, CH3), 4.49 (q, J ¼ 7.2 Hz, 2H, OCH2), 5.91 (bs,
2H, exchange with D2O, NH2), 7.47–7.48 (m, 5H, Ar-H),
10.26 (s, 1H, CHO). 13C-NMR (75 MHz DMSO-d6) 15.0,
61.9, 105.6, 125.5, 129.7 (2C’S), 130.6 (2C’S), 137.4, 143.0,
151.4, 162.2, 186.3. Anal. Calcd. for C13H13N3O3: C, 60.22;
H, 5.05; N,16.21. Found: C, 60.34; H, 5.23; N, 16.46.
EXPERIMENTAL
Ethyl-7-phenyl-7H-pyrazolo[3,4-d][1,2,3]triazene-5-car-
boxylate (5). Yellow needle (ethanol) mp. 216–217ꢁC, yield
Melting points were determined on a Gallenkamp melting
point apparatus and are uncorrected. IR spectra were recorded
as KBr pellets on a Schimadzu FFTIR-408 spectrophotometer.
1H, 13C-NMR spectra were recorded on a Varian XL-300 (300
MHz, 75 MHz) spectrometer in DMSO-d6 or CDCl3 using
TMS as an internal standard, and chemical shifts are expressed
in d (ppm) unit. Elemental analyses were carried out on Hosli
CH-Analyzer and are within 60.3 of the theoretical percen-
tages. All reactions were monitored by thin-layer chromatogra-
phy carried out on 0.2-mm silica gel (sd Fine Chemicals, 60–
120 mesh powder). Common reagent grade chemicals are either
commercially available and were used without further purifica-
tion or prepared by standard literature procedures.
4.61 g (20%), IR: 2980m, 1760s, 1710s, 1610m, 1510s cmꢀ1
.
1H-NMR (CDCl3): d 1.44 (t, J ¼ 6.2 Hz, 3H, CH3), 4.45 (q,
J ¼ 6.2 Hz, 2H, AOCH2), 7.43–7.48 (m, 5H, Ar-H), 8.31 (s,
1H, CH). Anal. Calcd. for C13H11N5O2: C, 57.99; H, 4.12; N,
26.01. Found: C, 57.82; H, 4.20; N, 26.18.
General procedure for the synthesis of 1-phenyl-1H-pyr-
azolo-[3,4-b]pyridine-3-carboxylate (7a–g). A mixture of 4
(0.2 g, 7.0 mmol) and substituted acetophenone 6 (0.12 g, 8.0
mmol) in ethanol (15–20 mL) with catalytic amount of pipere-
dine (0.5 mL) was refluxed for 3 h (TLC check. toluene/ace-
tone, 8:2). The reaction mixture was then cooled to room
temperature, and the obtained solid was collected by suction
filtration, washed with ethanol, and recrystallized.
Ethyl-5-chloro-4-formyl-4,5-dihydro-1H-pyrazole-3-car-
boxylate (2). To a solution of ethyl-4,5 dihydro-5-oxo-1-phe-
nyl-1H-pyrazole-3-carboxylate 1 (0.1 mol, 23.2 g) in dimethyl
formamide (0.5 mol, 37 mL) was added phosphorous oxychlor-
ide (0.3 mol, 46 mL) in small portions at 10–15ꢁC with stirring.
The reaction mixture was stirred at 65–70ꢁC for 4 h and poured
into ice-cold water (900 mL). The precipitated product was fil-
tered by suction, washed with water, and recrystallized. Color-
less prism (ethanol), mp. 135–136ꢁC, yield 24.5 g (78%), IR:
Ethyl-6-(2-hydroxyphenyl)-1-phenyl-1H-pyrazolo-[3,4-
b]pyridine-3-carboxylate (7a). Colorless prism (methanol)
mp. 140–141ꢁC, yield 1.5 g (60%), IR: 3450m, 1835s, 1730s,
1668m cmꢀ1
.
1H-NMR (DMSO-d6): d 1.43 (t, J ¼ 6.8 Hz,
3H, CH3), 4.45 (q, J ¼ 6.8 Hz, 2H, OCH2), 7.0 (t, J ¼ 7.1 Hz,
2H Ar-H), 7.2 (t, J ¼ 7.1 Hz, 2H, Ar-H), 7.6 (d, 1H, J ¼ 6.8
Hz, Ar-H), 8.0–8.1 (m, 5H, Ar-H), 8.3 (d, J ¼ 6.8 Hz,1H, Ar-
H), 11.90 (bs, 1H AOH). 13C-NMR (75 MHz, DMSO-d6)
15.1, 62.0, 115.2, 118.4, 119.6, 120.4, 122.2, 123.6 (2C),
128.9, 130.3, 130.5 (2C), 132.8, 133.1, 136.3, 138.7, 149.4,
157.9, 158.6, 162.0. Anal. Calcd. for C21H17N3O3: C, 70.18;
H, 4.77; N,11.69. Found: C, 70.24; H, 4.58; N,11.87. m/z (70
eV): 359 [M þ 1].
1
3417m, 2720, 1739s, 1671m, 1597w cmꢀ1. H-NMR (CDCl3):
d 1.34 (t, 3H, J ¼ 6.8 Hz, CH3), 4.41 (q, 2H, J ¼ 6.8 Hz,
OCH2), 7.54–7.61 (m, 5H, Ar-H), 10.31 (S, 1H, CHO). Anal.
Calcd. for C13H11Cl N2O3: C, 56.03; H, 3.98; N, 10.05. Found:
C, 56.25; H, 3.70; N, 10.23.
Ethyl-5-azido-4-formyl-4,5-dihydro-1-phenyl-1H-pyraz-
ole-3-carboxylate (3). To the solution of ethyl-5-chloro-4-
formyl-4,5-dihydro-1H-pyrazole-3-carboxylate 2 (27.869 g, 0.1
mol) in dimethylformamide (150 mL), sodium azide (7.15 g,
0.109 mol) was slowly added for 30 min. The reaction mixture
was stirred for 4 h (TLC check, toluene/acetone 8:2) and
poured in ice-cold water (1000 mL). The precipitated solid
was filtered on suction pump and dried to give colorless prism
(ethanol), mp. 75–76ꢁC. Yield 19.38 g (68%), IR: 3419m,
Ethyl-6-(3,5-bis(trifluoromethyl)phenyl)-1-phenyl-1H-pyr-
azolo[3,4-b]pyridine-3-carboxylate (7b). Colorless needle
(ethanol/water, 8:2), mp. 168–170ꢁC, yield 1.94 g (58%), IR:
1
3280m, 1710s, 1640w cmꢀ1. H-NMR (CDCl3): d 1.42 (t, J ¼
6.8 Hz, 3H, CH3), 4.46 (q, 2H, J ¼ 6.8 Hz, AOCH2), 7.45 (d,
J ¼ 8.1 Hz, 2H, Ar-H), 7.56 (d, J ¼ 8.1 Hz, 2H, Ar-H), 8.14
(s, 1H, Ar-H), 8.25 (d, J ¼ 7.6 Hz, 2H, Ar-H), 8.48 (d, J ¼
7.6 Hz, 2H, Ar-H), 8.70 (s, 1H, Ar-H). Anal. Calcd. for
C23H15F6N3O2: C, 57.63; H, 3.15; N, 8.77. Found: C, 57.48;
H, 3.29; N, 8.84; m/z (70 eV) ¼ 482 [M þ 1, 90%], 481 [M
þ 1, 60%], 480, 439, 338, 254.
3390m, 2164m, 1720s, 1668m, 1597w cmꢀ1
.
1H-NMR
(CDCl3): d 1.33 (t, J ¼ 6.8 Hz, 3H, CH3); 4.46 (q, J ¼ 6.8
Hz, 2H, AOCH2); 7.50–7.60 (m, 5H, Ar-H), 10.26 (s, 1H
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R. B. Toche, D. C. Bhavsar, M. A. Kazi, S. M. Bagul, and M. N. Jachak
Vol 47
1605s, 1510 w cmꢀ1
.
1H-NMR (CDCl3): d 1.52 (t, J ¼ 6.4
Ethyl-6-(4-bromophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyr-
idine-3-carboxylate (7c). Colourless needles (ethanol/water,
Hz, 3H, CH3), 2.10 (t, J ¼ 6.4 Hz, 4H, 2 (CH2), 2.90 (t, J ¼
6.4 Hz, 2H, CH2), 3.01 (t, 2H, J ¼ 6.4 Hz, CH2), 4.60 (q, J ¼
7.1 Hz, 2H, OCH3), 7.5–8.10 (m, 5H, Ar-H), 8.20 (s, 1H.
C4AH). Anal. Calcd. for C18H17N3O2: C, 71.01; H, 5.96; N,
13.08. Found: C, 71.11; H, 5.98; N, 13.11.
General procedure for the synthesis of pyrazolo [3,4-
b]quinoline-3-carboxylate (11a, b). The mixture of 4 (0.2 g,
7.0 mmol) and dimedone 10 (7.0 mmol) with catalytic amount
of piperedine (0.2 mL) was refluxed in ethanol (15 mL) for 4
h (TLC check). The reaction mixture was then cooled to room
temperature, and the obtained solid was collected by suction
filtration, washed with ethanol, and recrystallized to afford
compound 11.
Ethyl-5,6,7,8-tetrahydro-5-oxo-1-phenyl-1H-pyrazolo [3,4-
b]quinoline-3-carboxylate (11a). Colorless needles (ethanol/
DMF, 8:2), mp. 201–202ꢁC, yield 1.31 g (56%). IR: 2990w,
1740s, 1640s, 1620s, 1590w, 1410w cmꢀ1. H-NMR (CDCl3):
1.40 (t, J ¼ 6.8 Hz, 3H, CH3), 2.10 (t, 4H, J ¼ 6.3 Hz,
2CH2), 2.72 (t, 2H, J ¼ 6.8 Hz, CH2), 3.24 (t, J ¼ 6.3 Hz,
2H, CH2), 4.51 (q, 2H, J ¼ 6.8 Hz, CH2), 7.5–8.20 (m, 5H,
Ar-H), 8.90 (s, 1H, Ar-H). m/z (70 eV): 335 (M þ 1, 80%).
Anal. Calcd. for: C19H17N3O3: C, 68.05; H, 5.11; N, 12.53.
Found: C, 68.11; H, 5.06; N, 12.48.
Ethyl-5,6,7,8-tetrahydro-7,7-dimemehtyl-5-oxo-1-phenyl-
1H-pyrazolo[3,4-b]quinoline-3-carboxylate (11b). Colorless
needles (ethanol/DMF, 8:2), mp. 204–206ꢁC, yield 1.40 g
(60%), IR: 2980m, 1750m, 1700, 1640, 1410 cmꢀ1 1H-NMR
.
(DMSO-d6): d 1.42 (t, J ¼ 6.8 Hz, 3H, CH3), 2.47 (s, 2H,
CH2), 2.62 (s, 3H, CH3), 3.20 (s, 3H, CH3), 3.28 (s, 2H,
OCH2), 7.45 (t, 1H, Ar-H), 7.62 (t, J ¼ 7.1 Hz, 2H, Ar-H),
8.21 (d, J¼ 7.1 Hz 1H, Ar-H), 8.90 (s,1H, C4AH). m/z (70
eV): 363[M þ 1]. 13C-NMR(75 MHz, DMSO-d6), 144.2,
160.4, 60.9, 14.2, 110.3, 147.8, 135.9, 133.1, 168.1, 52.3, 33.2,
53.2, 196.9,26.7, 26.7, 139.7, 120.2, 129.4, 126.3, 129.3,
120.2. Anal. Calcd. for C21H21N3O3: C, 69.41; H, 5.82; N,
11.56. Found: C, 69.43; H, 5.78; N, 11.52.
8:2), mp. 170–172ꢁC, yield 1.76 g (60%), IR: 1760w, 1620m,
1
1091w cmꢀ1. H-NMR (300 MHz, CDCl3): d 1.50 (t, J ¼ 6.8
Hz, 3H, CH3), 4.60 (q, J ¼ 6.8 Hz, 2H, OCH2), 8.31 (dd, J ¼
8.2 and 2.3 Hz 2H, Ar-H), 7.92 (dd, J ¼ 8.2 and 2.3 Hz, 2H,
Ar-H), 7.23–7.7 (m, 5H, Ar-H), 9.01 (d, 1H, J ¼ 8.60 Hz, Ar-
H); 9.21 (d, 1H, J ¼ 8.60 Hz Ar-H). Anal. Calcd. for
C21H16BrN3O2: C, 59.73; H, 3.82; N, 9.95. Found C, 59.68;
H, 3.79; N, 9.90.
Ethyl-6-methyl-1-phenyl-1H-pyrazolo [3,4-b]pyridine-3-
carboxylate (7d). Colorless needles (ethanol/water, 8:2) mp.
136–137ꢁC, yield 1.21 g (62%), IR: 2350s, 1668m, 1610s,
1540w, 1410w cmꢀ1
.
1H-NMR (CDCl3): d 1.41 (t, J ¼ 6.8
Hz, 3H, CH3), 4.40 (q, J ¼ 6.8 Hz, 2H, CH2), 2.67 (s, J ¼
6.6 Hz, 3H, CH3), 7.22 (t, J ¼ 6.3 Hz, 2H, Ar-H), 7.61 (t, J ¼
6.3 Hz, 1H, Ar-H), 8.0–8.1 (m, 2H, Ar-H), 8.32 (d, J ¼ 7.3
Hz, 1H, Ar-H), 8.60 (d, J ¼ 7.2 Hz, 1H, Ar-H). Anal. Calcd.
for: C16H15N3O2 Calcd: C, 68.34, H, 5.37, N,14.94. Found: C,
68.33, H, 5.36, N, 14.90.
1
Ethyl-6-(4-chlorophenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyr-
idine-3-carboxylate (7e). Colorless needles (ethanol: water,
8:2) mp. 186–187ꢁC, yield 1.45 g (55%). IR: 2339m, 1668s,
1
1630w, 1576s cmꢀ1. H-NMR (CDCl3): d 1.70 (t, J ¼ 6.4 Hz,
3H, CH3), 4.41 (q, J ¼ 6.4 Hz, 2H, OCH2), 7.23–7.70 (m, 5H,
Ar-H), 7.75 (d, J ¼ 8.2 Hz, 2H, Ar-H), 7.99 (d, J ¼ 8.2 Hz,
2H Ar-H), 8.11 (d, J ¼ 8.2 Hz, 1H, Ar-H), 8.32 (d, J ¼ 8.3
Hz, 1H, Ar-H). Anal. Calcd. for C21H16ClN3O2: C, 66.76; H,
4.27; N, 11.12. Found: C, 59.54; H, 3.98; N, 11.32.
Ethyl-1,6 diphenyl-1H-pyrazolo [3,4-b] pyridine-3-car-
boxylate (7f). Colorless needles (ethylacetate), mp.176–177ꢁC,
yield 1.44 g (60%). IR: 2339m, 1587w cmꢀ1 1H-NMR
(CDCl3): d 1.70 (t, J ¼ 6.4 Hz, 3H, CH3), 4.45 (q, J ¼ 6.4
Hz, 2H, OCH2), 7.23–7.70 (m, 10H, Ar-H), 7.75 (d, J ¼ 8.1
Hz, 1H, Ar-H), 8.11 (d, J ¼ 8.1 Hz, 1H, Ar-H). Anal. Calcd.
for: C21H17N3O2: C, 73.45; H, 4.99; N, 12.24. Found: C,
73.26; H, 4.75; N, 12.42.
General procedure for the synthesis of pyrazolo-[3,4-
b]pyridine-3-carboxylate (13a–d). The mixture of 4 (0.2 g, 7.0
mmol), benzoylacetonitrile 12 (7.0 mmol), and catalytic amount
of piperedine (0.5 mL) were dissolved in ethanol (15 mL). The
reaction mixture was then refluxed for 4 h (TLC check, toluene/
acetone, 8:2). The mixture was then cooled to room temperature,
and the obtained solid was collected by suction filtration,
washed with ethanol, and recrystallized to afford compound 13.
Ethyl-6-(4-chlorophenyl)-5-cyano-1-phenyl-1H-pyrazolo-
[3,4-b]pyridine-3-carboxylate (13a). Colorless solid (etha-
nol/DMF, 8:2), mp. 246–247ꢁC, yield 1.74 g (62%), IR:
General procedure for the synthesis of pyrazolo-[4,3-
e]pyridine-3-carboxylate (9a, b). The mixture of 4 (0.2 g, 7.0
mmol) and aromatic ketones 8 (7.0 mmol) with catalytic
amount of piperedine (0.2 mL) was dissolved in ethanol (15
mL). The reaction mixture was then refluxed for 4 h (TLC
check, toluene/acetone, 8:2). The reaction mixture was then
cooled to room temperature, and the obtained solid was col-
lected by suction filtration, washed with ethanol, and recrystal-
lized to furnish compound 9.
Ethyl-1-phenyl-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo
[4,3-e]pyridine-3-carboxylate (9a). Colorless needles (etha-
3000w, 2240w, 1740m, 1680m, 1620s, 1510, 1420w cmꢀ1
.
nol/DMF, 5:1), mp.160–161ꢁC, yield 1.39
g (65%). IR:
1740m, 1605s, 1510 w cmꢀ1. H-NMR (DMSO-d6): d 1.43 (t,
3H, J ¼ 6.8 Hz, CH3), 2.21 (t, 2H, J ¼ 6.4 Hz, CH2), 3.21 (t,
J ¼ 6.4 Hz, CH2), 3.45 (t, 2H, J ¼ 6.4 Hz, CH2), 4.51 (q, 2H,
J ¼ 6.8 Hz, OCH2), 7.17–8.32 (m, 5H, Ar-H), 8.44 (s, 1H,
C4H). m/z (70 eV): 307 (M þ 1, 90%). 13C-NMR (75 MHz,
DMSO-d6). 144.2, 160.4, 60.9, 14.1, 110.3,147.8, 134.0, 33.1,
135.5, 165.1, 34.9, 25.3, 139.7, 120.2, 129.4, 126.3, 129.4,
120.2. Anal. Cacld. for C18H16N3O2: C, 70.34; H, 5.58; N,
13.67. Found: C, 70.30; H, 5.62; N, 13.60.
1
1H-NMR (DMSO-d6): d 1.62 (t, 3H, J ¼ 6.8 Hz, CH3), 4.70
(q, J ¼ 6.8 Hz, 2H, AOCH2), 7.1–7.82 (m, 5H, ArH), 7.92 (d,
J ¼ 6.8 Hz, 2H, CH2), 8.15 (d, J ¼ 8 Hz, 2H, CH2), 9.01 (s,
1H, C4H). 13C-NMR (75 MHz, DMSO-d6), 110.3, 147.8,
163.9, 108.7, 141.3, 134.4, 144.2, 160.4, 60.9, 14.1, 129.0,
129.4, 132.9, 129.4, 129.0, 139.7, 120.2, 129.4, 126.3, 129.4,
120.2, 117.0. Anal. Calcd. for C22H15ClN4O2: C, 65.59; H,
3.75; N, 13.91. Found: C, 65.59; H, 3.75; N, 13.91.
Ethyl-6-(4-bromophenyl)-5-cyano-1-phenyl-1H-pyrazolo[3,
4-b]pyridine-3-carboxylate (13b). Pale-yellow-color solid
(ethanol/DMF, 8:2), mp. 261–262ꢁC, yield 1.87 g (55–58%),
.
IR: 2240s, 1780s, 1680w, 1620s, 1510w, 1420w cmꢀ1 1H-
Ethyl-1-phenyl-5,6,7,8-tetrahydro-1H-pyrazolo-[3,4-b]
quinoline-3-carboxylate (9b). Colorless needles (ethanol/
DMF, 5:1), mp. 163–164ꢁC, yield 1.33 g (62%), IR: 1742w,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Synthesis of Pyrazolopyridine 3-Carboxylates by Friedlander Condensation
291
REFERENCES AND NOTES
NMR (CDCl3): d 1.60 (t, J ¼ 6.74 Hz, 3H, CH3), 4.70 (q, J ¼
6.74 Hz, 2H, OCH2), 7.20–7.80 (m, 5H, Ar-H), 7.92 (d, J¼
8.2 Hz, 2H, CH2), 8.18 (d, J ¼ 8.2 Hz, 2H, CH2), 9.03 (s, 1H,
Ar-H). Anal. Calcd. for C22H15BrN4O2: C, 59.08; H, 3.38;
N,12.53. Found: C, 59.13; H, 3.35; N, 12.48.
[1] Anton-Fos, G. M.; Garcia-Domenech, R.; Perez-Gimenez,
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Arzneimittel-Forschung 1994, 44, 821.
[2] (a) Feurer, A.; Luithle, J.; Wirtz, S.-N.; Koenig, G.; Stasch,
J. P.; Stahl, E.; Schreiber, R.; Wunder, F.; Lang, D. PCT. Int. Appl.
(Bayer Healthcare AG, Germany), 2004, WO2004009589; Feurer, A.;
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R.; Wunder, F.; Lang, D. Chem Abstr 2004, 140, 146157; (b) Ehlert, J.;
Ragan, P.; Chen, A.; Roeske, W. R.; Yamamura, H. I. Eur J Pharmacol
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Ethyl-6-(2,4-bis(trifluoromethyl)phenyl)-5-cyano-1-phenyl-
1H-pyrazolo[3,4-b]pyridine-3-carboxylate (13c). Pale-yellow-
color solid (ethanol/DMF, 8:2), mp. 190–192ꢁC, yield 2.10 g
(60%), IR: 3100s, 2250s, 1710m, 1610m, 1540w, 1410w
cmꢀ1
.
1H-NMR (CDCl3): d 1.51 (t, 3H, J ¼ 6.8 Hz, CH3),
4.60 (q, 2H, J ¼ 6.8 Hz, CH2), 7.58–7.61 (m, 5H, Ar-H), 8.08
(s, 1H, Ar-H), 8.82 (s, 1H, Ar-H), 8.46 (s, 1H, Ar-H), 9.11 (s,
1H, C4H). Anal. Calcd. for C24H14F6N4O2: C, 57.15; H, 2.80;
N, 11.11. Found: C, 57.10; H, 2.83; N, 11.08.
Ethyl-5-cyano-6-(3,5-difluorophenyl)-1-phenyl-1H-pyra-
zolo [3,4-b] pyridine-3-carboxylate (13d). Colorless needles
(ethanol/DMF, 8:2), mp. 204–206ꢁC. Yield 1.64 g (58–60%),
IR: 3080w, 2240s, 1745m, 1620s, 1540m, 1420w cmꢀ1 1H-
.
NMR (CDCl3): d 1.55 (t, J ¼ 6.8 Hz, 3H, CH3), 4.60 (q, J ¼
6.8 Hz, 2H, AOCH2), 7.10 (dd, J ¼ 8.3 and 2.3 Hz, 1H, Ar-
H), 7.40 (d, J ¼ 8 Hz, 1H, Ar-H), 7.50 (d, J ¼ 2.3 Hz, 1H,
Ar-H), 7.55–7.85 (m, 5H, Ar-H), 9.10 (s, 1H, Ar-H). Anal.
Calcd. for C22H14F2N4O2: C, 65.35; H, 3.49; N, 13.86. Found:
C, 65.31; H, 3.46; N, 13.84.
[3] Sanghvi, Y. S.; Larson, S. B.; Willis, R. C.; Robins, R. K.;
Ravankar, G. R. J Med Chem 1989, 32, 945.
[4] (a) Ludwig, S.; Planz, O.; Sedlack, H. H.; Pleschka, S.
PCT. Int. Appl. (Medinnova Ges.m.b. H., Germany), WO2004009589,
2004; Ludwig, S.; Planz, O.; Sedlack, H. H.; Pleschka, S. Chem Abstr
2004, 141, 307497; (b) Ludwig, S.; Planz, O.; Sedlack, H. H.;
Pleschka S. Ger. Offen. DE 10138912, 2003; Ludwig, S.; Planz, O.;
Sedlack, H. H.; Pleschka S. Chem Abstr 2003, 138, 198569.
[5] Mitsubishi Chem Corp. Eur. Pat. 658547-A1 (1996) (week
9622).
[6] (a)Tamaoki, J.; Isono, K.; Sakai, N.; Chiyotani, A.; Konno,
K. Res Commun Chem Pathol Pharnacol 1992, 77, 65; Tamaoki, J.;
Isono, K.; Sakai, N.; Chiyotani, A.; Konno, K. Chem Abstr 1992, 117,
1846304.
Ethyl-6-amino-5-cyano-1-phenyl-1H-pyrazolo[3,4-b]pyri-
dine-3-carboxylate (15). To the reaction mixture of 4 (0.2 g,
7.0 mmol) and malononitrile 14 (0.05 g, 8.0 mmol) in ethanol
(15 mL), catalytic amount of piperedine (0.5 mL) was added.
The reaction mixture was refluxed for 4 h (TLC check, tolu-
ene/acetone, 8:2) and then cooled to room temperature. The
separated solid was filtered by suction to afford colorless nee-
dles (ethanol/DMF, 8:2), mp. 206–207ꢁC, yield 1.40 g (65%),
[7] (a) Okada, S.; Asano, M.; Kimura, K.; Iijima, H.; Inone,
H.; Takishina, T. Kokyu 1990, 9, 1140; Okada, S.; Asano, M.;
Kimura, K.; Iijima, H.; Inone, H.; Takishina, T. Chem Abstr 1991,
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Pat. 14, 05331168, 1993; Ooe, T.; Kobayashi, H. Chem Abstr 1994,
121, 108778r.
IR: 3476w, 2240s, 1610s, 1590w, 1554w cmꢀ1 1H-NMR
.
(DMSO-d6): d 1.55 (t, J ¼ 6.8 Hz, 3H, CH3), 4.60 (q, J ¼ 6.8
Hz, 2H, OCH2), 5.40 (bs, 2H, NH2, D2O exchange), 7.20–8.10
(m, 5H, Ar-H), 8.6 (s, 1H, Ar-H). 13C-NMR (75 MHz,
DMSO-d6): d 15.0 (2C), 62.1 (2C), 91.9, 108.6, 117.5, 122.8,
128.2, 130.1, 139.1, 140.0, 152.4, 159.8,161.7. Anal. Calcd.
for C16H13N5O2: C, 62.51; H, 4.26; N, 22.79. Found: C,
62.53; H, 4.23; N, 22.75.
[9] Joshi, K. C.; Dubey, K.; Dandia, A. Pharmazie 1981, 36, 336.
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2003015770, 2003; Bischoff, H.; Stasch, J. Chem Abstr 2003, 138,
180718.
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2004219552, 2004 (Exonhit Therapeutics S.A., France); Aiet, I. A.;
Resink, A.; Schweighoffer, F. Chem Abstr 2004, 141, 388737; (b)
Aiet, I. A.; Resink, A.; Schweighoffer, F. PCT. Int. Appl. 2003,
WO2003016563; Aiet, I. A.; Resink, A.; Schweighoffer, F. Chem
Abstr 2003, 138, 203092.
Diethyl 6,7-dihydro-6-oxo-1-phenyl-1H-pyrazolo [3,4-
b]pyridine-3,5-dicarboxylate (17). A mixture of 4 (0.2 g, 7.0
mmol) and diethylmalonate 16 (0.14 g, 9.0 mmol) in ethanol
(15 mL) with catalytic amount of piperedine (0.5 mL) was
refluxed for 4 h (TLC check, toluene/acetone, 8:2). The reac-
tion mixture was cooled at room temperature. The separated
solid was filtered by suction to afford pale-yellow solid (etha-
nol/DMF, 8:2), mp. 142–143ꢁC, yield 1.73 g (70%), IR:
[12] Lynck, B.; Khan, M.; Teo, H.; Pedrotti, F. Can J Chem
1988, 66, 420.
[13] EI-Dean, A. M.; Aralla, A. A.; Mohammad, T. A.; Geies,
A. A. Z Naturforsch Teil B 1991, 46, 541.
[14] (a) Fujikawa, Y.; Suzuki, M.; Iwasaki, H.; Sakashita, M.; Kita-
hara, M. Eur. Pat. Appl. EP 339,358, 1989; Fujikawa, Y.; Suzuki, M.; Iwa-
saki, H.; Sakashita, M.; Kitahara, M. Chem Abstr 1990, 113, 23903.
[15] Hawes, E.; Gorecki, D. K. J. J Heterocycl Chem 1972, 9, 703.
[16] Reddy, K.; Moglilaiah, K.; Sreenivasulu, B. J Ind Chem
Soc 1984, 63, 443.
1
3450w, 1710s, 1674s, 1610s, 1595w cmꢀ1. H-NMR (DMSO-
d6): d 1.20 (t, J ¼ 6.4 Hz, 3H, CH3), 1.42 (t, J ¼ 6.8 Hz, 3H,
CH3), 4.11 (q, J ¼ 6.3 Hz, 2H, OCH2), 4.39 (q, J ¼ 6.3 Hz,
2H, AOCH2); 7.25–8.30 (m, 5H, Ar-H), 8.40 (s, 1H, C4H);
12.60 (bs, 1H, NH). m/z (70 eV): 354 [M ꢀ 1]. 13C-NMR (75
MHz, DMSO-d6): d 14.1 (2C), 61.0 (2C), 139.7, 120.2, 129.4,
126.3, 129.4, 120.2, 143.4, 97.0, 136.6, 161.2, 120.9, 135.8,
165.0, 160.4. Anal. Calcd. for C18H17N3O5: C, 60.84; H, 4.82;
N, 11.83. Found: C, 60.83; H, 4.85; N, 11.80.
[17] (a) Cheng, C. C.; Yan, S. Y. In Organic Reactions; Wiley:
New York, 1982; Vol. 28, p 37; (b) Mundy, B. P.; Ellerd, M. G. In
Name Reactions and Reagents in Organic Synthesis; Wiley: New
York, 1988; p 86; (c) Hassner, A.; Stumer, C. In Organic Synthesis
Based on Named and Unnamed Reactions (Tetrahedron Organic
Chemistry Series); Baldwin, J. E., Magnus, P. D., Eds.; Elsevier Sci-
ence: Oxford; 1994; Vol. 11, p 132; (d) Dias-Ortiz, A.; de la Hoz, A.;
Langa, F. Green Chem 2000, 2, 165; (e) Karthikeyan, G.; Perumal, P.
T. J. Heterocycl Chem 2004, 41, 1039.
Acknowledgment. The authors thank UGC and CSIR, New
Delhi, for the financial assistance and higher authorities of MVP
Samaj and K.T.H.M. College, Nashik, for facilities.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet